Reduction of Acetophenone using

The enantioselective reduction of acetophenone using pyrrolidine-oxazoline-derived ligand 6.77 and [IrCl(COD)]2 gave optically pure alcohol (41-49% ee). n OH... 

Polymer-supported chiral oxazoborolidines have also been used for the reduction of prochiral ketones. Enantiomeric excesses of 98% were obtained for the reduction of acetophenone using borane dimethyl sulfide as a stoichiometric reducing agent [77, 78]. 

The first attempt to use a chiral ligand to modify borane was Kagan s attempt at enantioselective reduction of acetophenone using amphetamine-borane and desoxy-ephedrine-borane in 1969 [18]. However, both reagents afforded 1-phenyl ethanol in <5% ee. The most successful borane-derived reagents are oxazaborolidines, introduced by Hirao in 1981, developed by Itsuno, and further developed by Corey several years later (reviews [19,20]). Figure 7.2 illustrates several of the Hirao-Itsuno and Corey oxazaborolidines that have been evaluated to date. All of these examples are derived from amino acids by reduction or Grignard addition. Hirao... 

In the presence of 10 mol% of the BH3/oxazaborolidine catalyst 14, an enantiomeric excess of 50% was obtained in the reduction of acetophenone. Use of a bulkier aromatic substituent such as 9-acetylphenanthrene led to a rise in enan-tioselectivity (62% ee). For the reduction of acetophenone, it was further found that catalyst precursor 16 with opposite absolute planar chirality but identical central chirality gave a drastic drop in enantioselectivity (25% ee). 

Locatelli et al. [13] investigated the hydride transfer reduction of prochiral ketones using a rhodium based catalyst on a polyurea support. The homogeneous reduction of acetophenone using a rhodium catalyst with two equivalents of (1 S, 2 5 )-iV,iV -dimethyl-l,2-diphenylethane diamine was conducted to establish an appropriate comparison for the imprinting studies. This control reaction resulted in formation of 1-(J ) -phenyl ethanol with 67% ee (Scheme 6). The low enantioselectivity was attributed to a poor coordination sphere surrounding the metal center. The selectivity from the hydride transfer is proposed to arise from the approach of the substrate to the metal center, as shown in Scheme 7. The metal... 

The hydride-donor class of reductants has not yet been successfully paired with enantioselective catalysts. However, a number of chiral reagents that are used in stoichiometric quantity can effect enantioselective reduction of acetophenone and other prochiral ketones. One class of reagents consists of derivatives of LiAlH4 in which some of die hydrides have been replaced by chiral ligands. Section C of Scheme 2.13 shows some examples where chiral diols or amino alcohols have been introduced. Another type of reagent represented in Scheme 2.13 is chiral trialkylborohydrides. Chiral boranes are quite readily available (see Section 4.9 in Part B) and easily converted to borohydrides. 

Finally, the use of S/P ligands derived from (i )-binaphthol has been considered by Gladiali et al. in the asymmetric rhodium-catalysed hydrogen-transfer reduction of acetophenone performed in the presence of i-PrOH as the hydrogen donor.It was noted that racemisation occurred when the reaction time increased and consequently the corresponding alcohol was obtained in only low enantioselectivities (< 5% ee) as shown in Scheme 9.21. Similar results were more recently reported by these authors by using iridium combined with the same ligands. ... 

Kragl and Wandrey made a comparison for the asymmetric reduction of acetophenone between oxazaborolidine and alcohol dehydrogenase.[59] The oxazaborolidine catalyst was bound to a soluble polystyrene [58] and used borane as the hydrogen donor. The carbonyl reductase was combined with formate dehydrogenase to recycle the cofactor NADH which acts as the hydrogen donor. Both systems were run for a number of residence times in a continuously operated membrane reactor and were directly comparable. With the chemical system, a space-time yield of 1400 g L"1 d"1 and an ee of 94% were reached whereas for the enzymatic system the space-time yield was 88 g L 1 d"1 with an ee of >99%. The catalyst half-life times were... 

The reduction of dialkylketones and alkylaryl ketones is also conveniently accomplished using chiral oxazaborolidines, a methodology which emerged from relative obscurity in the late 1980s. The type of borane complex (based on (,V)-diphenyl prolinol)[39] responsible for the reductions is depicted below (10). Reduction of acetophenone with this complex gives (/ )-1 -phenylethanol in 90-95% yield (95-99% ee) [40]. Whilst previously used modified hydrides such as BiNAL-H (11), which were used in stoichiometric quantities, are generally unsatisfactory for the reduction of dialkylketones, oxazaborolidines... 

In 1969, Fiaud and Kagan[U1 tested ephedrine boranes but achieved only 3.6-5% enantiomeric excess in the reduction of acetophenone. Itsuno et a/.[121 reported in 1981 an interesting enantioselective reduction of a ketone using an amino alcohol-borane complex as a catalyst. Buono[131 investigated and developed the reactivity of phosphorus compounds as ligands in borane complexes for asymmetric hydrogenation. 

In the later work, low optical activity (<30% ee) was observed for the products [e.g. 5] and the high asymmetric induction of the earlier work was attributed to carry over of the catalyst or chiral degradation derivatives (oxiranes) of the catalysts. Although the reported stereoselective reduction of acetophenone has been discredited, it has been suggested that the use of a chiral solvent, such as menthyl methyl ether, enhances the asymmetric reduction [7], The veracity of this claim has not been proven. 

A marked solvent effect on the sense of asymmetric induction was observed. For example, reduction of acetophenone with 65 in refluxing ether gave the (R)-alcohol in 48% optical yield, and reduction in boiling THF gave die (S)-alcohol in 9.5% optical yield. A number of other similar reversals were observed. In ether solvent, an empirical relationship can be drawn between the configuration of the alcohol used for preparation of the reducing complex and the configuration of the enantiomeric product alcohol formed in excess. The relationship depends on the type of substrate used and is summarized in Table 8. 

Antimony(III) trichloride can be used as a catalytic mediator in the electroreduction of carbonyl compounds. The advantage of the procedure is illustrated by the selective reduction of acetophenones (497), leading to the corresponding benzylic alcohols (498) (Scheme 173) [575]. The electroreduction is performed in an EtOH/BuOH(l/1.5)-aq.HCl-(Pt/Pb) system in the presence... 

A detailed kinetic study of the enantioselective reduction of acetophenones, ArCOMe, to arylethanols, using a propan-2-ol-acetone couple and a chiral rhodium diamine catalyst, has been undertaken.Non-linear effects on the % ee are observed, e.g. addition of achiral ketones can both slow the reaction and raise the ee. These effects can be rationalized in terms of the difference in reactivity of diastereomeric catalytic sites. The scope for exploiting such mechanistic insights so as to maximize the enantioselectivity is discussed. 

Scheme 5.4 shows some examples of enantioselective reduction of ketones using I. Adducts of borane with several other chiral /i-aminoalcohols are being explored as chiral catalyst for reduction of ketones.102 Table 5.6 shows the enantioselectivity of several of these catalysts toward acetophenone. 

The use of a chiral polymer instead of the achiral polymers in XXXIX and XXXX allows an asymmetric synthesis. An example is the stereoselective reduction of acetophenone to (I )-l-phenylethanol in 76-97% enantiomeric excess by using the indicated chiral support (Eq. 9-69) [Itsuno et al., 1985] ... 

A modified oxazaborolidine 2 catalyzing the enantioselective reduction of acetophenone or tetralone with borane proved to give ttn values in the same order of magnitude [10, 11]. Using a special hydroxyproUne-based polymer-enlarged oxazaborolidine 3, a ttn of 1400 for the reduction of tetralone was achieved (Fig. 3.1.3, 3) [5, 12]. 

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