488
J. Comb. Chem. 2010, 12, 488–490
Synthesis and Antitumor Evaluation of a Novel Class of
4-Substituted-1,4-Dihydroisoquinolin-3-ones
Ting Ma, Wenteng Chen, Guolin Zhang, and Yongping Yu*
Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang UniVersity,
Hangzhou 310058, P. R. China
ReceiVed February 10, 2010
An efficient method for the solution-phase parallel synthesis of 4-substituted-1,4-dihydroisoquinolin-3-ones
is developed. The isoquinolinones were constructed employing an intramolecular Heck reaction, providing
full regio- and stereoselectivity. Most of the synthesized compounds showed potent antiproliferative activities
against tumor cell lines.
1. Introduction
follows the cis addition, the regioselectivity was determined
and the ring size of the generated product was fixed as six
members.
The isoquinoline is an important heterocyclic scaffold
widely found in many natural alkaloids1 and pharmaceu-
ticals2 that exhibit antitumor,3 antimicrobial,4 antiplas-
modial activity,5 and noncompetitive inhibition to AMPA
receptor.6 The wide range of biological and pharmacologi-
cal importance of isoquinolinones promoted us to prepare
new derivatives of these compounds utilizing a simple and
efficient method. Although many syntheses of isoquino-
linones have been reported, they require troublesome
processes. Most of these methods involve the use of either
a preformed isoquinoline or homophthalic acid, which are
in turn obtained from a multistep synthesis.7 To the best
of our knowledge, very few such heterocyclic derivatives
with a multisubstituted exo double bond were reported.8
Palladium-catalyzed reductive reactions have successfully
been utilized for the preparation of various heterocyclic
compounds in a one-step procedure.9 Thus, we wish to
report a palladium-catalyzed process for the synthesis of
isoquinolinone applying the intramolecular Heck-carbocy-
clization. Additionally, we report the antitumor activities
of these products, most of which exhibited potent inhibi-
tion of tumor growth.
The optimal conditions for the intramolecular Heck
reaction (Table 1) were determined by utilizing the amide
4a as starting material. The reaction was performed under
heat in the presence of 3 mol % of Pd (PPh3)4 as the
catalyst and sodium formate as a reducing agent. Switch-
ing to other Pd catalysts (Table 1, entries 2 and 3), such
Scheme 1. Synthesis of 1,4-Dihydroisoquinolin-3-onesa
a Reagents and conditions: (a) NaBH4, CH3OH; (b) 1-hydroxypyrrolidine-
2,5-dione (1.1 equiv), DCC (2 equiv), 4-DMAP (1 equiv), dioxane; (c)
Pd(PPh3)4 (3 mol %), HCOONa, DMF/H2O
Table 1. Optimization of the Reaction Conditionsa
2. Result and Discussion
2.1. Synthesis and Optimization of 4-Substituted-1,4-
Dihydroisoquinolin-3-ones. 2-Bromophenylethylamines 2
were synthesized from commercially available 2-bromoben-
zaldehydes 1 and primary amines. After compounds 2 were
coupled with various 3-substituted 2-propynoic acids 3,
amides 4a-r (Scheme 1) were obtained in excellent yields,
which were ready for follow-up intramolecular cyclization.
Following intramolecular cyclization, the products 5 with
Z-configuration of the exocyclic double bond were obtained
exclusively. Moreover, because insertion to the triple bond
time
(h)
solvent
(v/v)
dilution yield
entry
catalyst
(nM)
(%)
1
2
3
4
5
6
3
3
3
3
6
DMF/H2O(3:1) Pd(PPh3)4
DMF/H2O(3:1) Pd(OAc)2 + 2PPh3
DMF/H2O(3:1) PdCl2 + 2PPh3
DMF/H2O(4:1) Pd(PPh3)4
DMF/H2O(3:1) Pd(PPh3)4
DMF/H2O(3:1) Pd(PPh3)4
70
70
70
70
140
140
79
75
65
68
65
61
12
a Reactions were run on a 0.4 mmol scale; the mixture was heated at
100 °C (oil bath temperature).
* To whom correspondence should be addressed. E-mail: yyu@
zju.edu.cn.
10.1021/cc100021t 2010 American Chemical Society
Published on Web 04/28/2010
Ma, Ting
