Reduction of amides and lactams

Amides and lactams can be reduced in ways similar to those used for the acids and esters. Catalytic hydrogenation over copper-chromium oxide as 

Appreciably shorter times are needed for reduction of primary, secondary, and tertiary amides to amines by diborane in tetrahydrofuran under nitrogen, and other reducible groups are unaffected.542 

Electrolytic reduction is also sometimes used. For instance, electrolysis of l-butyl-3-pyrrolidone in 30% sulfuric acid at 60° and at a cadmium cathode with a current density of 0.053-0.073 A/cm2 opens the ring, affording dibutyl-amine in 64% yield.543 

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Reduction of Amides and Lactams Containing Double Bonds and Reducible Functional Groups... 

Reductive amination amides and lactams.1 The a-nitro ketone 1, prepared as shown, on reduction with NaBH4 in the presence of ammonia gas is converted into the amide 2 in 30% yield. 

All that remains before the final destination is reached is the introduction of the C-l3 oxygen and attachment of the side chain. A simple oxidation of compound 4 with pyridinium chlorochro-mate (PCC) provides the desired A-ring enone in 75 % yield via a regioselective allylic oxidation. Sodium borohydride reduction of the latter compound then leads to the desired 13a-hydroxy compound 2 (83% yield). Sequential treatment of 2 with sodium bis(trimethylsilyl)amide and /(-lactam 3 according to the Ojima-Holton method36 provides taxol bis(triethylsilyl ether) (86 % yield, based on 89% conversion) from which taxol (1) can be liberated, in 80 % yield, by exposure to HF pyridine in THF at room temperature. Thus the total synthesis of (-)-taxol (1) was accomplished. 

Reduction of lactams to amines resembles closely the reduction of amides except that catalytic hydrogenation is much easier and was accomplished even under mild conditions. a-Norlupinone (l-azabicyclo[4.4.0]-2-oxodecane) was converted quantitatively to norlupinane (l-azabicyclo[4.4.0]decane) over platinum oxide in 1.25% aqueous hydrochloric acid at room temperature and atmospheric pressure after 16 hours [1122]. Reduction of the same compound by electrolysis in 50% sulfuric acid over lead cathode gave 70% yield [1122]. 

For a review, see Challis Challis, in Zabicky The Chemistry of Amides, Wiley New York, 1970, pp. 795-801. For a review of the reduction of amides, lactams, and imides with metallic hydrides, see Gaylord. Ref. 536. pp. 544-636. For a lisl of reagents, with references, see Ref. 21. pp. 432-433. 

Reduction. Carboxylic acids can be reduced satisfactorily to primary alcohols by a slight excess of TiCI and NaBH4 in the molar ratio 1 3. A molar ratio of 1 2 is the optimum for reduction of amides, lactams, and sulfoxides.1 The 1 2 system is also effective for reduction ol nitrosamines, R1 R3N—NO, to secondary amines.2... 

IV. Cathodic reduction of amides, lactams, imides, and hydrazides... 

IV. CATHODIC REDUCTION OF AMIDES, LACTAMS, IMIDES, AND HYDRAZIDES... 

An aminostannane intermediate is involved in the homolytic reduction of an azide to the corresponding amine,33 and in the conversion of a-azido-P-ketoesters into amides and lactams (equations 16-41 and 16-42).34... 

These reagents are strong Lewis acids that cleave THF and acetals (Section 2.4). Nevertheless, they leave bromo- and chloroderivatives intact (Section 2.1). The regioselectivity of the opening of epoxides is opposite to that observed for LAH in THF (Section 2.3). Diarylcarbinols can be reduced to hydrocarbons (Section 2.4), and a,p-unsaturated carbonyl compounds to allylic alcohols (Section 3.2.9). The reduction of amides to amines is easier than with LAH (Section 3.2.8), especially in the case of a,p-ethylenic amides or of -lactams. These reagents do not reduce NO2 groups. 

Lactams are cyclic amides and they are reduced by LiAlHq to the cyclic amine. The reduction of a typical lactam such as 2-pyrrolidinone derivative 36 presumably proceeds via initial formation of the a-amino alcohol (37), followed by elimination to an iminium salt (38), and then reduction by hydride to give the amine (39). This reaction is very useful in the synthesis of alkaloids, as seen in the reduction of 40 to 41 in 88% yield as part of Overman s synthesis of (-i-)-aloperine. O The lactam nitrogen is significantly less basic than the corresponding amine and cyclic amines are often protected as the lactam. The amine is then unmasked late in the synthetic sequence by hydride reduction. 

Recently, substituted amides and lactams, such as dimethylformamide (DMF) or 2-pyrrolidones, were used as electron donors in the photoalkylation of 1,2,4,5-tetracyanobenzene (TCB) [45], The success of the reaction was ascribed to the high reduction potential of TCB in the excited state that made the initial step-that is, the oxidation of amides [Ei/2 DMF = 2.29 V versus standard calomel electrode (SCE)]-possible. It should be noted here that the ensuing deprotonation step was found to be chemoselective when using N-methylpyrrolidone (NMP), as illustrated in Scheme 14.8b. Accordingly, deprotonation of the lactam radical cation intermediate occurred exclusively at the methylene, and not from the methyl group. Tricyano benzene 12 was thus isolated in 41% yield. 

In some groups of monomers, there are additional sources of strain, such as inhibition or reduction of amide-group resonance in lactams. The contribution of each type of strain depends on the chemical structure of the cyclic monomer, ring size, and its substitution. 

Another, less exploited, possibility for the synthesis of cyclic imines consists in a partial reduction of a lactam group. Usually, reduction of amides is achieved with aluminum or boron hydrides. Such harsh and... 

Amides are very weak nucleophiles, far too weak to attack alkyl halides, so they must first be converted to their conjugate bases. By this method, unsubstituted amides can be converted to N-substituted, or N-substituted to N,N-disubstituted, amides. Esters of sulfuric or sulfonic acids can also be substrates. Tertiary substrates give elimination. O-Alkylation is at times a side reaction. Both amides and sulfonamides have been alkylated under phase-transfer conditions. Lactams can be alkylated using similar procedures. Ethyl pyroglutamate (5-carboethoxy 2-pyrrolidinone) and related lactams were converted to N-alkyl derivatives via treatment with NaH (short contact time) followed by addition of the halide. 2-Pyrrolidinone derivatives can be alkylated using a similar procedure. Lactams can be reductively alkylated using aldehydes under catalytic hydrogenation... 

In our second approach, we considered reversal of these functional group transformations, wherein reduction of the nitro group followed by palladium-mediated intramolecular amidation would provide the desired tricylcic lactam (Scheme 6.6). One concern with this approach, however, was to identify reaction conditions that would selectively reduce the nitro functionality and not lead to... 

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