Ketones reductive acylation

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

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. 

A cobalt catalysed carbonylation reaction converts A-substituted 1-aza-1,3-dienes into A-allylacetamides by a reductive acylation process [31]. Acetamides are byproducts of the reaction. In contrast, Schiff bases undergo a double A,C-acetylation under the same conditions producing a-acetamido ketones and A,A-disubstituted acetamides [32],... 

Another example showing the utility of 1 is the asymmetric hydrogenation of vinyl esters which usually are used as acyl donors in enzymatic resolution. In this transformation, vinyl esters are converted to ketones which then undergo asymmetric reductive acylation to give chiral esters as described in Scheme 1.13. The overall reaction thus corresponds to the asymmetric hydrogenation of vinyl ester to the corresponding alkyl esters. 

The yields of thietanone depend on the number of methyl groups attached to the 1,3-dihaloketones, a relationship attributed to the gem effect. Thus the unsubstituted thietane failed to form. Thietanes have been synthesized by a series of reactions involving addition of thiolacetic acid to a vinyl ketone, reduction with LiAlH4, substitution of the acyl group by the nitrile function, and subsequent ring closure to a cis-trans mixture of 119 (Eq. 11). 

Tetralone 31 could also be synthesized much more efficiently by employing a chemoselective ketone reduction of 32 to give the lactone 33. A double Friedel-Crafts alkylation/acylation sequence employing a variety of Lewis or protic acids and benzene gave the tetralone 31 directly. Triflic acid and HF produced the highest yields of tetralone, presumably through the intermediacy of the diaryl acid 34 (Scheme 6)... 

Transition states for reduction according to our usual model of chelation-controlled 2-acyl 1,3-dithiane 1-oxide reactivity, together with steric approach control were proposed to rationalize the high levels of observed stereoselectivity. Previous work by Solladie suggests that ketone reduction by the DIBAL/ZnCl2 system does indeed involve such chelated transition states.15... 

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... 

Figure 5 Fatty acid biosynthesis catalyzed by fatty acid synthases. The growing acyl chain is tethered to the phosphopantetheinylated ACP domain, which enabies it to undergo cycles of condensation, ketone reduction, dehydration, and enol reduction catalyzed by different domains. AT, acyltransferase ACP, acyi-carrier protein KS, ketosynthase KR, ketoreductase DH, dehydratase ER, enoyireductase.

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... 

Together with enantioselective hydrolysis/acylation reactions, enantioselective ketone reductions dominate biocatalytic reactions in the pharma industry [10], In addition, oxidases [11] have found synthetic applications, such as in enantioselective Baeyer-Villiger reactions [12] catalyzed by, for example, cyclohexanone monooxygenase (EC 1.14.13) or in the TEMPO-mediated oxidation of primary alcohols to aldehydes, catalyzed by laccases [13]. Hence, the class of oxidoreductases is receiving increased attention in the field of biocatalysis. Traditionally they have been perceived as difficult due to cofactor requirements etc, but recent examples with immobilization and cofactor regeneration seem to prove the opposite. 

Pillai developed the 2 -nitrobenzhydryl PS resin [20] (8, NBH resin) as an a-substituted nitrobenzyl Hnker. The NBH resin was prepared from o-nitrobenzoyl chloride and 1% cross-Hnked PS resin by Friedel-Crafts acylation and ketone reduction (Scheme 17.7). Photolysis of single amino acids from the NBH resin... 

Ketones from acyl chlorides. Either dialkylirons or lithium trialkylferrates can be employed to react with acyl chlorides to furnish ketones. These reagents are prepared in situ from FeClj by reduction to FeCh and reaction with RLi or RMgX. Actually RMgX + FeCIi (cat.) is more convenient to use. 

Reductive cross-coupling of carbonyl compounds. The low-valent titanium species couples ketones to nitriles and carboxylic acid derivatives such as esters and acid chlorides. The products represent reductive acylation products of ketones. ... 

In the second class of synthesis two thiophene rings become joined through a carbon atom that is already a substituent of one of them by this means symmetrically and unsymmetrically substituted products in the 2,2, 2,3, and 3,3 series are available. Three main reaction types have been employed in this approach. In one of these a thiophene is alkylated with a thenyl halide (Eq. 3). Friedel-Crafts acylation of a thiophene by a thenoyl chloride or thenoic acid followed by reduction of the resulting dithienyl ketone provides a second route in this category. The last and most versatile synthesis in this class involves reaction of a thienyllithium (or Grignard reagent) with a thienylaldehyde or thienyl ketone reduction of the carbinol (see Eq. 2) then gives the dithienylalkane. 

This reaction was first reported by Nenitzescu in 1931. It is the formation of an a,p-unsaturated ketone directly by aluminum chloride-promoted acylation of alkenes with acyl halides. Therefore, it is known as the Darzens-Nenitzescu reaction (or Nenitzescu reductive acylation), or Nenitzescu acylation. Under such reaction conditions, Nenitzescu prepared 2-butenyl methyl ketone from acetyl chloride and 1-butene and dimethylacetylcyclohex-ene from acetyl chloride and cyclooctene. However, in the presence of benzene or hexane, the saturated ketones are often resolved, as supported by the preparation of 4-phenyl cyclohexyl methyl ketone from the reaction of cyclohexene and acetyl chloride in benzene, and the synthesis of 3- or 4-methylcyclohexyl methyl ketone by refluxing the mixture of cycloheptene and acetyl chloride in cyclohexane or isopentane. This is probably caused by the intermolecular hydrogen transfer from the solvent. In addition, owing to its intrinsic strain, cyclopropyl group reacts in a manner similar to an oleflnic functionality so that it can be readily acylated. It should be pointed out that under various reaction conditions, the Darzens-Nenitzescu reaction is often complicated by the formation of -halo ketones, 3,)/-enones, or /3-acyloxy ketones. This complication can be overcome by an aluminum chloride-promoted acylation with vinyl mercuric chloride, resulting in a high purity of stereochemistry. ... 

---