Novel Process to 4,4-Dialkyl-1,4-dihydro-6-methoxy-3-phenylcinnolines via Grignard Reaction

4,4-Dialkyl-1,4-dihydro-6-methoxy-3-phenylcinnolines were obtained from 2-(5-methoxy-2-nitrophenyl)acetonitrile analogues and phenylmagnesium bromide by one step, and the possible mechanism was speculated.Cinnolines have been used as Liver-X receptor modulators, cell proliferation inhibitors, antitumor agents， and anti-inflammatory agents recently. 1H. S. Lowrie synthesized 3-phenylcinnoline-4-carboxylic acids via Stolle-Becker cinnoline synthesis. 2Yoshio Matsubara synthesized cyanocinnolines from aromatic hydrazones and TCNE, 3 and 4(1H)-cinnolones from 4-cyancinnolines, 4 as well as some other processes to synthesize cinnolines. 5-8To the best of our knowledge, there are very limited reports describing the preparation of dihydrocinnolines. 9,10 In our estrogen receptor β ligands research, we found a new method to synthesis 4,4-dialkyl-1,4-dihydro-6-methoxy-3-phenylcinnoline with the biphenyl as the byproduct from 2-(5-methoxy-2-nitrophenyl)acetonitrile analogues with the phenylmagnesium bromide in THF solution at ice bath, When we used alkylmagnesium bromide or benzylmagnesium bromide instead of phenylmagnesium bromide, we didn't get the object 1,4-dihydro-3-substituted-cinnoline.The results were summarized in Table 1.It appears that several important factors are involved in this reaction.1) One opposite methoxy to the nitro group on the benzene ring is important, which is supposed as an electron donor that makes nitro's eletrophilic ability weaker than the nitrile.2) The dialkyl substitutes of the o-nitro phenylacetonitrile are important, which enlarge the steric hindrance to reduce the free rotation of nitrile to force the reaction between the nitrile and nitro groups.And the bulky groups are preferable.3) A proper temperature is also important to get a higher yield.