Aminomethylenemalonic acid

N,)V -Bis(cyclohexylaminocarbonyl)formamidine (310) was reacted with diethyl malonate in ethanol at 70°C for 60 hr to give N-(cyclohexylami-nocarbonyl)aminomethylenemalonate (311, R = Et) in 24% yield (53-JA671). The similar reaction of malonic acid at room temperature for 3-4 min afforded (cyclohexylaminocarbonyl)aminomethylenemalonic acid (311, R = H) in 65% yield. When bis(cyclohexylaminocarbonyl)for-mamidine (310) was reacted with 1 1 molar mixture of diethyl malonate and malonic acid in ethanol at 70°C for 5 min, only malonic acid (311, R = H) was obtained, in 76% yield. 

Dihydroxy-1,8-naphthyridine was prepared in 50% yield by the cy-clization of N-(6-hydroxy-2-pyridyl)aminomethylenemalonic acid in boiling diphenyl ether for 9 hr (84AJC1065). 

A mixture of o-hydroxyacetophenone, dimethylformamide dimethyl acetal, and abs. xylene heated to 120 bath temp, with distillation of methanol, after ca. 2 hrs. the temp, raised to 150-160 for 0.5 hr., then allowed to stand overnight o-hydroxy-co-dimethylaminomethyleneacetophenone (Y 80%) heated 75 min. at 100 bath temp, with aq. H2SO4 chromone (Y 71%). B. Fohlisch, B. 104, 348 (1971) aminomethylenemalonic acid esters (cf. Synth. Meth. 25, 759) by C-dimethylaminomethylenation s. N. D. Harris, Synthesis 1971, 220. 

Tetrahydroisoquinoline-l-acetic acids from aminomethylenemalonic acid esters s. 12, 540... 

Tetrahydroisoquinoline-l-acetic acids via aminomethylenemalonic acid esters... 

Tile same methodology as mentioned for the preparation of (9) was applied for the synthesis of 8-nitro-l,6-naphthyridines. Heating diethyl N- 3-nitropyridin-4-yl)aminomethylenemalonate (12) in diphenyl ether yields ethyl 8-nitro-l,6-naphthyridin-4(lH)-one 3-carboxylate (13) (63JCS4237, 30%) and acid treatment of 4-( y, y-diethoxypropylamino)-5-nitro-2-(/3,/3 -trifluoroethoxy)-pyridine (14) gives in a similar way 8-nitro-5-(/3, /3-triflu-oroethoxy)-l,2-dihydro-l,6-naphthyridine (15, 76%). Subsequent oxidation with chloranil, acid hydrolysis, and methylation with methyl iodide gives 8-nitro-6-methyl-l,6-naphthyridin-5(6H)-one (16,63%) (81JHC941). 

Among the aminomethylenemalonates, the A-aryl and A-hetaryl derivatives and their cyclization products are of great importance in organic chemistry, as some of them are key intermediates in the synthesis of different 4-aminoquinoline antimalarials (Scheme 1), in the preparation of anticoccidial 6,7-dialkoxy-4-hydroxyquinoline-3-carboxylates (Scheme 2), and in the production of antibacterial agents of the nalidixic acid type (Scheme 3). 

Aminosalicylamide reacted readily with EMME in boiling benzene for 4 hr to give aminomethylenemalonate in 75% yield, but the reactions of 4-aminosalicylamide and 4-aminosalicylic acid with EMME in boiling benzene or xylene for 4-24 hr were unsuccessful (75IJC1275). However, if the sodium salt of 4-aminosalicylic acid was reacted under similar conditions, the required aminomethylenemalonate (46) was obtained. 

Amino-(2-methylthio)thiazole-5-carboxylic acid was reacted with EMME in boiling toluene for 2 hr to give N-(2-methylthiothiazol-4-yl)aminomethylenemalonate in 62% yield (84JHC1361) (Scheme 14). 

The reaction of 3-aminopyrazole and EMME at 100°C for 30 min gave 10% of pyrazolo[l,5-a]pyrimidinecarboxylate (64) and 25% of 3-pyrazolylaminomethylenemalonate (70CB3252). When the reaction was carried out in boiling acetic acid for 3 hr, pyrazolo[l,5-n]pyrimidinecar-boxylate (64) was isolated in 60% yield (62CPB620 70CB3252). Heating of the reaction mixture of 5-substituted 2-amino-1,3,4-oxadiazoles and EMME at 130-140°C for 2-3 hr afforded N-(5-substituted 1,3,4-oxadiazol-2-yl)aminomethylenemalonates (65) in 40-92% yields [88IJC (B)293]. 

Amino-6-phenyl-7-hydroxy-l,8-naphthyridine reacted with an excess of diethyl alkoxymethylenemalonates in the presence of concentrated hydrochloric acid or in acetic acid to afford JV-(l,8-naphthyridin-2-yl)aminomethylenemalonate (78) in 44-63% yields (69G677). 

The reaction of 4,6-diamino-2-methylthiopyrimidine and EMME in boiling acetic acid overnight gave 7-oxopyridof2,3-[Pg.67]

N-Ethyl-yV-(6-methyl-2-pyridyl)aminomethylenemalonate (265, R = Me, R1 = R2 = Et) was prepared in 16-66% yields in the reaction of 2-(ethylamino)-6-methylpyridine, diethyl malonate, and ethyl orthoformate in the presence of acidic catalysts (AcOH, EtCOOH, Dianion WK-11) at 150-160°C for 2-3.5 hr [74JAP(K) 109383],... 

N-Substituted aminomethylenemalonates (275) were obtained in 5-56% yields in the reactions of diethyl aminomethylenemalonate (13) and ketones or ketals in the presence of phosphorus pentoxide in THF at room temperature for 1-5 days (method A) or by heating in the presence of a small amount of p-toluenesulfonic acid in o-xylene for 15-22 hr (method... 

Other variations of condensation agents (ethanolic hydrochloric acid, ZnCI2 in THF, Triton B in dioxane, using AIC1, TiCl4, or molecular sieves) to promote the reaction of cyclopentanone and diethyl aminomethylenemalonate (13) were unsuccessful (75JHC1245). 

Cycloalkanones were reacted with diethyl aminomethylenemalonate (13) in boiling toluene or xylene in the presence of dichloroacetic acid or p-toluenesulfonic acid monohydrate under nitrogen or argon for 2.5-7 days, and under a water separator, to give N-( 1 -cycloalkenyDaminomethy-lenemalonates (275, R = R1 = —(CH,)n—, n = 6-10) (88EUP270494). 

Diethyl aminomethylenemalonate (13) was reacted with tetrahydrothio-pyran-4-one in boiling toluene for 48 hr in the presence of p-toluenesulfonic acid to give A-(thiopyran-4-yl)aminomethylenemalonate (278, X = S) (86EUP168350 87USP4647566). 

Oxotetrahydrothiophene was condensed with diethyl aminomethylenemalonate in boiling toluene for 60 hr in the presence of p-toluenesul-fonic acid monohydrate under a Dean-Stark water collector to give a 1 1 mixture of N- 2,5- and 4,5-dihydro-3-thienyl)aminomethylenemalonates (279 and 280) (87USP4647566). 

The reaction of diethyl aminomethylenemalonate (13) and N,N-dimethylformamide diethyl acetal in boiling acetic acid gave diethyl N-(dimethylaminomethylene)aminomethylenemalonate (285) in 64% yield (87KFZ1249). 

V-Ethyl-/V-(3,4-methylenedioxy)aminomethylenemalonate (286) was prepared in 64% yield via the reaction of 7V-(dimethylaminomethylene)ami-nomethylenemalonate (285) and N-ethyl-3,4-methylenedioxyaniline in boiling acetic acid for 5-10 min (87KFZI249). 

N-(6-Methyl-2-pyridyl)aminomethylenemalonate (306) was also obtained in 95% yield in the reaction of N./V-dimethyl-N - -methyl -pyridyDformamidine and diethyl malonate at 100-130°C for 12-50 hr (76MIP2) or in 47-53% yields in acetic acid at 130-150°C for 45-60 min (84URP1097620). 

Amino-5-(pyridyl)thiophene-2-carboxylic acids (359) were reacted with diethyl methylenemalonate in DMF at 150°C for 2 hr to give N-[5-(pyridyl)thien-3-yl]aminomethylenemalonates (360) 61-62% yields [82-JAP(K) 116077],... 

Isopropylidene methoxymethylenemalonate (420) was reacted with amino esters, amino acids, and dipeptides at 95-100°C to give rise to the corresponding isopropylidene aminomethylenemalonates (424) in 54-85% yields (85MI3 86YZ154). 

Isopropylidene methoxymethylenemalonate (420), prepared from Mel-drum s acid (421) and methyl orthoformate, was reacted with urea and thiourea under reflux for 2 hr to give aminomethylenemalonates (439) in 82% and 72% yields, respectively (84SC961). 

Because of the higher CH acidity (by 7-8 pKa units) of alkylidene malonates (441), as compared with that of dialkyl malonates (87JA809), one-pot syntheses of alkylidene aminomethylenemalonates (442) could be carried out readily with a wide variety of primary and secondary aliphatic and cycloaliphatic amines, anilines, naphthylamines and heterocyclic amines, trialkyl orthoformate, and alkylidene malonates (83MI1 86MI9). It was proposed that the higher CH acidity of alkylidene malonates was a consequence of the electrostatic (dipole-dipole) repulsion effects... 

Anilines, bis(2-amino-4-chlorophenyl)disulfide, naphthylamine, 2- and 3-aminopyridines, 2-aminopyrimidines, 2-, 3-, 5-, 6-, 7-, and 8-aminoquino-lines, 6-aminocoumarin, and 2-aminopyrazine were reacted in the absence or presence of a solvent (ethanol, toluene) with ethyl orthoformate and isopropylidene or 4-heptylidene malonates to give alkylidene (het)aryl-aminomethylenemalonates (442, R = R2 = Me, Pr) in 32-100% yields [69BRP1147759 75USP3907798 88JAP(K)239269]. p-Toluenesulfonic acid monohydrate was sometimes applied as catayst. 

Alkylidene 5-acylmalonates were reacted with O-substituted hydroxyl-amine to give aminomethylenemalonates (451) [82JAP(K)62274], However, when 7/3-amino-ceph-3-em-4-carboxylic acids (452) were first reacted with A,0-bis(trimethyIsilyl)acetamide in THF and then with isopropylidene 5-acylmalonate (449, R1 = R2 = Me), instead of the corresponding aminomethylenemalonate, 7/3-acylamido-ceph-3-em-4-carboxylic acids (453) were obtained (83EUP54970). 

Meldrum s acid (421) was reacted with A-acylimidates in boiling chloroform in the presence of a few drops of triethylamine for 18 hr to give isopropylidene acylaminomethylenemalonates (455) in 67-86% yields (86CPB1980). Acylaminomethylenemalonates (455) could not be prepared from the corresponding isopropylidene aminomethylenemalonate by acylation. 

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