A2-thiazoline

Zwanenburg and Wagenaar148 have reported the rather unusual rearrangement of sulfone 81 to 82, after standing overnight at 0°, and suggested an elimination-addition mechanism, via initial isomerization of A3 to the A2-thiazoline-oxide with subsequent elimination and readdition of sulfmic acid, followed by spontaneous loss of water in a Pummerer-type aromatization reaction. 

A2-Imidazolines (416 Z = NH) are cyclic amidines and exhibit the characteristic resonance stabilization and high basicity. A2-Oxazolines (416 Z = O) are cyclic imino ethers, and A2-thiazolines (416 Z = S) are imino thioethers both are consequently easily hydrolyzed by dilute acid. 

The addition of 2-methyl-, 2-ethyl-, 4-ethyl-, and 4,4-dimethyl-A2-thiazolines to DMAD in DMF for several days gave 1 2-molar adducts. These have been formulated561 as 58, but their XH nmr spectra show543 that they have isomerized to 59, as in the case of most of the adducts of thiazole (see the foregoing). 2-Hydrazino-A2-thiazoline (60) with DMAD gave adduct (61).56a... 

The electrophilic properties of substituted 6//-l,3-thiazine-6-ones (208) in solution also shows reactivity at C-2 in acidic conditions and at C-6 in basic conditions. The regioselective reaction of 4-ethoxycarbonyl-2-phenyl-6//-l,3-thiazine-6-one with dimethylamine leads, after ring opening and reclosure, to two diasteriomeric 5-dimethylcarboxamido-4-ethoxy-carbonyl-2-phenyl-A2-thiazolines 209 and 210, whose structures were confirmed by X-ray diffraction studies on 210 (Scheme 84) (88BSF897). Com-... 

A conclusion of all these thermodynamic studies is the existence of thiazole-solvent and thiazole-thiazole associations. These associations are confirmed by the results of vis-cosimetric and diffusiometric studies on thiazole and binary mixtures of thiazole and cyclohexane or CCI4. In the case of cyclohexane, the solvent seems to destroy some thiazole self-associations (aggregates) existing in the pure liquid, whereas in the case of carbon tetrachloride there is association of two thiazole molecules with one solvent molecule (67BSF4465). The most probable mode of self-association of thiazole is of the n-u type from the lone electron pair of the nitrogen of one molecule to the LUMO of the other (73MI41901). The same methods applied to A2-thiazolines reveal self-association constants of 3 to 5 (67BSF4583). 

All available experimental data relative to protomerism of 2-amino-, 2-alkylamino-, 2-aryl or heterylamino-thiazoles or benzothiazole converge to the same result as that predicted by theoretical calculations these compounds exist predominantly in the amino form (8a X = NHR), associated in solution by hydrogen-bonding between the exocyclic NH groups and the ring nitrogen atoms. The same situation is observed in the case of the corresponding 2-alkylamino- and 2-arylamino-A2-thiazolines. 

In 4- and 5-substituted thiazoles the character of the protomerism is not so sharply defined. IR and lH NMR data indicate that in non-polar solvents, as in the solid state, A2-thiazolin-4-ones exist predominantly in the keto form (15b) but that polar solvents such as DMSO shift the keto-enol equilibrium towards the enol form (15a) in acetone equal amounts of (15 R2 = Ph, Rs = H) enol and keto form were found, whereas in DMSO more than 90% of the enol form exists at equilibrium (65ACS1215). The third form (15c) corresponds to the mesoionic 4-hydroxythiazole and its existence has been suggested from reactivity experiments but it could not be established spectroscopically. 

A2-Thiazolin-5-one may exist in three tautomeric forms (16a, b, c) the protomeric equilibrium has been studied by 1H NMR, IR and UV spectroscopies. Polar solvents favor the enolic (16a) and the mesoionic (16c) forms (Table 16), this latter form being detected by the yellow color (428 nm) which appears in polar solvents on high dilution (70TL169). 

Tautomerism of A2-thiazoline-5-thiones has not been investigated intensively. 2-Phenylthiazole-5-thione exists in the thiol form in both polar and non-polar solvents (76T579). This behavior is in contrast with that of the corresponding thiazolones. 

A2-Thiazolines are converted into the corresponding thiazoles on treatment with nickel peroxide at room temperature. Benzothiazolines are also very easily oxidized to the corresponding benzothiazoles, the aromatization of the heteroring being the driving force of the reaction which corresponds to hydride transfer. 

The simple 2-amino-A2-thiazolines are strong bases, readily soluble in water. Hot concentrated hydrochloric acid opens the ring affording mercapto-alkylamines. 2-Amino-A2-thiazolines are tautomeric alkylation of 2-amino-A2-thiazoline occurs at the ring nitrogen atom (140), whereas alkylation of 2-monoalkylamino-A2-thiazolines occurs at the exocyclic nitrogen atom (141 Scheme 67). Reaction of 2-amino-A2-thiazoline with malonic esters... 

A2-Thiazolin-4-one presents three nucleophilic centers (C-5, oxygen and nitrogen) and two electrophilic centers (C-4 and C-2). Catalyzed by acids, dimerization yields compound... 

CR(Q(262)1017>. The nucleophilic reactivity of the oxygen atom has been observed in the acetylation by acetic anhydride of 2-aryl- and 2-heteryl-A2-thiazolin-4-ones (Scheme 136). 2-Alkoxy and 2-methyl derivatives of A2-thiazolin-4-one (196) react with OPCl3 to yield thiazolylphosphoric esters (197) which have insecticidal uses (Scheme 137). An example of the electrophilic reactivity of the C-4 atom is the easy formation of oxime and phenylhydrazone derivatives. 5-Aryl-A2-thiazolin-4-one (198) gives the 1,3-dipolar cycloaddition product (199) with methyl fumarate and methyl maleate (Scheme 138). Under similar conditions, treatment of (198) with dimethyl acetylenedicarboxylate (DMAD) yields a thiophene derivative (202) when R = Ph and a pyridone derivative (203) when R = H (Scheme 139). The proposed mechanism involves the formation of a mesoionic intermediate (200) which reacts in a cycloaddition with a second molecule of DMAD, yielding (201), the decomposition of which depends on the R substituent. 

The reactivity of A2-thiazolin-5-ones is closely related to the protomeric equilibrium shown in Scheme 127. The nucleophilic activity of the C-5 oxygen atom is clearly demonstrated by its reaction with acetyl chloride, acetic anhydride, benzoyl chloride, methyl or phenyl isocyanate, carbamoyl chloride or phosphorus derivatives in the presence of bases, to give (205-208 Scheme 140). 

The mechanism of the Hantzsch synthesis has been established and is shown in Scheme 165. Substitution of the halogen atom of the a-halo ketone by the sulfur atom of the thioamide occurs first to give an open-chain a-thioketone (232), which under transprotonation proceeds to give a 4-hydroxy-A2-thiazoline (233) in aprotic solvents, or a thiazole (234) by acid-catalyzed dehydration of the intermediate thiazoline in protic solvents. 

The Hantzsch synthesis is applicable to a-halo acids and their derivatives, (324) leading to 2-substituted A2-thiazolin-4-ones (325 Scheme 214). 

Non-functionalized A2-thiazolines (328) are obtained by the classical Gabriel s synthesis which condenses a thioamide (326) with 1,2-dibromoalkanes (327 Scheme 215) (1890CB157). When an N-arylthioamide is employed, the product (329) is a 3-arylthiazolinium salt. This constitutes the only route to these salts with an aryl group substituted on the nitrogen atom. 

Thiourea and phenyldithiocarbamate (326 R2 = NR2, SPh) react with glycidic esters (332) to give A2-thiazolin-4-ones (333 Scheme 217) (71BSF4021). 

One of the most valuable methods for the preparation of A2-thiazolines is of this class. The reaction of 2-haloalkylamines (334) with thioamides, metal thiocyanates or carbon disulfide give 2-alkyl- or -aryl- (335), 2-amino- (336), and 2-mercapto- (337) A2-thiazolines, respectively (Scheme 218) (17CB804). A method derived from the last procedure leads to a convenient synthesis of 2-phenyl-A2-thiazolines (340) under very mild conditions and consists of the condensation between a-aminothiols (338) and thiobenzoylmercaptoacetic acid (339 Scheme 219) (74TL1863) (this method could be better classified under Type E, Section 4.19.3.2.5). 

This type of ring closure has been widely applied in the synthesis of A2-thiazolines. N-(fi -Substituted alkyl)amides (341 X=halogen, OH, SH, OAc) yield thiazolines (342) on treatment with phosphorus pentasulfide (Scheme 220) (35JA1079). A2-ThiazoIine itself... 

Cysteamine (350) treated with nitriles (351 R = C02Me, CN, Br) in ethanol yields the corresponding A2-thiazoline (Scheme 223) (77CR(C)(285)257). 

Cyclizations of this type, in which one reactant supplies only the carbon at position 2 of the ring, constitute the most important route for the preparation of A2-thiazolines. 

The ring expansion of aziridines and azirines corresponds to this type of ring closure leading to A2-thiazolines. iV-Thioacylaziridines (366) rearrange under acid conditions to 2-aryl-A2-thiazolines (368) either by an S l or S 2 mechanism, depending on the nature of the acid catalyst and the solvent used (69JA5835,69JA5841). 

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