Carbon, oxygen- and nitrogen (six membered ring) annulations

Abstract

The thesis entitled "Carbon-, Oxygen- and Nitrogen- (Six Membered Ring) Annulations by Vilsmeier Reaction" consists of six chapters. Chapter 1 describes the results of investigations of the Vilsmeier reaction on known ?,?,?-unsaturated alkenols (1) prepared from aldehydes, ketones, and acids. The study led to a one-step, simple, and convenient synthesis of various substituted benzene mono-, di-, and tricarboxaldehydes. The results indicate that at least five contiguous carbons are necessary for the benzocyclization to occur. One unique instance of the Vilsmeier reaction converting three ?,?,?-unsaturated alkenol substrates to uvitaldehyde (2) has been encountered in the study. Uvitaldehyde has been used as a synthon in the synthesis of a naturally occurring alkaloid. Other di- and tricarboxaldehydes reported in the work are not readily accessible by other conventional routes. Chapter 2 contains an account of a one-step benzoannulation procedure involving the synthesis, by the Vilsmeier reaction, of chlorobenzene mono-, di-, and tricarboxaldehydes (4) from ?,?-unsaturated ketones (3), obtained from the appropriate acids by the action of alkyllithium. The interesting incorporation of chlorobenzenecarboxaldehyde moiety is found in natural products like ascochlorin. Chapter 3 deals with the Vilsmeier reaction on the cyclic systems (5–8) containing 2-en-1-one, 2-en-1-ol, and 1,3-diene functionalities (e.g., isophorone and related compounds) and undergo (oxygen) heteroannulation in one step to give the benzopyran derivatives (9–11). Support in favour of the structures (9 and 11) was adduced by X-ray studies. 3,5-Dimethyl-2-cyclohexenone (8) gave the interesting hexasubstituted benzene tricarboxaldehyde (12). The benzopyran (9) undergoes acid-mediated methyl migration and aromatization to afford (13). In Chapter 4 is narrated a novel, versatile single-step synthesis of o-dichlorobenzenecarboxaldehydes (14) obtained by the Vilsmeier reaction route from acyclic ?,?-epoxy ketones (15). The study has been extended to cyclic epoxy ketones (16) which gave monochlorobenzenoids and o-dichlorobenzenoids. The epoxy ketones (15,16) were readily prepared from the corresponding enones by treatment with alkaline hydrogen peroxide. 2,3-Dichlorobenzenecarboxaldehydes have been reported to find application in the synthesis of diuretics. In Chapter 5 is presented a simple and versatile regioselective route for the synthesis of substituted mono- and bicyclic 2-chloronicotinonitriles (17,18). Alkylidenemalononitriles (19) prepared from aldehydes gave 5-substituted 2-chloronicotinonitriles (17, R'=H), while those prepared from acyclic ketones furnished 4,5-disubstituted 2-chloronicotinonitriles (18). The malononitriles prepared from cyclic ketones afforded fused 2-chloronicotinonitriles (19). The present one-step procedure of pyridoannulation leading to nicotinonitriles has considerable potential in the synthesis of drugs and drug intermediates. Chapter 6 is concerned with the Vilsmeier reaction on 1,3-diketones. 2,4-Dichlorobenzenecarboxaldehydes (20) were obtained in a single step from 2,4-pentanediones (21). The possible mechanisms of the formation of the variety of annulated products obtained by the Vilsmeier reaction have been discussed, wherever relevant, in all the chapters.