Acylated ketoximes

Generally, the Neber rearrangement is a base-catalysed conversion of 0-acylated ketoximes 523 (but not aldoximes) to a-amino ketones 525 via an isolable 2//-azirine intermediate 524 (equation 232). The azirine itself may be used as a valuable synthetic tooP and the Neber rearrangement is commonly used to produce it. 

This delightfully simple methodology is generally applicable to hydroxy-glycal esters and has provided acylated ketoximes of type 25 in large variety acylated pyranoid ketoximes, featuring such useful properties as high tendency for crystallization, ease of isolation and stability (29). 

Acyl halides with 3-unsubstituted indoxazenes give acylsalicylo-nitriles. The acyl group may be exclusively or chiefly in the ring (49) or on the oxygen atom (50). 3-Alkyl derivatives, on the other hand, form ring-acylated ketoximes (51), besides acylated indoxazenes.67... 

The first step of the mechanism is the deprotonation of the O-acylated ketoxime at its a-position, which gives rise to the corresponding enolate. This enolate then can react via two possible pathways 1) a concerted anionic pathway in which the leaving group is directly displaced to give the isolable 2H-azirine or 2) a nitrene pathway that leads to the same 2/-/-azirine intermediate via nitrene Insertion. The nitrene pathway has not been disproved experimentally. 

TV-Substituted imines were prepared by the copper-catalyzed N-imination of boronic acids and organostannanes with O-acyl ketoximes (eq 28). In this process, both CuTC and Cu(OAc)2 were equally effective to carry out the reaction. 

The photochemical cyclisation of p.y-unsaturated ketoximes to 2-isoxazolines, e.g., 16—>17, has been reported <95RTC514>. 2-Isoxazolines are obtained from alkenes and primary nitroalkanes in the presence of ammonium cerium nitrate and formic acid <95MI399>. Treatment of certain 1,3-diketones with a nitrating mixture generates acyl nitrile oxides, which can be trapped in situ as dipolar cycloadducts (see Scheme 3) <96SC3401>. 

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. 

Azido derivatives of furazans have proved to be particularly useful for the synthesis of heterocyclic systems. Thus, by 1,3-dipolar addition of l-azido(4-amino-l,2,5-oxadiazol-3-yl)aldoxime 186 to propargyl alcohol and phenylacetyl-ene, bicyclic 4-amino-l,2,5-oxadiazol-3-yl(4-R-l,2,3-triazol-l-yl)ketoximes 187 were obtained (Equation 34) which in reaction with acetic anhydride afforded the corresponding 0-acyl derivatives <2003RJ0574>. 

For example, the reaction of nitronates (123) with a zinc copper pair in ethanol followed by treatment of the intermediate with aqueous ammonium chloride a to give an equilibrium mixture of ketoximes (124) and their cyclic esters 125. Heating of this mixture b affords pyocoles (126). Successive treatment of nitronates (123) with boron trifluoride etherate and water c affords 1,4-diketones (127). Catalytic hydrogenation of acyl nitronates (123) over platinum dioxide d or 5% rhodium on aluminum oxide e gives a-hydroxypyrrolidines (128) or pyrrolidines 129, respectively. Finally, smooth dehydration of a-hydroxypyrrolidines (128) into pyrrolines (130f) can be performed. 

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 . 

Enehydroxylamines (102) are invoked as intermediates in the rearrangement of O-vinyl, acyl or aryl oximes (101) (equation 31). Varlamov and coworkers demonstrated that the heterocyclization of ketoximes (103) with acetylene in snper basic medium and in the presence of metal hydroxides proceeds by a [3,3]-sigmatropic rearrangement of the enehydroxylamine 105 of the corresponding oxime vinyl ethers 104 (equation 32). The unreactivity of 3-methyl-2-azabicyclo[3.3.1]nonan-9-one oxime (106) in the same reaction conditions was explained by its inability to isomerize to the corresponding enehydroxylamine. 

In the presence of indium(in) chloride, 3-acyl-l//-quinolin-4-ones ketoximes 278 rearrange to the corresponding oxazoloquinolines 279 (equation 86). Isooxazoloquinolines 280 are also formed as minor products. 

Beckmann rearrangements are useful to produce cycloalkylamines from ketoximes. This strategy was applied to produce cyclobutylamine derivatives 328 from the corresponding acyl derivatives during the synthesis of 4(3//)-quinazolinones " (equation 121). 

Both cyclic and acyclic ketoximes may be used in this transformation and the reaction is usually performed in an alcohol solution containing equimolar quantities of alkoxide. For a successful reaction, the starting material usually contains at least an a-methylene group but the presence of only one a-hydrogen may suffice. When treated with base the 0-acylated aldoximes do not react via the Neber rearrangement and instead they undergo an E2 elimination to cyanides or isocyanides. 

The Conversion of Ketoximes to Nitriles C-Acyl-ZV-hydroxy-elimination... 

The same concept is applicable to allylic alcohols, ketones, or ketoximes. Enol acetates or ketones were successfully converted in multi-step reactions to chiral acetates in high yields and optical yields through catalysis by Candida antarctica lipase B (CALB, Novozyme 435) and a ruthenium complex. 2,6-Dimethylheptan-4-ol served as a hydrogen donor and 4-chlorophenyl acetate as an acyl donor for the conversion of the ketones (Jung, 2000a). 

The EMCR has been extended from obtaining enantiomerically pure alcohols to obtaining such amines. Prochiral ketoximes were transformed to optically active amine acetates in a coupled CALB/palladium catalysis in the presence of an acyl donor at 1 atm hydrogen (Figure 18.15) (Choi, 2001). 

Alternatively, Kim and coworkers showed [26] that prochiral ketoximes could be converted into optically active amines by hydrogenation over Pd-on-C in the presence of CaLB and ethyl acetate as both acyl donor and solvent, presumably via DKR of the amine formed in situ (see Fig. 9.16). 

An identical rearrangment can be arrived at tiirou acylation of N-methyl nitrones," conveniently prepared from the kemne (155 to 156), althougb the process is apparently restricted to cyclic substrates, nnally a similar one-pot procedure for conversion of ketoximes to a-acetoxy ketones under the conditions shown (157 to 158), allows the transformation to be carried out simply and efficiently. In this case rearrangement produces a-acyloxyenimides, whose hydrolysis provides Ae keto equivalent. 

Acetylenes allenes. Nitrimines, prepared from ketoximes and nitrous acid, on acylation with acetic anhydride and pyridine with catalysis by 4-dimethylamino-pyridine fragment to alkynes and/or allenes. ... 

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... 

Ketoximes have been synthesized by Fujisawa using a catalytic Crul/Grignard addition to aci-nitroimi-nium chlorides, formed by 0-acylation of a nitroalkane with A(A(-dimethylchloromethyleninimium... 

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]. 

Zur Hydrierung spezieller Ketoxime mit Raney-Nickel zu Hydroxyiaminen s. Lit.5 6. i3) von O-Alkyl- bzw. O-Acyl-oximen... 

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. 

Hydroxamic acids. Oximino esters (1) are reduced by 1 equiv. of BH3 in THF at -78 to hydroxamic acids (2). The reaction involves an O to N acyl thift, (a) (b). Ketoximes are reduced completely to amines by excess diborane... 

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