Synthesis of 3-(Bromomethylene)isobenzofuran-1(3H)-ones through regioselective 5-exo-dig bromocyclization of 2-alkynylbenzoic acids

Article abstract of DOI:10.1016/j.tet.2018.11.045

A direct synthesis of 3-(bromomethylene)isobenzofuran-1(3H)-ones from 2-alkynylbenzoic acids is developed through a regioselective 5-exo-dig bromocyclization. The reaction proceeds smoothly with a broad substrate scope. The products can be further elaborated via a palladium-catalyze cross-coupling reaction, or can convert to other heterocycles through simple operation. Preliminary mechanistic studies reveal that this transformation undergoes a radical process.

Full text of DOI:10.1016/j.tet.2018.11.045

Accepted Manuscript
Synthesis of 3-(Bromomethylene)isobenzofuran-1(3H)-ones through regioselective
5-exo-dig bromocyclization of 2-alkynylbenzoic acids
Yannan Zheng, Mengli Liu, Guanyinsheng Qiu, Wenlin Xie, Jie Wu
PII:
S0040-4020(18)31400-5
https://doi.org/10.1016/j.tet.2018.11.045
TET 29956
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 11 October 2018
Revised Date: 14 November 2018
Accepted Date: 21 November 2018
Please cite this article as: Zheng Y, Liu M, Qiu G, Xie W, Wu J, Synthesis of 3-
(Bromomethylene)isobenzofuran-1(3H)-ones through regioselective 5-exo-dig bromocyclization of 2-
alkynylbenzoic acids, Tetrahedron (2018), doi: https://doi.org/10.1016/j.tet.2018.11.045.
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Synthesis of 3-
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(Bromomethylene)isobenzofuran-1(3H)-ones
through Regioselective 5-exo-dig
Bromocyclization of 2-Alkynylbenzoic Acids
Yannan Zheng, Mengli Liu, Guanyinsheng Qiu,* Wenlin Xie, and Jie Wu*
College of Biological, Chemical Science and Engineering, Jiaxing University, 118 Jiahang Road, Jiaxing 314001, China.
Department of Chemistry, Fudan University, 2005 Songhu Road, Shanghai 200438, China
O
O
TBAB (1.5 equiv)
oxone (2.0 equiv)
OH
O
R
R
DCE:H2O (v/v = 1:1)
60 oC
R1
R1
Br
53-82% yields

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of 3-(Bromomethylene)isobenzofuran-1(3H)-ones through Regioselective
5-exo-dig Bromocyclization of 2-Alkynylbenzoic Acids
Yannan Zheng,a Mengli Liu,a Guanyinsheng Qiu*a,b, Wenlin Xie,c and Jie Wu*b
a College of Biological, Chemical Science and Engineering, Jiaxing University, 118 Jiahang Road, Jiaxing 314001, China
b Department of Chemistry, Fudan University, 2005 Songhu Road, Shanghai 200433, 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
A direct synthesis of 3-(bromomethylene)isobenzofuran-1(3H)-ones from 2-alkynylbenzoic
acids is developed through a regioselective 5-exo-dig bromocyclization. The reaction proceeds
smoothly with a broad substrate scope. The products can be further elaborated via a palladium-
catalyze cross-coupling reaction, or can convert to other heterocycles through simple operation.
Preliminary mechanistic studies reveal that this transformation undergoes a radical process.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
2-alkynylbenzoic acid
isobenzofuran-1(3H)-one
bromocyclization
regioselective
Functionalization of alkyne has attracted continuous interest
of chemists due to its versatility towards construction of
privileged structures. In the past decades, we have witnessed the
achievements of alkyne-based transformations.1 Generally, the
chemists intensively devoted themselves to addressing two
central issues, which were always defined as reaction efficiency
and reaction regioselectivity of alkyne-based transformations.
Among them, regioselective functionalization of alkyne was
often controlled by substrates.2 According to the established
achievements, the use of substrates with ortho-directing group
would enable the regioselective functionalization of alkyne. For
example, Oliver and Gandour disclosed an initial example on
bromocyclization of 2-alkynylbenzoate.3 It was reported that this
Br2-mediated bromocyclization of 2-alkynylbenzoate was
regioselective, producing 4-bromoisocoumarins through 6-endo-
dig brominative oxy-cyclization. This precedence encouraged
numerous chemists to evaluate the regioselective transformation
of other ortho-alkynyl-containing dual-functionalized substrates.
Scheme
1
Proposed route for the synthesis of 3-
through
2a
So far, 2-alkynylbenzaldehyde,
2-alkynylbenzoxime,2c 2-
2-
(bromomethylene)isobenzofuran-1(3H)-ones
regioselective 5-exo-dig bromocyclization of 2-alkynylbenzoic
acids
a
alkynylarylhydrazide,2b,2e
2-alkynylbenzamide,4-7
alkynylacetamide,8-10 and 2-alkynylbenzoate11 were recognized as
efficient dual-functionalized substrates. Their regioselective
cyclization could be reached by tuning different reaction systems.
There were three major reaction systems regarding the use of
catalysts, including Bronsted acid/Lewis acid-catalyzed
cyclization, electrophilic cyclization and transition metal-
catalyzed cyclization, respectively. As our continuous interest in
alkyne-based chemistry,12 we would like to develop a new way to
realize regioslective cyclization of ortho-alkynyl-containing
dual-functionalized substrates. Recently, a radical pathway was
developed by our group to achieve regioselective
bromocyclization of internal alkynes.12a The combination of
TBAB/oxone/water enabled 5-exo-dig brominative oxy-
cyclization of 2-alkynylbenzamide (Scheme 1, eq a). The
mechanistic investigation suggested that the use of water as a
mixed solvent was highly important for the regioselective
bromocyclization of 2-alkynylbenzamide. A same 5-exo-dig
bromocyclization was observed when 2-enynylbenzoate was used

2
Tetrahedron
as the substrate in the presence of bromide/oxone/water.12b
functionalization of 2-alkynylbenzoic acids. Therefore, we
ACCEPTED MANUSCRIPT
Inspired by the above results, we envisioned that the combination
of bromide/oxone/water could be expanded to regioselective
bromocyclization of other ortho-alkynyl-containing dual-
functionalized substrates.
On the other hand, many efforts were made on exploring
regioselective cyclization of 2-alkynylbenzoic acid.13-14 To the
best of our knowledge, base-promoted cyclization of 2-
alkynylbenzoic acid was regioselective in a fashion of 5-exo-dig,
yielding isobenzofuran-1(3H)-ones.13 Recent advances suggested
that the use of transition metals could also control 5-exo-dig
cyclization of 2-alkynylbenzoic acids.14 However, electrophilic
cyclization of 2-alkynylbenzoic acids provided a mixture of 5-
exo-dig product and 6-endo-dig product (Scheme 1, eq. b).15 As
started to explore the transformation for the optimized conditions
(Table 1).
As illustrated in Table 1, a brief survey on reaction conditions
was carried out. Varying in different mixed solvents indicated
that DCE:H2O was the best choice (entry 1, Table 1), and other
mixed solvents such as MeCN:H2O and THF:H2O gave rise to
inferior results (entries 2-3, Table 1). No better yield was
observed when DCE was used (entry 4, Table 1). Moreover, 4-
bromoisocoumarin 3 was observed in 17% yield, thus supporting
our assumption that the use of water probably changed the
reaction pathway. Increasing temperature made slight impact on
the reaction outcome (entry 5, Table 1). An inferior yield was
obtained when the loading of oxone was reduced from 2.0 equiv
to 1.0 equiv (entry 6, Table 1). Increasing the amount of TBAB
did not make significant impact on the product yield (entry 7,
Table 1). A control experiment using 2.0 equiv of Br2 instead of
TBAB/oxone was carried out. To our surprise, a mixture of 5-
we know, 3-methyleneisobenzofuran-1-one is
a privileged
structural core,16 whichis ubiquitous in many useful molecules.
Considering the structural elaboration versatility of halo group,
halogenated 3-methyleneisobenzofuran-1-one would be
a
powerful building block towards the construction of its
derivatives for the evaluation of different biological assays. Thus,
we initially explored an indirect route for the synthesis of 3-
exo-dig
bromocyclization
product
and
6-endo-dig
bromocyclization product was achieved. The ratio was almost 1:1.
With the optimized reaction conditions in hand (entry 1, Table
1), we then examined the substrate scope of this transformation.
The results are summarized in Table 2. A range of 3-
(bromomethylene)isobenzofuran-1(3H)-one 2 was achieved as
expected. The substituent R1 could be replaced by aryl and alkyl
group. For example, under standard conditions the reaction of 2-
((3-fluorophenyl)ethynyl)benzoic acid 1b provided fluoro-
containing 3-(bromomethylene)isobenzofuran-1(3H)-one 2b in
59% yield. The electron effect of the substituents on the aromatic
ring of R1 showed that substrates with electron-donating groups
were favourable in the reaction. For instance, the reaction of 2-
(bromomethylene)isobenzofuran-1(3H)-ones
2
from
2-
alkynylbenzamides
through
regioselective
5-exo-dig
bromocyclization and hydrolysis process (Scheme 1, eq a).12a
Prompted the results as mentioned above, we anticipated that a
regioselective 5-exo-dig bromocyclization of 2-alkynylbenzoic
acids
1
would be accomplished for the access to 3-
with high
(bromomethylene)isobenzofuran-1(3H)-ones
2
efficiency when TBAB/oxone/water was used (Scheme 1, eq c).
To our delight, the utilization of 1.5 equiv of TBAB and 2.0
equiv of oxone at 60 oC in DCE:H2O (v/v = 1:1) enabled a
regioselective 5-exo-dig bromocyclization of 2-alkynylbenzoic
acid 1a. The expected product 2a was afforded in 75% isolated
yield (Scheme 1, eq c).
Table 2 synthesis of 3-(bromomethylene)isobenzofuran-1(3H)-
ones from 2-alkynylbenzoic acids a
Imaginably, to realize
a
regioselective 5-exo-dig
O
O
bromocyclization of 2-alkynylbenzoic acids not only provided a
TBAB (1.5 equiv)
oxone (2.0 equiv)
direct
procedure
for
the
synthesis
of
3-
OH
O
R
R
(bromomethylene)isobenzofuran-1(3H)-ones,
but
also
DCE:H2O (v/v = 1:1)
60 oC
represented an important supplement for the regioselective
R1
R1
2
1
Br
Table Initial studies for the synthesis of 3-
1
O
(bromomethylene)isobenzofuran-1(3H)-ones
from
2-
O
F
alkynylbenzoic acids a
2a, R1 = C6H5, 75%
2b, R1 = C6H4m-F, 59%
2c, R1 = C6H4p-Cl, 53%
2d, R1 = C6H4p-OMe, 79%
O
O
2i, 70%
Ph
R1
Br
Br
O
O
2e, R = 3-Me, 82%
2f, R = 4-Me, 78%
2g, R = 3-Cl, 72%
2h, R = 3-Br, 74%
O
R
O
2j, 67%
TBAB
Loading
(equ)
oxone
loading solvent
(equ)
yield of
temp
(oC)
entry
2a
(%)a,b
C6H4p-OMe
Br
Br
DCE:H2O
`1
2
1.5
1.5
2.0
2.0
60
60
75
46
O
O
O
O
(v/v = 1:1)
MeCN:H2O
(v/v = 1:1)
THF:H2O
O
O
Ph
3
4
5
1.5
1.5
1.5
2.0
2.0
2.0
60
60
90
27
41c
73
Bun
But
(v/v = 1:1)
Br
Br
2l, 79%
Br
DCE
2k, 68%
2m, 76%
DCE:H2O
(v/v = 1:1)
DCE:H2O
(v/v = 1:1)
DCE:H2O
(v/v = 1:1)
O
O
6
1.5
2.0
1.0
2.0
60
60
64.
74
O
O
7
Ph
a
2n, 81%
2o, 49%
I
Br
Reaction conditions: 1a (0.2 mmol), TBAB (x equiv), oxone (y
b
equiv), solvent, temp., 8 h. Isolated yield based on 2-alkynylbenzoic acid
a Isolated yield based on 2-alkynylbenzoic acid 1.
1a. c 4-bromoisocoumarin 3 was observed in 17% yield. TBAB = tetra-n-
butylammonium bromide; oxone = 2KHSO5·KHSO4·K2SO4

((4-methoxyphenyl)ethynyl)benzoic acid 1d afforded the desired
radical A. This radical intermediate would be reduced by the
bromo radical to deliver 2-alkynylbenzoic acid anion B and
bromo cation. The resulting 2-alkynylbenzoic acid anion B
would undergo a 5-exo-dig cyclization to produce isobenzofuran-
1-one anion C, since 5-exo-dig cyclization of alkynylbenzoic acid
anion B was well known.13 Subsequently, isobenzofuran-1-one
anion C would react with bromo cation, leading to the
corresponding product 2. However, we did not exclude another
pathway. In the pathway B, bromo radical added into triple bond
to form an intermediate D, followed by oxidation to provide
vinyl cation intermediate E. Cyclization of the intermediate E
and deprotonation gave a desired product 2.
ACCEPTED MANUSCRIPT
product 2d in 79% yield, while that of 2-((4-
chlorophenyl)ethynyl)benzoic acid 1c just provided the expected
product 2c in 53% yield. The reaction proceeded smoothly when
the substituent R1 was replaced by cyclohex-1-enyl group,
leading to the desired product 2j in a 67% yield. Additionally, the
substituent R1 could be equal to alkyl group. The substrates with
phenylpropanyl, n-butyl, t-butyl, and nonyl group were
compatible in the transformation, and the desired products 2k-2n
were afforded in good yields. Replacing TBAB with TBAI, the
reaction provided the final product 2o in 49% yield. However,
the reaction using TBAC or TBAF did not give rise to the
corresponding product.
Subsequently, the substituent effect of R was explored
accordingly. As mentioned above, the electron-donating
substituents on the aromatic ring at R1 position were helpful to
improve the reaction efficiency. Therefore, substrates with 4-
methoxyphenyl at R1 position were employed to investigate the
substituent effect of R. From the results, it seemed that the
substituents at R position did not make significant impact on the
final outcome. For example, reaction of 4-methyl-2-
(phenylethynyl)benzoic acid gave rise to the desired product 2f in
78%
yield,
while
the
reaction
of
5-bromo-2-
(phenylethynyl)benzoic acid provided product 2h in a similar
yield. Halo groups were tolerated under the standard conditions
as well.
O
O
THF:H2O
(v/v = 1:1)
60 oC
NH
N
O
NH2-NH2
+
89% yield
Ph
4
2a Br
HO
Ph
O
O
Pd(PPh3)4 (10 mol%)
p-Tol B(OH)2
+
O
O
K2CO3 (2.0 equiv)
toluene:H2O (v/v, 4:1)
110 oC, N2
Ph
Ph
p-Tol
2a Br
5
76% yield
Scheme
2.
Transformation
of
3-
(bromomethylene)isobenzofuran-1(3H)-one 2a
As showed in Scheme 2, the synthetic applications of 3-
(bromomethylene)isobenzofuran-1(3H)-one 2a were then
explored. Considering the ubiquity of phthalazin-1(2H)-one core
in many bioactive compounds,17 our initial endeavor was to
synthesize hydroxyl-containing phthalazin-1(2H)-one 4. As
expected, the corresponding phthalazin-1(2H)-one
achieved in 89% yield when 3-(bromomethylene)isobenzofuran-
1(3H)-one 2a was treated with hydrazine in
4 was
tetrahydrofuran:water (v/v = 1:1) at 60 oC. Interestingly,
hydroxyl-containing phthalazin-1(2H)-one 4 would be a powerful
building block due to the versatility of hydroxyl group for
structural elaboration. Next, a palladium-catalyzed Suzuki cross-
coupling reaction of 3-(bromomethylene)isobenzofuran-1(3H)-
one 2a with 4-methylphenylboronic acid was performed.
Pleasingly, the desired coupling product 5 was obtained in 76%
yield in the presence of Pd(PPh3)4 (10 mol %).
To gain more insight of the mechanism, a control experiment
with TEMPO (2,2,6,6-tetramethylpiperidinooxy) as an additive
was carried out. As presented in Scheme 3, the reaction was
dramatically retarded. However, we did not detect any radical
intermediate. In light of the above results and our previous
findings,12 a plausible mechanism was proposed in Scheme 3. We
reasoned that oxidation of bromo anion into bromo radical would
trigger the reaction.18 Then an intermolecular hydrogen
abstraction of 1a would occur, providing 2-alkynylbenzoic acid
Scheme 3 Proposed Mechanism
In conclusion, we have developed a direct route for the
synthesis of 3-(bromomethylene)isobenzofuran-1(3H)-ones from
2-alkynylbenzoic acids. The transformation proceeds with high
efficiency through a regioselective 5-exo-dig bromocyclization.
A broad reaction scope is observed. The products can be further
elaborated via a palladium-catalyze cross-coupling reaction, or
can convert to other heterocycles through simple operation.
Preliminary mechanistic studies reveal that this transformation
undergoes a radical process.
Experimental Section
General procedure for the synthesis of compound 2:

4
Tetrahedron
2-alkynylbenzoic acid 1 (0.2 mmol), oxone (2.0 equiv),
126.5, 125.1, 118.0, 113.4, 100.6, 55.4, 22.2; HRMS (ESI) calcd
ACCEPTED MANUSCRIPT
+
TBAB (1.5 equiv) were added to a test tube, and then DCE:H2O
(v/v = 1:1, 2.0 mL) was added. The mixture was stirred at 60 °C
overnight. After consumption of the substrate as indicated by
TLC, the mixture was filtrated and the resulting filtrate was
extracted by CH2Cl2 (3 x 2.0 mL). The combined organic layer
was dried by anhydrous Na2SO4. After evaporation of the filtrate,
the residue was purified by flash column chromatography, giving
rise to the desired product 2.
for C17H14BrO3 : 345.0121 (M++H), found: 345.0123
(E)-3-(bromo(4-methoxyphenyl)methylene)-6-
chloroisobenzofuran-1(3H)-one (2g) (yellow solid, 52.5 mg,
72%)
1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.85 (d, J = 8.7 Hz,
1H), 7.75-7.73 (m, 3H), 6.95 (d, J = 7.8 Hz, 2H), 3.85 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 161.0, 160.1, 151.9, 135.6, 135.4,
134.8, 131.3, 129.0, 128.3, 124.5, 121.3, 113.5, 99.6, 55.4;
+
(E)-3-(bromo(phenyl)methylene)isobenzofuran-1(3H)-one (2b)
(yellow solid, 45.0 mg, 75%)
HRMS (ESI) calcd for C16H11BrClO3 : 364.9575 (M++H), found:
364.9575
1H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 8.0 Hz, 1H), 8.00 (d, J
= 7.6 Hz, 1H), 7.87-7.82 (m, 1H), 7.75-7.64 (m, 3H), 7.47-7.37
(m, 3H); 13C NMR (100 MHz, CDCl3) δ 165.8, 142.6, 138.3,
136.2, 134.6, 130.6, 130.0, 129.4, 128.2, 125.8, 125.5, 125.3,
(E)-6-bromo-3-(bromo(4-
methoxyphenyl)methylene)isobenzofuran-1(3H)-one
(2h)
(yellow solid, 60.4 mg, 74%)
108.5; HRMS (ESI) calcd for C15H10BrO2 : 300.9859 (M++H),
1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.89 (d, J = 7.5 Hz,
1H), 7.82 - 7.71 (m, 3H), 6.97 (d, J = 7.6 Hz, 2H), 3.86 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 161.0, 160.0, 152.1, 138.4, 135.7,
132.1, 131.3, 128.3, 124.6, 122.6, 121.6, 113.5, 99.6, 55.4;
+
found: 300.9851
(E)-3-(bromo(3-fluorophenyl)methylene)isobenzofuran-1(3H)-
one (2b) (yellow solid, 35.7 mg, 59%)
HRMS (ESI) calcd for C16H11Br2O3 : 408.9069 (M++H), found:
+
1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 8.0 Hz, 1H), 7.96 (d, J
= 7.6 Hz, 1H), 7.82-7.80 (m, 1H), 7.66-7.63 (m, 1H), 7.51 (d, J =
408.9090
7.9 Hz, 1H), 7.45 - 7.34 (m, 2H), 7.06 (t, J = 7.9 Hz, 1H). 13
C
(E)-3-(bromo(4-methoxyphenyl)methylene)-6-
1
NMR (100 MHz, CDCl3) δ 165.5, 162.2 (d, JCF = 245 Hz),
143.2, 138.2 (d, JCF = 8 Hz), 138.1, 134.7, 130.9, 129.7 (d, JCF
= 9 Hz), 125.9, 125.9, 125.5, 125.4, 117.1 (d, JCF = 23 Hz),
fluoroisobenzofuran-1(3H)-one (2i) (white solid, 48.8 mg, 70%)
1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.1 Hz, 2H), 7.76 (d, J
= 8.6 Hz, 2H), 7.53 (d, J = 7.3 Hz, 1H), 6.98 (d, J = 8.6 Hz, 2H),
3.87 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 162.2 (d, 1JCF = 255
3
3
2
2
116.3 (d, JCF = 21 Hz), 106.4; HRMS (ESI) calcd for
+
3
C15H9BrFO2 : 318.9764 (M++H), found: 318.9768
Hz), 160.4, 151.1, 133.4, 131.6, 131.2, 129.3 (d, JCF = 8 Hz),
124.6, 123.5 (d, JCF = 23 Hz), 115.2 (d, JCF = 23 Hz), 113.6,
2
2
+
(E)-3-(bromo(4-chlorophenyl)methylene)isobenzofuran-1(3H)-
one (2d) (yellow solid, 35.4 mg, 53%)
113.5, 99.6, 55.4; HRMS (ESI) calcd for C16H11BrFO3 :
348.9870 (M++H), found: 348.9849
1H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 8.0 Hz, 1H), 7.98 (d, J
= 7.7 Hz, 1H), 7.84-7.80 (m, 1H), 7.67-7.64 (m, 3H), 7.41-7.39
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 165.6, 142.9, 138.2,
135.4, 134.7, 131.3, 130.8, 128.4, 125.9, 125.3, 106.9; HRMS
(E)-3-(bromo(cyclohex-1-en-1-yl)methylene)isobenzofuran-
1(3H)-one (2j) (yellow oil, 40.8 mg, 67%)
1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 7.8 Hz, 1H), 7.86 (d, J
= 8.0 Hz, 1H), 7.79-7.77 (m, 1H), 7.52 (d, J = 7.5 Hz, 1H), 6.29
(s, 1H), 2.42 - 2.18 (m, 4H), 1.82 - 1.63 (m, 4H); 13C NMR (100
MHz, CDCl3) δ 161.4, 154.3, 1368, 135.2, 135.1, 131.1, 129.6,
128.6, 126.5, 120.4, 99.8, 26.3, 25.3, 22.2, 21.5; HRMS (ESI)
(ESI) calcd for C15H9BrClO2 : 334.9469 (M++H), found:
+
334.9470
(E)-3-(bromo(4-methoxyphenyl)methylene)isobenzofuran-1(3H)-
one (2d) (yellow solid, 49.5 mg, 79%)
calcd for C15H14BrO2 : 305.0172 (M++H), found: 305.0172
+
1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 7.8 Hz, 1H), 7.93 (d, J
= 8.2 Hz, 1H), 7.85 - 7.81 (m, 1H), 7.79 (dd, J = 10.7, 5.0 Hz,
2H), 7.56-7.53 (m, 1H), 6.97 (d, J = 8.9 Hz, 2H), 3.86 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ 161.3, 160.9, 151.7, 136.8, 135.4,
131.3, 129.7, 128.8, 126.5, 125.0, 120.3, 113.4, 100.6, 55.4;
(E)-3-(1-bromo-4-phenylbutylidene)isobenzofuran-1(3H)-one
(2k) (white oil, 46.6mg, 68%)
1H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 8.0 Hz, 1H), 7.95 (d, J
= 7.7 Hz, 1H), 7.77 - 7.72 (m, 1H), 7.59 (d, J = 7.5 Hz, 1H),
7.28-7.26 (m, 2H), 7.20-7.18 (m, 3H), 3.01 - 2.94 (m, 2H), 2.73 -
2.67 (m, 2H), 2.04-2.01 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
165.8, 142.9, 141.5, 137.8, 134.5, 130.1, 128.4 128.4, 125.9,
125.8, 125.6, 124.5, 113.6, 36.0, 34.9, 29.7; HRMS (ESI) calcd
HRMS (ESI) calcd for C16H12BrO3 : 330.9964 (M++H), found:
+
330.9963
(E)-3-(bromo(4-methoxyphenyl)methylene)-6-
+
methylisobenzofuran-1(3H)-one (2e) (yellow solid, 56.5 mg,
82%)
for C18H16BrO2 : 343.0328 (M++H), found: 343.0331
1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.80-7.78 (m, 3H),
7.62 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 7.7 Hz, 2H), 3.86 (s, 3H),
2.50 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.5, 160.8, 150.8,
139.3, 136.6, 134.4, 131.2, 129.4, 126.5, 125.1, 120.2, 113.4,
(E)-3-(1-bromopentylidene)isobenzofuran-1(3H)-one
(2l)
(yellow oil, 44.3 mg, 79%)
1H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 8.0 Hz, 1H), 7.92 (d, J
= 7.6 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H),
2.90 (t, J = 7.4 Hz, 2H), 1.68-1.62 (m, 2H), 1.40-1.37 (m, 2H),
0.94 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.8,
142.6, 137.8, 134.5, 129.9, 125.8, 125.6, 124.4, 114.3, 36.1, 30.1,
+
100.6, 55.3, 21.2; HRMS (ESI) calcd for C17H14BrO3 : 345.0121
(M++H), found: 345.0117
+
(E)-3-(bromo(4-methoxyphenyl)methylene)-5-
21.8, 13.8; HRMS (ESI) calcd for C13H14BrO2 : 281.0172
methylisobenzofuran-1(3H)-one (2f) (white solid, 53.7 mg, 78%)
1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.0 Hz, 1H), 7.77 (d, J
= 8.8 Hz, 2H), 7.72 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 6.98 (d, J =
8.9 Hz, 2H), 3.87 (s, 3H), 2.55 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 161.3, 160.8, 151.7, 146.7, 136.8, 131.3, 130.1, 129.8,
(M++H), found: 281.0171
(E)-3-(1-bromo-2, 2-dimethylpropylidene)isobenzofuran-1(3H)-
one (2m) (white solid, 42.6mg, 76%)
1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 8.1 Hz, 1H), 7.93 (d, J
= 7.6 Hz, 1H), 7.75 - 7.70 (m, 1H), 7.58-7.56 (m, 1H), 1.48 (s,

9H); 13C NMR (100 MHz, CDCl3) δ 165.8, 141.8, 139.3, 134.4,
4. Examples for the 5-exo-dig N-attacked cyclization of o-
ACCEPTED MANUSCRIPT
alkynylbenzamides, see: (a) Li, D. Y.; Shi, K. J.; Mao, X. F.; Zhao,
Z. L.; Wu, X. Y.; Liu, P. N. Tetrahedron, 2014, 70, 7022; (b) Hu,
J.; Wang, X.; Hu, Y.; Yang, S.; Liang, Y. Green Substainable
Chem. 2011, 1, 165; (c) Kanazawa, C.; Terada, M. Asian. J.
Chem., 2009, 4, 1668; (d) Kundu, N. G.; Khan, M. W.
Tetrahedron, 2000, 56, 4777.
129.9, 125.8, 125.5, 125.2, 124.7, 40.4, 30.8; HRMS (ESI) calcd
+
for C13H14BrO2 : 281.0172 (M++H), found: 281.0171
(E)-3-(1-bromoundecylidene)isobenzofuran-1(3H)-one
(2n)
(yellow oil, 59.0 mg, 81%)
1H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 8.0 Hz, 1H), 7.93 (d, J
= 7.6 Hz, 1H), 7.74 (t, J = 7.7 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H),
2.93 - 2.87 (m, 2H), 1.70 - 1.61 (m, 2H), 1.27-1.23 (m, 14H),
0.86 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 165.9,
142.6, 137.9, 134.5, 129.9, 125.8, 125.6, 124.4, 114.4, 36.3, 31.9,
29.5, 29.5, 29.3, 29.3, 28.6, 28.0, 22.6, 14.1; HRMS (ESI) calcd
5. For selected examples on 6-endo-dig O-attacked cyclization of
o-alkynylbenzamides, see: (a) Madich, Y.; Alvarez, R.;
Aurrecoechea, J. M. Eur. J. Org. Chem., 2015, 6298; (b) Ding,
D.; Mou, T.; Xue, J.; Jiang, X. Chem. Commun., 2017, 53,
5279.
6. For selected examples on electrophilic cyclization of o-
alkynylbenzamides, see: (a) Neto, J. S. S.; Back, D. F.; Zeni, G.
Eur. J. Org. Chem., 2015, 1583; (b) Mehta, S.; Yao, T.; Larock,
R. C. J. Org. Chem., 2012, 77, 10938; (b) Schlemmer, C.;
Andernach, L.; Schollmeyer, D.; Straub, B. F.; Opatz, T. J.
+
for C19H26BrO2 : 365.1111 (M++H), found: 365.1100
(E)-3-(iodo(phenyl)methylene)isobenzofuran-1(3H)-one
(2o)
(yellow oil, 34.0 mg, 49%)12a
Org. Chem., 2012, 77, 10118.
1H NMR (400 MHz, CDCl3) δ 8.93 (d, J = 8.0 Hz, 1H), 7.96 (d, J
= 7.6 Hz, 1H), 7.84-7.80 (m, 1H), 7.66-7.62 (m, 1H), 7.56 (d, J =
7.6 Hz, 2H), 7.39 (t, J = 7.2 Hz, 2H), 7.32-7.29 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 165.5, 144.3, 140.0, 138.4, 134.3,
130.8, 130.1, 130.0, 129.0, 128.1, 126.0, 125.8, 124.9, 80.4
7. Transition metal-catalyzed 5-exo-dig O-attacked cyclization of
2-alkynylbenzamides, see: (a) Madich, Y.; Alvarez, R.;
Aurrecoechea, J. M. Eur. J. Org. Chem., 2014, 6263; (b)
Schlemmer, C.; Andernach, L. ; Schollmeyer, D.; Straub, B. F.;
Opatz, T. J. Org. Chem., 2012, 77, 10118; (c) Jithunsa, M.; Ueda,
M.; Miyata, O. Org. Lett., 2011, 13, 518; (d) Mancuso, R.;
Ziccarelli, I.; Armentano, D.; Marino, N.; Giofre, S. V.; Gabriele,
B. J. Org. Chem., 2014, 79, 3506; (e) Yao, B.; Jaccoud, C.; Wang,
Q.; Zhu, J. Eur. J. Chem., 2012, 18, 5864; (f) Yan, Z.-Y.; Tan,
C.-M.; Wang, X.; Li, F.; Cao, G.-L.; Chen, X.-M.; Wu, W.-S.;
Wang, J.-J. Synlett, 2011, 1863; (g) Bantreil, X.; Bourderioux, A. ;
Mateo, P.; Hagerman, C. E.; Selkti, M.; Brachet, E.; Belmont, P.
Org. Lett., 2016, 18, 4814.
4-(hydroxyl(phenyl)methyl)phthalazin-1(2H)-one 4 (light yellow
solid, 89%, 55.9 mg)
1H NMR (400 MHz, DMSO) δ 12.58 (s, 1H), 8.22-8.20 (m, 1H),
8.08-8.06 (m, 1H), 7.74-7.72 (m, 2H), 7.43-7.41 (d, J = 7.6 Hz,
2H, )7.32-7.28 (m, 2H), 7.21-7.17 (m, 1H), 6.46 (d, J = 4.8 Hz,
1H), 5.97 (d, J = 4.8 Hz, 1H). 13C NMR (100 MHz, DMSO) δ
159.9, 147.8, 142.8, 133.2, 131.6, 128.7, 128.6, 127.4, 126.9,
8. For selected examples, see: (a) Sandro, C.; Giancarlo, F.; Fabio,
M.; Leonardo, M.; Paola, P. Synlett., 1997, 1363; (b) Kraus, G.;
Wu, T. Tetrahedron, 2005, 61, 9502.
+
126.3, 126.2, 74.3; HRMS (ESI) calcd for C15H13N2O2 :
9. (a) Saito, T.; Ogawa, S.; Takei, N.; Kuttsumura, N.; Otani, T.; Org.
Lett., 2011, 13, 1098; (b) Lee, W.-C.; Shen, H.-C.; Hu, W.-P.; Lo,
W.-S.; Murali, C.; Vandavasi, J. K.; Wang, J.-J. Adv. Synth. Catal.,
2012, 354, 2218; (c) Sinai, A.; Meszaros, A.; Gati, T.; Kudar, V.;
Pallo, A.; Novak, Z. Org. Lett., 2013, 15, 5654; (d) Stein, A.;
Bilheri, F.; Back, D.; Zeni, G. Adv. Synth. Catal., 2014, 356, 501;
(e) Cai, Z.-J.; Yang, C.; Wang, S.-Y.; Ji, S.-J. Chem. Commun.,
2015, 51, 14267; (f) Vandanvasi, J. K.; Kuo, K.-K.; Wu, W.-P.;
Shen, H.-C.; Lo, W.-S.; Wang, J.-J. Org. Biomol. Chem. 2013, 11,
6520.
253.0972 (M++H), found: 253.0975
(E)-3-(phenyl(p-tolyl)methylene)isobenzofuran-1(3H)-one,
5
(sticky yellow solid, 76%, 47.2 mg)12c
1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 7.6 Hz, 1H), 7.93 (d, J
= 7.6 Hz, 2H), 7.35-7.25 (m, 9H), 6.42 (d, J = 8.0 Hz, 1H), 2.48
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.1, 142.3, 139.6,
138.6, 137.6, 134.5, 133.8, 130.4, 130.3, 130.0, 129.3, 128.1,
128.0, 125.1, 124.8, 123.6, 21.4
10. (a) Su, C.-F.; Hu, W.-P.; Vandavasi, J. K.; Liao, C.-C.; Hung, C.-
Y.; Wang, J.-J. Synlett, 2012, 23, 2132; (b) Xie, P.; Wang, Z.-Q.;
Deng, G.-B.; Song, R.-J.; Xia, J.-D.; Li, J.-H. Adv. Synth. Catal.,
2013, 355, 2257.
Acknowledgments
11. Iodocyclization of o-alkynylbenzoates: (a) Yao, T.; Larock, R. C.
J. Org. Chem. 2003, 68, 5936; (b) Yao, T.; Larock, R. C.
Tetrahedron Lett. 2002, 43, 7401; (c) Mehta, S.; Waldo, J. P.;
Larock, R. C. J. Org. Chem. 2009, 74, 1141; (d) Peuchmaur, M.;
Lisowski, V.; Gandreuil, C.; Maillard, L. T.; Martinez, J.;
Hernandez, J.-F. J. Org. Chem. 2009, 74, 4158; (e) Verma, A. K.;
Rustagi, V.; Aggarwal, T.; Singh, A. P. J. Org. Chem. 2010, 75,
7691; (f) Verma, A. K.; Aggarwal, T.; Rustagi, V.; Larock, R. C.
Chem. Commun. 2010, 46, 4064.
12. (a) Wang, R.-X.; Yuan, S.-T.; Liu, J.-B.; Wu, J.; Qiu, G. Org.
Biomol. Chem. 2018, 16, 4501; (b) Yuan, S.-T.; Zhou, H.; Gao, L.;
Liu, J.-B.; Qiu, G. Org. Lett. 2018, 20, 562; (c) Wang, Y.-H.; Liu,
J.-B.; Ouyang, B.; Zhou, H.; Qiu, G. Tetrahedron 2018, 74, 4429;
(d) Qiu, G.; Li, Y.; Ma, L.; Zhou, H. Org. Chem. Front. 2017, 4,
Financial supports from the Natural Science Foundation of
China (Nos: 21502069 and 21772067) and China postdoctoral
science foundation (2018M630396) is gratefully acknowledged.
References and notes
1. For selected reviews, see: (a) Boyarskiy, V. P.; Ryabukhin, D.
S.; Bokach, N. A.; Vasilyev, A. V. Chem. Rev., 2016, 116,
5894; (b) Zheng, Z.; Wang, Z.; Wang, Y.; Zhang, L. Chem.
Soc. Rev., 2016, 45, 4448; (c) Yoshida, H. ACS Catal., 2016, 6,
1799; (d) Pirnot, M.; Wang, Y.-M.; Buchwald, S. Angew.
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Chinchila, R.; Najera, C. Chem. Rev., 2014, 114, 1783; (h) Luo,
Y. X.; Pan, X.; Yu, X.; Wu, J. Chem. Soc. Rev., 2014, 43, 834;
(i) Fuerstner, A. Angew. Chem., Int. Ed., 2013, 52, 2794; (j) X.-
F. Wu, J.-L. Gong, X. Qi, Org. Biomol. Chem. 2014, 12, 5807;
(k) X.–F. Wu, Chem. Rec. 2015, 15, 949
2. For the selected reviews on applications of dual function synthons,
see: (a) Wang, H.; Kuang, Y.; Wu, J. Asian J. Org. Chem. 2012, 1,
302; (b) Qiu, G.; Wu, J. Chem. Rec. 2016, 16, 19; (c) Qiu, G.; Wu,
J. Synlett 2014, 25, 2703; (d) He, L.; Nie, H.; Qiu, G.; Gao, Y.;
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Chem. 2010, 12, 1397.
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B 1988, 27, 380; (b) Bellina, F.; Biagetti, M.; Carpita, A.; Rossi,
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6
Tetrahedron
16. (a) Gadakh, S. K.; Sudalai, A. RSC Adv. 2014, 4, 57658; (b)
Supplementary Material
ACCEPTED MANUSCRIPT
Dussart, N.; Trinh, H. V.; Gueyrard, D. Org. Lett. 2016, 18, 4790.
17. Monsieurs, K.; Tapolcsanyi, P.; Loones, K. T. J.; Neumajer, G.;
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18. Hussain, H.; Green, I. R.; Ahmed, I. Chem. Rev. 2013, 113, 3329.
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
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office.