Cu2(OTf)2-Catalyzed and Microwave-Controlled Preparation of Tetrazoles from Nitriles and Organic Azides under Mild, Safe Conditions

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Lluís Bosch, Jaume Vilarrasa*

Departament de Química Orgànica, Universitat de Barcelona, Av. Diagonal 647, 08028 Barcelona, Spain

A copper-catalyzed dipolar cycloaddition between organic azide and EWG-nitrile was reported. The report was dedicated to Profs. Rolf Huisgen and K. Barry Sharpless. Dipolar cycloaddition is also generally known as the Huisgen reaction.

Organic azide can react with organic nitrile attached to an electron withdrawing group to give an important class of compounds of pharmaceutical interest: tetrazole. The preparation of this class of compound, however, can be marred with danger of explosion due to high reactivity in organic azide starting materials and in tetrazole product.

The studies were commenced by investigation of a vast number of metal salt additives to probe the improvement of the reaction. The results are summarized in the table below. In addition to the salts shown in the table, several other additives were also tested, such as Cu powder, AgSbF6, AgBF4, AgF, AgOAc, AuCl3, Au(OTf)3, Ru/C, RuCl3, [Ru(C5Me5)(PPh3)2]Cl2, [Pd2(dba)3]·CHCl3, PdCl2, Pt/C, PtCl2, PtCl4, Sc(OTf)3, and LaCl3), none of which provided any product. Of all the additives tested, only some copper salts were found to promote the reaction led to lower reaction temperature, namely Cu2(OTf)2-Tol and Cu2(OTf)2-C6H6. These reactions were conducted under the homogeneous conditions.

The effect of triflic acid (HOTf) which may be present in commercial copper(I) triflate salt was ruled out (entry 12). Combinations of a few common organic nitriles and azides were explored and the results are presented below.

In these cases, mild conditions were employed. As seen in some cases, a microwave technology could also be applied to the reaction to reduce the reaction time. As seen in entries 7-12 in the table, 1,4-regioisomers (8a-11a) emerged when larger amount of copper salt was used (50-100 mol%) under the heterogeneous conditions. This is in contrast to the purely thermal conditions or with lower loading of copper catalyst (10 mol%) where only 1,5-regioisomers were observed. Thus when more copper salt was used, products 8a-11a could override and become the exclusive products.

As shown in entries 11 and 12, Bs-CN (Bs = benzenesulfonyl) and Ts-CN (Ts = toluenesulfonyl)could be used as H-CN equivalent in the cycloaddition as the sulfonyl group in the products could be easily reduced to hydrogen. The reaction could be carried out neat. But when a solvent is necessary to dissipate heat (to reduce the risk of explosion), CH2Cl2 was found to be superior (in term of yield) when tested in the synthesis of 5 (CH2Cl2 (85%), toluene (76%), THF (56%), CH3CN (0%; the solvent itself does not react), DMF (0%), and absolute EtOH (0%)).

The mechanism that explained the results is presented below.

As seen in the scheme, when more copper(I) was used, the copper species also coordinate to the azide at the internal nitrogen, thus changing the regiochemistry of the product (top right vs. bottom right). This method was then applied to a more sterically hindered aliphatic azide in the synthesis of 3’-azido-3’-deoxythymidine (AZT/zidovudine) derivative as shown below (yields were reported as excellent without numeric values). In this case, even when more copper salt was used in the synthesis of 12 (up to 200 mol%), only 1,5-regioisomer was obtained, demonstrating the inability of copper to coordinate to the internal nitrogen of the azide due to the steric hindrance (the bottom right species in Scheme 2).