Ketoximes, reductive acylation

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. 

The present methods for the preparation of N acyl a arylenamides include (i) reductive acylation of ketoximes with iron metal [2] or phosphines [3] in the presence of acyl chlorides or acyl anhydrides (Method A) (ii) metal catalyzed coupling of vinyl halides [4], triflates [5], or tosylates [6] with amides (Method B) (iii) reaction of imine intermediates derived from nitriles with acyl chlorides or anhydrides (Method C) [7] and(iv) Pd catalyzed coupling ofaryl tosylates with N acyl vinylamines (MethodD) [8]. 

Scheme 8.77 Enz)matic reductive acylation of a ketoxime with a palladium nanocatalyst.

In another area, the asymmetric reductive acylation of ketoxime of m-methoxyacetophenone was developed by Kim and co-workers, in 2010. This process was catalysed by a combination of lipase CALB with a palladium nanocatalyst in the presence of ethyl methoig acetate as an acyl donor, molecular sieves in toluene at 70 °C under 0.1 bar of hydrogen pressure. It allowed the formation of the corresponding almost enantiopure amide in high yields of up to 91% and with enantioselectivity of 98% ee, as shown in Scheme 8.77. The utility of this novel methodology was applied to the total synthesis of the calcimimetic (-l-)-NPS R-568. 

Metal-catalyzed reductive acylation reactions of ketoximes into N-acetyl enamides are known for long time [144, and references cited therein]. Recently, an example promoted by the ruthenium dimer [ RuCl(p-Cl)(t -p-cymene) 2] has been described (Scheme 37) [145]. Remarkably, the process was successfully applied to the synthesis of 49, a key intermediate in the preparation of leukocyte elastase inhibitor DMP 777. 

Scheme 37 Ruthenium-catalyzed reductive acylation of ketoximes...

As an alternative to palladium and ruthenium catalysts as racemization agents, De Vos and coworkers reported the use of Raney nickel for the DKR of aliphatic amines in toluene and a low pressure of hydrogen (0.01-0.02 MPa) at 70 °C. Its combination with CAL-B and EtOAcMeOAc led to the desired (R)-methoxyacetamides in 64—98% conversion and 80-98% ee [245], The production of optically active amines has been also possible using ketoximes instead of racemic amines as starting materials, and using metal catalysis for the racemization step. Thus, Kim and coworkers reported the asymmetric reductive acylation a system including the use of palladium on charcoal for the reduction/racemization sequence in combination with CAL-B, 2 equivalents of EtOAc, three equivalents of diisopropylethylamine, and 1 Hjatm in toluene at... 

Han K, Kim Y, Park J, Kim M-J. Chemoenzymatic synthesis of the calcimimetics (+)-NPS R-568via asymmetric reductive acylation of ketoxime intermediate. Tetrahedron Lett. 2010 51 3536-3537. 

Syn stereoselectivity in reduction of acylic chiral ketoxime ethers of type 91 (equation 63) can be obtained using bulky tetramethylammonium triacetoxyborohydride that produces FeUdn-type products with high selectivity . Reaction of a-tolylsulfinylketoximes 92 (equation 64) with L-Selectride also results in syn products 93. 

Ketoximes containing a-methylene group can be transformed into aziridines by the action of LAH or Grignard reagent. The reduction of dibenzyl ketoxime (1) with LAH in boiling THE led to c/i-2-phenyl-3-benzylaziridine (2) (equation 1). Similarly, 0-alkylated or acylated dibenzyl oxime derivatives were reduced . 

Low-valent metal salts have been used to bring about reductive cleavage of oximes. Corey and Rich-man used chromium(II) acetate to convert O-acetyl ketoximes into imines, which were hydrolyzed to ketones. " Aqueous titanium(III) chloride and vanadium(II) salts also reduce oximes again, the imines are usually hydrolyzed in situ, but some hindered imines, such as compound (37), are isolable." A method of preventing hydrolysis is to carry out the reduction in anhydrous conditions in the presence of an acylating agent. The products of such reactions, when applied to oximes of enolizable ketones, are en-amides. For example, these ketoximes are converted into A/-formylenamines when heated in acetonitrile with anhydrous titanium(III) acetate and acetic formic anhydride cyclohexanone oxime gives the en-amide (38 97% Scheme 22)." This type of reduction has been used by Barton and coworkers to prepare enamides from steroidal oximes. They reported that the reaction could be performed by acetic... 

One of the major problems encountered in this synthesis is the difficulty of obtaining the starting materials (either the a-aminocarbonyl compounds or their acylated derivatives). The former may be prepared by Neber rearrangement of ketoxime tosylates with a base such as ethoxide or pyridine.46 a-Acylamino carbonyl compounds can be prepared directly by the reductive acetylation of oximino ketones.28 38 Balaban and his collaborators47-60 have developed an excellent method for the synthesis of a-acylamino ketones (5). They are obtained in yields of 50-90% by the reaction of azlactones (2-aryl-5-oxazolone, 4) with aromatic hydrocarbons in the presence of aluminum chloride under Friedel-Crafts conditions the reaction may proceed either intermolecularly or intramolecularly. 

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