Formic reduction

Mercuric chloride test. Add mercuric chloride solution to formic acid or a solution of formate and w arm. A white precipitate of mercurous chloride, insoluble in dil. HCl, is produced. Sometimes the reduction proceeds as far as metallic mercury, which appears as a grey precipitate. 

The desired pyridylamine was obtained in 69 % overall yield by monomethylation of 2-(aminomethyl)pyridine following a literature procedure (Scheme 4.14). First amine 4.48 was converted into formamide 4.49, through reaction with the in situ prepared mixed anhydride of acetic acid and formic acid. Reduction of 4.49 with borane dimethyl sulfide complex produced diamine 4.50. This compound could be used successfully in the Mannich reaction with 4.39, affording crude 4.51 in 92 % yield (Scheme 4.15). Analogous to 4.44, 4.51 also coordinates to copper(II) in water, as indicated by a shift of the UV-absorption maximum from 296 nm to 308 nm. 

The conventional electrochemical reduction of carbon dioxide tends to give formic acid as the major product, which can be obtained with a 90% current efficiency using, for example, indium, tin, or mercury cathodes. Being able to convert CO2 initially to formates or formaldehyde is in itself significant. In our direct oxidation liquid feed fuel cell, varied oxygenates such as formaldehyde, formic acid and methyl formate, dimethoxymethane, trimethoxymethane, trioxane, and dimethyl carbonate are all useful fuels. At the same time, they can also be readily reduced further to methyl alcohol by varied chemical or enzymatic processes. 

Formic acid behaves differently. The expected octadienyl formate is not formed. The reaction of butadiene carried out in formic acid and triethylamine affords 1,7-octadiene (41) as the major product and 1,6-octadiene as a minor product[41-43], Formic acid is a hydride source. It is known that the Pd hydride formed from palladium formate attacks the substituted side of tt-allylpalladium to form the terminal alkene[44] (see Section 2.8). The reductive dimerization of isoprene in formic acid in the presence of Et3N using tri(i)-tolyl)phosphine at room temperature afforded a mixture of dimers in 87% yield, which contained 71% of the head-to-tail dimers 42a and 42b. The mixture was treated with concentrated HCl to give an easily separable chloro derivative 43. By this means, a- and d-citronellol (44 and 45) were pre-pared[45]. 

Formic acid is a good reducing agent in the presence of Pd on carbon as a catalyst. Aromatic nitro compounds are reduced to aniline with formic acid[100]. Selective reduction of one nitro group in 2,4-dinitrotoluene (112) with triethylammonium formate is possible[101]. o-Nitroacetophenone (113) is first reduced to o-aminoacetophenone, then to o-ethylaniline when an excess of formate is used[102]. Ammonium and potassium formate are also used for the reduction of aliphatic and aromatic nitro compounds. Pd on carbon is a good catalyst[103,104]. NaBH4 is also used for the Pd-catalyzed reduction of nitro compounds 105]. However, the ,/)-unsaturated nitroalkene 114 is partially reduced to the oxime 115 with ammonium formate[106]... 

Glycohc acid also undergoes reduction or hydrogenation with certain metals to form acetic acid, and oxidation by hydrogen peroxide ia the presence of ferrous salts to form glyoxylic acid [298-12A], HCOCOOH, and ia the presence of ferric salts ia neutral solution to form oxaHc acid, HOOCCOOH formic acid, HCOOH and Hberate CO2 and H2O. These reduction and oxidation reactions are not commercially significant. 

The Leuckart reaction uses formic acid as reducing agent. Reductive alkylation using formaldehyde, hydrogen, and catalyst, usually nickel, is used commercially to prepare methylated amines. These tertiary amines are used to prepare quaternary ammonium salts. 

Chlorine dioxide produced from the methanol reductant processes contains carbon dioxide and small amounts of formic acid. For this reason, sulfur dioxide and chloride-based chlorine dioxide processes are stih used for sodium chlorite production. This problem has been addressed by recycling a portion of the vapor from methanol-based generators so that formic acid further reacts to carbon dioxide ... 

Improvements to the methanol reductant processes may be found in the patent Hterature. These include methods of operation to reduce acidity in the crystallisation 2one of the generator to promote crystallisation of sodium sulfate and to reduce sulfuric acid consumption (48). Other improvements sought are the elimination of formic acid and chlorine impurities from the chlorine dioxide, as weU as methods of recovering acid and sodium hydroxide, or acid and neutral sodium sulfate from the soHd sodium sesquisulfate salt waste stream (48—52). 

ESCHWEILER CLARKE Amine methylation Reductive methylation of amines by a mixture of formaldehyde and formic acid... 

LEUCKART - WALLACH ReductiveAmination Reductive amination of cartx)nyi groups with amines arxl formic add or Hj-NI (Miquonac) or NaBH4 (see Botch). 

This group was developed for protection of the 5 -OH group in nucleosides. The derivative is prepared from the corresponding triaiylmethyl chloride, and is cleaved by reductive cleavage (Zn/AcOH) of the phenacyl ether to the p-hydroxyphenyl-diphenylmethyl ether followed by acidic hydrolysis with formic acid. ... 

The stereoselective reactions in Scheme 2.10 include one example that is completely stereoselective (entry 3), one that is highly stereoselective (entry 6), and others in which the stereoselectivity is modest to low (entries 1,2,4, 5, and 7). The addition of formic acid to norbomene (entry 3) produces only the exo ester. Reduction of 4-r-butylcyclohexanone (entry 6) is typical of the reduction of unhindered cyclohexanones in that the major diastereomer produced has an equatorial hydroxyl group. Certain other reducing agents, particularly sterically bulky ones, exhibit the opposite stereoselectivity and favor the formation of the diastereomer having an axial hydroxyl groi. The alkylation of 4-t-butylpiperidine with benzyl chloride (entry 7) provides only a slight excess of one diastereomer over the other. 

Meroquinenine, CgHjjOaN (meroquinene), formed by the oxidation of all four alkaloids and of cinchoninone or quininone and by the hydrolysis of quinenine or cinchenine (p. 489), crystallises from methyl alcohol in needles, m.p. 223-4° (dee.), [ajp -f- 27-5° (H2O). It gives a nitrosoamine, m.p. 67°, and a monoacetyl derivative, m.p. 110°, and can be esterified the ethyl ester hydrochloride has m.p. 165°. When oxidised by chromic acid it yields formic and cincboloiponic acids. On reduction with zinc dust and hydriodic acid, it adds on two atoms of hydrogen forming cincholoipon, CgH jOaN, and when heated with hydrochloric acid at 250-60° gives 3-ethyl-4-methylpyridine ()3-collidine). 

Another interesting fact to be noted is that the bicyclic enamine (87) and its pyrrolidine analogue failed to undergo reduction with 98% formic acid, whereas the pyrrolidine enamine of 2-bicyclo[2.2.1]hepten-5-carboxalde-hyde (94), which exists largely in the transoid form (49), was readily reduced to (95). However, the saturated amine-substituted norbornane can be obtained directly from norbornanone under the more vigorous conditions of the Leuckart reaction (49a). 

The reaction has been applied to more complex enamines 13) and to dienamines 19). The reduction may be rationalized by initial protonation at the enamine carbon and subsequent decarboxylation of formate ion and addition of the hydride ion to the iminium cation. This mechanism has been given support by the reaction of the enamine (205) with deuterated formic acid 143) to give the corresponding amines. The formation of 206 on reaction with DCOOH clearly indicates that protonation at the enamine carbon is the initial step. 

The reduction of the double bond of an enamine is normally carried out either by catalytic hydrogenation (MS) or by reduction with formic acid (see Section V.H) or sodium borohydride 146,147), both of which involve initial protonation to form the iminium ion followed by hydride addition. Lithium aluminum hydride reduces iminium salts (see Chapter 5), but it does not react with free enamines except when unusual enamines are involved 148). 

The reduction of iminium salts can be achieved by a variety of methods. Some of the methods have been studied primarily on quaternary salts of aromatic bases, but the results can be extrapolated to simple iminium salts in most cases. The reagents available for reduction of iminium salts are sodium amalgam (52), sodium hydrosulfite (5i), potassium borohydride (54,55), sodium borohydride (56,57), lithium aluminum hydride (5 ), formic acid (59-63), H, and platinum oxide (47). The scope and mechanism of reduction of nitrogen heterocycles with complex metal hydrides has been recently reviewed (5,64), and will be presented here only briefly. 

The remaining major method for the reduction of the C=N+ functionality is the reaction with formic acid. The first report was that of Luke , who found (95) that thermal cleavage of l,l-dimethyl-2-methylenepyrrolidinium formate was accompanied by reduction. Lukes then explored the generality... 

That the reduction with formic acid proceeds by a hydride transfer reaction was proposed by Lukes and Ji2ba 100) and finally proven by Leonard and Sauers 63). The use of variously deuterated formic acid allowed Leonard and Sauers to determine that (1) protonation or... 

Reduction of Iminium Salts with Formic Acid (96-99)... 

An interesting addition of ethyl acrylate has been reported in the case of l-methyl-2-ethylidenepyrrolidine. An unsaturated amino ketone 144 is formed, which rearranges to 1,7-dimethyloctahydroindole (145) on reduction with formic acid, as established by dehydrogenation to 1,7-dimethyl-indole (Scheme 12) 217). 

This method has been used for the reduction of l-methyl-2-alkyl-.d -pyrrolinium and l-methyl-2-alkyl-.d -piperideinium salts by Lukes et al. (42,249-251) and for the reduction of more complex bases containing the dehydroquinolizidine skeleton by Leonard et al. (252). The formic add reduction may be satisfactorily explained by addition of a hydride ion, or an equivalent particle formed from the formate anion, to the -carbon atom of the enamine (253), as shown in Scheme 13. 

Dihydro- and 1,4-dihydro derivatives are formed as intermediates in the reduction of quaternary pyridine salts and their homologues with sodium borohydride or formic acid. A proton is added to the present enamine grouping and the formed immonium salts are reduced to the l-methyl-l,2,5,6-tetrahydropyridine derivatives (157) and to completely saturated compounds (158) (254) (Scheme 14). 

The formic acid reduction has great stereospecificity. Reduction of (-)-zl -dehydrosparteine (159) and (—)-.d "-didehydrosparteine affords (—)-sparteine (160) and (—)-(x-isosparteine, respectively (252). 

Reduction of the quaternary immonium salt 161, obtained by treatment of l-methyl-2-ethylidenepyrrolidine with ethyl bromoacetate, by means of either sodium borohydride or formic acid, leads to (—)-erythro-2-(2-N-methylpyrrolidyl)butyric acid (162), in agreement with Cram s rule (196). 

In both cases, the hydride ion approaches the double bond from the sterically more accessible side of the molecule. Reduction of imines by metals and acids, electrolytically or by formic acid gives saturated secondary amines (38,255). 

Greater stereoselectivity for the formation of equatorial amines has been found in the reduction of enamines with formic acid or formamides (553-559). The selective formation of 3-a-amino-5- -steroids by this method and of 3- 3-amino-5- 3-steroids by catalytic reduction (5<50) of the corresponding enamines is of interest. 

---