Cyclic imines, transfer hydrogenation

Cyclic imines 8 and 9 are intermediates or models of biologically active compounds and can be reduced with ee-values of 88 to 96% using Ti-ebthi, Ir-bcpm or Ir-binap in the presence of additives (entries 5.7, 5.9), as well as with the transfer hydrogenation catalyst Ru-dpenTs (entries 5.8, 5.10-5.12). As pointed out earlier, Ru-diphosphine-diamine complexes are also effective for imines, and the best results for 7 and 8a were 88% and 79% ee, respectively [36]. Azirines 10 are unusual substrates which could be transfer-hydrogenated with a catalyst prepared in situ from [RuCl2(p-cymene)]2 and amino alcohol L12, with ee-values of 44 to 78% and respectable TOFs of up to 3000 (entry 5.13). 

The reduction of imines and iminium salts present a particular difficulty in that those which are N-substituted can exist in different geometrical isomers that are reduced at different rates and with different selectivities. One way to overcome this problem is to use cyclic imines that can exist only as cis isomers. Although these are good substrates, this is not a general solution. The cyclic amines produced by transfer hydrogenation, together with best reported enantiomeric excesses, are listed in Table 35.6. Primary amines are difficult to pre-... 

A RhCp complex (S,S)-6 (Cp =pentamethylcyclopentadienyl), which is iso-lobal with Ru(rj6-arene) complex (S,S)-5 (Scheme 13), effected the transfer hydrogenation of a cyclic imine substituted by an isopropyl group with an S/C of 200 in the presence of a 5 2 mixture of formic acid and triethylamine to give the R amine in 99% ee (Scheme 13) [31]. When the reaction was performed with an S/C of 1,000, the optical yield decreased to 93%. The methyl imine was reduced with a 91% optical yield. Reduction of a cyclic sulfonimide resulted in the R sul-tam in 81% ee. 

A water-soluble, recyclable ruthenium(II) complex including a chiral diamine ligand has been used for asymmetric transfer hydrogenation of cyclic imines and iminiums in water, with yields and ee up to 99%.49... 

Chiral amines can be prepared by asymmetric hydrogenation, transfer hydrogenation and hydrosilylation of imines. The piperidine 137 with 98% ee was obtained by highly efficient asymmetric hydrogenation of the cyclic imines 136 catalysed by the Ti catalyst 61 [82]. Pyrrolidine 139 with 99% ee was obtained in 34% after 50%... 

A chiral Ru hydride 23 is formed and it is assumed that the hydrogen transfer occurs via metal-ligand bifunctional catalysis. The N-H linkage may stabilize a transition state 24 by formation of a hydrogen bond to the nitrogen atom. Stereochemistry is determined by formal discrimination of the enantiofaces at the sp2 nitrogen atom of the cyclic imine. 

Rhodium-catalysed transfer hydrogenation of cyclic sulfamidate imine 4,5-diphenyl-5H-l,2,3-oxathiazole-2,2-dioxide using HCOOH/N(C2H5)3 mixture as a hydrogen source efficiently produces 4,5-diphenyl-l,2,3-oxathiazoUdine-2,2-dioxide with 98% ee as almost single diastereomer (Scheme 5.16) [57]. 

Asymmetric Transfer Hydrogenation of Imines. In spite of the great importance of optically active amines for pharmaceutical and agrochemical industries, the ATH of C=N imine bonds has been much less studied than that of ketone bonds (278,280,284,289,340). Cyclic imines are reduced with greater ee values than their acyclic counterparts. The existence of geometrical isomers for the latter is based on the encountered difference in selectivity. 

On the other hand, Backvall, Privalov and co-workers proposed an inner-sphere reaction mechanism based on experimental studies and DFT calculations for the reduction of imines with Shvo s catalyst (370,371). The same group demonstrated that imines have to be protonated before being reduced by ruthenium Noyori s catalyst (372). But kinetic studies on the reduction of cyclic imine I (Fig. 94) reported by Blackmond and coworkers (373) conclude that the un-protonated imine is reduced by a Rh(III) catalyst of the Noyori-type catalyst (Fig. 95), using formic acid as the hydrogen transfer agent. 

F. 8 Synthetic targets prepared by asymmetric transfer hydrogenation of cyclic imines... 

Fig. 25 Asymmetric transfer hydrogenation of a cyclic imine followed by diastereoselective reduction...

Secondary Amines.—The reduction of imines to the corresponding secondary amines can be effected by various methodologies. New additions are the sodium triacyloxyborohydrides (easily obtainable from sodium borohydride and AT-acyl derivatives of optically active amino-acids), which are used for the asymmetric reduction of cyclic imines. Also now available is a highly stereoselective reduction of N-benzylimines derived from substituted cyclohexanones, with alkali-metal borohydrides, in particular L-selectride. A fiuther addition is the first report of the reduction of aldimines by hydrogen transfer from propan-2-ol,... 

Asymmetric transfer hydrogenation of imines using HC02H/Et3N as a hydrogen donor and catalyzed by suitably designed chiral Ru(II)-complexes was developed by Noyori et al., and since then, it has become the method of choice in enantioselective reduction of cyclic imines. Using this protocol, several asymmetric syntheses of... 

Several approaches toward the syntheses of quinolacta-cins were published. ° In 2008, Silva Santos and coworkers applied Noyori asymmetric transfer hydrogenation of cyclic imine 218 to the total synthesis of (5)-(—)-quinolactacin B, which showed activity against mmor necrosis factor production. The hydrogenation of imine 218 was accomplished with the (/ ,/ )-Ts-DPEN-Ru(ll) complex in DMF and a HC02H/Et3N mixture to obtain amine (5)-(—)-219 in 89% yield and >90% ee (Scheme 30.43). 

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