Thioamides isomerism

With R] different from R2 two isomeric compounds (138 and 139) are possible, depending on the direction of ring closure (86). However, only one form is generally obtained. Finally, the trisubstituted thioureas such as N,N,N -trimethylthiourea react with chloroacetone to give a thiazolium salt, in a reaction identical to that of the N-monosubstituted thioamides (Scheme 67). 

A number of addition reactions to the salt (150) have been reported.140 With azide ion, the ylide (151) is formed. Diels-Alder addition of cyclopentadiene occurs to form isomeric adducts (152). With thioamides, a mixture of the salts (153) and (154) results, and with, e.g., 2-aminopyridine, the salt (155) is formed. 

When thioamides 24f-h were irradiated in benzene with a high-pressure mercury lamp, iV-isopropyl-P-thiolactam 26 and 1,3,5-dithiazine 28 were obtained (Scheme 15 and Table 10, entries 1,3, and 5). Considerably different photochemical behavior was observed between that in solution and in the solid state. Powdered thioamide 24f was irradiated in the solid state at 0 °C until 19% conversion, because the solid changed to amorphous at around 20% conversion. In this case, only dithiazine 28f was obtained as the sole photoproduct (entry 2). On the contrary, photolysis of 24g gave a new type of p-lactam 27g as a main product in 88% yield in addition to dithiazine 28g (12%) the P-lactam 26g was not detected at all (entry 4). Photochemical ( ,Z) isomerization of (Z)-24g was also observed in the early stage of the reaction, where the ratio of the photostationary state was ZIE=1.9. In the case of 24h, P-thiolactam 27h was ob-... 

Isomeric hexahydro[l,3]thiazolo[4,5-fc]azocine 208 is formed in the reaction between 3-bromo-2-oxoazocane 207 and thioamide in ethanol (96CPB2070 Scheme 58). 

Oxathiazolidinimine (180) containing the S—C=N thioamidate grouping can enter the cycloaddition-elimination reaction sequence with iso thiocyanates to give 1,2,4-dithiazolidindiimine (181) which in turn adds-eliminates RNCS to produce diimine (184) which isomerizes into thia-diazolidine (183). Another thiadiazolidine (182) is also formed directly from (180) which apparently... 

Photolysis of the four examples of 2,3-dihydro-6f/-l,3-thiazines 101-104 resulted in the formation of different products which is dependent on R and R (Scheme 3). When both groups are methyl (101), isomeric thiazolines 105 and 106 are isolated, the thiazoline 106 being the major isomer. The ethyl analogue 102 reacts differently and the thioamide 107 is formed. All four thioamide isomers are formed when the benzyl analogue 103 is photolyzed and the... 

Each of the scaffolds reported in Scheme 24 can be used for the production of a stereo-isomeric sublibrary based on the appropriate peptide sequence. For example, with the sequence A-B-C-D-E and scaffold (1) two types of stereoisomeric sublibraries can be prepared. One type includes the sublibraries A and B of Scheme 26 in which within a given sequence the configuration of each residue is successively inverted thus, retaining the identical connectivity as in the parent linear peptide. In the second type 265 of sublibraries C and D (Scheme 26) the direction of the amide bond is inverted and hence the connectivity is not maintained. In most members of these sublibraries the overall conformation of the scaffold is maintained and therefore these components constitute stereoisomeric sublibraries of the parent library. Conversely, by introducing amide bond surrogates such as reduced amide bonds1465 or thioamide bonds 260,466 the conformation of the scaffolds are changed and their conformational flexibility enhanced. 

More decisive evidence is provided by the interconvertibility of N-aryl-JV-arylamidinothioureas (28) and Hector s bases by oxidation-reduction.63, B4,67b The former compounds are accessible (as salts) (i) by the condensation of arylthioureas (24) with arylcyanamides (23),63 (ii) by the extrusion of sulfur from the recently described40,41 s-diaryldithioformamidine hydrobromidesB4a (22), (tit) by the oxidation of arylthioureas (24) with 0.5 moles of hydrogen peroxide in the presence of mineral acids,B4a and (iv) by the mild reduction of Hector s bases by hydrogen sulfide in acid media.B4a The first of these four reactions limitB the structure of the products to the three alternatives 25, 28, and 30. Of these, 25 is excluded by the non-identity of the product with authentic67 N-phenyl-i -phenylamidinothiourea (25 R = Ph). The monosulfide structure (30) is not reconciled as readily with the observedB4a hydrolytic fission of the products into diaryl-guanidines (29) and thiocyanic acid as is structure 28. Indeed, as in the case of thioamides and nitriles (see Section II, C, 1), the present condensation may involve the primary formation of an intermediate diimido-monosulfide (30) and its isomerization to 28. 

It is interesting to note that, due to the reversible character of the cycloaddition, isomerization favoring the product which is thermodynamically more stable may occur and an appropriate side-chain substituent may participate. For example, the thiazolo [4,5-b] quinoxalines 55, formed in the reaction of quinoxalinium salts with thioamides under kinetically controlled conditions, are able to undergo two different isomerizations (Scheme 45). When compound 55 contains an aryl group at C-2 (R2 = aryl) and this compound is heated in an ethanolic solution, the thiazoloquinoxaline 57 is formed. In the case of R2 = CH3, the methyl group participates in the isomerization process, yielding pyrrolo [2,3-b]quinoxalin-2-thione 58 (Scheme 45) (85KGS396). 

The rearrangement of S-allyl thioimidates to Al-allyl thioamides requires a catalyst because of double bond isomerization and deallylation during the thermal reaction. Palladium(II) salts, but not mercury(II) salts catalyze these reactions efficiently and selectively under mild conditions (see Table 5, entries 1-3). Cationic intermediates similar to those discussed for the allylimidate rearrangement are proposed61 63. Studies with nonracemic thioacetimidates have not been reported. 

Nicotinamide (118) forms the 1,6-dihydropyridine (119) and the 6,6 -dimer (120) upon polarography in aqueous solution. The 4-isomer (121 Scheme 24) generates the aldehyde (122) when reduced in 0.8 M hydrochloric acid and the alcohol (123) in an alcoholic citric acid buffer solution. The thioamides produce the 4-aminomethyl- or 4-cyano-pyridines under related conditions. The isomeric cyanopyridines... 

In a few cases, single-bond rotation is so slowed that cis and trans isomers can be isolated even where no double bond exists (see also p. 230). One example is N-methyl-A -benzylthiomesitylide (69 and 70), the isomers of which are stable in the crystalline state but interconvert with a half-life of 25 h in CDCI3 at 50°C. This type of isomerism is rare it is found chiefly in certain amides and thioamides, because resonance gives the single bond some double-bond character and slows rota-tion. (For other examples of restricted rotation about single bonds, see pp. 230-233). 

In a number of amides, thioamides, and related systems, rotation about the single bond is hindered, and distinct geometric isomers can be observed and even isolated. This type of geometric isomerism is referred to as atropisomerism and results from resonance contributions by the nitrogen atom that imparts significant double bond character to the system, thus slowing rotation. Such is the case for the thioamide aldose... 

In the latter case the S N allyl group migration is only efficient when Pd catalysis is employed, otherwise, at much higher temperatures, a double bond isomerization occurs first and is then followed by an S C allyl shift by means of a thio-Claisen rearrangement. As the appropriate 5-allyl thioimidates are easily prepared by alkylation of thioamides with allyl halides, the overall process is an 5n substitution of an allylic halide by an amine, a reaction which is difficult to achieve directly. 

Irradiation of asymmetrically substituted A -benzyl-A -isopropyl-aP-unsatu-rated thioamides (102) in benzene solution induces hydrogen abstraction by the alkenyl carbon from the benzyl and isopropyl groups to give a P-thiolactam (103) and 1,3,5-dithiazinane (104) as products. In the solid state, however, photolysis causes hydrogen abstraction from only the isopropyl group to give the isomeric P-thiolactam (105). 

The presence of bands in the infrared spectrum of hydroxy compound 27 in the region 1710-1760 cm has been taken to mean that the compound exists as the oxo compound 28. However, the isomeric compound 29 is reported to have bands in the infrared characteristic of hydroxyl groups and amide carbonyl functions. Accordingly it is suggested that this is evidence for the presence of the equilibrium 29 30. Similarly the mercapto derivative 31 shows evidence of the equilibrium 31 32. In contrast, the quinoxaline analogue 33 is completely in the thioamide form. ... 

The well-known rotational isomerism of thioamides has been studied in detail for monosaccharide derivatives bearing a thioacetamido substituent at a secondary or primary position.176177 188 189 As common features,... 

Direct excitation (A > 240 nm) of thiiran is followed by intersystem crossing to the lowest excited state. This species is capable of undergoing reversible addition to alkenes, thereby inducing Z, -isomerization inefficient irreversible addition has also been observed. The carbonyl sulphide, Ph2=6—S, has been proposed as a possible intermediate in the photodecomposition of diphenyloxathiiran, which is itself formed by irradiation of thiobenzophenone -oxide at 77 An unexpected photoinduced fragmentation and solvent incorporation was observed on irradiation of A-(6,7-dimethoxy-2-methyl-3-quinazolinio)ethoxythio-formamidate (289) in ethanol to give photoproducts (290)—(292). The photoreactions of some A-isoquinolinio(thioamidates) have been compared with those... 

The y0-imino thione is isomeric with its thiol form. Cyclization occurs by a nucleophilic substitution on the S-atom via 2. The reaction can tolerate wide variations in and R. For instance, y imino thioamides (Ri = NH2) yield 5-aminoisothiazoles. 

Activation of thioamides to thioimidates with alkylation is also applied to the synthesis of amidines. Dijkink et al. [28] applied this method to the synthesis of chiral bicyclic amidines from (5)-malic acid as a key step. However, the amidine was found to be unstable due to isomerization of the imine double bond followed by ehmination of the silyloxy group (Scheme 3.15). 

Dehaen and co-workers thermolyzed 5-azidothiazoles 1617 and prepared several 4-cyanooxazoles 1618 in modest yields (Scheme 1.413). The authors ruled out a Comforth-type rearrangement. Instead, they favored ring opening of 1617 to a thioamide followed by cis/trans isomerization and a 1,6-electrocyclization to produce an unstable oxathiazine 1619. Extrusion of sulfur from 1619 then affords 1618. 

---