<%BANNER%>

Applications of Tungsten-Catalyzed Oxidative Carbonylation of Amines to Ureas

Permanent Link: http://ufdc.ufl.edu/UFE0042484/00001

Material Information

Title: Applications of Tungsten-Catalyzed Oxidative Carbonylation of Amines to Ureas
Physical Description: 1 online resource (157 p.)
Language: english
Creator: Darko, Ampofo
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2010

Subjects

Subjects / Keywords: amines, arylamine, carbonylation, diarylurea, hexacarbonyl, hiv, protease, tungsten, ureas
Chemistry -- Dissertations, Academic -- UF
Genre: Chemistry thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Synthesis of ureas from amines generally involves the use of phosgene or phosgene derivative for the installation of the urea moiety. The health and environmental hazards associated with phosgene and its derivatives coupled with the prevalence of ureas in various areas have prompted research on alternative methods for the synthesis of ureas from amines. Of the alternatives, transition metal-catalyzed oxidative carbonylation has emerged as both an effective method and an environmentally friendly alternative, producing only protons and the reduced form of the oxidant as byproducts. Tungsten hexacarbonyl (W(CO)6) with iodine as the oxidant as the catalytic system was found to be successful in the catalytic carbonylation of amines to ureas. Various primary and secondary amines have been converted to their respective ureas in good yields. The method has been applied to the synthesis of the core cyclic urea moiety of the HIV protease inhibitor, DMP 450. Yields of the urea from the catalytic reaction were comparable to previously reported methods. In addition, analogs of the core structure can be synthesized without protection of the diol functionality. The catalytic system has also been successfully applied to the synthesis of symmetrical and unsymmetrical diarlyureas. This extended scope of the system can be applied to a new class of biologically active compounds that include aryl amines.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Ampofo Darko.
Thesis: Thesis (Ph.D.)--University of Florida, 2010.
Local: Adviser: McElwee-White, Lisa A.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2010
System ID: UFE0042484:00001

Permanent Link: http://ufdc.ufl.edu/UFE0042484/00001

Material Information

Title: Applications of Tungsten-Catalyzed Oxidative Carbonylation of Amines to Ureas
Physical Description: 1 online resource (157 p.)
Language: english
Creator: Darko, Ampofo
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2010

Subjects

Subjects / Keywords: amines, arylamine, carbonylation, diarylurea, hexacarbonyl, hiv, protease, tungsten, ureas
Chemistry -- Dissertations, Academic -- UF
Genre: Chemistry thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Synthesis of ureas from amines generally involves the use of phosgene or phosgene derivative for the installation of the urea moiety. The health and environmental hazards associated with phosgene and its derivatives coupled with the prevalence of ureas in various areas have prompted research on alternative methods for the synthesis of ureas from amines. Of the alternatives, transition metal-catalyzed oxidative carbonylation has emerged as both an effective method and an environmentally friendly alternative, producing only protons and the reduced form of the oxidant as byproducts. Tungsten hexacarbonyl (W(CO)6) with iodine as the oxidant as the catalytic system was found to be successful in the catalytic carbonylation of amines to ureas. Various primary and secondary amines have been converted to their respective ureas in good yields. The method has been applied to the synthesis of the core cyclic urea moiety of the HIV protease inhibitor, DMP 450. Yields of the urea from the catalytic reaction were comparable to previously reported methods. In addition, analogs of the core structure can be synthesized without protection of the diol functionality. The catalytic system has also been successfully applied to the synthesis of symmetrical and unsymmetrical diarlyureas. This extended scope of the system can be applied to a new class of biologically active compounds that include aryl amines.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Ampofo Darko.
Thesis: Thesis (Ph.D.)--University of Florida, 2010.
Local: Adviser: McElwee-White, Lisa A.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2010
System ID: UFE0042484:00001


This item has the following downloads:


Full Text

PAGE 1

1 APPLICATIONS OF TUNGSTEN CATALYZED OXIDATIVE CARBONYLATION OF AMINES TO UREAS By AMPOFO KWAME DARKO A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS F OR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2010

PAGE 2

2 2010 Ampofo Darko

PAGE 3

3

PAGE 4

4 ACKNOWLEDGMENTS I am indebted to my advisor, Professor Lisa McElwee White, for givin g me the freedom to make mistakes and learn from them, which for me, was the most effective learning tool. Her patience and support as a mentor was everpresent, even in the face of frustration. I also thank the rest of my committee Dr. William Dolbier, Dr. Adam Veige, Dr. Alan Katritzky, and Dr. Susan Percival for contributing to interesting discussions and experiences that will undoubtedly shape the way I think about Chemistry. I must also a c knowledge the support of my fellow group members, especially Dr. Phi l lip Shelton, and Dr. Seth Dumbris. Sharing the common bond of graduate student existence have brought us all closer together and will build lasting friendships. I have also had the pleasure of mentoring intelligent undergraduates and exchange s tudents. F. Chris Cur ran, Chlo Copin, Maxime Roche, and Lily Zhang have all contributed to my learning experience. I have learned much from the m as they have from me. Special thanks go to my beautiful wife Megan, and my boys, Kieran Yaw and Brendan Osei Akoto They have supported me throughout my graduate career and deserve as much of the recognition. Coming home to them was always the best part of my day. I am grateful to my brother, Kwame, for his continued encouragement when times were difficult I would like to tha nk my sister, affectionately known as Muffet, for being a great example of having strength in your convictions and beliefs. I would like to thank my parents, Eva Tagoe Darko and Charles Darko, for sacrificing so much of their time for the education and we ll being of their children. They have instilled the work ethic in me that gives me the drive to succeed.

PAGE 5

5 I must also thank Dr. Delmy Diaz and Dr. Keisha Gay Hylton for their previous work on catalytic carbonylations of amines to ureas. I also thank the d onors of the American Chemical Society Petroleum Research Fund for their support of this work through the Green Chemistry Institute. The research of F. Chris Cu r ran was supported by The Howard Hughes Medical Institute Science for Life program. The Ecole National Sup rieure de Chemie de Clermont Ferrand (ENSCCF) supported the research of Chlo Copin and Maxime Roche. The China Scholarship Council funded Lily Zhang during her exchange visit to the University of Florida.

PAGE 6

6 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 8 LIST OF FIGURES ................................ ................................ ................................ .......... 9 ABSTRACT ................................ ................................ ................................ ................... 12 CHAPTER 1 TRANSITION METAL CATALYZED OXIDATIVE CARBONYLATION OF AMINES TO UREAS ................................ ................................ ............................... 14 Introduction ................................ ................................ ................................ ............. 14 Palladium Catalyzed Oxidative Carbonylation of Amines ................................ ....... 15 Homogeneous Carbonylation of Amines to Ureas ................................ ............ 15 Pd Catalysis in Ionic Liquids ................................ ................................ ............. 18 Electrocatalytic Carbonylation ................................ ................................ .......... 19 N Heterocyclic Carbene Palladium Com plexes ................................ ................ 20 Supported Palladium Nanoparticles ................................ ................................ 21 Mechanistic Studies ................................ ................................ ......................... 22 Other Late Transition Metal Catalysts ................................ ................................ ..... 23 Nickel Catalyzed Oxidative Carbonylation ................................ ........................ 23 Ruthenium Catalyzed Oxidative Carbonylatio n ................................ ................ 24 Cobalt and Rhodium Catalyzed Oxidative Carbonylation ................................ 26 Gold Catalyzed Oxidative Carbonylation ................................ .......................... 29 Tungsten Catalyzed Oxidative Carbonylation of Amines ................................ ........ 30 Carbonylation of Primary Amines ................................ ................................ ..... 30 Ca rbonylation of Primary and Secondary Diamines to Cyclic Ureas ................ 33 Conclusions ................................ ................................ ................................ ............ 45 2 CATALYTIC CARBONYLATION OF FUNCTIONALIZED DIAMIN ES TO UREAS: APPLICATION TO DERIVATIVES OF DMP 450 ................................ ..... 46 Introduction ................................ ................................ ................................ ............. 46 Synthesis of DMP 323 and DMP 450 ................................ ................................ ..... 49 Synthesis of DMP Analogues by Tungsten Catalyzed Carbonylation ..................... 52 Carbonylation of Aminobutanediols ................................ ................................ .. 53 Carbonylation of Aminohexanediols ................................ ................................ 57 3 CATALYTIC OXIDATIVE CARBONYLATION OF ARYL AMINES TO UREAS ...... 62 Introduction ................................ ................................ ................................ ............. 62 Results and Discussion ................................ ................................ ........................... 63

PAGE 7

7 Optimization of Reaction Conditions for Oxidative Carbonylation of Aniline to N N Diphenylurea ................................ ................................ ..................... 64 Oxidative Carbonylation of p Substituted Aryl Amines to Symmetrical Diarylureas ................................ ................................ ................................ .... 65 Oxidative Carbonylation of Aryl Amines to Un symmetrica l Diarylureas ............ 68 Conclusions ................................ ................................ ................................ ............ 73 4 APPLICATION OF W(CO) 6 /I 2 CATALYZED CARBONYLATION TO THE SYNTHESIS OF THE LOPINAVIR SIDECHAIN ................................ ..................... 74 Introduction ................................ ................................ ................................ ............. 74 Literature Synthesis of the Lopinavir Sidechain ................................ ...................... 75 Tungsten Catalyzed Synthesis of Lopinavir Sidechain Derivative .......................... 78 Substrate Synthesis ................................ ................................ ......................... 78 Tungsten Catalyzed Carbonylation of N (3 aminopropyl)glycine methyl ester 80 ................................ ................................ ................................ ......... 79 Conclusion ................................ ................................ ................................ .............. 80 5 EXPERIMENTAL PROTOCOLS ................................ ................................ ............. 81 APPENDIX A SPECTRA OF SYNTHESIZED COMPOUNDS ................................ .................... 107 B TABLE OF MELTING POINTS ................................ ................................ ............. 143 LIST OF REFERENCES ................................ ................................ ............................. 146 BIOGRAPHICAL SKETCH ................................ ................................ .......................... 157

PAGE 8

8 LIST OF TABLES Table page 1 1 Tungsten catalyzed oxidative carbonylation of s ubstituted primary diamines .... 35 1 2 Tungsten catalyzed catalytic carbonylation of substituted benzylamines to ureas ................................ ................................ ................................ .................. 38 1 3 Tungsten catalyzed carbonylation of diamines 28 30 to ureas 31 33 ................ 40 1 4 Tungsten catalyzed oxidative carbonylation of aminoalcohols to ureas and carbamates. ................................ ................................ ................................ ........ 42 1 5 Yields of bicyclic ureas from diamines 39a 42a ................................ .................. 44 2 1 Carbonylation of diamines 60a 60f ................................ ................................ ..... 56 2 2 Carbony lation of diamines 60g 60h 28 and 30 ................................ ............... 58 2 3 Conditions attempted for the carbonylation of 60j m ................................ .......... 59 3 1 Optimization of the rea ction conditions for the W(CO) 6 /I 2 catalyzed carbonylation of aniline to N N diphenylurea. ................................ .................... 63 3 2 Oxidative carbonylation of various aryl amines to symmetrical N N ` diarylureas using the W(CO ) 6 /I 2 catalyst system. ................................ ............... 65

PAGE 9

9 LIST OF FIGURES Figure page 1 1 PdI 2 catalyzed oxidative carbonylation of amines to ureas. ................................ 16 1 2 Proposed mechanism of the PdI 2 catalyzed oxidative carbonylation of amines to ureas. ................................ ................................ ................................ 17 1 3 PdI 2 catalyzed oxidative carbonylation of 1,2 benzenediamine .......................... 17 1 4 Application of PdI 2 catalyzed oxidative carbonylation to the synthesis of neuropeptide Y5 receptor antagonist NPY5RA 972. ................................ .......... 17 1 5 Pd catalyzed carbonylation using ionic media. ................................ ................... 19 1 6 Pd(II)/Cu(II) catalyzed electrocatalytic carbonylation of aliphatic amines ........... 19 1 7 Pd NHC catalysts. ................................ ................................ .............................. 21 1 8 Representation of the immobilized palladium nanoparticle ([Pd] APTS Y) catalyst. ................................ ................................ ................................ .............. 22 1 9 Mechan ism for the Pd catalyzed conversion of primary amines to ureas. .......... 23 1 10 Pathways for the Ni catalyzed carbonylation of amines to ureas. ....................... 24 1 11 Mechanism of the [Ru(CO) 3 I 3 ]NBu 4 catalyzed carbonylation of aniline. ............. 25 1 12 Carbonylation mechanism of cobalt salen complexes. ................................ ....... 27 1 13 Co(salen) ( 15 ) and modified Co(salen) complexes ( 16 20 ). ............................... 27 1 14 Rhodium intercalated into titanium phosphate catalyzes the carbonylation of aniline to diphenylurea. ................................ ................................ ....................... 29 1 15 Carbonylation of aryl and aliphatic amines using a polymer supported gold catalyst ................................ ................................ ................................ ............... 30 1 16 Carbonylation of primary aliphatic and aromatic amines using a tungsten carbonyl complex. ................................ ................................ ............................... 32 1 17 Carbonylation of primary and secondary diamines using W(CO) 6 /I 2 as the catalyst. ................................ ................................ ................................ .............. 34 1 18 Gem dimethyl secondary diamines form ureas and tetrahydropyrimidine .......... 36 1 19 Substituent study of the W(CO) 6 /I 2 catalyzed carbonylation of benzylamines. ... 37

PAGE 10

10 1 20 Structures of the HIV protease inhibitors DMP 323 and DMP 450 ..................... 39 1 21 Tungsten catalyzed carbonylation of 28 30 ................................ ....................... 40 1 22 Oxazolidinone formation from the tungsten catalyzed carbonylation of diol 34 ................................ ................................ ................................ ...................... 41 1 23 Synthesis of biotin methyl ester ( 38b ) using the W(CO) 6 /I 2 catalyst system. ...... 43 1 24 Synthesis of biotin derivatives via the W(CO) 6 /I 2 catalytic system. ..................... 44 2 1 Comparison of binding motifs of peptid e derived HIVPR inhibitors to a generic 6 membered ring cyclic NPPI. ................................ ............................... 47 2 2 Structures A D show the path to the identification of the cyclic urea NPPI. ........ 47 2 3 Cyclic urea binding motif. ................................ ................................ ................... 48 2 4 Synthesis of DMP 323 and DMP 450 ................................ ................................ 50 2 5 Imine pathway for the synth esis of DMP 323 and DMP 450. .............................. 51 2 6 Phosphorus tether and RCM pathway to DMP 450 analogue. ........................... 51 2 7 Synthesis of the core DMP 450 st ructure by tungsten catalyzed carbonylation ................................ ................................ ................................ ...... 52 2 8 Unprotected amino alcohol carbonylation by tungsten hexacarbonyl. ................ 53 2 9 Synthe sis of protected aminobutanediols 60a 60d ................................ ............ 54 2 10 Synthesis of unprotected substrates 60e and 60f ................................ ............... 55 2 11 Tungsten catalyzed cata lytic carbonylation of 60a f ................................ ........... 55 2 12 Synthesis of diamines 60g and 60h ................................ ................................ .. 57 2 13 Hydrogenolysis of 44 to obtain diamine diol 34 ................................ ................. 58 2 14 Carbonylation of diamine 34 leads to mixed products ................................ ........ 59 2 15 Attempted synthesis of 63j m ................................ ................................ ............ 59 2 16 Conformational analysis of 7 membered cyclic ureas predicting that A is preferred when the nitrogens are not substituted, while B is preferred when the nitrogens are substituted 113 ................................ ................................ .......... 60 3 1 Synthesis of N N diphenylurea via W(CO) 6 /I 2 carbonylation. ............................. 63

PAGE 11

11 3 2 Oxidative carbonylation of various p substituted aryl amines to symmetrical N N diarylureas ................................ ................................ ................................ 65 3 3 Iodo deboronation of aminophenylboronic ester 67m ................................ ........ 67 3 4 Structure of the cancer drug sorafenib, a possible application of the tungsten catalyzed carbonylation of aryl amines ................................ ............................... 70 3 5 Proposed isocyanate pathway for the tungsten catalyzed synthesis of symmetrical and unsymmetrical aryl ureas ................................ ......................... 71 3 6 Attempted carbonylation of N methylaniline ................................ ....................... 71 3 7 Carbonylation of aniline and N methylaniline to provide unsymmetrical urea 69ap ................................ ................................ ................................ ................... 72 4 1 Structure of ritonavir ................................ ................................ ........................... 74 4 2 Structure of lopinavir. ................................ ................................ .......................... 75 4 3 Retrosynthetic st rategy for the synthesis of lopinavir ................................ .......... 76 4 4 Synthesis of the urea moiety of lopinavir ................................ ............................ 76 4 5 Alternate synthesis of 70 ................................ ................................ .................... 77 4 6 Synthesis of 70 using CDI ................................ ................................ .................. 78 4 7 Retrosynthesis of compound 78 ................................ ................................ ......... 78 4 8 Preparation of N (3 aminopropyl)glycine methyl ester 79 ................................ ... 79 4 9 Attempted W(CO) 6 /I 2 catalyzed carbonylation of glycine methyl ester 79 .......... 80

PAGE 12

12 Abstract of Disserta tion Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy APPLICATIONS OF TUNGSTEN CATALYZED OXIDATIVE CARBONYLATION OF AMINES TO UREAS By Ampofo Da rko December 2010 Chair: Lisa McElwee White Major: Chemistry Synthesis of ureas from amines generally involves the use of phosgene or phosgene derivative for the installation of the urea moiety. The health and environmental hazards associated with phos gene and its derivatives coupled with the prevalence of ureas in various areas have prompted r esearch on alternative methods f o r the synthesis of ureas from amines. Of the altern atives, transition metal cataly zed oxidative carbonylation has emerged as bot h an effective method and an environmentally friendly alternative, producing only protons and the reduced form of the oxidant as byproducts. T ungsten hexacarbonyl (W(CO) 6 ) with iodine as the oxidant as the catalytic system was found to be successful in th e catalytic carbonylation of amines to ureas. Various primary and secondary amines have been converted to their respective ureas in good yields. The method has been applied to the synthesis of the core cyclic urea moiety of the HIV protease inhibitor, DM P 450. Yields of the urea from the catalytic reaction were comparable to previously reported methods. In addition, analogs of the core structure can be synthesized without protection of the diol functionality. The catalytic system has also been successf ully applied to the synthesis

PAGE 13

13 of symme trical and unsymmetrical diarly ureas. This extended scope of the system can be applied to a new class of biologically active compounds that include aryl amines.

PAGE 14

14 CHAPTER 1 TRANSITION METAL CATALYZED OXIDATIVE CARBONY LATION OF AMINES TO UREAS Introduction The development of new synthetic protocols for the preparation of ureas has recently attracted interest because of the presence of this functional group in pharmaceutical candidates, 1 8 agrochemicals, resin precursors, dyes 9 and additives to petrochemicals and polymers. 10 The classical syntheses of ureas from amines have been based on the use of toxic and/or corrosive re agents, such as phosgene or isocyanates. 11,12 In recent years, however, alternative routes have been developed that utilize phosgene derivatives, CO 2 or CO itself as the source of the carbon yl moiety. 13 Particularly attractive from the standpoint of atom economy 14 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 bypro ducts. 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, 17 19 Fe, 20,21 Co, 22 26 Ni, 27 29 Ru, 30 34 Rh, 33,35,36 Pd, 37 53 W, 54 63 Pt, 64 Ir, 64 or Au 65 68 have been reported, and many different types of products, including ureas, 18,22,27,33,36,51,69 urethanes, 70,71 oxamides, 72 formamides, 73 78 and oxazolidinones, 79 81 have been obtained. These ca rbonyla tions are generally 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 chapter highlights some selected recent a dvances in the transition metal cata lyzed oxidative carbonylation of amines to ureas.

PAGE 15

15 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. 47 Methods for oxidative carbonylation using PdCl 2 as catalyst with copper oxidants or O 2 as the terminal oxidant and CuX or CuX 2 as a mediator have been developed for preparation of ureas, 82 84 carbamates, 38,85 and oxamides. 38,69,86,87 T his section will highlight a few notable examples of the Pd catalyzed carbonylation of amines Homogeneous Carbonylation of A mines to Ureas Fukuoka 88 and Chaudhari 89 reported the oxidative carbonylation of alkylamines using Pd/C as catalyst and iodide salts as promoters in the presence of O 2 which afforded the corresponding ureas and/or carbamates in good yields. Related results have been reported by Gabriele 81 for the oxidative carbonylation of amines using PdI 2 and O 2 which led to formation of ureas, carbamates, and their cyclic derivatives in good yields. New conditions for the PdI 2 catalyzed oxidative carbon y lation of amines to ureas (Figure 1 1 ), afforded ureas in high yields with turnover numbers as high as 4950. 41,90 Carbonylations o f primary aliphatic amines (Figure 1 1 R = alkyl) were carried out at 100 C under a mixture of CO, air, and CO 2 in the presence of a simple catalytic system consisting of PdI 2 in conjunction with a KI promoter. In the absence of CO 2 less satisfactory results were obtained. 90 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 predom inated 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 t he oxamide

PAGE 16

16 by reductive elimination. P rimary aromatic amines (Figure 1 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 aro matic amine enough to improve the activity. Figure 1 1. PdI 2 catalyzed oxidative carbonylation of amines to ureas. 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 comple x 1 formed in preequilibrium w ith starting materials (Figure 1 2 ). 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 t o Pd(II) by oxidative addition of I 2 which is regenerated through oxidation of HI by oxygen. This catalytic system proved to be effective for the synthesis of cyclic ureas from the corresponding diamines, with 1,3 dihydrobenzoimidazol 2 one o btained in 99 % isolated yield (Figure 1 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. 41

PAGE 17

17 Figure 1 2. Proposed m echanism of the PdI 2 catalyzed ox idative carbonylation of amines to ureas. Figure 1 3. PdI 2 cataly zed oxidative carbonylation of 1,2 benzenediamine Direct catalytic preparation of trisubstituted ure as with high selectivity (Figure 1 1 ) was possible under these con ditions if the primary amine were carbonylated in the presence of an excess of a secondary amine. 41 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 prim ary amino esters. A showcase synthesis of the neuropeptide Y5 receptor antagonist NPY5RA 972 was also reported (Figure 1 4 ). 41 Figure 1 4. Application of PdI 2 catalyzed oxidative carbonylation to the synthesis of neuropeptide Y5 receptor antagonist NPY5RA 972.

PAGE 18

18 Pd Cata lysis in Ionic Liquids Recently, many catalytic reactions have been reported to proceed in ionic liquids as reaction media with excellent results. 91 This approach has been adapted by Deng for Pd catalyzed carbonylation of amines to ureas. 92 A solubility s tudy of the catalyst Pd(phen)Cl 2 establishe d that the ionic liquids BMImBF 4 (BMIm = 1 but yl 3 methylimida zolium), BMImPF 6 BMImFeCl 4 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 t he presence of O 2 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 act s as a heterogenized catalyst for the 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 t he corres ponding ureas (Figure 1 5 ). 93 No additional oxidant is necessary since the nitrobenzene serves as both substrate and oxid ant. 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/O 2 mixtures. The authors suggested that the enhanced catalytic activity of this system may be deriv ed from the high concentration of ionic liquid containing the metal complex confined within the cavities of the silica gel matrix. 93 Experiments with the ionic liquids DMImBF 4 (1 decyl 3 methylimidazolium tetrafluoroborate) and EMImBF 4 (1 ethyl 3 methylimidazolium tetrafluoroborate) and the catalysts HRu(PPh 3 ) 2 Cl 2 Rh(PPh 3 ) 3 Cl, Pd(PPh 3 ) 2 Cl 2 and Co(PPh 3 ) 3 Cl 2 afforded good to

PAGE 19

19 e xcellent yields of N N diphenylurea (DPU) from nitrobenzene and aniline. The Rh DMImBF 4 /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 substitute d ureas could also be achieved with this particular catalyst. Figure 1 5. Pd catalyzed carbonylation using ionic media. Electrocatalytic Carbonylation Another method for the synthesis of alkylureas is the electrocatalyt ic carbonylation of aliphatic amines, as reported by Deng. 94 Electrocatalytic carbonylation of a series of aliphatic amines to dialkylureas and isocyanates using Pd(II) complexes with a Cu(II) coc atalyst could be achieved under mild reaction conditions, with particularly good results for primary amines (Figure 1 6 ). The additional steric hindrance in secondary amines apparently prevents the reaction, as diisopropyl amine was unreactive under the s ame 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. Figure 1 6. Pd (II)/ Cu(II) catalyzed elec trocatalytic carbonylation of aliphatic amines

PAGE 20

20 Although products were obtained with a single complex as catalyst [Cu(OAc) 2 PdCl 2 or Pd(OAc) 2 ], catalytic activity and selectivity for the urea were improved when both a Pd complex and Cu(OAc) 2 were present i n the reaction mixtures. Quantitative conversion and 98% selectivity for the urea were achieved in the case of n butylamine with Pd(PPh 3 ) 2 Cl 2 and Cu(OAc) 2 94 The authors suggested a synergistic e ffect between Pd(II) and Cu(II), as opposed to simple mediation of electron transfer, which had been invoked in a related case of electrocatalysis. 95 N Heterocyclic Carbene Palladium Complexes N H eterocyclic carbe ne (NHC) complexes h ave been studied extensively for their roles in carbonyla t i on reactions 96,97 Reactions such as hy d roformylations 97 have benefited from the use of NHC ligands. Reali zing their potential, Xia and coworkers used NHC ligands in a series of palladium complexes for the catalytic carbonylation of amines to ureas ( Figure 1 7 ) 98 Using CO and O 2 a liphatic and aryl amines were converted to their corresponding ureas in good yields and high selectivity, with as low as 0.02 mol% of catalyst. Yields of aryl ureas were greatly affected by electron donating or electron withdrawing substituen ts at the para position of the aniline with the latter hindering reaction yields Ali phatic amines were less selective due to the formation of formamides and oxamides as byproducts. Optimal results were obtained for aliphatic amines when the temperature was lowered and the solvent changed from DMF to dimethoxyethane.

PAGE 21

21 Figure 1 7. Pd NHC catalysts. Supported Palladium Nanoparticles While most palladium oxidative catalysts in carbonylation have been homogeneous, there hav e been some examples of the use of supported palladium catalysts. While testing a variety of catalysts for the oxidative carbonylation of methylamine, Chaudhari and coworkers found that the palladium containing ZSM 5 zeolite catalyst gave good conversion of amine with a high selectivity for the formation of the urea over the carbamate. 89 Very recently, Chaudhari has revisited the concept by employing Pd nanoparticles as a catalyst for the oxidative carbonylation of amines. 37 Palladium nanopar ticles were anchored on zeolites by using 3 aminopropyl trimethoxysilane (APTS) as an anchoring agent ( Figure 1 8). Using an 8:1 CO:O 2 gas mixture, simple aryl and aliphati c amines were converted to the corresponding ureas in high conversion and selectivi ty. The authors also found that catalyst turnover frequency (TOF) compared favorably to commercial Pd catalysts despite a previous report 66 that Pd nanoparticles were inactive for the reaction. Other parameters such as solvent, promoters, temperature and substrate concentration were studied to achieve optimal conditions. Moreo ver, the catalyst was recycled five times without any loss of conversion of the amine or selectivity for the urea. 37

PAGE 22

22 Figure 1 8. Representation of the i mmobilized pal ladium nanoparticle ([Pd] APTS Y) catalyst. Mechanistic S tudies P rogress has also been made in understanding the mechanism of the car bonylation of amines to ureas Shimizu and Yamamoto have reported a mechanistic study focusing on the role of the reoxidat ion 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. 72 Their work revealed the importance of the oxidant in selectivity as 1,4 dichloro 2 butene (DCB) afforded oxamides f rom primary and secondary amines while use of I 2 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 p reviously proposed by Alper. 69 The crucial step in the second possible route involves formation of an intermediate alkyl isocyanate from an N

PAGE 23

23 monoalkylcarbamoylpalladium speci es ( 3 Figure 1 9 ). 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 Gab riele for a related system. 90 Support for the isocyanate pathway came from the inability of secondary amines to form tetrasubstitute d 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 NEt 3 72 Figure 1 9 Mechanism for the Pd catalyzed conversion of primary amines to ureas. 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. 27 Giannoccaro obtained N N dialkylureas,

PAGE 24

24 rather than the previously reported oxamides, 28 by reacting aliphatic primary amines with the nickel amine complexes NiX 2 (RNH 2 ) 4 (X = Cl, Br; R = alkyl). However, yields lower temperatures the reductive step, in which amine carbonylation occurs, failed. The product selectivity depended on the amou nt of water present, with anhydrous conditions favoring the oxamide, while the presence of water p ro moted urea formation (Figure 1 10 ). The authors suggested that water could coordinate to the nickel center, allowing the formation of only one carbamoyl gr oup. Under aqueous conditions, this intermediate would then undergo nucleophilic attack by the amine to form the urea. In the absence of water, oxamide would arise from reductive elimination of two carbamoyl groups. 27 Figure 1 10 Pathways for the Ni catalyzed carbonylation of amines to ureas. Ruthenium Catalyzed Oxidative Carbonylation Gupte utilized ruthenium catalysts for the s elective formation of N N diphenylurea (DPU) from the oxidative carbonylation of aniline. 33 High selectivity (99%) for the formation of DPU was obtained with [Ru(CO) 3 I 3 ] N Bu 4 as the catalyst and NiI as the

PAGE 25

25 promoter. The key step in the proposed mechanism involves the formation of carbamoyl species 8 (Figure 1 11 ). Loss of CO from the catalyst precursor [Ru(CO) 3 I 3 ] generates intermediate 5 which reacts with aniline to fo rm 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 O 2 to regenerate the active species 6 (Fig ure 1 11 ). 33 Related chemistry with alkylamines has been reported by Chaudhari. 89,99 Figure 1 11 Mechanism of the [Ru(CO) 3 I 3 ]NBu 4 catalyzed carbonylation of aniline.

PAGE 26

26 Cobalt and Rhodium Catalyzed Oxidative Carbonylation Rindone reported the synthesis of acyclic and cyclic ureas fr om aromatic primary amines, using N N bis(salicylidene)ethylenediaminocobalt(II) ([Co(salen)]) as the catalyst. 22 Optimal reaction conditions varied with the substrate. For example, the urea yields from 4 methylaniline were higher at high pressure of O 2 while 4 fluoroaniline reacted better at lower O 2 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. 100 The proposed mechanism involved equilibrium between planar and non planar salen ligands ( 11 and 12 ) on a cobalt (III) amido complex, either of which could undergo carbon monoxide insertion to give an equilibrium mixture of carbamo yl complexes 13 and 14 Compound 13 having the planar salen ligand and a trans relationship between the carbamoyl and amine ligands, could lead to free isocyanate or carbamate, while complex 14 having a nonplanar salen and a cis relationship between the carbamoyl and amine ligands, would lead to t he urea (Figure 1 12 ). 22 Claver prepared modified [Co(salen)] complexes (Figure 1 13) and utilized them as catalysts for oxidative carbonylation of aniline. 101 Results revealed that the t butyl substituted catalyst 16 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 19 also showed high s electivity (94%) for the urea.

PAGE 27

27 Fi gure 1 12 Carbonylation mechanism of cobalt salen complexes. Figure 1 13. Co(salen) ( 15 ) and modified Co(salen) complexes ( 16 20 ).

PAGE 28

28 Efforts in the rhodium catalyzed carbonylation of amines to ureas have been sparse. An early study by Chaudhari investigated various factors that affect activity and selectivity of rhodium catalyzed oxidative carbonylation. 102 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 wa s determined to be best for the catalytic process. Using th is catalyst, polar solvents such as acetonitrile or DMF favored formation of diphenylurea, while most other solvents favored the carbamate. Modifying pressure, temperature, and concentration also affected selectivity and activity. 102 Giannoccaro reported preparation of Rh 3+ and Rh 3+ dia mine complexes titanium phosphate (TiP), and measured their activity towards oxidative carbonylation of aniline. 103 Intercalation provided a way to heterogenize an otherwise homogeneous catalyst. Typic al conditions involved acetonitrile or methanol as the solvent, a CO/O 2 mixture at atmospheric or higher pressure, temperatures between 70 3 + I as a promoter. The highest catalyst activities were obtained with increased press ure of the CO/O 2 mixture, higher temperature, and a molar ratio of co catalyst to Rh 3+ (PhNH 3 + I / Rh 3+ ) between 5 and 6. It was found that the materials containing simple Rh 3+ salts worked better than those prepared from Rh 3+ diamine complexes. The key in termediate in the postulated reaction mechanism (Figure 1 14) is the Rh 3+ carbamoyl complex 21 which reacts with molecular iodine to form the iodoformate intermediate, ICONHPh. The latter reacts with aniline to afford diphenylurea. 103

PAGE 29

29 Figure 1 14 Rhodium intercalated into tit anium phosphate catalyzes the c arbo nylation of aniline to diphenyl urea. Gold Catalyzed Oxidative Carbonylation Deng has investigated gold compounds as catalysts for t he carbonylation of amines. 66,78,104 106 Although simple Au(I) salts afforded carbamates from aniline, the reactions of aliphatic amines also yielded the urea in some cases. 104 Polymer immobilized gold catalysts, prepared from commercially available ion exchange resins and HAuCl 4 were found to catalyze the carbonylat ion of aryl amines to their methyl carbamates in the presence of methanol. 66 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 CO 2 could afford symmetrical dialkylureas with high yields and turnover frequencies (Figure 1 1 5 ). 106 The mechanism is unclear, but it was postulated that the high activity can be

PAGE 30

30 attributed to some synergistic relationship between gold nanoparticles and the polymer support. Figure 1 15 Carbonylation of aryl and a liphatic amines using a polymer supported gold catalyst Angelici used gold powder to convert primary amines to ureas in mild conditions with CO and O 2 68,107 With a 2.5:1 ratio of CO and O 2 at approximately 1 atm in acetonitrile at 45 C, ureas were the major products after 24 h of reaction time. Steric bulk and nucleophilicity of the amine played a role in the yields of the ureas. Alkyl and aryl amines were both suitable substrates, though yields were lower for a ryl ureas because of their lower nucleophilicity. The key species in the proposed mechanism is an isocyanate, which reacts with an additional amine to form the urea product. Trace isocyanate detected in some of the reactions support the claim. Furthermo r e, secondary amines do not form tetrasubstituted ureas, which is consistent with the isocyanate mechanism Unsymetrical ureas were synthesized when equimolar amounts of primary amine and secondary amine were used. Because secondary amines are more nucle ophilic towards isocyanates, unsymmetrical ureas were often the only product. 68 Tungsten Catalyzed Oxidative Carbonylation of Amines Carbonylation of Primary Amines Despite extensive investigation of transition me tal catalyzed carbonylation reactions, examples involving Group 6 metals still remain rare. During the last 15 years though, there have been examples of conversion s of amine substrates to the

PAGE 31

31 corresponding ureas using tungsten carbonyl complexes as the c atalysts and I 2 as the oxidant. The initial report described catalytic oxidative carbonylation of primary amines using the iodo bridged tungsten dimer [(CO) 2 W(NPh)I 2 ] 2 ( 22 ) as the precatalyst. 56 During those studies, it was shown that primary aromatic and aliphatic amines could be carbonylated to 1,3 disubstituted ureas, while secondary amines afforde d formamides in modest yields. Mechanistic studies on thi s process established that primary amines reacted stoichiometrically with dimer 22 to yield the amine complexes (CO) 2 I 2 W(NPh)(NH 2 R) ( 23 ) (Figure 1 16), which undergo reaction with excess amine to afford the corresponding ureas. 58 Nucleophilic attack of the amine on a carbonyl ligand of 24 followed by proton abstraction using a second equivalent of the amine would afford carbamoyl complex 2 5 IR spectra of the reaction mixtures were consistent with the presence of carbamoyl complexes. The intermediacy of carbamoyl complex 25 is precedented by Angelici's work on the carbonylation of CH 3 NH 2 by [( 5 C 5 H 5 )W(CO) 4 ]PF 6 108 for which the first step is conversion of [( 5 C 5 H 5 )W(CO) 4 ] + to the carbamoyl complex ( 5 C 5 H 5 )W(CO) 3 (CONHCH 3 ) upon reaction with 2 equiv of CH 3 NH 2 Assignment of the next step as oxidation was supported by IR spectra that showed the disappearance of the carbamoyl stretches after the reaction mixtur es were exposed to air. It is expected that following oxidation of the complex, the carbamoyl proton would be more acidic and deprotonation of 25 with the excess amine would produce the isocyanate complex 26 Nucleophilic attack of an amine on either coo rdinated or free

PAGE 32

32 isocyanate would afford the 1,3 disubstituted urea, producing coordinatively unsaturated complex 27 which could undergo addition of CO to regenerate cationic intermediate 24 and close the catalytic cycle (Figure 1 16). Figure 1 16. Carbonylation of primary aliphatic and aromatic amines using a tungsten carbonyl complex. The previous results implied that other tungsten carbonyl iodide complexes might also serve as catalysts. The simplest choice as precata lyst was the readily available, inexpensive, and air stable tungsten hexacarbonyl ( W(CO) 6 ) Preliminary studies were

PAGE 33

33 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 e quiv of iodine, and 100 equiv of K 2 CO 3 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. 58 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 /I 2 oxidative carbonylation system. 59 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 K 2 CO 3 and a chlorinated solvent such as CH 2 Cl 2 or CHCl 3 Using these conditions, though, the conve rsion of aniline to diphenylurea failed 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 11,12 Most of them are stoichiometric reactions based on nucleophilic attack of amines on phosgene and related derivatives. Catalytic oxidative carbonylation of diamine substrates provides a n 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 Mn 2 (CO) 10 catalyzed carbonylation of the diamines H 2 N(CH 2 ) n NH 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 was obser ved when n = 3. 109 The catalytic carbonylation of diamines to cyclic ureas was thus explored using W(CO) 6 as the cat alyst, I 2 as the oxidant, and CO

PAGE 34

34 as the carbonyl source. 57 Both primary and secondary diamines were substrates for the reaction, wit h 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 go od yields (Figure 1 17 ), 57 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, (+) (1 R ,2 R ) 1,2 diphenyl 1,2 ethanediamine was carbonylated to the 2 imidazolidinone in 46% yie ld with no epimerization. Reaction of the secondary diamines RNHCH 2 CH 2 NHR (Figure 1 17 R = Me, Et, i Pr, Bn) under similar conditions resulted in conversion of the diamines to the corresponding N,N disubstituted cyclic ureas. For both primary and second ary 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. 110 Figure 1 17 Carbonylation of primary and secondary diamines using W(CO) 6 /I 2 as the catalyst. Steric effects on the ring closure react ion were probed by the carbonylation of N N dimethyl, diethyl, diisopropyl, and dibenzyl diamines under the standard conditions. 57 As expected, 1,3 diethyl 2 imidazolidinone and 1,3 dimethyl 2 imidazolidinone were produced in nearly identical yields. Changing the substituents to

PAGE 35

35 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 b e 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 cycl ic urea in preference to acyclic urea formation through the more reactive primary amines. 57 A more extensive study on the carbonylation o f 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 I 2 as the oxidant. 111 Effects of solvent and temperature variation on th e 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 1 ). 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 effect and improved solubility in o rganic solvents during workup. Table 1 1 Tungsten c atalyzed oxidative carbonylation o f substituted primary d iamines Amine Product % Yield 52 80

PAGE 36

36 Table 1 1. Continued Amine Product % Yield 70 48 50 33 38 Figure 1 18. Gem dimethyl secondary diamines form ureas and tetrahydropyrimidine The carbonylation of N N dialkyl 2,2 dimethylpropane 1,3 diamines afforded tetrasubstituted ureas; however, the products were obtained in modest yields, and tetr ahydropyrimidine byproducts were formed in significant amounts when the substrates bore N alkyl substituents larger than methyl (Figure 1 18) Comparison of these results with the carbonylations of secondary diamines to form five membered

PAGE 37

37 cyclic ureas sug gested that the effects of ring size and N substituent size on the carbo nylation reaction are complex. Success with conversion of diamines to cyclic ureas suggested the use of W(CO) 6 catalyzed oxidative carbonylation in the synthesis of complex targets. H owever, 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 su bst ituted benzylamines ( Figure 1 19 Table 1 2) demonstrated that the oxidative carbonylation of amines using the W(CO) 6 /I 2 system is tolerant of a wide variety of functionality, including halides, esters, alkenes, and nitriles. A distinguishing feature i s the tolerance of unprotected alcohols, which would be problematic with phosgene derivatives. 59 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 ord er 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 (K 2 CO 3 ). The biphasic solvent system provides p hase transfer conditions in which the amine salt can be deprotonated by aqueous carbonate and then returned to the organic phase for carbonylation. Figure 1 19 Substituent study of the W(CO) 6 /I 2 catalyzed carbonylation o f benzylamines.

PAGE 38

38 Table 1 2 Tungsten c atalyzed c atalytic carbonylation of substituted benzylamines to u reas Amine %Yield 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 70 17 20 0 0 a Reaction conditions: amine (7.1 mmol), W(CO) 6 (0.14 mmol), I 2 (3.5 mmol), K 2 CO 3 (10.7 mmol), CH 2 Cl 2 b The solvent was CH 2 Cl 2 (21 mL) plus H 2 O (3 mL) After broad functional group tolerance during W(CO) 6 /I 2 catalyzed oxidative carbonylation of amines to ureas had been established, 59 use of this methodology to install the urea moiety into the core struc ture of the HIV protease inhibitors DMP 323 and DMP 450 (F igure 1 20 ) 112,113 was investigated 114 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.

PAGE 39

39 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 ph osgene derivative 1,1' carbonyldiimidazole (CDI) 113,115 117 followed by N alkylation as appropriate. The practical preparation of DMP 450 involves reaction of secondary diamine with phosgene to form the cyclic ure a. Since use of phosgene or CDI requires protection of the diol, extensive protecting group studies have been carried out. 115,118 Three of the previously described O protected diamine diols, acetonide 28 118 MEM ether 29 113,119 and SEM ether 30 113 were tested in the catalytic carbonylation reaction as r epresentative examples containing cyclic and acyclic protecting g roups, respectively (Figure 1 21 ). 114 Figure 1 20 Structures of the HIV protease inhibitors DMP 323 and DMP 450

PAGE 40

40 Figure 1 21 Tungsten catalyzed carbonylation of 28 30 Carbonylation of diamine substrates 28 30 (Figure 1 21 ) to the cyclic ureas 31 33 provided a means for comparison of the W(CO) 6 catalyzed process to the stoichiometric reactions of the phosgene derivative CDI. Varying results were obtained in the yields of the ureas from the catalytic reaction depending on the p rotecting group on the diol, as was also observed for ring closure with stoichiometric CDI (Table 1 3). These results demonstrate that the catalytic oxidative carbonylation reaction can be used to convert diamines to cyclic ureas in examples relevant to t he preparation of complex targets. Table 1 3 Tungsten c atalyzed carbonylation of d iamines 28 30 to u reas 31 33 Diamine Reagent Solvent Urea Yield Ref (%) 28 CDI CH 3 CN 15 115 28 CDI TCE 67 115 28 W(CO) 6 /CO CH 2 Cl 2 /H 2 O 38 114 28 W(CO) 6 /CO CH 2 Cl 2 23 114 29 CDI CH 2 Cl 2 62,76 113,116,119 29 W(CO) 6 /CO CH 2 Cl 2 /H 2 O 49 114 30 CDI CH 2 Cl 2 52,93 113 116 30 W(CO) 6 /CO CH 2 Cl 2 /H 2 O 75 114

PAGE 41

41 Efforts to avoid the protecting group chemistry in reported syntheses of DMP 323 and DMP 450 by carbonylating the diamine diol 34 were frustrated by the reaction of the diol hydroxyl gro ups to generate oxazolidinones 35 and 36 (Figure 1 22 ). 61 Oxazolidinone formation had also been reported as the result of reaction of 34 with CDI and phosgene. 120 The earlier functional group com patibility study had suggested that the catalyst was tolerant of OH groups ( Figure 1 19 Table 1 2) 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 p ossibility of formation of a cyclic carbamate. For that substrate, the corresponding urea was produced without competing carbamate or carbonate formation. 59 For diamine diol 34 oxazolidinone formation had been preferred under the reaction conditions tested. 61 Figure 1 22 Oxazolidin one formation from the tungsten catalyzed carbonylation of diol 34 More recently, the catalytic carbonylation of a series of amino alcohols of varying tether lengths and substitution patter ns was carried out to probe the selectivity of the W(CO) 6 /I 2 carbonylation system for reactivity of alcohols versus amines. The phosgene derivatives dimethyl dithiocarbamate (DMDTC) and 1,1' carbonyldiimidazole (CDI) were used as representative stoichiome tric reagents for comparison purposes. 61 A series of 1,2 1,3 1,4 and 1,5 aminoalcohol substrates was subjected to W(CO) 6 catalyzed oxidative carbonylation for evaluation of the selectivity of the W(CO) 6 /I 2 system towar d formation of the ureas or carbamates, either cyclic or acyclic (Table 1 4). As a

PAGE 42

42 comparison of the stoichiometric reactions of phosgene derivatives to the catalytic W(CO) 6 /I 2 methodology, the results of reaction of CDI and DMDTC with the amino alcohol s ubstrates also appear in Table 1 4. Table 1 4 Tungsten catalyzed o xidative c arbonylation of a minoalcohols to u reas and c arbamates. Substrate Reagent Urea (%) Cyclic Carbamate (%) W(CO) 6 /CO 64 2 CDI 80 trace DMDTC 45 0 W(CO) 6 /CO 93 0 CDI 70 trace DMDTC 93 0 W(CO) 6 /CO 95 trace CDI 36 60 DMDTC 30 8 W(CO) 6 /CO 72 14 CDI 49 30 DMDTC 34 47 W(CO) 6 /CO 60 5 CDI 55 28 DMDTC 32 29 W(CO) 6 /CO 78 10 CDI 18 22 DMDTC 72 trace W(CO) 6 /CO 79 14 CDI 30 52 DMDTC 73 trace The results indicated that the W(CO) 6 /I 2 methodology can indeed be applied to carbonylation of amino alcohols to the ureas without protection of the hydroxyl group. The W(CO) 6 catalyzed oxidative carbonylation was consistently selective for the urea

PAGE 43

43 over the cyclic carbamate for all tether lengths and substitution patterns studied. Acyclic carbamates were not detected in the reaction mixtures. In contrast, reactions of the phosgene derivatives CDI and DMDTC with 1,3 and 1,2 amino alcohol substra tes exhibited variable selectivities between ureas and cyclic carbamates. It is important to note that the reaction conditions for these studies were not the same as for the initial work on diamine diol 34 Optimized conditions for carbonylation of amino alcohols to the ureas involved use of pyridine as the base, removing the necessity for the biphasic solvent system used in the original functional group compatibility study. 59 Other interesting targets that were prepared to investigate the scope of the W(CO) 6 /I 2 system were biotin and r elated heterocyclic ureas. 121 Biotin ( 37b ), 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. 122 One recurring theme in these syntheses has been installation of the urea moiety by reaction of phosgene with a diaminotetrahydrothiophene derivative. Figure 1 23 Synthesis of biotin methyl ester ( 38b ) using the W(CO) 6 /I 2 catalyst system.

PAGE 44

44 Figure 1 24 Synthesis of biotin derivatives via the W(CO) 6 /I 2 catalytic system. A lthough biotin itself could not be produced directly from carboxylic acid 37a biotin methyl ester ( 38b ) was obtained in 84% yield upon W(CO) 6 catalyzed oxidative carbonylation of diamine 38a ( Figure 1 23 ) The related heterocycles 39b 42b were also prepared by the carbonylati on procedure and the yields compared to those obtained by reaction of the sam e substrates with CDI (Figure 1 24 Table 1 5). Yields of the ureas were moderate to good and depended on the solubility of the diamine a nd urea in methylene chloride. Table 1 5 Yields of bicyclic ureas from d iamines 39a 42a Amine Urea W(CO) 6 /I 2 a Yield CDI Yield 39a 39b Trace 20% 40a 40b 47% 67% 41a 41b 46% 37% 42a 42b 57% b 56% c a A ll reactions were carried out in CH 2 Cl 2 (40 mL) at room temperature under 80 atm of CO. Diam ine (1 mmol), W(CO) 6 (4 mol%), K 2 CO 3 (3 mmol), I 2 (1 mmol). b Yield based on diamine consumed (47%). c Yield based on diamine consumed (70%).

PAGE 45

45 Conclusions Transition m etal catalyzed carbonylation of a mines offers new and efficient methodology for the selec tive synthesis of ureas under relatively mild reaction conditions. Use of CO 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 stoichiome tric 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 oxid ative 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 transi tion 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 have 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 46

46 CHAPTER 2 CATALYTIC CARBONYLAT ION OF FUNCTIONALIZE D DIAMINES TO UREAS: APPLICATION TO DERIV ATIVES OF DMP 450 Introduct ion In response to the growing global pandemic that is the Acquired Immunodeficiency Syndrome (AIDS) considerable effort has been placed on researching novel therapy to treat its causative agent, Human Immunodeficiency Virus (HIV) Of the various treatme nt strategies under investigation, most have targeted the as partyl protease of the virus. As an alternative to multi drug cocktails or the modification of existing anti HIV drugs, novel agents were also used to improve medicinal profiles. An example of t hese novel agents were cyclic, non peptidic HIV protease inhibitors (NPPIs) 4 X ray crystal structures of HIV protease complexed with various p eptidic inhibitors showed the presence of a tightly bound water molecule between the inhibitor molecule and the beta strands of the HIV protease dimer ( Figure 2 1 ). This water molecule accepts two hydrogen bonds from amide backbone residues I1e 50 and I1e donates two hydrogen bonds to carbonyl groups in the inhibitor. Effective inhibition is achieved through the interactions between the two catalytic aspartyl residues and a hydroxyl group in the inhibitor molecule ( Figure 2 1 ). Comparative X ray structures of non peptidic protease inhibitors, however, revealed the absence of the water molecule. These inhibitors contained an already suitable hydrogen bond acceptor, such as a carbonyl or a sulfonyl group, which forms the necessary hydrogen bonds wi th the amide flaps directly, without the need for a water molecule. These cyclic protease inhibitors also contained hydroxyl groups in specific areas wh ich interacted with the aspartyl residues. It was anticipated that t he entropic advantage gained by th e absence of the

PAGE 47

47 water molecule coupled with the relatively constrained cyclic structure of the inhibitors would result in good selectivity against mammalian aspartyl proteases. 4 Figure 2 1. Comparison of binding motifs of peptide derived HIVPR inhibitors to a generic 6 membered ring cyclic NPPI. In 1994, the DuPont Merck grou p reported studies that led to the d iscovery of cyclic ureas as potent inhibitors of the HIV protease enzyme. 123 Using X ray structures and computational methods, the investigators found that a simple cyclohexanone ring A would be a suitable synthetic scaffold ( Figure 2 2 ) The ring was enlarged to a seven membered ring B and further modified to urea C Ureas, they reasoned, were already known as excellent hydrogen bond acceptors in nature an d in other synthetic systems. Additional studies also predicted the 4R,5S,6S, 7R stereochemistry as the optimal configuration as shown in structure D ( Figure 2 2 ). Figure 2 2. Structures A D show the path to the identification of the cyclic urea NPPI.

PAGE 48

48 Crystallographic data for the urea bound to the active site showed that the cyclic urea oxygen was positioned well to serve as a hydrogen bond acceptor to the aforementioned amide flaps of the host site. The data also showed that the diol functionality hy drogen bonds with the aspartyl residues ( Figure 2 3 ). A factor contributing to the potency was the preorganized, rigid conformation of the cyclic ureas, leading to complementary binding to the HIV protease (HIV PR) The preliminary data lead to the syste matic disc overy of the first generation cyclic urea compound, DMP 323. 123 Figure 2 3. Cyclic urea binding motif. DMP 323 was particularly highly pre org anized for binding at the active site of the HIV PR and performed well in preliminary in vitro studies and in animals. 113 However, clinical trials revealed poor aqueous solubility and variable human oral bioavailability. The compound was subsequently withdrawn from clinical trials Continued modification of the cyclic urea compounds focused on the N benzyl substituents. Extensive studies resulted in replacement of the p hydroxymethylbenzyl groups in DMP 323, with weakly basic m aminobenzyl substituents. This second genera tion cyclic urea DMP 450,

PAGE 49

49 exhibited similar potency as its predecessor, while the oral availability was significantly increased by the conversion to the bis mesylate salt. 119 Phase I clinical trials produced promising results, although it was found that large amounts and a multiple dosing schedule of DMP 450 were needed to reach proper levels for treatment. 119 At this time in the development of DM P 450, Avid Corporation acquired licensing rights to the drug, re named it Mozenavir, and continued the clinical t rials after merging with Triangle Pharmaceuticals 4,119 After concluding a phase I/II study comparing Mozenavir with leading HIV drug s the re sults suggested that Mozenavir w as well tolerated with only mild side e ffects. Despite the encouraging results, further studies were halted by Triangle Pharmaceuticals. 4 Synthesis of DMP 323 and DMP 450 In order t o obtain the necessary stereochemistry for optimum binding (RSSR), synthesis of DMP 323 and DMP 450 was derived from unnatural D phenylalanine. In the reported synthetic strategy ( Figure 2 4 ) 113 N (benzyloxycarbonyl) ( R) phenylalaninol 43 was oxidized under Swern conditions to the corresponding aldehyde. The aldehyde was then coupled using VCl 3 (THF) 3 and zinc to give diol 44 with a high diastereomeric purity o f the RSSR product (98:2, RSSR: RRRR). The diol was protected with (2 (trimethylsilyl) ethoxy) methyl chloride (SEMCl ) to afford 45 followed by removal of the benzyloxycarbonyl (Cbz) groups by hydrogenolysis. The diol could be protected with (2 methoxyethoxy)methyl chloride (MEMCl) as well. The crude diamine was cyclized with carbonyl diimidazole (CDI) to give the cy clic urea 33 Appropriate N alkylation of the urea followed by further reduction and deprotection of the diol produ ced the DMP co mpounds ( Figure 2 4 )

PAGE 50

50 Figure 2 4. Synthesis of DMP 323 and DMP 450 Synthesis of the cyclic urea HIVPR inhibitors was also achieved starting from L (+) tartaric acid ( Figure 2 5 ). Starting with isopropylidene dimethyl tartrate 47 reduction of the ester with DIBAL H and trapping the aldehyde with 1,1 dimethyl hydrazine produced 48 Chelation con trolled addition to the hydrazone gives the dihydrazine 49 H ydrogenolysis and c yclization with CDI produced urea 31 Cyclization to the urea was diffi cult when the diamine was acetonide protected due to ring strain imposed by the trans fused five member ed ring. This strain makes the approach of the two amino groups difficult. The ring strain was alleviated with the use of a six membered ring, trioxepane as the protecting group. 118

PAGE 51

51 Figure 2 5. Imine pathway for the synthesis of DMP 323 and DMP 450. A novel approach to the synthes is of the diamine precursors by Hanson and coworkers involved the use of phosphorus tethers in conjunction with ring closing metathesis (RCM) 124,125 Allylic amine 50 coupled with PCl 3 or RP(O)Cl 2 (R Cl), follow ed by RCM produced the P tethered 1,4 diamine 52 The P tether can be removed by treatment with HCl. Carbonylation with CDI or triphosgene and subsequent N benzylation afforded urea 54 Conversion of the olefin to the DMP 450 analogue 56 was accomplishe d via osmium mediated dihydroxylation of 55 (Figure 2 6) 124 Figure 2 6. Phosphorus tether and RCM pathway to DMP 450 analogue.

PAGE 52

52 Synthesis of DMP Analogues by Tungsten Cataly zed Carbonylation Although there are different synthetic pathways to the diamine precursor the installation of the urea moiety involved the use of phosgene, or a phosgene derivative This transformation, in addition to the health and environmental implica tions, also required protect ion of the diol functionality. Prior research using tungsten hexacarbonyl [W(CO) 6 ] as a catalyst for the catalytic oxidative carbonylation of diamines to ureas with iodine ( I 2 ) as the oxidant (Figure 1 17 ) 57,111 included its application to the synthesis of functionalized targets 61,114,121 It was fitting, then, to apply this methodology to the synthesis of the core urea structure of the DMP comp ounds 113,123 Since the use of phosgene or its derivatives such as CDI requires protection of the diol, an extensive study of protecting groups was carried out in order to find the best conditions. 115,120 Although protection of the diol functionality was integral to the success of the catalytic carbonylation reaction using the original reaction conditions, as it had been with stoichiom etric use of phosgene and its derivatives, yields from the carbonylation reaction were comparable to those obtain ed using stoichiometric methods (Figure 2 7) 114 Figure 2 7. Synthesis of the core DMP 450 structure by t ungsten catalyzed carbonylation Subsequent modification of the reaction conditions led to the selective catal ytic oxidative carbonylation of unprotected amino alcohols to ureas. 61 Using pyridine as the

PAGE 53

53 base and changing the work up allowed for good to excellent yields of ureas from a series of 1,2 1,3 1,4 and 1,5 amino alcoho ls. Good yields of urea 58 from the 1,2 amino alcohol 57 ( Figure 2 8 ) 61 suggested that it could be possible to synthesize the core structure of DMP 450 by catalytic carbonylation without protecting group chemistry. This pos sibility was explored by synthesizing a variety of diamine diols and converting them to the core structures of DMP 450 and its derivatives. Figure 2 8. Unprotected amino alcohol carbonylation by tungsten hexacarbonyl. S ubstrates for the carbonylation study were chosen from a series of primary and secondary diamine diols that would afford the core structure of DMP 450 and its derivatives. In order to assess the need for protecting group chemistry, the substrates included O protected, as well as unprotected hydroxyl substituents. All substrates were subjected to W(CO) 6 /I 2 catalyzed oxidative carbonylation. Depending on the substrate, carbonylation was achieved using two sets of reaction conditions the main differences b eing in base and solvent. In one procedure potassium carbonate was used as the base with a biphasic solvent system (CH 2 Cl 2 /H 2 O), while in a second procedure, the preferred base was pyridine with methylene chloride or dichloroethane (at 80C) as the solve nt. Carbonylation of Aminobutanediols The investigation began with the carbonylation of secondary diamines to tetrasubstituted ureas. The DuPont Merck synthetic procedures focused on making

PAGE 54

54 ureas from primary amines followed by alkylation of the urea. Us ing secondary amines as substrates could possibly allow for a complete structure after the carbonylation step, negating the need for N alkylation of ureas. The synthesis of the substrates started with a midation of the starting chiral tartrate 47 a 126 128 followed by reduction by lithium aluminum hydride 128,129 to afford the bis(amino)butanediol s 60a b in good yield s ( Figure 2 9 ). A simila r approach can be applied to obtain SEM protected diols 6 0 c and unprotected 60f (Figure 2 10) starting from the appropriate parent tartrate however, attempts at the reduction of 59d to provide 60d were unsuccessful. Due to purification issues, a different route was e mployed to synthesize c ompound 60 e Starting from the ditosylate 6 1 a minolytic ring opening of diepoxide 6 2 provided compound 60 e in quantitative yield ( Figure 2 10 ) Results from the carbonylation of aminobutanediols 60a f are summarized in Table 2 1. Figure 2 9. Synthesis of protected aminobutanediols 6 0a 60d

PAGE 55

55 Figure 2 10. Synthesis of u nprotected s ubstrate s 60 e and 60f Figure 2 11. Tungsten catalyzed catalytic carbonylat ion of 60a f From Table 2 1, it is apparent that the W(CO) 6 /I 2 catalytic carbonylation method can be applied to secondary diamines bearing the seven membered ring skeleton (Figure 2 11) The ureas were obtained in good yields whether or not the diol was p rotected. The method was also found to be somewhat substrate dependent; the unprotected N methyl variant 60 e took 48 hours to give a 42% yield of urea (Table 2 1, entry 4 ). Good yields were obtained for the acetonide protected substrates (Table 2 1, entr ies 1 and 2). The acetonide protected N methyl diamine 60a produced 58% of urea 63a and N benzyl diamine 60 c gave excellent yields of urea based on starting material consumed. When the protecting group was the acyclic SEM group, however, the diamine 60c did not react (Table 2 1 entry 3 ). The N benzyl, f ree diol 60 f produced only 10% of the corresponding urea (Table 2 1, entry 5) A portion of the starting material (25 %) was recovered in salt form, stemming from the inability of the base,

PAGE 56

56 pyridine, to deprotonate the resulting hydroiodide salt of the substrate. Substituting pyridine with DMAP or DBU did not increase the yield. It is important to note that the free diol substrates 60 e and 60 f formed their respective ureas without competitive formation of the cyclic carbamate. This is remarkable given the kinetic preference for the formation of 5 membered rings over the desired 7 membered rings. Table 2 1. Carbonylation of d iamines 60 a 60 f a Entry Aminobutanediol Product Yield b 1 60a 63a 58% 2 60b 63b 99% d 3 60c 63c 0% 4 60e 63e 42% c 5 60f 63f 10% a Reagents and c onditions: W(CO) 6 I 2 pyridine, 80 bar CO, CH 2 Cl 2 40C, 24h. b Isolated yields. c 48h. d Based on starting material consumed.

PAGE 57

57 Carbonylation of Aminohexanediols Given the success of the carbonylation of secondary diamines 60 a 60 f the method was applied to primary diamines with alkylation at the carbon alpha to the nitrogen. In orde r to extend the scope of the reaction methodology, the synthesis of bis(amino)hexanediols 60g and 60 h starting from the chiral amino alcohol 64 ( Figure 2 12 ) was employed 113,117,130 Swern oxidation of 64 followe d by vanadium mediated coupling affords diol 65 Protection of the diol to produce 66 a b and hydrogenolysis using cyclohexene as the hydrogen source gives O protected amines 60 g h Unprotected diol 34 can be obtained by the direct hydrogenolysis of 44 ( Figure 2 13 ) Figure 2 12 Synthesis of diamines 60 g and 60 h For methyl diamine s 60 f and 60 g ureas were obtained in good yields regardless of whether the protecting gro up was acetonide or SEM (Table 2 2 entr ies 1 and 2). The protecting group preference was more apparent with a benzyl gr oup in the position( Table 2 2, entries 3 and 4). 114 In addition, the core structure of DMP 450 could be obtained from diamine 34 without protection of the diol (Figure 2 14 ), though the reaction suffered from low conversion (54%) due to the formation of the amine salt, and

PAGE 58

58 also oxaxolidin one s 35 and 36 from participation of hydroxyl groups in the cyclization T he quantities of urea 6 3 i were highest after 16 hours with increased temperature (80 C) and dichloroethane as the solvent. Figure 2 13 Hydrogen olysis of 44 to obtain diamine diol 34 Table 2 2. Carbonylation of d iamines 60 g 60 h 28 and 30 a Entry Amine Product Yield b 1 60g 63g 83% 2 60h 63h 75% 3 28 31 36% 114 4 30 33 75% 114 a Reagents and c onditions: W(CO) 6 I 2 K 2 CO 3 80 bar CO, CH 2 Cl 2 /H 2 O, 40C, 24h. b Isolated yields.

PAGE 59

59 Figure 2 14 Carbonylation of diamine 34 leads to mixed products With the success of the carbonylation of the aminohexanediols (Tabl e 2 2) the methodology was applied to secondary diamines with alkylation at the position ( Figure 2 15 ). N Methylation of 66 a d followed by deprotection of the Cbz group affords 60 j m in modest to good yields. Figure 2 15 Attempted synthesis of 63j m Table 2 3. Conditions attempted for the car bonylation of 60j m Entry A mine Base Solvent, Temp (C) 1 60j Pyridine CH 2 Cl 2 80C 2 60j DBU CH 2 Cl 2 40C 3 60k Pyridine CH 2 Cl 2 40C 4 60k Pyridine DCE, 40C 5 60k Pyridine DCE, 80C 6 60k DBU CH 2 Cl 2 40C 7 60k DBU DCE, 80C 8 60l Pyridine CH 2 Cl 2 40 9 60m Pyridine CH 2 Cl 2 40C 10 60m Pyridine CH 2 Cl 2 80C

PAGE 60

60 Figure 2 16. Conformational analysis of 7 membered cyclic ureas predicting that A is preferred when the nitrogens are not substituted, while B is preferre d when the nitrogens are substituted 113 Attempts at the synthesis of ureas 63j m by carbonylation were met with difficulty (Table 2 3). The substrates did not react using standard conditions from the synthesis of ureas 63 a f ( W(CO) 6 /I 2 pyridine, 80 bar CO, CH 2 Cl 2 40 C, 24h ) Increasing the temperature to 80 C, while using dichloroethane as the solvent, also proved un successful. In addition, using the stronger base DBU often resulted in decomposition of the starting material. It seems that substitution at both the nitrogen carbon is a detriment to the success of the reaction, possibly due to steric reasons. As seven membered rings, the urea products can exist in two pseudo chair conformations. Conformational analysis of the urea product reveals that there is a p referred conformation (conformation B Figure 2 16 ) when the nitrogens are substituted due to allylic 1,2 strain. 113 The opposite configuration (conformation A Figure 2 16 ) is preferred when the nitrogens are not substituted due to 1,3 diaxial strain. Based on the

PAGE 61

61 analysis i t can be presumed that the second ary amines are unable to adopt the necessary configuration to form the urea when b ound to the metal Building on previous success with the synthesis of the O protected core str ucture of DMP 450, it is shown that the W(CO) 6 /I 2 catalyzed carbonylation reaction can be applied to similar functionalized diamine substrates. Furthermore, the subsequent ureas can be obtained without protection of the diol in several cases. The synthesis of tetrasubstituted ureas can also be achi eved, although steric constraints tend to lower the yields of the ureas. T he tetrasubstituted ureas cannot be synthesized however, with substitution at the carbon. Even with these limitations, the scope of the W(CO) 6 /I 2 catalyzed carbonylation of amin es to ureas has been successfully extended to include the synthesis of analogues of DMP 450.

PAGE 62

62 CHAPTER 3 CATALYTIC OXIDATIVE CARBONYLATION OF ARY L AMINES TO UREAS Introduction N,N D isubstituted urea s have numerous applications in areas such as pharmaceu ticals 131 133 pesticides 1,3 and dyes 9,134 Traditional synthetic route s for the synthesis of ureas involve the use of phosgene or phosgene derivatives However, phosgene poses handling issues due to its toxicity, while its derivatives produce undesirable byproduct s 13 I n light of these problems developing a less hazardous synthetic route for urea s ha s attracted considerable interest over the years 37,93,135 137 Transition metal catalysts have shown promise as an alternative route to the synthesis of ureas from amines 138 Reaction conditions typically involve amines, an oxidant, and CO as the carbonyl source. C atalyst s including complexes of Pd 37 53 Ni 27 29 Co, 22 26 Ru, 30 34 and Au 65 68 have been employed for the oxidative carbonylation of amines to ureas. For example, Pd ( OAc) 2 a fforded good to high yields of ureas from aryl and alkyl amines as well as carbamates from amino alcohols. 53 Other palla d ium complexes, such as Pd(PPh 3 ) 2 Cl 2 93 h ave also been utilized A NiI / [Ru(CO) 3 I 3 ]NBu 4 33 catalyst system showed excellent reactivity for the selective formation of N N diphenylurea from the oxidative ca r bonylation of aniline. P revious report s have shown th at W(CO) 6 is a good catalyst for the oxidative carbonylation of various aliphatic primary and secondary diamines 57,111 However, early experiments suggested that aryl amines were not suitable substrates for this reaction, as the oxidative carbonylation of aniline to N N di phenylurea was unsuccessful when K 2 CO 3 was used as base 59 Manipulating reaction conditions though, has led to the W(CO) 6 /I 2 catalyzed oxidative carbonyla tion of aniline ( Figure 3 1 ) and other p

PAGE 63

63 substituted aryl amines ( Figure 3 2 ) to their respective aromatic urea s. I n addition, in c ertain cases, aryl amines could be carbonylated to unsymmetrical ureas using this catalytic system. Results and Discussion Initially, carbonylation reaction conditions for the conversion of aniline to N N diphenylurea were screened ( Figure 3 1 ) Variable s such as temperature, solvent, CO pressure and equivalents of base were examined and the results are described below (Table 3 1). Fig ure 3 1. S ynthesis of N N diphenylurea via W(CO) 6 /I 2 carbonylation. Table 3 1 Optim ization of the reaction conditions for the W(CO) 6 / I 2 catalyzed carbonylation of a niline to N N diphenylurea. Entry Base Temp ( C) Time (h) CO (atm ) Equiv a (I 2 :Base) Yield (%) b,c 1 DBU 40 20 80 1 : 2 Trace 2 Pyridine 40 20 80 1 : 2 Trace 3 DMAP 40 20 8 0 1 : 2 81 4 DMAP 40 20 80 1 : 1 52 5 DMAP 40 20 80 1 : 3 59 6 DMAP 40 20 80 0.5 : 2 79 7 DMAP 25 20 80 1 : 2 60 8 DMAP 60 20 80 1 : 2 78 9 DMAP 80 20 80 1 : 2 72 10 DMAP 40 4 80 1 : 2 39 11 DMAP 40 8 80 1 : 2 85 12 DMAP 40 8 40 1 : 2 34 13 DMAP 40 20 60 1 : 2 61 a Based on 1 equiv aniline. b Isolated yield of diarylurea calculated per equivalent of aniline c Reaction conditions: aniline ( 5 .0 mmol), 3 mol % W(CO) 6 40 mL CH 2 Cl 2 others as listed in table.

PAGE 64

64 Optimization of R eaction C onditions fo r Oxidative Carbonylation of A niline to N N D iphenylurea Initial experiments involved the carbonylation of an i line (0.46 g, 5 mmol) in the presence of 1.5 mol % W(CO) 6 1.0 equiv of I 2 and 2.0 equiv of base in 40 mL CH 2 Cl 2 with 80 atm C O, stirred at 40 C for 20 h (Table 3 1) Using d iaza(1,3)bicyclo[5.4.0]undecane (DBU) or pyridine as the base only produced trace amounts of the desired product (Table 3 1, entries 1 and 2). Alternatively, substituting 4 d imethylaminopyridine (DMAP ) as the base dramatica lly increased the yield to 81% (Table 3 1, entry 3). Lowering the amount of DMAP to 1 equiv resulted in a reduced isolated yield of 52% and observation of unreacted starting material (Table 3 1, entry 4 ) Furthermore, increasing the amount of DMAP t o 3 e quiv alents produced a similar yield ( 59% Table 3 1, entr y 5). Following th ese experiments 2.0 equiv alents of DMAP was chose n for further optimization studies. Once DMAP had been established as the preferred base, the quantity of iodine was optimized L ower ing the amount of the oxidant to 0.5 equiv alents resulted in a 79% yield (Table 3 1, entry 6) The highest activity was obtained when the mole ratio of I 2 to D MA P was 1:2. The temperature was then var ied from 25 C to 80 C ( Table 3 1 entr ies 7 9 ). When the temperature was lower than 40C, only 60% yield was obtained The yield improved when the temperature was increase d to 60 C, but decreased slightly at 80C Further increases in the temperature caused the yields to decrease, most likely due to de gradation of the urea product at higher temperature or the appearance of other byproducts T he carbonylation yields were also determined as a function of time ( Table 3 1 entr ies 10 11 ) At 40 C and 4 h, the yield of N N diphenylurea decreased significan tly

PAGE 65

65 to 39%, while at 8 h the urea yield was 85% which was an improvement from previous trials at 20 h. Therefore, the optimal time for the carbonylation was determined to be 8 h. T he CO pressure was found to be critical to the yield of urea in this react ion ( Table 3 1 entries 11 12 ). A s the CO pressure was decrease d to 8 0 atm and 40 atm, the yield s were markedly lower ed to 85 % and 34%, respectively. At 60 atm of CO, the urea was obtained in moderate yield (Table 3 1, entry 13). Therefore, the optimal conditions for the carbonylation reaction were determined to be 40 C, 80 atm CO, 1 equiv of I 2 2 equiv of DMAP, and CH 2 Cl 2 as solvent. Selected primary aryl amines were then convert ed into the ir corresponding N N disubstituted ureas using these conditi ons. O xidative C arbonylation of p S ubstituted Aryl A mines to S ymmetrical D iarylureas To explore the scope of the reaction for possible application in organic synthesis, a study of functional group tolerance was undertaken. Various substituted aryl amine s ( Figure 3 2 ) were convert ed to symmetrical N N diarylureas under the o ptimized carbonylation conditions (Table 3 2) Figure 3 2. O xidative c arbonylation of v arious p substituted aryl amines to s ymmetrical N N d iaryl ureas Table 3 2. O xidative c arbonylation of various aryl a mines to symmetrical N N ` diarylureas u sing the W(CO) 6 / I 2 catalyst system E ntry Amine Urea Yield a,b (%) 1 67 a R = H 68 a R = H 8 5 2 67 b R = p Cl 68 b R = p Cl 6 8

PAGE 66

66 Table 3 2. Continued Entry Amine Urea Yield a,b (%) 3 67 c R = p I 68 c R = p I 68 4 67 d R = p Br 68 d R= p Br 64 5 67 e R = p OMe 68 e R = p OMe 38 6 67 f R = p NO 2 68 f R = p NO 2 84 7 67 g R = p CN 68 g R = p CN 48 8 67 h R = p COOEt 68 h R = p COOEt 83 9 67 i 68 i 4 1 10 67 j 68 j 0 11 67 k R = p CH 2 OH 68 k R = p CH 2 OH 0 12 67 l R = p COOH 68 l R = p COOH 0 a Reaction c onditions: 5.0 mmol of a ryl aniline, 3mol % W(CO) 6 5 .0 mmol I 2 10.0 mmol DMAP, in 40 mL CH 2 Cl 2 40 C, 80 atm CO 8 h. b Isolated yield based on aryl amine T he effect of halogen substituents was evaluated first. The yield of urea 68 b from 4 chloroaniline 67 b was good (68 % Tabl e 3 2, entry 2 ) Bromo ( 67 c ) and iod o substituted ( 67 d ) amines afforded their respective N N disubstituted ureas in nearly identical yield s (Table 3 2, entr ies 3 4) In contrast to the halogenated anilines, substitut ion with the electron donating metho xy group ( 67 e ) resulted in a significant decrease in the yield of urea ( 38% Table 3 2, entry 5), w hile the electron poor p nitroaniline 67 f was successfully carbonylated to its urea in 84% yield This trend of higher yields with electron withdrawing subs tituents is followed by e thyl aminobenzoate

PAGE 67

67 67 h ( 83% Table 3 2, entry 8 ). An exception is 4 aminobenzonit r ile 67 g which affords just 48% of the urea (Table 3 2, entr y 7 ) despite its electron withdrawing cyano substituent. However, the ability of the n itrile moiety to serve as ligand for the catalyst may be affecting the yield. In prior studies on p substituted benzyl amines, 59 amines with coordinating substituents such as carboxylates gave poor yields under the original reaction conditions. Figure 3 3. Iodo deboronation of aminophenylboronic ester 67 m I n addition, we also investigated the aromatic amine 67 i under the carbonylation conditions, which formed the cyclic urea 3,4 dihydro 2 quinazolinone in 41% yield This result was an improvement compa red to the original reaction conditions using K 2 CO 3 as base in which the yield of the urea was 10% yield. 59 Boronic esters were also tested for compatibility under carbonylation conditions. Interestingly, attempted catalytic carbonylation of 4 aminophenylboronic ester 67 m did not resul t in the formation of urea, but rather p iodoaniline 67 c (Figure 3 3). Control experiments found that the p iodoaniline 67 c was also formed from 67 m at room temperature in the absence of CO and the W(CO) 6 catalyst. This observation is not unprecedented, as iodo deboronation has been observed in the reaction of alkenylboranes in the presence of I 2 and sodium

PAGE 68

68 hydroxide in ethereal solvents. 139,140 F urther functional group studies included 4 aminostyrene, 4 aminoben zylalcohol, and 4 aminobenzoic acid ( 67 j 67 l ) U nfortunately, none of their corresponding ureas could be detected in the reaction mixtures (Table 3 2, entries 10 12) These results are also consistent with the prior study on substituted benzyl amines, whe re the same substituents resulted in lower yields of the dibenzyl ureas. O xidative C arbonylation of Aryl A mines to U n s ymmetrical D iarylureas C atalyzed carbonylation of aryl amines with various functional group s to symmetrical ureas suggested the possib ility that unsymmetrical ureas might also be synthesi zed with the same reaction conditions (Table 3 3) Table 3 3. Synthesis of symmetrical diaryl ureas with tungsten hexacarbonyl Entry Amines Ratio Ureas (% Yield) a,b 1 p NO 2 67 f p CN 67 g 1:1 69 fg (58) 68 f (0) 68 g (0) 2 p Cl 67 b p OMe 67 e 1:1 69 be (12) 68 b (19) 68 e (24) 3 67 b 67 e 1:2 69 be (0) 68 b (0) 68 e (36) 4 67 b 67 e 2:1 69 be (43) 68 b (11) 68 e (0) 5 67 b 67 e 5:1 69 be (11) 68 b (14) 68 e (0)

PAGE 69

69 Table 3 3. Continued Entry Amines Ratio Ureas (% Yield) a,b 6 p Cl, m CF 3 67n 67e 2:1 69 n e (12) 68n (0) 68e (24) 7 p Cl 67b p OPh 67 o 2:1 69b o (41) c 68b (4) c 68o (23) c 8 p Cl, m CF 3 67n p OPh 67 o 1:1 69n o (12) 68n (0) 68 o (41) a Isolated yield based on aryl amine b The reactions were carried out with aryl amine s (1 .0 mmol each, unless otherwi se noted), W(CO) 6 (0.06 mmol), I 2 (2 .0 mmol), DMAP (4 mmol), CH 2 Cl 2 (40 mL), 40 C, 80 atm CO, 20 h c NMR yield. T o explore the feasibility of aryl amines with electron withdrawing group s produc ing un symmetrical ureas, compounds 67 f ( p NO 2 ), and 67 g ( p C N) were subjected to the same reaction conditions T his reaction provide d the desired un symmetrical urea 69 fg as the major product in 5 8 % yield ( Table 3 3, entry 1 ), with out formation of the symmetrical ureas 68 f and 68 g in the product mixture The equim olar pair of aryl amines 67 b ( p Cl) and 67 e ( p OCH 3 ) provided t he desi red un symmetrical urea 69 be in low yield (12 % Table 3 3, entry 2 ) T he symmetrical products 1,3 bis(4 chlorophenyl)urea 68 b and 1,3 bis(4 methoxyphenyl) urea 68 e were also detected i n the mixture Although the yield of unsymmetrical urea 69 be wa s low, the yields of symmetrical ureas from electron rich aryl amines are also low and it is possible that 67 e is just moderately unreactive. T he presence of the unsymmetrical urea suggest s th at manipulation of the reaction conditions could tip the product mixture in its favor Whe n

PAGE 70

70 the ratio was 1:2 in favor of 67 e however, the symmetric urea 68 e was formed exclusively in 36% yield (Table 3 3, entry 3) Using more of the p chloroaniline 67 b (2:1, Table 3 3, entry 4) resulted in 43% yield of the unsymmetrical urea 69 be and 11% of 68 b (Table 3 3, entry 5). A large excess of 67 b resulted the formation of its respective symmetric urea 68 b and a low yield of the unsymmetrical urea (Table 3 3, e ntry 6). Compound 69 be is of particular interest because of its application to the synthesis of sorafenib, an FDA approved drug for cancer treatment (Figure 3 4) 133 As shown in Figure 3 4, 69 be represents a simplified derivative of the cancer drug. Upon further modification of the aryl amines, the W(CO) 6 /I 2 system was used to instal l a derivative of the urea moiety of sorafenib. Figure 3 4. Structure of the cancer drug sorafenib, a possible applic ation of the tungsten catalyzed carbonylation of aryl amines Coupling of 4 chloro 3 (trifluoromethyl)aniline ( 67 n ) with anisidine ( 67e ) produced mixed results with a 2:1 ratio of 67 n to 67e (Table 3 3, entry 6). The symmetric urea 68e was the major produc t (24% yield) while the unsymmetrical urea 69 n e was produced in low yield ( 12%). Only trace amounts of symmetric urea 68 n was detected. The electron deficiency of the parent aniline 67 n in addition to added steric bulk associated with two aryl substituen ts are probably the cause of the low conversion. This inactivity is useful since it enables the possibility of increasing the amounts of 67 n without competition of its symmetric urea. When 4 phenoxyaniline ( 67 o ) and p

PAGE 71

71 chloroaniline ( 67b ) were subjected t o carbonylation conditions, the unsymmetrical urea 69b o was obtained as the major product (Table 3 3, entry 7) Symmetrical urea 68 o was obtained in 23% yield, while 68b was present in small quantities (4% yield). Urea 6 9 n o exemplifies the structure of s orafenib most and was obtained in 12% yield from a 1:1 ratio of 67n to 67o (Table 3 3, entry 8) Symmetric urea 68o was the major product (41% yield). As mentioned earlier, increased amounts of 67n in the reaction could lead to increased yields of 69no w ithout competitive formation of 68n After this series of unsymmetrical amine synthesis, it seems that the electron poor counterpart is always the least reactive species when coupled with an electron rich aryl amine. This pattern possibly suggests the fo rmation of an isocyanate intermediate which is subsequently attacked by the more nucleophilic electon rich aryl amine (Figure 3 5) Figure 3 5. Proposed isocyanate pathway for the tungsten catalyzed synthesis of symmetr ical and unsymmetrical aryl ureas Figure 3 6. Attempted carbonylation of N methylaniline

PAGE 72

72 To probe whether the reaction proceeds through an isocyanate pathway, N methylaniline ( 67p ) was subjected to carbonylation condition s. After 20 hours under 80 atm of CO at 40 C urea 68p was not observed in the product mixture. Most of the starting material was recovered along with trace quantities of p iodo ( N methyl)aniline ( 67 q ), a result of the electrophilic aromatic substitution of N methylaniline with elemental iodine (Figure 3 6) The lack of urea in the product mixture serves to further validate the isocyanate pathway Furthermore, when N methylaniline ( 67p ) and aniline ( 67a ) were combined under optimized conditions, the maj or product was unsymmetrical urea 69ap (31% yield, Figure 3 7) when excess 67p was used. Diphenylurea ( 68a ) was detected in only trace amounts. Some aniline was also recovered due to incomplete conversion. Although a modest yield, the selectivity for th e unsymmetrical urea implies formation of isocyanate from the primary aryl amine followed by attack of the more nucleophilic secondary aryl amine. Figure 3 7. Carbonylation of aniline and N methylaniline to provide unsy mmetrical urea 69ap Past experiences with the carbonylation of amines to ureas led to the conclusion that aniline did not provide N,N diphenylurea because of its decreased nucleophilicity compared to aliphatic substrates under the conditions studied. The se recent results have proven the contrary From the results presented, the issue lies possibly in the deprotonation of a metal bound amine species in order to provide an isocyanate which

PAGE 73

73 is converted to the urea by nucleophilic attack of a second equiva lent of amine. Aryl amines are more acidic (pKa aniline = 4.58 ) than their aliphatic counterparts ( pKa methylamine = 10.62) which necessitates the use of a weaker base than previous conditions. Conclusions In conclusion, we ha ve demonstrated the catalytic carbonylat ion of aniline to N N diphenylurea using the W(CO) 6 /I 2 catalyst syste m After o ptimiz ing the conditions for the carbonylation of aniline v arious p substituted aryl amines were also oxidative ly carbonyla ted to symmetrical and un symmetrical dia rylurea s. T he results demonstrate the moderately broad tolerance of functionality during the oxidative carbonylation reaction and provide an alternative to the reaction of amines with phosgene and phosgene derivative s The results of the unsymmetrical dia rylureas show promise in the synthesis of biologically important diarylureas using the W(CO) 6 /I 2 system Some progress has been made in understand ing the most complimentary pairing of aryl amines to ensure maximum unsymmetrical urea formation. The result s have also led to valuable insights in the mechanistic pathway to urea formation.

PAGE 74

74 CHAPTER 4 APPLICATION OF W(CO) 6 /I 2 CATALYZED CARBONYLAT ION TO THE SYNTHESIS OF THE LOPINAVIR SIDECHAIN Introduction The introduction of highly active antiretroviral therap y (HAART) in 1996 led to a dramatic change in fighting HIV infection. The therapy involves using at least three drugs from two different classes of antivirals. Using this strategy, a protease inhibitor (PI) could be used in combination with two nucleosid e/nucleotide reverse transcriptase inhibitors (N(t) RTIs). 141 One of the first generat ion of drugs approved by the Food and Drug Administration (FDA) was ritonavir (Figure 4 1) a product of Abbott laboratories th at targeted the HIV protease. The structure of ritonavir took ad vantage of the C 2 symmetric nature of the HIV protease homodimer. 142 U nlike most peptidomimetics which suffered from low absorption, ritonavir showe d high bioavalability due to increased aqueous solubility in addition to high potency against HIV protease. The path to the discovery of ritonavir started with core symmetric or pseudo symmetric diamines. Structure activity studies of modifications of th e core structures identified heterocyclic side groups as a key component in increasing solubility. Incorporation o f thiazoles as the side groups led to the identification of ritonavir as a lead compound. 142 After successful clinical trials, ritonavir was licensed by the FDA and approved for use with reverse transcriptase inhibitors (RTIs) Figure 4 1. Structure of ritonavir

PAGE 75

75 Although ritonavir was effective when combined with RTIs it was affected by the development of drug resistance from virus mutations. Furthermore, the combination had modest oral availability and short plasma half life. This meant the admi nis tration of high doses of the drug to maintain the inhibitory effects 143 This led to the search for a second generation of drugs to overcome these dra wbacks. Abbott Laboratories addressed the shortcomings of ritonavir with the release of its next generation HIV inhibitor, lopinavir (Figure 4 2) Lopinavir, when co administered with small doses of ritonavir, showed a significant increase in bioavailabi lity and activity against wild strain HIV 1 and other mutations. 143 In contrast to rotinavir, lopinavir contained different terminal groups; a urea moiety on one side and a dimethyl phenolic moiety on the other. This was done in ord e r to both decrease the molecular weight of the compound and increase bioavailability and potency. 141 Figure 4 2. Structure of lopinavir. Literature Synthesis of the Lopinavir Sidechain The general strategy for the synthesis of lopinavir focused on acylation of the core diamine str ucture to each acid side chain (Figure 4 3) The core structure 7 1 was readily available through rotinavir manufacturin g starting from L phenylalanine and side chain 7 2 can be easily derived from published procedures. The synthesis of 7 0 however, proved more difficult 143

PAGE 76

76 Figure 4 3. Retrosynthetic s trategy for the synthesis of lopinavir The original synthetic route for 7 0 involved a low yielding six step synthesis with 3 aminopropanol and L valine methyl ester as starting materials. In an improved synthesis, L valine was converted to the carbamate 7 3 using phenyl chloroformate. Control of pH was essential for the success of this reaction in order to suppress byproduct formation Treatment of 73 with 3 chloropropylamine hydrochloride produces 7 4 in situ. Crude 7 4 is then cyclized with potassium ter t butoxide (KOtBu) to obtain compound 7 0 ( Figure 4 4 ) 143 A disadvantage of this m ethod, however, stems from the quality of 3 chloropropylamine hydrochloride. The reagent is prone to developing dark colored impurities which are difficult to remove. The use of high quality amine is critical to the success of the cyclization reaction. Figure 4 4. Synthesis of the urea moiety of lopinavir 143

PAGE 77

77 In an alternate route, the L valine is first reacted with acrylonitrile and methyl chloroformate to obtain 7 5 which is the n hydrogenated with Raney Ni to obtain 7 0 ( Figure 4 5 ) Apart from the low overall yield of this procedure, a second drawbac k involves the use of Raney Ni The reagent is classified as potentially carcinogenic and is also not diposed of easily 144 A s li ghtly different route utilizes rhodium as a hydrogenation ca talyst in place of Raney Ni but this reaction is done in the presence of ammomium gas 144 Figure 4 5. Alternate synthesis of 7 0 144 The most current reported synthesis of 7 0 utilizes a phosgene derivative, CDI to install the urea from the p arent amine (Figure 4 6) 145 Treatment of 7 6 with trifluoroacetic acid (TFA) followed by CDI affords 7 7 Subsequent hydrolysis of 77 p rovid ed compound 7 0 (Figure 4 6). Since two equivalents of imidazole are eliminated from the stoichiometric reaction with CDI, proper disposal of the waste is an issue, especially on the industrial scale. Using the W(CO) 6 /I 2 catalyst system is a viable a lternative to the use of CDI since the only byproducts from the catalytic reaction are protons and the reduced form of the oxidant.

PAGE 78

78 Figure 4 6. Synthesis of 7 0 using CDI 145 Tungsten Catalyzed Synthesis of Lopinavir Sidechain Derivative To begin the investigation on the synthesis of 7 0 with the W(CO) 6 /I 2 catalyst system, the glycine derivative of the side chain ( 79 ) was chosen as the target compound for steric reasons. In addition, the carboxylic acid was protected in the form of an ester to limit any side reactions and increase solubility of the substrate. Conditions for the carbonylation involved 5 mol % W(CO) 6 1 equiv of iodine, 4 equiv of K 2 CO 3 and 80 bar CO Substrate Synthesis The retrosynthetic analysis of the glycine derivative of the l opinavir sidechain is shown in F igure 4 7. Urea 7 8 could be obt ained from diamine 79 via catalytic carbonylat i on Synthesis of the diamine could be accomplished by reacting chloroacetic acid with 1,3 diaminopropane 8 0 (Figure 4 7). Figure 4 7. Retrosynthesis of compound 78 Even though the N (3 aminopropyl) glycine 8 1 is commer cially available as an HCl salt, it is expensive ($120 per gram). Laboratory synthesis using cheaper reagents was deemed a better alternative. However, the coupling reaction of diamine 8 0 with

PAGE 79

79 chloroacetic acid began with difficulty (Figure 4 8) The re action was performed several times with variatio ns of experimental conditions. It was found that when methylene chloride was the solvent, production of the hydrochloride salt of the diamine stopped reaction progress. Increasing the scale of the reaction without solvent produced the desired product 8 1 with 1,3 diami nopropane hydrochloride in a 2:1 ratio. Unreacted diamine was removed by distillation and the resulting crude paste was recrystallized using boiling acetic acid and ethanol. 146 Even though the yield of 8 1 was low (12%), the reagents are inexpensive and the unreacted diamine could be recycled. Esterification of 8 1 was first attempted with refluxin g methanol in the presence of concentrated sulfuric acid. After the reaction, the work up procedure was problematic due to the affinity of the product for the aqueous layer. After many extractions with 5:2 chloroform to ethanol, ester 79 was obtained wit h small amounts of unreacted starting material. Needing a pure substrate for the upcoming carbonylation reaction, another route to esterification was undertaken. Generation of hydrogen chloride gas in situ (by the reaction between concentrated HCl and ca lcium chloride) followed by reflux in methanol provided the glycine methyl ester 79 in 91% yield (Figure 4 8) 146 Figure 4 8. Preparation of N (3 aminopropyl)glycine methyl ester 79 Tungsten Catalyzed Carbonylation of N (3 aminopropyl)glycine methyl ester 80 The glycine compound 79 was subjected to W(CO) 6 /I 2 catalyzed carbonylation conditions. Using potassium carbonate as th e base, a biphasic system (methylene chloride and water) as the solvent, and 80 bar CO at 80 C for 24 h, preliminary results

PAGE 80

80 indicated that the desired urea 7 8 was not obtained (Figure 4 9) Mass spectral analysis of the white solid that was recovered rev ealed signals of 204.8310 and 234.9883 Da with the largest abundance in the spectrum. The solid was acquired from the aque ous layer of the reaction by ex tra c tion with a 3:1 solution of chloroform and ethanol. The expected ions of the desired product ( [M + H] + calcd, 173 0926 ) were not found. More work is needed to find the appropriate conditions for the reaction Success with the synthesis of urea 7 8 c ould lead to the catalytic c arbonylation of other derivatives with substituents alpha to the ester, and subsequently the valine derived lopinavir side chain 7 0 Figure 4 9. Attempted W(CO) 6 /I 2 catalyzed carbonylation of glycine methyl ester 79 Conclusion The W(CO) 6 /I 2 catalytic system has been applied to the synthesis of t he glycine derivative of the HIV protease inhibitor lopinavir however, preliminary results show the formation of an unknown product More experimentation is needed to indentify this product, and also to produce the desired urea. If successful, t his meth od would provide an alternative to the use of the phosgene derivative, CDI, in the preparation of the cyclic urea side chain of lopinavir

PAGE 81

81 CHAPTER 5 EXPERIMENTAL PROTOCOLS General Methods. All experimental procedures were carried out under nitrogen in o ven dried glassware unless otherwise indicated. Carbonylation reactions were conducted in a 300 mL glass liner in a Parr autoclave behind a blast shield. Solvents and reagents were obtained from commercial sources in the appropriate grade and used withou t purification unless otherwise noted. Syntheses of compounds 31 114 33 114 44 113 45 113 61 147 and 66 c 148 wer e carried out according to literature procedures. 1 H and 13 C NMR spectra were obtained on Varian Gemini 300 MHz VXR 300 MHz, and Mercury 300 MHz spectrometers. Infrared spectra were measured u sing a Perkin Elmer Spectum One FTIR. High resolution mass spectrometry was performed by the University of Florida analytical service 34 (2R, 3S, 4S, 5R) 2,5 D iamino 1,6 diphenyl 3,4 hexanediol (34). The procedure was a dapted from the literature. 130 A mixture of 44 (1.33 g, 2.34 mmol), ammonium formate (0.88 g, 0.014 mol), and 10% Pd/C (0.80 g) in DMF (20 mL) was heated to 120 C under an Ar atmosphere for 8 h. The reaction was allowed to cool and t he mixture was then filtered through Celite. The filter cake was rinsed with methanol and the combined filtrates were concentrated into a pale yellow oil. The oil was taken up in ethyl acetate and washed with water, saturated sodium bicarbonate, and sa turated sodium chloride, dried over magnesium sulfate, filtered, and concentrated to obtain 34 (0.40 g, 70% yield). The product was identified by comparison with literature data. 130 1 H

PAGE 82

82 NMR ( CDCl 3 ) 7.39 7.02 (m, 10H), 3.67 (s, 2H), 3.02 (dd, J = 5.6, 8.9 Hz, 2H), 2.91 (dd, J = 5.8, 13.2 Hz, 2H), 2.71 (dd, J = 8.9, 13.1 Hz, 2H) 47b (2R,3R) D imethyl 2,3 bis((2 (trimethylsilyl)ethoxy)methoxy)succinate (47b) Under Ar and at 0 C, SEM chloride (5.08 g, 30.5 mmol) was added dropwise to a stirring solution of dimethyl L tartrate (1.81 g, 10.2 mmol) and DIPEA (3.94 g, 30.5 mmol) in dry CH 2 Cl 2 After gas evolution ceased, the reaction was stirred at room temperature ove rnight. The solution was then washed with 1 M HCl (1X) followed by water (2X). The organic layer was dried over magnesium sulfate, filtered, and concentrated to afford 47b as a pale yellow oil in quantitative yield (4.43 g). 1 H NMR ( CDCl 3 ) 4.85 4.66 (m, 6H), 3.74 (s, 6H), 3.67 3.48 (m, 4H), 1.00 0.77 (m, 4 H), 0.02 (s, 18 H) 59a (4R,5R) N, N, 2,2 T etramethyl 1,3 dioxolane 4,5 dicarboxamide ( 59 a) Methyl amine (46 mL, 2.0 M in methanol) was added to dim ethyl 2,3 O isopropylidene L tartrate 47 a (4.20 mL, 22.9 mmol) in methanol (15 mL) and stirred at room temperature for 3 days. The solution was then concentrated to afford 59 a as a white solid (4.93 g,

PAGE 83

83 99% yield). The compound was identified by compariso n with literature data. 149 1 H NMR (CDCl 3 ) 7.06 (br s, 2H), 4.51 (s, 2 H), 2.89 (d, J = 4.9 Hz, 6H), 1.49 (s, 6 H). 59b (4R,5R) N N D ibenzyl 2,2 dimethyl 1,3 dioxolane 4,5 dicarboxamide (59 b) A mixture of 47 a (10.78 g, 49.40 mol), benzylamine (10.32 g, 96.30 mmol ), potassium carbonate (0.172 g, 1.24 mmol) and methanol (35 mL) was refluxed overnight. It was then cooled to room temperature and the solvent evaporated to afford an orange oil. The oil was purified by column chr omatography (1:1 ethyl acetate/ dichlorom ethane) to afford 59 b as a pale yellow solid (10.73 g, 67 % yield). The compound was identified by comparison with literature data. 128 1 H NMR ( CDCl 3 ) 7.38 7.24 (m, 10H), 4.63 (s, 2 H), 4.50 (d, J = 6.0 Hz, 4H), 1.46 (s, 6 H). 59c (2 R,3R) N N D imethyl 2,3 bis((2 (trimethylsilyl)ethoxy)methoxy)succinamide (59c) Using the same procedure for 59a 59c (1.54 g, 84% yield) was obtained from 47b (1.83 g, 4.17 mmol) 1 H NMR ( CDCl 3 ) 6.80 (d, J = 4.4 Hz, 2H), 4.85 4.62 (m, 6H), 3.74 3.52 (m, 4 H), 2.86 (d, J = 5.0 Hz, 6H), 1.06 0.82 (m, 4H), 0.01 (s, 18 H) 13 C NMR (CDCl 3 ) 170.3, 97.0, 79.5, 67.0, 26.2, 18.3, 1.2

PAGE 84

84 59d (2R,3R) N N D ibenzyl 2,3 bis((2 (trimethylsilyl)ethoxy)methoxy)succinamide (59d) Compound 59d was obtained in 62% yield from 47b using the procedure for 59b 1 H NMR ( CDCl 3 ) 7.35 7.14 (m, 10H), 4.73 (s, 2 H), 4.62 (dd, J = 6.4, 11.3 Hz, 4 H), 4.45 (d, J = 5.8 Hz, 4 H), 3.49 (td, J = 7.4, 10.0 Hz, 4H), 0.87 0.66 (m, 4H), 0.08 (s, 18 H) 59e (2R, 3R) 1,4 N,N D ibenzylamino 2,3 dihydroxysuccinamide (59 e ) Using the same procedure as fo r 59 b diethyl L tartrate (7.00 g, 0 .0339 mol) was employed to afford 59 c as a white solid. The crude product was filtered, washed with water, and recrystallized from 50% ethanol in water to obtain pure 59 c (10.0 g, 90% yield). The compound was identifie d by comparison with literature data. 150 1 H NMR (DMSO d 6 ) 8.25 (t, J = 6.3 Hz, 2H), 7.39 7.13 (m, 10 H), 5.74 (d, J = 7. 2 Hz, 2H), 4.48 4.17 (m, 6 H). 13 C NMR (DMSO d 6 ) 172.1, 139.4, 127.5, 126.5, 72.7, 41.9.

PAGE 85

85 60a 1,1' ((4S,5S) 2,2 D imethyl 1,3 dioxolane 4,5 diyl)bis(N me thylmethanamine) (60 a) Using a variation of the literature procedure, 128 a solution of diamide tartrate 59 a (3.51 g, 0.0162 mol) in dioxane (50 mL) was added slowly to a vigorously stirring suspension of lithium aluminum hydride (1.85 g, 0.0487 mol) in dioxane (160 mL). The reaction was refluxed overnight after addition was complete. After the reaction mixture cooled, it was quenched by careful addition of 3 mL water, 3 mL 15% NaOH, and 3 mL water. The solution was filtered and the filtrate concentrated to afford crude 60 a as a pale red oil (3.01 g, 98% yield). The product was identified by comparison with literature data. 149 1 H NMR ( CDCl 3 ) 3.93 3.88 (m, 2H), 2.76 2.72 (m, 4H), 2.46 (s, 6H), 1.40 (s, 6 H). 60b N N (((4S,5S) 2,2 D imethyl 1,3 dioxolane 4,5 diyl)bis(methylene))bis(1 phenylmethanamine) (60 b ) The procedure used to prepare 60 a was used with 59 b (4.00 g, 0 .0109 mol) to obtain 60 b in 71% yield (2.62 g) as a pale brown oil after purification by column chromatography with CH 3 OH/CH 2 Cl 2 as eluent. The product was identified by comparison wit h literature data. 128 1 H NMR ( CDCl 3 ) 7.31 7.19 (m, 10H),

PAGE 86

86 3.97 3.90 (m, 2H), 3.79 ( s, 4 H), 2.77 (dd, J = 2.1, 3.4 Hz, 4 H), 1.66 (br s, 2 H), 1.38 (s, 6 H). 60c (2S,3S) N N D imethyl 2,3 bis((2 (trimethylsilyl)ethoxy)methoxy)butane 1,4 diamine (60c) Compound 59c (2.28 g, 5.22 mmol) afforded 60c (0.760 g, 3 6% yield) using the procedure for 60a in refluxing THF (100 mL ) 1 H NMR ( CDCl 3 ) 4.8 1 4.67 (m, 4H), 3.89 3.75 (m, 2H), 3.69 3.54 (m, 4H), 2.82 2.59 (m, 4H), 2.42 (s, 6H), 1.03 0.85 (m, 4H), 0.00 (s, 18 H ). 13 C NMR ( CDCl 3 ) 95.6, 78.2, 65.7, 52.2, 36.7, 18.3, 1.2 HRMS calcd for C 18 H 44 N 2 O 4 Si 2 [M + H] + 409.2912, found 409. 2918 60e ( 2S,3S) 1,4 B is(methylamino)butane 2,3 diol (60e) Diepoxide 6 2 (0.232 g, 2.69 mmol) was added to methylamine ( 11.6 mL of a 2 .0 M solution in methanol, 0.0 23 2 mol) at 0C and then stirred at room temperature ov ernight. The reaction was then concentrated to yield 60e as a white solid (0.40 g, 99% ). The product was identified by comparison with literature data. 151 1 H NMR ( CDCl 3 ) 3.83 (t, J = 2.5 Hz, 2H), 3.05 (dd, J = 3.3, 12.0 Hz, 2H), 2.65 (dd, J = 2.5, 12.0 Hz, 2H), 2.42 (s, 6H).

PAGE 87

87 60f (2S,3S) 1,4 B is(benzylamino)butane 2,3 diol ( 60 f ). Diamide 59 e (4.00 g, 0.0122 mol) was placed in a Soxhlet thimble and extracted into a refluxin g suspension of lithium aluminum hydride (1.20 g, 0.0316 mol) in 200 mL of tetrahydrofuran. Refluxing was continued for 72 h and the suspension stirred at room temperature overnight. Water (3 mL) was then added dropwise to the mixture followed by 15% NaO H (3 mL), and additional water (3 mL). The mixture was filtered and the solids were washed with tetrahydrofuran. The filtrate concentrated and the resulting residue was purified by column chromatography with CH 3 OH/CH 2 Cl 2 as the eluent to afford 60 f (1.36 g, 37% yield) as a white solid. The product was identified by comparison with literature data. 151 1 H NMR ( CDCl 3 ) 7.34 7.17 (m, 10H), 3.85 3.69 (m, 6 H), 3.10 (dd, J = 3.8, 12.0 Hz, 2 H), 2.72 (dd, J = 2.1, 12.0 Hz, 2H), 1.54 (br. s., 2 H). 60g (1R,1'R) 1,1' ((4S,5S) 2,2 D imethyl 1,3 dioxolane 4,5 diyl)diethanamine (60 g ). The procedure was adapted from the literature. 117 Compound 66a (0.73 g 1.6 mmol), 45 mL ethanol, Pd(OH) 2 /C (108 mg) and cyclohexene (45 mL) were combined and refluxed overnight. After cooling to room temperature, t he reaction was filtered through a bed of c elite and the resulting liq uor was concentrated into an oil. Column

PAGE 88

88 chromatography with CH 3 OH / CH 2 Cl 2 provided 60 g as a pale brown oil (0.28 g, 93% yield). The product was identified by comparison with literature data. 152 1 H NMR ( CDCl 3 ) 3.55 (d, J = 5.2 Hz, 2H), 2.86 (quin, J = 5.1 Hz, 2H), 2.64 (br s, 4H), 1.34 (s, 6H), 1.04 (d, J = 6.6 Hz, 6H). 60h (2R,3S,4S,5R) 3,4 B is((2 (trimethylsilyl)ethoxy)methoxy)hexane 2,5 diamine (60 h ). The procedure for 60 g was used to produce 60 h (1.28 g, 86% yield) from 66b (2.46 g, 3.63 mmol). The product was identified by comparison with literature data. 117 1H NMR (CDCl 3 ) 4.73 (d, J = 7.0 Hz, 2 H), 4.62 (d, J = 7.0 Hz, 2H), 3.64 (s, 2 H), 3.62 3.47 (m, 6 H), 1.26 (d, J = 6.7 Hz, 6 H), 0.85 (ddd, J = 3.4, 7.3, 9.7 Hz, 4H), 0.00 (s, 18 H). 60j (1R,1'R) 1,1' ((4S,5S) 2,2 D imethyl 1,3 dioxolane 4,5 diyl)bis(N methylethanamine) (60j) Sodium hydride ( 0. 451 g, 18.8 m mol, 60% dispersion in mineral oil) wa s washed with dry hexanes DMF (35 mL) was added, followed by the N protect ed diamine diol 66a ( 1.43 g, 3.13 mmol) in DMF ( 35 mL ) via cannula A fter 1 hour, methyl iodide ( 2.68 g, 18.8 m mol ) was added and the reaction was left to stir overnight at room temperature. The reaction was poured into cold water, then extracted

PAGE 89

89 3 times with ethyl acetate. The combined organic layers were then washed wit h water 3 times, dried, and evaporated to obtain a crude residue. Flash chromatography using mixtures of ethyl acetate/hexanes afforded N methylated compound 1 H NMR (DMSO d 6 98 C) 7.42 7.25 (m, 10H), 5.21 4.93 (m, 4H), 4.27 (br. s., 2 H), 3.74 (d J = 3.2 Hz, 2H), 2.81 (s, 6H), 1.26 (s, 6 H), 1.12 (d, J = 7.0 Hz, 6 H) HRMS calcd for C 27 H 36 N 2 O 6 [M + H] + 485.2646, found 485.2664 The purified N methylated compound was then treated with .292 g of Pd(OH) 2 and cyclohexene (40 mL) in refluxing ethanol (40 mL) overnight. After cooling to room temperature, the mixture was filtered through celite. The filtrate was concentrated to afford 60j in 70% yield (0.480 g) over the two steps 1 H NMR ( CDCl 3 ) 3.79 (d, J = 5.3 Hz, 2H), 2.66 2.53 (m, 2H), 2.39 (s, 6H), 1.37 (s, 6 H), 1.02 (d, J = 6.3 Hz, 6 H) 13 C NMR (CDCl 3 ) 109.2, 82.5, 57.4, 33.9, 28.4, 16.4 60k (2R,3S,4S,5R) N N D imethyl 3,4 bis((2 (trimethylsilyl)etho xy )methoxy)hexane 2,5 diamine (60k ) The procedure for 60 j was used to produce 60k from 66b in 60 % yield over two steps 1 H NMR ( CDCl 3 ) 4.81 4.74 (m, 4H), 3.75 3.56 (m, 6H), 2.84 (br s, 2H), 2.42 (s, 6H), 1.14 (d, J = 6.6 Hz, 6H), 0.94 (t, J = 8.5 Hz, 4H), 0.02 (s, 18H). 13 C NMR ( CDCl 3 ) 96.8, 82.8, 66.1, 55.4, 33.9, 18.4, 16.4, 1.2. HRMS calcd for C 20 H 48 N 2 O 4 Si 2 [M + H] + 437.3225, found 437.3241.

PAGE 90

90 60l (1R,1'R) 1,1' ((4S,5S) 2,2 D imethyl 1,3 dioxolane 4,5 diyl)bis (N methyl 2 phenylethanamine) (60l) The procedure for 60j was used to produce 60l from 66c in 31% yield over two steps. 1 H NMR ( CDCl 3 ) 7.38 7.08 (m, 10H), 4.05 (s, 2H), 2.80 2.60 (m, 6H), 2.31 (s, 6H), 2.06 (br. s., 2H), 1.41 (s, 6 H) 60m (2R,3S,4S,5R) N N D imethyl 1,6 diphenyl 3,4 bis((2 (trimethylsilyl)ethoxy)methoxy)hexane 2,5 diamine (60m) The procedure for 60 j was used to produce 60 m from 45 in 23% yield over two steps. 1 H NMR ( CDCl 3 ) 7.39 7.09 (m, 10 H), 4.39 (d, J = 6.9 Hz, 2 H), 4.25 (d, J = 6.9 Hz, 2H), 3.77 (s, 2 H), 3.56 (dt, J = 7.1, 9.6 Hz, 2 H), 3.40 3.10 (m, 6 H), 2.73 (dd, J = 10.4, 13.6 Hz, 2H), 2.61 (s, 6H), 0.80 0.69 (m, 4H), 0.05 (s, 18 H) 13 C NMR ( CDCl 3 ) 137.4, 129.4, 129.0, 127.1, 95.1 74.9, 66.6, 56.8, 53.6, 34.0, 31.4, 18.1, 1.2 HRMS calcd for C 32 H 56 N 2 O 4 Si 2 [M + H] + 589.3851, found 589.3846. 62 (2S,2'S) 2,2' B ioxirane (62 ). Compound 6 1 147 (2.62 g, 6.09 mmol) was suspended in 30 mL ether. Pulverized potassium hydroxide (0.72 g, 0 .0 1 3 mol) was

PAGE 91

91 then added and the mixture refluxed for 6 hours. The reaction was filtered, and the fi ltrate concentrated into a c olorless oil. The residue was purified by fractional distillation to obtain 63 as an oil (0.231 g, 44% yield ). The product was identified by comparison with literature data. 153 1 H NMR ( CDCl 3 ) 2.94 2.88 (m, 2H), 2.87 2.82 (m, 2H), 2.77 2.73 (m, 2 H). 63a General Procedure A for Catalytic Oxidative Carbonylation of Diamine Diols with W(CO) 6 /I 2 : (3aS,8aS) 2,2,5,7 tetramethyltetrahydro 3aH [1,3]dioxolo[4,5 e][1,3]diazepin 6(7H) one (6 3 a) To a glass lined 300 mL Parr high pressure vessel containing CH 2 Cl 2 (40 mL) was added diamine 60a (200 mg, 1.06 mmol), W(CO) 6 (18.6 mg, 0.0531 mmol), I 2 (270 mg, 1.06 mmol), and pyridine (336 mg, 4.25 mmol). The vessel w as then charged with 80 bar of CO and heated at 40C for 24 h. The pressure was released and 10 mL of CH 2 Cl 2 was added to further dissolve any crude material. The solution was washed with a saturated solution of Na 2 SO 3 followed by 0.1M HCl, then dried ov er MgSO 4 and filtered. The solvent was removed by evaporation and the resulting residue was purified by column chromatography using mixtures of methanol and methylene chloride as the eluent to yield 6 3 a as a pale brown oil (133 mg, 58% yield). IR (neat) CO 1637 cm 1 1 H NMR ( CDCl 3 ) 3.65 3.54 (m, 2H), 3.32 3.17 (m, 4H), 2.91 (s, 6H), 1.45 (s, 6H). 13 C NMR ( CDCl 3 ) 165.0, 111.5, 79.5, 51.2, 40.3, 26.9. HRMS calcd for C 10 H 18 N 2 O 3 [M + Na] + 237.1210, found 237.1226.

PAGE 92

92 63b (3aS,8aS) 5,7 D ibenzyl 2,2 dimethyltetrahydro 3aH [1,3]dioxolo[4,5 e][1,3]diazepin 6(7H) one (6 3b ) Following Procedure A, urea 63b was obtained in 99% yield (53.2 mg) from 60b (50.0 mg, 0.147 mmol reacted) after column chromatography on silica using ethyl acetate/methylene chlori de as the eluent. IR (neat) CO 1638 cm 1 1 H NMR ( CDCl 3 ) 7.50 7.14 (m, 10H), 4.52 (s, 4H), 3.46 3.36 (m, 2H), 3.36 3.29 (m, 2H), 3.21 3.08 (m, 2H), 1.33 (s, 6H). 13 C NMR ( CDCl 3 ) 165.1, 138.3, 128.7, 128.7, 127.6, 111.5, 79.9, 55.5, 48.6, 26.8. HRMS calcd for C 22 H 26 N 2 O 3 [M + Na] + 389.1836, found 389 .1853. 63e (5S,6S) 5,6 D ihydroxy 1,3 dimethyl 1,3 diazepan 2 one (6 3e ) Following Procedure A, 6 3e (53.2 mg, 45 % yield) was obtained from 60 e (100 mg, 0.675 mmol) after 48 h. IR (neat) CO 1625 cm 1 1 H NMR ( CDCl 3 CD 3 OD) 3.96 (br s, 2H), 3.44 3.35 (m, 2H), 3.12 3.02 (m, 2H), 3.02 2.89 (m, 2H), 2.71 (s, 6H). 13 C NMR ( CDCl 3 ) 166.2, 72.7, 53.8, 39.1. HRMS calcd for C 7 H 14 N 2 O 3 [M + H] + 175.1077, found 175.1074.

PAGE 93

93 63f (5S,6S) 1,3 D ibe nzyl 5,6 dihydroxy 1,3 diazepan 2 one (6 3f ) Following Procedure A, urea 6 3f was obtained as a clear oil in 10% yield (40.1 mg) from 60 f (370 mg, 1.23 mmol). IR (neat) CO 1622 cm 1 1 H NMR ( CDCl 3 ) 7.45 7.13 (m, 10H), 4.43 (dd, J = 14.9, 67.8 Hz, 4H ), 3.33 3.25 (m, 2H), 3.21 3.00 (m, 4H). 13 C NMR ( CDCl 3 ) = 165.9, 138.2, 128.9, 128.7, 127.8, 73.1, 54.3, 51.2. HRMS calcd for C 19 H 22 N 2 O 3 [M + Na] + 349.1523, found 349.1540. 63g General Procedure B for Catalytic O xidative Carbonylation of Diamine Diols with W(CO) 6 /I 2 : (3aS,4R,8R,8aS) 2,2,4,8 tetramethyltetrahydro 3aH [1,3]dioxolo[4,5 e][1,3]diazepin 6(7H) one (6 3g ) To a glass lined 300 mL Parr high pressure vessel containing 40 mL of CH 2 Cl 2 and 10 mL of water wa s added diamine 60 g (200 mg, 1.06 mmol), W(CO) 6 (18.6 mg, 0.0531 mmol), I 2 (270 mg, 1.06 mmol), and K 2 CO 3 (587 mg, 4.25 mmol). The vessel was then charged with 80 bar of CO and heated at 80C for 24 h. The pressure was released and 10 mL of water was add ed. The organics were separated and washed with a saturated solution of Na 2 SO 3 followed by 0.1M HCl. Each of the collected aqueous layers was extracted with 3:1 CHCl 3 /EtOH.

PAGE 94

94 The organic layers were combined, dried over MgSO 4 and filtered. The solvents we re removed by evaporation and the residue was purified by column chromatography using mixtures of methanol and methylene chloride as the eluent to yield 6 3g as a pale yellow solid. IR (neat) CO 1639 cm 1 1 H NMR ( CDCl 3 CD 3 OD) 5.52 (d, J = 8.8 Hz, 2H) 4.09 3.85 (m, 2H), 3.70 (s, 2H), 1.39 (s, 6H), 1.19 (d, J = 6.7 Hz, 6H). 13 C NMR ( CDCl 3 CD 3 OD ) 158.2, 108.0, 80.3, 44.1, 25.9, 18.5. HRMS calcd for C 10 H 18 N 2 O 3 [M + H] + 215.1390, found 215.1387. 63h (4R,5S,6S,7R) 4 ,7 D imethyl 5,6 bis((2 (trimethylsilyl)ethoxy)methoxy) 1,3 diazepan 2 one (6 3h ) Following Procedure B, 60 h (400 mg, 0.979 mmol) was converted to 6 3h (320 mg, 75% yield). The product was identified by comparison with literature data. 117 IR ( neat ) CO 1683 cm 1 1 H NMR (CDCl 3 ) 4.81 (d, J = 7.2 Hz, 2 H), 4.70 (d, J = 7.0 Hz, 2H), 4.36 (s, 2 H), 3.75 (q, J = 6.6 Hz, 2 H), 3.65 (dd, J = 7.3, 9.6 Hz, 4H), 3.53 (s, 2 H), 1.27 (d, J = 6.9 Hz 6 H), 0.93 (dd, J = 7.6, 9.6 Hz, 4H), 0.02 (s, 18 H) 13 C NMR ( CDCl 3 ) 164.3, 95.7, 78.1, 65.9, 46.9, 19.4, 18.2, 1.3. HRMS calcd for C 19 H 42 N 2 O 5 Si 2 [M + Na] + 457.2525, found 457.2536.

PAGE 95

95 (4R,5S,6S,7R) 4,7 D ibenzyl 5,6 d ihydroxy 1,3 diazepan 2 one (63i), (4R,5S) 5 ((1S,2R) 2 amino 1 hydroxy 3 phenylpropyl) 4 benzyloxazolidin 2 one (35), and (4R,4'R,5S,5'S) 4,4' dibenzyl [5,5' bioxazolidine] 2,2' dione (36) To a glass lined 300 mL Parr high pressure vessel containing 1,2 dichloroethane (60 mL) was added diamine 34 (610 mg, 2.03 mmol), W(CO) 6 (71.0 mg, .203 mmol), I 2 (515 mg, 2.03 mmol), and pyridine (642 mg, 8.12 mmol). The vessel was then charged with 80 bar of CO and heated at 80C for 16 h. The pressure was released and 10 mL of CH 2 Cl 2 was added to further dissolve any crude material. The solution was washed with a saturated solution of Na 2 SO 3 followed by 0.1M HCl, then dried over MgSO 4 and filtered. The solvent was removed by evaporation and the resulting residue w as purified by column chromatography using mixtures of methanol and methylene chloride as the eluent to yield 63i (30 mg, 10% yield), 35 (32 mg, 11% yield), and 36 (42 mg, 13%). Urea 63i was identified by comparison with literature data. 120 IR (neat) CO 1662 cm 1 1 H NMR (CDCl 3 CD 3 OD) 7.29 7.08 (m, 10H), 3.82 (t, J = 7.6 Hz, 2H), 3.50 (s, 2H), 3.01 2.78 (m, 4H). Carbamate 35 : IR (neat) CO 1736 cm 1 1 H NMR (CDCl 3 CD 3 OD) 7.32 7.09 (m, 10H), 4.36 (d, J = 5.6 Hz, 1H), 4.24 (q, J = 6.5 Hz, 1H), 3.82 3.72 (m, 1H), 3.44 (br. s., 1H), 3.13 2.88 (m, 4H), 2.77 (dd, J = 7.4, 13.6 Hz, 2H). 13 C NMR (CDCl 3 CD 3 OD ) 159.4, 135.2, 134.5, 129.4, 129.3, 128.9, 127.7, 127.3, 82.5, 67.7, 55.6, 55.3, 40.9, 36.1, HRMS calcd for C 19 H 23 N 3 O 2 [M + H] + 327.1708, found 327.1714. Carbamate 36 was identified by comparison with literature data. 154 1 H NMR (CDCl 3 )

PAGE 96

96 7.38 7.18 (m, 7H), 7.06 (dd, J = 1.9, 7.5 Hz, 4H), 5.80 (s, 2H), 4.04 (q, J = 6.5 Hz, 2H), 3.93 (d, J = 5.3 Hz, 2H), 2.86 (dd, J = 6.7, 13.5 Hz, 2H), 2.70 (dd, J = 7.3, 13.5 Hz, 2H). 65 D ibenzyl ((2R,3S,4S,5R) 3,4 dihydroxyhexane 2,5 diyl )dicarbamate (65 ). Preparation of 65 was adapted from a literature procedure. 119 A solution of oxalyl chloride (18.0 mL of 2.0 M solution in CH 2 Cl 2 0.036 mol) in CH 2 Cl 2 (30 mL) was cooled to 78C, and anhydrous dimethylsulfoxide (3.40 mL, 0.0478 mol) in CH 2 Cl 2 (53 mL) was added over 20 min while the temperature was kept near 78 C. Immediately thereafter, a solution of N Z D ala ninol 64 (5.00 g, 0.0239 mol) in CH 2 Cl 2 (70 mL) was added over 30 min, followed by stirring at 78 C for 40 min. Triethylamine (9.67 g, 0.0956 mol) was added over 15 min, followed by stirring for 2 hr at 78 C to ensure completion of the reaction. Afte r 20% aqueous KHSO 4 (50 mL) was added, the reaction mixture was allowed to warm to room temperature and water (45 mL) was added. The aqueous phase was separated and washed twice with CH 2 Cl 2 (20 mL). The organic layers were combined and washed with satura ted sodium bicarbonate (50 mL x 2), water (50 mL x 3), and saturated sodium chloride (50 mL x 2), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the resulting aldehyde in quantitative yield as an oil (4.95 g, 99% yield). The c rude aldehyde was used without further purification to prevent possible racemization. Under an inert atmosphere, Zn dust (0.937 g, 0.0143 mol) was added to a solution of VCl 3 (THF) 3 (9.83 g, 0.0263 mol)

PAGE 97

97 in dry CH 2 Cl 2 (55 mL), resulting in a color change fr om reddish brown to green after stirring for 20 30 min. A solution of the aldehyde (4.95 g, 0.0239 mol) in CH 2 Cl 2 (55 mL) was added via cannula, causing a color change from green to brown. After being stirred at room temperature overnight, the reaction w as opened to air and poured into 1 M HCl (125 mL). The two phases were stirred together overnight resulting in a blue aqueous layer and the precipitated coupling product in the organic layer. Adding CH 2 Cl 2 and tetrahydrofuran dissolved all solids. The p hases were separated and the aqueous phase was extracted with CH 2 Cl 2 (85 mL). The combined organic layers were washed with saturated sodium bicarbonate (20 mL) and saturated sodium chloride (20 mL), and then dried, filtered, and evaporated to yield a whit e solid. Recrystallization from THF and hexanes afforded diol 65 (3.92 g, 84% yield). The product was identified by comparison with literature data. 117 1 H NMR (DMSO d 6 ) 7.38 7.2 6 (m, 10 H), 6.83 (d, J = 8.8 Hz, 2H), 5.08 4.93 (m, 4 H), 4.37 (d, J = 5.7 Hz, 2H), 3.84 3.70 (m, 2 H), 3.25 3.14 (m, 2 H), 1.00 (d, J = 6.4 Hz, 6 H). 66a Dibenzyl ((1R,1'R) ((4S,5S) 2,2 dimethyl 1,3 dioxolane 4,5 diyl)b is(ethane 1,1 diyl))dicarbamate ( 66 a ) The procedure was adapted from the literature. 155 To a suspension of diol 65 (1.14 g, 2.74 mmol) in 70 mL CH 2 Cl 2 was added 2,2 dimethoxypropane (1.99 g, 0 0192 mol) at 0C. A catalytic amount of ( + ) camphor 10 sulfonic acid (50.0 mg) was added and the mixture was stirred overnight at room

PAGE 98

98 temperature. The reaction was then concentrated into a dark oil. Column chromatography (30% ethyl acetate/hexanes) aff orded 66 a as a white solid (1.18 g, 94% yield). The product was identified by comparison with literature data. 152 1 H NMR ( CDCl 3 ) 7.44 7.27 (m, 10H), 5.19 5.01 (m, 4 H), 4.95 (d, J = 9.5 Hz, 2H), 4.00 3.82 (m, 2H), 3.61 (s, 2H), 1.35 (s, 6 H), 1.22 (d, J = 6.1 Hz, 6 H). 66b D ibenzyl ((2R,3S,4S,5R) 3,4 bis((2 (trimethylsilyl)ethoxy)methoxy)hexane 2,5 diyl)dicarbamate ( 66 b ) The procedure was adapted from the literature. 117 To a suspension of diol 65 (1.5 8 g, 3.79 mmol) in 65 mL CH 2 Cl 2 was added DIPEA (2.94 g, 0.0228 mol) and cooled to 0 C. SEM chloride (2.78 g, 0.0167 mol) was then added dropwise until gas evolution ceased. The mixture was then refluxed overnight. After cooling to room temperature, co ld water was added and the layers separated. The aqueous layer was extracted with methylene chloride. The organic layers were combined and washed with water, dried over magnesium sulfate, and concentrated into a yellow oil. Column chromatography using m ixtures of ethyl acetate and hexanes afforded pure 66 b as a pale yellow oil (2.52 g, 98% yield). The product was identified by comparison with literature data. 117 1 H NMR ( CDCl 3 ) 7.47 7.28 (m, 10H), 5.22 4.97 (m, 6H), 4.80 4.62 (m, 4H), 4.09 3.95 (m, 2H), 3.83 3.67 (m, 2H), 3.58 3.39 (m, 4 H), 1.21 (d, J = 6.6 Hz, 6H), 1.01 0.84 (m, 4H), 0.01 (s, 18 H).

PAGE 99

99 68a General procedure A for th e catalytic carbonylation of p substituted aryl amines: N N' diphenylurea ( 68 a ) Aniline 67 a (0.46 g, 4.9 mmol) was added to a glass lined 3 0 0 mL Parr high pressure vessel with W(CO) 6 (0.0527 g, 0. 0 15 mmol I 2 (1.27 g, 5.0 0 mmol ) DMAP (1.22 g, 10.0 mmol ) in CH 2 Cl 2 ( 40m L) The vessel was charged with 80 atm CO and the reaction was left to stir for 8 h at 40 C After that the autoclave was cooled, the excess CO gas was released, and the reaction mixture was filtered and washed with saturated Na 2 SO 3 T he r esulting solution was then dried with MgSO 4 filtered, and concentrated T he crude residue was purified by flash chromatograph y on silica gel using mixture s of e thyl a cetate and CH 2 Cl 2 as eluent to recover 68 a in 85 % yield (0.45 g) The product was iden tified by comparison with literature data. 156 IR (neat) CO 1635 cm 1 1 H NMR (DMSO d 6 ) 8.60 (s, 2H ) 7.40 (d, J = 8.5 Hz, 2 H) 7.2 2 (t, J = 7.6 Hz, 2 H) 6.84 6.97 (m, 1 H). 13 C NMR (DMSO d 6 ) 153.1, 140.3, 129.4, 122.4, 118.8 68b 1 ,3 B is(4 chlorophenyl)ure a (68 b ). Pr ocedure A afford ed urea 68 b from 4 c hlor o aniline 67 b (0. 255 g, 2.0 0 mmol) in 6 8 % yield (0.190 g) The product was identified by comparison with literature data. 157 IR (neat) CO 1643 cm 1 1 H NMR (DMSO d 6 ) 8.81 (s, 2 H) 7.45 (d, J = 8.8 Hz, 4 H) 7.30 (d, J = 8.8 Hz, 4 H) 13 C NMR

PAGE 100

100 (DMSO d 6 ) 153.0, 139.2, 129.3, 126.2, 120.5. HRMS calcd for C 13 H 10 Cl 2 N 2 O [M + H] + 281.0243, f ound [M + H] + 281.0239 68c 1,3 B is(4 iodophenyl)urea ( 68 c ). Pro cedure A afford ed urea 68 c from 4 i odoaniline 67 c (0. 219 g, 1 .0 0 mmol) in 7 6 % yield (0.176 g) IR (neat) CO 1634 cm 1 1 H NMR (300 MHz, DMSO d 6 ) 8.77 (s, 2 H) 7.55 (d, J = 8.5 Hz, 4 H) 7.25 (d, J = 8.5 Hz, 4 H) 13 C NMR (DMSO d 6 ) 152.8, 140.1, 138.0, 121.2, 85.5 HRMS calcd for C 13 H 10 I 2 N 2 O [M + H ] + 4 64.8955 f ound [M + H ] + 4 64.8947 68d 1,3 B is(4 bromophenyl)urea ( 68 d ). Pro cedure A afforded urea 68 d from 4 b ro moaniline 67 d (0. 172 g, 1.0 0 mmol) in 64% yield (0.120 g) The compound was identified by comparison with literature data. 158 IR (neat) CO 1644 cm 1 1 H NMR (DMSO d 6 ) 8.80 (s 1 H ) 7.38 (s, 4 H) 13 C NMR (DMS O d 6 ) 152.9, 139.6, 132.2, 120.9, 114.0 HRMS calcd for C 13 H 10 Br 2 N 2 O [M + H] + 370.9213 f ound [M + H] + 3 70 .9 238

PAGE 101

101 68e 1,3 B is(4 methoxyphenyl)urea ( 68 e ). Pro cedure A afford ed urea 68 e from p a nisidine 67 e (0. 61 5 g, 5 .0 0 mmol) in 38% yield (0.260 g) The compound was identified by comparison with literature data. 159 IR (neat) CO 1631 cm 1 1 H NMR (DMSO d 6 ) 8. 31 (s, 2 H) 7.28 (d, J = 9.1 Hz, 4 H) 6.80 (d, J = 8.9 Hz, 4H) 3.29 (s, 2 H) 13 C NMR (DMSO d 6 ) 154.9, 153.6, 133.6, 120.5, 115.6, 114.6, 55.8 HRMS calcd for C 15 H 16 N 2 O 3 [M + H] + 273.123 4 found [M + H] + 2 73 1239 68f 1,3 B is(4 nitrophenyl)urea ( 68 f ). Pro cedure A afford ed urea 68 f from p n itroaniline 67 f (0. 691 g, 5 .0 mmol) in 84% yield (0.638) The compound was identified by comparison with literature data. 160,161 IR (neat) CO 1635 cm 1 1 H NMR (300 MHz, DMSO d 6 ) 9.58 (br s, 2 H) 7.93 8.24 (m, 4 H) 7.30 7.79 (m, 4 H) 13 C NMR (75 MHz, DMSO d 6 ) 125.8, 118.6 HRMS calcd for C 13 H 10 N 4 O 5 [ M + H] + 301.0578, f ound [M + H] + 301.057 9 68g 1,3 B is(4 cyanophenyl)urea ( 68 g ). Pro cedure A afford ed urea 68 g from 4 aminobenzonitrile 67 g (0. 295 g, 2.5 0 mmol) in 48% yield (0.160 g) IR (neat) CO

PAGE 102

102 1643cm 1 1 H NMR (300 MHz, DMSO d 6 ) = 9.33 (s, 2 H) 7.66 7.78 (m, 4 H) 7.59 (d, J = 8.76 Hz, 4 H) 13 C NMR (75 MHz, DMSO d 6 ) 152.4, 144.3, 134.0, 119.9, 119.0, 104.5 HRMS calcd for C 15 H 10 N 4 O 5 [M + H ] + 2 63 .0 92 7, f ound [M + H ] + 2 63.0920 68h D iethyl 4,4' (carbonylbis(azanediyl))dibenzoate ( 68 h ). Pro cedure A afford ed urea 68 h from ethyl p aminobenzoate 67 h (0. 331 g, 2 .0 0 mmol) in 7 4 % yield (0.263 g) IR (neat) CO 1642cm 1 1 H NMR (C DCl 3 ) 7.85 (d, J = 8.6 Hz, 4 H) 7.41 (d, J = 8.6 Hz, 4 H) 4.23 (t, J = 7.1 Hz, 4 H) 3.53 (br s 2 H) 1.27 (t, J = 7.1 Hz 6 H) 13 C NMR (CDCl 3 ) 170.9, 156.5 147.5, 134.9, 128.2, 121.8, 65.0, 18.3 HRMS calcd for C 19 H 20 N 2 O 5 [M + H ] + 3 57.1445 f ound [M + H ] + 3 57.1418 68i 3,4 D ihydroquinazolin 2(1H) one ( 68 i ) Pro cedure A afford ed urea 68 i from 2 a minoben z ylamine 67 i (0. 122 g, 1 .0 0 mmol) in 41 % yield (60 mg) The product was identified by comparison with literature data. 162 IR (neat) CO 1643cm 1 1 H NMR (300 MHz, DMSO d 6 ) 8.95 (br s 2H) 6.94 7.15 (m, 2H) 6.64 6.86 (m, 2H) 4.25 (br s, 2 H). HRMS calcd for C 8 H 8 N 2 O [M + H ] + 1 49.0709 f ound [M + H ] + 149.0713

PAGE 103

103 69fg 1 (4 C yanophenyl) 3 (4 nit rophenyl)urea ( 69 fg ) Pro cedure A afford ed urea 69 fg from p n itroaniline 67 f (0. 138 g, 1 .0 0 mmol) and 4 a minobenzonitrile 67 g (0.118g, 1 .00 mmol) in 5 8 % yield (0.150 g) The product was identified by comparison with literature data. 163 IR (neat) CO 1644 cm 1 1 H NMR ( CDCl 3 ) 7.90 (d, J = 9.1 Hz, 2 H) 7.32 (d, J = 3.6 Hz, 4H) 7.22 (s, 4 H) HRMS calcd for C 14 H 10 N 4 O 3 [M + H] + 283.0826, f ound [M + H] + 283. 0755. 69be 1 (4 C hlorophenyl) 3 (4 methoxyphenyl)urea ( 69 be ) Pro cedure A afford ed urea 69 be from 4 c hlor o aniline 67 b (0. 255 g, 2 .0 0 mmol) and p a nisidine 67 e (0.123 g, 1 .00 mmol) in 43 % yield (0.118 g) IR (neat) CO 1633 cm 1 1 H NMR (DMSO d 6 ) 8.66 (s, 1H) 8.44 (s, 1 H) 7.41 (d, J = 8.9 Hz, 4H) 7.16 7.34 (m, 4 H) 6.81 (d, J = 8.9 Hz, 2H) 3.66 (s, 3 H) HRMS calcd C 14 H 13 ClN 2 O 2 [M + H] + 277.0738, f ound [M + H] + 277.07 42. 69ne 1 (4 Chloro 3 (trifluoromethyl)phenyl) 3 (4 methoxyphenyl)urea (69ne) Procedure A produced urea 69ne from p anisidine 67e (.123 g, 1.00 mmol) and 4

PAGE 104

104 chloro 3 (trifluoromethyl) aniline 67n (.391 g, 2.00 mmol) in 12% yield (0.042 g). IR (neat) CO 16 27 cm 1 1 H NMR ( DMSO d 6 ) 9.04 (s, 1H), 8.61 (s, 1H), 8.04 (s, 1H), 7.64 7.48 (m, 2 H), 7.31 (d, J = 8.9 Hz, 2 H), 6.82 (d, J = 8.9 Hz, 2H), 3.67 (s, 3 H) 13 C NMR ( DMSO d 6 ) 155.4, 153.2, 140.2, 132.6, 123.5, 121.2, 117.2, 114.6, 55.8, 23.4 HR MS calcd C 1 5 H 1 2 Cl F 3 N 2 O 2 [M + H] + 345 .0 612 f ound [M + H] + 345 .0 608. 69bo 1 (4 C hlorophenyl) 3 (4 phenoxyphenyl)urea ( 69bo ). Procedure A afforded 69bo from 4 phenoxyaniline 67o (.185 g, .999 mmol) and 4 chloroaniline 67b (.255 g, 2.00 mmol) in 41% yield (.138 g) by NMR (see Appendix A for mixed spectrum). 69no 1 (4 chloro 3 (trifluoromethyl)phenyl) 3 (4 phenoxyphenyl)urea (69no) Procedure A afforded 69no from 4 chloro 3 (trifluoromethyl )aniline 67n (.196 g, 1.00 mmol) and 4 phenoxyaniline 67o (.185 g, 1.00 mmol) in 12% yield (0.050 g). 1 H NMR ( DMSO d 6 ) 9.12 (s, 1H), 8.83 (s, 1 H), 8.09 (d, J = 2.1 Hz, 1H), 7.71 7.53 (m, 2 H), 7.46 (d, J = 9.1 Hz, 2 H), 7.34 (t, J = 7.9 Hz, 2 H), 7.14 7.03 (m, 1H), 7.01 6.88 (m, 3 H) 13 C NMR (DMSO d 6 ) 158.2, 153.2, 151.8, 140.1, 135.8, 132.6, 130.6, 123.5, 121.2, 120.4, 118.4

PAGE 105

105 69ap 1 Methyl 1,3 diphenylurea (69ap) Procedure A afforded 69ap from aniline 67a (0.09 3 g, 1.00mmol) and N methylaniline 67p (0.536 g, 5.00mmol) in 31% yield (0.070 g). 1 H NMR (CDCl 3 ) 7.56 7.16 (m, 9H), 7.04 6.94 (m, 1H), 6.25 (br. s., 1H), 3.34 (s, 3 H) 79 M ethyl 2 ((3 aminopropyl)amino)acetate hy drochloride (79) The 2 (3 aminopropylamino)acetic acid hydrochloride 81 (0.639g, 4.84 mmol) was suspended in anhydrous methanol (55 mL) and hydrogen chloride gas, produced by the dropwise addition of 37% hydrochloric acid (50 mL) to 60g of anhydrous CaCl 2 was bubbled through the reaction until complete consumption of CaCl 2 The reaction mixture was then refluxed for 3 hours, and the solvent evaporated under reduced pressure after cooling to room tempreature to give 79 as a white solid (0.756 g, 91 % yie ld ) The product was identified by comparison with literature data. 146 1 H NMR ( D 2 O ) 4.05 (s, 2H), 3.82 (s, 3 H), 3.23 (t, J = 7.7 Hz, 2 H), 3.10 (t, J = 7. 8 Hz, 2H), 2.21 2.03 (m, 2 H) 81

PAGE 106

106 2 ( ( 3 A minopropyl ) amino)acetic acid hydrochloride (81) Neat propylenediamine 80 (42.0 g, 0.318 mol) was rapidly stirred while being cooled in an ice bath (4 C). Chloroacetic acid (3.00 g, 0.0318 mol) was added portionwise ensuring for complete dissolution between each addition. The reaction was then stirred at room temperature for 48 h. The unreacted propylenediamine was removed by distillation under reduce d pressure. The remaining pas te was triturated with DMSO T he precipitate was collected by filtration an d washed with ethanol to give a white solid which was subsquently dissolved in boiling acetic acid (16 mL) and precipitated with ethanol (60 mL) with stirring at 0 C for 2 h. The s olids were filtered off, washed three times with ethanol to give 0.640 g of 81 as a white solid (12 % yield ) The product was identified by comparison with literature data. 146 1 H NMR ( D 2 O ) 3.24 (s., 2H), 2.92 (dt J = 6.6, 24.0 Hz, 2 H), 2.72 (t, J = 7.0 Hz, 2 H), 1.82 (t, J = 6.7 Hz, 2 H)

PAGE 107

107 APPENDIX A SPECTRA OF SYNTHESIZ ED COMPOUNDS 1 H NMR of (2R, 3S, 4S, 5R) 2,5 Diamino 1,6 diphenyl 3,4 hexanediol (34) 1 H NMR of (2R,3R) Dimethyl 2,3 bis((2 (trimethylsilyl)ethoxy)methoxy)succinate (47b)

PAGE 108

108 1 H NMR of (4R,5R) N,N, 2,2 Tetramethyl 1,3 dioxolane 4,5 dicarboxamide (59a) 1 H NMR o f (4R,5R) N,N Dibenzyl 2,2 dimethyl 1,3 dioxolane 4,5 dicarboxamide (59b )

PAGE 109

109 1 H NMR of (2R,3R) N,N Dimethyl 2,3 bis((2 (trimethylsilyl)ethoxy)methoxy)succinamide (59c) 13 C NMR of 59c

PAGE 110

110 1 H NMR of (2R,3R) N,N Dibenzyl 2,3 bis((2 (trimethylsilyl)ethoxy)methoxy)succinamide (59d) 1 H NMR of ( 2R, 3R) 1,4 N,N Dibenzylamino 2,3 dihydroxysuccinamide (59e)

PAGE 111

111 13 CNMR of 59e 1 H NMR of 1,1' ((4S,5S) 2,2 Dimethyl 1,3 dioxolane 4,5 diyl)bis(N methylmethanamine) (60a)

PAGE 112

112 1 H NMR of N N (((4S,5S) 2,2 D imethyl 1,3 dioxolane 4,5 diyl)bis(methylene))bis(1 phenylmethanamine) (60 b) 1 H NMR of (2S,3S) N N D imethyl 2,3 bis((2 (trimethylsilyl)ethoxy)methoxy)butane 1,4 diamine (60c)

PAGE 113

113 13 C NMR of 60c 1 H NMR of (2S,3S) 1,4 Bis(methylamino)butane 2,3 d iol (60e)

PAGE 114

114 1 H NMR of (2S,3S) 1,4 Bis(benzylamino)butane 2,3 diol (60f) 1 H NMR of (1R,1'R) 1,1' ((4S,5S) 2,2 D imethyl 1,3 dioxolane 4,5 diyl)diethanamine (60g)

PAGE 115

115 1 H N MR of (2R,3S,4S,5R) 3,4 B is((2 (trimethylsilyl)ethoxy)methoxy)hexane 2,5 diamine (60h) 1 H NMR of (1R,1'R) 1,1' ((4S,5S) 2,2 D imethyl 1,3 dioxolane 4,5 diyl)bis(N methylethanamine) (60j)

PAGE 116

116 13 CNMR of 60j 1 H NMR of (2R,3S,4S,5R) N N D imethyl 3,4 bis((2 (trimethylsilyl)etho xy)methoxy)hexane 2,5 diamine (60k )

PAGE 117

117 13 C NMR of 60k 1 H NMR of (1R,1'R) 1,1' ((4S,5S) 2,2 D imet hyl 1,3 dioxolane 4,5 diyl)bis(N methyl 2 phenylethanamine) (60l)

PAGE 118

118 1 H NMR of (2R,3S,4S,5R) N,N Dimethyl 1,6 diphenyl 3,4 bis((2 (trimethylsilyl)ethoxy)methoxy)hexane 2,5 diamine (60m) 13 C NMR of 60m

PAGE 119

119 1 H NMR of (2S,2'S) 2,2' B ioxirane (62) 1 H NMR of (3aS,8aS) 2,2,5,7 T etramethyltetrahydro 3aH [1,3]dioxolo[4,5 e][1,3]diazepin 6(7H) one (6 3 a)

PAGE 120

120 13 C NMR of 63 a 1 H NMR of (3aS,8aS) 5,7 Dibenzyl 2,2 dimethyltetrahydro 3aH [1,3]dioxolo[4,5 e][1,3]diazepin 6(7H) one (63b)

PAGE 121

121 13 C NMR of 63b 1 H NMR of (5S,6S) 5,6 D ihydroxy 1,3 dimethyl 1,3 diazepan 2 one (6 3e )

PAGE 122

122 13 C NMR of 63e 1 H NMR of (5S,6S) 1,3 D ibenzyl 5,6 dihydroxy 1,3 diazepan 2 one (6 3f )

PAGE 123

123 13 C NMR of 63f 1 H NMR of (3aS,4R,8R,8aS) 2,2,4,8 tetramethyltetrahydro 3aH [1,3]dioxolo[4,5 e][1,3]diazepin 6(7H) one (63g )

PAGE 124

124 13 C NMR of 63g 1 H NMR of (4R,5S,6S,7R) 4,7 D imethyl 5,6 bis((2 (trimethylsilyl)ethoxy)methoxy ) 1,3 diazepan 2 one (6 3h )

PAGE 125

125 13 C NMR of 63h 1 H NMR of (4R,5S,6S,7R) 4,7 D ibenzyl 5,6 dihydroxy 1,3 diazepan 2 one (63i)

PAGE 126

126 1 H NMR of (4R,5S) 5 ((1S,2R) 2 amino 1 hydrox y 3 phenylpropyl) 4 benzyloxazolidin 2 one (35) 1 H NMR of (4R,4'R,5S,5'S) 4,4' dibenzyl [5,5' bioxazolidine] 2,2' dione (36)

PAGE 127

127 1 H NMR of D ibenzyl ((2R,3S,4S,5R) 3,4 dihydroxyhexane 2,5 diyl)dicarba mate (65) 1 H NMR of Dibenzyl ((1R,1'R) ((4S,5S) 2,2 dimethyl 1,3 dioxolane 4,5 diyl)bis(ethane 1,1 diyl))dicarbamate (66 a )

PAGE 128

128 1 H NMR of D ibenzyl ((2R,3S,4S,5R) 3,4 bis((2 (trimethylsilyl)ethoxy)meth oxy)hexane 2,5 diyl)dicarbamate (66 b )

PAGE 129

129 1 H NMR of N N' diphenylurea ( 68 a ) 13 C NMR of 68a

PAGE 130

130 1 H NMR of 1 ,3 B is(4 chlorophenyl)ure a (68 b ) 13 C NMR of 68b

PAGE 131

131 1 H NMR of 1,3 Bis(4 iodophenyl)urea ( 68 c ) 13 C NMR of 68c

PAGE 132

132 1 H NMR of 1,3 Bis(4 bromophenyl)urea ( 68 d ) 13 C NMR of 68d

PAGE 133

133 1 H NMR of 1,3 B is(4 methoxyphenyl)urea ( 68 e ) 13 C NMR of 68e

PAGE 134

134 1 H NMR of 1 ,3 B is(4 nitrophenyl)urea ( 68 f )

PAGE 135

135 1 H NMR of 1,3 B is(4 cyanophenyl )urea ( 68 g ) 13 C NMR of 68g

PAGE 136

136 1 H NMR of Diethyl 4,4' (carbonylbis(azanediyl))dibenzoate ( 68 h ) 13 C NMR of 68h

PAGE 137

137 1 H NMR of 3,4 D ihydroquina zolin 2(1H) one (68i) 1 H NMR of 1 (4 C yanophenyl) 3 (4 nitrophenyl)urea ( 69fg )

PAGE 138

138 1 H NMR of 1 (4 Chlorophenyl) 3 (4 methoxyphenyl)urea (69be) 1 H NMR of 1 (4 Chloro 3 ( trifluoromethyl)phenyl) 3 (4 methoxyphenyl)urea (69ne)

PAGE 139

139 13 C NMR of 69ne 1 H NMR of 1 (4 C hlorophenyl) 3 (4 phenoxyphenyl)urea ( 69bo ) and 68o

PAGE 140

140 1 H NMR of 1 (4 chloro 3 (trifluoromethyl)phenyl) 3 (4 phenoxyphenyl)urea (69no) 13 C NMR of 69no

PAGE 141

141 1 H NMR of 1 Methyl 1,3 diphenylurea (69ap) 1 H NMR of Methyl 2 ((3 aminopropyl)amino)acetate hydrochloride (79)

PAGE 142

142 1 H NMR of 2 ((3 Aminopropyl)amino)acetic acid hydrochloride (81)

PAGE 143

143 APPENDIX B TABLE OF MELTING POI NT S Entry Compound Literature Melting Point ( C) Experimental Melting Point ( C) 1 35 -70 74 2 36 -159 162 3 59a 132 134 149 130 132 4 59b 83 84 164 82 84 5 59c -158 159 6 59d -144 145 7 59e 198 200 165 197 199

PAGE 144

144 Table of Melting Points. Continued Entry Compoun d Literature Melting Point ( C) Experimental Melting Point ( C) 8 60f 77 79 165 82 85 9 65 -170 173 10 68a 236 238 166 238.0 2 38.5 11 68b 302 158 295 296 12 68c >350 167 >300 13 68d 295 158 293 294 14 68e 240 158 233 234 15 68f 299 305 160 298 300 16 68g 273 168 270 271

PAGE 145

145 Table of Melting Points. Continued Entry Compound Literature Melting P oint ( C) Experimental Melting Point ( C) 17 68h -219 220 18 68i 2 31 233 169 222 224 19 69fg >250 163 277 279 20 69be 254 170 250 253 21 79 -166 168

PAGE 146

146 LIST OF REFERENCES ( 1) Anderson, M.; Yu, H.; Penaranda, C.; Maddux, B.; Goldfine, I.; Youngren, J.; Guy, R. Journal of Combinatorial Chemistry 2 006 784 790. ( 2) Drewe, W.; Nanjunda, R.; Gunaratnam, M.; Beltran, M.; Parkinson, G.; Reszka, A.; Wilson, W.; Neidle, S. Journal of Medicinal Chemistry 2008 7751 7767. ( 3) McCleland, B.; Davis, R.; Palovich, M.; Widdowson, K.; Werner, M.; Burman, M.; F oley, J.; Schmidt, D.; Sarau, H.; Rogers, M.; Salyers, K.; Gorycki, P.; Roethke, T.; Stelman, G.; Azzarano, L.; Ward, K.; Busch Petersen, J. Bioorganic & Medicinal Chemistry Letters 2007 1713 1717. ( 4) Chrusciel, R. A.; Strohbach, J. W. Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) 2004 4 1097 1114. ( 5) De Lucca, G. V.; Lam, P. Y. S. Drugs of the Future 1998 23 987 994. ( 6) 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. Journal of Medicinal Chemistry 1996 39 1872 1884. ( 7) 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. Journal of Medicinal Chemistry 1997 40 331 341. ( 8) vonGeldern, T. W.; Kester, J. A.; Bal, R.; WuWong, J. R.; Chiou, W.; Dixon, D. B.; Opgenorth, T. J. Journal of Medicinal Chemistry 1996 39 968 981. ( 9) Kumaran, R.; Ramamurthy, P. Journal of Physical Chemistry B 2006 23783 23789. ( 10) Vishnyakova, T. P.; Golubeva, I. A.; Glebova, E. V. Russian Chemical Reviews (English Translation) 1985 54 249 261. ( 11) Sa rtori, G.; Maggi, R. In Science of Synthesis ; Ley, S. V., Knight, J. G., Eds.; Thieme: Stuttgart, 2005; Vol. 18, p 665 758. ( 12) Hegarty, A. F.; Drennan, L. J. In Comprehensive Organic Functional Group Transformations ; Katritzky, A. R., Meth Cohn, O., Ree s, C. W., Eds.; Pergamon: Oxford, 1995; Vol. 6, p 499 526. ( 13) Bigi, F.; Maggi, R.; Sartori, G. Green Chemistry 2000 2 140 148. ( 14) Trost, B. M. Angewandte Chemie International Edition in English 1995 34 259 281.

PAGE 147

147 ( 15) Klausener, A.; Jentsch, J. D. In Applied Homogeneous Catalysis with Organometallic Compounds (2nd Edition) ; Cornils, B., Herrmann, W. A., Eds.; VCH: Weinheim, 2002; Vol. 1, p 164 182. ( 16) Gabriele, B.; Salerno, G.; Costa, M. In Catalytic Carbonylation Reactions ; Beller, M., Ed.; Spr inger: Heidelberg, 2006, p 239 272. ( 17) Li, K. T.; Peng, Y. J. Journal of Catalysis 1993 143 631 634. ( 18) Srivastava, S. C.; Shrimal, A. K.; Srivastava, A. Journal of Organometallic Chemistry 1991 414 65 69. ( 19) Wan, B. S.; Liao, S. J.; Yu, D. R. Applied Catalysis a General 1999 183 81 84. ( 20) Dombek, B. D.; Angelici, R. J. Journal of Catalysis 1977 48 433 435. ( 21) Liu, C.; Lu, W.; Yan, Y. Chinese Journal of Organic Chemistry 2010 843 848. ( 22) Bassoli, A.; Rindone, B.; Tollari, S.; Chio ccara, F. Journal of Molecular Catalysis 1990 60 41 48. ( 23) Benedini, F.; Nali, M.; Rindone, B.; Tollari, S.; Cenini, S.; Lamonica, G.; Porta, F. Journal of Molecular Catalysis 1986 34 155 161. ( 24) Park, J. H.; Kim, E.; Chung, Y. K. Organic Letters 2008 10 4719 4721. ( 25) Enquist, P. A.; Nilsson, P.; Larhed, M. Abstracts of Papers, 229th ACS National Meeting, San Diego, CA, United States, March 13 17, 2005 2005 ORGN 107. ( 26) Hong, F.; Huang, Y.; Chen, H. Journal of Organometallic Chemistry 200 4 689 3449 3460. ( 27) Giannoccaro, P.; Nobile, C. F.; Mastrorilli, P.; Ravasio, N. Journal of Organometallic Chemistry 1991 419 251 258. ( 28) Hoberg, H.; Faans, F. J.; Riegel, H. J. Journal of Organometallic Chemistry 1983 254 267 271. ( 29) Mull a, S. A. R.; Rode, C. V.; Kelkar, A. A.; Gupte, S. P. Journal of Molecular Catalysis a Chemical 1997 122 103 109. ( 30) Kondo, T.; Kotachi, S.; Tsuji, Y.; Watanabe, Y.; Mitsudo, T. Organometallics 1997 16 2562 2570. ( 31) Kotachi, S.; Kondo, T.; Watana be, Y. Catalysis Letters 1993 19 339 344.

PAGE 148

148 ( 32) Mulla, S. A. R.; Gupte, S. P.; Chaudhari, R. V. Journal of Molecular Catalysis 1991 67 L7 L10. ( 33) Mulla, S. A. R.; Rode, C. V.; Kelkar, A. A.; Gupte, S. P. Journal of Molecular Catalysis a Chemical 199 7 122 103 109. ( 34) Liu, G. W.; Hakimifard, M.; Garland, M. Journal of Molecular Catalysis a Chemical 2001 168 33 37. ( 35) Durand, D.; Lassau, C. Tetrahedron Letters 1969 2329 30. ( 36) Park, J.; Yoon, J.; Chung, Y. Advanced Synthesis & Catalysis 20 09 1233 1237. ( 37) Didgikar, M. R.; Roy, D.; Gupte, S. P.; Joshi, S. S.; Chaudhari, R. V. Industrial & Engineering Chemistry Research 2010 49 1027 1032. ( 38) Alper, H.; Vasapollo, G.; Hartstock, F. W.; Mlekuz, M.; Smith, D. J. H.; Morris, G. E. Organo metallics 1987 6 2391 2393. ( 39) Chiarotto, I.; Feroci, M. Journal of Organic Chemistry 2003 68 7137 7139. ( 40) Choudary, B. M.; Rao, K. K.; Pirozhkov, S. D.; Lapidus, A. L. Synthetic Communications 1991 21 1923 1927. ( 41) Gabriele, B.; Salerno, G .; Mancuso, R.; Costa, M. Journal of Organic Chemistry 2004 69 4741 4750. ( 42) Imada, Y.; Mitsue, Y.; Ike, K.; Washizuka, K.; Murahashi, S. Bulletin of the Chemical Society of Japan 1996 69 2079 2090. ( 43) Ozawa, F.; Soyama, H.; Yanagihara, H.; Aoyam a, I.; Takino, H.; Izawa, K.; Yamamoto, T.; Yamamoto, A. Journal of the American Chemical Society. 1985 107 3235 45. ( 44) Ozawa, F.; Sugimoto, T.; Yuasa, Y.; Santra, M.; Yamamoto, T.; Yamamoto, A. Organometallics 1984 3 683 692. ( 45) Ozawa, F.; Yamam oto, A. Chemistry Letters 1982 865 868. ( 46) Shi, F.; Deng, Y. Q.; SiMa, T. L.; Yang, H. Z. Tetrahedron Letters 2001 42 2161 2163. ( 47) Tsuji, J.; Iwamoto, N. Chemical Communications 1966 380. ( 48) Ragaini, F.; Gasperini, M.; Cenini, S.; Arnera, L.; Caselli, A.; Macchi, P.; Casati, N. Chemistry a European Journal 2009 15 8064 8077.

PAGE 149

149 ( 49) Giannoccaro, P.; Dibenedetto, A.; Gargano, M.; Quaranta, E.; Aresta, M. Organometallics 2008 27 967 975. ( 50) Zheng, S. Z.; Peng, X. G.; Liu, J. M.; Sun, W.; Xi a, C. G. Helvetica Chimica Acta 2007 90 1471 1476. ( 51) Giannoccaro, P.; Ferragina, C.; Gargano, M.; Quaranta, E. Applied Catalysis a General 2010 375 78 84. ( 52) Orito, K.; Miyazawa, M.; Nakamura, T.; Horibata, A.; Ushito, H.; Nagasaki, H.; Yuguchi, M.; Yamashita, S.; Yamazaki, T.; Tokuda, M. Journal of Organic Chemistry 2006 71 5951 5958. ( 53) Peng, X.; Li, F.; Hu, X.; Xia, C.; Sandoval, C. A. Chinese Journal of Catalysis 2008 129 638 642. ( 54) Hylton, K. G. Ph.D. Dissertation, University of F lorida, 2004. ( 55) McCusker, J. E. Ph. D. Dissertation, University of Florida, 1999. ( 56) McCusker, J. E.; Abboud, K. A.; McElwee White, L. Organometallics 1997 16 3863 3866. ( 57) McCusker, J. E.; Grasso, C. A.; Main, A. D.; McElwee White, L. Organic Letters 1999 1 961 964. ( 58) McCusker, J. E.; Logan, J.; McElwee White, L. Organometallics 1998 17 4037 4041. ( 59) McCusker, J. E.; Main, A. D.; Johnson, K. S.; Grasso, C. A.; McElwee White, L. Journal of Organic Chemistry 2000 65 5216 5222. ( 60) McCusker, J. E.; Qian, F.; McElwee White, L. Journal of Molecular Catalysis a Chemical 2000 159 11 17. ( 61) Daz, D. J.; Hylton, K. G.; McElwee White, L. Journal of Organic Chemistry 2006 71 734 738. ( 62) Main, A. D. Ph. D. Dissertation, University o f Florida, 2000. ( 63) Daz, D. J. Ph.D. Dissertation, University of Florida, 2007. ( 64) Fukuoka, S.; Chono, M.; Kohno, M. Journal of Organic Chemistry 1984 49 1458 1460. ( 65) Shi, F.; Deng, Y. Q.; Sima, T. L.; Gong, C. K. Gaodeng Xuexiao Huaxue Xuebao 2001 22 645 647.

PAGE 150

150 ( 66) Shi, F.; Deng, Y. Q. Journal of Catalysis 2002 211 548 551. ( 67) Angelici, R. J. Journal of Organometallic Chemistry 2008 693 847 856. ( 68) Zhu, B. L.; Angelici, R. J. Journal of the American Chemical Society 2006 128 1446 0 14461. ( 69) Pri Bar, I.; Alper, H. Canadian Journal of Chemistry Revue Canadienne De Chimie 1990 68 1544 1547. ( 70) Waller, F. J. In Eur. Pat. Appl. ; (du Pont de Nemours, E. I., and Co., USA). EP, 1986, p 31 pp. ( 71) McGhee, W. D.; Riley, D. P.; Chr ist, M. E.; Christ, K. M. Organometallics 1993 12 1429 1433. ( 72) Hiwatari, K.; Kayaki, Y.; Okita, K.; Ukai, T.; Shimizu, I.; Yamamoto, A. Bulletin of the Chemical Society of Japan 2004 77 2237 2250. ( 73) Bitsi, G.; Jenner, G. Journal of Organometall ic Chemistry 1987 330 429 435. ( 74) Byerley, J. J.; Rempel, G. L.; Takebe, N.; James, B. R. J. Chem. Soc. D. 1971 1482 3. ( 75) Jenner, G.; Bitsi, G. Appl. Catal. 1987 32 293 304. ( 76) S ss Fink, G.; Langenbahn, M.; Jenke, T. Journal of Organometall ic Chemistry 1989 368 103 109. ( 77) Tsuji, Y.; Ohsumi, T.; Kondo, T.; Watanabe, Y. Journal of Organometallic Chemistry 1986 309 333 344. ( 78) Sima, T. L.; Shi, F.; Deng, Y. Q. Fenzi Cuihua 2001 15 435 437. ( 79) Chiusoli, G. P.; Costa, M.; Gabriele B.; Salerno, G. Journal of Molecular Catalysis a Chemical 1999 143 297 310. ( 80) Peng, X. G.; Li, F. W.; Hu, X. X.; Xia, C. G.; Sandoval, C. A. Chinese Journal of Catalysis 2008 29 638 642. ( 81) Gabriele, B.; Salerno, G.; Brindisi, D.; Costa, M.; C hiusoli, G. P. Organic Letters 2000 2 625 627. ( 82) Giannoccaro, P. Journal of Organometallic Chemistry 1987 336 271 278. ( 83) Gupte, S. P.; Chaudhari, R. V. Journal of Catalysis 1988 114 246 258.

PAGE 151

151 ( 84) Sheludyakov, Y. L.; Golodov, V. A. 1984 57 251 253. ( 85) Alper, H.; Hartstock, F. W. Journal of the Chemical Society Chemical Communications 1985 1141 1142. ( 86) Murahashi, S.; Mitsue, Y.; Ike, K. Journal of the Chemical Society Chemical Communications 1987 125 127. ( 87) Tam, W. Journal of Org anic Chemistry 1986 51 2977 2981. ( 88) Fukuoka, S.; Chono, M.; Kohno, M. Journal of the Chemical Society Chemical Communications 1984 399 400. ( 89) Kelkar, A. A.; Kolhe, D. S.; Kanagasabapathy, S.; Chaudhari, R. V. Industrial & Engineering Chemistry R esearch 1992 31 172 176. ( 90) Gabriele, B.; Mancuso, R.; Salerno, G.; Costa, M. Chemical Communications 2003 486 487. ( 91) Welton, T. Chemical Reviews 1999 99 2071 2083. ( 92) Shi, F.; Peng, J.; Deng, Y. Journal of Catalysis 2003 219 372 375. ( 93 ) Shi, F.; Zhang, Q.; Gu, Y.; Deng, Y. Advanced Synthesis & Catalysis 2005 347 225 230. ( 94) Yang, H. Z.; Deng, Y. Q.; Shi, F. Journal of Molecular Catalysis a Chemical 2001 176 73 78. ( 95) Hartstock, F. W.; Herrington, D. G.; McMahon, L. B. Tetrahed ron Letters 1994 35 8761 8764. ( 96) Veige, A. S. Polyhedron 2008 27 3177 3189. ( 97) Chen, A. C.; Ren, L.; Decken, A.; Crudden, C. M. Organometallics 2000 19 3459 3461. ( 98) Zheng, S.; Peng, X.; Liu, J.; Sun, W.; Xia, C. Helvetica Chimica Acta 2007 1471 1476. ( 99) Kanagasabapathy, S.; Gupte, S. P.; Chaudhari, R. V. Industrial & Engineering Chemistry Research 1994 33 1 6. ( 100) Bolzacchini, E.; Meinardi, S.; Orlandi, M.; Rindone, B. Journal of Molecular Catalysis a Chemical 1996 111 281 287.

PAGE 152

152 ( 101) Orejn, A.; Castellanos, A.; Salagre, P.; Castilln, S.; Claver, C. Can. J. Chem. 2005 83 764 768. ( 102) Presad, K. V.; Chaudhari, R. V. Journal of Catalysis 1994 145 204 215. ( 103) Giannoccaro, P.; De Giglio, E.; Garganno, M.; Aresta, M.; Ferr agina, C. Journal of Molecular Catalysis A: Chemical 2000 157 131 141. ( 104) Shi, F.; Deng, Y. Q. Chemical Communications 2001 443 444. ( 105) Shi, F.; Deng, Y. Q.; Gong, C. K.; Sima, T. L.; Yang, H. Z. Huaxue Xuebao 2001 59 1330 1334. ( 106) Shi, F. ; Zhang, Q.; Ma, Y.; He, Y.; Deng, Y. Journal of the American Chemical Society 2005 127 4182 4183. ( 107) Angelici, R. Journal of Organometallic Chemistry 2008 847 856. ( 108) Jetz, W.; Angelici, R. J. Journal of the American Chemical Society 1972 94 3799 3802. ( 109) Dombek, B. D.; Angelici, R. J. Journal of Organometallic Chemistry 1977 134 203 217. ( 110) Davies, S. G.; Mortlock, A. A. Tetrahedron Letters 1991 32 4791 4794. ( 111) 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. ( 112) De Lucca, G. V. Journal of Organic Chemistry 1998 63 4755 4766. ( 113) Lam, P. Y. S.; Ru, Y.; Jadhav, P. K.; Aldrich, P. E.; DeLucca, G. V.; Eyermann, C. J.; Chang, C H.; Emmett, G.; Holler, E. R.; Daneker, W. F.; Li, L. Z.; Confalone, P. N.; McHugh, R. J.; Han, Q.; Li, R. H.; Markwalder, J. A.; Seitz, S. P.; Sharpe, T. R.; Bacheler, L. T.; Rayner, M. M.; Klabe, R. M.; Shum, L. Y.; Winslow, D. L.; Kornhauser, D. M.; J ackson, D. A.; EricksonViitanen, S.; Hodge, C. N. Journal of Medicinal Chemistry 1996 39 3514 3525. ( 114) Hylton, K. G.; Main, A. D.; McElwee White, L. Journal of Organic Chemistry 2003 68 1615 1617. ( 115) Confalone, P. N.; Waltermire, R. E. In Proce ss Chemistry in the Pharmaceutical Industry ; Gadamasetti, K. G., Ed.; Marcel Dekker: New York, 1999, p 201 219. ( 116) Lam, P. Y.; Jadhav, P. K.; Eyermann, C. J.; Hodge, C. N.; De Lucca, G. V.; Rodgers, J. D. In U.S. ; (The Du Pont Merck Pharmaceutical Comp any, USA). US, 1997, p 198 pp., Cont. in part of U.S. Ser. No. 47,330, abandoned.

PAGE 153

153 ( 117) Nugiel, D. A.; Jacobs, K.; Worley, T.; Patel, M.; Kaltenbach, R. F.; Meyer, D. T.; Jadhav, P. K.; DeLucca, G. V.; Smyser, T. E.; Klabe, R. M.; Bacheler, L. T.; Rayner, M. M.; Seitz, S. P. Journal of Medicinal Chemistry 1996 39 2156 2169. ( 118) Rossano, L. T.; Lo, Y. S.; Anzalone, L.; Lee, Y. C.; Meloni, D. J.; Moore, J. R.; Gale, T. M.; Arnett, J. F. Tetrahedron Letters 1995 36 4967 4970. ( 119) Hodge, C. N.; Aldri ch, P. E.; Bacheler, L. T.; Chang, C. H.; Eyermann, C. J.; Garber, S.; Grubb, M.; Jackson, D. A.; Jadhav, P. K.; Korant, B.; Lam, P. Y. S.; Maurin, M. B.; Meek, J. L.; Otto, M. J.; Rayner, M. M.; Reid, C.; Sharpe, T. R.; Shum, L.; Winslow, D. L.; EricksonV iitanen, S. Chemistry & Biology 1996 3 301 314. ( 120) Pierce, M. E.; Harris, G. D.; Islam, Q.; Radesca, L. A.; Storace, L.; Waltermire, R. E.; Wat, E.; Jadhav, P. K.; Emmett, G. C. Journal of Organic Chemistry 1996 61 444 450. ( 121) Zhang, Y.; Forina sh, K.; Phillips, C. R.; McElwee White, L. Green Chemistry 2005 7 451 455. ( 122) DeClercq, P. J. Chemical Reviews 1997 97 1755 1792. ( 123) Lam, P. Y. S.; Jadhav, P. K.; Eyermann, C. J.; Hodge, C. N.; Ru, Y.; Bacheler, L. T.; Meek, J. L.; Otto, M. J.; Rayner, M. M.; Wong, Y. N.; Chang, C. H.; Weber, P. C.; Jackson, D. A.; Sharpe, T. R.; Erickson Viitanen, S. Science 1994 263 380 384. ( 124) McReynolds, M. D.; Sprott, K. T.; Hanson, P. R. Organic Letters 2002 4 4673 4676. ( 125) Sprott, K. T.; McRey nolds, M. D.; Hanson, P. R. Organic Letters 2001 3 3939 3942. ( 126) Briggs, M. A.; Haines, A. H.; Jones, H. F. Journal of the Chemical Society Perkin Transactions 1 1985 795 798. ( 127) Levin, J. I.; Turos, E.; Weinreb, S. M. Synthetic Communications 1 982 12 989 993. ( 128) Angelovski, G.; Ker nen, M. D.; Eilbracht, P. Tetrahedron Asymmetry 2005 16 1919 1926. ( 129) Haines, A. H.; Morley, C.; Murrer, B. A. Journal of Medicinal Chemistry 1989 32 742 745. ( 130) Kempf, D. J.; Sowin, T. J.; Doherty, E. M.; Hannick, S. M.; Codavoci, L.; Henry, R. F.; Green, B. E.; Spanton, S. G.; Norbeck, D. W. Journal of Organic Chemistry 1992 57 5692 5700. ( 131) Drewe, W. C.; Nanjunda, R.; Gunaratnam, M.; Beltran, M.; Parkinson, G. N.; Reszka, A. P.; Wilson, W. D. ; Neidle, S. Journal of Medicinal Chemistry 2008 51 7751 7767.

PAGE 154

154 ( 132) Tao, Z. F.; Wang, L.; Stewart, K. D.; Chen, Z. H.; Gu, W.; Bui, M. H.; Merta, P.; Zhang, H. Y.; Kovar, P.; Johnson, E.; Park, C.; Judge, R.; Rosenberg, S.; Sowin, T.; Lin, N. H. Journa l of Medicinal Chemistry 2007 50 1514 1527. ( 133) Wilhelm, S.; Carter, C.; Lynch, M.; Lowinger, T.; Dumas, J.; Smith, R. A.; Schwartz, B.; Simantov, R.; Kelley, S. Nature Reviews Drug Discovery 2006 5 835 844. ( 134) Bekiari, V.; Lianos, P. Chemistry of Materials 2006 4142 4146. ( 135) Ferretti, F.; Ragaini, F.; Lariccia, R.; Gallo, E.; Cenini, S. Organometallics 2010 29 1465 1471. ( 136) Leung, M. K.; Lai, J. L.; Lau, K. H.; Yu, H. H.; Hsiao, H. J. Journal of Organic Chemistry 1996 61 4175 4179. ( 137) Pasha, M.; Reddy, M. Synthetic Communications 2009 2928 2934. ( 138) Daz, D. J.; Darko, A. K.; McElwee White, L. European Journal of Organic Chemistry 2007 4453 4465. ( 139) Brown, H. C.; Hamaoka, T.; Ravindra.N Journal of the American Chemical S ociety 1973 95 5786 5788. ( 140) Lightfoot, A. P.; Twiddle, S. J. R.; Whiting, A. Tetrahedron Letters 2004 45 8557 8561. ( 141) Mastrolorenzo, A.; Rusconi, S.; Scozzafava, A.; Barbaro, G.; Supuran, C. T. Current Medicinal Chemistry 2007 14 2734 2748. ( 142) Kempf, D. J.; Sham, H. L.; Marsh, K. C.; Flentge, C. A.; Betebenner, D.; Green, B. E.; McDonald, E.; Vasavanonda, S.; Saldivar, A.; Wideburg, N. E.; Kati, W. M.; Ruiz, L.; Zhao, C.; Fino, L. M.; Patterson, J.; Molla, A.; Plattner, J. J.; Norbeck, D W. Journal of Medicinal Chemistry 1998 41 602 617. ( 143) Stoner, E. J.; Cooper, A. J.; Dickman, D. A.; Kolaczkowski, L.; Lallaman, J. E.; Liu, J. H.; Oliver Shaffer, P. A.; Patel, K. M.; Paterson, J. B.; Plata, D. J.; Riley, D. A.; Sham, H. L.; Stenge l, P. J.; Tien, J. H. J. Organic Process Research & Development 2000 4 264 269. ( 144) Bertolini, G.; Losa, M.; Feliciotti, L.; Frigerio, M. In PCT Int. Appl. ; Clariant Life Science Molecules: Italy, 2003, p 14. ( 145) Sham, H. L.; Betebenner, D. A.; Ros enbrook, W.; Herrin, T.; Saldivar, A.; Vasavanonda, S.; Plattner, J. J.; Norbeck, D. W. Bioorganic & Medicinal Chemistry Letters 2004 14 2643 2645.

PAGE 155

155 ( 146) Hyrup, B.; Egholm, M.; Nielsen, P. E.; Wittung, P.; Norden, B.; Buchardt, O. Journal of the America n Chemical Society 1994 116 7964 7970. ( 147) Zhang, S. q.; Zhang, S. y. Tetrahedron: Asymmetry 1991 2 173 174. ( 148) Kaltenbach, R. F.; Nugiel, D. A.; Lam, P. Y. S.; Klabe, R. M.; Seitz, S. P. Journal of Medicinal Chemistry 1998 41 5113 5117. ( 149 ) Shainyan, B. A.; Nindakova, L. O.; Ustinov, M. V.; Chipanina, N. N.; Sherstyannikova, L. V. Russian Journal of Organic Chemistry 2002 38 1802 1805. ( 150) Chen, W.; Liu, Y.; Chen, Z. European Journal of Organic Chemistry 2005 2005 1665 1668. ( 151) S tar, A.; Goldberg, I.; Lemcoff, N. G.; Fuchs, B. European Journal of Organic Chemistry 1999 1999 2033 2043. ( 152) Shi, H.; Liu, K.; Leong, W. W. Y.; Yao, S. Q. Bioorganic & Medicinal Chemistry Letters 2009 19 3945 3948. ( 153) Robbins, M. A.; Devine, P. N.; Oh, T. Organic Syntheses 1999 76 101. ( 154) Dondoni, A.; Perrone, D.; Rinaldi, M. Journal of Organic Chemistry 1998 63 9252 9264. ( 155) Chandrasekhar, S.; Ramachandar, T.; Reddy, M. V. Synthesis 2002 1867 1870. ( 156) Capuano, B.; Crosby, I. T.; Lloyd, E. J.; Neve, J. E. Australian Journal of Chemistry 2007 60 214 217. ( 157) Lee, H. G.; Kim, M. J.; Park, S. E.; Kim, J. J.; Kim, B. R.; Lee, S. G.; Yoon, Y. J. Synlett 2009 2809 2814. ( 158) Li, Z.; Wang, Z. Y.; Zhu, W.; Xing, Y. L.; Zhao, Y. L. Synthetic Communications 2005 35 2325 2331. ( 159) Mizuno, T.; Mihara, M.; Iwai, T.; Ito, T.; Ishino, Y. Synthesis Stuttgart 2006 2825 2830. ( 160) McGeary, R. R.; Bennett, A. J.; Tran, Q. B.; Prins, J.; Ross, B. P. Tetrahedron 2009 65 3990 3997. ( 161) Sarveswari, S.; Raja, T. K. Indian Journal of Chemistry Section B Organic Chemistry Including Medicinal Chemistry 2006 45 546 547. ( 162) Paz, J.; Perez Balado, C.; Iglesias, B.; Munoz, L. Journal of Organic Chemistry 2010 75 3037 3046.

PAGE 156

156 ( 163) R eddy, L. S.; Chandran, S. K.; George, S.; Babu, N. J.; Nangia, A. Crystal Growth & Design 2007 7 2675 2690. ( 164) Choi, H. J.; Kwak, M. O.; Song, H. Synthetic Communications 1997 27 1273 1280. ( 165) Pecanha, E. P.; Figueiredo, L. J. O.; Brindeiro, R. M.; Tanuri, A.; Calazans, A.; Antunes, O. A. C. Il Farmaco 2003 58 149 157. ( 166) Kurzer, F.; Sanderson, P. M. Journal of the Chemical Society 1962 230 236. ( 167) Chattaway, F. D.; Constable, A. B. Journal of the Chemical Society 1914 105 124 131. ( 168) Bogert, M. T.; Wise, L. E. Journal of the American Chemical Society 1912 34 693 702. ( 169) Thanigaimalai, P.; Sharma, V. K.; Lee, K. C.; Yun, C. Y.; Kim, Y.; Jung, S. H. Bioorganic & Medicinal Chemistry Letters 2010 20 4771 4773. ( 170) Fahmy, A. F. M.; Aly, N. F.; Arief, M. H. Indian Journal of Chemistry Section B Organic Chemistry Including Medicinal Chemistry 1978 16 697 701.

PAGE 157

157 BIOGRAPHICAL SKETCH Ampofo Darko was born in Accra, Ghana, in 1982 to Eva Tagoe Darko and Charles Darko. Afte r receiving his Bachelor of Science in chemistry from Guilford College in 2004, he worked as a research assistant in the pharmaceutical industry for a year. Wanting to learn more about his craft of choice, Ampofo then enrolled in graduate school at the Un iversity of Florida. Under the guidance of Professor Lisa McElwee White, he worked with ext ending the scope of of tungsten catalyzed carbonylation reactions to include a variety of functionalized substrates. For his efforts, Ampofo has been the recipient of the M. A. Battiste Award for Creative Work in Synthe tic Organic Chemistry and an American Chemical Society D ivision of O rganic C hemistry travel award for the 238 th A merican C hemical S ociety National Meeting an d Exposition. Ampofo receive d his Ph.D fro m the University of Florida in December 2010, after which he was appointed as a po stdoctoral fellow at the University of Delaware under the direction of Professor Joseph Fox.