Carbamoyl radical

F. Minisci, F. Recupero, C. Putna, C. Gambarotti, F. Antonietti, F. Fontana, G. F. Pedulli, A novel, selective free-radical carbamoylation of heteroaromatic bases by Ce(lV) oxidation of formamide, catalysed by N-hydroxyphthalimide, Chem. Comm. (2002) 2496. 

Martin, I., Anvelt, J., Vares, L., Kiihn, I.. andClaesson, A., An altemahve synthesis of the NMDA antagonist CGS 19755 via free radical carbamoylation of ethyl isonicotinate, Acta Chem. Scand., 49, 230, 1995. 

An interesting method for the substitution of a hydrogen atom in rr-electron deficient heterocycles was reported some years ago, in the possibility of homolytic aromatic displacement (74AHC(16)123). The nucleophilic character of radicals and the important role of polar factors in this type of substitution are the essentials for a successful reaction with six-membered nitrogen heterocycles in general. No paper has yet been published describing homolytic substitution reactions of pteridines with nucleophilic radicals such as alkyl, carbamoyl, a-oxyalkyl and a-A-alkyl radicals or with amino radical cations. 

Similarly, a carbamoyl group can be introduced by the use of the radicals H2N—C or Mc2N—C- generated from formamide or DMF and H2SO4, H2O2, and... 

Other degradation products of the cytosine moiety were isolated and characterized. These include 5-hydroxy-2 -deoxycytidine (5-OHdCyd) (22) and 5-hydroxy-2 -deoxyuridine (5-OHdUrd) (23) that are produced from dehydration reactions of 5,6-dihydroxy-5,6-dihydro-2 -deoxycytidine (20) and 5,6-dihydroxy-5,6-dihydro-2 -deoxyuridine (21), respectively. MQ-photosen-sitized oxidation of dCyd also results in the formation of six minor nucleoside photoproducts, which include the two trans diastereomers of AT-(2-de-oxy-/j-D-eryf/iro-pentofuranosyl)-l-carbamoyl-4 5-dihydroxy-imidazolidin-2-one, h/1-(2-deoxy-J8-D-crythro-pentofuranosyl)-N4-ureidocarboxylic acid and the a and [5 anomers of N-(2-deoxy-D-eryfhro-pentosyl)-biuret [32, 53]. In contrast, formation of the latter compounds predominates in OH radical-mediated oxidation of the pyrimidine ring of dCyd, which involves preferential addition of OH radicals at C-5 followed by intramolecular cyclization of 6-hydroperoxy-5-hydroxy-5,6-dihydro-2 -deoxycytidine and subsequent generation of the 4,6-endoperoxides [53]. 

The silicon containing (5 5 5) heterocycle 32 has been efficiently synthesized starting from. Y-prolinc 375 via silanes 376, 378, and 379. The final step has been achieved via radical cyclization. The amine 377 was treated with COCl2 and the resulting carbamoyl chloride 378 reacted with PhSeNa to give the radical precursor 379 (84% overall yield from 376). Compound 379 when refluxed with Ph3SnH or Bu3SnH in the presence of AIBN afforded the desired heterocycle 32 in 75% yield (Scheme 81). 

Although the Capdevielle reaction for one-pot conversion of aldehydes to nitriles is a very convenient and widely applicable synthetic procedure, 3-substituted furoxans appear to be susceptible to rearrangement when substitutions with amine nucleophiles are attempted, even under relatively mild conditions (Scheme 29) <1999JOC8748>. The formation of the final product 107 in this reaction was explained via phenyl abstraction by carbamoyl radical cation from the second molecule of intermediate product 106 < 1999JOC8748>. 

A few examples are chosen in order to illustrate the potentialities of this remarkable methodology. In Reaction (6.6) the sequence is initiated by the removal of the PhSe group and the formation of a carbamoyl radical. It is worth mentioning that the stereochemical outcome of these cascade reactions is controlled by the stereochemistry of the oxygen-bearing asymmetric carbon in 29. Indeed, Reactions (6.6) and (6.7) show clearly the stereochemical control. On the other hand, Reactions (6.7) and (6.8) illustrate the role of R which is carried as a terminal group in the acetylenic moiety. For R = Ph the last step is the hydrogen abstraction, whereas for R = SnBus, the last step is the ejection of BusSn radical (cf. Scheme 6.7). 

Carbamoyl radicals can be easily obtained by hydrogen abstraction from formamides [Eq. (48)]. 

Carbamoyl radicals, like acyl radicals, show a net nucleophilic character which permits the amidation of protonated heteroaromatic bases. Quantitative studies concerning the polar character of the carbamoyl radicals have not yet been published, but the complete selectivity of attack at the a- and /-positions of protonated heteroaromatic bases indicates a definite nucleophilic character and synthetic value. 

As for ethers and alcohols, the ease of hydrogen abstraction is determined by polar factors when operating with electrophilic radicals (X ). The polar character is influenced by the same factors as for ethers and alcohols, i.e., a back-donation of charge from nitrogen to the a-C radical accentuates the nucleophilic character. The influence of the abstracting species in the case of dimethylformamide is shown by the results given in Table V, where the attack of carbamoyl and a-amidomethyl radicals... 

Radical source Carbamoyl radical (%) a-Amidomethyl radical (%)... 

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... 

Radicals similar to carbamoyl are the alkoxycarbonyl radicals, ROCO. Also, these radicals were successfully used to carboxylate protonated heteroaromatic bases with good yields and selectivity. " ... 

Useful sources of these radicals were the hydrogen abstraction from alkyl formate and especially the decomposition by ferrous salts of mixtures of hydrogen peroxide and a-keto esters. The alkoxy-carbonyl radicals appear to be less nucleophilic than carbamoyl radicals. 

Photosensitized decomposition of oxime oxalyl amides proceeded via carbamoyl radicals which underwent A-exo cyclizations forming four-membered /3-lactams as main products. Irradiation of solution of oxime derivative 22 and 4-methoxyacetophenone (MAP) in toluene at 100 °C with a 400 W UV lamp led to azetidinone 23 in 3 1 ratio of diastereoisomers (equation 10) . ... 

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>. 

Attack by alkoxycarbonyl radicals, which are isoelectronic with but less nucleophilic than carbamoyl radicals, has been less well studied than acylation and amidation. An example is provided by the reaction of quinoline with ethyl pyruvate, hydrogen peroxide and an iron(II) salt (Scheme 213) (73TL645). 

Acyl radicals obtained by the oxidation of aldehydes or the oxidative decarboxylation of a-keto acids react selectively at the a- or y-position of the protonated heterocyclic nitrogen. Pyridines, quinolines, pyrazines and quinoxalines all react as expected yields are typically 40 to 70%. Similarly, pyridines can be carbamoylated in acid media at C-2 (Scheme 38). 

Some other nitrogen compounds are also formed by carbamoylation of glycals using a photochemical regiospecific process which consists of the addition of the amide radical only to C-l [53]. The addition mixture remains complex because of stereoisomers 54 (mainly a) and competitive addition products with acetone such as 55. 

The use of amides as source of carbamoyl and a-aminoalkyl radicals has also been widely employed since the 1970s [11]. Fenton-type systems utilizing tert-butyl hydroperoxide or hydrogen peroxide in the presence of Fe(II) salts and the S2Os2 / Ag+ system have been applied in the functionalization of aromatic bases with amides (Equation 14.7). 

Scheme 14.4 Formation of photo induced carbamoyl radicals in the presence of Ti02.

This approach, in which a carbamoyl radical acts as a nucleophilic carboxylate synthon (Scheme 14.8a) in place of the nucleophilic ionic cyanide, may be regarded as a more efficient radical version of the Strecker synthesis (Scheme 14.8b). 

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