Structure and reactivity of 2-alkyl- and 2-alkoxy-thiazolin-5-ones

Abstract

2-AI kylthiazolin-5-ones resemble the 2-aryl compounds in that they are readily enolisable and can easily be acylated on oxygen. In contrast 2-alkoxythiazolin-5-ones do not enolise in polar solvents and can only be acylated with the aid of a strong base such as sodium hydride.Research Centre, Sitting bo urn e, Kent THERE are four possible structures [(I)-(IV)] for the 2,4-disubstituted thiazolin-5-ones (referred to throughout the text simply as thiazolinones). Examination of the i.r. spectra of 4-alkyl-2-phenylthiazolinones has shown that these compounds exist in a keto form [(I) or (11)] in solvents such as chloroform or in the undiluted state, but are enolised to a great extent in polar solvents such as dimethyl sulphoxide (DMSO). The salts of these compounds appear to exist in an enol form [protonated (111)], since they show an OH band in the i.r. spectrum.l The lH n.m.r. spectra of certain 4-alkyl-2-phenylthiazolinones have been examined.2 The spectrum of 4-isopropyl-2-phenylthiazolinone indicates that the two methyl groups of the isopropyl group are non-equivalent, since their signals appear as two separate doublets. As the signals do not coalesce on heating this must be due to fundamental asymmetry, not to restricted rotation.2 The structure of this compound must therefore be (I) (A2-form) rather than (11) (h3-form), since C-4 is asymmetric. The asymmetry is lost on salt formation.We have studied the n.m.r. spectra and chemical properties of 2-alkyl-and 2-alkoxy-thiazolinones in order to determine the structures of these compounds. 2,4-Dialkylthiazolinones resemble 4-alkyl-2-arylthiazolinones, but the alkoxy-compounds exhibit unexpected properties.2,4-Dialkylthiazolinones were made by cyclisation of N-thioacylamino-acids with phosphorus tribromide or dicyclohexylcarbodi-imide.4 As in the case of 2-phenylthiazolinones, treatment with acetic anhydride yields the thiazolyl a~e t a t e .~ The thiazolinones are stable, distillable liquids, provided that a 4-substituent is present.The i.r. spectra of the compounds indicate that they exist in a keto form [vmax. ca. 1730 (GO) and ca. 1635 cm-I (C=N)], and a comparison of the U.V. spectrum (cyclohexane) of 4-isobutyl-2-methylthiazolinone [ lmx. 245 nm (E 1-6 x 1071 with that of 2,4,4-trimethylthiazolinone [A,m,. 242 nm (E 1.67 x lo3)], which can only exist as structure (I), strongly supports this idea.The lH n.m.r. spectrum of 4-isopropyl-2-methylthiazolinone in CDCl, (Figure 1) confirms this view. The isopropyl methyl groups appear as a pair of doublets (6 0.82, 0.89, 1.14, and 1.21 p.p.m.) as they do in the spectrum of the 2-phenyl analogue.2 The isopropyl methine proton signal is a doublet of septets (centred at about 6 2.38 p.p.m.) and the 2-methyl signal is a doublet (6 2.44 and 2-65 p.p.m.). Addition of D20 to the CDC& solution ( Figure 2) causes almost complete disappearance of the 4-H signal, simplifies the isopropyl methine signal, and reduces the 2-methyl signal to a singlet. The 4-proton is thus shown to be readily exchangeable and also to be coupled a...

2-Alkoxy-5(4H)-oxazolones from N-alkoxycarbonylamino acids and their implication in carbodiimide-mediated reactions in peptide synthesis

“…As pointed out by them, it has already been clearly demonstrated that the 4-proton in the analogous 2-alkoxy-Y4H)-thiazolone is much less acidic than that in the corresponding 2-alkyl-5(4H)-thiazolone (12), so the observations are as expected.…”

On the Tautomerism of 2,4-Disubstituted Thiazolones

“…[1,4,5] In the infrared spectrum (KBr), all the 2-phenylthiazolones show a weak but broad carbonyl absorption at about 1730 cm Ϫ1 . In contrast, the 2-ethyl-, 2-ethoxy-, and 2-ethylthio analogs show a very strong and sharp peak in this region.…”

“…Such long range coupling has already been reported for thiophenes [14] and thiazolone. [4] The expanded spectrum of the methylene protons of the ethyl group at C-2 in keto form I is shown in Figure 2, together with the simulated spectrum of the same protons. Figure 3 gives the expanded spectrum of the methine proton at C-2 in keto form II, together with the simulated spectrum.…”

“…Interestingly, an early study on 4-isopropyl-2-methylthiazolone did not reveal the existence of keto form II in CDCl 3 , although the spectrum of this compound in [D 6 ]DMSO indicated that it was 35% enolized. [4] The heats of formation for 2-ethylthiazolon-5(4H)ones (keto form I) and 2-ethylthiazolon-5(2H)ones (keto form II) have been calculated at the AM1 level using the semiempirical SPARTAN program [21] , the results of which are shown in Table 1. It can be seen from this table that the calculated heats of formation for keto form I are lower than those of the keto form II in all cases examined.…”

Increasing protein stability by engineering the n → π* interaction at the β-turn

“…The two N-terminal fragments possibly result from the racemization of the L-Ala i+2 due to keto-enol tautomerization of the thiazolone intermediate. 63 The polypeptides are color coded and are shown in the HPLC chromatogram. (b) Spontaneous acid-catalyzed cleavage of the thioacylated Aib-Pro dipeptide in aqueous solution.…”