Thiazoline derivatives

The first preliminary studies towards the synthesis of penam derivatives by the Ugi reaction were carried out roughly 30 years ago. 3-Thiazoline derivatives (153) were allowed to react with isocyanides in the two-phase system water/petroleum ether to yield up to 95% of the penam derivatives (154). 

We were surprised to find that despite the general lability of penam derivatives, the products (154) could be purified by sublimation in vacuo. Using a similar scheme, Sjoberg synthesized the amide of a stereoisomer of penicillin G, but in very low overall yield, because formation of the required 3-thiazoline derivative by the Asinger condensation did not proceed satisfactorily. 

This reaction is useful in the preparation of 3-thiazoline derivatives. 

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). 

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),... 

Synthetic study of 4-thiazoline derivative curacin A, a novel antimitotic agent isolated from cyanobacterium Lyngbya majuscula 99YGK552. 

In 2005, another class of chiral ligands, bis(thiazolines) derivatives, was prepared by Nishio et al. from chiral bis-(A-acylamino alcohols) by using Lawesson s reagent. These new compounds have proved to be useful chiral ligands for the Zn-catalysed Diels-Alder reaction of 3-acryloyloxazolidine-2-one with cyclopentadiene, giving the corresponding cycloadducts as a 94 6 diastereomeric mixture, where the major diastereomer was formed with 92% ee (Scheme 5.14). 

Compounds bearing C(=S)-NH-C-C-OH fragment ((3-hydroxy thioamide) can also undergo cyclodehydration to form thiazoline derivatives. The utility of this strategy has been demonstrated in the synthesis of halipeptins A and D <06JA4460>. Exposure of 73a/b with (diethylamino)sulfur trifluoride (DAST) brings about intramolecular cyclization to provide thiazolines 74a/b, which are advanced precursors to halipeptins A and D. 

Oxazoline and thiazoline derivatives metalated at the 2-position can also be prepared by the combination of acyclic precursors, namely by the reaction of a-metalated isocyanides with ketones or thioketones (Scheme 141) [76LA183 77AG(E)339 79PAC1347]. Although this route is normally used to produce 2-unsubstituted derivatives via protonation, there is presumably no reason why other electrophiles could not also be utilized instead. 

Phosphonium ylides 66 attack 1,2,4-dithiazole derivatives 65 (Y = 0, S) mainly at the S-S bond to give intermediates 67, which can either afford thiazoline derivatives 68 or react further, with a second ylide molecule 66 at the C=Y bond, to finally yield new thiazole and dithiole derivatives 69 and 70. Compounds 70 are predominant in this mixture (yields > 50%). They are oxidized into known dithiole derivatives 71 (Scheme 8) <1993MI33, 1994PS105, 1995PS63, 1999PS393>. 

Tetramisole may also be prepared by cyclisation of thiazoline derivatives (28-30) under different conditions (Scheme 4) [22,23],... 

Major metabolite (in faeces) is 5,6-dihydro-6-(2-thienyl)imidazo[2,1-b]thiazole more potent antihelmintic than parent drug. Finding led to synthesis of tetramisole (corresp. 6-phenyl-thiazoline deriv.), potent broad-spectrum antihelmintic (39 0). 

Similarly, AT-allylthioamides derived from carboxylic acids cyclize to 2-thiazoline derivatives by the action of the bromine-dioxane complex <93PJCI043>. The Mitsunobu reaction can be eflSciently used for preparing 4-carboxy-2-thiazolines from -hydroxy-a-amino acids <92TL2807). Diethyl-... 

Certain 4-thiazolin derivatives (483) show significant activity as anti-convulsant agents <94FES133>. Thiazolo[3,4-a]benzimidazoies (484) show reproducible in vitro anti-HIV activity <91FES817,91FES925). The enantiomeric resolution of these compounds is achieved by HPLC on a chiral stationary phase <94Mi 306-04>. 

A series of l-acylimino-3if-thiazoline derivatives 104 are prepared by a one-pot three-component condensation of arylisothiocyanates 100, primary amines 101 and a-halocarbonyl derivatives 102 presumably via intermediates 103 <05TL419>. 

An interesting rearrangement was observed35,36 during the preparation of4-hydroxy-JV-(5-methyl-3-isoxazolyl)-2-methyl-2/M,2-benzothiazine-3-carboxamide 1,1-dioxide (43) (Eq. 9). Sodium methoxide cleaved the benziso-thiazoline derivative 40 to the expected benzoate ester 41, but this was cyclized by base to a 4-hydroxy-2//-1,2-benzothiazine (42) with simultaneous conversion of the isoxazole moiety to an oxadiazole. Compound 42 was N-methylated by methyl iodide and the product converted to the desired amide 43 by treatment with triethylamine in xylene, a process which simultaneously reconverts the oxadiazole side chain to an isoxazole. 

Benzothiazines have been reported to undergo a number of rearrangement reactions, one of the most commonly encountered involving ring contraction. Thus among the products of autoxidation of 1,4-benzothiazines are benzo-thiazoline derivatives.137,141,167 For example, the benzothiazine 135 on treatment with oxygen in acidified cyclohexane gave the acyl derivative 136. 

The fragment coupling between the thiazoline derivative of (129) and compound (130) was carried out in the presence of titanium tetrachloride, giving stereoselectively the corresponding aldol. Oxidation of this compound gave a ketone, which was then stereoselectively reduced to the desired secondary alcohol and finally methylated to yield the C5-C21... 

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