Synthesis of thiazolidin-4-one derivatives on the basis of α-Substituted thiocyanates

Yuri V. Ostapiuk, Vasyl S. Matiychuk, Mykola D. Obushak

Department of Organic Chemistry, Ivan Franko National University of Lviv,
Kyryla & Mefodiya 6, Lviv 79005, Ukraine.

 E-mail: obushak@in.lviv.ua 

Abstract: 2-Вromo-3-(4-bromophenyl)propionic acid 1 has been obtained by interaction of 4-bromobenzenediazonium bromide with acrylic acid (catalyst – CuBr). One has been used for the synthesis of amides 3 – 6. 5-(4-Bromobenzyl)-2-imino-3-R¹-thiazolydin-4-ones 7 – 10 have been obtained on account of intramolecular reaction by the nucleophilic substitution of bromine by thiocyanate ion of these amides. By the reaction of arenediazonium chlorides with acrolein (catalyst – CuCl₂) the 3-aryl-2-chloropropanales have been synthesized. By the interaction of ones with thiourea 5-R-benzyl-2-aminothiazoles 11 - 15 have been obtained, that have been transformed to corresponding N-(5-R-benzylthiazol-2-yl)-2-chloroacetamides 16 - 20 by action of chloroacetyl chloride. Compounds 16 - 20 are ring closing under action of thiocyanate ion and form 3-substituted 2-iminothiazolydin-4-ones 27 - 31. By alkilation benzothiazole-2-tiol and morpholine with compounds 16 - 20 corresponding N-(5-R-benzylthiazol-2-yl)-2-(benzothiazol-2-yl)tioacetamides 22 - 26 and 4-(5-R-benzylthiazol-2-yl)-4-morpholinecarboxamide 21 have been obtained.

Key words: thiazolidin-4-one derivatives, thiazole derivatives, cyclizations, thiocyanate, arylation.

Bifunctional reagents are used widely for the synthesis of heterocycles. Among them we mark functionalized thiocyanates, because a triatomic fragment (-SCN) and ability of many nucleophiles to add to C≡N bond give many scopes both for cyclocondensations, and for intramolecular cyclizations [1]. However, a number of such reagents is insufficiency [1-7]. Only thiocyanatoacetic esters and the some α-thiocyanatoketones were investigated in reactions of a ring closure.

The reaction of thiocyanatoarylation of unsaturated compounds by tetrafluoroborates or sulfates of arenediazonium in the presence of MSCN (M = K, Na, NH₄) is sufficiently perspective approach to the synthesis of reagents of such type, as shown in works [8, 9]. α-Thiocyanatoamides are interesting reagents, because the ring closure can take place spontaneously already at a stage of the formation of these compounds. Thus in the position 2 of thiazolidinones ring the imino-group would formed, which, probably, can hydrolyze in the reaction conditions to a carbonyl group. However, we have found that during the realization of thiocyanatoarylation of acrylamides the mixture of compounds І–ІV was received (scheme 1). As it turned out the synthetically attractive (one step!) method of synthesis of compounds ІІІ has appeared preparative of little use.

Scheme 1

We have realized this scheme, a little having complicated it. At first we synthesized similar bromoamides 3 - 6 (scheme 2, table 1) with usage of Meerwein arylation product 1. The corresponding thiocyanates were obtained by nucleophilic substitution of bromine by SCN^–. Thiocyanates V were not isolated. It is established, that compounds V in the reaction conditions have cyclizated intramolecularly, yielding the 2-imino-4-thiazolidinone derivatives 7 - 10 (scheme 2, table 2).

Scheme 2

Table 1. N-R¹ – 2-Вromo-3-(4-bromophenyl)propionamides

* - thiaz =

Table 2. 5-(4-Bromobenzyl)-2-imino-3-R¹-thiazolydin-4-ones

By thiocyanatoarylation of acrolein it would be possible to receive α-thiocyanatoaldehyde. Taking into account expected instability of adducts, we did attempts to cyclizate them without isolation with usage of amines (scheme 3):

Scheme 3

However, 5-R-benzylthiazoles VI were not isolated in the pure form. Similar thiazole derivatives 11 – 15 (scheme 4) were synthesized by reaction of chloroarylation products of acrolein with S, N-nucleophiles (for example, with thiourea) [10, 11]:

Scheme 4

By simple transformations aminothiazoles were modified in thiocyanato derivatives. At first acylation by chloroacetyl chloride was carried out and amides of 16 - 20 were received (scheme 5, table 3):

Scheme 5

Table 3. N-(5-R²-benzylthiazol-2-yl)-2-chloroacetamides

The chlorine atom in compounds 16-20 is easy substituted by S- and N-nucleophiles. Synthetic scope of these reagents have demonstrated by alkylation of morpholine (compound 21) and mercaptobenzothiazole (compounds 22 - 26) (scheme 6, tables 4).

Scheme 6

Table 4. 4-[5-(3-chlorobenzyl)thiazol-2-yl]-4- morpholinecarboxamide 21 and N-(5-R-benzylthiazol-2-yl)-2-(benzothiazol-2-yltio)acetamides 22 - 26

Interesting there was a result of interaction of compounds 16 - 20 with thiocyanate–ion. It was found out, that by action of potassium thiocianide reaction is not finished at a stage of nucleophilic substitution, and there is a spontaneous thiazole ring closure. As a result of reaction compounds 27 – 30 (scheme 7, table 5) were obtained, those contain two pharmacophore fragments - thiazole and thiazolidinone rings.

Scheme 7

Table 5. 5-R²-Benzyl-2'-imino-[2,3']bithiazolyl-4'-one 27 - 31

Thus, the carried out researches have shown new usage in the organic synthesis of α-functionalized thiocyanates, which can be obtained by Meerwein reaction or immediate thiocyanatoarylation of unsaturated compounds.

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