Copper nanoparticles catalyzed economical synthesis of 3-substituted isocoumarins from 2-chlorobenzoic acids/amides and 1,3-diketones

Article abstract of DOI:10.1016/j.tetlet.2017.07.001

Copper nanoparticles were utilized as a highly efficient catalyst for a facile and economical synthesis of 3-substituted isocoumarins with 2-chlorobenzoic acids and 1,3-diketones as starting materials. The copper nanoparticles catalyst showed highly catalytic activity for the 2-chloro-substituted substrates to afford 3-substituted isocoumarins in good to excellent yields. Furthermore, good catalytic activity was also observed when 2-chlorobenzoic amides were utilized as substrates instead of the benzoic acids.

Full text of DOI:10.1016/j.tetlet.2017.07.001

Accepted Manuscript
Copper nanoparticles catalyzed economical synthesis of 3-substituted isocou-
marins from 2-chlorobenzoic acids/amides and 1,3-diketones
Xiaowen Wang, Chaolong Wu, Youwen Sun, Xiaoquan Yao
PII:
S0040-4039(17)30836-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.001
TETL 49083
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
2 May 2017
27 June 2017
1 July 2017
Please cite this article as: Wang, X., Wu, C., Sun, Y., Yao, X., Copper nanoparticles catalyzed economical synthesis
of 3-substituted isocoumarins from 2-chlorobenzoic acids/amides and 1,3-diketones, Tetrahedron Letters (2017),
doi: http://dx.doi.org/10.1016/j.tetlet.2017.07.001
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Graphical Abstract
Copper nanoparticles catalyzed economical
synthesis of 3-substituted isocoumarins from
2-chlorobenzoic acids/amides and 1,3-
diketones
Leave this area blank for abstract info.
Xiaowen Wang, Chaolong Wu, Youwen Sun, Xiaoquan Yao*

1
Tetrahedron Letters
journal homepage: www.els evier.com
Copper nanoparticles catalyzed economical synthesis of 3-substituted isocoumarins
from 2-chlorobenzoic acids/amides and 1,3-diketones
Xiaowen Wang, Chaolong Wu, Youwen Sun, Xiaoquan Yao*
Department of Applied Chemistry, College of Material Science and Technology, Nanjing University of Aeronautics and Astronautics, Nanjing 210016, PR China
ARTICLE INFO
ABSTRACT
Article history:
Received
Copper nanoparticles were utilized as a highly efficient catalyst for a facile and economical
synthesis of 3-substituted isocoumarins with 2-chlorobenzoic acids and 1,3-diketones as starting
materials. The copper nanoparticles catalyst showed highly catalytic activity for the 2-chloro-
substituted substrates to afford 3-substituted isocoumarins in good to excellent yields. Further
more, good catalytic activity was also observed when 2-chlorobenzoic amides were utilized as
substrates instead of the benzoic acids.
Received in revised form
Accepted
Available online
Keywords:
3-Substituted isocoumarins
Copper nanoparticles catalyzed
2-Chlorobenzoic acids
2-Chlorobenzoic amides
1,3-Diketones
Isocoumarins, as an important natural lactone,1 show a variety
of pharmacologyical and biological activities,2 such as
immunomodulatory, antifungal, cytotoxic etc., in which 3-
substituted isocoumarins have a great influence on their
biological activities respect to other substituted isocoumarins.
Moreover, they are important organic synthetic intermediates,
especially for biologically heterocylic3 and carbocyclic
compounds.4 Therefore, the synthesis of 3-substituted
isocoumarins has attracted great attention of researchers.
strategy for the synthesis of isocoumarins is still under
investigation.
In recent years, much attention has been attracted to the use of
nanoparticles as catalysts in organic reactions.12 Because of their
easy preparation and relative stabilities in air, the nanoparticles of
coinage metals, such as copper, silver and gold, were widely
reported, and there are many excellent examples on their
applications as catalysts in organic reactions.13 Recently, our
group also developed some reactions catalyzed by copper
nanoparticles, and in most cases, the nanoparticle catalysts show
much higher catalytic activities than salts.14
Till now, various approaches for the synthesis of 3-substituted
isocoumarins have been reported,5-8 in which o-halobenzoic acid
and its derivatives were the very popular starting materials with
1-alkynes or 1,3-diketones together. There are many examples on
the transition metal-catalyzed tandem reaction of o-halobenzoic
acid and 1-alkynes reported to afford 3-substituted
isocoumarins.6,9 However, the methodology is usually nagged by
regioselectivities: there are 5-exo and 6-endo cyclization
combined products obtained during the domino Sonogashira
coupling-intramolecular cyclization process, which restrain its
application to a great extent.
Herein, we would like to report a copper nanoparticles
catalyzed coupling reaction of 2-halobenzoic acids/amides with
1,3-diketones to 3-substituted isocoumarins. In this approach, 2-
chlorobenzoic acids or amide can be utilized efficiently, and
good to excellent yields were achieved.
Initially, the reaction of 2-chlorobenzoic acid (1a) and
pentane-2,4-dione (2a) was selected as the prototype to start our
investigation for the optimized reaction conditions, and the data
were summarized in Table 1.
Recently, Xi and coworkers10 reported a domino process of 2-
halobenzoic acids and 1,3-diketones for the corresponding 3-
substituted isocoumarins with CuI as catalyst, which exhibited
high regioselectivity and good to excellent yields were achieved.
However, there are some limits on the scope of substrates: 2-
chlorobenzoic acids usually give much lower reactivities than 2-
iodo and 2-bromo-benzoic acids. On the other hand, Yao11 et al
also reported an approach for the synthesis of 3-substituted
isocoumarins with 2-halobenzoic amides and 1,3-diketones as
substrates, and the same limit on substrate was observed.
Therefore, to develop a facile, efficient and more economical
When 1a (0.2 mmol) and 2 equiv of 2a were treated with 10
mol % of Cu NPs 15 in 1.5 mL of DMSO at 100 oC with 2 equiv
of K2CO3 as the base under nitrogen for 2 h, 3a was achieved in
92% yield (entry 1, Table 1). Some copper salts, such as CuI,
Cu(OAc)2, and CuSO4 were then examined, and only ca. 55%
yields were observed (entries 2-4). On the other hand, a blanket
reaction was carried out in the absence of Cu NPs catalyst, and
no reaction occurred (entry 5). Increasing or decreasing the
loading of the catalyst were all led to worse yields (entries 6 and
7), and higher or lower temperature could result in the same thing
(entries 8 and 9).

2
Tetrahedron Letters
Different solvents, such as DMF, toluene, MeCN, 1,4-
Pr2NEt inhibited the reaction at all (entry 19). Further more, a
base-free condition was also tried, and no reaction occurred
(entry 20). On the other hand, shortening or extending the
reaction time could not improve the yields either (entries 21, 22).
dioxane and DCE, were then evaluated in the reaction, and
DMSO was found as the best of choices (entry 1 vs. 10-14).
Some other bases, such as Na2CO3, K3PO4, NaOH, KOH and i-
Pr2NEt, were also screened. It was found that the expected
product was obtained only in moderated yields in the presence of
inorganic bases except K2CO3 (entries 15-18 vs. entry 1), while i-
Thus, the optimal conditions involved the following
parameters: 10 mol % of Cu NPs and 2 equiv of K2CO3 in 1.5mL
of DMSO at 100 oC under nitrogen.
Table 1. The reaction of 2-chlorobenzoic acid and pentane-2,4-dione a
Entry
Catalyst
Solvent
Base
Temp (oC)
Time (h)
Yield b (%)
1
Cu NPs
CuI
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
K3PO4
NaOH
KOH
100
100
100
100
100
100
100
90
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
1
4
92
2
56
3
Cu(OAc)2
CuSO4
—
55
4
58
5
N.D.
81
6c
7d
8
Cu NPs
Cu NPs
Cu NPs
Cu NPs
Cu NPs
Cu NPs
Cu NPs
Cu NPs
Cu NPs
Cu NPs
Cu NPs
Cu NPs
Cu NPs
Cu NPs
Cu NPs
Cu NPs
Cu NPs
77
82
9
110
100
100
100
100
100
100
100
100
100
100
100
100
100
80
10
11
12
13
14
15
16
17
18
19
20
21
22
84
Toluene
MeCN
1,4-dioxane
DCE
N.D.
29
8
N.D.
40
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
65
62
70
i-Pr2NEt
—
N.D.
N.D.
73
K2CO3
K2CO3
84
a The reaction was performed with 1a (0.2 mmol), 2a (0.4 mmol), Cu NPs (0.02 mmol), and base (0.4 mmol) in solvent
(1.5 mL) under N2.
b Isolated yields; N.D. = no reaction.
c Cu NPs (0.0 1mmol).
d Cu NPs (0.03 mmol).
With the optimized reaction conditions, various substituted 2-
chlorobenzoic acids and 1,3-diketones were explored.16 The
results were listed in Table 2. As can be seen, 2-chlorobenzoic
acids with 3-CH3, 4-CH3, 6-CH3, 4-OCH3 ，and 4-F groups
reacted with pentane-2,4-dione (2a) to give the products 3b-3f in
moderate to excellent yields while 2,4-dichlorobenzoic acid gave
the product 3g in a low yield. Then, 1,3-diphenylpropane-1,3-
dione (2b) was used to react with the 2-chlorobenzioc acids

3
instead of 2a, and the corresponding products 3h-3l were formed
in good to excellent yields. When heptane-3,5-dione (2c) was
examined, the desired products 3m-3r were achieved in 41-87%
yields. From these results above, it demonstrated that electron-
donating substitutes on 2-chlorobenzoic acids seemed to be
favored to the reaction compared with electron-withdrawing
groups (3m-3p vs. 3q-3r). Subsequently, an unsymmetrical 1,3-
diketone, 6-methylheptane-2,4-dione (2d), was utilized in the
reaction. It can be seen that only the mixture of two isomeric
products were obtained in all of four examples with good
combined yields. The 3-isopropylisocoumarins were obtained as
the major products.
Table 2. The reaction of 2-chlorobenzoic acids and 1,3-diketones a
O
10 mol % Cu NPs
COOH
O
O
O
2eq. K2CO3
R1
R1
+
R2
R3
R2
100oC, DMSO, 2h, N2
Cl
3b
1
2
O
O
O
O
R
R
R = H, 3a, 92%
R = 4-OCH3, 3e, 81%c
R = H, 3h, 95%
R = 4-OCH3, 3l, 94%
R = 3-CH3, 3b, 85% R = 4-F, 3f, 59% c
R = 4-CH3, 3c, 61% R = 4-Cl, 3g, 18%c
R = 6-CH3, 3d, 55%c
R = 3-CH3, 3i, 78%
R = 4-CH3, 3j, 95%
R = 6-CH3, 3k, 78%
O
O
O
O
O
O
+
R
R
R
R = H, 3m, 82%
R = 4-F, 3q 41%c
R = 4-Cl, 3r, 43%c
R = H, 3s+3a (1.43:1), 90%c, d
R = 3-CH3, 3n, 82%
R = 4-CH3, 3o, 87%
R = 6-CH3, 3p, 82%
R = 3-CH3, 3t+3b (1.53:1), 83%c, d
R = 4-CH3, 3u+3c (1.45:1), 83%c, d
R = 4-F, 3v+3f (1.50:1), 30%c, d
a Reaction conditions: nitrogen atmosphere, 1 (0.2mmol), 2 (2 equiv), copper nanoparticles (10 mol %),
K2CO3 (2 equiv), DMSO (1.5mL), stirred at 100 oC under N2.
b Isolated yields.
c Reaction performed in 8 h.
d Combined yield.
In order to detect the adaptability of the Cu NPs catalyst, 2-
bromobenzoic acid was tested in the reaction under the optimized
conditions, and the desired products were isolated in an excellent
yield (Scheme 1). Obviously, Cu NPs catalyst shows almost
same catalytic activities on both 2-bromo and 2-cholo benzoic
acid substrates.
conditions (10 mol % of Cu NPs, 2 equiv of K3PO4 in DMF at
o
100 C under nitrogen), several kinds of amides were utilized to
react with pentane-2,4-dione (2a), and the results were
summarized in Scheme 2.
Scheme 1 Cu NPs-catalyzed reaction of 2-bromobenzoic acid
(4) and pentane-2,4- dione (2a).
Scheme 2 Cu NPs-catalyzed reaction of 2-halobenzoic amide
(5) and pentane-2,4- dione (2a).
The successful utilization of the Cu NPs catalyst in the
reaction of 2-cholobenzoic acids and 1,3-diketones encouraged
us to explore its catalytic ability in the coupling reaction of 2-
chlorobenzoic amides and 1,3-diketones. Under similar
It can be seen from Scheme 2, the Cu NPs catalyst showed
excellent catalytic activity to both 2-bromo- and 2-chloro-
substituted benzoic amide in the coupling reaction. It is also
worthy to mention that all of the reactions finished in 0.5 h.

4
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3.
A plausible mechanism was also proposed for the reaction of
2-cholobenzoic acids and 1,3-diketones: Initially, the
intermediate A was formed through the substrate 1 and 2 in the
presence of base, and give the intermediate B by the Hurtley
reaction.10, 17 The higher catalytic activity of Cu NPs for the
coupling reaction might be due to a multi-center synergistic
effect occurred on the surface of Cu NPs.18 The carbonyl group
of 1,3-diketone was then attacked by the carboxylate anion to
give C as intermediate. The alkoxy anion of C would activate
another keto moiety to generate intermediate D with a four-
member ring; and then, through the bond-breaking of the C-O
bond and C-C bond, the product 3 was achieved finally.10
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Yao, C.-F. J. Org. Chem. 2012, 77, 5022–5029.
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Scheme 3 Proposed reaction mechanism for the reaction of 2-
cholobenzoic acids and 1,3-diketones.
In conclusion, an efficient and economical strategy has been
demonstrated for the synthesis of 3-substituted isocoumarins
under Cu NPs catalyzed process of 2-chlorobenzioc acids and
1,3-diketones. In addition, the Cu Nps catalyst shows good
catalytic activities to the reaction of 2-chlorobenzoic amides and
1,3-diketones. The detailed mechanism, the effect of particle size
and particle support as well as the scope of the reaction are
currently under further investigations.
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Acknowledgments
15. Cu NPs catalyst was synthesized following a modified literature
method: (a) Sarkar, A.; Mukherjec, T.; Kapoor, S. J. Phy. Chem. C
2008, 112, 3334–3340; (b) Wang, Y.; Asefa, T. Langmuir 2010,
26, 7469–7474. The detailed procedure was also provided in SI.
16. Typical procedure for copper nanoparticles catalyzed sunthsis
of 3-substituted isocoumarins from 2-chlorobenzoic acids and
pentane-2,4-dione (entry 2, Table 1): 2-chlorobenzoic acids (1a,
0.2 mmol), pentane-2,4-dione (2a, 2eq), Cu NPs (1.3 mg, 10
mol%), K2CO3 (2.0 equiv) and 1.5 mL of DMSO were added into
a 5-mL sealed tube under N2. The mixture was stirred at 100oC for
2 hour. The reaction mixture was then purified by flash column
chromatography on silica gel (hexanes/EtOAc 15:1). Compound
3a was obtained in >92% of yield. 3-methyl-1H-isochromen-1-
one (3a). 1H NMR (400 MHz, CDCl3, ppm) δ 8.25 (d, J = 8.0 Hz,
1H), 7.67 (t, J = 8.2 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.34 (d, J =
7.9 Hz, 1H), 6.26 (s, 1H), 2.29 (s, 3H); 13C NMR (101 MHz,
CDCl3, ppm) δ 163.0, 154.6, 137.7, 134.8, 129.5, 127.6, 124.9,
120.0, 103.6, 19.7 (ref. 10a). The characterization data for all of
products were also provided in SI, 1H & 13C NMR Spectrum were
also attached.
We are grateful to the financial support from National Natural
Science Foundation of China (21472092 to XY). This is a project
funded by the Priority Academic Program Development of
Jiangsu higher education institutions.
References and notes
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5
ꢀ
ꢀ
ꢀ
A facile and economical catalytic synthesis of
3-substituted isocoumarins was achieved.
2-Chloro-benzoic acids/amides were utilized as
starting materials with 1,3-diketones.
Copper nanoparticle catalyst shows highly
catalytic activity for the 2-chloro-substituted
substrates.