Imines trichlorosilanes

Various chiral ligands with metal catalysts can be employed in the organosilane reduction of imines to amines. Many of these provide modest success. These include (oxazolino)diphenylphosphinoferrocene ligands with ruthenium,605 (—)-DIOP/Rh(I),606,607 3,3 -BINOL (l,l -bi-2-naphthol) and LiHMDS,608 and (S)-phenyl V-formylprolinamidc with trichlorosilane.609... 

Hydrogenation of imines, e.g. 45-48, with a chiral titanocene catalyst at 2000 psig gave the corresponding optically active secondary amines in high enantiomeric excess74. Imines are reduced to amines by trichlorosilane/boron trifluoride etherate in benzene75. 

Next, a few examples of asymmetric reductions with trichlorosilane are presented. An asymmetric reduction of ketones and imines was reported by Matsumura and coworkers by using trichlorosilane as reductant and A-formyl pyrrolidine derivative 36 as ligand (Scheme 28) [101, 102]. 

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... 

Table 7.7 Asymmetric reduction of imines 80 with trichlorosilanes catalyzed by chiral amides (10 mol%) derived from cyclic amino acids in CH2CI2 (Scheme 7.18 and Fig. 7.4) [3c, 79, 81, 82],...

Trichlorosilane (77 pL, 0.77 mmol) was added dropwise to a stirred solution of the imine (100 mg, 0.51 mmol) and catalyst (13.5 mg, 0.051 mmol) in anhydrous toluene (2 mL) at 0 °C, and the mixture was stirred at r.t. overnight under an argon atmosphere. The reaction was quenched with a saturated solution of NaHCC>3 (10 mL) and the product was extracted with ethyl acetate (3 x 30 mL). The extract was washed with brine, dried over anhydrous MgSC>4, and the solvent was evaporated. Purification using column chromatography on silica gel with a petroleum ether-ethyl acetate mixture (24 1) afforded the (S)-(+)-amine (81 mg, 81%, 92% ee) as an oil [a]D + 16.8 (c 0.5, MeOH). 

Reduction of Imines with Trichlorosilane Catalyzed by Chiral Lewis Bases... 

Silanes are widely recognized as efficient reagents for reduction of carbonyl and heterocarbonyl functionality. In the case of alkyl and arylsilanes, the reaction requires catalysis by Lewis acids or transition metal complexes 1, 3] however, with more Lewis acidic trichloro or trialkoxysilanes, an altemative metal free activation can be accomplished. Thus, it has been demonstrated that extracoordinate silicon hydrides, formed by the coordination of silanes to Lewis bases, such as tertiary amines 7a], DMF [7b] or MeCN, and so on [7], can serve as mild reagents for the reduction of imines to amines [8]. In the case of trichlorosilane, an inexpensive and relatively easy to handle reducing reagent, and DMF as a Lewis basic promoter, the intermediacy of hexacoordinate species has been confirmed by Si NMR spectro scopy [7b]. 

Table 4.7 Synthesis of esters of a substituted 3 amino acids 40 by reduction of enamines/imines 38/39 with trichlorosilane, catalyzed by Sigamide 35 (Scheme 4.4). ...

The experiments reported by Malkov and Kocovsky [12h] and by Sun [lla,b,e,f], indicate that the Lewis base catalyzed imine reduction with trichlorosilane is not affected by isomeric nonhomogeneity of the starting imines. Thus, for example, imines 9h-9j, which exist as 5 2 to 5 3 E/Z mixtures, were reduced to the corresponding amines with 94 97% ee (Table 4.5, entries 8 10). Appar ently, traces of HCl, naturally present in the moisture sensitive Cl3SiH, trigger an E/Z equilibration of imines 6-10, which is faster than the reduction (Scheme 4.5). 

More recently, in organocatalysis, Kocovsky [69] has reported asymmetric reduction of imine with trichlorosilane catalyzed by an (A-methylvaline)-derived formamide anchored to a polymer. Under the best conditions, with 15 mol% of the catalyst enantiomeric excesses were about 85% and the catalyst could be reuse. 

A contribution by Matsumura and co-workers [33] in 2006 paved the way toward the development of a novel class of catalysts for trichlorosilane-mediated reductions, derived from chiral amino alcohol. This group identified a series of IV-picolinoyl-pyrrolidine derivatives able to activate trichlorosilane in the reduction of aromatic imines, leading to good enantioselectivity (up to 80%). The authors proposed that both the nitrogen atom of the picolinoyl group and the carbonyl oxygen atom are involved in the coordination and activation of the silicon atom (Scheme 15.9). 

The presence of two stereogenic centers on the amino alcohol moiety with the correct relative configuration such as in (1/ , 25)-(—) ephedrine is necessary to stereodirect the imine attack by trichlorosilane. 

In order to enable the isolation procedure of the organocatalysts, Kocovsky s group also reported an alternative approach using a dendron-anchored organocat-alyst 103 to efficiently reduce the imines with trichlorosilane 2 [209]. The isolation procedure of the catalyst from the crude was substantially simplified, since most of the catalyst (>90 %) could be recovered by precipitation and centrifugation (Fig. 10). 

Although the reduction of imines has been widely explored, as described above, the reduction of carbonyl groups has been less studied until now. Specifically, the reduction of ketones is more limited due to the low reactivity shown by these compounds. In this field, the pioneering works using trichlorosilane as reducing agent and a chiral Lewis base were reported by Matsumura and co-workers in 1999,... 

A new addition to the variety of reagents already available for the reduction of imines to the corresponding secondary amines is trichlorosilane, and trimers of simple alicyclic imines have been shown to react with malonic acid derivatives to provide the corresponding amines with formation of a C—C bond at the a-position. ... 

Table 15.8 Asymmetric reduction of imines 106 derived from aromatic amines with trichlorosilanes catalyzed by chiral Lewis bases 110,112-115,118, and 120-124 (Scheme 15.25 and Figures 15.5 and 15.6).

After the methodology for asymmetric reduction of imines with trichlorosilane employing model substrates had been firmly estabhshed, the focus of research in the field gradually shifted towards the synthesis of functionahzed chiral amines, which represent important building blocks for pharmaceutical, agricultural, and fine chemical industries. 

Next to be investigated were the members of the homologous series, namely, P-imino nitriles 133 and P-imino esters 134, existing predominantly in the conjugated enamine forms 131 and 132, which cannot be reduced with trichlorosilane (Scheme 15.27) [97d]. However, Maikov and Kocovsky found that Bronsted acids can facilitate the enamine-imine equiUbrium and provide sufficient concentration of the desired imine form, whose reduction can now be accomphshed. In the case of Sigamide 114b, acetic acid (1 equiv) was identified as an optimal additive the reduction, carried out in its presence, afforded the expected P-amino nitriles 135 and P-amino esters 136 in high yields and enantioselectivities (Table 15.12, entries 1 and 2). 

Recently, the methodology was successfully employed for the enantioselective reduction of indoles 137 into indolines 138 using catalysts 113c and 118b (Scheme 15.28) [98gj. To faciUtate the enamine/imine tautomeric equiUbrium, the required Br0nsted acid was generated by a controlled hydrolysis of excess trichlorosilane with water. 

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