Substrates imine

Another example for the use of hydrogen as reductant is observed in the reduction of imine [5b]. New imine reductase activity has been discovered in the anaerobic bacterium Acetobacterium woodii by screening a dynamic combinatorial library of virtual imine substrates, using a biphasic water-tetradecane solvent system. 

PreUminary studies on the racemic reaction of protected imines with ni-tromethane showed that the thiourea and the amine mutually weakened their reactivities. However, the bifunctional amino-thiourea led to good results. Enantioselectivity of the adduct depended on the protecting group, P(0)Ph2 affording the best results (76% ee). Then, other aromatic imines substrates were successfully phosphorylated with good to high enantioselec-tivities (63-76% ee). 

Fig. 25.18 Structures of ketone and imine substrates listed in Table 25.9.

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. 

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. 

Scheme 3-56 shows an example of the generation of chiral amines via nucleophilic attack onto an imine substrate in the presence of an external homochiral auxiliary. Moderate ee can be obtained from 161-induced reactions, and moderate to high ee can be expected from 162-induced reactions. For instance, when 161 (R1 = Et, R2 = t-Bu) is involved in the reaction, nucleophilic attack of RLi (R = Me, -Bu. and vinyl) on imine 163 gives product 164 with 81-92%... 

Kobayashi and his team have utilized a catalytic system similar to that used in their development of a Zr-catalyzed Mannich reaction (Schemes 6.27—6.29) to develop a related cycloaddition process involving the same imine substrates as used previously (Scheme 6.35) [105]. As the representative examples in Scheme 6.35 demonstrate, good yields and enantioselectivities (up to 90% ee) are achieved. Both a less substituted version of the Danishefsky diene (—> 110) and those that bear an additional Me group (e. g.— 111) can be utilized. Also as before, these workers propose complex 89, bearing two binol units, to be the active catalytic species. 

Figure 1.31 illustrates a mechanism proposed for this hydrogenation. The titanocene hydride 31A is expected to be a catalytic species. The imine substrate is inserted into the Ti—H bond of 31A with a 1,2-fashion to form a titanocene amide complex 31B. Then the hydrogenolysis of 31B through a a-bond metathesis produces the amine product with regeneration of 31A. The enantioface selection... 

Interestingly, fundamentally different stereoinduction mechanisms have been proposed for the activation of a number of related imine substrates, studies that resulted in the development of simple and highly effective new catalytic systems (27) for the addition of silyl ketene acetals to Al-Boc-protected aldimines (Mannich reaction) (Scheme 11.12c). ... 

Furthermore, a highly efficient route to A-tert-butoxycarbonyl (Boc)-protected p-amino acids via the enantioselective addition of silyl ketene acetals to Al-Boc-aldimines catalyzed by thiourea catalyst 4 has been reported (Scheme 12.2)." From a steric and electronic standpoint, the A-Boc imine substrates used in this reaction are fundamentally different from the A-alkyl derivatives used in the Strecker reaction. 

Prior to Yamamoto s entry into this field, the scope of chiral phosphoric acid catalysis was strictly limited to electrophiUc activation of imine substrates. By designing a catalyst with higher acidity it was suspected that activation of less Lewis basic substrates might be possible. To this end, Yamamoto reported incorporation of the strongly electron accepting N-triflyl group [57] into a phosphoric acid derivative to yield the highly acidic N-triflyl phosphoramide 13 (Scheme 5.32)... 

While all of the aryl imine substrates examined for this Strecker methodology existed predominantly or exclusively as the E-isomers, this did not appear to be a requirement for high enantioselectivity as demonstrated in the asymmetric 42-cat-alyzed (2 mol% loading) hydrocyanation of the cyclic Z-imine 3,4-dihydroisoquino-line, which was converted to the corresponding adduct (88% yield, 91% cc) with the same sense of stereoinduction with respect to the benzylic stereogenic center as the examined acyclic E-imines (Schemes 6.41 and 6.42) [196]. 

With thiourea 52 as the catalyst (5-10 mol%), a range of substituted S-configured tetrahydro- 3-carbolines 1-5 were accessible in good yields (65-81%) and high enantioselectivities (85-95%) as shown in Scheme 6.50. The imine substrates of this two-step procedure were generated in situ by condensation of the tryptamine with the respective aldehyde (1.05 equiv.) and were directly used without further purification (Scheme 6.50). Recovered (by chromatography) pyrrole thiourea catalyst 52 could be reused without the loss of activity or selectivity. 

The Zr-catalyzed asymmetric alkylation shown in Eq. (2) [8] illustrates two important principles (1) The catalytic asymmetric protocol can be readily applied to the synthesis of non-aryl imines to generate homochiral amines that cannot be prepared by any of the alternative imine or enamine hydrogenation protocols. (2) The catalytic amine synthesis involves a three-component process that includes the in situ formation of the imine substrate, followed by its asymmetric alkylation. This strategy can also be readily applied to the preparation of arylamines. The three-component enantioselective amine synthesis suggests that such a procedure maybe used to synthesize libraries of homochiral amines in a highly efficient and convenient fashion. 

As shown in Scheme 1.95, the chiral titanocene catalyst 34 (see Scheme 1.10) prepared from 33, n-C4HgLi, andC6H5SiH3 shows a moderate-to-good enantioselectivity in the hydrogenation of /V-benzyl i mines of aryl methyl ketones, whereas the catalytic activity is rather low even at 137 atm [346]. The ketimine with R1 = 4-CH3OC6H4 is hydrogenated with (/ )-34 to give the R amine with 86% ee. The E Z of the imine substrate affects the enantioselection. The optical... 

Asymmetric hydrogenation of Scheme 1.101 provides a general route to isoquinoline alkaloids (see Section 1.3.1.1). An imine substrate is hydrogenated with the chiral titanocene (/ )-34 to give the S product with 98% ee [346a,b,352], A neutral BCPM-Ir complex with phthalimide in toluene also shows high enantioselection [358]. The choice of a weakly polar... 

The structure of the imine substrate was also optimized. Since the use of amino acid methyl ester-derived substrates was highly desirable, the only aspect of substrate... 

Formamides derived from L-pipecolinic acid act as Lewis base organocatalysts for reduction of A-arylimines with trichlorosilane, giving yields and ees in the high 90s for a wide range of imine substrates.54... 

Solin N, Kjellgren J, Szabo KJ (2004) Pincer complex-catalyzed allylation of aldehyde and imine substrates via nucleophilic ri -allyl palladium intermediates. J Am Chem Soc 126 7026-7033... 

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