C=N, functionality

Nitriles contain the —C=N functional group We have already discussed the two mam procedures by which they are prepared namely the nucleophilic substitution of alkyl halides by cyanide and the conversion of aldehydes and ketones to cyanohydrins Table 20 6 reviews aspects of these reactions Neither of the reactions m Table 20 6 is suitable for aryl nitriles (ArC=N) these compounds are readily prepared by a reaction to be dis cussed m Chapter 22... 

There have been only a few examples of reduction of the C=N+ function of catalytic hydrogenation since the reductions with complex hydrides are so easy to do in the laboratory. A possible reduction of an iminium salt 45 to 46 with platinum oxide was reported by McKay et al. (91). A report that platinum oxide reduces 2l tio).jgj yjj.Qqyjp Qjj2idijjjujn perchlorate (25) in quantitative yield to 47 indicates that such reduction should be facile (47). 

The remaining major method for the reduction of the C=N+ functionality is the reaction with formic acid. The first report was that of Luke , who found (95) that thermal cleavage of l,l-dimethyl-2-methylenepyrrolidinium formate was accompanied by reduction. Lukes then explored the generality... 

Compounds containing the -C=N functional group are called nitriles and undergo some chemistry similar to that of carboxylic acids. Simple open-chain nitriles are named by adding -nitrile as a suffix to the alkane name, with the nitrile carbon numbered Cl. 

Nitrile (Section 20.1) A compound containing the C=N functional group. 

Table 25.9 Best catalysts for the hydrogenation of C=0 and C=N functions (for substrates, see Fig. 25.18).

Chiral amines were always considered important targets for synthetic chemists, and attempts to prepare such compounds enantioselectively date back to quite early times. Selected milestones for the development of enantioselective catalysts for the reduction of C = N functions are listed in Table 34.1. At first, only heterogeneous hydrogenation catalysts such as Pt black, Pd/C or Raney nickel were applied. These were modified with chiral auxiliaries in the hope that some induction - that is, transfer of chirality from the auxiliary to the reactant -might occur. These efforts were undertaken on a purely empirical basis, without any understanding of what might influence the desired selectivity. Only very few substrate types were studied and, not surprisingly, enantioselectivities were... 

Table 34.1 Selected milestones for the enantioselective hydrogenation of C = N functions.

Generally, the imine substrates are prepared from the corresponding ketone and amine and are hydrogenated as isolated (and purified) compounds. However, reductive animation where the C = N function is prepared in situ is attractive from an industrial point of view, and indeed there are some successful examples reported below [18, 19]. It is reasonably certain that most catalysts described in this chapter catalyze the addition of H2 directly to the C=N bond and not to the tautomeric enamine C = C bond, even though enamines can also be hydrogenated enantioselectively. 

The nature of the substituent directly attached to the N-atom influences the properties (basicity, reduction potential, etc.) of the C = N function more than the substituents at the carbon atom. For example, it was found that Ir-dipho-sphine catalysts that are very active for N-aryl imines are deactivated rapidly when applied for aliphatic imines [7], or that titanocene-based catalysts are active only for N-alkyl imines but not for N-aryl imines [8, 20, 21]. Oximes and other C = N-X compounds show even more pronounced differences in reactivity. 

The following sections provide an overview on the state of the art for the enantioselective hydrogenation (including transfer hydrogenation) of various classes of C = N groups, together with a short, critical assessment of the presently known catalytic systems. Only selective (ee >80%) or otherwise interesting catalysts are included and, furthermore, other reduction methods for C = N functions (hydride reduction, hydrosilylation) are only covered summarily. 

The situation for the hydrosilylation of C = N functions with regard to ecology and economy is somewhat similar as for the hydride reduction, except that fewer effective catalytic systems have been developed [91]. Despite some recent progress with highly selective Ti-based [92] and Cu-based [93] catalysts using cheap polymethylhydrosiloxane as reducing agent, hydrosilylation will see its major applications in small-scale laboratory synthesis. 

Table 34.8 Typical ranges of reaction conditions, optical yields, turnover frequencies (TOF) and substratexatalyst ratios (SCR) for the hydrogenation of C = N functions using various chiral catalytic systems.

Rhodium diphosphine catalysts can be easily prepared from [Rh(nbd)Cl]2 and a chiral diphosphine, and are suitable for the hydrogenation of imines and N-acyl hydrazones. However, with most imine substrates they exhibit lower activities than the analogous Ir catalysts. The most selective diphosphine ligand is bdppsuif, which is not easily available. Rh-duphos is very selective for the hydrogenation of N-acyl hydrazones and with TOFs up to 1000 h-1 would be active enough for a technical application. Rh-josiphos complexes are the catalysts of choice for the hydrogenation of phosphinyl imines. Recently developed (penta-methylcyclopentyl) Rh-tosylated diamine or amino alcohol complexes are active for the transfer hydrogenation for a variety of C = N functions, and can be an attractive alternative for specific applications. 

Reductive sequences involving flavoproteins may be represented as the reverse reaction, where hydride is transferred from the coenzyme, and a proton is obtained from the medium. The reaction mechanism shown here is in many ways similar to that in NAD+ oxidations, i.e. a combination of hydride and a proton (see Box 11.2) it is less easy to explain adequately why it occurs, and we do not consider any detailed explanation advantageous to our studies. We should register only that the reaction involves the N=C-C=N function that spans both rings of the pteridine system. 

If the C=N function is attached to an electron-withdrawing group, 1,3-dipolar cycloaddition with diazoalkanes occurs leading to 1,2,3-triazoles (5, 276). When diazomethane is used, the initially formed NH-triazole is not isolated due to a rapid subsequent NH deprotonation followed by N-methylation. Consequently, a mixture of the three Wmethyltriazoles is formed when methyl cyanoformate (71) (216) or trichloroacetonitrile (276) (217) is treated with excess diazomethane (Scheme 8.51). Huisgen and co-workers found that methyl diazoacetate reacts with TCNE by a 1,3-dipolar cycloaddition at the C=C bond and not, as published earlier by other authors, at one of the nitrile functions (72). 

In this Section we will mainly concentrate on stereoselective addition reactions involving the transformation of sp2 carbon atoms in C = C, C=O and C=N functions to sp3 hybridization these reactions do not include hydrogenation- and reduction-type transformations which were addressed in Sect. 2.1, 2.2, and 3.1. 

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