Oxime ethers acylation

In qualitative terms, the rearrangement reaction is considerably more efficient for the oxime acetate 107b than for the oxime ether 107a. As a result, the photochemical reactivity of the oxime acetates 109 and 110 was probed. Irradiation of 109 for 3 hr, under the same conditions used for 107, affords the cyclopropane 111 (25%) as a 1 2 mixture of Z.E isomers. Likewise, DCA-sensitized irradiation of 110 for 1 hr yields the cyclopropane derivative 112 (16%) and the dihydroisoxazole 113 (18%). It is unclear at this point how 113 arises in the SET-sensitized reaction of 110. However, this cyclization process is similar to that observed in our studies of the DCA-sensitized reaction of the 7,8-unsaturated oximes 114, which affords the 5,6-dihydro-4//-l,2-oxazines 115 [68]. A possible mechanism to justify the formation of 113 could involve intramolecular electrophilic addition to the alkene unit in 116 of the oxygen from the oxime localized radical-cation, followed by transfer of an acyl cation to any of the radical-anions present in the reaction medium. 

Recently, Kim and colleagues have described a new efficient method for the preparation of a-keto esters 48 via a free-radical acylation approach using (phenylsulfonyl) methoxycarbonyl oxime ether 46 as carbonyl equivalent radical acceptor (Scheme 28). The oxime 46 was conveniently prepared from readily available methylphenylsulfonyl acetate 44 by a two-step sequence (via oxime 45) as shown in Scheme 28. Nitrosation of 44 with isoamyl nitrite in the presence of sodium methoxide gave oxime 47 in 78% yield. 

A new synthetic method of benzofuran was reported (equation 39). The [3,31-sigma-tropic rearrangement of Af-trifluoroacetyl enehydroxylamines 136 obtained in situ by acylation of oxime ethers 135 in the presence of trifluoroacetic anhydride lead to the synthesis of cyclic or acyclic dihydrobenzofurans 138. The effects of base and temperature on the reaction products were studied. A similar pathway to that of Fisher indolization was proposed. The acylimine formed by the [3,3]-sigmatropic rearrangement of the V-trifluoroacetyl enehydroxylamine 136 gave the dihydrobenzofuran 137 by an intramolecular cyclization or the benzofuran 138 after elimination. 

In contrast, oxime ethers and esters are usually stable in solution but the E/Z isomerization can be induced by acids " or by irradiation ". Recently, Narasaka and colleagues"" "" studied the equilibration-isomerization of (E)-O-acyl oximes 239 in the presence of an acid in a nucleophilic solvent (equation 71). Isomerization probably proceeds via protonation of the oxime nitrogen followed by addition-elimination of a nucleophilic solvent until the equilibrium of E and Z isomers is achieved. The isomerization of the more labile 0-acyloximes occurs either by an Sjv2 substitution at the oxime nitrogen with acids and/or by acyl exchange through the formation of a mixed anhydride and the free oxime. 

Strategies that lead to the formation of isoxazoles during cleavage from an insoluble support include the oxidative cleavage of /V-(4-alkoxybenzyl)isoxazolidincs with DDQ to yield isoxazolines (Entry 14, Table 15.16), the nucleophilic cleavage of 2-acyl enamines with hydroxylamine (Entry 15, Table 15.16), and the acidolysis of 2-cyano-phenols etherified with an oxime resin (Entry 17, Table 15.16). The required oxime ethers for the latter synthesis were prepared by reaction of the corresponding 2-fluorobenzonitriles with Kaiser oxime resin [203],... 

The radical C-H transformation of ethers is generally initiated by a-hydrogen abstraction with highly reactive radicals generated from such initiators as peroxides [3a, g], photo-activated carbonyl compounds [3b—d], metallic reagents [3i, j], and redox systems [3f, h[. Various combinations of ethers, radical initiators, and radical acceptors (e.g. carbon-carbon multiple bonds) may be used as the reaction components [6], Several notable means of direct C-C bond formation via the radical a-C-H transformation of ethers involve the use of triflon derivatives [7], the phthalimide-N-oxyl (PINO) radical [8], 2-chloroethylsulfonyl oxime ethers [9], and N-acyl aldohydrazones [10],... 

Up until the end of the 1980s, radical carbonylation chemistry was rarely considered to be a viable synthetic method for the preparation of carbonyl compounds. In recent years, however, a dramatic change has occurred in this picture [3]. Nowadays, carbon monoxide has gained widespread acceptance in free radical chemistry as a valuable Cl synthon [4]. Indeed, many radical methods can allow for the incorporation of carbon monoxide directly into the carbonyl portion of aldehydes, ketones, esters, amides, etc. Radical carboxylation chemistry which relies on iodine atom transfer carbonylation is an even more recent development. In terms of indirect methods, the recent emergence of a series of sulfonyl oxime ethers has provided a new and powerful radical acylation methodology and clearly demonstrates the ongoing vitality of modem free radical methods for the synthesis of carbonyl compounds. 

Very recently, Kim and co-workers have reported a new useful radical acylation approach which uses a series of sulfonyl oxime ethers, some of which function as a viable radical Cl synthon. Unlike carbon monoxide and isonitriles, which operate as a radical acceptor/radical precursor type Cl synthon, sulfonyl oxime ethers... 

Radical Acylation with Sulfonyl Oxime Ethers... 

One of the principal deficiencies of the older cephalosporins was the lack of resistance to P-lactamases. Compounds with improved (3-lactamase resistance have one or more of the following characteristics a second, monovalent substituent on the CC-carbon of the C-7 acyl group such as found in cefamandole (30) and cefoperazone (34) a syn-oxime substituent, eg, cefuroxime (35) and ceftriaxone (39) a methoxy, or formamido, substituent on the (3-lactam ring at the 7cc-position such as in cefoxitin (23). However, these various substituents have different effects, and increased resistance to one enzyme does not indicate resistance to all P-lactamases. The 7cc-methoxy, or formamido, group is the most effective in imparting a broad spectmm of resistance to P-lactamases, followed by acyl side-chain oxime ether substituents. Thus cefuroxime (35), the first oximino—cephalosporin, has a P-lactamase resistance spectmm similar to that of cefotaxime (36) whereas the less resistant cefamandole (30) is similar to cefoperazone (34). 

This free-radical acylation approach is extended for the synthesis of a-keto esters and ketones using phenylsulfonyl methoxycarbonyl oxime ether 5 [23] and bis-methanesulfonyl oxime ether 6, respectively (Scheme 6) [24], 5 is more reactive and effective than 2b. For instance, radical reaction of tert-butyl iodide with 5 gave tert-butyl oxime ester in 65% yield, whereas the use of 2b gave the corresponding tert-butyl oxime ether in 15% yield. In free-radical-mediated ketone synthesis via a sequential radical acylation approach, 6 is used as a carbonyl equivalent geminal radical acceptor. This method works well with primary alkyl iodides but somewhat less efficiently with secondary iodides and can be applied to prepare unsymmetrical acyclic ketones as well as cyclic ketones. It is noteworthy that stable allylic and benzylic radicals react smoothly with 6. 

The radical carbonylation of an alkyl iodide in the presence of Kim s sulfonyl oxime ethers [58, 59, 60] provides a new type of multicomponent coupling reaction where plural radical Cl synthons are consecutively combined [61]. In the transformation, allyltin was used to serve as a trap of benzenesulfonyl radical which converts sulfonyl radical to a tin radical, thus creating a chain. Scheme 14 illustrates such an example, where the product was easily dehydroxylated to give the corresponding tricarbonyl compound on treatment with zinc/AcOH. The radical acylation reaction by Kim s sulfonyl oxime ethers can be conducted under irradiation with the addition of hexamethylditin. This is an alternative path for achieving a similar transformation without the use of photolysis equipment. Scheme 15 illustrates several examples where carbon monoxide and Kim s sulfonyl oxime ethers are successfully combined to create new tandem radical reaction sequences [61],... 

Scheme 15. Synthesis of singly and doubly acylated oxime ethers by radical cascade reactions...

Other alkylation processes include the O-methylation of oximes, A-oxides, hydroxylamines, and hydroxamic acids. The preparation of oxime ethers using dimethyl sulfate has proven an effective methodology for the construction of sidechains designed for new cephalosporin antibiotics. Treatment of a-oxime esters with dimethyl sulfate afforded the a-methoximino esters, which were subsequently hydrolyzed to the acid and used as sidechains via acylation chemistry (eq 8). ... 

As in the Japp-Klingemann reaction, when Z is an acyl or carboxyl group (in the case of R2CH—Z), it can be cleaved. Since oximes and nitroso compounds can be reduced to primary amines, this reaction often provides a route to amino acids. As in the case of 12-4, the silyl enol ether of a ketone can be used instead of the ketone itself. Good yields of a-oximinoketones (20) can be obtained by treating ketones with fert-butyl thionitrate. ... 

The chemistry of O-acyl derivatives of trinitromethane was studied in more detail. By analogy with O-silyl ethers of trinitromethane, for intermediate (120) (Scheme 3.103, Eq. 1) it was suggested (222a) that the reaction involves elimination of acetyl nitrate to form the very unstable N-oxide A, which adds acetyl chloride to give derivative (121). Saponification of the latter affords isolable oxime (122). 

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. 

The second arm of the scheme involves first a reaction of the (3-beta ketoester (7-1) with nitrous acid. The first product from nitrosation on the activated carbon spontaneously rearranges to afford oxime (7-2). Treatment with acetyl chloride then affords the (9-acylated oxime (7-3). Condensation of that compound with the imino ether from propionitrile leads to the formation of the imidazole (7-4). 

The incorporation of complex side chains at the 7 position based on alkyloximes of 2-amino-thiazole-5-gyloxylamides has provided drugs with very wide antibacterial activity that extend to hitherto resistant species such as pseudomonas. The preparation of one of the simpler side chains involves, first, the formation of the methyl ether from the oxime obtained by the nitrosation of methyl acetoacetate. Chlorination of the product, for example with sulfuryl chloride, gives the intermediate (21-1). The aminothiazole ring is then formed by reaction of that with thiourea to give (21-2). The free acid (21-3) is obtained by saponification of the product. The protected acid chloride (21-5) is obtained by sequential acylation of the amino group with chloroacetyl chloride and then reaction with thionyl chloride. 

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