Imine reduction

Reduction of nitrostyrene with aqueous TiCl3 gives a 3,4-diarypyrrole directly in moderate yield (Eq. 10.46).52 The reaction proceeds via dimerization of anion radicals of nitrostyrene and reduction of the nitro function in the dimer to imines. Reduction of dinitrile with diisobutylalu-minum hydride (DIBAL) gives a-free pyrroles (Eq. 10.47) 53 both reactions may proceed in a similar mechanism. These pyrroles are useful intermediates for functionalized porphyrins. 

In other studies, imine reduction by [Ir(cod)(PPh3)2]BF4 in THF has been shown to be first order in each of the catalyst, the H2, and the substrate. Initial formation of [IrH2(imine)2(PPh3)2]+ was proposed to lead to amine and [Ir(im-ine)2(PPh3)2], Oxidative addition regenerates the Ir(III) species [34]. 

The isolation of product is usually possible after evaporation of the solvent and extraction with hexane, ether, or toluene. Supported versions, for example on polystyrene grafted with PPh2 groups, have proved unsatisfactory because the rate of deactivation is greatly enhanced under these conditions [37]. Asymmetric versions exist, but the ee-values tend to be lower than in the Rh series [38]. With acid to neutralize the basic N lone pair, imine reduction is fast. Should it be necessary to remove the catalyst from solutions in order to isolate a strictly metal-free product, a resin containing a thiol group should prove satisfactory. A thiol group in the substrate deactivates the catalyst, however. 

A recent development is the transfer hydrogenation of heterocyclic systems such as pyrrole, pyridinium and quinoline systems. Whilst at present the yields and enantioselectivities are modest, further development may improve this situation. For example, 1-methyl-isoquinoline has been reduced to the tetrahydro species and 1-picoline has been reduced to 1-methylpiperidine [86]. Interestingly, these reductions involve alkene as well as imine reduction. 

One of the interesting application of 12 (R= allyl, X=Br) will be the synthesis of cyclic amino acid, (S)-pipecolic acid, as its tert-butyl ester 271251 Monoalkylation of the O Donnell imine 23 with l-chloro-4-iodobutane afforded the alkylated product 26 with 99 % ee. The conversion of 26 to the tert-butyl ester of pipecolic acid 27 was achieved in high yield by the sequence imine reduction, cyclization, and hydrogenolytic removal, as shown in Scheme 8. 

Under the conditions of iridium-catalyzed hydrogenation, alkyne-carbonyl and alkyne-imine reductive coupling occurs in the absence of stoichiometric byproducts. For example, iridium-catalyzed hydrogenation of nonconjugated alkynes in the presence of ot-ketoesters delivers the corresponding a-hydroxy esters in... 

The DCL was first composed in the absence of the CA template, a so-called blank DCL. Equilibration was complete in 24 hours, with each of the expected imine reduction products being observed in the HPLC trace (Fig. 2.2). Reconstitution of the DCL in the presence of a stoichiometric quantity of enzyme afforded the second trace. Equilibration was significantly retarded in the presence of the protein, 2 weeks being necessary for a dynamic equilibrium to be realized. A thermal denaturation step preceded HPLC analysis. 

In 2004, Rayner and coworkers reported a dynamic system for stabilizing nucleic acid duplexes by covalently appending small molecules [34]. These experiments started with a system in which 2-amino-2 -deoxyuridine (U-NH ) was site-specifically incorporated into nucleic acid strands via chemical synthesis. In the first example, U-NH was incorporated at the 3 end of the self-complementary U(-NH2)GCGCA DNA. This reactive amine-functionalized uridine was then allowed to undergo imine formation with a series of aldehydes (Ra-Rc), and aldehyde appendages that stabilize the DNA preferentially formed in the dynamic system. Upon equilibration and analysis, it was found that the double-stranded DNA modified with nalidixic aldehyde Rc at both U-NH positions was amplified 34% at the expense of Ra and Rb (Fig. 3.16). The Rc-appended DNA stabilizing modification corresponded to a 33% increase in (melting temperature). Furthermore, imine reduction of the stabilized DNA complex with NaCNBH, resulted in a 57% increase in T. ... 

The use of eontinuous-flow for rapid optimization followed by seale up was demonstrated by Steven Ley s group [66]. Imine reductions were performed in the presenee of Pd/C as eatalyst on the H-Cube flow hydrogenation system. After optimization of eonditions on small quantities, 1.0 g of desired product was synthesized within 70 min with quantitative yield and exeellent purity. Worth noting is that the reactions progressed quantitatively without the need for further purifieation. 

The reaction involves formation of an imine through reaction of ammonia with the ketone, followed by reduction of this imine (see Section 7.7.1). As we noted earlier (see Section 15.1.1), nicotinamide coenzymes may also participate in imine reductions as well as aldehyde/ketone reductions, further emphasizing the imine-carbonyl analogy (see Section 7.7.1). The reverse reaction, removal of ammonia from glutamate, is also of importance in amino acid catabolism. 

Since imines derived from alkyl-alkyl ketones are relatively unstable, reductive amination may be more practical compared to imine reduction. Compared to the reductive amination, which employs three equivalents of the ketone substrate, the in situ imine generation/one-pot reduction protocol has the significant advantage that it does not require an excess of the carbonyl compound. 

In the special case of a-alkyl-a -nitro-substituted imines, reduction with sodium borohydride/ cerium(III) chloride and elimination of the chiral auxiliary generated the nitroalkene without racemization22. 

Adolfsson published an overview of these types of reactions and these systems are also reported to be active for imine reduction (see Section 1.3). 

A good example of conventional gaseous hydrogenation methodology is the very efficient imine reduction shown in Figure 1.21 using iridium XYLIPHOS catalyst. 

Figure 1.21 Syngenta imine reduction for Dual Magnum intermediate.

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