Malonic aminomethylation

Some functionalized thiophenes have been investigated in order to assess the scope of ylide-derived chemistry. As already mentioned, 2-(hydroxymethyl)thiophene still gives the S-ylide upon Rh2(OAe)4-catalyzed reaction with dimethyl diazomalonate 146 but O/H insertion instead of ylide formation seems to have been observed by other workers (Footnote 4 in Ref. 2S4)). From the room temperature reaction of 2-(aminomethyl)thiophene and dimethyl diazomalonate, however, salt 271 was isolated quite unexpectedly 254). Rh2(OAc)4, perhaps deactivated by the substrate, is useless in terms of the anticipated earbenoid reactions. Formation of a diazo-malonic ester amide and amine-catalyzed cyclization to a 5-hydroxytriazole seem to take place instead. 

Snyder and Jones obtained ethyl N-(3-chlorophenyl)aminomethyl-enemalonamate (244) in 77% yield when 2 mol of 3-chloroaniline was reacted with 1 mol of diethyl malonate and 1 mol of ethyl orthoformate at 160-165°C. The ethanol formed during the reaction was distilled off (46JA1253). 

Egri et al. investigated the one-pot synthesis of N-(3-chlorophenyl)-aminomethylenemalonate (250), starting from equimolar amounts of 3-chloroaniline, diethyl malonate, and ethyl formimidate hydrochloride or ethyl orthoformate (73ACH217). The reaction involving ethyl formimidate hydrochloride was conducted in the presence of triethylamine at 120-130°C for 2 hr and then at 140°C for 80 hr. The ethanol formed in the reaction was continuously distilled off. N-(3-Chlorophenyl)aminomethyl-enemalonate (250) was obtained in 98-99% yields. 

The first example of absolute chiral recognition of a prochiral centre by a small molecule (cf. enzyme reactions) is the reaction of A( — )436-oc[(2S,9S)-2,9-diamino-4,7-diazadecanecobalt(m)]dichloride with a,a-aminomethylmalonate, which produces A( — )436-P2[(2S,9S)-2,9-diamino-4,7-diazadecanecobalt(in)-(R)-aminomethyl-malonate]+,401 and a crystal structure determination of the product has been performed.402... 

Heptaplatin (cis-malonate[(4i ,5i )-4,5-bis(aminomethyl)-2-isopropyl-l,3-dioxolane]platinum(II), SKT2053R, Sunpla) has high antitumor activity against various cancer cell lines, including cisplatin-resistant tumor cells. PreUminary results suggested that it is less nephrotoxic than cisplatin. However, a comparative trial showed that intravenous heptaplatin 400 mg/m was more nephrotoxic than intravenous cisplatin 60 mg/m in terms of uremia and proteinuria, which occurred despite the use of hyperosmolar mannitol and appropriate concomitant hydration (fluid intake at least 3500 ml/day) (34,35). 

Glusker, J. P., Carrell, H. L., Job, R., and Bruice, T. C. Mechanism for chiral recognition of a prochiral center, and for amino acid complexation to a Co(III) tetramine. The crystal structure, absolute configuration and circular dichro-ism of A(-)436-/ -[ (25 95)-2,9-diamino-4,7-diazadecanecobalt(III)aminomethyl-malonate] perchlorate monohydrate. J. Amer. Chem. Soc. 96, 5741-5751 (1974). 

In the case of tribenzyl and trimethyl amine, a-substitution products could be obtained using diethyl malonate or diethylphosphonate as nucleophiles, if 2,4,6-collidine was used as base in an acetonitrile electrolyte [20]. In this way, dialkyl aminomethyl phosphonates and malonates could be obtained in good yield. 

An alternative preparation of a nitrile is illustrated by the reaction of the half-ester of 2,2-diethyl malonate 1.51) ivith SOCI2 and then NH3 to give the amide. Subsequent heating with phosphorus pentoxide led to dehydration and gave nitrile 1.52 Catalytic hydrogenation reduced the nitrile to an aminomethyl group, and acid hydrolysis gave 2,2-diethyl-3-aminopropanoic acid 1.53). 2-Ethyl-2-cyclohexyl-3-aminopropanoic acid and 2-ethyl-2-benzyl-3-aminopropanoic acid were also prepared by this method.30... 

C12H2 9CIC0N5O9, 2,9-Diamino-4,7-diazadecanecobalt(III) aminomethyl-malonate perchlorate monohydrate, 40B, 873 C12H32CIuNu02sRh2 2 H2O, Diaquo-tetrakis-M"P-alaninatoniumdirhodi-um(II) perchlorate dihydrate, 45B, 1143 Cl2H32C0N11O13, (+)-Dinitrobis-(L-argininato)cobalt(III) nitrate di-hydrate, 38B, 892... 

Finally, the author investigated the synthesis of 2-(aminomethyl)indene-l,l-dicarboxylate 17 using this domino Mannich-type reaction/cyclization strategy (Table 9). Disappointingly, the reaction of malonate derivative 16 with (HCHO) 2a and (i-Pr)2NH 3a in dioxane in the presence of CuBr (5 mol.%) did not afford... 

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