64-ThiaZolines, aromatization

Polar solvents shift the keto enol equilibrium toward the enol form (174b). Thus the NMR spectrum in DMSO of 2-phenyl-A-2-thiazoline-4-one is composed of three main signals +10.7 ppm (enolic proton). 7.7 ppm (aromatic protons), and 6.2 ppm (olefinic proton) associated with the enol form and a small signal associated with less than 10% of the keto form. In acetone, equal amounts of keto and enol forms were found (104). In general, a-methylene protons of keto forms appear at approximately 3.5 to 4.3 ppm as an AB spectra or a singlet (386, 419). A coupling constant, Jab - 15.5 Hz, has been reported for 2-[(S-carboxymethyl)thioimidyl]-A-2-thiazoline-4-one 175 (Scheme 92) (419). This high J b value could be of some help in the discussion on the structure of 178 (p. 423). 

A -Imidazolines, -oxazolines and -thiazolines (291), and their benzo derivatives (292), are very easily aromatized (292 293), and syntheses which might be expected to yield... 

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). 

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. 

The oxidation state of thiazolines and oxazolines can be adjusted by additional tailoring enzymes. For instance, oxidation domains (Ox) composed of approximately 250 amino acids utilize the cofactor FMN (flavin mononucleotide) to form aromatic oxazoles and thiazoles from oxazolines and thiazolines, respectively. Such domains are likely utilized in the biosynthesis of the disorazoles, " diazonimides, bleomycin, and epothiolone. The typical domain organization for a synthetase containing an oxidation domain is Cy-A-PCP-Ox however, in myxothiazol biosynthesis one oxidation domain is incorporated into an A domain. Alternatively, NRPSs can utilize NAD(P)H reductase domains to convert thiazolines and oxazolines into thiazolidines and oxazolidines, respectively. For instance, PchC is a reductase domain from the pyochelin biosynthetic pathway that acts in trans to reduce a thiazolyinyl-Y-PCP-bound intermediate to the corresponding thiazolidynyl-Y-PCP. ... 

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. 

Saidi and co-workers [141] have reported a three-component reaction of different thiosemicarbazides with dimethyl or diethyl acetylenedicarboxylate and an aldehyde under solvent-free conditions applying a domestic microwave oven. Thiazolines 102 were obtained in good to excellent yields. Interestingly, the presence of electron-donating groups on the aromatic aldehyde resulted in faster reactions and higher product yields (Scheme 79). 

The best known of the potential mercaptoimidazoles are the imidazoline-2- and benz-imidazoline-2-thiones, which resemble imidazolin-2-ones in that the tautomeric form (53 X = S) is the preferred form. The crystal structure and the HNMR spectrum of 1,3-dimethyl-3H-imidazoline-2-thione have been interpreted as showing partial double bond character in the N—C—N system, but no aromaticity (70CC56). However, the preference for a betaine structure (56) rather than (57) or (58) should be accepted with caution since it is really only a resonance structure similar to others which undoubtedly contribute to the overall structures of oxo-, thio- and amino-imidazoles. Measurement of the piSTa values for a series of imidazoline-2-thiones substituted variously on C-4, C-5, N-1 and N-3 by hydrogen, phenyl or methyl shows that all of the values are similar. Approximate Kr values calculated show that these compounds exist even more in the thione forms (53, X = S 58) than do the corresponding thiazoline-2-thiones and oxazoline-2-thiones. The UV spectra in aqueous solution support thione structures, as do dipole moment and X-ray studies (76AHC(S1)280, p. 400). 

The thiazole ring is synthesized biochemically by enzymatic post-translational modifications of cysteine-containing peptides. Heterocyclization between cysteine side-chains and neighboring carbonyl groups produces dihydrohetero-aromatic thiazolines as initial products followed by a two-electron redox reaction yielding either thiazole or thiazo-lidine rings (Scheme 104). All three oxidation states are seen in natural products. 

Pyridine, pyrrols and quinoline derivatives are found in Group 28. Thiazole, thiophenes, thiazolines and thienyl derivatives are summarised in Group 29. Among miscellaneous compounds Group 30 lists hydrogen sulphide and ammonia. In Group 31 we find aliphatic and aromatic hydrocarbons like limonene (Flavis 01.001, FEMA 2633). 

A number of phosphonate and phosphinate derivatives where the phosphorus atom is directly bonded to non-aromatic cyclic systems have been reported. The synthesis and reactions of a number of compounds with the general structure 103 have been reported. Enantiomerically pure cyclopropanephosphonic acids which are constrained analogues of the GABA antagonist phaclophen, have been prepared by stereocontrolled Michael addition of a-anions derived from chiral chloromethylphosphonamides 104 to a,P-unsaturated esters followed by in situ cyclisation. Other asymmetric syntheses include those of (/ )- and (S)-piper-idin-2-ylphosphonic acid (105) via the addition to trialkyl phosphites to iminium salt equivalents and 4-thiazolidinylphosphonate 106 by catalytic asymmetric hydrophosphonylation of 3-thiazoline. In the latter case both titanium and lanthanoid (which give much better e.e. values) chiral catalysts are used. 

The intermediates of the reaction of dithiocarbamic acids with a-halo ketones, the 4-hydroxy thiazohdine-2-thiones (CXCIIb), can sometimes be isolated 184, 257, 863 ). On treatment with acid these split off water and are converted into Zl4-thiazoline-2-thiones. However, when there is no hydrogen on the Cg carbon atom, as with the thiazolidine-2-thione obtained from -bromobenzylideneacetone, the elimination of water involves the hydrogen atom of the 4-alkyl group so that 4-alkylidene-5-benzylidene thiazolidme-2-thiones (CXCIII) are formed. Il, in (CXCIIb), Ra is an aromatic group as in the thiazolidine-2-thione obtained from... 

The hydrogen atoms at position 2 of dihydrothiazines of types 51 and 80 are expected to display acidic properties this behavior has been reported only in the case of the thiazolium salt 54, which afforded the arylidene derivative 134 with an aromatic aldehyde. When treated with hydrogen peroxide in acetic acid, the dihydrothiazinone 135a was converted into the 2-hydroxy derivative 135b by contrast, compound 97 afforded the thiazoline 136 (Section V,C,2,b). Clearly the position of the equilibrium between the two possible products is dramatically influenced by the nature of the Af-substituent. 

Thiazolines and 3-thiazolines are easily aromatized to the corresponding thiazoles by the action of oxidants such as nickel peroxide <94TL1379>, 2,3-dichloro-5,6-dicyano-l,4-dibenzoquinone, or t-butyl perbenzoate via the Kharasch-Sosnovsky reaction <94TL248l, 94TL6803). The aromatization of... 

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