Regioselective cyclization of 2-alkynylbenzoic acid in water for the synthesis of isocoumarin

Article abstract of DOI:10.1016/j.tet.2019.06.012

In this work, a regioselective synthesis of isocoumarins from 2-alkynylbenzoic acid is reported. The transformations proceed smoothly with good yields in water via a metal-free radical pathway. When catalytic TBAB is employed, the reaction provides various isocoumarin derivatives according to the structures of the corresponding precursors. It is believed that TBAB serves as a phase transfer catalyst and radical initiator in the reaction. Compared to previous methodologies, the synthetic procedure reported herein provides a more environmentally benign route for the synthesis of isocoumarins.

Full text of DOI:10.1016/j.tet.2019.06.012

Accepted Manuscript
Regioselective cyclization of 2-alkynylbenzoic acid in water for the synthesis of
isocoumarin
Yan-Hua Wang, Guanyinsheng Qiu, Hongwei Zhou, Wenlin Xie, Jin-Biao Liu
PII:
S0040-4020(19)30652-0
https://doi.org/10.1016/j.tet.2019.06.012
TET 30404
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 26 March 2019
Revised Date: 17 May 2019
Accepted Date: 6 June 2019
Please cite this article as: Wang Y-H, Qiu G, Zhou H, Xie W, Liu J-B, Regioselective cyclization of
2-alkynylbenzoic acid in water for the synthesis of isocoumarin, Tetrahedron (2019), doi: https://
doi.org/10.1016/j.tet.2019.06.012.
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ACCEPTED MANUSCRIPT
Regioselective Cyclization of 2-Alkynylbenzoic Acid
in Water for the Synthesis of Isocoumarin
Yan-Hua Wang,a Guanyinsheng Qiu,b Hongwei Zhou,b* Wenlin Xiec, and Jin-Biao
Liua
a School of Metallurgical and Chemical Engineering, Jiangxi University of Science and Technology, 86 Hongqi Road, Ganzhou
341000, China
b College of Biological, Chemical Science and Engineering, Jiaxing University, 118 Jiahang Road, Jiaxing 314001, China.
c School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Hunan 411201, China
G. Qiu, Tel.: +86-0573-83642057; fax: +86-0573-83642057; e-mail: 11110220028@fudan.edu.cn
J.-B. Liu, Tel.: +86-0797-88120380; fax: +86-0797-88120380; e-mail: liujbgood@hotmail.com

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Regioselective Cyclization of 2-Alkynylbenzoic Acid in Water for
the Synthesis of Isocoumarin
Yan-Hua Wang,a Guanyinsheng Qiu,b* Hongwei Zhou,b* Wenlin Xie,c and Jin-Biao Liu a*
a School of Metallurgical and Chemical Engineering, Jiangxi University of Science and Technology, 86 Hongqi Road, Ganzhou 341000, China
b College of Biological, Chemical Science and Engineering, Jiaxing University, 118 Jiahang Road, Jiaxing 314001, China.
C School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Hunan 411201, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
In this work, a regioselective synthesis of isocoumarins from 2-alkynylbenzoic acid is
reported. The transformations proceed smoothly with good yields in water via a metal-free
radical pathway. When catalytic TBAB is employed, the reaction provides various isocoumarin
derivatives according to the structures of the corresponding precursors. It is believed that TBAB
serves as a phase transfer catalyst and radical initiator in the reaction. Compared to previous
methodologies, the synthetic procedure reported herein provides a more environmentally benign
route for the synthesis of isocoumarins.
Available online
Keywords:
2-Alkynylbenzoic Acid;
Radical cyclization;
Isocoumarin;
2009 Elsevier Ltd. All rights reserved
.
Isobenzofuran;
Metal-free
Alkyne-based chemistry has attracted increasing attention in the
scientific community due to its versatility for the synthesis of
diverse synthons and biologically useful architectures.1 Although
Furthermore, 2-alkynylbenzoic acid, an analogue of 2-
alkynylbenzoate, has been found to produce isocoumarins with
higher atom efficiency. Therefore, Larock et al. extensively
studied the regioselective 6-endo-dig cyclization of 2-
alkynylbenzoic acid with an aim to synthesize various
isocoumarins in an efficient manner.9 In contrast to 2-
alkynylbenzoate,5 the electrophilic cyclization of 2-
alkynylbenzoic acid resulted in a mixture of both 5-exo-dig
cyclization and 6-endo-dig cyclization products. Although the
base-mediated cyclization of 2-alkynylbenzoic acid proceeds
mainly in a 5-exo-dig fashion,10 the development of an alternative
approach for realising the regioselective cyclization of 2-
alkynylbenzoic acid is still highly desired. Considering the
importance of the isocoumarin core,3 the regioselective
cyclization of 2-alkynylbenzoic acids could be used to synthesize
isocoumarin derivatives. Recently, the Gabriele 11 and Bourissou
alkyne-based reactions provide
a
number of attractive
applications, reaction efficiency and regioselectivity remain
major issues which need to be addressed. Generally, the
regioselectivity of a reaction is controlled by the nature of the
substrate. Therefore, a series of dual-functionalized substrates
bearing alkynyl and reactive groups at the ortho position of
aromatic compounds have been used to investigate the
regioselectivity of alkyne-based transformations, and have also
been applied to the synthesis of various privileged skeletons
under mild conditions.2
The isocoumarin skeleton represents an ubiquitous structural core
present in a number of useful molecules and natural products.3
For example, Thunberginol A, exhibiting a range of cytotoxicities,
is a type of isocoumarin found in Hydrangea macrophylla. To
date, tremendous effort has been devoted to the development of
new synthetic ruotes for the preparation of isocoumarins due to
their potential applications.4-8 For example, Oliver et al. reported
an 6-endo-dig electrophilic bromocyclization of 2-
alkynylbenzoate in 1984 and found that the reaction specifically
produces 4-bromoisocoumarin.5 The ensuing decades witnessed
intense interest in the studies of regioselectivie reactions. To date,
the 6-endo-dig cyclization of 2-alkynylbenzoate is braodly
recognized as an important transformation for the construction of
the isocoumarin core.6-8
12
groups proposed that using an ionic liquid as a solvent or
transitional metals as Lewis acid catalysts, enabled
a
regioselective 6-endo-dig cyclization of 2-alkynylbenzoic acids
for the synthesis of isocoumarins. However, most of the reported
reactions provide products containing both 5-exo-dig and 6-
endo-dig cyclization products. Very recently, our group
developed
a
TBAB-mediated regioselective oxidative
bromocyclization of 2-alkynylbenzoic acids for the synthesis 3-
metheneisobenzofurans.13e In this work, we report a new strategy
for the regioselective 6-endo-dig cyclization of 2-alkynylbenoic
acids to afford isocoumarins.

2
Tetrahedron
ACCEPTED MANUSCRIPT
Table 1 Initial studies for the reaction of regioselective 6-
endo-dig cyclization of 2-alkynylbenzoic acid a
Entr
y
Additive
(equiv)
Oxidant
(equiv)
Oxone
(2.0)
T
Yield of 2a
(oC)
(%)a,b
Scheme 1 Proposed route for the synthesis of isocoumarins
from 2-alkynylbenzoic acid
1
-
80
80
43
62
Sodium
dodecyl
sulfate
Over the past few years, our group has strived towards
developing cleaner, safer and more economic methodologies for
the regioselective transformation of alkynes.13 For example, we
Oxone
(2.0)
2
(0.1)
recently reported
a
TBAB/oxone/water-promoted 2, 4-
Tetrabutyl
ammonium
iodide (0.1)
Tetrabutyl
ammonium
bromide
(TBAB,
0.1)
Tetrabutyla
mmonium
chloride
(TBAC,
0.1)
TBAB
(0.1)
TBAB
(0.5)
TBAB
(2.0)
TBAB
(0.1)
Oxone
(2.0)
3
4
80
80
71
78
dibromohydration of 2-enynylbenzoate, suggesting that the
regioselectivity of this reaction was attributed to the use of water
as a solvent.13a We hypothesize that using water as a solvent in
this reaction would modify the reaction pathway. Moreover, the
expansion of the TBAB/oxone/water system to the reaction of 2-
alkynylbenamides enabled the cyclization of 2-alkynylbenamides
in a regioselective 5-exo-dig manner for the synthesis of
isobenzofurans.13b Mechanistic studies suggest that the
regioselective reaction proceeds via a radical pathway.
Additionally, we envisioned that the regioselective 6-endo-dig
cyclization of 2-alkynylbenoic acids for the preparation of
isocoumarins could be realized via a radical pathway using water
as the solvent (Scheme 1). It is hypothesized that 2-
alkynylbenzoic acid oxygen radical A, generated from oxidation
Oxone
(2.0)
Oxone
(2.0)
5
80
66
Oxone
(2.0)
Oxone
(2.0)
Oxone
(2.0)
Oxone
(1.0)
Oxone
(2.0)
Oxone
(2.0)
K2S2O8
(2.0)
Oxone
(2.0)
6c
7
80
80
80
80
50
rt
19
40
of 2-alkynylbenzoic acid 1, subsequently undergoes
a
8d
9
trace
64
regioselective 6-endo-dig cyclization to form isocoumarin radical
B. Hydrogen abstraction of the isocoumarin radical B affords the
final product 2 (Scheme 1). The projected transformation
represents a more environmentally benign protocol for the
synthesis of isocoumarins from 2-alkynylbenzoic acid via a
regioselective 6-endo-dig radical cyclization. To verify the
transformation as outlined in Scheme 1, optimization
experiments were performed.
Oxone was first employed as an oxidant based on our previously
reported works.13 Encouragingly, the model reaction of 2-((4-
methoxyphenyl)ethynyl)benzoic acid 1a afforded the desired 6-
endo-dig cyclization product isocoumarin 2a in 43% isolated
yield (entry 1, Table 1); the 5-exo-dig cyclization product,
isobenzofuran 2a’, was not observed. Compound 2a was
characterized using H-NMR, C-NMR and HRMS.7a, 7d The results
are consistent with the assumption that regioselective 6-endo-dig
cyclization of 2-alkynylbenzoic acid could be achieved in water
through a radical pathway.
TBAB
(0.1)
TBAB
(0.1)
TBAB
(0.1)
10
11
12
13
14
15
16f
36
trace
48
80
80
80
80
80
KBr (0.1)
39
ZnBr2
(0.05)
Oxone
(2.0)
Oxone
(2.0)
Oxone
(2.0)
17
11(77e)
79
NBS (0.1)
TBAB
(0.1)
aIsolated yield based on 2-alkynylbenzoi acid 1a; Standard
b
Inspired by this promising outcome, we next optimized other
influential factors, the results of which are illustrated in Table 1.
To improve the solubility of 2-alkynylbenzoic acid in water,
various phase transfer catalysts (PTC) were studied (entries 2-4,
Table 1). As expected, PTC was favourable to reaction efficiency.
Reaction using sodium dodecyl sulfate gave rise to the desired
product 2a in a 62% yield (entry 2, Table 1), while TBAI, TBAB
and TBAC provided 2a in 71%, 78% and 66% yields,
respectively (entries 3-5, Table 1). Conducting the reaction using
TBAB and K2CO3 as a co-additive was unfavourable to the yield
of 2a and resulted in an increase in the yield of the side product
2a’ (entry 6, Table 1). Surprisingly, increasing the loading of
TBAB altered the reaction pathway (entries 7-8, Table 1). In the
presence of 2.0 equiv TBAB, the reaction only provided a trace
conditions: 2-alknylbenzoic acid 1a (0.2 mmol), additive (0.1
o
equiv), Oxone (2.0 equiv), solvent (2 mL), 80 C, 8 h, under
c
air; 2.0 equiv K2CO3 was added, and isobenzofuran 2a’ was
d
obtained in 29% yield;
(E)-3-(bromo(4-methoxyphenyl)-
methylene)isobenzofuran-1(3H)-one 3a was afforded in 74%
e
f
yield; AIBN (15 mol%) was added; THF/H2O (v/v = 1:4,
2.0 mL) as the co-solvent. Oxone = 2KHSO5·KHSO4·K2SO4.
methoxyphenyl)-methylene)-isobenzofuran-1(3H)-one 3a (see
Scheme S1 in ESI and Ref 13e) was obtained in a yield of 74%
(entry 8, Table 1). Moreover, reducing either the loading of
oxone or reaction temperature (entries 9-11, Table 1) did not
improve the product yield. Compared to other oxidants, oxone
was found to be the best choice (entry 12, Table 1).Use of other
amount
of
isocoumarin
2a,
while
(E)-3-(bromo(4-

bromo sources, including KBr, NaBr, and NBS, did not benefit
chloroaryl group gave the desired product with a slightly lower
yield of 63%. Trimethoxyl-substituted isocoumarin 2i was also
obtained in 82% yield under the standard conditions.
Interestingly, isocoumarin 2i has a high structural similiarity with
the natural product Thunberginol A. Additionally, 2-(cyclohex-1-
en-1-ylethynyl)benzoic acid was also amenable to the reaction
conditions, with the corresponding isocoumarin 2l being prepared
in 60% yield. The reactions of various alkyl group-linked
substrates worked well, with the formation of a diverse range of
isocoumarins 2m-2q in good yields. Remarkably, the substrate
2,2'-(octa-1,7-diyne-1,8-diyl)dibenzoic acid is an efficient
reaction partner, giving the corresponding isocoumarin 2r in 72%
yield.
To gain more insight into the mechanism, control experiments
with TEMPO, BHT and 1,1-diphenylethene as radical scavengers
were carried out (Scheme 2). The results show that the reaction is
retarded drastically when radical scavengers are employed.
However, none of the radical-trapped species were observed
using mass spectroscopy. The control reaction involving the
formation of brominated 1,1-diphenylethane product 4 provides
unambiguous proof that the reaction proceeds via a radical
pathway. Additionally, reaction using D2O as a solvent produced
the deuterized isocoumarin 2a-D in 72% yield, which implied
that the H atom at the C4 position in isocoumarin most likely
originates from water.
ACCEPTED MANUSCRIPT
the reaction (entries 13-15, Table 1). Furthermore, in order to
verify the plausible radical pathway, we added AIBN (15 mol%)
to the NBS conditions and found that the yield of the reaction
increased (entry 15, Table 1). We have also implemented a co-
solvent system consisting of THF/H2O (v/v = 1:4), and a
comparable yield was obtained (entry 16, Table 1). Therefore, the
optimized conditions are 0.1 equiv of TBAB and 2.0 equiv of
oxone in water, and conducting the reaction at a temperature of
80 oC.
After optimizing the conditions, we then explored the
generality of the reaction . The results are outlined in Table 2. As
shown in Table 2, a series of substituted isocoumarins were
prepared in good yields. The substituent effects of R1 were also
investigated. The results reveal that electronic effects only have a
slight impact on the yield of the desired product. For example,
reaction with a substrate containing a 4-methyl group as R1
Table
2 Generation of isocoumarins 2 through a
regioselective 6-endo-dig radical cyclization of various 2-
alkynylbenzoic acids a
In light of the above results, a plausible mechanism has been
proposed, as shown in Scheme 2. The bromide is oxidized to a
bromo radical.14 Reaction of 2-alkynylbenzoic acid 1 with the
bromo radical results in the conversion of the hydroxyl group to
oxygen radical species A.15 The oxygen radical species A
undergoes a 6-endo-dig radical cyclization to form isocoumarin
radical B. Hydrogen abstraction with water occurs on the
isocoumarin radical B, providing the final isocoumarin 2. In the
presence of base, 2-alkynylbenzoic acid anion C undergoes a
well known 5-exo-dig cyclization to produce isobenzofuran-1-
one anion D 10. Subsequently, the protonation of isobenzofuran-
1-one anion D results in the formation of the corresponding
product 2a
’.
In conclusion, we have developed
a
TBAB-catalyzed
synthetic strategy towards the preparation of isocoumarins from
various 2-alkynylbenzoic acids. The transformation proceeds
smoothly in water. Mechanistic studies showed that the reaction
proceeds in a regioselective manner via a metal-free radical
pathway. For the synthesis of isocoumarins, it is believed that
TBAB serves as a phase transfer catalyst and allows for the
generation of a benzoic acid oxygen radical. Compared to
previous methodologies, the synthetic procedure reported herein
provides a more environmentally benign route for the preparation
of isocoumarins.
a Isolated yield based on 2-alkynylbenzoic acid 1.
Experimental Section
General procedure for the synthesis of compound 2:
afforded the desired isocoumarin 2b in 79% yield, while a
substrate bearing a 3-fluoro group gave the corresponding
product 2g in a 68% yield. Other substituents including methoxy,
chloro, and bromo groups were compatible with the reaction
conditions, leading to the corresponding products 2c-2f in 70-
82% yields.
Subsequently, we explored the tolerance of R2 substituents.
Encouragingly, R2 substituents could be replaced by aryl, vinyl,
and alkyl groups. The corresponding products 2h-2q were
obtained in 60-79% yields. For instance, reaction of a substrate
bearing a 2-methoxylaryl substituent produced the desired
isocoumarin 2j in 67% yield, whereas a substrate bearing a 2-
2-alkynylbenzoic acid 1 (0.2 mmol), TBAB (0. 1 equiv), and
Oxone (2.0 equiv) were added to a test tube, and then H2O (2.0
mL) was added. The mixture was stirred at 80°C for 8 h, under
air. After the disappearance of the substrate as indicated by TLC,
the mixture was filtered and the resulting filtrate was extracted
with DCM (3*2 mL). The organic layers were combined and
dried over Na2SO4. Filtration, evaporation of the solvent and
purification by flash column chromatography provided the
desired product 2.

4
Tetrahedron
+
798 cm-1; HRMS (ESI) calcd for C H O : 267.1016 (M++H),
ACCEPTED MANUSCRIPT
17 15
3
found: 267.1017
7-methoxy-3-(4-methoxyphenyl)-1H-isochromen-1-one (2d)
(yellow solid, 44.6 mg, 79%)
1H NMR (400 MHz, CDCl3) δ 7.75 (s, 2H), 7.69-7.67 (m, 1H),
7.37 (d, J = 8.6 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 6.94 (d, J = 8.9
Hz, 2H), 6.77 (s, 1H), 3.89 (s, 3H), 3.84 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 162.6, 160.7, 159.2, 151.8, 131.6, 131.3, 127.3,
126.4, 124.7, 121.1, 114.1, 109.8, 100.0, 55.7, 55.3; IR (KBr):
3172, 2924, 1760, 1680, 1585, 1379, 1259, 1059, 876, 636 cm-1;
+
HRMS (ESI) calcd for C17H15O4 : 283.0965 (M++H), found:
283.0962
7-chloro-3-(4-methoxyphenyl)-1H-isochromen-1-one
(2e)
(yellow solid, 40.7 mg, 71%)
1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.77 (d, J = 8.6
Hz, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 6.94
(d, J = 8.6 Hz, 2H), 6.77 (s, 1H), 3.85 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 161.3, 161.2, 154.0, 136.2,
135.1, 133.2, 129.0, 127.1, 126.8, 124.0, 121.1, 114.2, 99.3, 55.4;
IR (KBr): 3122, 2878, 1802, 1677, 1582, 1391, 1247, 1083, 833
+
cm-1; HRMS (ESI) calcd for C16H12ClO3 : 287.0469 (M++H),
found: 287.0470
7-bromo-3-(4-methoxyphenyl)-1H-isochromen-1-one
(2f)
(yellow solid, 46.2 mg, 70%)
1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.76-7.72 (m, 3H),
7.30 (d, J = 8.3 Hz, 1H), 6.93 (d, J = 8.5 Hz, 2H), 6.74 (s, 1H),
3.84 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 161.2, 161.1, 154.1,
137.8, 136.6, 132.0, 127.2, 126.8, 124.0, 121.3, 120.82, 114.2,
99.4, 55.4; IR (KBr): 3118, 2915, 1802, 1677, 1582, 1374, 1202,
1010, 853, 623 cm-1; HRMS (ESI) calcd for C16H12BrO3 :
Scheme 2 Control experiments and plausible mechanism
+
330.9964 (M++H), found: 330.9976
3-(4-methoxyphenyl)-1H-isochromen-1-one (2a) (yellow solid,
39.4 mg, 78%)
1H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 8.1 Hz, 1H), 7.81 (d, J
= 8.9 Hz, 2H), 7.68 (t, J = 7.6 Hz, 1H), 7.48 - 7.42 (m, 2H), 6.96
(d, J = 8.9 Hz, 2H), 6.82 (s, 1H), 3.85 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 162.5, 161.0, 153.7, 137.9, 134.8, 129.6, 127.6,
126.8, 125.9, 124.5, 120.1, 114.2, 100.2, 55.4; IR (KBr): 3032,
2840, 1739, 1632, 1510, 1354, 1237, 1022, 925, 880, 792, 683
7-fluoro-3-(4-methoxyphenyl)-1H-isochromen-1-one
(2g)
(white solid, 36.8 mg, 68%)
1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.6 Hz, 1H), 7.76
(d, J = 8.2 Hz, 2H), 7.47 - 7.36 (m, 2H), 6.94 (d, J = 8.3 Hz, 2H),
6.78 (s, 1H), 3.84 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 161.6,
1
3
161.5 (d, JCF = 248 Hz), 161.1, 153.1, 134.4, 127.9 (d, JCF = 8
Hz), 126.7, 124.1, 123.3 (d, 2JCF = 23 Hz), 121.5 (d, 3JCF = 8 Hz),
115.0 (d, 2JCF = 23 Hz), 114.2, 99.4, 55.4; IR (KBr): 3128, 2857,
1764, 1637, 1532, 1381, 1247, 1054, 771, 540 cm-1; HRMS (ESI)
+
cm-1; HRMS (ESI) calcd for C16H13O3 : 253.0859 (M++H), found:
253.0856
+
calcd for C16H12FO3 : 271.0765 (M++H), found: 271.0769
3-(4-methoxyphenyl)-6-methyl-1H-isochromen-1-one
(2b)
(white solid, 42.1 mg, 79%)
1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 7.8 Hz, 1H), 7.77
(d, J = 8.2 Hz, 2H), 7.27 - 7.16 (m, 2H), 6.93 (d, J = 8.3 Hz, 2H),
6.71 (s, 1H), 3.83 (s, 3H), 2.43 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 162.5, 160.9, 153.6, 145.8, 137.9, 129.5, 129.0, 126.7,
125.6, 124.6, 117.7, 114.1, 100.1, 55.3, 21.9; IR (KBr): 3173,
2957, 1764, 1680, 1526, 1354, 1274, 1046, 816, 659 cm-1;
3-(3,4-dimethoxyphenyl)-1H-isochromen-1-one (2h) (blue
solid, 44.0 mg, 78%)
1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 8.2 Hz, 1H), 7.67 (t,
J = 7.6 Hz, 1H), 7.45-7.41 (m, 3H), 7.34 (s, 1H), 6.90 (d, J = 7.9
Hz, 1H), 6.81 (s, 1H), 3.96 (s, 3H), 3.91 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 162.4, 153.6, 150.6, 149.1, 137.8, 134.8, 129.6,
127.7, 125.7, 124.8, 120.1, 118.4, 111.1, 108.1, 100.5, 56.1, 56.0;
IR (KBr): 3028, 2867, 1734, 1637, 1512, 1371, 1260, 788, 572
HRMS (ESI) calcd for C17H15O3 : 267.1016 (M++H), found:
267.1021
+
+
cm-1; HRMS (ESI) calcd for C17H15O4 : 283.0965 (M++H), found:
283.0965
3-(4-methoxyphenyl)-7-methyl-1H-isochromen-1-one
(2c)
(white solid, 43.7 mg, 82%)
1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.77 (d, J = 8.7
Hz, 2H), 7.47 (d, J = 8.1 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 6.93
(d, J = 8.8 Hz, 2H), 6.76 (s, 1H), 3.83 (s, 3H), 2.43 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ 162.6, 160.8, 152.8, 137.9, 136.1,
135.4, 129.2, 126.6, 125.6, 124.6, 119.9, 114.1, 100.1, 55.3, 21.3;
IR (KBr): 3121, 2914, 1747, 1688, 1581, 1373, 1254, 1059, 873,
3-(3,4-dimethoxyphenyl)-7-methoxy-1H-isochromen-1-one
(2i) (blue solid, 51.2 mg, 82%)
1H NMR (400 MHz, CDCl3) δ 7.69-7.65 (m, 1H), 7.42 - 7.36
(m, 2H), 7.34-7.30 (m, 1H), 7.27 (d, J = 8.7 Hz, 1H), 6.89 (d, J =
8.5 Hz, 1H), 6.79 (s, 1H), 3.96 (s, 3H), 3.91 (s, 3H), 3.89 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 162.6, 159.2, 151.7, 150.3, 149.1,

131.5, 127.3, 125.0, 124.7, 121.1, 118.0, 111.1, 109.9, 107.9,
J = 7.4 Hz, 2H), 2.55 (t, J = 7.5 Hz, 2H), 2.10 - 2.01 (m, 2H). 13C
NMR (100 MHz, CDCl3) δ 163.0, 157.7, 141.3, 137.5, 134.7,
129.5, 128.4, 128.4, 127.6, 126.0, 125.0, 120.1, 103.2, 35.1, 32.9,
28.4; IR (KBr): 3111, 2980, 1625, 1578, 1389, 1254, 1022, 773
ACCEPTED MANUSCRIPT
100.3, 56.1, 55.9, 55.7; IR (KBr): 3020, 2872, 1735, 1655, 1381,
1265, 760, 552 cm-1; HRMS (ESI) calcd for C18H17O5 : 313.1071
+
(M++H), found: 313.1073
cm-1; HRMS (ESI) calcd for C18H17O2 : 265.1223 (M++H), found:
+
3-(2-methoxyphenyl)-1H-isochromen-1-one (2j) (yellow solid,
33.8 mg, 67%)
265.1207
1H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 7.8 Hz, 1H), 7.91
(d, J = 7.9 Hz, 1H), 7.86 - 7.80 (m, 1H), 7.59 (t, J = 7.6 Hz, 1H),
7.50 - 7.39 (m, 2H), 7.04-7.00 (m, 2H), 3.84 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 161.6, 157.3, 150.6, 136.4, 135.3, 131.8,
131.1, 129.8, 129.0, 126.3, 122.3, 120.8, 120.3, 111.3, 103.8,
55.7; IR (KBr): 3010, 2892, 1744, 1650, 1380, 1264, 756 cm-1;
3-cyclopropyl-1H-isochromen-1-one (2p) (white solid, 23.8
mg, 64%)
1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 7.9 Hz, 1H), 7.64 (t,
J = 7.6 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H),
6.30 (s, 1H), 1.82-1.74 (m, 1H), 1.10-1.03 (m, 2H), 0.96-0.89 (m,
2H). 13C NMR (100 MHz, CDCl3) δ 162.7, 158.4, 137.9, 134.7,
129.5, 127.1, 124.6, 119.9, 101.3, 13.8, 6.9; IR (KBr): 3120,
3005, 2920, 1644, 1580, 1378, 1026, 878 cm-1; HRMS (ESI)
+
HRMS (ESI) calcd for C16H13O3 : 253.0859 (M++H), found:
253.0871
calcd for C12H11O2 : 187.0754 (M++H), found: 187.0751
+
3-(2-chlorophenyl)-1H-isochromen-1-one (2k) (white solid,
32.3 mg, 63%)
3-(tert-butyl)-1H-isochromen-1-one (2q) (white solid, 32.0
mg, 79%)
1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 7.9 Hz, 1H), 7.77 -
7.67 (m, 2H), 7.52-7.48 (m, 3H), 7.37-7.33 (m, 2H), 6.97 (s, 1H).
13C NMR (100 MHz, CDCl3) δ 162.3, 151.4, 137.0, 134.9, 132.3,
131.6, 130.7, 130.6, 130.63, 129.6, 128.7, 127.0, 126.2, 120.6,
107.7; IR (KBr): 3074, 2920, 2872, 1740, 1625, 1600, 757, 560
1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 7.9 Hz, 1H), 7.66 (t,
J = 7.6 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H),
6.30 (s, 1H), 1.32 (d, J = 1.0 Hz, 9H). 13C NMR (100 MHz,
CDCl3) δ 165.1, 163.0, 137.6, 134.6, 129.3, 127.6, 125.4, 120.1,
99.7, 35.6, 27.9; IR (KBr): 3180, 2975, 1625, 1580, 1381, 1250,
+
cm-1; HRMS (ESI) calcd for C15H10ClO2 : 257.0364 (M++H),
+
found: 257.0372
1002, 778 cm-1; HRMS (ESI) calcd for C13H15O2 : 203.1067
(M++H), found: 203.1067
3-(cyclohex-1-en-1-yl)-1H-isochromen-1-one (2l) (yellow
solid, 27.2 mg, 60%)
3,3'-(butane-1,4-diyl)bis(1H-isochromen-1-one) (2r) (white
solid, 49.9 mg, 72%)
1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 7.7 Hz, 1H), 7.67 -
7.61 (m, 1H), 7.42-7.38 (m, 2H), 6.83-6.79 (m, 1H), 6.36 (s, 1H),
1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 7.9 Hz, 1H), 7.65 (t,
J = 7.3 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H),
2.31 - 2.23 (m, 4H), 1.80-1.73 (m, 2H), 1.67-1.60 (m, 2H). 13
C
NMR (100 MHz, CDCl3) δ 162.3, 154.3, 137.8, 134.6, 130.1,
129.5, 128.2, 127.5, 125.7, 120.6, 100.0, 25.6, 24.1, 22.3, 21.8;
IR (KBr): 3083, 2930, 1682, 1625, 1553, 1280, 1220, 1111, 881
6.26 (s, 1H), 2.55 (d, J = 6.4 Hz, 2H), 1.82 - 1.76 (m, 2H). 13
C
NMR (100 MHz, CDCl3) δ 163.0, 157.3, 137.4, 134.8, 129.4,
127.7, 125.1, 120.1, 103.3, 33.2, 26.2; IR (KBr): 3173, 2936,
1680, 1560, 1380, 1252, 1140, 775 cm-1; HRMS (ESI) calcd for
+
cm-1; HRMS (ESI) calcd for C15H15O2 : 227.1067 (M++H), found:
+
227.1066
C22H19O4 : 347.1278 (M++H), found: 347.1302
Acknowledgments
3-butyl-1H-isochromen-1-one (2m) (yellow oil, 31.6 mg, 78%)
1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 7.9 Hz, 1H), 7.67-
7.63 (m, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H),
6.24 (s, 1H), 2.51 (t, J = 7.6 Hz, 2H), 1.72 - 1.64 (m, 2H), 1.44 -
1.34 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ 163.1, 158.3, 137.6, 134.7, 129.4, 127.5, 125.0, 120.1,
102.8, 33.2, 28.9, 22.1, 13.7; IR (KBr): 3120, 3080, 2925, 1650,
1575, 1381, 1250, 1011, 878 cm-1; HRMS (ESI) calcd for
Financial supports from the Natural Science Foundation of China
(Nos: 21762018 and 21772067), the Natural Science Foundation
of Zhejiang (LY19B020004), and the program of Qingjiang
Excellent Young Talents of JXUST (No. JXUSTQJYX2017004)
is gratefully acknowledged. We are especially thankful for Ms.
Ko Chung-Nga from the Hong Kong Baptist University who
substantially improved English throughout the manuscript.
+
C13H15O2 : 203.1067 (M++H), found: 203.1073
References and notes
3-decyl-1H-isochromen-1-one (2n) (yellow oil, 43.5 mg, 76%)
1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 7.9 Hz, 1H), 7.65 (t,
J = 7.6 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H),
6.23 (s, 1H), 2.50 (t, J = 7.6 Hz, 2H), 1.73 - 1.63 (m, 2H), 1.30-
1.20 (m, 14H), 0.86 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ 163.1, 158.3, 137.6, 134.6, 129.4, 127.5, 125.0, 120.1,
102.8, 33.5, 31.8, 29.5, 29.5, 29.3, 29.3, 29.0, 26.9, 22.6, 14.1; IR
(KBr): 3122, 3083, 2930, 1625, 1578, 1380, 1252, 1006, 880 cm-
1
2
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