Reduction of acetophenone

The present procedure was developed from those of Wallach and Freylon, based upon the general method discovered by Leuckart. a-Phenylethylamine also can be prepared satisfactorily by the reduction of acetophenone oxime with sodium and absolute alcohol or sodium amalgam, but the reagents are more expensive and the processes less convenient. The amine has been obtained by reducing acetophenone oxime electro-lytically, by reducing acetophenone phenylhydrazone with sodium amalgam and acetic acid, from a-phenylethyl bromide and hexamethylenetetramine, and by the action of methyl-magnesium iodide upon hydrobenzamide, as well as by other methods of no preparative value. 

The most successful of the Lewis acid catalysts are oxazaborolidines prepared from chiral amino alcohols and boranes. These compounds lead to enantioselective reduction of acetophenone by an external reductant, usually diborane. The chiral environment established in the complex leads to facial selectivity. The most widely known example of these reagents is derived from the amino acid proline. Several other examples of this type of reagent have been developed, and these will be discussed more completely in Section 5.2 of part B. 

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 One class of reagents consists of derivatives of LiAlH4 in which some of die hydrides have been replaced by chiral ligands.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. 

Reaction without 2-hexanol. 1 Reduction of acetophenone in hexane by the ed resting cell ofCeothchumcondWwni and 2-hexanol [18aj. ... 

In one case, the insertion of the whole chiral hgand into a Co-exchanged zeohte by subhmation was described [24], Only small ligands, such as li and 2i, can be efficiently introduced into the micropores of the Y zeohte, whereas the bulkier Jacobsen s hgand la only remains on the external surface of the sohd. Unfortunately, these occluded (salen)Co complexes led to very low enantioselectivities (up to 8% ee) in the reduction of acetophenone with NaBH4. 

BHj-Carbonyl Hydrogenations Investigated in Micro Reactors Organic synthesis 76 [OS 76] Reduction of acetophenone... 

Reduction of acetophenone by PrOH/H has been studied with the ruthenium complexes [Ru(H)(ri2-BH )(CO)L(NHC)], (L = NHC, PPh3, NHC = IMes, IPr, SIPr). The activity of the system is dependent on the nature of the NHC and requires the presence of both PrOH and H, implying that transfer and direct hydrogenation mechanisms may be operating in parallel [15]. 

In the same study, these authors also described the synthesis of other S/N ligands derived from various amino acids, such as proline, valine and cysteine. These dithioether and azathioether ligands were further tested as potential palladium ligands for the reduction of acetophenone, but no significant induction was observed in each case of ligand (Scheme 8.26). 

In the same study, these authors have prepared another series of amino-sulf(ox)ide ligands based on the (Nor)ephedrine and 2-aminodiphenylethanol skeletons, bearing two chiral centres in the carbon backbone.Their application to the iridium-catalysed hydrogen-transfer reduction of acetophenone generally gave better yields, but the enantioselectivity never exceeded 65% ee (Scheme 9.4). 

Scheme 9.2 Ir-catalysed reduction of acetophenone with aminosulf(ox)ide ligands.

In the same study, several ligands variously functional on both the nitrogen and the sulfur atoms have been developed, providing a new class of cyclo-hexylamino sulfide ligands derived from cyclohexene oxide. All the ligands depicted in Scheme 9.7 were evaluated for the Ir-catalysed hydride-transfer reduction of acetophenone in the presence of i-PrOH as the hydrogen donor, providing enantioselectivities of up to 70% ee. 

Scheme 9.13 Ru-catalysed reduction of acetophenone with phosphino-oxazoline ligands.

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. ... 

Scheme 9.21 Rh- and Ru-catalysed reductions of acetophenone with BINOL-derived S/P ligands.

Scheme 10.54 Borane reduction of acetophenone with sulfoximine ligand.

Scheme 10.64 Heterogeneous borane reduction of acetophenone with MerCO ligand.

Recently, enantioselective procedures involving chiral catalysts have been developed. The combination of BINOL and A1(CH3)3 can achieve 80% e.e. in the reduction of acetophenone.192 Compound J is also an effective catalyst.193... 

In a similar vein, the keto bridge in 5 can be replaced by oxygen with retention of activity. Reduction of acetophenone derivative 19 by means of sodium borohydride leads to the corresponding alcohol (20). Reaction with phosphorus tribromide with cyanide gives... 

Figure 7.10 Reduction of acetophenones with designer cells ...

The ruthenium complex of NH-benzyH 17T2,S )-norephedrine covalently tethered to silica showed a high activity and enantioselectivity in the reduction of acetophenone.310... 

Certain catalysts promote the reduction of ketones with organosilanes. The reduction of acetophenone with Et3SiH is catalyzed by the diphosphine 65 and gives only a small amount of overreduction to ethylbenzene.377 Aryl alkyl enones and ynones are reduced to the corresponding alcohols with triethoxysilane and the titanium-based catalyst 66.378 Trichlorosilane reduces acetophenone in 90% yield with /V-formylpyrrolidinc catalysis.379... 

The reduction of acetophenone was carried out at r.t. giving 86% yield with an ee of 97%. This is similar to the ee obtained with unbound analogues. A limited study was conducted on the retention of the catalyst by nanofiltration. It was found that the compound could be retained in the membrane reactor but no specific details were given about these measurements. 

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