4- -2-aminothiazole

2-Aminothiazole (III) is prepared by the condensation of chloroacetalde-hyde (II) with thiourea (I). The reaction may be represented as follows  

Chloroacetaldehyde is unstable and lachrymatory it is therefore usually generated in situ by the action of water upon ap-dichloroethyl ethyl ether  

2-Amino-5-methylthiazole. Suspend 76 g. of thiourea in 200 ml. of water in a 500 ml. three-necked flask equipped as in the preceding preparation. Stir and add 92-5 g. (80 ml.) of monochloroacetone (1) over a period of 30 minutes. The thiourea dissolves as the reaction proceeds and the temperature rises. Reflux the yellow solution for 2 hours. To the cold solution immersed in an ice bath add, with stirring, 200 g. of solid sodium hydroxide. Transfer to a separatory funnel, add a httle ice water, separate the upper oil layer and extract the aqueous layer with three 100 ml. portions of ether. Dry the combined oil and ether extracts with anhydrous magnesium sulphate, remove the ether by distillation from a steam bath, and distil the residual oil under diminished pressure. Collect the 2-amino-5-methylthiazole at 130-133°/18 mm. it solidifies on cooling in ice to a solid, m.p. 44-45°. The yield is 84 g. 

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Note that p-acetamidobenzenesulphonyl chloride will similarly react with primary and secondary amines, and the products, after hydrolysis of the acetyl group, may furnish notable drugs e.g., the condensation products with 2-amino-pyridine and 2-aminothiazole, after remo al of the acetyl groups, provide the drugs commonly known as sulphapyridine (M B 693) and sulphathidzole respectively. 

Halothiazoles are usually obtained from 2-aminothiazoles through the Sandmeyer reaction. Nevertheless, ammonolysis has sometimes proved useful for the preparation of 2-aminothiazole derivatives. Detweiler et al. (18) obtained 2-(u-pyridinylamino)thiazole (1) from 2-bromothiazole (Scheme 1). The reaction is easier if a nitro group occupies the 5-position of the thiazole ring (19-21). Ethylene diamine derivatives undergo this reaction with 2-haiothiazoles (22-24). 

Aminothiazole and derivatives have been reported in reactivity studies starting from 2-p-nitrophenylsulfenylaminothiazole (4) (32), 2-tritylaminothiazole (5) (33), 2-nitrothiazole (34,35), and 5-methyI-2-phenylimino-4-thiazolidinone (36) (Scheme 4). 

These amines are also synthesized by refluxing 2-aminothiazole with paraformaldehyde and acetophenone in ethanol (Scheme 6) (39) or by alkaline alkylation of 2-acetamidothiazole followed by hydrolysis (40-44). 

Charge diagrams for 2-aminothiazole and 2-imino-4-thiazoline, calculated using HMO. PPP, and CNDO approximations, are illustrated in Fig. VI-1. When compared to Table 1-2 for thiazole itself it appears that the... 

Fig. VI-1. Charge densities on 2-aminothiazoie and 2-imino-4-thiazolinc. (aI 2-aminothiazole. PPP (63) (h) 2-aminothiazole. CNDO (64l (c) 2-imino-4-thiazoline. PPP (63).

As expected. 2-aminothiazole is more basic (piVj, = 5.28) than thiazole (pXj = 2.52) (681. Ultraviolet absorption properties as a function of pH... 

Angyal and Angyal measured the pK of 2-aminothiazoles and 2-imino-4-thiazolines to obtain the protomeric equilibrium constants (Scheme l4) (74). The higher pK values of the imino derivative (9.65) compared with that of 2-aminothiazole (5.68) prove that the amino form is highly predominant, Xp = 2x 10" (72), The limitations of such a method of Kp determination are discussed by Elguero. Marzin and Katntzky in a review of protomeric equilibria in heterocycles (75). 

TABLE VI-L REPRESENTATIVE pK VALUES OF 2-AMINOTHIAZOLES AND 2-IMlNO-4-THIAZOLINES... 

An intramolecular charge transfer toward C-5 has been proposed (77) to rationalize the ultraviolet spectra observed for 2-amino-5-R-thiazoles where R is a strong electron attractor. Ultraviolet spectra of a series of 2-amino-4-p-R-phenylthiazoles (12) and 2-amino-5-p-R-phenylthiazoles (13) were recorded in alcoholic solution (73), but, reported in an article on pK studies, remained undiscussed. Solvent effects on absorption spectra of 2-acetamido and 2-aminothiazoles have been studied (92). 

The PES of 2-aminothiazole and derivatives have been interpreted the first peak (8, 45 eV) is associated with an MO of tr symmetry mainly located on C-5 and N-3 the weiehts" of the atomic orbital in this MO... 

Infrared absorption properties of 2-aminothiazole were reported with those of 52 other thiazoles (113). N-Deuterated 2-aminothiazole and 2-amino-4-methylthiazo e were submitted to intensive infrared investigations. All the assignments were performed using gas-phase studies of the shape of the vibration-rotation bands, dichroism, isotopic substitution, and separation of frequencies related to H-bonded and free species (115). With its ten atoms, this compound has 24 fundamental vibrations 18 for the skeleton and 6 for NHo. For the skeleton (Cj symmetry) 13 in-plane vibrations of A symmetry (2v(- h, 26c-h- Irc-N- and 7o)r .cieu.J and... 

N-Methyl-2-acetamidothiazole is representative of the 2-aminothiazole structure, absorbing at 1542 and 1648 cm its isomeric imino counterpart, 2-acetylimino-3-methyl-4-thiazoline (16), has only one band at 1588 cm . As all acetylated 2-aminothiazoles absorb at 1535 and 1650 cm their amino structure is clearly established (105. 121). 

Intensities of the deformation vibration band near 1600 cm plotted for 2-aminothiazole and other 2-substituted thiazoles versus the Hammett constant give a linear relationship (123). 

Raman spectra of 2-aminothiazoles have been described (124). 

Nuclear magnetic resonance spectra of 2-aminothiazole and of 2-imino-4-thiazoline were reported during the studies related to protomeric equilibria (125-127) ring protons in the former are centered at 6.48 and 7.14 ppm (internal Me4Si), while those in the latter are shifted upheld to 5.8 and 6.5 ppm (125). 

The mass spectra of 2-aminothiazole and 2-amino-4-methylthiazole are characterized by the following peaks (136). 

The main features are the molecular ions as the base peak and the M-t-1 ions arising from another species. For 2-aminothiazole the m/e 73 ion (M-HCN) is shifted to m/e 75 in the spectrum of the dideuteroamino derivative and, therefore, largely arises via rupture of 2-3 and 4-5 bonds (Scheme 18). This fragmentation process could involve the kind of intermediates postulated in photochemical rearrangements (see Chapter III, Section IX.3.B). The other fragments fit well the general pattern of fragmentation proposed by Clarke (136). 

Magnetic susceptibilities of 2-aminothiazole have been measured (139) in order to evaluate the aromatic character of the compound. 

The dipole moment of thiazole is increased by 2-amino group substitution (140). 2-lmino-4-thiazolines are more polar than their 2-aminothiazoles isomers (141). 

Aminothiazole present in urine or blood plasma forms a colored Schiff base when 5-nitrofurfural is added the colorimetric analysis of the Schiff base allows the quantitative determination of this thiazole (1571). The Schiff base may also be dosed by polarographic of spectro-photometric methods (1572). 

The addition of (BuO)3B and PhsP to an aqueous solution of 2-aminothiazole mixed to 15% impure substances, followed by evaporation of the solvent and sublimation of the residue, provides 97.8% pure 2-aminothiazole (1573). 

Aminothiazole is efficiently purified by treating an aqueous solution of 2-aminothiazole hydrochloride with H2SO4 at 25 to 105°C, filtering the precipitated reaction product and transforming it back to 2-aminothiazole... 

Most of the reactivity studies on 2-aminothiazole and its derivatives are related either to exocydic nitrogen reactivity or to ring nitrogen reactivity. Active species involved in such reactions may depend on the pH. the... 

Thus in neutral medium the reactivity of 2-aminothiazoles derivatives toward sp C electrophilic centers usually occurs through the ring nitrogen. A notable exception is provided by the reaction between 2-amino-thiazole and a solution (acetone-water, 1 1) of ethylene oxide (183) that yields 2-(2-hydroxyethylamino)thiazole (39) (Scheme 28), Structure 39... 

Similarly, coupling 2-aminothiazole with 2-dimethylaminoethylchloride in the presence of sodium amide yields 2-(2-dimethyla.minoethylamino)-thiazole (42) (186, 187). 

Reaction of 2-aminothiazole with -phenethylchloride in anhydrous pyridine is reported to yield 76% 2-(/3-phenethylamino)thia2ole (43), the remaining 24% could be 2-imino-30-phenethylamino)-4-thiazoline (44) (Scheme 32) (188). 

Dyatlova (193) reports the preparation of product 49, resulting from the dialkylation of 2-aminothiazole with a-chloroacetic acid under mild conditions (Scheme 36). 

These methods are now obsolete in comparison with spectroscopic methods. Werbel has shown that the structures of these isomers are easily determined by NMR (125) (see also Table VI-5). Furthermore. 2-imino-4-thiazoline derivatives are characterized by their stretching C=N vibration at 1580 cm , absent in their 2-aminothiazole isomers, and by the stretching NH vibration that appears in the range of 3250 to 3310 cm for the former and between 3250 to 3340 cm" for the latter (131). Ultraviolet spectroscopy also differentiates these isomers (200). They can be separated by boiling in ethanol the thiazoline isomer is usually far less soluble in this solvent (131),... 

Thus the reactivity of 2-aminothiazole derivatives toward reactants bearing a sp C hybridized electrophilic center follows the general pattern ... 

Nucleophilic addition of 2-aminothiazole to the double bond of di-maleic acid hydrazine has been reported (206). No spectroscopic proof, however, is given to establish the proposed structure (60) for the resulting product (Scheme 41). 

The exocyclic nitrogen atom is involved when 2-aminothiazoles and aromatic aldehydes react under mild conditions yielding 61 (Scheme 42)... 

Both carbonyl groups of terephthaldehyde are reported to react with the exocyclic nitrogen of 2-aminothiazole yielding 1.4-phenylene bis(2-methyleneamino)thiazole. The same report describes the reactions of 2-amino-4-phenylthiazole with terephth aldehyde and salicylaldehyde as yielding 64 and 65, respectively (Scheme 45) (215), whose structures are based on ultraviolet and infrared spectra. 

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