Hydrides reduction of nitriles

Woodward s strychnine synthesis commences with a Fischer indole synthesis using phenylhydrazine (24) and acetoveratrone (25) as starting materials (see Scheme 2). In the presence of polyphosphor-ic acid, intermediates 24 and 25 combine to afford 2-veratrylindole (23) through the reaction processes illustrated in Scheme 2. With its a position suitably masked, 2-veratrylindole (23) reacts smoothly at the ft position with the Schiff base derived from the action of dimethylamine on formaldehyde to give intermediate 22 in 92% yield. TV-Methylation of the dimethylamino substituent in 22 with methyl iodide, followed by exposure of the resultant quaternary ammonium iodide to sodium cyanide in DMF, provides nitrile 26 in an overall yield of 97%. Condensation of 2-veratryl-tryptamine (20), the product of a lithium aluminum hydride reduction of nitrile 26, with ethyl glyoxylate (21) furnishes Schiff base 19 in a yield of 92%. 

Although the hydride reduction of nitriles frequently requires the use of vigorous conditions (LiAlH4, B2H6), aryl nitriles and benzyl nitriles are reduced to the... 

The complex hydride reductions of nitriles to aldehydes compare favorably with the classical Stephen reduction which consists of treatment of a nitrile with anhydrous stannous chloride and gaseous hydrogen chloride in ether or diethylene glycol and applies to both aliphatic and aromatic nitriles [183,285, 1152]. An advantage of the Stephen method is its applicability to polyfunctional compounds containing reducible groups such as carbonyl that is reduced by hydrides but not by stannous chloride [1153]. 

Amines are used as bases and also as nucleophiles throughout portions of this book. The structure and nomenclature of simple amines were introduced in Chapter 5 (Section 5.6.2), but only a few reactions were discussed that form an amine. Exceptions are the formation and reactions of the aromatic amine, aniline (see Chapter 21, Sections 21.2 and 21.3), and the hydride reduction of nitriles and amides in Chapter 19 (Section 19.2.2). This chapter will first review some fundamentals of amine chemistry and then proceed into new areas. 

FIGURE 18.48 The metal hydride reduction of nitriles followed by hydrolysis yields primary amines. 

The Stephen s method allows the reduction of nitriles by stannous chloride in acid medium. If the amine chlorhydrate initially formed is hydrolyzed, the corresponding aldehyde is obtained (37, 91). Harington and Moggridge (37) have reduced 4-methyl-5-cyanothiazole by this method (Scheme 23). However, Robba and Le Guen (91) did not obtain the expected products with 4.5-dicyanothiazole and 2-methyl-4,5-dicyanothiazole. These compounds have been reduced with diisobutyl-aluminium hydride with very low yields (3 to 6%) (Scheme 24). In other conditions the reaction gives a thiazole nitrile aldehyde with the same yield as that of the dialdehyde. 

Reduction of nitriles (Section 22.9) Nitriles are reduced to primary amines by lithium aluminum hydride or by catalytic hydrogenation. 

Aldehydes have also been obtained by lithium trialkoxyaluminum hydride reduction of 5-nitriles or 5-acid chlorides, and, as the thio-semicarbazones, by the McFadyen-Stevens reaction in surprisingly good yields (50-60%) considering the severity of the reaction conditions. ... 

TV-aluminum imines are another example of masked inline derivatives of ammonia. They are easily synthesized by partial reduction of nitriles with diisobutylaluminum hydride (D1BAL-H)6. Addition of lithium organic reagents to /V-aluminum iniines 7 derived from O-protected cyanohydrins 6 provides a-amino alcohols 8a and 8b in moderate yields and low to good diastereo-selectivities n 12. 

Another useful approach to aldehydes is by partial reduction of nitriles to imines. The reduction stops at the imine stage because of the low electrophilicity of the deprotonated imine intermediate. The imines are then hydrolyzed to the aldehyde. Diisobutylaluminum hydride seems to be the best reagent for this purpose.88,89... 

In a similar procedure, through diisobutylaluminium hydride (DIBALH)-reduction of nitrile into imine and condensation with A-benzylhydroxylamine, C-(l-fluorovinyl) nitrones were synthesized (Scheme 2.30, Table 2.4) (228). 

Aromatic nitriles were converted to aldehydes in 50-95% yields on treatment with 1.3-1.7mol of sodium triethoxy aluminum hydride in tetrahydrofuran at 20-65° for 0.5-3.5 hours [1149. More universal reducing agents are lithium trialkoxyaluminum hydrides, which are applicable also to aliphatic nitriles. They are generated in situ from lithium aluminum hydride and an excess of ethyl acetate or butanol, respectively, are used in equimolar quantities in ethereal solutions at —10 to 12°, and produce aldehydes in isolated ytelds ranging from 55% to 84% [1150]. Reduction of nitriles was also accomplished with diisobutylalane but in a very low yield [7/5/]. 

REDUCTION WITH ALANE (ALUMINUM HYDRIDE) IN SITU Reduction of Nitriles to Amines [787]... 

Precursors of type E (erythro fragment) (Scheme 6.69) were obtained by cycloaddition of a nitrile oxide dipole to a-alkoxyalkenes. This strategy was used in the syntheses of dl- and D-hvidosamine (298) (Scheme 6.73). Fithium aluminum hydride reduction of the erythro adduct 130 produced aminoalcohols 135 in a 78 22 ratio (2,4-erythro/threo) in high yield. The mixture was subjected to HCl hydrolysis to give the hexosamine hydrochlorides 136, which after several steps, produced D-hvidosamine 137 possessing the D-ribo configuration (298). 

Reduction of nitriles and amides.1 These compounds are selectively reduced to the corresponding amines by this metal hydride in refluxing methylene chloride. Under the same conditions indoles can be reduced to indolenes in moderate yield. 

In order to avoid the rather vigorous conditions of nitrile hydrolysis a sequence involving hydride reduction of the nitrile71 was investigated. 

Excellent procedures are available for the preparation of primary, secondary, and tertiary amines by the reduction of a variety of nitrogen compounds. Primary amines can be obtained by hydrogenation or by lithium aluminum hydride reduction of nitro compounds, azides, oximes, imines, nitriles, or unsubstituted amides [all possible with H2 over a metal catalyst (Pt or Ni) or with LiAlH4] ... 

Lithium aluminium hydride has also been used for the reduction of nitriles to amines a recommended procedure involves the slow addition of the nitrile to at least one molar proportion of the reducing agent in a cooled ethereal solution.205 The reduction of nitriles is also effected by the use of sodium trifluoro-acetoxyborohydride (from sodium borohydride and trifluoroacetic acid) in tetrahydrofuran solution.206... 

The reduction of nitriles by the nucleophilic attack of hydride transfer reagents has also been widely investigated and is a process with considerable synthetic potential. The reduction yields amine complexes, and rates are typically about ten thousand times faster than for reduction of the free ligand (Fig. 4-19). Once again, the principal effect appears to be associated with the build-up of positive charge on the ligand. 

Another method that can be used to prepare primary amines is the reduction of nitriles with lithium aluminum hydride. The mechanism for this reaction involves sequential addition of two hydride nucleophiles to the electrophilic carbon of the cyano group. The addition of water in the workup step supplies the two protons on the nitrogen in the product. An example follows ... 

Aluminum hydrides can reduce nitriles to the corresponding aldehydes. Diisobutylaluminum hydride, abbreviated (i-Bu AlH or DIBAL-H, is commonly used for the reduction of nitriles. The initial reaction forms an aluminum complex that hydrolyzes in the aqueous workup. 

Formation and Reduction of Nitriles Like the azide ion, cyanide ion (- C=N ) is a good Sn2 nucleophile it displaces leaving groups from unhindered primary and secondary alkyl halides and tosylates. The product is a nitrile (R—C=N), which has no tendency to react further. Nitriles are reduced to primary amines by lithium aluminum hydride or by catalytic hydrogenation. 

Base-Catalyzed Hydrolysis of a Nitrile 1014 Hydride Reduction of an Ester 1015 Reduction of an Amide to an Amine 1016 Reaction of an Ester with Two Moles of a Grignard Reagent 1018... 

The reduction of nitriles and amides to the amines is a very important, but not so easy, organic transformation. Several methods for the reduction of nitriles and amides with complex metal hydrides have been reported so far. 

Complex hydride reductions of Nj, N O, [CN] and nitriles in reactions containing complex mixtures of metal-ion species produce N—H bonded products " by reactions that may relate to those of the biological nitrogenases". Complete reaction stoichiometries are not well established. These reactions are not competitive with other methods for NH or amine synthesis. Nitrogen reacts in H O with a mixture of NaBH, S-donor ligands (e.g., NH CjM SH) and Mo and Fe salts to form NHj and NjH in low yield . In similar systems, nitriles and isonitriles are reduced to NHj and amines in low yield . 

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