Lithium aluminum hydride nitriles

Reduction of an azide a nitrile or a nitro compound furnishes a primary amine A method that provides access to primary secondary or tertiary amines is reduction of the carbonyl group of an amide by lithium aluminum hydride... 

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). 

Lithium aluminum hydride (LiAlH4) is the most powerful of the hydride reagents. It reduces acid chlorides, esters, lactones, acids, anhydrides, aldehydes, ketones and epoxides to alcohols amides, nitriles, imines and oximes to amines primary and secondary alkyl halides and toluenesulfonates to... 

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

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%. 

Related to the nitrile oxide cycloadditions presented in Scheme 6.206 are 1,3-dipolar cycloaddition reactions of nitrones with alkenes leading to isoxazolidines. The group of Comes-Franchini has described cycloadditions of (Z)-a-phenyl-N-methylnitrone with allylic fluorides leading to enantiopure fluorine-containing isoxazolidines, and ultimately to amino polyols (Scheme 6.207) [374]. The reactions were carried out under solvent-free conditions in the presence of 5 mol% of either scandium(III) or indium(III) triflate. In the racemic series, an optimized 74% yield of an exo/endo mixture of cycloadducts was obtained within 15 min at 100 °C. In the case of the enantiopure allyl fluoride, a similar product distribution was achieved after 25 min at 100 °C. Reduction of the isoxazolidine cycloadducts with lithium aluminum hydride provided fluorinated enantiopure polyols of pharmaceutical interest possessing four stereocenters. 

The nitrile group in 82 has been transformed into other versatile functional groups, and the derivatives so obtained have been used in the synthesis of various naturally occurring C-nucleosides and their analogs. Reduction of 82 with lithium aluminum hydride gave the amine 90 which was, in turn, transformed84 into the ureido and N-ni-troso derivatives (91-93) by treatment with nitrourea, followed by benzylation, and nitrosation.85 The diazo derivative 94, obtained by treatment of 93 with alcoholic potassium hydroxide, was a key intermediate in the synthesis of formycin B and oxoformycin B (see Section III,2,a,b). 

Intramolecular nitrile oxide—olefin cycloaddition of oxazolidine and thiazoli-dine oximes 407 (R = H, Me R1 =H, Me X = 0, S n = 1,2) proceed stereose-lectively, yielding tricyclic fused pyrrolidines and piperidines. Thus, 407 (n =2 R = H R1 =Me X=S) has been oxidized to the nitrile oxides with sodium hypochlorite, in the presence of triethylamine in methylene chloride, to give the isoxazolothiazolopyridine 408 in 68% yield. Reduction of 408 with lithium aluminum hydride affords mercaptomethylmethylpiperidine 409 in 24% yield (448). 

A different approach involving cyanohydrin formation from the 3-keto sugar was also explored in the D-Fru series (Scheme 17). A mixture of epimeric cyanohydrins was quantitatively formed by reaction with sodium cyanide in methanol, albeit without stereoselectivity. Chromatographic separation of (R)- and (A)-isomers was straightforward and the former epimer was selected to exemplify the two-step transformation into an OZT. Reduction of this nitrile by lithium aluminum hydride led to the corresponding aminoalcohol, which was further condensed with thiophosgene to afford the (3i )-spiro-OZT in ca. 30% overall yield. Despite its shorter pathway, the cyanohydrin route to the OZT was not exploited further, mainly because of the disappointing yields in the last two steps. 

The stoichiometry of lithium aluminum hydride reductions with other compounds such as nitriles, epoxides, sulfur- and nitrogen-containing com-... 

If the reduction has been carried out in ether, the ether layer is separated after the acidification with dilute hydrochloric or sulfuric acid. Sometimes, especially when not very pure lithium aluminum hydride has been used, a gray voluminous emulsion is formed between the organic and aqueous layers. Suction filtration of this emulsion over a fairly large Buchner funnel is often helpful. In other instances, especially in the reductions of amides and nitriles when amines are the products, decomposition with alkalis is in order. With certain amounts of sodium hydroxide of proper concentration a granular by-product - sodium aluminate - may be separated without problems [121],... 

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/]. 

Even better yields are obtained with alane produced in situ from lithium aluminum hydride and 0.5mol of 100% sulfuric acid in tetrahydrofuran [994], or 1 mol of aluminum chloride in ether [787] Procedure 17, p. 208). One or 1.3 mol of the alane is used per mole of the nitrile and the reduction is carried out at room temperature. Comparative experiments showed somewhat higher yields of amines than those obtained by lithium aluminum hydride alone [787]. 

Since sodium borohydride usually does not reduce the nitrile function it may be used for selective reductions of conjugated double bonds in oc,/l-un-saturated nitriles in fair to good yields [7069,1070]. In addition some special reagents were found effective for reducing carbon-carbon double bonds preferentially copper hydride prepared from cuprous bromide and sodium bis(2-methoxyethoxy)aluminum hydride [7766], magnesium in methanol [7767], zinc and zinc chloride in ethanol or isopropyl alcohol [7765], and triethylam-monium formate in dimethyl formamide [317]. Lithium aluminum hydride reduced 1-cyanocyclohexene at —15° to cyclohexanecarboxaldehyde and under normal conditions to aminomethylcyclohexane, both in 60% yields [777]. 

Nitriles of keto acids are reduced with lithium aluminum hydride at both functions. Benzoyl cyanide afforded 2-amino-1-phenylethanol in 86% yield... 

A number of organic species, including amides, oximes, and nitriles, undergo reductive amination, a variety of reduction reactions that produce cimines. In general, these processes involve imines, R=N-R, or related species. Reduction processes include hydrogenation using Raney nickel as the catalyst (for nitriles), the reaction with sodium/EtOH (for oximes), and the use of lithium aluminum hydride, LiAlH (for amides or nitriles). Figure 13-16 illustrates the preparation of amphetamine by reductive amination. 

Similarly, lipase-catalyzed kinetic resolution has also been applied to intermediate nitrile alcohol 46 (Scheme 14.14). Best results were obtained by using immobilized Pseudomonas cepacia (PS-D) in diisopropyl ether, leading to excellent yield and enantiomeric excess of the desired (5)-alcohol 46a, along with (/J)-nitrile ester 47. Reduction of 46a with borane-dimethylsulhde complex, followed by conversion to the corresponding carbamate and subsequent lithium aluminum hydride reduction gave rise to the desired (S)-aminoalcohol intermediate 36, a known precursor of duloxetine (3). 

The benzodioxan ring also serves as the aromatic moiety for one of the ubiquitous analogues of the spirone anxiolytic agents discussed in Chapter 9. In the absence of a specific reference, the requisite intermediate (62-1) could be obtained by reducing the cyano group in nitrile (60-1) with lithium aluminum hydride. Alkylation with the spirone side chain chloride (62-2) would then afford binospirone (62-3). 

Lithium aluminum hydride in tetrahydrofuran has been found to reduce aromatic nitriles to give an amine and to give an imine which is formed from the addition of the amine to the nonisolatable imine intermediate followed by an elimination of ammonia [24] (Eq. 14). This is simpler than catalytic hydrogenation of nitriles [25], which gives poor yields of imines. 

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-lividosamine (298) (Scheme 6.73). Lithium 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 HC1 hydrolysis to give the hexosamine hydrochlorides 136, which after several steps, produced D-lividosamine 137 possessing the D-ribo configuration (298). 

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