Reduction of Amides and Imides

py NaBH4, A1C13 Chem Pharm Bull 17 98 (1969) JACS 78 2582 (1956) 

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Reduction of amides and imides to amines. Tertiary amides (1) can be reduced to amines (3) by conversion to the Vilsmeier complex (2) followed by reduction with NaBHi. The method is applicable to secondary amides, (4) -> (6), but primary amides are converted into nitriles. ... 

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

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

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. 

An indirect method for the reduction of amides to amines by NaBHa (applicable only to tertiary amides) involves conversion into a Vilsmeier complex [(R2N=C(C1)R)+C1 ], by treatment with Phosphorus Oxychloride, followed by its reduction. In a related methodology, primary or secondary (also cyclic) amides are first converted into ethyl imidates by the action of Triethy-loxonium Tetrafluoroborate, and the latter reduced to amines with NaBHa in EtOH or, better, with NaBHa-Tliiif/V) Chloride in Et20. ... 

Anhydrides can be converted to ra-amino acids via reaction with amines and reduction of the resultant imide or acyclic amide product. When succinic anhydride was treated with two equivalents of diethylamine. amido acid 2.37 was produced. ... 

Reductive amination was the first method described for amine production on solid phase. It was first mentioned in 1987 by Coy et al. [260,261]. They used a combination of Na(CN)BH3 and HOAc for the subsequent reduction of intermediately formed imides in the synthesis of somatostatin octapep-tide analogs. Due to its early development, this alkylation method has found entry to the synthesis of diverse substance classes like N-terminal-modified peptides, carbohydrate mimetics [262], glycopeptides [263,264], oligonucleotides [265], and of course polyamines [174,175,222,232,248,266,267]. For the same reasons as the amide reduction approach, it is powerful enough to be used in the production of several compound libraries [177,262-264, 268]. 

The imides, primaiy and secondary nitro compounds, oximes and sulphon amides of Solubility Group III are weakly acidic nitrogen compounds they cannot be titrated satisfactorily with a standard alkaU nor do they exhibit the reactions characteristic of phenols. The neutral nitrogen compounds of Solubility Group VII include tertiary nitro compounds amides (simple and substituted) derivatives of aldehydes and ketones (hydrazones, semlcarb-azones, ete.) nitriles nitroso, azo, hydrazo and other Intermediate reduction products of aromatic nitro compounds. All the above nitrogen compounds, and also the sulphonamides of Solubility Group VII, respond, with few exceptions, to the same classification reactions (reduction and hydrolysis) and hence will be considered together. 

Industrial Synthetic Improvements. One significant modification of the Stembach process is the result of work by Sumitomo chemists in 1975, in which the optical resolution—reduction sequence is replaced with a more efficient asymmetric conversion of the meso-cyc. 02Lcid (13) to the optically pure i7-lactone (17) (Fig. 3) (25). The cycloacid is reacted with the optically active dihydroxyamine [2964-48-9] (23) to quantitatively yield the chiral imide [85317-83-5] (24). Diastereoselective reduction of the pro-R-carbonyl using sodium borohydride affords the optically pure hydroxyamide [85317-84-6] (25) after recrystaUization. Acid hydrolysis of the amide then yields the desired i7-lactone (17). A similar approach uses chiral alcohols to form diastereomic half-esters stereoselectivity. These are reduced and direedy converted to i7-lactone (26). In both approaches, the desired diastereomeric half-amide or half-ester is formed in excess, thus avoiding the cosdy resolution step required in the Stembach synthesis. 

The analgesic and anti-inflammatory Indoprofene (42) can be made by several routes, two of which involve cyclisations. Treatment of phthalic anhydride with amino acid (43) gives imide (45) in one step - the cyclisatlon of (44) must be faster than the inter-molecular reaction by which it is formed. Reduction of (45) give.s Indoprofene as the reactive imide is easily reduced as far as the unreactive amide. 

For the same reason that they resist attack at C=0 by alkyllithiums, tertiary amides can be extremely difficult to hydrolyse—almost impossible in the case of —CONPr-i2, and even —CONEt2 amides are stable to 6 M HCl for 72 h. For reactions in which an amide is not required in the product, it is preferable to use —CONEt2 and to remove the amide from the product by reduction, as in Scheme 14 (note the cooperative effect of the amide and methoxy group in the first step) . Hydrolysis can also be achieved via an imidate (see Scheme 12). 

Another approach to reduction of an amide group in the presence of more easily reduced groups is to convert the amide to a more reactive species. One such method is conversion of the amide to an O-alkyl imidate with a positive charge on nitrogen.63 This method has proven successful for tertiary and secondary, but not primary, amides. Other compounds which can be readily derived from amides and that are more reactive than amides toward hydride reducing agents are a-alkylthioimmonium ions64 and a-chloroim-monium ions.65... 

The lower members of the homologous series of 1. Alcohols 2. Aldehydes 3. Ketones 4. Acids 5. Esters 6. Phenols 7. Anhydrides 8. Amines 9. Nitriles 10. Polyhydroxy phenols 1. Polybasic acids and hydro-oxy acids. 2. Glycols, poly-hydric alcohols, polyhydroxy aldehydes and ketones (sugars) 3. Some amides, ammo acids, di-and polyamino compounds, amino alcohols 4. Sulphonic acids 5. Sulphinic acids 6. Salts 1. Acids 2. Phenols 3. Imides 4. Some primary and secondary nitro compounds oximes 5. Mercaptans and thiophenols 6. Sulphonic acids, sulphinic acids, sulphuric acids, and sul-phonamides 7. Some diketones and (3-keto esters 1. Primary amines 2. Secondary aliphatic and aryl-alkyl amines 3. Aliphatic and some aryl-alkyl tertiary amines 4. Hydrazines 1. Unsaturated hydrocarbons 2. Some poly-alkylated aromatic hydrocarbons 3. Alcohols 4. Aldehydes 5. Ketones 6. Esters 7. Anhydrides 8. Ethers and acetals 9. Lactones 10. Acyl halides 1. Saturated aliphatic hydrocarbons Cyclic paraffin hydrocarbons 3. Aromatic hydrocarbons 4. Halogen derivatives of 1, 2 and 3 5. Diaryl ethers 1. Nitro compounds (tertiary) 2. Amides and derivatives of aldehydes and ketones 3. Nitriles 4. Negatively substituted amines 5. Nitroso, azo, hy-drazo, and other intermediate reduction products of nitro com-pounds 6. Sulphones, sul-phonamides of secondary amines, sulphides, sulphates and other Sulphur compounds... 

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