Radical acylation

Beyer synthesis, 2, 474 electrolytic oxidation, 2, 325 7r-electron density calculations, 2, 316 1-electron reduction, 2, 282, 283 electrophilic halogenation, 2, 49 electrophilic substitution, 2, 49 Emmert reaction, 2, 276 food preservative, 1,411 free radical acylation, 2, 298 free radical alkylation, 2, 45, 295 free radical amidation, 2, 299 free radical arylation, 2, 295 Friedel-Crafts reactions, 2, 208 Friedlander synthesis, 2, 70, 443 fluorination, 2, 199 halogenation, 2, 40 hydrogenation, 2, 45, 284-285, 327 hydrogen-deuterium exchange, 2, 196, 286 hydroxylation, 2, 325 iodination, 2, 202, 320 ionization constants, 2, 172 IR spectra, 2, 18 lithiation, 2, 267... 

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. 

Free radical acylation of pyridines generally results in predominant or exclusive formation of the 2- and 4-substituted isomers, and carbamoylation, carboxylation and halogenation show similar product distributions. In certain of these reactions, most notably carbamoylation, synthetically significant yields of substitution products can be realized, but in many cases while quoted yields can look impressive, actual conversions can be very low <74AHC(16)123>. 

Table 28 Free Radical Acylation of Protonated Pyridines ...

Other thiohydroxamic acid derivatives have been used for the generation of radicals. Acyl derivatives of iV-hydroxythiazole-2-thione (75) have been explored by Barton as precursors for carbon radicals [86JCS(P1)39]. It has also been shown that similar precursors can be used for the generation of dialkylaminium cation radicals, N-hydroxy-4-methyl-thiazole-2-thione carbamates, TTOC carbamates 76 (91JOC1309). In contrast to... 

As mentioned before, alkyl radicals and acyl radicals have a nucleophilic character therefore, radical alkylation and acylation of aromatics shows the opposite reactivity and selectivity to polar alkylation and acylation with the Friedel-Crafts reaction. Thus, alkyl radicals and acyl radicals do not react with anisole, but may react with pyridine. Eq. 5.1 shows the reaction of an alkyl radical with y-picoline (1). The nucleophilic alkyl radical reacts at the 2-position of y-picoline (1), where electron density is lower than that of the 3-position. So, 2-alkyl-4-methylpyridine (2) is obtained with complete regioselectivity. When pyridine is used instead of y-picoline, a mixture of 2-alkylpyridine and 4-alkylpyridine is obtained. Generally, radical alkylation or radical acylation onto aromatics is not a radical chain reaction, since it is just a substitution reaction of a hydrogen atom of aromatics by an alkyl radical or an acyl radical through the addition-elimination reaction. Therefore, the intermediate adduct radical (a complex) must be rearomatized to form a product and a hydrogen atom (or H+ and e ). Thus, this type of reactions proceeds effectively under oxidative conditions [1-6]. 

Acyl radicals. Acyl radicals obtained by the oxidation of aldehydes or the oxidative decarboxylation of -keto acids react selectively at the - or -position to the nitrogen of protonated pyridines, quinolines, pyrazines, and quinoxalines, in yields typically in the range 4070% for example, 4-cyanopyridine gives 2-benzoyl-4-cyanopyridine in 96% yield <2003JHC325>. Similarly, pyridines can be carbamoylated in acid media at C(2)/C(4) (Scheme 53). 

Intramolecular radical substitution of pyrroles and indoles has been well studied this is exemplified in Schemes 90 <1997TL7937> and 91 <2000TL10181>. Intramolecular radical acylation of l-(-halogenoalkyl)-2-methylsulfonyl-5-substituted pyrroles leads to bicyclic ketones with displacement of the sulfonyl moiety <2000TL3035>. Similar cyclizations can be achieved using acyl selenide precursors to generate an acyl radical... 

Intramolecular radical acylation of l-(co-halogenoalkyl)-2-methylsulfonylpyrroles led to bicyclic ketones with retention or loss of the sulfonyl moiety (Scheme 189, Equations 232-234) <2000TL3035>. Under standard conditions, l-(2-bromoethyl)-2-(methylsulfonyl)-l/7-pyrroles 980 gave the expected 2,3-dihydro-177-pyrrolizin-l-ones 981 in moderate to good yields, and a small amount of the reductive dehalogenation products 982 (Equation 232). 

In addition to the exchange of purine hydrogens by alcohol, amine, ether, or aryl free radicals, acyl groups can also be introduced in general, 8-acylpurine derivatives are formed. The mild reactions can also be performed on nucleoside 3, 5 -cyclic phosphates. As a typical example, the synthesis of 8-acetylguanosine 3, 5 -cyclic phosphate (12) is given. ... 

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... 

The acyl radicals thus produced acylate heteroaromatic bases. Thus benzo-thiazole is converted into 2-acetylbenzothiazole when acetaldehyde is used as the radical precursor. Aromatics such as N,N-dimethylaniline do not react, and hence this new type of free-radical acylation is opposite to the usual electrophilic aromatic acylation. 

Radical methylation of pyridazine and 3- or 4-methylpyridazine occurs preferentially at the 4,5-positions, but selectivity is less marked than for radical acylation. Thus all of the possible methylation products were observed and preparative isolation of the individual products, which were identified by GC-MS, was not possible (Scheme 27). Similarly, the major product from ethyl pyridazine-4-carboxylate, the 5-methyl derivative, could not be purified, but was characterized as readily isolable benzylidene derivatives <84H(22)1395>. 

The xanthene-based dialkynol 52 undergoes a cycloaromatisation on treatment with SOCI2 to give a benzo[6]fluorene 53. Acidic thermolysis yields the p-methylenequinone derivative 54 through an intramolecular radical acylation <04TL4711>. 

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 free-radical acylation approaches appear to be highly useful for the synthesis of a variety of carbonyl compounds and have great synthetic potential because the present methods succeed in complex molecules under mild conditions, where more conventional methods would be inappropriate. 

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