Hydrogenation cyclic imine

Scheme 8.5 Buchwald s example of asymmetric hydrogenation of cyclic imine.

Asymmetric hydrogenation of a cyclic enamide (Approach B) had very sparse literature precedents [7]. It should also be noted that preparation of these cyclic imines and enamides is not straightforward. The best method for the synthesis of cyclic imines involves C-acylation of the inexpensive N-vinylpyrrolidin-2-one followed by a relatively harsh treatment with refluxing 6M aqueous HC1, which accomplishes deprotection of the vinyl group, hydrolysis of the amide, and decarboxylation (Scheme 8.6) [8]. 

The asymmetric hydrogenation of acyclic imines with the ansa-titanocene catalyst 102 gives the chiral amines in up to 92% ee.684,685 This same system applied to cyclic imines produces the chiral amines with >97% ee values.684,685 The mechanism of these reductions has been studied 686... 

As illustrated in the hydrogenation of cyclic imines, the system is compatible with a wide range of functional groups, such as olefins, protected or unpro-... 

Table 6.5 Enantioselective hydrogenation of cyclic imines catalyzed by [(R,R,R)-(EBTHI)TiX2],...

Ru-diphosphine-diamine complexes developed originally by Noyori for the hydrogenation of aryl ketones are also suitable for the hydrogenation of imines. The best results are obtained for N-aryl imines where a Ru-duphos-diamine complex achieved up to 94% ee, albeit with relatively low activity and productivity (entry 3.7) (for data relating to cyclic imines, see Table 34.5). 

Cyclic imines do not have the problem of syn/anti isomerism and therefore, in principle, higher enantioselectivities can be expected (Fig. 34.8). Several cyclic model substrates 6 were hydrogenated using the Ti-ebthi catalyst, with ee-val-ues up to 99% (Table 34.5 entry 5.1), whereas enantioselectivities for acyclic imines were <90% [20, 21]. Unfortunately, these very selective catalysts operate at low SCRs and exhibit TOFs <3 h-1. In this respect, iridium-diphosphine catalysts, in the presence of various additives, seem more promising because they show higher activities. With several different ligands such as josiphos, bicp, bi-... 

Table 34.5 Selected results for the enantioselective hydrogenation of cyclic imines (for structures, see Fig. 34.8) Catalytic system, reaction conditions, enantioselectivity, productivity and activity.

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-... 

Particularly noteworthy is the discovery of a new type of the active catalyst 99,103,104 a crystalline, air-stable yellow-orange solid, which can serve as a highly enantioselective tool in the titanium-catalyzed hydrosilylation of imines. The reaction can be highly stereoselective for both acyclic and cyclic imines under a wide range of hydrogen pressures (Scheme 6-46). 

The Brintzinger-type C2-chiral titanocene catalysts efficiently promote asymmetric hydrogenation of imines (Figure 1.30). A variety of cyclic and acyclic imines are reduced with excellent enantioselectivity by using these catalysts. The active hydrogenation species 30B is produced by treatment of the titanocene binaphtholate derivative 30A with n-butyllithium followed by phenylsilane. 

Highly enantioselective hydrogenation of geometry-fixed cyclic imines has been achieved by the use of certain chiral Ti and Ir catalysts [14,17]. In particular, a chiral titanocene catalyst developed by Buchwald possess excellent enanti-odifferentiating ability for a variety of cyclic substrates [18]. 

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. 

The activity and enantioselectivity of chiral Ir catalysts have been tested by using 2,3,3-trimethylindolenine as a model substrate. Hydrogenation of the cyclic imine with [Ir(bdpp)Hl2 2 gives the corresponding chiral amine with 80% ce (Scheme 1.99) [350]. The stereoselectivity is somewhat better than that with acyclic substrates (see Scheme 1.94). A neutral BCPM-Ir complex with Bil3 effects asymmetric hydrogenation in 91% optical yield [354], A complex of MCCPM shows similar enantioselection [354], These complexes are not applicable to the reaction of other acyclic and six-membered cyclic imines. An MOD-DIOP-Ir complex is also usable with the aid of ( -C4H9)4NI [355], An Ir complex of BICP with phthalimide effectively... 

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. 

Lonza has performed the asymmetric hydrogenation of a cyclic imine 64 with iridium catalysts that contain 4j to form dextromethorphan (65), an antitussive, in 90% ee (Scheme 12.20) at the multi-kilogram scale (>100 kg produced).87... 

The Pictet-Spengler reaction, the cyclization of an electron-rich aryl or heteroaryl group onto an imine electrophile, is the established method for the synthesis of tetrahydroisoquinoline and tetrahydro-/ -carboline ring systems. Catalytic asymmetric approaches to these synthetically important structures are mostly restricted to asymmetric hydrogenations of cyclic imines [77, 78]. In a noteworthy... 

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