STUDIES IN SYNTHETIC METHODOLOGY: ROUTES TO SULFURAND NITROGEN-CONTAINING COMPOUNDS By RACHEL M. WITEK 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 2005 i
Copyright 2005 by Rachel M. Witek ii
I dedicate this work to my mother Cheryl Lynn Fuller and to my father Kenneth Ray Fuller. This is also for my grandmother Lillie Grace Fuller, my grandfather Joseph Ivy Fuller, and my husband Rafal Piotr Witek. I never would have achieved any of this without their love and words of wisdom. iii
ACKNOWLEDGEMENTS I am greatly indebted to many people in the preparation of this manuscript. First, I am fortunate to have had the opportunity of working for Prof. Alan R. Katritzky, whose drive and dedication compel those around him to strive for higher goals. I thank my committee members (Dr. Hartmut Derendorf, Dr. Kirk S. Schanze, Dr. Michael J. Scott, and Dr. Jon D. Stewart) for their helpful suggestions and instructions. I would like to thank all of the members of Dr. Katritzkys laboratory, my colleagues, and my dear friends: Dr. Valerie Rodriguez-Garcia, Dr. Stephane Ledoux, Hongfang Yang, Jim W. Rogers, Chaya Pooput, Dr. Ken Suzuki, Rong Jiang, Dr. Anya Gromova, Dr. Aleksander Shestopalov, Niveen Khashab, Chunming Cai, Hui Tao, Parul Angrish, Dr. Sanjay Singh, Dr. Ashraf A. A. Abdel-Fattah, and Dr. Rufine Aku-Gedu. Very special thanks go to Dr. Anatoliy Vakulenko, Mrs. Galina Vakulenko, Elizabeth Cox, Dr. Novruz Akhmedov, Mrs. Rena Akhmedova, Dr. Ference Soti, Mrs. Marta Soti, Mr. Zuoquan Wang, Dr. Zehui Cao, Dr. Dennis Hall, Dr. Eric Scriven, and Dr. Satheesh Nair for all their help. iv
TABLE OF CONTENTS Page ACKNOWLEDGEMENTS...............................................................................................iv LIST OF TABLES............................................................................................................vii LIST OF FIGURES.........................................................................................................viii LIST OF SCHEMES..........................................................................................................ix ABSTRACT.......................................................................................................................xi CHAPTER 1 GENERAL INTRODUCTION.......................................................................................1 2 THIOACYLBENZOTRIAZOLES AS PRECURSORS TO THIOAMIDES..............15 2.1 Introduction............................................................................................................15 2.2 Results and Discussion..........................................................................................18 2.2.1 Preparation of Thiocarbonylbenzotriazoles (RCSBt)................................18 2.2.2 Synthesis of Thioamides from Thiocarbonylbenzotriazoles (RCSBt).......20 2.3 Conclusion.............................................................................................................20 2.4 Experimental Section.............................................................................................22 2.4.1 General Procedure for the Preparation of Thiocarbonylbenzotriazoles.....22 2.4.2 General Procedure for the Preparation of Thioamides..............................23 3 THIOACYLBENZOTRIAZOLES AS PRECURSORS TO THIONOESTERS.........26 3.1 Introduction............................................................................................................26 3.2 Results and Discussion..........................................................................................27 3.2.1 Preparation of Thiocarbonylbenzotriazoles (RCSBt)................................27 3.2.2 Synthesis of Thionoesters from Thiocarbonylbenzotriazoles (RCSBt).27 3.2.3 Attempted Preparation of Dithioesters.......................................................28 3.3 Conclusion.............................................................................................................29 3.4 Experimental Section.............................................................................................30 3.4.1 General Procedure for the Preparation of Thiocarbonylbenzotriazoles.....30 3.4.2 General Procedure for the Preparation of Thionoesters.............................30 3.4.3 General Procedure for the Preparation of a Dithioester.............................32 v
4 1-(ALKYL/ARYLTHIOCARBAMOYL)BENZOTRIAZOLES AS STABLE ISOTHIOCYANATE EQUIVALENTS: SYNTHESIS OF DIAND TRISUBSTITUTED THIOUREAS.............................................................................33 4.1 Introduction............................................................................................................33 4.2 Results and Discussion......................................................................................36 4.2.1 Preparation of (Alkyl/arylthiocarbamoyl)benzotriazoles..................36 4.2.2 Preparation of Diand Trisubstituted Thioureas...................38 4.2.3 N, N-Disubstituted(thiocarbamoyl)benzotriazoles.....................39 4.2.4 One-Pot Synthesis of Unsymmetrical Thioureas............... 4.3 Conclusion.....................41 4.4 Experimental Section.....................42 4.4.1 General Procedure for the Preparation of Reagents...............................42 4.4.2 General Procedure for the Preparation of Thioureas.................................44 4.4.3 General Procedure for the One-Pot Preparation of Thioureas...................47 5 SYNTHESIS OF 3,3-DIARYLPYRROLIDINES FROM DIARYL KETONES........50 5.1 Introduction........................50 5.2 Results and Discussion.................. 5.3 Conclusion.....................................................................56 5.4 Experimental Section.............................................................................................57 5.4.1 General Procedure for the Preparation of 2-Cyano-3,3-diarylacrylates....57 5.4.2 General Procedure for the Preparation of Diaryl-pyrrolidine-2,5-diones..59 6 SYNTHESIS AND CHARACTERIZATION OF BLOWING AGENTS........... 6.1 Introduction........................62 6.2 Results and Discussion...................... 6.2.1 Thermoanalyses of Blowing Agents with Reported Decompositions.......64 6.2.2 Synthesis and Thermoanalyses of Pentaerythritol Tetranitrate.............67 6.2.3 Synthesis and Thermal Testing of Non-commercially Available Agents.69 22.214.171.124 Blowing Agents Derived from Disulfonyl Dichlorides..........69 126.96.36.199 N-(Hydrazinocarbonyl)-4-methylbenzenesulfonamide..............71 6.3 Conclusion.........................72 6.4 Experimental Section.................73 6.4.1 Synthesis of Pentaerythritol Tetranitrate........................... 6.4.2 Disulfonyl Dichloride Derivatives.............................................74 6.4.3 Synthesis of N-(Hydrazinocarbonyl)-4-methylbenzenesulfonamide.....77 7 CONCLUSION.............................................................................................................78 REFERENCES.......... BIOGRAPHICAL SKETCH.........................................................................91 vi
LIST OF TABLES Table Page 2-1 Preparation of thiocarbonylbenzotriazoles 2.3ad................................18 2-2 Preparation of thioamides 2.4af.......................20 3-1 Synthesis of thionoesters 3.3 from thioacylation agents 2.3..............................28 4-1 Thiocarbamoybenzotriazoles 4.4 prepared................ 4-2 Di-and trisubstituted thioureas 4.5 prepared..................................38 4-3 Thioureas prepared using 4.3 in one-pot reactions with 1 o and 2 o amines........41 5-1 3,3-Diarylpyrrolidines prepared and the intermediates.....................55 vii
LIST OF FIGURES Figure Page 1-1 Biologically active thioamides............................................................. 1-2 Thionoesters as probes of enzyme binding sites..........................................9 1-3 3,3-Diarylpyrrolidine structure..........................................................11 1-4 Common blowing agents...................................................................13 1-5 Synthesized blowing agents.......................................................................14 5-1 1 H NMR of ethyl [2-cyano-3-phenyl-3-(4-methoxyphenyl)]acrylate (5.2b).....51 5-2 13 C NMR of ethyl [2-cyano-3-phenyl-3-(4-methoxyphenyl)]acrylate (5.2b)... 5-3 1 H NMR of ethyl (2-cyano-3-phenyl-3-pyridinyl)acrylate (5.2i)......................53 6-1 Blowing agents with reported Differential Scanning Calorimetry (DSC) values.........................................................................................63 6-2 Literature blowing agents without reported DSC values.......................64 6-3 Thermoanalyses of (E)-1,2-diazenedicarboxamide (6.1)...................................65 6-4 Thermoanalyses of Nitrosan (6.2)..............................................................66 6-5 Thermoanalyses of dinitrosopentaethylenetetramine (6.4)................................67 6-6 Thermoanalyses of pentaerythritol tetranitrate (6.5).................68 6-7 Thermogravimetric analyses of compounds 6.6.8.............................................70 viii
LIST OF SCHEMES Schemes Page 1-1 Introduction of the benzotriazole group into molecules......................................2 1-2 Selective activation of a molecule by benzotriazole................................ 1-3 Isomers of benzotriazole..............................................4 1-4 Synthesis of asymmetric thioureas from bis(benzotriazol-1-yl)methanethione......5 1-5 Preparation of symmetrical thioureas..........................................5 1-6 Classical syntheses of asymmetric thioureas...........................................................6 1-7 Benzotriazole-assisted thioacylation....................................................................6 1-8 Applications of N-acylbenzotriazoles......................................................................7 1-9 Classical routes to thioamides and thionoesters.......................................................9 1-10 Thiocarbonyl and thioformate derivatives of classical thioacylation reagents......10 1-11 3,3-Diarylpyrrolidine preparation from diarylacetonitriles...................................11 1-12 [4+2] Cycloadditions of nitroalkenes and activated alkenes.................................12 1-13 3,3-Diarylpyrrolidine preparation from 4-amino-3,3-diphenylbutan-1-ol.............12 1-14 Synthesis of 3,3-diarylpyrrolidines........................................................................12 2-1 Syntheses of heterocycles from thioamides...........................................................16 2-2 Classical routes to thioamides....................................................................17 2-3 Benzotriazole-mediated syntheses of thioamides..................................................18 2-4 Rapoports method for thiocarbonyl-6-nitro-1H-benzotriazoles 2.8.............19 3-1 Classical syntheses of thionoesters................................................27 ix
3-2 Synthesis of thionoesters from thiocarbonylbenzotriazoles..................................27 3-3 Benzyl dithiobenzoate (3.4) from thiocarbonylbenzotriazoles..............................29 4-1 Literature methods to prepare symmetrical thioureas............................................34 4-2 Literature methods for unsymmetrical thioureas...................................................35 4-3 Preparation of thioureas from bis(benzotriazol-1-yl)methanethione.....................36 4-4 Comparison of benzotriazole and imidazole reagents...........................40 5-1 Preparation of 3,3-diarylpyrrolidines.............................................54 5-2 Mono-reduction of succinimide 5.7h.................................56 6-1 Synthesis of pentaerythritol tetranitrate (6.5).... 6-2 Synthesis of disulfonyl azide 6.6.......................69 6-3 Preparation of disulfonyl azide 6.7........................................71 6-4 Preparation of disulfonylhydrazine 6.8..............................................71 6-5 Synthesis of N-(hydrazinocarbonyl)-4-methylbenzenesulfonamide (6.9).............72 x
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 STUDIES IN SYNTHETIC METHODOLOGY: ROUTES TO SULFURAND NITROGEN-CONTAINING COMPOUNDS By Rachel M. Witek August 2005 Chair: Alan R. Katritzky Major Department: Chemistry Development of novel methodologies for the preparation of a diverse array of synthetic targets is the theme of this work. The first four chapters cover the development of benzotriazole methodologies as alternative routes to conventional syntheses. The focus in this area is on the syntheses of thioureas, thionoesters, and thioamides. The second part of this dissertation (Chapters 5 and 6) describes collaborative investigations with Merck and the US Army. Development of routes to 3,3-diarylpyrrolidines and blowing agents involved compilation and modification of classical syntheses. Chapter 1 provides a general overview of the methodologies employed in the preparation of the target compounds and includes an overview of cognate work carried out in these fields. Chapters 2 and 3 describe investigations of the synthesis and reactivity of benzotriazole reagents for thioacylation (RCSBt). Syntheses of thioamides (Chapter 2) and thionoesters (Chapter 3) are also reported. xi
In Chapter 4, a route to asymmetric thioureas using benzotriazole methodology is described. 1-(Alkyl/arylthiocarbamoyl)benzotriazoles were synthesized in 91% yields from bis(benzotriazolyl)methanethione and were used as isothiocyanate equivalents for the efficient synthesis of seven secondary and eight tertiary thioureas in high yielding, convenient processes. Access to bioactive 3,3-diarylpyrrolidines (Chapter 5) was provided by 3,3-diarylsuccinic acids, which were prepared from diaryl ketones by Knoevenagel condensation with ethyl cyanoacetate followed by KCN addition and hydrolysis. These succinic acids were cyclized using primary amines to the respective diarylpyrrolidones, which were reduced to 3,3-diarylpyrrolidines using BH 3 THF. Chapter 6 details the preparation of blowing agents (energetic additives that reduce the cook off violence of explosive mixtures) for the US Army. Described herein are reasonable syntheses that potentially can be scaled to produce 50 g quantities of blowing agents possessing the following desirable properties: quick generation of gas, mp >75 o C, stable to shock and friction, and a DSC-indicated gas evolution of ~180 o C. xii
CHAPTER 1 GENERAL INTRODUCTION Development of novel routes to target compounds possessing synthetic utility, biological activity, and desirable physical properties is the central theme tying together the diverse applications of synthetic organic chemistry covered in this dissertation. Utilization of convenient starting materials, which permit facile conversion to intermediates and desired products under mild and tolerant conditions, is a key component of an efficient methodology, and one for which we have strived. For the past twenty years, the Katritzky group has developed synthetic methodologies employing the benzotriazolyl group, as a selective auxiliary and masked synthon to carry out organic functional group transformations and for the synthesis of diverse heterocycles [95SL99, 95S1497, 95T13271, 97JOC4155, 99JHC1501, 00PAC1597, 01ARK19, 02ARK134, 03JOC5720, 03JOC1443, 03JOC4932, 04JOC811, 04JOC2976]. The benzotriazole group is easily introduced into a molecule (Scheme 1-1) by either nucleophilic substitution of various leaving groups (halide, alkoxide, aryloxide, alkylsulphide, or arylsulphide anions, etc.), addition to C-heteroatom multiple bonds, Michael addition to electron deficient C-C double or triple bonds, addition to electron rich C-C multiple bonds, or three component condensations of ketones, benzotriazole, and N, O, or S nucleophiles. 1
2 RX BtNaRBt ROH BtHX = Cl, Br, I, OR, SR, etc.RBt R X O R Bt O R X S R Bt S BtNaBtNaOR' R R OR' BtHBt R R OR' R R Y R R YH Bt BtHY = O, S, NR, NR2 O R'' R R' BtH O R'' R R' Bt R R' R'' Z = OR, NR, SR, NCOR BtH R R' R'' Bt R R R' BtH Bt R R ZR' NNN Nucleophilic Substitutions Addition Reactions+ Three Component Condensations + + Z Z Z Z Bt = Scheme 1-1. Introduction of the benzotriazole group into molecules.
3 Benzotriazole functions in a dual role as a selective activator of the part of the molecule to which it is attached (Scheme 1-2) and also as a good leaving group that is stable, non-toxic and easily removed in workup by a mild base wash. RCH X Bt R X+ X = NRR', OR, SR, etc. Bt OEtBt OEt nBuLiBtR Bt H H nBuLiR Bt H Li Bt Y R R Bt Y Li E = electrophile Bt OEtE Y = OR, OCOCH3, etc. i) ii) iii) iv)+solvolysis Scheme 1-2. Selective activation of a molecule by benzotriazole. Benzotriazole activates a molecule primarily in four ways: i) as a leaving group, ii) as a proton activator, iii) as an ambident anion directing group, and iv) as a cation stabilizer [00PAC1597]. These properties of benzotriazole are harnessed to provide benzotriazole reagents [98AA33, 98CR409], synthesis of heterocycles [98JCSPT(1)1059, 98JHC467, 98JOC3445, 98JOC9989, 99JHC371, 99JHC473, 99JHC755, 99JOC6076], and various organic group transformations [98AA33, 98CCCC599, 98CR409, 99T8263]. N-Substituted benzotriazoles are generally more stable, easier to prepare, and more versatile than their halogen and imidazole analogues [98CR409]. Some N-substituted benzotriazoles (usually -aminoalkyl, -alkoxyalkyl, or -alkylthiolalkyl)
4 exist as 1and 2-substituted isomers equilibrating through an ionic form in which the benzotriazole dissociates and then re-attaches (Scheme 1-3) [98CR409]. These isomers show similar stability and reactivity; thus, separation usually is not required before further reactions. NN N NNN X R X+ R NNN R X 1-substituted Bt 2-substituted Bt X = NR2, OR, SR Scheme 1-3. Isomers of benzotriazole. Over the past twenty years, the Katritzky group has applied benzotriazole methodology to numerous synthetic targets. As part of our on-going research into providing convenient and efficient benzotriazole alternatives to hazardous and poor yielding classical synthetic routes, the development and application of novel benzotriazole thioacylating agents (Chapters 2) are disclosed in this dissertation. The first class of benzotriazole thioacylation reagents developed by our lab was thiocarbamoylbenzotriazoles. These reagents were first applied [04JOC2976] to the synthesis of novel asymmetrical thioureas (Chapter 4, Scheme 1-4), which are antibacterials [81JCSPT12186], fungicides [55CR181, 85JHC137], phenoloxidase enzymatic inhibitors [69CA101668v], and synthetic precursors to fiveand six-membered heterocycles[75AHC99]. Thiocarbamoylating benzotriazole reagents behave as isothiocyanate synthons and react with a variety of amines under mild conditions providing asymmetrical thioureas in high yields.
5 SBtBtNHR1R2NH2RSNHBtRNHR1R2SNHNRR1R2(Stable)1)NH2R2)SNHNRR1R2one-pot Scheme 1-4. Synthesis of asymmetric thioureas from bis(benzotriazol-1-yl)methanethione. Traditional routes to thioureas usually employ thiophosgene or a thiophosgene equivalent like 1,1'-thiocarbonyldiimidazole in reactions with amines and have mainly focused on the preparation of symmetrical thioureas (Scheme 1-5) [62ACIE351, 62LA98, 78S803]. RR'NHS Cl Cl S N N R' R R' R RR'NHS N N N N 2 + 2 + Scheme 1-5. Preparation of symmetrical thioureas. The few reported syntheses of asymmetric thioureas (Scheme 1-6) fall into three main categories: i) reaction of amines with a thiocarbonyl transfer reagent (1-(methyl-dithiocarbonyl)imidazole) [00T629]; ii) reaction of isothiocyanates with amines [40CB1420]; iii) direct displacement, by amines, from 1,3-diphenylthiourea [93TL6447] or thiuram disulfide [95SC3381].
6 S N N R R R R S SMe N N S X N R R X = NHPh, SCSNR NCS1) R1R2NH2) R3R4NH 31 2 4 i) ii) iii)1 2 1R2R3R4NH R1 R2 = H +R3R4NH Scheme 1-6. Classical syntheses of asymmetric thioureas In classical preparations of asymmetric thioureas, usually isothiocyanates are employed in reactions with amines [40CB1420, 55JACS4328, 63CJC2123, 89SC965]; however, isothiocyanates are poor reagents with most being oils that are difficult to handle. Furthermore, access to functionalized isothiocyanates is limited by synthesis constraints. In comparison, the benzotriazole-derived isothiocyanates disclosed in this work are stable, readily prepared solids (in all but two examples) that react easily with amines to provide asymmetrical thioureas. We have recently extended the methodology investigated in the synthesis of asymmetric thioureas to the preparation of other benzotriazole-containing thioacylating reagents (Scheme 1) and their application in the synthesis of thioamides (Chapter 2) and thionoesters (Chapter 3). R'R''NHS OR' R S N R NN S N R R''R' R'OH Scheme 1-7. Benzotriazole-assisted thioacylation.
7 Acid chlorides are classical acylation reagents; however, their instability and hazards associated with their use have prompted research into more stable and environmentally friendly reagents such as N-acylimidazoles and N-acylpyrazoles [98MI]. In recent years, the Katritzky group has developed several novel benzotriazole acylating reagents and has applied these compounds quite successfully to the synthesis of: i) amides [00JOC8210], ii) -keto sulfones [03JOC1443], iii) -substituted -ketonitriles [03JOC4932], iv) oxazolines and v) thiazolines [04JOC811], and vi) C-acylated-pyrroles and vii) C-acylated-indoles (Scheme 1-8) [03JOC5720]. R NC O R' O N R NN O N R R''R' NH O R NH O R O R S O O R' ON R SN R i) ii) iii) iv) v) vi) vii) Scheme 1-8. Applications of N-acylbenzotriazoles. These studies led to investigations of analogous thioacylation reagents and their reactions (Chapters 2 and 3). Thioamides and thionoesters were selected as a test of nucleophilic reactivity of alcohols and amines towards the thioacylation reagents and also for their utility as biologically active molecules and importance as synthetic
8 intermediates. Thioamides are pesticidal [96CA455871], fungicidal [94CA533719, 03CA132360], and anthelmintic agents (Figure 1-1) [01CA839295]. Azadecalinthioamide moieties are included in drugs used to treat patients with high cholesterol levels [93CA191562]. NHOC5H11SC5H11OPesticidal and Fungicidal AgentNS(CH2)4SCH2CH2NMe2MeHHOMeInhibitor of Cholesterol BioynthesisNOSNOMeMeMeMeMeOOSNMeMeMeOOSNMeMeMeOOSMeR1R1MeMeAnthelmintic Agent Figure 1-1. Biologically active thioamides Thioamides are used as synthons for the preparation of heterocycles. [88H1953, 03CR197]. For example, thiazoles are commonly prepared via Hantzsch reaction of -haloketones with thioamides [75JHC643, 03JOC7887]. Thionoesters are attractive synthetic targets because of their incorporation into synthetically useful macrocycles such as crown ethers [83JOC2653] and also for their application as chemical probes of the enzyme binding sites of cysteine [04BJ699] and serine [83JBC59] proteases (Figure 1-2).
9 NH CH3 O O NH O S CH3 Probe of Cysteine ProteaseCysteine Protease Enzyme Figure 1-2. Thionoesters as probes of enzyme binding sites. Classical routes to thioamides and thionoesters involve reaction of thiophosgene [78S803] or thiophosgene equivalents (e.g., 1,1'-thiocarbonyldiimidazole [62LA98]) with the respective amines or alcohols (Scheme 1-9). Thiocarbonyl [83TL4927] [70LA201] [73LA636][68LA209] and thioformate [68CB3517] [74JOC3641] [62ACIE351] derivatives of these classical thioacylating agents are also employed (Scheme 1-10). Alternatively, thionating agents such as sulfur dihydride, [85T5061] phosphorus pentasulfide [70BSCF2272, 73S149], and Lawessons reagent convert the carbonyl groups of esters and amides into thiocarbonyls. Cl Cl S N N S N N ROH or RNH2 ROH or RNH2RY Cl S RRY R S Y = O, NHRY N S RRY R S Y = O, NH 1 1 MX 1 1 MX Scheme 1-9. Classical routes to thioamides and thionoesters.
10 RO Cl S R Cl S R N S N RO N S N Scheme 1-10. Thiocarbonyl and thioformate derivatives of classical thioacylation reagents. Benzotriazole-assisted thioacylations offer competitive alternatives to classical syntheses providing thioamides in higher yields and access to novel compounds. In addition, the use of unstable or hazardous reagents is avoided and the mild conditions employed are tolerated by a large variety of functional groups. The two later chapters of this dissertation cover studies conducted in collaboration with Merck (Chapter 5) and the US Army (Chapter 6). In chapter 5, the development of an efficient route to 3,3-diarylpyrrolidines is detailed. The Katritzky group was approached by Merck to develop a general route to 3,3-diarylpyrrolidines due to interest in pyrrolidines as scaffold molecules in drug development (Scheme 1-3). Nitrogen containing five-membered rings are well known for their antibacterial, antiprotozoal, anticonvulsant, and anti-inflammatory properties [51JOC4895, 97BMCL979, 98JOC4481]. 3,3-Diaryl N-heterocycles such as succinimides and hydantoins show particularly potent anticonvulsant activity [51JOC4895].
11 N R R' X Figure 1-3. 3,3-diarylpyrrolidine structure. Traditional routes to 3,3-diarylpyrrolidines suffer from the use of difficult-toaccess, non-commercially available starting materials, the need for expensive catalysts, or poor yields. Additionally, only a few syntheses are reported in the literature: i) preparation from diarylacetonitriles (Scheme 1-11) [53JACS2986], ii) [4 +2] cycloadditions of nitroalkenes and activated alkenes (Scheme 1-12) [93JOC3857], and iii) synthesis from 4-amino-3,3-diphenylbutan-1-ol hydrochloride (Scheme 1-13) [58JACS2519]. R R' H CN R R' O O CNEt NH O R R' NH R' R N Me R' R HCHOHCOOHLiAlH4BrCH2COOEtNaNH2H2, Raney nickel Scheme 1-11. 3,3-Diarylpyrrolidine preparation from diarylacetonitriles.
12 N+ O O On-Bu N+O O On-Bu N H MADR1R2R2R2R1R1 + O Me Al O Me Me MAD = Scheme 1-12. [4 +2] Cycloadditions of nitroalkenes and activated alkenes O NH PhPhMe EtMgBrNH4Cl O NH2 PhPhMe Et LiAlH4 OH Me NH2 Et PhPh NH Et Me PhPh +1) HCl2) pyrolysis Scheme 1-13. 3,3-Diarylpyrrolidine preparation from 4-amino-3,3-diphenylbutan-1-ol hydrochloride. A new route to 3,3-diarylpyrrolidines was developed that utilizes readily available benzophenones (Scheme 1-14). Good to moderate yields of diversely functionalized 3,3-diarylpyrrolidines were obtained demonstrating the generality and efficiency of the new route as compared to previous methods. ArAr O COOHHOOCAr Ar N Ar Ar R 3 steps 4 steps Scheme 1-14. Synthesis of 3,3-diarylpyrrolidines.
13 As part of a collaborative project with the US Army to develop novel munition formulations (Chapter 6), we have investigated the synthesis of a select group of energetic additives known as blowing agents and characterized their decomposition. The utility of blowing agents is not only limited to the development of explosive formulations. Blowing agents, such as dinitropentamethylenetetramine (DNPT) and p-tolysulfonylhydrazine (PTS) (Figure 1-3), are employed in the production of microcellular rubber [85PRPA281]. Azodicarbonamide (ADCA) (Figure 1-4) is a gas-generating agent commonly used in the plastics industry to provide polymer foams [99CP35,02HK427, 02JCED554]. Another significant application of blowing agents is their use in propellant formulations [95JPP838, 97HC153, 03JTAC931]. NN O NH2 NH2 O Me S O O NH NH2 N N N N ONNO (mp 200-206 oC) DSC 225 oC ADCA (mp 103 oC) PTS DSC 195 oC DNPT Figure 1-4. Common blowing agents. For Army applications to trinitrotoluene (TNT) and cyclotrimethylenetrinitramine (RDX) formulations, blowing agents that display separate isotherms from the other components of the explosive mixtures are required. Inclusion of these energetic additives in formulations provides a means of tempering the violence of explosions. Simple and convenient methodologies that allow scale-up of syntheses of blowing agents have been developed for five compounds (Figure 1-5).
14 O S O O S O O N3N3 S S O O S O O N3N3 S S O O NH NH2 S NH O O NH2 Me S O O NH O NH NH2 (mp 97 98 oC) (mp 163 oC) (mp 200 oC) (mp 75 77 oC) ONO2 ONO2 ONO2 O2NO (mp 141 oC) Figure 1-5. Synthesized blowing agents. Chapter 5 provides the evaluation of the thermal and physical properties of the synthesized gas-generating agents. In summary, we have developed efficient syntheses of blowing agents, provided characterization of their hitherto unreported physical properties and evaluated their utility as munition additives based on their decomposition profiles. Also, a general route to 3,3-diarylpyrrolidines has been developed that provides access to biologically active scaffolds, which have the potential to be incorporated into new drugs. The most significant work disclosed in this dissertation is the development of methodologies utilizing benzotriazole thioacylation reagents as alternatives to problematic traditional routes. These general and convenient procedures provided access to numerous novel thioamides, thionoesters, and asymmetric thioureas.
15 CHAPTER 2 THIOACYLBENZOTRIAZOLES AS PRECURSORS TO THIOAMIDES 2.1 Introduction Classical thioacylating agents include thiophosgene [78S803], carbon disulfide [03ARK155], and 1,1'-thiocarbonyldiimidazole[62LA98]. These reagents provide access to a wide variety of diversely functionalized thioamides. Thiocarbonyl [68LA209, 70LA201, 73LA636, 83TL4927] and thiocarbamate [65CB1293, 95JMC4929] derivatives can also be prepared from these classical thioacylating agents and reacted further with the appropriate nucleophile to afford the thioamides. Alternatively, thionating agents such as sulfur dihydride [85T5061], phosphorus pentasulfide [70BSCF2272, 73S149], and Lawessons reagent convert carbonyls into thiocarbonyl compounds. Thioamides exhibit a broad range of biological activity and have been implemented as pesticidal [96CA455871], fungicidal [94CA533719, 03CA132360], and anthelmintic [01CA839295] agents. In particular, N-substituted p-alkoxythiobenzamides have been shown to possess potent anti-tubercular activity [65BSCF3623]. Recently, azadecalinthioamides were proven to be inhibitors of cholesterol biosynthesis [93CA191562]. Much interest in thioamides concerns their functionalization and use as intermediates in organic synthesis [49BSCF172, 79JIC545], notably as synthons for the preparation of heterocycles (Scheme 2-1) [88H1953, 03CR197]. 15
16 R N S R' R" SN R"' R i) R', R" = H N S R" EWG R"' N R" R i)ii)iii)iv) N N R R" ii) R' = CH2-EWGiii) R' = CH2Btiv) R' = CH2BtR'" R" = HEWG R"' R" = H Scheme 2-1. Syntheses of heterocycles from thioamides. Thiazoles are commonly prepared via Hantzsch reaction of -haloketones with thioamides (Scheme 2-1) [75JHC643, 03JOC7887]. Also, thioamides with active hydrogens are known to undergo addition-cyclization reactions with alkylidene derivatives of ketones to afford pyridine-2-thione derivatives [99PSS253]. Derivatives of pyrrole can be synthesized from N-(benzotriazolylmethyl)thioamides and ,-unsaturated esters, ketones, or nitriles [95T13271]. Similarly, imidazole derivatives can be prepared by reaction of N-(benzotriazolylmethyl)thioamides with imines. Retrosynthetically, thioamides have been synthesized via three main approaches (see Scheme 2-2): Route A typically involves thionation (A.i) of an amide by utilization of phosphorus pentasulfide[49BSCF172] or Lawessons reagent [85T5061]. Another method (A.ii) uses thiocarbonyl transfer reagents; 1,1'-thiocarbonyldiimidazole and bis-(1,2,4-triazole)methanethione have been shown to react with aldolnitrones to give thioamides in good yields [83TL4927].
17 R2NCSSSSNR1R2NR1R2RMgXRLiRMgXSNMeMeClHNR1R2SRNR1R2SRNR1R2RSYP2S5 or Lawesson's Reagent(Im)2CSRN+O-MeORNR1R2A (i)+RouteARoute BRoute C B (i)NiCl2(dppe)Route CY= Cl, OEt, Im, BtNote: Im = Imidazolyl, Bt = BenzotriazolylA (ii)RoutesB (ii)B (iii) Scheme 2-2. Classical routes to thioamides. Through Route B, thioamides can be prepared by reactions of B.i) thiuram monosulfides with organolithium reagents [93S483], B.ii) aryl isothiocyanates with Grignard reagents[66JPC259, 71JICS791], or B.iii) N,N-dimethylthiocarbamoyl chloride and Grignard reagents catalyzed by NiCl 2 (dppe) [94SL719]. Access to thioamides by Route C is provided by reaction of amines with thiol esters [65BSCF3623], with thiobenzoylchlorides [68LA209], or with thioazolides [70LA201, 73LA636]. In our groups previously reported syntheses of thioamides (Scheme 2-3) in one-pot reactions from Grignard reagents, carbon disulfide, and amines mediated by 1-trifluoromethyl-sulfonylbenzotriazole [95S1497, 95SL99]; the putative intermediate thiocarbonylbenzotriazoles 2.3 were evidently formed, but were not isolated. Decomposition of analogous methyl-substituted thioacylimidazoles has been reported [73LA636]. We now report that the use of 1-chlorobenzotriazole (instead of 1-trifluoromethylsulfonylbenzotriazole) as the mediating reagent allows isolation of 2.3 in
18 some cases (Scheme 2-3) and that thioacylbenzotriazole 2.3 are highly efficient thioacylation reagents. RMgBrCS2THFRSSMgBr2 BtXRSBtRSNR1R2R1R2NH2.1 2.2 2.3 2.4X = SO2CF3, Cl Scheme 2-3. Benzotriazole-mediated syntheses of thioamides. 2.2 Results and Discussion 2.2.1 Preparation of Thiocarbonylbenzotriazoles (RCSBt). Thiocarbonylbenzotriazoles 2.3ad were prepared from carbon disulfide, 1-chlorobenzotriazole and the respective Grignard or organolithium reagents (Table 2-1). The benzenoid thiocarbonylbenzotriazoles (42%, average 68%) are all stable reddish solids. Benzotriazol-1-yl-(4-methylphenyl)methanethione (2.3a) displays the characteristic 1 H NMR shifts for benzotriazole overlapping with aromatic shifts of the p-tolyl group 7.39 (d, J = 8.4 Hz, 2H), 7.55 (t, J = 7.5 Hz, 1H), 7.71 (t, J = 7.5 Hz, 1H), 8.14.19 (m, 3H), 8.39 (d, J = 8.4 Hz, 1H)}. A 13 C NMR shift ~170 ppm is common for the thiocarbonyl in compounds 2.3ad. Table 2-1. Preparation of thiocarbonylbenzotriazoles 2.3ad. 2.3 R % Yield a 4-Tolyl 63 b 4-Methoxyphenyl 89 c Phenyl 76 d 4-Chlorophenyl 42
19 One limitation of this method is that use of Grignard reagent restricts this method to Grignard compatible functionalities. In addition, benzenoid aryl Grignard reagents react quite smoothly; however, alkyl, alkynyl, and heteroaryl Grignard and organo-lithium reagents either fail or give poor yields. Attempts to obtain n-butyl substituted thiocarbonylbenzotriazole in higher yield by conducting the reactions at 0 o C and at -78 o C failed. Likewise conversion of n-butyllithium to n-butylzinc bromide or n-butylcupric bromide for reactions with carbon disulfide and 1-chlorobenzotriazole failed. The stability of non-benzenoid thiocarbonylbenzotriazoles thus appears to be poor. Rapoport showed an electron-withdrawing nitro group on the benzotriazole moiety improves the stability and allows the isolation of aliphatic thiocarbonylbenzotriazoles (Scheme 2) [99JOC1065]. NH S R NH2 NO2N S R NN NO2 NH2 NH2 O2NHONO NH O R NH2 NO2 RCOClP2S5 2.5 2.6 2.7 2.8 Scheme 2-4. Rapoports method for thiocarbonyl-6-nitro-1H-benzotriazoles 2.8. This alternative method, however, is rather lengthy (carried out in three steps) and provides the desired thioacylation reagents in overall yields of only 48%. Thus, unless alkyl or nitrosubstituted thiocarbonyl-6-nitro-1H-benzotriazoles are the target, our Grignard method (Scheme 2-2) is the preferred means of obtaining thiocarbonylbenzotriazoles.
20 2.2.2 Synthesis of Thioamides from Thiocarbonylbenzotriazoles (RCSBt). N-Monoand N,N-di-substituted thioamides 2.4af were readily prepared by reactions of thiocarbonylbenzotriazoles 2.3ad with the appropriate 1 o and 2 o amines, respectively (Scheme 2-2, Table 2-2). Table 2-2. Preparation of thioamides 2.4af. 2.4 R R 1 R 2 % Yield a 4-MeC 6 H 4 C 6 H 5 CH 2 H 99 b 4-MeOC 6 H 4 -(CH 2 ) 5 = R 1 93 c 4-MeC 6 H 4 C 2 H 5 C 2 H 5 87 d C 6 H 5 C 6 H 5 CH 2 H 97 e C 6 H 5 -(CH2) 2 O(CH2) 2 = R 1 78 f 4-ClC 6 H 5 PhCH 2 CH 2 H 66 Reaction of p-tolylthiocarbonylbenzotriazole (2.6a) with benzylamine afforded N-benzyl-(4-methylphenyl)thioamide (2.4a) in 99% yield. Simple base wash (5% sodium carbonate solution) followed by acidification with 1N HCl to remove benzotriazole and residual amines allows purification by recrystallization (5% ethyl acetate/hexanes). In this manner, thioamides 2.4af were provided in 66% to near quantitative yields. Formation of the thioamide is indicated by loss of benzotriazole signals in 1 H and 13 C NMR spectra and the shift of the thiocarbonyl peak to ~200 ppm. 2.3 Conclusion Routes to thioamides utilizing traditional thioacylation reagents, such as thiophosgene or 1,1'-thiocarbonyldiimidazole, suffer from the drawbacks that these reagents are inconvenient to handle either for being unstable to storage or for their high
21 toxic, particularly in the case of thiophosgene, which can be lethal if spilled on the skin and is known to induce lung tumors upon exposure to mere trace amounts of vapors. Thus, the development of alternative thioacylation reagents that are safe, stable, non-toxic, and environmentally-friendly is indeed a significant advance in the area of sulfur chemistry. Our method to produce thioacylbenzotriazoles, although limited to synthesis of benzenoid derivatives, avoids highly toxic reagents and provides highly efficient thioacylating agents, which are safe, easy to handle solids that are stable to months of storage on the bench. Moreover, in comparison to previously described routes to thioamides, the use of our thioacylbenzotriazole reagents offers the advantages of: i) diversification of functional groups attached to the thioamide nitrogen (only N,N-dimethyl or N, N-diethyl substitutions are reported for NiCl 2 (dppe) catalyzed reactions of Grignard reagents with thiocarbamoyl chlorides) [94SL719]; ii) ease of purification in that mild base wash (5% sodium carbonate solution) followed by treatment with 1N HCl is sufficient to remove both benzotriazole and any residual amines allowing purification by recrystallization (methods employing Lawessons reagent or phosphorus pentasulfide often suffer from significant byproduct formation, which complicates purification by requiring at minimum column chromatography); and iii) high to near quantitative yields (alternative procedures involving the use of organolithium reagents with thiuram monosulfides [93S483] or Grignard reagents with isothiocyanates [66JPC259, 71JICS791] provide thioamides in only low to moderate yields). In conclusion, we have developed and applied a benzotriazole reagent for thioacylation (RCSBt) that avoids use of hazardous reagents, employs mild conditions, and provides yields of thioamides that are higher or comparable to known thioacylation
22 methods. Ease of purification and high yields of both secondary and tertiary thioamides make our method choice for thioamide synthesis. 2.4 Experimental Section Melting points were uncorrected. 1 H (300 MHz) and 13 C (75 MHz) NMR spectra were recorded on a 300 MHz NMR spectrometer in chloroform-d solution unless stated. Column chromatography was performed on silica gel. THF was distilled from sodium-benzophenone ketyl prior to use. Commercially available Grignard reagents were used for the preparation of thioamides. The organometallic reactions were performed under a nitrogen atmosphere and in oven dried glasswares. 2.4.1 General Procedure for the Preparation of Thiocarbonylbenzotriazoles 2.3ad. To the appropriate Grignard reagent (10 mL, 1 M) in THF at rt, was added carbon disulfide (0.9 mL, 10 mmol). The reaction mixture was refluxed at 60 o C for 3hrs, then cooled to rt and 1-chlorobenzotriazole (3.06 g, 20 mmol) was added. After stirring overnight at rt, solvent was removed in vacuo and the mixture separated on silica gel column (2% ethyl acetate/hexanes). Recrystallization from ethyl acetate/ hexanes provided the desired thiocarbonylbenzotriazoles 2.3ad. Benzotriazol-1-yl-(4-methylphenyl)methanethione (2.3a). Red needles (63%), mp 140 o C. 1 H NMR 2.49 (s, 3H), 7.39 (d, J = 8.4 Hz, 2H), 7.55 (t, J = 7.5 Hz, 1H), 7.71 (t, J = 7.5 Hz, 1H), 8.14.19 (m, 3H), 8.39 (d, J = 8.4 Hz, 1H). 13 C NMR 21.8, 114.8, 120.1, 126.2, 128.6, 129.2, 130.3, 131.9, 144.9, 171.8. Anal. Calcd. For C 14 H 11 N 3 S: C, 66.38; H, 4.38; N, 16.59. Found: C, 66.83; H, 4.34; N, 16.66. Benzotriazol-1-yl-(4-methoxyphenyl)methanethione (2.3b). Red-orange needles (89%), mp 131 o C. 1 H NMR 3.92 (s, 3H), 6.93.98 (m, 2H), 7.55 (t, J =
23 8.1 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.83.86 (m, 2H), 8.18 (d, J = 8.1 Hz, 1H), 8.52 (d, J = 8.4 Hz, 1H). 13 C NMR 55.7, 113.6, 113.9, 114.8, 115.2, 120.1, 120.4, 126.1, 126.4, 133.7, 134.4, 147.0, 164.1. Anal. Calcd. For C 14 H 11 N 3 OS: C, 62.43; H, 4.12; N, 15.60. Benzotriazol-1-yl-phenylmethanethione (2.3c). Red-pink needles (76%), mp 134 o C, (Lit. mp 139 o C)[73LA636]. 1 H NMR 7.46 (t, J = 7.5 Hz, 2H), 7.647.56 (m, 2H), 7.70.79 (m, 3H), 8.19 (d, J = 8.4 Hz, 1H), 8.63 (d, J = 8.4 Hz, 1H). 13 C NMR 115.4, 120.5, 126.8, 128.0, 130.6, 130.7, 132.5, 133.2, 142.7, 147.0, 202.1. Benzotriazol-1-yl-(4-chlorophenyl)methanethione (2.3d). Red-pink needles (42%), mp 123 o C. 1 H NMR 3.92 (s, 3H), 6.93.98 (m, 2H), 7.55 (t, J = 8.1 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.83.86 (m, 2H), 8.18 (d, J = 8.1 Hz, 1H), 8.52 (d, J = 8.4 Hz, 1H). 13 C NMR 115.4, 120.6, 127.0, 128.3, 130.9, 131.9, 133.1, 139.1, 140.9, 147.0, 200.2. Anal. Calcd. For C 13 H 8 ClN 3 S: C, 57.04; H, 2.95. Found: C, 56.70; H, 2.80. 2.4.2 General Procedure for the Preparation of Thioamides 2.4af. The appropriate amine (5 mmol) and triethylamine (0.5 g, 5 mmol) were added to the respective thiocarbonylbenzotriazole 2.3 (5 mmol) dissolved in methylene chloride (30 mL) at rt. Stirring was continued overnight, then solvent was removed by rotary evaporation. The residue was redissolved in ethyl acetate (100 mL), washed with 5% Na 2 CO 3 solution (3 x 100 mL), 1M HCl (2 x 100 mL), water, and brine. The collected organic layers were dried with sodium sulfate, then solvent was removed under vacuum. Recrystallization from ethyl acetate/ hexanes afforded thioamides 2.4af in 66 % yields.
24 4-Methylthiobenzoic acid benzylamide (2.4a). Colorless needles (99%), mp 7879 o C, (Lit. mp 87.5.5 o C) [49BSCF172]. 1 H NMR 2.37 (s, 3H), 5.00 (d, J = 5.1 Hz, 2H), 7.17 (d, J = 8.1 Hz, 2H), 7.39.41 (m, 5H), 7.67 (d, J = 8.1 Hz, 3H). 13 C NMR 21.3, 51.0, 126.7, 128.2, 128.4, 129.0, 129.1, 136.3, 138.8, 141.8, 198.9. Anal. Calcd. For C 15 H 15 NS: C, 74.65; H, 6.26; N, 5.80. Found: C, 74.43; H, 6.31; N, 6.38. 1-(4-Methoxythiobenzoyl) piperidine (2.4b). Yellow needles (93%), mp 94 o C, (Lit. mp 107 o C) [65JOC2228]. 1 H NMR 1.58.59 (m, 2H), 1.77.82 (m, 4H), 3.58 (t, J = 5.4 Hz, 2H), 3.82 (s, 3H), 4.34 (t, J = 5.1 Hz, 2H), 6.84.89 (m, 2H), 7.25.28 (m, 2H). 13 C NMR 24.2, 25.5, 26.9, 51.0, 53.3, 55.3, 113.6, 127.5, 128.8, 135.9, 159.8, 199.8. N, N-Diethyl-4-methylthiobenzamide (2.4c). Yellow powder (87%) mp 89 o C. 1 H NMR 1.05 (t, J = 6.9 Hz, 3H), 1.29 (t, J = 6.9 Hz, 3H), 2.26 (s, 3H), 3.36 (q, J = 7.2 Hz, 2H), 4.03 (q, J = 7.2 Hz, 2H), 7.05 (s, 4H). 13 C NMR 11.1, 13.7, 21.0, 45.9, 47.6, 124.8, 127.7, 128.7, 137.7, 140.9, 200.4. Anal. Calcd. For C 13 H 19 NS: C, 70.53; H, 8.65; N, 6.33. Found: C, 70.58; H, 8.61; N, 6.76. N-Benzyl thiobenzamide (2.4d). White needles (97%), mp 86 o C, (Lit. mp 87 o C) [80JCSPT(1)665]. 1 H NMR 4.99 (d, J = 4.8 Hz, 1H), 7.35.46 (m, 8H), 7.75 (d, J = 7.5 Hz, 3H). 13 C NMR 51.0, 126.7, 128.2, 128.4, 128.5, 129.0, 131.1, 136.1, 141.6, 199.1. 1-Thiobenzoyl morpholine (2.4e). Clear needles (78%), mp 135 o C, (Lit. mp 137 o C) [78JOC2914]. 1 H NMR 3.62 (d, J = 5.4 Hz, 4H), 3.89 (t, J = 4.8 Hz, 2H), 4.45 (t, J = 4.8 Hz, 2H), 7.26.32 (m, 2H), 7.34.38 (m, 3H). 13 C NMR 49.5, 52.5, 66.5, 66.7, 125.9, 128.5, 128.9, 142.5, 201.0.
25 4-Chlorothiobenzoic acid phenethylamide (2.4f). Yellow needles (66%), mp 103 o C. 1 H NMR 3.07 (s, 2H), 4.08 (d, J = 5.1 Hz, 2H), 7.27.32 (m, 7H), 7.55 (d, J = 7.2 Hz, 3H). 13 C NMR 33.7, 47.5, 126.9, 127.8, 128.6, 128.7, 128.9, 137.2, 138.1, 140.1, 197.7. Anal. Calcd. For C 15 H 14 ClNS: C, 65.32; H, 5.12; N, 5.08. Found: C, 64.99; H, 5.13; N, 4.99.
26 CHAPTER 3 THIOACYLBENZOTRIAZOLES AS PRECURSORS TO THIONOESTERS 3.1 Introduction Successful application of thioacylbenzotriazole reagents to the synthesis of novel thioamides (Chapter 2) naturally led to the extension of our methodology to thionoesters, which are generally less studied than thioamides or their thiol ester counterparts because few reported syntheses for thionoesters provide sufficiently general access to these compounds; i. e., most literature methods are limited to the preparation of O-phenyl thionoesters [73S149, 95JCR1551]. Despite the lack of efficient methods to provide diverse thionoesters, these compounds are attractive synthetic targets because of their utility when incorporated into macrocycles, such as crown ethers [83JOC2653], and also for their application as chemical probes of the enzyme binding sites of cysteine [04BJ699] and serine [83JBC59] proteases. Application of our benzotriazole thioacylation reagents to the preparation of thionoesters compares favorably to classical syntheses (Scheme 3-1), which have involved: i) treatment of esters with phosphorus pentasulfide [70BSCF2272, 73S149] or Lawessons reagent, both often requiring a large excess of reagent and long reaction times [77BSCB679]; ii) reactions of imino ester with hydrogen sulphide, which often results in significant by-product formation [85T5061]; iii) low yielding reactions of dithioacids with 2-halo-1-methylpyridinium salts and subsequent treatment with the 26
27 respective alcohols [90CA131954]; and iv) Friedel-Crafts acylations of unstable 1-chlorothioformates with aromatics [68CB3517]. CNH2ORR1SOR1RNMeClROHXR1SSH++(i)(ii)(iii)R1SClROH(iv)R1OORP2S5H2S+or Lawesson's Scheme 3-1. Classical syntheses of thionoesters. We now report a high-yielding, general and efficient methodology for the preparation of diverse thionoesters. 3.2 Results and Discussion 3.2.1 Preparation of Thiocarbonylbenzotriazoles (RCSBt). As previously described in detail in Chapter 2, the stable, reddish-colored crystalline thioacylation reagents, thiocarbonylbenzotriazoles 2.3ad, were prepared from carbon disulfide, 1-chlorobenzotriazole and the respective Grignard reagents in 42% yields (average 68%).(See Scheme 2-3, Table 2-1) 3.2.2 Synthesis of Thionoesters from Thiocarbonylbenzotriazoles (RCSBt). Thiocarbonylbenzotriazoles 2.3b and 2.3d were reacted with alcohols in the presence of triethylamine to provide representative examples of O-alkyland O-arylthionoesters, 3.3a and 3.3b, in 60 and 77% yields, respectively (Scheme 3-3). O S R R S R BtOHR 11 2.3 3.3 Scheme 3-2. Synthesis of thionoesters from thiocarbonylbenzotriazoles.
28 Table 3-1. Synthesis of thionoesters 3.3 from thioacylating agents 2.3. Thionoesters 3.3 Alcohol R 1 = Thioacylating Agent R = Yield (%) a Ethyl 4-Chlorophenyl (3.3d) 60 b 4-Methoxyphenyl 4-Methoxyphenyl (3.3b) 77 c 2-Naphthyl 4-Methoxyphenyl (3.3b) 88 d Phenyl 4-Chlorophenyl (3.3d) 82 e Diphenylmethyl Phenyl (3.3c) 68 In a similar manner, additional thionoesters 3.3ce were prepared in 68% yields. Simple extraction of the reaction mixture with ethyl acetate and washing of the combined organic layers with 5% Na 2 CO 3 solution, 1M HCl, and brine provided clean isolation of the desired products, which were recrystallized from solutions of ethyl acetate/hexanes and characterized by NMR and elemental analysis. O-Ethyl 4-chlorothiobenzoate (3.3a) displays NMR spectra typical of thionoesters: the disappearance of benzotriazole peaks in the 1 H and 13 C NMR spectra indicates conversion of 2.3d to 3.3a by nucleophilic displacement of benzotriazole by the ethoxide anion. The shift of the thiocarbonyl peak in the carbon spectrum from 200.2 ppm to 209.8 ppm indicates transformation of the functional group to a thionoester. 3.2.3 Attempted Preparation of Dithioesters. In contrast to reactions of thioacylbenzotriazole 2.3 with alcohols, attempts to extend our methodology to analogous dithioesters were largely unsuccessful. Reactions of 2.3 with phenylthiol or its sodium salt (under reflux conditions and in the presence of triethylamine, pyridine, or 4-dimethylaminopyridine) failed. Refluxing 2.3c with benzyl
29 mercaptan in acetonitrile in the presence of triethylamine provided benzyl dithiobenzoate (3.4) in only 14% yield (Scheme 3-3). S S R S R Bt PhCH2SH 2.3 3.4 14% Scheme 3-3. Benzyl dithiobenzoate (3.4) from thiocarbonylbenzotriazoles. 3.3 Conclusion Although our benzotriazole-assisted thioacylation method cannot be extended to dithioesters, the method has advantages for thionoesters in that use of unstable or hazardous reagents (e.g. H 2 S) is avoided, a simple purification procedure is employed, and good yields are attained. These points of merit address significant problems that were unresolved by current routes to thionoesters. For example, both treatment of esters with thionating agents (Lawessons reagent and phosphorous pentasulfide) and reaction of imino esters with hydrogen disulfide utilize toxic or inconvenient reagents, require long reaction times, and provide thionoesters in low yields due to substantial by-product formation. The limitations of traditional routes to thionoesters have hindered studies of their utility as organic synthons, their potential material applications, and possible biological activity. The promise of thionoesters in these diverse areas of application is highlighted by studies of their incorporation into crown ethers [83JOC2653] and also their utility as chemical probes of the enzyme binding sites [83JBC59, 04BJ699]. Our benzotriazole thioacylation methodology now provides broadened access to thionoesters, which should
30 in turn lead to further developments in applications of this class of sulfur-containing compounds. 3.4 Experimental Section Melting points were uncorrected. 1 H (300 MHz) and 13 C (75 MHz) NMR spectra were recorded on a 300 MHz NMR spectrometer in chloroform-d solution unless stated. Column chromatography was performed on silica gel. THF was distilled from sodium-benzophenone ketyl prior to use. Commercially available Grignard reagents were used for the preparation of thioamides. The organometallic reactions were performed under a nitrogen atmosphere and in oven dried glasswares. 3.4.1 General Procedure for the Preparation of Thiocarbonylbenzotriazoles 2.3ad. To the appropriate Grignard reagent (10 mL, 1 M) in THF at rt, was added carbon disulfide (0.9 mL, 10 mmol). The reaction mixture was refluxed at 60 o C for 3hrs, then cooled to rt and 1-chlorobenzotriazole (3.06 g, 20 mmol) was added. After stirring overnight at rt, solvent was removed in vacuo and the mixture separated on silica gel column (2% ethyl acetate/hexanes). Recrystallization from ethyl acetate/ hexanes provided the desired thiocarbonylbenzotriazoles 2.3ad. (See Section 2.4.1 for characterization details) 3.4.2 General Procedure for the Preparation of Thionoesters 3.3ae. The appropriate alcohol (0.5 mmol) and triethylamine (0.05 g, 0.5 mmol) were added to the respective thiocarbonylbenzotriazole 2.3 (0.5 mmol) dissolved in methylene chloride (30 mL) at rt. Stirring was continued overnight, then solvent was removed by rotary evaporation. The residue was redissolved in ethyl acetate (100 mL), washed with 5% Na 2 CO 3 solution (3 x 100 mL), 1M HCl (2 x 100 mL), water, and brine. The
31 collected organic layers were dried with sodium sulfate, and the solvent was removed under vacuum. Recrystallization from ethyl acetate/ hexanes afforded thionoesters 3.3ae. O-Ethyl 4-chlorothiobenzoate (3.3a). Yellow powder (60%), mp 34 o C, (Lit. mp 36 o C).[80CPB177] 1 H NMR 1.53 (t, J = 7.2 Hz, 3H), 4.72 (dd, J = 7.2, 6.9 Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H), 8.12 (d, J = 8.4 Hz, 2H). 13 C NMR 13.7, 68.7, 128.2, 130.0, 136.6, 139.2, 209.8. O-(4-Methoxyphenyl)-4-methoxythiobenzoate (3.3b). Yellow powder (77%), mp 105 o C. 1 H NMR 3.83 (s, 3H), 3.89 (s, 3H), 6.92 (d, J = 9 Hz, 2H), 6.96 (d, J = 9 Hz, 2H), 7.03 (d, J = 9 Hz, 2H), 8.34 (d, J = 9 Hz, 2H). 13 C NMR 55.6, 113.4, 114.4, 122.9, 131.1, 131.7, 148.3, 157.5, 164.1, 210.5. Anal. Calcd. For C 15 H 14 O 3 S: C, 65.67; H, 5.14; N, 0. Found: C, 65.47; H, 5.14; N, 0.03. O-Naphth-1-yl 4-methoxythiobenzoate (3.3c). Yellow needles (88%), mp 93 o C. 1 H NMR 3.91 (s, 3H), 6.98 (d, J = 8.7 Hz, 2H), 7.24.27 (m, 1H), 7.44.56 (m, 3H), 7.80 (t, J = 6.3 Hz, 2H), 7.90 (d, J = 7.8 Hz, 1H), 8.47.50 (m, 2H). 13 C NMR 55.7, 113.7, 119.0, 121.6, 125.4, 126.4, 126.6, 126.8, 128.2, 131.0, 131.8, 134.8, 151.0, 164.3, 209.6. Anal. Calcd. For C 18 H 14 O 2 S: C, 73.44; H, 4.79; N, 0. Found: C, 72.65; H, 4.89; N, 0.03. O-Phenyl 4-chlorothiobenzoate (3.3d). Yellow powder (68%), mp 94 o C, (Lit. mp 92 o C).[95JCR1551] 1 H NMR 7.18.57 (m, 7H), 8.10 (d, J = 8.1 Hz, 2H). 13 C NMR 126.1, 128.1, 128.2, 129.1, 130.0, 134.1, 136.6, 139.2, 209.8. O-Benzhydryl thiobenzoate (3.3e). Yellow cubes, (from ethyl acetate) (82%), mp 102 C. 1 H NMR 7.097.49 (m, 16 H). 13 C NMR 83.3, 126.1, 126.8, 127.6,
32 128.3, 129.2, 130.0, 140.3, 143.5, 210.3. Anal. Calcd. For C 20 H 16 OS: C, 75.64; H, 5.74; N, 4.20. Found: C, 75.65; H, 5.91; N, 4.17. 3.4.3 General Procedure for the Preparation of a Dithioester 3.4. Benzyl mercaptan (0.061 g, 0.5 mmol) and triethylamine (0.052 g, 0.5 mmol) were added to benzotriazol-1-yl-phenyl methanethione 2.3c (0.119 g, 0.5 mmol) dissolved in methylene chloride (30 mL) at rt. Stirring was continued overnight, then solvent was removed by rotary evaporation. The residue was redissolved in ethyl acetate (100 mL), washed with 5% Na 2 CO 3 solution (3 x 100 mL), 1M HCl (2 x 100 mL), water, and brine. The collected organic layers were dried with sodium sulfate, and the solvent was removed under vacuum. Recrystallization from ethyl acetate/ hexanes afforded dithioester 3.4. Benzyl dithiobenzoate (3.4). Red-orange microcrystals (14%), mp 49 o C, Lit. [73S149] mp 51 o C. 1 H NMR 4.60 (s, 2H), 7.22.55 (m, 8H), 7.99.01 (m, 2H). 13 C NMR 42.3, 126.9, 127.7, 128.3, 128.5, 128.7, 129.3, 129.4, 132.4, 134.9, 144.7, 229.0.
33 CHAPTER 4 1-(ALKYL/ARYLTHIOCARBAMOYL)BENZOTRIAZOLES AS STABLE ISOTHIOCYANATE EQUIVALENTS: SYNTHESIS OF DIAND TRISUBSTITUTED THIOUREAS 4.1 Introduction Thioureas are of importance in medicinal chemistry [96JOC8811] due to their biological activity [96JMC1157, 98JMC975, 98JMC3159]; e.g. against bacteria and microbial infections [81JCSPT12186], as fungicides, herbicides, and rodenticides [55CR181, 85JHC137], and as phenoloxidase enzymatic inhibitors [69CA101668v]. Thioureas are routinely incorporated into peptides as biomimetic models [96JOC8811, 97TL4791]. Thioureas are also valuable building blocks for the synthesis of fiveand six-membered heterocycles [75AHC99]. A common functional group transformation is the derivatization of amines as stable thioureas [79COC465]. Treatment of two equivalents of a primary or secondary amine with thiophosgene is the easiest method of making symmetrical thioureas [78S803]; the unpleasant nature of thiophosgene can be avoided by using thiophosgene equivalents like 1,1'-thiocarbonyldi-imidazole [62ACIE351, 62LA98]. However, 1,1'-thiocarbonyldiimidazole is also not an ideal reagent, for decomposition occurs within 2 days of storage at room temperature; thus, 1,1'-thiocarbonyldiimidazole must always be freshly prepared before use [86JOC2613]. Reaction of isothiocyanates with primary or secondary amines is a common method of making unsymmetrical thioureas [55JACS4328, 63CJC2123, 89SC965], but suffers from side reactions like urethane formation (in alcoholic medium where the 33
34 reaction is often carried out) or exchange between the amine and the isothiocyanate [40CB1420]. Many isothiocyanates are tedious to prepare and display poor long-term stability. Hence, numerous alternative methods have been developed for the synthesis of both symmetrical and unsymmetrical thioureas avoiding the use of isothiocyanates. Thus, symmetrical thioureas are formed as shown in Scheme 4-1 by i) either the direct [55OS394] or catalyzed [74TL1191, 99JOC1029] reaction of carbon disulfide and amines; ii) the reaction of carbodiimides with hydrogen sulphide [67CR107]; iii) the reaction of 2-chloropyridinium salts with sodium trithiocarbonate and amines [82CL641]; or iv) the reaction of 1,1-thiocarbonyldiimidazole [62ACIE351, 62LA98] with amines. RNCNRRNH2CS2H2SSNHNHRRNMeCl2 RNH2ISNNNa2CS32 RNH2+2direct orcatalyzed+++(i)(ii)(iii)(iv)NN Scheme 4-1. Literature methods to prepare symmetrical thioureas. Methods for the preparation of unsymmetrical thioureas (Scheme 4-2) comprise: i) the use of 1-(methyldithiocarbonyl)imidazole as a thiocarbonyl transfer reagent [00T629]; ii) the activation of a dithiocarbamate with a 2-halothiazolium salt and subsequent reaction with an amine [88JOC2263]; iii) direct displacement, by amines, from 1,3-diphenylthiourea (iiia) [93TL6447], nitrosothiourea (iiib) [99TL1957], or thiuram disulfide (iiic) [95SC3381]; or iv) the reaction of carbon disulfide with primary amines in the presence of a triaryl phosphite or a hexaalkyl phosphoroustriamide
35 [75S384]. 1,1-Disubstituted thioureas are formed by the reaction of secondary amines with triphenylphosphine-thiocyanogen (v) [78TL1753, 79CPB1636]. Although these additional methods are of great utility in the synthesis of many thioureas, a synthetic equivalent to isothiocyanate or a protected form of it, which is stable, readily available, and easy to handle would be of considerable benefit. In this chapter, we describe the preparation and utility of 1-(alkyl/arylthiocarbamoyl)benzotriazoles which, in keeping with other classes of acylbenzotriazoles [00JOC8210, 01ARK41, 02ARK39, 01ARK19, 02ARK134], are highly effective thioacylating agents behaving as masked isothiocyanates. NCS NaR1RSSSMeNNNSR5PhClBF4NHR3R4RR1NCNHPhSSSMeNNMeINHR3R4Ph3P(SCN)2H2ONHR1RSNNR3RR4R1NCNRR1MeNOSNHR3R4PNR1RNR1RNR1RSCNSR1RSNCSR1R3 CS2NHR3R4or+R1 = H+R = PhR1= R4=H++R=H,R1=Me+R3=H+++R3=R4=H(i)(ii)(iiia)(iiib)(iiic)(iv)(v)R1NHRR4NHR3R4NHR3R=R1=CH34R4=HR, R1, R2, R3, R4 = alkyl or aryl, unless specified Scheme 4-2. Literature methods for unsymmetrical thioureas.
36 4.2 Results and Discussion 4.2.1 Preparation of (Alky/arylthiocarbamoyl)benzotriazoles 4.4. Bis(benzotriazol-1-yl)methanethione (4.3) is easily prepared from 1-trimethylsilybenzotriazole and thiophosgene in quantitative yield (Scheme 4-3) [78JOC337]. The literature shows only one reaction of this compound with an amine, with aniline to give diphenylthiourea [78JOC337]. As part of our ongoing research on the synthesis and utility of benzotriazole-functionalized reagents [99JHC1501], we considered the possibility of using 4.3 as a thiophosgene equivalent in the synthesis of unsymmetrical thioureas. Thus, the reactivity of 4.3 with various primary amines was investigated first. Treatment of 4.3 with 1,5-dimethylhexylamine in methylene chloride at 20 o C followed by a 5% Na 2 CO 3 wash and re-crystallization afforded benzotriazole-1-carbothioic acid 1,5-dimethylhexylamide (4.4a) in 99% yield (Scheme 4-3, Table 4-1). SClClSiMe3BtNNNSBtBtSNBtR1R2NHR1R2NH2RSNHBtRNHR1R2SNHNRR1R2Bt = +1o or 2o amineNo reaction (R', R2 = H)188.8.131.52.44.54.4i (R1=R2= -(CH2)4-) See Table 4-2 for the designations of R, R 1 and R 2 Scheme 4-3. Preparation of thioureas from bis(benzotriazol-1-yl)methanethione 4.3.
37 Table 4-1. Thiocarbamoybenzotriazoles 4.4 prepared. Entry 1 o Amine Thiocarbamoyl benzotriazoles 4.4 Yield (%) a 1,5-Dimethylhexylamine NH S Bt 99 b 2-Thiazolylamine NH S Bt NS 91 c 2-Furfurylamine NH S Bt O 99 d -(R)-Methylbenzylamine NH S Bt 99 e Benzylamine NH S Bt 97 f Pyrrolidine N S Bt 99 The 1 H NMR spectrum of benzotriazole-1-carbothioic acid 1,5-dimethylhexylamide (4.4a) displays the typical 1H-benzotriazole and thiocarbamoyl NH peaks in the aromatic region. The 13 C NMR spectrum of benzotriazole-1-carbothioic acid 1,5-dimethylhexylamide (4.4a) also displays a distinctive thioamide peak at 173.4 indicating conversion. Significantly, 4.4a was stored at room temperature for weeks without decomposition. Similarly, compounds 4.4be from other primary amines were also prepared in nearly quantitative yields (Table 4-1). Reagents 4.4ae are masked isothiocyanates and are useful alternatives for isothiocyanates in the preparation of secondary and tertiary thioureas.
38 4.2.2 Preparation of Diand Trisubstituted Thioureas. Thiocarbamoylbenzotriazoles 4.4ad were reacted with a second primary amine to generate the corresponding disubstituted thioureas. Thus, when benzotriazole-1-carbothioic acid 1,5-dimethylhexylamide (4.4a) was treated with 4-methoxybenzylamine, thiourea 4.5a was isolated in 99% yield (Scheme 4-3, Table 4-2). The reaction was carried out in methylene chloride and the byproduct, benzotriazole, was removed by 5% sodium carbonate wash. Similar reactions of 4.4ad with other primary amines afforded the corresponding secondary thioureas 4.5bh in 57% yields (Table 4-2). Table 4-2. Di-and trisubstituted thioureas 4.5 prepared. 4.5 R R 1 R 2 Yield (%) a 1,5-Dimethylhexyl 4-MeOC 6 H 4 CH 2 H 99 b -(R)-Methylbenzyl EtO(CH 2 ) 2 H 99 c Furfuryl 4-CO 2 EtC 6 H 4 H 57 d 2-Thiazolyl Phenethyl H 95 e 1,5-Dimethylhexyl Phenyl Methyl 61 f -(R)-Methylbenzyl (CH 2 ) 2 O(CH 2 ) 2 92 g Furfuryl (CH 2 ) 5 94 h 2-Thiazolyl 3-Methylpiperidinyl 87 The 1 H NMR spectrum of 3-(1,5-dimethylhexyl)-1-methyl-phenylthiourea (4.5e) indicates conversion by the loss of the benzotriazole peaks present in the 1 H NMR spectrum of 4.4a. A shift of the thiocarbonyl peak in the 13 C NMR spectra from 173.4 ppm for the thiocarbamoylbenzotriazole reagent 4.4a to 181.0 ppm for the thiourea 4.5e indicates conversion.
39 4.2.3 N, N-Disubstituted(thiocarbamoyl)benzotriazoles Reaction of secondary amines with bis(benzotriazol-1-yl)methanethione (4.3) also proceeded smoothly. Thus, the thiocarbamoylbenzotriazole 4.4f was prepared in 99% yield from pyrrolidine and 4.3. The reaction of 4.4f with a second secondary amine was attempted with the expected formation of the corresponding tetrasubstituted thiourea. However, in this case substitution of the second benzotriazole group did not proceed even with a primary amine under forcing conditions (refluxing DMF) and unreacted reagent 4.4f was recovered. We believe that reactions of 4.4ae with primary amines proceed with the intermediate formation of isothiocyanates, which add the amine to form the thiourea. This is supported by the observation that 4.4f failed to give thiourea by the reaction with a second amine. (Evidently, electronic assistance from a nitrogen lone pair is insufficient to energetically favor benzotriazole group displacement.) Moreover, on reaction with 4.3, aromatic amines (p-anisidine, p-ethoxycarbonylaniline) gave the corresponding isothiocyanates instead of the expected thiocarbamoyl reagents. This result could be advantageous since such isothiocyanate formation was observed only in those cases where the isothiocyanate is stabilized as in aromatic isothiocyanates. In cases where the isothiocyanate has a low stability (e. g. alkyl isothiocyanates), the reaction stops at the thiocarbamoylbenzotriazole-formation stage, which is in fact a protected isothiocyanate. Thus reagents 4.4ae can potentially replace unstable isothiocyanates. Reagent 4.3 also has advantages over its close counterpart, 1,1'-thiocarbonyldi-imidazole (4.7), which is hygroscopic and relatively unstable [86JOC2613] even though 4.7 has been extensively used as a thiocarbonyl transfer reagent [62ACIE351, 62LA98,
40 83TL4927, 85CJC951]. Bis(benzotriazol-1-yl)methanethione 4.3 is stable at room temperature for months without any loss in reactivity. On reaction with primary amines (e.g. benzylamine), 1,1'-thiocarbamoyldiimidazole (4.7) reportedly produced a mixture of the corresponding thiocarbamoylimidazole 4.8, isothiocyanate 4.9, and the bisthiourea 4.10 in yields of 48%, 38%, and 6%, respectively (Scheme 4-4) [86JOC2613]. In contrast, 4.3 afforded the thiocarbamoylbenzotriazole 4.4e (Table 4-1) as the sole product in 97% yield from benzylamine. The bis-substitution product was never detected in the reactions of 4.3 with one equivalent of a primary amine unlike the case of thiophosgene, where the reaction mixture is often contaminated by the bis-substitution product [55CR181]. NNNNNBt =Im =SBtBtNH2SImImNHImSNHBtSPhNCSPhNHNHSPh4.4h, 97%++4.8, 48%4.9, 38%4.10, 6%184.108.40.206 Scheme 4-4. Comparison of benzotriazole and imidazole reagents. 4.2.4 One-Pot Synthesis of Unsymmetrical Thioureas. In a further demonstration of the utility of intermediate thiocarbamoyl-benzotriazoles in the preparation of unsymmetrical thioureas, we have utilized 4.3 in a one-pot reaction with two different primary amines in a sequential fashion. Thus, when 4.3 was treated with phenethylamine in methylene chloride followed by the addition of 4-methoxyaniline, the corresponding trisubstituted thiourea 4.11 was isolated in 94 % yield.
41 A distinct advantage is that the purification requires only a mild base (5% Na 2 CO 3 ) wash to remove the eliminated benzotriazole. Other disubstituted thioureas 4.15 and 4.16 were afforded in 97 and 89% yields, respectively. (Table 4-3). Trisubstituted thioureas 4.12 and 4.17 were also prepared in good to excellent yields by reacting, sequentially, the appropriate primary and secondary amine respectively with 4.3 (Table 4-3). Table 4-3. Thioureas prepared using 4.3 in one-pot reactions with 1 o and 2 o amines. PhHNHNSOMeHNNSEtO2COHNNSMePhNHNSPhOEtONNHNSNHPhSNHNHNMeMePhSNNHNSC3H7Me4.11 (94%)4.12 (87%)4.13 (76%)4.14 (52%)4.15 (97%)4.16 (89%)4.17 (68%)Calculation of yields is based on conversion of bis(benzotriazolyl)methanethione (4.3) to thioureas 4.11-4.17. 4.3 Conclusion In conclusion, we have demonstrated the utility of 1(alkyl/arylthiocarbamoyl)-benzotriazoles (4.4) as masked isothiocyanates and bis(benzotriazol-1-yl)methanethione (4.3) as a thiophosgene equivalent. Reactions of 4.4 with amines are faster, high yielding, and less laborious in isolation and purification procedures than those with isothiocyanates. Our route to unsymmetrical thioureas utilizes stable reagents that are
42 now commercially available (from Aldrich); whereas, traditional methodologies employ unstable reagents (e.g., isothiocyanates, 1,1-thiocarbonyl-diimidazole, triaryl phosphites, hexaalkyl phosphoroustriamides, and triphenylphosphine-thiocyanogen ) or difficult to access starting materials, such as nitrosothioureas or thiuram disulfides. The benzotriazole thiocarbamoylation methodologies described in this work are versatile, simple, and clean, providing access to diand tri-substituted thioureas by both one pot and two-step procedures. In all, these developments in benzotriazole thiocarbamoylation methodology constitute a significant advance in providing convenient and efficient access to diversely functionalized unsymmetrical thioureas. 4.4 Experimental Section Melting points were determined on a hot-stage apparatus and are uncorrected. 1 H (300 MHz) and 13 C (75 MHz) NMR spectra were recorded on a 300 MHz NMR spectrometer in chloroform-d or DMSO-d 6 solution with tetramethylsilane as an internal reference for 1 H and solvent as an internal reference for 13 C. Column chromatography was performed on silica gel (230 mesh). 4.4.1 General Procedure for the Preparation of Reagents 4.4af. Bis(benzotriazol-1-yl)methanethione [78JOC337] (4.3) (0.56 g, 2 mmol) was dissolved in methylene chloride at room temperature. The appropriate primary amine (2 mmol) was added dropwise, and the reaction mixture was stirred for 18 h. Solvent was removed under vacuum and the residue was re-dissolved in EtOAc, washed with 5% aqueous sodium carbonate, water and brine before drying over anhydrous sodium sulfate. Solvent was removed under vacuum and 1-thiocarbamoylbenzotriazole was recrystallized from ethyl acetate.
43 Benzotriazole-1-carbothioic acid (1,5-dimethylhexyl)amide (4.4a). Yellow oil, 99%. 1 H NMR (CDCl 3 ) 0.86 (d, J = 6.6 Hz, 6H), 1.201.28 (m, 2H), 1.391.81 (m, 8H), 4.664.71 (m, 1H), 7.45.50 (m, 1H), 7.62.67 (m, 1H), 8.09 (d, J = 8.2 Hz, 1H), 8.90.95 (m, 2H). 13 C NMR (CDCl 3 ) 19.5, 22.5, 23.7, 27.8, 36.2, 38.6, 51.0, 116.2, 120.2, 125.6, 130.2, 132.5, 147.1, 173.4. Anal. Calcd For C 15 H 22 N 4 S: C, 62.03; H, 7.64; N, 19.29. Found: C, 62.48; H, 7.70; N, 19.52. Benzotriazole-1-carbothioic acid thiazol-2-ylamide (4.4b). Yellow microcrystals, 91%, mp 160161 o C. 1 H NMR (DMSO-d 6 ) 7.457.58 (m, 3H), 7.73 (t, J = 7.3 Hz, 1H), 7.96 (d, J = 4.4 Hz, 1H), 8.18 (d, J = 8.2 Hz, 1H), 8.88 (d, J = 8.4 Hz, 1H). 13 C NMR (DMSO-d 6 ) 112.2, 116.3, 119.4, 125.1, 125.9, 129.0, 130.6, 130.9, 146.0, 170.3. Anal. Calcd For C 10 H 7 N 5 S 2 : C, 45.96; H, 2.70; N, 26.80. Found: C, 45.48; H, 2.66; N, 26.26. Benzotriazole-1-carbothioic acid (furan-2-ylmethyl)amide (4.4c). Brown needles (from EtOAc/Hexanes), 99%, mp 117119 o C. 1 H NMR (CDCl 3 ) 5.03 (d, J = 5.4 Hz, 2H), 6.376.45 (m, 2H), 7.437.50 (m, 2H), 7.61.67 (m, 1H), 8.09 (d, J = 8.1 Hz, 1H), 8.90 (d, J = 8.4 Hz, 1H), 9.32 (br s, 1H). 13 C NMR (CDCl 3 ) 41.8, 109.3, 110.6, 115.9, 120.3, 125.7, 130.4, 132.4, 143.0, 147.0, 148.5, 174.2. Anal. Calcd For C 12 H 10 N 4 OS: C, 55.80; H, 3.90; N, 21.69. Found: C, 56.04; H, 3.85; N, 21.81. Benzotriazole-1-carbothioic acid [(R)-1-phenylethyl]amide (4.4d). Yellow oil, 99%. 1 H NMR (CDCl 3 ) 1.77 (d, J = 7.2 Hz, 3H), 5.745.84 (m, 1H), 7.307.50 (m, 6H), 7.61-7.66 (m, 1H), 8.09 (d, J = 8.2 Hz, 1H), 8.90 (d, J = 8.5 Hz, 1H), 9.32 (d, J = 6.3 Hz, 1H). 13 C NMR (CDCl 3 ) 21.0, 54.1, 116.1, 120.2, 125.7, 126.5, 128.0, 128.9,
44 130.3, 132.5, 141.1, 147.1, 173.4. Anal. Calcd For C 15 H 14 N 4 S: C, 63.80; H, 5.00; N, 19.84. Found: C, 64.06; H, 4.93; N, 20.29. Benzotriazole-1-carbothioic acid benzylamide (4.4e). White needles (from EtOAc/Hexanes), 97%, mp 108 o C. 1 H NMR (CDCl 3 ) 5.04 (d, J = 4.2 Hz, 2H), 7.337.52 (m, 6H), 7.66 (t, J = 7.2 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.94 (d, J = 8.7 Hz, 1H), 9.32 ( br s, 1H). 13 C NMR (CDCl 3 ) 49.0, 116.0, 120.3, 125.7, 128.2, 128.3, 129.0, 130.4, 132.4, 135.5, 147.1, 174.4. Anal. Calcd For C 14 H 12 N 4 S: C, 62.66; H, 4.51; N, 20.88. Found: C, 62.79; H, 4.44; N, 20.82. Benzotriazol-1-ylpyrrolidin-1-ylmethanethione (4.4f). White needles (from EtOAc/Hexanes), 99%, mp 144145 o C. 1 H NMR (CDCl 3 ) 2.022.09 (m, 2H), 2.112.18 (m, 2H), 3.98 (t, J = 6.9 Hz, 1H), 4.11 (t, J = 6.9 Hz, 2H), 7.46.52 (m, 1H), 7.62.67 (m, 1H), 8.13 (dd, J = 8.1, 0.9 Hz, 1H), 8.30 (dd, J = 8.4, 0.6 Hz, 1H). 13 C NMR (CDCl 3 ) 24.3, 26.4, 54.3, 54.6, 114.5, 119.8, 125.1, 128.8, 133.0, 145.8, 172.0. Anal. Calcd For C 11 H 12 N 4 S: C, 56.87; H, 5.21; N, 24.12. Found: C, 56.64; H, 5.02; N, 23.89. 4.4.2 General Procedure for the Preparation of Thioureas 4.5ah. The appropriate thiocarbamoylbenzotriazole 4.4 (1 mmol) was dissolved in methylene chloride at room temperature. The corresponding amine (1 mmol) was added followed by triethylamine (0.3 mL, 2 mmol) and the reaction mixture was stirred for 24 h. Solvent was removed under vacuum and the residue was re-dissolved in EtOAc, washed with 5% aqueous sodium carbonate, 1 M HCl, water and brine before drying over anhydrous sodium sulfate. Solvent was removed under vacuum and the thioureas 4.5ah
45 were purified by re-crystallization (in the case of solids) or column chromatography (in the case of oils), on silica gel (200 Mesh, EtOAc/hexanes). 1-(1,5-Dimethylhexyl)-3-(4-methoxybenzyl)thiourea (4.5a). Orange needles (from EtOAc/Hexanes), 100%, mp 5762 o C. 1 H NMR (CDCl 3 ) 0.84 (m, J = 6.6 Hz, 6H), 1.071.55 (m, 10H), 3.80 (s, 3H), 4.04 (br s, 1H), 4.55 (br s, 2H), 5.56 (br s, 1H), 5.94 (br s, 1H), 6.87.90 (m, 2H), 7.25 (d, J = 8.4 Hz, 2H). 13 C NMR (CDCl 3 ) 20.5, 22.5, 23.5, 27.8, 36.9, 38.7, 47.8, 50.4, 55.2, 114.3, 128.9, 159.3, 180.7. Anal. Calcd For C 17 H 28 N 2 OS: C, 66.19; H, 9.15; N, 9.08. Found: C, 66.41; H, 9.19; N, 9.33. 1-(2-Ethoxyethyl)-3-[(R)-1-phenylethyl]thiourea (4.5b). Yellow oil, 99%.  D 25 = + 0.1 o (c 0.04, CH 2 Cl 2 ); 1 H NMR (CDCl 3 ) 1.05 (t, J = 6.9 Hz, 3H), 1.53 (d, J = 6.6 Hz, 3H), 3.323.60 (m, 7H), 5.02 (br s, 1H), 6.11 (br s, 1H), 7.217.38 (m, 5H). 13 C NMR (CDCl 3 ) 14.8, 22.9, 44.7, 53.8, 66.3, 69.0, 125.8, 127.4, 128.6, 142.4, 181.3. Anal. Calcd For C 13 H 20 N 2 OS: C, 61.87; H, 7.99; N, 11.10. Found: C, 61.65; H, 8.22; N, 11.10. 4-(3-Furan-2-ylmethylthioureido)benzoic acid ethyl ester (4.5c). Green needles (from EtOAc/Hexanes), 57%, mp 115116 o C. 1 H NMR (CDCl 3 ) 1.39 (t, J = 7.2 Hz, 3H), 4.36 (q, J = 7.2 Hz, 2H), 4.86 (d, J = 5.1 Hz, 2H), 6.316.34 (m, 2H), 6.55 (br s, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.357.36 (m, 1H), 8.06 (d, J = 8.4 Hz, 2H), 8.38 (s, 1H). 13 C NMR (CDCl 3 ) 14.2, 42.4, 61.2, 108.5, 110.5, 123.0, 128.1, 131.5, 140.4, 142.6, 149.7, 165.6, 180.1. Anal. Calcd For C 15 H 16 N 2 O 3 S: C, 59.19; H, 5.30; N, 9.20. Found: C, 59.06; H, 5.25; N, 9.34. 1-Phenethyl-3-thiazol-2-ylthiourea (4.5d). Orange needles (from EtOAc/Hexanes), 95%, mp 162 o C (lit. [95JMC659] mp 169.5.5 o C). 1 H NMR
46 (CDCl 3 ) 3.03 (t, J = 7.2 Hz, 2H), 3.99 (q, J = 7.2 Hz, 2H), 6.80 (d, J = 3.6 Hz, 1H), 7.207.35 (m, 6H), 10.50 (br s, 1H), 10.83 (br s, 1H). 13 C NMR (CDCl 3 ) 34.8, 47.0, 111.1, 126.6, 128.6, 128.9, 137.6, 138.5, 161.6, 177.6. Anal. Calcd For C 12 H 13 N 3 S 2 : C, 54.72; H, 4.97; N, 15.95. Found: C, 54.99; H, 4.80; N, 15.93. 3-(1,5-Dimethylhexyl)-1-methyl-1-phenylthiourea (4.5e). Orange oil, 61%. 1 H NMR (CDCl 3 ) 0.820.85 (dd, J = 6.6, 1.5 Hz, 6H), 1.071.52 (m, 10H), 3.66 (s, 3H), 4.404.51 (m, 1H), 5.06 (d, J = 8.1 Hz, 1H), 7.21 (d, J = 7.2 Hz, 2H), 7.39 (t, J = 7.5 Hz, 1H), 7.47.51 (m, 2H). 13 C NMR (CDCl 3 ) 20.3, 22.4, 23.5, 27.7, 36.6, 38.6, 43.1, 51.4, 127.1, 128.4, 130.5, 142.9, 181.0. Anal. Calcd For C 16 H 26 N 2 S: C, 69.01; H, 9.41; N, 10.06. Found: C, 69.33; H, 9.61; N, 10.29. Morpholine-4-carbothioic acid [(R)-1-phenylethyl]amide (4.5f). White needles (from EtOAc/Hexanes), 92%, mp 117 o C.  D 25 = 3.5 o (c 0.04, CH 2 Cl 2 ); 1 H NMR (CDCl 3 ) 1.61 (d, J = 6.6 Hz, 3H), 3.723.84 (m, 8H), 5.66 (br s, 1H), 5.775.87 (m, 1H), 7.267.44 (m, 5H). 13 C NMR (CDCl 3 ) 21.4, 47.4, 54.6, 66.1, 126.4, 127.5, 128.7, 142.9, 181.9. Anal. Calcd For C 13 H 18 N 2 OS: C, 62.36; H, 7.25; N, 11.19. Found: C, 62.05; H, 7.25; N, 11.62. Piperidine-1-carbothioic acid (furan-2-ylmethyl)amide (4.5g). White needles (from EtOAc/Hexanes), 94%, mp 104 o C. 1 H NMR (CDCl 3 ) 1.66 (br s, 6H), 3.783.80 (m, 4H), 4.87 (d, J = 4.8 Hz, 2H), 5.64 (br s, 1H), 6.30.34 (m, 2H) 7.38 (s, 1H). 13 C NMR (CDCl 3 ) 24.2, 25.4, 43.1, 48.8, 108.0, 110.5, 142.2, 151.1, 181.0. Anal. Calcd For C 11 H 16 N 2 OS: C, 58.90; H, 7.19; N, 12.49. Found: C, 58.35; H, 7.31; N, 12.28. 3-Methylpiperidine-1-carbothioic acid thiazol-2-ylamide (4.5h). Orange oil, 87%. 1 H NMR (CDCl 3 ) 0.89 (d, J = 6.6 Hz, 3H), 1.101.26 (m, 1H), 1.451.85 (m,
47 4H), 2.66 (t, J = 11.1 Hz, 1H), 2.893.03 (m, 1H), 4.84 (t, J = 14.1 Hz, 2H) 6.62 (d, J = 4.2 Hz, 1H), 7.16 (d, J = 4.2 Hz, 1H). 13 C NMR (CDCl 3 ) 18.9, 25.1, 31.3, 33.0, 48.6, 55.2, 109.9, 127.6, 167.8, 180.6. Anal. Calcd For C 10 H 15 N 3 S 2 : C, 49.76; H, 6.26; N, 17.41. Found: C, 49.99; H, 6.28; N, 17.11. 4.4.3 General Procedure for the One-Pot Preparation of Thioureas 4.11. To 0.56 g of bis(benzotriazol-1-yl)methanethione (4.3) (2 mmol) in 30 mL of THF, the appropriate primary amine (2 mmol) was added and the mixture was stirred 36 h. Then, triethylamine (0.6 mL, 4 mmol) and the second primary amine or a secondary amine (2 mmol) were added, and the mixture was stirred for an additional 36 h. Solvent was evaporated and the remaining oil was dissolved in ethyl acetate and washed with 1M HCl, 10 % aqueous solution sodium carbonate, water, and brine. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by re-crystallization or column chromatography (10 % EtOAc/ Hexanes). 1-(4-Methoxyphenyl)-3-phenethylthiourea (4.11). Gray needles (from EtOAc/Hexanes), 94%, mp 104105 o C. 1 H NMR (CDCl 3 ) 2.89 (t, J = 6.9 Hz, 2H), 3.81 (s, 3H), 3.86 (q, J = 6.9 Hz, 2H), 5.75 (br s, 1H), 6.826.86 (m, 2H), 6.95 (d, J = 8.7 Hz, 2H), 7.107.13 (m, 2H), 7.217.29 (m, 3H), 7.51 (br s, 1H). 13 C NMR (CDCl 3 ) 34.8, 46.1, 55.4, 115.1, 126.5, 127.6, 128.1, 128.6, 128.7, 138.4, 158.8, 180.9. Anal. Calcd For C 16 H 18 N 2 OS: C, 67.10; H, 6.33; N, 9.78. Found: C, 67.29; H, 6.38; N, 9.96. 4-[(2,3-Dihydroindole-1-carbothioyl)amino]benzoic acid ethyl ester (4.12). Gray needles (from EtOAc/Hexanes), 87%, mp 122123 o C. 1 H NMR (CDCl 3 ) 1.38 (t, J = 7.2 Hz, 3H), 3.12 (t, J = 8.1 Hz, 2H), 4.35 (q, J = 7.2 Hz, 2H), 4.45 (t, J = 8.1 Hz, 2H), 7.04 (t, J = 7.5 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 7.29 (d, J = 7.5 Hz, 1H), 7.43.50
48 (m, 3H), 7.83 (br s, 1H), 8.00 (d, J = 8.4 Hz, 2H). 13 C NMR (CDCl 3 ) 14.4, 27.3, 55.0, 60.9, 114.9, 121.7, 124.4, 126.3, 126.6, 127.5, 130.6, 134.7, 141.5, 143.1, 166.1, 177.7. Anal. Calcd For C 18 H 18 N 2 O 2 S: C, 66.23; H, 5.56; N, 8.58. Found: C, 66.53; H, 5.61; N, 8.60. 1-Butyl-1-methyl-3-[2-(4-methylbenzoyl)phenyl] thiourea (4.13). Yellow oil, 76%. 1 H NMR (CDCl 3 ) 0.98 (t, J = 7.2 Hz, 3H), 1.381.46 (m, 2H), 1.671.77 (m, 2H), 2.44 (s, 3H), 3.38 (s, 3H), 3.87 (br s, 2H), 7.05.11 (m, 1H), 7.28 (d, J = 8.1 Hz, 2H), 7.497.56 (m, 2H), 7.67 (d, J = 8.1 Hz, 2H), 8.72 (d, J = 8.4 Hz, 1H), 10.69 (s, 1H). 13 C NMR (CDCl 3 ) 13.9, 20.1, 21.7, 29.2, 53.7, 122.1, 125.0, 125.9, 129.0, 130.5, 132.4, 132.6, 135.5, 142.2, 143.6, 179.6, 199.1. Anal. Calcd For C 20 H 24 N 2 OS: C, 70.55; H, 7.10; N, 8.23. Found: C, 70.19; H, 7.18; N, 8.64. (3-Benzyl-1-phenylthioureido)acetic acid ethyl ester (4.14). Red oil, 52%. 1 H NMR (CDCl 3 ) 1.30 (t, J = 7.2 Hz, 3H), 4.24 (q, J = 7.2 Hz, 2H), 4.82 (d, J = 5.4 Hz, 2H), 4.89 (s, 2H), 5.76 (br s, 1H), 7.177.48 (m, 10H). 13 C NMR (CDCl 3 ) 14.1, 49.9, 56.4, 61.2, 127.2, 127.4, 127.9, 128.6, 129.1, 130.6, 137.7, 141.4, 169.3, 182.9. Anal. Calcd For C 18 H 20 N 2 O 2 S: C, 65.83; H, 6.14; N, 8.53. Found: C, 66.19; H, 6.20; N, 8.62. 1-(3-Dimethylaminopropyl)-3-phenyl thiourea (4.15). Yellow needles (from EtOAc/Hexanes), 97%, mp 99100 o C. 1 H NMR (CDCl 3 ) 1.651.72 (m, 2H), 1.88 (s, 6H), 2.38 (t, J = 5.7 Hz, 2H), 3.74 (br s, 2H), 7.237.29 (m, 3H), 7.39 (t, J = 7.8 Hz, 2H), 8.00 (br s, 1H), 8.82 (br s, 1H). 13 C NMR (CDCl 3 ) 24.2, 44.5, 47.0, 59.0, 115.0, 125.6, 126.6, 129.2, 129.5, 136.8, 180.3. Anal. Calcd For C 12 H 19 N 3 S: C, 60.72; H, 8.07; N, 17.70. Found: C, 60.40; H, 8.01; N, 17.72.
49 1-Benzyl-3-(3-imidazol-1-ylpropyl)thiourea (4.16). Colorless oil, 89%. 1 H NMR (CDCl 3 ) 1.962.06 (m, 2H), 3.48 (q, J = 5.7 Hz, 2H), 3.89 (t, J = 6.6 Hz, 2H), 4.65 (d, J = 3.6 Hz, 2H), 6.86 (s, 2H), 7.19 (s, 1H), 7.267.33 (m, 7H). 13 C NMR (CDCl 3 ) 30.3, 41.2, 44.3, 48.0, 119.1, 127.4, 127.5, 128.6, 128.7, 136.8, 137.5, 183.0. Anal. Calcd For C 14 H 18 N 4 S: C, 61.28; H, 6.61; N, 20.42. Found: C, 60.93; H, 6.79; N, 20.02. 1-Benzothiazolyl-3-methyl-3-(butyl)thiourea (4.17). Yellow powder (from EtOAc/Hexanes), 68%, mp 114 o C. 1 H NMR (DMSO-d 6 ) 0.92 (t, J = 7.2 Hz, 3H), 1.22 (d, J = 6.6 Hz, 3H), 1.32.43 (m, 2H), 1.48.67 (m, 2H), 4.30.39 (m, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.41 (t, J = 6.9 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.90 (d, J = 7.8 Hz, 1H), 9.84 (br s, 1H), 11.74 (br s, 1H). 13 C NMR (DMSO-d 6 ) 13.8, 18.6, 19.7, 37.6, 49.8, 119.1, 121.7, 123.6, 126.2, 129.6, 161.5, 178.1. Anal. Calcd For C 13 H 17 N 3 S 2 : C, 55.88; H, 6.13; N, 15.04. Found: C, 55.20; H, 5.99; N, 15.04.
50 CHAPTER 5 SYNTHESIS OF 3,3-DIARYLPYRROLIDINES FROM DIARYL KETONES 5.1 Introduction Nitrogen-containing five membered rings are the basis of many natural and bioactive products [96JACS8266]; thus, these molecules are interesting synthetic targets. 3,3-diaryloxindoles exhibit antibacterial, antiprotozoal and antiinflammatory activities [98JOC4481]. Succinimides and hydantoins show antimuscarinic and anticonvulsant activity [97BMCL979] with the 3,3-diphenyl derivatives of these compounds being particularly potent anticonvulsants [51JOC4895]. For all the above-mentioned compounds, there is a notable trend that the 3,3-diaryl derivatives are more biologically important. Pyrrolidines are another important class of bioactive molecules shown to inhibit glycosidases [87ARB497, 92G199]. However, despite extensive study [88TL573, 90TL1741, 93T10793] there are hardly any reports in the literature on the general synthesis of 3,3-diarylpyrrolidines. Methods to 3,3-diarylpyrrolidines reported in the literature include the preparation of 3,3-diphenylpyrrolidine from: i) diarylacetonitriles [53JACS2986] (Scheme 1-11), ii) 4-phenoxyor 4-bromo-2,2-diphenylbutylamine hydrochloride [55JACS1083], and iii) 4-amino-3,3-diphenylbutan-1-ol hydrochloride [58JACS2519] (Scheme 1-13). Considering the significant biological importance of pyrrolidines and their derivatives [97TL2677, 98JOC4481], we have investigated synthesis of their 3,3-diaryl derivatives from readily available benzophenones and herein report the results of our studies. 50
51 5.2 Results and Discussion Condensation of benzophenone 5.1a with ethyl cyanoacetate under Knoevenagel conditions was carried out following a literature procedure [50JOC381] with a slight modification (use of a three-fold excess of ammonium acetate catalyst) to afford ethyl [2-cyano-3-phenyl-3-(4-trifluoromethylphenyl)]acrylate 5.2a in 57% yield. Under this methodology, other diaryl ketones were also reacted with ethyl cyanoacetate to yield the corresponding diaryl acrylates 5.2bg and 5.2i in moderate to good yields. NMR spectra of all diaryl acrylates (except for 5.2i) indicated the presence of E and Z isomers in CDCl 3 solution (Figure 5-1, 1 H NMR of 5.2b) (Figure 5-2, 13 C NMR of 5.2b). Figure 5-1. 1 H NMR of ethyl [2-cyano-3-phenyl-3-(4-methoxyphenyl)]acrylate (5.2b).
52 Figure 5-2. 13 C NMR of ethyl [2-cyano-3-phenyl-3-(4-methoxyphenyl)]acrylate (5.2b). Full substitution of the double bond rendered the determination of the isomer ratio difficult and precluded clear assignment of each signal to the respective isomer. Since racemic mixtures of 3,3-diarylpyrrolidines were the synthetic targets, isomer mixtures of diaryl acrylates 5.2 were not separated, but taken for further reactions. As noted above, diarylacrylate 5.2i derived from pyridyl phenyl ketone exists as a single isomer in CDCl 3 as seen from the 1 H NMR (Figure 5-3).
53 Figure 5-3. 1 H NMR of ethyl (2-cyano-3-phenyl-3-pyridinyl)acrylate (5.2i). The subsequent conversion of 5.2a into 2,2-diphenylsuccinic acid 5.4a through the dicyanoester 5.3a was achieved through hydrolysis and decarboxylation [50JOC381]. Succinic acid 5.4a was cyclized to the anhydride 5.5a by treatment with acetyl chloride. Subsequent reaction of 5.5a with benzhydryl amine gave the succinimic acid 5.6a, which was cyclized to succinimide 5.7a in refluxing acetic anhydride (Scheme 5-1) [51JOC4895]. Other succinimides 5.7bd were prepared following this procedure. These were characterized by 1 H and 13 C NMR and were directly used for the reduction without further analytical characterization.
54 EtCO2CH2CNNH4OAc, C6H6 KCN -CO2RR COOHCOOH1O R R 1 R R CO2EtNC1 R R CO2EtCNNC1 H2SO4/AcOH/H2O 5.1 5.2 5.3 5.4 AcCl R NH2AcONa/Ac2O222 O O O R R 1 O NH HOOCR R R 1 N O O R R R 1 N R R R 12NaBH4/I2 5.5 5.6 5.7 5.8 a a Preparation of compounds 5.8 by reduction of succinimic acids 5.7 was carried out by Dr. Satheesh Nair. Scheme 5-1. Preparation of 3,3-diarylpyrrolidines. 2-Cyano-3,3-diarylacrylates, 5.2e and 5.2i, prepared from the corresponding benzophenones were treated with KCN and the intermediate dicyano derivatives obtained were subjected to acid hydrolysis. However, in these cases, isolation of the expected acids was not possible. In addition to the normal hydrolytic treatment (H 2 SO 4 /H 2 O/AcOH), attempts to isolate the acids 5.4 were made using HCl, but these were conducted without success. Other work up modifications such as neutralization of pH also did not aid in isolation of the succinic acids 5.4e and 5.4i. Succinimic acid 5.6f, derived from 4-nitrobenzophenone and aniline, failed to ring close under the conditions applied. Apart from our normal procedure, neat heating of 5.6f at 150 o C was tried, which led to a complex mixture that could not be characterized. Whereas, anthrone and o-chloro benzophenone failed to undergo the condensation with ethyl cyanoacetate, o,o'-dichlorobenzophenone did react, surprisingly, but the isolated yield (<10%) of 5.2g was insufficient to proceed to subsequent steps.
55 Dr. Nair carried out reduction of succinimides to the final pyrrolidine by treatment with BH 3 THF, which was generated in situ from NaBH 4 and I 2 following the method by Periasamy [92T4623]. Thus, refluxing 5.7a with an excess of BH 3 THF, generated from NaBH 4 and I 2 for 12h afforded 65% of 3-phenyl-3-(4-trifluoromethylphenyl)pyrrolidine 5.8a (Scheme 5-2). Other pyrrolidone diones 5.7b and 5.7c also reacted similarly giving the corresponding pyrrolidines 5.8b and 5.8c in reasonably good yields. Table 5-1. 3,3-Diarylpyrrolidines prepared and the intermediates. Percentage isolated yield Entry R R 1 R 2 5.2 5.4 5.7 5.8* a p-F 3 CC 6 H 4 Ph (Ph) 2 CH 57 b 70 72 b p-MeOC 6 H 4 Ph CF 3 CH 2 62 b 53 72 c Ph p-Br-C 6 H 4 PhCH 2 87 b 67 59 d 2-Naphthyl Ph t-Bu 35 b 63 e p-Me 2 NC 6 H 4 Ph 69 a f p-O 2 NC 6 H 4 Ph Ph 42 b a g o-ClC 6 H 4 o-ClC 6 H 4 10 h o-ClC 6 H 4 Ph a i 4-Pyridyl Ph 30 a j Anthrone a (a) No reaction observed, (b) Crude product used in the next step without purification, Product obtained by Dr. Satheesh Nair. 3-Phenyl-3-(2-naphthyl)-1-tert-butylpyrrolidine-2,5-dione 5.7d was prepared starting from 2-naphthyl phenyl ketone in 61% yield. When Dr. Nair carried out the reduction of 5.7d using BH 3 THF, only the mono reduced product 5.9 was isolated in 89% yield (Scheme 5-2).
56 Use of a large excess (10 eq.) of the reagent and prolonged refluxing did not give the expected pyrrolidine. When Dr. Nair attempted reduction using LiAlH 4, the result was complete decomposition of the material. This could probably be due to two factors: 1) the steric hindrance by the bulky t-butyl group and (2) the reduced electrophilicity of the amide carbonyl by the electron donating t-butyl group. N Ph O O N Ph O BH3.THF 5.7h 5.9 Scheme 5-2. Mono-reduction of succinimide 5.7h. (Reaction conducted by Dr. Nair) 5.3 Conclusion Although pyrrolidines are a well-known class of bioactive heterocycles, few methods have been reported for the synthesis of 3,3-diarylpyrrolidines. Of those reported methods, none are general: these routes require the use of difficult-to-access or non-commercially available starting materials, such as diarylacetonitriles, 4-phenoxyor 4-bromo-2,2-diphenylbutylamine hydrochloride, or 4-amino-3,3-diphenylbutan-1-ol hydrochloride; involve steps that limit tolerance of functionality (e.g., pyrolysis); and only one limited method ([4 +2] cycloadditions of nitroalkenes and activated alkenes) provides 3,3-diarylpyrrolidines in moderate yields. In comparison, we have elaborated a general synthesis of 3,3-diarylpyrrolidines from readily available benzophenones. Benzophenones with electron withdrawing as well as electron donating substituents could be used effectively for the preparation of the
57 respective succinic acids. However, under our specific acidic hydrolytic conditions, the use of benzophenones containing basic nitrogens is not recommended. Generally, while any primary amine could be used for the preparation of pyrrolidones 5.7, the final reduction restricts the use of amines like t-butylamine, which offers significant steric hindrance. Given the above-described caveats, this procedure has proven itself useful for the preparation of 3,3-diarylpyrrolidines. 5.4 Experimental Section Melting points were determined using a Bristoline hot-stage microscope and are uncorrected. 1 H (300 MHz) and 13 C (75 MHz) NMR spectra were recorded on a 300 MHz NMR spectrometer in chloroform-d solution. Column chromatography was performed on silica gel (230400 mesh). Elemental analyses were performed on a Carlo Erba-1106 instrument. 5.4.1 General Procedure for the Preparation of 2-Cyano-3,3-diarylacrylates 5.2ai. Diarylketone (50 mmol) was taken in benzene (50 mL) along with ethyl cyanoacetate (50 mmol). Ammonium acetate (150 mmol) was added in 2h intervals (50 mmol each time) and the mixture was refluxed for 24h with azeotropic water removal. The reaction mixture was cooled and washed with water (3x100 mL) followed by saturated solution of sodium chloride (100 mL). The organic layer was dried over sodium sulfate, concentrated and the crude mixture was purified by crystallization. Ethyl (2-cyano-3-(4-trifluoromethylphenyl)-3-phenyl)acrylate (5.2a). Obtained as a colorless liquid (57%, E/Z ~50:50). 1 H NMR 1.051.09 (m, 6H), 4.064.13 (m, 4H), 7.06 (d, J = 7.8 Hz, 4H), 7.20.39 (m, 6H), 7.15 (d, J = 7.8 Hz, 4H), 7.567.62 (m, 4H). 13 C NMR 13.6, 62.4, 105.6, 116.1, 121.7, 125.1, 125.2, 125.3,
58 125.5, 125.6, 128.4, 128.7, 129.1, 129.3, 130.0, 130.4, 130.7, 131.7, 132.5, 133.0, 137.5, 137.7, 141.6, 161.9, 162.1, 167.0. Ethyl (2-cyano-3-(4-methoxyphenyl)-3-phenyl)acrylate (5.2b). Obtained as a yellow liquid (62%, E/Z ~50:50) 1 H NMR 0.98 (t, J = 7.2 Hz, 3H), 1.19 (t, J = 7.2 Hz, 3H), 3.35 (s, 3H), 3.71 (s, 3H), 3.98 (q, J = 7.2 Hz, 2H), 4.12 (q, J = 7.2 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 8.7 Hz, 2H), 7.267.40 (m, 5H). 13 C NMR 13.4, 13.6, 24.4, 55.1, 55.2, 61.6, 62.5, 101.4, 113.1, 113.3, 113.6, 117.3, 127.8, 128.1, 129.1, 129.9, 130.0, 130.2, 130.3, 131.1, 131.6, 132.3, 138.7, 162.8, 168.7. Ethyl (2-cyano-3-(4-bromophenyl)-3-phenyl)acrylate (5.2c). Obtained as a yellow powder (87%, E/Z ~50:50) mp 89-90 o C. 1 H NMR 1.11.22 (m, 6H), 4.114.22 (m, 4H), 7.01.04 (m, 2H), 7.13.30 (m, 6H), 7.357.57 (m, 1H). 13 C NMR 13.6, 13.7, 62.2, 62.3, 104.2, 111.2, 116.6, 124.9, 126.2, 126.8, 128.3, 128.5, 129.2, 130.1, 130.4, 130.5, 131.4, 131.6, 131.8, 136.9, 137.3, 137.7, 137.9, 146.4, 162.2, 162.3. Ethyl (2-cyano-3-naphthyl-3-phenyl)acrylate (5.2d). Obtained as yellow crystals (35%, E/Z ~50:50) mp 8990 o C. 1 H NMR 1.07 (t, J = 7.2 Hz, 3H), 1.15 (t, J = 7.2 Hz, 3H), 4.15 (m, 4H), 7.187.24 (m, 2H), 7.367.64 (m, 14H), 7.777.96 (m, 8H). 13 C NMR 13.6, 62.1, 116.9, 117.0, 126.3, 126.4, 126.7, 126.8, 127.5, 127.6, 127.7, 127.8, 128.1, 128.2, 128.4, 128.5, 128.9, 129.3, 129.5, 130.3, 130.4, 131.1, 131.4, 132.4, 133.8, 134.3, 135.5, 135.9, 138.3, 138.6, 162.6, 169.1. Ethyl (2-cyano-3-(4-N,N-dimethylaminophenyl)-3-phenyl)acrylate (5.2e). Obtained as pale brown crystals (ethanol) (69%) mp 128129 o C. 1 H NMR 1.12 (t, J = 3.3 Hz, 3H), 4.10 (q, J = 3.3 Hz, 2H), 6.606.64 (m, 2H), 7.187.41 (m, 7H). 13 C NMR
59 13.7, 39.9, 61.4, 110.7, 118.9, 124.6, 127.8, 129.6, 130.8, 133.1, 139.7, 152.4, 152.7, 163.7. Ethyl (2-cyano-3-(4-nitrophenyl)-3-phenyl)acrylate (5.2f). Obtained isomers as yellow crystals (ethanol, 42%, E/Z ~50%) mp 124 o C. 1 H NMR 1.22 (t, J = 7.2 Hz, 3H), 4.19 (q, J = 7.2 Hz, 2H), 7.137.58 (m, 7H), 8.248.30 (m, 2H). 13 C NMR 13.6, 13.7, 62.6, 105.7, 115.8, 115.9, 123.4, 123.7, 128.5, 128.8, 129.0, 129.7, 129.8, 130.9, 131.9, 137.0, 137.2, 144.2, 144.8, 148.4, 148.9, 161.0, 161.7. Ethyl (2-cyano-3-(4-pyridyl)-3-phenyl)acrylate (5.2i). Obtained as yellow crystals (ethanol) (30%), mp 9597 o C. 1 H NMR 1.20 (t, J = 7.2 Hz, 3H), 4.20 (q, J = 7.2 Hz, 2H), 7.327.52 (m, 6H), 8.44 (d, J = 1.2 Hz, 1H), 6.67 (dd, J = 1.5, 4.90 Hz, 1H). 13 C NMR 13.7, 62.5, 116.3, 123.0, 128.8, 130.0, 134.6, 136.5, 137.6, 149.0, 151.0, 162.0, 165.9. 5.4.2 General Procedure for the Preparation of 2,2-Diaryl-pyrrolidine-2,5-diones 5.7 i) Preparation of dicyanoesters 5.3. The appropriate Knoevenagel condensation product 5.2 (50 mmol) was dissolved in 95% ethanol (50 mL) and added dropwise to a solution of KCN (100 mmol) in water (20 mL). The resulting mixture was heated and stirred at 90 o C for 2h. After cooling, conc. HCl was added until the pH of the solution became acidic (pH 3) to litmus. In most of the cases, the dicyano derivative precipitated out (if not, it was extracted with ethyl acetate). The precipitate was washed with water (3x50 mL) and was used without any further purification for subsequent steps. ii) Preparation of diaryl succinic acids 5.4. The obtained dicyanoester 5.3 (50 mmol) was dissolved in acetic acid (30 mL) and refluxed with 80% H 2 SO 4 (30 mL) for 12h. Cooled and poured into crushed ice, the resulting solid was filtered and washed with
60 water (3x50 mL). This was directly taken in 20% KOH (50 mL) and refluxed for 72 h. The reaction mixture was cooled and acidified with con. HCl (until the pH of the solution became acidic (pH 3) to litmus) to precipitate the diaryl succinic acid (~4050% yields), which was filtered, washed with water (3x100 mL) and dried in oven. No purification was attempted and the acid was used directly for subsequent reactions. iii) Preparation of succinic anhydrides 5.5. The succinic acid 5.4 (20 mmol) was refluxed with acetyl chloride (10 mL) for 2h. The resulting mixture was concentrated under vacuum and the residue dissolved in ethyl acetate (50 mL). The organic layer was washed with water (3x50 mL), dried over sodium sulfate and concentrated to obtain the anhydride in quantitative yield (from the acid). iv) Preparation of 3,3-diaryl-pyrrolidine-2,5-diones 5.7. The anhydride 5.5 (10 mmol) was treated with the corresponding primary amine (10 mmol) in refluxing acetone (20 mL) for 2h, concentrated, and the succinimic acid 5.6 was taken in acetic anhydride (20 mL) with sodium acetate (10 mmol). The mixture was heated at 70 o C for 2h. Acetic anhydride was removed under vacuum and the crude material was purified by column chromatography over silica gel using ethyl acetate/hexane (95:5). Yields of 5.7ad refer to the yield from the corresponding diarysuccinic acids 5.4ad. 3-Phenyl-3-(4-trifluoromethylphenyl)-1-benzhydrylpyrrolidine-2,5-dione (5.7a). Obtained as a colorless oil (70%) 1 H NMR 3.41 (d, J = 18.2 Hz, 1H), 3.53 (d, J = 18.3 Hz, 1H), 6.61 (s, 1H), 7.207.36 (m, 17H), 7.54 (d, J = 8.4 Hz, 2H). 13 C NMR 44.5, 56.7, 58.8, 125.5, 125.6, 125.7, 127.3, 127.8, 127.9, 128.0, 128.3, 128.4, 128.4, 129.0, 130.0, 137.0, 137.1, 140.7, 145.4, 173.8, 177.1.
61 3-Phenyl-3-(4-methoxyphenyl)-1-trifluoroethylpyrrolidine-2,5-dione (5.7b). Isolated as a colorless oil (53%) 1 H NMR 3.47 (d, J = 18.3 Hz, 1H), 3.55 (d, J = 18.3 Hz, 1H), 3.78 (s, 3H), 4.17 (d, J = 8.7 Hz, 1H), 4.23 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 9.0 Hz, 2H), 7.187.37 (m, 7H). 13 C NMR 39.5, 39.9, 44.8, 114.2, 127.1, 127.7, 128.4, 128.9, 132.6, 141.4, 159.0, 173.4, 177.2. 3-Phenyl-3-(4-bromophenyl)-1-benzylpyrrolidine-2,5-dione (5.7c). Isolated as a pale yellow oil (67%). 1 H NMR 3.35 (d, J = 18.3 Hz, 1H), 3.43 (d, J = 18.3 Hz, 1H), 4.71 (s, 2H), 7.10 (d, J = 8.7 Hz, 2H), 7.167.19 (m, 2H), 7.247.31 (m, 8H), 7.40 (d, J = 8.7 Hz, 2H). 13 C NMR 42.7, 44.6, 56.4, 121.8, 127.1, 127.7, 128.0, 128.4, 128.6, 128.8, 129.1, 131.7, 135.3, 140.5, 141.1, 174.1, 177.5. 3-Phenyl-3-naphthyl-1-tert-butylpyrrolidine-2,5-dione (5.7d). Isolated as a colorless oil (63%). 1 H NMR 1.62 (s, 9H), 3.39 (d, J = 18.3 Hz, 1H), 3.46 (d, J = 18.3 Hz, 1H), 7.277.33 (m, 6H), 7.467.49 (m, 2H), 7.747.81 (m, 4H). 13 C NMR 28.4, 45.1, 56.5, 58.9, 125.7, 125.9, 126.4, 127.4, 127.5, 128.2, 128.6, 128.7, 132.3, 132.9, 139.2, 142.1, 175.8, 179.2.
62 CHAPTER 6 SYNTHESIS AND CHARACTERIZATION OF BLOWING AGENTS 6.1 Introduction The rubber industry employs blowing agents (gas generating agents), such as dinitropentamethylenetetramine and p-tolysulfonylhydrazine, in the production of microcellular rubber [85PRPA281]. Azodicarbonamide, Exocerol 232, and Hyderocerol BIH are blowing agents (now replacing CFCs) that are commonly used in the plastics industry to provide polymer foams [99CP35, 02HK427, 02JCED554]. Another significant application of blowing agents is their use in propellant formulations [95JPP838, 97HC153, 03JTAC931]. In a collaborative effort to develop novel munition formulations, we have investigated the synthesis and characterization of energetic compounds to provide new blowing agents. The US Army has previously applied blowing agents (e.g. 2,4-dinitrophenylhydrazine) as energetic material additives in explosive mixtures to modify general munition properties. Inclusion of blowing agents that display separate isotherms from the other components of explosive mixtures is a means of tempering the violence of explosions. For a particular Army formulation containing trinitrotoluene (TNT) and cyclotrimethylenetrinitramine (RDX), inclusion of blowing agents possessing a differential scanning calorimetry (DSC) indicated decomposition of ~180 o C provides a means of bursting open any confinement before reaction of the main constituents; thus mitigating cook off violence. 62
63 Of particular interest are blowing agents with the following characteristics: quick generation of gas, mp higher than 75 o C, stable, and with DSC that indicates gas evolution at 140 o C. There are a few stable blowing agents 6.1.5 (utilized in the plastics and rubber industry) reported to possess higher melting points and suitable DSCs (Figure 6-1) [77JTA75, 77PT97, 99PEP168, 02HK427, 04ACIE4924]. Among these compounds, commercially available ADCA 6.1, Nitrosan 6.2, and DNPT 6.4 were tested by DSC-TG. A non-commercially available compound with a reported DSC-indicated decomposition (PETN 6.5) was also selected for synthesis and testing. 4-Phenyltetrazole (PT) 6.3 was previously tested by the Army and found unsuitable for application as a blowing agent in RDX formulations; thus, further characterization of 6.3 was not merited. NN O NH2 NH2 O N Me O NON O Me NO NHNNN ONO2 ONO2 ONO2 O2NO N N N N ONNO (mp 200-206 oC) 6.1 DSC 225 oC (mp 118 oC) DSC 145 oC 6.2 6.3 DSC 195 oC (mp 215 oC) 6.4 DSC 221-243 oC DNPT Nitrosan ADCA PT 6.5 DSC 178 oC PETN (mp 141 oC) Figure 6-1. Blowing agents with reported Differential Scanning Calorimetry (DSC) values. In the literature, there are also several syntheses of energetic additives 6.6.9 that possess the higher melting points, but do not have reported DSCs values (Figure 6-2). In order to obtain DSC data for the evaluation of the suitability of energetic additives
64 6.6.9 as blowing agents, we have developed reasonable syntheses that can potentially be scaled to provide 50100 g quantities of these compounds. Additionally, we have taken thermogravimetric analyses (TG) of compounds 6.6.9 to provide supplementary data for comparison with DSC analyses. O S O O S O O N3N3 S S O O S O O N3N3 S S O O NH NH2 S NH O O NH2 Me S O O NH O NH NH2 6.6 6.7 (mp 97 98 oC) (mp 163 oC) 6.8 6.9 (mp 200 oC) (mp 75 77 oC) Figure 6-2. Literature blowing agents without reported DSC values. 6.2 Results and Discussion 6.2.1 Thermoanalyses of Blowing Agents with Reported Decompositions. DSC-TG analysis of (E)-1,2-diazenedicarboxamide (ADCA) (6.1) shows concurrent mass loss and positive heat flow starting at 201 o C (Figure 6-3). The loss in mass stabilizes at 235 o C just after the exothermal peak at 232 o C. A net mass loss of 60% is recorded and a heat flow of +4 mW is observed for this process. (E)-1,2-diazenedicarboxamide (6.1) does not fully meet the Armys criteria of a DSC-indicated decomposition occurring in the range of 140 o C; thus further testing of 6.1 for the specific application as a blowing agent for RDX formulations was not carried out.
65 Figure 6-3. Thermoanalyses of (E)-1,2-diazenedicarboxamide (6.1). TG plot (dotted line); DSC plot (solid line). Nitrosan (6.2) shows a sharp decomposition slope (beginning at 119 o C) that corresponds with a huge exotherm (+10 mW), which peaks at 126 o C (Figure 6-4). The temperature at which gas is generated occurs lower than the desired range of 140 o C to 200 o C; thus nitrosan is also not a suitable blowing agent under the given specification of DSC ~180 o C. However, compound 6.2 may prove useful for other Army applications due to its highly exothermic decomposition as indicated by DSC-TG.
66 Figure 6-4. Thermoanalyses of Nitrosan (6.2). TG plot (dotted line); DSC plot (solid line). Upon heating, dinitrosopentaethylenetetramine (DNPT) (6.4) loses mass beginning at 195 o C (Figure 6-5). At 207 o C, the onset of rapid decomposition occurs and is concurrent to a sharp increase in positive heat flow (+12 mW). Initial loss of NO followed by decomposition of the ring system is reflected in the double peaks in the measurement of heat flow and the change to a more gradual rate in mass loss (total loss 95%) after 208 o C. DNPT (6.4) is a good blowing agent candidate and has been sent to the Army for additional testing, such as friction and shock sensitivity determination.
67 Figure 6-5. Thermoanalyses of dinitrosopentaethylenetetramine (6.4). TG plot (dotted line); DSC plot (solid line). Of the commercially available compounds with reported DSC values, only DNPT (6.4) met the requirement of DSC-indicated gas evolution in the range of 140 o C. Further testing of the physical characteristics of DNPT (6.4) are required to definitively determine the suitability of 6.4 as a blowing agent for RDX formulations; however, initial test results for shock sensitivity are promising, for 6.4 is insensitive to shock when struck with a metal weight. 6.2.2 Synthesis and Thermoanalyses of Pentaerythritol Tetranitrate (PETN) (6.5). Synthesis of PETN (6.5) was accomplished in near quantitative yield (99%) using concentrated nitric (90%) and sulfuric acid (96%) (Scheme 6-1). Use of concentrated
68 sulfuric acid is critical; it has been reported that using 80 % sulfuric acid leads instead to the isolation of the pentaerythritol trinitrate as the major product in 52% yield [55JACS751]. Scale up of the nitration using concentrated sulfuric acid is facile; Camp et al. [55JACS751] have previously described kilogram scale synthesis of PETN (6.5). ONO2 ONO2 ONO2 O2NO OH OH OH OH HNO3 90%H2SO4 96% 6.10 6.5 Scheme 6-1. Synthesis of pentaerythritol tetranitrate (6.5). Figure 6-6. Thermoanalyses of pentaerythritol tetranitrate (6.5). DSC analysis preformed on 2.9925 mg of PETN (1) showed a sharp loss in mass (52 %) at 175 o C and also indicated a large exothermic peak (+32 mW) at ~180 o C
69 (Figure 6-6). Calculation of the generated heat flow per mmol is determined to be +3.38 W/mmol. These observations indicate that PETN (6.5) is an excellent blowing agent candidate. 6.2.3 Synthesis and Thermal Testing of Non-commercially Available Agents 6.6.9. Since literature search produced only a few compounds with DSC decompositions that matched our requirements for blowing agents, screening of promising energetic materials without reported DSC values was necessary. Synthesis of four energetic materials possessing sulfonyl and azide or hydrazine moieties were carried out and analyzed by TG. 220.127.116.11 Blowing Agents Derived from Disulfonyl Dichlorides. Both disulfonyl azides 6.6 and 6.7 [88ZAK1128] and disulfonylhydrazine 6.9 [84IJCB962] can be prepared from the respective disulfonyl dichlorides 6.12 and 6.14, which are accessible from diphenyl ether (6.11) and diphenyl sulfide (6.13) (Schemes 6-2, 6-3, and 6-4). O S O O S O O N3N3 O O S Cl O O S O O Cl NaN3 ClSO3H 6.11 6.12 (74%) 6.6 (83%) Scheme 6-2. Synthesis of disulfonyl azide 6.6.
70 Starting from diphenyl ether (6.11), disulfonyl dichloride 6.12 was prepared in 74% yield (Scheme 6-2). Reaction of 6.12 with sodium azide provided disulfonyl azide 6.6 in 83% yield. TG data (obtained with 1.755 mg of 6.6 heating from 50 o C with a rate of 10 o C/min.) show as temperature increases, a gradual decline in mass that begins from ~ 140 o C and ends at ~ 175 o C with a total loss in mass of 14% corresponding to the expected loss of two molecules of N 2 per molecule of blowing agent 6.6 (Figure 6-7). Since off-gassing falls near 180 o C, 6.6 is a good candidate for further DSC testing and Army analysis. Figure 6-7. Thermogravimetric analyses of compounds 6.6.8. 6.7 6.6 6.8 Disulfonyl azide 6.7 was obtained in 18% yield (Scheme 6-3) from the disulfonyl dichloride 6.14, prepared from diphenyl sulfide (6.13) in 40% yield. The TG run conducted with 4.356 mg of disulfonyl azide 6.7 closely resembles that of 6.6 (Figure 6
71 7). The loss of mass (12%, roughly 2 molecules N 2 per molecule 6.7) was gradual starting around 140 o C and ending at ~170 o C. S S O O S O O N3N3 S S S Cl O O S O O Cl NaN3 ClSO3H 6.14 (41%) 6.7 ( 18%) 6.13 Scheme 6-3. Preparation of disulfonyl azide 6.7. Disulfonylhydrazide 6.8 was obtained in 72% yield from reaction of disulfonyl chloride 6.14 with hydrazine (Scheme 6-4). In determining the melting point, it was observed that 4,4'-thiobis(benzenesulfonyl hydrazide) (6.8) simultaneously melts and off-gasses at 162 o C. This rapid off-gassing, however, was not as strongly evident in the TG, which displays only a slightly more rapid decrease in mass with heating (a 22% loss over a range of 130 o C) as compared to 6.6 and 6.7 (Figure 6-7). To resolve these questions, further analysis of 6.8 will be carried out by the Army. S S O O NH NH2 S NH O O NH2 S S Cl O O S O O Cl N2H4, EtOH 6.14 6.8, 72% Scheme 6-4. Preparation of disulfonylhydrazide 6.8. 18.104.22.168 N-(Hydrazinocarbonyl)-4-methylbenzenesulfonamide (6.9). A facile route to N-(hydrazinocarbonyl)-4-methylbenzenesulfonamide (6.9) proceeded via the intermediate, N-methoxycarbonyl-(4-methylphenyl)sulfonamide (6.16) [86IJCB934], prepared from p-tolylsulfonamide (6.15) (Scheme 6-5) [68JOC4442].
72 Intermediate 6.16 was prepared in 69% yield by the reaction of ethyl chloroformate with p-tolylsulfonamide in the presence of triethylamine. Conversion of the carbamate 6.16 to 6.9 (92% yield) by reaction with hydrazine monohydrate in refluxing ethanol was successful (Scheme 6-5). Me S O O NH O NH NH2 Me S O O NH2 Me S O O NH O OEtN2H4, EtOHCl O OEt 6.15 6.16 6.9 reflux +Et3N MeCN Scheme 6-5. Synthesis of N-(hydrazinocarbonyl)-4-methylbenzenesulfonamide (6.9). TG analysis performed on N-(hydrazinocarbonyl)-4-methylbenzenesulfonamide (10) showed two distinctive regions, an area starting around 100 o C indicating loss of hydration (hydrazine ureas are hydroscopic) and a second area showing a broad decline in mass ~200 o C due to decomposition. Lack of a sharp decomposition profile and potential difficulties with storage of 6.9 concerning its hydroscopic nature have ruled out its utility as a blowing agent for incorporation into RDX munition formulations. 6.3 Conclusion Nine energetic additives 6.1.9 were evaluated for use as blowing agents. Based on DSC-TG and TG results, PETN (6.5) and disulfonyl azides 6.6.8 are the most promising candidates, for they show quick gas-generation, possess melting points higher than 75 o C, and decompose in the range of 140 o C. Commercially available DNPT (6.4) possesses a higher DSC value (near 200 o C); however, its sharp decomposition profile and high energy output per mole merit further investigation of its suitability for inclusion in RDX formulations. Further Army testing of these agents in comparison with
73 RDX is required to determine whether or not these compounds maintain separate isotherms from the main explosive mixture and can be employed as blowing agents. Unfortunately, although commercially available (E)-1,2-diazenedicarboxamide (6.1) and Nitrosan (6.2) are insensitive to shock and quickly generate gas upon decomposition, these agents were found to decompose at temperatures outside of the desired range. Likewise, sulfonamide 6.9 was found unsuitable due to its high decomposition temperature and concerns about its hydroscopic nature. While applications in these specific RDX formulations are ruled out for 6.1, 6.2, and 6.9, these agents may find other applications as energetic materials. The utility of the blowing agent candidates examined in this study is not limited only to their incorporation into RDX munitions, since their properties of stability, insensitivity to shock and friction, and moderate temperatures for onset of decomposition are also of value for propellant formulations and for the preparation of foam polymers. The thermoanalyses conducted for these blowing agents have provided valuable information previously unavailable to researchers in the area of energetic materials. 6.4 Experimental Caution! Although we have not experienced any problems in synthesizing or handling these compounds, proper safety precautions should be followed and these materials should be treated with extreme care. Melting points were determined using a Bristoline hot-stage microscope and are uncorrected. 1 H (300 MHz) and 13 C (75 MHz) NMR spectra were recorded on a 300 MHz NMR spectrometer in DMSO-d 6 or chloroform-d solution as indicated. THF was distilled from sodium-benzophenone ketal prior to use. Column chromatography was
74 performed on silica gel (300 mesh). Elemental analyses were performed on a Carlo Erba-1106 instrument. Thermogravimetric analyses were conducted with a PerkinElmer thermoanalyzer. DSC-TG analyses were performed on a Universal TA model #2960 SDT V3 instrument. 6.4.1 Synthesis of Pentaerythritol Tetranitrate (6.5). Pentaerythritol (4.80 g, 0.015 moles) was added to a mixture of 19.80 g of 90% concentrated nitric acid with an added trace of urea (0.03 g) cooled to 0 o C. Stirring was continued for 15 min., then 96% concentrated sulfuric acid (19.80 g) was added, and the reaction mixture was left to stir at 0 o C for 2h. The reaction mixture was poured onto ice, filtered and washed with water (400 mL). The precipitate was dissolved in 250 mL of acetone containing 0.75 g of ammonium carbonate by heating in a water bath at 50 o C. Ethanol and water were added to form a solvent mixture that was 7 parts acetone, 3 parts water and 2 parts ethanol from which pentaerythritol tetranitrate (6.5) was allowed to precipitate over 2h. Filteration and washing the precipitate with ethanol afforded a near quantitative yield (99%) of pentaerythritol tetranitrate (6.5) as white needles, mp 140 o C, (Lit. 17-[55JACS751] mp 141 o C). 1 H NMR (Acetone-d 6 / DMSO-d 6 ppm): 4.77 (s, 8H). 13 C NMR (Acetone-d 6 / DMSO-d 6 ppm): 68.6, 41.0. 6.4.2 Disulfonyl Dichloride Derivatives 6.6.8. 4-[4-(Chlorosulfonyl)phenoxy]benzenesulfonyl chloride (6.12). In a round bottom flask at room temperature, chlorosulfonic acid (20mL) was slowly added to neat diphenyl ether (6.11) (8.5 g, 0.05 mol). (Caution: reaction very exothermic) The reaction mixture was stirred at rt for 2 h. The mixture was then poured into ice water (200 mL),
75 and the crude disulfonyl dichloride collected by filtration and thoroughly washed with water. Drying under vacuum gave 6.12 as off-white powder in 74% yield, mp 126 o C. 1 H NMR (DMSO-d 6 ppm): 8.10 (d, J = 9.0 Hz, 4H), 7.30 (d, J = 9.0 Hz, 4H). 13 C NMR (DMSO-d 6 ppm): 157.6, 138.3, 127.5, 118.0. Elemental analysis: Theory: % C, 39.25; % H, 2.20; % N, 0. Found: % C, 38.88; % H, 2.06; % N, 0.01. Bis[4-(azidosulfonyl)phenyl] ether (6.6). To disulfonyl dichloride 6.12 (0.37g, 1 mmol) dissolved in acetone at 0 o C, was added sodium azide (0.16g, 2.4 mmol). Stirring was continued for 18 h with the reaction mixture allowed to slowly warm to rt. Water (100 mL) was added and the precipitate filtered and recrystallized from acetone/water to give the desired sulfonyl azide 6.6 as a colorless microcrystals in 83% yield, mp 84 o C (Lit. 13-[88ZAK1128] mp 97 o C). 1 H NMR (DMSO-d 6 ppm): 8.01 (d, J = 9.0 Hz, 4H), 7.25 (d, J = 9.0 Hz, 4H). 13 C NMR (DMSO-d 6 ppm): 160.6, 134.2, 130.3, 119.9. Elemental analysis: Theory: % C, 37.89; % H, 2.12; % N, 22.09. Found: % C, 38.00; % H, 1.95; % N, 21.40. 4,4'-Sulfanediyl-bis-benzenesulfonyl chloride (6.14). In a round bottom flask at room temperature, chlorosulfonic acid (4 mL, excess) was slowly added to neat diphenyl sulfide (6.13) (1.7 mL, 0.010 mol). (Caution: reaction very exothermic) The reaction mixture was stirred at rt for 4 h and then poured into ice water (200 mL). The crude disulfonyl dichloride was collected by filtration and thoroughly washed with water. Drying under vacuum gave 6.14 as a white powder in 41% yield, mp 149 o C.
76 1 H NMR (DMSO-d 6 ppm): 7.60 (d, J = 8.1 Hz, 4H), 7.28 (d, J = 8.1 Hz, 4H). 13 C NMR (DMSO-d 6 ppm): 147.2, 135.1, 130.0, 126.8. Elemental analysis: Theory: % C, 37.60; % H, 2.10; % N, 0. Found: % C, 37.60; % H, 1.94; % N, 0.01. 4,4'-Thiobis-benzenesulfonyl azide (6.7). To disulfonyl dichloride 6.14 (0.39g, 1 mmol) dissolved in acetone at 0 o C, was added sodium azide (0.16g, 2.4 mmol). Stirring was continued for 18 h with the reaction mixture allowed to slowly warm to rt. Water (100 mL) was added and the precipitate filtered and recrystallized from acetone/water to give the desired sulfonyl azide 6.7 as colorless microcrystals in 18% yield, mp 75 o C. 1 H NMR (DMSO-d 6 ppm): 7.93 (d, J = 8.4 Hz, 4H), 7.56 (d, J = 8.4Hz, 4H). 13 C NMR (DMSO-d 6 ppm): 142.7, 137.7, 131.4, 128.5. Elemental analysis: Theory: % C, 36.36; % H, 2.03; % N, 21.20. Found: % C, 36.47; % H, 1.84; % N, 20.20. 4,4'-Thiobis(benzenesulfonyl hydrazide) (6.8). The disulfonyl dichloride 6.14 (0.39 g, 1 mmol) was dissolved in ethanol at 0 o C. Hydrazine (0.1 mL, 5 mmol, 5 equiv.) was added dropwise and the reaction was stirred at 0 o C for 2 h. Then, ice water (50 mL) was added and the precipitate filtered to give crude product, which was recrystallized from ethanol providing colorless microcrystals in 72% yield, mp 162 o C, (Lit. 13-[88ZAK1125] mp 163 o C). 1 H NMR (DMSO-d 6 ppm): 8.16 (s, 2H), 7.88 (d, J = 8.7 Hz, 4H), 7.48 (d, J = 8.4 Hz, 4H), 3.63 (br s, 4H). 13 C NMR (DMSO-d 6 ppm): 139.3, 136.9, 130.4, 128.7. Elemental analysis: Theory: % C, 38.49; % H, 3.77; % N, 14.96.
77 Found: % C, 38.47; % H, 3.73; % N, 14.17. 6.4.3 Synthesis of N-(Hydrazinocarbonyl)-4-methylbenzenesulfonamide (6.9). N-Ethoxycarbonyl-(4-methylphenyl)sulfonamide (6.16). Triethylamine (14 mL, 0.1 mol) and the sulfonamide 6.15 (6.48 g, 0.04 mol) were dissolved in acetonitrile (40 mL) at rt. Ethyl chloroformate (5.7 mL, 0.06 mol) was slowly added over 5 min. The reaction mixture was left to stir at rt for 18h. Ethyl acetate (100 mL) was added, and a 5% solution of sodium bicarbonate (100 mL x 3) was used to wash the organic layer. The aqueous layers were collected, combined, and treated with concentrated HCl until congo red to Litmus test. The product precipitated from the acidified solution to provide N-ethoxycarbonyl-(4-methylphenyl)sulfonamide (6.16) in 69% yield as white cubes, mp 80 o C, (Lit. 16-[68JOC4442] mp 80 o C). 1 H NMR (CDCl 3 ppm): 7.93 (d, J = 8.4 Hz, 2H), 7.57 (s, 1H), 7.34 (d, J = 8.1 Hz, 2H), 4.13 (q, J = 7.8 Hz, 2H), 2.45 (s, 3H), 1.21 (t, J = 7.8 Hz, 3H). 13 C NMR (CDCl 3 ppm): 150.5, 145.0, 135.5, 129.5, 128.3, 63.0, 21.6, 14.0. N-(Hydrazinocarbonyl)-4-methylbenzenesulfonamide (6.9). A mixture of hydrazine monohydrate (0.10 g, 0.02 mol, 2 equiv.) and N-ethoxycarbonyl-(4-methylphenyl)-sulfonamide (6.16) ( 2.43 g, 0.01 mol) in ethanol (20 mL) and water (10 mL) was refluxed for 18 hours. The mixture was then concentrated in vacuo and the residue was crystallized from methanol to give 6.9 in 92 % yield as white microcrystals, mp 200 o C. 1 H NMR (CDCl3, ppm): 7.95 (d, J = 8.4 Hz, 2H), 7.75 (s, 1H), 7.43 (d, J = 8.1 Hz, 2H), 4.32 (m, 2H), 2.53 (s, 3H). 13 C NMR (CDCl 3 ppm): 190.5, 151.5, 146.0, 137.5, 129.8, 122.3, 20.6.
CHAPTER 7 CONCLUSION The aim of developing novel routes to target nitrogen and sulfur containing compounds possessing synthetic utility, biological activity, and desirable physical properties was achieved. The successful syntheses described herein employed convenient starting materials and mild conditions, and offered competitive alternatives to classical routes often with distinct advantages. Chapters 14 highlighted the versatility of synthetic methodologies employing the benzotriazolyl group as a selective auxiliary and masked synthon to carry out organic functional group transformations. Notably, the novel benzotriazole thioacylation and thiocarbamoylation reagents developed in the progress of this study were proven to be stable, easy to store, tolerant of functional diversity, and able to provide efficient conversions in high yields. Thiocarbamoylbenzotriazoles, which were shown to behave as isothiocyanate synthons and undergo reactions with a variety of amines under mild conditions provided asymmetrical thioureas (Chapter 4), which were previously problematic to obtain or inaccessible under previous methodologies. Logical extension of the methodology investigated in the synthesis of asymmetric thioureas led to the preparation of other benzotriazole-containing thioacylating reagents providing new routes to thioamides (Chapter 2) and thionoesters (Chapter 3). The common advantages of benzotriazole-assisted thioacylations over classical syntheses are access to novel compounds, simple purification procedures, and avoidance 78
79 of the use of unstable or h azardous reagents. These genera l and convenient procedures provided access to numerous novel thioamides, thionoesters, and asymmetric thioureas. In separate collaborative efforts with Merck (Chapter 5) and with the US Army (Chapter 6), we investigated routes to 3,3-diarylpyrrolidi nes and blowing agents. A new route to 3,3-diarylpyrrolidi nes was developed that u tilizes readily available benzophenones and provides good to moderate yields of diversely functionalized 3,3diarylpyrrolidines, which are biologically active scaffolds that can be potentially incorporated into new drugs. In the case of the investigation of bl owing agents, simple and convenient methodologies that allow scal e-up of syntheses were developed, the physical properties of five blowing agents were characterized, and evaluation of their decomposition profiles provided lead compounds for further testing as munition additives.
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91 BIOGRAPHICAL SKETCH Rachel Melissa Witek, ne Rachel Melissa Fuller, was born in Albany, Georgia, on January 2 nd 1981, to Kenneth Ray Fuller and Cheryl Lynn Fuller. Until the age of 12, she lived in Lee county, Georgia. The family moved to LaGrange, Georgia, in 1993. Two weeks after moving to LaGrange, Cheryl Lynn Fuller died in a car accident. After her junior year in high school, Rachel left for college early joining the Advanced Academy of Georgia at West Georgia State University. After one year as a jointly enrolled college-high school student and two years as an undergraduate in the honors program doing research under Professors Ben DeMayo (physics) and Victoria Geisler (organic chemistry), she graduated with a Bachelor of Arts in chemistry at age 20. In the fall of 2001, she began her PhD study in organic chemistry at the University of Florida as an Alumni Fellow working under the mentorship of Professor Alan Katritzky. In 2002, she married Rafal Piotr Witek, a PhD student in the Interdisciplinary Program of the Medical College of the University of Florida. 91