Reductive acylation, of ketones

Aldehydes and ketones can be converted to ethers by treatment with an alcohol and triethylsilane in the presence of a strong acid or by hydrogenation in alcoholic acid in the presence of platinum oxide. The process can formally be regarded as addition of ROH to give a hemiacetal RR C(OH)OR", followed by reduction of the OH. In this respect, it is similar to 16-14. In a similar reaction, ketones can be converted to carboxylic esters (reductive acylation of ketones) by treatment with an acyl chloride and triphenyltin hydride. " ... 

After succeeding in the asymmetric reductive acylation of ketones, we ventured to see if enol acetates can be used as acyl donors and precursors of ketones at the same time through deacylation and keto-enol tautomerization (Scheme 8). The overall reaction thus corresponds to the asymmetric reduction of enol acetate. For example, 1-phenylvinyl acetate was transformed to (f )-l-phenylethyl acetate by CALB and diruthenium complex 1 in the presence of 2,6-dimethyl-4-heptanol with 89% yield and 98% ee. Molecular hydrogen (1 atm) was almost equally effective for the transformation. A broad range of enol acetates were prepared from ketones and were successfully transformed into their corresponding (7 )-acetates under 1 atm H2 (Table 19). From unsymmetrical aliphatic ketones, enol acetates were obtained as the mixtures of regio- and geometrical isomers. Notably, however, the efficiency of the process was little affected by the isomeric composition of the enol acetates. 

The strategy for the asymmetric reductive acylation of ketones was extended to ketoximes (Scheme 9). The asymmetric reactions of ketoximes were performed with CALB and Pd/C in the presence of hydrogen, diisopropylethylamine, and ethyl acetate in toluene at 60° C for 5 days (Table 20) In comparison to the direct DKR of amines, the yields of chiral amides increased significantly. Diisopropylethylamine was responsible for the increase in yields. However, the major factor would be the slow generation of amines, which maintains the amine concentration low enough to suppress side reactions including the reductive aminafion. Disappointingly, this process is limited to benzylic amines. Additionally, low turnover frequencies also need to be overcome. 

Ketones Reductive acylation of ketones by nitriles is accomplished using TiCU-Sm in THF. 

TiCLi-Zn is found to induce reductive acylation of ketones with acylsilanes 40 although a stoichiometric amount of low-valent titanium species is required (Scheme 2.28) [75]. 

We applied the DKR procedme to the asymmetric reductive acylation of ketones and the asymmetric hydrogenation of enol acetates [16]. In the asymmetric reductive... 

Products from the asymmetric reductive acylation of ketones. 

The catalytic alcohol racemization with diruthenium catalyst 1 is based on the reversible transfer hydrogenation mechanism. Meanwhile, the problem of ketone formation in the DKR of secondary alcohols with 1 was identified due to the liberation of molecular hydrogen. Then, we envisioned a novel asymmetric reductive acetylation of ketones to circumvent the problem of ketone formation (Scheme 6). A key factor of this process was the selection of hydrogen donors compatible with the DKR conditions. 2,6-Dimethyl-4-heptanol, which cannot be acylated by lipases, was chosen as a proper hydrogen donor. Asymmetric reductive acetylation of ketones was also possible under 1 atm hydrogen in ethyl acetate, which acted as acyl donor and solvent. Ethanol formation from ethyl acetate did not cause critical problem, and various ketones were successfully transformed into the corresponding chiral acetates (Table 17). However, reaction time (96 h) was unsatisfactory. 

Wock-Hardt Ltd.54 reported a manufacturing process for the preparation of 2 (Scheme 8). In their approach, reductive amination of ketone 41 with dimethylamine hydrochloride using NaCNBH3 afforded amine 42 in 69% yield. The phenol was acylated with iV-ethyl-/V-methyl carbamoyl chloride (40) using KO/-Bu as the base instead of NaH to provide racemic carbamate 2 in 88% yield (98% pure by HPLC). Racemic 2 was further purified by making the oxalate salt, which provided 2 as a colorless crystalline oxalate salt in 100% purity. Resolution with DTTA followed by salt formation with tartaric acid afforded chiral tartrate salt 2. The overall yield of this process was 20%. 

The acid or base elimination of a diastereoisomerically pure p-hydroxysilane, 1, (the Peterson olefination reaction4) provides one of the very best methods for the stereoselective formation of alkenes. Either the E- or Z-isomer may be prepared with excellent geometric selectivity from a single precursor (Scheme 1). The widespread use of the Peterson olefination reaction in synthesis has been limited, however, by the fact that there are few experimentally simple methods available for the formation of diastereoisomerically pure p-hydroxysilanes.56 One reliable route is the Cram controlled addition of nucleophiles to a-silyl ketones,6 but such an approach is complicated by difficulties in the preparation of (a-silylalkyl)lithium species or the corresponding Grignard reagents. These difficulties have been resolved by the development of a simple method for the preparation and reductive acylation of (a-chloroalkyl)silanes.7... 

In reductive acylation and dimerization, the cathode is often superior to dissolving metal or radical anions reductants. So a, j6-unsaturated ketones or esters can be acylated in high yield to 1,4-dicarbonyl compounds at the mercury cathode [39], but the corresponding reaction with sodium in tetrahydrofuran (THE) fails [40]. On the other hand, reductive acylation of double bonds becomes possible in high yield, when vitamin Bj2 is used as mediator [41]. Here cobalt-alkyl complexes play a decisive role as intermediates. 

The reaction of a ketone with an acid chloride and triphenyltin hydride results in reductive acylation of the ketone in high yield 11... 

Ligand-promoted reductive elimination of ketones is directly observed with alkyl-acyl rhodium complexes formed via oxidative addition of either Wilkinson s catalyst or [ethylene insertion into the metal hydride bond33-37. 

The synthetic utility of this reaction may be limited because both ester and aldehyde are formed. Nevertheless, some control of the product distribution appears to be possible because use of a solvent causes a marked increase in the yield of aldehyde. The reaction sequence (59-60) constitutes a reductive acylation of the aldehyde. A number of added aldehydes and ketones have been found to function in this manner. This provides a means of comparing the relative efficiencies of such compounds as traps for the acyl radicals. Apparently the polar factor is an important one in this case since the carbonyl compound competes effectively with the tin hydride for the acyl radical, whereas this is not the case for the alkyl radicals which are intermediates in reductions of alkyl halides. 

Reductions of aldehydes and ketones to alcohols proceed at slower rates with AERs in BH4 form than with NaBH4 in ethanol.a,j8-Unsaturated carbonyl compounds are reduced by BH4 in a gel AER to the allylic alcohols. Cyanoborohydride ion in a macroporous AER effects reductive aminations of ketones and ammonia to primary amines, reductive methylations of primary amines to the N,iV-dimethyl tertiary amines with aqueous formaldehyde, reductions of N-alkyl- and AT-acyl-pyridinium ions to tetrahydropyridines, and reductions of primary alkyl halides to alkanes. Nitroarenes are reduced to amines, the bromide of a-bromocarbonyl compounds is replaced by hydride, and 1,2-dibromoalkanes give alkenes by treatment with HFe(CO)4 in a macroporous AER. 

In this reserpine synthetic route (Scheme 3.21), Diels-Alder reaction of dihydropyridine 133 (100) and methyl a-acetoxyacrylate 134 afforded iso-quinuclidenes 135 and 136 (36). Addition of lithium r-butyl acetate to 135 afforded the )8-ketoester 137 which was converted to the corresponding enol ester 138. When 138 was refluxed in xylenes, the cis-fused hexahydroiso-quinoline 139, in which the reserpine C(15), C(16), and C(20) stereocenters are in place, formed in good yield. Hydrogenation of the enamine function in 139 followed by reduction of the enol ester afforded 140 which has the C(17)-methoxy group with the required relative stereochemistry. Acylation of ketone 140 yielded the C(18), C(19) enol ester which was hydrogenated stereoselectively to produce 141 in which the C(18) stereochemistry is set. Deprotection of the nitrogen function followed by tryptophylation afforded 142 which was then cyclized to provide the anticipated isoreserpine diol 143... 

The reaction of benzoyl chloride with (Me3Si)2 affords benzoyltrimethylsi-lane (878)[626,749,750]. Hexamethyldigermane behaves similarly. The siloxy-cyclopropane 879 forms the Pd homoenolate of a ketone and reacts with an acyl halide to form,880. The 1,4-diketone 881 is obtained by reductive elimination of 880 without undergoing elimination of /7-hydrogen[751]. 

One route to o-nitrobenzyl ketones is by acylation of carbon nucleophiles by o-nitrophenylacetyl chloride. This reaction has been applied to such nucleophiles as diethyl malonatc[l], methyl acetoacetate[2], Meldrum s acid[3] and enamines[4]. The procedure given below for ethyl indole-2-acetate is a good example of this methodology. Acylation of u-nitrobenzyl anions, as illustrated by the reaction with diethyl oxalate in the classic Reissert procedure for preparing indolc-2-carboxylate esters[5], is another route to o-nitrobenzyl ketones. The o-nitrophenyl enamines generated in the first step of the Leimgruber-Batcho synthesis (see Section 2.1) are also potential substrates for C-acylation[6,7], Deformylation and reduction leads to 2-sub-stituted indoles. 

While enamines can usually be obtained directly from ketones and secondary amines their formation by an indirect route may bo advantageous. The previously mentioned condensation of rnethyl ketones during azeotropic enamine formation has prompted the alklyation (J) or acylation and reduction (59) of Schiff s bases. A parallel method uses the formation and desulfurization of N-acylthiazolines followed by hydride reduetion (60,61). 

The oxygen atom in these molecules can in many cases be dispensed with as well substitution of sulfur for nitrogen affords a molecule whose salient biologic properties are those of a sedative and tranquilizer. Friedel-Crafts acylation of the n-butyl ether of thiophenol with benzoyl chloride gives the corresponding benzophenone. Reduction of the ketone (15) followed by... 

A compound closely related to classical adrenergic agonists in which the para hydroxy function is however replaced by an amino group has been investigated for its activity as a growth promoter in domestic animals. Acylation of the aniline derivative 26 with chloracetyl chloride will afford acetophenone 27 the amino-ketone 28 is obtained on reaction with isopropylamine. Removal of the protecting group (29) followed by reduction of the ketone affords cimaterol (30) 5J. 

In a similar vein, acylation of the corticoid 50 with furoyl chloride gives the diacyl derivative 51. Reduction with sodium borohydride serves to convert the 11-ketone to the alcohol 52. Hydrolysis under mild acid conditions preferentially removes the acyl group at the less hindered 21 position. The hydroxyl group in that derivative (53) is then converted to the mesylate 54. Replacement by chlorine affords mometasone (55) [12]. 

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