Reduction of carboxamides

In 2009, Beller (Scheme 45) [147] and Nagashima (Scheme 46) [148] independently reported an iron-catalyzed hydrosilane reduction of carboxamides to amines. Although inexpensive PMHS and TMDS as an H-Si source are usable, the yield of product considerably decreased when hydrosilane containing only one H-Si moiety or iron sources such as Fe(acac)2 and FeX2 (X = F, Cl) was used. In both thermal and photoassisted conditions, almost the same reactivities were observed upon using a combination of Fe catalyst with TMDS (Scheme 46). 

Reduction of the nitro compounds (193 R = R = H, or R = Me, R = OH) with lithium aluminum hydride affords the corresponding saturated amine.556 Similar reduction of carboxamides with the general formula (194) affords the corresponding amines143,8n 313, 568,569. jn t,]ie Case of 194 (R = H, R = 6-OMe), reduction with borane tetrahydrofuranate is more satisfactory.312... 

The electrochemical reduction of carboxamides (R CONR R ) has been used to prepare aldehydes (R CHO), amines (R CH2NR R ) or primary alcohols (R CH20H) depending on the structure of the substrate and reaction conditions. Aldehyde formation may be favored by increasing the lifetime of the... 

RCONH2 — RCHO.1 Reduction of carboxamides to aldehydes with LiAlH4 is useful only with N,N-disubstitutcd carboxamides. This new hydride (1) can reduce primary carboxamides to aldehydes al 25° in 12 hours in yields of 50-90%. 

Reduction of carboxamides to amines. Primary and secondary amides are reduced by this complex hydride to amines in about 40-90y yield. Tertiary amides can be reduced by sodium trifluoroaeetoxyborohydride N-acetylindoline is converted into N-ethylindoIine in 64% yield. ... 

The heptanuclear iron carbonyl cluster [Fe3(CO)u(/u-H)]2-Fe(DMF)4 (178) acted as an efficient catalyst in the reduction of carboxamides by l,2-bis(dimethylsilyl)benzene in toluene to the corresponding amines in high yields. Several tertiary and secondary amides including a sterically crowded amide were also reduced smoothly A review of the development of optically active cobalt complex catalysts for enan-tioselective synthetic reactions has addressed the applications of ketoiminatocobalt(II) complexes such as (5)-MPAC (179) and (5)-AMAC (180), transition-state models for borohydride reduction, halogen-free reduction by cobalt-carbene complexes. 

Aldehydes are also obtained in variable yields from the lithium-methylamine reduction of carboxamides/ Cinnamaldehyde or 3-phenylpropanal can be prepared by the Raney nickel-catalysed hydrogenation of cinnamonitrile, though the generality of the method is not reported/ ... 

Other methods for the preparation of cyclohexanecarboxaldehyde include the catalytic hydrogenation of 3-cyclohexene-1-carboxaldehyde, available from the Diels-Alder reaction of butadiene and acrolein, the reduction of cyclohexanecarbonyl chloride by lithium tri-tcrt-butoxy-aluminum hydride,the reduction of iV,A -dimethylcyclohexane-carboxamide with lithium diethoxyaluminum hydride, and the oxidation of the methane-sulfonate of cyclohexylmethanol with dimethyl sulfoxide. The hydrolysis, with simultaneous decarboxylation and rearrangement, of glycidic esters derived from cyclohexanone gives cyclohexanecarboxaldehyde. 

The complex thioamide lolrestat (8) is an inhibitor of aldose reductase. This enzyme catalyzes the reduction of glucose to sorbitol. The enzyme is not very active, but in diabetic individuals where blood glucose levels can. spike to quite high levels in tissues where insulin is not required for glucose uptake (nerve, kidney, retina and lens) sorbitol is formed by the action of aldose reductase and contributes to diabetic complications very prominent among which are eye problems (diabetic retinopathy). Tolrestat is intended for oral administration to prevent this. One of its syntheses proceeds by conversion of 6-methoxy-5-(trifluoroniethyl)naphthalene-l-carboxyl-ic acid (6) to its acid chloride followed by carboxamide formation (7) with methyl N-methyl sarcosinate. Reaction of amide 7 with phosphorous pentasulfide produces the methyl ester thioamide which, on treatment with KOH, hydrolyzes to tolrestat (8) 2[. 

Reduction of 3-benzyl-8-chloro-4-oxo-4//-pyrido[l,2- ]pyrimidine-2-carboxylate <2004W004/064741> and 2-methyl-4-oxo-4//-pyrido[l,2-tf]pyrimidine-3-carboxylate <2003T4123> with DIBAL-H afforded 2- and 3-formyl derivatives, respectively. Reduction of /V-(4-fluorobenzyl)-3-hydroxy-8-[methoxy(methyl)amino]-4-oxo-6,7,8,9-tetra-hydro-4//-pyrido[l,2- ]pyrimidine-2-carboxamide with Zn-dust in aqueous AcOH afforded the 8-methylamino derivative, which was acylated with AcOH in the presence of Hiinig s base, HOBt, and l-(3-dimethylaminopro-pyl)-3-ethylcarbodiimide-HCl <2004W004/058756>. 3-(Perhydropyrido[l,2- ]pyrimidin-2-yl)propylamine was obtained by catalytic hydrogenation of 2-(perhydropyrido[l,2- ]pyrimidin-2-yl)propionitrile over a Pt02 catalyst <2003FRP1275647>. 

An interesting example of asymmetric induction has been used for the synthesis of (—)-l from L-tryptophan. Pictet-Spengler cyclization of the corresponding amide (127) with 5-chloropentanal afforded (—)-128 as the sole product. Removal of the unwanted carboxamide function was achieved in good yield by sodium borohydride reduction of die corresponding a-amino nitrile (—)-129, resulting in (—)-l (98). 

The catalysed two-phase alkylation of carboxamides has the advantages of speed and simplicity over the traditional procedures and provides a valuable route to secondary and tertiary amines by hydrolysis or reduction of the amides, respectively. The procedure appears to be limited, however, to reactions with primary haloalkanes and dialkyl sulphates, as secondary haloalkanes are totally unreactive [6, 7]. The use of iodoalkanes should be avoided, on account of the inhibiting effect of the released iodide ion on the catalyst. Also, the A-alkylation reaction is generally susceptible to steric effects, as seen by the low yields in the A -cthylation of (V-/-butylacetamide and of A-ethylpivalamide [6]. However, the low steric demand of the formyl group permits A,A-dialkylation and it is possible to obtain, after hydrolysis in 60% ethanolic sulphuric acid, the secondary amines having one (or, in some cases, two) bulky substituent(s) [7]. 

Reduction of 3-aryl-4-oxo-4//-pyrido[2,l-fl]phthalazine-l-carboxamides with sodium cyanoborohydride in acidified methanol or lithium borohy-dride in tetrahydrofuran afforded 6,7-dihydro derivatives 47 (R = H) (88EUP294599). 

Reductive alkylation of carboxamides 262 with sodium borohydride in the presence of an oxo compound furnished the carboxamides 265. In this process for the cis or trans isomers of 262 with acetone or cyclohexanone, the quinazolinone intermediates 266 [R = R = Me R, R = (CH2)s] of the reductive alkylation were also isolated and characterized [87-ACSA(B)228 91AX(C)2632]. 

Halotriazoles 249 (X = Cl, Br, I) were obtained by Sandmeyer reactions of 4-diazotriazoles [66JMC733 83DIS(B)(43)2557]. Reduction of 4-diazo-l,2,3-triazole-5-carboxamide with semicarbazide led to a mixture of the corresponding azido- and amino-triazoles (73JHC839). 

USP482361). Compound 184 is converted into the pyrazolo[4,3- /]-pyrimidine derivative 185 by formamide. Amines convert 184 into carboxamide 186, which affords 187 upon treatment with formamide (78MI1). Reduction of 181 in the presence of formic acid gives the pyrazole derivative 183, which when treated with DMF affords the pyrazolo[4,3-d]pyrimidine derivative 182 (81USP4822361 83FES369). 

The Ni(II) complex of the hexaaza macrocyclic ligand 1 is reported to show a high activity for the electrocatalytic reduction of C02 to CO when a rotating copper disc electrode is used (85). In addition, water-soluble Niu-azacyclam complexes, 3a-3g, where R = carboxamide or sulfonamide, either aliphatic or aromatic, are found to be active in the electrocatalytic reduction of C02 at a mercury cathode. The efficiency is comparable to that of [Ni(cyclam)]2+ (14). 

Chemical reduction of pyrroles by hydriodic acid and phosphorus leads to the formation of pyrrolidines (B-77MI30507) except when the 2-position is substituted by electron-withdrawing groups, which reduce the ease of protonation at the 3-position and, consequently, promote the formation of 2-substituted A3-pyrrolines (cf. Scheme 54) (B-74MI30500, 79MI30504). The analogous reduction of indole-2-carboxamide yields indoline-2-carboxamide (72HC(25-l)l). 

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