Imino thiazoline

Thiazoles bearing hydroxy, thio, or amino groups at C-2, C, or C-5 are in tautomeric equilibrium with the corresponding oxo, thioxo, or imino thiazolines. Thiazoles bearing more than one of these groups also display similar prototropic tautomerism, although with some restrictions. 

Other examples of plateaus in atropisomeric N-aryl-N -aryl-2-imino-thiazoline (08ARK(viii)28, 08JOC403) or in A)-aryl-thiazolin-2-one series have been reported (05LOC433). 

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).

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). 

Sheinker et al. thoroughly studied protomeric equilibria by a study of the infrared properties of 2-aminothiazoie and 2-imino-4-thiazoline derivatives (94, 105, 119). His results confirm that the amino form is predominant, a conclusion also drawn from the infrared absorption study of 2-anilinothiazole (120) and 2-heteroarylaminothiazoles (1569). 

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). 

The typical infrared frequencies of a set of 2-imino-4-thiazolines were recently reported, however, their complete assignment is still to be made (101, 107, 122). 

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). 

Quaternary salts (33) obtained from aminothiazole derivatives liberate 2-imino-4-thiazolines in basic medium (Scheme 24). This reaction is general and independent of the nature of R in 33 (160-167). The same result was found when 2-propynylbromide (168) or 3-chloropropionic acid (169) were the quaternizing reagents. This method is particularly... 

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). 

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),... 

Acetylation of 2-phenyl-4-amino-5-benzoylthiazole takes place on the exocyclic nitrogen (49). This exocyclic nitrogen remains the reactive center even with 2-imino-3-aryl-4-amino-5-carboxamido-4-thiazoline (111). Its acetylation with acetic anhydride gives the 4-acetamido derivative (112), which reacts further on heating to yield 2-(acetylimino)-(3H)-3-aryl-5-methylthiazolo[4,5-d]pvrimidin-7-(6H)-one (113) (Scheme 76) (276). 

The amino group of 2-imino-3-phenyl-4-amino-5-carbethoxy-A4-thiazoline is very reactive and displaces the chlorine atom of various 2-chlorothiazoles (1577). 

Condensation of 2-phenyl-4-amino-5-benzoylthiazole with cyanamide yields the pyrimidothiazole (Scheme 88) (133) (49) 2-imino-3-aryl-4-amino-5-carbethoxy-4-thiazolines condense similarly with alkyl isothiocyanates (276). 

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). 

Treatment of 2-imino-3-phenyl-4-amino-(5-amido)-4-thiazoline with isocyanates or isothiocyanates yields the expected product (139) resulting from attack of the exocyclic nitrogen on the electrophilic center (276). Since 139 may be acetylated to thiazolo[4,5-d]pyrimidine-7-ones or 7-thiones (140). this reaction provides a route to condensed he erocycles (Scheme 92). 

Taurins reported that nitration of 2-nitramino-5-nitrothiazole yields the fully nitrated 2-imino-4-thiazoline (184) (Scheme 117) (87). This interesting compound should be studied by spectroscopic methods. 

In this section, only salient features of the synthesis, physicochemical properties, and reactivity of major derivatives of 2-aminothiazole and 2-imino-4-thiazoline are summarized. Further details on each compound are found in associated references collected in Section VII. The synthetic methods reported in this section exclude heterocydization methods treated in Chapter II but given in specific references found in Section VII. 

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). 

The 1,3-diester derivative of 2-imino-4-thiazoline (369) is obtained by the Schotten-Bauman reaction (Scheme 213) (263). 

Refluxing, 5.6-dihydro-7H-thiazolo[3,2-a]pyrimidine-7-one (370j with isopropylamine led to 2-imino-3-[2-(isopropylaminocarbonyl)ethyl]-thiazoline (371) (108). Similarly. tetrahydrobenzothiazolo[3,2-fl][2.3-f>]-quinazoline is opened by potassium hydroxide, yielding 373 (Scheme 214)... 

This kind of nucleophilic reaction, when performed with 7H-thiazolo[3,2-a]pyrimidine-7-one (374), however, is reported to give 2-[(/3-aminoacryloyl)imino]-4-thiazoline (375) (Scheme 215) (273, 703),... 

Thiochrome (377), the well-known derivative of the 2-imino-4-thiazoline ring, is synthesized according to the set of reactions shown in Scheme 216 (704, 732). 

Most of the spectroscopic properties of 2-imino-4-thiazolines have been treated in Section II. Paper chromatography and thin-layer chromatography are particularly suitable for distinguishing 2-atnino-thiazoles from 2-imino-4-thiazolines their RfS and characteristic reactions are different (148, 494. 705). 

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). 

Reaction of 2-imino-3-alkyl-4-thiazolines with alkyl isocyanates gives the ureas (382), which when nitrated on C-5 give the schistosomicide class of compounds (383) (Scheme 219), When nitration takes place on the ring... 

The anionic form of 2-imino-4-thiazoline is involved in the alkaline cycUsation of 393 (Scheme 224) (176). 

Acylated derivatives of 2-imino-3-alkyl-4-thiazoIines are reduced to 2-alkylimino-3-alkyl-4-thiazolines by the action of LiAlH4 (477). The acyl... 

The synthesis of 9H-benzo[2,l-e]thiazolo-[2,3-c]-as-triazine (401) was achieved by oxydative cyclization of 2-imino-3-(o-aminophenyl)-4-phenyl-4-thiazoline (718, 719). This latter reacts also with paraformaldehyde in hot toluene yielding 3-phenyl-9H.10H-benzo[l,2-/]thiazolo-[2,3-d][l,3,5]triazepine (402) (720). This heterocyclic sytem is also formed when carboxylic acids replace paraformaldehyde (Scheme 230) (721). 

Little is known about the photochemical behavior of 2-imino-4-thiazolines the only data concerns the photolysis of 3,4-diphenyl-2-nitrosoiniino-2,3-dihydrothia2ole (403) (Scheme 231) (722). 

Attack on the electrophilic C-2 may occur as in the 2-aminothiazoles series, which probably explains the rearrangements observed in acidic medium (121, 711, 712, 723, 724), in aqueous medium with NaOAc (725), or with aqueous NaHCOj (725) (Scheme 232). That the initial attack probably involves the C-2 atom is substantiated by the fact that this rearrangement occurs under extremely mild conditions for 2-iinino-3-substituted-5-nitro-4-thiazolines (725). As the whole mechanism proposed (see p. 92) is reversible, when imino derivatives are submitted to such rearrangement conditions the rearrangement is expected to occur faster if steric interaction between 3- and 4-substituents exists in the 2-imino isomer. Another reaction may occur in acidic medium phenylimino-2-bipheny]-3,4-4-thiazoline hydrolyzed with hydrochloric acid gives the corresponding 4-thiazoline-2-one and aniline (717). 

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). 

This section includes veterinary applications. The antiviral, bactericidal, and antimicrobial applications of 2-aminothiazoles and 2-imino-4-thiazolines are summarized in Table VI-7. They show a marked anti-trichonomicidal activity, which has even been quantitatively measured by the Hansch approach (797). The antiparasitic action of these compounds has been investigated for some compounds and is summarized in Table VI-8 interesting results were obtained with aminotrozal (1348). 

The most studied properties of 2-aminothiazoles and 2-imino-4-thiazolines are related to their antiinflammatory activity (Table VI-9). Two classes of compounds have even been given trade names Sudoxicam (418) and Niridazole. also named Ambilhar (419) (Scheme 238). 

TABLE Vl-8. PARASmCIDAL PROPERTIES OF 2-AMlNOTHIAZOLE (A) AND 2-IMINO-4 THIAZOLINE (B)... 

The 2-imino-4-thiazolines may be used as ultraviolet-light stabilizers of polyolefin compositions (1026). 2-Aminothiazole improves adhesive properties of wood to wood glue (271). Cbmpound 428 exhibits antioxidant properties (Scheme 242) (1027). Ammonium N-(2-thiazolyl)dithio-carbamate (429) is a bactericide and fungicide used in industrial products such as lumber, paint, plastics, and textiles (1037). Compound 430 is reported (1038) to form an excellent volume of foam coating in aluminum pans when ignited with propane. 

Imino-A-4-thiazolines (27) when treated with hydrochloric acid give the A-4-thiazoline-2-ones (28) (Scheme 12). This reaction has been used as a structural proof of the parent compounds (19, 27, 28). 

Ring opening and further ring closure of 2-imino-oxythiolan-l,3 derivatives (32) by water and/or methanol lead to the corresponding A-4-thiazoline-2-one (26) (Scheme 14) (30-32). 

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