Amino acids, synthesis from thiophenes

Raney nickel desulfurization has been applied especially to the synthesis of different kinds of amino acids. a-Amino acids have been prepared by the Strecker synthesis of substituted thiophenealdehydes, followed by desulfurization of the thiophene a-amino acids. a-Amino-n-enantic acid, a-amino-n-caprylic acid, and norleucin have been obtained in about 50% yield from the appropriate thiophene aldehydes. From the desulfurization of thiophene -amino acids, obtained from the reaction of thiophenealdehydes with malonic acid in ammonia, aliphatic j8-amino acids, isolated as acetates, have been obtained in high yields. The desulfurization of 3-nitrothiophenes, such as (232), in ammonia leads to y-substituted amino acids (233). ... 

A simple two-step synthesis of 4-arylthieno[3,2-c]pyridine-6-carboxylic acids has recently been presented by Eweiss (Scheme 74) (B-81MI31703). The condensation of thiophene-2-carbaldehyde with an N -aroylated a-amino acid yields a thienylidene azlactone (281) which on treatment with AICI3 is converted to a thieno[3,2-c]pyridine (283). A nitrilium ion (282) resulting from a vinyl-oxygen fission is probably involved as an intermediate. Sandberg s method already mentioned in the previous section has also been applied to the synthesis of thieno[3,2-c]pyridines (Scheme 75). 

Pyrimidine-fused Systems.—The Gewald synthesis of thiophen analogues of anthranilic acid has opened the synthetic route to pyrimidine-fused thiophens. The interest in this field is mainly due to the potential pharmacological properties of these systems. Condensation of (603) with forma-mide at 200 °C yields (604). Similarly, (605) was prepared from 3-amino-2-methoxycarbonylthiophen or from its formamide derivative. Derivatives of (604) were also obtained by cyclization of the 2-amino-3-carboxamide... 

The usefulness of the Gewald reaction for the synthesis of 2-amino-3-carbonyl-substituted thiophens has been amply demonstrated during the past two years (c/. ref. 6fl). These thiophens are very useful starting materials for complex condensed systems of pharmacological interest. I.r. and n.m.r. studies showed some anomalies which were interpreted in terms of electron delocalization in the enaminocarbonyl structure. From cyanoacetamide, benzylacetone, and sulphur, the thiophen (9) was obtained. 3-Aryl-substituted derivatives such as (10) were obtained from the appropriate aryl methyl ketone, ethyl cyanoacetate, and sulphur. It has been claimed that (11) is obtained from the reaction of acetoacetic acid anilide with malononitrile and sulphur. This hardly seems to be correct, as (12) is the product expected in the Gewald reaction. It was found that 2-amino-3-ethoxycarbonyl-thiophens (13) react with sodium ethoxide in ethanol, pre-... 

When 2 -methoxy-2-biphenylamine is diazotized in fluoroboric acid, an 85% yield of solid 2 -methoxy-2-biphenylyldiazonium tetrafluoroborate is produced. On heating in dry benzene, this salt loses nitrogen and provides 0-methyldibenzofuranium tetrafluoroborate as an unstable solid. The latter salt, on account of the low basicity of dibenzofuran, reacts with a range of nucleophiles that undergo methylation with the release of dibenzofuran. Pyridine and pentachloropyridine are N-methylated, benzo[fc]thiophene is S-methylated, and tetrahydrofuran and phenetole are 0-methylated. ° Thus it is no surprise that diazotization of 2 -methoxy-2-biphenylamine, followed by boiling of the diazonium salt in acidic solution, provides dibenzofuran in 90% yield.The scope of this method of dibenzofuran synthesis (Scheme 18) has been little explored probably because of the difficulty of preparing the requisite biphenyls, which is usually accomplished by a crossed Ullmann reaction. A similar synthesis of xanthones from 2-amino-2 -methoxybenzophenones is known. ° ... 

A new promising method for the synthesis of mixed biaryls consists in the reaction of the ethanolamine esters of diarylboronic acids with NBS in dichloro-methane/aqueous buffer at pH 9. In this way, 2- and 3-phenylthiophen, 2,2 -bi-thienyl, and 2-(2-thienyl)furan were obtained. The nitration of 2,3 -bithienyl has been studied. 2-Nitro-2 -amino-3,3 -bithienyl and 3-nitro-3 -amino-2,2 -bithienyl have been found to be stable. Carbonyl derivatives of 2-aryl-thiophens have been prepared, and reactivity constants for 2-aryl-thiophens determined. Some 2,5-bis(4 -n-alkyldiphenyl-4"-yl)thiophens, which are liquid crystals, have been prepared from the corresponding 1,4-diketones and P4S10. Various naphthyl-thiophens have been synthesized in order to study their anti-inflammatory and antibacterial properties. ... 

Reactions Leading to Destruction of the Thiophen Ring.—Raney-nickel desulphurization has been used for the synthesis of aliphatic compounds and for structure determination. From (158) and (159) aliphatic y-diketones and y-keto-carboxylic acids have been obtained. " c-Caprolactams and e-enantholactams such as (199) have been prepared by desulphurization and transformed to amino-... 

The reaction between 2-nitrothiophen and secondary aliphatic amines leads most probably to the ring-opened product (213). Raney-Nickel desulphurization continues to play an important role in the structure determination of thiophen derivatives, and for the synthesis of macrocyc-lic compounds, such as a-alkylcycloalkanones, amino-lactams of aliphatic diaminocarboxylic acids, and of dethiobiotin. The nickel boride catalyst (NiBo), prepared from nickel(ii) chloride and sodium borohydride in methanol, gives olefins in 50—55% yield. From (214) a mixture of methyl... 

Contrary to benzo[b]thiophen, benzo[b]selenophen is acylated at position 2. 2-Bromobenzo[b]selenophen, prepared from the 2-lithium derivative and bromine, is acylated at position 3, and from this derivative the 3-isomers could be synthesized. A large number of 2- and 3-aroylbenzo[b]seleno-phens were synthesized, either by Friedel-Crafts reaction of benzo-[bjselenophencarboxylic acid chlorides and benzenes or from benzol bjselenophens and benzoic acid chlorides. Also the reaction between Grignard reagents and nitriles was used for the synthesis of aroylbenzo[b]selenophens. 4,S-Diaminobenzo[b]selenophen has been synthesized via nitration of 5-aminobenzo[b]selenophen or via the reaction of the diazonium salt derived from the S-amino-derivative with p-sulphanilic acid. From the diamino-derivative, several fused benzo[b]selenophens, e.g. (525), (526), and (527), were prepared. Reaction of the phenyl-... 

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