Aryl alkylation, reductive

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. 

Subsequently, a number of reactions at poly-L-valine coated carbon electrodes 237-243) gj.g reported to yield optically active products. Reductions, e.g. of citraconic acid or l,l-dibromo-2,2-diphenylcyclopropane as well as the oxidation of aryl-alkyl sulfides proceeded with chiral induction at such electrodes... 

Moreover, because of the involvement of cationic intermediates, rearrangements can occur in systems in which a more stable cation can result by aryl, alkyl, or hydrogen migration. Oxymercuration-reduction, a much milder and more general procedure for alkene hydration, is discussed in the next section. 

R = H (reductive coupling), R = alkyl or aryl (alkylative coupling)... 

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. 

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. 

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 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... 

In the asymmetric reduction of ketones, stereodifferentiation has been explained in terms of the steric recognition of two substituents on the prochiral carbon by chirally modified reducing agents40. Enantiomeric excesses for the reduction of dialkyl ketones, therefore, are low because of the little differences in the bulkiness of the two alkyl groups40. In the reduction of ketoxime ethers, however, the prochiral carbon atom does not play a central role for the stereoselectivity, and dialkyl ketoxime ethers are reduced in the same enantiomeric excess as are aryl alkyl ketoxime ethers. Reduction of the oxime benzyl ethers of (E)- and (Z)-2-octanone with borane in THF and the chiral auxiliary (1 R,2S) 26 gave (S)- and (R)-2-aminooctane in 80 and 79% ee, respectively39. 

Sulphoxides and sulphoximines are reduced to thioethers by similar reaction sequences [3, 4], In most cases, the yields of the thioethers are higher (>70%) from the diaryl compounds, than from dialkyl or aryl alkyl derivatives but, when the reductions are conducted in an excess of chloroform, the yields of the thioethers are diminished [3], This observation suggests that the thioethers are reacting with dichlorocarbene and that the dialkyl and aryl alkyl compounds are more susceptible than the diaryl derivatives (Table 11.20). 

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. 

The Birch reduction has been used by several generations of synthetic organic chemists for the conversion of readily available aromatic compounds to alicyclic synthetic intermediates. Birch reductions are carried out with an alkali metal in liquid NH3 solution usually with a co-solvent such as THF and always with an alcohol or related acid to protonate intermediate radical anions or related species. One of the most important applications of the Birch reduction is the conversion of aryl alkyl ethers to l-alkoxycyclohexa-l,4-dienes. These extremely valuable dienol ethers provide cyclohex-3-en-l-ones by mild acid hydrolysis or cyclohex-2-en-l-ones when stronger acids are used (Scheme 1). 

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... 

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