An efficient one-pot copper-catalyzed approach to isoquinolin-1(2h)-one derivatives

Article abstract of DOI:10.1021/ol900847t

A simple and efficient copper-catalyzed method for synthesis of 3,4-disubstituted isoquinolin-1(2H)-one derivatives via cascade reactions of substituted 2-halobenzamides with β-keto esters under mild conditions has been developed, and the method has econo

Full text of DOI:10.1021/ol900847t

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2469-2472
An Efficient One-Pot Copper-Catalyzed
Approach to Isoquinolin-1(2H)-one
Derivatives
Feng Wang,† Hongxia Liu,‡ Hua Fu,*,† Yuyang Jiang,*,‡ and Yufen Zhao†
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry
of Education), Department of Chemistry, Tsinghua UniVersity,
Beijing 100084, P. R. China, and Key Laboratory of Chemical Biology (Guangdong
ProVince), Graduate School of Shenzhen, Tsinghua UniVersity,
Shenzhen 518057, P. R. China
fuhua@mail.tsinghua.edu.cn; jiangyy@sz.tsinghua.edu.cn
Received April 9, 2009
ABSTRACT
A simple and efficient copper-catalyzed method for synthesis of 3,4-disubstituted isoquinolin-1(2H)-one derivatives via cascade reactions of
substituted 2-halobenzamides with ꢀ-keto esters under mild conditions has been developed, and the method has economical and practical
advantages.
Isoquinolin-1(2H)-one derivatives are found in natural
products such as thalifoline,1 dorianine,2 ruprechstyril,3
narciclasine,4 pancratistatin,4 and lycoricidine4b in Figure 1,
and they are also versatile building blocks for the total
synthesis of natural alkaloids.5 Substituted isoquinolin-1(2H)-
ones exhibit various biological and medicinal activities such
as antihypertensive activity6a,b and function as NK3 antag-
onists,6c melatonin MT1 and MT2 receptor agonists,6d Rho-
kinase inhibitors,6e and JNK inhibitors.6f Some of them are
also used as novel orally active 5-HT3 antagonists7a and
† Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical
Figure 1. Isoquinolin-1(2H)-one derivatives of related natural
products.
Biology.
‡ Key Laboratory of Chemical Biology.
(1) Krane, B. D.; Shamma, M. J. Nat. Prod. 1982, 45, 377.
(2) Glushkov, V. A.; Shklyaev, Y. V. Chem. Heterocycl. Compd. 2001,
37, 663, and references cited therein.
thymidylate synthase (TS) inhibitors7b or for the treatment
of stomach tumors and diseases of human brain cells.2 Some
approaches to isoquinolin-1(2H)-one derivatives have been
developed, such as the rearrangement of 2-(2-benzofuranyl)-
benzonitriles,8 base-promoted condensation of 2-(bromo-
methyl)benzonitrile,9 transformation of isocoumarins or
3-hydroxyphthalides,10 double metalation of arylbenza-
(3) Pettit, G. R.; Meng, Y. H.; Herald, D. L.; Graham, K. A. N.; Pettit,
R. K.; Doubek, D. L. J. Nat. Prod. 2003, 66, 1065.
(4) (a) Rigby, J. H.; Maharoof, U. S. M.; Mateo, M. E. J. Am. Chem.
Soc. 2000, 122, 6624. (b) Hudlicky, T.; Rinner, U.; Gonzalez, D.; Akgun,
H.; Schilling, S.; Siengalewicz, P.; Martinot, T. A.; Pettit, G. R. J. Org.
Chem. 2002, 67, 8726.
(5) (a) Coelho, F.; Veronese, D.; Lopes, E. C. S.; Rossi, R. C.
Tetrahedron Lett. 2003, 44, 5731. (b) Heaney, H.; Shuhaibar, K. F. Synlett
1995, 47.
10.1021/ol900847t CCC: $40.75
Published on Web 05/07/2009
 2009 American Chemical Society

mides,11 the cyclization of 2-chlorobenzonitriles with ꢀ-keto
esters,12 intramolecular Diels-Alder reactions,13 Wittig
reactions,14 as well as photochemical reactions.6b,15 Although
these methods are effective, some starting materials are not
readily available or are difficult to prepare. Recently,
transition-metal-based catalysis has often been utilized for
the synthesis of various heterocyclic compounds;16 however,
only limited examples applicable to the synthesis of iso-
quinolin-1(2H)-ones have appeared.17 Recently, great progress
for copper-catalyzed Ullmann couplings have been made,18
and we have also developed some copper-catalyst systems
that were used in N-arylations.19 Some N-heterocycles have
been constructed via the Ullmann couplings by us20 and other
research groups.21 Herein, we report an efficient one-pot
copper-catalyzed approach to isoquinolin-1(2H)-one deriva-
tives via cascade reactions of o-halobenzamides with ꢀ-keto
esters under mild conditions.
As shown in Table 1, 2-bromobenzamide (1a) and ethyl
acetoacetate (2a) were chosen as the model substrates to
Table 1. Copper-Catalyzed Coupling of 2-Bromobenzamide
with Ethyl Acetoacetate: Optimization of the Reaction
Conditionsa
(6) (a) Saeed, A.; Ashraf, Z. Pharm. Chem. J. 2008, 42, 277, and
references therein. (b) Guastavino, J. F.; Barolo, S. M.; Rossi, R. A. Eur.
J. Org. Chem. 2006, 17, 3898, and references therein. (c) Simonsen, K. B.;
Kehler, J.; Juhl, K.; Khanzhin, N.; Nielsen, S. M. Patent WO2008131779A1.
(d) Wong, Y. H.; Ho, M. K. C.; Hu, Y. Q.; New, D. C.; He, X. X.; Pang,
H. H. Patent WO2008092292A1. (e) Plettenburg, O.; Lorenz, K.; Goerlitzer,
J.; Loehn, M. Patent WO2008077555A2. (f) Asano, Y.; Kitamura, S.; Ohra,
T.; Itoh, F.; Kajino, M.; Tamura, T.; Kaneko, M.; Ikeda, S.; Igata, H.;
Kawamoto, T.; Sogabe, S.; Matsumoto, S.; Tanaka, T.; Yamaguchi, M.;
Kimura, H.; Fukumoto, S. Bioorg. Med. Chem. 2008, 16, 4699.
(7) (a) Matsui, T.; Sugiura, T.; Nakui, H.; Iguch, S.; Shigeoka, S.;
Tukedu, H.; Odagaki, T.; Ushio, Y.; Ohmoto, K.; Iwamani, M.; Yamazaki,
S.; Arai, T.; Kawamura, M. J. Med. Chem. 1992, 35, 3307. (b) Li, S. W.;
Nair, M. G.; Edwards, D. M.; Kisluick, R. L.; Gaument, Y.; Dev, I. K.;
Duch, D. S.; Humphreys, J.; Smith, G. K.; Ferone, R. J. Med. Chem. 1991,
34, 2746.
entry catalyst
base
solvent
temp /time yield (%)b
1
2
3
4
CuI
CuI
CuI
-
Cs2CO3 dioxane 25 °C/16 h
Cs2CO3 dioxane 80 °C/16 h
Cs2CO3 dioxane
Cs2CO3 dioxane
trace
80
120 °C/16 h
80 °C /36 h
80 °C/16 h
80 °C/16 h
80 °C/16 h
80 °C/16 h
80 °C/16 h
80 °C/16 h
80 °C/16 h
80 °C/16 h
80 °C/16 h
82
33
trace
29c
67
51
72
63
79
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl2
-
dioxane
Cs2CO3 dioxane
K3PO4
K2CO3
NaOEt
Cs2CO3 toluene
Cs2CO3 DMF
dioxane
dioxane
ethanol
9
(8) Gutillaumel, J.; Boccara, N.; Demersemann, P.; Royer, R. J. Chem.
Soc., Chem. Commun. 1998, 1604.
10
11
12
13
(9) Jagtap, P. G.; Baloglu, E.; Southan, G.; Williams, W.; Roy, A.;
Nivorozhkin, A.; Landrau, N.; Desisto, K.; Salzman, A. L.; Szabo, C. Org.
Lett. 2005, 7, 1753.
Cs2CO3 dioxane
Cs2CO3 dioxane
76
38
(10) Otha, S.; Kimoto, S. Tetrahedron Lett. 1975, 16, 2279.
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1992, 57, 2700. (b) Davis, S. E.; Church, A. C.; Griffith, C. L.; Beam,
C. F. Synth. Commun. 1997, 27, 2961.
a Reaction conditions: nitrogen atmosphere, 2-bromobenzamide (0.5
mmol), ethyl acetoacetate (0.75 mmol), catalyst (0.05 mmol), base (1 mmol),
solvent (3 mL). b Isolated yield. c In the absence of nitrogen atmosphere.
(12) Snow, R. J.; Butz, T.; Hammach, A.; Kapadia, S.; Morwick, T. M.;
Prokopowicz, A. S.; Takahashi, H.; Tan, J. D.; Tschantza, M. A.; Wang,
X. J. Tetrahedron Lett. 2002, 43, 7553.
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4335.
optimize reaction conditions including catalysts, bases,
solvents, and temperature. First, the reaction temperature was
investigated by using 0.1 equiv of CuI as the catalyst and 2
equiv of Cs2CO3 as the base (relative to amount of 1a) in
dioxane (entries 1-3). The yield of the target product was
greatly improved as the reaction temperature was increased,
and higher yields were provided at more than 80 °C (entries
2 and 3). The coupling efficiency was evidently decreased
in the absence of catalyst (entry 4), and only a trace amount
of product was observed without addition of base (entry 5).
The yield of target product decreased and byproduct in-
creased in the absence of nitrogen atmosphere (entry 6).
Other bases, K3PO4 and K2CO3, were screened at 80 °C
(entries 7 and 8), and the results showed that Cs2CO3
provided the highest yield (entry 2). Sodium ethoxide was
also an effective base in ethanol (entry 9). The effect of
solvent was investigated (entries 2 and 9-11), and toluene
(14) Epsztajin, J.; Grzelak, R.; Jozwiak, A. Synthesis 1996, 1212.
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Tetrahedron 1997, 53, 3475
.
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Org. Lett., Vol. 11, No. 11, 2009

Table 2. Copper-Catalyzed Synthesis of Isoquinolin-1(2H)-one Derivativesa
a Reaction conditions: nitrogen atmosphere, 2-halobenzamide (1 mmol), ꢀ-keto ester (1.5 mmol), CuI (0.1 mmol), Cs2CO3 (2 mmol), dioxane (5 mL).
b Isolated yield.
and DMF provided slightly lower yields (entries 10 and 11).
Several copper salts were also tested (compare entries 2, 12,
and 13), and CuI was proven to be the most effective catalyst
(entry 2).
yield (60%). For ꢀ-keto esters, the steric hindrance is a key
factor, and the ꢀ-keto esters containing bigger groups such
as phenyl (entry 16), isopropyl (entry 17) provided lower
yields. The reactions above did not need addition of any
ligand or additive. Interestingly, nucleophilic attack of amino
group only occurred on the ketone rather than on ester of
ꢀ-keto ester. In addition, the cascade reactions could tolerate
some functional groups such as ester, C-Cl bond (entries
6, 9, and 15).
In summary, we have developed a simple and highly
efficient method for synthesis of 3,4-disubstituted isoquino-
lin-1(2H)-one derivatives. The couplings of 2-bromo- and
-iodobenzamides or 2-chloronicotinamide with ꢀ-keto esters
were performed well at 80 °C without addition of any ligand
The scope of copper-catalyzed coupling reactions of
substituted 2-halobenzamides with ꢀ-keto esters was inves-
tigated under the optimized conditions (10 mol % CuI as
the catalyst, 2 equiv of Cs2CO3 as the base, dioxane as the
solvent at 80 °C under nitrogen atmosphere). As shown in
Table 2, most of the substrates examined provided good
yields. For the substituted 2-halobenzamides, their relative
reactivity was in the order of aryl iodides > aryl bromides >
aryl chlorides. Reaction of 2-chloronicotinamide with ethyl
acetoacetate also provided the target product 3e in moderate
Org. Lett., Vol. 11, No. 11, 2009
2471

or additive. The present method shows economical and
practical advantages over the previous methods and uses a
readily available starting material, so it will provide a new
strategy for construction of diverse and useful isoquinolin-
1(2H)-one derivatives in organic chemistry and medicinal
chemistry.
tury Excellent Talents in University (NCET-05-0062) and
Changjiang Scholars and Innovative Research Team in
University (PCSIRT) (No. IRT0404) in China, and the Key
Subject Foundation from Beijing Department of Education
(XK100030514).
Supporting Information Available: Synthetic procedures,
1
characterization data, and H, 13C NMR spectra of these
Acknowledgment. This work was supported by the
National Natural Science Foundation of China (Grant No.
20672065, 20732004), Chinese 863 Project (Grant No.
2007AA02Z160, 2006DFA43030). Programs for New Cen-
synthesized compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL900847T
2472
Org. Lett., Vol. 11, No. 11, 2009