Aryl alkyl ketones, reduction

Cundari, T.R., Dinescu, A., Zhu, D. andHua, L. (2007) A molecular modeling study on the enantioselectivity of aryl alkyl ketone reductions by a NADPH-dependent carbonyl reductase. Journal of Molecular Modeling, 13 (6-7), 685-690. 

The carbonylation of aryl iodides in the presence of alkyl iodides and Zn Cu couple affords aryl alkyl ketones via the formation of alkylzinc species from alkyl iodides followed by transmetallation and reductive elimination[380]. The Pd-catalyzed carbonylation of the diaryliodonium salts 516 under mild conditions in the presence of Zn affords ketones 517 via phenylzinc. The a-diketone 518 is formed as a byproduct[381],... 

The principles outlined above are, of course, important in electro-synthetic reactions. The pH of the electrolysis medium, however, also affects the occurrence and rate of proton transfers which follow the primary electron transfer and hence determine the stability of electrode intermediates to chemical reactions of further oxidation or reduction. These factors are well illustrated by the reduction at a mercury cathode of aryl alkyl ketones (Zuman et al., 1968). In acidic solution the ketone is protonated and reduces readily to a radical which may be reduced further only at more negative potentials. 

Figure 7.19 Reduction of aryl alkyl ketones by a carbonyl reductase from Sporobolomyces salmonicolor (SSCR)...

Zhu, D. and Hua, L. (2006) Enantioselective enzymatic reductions of sterically bulky aryl alkyl ketones catalyzed by a NADPH-dependent carbonyl reductase. The Journal of Organic Chemistry, 71 (25), 9484—9486. 

The asymmetric organosilane reduction of prochiral ketones has been studied as an alternative to the asymmetric hydrogenation approach. A wide variety of chiral ligand systems in combination with transition metals can be employed for this purpose. The majority of these result in good to excellent chemical yields of the corresponding alcohols along with a trend for better ee results with aryl alkyl ketones than with prochiral dialkyl ketones. 

A chiral oxazolinoferrocene ligand with iridium(I) is used for the diphenylsilane reduction of aryl alkyl ketones in nearly quantitative yields and >83% ee... 

Reduction of aryl alkyl ketones with moderate to good (ee 30-80%) entantio-selectivity has been achieved using trialkoxysilanes in the presence of chiral quininium fluorides (or hydroxides) [20]. Greater selectivities were noted (ee >65%) when tris(trimethylsiloxy)silane was used. 

Seebach and Daum (75) investigated the properties of a chiral acyclic diol, 1,4-bis(dimethylamino)-(2S,35)- and (2K,3/ )-butane-2,3-diol (52) as a chiral auxiliary reagent for complexing with LAH. The diol is readily available from diethyl tartrate by conversion to the dimethylamide and reduction with LAH. The diol 52 could be converted to a 1 1 complex (53) with LAH (eq. [18]), which was used for the reduction of aldehydes and ketones in optical yields up to 75%. Since both enantiomers of 53 are available, dextro- or levorotatory products may be prepared. The chiral diol is readily recoverable without loss of optical activity. The (- )-52-LAH complex reduced dialkyl and aryl alkyl ketones to products enriched in the (S)-carbinol, whereas (+ )-52-LAH gives the opposite result. The highest optical yield of 75% was obtained in the reduction of 2,4,6-... 

On the basis of this empirical relationship, the absolute configuration of the dextrorotatory alcohols formed in the reduction of a series of aryl alkyl ketones (75) with (—)-quinine-LAH in ether was assigned as R (84). Reduction of a series of a,p-unsaturated ketones (76) with (- )-quinine-LAH gave a product mixture consisting mainly of dextrorotatory unsaturated alcohols (77) (85). The unsaturated alcohols 77 were shown to have the R configuration. 

The optical yield was found to be very sensitive to structural modifications of the achiral agent. For example, use of the more bulky FV or Bu substituents in the 3,5-positions of phenol resulted in lower optical yields. In some cases a reversal of the sense of asymmetric induction was observed. Systematic variation of reaction conditions using the best achiral component, 3,5-xylenol, established that optimum results were obtained in ether solvent at about - 15°C. There was also a minor but definite influence of the rate of addition of ketone as well as an effect of concentration on optical yield, with a slower rate being advantageous. The results of reduction of aryl alkyl ketones are shown in Table 9, along with comparative results of reduction with similar chiral auxiliary reagents. 

Reduction of aryl alkyl ketones with 78 was quantitative and (- )-/V-meth-ylephedrine was recovered with no loss in rotatory power. High optical yields were obtained with linear aliphatic chains in the ketone, but branching a to the carbonyl group lowered the optical yields significantly. Reduction of aliphatic methyl ketones with 78 at 0°C gave (S)-carbinols in low optical yield (14 to 46%). 

Asymmetric Reduction of Aryl Alkyl Ketones with Amino Alcohol-LAH Reagents... 

In summary, a number of effective chiral reducing agents have been developed based on the modification of LAH. Excellent results have been obtained with aryl alkyl ketones and a,p-acetylenic ketones. However, dialkyl ketones are reduced in much lower enantiomeric excess. This clearly indicates that steric effects alone do not control stereoselectivity in these reductions. Systematic studies have been carried out with the objective of designing improved reagents. A better understanding of the mechanisms and knowledge of the active species is required in order to provide more accurate models of the transition states of the key reduction steps. 

The modification of lithium aluminum hydride with chiral auxiliary reagents has resulted in several highly effective reagents, particularly for the reduction of aryl alkyl ketones and a,0-acetylenic ketones. Applications of several of these reagents to key reduction steps in more complex syntheses have been highly successful. Chiral tricoordinate aluminum reagents have given lower enantiomeric excesses of alcohols. 

If combined with an alkaline or amine base (l-5equiv.) in MeOH under 10-50bar (1-5 x 10 hPa) of H2 and temperatures ranging from 25 to 50°C, all complexes catalyze the reduction of aryl alkyl ketones to the corresponding 1-arylalkanols. The role of the base was described by the authors as metal-assisted direct transfer of to the C=0 function , and higher rates were obtained... 

Sinou and coworkers evaluated a range of enantiopure amino alcohols derived from tartaric acid for the ATH reduction of prochiral ketones. Various (2R,iR)-i-amino- and (alkylamino)-l,4-bis(benzyloxy)butan-2-ol were obtained from readily available (-I-)-diethyl tartrate. These enantiopure amino alcohols have been used with Ru(p-cymene)Cl2 or Ir(l) precursors as ligands in the hydrogen transfer reduction of various aryl alkyl ketones ee-values of up to 80% have been obtained using the ruthenium complex [93]. Using (2R,3R)-3-amino-l,4-bis(benzyloxy)butan-2-ol and (2R,3R)-3-(benzylamino)-l,4-bis(benzyloxy)butan-2-ol with [lr(cod)Cl]2 as precursor, the ATH of acetophenone resulted in a maximum yield of 72%, 30% ee, 3h, 25 °C in PrOH/KOH with the former, and 88% yield, 28% ee, 120 h with the latter. 

The chiral Rh catalyst systems described above for the reduction of 1 have been shown to achieve high enantioselectivity (>90% ee) for aryl alkyl ketones 30-37. Propiophenone 30 and... 

Reduction The asymmetric reduction of a series of aryl alkyl ketones with quaternary ammonium fluorides and silanes was reported by Drew and Lawrence [55]. In these reactions, the best catalysts (e.g., 6f) were from the qui ni ne/quinidine series in fact, a fluoride salt prepared from cinchonine gave no induction. The use of trimethoxysilane resulted in faster rates but lower enantioselectivites when compared with tris(trimethoxy)silane. It is interesting that, with the... 

Aryl alkyl ketones are readily prepared by the Friedel-Crafts acylation process (see Section 6.11.1, p. 1006) and their Clemmensen reduction constitutes a more efficient procedure for the preparation of monoalkylbenzenes than the alternative direct Friedel-Crafts alkylation reaction (see below). Alternatively aldehydes and ketones may be reduced to the corresponding hydrocarbon by the Wolff-Kishner method which involves heating the corresponding hydrazone or semicarbazone with potassium hydroxide or with sodium ethoxide solution. 

Ethylpyridinium tetrafluoroborate, a readily accessible ionic liquid, is an effective solvent for BINOL-promoted enantioselective reduction of aryl alkyl ketones by LAH.324 A chiral diol modifies LAH reagents to give up to 98% ee.325... 

BH3.Me2S reduction of aryl alkyl ketones can be carried out with ees up to 98% using 3 mol% of a chiral oxazaborolidine derived from (-)-/l-pinenc.3 5... 

The asymmetric organocatalytic transformation of a ketone into an alcohol may be realized with the combination achiral silanexhiral phase-transfer catalyst, such a quaternary ammonium salt. The final alcohol is then recovered by an additional hydrolytic step. The asymmetric reduction of aryl alkyl ketones with silanes has been reported (ee-values up to 70%), the catalysts utilized being ammonium fluorides prepared from the quinine/quinidine series (e.g., 18 in Scheme 11.6) [19]. (For experimental details see Chapter 14.21.1). The more appropriated silanes were (Me3SiO)3SiH or (MeO)3SiH (some examples are... 

The binaphthol-modified lithium aluminum hydride reagents (BINAL-Hs) are also effective in enantioselective reduction of a variety of alkynyl and alkenyl ketones2 (Scheme 4.3b). When the reaction is carried out with 3 equivalents of (S)-BINAL-H at —100 to —78 C, the corresponding propargylic alcohol 3 and allylic alcohol 4 are obtained in high chemical yields with good to excellent levels of enantioselectivity. As is the case with aryl alkyl ketones, the alcohols with (.V)-con figuration are obtained when (S)-BINAL-H is employed. 

The oxazaborolidine-catalyzed enantioselective reduction of aryl alkyl ketones was used in the asymmetric synthesis of the naturally occurring molecule (15 )-(—)-salsolidine 4119 (Scheme 4.3o). The ketone 42 underwent oxazaboroli-dine-mediated reduction to furnish the alcohol 43 in excellent yield and greater than 95% ee. The alcohol 43 was then coupled with the reagent 44 under Mit-sunobu conditions to produce the aminoacetal 45. 

---