pubs.acs.org/joc
Isoquinoline-fused polycyclic compounds such as pyrimi-
Rapid Access to 3-(Aminomethyl)isoquinoline-Fused
Polycyclic Compounds by Copper-Catalyzed Four-
Component Coupling, Cascade Cyclization, and
Oxidation
do[2,1-a]isoquinolines and imidazo[2,1-a]isoquinolines exert
various biological effects3 including antitumor activity.4
Considerable efforts have been made to develop efficient
methods for the synthesis of this class of compounds, in
which stepwise introduction/construction of the desired ring
system is generally required.5 As a part of our ongoing
program directed toward development of copper-catalyzed
domino multicomponent coupling and cyclization,6 we re-
ported a novel synthesis of 3-(aminomethyl)isoquinolines by
four-component coupling-cyclization (Scheme 1).7 In this
reaction, a copper-catalyzed Mannich-type reaction of a
2-ethynylbenzaldehyde 1 with paraformaldehyde 2 and a
secondary amine 3 followed by imine formation with
t-BuNH2 4 promotes isoquinoline formation to afford 7
through cleavage of a tert-butyl group.
Yusuke Ohta, Yushi Kubota, Tsuyoshi Watabe,
Hiroaki Chiba, Shinya Oishi, Nobutaka Fujii,* and
Hiroaki Ohno*
Graduate School of Pharmaceutical Sciences, Kyoto
University, Sakyo-ku, Kyoto 606-8501, Japan
nfujii@pharm.kyoto-u.ac.jp; hohno@pharm.kyoto-u.ac.jp
Received May 24, 2009
SCHEME 1. Four-Component Synthesis of 3-(Aminomethyl)
isoquinoline Using Copper Catalysis
A novel copper-catalyzed synthesis of 3-(aminomethyl)
isoquinoline-fused polycyclic compounds, through four-
component coupling, cyclization, and oxidation, has been
developed. A Mannich-type reaction of 2-ethynylbenzal-
dehyde with paraformaldehyde and a secondary amine
followed by treatment with a diamine component gave
tricyclic isoquinolines through cascade cyclization and
oxidation. Construction of fused isoquinolines of various
ring sizes is also presented.
On the basis of this chemistry, we expected that the use of a
primary amine containing a tethered nucleophilic group
instead of t-BuNH2 could bring about an intramolecular
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(d) Smith, L. V.; Parenty, A. D. C.; Guthrie, K. M.; Plumb, J.; Brown, R.;
Cronin, L. ChemBioChem 2006, 7, 1757–1763.
Cascade reactions1 and multicomponent reactions2 in
which several bond-forming steps take place in a single
reaction vessel play an important role in atom-economical
organic chemistry. Recently, considerable attention has been
paid to this research area since complex molecules can be
produced from readily accessible components in a simple
manner.
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DOI: 10.1021/jo901090u
r
Published on Web 07/02/2009
J. Org. Chem. 2009, 74, 6299–6302 6299
2009 American Chemical Society