|UFDC Home||myUFDC Home | Help|
This item has the following downloads:
CATALYTIC OXIDATIVE CARBONYLATION OF AMINO ALCOHOLS AND DIAMINES
TO UREAS AS AN ALTERNATIVE TO PHOSGENE DERIVATIVES: SYNTHESIS OF
A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY
UNIVERSITY OF FLORIDA
O 2007 Delmy Diaz-M.
To my daughters Paola and Anabella; and to my husband, Alvaro, for their unconditional love
First I would like to thank my daughters Paola and Anabella, who have been there for me
always with their constant love and support along the duration of my studies. They suffered the
most from my long hours at the lab, my frustrations, and my absences without complaint. On the
contrary, they were always understanding and waiting for me patiently. Special thanks go to my
husband Alvaro, for his unconditional love, support, and enthusiasm, and for always believing in
me. I thank my family in Honduras for their never-ending support and encouragement
throughout all these long years of studying away.
I also want to express my gratitude to my advisor, Professor Lisa McElwee-White, for her
guidance and valuable comments and suggestions throughout this academic program and
experimental investigation. I can not thank her enough for all her assistance and for always being
willing to listen to new ideas and encouraging me to try things I never thought were possible. I
also want to thank the members of my committee, Dr. Castellano, Dr. Dolbier, Dr. Lyons and Dr.
Percival, for their helpful suggestions and wise advice.
Special thanks must go to the members of the group for making my life easier and
providing a nice environment to work in. I thank my good friends Ece, Laurel and Marie for
always being there, and for sharing with me many coffee breaks. I also need to thank Phil, Seth,
and Ampofo, with whom I was working every day for the last three years.
Acknowledgement is made to the Pedagogic University Francisco Morazan for their
TABLE OF CONTENTS
ACKNOWLEDGMENT S .............. ...............4.....
LI ST OF T ABLE S ................. ...............7..._.........
LI ST OF FIGURE S .............. ...............8.....
LIST OF ABBREVIATIONS............... ..............
AB S TRAC T ........._. ............ ..............._ 1 1...
1 INTRODUCTION AND LITERATURE REVIEW .............. ...............12....
Literature Review .............. ......... ..... ..... ... ...............1
Transition Metal-Catalyzed Oxidative Carbonylation of Amines to Ureas ................... .13
Palladium-catalyzed oxidative carbonylation of amines............. ..__.........__ ....14
Homogeneous carbonylation of amines to ureas ....._____ .........__ ..............14
Pd cataly si s in ionic liqui ds ................. ..............._ 17......... ..
Electro catalytic carbonylation............... .............1
Mechanistic studies ................... ...............19..
Other Late Transition Metal Catalysts .............. ...............20....
Nickel-catalyzed oxidative carbonylation ...._ ......_____ ...... ......_........20
Ruthenium-catalyzed oxidative carbonylation ......____ ........_ ................21
Cobalt- and Rhodium-catalyzed oxidative carbonylation .............. ............. ..26
Gold-catalyzed oxidative carbonylation............... .............2
Tungsten-Catalyzed Oxidative Carbonylation of Amines ............_.. ......__..........30
Carbonylation of primary amines ............_... ...._ ...... ............3
Carbonylation of primary and secondary diamines to cyclic ureas .......................32
2 SELECTIVE CATALYTIC OXIDATIVE CARBONYLATION OF
AMINOALCOHOLS TO UREAS .............. ...............44....
Results and Discussion .............. .. ...............45.
C arb onyl ati on of 5 -Aminopentanol ......___ ......... ...............46_.. ...
C arb onyl ati on of 4 -Amino-2-methylbutan-1l-ol ................ ...............47.............
C arb onyl ation of 1, 3-Aminoalcohols .................... ...............4
C arb onyl ation of 1,2-Aminoalcohols .................... ...............5
3 THE W(CO)6 12 CATALYZED OXIDATIVE CARBONYLATION OF DIAMINES:
ANALOGS OF THE CORE STRUCTURES OF THE HIV PROTEASE INHIBITORS
DMP 323 AND DMP450. ............. ...............56.....
Back ground ............ ..... ._ ...............56....
Results and Discussion .............. ....... ........... ... .. ... .......6
Synthesis of Seven-Membered Ring Cyclic Ureas 84 and 89............... ...................6
4 CATALYTIC OXIDATIVE CARBONYLATION OF ENANTIOMERICALLY PURE
a-AMINO AMIDES TO PRODUCE HYDANTOIN DERIVATIVES ................ ...............65
Back ground .................. ................ ...............65 .....
Classic Ways to Synthesize Hydantoins ........._._._ ...._. ...............65..
Solution Phase Synthesis............... ...............6
Solid-Phase Organic Synthesis...................... .. ...................6
Synthesis of Hydantoins Using W(CO)6 12 Catalytic System ........._._.... ......_._.......70
Results and Discussion .............. ...............71....
5 EXPERIMENTAL SECTION............... ...............77
General Procedures .........._.... ....... ..__ .........._._. .... ...............7
Procedure A for Carbonylation of Amino Alcohols with CDI............. ... .........___...77
Procedure B for carbonylation of aminoalcohols with DMDTC ....................................77
Procedure C for Catalytic Carbonylation of Amino Alcohols with W(CO)6 12 .............78
Synthesis of Cyclic Ureas .............. .. ... ... ... ... ... .... .... .......8
General Procedure for the Synthesis of a-Amino Amides 103a-103e .................. ...............84
General Procedure for the Carbonylation of a-Amino Amides 103a-e to Afford
Hydantoins 104a-e. ............. ...............84.....
LIST OF REFERENCES .....___ ............... ...............87 .....
BIOGRAPHICAL SKETCH .............. ...............96....
LIST OF TABLES
1-1. Oxidative Carbonylation of Primary Amines to Ureas under Optimized Conditions. ..........33
1-2. Oxidative Carbonylation of Sub stituted Primary Diamines ................ ......._. ........._.3 6
1-3. Catalytic Carbonylation of Substituted Benzylamines to Ureas .............. ....................3
1-4. Yields of Bicyclic Ureas from Diamines 46a-49a .............. ...............42....
2-1. Carbonylation of aminoalcohols to ureas and carbamates. ............. .....................4
3-1. Structures of cyclic urea inhibitors ................. ...............58...............
3-2. Carbonylation of compounds 35-37 to Ureas 38-40 .............. ...............60....
4-1. Carbonylation conditions for ot-amino amide 103a. ............. ...............72.....
4-2. Synthesis of a-amino amides 103a-d .............. ...............74....
4-3. Catalytic carbonylation of a-amino amides 103a-e to hydantoins 104a-e. .........................75
LIST OF FIGURES
1-1. Co(salen) (22) and modified Co(salen) complexes (23-27) ................. .................2
1-2. Structures of the HIV protease inhibitors DMP 323 and DMP 450............... ..................39
4-1. Hydantoin ring structure. .............. ...............66....
4-2. Synthetic strategies and building blocks for hydantoin synthesis. ............. ....................66
4-3. a-Amino amide substrates to be converted to hydantoins ........._...... ....___.. .............73
LIST OF ABBREVIATIONS
1 ,1 '-Carb onyl diimi dazol e
1 -decyl-3 -methylimi dazolium tetrafluorob orate
Di -2-pyri dylthi oc arb onate
1 -ethyl -3 -methylimi dazolium tetrafluorob orate
Gas chromatograph-mass spectrometer
Gas liquid chromatography
Human immunodeficiency virus
Mixed anhydrides coupling
SEM 2-(trim ethyl silyl)ethoxymethyl
SPOS Solid-phase organic synthesis
TLC Thin layer chromatography
Abstract of Dissertation Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy
CATALYTIC OXIDATIVE CARBONYLATION OF AMINO ALCOHOLS AND DIAMINES
TO UREAS AS AN ALTERNATIVE TO PHOSGENE DERIVATIVES: SYNTHESIS OF
Chair: Lisa McElwee-White
The synthesis of ureas from amines has traditionally been accomplished with
stoichiometric reactions of phosgene or its derivatives, which are associated with environmental
and health issues. Because of the prevalence of urea moieties in molecules of interest for several
applications, alternative catalytic routes for the oxidative conversion of amines to ureas using CO
or CO2 as the carbonyl source have been developed. W(CO)6-catalyzed oxidative carbonylation
of amines to ureas in the presence of CO provides an alternative to stoichiometric reaction of
amines with phosgene or its derivatives such as 1,1 -carbonyldiimidazole (CDI). Synthesis of the
core structure of the HIV protease inhibitors DMP 323 and DMP 450 has been achieved via
W(CO)6 12-catalyzed carbonylation of diamine intermediates. This methodology also has been
successfully applied to the carbonylation of amino alcohols to selectively form hydroxyalkyl
ureas. Selected examples of 1,2-, 1,3-, 1,4- and 1,5-aminoalcohols were converted to the
corresponding ureas in good to excellent yields, with only trace amounts of the cyclic carbamates
being present. Other interesting targets such as hydantoins have also been prepared using
W(CO)6 12. Optically pure a-amino amides have been shown to produce the corresponding
hydantoins in good yields.
INTRODUCTION AND LITERATURE REVIEW
There is a growing interest in the synthesis of substituted ureas because of their wide field
of applications. Ureas have been known to exhibit very important biological activity, for
example, as structural components of drug candidates such as HIV protease inhibitors, 1,2 CCK-B
receptor antagonists, and endothelin antagonists. Additionally, they have shown widespread
usage as agricultural chemicals, dyes, and as additives to petroleum compounds and polymers.
From the synthetic point of view, they are used as intermediates en route to carbamates.
The classical methodology for the preparation of substituted ureas is generally based on the
nucleophilic attack of amines on phosgene or phosgene derivatives. Phosgene is useful for the
carbonylation of primary and secondary amines. The maj or drawback of phosgene is that it is a
highly toxic and corrosive gas. Because of its toxic nature, it requires special handling. This has
discouraged its use in laboratory settings.
Phosgene production and use on an industrial scale raise serious environmental risks and
problems connected with the use and storage of large amounts of chlorine, and the transportation
and storage of a highly toxic and volatile reagent. Other safer derivatives such as 1,1-
carbonylimidazole, triphosgene, and a variety of other reagents have been used in the
carbonylation of amines to form substituted ureas, and are more common in the laboratory
setting. Another variant involves the use of isocyanates, which is undesirable because of their
toxic nature and the need to synthesize them from phosgene.
Various other methods have been used to convert amines to ureas. These include the use of
phenyl chloroformate to form substituted ureas from primary amines. The drawback to this
method is the use of DMSO as solvent. DMSO is known to be toxic and a possible carcinogen.
Furthermore, it is difficult to remove because of its high boiling point.
The necessity of a catalytic alternative to stoichiometric reagents such as phosgene was
obvious. This new methodology has to be compatible with complex highly functionalized
substrates in order to be widely applied. An alternative to the reaction of nucleophiles with
phosgene is the metal catalyzed oxidative carbonylation of amines. Several examples of this
methodology have been reported in the literature.
In this regard, the McElwee-White group reported the catalytic oxidative carbonylation of
amine using W(CO)6 as catalyst and I2 as the oxidant. The system converts primary and
secondary amines and diamines to the corresponding ureas in the presence of CO. The reaction
conditions are relatively mild and one big advantage of this methodology is that it can be used
with complex highly functionalized substrates as demonstrated by previous studies of functional
Due to the commercial availability and ease of handling of the catalyst, the W(CO)6 12
catalytic system would be an alternative to phosgene derivatives and main group catalysts for
laboratory scale syntheses. In addition, its compatibility with various functional groups makes it
a good candidate for carbonylation of complex molecules to the corresponding ureas. This work
reports the application of W(CO)6 12 catalyzed carbonylation to several complex substrates.
Transition Metal-Catalyzed Oxidative Carbonylation of Amines to Ureas
The development of new synthetic protocols for the preparation of ureas has recently
attracted a lot of interest because of the presence of this functional group in pharmaceutical
candidates,6-10 agrochemicals, resin precursors, dyes and additives to petrochemicals and
polymers." The classical syntheses of ureas from amines have been based on the use of toxic
and/or corrosive reagents, such as phosgene or isocyanates.12,13 In recent years, however,
alternative routes have been developed that utilize phosgene derivatives, CO2, or CO itself as the
source of the carbonyl moiety.3 Particularly attractive from the standpoint of atom economyl4 is
oxidative carbonylation,15,16 which employs amines, carbon monoxide and an oxidant as starting
materials and produces only the reduced form of the oxidant and protons as byproducts.
In an effort to develop new methodologies for preparing moieties with carbonyl-nitrogen
bonds, metal-catalyzed carbonylation of amines has been extensively studied. Mono- and
dicarbonylations of amines catalyzed by Mn,l7l Fe,19 CO,20,21 Ni,22,23 Ru,24-27 Rh27,28 Pd,29-38
W,39-47 Pt,48 Ir48 or Au49,50 have been reported, and many different types of products, including
ureas, 1,02,75 urethanes,5 oxamides,5 formamides,54 5 and oxazolidinones,5 have been
obtained. These carbonylations have generally been carried out at high temperatures under
moderate-to-high pressures of CO and efforts to find catalysts that are effective under mild
conditions continue. This section highlights some selected recent advances in the transition
metal catalyzed oxidative carbonylation of amines to ureas.
Palladium-catalyzed oxidative carbonylation of amines
Carbonylation of amines using Pd catalysts has been extensively studied since Tsuji
reported the first Pd-catalyzed carbonylation of amines in 1966.38 Methods for oxidative
carbonylation using PdCl2 as catalyst with copper oxidants or Ol as the terminal oxidant and
CuX or CuX2 aS a mediator have been developed for preparation of ureas,60-62 carbamates,29,63
and oxamides.29,51,64,65 Since a recent review of Pd-catalyzed reactions is available,16 in this
work a few selected examples will be highlighted.
Homogeneous carbonylation of amines to ureas
Fukuoka66 and Chaudhari67 reported the oxidative carbonylation of alkylamines using Pd/C
as catalyst and iodide salts as promoters in the presence of Ol, which afforded the corresponding
ureas and/or carbamates in good yields. Related results have been reported by Gabriele68 for the
oxidative carbonylation of amines using Pdl2 and Ol, which led to formation of ureas,
carbamates, and their cyclic derivatives in good yields. New conditions for the Pdl2-catalyzed
oxidative carbonylation of amines to ureas (Eq.1i), afforded ureas in high yields with turnover
numbers as high as 4950.32,69 Carbonylations of primary aliphatic amines (Eq.1i, R = alkyl) were
carried out at 100 OC under a 4: 1:10 mixture of CO:air:CO2 (60 atm total pressure at 25 OC) in
the presence of a simple catalytic system consisting of Pdl2 in COnjunction with a KI promoter.
In the absence of CO2, leSS satisfactory results were obtained.69 The choice of solvent was
critical to product selectivity. Monocarbonylation to the urea was favored in dioxane or 1,2-
dimethoxyethane (DME), while double carbonylation to the oxamide predominated in the more
polar solvents N,N-dimethylacetamide (DMA) or N-methylpyrrolidinone (NMP). The
selectivity was attributed to higher nucleophilicity of the amine substrates in DMA or NMP,
which favors the formation of Pd(CONHBu)2 species that generate the oxamide by reductive
elimination. Primary aromatic amines (Eq. 1, R = Ar) were generally less reactive than primary
aliphatic amines under these conditions but addition of an electron-donating methoxy group
increased the nucleophilicity of the aromatic amine enough to improve the activity.
Pd cat Oj(1
2 RH 12 O RHN NHR
Pd cat Oi<2
RNH2 + R2'NH + CO + 1/2 02RHN NR'(2
The mechanism for the carbonylation of primary amines was examined in more detail after
it was determined that the secondary amines diethylamine, dibutylamine, and morpholine were
unreactive under the same conditions. The difference in reactivity was attributed to the
formation of isocyanate intermediates from the primary amine, with carbamoylpalladium
complex 1 formed in preequilibrium with starting materials (Scheme 1). In agreement with this
hypothesis, isocyanates were detected (by GLC, TLC, and GLC/MS) in the reaction mixtures in
low-conversion experiments. Under these conditions, Pd(0) is reoxidized to Pd(II) by oxidative
addition of 12, which is regenerated through oxidation of HI by oxygen.
Pd 12 + RNH2 + CO
RHN NHR RN2 R-N=C=0
This catalytic system proved to be effective for the synthesis of cyclic ureas from the
corresponding diamines, with 1,3-dihydrobenzoimidazol-2-one obtained in 99% isolated yield
(Eq. 3). This particularly high reactivity was attributed to increased nitrogen nucleophilicity and
a less negative entropy of activation due to the proximity of the ortho amino groups.32
NH, PdI, cat N
+ CO + 1/2 O OI
2 H (3)
Direct catalytic preparation of trisubstituted ureas in high selectivity (Eq. 2) was possible
under these conditions if the primary amine was carbonylated in the presence of an excess of the
less reactive secondary amine.32 This methodology has proven to be effective for the synthesis
of several types of urea derivatives, such as cyclic ureas from primary diamines and N,N-
bis(methoxycarbonylalkyl)ureas from primary a-amino esters. A showcase synthesis of the
neuropeptide Y5 receptor antagonist NPY5RA-972 was also reported (Eq. 4).32
1/2 02 (4)
x ~NPY5 RA-9 72
Pd catalysis in ionic liquids
Recently, many catalytic reactions have been reported to proceed in ionic liquids as
reaction media with excellent results.70 This approach has been adapted by Deng for Pd-
catalyzed carbonylation of amines to ureas.n1 A solubility study of the catalyst Pd(phen)Cl2
established that the ionic liquids BMImBF4 (BMIm = 1-butyl-3 -methylimidazolium), BMImPF6,
BMImFeCl4, and BMImCl were candidate media for the carbonylation reaction and that catalyst
solubility could be adjusted through the tuning of either the cation or anion of the ionic liquids.
Carbonylation of aniline to the carbamate in the presence of 02 and methanol was used to
demonstrate catalytic activity and recyclability of the catalyst/ionic liquid mixture.
Subsequent work by the Deng group developed a new method using silica gel-immobilized
ionic liquids, in which a Pd-complex acts as a heterogenized catalyst for the catalyzed
carbonylation of amines and nitrobenzene to ureas. Heterogenization of the metal catalyst by
preparation of a silica gel confined ionic liquid was followed by the carbonylation of amines and
nitrobenzene to the corresponding ureas (Scheme 2).72 No additional oxidant is necessary since
the nitrobenzene serves as both substrate and oxidant. In terms of green chemistry, the
advantages of this method are the low quantities of ionic liquids used and the avoidance of
potentially explosive CO/02 mixtures. The authors suggested that the enhanced catalytic activity
of this system may be derived from the high concentration of ionic liquid containing the metal
complex confined within the cavities of the silica gel matrix.72
Experiments with the ionic liquids DMImBF4 (1-decyl-3 -methylimidazolium
tetrafluoroborate) and EMImBF4 (1-ethyl-3 -methylimidazolium tetrafluoroborate) and the
catalysts HRu(PPh3)2 12, Rh(PPh3)3C1, Pd(PPh3)2 12 and Co(PPh3)3 12 afforded good to
excellent yields of N,N'-diphenylurea (DPU) from nitrobenzene and aniline. The Rh-
DMImBF4/silica gel catalyst produced 93% conversion of starting materials with a selectivity of
92% for the urea. Conversion of aliphatic amines and nitrobenzene to the unsymmetrically
substituted ureas could also be achieved with this particular catalyst.
NO22 + RNH2 ONHOH
ionic liquid/silica gel
R = phenyl, butyl, hexyl, cyclohexyl, p-methylphenyl
Another method for the synthesis of alkylureas is the electrocatalytic carbonylation of
aliphatic amines, as reported by Deng.73 Electrocatalytic carbonylation of a series of aliphatic
amines to dialkylureas and isocyanates using Pd(II) complexes with a Cu(II) cocatalyst could be
achieved under mild reaction conditions, with particularly good results for primary amines (Eq.
5). The additional steric hindrance in secondary amines apparently prevents the reaction, as
diisopropyl amine was unreactive under the same conditions. In addition, no conversion of
primary diamines to cyclic ureas was observed although one long chain diamine did afford a low
yield of the corresponding isocyanate.
Pd(PPh3)2Ch + Cu(OAc)2O
2 RNH2 +CO j
Bu4NCIO4, 300C, 1 atmRH NR
0.9 V versus SCE(5
Although products were obtained with a single complex as catalyst [Cu(OAc)2, PdCl2 Of
Pd(OAc)2], catalytic activity and selectivity for the urea were improved when both a Pd complex
and Cu(OAc)2 were present in the reaction mixtures. Quantitative conversion and 98%
selectivity for the urea were achieved in the case of n-butylamine with Pd(PPh3)2C 2 and
Cu(OAc)2.73 The authors suggested a synergistic effect between Pd(II) and Cu(II), as opposed to
simple mediation of electron transfer, which had been invoked in a related case of
Recent progress has also been made in understanding the mechanism of the carbonylation
of amine nucleophiles. Shimizu and Yamamoto have reported a mechanistic study focusing on
the role of the reoxidation of Pd(0) species formed in the principal catalytic cycle to electrophilic
Pd(II) species during the selective carbonylation of amines to oxamides and ureas.53 Their work
revealed the importance of the oxidant in selectivity as 1,4-di chloro-2-butene (DCB) afforded
oxamides from primary and secondary amines while use of 12 as the oxidizing agent resulted in
formation of ureas. Further insight was obtained through independent generation of
carbamoylpalladium complexes as models for species in the catalytic cycle.
Two possible mechanisms for the conversion of primary amines to ureas by palladium-
catalyzed carbonylation were discussed in conjunction with this study. In the first, the critical
step is reductive elimination of carbamoyl and amido ligands to generate the urea, as previously
proposed by Alper.s1 The crucial step in the second possible route involves formation of an
intermediate alkyl isocyanate from an N-monoalkylcarbamoylpalladium species 3, (Scheme 3).
The urea product is then derived from nucleophilic attack of a primary or secondary amine on the
isocyanate to release a symmetrically or unsymmetrically substituted urea. This second
possibility is based on an earlier proposal by Gabriele for a related system.69 Support for the
isocyanate pathway came from the inability of secondary amines to form tetra substituted ureas,
the presence of trisubstituted ureas upon carbonylation of mixtures of primary and secondary
amines and the kinetics of conversion of model compounds for 3 to ureas in the presence of
is ocya nate
O L2Pd, NHR L2Pd X
R, ,R X
NH NH 3X= Cl or l
-RNH3X 2RNH2, CO
Other Late Transition Metal Catalysts
Nickel-catalyzed oxidative carbonylation
The extensive development of palladium-catalyzed oxidative carbonylation reactions along
with the ability of Ni complexes to undergo carbonylation and produce stable carbamoyl
derivatives suggested investigation of nickel complexes as catalysts for the oxidative
carbonylation of amines.22 Giannoccaro obtained N,N'-dialkylureas, rather than the previously
reported oxamides,23 by reacting aliphatic primary amines with the nickel amine complexes
NiX2(RNH2)4 (X = Cl, Br; R = alkyl). However, yields were low, with a maximum of 55%
obtained for the carbonylation of butylamine in acetonitrile at 50.C for 8 hours under 30 atm CO
and 5 atm Ol. At temperatures higher than 50.C, side reactions became significant and at lower
temperatures the reductive step, in which amine carbonylation occurs, failed. The product
selectivity depended on the amount of water present, with anhydrous conditions favoring the
oxamide, while the presence of water promoted urea formation (Scheme 4). The authors
suggested that water could coordinate to the nickel center, allowing the formation of only one
carbamoyl group. Under aqueous conditions, this intermediate would then undergo nucleophilic
attack by amine to form the urea. In the absence of water, oxamide would arise from reductive
elimination of two carbamoyl groups.22
Nill + CO
H20, a nhyd rous
~ CONHR ~ CONHR
/Ni, OH2 CONHR
+ RN H2
Ruthenium-catalyzed oxidative carbonylation
Gupte utilized ruthenium catalysts for the selective formation ofN,N'-diphenylurea (DPU)
from the oxidative carbonylation of aniline.27 High selectivity (99%) for the formation of DPU
was obtained with [Ru(CO)3I3]NBu4 as the catalyst and Nil as the promoter. The key step in the
proposed mechanism involves the formation of carbamoyl species 8 (Scheme 5). Loss of CO
from the catalyst precursor [Ru(CO)3I3]- generates intermediate 5, which reacts with aniline to
form 6 and HI. Addition and insertion of CO affords carbamoyl complex 8, which reacts with
aniline to yield the urea and the hydride carbonyl species 9. Addition of aniline to form 10 is
followed by oxidation with 02 to regenerate the active species 6 (Scheme 5).27 Related
chemistry with alkylamines has been reported by Chaudhari.67,75
[Ru (CO)3 3]- [Ru (CO)2 3~
[(ArNH)O Ru (CO)2 21
[(rH2)Ru (HO),ll (C) (rN)R C)
Dixneuf reported the synthesis of symmetrical ureas by reacting primary amines with CO2
and a ruthenium complex, in the presence of a terminal alkyne (Scheme 6).76 Yields ranged from
low to moderate, with the best yield of N,N'-dicyclohexylurea (61%) obtained with RuCl3-H20
as catalyst in the presence of 2 equiv of tri-n-butylphosphine (n-Bu3P). Further optimization
studies established the importance of running the reaction in the presence of excess alkyne but
with no solvent.
2 RNH2 + CO2 [Ru]
from R'C2H + H20
The proposed catalytic cycle (Scheme 7) begins with coordination of the alkyne to the
metal center. The nucleophilic ammonium carbamate, formed in situ from the primary amine
and CO2, then adds to the triple bond to give the ruthenium coordinated vinyl carbamate species
11. Nucleophilic attack of the amine on carbamate 11 would then afford the urea and ruthenium-
coordinated enol 12. Protonation of the enol and decoordination regenerates the active
ruthenium species. According to this mechanism, the organic product derived from the alkyne
would be a-hydroxy-ketone 13. This ketone was not detected experimentally but would be
expected to react further under the reaction conditions (Scheme 7).76
Kondo reported the application of RuCl2(PPh3)3 as a precatalyst for the preparation of
ureas from amines, using formamide as the carbonyl source.24 Using this system, symmetrical
ureas could be prepared from the parent formamide, while unsymmetrical ureas were available
from N-substituted formamides (Scheme 8). High yields of N,N'-diarylureas were obtained from
N-arylformamides and aniline derivatives, but the yields of symmetrical ureas from formamide
were variable. Secondary amines underwent the reaction, but N,N-substituted formamides did
R1 HN NR1R2
+ 2 RNH2
2 RuCl2 (PPh3 3
Ph3P~ Ru~ .Cl
CI~Rl ClR ) PPh3
Ph3P 14 PPh3
u 0 P~h3PhC3P RuC Ru C
Ph3P PPh3 Cl \PPh3
15 ~Ph3P 1 PPh3
A proposed mechanism that accounted for these and other observations began with
formation of oxygen-bridged dinuclear complex 14 by coordination of the formamide to two
molecules of RuCl2(PPh3)3 and dissociation of two triphenylphosphine ligands (Scheme 9).
Oxidative addition of the N-H bond to the ruthenium center would then afford 15 followed by a
second oxidative addition to yield isocyanate complex 16. Reductive elimination of molecular
hydrogen produces 17, which is attacked by the amine at the isocyanate ligand to yield the
corresponding urea and regenerate the active species. In this scheme, reaction of N,N-
disubstituted formamides is not possible because they cannot form an isocyanate ligand.24
Cobalt- and Rhodium-catalyzed oxidative carbonylation
Rindone reported the synthesis of acyclic and cyclic ureas from aromatic primary amines,
using N,N'-bi s(sali cyli dene)ethyl enedi aminocob alt(II) ([Co(salen)]) as the catalyst. 20 Optimal
reaction conditions varied with the substrate. For example, the urea yields from 4-methylaniline
were higher at high pressure of Ol, while 4-fluoroaniline reacted better at lower Ol preSSUTC.
Substituent effects were also examined. Electron-withdrawing groups in the para position
lowered the conversion of the starting amine while ortho-aminophenol was more reactive than
the other amines. The substituent effects were elaborated in a subsequent paper.n
The proposed mechanism involved equilibrium between planar and non-planar salen
ligands (18 and 19) on a cobalt (III) amido complex, either of which could undergo carbon
monoxide insertion to give an equilibrium mixture of carbamoyl complexes 20 and 21.
Compound 20, having the planar salen ligand and a transrt~t~rt~t~rt~t~rt~ relationship between the carbamoyl
and amine ligands, could lead to free isocyanate or carbamate, while complex 21, having a
nonplanar salen and a cis relationship between the carbamoyl and amine ligands, would lead to
the urea (Scheme 10).20
Dicobalt octacarbonyl has also been used in the microwave synthesis of ureas. Larhed
drastically reduced reaction time by running the reaction under microwave irradiation. The
carbonyl complex served as the source of CO, eliminating the need for CO pressure in the
reaction vessel. Symmetrical and unsymmetrical ureas were obtained in as little as 10 seconds,
with yields generally better for symmetrical ureas.
1s- 0~ Nj1-O
NHAr O r ioynt
~Co NHArC NH~N2Ar
19 ~ArHN 2
Claver prepared modified [Co(salen)] complexes (Figure 1-1) and utilized them as
catalysts for oxidative carbonylation of aniline.' Results revealed that the t-butyl-substituted
catalyst 23 produced 100% selectivity for diphenylurea in the presence of butanol, while the
other complexes afforded mixtures of the urea and the corresponding butyl carbamate. The
phenanthroline derivative 26 also showed high selectivity (94%) for the urea.
Efforts in the rhodium-catalyzed carbonylation of amines to ureas have been sparse in
recent years. An early study by Chaudhari investigated various factors that affect activity and
selectivity of rhodium-catalyzed oxidative carbonylation.79 Although the primary obj ective was
the synthesis of carbamates, some conditions were found to favor the formation of ureas. In
studies focused on the oxidative carbonylation of aniline, a Rh/C-Nal system was determined to
be best for the catalytic process. Using this catalyst, polar solvents like acetonitrile or DMF
favored formation of diphenylurea, while most other solvents favored the carbamate. Modifying
pressure, temperature, and concentration also affected selectivity and activity.79
N N -Ns,N-
cNO /NO t~u O OBu
22 tBu tBu 23
02N ;O 2O NO2=N N, ,N
N, N N. ,N'
Figure 1-1. Co(salen) (22) and modified Co(salen) complexes (23-27)
Giannocaro reported preparation of Rh3+ and Rh3+-diamine complexes intercalated into y-
titanium phosphate (TiP), and measured their activity towards oxidative carbonylation of
aniline.so Intercalation provided a way to heterogenize an otherwise homogeneous catalyst.
Typical conditions involved acetonitrile or methanol as the solvent, a CO/02 mixture at
atmospheric or higher pressure, temperatures between 70-120oC, and the presence of PhNH3'
as a promoter. The highest catalyst activities were obtained with increased pressure of the
CO/02 mixture, higher temperature, and a molar ratio of co-catalyst to Rh3+(PhNH3 T/ Rh3+)
between 5 and 6. It was found that the materials containing simple Rh3+ salts worked better than
those prepared from Rh3+-diamine complexes. The key intermediate in the postulated reaction
mechanism (Scheme 11) is the Rh3+-carbamoyl complex 28 which reacts with molecular iodine
to form the iodoformate intermediate, ICONHPh. The latter reacts with aniline to afford
Ph NHCON HP h
H ,02 H TiP-HxRh,
12 / Ti P-H xy)Rh -(CO NH Ph),
Gold-catalyzed oxidative carbonylation
Deng has investigated gold compounds as catalysts for the carbonylation of amineS.50,81-84
Although simple Au(I) salts afforded carbamates from aniline, the reactions of aliphatic amines
also yielded the urea in some cases.8 Polymer immobilized gold catalysts, prepared from
commercially available ion exchange resins and HAuCl4, WeTO found to catalyze the
carbonylation of aryl amines to their methyl carbamates in the presence of methanol.so In the
absence of methanol, the diarylureas became the maj or products. In contrast to previously
reported gold catalysts, the polymer immobilized variety showed enhanced catalytic efficiency,
could easily be separated from the product, and could be used in the absence of organic solvents.
Subsequent work demonstrated that use of this system with aliphatic amines and CO2 COuld
afford symmetrical dialkylureas, with high yields and turnover frequencies (Scheme 12).84 The
mechanism is unclear, but it was postulated that the high activity can be attributed to some
synergistic relationship, between gold nanoparticles and the polymer support.
R2NH Auplmr'R2NHC ON HR2
CO + 02
Tungsten-Catalyzed Oxidative Carbonylation of Amines
Carbonylation of primary amines
Despite extensive investigation of transition metal-catalyzed carbonylation reactions,
examples involving Group 6 metals still remain rare. During the last decade, we have been
exploring conversion of amine substrates to the corresponding ureas using tungsten carbonyl
complexes as the catalysts and I2 as the oxidant.
The initial report described catalytic oxidative carbonylation of primary amines using the
iodo-bridged tungsten dimer [(CO)2W(NPh)I2 2 (29) as the precatalyst.41 During those studies, it
was shown that primary aromatic and aliphatic amines could be carbonylated to 1,3-disubstituted
ureas, while secondary amines afforded formamides in modest yields.
Mechanistic studies on this process established that primary amines reacted
stoichiometrically with dimer 29 to yield the amine complexes (CO)2I2W(NPh)(NH2R) (30)
(Scheme 13), which undergo reaction with excess amine to afford the corresponding ureas.43
Nucleophilic attack of the amine on a carbonyl ligand of 31, followed by proton abstraction
using a second equivalent of the amine would afford carbamoyl complex 32. IR spectra of the
reaction mixtures were consistent with the presence of carbamoyl complexes. The intermediacy
of carbamoyl complex 32 is precedented by Angelici's work on the carbonylation of CH3NH2 by
[(rl,-C5HS)W(CO)4]PF6,85 for which the first step is conversion of [(r15-CsHS)W(CO)4]+ to the
carbamoyl complex ('ls-CsHs)W(CO)3(CONHCH3) upon reaction with 2 equiv of CH3NH2.
1/2 C;, 1/,, \CO 1 equiv NH2R OC 1
OC I ~llCO OCI INH2R
OC/, II \NH2R
,________ OC/, I \NH2R
1 equiv NH2R O~c C NH2R
Assignment of the next step as oxidation was supported by IR spectra that showed the
disappearance of the carbamoyl stretches after the reaction mixtures were exposed to air. It is
expected that following oxidation of the complex, the carbamoyl proton would be more acidic
and deprotonation of 32 with the excess amine would produce the isocyanate complex 33.
Nucleophilic attack of an amine on either coordinated or free isocyanate would afford the 1,3-
disubstituted urea, producing coordinatively unsaturated complex 34, which could undergo
addition of CO to regenerate cationic intermediate 31 and close the catalytic cycle.
The previous results implied that other tungsten carbonyl iodide complexes might also
serve as catalysts. The simplest choice as precatalyst was the readily available, inexpensive, and
air stable W(CO)6. Preliminary studies were carried out using W(CO)6 as catalyst for the
catalytic carbonylation of n-butylamine. Reaction of W(CO)6, 100 equiv of n-butylamine, 50
equiv of iodine, and 100 equiv of K2CO3 in a 125 mL Parr high-pressure vessel pressurized with
100 atm CO produced di-n-butylurea in an amount corresponding to 39 turnovers per equivalent
of W(CO)6, or 80% yield with respect to amine.43
Subsequent optimization studies using n-propylamine established that N,N'-disubstituted
ureas could be obtained in good to excellent yields using the W(CO)6 12 oxidative carbonylation
system (Table 1-1).44 Once W(CO)6 (2 mol %) was established as the preferred catalyst, other
variables were examined. Optimal conditions were 900C, 80 atm CO, 1.5 equiv of K2CO3, and a
chlorinated solvent such as CH2 12 or CHCl3. Note that conditions could not be found for
conversion of aniline to diphenylurea, presumably due to lower nucleophilicity of the aryl amine.
Carbonylation of primary and secondary diamines to cyclic ureas
Many methods for conversion of diamines to the corresponding cyclic ureas have been
reported.12,13 Most of them are stoichiometric reactions based on nucleophilic attack of amines
on phosgene and related derivatives. Catalytic oxidative carbonylation of diamine substrates
provides an alternative route to cyclic ureas in which CO is used as the carbonyl source.
However, the synthesis of cyclic ureas via metal-catalyzed carbonylation has received limited
attention. Early reports of transition metal-catalyzed carbonylation of diamines mentioned cyclic
ureas only as very minor or side products. In the case of Mn2(CO)l0-catalyzed carbonylation of
the diamines H2N(CH2),n 2 (n = 2-4 and 6), no cyclic products were observed when n = 2, 4, or
6 and only 6% of the six-membered urea when n = 3.86
Table 1-1. Oxidative Carbonylation of Primary Amines to Ureas under Optimized
Conditions: W(CO)6 (2 mol %), Il (0.5 equiv),
CH2 12 aS the solvent.
1.5 equiv of K2CO3, 900C, 80 atm CO,and
We thus explored the catalytic carbonylation of diamines to cyclic ureas using W(CO)6 as the
catalyst, Il as the oxidant, and CO as the carbonyl source.42 Both primary and secondary ot,co-
diamines were substrates for the reaction, with secondary diamines being converted directly to
the corresponding N,N'-disubstituted cyclic ureas.
Synthesis of the five-, six-, and seven-membered cyclic ureas from the primary diamines
could be achieved in moderate to good yields (Eq 6),42 with the highest isolated yield for the six-
membered cyclic urea. Only trace amounts of the eight-membered ring compound could be
detected in the reaction mixtures, which was not surprising as there are no reports in the
literature of preparation of this compound from 1,5-pentanediamine. In addition, (+)-(1R,2R)-
1,2-diphenyl-1 ,2-ethanediamine was carbonylated to the 2-imidazolidinone in 46% yield with no
epimerization. Reaction of the secondary diamines RNHCH2CH2NHR (Eq 6, R = Me, Et, iPr,
Bn) under similar conditions resulted in conversion of the diamines to the corresponding N,N'-
disubstituted cyclic ureas. For both primary and secondary substrates, it was necessary to
employ high dilution conditions to minimize formation of oligomers, a problem also encountered
during the reactions of phosgene and its derivatives with diamines."7
NHR NHR W( CO)6 RN N ,R(6
n ~CO / 12 / K2CO3
R = H, alkyl
Steric effects on the ring closure reaction were probed by carbonylating N,N'-dimethyl,
diethyl, diisopropyl, and dibenzyl diamines under the standard conditions.42 As expected, 1,3-
diethyl-2-imidazolidinone and 1,3 -dimethyl-2-imidazolidinone were produced in nearly identical
yields. Changing the substituents to benzyl groups lowered the yield only modestly but the
presence of bulky isopropyl groups dramatically reduced the yield of the imidazolidinone to only
10%. Yields in the sterically hindered cases could not be improved by raising the reaction
temperature. Although primary amines reacted much more readily than secondary amines, N-
methylpropanediamine reacted under the oxidative carbonylation conditions to produce the
corresponding monosubstituted N-methyl cyclic urea in preference to acyclic urea formation
through the more reactive primary amines.42
A more extensive study on the carbonylation of ac~o-diamines to cyclic ureas involved
further optimization of the conditions using propane-1,3 -diamine as the test substrate, W(CO)6 aS
catalyst and I2 as the oxidant.2 Effects of solvent and temperature variation on the yields of the
cyclic urea from propane-1,3-diamine were examined. Additional experiments probed the effect
of alkyl substituents in the linker of primary diamines (Table 1-2). In the cases of simple n-alkyl
substituents, the yields of cyclic ureas are significantly higher for the 2,2-dialkyl-1,3-
propanediamines than for the parent propane-1,3 -diamine as a result of the Thorpe-Ingold
effects and improved solubility in organic solvents during workup.
The carbonylation of N,N' -dialkyl-2,2-dimethylpropane- 1,3 -diamines afforded
tetrasubstituted ureas; however, the products were obtained in modest yields, and
tetrahydropyrimidine byproducts were formed in significant amounts when the substrates bore
N-alkyl substituents larger than methyl. Comparison of these results with the carbonylations of
secondary diamines to form five-membered cyclic ureas suggested that the effects of ring size
and N-substituent size on the carbonylation reaction are complex.
Success with conversion of diamines to cyclic ureas suggested the use of W(CO)6-
catalyzed oxidative carbonylation of amines can be used for the the synthesis of complex targets.
Table 1-2. Oxidative Carbonylation of Substituted Primary Diamines
Amine Product % Yield
H 2N r~NH2
H 2N NH2
Before considering applications in synthesis, it was necessary to evaluate the functional
group compatibility of the catalyst, often a critical issue in the use of early metal systems.
Studies of functional group compatibility using a series of substituted benzylamines (Eq. 7,
Table 1-3) demonstrated that the oxidative carbonylation of amines using the W(CO)6 12 system
is tolerant of a wide variety of functionality, including halides, esters, alkenes, and nitriles. A
distinguishing feature is the tolerance of unprotected alcohols, which would be problematic with
phosgene derivatives.44 A critical result of this study is the observation that the addition of water
to generate a biphasic solvent system produced dramatic increases in the yields of functionalized
ureas. In order for the reaction to work efficiently, it is necessary to solubilize the catalyst, the
starting amine, the hydroiodide salt of the starting material which is formed when protons are
scavenged, and the base (K2CO3). The biphasic solvent system sets up phase transfer conditions
in which the amine salt can be deprotonated by aqueous carbonate and then returned to the
organic phase for carbonylation.
After broad functional group tolerance during W(CO)6 12-catalyzed oxidative
carbonylation of amines to ureas had been established,44 USe of this methodology to install the
urea moiety into the core structure of the HIV protease inhibitors DMP 323 and DMP 450
(Figure 1-2)89,90 WaS investigated.4
R~" NH2), 3 NN
Table 1-3. Catalytic Carbonylation of Substituted Benzylamines to Ureas
%Yielda~ %Yielda~ %Yielda %Yieldb
AmineCH2 12 CH2 12/H20 mn CH2 12 CH2 12/H20
H NH2 63 73 Et NH2; 36 55
Cl NH2 35 77 H NH 0 37
B NH2" 30 77 NH2 416
I--2" 39 70 02N245 76
MeO NH 47 70 NC NH2 37 68
MeS NH 24 81 H2 NH2; 28 14
HNH2 5 58 NHN2 17 20
HISQNI NH 0
a Reaction conditions: amine (7.1 mmol), W(CO)6 (0.14 mmol), Il (3.5 mmol), K2CO3 (10.7
mmol), CH2 12 (20 mL), 70 oC, 80 atm CO, 24 h.
b The solvent was CH2 12 (21 mL) plus H20 (3 mL). Other conditions are as in footnote a.
Direct comparison of the catalytic carbonylation reaction with stoichiometric reaction of
the same substrates with phosgene derivatives was possible due to the extensive literature on the
synthesis of these targets.
~ Q H2N NH2
NNI N N
Ph P Ph II Ph
HO O6H HO OcH
DMP 323 DMP 450
Figure 1-2. Structures of the HIV protease inhibitors DMP 323 and DMP 450
It has been reported in the literature that the urea moiety of DMP 323 and DMP 450 was
installed by reaction of phosgene or a phosgene equivalent with an O-protected diamine diol. In
the initial small-scale preparations, a primary diamine was reacted with the phosgene derivative
1,1 '-carbonyldiimidazole (CDI)90-93 followed by N-alkylation as appropriate. The practical
preparation of DMP 450 involves reaction of secondary diamine with phosgene to form the
cyclic urea. Since use of phosgene or CDI requires protection of the diol, extensive protecting
group studies have been carried out.91,94 Three of the previously described O-protected diamine
diols, acetonide 35,94 MEM ether 36,90,95 and SEM ether 3790 were tested in the catalytic
carbonylation reaction as representative examples containing cyclic and acyclic protecting
groups, respectively (Eq. 8).4
Carbonylation of diamine substrates 35-37 (Eq 8) to the cyclic ureas 38-40 provided a
means for comparison of the W(CO)6-catalyzed process to the stoichiometric reactions of the
phosgene derivative CDI. More extensive discussion of the results obtained from these
experiments will be submitted in subsequent chapter.
NH2 NH2, Hs ,H
Ph .,,Ph W(CO), /C30 Ph .,,,Ph
PO0 OP2 plo O P2
35 Pl, P2 = C(CH3)2 38 pl, P2 =/ C(CH3)2
36 Pl, P2 = MEM, MEM 39 Pl, P2= MEM, MEM
37 Pl,P2= SEM,SEM 40 Pl,P2= SEM, SEM
Efforts to avoid the protecting group chemistry in reported syntheses of DMP 323 and
DMP 450 by carbonylating the diamine diol 41 were frustrated by the reaction of the diol
hydroxyl groups to generate oxazolidinones 42 and 43 (Eq. 9).46 Oxalzolidinone formation had
also been reported as the result of reaction of 41 with CDI and phosgene.96 The earlier
functional group compatibility study had suggested that the catalyst was tolerant of -OH groups
(Eq 7, Table 3) but the test substrate in that study was [4-(aminomethyl)phenyl]methanol, in
which the -OH group is para with respect to the amine so as to eliminate the possibility of
formation of a cyclic carbamate. For that substrate, the corresponding urea was produced
without competing carbamate or carbonate formation.44 For diamine diol 41, oxazolidinone
formation had been preferred under the reaction conditions tested.
More recently, the catalytic carbonylation of a series of amino alcohols of varying tether
lengths and substitution patterns was carried out to probe the selectivity of the W(CO)6 12
carbonylation system for reactivity of alcohols versus amines. The phosgene derivatives
dimethyl dithiocarbamate (DMDTC) and 1,1'-carbonyldiimidazole (CDI) were used as
representative stoichiometric reagents for comparison purposes, the results are discussed in a
separate chapter, later on in this work.46
s\\s NH 2
Bn* W(CO)6, 12
HO OH CO, K2CO3
Other interesting targets that were prepared to investigate the scope of the W(CO)6 12
system were biotin and related heterocyclic ureas.97 Biotin (44b), also known as Vitamin H, is
produced on large scale as a feed additive for poultry and swine. It has also been the target of
more than 40 total and formal syntheses.98 One recurring theme in these syntheses has been
installation of the urea moiety by reaction of phosgene with a di aminotetrahydrothi ophene
44b R =H (0%)
45b R =Me (84%)
+H3N / NH3
44a R = H
45a R = Me
H N NH
R1 X R2
R1 X R2
Although biotin itself could not be produced directly from carboxylic acid 44a (Eq. 10),
biotin methyl ester (45b) was obtained in 84% yield upon W(CO)6-catalyzed oxidative
carbonylation of diamine 45a. The related heterocycles 46b-49b were also prepared by the
carbonylation procedure and the yields compared to those obtained by reaction of the same
substrates with CDI (Eq 11, Table 1-4). Yields of the ureas were moderate to good and
depended on the solubility of the diamine and urea in methylene chloride.
Table 1-4. Yields of Bicyclic Ureas from Diamines 46a-49a
.mn Ue W(CO)6 12 CDI
46a 46b Trace 20%
47a 47b 47% 67%
48a 48b 46% 37%
49a 49b 57% 56%
Transition metal-catalyzed carbonylation of amines offers new and efficient methodology
for the selective synthesis of ureas under relatively mild reaction conditions. Use of CO or CO2
as the carbonyl source in the presence of a catalyst and an oxidant provides an alternative to the
traditional methods for conversion of amines to ureas, which involve stoichiometric use of
phosgene and its derivatives. From the perspective of green chemistry, the replacement of
phosgene and the minimization of the waste streams associated with phosgene derivatives would
Recent developments in metal-catalyzed oxidative carbonylation of amines include new
techniques such as the use of ionic liquids, microwave irradiation and electrocatalytic
carbonylation. In addition to extensive work with palladium complexes, carbonylation reactions
that utilize other late transition metals, such as Ni, Ru, Rh, Co, Au, have also been demonstrated
to afford ureas. Indications that tungsten-catalyzed oxidative carbonylation of functionalized
amines could be of use in the synthesis of complex targets had also been reported. Given the
prevalence of urea functionality in compounds with a wide range of applications, further work in
this area is no doubt forthcoming.
SELECTIVE CATALYTIC OXIDATIVE CARBONYLATION OF AMINOALCOHOLS TO
Conversion of amines to ureas commonly involves nucleophilic displacement of leaving
groups from phosgene or a phosgene derivative.13 Phosgene and its derivatives are not selective
for the carbonylation of amines, reacting with other functionality such as hydroxyl groups. In
fact, phosgene reacts with both functional groups of aminoalcohols to form products such as
cyclic carbamateS99 Of isocyanate chloroformates (Scheme 14).100,101 Although transamination of
ureas,102 Selenium-catalyzed carbonylation,103 and condensation with S,S'-dimethyl
dithiocarbonate (DMDTC)104 have been used to generate hydroxyalkylureas from aminoalcohols
under circumstances where formation of the cyclic carbamate is disfavored, selective reactivity
of aminoalcohols with a phosgene derivative often requires protection of one functional group to
avoid forming mixtures of ureas and carbamates.
n = 3, 5
As an alternative to phosgene and phosgene derivatives, we recently reported the catalytic
carbonylation of aliphatic amines to ureas using W(CO)6 as the catalyst and I2 as the oxidant.41,43-
45 A functional group compatibility study demonstrated that the catalyst was tolerant of OH
groups (Eq. 12), at least in the case of [4-(aminomethyl)phenyl]methanol, in which the
corresponding urea was produced without competing carbamate or carbonate formation.44
However, in the carbonylation reaction of Eq 12, the -OH group is para with respect to the
amine so as to eliminate the possibility of intramolecular formation of a cyclic carbamate. We
now report the catalytic carbonylation of a series of aminoalcohols of varying tether lengths and
substitution patterns in order to evaluate the selectivity of the W(CO)6 12 carbonylation system
for reactivity of alcohols vs. amines. These results are compared to reaction of the same
aminoalcohol substrates with the phosgene derivatives DMDTC and 1,1'-carbonyldiimidazole
~I~NH2 W(CO)6, 2 HO N N OH (12)
HO CO, K2CO3
O 71 %
Results and Discussion
The aminoalcohol substrates for this study were chosen with varying tether lengths
between the functional groups and varying steric hindrance at the active sites. The substrates
were then subj ected to W(CO)6-catalyzed oxidative carbonylation for evaluation of the
selectivity of the W(CO)6 12 system towards formation of the ureas or carbamates, either cyclic
or acyclic. As a comparison of the stoichiometric reactions of phosgene derivatives to the
catalytic W(CO)6 12 methodology, 1,1'-carbonyldiimidazole (CDI) and dimethyl dithiocarbonate
(DMDTC) were also used for the carbonylation of the aminoalcohol substrates.
Carbonylation of 5-Aminopentanol
Carbonylation of 5-aminopentanol 50 was investigated to determine the preference of a
1,5-aminoalcohol to form the corresponding acyclic urea 51 or the 8-membered cyclic carbamate
52 (Eq. 2). The optimal reaction conditions of a substrate concentration of 4M, 40 oC, 80 atm
CO and a reaction time of 18 hours afforded the bis(hydroxyalkyl)urea 51 in 64% yield and the
cyclic carbamate 52 in only 2% yield. The acyclic carbamate 53 was not detected in the reaction
mixtures. However, the presence of unreacted starting material was observed by TLC prior to
purification of the products.
HO N N OH
HO NH2 W(CO)6, CO Q
50 12~ 9 13
When potassium carbonate was used as the base, as was reported in prior studies,42,44
formation of urea 51 was confirmed by various spectroscopic methods. No evidence of the
acyclic carbamates 53 was found. Purification of 51 by the previously described method proved
difficult. The problem is similarity in the solubilities of the hydroxyalkylurea product and
potassium iodide, which is a byproduct of carbonylation in the presence of K2CO3
Consequently, it was difficult to purify the urea by methods such as chromatography or selective
extraction. These difficulties with the workup could be avoided by changing the base to
pyridine, which allowed purification of the products to be carried out without chromatography.
The modified workup for the recovery of the urea and carbamate is described in detail in the
The selectivity of the W(CO)6-catalyzed carbonylation of 5-aminopentanol is comparable
to the selectivity when phosgene derivatives are used as the carbonylation agents. Carbonylation
of aminoalcohol 50 using CDI afforded urea 51 in 80% yield, while just trace amounts of the
cyclic carbamate 52 and none of the acyclic carbamate 53 were observed. The other phosgene
derivative, DMDTC, produced urea 51 from aminoalcohol 50 in 45% yields with no evidence of
the formation of 52 or 53 (Table 2-1, entryl).
Carbonylation of 4-Amino-2-methylbutan-1-ol
The selectivity between conversion of a 1,4-aminoalcohol to a seven-membered cyclic
carbamate, an acyclic carbamate or the corresponding urea was investigated using 4-amino-2-
methylbutan-1-ol (54) as a representative substrate. The optimal reaction conditions were found
to be the same as for 5-aminopentanol; with a substrate concentration of 4M, 40 oC and a
reaction time of 18 hours producing urea 55 in 93% yield. Compounds 56 and 57 were not
detected in the reaction mixtures by NMR or IR.
To compare the carbonylation of 54 to results using phosgene derivatives, 4-amino-2-
methylbutanol was treated with CDI at a concentration of 4 M or DMDTC at a concentration of
4.5 M. All three carbonylation methods produced similar selectivity for the formation of urea 55
over products 56 and 57. When CDI was used as the carbonylating agent, compound 55 was
formed in 70 % yield as the maj or component of the product mixture while 56 was detected in
trace amounts (Eq. 3). There was no evidence for the formation of 57. Likewise, in the case of
DMDTC, urea 55 was produced in 93% yield as the only product (Table 2-1, Entry 2).
Table 2-1. Carbonylation of aminoalcohols to ureas and carbamates.
Entry Substrate Reagent Urea Cyclic
(%) Carbamate (%)
W(CO)6 /CO 64 2
1 H2N OH CDI 80 trace
DMDTC 45 0
W(CO)6 /CO 93 0
2 ON2 CDI 70 trace
54 DMDTC 93 0
W(CO)6 /CO 95 trace
3 OH NH2
CICDI 36 60
59 C2h DMDTC 30 8
W(CO)6 /CO 72 14
4 .~"" i CDI 49 30
Ph DMDTC 34 47
W(CO)6 /CO 60 5
5 OH NH2
CDI 55 28
/ DMDTC 32 29
W(CO)6 /CO 78 10
6 "e~Ph CDI 18 22
75 DMDTC 72 trace
W(CO)6 /CO 79 14
7 HO NH2
t/ CDI 30 52
DMDTC 73 trace
HO NN N OH
HO ~ NH2 W(CO)6, CO NOO
I 5 14
HO N" KO N/H2
The carbonylation of a 1,3-aminoalcohol to a six-membered cyclic carbamate or an acyclic
carbamate vs. formation of the corresponding urea was first investigated using 3 -amino-4-
phenyl-butanol (59) as a representative substrate. Substrate 59 was synthesized by reduction of
DL-P-homophenylalanine (58) with BH3-THF at 0 oC (Eq. 15).
\ ~BH .THF\
3 (1 5)
O~ 4.5 hrs
Aminoalcohol 59 was then subj ected to oxidative carbonylation using the W(CO)6 12
catalytic system under the previously determined optimal reaction conditions (Eq. 16, Table 6,
Entry 3). Urea 60 was isolated in 95% yield with carbamate 61 formed in trace amounts as a
minor product. Acyclic carbamate 62 was not observed.
12, py O ,1 (16)
In order to compare the carbonylation results to phosgene derivatives, 59 was treated with
DMDTC and CDI, respectively. In contrast to the excellent yield of urea 60 from the W(CO)6-
catalyzed carbonylation, reaction of amine 59 with DMDTC afforded 60 and 61 in yields of 30%
and 8%, respectively. Compound 62 was once again not detected. The reaction also produced a
number of side products which were detected by TLC analysis. When CDI was used as the
carbonylating agent, 60 and 61 were produced with 61 being the major product (60% yield)
while 60 was formed in 36% yield. Once again, compound 62 was not observed (Table 2-1,
A second example of the preference for conversion of 1,3 aminoalcohols to the urea vs. the
cyclic carbamate was obtained by carbonylation of 1 -phenyl-3-aminopropanol (63). Amino
alcohol 63 was synthesized by treating benzaldehyde with acetonitrile under basic conditions
followed by reduction of the resulting cyanohydrin with borane dimethylsulfide.5 Carbonylation
of 63 using the W(CO)6 12 catalytic conditions provided the corresponding urea 64 in 72% yield,
with the minor product being cyclic carbamate 65 in 14% yield after crystallization. The acyclic
carbamate 66 was not formed in the reaction.
OH W(CO)6, 2 HO 6
CO, pyO N NH2` (17)
63NH2 O N
For comparison, 1-phenyl-3 -aminopropanol was subj ected to carbonylation with the
phosgene derivatives CDI and DMDTC (Table 2-1, entry 4). When CDI was used as
carbonylating agent, the urea 64 was formed in 49% yield, and the cyclic carbamate 65 in 30%
yield. Once again, the acyclic carbamate was not observed in the product mixture. In contrast,
when DMDTC was used as carbonylating agent, cyclic carbamate 65 was the maj or product
(47% yield), while the urea was recovered in 34% yield.
F finally, 3 -ami no-2,2 -dim ethyl prop anol (6 7) was studi ed under the opti mal W(CO0)6 12
catalytic conditions (Eq. 18). Compound 67 was chosen in order to examine the effect of steric
bulk at the position P to the nucleophilic nitrogen and the Thorpe-Ingold effect of the gem-
dimethyl substituents at C3. Accordingly, the carbamate was expected to be favored by the
presence of the gem-dimethyl substituents. However, when carried out under the W(CO)6 12
carbonylation conditions, the reaction did not go to completion and 12% of the starting material
was recovered. This may be due in part to steric bulk in the substrate. Nevertheless, urea 68 and
carbamate 69 were obtained in 60% and 5% yield, respectively (Table 2-1, entry 5). There was
no evidence for the formation of the acyclic carbamate 70.
OH HN NH OH HN O
NH2 OH W(CO)6, CO 68 O69
12, PY NH2 O HOH
In contrast, when 3 -ami no-2,2 -di methyl prop anol (6 7) was tre ated with CD I or DMD TC,
much higher proportions of carbamate were generated than with the W(CO)6-catalyzed
carbonylation (Table 2-1, Entry 5). Urea 68 was still the maj or product for both carbonylation
reactions, being isolated in 55% yield and 32% yield, respectively. However, cyclic carbamate
69 was recovered in 28% yield from the reaction with CDI and in 29% yield when DMDTC was
used in the carbonylation. Overall, there is a strong selectivity favoring formation of urea over
carbamate in the W(CO)6-catalyzed carbonylation for all three 1,3-aminoalcohols that were
investigated. In comparison, the selectivity for formation of the urea over formation of the
carbamate is significantly lower when CDI or DMDTC is used as the carbonylating agent.
Carbonylation of 1,2-Aminoalcohols
Our interest in the carbonylation of 1,2-aminoalcohols began with our preparation of the
core structure of the HIV protease inhibitors DMP 323 and DMP 450 by W(CO)6-catalyzed
carbonylation of O-protected derivatives of diamine diol 71.4 As part of these investigations, it
was determined that under the initially reported conditions, oxidative carbonylation of 71
afforded oxazolidinones 73 and 74 instead of the diol urea 72 (Eq. 19).39 A similar preference
had previously been reported for the reactions of 71 with CDI and phosgene.96
BnC "''Bn HN
Bn '.Bn W(CO)6 2
HO OH CO, K2CO3
These prior results provided motivation for additional study of 1,2-aminoalcohols. The
initial substrate was p-amino alcohol 75 (Eq. 20), chosen for its structural similarity to half of 71
To further investigate formation of the oxazolidinone ring vs. coupling to the urea, oxidative
carbonylation of p-amino alcohol 75 was carried out using the W(CO)6 12 catalytic system (Eq.
20). The conditions were the same as described for the previous aminoalcohol substrates. Upon
carbonylation of 75, urea 76 and cyclic carbamate 77 were obtained in 78% and 10% yield,
respectively, with urea formation once again strongly preferred (Table 2-1, entry 6). Although
the phosgene derivative DMDTC afforded similar results, carbonylation of 75 with CDI
produced only low yields of a roughly equal mixture of urea 76 and carbamate 77.
W(CO)6, 12 HN NH
CO, py ,J Ph ,,,Ph
To further investigate the carbonylation of 1,2-aminoalcohol substrates, (R)-(-)-2-amino-1-
phenylethanol (78) was also subjected to the W(CO)6-catalyzed carbonylation (Eq. 21). Urea 79
and cyclic carbamate 80 were obtained in 79% and 14% yield, respectively. As observed for
1,2-aminoalcohol 75, there was a high selectivity for conversion of 78 to the urea in preference
to the oxazolidinone.
h HN NH r
H2 H W(CO)6, 12 Phh+H O (21)
CO, py OH OH O
78 79 80
The phosgene derivatives CDI and DMDTC were also used in the carbonylation of 78 for
comparison. In the former reaction, the cyclic carbamate 80 was the major product (52% yield)
while the urea 79 was recovered in 30% from the mixture. On the other hand, when DMDTC
was used as the carbonylating agent, urea 79 was the maj or product of the reaction (73% yield)
while oxazolidinone 80 was isolated in just trace amounts (Table 2-1, Entry 7). Note that for
1,2-aminoalcohols 75 and 78, both the W(CO)6-catalyzed carbonylation and DMDTC afforded
the hydroxyalkyl ureas as the maj or products but carbonylation with CDI favored the cyclic
In summary, the W(CO)6 12 methodology can be applied to carbonylation of aminoalcohols
to the ureas without protection of the hydroxyl group. The W(CO)6-catalyzed oxidative
carbonylation is consistently selective for the urea over the cyclic carbamate in all cases studied.
Acyclic carbamates are not detected in the reaction mixtures. In contrast, reactions of the
phosgene derivatives CDI and DMDTC with 1,3- and 1,2-aminoalcohol substrates exhibit
variable selectivities between ureas and cyclic carbamates.
THE W(CO)6 12 CATALYZED OXIDATIVE CARBONYLATION OF DIAMINES:
ANALOGS OF THE CORE STRUCTURES OF THE HIV PROTEASE INHIBITORS DMP
323 AND DMP450.
The syntheses of new improved and more efficient HIV inhibitors against mutant proteases
continue to be an important target in medicinal and synthetic chemistry. In order to design and
synthesize more potent inhibitors of HIV protease, it is crucial to understand the basics of
molecular recognition for the protease. Extensive studies have been done in this regard and two
distinctive characteristics have been identified.'os First, it was found that the active form of the
viral enzyme is a homodimer, in which each monomer contributes equally to the active site.
Also, the occurrence of structural water that bridges linear inhibitors to the flap of the protein
through hydrogen bonds has been confirmed. One of the first sets of C2 symmetric molecules
that were reported to displace the structural water was the C2 symmetric cyclic urea-based
Since these inhibitors were first reported, the number of cyclic urea scaffolds has rapidly
increased and this class of cyclic compounds has become a feasible alternative to the existing
antiretroviral agents. DMP 323 and DMP450 are among these HIV protease inhibitors reported
as discussed earlier in this work (Fig. 2).
HO OH HOI OH
DMP 450 DMP 323
Figure 2. Structures of the HIV protease inhibitors DMP 323 and DMP 450
Studies on the interaction of the cyclic urea inhibitors XK216, XK263, DMP323, DMP450,
XV63 8, and SD146 with HIV-1 protease, has revealed that these cyclic ureas are symmetrical
molecules that posses a common central structural unit: a seven membered heterocyclic ring a
urea moiety and diols. Their Pl(Pl') and P2(P2') substituents are attached to C3(C6) (atoms
adj acent to the diols) and the urea nitrogen atoms respectively (Table 3-1).105
Synthesis of DMP 323 and DMP 450 was first reported by DuPont Merck
Pharmaceuticals.91 The key feature of DMP 323 and DMP 450 is the C2 symmetric diol which
provides the correct binding site configuration for the protease enzyme. The 7-membered cyclic
urea moiety provides a scaffold for the diol. Many different routes for the synthesis of DMP 323
and DMP 450 derivatives are available in the literature. Generally, the urea moiety of DMP 323
and DMP 450 was installed by reaction of phosgene or a phosgene equivalent with an O-
protected diamine diol. In the initial small-scale preparations, a primary diamine was reacted
with the phosgene derivative 1,1'-carbonyldiimidazole (CDI),909193106 followed by N-alkylation
as appropriate (Scheme 15).
The practical route to DMP 450 utilizes phosgene to form the cyclic urea from a secondary
diamine.91 The protection of the diol is essential in all these synthetic routes, thus a large amount
of information concerning protection of the diol is available.91,96
As discussed in previous chapters, oxidative catalytic carbonylation of the corresponding
diamines using W(CO)6 12 has also been applied in an effort to install the urea moiety into the
core structure of the HIV protease inhibitors DMP 323 and DMP 450.4,39
In this study, protecting groups such as acetonide 35,27 MEM ether 36107 and SEM ether
37,107 were chosen as representative examples bearing cyclic and acyclic protecting groups,
Cyclic Ureas P2/P2'
SD146 H~NH H11
Table 3-1. Structures of cyclic urea inhibitors
HF~K ('OMe b~ '
SSEM = 2-(Trimethylsilyl)ethoxymethyl
Reagents and conditions: (a) i-BuOCOC1, CH30NHCH3.HCl; (b) LiAlH4
(c) VCl3(THF)3, Zn-Cu; (d) SEMCl; (e) cat. Pd(OH)2; (f) 1,1'-carbonyldiimidazole;
(g) PhCH2Br, NaH; (h) HC1, dioxane/MeOH.
respectively. Carbonylation of 35-37 allows comparison of the W(CO)6-catalyzed process to the
stoichiometric reactions of the phosgene derivative CDI (Table 3-2).10s Varying results were
obtained in the yields of the ureas from the catalytic reaction depending on the protecting group
on the diol, as was also observed for ring closure with stoichiometric CDI. These results
demonstrate that the catalytic oxidative carbonylation reaction can be used to convert diamines
to cyclic ureas in examples relevant to the preparation of complex targets.
.,,~H ~ W(CO)F;/ CO /HN NH
12, K2CO3 .,,,
35 Pl, P2, C(CH3)2 38 Pl, P2, C(CH3)2
36 Pl, P2 = MEM, MEM 39 Pl, P2 = MEM, MEM
37 Pl, P2 = SEM, SEM 40 Pl, P2 = SEM, SEM
Table 3-2. Carbonylation of compounds 35-37 to Ureas 38-40
Diamine Reagent Solvent T (oC) % Yield Urea Ref
35 CDI CH3CN NRb 15
35 CDI TCE 14 732
35 W(CO)6/CO CH2 12/H20 80 3
35 W(CO)6/CO CH2 12 80 2
36 CDI CH2 12 rt 62,76c 30,33,34
36 W(CO)6/CO CH2 12/H20 80 4
37 CDI CH2 12 rt 52,93c 30,33
37 W(CO)6/CO CH2 12/H20 80 7
aTypical reaction conditions: Diamine 35 (0.200 mmol), W(CO)6 (0.0242 mmol), K2CO3 (0.635
mmol) and I2 (0.239 mmol), solvent (32 mL CH2 12 : 8 mL of water), 80 atm CO, 80 oC, 18 h.
bNot reported. "Yields are from two-step sequence involving deprotection of the Cbz-protected
diamine. Deprotection is assumed to be quantitative for purposes of the table.
Overall, catalytic oxidative carbonylation of 35 in the biphasic CH2 12/H20 solvent system
afforded 38 in 38% yield. As had been observed for the carbonylation of functionalized benzyl
amines,44 yields obtained by using the biphasic solvent system were higher than those in CH2 12.
Efforts to optimize the reaction conditions by varying CO pressure, temperature, concentration
and solvent did not result in higher yields of 38. Although the yields of 38 from 35 are modest,
results from the catalytic carbonylation compare favorably to those obtained with CDI under
Reaction of 35 with CDI in acetonitrile under standard conditions results in a 15% yield of
38, with the low conversion attributed to strain in the bicyclic product (Table 3-2). Carbonylation
of 36 and 37 was carried out under the conditions used for 35, with the exception of substrate
concentration, which was optimized for 36 and the same used for 37 (Table 3-2). In comparison
to the literature yields of 62 and 76 % for formation of urea 39 from Cbz protected MEM ether
36 and CDI under slightly different conditions, the catalytic carbonylation reaction provided 39
in 42% yield from 36. Promising results were also obtained for SEM ether 37, for which
catalytic carbonylation afforded urea 40 in 75% yield, a value intermediate between the reported
yields for reaction of 37 with CDI.
With these preliminary results it was established that oxidative catalytic carbonylation of
amines can be applied successfully in the preparation of functionalized ureas. These studies also
offered the first demonstration of catalytic amine carbonylation as synthetic methodology. Yields
of the ureas from the catalytic reaction vary with the protecting group on the diol, as do those
reported for ring closure with stoichiometric CDI.
Results and Discussion
Synthesis of Seven-Membered Ring Cyclic Ureas 84 and 89
In a continuing effort to optimize the carbonylation conditions for the synthesis of 7-
membered cyclic ureas, simple targets were envisaged. Therefore the synthesis was began on
diamine 83 and 88, which contain no substituent and methyl groups, respectively, in the C2
Diamine 83, which is the precursor to cyclic urea 84, was synthesized as described in
Scheme 16. Commercially available 2,3 -O-isopropylidene-L-tartrate, is treated with concentrated
aqueous ammonia solution and methanol for three days to afford (4R,5SR)-2,2-dimethyl-1 ,3-
dioxolane-4,5-dicarboxamide 82.109 The next step is the reduction of the dicarboxamide to
furnish diamine 83.
HN H3CI J'"CH3
It is important to point out that the reduction of compound 82 was much more difficult
than anticipated. Standard reducing agents that are commonly used did not carry out the reaction
to completion. Partially reduced product was the result even though the reaction conditions were
adjusted several times. Fortunately, the reduction was accomplished at last using borane-
dimethyl sulfide complex in THF. After purification of the diamine 83, the oxidative
carbonylation using W(CO)6 12 system was set up and allowed to react for 24 hours. After
workup the cyclic urea 84 was obtained in 74% yield. The synthesis of diamine 88 was
carried out according to literature procedures described in Scheme 17.75 Dimethyl 2,3-o-
i sopropyli dene-L-tartrate 85 was di ssolved in dry toluene at -40 oC. DIBAL was added to thi s
solution dropwise with constant stirring. After one hour, anhydrous methanol was added to the
mixture reaction and the reaction was warmed to -10 oC. Next, dimethylhydrazine was added and
the reaction was warmed to -10 oC. Next, dimethylhydrazine was added and the reaction was
allowed to run one more hour to afford hydrazone 86 in good yield.
~O O OCH3
Conc. aqueous NH3
3 days, r.t.
W(CO)6 2 ,
Py, CH2 12
80 atm, 24 hrs, ~68 OC
Dry THF, reflux
88% yield y
O O -
Raney Nil H2
Without further purification, the hydrazone was treated with MeLi in dry diethyl ether to produce
intermediate 87. Finally, diamine 88 was obtained upon hydrogenation of the hydrazine 87.
Once the diamine 88 was available, the oxidative carbonylation with W(CO)6 WaS pursued,
using the conditions described in Scheme 18.
I 2C3H3CH CH
"7(Y CH2 12/H20
88 80 atm, 24 hrs, ~105 OC 89
The conditions for the carbonylation reaction have to be adjusted for different substrates.
The yields for cyclic ureas 84 and 89 are unoptimized and it is expected that they could be
improved. Other substrates containing secondary diamines are currently under investigation.
In summary, we have established that catalytic oxidative carbonylation of diamines
provides an alternative to phosgene and phosgene derivatives in the preparation of cyclic ureas.
More detailed studies need to be done in the preparation of cyclic ureas using this methodology.
One interesting experiment that is currently being developed is the carbonylation of the diamine
diol without any protecting group present since it was demonstrated in previous experiments
with aminoalcohols that this system is tolerant to the presence of hydroxyl functional groups.
CATALYTIC OXIDATIVE CARBONYLATION OF ENANTIOMERICALLY PURE ot-
AMINO AMIDES TO PRODUCE HYDANTOIN DERIVATIVES
Hydantoins and cyclic ureas have long been the focus of considerable attention since they
are frequently found as crucial moieties in many biologically active molecules with
pharmaceutical relevance. More specifically, hydantoins substituted at C-5 constitute an
important class of heterocycles in medicinal chemistry since many derivatives are associated
with a wide range of biological properties including anticonvulsant, no0 antidepressant, 111,112
antiviral,111,112 and platelet inhibitory activities.113 Moreover, C-5 substituted hydantoin
derivatives are of synthetic utilityll4-116 as precursors to ot-amino acid derivatives after hydrolytic
degradation (Figure 4-1).
Classic Ways to Synthesize Hydantoins
A wide variety of methods for the synthesis of hydantoins have been reported starting from
different building blocks. Information concerning different approaches to hydantoins including
solution phase syntheses and more recently solid-phase organic syntheses, as well as polymer
bound reagents can be found in the literature.ll '"1 Under solution phase conditions, there are
several ways to afford hydantoins starting from different substrates. Figure 4-2 describes
different strategies to afford hydantoins from various starting materials.ll
Figure 4-1. Hydantoin ring structure.
e) R3 N
+ KCN + (N H4)2 CO3
I HOOC NR
R ,3 R1 + Ri NC,
I HOOC N2S
f) R3 R 2` r 3R4 + KSCN
Figure 4-2. Synthetic strategies and building blocks for hydantoin synthesis.ll
Hydantoins can be prepared from ureas and carbonyl compounds as reported by Beller et
al.ll Several examples of these procedures can be found in the literature including the Biltz
synthesis, which is still applied to the synthesis of hydantoins (Figure 4-21a). Another classic
way to afford hydantoins is the Bucherer-Bergs methodology, the reaction of carbonyl
compounds and inorganic cyanide. Introducing the second nitrogen and carbonyl unit would
afford N-1 and N-3 unsubstituted hydantoins (Figure 4-2b). Moreover, another classic way to
form hydantoins is the Read-type reaction (Figure 4-2c) of amino acids or derivatives with
inorganic isothiocyanate, which will produce the hydantoin with no substituent in the N-3
position. Hydantoins with substituents at N-3 can be synthesized using alkyl or aryl
iso(thio)cyanates as marked (Figure 4-2d). Hydantoins from amino amides can be afforded by
introducing the C-1 unit (highlighted) to a substrate that already contains four atoms of the
hydantoin ring (Figure 4-2e). Finally, hydantoins that possess a substituent at N-1 can be
generated starting from a-halo amides and inorganic isothiocyanates (Figure 4-2f).11
Solution Phase Synthesis
As mentioned above, the Bucherer-Bergs strategy is among the classic ways to produce
ureas. This practical and easy method yields 5-substituted hydantoins from aldehydes and
ketones. The synthesis involves the reaction of a carbonyl compound with potassium cyanide and
ammonium carbonate. Sarges et al. applied this methodology to prepare the aldose reductase
inhibitor sorbinil (Scheme 19).119
O O N\H ON
F ~KNCH2O ,F HN 3O 1. Brucine F O
O C2HsOH, H20O 2. HCL O
90 91 92
The Read synthesis is also frequently applied for the synthesis of hydantoins and
thiohydantoins. Smith et al. reported the synthesis of silicon-containing hydantoins starting from
silylated amino acid 93, which upon treatment with potassium cyanate in pyridine and
subsequent acid cyclization afforded hydantoin 95 (Scheme 20).120
H3 \ Si Si H3-S
iKOCN R R3-S N
HOOC NH2 pyridine HOOC NHH20 O N
93 94 95
The previous examples have long been known to be applicable to the production of
hydantoins. However, during the last decades, much progress has been made in the development
of new strategies to produce hydantoins, since more cases of interesting biological activity have
More recent methodologies for the synthesis of hydantoins have been developed. Among
them is the synthesis of thiohydantoins reported by Le Tiran and coworkers.121 This synthesis
affords thiohydantoins starting with amino acid amides and carbon disulfide. As described in
Scheme 21, amino amide 96 was treated with di-2-pyridylthiocarbonate (DPT) in THF at room
temperature furnishing disubstituted hydantoin 97.
HN DPT, THF O
H2N rt, 24h \I
Hydantoins with different substituent patterns can also be produced from other
heterocyclic compounds. One example is the synthesis of 1,5-disubstituted hydantoins 100, that
can be prepared from aziridinone 98 and cyanamide, followed by treatment of the resulting
iminohydantoin with HNO2 (Scheme 22).122
R N'R NH2CN RH H R N HNO R H
H RH R'NH R' O
98 99 100
Another recent example is the synthesis of hydantoins using multi-component reactions.
Hulme and coworkers reported the synthesis of trisubstituted hydantoins using Ugi/De-
Boc/Cyclization methodology.123 For the preparation of these trisubstituted hydantoins, they
started with five substrates that included aldehydes or ketones, amines, isonitriles, methanol and
carbon dioxide. The mechanism of this five-component reaction is described in Scheme 23.
Phosgene and its derivatives have also been used for the synthesis of hydantoins."'5 One
recent report that uses phosgene derivatives for the preparation of enantiomerically pure
hydantoins was made by Zhang and coworkers.124 They reported the synthesis of several
hydantoin molecules using phosgene and its derivative 1,1' -carbonyldiimidazole (CDI).
Solid-Phase Organic Synthesis
The synthesis of structurally challenging heterocyclic molecules bearing one or more
nitrogen atoms using solid support synthesis has developed very quickly in the last decade. There
are several reviews on the synthesis of hydantoins by means of solid-phase organic synthesis
(SPOS)."1 Gutschow et al. address examples of the most recent efforts on the synthesis of
hydantoins via SPOS.
H3 'O bl N'R3H
CH30H, THF, H20
Synthesis of Hydantoins Using W(CO)6/ 2 Catalytic System
It was anticipated that catalytic carbonylation of ot-amino amides with W(CO)6 12 in the
presence of CO might be feasible upon optimization of the reaction conditions. Formation of the
five-membered ring should be facile since it is kinetically favored. Therefore, an effort toward
the synthesis of a series of different hydantoins was begun.
R N ,R'
A short and efficient synthesis starts with enantiomerically pure co-amino amides, which
should afford the corresponding enantiomerically pure hydantoins (Eq. 22). In order to increase
our knowledge concerning the efficiency of the catalytic system for the synthesis of different
substituted hydantoins, it was decided to explore a series of enantiomerically pure a-amino
amide as substrates for this reaction.
Results and Discussion
In the present work it is reported that five disubstituted hydantoins carrying aromatic or
aliphatic side chains at the 3- and 5- positions were synthesized from the corresponding a-amino
amides in good yields using the W(CO)6 12 system in the presence of CO. Amino amide 103a
was synthesized according to the procedure reported in the literature.125 Treatment of the
corresponding amino acid methyl ester hydrochloride with methylamine leads to compound 103a
(Eq. 23). After purification of compound 103, the next step is the cyclization of the a-amino
amide using the W(CO)6 12 system in the presence of CO (Eq. 24). Optimization of the reaction
conditions was carried out using amino amide 103a. Initially, the original conditions used for the
amino alcohols were tested, but the reaction did not produce the hydantoin and starting material
was recovered (Table 8, Entry 1). This was not surprising since the amide is less nucleophilic
than the amines present in the amino alcohol substrates. Next, different sets of conditions were
tested, including longer times, higher temperatures and different bases. Some of these conditions
are described in Table 4-1.
HOCH3NH2 N (3
102 3 as t103a
/ W O) (2 4)
103a ~Base, Solvent 14
Table 4-1. Carbonylation conditions for ot-amino amide 103a.
Entry Time (h) Pressure (atm) Temp (oC) Base/eq. Solvent (M
1 18 80 40 Py/2 CH2 12 4 0
2 24 80 70 Py/2 CH2 12 4 0
3 36 90 105 Py/2 CH2 12 0.11 40
4 45 80 40 Py/2 CH2 12 0.11 0
5 36 90 100 K2CO3 CH2 12/H20 0.05 20
6 42 90 100 DMAP/2 CH2 12 0.03 0
7 36 85 78 DMAP/3 Toluene 0.03 0
8 36 85 78 DMAP/3 CH2 12/H20 0.03 50
9 36 85 78 DMAP/4 CH2 12/H20 0.03 50
10 48 85 90 DMAP/4 CH2 12/H20 0.03 traces
11 36 80 76 DBU/4 DCE 0.03 72
The data in the table show that the best conditions so far are those described in Entry 11. It
was expected that the conditions for the carbonylation of this substrate would be different from
the optimized for amino alcohols. Since the nucleophilicity of the nitrogen amide is lower than
that of the amines previously investigated, the main variable to be addressed was the base. It was
likely that a stronger base would be needed to to take the reaction to completion, and indeed this
was confirmed later in the investigation. Time was another variable to consider. As shown in
Entry 11, 36 hours was optimal for the reaction conditions. At longer reaction times, the product
began to decompose (Entry 10).
With these optimized conditions, different substrates for the synthesis of hydantoins were
started. Figure 4-3 shows the substrates submitted to investigation for the catalytic carbonylation
of ot-amino amides to afford the corresponding hydantoins. Amino amide 103e was included in
the study because it contains the hydroxyl functionality that was present in the amino alcohols
N, Me NEt
Figure 4-3. a-Amino amide substrates to be converted to hydantoins
Amino amides 103a-d were prepared following a literature procedure (Eq. 23).124 Using
the same starting material, the enantiomerically pure amino amides 103a-d were obtained by
adding the corresponding alkyl amine in methanol (Table 4-2).
All products (103-a-d) were recovered in very good yield after purification by column
chromatography on silica gel. The synthesis of amino amide 103e was initially carried out
following available methodology.126 The hydrochloride salt of the serine methyl ester (105) was
treated with benzylamine to yield 103e in 35 % isolated yield, a result is similar to that reported
in the literature.
O RN2 NR (25)
Table 4-2. Synthesis of a-amino amides 103a-103d
entry R Product Yield (%)
1 CH3 103a 90
2 CH3CH2 103b 82
3 (CH3 )2CH2 103c 74
4 PhCH2 103d 84
HO OCH3 ~PhCH2NH2 HON(5
NH2'HCI MeOH NH2
105 reflux, 18 hrs 103e
However, because of the low yield observed with this procedure, a different method was
used to prepare amino amide 103e, and the product was obtained in higher yields.127 This
strategy proceeded through Cbz-serine, which was treated with benzylamine and the mixed
anhydride coupling (MAC) procedure.128 to afford 105 stereospecifically (Scheme 24). The next
step to obtain the carbonylation substrate was the hydrogenation of protected amino-3-
hydroxypropionamide to afford 103e in 89% yield.
Substrates 103a-e were then subj ected to the optimized carbonylation conditions
determined for 103a. The results are described in Table 4-3. Most of the hydantoins were
obtained in good yields (Table 4-3), except in the case of 104c, which was produced in trace
amounts. This is probably because the steric hindrance of the bulky isopropyl group present in
the amide substrate, since similar results have been observed before in the carbonylation of
diamines containing isopropyl substituents.42 Further optimization of the reaction is necessary,
testing different substrates and different conditions, but these preliminary results are promising.
H~bOH N-h lIne HONC2h H2/Pd-C ,H HhP
I so butylI NHCbz 89% NH2
PhCH2NH2 105 103e
R $ N, R2 RiNR2
Table 4-3. Catalytic carbonylation of ot-amino amides 103a-e to hydantoins 104a-e.
entry R1 R2 Product yield
1 PhCH2 CH3 104a 73
2 PhCH2 CH3CH2 104b 61
3 PhCH2 (CH3 )2CH2 104c traces
4 PhCH2 PhCH2 104d 75
5 HOCH2 PhCH2 104e 50
In the past, other group VI metals carbonyls such as chromium hexacarbonyl and
molybdenum hexacarbonyl have been also investigated as catalysts for the carbonylation of
aliphatic secondary amines.45 However, the results of those experiments showed that tungsten
hexacarbonyl was the best catalyst for the catalytic carbonylation in the case of primary and
secondary aliphatic amines. Similar experiments were carried out for the amino amide substrates,
in which amino amide 103a was selected to undergo the catalytic reaction using Mo(CO)6 and
Cr(CO)6 as catalysts under the previously optimized conditions. However, as observed
previously the carbonylation reaction using Mo and Cr catalysts did not gave good results. In the
case of Mo(CO)6 the yield was less than 20% and for Cr(CO)6 it was impossible to identify the
The W(CO)6 catalytic carbonylation, using I2 aS Oxidant in the presence of CO, has
proven to be effective for the synthesis of disubstituted hydantoins starting from
enantiomerically pure a-amino amides. Other group VI metal carbonyl catalysts have been
investigated for this carbonylation reaction. However, W(CO)6 is a more effective catalyst for
the oxidative carbonylation of a-amino amides to afford the corresponding hydantoins. Further
experiments with this type of substrate are currently underway.
All experimental procedures described were carried out under nitrogen and in oven dried
glassware unless stated otherwise. Solvents used for carbonylation reactions were passed
through a solvent purification systeml29 prior to use. Most of the aminoalcohol substrates were
commercially available and were used without further purification. The aminoalcohols 3-amino-
4-phenyl butanoll30 and 3-amino-1-phenyl propanol5 were prepared as described in the literature.
'H and 13C NMR spectra were obtained on a Varian Gemini 300 or VXR 300 MHz
spectrometer. Infrared spectra were recorded on a Perkin-Elmer 1600 FT-IR. High-resolution
mass spectrometry and elemental analyses were performed by the University of Florida
Procedure A for Carbonylation of Amino Alcohols with CDI
The aminoalcohol (2 equiv) was dissolved in dry THF and placed into the flask under a
flow of N2. One equivalent of CDI was then added. The reaction was left to stir for 18 hours,
then the solvent was evaporated under a flow ofN2. The residue was dissolved in a 1:1 mixture
of CH2 12: H20. The mixture was placed in a separatory funnel. After the layers were
separated, the aqueous layer was washed with CH2 12, then with a 2: 1 solution of
chloroform/ethanol. The combined organic layers were dried and filtered, then the solvent was
removed. The crude product was purified by flash chromatography on silica gel with 5%
MeOH/CH2 12 as eluent for the carbamate and 30% MeOH/CH2 12 for the urea.
Procedure B for carbonylation of aminoalcohols with DMDTC
The aminoalcohol (2 equiv) was dissolved in dry methanol and placed into the flask under
a flow of N2. DMDTC (1 equiv) was then added and the reaction was left to stir for 18 hours
under N2. The solvent was then evaporated under N2 and the product was immediately
chromatographed on silica gel using a mixture of 5 to 30% MeOH/CH2C 2 as eluent to recover
the carbamate and urea, depending on the substrate.
Procedure C for Catalytic Carbonylation of Amino Alcohols with W(CO)6 2~
1 ,3-Bis-(5-hydroxypentyl)urea (51). To a 15 mL glass vial in a multi-compartment Parr
high pressure vessel containing 1.9 mL of CH2C 2, were added 50 (800 mg, 7.7 mmol), W(CO)6
(136 mg, 0.38 mmol), pyridine (0.93 ml, 11.5 mmol) and I2 (977 mg, 3.8 mmol). The vessel was
then charged with 80 atm CO and heated at 40 OC for 18 hours. The pressure was released and
methylene chloride (5 mL) was added to the reaction mixture to further dissolve the crude
product. The solution was washed successively with saturated sodium sulfite, then saturated
sodium bicarbonate. Each of the collected aqueous layers was washed with 2:1 CHCl3/EtOH (4
x 30 mL). The combined CHCl3/EtOH layers were dried with MgSO4 and the solvents removed
by evaporation to afford urea 51 as a white solid in 64% yield. In order to recover the
carbamate, the methylene chloride layer from the original extractions was washed with 0.1M
aqueous HC1, then dried with MgSO4. The solvent was removed under vacuum to afford
carbamate 52 in 2% yield. The urea was identified by comparison with literature data (elemental
analysis and melting point).' Urea 51: 'H NMR (D20) 8: 1.22 (m, 4H), 1.37 (m, 4H), 1.52 (m,
4H), 2.88 (m, 4H), 3.42 (m, 4H). MS (LSIMS) [M+H] called for C11H 4N 03 232.18, found
232.18. IR CHCl3) 1 ICO 1654 cm- Anal. called for C11H 4N 03: C 56.87%, H 10.41%, N
12.06%; C 56.96%, H 10.80%, N 11.89%. M.p., reported 106.6-108.5, found 106.3-108.5 oC.
Carbamate 52: 1H NMR (CDCl3) 6: 1.49 (m, 2H), 1.50 (m, 2H), 1.52 (m, 2H), 3.30 (m, 2H),
3.65 (t, 2H), 5.9 (br, 1H); 13C NMR (CDCl3) 6: 22.9, 29.3, 32. 1, 41.2, 62.6, 147.2; IR (CH2C 2):
T'co 1708 cm- ; MS (LSIMS) [M+H] called for 130.08, C6HllNO2 found 130.08.
H H Q
HO NK N~O OH N
1,3-Bis-(4-hydroxy-3-methylbutyl)urea (55). Procedure C afforded 55 from 54 (0.20
mL, 1.8 mmol) in 93% yield. 'H NMR (CDCl3) 6: 0.86 (d, 6H, J = 6.6 Hz), 1.22 (m, 2H), 1.59
(m, 4H), 3.07 (m, 4H), 3.38 (m, 4H), 6.08 (s, 2H); 13C NMR (CDCl3) 6: 16.4, 33.0, 33.4, 38.4,
67.4, 161.0; IR (CHCl3): vCO 1648 cm l; MS (LSIMS) [M+H]+ C11H 4N 03, called 233.1865,
HO N N OrH
3-Amino-4-phenyl-1-butanol (59). DL-P-homophenyl alanine (1000 mg, 5.57 mmol)
was added to 2.2 mL THF and the mixture was cooled to 0 oC. BH3*THF (lM, 8.36 mL, 8.36
mmol) was added dropwise to the suspension. The resulting mixture was stirred at room
temperature for 4.5 hours. The mixture was then cooled to 0 oC, 4 mL of 3N sodium hydroxide
was slowly added and the mixture was stirred at room temperature overnight. The pH of the
solution was adjusted to 11 by adding a few pellets of sodium hydroxide. The aqueous phase
was saturated with potassium carbonate, the THF phase was separated and the aqueous phase
was extracted with (50 mL x 6) diethyl ether. The combined organic layers were dried over
magnesium sulfate. The solvents were evaporated and the product was obtained in 82% yield.
The product was identified by comparison with literature data.130
N,N'-Bis(1-benzyl-3-hydroxypropyl)urea (60) and 4-Benzyl-1 ,3-oxazinan-2-one (61).
Procedure C afforded urea 60 from 59 (760 mg, 4.6 mmol) as a pale yellow oil in 95% yield.
Carbamate 61 was recovered in trace amount. The products were identified by comparison with
authentic samples prepared as described below.
Authentic samples of N,N'-bis(1-benzyl-3-hydroxypropyl)urea (60) and 4-benzyl-1,3-
oxazinan-2-one (61). Procedure B afforded compounds 60 and 61 from 59 (600 mg, 2.97 mmol)
as white solids in 30% and 8% yield, respectively. For urea 60: 1H NMR (CDCl3) 6: 1.22 (m,
2H), 1.77 (m, 2H), 2.70 (m, 4H), 3.42 (m, 4H), 4.10 (s, 2H), 4.82 (s, 2H), 7.39 (m, 10H); 13C
NMR (CDCl3) 6: 38.4, 42.0, 48.0, 58.6, 126.6, 128.6, 129.2, 138.2, 159.9; IR (CH2C 2): I'CO
1600 cm- ; MS (LSIMS) [M+H]+ called for C21H28N203 257.2178, found 257.2161. For
carbamate 61: 1H NMR (CDCl3) 6: 1.68 (m, 1H), 1.87 (m, 1H), 2.78 (m, 1H), 2.89 (m, 1H), 3.67
(m, 1H), 4.14 (m, 1H), 4.27 (m, 1H), 6.81 (s, 1H), 7.24 (m, 5H); 13C NMR (CDCl3) 6: 26.5,
42.3, 51.8, 65.4, 126.8, 128.6, 129.1, 136.2, 154.5; IR (CH2C 2): l'CO 1710 cm l; MS (LSIMS)
[M+H]' called for CllH13NO2 192.1024, found 192.1020.
1 ,3-Bis-(3-hydroxy-3-phenylpropyl)urea (64) and 6-Phenyl-1 ,3-oxazinan-2-one (65):
Procedure C afforded urea 64 from 65 (320 mg, 2.12 mmol) in 72% yield. 1H NMR (CDCl3) 6:
1.87 (m, 4H), 3.30 (m, 2H), 3.6 (m, 2H), 4.72 (t, 2H), 6.19 (s, 2H), 7.32 (m, 10H); 13C NMR
(CDCl3) 6: 38.4, 38.7, 72.3, 125.8, 127.5, 128.4, 143.8, 160.1. IR (CHCl3): vco 1646 cml
Cyclic carbamate 65 was recovered in 14% yield; it was identified by comparison with literature
N,N'-Bis(3-hydroxy-2,2-dimethylpropyl)urea(68) and 5,5-dimethyl-1,3-oxazinan-2-
one (69). Procedure C afforded urea 68 from 67 (600 mg, 5.81 mmol) as a white solid in 60%
yield. 1H NMR (CDCl3) 6: 0.73 (s, 12H), 2.85 (d, 4H, 6.3 Hz), 3.03 (d, 4H, 6 Hz), 4.61 (t, 2H, 6
Hz), 6.02 (t, 2H, 6.3 Hz), 13C NMR (CDCl3) 6: 22.3, 36.6, 46.2, 67.6, 159.7; IR (CHCl3): vco
1666 cm -; MS (LSIMS) M+H calledd for C1H 4N 03 233.1751, found 233.1750. Anal. Called
for C11H 4N 03: C 56.89%, H: 10.41%, N: 12.06%; Found: C 57.69%, H 10.63%, N 12.01%.
Carbamate 69: yield 5%; 1H NMR (CDCl3) 6: 0.96 (s, 6H), 2.88 (s, 2H), 3.80 (s, 2H), 7. 12 (br
s, 1H); 13C NMR (CDCl3) 6: 22.1, 27.3, 50.6, 75.1, 152.4; IR (CHCl3): vco 1702 cm- ; MS
(LSIMS) [M+H] called for 130.0868, C6HllNO2 found 130.0867.
OHHN NH OH HN O
1 ,3-Bis-(1-benzyl-2-hydroxyethyl)urea (76) and 6-Phenyl-6-oxazolidin-2-one (77)
Procedure C afforded urea 76 from 75 (800 mg, 5.3 mmol) in 78% yield. Carbamate 77 was
recovered in 10% yield. The products were identified by comparison with literature data.89
HN NH P
Ph~ ,,, Ph H N O
HO OH O
1,3-Bis-(3-hydroxy-2-phenylethyl)urea (79) and 5-Phenyl-oxazolidine-2-one (80).
Procedure C afforded urea 79 from 78 (800 mg, 5.83 mmol) in 79% yield. 'H NMR (CDCl3) 6:
2.85 (m, 2H), 3.08 (m, 2H), 4.78 (t, 2H), 5.64 (br, 2H), 7.38 (m, 10H); 13C NMR (CDCl3) 6:
49.2, 74.2, 125.8, 127.5, 128.4, 147.2, 159.5; IR (CHCl3): vco 1649 cm l. Cyclic carbamate 80
was isolated in 14% yield; it was identified by comparison with literature data.2
Ph~ ~.Ph HN O
OH OH O
Synthesis of Cyclic Ureas
To a glass-lined 300 mL Parr high pressure vessel containing 40 mL of CH2C 2 H20 4: 1 ratio
were added diamine 83 (200.0 mg, 1.24 mmol), W(CO)6 (20 mg, 0.62 mmol), pyridine (294.25
mg, 3.72 mmol) and I2 (157.30 mg, 0.62 mmol). The vessel was then charged with 80 atm CO
and heated at 680C overnight. After 24 hours, the pressure was released and 10 mL of water was
added. The organic were then separated and washed successively with saturated sodium sulfite
(Na2SO3), then saturated sodium bicarbonate (NaHCO3), and finally with 0. 1N aqueous HCI
solution. The resulting solution was dried over magnesium sulfate and filtered. The solvent was
removed by evaporation and the resulting residue was purified via column chromatography on
silica using ether as eluent. After concentration, cyclic urea 84 was afforded in 64% yield. 1H
NMR (CDCl3) 6: 1.39 (s, 6H), 3.19-3.40 (m, 4H), 4.20-4.30 (m, 2H), 5.1 (br, s, 2H); 13C NMR
(CDCl3) 6: 27.2, 44.7, 81.8, 108.9, 164.3; IR (CHCl3): IR (CDCl3): vCO 1640 cm
To a glass-lined 300 mL Parr high pressure vessel containing 40 mL of CH2 12 H20 4: 1 ratio
were added diamine 88 (200.0 mg, 1.06 mmol), W(CO)6 (14 mg, 0.04 mmol), K2CO3 (410.0 mg,
3.0 mmol) and I2 (269 mg, 1.06 mmol). The vessel was then charged with 80 atm CO and heated
at 1000C overnight. After 24 hours, the pressure was released and 10 mL of water was added.
The organic were then separated and washed successively with saturated sodium sulfite
(Na2SO3), then saturated sodium bicarbonate (NaHCO3), and finally with 0. 1N aqueous HCI
solution. The resulting solution was dried over magnesium sulfate and filtered. The solvent was
removed by evaporation and the resulting residue was purified via column chromatography on
silica using ether as eluent. After concentration, cyclic urea 89 was afforded as a white solid in
71% yield. 'H NMR (CDCl3) 6: 1.26 (d, 6H), 1.40 (s, 6H), 3.59-3.80 (m, 2H), 3.90-4. 10 (m, 2H)
5.17 (br, s, 2H); 13C NMR (CDCl3) 6: 14.2, 27.3, 45.9, 83.2, 110.1, 163.8; IR (CHCl3): IR
(CDCl3): vco 1636 cml
General Procedure for the Synthesis of a-Amino Amides 103a-103e.
The amino acid methyl ester hydrochloride (4 mmol) and the alkylamine (40 mmol) were
dissolved in anhydrous methanol (~20 ml) and stirred at room temperature for 3 days. The
reaction mixture was concentrated, and the residue was purified by column chromatography on
silica gel using ethyl acetate/methanol (96:4) as eluant affording the a-amino amides 103a-103d
in very good yields (80-90%). Amino amide 103e was prepared following a three step procedure
described in the literature, starting with Cbz-serine.127
R, NH/ R2
103a; R1 = Bn, R2 = Me
103b; R, = Bn, R2 = Et
103c; R, = Bn, R2 = iPr
103d; R, = Bn, R2 = Bn
103e; R, = CH20H, R2 = Bn
General Procedure for the Carbonylation of a-Amino Amides 103a-e to Afford Hydantoins
a-Amino amide 103a (400 mg, 2.2 mmol) was placed in a glass-lined 300 mL Parr high pressure
vessel containing 30 mL of dichloroethane (DCE). Next, W(CO)6 (0. 16 mmol) was added
followed by DBU (8.96 mmol) and I2 (1.56 mmol). The vessel was then charged with 80 atm
CO and heated at about 760C for 36 hours with constant stirring. The pressure was released and
15 mL of water was added. The organic were then separated and washed successively with
saturated sodium sulfite (Na2SO3), and then with 0. 1N aqueous HCI solution. The aqueous layer
was extracted with ethyl acetate (20 mL x 4). The combined organic layers were dried over
magnesium sulfate, filtered and concentrated. The resulting residue was purified via column
chromatography- on silica using methylene chloride/ethyl acetate (80:20) to afford the hydantoin
104a. The same procedure was applied to prepare hydantoins 104b-e. The products were
identified by comparison with literature data.12,3,3
(S)-5-Benzyl-3-methylimidazolidine-2,4-din (104a). 1H NMR (CDCl3) 6: 2.80 (t, 1H), 3.0 (s,
3H), 3.32 (dd, 1H), 4.25 (dd, 1H), 5.19 (br, s, 1H), 7.21-7.40 (m, 5H); 13C NMR (CDCl3) 6: 25.8,
41.0, 56.4, 126.7, 128.6, 129.2, 155.4, 174.4; IR (CDCl3): vCO 1772, 1709 cml
(S)-5-Benzyl-3-ethylimidazolidine-2,4-dion (104b). 1H NMR (CDCl3) 6: 1.19 (t, 3H), 2.82
(dd, 1H), 3.24 (dd, 1H), 3.43-3.60. (m, 2H), 4.21 (dd, 1H), 7.19-7.39 (m, 5H); 13C NMR (CDCl3)
8: 12.0, 33.9, 38.1, 58.1, 127.0, 130.0, 131.2, 134.5, 157.5, 172.4.
(S)-5-Benzyl-3-benzylimidazolidine-2,4-din (104d). 1H NMR (CDCl3) 6: 2.82 (dd, 1H), 3.24
(dd, 1H), 4.22 (s, 2H), 4.60 (t, 1H), 5.38 (br, s, 1H), 7.23-7.42 (m, 10H); 13C NMR (CDCl3) 6:
38.4, 43.9, 61.7, 125.8, 126.7, 126.9, 127.7, 128.5, 128.9, 135.5, 135.7, 158.5, 169.5.
(S)-3-Benzyl-5-(hydroxymethyl)imidazolidin-,-in (104e). 1H NMR (DMSO-d6) 6: 4.26
(t, 1H), 3.46 (dd, 1H), 3.53 (dd, 1H), 4.48 (d, 2H), 4.77 (br, s, 1H), 7.21-7.26 (m, 3H), 7.30 (m,
2H); 13C NMR (DMSO-d6) 6: 42.3, 59.9, 60.4, 126.4, 127.0, 127.9, 138.7, 157.5, 172.3; IR
(neat): vco 1765, 1708 cml
LIST OF REFERENCES
(1) Lam, P. Y.-S.; Jadhav, P. K.; Eyermann, C. J.; Hodge, C. N.; De, L. G. V.; Rodgers, J. D.
In PCThzt. Appl. (Du Pont Merck Pharmaceutical Co., USA). WO, 1994; 525 pp.
(2) Qian, F.; McCusker, J. E.; Zhang, Y.; Main, A. D.; Chlebowski, M.; Kokka, M.;
McElwee-White, L. Journal of Organ2ic Chentistry 2002, 67, 4086-4092.
(3) Bigi, F.; Maggi, R.; Sartori, G. Green Chentistry 2000, 2, 140-148.
(4) Hylton, K.-G.; Main, A. D.; McElwee-White, L. Journal of Organic Chentistry 2003, 68,
(5) Koenig, T. M.; Mitchell, D. Tetr~rt~rt~raheron~rt~t~rt Lett. 1994, 35, 1339-1342.
(6) Chrusciel, R. A.; Strohbach, J. W. Current Topics in M~edicinal Chentistry (Sharjah,
United Arab Emirates) 2004, 4, 1097-1114.
(7) De Lucca, G. V.; Lam, P. Y. S. Drugs of the Future 1998, 23, 987-994.
(8) Dragovich, P. S.; Barker, J. E.; French, J.; Imbacuan, M.; Kalish, V. J.; Kissinger, C. R.;
Knighton, D. R.; Lewis, C. T.; Moomaw, E. W.; Parge, H. E.; Pelletier, L. A. K.; Prins,
T. J.; Showalter, R. E.; Tatlock, J. H.; Tucker, K. D.; Villafranca, J. E. J. Med. Chent.
1996, 39, 1872-1884.
(9) Semple, G.; Ryder, H.; Rooker, D. P.; Batt, A. R.; Kendrick, D. A.; Szelke, M.; Ohta, M.;
Satoh, M.; Nishida, A.; Akuzawa, S.; Miyata, K. J. Med. Chent. 1997, 40, 331-341.
(10) vonGeldern, T. W.; Kester, J. A.; Bal, R.; WuWong, J. R.; Chiou, W.; Dixon, D. B.;
Opgenorth, T. J. J. Med. Chent. 1996, 39, 968-981.
(11) Vishnyakova, T. P.; Golubeva, I. A.; Glebova, E. V. Russian ChenticalReviews (English
Translation) 1985, 54, 249-261.
(12) Sartori, G.; Maggi, R. In Science ofSynthesis; Ley, S. V., Knight, J. G., Eds.; Thieme:
Stuttgart, 2005; Vol. 18, pp 665-758.
(13) Hegarty, A. F.; Drennan, L. J. In Comprehensive Organic Functional Group
Transfornzations; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.; Pergamon: Oxford,
1995; Vol. Vol. 6, pp 499-526.
(14) Trost, B. M. Angewand'te Chenzie-1nternational Edition in English 1995, 34, 259-28 1.
(15) Klausener, A.; Jentsch, J.-D. In Applied Homogeneous Catalysis nI ithr Organometallic
Compounds (2ndEdition); Cornils, B., Herrmann, W. A., Eds.; VCH: Weinheim, 2002;
Vol. 1, pp 164-182.
(16) Gabriele, B.; Salerno, G.; Costa, M. In Catalytic Carbonylation Reactions; Beller, M.,
Ed.; Springer: Heidelberg, 2006; pp 239-272.
(17) Li, K. T.; Peng, Y. J. Journal of Catalysis 1993, 143, 63 1-634.
(18) Srivastava, S. C.; Shrimal, A. K.; Srivastava, A. Journal of Organometallic Chemistry
1991, 414, 65-69.
(19) Dombek, B. D. ; Angelici, R. J. Journal of Catalysis 1977, 48, 433-435 .
(20) Bassoli, A.; Rindone, B.; Tollari, S.; Chioccara, F. Journal of2~olecular Catalysis 1990,
(21) Benedini, F.; Nali, M.; Rindone, B.; Tollari, S.; Cenini, S.; Lamonica, G.; Porta, F.
Journal of2~olecular Catalysis 1986, 34, 155-161.
(22) Giannoccaro, P.; Nobile, C. F.; Mastrorilli, P.; Ravasio, N. Journal of Organometallic
Chemistry 1991, 419, 251-258.
(23) Hoberg, H.; Fafianas, F. J.; Riegel, H. J. Journal ofOrganometallic Chemistry 1983, 254,
(24) Kondo, T.; Kotachi, S.; Tsuji, Y.; Watanabe, Y.; Mitsudo, T. Organometallics 1997, 16,
(25) Kotachi, S.; Kondo, T.; Watanabe, Y. Catalysis Letters 1993, 19, 339-344.
(26) Mulla, S. A. R.; Gupte, S. P.; Chaudhari, R. V. Journal of2~olecular Catalysis 1991, 67,
(27) Mulla, S. A. R.; Rode, C. V.; Kelkar, A. A.; Gupte, S. P. Journal of2~olecular Catalysis
A-Chemical 1997, 122, 103-109.
(28) Durand, D.; Lassau, C. Tetrahedron Lett. 1969, 2329-2330.
(29) Alper, H.; Vasapollo, G.; Hartstock, F. W.; Mlekuz, M.; Smith, D. J. H.; Morris, G. E.
Organometallics 1987, 6, 2391-2393.
(3 0) Chiarotto, I.; Feroci, M. Journal of Organic Chemistry 2003, 68, 7 1 37-7 1 39.
(31) Choudary, B. M.; Rao, K. K.; Pirozhkov, S. D.; Lapidus, A. L. Synthetic
Communications 1991, 21, 1923-1927.
(32) Gabriele, B.; Salerno, G.; Mancuso, R.; Costa, M. Journal of Organ2ic Chemistry 2004,
(33) Imada, Y.; Mitsue, Y.; Ike, K.; Washizuka, K.; Murahashi, S. Bulletin of the Chemical
Society ofJapan 1996, 69, 2079-2090.
(34) Ozawa, F.; Soyama, H.; Yanagihara, H.; Aoyama, I.; Takino, H.; Izawa, K.; Yamamoto,
T.; Yamamoto, A. Journal of the American Chemical Society. 1985, 107, 3235-3245.
(35) Ozawa, F.; Sugimoto, T.; Yuasa, Y.; Santra, M.; Yamamoto, T.; Yamamoto, A.
Organometallics 1984, 3, 683-692.
(3 6) Ozawa, F.; Yamamoto, A. Chemistry Letters 1982, 865-868.
(3 7) Shi, F.; Deng, Y. Q.; SiMa, T. L.; Yang, H. Z. Tetrahed'ron Lett. 2001, 42, 2161-2163.
(38) Tsuji, J.; Iwamoto, N. Chemical Communications 1966, 380.
(39) Hylton, K.-G. In Chemistry; University of Florida: Gainesville, FL, 2004; p 84.
(40) McCusker, J. E. In Department of Chemistry; University of Florida: Gainesville, FL,
1999; p 80 pp.
(41) McCusker, J. E.; Abboud, K. A.; McElwee-White, L. Organometallics 1997, 16, 3863-
(42) McCusker, J. E.; Grasso, C. A.; Main, A. D.; McElwee-White, L. Organic Letters 1999,
(43) McCusker, J. E.; Logan, J.; McElwee-White, L. Organometallics 1998, 1 7, 4037-4041.
(44) McCusker, J. E.; Main, A. D.; Johnson, K. S.; Grasso, C. A.; McElwee-White, L. Journal
of Organ2ic Chemistry 2000, 65, 5216-5222.
(45) McCusker, J. E.; Qian, F.; McElwee-White, L. Journal of2~olecular Catalysis A-
Chemical 2000, 159, 11-17.
(46) Diaz, D. J.; Hylton, K. G.; McElwee-White, L. Journal of Organ2ic Chemistry 2006, 71,
(47) Main, A. D. In Department of Chemistry; University of Florida: Gainesville, FL, 2000.
(48) Fukuoka, S.; Chono, M.; Kohno, M. Journal of Organic Chemistry 1984, 49, 1458-1460.
(49) Shi, F.; Deng, Y.-Q.; Sima, T.-L.; Gong, C.-K. Gaodeng Xuexiao Huaxue Xuebao 2001,
(50) Shi, F.; Deng, Y. Q. Journal of Catalysis 2002, 211, 548-551.
(51) Pri-Bar, I.; Alper, H. Canaadian Journal of Chemistry-Revue Canaadienne De Chimie
1990, 68, 1544-1547.
(52) Waller, F. J. In Eur. Pat. Appl. (du Pont de Nemours, E. I., and Co., USA). EP, 1986; pp
(53) Hiwatari, K.; Kayaki, Y.; Okita, K.; Ukai, T.; Shimizu, I.; Yamamoto, A. Bulletin of the
Chemical Society ofJapan 2004, 77, 2237-2250.
(54) Bitsi, G.; Jenner, G. Journal of Organometallic Chemistry 1987, 330, 429-43 5.
(55) Byerley, J. J.; Rempel, G. L.; Takebe, N.; James, B. R. J. Chem. Soc. D. 1971, 1482-
(56) Jenner, G.; Bitsi, G. Appl. Catal. 1987, 32, 293-304.
(57) Stiss-Fink, G.; Langenbahn, M.; Jenke, T. Journal of Organometallic Chemistry 1989,
(58) Tsuji, Y.; Ohsumi, T.; Kondo, T.; Watanabe, Y. Journal of Organometallic Chemistry
1986, 309, 333-344.
(59) Chiusoli, G. P.; Costa, M.; Gabriele, B.; Salerno, G. Journal of2~olecular Catalysis a-
Chemical 1999, 143, 297-310.
(60) Giannoccaro, P. Journal of Organometallic Chemistry 1987, 336, 27 1-278.
(61) Gupte, S. P.; Chaudhari, R. V. Journal of Catalysis 1988, 114, 246-258.
(62) Sheludyakov, Y. L.; Golodov, V. A. 1984, 57, 251-253.
(63) Al per, H.; Hartstock, F. W. Journal of the Chemical Society-Chemical Communications
(64) Murahashi, S.; Mitsue, Y.; Ike, K. Journal of the Chemical Society-Chemical
Communications 1987, 125-127.
(65) Tam, W. Journal of Organ2ic Chemistry 1986, 51, 2977-2981.
(66) Fukuoka, S.; Chono, M.; Kohno, M. Journal of the Chemical Society-Chemical
Communications 1984, 399-400.
(67) Kelkar, A. A.; Kolhe, D. S.; Kanagasabapathy, S.; Chaudhari, R. V. Industrial &
Engineering Chemistry Research 1992, 31, 172-176.
(68) Gabriele, B.; Salerno, G.; Brindisi, D.; Costa, M.; Chiusoli, G. P. Organic Letters 2000,
(69) Gabriele, B.; Mancuso, R.; Salerno, G.; Costa, M. Chemical Communications 2003, 486-
(70) Welton, T. Chem. Rev. 1999, 99, 2071-2083.
(71) Shi, F.; Peng, J.; Deng, Y. Journal of Catalysis 2003, 219, 372-375.
(72) Shi, F.; Zhang, Q.; Gu, Y.; Deng, Y. Advanced Synthesis & Catalysis 2005, 347, 225-
(73) Yang, H. Z.; Deng, Y. Q.; Shi, F. Journal of2~olecular Catalysis A-Chemical 2001, 1 76,
(74) Hartstock, F. W.; Herrington, D. G.; McMahon, L. B. Tetrahedron Lett. 1994, 35, 8761-
(75) Kanagasabapathy, S.; Gupte, S. P.; Chaudhari, R. V. Industrial & Engmneering Chemistry
Research 1994, 33, 1-6.
(76) Fournier, J.; Bruneau, C.; Dixneuf, P. H.; Lecolier, S. Journal of Organ2ic Chemistry
1991, 56, 4456-4458.
(77) Bolzacchini, E.; Meinardi, S.; Orlandi, M.; Rindone, B. Journal of2~olecular Catalysis
a-Chemical 1996, Ill, 281-287.
(78) Orej6n, A.; Castellanos, A.; Salagre, P.; Castill6n, S.; Claver, C. Can. J. Chem. 2005, 83,
(79) Presad, K. V.; Chaudhari, R. V. Journal of Catalysis 1994, 145, 204-2 15 .
(80) Giannoccaro, P.; De Giglio, E.; Garganno, M.; Aresta, M.; Ferragina, C. Journal of
Molecular Catalysis A: Chemical 2000, 157, 13 1-141.
(81) Shi, F.; Deng, Y. Q. Chemical Communications 2001, 443-444.
(82) Sima, T.-L.; Shi, F.; Deng, Y.-Q. Fenzi Cuihua 2001, 15, 435-437.
(83) Shi, F.; Deng, Y.-Q.; Gong, C.-K.; Sima, T.-L.; Yang, H.-Z. H~uaxue Xuebao 2001, 59,
(84) Shi, F.; Zhang, Q.; Ma, Y.; He, Y.; Deng, Y. Journal of the American Chemical Society
2005, 12 7, 4182-4183.
(85) Jetz, W.; Angelici, R. J. Journal of the American Chemical Society 1972, 94, 3799-3 802.
(86) Dombek, B. D.; Angelici, R. J. Journal of Organometallic Chemistry 1977, 134, 203-
(87) Davies, S. G.; Mortlock, A. A. Tetrahedron Lett. 1991, 32, 4791-4794.
(88) Smith, S. W.; Newman, M. S. Journal of the American Chemical Society 1968, 90, 1249-
(89) De Lucca, G. V. Journal of Organ2ic Chemistry 1998, 63, 4755-4766.
(90) 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.; Jackson, D. A.; EricksonViitanen, S.; Hodge, C. N. J. Med. Chem. 1996, 39,
(91) Confalone, P. N.; Waltermire, R. E. In Process Chemistry in the Pharmaceutical
Industry; Gadamasetti, K. G., Ed.; Marcel Dekker: New York, 1999; pp 201-219.
(92) 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 Company, USA). US, 1997; pp 198,
Cont.-in-part of U.S. Ser. No. 147,330, abandoned.
(93) 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. J. Med. Chem. 1996, 39, 2156-2169.
(94) Rossano, L. T.; Lo, Y. S.; Anzalone, L.; Lee, Y. C.; Meloni, D. J.; Moore, J. R.; Gale, T.
M.; Arnett, J. F. Tetrahedron Lett. 1995, 36, 4967-4970.
(95) Hodge, C. N.; Aldrich, 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.; EricksonViitanen, S. Chemistry & Biology 1996, 3, 301-314.
(96) 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 Organ2ic Chemistry 1996, 61, 444-450.
(97) Zhang, Y.; Forinash, K.; Phillips, C. R.; McElwee-White, L. Green Chentistry 2005, 7,
(98) DeClercq, P. J. ChenticalReviews. 1997, 97, 1755-1792.
(99) Scholtissek, C. Chentische Berichte-Recueil 1956, 89, 2562-2565.
(100) Hayashi, K.; Iwakura, Y. Ma~~ikronolekulare Chemie 1966, 94, 132-139.
(101) Kurita, K.; Matsumura, T.; Iwakura, Y. Journal of Organ2ic Chentistry 1976, 41, 2070-
(102) Kielbania, A. J.; Kukkala, P.; Lee, S.; Leighton, J. C. In PCTlnt. Appl. (National Starch
and Chemical Investment Holding Corp., USA). US, 1999; pp 29.
(103) Sonoda, N.; Yamamoto, G.; Natsukawa, K.; Kondo, K.; Murai, S. Tetr~rt~rt~raheron~rt~t~rt Lett.
(104) Leung, M. K.; Lai, J. L.; Lau, K. H.; Yu, H. H.; Hsiao, H. J. Journal of Organ2ic
Chentistry 1996, 61, 4175-4179.
(105) Ala, P. J.; DeLoskey, R. J.; Huston, E. E.; Jadhav, P. K.; Lam, P. Y. S.; Eyermann, C. J.;
Hodge, C. N.; Schadt, M. C.; Lewandowski, F. A.; Weber, P. C.; McCabe, D. D.; Duke,
J. L.; Chang, C. H. Journal of Biological Chentistry 1998, 273, 12325-12331.
(106) Nugiel, D. A.; Jacobs, K.; Cornelius, L.; Chang, C. H.; Jadhav, P. K.; Holler, E. R.;
Klabe, R. M.; Bacheler, L. T.; Cordova, B.; Garber, S.; Reid, C.; Logue, K. A.;
GoreyFeret, L. J.; Lam, G. N.; EricksonViitanen, S.; Seitz, S. P. Journal of M~edicinal
Chentistry. 1997, 40, 1465-1474.
(107) Mei, J. T.; Yang, Y.; Xue, Y.; Lu, S. W. Journal of2~olecular Catalysis A-Chentical
2003, 191, 135-139.
(108) Liu, G. W.; Hakimifard, M.; Garland, M. Journal of2~olecular Catalysis a-Chentical
2001, 168, 33-37.
(109) Briggs, M. A.; Haines, A. H.; Jones, H. F. Journal of the Chemical Society-Perkin Trans.
1 1985, 795-798.
(110) Mehta, N. B.; Diuguid, C. A. R.; Soroko, F. E. Journal of2~edicinal Chentistry 1981, 24,
(111) Gutschow, M.; Hecker, T.; Eger, K. Syinhesis\i 1999, 410-414.
(112) Wessels, F. L.; Schwan, T. J.; Pong, S. F. Journal ofPharnzaceutical Science 1980, 69,
(113) Caldwell, A. G.; Harris, C. J.; Stepney, R.; Whittaker, N. Journal of the Chemical
Society.-Perkin Transactions. 1 1980, 495-505.
(114) Lopez, C. A.; Trigo, G. G. Advances in Heterocyclic Chentistry 1985, 38, 177-228.
(115) Ware, E. ChenticalReviews 1950, 46, 403-470.
(116) Zorc, B.; Cetina, M.; Mrvos-Sermek, D.; Raic-Malic, S.; Mintas, M. Journal of Peptide
Research. 2005, 66, 85-93.
(117) Meusel, M.; Gutschow, M. Organic Preparations Procedures International. 2004, 36,
(118) Beller, M.; Eckert, M.; Moradi, W. A.; Neumann, H. Angewandte Chenzie-hiternational
Edition. 1999, 38, 1454-1457.
(119) Sarges, R.; Bordner, J.; Dominy, B. W.; Peterson, M. J.; Whipple, E. B. Journal of
Medicinal Chentistry. 1985, 28, 1716-1720.
(120) Smith, R. J.; Bratovanov, S.; Bienz, S. Tetrahedron 1997, 53, 13695-13702.
(121) LeTiran, A.; Stables, J. P.; Kohn, H. Bioorgan2ic and2~edicinal Chentistry. 2001, 9,
(122) Talaty, E. R.; Yusoff, M. M.; Ismail, S. A.; Gomez, J. A.; Keller, C. E.; Younger, J. M.
Synlett 1997, 683-684.
(123) Hulme, C.; Ma, L.; Romano, J. J.; Morton, G.; Tang, S. Y.; Cherrier, M. P.; Choi, S.;
Salvino, J.; Labaudiniere, R. Tetr~rt~rt~raheron~rt~t~rt Lett. 2000, 41, 1889-1893.
(124) Zhang, D.; Xing, X. C.; Cuny, G. D. Journal of Organ2ic Chentistry 2006, 71, 1750-1753.
(125) Brown, H. C.; Choi, Y. M.; Narasimhan, S. Journal of Organic Chentistry 1982, 47,
(126) Choi, D.; Stables, J. P.; Kohn, H. Journal of2~edicinal Chentistry. 1996, 39, 1907-1916.
(127) Andurkar, S. V.; Stables, J. P.; Kohn, H. Tetr~rt~rt~raheron:t~r~rtr Asynametry 1998, 9, 3841-3854.
(128) Anderson, G. W.; Zimmerman, J. E.; Callahan, F. M. Journal of the American Chemical
Society 1967, 89, 5012-5017.
(129) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.
Organonsetallics 1996, 15, 1518-1520.
(130) Ueno, K.; Ogawa, A.; Ohta, Y.; Nomoto, Y.; Takasaki, K.; Kusaka, H.; Yano, H.;
Suzuki, C.; Nakanishi, S. In PCTlnt. Appl. (Kyowa Hakko Kogyo Co., Ltd., Japan). WO,
2001; pp 26.
(131) Lazarus, R. A. Journal of Organ2ic Chemistry 1990, 55, 4755-4757.
(132) Pham Tien, Q.; Pyne Stephen, G.; Skelton Brian, W.; White Allan, H. Journal of Organ2ic
Chemistry 2005, 70, 6369-6377.
Delmy J. Diaz was born on November 14, 1967, in San Pedro Sula, Honduras. She was
the second of six brothers and sisters. As a child, she was always curious of why everything
happens; as a consequence, she was always asking many questions driving crazy any adults
around her, since usually one answer will lead to more and more questions. She spent her
formative years at Santa Rosa Elementary School and later she attended part of her high school
studies at Public High School El Patria, moving later on to continue studies to become an
elementary school teacher to Escuela Normal de Occidente en la Esperanza Intibuca.
Throughout her high school formation she was an active and enthusiast member of the science
club. In the spring of 1987 she started her major in science at the Natural Science Department at
the Pedagogic University Francisco Morazan, from were she graduated 4 years later. She started
to work as a chemistry and physics teacher at the high school level. After two years working as a
science teacher she went back to the University to pursue a License in Biology-chemistry
emphasis, and she started working as a chemistry T.A. at the National Pedagogic University. In
2001, she traveled to the USA after she was awarded a Fulbright Scholarship to do her master's
degree in organic chemistry at the University of Vermont, Burlington, which she completed in
2003. That same year she moved to the University of Florida to pursue her Ph.D. studies,
specializing in the area of organic chemistry. After graduating she will go back to her country
Honduras and will start working as a professor at the Science Department of the National
Pedagogic University Francisco Morazan.