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Catalytic Oxidative Carbonylation of Amino Alcohols and Diamines to Ureas as an Alternative to Phosgene Derivatives: Syn...


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1 CATALYTIC OXIDATIVE CARBONYLATION OF AMINO ALCOHOLS AND DIAMINES TO UREAS AS AN ALTERNATIVE TO PHOSGENE DERIVATIVES: SYNTHESIS OF DISUBSTITUTED HYDANTOINS By DELMY DIAZ-MONTERROSO A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2007

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2 2007 Delmy Daz-M.

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3 To my daughters Paola and Anabella; and to my husband, Alvaro, for their unconditional love and support.

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4 ACKNOWLEDGMENTS First I would like to thank my daughters Paola and Anabella, who have been there for me always with their constant love and support along the duration of my studies. They suffered the most from my long hours at the lab, my frustrations, and my absences without complaint. On the contrary, they were always understanding and waiting for me patiently. Special thanks go to my husband Alvaro, for his unconditional love, support, and enthusiasm, and for always believing in me. I thank my family in Honduras for their never-ending support and encouragement throughout all these long years of studying away. I also want to express my gratitude to my advisor, Professor Lisa McElwee-White, for her guidance and valuable comments and suggestions throughout this academic program and experimental investigation. I can not thank her enough for all her assistance and for always being willing to listen to new ideas and encouraging me to try things I never thought were possible. I also want to thank the members of my committee, Dr. Castellano, Dr. Dolbier, Dr. Lyons and Dr. Percival, for their helpful suggestions and wise advice. Special thanks must go to the members of the group for making my life easier and providing a nice environment to work in. I thank my good friends Ece, Laurel and Marie for always being there, and for sharing with me many coffee breaks. I also need to thank Phil, Seth, and Ampofo, with whom I was working every day for the last three years. Acknowledgement is made to the Pedagogic University Francisco Morazn for their financial support.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS ...............................................................................................................4 LIST OF TABLES ...........................................................................................................................7 LIST OF FIGURES .........................................................................................................................8 LIST OF ABBREVIATIONS ..........................................................................................................9 ABSTRACT ...................................................................................................................................11 CHAPTER 1 INTRODUCTION AND LITERATURE REVIEW ..............................................................12 Literature Review ...................................................................................................................13 Transition Metal-Catalyzed Oxidative Carbonylation of Amines to Ureas ....................13 Palladium-catalyzed oxidative carbonylation of amines ..........................................14 Homogeneous carbonylation of amines to ureas ......................................................14 Pd catalysis in ionic liquids ......................................................................................17 Electrocatalytic carbonylation ..................................................................................18 Mechanistic studies ..................................................................................................19 Other Late Transition Metal Catalysts ............................................................................20 Nickel-catalyzed oxidative carbonylation ................................................................20 Ruthenium-catalyzed oxidative carbonylation .........................................................21 Cobaltand Rhodium-catalyzed oxidative carbonylation ........................................26 Gold-catalyzed oxidative carbonylation ...................................................................29 Tungsten-Catalyzed Oxidative Carbonylation of Amines ..............................................30 Carbonylation of primary amines .............................................................................30 Carbonylation of primary and secondary diamines to cyclic ureas .........................32 Conclusions.............................................................................................................................42 2 SELECTIVE CATALYTIC OXIDATIVE CARBONYLATION OF AMINOALCOHOLS TO UREAS .........................................................................................44 Results and Discussion ...........................................................................................................45 Carbonylation of 5-Aminopentanol .................................................................................46 Carbonylation of 4-Amino-2-methylbutan-1-ol ..............................................................47 Carbonylation of 1,3-Aminoalcohols ..............................................................................49 Carbonylation of 1,2-Aminoalcohols ..............................................................................52 Conclusions.............................................................................................................................54

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6 3 THE W(CO)6/I2 CATALYZED OXIDATIVE CARBONYLATION OF DIAMINES: ANALOGS OF THE CORE STRUCTURES OF THE HIV PROTEASE INHIBITORS DMP 323 AND DMP450. ......................................................................................................56 Background .............................................................................................................................56 Results and Discussion ...........................................................................................................61 Synthesis of Seven-Membered Ring Cyclic Ureas 84 and 89 .........................................61 Conclusions.............................................................................................................................64 4 CATALYTIC OXIDATIVE CARBONYLATION OF ENANTIOMERICALLY PURE -AMINO AMIDES TO PRODUCE HYDANTOIN DERIVATIVES ................................65 Background .............................................................................................................................65 Classic Ways to Synthesize Hydantoins .................................................................................65 Solution Phase Synthesis .................................................................................................67 Solid-Phase Organic Synthesis ........................................................................................69 Synthesis of Hydantoins Using W(CO)6/I2 Catalytic System .........................................70 Results and Discussion ...........................................................................................................71 Conclusions.............................................................................................................................76 5 EXPERIMENTAL SECTION ................................................................................................77 General Procedures ..........................................................................................................77 Procedure A for Carbonylation of Amino Alcohols with CDI ........................................77 Procedure B for carbonylation of aminoalcohols with DMDTC ....................................77 Procedure C for Catalytic Carbonylation of Amino Alcohols with W(CO)6/I2 ..............78 Synthesis of Cyclic Ureas .......................................................................................................82 General Procedure for the Synthesis of -Amino Amides 103a-103e. ..................................84 General Procedure for the Carbonylation of -Amino Amides 103a-e to Afford Hydantoins 104a-e. .............................................................................................................84 LIST OF REFERENCES ...............................................................................................................87 BIOGRAPHICAL SKETCH .........................................................................................................96

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7 LIST OF TABLES Table page 1-1. Oxidative Carbonylation of Primary Amines to Ureas under Optimized Conditions. ..........33 1-2. Oxidative Carbonylation of Substituted Primary Diamines ..................................................36 1-3. Catalytic Carbonylation of Substituted Benzylamines to Ureas ..........................................38 1-4. Yields of Bicyclic Ureas from Diamines 46a-49a ................................................................42 2-1. Carbonylation of aminoalcohols to ureas and carbamates. ....................................................48 3-1. Structures of cyclic urea inhibitors ........................................................................................58 3-2. Carbonylation of compounds 35-37 to Ureas 38-40 .............................................................60 4-1. Carbonylation conditions for -amino amide 103a. ..............................................................72 4--amino amides 103a-d ....................................................................................74 4--amino amides 103a-e to hydantoins 104a-e. ...........................75

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8 LIST OF FIGURES Figure page 1-1. Co(salen) (22) and modified Co(salen) complexes (23-27) ..................................................28 1-2. Structures of the HIV protease inhibitors DMP 323 and DMP 450 ......................................39 4-1. Hydantoin ring structure. .......................................................................................................66 4-2. Synthetic strategies and building blocks for hydantoin synthesis. ........................................66 4--Amino amide substrates to be converted to hydantoins .....................................................73

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9 LIST OF ABBREVIATIONS CDI 1,1'-Carbonyldiimidazole DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCB 1,4-dichloro-2-butene DCE Dichloroethane DCM Dichloromethane DEA Diethylamine DIBAL Diisobutylaluminium hydride DMA N,N-dimethylacetamide DMAP 4-dimethyl aminopyridine DMDTC S,S'-dimethyl dithiocarbonate DME 1,2-dimethoxyethane DMF Dimethylformamide DMImBF4 1-decyl-3-methylimidazolium tetrafluoroborate DMSO Dimethyl sulfoxide DPT Di-2-pyridylthiocarbonate DPU Diphenylurea EMImBF4 1-ethyl-3-methylimidazolium tetrafluoroborate GC-MS Gas chromatograph-mass spectrometer GLC Gas liquid chromatography HIV Human immunodeficiency virus MAC Mixed anhydrides coupling MEM 2-methoxyethoxymethyl

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10 NMP N-methylpyrrolidinone SEM 2-(trimethylsilyl)ethoxymethyl SPOS Solid-phase organic synthesis THF Tetrahydrofuran TLC Thin layer chromatography

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11 Abstract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy CATALYTIC OXIDATIVE CARBONYLATION OF AMINO ALCOHOLS AND DIAMINES TO UREAS AS AN ALTERNATIVE TO PHOSGENE DERIVATIVES: SYNTHESIS OF DISUBSTITUTED HYDANTOINS By Delmy Daz-Monterroso May 2007 Chair: Lisa McElwee-White Major: Chemistry The synthesis of ureas from amines has traditionally been accomplished with stoichiometric reactions of phosgene or its derivatives, which are associated with environmental and health issues. Because of the prevalence of urea moieties in molecules of interest for several applications, alternative catalytic routes for the oxidative conversion of amines to ureas using CO or CO2 as the carbonyl source have been developed. W(CO)6-catalyzed oxidative carbonylation of amines to ureas in the presence of CO provides an alternative to stoichiometric reaction of amines with phosgene or its derivatives such as 1,1-carbonyldiimidazole (CDI). Synthesis of the core structure of the HIV protease inhibitors DMP 323 and DMP 450 has been achieved via W(CO)6/I2-catalyzed carbonylation of diamine intermediates. This methodology also has been successfully applied to the carbonylation of amino alcohols to selectively form hydroxyalkyl ureas. Selected examples of 1,2-, 1,3-, 1,4and 1,5-aminoalcohols were converted to the corresponding ureas in good to excellent yields, with only trace amounts of the cyclic carbamates being present. Other interesting targets such as hydantoins have also been prepared using W(CO)6/I2. -amino amides have been shown to produce the corresponding hydantoins in good yields.

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12 CHAPTER 1 INTRODUCTION AND LITERATURE REVIEW There is a growing interest in the synthesis of substituted ureas because of their wide field of applications. Ureas have been known to exhibit very important biological activity, for example, as structural components of drug candidates such as HIV protease inhibitors, 1,2 CCK-B receptor antagonists, and endothelin antagonists. Additionally, they have shown widespread usage as agricultural chemicals, dyes, and as additives to petroleum compounds and polymers. From the synthetic point of view, they are used as intermediates en route to carbamates. The classical methodology for the preparation of substituted ureas is generally based on the nucleophilic attack of amines on phosgene or phosgene derivatives. Phosgene is useful for the carbonylation of primary and secondary amines. The major drawback of phosgene is that it is a highly toxic and corrosive gas. Because of its toxic nature, it requires special handling. This has discouraged its use in laboratory settings. Phosgene production3 and use on an industrial scale raise serious environmental risks and problems connected with the use and storage of large amounts of chlorine, and the transportation and storage of a highly toxic and volatile reagent. Other safer derivatives such as 1,1-carbonylimidazole, triphosgene, and a variety of other reagents have been used in the carbonylation of amines to form substituted ureas, and are more common in the laboratory setting. Another variant involves the use of isocyanates, which is undesirable because of their toxic nature and the need to synthesize them from phosgene. Various other methods have been used to convert amines to ureas. These include the use of phenyl chloroformate to form substituted ureas from primary amines. The drawback to this method is the use of DMSO as solvent. DMSO is known to be toxic and a possible carcinogen. Furthermore, it is difficult to remove because of its high boiling point.

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13 The necessity of a catalytic alternative to stoichiometric reagents such as phosgene was obvious. This new methodology has to be compatible with complex highly functionalized substrates in order to be widely applied. An alternative to the reaction of nucleophiles with phosgene is the metal catalyzed oxidative carbonylation of amines. Several examples of this methodology have been reported in the literature. In this regard, the McElwee-White group reported the catalytic oxidative carbonylation of amine using W(CO)6 as catalyst and I2 as the oxidant. The system converts primary and secondary amines and diamines to the corresponding ureas in the presence of CO. The reaction conditions are relatively mild and one big advantage of this methodology is that it can be used with complex highly functionalized substrates as demonstrated by previous studies of functional group compatibility.4,5 Due to the commercial availability and ease of handling of the catalyst, the W(CO)6/I2 catalytic system would be an alternative to phosgene derivatives and main group catalysts for laboratory scale syntheses. In addition, its compatibility with various functional groups makes it a good candidate for carbonylation of complex molecules to the corresponding ureas. This work reports the application of W(CO)6/I2 catalyzed carbonylation to several complex substrates. Literature Review Transition Metal-Catalyzed Oxidative Carbonylation of Amines to Ureas The development of new synthetic protocols for the preparation of ureas has recently attracted a lot of interest because of the presence of this functional group in pharmaceutical candidates,6-10 agrochemicals, resin precursors, dyes and additives to petrochemicals and polymers.11 The classical syntheses of ureas from amines have been based on the use of toxic and/or corrosive reagents, such as phosgene or isocyanates.12,13 In recent years, however, alternative routes have been developed that utilize phosgene derivatives, CO2, or CO itself as the

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14 source of the carbonyl moiety.3 Particularly attractive from the standpoint of atom economy14 is oxidative carbonylation,15,16 which employs amines, carbon monoxide and an oxidant as starting materials and produces only the reduced form of the oxidant and protons as byproducts. In an effort to develop new methodologies for preparing moieties with carbonyl-nitrogen bonds, metal-catalyzed carbonylation of amines has been extensively studied. Monoand dicarbonylations of amines catalyzed by Mn,17,18 Fe,19 Co,20,21 Ni,22,23 Ru,24-27 Rh,27,28 Pd,29-38 W,39-47 Pt,48 Ir,48 or Au49,50 have been reported, and many different types of products, including ureas,18,20,22,27,51 urethanes,52 oxamides,53 formamides,54-58 and oxazolidinones,59 have been obtained. These carbonylations have generally been carried out at high temperatures under moderate-to-high pressures of CO and efforts to find catalysts that are effective under mild conditions continue. This section highlights some selected recent advances in the transition metal catalyzed oxidative carbonylation of amines to ureas. Palladium-catalyzed oxidative carbonylation of amines Carbonylation of amines using Pd catalysts has been extensively studied since Tsuji reported the first Pd-catalyzed carbonylation of amines in 1966.38 Methods for oxidative carbonylation using PdCl2 as catalyst with copper oxidants or O2 as the terminal oxidant and CuX or CuX2 as a mediator have been developed for preparation of ureas,60-62 carbamates,29,63 and oxamides.29,51,64,65 Since a recent review of Pd-catalyzed reactions is available,16 in this work a few selected examples will be highlighted. Homogeneous carbonylation of amines to ureas Fukuoka66 and Chaudhari67 reported the oxidative carbonylation of alkylamines using Pd/C as catalyst and iodide salts as promoters in the presence of O2, which afforded the corresponding ureas and/or carbamates in good yields. Related results have been reported by Gabriele68 for the oxidative carbonylation of amines using PdI2 and O2, which led to formation of ureas,

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15 carbamates, and their cyclic derivatives in good yields. New conditions for the PdI2-catalyzed oxidative carbonylation of amines to ureas (Eq.1), afforded ureas in high yields with turnover numbers as high as 4950.32,69 Carbonylations of primary aliphatic amines (Eq.1, R = alkyl) were carried out at 100 C under a 4:1:10 mixture of CO:air:CO2 (60 atm total pressure at 25 C) in the presence of a simple catalytic system consisting of PdI2 in conjunction with a KI promoter. In the absence of CO2, less satisfactory results were obtained.69 The choice of solvent was critical to product selectivity. Monocarbonylation to the urea was favored in dioxane or 1,2-dimethoxyethane (DME), while double carbonylation to the oxamide predominated in the more polar solvents N,N-dimethylacetamide (DMA) or N-methylpyrrolidinone (NMP). The selectivity was attributed to higher nucleophilicity of the amine substrates in DMA or NMP, which favors the formation of Pd(CONHBu)2 species that generate the oxamide by reductive elimination. Primary aromatic amines (Eq. 1, R = Ar) were generally less reactive than primary aliphatic amines under these conditions but addition of an electron-donating methoxy group increased the nucleophilicity of the aromatic amine enough to improve the activity. The mechanism for the carbonylation of primary amines was examined in more detail after it was determined that the secondary amines diethylamine, dibutylamine, and morpholine were unreactive under the same conditions. The difference in reactivity was attributed to the formation of isocyanate intermediates from the primary amine, with carbamoylpalladium

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16 complex 1 formed in preequilibrium with starting materials (Scheme 1). In agreement with this hypothesis, isocyanates were detected (by GLC, TLC, and GLC/MS) in the reaction mixtures in low-conversion experiments. Under these conditions, Pd(0) is reoxidized to Pd(II) by oxidative addition of I2, which is regenerated through oxidation of HI by oxygen. Scheme 1 This catalytic system proved to be effective for the synthesis of cyclic ureas from the corresponding diamines, with 1,3-dihydrobenzoimidazol-2-one obtained in 99% isolated yield (Eq. 3). This particularly high reactivity was attributed to increased nitrogen nucleophilicity and a less negative entropy of activation due to the proximity of the ortho amino groups.32 (3) Direct catalytic preparation of trisubstituted ureas in high selectivity (Eq. 2) was possible under these conditions if the primary amine was carbonylated in the presence of an excess of the less reactive secondary amine.32 This methodology has proven to be effective for the synthesis of several types of urea derivatives, such as cyclic ureas from primary diamines and N,N-bis(methoxycarbonylalkyl)ureas from primary -amino esters. A showcase synthesis of the neuropeptide Y5 receptor antagonist NPY5RA-972 was also reported (Eq. 4).32

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17 Pd catalysis in ionic liquids Recently, many catalytic reactions have been reported to proceed in ionic liquids as reaction media with excellent results.70 This approach has been adapted by Deng for Pd-catalyzed carbonylation of amines to ureas.71 A solubility study of the catalyst Pd(phen)Cl2 established that the ionic liquids BMImBF4 (BMIm = 1-butyl-3-methylimidazolium), BMImPF6, BMImFeCl4, and BMImCl were candidate media for the carbonylation reaction and that catalyst solubility could be adjusted through the tuning of either the cation or anion of the ionic liquids. Carbonylation of aniline to the carbamate in the presence of O2 and methanol was used to demonstrate catalytic activity and recyclability of the catalyst/ionic liquid mixture. Subsequent work by the Deng group developed a new method using silica gel-immobilized ionic liquids, in which a Pd-complex acts as a heterogenized catalyst for the catalyzed carbonylation of amines and nitrobenzene to ureas. Heterogenization of the metal catalyst by preparation of a silica gel confined ionic liquid was followed by the carbonylation of amines and nitrobenzene to the corresponding ureas (Scheme 2).72 No additional oxidant is necessary since

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18 the nitrobenzene serves as both substrate and oxidant. In terms of green chemistry, the advantages of this method are the low quantities of ionic liquids used and the avoidance of potentially explosive CO/O2 mixtures. The authors suggested that the enhanced catalytic activity of this system may be derived from the high concentration of ionic liquid containing the metal complex confined within the cavities of the silica gel matrix.72 Experiments with the ionic liquids DMImBF4 (1-decyl-3-methylimidazolium tetrafluoroborate) and EMImBF4 (1-ethyl-3-methylimidazolium tetrafluoroborate) and the catalysts HRu(PPh3)2Cl2, Rh(PPh3)3Cl, Pd(PPh3)2Cl2 and Co(PPh3)3Cl2 afforded good to -diphenylurea (DPU) from nitrobenzene and aniline. The Rh-DMImBF4/silica gel catalyst produced 93% conversion of starting materials with a selectivity of 92% for the urea. Conversion of aliphatic amines and nitrobenzene to the unsymmetrically substituted ureas could also be achieved with this particular catalyst. Scheme 2 Electrocatalytic carbonylation Another method for the synthesis of alkylureas is the electrocatalytic carbonylation of aliphatic amines, as reported by Deng.73 Electrocatalytic carbonylation of a series of aliphatic amines to dialkylureas and isocyanates using Pd(II) complexes with a Cu(II) cocatalyst could be achieved under mild reaction conditions, with particularly good results for primary amines (Eq. 5). The additional steric hindrance in secondary amines apparently prevents the reaction, as

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19 diisopropyl amine was unreactive under the same conditions. In addition, no conversion of primary diamines to cyclic ureas was observed although one long chain diamine did afford a low yield of the corresponding isocyanate. (5) Although products were obtained with a single complex as catalyst [Cu(OAc)2, PdCl2 or Pd(OAc)2], catalytic activity and selectivity for the urea were improved when both a Pd complex and Cu(OAc)2 were present in the reaction mixtures. Quantitative conversion and 98% selectivity for the urea were achieved in the case of n-butylamine with Pd(PPh3)2Cl2 and Cu(OAc)2.73 The authors suggested a synergistic effect between Pd(II) and Cu(II), as opposed to simple mediation of electron transfer, which had been invoked in a related case of electrocatalysis.74 Mechanistic studies Recent progress has also been made in understanding the mechanism of the carbonylation of amine nucleophiles. Shimizu and Yamamoto have reported a mechanistic study focusing on the role of the reoxidation of Pd(0) species formed in the principal catalytic cycle to electrophilic Pd(II) species during the selective carbonylation of amines to oxamides and ureas.53 Their work revealed the importance of the oxidant in selectivity as 1,4-dichloro-2-butene (DCB) afforded oxamides from primary and secondary amines while use of I2 as the oxidizing agent resulted in formation of ureas. Further insight was obtained through independent generation of carbamoylpalladium complexes as models for species in the catalytic cycle. Two possible mechanisms for the conversion of primary amines to ureas by palladium-catalyzed carbonylation were discussed in conjunction with this study. In the first, the critical

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20 step is reductive elimination of carbamoyl and amido ligands to generate the urea, as previously proposed by Alper.51 The crucial step in the second possible route involves formation of an intermediate alkyl isocyanate from an N-monoalkylcarbamoylpalladium species 3, (Scheme 3). The urea product is then derived from nucleophilic attack of a primary or secondary amine on the isocyanate to release a symmetrically or unsymmetrically substituted urea. This second possibility is based on an earlier proposal by Gabriele for a related system.69 Support for the isocyanate pathway came from the inability of secondary amines to form tetra substituted ureas, the presence of trisubstituted ureas upon carbonylation of mixtures of primary and secondary amines and the kinetics of conversion of model compounds for 3 to ureas in the presence of NEt3.53 Scheme 3 Other Late Transition Metal Catalysts Nickel-catalyzed oxidative carbonylation The extensive development of palladium-catalyzed oxidative carbonylation reactions along with the ability of Ni complexes to undergo carbonylation and produce stable carbamoyl derivatives suggested investigation of nickel complexes as catalysts for the oxidative

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21 carbonylation of amines.22 -dialkylureas, rather than the previously reported oxamides,23 by reacting aliphatic primary amines with the nickel amine complexes NiX2(RNH2)4 (X = Cl, Br; R = alkyl). However, yields were low, with a maximum of 55% under 30 atm CO and 5 atm O2nd at lower temperatures the reductive step, in which amine carbonylation occurs, failed. The product selectivity depended on the amount of water present, with anhydrous conditions favoring the oxamide, while the presence of water promoted urea formation (Scheme 4). The authors suggested that water could coordinate to the nickel center, allowing the formation of only one carbamoyl group. Under aqueous conditions, this intermediate would then undergo nucleophilic attack by amine to form the urea. In the absence of water, oxamide would arise from reductive elimination of two carbamoyl groups.22 Scheme 4 Ruthenium-catalyzed oxidative carbonylation Gupte utilized ruthenium catalysts for the selective formation -diphenylurea (DPU) from the oxidative carbonylation of aniline.27 High selectivity (99%) for the formation of DPU was obtained with [Ru(CO)3I3]NBu4 as the catalyst and NiI as the promoter. The key step in the

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22 proposed mechanism involves the formation of carbamoyl species 8 (Scheme 5). Loss of CO from the catalyst precursor [Ru(CO)3I3]generates intermediate 5, which reacts with aniline to form 6 and HI. Addition and insertion of CO affords carbamoyl complex 8, which reacts with aniline to yield the urea and the hydrido carbonyl species 9. Addition of aniline to form 10 is followed by oxidation with O2 to regenerate the active species 6 (Scheme 5).27 Related chemistry with alkylamines has been reported by Chaudhari.67,75 Scheme 5 Dixneuf reported the synthesis of symmetrical ureas by reacting primary amines with CO2 and a ruthenium complex, in the presence of a terminal alkyne (Scheme 6).76 Yields ranged from low to moderate, with the best yi-dicyclohexylurea (61%) obtained with RuCl32O as catalyst in the presence of 2 equiv of tri-n-butylphosphine (n-Bu3P). Further optimization

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23 studies established the importance of running the reaction in the presence of excess alkyne but with no solvent. Scheme 6 The proposed catalytic cycle (Scheme 7) begins with coordination of the alkyne to the metal center. The nucleophilic ammonium carbamate, formed in situ from the primary amine and CO2, then adds to the triple bond to give the ruthenium coordinated vinyl carbamate species 11. Nucleophilic attack of the amine on carbamate 11 would then afford the urea and ruthenium-coordinated enol 12. Protonation of the enol and decoordination regenerates the active ruthenium species. According to this mechanism, the organic product derived from the alkyne -hydroxy-ketone 13. This ketone was not detected experimentally but would be expected to react further under the reaction conditions (Scheme 7).76 Kondo reported the application of RuCl2(PPh3)3 as a precatalyst for the preparation of ureas from amines, using formamide as the carbonyl source.24 Using this system, symmetrical ureas could be prepared from the parent formamide, while unsymmetrical ureas were available from N-substituted formamides (Scheme 8). High yields of N,N-diarylureas were obtained from N-arylformamides and aniline derivatives, but the yields of symmetrical ureas from formamide were variable. Secondary amines underwent the reaction, but N,N-substituted formamides did not.

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24 Scheme 7 Scheme 8

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25 Scheme 9 A proposed mechanism that accounted for these and other observations began with formation of oxygen-bridged dinuclear complex 14 by coordination of the formamide to two molecules of RuCl2(PPh3)3 and dissociation of two triphenylphosphine ligands (Scheme 9). Oxidative addition of the N-H bond to the ruthenium center would then afford 15 followed by a second oxidative addition to yield isocyanate complex 16. Reductive elimination of molecular hydrogen produces 17, which is attacked by the amine at the isocyanate ligand to yield the

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26 corresponding urea and regenerate the active species. In this scheme, reaction of N,N-disubstituted formamides is not possible because they cannot form an isocyanate ligand.24 Cobaltand Rhodium-catalyzed oxidative carbonylation Rindone reported the synthesis of acyclic and cyclic ureas from aromatic primary amines, -bis(salicylidene)ethylenediaminocobalt(II) ([Co(salen)]) as the catalyst.20 Optimal reaction conditions varied with the substrate. For example, the urea yields from 4-methylaniline were higher at high pressure of O2, while 4-fluoroaniline reacted better at lower O2 pressure. Substituent effects were also examined. Electron-withdrawing groups in the para position lowered the conversion of the starting amine while ortho-aminophenol was more reactive than the other amines. The substituent effects were elaborated in a subsequent paper.77 The proposed mechanism involved equilibrium between planar and non-planar salen ligands (18 and 19) on a cobalt (III) amido complex, either of which could undergo carbon monoxide insertion to give an equilibrium mixture of carbamoyl complexes 20 and 21. Compound 20, having the planar salen ligand and a trans relationship between the carbamoyl and amine ligands, could lead to free isocyanate or carbamate, while complex 21, having a nonplanar salen and a cis relationship between the carbamoyl and amine ligands, would lead to the urea (Scheme 10).20 Dicobalt octacarbonyl has also been used in the microwave synthesis of ureas. Larhed drastically reduced reaction time by running the reaction under microwave irradiation. The carbonyl complex served as the source of CO, eliminating the need for CO pressure in the reaction vessel. Symmetrical and unsymmetrical ureas were obtained in as little as 10 seconds, with yields generally better for symmetrical ureas.

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27 Scheme 10 Claver prepared modified [Co(salen)] complexes (Figure 1-1) and utilized them as catalysts for oxidative carbonylation of aniline.78 Results revealed that the t-butyl-substituted catalyst 23 produced 100% selectivity for diphenylurea in the presence of butanol, while the other complexes afforded mixtures of the urea and the corresponding butyl carbamate. The phenanthroline derivative 26 also showed high selectivity (94%) for the urea. Efforts in the rhodium-catalyzed carbonylation of amines to ureas have been sparse in recent years. An early study by Chaudhari investigated various factors that affect activity and selectivity of rhodium-catalyzed oxidative carbonylation.79 Although the primary objective was the synthesis of carbamates, some conditions were found to favor the formation of ureas. In studies focused on the oxidative carbonylation of aniline, a Rh/C-NaI system was determined to be best for the catalytic process. Using this catalyst, polar solvents like acetonitrile or DMF favored formation of diphenylurea, while most other solvents favored the carbamate. Modifying pressure, temperature, and concentration also affected selectivity and activity.79

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28 Figure 1-1. Co(salen) (22) and modified Co(salen) complexes (23-27) Giannocaro reported preparation of Rh3+ and Rh3+-di-titanium phosphate (TiP), and measured their activity towards oxidative carbonylation of aniline.80 Intercalation provided a way to heterogenize an otherwise homogeneous catalyst. Typical conditions involved acetonitrile or methanol as the solvent, a CO/O2 mixture at atmospheric or higher pressure, temperatures between 70-3+Ias a promoter. The highest catalyst activities were obtained with increased pressure of the CO/O2 mixture, higher temperature, and a molar ratio of co-catalyst to Rh3+(PhNH3+I-/ Rh3+) between 5 and 6. It was found that the materials containing simple Rh3+ salts worked better than those prepared from Rh3+-diamine complexes. The key intermediate in the postulated reaction mechanism (Scheme 11) is the Rh3+-carbamoyl complex 28 which reacts with molecular iodine

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29 to form the iodoformate intermediate, ICONHPh. The latter reacts with aniline to afford diphenylurea.80 Scheme 11 Gold-catalyzed oxidative carbonylation Deng has investigated gold compounds as catalysts for the carbonylation of amines.50,81-84 Although simple Au(I) salts afforded carbamates from aniline, the reactions of aliphatic amines also yielded the urea in some cases.81 Polymer immobilized gold catalysts, prepared from commercially available ion exchange resins and HAuCl4, were found to catalyze the carbonylation of aryl amines to their methyl carbamates in the presence of methanol.50 In the absence of methanol, the diarylureas became the major products. In contrast to previously reported gold catalysts, the polymer immobilized variety showed enhanced catalytic efficiency, could easily be separated from the product, and could be used in the absence of organic solvents. Subsequent work demonstrated that use of this system with aliphatic amines and CO2 could afford symmetrical dialkylureas, with high yields and turnover frequencies (Scheme 12).84 The mechanism is unclear, but it was postulated that the high activity can be attributed to some synergistic relationship between gold nanoparticles and the polymer support.

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30 Scheme 12 Tungsten-Catalyzed Oxidative Carbonylation of Amines Carbonylation of primary amines Despite extensive investigation of transition metal-catalyzed carbonylation reactions, examples involving Group 6 metals still remain rare. During the last decade, we have been exploring conversion of amine substrates to the corresponding ureas using tungsten carbonyl complexes as the catalysts and I2 as the oxidant. The initial report described catalytic oxidative carbonylation of primary amines using the iodo-bridged tungsten dimer [(CO)2W(NPh)I2]2 (29) as the precatalyst.41 During those studies, it was shown that primary aromatic and aliphatic amines could be carbonylated to 1,3-disubstituted ureas, while secondary amines afforded formamides in modest yields. Mechanistic studies on this process established that primary amines reacted stoichiometrically with dimer 29 to yield the amine complexes (CO)2I2W(NPh)(NH2R) (30) (Scheme 13), which undergo reaction with excess amine to afford the corresponding ureas.43 Nucleophilic attack of the amine on a carbonyl ligand of 31, followed by proton abstraction using a second equivalent of the amine would afford carbamoyl complex 32. IR spectra of the reaction mixtures were consistent with the presence of carbamoyl complexes. The intermediacy of carbamoyl complex 32 is precedented by Angelici's work on the carbonylation of CH3NH2 by [( 5-C5H5)W(CO)4]PF6,85 for which the first step is conversion of [( 5-C5H5)W(CO)4]+ to the carbamoyl complex ( 5-C5H5)W(CO)3(CONHCH3) upon reaction with 2 equiv of CH3NH2.

PAGE 31

31 Scheme 13 Assignment of the next step as oxidation was supported by IR spectra that showed the disappearance of the carbamoyl stretches after the reaction mixtures were exposed to air. It is expected that following oxidation of the complex, the carbamoyl proton would be more acidic and deprotonation of 32 with the excess amine would produce the isocyanate complex 33. Nucleophilic attack of an amine on either coordinated or free isocyanate would afford the 1,3-disubstituted urea, producing coordinatively unsaturated complex 34, which could undergo addition of CO to regenerate cationic intermediate 31 and close the catalytic cycle.

PAGE 32

32 The previous results implied that other tungsten carbonyl iodide complexes might also serve as catalysts. The simplest choice as precatalyst was the readily available, inexpensive, and air stable W(CO)6. Preliminary studies were carried out using W(CO)6 as catalyst for the catalytic carbonylation of n-butylamine. Reaction of W(CO)6, 100 equiv of n-butylamine, 50 equiv of iodine, and 100 equiv of K2CO3 in a 125 mL Parr high-pressure vessel pressurized with 100 atm CO produced di-n-butylurea in an amount corresponding to 39 turnovers per equivalent of W(CO)6, or 80% yield with respect to amine.43 Subsequent optimization studies using n-propylamine established that N,N'-disubstituted ureas could be obtained in good to excellent yields using the W(CO)6/I2 oxidative carbonylation system (Table 1-1).44 Once W(CO)6 (2 mol %) was established as the preferred catalyst, other variables were examined. Optimal conditions were 90C, 80 atm CO, 1.5 equiv of K2CO3, and a chlorinated solvent such as CH2Cl2 or CHCl3. Note that conditions could not be found for conversion of aniline to diphenylurea, presumably due to lower nucleophilicity of the aryl amine. Carbonylation of primary and secondary diamines to cyclic ureas Many methods for conversion of diamines to the corresponding cyclic ureas have been reported.12,13 Most of them are stoichiometric reactions based on nucleophilic attack of amines on phosgene and related derivatives. Catalytic oxidative carbonylation of diamine substrates provides an alternative route to cyclic ureas in which CO is used as the carbonyl source. However, the synthesis of cyclic ureas via metal-catalyzed carbonylation has received limited attention. Early reports of transition metal-catalyzed carbonylation of diamines mentioned cyclic ureas only as very minor or side products. In the case of Mn2(CO)10-catalyzed carbonylation of the diamines H2N(CH2)nNH2 (n = 2-4 and 6), no cyclic products were observed when n = 2, 4, or 6 and only 6% of the six-membered urea when n = 3.86

PAGE 33

33 Table 1-1. Oxidative Carbonylation of Primary Amines to Ureas under Optimized Conditions. Amine Product %Yield CH 2 Cl 2 90 84 53 55 72 0 Conditions: W(CO)6 (2 mol %), I2 (0.5 equiv), 1.5 equiv of K2CO3, 90C, 80 atm CO,and CH2Cl2 as the solvent.

PAGE 34

34 We thus explored the catalytic carbonylation of diamines to cyclic ureas using W(CO)6 as the catalyst, I2 as the oxidant, and CO as the carbonyl source.42 Both primary and secondary ,-diamines were substrates for the reaction, with secondary diamines being converted directly to the corresponding N,N'-disubstituted cyclic ureas. Synthesis of the five-, six-, and seven-membered cyclic ureas from the primary diamines could be achieved in moderate to good yields (Eq 6),42 with the highest isolated yield for the six-membered cyclic urea. Only trace amounts of the eight-membered ring compound could be detected in the reaction mixtures, which was not surprising as there are no reports in the literature of preparation of this compound from 1,5-pentanediamine. In addition, (+)-(1R,2R)-1,2-diphenyl-1,2-ethanediamine was carbonylated to the 2-imidazolidinone in 46% yield with no epimerization. Reaction of the secondary diamines RNHCH2CH2NHR (Eq 6, R = Me, Et, iPr, Bn) under similar conditions resulted in conversion of the diamines to the corresponding N,N'-disubstituted cyclic ureas. For both primary and secondary substrates, it was necessary to employ high dilution conditions to minimize formation of oligomers, a problem also encountered during the reactions of phosgene and its derivatives with diamines.87 Steric effects on the ring closure reaction were probed by carbonylating N,N'-dimethyl, diethyl, diisopropyl, and dibenzyl diamines under the standard conditions.42 As expected, 1,3-diethyl-2-imidazolidinone and 1,3-dimethyl-2-imidazolidinone were produced in nearly identical yields. Changing the substituents to benzyl groups lowered the yield only modestly but the

PAGE 35

35 presence of bulky isopropyl groups dramatically reduced the yield of the imidazolidinone to only 10%. Yields in the sterically hindered cases could not be improved by raising the reaction temperature. Although primary amines reacted much more readily than secondary amines, N-methylpropanediamine reacted under the oxidative carbonylation conditions to produce the corresponding monosubstituted N-methyl cyclic urea in preference to acyclic urea formation through the more reactive primary amines.42 A more extensive study on the carbonylation of ,-diamines to cyclic ureas involved further optimization of the conditions using propane-1,3-diamine as the test substrate, W(CO)6 as catalyst and I2 as the oxidant.2 Effects of solvent and temperature variation on the yields of the cyclic urea from propane-1,3-diamine were examined. Additional experiments probed the effect of alkyl substituents in the linker of primary diamines (Table 1-2). In the cases of simple n-alkyl substituents, the yields of cyclic ureas are significantly higher for the 2,2-dialkyl-1,3-propanediamines than for the parent propane-1,3-diamine as a result of the Thorpe-Ingold effect88 and improved solubility in organic solvents during workup. The carbonylation of N,N'-dialkyl-2,2-dimethylpropane-1,3-diamines afforded tetrasubstituted ureas; however, the products were obtained in modest yields, and tetrahydropyrimidine byproducts were formed in significant amounts when the substrates bore N-alkyl substituents larger than methyl. Comparison of these results with the carbonylations of secondary diamines to form five-membered cyclic ureas suggested that the effects of ring size and N-substituent size on the carbonylation reaction are complex. Success with conversion of diamines to cyclic ureas suggested the use of W(CO)6-catalyzed oxidative carbonylation of amines can be used for the the synthesis of complex targets.

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36 Table 1-2. Oxidative Carbonylation of Substituted Primary Diamines Amine Product % Yield 52 80 70 48 50 33 38

PAGE 37

37 Before considering applications in synthesis, it was necessary to evaluate the functional group compatibility of the catalyst, often a critical issue in the use of early metal systems. Studies of functional group compatibility using a series of substituted benzylamines (Eq. 7, Table 1-3) demonstrated that the oxidative carbonylation of amines using the W(CO)6/I2 system is tolerant of a wide variety of functionality, including halides, esters, alkenes, and nitriles. A distinguishing feature is the tolerance of unprotected alcohols, which would be problematic with phosgene derivatives.44 A critical result of this study is the observation that the addition of water to generate a biphasic solvent system produced dramatic increases in the yields of functionalized ureas. In order for the reaction to work efficiently, it is necessary to solubilize the catalyst, the starting amine, the hydroiodide salt of the starting material which is formed when protons are scavenged, and the base (K2CO3). The biphasic solvent system sets up phase transfer conditions in which the amine salt can be deprotonated by aqueous carbonate and then returned to the organic phase for carbonylation. After broad functional group tolerance during W(CO)6/I2-catalyzed oxidative carbonylation of amines to ureas had been established,44 use of this methodology to install the urea moiety into the core structure of the HIV protease inhibitors DMP 323 and DMP 450 (Figure 1-2)89,90 was investigated.4 (7)

PAGE 38

38 Table 1-3. Catalytic Carbonylation of Substituted Benzylamines to Ureas Amine %Y ield a,b CH 2 Cl 2 %Yield a,c CH 2 Cl 2 /H 2 O Amine %Yield a CH 2 Cl 2 %Yield b CH 2 Cl 2 /H 2 O 63 73 36 55 35 77 0 37 30 77 41 69 39 70 45 76 47 70 37 68 24 81 28 14 5 58 17 20 0 0 a Reaction conditions: amine (7.1 mmol), W(CO)6 (0.14 mmol), I2 (3.5 mmol), K2CO3 (10.7 mmol), CH2Cl2 b The solvent was CH2Cl2 (21 mL) plus H2O (3 mL). Other conditions are as in footnote a.

PAGE 39

39 Direct comparison of the catalytic carbonylation reaction with stoichiometric reaction of the same substrates with phosgene derivatives was possible due to the extensive literature on the synthesis of these targets. Figure 1-2. Structures of the HIV protease inhibitors DMP 323 and DMP 450 It has been reported in the literature that the urea moiety of DMP 323 and DMP 450 was installed by reaction of phosgene or a phosgene equivalent with an O-protected diamine diol. In the initial small-scale preparations, a primary diamine was reacted with the phosgene derivative 1,1'-carbonyldiimidazole (CDI)90-93 followed by N-alkylation as appropriate. The practical preparation of DMP 450 involves reaction of secondary diamine with phosgene to form the cyclic urea. Since use of phosgene or CDI requires protection of the diol, extensive protecting group studies have been carried out.91,94 Three of the previously described O-protected diamine diols, acetonide 35,94 MEM ether 36,90,95 and SEM ether 3790 were tested in the catalytic carbonylation reaction as representative examples containing cyclic and acyclic protecting groups, respectively (Eq. 8).4 Carbonylation of diamine substrates 35-37 (Eq 8) to the cyclic ureas 38-40 provided a means for comparison of the W(CO)6-catalyzed process to the stoichiometric reactions of the phosgene derivative CDI. More extensive discussion of the results obtained from these experiments will be submitted in subsequent chapter.

PAGE 40

40 Efforts to avoid the protecting group chemistry in reported syntheses of DMP 323 and DMP 450 by carbonylating the diamine diol 41 were frustrated by the reaction of the diol hydroxyl groups to generate oxazolidinones 42 and 43 (Eq. 9).46 Oxazolidinone formation had also been reported as the result of reaction of 41 with CDI and phosgene.96 The earlier functional group compatibility study had suggested that the catalyst was tolerant of -OH groups (Eq 7, Table 3) but the test substrate in that study was [4-(aminomethyl)phenyl]methanol, in which the -OH group is para with respect to the amine so as to eliminate the possibility of formation of a cyclic carbamate. For that substrate, the corresponding urea was produced without competing carbamate or carbonate formation.44 For diamine diol 41, oxazolidinone formation had been preferred under the reaction conditions tested. More recently, the catalytic carbonylation of a series of amino alcohols of varying tether lengths and substitution patterns was carried out to probe the selectivity of the W(CO)6/I2 carbonylation system for reactivity of alcohols versus amines. The phosgene derivatives dimethyl dithiocarbamate (DMDTC) and 1,1'-carbonyldiimidazole (CDI) were used as representative stoichiometric reagents for comparison purposes, the results are discussed in a separate chapter, later on in this work.46

PAGE 41

41 Other interesting targets that were prepared to investigate the scope of the W(CO)6/I2 system were biotin and related heterocyclic ureas.97 Biotin (44b), also known as Vitamin H, is produced on large scale as a feed additive for poultry and swine. It has also been the target of more than 40 total and formal syntheses.98 One recurring theme in these syntheses has been installation of the urea moiety by reaction of phosgene with a diaminotetrahydrothiophene derivative.

PAGE 42

42 Although biotin itself could not be produced directly from carboxylic acid 44a (Eq. 10), biotin methyl ester (45b) was obtained in 84% yield upon W(CO)6-catalyzed oxidative carbonylation of diamine 45a. The related heterocycles 46b-49b were also prepared by the carbonylation procedure and the yields compared to those obtained by reaction of the same substrates with CDI (Eq 11, Table 1-4). Yields of the ureas were moderate to good and depended on the solubility of the diamine and urea in methylene chloride. Table 1-4. Yields of Bicyclic Ureas from Diamines 46a-49a Amine Urea W(CO) 6 /I 2 Yield CDI Yield 46a 46b Trace 20% 47a 47b 47% 67% 48a 48b 46% 37% 49a 49b 57% 56% Conclusions Transition metal-catalyzed carbonylation of amines offers new and efficient methodology for the selective synthesis of ureas under relatively mild reaction conditions. Use of CO or CO2 as the carbonyl source in the presence of a catalyst and an oxidant provides an alternative to the traditional methods for conversion of amines to ureas, which involve stoichiometric use of phosgene and its derivatives. From the perspective of green chemistry, the replacement of phosgene and the minimization of the waste streams associated with phosgene derivatives would be beneficial. Recent developments in metal-catalyzed oxidative carbonylation of amines include new techniques such as the use of ionic liquids, microwave irradiation and electrocatalytic carbonylation. In addition to extensive work with palladium complexes, carbonylation reactions that utilize other late transition metals, such as Ni, Ru, Rh, Co, Au, have also been demonstrated

PAGE 43

43 to afford ureas. Indications that tungsten-catalyzed oxidative carbonylation of functionalized amines could be of use in the synthesis of complex targets had also been reported. Given the prevalence of urea functionality in compounds with a wide range of applications, further work in this area is no doubt forthcoming.

PAGE 44

44 CHAPTER 2 SELECTIVE CATALYTIC OXIDATIVE CARBONYLATION OF AMINOALCOHOLS TO UREAS Conversion of amines to ureas commonly involves nucleophilic displacement of leaving groups from phosgene or a phosgene derivative.13 Phosgene and its derivatives are not selective for the carbonylation of amines, reacting with other functionality such as hydroxyl groups. In fact, phosgene reacts with both functional groups of aminoalcohols to form products such as cyclic carbamates99 or isocyanate chloroformates (Scheme 14).100,101 Although transamination of ureas,102 selenium-catalyzed carbonylation,103 and condensation with S,S'-dimethyl dithiocarbonate (DMDTC)104 have been used to generate hydroxyalkylureas from aminoalcohols under circumstances where formation of the cyclic carbamate is disfavored, selective reactivity of aminoalcohols with a phosgene derivative often requires protection of one functional group to avoid forming mixtures of ureas and carbamates. Scheme 14 As an alternative to phosgene and phosgene derivatives, we recently reported the catalytic carbonylation of aliphatic amines to ureas using W(CO)6 as the catalyst and I2 as the oxidant.41,43-45 A functional group compatibility study demonstrated that the catalyst was tolerant of OH

PAGE 45

45 groups (Eq. 12), at least in the case of [4-(aminomethyl)phenyl]methanol, in which the corresponding urea was produced without competing carbamate or carbonate formation.44 However, in the carbonylation reaction of Eq 12, the OH group is para with respect to the amine so as to eliminate the possibility of intramolecular formation of a cyclic carbamate. We now report the catalytic carbonylation of a series of aminoalcohols of varying tether lengths and substitution patterns in order to evaluate the selectivity of the W(CO)6/I2 carbonylation system for reactivity of alcohols vs. amines. These results are compared to reaction of the same aminoalcohol substrates with the phosgene derivatives DMDTC and 1,1'-carbonyldiimidazole (CDI). Results and Discussion The aminoalcohol substrates for this study were chosen with varying tether lengths between the functional groups and varying steric hindrance at the active sites. The substrates were then subjected to W(CO)6-catalyzed oxidative carbonylation for evaluation of the selectivity of the W(CO)6/I2 system towards formation of the ureas or carbamates, either cyclic or acyclic. As a comparison of the stoichiometric reactions of phosgene derivatives to the catalytic W(CO)6/I2 methodology, 1,1'-carbonyldiimidazole (CDI) and dimethyl dithiocarbonate (DMDTC) were also used for the carbonylation of the aminoalcohol substrates.

PAGE 46

46 Carbonylation of 5-Aminopentanol Carbonylation of 5-aminopentanol 50 was investigated to determine the preference of a 1,5-aminoalcohol to form the corresponding acyclic urea 51 or the 8-membered cyclic carbamate 52 (Eq. 2). The optimal reaction conditions of a substrate concentration of 4M, 40 C, 80 atm CO and a reaction time of 18 hours afforded the bis(hydroxyalkyl)urea 51 in 64% yield and the cyclic carbamate 52 in only 2% yield. The acyclic carbamate 53 was not detected in the reaction mixtures. However, the presence of unreacted starting material was observed by TLC prior to purification of the products. When potassium carbonate was used as the base, as was reported in prior studies,42,44 formation of urea 51 was confirmed by various spectroscopic methods. No evidence of the acyclic carbamates 53 was found. Purification of 51 by the previously described method proved difficult. The problem is similarity in the solubilities of the hydroxyalkylurea product and potassium iodide, which is a byproduct of carbonylation in the presence of K2CO3. Consequently, it was difficult to purify the urea by methods such as chromatography or selective extraction. These difficulties with the workup could be avoided by changing the base to

PAGE 47

47 pyridine, which allowed purification of the products to be carried out without chromatography. The modified workup for the recovery of the urea and carbamate is described in detail in the experimental section. The selectivity of the W(CO)6-catalyzed carbonylation of 5-aminopentanol is comparable to the selectivity when phosgene derivatives are used as the carbonylation agents. Carbonylation of aminoalcohol 50 using CDI afforded urea 51 in 80% yield, while just trace amounts of the cyclic carbamate 52 and none of the acyclic carbamate 53 were observed. The other phosgene derivative, DMDTC, produced urea 51 from aminoalcohol 50 in 45% yields with no evidence of the formation of 52 or 53 (Table 2-1, entry1). Carbonylation of 4-Amino-2-methylbutan-1-ol The selectivity between conversion of a 1,4-aminoalcohol to a seven-membered cyclic carbamate, an acyclic carbamate or the corresponding urea was investigated using 4-amino-2-methylbutan-1-ol (54) as a representative substrate. The optimal reaction conditions were found to be the same as for 5-aminopentanol; with a substrate concentration of 4M, 40 C and a reaction time of 18 hours producing urea 55 in 93% yield. Compounds 56 and 57 were not detected in the reaction mixtures by NMR or IR. To compare the carbonylation of 54 to results using phosgene derivatives, 4-amino-2-methylbutanol was treated with CDI at a concentration of 4 M or DMDTC at a concentration of 4.5 M. All three carbonylation methods produced similar selectivity for the formation of urea 55 over products 56 and 57. When CDI was used as the carbonylating agent, compound 55 was formed in 70 % yield as the major component of the product mixture while 56 was detected in trace amounts (Eq. 3). There was no evidence for the formation of 57. Likewise, in the case of DMDTC, urea 55 was produced in 93% yield as the only product (Table 2-1, Entry 2).

PAGE 48

48 Table 2-1. Carbonylation of aminoalcohols to ureas and carbamates. Entry Substrate Reagent Urea (%) Cyclic Carbamate (%) 1 50 W(CO) 6 /CO 64 2 CDI 80 trace DMDTC 45 0 2 54 W(CO) 6 /CO 93 0 CDI 70 trace DMDTC 93 0 3 59 W(CO) 6 /CO 95 trace CDI 36 60 DMDTC 30 8 4 63 W(CO) 6 /CO 72 14 CDI 49 30 DMDTC 34 47 5 67 W(CO) 6 /CO 60 5 CDI 55 28 DMDTC 32 29 6 75 W(CO) 6 /CO 78 10 CDI 18 22 DMDTC 72 trace 7 78 W(CO) 6 /CO 79 14 CDI 30 52 DMDTC 73 trace

PAGE 49

49 Carbonylation of 1,3-Aminoalcohols The carbonylation of a 1,3-aminoalcohol to a six-membered cyclic carbamate or an acyclic carbamate vs. formation of the corresponding urea was first investigated using 3-amino-4-phenyl-butanol (59) as a representative substrate. Substrate 59 was synthesized by reduction of DL--homophenylalanine (58) with BH315). Aminoalcohol 59 was then subjected to oxidative carbonylation using the W(CO)6/I2 catalytic system under the previously determined optimal reaction conditions (Eq. 16, Table 6, Entry 3). Urea 60 was isolated in 95% yield with carbamate 61 formed in trace amounts as a minor product. Acyclic carbamate 62 was not observed.

PAGE 50

50 In order to compare the carbonylation results to phosgene derivatives, 59 was treated with DMDTC and CDI, respectively. In contrast to the excellent yield of urea 60 from the W(CO)6-catalyzed carbonylation, reaction of amine 59 with DMDTC afforded 60 and 61 in yields of 30% and 8%, respectively. Compound 62 was once again not detected. The reaction also produced a number of side products which were detected by TLC analysis. When CDI was used as the carbonylating agent, 60 and 61 were produced with 61 being the major product (60% yield) while 60 was formed in 36% yield. Once again, compound 62 was not observed (Table 2-1, Entry 3). A second example of the preference for conversion of 1,3 aminoalcohols to the urea vs. the cyclic carbamate was obtained by carbonylation of 1-phenyl-3-aminopropanol (63). Amino alcohol 63 was synthesized by treating benzaldehyde with acetonitrile under basic conditions followed by reduction of the resulting cyanohydrin with borane dimethylsulfide.5 Carbonylation of 63 using the W(CO)6/I2 catalytic conditions provided the corresponding urea 64 in 72% yield,

PAGE 51

51 with the minor product being cyclic carbamate 65 in 14% yield after crystallization. The acyclic carbamate 66 was not formed in the reaction. For comparison, 1-phenyl-3-aminopropanol was subjected to carbonylation with the phosgene derivatives CDI and DMDTC (Table 2-1, entry 4). When CDI was used as carbonylating agent, the urea 64 was formed in 49% yield, and the cyclic carbamate 65 in 30% yield. Once again, the acyclic carbamate was not observed in the product mixture. In contrast, when DMDTC was used as carbonylating agent, cyclic carbamate 65 was the major product (47% yield), while the urea was recovered in 34% yield. Finally, 3-amino-2,2-dimethylpropanol (67) was studied under the optimal W(CO)6/I2 catalytic conditions (Eq. 18). Compound 67 was chosen in order to examine the effect of steric -Ingold effect of the gem-dimethyl substituents at C3. Accordingly, the carbamate was expected to be favored by the presence of the gem-dimethyl substituents. However, when carried out under the W(CO)6/I2 carbonylation conditions, the reaction did not go to completion and 12% of the starting material was recovered. This may be due in part to steric bulk in the substrate. Nevertheless, urea 68 and

PAGE 52

52 carbamate 69 were obtained in 60% and 5% yield, respectively (Table 2-1, entry 5). There was no evidence for the formation of the acyclic carbamate 70. In contrast, when 3-amino-2,2-dimethylpropanol (67) was treated with CDI or DMDTC, much higher proportions of carbamate were generated than with the W(CO)6-catalyzed carbonylation (Table 2-1, Entry 5). Urea 68 was still the major product for both carbonylation reactions, being isolated in 55% yield and 32% yield, respectively. However, cyclic carbamate 69 was recovered in 28% yield from the reaction with CDI and in 29% yield when DMDTC was used in the carbonylation. Overall, there is a strong selectivity favoring formation of urea over carbamate in the W(CO)6-catalyzed carbonylation for all three 1,3aminoalcohols that were investigated. In comparison, the selectivity for formation of the urea over formation of the carbamate is significantly lower when CDI or DMDTC is used as the carbonylating agent. Carbonylation of 1,2-Aminoalcohols Our interest in the carbonylation of 1,2-aminoalcohols began with our preparation of the core structure of the HIV protease inhibitors DMP 323 and DMP 450 by W(CO)6-catalyzed carbonylation of O-protected derivatives of diamine diol 71.4 As part of these investigations, it was determined that under the initially reported conditions, oxidative carbonylation of 71

PAGE 53

53 afforded oxazolidinones 73 and 74 instead of the diol urea 72 (Eq. 19).39 A similar preference had previously been reported for the reactions of 71 with CDI and phosgene.96 These prior results provided motivation for additional study of 1,2-aminoalcohols. The initial substrate was -amino alcohol 75 (Eq. 20), chosen for its structural similarity to half of 71. To further investigate formation of the oxazolidinone ring vs. coupling to the urea, oxidative carbonylation of -amino alcohol 75 was carried out using the W(CO)6/I2 catalytic system (Eq. 20). The conditions were the same as described for the previous aminoalcohol substrates. Upon carbonylation of 75, urea 76 and cyclic carbamate 77 were obtained in 78% and 10% yield, respectively, with urea formation once again strongly preferred (Table 2-1, entry 6). Although the phosgene derivative DMDTC afforded similar results, carbonylation of 75 with CDI produced only low yields of a roughly equal mixture of urea 76 and carbamate 77.

PAGE 54

54 To further investigate the carbonylation of 1,2-aminoalcohol substrates, (R)-(-)-2-amino-1-phenylethanol (78) was also subjected to the W(CO)6-catalyzed carbonylation (Eq. 21). Urea 79 and cyclic carbamate 80 were obtained in 79% and 14% yield, respectively. As observed for 1,2-aminoalcohol 75, there was a high selectivity for conversion of 78 to the urea in preference to the oxazolidinone. The phosgene derivatives CDI and DMDTC were also used in the carbonylation of 78 for comparison. In the former reaction, the cyclic carbamate 80 was the major product (52% yield) while the urea 79 was recovered in 30% from the mixture. On the other hand, when DMDTC was used as the carbonylating agent, urea 79 was the major product of the reaction (73% yield) while oxazolidinone 80 was isolated in just trace amounts (Table 2-1, Entry 7). Note that for 1,2-aminoalcohols 75 and 78, both the W(CO)6-catalyzed carbonylation and DMDTC afforded the hydroxyalkyl ureas as the major products but carbonylation with CDI favored the cyclic carbamate. Conclusions In summary, the W(CO)6/I2 methodology can be applied to carbonylation of aminoalcohols to the ureas without protection of the hydroxyl group. The W(CO)6-catalyzed oxidative carbonylation is consistently selective for the urea over the cyclic carbamate in all cases studied. Acyclic carbamates are not detected in the reaction mixtures. In contrast, reactions of the

PAGE 55

55 phosgene derivatives CDI and DMDTC with 1,3and 1,2-aminoalcohol substrates exhibit variable selectivities between ureas and cyclic carbamates.

PAGE 56

56 CHAPTER 3 THE W(CO)6/I2 CATALYZED OXIDATIVE CARBONYLATION OF DIAMINES: ANALOGS OF THE CORE STRUCTURES OF THE HIV PROTEASE INHIBITORS DMP 323 AND DMP450. Background The syntheses of new improved and more efficient HIV inhibitors against mutant proteases continue to be an important target in medicinal and synthetic chemistry. In order to design and synthesize more potent inhibitors of HIV protease, it is crucial to understand the basics of molecular recognition for the protease. Extensive studies have been done in this regard and two distinctive characteristics have been identified.105 First, it was found that the active form of the viral enzyme is a homodimer, in which each monomer contributes equally to the active site. Also, the occurrence of structural water that bridges linear inhibitors to the flap of the protein through hydrogen bonds has been confirmed. One of the first sets of C2 symmetric molecules that were reported to displace the structural water was the C2 symmetric cyclic urea-based inhibitors. Since these inhibitors were first reported, the number of cyclic urea scaffolds has rapidly increased and this class of cyclic compounds has become a feasible alternative to the existing antiretroviral agents. DMP 323 and DMP450 are among these HIV protease inhibitors reported as discussed earlier in this work (Fig. 2). Figure 2. Structures of the HIV protease inhibitors DMP 323 and DMP 450

PAGE 57

57 Studies on the interaction of the cyclic urea inhibitors XK216, XK263, DMP323, DMP450, XV638, and SD146 with HIV-1 protease, has revealed that these cyclic ureas are symmetrical molecules that posses a common central structural unit: a seven membered heterocyclic ring a urea moiety and diols. Their P1(P1) and P2(P2) substituents are attached to C3(C6) (atoms adjacent to the diols) and the urea nitrogen atoms respectively (Table 3-1).105 Synthesis of DMP 323 and DMP 450 was first reported by DuPont Merck Pharmaceuticals.91 The key feature of DMP 323 and DMP 450 is the C2 symmetric diol which provides the correct binding site configuration for the protease enzyme. The 7-membered cyclic urea moiety provides a scaffold for the diol. Many different routes for the synthesis of DMP 323 and DMP 450 derivatives are available in the literature. Generally, the urea moiety of DMP 323 and DMP 450 was installed by reaction of phosgene or a phosgene equivalent with an O-protected diamine diol. In the initial small-scale preparations, a primary diamine was reacted with the phosgene derivative 1,1'-carbonyldiimidazole (CDI),90,91,93,106 followed by N-alkylation as appropriate (Scheme 15). The practical route to DMP 450 utilizes phosgene to form the cyclic urea from a secondary diamine.91 The protection of the diol is essential in all these synthetic routes, thus a large amount of information concerning protection of the diol is available.91,96 As discussed in previous chapters, oxidative catalytic carbonylation of the corresponding diamines using W(CO)6/I2 has also been applied in an effort to install the urea moiety into the core structure of the HIV protease inhibitors DMP 323 and DMP 450.4,39 In this study, protecting groups such as acetonide 35,27 MEM ether 36107 and SEM ether 37,107 were chosen as representative examples bearing cyclic and acyclic protecting groups,

PAGE 58

58 Table 3-1. Structures of cyclic urea inhibitors Cycl ic Ureas P2/P2

PAGE 59

59 Scheme 15

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60 respectively. Carbonylation of 35-37 allows comparison of the W(CO)6-catalyzed process to the stoichiometric reactions of the phosgene derivative CDI (Table 3-2).108 Varying results were obtained in the yields of the ureas from the catalytic reaction depending on the protecting group on the diol, as was also observed for ring closure with stoichiometric CDI. These results demonstrate that the catalytic oxidative carbonylation reaction can be used to convert diamines to cyclic ureas in examples relevant to the preparation of complex targets. Table 3-2. Carbonylation of compounds 35-37 to Ureas 38-40 aTypical reaction conditions: Diamine 35 (0.200 mmol), W(CO)6 (0.0242 mmol), K2CO3 (0.635 mmol) and I2 (0.239 mmol), solvent (32 mL CH2Cl2 : 8 mL of water), 80 atm CO, 80 C, 18 h. bNot reported. cYields are from two-step sequence involving deprotection of the Cbz-protected diamine. Deprotection is assumed to be quantitative for purposes of the table. Overall, catalytic oxidative carbonylation of 35 in the biphasic CH2Cl2/H2O solvent system afforded 38 in 38% yield. As had been observed for the carbonylation of functionalized benzyl amines,44 yields obtained by using the biphasic solvent system were higher than those in CH2Cl2. Diamine Reagent Solvent % Yield Urea Ref 35 CDI CH 3 CN NR b 15 32 35 CDI TCE 140 67 32 35 W(CO) 6 /CO CH 2 Cl 2 /H 2 O 80 38 15 35 W(CO) 6 /CO CH 2 Cl 2 80 26 15 36 CDI CH 2 Cl 2 rt 62,76 c 30,33,34 36 W(CO) 6 /CO CH 2 Cl 2 /H 2 O 80 42 15 37 CDI CH 2 Cl 2 rt 52,93 c 30,33 37 W(CO) 6 /CO CH 2 Cl 2 /H 2 O 80 75 15

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61 Efforts to optimize the reaction conditions by varying CO pressure, temperature, concentration and solvent did not result in higher yields of 38. Although the yields of 38 from 35 are modest, results from the catalytic carbonylation compare favorably to those obtained with CDI under typical conditions.2 Reaction of 35 with CDI in acetonitrile under standard conditions results in a 15% yield of 38, with the low conversion attributed to strain in the bicyclic product (Table 3-2). Carbonylation of 36 and 37 was carried out under the conditions used for 35, with the exception of substrate concentration, which was optimized for 36 and the same used for 37 (Table 3-2). In comparison to the literature yields of 62 and 76 % for formation of urea 39 from Cbz protected MEM ether 36 and CDI under slightly different conditions, the catalytic carbonylation reaction provided 39 in 42% yield from 36. Promising results were also obtained for SEM ether 37, for which catalytic carbonylation afforded urea 40 in 75% yield, a value intermediate between the reported yields for reaction of 37 with CDI. With these preliminary results it was established that oxidative catalytic carbonylation of amines can be applied successfully in the preparation of functionalized ureas. These studies also offered the first demonstration of catalytic amine carbonylation as synthetic methodology. Yields of the ureas from the catalytic reaction vary with the protecting group on the diol, as do those reported for ring closure with stoichiometric CDI. Results and Discussion Synthesis of Seven-Membered Ring Cyclic Ureas 84 and 89 In a continuing effort to optimize the carbonylation conditions for the synthesis of 7-membered cyclic ureas, simple targets were envisaged. Therefore the synthesis was began on diamine 83 and 88, which contain no substituent and methyl groups, respectively, in the C2 position.

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62 Diamine 83, which is the precursor to cyclic urea 84, was synthesized as described in Scheme 16. Commercially available 2,3-O-isopropylidene-L-tartrate, is treated with concentrated aqueous ammonia solution and methanol for three days to afford (4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-dicarboxamide 82.109 The next step is the reduction of the dicarboxamide to furnish diamine 83. It is important to point out that the reduction of compound 82 was much more difficult than anticipated. Standard reducing agents that are commonly used did not carry out the reaction to completion. Partially reduced product was the result even though the reaction conditions were adjusted several times. Fortunately, the reduction was accomplished at last using borane-dimethyl sulfide complex in THF. After purification of the diamine 83, the oxidative carbonylation using W(CO)6/I2 system was set up and allowed to react for 24 hours. After workup the cyclic urea 84 was obtained in 74% yield. The synthesis of diamine 88 was carried out according to literature procedures described in Scheme 17.75 Dimethyl 2,3-o-isopropylidene-L-tartrate 85 was dissolved in dry toluene at -40 C. DIBAL was added to this solution dropwise with constant stirring. After one hour, anhydrous methanol was added to the mixture reaction and the reaction was warmed to -10 C. Next, dimethylhydrazine was added and

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63 the reaction was warmed to -10 C. Next, dimethylhydrazine was added and the reaction was allowed to run one more hour to afford hydrazone 86 in good yield. Scheme 16 Scheme 17

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64 Without further purification, the hydrazone was treated with MeLi in dry diethyl ether to produce intermediate 87. Finally, diamine 88 was obtained upon hydrogenation of the hydrazine 87. Once the diamine 88 was available, the oxidative carbonylation with W(CO)6 was pursued, using the conditions described in Scheme 18. Scheme 18 The conditions for the carbonylation reaction have to be adjusted for different substrates. The yields for cyclic ureas 84 and 89 are unoptimized and it is expected that they could be improved. Other substrates containing secondary diamines are currently under investigation. Conclusions In summary, we have established that catalytic oxidative carbonylation of diamines provides an alternative to phosgene and phosgene derivatives in the preparation of cyclic ureas. More detailed studies need to be done in the preparation of cyclic ureas using this methodology. One interesting experiment that is currently being developed is the carbonylation of the diamine diol without any protecting group present since it was demonstrated in previous experiments with aminoalcohols that this system is tolerant to the presence of hydroxyl functional groups.

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65 CHAPTER 4 CATALYTIC OXIDATIVE CARBONYLATION OF ENANTIOMERICALLY PURE -AMINO AMIDES TO PRODUCE HYDANTOIN DERIVATIVES Background Hydantoins and cyclic ureas have long been the focus of considerable attention since they are frequently found as crucial moieties in many biologically active molecules with pharmaceutical relevance. More specifically, hydantoins substituted at C-5 constitute an important class of heterocycles in medicinal chemistry since many derivatives are associated with a wide range of biological properties including anticonvulsant, 110 antidepressant,111,112 antiviral,111,112 and platelet inhibitory activities.113 Moreover, C-5 substituted hydantoin derivatives are of synthetic utility114-116 -amino acid derivatives after hydrolytic degradation (Figure 4-1). Classic Ways to Synthesize Hydantoins A wide variety of methods for the synthesis of hydantoins have been reported starting from different building blocks. Information concerning different approaches to hydantoins including solution phase syntheses and more recently solid-phase organic syntheses, as well as polymer bound reagents can be found in the literature.115,117 Under solution phase conditions, there are several ways to afford hydantoins starting from different substrates. Figure 4-2 describes different strategies to afford hydantoins from various starting materials.117

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66 Figure 4-1. Hydantoin ring structure. Figure 4-2. Synthetic strategies and building blocks for hydantoin synthesis.117 Hydantoins can be prepared from ureas and carbonyl compounds as reported by Beller et al.118 Several examples of these procedures can be found in the literature including the Biltz synthesis, which is still applied to the synthesis of hydantoins (Figure 4-21a). Another classic

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67 way to afford hydantoins is the Bucherer-Bergs methodology, the reaction of carbonyl compounds and inorganic cyanide. Introducing the second nitrogen and carbonyl unit would afford N-1 and N-3 unsubstituted hydantoins (Figure 4-2b). Moreover, another classic way to form hydantoins is the Read-type reaction (Figure 4-2c) of amino acids or derivatives with inorganic isothiocyanate, which will produce the hydantoin with no substituent in the N-3 position. Hydantoins with substituents at N-3 can be synthesized using alkyl or aryl iso(thio)cyanates as marked (Figure 4-2d). Hydantoins from amino amides can be afforded by introducing the C-1 unit (highlighted) to a substrate that already contains four atoms of the hydantoin ring (Figure 4-2e). Finally, hydantoins that possess a substituent at N-1 can be generated starting from -halo amides and inorganic isothiocyanates (Figure 4-2f).117 Solution Phase Synthesis As mentioned above, the Bucherer-Bergs strategy is among the classic ways to produce ureas. This practical and easy method yields 5-substituted hydantoins from aldehydes and ketones. The synthesis involves the reaction of a carbonyl compound with potassium cyanide and ammonium carbonate. Sarges et al. applied this methodology to prepare the aldose reductase inhibitor sorbinil (Scheme 19).119 Scheme 19 The Read synthesis is also frequently applied for the synthesis of hydantoins and thiohydantoins. Smith et al. reported the synthesis of silicon-containing hydantoins starting from

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68 silylated amino acid 93, which upon treatment with potassium cyanate in pyridine and subsequent acid cyclization afforded hydantoin 95 (Scheme 20).120 Scheme 20 The previous examples have long been known to be applicable to the production of hydantoins. However, during the last decades, much progress has been made in the development of new strategies to produce hydantoins, since more cases of interesting biological activity have been discovered. More recent methodologies for the synthesis of hydantoins have been developed. Among them is the synthesis of thiohydantoins reported by Le Tiran and coworkers.121 This synthesis affords thiohydantoins starting with amino acid amides and carbon disulfide. As described in Scheme 21, amino amide 96 was treated with di-2-pyridylthiocarbonate (DPT) in THF at room temperature furnishing disubstituted hydantoin 97. Scheme 21

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69 Hydantoins with different substituent patterns can also be produced from other heterocyclic compounds. One example is the synthesis of 1,5-disubstituted hydantoins 100, that can be prepared from aziridinone 98 and cyanamide, followed by treatment of the resulting iminohydantoin with HNO2 (Scheme 22).122 Scheme 22 Another recent example is the synthesis of hydantoins using multi-component reactions. Hulme and coworkers reported the synthesis of trisubstituted hydantoins using Ugi/De-Boc/Cyclization methodology.123 For the preparation of these trisubstituted hydantoins, they started with five substrates that included aldehydes or ketones, amines, isonitriles, methanol and carbon dioxide. The mechanism of this five-component reaction is described in Scheme 23. Phosgene and its derivatives have also been used for the synthesis of hydantoins.115 One recent report that uses phosgene derivatives for the preparation of enantiomerically pure hydantoins was made by Zhang and coworkers.124 They reported the synthesis of several hydantoin molecules using phosgene and its derivative 1,1-carbonyldiimidazole (CDI). Solid-Phase Organic Synthesis The synthesis of structurally challenging heterocyclic molecules bearing one or more nitrogen atoms using solid support synthesis has developed very quickly in the last decade. There are several reviews on the synthesis of hydantoins by means of solid-phase organic synthesis

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70 (SPOS).117 Gutschow et al. address examples of the most recent efforts on the synthesis of hydantoins via SPOS. Scheme 23 Synthesis of Hydantoins Using W(CO)6/I2 Catalytic System It was anticipated that catalytic carbonylation of -amino amides with W(CO)6/I2 in the presence of CO might be feasible upon optimization of the reaction conditions. Formation of the five-membered ring should be facile since it is kinetically favored. Therefore, an effort toward the synthesis of a series of different hydantoins was begun.

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71 A short and efficient synthesis starts wi-amino amides, which should afford the corresponding enantiomerically pure hydantoins (Eq. 22). In order to increase our knowledge concerning the efficiency of the catalytic system for the synthesis of different substituted hydantoins, it was decided to explore a series of enantiomerically pure -amino amide as substrates for this reaction. Results and Discussion In the present work it is reported that five disubstituted hydantoins carrying aromatic or aliphatic side chains at the 3and 5positions were synthesized from the corresponding -amino amides in good yields using the W(CO)6/I2 system in the presence of CO. Amino amide 103a was synthesized according to the procedure reported in the literature.125 Treatment of the corresponding amino acid methyl ester hydrochloride with methylamine leads to compound 103a (Eq. 23). After purification of compound 103, the next step is the cyclization of the -amino amide using the W(CO)6/I2 system in the presence of CO (Eq. 24). Optimization of the reaction conditions was carried out using amino amide 103a. Initially, the original conditions used for the amino alcohols were tested, but the reaction did not produce the hydantoin and starting material was recovered (Table 8, Entry 1). This was not surprising since the amide is less nucleophilic than the amines present in the amino alcohol substrates. Next, different sets of conditions were tested, including longer times, higher temperatures and different bases. Some of these conditions are described in Table 4-1.

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72 Table 4-1. Carbonylation conditions for -amino amide 103a. Entry Time (h) Pressure (atm) Temp (C) Bas e/eq. Solvent Conc. (M) Product 1 18 80 40 Py/2 CH 2 Cl 2 4 0 2 24 80 70 Py/2 CH 2 Cl 2 4 0 3 36 90 105 Py/2 CH 2 Cl 2 0.11 40 4 45 80 40 Py/2 CH 2 Cl 2 0.11 0 5 36 90 100 K 2 CO 3 CH 2 Cl 2 /H 2 O 0.05 20 6 42 90 100 DMAP/2 CH 2 Cl 2 0.03 0 7 36 85 78 DMAP/3 Toluene 0.0 3 0 8 36 85 78 DMAP/3 CH 2 Cl 2 /H 2 O 0.03 50 9 36 85 78 DMAP/4 CH 2 Cl 2 /H 2 O 0.03 50 10 48 85 90 DMAP/4 CH 2 Cl 2 /H 2 O 0.03 traces 11 36 80 76 DBU/4 DCE 0.03 72 The data in the table show that the best conditions so far are those described in Entry 11. It was expected that the conditions for the carbonylation of this substrate would be different from the optimized for amino alcohols. Since the nucleophilicity of the nitrogen amide is lower than that of the amines previously investigated, the main variable to be addressed was the base. It was likely that a stronger base would be needed to to take the reaction to completion, and indeed this was confirmed later in the investigation. Time was another variable to consider. As shown in Entry 11, 36 hours was optimal for the reaction conditions. At longer reaction times, the product began to decompose (Entry 10). With these optimized conditions, different substrates for the synthesis of hydantoins were started. Figure 4-3 shows the substrates submitted to investigation for the catalytic carbonylation -amino amides to afford the corresponding hydantoins. Amino amide 103e was included in

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73 the study because it contains the hydroxyl functionality that was present in the amino alcohols reported previously. Figure 4--Amino amide substrates to be converted to hydantoins Amino amides 103a-d were prepared following a literature procedure (Eq. 23).124 Using the same starting material, the enantiomerically pure amino amides 103a-d were obtained by adding the corresponding alkyl amine in methanol (Table 4-2). All products (103-a-d) were recovered in very good yield after purification by column chromatography on silica gel. The synthesis of amino amide 103e was initially carried out following available methodology.126 The hydrochloride salt of the serine methyl ester (105) was treated with benzylamine to yield 103e in 35 % isolated yield, a result is similar to that reported in the literature.

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74 Table 4--amino amides 103a-103d entry R 1 Product Yield (%) 1 CH 3 103a 90 2 CH 3 CH 2 103b 82 3 ( CH3 ) 2 CH 2 103c 74 4 PhCH 2 103d 84 However, because of the low yield observed with this procedure, a different method was used to prepare amino amide 103e, and the product was obtained in higher yields.127 This strategy proceeded through Cbz-serine, which was treated with benzylamine and the mixed anhydride coupling (MAC) procedure.128 to afford 105 stereospecifically (Scheme 24). The next step to obtain the carbonylation substrate was the hydrogenation of protected amino-3-hydroxypropionamide to afford 103e in 89% yield. Substrates 103a-e were then subjected to the optimized carbonylation conditions determined for 103a. The results are described in Table 4-3. Most of the hydantoins were obtained in good yields (Table 4-3), except in the case of 104c, which was produced in trace amounts. This is probably because the steric hindrance of the bulky isopropyl group present in the amide substrate, since similar results have been observed before in the carbonylation of diamines containing isopropyl substituents.42 Further optimization of the reaction is necessary, testing different substrates and different conditions, but these preliminary results are promising.

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75 Scheme 24 Table 4--amino amides 103a-e to hydantoins 104a-e. entry R 1 R 2 Product yield 1 PhCH 2 CH 3 104a 73 2 PhCH 2 CH 3 CH 2 104b 61 3 PhCH 2 ( CH3 ) 2 CH 2 104c traces 4 PhCH 2 PhCH 2 104d 75 5 HOCH 2 PhCH 2 104e 50 In the past, other group VI metals carbonyls such as chromium hexacarbonyl and molybdenum hexacarbonyl have been also investigated as catalysts for the carbonylation of aliphatic secondary amines.45 However, the results of those experiments showed that tungsten hexacarbonyl was the best catalyst for the catalytic carbonylation in the case of primary and secondary aliphatic amines. Similar experiments were carried out for the amino amide substrates, in which amino amide 103a was selected to undergo the catalytic reaction using Mo(CO)6 and Cr(CO)6 as catalysts under the previuously optimized conditions. However, as observed previously the carbonylation reaction using Mo and Cr catalysts did not gave good results. In the

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76 case of Mo(CO)6 the yield was less than 20% and for Cr(CO)6 it was impossible to identify the expected hydantoin. Conclusions The W(CO)6 catalytic carbonylation, using I2 as oxidant in the presence of CO, has proven to be effective for the synthesis of disubstituted hydantoins starting from enanti-amino amides. Other group VI metal carbonyl catalysts have been investigated for this carbonylation reaction. However, W(CO)6 is a more effective catalyst for -amino amides to afford the corresponding hydantoins. Further experiments with this type of substrate are currently underway.

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77 CHAPTER 5 EXPERIMENTAL SECTION General Procedures All experimental procedures described were carried out under nitrogen and in oven dried glassware unless stated otherwise. Solvents used for carbonylation reactions were passed through a solvent purification system129 prior to use. Most of the aminoalcohol substrates were commercially available and were used without further purification. The aminoalcohols 3-amino-4-phenyl butanol130 and 3-amino-1-phenyl propanol5 were prepared as described in the literature. 1H and 13C NMR spectra were obtained on a Varian Gemini 300 or VXR 300 MHz spectrometer. Infrared spectra were recorded on a Perkin-Elmer 1600 FT-IR. High-resolution mass spectrometry and elemental analyses were performed by the University of Florida analytical service. Procedure A for Carbonylation of Amino Alcohols with CDI The aminoalcohol (2 equiv) was dissolved in dry THF and placed into the flask under a flow of N2. One equivalent of CDI was then added. The reaction was left to stir for 18 hours, then the solvent was evaporated under a flow of N2. The residue was dissolved in a 1:1 mixture of CH2Cl2: H2O. The mixture was placed in a separatory funnel. After the layers were separated, the aqueous layer was washed with CH2Cl2, then with a 2:1 solution of chloroform/ethanol. The combined organic layers were dried and filtered, then the solvent was removed. The crude product was purified by flash chromatography on silica gel with 5% MeOH/CH2Cl2 as eluent for the carbamate and 30% MeOH/CH2Cl2 for the urea. Procedure B for carbonylation of aminoalcohols with DMDTC The aminoalcohol (2 equiv) was dissolved in dry methanol and placed into the flask under a flow of N2. DMDTC (1 equiv) was then added and the reaction was left to stir for 18 hours

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78 under N2. The solvent was then evaporated under N2 and the product was immediately chromatographed on silica gel using a mixture of 5 to 30% MeOH/CH2Cl2 as eluent to recover the carbamate and urea, depending on the substrate. Procedure C for Catalytic Carbonylation of Amino Alcohols with W(CO)6/I2 1,3-Bis-(5-hydroxypentyl)urea (51). To a 15 mL glass vial in a multi-compartment Parr high pressure vessel containing 1.9 mL of CH2Cl2, were added 50 (800 mg, 7.7 mmol), W(CO)6 (136 mg, 0.38 mmol), pyridine (0.93 ml, 11.5 mmol) and I2 (977 mg, 3.8 mmol). The vessel was then charged with 80 atm CO and heated at 40 C for 18 hours. The pressure was released and methylene chloride (5 mL) was added to the reaction mixture to further dissolve the crude product. The solution was washed successively with saturated sodium sulfite, then saturated sodium bicarbonate. Each of the collected aqueous layers was washed with 2:1 CHCl3/EtOH (4 x 30 mL). The combined CHCl3/EtOH layers were dried with MgSO4 and the solvents removed by evaporation to afford urea 51 as a white solid in 64% yield. In order to recover the carbamate, the methylene chloride layer from the original extractions was washed with 0.1M aqueous HCl, then dried with MgSO4. The solvent was removed under vacuum to afford carbamate 52 in 2% yield. The urea was identified by comparison with literature data (elemental analysis and melting point).1 Urea 51: 1H NMR (D2O) : 1.22 (m, 4H), 1.37 (m, 4H), 1.52 (m, 4H), 2.88 (m, 4H), 3.42 (m, 4H). MS (LSIMS) [M+H]+calcd for C11H24N2O3 232.18, found 232.18. IR (CHCl3): vCO 1654 cm-1. Anal. calcd for C11H24N2O3: C 56.87%, H 10.41%, N 12.06%; C 56.96%, H 10.80%, N 11.89%. M.p., reported 106.6-108.5, found 106.3-108.5 C. Carbamate 52: 1H NMR (CDCl3) : 1.49 (m, 2H), 1.50 (m, 2H), 1.52 (m, 2H), 3.30 (m, 2H), 3.65 (t, 2H), 5.9 (br, 1H); 13C NMR (CDCl3) : 22.9, 29.3, 32.1, 41.2, 62.6, 147.2; IR (CH2Cl2): vCO 1708 cm-1; MS (LSIMS) [M+H]+calcd for 130.08, C6H11NO2 found 130.08.

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79 1,3-Bis-(4-hydroxy-3-methylbutyl)urea (55). Procedure C afforded 55 from 54 (0.20 mL, 1.8 mmol) in 93% yield. 1H NMR (CDCl3) : 0.86 (d, 6H, J = 6.6 Hz), 1.22 (m, 2H), 1.59 (m, 4H), 3.07 (m, 4H), 3.38 (m, 4H), 6.08 (s, 2H); 13C NMR (CDCl3) : 16.4, 33.0, 33.4, 38.4, 67.4, 161.0; IR (CHCl3): vCO 1648 cm-1; MS (LSIMS) [M+H]+ C11H24N2O3, calcd 233.1865, found 233.1913. 55 3-Amino-4-phenyl-1-butanol (59). DL--homophenylalanine (1000 mg, 5.57 mmol) BH3THF (1M, 8.36 mL, 8.36 mmol) was added dropwise to the suspension. The resulting mixture was stirred at room was slowly added and the mixture was stirred at room temperature overnight. The pH of the solution was adjusted to 11 by adding a few pellets of sodium hydroxide. The aqueous phase was saturated with potassium carbonate, the THF phase was separated and the aqueous phase was extracted with (50 mL x 6) diethyl ether. The combined organic layers were dried over magnesium sulfate. The solvents were evaporated and the product was obtained in 82% yield. The product was identified by comparison with literature data.130

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80 59 N,N'-Bis(1-benzyl-3-hydroxypropyl)urea (60) and 4-Benzyl-1,3-oxazinan-2-one (61). Procedure C afforded urea 60 from 59 (760 mg, 4.6 mmol) as a pale yellow oil in 95% yield. Carbamate 61 was recovered in trace amount. The products were identified by comparison with authentic samples prepared as described below. Authentic samples of N,N'-bis(1-benzyl-3-hydroxypropyl)urea (60) and 4-benzyl-1,3-oxazinan-2-one (61). Procedure B afforded compounds 60 and 61 from 59 (600 mg, 2.97 mmol) as white solids in 30% and 8% yield, respectively. For urea 60: 1H NMR (CDCl3) : 1.22 (m, 2H), 1.77 (m, 2H), 2.70 (m, 4H), 3.42 (m, 4H), 4.10 (s, 2H), 4.82 (s, 2H), 7.39 (m, 10H); 13C NMR (CDCl3) : 38.4, 42.0, 48.0, 58.6, 126.6, 128.6, 129.2, 138.2, 159.9; IR (CH2Cl2): vCO 1600 cm-1; MS (LSIMS) [M+H]+ calcd for C21H28N2O3 257.2178, found 257.2161. For carbamate 61: 1H NMR (CDCl3) : 1.68 (m, 1H), 1.87 (m, 1H), 2.78 (m, 1H), 2.89 (m, 1H), 3.67 (m, 1H), 4.14 (m, 1H), 4.27 (m, 1H), 6.81 (s, 1H), 7.24 (m, 5H); 13C NMR (CDCl3) : 26.5, 42.3, 51.8, 65.4, 126.8, 128.6, 129.1, 136.2, 154.5; IR (CH2Cl2): vCO 1710 cm-1; MS (LSIMS) [M+H]+ calcd for C11H13NO2 192.1024, found 192.1020. 1,3-Bis-(3-hydroxy-3-phenylpropyl)urea (64) and 6-Phenyl-1,3-oxazinan-2-one (65): Procedure C afforded urea 64 from 65 (320 mg, 2.12 mmol) in 72% yield. 1H NMR (CDCl3) : 1.87 (m, 4H), 3.30 (m, 2H), 3.6 (m, 2H), 4.72 (t, 2H), 6.19 (s, 2H), 7.32 (m, 10H); 13C NMR

PAGE 81

81 (CDCl3) : 38.4, 38.7, 72.3, 125.8, 127.5, 128.4, 143.8, 160.1. IR (CHCl3): vCO 1646 cm-1. Cyclic carbamate 65 was recovered in 14% yield; it was identified by comparison with literature data.90 N,N'-Bis(3-hydroxy-2,2-dimethylpropyl)urea (68) and 5,5-dimethyl-1,3-oxazinan-2-one (69). Procedure C afforded urea 68 from 67 (600 mg, 5.81 mmol) as a white solid in 60% yield. 1H NMR (CDCl3) : 0.73 (s, 12H), 2.85 (d, 4H, 6.3 Hz), 3.03 (d, 4H, 6 Hz), 4.61 (t, 2H, 6 Hz), 6.02 (t, 2H, 6.3 Hz), 13C NMR (CDCl3) : 22.3, 36.6, 46.2, 67.6, 159.7; IR (CHCl3): vCO 1666 cm-1; MS (LSIMS) [M+H]+calcd for C11H24N2O3 233.1751, found 233.1750. Anal. Calcd for C11H24N2O3: C 56.89%, H: 10.41%, N: 12.06%; Found: C 57.69%, H 10.63%, N 12.01%. Carbamate 69: yield 5%; 1H NMR (CDCl3) : 0.96 (s, 6H), 2.88 (s, 2H), 3.80 (s, 2H), 7.12 (br s, 1H); 13C NMR (CDCl3) : 22.1, 27.3, 50.6, 75.1, 152.4; IR (CHCl3): vCO 1702 cm-1; MS (LSIMS) [M+H]+calcd for 130.0868, C6H11NO2 found 130.0867. 1,3-Bis-(1-benzyl-2-hydroxyethyl)urea (76) and 6-Phenyl-6-oxazolidin-2-one (77) Procedure C afforded urea 76 from 75 (800 mg, 5.3 mmol) in 78% yield. Carbamate 77 was recovered in 10% yield. The products were identified by comparison with literature data.89

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82 1,3-Bis-(3-hydroxy-2-phenylethyl)urea (79) and 5-Phenyl-oxazolidine-2-one (80). Procedure C afforded urea 79 from 78 (800 mg, 5.83 mmol) in 79% yield. 1H NMR (CDCl3) : 2.85 (m, 2H), 3.08 (m, 2H), 4.78 (t, 2H), 5.64 (br, 2H), 7.38 (m, 10H); 13C NMR (CDCl3) : 49.2, 74.2, 125.8, 127.5, 128.4, 147.2, 159.5; IR (CHCl3): vCO 1649 cm-1. Cyclic carbamate 80 was isolated in 14% yield; it was identified by comparison with literature data.2 Synthesis of Cyclic Ureas (5S,6S)-Hexahydro-5,6-O-isopropylidene-2H-1,3-diazapin-2-one (84). To a glass-lined 300 mL Parr high pressure vessel containing 40 mL of CH2Cl2/H2O 4:1 ratio were added diamine 83 (200.0 mg, 1.24 mmol), W(CO)6 (20 mg, 0.62 mmol), pyridine (294.25 mg, 3.72 mmol) and I2 (157.30 mg, 0.62 mmol). The vessel was then charged with 80 atm CO and heated at 68C overnight. After 24 hours, the pressure was released and 10 mL of water was added. The organics were then separated and washed successively with saturated sodium sulfite (Na2SO3), then saturated sodium bicarbonate (NaHCO3), and finally with 0.1N aqueous HCl solution. The resulting solution was dried over magnesium sulfate and filtered. The solvent was removed by evaporation and the resulting residue was purified via column chromatography on

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83 silica using ether as eluent. After concentration, cyclic urea 84 was afforded in 64% yield. 1H NMR (CDCl3) : 1.39 (s, 6H), 3.19-3.40 (m, 4H), 4.20-4.30 (m, 2H), 5.1 (br, s, 2H); 13C NMR (CDCl3) : 27.2, 44.7, 81.8, 108.9, 164.3; IR (CHCl3): IR (CDCl3): vCO 1640 cm-1. 84 (4R,5S,6S,7R)-Hexahydro-5,6-O-isopropylidene-4,7-dimethyl-2H-1,3-diazapin-2-one (89). To a glass-lined 300 mL Parr high pressure vessel containing 40 mL of CH2Cl2/H2O 4:1 ratio were added diamine 88 (200.0 mg, 1.06 mmol), W(CO)6 (14 mg, 0.04 mmol), K2CO3 (410.0 mg, 3.0 mmol) and I2 (269 mg, 1.06 mmol). The vessel was then charged with 80 atm CO and heated at 100C overnight. After 24 hours, the pressure was released and 10 mL of water was added. The organics were then separated and washed successively with saturated sodium sulfite (Na2SO3), then saturated sodium bicarbonate (NaHCO3), and finally with 0.1N aqueous HCl solution. The resulting solution was dried over magnesium sulfate and filtered. The solvent was removed by evaporation and the resulting residue was purified via column chromatography on silica using ether as eluent. After concentration, cyclic urea 89 was afforded as a white solid in 71% yield. 1H NMR (CDCl3) : 1.26 (d, 6H), 1.40 (s, 6H), 3.59-3.80 (m, 2H), 3.90-4.10 (m, 2H) 5.17 (br, s, 2H); 13C NMR (CDCl3) : 14.2, 27.3, 45.9, 83.2, 110.1, 163.8; IR (CHCl3): IR (CDCl3): vCO 1636 cm-1.

PAGE 84

84 89 General Procedure for the Synthesis of -Amino Amides 103a-103e. The amino acid methyl ester hydrochloride (4 mmol) and the alkylamine (40 mmol) were dissolved in anhydrous methanol (~20 ml) and stirred at room temperature for 3 days. The reaction mixture was concentrated, and the residue was purified by column chromatography on silica gel using ethyl acetate/methanol (96:4) as eluant affording the -amino amides 103a-103d in very good yields (80-90%). Amino amide 103e was prepared following a three step procedure described in the literature, starting with Cbz-serine.127 General Procedure for the Carbonylation of -Amino Amides 103a-e to Afford Hydantoins 104a-e. -Amino amide 103a (400 mg, 2.2 mmol) was placed in a glass-lined 300 mL Parr high pressure vessel containing 30 mL of dichloroethane (DCE). Next, W(CO)6 (0.16 mmol) was added followed by DBU (8.96 mmol) and I2 (1.56 mmol). The vessel was then charged with 80 atm CO and heated at about 76C for 36 hours with constant stirring. The pressure was released and

PAGE 85

85 15 mL of water was added. The organics were then separated and washed successively with saturated sodium sulfite (Na2SO3), and then with 0.1N aqueous HCl solution. The aqueous layer was extracted with ethyl acetate (20 mL x 4). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified via column chromatography on silica using methylene chloride/ethyl acetate (80:20) to afford the hydantoin 104a. The same procedure was applied to prepare hydantoins 104b-e. The products were identified by comparison with literature data.124,131,132 (S)-5-Benzyl-3-methylimidazolidine-2,4-dione (104a). 1H NMR (CDCl3) : 2.80 (t, 1H), 3.0 (s, 3H), 3.32 (dd, 1H), 4.25 (dd, 1H), 5.19 (br, s, 1H), 7.21-7.40 (m, 5H); 13C NMR (CDCl3) : 25.8, 41.0, 56.4, 126.7, 128.6, 129.2, 155.4, 174.4; IR (CDCl3): vCO 1772, 1709 cm-1. (S)-5-Benzyl-3-ethylimidazolidine-2,4-dione (104b). 1H NMR (CDCl3) : 1.19 (t, 3H), 2.82 (dd, 1H), 3.24 (dd, 1H), 3.43-3.60. (m, 2H), 4.21 (dd, 1H), 7.19-7.39 (m, 5H); 13C NMR (CDCl3) : 12.0, 33.9, 38.1, 58.1, 127.0, 130.0, 131.2, 134.5, 157.5, 172.4. (S)-5-Benzyl-3-benzylimidazolidine-2,4-dione (104d). 1H NMR (CDCl3) : 2.82 (dd, 1H), 3.24 (dd, 1H), 4.22 (s, 2H), 4.60 (t, 1H), 5.38 (br, s, 1H), 7.23-7.42 (m, 10H); 13C NMR (CDCl3) : 38.4, 43.9, 61.7, 125.8, 126.7, 126.9, 127.7, 128.5, 128.9, 135.5, 135.7, 158.5, 169.5.

PAGE 86

86 (S)-3-Benzyl-5-(hydroxymethyl)imidazolidine-2,4-dione (104e). 1H NMR (DMSO-d6) : 4.26 (t, 1H), 3.46 (dd, 1H), 3.53 (dd, 1H), 4.48 (d, 2H), 4.77 (br, s, 1H), 7.21-7.26 (m, 3H), 7.30 (m, 2H); 13C NMR (DMSO-d6) : 42.3, 59.9, 60.4, 126.4, 127.0, 127.9, 138.7, 157.5, 172.3; IR (neat): vCO 1765, 1708 cm-1.

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87 LIST OF REFERENCES (1) Lam, P. Y.-S.; Jadhav, P. K.; Eyermann, C. J.; Hodge, C. N.; De, L. G. V.; Rodgers, J. D. In PCT Int. Appl. (Du Pont Merck Pharmaceutical Co., USA). WO, 1994; 525 pp. (2) Qian, F.; McCusker, J. E.; Zhang, Y.; Main, A. D.; Chlebowski, M.; Kokka, M.; McElwee-White, L. Journal of Organic Chemistry 2002, 67, 4086-4092. (3) Bigi, F.; Maggi, R.; Sartori, G. Green Chemistry 2000, 2, 140-148. (4) Hylton, K.-G.; Main, A. D.; McElwee-White, L. Journal of Organic Chemistry 2003, 68, 1615-1617. (5) Koenig, T. M.; Mitchell, D. Tetrahedron Lett. 1994, 35, 1339-1342. (6) Chrusciel, R. A.; Strohbach, J. W. Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) 2004, 4, 1097-1114. (7) De Lucca, G. V.; Lam, P. Y. S. Drugs of the Future 1998, 23, 987-994. (8) Dragovich, P. S.; Barker, J. E.; French, J.; Imbacuan, M.; Kalish, V. J.; Kissinger, C. R.; Knighton, D. R.; Lewis, C. T.; Moomaw, E. W.; Parge, H. E.; Pelletier, L. A. K.; Prins, T. J.; Showalter, R. E.; Tatlock, J. H.; Tucker, K. D.; Villafranca, J. E. J. Med. Chem. 1996, 39, 1872-1884. (9) Semple, G.; Ryder, H.; Rooker, D. P.; Batt, A. R.; Kendrick, D. A.; Szelke, M.; Ohta, M.; Satoh, M.; Nishida, A.; Akuzawa, S.; Miyata, K. J. Med. Chem. 1997, 40, 331-341. (10) vonGeldern, T. W.; Kester, J. A.; Bal, R.; WuWong, J. R.; Chiou, W.; Dixon, D. B.; Opgenorth, T. J. J. Med. Chem. 1996, 39, 968-981. (11) Vishnyakova, T. P.; Golubeva, I. A.; Glebova, E. V. Russian Chemical Reviews (English Translation) 1985, 54, 249-261. (12) Sartori, G.; Maggi, R. In Science of Synthesis; Ley, S. V., Knight, J. G., Eds.; Thieme: Stuttgart, 2005; Vol. 18, pp 665-758. (13) Hegarty, A. F.; Drennan, L. J. In Comprehensive Organic Functional Group Transformations; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.; Pergamon: Oxford, 1995; Vol. Vol. 6, pp 499-526. (14) Trost, B. M. Angewandte Chemie-International Edition in English 1995, 34, 259-281.

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96 BIOGRAPHICAL SKETCH Delmy J. Daz was born on November 14, 1967, in San Pedro Sula, Honduras. She was the second of six brothers and sisters. As a child, she was always curious of why everything happens; as a consequence, she was always asking many questions driving crazy any adults around her, since usually one answer will lead to more and more questions. She spent her formative years at Santa Rosa Elementary School and later she attended part of her high school studies at Public High School El Patria, moving later on to continue studies to become an elementary school teacher to Escuela Normal de Occidente en la Esperanza Intibuca. Throughout her high school formation she was an active and enthusiast member of the science club. In the spring of 1987 she started her major in science at the Natural Science Department at the Pedagogic University Francisco Morazn, from were she graduated 4 years later. She started to work as a chemistry and physics teacher at the high school level. After two years working as a science teacher she went back to the University to pursue a License in Biology-chemistry emphasis, and she started working as a chemistry T.A. at the National Pedagogic University. In 2001, she traveled to the USA after she was awarded a Fulbright Scholarship to do her master degree in organic chemistry at the University of Vermont, Burlington, which she completed in 2003. That same year she moved to the University of Florida to pursue her Ph.D. studies, specializing in the area of organic chemistry. After graduating she will go back to her country Honduras and will start working as a professor at the Science Department of the National Pedagogic University Francisco Morazn.


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Title: Catalytic Oxidative Carbonylation of Amino Alcohols and Diamines to Ureas as an Alternative to Phosgene Derivatives: Synthesis of Disubstituted Hydantoins
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Title: Catalytic Oxidative Carbonylation of Amino Alcohols and Diamines to Ureas as an Alternative to Phosgene Derivatives: Synthesis of Disubstituted Hydantoins
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Copyright Date: 2008

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CATALYTIC OXIDATIVE CARBONYLATION OF AMINO ALCOHOLS AND DIAMINES
TO UREAS AS AN ALTERNATIVE TO PHOSGENE DERIVATIVES: SYNTHESIS OF
DISUBSTITUTED HYDANTOINS



















By

DELMY DIAZ-MONTERROSO


A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY

UNIVERSITY OF FLORIDA

2007




























O 2007 Delmy Diaz-M.


































To my daughters Paola and Anabella; and to my husband, Alvaro, for their unconditional love
and support.









ACKNOWLEDGMENTS

First I would like to thank my daughters Paola and Anabella, who have been there for me

always with their constant love and support along the duration of my studies. They suffered the

most from my long hours at the lab, my frustrations, and my absences without complaint. On the

contrary, they were always understanding and waiting for me patiently. Special thanks go to my

husband Alvaro, for his unconditional love, support, and enthusiasm, and for always believing in

me. I thank my family in Honduras for their never-ending support and encouragement

throughout all these long years of studying away.

I also want to express my gratitude to my advisor, Professor Lisa McElwee-White, for her

guidance and valuable comments and suggestions throughout this academic program and

experimental investigation. I can not thank her enough for all her assistance and for always being

willing to listen to new ideas and encouraging me to try things I never thought were possible. I

also want to thank the members of my committee, Dr. Castellano, Dr. Dolbier, Dr. Lyons and Dr.

Percival, for their helpful suggestions and wise advice.

Special thanks must go to the members of the group for making my life easier and

providing a nice environment to work in. I thank my good friends Ece, Laurel and Marie for

always being there, and for sharing with me many coffee breaks. I also need to thank Phil, Seth,

and Ampofo, with whom I was working every day for the last three years.

Acknowledgement is made to the Pedagogic University Francisco Morazan for their

financial support.











TABLE OF CONTENTS


page

ACKNOWLEDGMENT S .............. ...............4.....

LI ST OF T ABLE S ................. ...............7..._.........


LI ST OF FIGURE S .............. ...............8.....

LIST OF ABBREVIATIONS............... ..............


AB S TRAC T ........._. ............ ..............._ 1 1...

CHAPTER


1 INTRODUCTION AND LITERATURE REVIEW .............. ...............12....

Literature Review .............. ......... ..... ..... ... ...............1
Transition Metal-Catalyzed Oxidative Carbonylation of Amines to Ureas ................... .13
Palladium-catalyzed oxidative carbonylation of amines............. ..__.........__ ....14
Homogeneous carbonylation of amines to ureas ....._____ .........__ ..............14
Pd cataly si s in ionic liqui ds ................. ..............._ 17......... ..
Electro catalytic carbonylation............... .............1
Mechanistic studies ................... ...............19..
Other Late Transition Metal Catalysts .............. ...............20....
Nickel-catalyzed oxidative carbonylation ...._ ......_____ ...... ......_........20
Ruthenium-catalyzed oxidative carbonylation ......____ ........_ ................21
Cobalt- and Rhodium-catalyzed oxidative carbonylation .............. ............. ..26
Gold-catalyzed oxidative carbonylation............... .............2
Tungsten-Catalyzed Oxidative Carbonylation of Amines ............_.. ......__..........30
Carbonylation of primary amines ............_... ...._ ...... ............3
Carbonylation of primary and secondary diamines to cyclic ureas .......................32
Conclusions............... ..............4

2 SELECTIVE CATALYTIC OXIDATIVE CARBONYLATION OF
AMINOALCOHOLS TO UREAS .............. ...............44....

Results and Discussion .............. .. ...............45.
C arb onyl ati on of 5 -Aminopentanol ......___ ......... ...............46_.. ...
C arb onyl ati on of 4 -Amino-2-methylbutan-1l-ol ................ ...............47.............
C arb onyl ation of 1, 3-Aminoalcohols .................... ...............4
C arb onyl ation of 1,2-Aminoalcohols .................... ...............5
Conclusions.............. .............54











3 THE W(CO)6 12 CATALYZED OXIDATIVE CARBONYLATION OF DIAMINES:
ANALOGS OF THE CORE STRUCTURES OF THE HIV PROTEASE INHIBITORS
DMP 323 AND DMP450. ............. ...............56.....


Back ground ............ ..... ._ ...............56....
Results and Discussion .............. ....... ........... ... .. ... .......6
Synthesis of Seven-Membered Ring Cyclic Ureas 84 and 89............... ...................6
Conclusions............... ..............6


4 CATALYTIC OXIDATIVE CARBONYLATION OF ENANTIOMERICALLY PURE
a-AMINO AMIDES TO PRODUCE HYDANTOIN DERIVATIVES ................ ...............65


Back ground .................. ................ ...............65 .....
Classic Ways to Synthesize Hydantoins ........._._._ ...._. ...............65..
Solution Phase Synthesis............... ...............6
Solid-Phase Organic Synthesis...................... .. ...................6
Synthesis of Hydantoins Using W(CO)6 12 Catalytic System ........._._.... ......_._.......70
Results and Discussion .............. ...............71....
Conclusions............... ..............7


5 EXPERIMENTAL SECTION............... ...............77


General Procedures .........._.... ....... ..__ .........._._. .... ...............7
Procedure A for Carbonylation of Amino Alcohols with CDI............. ... .........___...77
Procedure B for carbonylation of aminoalcohols with DMDTC ....................................77
Procedure C for Catalytic Carbonylation of Amino Alcohols with W(CO)6 12 .............78
Synthesis of Cyclic Ureas .............. .. ... ... ... ... ... .... .... .......8
General Procedure for the Synthesis of a-Amino Amides 103a-103e .................. ...............84
General Procedure for the Carbonylation of a-Amino Amides 103a-e to Afford
Hydantoins 104a-e. ............. ...............84.....

LIST OF REFERENCES .....___ ............... ...............87 .....

BIOGRAPHICAL SKETCH .............. ...............96....










LIST OF TABLES


Table page

1-1. Oxidative Carbonylation of Primary Amines to Ureas under Optimized Conditions. ..........33

1-2. Oxidative Carbonylation of Sub stituted Primary Diamines ................ ......._. ........._.3 6

1-3. Catalytic Carbonylation of Substituted Benzylamines to Ureas .............. ....................3

1-4. Yields of Bicyclic Ureas from Diamines 46a-49a .............. ...............42....

2-1. Carbonylation of aminoalcohols to ureas and carbamates. ............. .....................4

3-1. Structures of cyclic urea inhibitors ................. ...............58...............

3-2. Carbonylation of compounds 35-37 to Ureas 38-40 .............. ...............60....

4-1. Carbonylation conditions for ot-amino amide 103a. ............. ...............72.....

4-2. Synthesis of a-amino amides 103a-d .............. ...............74....

4-3. Catalytic carbonylation of a-amino amides 103a-e to hydantoins 104a-e. .........................75










LIST OF FIGURES


Fiare page

1-1. Co(salen) (22) and modified Co(salen) complexes (23-27) ................. .................2

1-2. Structures of the HIV protease inhibitors DMP 323 and DMP 450............... ..................39

4-1. Hydantoin ring structure. .............. ...............66....

4-2. Synthetic strategies and building blocks for hydantoin synthesis. ............. ....................66

4-3. a-Amino amide substrates to be converted to hydantoins ........._...... ....___.. .............73









LIST OF ABBREVIATIONS


CDI

DBU

DCB

DCE

DCM

DEA

DIBAL

DMA

DMAP

DMDTC

DME

DMF

DMImBF4

DMSO

DPT

DPU

EMImBF4

GC-MS

GLC

HIV

MAC

MEM


1 ,1 '-Carb onyl diimi dazol e

1,8-diazabicyclo[5.4.0]undec-7-ene

1,4-dichloro-2-butene

Dichloroethane

Dichloromethane

Diethylamine

Diisobutylaluminium hydride

N,N-dimethyl acetamide

4-dimethyl aminopyridine

S,S'-dimethyl dithiocarbonate

1,2-dimethoxyethane

Dimethylformamide

1 -decyl-3 -methylimi dazolium tetrafluorob orate

Dimethyl sulfoxide

Di -2-pyri dylthi oc arb onate

Diphenylurea

1 -ethyl -3 -methylimi dazolium tetrafluorob orate

Gas chromatograph-mass spectrometer

Gas liquid chromatography

Human immunodeficiency virus

Mixed anhydrides coupling

2-methoxyethoxym ethyl









NMP N-methylpyrrolidinone

SEM 2-(trim ethyl silyl)ethoxymethyl

SPOS Solid-phase organic synthesis

THF Tetrahydrofuran

TLC Thin layer chromatography









Abstract of Dissertation Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy

CATALYTIC OXIDATIVE CARBONYLATION OF AMINO ALCOHOLS AND DIAMINES
TO UREAS AS AN ALTERNATIVE TO PHOSGENE DERIVATIVES: SYNTHESIS OF
DISUBSTITUTED HYDANTOINS

By

Delmy Diaz-Monterroso

May 2007

Chair: Lisa McElwee-White
Major: Chemistry

The synthesis of ureas from amines has traditionally been accomplished with

stoichiometric reactions of phosgene or its derivatives, which are associated with environmental

and health issues. Because of the prevalence of urea moieties in molecules of interest for several

applications, alternative catalytic routes for the oxidative conversion of amines to ureas using CO

or CO2 as the carbonyl source have been developed. W(CO)6-catalyzed oxidative carbonylation

of amines to ureas in the presence of CO provides an alternative to stoichiometric reaction of

amines with phosgene or its derivatives such as 1,1 -carbonyldiimidazole (CDI). Synthesis of the

core structure of the HIV protease inhibitors DMP 323 and DMP 450 has been achieved via

W(CO)6 12-catalyzed carbonylation of diamine intermediates. This methodology also has been

successfully applied to the carbonylation of amino alcohols to selectively form hydroxyalkyl

ureas. Selected examples of 1,2-, 1,3-, 1,4- and 1,5-aminoalcohols were converted to the

corresponding ureas in good to excellent yields, with only trace amounts of the cyclic carbamates

being present. Other interesting targets such as hydantoins have also been prepared using

W(CO)6 12. Optically pure a-amino amides have been shown to produce the corresponding

hydantoins in good yields.









CHAPTER 1
INTRODUCTION AND LITERATURE REVIEW

There is a growing interest in the synthesis of substituted ureas because of their wide field

of applications. Ureas have been known to exhibit very important biological activity, for

example, as structural components of drug candidates such as HIV protease inhibitors, 1,2 CCK-B

receptor antagonists, and endothelin antagonists. Additionally, they have shown widespread

usage as agricultural chemicals, dyes, and as additives to petroleum compounds and polymers.

From the synthetic point of view, they are used as intermediates en route to carbamates.

The classical methodology for the preparation of substituted ureas is generally based on the

nucleophilic attack of amines on phosgene or phosgene derivatives. Phosgene is useful for the

carbonylation of primary and secondary amines. The maj or drawback of phosgene is that it is a

highly toxic and corrosive gas. Because of its toxic nature, it requires special handling. This has

discouraged its use in laboratory settings.

Phosgene production and use on an industrial scale raise serious environmental risks and

problems connected with the use and storage of large amounts of chlorine, and the transportation

and storage of a highly toxic and volatile reagent. Other safer derivatives such as 1,1-

carbonylimidazole, triphosgene, and a variety of other reagents have been used in the

carbonylation of amines to form substituted ureas, and are more common in the laboratory

setting. Another variant involves the use of isocyanates, which is undesirable because of their

toxic nature and the need to synthesize them from phosgene.

Various other methods have been used to convert amines to ureas. These include the use of

phenyl chloroformate to form substituted ureas from primary amines. The drawback to this

method is the use of DMSO as solvent. DMSO is known to be toxic and a possible carcinogen.

Furthermore, it is difficult to remove because of its high boiling point.









The necessity of a catalytic alternative to stoichiometric reagents such as phosgene was

obvious. This new methodology has to be compatible with complex highly functionalized

substrates in order to be widely applied. An alternative to the reaction of nucleophiles with

phosgene is the metal catalyzed oxidative carbonylation of amines. Several examples of this

methodology have been reported in the literature.

In this regard, the McElwee-White group reported the catalytic oxidative carbonylation of

amine using W(CO)6 as catalyst and I2 as the oxidant. The system converts primary and

secondary amines and diamines to the corresponding ureas in the presence of CO. The reaction

conditions are relatively mild and one big advantage of this methodology is that it can be used

with complex highly functionalized substrates as demonstrated by previous studies of functional

group compatibility.4,5

Due to the commercial availability and ease of handling of the catalyst, the W(CO)6 12

catalytic system would be an alternative to phosgene derivatives and main group catalysts for

laboratory scale syntheses. In addition, its compatibility with various functional groups makes it

a good candidate for carbonylation of complex molecules to the corresponding ureas. This work

reports the application of W(CO)6 12 catalyzed carbonylation to several complex substrates.

Literature Review

Transition Metal-Catalyzed Oxidative Carbonylation of Amines to Ureas

The development of new synthetic protocols for the preparation of ureas has recently

attracted a lot of interest because of the presence of this functional group in pharmaceutical

candidates,6-10 agrochemicals, resin precursors, dyes and additives to petrochemicals and

polymers." The classical syntheses of ureas from amines have been based on the use of toxic

and/or corrosive reagents, such as phosgene or isocyanates.12,13 In recent years, however,

alternative routes have been developed that utilize phosgene derivatives, CO2, or CO itself as the









source of the carbonyl moiety.3 Particularly attractive from the standpoint of atom economyl4 is

oxidative carbonylation,15,16 which employs amines, carbon monoxide and an oxidant as starting

materials and produces only the reduced form of the oxidant and protons as byproducts.

In an effort to develop new methodologies for preparing moieties with carbonyl-nitrogen

bonds, metal-catalyzed carbonylation of amines has been extensively studied. Mono- and

dicarbonylations of amines catalyzed by Mn,l7l Fe,19 CO,20,21 Ni,22,23 Ru,24-27 Rh27,28 Pd,29-38

W,39-47 Pt,48 Ir48 or Au49,50 have been reported, and many different types of products, including

ureas, 1,02,75 urethanes,5 oxamides,5 formamides,54 5 and oxazolidinones,5 have been

obtained. These carbonylations have generally been carried out at high temperatures under

moderate-to-high pressures of CO and efforts to find catalysts that are effective under mild

conditions continue. This section highlights some selected recent advances in the transition

metal catalyzed oxidative carbonylation of amines to ureas.

Palladium-catalyzed oxidative carbonylation of amines

Carbonylation of amines using Pd catalysts has been extensively studied since Tsuji

reported the first Pd-catalyzed carbonylation of amines in 1966.38 Methods for oxidative

carbonylation using PdCl2 as catalyst with copper oxidants or Ol as the terminal oxidant and

CuX or CuX2 aS a mediator have been developed for preparation of ureas,60-62 carbamates,29,63

and oxamides.29,51,64,65 Since a recent review of Pd-catalyzed reactions is available,16 in this

work a few selected examples will be highlighted.

Homogeneous carbonylation of amines to ureas

Fukuoka66 and Chaudhari67 reported the oxidative carbonylation of alkylamines using Pd/C

as catalyst and iodide salts as promoters in the presence of Ol, which afforded the corresponding

ureas and/or carbamates in good yields. Related results have been reported by Gabriele68 for the

oxidative carbonylation of amines using Pdl2 and Ol, which led to formation of ureas,









carbamates, and their cyclic derivatives in good yields. New conditions for the Pdl2-catalyzed

oxidative carbonylation of amines to ureas (Eq.1i), afforded ureas in high yields with turnover

numbers as high as 4950.32,69 Carbonylations of primary aliphatic amines (Eq.1i, R = alkyl) were

carried out at 100 OC under a 4: 1:10 mixture of CO:air:CO2 (60 atm total pressure at 25 OC) in

the presence of a simple catalytic system consisting of Pdl2 in COnjunction with a KI promoter.

In the absence of CO2, leSS satisfactory results were obtained.69 The choice of solvent was

critical to product selectivity. Monocarbonylation to the urea was favored in dioxane or 1,2-

dimethoxyethane (DME), while double carbonylation to the oxamide predominated in the more

polar solvents N,N-dimethylacetamide (DMA) or N-methylpyrrolidinone (NMP). The

selectivity was attributed to higher nucleophilicity of the amine substrates in DMA or NMP,

which favors the formation of Pd(CONHBu)2 species that generate the oxamide by reductive

elimination. Primary aromatic amines (Eq. 1, R = Ar) were generally less reactive than primary

aliphatic amines under these conditions but addition of an electron-donating methoxy group

increased the nucleophilicity of the aromatic amine enough to improve the activity.

Pd cat Oj(1
2 RH 12 O RHN NHR
-H20



Pd cat Oi<2
RNH2 + R2'NH + CO + 1/2 02RHN NR'(2
-H20


The mechanism for the carbonylation of primary amines was examined in more detail after

it was determined that the secondary amines diethylamine, dibutylamine, and morpholine were

unreactive under the same conditions. The difference in reactivity was attributed to the

formation of isocyanate intermediates from the primary amine, with carbamoylpalladium









complex 1 formed in preequilibrium with starting materials (Scheme 1). In agreement with this

hypothesis, isocyanates were detected (by GLC, TLC, and GLC/MS) in the reaction mixtures in

low-conversion experiments. Under these conditions, Pd(0) is reoxidized to Pd(II) by oxidative

addition of 12, which is regenerated through oxidation of HI by oxygen.

Scheme 1
HI O
Pd 12 + RNH2 + CO
IPd NHR



-[Pd(0) +HI]


RHN NHR RN2 R-N=C=0


This catalytic system proved to be effective for the synthesis of cyclic ureas from the

corresponding diamines, with 1,3-dihydrobenzoimidazol-2-one obtained in 99% isolated yield

(Eq. 3). This particularly high reactivity was attributed to increased nitrogen nucleophilicity and

a less negative entropy of activation due to the proximity of the ortho amino groups.32


NH, PdI, cat N
+ CO + 1/2 O OI
NH -H,ON
2 H (3)


Direct catalytic preparation of trisubstituted ureas in high selectivity (Eq. 2) was possible

under these conditions if the primary amine was carbonylated in the presence of an excess of the

less reactive secondary amine.32 This methodology has proven to be effective for the synthesis

of several types of urea derivatives, such as cyclic ureas from primary diamines and N,N-

bis(methoxycarbonylalkyl)ureas from primary a-amino esters. A showcase synthesis of the

neuropeptide Y5 receptor antagonist NPY5RA-972 was also reported (Eq. 4).32










NH2





Pd cat
CO
1/2 02 (4)

-HO







x ~NPY5 RA-9 72

Pd catalysis in ionic liquids

Recently, many catalytic reactions have been reported to proceed in ionic liquids as

reaction media with excellent results.70 This approach has been adapted by Deng for Pd-

catalyzed carbonylation of amines to ureas.n1 A solubility study of the catalyst Pd(phen)Cl2

established that the ionic liquids BMImBF4 (BMIm = 1-butyl-3 -methylimidazolium), BMImPF6,

BMImFeCl4, and BMImCl were candidate media for the carbonylation reaction and that catalyst

solubility could be adjusted through the tuning of either the cation or anion of the ionic liquids.

Carbonylation of aniline to the carbamate in the presence of 02 and methanol was used to

demonstrate catalytic activity and recyclability of the catalyst/ionic liquid mixture.

Subsequent work by the Deng group developed a new method using silica gel-immobilized

ionic liquids, in which a Pd-complex acts as a heterogenized catalyst for the catalyzed

carbonylation of amines and nitrobenzene to ureas. Heterogenization of the metal catalyst by

preparation of a silica gel confined ionic liquid was followed by the carbonylation of amines and

nitrobenzene to the corresponding ureas (Scheme 2).72 No additional oxidant is necessary since










the nitrobenzene serves as both substrate and oxidant. In terms of green chemistry, the

advantages of this method are the low quantities of ionic liquids used and the avoidance of

potentially explosive CO/02 mixtures. The authors suggested that the enhanced catalytic activity

of this system may be derived from the high concentration of ionic liquid containing the metal

complex confined within the cavities of the silica gel matrix.72

Experiments with the ionic liquids DMImBF4 (1-decyl-3 -methylimidazolium

tetrafluoroborate) and EMImBF4 (1-ethyl-3 -methylimidazolium tetrafluoroborate) and the

catalysts HRu(PPh3)2 12, Rh(PPh3)3C1, Pd(PPh3)2 12 and Co(PPh3)3 12 afforded good to

excellent yields of N,N'-diphenylurea (DPU) from nitrobenzene and aniline. The Rh-

DMImBF4/silica gel catalyst produced 93% conversion of starting materials with a selectivity of

92% for the urea. Conversion of aliphatic amines and nitrobenzene to the unsymmetrically

substituted ureas could also be achieved with this particular catalyst.

Scheme 2



NO22 + RNH2 ONHOH
metal complex-
ionic liquid/silica gel


R = phenyl, butyl, hexyl, cyclohexyl, p-methylphenyl
p-methoxyphenyl, o-nitrophenyl

Electrocatalytic carbonylation

Another method for the synthesis of alkylureas is the electrocatalytic carbonylation of

aliphatic amines, as reported by Deng.73 Electrocatalytic carbonylation of a series of aliphatic

amines to dialkylureas and isocyanates using Pd(II) complexes with a Cu(II) cocatalyst could be

achieved under mild reaction conditions, with particularly good results for primary amines (Eq.

5). The additional steric hindrance in secondary amines apparently prevents the reaction, as









diisopropyl amine was unreactive under the same conditions. In addition, no conversion of

primary diamines to cyclic ureas was observed although one long chain diamine did afford a low

yield of the corresponding isocyanate.


Pd(PPh3)2Ch + Cu(OAc)2O
2 RNH2 +CO j
Bu4NCIO4, 300C, 1 atmRH NR
0.9 V versus SCE(5

Although products were obtained with a single complex as catalyst [Cu(OAc)2, PdCl2 Of

Pd(OAc)2], catalytic activity and selectivity for the urea were improved when both a Pd complex

and Cu(OAc)2 were present in the reaction mixtures. Quantitative conversion and 98%

selectivity for the urea were achieved in the case of n-butylamine with Pd(PPh3)2C 2 and

Cu(OAc)2.73 The authors suggested a synergistic effect between Pd(II) and Cu(II), as opposed to

simple mediation of electron transfer, which had been invoked in a related case of

electrocatalysis.74

Mechanistic studies

Recent progress has also been made in understanding the mechanism of the carbonylation

of amine nucleophiles. Shimizu and Yamamoto have reported a mechanistic study focusing on

the role of the reoxidation of Pd(0) species formed in the principal catalytic cycle to electrophilic

Pd(II) species during the selective carbonylation of amines to oxamides and ureas.53 Their work

revealed the importance of the oxidant in selectivity as 1,4-di chloro-2-butene (DCB) afforded

oxamides from primary and secondary amines while use of 12 as the oxidizing agent resulted in

formation of ureas. Further insight was obtained through independent generation of

carbamoylpalladium complexes as models for species in the catalytic cycle.

Two possible mechanisms for the conversion of primary amines to ureas by palladium-

catalyzed carbonylation were discussed in conjunction with this study. In the first, the critical










step is reductive elimination of carbamoyl and amido ligands to generate the urea, as previously

proposed by Alper.s1 The crucial step in the second possible route involves formation of an

intermediate alkyl isocyanate from an N-monoalkylcarbamoylpalladium species 3, (Scheme 3).

The urea product is then derived from nucleophilic attack of a primary or secondary amine on the

isocyanate to release a symmetrically or unsymmetrically substituted urea. This second

possibility is based on an earlier proposal by Gabriele for a related system.69 Support for the

isocyanate pathway came from the inability of secondary amines to form tetra substituted ureas,

the presence of trisubstituted ureas upon carbonylation of mixtures of primary and secondary

amines and the kinetics of conversion of model compounds for 3 to ureas in the presence of

NEt3.53

Scheme 3
Oxidant
-RNH3X PdL2
N=C= O

is ocya nate

+RNH2+RNH2


II X
,C\
O L2Pd, NHR L2Pd X
R, ,R X
NH NH 3X= Cl or l
L =ligand

-RNH3X 2RNH2, CO

Other Late Transition Metal Catalysts

Nickel-catalyzed oxidative carbonylation

The extensive development of palladium-catalyzed oxidative carbonylation reactions along

with the ability of Ni complexes to undergo carbonylation and produce stable carbamoyl

derivatives suggested investigation of nickel complexes as catalysts for the oxidative









carbonylation of amines.22 Giannoccaro obtained N,N'-dialkylureas, rather than the previously

reported oxamides,23 by reacting aliphatic primary amines with the nickel amine complexes

NiX2(RNH2)4 (X = Cl, Br; R = alkyl). However, yields were low, with a maximum of 55%

obtained for the carbonylation of butylamine in acetonitrile at 50.C for 8 hours under 30 atm CO

and 5 atm Ol. At temperatures higher than 50.C, side reactions became significant and at lower

temperatures the reductive step, in which amine carbonylation occurs, failed. The product

selectivity depended on the amount of water present, with anhydrous conditions favoring the

oxamide, while the presence of water promoted urea formation (Scheme 4). The authors

suggested that water could coordinate to the nickel center, allowing the formation of only one

carbamoyl group. Under aqueous conditions, this intermediate would then undergo nucleophilic

attack by amine to form the urea. In the absence of water, oxamide would arise from reductive

elimination of two carbamoyl groups.22

Scheme 4
Nill + CO


H20, a nhyd rous



~ CONHR ~ CONHR

/Ni, OH2 CONHR


+ RN H2

Urea Oxamide
Ruthenium-catalyzed oxidative carbonylation

Gupte utilized ruthenium catalysts for the selective formation ofN,N'-diphenylurea (DPU)

from the oxidative carbonylation of aniline.27 High selectivity (99%) for the formation of DPU

was obtained with [Ru(CO)3I3]NBu4 as the catalyst and Nil as the promoter. The key step in the









proposed mechanism involves the formation of carbamoyl species 8 (Scheme 5). Loss of CO

from the catalyst precursor [Ru(CO)3I3]- generates intermediate 5, which reacts with aniline to

form 6 and HI. Addition and insertion of CO affords carbamoyl complex 8, which reacts with

aniline to yield the urea and the hydride carbonyl species 9. Addition of aniline to form 10 is

followed by oxidation with 02 to regenerate the active species 6 (Scheme 5).27 Related

chemistry with alkylamines has been reported by Chaudhari.67,75

Scheme 5
-CO
[Ru (CO)3 3]- [Ru (CO)2 3~
4 5


H20 ArNH2






ArNHH20
[(ArNH)O Ru (CO)2 21


[(rH2)Ru (HO),ll (C) (rN)R C)









(ArNH)2CO ArNH2

Dixneuf reported the synthesis of symmetrical ureas by reacting primary amines with CO2

and a ruthenium complex, in the presence of a terminal alkyne (Scheme 6).76 Yields ranged from

low to moderate, with the best yield of N,N'-dicyclohexylurea (61%) obtained with RuCl3-H20

as catalyst in the presence of 2 equiv of tri-n-butylphosphine (n-Bu3P). Further optimization










studies established the importance of running the reaction in the presence of excess alkyne but

with no solvent.

Scheme 6

H -R'


2 RNH2 + CO2 [Ru]
RHN NHR

organic products
from R'C2H + H20

The proposed catalytic cycle (Scheme 7) begins with coordination of the alkyne to the

metal center. The nucleophilic ammonium carbamate, formed in situ from the primary amine

and CO2, then adds to the triple bond to give the ruthenium coordinated vinyl carbamate species

11. Nucleophilic attack of the amine on carbamate 11 would then afford the urea and ruthenium-

coordinated enol 12. Protonation of the enol and decoordination regenerates the active

ruthenium species. According to this mechanism, the organic product derived from the alkyne

would be a-hydroxy-ketone 13. This ketone was not detected experimentally but would be

expected to react further under the reaction conditions (Scheme 7).76

Kondo reported the application of RuCl2(PPh3)3 as a precatalyst for the preparation of

ureas from amines, using formamide as the carbonyl source.24 Using this system, symmetrical

ureas could be prepared from the parent formamide, while unsymmetrical ureas were available

from N-substituted formamides (Scheme 8). High yields of N,N'-diarylureas were obtained from

N-arylformamides and aniline derivatives, but the yields of symmetrical ureas from formamide

were variable. Secondary amines underwent the reaction, but N,N-substituted formamides did

not.

















































RuCl2 (PPh3)3
mesitylene
reflux, -H2


Scheme 7

H- I



OH













RNH2 B


RN HCO2
RN H3.


11t NHR
OH H2NR


-C(CH3)20H


RHN


Scheme 8

C I

R1HN CH


O
C (
H2N CH


O

/C
R1 HN NR1R2


RuCl2 (PPh3)3
mesitylene
reflux, -H2


+ R1R2NH


O

RHN NHR


+ 2 RNH2


NHR






12
HI


RuH



OH
































H2


Scheme 9


RHN NHR'


2 RuCl2 (PPh3 3


OB


2 PPh3


H


R'NH2


RHN


Ph3P~ Ru~ .Cl

CI~Rl ClR ) PPh3
Ph3P 14 PPh3


H
R
N
Ph3


u 0 P~h3PhC3P RuC Ru C

Ph3P PPh3 Cl \PPh3
15 ~Ph3P 1 PPh3


A proposed mechanism that accounted for these and other observations began with

formation of oxygen-bridged dinuclear complex 14 by coordination of the formamide to two

molecules of RuCl2(PPh3)3 and dissociation of two triphenylphosphine ligands (Scheme 9).

Oxidative addition of the N-H bond to the ruthenium center would then afford 15 followed by a

second oxidative addition to yield isocyanate complex 16. Reductive elimination of molecular

hydrogen produces 17, which is attacked by the amine at the isocyanate ligand to yield the


RN i









corresponding urea and regenerate the active species. In this scheme, reaction of N,N-

disubstituted formamides is not possible because they cannot form an isocyanate ligand.24


Cobalt- and Rhodium-catalyzed oxidative carbonylation

Rindone reported the synthesis of acyclic and cyclic ureas from aromatic primary amines,

using N,N'-bi s(sali cyli dene)ethyl enedi aminocob alt(II) ([Co(salen)]) as the catalyst. 20 Optimal

reaction conditions varied with the substrate. For example, the urea yields from 4-methylaniline

were higher at high pressure of Ol, while 4-fluoroaniline reacted better at lower Ol preSSUTC.

Substituent effects were also examined. Electron-withdrawing groups in the para position

lowered the conversion of the starting amine while ortho-aminophenol was more reactive than

the other amines. The substituent effects were elaborated in a subsequent paper.n

The proposed mechanism involved equilibrium between planar and non-planar salen

ligands (18 and 19) on a cobalt (III) amido complex, either of which could undergo carbon

monoxide insertion to give an equilibrium mixture of carbamoyl complexes 20 and 21.

Compound 20, having the planar salen ligand and a transrt~t~rt~t~rt~t~rt~ relationship between the carbamoyl

and amine ligands, could lead to free isocyanate or carbamate, while complex 21, having a

nonplanar salen and a cis relationship between the carbamoyl and amine ligands, would lead to

the urea (Scheme 10).20

Dicobalt octacarbonyl has also been used in the microwave synthesis of ureas. Larhed

drastically reduced reaction time by running the reaction under microwave irradiation. The

carbonyl complex served as the source of CO, eliminating the need for CO pressure in the

reaction vessel. Symmetrical and unsymmetrical ureas were obtained in as little as 10 seconds,

with yields generally better for symmetrical ureas.










Scheme 10
NH2Ar NH2Ar

1s- 0~ Nj1-O

or carbamate
NHAr O r ioynt
ArHN
18 20







~Co NHArC NH~N2Ar


I urea
N HArO
19 ~ArHN 2


Claver prepared modified [Co(salen)] complexes (Figure 1-1) and utilized them as

catalysts for oxidative carbonylation of aniline.' Results revealed that the t-butyl-substituted

catalyst 23 produced 100% selectivity for diphenylurea in the presence of butanol, while the

other complexes afforded mixtures of the urea and the corresponding butyl carbamate. The

phenanthroline derivative 26 also showed high selectivity (94%) for the urea.

Efforts in the rhodium-catalyzed carbonylation of amines to ureas have been sparse in

recent years. An early study by Chaudhari investigated various factors that affect activity and

selectivity of rhodium-catalyzed oxidative carbonylation.79 Although the primary obj ective was

the synthesis of carbamates, some conditions were found to favor the formation of ureas. In

studies focused on the oxidative carbonylation of aniline, a Rh/C-Nal system was determined to

be best for the catalytic process. Using this catalyst, polar solvents like acetonitrile or DMF

favored formation of diphenylurea, while most other solvents favored the carbamate. Modifying

pressure, temperature, and concentration also affected selectivity and activity.79












N N -Ns,N-

cNO /NO t~u O OBu

22 tBu tBu 23


.NO2
Co
02N ;O 2O NO2=N N, ,N
Co

25




N, N N. ,N'


26 27
Figure 1-1. Co(salen) (22) and modified Co(salen) complexes (23-27)



Giannocaro reported preparation of Rh3+ and Rh3+-diamine complexes intercalated into y-

titanium phosphate (TiP), and measured their activity towards oxidative carbonylation of

aniline.so Intercalation provided a way to heterogenize an otherwise homogeneous catalyst.

Typical conditions involved acetonitrile or methanol as the solvent, a CO/02 mixture at

atmospheric or higher pressure, temperatures between 70-120oC, and the presence of PhNH3'

as a promoter. The highest catalyst activities were obtained with increased pressure of the

CO/02 mixture, higher temperature, and a molar ratio of co-catalyst to Rh3+(PhNH3 T/ Rh3+)

between 5 and 6. It was found that the materials containing simple Rh3+ salts worked better than

those prepared from Rh3+-diamine complexes. The key intermediate in the postulated reaction

mechanism (Scheme 11) is the Rh3+-carbamoyl complex 28 which reacts with molecular iodine









to form the iodoformate intermediate, ICONHPh. The latter reacts with aniline to afford

diphenylurea.so

Scheme 11
Ph NHCON HP h




PhNH

ICONHPh

H ,02 H TiP-HxRh,
CO+ PhNH2




H20
12 / Ti P-H xy)Rh -(CO NH Ph),


Gold-catalyzed oxidative carbonylation

Deng has investigated gold compounds as catalysts for the carbonylation of amineS.50,81-84

Although simple Au(I) salts afforded carbamates from aniline, the reactions of aliphatic amines

also yielded the urea in some cases.8 Polymer immobilized gold catalysts, prepared from

commercially available ion exchange resins and HAuCl4, WeTO found to catalyze the

carbonylation of aryl amines to their methyl carbamates in the presence of methanol.so In the

absence of methanol, the diarylureas became the maj or products. In contrast to previously

reported gold catalysts, the polymer immobilized variety showed enhanced catalytic efficiency,

could easily be separated from the product, and could be used in the absence of organic solvents.

Subsequent work demonstrated that use of this system with aliphatic amines and CO2 COuld

afford symmetrical dialkylureas, with high yields and turnover frequencies (Scheme 12).84 The

mechanism is unclear, but it was postulated that the high activity can be attributed to some

synergistic relationship, between gold nanoparticles and the polymer support.









Scheme 12

R2NH Auplmr'R2NHC ON HR2
CO + 02
or CO2

Tungsten-Catalyzed Oxidative Carbonylation of Amines

Carbonylation of primary amines

Despite extensive investigation of transition metal-catalyzed carbonylation reactions,

examples involving Group 6 metals still remain rare. During the last decade, we have been

exploring conversion of amine substrates to the corresponding ureas using tungsten carbonyl

complexes as the catalysts and I2 as the oxidant.

The initial report described catalytic oxidative carbonylation of primary amines using the

iodo-bridged tungsten dimer [(CO)2W(NPh)I2 2 (29) as the precatalyst.41 During those studies, it

was shown that primary aromatic and aliphatic amines could be carbonylated to 1,3-disubstituted

ureas, while secondary amines afforded formamides in modest yields.

Mechanistic studies on this process established that primary amines reacted

stoichiometrically with dimer 29 to yield the amine complexes (CO)2I2W(NPh)(NH2R) (30)

(Scheme 13), which undergo reaction with excess amine to afford the corresponding ureas.43

Nucleophilic attack of the amine on a carbonyl ligand of 31, followed by proton abstraction

using a second equivalent of the amine would afford carbamoyl complex 32. IR spectra of the

reaction mixtures were consistent with the presence of carbamoyl complexes. The intermediacy

of carbamoyl complex 32 is precedented by Angelici's work on the carbonylation of CH3NH2 by

[(rl,-C5HS)W(CO)4]PF6,85 for which the first step is conversion of [(r15-CsHS)W(CO)4]+ to the

carbamoyl complex ('ls-CsHs)W(CO)3(CONHCH3) upon reaction with 2 equiv of CH3NH2.










Scheme 13


Ph Ph
NI N
1/2 C;, 1/,, \CO 1 equiv NH2R OC 1
OC I ~llCO OCI INH2R

29 30
Ph
1 equiv
NH2R


Ph
CO N
OC/, II \NH2R
OC1 NH2R

31


||2 equiv
|NH2R



Ph

[Ox] N
,________ OC/, I \NH2R
1 equiv NH2R O~c C NH2R

32


34


RHN NHR


1 equiva
NH2R


Assignment of the next step as oxidation was supported by IR spectra that showed the

disappearance of the carbamoyl stretches after the reaction mixtures were exposed to air. It is

expected that following oxidation of the complex, the carbamoyl proton would be more acidic

and deprotonation of 32 with the excess amine would produce the isocyanate complex 33.

Nucleophilic attack of an amine on either coordinated or free isocyanate would afford the 1,3-

disubstituted urea, producing coordinatively unsaturated complex 34, which could undergo

addition of CO to regenerate cationic intermediate 31 and close the catalytic cycle.









The previous results implied that other tungsten carbonyl iodide complexes might also

serve as catalysts. The simplest choice as precatalyst was the readily available, inexpensive, and

air stable W(CO)6. Preliminary studies were carried out using W(CO)6 as catalyst for the

catalytic carbonylation of n-butylamine. Reaction of W(CO)6, 100 equiv of n-butylamine, 50

equiv of iodine, and 100 equiv of K2CO3 in a 125 mL Parr high-pressure vessel pressurized with

100 atm CO produced di-n-butylurea in an amount corresponding to 39 turnovers per equivalent

of W(CO)6, or 80% yield with respect to amine.43

Subsequent optimization studies using n-propylamine established that N,N'-disubstituted

ureas could be obtained in good to excellent yields using the W(CO)6 12 oxidative carbonylation

system (Table 1-1).44 Once W(CO)6 (2 mol %) was established as the preferred catalyst, other

variables were examined. Optimal conditions were 900C, 80 atm CO, 1.5 equiv of K2CO3, and a

chlorinated solvent such as CH2 12 or CHCl3. Note that conditions could not be found for

conversion of aniline to diphenylurea, presumably due to lower nucleophilicity of the aryl amine.

Carbonylation of primary and secondary diamines to cyclic ureas

Many methods for conversion of diamines to the corresponding cyclic ureas have been

reported.12,13 Most of them are stoichiometric reactions based on nucleophilic attack of amines

on phosgene and related derivatives. Catalytic oxidative carbonylation of diamine substrates

provides an alternative route to cyclic ureas in which CO is used as the carbonyl source.

However, the synthesis of cyclic ureas via metal-catalyzed carbonylation has received limited

attention. Early reports of transition metal-catalyzed carbonylation of diamines mentioned cyclic

ureas only as very minor or side products. In the case of Mn2(CO)l0-catalyzed carbonylation of

the diamines H2N(CH2),n 2 (n = 2-4 and 6), no cyclic products were observed when n = 2, 4, or

6 and only 6% of the six-membered urea when n = 3.86














%Yield
Ammne Product

CH2 12


Table 1-1. Oxidative Carbonylation of Primary Amines to Ureas under Optimized


Conditions.


2 II









NH2


O

SH


H


Conditions: W(CO)6 (2 mol %), Il (0.5 equiv),
CH2 12 aS the solvent.


1.5 equiv of K2CO3, 900C, 80 atm CO,and


N N
H H

O
NN
H H



H H


H H



HaI H









We thus explored the catalytic carbonylation of diamines to cyclic ureas using W(CO)6 as the

catalyst, Il as the oxidant, and CO as the carbonyl source.42 Both primary and secondary ot,co-

diamines were substrates for the reaction, with secondary diamines being converted directly to

the corresponding N,N'-disubstituted cyclic ureas.

Synthesis of the five-, six-, and seven-membered cyclic ureas from the primary diamines

could be achieved in moderate to good yields (Eq 6),42 with the highest isolated yield for the six-

membered cyclic urea. Only trace amounts of the eight-membered ring compound could be

detected in the reaction mixtures, which was not surprising as there are no reports in the

literature of preparation of this compound from 1,5-pentanediamine. In addition, (+)-(1R,2R)-

1,2-diphenyl-1 ,2-ethanediamine was carbonylated to the 2-imidazolidinone in 46% yield with no

epimerization. Reaction of the secondary diamines RNHCH2CH2NHR (Eq 6, R = Me, Et, iPr,

Bn) under similar conditions resulted in conversion of the diamines to the corresponding N,N'-

disubstituted cyclic ureas. For both primary and secondary substrates, it was necessary to

employ high dilution conditions to minimize formation of oligomers, a problem also encountered

during the reactions of phosgene and its derivatives with diamines."7



NHR NHR W( CO)6 RN N ,R(6


n ~CO / 12 / K2CO3
n=0-2n
R = H, alkyl


Steric effects on the ring closure reaction were probed by carbonylating N,N'-dimethyl,

diethyl, diisopropyl, and dibenzyl diamines under the standard conditions.42 As expected, 1,3-

diethyl-2-imidazolidinone and 1,3 -dimethyl-2-imidazolidinone were produced in nearly identical

yields. Changing the substituents to benzyl groups lowered the yield only modestly but the









presence of bulky isopropyl groups dramatically reduced the yield of the imidazolidinone to only

10%. Yields in the sterically hindered cases could not be improved by raising the reaction

temperature. Although primary amines reacted much more readily than secondary amines, N-

methylpropanediamine reacted under the oxidative carbonylation conditions to produce the

corresponding monosubstituted N-methyl cyclic urea in preference to acyclic urea formation

through the more reactive primary amines.42

A more extensive study on the carbonylation of ac~o-diamines to cyclic ureas involved

further optimization of the conditions using propane-1,3 -diamine as the test substrate, W(CO)6 aS

catalyst and I2 as the oxidant.2 Effects of solvent and temperature variation on the yields of the

cyclic urea from propane-1,3-diamine were examined. Additional experiments probed the effect

of alkyl substituents in the linker of primary diamines (Table 1-2). In the cases of simple n-alkyl

substituents, the yields of cyclic ureas are significantly higher for the 2,2-dialkyl-1,3-

propanediamines than for the parent propane-1,3 -diamine as a result of the Thorpe-Ingold

effects and improved solubility in organic solvents during workup.

The carbonylation of N,N' -dialkyl-2,2-dimethylpropane- 1,3 -diamines afforded

tetrasubstituted ureas; however, the products were obtained in modest yields, and

tetrahydropyrimidine byproducts were formed in significant amounts when the substrates bore

N-alkyl substituents larger than methyl. Comparison of these results with the carbonylations of

secondary diamines to form five-membered cyclic ureas suggested that the effects of ring size

and N-substituent size on the carbonylation reaction are complex.

Success with conversion of diamines to cyclic ureas suggested the use of W(CO)6-

catalyzed oxidative carbonylation of amines can be used for the the synthesis of complex targets.








Table 1-2. Oxidative Carbonylation of Substituted Primary Diamines
Amine Product % Yield


H2N NH2



H 2N r~NH2



H2N NH2
Bu Bu



H2N NH2
PhH2C CH2Ph


H2NNH2




H2NNH2


O



HN NH



HN NH


Bu


B Bu
H 2N NH2


O
HN NH


O
HN NH


O

HN NH

Bu Bu
O
HN NH

PhH2C CH2Ph









Before considering applications in synthesis, it was necessary to evaluate the functional

group compatibility of the catalyst, often a critical issue in the use of early metal systems.

Studies of functional group compatibility using a series of substituted benzylamines (Eq. 7,

Table 1-3) demonstrated that the oxidative carbonylation of amines using the W(CO)6 12 system

is tolerant of a wide variety of functionality, including halides, esters, alkenes, and nitriles. A

distinguishing feature is the tolerance of unprotected alcohols, which would be problematic with

phosgene derivatives.44 A critical result of this study is the observation that the addition of water

to generate a biphasic solvent system produced dramatic increases in the yields of functionalized

ureas. In order for the reaction to work efficiently, it is necessary to solubilize the catalyst, the

starting amine, the hydroiodide salt of the starting material which is formed when protons are

scavenged, and the base (K2CO3). The biphasic solvent system sets up phase transfer conditions

in which the amine salt can be deprotonated by aqueous carbonate and then returned to the

organic phase for carbonylation.

After broad functional group tolerance during W(CO)6 12-catalyzed oxidative

carbonylation of amines to ureas had been established,44 USe of this methodology to install the

urea moiety into the core structure of the HIV protease inhibitors DMP 323 and DMP 450

(Figure 1-2)89,90 WaS investigated.4





R~" NH2), 3 NN


0 (7)









Table 1-3. Catalytic Carbonylation of Substituted Benzylamines to Ureas
%Yielda~ %Yielda~ %Yielda %Yieldb
AmineCH2 12 CH2 12/H20 mn CH2 12 CH2 12/H20


H NH2 63 73 Et NH2; 36 55



Cl NH2 35 77 H NH 0 37


B NH2" 30 77 NH2 416


I--2" 39 70 02N245 76


MeO NH 47 70 NC NH2 37 68


MeS NH 24 81 H2 NH2; 28 14

HNH2 5 58 NHN2 17 20


HISQNI NH 0
a Reaction conditions: amine (7.1 mmol), W(CO)6 (0.14 mmol), Il (3.5 mmol), K2CO3 (10.7
mmol), CH2 12 (20 mL), 70 oC, 80 atm CO, 24 h.
b The solvent was CH2 12 (21 mL) plus H20 (3 mL). Other conditions are as in footnote a.









Direct comparison of the catalytic carbonylation reaction with stoichiometric reaction of

the same substrates with phosgene derivatives was possible due to the extensive literature on the

synthesis of these targets.


HO OH
~ Q H2N NH2

NNI N N
Ph P Ph II Ph

HO O6H HO OcH
DMP 323 DMP 450


Figure 1-2. Structures of the HIV protease inhibitors DMP 323 and DMP 450

It has been reported in the literature that the urea moiety of DMP 323 and DMP 450 was

installed by reaction of phosgene or a phosgene equivalent with an O-protected diamine diol. In

the initial small-scale preparations, a primary diamine was reacted with the phosgene derivative

1,1 '-carbonyldiimidazole (CDI)90-93 followed by N-alkylation as appropriate. The practical

preparation of DMP 450 involves reaction of secondary diamine with phosgene to form the

cyclic urea. Since use of phosgene or CDI requires protection of the diol, extensive protecting

group studies have been carried out.91,94 Three of the previously described O-protected diamine

diols, acetonide 35,94 MEM ether 36,90,95 and SEM ether 3790 were tested in the catalytic

carbonylation reaction as representative examples containing cyclic and acyclic protecting

groups, respectively (Eq. 8).4

Carbonylation of diamine substrates 35-37 (Eq 8) to the cyclic ureas 38-40 provided a

means for comparison of the W(CO)6-catalyzed process to the stoichiometric reactions of the

phosgene derivative CDI. More extensive discussion of the results obtained from these

experiments will be submitted in subsequent chapter.













NH2 NH2, Hs ,H
Ph .,,Ph W(CO), /C30 Ph .,,,Ph

PO0 OP2 plo O P2

35 Pl, P2 = C(CH3)2 38 pl, P2 =/ C(CH3)2
36 Pl, P2 = MEM, MEM 39 Pl, P2= MEM, MEM
37 Pl,P2= SEM,SEM 40 Pl,P2= SEM, SEM


Efforts to avoid the protecting group chemistry in reported syntheses of DMP 323 and

DMP 450 by carbonylating the diamine diol 41 were frustrated by the reaction of the diol

hydroxyl groups to generate oxazolidinones 42 and 43 (Eq. 9).46 Oxalzolidinone formation had

also been reported as the result of reaction of 41 with CDI and phosgene.96 The earlier

functional group compatibility study had suggested that the catalyst was tolerant of -OH groups

(Eq 7, Table 3) but the test substrate in that study was [4-(aminomethyl)phenyl]methanol, in

which the -OH group is para with respect to the amine so as to eliminate the possibility of

formation of a cyclic carbamate. For that substrate, the corresponding urea was produced

without competing carbamate or carbonate formation.44 For diamine diol 41, oxazolidinone

formation had been preferred under the reaction conditions tested.

More recently, the catalytic carbonylation of a series of amino alcohols of varying tether

lengths and substitution patterns was carried out to probe the selectivity of the W(CO)6 12

carbonylation system for reactivity of alcohols versus amines. The phosgene derivatives

dimethyl dithiocarbamate (DMDTC) and 1,1'-carbonyldiimidazole (CDI) were used as

representative stoichiometric reagents for comparison purposes, the results are discussed in a

separate chapter, later on in this work.46










IH

s\\s NH 2


NH2 NH2
Bn* W(CO)6, 12
HO OH CO, K2CO3

41


HN O
O


Other interesting targets that were prepared to investigate the scope of the W(CO)6 12

system were biotin and related heterocyclic ureas.97 Biotin (44b), also known as Vitamin H, is

produced on large scale as a feed additive for poultry and swine. It has also been the target of

more than 40 total and formal syntheses.98 One recurring theme in these syntheses has been

installation of the urea moiety by reaction of phosgene with a di aminotetrahydrothi ophene

derivative.


HNKNH(10)
HNN

S CO2R

44b R =H (0%)
45b R =Me (84%)


SO42-
+H3N / NH3


S'9MCO2R

44a R = H
45a R = Me


W(CO)6 /I2

CO /K2CO3


H N NH


R1 X R2
46b-47b, 48b-49b

R2

(CH2 4CH3
13 CH3


H2N/, 2NH2

R1 X R2

46a-47a, 48a-49a


W(CO)6 /I2
CO /K2CO3


O
O
N-BOC
CH2CH2









Although biotin itself could not be produced directly from carboxylic acid 44a (Eq. 10),

biotin methyl ester (45b) was obtained in 84% yield upon W(CO)6-catalyzed oxidative

carbonylation of diamine 45a. The related heterocycles 46b-49b were also prepared by the

carbonylation procedure and the yields compared to those obtained by reaction of the same

substrates with CDI (Eq 11, Table 1-4). Yields of the ureas were moderate to good and

depended on the solubility of the diamine and urea in methylene chloride.


Table 1-4. Yields of Bicyclic Ureas from Diamines 46a-49a
.mn Ue W(CO)6 12 CDI
Yield Yield
46a 46b Trace 20%

47a 47b 47% 67%

48a 48b 46% 37%

49a 49b 57% 56%

Conclusions

Transition metal-catalyzed carbonylation of amines offers new and efficient methodology

for the selective synthesis of ureas under relatively mild reaction conditions. Use of CO or CO2

as the carbonyl source in the presence of a catalyst and an oxidant provides an alternative to the

traditional methods for conversion of amines to ureas, which involve stoichiometric use of

phosgene and its derivatives. From the perspective of green chemistry, the replacement of

phosgene and the minimization of the waste streams associated with phosgene derivatives would

be beneficial.

Recent developments in metal-catalyzed oxidative carbonylation of amines include new

techniques such as the use of ionic liquids, microwave irradiation and electrocatalytic

carbonylation. In addition to extensive work with palladium complexes, carbonylation reactions

that utilize other late transition metals, such as Ni, Ru, Rh, Co, Au, have also been demonstrated









to afford ureas. Indications that tungsten-catalyzed oxidative carbonylation of functionalized

amines could be of use in the synthesis of complex targets had also been reported. Given the

prevalence of urea functionality in compounds with a wide range of applications, further work in

this area is no doubt forthcoming.









CHAPTER 2
SELECTIVE CATALYTIC OXIDATIVE CARBONYLATION OF AMINOALCOHOLS TO
UJREAS

Conversion of amines to ureas commonly involves nucleophilic displacement of leaving

groups from phosgene or a phosgene derivative.13 Phosgene and its derivatives are not selective

for the carbonylation of amines, reacting with other functionality such as hydroxyl groups. In

fact, phosgene reacts with both functional groups of aminoalcohols to form products such as

cyclic carbamateS99 Of isocyanate chloroformates (Scheme 14).100,101 Although transamination of

ureas,102 Selenium-catalyzed carbonylation,103 and condensation with S,S'-dimethyl

dithiocarbonate (DMDTC)104 have been used to generate hydroxyalkylureas from aminoalcohols

under circumstances where formation of the cyclic carbamate is disfavored, selective reactivity

of aminoalcohols with a phosgene derivative often requires protection of one functional group to

avoid forming mixtures of ureas and carbamates.



Scheme 14





HHN







n = 3, 5

As an alternative to phosgene and phosgene derivatives, we recently reported the catalytic

carbonylation of aliphatic amines to ureas using W(CO)6 as the catalyst and I2 as the oxidant.41,43-

45 A functional group compatibility study demonstrated that the catalyst was tolerant of OH









groups (Eq. 12), at least in the case of [4-(aminomethyl)phenyl]methanol, in which the

corresponding urea was produced without competing carbamate or carbonate formation.44

However, in the carbonylation reaction of Eq 12, the -OH group is para with respect to the

amine so as to eliminate the possibility of intramolecular formation of a cyclic carbamate. We

now report the catalytic carbonylation of a series of aminoalcohols of varying tether lengths and

substitution patterns in order to evaluate the selectivity of the W(CO)6 12 carbonylation system

for reactivity of alcohols vs. amines. These results are compared to reaction of the same

aminoalcohol substrates with the phosgene derivatives DMDTC and 1,1'-carbonyldiimidazole

(CDI).







~I~NH2 W(CO)6, 2 HO N N OH (12)
HO CO, K2CO3
O 71 %

Results and Discussion

The aminoalcohol substrates for this study were chosen with varying tether lengths

between the functional groups and varying steric hindrance at the active sites. The substrates

were then subj ected to W(CO)6-catalyzed oxidative carbonylation for evaluation of the

selectivity of the W(CO)6 12 system towards formation of the ureas or carbamates, either cyclic

or acyclic. As a comparison of the stoichiometric reactions of phosgene derivatives to the

catalytic W(CO)6 12 methodology, 1,1'-carbonyldiimidazole (CDI) and dimethyl dithiocarbonate

(DMDTC) were also used for the carbonylation of the aminoalcohol substrates.









Carbonylation of 5-Aminopentanol

Carbonylation of 5-aminopentanol 50 was investigated to determine the preference of a

1,5-aminoalcohol to form the corresponding acyclic urea 51 or the 8-membered cyclic carbamate

52 (Eq. 2). The optimal reaction conditions of a substrate concentration of 4M, 40 oC, 80 atm

CO and a reaction time of 18 hours afforded the bis(hydroxyalkyl)urea 51 in 64% yield and the

cyclic carbamate 52 in only 2% yield. The acyclic carbamate 53 was not detected in the reaction

mixtures. However, the presence of unreacted starting material was observed by TLC prior to

purification of the products.

H H
HO N N OH




HO NH2 W(CO)6, CO Q

50 12~ 9 13







53

When potassium carbonate was used as the base, as was reported in prior studies,42,44

formation of urea 51 was confirmed by various spectroscopic methods. No evidence of the

acyclic carbamates 53 was found. Purification of 51 by the previously described method proved

difficult. The problem is similarity in the solubilities of the hydroxyalkylurea product and

potassium iodide, which is a byproduct of carbonylation in the presence of K2CO3

Consequently, it was difficult to purify the urea by methods such as chromatography or selective

extraction. These difficulties with the workup could be avoided by changing the base to










pyridine, which allowed purification of the products to be carried out without chromatography.

The modified workup for the recovery of the urea and carbamate is described in detail in the

experimental section.

The selectivity of the W(CO)6-catalyzed carbonylation of 5-aminopentanol is comparable

to the selectivity when phosgene derivatives are used as the carbonylation agents. Carbonylation

of aminoalcohol 50 using CDI afforded urea 51 in 80% yield, while just trace amounts of the

cyclic carbamate 52 and none of the acyclic carbamate 53 were observed. The other phosgene

derivative, DMDTC, produced urea 51 from aminoalcohol 50 in 45% yields with no evidence of

the formation of 52 or 53 (Table 2-1, entryl).

Carbonylation of 4-Amino-2-methylbutan-1-ol

The selectivity between conversion of a 1,4-aminoalcohol to a seven-membered cyclic

carbamate, an acyclic carbamate or the corresponding urea was investigated using 4-amino-2-

methylbutan-1-ol (54) as a representative substrate. The optimal reaction conditions were found

to be the same as for 5-aminopentanol; with a substrate concentration of 4M, 40 oC and a

reaction time of 18 hours producing urea 55 in 93% yield. Compounds 56 and 57 were not

detected in the reaction mixtures by NMR or IR.

To compare the carbonylation of 54 to results using phosgene derivatives, 4-amino-2-

methylbutanol was treated with CDI at a concentration of 4 M or DMDTC at a concentration of

4.5 M. All three carbonylation methods produced similar selectivity for the formation of urea 55

over products 56 and 57. When CDI was used as the carbonylating agent, compound 55 was

formed in 70 % yield as the maj or component of the product mixture while 56 was detected in

trace amounts (Eq. 3). There was no evidence for the formation of 57. Likewise, in the case of

DMDTC, urea 55 was produced in 93% yield as the only product (Table 2-1, Entry 2).









Table 2-1. Carbonylation of aminoalcohols to ureas and carbamates.
Entry Substrate Reagent Urea Cyclic
(%) Carbamate (%)
W(CO)6 /CO 64 2
1 H2N OH CDI 80 trace
50
DMDTC 45 0
W(CO)6 /CO 93 0
2 ON2 CDI 70 trace

54 DMDTC 93 0

W(CO)6 /CO 95 trace
3 OH NH2
CICDI 36 60

59 C2h DMDTC 30 8

W(CO)6 /CO 72 14
4 .~"" i CDI 49 30
Ph DMDTC 34 47
63

W(CO)6 /CO 60 5
5 OH NH2
CDI 55 28
/ DMDTC 32 29
67

W(CO)6 /CO 78 10
6 "e~Ph CDI 18 22
75 DMDTC 72 trace

W(CO)6 /CO 79 14
7 HO NH2
t/ CDI 30 52
Ph
78
DMDTC 73 trace









H H
HO NN N OH

55

HO ~ NH2 W(CO)6, CO NOO
HOp
HN1 O
I 5 14

56


HO N" KO N/H2



57

Carbonylation ofl1,3-Aminoalcohols

The carbonylation of a 1,3-aminoalcohol to a six-membered cyclic carbamate or an acyclic

carbamate vs. formation of the corresponding urea was first investigated using 3 -amino-4-

phenyl-butanol (59) as a representative substrate. Substrate 59 was synthesized by reduction of

DL-P-homophenylalanine (58) with BH3-THF at 0 oC (Eq. 15).

NH2 H
\ ~BH .THF\
3 (1 5)
O~ 4.5 hrs
OH OH
58 59

Aminoalcohol 59 was then subj ected to oxidative carbonylation using the W(CO)6 12

catalytic system under the previously determined optimal reaction conditions (Eq. 16, Table 6,

Entry 3). Urea 60 was isolated in 95% yield with carbamate 61 formed in trace amounts as a

minor product. Acyclic carbamate 62 was not observed.



















NH2~~ W(O6,C
12, py O ,1 (16)
OH



NH2 OH







In order to compare the carbonylation results to phosgene derivatives, 59 was treated with

DMDTC and CDI, respectively. In contrast to the excellent yield of urea 60 from the W(CO)6-

catalyzed carbonylation, reaction of amine 59 with DMDTC afforded 60 and 61 in yields of 30%

and 8%, respectively. Compound 62 was once again not detected. The reaction also produced a

number of side products which were detected by TLC analysis. When CDI was used as the

carbonylating agent, 60 and 61 were produced with 61 being the major product (60% yield)

while 60 was formed in 36% yield. Once again, compound 62 was not observed (Table 2-1,

Entry 3).

A second example of the preference for conversion of 1,3 aminoalcohols to the urea vs. the

cyclic carbamate was obtained by carbonylation of 1 -phenyl-3-aminopropanol (63). Amino

alcohol 63 was synthesized by treating benzaldehyde with acetonitrile under basic conditions

followed by reduction of the resulting cyanohydrin with borane dimethylsulfide.5 Carbonylation

of 63 using the W(CO)6 12 catalytic conditions provided the corresponding urea 64 in 72% yield,









with the minor product being cyclic carbamate 65 in 14% yield after crystallization. The acyclic

carbamate 66 was not formed in the reaction.





-HN HNK


65
OH W(CO)6, 2 HO 6
CO, pyO N NH2` (17)


63NH2 O N

66

For comparison, 1-phenyl-3 -aminopropanol was subj ected to carbonylation with the

phosgene derivatives CDI and DMDTC (Table 2-1, entry 4). When CDI was used as

carbonylating agent, the urea 64 was formed in 49% yield, and the cyclic carbamate 65 in 30%

yield. Once again, the acyclic carbamate was not observed in the product mixture. In contrast,

when DMDTC was used as carbonylating agent, cyclic carbamate 65 was the maj or product

(47% yield), while the urea was recovered in 34% yield.



F finally, 3 -ami no-2,2 -dim ethyl prop anol (6 7) was studi ed under the opti mal W(CO0)6 12

catalytic conditions (Eq. 18). Compound 67 was chosen in order to examine the effect of steric

bulk at the position P to the nucleophilic nitrogen and the Thorpe-Ingold effect of the gem-

dimethyl substituents at C3. Accordingly, the carbamate was expected to be favored by the

presence of the gem-dimethyl substituents. However, when carried out under the W(CO)6 12

carbonylation conditions, the reaction did not go to completion and 12% of the starting material

was recovered. This may be due in part to steric bulk in the substrate. Nevertheless, urea 68 and









carbamate 69 were obtained in 60% and 5% yield, respectively (Table 2-1, entry 5). There was

no evidence for the formation of the acyclic carbamate 70.



O O
OH HN NH OH HN O



NH2 OH W(CO)6, CO 68 O69

12, PY NH2 O HOH
67 (18)



In contrast, when 3 -ami no-2,2 -di methyl prop anol (6 7) was tre ated with CD I or DMD TC,

much higher proportions of carbamate were generated than with the W(CO)6-catalyzed

carbonylation (Table 2-1, Entry 5). Urea 68 was still the maj or product for both carbonylation

reactions, being isolated in 55% yield and 32% yield, respectively. However, cyclic carbamate

69 was recovered in 28% yield from the reaction with CDI and in 29% yield when DMDTC was

used in the carbonylation. Overall, there is a strong selectivity favoring formation of urea over

carbamate in the W(CO)6-catalyzed carbonylation for all three 1,3-aminoalcohols that were

investigated. In comparison, the selectivity for formation of the urea over formation of the

carbamate is significantly lower when CDI or DMDTC is used as the carbonylating agent.

Carbonylation of 1,2-Aminoalcohols

Our interest in the carbonylation of 1,2-aminoalcohols began with our preparation of the

core structure of the HIV protease inhibitors DMP 323 and DMP 450 by W(CO)6-catalyzed

carbonylation of O-protected derivatives of diamine diol 71.4 As part of these investigations, it

was determined that under the initially reported conditions, oxidative carbonylation of 71









afforded oxazolidinones 73 and 74 instead of the diol urea 72 (Eq. 19).39 A similar preference

had previously been reported for the reactions of 71 with CDI and phosgene.96


I-I P
HN NH

BnC "''Bn HN
HO OH
72

SPhH
,NH2

HNKO Ph


NH2 NH2
Bn '.Bn W(CO)6 2
HO OH CO, K2CO3

71


(1 9)


These prior results provided motivation for additional study of 1,2-aminoalcohols. The

initial substrate was p-amino alcohol 75 (Eq. 20), chosen for its structural similarity to half of 71

To further investigate formation of the oxazolidinone ring vs. coupling to the urea, oxidative

carbonylation of p-amino alcohol 75 was carried out using the W(CO)6 12 catalytic system (Eq.

20). The conditions were the same as described for the previous aminoalcohol substrates. Upon

carbonylation of 75, urea 76 and cyclic carbamate 77 were obtained in 78% and 10% yield,

respectively, with urea formation once again strongly preferred (Table 2-1, entry 6). Although

the phosgene derivative DMDTC afforded similar results, carbonylation of 75 with CDI

produced only low yields of a roughly equal mixture of urea 76 and carbamate 77.


W(CO)6, 12 HN NH

CO, py ,J Ph ,,,Ph
HO OH
76


Phh

HN O
O
77


P"h
H2N OH

75


(20)









To further investigate the carbonylation of 1,2-aminoalcohol substrates, (R)-(-)-2-amino-1-

phenylethanol (78) was also subjected to the W(CO)6-catalyzed carbonylation (Eq. 21). Urea 79

and cyclic carbamate 80 were obtained in 79% and 14% yield, respectively. As observed for

1,2-aminoalcohol 75, there was a high selectivity for conversion of 78 to the urea in preference

to the oxazolidinone.




I-I Ph
h HN NH r
H2 H W(CO)6, 12 Phh+H O (21)
CO, py OH OH O

78 79 80

The phosgene derivatives CDI and DMDTC were also used in the carbonylation of 78 for

comparison. In the former reaction, the cyclic carbamate 80 was the major product (52% yield)

while the urea 79 was recovered in 30% from the mixture. On the other hand, when DMDTC

was used as the carbonylating agent, urea 79 was the maj or product of the reaction (73% yield)

while oxazolidinone 80 was isolated in just trace amounts (Table 2-1, Entry 7). Note that for

1,2-aminoalcohols 75 and 78, both the W(CO)6-catalyzed carbonylation and DMDTC afforded

the hydroxyalkyl ureas as the maj or products but carbonylation with CDI favored the cyclic

carbamate.

Conclusions

In summary, the W(CO)6 12 methodology can be applied to carbonylation of aminoalcohols

to the ureas without protection of the hydroxyl group. The W(CO)6-catalyzed oxidative

carbonylation is consistently selective for the urea over the cyclic carbamate in all cases studied.

Acyclic carbamates are not detected in the reaction mixtures. In contrast, reactions of the










phosgene derivatives CDI and DMDTC with 1,3- and 1,2-aminoalcohol substrates exhibit

variable selectivities between ureas and cyclic carbamates.









CHAPTER 3
THE W(CO)6 12 CATALYZED OXIDATIVE CARBONYLATION OF DIAMINES:
ANALOGS OF THE CORE STRUCTURES OF THE HIV PROTEASE INHIBITORS DMP
323 AND DMP450.

Background

The syntheses of new improved and more efficient HIV inhibitors against mutant proteases

continue to be an important target in medicinal and synthetic chemistry. In order to design and

synthesize more potent inhibitors of HIV protease, it is crucial to understand the basics of

molecular recognition for the protease. Extensive studies have been done in this regard and two

distinctive characteristics have been identified.'os First, it was found that the active form of the

viral enzyme is a homodimer, in which each monomer contributes equally to the active site.

Also, the occurrence of structural water that bridges linear inhibitors to the flap of the protein

through hydrogen bonds has been confirmed. One of the first sets of C2 symmetric molecules

that were reported to displace the structural water was the C2 symmetric cyclic urea-based

inhibitors.

Since these inhibitors were first reported, the number of cyclic urea scaffolds has rapidly

increased and this class of cyclic compounds has become a feasible alternative to the existing

antiretroviral agents. DMP 323 and DMP450 are among these HIV protease inhibitors reported

as discussed earlier in this work (Fig. 2).

HO OH
H2N NH2





HO OH HOI OH
DMP 450 DMP 323

Figure 2. Structures of the HIV protease inhibitors DMP 323 and DMP 450









Studies on the interaction of the cyclic urea inhibitors XK216, XK263, DMP323, DMP450,

XV63 8, and SD146 with HIV-1 protease, has revealed that these cyclic ureas are symmetrical

molecules that posses a common central structural unit: a seven membered heterocyclic ring a

urea moiety and diols. Their Pl(Pl') and P2(P2') substituents are attached to C3(C6) (atoms

adj acent to the diols) and the urea nitrogen atoms respectively (Table 3-1).105

Synthesis of DMP 323 and DMP 450 was first reported by DuPont Merck

Pharmaceuticals.91 The key feature of DMP 323 and DMP 450 is the C2 symmetric diol which

provides the correct binding site configuration for the protease enzyme. The 7-membered cyclic

urea moiety provides a scaffold for the diol. Many different routes for the synthesis of DMP 323

and DMP 450 derivatives are available in the literature. Generally, the urea moiety of DMP 323

and DMP 450 was installed by reaction of phosgene or a phosgene equivalent with an O-

protected diamine diol. In the initial small-scale preparations, a primary diamine was reacted

with the phosgene derivative 1,1'-carbonyldiimidazole (CDI),909193106 followed by N-alkylation

as appropriate (Scheme 15).

The practical route to DMP 450 utilizes phosgene to form the cyclic urea from a secondary

diamine.91 The protection of the diol is essential in all these synthetic routes, thus a large amount

of information concerning protection of the diol is available.91,96

As discussed in previous chapters, oxidative catalytic carbonylation of the corresponding

diamines using W(CO)6 12 has also been applied in an effort to install the urea moiety into the

core structure of the HIV protease inhibitors DMP 323 and DMP 450.4,39

In this study, protecting groups such as acetonide 35,27 MEM ether 36107 and SEM ether

37,107 were chosen as representative examples bearing cyclic and acyclic protecting groups,













01
P2N ~,P






Cyclic Ureas P2/P2'


XK216




XK263



DMP323 O



DMP450 ~,



XV638 NH





SD146 H~NH H11


Table 3-1. Structures of cyclic urea inhibitors









Scheme 15


Cbz /Cbz
'NH HN

H3C 'CH3


H-
NCbz CH3
HF~K ('OMe b~ '


NHCbz

H~C OH
O


a ,


H3C 'r..CH3
SEMO OSEM


Cbz, ,Cbz
NH HN

SEMO OSEM


d


SSEM = 2-(Trimethylsilyl)ethoxymethyl


N N~g~~

H3C~ ..CH3
HO OH


g,h


Reagents and conditions: (a) i-BuOCOC1, CH30NHCH3.HCl; (b) LiAlH4
(c) VCl3(THF)3, Zn-Cu; (d) SEMCl; (e) cat. Pd(OH)2; (f) 1,1'-carbonyldiimidazole;
(g) PhCH2Br, NaH; (h) HC1, dioxane/MeOH.









respectively. Carbonylation of 35-37 allows comparison of the W(CO)6-catalyzed process to the

stoichiometric reactions of the phosgene derivative CDI (Table 3-2).10s Varying results were

obtained in the yields of the ureas from the catalytic reaction depending on the protecting group

on the diol, as was also observed for ring closure with stoichiometric CDI. These results

demonstrate that the catalytic oxidative carbonylation reaction can be used to convert diamines

to cyclic ureas in examples relevant to the preparation of complex targets.



,- O
.,,~H ~ W(CO)F;/ CO /HN NH
12, K2CO3 .,,,
PlO OP2
POd OP2

35 Pl, P2, C(CH3)2 38 Pl, P2, C(CH3)2
36 Pl, P2 = MEM, MEM 39 Pl, P2 = MEM, MEM
37 Pl, P2 = SEM, SEM 40 Pl, P2 = SEM, SEM

Table 3-2. Carbonylation of compounds 35-37 to Ureas 38-40
Diamine Reagent Solvent T (oC) % Yield Urea Ref
35 CDI CH3CN NRb 15
35 CDI TCE 14 732
35 W(CO)6/CO CH2 12/H20 80 3
35 W(CO)6/CO CH2 12 80 2
36 CDI CH2 12 rt 62,76c 30,33,34
36 W(CO)6/CO CH2 12/H20 80 4
37 CDI CH2 12 rt 52,93c 30,33
37 W(CO)6/CO CH2 12/H20 80 7
aTypical reaction conditions: Diamine 35 (0.200 mmol), W(CO)6 (0.0242 mmol), K2CO3 (0.635
mmol) and I2 (0.239 mmol), solvent (32 mL CH2 12 : 8 mL of water), 80 atm CO, 80 oC, 18 h.
bNot reported. "Yields are from two-step sequence involving deprotection of the Cbz-protected
diamine. Deprotection is assumed to be quantitative for purposes of the table.

Overall, catalytic oxidative carbonylation of 35 in the biphasic CH2 12/H20 solvent system

afforded 38 in 38% yield. As had been observed for the carbonylation of functionalized benzyl

amines,44 yields obtained by using the biphasic solvent system were higher than those in CH2 12.









Efforts to optimize the reaction conditions by varying CO pressure, temperature, concentration

and solvent did not result in higher yields of 38. Although the yields of 38 from 35 are modest,

results from the catalytic carbonylation compare favorably to those obtained with CDI under

typical conditions.2

Reaction of 35 with CDI in acetonitrile under standard conditions results in a 15% yield of

38, with the low conversion attributed to strain in the bicyclic product (Table 3-2). Carbonylation

of 36 and 37 was carried out under the conditions used for 35, with the exception of substrate

concentration, which was optimized for 36 and the same used for 37 (Table 3-2). In comparison

to the literature yields of 62 and 76 % for formation of urea 39 from Cbz protected MEM ether

36 and CDI under slightly different conditions, the catalytic carbonylation reaction provided 39

in 42% yield from 36. Promising results were also obtained for SEM ether 37, for which

catalytic carbonylation afforded urea 40 in 75% yield, a value intermediate between the reported

yields for reaction of 37 with CDI.

With these preliminary results it was established that oxidative catalytic carbonylation of

amines can be applied successfully in the preparation of functionalized ureas. These studies also

offered the first demonstration of catalytic amine carbonylation as synthetic methodology. Yields

of the ureas from the catalytic reaction vary with the protecting group on the diol, as do those

reported for ring closure with stoichiometric CDI.

Results and Discussion

Synthesis of Seven-Membered Ring Cyclic Ureas 84 and 89

In a continuing effort to optimize the carbonylation conditions for the synthesis of 7-

membered cyclic ureas, simple targets were envisaged. Therefore the synthesis was began on

diamine 83 and 88, which contain no substituent and methyl groups, respectively, in the C2

positi on.









Diamine 83, which is the precursor to cyclic urea 84, was synthesized as described in

Scheme 16. Commercially available 2,3 -O-isopropylidene-L-tartrate, is treated with concentrated

aqueous ammonia solution and methanol for three days to afford (4R,5SR)-2,2-dimethyl-1 ,3-

dioxolane-4,5-dicarboxamide 82.109 The next step is the reduction of the dicarboxamide to

furnish diamine 83.






HN H3CI J'"CH3




84 89


It is important to point out that the reduction of compound 82 was much more difficult

than anticipated. Standard reducing agents that are commonly used did not carry out the reaction

to completion. Partially reduced product was the result even though the reaction conditions were

adjusted several times. Fortunately, the reduction was accomplished at last using borane-

dimethyl sulfide complex in THF. After purification of the diamine 83, the oxidative

carbonylation using W(CO)6 12 system was set up and allowed to react for 24 hours. After

workup the cyclic urea 84 was obtained in 74% yield. The synthesis of diamine 88 was

carried out according to literature procedures described in Scheme 17.75 Dimethyl 2,3-o-

i sopropyli dene-L-tartrate 85 was di ssolved in dry toluene at -40 oC. DIBAL was added to thi s

solution dropwise with constant stirring. After one hour, anhydrous methanol was added to the

mixture reaction and the reaction was warmed to -10 oC. Next, dimethylhydrazine was added and









the reaction was warmed to -10 oC. Next, dimethylhydrazine was added and the reaction was

allowed to run one more hour to afford hydrazone 86 in good yield.

Scheme 16


O~N

O` NH2
O

82


OCH3

~O O OCH3
81


Conc. aqueous NH3

MeOH
3 days, r.t.
92% yield


"~NH


O-NH2

O N'~H2

83


W(CO)6 2 ,
Py, CH2 12
80 atm, 24 hrs, ~68 OC
74% yield


BH3* SMe2
Dry THF, reflux
4h
64% yield


Scheme 17


88% yield y


O O
-0 O







MeLi
Et20 (dry)
75% yield


O O -

H H


DIBAL ,
Dry Toluene


'N N'
NH HN

o


87


Raney Nil H2

800 PIO1H50C
24 hr


NH, NH2

Oi O


88









Without further purification, the hydrazone was treated with MeLi in dry diethyl ether to produce

intermediate 87. Finally, diamine 88 was obtained upon hydrogenation of the hydrazine 87.

Once the diamine 88 was available, the oxidative carbonylation with W(CO)6 WaS pursued,

using the conditions described in Scheme 18.

Scheme 18





I 2C3H3CH CH

"7(Y CH2 12/H20

88 80 atm, 24 hrs, ~105 OC 89
71% yield

The conditions for the carbonylation reaction have to be adjusted for different substrates.

The yields for cyclic ureas 84 and 89 are unoptimized and it is expected that they could be

improved. Other substrates containing secondary diamines are currently under investigation.

Conclusions

In summary, we have established that catalytic oxidative carbonylation of diamines

provides an alternative to phosgene and phosgene derivatives in the preparation of cyclic ureas.

More detailed studies need to be done in the preparation of cyclic ureas using this methodology.

One interesting experiment that is currently being developed is the carbonylation of the diamine

diol without any protecting group present since it was demonstrated in previous experiments

with aminoalcohols that this system is tolerant to the presence of hydroxyl functional groups.









CHAPTER 4
CATALYTIC OXIDATIVE CARBONYLATION OF ENANTIOMERICALLY PURE ot-
AMINO AMIDES TO PRODUCE HYDANTOIN DERIVATIVES



Background

Hydantoins and cyclic ureas have long been the focus of considerable attention since they

are frequently found as crucial moieties in many biologically active molecules with

pharmaceutical relevance. More specifically, hydantoins substituted at C-5 constitute an

important class of heterocycles in medicinal chemistry since many derivatives are associated

with a wide range of biological properties including anticonvulsant, no0 antidepressant, 111,112

antiviral,111,112 and platelet inhibitory activities.113 Moreover, C-5 substituted hydantoin

derivatives are of synthetic utilityll4-116 as precursors to ot-amino acid derivatives after hydrolytic

degradation (Figure 4-1).

Classic Ways to Synthesize Hydantoins

A wide variety of methods for the synthesis of hydantoins have been reported starting from

different building blocks. Information concerning different approaches to hydantoins including

solution phase syntheses and more recently solid-phase organic syntheses, as well as polymer

bound reagents can be found in the literature.ll '"1 Under solution phase conditions, there are

several ways to afford hydantoins starting from different substrates. Figure 4-2 describes

different strategies to afford hydantoins from various starting materials.ll










Figure 4-1. Hydantoin ring structure.

RR


O
R2 +


R3 R4


R3 R4


b) R3







RJ



R3 N
d)
ON S


R3



e) R3 N

R2


+ KCN + (N H4)2 CO3


R4 R3
I HOOC NR


+ KSCN


R ,3 R1 + Ri NC,
I HOOC N2S




NH





R1


f) R3 R 2` r 3R4 + KSCN


R2

Figure 4-2. Synthetic strategies and building blocks for hydantoin synthesis.ll

Hydantoins can be prepared from ureas and carbonyl compounds as reported by Beller et

al.ll Several examples of these procedures can be found in the literature including the Biltz

synthesis, which is still applied to the synthesis of hydantoins (Figure 4-21a). Another classic










way to afford hydantoins is the Bucherer-Bergs methodology, the reaction of carbonyl

compounds and inorganic cyanide. Introducing the second nitrogen and carbonyl unit would

afford N-1 and N-3 unsubstituted hydantoins (Figure 4-2b). Moreover, another classic way to

form hydantoins is the Read-type reaction (Figure 4-2c) of amino acids or derivatives with

inorganic isothiocyanate, which will produce the hydantoin with no substituent in the N-3

position. Hydantoins with substituents at N-3 can be synthesized using alkyl or aryl

iso(thio)cyanates as marked (Figure 4-2d). Hydantoins from amino amides can be afforded by

introducing the C-1 unit (highlighted) to a substrate that already contains four atoms of the

hydantoin ring (Figure 4-2e). Finally, hydantoins that possess a substituent at N-1 can be

generated starting from a-halo amides and inorganic isothiocyanates (Figure 4-2f).11

Solution Phase Synthesis

As mentioned above, the Bucherer-Bergs strategy is among the classic ways to produce

ureas. This practical and easy method yields 5-substituted hydantoins from aldehydes and

ketones. The synthesis involves the reaction of a carbonyl compound with potassium cyanide and

ammonium carbonate. Sarges et al. applied this methodology to prepare the aldose reductase

inhibitor sorbinil (Scheme 19).119

Scheme 19



O O N\H ON

F ~KNCH2O ,F HN 3O 1. Brucine F O

O C2HsOH, H20O 2. HCL O
90 91 92

The Read synthesis is also frequently applied for the synthesis of hydantoins and

thiohydantoins. Smith et al. reported the synthesis of silicon-containing hydantoins starting from










silylated amino acid 93, which upon treatment with potassium cyanate in pyridine and

subsequent acid cyclization afforded hydantoin 95 (Scheme 20).120

Scheme 20



R R
R H3C
H3 \ Si Si H3-S
iKOCN R R3-S N

HOOC NH2 pyridine HOOC NHH20 O N
H2N O
93 94 95

The previous examples have long been known to be applicable to the production of

hydantoins. However, during the last decades, much progress has been made in the development

of new strategies to produce hydantoins, since more cases of interesting biological activity have

been discovered.

More recent methodologies for the synthesis of hydantoins have been developed. Among

them is the synthesis of thiohydantoins reported by Le Tiran and coworkers.121 This synthesis

affords thiohydantoins starting with amino acid amides and carbon disulfide. As described in

Scheme 21, amino amide 96 was treated with di-2-pyridylthiocarbonate (DPT) in THF at room

temperature furnishing disubstituted hydantoin 97.

Scheme 21

H3CO

H3CO

HN DPT, THF O
H2N rt, 24h \I
96 97









Hydantoins with different substituent patterns can also be produced from other

heterocyclic compounds. One example is the synthesis of 1,5-disubstituted hydantoins 100, that

can be prepared from aziridinone 98 and cyanamide, followed by treatment of the resulting

iminohydantoin with HNO2 (Scheme 22).122

Scheme 22







R N'R NH2CN RH H R N HNO R H
H RH R'NH R' O

98 99 100

Another recent example is the synthesis of hydantoins using multi-component reactions.

Hulme and coworkers reported the synthesis of trisubstituted hydantoins using Ugi/De-

Boc/Cyclization methodology.123 For the preparation of these trisubstituted hydantoins, they

started with five substrates that included aldehydes or ketones, amines, isonitriles, methanol and

carbon dioxide. The mechanism of this five-component reaction is described in Scheme 23.

Phosgene and its derivatives have also been used for the synthesis of hydantoins."'5 One

recent report that uses phosgene derivatives for the preparation of enantiomerically pure

hydantoins was made by Zhang and coworkers.124 They reported the synthesis of several

hydantoin molecules using phosgene and its derivative 1,1' -carbonyldiimidazole (CDI).

Solid-Phase Organic Synthesis

The synthesis of structurally challenging heterocyclic molecules bearing one or more

nitrogen atoms using solid support synthesis has developed very quickly in the last decade. There

are several reviews on the synthesis of hydantoins by means of solid-phase organic synthesis










(SPOS)."1 Gutschow et al. address examples of the most recent efforts on the synthesis of

hydantoins via SPOS.



Scheme 23


CH3 NH
R2


R3- +
N1 R1
NH
R2


CRH30 HICO2

R2NH2
R3No


SrRI
N


R2 .

R N-R3


101


O R1
H3 'O bl N'R3H

R~2 O


1N KOH

CH30H, THF, H20


Synthesis of Hydantoins Using W(CO)6/ 2 Catalytic System

It was anticipated that catalytic carbonylation of ot-amino amides with W(CO)6 12 in the

presence of CO might be feasible upon optimization of the reaction conditions. Formation of the

five-membered ring should be facile since it is kinetically favored. Therefore, an effort toward

the synthesis of a series of different hydantoins was begun.


R ONR'
HNg
O


R N ,R'
NH


W(CO)612










A short and efficient synthesis starts with enantiomerically pure co-amino amides, which

should afford the corresponding enantiomerically pure hydantoins (Eq. 22). In order to increase

our knowledge concerning the efficiency of the catalytic system for the synthesis of different

substituted hydantoins, it was decided to explore a series of enantiomerically pure a-amino

amide as substrates for this reaction.

Results and Discussion

In the present work it is reported that five disubstituted hydantoins carrying aromatic or

aliphatic side chains at the 3- and 5- positions were synthesized from the corresponding a-amino

amides in good yields using the W(CO)6 12 system in the presence of CO. Amino amide 103a

was synthesized according to the procedure reported in the literature.125 Treatment of the

corresponding amino acid methyl ester hydrochloride with methylamine leads to compound 103a

(Eq. 23). After purification of compound 103, the next step is the cyclization of the a-amino

amide using the W(CO)6 12 system in the presence of CO (Eq. 24). Optimization of the reaction

conditions was carried out using amino amide 103a. Initially, the original conditions used for the

amino alcohols were tested, but the reaction did not produce the hydantoin and starting material

was recovered (Table 8, Entry 1). This was not surprising since the amide is less nucleophilic

than the amines present in the amino alcohol substrates. Next, different sets of conditions were

tested, including longer times, higher temperatures and different bases. Some of these conditions

are described in Table 4-1.



O O

HOCH3NH2 N (3
MeOH (anh.)
102 3 as t103a











/ W O) (2 4)


103a ~Base, Solvent 14




Table 4-1. Carbonylation conditions for ot-amino amide 103a.
Conc. Product
Entry Time (h) Pressure (atm) Temp (oC) Base/eq. Solvent (M
1 18 80 40 Py/2 CH2 12 4 0
2 24 80 70 Py/2 CH2 12 4 0
3 36 90 105 Py/2 CH2 12 0.11 40
4 45 80 40 Py/2 CH2 12 0.11 0
5 36 90 100 K2CO3 CH2 12/H20 0.05 20
6 42 90 100 DMAP/2 CH2 12 0.03 0
7 36 85 78 DMAP/3 Toluene 0.03 0
8 36 85 78 DMAP/3 CH2 12/H20 0.03 50
9 36 85 78 DMAP/4 CH2 12/H20 0.03 50
10 48 85 90 DMAP/4 CH2 12/H20 0.03 traces
11 36 80 76 DBU/4 DCE 0.03 72

The data in the table show that the best conditions so far are those described in Entry 11. It

was expected that the conditions for the carbonylation of this substrate would be different from

the optimized for amino alcohols. Since the nucleophilicity of the nitrogen amide is lower than

that of the amines previously investigated, the main variable to be addressed was the base. It was

likely that a stronger base would be needed to to take the reaction to completion, and indeed this

was confirmed later in the investigation. Time was another variable to consider. As shown in

Entry 11, 36 hours was optimal for the reaction conditions. At longer reaction times, the product

began to decompose (Entry 10).

With these optimized conditions, different substrates for the synthesis of hydantoins were

started. Figure 4-3 shows the substrates submitted to investigation for the catalytic carbonylation

of ot-amino amides to afford the corresponding hydantoins. Amino amide 103e was included in










the study because it contains the hydroxyl functionality that was present in the amino alcohols

reported previously.


N, Me NEt



H H
SH2 NH2

103c 103d


HO NB



NH2
103e

Figure 4-3. a-Amino amide substrates to be converted to hydantoins


Amino amides 103a-d were prepared following a literature procedure (Eq. 23).124 Using

the same starting material, the enantiomerically pure amino amides 103a-d were obtained by

adding the corresponding alkyl amine in methanol (Table 4-2).

All products (103-a-d) were recovered in very good yield after purification by column

chromatography on silica gel. The synthesis of amino amide 103e was initially carried out

following available methodology.126 The hydrochloride salt of the serine methyl ester (105) was

treated with benzylamine to yield 103e in 35 % isolated yield, a result is similar to that reported

in the literature.





O RN2 NR (25)
MeOH (anh.)









Table 4-2. Synthesis of a-amino amides 103a-103d
entry R Product Yield (%)
1 CH3 103a 90
2 CH3CH2 103b 82

3 (CH3 )2CH2 103c 74
4 PhCH2 103d 84



HO OCH3 ~PhCH2NH2 HON(5

NH2'HCI MeOH NH2
105 reflux, 18 hrs 103e
35%


However, because of the low yield observed with this procedure, a different method was

used to prepare amino amide 103e, and the product was obtained in higher yields.127 This

strategy proceeded through Cbz-serine, which was treated with benzylamine and the mixed

anhydride coupling (MAC) procedure.128 to afford 105 stereospecifically (Scheme 24). The next

step to obtain the carbonylation substrate was the hydrogenation of protected amino-3-

hydroxypropionamide to afford 103e in 89% yield.

Substrates 103a-e were then subj ected to the optimized carbonylation conditions

determined for 103a. The results are described in Table 4-3. Most of the hydantoins were

obtained in good yields (Table 4-3), except in the case of 104c, which was produced in trace

amounts. This is probably because the steric hindrance of the bulky isopropyl group present in

the amide substrate, since similar results have been observed before in the carbonylation of

diamines containing isopropyl substituents.42 Further optimization of the reaction is necessary,

testing different substrates and different conditions, but these preliminary results are promising.















H~bOH N-h lIne HONC2h H2/Pd-C ,H HhP
I so butylI NHCbz 89% NH2
Chloroformate
PhCH2NH2 105 103e
80%




R $ N, R2 RiNR2
NH2HN

Table 4-3. Catalytic carbonylation of ot-amino amides 103a-e to hydantoins 104a-e.
entry R1 R2 Product yield
1 PhCH2 CH3 104a 73

2 PhCH2 CH3CH2 104b 61

3 PhCH2 (CH3 )2CH2 104c traces
4 PhCH2 PhCH2 104d 75

5 HOCH2 PhCH2 104e 50


In the past, other group VI metals carbonyls such as chromium hexacarbonyl and

molybdenum hexacarbonyl have been also investigated as catalysts for the carbonylation of

aliphatic secondary amines.45 However, the results of those experiments showed that tungsten

hexacarbonyl was the best catalyst for the catalytic carbonylation in the case of primary and

secondary aliphatic amines. Similar experiments were carried out for the amino amide substrates,

in which amino amide 103a was selected to undergo the catalytic reaction using Mo(CO)6 and

Cr(CO)6 as catalysts under the previously optimized conditions. However, as observed

previously the carbonylation reaction using Mo and Cr catalysts did not gave good results. In the


Scheme 24









case of Mo(CO)6 the yield was less than 20% and for Cr(CO)6 it was impossible to identify the

expected hydantoin.

Conclusions


The W(CO)6 catalytic carbonylation, using I2 aS Oxidant in the presence of CO, has

proven to be effective for the synthesis of disubstituted hydantoins starting from

enantiomerically pure a-amino amides. Other group VI metal carbonyl catalysts have been

investigated for this carbonylation reaction. However, W(CO)6 is a more effective catalyst for

the oxidative carbonylation of a-amino amides to afford the corresponding hydantoins. Further

experiments with this type of substrate are currently underway.









CHAPTER 5
EXPERIMENTAL SECTION

General Procedures

All experimental procedures described were carried out under nitrogen and in oven dried

glassware unless stated otherwise. Solvents used for carbonylation reactions were passed

through a solvent purification systeml29 prior to use. Most of the aminoalcohol substrates were

commercially available and were used without further purification. The aminoalcohols 3-amino-

4-phenyl butanoll30 and 3-amino-1-phenyl propanol5 were prepared as described in the literature.

'H and 13C NMR spectra were obtained on a Varian Gemini 300 or VXR 300 MHz

spectrometer. Infrared spectra were recorded on a Perkin-Elmer 1600 FT-IR. High-resolution

mass spectrometry and elemental analyses were performed by the University of Florida

analytical service.

Procedure A for Carbonylation of Amino Alcohols with CDI

The aminoalcohol (2 equiv) was dissolved in dry THF and placed into the flask under a

flow of N2. One equivalent of CDI was then added. The reaction was left to stir for 18 hours,

then the solvent was evaporated under a flow ofN2. The residue was dissolved in a 1:1 mixture

of CH2 12: H20. The mixture was placed in a separatory funnel. After the layers were

separated, the aqueous layer was washed with CH2 12, then with a 2: 1 solution of

chloroform/ethanol. The combined organic layers were dried and filtered, then the solvent was

removed. The crude product was purified by flash chromatography on silica gel with 5%

MeOH/CH2 12 as eluent for the carbamate and 30% MeOH/CH2 12 for the urea.

Procedure B for carbonylation of aminoalcohols with DMDTC

The aminoalcohol (2 equiv) was dissolved in dry methanol and placed into the flask under

a flow of N2. DMDTC (1 equiv) was then added and the reaction was left to stir for 18 hours









under N2. The solvent was then evaporated under N2 and the product was immediately

chromatographed on silica gel using a mixture of 5 to 30% MeOH/CH2C 2 as eluent to recover

the carbamate and urea, depending on the substrate.

Procedure C for Catalytic Carbonylation of Amino Alcohols with W(CO)6 2~

1 ,3-Bis-(5-hydroxypentyl)urea (51). To a 15 mL glass vial in a multi-compartment Parr

high pressure vessel containing 1.9 mL of CH2C 2, were added 50 (800 mg, 7.7 mmol), W(CO)6

(136 mg, 0.38 mmol), pyridine (0.93 ml, 11.5 mmol) and I2 (977 mg, 3.8 mmol). The vessel was

then charged with 80 atm CO and heated at 40 OC for 18 hours. The pressure was released and

methylene chloride (5 mL) was added to the reaction mixture to further dissolve the crude

product. The solution was washed successively with saturated sodium sulfite, then saturated

sodium bicarbonate. Each of the collected aqueous layers was washed with 2:1 CHCl3/EtOH (4

x 30 mL). The combined CHCl3/EtOH layers were dried with MgSO4 and the solvents removed

by evaporation to afford urea 51 as a white solid in 64% yield. In order to recover the

carbamate, the methylene chloride layer from the original extractions was washed with 0.1M

aqueous HC1, then dried with MgSO4. The solvent was removed under vacuum to afford

carbamate 52 in 2% yield. The urea was identified by comparison with literature data (elemental

analysis and melting point).' Urea 51: 'H NMR (D20) 8: 1.22 (m, 4H), 1.37 (m, 4H), 1.52 (m,

4H), 2.88 (m, 4H), 3.42 (m, 4H). MS (LSIMS) [M+H] called for C11H 4N 03 232.18, found

232.18. IR CHCl3) 1 ICO 1654 cm- Anal. called for C11H 4N 03: C 56.87%, H 10.41%, N

12.06%; C 56.96%, H 10.80%, N 11.89%. M.p., reported 106.6-108.5, found 106.3-108.5 oC.

Carbamate 52: 1H NMR (CDCl3) 6: 1.49 (m, 2H), 1.50 (m, 2H), 1.52 (m, 2H), 3.30 (m, 2H),

3.65 (t, 2H), 5.9 (br, 1H); 13C NMR (CDCl3) 6: 22.9, 29.3, 32. 1, 41.2, 62.6, 147.2; IR (CH2C 2):

T'co 1708 cm- ; MS (LSIMS) [M+H] called for 130.08, C6HllNO2 found 130.08.










H H Q
HO NK N~O OH N

51 52

1,3-Bis-(4-hydroxy-3-methylbutyl)urea (55). Procedure C afforded 55 from 54 (0.20

mL, 1.8 mmol) in 93% yield. 'H NMR (CDCl3) 6: 0.86 (d, 6H, J = 6.6 Hz), 1.22 (m, 2H), 1.59

(m, 4H), 3.07 (m, 4H), 3.38 (m, 4H), 6.08 (s, 2H); 13C NMR (CDCl3) 6: 16.4, 33.0, 33.4, 38.4,

67.4, 161.0; IR (CHCl3): vCO 1648 cm l; MS (LSIMS) [M+H]+ C11H 4N 03, called 233.1865,

found 233.1913.

H H
HO N N OrH

55

3-Amino-4-phenyl-1-butanol (59). DL-P-homophenyl alanine (1000 mg, 5.57 mmol)

was added to 2.2 mL THF and the mixture was cooled to 0 oC. BH3*THF (lM, 8.36 mL, 8.36

mmol) was added dropwise to the suspension. The resulting mixture was stirred at room

temperature for 4.5 hours. The mixture was then cooled to 0 oC, 4 mL of 3N sodium hydroxide

was slowly added and the mixture was stirred at room temperature overnight. The pH of the

solution was adjusted to 11 by adding a few pellets of sodium hydroxide. The aqueous phase

was saturated with potassium carbonate, the THF phase was separated and the aqueous phase

was extracted with (50 mL x 6) diethyl ether. The combined organic layers were dried over

magnesium sulfate. The solvents were evaporated and the product was obtained in 82% yield.

The product was identified by comparison with literature data.130









OH NH2

CH2Ph



N,N'-Bis(1-benzyl-3-hydroxypropyl)urea (60) and 4-Benzyl-1 ,3-oxazinan-2-one (61).

Procedure C afforded urea 60 from 59 (760 mg, 4.6 mmol) as a pale yellow oil in 95% yield.

Carbamate 61 was recovered in trace amount. The products were identified by comparison with

authentic samples prepared as described below.

Authentic samples of N,N'-bis(1-benzyl-3-hydroxypropyl)urea (60) and 4-benzyl-1,3-

oxazinan-2-one (61). Procedure B afforded compounds 60 and 61 from 59 (600 mg, 2.97 mmol)

as white solids in 30% and 8% yield, respectively. For urea 60: 1H NMR (CDCl3) 6: 1.22 (m,

2H), 1.77 (m, 2H), 2.70 (m, 4H), 3.42 (m, 4H), 4.10 (s, 2H), 4.82 (s, 2H), 7.39 (m, 10H); 13C

NMR (CDCl3) 6: 38.4, 42.0, 48.0, 58.6, 126.6, 128.6, 129.2, 138.2, 159.9; IR (CH2C 2): I'CO

1600 cm- ; MS (LSIMS) [M+H]+ called for C21H28N203 257.2178, found 257.2161. For

carbamate 61: 1H NMR (CDCl3) 6: 1.68 (m, 1H), 1.87 (m, 1H), 2.78 (m, 1H), 2.89 (m, 1H), 3.67

(m, 1H), 4.14 (m, 1H), 4.27 (m, 1H), 6.81 (s, 1H), 7.24 (m, 5H); 13C NMR (CDCl3) 6: 26.5,

42.3, 51.8, 65.4, 126.8, 128.6, 129.1, 136.2, 154.5; IR (CH2C 2): l'CO 1710 cm l; MS (LSIMS)

[M+H]' called for CllH13NO2 192.1024, found 192.1020.





HO O

60 61

1 ,3-Bis-(3-hydroxy-3-phenylpropyl)urea (64) and 6-Phenyl-1 ,3-oxazinan-2-one (65):

Procedure C afforded urea 64 from 65 (320 mg, 2.12 mmol) in 72% yield. 1H NMR (CDCl3) 6:

1.87 (m, 4H), 3.30 (m, 2H), 3.6 (m, 2H), 4.72 (t, 2H), 6.19 (s, 2H), 7.32 (m, 10H); 13C NMR









(CDCl3) 6: 38.4, 38.7, 72.3, 125.8, 127.5, 128.4, 143.8, 160.1. IR (CHCl3): vco 1646 cml

Cyclic carbamate 65 was recovered in 14% yield; it was identified by comparison with literature

data.90




HO -"



64 65

N,N'-Bis(3-hydroxy-2,2-dimethylpropyl)urea(68) and 5,5-dimethyl-1,3-oxazinan-2-

one (69). Procedure C afforded urea 68 from 67 (600 mg, 5.81 mmol) as a white solid in 60%

yield. 1H NMR (CDCl3) 6: 0.73 (s, 12H), 2.85 (d, 4H, 6.3 Hz), 3.03 (d, 4H, 6 Hz), 4.61 (t, 2H, 6

Hz), 6.02 (t, 2H, 6.3 Hz), 13C NMR (CDCl3) 6: 22.3, 36.6, 46.2, 67.6, 159.7; IR (CHCl3): vco

1666 cm -; MS (LSIMS) M+H calledd for C1H 4N 03 233.1751, found 233.1750. Anal. Called

for C11H 4N 03: C 56.89%, H: 10.41%, N: 12.06%; Found: C 57.69%, H 10.63%, N 12.01%.

Carbamate 69: yield 5%; 1H NMR (CDCl3) 6: 0.96 (s, 6H), 2.88 (s, 2H), 3.80 (s, 2H), 7. 12 (br

s, 1H); 13C NMR (CDCl3) 6: 22.1, 27.3, 50.6, 75.1, 152.4; IR (CHCl3): vco 1702 cm- ; MS

(LSIMS) [M+H] called for 130.0868, C6HllNO2 found 130.0867.

O O
OHHN NH OH HN O



68 69

1 ,3-Bis-(1-benzyl-2-hydroxyethyl)urea (76) and 6-Phenyl-6-oxazolidin-2-one (77)

Procedure C afforded urea 76 from 75 (800 mg, 5.3 mmol) in 78% yield. Carbamate 77 was

recovered in 10% yield. The products were identified by comparison with literature data.89











HN NH P

Ph~ ,,, Ph H N O
HO OH O
76 77

1,3-Bis-(3-hydroxy-2-phenylethyl)urea (79) and 5-Phenyl-oxazolidine-2-one (80).

Procedure C afforded urea 79 from 78 (800 mg, 5.83 mmol) in 79% yield. 'H NMR (CDCl3) 6:

2.85 (m, 2H), 3.08 (m, 2H), 4.78 (t, 2H), 5.64 (br, 2H), 7.38 (m, 10H); 13C NMR (CDCl3) 6:

49.2, 74.2, 125.8, 127.5, 128.4, 147.2, 159.5; IR (CHCl3): vco 1649 cm l. Cyclic carbamate 80

was isolated in 14% yield; it was identified by comparison with literature data.2




Ph~ ~.Ph HN O
OH OH O
79 80

Synthesis of Cyclic Ureas



(5S,6S)-Hexahydro-5,6-O-isopropylidene-2H13dzpi-on (84).

To a glass-lined 300 mL Parr high pressure vessel containing 40 mL of CH2C 2 H20 4: 1 ratio

were added diamine 83 (200.0 mg, 1.24 mmol), W(CO)6 (20 mg, 0.62 mmol), pyridine (294.25

mg, 3.72 mmol) and I2 (157.30 mg, 0.62 mmol). The vessel was then charged with 80 atm CO

and heated at 680C overnight. After 24 hours, the pressure was released and 10 mL of water was

added. The organic were then separated and washed successively with saturated sodium sulfite

(Na2SO3), then saturated sodium bicarbonate (NaHCO3), and finally with 0. 1N aqueous HCI

solution. The resulting solution was dried over magnesium sulfate and filtered. The solvent was

removed by evaporation and the resulting residue was purified via column chromatography on









silica using ether as eluent. After concentration, cyclic urea 84 was afforded in 64% yield. 1H

NMR (CDCl3) 6: 1.39 (s, 6H), 3.19-3.40 (m, 4H), 4.20-4.30 (m, 2H), 5.1 (br, s, 2H); 13C NMR

(CDCl3) 6: 27.2, 44.7, 81.8, 108.9, 164.3; IR (CHCl3): IR (CDCl3): vCO 1640 cm



O








(4R,5S,6S,7R)-Hexahydro-5,6-O-isopropylidee47dmehl2-,3-diazapin-2-one (89).

To a glass-lined 300 mL Parr high pressure vessel containing 40 mL of CH2 12 H20 4: 1 ratio

were added diamine 88 (200.0 mg, 1.06 mmol), W(CO)6 (14 mg, 0.04 mmol), K2CO3 (410.0 mg,

3.0 mmol) and I2 (269 mg, 1.06 mmol). The vessel was then charged with 80 atm CO and heated

at 1000C overnight. After 24 hours, the pressure was released and 10 mL of water was added.

The organic were then separated and washed successively with saturated sodium sulfite

(Na2SO3), then saturated sodium bicarbonate (NaHCO3), and finally with 0. 1N aqueous HCI

solution. The resulting solution was dried over magnesium sulfate and filtered. The solvent was

removed by evaporation and the resulting residue was purified via column chromatography on

silica using ether as eluent. After concentration, cyclic urea 89 was afforded as a white solid in

71% yield. 'H NMR (CDCl3) 6: 1.26 (d, 6H), 1.40 (s, 6H), 3.59-3.80 (m, 2H), 3.90-4. 10 (m, 2H)

5.17 (br, s, 2H); 13C NMR (CDCl3) 6: 14.2, 27.3, 45.9, 83.2, 110.1, 163.8; IR (CHCl3): IR

(CDCl3): vco 1636 cml













H3C '"CH3




89

General Procedure for the Synthesis of a-Amino Amides 103a-103e.

The amino acid methyl ester hydrochloride (4 mmol) and the alkylamine (40 mmol) were

dissolved in anhydrous methanol (~20 ml) and stirred at room temperature for 3 days. The

reaction mixture was concentrated, and the residue was purified by column chromatography on

silica gel using ethyl acetate/methanol (96:4) as eluant affording the a-amino amides 103a-103d

in very good yields (80-90%). Amino amide 103e was prepared following a three step procedure

described in the literature, starting with Cbz-serine.127



R, NH/ R2
NH2

103a; R1 = Bn, R2 = Me
103b; R, = Bn, R2 = Et
103c; R, = Bn, R2 = iPr
103d; R, = Bn, R2 = Bn
103e; R, = CH20H, R2 = Bn




General Procedure for the Carbonylation of a-Amino Amides 103a-e to Afford Hydantoins
104a-e.

a-Amino amide 103a (400 mg, 2.2 mmol) was placed in a glass-lined 300 mL Parr high pressure

vessel containing 30 mL of dichloroethane (DCE). Next, W(CO)6 (0. 16 mmol) was added

followed by DBU (8.96 mmol) and I2 (1.56 mmol). The vessel was then charged with 80 atm

CO and heated at about 760C for 36 hours with constant stirring. The pressure was released and









15 mL of water was added. The organic were then separated and washed successively with

saturated sodium sulfite (Na2SO3), and then with 0. 1N aqueous HCI solution. The aqueous layer

was extracted with ethyl acetate (20 mL x 4). The combined organic layers were dried over

magnesium sulfate, filtered and concentrated. The resulting residue was purified via column

chromatography- on silica using methylene chloride/ethyl acetate (80:20) to afford the hydantoin

104a. The same procedure was applied to prepare hydantoins 104b-e. The products were

identified by comparison with literature data.12,3,3

(S)-5-Benzyl-3-methylimidazolidine-2,4-din (104a). 1H NMR (CDCl3) 6: 2.80 (t, 1H), 3.0 (s,

3H), 3.32 (dd, 1H), 4.25 (dd, 1H), 5.19 (br, s, 1H), 7.21-7.40 (m, 5H); 13C NMR (CDCl3) 6: 25.8,

41.0, 56.4, 126.7, 128.6, 129.2, 155.4, 174.4; IR (CDCl3): vCO 1772, 1709 cml




OIN



(S)-5-Benzyl-3-ethylimidazolidine-2,4-dion (104b). 1H NMR (CDCl3) 6: 1.19 (t, 3H), 2.82

(dd, 1H), 3.24 (dd, 1H), 3.43-3.60. (m, 2H), 4.21 (dd, 1H), 7.19-7.39 (m, 5H); 13C NMR (CDCl3)

8: 12.0, 33.9, 38.1, 58.1, 127.0, 130.0, 131.2, 134.5, 157.5, 172.4.



O\





(S)-5-Benzyl-3-benzylimidazolidine-2,4-din (104d). 1H NMR (CDCl3) 6: 2.82 (dd, 1H), 3.24

(dd, 1H), 4.22 (s, 2H), 4.60 (t, 1H), 5.38 (br, s, 1H), 7.23-7.42 (m, 10H); 13C NMR (CDCl3) 6:

38.4, 43.9, 61.7, 125.8, 126.7, 126.9, 127.7, 128.5, 128.9, 135.5, 135.7, 158.5, 169.5.









-"O


(S)-3-Benzyl-5-(hydroxymethyl)imidazolidin-,-in (104e). 1H NMR (DMSO-d6) 6: 4.26
(t, 1H), 3.46 (dd, 1H), 3.53 (dd, 1H), 4.48 (d, 2H), 4.77 (br, s, 1H), 7.21-7.26 (m, 3H), 7.30 (m,
2H); 13C NMR (DMSO-d6) 6: 42.3, 59.9, 60.4, 126.4, 127.0, 127.9, 138.7, 157.5, 172.3; IR
(neat): vco 1765, 1708 cml


HO-~-












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BIOGRAPHICAL SKETCH

Delmy J. Diaz was born on November 14, 1967, in San Pedro Sula, Honduras. She was

the second of six brothers and sisters. As a child, she was always curious of why everything

happens; as a consequence, she was always asking many questions driving crazy any adults

around her, since usually one answer will lead to more and more questions. She spent her

formative years at Santa Rosa Elementary School and later she attended part of her high school

studies at Public High School El Patria, moving later on to continue studies to become an

elementary school teacher to Escuela Normal de Occidente en la Esperanza Intibuca.

Throughout her high school formation she was an active and enthusiast member of the science

club. In the spring of 1987 she started her major in science at the Natural Science Department at

the Pedagogic University Francisco Morazan, from were she graduated 4 years later. She started

to work as a chemistry and physics teacher at the high school level. After two years working as a

science teacher she went back to the University to pursue a License in Biology-chemistry

emphasis, and she started working as a chemistry T.A. at the National Pedagogic University. In

2001, she traveled to the USA after she was awarded a Fulbright Scholarship to do her master's

degree in organic chemistry at the University of Vermont, Burlington, which she completed in

2003. That same year she moved to the University of Florida to pursue her Ph.D. studies,

specializing in the area of organic chemistry. After graduating she will go back to her country

Honduras and will start working as a professor at the Science Department of the National

Pedagogic University Francisco Morazan.