Secondary amines, from nitriles

The iminium ion is, of course, more electrophilic than the starting amides (amide carbonyl groups are about the least electrophilic of any ), so it gets reduced to the secondary amine. This reaction can be used to make secondary amines from primary amines and acyl chlorides. A similar reduction with lithium aluminium hydride gives a primary amine from a nitrile. 

There are two common methods for the manufacture of fatty amines from fatty acid via the nitrile route or from fatty alcohols. For the production of primary and secondary amines the nitrile route is favoured while for tertiary amines both nitrile and alcohol routes may be used. As already mentioned the manufacture of fatty amine has been previously reviewed in detail by the author [4]. 

The tertiary amine is formed in a similar manner from the imine and a secondary amine. This side reaction can be minimized by carrying out the hydrogenation in the presence of ammonia, which tends to shift the equiHbrium back towards the imine. When a compound with two or more nitrile groups is hydrogenated, the formation of both cycHc and acycHc secondary and tertiary amines is possible, depending on whether the side reaction is intramolecular or intermolecular. For example, for the hydrogenation of adiponitfile ... 

Nitrile Intermediates. Most quaternary ammonium compounds are produced from fatty nitriles (qv), which are ia turn made from a natural fat or oil-derived fatty acid and ammonia (qv) (Fig. 2) (see Fats AND FATTY oils) (225). The nitriles are then reduced to the amines. A variety of reduciag agents maybe used (226). Catalytic hydrogenation over a metal catalyst is the method most often used on a commercial scale (227). Formation of secondary and tertiary amine side-products can be hindered by the addition of acetic anhydride (228) or excess ammonia (229). In some cases secondary amines are the desired products. 

Nitriles and oximes are considered together because of common features. Both functions are reduced to primary amines, both undergo coupling reactions to secondary amines, and both are subject to reductive hydrolysis. These similarities arise from a common intermediate, an imine. The imine is... 

The addition of Grignard reagents to aldehydes, ketones, and esters is the basis for the synthesis of a wide variety of alcohols, and several examples are given in Scheme 7.3. Primary alcohols can be made from formaldehyde (Entry 1) or, with addition of two carbons, from ethylene oxide (Entry 2). Secondary alcohols are obtained from aldehydes (Entries 3 to 6) or formate esters (Entry 7). Tertiary alcohols can be made from esters (Entries 8 and 9) or ketones (Entry 10). Lactones give diols (Entry 11). Aldehydes can be prepared from trialkyl orthoformate esters (Entries 12 and 13). Ketones can be made from nitriles (Entries 14 and 15), pyridine-2-thiol esters (Entry 16), N-methoxy-A-methyl carboxamides (Entries 17 and 18), or anhydrides (Entry 19). Carboxylic acids are available by reaction with C02 (Entries 20 to 22). Amines can be prepared from imines (Entry 23). Two-step procedures that involve formation and dehydration of alcohols provide routes to certain alkenes (Entries 24 and 25). 

The selectivity of RNH2 on M/A1203 and Raney catalysts decreased in the order Co Ni Ru>Rh>Pd>Pt. This order corresponds to the opposite sequence of reducibility of metal-oxides [8] and standard reduction potentials of metalions [9], The difference between Group VIII metals in selectivity to amines can probably been explained by the difference in the electronic properties of d-bands of metals [3], It is interacting to note that the formation of secondary amine, i.e. the nucleophilic addition of primary amine on the intermediate imine can also take place on the Group VIII metal itself. Therefore, the properties of the metal d-band could affect the reactivity of the imine and its interaction with the amine. One could expect that an electron enrichment of the metal d-band will decrease the electron donation from the unsaturated -C=NH system, and the nucleophilic attack at the C atom by the amine [3], Correlation between selectivity of metals in nitrile hydrogenation and their electronic properties will be published elsewhere. 

Catalysed oxidation of primary and secondary amines generally has little synthetic value. Primary amines yield either a mixture of nitriles and amides (ca. 30%) or, in the case of arylamines, the azo derivatives (42-99%) [39], Symmetrical and non-symmetrical azoarenes are also produced in good yields ( 60%) from the reaction of acetanilides with nitroarenes under basic solidtliquid conditions, although higher yields are obtained using TDA-1 [40],... 

Platinum-catalyzed hydrolytic amidation of unactivated nitriles was reported by Cobley and coauthors. The platinum(ii) complex, [(Me2PO- H- PMe2)PtH (PMe2OH)], efficiently catalyzes the direct conversion of unactivated nitriles into N-substituted amides with both primary and secondary amines. Possible mechanisms for this reaction are discussed and evidence for initial amidine formation is reported. Isolated yields vary from 51 to 89% [25]. 

In the course of the catalytic hydrogenation of a,us dinitriles over Raney nickel, by-products are obtained from C-N and C-C bond formation. The mechanism of the formation of these compounds was investigated. Cyclic and linear secondary amines can result from the same secondary imine through a transimination process involving a ring-chain tautomerism. Stereochemical results for 2-aminomethyl-cyclopentylamine (AMCPA) are in accordance with a specific cyclisation pathway favored by an intramolecular hydrogen bond giving rise to the cis isomer from aminocapro-nitrile, unfavored in the case of adiponitrile which leads to the trans AMCPA as the major isomer. 

Palladium acetate triarylphosphine complexes catalyze the addition of vinylic groups from vinylic halides to olefinic compounds in the presence of amines. Conjugated dienes are major products from 0,/3-unsaturated acids, esters, or nitriles while unactivated olefinic compounds react best in the presence of secondary amines where allylic amines are major products. The reactions are usually regio- and stereospecific. The synthetic utility of the reaction is illustrated with a wide variety of examples. 

Supposing there is no oxygen-based functionality at all, as in the diamine 23 It is not necessary to have a carbonyl group for conjugate addition, in fact a nitrile is much better. So we do FGI on the primary amine and disconnect the secondary amine Et2NH from acrylonitrile 25. The synthesis is to mix those two and reduce 24 catalytically or with LiAlH4-... 

The first enantioselective catalytic Strecker reaction of ketoimines to give chiral quaternary cyanohydrins was demonstrated by the Jacobsen group using 45b (Scheme 6.7) [41]. A series of substituted aryl and aliphatic N-benzyl methylketo-imines (48) reacted with HCN in the presence of 45b to provide essentially quantitative yields of the Strecker adducts in high optical purities (70-95% ee). The adducts were crystalline, and their recrystallization from hexanes increased their enantiopurities to >99.9% ee. The a-quaternary Strecker adducts (49) could be converted to a-quaternary a-amino acids through formamide protection of the secondary amine, followed by sequential hydrolysis of the nitrile and the formamide, followed by hydrogenolytic debenzylation. 

The nitrile is then hydrogenated to a primary amine from which amine derivatives can be made by utilization of a variety of reagents [6, 7]. The example in eqns 6.1.1-6.1.3 shows the conversion of fatty acid to dialkyl secondary amine via catalytic deammoniafication (for this and all subsequent structures n = 80-20 unless otherwise noted) ... 

Vinylic substitution of bromine by noncyclic primary and secondary amines in 3-bromo-4,4-dimethoxy-2-butenoates and corresponding nitriles occurs in a stereocontrolled fashion. Regardless of the starting stereochemistry, the product possesses trans amino and ester (or nitrile) groups (equation 20)174. Also, displacement of bromine from 5-bro-mouracils, by cyclic amines, has been used as a preparation of novel pyrimidine inhibitor intermediates1. This reaction has been shown to be assisted by the presence of fluoride ion... 

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