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

By DELMY DIAZ-MONTERROSO

A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2007

 2007 Delmy Daz-M.

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

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

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

THE W(CO)6/I2 CATALYZED OXIDATIVE CARBONYLATION OF DIAMINES: ANALOGS OF THE CORE STRUCTURES OF THE HIV PROTEASE INHIBITORS DMP 323 AND DMP450. ......................................................................................................56 Background .............................................................................................................................56 Results and Discussion ...........................................................................................................61 Synthesis of Seven-Membered Ring Cyclic Ureas 84 and 89 .........................................61 Conclusions.............................................................................................................................64

CATALYTIC OXIDATIVE CARBONYLATION OF ENANTIOMERICALLY PURE -AMINO AMIDES TO PRODUCE HYDANTOIN DERIVATIVES ................................65 Background .............................................................................................................................65 Classic Ways to Synthesize Hydantoins .................................................................................65 Solution Phase Synthesis .................................................................................................67 Solid-Phase Organic Synthesis ........................................................................................69 Synthesis of Hydantoins Using W(CO)6/I2 Catalytic System .........................................70 Results and Discussion ...........................................................................................................71 Conclusions.............................................................................................................................76

EXPERIMENTAL SECTION ................................................................................................77 General Procedures ..........................................................................................................77 Procedure A for Carbonylation of Amino Alcohols with CDI........................................77 Procedure B for carbonylation of aminoalcohols with DMDTC ....................................77 Procedure C for Catalytic Carbonylation of Amino Alcohols with W(CO)6/I2 ..............78 Synthesis of Cyclic Ureas .......................................................................................................82 General Procedure for the Synthesis of -Amino Amides 103a-103e. ..................................84 General Procedure for the Carbonylation of -Amino Amides 103a-e to Afford Hydantoins 104a-e. .............................................................................................................84

LIST OF REFERENCES ...............................................................................................................87 BIOGRAPHICAL SKETCH .........................................................................................................96

LIST OF TABLES Table page

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

LIST OF FIGURES Figure page

1-1. Co(salen) (22) and modified Co(salen) complexes (23-27) ..................................................28 1-2. Structures of the HIV protease inhibitors DMP 323 and DMP 450 ......................................39 4-1. Hydantoin ring structure. .......................................................................................................66 4-2. Synthetic strategies and building blocks for hydantoin synthesis. ........................................66 4-3. -Amino amide substrates to be converted to hydantoins .....................................................73

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

NMP SEM SPOS THF TLC

N-methylpyrrolidinone 2-(trimethylsilyl)ethoxymethyl Solid-phase organic synthesis Tetrahydrofuran Thin layer chromatography

10

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

11

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

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

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

carbamates, and their cyclic derivatives in good yields. New conditions for the PdI2-catalyzed oxidative carbonylation of amines to ureas (Eq.1), afforded ureas in high yields with turnover numbers as high as 4950.32,69 Carbonylations of primary aliphatic amines (Eq.1, R = alkyl) were carried out at 100 C under a 4:1:10 mixture of CO:air:CO2 (60 atm total pressure at 25 C) in the presence of a simple catalytic system consisting of PdI2 in conjunction with a KI promoter. In the absence of CO2, less satisfactory results were obtained.69 The choice of solvent was critical to product selectivity. Monocarbonylation to the urea was favored in dioxane or 1,2dimethoxyethane (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 2 RNH 2 + CO + 1/2 O2 - H 2O RHN O NHR (1)

Pd cat RNH 2 + R2'NH + CO + 1/2 O 2 - H 2O RHN

O NR' 2 (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

15

complex 1 formed in preequilibrium with starting materials (Scheme 1). In agreement with this hypothesis, isocyanates were detected (by GLC, TLC, and GLC/MS) in the reaction mixtures in low-conversion experiments. Under these conditions, Pd(0) is reoxidized to Pd(II) by oxidative addition of I2, which is regenerated through oxidation of HI by oxygen. Scheme 1
- HI Pd I2 + RNH 2 + CO IPd 1 NHR O

-[Pd(0) +HI] O RHN NHR RNH2 R N C O

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 2 NH 2 PdI2 cat - H 2O H N O N H

CO + 1/2 O 2

(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,Nbis(methoxycarbonylalkyl)ureas from primary -amino esters. A showcase synthesis of the neuropeptide Y5 receptor antagonist NPY5RA-972 was also reported (Eq. 4).32

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NH2 H N + N O Pd cat CO 1/2 O 2 - H 2O O H N O N NPY5RA-972 N

(4)

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

17

the nitrobenzene serves as both substrate and oxidant. In terms of green chemistry, the advantages of this method are the low quantities of ionic liquids used and the avoidance of potentially explosive CO/O2 mixtures. The authors suggested that the enhanced catalytic activity of this system may be derived from the high concentration of ionic liquid containing the metal complex confined within the cavities of the silica gel matrix.72 Experiments with the ionic liquids DMImBF4 (1-decyl-3-methylimidazolium tetrafluoroborate) and EMImBF4 (1-ethyl-3-methylimidazolium tetrafluoroborate) and the catalysts HRu(PPh3)2Cl2, Rh(PPh3)3Cl, Pd(PPh3)2Cl2 and Co(PPh3)3Cl2 afforded good to excellent yields of N,N-diphenylurea (DPU) from nitrobenzene and aniline. The RhDMImBF4/silica gel catalyst produced 93% conversion of starting materials with a selectivity of 92% for the urea. Conversion of aliphatic amines and nitrobenzene to the unsymmetrically substituted ureas could also be achieved with this particular catalyst. Scheme 2
CO metal complexionic liquid/silica gel

NO 2

RNH 2

NHCONHR

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

Electrocatalytic carbonylation Another method for the synthesis of alkylureas is the electrocatalytic carbonylation of aliphatic amines, as reported by Deng.73 Electrocatalytic carbonylation of a series of aliphatic amines to dialkylureas and isocyanates using Pd(II) complexes with a Cu(II) cocatalyst could be achieved under mild reaction conditions, with particularly good results for primary amines (Eq. 5). The additional steric hindrance in secondary amines apparently prevents the reaction, as

18

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.
O RHN NHR

2 RNH 2 + CO

Pd(PPh3 )2Cl2 + Cu(OAc) 2 Bu4NClO4 , 30C, 1 atm 0.9 V versus SCE

(5)

Although products were obtained with a single complex as catalyst [Cu(OAc)2, PdCl2 or Pd(OAc)2], catalytic activity and selectivity for the urea were improved when both a Pd complex and Cu(OAc)2 were present in the reaction mixtures. Quantitative conversion and 98% selectivity for the urea were achieved in the case of n-butylamine with Pd(PPh3)2Cl2 and Cu(OAc)2.73 The authors suggested a synergistic effect between Pd(II) and Cu(II), as opposed to simple mediation of electron transfer, which had been invoked in a related case of electrocatalysis.74 Mechanistic studies Recent progress has also been made in understanding the mechanism of the carbonylation of amine nucleophiles. Shimizu and Yamamoto have reported a mechanistic study focusing on the role of the reoxidation of Pd(0) species formed in the principal catalytic cycle to electrophilic Pd(II) species during the selective carbonylation of amines to oxamides and ureas.53 Their work revealed the importance of the oxidant in selectivity as 1,4-dichloro-2-butene (DCB) afforded oxamides from primary and secondary amines while use of I2 as the oxidizing agent resulted in formation of ureas. Further insight was obtained through independent generation of carbamoylpalladium complexes as models for species in the catalytic cycle. Two possible mechanisms for the conversion of primary amines to ureas by palladiumcatalyzed carbonylation were discussed in conjunction with this study. In the first, the critical 19

step is reductive elimination of carbamoyl and amido ligands to generate the urea, as previously proposed by Alper.51 The crucial step in the second possible route involves formation of an intermediate alkyl isocyanate from an N-monoalkylcarbamoylpalladium species 3, (Scheme 3). The urea product is then derived from nucleophilic attack of a primary or secondary amine on the isocyanate to release a symmetrically or unsymmetrically substituted urea. This second possibility is based on an earlier proposal by Gabriele for a related system.69 Support for the isocyanate pathway came from the inability of secondary amines to form tetra substituted ureas, the presence of trisubstituted ureas upon carbonylation of mixtures of primary and secondary amines and the kinetics of conversion of model compounds for 3 to ureas in the presence of NEt3.53 Scheme 3
Oxidant -RNH3 X N C O R isocyanate +RNH2 O C O R N H N H R L 2Pd X 3 2 X NHR L2 Pd X X = Cl or I L = ligand PdL 2

+RNH2

-RNH 3X

2RNH 2, 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 20

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 50C for 8 hours under 30 atm CO and 5 atm O2. At temperatures higher than 50C, side reactions became significant and at lower temperatures the reductive step, in which amine carbonylation occurs, failed. The product selectivity depended on the amount of water present, with anhydrous conditions favoring the oxamide, while the presence of water promoted urea formation (Scheme 4). The authors suggested that water could coordinate to the nickel center, allowing the formation of only one carbamoyl group. Under aqueous conditions, this intermediate would then undergo nucleophilic attack by amine to form the urea. In the absence of water, oxamide would arise from reductive elimination of two carbamoyl groups.22 Scheme 4
NiII + CO RNH 2

H 2O CONHR Ni OH2 + RNH2 Urea Ni

anhydrous CONHR CONHR

Oxamide

Ruthenium-catalyzed oxidative carbonylation Gupte utilized ruthenium catalysts for the selective formation of N,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 NiI as the promoter. The key step in the

21

proposed mechanism involves the formation of carbamoyl species 8 (Scheme 5). Loss of CO from the catalyst precursor [Ru(CO)3I3]- generates intermediate 5, which reacts with aniline to form 6 and HI. Addition and insertion of CO affords carbamoyl complex 8, which reacts with aniline to yield the urea and the hydrido carbonyl species 9. Addition of aniline to form 10 is followed by oxidation with O2 to regenerate the active species 6 (Scheme 5).27 Related chemistry with alkylamines has been reported by Chaudhari.67,75 Scheme 5
[Ru (CO) 3I3]4 -CO [Ru (CO) 2I3]5 ArNH 2 HI H 2O [(ArNH) Ru (CO) 2I 2 ]6 CO

1/2 O 2
[(ArNH) Ru (CO) 3I2 ]7

[(ArNH2 ) Ru (H) (CO) 2I 2]10

ArNH 2 [HRu (CO)2 I2 9 ][(ArNHCO) Ru (CO) 2I2 ]8

(ArNH)2 CO

ArNH2

Dixneuf reported the synthesis of symmetrical ureas by reacting primary amines with CO2 and a ruthenium complex, in the presence of a terminal alkyne (Scheme 6).76 Yields ranged from low to moderate, with the best yield of N,N-dicyclohexylurea (61%) obtained with RuCl3H2O as catalyst in the presence of 2 equiv of tri-n-butylphosphine (n-Bu3P). Further optimization 22

studies established the importance of running the reaction in the presence of excess alkyne but with no solvent. Scheme 6
H R' O [Ru] 2 RNH2 + CO2 RHN organic products from R'C2 H + H2 O NHR

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 rutheniumcoordinated 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 -hydroxy-ketone 13. This ketone was not detected experimentally but would be expected to react further under the reaction conditions (Scheme 7).76 Kondo reported the application of RuCl2(PPh3)3 as a precatalyst for the preparation of ureas from amines, using formamide as the carbonyl source.24 Using this system, symmetrical ureas could be prepared from the parent formamide, while unsymmetrical ureas were available from N-substituted formamides (Scheme 8). High yields of N,N-diarylureas were obtained from N-arylformamides and aniline derivatives, but the yields of symmetrical ureas from formamide were variable. Secondary amines underwent the reaction, but N,N-substituted formamides did not.

23

Scheme 7
H Ru + RNHCO2 RNH3 + Ru H O O OH OH NHR H2 NR

11

C(CH 3) 2OH RHN

O NHR

O RNH 2

Ru

12 13
OH OH OH

Scheme 8
O C R HN
1

O + H R 1R 2NH RuCl2 (PPh3 )3 mesitylene reflux, -H2 R1 HN C NR 1R 2

O C H 2N + H 2 RNH 2 RuCl2 (PPh3 )3 mesitylene reflux, -H2 RHN

O C NHR

24

Scheme 9
O RHN 2 RuCl2 (PPh 3) 3 O O 2 PPh3 RHN RHN H H NHR'

R'NH 2 RHN O Ru Ph 3P Cl Cl 14 Cl Ru PPh3 PPh3 Ph3 P Cl Ph 3P O Ru Cl Cl 17 Ru PPh3 PPh3 NR Cl

Ph3 P Cl

H2 H O Cl Ru Ph3 P 15 N R Cl PPh 3 PPh 3 Ph3 P Cl O Ru Ph 3P H Ru Cl H 16 Cl NR Cl PPh3 PPh3

Ph3P Cl

H Ru Cl

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

25

corresponding urea and regenerate the active species. In this scheme, reaction of N,Ndisubstituted 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-bis(salicylidene)ethylenediaminocobalt(II) ([Co(salen)]) as the catalyst.20 Optimal reaction conditions varied with the substrate. For example, the urea yields from 4-methylaniline were higher at high pressure of O2, while 4-fluoroaniline reacted better at lower O2 pressure. Substituent effects were also examined. Electron-withdrawing groups in the para position lowered the conversion of the starting amine while ortho-aminophenol was more reactive than the other amines. The substituent effects were elaborated in a subsequent paper.77 The proposed mechanism involved equilibrium between planar and non-planar salen ligands (18 and 19) on a cobalt (III) amido complex, either of which could undergo carbon monoxide insertion to give an equilibrium mixture of carbamoyl complexes 20 and 21. Compound 20, having the planar salen ligand and a trans relationship between the carbamoyl and amine ligands, could lead to free isocyanate or carbamate, while complex 21, having a nonplanar salen and a cis relationship between the carbamoyl and amine ligands, would lead to the urea (Scheme 10).20 Dicobalt octacarbonyl has also been used in the microwave synthesis of ureas. Larhed drastically reduced reaction time by running the reaction under microwave irradiation. The carbonyl complex served as the source of CO, eliminating the need for CO pressure in the reaction vessel. Symmetrical and unsymmetrical ureas were obtained in as little as 10 seconds, with yields generally better for symmetrical ureas.

26

Scheme 10
NH 2 Ar N Co O NHAr 18 O N NH 2Ar N Co O O ArHN 20 O free isocyanate or carbamate

O N Co O NHAr 19 ArHN NH 2 Ar N

O N Co O O 21 NH 2Ar urea

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

27

N Co O 22

N O
t

N Co Bu
t

N O
t t

O Bu

Bu

Bu

23

NO 2 N Co N O

O2 N

NO2

N Co O

N O 25

24

N Co

N Co

O O 26

O O 27

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

Giannocaro reported preparation of Rh3+ and Rh3+-diamine complexes intercalated into titanium phosphate (TiP), and measured their activity towards oxidative carbonylation of aniline.80 Intercalation provided a way to heterogenize an otherwise homogeneous catalyst. Typical conditions involved acetonitrile or methanol as the solvent, a CO/O2 mixture at atmospheric or higher pressure, temperatures between 70-120C, and the presence of PhNH3+Ias a promoter. The highest catalyst activities were obtained with increased pressure of the CO/O2 mixture, higher temperature, and a molar ratio of co-catalyst to Rh3+(PhNH3+I-/ Rh3+) between 5 and 6. It was found that the materials containing simple Rh3+ salts worked better than those prepared from Rh3+-diamine complexes. The key intermediate in the postulated reaction mechanism (Scheme 11) is the Rh3+-carbamoyl complex 28 which reacts with molecular iodine 28

to form the iodoformate intermediate, ICONHPh. The latter reacts with aniline to afford diphenylurea.80 Scheme 11
PhNHCONHPh HI

PhNH 2 ICONHPh H+,O2 HI TiP-HxRhy CO + PhNH2

H2 O I2

TiP-H (x+y)Rh-(CONHPh)y 28

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

Scheme 12
R2NH Au/polymer CO + O 2 or CO 2 R 2NHCONHR2

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

30

Scheme 13
Ph N 1/2 OC W OC I 29 I N Ph I W CO I CO 1 equiv NH2R OC W OC I 30 NH2R Ph N I

1 equiv NH2R + CO NH2R NH2R 34 O RHN NHR 2 equiv NH2R OC W OC I 31 + NH2R NH2R

Ph N OC W I

Ph N

1 equiv NH2R Ph N O OC C N R I W NH2R NH2R 33 + [Ox] 1 equiv NH2R R O C N H I 32 OC W Ph N NH2R 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 1,3disubstituted urea, producing coordinatively unsaturated complex 34, which could undergo addition of CO to regenerate cationic intermediate 31 and close the catalytic cycle.

31

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

32

Table 1-1. Oxidative Carbonylation of Primary Amines to Ureas under Optimized Conditions. Amine Product %Yield CH2Cl2
O

NH2

N H
O

N H

90

NH2

N H

N H

84

O
NH 2

N H
O

N H

53

NH2

N H
O

N H

55

NH 2

N H

N H

72

O
NH 2

N H

N H

Conditions: W(CO)6 (2 mol %), I2 (0.5 equiv), 1.5 equiv of K2CO3, 90C, 80 atm CO,and CH2Cl2 as the solvent.

33

We thus explored the catalytic carbonylation of diamines to cyclic ureas using W(CO)6 as the catalyst, I2 as the oxidant, and CO as the carbonyl source.42 Both primary and secondary ,diamines were substrates for the reaction, with secondary diamines being converted directly to the corresponding N,N'-disubstituted cyclic ureas. Synthesis of the five-, six-, and seven-membered cyclic ureas from the primary diamines could be achieved in moderate to good yields (Eq 6),42 with the highest isolated yield for the sixmembered cyclic urea. Only trace amounts of the eight-membered ring compound could be detected in the reaction mixtures, which was not surprising as there are no reports in the literature of preparation of this compound from 1,5-pentanediamine. In addition, (+)-(1R,2R)1,2-diphenyl-1,2-ethanediamine was carbonylated to the 2-imidazolidinone in 46% yield with no epimerization. Reaction of the secondary diamines RNHCH2CH2NHR (Eq 6, R = Me, Et, iPr, Bn) under similar conditions resulted in conversion of the diamines to the corresponding N,N'disubstituted cyclic ureas. For both primary and secondary substrates, it was necessary to employ high dilution conditions to minimize formation of oligomers, a problem also encountered during the reactions of phosgene and its derivatives with diamines.87
O NHR NHR n n=0-2 R = H, alkyl W(CO) 6 CO / I2 / K2CO3 n R N N R (6)

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, 1,3diethyl-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 34

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, Nmethylpropanediamine reacted under the oxidative carbonylation conditions to produce the corresponding monosubstituted N-methyl cyclic urea in preference to acyclic urea formation through the more reactive primary amines.42 A more extensive study on the carbonylation of ,-diamines to cyclic ureas involved further optimization of the conditions using propane-1,3-diamine as the test substrate, W(CO)6 as catalyst and I2 as the oxidant.2 Effects of solvent and temperature variation on the yields of the cyclic urea from propane-1,3-diamine were examined. Additional experiments probed the effect of alkyl substituents in the linker of primary diamines (Table 1-2). In the cases of simple n-alkyl substituents, the yields of cyclic ureas are significantly higher for the 2,2-dialkyl-1,3propanediamines than for the parent propane-1,3-diamine as a result of the Thorpe-Ingold effect88 and improved solubility in organic solvents during workup. The carbonylation of N,N'-dialkyl-2,2-dimethylpropane-1,3-diamines afforded tetrasubstituted ureas; however, the products were obtained in modest yields, and tetrahydropyrimidine byproducts were formed in significant amounts when the substrates bore N-alkyl substituents larger than methyl. Comparison of these results with the carbonylations of secondary diamines to form five-membered cyclic ureas suggested that the effects of ring size and N-substituent size on the carbonylation reaction are complex. Success with conversion of diamines to cyclic ureas suggested the use of W(CO)6catalyzed oxidative carbonylation of amines can be used for the the synthesis of complex targets.

35

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

O

% Yield

H2N

NH 2

HN

NH

52

H 2N

NH2

HN

NH

80

H 2N Bu Bu

NH2

HN Bu

NH Bu

70

H 2N PhH 2C

NH2 CH2Ph

HN PhH 2C

NH CH2 Ph

48

H 2N

NH2
HN NH

50

O
H 2N NH2

HN

NH

33

O
Et H 2N Bu NH2

HN

NH Et Bu

38

36

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

NH2 R

W(CO)6, I2 CO, K2 CO3

R HN O NH R

(7)

37

Table 1-3. Catalytic Carbonylation of Substituted Benzylamines to Ureas %Yielda,b %Yielda,c Amine Amine CH2Cl2 CH2Cl2/H2O
NH2

%Yielda CH2Cl2 36

%Yieldb CH2Cl2/H2O 55

NH2 H
NH2 Cl

63

73

EtO O

35

77

NH2 HO O

37

NH2 Br I

30 39 47 24 5 0

77 70
O2N

NH2

41 45 37 28 17

69 76 68 14 20

NH2

NH2

NH2 MeO NH2 MeS NH2 HO NH2 HS

a b

70
NC

NH2

81
H2N

NH2

58 0

NH2 NH2

Reaction conditions: amine (7.1 mmol), W(CO)6 (0.14 mmol), I2 (3.5 mmol), K2CO3 (10.7 mmol), CH2Cl2 (20 mL), 70 C, 80 atm CO, 24 h. The solvent was CH2Cl2 (21 mL) plus H2O (3 mL). Other conditions are as in footnote a.

38

Direct comparison of the catalytic carbonylation reaction with stoichiometric reaction of the same substrates with phosgene derivatives was possible due to the extensive literature on the synthesis of these targets.
HO OH H2N O Ph N N Ph HO OH Ph N O N Ph HO OH NH2

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.

39

O NH2 Ph P 1O NH2 Ph OP 2 W(CO) 6 / CO I2 / K2 CO 3 Ph H N N H Ph P1 O 38 P1, P2 = OP2

(8)

35 P1, P2 =

C(CH3)2

C(CH3)2

36 P1, P2 = MEM, MEM 37 P1, P2 = SEM, SEM

39 P1, P2 = MEM, MEM 40 P1, 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 Oxazolidinone formation had also been reported as the result of reaction of 41 with CDI and phosgene.96 The earlier functional group compatibility study had suggested that the catalyst was tolerant of -OH groups (Eq 7, Table 3) but the test substrate in that study was [4-(aminomethyl)phenyl]methanol, in which the -OH group is para with respect to the amine so as to eliminate the possibility of formation of a cyclic carbamate. For that substrate, the corresponding urea was produced without competing carbamate or carbonate formation.44 For diamine diol 41, oxazolidinone formation had been preferred under the reaction conditions tested. More recently, the catalytic carbonylation of a series of amino alcohols of varying tether lengths and substitution patterns was carried out to probe the selectivity of the W(CO)6/I2 carbonylation system for reactivity of alcohols versus amines. The phosgene derivatives dimethyl dithiocarbamate (DMDTC) and 1,1'-carbonyldiimidazole (CDI) were used as representative stoichiometric reagents for comparison purposes, the results are discussed in a separate chapter, later on in this work.46

40

NH 2 Bn HO

NH 2 Bn OH

Ph

OH NH 2 HN O O

Ph

O O NH

W(CO)6, I2 CO, K2CO3

+
Ph

HN O

Ph

41

43

42

(9)

Other interesting targets that were prepared to investigate the scope of the W(CO)6/I2 system were biotin and related heterocyclic ureas.97 Biotin (44b), also known as Vitamin H, is produced on large scale as a feed additive for poultry and swine. It has also been the target of more than 40 total and formal syntheses.98 One recurring theme in these syntheses has been installation of the urea moiety by reaction of phosgene with a diaminotetrahydrothiophene derivative.
O SO4 2+

H 3N

NH 3+

W(CO)6 / I2 CO 2R CO / K2CO3

HN

NH

(10)

S 44a R = H 45a R = Me

S 44b R = H 45b R = Me

CO2 R (0%) (84%)

O H2 N R1 X NH2
W(CO)6 / I2

HN

NH
(11)

R2

CO / K2CO 3

R1

R2

46a-47a, 48a-49a X O O N-BOC CH2CH2 R1 H H CH3 H

46b-47b, 48b-49b R2 H (CH2)4CH3 CH3 H

46a 47a 48a 49a

46b 47b 48b 49b

41

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 W(CO)6/I2 CDI Amine Urea Yield Yield 46a 47a 48a 49a 46b 47b 48b 49b Trace 47% 46% 57% 20% 67% 37% 56% Conclusions Transition metal-catalyzed carbonylation of amines offers new and efficient methodology for the selective synthesis of ureas under relatively mild reaction conditions. Use of CO or CO2 as the carbonyl source in the presence of a catalyst and an oxidant provides an alternative to the traditional methods for conversion of amines to ureas, which involve stoichiometric use of phosgene and its derivatives. From the perspective of green chemistry, the replacement of phosgene and the minimization of the waste streams associated with phosgene derivatives would be beneficial. Recent developments in metal-catalyzed oxidative carbonylation of amines include new techniques such as the use of ionic liquids, microwave irradiation and electrocatalytic carbonylation. In addition to extensive work with palladium complexes, carbonylation reactions that utilize other late transition metals, such as Ni, Ru, Rh, Co, Au, have also been demonstrated

42

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.

43

CHAPTER 2 SELECTIVE CATALYTIC OXIDATIVE CARBONYLATION OF AMINOALCOHOLS TO UREAS Conversion of amines to ureas commonly involves nucleophilic displacement of leaving groups from phosgene or a phosgene derivative.13 Phosgene and its derivatives are not selective for the carbonylation of amines, reacting with other functionality such as hydroxyl groups. In fact, phosgene reacts with both functional groups of aminoalcohols to form products such as cyclic carbamates99 or isocyanate chloroformates (Scheme 14).100,101 Although transamination of ureas,102 selenium-catalyzed carbonylation,103 and condensation with S,S'-dimethyl dithiocarbonate (DMDTC)104 have been used to generate hydroxyalkylureas from aminoalcohols under circumstances where formation of the cyclic carbamate is disfavored, selective reactivity of aminoalcohols with a phosgene derivative often requires protection of one functional group to avoid forming mixtures of ureas and carbamates.

Scheme 14
O HN O

COCl2 H2N n OH

n=2 O O C N
nO

Cl

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.41,4345

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

44

groups (Eq. 12), at least in the case of [4-(aminomethyl)phenyl]methanol, in which the corresponding urea was produced without competing carbamate or carbonate formation.44 However, in the carbonylation reaction of Eq 12, the OH group is para with respect to the amine so as to eliminate the possibility of intramolecular formation of a cyclic carbamate. We now report the catalytic carbonylation of a series of aminoalcohols of varying tether lengths and substitution patterns in order to evaluate the selectivity of the W(CO)6/I2 carbonylation system for reactivity of alcohols vs. amines. These results are compared to reaction of the same aminoalcohol substrates with the phosgene derivatives DMDTC and 1,1'-carbonyldiimidazole (CDI).

NH 2 HO

W(CO)6, I2 CO, K2 CO 3

HO HN O NH 71 %

OH (12)

Results and Discussion The aminoalcohol substrates for this study were chosen with varying tether lengths between the functional groups and varying steric hindrance at the active sites. The substrates were then subjected to W(CO)6-catalyzed oxidative carbonylation for evaluation of the selectivity of the W(CO)6/I2 system towards formation of the ureas or carbamates, either cyclic or acyclic. As a comparison of the stoichiometric reactions of phosgene derivatives to the catalytic W(CO)6/I2 methodology, 1,1'-carbonyldiimidazole (CDI) and dimethyl dithiocarbonate (DMDTC) were also used for the carbonylation of the aminoalcohol substrates.

45

Carbonylation of 5-Aminopentanol Carbonylation of 5-aminopentanol 50 was investigated to determine the preference of a 1,5-aminoalcohol to form the corresponding acyclic urea 51 or the 8-membered cyclic carbamate 52 (Eq. 2). The optimal reaction conditions of a substrate concentration of 4M, 40 C, 80 atm CO and a reaction time of 18 hours afforded the bis(hydroxyalkyl)urea 51 in 64% yield and the cyclic carbamate 52 in only 2% yield. The acyclic carbamate 53 was not detected in the reaction mixtures. However, the presence of unreacted starting material was observed by TLC prior to purification of the products.
HO H N O 51 HO 50 NH2 W(CO) 6, CO HN I2, py 52 H N O 53 O O (13) H N OH

HO

NH2

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

46

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

47

Table 2-1. Carbonylation of aminoalcohols to ureas and carbamates. Entry Substrate Reagent Urea Cyclic (%) Carbamate (%) W(CO)6 /CO 64 2 1 H2N OH CDI 80 trace 50 DMDTC 45 0 2
HO NH2

W(CO)6 /CO CDI DMDTC W(CO)6 /CO CDI DMDTC W(CO)6 /CO CDI DMDTC W(CO)6 /CO CDI DMDTC W(CO)6 /CO CDI DMDTC W(CO)6 /CO

93 70 93 95 36 30 72 49 34 60 55 32 78 18 72 79 30 73

0 trace 0 trace 60 8 14 30 47 5 28 29 10 22 trace 14 52 trace

54 3 59 4
Ph OH NH2
OH NH2 CH2Ph

63 5 67 6 75 7 78
HO NH2 Ph
OH NH2

HO Ph

NH2

CDI DMDTC

48

HO

H N O 55

H N

OH

HO

NH2

W(CO) 6, CO I2 , py HN

O O (14)

54 56 H N O 57

HO

NH 2

Carbonylation of 1,3-Aminoalcohols The carbonylation of a 1,3-aminoalcohol to a six-membered cyclic carbamate or an acyclic carbamate vs. formation of the corresponding urea was first investigated using 3-amino-4phenyl-butanol (59) as a representative substrate. Substrate 59 was synthesized by reduction of DL--homophenylalanine (58) with BH3THF at 0 C (Eq. 15).
NH 2 BH 3.THF O OH 58 4.5 hrs OH 59 NH 2 (15)

Aminoalcohol 59 was then subjected to oxidative carbonylation using the W(CO)6/I2 catalytic system under the previously determined optimal reaction conditions (Eq. 16, Table 6, Entry 3). Urea 60 was isolated in 95% yield with carbamate 61 formed in trace amounts as a minor product. Acyclic carbamate 62 was not observed.

49

HO NH NH HO O 60 O O NH (16)

NH2

W(CO) 6, CO I2, py

OH 59

61

NH2 O O 62

OH

N H

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

with the minor product being cyclic carbamate 65 in 14% yield after crystallization. The acyclic carbamate 66 was not formed in the reaction.
HO O HN O NH OH W(CO) 6, I2 CO, py NH 2 O 63 N H 66 HO 64 NH 2 O OH 65 (17) HN O

For comparison, 1-phenyl-3-aminopropanol was subjected to carbonylation with the phosgene derivatives CDI and DMDTC (Table 2-1, entry 4). When CDI was used as carbonylating agent, the urea 64 was formed in 49% yield, and the cyclic carbamate 65 in 30% yield. Once again, the acyclic carbamate was not observed in the product mixture. In contrast, when DMDTC was used as carbonylating agent, cyclic carbamate 65 was the major product (47% yield), while the urea was recovered in 34% yield.

Finally, 3-amino-2,2-dimethylpropanol (67) was studied under the optimal W(CO)6/I2 catalytic conditions (Eq. 18). Compound 67 was chosen in order to examine the effect of steric bulk at the position to the nucleophilic nitrogen and the Thorpe-Ingold effect of the gemdimethyl substituents at C3. Accordingly, the carbamate was expected to be favored by the presence of the gem-dimethyl substituents. However, when carried out under the W(CO)6/I2 carbonylation conditions, the reaction did not go to completion and 12% of the starting material was recovered. This may be due in part to steric bulk in the substrate. Nevertheless, urea 68 and 51

carbamate 69 were obtained in 60% and 5% yield, respectively (Table 2-1, entry 5). There was no evidence for the formation of the acyclic carbamate 70.

O OH HN NH OH HN

O O

NH2 OH

W(CO)6, CO I2 , py

68 NH 2 O

O NH OH

69

(18)

67 70

In contrast, when 3-amino-2,2-dimethylpropanol (67) was treated with CDI or DMDTC, much higher proportions of carbamate were generated than with the W(CO)6-catalyzed carbonylation (Table 2-1, Entry 5). Urea 68 was still the major product for both carbonylation reactions, being isolated in 55% yield and 32% yield, respectively. However, cyclic carbamate 69 was recovered in 28% yield from the reaction with CDI and in 29% yield when DMDTC was used in the carbonylation. Overall, there is a strong selectivity favoring formation of urea over carbamate in the W(CO)6-catalyzed carbonylation for all three 1,3aminoalcohols that were investigated. In comparison, the selectivity for formation of the urea over formation of the carbamate is significantly lower when CDI or DMDTC is used as the carbonylating agent. Carbonylation of 1,2-Aminoalcohols Our interest in the carbonylation of 1,2-aminoalcohols began with our preparation of the core structure of the HIV protease inhibitors DMP 323 and DMP 450 by W(CO)6-catalyzed carbonylation of O-protected derivatives of diamine diol 71.4 As part of these investigations, it was determined that under the initially reported conditions, oxidative carbonylation of 71

52

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
O HN Bn HO NH 2 Bn HO 71 OH NH2 Bn W(CO)6 , I2 Ph CO, K2 CO 3 HN O 74 O 72 OH NH 2 Ph (19) OH NH Bn HN O 73 O Ph O O NH Ph

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

O Ph H2N OH 75 W(CO) 6, I2 CO, py Ph HO 76 OH HN NH Ph

Ph + HN O 77 O (20)

53

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

O Ph H 2N 78 OH W(CO)6, I2 CO, py HN Ph OH 79 NH Ph + OH HN O 80

Ph O (21)

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

54

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

55

CHAPTER 3 THE W(CO)6/I2 CATALYZED OXIDATIVE CARBONYLATION OF DIAMINES: ANALOGS OF THE CORE STRUCTURES OF THE HIV PROTEASE INHIBITORS DMP 323 AND DMP450. Background The syntheses of new improved and more efficient HIV inhibitors against mutant proteases continue to be an important target in medicinal and synthetic chemistry. In order to design and synthesize more potent inhibitors of HIV protease, it is crucial to understand the basics of molecular recognition for the protease. Extensive studies have been done in this regard and two distinctive characteristics have been identified.105 First, it was found that the active form of the viral enzyme is a homodimer, in which each monomer contributes equally to the active site. Also, the occurrence of structural water that bridges linear inhibitors to the flap of the protein through hydrogen bonds has been confirmed. One of the first sets of C2 symmetric molecules that were reported to displace the structural water was the C2 symmetric cyclic urea-based inhibitors. Since these inhibitors were first reported, the number of cyclic urea scaffolds has rapidly increased and this class of cyclic compounds has become a feasible alternative to the existing antiretroviral agents. DMP 323 and DMP450 are among these HIV protease inhibitors reported as discussed earlier in this work (Fig. 2).
HO H2N O N N N NH2 O N OH

HO

OH

HO

OH

DMP 450

DMP 323

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

56

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

57

Table 3-1. Structures of cyclic urea inhibitors

O1 P2 N 3 N 6 P2'

4 5

HO

OH

Cyclic Ureas

P2/P2

XK216

XK263

DMP323

OH

NH2

DMP450
N

XV638

NH S O N

SD146

NH O NH

58

Scheme 15

NHCbz H 3C O OH

H a H 3C

Cbz NCbz CH 3 N OMe O b,c H 3C

NH

HN

Cbz CH3

HO O

OH

Cbz d

NH

HN

Cbz e,f

HN H3 C SEMO

NH CH 3 OSEM

H 3C SEMO

CH3 OSEM

SEM = 2-(Trimethylsilyl)ethoxymethyl

O g,h H 3C HO OH N N CH 3

Reagents and conditions: (a) i-BuOCOCl, CH 3ONHCH 3.HCl; (b) LiAlH 4; (c) VCl3(THF) 3, Zn-Cu; (d) SEMCl; (e) cat. Pd(OH)2; (f ) 1,1'-carbonyldiimidazole; (g) PhCH 2Br, NaH; (h) HCl, dioxane/MeOH.

59

respectively. Carbonylation of 35-37 allows comparison of the W(CO)6-catalyzed process to the stoichiometric reactions of the phosgene derivative CDI (Table 3-2).108 Varying results were obtained in the yields of the ureas from the catalytic reaction depending on the protecting group on the diol, as was also observed for ring closure with stoichiometric CDI. These results demonstrate that the catalytic oxidative carbonylation reaction can be used to convert diamines to cyclic ureas in examples relevant to the preparation of complex targets.

O NH 2 NH2 W(CO)6 / CO I2 , K2 CO 3 HN NH

P1 O

OP2 P1 O OP2

35 P1 , P2 = C(CH 3) 2 36 P1 , P2 = MEM, MEM 37 P1 , P2 = SEM, SEM

C(CH 3) 2 38 P1 , P2 = 39 P1, P2 = MEM, MEM 40 P1 , P2 = SEM, SEM

Table 3-2. Carbonylation of compounds 35-37 to Ureas 38-40 Diamine Reagent Solvent T (C) % Yield Urea Ref b 32 CDI CH3CN NR 15 35 32 CDI TCE 140 67 35 15 W(CO)6/CO CH2Cl2/H2O 80 38 35 15 W(CO)6/CO CH2Cl2 80 26 35 c 30,33,34 CDI CH2Cl2 rt 62,76 36 15 W(CO)6/CO CH2Cl2/H2O 80 42 36 c 30,33 CDI CH2Cl2 rt 52,93 37 15 W(CO)6/CO CH2Cl2/H2O 80 75 37 a Typical reaction conditions: Diamine 35 (0.200 mmol), W(CO)6 (0.0242 mmol), K2CO3 (0.635 mmol) and I2 (0.239 mmol), solvent (32 mL CH2Cl2 : 8 mL of water), 80 atm CO, 80 C, 18 h. b Not reported. cYields are from two-step sequence involving deprotection of the Cbz-protected diamine. Deprotection is assumed to be quantitative for purposes of the table. Overall, catalytic oxidative carbonylation of 35 in the biphasic CH2Cl2/H2O solvent system afforded 38 in 38% yield. As had been observed for the carbonylation of functionalized benzyl amines,44 yields obtained by using the biphasic solvent system were higher than those in CH2Cl2.

60

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

Diamine 83, which is the precursor to cyclic urea 84, was synthesized as described in Scheme 16. Commercially available 2,3-O-isopropylidene-L-tartrate, is treated with concentrated aqueous ammonia solution and methanol for three days to afford (4R,5R)-2,2-dimethyl-1,3dioxolane-4,5-dicarboxamide 82.109 The next step is the reduction of the dicarboxamide to furnish diamine 83.

O HN NH HN H3 C O O

O NH CH3 O O

84

89

It is important to point out that the reduction of compound 82 was much more difficult than anticipated. Standard reducing agents that are commonly used did not carry out the reaction to completion. Partially reduced product was the result even though the reaction conditions were adjusted several times. Fortunately, the reduction was accomplished at last using boranedimethyl sulfide complex in THF. After purification of the diamine 83, the oxidative carbonylation using W(CO)6/I2 system was set up and allowed to react for 24 hours. After workup the cyclic urea 84 was obtained in 74% yield. The synthesis of diamine 88 was carried out according to literature procedures described in Scheme 17.75 Dimethyl 2,3-oisopropylidene-L-tartrate 85 was dissolved in dry toluene at -40 C. DIBAL was added to this solution dropwise with constant stirring. After one hour, anhydrous methanol was added to the mixture reaction and the reaction was warmed to -10 C. Next, dimethylhydrazine was added and

62

the reaction was warmed to -10 C. Next, dimethylhydrazine was added and the reaction was allowed to run one more hour to afford hydrazone 86 in good yield. Scheme 16
O O O 81 O OCH3 OCH 3 Conc. aqueous NH3 MeOH 3 days, r.t. 92% yield O O O 82 O NH2 NH 2

O BH3 SMe 2 Dry THF, reflux 4h 64% yield O O 83 NH 2 W(CO) 6 I2, NH2 Py, CH2 Cl2 80 atm, 24 hrs, ~68 C 74% yield O HN NH

O 84

Scheme 17
N H O O Dry MeOH Me 2NNH 2 88% yield H O O N H

O O O

O O O DIBAL Dry Toluene H

85 N NH N HN

86

MeLi Et2 O (dry) 75% yield

Raney Ni/ H 2 MeOH 800 PSI, 105C 24 hr

NH 2

NH 2

87

88

63

Without further purification, the hydrazone was treated with MeLi in dry diethyl ether to produce intermediate 87. Finally, diamine 88 was obtained upon hydrogenation of the hydrazine 87. Once the diamine 88 was available, the oxidative carbonylation with W(CO)6 was pursued, using the conditions described in Scheme 18. Scheme 18
O NH 2 H 2N W(CO)6 O I2 , K2CO3 CH2Cl2/H2O 88 80 atm, 24 hrs, ~105 C 71% yield 89 HN H3C O NH CH 3 O

The conditions for the carbonylation reaction have to be adjusted for different substrates. The yields for cyclic ureas 84 and 89 are unoptimized and it is expected that they could be improved. Other substrates containing secondary diamines are currently under investigation. Conclusions In summary, we have established that catalytic oxidative carbonylation of diamines provides an alternative to phosgene and phosgene derivatives in the preparation of cyclic ureas. More detailed studies need to be done in the preparation of cyclic ureas using this methodology. One interesting experiment that is currently being developed is the carbonylation of the diamine diol without any protecting group present since it was demonstrated in previous experiments with aminoalcohols that this system is tolerant to the presence of hydroxyl functional groups.

64

CHAPTER 4 CATALYTIC OXIDATIVE CARBONYLATION OF ENANTIOMERICALLY PURE AMINO AMIDES TO PRODUCE HYDANTOIN DERIVATIVES

Background Hydantoins and cyclic ureas have long been the focus of considerable attention since they are frequently found as crucial moieties in many biologically active molecules with pharmaceutical relevance. More specifically, hydantoins substituted at C-5 constitute an important class of heterocycles in medicinal chemistry since many derivatives are associated with a wide range of biological properties including anticonvulsant, 110 antidepressant,111,112 antiviral,111,112 and platelet inhibitory activities.113 Moreover, C-5 substituted hydantoin derivatives are of synthetic utility114-116 as precursors to -amino acid derivatives after hydrolytic degradation (Figure 4-1). Classic Ways to Synthesize Hydantoins A wide variety of methods for the synthesis of hydantoins have been reported starting from different building blocks. Information concerning different approaches to hydantoins including solution phase syntheses and more recently solid-phase organic syntheses, as well as polymer bound reagents can be found in the literature.115,117 Under solution phase conditions, there are several ways to afford hydantoins starting from different substrates. Figure 4-2 describes different strategies to afford hydantoins from various starting materials.117
R3 R4 N 5 1 4 3 2 N R2 R1

65

Figure 4-1. Hydantoin ring structure.

R3 O R4 N N R2 R1 O R1 N H O N H R2 + R3 O R4

a)

R3 b) O

R4 NH N H O R3

O R4 + KCN + (NH4 )2 CO 3

R3 c) O

R4 N N H

R1 S

R 4 R3 HOOC N H R1 + KSCN

R3 d) O

R4 N N R2

R1 S

R 4 R3 HOOC N H R1 + R2

e)

R3 O

R4 N N R2

R1 X

O R2 N H

X R3 R4 Cl + Cl NH R1

f)

R3 O

R4 NH N R2 S

O R2 N H R3 R4 Br + KSCN

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

66

way to afford hydantoins is the Bucherer-Bergs methodology, the reaction of carbonyl compounds and inorganic cyanide. Introducing the second nitrogen and carbonyl unit would afford N-1 and N-3 unsubstituted hydantoins (Figure 4-2b). Moreover, another classic way to form hydantoins is the Read-type reaction (Figure 4-2c) of amino acids or derivatives with inorganic isothiocyanate, which will produce the hydantoin with no substituent in the N-3 position. Hydantoins with substituents at N-3 can be synthesized using alkyl or aryl iso(thio)cyanates as marked (Figure 4-2d). Hydantoins from amino amides can be afforded by introducing the C-1 unit (highlighted) to a substrate that already contains four atoms of the hydantoin ring (Figure 4-2e). Finally, hydantoins that possess a substituent at N-1 can be generated starting from -halo amides and inorganic isothiocyanates (Figure 4-2f).117 Solution Phase Synthesis As mentioned above, the Bucherer-Bergs strategy is among the classic ways to produce ureas. This practical and easy method yields 5-substituted hydantoins from aldehydes and ketones. The synthesis involves the reaction of a carbonyl compound with potassium cyanide and ammonium carbonate. Sarges et al. applied this methodology to prepare the aldose reductase inhibitor sorbinil (Scheme 19).119 Scheme 19
O O F O 90 KCN (NH4)2 CO 3 F NH HN O O 91 1. Brucine 2. HCL 92 F HN O NH O O

C2 H5 OH, H 2O

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

67

silylated amino acid 93, which upon treatment with potassium cyanate in pyridine and subsequent acid cyclization afforded hydantoin 95 (Scheme 20).120 Scheme 20

H 3C

R Si R

H 3C KOCN NH 2 pyridine

R Si R NH O

HCl H 2O

R H3 C Si R O

H N O N H 95

HOOC

HOOC H2 N

93

94

The previous examples have long been known to be applicable to the production of hydantoins. However, during the last decades, much progress has been made in the development of new strategies to produce hydantoins, since more cases of interesting biological activity have been discovered. More recent methodologies for the synthesis of hydantoins have been developed. Among them is the synthesis of thiohydantoins reported by Le Tiran and coworkers.121 This synthesis affords thiohydantoins starting with amino acid amides and carbon disulfide. As described in Scheme 21, amino amide 96 was treated with di-2-pyridylthiocarbonate (DPT) in THF at room temperature furnishing disubstituted hydantoin 97. Scheme 21
H 3CO H 3CO H 2N O 96 H N DPT, THF rt, 24h 97 O NH S

68

Hydantoins with different substituent patterns can also be produced from other heterocyclic compounds. One example is the synthesis of 1,5-disubstituted hydantoins 100, that can be prepared from aziridinone 98 and cyanamide, followed by treatment of the resulting iminohydantoin with HNO2 (Scheme 22).122 Scheme 22

O O R H 98 N R' NH2 CN NH NH C R' N R H R

O N H N R' 99 NH 2 HNO2 R

O NH H N R' 100 O

Another recent example is the synthesis of hydantoins using multi-component reactions. Hulme and coworkers reported the synthesis of trisubstituted hydantoins using Ugi/DeBoc/Cyclization methodology.123 For the preparation of these trisubstituted hydantoins, they started with five substrates that included aldehydes or ketones, amines, isonitriles, methanol and carbon dioxide. The mechanism of this five-component reaction is described in Scheme 23. Phosgene and its derivatives have also been used for the synthesis of hydantoins.115 One recent report that uses phosgene derivatives for the preparation of enantiomerically pure hydantoins was made by Zhang and coworkers.124 They reported the synthesis of several hydantoin molecules using phosgene and its derivative 1,1-carbonyldiimidazole (CDI). Solid-Phase Organic Synthesis The synthesis of structurally challenging heterocyclic molecules bearing one or more nitrogen atoms using solid support synthesis has developed very quickly in the last decade. There are several reviews on the synthesis of hydantoins by means of solid-phase organic synthesis

69

(SPOS).117 Gutschow et al. address examples of the most recent efforts on the synthesis of hydantoins via SPOS.

Scheme 23
R3 CH 3OH/CO2 R1 CHO R2 NH 2 R3 NC R1 R2 N R2 R3 N+ O R1 NH O CH 3 O R2 N R1 NH

R2 N R1 O 101

O N R3 1N KOH CH 3OH, THF, H 2O O H 3C O N R

2

R1

H N O

R3

Synthesis of Hydantoins Using W(CO)6/I2 Catalytic System It was anticipated that catalytic carbonylation of -amino amides with W(CO)6/I2 in the presence of CO might be feasible upon optimization of the reaction conditions. Formation of the five-membered ring should be facile since it is kinetically favored. Therefore, an effort toward the synthesis of a series of different hydantoins was begun.

O R NH 2 N H R' W(CO)6 /I2 R HN

O N O R' (22)

70

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

O O NH 2 HCl 102 CH 3NH 2 MeOH (anh.) 3 days, rt

O N H

NH 2 103a

(23)

71

O N H W(CO)6 I2, CO Base, Solvent 103a HN 104a

O N (24) O

NH 2

Table 4-1. Carbonylation conditions for -amino amide 103a. Entry 1 2 3 4 5 6 7 8 9 10 11 Time (h) 18 24 36 45 36 42 36 36 36 48 36 Pressure (atm) 80 80 90 80 90 90 85 85 85 85 80 Temp (C) 40 70 105 40 100 100 78 78 78 90 76 Base/eq. Py/2 Py/2 Py/2 Py/2 K2CO3 DMAP/2 DMAP/3 DMAP/3 DMAP/4 DMAP/4 DBU/4 Solvent CH2Cl2* CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2/H2O CH2Cl2 Toluene CH2Cl2/H2O CH2Cl2/H2O CH2Cl2/H2O DCE

Conc. (M) 4 4 0.11 0.11 0.05 0.03 0.03 0.03 0.03 0.03 0.03

Product 0 0 40 0 20 0 0 50 50 traces 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 -amino amides to afford the corresponding hydantoins. Amino amide 103e was included in

72

the study because it contains the hydroxyl functionality that was present in the amino alcohols reported previously.
O Me NH 2 103a O iPr NH2 N H N H NH2 O Et N H

103b O Bn NH 2 O Bn HO NH 2 103e N H N H

103c

103d

Figure 4-3. -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 O HCl R 1NH 2 MeOH (anh.)

O N H R1 (25)

NH 2

NH2

73

Table 4-2. Synthesis of -amino amides 103a-103d entry R1 Product 1 2 3 4

O HO O NH 2 HCl 105 CH 3

Yield (%) 90 82 74 84
O HO N H (25)

CH3 CH3CH2 (CH3)2CH2 PhCH2

103a 103b 103c 103d

PhCH2NH 2 MeOH ref lux, 18 hrs 35%

NH 2

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-3hydroxypropionamide to afford 103e in 89% yield. Substrates 103a-e were then subjected to the optimized carbonylation conditions determined for 103a. The results are described in Table 4-3. Most of the hydantoins were obtained in good yields (Table 4-3), except in the case of 104c, which was produced in trace amounts. This is probably because the steric hindrance of the bulky isopropyl group present in the amide substrate, since similar results have been observed before in the carbonylation of diamines containing isopropyl substituents.42 Further optimization of the reaction is necessary, testing different substrates and different conditions, but these preliminary results are promising.

74

Scheme 24
O HO OH NHCbz N-methyl morpholine Isobutyl Chlorof ormate PhCH2 NH2 80% HO

O NHCH 2Ph NHCbz 105 H 2 /Pd-C 89% HO

O NHCh2 Ph NH2 103e

O R1 NH 2 R2 N H R1

O N HN O R2

Table 4-3. Catalytic carbonylation of -amino amides 103a-e to hydantoins 104a-e. entry R1 R2 Product yield 1 2 3 4 5 PhCH2 PhCH2 PhCH2 PhCH2 HOCH2 CH3 CH3CH2 (CH3)2CH2 PhCH2 PhCH2 104a 104b 104c 104d 104e 73 61 traces 75 50

In the past, other group VI metals carbonyls such as chromium hexacarbonyl and molybdenum hexacarbonyl have been also investigated as catalysts for the carbonylation of aliphatic secondary amines.45 However, the results of those experiments showed that tungsten hexacarbonyl was the best catalyst for the catalytic carbonylation in the case of primary and secondary aliphatic amines. Similar experiments were carried out for the amino amide substrates, in which amino amide 103a was selected to undergo the catalytic reaction using Mo(CO)6 and Cr(CO)6 as catalysts under the previuously optimized conditions. However, as observed previously the carbonylation reaction using Mo and Cr catalysts did not gave good results. In the

75

case of Mo(CO)6 the yield was less than 20% and for Cr(CO)6 it was impossible to identify the expected hydantoin. Conclusions The W(CO)6 catalytic carbonylation, using I2 as oxidant in the presence of CO, has proven to be effective for the synthesis of disubstituted hydantoins starting from enantiomerically pure -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 -amino amides to afford the corresponding hydantoins. Further experiments with this type of substrate are currently underway. .

76

CHAPTER 5 EXPERIMENTAL SECTION General Procedures All experimental procedures described were carried out under nitrogen and in oven dried glassware unless stated otherwise. Solvents used for carbonylation reactions were passed through a solvent purification system129 prior to use. Most of the aminoalcohol substrates were commercially available and were used without further purification. The aminoalcohols 3-amino4-phenyl butanol130 and 3-amino-1-phenyl propanol5 were prepared as described in the literature.
1

H and 13C NMR spectra were obtained on a Varian Gemini 300 or VXR 300 MHz

spectrometer. Infrared spectra were recorded on a Perkin-Elmer 1600 FT-IR. High-resolution mass spectrometry and elemental analyses were performed by the University of Florida analytical service. Procedure A for Carbonylation of Amino Alcohols with CDI The aminoalcohol (2 equiv) was dissolved in dry THF and placed into the flask under a flow of N2. One equivalent of CDI was then added. The reaction was left to stir for 18 hours, then the solvent was evaporated under a flow of N2. The residue was dissolved in a 1:1 mixture of CH2Cl2: H2O. The mixture was placed in a separatory funnel. After the layers were separated, the aqueous layer was washed with CH2Cl2, then with a 2:1 solution of chloroform/ethanol. The combined organic layers were dried and filtered, then the solvent was removed. The crude product was purified by flash chromatography on silica gel with 5% MeOH/CH2Cl2 as eluent for the carbamate and 30% MeOH/CH2Cl2 for the urea. Procedure B for carbonylation of aminoalcohols with DMDTC The aminoalcohol (2 equiv) was dissolved in dry methanol and placed into the flask under a flow of N2. DMDTC (1 equiv) was then added and the reaction was left to stir for 18 hours

77

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

78

O HO H N O H N OH HN O

51

52

1,3-Bis-(4-hydroxy-3-methylbutyl)urea (55). Procedure C afforded 55 from 54 (0.20 mL, 1.8 mmol) in 93% yield. 1H NMR (CDCl3) : 0.86 (d, 6H, J = 6.6 Hz), 1.22 (m, 2H), 1.59 (m, 4H), 3.07 (m, 4H), 3.38 (m, 4H), 6.08 (s, 2H); 13C NMR (CDCl3) : 16.4, 33.0, 33.4, 38.4, 67.4, 161.0; IR (CHCl3): vCO 1648 cm-1; MS (LSIMS) [M+H]+ C11H24N2O3, calcd 233.1865, found 233.1913.
H N O H N

HO

OH

55 3-Amino-4-phenyl-1-butanol (59). DL--homophenylalanine (1000 mg, 5.57 mmol) was added to 2.2 mL THF and the mixture was cooled to 0 C. BH3THF (1M, 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 C, 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

79

OH

NH2 CH2Ph

59 N,N'-Bis(1-benzyl-3-hydroxypropyl)urea (60) and 4-Benzyl-1,3-oxazinan-2-one (61). Procedure C afforded urea 60 from 59 (760 mg, 4.6 mmol) as a pale yellow oil in 95% yield. Carbamate 61 was recovered in trace amount. The products were identified by comparison with authentic samples prepared as described below. Authentic samples of N,N'-bis(1-benzyl-3-hydroxypropyl)urea (60) and 4-benzyl-1,3oxazinan-2-one (61). Procedure B afforded compounds 60 and 61 from 59 (600 mg, 2.97 mmol) as white solids in 30% and 8% yield, respectively. For urea 60: 1H NMR (CDCl3) : 1.22 (m, 2H), 1.77 (m, 2H), 2.70 (m, 4H), 3.42 (m, 4H), 4.10 (s, 2H), 4.82 (s, 2H), 7.39 (m, 10H); 13C NMR (CDCl3) : 38.4, 42.0, 48.0, 58.6, 126.6, 128.6, 129.2, 138.2, 159.9; IR (CH2Cl2): vCO 1600 cm-1; MS (LSIMS) [M+H]+ calcd for C21H28N2O3 257.2178, found 257.2161. For carbamate 61: 1H NMR (CDCl3) : 1.68 (m, 1H), 1.87 (m, 1H), 2.78 (m, 1H), 2.89 (m, 1H), 3.67 (m, 1H), 4.14 (m, 1H), 4.27 (m, 1H), 6.81 (s, 1H), 7.24 (m, 5H);
13

C NMR (CDCl3) : 26.5,

42.3, 51.8, 65.4, 126.8, 128.6, 129.1, 136.2, 154.5; IR (CH2Cl2): vCO 1710 cm-1; MS (LSIMS) [M+H]+ calcd for C11H13NO2 192.1024, found 192.1020.
HO NH NH HO O O O NH

60

61

1,3-Bis-(3-hydroxy-3-phenylpropyl)urea (64) and 6-Phenyl-1,3-oxazinan-2-one (65): Procedure C afforded urea 64 from 65 (320 mg, 2.12 mmol) in 72% yield. 1H NMR (CDCl3) : 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 80

(CDCl3) : 38.4, 38.7, 72.3, 125.8, 127.5, 128.4, 143.8, 160.1. IR (CHCl3): vCO 1646 cm-1. Cyclic carbamate 65 was recovered in 14% yield; it was identified by comparison with literature data.90
HO

O HN O NH HO HN O

64

65

N,N'-Bis(3-hydroxy-2,2-dimethylpropyl)urea (68) and 5,5-dimethyl-1,3-oxazinan-2one (69). Procedure C afforded urea 68 from 67 (600 mg, 5.81 mmol) as a white solid in 60% yield. 1H NMR (CDCl3) : 0.73 (s, 12H), 2.85 (d, 4H, 6.3 Hz), 3.03 (d, 4H, 6 Hz), 4.61 (t, 2H, 6 Hz), 6.02 (t, 2H, 6.3 Hz), 13C NMR (CDCl3) : 22.3, 36.6, 46.2, 67.6, 159.7; IR (CHCl3): vCO 1666 cm-1; MS (LSIMS) [M+H]+calcd for C11H24N2O3 233.1751, found 233.1750. Anal. Calcd for C11H24N2O3: C 56.89%, H: 10.41%, N: 12.06%; Found: C 57.69%, H 10.63%, N 12.01%. Carbamate 69: yield 5%; 1H NMR (CDCl3) : 0.96 (s, 6H), 2.88 (s, 2H), 3.80 (s, 2H), 7.12 (br s, 1H); 13C NMR (CDCl3) : 22.1, 27.3, 50.6, 75.1, 152.4; IR (CHCl3): vCO 1702 cm-1; MS (LSIMS) [M+H]+calcd for 130.0868, C6H11NO2 found 130.0867.
O OH HN NH OH HN O O

68

69

1,3-Bis-(1-benzyl-2-hydroxyethyl)urea (76) and 6-Phenyl-6-oxazolidin-2-one (77) Procedure C afforded urea 76 from 75 (800 mg, 5.3 mmol) in 78% yield. Carbamate 77 was recovered in 10% yield. The products were identified by comparison with literature data.89 81

O Ph HN Ph HO OH NH Ph HN O O

76

77

1,3-Bis-(3-hydroxy-2-phenylethyl)urea (79) and 5-Phenyl-oxazolidine-2-one (80). Procedure C afforded urea 79 from 78 (800 mg, 5.83 mmol) in 79% yield. 1H NMR (CDCl3) : 2.85 (m, 2H), 3.08 (m, 2H), 4.78 (t, 2H), 5.64 (br, 2H), 7.38 (m, 10H); 13C NMR (CDCl3) : 49.2, 74.2, 125.8, 127.5, 128.4, 147.2, 159.5; IR (CHCl3): vCO 1649 cm-1. Cyclic carbamate 80 was isolated in 14% yield; it was identified by comparison with literature data.2
O HN Ph OH NH Ph OH HN O O Ph

79

80
Synthesis of Cyclic Ureas

(5S,6S)-Hexahydro-5,6-O-isopropylidene-2H-1,3-diazapin-2-one (84). To a glass-lined 300 mL Parr high pressure vessel containing 40 mL of CH2Cl2/H2O 4:1 ratio were added diamine 83 (200.0 mg, 1.24 mmol), W(CO)6 (20 mg, 0.62 mmol), pyridine (294.25 mg, 3.72 mmol) and I2 (157.30 mg, 0.62 mmol). The vessel was then charged with 80 atm CO and heated at 68C overnight. After 24 hours, the pressure was released and 10 mL of water was added. The organics were then separated and washed successively with saturated sodium sulfite (Na2SO3), then saturated sodium bicarbonate (NaHCO3), and finally with 0.1N aqueous HCl solution. The resulting solution was dried over magnesium sulfate and filtered. The solvent was removed by evaporation and the resulting residue was purified via column chromatography on 82

silica using ether as eluent. After concentration, cyclic urea 84 was afforded in 64% yield. 1H NMR (CDCl3) : 1.39 (s, 6H), 3.19-3.40 (m, 4H), 4.20-4.30 (m, 2H), 5.1 (br, s, 2H); 13C NMR (CDCl3) : 27.2, 44.7, 81.8, 108.9, 164.3; IR (CHCl3): IR (CDCl3): vCO 1640 cm-1.
O HN NH

84

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

83

O HN H 3C O O NH CH 3

89 General Procedure for the Synthesis of -Amino Amides 103a-103e. The amino acid methyl ester hydrochloride (4 mmol) and the alkylamine (40 mmol) were dissolved in anhydrous methanol (~20 ml) and stirred at room temperature for 3 days. The reaction mixture was concentrated, and the residue was purified by column chromatography on silica gel using ethyl acetate/methanol (96:4) as eluant affording the -amino amides 103a-103d in very good yields (80-90%). Amino amide 103e was prepared following a three step procedure described in the literature, starting with Cbz-serine.127
O R1 NH2 R2 N H

103a; R 1 = Bn, R 2 = Me 103b; R1 = Bn, R2 = Et 103c; R 1 = Bn, R 2 = i Pr 103d; R1 = Bn, R2 = Bn 103e; R 1 = CH 2OH, R 2 = Bn

General Procedure for the Carbonylation of -Amino Amides 103a-e to Afford Hydantoins 104a-e. -Amino amide 103a (400 mg, 2.2 mmol) was placed in a glass-lined 300 mL Parr high pressure vessel containing 30 mL of dichloroethane (DCE). Next, W(CO)6 (0.16 mmol) was added followed by DBU (8.96 mmol) and I2 (1.56 mmol). The vessel was then charged with 80 atm CO and heated at about 76C for 36 hours with constant stirring. The pressure was released and

84

15 mL of water was added. The organics were then separated and washed successively with saturated sodium sulfite (Na2SO3), and then with 0.1N aqueous HCl solution. The aqueous layer was extracted with ethyl acetate (20 mL x 4). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified via column chromatography on silica using methylene chloride/ethyl acetate (80:20) to afford the hydantoin 104a. The same procedure was applied to prepare hydantoins 104b-e. The products were identified by comparison with literature data.124,131,132 (S)-5-Benzyl-3-methylimidazolidine-2,4-dione (104a). 1H NMR (CDCl3) : 2.80 (t, 1H), 3.0 (s, 3H), 3.32 (dd, 1H), 4.25 (dd, 1H), 5.19 (br, s, 1H), 7.21-7.40 (m, 5H); 13C NMR (CDCl3) : 25.8, 41.0, 56.4, 126.7, 128.6, 129.2, 155.4, 174.4; IR (CDCl3): vCO 1772, 1709 cm-1.
O N HN O

(S)-5-Benzyl-3-ethylimidazolidine-2,4-dione (104b). 1H NMR (CDCl3) : 1.19 (t, 3H), 2.82 (dd, 1H), 3.24 (dd, 1H), 3.43-3.60. (m, 2H), 4.21 (dd, 1H), 7.19-7.39 (m, 5H); 13C NMR (CDCl3) : 12.0, 33.9, 38.1, 58.1, 127.0, 130.0, 131.2, 134.5, 157.5, 172.4.
O N HN O

(S)-5-Benzyl-3-benzylimidazolidine-2,4-dione (104d). 1H NMR (CDCl3) : 2.82 (dd, 1H), 3.24 (dd, 1H), 4.22 (s, 2H), 4.60 (t, 1H), 5.38 (br, s, 1H), 7.23-7.42 (m, 10H); 13C NMR (CDCl3) : 38.4, 43.9, 61.7, 125.8, 126.7, 126.9, 127.7, 128.5, 128.9, 135.5, 135.7, 158.5, 169.5. 85

O N HN O

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

86

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BIOGRAPHICAL SKETCH Delmy J. Daz was born on November 14, 1967, in San Pedro Sula, Honduras. She was the second of six brothers and sisters. As a child, she was always curious of why everything happens; as a consequence, she was always asking many questions driving crazy any adults around her, since usually one answer will lead to more and more questions. She spent her formative years at Santa Rosa Elementary School and later she attended part of her high school studies at Public High School El Patria, moving later on to continue studies to become an elementary school teacher to Escuela Normal de Occidente en la Esperanza Intibuca.

Throughout her high school formation she was an active and enthusiast member of the science club. In the spring of 1987 she started her major in science at the Natural Science Department at the Pedagogic University Francisco Morazn, from were she graduated 4 years later. She started to work as a chemistry and physics teacher at the high school level. After two years working as a science teacher she went back to the University to pursue a License in Biology-chemistry emphasis, and she started working as a chemistry T.A. at the National Pedagogic University. In 2001, she traveled to the USA after she was awarded a Fulbright Scholarship to do her masters degree in organic chemistry at the University of Vermont, Burlington, which she completed in 2003. That same year she moved to the University of Florida to pursue her Ph.D. studies, specializing in the area of organic chemistry. After graduating she will go back to her country Honduras and will start working as a professor at the Science Department of the National Pedagogic University Francisco Morazn.

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