Literature data are reviewed.ft." the first time on tile use of 4-halocrotonic acid derivatives in the synthesis of five-and six-memhered heterocvcles containing one or several heteroatoms in the ring, attd their atmelated attalogs.Keywords: enethiolatonitriles, condensed pyridines and pyrimidines, crotOnic acid derivatives, cascade heterocyclization.Functionally substituted crotonic acids possess a high synthetic potential, especially for obtaining various types of heterocycles. In this respect a special place is held by derivatives of 4-hatocrotonic acid containing functional groupings Z such as ester, nitrile, or carboxyl, and chlorine or bromine atoms as halogen. ,,,,~,tlal~['~ZSubstituted 4-halocrotonic acids contain several reaction centers predetermining the type of interactions in which they may participate.1. Halogen atom, readily reacting by nucleophilic substitution. 2. Methylene group in the vinylogic position to an electron-withdrawing Z group. 3. Double bond activated towards nucleophilic addition and cycloaddition by the presence of the conjugated Z group.4. Substituent R (from hydrogen atom and hydrocarbon radicals to functional groups analogous to the Z group}.5. Electron-withdrawing group Z able to being subjected to nucleophilic attack.Conversions in which derivatives of 4-halocrotonic acid are involved have been classified by us according to the reaction center participating in the reaction. Since the halogen atom is practically always subjected to nucleophilic substitution the main accent in this review is directed towards the reactions proceeding at other reaction centers.
Condensed cinnolines hold great interest in light of the broad spectrum of their useful properties [1]. The major method for constructing such heterocyclic systems involves intramolecular cyclization of aryldiazonium salts [1]. This approach has been used for the synthesis of such condensed heterocyclic systems as benzo [c]cirmolines [1, 2] and thieno-[2,3-c(3,2-c)]cirmolines [3]. However, o-aryl-or o-hetarylanilines, the starting compounds for these syntheses, are usually difficult to obtain. This lack of availability has limited the compounds of this class, as described [1].In the present work, we propose a new approach for construction of the cinnoline system involving formation of a -N=N-double bond by the reaction of NH 2 and NO 2 groups in P(OEt) 3. lntermolecular reactions of this type leading to arylazo compounds have not yet been reported. A similar method has been proposed for ring closure in 2-amino-2'-nitrodiphenyl, which, upon treatment with trimethylbenzylammonium hydroxide, gives a cyclic azoxy compound, namely, benzo[c]cinnoline oxide [4, 5].Previously unreported 3-amino-2-(2-nitrophenyl)thieno[2,3-b]pyridines (Ia-Ig, see Scheme) were selected as the starting compounds for the synthesis of fused cinnolines. Several published studies have been devoted to the synthesis of analogous compounds (R 1, R 2, R 3 = H, Me, R 4 = H, R 5 = NO2) containing a 4-nitrophenyl substituent by cyclization of the corresponding 2-(4-nitrobenzyl)thio-3-cyanopyridines in the presence of sodium ethylate in ethanol [6][7][8].According to the proposed scheme, alkylation of deprotonated 3-cyano-l(2H)-pyridinethiones (IIa-IIg) by 2-or 4-nitrobenzyl bromide leads to benzylthiopyridines (llIa-llIg). The next step involves deprotonation of the acidic methylene group in III by the action of KOH as a base and subsequent closure of the thiophene ring by a Thorpe-Ziegler reaction to give thienopyridines (Ia-Ig). We have shown that the nitrophenyi group in this case is also a sufficiently strong electron-withdrawing substituent for carrying out such a cyclization. The feasibility of obtaining I directly from starting pyridinethiones II without isolation of intermediate pyridines III is not excluded though isolation of the intermediate is desirable for obtaining the desired thienopyridine in pure form and good yield.The PMR and IR spectral data were sufficiently informative to establish the structures of I and III. Thus, the IR spectra of pyridines III have a band for the 3-CN group in the vicinity of 2220 cm -l. This band disappears after closure of the thiophene ring and formation of I and several bands appear at -3360 cm-1 characteristic for the NH 2 group. The PMR signal for the methylene group in pyridines III at -4.80 ppm is also diagnostic. This signal is lacking in the spectra of I, and a broad singlet at 4.50-6.00 ppm appears for the amino group.
Functionally-substituted pyrido [3',2':4,5]thieno [3,2-d]pyrimidinones hold interest as compounds, which may possess a broad range of biological activity. The known methods for the preparation of such compounds involve the reaction of 3-amino-2-carbamoylthienopyridines with acetonitrile in the presence of HC1 in dioxane [1], acylation of 3-amino-2-ethoxycarbonylthienopyridines by acetic anhydride followed by treatment with ammonia [2], reaction of 3-amino-2-carbamoylthienopyridines with acetic anhydride [3][4][5] or triethyl orthoformate [6], and also acylation of 3-aminothieno-2-pyridinecarboxylic acid with subsequent reaction of the pyridothienooxazinone formed with ammonia [6]. These multistep procedures require vigorous conditions and do not always provide high yields. Furthermore, compounds with fused carbocyclic fragments containing an odd number of carbon atoms cannot be obtained using these methods.We propose a new convenient method for the regioselective synthesis of functionally-substituted pyrido-[3',2':4,5]thieno[3,2-d]pyrimidin-4(3H)-ones starting from N-acetylchloroacetamide (I) and 3-cyano-2(1H)-pyridinethiones (IIa-IIf), which avoids the indicated drawbacks.N-Acetylchloroacetamide I may be obtained by the acylation of chloroacetamide by acetic anhydride in the presence of acetyl chloride [7], reaction of chloroacetonitrile with glacial acetic acid [8], reaction of acetamide with chloroacetamide in the presence of HC1 [8], and also the reaction of acetamide with chloroacetyl chloride [9].
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