Heterogeneous copper-catalysed cascade reactions of 2-bromobenzamides with β-keto esters leading to isoquinolin-1(2H)-one derivatives

Article abstract of DOI:10.3184/174751914X14117512932816

The heterogeneous copper-catalysed cascade reaction of 2-bromobenzamides with β-keto esters was achieved in dioxane at 80 °C in the presence of the MCM-41-immobilised bidentate nitrogen copper(I) complex [MCM-41-2N-CuI] with Cs2CO3 as base, affording a variety of isoquinolin-1(2H )-one derivatives in moderate to good yields. This heterogeneous copper catalyst can be recovered by a simple filtration and reused 10 times without significant loss of activity.

Full text of DOI:10.3184/174751914X14117512932816

634 RESEARCH PAPER
VOL. 38 OCTOBER, 634–638
JOURNAL OF CHEMICAL RESEARCH 2014
Heterogeneous copper-catalysed cascade reactions of 2-bromobenzamides
with β-keto esters leading to isoquinolin-1(2H)-one derivatives
Hong Zhaob, Yichao Wua, Tin Weia and Mingzhong Caia*
aKey Laboratory of Functional Small Organic Molecule, Ministry of Education and Department of Chemistry, Jiangxi Normal University, Nanchang
330022, P.R. China
bSchool of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Guangzhou 510006, P.R. China
The heterogeneous copper-catalysed cascade reaction of 2-bromobenzamides with β-keto esters was achieved in dioxane at
80 °C in the presence of the MCM-41-immobilised bidentate nitrogen copper(I) complex [MCM-41-2N-CuI] with Cs2CO3 as
base, affording a variety of isoquinolin-1(2H)-one derivatives in moderate to good yields. This heterogeneous copper catalyst
can be recovered by a simple filtration and reused 10 times without significant loss of activity.
Keywords: supported copper catalyst, cascade reaction, isoquinolin-1(2H)-one, 2-bromobenzamide, β-keto ester
The isoquinolin-1(2H)-one scaffold is present in many natural
processes. In spite of tremendous effort dedicated to the
immobilisation of homogeneous palladium complexes over
the last two decades,43 very few examples of carbon–carbon
or carbon–heteroatom bond formation reactions catalysed by
heterogeneous copper catalysts have appeared.44–47 Therefore,
the development of a stable heterogeneous copper catalyst
that allows for the highly efficient cascade reaction of a wide
range of substrates (2-halobenzamides and β-keto esters) is
worthwhile.
Developments on the mesoporous material MCM-41
provided a new possible candidate for a solid support for the
immobilisation of homogeneous catalysts.48 To date, some
palladium and rhodium complexes on functionalised MCM-41
support have been prepared and successfully used in organic
reactions.49–53 Recently, we have reported the synthesis of
the first MCM-41-immobilised bidentate nitrogen copper(I)
complex [MCM-41-2N-CuI] and found that it is a highly
efficient and recyclable heterogeneous catalyst for the homo-
and heterocoupling of terminal alkynes46 and the N-arylation
of indoles.47 However, to the best of our knowledge, the cascade
reaction of 2-halobenzamides with β-keto esters catalysed by
immobilisation of copper in MCM-41 has not been described
in the literature. In continuation of our efforts to develop
greener synthetic pathways for organic transformations, we
now report a highly efficient, heterogeneous cascade reactions
of 2-bromobenzamides with β-keto esters catalysed by an
MCM-41-immobilised bidentate nitrogen copper(I) complex
[MCM-41-2N-CuI] under mild reaction conditions.
products such as thalifoline,1 dorianine,2 ruprechstyril,3
narciclasine
and
pancratistatin.4,5
Isoquinolin-1(2H)-
one derivatives are versatile building blocks for the total
synthesis of natural alkaloids6,7 and have also been shown
to have various biological and medicinal activities such
as antihypertensive activity.8,9 They also function as NK3
antagonists,10 melatonin MT1 and MT2 receptor agonists,11
Rho kinase inhibitors12 and JNK inhibitors.13 Traditional
synthetic routes to isoquinolin-1(2H)-one derivatives include
the rearrangement of 2-(2-benzofuranyl)benzonitrile,14 the
base-promoted condensation of 2-(bromomethyl)benzonitrile,15
transformation of isocoumarins or 3-hydroxyphthalides,16
the double metalation of arylbenzamides,17 the cyclisation
of 2-chlorobenzonitriles with β-keto esters,18 intramolecular
Diels–Alder reactions,19 Wittig reactions,20 and photochemical
reactions.21 However, these methods have limited applications
because some starting materials are not readily available or
are difficult to prepare. Although transition-metal-catalysed
coupling reactions have been widely used in the synthesis of
heterocyclic compounds,22–24 only limited examples of the
synthesis of isoquinolin-1(2H)-ones have been reported.25–28
Recently, copper-catalysed Ullmann coupling reactions
have received much attention29–34 and some N-heterocycles
have been prepared via the Ullmann-type N-arylations.35–40
Fu and coworkers reported an efficient one-pot approach to
isoquinolin-1(2H)-one derivatives by copper-catalysed cascade
reactions of 2-halobenzamides with β-keto esters.41
Although this copper-catalysed cascade reaction of
2-halobenzamides with β-keto esters is highly efficient,
the problem with homogeneous catalysis is the difficulty of
separating the catalyst from the reaction mixture and the
impossibility reusing it in consecutive reactions. It is also
generally accepted that homogeneous catalysis might result
in unacceptable copper contamination of the desired isolated
product, which is a particularly significant drawback for its
application in the pharmaceutical industry. To overcome
these problems, the development of highly efficient and
recyclable heterogeneous catalysts, such as those involving
the immobilisation of catalytically active species, e.g.
organometallic complexes, onto a solid support to produce a
molecular heterogeneous catalyst is essential.42 Heterogeneous
catalysis also helps to minimise wastes derived from reaction
workup, contributing to the development of green chemical
The MCM-41-immobilised bidentate nitrogen copper(I)
complex [MCM-41-2N-CuI] was conveniently prepared
starting from commercially available and inexpensive
3-(2-aminoethylamino)propyltrimethoxysilane
and
CuI
according to our previous procedure46 (Scheme 1), and the
copper content was determined to be 0.45 mmol g–1.
In our initial screening experiments, the cascade reaction of
2-bromobenzamide with ethyl acetoacetate under argon was
investigated to optimise the reaction conditions, and the results
are summarised in Table 1. First, the reaction temperature was
examined by using 10 mol% MCM-41-2N-CuI as the catalyst
and 2 equiv. of Cs2CO3 as the base in dioxane (entries 1–4).
The yield of the desired product 3a increased greatly with the
increase in the reaction temperature and 80 °C gave the best
result. Our next studies focused on the effect of base on the
model reaction. Among the bases examined, Cs2CO3 was found
to be the most effective (entry 3), while other bases such as
K2CO3, K3PO4, and Na2CO3 were substantially less effective
(entries 5–7). The cascade reaction did not occur without
base (entry 8). The effect of solvent was also investigated and
* Correspondent. E-mail: caimzhong@163.com

JOURNAL OF CHEMICAL RESEARCH 2014 635
Scheme 1
DMF and toluene gave slightly lower yields (entries 9 and 10).
Reducing the amount of the catalyst resulted in a decreased
yield (entry 11). Increasing the amount of the catalyst could
shorten the reaction time, but did not improve the yield (entry
12). Thus, the optimised reaction conditions for this cascade
reaction of 2-bromobenzamide with ethyl acetoacetate are the
MCM-41-2N-CuI (10 mol%) in dioxane using Cs2CO3 as base
at 80 °C under Ar for 24 h (Table 1, entry 3).
Following this promising result, we started to investigate
the scope of this reaction under the optimised conditions.
The scope of both 2-bromobenzamides and β-keto esters was
explored, and the results are summarised in Table 2. Most of
the substrates examined gave good yields. For example, the
cascade reactions of the substituted 2-bromobenzamides such as
2-bromo-5-methylbenzamide, 2-bromo-5-methoxybenzamide,
and 2-bromo-5-chlorobenzamide with ethyl acetoacetate
proceeded smoothly under the optimised conditions to give the
corresponding isoquinolin-1(2H)-one derivatives 3b–d in good
yields (entries 2–4). The electronic features of the substituents
on 2-bromobenzamides 1 have limited influence on the cascade
reaction. Both electron-withdrawing and electron-donating
groups were well tolerated. Most of the β-keto esters examined
were good substrates and underwent the cascade reactions with
various 2-bromobenzamides to afford a variety of isoquinolin-
1(2H)-one derivatives 3e–k in moderate to good yields (entries
5–11). However, the β-keto esters with bigger groups such as
phenyl and isopropyl gave lower yields due to steric hindrance
(entries 12 and 13). Note that nucleophilic attack of amino
group occurred selectively on the ketone rather than on ester
of β-keto ester.
Table 1 Screening of reaction conditions for coupling of 2-bromobenzamide with ethyl acetoacetate
catalysed by MCM-41-2N-CuIa
O
O
NH
O
10 mol% MCM-41-2N-CuI
base, solvent, temp.
O
O
NH2
+
O
Br
O
1a
2a
3a
Entry
Base
Solvent
Temp./°C
Time/h
Yield/%b
1
2
3
4
5
6
7
8
9
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
Na2CO3
–
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
DMF
25
60
80
100
80
80
80
80
80
80
80
80
48
48
24
24
24
24
24
48
24
24
48
16
0
32
78
77
45
59
46
0
72
61
62
79
10
11c
12d
Toluene
Dioxane
Dioxane
aReaction conditions: 2-bromobenzamide (0.5 mmol), ethyl acetoacetate (0.75 mmol), base (1 mmol),
MCM-41-2N-CuI (0.05 mmol), solvent (3 mL) under Ar.
bIsolated yield.
c5 mol% of copper catalyst.
d20 mol% of copper catalyst.

636 JOURNAL OF CHEMICAL RESEARCH 2014
Table 2 Heterogeneous copper-catalysed synthesis of isoquinolin-1(2H)-one derivativesa
O
O
R1
R1
NH
O
NH2
O
O
10 mol% MCM-41-2N-CuI
dioxane, Cs2CO3, 80 oC, 24 h
R2
+
OR3
R2
Br
R3O
1
2
3
Entry
R1
R2
R3
Et
Et
Et
Et
t-Bu
PhCH2
Et
t-Bu
PhCH2
Et
Product
Yield/%b
1
2
3
4
5
6
7
8
9
10
11
12
13
H
Me
Me
Me
Me
Me
Me
n-C3H7
Me
Me
3a
3b
3c
3d
3e
3f
3g
3h
3i
78
82
68
65
79
74
72
60
62
73
78
48
30
Me
MeO
Cl
H
H
H
Cl
Me
Me
Cl
n-C3H7
n-C3H7
Ph
3j
3k
3l
Et
Et
Et
H
H
i-C3H7
3m
aReaction conditions: 2-bromobenzamide (0.5 mmol), β-keto ester (0.75 mmol), MCM-41-2N-CuI
(0.05 mmol), Cs2CO3 (1 mmol), dioxane (3 mL) at 80 °C under Ar for 24 h.
bIsolated yield.
In order to determine whether the catalysis was due to the
using the cascade reaction of 2-bromo-5-methylbenzamide with
ethyl acetoacetate. After carrying out the reaction, the catalyst
was separated by simple filtration and washed with distilled
water, ethanol and diethyl ether. After being air-dried, it was
reused directly without further purification. Almost consistent
activity was observed for 10 consecutive cycles (Table 3). In
addition, copper leaching from the immobilised catalyst was
also determined. The copper content of the catalyst was found
by ICP analysis to be 0.44 mmol g–1 after 10 consecutive
runs, only 2.2% of copper had been lost from the MCM-41
support. The high stability and excellent reusability of the
catalyst could result from the chelating action of the bidentate
2-aminoethylamino ligand on copper and the mesoporous
structure of the MCM-41 support. The result is important from
a practical point of view. The good catalytic activity, excellent
reusability and the easy accessibility of the MCM-41-2N-CuI
make it a highly attractive heterogeneous copper catalyst for
the parallel solution phase synthesis of diverse libraries of
compounds.
MCM-41-2N-CuI complex or to a homogeneous copper species
that comes off the support during the reaction and then returns
to the support at the end, we performed a hot filtration test.54
We focused on the tandem reaction of 2-bromobenzamide
with ethyl acetoacetate. We filtered off the MCM-41-2N-CuI
complex after 10 h of reaction time and allowed the filtrate
to react further. The catalyst filtration was performed at
the reaction temperature (80 °C) in order to avoid possible
recoordination or precipitation of soluble copper upon cooling.
We found that, after this hot filtration, no further reaction was
observed. We also ascertained the Cu-content in the filtrate by
ICP analysis and only 0.3 ppm of copper was found in the clear
solution. This result suggests that the copper catalyst remains
on the support at elevated temperatures during the reaction and
points to a process of a heterogeneous nature.
For a heterogeneous transition-metal catalyst, it is important
to examine its ease of separation, recoverability and reusability.
We investigated the recyclability of the MCM-41-2N-CuI by
Table 3 Cascade reaction of 2-bromo-5-methylbenzamide with ethyl
acetoacetate catalysed by the recycled catalysta
O
O
Me
NH
Me
Me
O
O
10 mol% MCM-41-2N-CuI
dioxane, Cs2CO3, 80°C, 24 h
NH2
+
OEt
Me
Br
EtO
O
3b
Cycle
Yield/%b
Cycle
Yield/%b
1
3
5
7
9
82
82
81
80
80
2
4
81
82
80
79
79
6
8
10
aReaction was carried out with 2-bromo-5-methylbenzamide (1 mmol),
ethyl acetoacetate (1.5 mmol), MCM-41-2N-CuI (0.1 mmol), Cs2CO3
(2.0 mmol), dioxane (6.0 mL) at 80 °C under Ar for 24 h.
bIsolated yield.

JOURNAL OF CHEMICAL RESEARCH 2014 637
(s, 9H); 13C NMR (75 MHz, CDCl3): δ 166.5, 163.3, 139.8, 136.3, 135.4,
133.3, 127.5, 126.4, 124.4, 111.3, 82.4, 28.5, 18.8.
In summary, we have developed a novel, practical and
environmentally friendly method for the synthesis of
isoquinolin-1(2H)-one derivatives through the cascade
reaction of 2-bromobenzamides and β-keto esters by using an
MCM-41-immobilised bidentate nitrogen copper(I) complex
as catalyst under mild reaction conditions. The reactions
generated the corresponding isoquinolin-1(2H)-one derivatives
in moderate to good yields and were applicable to various
2-bromobenzamides and β-keto esters. This heterogeneous
copper catalyst could be easily recovered and reused for at least
10 cycles, thus making this procedure environmentally more
acceptable.
Benzyl 1,2-dihydro-3-methyl-1-oxoisoquinoline-4-carboxylate
1
(3f): White solid, m.p. 197–198 °C (lit.41 m.p. 199–200 °C). H NMR
(300 MHz, CDCl3): δ 11.84 (br, 1H), 8.41 (d, J=8.0 Hz, 1H), 7.92 (d,
J=8.4 Hz, 1H), 7.68–7.65 (m, 1H), 7.50–7.34 (m, 6H), 5.44 (s, 2H), 2.55
(s, 3H); 13C NMR (75 MHz, CDCl3): δ 167.1, 164.3, 141.9, 136.1, 133.7,
133.5, 128.9, 128.8, 128.7, 127.6, 126.6, 124.6, 124.1, 109.3, 67.4, 19.3.
Ethyl 1,2-dihydro-1-oxo-3-propylisoquinoline-4-carboxylate (3g):
White solid, m.p. 188–189 °C (lit.41 190–191 °C). 1H NMR (300 MHz,
CDCl3): δ 11.90 (br, 1H), 8.40 (d, J=7.6 Hz, 1H), 7.87 (d, J=8.3 Hz,
1H), 7.70 (t, J=8.6 Hz, 1H), 7.49 (t, J=7.2 Hz, 1H), 4.46 (q, J=7.2 Hz,
2H), 2.83 (t, J=7.0 Hz, 2H), 1.87–1.77 (m, 2H), 1.44 (t, J=7.2 Hz, 3H),
1.09 (t, J=7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 167.3, 164.3,
144.7, 134.5, 133.4, 128.6, 127.5, 126.7, 124.6, 109.7, 61.5, 34.6, 23.2,
14.5, 14.2.
tert-Butyl 7-chloro-1,2-dihydro-3-methyl-1-oxoisoquinoline-4-
carboxylate (3h): White solid, m.p. 183–184 °C (lit.41 185–186 °C).
1H NMR (300 MHz, CDCl3): δ 11.54 (br, 1H), 8.36 (s, 1H), 7.94 (d,
J=8.9 Hz, 1H), 7.63 (d, J=8.9 Hz, 1H), 2.56 (s, 3H), 1.65 (s, 9H);
13C NMR (75 MHz, CDCl3): δ 166.1, 163.2, 140.6, 134.8, 133.7, 131.7,
130.1, 126.7, 126.3, 110.9, 82.6, 28.5, 18.9.
Experimental
All chemicals were reagent grade and used as purchased. All solvents
were dried and distilled before use. The products were purified by
flash chromatography on silica gel and a mixture of EtOAc and
1
petroleum ether was generally used as eluent. H NMR spectra were
recorded on a Bruker Avance 300 (300 MHz) spectrometer with TMS
as an internal standard using CDCl3 as the solvent. 13C NMR spectra
were recorded on a Bruker Avance 300 (75 MHz) spectrometer using
CDCl3 as the solvent. Melting points are uncorrected.
Benzyl 1,2-dihydro-3,7-dimethyl-1-oxoisoquinoline-4-carboxylate
(3i): White solid, m.p. 208–210 °C (lit.41 210–211 °C). 1H NMR
(300 MHz, DMSO-d6): δ 11.52 (br, 1H), 8.02 (d, J=8.4 Hz, 1H),
7.48–7.27 (m, 7H), 5.34 (s, 2H), 2.31 (s, 3H), 2.26 (s, 3H); 13C NMR
(75 MHz, DMSO-d6): δ 167.1, 162.0, 143.5, 142.6, 136.4, 135.6, 129.4,
129.1, 128.9, 128.2, 127.3, 124.1, 122.3, 107.3, 67.2, 22.1, 18.6.
Ethyl 1,2-dihydro-7-methyl-1-oxo-3-propylisoquinoline-4-
carboxylate (3j): White solid, m.p. 230–231 °C (lit.41 232–233 °C).
1H NMR (300 MHz, CDCl3): δ 11.67 (br, 1H), 8.29 (d, J=7.9 Hz, 1H),
7.64 (s, 1H), 7.30 (d, J=7.2 Hz, 1H), 4.45 (q, J=7.2 Hz, 2H), 2.79 (t,
J=7.6 Hz, 2H), 2.48 (s, 3H), 1.86–1.79 (m, 2H), 1.45 (t, J=7.2 Hz, 3H),
1.07 (t, J=7.6 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 167.4, 164.2,
144.5, 143.8, 135.8, 128.2, 127.3, 126.5, 124.2, 109.5, 61.4, 34.5, 23.1,
22.4, 14.4, 14.1.
Ethyl 7-chloro-1,2-dihydro-1-oxo-3-propylisoquinoline-4-
carboxylate (3k): White solid, m.p. 221–223 °C (lit.41 224–225 °C).
1H NMR (300 MHz, DMSO-d6): δ 11.82 (br, 1H), 8.12 (s, 1H),
7.82–7.73 (m, 2H), 4.36 (q, J=7.0 Hz, 2H), 2.61 (t, J=7.6 Hz, 2H),
1.68–1.57 (m, 2H), 1.32 (t, J=7.0 Hz, 3H), 0.91 (t, J=7.2 Hz, 3H);
13C NMR (75 MHz, DMSO-d6): δ 166.7, 161.4, 146.5, 134.2, 133.6,
131.4, 127.2, 126.1, 125.9, 107.5, 61.5, 33.9, 23.1, 14.5, 14.2.
Synthesis of isoquinolin-1(2H)-ones (3a–m); general procedure
Dioxane (3 mL), 2-bromobenzamide (100 mg, 0.5 mmol), β-keto ester
(0.75 mmol), Cs2CO3 (326 mg, 1 mmol) were added to a flask with a stir
bar and the mixture was stirred for 10 min under argon atmosphere.
Then, MCM-41-2N-CuI (111 mg, 0.05 mmol) was added and the
mixture was stirred at 80 °C for 24 h under an argon atmosphere. After
completion of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate (5 mL), and filtered. The MCM-
41-2N-CuI complex was washed with distilled water (2×5 mL), ethanol
(2×5 mL), and Et2O (2×5 mL) and reused in the next run. The filtrate
was concentrated under reduced pressure and the residue was purified
by flash column chromatography on silica gel (petroleum ether/ethyl
acetate=3:1 to 1:1) to provide the desired product.
Ethyl 1,2-dihydro-3-methyl-1-oxoisoquinoline-4-carboxylate (3a):
White solid, m.p. 187–188 °C (lit.41 188–189 °C). 1H NMR (300 MHz,
CDCl3): δ 11.87 (br, 1H), 8.43 (d, J=7.9 Hz, 1H), 7.94 (d, J=8.3 Hz,
1H), 7.72–7.66 (m, 1H), 7.51–7.45 (m, 1H), 4.45 (q, J=7.2 Hz, 2H), 2.58
(s, 3H), 1.43 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 167.2,
164.3, 141.2, 136.1, 133.4, 127.4, 126.4, 124.6, 124.2, 109.6, 61.5, 19.1,
14.5.
Ethyl 1,2-dihydro-3,7-dimethyl-1-oxoisoquinoline-4-carboxylate
(3b): White solid, m.p. 189–191 °C (lit.41 191–192 °C). 1H NMR
(300 MHz, CDCl3): δ 11.99 (br, 1H), 8.29 (d, J=7.9 Hz, 1H), 7.70 (s,
1H), 7.30 (d, J=7.9 Hz, 1H), 4.47 (q, J=7.2 Hz, 2H), 2.58 (s, 3H), 2.48
(s, 3H), 1.43 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 167.5,
164.4, 144.2, 141.3, 136.1, 128.2, 127.4, 124.3, 109.5, 61.4, 22.4, 19.1,
14.6.
Ethyl 1,2-dihydro-1-oxo-3-phenylisoquinoline-4-carboxylate (3l):
White solid, m.p. 163–164 °C (lit.41 165–167 °C). 1H NMR (300 MHz,
CDCl3): δ 10.88 (br, 1H), 8.35 (d, J=7.9 Hz, 1H), 7.96 (d, J=8.3 Hz,
1H), 7.76–7.71 (m, 1H), 7.56–7.49 (m, 6H), 4.09 (q, J=7.2 Hz, 2H), 0.92
(t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 167.3, 164.1, 142.2,
135.5, 134.8, 133.6, 130.1, 128.8, 128.3, 127.7, 127.2, 124.7, 110.3, 61.4,
13.6.
Ethyl 1,2-dihydro-7-methoxy-3-methyl-1-oxoisoquinoline-4-
carboxylate (3c): White solid, m.p. 184–186 °C (lit.41 185–186 °C).
1H NMR (300 MHz, CDCl3): δ 11.87 (br, 1H), 7.93 (d, J=8.9 Hz, 1H),
7.81 (s, 1H), 7.32–7.30 (m, 1H), 4.46 (q, J=7.2 Hz, 2H), 3.96 (s, 3H),
2.58 (s, 3H), 1.42 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ
167.3, 164.1, 158.3, 139.2, 130.2, 128.4, 126.5, 123.7, 109.4, 107.3, 61.5,
55.7, 19.0, 14.5.
Ethyl 1,2-dihydro-3-isopropyl-1-oxoisoquinoline-4-carboxylate
1
(3m): White solid, m.p. 162–163 °C (lit.41 m.p. 164–165 °C). H NMR
(300 MHz, CDCl3): δ 10.72 (br, 1H), 8.42–8.40 (m, 1H), 7.75–7.64 (m,
2H), 7.51–7.46 (m, 1H), 4.45 (q, J=7.2 Hz, 2H), 3.32–3.25 (m, 1H),
1.46–1.42 (m, 9H); 13C NMR (75 MHz, CDCl3): δ 167.6, 147.2, 133.5,
131.8, 130.5, 129.1, 127.8, 126.7, 124.7, 109.1, 61.7, 30.9, 21.2, 14.5.
Ethyl 7-chloro-1,2-dihydro-3-methyl-1-oxoisoquinoline-4-
carboxylate (3d). White solid, m.p. 215–217 °C (lit.41 217–218 °C).
1H NMR (300 MHz, DMSO-d6): δ 11.85 (br, 1H), 8.12 (s, 1H), 7.88 (d,
J=8.9 Hz, 1H), 7.75 (d, J=8.9 Hz, 1H), 4.37 (q, J=7.2 Hz, 2H), 2.37 (s,
3H), 1.33 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, DMSO-d6): δ 166.6,
161.1, 143.4, 134.3, 133.4, 131.2, 127.1, 126.2, 125.7, 107.2, 61.5, 18.8,
14.6.
Financial support from the National Natural Science
Foundation of China (No. 21272044), Scientific Research Fund
of the Education Department of Jiangxi Province (KJLD13022)
and the Key Laboratory of Functional Small Organic Molecule,
Ministry of Education (No. KLFS-KF-201213) are gratefully
acknowledged.
tert-Butyl 1,2-dihydro-3-methyl-1-oxoisoquinoline-4-carboxylate
(3e): White solid, m.p. 205–206 °C (lit.41 207–208 °C). 1H NMR
(300 MHz, CDCl3): δ 12.01 (br, 1H), 8.42 (d, J=7.6 Hz, 1H), 7.92 (d,
J=8.0 Hz, 1H), 7.73–7.67 (m, 1H), 7.50–7.46 (m, 1H), 2.57 (s, 3H), 1.66
Received 15 September 2014; accepted 21 September 2014
Paper 1402778 doi: 10.3184/174751914X14117512932816
Published online: 17 October 2014

638 JOURNAL OF CHEMICAL RESEARCH 2014
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