An Antimalarial Alkaloid From Hydrangea. Xix. Thiophene Isosters

Abstract

The general method for the synthesis of the Hydrangea alkaloid (I) involved coupling of 1 -carbethoxy-2-( -bromoacetonyl) -3-methoxypiperidine with 4-quin-O II HO ,C\ NCHsCOCH, CH 2\nZ H.2HC1nZ azolone followed by removal of the blocking groups by two stage strong acid hydrolysis (1). A series of related compounds with the benzene ring replaced by a heterocycle could theoretically be synthesized. However, it is imperative that the heterocycle be stable to strong acid. Secondly, the heterocycle should not be basic such as pyrimidine, pyridine, or imidazole since substitution of a basic group on the benzene ring of the alkaloid (I) caused loss of activity (2). One of the few heterocycles satisfying these conditions is thiophene. This communication describes the syntheses of 6,7-and 7,8-thia-4-quinazolones, two of the three possible thienopyrimidones, and conversion of the 6,7-thia-4-quinazolone to the alkaloid isoster (IX).The most general method of synthesizing 4-quinazolone and its derivatives is by the Niementowski reaction (3), involving fusion of the proper anthranilic acid with formamide (3). This would require the preparation of the proper o-aminothenoic acid, none of which are described in the literature. However, Cheney and Piening (4) have described a synthesis of 2-alkyl-3-amino-4-thenoic esters by a general method. The parent amino ester (IV) has now been synthesized by their procedure.3-Carbomethoxy-4-ketothiophane (II) (5) was converted to the oxime (III) and rearranged with hydrogen chloride (4) to the desired 3-amino-4-carbomethoxythiophene hydrochloride (IV). Saponification gave impure 3-amino-4-thenoic acid (VII) in low yield which was not readily purified due to its apparent instability. It seemed desirable at this point to convert the amino ester base (IV) directly to the thiaquinazolone (V). A test reaction with methyl anthranilate and formamide at 175°g ave only 35% of 4-quinazolone after four hours. However, addition of ammonium formate to the fusion mixture raised the yield of 4-quinazolone to 71%. Application of these conditions to IV free base gave only traces of the desired V along with large amounts of tar. Since aminothiophene bases are notoriously unstable, the molecule was stabilized by formylation to VI.

Synthesis of Thienopyrimidine Derivatives Starting From Thiophene Ring and Pyrimidine Ring

“…Aryl acetonitrile (16) reacted with ethyl formate in the presence of sodium methoxide to afford the corresponding sodium 2-cyano-2-arylethenolate (17) which was reacted with p-toluenesulfonyl chloride in DMF affording 2-aryl-3-(p-toluenesulfonato) acylonitriles (18).…”

“…The latter compound underwent acidic hydrolysis to give 2-formyl-2-arylacylonitriles (19) which reacted with ptoluenesulfonyl chloride in the presence of excess 4-methylmorpholine in dichloromethane to give 2-cyano-2-arylylvinyl toluenesulfonate (18). The obtained compound, when treated with methyl thioglycolate, gave the thiophene (20).…”

“…Methyl 4-amino thiophene-3-carboxylate (4) was converted into thieno [3,4-d]pyrimidin-4(3H)-one (3) by reacting with formamide at 175 0 C in the presence of ammonium formate in 71 % yield. 4 Application of these conditions in the case of the free base, compound (3) gave only traces of the desired (4) along with large amounts of tar. Since aminothiophene bases are notoriously unstable, the molecule was stabilized by formylation with formic acid in the presence of sodium acetate to give (5) in 59 % yield, which when treated with ammonium formate and formamide at 145 0 C gave a 50 % yield of the thienopyrimidine (4 On the other hand, methyl 4-formamidothiophene-3-carboxylate (5) was converted into the corresponding 4-formamidothiophene-3-carboxamide (6) using methanolic ammonia solution which easily gave thienopyrimidine (4) with methanolic sodium methoxide in 93 % yield (Scheme 1).…”

Synthesis of substituted 4-oxo-3,4-dihydro-thieno[3,4-d]pyrimidines and comparison of their properties with those of positionally isomeric thienopyrimidinones and benzo isosteres

“…In connection with the known instability of the amino ester starting material [12], the latter was obtained in situ from its hydrochloride 2 by adding to the reaction mixture the calculated amount of Et 3 N. The proposed new method allowed the yield of product 3A to increase to 90%. For the others the conditions for obtaining derivatives 3-6 of series A were analogous to those we described previously for the synthesis of compounds 3-6 of series B-D [1, 10,11].…”

Synthesis of Cyclobuta[b]quinoxalines

“…The a-hydrazino-0-mesylates formed with inversion as primary products contain trans-hydrogen atoms and U-mesylate groups, so that elimination follows as a secondary reaction, leading to alkenylhydrazines which can be isolated, after acetylation, as rearranged deoxy-dose acetylhydrazones. Reaction of (10) and (11) in this way yields a mixture of (12) and (14), wherein (12) preponderates since nucleophilic attack on C-2 is apparently easier than on C-3. Transhydrazonization of (12) and (14) with benzaldehyde in weakly acidified dioxane solution makes accessible the 3-deoxy-2-ulose derivative (13) (53.7 % yield, m.p.…”