Reduction, of nitriles

Nitriles of carboxylic acids are an important source of primary amines which are produced by many reducing agents. However, a few reagents effect partial reduction to aldehydes 285.  

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/]. 

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]. 

An alternative method for the conversion of aromatic nitriles to aldehydes is their heating with Raney nickel and sodium hypophosphite in water-acetic acid-pyridine (1 1 2) at 40-45° for 1-1.5 hours (yields 40-90%) [1154], or heating with Raney nickel and formic acid at 75-80° for 30 minutes (yields 35-83%) [7/55], or even their refluxing for 30 minutes with Raney nickel alloy in 75% aqueous formic acid (yields 44-100%) [1156]. 

Excellent yields of primary amines were obtained by hydrogenation of nitriles over 5% rhodium on alumina in the presence of ammonia. The reaction was carried out at room temperature and at a pressure of 2-3 atm and was finished in 2 hours, giving 63-92.5% yields of primary amines. Under such conditions no hydrogenolysis of benzyl residues was noticed [1157]. Hydrogenation over Raney nickel at room temperature and atmospheric [1158] or slightly elevated pressures [45] also gave high yields of primary amines, especially in the presence of ammonia [7/55]. Comparable results 

Reduction of tertiary nitriles with lithium in ethylamine or sodium in ammonia often affords reductive decyanation products exclusively. Primary and secondary nitriles give both the expected amine and decyanation products [29, 30]. Doumaux [31] found that calcium in ammonia reduces primary, secondary, and tertiary nitriles to produce modest, synthetically useful amounts of the expected amines. Little decyanation occurs on the basis of the results obtained by use of dodecylcya-nide as the substrate. 

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By the reduction of nitriles with sodium and absolute alcohol, for example ... 

R4N= BnEtsN or BU4N Heterocylces 1980, 14, 1437, 1441 reduction of amides to amines reduction of nitriles to amines... 

Analysis There are two general ones based on reduction of nitrile or nitro compound (a) nitrile route... 

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. 

As mentioned previously, aldehydes can be prepared by Stephen s method of reduction of nitriles by stannous chloride (37, 91). Polaro-graphic reduction of thiazolecarboxylic acids and their derivatives gives lower yields of aldehydes (58). Ozonolysis of styrylthiazoles, for example, 2-styryl-4-methylthiazole, followed by catalytic reduction gives aldehyde with 47% yield of crude product (30). 

Reductions of Nitriles. In the reduction of nitriles, hydrogen is added progressively across the carbon—nitrogen triple bond, forming first the imine and then the amine. 

Nitriles. The electrolytic reduction of nitriles requires a high negative potential, but can lead to amines in good yields under the right conditions. This reaction occurs in acidic media according to the following equation (62). 

In general, however, the electrochemical reduction of nitriles offers no significant advantages over traditional chemical methods and has not been widely used. 

One development involves the use of vitamin B 2 to cataly2e chemical, in addition to biochemical processes. Vitamin B 2 derivatives and B 2 model compounds (41,42) cataly2e the electrochemical reduction of alkyl haUdes and formation of C—C bonds (43,44), as well as the 2inc—acetic acid-promoted reduction of nitriles (45), alpha, beta-unsaturated nitriles (46), alpha, beta-unsaturated carbonyl derivatives and esters (47,48), and olefins (49). It is assumed that these reactions proceed through intermediates containing a Co—C bond which is then reductively cleaved. 

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

Braun i has shown that alcohols of the type of phenyl-ethyl alcohol, containing an aliphatic and an aromatic radicle, can be prepared by the reduction of nitriles of the general formula X. CN with the corresponding... 

Nickel in the presence of ammonia is often used for reduction of nitriles to primary amines. The reaction is done at elevated temperatures and pressures ( 100 C, 1000 psig) unless massive amounts of nickel are used. Cobalt is used similarly but mainly under even more vigorous conditions. Nitriles containing a benzylamine can be reduced over Raney nickel to an amine without hydrogenolysis of the benzyl group (7). A solution of butoxycarbonyl)-3-aminopropyl]-N-<3-cyanopropyl)benzylamine (13.6 g) in 100 ml of ethanol containing 4 g. NaOH was reduced over 3.0 g Raney nickel at 40 psig for 28 h. The yield of A/ -benzyl-Air -(f-butoxycarbonyl)s >ermidine was 95% (7). 

We ve already seen in Sections 20.7 and 21.7 how amines can be prepared by reduction of nitriles and amides with LiAlH4. The two-step sequence of 5 2 displacement with C followed by reduction thus converts an alkyl halide into a primary alkylamine having one more carbon atom. Amide reduction converts carboxylic acids and their derivatives into amines with the same number of carbon atoms. 

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%. 

The key intermediate 25 was prepared efficiently from aldehyde 23, obtained by reduction of nitrile 22 with Dibal-H. Treatment of 23 with the lithium salt of frans-diethyl cinnamylphosphonate furnishes compound 24 in 75 % yield and with a 20 1 ratio of E Z olefin stereoisomers. The stage is now set for the final and crucial operations to complete the molecular skeletons of endiandric acids A and B. 

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. 

Enantiomerically pure alkylboranes arc known to be excellent reagents for asymmetric reduction but they can also be used to generate enantiomerically pure /V-borylimines by partial reduction of nitriles. Addition of organolithium and Grignard reagents to these compounds affords secondary carbinamines in moderate to good yield but low enantioselectivity13,14. The best results reported so far are shown below. 

Scheme 17 Reduction of nitriles using borane dimethyl sulfide and microwave irradiation...

There are two principal methods for the reduction of nitriles to aldehydes. In one of these, known as the Stephen reduction, the nitrile is treated with HCl to form... 

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... 

Most of the methods for preparation of /3-naphthaldehyde have been given previously.2 A recent procedure describes the preparation of /3-naphthaldehyde from 2-bromomethylnaphthalene and hexamethylenetetramine in boiling acetic acid.3 The method of reduction of nitriles by stannous chloride was discovered by Stephen.4... 

Reductive hydrolysis86 of organic nitriles is known to lead to the corresponding aldehydes. Application of Backeberg and Staskun s87 modification of this reaction to reduction of nitrile 82 was reported... 

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