An efficient synthetic route to carbocyclic enaminonitriles via Lewis acid catalysed domino-ring-opening-cyclisation (DROC) of donor–acceptor cyclopropanes with malononitrile

Abstract

A highly efficient strategy for the synthesis of functionalised carbocyclic enaminonitriles in excellent yields has been described. The reaction utilises Yb(OTf)3 catalysed C-C bond cleavage and two simultaneous C-C bond formations of donor-acceptor (DA)-cyclopropanes with malononitrile anions in a domino fashion.

Carbocycles from donor–acceptor cyclopropanes

“…In another example of this chemistry, the Ghorai group showed the analogous reaction of malononitriles with 1,1-cyclopropane diesters 211, under NaH and Lewis acid conditions to give carbocyclic enaminonitriles 212 (Scheme 52). 67 A large scope was displayed and in general the yields were high. Additionally, the reaction conditions were suitable for not only aromatic cyclopropanes, but also heteroaromatic and styrenyl examples.…”

Temperature controlled condensation of nitriles: efficient and convenient synthesis of β-enaminonitriles, 4-aminopyrimidines and 4-amidinopyrimidines in one system

“…b-Enaminonitriles were commonly synthesized by condensation of two functional amide/nitrile molecules under high temperature and/or strong base conditions (Scheme 2a and b). 1,12,13 Other methods were also developed to obtain b-enaminonitriles, including the reuxing of methylenecarbonitriles with triethyl orthoformate and amine (Scheme 2c), 14 the metal-catalysed condensation of active nitriles with isocyanides or cyclopropanes (Scheme 2d and e), 15,16 the cyclization of chloromethyl p-tolyl sulfoxide with cyanomethyl lithium and (Scheme 2f), 17 and the Thorpe-Ziegler condensation of aliphatic nitriles (Scheme 2g). 18 However, all these reactions show limited tolerance for the synthesis of various enaminonitriles due to the rigorous reaction conditions and/or limited reaction substrates.…”

Domino‐Ring Opening‐Cyclization (DROC) of Donor‐Acceptor (DA) Cyclopropanes

“…When we reacted DA cyclopropane 3a with malononitrile 2 using NaH as the base in the presence of a catalytic amount of Yb(OTf) 3 as a Lewis acid (LA) in THF at 60 °C, carbocyclic β‐enaminonitrile 1a was produced in 88 % yield in 15 min (Scheme ). Lowering the LA amount only resulted in a decrease of the product yield …”

“…Inspired by our decade‐long achievements on S N 2‐type ring opening followed by alkylative cyclizations of activated aziridines and azetidines for the synthesis of various nonracemic aza‐heterocyclic compounds, we introduced a new concept and terminology: domino‐ring opening‐cyclization (DROC) ,. We synthesized carbocyclic β‐enaminonitriles from the reaction of DA cyclopropanes with malononitriles via a DROC‐tautomerization sequence . Interestingly, when 2‐alkyl malononitriles were employed as the nucleophiles, carbocyclic β‐enaminoesters were produced via DROC, followed by a decarboxylative tautomerization step, due to unavailability of the acidic proton α to the nitrile functionality in the intermediate species …”