Radical 1-amidoalkyl

Aliphatic amides possess more strong a-C—H bonds in comparison with amines. This is the result of the carbonyl group influence on the stabilization of the formed a-amidoalkyl radical formed from amide in the reaction with the peroxyl radical. This influence is not so strong as that of the amine group. The values of the a-C—H bond in a few amides were estimated recently by the IPM method [4] and are given here. 

The synthetic interest in direct substitution of protonated heteroaromatic bases by carbamoyl and a-amidoalkyl radicals arises because the reaction is applicable to a variety of heteroaromatic bases having highly reactive nucleophilic positions and because a variety of amides can be used. The selectivity of attack is complete at the a- and y-positions of the heterocyclic system owing to the nucleophilic character of both carbamoyl and a-amidoalkyl radicals, The results with formamide are shown in Table VI. Quinoline with dimethylformamide gave a variety... 

With unprotonated heterocyclic bases, nucleophilic radicals either do not react (t-alkyl, benzyl, acyl, a-oxoalkyl, a-N-amidoalkyl) or react more slowly (3 to 6 orders of magnitude less) leading poor synthetic value (low yields and low chemo- and regioselectivity). 

The azetidinone ring system 43 is an important structural feature of the powerful b-lactam famiUes of antibiotics and appears in many other natural products such as clavulanic acid. Free radical-based routes to this ring system are remarkable for their variety and range. Four distinct radical-based disconnections have been investigated for azetidinone preparation. Disconnection a impUes closure of a carbamoyl-type radical onto an imsaturated acceptor group. Disconnection b imphes a closure of an amidoalkyl (a-carbamoyl) radical onto an enamide acceptor. Disconnection c points to an amidyl radical ring closure onto an alkene acceptor. Finally, disconnection d connotes ring closure of an acyl radical onto an imine acceptor (Scheme 11). 

Among others, selenides have been used for the generation of alkyl, 1-EWG-substituted alkyl (EWG = electron withdrawing group), acyl, 1-alkoxyalkyl 1-aminoalkyl and 1-amidoalkyl radicals. Significant examples have been selected and are presented below. The availability of the starting selenides will be emphasized. 

Commercially available glycine derivatives were used by C.J. Cowden to generate 1-amidoalkyl radicals for the alkylation of 3,6-dichloropyridazine in moderate to good yields. ... 

Stojanovic, A., Renaud, P. Generation of 1-amidoalkyl radicals from N-protected amino acids. An alternative to the Barton decarboxylation... 

Citterio, A., Gentile, A., Minisci, F., Serravalle, M., Ventura, S. Polar effects in free-radical reactions. Carbamoylation and a-N-amidoalkylation of heteroaromatic bases by amides and hydroxylamine-O-sulfonic acid. J. Org. Chem. 1984,49, 3364-3367. 

Carbamoyl and a-N-amidoalkyl radicals can be easily obtained by hydrogen abstraction from formamides and N-alkylamides. They have a close analogy with acyl and a-oxyalkyl radicals. The nucleophilic character of the carbamoyl radical is explained by the fact that it can be considered an acyl radical in which the alkyl or aryl group is substituted by an amino group it can be related with resonance structures like 16... 

The amino group would affect the polar character only by inductive effect owing to the a nature of the radical. The nucleophilicity of the a-N-amidoalkyl radicals can be explained in the ground state by a conjugative electron-releasing effect (77), which causes a higher electron availability on the C-radical, and in transition state by the stability of the corresponding carbonium ion 18)... 

Scheme 31. Synthetic application of the benzoyl promoted generation of 1-amidoalkyl radicals...

Scheme 34. Generation of 1 -amidoalkyl radical with an ort/io-bromobenzyl PRT groups...

Similar results have been obtained for the formation of 1-amidoalkyl radicals starting from A -ort/fo-halobenzyl amides. For instance, the synthesis of y-lactam from glycine derivatives was reported (Scheme 34, Eq. 34.1) [126]. A new route to spirooxindole based on 1,5-hydrogen transfer followed by cyclization onto an activated indole was recently published (Eq. 34.2) [127]. 

N-acetylated derivatives leads to the formation of Fe(II) porphyrins together with the acyloxy radical which undergoes decarboxylation to give ammonio-alkyl or amidoalkyl radicals. Large differences in the observed rates of Fe(II) porphyrin formation can be accounted for in terms of two factors, the binding affinity of the carboxyl to form a photoactive complex, and competitive reactions of acyloxy radicals following photolysis. 

Masson and coworkers reported a-alkylation of imines through a three-component radical/cation domino process using bromomalonate 11, an enamide 13, and an alcohol as starting materials. First, an iridium species forms the alkyl radical 12 from 11 by single electron transfer (SET). Then enamide 13 reacts with 12 to produce the amidoalkyl radical 14. An oxidative radical-polar crossover reaction then furnishes an N-acyliminium cation 15, which finally reacts with nucleophilic alcohol to produce a-alkylated a-amido ether 16 (Scheme 5.5) [11]. 

Unlike previous examples, the proposed mechanism for the Friedel-Crafts amidoalkylation does not involve initial oxidation of the amide substrate via a Ru /Ru redox cycle (see Scheme 10.19). Rather, given the strong oxidizing ability of 8203 and the relatively weaker reducing ability of amides compared with amines, the authors proposed a predominantly Ru /Ru redox cycle (Scheme 10.21). Visible light excitation of Ru forms Ru, which then reduces persulfate to the sulfate radical anion (S04 ). This species can directly abstract the a-C-H of the amide to form a-amido radical... 

In an extensive study of the selective homolytic amidation of heteroaromatic bases, the behaviour of benzothiazole has been described." Carbamoyl and a-N-amidoalkyl radicals (generated from formamide or N-alkylacetamides) attack its 2-position, producing 2-carboxamido- or 2-acetamidomethyl-benzothiazoles, generally in satisfactory yields."... 

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