Reduction of chloroacetophenone

ASYMMETRIC REDUCTION OF CHLOROACETOPHENONE USING A SULFOXIMINE CATALYST S]... 

On the basis of such hypothesis, the synthesis and use of new phosphine oxides from (S)-prolinol has been realized. Thus, enantioselective borane reduction of chloroacetophenone at 60 °C in THF in presence of 1 mol% of 24 led to the expected alcohols in up to 94% ee [34]. 

A more appealing feature is that one-pot synthesis of chiral styrene oxides can be performed by sequential asymmetric reduction of chloroacetophenones with the chiral Rh in 2-propanol followed by treatment of the reaction mixture with NaOH aqueous solution, leading to the desired products in isolated yields of 80-90% with 96-98% ee in a single reactor (Fig. 7) [37]. For example, (5)-w-chlorostyrene oxide, which is a key intermediate for the preparation of several p3-adrenergic receptor agonist compounds, is easily obtained from a one-pot procedure. 

Figure 7.9 Reduction of a-chloro-3 -chloroacetophenone catalyzed by a whole-cell biocatalyst and the corresponding purified enzyme...

This enantioselective reduction can be used for synthesis of chiral 1-substituted oxiranes.1 2 3 Thus reduction of 2-chloroacetophenone with B2H6 catalyzed by 1 (1 mole %) results in (S)-( + )-(chloromethyl)benzenemethanol, which in the presence of base converts to (S)-( - )-phenyloxirane (styrene oxide). 

The mechanisms of electrochemical reduction of 9-chloroanthracene, 3-nitrobenzyl chloride, and 3-chloroacetophenone have been investigated by means of cyclic voltammetryThe effect of different aprotic solvents was studied and, in the case of... 

The reduction of a dinitro ketone to an azo ketone is best achieved with glucose. 2,2 -Dinitrobenzophenone treated with glucose in methanolic sodium hydroxide at 60° afforded 82% of dibenzo[c,f [i 2]diazepin-l 1-one whereas lithium aluminum hydride yielded 24% of bis(o-nitrophenyl)methanol [575], Conversion of aromatic nitro ketones with a nitro group in the ring into amino ketones has been achieved by means of stannous chloride, which reduced 4-chloro-3-nitroacetophenone to 3-amino-4-chloroacetophenone in 91% yield [178]. A more dependable reagent for this purpose proved to be iron which, in acidic medium, reduced m-nitroacetophenone to m-aminoacetophenone in 80% yield and o-nitrobenzophenone to o-aminobenzophenone in 89% yield (stannous chloride was unsuccessful in the latter case) [903]. Iron has also been used for the reduction of o-nitrochalcone, 3-(o-nitrophenyl)-l-phenyl-2-propen-l-one, to 3-(o-aminophenyl)-l-phenyl-2-propen-l-one in 80% yield [555]. 

The reduction of 4-chloroacetophenone mediated by L. kefir stopped at 46% conversion owing to the reactant and/or the product being toxic to the cell membrane [100]. The addition of TBME (20%, v/v) made the situation worse because... 

Related catalysts for asymmetric borane reduction of ketones are open chain and cyclic phosphoric amides, in the oxidation state +3 or +5 (Scheme 11.3) [10, 11]. Early examples are the phosphonamides and phosphinamides 5a and 5b of Wills et al. [12] and the oxazaphospholidine-borane complex 6a of Buono et al. [13]. In the presence of 2-10 mol% catalysts 5a,b, co-chloroacetophenone was reduced by BH3 SMe2 with 35-46% ee [12]. For catalyst 6a a remarkable 92% ee was reported for the catalytic reduction of methyl iso-butyl ketone and 75% ee for acetophenone... 

A solution of 400 g of co-bromo-o-chloroacetophenone in one liter of methanol was cooled to about 25°C. A cold solution of 92.5 g of sodium borohydride in one liter of methanol was added as rapidly as possible to this cooled solution while maintaining the temperature below about 25°C. After the addition had been completed, the reaction mixture was allowed to stand for 4 hours at ambient room temperature, to complete the reduction of the keto group of the (o-bromo-o-chloroacetophenone. The reaction mixture containing a mixture of o-chlorophenyl ethylene-p-bromohydrin and o-chlorophenyl ethylene oxide was then evaporated in vacuo at room temperature to a syrup which was poured into about one liter of 5% hydrochloric acid to decompose any borate-alcohol complexes. 

When one plots enantiomeric excess versus temperature, all reductions show the same shape of curve. At low temperature, lower enantiomeric excesses are obtained. When the temperature is increased, the enantiomeric excess reaches a maximum value that depends on the reducing agent, the structure of the amino alcohol and of the catalyst itself (methyl, butyl, and phenyl oxazaboro-lidines do not give the same result), and the substrate. Then, as the temperature increases further, the enantiomeric excess decreases once again. This general behavior was experienced in the reduction of p-chloro-a-chloroacetophenone (5) where the range of optimal reaction temperature is broad and very practical. Indeed, a very high enantiomeric excess could be obtained at 20°C (Scheme 16.3). 

Reactions with these compounds suffer from very low substrate concentrations due to the low solubility of hydrophobic ketone substrates in aqueous media, which leads to unsatisfactory volumetric productivities. To achieve higher substrate concentrations, a biphasic reaction medium was introduced. The system water/ n-heptane (4 1) proved to be the most suitable system with regard to stability of the examined enzymes. The large-scale available (S)-specific ADH from R. erythropolis as well as FDH from C. boidinii are stable for long periods of time in this aqueous-organic solvent system. Preparative conversions with a variety of aromatic ketone substrates were carried out with this reaction medium. For example, p-chloroacetophenone was converted into the corresponding (S )-alcohol with >99% ee and 69% conversion. The obvious increase in volumetric productivity is due to the higher substrate concentrations. The reduction of p-chloroacetophenone... 

Reduction of a-chloroacetophenone using the catalyst prepared from the related (5)-diphenylisoleucinol (4) and borane gives (5)-chlorohydrin (5), which is readily transformed to (S)-... 

Other selected examples are summarized in Table 2. In addition to aldehydes, both cyclic and acyclic ketones can be reduced equally well. sec-Phenethyl alcohol (11, R = Ph) as hydride source works more effectively than t-PrOH. On the basis of this finding, the asymmetric MPV reduction of unsymmetrical ketones with chiral alcohol in the presence of catalyst 10 was examined [30]. Treatment of 2-chloroacetophenone (12) with optically pure (R)-(+)-sec-phenethyl alcohol (1 equiv.) under the influence of catalytic 10 at 0 °C for 10 h afforded (5)-(+)-2-chloro-l-phenylethanol (13) with moderate asymmetric induction (82 %, 54 % enantiomeric excess, ee Sch. 8). Switch-... 

An asymmetric MPV reduction that uses i-PrOH, MCjAl, and a chiral bi-naphfhol has also been reported [169]. (P)-BINOL and Me Al were mixed in a 1 1 ratio in toluene and the resulting white precipitate was treated with a prochiral ketone (tenfold excess) and i-PrOH (40-fold excess) (Scheme 6.129). This simple method was found to effect the catalytic reduction of 2-chloroacetophenone at r.l. to give the alcohol in 80% ee and 99% yield. 

Equilibrium distribution coefficient (log P or log D) is an important parameter to assess the solvent effect. Asymmetric reduction of 4-chloroacetophenone to (R)-l-(4-chlorophenyl)ethanol by Lactobacillus kefir showed an increase in product yield with increase in log D value of the ILs [104]. However, auother study [117], which used ILs as coating of lipase (Novozyme 435) for esterification of methyl a-o-glucopyranoside with fatty acids, showed a remarkable increase in the product yield with increase in the polarity of the IL used for coating which is opposite in trend to that observed when ILs were used as solvent as discussed above. This altered effect of more polar IL coating on product yield was attributed to their better absorption ability on the polyacrylate beads used for immobilization of enzymes in this case [117]. 

The aminoketone 55 could also be prepared directly from 2-chloroacetophenone 53 using an excess of tert-butylamine (25 equiv) and microwave dielectric heating at 160°C for 200 sec. However, it was necessary to use MgS04 as a water scavenger to prevent oxidative decomposition of 55 and to be able to run the reaction to completion. Subsequent treatment of the aminoketone derivative 56 with NaBH4 in EtOH at 140°C for 5 min resulted in the reduction of both the keto and aldehyde functionahties, providing the target compound 51 in 89% yield. 

Reduction of the ketones cyclohexanone, / -chloroacetophenone, acetophenone, butanone, and /7-methylacetophenone by phase transfer catalysis with the application of [NMe(C8Hi7)3]Cl, [NEt3(CH2Ph)]Cl, and 18-crown-6 as phase transfer agents and isopropanol and 1-phenylethanol as hydrogen donors as well as iron carbonyls as catalysts, represents a very interesting reaction. 

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