Tetrahedron Letters
One-pot synthesis of isoquinoline and related compounds via
Cu-mediated tandem cross-coupling and cyclization
⇑
Shubhendu Dhara, Raju Singha, Yasin Nuree, Jayanta K. Ray
Indian Institute of Technology, Kharagpur 721302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
One-pot synthetic strategy has been developed to access isoquinolines and its analogs via Cu-mediated
tandem cross-coupling and cyclization in good yields under mild reaction conditions. A mixture of suit-
Received 8 October 2013
Revised 15 November 2013
Accepted 18 November 2013
Available online 7 December 2013
ably substituted
system afforded the 3-substituted isoquinoline regio-selectively in good to excellent yields.
Ó 2013 Elsevier Ltd. All rights reserved.
a-bromoaldehyde, terminal alkyne, and aq NH3 in CuI/1,10-phenanathroline catalytic
Keywords:
Cross-coupling
Cyclization
Isoquinoline
Copper–iodide
1,10-Phenanthroline
Nitrogen containing hetero-cycles comprise a major portion of
natural and unnatural compounds of important biological activity.1
Isoquinolines and their dihydroderivatives attract much attention
owing to their potential pharmacological activity.2 Important
examples of this class of compounds are kibdelones A–C (and iso-
meric cervinomycin A2 and SCH56036),3, fredericamycin A,4 and
alternarlactam.5 Their immense importance in biology as well as
chemistry requires development of efficient synthetic methodol-
ogy. Although classic method of Bischler–Napieralski,6 Pictet–
Spengler,7 and Pomeranz–Fritsh8 has frequently been employed
to construct isoquinoline moiety, these approaches have some
drawbacks. Recently transition metal catalyzed annulations of al-
kynes have been extensively exploited for the synthesis of isoquin-
olines.9 An efficient and short method of synthesis is still in
demand as some limitations have remained with the reported pro-
cedures regarding the starting material and the reaction
conditions.
Unprecedentedly, we observed that when a mixture of 2-bromo-
benzaldehyde (1a), phenylacetylene, and aq NH3 were heated at
80 °C temperature in the presence of only CuI, it gave regioselec-
tive 3-phenylisoquinoline (2a) in 40% yield (Table 1). This result
prompted us to find the optimal conditions for this reaction. We
further tried to improve the yield of the reaction by varying bases,
solvent, and temperature. In the absence of any base yield was
poor. Among the bases, Et3N was found to be the best. DMF was
proved to be the most yielding solvent at 95 °C temperature. Most
promising result was obtained with the addition of a ligand. With-
out any ligand, reaction gave only 40% of 3-phenylisoquinoline.
1,10-Phenanthroline gave the best result with CuI as catalyst
(Table 1, entry 3).
With the optimized reaction conditions (Table 1, entry 3) we
generalized our reaction of 3-phenylisoquinoline formation
(Table 2). The procedure tolerates a range of electron donating as
well as electron withdrawing groups in both the bromoaldehyde
and alkyne parts. Electron donating groups like OMe, Me, and
tBu-groups in the bromoaldehyde and alkyne part gave very low
yields making aldehyde and alkyne less reactive. On the contrary,
We herein report a reaction where suitably substituted ortho-
bromoaldehyde, terminal alkyne, and aqueous ammonia in the
presence of Cu-catalyst offer a direct route to 3-substitued isoquin-
oline (Scheme 1).
Our initial studies focused on developing an optimal set of
reaction conditions for Cu-catalyzed tandem cross-coupling and
cyclization. We began our investigation with the Cu-mediated
tandem cross-coupling and cyclization of 2-bromobenzaldehyde
and phenylacetylene in the presence of aqueous ammonia.
R1
R1
CuI
R2
R3
R4
R2
R3
Br
CHO
1,10-Phenanthroline
R4
+
N
Et3N, DMF, 95 o
NH3(aq.)
C
⇑
Corresponding author. Tel.: +91 3222283326; fax: +91 3222282252.
Scheme 1. Synthesis of isoquinoline.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
Dhara, Shubhendu
