Nitriles metal hydrides

Hydrolysis of primary amides cataly2ed by acids or bases is very slow. Even more difficult is the hydrolysis of substituted amides. The dehydration of amides which produces nitriles is of great commercial value (8). Amides can also be reduced to primary and secondary amines using copper chromite catalyst (9) or metallic hydrides (10). The generally unreactive nature of amides makes them attractive for many appHcations where harsh conditions exist, such as high temperature, pressure, and physical shear. 

AletalHydrides. Metal hydrides can sometimes be used to prepare amines by reduction of various functional groups, but they are seldom the preferred method. Most metal hydrides do not reduce nitro compounds at all (64), although aUphatic nitro compounds can be reduced to amines with lithium aluminum hydride. When aromatic amines are reduced with this reagent, a2o compounds are produced. Nitriles, on the other hand, can be reduced to amines with lithium aluminum hydride or sodium borohydride under certain conditions. Other functional groups which can be reduced to amines using metal hydrides include amides, oximes, isocyanates, isothiocyanates, and a2ides (64). 

The other way of reducing nitriles to aldehydes involves using a metal hydride reducing agent to add 1 mol of hydrogen and hydrolysis, in situ, of the resulting imine (which is undoubtedly coordinated to the metal). This has been carried out with LiAlH4, LiAlH(OEt)3, LiAlH(NR2)3, and DIBAL-H. The metal hydride method is useful for aliphatic and aromatic nitriles. 

Amides, azides and nitriles are reduced to amines by catalytic hydrogenation (H2/Pd—C or H2/Pt—C) as well as metal hydride reduction (LiAlH4). They are less reactive towards the metal hydride reduction, and cannot be reduced by NaBITj. Unlike the LiAlIU reduction of all other carboxylic acid derivatives, which affords 1° alcohols, the LiAlIU reduction of amides, azides and nitriles yields amines. Acid is not used in the work-up step, since amines are basic. Thus, hydrolytic work-up is employed to afford amines. When the nitrile group is reduced, an NH2 and an extra CH2 are introduced into the molecule. 

LiAIH(OEt)3,345 DIBALH,346 and NaAIH4.347 The metal hydride method is useful for aliphatic and aromatic nitriles. Reduction to the aldehyde has also been accomplished by treatment of the nitrile with sodium hypophosphate and Raney nickel in aqueous acetic acid-pyridine or formic acid,348 and with zinc and a Cob(I)alamin catalyst in aqueous acetic... 

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. 

Metal hydrides, such as lithium aluminum hydride, also can be used to reduce derivatives of carboxylic acids (such as amides and nitriles see Table 16-6) to aldehydes. An example follows ... 

Addition of metal hydride or metal alkyl to a nitrile 126... 

The concept has been extended to the C-H activation of nitriles, which coordinate strongly with metals. As shown in Scheme 3, coordination of a nitrile to low-valent metal complex (M) would increase both the basicity of the metal complex and the acidity of the C-H bond adjacent to the nitrile, and hence oxidative addition of the metal into the a-C-H bond of the nitrile would occur readily to afford an a-cya-noalkyl metal hydride complex (7), which undergoes isomerization to a N -bonded nitrile complex (8). The reaction of 8 with an C-electrophile forms a carbon-carbon... 

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. 

The new metallic hydrides are excellent reducing agents for carbonyl compounds. These hydrides now include lithium aluminum hydride, lithium borohydride, and sodium borohydride. The last reagent may be used in either aqueous or methanolic solutions. It does not reduce esters, acids, or nitriles and, for this reason, is superior for certain selective reductions. Other groups which are unaffected by this reagent include a,/S-double bonds and hydroxyl, methoxyl, nitro, and dimethylamino groups. ... 

Nitriles are reduced with metal hydride reagents to form either 1 ° amines or aldehydes, depending on the reducing agent. 

Low-valent Ru(II) [150] and Rh(I) complexes catalyze aldol and Michael reactions of 2-nitrilo esters. The sequence is thought to be initiated by nitrile complexation to the transition metal. This Lewis acid-activation is followed by an oxidative addition to give a metal hydride and a nitrile complexed enolate as shown in Sch. 36. Examples including diastereoselective Ru(II) catalyzed reactions [151] and enantioselective Rh(I)-catalyzed reactions [152-154] with the large trans-chelating chiral ligand PhTRAP are shown in Tables 8 and 9. 

Transition-metal hydrides react with nitrogen compounds to form N—H bond-containing organometallic products. The [HFe3(CO),J cluster anion reacts with nitriles to form a coordinated RCNH species, along with the RCHN-coordinated isomer ... 

Nitriles are resistant to hydrometallation by transition metal hydride complexes. The complex Cp2ZrHCl reacts with nitriles A rhenium complex bridged by adinuc-lear hydride undergoes insertion with several isonitriles and with acetonitrile. The product in the case of the isonitrile results from a 1,1-inertion (see 11.2.8) ... 

The olefinic bond of a,g-unsaturated carbonyl compounds can also be reduced by two transition metal hydrides, NaHFe2(CO)881 and NaHCr2(CO)10 82 Neither reagent reduces nitriles, ketones, aldehydes or non-conjugated carbon-carbon double bonds. 

The choice of metal hydride reducing agent is important, and the selection of the reagents is dictated by the need to prevent concomitant reduction of the double bond. With LAH it is recommended that the reaction be carried out in EtjO at room temperature with a molar ratio nitrile/LAH = 1/0.9 to favor the nitrile reduction. 46 , 5 , 58 However, even at low temperature, it is not possible to... 

For electrophilic attack, Markovnikov addition is that in which the positive portion of the reagent adds to the least substituted carbon atom of the double bond undergoing reaction.) This may result from a steric preference for the least-substituted metal alkyl intermediate formed by insertion of olefin into the metal hydride bond . Vinylarenes comprise an exception, where interaction of nickel with the aromatic ring stabilizes the precursor of the branched nitrile, leading primarily to a Markovnikov addition product . 

Most pyrimidine carbonitriles show normal nitrile chemistry reductive reactions to methylamines by metal hydrides, hydrolytic reactions, reduction to aldehydes and formation of ketones with Grignard reagents. However, in highly electron-deficient pyrimidines, competition may arise between addition to an electrophilic substituent and the electrophilic pyrimidine ring. In the 5-cyano derivative (426), specific attack of organometallics is in the 4-position, with formation of the dihydro derivatives (427) instead of a ketone <83ACS(B)6I3>. 

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