Reaction of Methoxy-N-heteroarmatics with Phenylacetonitrile under Basic Conditions

Abstract

AbstLact -The monomethoxyl derivatives of various nelectron-deficient N-heteroaromatics reacted with phenylacetonitrile in tetrahydrofuran in the Presence of sodium hydride to give a-phenyl-N-heteraareneacetonitriles in the yields ranging from 45 to 7 8 % . On the contrary, the reaction of these methoxyl derivatives with ethyl cyanoacetate or malononitrile under Similar conditions was restricted within narrov limits. The synthesis of benzoyl-N-heteroaromatics by the air-oxidation of a-Phenyl-N-heteroareneacetonitriles was described additionally. In nucleophilic substitution at the a-and r-positions (active positions) of nelectron-deficient N-heteroaromatic compounds, aikoxyl groups are recognized to be very weak leaving groups, so that the reaction of the aikoxyl derivatives with nuCleOPhilic reagents, particularly with carbanions generated from active methylene compounds. is not uell investigated.' The reaction of 4-methoxyquinazol ine With nitrile-stabilized carbanions is an exceptional example, and the corresponding 4-subst i tuted products obtained.' As 11-lustrated in Scheme I. t t was suggested that at the highly active position of n-electron-deficient N-heteroaromatics, even aikoxyl groups might be replaced with nucleophilic reagents. Scheme 1 On the other hands, in 1954. Mizuno & LL have reported that phenylacetonitrile widely reacted with various chloro-N-heteroaromatics under basic conditions. and the a-phenyl-N-heteroareneacetonitriles were obtained in the yields ranging from 43 to Further, Panizzon has presented that phenylacetonitrile smoothly reacted with 2-chloropyridine which is known to be an inactive heteroaryl chlaride. although i t has a chlorine substituent at the u -~o s i t i o n .~ These findings demonstrate that phenylacetonitrile is an extremely powerful reagent comparing with Other active methylene compounds such as ethyl cyanoacetate, malononitrile, diethyl malonate, and acetylacetone From these points of view, we investigated the reaction o f various n-electrondeficient N-heteroaromaties containing a methaxyl group at their active Position with phenylacetonitrile under basic conditions in order to compare the reactivity of n-electron-deficient N-heteroaromatics for addition-elimination type nucleophilic substitutions. C, \ N OMe 6 m d q N N -OMe

Clotrimazole Scaffold as an Innovative Pharmacophore Towards Potent Antimalarial Agents: Design, Synthesis, and Biological and Structure–Activity Relationship Studies

“…7,8 Biological activities of CLT are mediated by its ability to interact with ferri-protoporphyrin IX (Fe(III)-FP), which is present as the prosthetic group in several enzymes, such as (i) 14R-lanosteroldemethylase (14-LD), the fungal cytochrome inhibited by CLT, (ii) human P450 cytochromes, which are inhibited by CLT causing altered metabolism of both xenobiotics and endogenous presence of sodium hydride, to afford nitriles 25a and 25b, respectively, which were subsequently converted into the corresponding ketone derivatives 26a,b. 19 Following the synthetic procedure already described, Grignard reaction, followed by Table 1. Antiplasmodial Activity of Compounds 3a-h a Percentage of ionic form in brackets; TP ) triprotonated form; DP ) diprotonated form; P ) protonated form; and N ) neutral form (ACD/pKa DB version 10.00 software -Advanced Chemistry Development, Inc., Toronto, Canada-).…”

Six‐Membered Heterocycles: 1,2‐, 1,3‐, and 1,4‐Diazines and Related Systems

“…The relative reactivity is summarized here. Methoxy groups can also serve as leaving groups that can be exchanged by carbanions via an addition/elimination process (Scheme 19.147) [165]. Unsymmetrical 3,6-disubstituted pyridazines 139 can be prepared in a mild, efficient manner from commercially available 3,6-halopyridazines through stepwise nucleophilic mono-substitution followed by palladium-catalyzed coupling with an arylboronic acid (Scheme 19.148) [166].…”

The azaphilic addition of organometallic reagents on tetrazines: scope and limitations

“…The analogous reactions introducing carbon nucleophiles would also be of synthetic importance, but there are only a few know examples utilizing potassium cyanide 15 or malonates. 20,21 The cross-coupling reactions on tetrazines, also recently reported have only a limited scope. 22 The use of reactive carbon nucleophiles, such as organolithium or Grignard reagents in an attempt to substitute 3,6-bis(methylthio)tetrazine led to the addition of the organic group onto a ring nitrogen atom.…”