Acetophenone, reduction with chiral

Asymmetric reductions with chiral complex metal hydrides and tricoordinate hydride reagents are rare. Iminium salts25 26 and imines27 have been reduced by chiral complex aluminum hydrides. Optically active 2-substituted Ar-methylpiperidine was obtained by reduction of the corresponding 3,4,5,6-tetrahydropyridinium perchlorate with (—)-menthol lithium aluminum hydride. The optical purity for the -propyl derivative was 12% in favor of the S configuration. Similar reductions of imines prepared from acetophenone and propiophenonc with (-)-mcn-thol-lithium aluminum hydride and ( + )-borneol-lithium aluminum hydride reagents resulted in low (<10%) optical yields in those examples where optical yields could be calculated. 

A chiral aminoalane (117) has been synthesized (eq. [30]) as well as a novel polymeric aminoalane (118) (139). Reduction of acetophenone by 117 in ether at -71°C gave the (S)-carbinol in an 85% optical yield (51% synthetic yield). Reduction of dialkyl ketones with 117 gave considerably lower optical yields, as did reductions with 118. 

Organic molecules that contain sp2 hybridized carbons can also be prochiral if the substituent pattern is correct. An example is provided by phenylethanone (acetophenone, 9), which has three different groups attached to the carbonyl carbon. After reduction with, say, LiAlH4, the product is the chiral alcohol 10 and a 50 50 mixture of enantiomers is observed. The same racemic mixture is obtained from the reaction of the Grignard reagent MeMgBr with benzaldehyde (11). In contrast, the product of reduction of propanone (12) with LiAlH4 is propan-2-ol (13), which is not chiral. 

The resulting achiral iminium cations, with chiral phosphate counteranion, were then enantioselectively reduced using an achiral Hantzsch ester (dihydropyridine) providing enantioenriched amines. During this imine reduction study, one example was shown in which acetophenone and p anisidine [16] were prestirred in the presence of toluene and 4 A molecular sieves [17] for 9h (imine formation), after which the temperature was raised to 35 °C, and the Hantzsch ester (1.4 equiv) and phosphoric acid (TRIP, 5 mol%) were added to give the amine product in 88% ee over an additional 45 h. This is an exciting observation and while not a reductive amination, it is an operational improvement over simple imine reduction which requires imine isolation. 

The extent of asymmetric induction with chiral Rh(I) complexes remains unsatisfactory. Enantioselective reduction of acetophenone catalyzed by a Rh complex of the chiral phenanthroline 11 in 2-propanol containing KOH at 60 °C af-... 

Since the first asymmetric reduction of ketones with chiral borohydrides by Itsuno et al. [ 1 ], a number of studies on the asymmetric reduction of ketones with chiral borane reagents have been demonstrated [2]. Corey s oxazaborolidines are some of the most successful reagents [3 ]. The effect of fluorine substituents was examined in the asymmetric reduction of acetophenone with LiBH4 by the use of chiral boronates (73) obtained from substituted phenyl boronic acid and tartaric acid [4]. Likewise, 3-nitro, fluorine, and trifluoromethyl groups on the 3- or 4-position provided enhanced stereoselection (Scheme 5.20). 

Amino-l-(3-hydroxyphenyl)ethanol has been prepared by an improved and possibly general method for this class of compounds.16 An interesting report on the partial asymmetric induction in the reduction of acetophenone-N-benzylimine at the mercury cathode with chiral supporting electrolytes may have potential for the chiral synthesis of alkaloids.17 For example, using ( -)-(R, S)-JV-methyI-ephedrine methiodide as the electrolyte resulted in the formation of (—)-(R)-N-benzyl-a-phenethylamine of 7.3% optical purity. Of interest for biosynthetic studies are the reports of the preparation of specifically labelled substituted -phenethylamines18 and of (+)-N-(o-chlorobenzyl)-a-methylphenethylamine hydrochloride 14C-labelled at the -carbon.19... 

The asymmetric reaction of cyclic ketones can be performed with chiral bi-naphthylphosphines (Eq. 8) [47-50]. The reaction of acetophenones with ortho-bromonitrobenzenes followed by reduction affords indole derivatives (Eq. 9)... 

Several new chiral modifications of lithium aluminium hydride have been reported, including those formed by reaction with chiral secondary benzylamines (14), with diols such as (15) derived from D-mannitol, or with terpenic glycols such as (16). These complexes reduce phenyl alkyl ketones to optically active phenyl carbinols, and enantiomeric excesses of up to 50% have been observed in the case of reagents derived from (14). However, in the diol complexes, believed to have structures of the type shown in (17), lower chiral selectivity is observed, e.g. up to ca. 12% in the case of (15), or up to an optical yield of 30% with an ethanol-modified complex of (16). Better results have been reported with the chiral diamine complex (18), derived originally from L-proline, which reduces acetophenone in 92% optical yield. Asymmetric induction with reagents in this class (i.e. derivatives of lithium aluminium hydride) is usually low in the reduction of aliphatic ketones, but a complex of UAIH4 and the amino-alcohol (19) has been shown to reduce... 

In homogeneous eatalysis using chiral diamine 18 complexed with Rh, the acetophenone was reduced quantitatively with 55% ee, in 7 days. In the case of polymerized complex 36a, acetophenone reduction leads to 33% ee and with its templated analog 43% ee. With 36b, an increase of about 20% ee is observed between polymerized and templated ligand. These increases in ee were ascribed to a favonrable molecnlar imprinting effect of the PM, creating chiral pockets within the polymer network. 

Table 26.22 Asymmetric reduction of acetophenone and 3-methyl-2-butanone with chiral dial-kylmonoalkoxyborohydride [3]...

Figure 7. Reduction of acetophenone with chiral lithium dialkoxyaminoborohydrides.

In a demonstration of a reductive acoination in water, acetophenone reacts with anilines to give A-alkylated products, PhCH(Me)-NH-Ar, in high yield, using an iridium complex. " " A bell-shaped pH-rate profile shows a maximum at ca 4-5 this may opti- 0 mally protonate an imine intermediate, while leaving the ketone neutral. Excessively low pH would suppress imine formation. The reaction has been extended to other acetophenones and to acetone, and the aniline can be substituted with benzylamine or other alkylamines, and a test with a chiral amine gave >98% de. 

---