Unexpected reactions of organozinc reagents with N - acylbenzotriazoles

Coupling N -acylbenzotriazoles with aliphatic and benzylic organozinc reagents in the presence of zinc bromide / Pd(II) catalyst (or zinc bromide / Ni(0) catalyst) did not result in formation of the expected ketones, but instead gave the corresponding carboxylic acid esters. This reaction apparently occurs by the insertion of oxygen dissolved in the solvent into the organozinc compound


Scheme 1
The high reactivity of acyl halides and their incompatibility with acid-sensitive functionalities have driven efforts to find alternative solutions, with the major emphasis on amides.N,N-Dialkylamides with alkyl-, aryl-8 or vinyl-9 lithium and Grignard 10 reagents afford ketones in good yields.Various non-aromatic N-acylheterocycles, such as N-acyl-aziridines, 11 pyrrolidines, -isoxazolines, and -isoxazines, 12 react cleanly with alkyl-and alkynyl-lithiums providing the corresponding ketones.
N-Acylimidazoles are converted into ketones by treatment with organolithium or organosodium derivatives of nitro compounds, sulfones, esters, etc. 13 Recently, nucleophilic substitution of an imidazolyl group with a 1-lithioalkene was used successfully for the stereoselective synthesis of α,β-unsaturated ketones. 14Cleavage with Grignard reagents in solution in the absence of any catalyst is reported only for α-keto-substituted substrates. 15N-Aroylimidazoles give with Grignards almost exclusively tertiary alcohols 3 even at low temperatures. 16However, in the reactions of N-acylimidazoles with Grignard reagents two approaches could be used to prevent a significant formation of tertiary alcohols: i) using certain additives, such as equimolar amounts of TMSOTf or boron trifluoride etherate 17 or catalytic amount (10 mol%) of FeCl 3 ; 18 or ii) hindering access of the Grignard reagent to the carbonyl group by applying resin-bound acylimidazoles. 19Reactions of 1-acyl-3,5-dimethylpyrazoles with Grignards usually afford mixtures of the corresponding ketones and tertiary alcohols, 20 although the cleavage with Reformatsky reagents leads only to the ketone formation. 21ucleophilic substitution using other organometallics can sometimes be advantageous for performing the clean and high-yielding transformations of this type.Thus, N-acylimidazoles react with organotitanium compounds to afford the corresponding ketones in high yield, 16 as do N-acyl-imidazoles, -benzimidazoles and -benzotriazoles with organoaluminium compounds. 22owever, indium mediated coupling of allylic bromides with acylimidazoles provides mixtures of ketones and tertiary alcohols in ratios depending on the substrate structures. 23-Acylbenzotriazoles are advantageous carboxylic acid derivatives in that they are stable and easily prepared in one step from the carboxylic acids even in cases where an acid-sensitive functionality is present. 25Their reactivity is significantly enhanced by Lewis acids (especially, Zn 2+ salts), and that makes them convertible by less active organometallic reagents.Viewing these compounds as potentially useful intermediates for transformations of carboxylic acids into ketones, we attempted the reaction of readily available N-acylbenzotriazoles with a number of organozinc reagents in the presence of a Lewis acid and a Pd 2+ or Ni catalyst.

Results and Discussion
The starting N-acylbenzotriazoles 4a-i (Table 1) were easily prepared by acylation of benzotriazole with acyl chlorides in the presence of a base (method A) 24 or, for acid-sensitive substrates, by the reaction of the corresponding carboxylic acid with readily available 1benzenesulfonylbenzotriazole (method B). 25 N-Acylbenzotriazoles were unaffected by heating with Grignard reagents or organozinc reagents in the presence of an equivalent of anhydrous zinc bromide (the starting materials were recovered).Neither was reaction observed in the presence of a catalytic amount of bis(triphenylphosphino)palladium(II) dichloride.However, the simultaneous presence of zinc bromide and the palladium(II) catalyst promoted the complete conversion of the starting N-acylbenzotriazoles into single products in a rate depending on a type of the Grignard reagent used.To our surprise, the products formed were not the expected ketones 5, but the corresponding esters 6a-i (Scheme 2, Table 2).The structures of the products were assigned by comparison of their 1 H and 13 C NMR data with those published in literature, by GC/MS analysis (for 6d) and by independent preparation of n-propyl 2-furoate 6e following the known literature procedure. 26The analogous formation of esters instead of ketones was previously reported as a concurrent reaction occurring on interaction of N-acylimidazoles with Grignard reagents at elevated temperatures.17b Recently, in our group the very great ease of the oxidation of alkylzinc reagents, in contrast to their arylzinc counterparts, during the reactions with benzotriazolyl-substituted imidazolidinones and pyrrolidines has been demonstrated.All the reactions described in the present paper have been carried out under nitrogen atmosphere, the formation of these oxygen insertion products could be ascribed to the presence of molecular oxygen either in the nitrogen flow or in a solvent.To find out the source of oxygen and exclude it, first we carried out the reaction of 1-benzoylbenzotriazole 4d with benzylzinc chloride under argon protection (other reaction conditions being the same as previously applied).However, the outcome of this reaction did not change: only the corresponding ester 6b was obtained.Deoxygenating the solvent (a mixture of THF and toluene) was achieved by bubbling dry argon through the reaction mixture for 30 min prior heating and throughout the course of the reaction.Under these conditions, the formation of the ester 6b was greatly suppressed (full conversion of the starting 1-benzoylbenzotriazole 4d required a prolonged reaction time and the yield of 6b was significantly lower); however, the ester 6b was still obtained as the main product, while only traces of the corresponding ketone were observed in the 1 H NMR spectrum of the reaction mixture.
We have found that the rate of ester formation and the product yields also depend markedly on the nature of the R and R 1 substituents.Thus, reactions with aliphatic organozinc reagents requires 40-50 h of refluxing in THF/toluene under nitrogen while the analogous reactions with more active benzylzinc bromide were complete in 14-16 h (Table 2).Attempts to displace the benzotriazole moiety in N-trifluoroacetylbenzotriazole 4b and N-t-butylcarbonylbenzotriazole 4c by benzylzinc bromide, or in N-(3-pyridylcarbonyl)benzotriazole 4i with PhZnBr or n-BuZnBr, failed under these conditions.
N-Acylbenzotriazoles 4d and 4e with a Reformatsky reagent prepared in situ gave the corresponding ethyl esters of arylcarboxylic acids 8a,b in moderate yields, probably via sixmembered cyclic transition state 7 (Scheme 3).

Scheme 3
The possible application of catalysts based on other transition metals was studied using 2furylcarbonylbenzotriazole 4f as a model compound.The results of the reaction of 4f with prepared in situ n-PrZnI in the presence of NiCl 2 , instead of PdCl 2 (PPh 3 ) 2 , in various reaction conditions are summarized in Table 3.However, even the best yield obtained (entry 7) is significantly lower than the one obtained with palladium catalyst (25% vs. 55%), although in the first case the reaction is much faster.The reaction of N-benzoylbenzotriazole 4d with npropylzinc iodide under the reaction conditions shown in entry 7 gave propyl benzoate in surprisingly high 46% yield.The application of iron(III) acetylacetonate as a transition metal catalyst was less successful: in its presence the reaction of 4f with n-PrZnBr gave propyl 2furoate 6e in only 20% yield.• some starting material was recovered During our work with NiCl 2 as a catalyst, we observed that in the presence of 1 equiv of Zn dust a reaction achieves its completion significantly faster than when only traces of metallic Zn, brought in with an organozinc reagent, were present in the reaction mixture (cf.entries 4 and 5, Table 3).This led us to the conclusion that Ni(0) species, formed in situ by the reduction of NiCl 2 with Zn dust, but not Ni(II) species, is the active catalytic form.Therefore, we investigated the effect of the direct introduction of the commercially available Ni(0) catalyst, Ni(COD) 2 .The results of a series of reactions of N-acylbenzotriazoles with organozinc reagents in the presence of Ni(COD) 2 are given in Table 2.As follows from these results, the catalysis with Ni(COD) 2 affords the corresponding esters in the yields comparable to those obtained with Pd(II) catalyst.Moreover, the reactions with aliphatic organozinc reagents catalyzed with a Ni(0) catalyst (either Ni(COD) 2 or the one, formed in situ from NiCl 2 ) have considerably higher reaction rates (for example, compare entries 6 and 11, Table 2).
In summary, we have shown that on treatment with an organozinc reagent in the presence of zinc bromide and a catalytic amount of a transition metal catalyst [Pd(II) or Ni(0)], Nacylbenzotriazoles undergo unexpected transformation into the corresponding carboxylic acid esters.