posted on 2015-05-15, 00:00authored byStephen
R. Slauson, Ryan Pemberton, Partha Ghosh, Dean J. Tantillo, Jeffrey Aubé
The development of the domino reaction
between an aminoethyl-substituted
diene and maleic anhydride to afford an N-substituted octahydroisoquinolin-1-one
is described. A typical procedure involves the treatment of a 1-aminoethyl-substituted
butadiene with maleic anhydride at 0 °C to room temperature for
20 min under low-solvent conditions, which affords a series of isoquinolinone
carboxylic acids in moderate to excellent yields. NMR monitoring suggested
that the reaction proceeded via an initial acylation step followed
by an intramolecular Diels–Alder reaction. For the latter step,
a significant rate difference was observed depending on whether the
amino group was substituted by a phenyl or an alkyl (usually benzyl)
substituent, with the former noted by NMR to be substantially slower.
The Diels–Alder step was studied by density functional theory
(DFT) methods, leading to the conclusion that the degree of preorganization
in the starting acylated intermediate had the largest effect on the
reaction barriers. In addition, the effect of electronics on the aromatic
ring in N-phenyl substrates was studied computationally
and experimentally. Overall, this protocol proved considerably more
amenable to scale up compared to earlier methods by eliminating the
requirement of microwave batch chemistry for this reaction as well
as significantly reducing the quantity of solvent.