Thiazoline preparation

The high reactivity of the exocyclic 4-NH- group is again illustrated by the reaction of 2-imino-3-phenyl-4-amino-5-(ethoxycarbonyl)-4-thiazoline with EtOjCCH SCN, which yields 134 (296), and by the intramolecular preparation of the dihydrothiazolo[4,5-h]pyridine derivative 136 (297) (Scheme 89). 

The first member of the series. 2-imino-3,4-dimethyl-4-thiazoline (363) is obtained when the di-HBr salt of bis(methylformamidine)disulfide (362i is refluxed for 16 hr in acetone (Scheme 209) (700). The most common preparative methods involve direct heterocyclization by the Hantzsch method (see Chapter II. Section II.4), though the mechanism of this reaction suggests certain limitations according to the respective natures of R2, R3, and in 364 (Scheme 210). 

Imino-4-thiazolines are far more basic than their isomeric 2-aminothiazoles (see Table VI-1). They react with most electrophDic centers through the exocyclic nitrogen and are easily acylated (37, 477, 706) and sulfonated (652). The reaction of 2-imino-3-methyi-4-thiazoline (378) with a-chloracetic anhydride yields 379 (Scheme 217) (707). This exclusive reactivity of the exocyclic nitrogen precludes the direct synthesis of endocyclic quaternary salts of 2-imino-4-thiazolines. although this class of compounds was prepared recently according to Scheme 218 (493). 

An interesting class of 2-imino-3-amino-4-thiazolines (408) has been described (578, 701, 726). These 3-amino derivatives of 4-thiazoiine may also be prepared from 2,3-diaminothiazolium salts (406) in basic medium (101) or through the acid-catalyzed rearrangement of 2-acylaminoimino-3-phenyl-4-phenyl-4-thiazolines (407) (Scheme 233) (99, 724). 

Recently, Koitai et al. (17) have shown that 5,5-diphenyl-2,4-thiazolidinedithione (15) with aluminum chloride in refluxing toluene gives 4,5-diphenyl-A-4-thia2oline-2-thione (16) (Scheme 7). 3-Methyl-4,5-diphenyl (17) and 4,5-diphenyl-A-4-thia2oline-2-thiones (16) are obtained in very low yields (1 to 5%) as by-products of the reaction between deoxybenzoin. benzoin. l,2-diphenyl-1.2-ethanediol. 1.2-diphenylethanol, or benzil, and Sg in hexamethylphosphoamide (18), The transformation of A-4-thiazoline-2-ones to the corresponding thiones by P2S5 (19) is of little synthetic value since the latter are more easily prepared. 

A-4-Thiazoline-2-ones and ring substituted derivatives are usually prepared by the general ring-closure methods described in Chapter II. Some special methods where the thiazole ring is already formed have been used, however. An original synthesis of 4- 2-carboxyphenyl)-A-4-thiazoline-2-one (18) starting from 2-thiocyanato-2-halophenyl-l-3-indandione (19) has been proposed (Scheme 8) (20, 21). Reaction of bicyclic quaternary salts (20) may provide 3-substituted A-4-thiazoline-2-one derivatives (21) (Scheme 9) (22). Sykes et al. (23) report the formation of A-4-thiazoline-2-ones (24) by treatment ef 2-bromo (22) or 2-dimethylaminothiazole (23) quaternary salts with base (Scheme 10). 

The preparation of a series of transition metal complexes (Co. Ni. Pd. Pt, Ir. Au. Cu. Ag) with ambident anion (70) and phosphines as ligands has been reported recently (885). According to the infrared and NMR spectra the thiazoline-2-thione anion is bounded through the exocyclic sulfur atom to the metal. The copper and silver complexes have been found to be dimeric. 

The nucleophUic reactivity in neutral medium has been used extensively to prepare various thioethers of thiazole (122). In acidic medium, alkylation may be performed with alcohols (123, 124). An unexpected reaction encountered was the decarboxylation of 2-mercapto-4-methyl-5-thiazolecarboxyhc acid (60) when treated with butyl alcohol under acidic conditions (Scheme 27) (123). Reaction between A-4-thiazoline-2-thione... 

The rearrangement discovered by Kolosova et al. probably involves such reactivit (159). This reaction provides a good preparative method for various 5-amino-methylthiazoles (Scheme 43). No mechanism is proposed in the report, and it is not easy to understand how the C-5 enamine-like position competes with the very nucleophilic thiocarbonyl group of the formed A-4-thiazoline-2-thione. An alternative mechanism could start with ethanol addition at C-2. leading to the A-4-thiazoline (90) (Scheme 44). In this intermediate, C-5 nucleophilic reactivity would be favored bv the true enaminic structure. After alkylation on C-5,... 

Because of their use in the rubber industry various sulfenamido thiazoles (131) have been prepared. They are obtained in good yields through the oxidation of A-4-thiazoline-2-thiones (130) in aqueous alkaline solution in the presence of an amine or ammonia (Scheme 66) <123, 166, 255, 286, 308, 309). Other oxidizing agents have been proposed (54, 148. 310-313) such as iodine (152), chlorine, or hydrogen peroxide. Disulfides can also be used as starting materials (3141. 

More commonly. 2-sulfonic acids (139) are prepared by oxidation of the corresponding A-4-thiazoline-2-thione (Scheme 72). Oxidation can be... 

A-2-Thiazoline-5-thiones are generally not obtained by direct heterocyclization reactions (352). Instead, most of the reported preparations involve reactions in which the thiazole ring is already formed with the suitable mercapto precursors in the 5-position. 

Goto et al. (386) have qualitatively studied the relationship between the structure and the ease of formation of some 2-aryl- and 2-heteroaryl-A-2-thiazolin-4-one derivatives. It is found that 2-pyridyI, 2-benzimidazoyl, and 2- 6 hydroxy-5 -methyl)-benzothiazolyl derivatives are too unstable to be isolated. 6 -Hydroxy-, 6 -methyl-, and unsubstituted 2-benzothiazoiyl derivatives, as well as naphtothiazolyl derivatives are unstable but isolable. On the other hand, 6 -methoxy-. 6 -acetoxy-. and 5, 7 -dimethyl-6 -hvdroxybenzothiazolyl derivatives as well as most of their 5-methyl substituted derivatives are stable and easily prepared. 

Alkoxythiazoles are prepared by heterocyclization (274, 462). The Williamson method using catalytic amounts of KI and cupric oxide is also possible (278. 288, 306). 5-Acetoxy-4-alkenylthiazoles are obtained by treatment of 242 with acetyl chloride and triethylamine or with acetic anhydride and pyridine (450). Similarly, the reaction of diphenylketene with 242 affords 5-acyloxy-4-alkenylthiazoles (243) (Scheme 120) (450). The readiness of these o-acetylations suggests that 4-alkylidene thiazoline-5-one might be in equilibrium with 4-alkenyl-5-hydroxythiazoles (450). 

Schatzmann, in 1891, tried to prepare 2-thiazolines by hydrogenation of thiazoles and by the action of sodium and ethanol on 2,4-dimethyl-thiazole, 2-methylthiazole, and 2-methyl-4-phenylthiazole (476). None of these substrates was reduced to thiazoline the second gave no reaction and the first underwent ring cleavage, leading to a mixture of n-propylmercaptan and ethylamine (Scheme 90). Three years later the same... 

Thiazole carboxylic acid hydrazides were prepared in a similar way (444, 445). Thus by refluxing thioacetamide or thiobenzamide with y-bromoaceto acetic ester arylhydrazones (83) for several hours in alcohol the 4-carboxythiazole derivatives (84) listed in Table II-ll were obtained (Scheme 36) (656). This reaction is presumed to proceed via dehydration of the intermediate, thiazoline-S-oxide. 

The preparation of 2-phenylthiazole from thiobenzamidoacetal (203) (readily prepared from aminoacetal) has also been reported (Scheme 107) (440). Compound 203 loses 1 mole of ethanol under mild dehydrating conditions to give 5-ethoxy-2-phenyl-A-2-thiazoline (204). This then loses a second mole of ethanol under more vigorous conditions to give 2-phenylthiazole (205). 

Asinger et a], have developed a simple preparative method for variously substituted A3-thiazolines by the action of sulfur and ammonia on ketones. 

A more recent method (31) is to prepare the Aj-thiazoline from the mercaptoacetaldehyde dimer, ammonia, and an aldehyde using Asinger s method (32). 

Thiazolines and thiazolidines may also be prepared in this fashion, the structure of the final product determining the substitution pattern to be chosen in the reaction components. Reaction of ethyl bromoacetate with the substituted thioamide (71) resulted in formation of the thiazolidin-4-one (72) (70KGS1621). 

Because of the structural requirements of the bielectrophile, fully aromatized heterocycles are usually not readily available by this procedure. The dithiocarbamate (159) reacted with oxalyl chloride to give the substituted thiazolidine-4,5-dione (160) (see Chapter 4.19), and the same reagent reacted with iV-alkylbenzamidine (161) at 100-140 °C to give the 1 -alkyl-2-phenylimidazole-4,5-dione (162) (see Chapter 4.08). Iminochlorides of oxalic acid also react with iV,iV-disubstituted thioureas in this case the 2-dialkylaminothiazolidine-2,4-dione bis-imides are obtained. Thiobenzamide generally forms linear adducts, but 2-thiazolines will form under suitable conditions (70TL3781). Phenyliminooxalic acid dichloride, prepared from oxalic acid, phosphorus pentachloride and aniline in benzene, likewise yielded thiazolidine derivatives on reaction with thioureas (71KGS471). 

Thiazolo[2,3-c][l,2,4]triazines 658 were prepared (84LA1302) regio-specifically by cyclizing 2-hydrazono-2-thiazoline 659 with glyoxylic acid or ester. They had herbicidal activity. Condensation of 659 with oxamic acid ethyl ester gave hydrazide 660, which was cyclized with sodium... 

Alternatively, the thiazolotriazine ring was prepared from l-nitro-2-aminonaphthalene with an isothiocyanate to give naphthylpyrimidine 669, whose reaction with phenacyl bromide gave thiazoline 670. Reduction with stanous chloride and cyclization with (V-bromosuccinimide gave naphthothiazolotriazine 671 (74JIC631) (Scheme 138). 

A. 2-Allylthio-2-thiazoline [Thiazole, 4,5-dihydro-2-(2-propenyltliio)-]. A solution of 11.9 g. (0.100 mole) of 2-mercapto-2-thiazoline [2-Thiazoli-dinethione] (Note 1) in 00 ml. of tetrahydrofuran is prepared in a 200-ml., one-necked, round-bottomed flask fitted with a 25-ml.,... 

Thiazolines (2,3-dihydrothiazoles) were also prepared under microwave irradiation. Hamelin and coworkers have described the alumina-supported solvent-free synthesis of various 4-iminothiazolines by condensation of disymmetric thioureas and a-chloro ketone (Scheme 10). The experiments... 

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