Tertiary amines, from nitriles

Liu S, Chen R, Deng GJ (2011) Ruthenium-catalyzed formation of tertiary amines from nitriles and alcohols. Chem Lett 40(5) 489—491... 

The thermal isomerization of higher terminal alkynes also delivered some allene, from 1-hexyne and 1-heptyne, for example, some 1,2-diene was formed [30]. With an ,/l-unsaturated unit in the alkyne 9, a photochemical isomerization to 10 was successful but delivered only a low yield and 11 as a significant side-product [31]. These reactions tolerate different functional groups alcohols, ethers or, as in 12, tertiary amines and nitriles have been used (Scheme 1.5) [32, 33],... 

The stereochemistry at the Cu11 centres in these complexes is square-based pyramidal with two inline donors from the pendant arms and two tertiary amines from the macrocyclic framework occupying the basal positions. The apical position is occupied by the remaining N-donor of the [9]aneN3 moiety bearing a nitrile-functionalised pendant arm (Fig. 3). 

Aminocyclopropane derivatives were similarly obtained from tertiary amines or nitriles. Whereas the reaction starting from amides requires the use of stoichiometric amount of titanium complexes, the reaction is catalytic with cyanoesters, giving l-azaspirocompounds. In all cases, the enantioselectivity remains too low to be synthetically useful, and efforts are thus needed to improve the enantioselectivity and/or to reduce the amount of catalyst. 

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. 

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). 

Titration experiments on the nitrile-terminated dendrimers in water show for DAB-dendr-(CN)A pKa values of 3.2 and 4.8. The corresponding calculated pKa values are 3.1 and 4.1 respectively (using the pKalc program, version 2.0, Com-pudrug chemistry). For DAB-dendr-(CN)s only the two inner nitrogen atoms can be protonated in acetonitrile, due to the low basicity of the four other ones. This is confirmed with calculated pKa values of the four outer tertiary nitrogen atoms in DAB-dendr-(CN)s, ranging from 2.0 to 3.2. The presence of the electropositive nitrile-functions and the protonated inner tertiary amines can account for this phenomenon. 

Trimerization of imidates is a valuable route to 1,3,5-triazines. Imidates can be considered as activated nitriles and cyclotrimerize more readily. Most symmetrical 2,4,6-trialkyl-1,3,5-triazines are easily formed, although large alkyl substituents may give rise to steric hindrance (61JOC2778). Symmetrical isocyanurates (525) are readily available from isocyanates, RNCO catalysts include tertiary amines, phosphines and sodium methoxide. Aldehydes RCHO and ammonia give hexahydro-1,3,5-triazines (526), known as aldehyde ammonias (73JOC3288). 

Catalytic hydrogenation of nitriles over Raney nickel leads to primary amines with variable amounts of secondary and tertiary amines depending on reaction conditions (Ref. 1). These by-products result from hydrogenation of secondary imines and enamines respectively. 

The reduction is usually effected catalytically in ethanol solution using hydrogen under pressure in the presence of Raney nickel. As in the reduction of nitriles (Section 5.16.1, p. 771), which also involves the intermediate imine, ammonia or the amines should be present in considerable excess to minimise the occurrence of undesirable side reactions leading to the formation of secondary and tertiary amines. These arise from the further reaction of the carbonyl compound with the initially formed amine product. Selected experimental conditions for these reductive alkylation procedures have been well reviewed.210 Sodium borohydride has also been used as an in situ reducing agent and is particularly effective with mixtures of primary amines and aliphatic aldehydes and ketones.211... 

Reduction Nitriles and amides can be easily reduced to alkylamines using lithium aluminium hydride (LiAlH4). In the case of a nitrile, a primary amine is the only possible product. Primary, secondary, and tertiary amines can be prepared from primary, secondary and tertiary amides, respectively. 

The mechanism of von Braun et al. is further supported by the formation of mixed secondary and tertiary amines when a nitrile is hydrogenated in the presence of a primary or secondary amine that is different from the one formed from the nitrile. Thus the hydrogenation of phenylacetonitrile in the presence of dipropylamine over a palladium black in alcohol resulted in extensive formation of V,lV-dipropylphenethy-lamine,3 and the hydrogenation of valeronitrile over Raney Ni in the presence of benzylamine and substituted benzylamines led to the formation of corresponding mixed secondary amines.16... 

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