THE C}1ISTRY OF 1, 3, -OXAHIAZOL-2-ES SAND RELATED SYSTEMS.
MARION CATHERINE McKlE
Ph.D. University of Edinburgh, 1988.
CA (i)
ABSTRACT The reactions of nitrile sulphides, generated from
1, 3,Li-oxathiazol-2-ones, with various novel dipolarophiles are described. With O(-ketonitriles (R'COCN) reaction occurs exclusively at the nitrile function to give 5-acyl-1,2,4- thiadiazoles. Reaction with norbornene yields an exo-2- isothiazoline and the ability of nitrile sulphides to effect cis-trans isomerisation of alkenes is also demonstrated. 3-Arylisothiazoles have been prepared by two methods based on nitrile sulphide chemistry: reaction with norbornadiene gives the 4,5-unsubstituted isothiazole in one step. The mechanism is believed to involve formation of a 2-isothiazoline via 1,3-dipolar cycloaddition, followed by retro Diels-Alder extrusion of cyclopentadierie. Flash vacuum pyrolysis of 3-arylisothiazole- 4- and S- carboxylates and ii, S-dicarboxylates, which are synthesised from ethyl propiolate and diethyl acetylenedicarboxylate respectively, provides an alternative approach to Li, 5-unsubstituted isothiazoles. The cyclosubstitution reactions of 1,4,2-dithiazole-5-thiones with electron deficient nitriles have been examined. This provides a route to previously inaccessible dithiazolethiones. Two possible mechanisms are considered : a concerted process and a two step pathway involving an intermediate with a bridgehead hype rvalent sulphur. (ii)
The reaction of 1,3,4-oxathiazo1-2-ones with nucleophiles is described. Secondary amines give isolable thiohydror1amine derivatives, whereas primary amines afford amides, sulphur and ureas. Reactions with a variety of other nucleophiles are examined and all the results correlated with molecular orbital calculations. There are similar-considerations for 1,4,2.-dithiazol-5-(thi)ones and 1,4,2-dioxazol-5-(thi)ones. (iii)
Acknowledgements I would especially like to thank Dr. R.Michael Paton for his guidance and assistance over the years • I am also very grateful to the members of the technical staff in the department who run the various services, without whom this thesis would have been impossible. My thanks to P.Gregory, I.C.I. PLC, Organics Division, Blakely, for access to the molecular orbital calculations and Mrs J • Curria for her patience in typing this manuscript. Finally my thanks to the SERC for providing maintenance and funding for my studentship.
Post-graduate Lectures The following post-graduate lecture courses were attended
1uring 1984-87. Strategic Synthesis (R.Raxnage), 5 lectures. Medicinal Chemistry (I .0 .1. and Beecham Pharmaceuticals),
5 lectures. Carbohydrate Chemistry (R.Ramage), 5 lectures.
Mxnr Spectroscopy ( I.H. Sadler), S lectures. Medicinal Chemistry (P.G .Satumes), 5 lectures. Current Topics in Organic Chemistry (Various lecturers),
10 lectures. Departmental Seminars, three years attendance. (i'ir)
Declaration I declare that the research presented in this thesis is entirely my own work, which was carried out in Edinburgh between October 1984 and September 1987. (v)
C(TENTS Page
1 • 3NTR0DUCTI0N 1 1 1.1 The 10-dipole 1.2 The 1,3-dipolar cycloaddition reaction 2 6 1 .3 Frontier molecular orbital theory. 1 .4 Nitrile sulphides 8 1. 5 Generation of nitrile sulphides. 10 1.5.1 Photolytic generation 10 1.5.2 Thermal generation 12
1.5.2.1 Thermal elimination reactions 12 1.5.2.2. Thermal cycloreversion reactions iS 1.5.3 Oxidativediinerisation of thio&iides 18 1.6 Cycloaddition reactions of nitrile sulphides 20
1.6.1 .Acetylenes. 20
1.6.2 Olefins 21 1.6.3 Nitriles 25 1.6.4 Imines 27 1.6.5 Carbonyl compounds 28
1.6.6 Phosphaalkynes 28
1.6.7 Aryl thiocyanates and selenocyanates 29 1.6.8 Reactions of 0-substituted benzonitrile sulphides 30 i .6.9 Reactions of polymer bound nitrile sulphides 33 (vi)
Page
1.7 Isothiazoles 33 1.7.1 Synthesis of isothiazoles 3 34 1.7.1.1 Synthesis from acyclic precursors 35 1.7-1.2 Synthesis from other heterocyclic precursors 38 1.7.2 Properties of the isothiazole ring 39 1.7.3 Applications of isothiazoles 1.8 1, 3,b-Oxathiazol-2-ones and related Ia heterocycles. 43 1.8.1 1,3,4-Oxathiazol-2-ones Preparation 43
1.8.1.2 Properties 44 1.8-1 .3 Reactions 45 1.8.2 1,4,2-Dithiazole--thiones and 1,4,2- 52
dithiazol-S-ones. 1.8.2.1 Preparation 52 1.8.2.2 Reactions 54 1.8.3 1,4,2-Dioxazol-5-ones and 1,4,2-dioxazole-5- 58 thiones. 1.893.1 Preparation 58 1.8.3.2 Reactions 59 1.9 Objectives of research 63 - (vii)
Page
2 DISCUSSICN 6 2.1 Thermolysis of 1,3,4-oxathiazol-2-ones 64
in the presence of 0< -ketonitriles. 2.2 Reaction of nitrile sulphides with alkenes. 74 2.2.1 Reaction of aryl nitrile sulphides with 76 norbornadiene. 89 2.2.2 Reaction of para-toluonitrile sulphide with Z-1, 2-his (phenylsuJ.phonyl )ethylene
2.2.3 Decarboxylation of isothiazole-L.-and S- 101 carboxylic acids.
2.2.4 Summary. 115 2.3 Thermolysis of 1,3,4-oxathiazol-2-ones in 117 the presence of miscellaneous dipolarophiles. 2.3.1 Maleic anhydride 117 2.3.2 Phenylaoetylene and 20-dimethylbut-2-ene 118 2.3.3 Coumarin 120 2.3.4 Thermolysis of 1,3,4-oxath.iazol-2-one in the presence of ethyl cyanoformate. 123
2.4 Sigmatropic addition and cyclosubstitution 12 reactions of 1,4,2-dithiazole-5-thiones and related heterocycles.
2.5 Reactions of 1,3,4-oxathiazol-2-ones and 12 related heterocyclic compounds icrith nucleophiles.
2.5.1 1,3,14-Oxathiazol-2-ones 142 (viii)
Page 143 2.5.1.1. Nitrogen nucleop1iles 2.5-1.2 Oxygen nucleophiles 155 2.5.1.3 Carbon nucleophiles 157 2.5-1 .4 Miscellaneous nucleophiles 160 2.5.1.5 summary 165 2.5.2 3-Phenyl-1,4,2-dithiazole-5-thione 1.70 2.5.3 3-Phenyl-1,4,2-dithiazol-5-one 178 2.5.4 1,,2-Dioxazol-5-ones and 1,4,2- 183 dioxazole-5-thiones. 2.5.4.1 3-Phenyi-1,4,2-dioxazol-5-one 184 2.5-4.2 3-Phenyl-1,4, 2-dioxazole-S-thione 197 2.5.5 Summary 199
3. EXPERIMENTAL 201 3.1 General 201 3.1 .1 Glossary of terins,symbols and abbreviations 201 3.1.2 Instrumentation 204 3.1.3 Chromatography 205 3.104 Solvents and reagents 208 3.2 Synthesis of chlorocarbonylsu.lphenyl 209 chloride 3.3 Synthesis of 1,3,4-oxathiazol-2-ones 210 (ix)
Pag e 212 3.4 .Tharmolysis of oxathiazolones in the presence of O(-ketonitriles 2124 3.5 Synthesis of 5-dichloromethyl-3pheny1 1, 2,b-thiadiazole. 3.6 Attempted hydrolysis of 5-dichloromethyl- 2114 3-phenyl-1, 2, li.-thiadiazole. 215 3.7 Thermolysis of 5phenyl-10,14.-oxathiazol- 2-one in the presence of ethyl cyanoformate and benzoyl cyanide. 216 3.8 Thernolysis of 1,3,4-oxathiazol-2-ones in the presence of alkenes. 216 3 • 8.1 Thermolysis of 5.-phenyl-1, 3, LL-oxathiaz ol- 2-one in the presence of norbornene. 217 3.8.2 Reaction of arylnitrile sulphides with norbornadiene. 217 398.2.1 1,3,4-Oxathiazol-2-one and norbornadiene mixed at the outset. 219 3.8.2.2 Under conditions of high dilution 3.8.3 Thermolysis of 5-(7tolyl)-1,3,4- 220 oxathiazol-2-one in the presence of Z-1, 2-bis (phenylsuiphonyl )ethylene 221 3.8.14 Thermal stability of Z-1,2-bs- (phenylsuiphonyl )ethylene. (x)
Page 221 3.8.5 Thermolysis of 5-(27to1y1)-1,3,4- oxathiazol-2-one in the presence of diethyl fuiarate 222 3.8.6 Thermolysis of 5-(7toly1)-1,3,4- oxathiazol-2-one in the presence of diethy]. maleate 222 3.8.7 Isomerisation of diethyl maleate to diethyl fumarate 3.8.8 Thermolysis of 5-(-tolyl)-1,3,b-oxathiazol- 2-one in the presence of E-stilbene 223
3.8.9 Thermolysis of 5-(27tolyl)-1,3,4-oxathiazol- 224 2-one in the presence of Z-stilbene
3.9 Thermolysis of 5-aryl-1,3,4-oxathiazol-2- 225 ones in the presence of aoetylenic esters. 3.9.1 Ethyl propiolate 225
3.9.2 Dimethyl acetylenedicarbocrlate 226
3.9.3 Diethyl acetylened!carboçrlate 226
3.9.4 Synthesis of 3-ar'ylisothiazole carbolic 227 acids 3.9.4.1 General procedure. 227 228 3.9 -4.2 3-(7Tolyl)isothiazole-4-carbOxy1ic acid
3.9-4.3 Ethyl 3-(7tolyl)isothiazole-4-carbolate 228 3.10 Attempted solution phase decarboxylation of 230 3-arylisothiazole-5-carbolic acids. (xi)
Page 230 3.10.1 3_(p7MethopheflY)iS0taZ95 carboxylic acid. 3%1.0.2 3-(27Tolyl)isothiazole-5-carbOXyliC acid 230 3.11 Synthesis of 3-arylisothiazoles by flash 230 vacuum pyrolysis of isothiazole mono - and di-carboxylates.
3.11 • 1 Ethyl 3- (-tolyl )isothiazole-5-carboxylate 231 3.11.2 Ethyl 3-(7toly1)isothiazole-14-carbOxylate 232 3.11.3 Diethyl 3-(7toly1)isothiazole-,5- 233 dicarboxylate 2314 3-11-4 3-(7Tolyl)isothiazole-4-carboxyliC acid 3.11 .5 3-(7Tolyl)isothiazole-4,5-diCarbOXyliC acid 2314 3.11.6 3-(7Tolyl)isothiazole 2314 3.1.2 Thermolysis of 1,3,14-oxathiazol-2-ones in the presence of various dipolarophiles. 235
3.1.2.1 Maleic anhydride 235 235 3.12.2 2,3-Dimethylbut-2-ene 3.12.3 Phenylacetylene 236 3.12.4 Coumarin 236 3.12.5 Thermolysis of 1,3,4-oxathiazol-2-one in the 237 presence of ethyl cyanoformate. 3.13 Synthesis and reactions of 1,14,2-dithiazole- 5-thiones. 237 (xii)
Page 237 3.1.3.1 Synthesis from thioamides 3.1-3.2 The cyclosubstitution reaction of 1,4,2-dithiazole--thiones with electron 238
deficient nitriles.
3.1.3.2. 1 3-Phenyl-1,4, 2-dithiazole-5-thione 238 3.13.2.2 3-Methyl-1,4, 2-dithiazole-S-thione 240 3.13.2.3 Competition reaction between 3-phenyl- 1,4,2-dithiazole-5-thione and 3-methyl- 243 1,4,2-dithiazole--thione with ethyl cyanoforxnate. 3.13.3 Reaction of 3-methyl-1,4,2-dithiazole- 2414 -thione with diethyl fumarate 3.13J4 Reaction of 1,3-dith.iolane-2-thione with 2414 ethyl cyanoformate. 3.13.5 Reaction of 1,3-dithiole-2-thione with 245 ethyl cyanoforinate.
3.13.6 Reaction of 5-phenyl-1,2,4-dithiazole- 245 3-thione with ethyl cyanoformate 3.14 Reaction of 1,3,4-oxathiazol-2-ones with 246 nuoleophiles. 246 3.14.1 Nitrogen nucleophiles 3.14.1.1 Piperidine 246 3.14.1.2 Morpholine 246 (xiii)
Page
3.114.1.3 Excess piperidine 2148 3.114.1.11 Butylamine 2148 3.114.1.5 Triethylainine 2119 3.114.1.6 Ammonia 249
3.114.1.7 Aniline 250 3.14.1.8 Reaction of N-benzoyl-S-piperidino- 250 carbonylthiohydroxylamine with butylaxnine
3.14.2 Oxygen nuoleophiles. 21
3.14.2.1 Benzyl alcohol 251
3.14.2.2 Potassium hydroxide 2,1
3.114.2.3 Sodium ethoxide 22
3.114.2.14 Sodium benzyloxide 23
3.114.3 Carbon nucleophiles 2,3
3.114.3.1 3u.tylisonitrile 253
3.114.3.2 Phenylmagnesiuzn bromide 254
3.14.14 Miscellaneous nucleophiles 255
3 .14-4.1 Ethanethiol 255 3.114.14.2 Triphenyiphosphine 26
3.114.5 Reaction of 5-(7methoxypheny1)-1,3,14- 256 oxathiazol-2-one with carbon disulphide
3.114. 6 Reaction of 5-(-inethoxyphenyl)-1,3,14- 256 oxathiazol-2-one with j,N-
dime thylthioformamide (xiv)
Page 257 3.15 Synthesis of n-butylisonitrile
3.16 Preparation of ureas 258
3.16.1 From isocyanates 258 3.16.2 Bis-pentamethyleneurea 259
3.16.3 Bis-pentainethyleneth±ourea 260
3.17 Reaction of 3-phen7l-1,4,2-dithiazole- 260 5-thione with a variety of nucleophiles
3.17.1 Piperidine 260
3.17.2 n-Butylainine 262
3.17.3 Triphenyiphosphine 263
3.18 Synthesis of 3-Phen7l-1,4,2-dithiazol- 263 5-one
3.19 Reaction of 3-phen7l-1,4,2-dithiazol- 264 5-one with various nucleophiles
3.19.1 Piperidine 264
3.19.2 n-Butylamine 264
3.19.3 Triphenyiphosphine 264 3.20 Synthesis of 3-pheny1-1,4,2-dioxazo1-5-one 265
3.21 Reaction of 3-pheny1-1,4,2-dioxazo1-5-one 255 with various nucleophiles
3.21.1 Piperidine 265
3.21.2 n-Butylainine 266
3.21.3 Triphenyiphosphine 266
3.22 Synthesis of amidoxiines 267 (xv)
Pa
3.22.1 Phenylpiperidinoainidoxizae 267 3.22.2 Butyiphenylainidoxime 268 268 3.23 Reaction of phenylisocyanate with triphenylphosphine.
3.24 Reaction of benzonitrile oxide with 268 triphenylphosphi.ne.
3.25 Synthesis of 3-pheny1-1,4,2-dioxazo1e- 268 5-thione 3.26 Reaction of 3-phenyl-12422-dioxazole- 269 5-thione with nucleophiles. 3.26.1 Piperidine 269 3.26.2 Butylamine 270 3.26.3 Triphenyiphosphine 270
4. APPENDICES 271 4.1 1,3,4-Oxathiazol-2-ones 272 4.2 5-Acy1-1 1 2,4-thiadiazo1es 273 4.3 5-DichJ.oromethyl-3-phenyl-1, 2,b-thiadiazole 275 4.4 exo-3a,7a-4, 5,6, 7-Hexahydro-ti,, .. 276 niethan-3-pheny1-1,2-benzisothiazole 4.5 Arylisothiazoles 280 4.6 Diethyl 3-(7to1y1)-2-isoth.iazo1ine-4,5- 282 dicarboxyl ate
LL. 7 Bis-1,2- (phenylsuiphony]. )ethylenes 283 4.8 5-(Phenylsulphonyl)-3-pheny].isothiazole 284 4.9 3-Arylisothiazole-5-carboxylates 285 Page
4-.1 0 3-y1isothiazo1e-4-carbo1ates 287 4- 11 3-(7To1y1)isoth1azo1e-4,5-dicarboxy1ates 289 Li.i 2 N-Acy1-S-ainnocarbony1thiohydro1amines 291 4.1 3 114,2-Dlthiazole-5-thiones 293 Li..l Li. 3-Phenyl-.1,4, 2-dithiazol-5-one 294 294 4.15 3-Pheny1-1,4,2-dioxazo1-5-one and 3-phenyl-1 , Li., 2-dioxazole-S-thione 4.16 Miscellaneous compounds 295 4.16.1 Syimnetrica]. ureas 295 4.16.2 ljnsyinrnetricaj. u.reas 296 4.16.3 Bis-(pentajnethylene)thiOurea 297 4.16.4 Ajnidoxinies 297 4.16.5 &itylisonitrile 298 4.17 Mass spectral data for 1,2,4-thiadiazoles 299 4.18 Mass spectral data for 3-aryl-isothiazoles 300 4.19 Crystallographic data for N-benzoyl-S- 301 morpho1inocarbonylthiohydrolamine
S REFERENCES 305 (xvii)
The Road goes ever on and on
Down from the door where it began. Now far ahead the Road has gone, And I must follow, if I can, Pursuing it with weary feet, Until it joins some larger way. Where many paths and errands meet. And whither then? I cannot say. J .LR, Tolkien. For lain and our parents. 1
1. INTRODUCTION
Cyclôaddition reactions are among the most extensively studied and most generally utilised organic chemical syntheses.
There are many types of cycloaddition processes, among these are the 1,3-dipolar cycloaddition'.
These are an established, and increasingly used, synthetic route to many heterocyclic systems. The majority of 1,3-dipoles are based on carbon, nitrogen and oxygen.
1.1. The 1,3-dipole 2 The formal description of a 1,3-dipole is in the terms of an ally1 anion type )- system. In terms of actual charge however, the 1,3-dipole is ambivalent, the charges at either end being interchangeable. This is illustrated by the sextet structures below (D, E,11 and I). These give the systems their generic name and are envisaged to give rise to their characteristic cycloaddition reactions. Those 1,3-dipole3 which have a -'oond in the plane perpendicular to the heteroallyl anion molecular orbital responsible '4 for the L,3-dipoiar ccioaddition reaction are of the prop argyl-allenyl type and are mainly linear; for example nitrile sulphides (i). Thoe dipoles iithout the additional FO
It -bond are of the ally1 type and are usually bent e.g. nitrones (ii).
(I) R- C=N - S---> R-C=N -S: + y, (B) - (E
R-C N -S------> R-C=N=-S----R-C-N =S (A) (-B) (C) - + R + ,. R R2CN\ - RC-N - RC-N. L0 (F) .0:- (H) -
R2C-N (I)
1.2 The 1,3-dipolar eycloaddition Reaction
The characteristic cycloaddition reaction of 1,3-dipoles
involves the combination of a set of heteroallyl anion molecular 3
orbitals containing four )r-electrons with two 7t-electrons from a 7T-orbital of a multiply bonded system (the dipolarophile). The product of this [3 + 29S I cycloaddition is a five membered heterocycle.
b
The mechanism of the cycloaddition reaction is generally accepted to be a concerted process, as first suggested by
Huisgen Two new -bonds are formed simultaneously although not necessarily in a synchronous manner. It is a thermally allowed process by Woodward-Hoffmann rules 14
involving a two plane orientation complex . Linear dipoles
such as nitrile sulphides must bend on going from the orientation complex (iii) to the transition state (iv)
0
0- O £ 0 •0 '1-i d-e
(iii) (iv)
A two step process would require the intermediacy of a zwitterion or a biradica]- 8 The biradical mechanism has not found strong support since 1968 from sources other than Firestone.
Huisgen, however, has recently argued that a two step process via a zwitterion is possible if there is a large enough difference in the YT-niolecular orbital energy levels of the reactants. These special circumstances lead to a situation where
one HOMO-LIJNO. interaction is strongly dominant in the
transition state. Such special requirements are met by a
1,3-dipole with if-MO energy levels approaching those of the
allyl anion and an ethylene derivative bearing four electron
attracting substituents. Since the introduction of
electronegative heteroatoms into the ally1 anion framework
re.cee the 7r-MO energy levels, the 1,3-dipole must therefore consist of atoms with a similar electronegativity to carbon and
bearing non-conjugating substituents. Aliphatic thiocarbonyl
ylide (1) satisfies these requirements. Isolation of both
and trans adducts supports this hypothesis.
Scheme 1 MeO2C CN R'CH2 + CQ2Me (1) NC
+ + R2C I R 2
NC -4COZMe Me OZ fit MeO2C - CN N
\11 Rzç") R2 N Me OC 02 Me Me C2 CN TRANS C'S 6
It is the great structural variety of both the possible 1,3-dipole and dipolarophile components that makes this class of cycloaddition reaction so valuable and versatile in organic synthesis.
1.3 Frontier Molecular Orbital Theory 10 The question of reactivity and regioselectivity 11 in 1,3-dipolar cycloaddition reactions can be approached using Frontier Molecular Orbital (FMO) theory in much the same way as the classical ie1s-AlderzeaCtiQfl 12 . The rate of a 1,3-dipolar cycloaddition reaction is related
to the HOMO-LUNO energy separation of the reactants. The dipole HOMO, the dipole LUMO or both may be involved in the dominant interaction, depending on the relative energies of the dipole
orbitals. For nitrile sulphides, Sanders and co-workers calculated the FMO levels and atomic orbital (AO) coefficents for benzonitrile sulphide 13 These are ilustrated in Figure 1 with those of benzonitrile oxide for comparison. 7
Figure 1 + - + - Ph-CNN-S H C=C-CR Pt'rCN -O
-c-c-• 0. o • 110-0 -10 S 0 0 r - C- N--O o,Oo .0 I C -N -S-10 -19 OO O
eV •00 C- N-S 7' 0 0 O
- - C- N - 0 0 0 am S
L C_C5 0 Footnote: Propiolate AO coefficients unavailable but assumed
similar to those' for aery]ate All calculations by CNDO/2
method 13. As can be seen the HOMO and LUMO energy levels of benzonitrile sulphide are compressed with respect to benzonitrile oxide. They are approximately midway between the corresponding levels for the propiolate esters. Therefore, with respect to this type of dipolarophile, benzonitrile sulphide ii can be considered a member of the Sustmann uype II class; that is both sets of HO-LUmolecular orbital interactions must be considered in explaining regiochemistry. Consideration of the size of AO coefficients of the HO-W pairs (Fig. 1) shows that the b-carbocrlate product in these reactions is the result of the dipole HOMO-dipolarophile LUMO interaction and the -carboxylate from the dipole LUI4O- dipolarophile HOMO interaction. The Lj.-carboxylate: S-carboxylate ratio 15,16,17 for the reaction of arenenitrile sulphides with propiolate esters is approximately unity. This indicates .a greater extent of dipole HOMO control with nitrile sulphides than for the corresponding reaction of nitrile oxides 18 where the -carboxylate product predominates l.).i. Nitrile Sulphides. Evidence for the existence of nitrile sulphides as short 9
lived intermediates was first obtained in 1970 by Franz 15 and Black. Thermolysis of 5-phenyl-1,3,14-oxathiazol-2-one (2 a) gave benzonitrile and sulphur with the evolution of carbon dioxide (Scheme 2). When the reaction was repeated in the presence of dimethyl acetylenedicarboçr1ate (DMAD), the
isothiazole (l) was formed in 90% yield. This was taken as good evidence for the intermediaoy of benzonitrile sulphide(3).
Scheme 2
Ph PhCN + S Ph C N -SI (3) PhO2M e (2)
- C CO2Me (4) 10
Since this first report, nitrile sulphides have been generated by various photochemical and thermal routes and trapped by a variety of dipolarophiles.
Direct evidence of their existence is however limited.
Nitrile sulphides generated photolyticafly have been trapped at low temperatures in glasses or films and studied spectroscopically. The u.v. and i.r. spectra of benzonitrile sulphide in a poly (vinyl chloride) film have been recorded,over a temperature range of 15-50K-, u.v. absorptions were observed 19 at 240nln and 340 rim and at 18K. An i.r. absorption at 2185 cm-1 is reported 20•
1.5 Generation of Nitrile Silphides.
A variety of photochemical and thermal routes to this transient intermediate are available; however, they are of ranging efficiency and hence synthetic utility.
1.5.1 Photolytic Generation
Photolysis of various sulphur-nitrogen heteroeycles,with concomitant loss of a small molecule such as N 2 ,leads to the formation of nit- rile sulphides. These can be trapped with a dipô1rohile for example DMAD (Scheme 3). 11
Scheme 3
AA r A
'SS S)( \E ,J
L ANC—S I / ArCN+ S A rr_CQzMe SLCOZMe
X-Y-Z = CO, Cos, CO2 ,CS21 N 2
19 It has been suggested that the initial intermediate formed in each case is the thiazirine (5), which subsequently undergoes thermal ring opening to give the nitrile sulphide. The yields 12
of the DMA]) cycloadduct derived from photochemicafly 21 generated nitrile sulphides are generally low (5-21%)
1 7 when compared to those for the thermal route from 1,3,4-oxathiazol-2-ones (2). This has been attributed 21 to the destruction of the nitrile sulphide by energy transfer from excited species or via photolytically induced decomposition.
1.5.2 Thermal Generation. There are many examples of thermal generation of nitrile sulphides, but they can be split into two broad groups: those involving a thermal elimination reaction and those occurring by a cycloreversion process. 1.5.2.1 Thermal Elimination Reactions. These nitrile sulphide precursors are acyclic compounds with good leaving groups.
(a) N-Thiocarbonyl diphenylsuiphimides N-Thiocarbonyl diphenylsulphiinides (6) decompose at 70 0C to diphenyl sulphide, nitrile and sulphur. However, in the 13
presence of an electron deficient acetylene isothiazoles
are formed 22 (Scheme We
Scheme L
Ph2SN -C-Ar e-> Ph 2 S1NC-k (6) V
ArCN + S L ArCN -S CCR
A
The thiaziri.ne intermediate is the same as that proposed for photochemical sources of nitrile sulphide (Section 1.5.1).
The yields of cy-cloadduct obtained using DMAD as the dipolarophile lb
are moderate (27-34); this may be due to the instability
of the precursor (6) at room temperature. This therefore
limits the synthetic utility of this approach.
(b) Liiinosulphur Difluorides.
Iminosulphur difluoride (7) undergoes a rare l3- elimination of two moles of hydrogen fluoride at 132 0C to
give nitrile sulphides 23
Scheme S
RZF +R1 R-CH--NS R-CS- - R-C= NS: QF~ 'ii F H F- (7)
R - C=- N - S 15
The yields of the DMAD cycloadduct are reasonable (Ca 65). It is a noteworthy feature of this route that, when using an unsymmetrical- dipolarophile such as ethyl propiolate (EP) the regioselectivity of the reaction may be affected by the action of hydrogen fluoride on the dipolarophile. For example, in the reaction of benzonitrile sulphides with EP the ratio of the L-carboxylate to - carboçrlate was 3:2 compared with 1:1 when the source of benzonitrile sulphide was the oxathiazolone (2a). This was considered to be due to protonation of the carbonyl oxygen of EP by hydrogen fluoride with a consequent change in orbital energies and coefficients 13•
1..2.2. Thermal Cycloreversion Reactions.
Pour heterocyclic systems have been found to give nitrile sulphides on therniolysis. The efficiency of these sources and hence the synthetic utility of these sources vary.
1r- - RC-S1
X=Y = (2) C 02, (8) COS, (9)0:CR 2' (1O)R'N:CR2 16
a) 1 ,Lj.-Oxathiazol-2-ones (2) and 1, )4., 2-dithiazol.-S-ones (3)
TherDlolysis of 1,3,4-oxathiazol-2-ones (2) was historically the first reported source of nitrile sulphides and it remains the first choice in synthesis. i,3,b- oxathiazol-2-ones (2) are easily prepared and have a good shelf life. They decompose smoothly at temperatures above 130°C to give nitrile suiphides which can be trapped almost quantitatively by good dipolarophiles.
Kinetic studies of the thermolysis of 5-pheny1-1,3,4- oxathiazoi-2-one (2a) in the presence and absence of a 16,2)4.• dipolarophile have been performed These show the rate of disappearance of (2a) and the rates of formation of the isothiazole adduct (LL) and benzonitrile are all equal, first order and independent of dipolarophile concentration. These findings are consistent with the existence of benzonitrile sulphide as a discrete intermediate in the reaction pathway. 17
They also preclude an associative mechanism (Scheme 6), which was initially considered as a possible alternative for the formation of the isothiazole (L).
(Scheme •)
Ph 1hCO2Me1 EJIAD > L+ -J
Ph CQ2Me -CO2 > CMe 18
1,4,2-Dithiazol-5-ones (8) provide a similar source of nitrile sulphides. They are, however, less easily prepared 25 and require higher temperatures and longer reaction times. Furthermore the cycloadduct yields 26 are generally lower. b) 1,3,4-0xathiazoles (9) and 1,2,4-Thiadiazolines (10) Both these heterocycles cyclorevert to give nitrile sulphides; but they are difficult to prepare except via the forward reaction of a nitrile sulphide with an electron deficient carbonyl compound 27 orimine. The 1,3,4-oxathiazoles (9) are an efficient source of nitrile 28• sulphides Alternatively, the 1,2,4-thiadiazol3'nes (10) may decompose thermally by routes other than cycloreversion and are therefore not an efficient source of nitrile sulphides correspondingly only low yields of cycloadducts have been obtained 29 1.5.3 Oxidative Dimeisatnof Thioamides 30-33 A number of reports have mentioned the possibility of nitrile sulphide intermediates being formed during the oxidative dime?isation of thioairiides to 1,2,4-thiadiazoles (Scheme 7). Other mechanisms are possible and the evidence for the participation of nitrile sulphides as a discrete intermediate are conflicting. Several sets of conditions have bean used for this reaction and it is possible that different mechanisms are operating in each case. 19
Scheme 7
R CC' 2 R-C :-~ R-C s. +sx 'I,- -
NH R, RCSN C-- f R K-L > RC ' tR- S-N'** hX, sx SX NH HX
-HXI
+ - R-C;N -s
tRC;N 2
1,.6 Cycloaddition Reactions of Nitrile Sulphides Nitrile sulphides undergo 1,3-dipolar cycloaddition
reaction with a variety of unsaturated groups: CC,C=C, CN, CN, CP and C0. The reaction with each of these types of dipolarophile will be reviewed generally and unless otherwise stated the 1,3-dipole was generated by thermal de carboçr1ation of the appropriate 1,3, 14.-oxathiazol-2-one (2).
1.6.1 Acetylenes Nitrile sulphides react with electron deficient alk,ynes
to give isothiazoles.
+ - RCN -S 1 2 RR +
RkC-R
DMA, for example, has been used to trap nitrile sulphides from
all possible sources. Ethyl and methyl propiolates give a mixture of isothiazo1e-4 and S-carboxylates. The isomer ratios
for this reaction are usually ca 1:1 (see Section 1..2) and the combined yields are high particularly with nitrile sulphides generated from 1,3,4-oxathiazol-2-ones (2). 21
Nitrile sulphides derived from N-thiocarbonyl
diphenylsuiphimides (6) have also been reacted with dibenzoylacetylenes to-give isothiazoles in moderate yield_ 22 . It has been claimed that benzonitrile sulphide formed during the aerobic photolysis of thiobenzamide can be trapped with phenylacetylene; a single product 3,4-dipheny1isothiazo1e is
reported 32 in 22% yield. In direct contraet however, benzonitrile sulphide derived from N-benzyliminosulphur difluoride
gave no cycloadduct with pheny1acety1ene and nitrile sulphides generated from N-thiocarbonyl diphenylsulphimides (6) cannot be trapped with dLiphenylacetylene 22 • This conflicting evidence for the involvement of nitrile sulphide in the oxidation of
thioamide has yet to be resolved. 1.6.2 Olefins Various activated carbon - carbon double bonds react with nitrile sulphides to give 2-isothiazoline derivatives.
1 R- CEN --S
+ ___ 1R2
2 4 R1,,
The stereochemistry of the 2-isothiazoline is usually the sane as that of the alkene. In the case of diethyl maleate,however, the trans - product identical to that obtained from diethyl
fumarate is formed.
22
The first olefin to be used as a dipolarophile was maleic anhydride, which was reaôtdth benzonitrile sulphide derived from N-benzyliminosulphur difluoride to give the
cis-fused isothiazoline derivative (ii) in 20% yield 23
Since this first report several other symmetrical olefins
have been reacted with nitrile sulphides generated from
1,3,4-oxathiazol-2-ones(2). These include the norbornene derivative (12) and N-ethyl-and N-pheny1-maleimides.
Ph
OMe OMe (11) -
1,4-Naphtho-and benzo-quinones also cycloadd to nitrile
sulphides. 1,4-Naphthoquinones give an isothiazole product (13),
thought to arise via oxidation of the initial i3othiazoline by 23
unreacted 1,4-naphthoquinone 36,3? Benzoquinones undergo a similar reaction, but with two moles of nitrile sulphide to give this bis-i8othiazole adducts 36 (14)and (iS). Trifiuoroacetonitrjie sulphide derived from an iminosuiphur difluoride has been reacted with 5-hydroxy-1,4-naphthoquinone to give a single isothiazole adduct (14%) thought to have the structure (16) 37.
Acetonitrile sulphide generated from 5-methyl-1,3,4-. oxathiazoi-2-one (2 b) in the presence of 5-acetamido -1,4- naphthøquinone gave only trace quantities of isothiazole adducts.
IV
(13) (14)
F3C74 *HR (15) (16) 24
Acr7late esters and their derivatives undergo cycloaddition with nitrile sulphides to give mixtures of the 2-isothiazoline- 4- and S-ca,rboxylates. The reglochemistry of this process is similar to that for propiolate esters (see Section 1.3). Reaction of nitrile sulphides with ethyl 2-chloroacrylate
and ethyl pyrrolidinyl-acrjlate gave a mixture of isothiazole-
LL-and -carboxylat.,presuinably via loss of HCl and pyrrolidine respectively from the initial 2-isothiazoline adducts (Scheme 8). Scheme 8
FC-COaEt RJj_CQ2Et CE R GZEt
t.< I Q+ç=ç -c Q2Et H
Yields: R R 4- 5- 4C106H5 Ct 2 49 Ph 8 2
Nitrile sulphides are reported not to react with the 2
carbon-carbon double bond in -nitrostyrene, 3-nitro st3rrene, 39. tetraethyl ethylenetetracbolate or tetracyanoethylene
There is also, an as yet unconfirmed report of nitrile sulphides being formed during thioamide oxidation and reacting 32 . with 2,3-dimethylbut-2-ene an electron rich olefin
1.6.3 Nitriles
Various nitriles, such as ethyl cyanoforinate benzonitrile and trichioroacetonitrile react with nitrile sulphides to give 1,2,4-thiadiazoles.
1 R-CN-S 1
+ I
R2-CN
This approach is an ideal route to non-symmetrically substituted 1,2,4-thiadiazoles, i.e. R 1 This reaction has been exploited to synthesise dendrodoine (17),a marine metabolite which contains a 1,2,4-thiad!azole moiety 42 (Scheme 9). The dime thylaminonitrile sulphide (18) was generated from a 1,3,4-oxathiazo1-2-one prepared in the usual manner 43 Scheme 9 C= N
+ T N - Me2 Me2N-CEN—S ( 1 8 ) (17)
Nitrile sulphides also react periselectively with the
nitrile groups of tetracyanoethylene to give mono-and various bis - adducts for example (19) and (20).
R \ C=C AS N NV C NC (19) C=C
R-" NCN (20) 27
1.6.4 Lnines
Some Schiff's bases have been found react with
nitrile sulphides to give 1,2,4-thiadiazo1ines (21) in low
yield (Scheme 10). These cycloadducts are not very stable
under the reaction conditions and (21) may cyclorevert to the
nitrile sulphide and iinine or decompose via another as yet
unidentified route.
Scheme 10
1 R- CN-S R1 2
R- N=C H R3 21)
R1 = 4-MeOC6H4 RFh
R 3 Ph 4C1061-f4 Yields (%) 2 7 13 28
L.6. Carbonyl Compounds
Nitrile sulphides react with the carbonyl group of
chloral, hexachloroacetone and O(,,o(trif4aoroacetophenone
to give 1,3,14-,3,4 • I' 22)\ / Scheme 11)• These oxathazc1es cyclorevert to the carbonyl compound and nitrile suiphide when
0 C.27,28, heated to ca 160
Scheme 11
1- 5r_Rg Ri 13 5°C + rc e3 16SC R2••• (22) 3 C0 R1 ALkyl ,aryt R = C CE3, CF R 3= H, Ph, CCI3
1.6 .. Phosphaalkynes
Rösch and Regitz have recently reported the cycloadditin
reaction of benzonitrile sulphide with the sLable phosphaalk3ie(23).
The 1,4,2-thiaphosphazole (24), the first ring system c this
type, was isolated in 32% yield. 29
Scheme 12 Ph Ph + PEC-CMe3 Me3 (2a) (23) (, 24)
1.6.7 Aryl Thiocyanates and Se14oyanates
Like other nitrilium betaines, nitrie sulphides will
undergo a 1,3-dipolar cycloadditicn reaction to tho carbon-
nitrogen triple bond of anyl thiocyeriates and ce1enocyanates 7
(Scheme 13) to yield -arylthio or -arylse1eno-1,2,i.-
thiacliazoles (2)
Scheme 13
A N&-XAr —?' ! ZZO XI Ar ( 2 ) (25
X = S, Se 30
1.4.8 Reactions of o-Substituted Benzonitrile Sulphides
These nitrile sul phides were generated from 1,3,4-
oxathiazol-2-ones of the type 261
II
(26) X = a) OH, b)OAc, c)NHAc
When the ortho - sub stituent X contains no unsaturated
linkages which may act as a dipolarophil2, the nitrile
suiphicle undergoes facile intermolecular cycloaddition reaction.
w!th ethyl cyanoformae or DMAD
However, o- roxyphenyl-, 3 ) h-oathia:o-2-cno 2a) iLJ.
IT3 he exected i:ciaole ad:Lic; (27) rL:': 1AD
:J..). In3tc adhl ety L- :o-L42-ciromcno [L,3 -c lisothiazole - -carbo;ylate (22) as iscla ;ed.. Pr.y (2)is fcrmed rcn
the initial achiuct (27) vai intramolecular f thc1.
If the ortho - substituent K contains an electron deficiont albync
------ -- (or- alkene) then -a- poly cyclic system can- be- f-rmcd ria-an-- - -
intr-amc1ecuir cycloaddition reaction of the nitrile ulphide
:abh the dpoaropnaie Ir, cnerne
31
NS
OMAD --- -0O2 OHnH IIOH (26a)
/ CO2Me CQ2Me
OHnw cc (27) (2)
+ CEN—S
c CCAr (26d) N—S Ar LJ 0 Jo (29) 32
When the dipol arc phiie was an olefin, the initial
2-isothiazoline (30) cycloadduct undergoes facile oxidation to the isothiazole products (29). In some cases, however, quinoline (32) and aminochromene (33) are also formed. These products may result from the 2-isotiiiazoline ( 30) via isomerisation to the 3-isothiazoline (31), followed by extrusion of sulphur.
N-S HN-S Ar
-IL - -~
30) (31
WI x
N
H-
OO 32) (33) 1..9 Reactions of Polymer Bound Nitrile Sulphides
S-Isoprenyl - and -vinyl-1,3,4-oxathiazol-2-ones (31),
prepared using a method modified to take account of the tendency of o-alkenyl compounds to polymerise, can be
co-polymerised with styrene and methyl. methacrylate 3 When
these co-polymers are heated at 13-140 0C, the polymeric oxiathiazolones (34a) decarborlate to give polymer bound nitrile sulphides. T iese 1,3-dipoles may be trapped with a
dipolarophile such as DMAD or be converted to nitrile via
decomposition. H rr_'R CH2-çR
(34 L (36a) In R = H ,Me 1.7 Isothiazoies The last major review of mono-nuclear isothiazoles was
by Pain in 1984. Therefore, only those topics relevant to
present work are discussed here. 314
1.7.1 Synthesis of Isothiazoles
Isothiazoles can be synthesised by a variety of routes
from both heterocyclic and acyclic precursors.
1.7.1.1. Synthesis fro m Acyclic Precursors.
The parent compound, isothiazole, is best prepared by
the reaction of rrcpynal with ammonia and sodium thiosuphate 7 .
For substituted isothiazoics () only the 3-30stituents have
to be in place prior to ring formations 14-substi;uents are
readily introduced by electrophilic reagents, whilst 5-ibsoituents
may be introduced via lithiation.
One of the most versatile methods of synthesis is based on
the oxidation of compounds which may be represented by
56 - 59 iminc-ene thiols (3) as one of their tautomeric forms
(Scheme 17)
Scheme 17
4R-C=C-R3 4R- CH-C-R3 4 R-C-C--R3 .11 11 5R 2 ç NH 5 R C~ NH 5 R C NH SH In, (35) 4R R3
(36) 3;
Oxidation may be carried out with peracids, sulphur or more commonly halogens. This approach is dependant on the availability of the requisite intermediates, for which numerous synthetic routes have been devised. The subsituents represent a wide range of groups. The oxidising agent however may also cause further reaction subsequent to ring closure.
1.7.12 Synthesis from Heterocyclic Precursors. 62 Isozazoles (37) can be converted into isothiazoles by successive catalytic hydrogenation, sulphurat.ion with phosphorous pentasuiphide, followed by oxidation with chioranil
(Scheme 18).
Scheme 18
R4 3 R RS (u)3 Rd 4 N-"O IH,)' YO (37) (36) (I) R, a. ney Ni/H2 (Ii) R2 S 5/chloranil. 36
1,2-Dithioliuin salts (38), particularly those with aryl
substituents, react with ammonia to give isothiazoles. A 63 mechanism for this reaction was proposed by Olofson et al
(Scheme 19).
Scheme 19
Ph Ph N Ph >Ph - so Ph 'C I , (38) cio,: SH
Ph Ph
The 1,3,2-oxathiazo1--one (39), a mesoionic compound,
undergoes two different reactions with DMA]) 64 Photolysis of
these compounds leads to the formation of nitrile sulphides which
are subsequently trapped by DMAD. Heating the same reaction
.37
mixture in the dark, however, produces the isomeric
isothiazole (Lo) presumably via the cycloadduct (Lii)
(Scheme 20).
Scheme 20
Ph C 02Me EPh-C -J Nc)CO2Me h1 (4) 02
Ph.- (39)
OAR
rMeo2C _CO2M1 S-1 -o P h JS L ] (40) (41
Cephalosporin S-oxides and penicillin S-oxides (42)
can be converted into isothiazol-3-ones (i3) by tlLe action of 65,66 base .. (Scheme 21). These reactions proceed via an Li' intermediate azetidnesU1phefliC acid
Scheme 21 0 9H RS Me R E Base 0 02R'.. (62) R'02C" "Me (44) R. > Me SiC=C' R'0C 'Me (43)
1.7.2 Properties of the Isothiazole Ring
Isothiazoles behave as typical, stable aromatic
molecules, which is consistent with 'H nmr spectra 39
and bond order calculation. Bird 67 devised an aromaticity index for five membered heterocycles based on bond lengths. This predicts that isothiazoles will be more aromatic than isoxazoles; consistent with the ring lability of the latter compounds which is utilised so often in organic synthesis 68 . The isothiazole ring is very stable to moderate heating, but thermolysis of substituted isothiazoles at 590 °C leads to
the formation of thioketenes 69 0 Electrophilic substitution occurs at the 4-position; isothiazoles however, require more vigorous nitration conditions than benzene although halogenation is easier. S-Lithioisothiazoles are easily prepared by the action of butyflithiuin. 1.7.3 Applications of Isothiazoles The most important synthetic isothiazole derivative is saccharin (45). This was the first non-carbohydrate sweetening agent to be discovered and is approximately 300 times as sweet as sucrose.
H 00 (45) Lo
The isothiazole ring has been incorporated into a wide range of known biologically active systems; either as a substituent group or taking the place of another cyclic system.
The greatest interest has been shown in the area of , .-lactam antibiotics. Isothiazoylacetic acids 70 (46) were converted into their acid chlorides and condensed with a 7-aminocephalosporanic acid derivative 71 (47) (Scheme 22).
Scheme 22 S 2R,O2CO2H H2 NI 0 L—NCAc
(46) (47) CO2Me
H N *N , ~r CMe
More importantly, probably due to their similarity to Oölbenin(48) 141
which is active against penicillinase producing organisms, isothiazole-Li.-carboxylic acid derivatives have been condensed 72• with 6-aminopenicillanic acid The penicillin derivatives(49) are also active against penicillinase producing bacteria.
.-.S\ ,Ph /7 ' Me
CO7R OMe IT - (4 9j)
le CO2H (48)
Other mono-nuclear isothiazoles have been found to possess a very wide range of properties; for example (so) is a plant 42
fungicide 73 , ( Si) an analgesic and (52) atherapeutic agent in organo-phosphorous poisoning.
RC °2 Me HO'NC
(50) M NS. Ts0 (52) Me 0
Me (51)
1.8 1,3,4-Oxathiazol-2-ones and Related Heterocycles.
The heterocyclic compounds considered here may all be represented by the same general structural formula.
NNX2Z
x,Y)z = Q,S L3
-- 1.8.1. 1,3,14-Oxathiazol-2-ones (2) 1.8.1.1. Preparation There are two general methods for preparing these compounds. The first was reported in 1965 by Miihlbauer and Weiss. When equivalent amounts of carboxamide and chiorocarbonylsuiphenyl- chloride (53) were heated together in refluxing chloroform, the product isolated was (2) (Scheme 23). Chlorocarbonylsulphenyl- chloride (53) is easily obtained from perch1oromethy1inercaptan(54) by partial hydrolysis using concentrated sulphuric acid 75,76 Scheme 23
_ 0 R (I R CONFI 2 CI3C-S-CLc.SG ° > Cl C-S-Cl -N
54) (53) ( 2 )
Senning used perchloromethy].mercaptan (54) directly, forming the N-trichloromethylsulphenylainide derivative (55), which could then be cyclised to (2) by the action of a second mole of L)4
77,78 carboxamide (Scheme 24). Other agents for the second ring closure step have subsequently been discovered,for example 79 80 n 81 water , acid or alkali and triethylaine Scheme 24 RCN RCONH2 R ro RCONH2 + R + HNs,CQ c1.s Cd. 3 (55) (54) (2)
Both these general methods can be carried out in a variety of
solvents. The reaction therefore, can be tailored to suit a
particular substituent. In recent work chlorocarbonylsulphenyl -
chloride (53) has generally been the reagent of choice. 1.8.1.2 Properties.
The molecular structure of the parent compound ('2f,RH)
has been studied in the gas phase using a variety of analytical 145
techniques. Microwave, Raman, infra-red spectroscopy and electron diffraction all indicate a co-planar. structure 82
1.8.1.3. Reactions Aside from the thermolytic and photolytic 83 cycloreversions of 1,3,4-oxathiazo1-2-Ones to give the nitrile
sulphide 1,3-dipole (see Section i.S) fw reactions of (2) are known. Amines are reported 84 to react with 5-phenyl-1,3,4- oxathiazol-2-ones to give _benzoyl_-aiflocarbOflYlthiohYdrOXY1aLT11neS
(6) (Scheme 2). Scheme 25
0 ______ II Ph 1 2 R1R2NH H 11 (2a) (56)
This reaction was extended when Rajca and co-workers used the 146
1,3,4-oxathiazol-2-ones (2) as a carbonylating agent for bifunctional compounds; for example, 2-amino-alcohols, 8• 1, 2-diainines and o-aminophenols The yields of the oxazoles and imidazoles are high. Scheme 26
R2ç U 1-OH
R2)N H NHR4 R4 Riro iNH "NM- XH 3 (2) R
~a,N H2 x
:IN )=O X=0,NH H 47
Qxidative addition of 1,3 1 4-oxathiazol-2-ones to bis(triphenylphosphine)(ethylene)platinum (0) has been 86 reported to give carbon monoxide and complexes with the dianion of N-thiohydroxainic acid and its derivatives as
chelating agents (57) (Scheme 27). Scheme 27
R 0 N NS + > (P PhB)2Pt ) R
Pt (P Ph3 ) 2 ( C2 H4) (57)
However, when tetrakis(triphenylphosphine)palladiuixi (0) is
used nitrile, carbon dioxide and triphenylphosphine sulphide are produced as well as the expected complex (58) (Scheme 28). On first consideration this reaction appears to be analogous to the deo'genation of nitrile oxides by triphenylphosphine 87 It must be noted, however, that triphenyiphosphine is known 88 to desuiphurate hetereocyclic compounds and there is no evidence 48
for the involvement of nitrile sulphide in this case.
Scheme 28
(Ph3 P)2Pd R -Co + ( 58) N :( P1 3P)4 Pd ____> s RCN + C 0 + Ph3 P=S
99 Since this first report it has been shown that triphenylphosphine will desulphurate an equivalent of
5-( -methoiphenyl)-1,i3 , 4-oxathiazo1-2-one (2d.) at room temperature in dichioromethane to give -anisonitrile and
triphenylphosphine sulphide with the liberation of carbon
dioxide. It is unlikely, therefore, that the reaction
proceeds either via nitrile sulphide or a metallated species. 149
It is more. likely to proceed by attack at sulphur and ring fragentaticn (Scheme 29). Scheme 29
4'-M e 4 -MeOC6 j-j4CN +
C 0 +Ph3P=S PPh3
SUSrl.-1,3,Li.-oxathiazol_2-ones react with a 1.1 molar
equivalent of a diazo compound in the presence of a catalytic
amount of rhodium (II) acetate to give nitrile, carbon dioxide
and a thiocarbonyl compound 90• Presumably the reaction
proceeds via the l,3,-oxathiazin_2(14jj)_one (9) (Scheme 30). 50
The thiooarbonyl compounds are not isolated as discrete
molecules but as OUo*ers.
Scheme 30 A Nt' JyO + HNI N2:C R1 R2 .] 2 RYt"R2 L ~ LH (59)
(59) - ArCN+ CO2 +R1 R2CS
There is, however, a departure from this mechanism in
one instance. 1,1hen methyl diazoacetoacetate (60)was reacted
with 5-(-methoçrphenyl)-1, 3,L-oxathiazol-2--one(2d) a small
amount of oxathiazine (61) was formed as well as the usual
nitrile and thiocarbonyl derived products (Scheme 31). The
most likely mechanism for the formation of (61) is thought to Si
be via intramolecular displacement of carbon dioxide in
the enolate anion canonical form (62) of the initial
sulphur Aide (63).
Scheme 31
rc, A1.1 0 A'O
" MeCO , S-:0)e S "CN2 OCMe MeO2C" LMe CM Me (60) J (62) 63)
ArT_1O Me Ar = 4-MeOC6H 4 COMe (61) The structure of (61) which could not be absolutely
assigned on the basis of spectroscopic evidence was confirmed
by a single crystal x-ray diffraction study. 52
Nitration 91 of -phenyl-1,3,4--oxathiazo1--2-one (2a)
at -150C gave the substitution pattern shown below. The L&-nitro product was isolated from the reaction mixture in O% yield by crystallisation. The reaction mixture was subsequently pyrolysed to .decarboxylate any 1,3,4-oxathiazol-2-ones remaining and the nitrile yields determined by gas chromatography. The results obtained, suggest that the oxathiazolone is a weakly activating substituent for nitration of a benzene ring.
54% - 0 60
Ic 28%
1.8.2 1,4,? -Dithiazole--thiones (614.) and 1,4, 2-Dithiazo1--ones (8) 1.8.2.1 Preparation 3-Phenyl-1, 14., 2-.ditbiazole-S-thione (64a) was first prepared 92 in low yield (< 20) by adding thiophosgene to a solution of 53
thiobenzamide in carbon disulphide. There was also a brief
report 25 of the formation of (64a) when perchloromethylmercaptan (54)was reacted with thiobenzainide. Subsequent work on this second approach led to the proposed mechanism 93 (Scheme 32).
The dichiorodithiazole intermediate (65) is similar to the 78 dichlorooxathiazole believed to be involved in the formation
of 1,3,4-oxathiazol-2-ones from carbozamides with
perchloromethylmercaptan. The 3, 5-diphenyl-1, 2,1.i-thiadiazole side product in this reaction may arise from side reaction of thiobenzamide with (65) or the thioamide derivative (66).
Scheme 32 S O.3 it Ph Ik ccsc' __ CNS PhNN NH2 (66)
EL Ph ~/- hrs PhCSN 112 + PhCN +HCI 65 (64a) 54
1,4,2-Dithiazol-5-ones (8) are best prepared by oxidation of the corresponding 1,4,2-dithiazole-5-thione (64). There are a variety of methods available ; treatment of (614) with mercuric acetate 2, potassium permanganate in acetone or benzonitrile oxide 25 In the final reaction, benzonitrile oxide undergoes a 1,3-dipolar cycloaddition reaction with the carbon- sulphur double bond of (614) (Scheme 33) to give the spiro-adduct (67). This decomposes on warming to give (8) and pheny]. isothiocyanate. Scheme 33 R_ Rys (8 ksS -. + (64) 67 PhNCS
1.8.2.2. Reactions Unlike 1,3,4-oxathiazol-2-ones (2), the thiones (614)do not undergo thermal fragmentation to give nitrile sulphides 93. When they are heated in the presence of dipola.rophiles, such as
DMA]) 25 or ethyl cyanoformate 93 they undergo cyclosubstitution 5 5
reactions (Scheme 34).
Scheme 34 Me02C Ph CN e 02 C S P
E t 7—S (64a) + PhC N NNS s
The mechanism for these reactions may be concerted
(Scheme 35). This process has - been designated as a [2' +(1,2,3)3 cyclodismutacion or cyciosubstitution. Scheme 3 X\
R' 02C—S + RCN Ju -):s. x% s
R iJs X=N ,REt XC CO2R' X=CCQ2 Me , R =Me Alternatively, the reaction may proceed in two steps; cycloaddition to give a bicyclic intermediate, for example
(68) with a hypervalent sulphur at one of the bridgeheads, followed by c;rclofragmentation to the observed products. A 96 similar intermediate (69) has been proposed to explain the interconversion of Lj., -dimethoxycarbonyl-1, 3-dithiole-2-selone and 4,-diiiiethoxycarbonyl-1,3-thiaselenole-2-thione. The corresponding intermediates for the reaction of (64a) with ethyl cyanoforraate would be (70) and (71).
MeQ2 C Ph MeQ2C-s
MeQ2Me MeCMe (69) (68)
Ph Phs 77--S
CO2Et EtO 2C (71) (70) 57
The carbon-sulphur double bond of (6I) acts as a dipolarophile for benzonitrile oxide 25 and benzon.itrile-N- pheny].imine (72). The diphenylnitrile irnine (72), generated from N-phenylbenzohydroxonoyl chloride by dehydrochiorination, reacts with (64) to give a spiro-adduct (73)(Scheme 36). The initial adduct collapses to diphenyithiadiazole (Th) with loss of p7chlorobenzonitrile. Further reaction of (72) with the thiocarbonyl group of (Th) affords the spirothiadiazole (75). Scheme 36
Ar ArCN
Ah + - + -. Phs
PhC-NPh (73) (72) Ph (74.) Ph S Ph (74) ,ksPh Ph (75) Ar = 4-Ct C6H4 '0
Both (74) and (75) were characterised by comparison with authentic samples prepared by reaction of
N-phenylbenzohyth'azonyl chloride with carbon disulphide and trietliyiamine 97.
Photolysis of (64a) in the presence of DMAD gives dimethyl
3-phen3rlisothiazole-, 5-dicarboxylate (ti) presumably via the nitrile sulphide.
In contrast to (64) the 1,4,2-dithiazol-5-ones (8) undergo 26, thermal fragmentation with the loss of carbonyl sulphide, to give a nitrile sulphide which can be trapped by a variety of dipolarophiles.
1.8.3. 1,4,2 - Dioxazol -- ones (76) and 1,4,2 - Dioxazole - -
thiones (77). 1.8.3.1 Preparation
These heterocyclic compounds are best prepared by cyclisation of a hyd.roxanic acid derivative with phosgene or 98 thiophosgene in the presence of tertiary amine
Scheme 37
R 0 ' IN + X=C C12
R' r- ~ OH x X = (76)0 ,(77)S S9
1.8.3.2 Reactions
Thervolysis of these heterocycles leads to cyclofragmentation, with the loss of carbon dioxide or carbonyl sulphide, to give an acyl nitrene fragment (78) which subsequently rearranges (Scheme 38) to isocyanate 99(79)• The intermediate acyl nitrene (78) can be trapped with DM30. Scheme 38
R- NCO (79)
LtJ so. t'1e (78) / N SO Me xo,s 0
The thermolysis of (76) and (77) provide a route to isoyanates which are used as precursors for simple carbamates, polyurethanes, and co-polymers. Furthermore, the caibon dioxide released from(76) may also function as a blowing agent in the formation of foams.
1,4,2-Dioxazol-5-ones (76) also extrude carbon dioxide when 60
subjected to photolysis 990 Again the intermediate acyl nitrene (78) can either be trapped or rearrange to isocyanate. When the substituent is a mesit.yl group (76b) the acyl nitrene
undergoes an intramolecular insertion reaction to give the
isoindolinone (80) (Scheme 39).
Scheme 39
Me Me Me hy
(76b) Me e
(80)
If, however, the substituent is 2-hydroxiphenyl (76c), a
Wolff rearrangement precedes the cyclisation. This leads to the formation of (81) which is different to the product (82) 61
obtained by thermolysis of (76c) (Scheme 40). Scheme Lo
/>/2 (82) Ut-i
OH0 OH
(Si) H
1-.}thy1-2--(M-diethy1)acety1ene (83) reacts with 3-pheny1-.1,4,2,-dithiazo1-5-one (76a) to give the 62
100 isoxazolone (84), presumably via nucleophilic attack
of (83) at C-S of (76a).
Scheme 41
Ph-C 0 Ph NNO o"'~O+ ENCECMe J E 2 N 0 (83) (76a) Me (84)
Hydrogenation of (76a) over Raney nickel, using one mole
of hydrogen, results in cleavage of the nitrogen-o xygen bond 101 to give benzard.de and carbon dioxide 63
1.9 Objectives of Research
The original objective of this project was to investigate 1,3-ciipolar cycloaddition reactions of nitrile sulphides, generated from 1,3,4-oxathiazol-2-ones, with novel dipolarophiles. An area of special interest was the reaction of nitrile sulphides with acetylene equivalents in order to prepare 4,5-unsubstituted isothiazoles.
Since the chemistry of 1,3,4-oxathiazol-2-ones, apart from nitrile sulphide generation is largely unknown, the intention was to study the reaction of a range of nucleophiles with oxathiazolones and related heterocycles (1,4,2-dithiazol-
)-(thi) ones and 1,4,2-dioxazol-S-(thi) ones). 2 DISCUSSION 2.1 Thermolysis of 1,3,4-Oxathiazol-2-ones (2) in the Presence of oc.-Ketonitriles (8). Nitriliuin betaines are known to react with both nitrile
and carbonyl functionalities. OK -Ketonitriles (85)possess two potential dipolarophiles which are mutually activating;
therefore, there is an opportunity for the 1,3-dipole to exhibit a degree of periselectivity. 102 It has been reported that nitrile oxides react with 0< -ketonitriles to give 5-acyl-1,2,4-oxadiazo1es (86) and there
is no trace of the 2-cyano-1,3,4-dioxazole (87) from addition
of the nitrile oxide at the carbonyl function. This is rather unexpected since nitrile oxides react readily with activated carbonyl compounds such as chloral 103
Scheme 42 R N P' /
0 (86) + - RC=N-0 + EN (85)
C (87) 0
The conjugation of the to functional groups in the O(.-ketonjtrjle (85) apparently activates the nitrile function toward 1.3-dipolar cycloaddjtjon whilst the carbonyl is deactivated.
With nitrile sulphides the corresponding products wc.J.d be a 5 acyl 1 ,2,4_thjadjazole (88) and the 2-cyano-1,3, oxathiazole (89) (Scheme 43). A series of readily accessible O(-ketonitriles were therefore utilised to examine the
periselectivjty of a range of nitrile sulphides. In all the reactions examined only thiadiazole (88) was isolated. From the data listed in Table 1 it is noted that Yields-varied greatly with substjtuent. Scheme 43
+ - (as) RCN—S + R"'CN
R0 C N NS R' (89 66
Table 1 "et oc 5- Z,4
Reactant Ratio Product Yield
R R' (85) (2) (88)a S8
Ph Ph 4 1 57 (b)
Ph 1 : 1 36 19
Ph Me 1 : 1 25 (b)
Ph n-C61-1 13 1 : 1 17 26
a) 4 MeC6H4 Ph 4 : 1 78 12 f) Me Ph 4 : 1 15 57
Footnotes: a) after purification by sublimation and crystallisation from ethanol. b) not determined. 67
The yields of nitrile by-product, resulting from competing decomposition of the nitrile sulphide, were difficult to determine. Most were removed from the reaction mixture when the excess dipolarophile was distilled off under reduced pressure. Furthermore, in the case of R-toluonitrile the
~extinction coefficient at 254 nrn is so small that it was not possible to accurately determine the amount of nit-rile present in the reaction mixture below 20% using hplc analysis. This figure is consistent with the amount of sulphur by-product isolated (12%) and the hplc determined yield for the thiadiazole (88%).
From the data available it can be concluded that those nitriles with aromatic substituents are more reactive. Indeed they show a reactivity comparable with ethyl cyanoformate (ECF).
In a competition experiment between benzoyl cyanide and 1.006. equivalents of ECF (Scheme Lh) the ratio of the products was close to unity. 68
Scheme 1414 Ph r---'S,\ CO2Et (90) Ph o,o + EtO2CCN 490/ 139C +
(2a) +PhCOCN Ph
/11-S) ~C 0 Ph (88a)
'10/ I /0 From a preparative point of view higher yields of the
thiadiazole (88) are obtained at high reactant ratios. The spectroscopic properties of the 5-acyl-1,2,4-
thiadiazoles (88), are broadly similar to those of the other
1,2,14-thiadiazoles. For example, the 13C-ninr chemical shifts
for C-3 and C - S are listed in Table 2 for a variety of
1,2, 14-thiadiazoles. 69
r
RN NNSRS
Table 2 Sele4-ed coc -.t. ftv 1f c a o (
&/ppm R R C-3 C-5
Ph COPh 1743 1870
Ph A 1743 18S7
Ph COMe 1744 1859 Ph CO 16H13 1744 161
4MeC6H4 COPh 1743 1868 Me COPh 1746 1867 Ph CO2Et41 1745 17S9
Ph CHCl 2 1736 189 Ph CC1 1739 1902 41 Ph Ph 1735 1878 Ph SAr'7 1725 1802
In the mass spectra all the fragments can be attributed to cleavage at C(3)-N(4) and C()-S(l) (i.e. retro 1,3-dipolar cycloaddition), or at S(1)-N(2) and C(3)-N(4). This
70
is similar to those reported for simple 3,5-diar7l-1,2,1- lOLt thiadiazoles There is also evidence for cleavage
between the heterocycle and the acyl group.
The only previous example of 1,3-dipolar cycloaddition
of a nitrile sulphide to an O( -ketonitrile was that by Hogan
and Sainsbury who synthesised a marine metabolite containing
a 1,2,4-thiadiazole moiety by this approach.
This work establishes that a range of 5-acyl-1,2,4-
thiadiazoles (88) are accessible by this approach. The S-formyl
derivative (91) however, cannot be prepared by this method due
to the unavailability of the required dipolarophile. An
alternative route to this compound is outlined in Scheme 45. Scheme 45
Z(~-'
+ Ph N H0 Ph Cl2 CS C HO Cl2CHCN (92) (91) 7'
It is reported 41that when 3-phenyl--trichloromethyl- 1,2,4-thiadiazole is treated with piperidine the final product is (93) and not (91) as expected. The thiad.iazole(93) is probably formed by hydrolysis of the initial dichloro-adduct (Scheme 46). Therefore, the dichioromethyl derivative (92) was considered to be susceptible to hydrolysis in a manner similar to c,o-dichlorotoluene 105• Scheme 46
U2ND hç 93) - HC Ph /
C C Ct 3 Ph
6 (94.) 72
On treatment with concentrated aqueous sodium hydroxide
in ethanol at 800C, however, there was no trace of the desired thiadiazole (91) (mass spectrum). Furthermore, comparison of the crude product with authentic 3-pheny1-1,2,4-thiadiazole- -carboxy1ic acid, which had been prepared from the ECF cycloadduct (90) by mild hydrolysis, showed that this compound had not been formed via oxidation of aldehyde (91). The parent compound is quite sensitive to cold aqueous alkali and is rapidly decomposed to ammonia, hydrogen sulphide 106• and sulphur Although substituents in the 3- and S- positions exert a marked stabilising influence on the heterocyclic nucleus 107,, the aldehyde (91) may be unstable under the reaction conditions. Nucleophilic attack at the C-5 of the 1,2,4- thiadiazoles has been proposed as a reaction mechanism for many of the ring transformations undergone by this heterocyclic lOu system Examination of the crude reaction mixture from the 73
attempted hydrolysis of (92) indicated that elemental sulphur
(mass spectrum) was present. A possible mechanism is outlined in Scheme 47. Scheme 47
Ph Ph H H H Ph / _j__ G2 _ct2 .-f--- C C12 H SYHH H N 0 (9 2)
> FURTHER REACTION
The exact nature of the other products present in the crude
reaction mixture is unknown. The i.r. spectrum confirms the
absence of benzonitrile but a peak in the spectrum (1700 cm -1 )
also indicates the presence of a carbonyl group.
Although benzal chloride can be smoothly converted to
benzaldehyde loS a similar reaction for the thiadiazole (92) is impossiblei This is probably due to the lability of the
heterocyclic ring under the reaction conditions. 74
2.2 Reaction of Nitrile Sulphides with Alkenes The objective of this study was to react various nitrile
sulphides- with alkenes which 'rere capahie of acting as 108 acetylene equivalents . The use of the.compoimds was
necessary because nitrile sulphides would probably not react with
acetylene itself. This would provide a new synthetic approach
to 4,5-unsubstituted isothiazoles which are difficult to obtain
by other means (see Section 1.7). Two routes are currently
available,; the first involves treatment of dithioliuni salts(95),
particularly those with aryl substituents, with ammonia. The original substitution pattern remains unchanged, with the trivalent
sulphur being replaced by nitrogen (Scheme uS). In all cases, the 5-isomer (97) predominates and in some instances is the sole
product. The ratio (96):(97) is highly sensitive to temperature
and the yields of (96) are low.
Scheme 48
NH 3 Ar} A r + A rJO ci.o1: (97) (96) (95) 7
56-59 The second method involves oxidative cyclisation of 6-iminothiols (3); the 3-substituent must be present at the outset since it cannot be introduced later (see Section
1.7.1.1) (Scheme 49). A wide variety of groups can be accommodated at the 3-position and the usual oxidising agents are halogens or hydrogen perod.de; such reagents however may cause further reaction subsequent to ring closure. Scheme 49
H 1 01
ZCIH H e.,,-N (96) 31)
The three acetylene equivalents considered for the present work were bicyclo [2-2.1] hepta-2,5-diene (norboradiene,
NBD), cis-1,2-bis (phenylsulphonyl) ethylene (cis-PSE) and the 76
esters of acetylenic carboxylic acids, for example ethyl
propiolate. These routes are summarised in Scheme 50.
Scheme 50 RCO2Et C O2Et
EP R IV RC -D,"S \
2Ph
IN Ph
2.2.1 Reaction of Aryl Nitrile Sulphides with Narbornad-iene.
The cycloaddition of norbornadiene (98) with nitrile
odes and nitrile imines has previously been used to
33rnthesise 4,-unsubstituted isoxazoles and pyrazoles 110
The process involves two stages: cycloaddition of the nitrilium 77
betaine to the NBD followed by a retro Diels-Alder reaction
of the 1:1 cycloadduct (99) with etilsion of cyclopentadiene (CFD) (Sähenie si). In both instances the 1:1 cycloadduct (99) was isolated and fully characterised.
Scheme 51
6 R (98) +>N)
+ - RCN—X Xa)O ,b)NPh,.c)S
The corresponding reaction with nitrile sulphides would
afford 3-arylisotlüazoles via the 2-isothiazoline (99c). This approach depends on the dipolarophilicity of the norbornene-type
unsaturation being sufficiently reactive to undergo cycloaddition
to nitrile sulphides. This was tested by heating a solution of
-phenyl-1,3,4-oxathiazol-2-one (2a) and norbornene (16 fold excess) 78
in xnesitylene for 141h. Purification of the crude product
by flash column chromatography gave benzonitrile (30) and
the cycloaddition product exo-3a,?.,446,7 -hexahydro-4,7-
methano-3-pheny7l-1,2-benz 4-.eothiazole (Oo) in 19% yield.
(Scheme 2).
Scheme 52
+ - Ph-CN-S Ph H6 +
U6 6 INIO (100)
The stereochemistry of the ring junction protons H-3a
and H-7a was deduced from the 200 MHz 1 H nnir spectrum (Fig.2) 5 the absence of a large coupling constant between the ring junction
protons (3a, 7a) and the bridgehead protons (7,b) is indicative of exo stereochemistry at the ring junctic..n. This T.ias confirmed
using irradiation experiments (Fig.3)(Appendix 4.3.3.). Irradiation at 2870 and 2823 Hz ppm and 2.4ppm respectively)
had no effect on the ring junction protons. Irradiation at 79
1 H nmr Spectrum (200 MHz) of exo.-3a,7a-t,5,6,7-hexahydro- L,7inethaxio-3-pheny1-1,2-benzisothiazo1e (100)
CP
0'
Ui
LU
I)
Figure 2 83
Irradiation Ex,eriirients Effect on H.-3a and H-7a
Ui 12 ppm 2Lf
:U
265 3.8 3.9 5 pm Figure 3 p 81
286 Hz(l.2 ppm) removed the small couplings to H-3a and. H-la
leaving J 3a, 7a 9.5Hz. The absence of coupling between
H-3a,I-4 andH-7,H-7a is a clear indication of the exo geometry
of the adduct (iOo). This is in accord with previous 1,3-
dipolar cycloaddition reactions with bicyclic alkenes ill,
and compliments the work of Howe and Franz who showed that
the dicarboxylate analogue (12) of norbornene would react with
benzonitrile sulphide to give the exo adduct (101) in 28 yield
(Scheme 3). Scheme 53
+ - Ph-C=N—S
+ 2' O2Me (101) %Me LO2Me (12) CO2Me
Encouraged by this result, 'oenzonitrile sulphide was then
reacted with NB]). Thermolysis of phenyl oxathi azo lone (2a) in
the presence of a 9-fold excess of norbornadiene, using rlene 82
as solvent, gave 3-phenylisothiazole (96a; ArPh) in 19 yield together with benzonitrile (80). Under the reaction conditions there was no trace of the expected 1:1 adduct (99c; R=Ph). Presumably, the temperature required for smooth decarbocrlation of the oxathiazolone (2a) (ea 120°C), is sufficient to cause the retro Diels-Alder fragmentation of the 2-isothiazoline adduct (99c). Using similar conditions 3-(-methopheny1) isothiazole (96b;Ar4-MeOC6H) was isolated together with 27methoxybenzonitrile (81). Raising the reaction temperature, by altering the solvent from reflwdng xylene (ca 122 00) to refluxing mesitylene
(Ca 1300C), increased the yield of (96b) from 16% to 31% and the amount of nitrile side product decreased to 22%. A variety of 3-arylisothiazoles (96) were prepared using this approach (Scheme 83
Scheme S)4 A o
rNs , ~ , Ar + ArCNS
(96)
Table 3 Yields of isothiazole (96)
Ar Reaction Temp. (°C) Yield (%)
96a Ph i20 19 96b 4-MeOC6H4 122 16
130 31 9 6 c 4-MeC6H4 125 26
96d 4 CIC 6H 4 130 18 84
112 It has previously been reported that yields of
1,2,4-thiadiazoles synthesised by cycloaddition of nitrile
sulphides to nitriles can be improved by using a large excess
of dipolarophile under conditions of high dilution. This was
achieved by dropwise addition of the nitrile sulphide precursor
to the refluxing reaction mixture. For example by increasing
the concentration of the nitrile from 10-fol1 excess to 100-fold the yield of cycloadduct (102) increased from 111% to 74. These observations are inconsistent with a first order process
for the decomposition of the nitrile sulphide (3) to nitrile and sulphur (Scheme SS). Scheme 55 PhCN
kl
Ph ZZ_ 0\ PhC- t 2 (3) k 2 C 2a Ph 7-N NS'Ar - (102) 0
If the decomposition of (3) was to occur via a unimolecular process then:
dUlO2)]/dt = k2[(3)] [ArCNI
d[PhCN]/dt= k1[(3) 1.
The observed dramatic increase of thiadiazole (102) yields with increased numbers of molar equivalents of nitrile is not consistent with a uniinolecular process. The marked dependaxice of yield on the conôentration of nitrile is in accordance with decomposition of nitrile sulphide (3) by reaction with short sulphur chains. The chain growth would involve a series of bimolecular reactions, the rate of which, and therefore that of formation of the nitrile by-product, would be slowed to a greater extent by dilution than that of a simple unimolecular decomposition of nitrile sulphide (3).
In order to test this hypothesis further , and hopefully achieve greater yields of the isothiazoles (96), the reactions of nitrile sulphides with NBD were repeated under conditions designed to ensure high dilution of the nitrile sulphide and
hence maximising the dipolarophile; dipole ratio. A solution
of oathiazolone (2) in Inesitylene was delivered to a mixture
of mesitylene and norbornadiene heated under reflux over a
period of 85h using a syringe pump. During the course of the
reaction the temperature rose from 102 °C to 1350 as the proportion of the lower boiling NBD in the reaction mixture decreased. Utilising these conditions the yield of 3-(- metho)rphenyl)isothiazole (96b) rose to 70% with p7anisonitrile
(30%) accounting for the rest of the product. 3-(-Tolyl)- and
3-phenylisothiazole were prepared similarly in 78% and 53% yields respectively. In each case the amount of nitrile by-product was
substantially lower (Table Li.) than that obtained when the
reactants were mixed at the outset. This confirms that improved yields of cycloadducts can be obtained under conditions of high
dilution. This approach is to be recrnznended for less reactive
dipolarophiles. The technique however is limited by the low
solubility of the oxathiazolone (2) in mesitylene. 87
Table IL F,ek jtd_ fc 1ov oF 0 i4yii e I- ,%;L0 YIELD (%)
Isothiazole (96) Nitrite
a 53 b 70 30 C 78 20
To overcome this problem a mixed solvent (chloroform: mesitylene; 1:10) in which the oxathiazolone (2) is highly soluble was employed. Thi combination however, also causes a drop in reaction temperature (101-102 °C) and therefore an increased reaction time is needed.
The 3-substituted isothiazoles are easily identifiable by
1 H nxnr spectroscopy.
For example that of - ( p—t 0 1. y I ) isothiazole shown in Fig.Li. H-S has a chemical shift of ca 8.6 ppm and H-IL of ca 7.6ppm. The H-coupling between the adjacent protons H-LL and
H-S is IL.7Hz. VIJ
nmr Spectrum
co
w
Figure 4 39
2.2.2. Reaction of p-Toluonitrile Sulphide with Z-1, 2-bis (Phenylsulphonyl)ethylene. The second acetylene equivalent considered was
Z-1,2-bis (phenylsulphonyl)ethylene (10 6) (c-PSE). Whilst this compound is less reactive than the E-isomer in the Diels-Alder reaction 113, both products are equally labile to reductive elimination of the phenylsuiphonyl groups with
sodium amalgam in methanol 114 .The alkene (106) has net been used as a dipolarophile before but is a very reactive dienophile 113 There are however, reports in the literature of 1,3-dipolar cycloaddition reactions with a variety of dipoJ.arophiles activated uS by a phenylsulphonyl group 115-118 • For example, the reactions of the phenylsulphonylethylenes (103) with nitrile imines and nitrile oxides have been studied (Scheme 56).
Scheme 56 + - ArCN—X A r.SO2Ph A
,çSO2Ph > 'SO 2Ph (104) (1O)
(103)
Xa)O,b)NPh R=H,Me, Ph, COPh. I.
90
For the isoxazole (10a) elimination of phenylsulphonic
acid can be achieved by reaction with 1,4-diazabicyc1o[2.2.2] octane (Dp.BC0). When R=C3Ph both regioisomers (104a) and (lOSa) undergo elimination even on silica gel and the pyrazolinés (10b) cannot be isolated. Elimination of pheriylsulphonic acid from these compounds is facile and is in agreement with previous observation on the ease of elimination 119 from the s-position in pyrazolines and isoxazolines 20•
Thermolysis of-(-to1yl)-1,3,14.-oxathiazoi-2-one (2c) and
Z-1,2-bis(phenylsulphonyl)ethylene (iO) in refludng Xylene at
ca 13 0C for 20h under a nitrogen atmosphere did not give the expected isothiazoline product (107). instead isothiazole (108) was isolated (38%). Presumably the initial isothiazoline
cycloadduct (107) undergoes elimination of H-S0 2 RI between the
- and s-positions to .ive the observed product (Scheme 7). Scheme 57 -
+ A S02-Ph
2 ArO2PhNNS SO2Ph CSO2Ph / (107) (108) SO2Ph Ar = 4MeC6H4 (106) 91
That the product was the Li-phenylsulphonyl isomer rather than 1 the 5-isomer was confirmed by H rimr spectroscopy. The observed chemical shift for the isothiazole proton S 1,=9.5 ppm) is characteristic of H-S 16• Examination of the unreacted alkene revealed, however, that it was not the cis-compound originally used but its trans-isomer. It is concluded that under the reaction
conditions the dipolarophile has undergone a cis-trans isoinerisation. The alkene itself is thermally stable at these
temperatures (ca 1350C). 121 It has previously been noted that thermolysis of 5_(7metho,çrphenyl)-1,3,4-oxathiazol-2-one (2d) in the presence of diethyl maleate gave the adduct (109a) (23%) with the trans- stereochemistry (J 5 hHz). This product was identical to that prepared from diethyl fumarate (Scheme 58). Scheme 58 Ar CO2Et Ar CO2Et A
- + CO2Et -0O2 S"C O2 Et (109 Ar CO2Et 1' CO 2Et
Ar ma)4-MeOC6H 4 b) 4- Me C14
92
It was assumed that the initial cis-adduct, was undergoing isomerisation to the more stable trans-isomer (109a) in a manner similar to that observed for 2-is oxazolines 122 derived from nitrile oxides (Scheme 9). In polar solvents both diastereoisoniers, possibly through enolization of the !i.-carbolate group, establish an equilibrium in which the
lower melting trans-isomer (111) dominates. Scheme S9. /OH r
• [tO2
A ?rCO2R ___ ___ A 0 t NH O2R 0 t02R (110) 1L (111)
[02 'I
NN
The reactions of nitrile sulphides with diethyl maleate was
therefore re-examined. Therniolysis of 3-(-to1yl)-1,3,4-
oxathiazol-2-one (2c) in the presence of an ca 10-fcld. excess
of diethyl rnaleate (D4) gave a lOW yield of cycloadduct (109b)
together with E7toluonitrile 80% by hplo analyi•. Careful examination of the unreacted alkene by 1 H nmr
spectroscopy revealed that only diethyl fu.marate was present;
no diethyl maleate could be detected. Diethyl fumarate and
diethyl maleate are readily distinguished by 1 H ninr spect:.'cscopy,
the alkeneprotons have chemical shifts of 6.5 and 6.0 ppm
respectively. Two possible r.echanisms can account for this isomerisation.
The first is a reversible 1,3-dipolar cycloaddition reaction,
in which the reverse reaction is a non-concerted two-step process
via an intermediate (112) in which rotation about the carbon-
carbon bond is possible. This intermediate (112) could then give
the trans-isomer by recombination or dissociate to give nitrile
sulphide and trans-alkene (Scheme 60). A similar mechanism Off
involving a diradical intermediate rather than a
zwitterion is also possible.
Scheme 60. Ar P/~ AçCG2Et Ar,CO2Et + (( )O2EF CQ2Et ( CO2Et S
(112) Lc: O2Et
CO Et Ar CO2Et + - 4 rl EtO2C" r-' S "CO2Et
Alternatively, the alkene may undergo isomerisation from
cis to trans before the cycloaddition reaction occurs. Diethyl
maleate is thermally stable under these reaction :iditions
(ca 13 0C) and indeed can be heated at reflux with no apparent
isoInerisation. 9;
In order to help distinguish between these mechanisms an alkene was selected which was expected to be of too low reactivity to undergo cycloaddition to nitrile sulphide. Cis- and trans -stilbene were considered suitable for this purpose.
Thermolysis of tolyl-oxathiazolone (2c) in the presence of a
2-fold excess of trans -thtilbene gave only sulphur (95%) and
,-toluonitrile (92%) together with recovered trans-stilbene (90%)
No cycloadduct could be detected (mass spectroscopy). However, when c-stilbene (2-fold excess) was used, sulphur (94%) and -toluonitrile (90%) were recovered together with trans-stilbene
(9o). Its identity was established by H ninr and by melting point and mixed melting point (Scheme 61). The ability of nitrile sulphides to effect cis to trans isomerisation of alkenes is thus confirmed.
Scheme 61. Ph Ph
=CO2 > ArCN S Ph )I Ph+ 5 +
Ar = 4-MeC6H4 Ns
+ Ph v-Ph --_>ArCNS II Ph6) CPh 96
The conversion of maJ.eate to fuinarate esters has been
thoroughly investigated under thermal 123, free radical 124, 125 126 acidic and basic catalysis. The only report of such catalysis under neutral. conditions is that of Doyle and co- 127 workers. who described the reaction of alchlorocarbenes,
generated from the diazirine (113), and diethyl maleate.
Under the reaction conditions the formation of the cyclopropane
adducts was accompanied by isomerisation of the diethyl maleate
A. fuinarate. The proposed mechanism is outlined in Scheme 62.
Scheme 62 R •R ArC
C P Ct + V Ar H1, 1H H:ç1R C> R
7ocTz
C 41 R R ( 113 ) H,Ci H C I >R( H A RCO2Ef .-.- .. 97
By using catalytic amounts of 3-bromo-3-phenyldiazirine, diethyl maleate can be converted completely to fumarate at
0 128 30 C. . The process is believed to involve formation of 3-phenyldiazinium bromide (iii.i.) which exists as a tight ion pair and catalyses the reaction (Scheme 63). Triphenylniethyl bromide was also found to be all effective catalyst.
Scheme 63
Ph 30*C B r>41 Br (114) ,A_ Br CO2Et ):-OEt (114) '0 EtO2C>-0Et CCO2Et (,C O Ft Esr
A U 'I COEt (114) '. HL )..OEt j_CO2Et
B r1 O2Et EtO2C EtO2C
A Ph- AS. 98
Since the nitrile sulphide mediated isomerisation of an unreactive alkene, such as cis-stilbene, precludes a reversible cycloaddition reaction as outlined in Scheme 60; the reaction mixture must contain a species capable of catalysing such an isomerisation. It has long been recognised that the cis-trans isomerisation of unsaturated fatty acids is an equilibration reaction and that complete conversion of all cis bonds to trans in one reaction is impossible. Equilibration however, zny be 130 . caused by thols 129 , thiyl radicals and other species 131
Presumably when nitrile sulphides decompose to nitrile and sulphur, there are many "reactive" sulphur species present in the reaction mixture, for example S 2 , S. These may then interact with the olefinic bond to produce a short lived, zwitterionic or cliradical, intermediate which undergoes rotation and thus forms the more stable trans-isomer (Scheme 64). Scheme 64
C Et %Et S-S-CQ2Et Sn CO2Et H"tEt EtO2C Sulphur reacts with alkenes, even below 160°C, to form 132, polysulphides although below 130°C the tteraction of sulphur with olefins is extremely slow 133• However, above this temperature the primary products from mono-olefins are complex mixtures of organic polysulphides as well as products formed by cis-trans isomerisation and bond migration. Indeed oleic acid can be converted to its trans-isomer, e'laidic acid, o 134 by heating at 200 C with sulphur in an open vessel for 3h
In order to test the effect of sulphur on the maleate- fumarate system, a solution of diethyl maleate and sulphur were heated together at ca 135°C. After 7h there was no sign of isomerisation by 1 H nmr spectroscopy. However, when diethyl maleate and sulphur were heated together under reflux (Ca 220 °C) for lh, the 1 H nmr spectrum indicated that complete isomerisation to diethyl fuiaarate had occurred.
These results suggest an alternative explanation for the 121 result observed by Ross . Formation of the trans 2- isothiazoline (109a)may be due to reaction of the - methoxybenzonitrile sulphide with diethyl fumarate formed by isomerisation of the maleate rather than the isomerisation of 130
the less stable cis adduct. The trans-fumarate is more reactive than the cis-rnaleate in cycloaddiion reactions 137, therefore only the fuinarate cycloadduct (109'a) woaid 1e formed.
(#'CO2Et A O2Et ArCNS CO2EF LCO2Et Is
Ar C N S
EtO2C ArCO2 Et ArCNS
CG2Et O2Et 101
2.2.3. Decarbojrlation of Isothiazo1e-4 and 5-Carbo71ic Acids
The third approach to L-unsubstituted isothiazoles
was prompted by the observation that 3-ary1isothiazole-4- dicarboçrlic acids (uS) undergo facile thermal mono- -16 decarbor1ation to give the 3-az7lisothiazo1e-4-carboJcrlic acids
(116) (Scheme 65). Scheme 65
A r Q2Me A r 02H A r 02H
02Me zS 02 H -c (115) (116)
Ar = 4-Me C6H4
Provided both carboxylic acid groups can be removed, the reaction
of nitrile sulphides with DMAD could provide another route to
4,5-unsubstituted isothiazoles (96). Since the L.,-dicarboxylic
acids (115) preferentially decarboxylate at the '-position, it was decides to attempt to decarboxylate the 3-ry1isothiazole-5- carboxylic acids (119). These were prepared by thermolysis of
132
a suitable 1,3,14-oxathiazol-2-one(2) in the presence of
an excess of ethyl propiolate (EP). The two regio-isomers (117a) and (liSa) were separated by flash column chromatography
on silica eluting with dichlcromethane : petroleuit ether (4:5). In the case of ethyl 3-(-tolyl) isothiazole-b- and 5- carbolates, the 4-isomer was an oil and they were separated
by selective crystallisation of the -carbo:rlate (1l'3b). The
5-carbor1ic acids (119) were generated by alkaline hydro1yss
of the esters (Scheme 66).
Scheme 66
Ar Ar CO2EtAr HC EC C 02Et CO2 :S S +O2Et (2) (117) (11 8)
(118) o- CO2H (119) - Ar =a)4MeQC6H 4 ,b) 4-MeC6H4 103
Thermolysis of 3_(-methorphenyl) isothiazole--
carbor1ic acid (119a) in refluxing O-dichlorobenzene
(Ca 1800C) for 2.h gave only unreacted starting material and 3-( 7methoxyphenyl)isOthiazOle (9b) could not be detected by hplc. Similarly, thermolysis of 3-( 7tolyl)
isothiazole--carboxylic acid (119b)in o.-dichlorobenzene for
3h resulted in some decomposition of the starting material, but only small traces of 3-(P-tolyl)isothiazole (9c) could
be detected by hplc analysis and 1 H nnir spectroscopy. These results suggest that the second carboTl group in
the 4,55-dicarborlic acids (il) is necessary for decarborlation.
A possible mechanism for this reaction is outlined in Scheme A7i
examination of a model of he molecule supports this hypothesis,
The two carbc:l groups are in close enough proxiraity -1 -k
easy migration of a proton.
Scheme 7 -
OH R HO-. d'H R 17__c02 1-I NS 2 H Ns/ 0 (116) (115) 104
After failure of simple liquid phase thermolysis to effect decarbo1ation of isothiazole_-carbwçrlic acids (119), it was decided to attempt decarbocrlation in the gas phase using .a technique known as flash vacuum pyrolysis (FVF).
FVP has been used previously to decarbocr1ate indo1e-4- carbo1ic acid 136 (120) and 2,3-dihydro-4-methyl-3- 137 oxopyradizine-6-carboxylic acid (121).
C 02 I-i O2CaCH 3 N---O H ( 121 ) (120)
The FVP apparatus used is shown in Fig.. The sample
to he pyrolysed is placed in the inlet tube and the systera is FVP Apparatus used in Pyrolysis Experiments
Thermolyeie tube inert gas inlet
Product trap
To Pump (D
Ln 1E_ . I.
Inlet tube Liquid Furnace N2 106
then evacuated (pressure ca 2 x iO rnrni -lg). Heat is then applied to the inlet tube by means of a Kugelrohr oven and the sample sublimes (or distills if liquid) into the thermolysis tube. This silica tube is heated by a furnace to 0 temperatures above 850 C. The pyrolysate is trapped at liquid nitrogen temperatures. When sublimation is complete, the trap is allowed to warm to room temperature and an inert atmosphere
(usually N ) introduced into the system. The product can then 2 be dissolved in either deuteriochloroform or d6-acetone and examined by nmi' spectroscopy.
Since the ethyl esters (117)and (118) sublime at lower temperatures than the corresponding carboxylic acids (116) and
(119), it was decided to attempt both the de-ethylation and the decarborylation reactions by FVP.
Initial work with ethyl 3-(-methophenyl) isothiazole-
carbolate (118a) had th be abandoned because, under the- conditions required for de-ethylation and decarborlation,there was concomitant loss of the methor group, giving rise to a coxap1. mixture of products. In order to circumvent this unwanted side reaction, the -tolyl analogue was used. 137
Flash vacuum pyrolysis of ethyl 3-(7toly1)isothiazo1e-.
5-carboxylate (118b) was carried out over a range of 0 temperatures (8500c-1000 C) and the pyrolysate separated into deuteriochlôroform soluble and d-acetone soluble portions. These solutions were then examined by 1 H nmr spectroscopy for traces of the 3-(-to1y1)isothiazo1e (96c) and the isothiazole-
5-carboxylate acid (119b). At 850 °C only the 5-carboxylic acid
(119b) was formed, presumably via extrusion of ethylene from the ester (118b). When the furnace temperature was raised to 900 °C , the isothiazole (96c) was detected as well as the 5-carboxylic acid (119b). On raising the temperature to 950°C, the deuteriochloroform solution of the pyrolysate also contained
-toluonitrile. At 1000°C only the isothiazole (96b) and p7toluonitrile were detected with increasing amounts of intractable tars. 0 The most convenient temperature for preparative work was 950 C, since the amount of insolu. ble products was minimal and the -toluonitrile could be easily separated from isothiazole (96c) by flash column chromatrography. From pyrolysis of the ethyl ester (118b) at this temperature, 3-(-tolyl)isothiazo1e (96c) was isolated in 35 yield. 108
These results are consistent with loss of ethylene to form the isothiazo1e_.caroçrlic acid (119b) which subsequently decarbolates to give the isothiazole (96c) (Scheme 68; Mechanism A), although synchronous loss of ethylene and carbon dioxide at higher temperatures cannot be excluded (Scheme 68; Mechanism B). Scheme 68
A H -c2,.I > 04 KIIS (9&) (119b) 11&b)
Mechanism A
I P -c2 A NrlHlPC 0 C 02 (96e) 119b)
Mechanism B Ar = 4-MeC6H4 109
Having established that the 5-isomer (118b) could be de-ethylated and decarboxylated, attention was turned to the corresponding L-carboxylate (117b). Initial attempts to obtain this compound from reaction of nitrile sulphides with EP had to be abandoned since it proved to be impossible to remove all
traces of the 5-isomer. The Li-isomer (117b) was therefore synthesised from the DMAD adduct via mono-decarboxylation of the di-acid (115 ) followed by re-esterification (Scheme 69).
Scheme 69
Ar CO7Me Ar CO2H Ar CEt — 1) - > \ 1)socI,> CMe n 2) EtOH 11 6) C 117b)
Ar= 4-MeC6H4
FVP of the 4-carboxy1ate (117b) at 900°C yielded a mixture
of the 4,5-unsubstituted isothiazole (96c) and the carboxylic
acid (116 ). On raising the temperature to 10000C only the isothiazole (96c) could be detected. IL)
S.
Having established that both the isothiazole-b-and
-carboxylates (117b) and (118b), could be de-ethylated and
decarboqlated by FVP, attention was turned to diethyl
3-(-tolyl)isothiazole-4-dicarborlate (112). This product was synthesised by 1,3-dipolar cycloaddition of R_toluQflitrile
sulphide, with diethyl acetylenedi.carborlate (DEAD) in
approximately 40% yield. The poor yield was due to the large amount of intractable oils formed, presumably due to polymerisation of the DEAD under the reaction conditions
(Scheme 70).
Scheme 70 + - Ar CEN-S A
A + C CC2Ef Et 02C- CEC-CO2Et (12.2) Ar = 4-Me C6H 4
Pyrolysis of the diester (.122 ) at 9 C gave a raxture of the 4,5-unsub3tituted isothiazole (9c) (24%), -to1uonitri1e (3)) and the isothiazole-L-carboxylic acid (11E. ). 111
When the furnace temperature was raised to 1000 °C, only
7to1uonitrile and the isothiazole (96c) were detectable.
Flash vacuum pyrolysis was also used to effect decarboxylation at 950°C of the t-carboxylic acid (n6 ) and the 4,5-dicarboxylic acid (115 ). In the case of the mono-carboxylic acid (116 ) the 4,5-unsubstituted isothiazole
(96c) and E-toluonitrile were detected by hplc analysis. The 1 H nmr spectrum of the reaction mixture also indicated the presence of starting material (116 ). The dicarboxylic acid
(115 ) gave the same products as the diethyl ester (122 ). However, the temperature required for sublimation of the 4,5- dicarboxylic acid (115) was 200 °C (2x 10 mmHg). This temperature may have been high enough to effect mono- decarboxylation before the substrate reached the thermolysis tube. The resulting 14-carboxylic acid (116) would then be pyrolysed in the normal manner.
3-(7to1y1)isothiazo1e (96c) is itself unstable under the
FVP conditions employed. Pyrolysis of isothiazole (96c) at 0 90 C gave traces of -toluonitrile in the recovered pyrolysate. 112
These results are summarised in Table S. Table S Results of FVP Experiments
1'yocL, c okx,ved. bj 'Ft r, Mr ecr
Furnace Carboxytic Isothiazole Reactant Temp (°C) Acid (96c) 4MeC6H4CN llBb 850 119b — — 900 119b — 950 119b (33%) / 1000 — / - 117b 900 116 1000 - — 3 %) 122 950 116 ( 24%) ( 1000 115 950 116 116 950 116 96c 950 -
By comparing the 1 H nmr spectrum for the crude
duteriochloroforin soluble pyrolysate. from ethyl 113
3-(--tolyl) isothiazole-S-ca,rboxylate (118b), shown in Figure 6, with that shown in Figure 4 (p. 88) for isothiazole (96c) synthesised via MBD it can be seen that FVP results in a clean reaction. Flash vacuum pyrolysis of ethyl 3-arylisothiazole carborlates provides another approach to 4,5-unsubstituted isothiazoles (96). The technique, however, is limited to aryl groups which are not labile under the FVP conditions. 114
nmr Spectrum of Crude CDC1 3 Soluble Pirolys ate.
CKY
1.2
U,
Ui
NJ
Figure 6 11 ii
2.2.4. s ummary Of the three possible approaches to 4;5-unsubstituted iothiazoles described here (Scheme 71), the first via reaction of nitrile sulphides with norbornadiene (Route A)
is considered the most viable. Although the yield from the 1,3-dipolar cycloaddition reaction is only 20-30, the one-pot nature of the route is a distinct advantage. The pyrolytic
route (B) from ethyl esters (117),(118) and (122), is dependant on the stability of the 3-su.bstituent under the pyrolysis conditions. The third approach (Route C) via reaction with cis _1,2-(phenylsu1phOflYl) ethylene was not investigated further. The formation of isothiazole (108) was unexpected and it was
uncertain whether the Li-(phenylsulphonyl) group could be removed
by the literature method 114. 116
Scheme 71
A CO2Et nc~ CO2Ef sS EP FVP (118) (117)
ArCs
5)
(10 8)
117
2.3 Thermolysis of 1,3,4-Oxathiazol-2-ones in the
Presence of Miscellaneous Dipolarophiles
Most of the dipolarophiles considered in this section had previously been used to trap nitrile sulphides generated from sources other than 1,3,4-oxathiazol-2-ones. 2.3.1. MaleIc Anhydride It has been reported 23 that benzonitrile sulphide derived from N-benzyliininosulphur difluoride (7a)reacts with xnaleic
anhydride to give the cis-fused isothiazoline (fl)(Scheme 72).
Furthermore, IL-substituted maleimides have been reported to give cycloadducts with 27chlorobenzonitrile sulphide generated
from the oxathiazolone (2e). Scheme 72 0 0 + Ph Ph Cs N -S + ii0 L.C .0 (11)
PhCH2-Nz.SF2 (72)
.LL LI
5-(7Methoxyphenyl)-1, 3,Li-oxathiazol-2-one (2d) was dissolved in mesitylene and this solution was then added to a reflud.ng mixture of maleic anhydride and mesitylene over 36h. A nitrogen atmosphere was maintained throughout the reaction. Evaporation of the solvent gave a black solid, which contained
no identifiable products. When maleic anhydride, sulphur and
mesitylene are heated together under reflux for 17h, however sulphur (99%) was recovered together with unchanged maleic
anhydride. The nitrile sulphide is possibly inducing polymerisation of the maleic anhydride, although the exact
nature of the reaction is unknown. 2.3.2 Phenylacetylene and 2,3-Dimethylbut-2-ens 32 Machida and co-workers have recently reported that nitrile sulphides, generated from arylthioamides by photolysis
in the presence of 02, could be trapped with phenylacetylene and 2,3-dimethylbut-2-ene (Scheme 73). Scheme 73 Ar Ph
NS Ph CE C H
Ar,f h 02 NH2
Me M e2
4r Ph, 01 ,, 0 S zC.
119
However, benzonitrile sulphide generated from N-
benzylimino sulphur difluoride gave no cycloadduct with
phenylacetylene 34, and nitrile sulphides derived from -
thiocarbonyl diphenylsulphixnides cannot be trapped with 22 diphenylacetylene It was therefore decided to test these
results using nitrile sulphides produced from another established
source.
When -phenyl-1,3,4-oxathiazo1-2-one (2a) and
phenylacetylene were heated together under reflux for 1h,
H S was formed during the course of the reaction; Kugelrohr 2 distillation of the crde reaction mixture gave only benzonitrile
(82%). The residue could not be purified further,presumably
A- he sulphur produced is reacting with the phenylacetylene i 8 to produce a complex mixture of products. The exact
mechanism for the evolution of hydrogen sulphide in this
reaction is unknown; perhaps the sulphur is interacting with
the acidic hydrogen of the phenylacetylene. 120
2,3-Dimethylbut -2- ene is an example of an electron rich olefin. To date only electron deficint alkenes have been used as dipolarophiles with nit- rile sulphides.
Thermoiysis of 5-phenyl-1,3,4-oxathiazol-2--one (2a) in the presence of an excess of tetrarriethylethylene gave sulphur (20%) and benzonitrile (80%) together with a large amount of intractable black tars. There was no indication of the formation of the tetramethyl -2-isothiazoline (12L4;ArPh). These results are ancL in direct contrast to those reported by Machida at alia,Lin consequence their findin require re-examination.
2.3.3. Coumarin Previous work 8 has established that 3-aryl-4-oxo -4H- chromeno [ 4,3c] isothiazoles (29) can be prepared by intramolecular c;rcloaddition of benzonitrile sulphides with an 121
ortho-propiolate ester substituent (125) (Scheme 7I). Scheme Th
Ar - II n O- C CAr a'n 0 - ( 29 ) (125)
The reaction of an arylnitrile sulphide with coumarin should therefore provide access 0 the L3cm3ric 3-.ary1-2-oxo-
07chrcmeno 13,4 -d ] isothiazoi35 (126) and 3-aryl-4- o:o-
L.H-chronienc[ 4,3-] isothiazoles (127) by oxidation of the initial cycloadducts (Scheme 7). 122
Scheme 75 -N \ r
+ - Ar-C=N-S (126) (128) + r J oo Ar
0 (177) (129)
Diphenylnitrilimine has previously been reatad with -
various coumarin derivatives to gie the chromcnpazo1ines.
(I3O),rhich could be c:ddiged to the corresponding pazole(131)
in the case of coumarin 139 (Scheme 76). 123
Scheme 7
R Ph Ph CN-NPh > " Oln0 ( 130 )
• N—N. L \)—Ph -2H R = H (131)
When -(7methoxypheny1)-.1,3 ,!-oxathiazol--2-one(2d) and
an excess of cowarin were heated together under reflux in 1ene for 48h, sulphur (100%), 27anisonitrile (89%) and cou.marin (100%) were recovered. It is concluded, therefore, that the olefinic bond in coumarin is too poor a dipolarophile for 1,3- dipolar cycloaddition to nitrile sulphides. 2.3.4. Thermolysis of 1,3,4-Oxathiazol-2-one in the presence of Ethyl Cyanoformate. Bak and co-workers reported that pyrolysis of 1,3,4-
oxathiazol-2-one (2f) at 7000C gave isothiocyanic acid (132) and not thiofulininic acid (133) as expected 82,140. (scheme 77) 124
Scheme 77 H-C=N-S 133
(2f) H-N:CS (12
In order to verify that this gas-phase reaction ocira in the solution phase, freshly prepared 1,3,4-oxathiazol-2-one
(2f) and ethyl cyanoformate (ECF) were heated together under reflux for 1.5h. The excess ECF was carefully distilled off and the residue analysed by H nmr spectroscopy; there was no trace of a 12,4-thiadiazole adduct. This confirms the result obtained by Bak and co-workers, and that the parent 1,3,- oxathiazol-2-one does not undergo thermal decarboçrlation in a manner similar to substituted oxathiazoiones. 125
2 .Li Sigmatropic Addition and Cyclosubstitution Reactions
of 1,4,2-Dithiazole-5-thiones (64)and aelated
Heterocycles. The thermal decarbo1ation of 1,3, LL-oxathiazol-2-ones is the most commonly used method for the generation of nitrile
sulphides. The synthesis and thermal stability of these compounds have therefore been the subject of detailed examination.
In contrast, the analogous 1,4,2-dithiazole-5-thiones (64),which on extrusion of carbon disulphide would also afford nitrile sulphides, have received much less attention. Dithiazolethiones (64) are readily prepared by heating together a mixture of perch.loromethylmercaptan (Sb) and two molar equivalents of the thioamide in chloroform. The mechanism for this reaction is
outlined in Scheme 78 (see also Section 1.8.2).
Scheme 78. R ,' RSH -1'S C(CSCL I ----- RCSNHSCCt 3 C!.3 NH2
R RCSNH2 _Q_ + RCN N. S 7 C1 N s ) (64)
Photolysis of the dithiazo1ethione(64) in the presence 126
of dimethyl acetylenedicarbocrlate (DNAD) does give a small
amount of the isothiazole cycloadduct (134), presumably via
the nitrile sulphide (Scheme 79).
Scheme 79. R,CO2Me DMAD NS' RC - NLs CO2Me (64 (134)
25 However, Noel and Vial-le reported that the thermal reaction
follows a different pathway yielding the dithiolethione (13).
This observation was confirmed by Greig and co-workers,using
3-phenyl-1,4,2-dithiazole-S-th 4Lone (64a) and "a three-fold
excess of D14 3 (Scheme 80).
Scheme 80
Phs MeO2C + PhCN
(64a) . (135)
127
The formation of the 4,5-dimethoxycarbony1-1,3-dithiO1e..
2-thione (135) involves cycloaddition of the alkyne to the
exocyclic sulphur and one of the ring sulphur atoms and is
accompanied by expulsion of a nitrile fragment. There are
two possible mechanisms to account for this transformation.
The reaction may proceed in two steps, cycloaddition followed by cyciofragmentation, via a heteropentalene (Scheme 81)
Scheme 81
P _ Ph_
s s ,PhCN
szcs' ' E
Ph r Ph hCN /s, ~®r\ -N---'S ~ks 0~1S
E E
- E = CQ1e 128
Lakshmikantham and Cava proposed a similar mechanism for the interconversion of Li, S-dimethoxycarbonyl-1, 3- dithiole-2-selone and Li, -dimethocarbonyl-1, 3-thiaselenole-2- thione 96 Alternatively, the reaction may proceed by a concerted mechanism. This reaction is an example of an eight centred process, which Drozd and Zefirat describe as a cyclosubstitution
or a [ 2 + (1 2 2 2 3)] cyclodismutation reaction (Scheme 82). Scheme 82
Ph
s CQ2Me S :%C O2Me
129
There have been many reports of reactic&.Of" thI3 type
in the literature; some are shown in Table 6 . Table 6 Examples of Cyclosubstitution Reaction Ref. Ph? S MeO2C.ç\ . ->. II KS ~,S MeO2C52S 25,93
Ph EtO2C ECF ? 93 S rs~
MeO2C c OMM 141 M e 0
Me0C s Me Me 02czs,~, Ni-Me tAD1 + 4. 142 PhJ S)S Me MeO2C.., .4..Me Me02 CS s 130
In order to develop a general route to
1,4,2-dithiazole-5-thiones (64), which are difficult to obtain from the thioaxnide (e.g. due to the 14navai1ibiity of the
thioainide) the reactions of 3-phenyl-1,4,2-dithiazole-5- thione (64a) with a range of nitriles were examined.
Heating phenyldithiazolethicne (64a) with trichioroacetonitrile (TCA) in xylene under reflu.x afforded
3-trichlorornethyl-1,4,2-dithiazole-5thiOfle (64d) in 70% yield.
Repeating this reaction in the absence of solvent increased
the yield of the thione (64d) to 83/-0'but the reaction time was
longer (161th), probably due to the lower reaction temperature.
When dithiazolethione (64a) ws refluxed with dichloroacetonitrile for 27h the expected product, 3-
dichloromethyl-1,4,2-dithiazole--thione (64e), proved to be
inseparable from the starting material (64a). The presence of
the product (64e) was confirmed by hplc analysis and comparison
with an authentic sample.
Heating phenyldithiazolethione (64a), benzoyl cyanide and
lene at reflux (ca 139 °C) for 192h yielded very little of
the expected 3-benzoyl-1,4,2-dithiazole--thione (64f)(< 7). 131
This result was a little surprising, since benzoyl cyanide and
ECF are of very similar dipolarophilic strength with respect to benzonitrile sulphide. Since no starting material was recovered, it was assumed that it was decomposing by another unknown mechanism.
The cyclosubstitution reactions of phenyldithiazolethione
(64a) described so far are limited to highly electron deficient nitriles, but there have been problems with separation of the products. in order to simplify the purification process, it was decided to use the methyl analogue (6Lb) as a substrate,
since the nitrile side-product would be easily removed by distillation.
Heating meth3rldithiazolethione (64b) in refluxing trichloracetonitriiè for lOh. gave the ...... trichioromethyldithiazolethione (L.d) in near quantitative yield (96% after crystallisation). when thione (64b) was heated with dichioroac etonitrile, 3-dichlc romthyl-1, Li., 2- dithiazole--thione (64e) was isolated (90%) as a yellow oil. 132
Both chioroacetonitrile a.ndo -oxo-2-furanacetonitrile gave inconclusive results. For chioroacetonitrile methyl- dithiazolethione was recovered (85%), and only traces of the chloromethyl product (64g) could be observed (mass spectroscopy).
With oc-oxo-2-furanacetonitrile, 80% starting material was recovered together with a yellow solid (67mg) which was identified as the expected product (614h) by 1 H nmr and mass spectroscopy, the carbon- 13 nmr spectrum however was inconclusive.
Other less electron deficient nitriles were also tested, but no cyclosubstitution products were isolated; in all cases
3-methyl-1,4,2-dithiazole--5-th 4-one (64b) was recovered unchanged.
These results, which are summarised in Table 7, indicated that the methyl analogue (L1.b) was more reactive than the phenyldithiazolethione (64a) in cyclosubstitution reactions with eleôtron deficient nitriles. This was confirmed by heating an equimolar mixture of the methyl-(64b) and 133
phenyl-dithiazolethione (64a)with one molar equivalent of ethyl cyanoforinate at 130 °C for 6h; 71/--0' of the phenyldithiazolethione (64a) was recovered compared with 47 of the methyl analogue. The mechanism for this transformation probably parallels the aJJcyne case.
R, R ____ R' N?, S \ RCN+ S3R'
R _R /
CR > R R= a) Ph, b)Me Rc)CO2Etd)CC13 , e) CHCt2 ,f)PhCO,g) CH2CI, h) 13)4.
Table 7. Cycl03ubs ution React..ons of 1,4,2- Dithiazol -5hiones with Electron Deficient Nitriles
Reaction Temp/°C
Di -hiazolethione Nitrile ( Time/ h) Product 'field(%)
ECF 115 (72) 64c 71 T C A 83 (164) 64d 83 64a OCA 110 (27) 64a+64e PhCOCN 139 (192) 64a+64f
TCA 83 (10) 64d 96 OCA 110 (12) 64e 90 CICH2CN 124 (9) 64b 85
139 (82) 64b 80 64 b F% PrCN 115 (17) 64b 89 MeCOcN 71 (24) 64b 75 EtO2CCH2CN 110 ( 48) 64b 93 PhCN I 140 (42) 64b 96 Footnote ECF Ethyl Cyanoformate T CA Trichior oacetoni fri le OCA Dichloroacetonitri Le 135
All the 1,4,2-dithiazole-5-thiones are bright yellow compounds with distinctive carbon-13 nmr spectra, in particular the chemical shift for the ring C-5. Table 8 Carbon-13 nxnr Chemical Shifts for 1,42- Dithiazole-5-Thiones.
sc/PPm
3-Substituent C- 3 C-5
Ph 1725 2189 Me 1719 2201 Et02C 1636 2173
CI 3C 169•7 2164
CL 2CH 1704 2155
3-Fhenyl-1,4, 2-dithiazole--thione (6ha) undergoes cyclosubstitution tdth electron deficient alkynes 93 , but
there has been no report of a reaction with electron deficient 136
alkenes. When methyldithiazolethione (64b) was heated
with an excess of diethyl fuinarate in xylene for 6h, only
unchanged methyldithiazolethione (611 'c) and diethyl fumazate
were recovered. Assuming a two-step mechanism for the reaction
(See 3eheme 31,page 127 ) the corresponding reaction with
diethyl fumarate would require intermediates (136) and (137).
H COEt R O2Et s (137) EtO2C CO2Et
(136)
Presumably, J.ue o the absence of a hird double bond, these
intermediates are less stable than those involved in bhe
a1kye and nitrile reaction(Schema 5i). Similarly the
transition state for tiI one-step mechanism (of Scheme J)
would also be expected to be less stable. i3-Dithioiane-2-thione (i33) reacts with DM at l)400C
to give the 10-dithiole-2-thione (135) in virtually 137
quantitative yield Th(Scheme 83) and also reacts with a variety of other alkynes 143
Scheme 83
S 0 MAO 140C >C2H4 + SSCMe 138) (135)
-S S S
(139)
The corresponding cyclosubstitution reaction of the dithiolanethione (138) with nitriles would therefore provide an alternative route to 1,4,2-dithiazole--thiones (64). The advantage of this approach is the gaseous side product (ethylene) formed. However, when 1,3-dithiolane-2-thione (138) and ethyl cyanoforinate were heated together for 240h in a bath of refluxing toluene only unchanged (138) was recovered. When
1,3-dithiole-2-thione (139 )and ethyl cyanoformate were heated G
138
together under reflux in a nitrogen atmosphere, the only
product identified in the crude reaction mixture was sulphur
(mass spectroscopy). No dithiolethione (139) could be detected,
presumably the thione (139) was decomposing via an unknown
mechanism. 1,2, 14-dithiazole-3-thiones (1140) undergo sigmatropic
addition reactions with acetylenes. Examples of this type of
reaction are shown in Table 9. Use of an excess of DMAD leads to the formation of a 1:2 adduct (1141) (Scheme 814). Table 9 Sigmatropic Addition Reactions Ref ZO2Me DMAD S s ArN Me
- S
A r ,LL, N ,'t s C' R 2
R1 C.CR2 + 11,5 ArJ(t S s—s A r JL N R
NR1 CN 146 147 R 2 NS4P A r N.N/R2 R1 139
Scheme 84
S s_—çCO2Me OHAD A > A rN Me (140)
OMAD
Me 02C Ar (141)
The more reactive 3-(me'hrlimino)-S-(diinethyialV-!no)-1,2,)4-
dithiazole (142) reacts with a large excess of acet.nitrile
to give the sigmatropic addition product (J43)(Scherne 3).
ibo.
Schene - 8 51
We S MeCN )LNØ(NMe MeN2 S#S MeN Me (162) (143)
When -pheny1-1,2,4-dithiazole-3-thione (llLQa; ArFh.) is
heated with reflu.xing ethyl cyanoforinate,sulphur is the
only identifiable product (mass spectroscopy). Presumably, the dithiazolethiOfle. (lbOa) was decomposing by an unimown pathway. It can be concluded therefore, that 3-methyl-1,h,2-
dithiazole--thione (64b) does provide a useful route to novel
l,4,2-dithiazole--thiones via the cyclosubstitution reaction
with nitriles. However, this reaction is restricted to elestron
deficient nitriles such as ethyl c:ranoforma:e and
tricnloroacetonitrle, and therefore, has only a limtec synthetic
potential. Treatment of the l,4,2-dithiazole-5-thiones with 14J-
mercuric acetate or benzcnitrile oxide would resuit in a l,ii.,2-dithiazol--cne (8). These are morn to undergo therirai fragmentation, with loss of carbonyl sulphide, to give a nitrile sulphide which can be trapped by a variety of dipolarophiles 26 This strategy could provide useful access to nitrile sulphidEs an electron withdrawing substituent.
These intermediates are not readily accessible from the
corresponding 1,3,4-oxathiazol-2-one (2) due to the difficulties
in synthesising the precursor. For example, -trichioromethyl-
1,3,4-oxathi,azol-2-one (2g), is only formed in 3 eld from
the reaction of trichioroacetanide with chlorocarbonylsuiphenyl
chloride. 142
2.5 Reaction of 1,3,4-Oxathiazol-2-ones (2) and related
Heterocyclic Compounds with Nucleophiles.
The heterocyclic compounds considered in this section can be represented by the general structural formula below:
R ry, x,Y,z = o,s
Of the eight possible combinations only five are studied here:
1,3,4-oxathiazol-2-ones, 1,4, 2-dithiazol--(thi)ones and i,b, 2-dioxazol-S-(thi)ones. 2..1. 1,3,4-Oxathiazol-2-ones. To date very little Is known about the chemistry of
1,3 2 4-oxathiazol-2-ones except for their use as nitrile sulphide sources. It has been previously observed that the
oxathiazolone cannot be made if a nucleophillc centre is present. For example, when anthranilaniide was treated with C1COSC1 in an attempt to synthesise 5- (o-ami.nophenyl )-i , 3, )4-oxathiazol-2-one, the only product isolated was 2,4 [ 1H,3H] - quinazolinedione(52%). 143
In addition there have been two isolated reports of
1,3,4-oxathiazol-2-ones reacting with nitrogen nucleophiles for example, piperidine and bifunctional amines . The intention therefore was to investigate these reactions in more detail, not only to increase understanding of the 1,3,4- oxathiazol-2-one ring system, but also to facilitate nitrile sulphide chemistry. 1,3, Li-oxathiazol-2-ones were therefore treated with a variety of nucleophiles including amines and alcohols and the observed results correlated with the
M.O.ca].culations.
2..1.1. Nitrogen Nucleophiles
The first amine to be examined was piperidine. A solution of _phenyl_1,3,4_oxathiazo1-2-Ofle (2a) was treated with one
0 equivalent of piperidine in ether at ca-12 C for lh. From the reaction mixture was isolated N-benzoyl-2- piperidinocarbonylthi0hYrOlaXfline ( lLiLia) (92%). It was identified by its analytical and spectroscopic properties. The
nmr shows characteristic peaks for phenyl (7.3 and 7.9 ppm) and piperidinyl (1.6 and 3J4 ppm)residues. The amide proton was under the resonances for the phenyl ring (7.9ppm) as 0 shake. determined by the drop in the integral after a D 2 11.&lj.
The 13C nmr spectrum shows characteristic chemical shifts for the amide carbonyl carbons at 168.9 and 165.9 ppm. This data indicates that the amide links in this thiohydroxyla2nine derivative (144a)are typical; a fact confirmed by the carbonyl (1640 and 1690 cm-1 ) and N-H (3270 am-') peaks in the infra-red spectrum. Phenyloxathiazolone (2a) reacts similarly with morpholine to give N-benzoyl-S-morpholinocarbonylthiohydroxylaniine (144b). This compound was found to have similar spectroscopic properties to (14a) (Table 10). The structure of the thiohydro1amine derivative (14b) was confirmed by x-ray crystal structure. Inspection of bond angles and torsion angles (Tables 16 and 17, Appendix 1.19) shows that PhCONHS form one plane and
SNC(R1 R2 form another which is ca perpendicular to the first. In addition, the torsion angles C(7)-S-N(l0)-C(ll) and C(7)-S- N(10)-H(10) are 940 and 8 0 respectively, this implies the two planes are nearly orthogonal. The proposed mechanism involves initial nucleophilic attack 145
Atom Numbering for Compound (1J44b) used in Tables of
Crystallographic Data.
LUJ
Figure 7 146
at C-2 followed by ring fission (Scheme 36).
Scheme 86
R 0 r/ 0- R N S S NRq 1 R 2
' 1 HNR R 2
0 1 R2 R J'--N`SI.(N R H 0
146) a) RPh, Rl R2 = C5H10 ; b) RPh, R l R = C4H80; 2 c) R Me, R1 , R -C4H80; d) R = C Et , R1, R2
C4H80 ; e) R=H, R1 ,R2=C4H0. 147
The reaction of morpholine with other 1,3,4- oxathiazol-2ones, particularly those with a non-aryl
11 .-.) _'V_ proved the versatility of this reaction. Both 5-methyl and -ethoycarbony1-1 , 3, Ij.-oxathiaz ol-2-one react with morpholine under similar conditions to give thiohydrorjl amine derivatives (1440 and (144d) respectively. The spectroscopic properties of the products are very similar
(Table lo). Table 10 44 vw'r c"tWC.l 6ff fo.-
YtvcWe 044)
S H/PPm sc/PPm R •R1 -R 2 N-H C0
144ä Ph C 5H10 78 -79 1689 , 1659
144b Ph C 4H80 78 1689, 1665
144c Me C4H 80 71 171- 9, 1664
14d EtOC CLHBO 37. 164-0, 159 . 0,158 -2 1148
The parent 1,3,4-oxathiazol-2-one (2±') was synthesised from formainide and chlorocarbolz7lsulphenyl chloride in the usual manner. Due to the instability of this compound (it decomposes to hydrogen cyanide, carbon dioxide and sulphur even at -40C) it had to be freshly prepared and used immediately. Unlike the 5-substituted 1,3,14-oxathiazol-2-ones, the parent compound does not give thiofulminic acid when pyrolysed; the product is found to be isothiocyanic acid 1140 Therinolysis of 1,3,14-oxathiazol-2-one in the presence of ethyl cyanoforxnate gave no 1,2,14-thiadiazole cycloadduct (see Section 2.3.14).
Since ECF is an excellent dipolarophile for nitrile sulphides, it can be assumed that formonitrile sulphide (HC-) is not generated.
The parent 1,3,14-oxathiazol-2-one (2±') reacts with morpholine to give N-formyl-S-morpholinocarbonylthiohydrOxylaiuine
(lL&he) (30%). The product is identified by its analytical and spectroscopic properties. Elemental analysis and exact mass measurements indicated a molecular formula of C 6}LN 203 and the i.r. spectrum confirmed the presence of a carbonyl function
(1650 cm 1 ) and an NH (3300 cm1). 1149
All the reactions described so far have involved
equimolar quantities of oxathiazolone and amine. Treatment
of S-phenyl-1,3,4-oxathiazo1-2-one with a three fold excess
of piperidine at -10°C yielded only sulphur, benzaidde and
bis-pentamethyleneurea. When N-benzoyl-S- piperidinocarbonylthiohydroQrlaflhifle (l!jLa) is treated with one equivalent of n_but3rlamine at 340C the major product isolated was unreacted (144a). However, reverse phase hpic analysis
indicated the presence of traces of benzamide but the mixed urea,
N-butyl-N 1 -pentamethyleneurea, c-ou.ld not be observed at 2nm
in small concentrations. Presumably pipèridine is reacting with -phenyl-1, 3, L-oxathiazol-2-one to give the thiohydro1amine derivative (lL.ha) which is then subsequently
attacked by piperidine (Scheme 37) to give the observed .prodct8.
Scheme 47 0 Ph ND H
H-NR1 R 2 + nN PhfO Ph .-W NH2 )2eKI...n" l 1p'R2 f( R R1R2 C5}-t10 , R1 H ,R 2 = n - Bu
150
It is concluded that the primary amine is less
reactive than piperidine toward the thiohydrolamnine
derivative (ila) since benzamnide is formed in such minor
quantities.
A s imil ar mechanism explains the cyclocarbonylating
reaction of S-aryl-1, 3 ,1.i-oxathiazol-2-ones with bifunctionaJ. amines 8• Here, however, the attack by a second nucleophile is intramolecular (Scheme 88) and presumably occurs more readily.
Scheme 88 A A
rsi:O HSX H N H2 H CXH
0HX.' H ~ ~; +X ArNS N%H > ArL~ - , S H 01 H
Ar° + NH NH2 X)-f
X NH,Q 151
dhen 5-phenyl-1,3,Lj.-oxathiazol-2-one (2a) was treated
with one equivalent of n-butylarnine in ether at -10 0 C, the
,expected thiohydroçrlamine derivative (1145) was not isolated.
Instead, unreacted starting material (10%) was recovered,
together with sulphur (501%) and a mixture of benzamide and
N,N'-dibutylurea (146). Presumably the initial adduct (1145)
is more reactive toward n-butylaiaine than the oxathiazolone (2a).
Further reaction of (1145) with butylaxnine gives the observed
products (Scheme 89). Scheme 89 Ph
0 - NS NH RNH2 H 0H oHj) H '--s R Ph--J~ - PhN-S'4 R H (145) RNH2 H . NH -PhC0NH 2 + s+ OHR (146) R = n-Butyl. 152
It is noteworthy that the secondary amine derivative (]M) is less susceptible to attack by nucleophiles than the primary amine analogue. Hence the thiohydroxylamine derivatives (114) can be isolated. Tertiary amines., such as triethylamine, do not react with the phenyloxathiazolone (2a) over the range 250-350C. This was 2 to be expected, since it as reported that treatment of a suspension of j,N-dimethy1urea in acetonitrile with C1COSC1 gave S -dimethylamino-1, 3 ,lj-oxathiazol-2-one (75%). No reaction was observed with ammonia at 35' C; however, when an equimolar mixture of the oxathiazolone (2a) and ammonia were heated together on a steam bath, benzamide and sulphur were recovered. At this temperature decarbolation of the phenyloxathiazolone (2a) to give benzonitrile sulphide is possible.
However, since there was no trace of banzonitrile from decomposition of the nitrile sulphide,it can be assumed that this reaction had not occurred. Presumably the ammonia is reacting with the oxathiazolone in a manner similar to other nitrogen nucleophiles.
13
When an excess of aniline was mixed with -phenyl-1,3,4-
oxathiazol-2-one and stirred at room temperature for 6 days, benzainide and N,N'-diphenylurea (iSo) were isolated. Presumably
the benzainide and urea (150) are formed by reaction of (2a) with
aniline via the same mechanism as other amines (Scheme 90). Scheme 90
0 SNH2Ph ~ , ,O P . H PhNH2 0
Ph0 + S + (PhNH)2C0 NH2 (150)
Traces of bensonitrile were found in the distillate when the
excess aniline was removed under reduced pressure (ca 3O °C ;
1 mmHg). The nitrile may have been formed r thermal
ziecarboxylaticn of urireacted oxathiazc'lo:e (2a) to ?ive 154
benzonitrile sulphide which subsequently decomposed. 'S This work provides an explanation for the reported formation of quinazoiineone.- (143) from anthranilanide and
C1COSC1. Thtrarr.oiecular attack by the anilino group at the carbonyl group of the oxathiazolone affords an intermediate
(149) which extrudes sulphur to give the observed product
(Scheme 91).
Scheme 91 NH2 ocosci NH2 CONH2 7
—N H r- "0
(14)
S ) (14.8) 155
2.5.1.2 Oxygen Nucleophiles
Having established that 1,3,14-oxathiazol-2-ones will
react with amines, attention was turned to the oxygen based nucleophiles - alcohols and alkoxides.
There was no reaction when equimolar amounts of 5-pheny].
-1,3 1 4-oxathiazol-2-one (2a) and benzyl alcohol were refluxed
together in an ether solution for llh. From this, it can be
assumed that the mechanism outlined in, Scheme 88 for the
cyclocarbonylation of 2-aniinoalcohols and o-azninophenol is correct. That is, the amino function attacks the oxathiazolone
and addition of the hydroxyl to the amide is the ring closure
step.
Treatment of a solution of -phenyl-1,3,4--oxathiazol-2- one (2a) in ethanol with ethanolic potassium hydroxide at
-200C gave benzainide and sulphur. Oxathiazolone (2a) reacted
similarly with ethanolic sodium ethoxide at room temperature and -methoxyphenyloxathiazolone (2d) gave Li-methoxybenzainide and sulphur when stirred with sodium benzyloxide (PhCH 20Na) for l.h at room temperature. Since amide is formed in these reactions it may be assumed that they are proceeding via a
16
mechanism similar to that already encountered for nitrogen
nucleophiles (Scheme 92).
Scheme 92 R 0 0 -k~® rr- Z/ RN-SyOR' OR H R'O o
> RTO R0 + S + (R0)2CO (Thi) NH2 R =Ph, 4-MeOC6H4 R'=H ,Et,CH 2Ph
The failure to isolate any products containing alodde deri'ied
fragments reflects the instability of the expected carbonate derivates (cl). 157
25.1.3 Carbon Nucleophiles Isonitriles are a unique class of compounds. They are the only
stable organic molecules containing formally bivalent carbon. n-Butylisonitrile (152) can be easily prepared via the
"carbylamine reaction" (Scheme 93) of n-butylamine with chloroform and sodium hydroxide 149 using a phase transfer catalyst (PTC).
Scheme 93
CHCI3 NaOH ----U2C: BuN>BHC
+ -2 HO -= 152)
PTC PhCH2Et3NCi
It was hoped that n-butylisonitrile (352) would react with oxathiazolones (2),possibly via a mechanism different to that already encountered for amines and alkoxides. However, 158
when 5-phenyl-1, 3, LL-oxathiazol-2-one and an equivalent of buthylisonitrile (152) were heated together in ether at
reflux (350C), starting material (96%) was recovered unchanged. / Organometallic agents such as a Grignard reagent m4gX are formally a source of the carbanion R. When a solution of 5-( 7methoxyphenyl)-1,3,4-oxathiazol-2-one (2d) was heated with approximately one equivalent of ethereal phenylinagnesium bromide at room temperature there was immediate effervescence, probably due to the liberation of carbon dioxide. After quenching the reaction by pouring onto crushed ice and extraction with ether the mixture was chromatographed (silica; ether : petroleum ether; 1:14). Small amounts of sulphur (90mg) and unreacted starting material were recovered as well as a mixed fraction containing 14-anisonitrile, thiophenol and diphenyl disulphide. The infra- red spectrum of this mixed material had absorbance maxima at
1)max 2560 (SH) and 2230 cm 1 (CN). Such products are consistent with attack at sulphur accompanied by ring fragmentation
(Scheme 914). 159
Scheme 914
- RCN +CO2+PhS H20
Ph-MgBr PhSH ) PhSSPh
The small amount of sulphur isolated may be formed by a side reaction of thiophenolate ion (PhS) with the oxathiazolone.
Attack at the sulphur atom would lead to the FkISS species which could form S 8 by a chain lengthening process. When oxathiazolone (2a) was treated with a large excess of phenylmagnesium bromide (7 equivalents) in a solution of refluxing ether for lh, the major product isolated was triphenylmethanol, ma p and mixed m p 157-1580C. The residue contained thiophenol and diphenyl disulphide as well as
small traces of benzophenone. The triphenycarbinol was probably formed from benzonitrile by reaction with the Grignard reagent to give the ketimirie (13) (Scheme 95), which would react further with PhNgBr to give
triphenymethanol on hydrolysis.
Scheme 9 Ph PhHQBrp PhSSPhPiCN
Ph PhMgBr Ph MgBr 1NMgBr=: Ph3C-N(MgBr)2 Ph 153)
N3O > Ph3C-OH
2.5.1d4 Miscellaneous Nucleophiles It is known that triphenyiphosphine desuiphurates
5-(-methoxypheny1)-1,3,4-oxathiazo1-2-one (2d) with the 161
liberation of carbon dioxide to give Lj.-anisonitrile and 89 triphenyiphosphine sulphide There are two possible
mechanisms for this reaction (Scheme 96). Mechanism A
involves attack at sulphur followed by ring fragmentation.
Mechanism B proceeds by attack at C-5 to give an intermediate
of the type (iii.) which undergoes a Wittig type rearrangement
to give triphenylphosphine sulphide and nitrile.
Scheme 96 R PhCN +c02 +Ph3 P=S
p)
Mechanism A-
R çh3 PPh3 + R PPh 3
N S ~~O > - S) k s - (154) > + iNc Ph3 RCN SPPh3 Mechanism B 162
Of the two, mechanism A seems the most likely,
especially when the elimination of sulphur from other
heterocycles with tertiary phosphines are considered 08
(Scheme 97). Scheme 97 R2N R2NS + S -- PPh3 jPPh3 N- _C—_S
Ph,f + S=PPh3 .<- -, PPh - -ftft i 3 N R' NR'
e Me,NR + S=PPh3 Rh3 CNR 4NR" 163
Ethanethiol (EtSH) did not react with 5-phenyl-1,3,4- oxathiazol-2-one; when an ether solution of (2a) and EtSH was stirred at room temperature for 21th, only unreacted oxathiazolone (100%) was recovered. Likewise carbon disulphide did not cause any apparent decomposition of -(-methoxyphenyl)-
1,3,Li-oxathiazol-2-one (2d) and the oxathiazolone was recovered unchanged. However, when a mixture of N,N-dimethylthioformaiiiide
(17) and an equivalent of 5-( 7methoxyphenyl)-1,3,4- oxathiazol-2-one ( 2d) was left to atand for 3 days, there was evidence for decomposition of the oxathiazolone ( 2d) to
anisonitrile and sulphur. A thioainide is quite polar and therefore there is a strong preference for polar resonance structures of the type 150 (156). This implies that there is a partial carbon-nitrogen double bond and the sulphur atom carries a partial negative charge. R,.,f RiS
i' N R1 R 2 R R 156) (155) C.
164
It is possible therefore, that a contribution from a structure of the type (157) reacts with oxathiazolone (2d) as a nucleophile (Scheme 93).
Scheme 98
_+ AcN+ CO 2 ; F 0 6-S HNMe2 + Me2N:C—S --S (157) H
+ - — —Me2NC—S + S H
Ar = 4-MeOC6H4 -
There is no evidence (mass spectrum) for the oxidation of
(i7) to N,r-dimethyiformamide 165
2.5.i.. Summary
These results are consistentrlth molecular orbital calculations performed on 5-( 7metho'phenyl)-i, 3,L.- oxathiazol-2-one (2d) by the CDO/2 method (Table 11).
4 - MeOC6H4 5 0 1
( 2d)
Table 11 M. 0. Ccl-ovs -r o\e (2-d3
Electron LUMO Orbi tat Atom Density Coefficient 0-1 -023 C-2 +036 003 S-3 -0075 072 N-4 -022 C - S +033 065 1 rn
Hard nucleophiles, such as ajnines, alkoxide and hydroxyl ions, have a low energy HOMO and usually carry a
negative charge. Therefore, for a strong interaction,attack by this type of nucleophile should occur at positively charged atoms. The important parameter for these hard-hard reactions is therefore electron density; and the most likely site of attack is the atom with the smallest electron density. Hence the most probable site of attack by hard nucleophiles is C(2).
(Scheme 99). Scheme 99
0 Nu RN S
H5k &SkJ H 0 Nu
Only secondary amines such as piperidine and morpholine give isolable adducts. For other nucleophiles, these 67
thiohydroxylaniine derivatives are not isolated. They undergo facile reaction with the nucleophile to give amide
(RCONH7 ) and sulphur
Soft nucleophiles, e.g. thiols and triphenylphosphine, have a high energy HOMO and do not necessarily carry anegtive charge. The larger the coefficient in the appropriate frontier orbital of the atomic orbital at the reaction centre the softer the reagent. Therefore, fcr a large interaction, soft nucleophiles are more likely to attack 1,3,4-oxathiazoi-2-ones at the atom with the largest orbital coefficient in the LIJMO. in the case of (2d) this is sulphur (Scheme 103).
Scheme 100
11 o k > RCN + S+CO 2
Indeed, this mechanism for reaction of soft nuceophiles with 1,3, Li.-oxathiazcl-2-ones provides another e;,-planation for 16.8
the decomposition of nit- rile sulphides to nitrile 2.nd sulphur. Kinetic experiments have shorn that this is not a simple unimolecular process. It has been proposed 1'2 that the reaction proceeds via interaction of the nit- rile sulphide th short sulphur chains. This bimolecular reaction would therefore be slowed by conditions of high dilution. However, another possibility is the nitrilo suphio acts as a soft nucleophile attacking at S-3 of the oxathiazolone to give a nitrile disuiphide (1a) which could react further with the oxathiazolone or decompose to nitrile and S 2 . This reaction would also be slowed by conditions of high dilution as observed. This mechanism (Shem 101) may also account for the observation that an increase in temperature (up to a limiting factor) leads to an incrase of the 1,3-dipolar cycloaddition product (see Sectián 2.2.1 page 76 ) At high temperature the half-life for the oxathiazolone would be 169
shorter and therefore, its overall concentration lower.
Scheme 101
+ -p - R—C=N -s Or RCNRCEN—S-S (158) I CO2
Further Reaction With (2) (15 8) RCN S2 170
2.5-2. 3-Phenyl-1, L, 2-dithiazole--thione (64a)
Unlike 1,3,4-oxathiazo1--2-ones (2), these compounds do not decompose via 'a nitrile sulphide when heated. Instead i,4, 2-dithiazole-S-thiones (64) undergo cyclosubstitution reactions with electron deficient alkynes and nitriles (see
Section 2.4). Aside from this, no other reactions of this system are known.
3-Fhenyl-1, L, 2-dithiazole---thione (64a) and an equimolar amount of piperidine were heated together 'in ether
at reflux for Sh, followed by 48h of stirring at room temperature. The resultant yellow solid was purified by flasn coiuirin chromatography on silica eluting with dichlorome than 3:
petroleum ether (3:10) to give sulphur (40 mg) and unreacted phenyldithiazolethione (0.153g) (mass spectroscopy). On passing methanol through the column, an off-white solid was isolated.
This was shown to contain N,N-bis-pentamethylene thiourea (160) by hplc analysis and mass .spectroscopy but no thiobenzamide could be detected. By analogy with 7-,3.4-oxathiazol-2-ones(2)
(see Section 2..1), the thiourea may be formed in a two step
Process via a thiohydror1amine derivative (19) (Scheme 102). 171
Scheme 102
Ph S S SS• H (159)
-Ph CSNH2 - + S8 Cui QO S (160)
In an attempt to isolate this intermediate (159) the reaction was repeated at room temperature. Examination of the crude reaction mixture by mass spectroscopy indicated the presence of a compound with m/z 295 which was tentatively assigned as for the thiohydro-1amine derivative (159).
Isolation of this material was hampered by the large excess of 172
starting material; therefore, unequivocable assignment of the structure was impossible. This meant the alternative structure
(161), which could result from nucleophilic attack at C-3 of the dithiazolethione (614a), could not be eliminated,but in view of the formation of the thiourea (160) this mechanism is considered less likely. Hplc analysis indicated that thiobenzamide was not present in the reaction mixture. Its absence is not surprising since other thioamides such as thioacetaide (162) are known 12 to react with piperidine in ether to give an N-substituted thioamide (163) (Scheme 103).
Presumably thiobenzamide reacts similarly yielding
N-pentainethylenethiobenzanhide (163b). Re-examination of the mass spectra shows a peak at m/z 205 which corresponds to for (163b).
Ok, Ph-L S
' :~"s (161) 173
Scheme 103
R-s Rs + NH 2 OM
(162) 0 RMe (163) R =a) Me,b)Ph
1 Ihen the reaction was repeated in chloroform at reflux
the products iJ.entified were sulphur,benzonitrile and
bis-pentaiaethylenethiourea; no thiobenzarriide was isolated.
The benzonitrile may have been formed by thermal decomposition 12 of the thioa2n!de with expulsion of hydrogen sulphide 174
On heating dithiazolethione (64a) with a molar equivalent of n-butylarnine in ether at reflux for 5h 43% of the phenyldithiazolethione (64a) was recovered unchanged. Other
products identified were sulphur, N,N 1 -dibutylthiourea (mass
spectroscopy) and thiobenzaraide (mass spectroscopy and hp--, c
analysis).
3-Phenyl-1,4,2-dithiazole-5-thione (64a) is not as
reactive as 5-phenyl-1,3,4-oxathiazol-2-one (2a) toward nitrogen nucleophiles, approximately LO% of the dithiazolethione (64a) being recovered unchanged. However, both the dithiazolethione
(64a) and the oxathiazolone (2a) appear to react with nitrogen
nucleophiles via analogous mechanisms (Scheme 104).
Scheme 1011. Ph X P hJJ,N R 2 H y HNR1R2
PhX HNR2 + S + Y=C(NR1 R2 ) 2 NH2
X=0 , '(=0 x=s, Y=S. 175
When 3-phenyl-1,4, 2-dithiazole-S-thione (64a) and an equivalent amount of triphenyiphosphine in ether were stirred together at room temperature for 7 days, a yellow solid was obtained. Hplc analysis of the product mixture indicated the
presence of thiobenzaniide and benzonitrile. The formation of
both the thioamide and the nitrile shows that the
triphenyiphosphine is reacting with the phenyldithiazole thione (64a) at two sites; probably C-5 and S-i (Scheme io). Scheme 10 5.
PhCSNH2
Ph Ph C N + C S2 + SPP h3 s
t:PPh3 176
These observations can be explained with the aid of the CND0/2 molecular orbital calculations for 3-(- metho,phenyl)-1,4,2-d!thiazO1e--thiOfle (64i) (Table 12).
Table 12 M. 0. çv- (d') MeO-
15 2 \S (64.1)
Electron LUMO Orbital Atom Density Coefficient
S-i -0060 062
N-'2 -0152 - C-3 +0•163 006
S-4 +0019 -
C - S + 0.002 045 177
Hard nucleophiles, such as ami.nes, prefer to attack at sites of low electron density. The atom with the highest proportion of positive charge is C-3. However, since thioamide and thiourea are formed it is assumed this reaction proceeds via a mechanism similar to that encountered for 1,3,4 oxathiazol-2-ones (2); that is, attack at C- to give a thiohydrolairiine derivative (159). This is then converted to the thioainide, sulphur and thiourea by further reaction with the amine. Reaction of the amine at C-3 of the dithiazolethione
(64) is possibly reversible, and would explain the poor reactivity of the thione (64) with piperidine and butylaniine. Soft nucleophiles, such as triphenylphosphine, react with the atom which has the largest LUMO orbital coefficient. Of the possible sites of atack, it can be seen bhat both 2-1 and 0-5 have sizeabie orbital coefficients and a'e therefore the preferred points of reaction 173
2..3 3-Phenyl-1,4, 2-dithiazol-S-one (8a) Little is known about the chemistry of the 1,4,2- dithiazol--one (8) ring system; the only reaction reported to date involves thermolysis to give nitrile sulphides 26
3-Phenyl-1,4,2-dithiazol-5-One (8a) was synthesised from 3- phenyl-1,4,2-dithiazole-5-thiOfle (64a) in 55% yield using mercuric acetate as oxidant. Treatment of 3-phenyl-1,4,2-dithiazOl-5-Ofle (8a) with an equimolar amount of piperidine gave a yellow solid which contained sulphur and unreacted starting material (mass spectroscopy). Analysis of the crude product using hplc confirmed the absence of thiobenzamide, although N-N' -pentainethylene urea was present. By analogy with 1,4,2-dithiazolethione (64a), it is assumed that any thioamide formed is reacting with the piperidine to give N-pentamethylenethiobenzamide (163b) (see Section 2.5.2). 179
When 3-phenyl-1,4, 2-dithiazol-5-one (8a) was treated
with a molar equivalent of n-butylamine, a yellow solid was
isolated which was shown to contain sulphur, unchanged
starting material (8a) (mass spectroscopy) and thiobenzaxnide
(mass spectroscopy and hplc analysis).
Presumably, dithiazol one (8a) reacts with nitrogen
nucleophiles in a manner similar to 1,3,4-oxathiazol-2-ones(2)
and 3-phenyl-1,4, 2-dithiazole-S-thione (64a) to give thioamide
and the urea via the thiohydroxylainine derivative (164)
(Scheme 106).
Scheme 106.
Ph S S >Ph&NSNR1 R 2 N -0)A' H
(8a ) H~ pjR2 (164)
HNi1R2 1 2 > PhCSNH2 SOC(NRR 2 ISO
On heating dithiazolone (8a) and triphenylphosphine in toluene at reflux for 30 min an off-white solid was
obtained which was purified by flash column chromatography on silica eluting with dichioromethane : petroleum ether (1:1).
TJnreacted starting material (8a) (30 mg) was recovered followed by a mixed fraction containing triphenylphosphune sulphide (mass
spectroscopy) and benzonitrile (mass spectroscopy and i.r. soectrum). By analogy with 1,3,13-oxathiazolones (2), it is assumed the triphenyiphosphune desulphurates the i,IL,2-
d1thiazolone (8a) with expulsion of carbon osulphide to give benzonitrile (Scheme 107).
Scheme 107
Ph > PhCN + S=PPh3 + cos
t-?Ph3 181
These observations are in agreement rith the cNDO/2 molecular orbital calculations for - -(p_ MethoQphenyl)-1, 4,2-dithiazci--one l)l(gb) shown in Table 13.
Table 13 M. 0. foi è1-aOie () e
(8b)
Electron LUMO Orbital Atom Density Coefficient S-i -00422 073
N-2 -0i42 - C-3 +0. 174 052
S-4 -0132 - C - S +02262 013 'C) LU
Hard nucleophiles, such as amines, will tend to attack at the site of greatest positive charge. The atom with the lowest electron density is c-5, therefore this is the preferred place of attack. For soft nucleophiles, e.g. triphenylphosphine, the strongest interaction will be with atoms which have a large IZJMO orbital coefficient. In the case of 1,4,2-dithiazolones(8)
S-i would be the site of reaction. 183
2. 5 .4 i,h, 2-Dioxazol-5-ones (76) and l,li, 2-Dioxazole-5- thiones (77). There has been little investigation of the chemistry of 1,4,2-dioxazol-5-ones (76) and 1,4,2-dioxazole-5-thiones (77) aside from the thermal and photolytic generation of isocyanate.
These are important raw materials in polymer chemistry,
particularly in foam manufacture when the gaseous CO or COS
formed by decomposition of the dioxazolone (76) or dioxazolethione
is used as a blowing agent. The intermediate any1 nitrene may be trapped with rJMS099 (Scheme 108). Scheme 108
R RYO J -0 O~6 or hv 0X. >RNzC=O N. --.-9
X = (76)0, (77) S 15)4
The aim of the present work was to expand the known
chemistry of the dioxàzoles (76) and (77) beyond iocyanate
production. 3-Pheny1-1,4,2-dioxazOle-5-ofle(7'a)afld 3-.phenyl-1,4,2-
dioxazole--thione (77a) were prepared from benzohydroxamic
acid using phosgene and thiophosgene, respectively, in the
presence of triethylamine (Scheme 109).
Scheme 109 Phf > Ph H-O•H Et3N + -2HCL MnX NIO x=cc1 2 X=(76a) 0 ,(77a) S
2.j.4.1. 3-Pheny1-1,4,2-dioxazo1---one (76a)
When a molar eqUivalent of pip eridine was added to a
solution of phenyldioxazolone (76a) in ether, there was 18
immediate effervescence due to the evolution of carbon dioxide. no (silica) showed no starting material (76a) remained after 15' min. Evaporation of the solvent gave an off-white solid which was analysed by mass spectroscopy. A peak at m/z 204 (M) indicated the formation of either phenylpiperidinoamidoxilTie (16) or N-pentwnethylene-j- phenylurea (166). The amidoxime (165) would be formed by reaction of piperidine at C-3 of the dioxazolone (76a)(Scheme 110; Mechanism A) and the urea (166) from reaction of piperidine with phenyl isocyanate liberated during the reaction
(Mechanism B). 136
Scheme 11C
Ph-1 nN Ph Ph ND - (fO E2LTI NO OH II (165)
Mechanism A
Ph Q / N H Ph -c PhNC.O -f oc ND (166)
Mechanism B 187
The identity of the product from this reaction was confirmed by comparison with authentic samples of the amidoxiae (165)
and the urea (166). The amidoxime (16) was prepared by reaction of benzonitrile oxide with an equivalent of piperidine. The
crude product was crystallised from ethanol m p 131-133°C. The unsymmetrical urea (166) was synthesised by reaction of phenyl isocyanate with a molar equivalent of piperidine. The crude product was washed with cold ether to give a white solid
in p 166-1680C. The 13C nmr chemical shifts for these compounds are shown in Table l4 as well as those for the unknown product.
e amlcl OCV u,$), u riiit.&) Table lii. ' 3C CtLwc. kf-1-s -ço v'cL 'f. t(-osJ" rtkcø prod.'cE
S C /PPM Aromatic Piperidinyl Other
131- 3 1287, 7'8, 25•1, 24•2 1600(C=N) Amidoxime 127.8
140- 8, 12-9- 0 , 447, 254, 24•0 154.9 (C=O) Urea 121. 4, 1196
1406, 1281 , 448 , 24, 241 1551 Product 1214 , 1197 188
These indicate that the product formed in this reaction is N-pentamethylene-N' -phenylurea (166) and not the aimidodine
(165). The identity of the product was confirmed by hplc analysis.
Treatment of phenyldioxazolone (76a) with an equivalent of n-butylamine gave a white solid. The 13C niia' spectrum of this product (d6 -DMSO; OME) had resonances atcS 135.3, i1O.6, 128.3, 120.8, 117.7, 31 -3, 19.4, 13.5 ppm. Comparison with butyiphenylamidoxinie (167) and N-butyl4l -phenylurea (168), synthesised by reaction of butylamine with bensonitrile oxide and phenyl isocyanate respectively, showed the product was the urea (148). The identity of the solid was confirmed by hplc analysis. j IJ •
ii
,NHPh BuNH BiN H2 PhNCO 0C\ NH Bu 1681 Ph (762)
Ph OOINH Bu BuN 112
OH
ef1xinE diD:azo1ore 76.) iith an •3cjumo1a afflCLfl Cl triphenyiphosphine afforded triphenyiphosphine oxide and an unknown compound for which exact mass measurement gave the
molecular formula CH20NOP. The 1 H and 13C ninr spectra 193
indicated more than two types of phenyl group were present. 31 The nmr shift was 21.5ppm. Two structures (169) and (170) are considered possible.
PhfPh3 Ph3 (4 NPh (169) (170)
Triethyiphosphine is reported 154,155 to catalyse the dimerisation of phenyl isocyaxiate to 1,3-diphenyl-1,3- diazetidine-2,4-dione (171). Ultimately the isocyanate 191
trimer (172) is formed (Scheme 112). Scheme 112
0 0
Ph N C 0 -----? Ph N h PhNCO PhNNPh 0 N Ph (171) ( 172 )
However, when phenyl isocyanate was refluxed with an equizuolar amount of triphenyiphosphine in toluene, the phosphine was recovered and there was no trace of the phenyl isocyanate diner (171) or trimer (172). Treatment of benzonitrile oxide with a molar equivalent of triphenyiphosphine 192
gave, as expected triphenyiphosphine oxide and
benzonitrile.
Tertiary phosphins are known to react with
cumulated systems such as carbon disulphide and ' " 8 diphenylketene --'A- (Scheme 113).
Scheme 113 "-S Et3P CS2 - Et3P.4
(173)
Et3P + OCCPh-Et3 P4 (174) CPh
1)7 Staudinger and Meyer however, could not isolate the phosphaoxirane (17); instead the phenyl isocyanate trimer (172) 193
was obtained (Scheme liii).
Scheme l]Jj.
Et3
NPh PhNCO + Et3 P 175)
0 N P h Ph OLNO Ph (172)
In the present case it is possible that the triphenyiphosphine is reacting with a phenyl isocyanate equivalent, rather than free isocyanate, to give the
phosphaoxirane derivative (169) (Scheme 115). 19h.
Scheme 1)5
Ph 0 + Ph P Ph 3P 3 -0O2 NPh (1 69)
An alternative mechanism for the formation of a compound
with molecular formula C24NOP is shown in Scheme 116. Attack by triphenylphosphine at C-3 of the phenylcitoxazolone (76a) rr'
followed by expulsion of carbon dioxide leads to the
formation of the Wittig type intermediate (170), which may
collapse to benzonitrile and triphenyiphosphine oxide via a
Wittig rearrangement or possibly undergo a phenyl migration
from phosphorous to oxygen.
Scheme 11
PPh + Ph13 3 Ph Ph PPh ZO 10 (170)
Ph PPh 2
~,Ph (0)17 Ph PPh -f 3PhCNPh3P=O ~NT 196
There is no literature precedent for a phenyl group migration of this type., although priiiary and secondary phosphines are Imown to undergo a proton migration when
reacted with ketenes and phenyl isothiocyanate l29
The unambigous assignment of a structure for this compound
r,j1l require an x-ray crystal structure.
197
2..)-L.2. 3-enl-1, 4 ,2--±ioxazcTh--thione (77a)
Treatment of 3-phenyi- 7-1, Ii., 2-dioxazole-5-thione (77a)
with an equimolar amount of piperidine in other gave a white solid. By comparison with authentic samples, hplc analysis
indicated the prssence of henzamide and N-pentamethylene-N 1 -
phenylurea (16). Exanination of the carbon-13 ninr spectrum
(d6-DMSO; IHz) confirmed the presence of both the amine
and the urea (166).
Stirring an equiiuoiar mixture of phenyldioxazoiethione(77a)
and n-butylamine in ether for ih gave a white solid, which
was shown to contain N-butyl-N' -phenylurea (163) and benzarnido
(mass spectroscopy qnd hplc analysis).
These results are similar to those observed for the
phenyldioxazolone (7Aa); except for the formation of henzamide
which is not observed when the lioxazolone was treated with an
equimolar quantity of amine.
17
/770t.t')Z, PhNCOHN PhNHCONR2 P4 Z
(166) Cshio
(168) R1 =H , R2=C4H9 198
3-Phenyl-1, , 2-dioxazole--thicne (77a) and trip henylphcsrhine were heated together in toluene under reflux for 23h. Evaporation of the solvent gave a SOI:Ld which was purified by flash column chromatography on silica eluting with dichioroinethane petroleum ether (2:L75)'. Triphenyiphosphine sulphide (30 mg) was isolated. A polar residue was obtained by flushing the colur:in with methanol and this was shown to contain the compound C,H 0P by exact mass 2 01 measurements. Presumably this compound is formed via the .sae mechanism from both the phenyldioxazolone (7a) and the phenyldioxazolthione (77a).
Hard and soft nuclecphiles appear to promote isocyanate formation from 1,L4,2-dioxazol--ones (7() and 1,,2-dioxazole-
-thiones (77). The use of amines leads to the formation of a urea whereas triphenyiphosphine gives an adduct which is formally the product from reaction of triphenyiphosphine with isocyanate. 199
2.. 5) Summary
The five heterocyclic ring systems considered in this
Section can be broadly split into two classes: those which produce isocyanates when heated or photoiysed (1,4,2- dioxazol--(thi) ones) and those which produce nitrile sulphides on heating or photolysis (1,3,4-oxathiazoi-2-ones and l,,2- dithiazol-5(thi) ones ). The first class react with both hard end. soft nuclecphiles to give prorncts which are formally d31-vatives of i.soc ate, or e:ample, ureas on treatment with ainines. The second group react with hard and soft nucleophilos vIa separabe mechanisms. hard nucleophiles such as ainines attack thering carbon bearing the ketCila or thione) o give a thiohydroçjlaniine derivative which can then react with another molecule of amine producing (thio )amaice, sulphur and sninnetric urea. Soft nucleophiles such as triphenyiphosphine desuiphurate the heterocycle with expulsion of carbon dio;dde (or COS or 032).
Th the case of 1,4,2-dithiazole--thiones thioanide is also formed, possible via attack at C-i.
For l,3,-oxathiazol-2-ones and 1,i.,2-dithiazol---(ti)hones, 200
these patterns of reactivity correspond very well with molecular orbital calculations performed using the
CNDO/2 method. 201
3. EXPERD1.EM1AL 3.1 General 3.1.1 Glossary of Terms, Symbols and Abbreviations AC) atomic orbital bp boiling point br broad CNDO complete neglect of d-orbitals S chemical shift d doublet decomp decomposed
DCA dichloroacetontrile
DEAD diethyl acetylenedicarbolate DEF diethyl fumarate DEM diethyl maleate
DMAD diethyl acetylenedicarboxylate
DMSO dimethyl suiphoxide
FE extinction coefficient
ECF ethyl cyanoformate EP ethyl propiolate eq molar equivalent ether diethyl ether
eV electron volt FVP flash vacuum pyrolysis h hour 202
kv photolytic energy HOMO highest occupied molecular orbital hplc high performance liquid chromatography hz hertz i.r. infra red J coupling constant
A max wavelength of absorbance maximum (u,v.) LUI4O lowest unoccupied molecular orbital m multiplet N molar
mass of molecular ion
mg milligram min minute nunol millimole NO molecular orbital mp melting point
ni/z mass to charge ratio ))max wavenumber of absorbance maximum (i.r.) ninr nuclear magnetic resonance petroleum ether petroleum ether (b.p. 40-60 0C) ppm parts per million 203
q quartet
RT room temperature
Rt retention time (hplc) g singlet t triplet tic thin layer chromatrography
U.V. ultra violet cylene mixed o,ra, p - xylenes. 204
3.1.2 Instrumentation Elemental Analysis Elemental analyses were performed by Mrs E.McDougal using a Carlo Erba Elemental Analyser Model 1106. Infra Red Spectroscopy I.r. Spectra were recorded as Nujol mulls or liquid films on a Perkin-Elmer 781 spectrophotometer.
Mass Spectroscopy Mass spectra were obtained on an A.E.I. M.S. 902 by Miss E. Stevenson and exact mass measurements and FAB mass spectra were performed by Mr A.Thomson using a Kratos MS 50TC instrument. Melting Points Melting points were measured using a Kofler hot stage apparatus and are uncorrected. Nuclear Magnetic Resonance Spectroscopy Proton nmr spectra were recorded on two Brucker instruments, either the i.P.80 operated by Mr L.H. Bell and
Miss H.Grant or the W.P. 200 operated by Mr J.R.A.Miller. Carbon - 13 nmr spectra were recorded on a Varian CFT20 by Miss E.Stevenson or on a. Brucker i.P.200 spectrometer operated by Mr J.R.A.Mifler. Phosphorous-31 nmr spectra were recorded on a Brucker W.P.200 spectrometer operated by Mr J.R.A.Miller. CheinicaJ. shifts (S ) in all nmr spectra were measured parts per minion (ppm) downfield from tetra.methylsilane C 8 =0.0). Phosphorous - 31 spectra are measured relative to phosphoric acid. U.V. Spectroscopy tJ.V. spectra were recorded using a Pye-Unicam SP 8-400 spectrophotometer.
X-Ray Diffraction Analysis The x-ray diffraction of compound(114b) was performed by Dr. A.Blake using a STADI-2-diffractometer. 3.1.3 Chromatography (i) Flash Column Chromatography Flash column chromatography was performed on 15 x 2, b or 6 cm silica gel columns (Merck, type 60, 230-400 mesh) under an applied nitrogen pressure of 0.5-1.0 atmospheres. The silica gel was regenerated by heating at 600 0C for Th. 2',A
Thin Layer Chromatography Tic was carried out using glass plates coated with silica gel containing a green fluorescent indicator (Merck Silica gel G, type 60). The spots were visualised by u.v.
(254 or 359 nm) and or iodine. High Performance Liquid Chromatography Peak detection employed a Cecil CE212 uv monitor set at 254 nm linked to a chart recorder and a Venture Mark II digital integrator. Normal phase hp].c analyses were performed using a 15 x 0.5 cm stainless steel column packed with Spherisorb silica gel (S )nn) which was 50% water deactivated and eluted with isochratic mixtures of ether or diohloromethane in hexane (50% water saturated). Quantitative analyses were carried out using an internal standard by comparing peak area ratios of mixtures of known concentration with 1% of crude reaction mixture.
Reverse .-phase hplc analyses were performed using a iS x 0.5 cm stainless steel column packed with octadecylsilyl/ trimethylsilane silica gel (S yin) and eluted with isochratic mixtures of methanol and water. Peak identification was done by comparing retention times with those of authentic samples and peak enhancement. 207
Table 1 Retention Times for Authentic Samples
Solvent Compound Rf/min.
Benzamide 5•5 50%MeOtjI 4-Methoxybenzamide 60 H20
Benzamide 46 Thi obe nzamide 4•7 Ben zonitrile 5.1 -Pheny1-JL1 -pentamett!y[eneurea 6.1 j,-DiphenyI.urea 6'4 25%MeOH/ Triphenylphosphtne oxide 65 H20 jj-Buty1j'-pentamethyteneure a 6.6 N,N'-bis-Pentamefhyleneurea 7-2
N, entam ethyl e neth i cure a 77 Phenylpiperidi nylamidoxime 10.1 208
3.1.4 Solvents and Reagents All solvents and reagents used were standard commercial grades with the exceptions noted below. Ether, toluene and mesitylene were dried over sodium wire as required. Alcohol free chloroform was distilled from anhydrous calcium chloride when needed. Petroleum ether (40-60 0 C)was re-distilled. Xylene was distilled from phosphorous pentoxide and stored over sodium wire.
3.1.5 Full nmr data for the majority of compounds is presented in the Appendices. 209
3.2 Synthesis of Chiorocarbonylsuiphenyl Chloride (53) (53) was prepared by the method Weiss 75. Concentrated sulphuric acid (100 ml) was added to water (8.6g; 0.148 mol) with stirring and cooling (ice-bath). Perchioroinethylmercaptan (52.1 ml; 0.5 mol) was added and the mixture warmed to 145°C with vigorous mechanical stirring (ca 2h). Care was taken to ensure the temperature did not exceed 480C. On standing the mixture forms two layers; the lower aqueous phase is run off and the orange organic phase retained for further purification. The orange liquid can be conveniently distilled using a Buchi "Rotavapour" fitted with a liquid nitrogen trap at a pressure of 10 mmHg by heating gently with a hot air blower. The product is a pale yellow oil (66%) b.p. 980C (lit. 7.6 980C) and is stored over molecular sieve (type 14A) at a temperature below 0 °C. ) max (liquid film) 1785(C0), 805 cm-1 (c-cl). 210
3.3 Synthesis of 1,3,4-Oxathiazol-2-ones (2) General Procedure The aide (0. 05 niol) was dissolved in dry chloroform and chlorocarbonylsulphenyl chloride (0.07 inol) added dropwise keeping the temperature in the range of 10-.500C. The reaction mixture was heated under reflux until the evolution of HC1 had become negligible. Evaporation of the solvent in vacuo gave the crude product which was distilled under reduced pressure if liquid or triturated with ethanol and crystallised if solid.
(a) 5-Phenyl-1,3 ,I-oxathiazol-2-one (2a) The product was prepared from benzamide by the above. procedure, reaction time Sh. The crude product was obtained as a yellow oil which was triturated and crystallised from ethanol
(50%)m p 66-68 0C (lit. 78 68.5-700C). (b )p-Tolyl )-i , 3, Ii-oxathiazol-2-one (2c) The product was prepared from 27toluamide using the above procedure, reaction time Sh. The crude product was obtained as an off-white solid which was crystallised from ethanol (57%) in p 8-88°C (lit. 16 91-92°C).
(o)5-Methyl-1,3,4-oxathiazol-2-one (2b) The product was prepared from acetamide in the manner
described above, reaction time 7.5h. The crude product was isolated as a yellow oil and was distilled at reduced pressure 211
(60°C; 12 mmHg) to give a colourless liquid (37%) (lit. 160 600C; 12 minHg) ).)max (liquid film) 1750 (Co)
1615 cm 1 (CN) 1 H nmr (neat; 60 MHz) ç)H 2.5 (8). 1,3,4-Qxathiazol-2-one (21') The parent compound was prepared from formanide (dried and re-distilled) using the procedure described above. The crude product was a yellow oil which was purified by distillation 140 at reduced pressure b p 55°c; 1 mmHg (lit. LL7-L18 °C; 12 torr) (32%). 2) max (liquid film) 1800 and 1750 cm-1 (C0) 1 H nmr
(CDC13 ; 60 MHz) S, H 7.7 ppm 13C-nmr (CDC1 3 , 50 MHz) 172.8(C-2), 1J47.9(C-5). 5-Trichloromethyl-1, 3, li-oxathiazol-2-one (2g) Trichloroacetamide (5g; 30.8 mmol) and chiorocarbonyl- sulphenyl chloride (5g; 260 imnol) were heated together under reflux in dry toluene (30 ml) for 16h. The toluene was removed in vacuo to give a brown oil which was treated with methanol to destroy the excess chlorocarbonylsulphenyl chloride. The residue was Kugelrohr distilled (100 °C; 10 mmHg) twice and the colourless distillate cooled in the freezer where it solidified
(3%) in p 55-560C. (Found: C,16.1; N,6.1 C 3C13NO2S requires C. 6.3;N,6.3%)m/z 218.8718(M) C 3 5C13NO2S requires rn/z 218.87153 (I4). 2) max (Nujol) 1875cm 1 (co) 13Cnmr (CDC13 ;50 MHz) S c 170.5(C-2), 152.9 (c-5) 2 811.7(cc13). 212
3.11 Therinolysis of Oxathiazolones (2) in the Presence
of o(-Ketonitriles (85)
General Procedure
The 1,3,4-oxathiazol-2-ozle was dissolved in xylene
(20 ml) and the D(-ketonitrile added; the reaction mixture
was heated under reflux for 20h. After removal of the solvent
under reduced pressure, the residue was purified by
distillation and or flash column chromatography.
(a )5-Benzoyl-3-phenyl-1 , 2 ,Ls.-thiadiazole (88a) Kugelrohr distillation (11.0°C; 0.1 mmHg) removed the excess benzoyl cyanide and the solid residue was then treated with
ethanol to remove sulphur (11%). The desired product (BSa) was crystallised from ethanol as white needles (57%); in p 91-92 0C (Found: C,67.6; H,3.7; N,10.4; S,12.2 C 1r HN20S requires
C,67.7; H,3.8; N,10.5; S,12.0%))InLax (Nujol)1635 (C0),1590 and
175 cm-1 (CN) m/z 266 (M). (b) 54_Op_2inethylfuran)-3-phefly1-1, 2, Li.-thiadiazole (88b)
The solid residue was purified by flash column
chromatography (silica; dichioromethane : n-hexane; 4:1) to give
sulphur (19%) and crude (88b) (77%) which was further purified
by crystallisation from ethanol followed by sublimation (100 °C;
15 mmHg) in p 147.5-1480C (Found: C,60.7; H,3.0;N,10.7
C13H8N202S requires C,60.9; H,3.1; N,10.9%)pmax (Nujol)1630(C0), -1 1558 cm (CN) m/z 256 (M ' ) (c)5-.Acetyl-3-phenyl-1, 2,b-thiadiazole (88c)
The solid residue was purified by sublimation (50 0C;0.1 mmHg) 213
followed by crystallisation from ethanol to give white needles
(21%) nip 92-93°C (Found: m/z 204.0357(M) C 10H8N20S requires mhz 204.03573 (M) ) ))max (Nujol) 1693 (C0) and 1600 cni1 (C1).
(d) _(c( -0xohepty1)-3-phenyl-1,2-thiadiazole (88d)
The residual oil was purified by flash column chromatography
(silica; dichioromnethane: n -hexane; 3:17) to give sulphur (21) and the desired product as an oil which solidified on standing.
Crystallisation from ethanol gave white needles (17%) mp 29-30°C
(Found: mhz 274.1111 (M) C1 H18N20S requires m/z 274.11398(M) ).
Lmax (liquid film) 1690 cm 1 (C'0).
(e )5-Benzoyl-3-(p-tolyl)-1, 2 ,b-thiadiazole (88e)
Kugelrohr distillation (41°C; 0.1 mmHg) removed the excess dipolarophile and the solid residue was crystallised from ethanol to give pale yellow needles (78,cl ) rnp 103-1350 C (Found: C,68.7;
H,4.3; 11,10.0 C10H12N20S requires c,68.6; H,4.3; 11,10.0)1.)max
(!Iujol) 1635 (C0),1590 and 1575 cm 1 (CN). n/z 280 (M ' ).
(f)5-Benzoyl-3-methyl-1, 2,b-thiadiazole (881)
The excess benzoyl cyanide was removed by Kugelrohr
• distillation (40O C; 3.1 mmHg). The residue was traated with ethanol to remove sulphur and then crystallised from methanol to give white needles (ii). mp 71-72 °C Found: nh/Z 204-03')7
C10H3N2 0S requires m/z 204.03573 (M') )...)max (Nujol) 2114
1638 (c=o), 1590, 1573 cm 1 (CN). 3.5 Synthesis of 5-Dichloromethyl-3-Phenyl-1,2,4-
thiadiazole (92). Dichioroacetonitrile (0.6 ml; 9.8 nmioi) and 5-phenyl-
1,3,4-oxathiazol-2-.one (1.79g; 10 nunol) were suspended together in xylene (20 ml) and the reaction mixture heated under reflux for 21h. Removal of the solvent in vacuo gave a yellow oil which solidified on standing. The solid was washed with chloroform and sulphur (35%) filtered off. The filtrate was evaporated to dryness and sublimed (950C; iS mmHg) to give off-white needles (141%) in p 63-6140C. (Found: m/z 2147.9566 (M) C9H637C12N2S requires in/z 2147.95697 (}1').m/z 2145.9595 () C9H635C137C1 NS requires m/z 2145.95992 (7). in/z 2143.9628 C9H6 5C12N2S requires m/z 2143.96287 (7) ). 3.6 Attempted hydrolysis of 5-Dichloromethyi-3-phenyl-1,2,4- thiadiazole (92).
5-Dichloromethyl-3-phenyl-1, 2,14-thiadiazole (0.247g; 1 mmol) was dissolved in ethanol (10 ml) and concentrated aqueous sodium hydroxide (20 ml) added. After refluxing for lh the reaction mixture was concentrated in vacuo to ca two thirds volume. The residue was acidified with dilute HCl (200 ml) before extracting into ether 0 x 70 ml). The organic phase was dried (NgSO14 ) and filtered. Evaporation of the ether gave a yellow solid (0.103g) m/z 256 S 8 (M) Jinax (Nujol) 1700 cm-1 (c0). 215
3.7 Thermolysis of 5-.Phenyl-1,3,4-oxathiazol-2-one (2a)
in the Presence of ECF and Benzoyl Cyanide.
A mixture of -phenyl-1,3,4-oxathiazOl-2-Ofle
(0.178g; 0.99 minol), benzoyl cyanide (1 ml; 9.07 mmol) and
ECF (0.9 ml; 9.12 minol) was placed in a sealed tube and immersed in a bath of refluxing xylene (ca 139 °C) for 12h.
Hplc analysis of the crude reaction mixture gave the adduct ratio of ..benzoy1-3-pheny11,2,4-thiadiaZole (88a) to ethyl
3_pheny1_1,2,4_thiadiazo1e-5-carbOlate (90) as 1.06 : 1. 21
3.8 Thermolysis of 1,3,14-Oxathiazol-2-ones (2) in the Presence of Alkenes. 3.8.1 Thermolysis of -heny1-1,3,4-oxathiazol-2-one (2a)
in the Presence of Norbornene. (a) 5-Phenyl-1,3,14-oxathiazol-2-one (1.87g; 10.14 mmol) and norbornene (10.5g; 0.11 niol) were refluxed together in xylene (140 nil) (ca 119 00 until no oxathiazolone remained by hplc analysis (168h). Evaporation of the solvent gave a brown oil which was triturated with cold ether and the resulting solid crystallised from ethanol to give pale beige needles (5%) nip 55-570C. (b) Norbornene (11.359; 0.12 mol) and 5-phenyl-1,3,14- oxathiazol-2-one (2.88g; 16.1 mmol) were suspended in mesitylene (140 nil) and heated under reflux (ca 139 °C) until hplc analysis indicated no oxathiazolone remained (141 h). Evaporation of the solvent gave a dark brown oil which was purified by flash column chromatography (silica; dichiorometharie: petroleum ether; 1:1) to give benzonitrile (30%)llinax (liquid film) 2230 cm (CE and a yellow oil (L.Sg). The oil was triturated with cold ether to give exo-3a,7a-4,5,6,7-hexahydro-
14,7-methano-3.pheny1-1,2-benztsothiazole (19%) in p 58.5-59 0C.
(Found: C,73.0; H,6.5, N,6.3; C114HJ NS requires C,73.0; H,6.6;
N,6.1%) in/z 229 (N). 217
3.8.2 Reaction of Ary].nitrile Sulphides with Norbornadiene
3.8.2.1 13-'Oxathiazol-2-'ones (2) and Norbornadiene Mixed at Outset. The general method was to heat a solution of the 1,3,4- oxathiazol-2-one (2) with an excess of norbornadiene in an approrpiate solvent as described below for 3-(E7methox7pheny1)- isothiazole (96b). 3-(p-Methox3,pheny1)isothiazole (96b) A solution of - (-methoxyphenyl )-1, 3, L-oxathiazol-2 -one (2d) (2.15g; 10.3 mmol) and norbornadiene (10 ml; 93 mmcl) in xylene (ho ml) was heated at reflux(122 0C) until hplc analysis showed no oxathiazolOme (2d) remained (91h). Evaporation of the solvent gave a brown oil, which was purified by flash column chromatography (silica; dichloromethane:petroleum ether:
1:1) to give sulphur, LL-methoxybenzonitrile (81%) and 3- (P-7 methoxyphenyl)isothiazole. (96b) was crystallised from toluene: hezane (1:3) as white plates (16%) mp 66 0c (iit. 6 6-57.5°C)
(Found: C,63.2; H,4.8;N,7.5 ClOH9NOS requires C,62.8;H,4.7; N,7.3%) m/z 191 (N) In a repeat experiment using mesitylene as solvent (reaction temperature ca 1300C) isothiazole (96b) was isolated in 31% yield. 3-Phenylisothiazole (96a) This was prepared from S-phenyl-J. , 3, Li-oxathiazol-2-one 213
(1.91g; 10.7 nnnol) and norbornadiene (10 ml; 93 inmol ) in xylene (16 ml). Reaction time lli.Oh at ca 120 0C. The brown oil residue was purified by Kugelrohr distillation (65°C; 161 0.1 nnnHg) (lit. b p 1142-11440C; 16 mmHg) to give (96a) as a pale yellow oil (19%) (Found: m/z 161.0299 (M)C8H7NS requires m/z 161.0300 (M'). p-To1y1)isothiazo1e (96c) (96c) was prepared from 5-(7to1y1)-1,3,14-oxathiazo1- 2-one (6.07g; 0.031 mol) and norbornadiene (50 ml; 0.5 mol) in t-butylbenzene (ioo ml). Reaction time 140h at ca 118-128 °C. The brown oil residue was Kugelrohr distilled (100 °C; 0.5 nnnHg) and the solidified distillate crystallised from toluene: petroleum (1:3) as white needles (26%) nip 31j-36°C (lit. 162
850C) (Found: C,68.7; H,5.5;N,8.0 C 10H9NS requires c,68.5; H,5.2; N,8.0%) m/z 175 (I4). (P-Chloropheny1)isothiazo1e (96d)
Isothiazole (96d) was prepared from 5- (-chloropheny1 )-•.
1,3,14-oxathiazol-2-one (1.01g; 4.7 xnmol) and norbornadiene(2ul; 0.2 mol) in mesitylene (lj,O ml). Reaction time 110h at ca 120- 132°C. The orange oil residue was purified by flash column chromatography (silica; ether:petroleum ether; 1:4) to give a white solid which was crystallised from toluene:hexane (1:3) as white needles (16%) nip 40-42 0C (Found: C,55.2;H,3.1;N,7.1 C9H6C1NS requires C,55.2;H,3.1;N,7.1).m/z 197, 195(14'). 219
3.8.2.2 Under Conditions of High Dilution
General Procedure
A solution of the oxathiazolone (2) (0.48 mmol) in mesitylene (50 nil) was added to a refluxing mixture of norbornadiene (20 ml; 186 inmol) and mesitylene over BSh using a syringe pump. During the course of the addition, the reaction temperature rose from 1020 to 135°C. Hpic analysis of the reaction mixture indicated no oxathiazolone remained. Evaporation of the solvent gave a brown oil which was purified by flash column chromatography On silica or
Kugelrohr distillation.
(a) 3-Phenylisothiazole (96a) was prepared from 5-phenyl-
1,3,4-oxathiazol-2-one (2a) as described above. The oily
residue was purified by Kugelrohr distillation (100 °C;20 mmHg)
to give a yellow oil (53%). 1 H nm.r spectrum identical to that
of sample previously obtained.
(b)3-p-To1y1) isothiazole (96c) was prepared from 5-( 7toly1)
-1,3,1-oxathiazo1-2-one (2c) as described above. The oily
residue was purified by flash column chromatography (silica;
dichlorontethane:hexane; 1:4) to give sulphur (20%) and (96c)
(70%) identical to previously prepared sample by 1 H nmr.
(d) 3-(p-{ethopheny1)isothiazo1e (96b) was prepared from
5-( 7methoxyphenyl)-1,3 ,4-oxathiazol-2-one (2d) as described
previously. The oily residue was purified by flash column
chromatography (silica; dichloromethaxie:hexane; l:Li.) to give 220
sulphur (20%), h-anisonitrile (lh%) and 3-(7axiisyl) isothiazole (96b) (61%). In a repeat experiment using a mixed solvent to dissolve the oxathiazolone (2d) (chlorofonn:mesitylene; 1:10), the
reaction temperature was lower (101-12000 and the reaction time longer (had to be refluxed for a further 48h after addition to ensure complete thermolysis of (2d) ). Hplc analysis of the reaction mixture indicated yields of isothiazole (96b) (70%) and R-anisonitrile (30%).
3.8.3 Thermolysis of -(p-Tolyl)-l 1 3,4-oxathiazol-2-one(2c) in the presence of Z-bis(phenylsulphonyl) ethylene(106)
5-(-Tolyl)-1,3,Li-oxathiazo1-2-one (0.685g; 3.5 imnol) and Z-bis(phenylsulphonyl)ethylene (39;9.7 inmol) were suspended together in xylene (ho ml) and the mixture heated under reflux in a nitrogen atmosphere for 20h. Evaporation of the solvent gave a dark brown solid which was washed with dichlorometha,ne and E-bis(phenyl sulphonyl)ethylene (1.42g) recovered mp 209- 113 211°C (lit. 226-2290C). 1 H ninr (CDC1 3 80 MHz)&H 7.5-8.Oppm (m,10H, PhH)7.4 ppm (s,2Halkene CH Is).. 13C nmr spectrum
(CDC13 ;OMHz) &c 140.4 (CH), 139.6 (PhC),134.8, 129.7, 128.4ppm
(PhCH). The filtrate was purified by flash column chromatography (silica; dichloromethane:petroleum ether; 1:1)
to give sulphur (0.09g), p 7to1uonitrile (0.52g) )..max (Nujol)
2225 cm 1 (0), E-bis(phenylsulphonyl)ethylene (0.25g) in p 220-
223°C and 4_(pheny1sulphony1)-3-(7tolyl)isothiazo 1e (0.42g) (Found: mlz 315.0383 (14 ' ) C16HNO 2S 2 requires mhz 315.03877()) U
1 (SO ).)max (Nujol) 1340,1120 cm 2 ). 3.8.4 Thermal stability of Z-bis(phenylsulphonyl)ethylene The alkene (0.242.g; 0.8 miiiol) wau suspended in xylene
(50 ml) and the mixture heated under ref lux for 20h in a nitrogen atmosphere. There was no significant colouration of the solution and evaporation of the solvent gave a white
crystalline solid (0.265g). 13C ninr (CDC13; 5C4Hz) c 140.1, 139.3,134.2,129.1,128.2 ppm. Authentic sample (CDC1 3 ;20MHz Ze 140.2, 139.3,134.3, 129.2,128.4 ppm. Therefore, there was no appreciable isomerisation to E-bis(phenylsulphonyl)- ethylene under these conditions. 3.8.5 Thermolysis of 5- -p-tolyl)-1,3 ,4-oxathiazol-2-oneL2c) in the Presence of Diethyl Fuinarate. 5-(-To1yl)-1,3,4-oxathiazol-2-one (4.8g; 24.9 nunol) and
DEF (30 ml; 0.251 mmol) were dissolved in xylene (50 ml) and the mixture heated under reflux (ca lbS°C) for th. Evaporation of the solvent gave a brown oil which was suspended in cold ethanol and sulphur (20%) was filtered off. The remaining DEF
was removed by Kugelrohr distillation (1000C; 0.1 mmHg) and the residue purified by flash column chromatography (silica;
ether:petroleum ether; 3:7) to give diethyl 3-( 7tolyl)-2-
isothiazoline-,5-dicarbOlate (109b)as a pale yellow oil (40%)
(Found: m/z 321.1034 (M) C16H,19N00 requires rrl/z 321.10347(j) )
).)nax (liquid film) 1735 cm-1 (C1i0). 1 H ninr spectrum (CDC1 3 ; 8O MHz) SH 7.7 (d,2H, ArCH), 7.l(d,2H,ArCH),5.1 (d,H,JLi.Hz ,H-),
4.8(d,H,J4Hz , H-Lj), 4.2(m, LLH, OCH2 ),2.3 (s,3H,ArCH3 ),1.2ppm (tn,6H, ester CH3). 222
3.8.6 Thermolysis of 5-(p-Tolyl)-1, 3,4-oxathiazol-2- one(2c) in the presence of Diethyl Maleate.
5-(7Tolyl)-1,3 ,b-oxathiazol-2-one (6.1g; 0.032 mol) and diethyl maleate (40 ml; 0.25 mol) were dissolved in xylene (10 ml) and the mixture heated under reflux for 11h.
The solvent (aspirator) and excess alkene (oil-pump) were removed under reduced pressure to give a brown oil which contained mainly R7toluonitrile by tic (silica; ether: petroleum ether; 1:1). Hplc analysis of the crude reaction
mixture indicated a nitrile yield in excess of 80%. 1 H nmr spectrum of recovered dipolarophile (neat; 601Hz)8H Sii.
(g,2H,alkene CH), 3.8 (q,hH, OCH2 ), 0.9 ppm (t,6H,CH3 ) which was identical to that for an authentic sample of DEF. 3.8.7 Isomerisation of Diethyl Maleate to Fuinarate
Diethyl maleate (i ml) was placed in a tube and immersed
0 in a bath of refluxing xylene (ca 13 5) C) for 7h. 1 H ninr spectrum (neat; 60 MHz)8H 6.0(s,2H,alkene CH), 3.8 (q,4H2 OCH2 ) 0.9 ppm (t,6H,CH3 ) which was identical to an authentic sample of DEN.
Diethyl nialeate (1 ml) and sulphur (20 mg) were placed in
a tube and immersed in a bath of ref luxing çrlene (ca 135°C) for 7h. 1 H nmr spectrum (neat; 60 M!)56.0 (s,2H,alkene CH),
3.8 (q,4H,0CH2 ), 0.9 ppm (t,6H,CH3 )which was identical to that 223
of an authentic sample of DEM. Cc) Diethyl maleate (20 ml; 0.17 mol) and sulphur (0.68g; 0.021 mol) were heated together under reflux (ca 2200C) for lh. 1 H nrnr spectrum (neat; 60 MHz)SH 6.14 (s,2H,alkene CH),
3.8 (q,4H2 OCH2 ) 0.9 ppm (t,6H,CH3 ) which was identical to that of an authentic sample of DEF. There was no trace of any DEM.
Cd) Diethy]. maleate (20 ml) was heated under reflux for 1 h. There was no change in the 1 H nmr spectrum (neat;60 MHz) 3.8.8 Thermo1sis of 5-(D-Tolyl)-1,3 ,).&-Oxathipzol-2-one (2d) in the Presence of E-Stilbene.
Trans-stilbene (1.1425g; 7.9 mmol) and 5-(7toly1)-1,3,4- oxathiazol-2-one (0.75g; 3.9 xnmol) were suspended together in xylene (35 ml) and the mixture heated under reflux for 17.5h. Evaporation of the solvent gave a yellow solid which was dissolved in the minimum amount of dichioromethane and left to stand for lSh. A white crystalline solid was filtered off, this was proven to be trans -stilbene (90%) mp and mixed nip 121-122 0C. 163 (lit. 122-12140C). The residue was purified by flash column chromatography (silica; dichloromethane :petroleuni ether; 1:1) to give sulphur (95%) m/z 256 (s8) artd7to1u.onitrile (92%) ).)max (Nujo1)25 cm 1 (CE N). 221.
3.8.9 Thermolysis of 5-(p-Tolyl)-1,3 ,1.i-Oxathiazol-2-one
in the Presence of Z-Stilbene
5-(-Tolyl)-1,3,4-oxathiazol-2-one (l.14l4g; 7.5 mrnoi) and cis-stilbene (2 ml; 11.2 inmol) were suspended in r1ene (!iO nil) and the mixture heated under reflu.x for 7h. Evaporation of the solvent gave a yellow solid which was washed with hot ethanol and sulphur (95) recovered. The filtrate was allowed to cool and a white crystalline solid filtered off. This was proven to be trans-stilbene (95%) mp 165 and mixed nip 121-122°C (lit. 122-1240C). The residue contained n7toluonitrile (90%). 22)
3.9 Thermolysis of 5-Aryl-1,3,4-Oxathiazol-2-ones in the Presence of Acetylenic Esters. 3.9.1 Ethyl Proplolate 5-(7Methoxyphenyl)-1, 3,LL-oxathiazol-2-one (2.26g; 10.8 inmol), ethyl propiolate 0 ml;31.6 mmol) and xylene (140 ml) were heated together under reflux for 214h (no oxathiazolone
remained by hplc). Evaporation of the solvent gave an amber
oil which was purified by flash column chromatography (silica; dichloromethane:petroleum ether; 14:5) to give two fractions. The first fraction (1.023g) was the 5-isomer and was
crystallised from methanol as white needles (30%) mp 76-77 0C 164 (lit. 78°C). ))max (Nujol) 1730 cm-1 (C3) m/z 263 (M). 1 H nmr spectrum (CDC1 3 ; 80A11z )6H S.Oppm (s,H,H-14). The second fraction was crystallised from methanol to 0 give the 14-isomer (30) mp 73-7140C (lit. 164 75 C)2)inax (Nujol) 1730 cm-1 (C0). m/z 263 (M). 1 H nmr spectrum (CDC13 ;8DMHz) 82.3PPm (s,H,H-S). 5-( 7Tolyl)-1, 3,b-oxathiazol-2-one (2.7g; 114.0 nunol), ethyl propiolate (5 inl;52.7 mmol) and xylene (20 ml) were heated together under reflux for 21h. Evaporation of the solvent gave
a brown oil which was purified by Kugelrohr distillation (70 °C;
0.1 mmHg) to remove the E7toluonitrile, and flash column chromatography (silica; dichloromethane). A brown oil was 226
isolated which was triturated with cold methanol and the - resulting solid crystallised from methanol to give the - isomer (25%) mp 8S-87 °C (Found: C,62.8; 4.,-5-10,5.6 C 13H, 3NO2S requires C,63.1; IL5.3; N,5.7%) )/max (Nujol) 1725 cm (c0) in/z 247 1 H nmr spectrum (CDC13; 30 IIH )SH 8 .lppm(s, H, H-s) The oily residue contained the 4-isomer but it could not be purified further. 3.9.2 Dimethyl Acetylenedicarbolate
5-(27Tolyl)-1,3,4-oxathiazol-2-one (3.432 g; 18 inmol), dimethyl acetylenedicarbolate (5 ml; LiO inmol) and xylene
(iS ml) were heated together under reflux for 6h. Evaporation of the solvent and excess DMA]) gave a brown oil which was triturated with cold methanol and the resulting solid crystallised from ether to give white needles (80%) nip 87-89 0C 16 (lit. 72-730C). (Found: rnlz 291.0563 (M) C1 H13N%S requires lfl/Z 291e05652 (M)),))inax (Nujol) 172S cm (co).
3.9.3 Diethyl Acety1enedica.rbo1ate S-(To1y1)-1,3 ,b-oxathiazol-2-one (3 -49; 17.6 mmol), diethyl acety1enedicarbo1ate (5 ml; 31.3 znxaol) and xylene (15 ml) were heated together under reflux for 6h. Evaporation of the solvent gave a dark brown liquid which was purified by
Kugelrohr distillation (135 °C; 0.4 mmHg). The residue was triturated with cold methanol and the resulting solid crystallised from ether (40%) nip 58-59°C (Found: C,60.4;H,5.4; N,lJ..LL 227
C16 7N0,I S requires C,60.2; H,5.4; N,1.4%))1Inax(Nuj9l) 1725 cm71 (C0) m/z 319 (M ' ) 3.9.4 Synthesis of 3-Arylisothiazole Carboxylic Acids These were synthesised by base hydrolysis of a suitable ester. 3.9.4.1 General Procedure. The ester (3.4 inmol) was dissolved in SO% aqueous ethanol () ml), 4 14 aqueous sodium hydroxide (h nil) was added and the mixture heated under reflux for 2h. The volume of the reaction mixture was reduced by ca half and the residue acidified with dilute MCi. The resulting white precipitate was filtered off and was used without further purification. (a)3_(p-Methoxyphenyl)isothiazole5carbóxylic acid (119a) The product was prepared as described from ethyl 3-(,7methoxypheny1 )lsothiazole-S-carboxylate (90%) nip 154-157 °C (Found: m/z 235.0303 (M) C 11H9NO3S requires m/z 235.03031(14)) .)max (Nujol) 2600 (OH),1675 cm(C0). 1 Hnmr spectrum (d6-DMSO;
80 MHz) SH 8.2ppm (s,H,H-ti). (b ) 3-(p-Tolyl )isothiazole-S-carboxylic Aid (119b) The product was prepared from ethyl 3- (-toly1 )- isothiazole-S-carboxylate as described above (90%) nip 230°C
(decoxftp ) (Found: In/z 219.0354 (M) C11H9NO2S requires m/z 219.0347 (14 ' ) ).).)max (Nujo1)171 cm (C0)H ninr spectrum (d6-DMSO; 60 MHz) cS H 8.3 ppm (s,H,H-L). 225
(c) 3-.(p-Toly]. )isothiazole-L&, 5-dicarboxylic Acid (115) This product was prepared from dime thyl 3-(E7toly1 )- isothiazole-Ii,S-dicarboxylate (80%) in p >260°C (Found: m/z 263.0249 (M ' ) C12H9NO11S requires m/z 263.02522 (M)) )) max (Nujol) 1700 cm 1 3.9.4.2 (p-To1y1)isothiazole-4-carboxy1ic Acid (116) This was synthesised by solution phase decarbo1ation of the di-acid (us). 3-(-To1yl)isothiazo1e-4,5-dicarbolic acid (0.24g; 0.93 mmol) was heated with 1, 2-dichlorobenzene at reflux for
15 mm. Evaporation of the solvent gave the desired product
(116) in 85% yield. in p 17 -179°C (lit) 6 179.5-1820 (Found: zn/z 219.0344 (!4) C11H9NO2S requires m/z 219.03540(14 ' ) ). max (Nujol) 3400 (OH), 1580 cm-1 (C0). 1 H nmr spectrum (d6-acetone; 60 MHz) SH 9.6 ppm (s,H,H-5). 3.9.4.3 Ethyl 3-(p-Tolyl)isothiazole-4-carboxylate (117b) 3-(7To1y1 )isothiazole-L-carboxy1ic acid (0-073g; 0.33 mmol) and thionyl chloride (0.1 ml; 1.4 imnol) were refluxed together for 30 mm. The excess SOC1 2 was distilled off (bp 77-78 °C).
Ethanol (20 ml) was added to the residue and the mixture heated under reflux for a further 30 mm. Evaporation of the excess ethanol gave the desired product(117b) as a brown oil bp 160 0c; 1.5 mmHg (Found: m/z 247.0670 (M) C13H13NO2S requires m/z
217.06669 (M) ). )) max (liquid film) 3100 (OH) 2 1725 cm-'(C=O) 1 H nmr spectrum (CDC1 3;80 MHz) cH 9.3ppm (s, H,H-S). FVP Apparatus used in Pyrolysis Experiments
Thermolysis tube inert gas /inlet
-n - To Pump UO C 1\) 1.0 w 230
3.10 Attempted Solution Phase Decarboxylation of
3-Arylisothiazole -5-*arboxylic Acids 3.10.1 3-(p-Methoheny1 )isothiazole--carbolic A--id(119a)
3_(27Methoxyphenyl)isothiazOle-5-CarbOXYliC acid (49 mg; 0.21 inmol) was refluxed with 1,2-dichlorobenzene (10 ml) for
2.h. Solvent evaporation gave a brown oil which was 1 deuteriochioroforni soluble. However, the H nmr spectrum
(60 MHz) had no trace of the desired product 3-(7 methoxyphen7l )isothiazole. (96b). Hplc analysis confirmed the absence of (96b). 3.10.2 (p-Toly1 )isothiazole-5-carboxylic Acid (119b)
3-(27Tolyl)isothiazole-5-carboxylic acid (60 tug; 0.27 inmol) was refluxed with 1,2-dichlorobenzene (20 ml) for 3h. Evaporation of the solvent gave a brown oil which was deuteriochioroform soluble. Hplc analysis however, indicated that only traces of 3-(.-toly1)isothiazole were present.
3. 11 Synthesis of 3-Arylisothiazoles by Flash Vacuum Pyrolysis of Isothiazole Mono- and Di-carboxylates.
General Method
3-Arylisothiazole mono- or di-carboxylic acids and their ethyl esters were pyrolysed using standard FVP apparatus (Fig. 5 ). The material to be pyrolysed was sublimed through an empty silica tube and the pyrolysate divided into two 231
portions: the material in the cold trap, was dissolved in
CDC13 for 1 H nmr analysis and subsequent work. up, and contained
3-arylisothiazole and nitrile. The white solid deposited near the outlet was dissolved in d6-acetone and usually contained carboxylic acid products.
3.11.1 Ethyl 3- (p-Tolyl )isothiazole-5-carboxylate (118b) (a) Ethyl 3_(7to1y1)isothiazole_5_carbor1ate (30 mg;
0.12 mmol) was sublimed (130°C; 2 x 10-3 mmHg)through an empty 0 silica tube at 850 C. The deuteriochioroform portion of the pyrolysate contained no Identifiable products. The d 6-acetone portion contained 3- (-tolyl )isothiazole-5-carboxylic acid
nmr (d6-acetone; 60 MHZ)SH 7.7(s; H,H-t), 7.4 (d,2H),
6.7 (d,2H), 1.8 ppm (s,3H).))max (Nujol) 2780,2580 (OH),1705cm' 1 (c=o).
(b) Ethyl 3-(p-Tolyl)isothIazole-5-carboxylate (80 mg; 0.32ininol) was sublimed (1250C; 2 x 10 -3mmHg) through an empty silica tube at 900°C. The CDC1 3 soluble portion contained isothiazole
(96c). 1 H nmr spectrum (CDC1 3 ; 60 MHZ)8H 8.7 (d,H,J4.7Hz,H-5),
7.9 (d,2H), 7.6 (d,H,J4.7Hz,H-4), 7.3 (d,2H), 2.4ppm (s,3H)
13 ninr spectrum (CDC1 3 ; 53 Wz)Sc 167.30-3),1J48.60-5),139.1, 132.0 (ArC), 129.4, 126.8 (ArCH), 121.00-4), 21.2 ppm(CH 3 ).
The d6-acetone portion contained traces of the 5-carboxylic acid
(119b). 1 H nmr spectrum (d6-acetone; 60 MHz)SH 7.8ppm (s). 232
Ethyl 3-(p-tolyl)isothiazole -5-carboxylate (0.155g; 0.63 nimol) was sublimed (120°C; 2 x 1o 3 rnmHg) through an empty silica tube at 90 °C. The d6-acetone solution contained
3-( 7tolyl) isothiazole--carboxylic acid. H nmr spectrum
(c16-cetone, 60 MHz )5H 7.7 (s,H,H-Li), 7.4 (d,2H), 6.7(d,2H), 1.8 ppm (s,3H).i)max (Nujol) 2780,280 (OH), 1705 cm- (C=O).
The deuteriochioroform solution contained -toluonitrile and
3-(7tolyl ) isothiazole by hplc analysis. 1 H nmr spectrum (CDC13 ; 60 MHz) SH 8.7 (d,H,H-5), 7.9(d,2H), 7.6(d,H,H-4),
7.3 (d,2H), 2.4 ppm (s,3H). This fraction was purified by flash column chromatography (silica; dichiorometharie: petroleum ether; 1:3) to give isothiazole (96o) in 34% yield. Ethyl 3-(P-tolyl)isothiazole--carboxylate (37 mg; 0.15 mmoi) was sublimed (1250C; 2 x 10 -3mmHg) through an empty silica tube at 10000C. The d6-acetone solution contained no identifiable products by 1 H nmr.Hplc analysis of the CDC1 3 fraction indicated that isothiazole (96c) and p7toluonitrile were present. 1 H nmr (CDC1 3 ; 60 MHz)6H 8.7(d),7.9 (d), 7.6(m), 7.3(m), 2J4 ppm (s).
3.11.2 Ethyl 3-(p-Toly1)isothiazole-4-Carbox3rlate (iim)
(a) Ethyl 3-(7toly1)isothiazo1e-4-carboclate (8mg; 0.19 nnnol) was distilled (140 °C; 2 x 10 3xnmHg) through an empty silica tube at 900°C. The d6-acetone fraction contained the 4-carboxy1ic acid (116 ). 1 H runr spectrum (d6-acetone; 60MHz) 233
9.2 (s,H,H-S), 7.2 (d,2H), 6.8(d,2H), 2.0 ppm (s,30. The deuteriochloroform fraction contained 3- (-to1y1 )- isothiazole (96c). 1 H nmr spectrum (CDC13;60 MHz) 6H 8.7 (d,H,H-5), 7.9 (d,2H), 7.6(d,H,H-4),7.3(d,2H) 2.4 ppm (s,3H). (b) Ethyl 3-(p-tolri)isothiazoie-ii-carboxylate (0.39; 1.21 inmol) was distilled (130°C; 2 x 10 3xnmHg) through an empty silica tube at 1000°C. The d6-acetone portion contained the 14-carboxylic acid (116). 1 H nmr spectrum (d6-acetone; 60 MHz) S H 9.2(s), 7.2(d), 6.8(d),2.0 ppm(d). The deuteriochloroform solution contained 3-(7to1y1)isoth&azole 1 H nmr spectrum (CDC13 ;60 MHz) S H 8.7(d,H,H-5), 7.9(d,2H), 7.6(d,H,H-4), 7.2 ppm(d,2H). 3.11.3 Diethyl 3-(p-Tolyl)isothiazole-4, S-dicarboxyiate (122) Diethyl 3-(toly1)isothiazo1e-4,5dicarboc'1ate (0.262g; 0.82 mmol) was sublimed (150 °C; 2 x 10 3inmHg) through an empty silica tube at 90°C. The deuteriochloroform solution contained -toluonitrile )) max (liquid film) 2230 cm-1(C N) and 3-(P. 7 ) isothiazole 1 H nmr spectrum (CDC13;60 MHz) 234 E7to1uon1tri1e )) max (liquid film) 2220 cm ' (CN) and 3-(7to17l):isothiazo1e 1 H runr spectrum (CDC1 3; 60 MHz) 5 H 8.7(d,H), 7.9(d,2H),7.6(d,H),7.2(d,2H),2.5 ppm (s,3H). 3.11.14 p-Toly1)isothiazole-14-carboxylic Acid (116) 3-(27To1y1)isothiazo1e.-4-carboxy1ic acid (62mg; 0.28 minol) was sublimed (170°C; 2 x 10 3mmHg) through an empty silica tube at 9500C and the pyrolysate was dissolved in d6-acetone. 1 H ninr spectrum (d6-acetone; 60 MHz) SH 9.2(),8.7 ppin(d) indicated the presence of both. unpyrolysed (116) and 3-(7to1y1)isothiazo1e (96c). Hplc analysis confirmed the presence of (96c) and Z7 toluonitrile. 3.11 .5 p-Toly1)isothiazo1e-4,5-dicarboxylic Acid (US) 3_(7To1yl)isothiazo1e.4,5_dicarboJr1ic acid (114 mg;0.05 nnnol) was sublimed (200°C; 2 x 10-3 mmHg)through an empty silica tube at 9500C. The pyrolysate was dissolved in d 6 -acetone and was shown to contain 3-(7to1y1 )isothiazole and .-to1uonitrile by hplc. ninr (d6-acetone; 60 MHz) SH 9.2(s) therefore 4-carboxylic. acid present. 3.11.6 3-(E-Tolyl)isothiazole (96c) 3-( 7To1y1)isoth1azo1e (Si mg; 0.29 mmol) was sublimed (100°C; 2 x 10 3xnmHg) through an empty silica tube at 9500C. The pyrolysate was dissolved in deuteriochloroform. 1 H nmr (CDC13; 60 MHz) (SH 8.7(d), 7.9(d),7.6(m),7.3(m),2.4 ppm (s). max (liquid film) 2225 cm 1 (CN). The presence of -toluonitrile was confirmed by hplc. ,, c ) 3.12 Thermolysis of 1,3,4-Oxathiazol-2-ones (2) in the •?resence of arious Dipolarophiles. 3.12.1 I4aleic .Anhydride. (a) 5-(7Methoxyphenyl)-1,3 ,Li-oxathiazo1 -2-one (0.067g; 0.32 nimol) was dissolved in mesitylene (20 ml). This solution was added to a refluxing mixture of maleic anhydride (0.331g; 3.4 mmcl) and mesitylene (20 ml) over a period of 3h. A nitrogen atmosphere was maintained throughout the reaction. After addition was completed the solution was refluxed for a further 12h. Evaporation of the solvent gave a black solid (66mg) which did not contain Li,-axiiàonitrile by i r hplc or tic (si].ioa;eter: petroleum ether; 1:1). (b) Heating of Maleic Anhydride in the presence of Sulphur. Maleic anhydride (0.564g; 5.8 mol), sulphur (1.665g; S2inmol) and mesitylene (40 nil) were heated together under reflux for 17h. Evaporation of the solvent gave a yellow solid which was washed with ether, filtered and the filtrate evaporated to dryness. This process was repeated and the total sulphur recovered in this manner was 1.6g (99%). The second filtrate gave an off-white solid (0.7g). 1 H ninr spectrum (CDC1 3 ;60 MHz) H 7.1 ppm(s) which was superimposable on that of an authentic sample of maleic anhydride. 3.12.2 2,3-Dimethylbut-2-ene Tetramethylethylene (2 ml;16 .9 nimol),S-phenyl-1, 3,L- oxathiazol-2-one (0.3g; 1.68 nimol) and xylene (20 xnl)were heated 236 together under reflu.x (132-1400C) for 72h. Evaporation of the solvent gave a brown oil which was triturated with cold .thioI and sulphur (2) filtered off. The filtrate was evaporated to dryness and the residue Kugelrohr distilled (80°C;0.lmmHg) to give benzonitrile (80%)1max (liquid film) 2230 cin_ 1 (CN). The residue was an intractable black tar. 3.12.3 Phenylacetylene -Phenyl-.l ,3 ,h-oxathiazol-2-one (1-74g; 9.7 inmol) and phenylacetylene (ii ml; 0.1 mol) were heated under reflu.x for 18h. Kugelrohr distillation of the reaction mixture gave ben.nitrile ( 8 2%).Vmax (liquid film) 2230 cm' 1 (CN). The black tar residue could not be purified further. During the course of the reaction hydrogen sulphide was produced (positive test-to lead acetate paper). 3.12.4 Coumarin 5_( 7Methoxypheny1)-1,3,4-oxathiazo1-2-one (1.84g;8 .8 mmol), cournarin (1.97g; 13.6 xnmol) and xylene (ho ml) were heated together under reflux for 48h. (Hplc analysis of the reaction mixture showed no oxathiazolone remained). Solvent evaporation gave a pale orange solid which was washed with ethanol and sulphur (0.21g) recovered. The filtrate was purified by flash column chromatography (silica; ethyl acetat.e:petroleuin ether; 1:10) to give sulphur (83 mg), p7anisonitrile (1.02g)))max (Nujol) 2230 cm 1 (CN) and coumarin, 1 H ninr spectrum (CDC13 ; 60MHz) superimposable on that of an authentic sample. 237 3.12.5 Thermolysis of 1 9 3,4-Oxathiazol-2-one in the Presence of ECF. 1,3,1-Oxathiazo1-2-one (0.28g; 3 nmiol) and ECF (log) were heated together under reflux for 1.5h. The excess ECF was distilled off at atmospheric pressure b.p. Ub-US°C (lit. 163 1J.S-116°C). Examination of the brown liquid residue by 1 H showed no trace of a 1,2,4-thiadiazole adduct or urireacted oxathiazolone. 3.13 Synthesis and Reaction of 1,4,2-Dithiazole-5-thiones (64) 3.13.1 Synthesis from Tioamides. Genera]. Procedure The thioainide (0.174 mol) was dissolved in chloroform (800 ml) ad the solution warmed to 40-50 0C. Perchloromethylmercaptan (0.088 mol) in chloroform (20 ml) was added dropwise over 10 mm. After complete addition the reaction mixture was refluxed for a further 7h. Evaporation of the solvent gave a yellow residue which was purified by flash column chromatography. (a) 3-Phenyl-1,4, 2-dithiazole-5-thione (64a) The product was prepared from thiobenzamide as described above. The residue was purified by flash column chromatography (silica; dichioromethane :petroleum ether; 1:2) to give (64a) in 30% yield mp 116-117.50C (lit. 5 11890)) max (Nujol)1060 cm-1 (CS).?,max (dichioromethane) 353,253 rim max 211000, 377163 respectively. 13C nmr spectrum (CDC13; 5Q4Hz)4'c 218.9(C-5) 172.5 ppm (c-3). 238 (b) 3-Methyl-1, lj, 2-4ithiazole-S-thione (64b) The product was prepared from thioacetamide as described previously. The residue was purified by flash column chromatography (silica; dichioromethane:petroieum ether; 2:3) to give (64b) (9%) as:a yellow oil which solidified on standing. This was crystallised from ethanol to give yellow plates nip 30-33 0C (Found: m/z 1118.9430 (M) C3H3NS3 requires ni/z 148.911277 (M) ).).)max (liquid film) 1515,1550. (CN), 1075 cm-1 (C=S)./max (dichioromethane) 344,283,234 nmmax 293530,59600, 37080 respectively. 13C nmr spectrum (CDC13 ; 50 MHz) Sc 220.1 (c-5), 171.9 ppm (C-3). 3.13.2 The Cvclosubstitution Reactions of 1j4,2-Dithiazole- 5-thiones with Electron Deficient Nitriles 3.13.2.1 3-Phenyl-1,4,2-dithiazole-5-thione (64a) (a) Ethyl C-yanoformate 3-Phenyl-1,4,2-d1thiazo1e-5-thione (0.474g; 2.25 nimol) and ECF (10 ml; 0.101 mol) were heated together under reflux for 70h (Ca 1150c). The excess ECF was removed by distillation under reduced pressure (60°c; 60 mmHg). The benzonitrile side product was removed by Kugelrohr distillation (2 0C;2xnmHg) and the yellow oil residue purified by flash column chromatography (silica; dichloromethane:petroleum ether; 1:1) to give 3- ethoçrcarbonyl-1,4,2-dithiazo1e-5-thiofle (71,u) nip 43-440C. (lit. 93 hh°C).Vinax (Nujol) 173S (c0), 1250 cm-1 (CS) m/z 207 (M +).13C nmr (CDC1 3 ; 50 mHz) 5c 217.3(C-S),l63.6 ppm (C-3). 239 Trichloroacetonitrle (1) Trichlorogcetonitrile (iS ml; 0.15 mol), 3-phenyl- 1,4,2-dithiazole-5-thione (0. 555g; 2.61 nunol) and xylene (10 ml) were heated together under reflux (Ca 1250C) for 48h. The excess TCA was removed by distillation (bp 84 0C) and the solvent evaporated under reduced pressure to give a brown oil which was purified by flash column chromatography (silica;dichloromethane: petroleum ether; 2:3) to give a yellow oil. The oil was crystaflised from ethanol to give yellow needles (70%) nip 60.- 61°C. (Found: C,14.5; H,0.1; N,5.7; S,37.9 C3013NS3 requires 0,14.3, H,0.03 N,5.6, S,38.1%)-)max (Nujol) 1515 (CN), 1070cm 1 (c=s). m/z 257,255,253, 251 (M) ratio 1:6: 14u13 Cl3 requires 1:9:28:29.13C nmr spectrum (CDC1 3 ; SOMHZ)eC 216.4 (c-5), 169.7 ppm (C-3). (ii) 3-Pheny1-1,4, 2-dithiazole-5-thione (2.111 .9= ; 10.1 mmcl) and TCA (15 ml; 0.15 mol) were heated together under reflux for 164th. The excess TCA was removed by distillation (bp 840C) and the residue purified by flash column chromatography (silica; toluene:petroleum ether; 2:3) to give a yellow solid which was crystallised from ethanol to afford yellow needles (83%) nip 60-610C.)max (Nujol) 1515 (CN), 1070 cm (Cs) 13C nmr spectrum (aDd 3 ; 50 MHz) 'c 216.1 (C-5),169.7 ppm (C-3). Dtchloroacetonitrile 3-Phenyl-1,4,2-dithiazole--thione (2.16g; 10.2 mmcl) and dichioroacetonitrile (11 ml; 0.14 mci) were heated together 2)33 under reflux (ca.1110C) for 27h. Evaporation of the excess DCA under reduced pressure gave a brown oil which contained both the starting dithiazolethione (64a) and the expected product (64e) by hplc analysis; comparison of retention times and peak enhancement on addition of authentic (64e). m/z 217 (N; (64e) ),211 (M;(64a) ). However, they proved to be impossible to separate using normal chromatographic techniques. (d) Benzoyl Cyanide 3-Phenyi-1,4,2-dithiazole--thione (0.58$g; 2.77 mmol), benzoyl cyanide (b ml; 0.031 mol) and xylene (ho ml) were heated together under reflux (Ca 139 0C) for 192h. The solvent and excess nitrile were removed under reduced pressure to give a browa oil which was purified by flash column chromatography (silica; dichloromethane:petroleum ether; 1:1). A yellow oil (50 mg) was isolated. m/z 309 (M, 2,4,6-triphenyl-1,3,5- triazine), 26 (s8 ), 239 (M, 3.-benzoyi-1,4,2-dithiazole-5- thione). 3.13.2.2 3-Methyl-1,4, 2-dithiazoie-5-thione (64b) (a) Trichioroacetonitrile 3-Methy1-1,4,2-dithiazo1e-S-thione (0.74g; 4.99 mmol) and trichioroacetonitrile (20 ml; 0.2 rnmol) were heated together under reflux for lOh. Tic (silica;dichloromethane:petroleum ether; 2:3) and hplc analysis indicated no starting material (hb) remained. Evaporation of the excess TCA gave a yellow- brown solid which was crystallised from ethanol to give.-yellow 241 needles (96%) mp 61 -63.5°C. ))max (Nuol.) 1515 (C=N),1070 cm -1 (cs) in/z 257 (N). Identical to authentic sample of 3-trichloroiuethyl-1 ,LL, 2-dithiazole-5-thione. Dichioroacetonitrile 3-Methyl-1,Li., 2-dithiazole-.5-thione (0.4614g; 3.11 mmol) and dichioroacetonitrile (13 ml; 0.17 mol) were heated together wider refiux (ca 111°c) for 12 h. Evaporation of the excess DCA gave a brown solid residue which was purified by flash column chromatography (silica; dichloromethane :petroleuin ether; 1 :4). tJnreacted starting material (b mg) was recovered m/z 211 (M) and the 3dich1oromethyl-1,4,2-dithiazo1e-5-thiOfle was isolated as a yellow oil (90% based on unrecovered starting material). (Found: m/z 220.85 (M) C3H37G1 2NS 3 requires in/z 220.85892(M), m/z 218.619 (H) C 3H37C135C1Ns 3 requires m/z 218.86187 (M 4 ), m/z C3H35C12N3 3 requires m/z 216.86482 (M);ratio 1:4:6 216.8652 QM— +) Cl3 requires 1:6:9). ))max (liquid film) 1065 (0S),755 ci 1 (C-C1). Chioroacetonitrile Chioroacetonitrile (10 ml; 159 imuol) and 3-methyl-1,4 1 2- dithiazole-5-thione (0.44.7g; 3 inmol) were heated together under reflux (ca 120°C) for 9h. Evaporation of the excess nitrile gave a brown oil which was purified by flash column chromatography (silica; dichloromethane:petroleum ether; 1:3). tjnreacted starting material (85%) was isolated as a yellow oil. 1 H nmr spectrum (CDC1 3 ; 80 MHz)5 H 2.5 ppm(s) 13C ninr spectrum (CDC1 3 ; 50 MHz) S c220.3, 171.9,21.3 ppm nl/z 183 (M,3-chloromethy1 -1, Li., 2-dithiazole-5-thione), 149 (M, starting material). 242 o -Oxo-2-Furaacetonitri1e 3-Methyl-1,4-2-dithiazole-5-thione (0.25g; 1.68 inmol) and 0(-oxo-2-furanacetonitrile (0.416g; 3.144 mmol) were suspended together in xylene (140 ml) and the mixture heated under reflu.x for 82h. Evaporation of the solvent gave a brown oil which was purified by flash column chromatography (silica; dichloromethane:petroieum ether; 2:5) to give unreacted starting material (80%) mhz 1149 (M) and a yellow solid (67 mg) which 1 may have been the cyclosubstitution product (614h) H nmr spectrum (ODd 3 ; 200 MHz)c5H 7.9(dd), 7.8 (ma), 7.2(m), 6.7 ppm (ma), mhz 229 (Mproduct), 1149 (M, starting material). Pyruvonitrile 3-Methyl-1 ,14, 2-dithiazole-5-thione (0.42g; 2.9 mmol) and pyruvonitrile (12 ml) were heated together under reflux (ca.710 C) for 12h. Evaporation of the excess nitrile under reduced pressure gave a yellow-brown oil (0.59) which was crystallised from ethanol to give unreac ted starting material (75%) H mar spectrum (ODd 3 ; 80MHz) SH 2.Sppm(s). Benzonitrile Benzonitrile (20 ml; 196 mnmol), 3-niethyl-1,4,2-dithiazole- 5-thione (0.666g; 4.5 mamol) and xylene (20 ml) were heated together under reflux for 42h. Evaporation of the solvent and excess PhCN gave a yellow-brown oil which partially solidified on standing and was shown to be unreacted starting material (96%) mnjz 149 (M) 243 Butyronitriie 3-Methyi-1,41 2-dithiazole-Li-thione (0.332g; 2.2 mmol) and n-butyronitrile (20 ml) were heated together under reflux (Ca 11500 for 17h. Evaporation of the excess nitrile gave a yellow-brown oil which was proven to be unreacted starting material (89%).Vina.x (liquid film) 1550,1515 (CN), 1075 cm (C 3 ). 1 H nmr spectrum (CDC1 3 ; 6(Hz)6H 2.5 ppm(s). Ethyl Cyanoacetate Ethyl cyaxioacetate (5 ml; 48 mmol), 3-methyi-1,4,2- dithiazole-5-thione (0.164g; 1.1 mmol) and toluene (20 ml) were heated together under reflux (Ca 108 0 C) for 48h. There was no apparent reaction by tic (silica; dichloromethane:petroleuxn ether; 1:1) or by hplc analysis. Evaporation of the solvent and excess nitrile under reduced pressure gave a brown solid which was crystallised from ethanol to give starting material (90%) mp 30-330C. (Ii) A repeat experiment with ethyl cyanoacetate as sole solvent, reflux temperature (Ca 208 0C) and reaction time lh gave sulphur (112 mg) as the only isolable product mhz 256(S3 ). 3.13.2.3 Competition Reaction aetween the i,4, 2'D.thiazo1e- 5-thiones (64a) and (64b) and Ethyl Cyanoformate. Ethyl cyanoformate (0.215 ml; 2.18 miaol),3-phenyl-1,4,2- dithiazole-5-thione (0.459g; 2.18 inmol) and 3-methyl-1,4,2- dithiazole-5-thione (0.325g; 2.18 inmol) were heated together in an oil bath (ca 130° C) for 6h. Evaporation of the excess 244 ECF gave a yellow-brown gum which was purified by flash column chromatography( silica; dich].oromethane :petroleuin ether; 1:3) to give unreacted 3-phenyl-1,4,2-dithiazole-5- thione (71%) mJz 211 (M), unreacted 3-methyl-1,4,2- dithiazole--thione (47%) mJz 149 (M t ) and 3-ethoxycarbonyl- 1,1,2-dithiazole-5-thione (44%-)rii/z 207 (M). The yield of (64e) is based on recovered starting material. 3.13.3 Reaction of 3-Methyl-1,4,2-dithiazole-5-thione (64b) with Diethyl Fumarate. 3-Methyl-1,4,2-dithiazole-S-thione (0.934g;6.3 niinol), diethyl fumarate (20 ml; 0.12 inol) and xylene (20 nil) were heated together under reflux Lea 1350C) for 6h. The solvent was evaporated under reduced pressure and the excess DEF was removed by Kugelrohr distillation (80°C; 2 mmHg) to give a brown solid residue. This solid was shown to contain mainly unreacted starting material by hplc analysis, xn/z 119 (M). 3.13.4 Reaction of 1,3-Dithiolane-2-thione (138) with Ethyl Cyanoformate. () 1,3-Dithiolaxie-2-thione (52 mg; 0.38 nunol) and ethyl cyanoformate (3 ml; 30.4 inmol) were heated together under reflux for 2h. Evaporation of the excess ECF gave a brown oil which 1 contained mainly starting material H ninr spectrum (CDC1 3 ; 60 MHZ)5H 4ppm(s). (ii) Ethyl cyanoforinate (1 ml; 10.1 nimol). and ethylene trithiocarbonate (0.118g; 0.87 inmol) were immersed in a bath of 21 refluxing toluene (Ca iio°c) for 240h. Kugelrohr distillation (0°C; 60 mmHg) gave a yellow liquid distillate which contained 1 only starting material and ECF H nmr spectrum (CDC13 ;60 MHz) H L(q), 1.4 ppm (t) ECF, 1 ppm (138). The residue did not contain any identifiable products by hplc. 3.13.; Reaction of 1,3-Dithiole-2-thione (139) with Ethyl Cyarioformate. Vinylene trithiocarbonate (1 g; 7.5 inmol) and ethyl cyanoformate (5 ml; 50.7 inmol) were heated together under reflux in a nitrogen atmosphere for 9h. Tic (silica;dichlorometharie: petroleum ether; 2:5) indicated that the 1,3-dithiole-2-thione was decomposing but there was no trace of the expected 3- ethoxycarbonyl-1,4,2-dithiazole-5-thione product by hplc. Evaporation of the excess ECF gave a brown solid m/z 256 (S 8' 134 (M , starting material). 3.13.6 Reaction of 5-Phenyl-1,2,1-d:ithiazo1e-3-thione (10a) with Ethyl Cyanoforiate. 5-Phenyl-1,2,4-dithiazole-3-thione (0.163g; 0.77 mmol) and ethyl cyanoformate (10 ml; 0.1 inol) were heated together under reflu.x for Sh. }lc analysis of the crude reaction mixture indicated no starting material remained. Evaporation of the excess ECF gave an orange solid m/z 25e (S 3 ). There were no other identifiable products. 2L 3.14 Reaction of 1,3,4-Oxathiazol-2-ones (2) with Nucleophiles. 3.14.1 Nitrogen Nucleophiles General Procedure The 1,3,4-oxathiazol -2-one was dissolved in ether and a solution of the amine (ieq) in ether was added dropwise over 20-30 mm. The temperature of the reaction mixture was maintained at ca-12°C 2°C throughout by means of an ice-salt bath. After stirring at -12°C for a further 30min the mixture was warmed to room temperature and the solvent evaporated to afford a white solid, which was crystallised from ethanol. 3.14.1.1 Piperidine Piperidine (1 ml; 10 rnmnol) in dry ether (50 ITIJ.) was added as described above to a solution of S-phenyl-1,3,4-oxathiazol- 2-one (1.81g; 10 mmoi) in ether (200 ml). N-Benzoyl-S- piperidinocarbonylthiohydroxylamine was isolated (92%) ma p 147- 84 148'C (lit. 1)450C). (Found: C,59.4;H,6.2;N,l0.6 C 13H16N202S requires C,59.l;H,6.1;N,l0.6%) haax (Nujol) 3270 (NH),1640,1690 -1 + cmii (c0) m/z 264 (N ) 3.14.1.2 Morpholine (a) Morpholine (1.57 ml;18.0 mmol) in dry ether (20 ml) was added to a solution of 5-phenyl-1,3,4-oxathiazol-2-one (3.24g; 18.1 unmnol) in dry ether (200 ml) using the procedure outlined above. N-Benzoyl-S-niorpholinocarbonyithiohydroxylaiiiine (96%) 247 84 was isolated in p 174-175°C (lit. 175-1760C). (Found: C,3 .9;H,S.3;N,10.LL C 12 H. J N203S requires C,54.1;H,.3; N 5 10.%).1)max (Nujol) 3290 (NH), 165,1680 cni(C0). m/z 266(C). Morpholine (1.1 ml; 12.6 xnmol) in ether (10 ml) was added to a solution of 5-inethyl-1,3,4-oxathiazol-2-one (1.532g; 13.1 inmol) in ether (24 ml) using the procedure described above. N-Acetyl-S-morpholinocarbonylthiohydroxylamine was isolated (50%) in p 167.5 - 169 0C (Found: C,40.9;H,.8; N,13.7 C7H 2N 203S requires C,41-2; H 5 .2; N,13.7%).)max (Nujol) 3240 (NH), 1670 cm-1 (c=o). m/z 204 (M) Morpholine (0.52imml; 6 inmnol) in ether (10 ml) was added to a solution of 5-ethoxycarbonyl-1 , 3, 1i-oxathiazo1-2-one (1-052g; 6 nunol) in ether (25 ml) using the procedure described earlier. N- ( 2-Etho)cy-1, 2-dioxoethyl )-S-morpholinothiohydroxylaimiine was isolated (18%) in p 127-1280C (Found: mhz 262.0622 (M) C9HN205S requires rri/z 262.06234 (M) )))max (Nujol) 3230 (NH), 1730, 1690 cm 1 (c0). Morpholine (0.99m1; 0.01.1 inol) in ether (S ml) was added to a solution of freshly prepared 1,3,4-oxathiazo1-2-one (1.174g; 0.011 mol) in ether (iS ml) using the procedure described earlier. N-Formyl-S-morpholinocarbonylthiohydroxylaxnine was isolated (30%) in p ]J46-147 0C.(Found: C,37.6;H,5.3;N,14.4 C6HN203S requires C,37.9; H,5.3; N,14.7) m/z 190.0412 (M t ) C61d203S requires /z 190.01121 (N) .)max (Niujol)3300 (NH) 1650 cm (c=o). 243 3.14.1.3 Excess Piperidine Piperidine (3 ml; 30.4 inmol) in ether (50 ml) was added to a solution of 5-phenyl-1,3,4-oxathiazol-2-one (1.8839; 10.5 imnol) using the general procedure described earlier. Evaporation of the solvent gave a yellow-white solid which was purified by flash column chromatography (silica; methanol: chloroform; 1:20). Sulphur (0.25g), benzainide (0.93g) and ]Lis-pentamethyleneurea (i.Bg) were isolated. m/z 256 (s8 ), 196 (urea,M), 121(PhC0NH,). 130 ninr (d,-DMSO, SHz)c 163.7,47.5,25.i,24.0 ppm(urea); 167.9, 134.3, 131.1,128.2, 127.2 ppm (PhCONH2 ). 3.14.1.4 ]3utylainine (a) n-Butylainine (0.9 ml; 9.1 imnol) in ether (50 ml) was added to a solution of 5-pheny1-1,3,4-oxathiazol-2-one (1.36g; 9.1 nimol) in ether (200 nil) using the general procedure described earlier. Evaporation of the solvent gave a yellow-white solid which was purified by flash column cbromatography(silica; dichioromethane: petroleum ether; 2:5) to give sulphur (48%) and starting material (bo%). When methanol was passed through the column a white solid was recovered. This was proven to be a mixture of M,Ndibutylurea and benzamide by comparison with authentic samples. in/z 172 (urea, 121 (benzamide,M ' ).130 nmr (d6-DMSO; 50 14Hz) Sc 167.9(C0), 134.3 (PhC), 131.0, 128.0,127.4 ppm (PhCH), of benzamide; 158.1 (0=0)32.2, 19.5 (CH 2 ) 13.6 ppm (CH 3 )of the urea. 2)49 (b) n-Butylamine (0.3m1; 3 nuaoi) was added to a solution of 5-phenyl-1,3,4-oxathiazol-2-one (0.569g; 3.2 mmol) in ether (10 ml). The reaction mixture was left to stir at R T for 15h.- Evaporation of the solvent gave a white solid which was shown to be a mixture of starting material, benzaniide and dibutylurea by comparison with authentic samples. 13C ninr (CDC13; 50 MHz) Sc 169.7, 133.1, 131.4,128.1,127.2 ppni(benzamide) 173.1&,157.0,132.3,128.6,127.0,l25.li ppm (oxathiazolone); 159.1, 39.6,32.2,19.7,13.4 ppm(urea). 3.14.1.5 Triethylainine A mixture of triethylainine (l.Sml; 10.3 mmol) in ether (20 ml) was added to a solution of 5-phenyl-1,3,4-oxathiazol- 2-one (1.899g; 10.6 inxnol) in ether (50 ml) using the general procedure outlined earlier. Evaporation of the solvent and excess triethylamine gave a white solid (1.8g) which was shown + to be starting material m/z 179 (oxathiazolone,M ).)hiax (Nujol) 1735 cm 1 (C0). 3.14.1.6 Ammonia (a) Ammonia (d.0.88) (0.2 ml; 10.4 mmol) in ether (50 ml) was added dropwise over 30 min to a refluxing solution of 5-phenyl- 1,3,4-oxathiazol-2-one (1.816g; 10.3 mmcl) in ether (200 ml). The reaction mixture was heated under ref lux for a further 2h and evaporation of the solvent gave a white solid (1.8g). This was shown to be starting material by comparison with an authentic 23 sample. ) max (Nujol) 1735 cm (CiiO). 13C nmr (CDC13,50 MHz) Sc 173.6,157.2,132.1,129.0,126.9,125.8 ppm. (b) 5-Phenyl-1,3,4-oxathiazol-2-one (1.3999; 7.8 mmol) and ammonia (d.0.88) (10 ml; 0.52 mol) were heated together on a steam bath for 30 mm. After cooling,the reaction mixture was washed with dichloromethane (3 x 30 ml). The combined organic fractions were dried (Mgs%), and evaporated to dryness. The white solid residue was proven to be a mixture of benzamide and sulphur by comparison with authentic samples. m/z 256(S 5 ), 121 (benzamide, M). Reverse phase hplc analysis Rt 5.5 mm with peak enhancement on addition of PhCONH 2 . 3.14.1.7 Aniline 5-Pheny1-1,3,4-oxathiazol-2-one (0.304g; 1.7 mmol) and aniline (1 ml; 11 inmol) were dissolved in ether (2 ml) and stirred at R T for 6 days. After evaporation of the ether the remaining aniline was distilled off (ca 80 °C; 1 mmHg). The distillate contained traces of benzonitrile 2) max (liquid film) 2230 cm 1 (C.N). The residue, a pale brown solid, was shown to contain benzamide and N,N-diphenylurea. 13C nmr (d6-WO., 50 MHz) 167.9, 13t.3,13l.1,128.1,127.Li. ppm (PhCONH2 ), 152.6, 139.7, 128.7, 121.8,118.2 ppm (urea). 3.14.1.8 Reaction of N-Benzoyl-S-pipericitnocarbonyl- thi ohydroxyl amine (1W-,a) with Butyl amine N-Benzoyl-S-piperidinocarbonylthiohydroxylamine (0.217g; 251 0.82 inmol), n-butylanzirie (0.08 ml; 0.81 inmol) and dry ether (20 ml) were heated together under reflux for 2141. Evaporation of the solvent gave a white solid (0.29g) which was mainly starting material. 13C nmr (CDC13 ; 50MHz)c5c 169.0, 165.8, 133.l,131.9,128.3,127.6,bS.5,2.b,21i.l ppm. By comparison with an authentic sample however, on reverse phase hplc presence of benzamide was confirmed Rt 5.5 min with peak enhancement. 3.14.2 Oxygen Nucleophiles 3.14.2.1 Benzyl Alcohol S-Phenyl-1, 3 ,L-oxathiazol-2-one (0.864g; 4.8 mmol), benzyl alcohol (0.5 ml;4.8 mmol) and ether (50 ml) were heated together under reflux for llh. Evaporation of the solvent and excess alcohol under reduced pressure gave a white solid (0.87g) which was shown to be starting material by comparison with an authentic sample.1)max (Nujol) 1735 cm 1 (C0). m/z 179 (M). 3.14.2.2. Potassium Hydroxide A solution of 5-phenyl-1,3,b-oxathiazol-2-one (0.519g; 2.9 mmol) in ethanol (100 ml) was cooled to ca-20 °C by means of an ice-salt bath. Freshly prepared 0.14 M ethanolic potassium hydroxide (20.7 ml; 2.9 inmol) in ethanol (30 ml) was added dropwise over 45 mm. After warming to R T , the solvent was evaporated under reduced pressure to give a pale yellow solid. The residue was treated with water (20 ml) and dichioromethane (20 ml), the two layers separated and the 2)2 aqueous portion washed with dichiorometharie (2 x 30 nil). The organic extracts were combined and dried (Mg SO 4) evaporation of the solvent gave a yellow solid which was proven to be a mixture of sulphur and benzainide by comparison with authentic samples. m/z 256 121 (benzainide,M). Reverse phase hplc analysis Rt. 5.5 min peak enchaxicement on addition of PhCONH2 . The aqueous fraction was acidified with dilute HC1 (SO ml) before extracting iith dichioroinethane (2 x 30 ml). The combined organic extracts were dried (MgS%) and the solvent evaporated to give a pale yellow solid m/z 121(benzaxnide,M ). Reverse phase hplc analysis Rt 5.5 min peak enchancement on addition of PhCONH2 . 3.14.2.3 Sodium Ethoxide 1.5'M Ethanolic sodium ethoxide (!. ml; 6 mmol) in ethanol (6 ml) was added dropwise over 15 min to a stirring solution of -phenyl-1,3,4-oxathiazol-2-one (1 g;.6 mmol) in ethanol (10 ml). The reaction mixture was stirred at R T for a further bh. A pale yellow solid (78 mg) was filtered off and shown to contain benzamide by comparison with an authentic sample. The filtrate was acidified with dilute HCl and the precipitated NaCl filtered off. The filtrate was concentrated under reduced pressure and the aqueous residue extracted with dichloromethane (2 x 25xnl). The organic extracts were combined, dried (MgS0) 253 and evaporated to dryness to give a yellow solid (0.77g) which was shown to contain sulphur and benzainide by comparison with authentic samples rclz 256 121(banzainide, M). Reverse phase hplc analysis Rt 5.6 min peak enhancement on addition of PhCCNH2 .. 3.14.2.4 Sodium Benzyloxide 2.8 M Sodium benzylo.de (i.Li, ml; 39 mmol) was added in one portion to a suspension of 5-(a7methoxypheny1)-1,3,4- oxathiazol-2-one (0.826g; t inmol) in ethanol (20 ml). The reaction mixture was stirred at R T for l.Sh. Evaporation of the solvent gave a red-orange oil which partially solidified on standing. A pale orange solid was filtered off and was shown to contain LL-inethoxybenzamide by comparison with an authentic sample m/z 151 (amide, M ' ). Reverse phase hplc analysis Rt 6.0 min peak enhancement on addition of 4-methoxybenzamide. 3.14.3 Carbon Nucleophiles 3. 14-3.1 Butylisonitrile (a) 5-Fhenyl-1,3,4-oxathiazol-2-one (0.408g; 2.3 ininol) was dissolved in dry ether (10 ml) and n-butylisonitrile (0.2m1; 1.9 inmol) was added in one portion. The reaction mixture was stirred at R T , with periodic checking by tic (silica; ether: petroleum ether; 3:10) for lbO h. There was no indication of a reaction occuring. Evaporation of the solvent gave a white solid (0.40g) which was proven to be starting material by comparison with an authentic sample ))max (Nujol) 1730 cm-1 254 (C=O) mJz 179 (M) (b) -Phenyl-1,3 1 14-oxathiazol-2-one (0.426g;2.4 mmol), n-butylisonitrile (0.2 ml; 1.9 nimol) and ether (10 ml) were heated together under reflux for 8h. Evaporation of the solvent gave a pale yellow solid (0.41g) which proved to be starting material by comparison with an authentic sample)max (Nujol) 1730 oxn 1 (C0)th/z 179 (M) 3.114.3.2 Fhenylinagnesium Bromide (a) 0.814 Phenylmagnesium bromide (3.9mJ.; ca 3.3 mmol) was added in one portion to a stirring solution of 5-(-methorpheny1)- 1,3,b-oxathiazol-2-one (0.684g; 3.3 nimol) in ether (10 ml). There was immediate effervescence and after 10 min the mixture was poured onto crushed ice and acidified with dilute 1W1. The two layers were separated and the aqueous phase washed with ether (2 x 25 ml). The combined ethereal extracts were washed successively with brine (25 nil) and water (25 ml) then dried (14gS014). Evaporation of the solvent gave a yellow solid which was purified by flash column chromatography (silica; ether: petroleum ether; 1:14) to give sulphur (90 mg) m/z 256 (S 8)) starting oxathiazolone (iS mg) m/z 209 (Mt ), and a mixed fraction containing diphenyldisulphide, thiophenol and 14-anisonitrile. )max (Nujol) 2560 (SH), 2230 cm 1 (CsN). m/z 218 (PhssPh,M), 133(4-44eOC6H14CN,11 ' ), 110 (PhSH,H). 13C nmr(CDC13 ,50 14Hz) c$c 162. (c-14),133.5(c-3 2 5), 118.7(c-l),n4.14(c-2,6),103.1(cN), 55.1 ppm (CH3)4-anisonitrile. (b) A solution of 5-phenyl-1,3,4-oxathiazol-2-one (1.019g; 5.7 mmol) in ether (10 ml) was added dropwise to a refluxing ethereal solution of phenylmagnesiuin bromide (Ca 0.04 mol). The reaction mixture was heated at reflux for a further hour, cooled, poured onto crushed ice and acidified with dilute HC1. The two lasers were separated and the organic portion washed with water (2 x 25 ml). Tie ethereal extract was dried (MgsO) and evaporated to dryness to give a mobile yellow oil from which a white solid crystallised out. By comparison with an authentic sample this was proven to be triphenylmethanol m p and mixed m p 157-.158 0C (lit. 163 160-163 0C). 1) max (Nujol) 3100 cm-'(OH). m/z 259 (M) 13C nmr 8c 1J46.7 (PhC),127.9 (PhCHx 3),127.2(PhCN), 81.7 ppm (C-OH). The residue contained thiophenol, diphenyldisulphide and a small trace of benzophertone. 1) max(liquid film) 2560 (SH),17004650 cm 1 (C'O).m/z 218 (PhssPh,M), 182 (Ph 2co,M), 110 (PhsH,M). 3.14.4 Miscellaneous Nucleophile 3.14-4.1 Ethanethiol A mixture of ethanethiol (0.75 ml; 10 mmol) and ether (So ml) was added to a solution of 5-phenyl-1,3,4-oxathiazol-2-one (1.839; 10.2 mmol) in ether (200 ml). The reaction mixture was stirred at R T for 24h. Evaporation of the solvent under reduced pressure gave a white solid (1.8g) which was shown to be starting material by comparison with an authentic sample ))max (Nujol) 1735 cm 1 (C0), in/z 179 (M). 25' 3 .14-4.2 Triphenyiphosphine Triphenyiphosphine (0.5g; 1.9 minol) was added in one portion to a stirring solution of 5-(7methoxypheny1)-1,3,1- oxathiazol-2-one (0.387g; 1.9 mmol). There was immediate effervescence which subsided within 10 min. The mixture was stirred at R T for a further 2h, and evaporation of the solvent gave a white solid. This was shown to contain .triphenyiphosphune, 4-anisonitri1e and triphenylphosphune sulphide by comparison with authentic samples. 2.)max (Nujol) 2230 cm 1 (CN).m/z 294(Ph3PS,M' ), 262 (P 3P,M), 133 (-Me0C6HCN,M).13C nmr (CDC1 3 ;50 MHz) Sc 162.3, i33.2,U8.b,UL.S,103.2,SS.0 ppm(anisonitrile), nmr (CDC13;80 MHz) (çp .-6(Ph3P), 20 ppm (Ph 3P=s). 3.14. Reaction of 5-(p-Methox'pheny1)--1, 3,1i-oxathiazo1-2-one with Carbon Disulphide 5-(7Methoxyphenyl)-1,3,4-oxathiazo1-2-one (0.352g; 1.7mmol) and carbon disulphide (S ml) were heated together under refiux for %. There was no apparent reaction by tic (silica; dichloroinethane:petroleum ether; 1:1). Toluene (lOmi) was added and the mixture refluxed for a further 7h. Evaporation of the solvent gave a white solid (O.Lg) which was proven to be unreacted oxathiazolone by comparison with an authentic sample. )) max 1750 cm (c0) m/z 209 (M ' ) 3 .3J.6 Reaction of 5- (p-Methoxyphenyl )-i, 3, L.-oxathiazo1-2-one with N,N-Dimnethylthioformainide. 5-( 7Methox7pheny1)-1,3,4-oxathiazol-2-one (1.833g; 8.8mmoi) and N,N-dimethylthioformainide (0.75 ml; 8.8 inniol) 27 with ether (20 ml) were heated under refJ.ux for 5h. Tic (silica; ether : petroleum ether; 3:10) indicated no apparent decomposition of the oxathiazolone. Evaporation of the ether gave a white solid which turned yellow on standing for 3 days. ))max (liquid film) 2225 (CN), 1750 cm 1 00). in/z 256 (S 8' 209 (oxathiazolone,M), 133 (4_MeOC6H4CN, M), 89 (Me 2 NCHSj). 3.15 Synthesis of n-Butylisonitrile 1149 (S2) Butylamine (40 ml; 0.40 mol), dry alcohol free chloroform (36m1; 0.45 mol) and benzyltriethylauimonium chloride (0.6g) were dissolved in dichioroinetharie (60 ml; hplc grade). 50% Aqueous sodium hydroxide (60 ml) was added in one portion with stirring. After a short induction period (Ca 10 mm) the solution began to reflux gently, when this had ceased the reaction mixture was left to stir for a further hour before diluting with water (200 ml). The lower layer was run off and the upper aqueous phase washed with dichioromethane (2 x 50 ml). The three organic portions were combined, washed with water (50 ml) and brine (SOml) and dried (MgS%). Evaporation of the solvent gave a red-brown oil which was purified by Kugelrohr distillation (6 C;6omnmHg) to give a colourless liquid (30%) (1it. 9 b p 140-4200; 11 torr). )max (liquid film) 2160 cm 1 (NC). NOTE: A liquid nitrogen trap was necessary during distillation to prevent the odour escaping into the fume hood. 258 3.16 Preparation of Ureas 3.16.1 From Isocyanates General Procedure. Isocyanate was added to dry ether (50 ml) and the solution cooled to ca -10°C by means of an ice-salt bath. 1 eq of amine in ether, (15 ml) was added dropwise over 15 mm. The reaction mixture was allowed to warm to room temperature and the ether removed under reduced pressure. The crude product was then crystallised from an appropriate solvent. (a)NN-Dibuty1urea (116) This was synthesised, using the procedure described above, from n-butylisocyanate (6 ml; 0.05 mol) and n-butylainine (5 ml; 0.05 inol). The crude material was crystallised from ethanol 163 p 72-740C (lit. 71°C) (Found: C,63.0; 11,12.0; N,16.3 C9H20N20 requires C 1 62.8; H,11.7; T,16.3%)))inax (Nujol) 3335(NH), 1620 cm 1 (C0). FAB m/z 173[ M+H (b) -Butyl-N'-pentamethyleneureaN.: This urea was synthesised from n-butylisocyanate (1.1 nil; 9.8 mniol) and piperidine (1 ml; 10.1 mmol) by the method described above. The crude material was crystallised from ethanol (85%) in p 6I 0C.(Found: C,65.3; H,11.2,N,15.2 C10H20N20 requires C,6.2; H,10.9;N,l5.3,Z)),)max (Nujol)3340 (NH), 1615 cm-1 (co) in/z 184 (x'). '7 (c )_N,N'-Diphy1urea (150) Carbanilide was synthesised from phenylisocyanate (1 ml; 9.2 mmoi) and aniline (0.81 ml; 9.2 mmol) using the procedure described above. The crude product was crystallised from 0 water in p 2450C (decomp ) (lit- '63 in p 238-9 C).1) max (Nujol) 3320 (UN), 1625 cm (C0), FAB rn/z 213[11+H ] . (d)_N-Pentamethy1ene-NI.pheny1urea (166) This compound was synthesised from phenylisocyaxiate (1 in]. ; 9.21 mao!) and piperidine (0.91 ml; 9.22 mnmol) using the procedure outlined above. The crude product was washed with cold ether to give a white solid ma p 166-168 °C. (Found:C,70.6; H,8.0; N,13.6 C12H16N20 requires C,70.6; H,7.9;N,13.7%) ))inax (Nujol) 3290 (NH), 1615 cm 1 (C0) m/z 204(M). (e )_N-Butyl N 1 -phenylur2a (168) This compound was prepared from phenylisocyanate (1 ml; 9.21 mmol) and n-butylainine (0.91 ml; 9.22 mmol). The crude product was washed with cold ether to give a white solid in p 126-1270C (Found: C,68.7; H,8.5; N,14.5 C 11H10N20 requires C,68.7;H,8.4;N,14.6%)2)inax (Nujol) 3390,3300 (NH), 165 cn1 1 (C0) m/z 192 (M) 3.16.2 Bispentainethy1eneurea A solution of piperidine (20 ml) in toluene (20 ml) was cooled to ca 0°C by means of an ice-bath. 12.5% w/w phosgene 260 in toluene (io ml; U.S inmol) was then added dropwise over 20 min. The reaction mixture was allowed to warm to room temperature before flushing with N22 any excess phosgene present was destroyed in a 20% aqueous sodium hydroxide trap. Piperidine hydrochloride was filtered off and the filtrate evaporated to dryness to give a yellow oil which was triturated with cold ether. The Crude product was crystallised from 0 165 ethanol m p 43.5-I4.5 C (lit. 136C)))max 1650 em 1 (C0) m/z 196 (M) 3.16.3 Bis-pentwnethylenethioure(l60) A mixture of piperidine (8 ml) in dry ether (15 ml) was cooled to ca 0°C by means of an ice bath. Thiophosgene (1 ml; 0.013 mol) in ether (5 ml) was added dropwise over 15 mm. The reaction mixture was warmed slowly to room temperature and the piperidine hydrochloride filtered off. Evaporation of the filtrate gave a brown oil which was triturated with cold ethanol to give an off-white solid m 233-2350C (decomp ). (Found: m/z 212.1341 (M) C11HN2S requires mhz 212.13471 (M) ).)Jmax (Nujol) 195cm 1 (CS). 3.17 Reaction of 3-Fhenyl-1,4,2-dithiazole-5-thione (64a) with a Variety of Nucleophiles. 3.17.1 Piperidine (i) 3-Phenyl-1,4,2-dithiazoie-5-thione (0.357g; 1.69 mnmol) was dissolved in ether (20 ml) and 0.2M ethereal 261 piperidine (8.5 ml; 1.7 mmol) was added. The reaction mixture was heated under reflux for 8h and left to stir at R T for a further 48h. Evaporation of the solvent gave a yellow solid which was purified by flash column chromatography (silica;dichloroinethane' :petroleum ether; 3:10) to give sulphur (to mg) m/z 256 (S 8 ) and unreacted starting material (0.1539) in/z 211 (M). When methanol was passed through the column an off-white solid was isolated m/z 212, 205. lipic analysis indicated the presence of N,N' -bis- pentwuethylenethiourea Rt 7.6 min and the absence of thiobenzaniide. Ethereal 0.3M piperidine (3 ml; 0.6 mmol) was added to a solution of 3-phenyl-1,b,2-dithiazole--thione (0.134g; 0.63 inmol) in ether (5 ml) and the reaction mixture stirred at room temperature for 18.5h. Evaporation of the solvent gave a yellow solid /z 295, 211,205. Due to the large excess of starting material (rn/z 211) the isolation of the other materials present was impossible. Tentatively assigned m/z 295 as[ !!-H]-H] + peak for N-thiob enzoyl-S-pip eridinothiocarbonylthiohydro?iaznine (159) and m/z 205 as peak for the N-substituted thioamide (163b). Piperidine (5 ml; 50 mmol),3-phenyl-1,)4,2-dithiazole-5- thione (0.6g; 2.8 inmol) and dry chloroform (30 ml) were heated together under reflux for 1 h. Evaporation of the solvent under 262 reduced pressure gave a red-brown gum which was purified by flash column chromatography (silica; ether: petroleum ether; 1:10) to give sulphur (0.36g) m/z 256(S 5 ), banzonitrile (0.239) m/z 103 (14)))max 2225 cm -'( m). The most polar fraction mhz 212, 205 ),)max 1595 cm 1 (CS) 13C nmr (CDC13; 50 MHz)Sc 132.5, 131.8, 128.7 1 52.5, 45.0, 25.9, 23.0 ppm, contained the N-substituted thiobenzajnide (163b) and N,N'-entamethy1enethiourea (Rt 7.6 mm). The absence of PhCSNH2 was confirmed by hplc. 3.17.2 Butylainine n-Butylanine (0.1 ml; 1 mmo1) was added to a solution of 3-phenyl-1,4, 2-dithiazole-5-thione (0.219g; 1 inmol) in ether (10 ml) and the mixture was stirred at R T for 19h. Tic (silica; dichioromethane: petroleum ether; 1:1) showed no apparent reaction therefore the mixture was heated under reflux for a further Sh. Evaporation of the solvent gave a yellow solid which was purified by flash column chromatography (silica; dichloromethane:petroleuin ether; 3:10) to give sulphur (20 mg), mhz 256 (s8 ) and unreacted starting material (95 mg) mhz 211 (M). Passing methanol down the column gave a brown solid which contained N ,N' -dibutyithiourea m/z 116 (M) and thiobenzamide mhz 137 (M) Rt 5.0 min with peak enhancement on addition of PIICSNH2. 263 3.17.3 Tripheriylphosphine Triphenyiphosphine (0.3069; 1.2 mmol) was added in one portion to a solution of 3-pheny1-1,4,2-dithiazo1e--thione (0.247g; 1.2 mmol) in ether (10 ml). The reaction mixture was stirred at R T for 7 days. Evaporation of the solvent gave a yellow solid. Hplc analysis indicated the presence of thiobenzamide Rt 5.0 mm, benzonitrile Rt .4 min and triphenyiphosphine oxide Rt 6.6 min, all with peak enhancement. The presence of triphenyiphosphine sulphide in the crude product was indicated by rolz 294 (M, Ph3P:S) in the mass spectrum. 3.18; SynthesIs • 3-Phenyl-1,LL, 2-4ithiazol--one (8a) Glacial acetic acid (10 ml), water (1 ml) and finely powdered mercuric acetate (1.3199) was added to a solution of 3-phenyl-1,4,2-dithiazole-5-thione (1.049g; 6.7 nunol) in chloroform (10 ml) and stirred for 21 h before filtering. The pale yellow filtrate was evaporated to dryness and the residue thoroughly washed with chloroform and filtered. The evaporation of this second filtrate gave a white solid which was crystallised from ethanol (S) m p 74_7 0 0(1it. 2 7-760C). (Found: C,49.; H,2.6; N,7.2 C 8HN0S2 requires C,49.2; H,2.6; N,7.2%)))Tiiax (Nujol) 1670, 1630 cm 1 (C0) m/z 195(M). 13C nmr spectrum (CDC1 3 ; 50 MHz)5'c 197.6(C-5), 164.3 ppm (C-3) 2614. 3.19 Reaction, of 3-Phenyl-1,4,2-dithiazol -5-one (8a) with Various Nucleophiles. 3.19.1 Piperidine Ethereal 0.214 piperidine (3.8 ml; 0.76 mmol) was added to a solution of 3-pheny1-1,4,2-dithiazo1-5-one (0.148g; 0.76 znmol) and stirred at R T for 6h. Evaporation of the solvent gave a yellow solid m/z 256 (s8 ), 205, 195 (M, starting material). Hplc analysis confirmed the absence of thiobenzaiuide and the presence of N,N'-pentamethyleneurea. 3.19.2 Butylamine n-Butylaiuine (0.07 ml; 0.69 inmol) was added to a solution of 3-pheny1-1,4,2-dithiazol-5-one (0.135g; 0.69 inmol) in ether (S ml) and stirred at R T for 24h. Evaporation of the solvent gave a yellow solid which was shown to contain thiobenzamide (Rt.L4..8 mm) by hplc analysis. nh/z 256(S8 ),195 (14, starting material), 137 (M, PhCSNH2 ). 3.19.3 Triphenyiphosphine Triphenylphosphine (0.103g; 0.39 imo1) was added in one portion to a solution of 3-phenyl-1,4,2-dithiazol-5-one (77 m; 0.39 inmol) in toluene (30 ml) and the mixture heated under reflux for 30 mm. Evaporation of the solvent gave an off- white solid which was purified by flash column chromatography (silica; dichiorontethane : petroleum ether; 1:1). Starting material (30 mg) was recovered mhz 195 (M) and a mixed fraction 265 containing triphenylphosphine sulphide and benzonitrile in/z 294 (M, Ph 3PS),103 (M,FhCN).Vmax 2225 cm 1 (0). Hplc analysis Rt 5.3 min with peak enhancement on addition of P1iCN. 3.20 Synthesis of 3-Pheny1-1,4,2-dioxazol-5-one (76a) Benzohydroxainic acid (0.517g; 3.8 nunol) was suspended in toluene (25 ml) and triethylauune (1.5 ml) added. 12.% w/w phosgene solution in toluene (3 ml;3.5 ininol) was added dropwise over 15 min. After stirring for a further 30 min , the excess phosgene was flushed from the solution with nitrogen and destroyed in a trap (20% aqueous sodium hydroxide). The triethylainine hydrochloride was filtered off and the filtrate evaporated to dryness to give a brown gum which was purified by flash column chromatography (silica; ether:petroleuin ether; 3:7) to give a white solid. This was crystallised from ethanol (Lo) in p 61-63°C (lit. 98 63°C) (Found: C,59.0; H,3;N,8.5 C 8H5NO3 requires C,8.9; H,3.1; N,8.6% )))max (Nujol) 1820 cm 1 (C=0) mhz 163 (M)) 3C nmr spectrum (d6-acetone, 50 MHz) Sc 163.0 (C-s), 153.3 ppm (C-3). 3.21 Reaction of 3-Phenyl-1,4,2-dioxa1-5-one (76a) with Various Nucleophiles. 3.21.1 Piperidune Ethereal 0.2)! piperidune (6.4 ml; 1.3 mnmol) was added to a solution of 3-phenyl-1,4,2-dioxazol-5-one (0.208g; 1.3 nimol) in ether (10 ml), there was immediate effervescence and a white 266 precipitate formed. Tic (silica; ethyl acetate:petroleuin ether; 3:10) showed no starting material remained after 1511 nun. Evaporation of the solvent gave an off-white solid nh/z 204.))max (Nujol) 3290 (NH),1615 cm (CO) 3C nmr (d6-DMSO) 50 MHz)c 155.1, 140.6, 128.1, 121.4, 119.7, 44.8, 25.4, 24.1 ppm. Hplc analysis Rt 6.2 min peak enhancement on addition of PhNHCON 3.21.2 Butylamine n-Butyiainine (0.15 ml; 1.5 nunol) was added to a solution of 3-phenyl-1,4,2-dioxazol-5-one (0.232g; 1.4 imnol) in ether (20 mJ.). Tic (silica; ethyl acetate:petroleuin ether; 3:10) indicated no starting material remained after 30 min. Evaporation of the solvent gave a white solid m/Z 192.)nax (Nujol) 3390,3330 (NH), 1655, 1600 ciui 1 (C=0). 13C nmr(c16 -DMSO; SO MHz) Sc 1 5-') .3, 140.6, 128.3, 120.8, 117.7, 31.8, 19.4, 13.5 ppm. Hplc analysis Rt 6.1 min peak enhancement on addition of PhNHCONHBu. 3.21.3 Triphenylphosphine. 3-Phenyl-1,4,2-dioxazol-5-one (0.842g; 5.2 numol), triphenylphosphine (1.35g; 5.2 nunol) and toluene (ho ml) were heated together under reflux for 48h. Evaporation of the solvent gave a brown oil which was purified by flash column chromatography (silica; dichloromethane:petroleum ether; 2:5) to give unreacted triphenyiphosphine (0.85g) and triphenylphosphine oxide (0.47g). Passing methanol down the column gave an off- 267 white solid which contained triphenyiphosphirie oxide m/z 278 and another compound rn/z 381. The solid was triturated with cold methanol and Ph 3PO filtered off (93 mg). The filtrate was left to stand for 3 days and a white crystalline solid (73 mg) filtered off m p 198-200 0 C. (Found: m/z 381.128 (M) C 25H20N0P requires m/z 381.12824 (i()). 1 H nmr spectrum (CDC1 3 ; 200 MHz) 5H 8.4 (ni,2H),7.9 (m,6H), 7.5 ppm (m,12H). 13C nmr (CDC1 3 ; 50 MHz)cSc 176.1, 138.1, 133.0, 132.8, 132.0, 131.7, 131.1, 130.4,129.3,129.1, 128.5, 128.3, 127J4 ppm. 31P nmr (CDC1 3 ; 81 MHz)Sp 21.5 ppxn.)imax (Nujol) 1600, 1560, 1340 cm 1 . 3.22 Synthesis of Amidoximes General Procedure Benzohydroximoyl chloride was dissolved in ether (So ml) and 1.5 eq of triethylaxriine added. After stirring for 5 mm the triethylatnine hydrochloride was filtered off and 1 eq of amine added to the filtrate. The reaction mixture was left to stir at R T for 20h. Evaporation of the ether in vacuo gave the crude product. 3.22.1 Phenylpiperidinylamidoxiine (165) This was synthesised from benzonitrile oxide and piperidine (0.33 ml; 3.1 inmol) as described above. The crude product was an off-white solid which was crystallised from ethanol as white needles in p 131-133 °C (Found: C,70.6; H,8.0; I'I,13.5 C12H 6N20 requires C,70.6;. H,7.9; N,13.7%)..)hn.ax (Nujol) 3250 (OH), 2'8 1635 c1n 1 (C=N) m/z 204 (M) 3.22 • 2 xi-Butylphenylaiuidôxiine (167) This was synthesised as described above from - benzonitrlle oxide and n-butylaniine (0.23 ml; 2.3 mmol). The crude product was isolated as a brown oil. (Found: m/z 192.1254 CH16N20 requires m/z 192.12626).').)max (liquid film) 3240 (OH,NH), 1630 cxii 1 (CN). 3.23 Reaction of Phenyl Isocyanate with Triphenyiphosphine Triphenyiphosphine (2.41g; 9.2 mmol) and phenyl isocyanate (i ml; 9.2 nunol) in toluene (So ml) were heated together under reflux for 7 h. Evaporation of the solvent gave a pale yellow liquid which solidified on standing mlz 277, 262 , 18 ,1814,183, 108 3.24 Reaction of Benzonitrile Oxide with Triphenyiphosphine Benzbh.ydroximoyl chloride (0.623g; L mmcl) was dissolved in ether (O ml) and triethylaniine (i ml; 7.2 mmol)added in one portion. After stirring for 15 min the triethylaine hydrochloride was filtered off and triphenylphosphine (l.0149g; 1 nunol) added to the filtrate in one portion. The mixture was stirred at R T for 5h. Evaporation of the solvent gave a white solid with a clear liquid m/z 278 (M, Ph 3 PO), 103 (M, PhCN).2)max (liquid film) 2225 cm 1 (CN). 3.25 Synthesis of 3-Phenyl-1,4,2-dioxazole-5-thione (77a) A solution of thiophosgene (1 ml; 0.013 mnol) in ether (Smi) was added dropwise over 15 min to a mixture of benzohydroxamic acid (1.78g; 0.013 mol), triethylainine (2 ml) 269 and ether (70 ml). After stirring for a further 30 main, the reaction mixture was filtered to remove triethylainine hydrochloride and the filtrate evaporated to dryness. The brown oil residue was purified by flash column chromatography (silica; ether:petroleum ether; 3:7) to give a beige solid 0 which was crystallised from ethanol (20%) ma p 49- 1 C 9 (lit. 8 490c) (Found: m/z 179.0040 (N ' ) C8HNO2S requires m/z 179.00410 (M) ).'))max (Nujol) 1300 cm-1 (Cs) 13C nmr spectrum (CDC1 3 ; SOMHz) 6 c 18. (C-s), 165.4 ppm (C-3). 3.26 Reaction. of 3-Phenyl-1,4,2-dioxazole--thione (77a) with Nucleophiles. 3.26.1 Piperidine Ethereal 0.2M piperidine (3.7 ml;0.74 mnniol) was added to a solution of 3-phenyl-1,4,2-dioxazole-5-thione (0.134g;0.7$ nunol) in ether (10 nil) and stirred at R T for 1 h. Evaporation of the solvent gave a white solid (0.192g) m/z 201, 121. 13 C ninr spectrum (d 6-4S0; 0 MHz) 6c 155.1, 140.8, 128.1, 121.1, 119.7, 4.5, 25.4, 21.0 ppm (PhNHcoNI ), 167.9, 134.3, 131.1,128.1,127.4 ppm (PhCONH2 ). Hplc analysis Rt 6.1 main peak enhancement on addition of pentamethylene-N'-phenylurea, Rt 4.6m1n peak enhancement on addition of PhCONH2. 270 3.26.2 Butylajnune n-Butylamune (0.08 ml; 0.8 inmol) and 3-pheny1-1,b,2- dioxazole -S-thione (0.1439; 0.8 mmol) in ether (20 ml) were stirred at R T for 1h.. Evaporation of the solvent gave a white solid mhz 192, 121. }lc analysis Rt 6.1 main peak enhancement on addition of PhNHC0N}u, Rt 4.6 main peak enhancement on addition of PhCONH2 . 3.26.3 Triphenylphosphine Triphenyiphosphine (0.391 g; 1.5 mnmol)and 3-phenyl-1,4,2- dioxazole-5-thione (0.267g; 1.5 mmol) were dissolved in toluene (20 ml) and heated under reflux for 23h. Evaporation of the solvent gave an off-white solid (0.64g) which was purified by flash column chromatography (silica; dichloromethane: petroleum ether; 2:) to give triphenyiphosphine sulphide (30mg) m/z 294 (M). Flushing the column with methanol gave a polar residue which contained triphenyiphosphune oxide mhz 278 and the compound C2 ,.H20N0P mhz 381. Exact mass measuremuents:m/z 381.127 C 2 H20 requires m/z 381.12824 (M) 271 IL. APPENDICES. The following Appendices contain the full nmr data for most of the compounds prepared in this work (Appendices 14.1-14.16) and the principal fragmentation pathways for the 1,2,14- thiadiazoles (14.17) and the 3-substituted isothiazoles (14.18). They also contain details of the single crystal x-ray structure determination of N-benzoyl-S-morpholinocarbonylthlohydroxylainine (144b)(Appendix 14.19). Notes for Tables of nmr Data. Unless otherwise stated all spectra were recorded at room temperature using deuteriochioroform (CDC1 3 ) as sole solvent. The operating frequencies were 80MHz 1 H nmr and SCMBz 13 C nmr unless stated. 272 11 •1,3,4-Oxathlazol-2-ones (2) Zk 4.1.1 1 H nmr spectrum (60 MHz) R=H SH_77PPm. 4.1.2 13C nmr spectra cSc/PPm R C-2 C-5 Other H 172B 1479 C13C 1705 1529 847 273 4.2 -Acy1-1,2,4-thiadiazo1es (88) ~y 0 4.2.1 'H nmr spectra H/ppm R R ' Aromatic Aliphatic Ph Ph 8.3 (m)and 7•4 (s) 83 (rn,3H ; PhCH) Ph 78 (dd,H ,J' 17,J2 O7Hz; -H-10) 7•5 (m,3H,H-,PhCH) 6.7(dd,H,i1.7,J3LvOHz ; R-9) Ph M e S Cm) and 73 Cm) 2 - 8(s) 32(t, 2H,J7Hz,H-7) 18 (m, 2H,H - 8) Ph :6 H13 84 (m) and 75(m) 1'4(m,6H, H-9, 10, 11) 09( t ) 3H,J6Hz, H-12) 87(m,2H,PhcH) ; 83 Ph (d,2H,To[yt);76(m, 4- MeC&j 2•4 (s) 3H,PhCI-1 ); 73(d, 2H,Toyt. Me Ph 85(m) and 7•5(m) 28 (s) 274 4.2.2 13c; ninr spectra (24Hz) SC/ppm R R' C-5 C-6 [-3 Other 1340, 1323 (Ph C); 1345, Ph Ph 187-0 182•B 1743 1316 1 1306 1 128-7 1 128.6, 1 Th•2 (Ph CH). 1497 ; 1491; 1321 (Ph C ); 1857 1 69 - 4 1743 Ph 130-7,12 8-7 1 128-1 (PhCH)1 1253; 1130. 13 2- 0 (Ph C) Ph Me 1859 1907 1744 1 30'7,1281, 12S6;_26•e 132•213O6, 1287, 1282 ; 314 Ph [61-113 1861 193'3 174'4 394, 1 287 , 284, 223,_139. 140-8 1 129-6; 131- 0 1293k 4-fr1eC6I-! Ph 18660 1827 174'3 1340;134'4, 128-5,128-1 213 1341,1344, Me Ph Th6•7 182•9 1746 1309,1285, 190 27 .3 5-.Dichloromethy3--3-phenyl-1,2,4-thiadiazole (92) 2 )HC1 L. 3.1 1 H nmr spectrum S H (PPM ) 70 s, H, H-6. 7.5 m,3H, Ph. 83 m,2H,Ph. 4.3.2 130 rmr spectrum (20 MHz) C-S C-3 C-6 Ph 132-0 1889 1736 639 1307 ppm 1287 ______/ ______1282 276 4.4 exo-3a,.7a-4, 5,6,7-ti exahydro-4,7-niethano-3-pheny1-I,.2-benz- isothiazole .00 ). Ph 13 \ 2 ka H7 H 7 1 H nmr Spectrum (200 MHz) H/ppm Ring Junction. Bridgehead Other 7.7 (m 2H Ph 39 (dd,,J A 1 96 , .? 18 26(sbr,H,H-7 73 (m, 3H,Ph) Hz, H-7a 24(sbr,H,H-4) 17-11Cm ,6H) 38(dm,H ,J1 96Hz H- 3a ) 130 nmr Spectrum (20 MHz) Sc /ppm Ring Junction Bridgehead Other 1.667(C-3)1337(PhC1. 631 (C-7a) 448 (C-7) 567 (C-3a ) 422 (C-k) (PhCH), 332 (C-8) 285(C6); 272(C-5). 277 4.4.3 Irradiation Experiments Irradiation Frequency/Hz (cSH/ppm) Effect H-3a collapses to 3129 (3.95) singlet with fine splittings. 3098 (3.8) H-7a collapses to a doublet J'-'2Hz 2870 (2.65) 2823 (2.LL) H-3a collapses to 2672 (1.6) doublet J-9Hz H-7a collapses to 2586 (1.2) doublet J9.5Hz. H-3a collapses to doublet J9.5Hz. 273 11 279 I Figure 280 4S 3-Arylisothiazoles (96) r 4.5.1 1 H ninr spectra oH/ppm Ar H-5(J HH-4(J Hz) Other. Ph 8.6(4-7) 76 (4•7) 8- 1 75 87 7 7.9 7.5, 3 ,9 - MeO -L ..p-MeC6H4 7 (4.7) 7'6 (47) 7"9 , 72, 24 .p-CIC6 H4 87 (47) 7*5 (4.7) 7.9 7.5 281 13 4.5.2 nmr spectra (20 MHz) &/ppm______ Ar C-3 [-4 [-B Other. 134 - 5 ; 1290,1287, Ph 1675 121•1 148'8 1265. 160'3 ,127'5 ; 1282, MeO 1672 1206 1140 ; 551 13 91, 132'0 1294, MeH 4 16 77 121 O 148 6 126- 8 ; 212 135'0,1330 ;12&8, UC6 H 1663 1210 1490 1281 Footnote: RUNAT 50MHz. 282 14.6 Diethyl 3- ( -tolyl )-2-is othiazoline-14, 5-dicarboxylate (109b) Me y C O2Et /\ f.' NS "'C 02 14.6.1 1H nmr spectrum Oi- ippm IsothiazoUne (Aromatic Other 51 (d,H,J4Hz,H- 5) 77 , 7•1 42 (m,4H) 48 (d ,H,J 4Hz,H- 4) 23(s,3H) 12(m ,6H 14.6.2 13C ninr spectrum sc /ppm C-3 C-4 C-5 Other 1700 1682 (C=O) 1400 ,1302(ArC) 161-5 53'2 591 129, 1275 (ArCH) 618 , 616(CH2), 209 (ArCH3), 134(CH3) 283 tj.. 7 Bis- (phenylsuiphonyl )ethylenes so2Ph SOr2Ph 13 runrspéetia Cc/PPm CH PhC PhCH CIS 1401 13 9-3 1342 ,129•1, 128•2 TRANS 1400 1396 134'8 ,1297,1284 284 IL. 8 )4-(Phenylsulphonyl )-3-phenylisothlazole (108) M O2Ph 468 01 1 H nmr spectrum SH / PPM 9.45 (s,H,H-5 ) 84-74 (m,9H, ArH) 2.3 (s,3H,Me) 4.8.2 13C nmr spectrum 5c/ppm C- 3 C-4 C-5 Aromatic Me 1399 (PhC) 1 1327, 1303(ArC) ; 1289, - 1391 1562 206 128'3 ,1280 , 1273 1270 285 14.9 3Ary1isothiazo1e-5-CarbOXY1ate5 Fool, LJ 14.9.1 1 H rimr spectra 5H /PPm R' R H-4 Aromatic Other. 4.4 (q,2H,J72Hz) Et Me 8'0 78 , 69 3-8 (OH) 14 (t,3H,J72Hz) 44(q,2H,J 7•2Hz) Et Me 81 76 ,72 24(s,3H) 14(t,3H ,J72ft) MeO 82 79, 69 36 H Me 78 ) 71 21 Footnote : d6 -OMSO sotven. 286 4.9.2 13C nmr spectra & ppm R R C- 3 C-4 CO C-5 Other 160-1, 1271 128-2, 1677 1243 1608 1574 Et Me 1142 61-81 55-2, 141 139.6 131 129-4 Et Me 1680 1245 160 1575 126-6 618,214 14-0 1598 128•3 H MeO 1 676 1245 160•8 1604 1302 1132 55-1 1394 1314 168 , 0 124-9 1609 1593 Me 1367 129'5;209 Foot-note: # c — OMSO stnf 287 4. 10 3-Axy1i8othiazo1e-4-carbOxY1ateS R CO R S 4.10.1 1 H niw spectra 6H/PPM R' R H-S Aromatic Other 4.3 (q,2H,J72Hz) Et MeO 9.3 76, 69 38(s,3H) 13 (t,3H,J72Hz) 43(q,2H, J7iHz) Et Me 93 76, 72 24(s,3H 12 (F, 3H ,J 71 Hz) AL H Me 96 76 , 72 24 Footnote:#c - ACETONE svenf 288 4.10.2 13C nmr spectra sc/ppm R" R C- 3 C-4 C- 5 C0 Other 16 0-4,1275wo 130- 5,113-2 (ArCH) Et MeO 1682 1290 155- 8 1621 610 (C H 2 ) 552(ArMe) 14 0 (Me) 1321(ArC) 1 1289 1684 1388 155- 6 1620 Et Me (VC H), 609 (CH2) 21'2(ArMe),139(Me). 131' 8,12 8"5( ArC H M e 167-5 1379 1557 161-9 128.'2,127'4(AICH) 196 (Me) Footnote :#a6 -ACETONE solvent. 289 4.11 p-To1y1)isothiazo1e-4, 5-dicarbo1ates Me.. C 02 C 02 4.11.1 1H nnir spectra &/PPM R Aromatic Atiphatic 3•93 (s, 3H 2 OMe) Me 77, 72 391 (s,3H 2 OMe) 2.4 (s,3H) 44(q ,4H, 2CH2) 2L# (s, 3H,ArMe) Et 7 7 7•2 135 (t, 3H ,Me) 129 (t,3H,Me) H 77, 73 24 (s,3H FooFnote: d6-ACETONE solvent 290 4.11.2 13C nxnr spectra SC/ppm R [-3 [-4 [-5 [=0 Other. 132- 5 ,131'0(ArC) 1649 1292, 1274(ArCH) 165-7 13 9-8 155-3 M e (OMe 1592 53- 0 , 52- 8 21 4 ( A r M e) 1327, 1311 (ArC 1291,1275 (ArCH) 1648 Et 1658 1396 15S'7 622 ( 2 0 C H 2 ) 1588 211 (Arm e),138, 136( Me) 1384 ,1318(ArC) 1668 1595 1636 1280 7 1273(ArCH) 196 (ArMe) FooFnote: :• d6 -ACETONE solvent. * Possibly equilibrating 291 Ii.. 12 N—.Acyl—S—axninocarbonylthiohyth'OXYlamines 0 RNL 4.12.1 1 H nmr spectra X R H/ppm 020 shake 7•8-79 (m,3H,NH,Ph) 78-79ppm 73 (m,3H,Ph) CH2 Ph INTEGRAL 2H. tsbr,4H ) 16 (sbr,6H) 78 (m,3H,NH,Ph) o Ph 73 (m , 3H ,Ph ) INTEGRAL 2H 37 (m, 4H), 35(m,4H ) 71 (sbr,H,NH)3.7(m,4H), Peak at 71ppn 0 Me disappeared. 35 (m, 4H) 22 (s,3H ,Me) 4.3 (q,2H,J7.lHz) 3.7 ppm 0 EtO.2C 3' 7Cm, SH, 2CH2,NH ) INTEGRAL 33 (m, 4H ),13(t,3H,J71Hz) 8-0 - 85 (CH 0 ,NH,equitibrhng) 0H 37(m,4H), 34(m,4H) Footflote:d6ACETONE solvent 292 13 4.12.2 C nmr spectra sc/ppm X R :zo Aromatic Other 168.9 1329(ArC), 1318, 45- 4 , 253, 24 1 Ph CH2 1659 1282 ,1276ArcF 168'9 1327( Arc) i32O, O Ph 660 , 444 1665 128.2,1276ArCH) 1719 661,444cH2 O Me 1664 230(CH3) 1640 66.5'cH2 , 661 O Et02C 1590 44-6(cH 2 ,morphM38cH 15 82 0 - 652 , 437 Footnote:#d6 - ACETONE solvent 293 4.13 1,4,2-Dithiazole-5-thiones (6I) R N~ S :)~,.-s .13.1 1 H onir spectra CSH / ppm R Miphatic Aromatic Ph 8•8, 76 Me 25 CHCI. 2 44 (q ,2H,J7Hz) Et O2C 13 (t,H,J7Hz) 4.13.2 13C ninr spectra (&/ppm R C-3 C-5 Other Ph 1725 2189 133&,1310,1299,126'7 Me 171'9 2201 21S CNC2 1704 2155 648 CCI. 3 169-7 2164 885 Et02C 1636 2173 1558(CO), 639, 138 2014 4.14 3-Phenyl-1, L, 2-dithiazol-S-One (Ba) Ph Z:)z7,- (SC/ ppm C- 3 C-5 Phenyl 1335(PhC),1316, 1290 1643 197 - 6 127•2 (Ph CH) 4.15 3-Pheny1-1,4, 2-dioxazol-S-one (76a) and 3-Phenyl- 1, b, 2-dioxazole-S-thione (77a). Ph zn "'~ 130 nxnr spectra s c /ppm______ X C-3 C - S Phenyl. 1329(C),128 - 7,12 5 - 8 0 153 - 3 163 - 0 120•1 (CH) 118'9(C), 1339,1294 S 1654 1858 1271 (CH) 295 I.16 Miscellaneous 4.16.1 Symmetric Ureas R1 R2N R1 R2N> 4.16.1.1 'H nmr spectra SH/ppm R1 R 2 N - H Aromatic Other H nC4H9 4•9 31 ,14, 09(br) H Ph 86 69-75 3•1(sbr,4H) 1 (sbr, 6H) 4.16.1.2 C ninr spectra /ppm R1 R 2 CO Aromatic Other 396 ,32'3,19 H n-CH9 1594 CH 2 ) 13 -4(C H3) 139•7(PhC) H Ph 1525 128'7,1218, 11 82 (Ph CH) C5H10 4'-1 1_ 63 - 5 47.3, 25'3,242 Footnote: # d-Dt1SO solvent 4.16.2 Ungymmetric Ureas H 2 R R 3 N) =:o 4.16.2.1 1 H nmr spectra 5H./PPM R1 R 2 R3 N-H Aromatic Other # 84 31(q,2H), 14 Ph n-C4}-1 H 73(mbr) 9 61(1-br) (m,4H),09(m,3H) 7S(d,2H), 7•2 34(sbr, 4H) 8-4 Ph C5H10 (t,2H),6•9(t,H) 1'5(sbr,6H) 31(mbr,6H n-C4I- C5H10 4•8 14(mbr,10H) 08(mbr,3H) 4.16.2.2 13C ninr spectra Sc /pm R 1 R2 P 3 C0 Aromatic at-her 140-6(c) ,12 84, 3 87'31-8, 19[- c Ph n-C, H H 1552 9 (CH3) 120 - 8,117.7 ( C H) 13-4 140•&o128-0, Ph C5H10 1'549 254, 240 CH) 1214, 119 - 6( 44 - 5(2CH2),40•3 1 n-C4H9 CS H10 1577 321, 253, 241 199 (CH,),134 Footnotes; # cI-DMSO solvent. Under solvent pea. 297 4.16.3 Bis-(pentamethylene )thiourea ts 11 nmr spectrum SH/ppm 15 sbr, 6H 31 sbr, 4H 4.16.4 Ainidoxiiues Ph ,NR1 R 2 NOH 1.16.4.1 1 H nmr spectra I ccH/ppm i R1 R 2 Phenyl Other 20 shake 6'9 (sbr, H) 72 ppm integral 28 (tbr,2H) drops to SH. H n-C4H97.2(sbr,6H) 69ppm 1.1 (mbr,L+H) Disappears 06 (mbr,3H 80 (sbr,H) 80 ppm 7•4(s,5H) 30 (sbr,4H ) Disappears 15 (s,6H) 298 4416.4.2 13C nmr spectra A--C / p p m _ R1 R 2 CN Phenyl Other 2 131 - 0 ( c),128 - 6 ,1278 425 ,326, 188 (C H ) H nC4H 9 1561 1275 (CH ' 128 1600 ~ 31 - 3 ( c ) ,128 -7,127- 8(CH)47.8,25.1,24'2(C)z) 4.16.5 n-Batylisonitrile NEC 1 H nm.r spectrum a/p p m 07 (m, 3H) 1'3(m, L+H) 31 (m,2H) I.16.5.2 13C nmr spectrum Sc /Ppm 1559 ( NEC 353,304, 192 (CH 2) 130 (CH3) 299 4.17 Mass Spectral Data for 1,2,I7,Thiadiazoles R R' m/z 266(ff) ,161(.M-COPh) ,135(PhCNS) Ph COPh 131 (PhCOCN),105 (Ph CO)..103 (Ph CN) 256(M),161(..M.. - R') ,135 (Ph CNS) Ph 121(R'CN),103_(PhCN),_95(R') 204 (M) ,161 (- COMe) , 135(PhCNS), COMe Ph 103 (PhCN ) , 69(MeCOCN ), 43 (M eCO) 274(li) ,161 (M!-R') , 139(RtN) , 135 Ph :oç: PhCNS) ,113(R') ,103 (PhCN) 280(M), 175(M-COPh) ,149 (RCNS) 4MeC6H COPh 131 (PhCOCN ),117(RCN), 10S (Ph CO) 204 (.t + ), 131(PhCOCN).105(PhCO), 99 Me COPh (M -COPh), 73 (MeCNS) , 41 (MeCN) 268 , 246, 244 (M) ratio 1:6:9 Ph CHCl2 135 (PhCNS) ,109(R'CN) 103(PhCN) 300 4.18 Mass Spectral Data for 3-Arylisothiazoles (96) A / D\ Ar m/z 161 (M+),135 (Ph CNS),128(MtSH) ,103 (Ph CN) Ph 58(b) 191(M') 1 165(ArCNS) 1 158(M - SH) 4-MeOq~j 133 (ArCN), S8 ( ~) ) 175(M),149(ArCNS) 1 142(M-SH),117(ArCN) MeC6H4 - 53( ) - 197,19S(M) ratio 1:3 ,171 ,169 (ArCNS) C1.0 H ratio 1:3, 164,162 (MtSH) ratio 1:3, 139,137 (ArCN) ratio 1:3, 58( D ) 301 4.19 Crystallographic Data for N-.Benzoyl-S-niorpholino- carbonylthiohydroxylaflhifle (14ib) The atom numbering employed in the crystallographic data is shown in Figure 7. The tables that follow display part of the crystallographic data for this compound. Atom Numbering for Compound (iilib) used in Tables of Crystallographic Data. LIJ Figure 7 303 Table 16 Bond Lengths iith Standard Deviations S(9)-C(7) 1- 812 (3) C(2) - 0(3) 1413(4) S(9)-N(10) 1•678 (3) 0(3) - C(+) 1'410(4) C(7)-O(8) 1217(4) C(4) - C(S) 1507 (5) C(7)-N(6) 1345(4) N(10) - C(11) 1•351 (4) N(6)-C(1) 1455(4) N(10)-H(10) 088(3) N(6)-C(5) 1472(4) C(11 )-0(12) 1229(3) C(1)-C(2) 1499(5) C(11)-C(13) 1'482(3) Table 17 Angles (Degrees) with Standard Deviations. C (7) -S(9)-N(10) 98-24(13) O(3)-C(4)-C(5) 1122 (3) S(9)-C(7)-0(8) 120-49(22) N(6)-C(S)-C(4) 1092 ( 3) S (9)-C(7) - N(6) 11439(20) S(9)-N(10)-C(11) 123-13(20) 0(8)-C(7)-N(6) 1251 ( 3) S(9)-N(10)-H(10) 1152 (22) C(7)-N(6)-C(1) 119-96(24) H(10)-N(10)- C(11) 121'4 (22) C(7)-N(6)-- C( 5) 122-90 (24 N(10)-C(11)-0(12) 12101(24) C(l )-N(6)-C( 5) 11434 () N(10)-C(11)-C(13) 117-32(21) N (6)-C(1)-C( 2) 1098 C 3) 0(12)-C(11 -C( 13) 12166(22) C(1)-C(2)-0(3) flD'9 ( 3) C(11 ) -C(13) -C(14) 122-87(16) C(2)-0(3)-C(4) 1099 2(25) C(11)-C(13)-C( 18) 1 11712(16) 3o'. Table 18 Torsion Angles (Degrees) with Standard Deviations. 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Michael P aton* Department of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3.1.1, UK Reprinted from JOURNAL OF CHEMICAL RESEARCH (S) 1987 J. CHEM. RESEARCH (S), 1987 245 9•1 J. (Them. Research (S). Nitrile Sulphides. Part Synthesis of 3-Arylisothiazoles 1987. 245 J. Chem. Research (M). Marion C. McKie and R. Michael Paton* 1987.2051-2066 Department of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, UK 3-Arylisothiazoles. unsubstituted at both 4- and 5-positions, R have been synthesised by two methods based on nitrite sulphide chemistry. Although various isothiazoles have been prepared by 1,3- 1:0 dipolar cycloaddition of nitrite sulphides (RCN 4 —S) to (6) alkynes the method has been restricted by the need to incor- porate an electron-withdrawing group in the dipolarophile. We now describe two routes, both involving nitrite sulphides, Et for the preparation of 3-arylisothiazoles (5) which are for- mally cycloadducts of arenenitrile sulphides with acetylene R 0 I (12) R itself. heat + EP T - RC EN—S The first is based on an approach previously used for N 5 -CO2 3-arylisoxazoles 7 and pyrazoles involving 1,3-dipolar cyclo- f.vV .P. (7) I CO2Et addition of the appropriate mtrilium betaine (RCN—X; R I X=O, NR). to norbornadiene followed by expulsion of aR=Ph 'DEAD cyclopentadiene. To test the reactivity of norbornene-type R=p-MeOC6 H4 double bonds towards nitrile sulphides, the reaction between R=p-MeC6H4 benzonitrile sulphide, generated by decarboxylation of the d; R =p-CtC6H4 CO2Et a),2a 1,3,4-oxathiazol-2-one (7 with the parent norbornene R I was examined. Thermolysis of a solution of the oxathiaz- f.v.p. CO2 Et olone (7a) with norbornene (1:6 molar ratio) in mesitylene N-.. under reflux yielded the isothiazoline (8) (19%). The exo- s configuration of the product is confirmed by the absence of (15) discernible coupling in the 'H ri.m.r. spectrum between adja- Scheme EP = Ethyl propiolate, DEAD = diethyl acetylene- cent norbornane bridgehead and isothiazoline protons. dicarboxylate cation .21 Pyrolysis at 900-950 °C yielded the isothiazole (5c) (25-35%) together with the corresponding carboxylic acids Ph and traces of p-toluonitrile as by-products. At higher temperatures increased amounts of p-toluonitrile and intractable tars were formed due to partial decomposition of S 3a the product. These results are consistent with initial loss of ethylene followed by decarboxylation of the resulting H 7° carboxylic acid, although a pathway involving concerted loss (8) of C,H4 and CO, cannot be excluded. Heating a solution of the p-methoxyphenyloxathiazolone Although the literature" describes a number of routes to (7a) with norbornadiene (1:9 molar ratio) in mesitylene isothiazoles bearing a variety of substituents, few of these are afforded 3-p-methoxyphenylisothiazole (5b) (31%), together useful for simple 3-aryl derivatives unsubstituted at both 4- with p-methoxybenzonitrile and sulphur as byproducts. 2 a and 5-positions. Most are fairly low yielding and/or involve The isothiazoline (6b) was not detected, although it is pre- several stages. The two methods described in this paper offer sumably formed as a short-lived intermediate which under- a simpler and relatively cheap alternative. goes rapid cycloreversion with loss of cyclopentadiene under the reaction conditions. Benzonitrile sulphide and its p- methyl and p-chloro derivatives reacted similarly forming the Techniques used: Flash vacuum pyrolysis. 1 H and ' 3 C n.m.r.. I.r., isothiazoles (5a) (7%), (5c) (26%), and (Sd) (45%) respec- mass spec. tively. Improved yields were achieved by adding a solution Table I: N.m.r. data for 3-arvlisothiazoles of the oxathiazolone gradually to a refluxing solution of the alkene thus ensuring generation of the nitnle sulphide at Table 2: Products from f.v.p. of 3-arylisothiazole mono- and di- high dilution.' Under these conditions the yield of isothia- carboxylates zole (5b) rose to 70%, p-methoxybenzonitrile (30%) and sulphur accounting for the remainder of the product. The Received, 9th March 1987; Paper E1050187 isothiazoles (5a) (53%) and (5c) (78%) were also prepared by the same technique. References cited in this synopsis The second approach to 3-arylisothiazoles involves sub- I Part 8. R. M. Mortier, R. M. Paton. G. Scott. and I. Stobie, Br. jecting the ethyl esters of the corresponding isothiazole-4- Polvm. J., in the press. and -5-carboxylic and the 4,5-dicarboxylic acids I(13c), 2 (a) R. K. Howe. T. A. Gruner. L. L. Black, and J. E. Franz.]. Org. (12c), (15c)J to flash vacuum pyrolysis (f.v.p.). 15 The dicar- Chem., 1978, 43. 3736. boxylate (15c) is readily accessible by cycloaddition of p- 4 R. K. Howe and J. E. Franz. J. Org. Chem., 1981, 46, 771 and toluonitrile sulphide to diethyl acetylenedicarboxylate, while references cited therein. 7 R. Huisgen and M. Chrisil. Angew. Chem., mt. Ed. Engl., 1967, the 4- and 5-monocarboxylates (13c) and (12c) may be pre- 6,456. pared as a separable mixture of regioisomers from the corrc- 8 R. Huisgen. M. Seidel, G. Wallbillich. and H. Knupper. Tetra- sponding reaction with ethyl propiolate. Compound (13c) hedron. 1962. 17.3. may also be formed from the dicarboxylate (15c) by a 11 D. L. Pain. B. J. Peart. and K. R. H. Wooldridge in Comprehen- sequence involving hydrolysis. decarboxylation, and esterifi- sive Heterocyclic Chemistry,' ed. K. T. Potts, Pergamon Press, Oxford. 1984, vol.6, p. 131 and references cited therein. 18 See, e.g., G. Seybold, Angew. Chem., mt. Ed. EngI., 1977, 16. *To receive any correspondence. 365.