1 Aryl 3 ferrocenyl 4 formylpyrazoles were obtained from appropriate acetylferrocene arylhydrazones by the Vilsmeier-Haack reaction. Direct reductive amination of the resulting aldehydes with primary and secondary amines and amino acid esters in the presence of NaBH(OAc) 3 was studied.Pyrazole derivatives exhibit a wide spectrum of phar macological activity. 1 Introduction of a ferrocenyl frag ment into a heterocyclic molecule often imparts a new biological activity to it or modifies its inherent activity. For instance, ferrocene containing pyrazoles have antibac terial 2 and antitumor effects in combination with low tox icity 3 and are plant growth regulators. 4 In addition, opti cally active ferrocenylpyrazole derivatives are suitable as ligands in asymmetric catalysis and can catalyze hydroge nation, silylation, and cyanation of carbonyl compounds. 5 In the present work, we studied direct reductive ami nation of 1 aryl 3 ferrocenylpyrazole 4 carbaldehydes in reactions with primary and secondary aliphatic amines.
Results and DiscussionAryl methyl ketones are easily accessible reagents for the preparation of pyrazolecarbaldehydes. The synthesis involves condensation of ketones with arylhydrazines fol lowed by intramolecular cyclization of the resulting hydrazones under the conditions of the Vilsmeier-Haack formylation (Scheme 1).Reactions of acetylferrocene (1) with phenyl and β naphthylhydrazines gave the corresponding hydrazones in high yields, which were used in room temperature re actions with three equivalents of the Vilsmeier-Haack complex (DMF-POC1 3 ) in DMF. Upon hydrolysis of the iminium salts with aqueous Na 2 CO 3 , the correspond ing 1 aryl 3 ferrocenylpyrazole 4 carbaldehydes 2a,b were isolated in 84 and 65% yields, respectively.Aldehydes and ketones react with ammonia and pri mary and secondary amines in the presence of reducing agents to give primary, secondary, and tertiary amines, respectively. These reactions are known as reductive ami nation of carbonyl compounds or reductive alkylation of amines and can be effected in direct and stepwise ways. In the former case, a carbonyl compound and an amine are mixed with an appropriate reducing agent without isolating an intermediate imine or iminium salt. In the latter case, the formation of an intermediate imine is followed by its re duction. Secondary amines from pyrazolecarbaldehydes were obtained in the second way with sodium borohydride as a reducing agent, 6 while direct reductive amination of arylformylpyrazoles has not been implemented hitherto.Using sodium borohydride as a reducing agent in di rect reductive amination of 1 aryl 3 ferrocenylpyrazole 4 carbaldehydes in different solvents and at different tem peratures, we isolated the corresponding alcohols only. Modification of sodium borohydride with the electron withdrawing cyano or acetoxy group enhances the selec Scheme 1 Ar = Ph (a), β C 10 H 7 (b) Yield (%): 84 (2a), 65 (2b)