Lactonization of 2-Alkynylbenzoates for the Assembly of Isochromenones Mediated by BF3·Et2O

Article abstract of DOI:10.1021/acs.joc.9b01601

A general and efficient lactonization method of readily available 2-alkynylbenzoates affording biologically important isochromenones has been realized via a solely BF₃·Et₂O-mediated 6-endo-dig cyclization process under mild condition

Full text of DOI:10.1021/acs.joc.9b01601

Subscriber access provided by UNIV OF SOUTHERN INDIANA
Article
Lactonization of 2-Alkynylbenzoates for the
Assembly of Isochromenones Mediated by BF3•Et2O
Xiang Zhang, Xintong Wan, Ying Cong, Xiaohua Zhen,
Qiao Li, Daisy Zhang-Negrerie, Yunfei Du, and Kang Zhao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01601 • Publication Date (Web): 22 Jul 2019
Downloaded from pubs.acs.org on July 24, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
Lactonization of 2-Alkynylbenzoates for the Assembly of Isochromenones
Mediated by BF3•Et2O
8
9
Xiang Zhang,† Xintong Wan,† Ying Cong,† Xiaohua Zhen,† Qiao Li,† Daisy Zhang-Negrerie,†
Yunfei Du*,†,‡ and Kang Zhao*,†
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
† Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of
Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
‡ Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin
300072, China
O
BF3
O
O
OR2
H2O or AcylCl
O
OR2
BF3 Et2O
R
R
R
R1
27 examples
up to 99% yield
R1
R3
R1
R3 = H, D or Acyl
Applications (one to three steps):
O
O
O
O
O
Br
O
O
Br
Br
O
O
N
O
H
Abstract: A general and efficient lactonization of readily available 2-alkynylbenzoates
affording biologically important isochromenones has been realized via a solely
BF3•Et2O-mediated 6-endo-dig cyclization process under mild conditions. An alternative
mechanistic pathway in which BF3•Et2O activates the carbonyl of the ester moiety, rather
than the alkyne triple bond, was postulated on the basis of control experiment results.
Gram-scale reaction and further application for the assembly of more complex molecules
demonstrated the practicability of the protocol.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 40
1
2
3
4
INTRODUCTION
5
6
7
8
The isochromenone framework is found in numerous naturally occurring and artificially
synthesized compounds with various bioactivities1 including antiallergic and antimicrobial,2,3
immunomodulatory,4 cytotoxic,5 antifungal,6 anti-inflammatory,7 and anti-angiogenic8 effects.
Due to the biological importance of isochromenone compounds, numerous synthetic methods
have been developed for the assembly of this privileged skeleton. A survey of the literature
indicated that this class of compounds is generally derived from homophthalic acid,9 arynes,10
2-(2',2'-dibromovinyl)benzoates,11 1,3-diketones,12 2-(2-oxopropyl) benzaldehydes13 and
benzoic acids,14,15 via condensation transformation,9 CO2-insertion,10 palladium-catalyzed
cyclization,11 Ullmann-type coupling−rearrangement,12 iridium-catalyzed oxidative
lactonization,13 thallation-olefination,14 or Rh(III)-catalyzed oxidative coupling.15 It is
apparent that the above approaches have their respective merits in synthesizing the
corresponding isochromenone compounds bearing various substituents. However, the usage
of transition metals or harsh reaction conditions is a prerequisite in many cases.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Among the synthetic strategies, the 6-endo-dig cyclization reaction of 2-alkynylbenzoates,
generally via activation of the triple bond, is an efficient protocol for construction of the
isochromenone skeleton. In general, these methods can be categorized into the following
types: a) protic acid-mediated lactonization approaches via activation of the internal alkyne
subunit, furnishing two types of cyclic products (Scheme 1a);16 b) transition metal-catalyzed
carboxylation leading to the formation of 6- or 5-membered lactones with high selectivity and
reactivity, generally accompanied by the use of complex ligands (Scheme 1b);17-24,26a c) E+
ACS Paragon Plus Environment

Page 3 of 40
The Journal of Organic Chemistry
1
2
3
4
5
Scheme 1. BF3•Et2O-Mediated Lactonization Reactions of 2-Alkynylbenzoates
6
7
a) Acids catalysis16
OR2
8
9
CO2R2
O
O
Protic acids
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
+
R1
R1
R1
H+
R1
Protic acids
: p-TsOH, CF3CO2H, etc.
b) Transition metal-catalyzed carboxylations11,17-24,26a
O
CO2R2
CO2R2
LA
O
Lewis acid
O
O
+
R1
R1
Lewis acids
R1
: Pd,11 Au,17 Hg,18 Ir,19 Pt,20 Ag,21 Fe,22 Cu,23 Re24...
c) E+ sources induced intramolecular cyclizations25,26b
R1
O
O
CO2R2
R1
CO2R2
E+ source
O
O
+
R1
E = Cl, Br, I
+
E
R1
R1
E
E
d) Electrophilic oxyboration reaction27
OR2
O
O
CO2R2
pinacol
or H2O
ClBcat
O
O
O
toluene, 100 oC
R1
R1
R1
R1
[B]
Bcat
Bcat
e) This work: Controllable stepwise lactonization and functinaliaztion
O
O
OR2
BF3 Et2O/H2O
- R2OH
O
R
R
R1
R1
2
1
BF3 Et2O
R2COCl
BF3 Et2O
H2O
O
BF3
F3B
O
O
O
R2
R2
O
R3COCl
OR2
-BF3
R
O
O
R
R
R1
R
R1
O
R3
R1
R1
B
C
A
4
source (NCS, NBS, NIS)-induced intramolecular cyclization providing the corresponding
halogenated isochromenone from the alkyne reacting with the electrophile (Scheme 1c);25,26b
Notably, the cylization reactions carried out in ionic liquids, namely, Mor1,2N(CN)2
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 40
1
2
3
4
5
6
7
8
9
(5-exo-dig) or EmimEtSO4 (6-endo-dig) demonstrated promising chemoselectivity.26 d)
electrophilic oxyboration of 2-alkenyl benzoates affording a variety of borylated 6-membered
lactones (Scheme 1d).27
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
It is evident that nearly all of the crucial steps in the above existing methods involve
activation of a triple bond via either protic acid, Lewis acid, or electrophile for the cyclization
to occur, and the reactions undergo a collaborative process to form either C3 functionalized
or C3,C4 difunctionalized isochromenones. Notably, nearly all of the Lewis acids applied to
this transformation have been transition metals. To the best of our knowledge, BF3•Et2O, a
commonly used Lewis acid, has seldom been reported for this class of lactonization
reaction.28 In this communication, we report that BF3•Et2O alone efficiently enables a
controllable stepwise lactonization of 2-alkynylbenzoates with high selectivity. Differing
from previous transition metal-mediated mechanistic models, an alternative lactonization
pathway in which BF3•Et2O activates the ester group rather than the alkyne moiety is
tentatively proposed (Scheme 1e).
RESULTS AND DISCUSSION
At the outset of the study, we treated readily available 2-alkynylbenzoate 1ab with
BF3•Et2O to investigate whether the lactonization reaction29 would occur to afford either the
5-exo-dig or 6-endo-dig product. When 1ab was treated with 1.0 equiv of BF3•Et2O in
dichloroethane (DCE), the reaction gave a mixture of isochromenone product 2a and
benzofuran 3a in an 87:3 ratio (Table 1, entry 1). Increasing the amount of catalyst apparently
improved the reaction efficiency, leading to the formation of products 2a and 3a in a 95:5
ratio (Table 1, entry 2). It was further confirmed that the reactivity could be equally improved
ACS Paragon Plus Environment

Page 5 of 40
The Journal of Organic Chemistry
1
2
3
4
5
Table 1. Optimization of the BF3•Et2O-Mediated 6-endo-dig Cyclization of
6
7
2-Alkynylbenzoatesa
8
9
O
CO2Me
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Conditions
O
+
O
Ph
Ph
Ph
1ab
2a
3a
Yield(%)of
Entry Catalyst (equiv)
Solvent
T (oC)
Time (h)
2a:3a
1
BF3•Et2O (1)
BF3•Et2O (3)
BF3•Et2O (1)
BF3•Et2O (0.2)
BF3•Et2O (1)
BF3•Et2O (1)
BF3•Et2O (1)
AcOH (1)
DCE
DCE
DCE
DCE
THF
MeCN
DMF
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
rt
rt
72
24
8
87 : 3
95 : 5
95 : 5
95 : 5
95 : 5
95 : 5
95 : 5
NR
2
3b
4c
5
80
80
48
12
24
24
24
24
24
5
80
6
80
7
80
8
80 to 100
80 to 100
80 to 100
80
9
TFA (1)
NR
10
11
12
13
14
15
TsOH (1)
NR
TMSOTf (1)
CuO (1)
78:4
NR
rt to 120
rt to 120
rt to 120
rt to 120
rt to 120
24
24
24
24
24
CuI (1)
NR
PdCl2 (1)
NR
FeCl3 (1)
61:2
NR
16
AgCl (1)
a
Reaction conditions: substrate 1ab (0.4 mmol), catalyst (0.4 mmol) in solvent
b
(4 mL) until total consumption of the substrate unless stated otherwise. The
c
reaction was carried out with 1.2 mmol of BF3•Et2O. The reaction was carried
out with 80 μmol of BF3•Et2O.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 40
1
2
3
4
5
6
7
8
9
with one equivalent of BF3•Et2O and an increase in the reaction temperature (Table 1, entry
3). Catalytic amount of BF3•Et2O resulted in same result with a relatively lower reactivity
(Table 1, entry 4). Solvent optimization indicated that changing the solvent to THF, MeCN,
or DMF, was not beneficial for the outcome of the reaction (Table 1, entries 5-7). Further
screening of catalysts indicated that Brønsted acids (AcOH, TFA, TsOH) were ineffective for
this transformation (Table 1, entries 8-10). The transformation was also realized by changing
BF3•Et2O to TMSOTf, another commonly used Lewis acid, albeit in inferior yield (Table 1,
entry 11). Taking into consideration that 1ab might undergo a similar transition-metal
catalyzed cyclization, we evaluated catalysts including CuO, CuI, Pd, Fe, and Ag for this
selective lactonization reaction. While FeCl3 converted the substrate to the desired product, in
reactions with other metal catalysts, the desired product was not detected even after heating
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
to 120 C (Table 1, entries 12-16). The optimal conditions were finally confirmed to be: 1.0
o
equiv of substrate with 1.0 equiv of BF3•Et2O in DCE at 80 C, to obtain the 6-endo-dig
product 2a in 95% yield (Table 1, entry 3).
Further study with the carboxyl moiety indicated that 2-alkynylbenzoic acid and other
2-alkynylbenzoate substrates (R = Et, iPr, Ph) were equally amenable to this selective
lactonization reaction (Table 2, entries 1-5). Notably, the methyl benzoate was more reactive
than the acid-type and more sterically hindered substrates, as shorter reaction times ensured
complete consumption of the substrate and a high yield of the desired product (Table 2, entry
2).
ACS Paragon Plus Environment

Page 7 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
Table 2. Reaction Comparison between 2-Alkynylbenzoic Acid and 2-Alkynylbenzoate
Substratesa
8
9
O
O
CO2R
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
BF3•Et2O
O
O
+
DCE, 80 ºC
Ph
Ph
Ph
1
2a
3a
Yield(%)
of 2a
Yield(%)
of 3a
Entry
Substrate 1
R
Time (h)
1
1aa
1ab
1ac
1ad
1ae
H
12
8
95%
5%
2
Me
Et
95%
96%
41%
95%
5%
4%
2%
5%
3c
4
12
>72
36
iPr
Ph
15
a
Reaction conditions: substrate 1 (0.4 mmol), BF3•Et2O (0.4 mmol) in DCE (4
mL) until total consumption of the substrate unless stated otherwise..
Utilizing the optimal conditions, we investigated the scope and limitations of the newly
established regioselective BF3•Et2O-mediated lactonization reaction. The electronic nature of
substituents on the benzoate ring was first studied. It was found that substrates bearing either
electron-donating (MeO, Me) or electron-withdrawing groups (F, Br) on the benzene ring
exhibited high reactivities, affording the desired products in excellent yields (Scheme 2, 2a-e).
Much to our delight, the method was also applicable to a gram-scale reaction of 1ab (6
mmol), which resulted in synthesis of product 2a in 86% yield using catalytic amount of
BF3•Et2O (1 mmol) in DCE (15 mL). Next, variation of the R1 substituent indicated that
substrates with R1 representing a phenyl ring bearing a methoxyl or bromo group or a
naphthyl ring were equally effective for the transformation, furnishing the desired products 2f,
2g, and 2i in high yields. However, reaction of the substrate bearing a 3,4-dichlorophenyl ring
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 40
1
2
3
4
5
6
7
Scheme 2. Scope Study of the BF3•Et2O-Mediated Conversion of 2-Alkynylbenzoates 1
to Isochromenones 2a,b
8
9
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
BF3•Et2O, DCE
80 oC
OMe
R1
O
R
R
R1
2
1
O
O
O
O
Me
F
O
O
O
O
Ph
MeO
Ph
Ph
Ph
2a
2b
2c
2d
4 h, 93%
10 h, 96%
10 h, 97%
8 h, 95%
10 h, 86%c
O
O
O
O
O
O
O
Br
Cl
Cl
O
Ph
OMe
Br
2e
2f
2g
2h
4 h, 93%
2 h, 94%
5 h, 94%
12 h, 74%
O
O
O
O
O
O
TsHN
2j
4 h, 99%
HO
2i
4 h, 96%
2k
4 h, 99%
O
O
O
O
O
O
O
S
O
OH
Ph
MeOOC
2l
10 h, 88%
Br
2n
2o
2m
2 h, 98%
8 h, 81%
2 h, 89%
aSubstrate 1 (0.4 mmol), BF3•Et2O (0.4 mmol) in DCE (4 mL) until total consumption of the
b
c
substrate unless stated otherwise. Yield of product 2 after column chromatography. Yield
of gram-scale reaction.
1h resulted in a relatively lower yield of 74% due to formation of more five-membered
byproduct. In addition, tosylamide/ester/phenol substituents on the phenyl ring of the R1
ACS Paragon Plus Environment

Page 9 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
substituent were well tolerated in these conversions, affording the corresponding
isochromenones in nearly quantitative yields (Scheme 2, 2j-l). Replacement of the aryl group
with a cyclopropyl group smoothly led to formation of isochromenone 2m in 89% (Scheme 2,
2m). It is noteworthy that a terminal hydroxyl group also survived the reaction conditions
affording the desired product 2n in nearly quantitative yield. Furthermore, the phenyl ring
could be replaced with a thiophene ring to afford the corresponding lactone 2o in 81% yield.
During further studies on product diversity using this strategy, we found that when R2 was
a t-butyl or TMS group, the reaction underwent highly selective 5-exo-dig cyclization to give
3p or 3q as the sole product, respectively (Scheme 3). Interestingly, the TMS group was
removed during the cyclization process under the reaction conditions in this special case. We
tentatively propose that these results might suggest that the reaction may go through the
alkyne-activation pathway (Scheme 1a/b) to generate 5-membered products once the
6-endo-dig cyclization pathway was blocked by the steric hindrance of the terminal bulky
substituent.30
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Investigation of the Steric Effect with 2-Alkynylbenzoate Substrates
O
O
O
OMe
BF3•Et2O, DCE
O
O
+
+
80 oC, 2 h
1p
2p
3p
, 0%
O
, 85%
O
O
BF3•Et2O, DCE
80 oC, 30 h
OMe
O
O
SiMe3
1q
2q
3q
, 87%
, 0%
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 40
1
2
3
4
5
6
7
8
9
Furthermore, we found that substrate 1r, in which a methoxyl group on the benzoate ring is
para-substituted to the alkyne moiety, subjected to the reaction conditions afforded the
6-membered 2r and the 5-membered 3r in 15% and 81%, respectively. The substrate bearing
a para-nitro phenyl substituent afforded the 6-membered 2s and 5-membered 3s in 32% and
49% yield, respectively (Scheme 4).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Electronic Control of Substituents in the Substrate to Study the Selectivity of
the Lactonization
O
O
O
MeO
MeO
OMe BF3•Et2O
Ph
O
O
MeO
+
a)
Ph
1r
2r
3r
, 15%
, 81%
Ph
BF3
O
unfavored
favored
BF3
BF3
BF3
O
O
MeO
MeO
MeO
OMe
OMe
OMe
Ph
Ph
D
E
F
Ph
O
O
O
O
BF3•Et2O
O
OMe
BF3
+
b)
NO2
NO2
2s
3s
, 32%
, 49%
favored
BF3
1s
NO2
unfavored
BF3
BF3
O
O
O
OMe
OMe
OMe
BF3
O
O BF3
O BF3
N
O
G
I
N
O
H
N
O
favored
unfavored
ACS Paragon Plus Environment

Page 11 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Based on the above experimental results, we tentatively propose an alternative mechanistic
pathway for this selective lactonization process. Firstly, activation of the carbonyl group by
BF3•Et2O gives intermediate A, which equals to its resonance forms B though conjugation
(Scheme 1e). We tentatively propose that the intramolecular O-attack of the ester oxygen to
the alkenyl cation with simultaneous conjugation gives an ylide intermediate C, which reacts
with H2O during the work-up to give the final product. While for the special cases of
substrates 1r and 1s, due to the strong electron-donating effect of the methoxy group and the
electron-withdrawing effect of the nitro group, the alkenyl cation intermediates E and H were
less stable than the corresponding intermediates F and I, respectively. Thus the reaction
adopted alternative pathways to give the more favorable 5-membered products 3r and 3s
(Scheme 4).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In order to further corroborate the proposed reaction mechanism, we carried out some
control experiments. Subjecting substrate 1af, a benzyl analogue of 1ab, to the standard
conditions provided the isochromenone 2a in 32% yield, with the simultaneous isolation of
benzyl alcohol in 32% yield (Scheme 5, a). Furthermore, we proved that water is necessary
for the process by quenching the reaction with D2O, which generated the deuterated product
2a' in 35% yield (Scheme 5, b). The results of the above two control experiments support the
postulated reaction mechanism.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 40
1
2
3
4
5
Scheme 5. Control Experiments with the Benzyl Ester and Isotope Exchange Study
6
7
8
9
O
O
OBn
BF3•Et2O, DCE
a)
O
BnOH
32%
+
80 oC, 2 h
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aqueous work-up
Ph
2a
, 32%
1af
O
O
O
O
BF3•Et2O, DCE
OMe
O
b)
+
Sealed tube
80 oC, 24 h
then D2O
Ph
Ph
Ph
D
1ab
2a'
2a
, 86%
, 9%
With a better understanding of the reaction mechanism, we set out to investigate whether
the method could be applied to the synthesis of other isochromenone derivatives, as one
could easily conceive that the potential intermediate C might be captured by electrophiles.
When acetyl chloride 5a was added to the reaction system to investigate whether a follow-up
acylation reaction would occur, as expected the corresponding 4-acetyl isochromenone 4a
was obtained in 94% yield (Scheme 6a, 4a). Parallel studies indicated that longer aliphatic
acyl chlorides slowed down the cascade process, accompanied by the comparable formation
of byproduct 2a, thus leading to poor yields of the desired products 4b and 4c (Scheme 6a, 4b
and 4c). Notably, benzoyl chloride 5d was also effective for the conversion of 1a into 4d in
good yield (Scheme 6a, 4d). Further replacement of 5a with aromatic carbonyl and
cinnamoyl chlorides 5e and 5f showed the possibility for more complex acyl groups at the C4
position of isochromenones under the lactonization-acylation cascade conditions (Scheme 6a,
4e and 4f). More interestingly, treating isochromenone 2a with acetyl chloride under the
reaction conditions for 12 h led to no formation of product 4a. The above results further
support the proposed mechanism based on the following fact: acylation did not occur from
ACS Paragon Plus Environment

Page 13 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
the reaction between the isolated isochromenone and acetyl chloride, but might result from
consumption of the proposed intermediate C by acetyl chloride. It is worth noting that the
reaction between substrate 1t and BF3•Et2O in the presence of triphosgene led to the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
formation of
3-bromo-6H-isochromeno[4,3-c]quinoline-6,11(12H)-dione 4t in excellent
yield (Scheme 6b).
Scheme 6. Synthesis of 4-Acyl isochromenones
O
O
O
Me
Ph
3
O
O
5
OMe
BF3•Et2O, R COCl ( )
O
a)
DCE, 80 oC, 4-24 h
Ph
Ph
C
O
R3
1ab
4
O
O
O
O
O
O
O
Ph
Ph
Ph
Ph
O
O
O
O
4c
24 h, 38%
4a
4h, 94%
4b
24 h, 56%
4d
24 h, 78%
O
O
O
standard
conditions
O
Ph
Ph
O
O
O
O
OMe
Ph
4e
4f
2a
24 h, 62%
24 h, 58%
O
O
O
OMe
BF3•Et2O, DCE
b)
Br
Br
Triphosgene, 80 oC
4 h, 87%
O
N
H
H2N
1t
4t
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 40
1
2
3
4
5
6
7
8
9
In addition, the extensive tolerance of R1 group could be further used for manipulation of
the isochromenone products (Scheme 7). For example, product 2l, with a methoxycarbonyl
subunit at the ortho position, after being transferred to the corresponding carboxylic acid
intermediate 5l, could undergo either an intramolecular Fridel-Crafts acylation or a
spirocyclization reaction to generate the novel 9-bromoindeno[1,2-c]isochromene-5,11-dione
6l or 5-bromo-3H-spiro[isobenzofuran-1,3'-isochroman]-1',3-dione 7l in 75% and 53% yields,
respectively.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 7. Construction of Complex Isochromenone Derivatives
O
O
BF3•Et2O, DCE
80 oC, 10 h
O
O
NaOH (aq), MeOH
40 oC, 4 h
53% over 2 steps
then, 1 M HCl
HO2C
Br
MeO2C
2l
Br
5l
SOCl2, DCM, rt, 1 h
75% over 2 steps
O
O
O
Br
O
O
O
O
Br
6l
7l
CONCLUSION
In conclusion, we have reported an exclusive BF3•Et2O-mediated regioselective
lactonization reaction of 2-alkynylbenzoates, leading to selective formation of
isochromenones in good to excellent yields. A different mechanistic pathway involving
activation of the carbonyl of the ester moiety, rather than the triple bond, was postulated.
Related isobenzofuranone products were also generated through control of the electronic
ACS Paragon Plus Environment

Page 15 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
nature and steric effect of substituents. Furthermore, the method could find application to the
controllable syntheses of C3,C4 difunctionalized isochromenones and many other complex
derivatives. Further studies on the reaction mechanism and the application of the method are
in progress in our lab.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
EXPERIMENTAL SECTION
I. General Information
13
o
1H and C NMR spectra were recorded on a 600, 400 or 300 MHz spectrometer at 25 C.
Chemical shifts values are given in ppm and referred as the internal standard to TMS: 0.00
ppm. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, br = broad, m = multiplet). The coupling constants J, are reported in Hertz
(Hz). High resolution mass spectrometry (HRMS) was obtained on a Q-TOF micro
spectrometer. Melting points were determined with a Micromelting point apparatus. TLC
plates were visualized by exposure to ultraviolet light. Reagents and solvents were purchased
as reagent grade and were used without further purification. Flash column chromatography
was performed over silica gel (200-300 m) using a mixture of ethyl acetate (EtOAc) and
petroleum ether (PE).
II. Preparation of Substrates 1
General Procedure:31 Under an atmosphere of nitrogen, aryliodide (10 mmol) and the
alkyne compound (12 mmol) were dissolved in triethylamine (7 mol, 50 mL) at room
temperature in a flask with a magnetic stirring bar. Then PdCl2(Ph3P)2 (0.1 mmol, 72 mg) and
o
CuI (0.1 mmol, 19 mg) were added sequentially and the mixture was stirred at 80 C
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 40
1
2
3
4
5
6
7
8
9
(temperature of oil bath) for 1-18 h. After consumption of the aryliodide, the resulting
mixture was filtered through a short pad of silica gel (30 g) and the filtrate was extracted with
EtOAc (3 x 100 mL). The combined organic phases were dried over anhydrous Na2SO4 and
evaporated under reduced pressure to remove the solvent. The given residue was purified by
flash chromatography using a mixture of EtOAc and PE as eluent to provide the intermediate
1. It is worth noting that 1j was obtained through the method developed in our previous
work.32
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
The properties and H NMR data of 1aa−d,27,33,34 1f,34 1g,34 1k,32 1m,35 1o,35 1q,27 1s34 and
1t32 were in consistent with those in our previous work. Other compounds were characterized
as follows:
Phenyl 2-(phenylethynyl)benzoate (1ae). Following the general procedure, 1ae was purified
by silica gel chromatography (5% EtOAc/PE). Yield: 2.70 g, 91%, white solid, mp. 84–85 oC.
1H NMR (600 MHz, CDCl3) δ 8.16 (d, J = 7.9 Hz, 1H), 7.71 (d, J = 7.7 Hz, 1H), 7.56 (td, J =
13
7.6, 1.3 Hz, 1H), 7.52 – 7.47 (m, 2H), 7.46 – 7.40 (m, 3H), 7.32 – 7.24 (m, 6H). C {1H}
NMR (150 MHz, CDCl3) δ 164.7, 151.0, 134.3, 132.3, 131.9, 131.1, 131.1, 129.5, 128.6,
128.3, 128.0, 125.9, 124.4, 123.2, 121.8, 95.1, 88.1. HRMS (ESI) calcd for C21H15O2 [M +
H]+ 299.1067, found 299.1069.
Benzyl 2-(phenylethynyl)benzoate (1af). Following the general procedure, 1af was purified
by silica gel chromatography (5% EtOAc/PE). Yield: 2.81 g, 90%, pale yellow oil. 1H NMR
(600 MHz, CDCl3) δ 8.02 (d, J = 7.9 Hz, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.50 (t, J = 7.6 Hz,
1H), 7.46 (d, J = 6.0 Hz, 2H), 7.43 (d, J = 7.7 Hz, 2H), 7.38 (t, J = 7.7 Hz, 1H), 7.35 – 7.29
(m, 6H), 5.41 (s, 2H). 13C {1H} NMR (150 MHz, CDCl3) δ 166.2, 135.9, 134.2, 131.8, 131.8,
ACS Paragon Plus Environment

Page 17 of 40
The Journal of Organic Chemistry
1
2
3
4
5
131.7, 130.7, 128.6, 128.5, 128.4, 128.3, 128.2, 127.9, 123.8, 123.3, 94.5, 88.3, 67.1. HRMS
6
7
+
(ESI) calcd for C22H17O2 [M + H]+ 313.1223, found 313.1221.
8
9
Methyl 4-methoxy-2-(phenylethynyl)benzoate (1b). Following the general procedure, 1b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
was purified by silica gel chromatography (10% EtOAc/PE). Yield: 2.34 g, 88%, pale yellow
1
oil. H NMR (600 MHz, CDCl3) δ 7.97 (d, J = 8.8 Hz, 1H), 7.59 (dt, J = 4.4, 2.5 Hz, 2H),
7.38 – 7.32 (m, 3H), 7.12 (d, J = 2.7 Hz, 1H), 6.88 (dd, J = 8.8, 2.7 Hz, 1H), 3.92 (s, 3H),
13
3.85 (s, 3H). C {1H} NMR (150 MHz, CDCl3) δ 166.2, 162.1, 132.7, 131.8, 128.6, 128.4,
125.7, 124.1, 123.3, 118.4, 114.4, 94.3, 88.5, 55.6, 51.9. HRMS (ESI) calcd for C17H15O3 [M
+ H]+ 267.1016, found 267.1015.
Methyl 5-methyl-2-(phenylethynyl)benzoate (1c). Following the general procedure, 1c was
purified by silica gel chromatography (5% EtOAc/PE). Yield: 2.30 g, 92%, pale yellow oil.
1H NMR (600 MHz, CDCl3) δ 7.79 (s, 1H), 7.56 (dd, J = 7.8, 1.6 Hz, 2H), 7.53 (d, J = 7.9 Hz,
1H), 7.37 – 7.32 (m, 3H), 7.30 (dd, J = 7.9, 1.1 Hz, 1H), 3.96 (s, 3H), 2.40 (s, 3H). 13C {1H}
NMR (150 MHz, CDCl3) δ 166.9, 138.2, 133.9, 132.6, 131.7, 131.7, 131.1, 128.3, 123.5,
120.7, 93.5, 88.4, 52.2, 21.3. HRMS (ESI) calcd for C17H15O2 [M + H]+ 251.1067, found
251.1068.
Methyl 5-fluoro-2-(phenylethynyl)benzoate (1d). Following the general procedure, 1c was
1
purified by silica gel chromatography (10% EtOAc/PE). Yield: 2.16 g, 85%, yellow oil. H
NMR (600 MHz, CDCl3) δ 7.68 (dd, J = 9.2, 2.8 Hz, 1H), 7.63 (dd, J = 8.6, 5.4 Hz, 1H), 7.58
– 7.55 (m, 2H), 7.39 – 7.33 (m, 3H), 7.24 – 7.18 (m, 1H), 3.97 (s, 3H). 13C {1H} NMR (150
MHz, CDCl3) δ 165.5, 161.6 (d, J = 250.7 Hz), 135.9 (d, J = 7.9 Hz), 133.8 (d, J = 7.5 Hz),
131.7, 128.6, 128.4, 123.2, 120.0, 119.9, 119.3 (d, J = 22.0 Hz), 117.6 (d, J = 24.1 Hz), 94.1,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 40
1
2
3
4
5
6
7
8
9
87.2, 52.5. HRMS (ESI) calcd for C16H12FO2 [M + H]+ 255.0816, found 255.0812.
Methyl 5-bromo-2-(phenylethynyl)benzoate (1e). Following the general procedure, 1e was
purified by silica gel chromatography (5% EtOAc/PE). Yield: 2.86 g, 91%, pale yellow solid,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
1
mp. 67–68 C. H NMR (600 MHz, CDCl3) δ 7.99 (d, J = 7.9 Hz, 1H), 7.64 (d, J = 7.7 Hz,
1H), 7.52 – 7.47 (m, 3H), 7.44 (d, J = 8.4 Hz, 2H), 7.40 (t, J = 7.7 Hz, 1H), 3.96 (s, 3H). 13C
{1H} NMR (150 MHz, CDCl3) δ 166.5, 134.0, 133.2, 131.9, 131.8, 131.7, 130.6, 128.1,
123.5, 122.8, 122.3, 93.2, 89.4, 52.2. HRMS (ESI) calcd for C16H12BrO2 [M + H]+ 315.0015,
found 315.0014.
Methyl 2-((3,4-dichlorophenyl)ethynyl)benzoate (1h). Following the general procedure, 1h
was purified by silica gel chromatography (10% EtOAc/PE). Yield: 2.63 g, 86%, white solid,
o
1
mp. 50–51 C. H NMR (600 MHz, CDCl3) δ 8.00 (d, J = 7.9 Hz, 1H), 7.66 (d, J = 1.8 Hz,
1H), 7.63 (d, J = 7.7 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.44 – 7.38 (m, 3H), 3.96 (s, 3H). 13C
{1H} NMR (150 MHz, CDCl3) δ 166.4, 134.1, 133.3, 132.9, 132.6, 131.9, 131.8, 130.9,
130.6, 130.4, 128.4, 123.4, 123.1, 91.8, 90.1, 52.3. HRMS (ESI) calcd for C16H11Cl2O2 [M +
H]+ 305.0131, found 305.0132.
Methyl 2-(naphthalen-2-ylethynyl)benzoate (1i). Following the general procedure, 1i was
purified by silica gel chromatography (5% EtOAc/PE). Yield: 2.40 g, 84%, pale yellow oil.
1H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 8.4 Hz, 1H), 8.01 (dd, J = 7.9, 1.0 Hz, 1H), 7.84
(dd, J = 8.2, 4.8 Hz, 2H), 7.80 (dd, J = 7.2, 1.0 Hz, 1H), 7.75 (dd, J = 7.7, 0.9 Hz, 1H), 7.61
(ddd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.55 – 7.48 (m, 2H), 7.45 (dd, J = 8.2, 7.3 Hz, 1H), 7.39 (td, J
= 7.8, 1.3 Hz, 1H), 3.98 (s, 3H). C {1H} NMR (100 MHz, CDCl3) δ 166.8, 134.3, 133.5,
13
133.3, 131.8, 131.7, 130.8, 130.6, 129.1, 128.3, 128.0, 126.9, 126.5, 126.5, 125.3, 123.9,
ACS Paragon Plus Environment

Page 19 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
121.1, 93.1, 92.7, 52.3. HRMS (ESI) calcd for C20H15O2 [M + H]+ 287.1067, found 287.1066.
Methyl 2-((2-(4-methylphenylsulfonamido)phenyl)ethynyl)benzoate (1j). Following the
general procedure of our previous work,31 1j was purified by silica gel chromatography (20%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
1
EtOAc/PE). Yield: 3.44 g, 85%, pale yellow solid, mp. 89–91 C. H NMR (600 MHz,
CDCl3) δ 9.04 (s, 1H), 8.09 (d, J = 7.9 Hz, 1H), 7.77 – 7.74 (m, 2H), 7.71 (d, J = 8.4 Hz, 1H),
7.58 (d, J = 7.7 Hz, 1H), 7.54 (dt, J = 8.8, 4.4 Hz, 1H), 7.43 (dd, J = 12.2, 4.4 Hz, 1H), 7.38
(d, J = 7.6 Hz, 1H), 7.30 – 7.26 (m, 1H), 7.11 (d, J = 8.2 Hz, 2H), 7.01 (td, J = 7.6, 1.0 Hz,
1H), 4.08 (s, 3H), 2.30 (s, 3H). C {1H} NMR (150 MHz, CDCl3) δ 166.3, 143.4, 139.8,
13
137.1, 133.4, 132.3, 131.9, 130.7, 130.5, 130.0, 129.4, 128.2, 127.3, 123.9, 123.5, 119.3,
113.5, 94.5, 90.3, 52.9, 21.5. HRMS (ESI) calcd for C23H20NO4S [M + H]+ 406.1108, found
406.1106.
Methyl 5-bromo-2-((2-(methoxycarbonyl)phenyl)ethynyl)benzoate (1l). Following the
general procedure, 1l was purified by silica gel chromatography (20% EtOAc/PE). Yield:
o
1
3.21 g, 86%, pale yellow solid, mp. 79–80 C. H NMR (600 MHz, CDCl3) δ 8.13 (s, 1H),
7.99 (d, J = 7.9 Hz, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.59 (d, J = 8.3
Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 3.96 (s, 3H), 3.95 (s, 3H). 13C {1H}
NMR (150 MHz, CDCl3) δ 166.5, 165.3, 135.6, 134.8, 134.3, 133.5, 133.2, 131.8, 131.8,
130.5, 128.4, 123.6, 122.9, 122.1, 94.4, 92.2, 52.5, 52.2. HRMS (ESI) calcd for C18H14BrO4
[M + H]+ 373.0070, found 373.0069.
Methyl 2-(4-hydroxybut-1-yn-1-yl)benzoate (1n). Following the general procedure, 1n was
purified by silica gel chromatography (20% EtOAc/PE). Yield: 1.84 g, 90%, pale yellow oil.
1H NMR (600 MHz, CDCl3) δ 7.97 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.47 (t, J =
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 40
1
2
3
4
5
7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 3.92 (s, 3H), 3.85 (t, J = 5.5 Hz, 2H), 3.44 (s, 1H), 2.71
6
7
13
(t, J = 5.4 Hz, 2H). C {1H} NMR (150 MHz, CDCl3) δ 166.6, 133.6, 132.0, 131.4, 130.5,
8
9
127.6, 124.4, 93.3, 82.0, 61.0, 52.4, 24.2. HRMS (ESI) calcd for C12H13O3 [M + H]+
205.0859, found 205.0861.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methyl 2-(3,3-dimethylbut-1-yn-1-yl)benzoate (1p). Following the general procedure, 1p
was purified by silica gel chromatography (15% EtOAc/PE). Yield: 1.75 g, 81%, pale yellow
1
oil. H NMR (400 MHz, CDCl3) δ 7.86 (dd, J = 7.9, 1.3 Hz, 1H), 7.48 (dd, J = 7.7, 1.2 Hz,
1H), 7.39 (td, J = 7.6, 1.4 Hz, 1H), 7.29 (td, J = 7.7, 1.4 Hz, 1H), 3.91 (s, 3H), 1.34 (s, 9H).
13C {1H} NMR (100 MHz, CDCl3) δ 167.3, 133.9, 132.3, 131.4, 130.1, 127.1, 124.2, 103.6,
77.9, 51.9, 30.9, 30.6, 28.2. HRMS (ESI) calcd for C14H17O2 [M + H]+ 217.1223, found
217.1224.
Methyl 5-methoxy-2-(phenylethynyl)benzoate (1r). Following the general procedure, 1r
was purified by silica gel chromatography (10% EtOAc/PE). Yield: 2.12 g, 80%, pale yellow
oil. 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 4.7 Hz, 1H), 7.55 – 7.53 (m, 2H), 7.48 (d, J =
2.8 Hz, 1H), 7.37 – 7.31 (m, 3H), 7.03 (dd, J = 8.6, 2.8 Hz, 1H), 3.96 (s, 3H), 3.86 (s, 3H).
13C {1H} NMR (100 MHz, CDCl3) δ 166.6, 159.1, 135.4, 133.3, 131.6, 128.3, 128.2, 123.7,
118.4, 115.9, 115.1, 92.6, 88.2, 55.6, 52.3. HRMS (ESI) calcd for C17H15O3 [M + H]+
267.1016, found 267.1015.
III. Construction of Isochromenone Products 2 and Derivatives 3
1. Standard Condition
General Procedure: To a solution of substrates 1 (0.4 mmol) in DCE (4 mL) was added
o
BF3•Et2O (0.4 mmol, 50 μL) at room temperature. Then the mixture was stirred at 80 C
ACS Paragon Plus Environment

Page 21 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(temperature of oil bath). After the complete consumption of the substrate, H2O (10 mL) was
added. Then the reaction mixture was extracted with EtOAc (15 mL x 3). The combined
organic phase was dried with anhydrous Na2SO4 and concentrated in vacuo. The residue was
purified by flash chromatography using a mixture of 10-30% EtOAc/PE (V/V) as eluent to
afford isochromenone products 2 and derivatives 3.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-Phenyl-1H-isochromen-1-one (2a). Following the general procedure, 2a was purified by
o
silica gel chromatography (10% EtOAc/PE). Yield: 84 mg, 95%, white solid, mp. 87–88 C
(lit36 86–87 oC). 1H NMR (600 MHz, CDCl3) δ 8.29 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 7.7 Hz,
2H), 7.70 (t, J = 7.5 Hz, 1H), 7.50 – 7.40 (m, 5H), 6.94 (s, 1H).
6-Methoxy-3-phenyl-1H-isochromen-1-one (2b). Following the general procedure, 2b was
purified by silica gel chromatography (15% EtOAc/PE). Yield: 97 mg, 96%, pale yellow
solid, mp. 165–166 oC((lit37 165-167 oC). 1H NMR (600 MHz, CDCl3) δ 8.22 (d, J = 8.8 Hz,
1H), 7.89 – 7.85 (m, 2H), 7.48 – 7.42 (m, 3H), 7.03 (dd, J = 8.8, 2.4 Hz, 1H), 6.89 (s, 1H),
6.87 (d, J = 2.4 Hz, 1H), 3.93 (s, 3H).
7-Methyl-3-phenyl-1H-isochromen-1-one (2c). Following the general procedure, 2c was
purified by silica gel chromatography (10% EtOAc/PE). Yield: 92 mg, 97%, pale yellow
solid, mp. 111–112 oC (lit37 110–113 oC). 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.87 –
7.83 (m, 2H), 7.51 (dd, J = 8.0, 1.5 Hz, 1H), 7.47 – 7.36 (m, 4H), 6.91 (s, 1H), 2.47 (s, 1H),
2.45 (s, 3H).
7-Fluoro-3-phenyl-1H-isochromen-1-one (2d). Following the general procedure, 2d was
purified by silica gel chromatography (15% EtOAc/PE). Yield: 89 mg, 93%, pale yellow
solid, mp. 154–157 oC (lit36 154–156 oC). 1H NMR (400 MHz, CDCl3) δ 7.96 (dd, J = 8.5, 2.5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 40
1
2
3
4
5
Hz, 1H), 7.86 (dd, J = 8.1, 1.5 Hz, 2H), 7.54 – 7.41 (m, 5H), 6.94 (s, 1H).
6
7
8
9
7-Bromo-3-phenyl-1H-isochromen-1-one (2e). Following the general procedure, 2e was
purified by silica gel chromatography (20% EtOAc/PE). Yield: 112 mg, 93%, pale yellow
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
1
solid, mp. 184–188 C. H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 2.0 Hz, 1H), 7.86 – 7.82
(m, 2H), 7.78 (dd, J = 8.4, 2.1 Hz, 1H), 7.48 – 7.41 (m, 3H), 7.36 (d, J = 8.4 Hz, 1H), 6.89 (s,
1H). C {1H} NMR (100 MHz, CDCl3) δ 170.0, 154.1, 138.0, 136.2, 132.2, 131.6, 130.3,
13
128.9, 127.6, 125.3, 121.9, 121.5, 101.1. HRMS (ESI) calcd for C15H10BrO2 [M + H]+
300.9859, found 300.9860.
3-(4-Methoxyphenyl)-1H-isochromen-1-one (2f). Following the general procedure, 2f was
purified by silica gel chromatography (15% EtOAc/PE). Yield: 95 mg, 94%, white solid, mp.
114–116 C (lit36 114–116 C). H NMR (400 MHz, CDCl3) δ 8.31 – 8.24 (m, 1H), 7.84 –
7.77 (m, 2H), 7.68 (td, J = 7.8, 1.3 Hz, 1H), 7.44 (ddd, J = 8.1, 3.8, 1.7 Hz, 2H), 6.99 – 6.93
(m, 2H), 6.81 (s, 1H), 3.85 (s, 3H).
o
o
1
3-(4-Bromophenyl)-1H-isochromen-1-one (2g). Following the general procedure, 2g was
purified by silica gel chromatography (10% EtOAc/PE). Yield: 113 mg, 94%, white solid, mp.
135–137 oC (lit38 133–137 oC). 1H NMR (400 MHz, CDCl3) δ 8.28 (dd, J = 7.9, 0.5 Hz, 1H),
7.75 – 7.68 (m, 3H), 7.60 – 7.54 (m, 2H), 7.53 – 7.46 (m, 2H), 6.92 (s, 1H).
3-(3,4-Dichlorophenyl)-1H-isochromen-1-one
(2h)
&
(Z)-3-(3,4-dichlorobenzylidene)isobenzofuran-1(3H)-one (3h). Following the general
procedure, 2h and 3h were obtained as a mixture. Yield: 111 mg, 95% (2h:3h = 74:21),
white solid, mp. 208–210 oC. Major isomer (2h): 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J =
7.9 Hz, 1H), 7.98 (d, J = 2.1Hz, 1H), 7.74 – 7.76 (m, 1H), 7.70 (dd, J = 8.5, 2.1 Hz, 1H), 7.56
ACS Paragon Plus Environment

Page 23 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
– 7.48 (m, 3H), 6.95 (s, 1H). 13C {1H} NMR (100 MHz, CDCl3) δ 161.7, 151.3, 136.9, 135.1,
134.1, 131.9, 130.9, 129.8, 129.1, 128.8, 127.1, 126.2, 124.3, 120.7, 102.9. HRMS (ESI)
calcd for C15H9Cl2O2 [M + H]+ 290.9974, found 290.9973.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-(Naphthalen-2-yl)-1H-isochromen-1-one (2i). Following the general procedure, 2i was
purified by silica gel chromatography (10% EtOAc/PE). Yield: 104 mg, 96%, white solid, mp.
156–158 oC (lit36 157–159 oC). 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 8.0 Hz, 1H), 8.28 –
8.21 (m, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.94 – 7.89 (m, 1H), 7.76 (ddd, J = 7.1, 5.1, 1.2 Hz,
2H), 7.60 – 7.50 (m, 5H), 6.82 (s, 1H).
4-Methyl-N-(2-(1-oxo-1H-isochromen-3-yl)phenyl)benzenesulfonamide (2j). Following
the general procedure, 2j was purified by silica gel chromatography (10% EtOAc/PE). Yield:
o
o
1
155 mg, 99%, pale yellow solid, mp. 128–129 C (lit39 128–129 C). H NMR (600 MHz,
CDCl3) δ 8.69 (d, J = 8.2 Hz, 1H), 8.40 (d, J = 7.9 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.93 –
7.88 (m, 1H), 7.59 (t, J = 8.3 Hz, 1H), 7.58 (t, J = 7.9 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.37
(t, J = 7.5 Hz, 1H), 7.12 (d, J = 8.3 Hz, 2H), 6.93 (d, J = 8.2 Hz, 2H), 2.24 (s, 3H).
3-(2-Hydroxyphenyl)-1H-isochromen-1-one (2k). Following the general procedure, 2k was
purified by silica gel chromatography (20% EtOAc/PE). Yield: 94 mg, 99%, white solid, mp.
180–182 oC (lit40 180–181 oC). 1H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.17 (d, J =
7.9 Hz, 1H), 7.84 (td, J = 7.1, 2.2 Hz, 1H), 7.78 – 7.69 (m, 2H), 7.62 – 7.54 (m, 2H), 7.29 (dd,
J = 11.2, 4.1 Hz, 1H), 7.07 – 7.02 (m, 1H), 6.97 (t, J = 7.6 Hz, 1H).
Methyl 5-bromo-2-(1-oxo-1H-isochromen-3-yl)benzoate (2l). Following the general
procedure, 2l was purified by silica gel chromatography (25% EtOAc/PE). Yield: 126 mg,
88%, pale yellow solid, mp. 185–187 oC. 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.6 Hz,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 40
1
2
3
4
5
6
7
8
9
1H), 8.12 (d, J = 2.2 Hz, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.77 – 7.72
(m, 1H), 7.68 (dd, J = 8.6, 2.2 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.49 (s, 1H), 3.95 (s, 3H).
13C {1H} NMR (150 MHz, CDCl3) δ 166.8, 166.4, 145.9, 140.5, 135.3, 134.7, 133.8, 133.3,
132.9, 130.4, 130.2, 125.6, 123.6, 121.7, 120.5, 103.2, 52.6. HRMS (ESI) calcd for
C17H12BrO4 [M + H]+ 358.9913, found 358.9915.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-Cyclopropyl-1H-isochromen-1-one (2m). Following the general procedure, 2m was
purified by silica gel chromatography (10% EtOAc/PE). Yield: 66 mg, 89%, pale yellow
solid, mp. 70–73 oC (lit41 70–72 oC). 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 8.0 Hz, 1H),
7.63 (td, J = 7.8, 1.3 Hz, 1H), 7.42 – 7.35 (m, 1H), 7.32 – 7.27 (m, 1H), 6.29 (s, 1H), 1.80 (tt,
J = 8.3, 5.1 Hz, 1H), 1.07 – 1.03 (m, 2H), 0.92 (ddd, J = 11.2, 6.9, 4.4 Hz, 2H).
3-(2-Hydroxyethyl)-1H-isochromen-1-one (2n). Following the general procedure, 2n was
purified by silica gel chromatography (25% EtOAc/PE). Yield: 75 mg, 98%, pale yellow
solid, mp. 59–61 oC (lit42 60–62 oC). 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 7.9 Hz, 1H),
7.68 (t, J = 7.6 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 6.39 (s, 1H), 4.00
(t, J = 6.1 Hz, 2H), 2.80 (t, J = 6.1 Hz, 2H), 1.94 (brs, 1H).
5-Phenyl-7H-thieno[2,3-c]pyran-7-one (2o). Following the general procedure, 2o was
purified by silica gel chromatography (15% EtOAc/PE). Yield: 74 mg, 81%, pale yellow
o
o
1
solid, mp. 120–123 C (lit42 121–123 C). H NMR (600 MHz, CDCl3) δ 7.85 (dd, J = 14.4,
6.1 Hz, 3H), 7.48 – 7.41 (m, 3H), 7.24 (d, J = 5.0 Hz, 1H), 7.13 – 7.10 (m, 1H).
3-(2,2-Dimethylpropylidene)isobenzofuran-1(3H)-one (3p)
Following the general procedure, 3p was purified by silica gel chromatography (10%
o
o
1
EtOAc/PE). Yield: 69 mg, 85%, pale yellow solid, mp. 88–89 C (lit43 89–90 C). H NMR
ACS Paragon Plus Environment

Page 25 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
(400 MHz, CDCl3) δ 7.87 (d, J = 7.7 Hz, 1H), 7.70 – 7.59 (m, 2H), 7.49 (dd, J = 10.2, 4.5 Hz,
1H), 5.60 (s, 1H), 1.32 (s, 9H).
8
9
3-Methyleneisobenzofuran-1(3H)-one (3q). Following the general procedure, 3q was
purified by silica gel chromatography (10% EtOAc/PE). Yield: 51 mg, 87%, pale yellow
solid, mp. 50–51 oC (lit44 50–53 oC). 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 7.7 Hz, 1H),
7.73 (d, J = 4.1 Hz, 2H), 7.59 (td, J = 8.3, 4.2 Hz, 1H), 5.24 (d, J = 3.0 Hz, 1H), 5.23 (d, J =
3.0 Hz, 1H).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(Z)-3-Benzylidene-6-methoxyisobenzofuran-1(3H)-one
(3r)
&
7-methoxy-3-phenyl-1H-isochromen-1-one (2r). Following the general procedure, 3r and
2r were obtained as a mixture. Yield: 82 mg, 81% (3r:2r = 81:15), pale yellow solid, mp.
o
1
108–113 C. Major isomer (3r): H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 7.6 Hz, 2H),
7.65 (d, J = 8.5 Hz, 1H), 7.40 (dd, J = 12.9, 5.4 Hz, 2H), 7.30 (ddd, J = 10.6, 8.7, 2.3 Hz, 3H),
6.28 (s, 1H), 3.90 (s, 3H).
(Z)-3-(4-Nitrobenzylidene)isobenzofuran-1(3H)-one
(3s)
&
3-(4-nitrophenyl)-1H-isochromen-1-one (2s). Following the general procedure, 3s and 2s
were obtained as a mixture. Yield: 87 mg, 81% (3s:2s = 49:32), pale yellow solid, mp.
188–194 oC (lit45 213-216 oC). Major isomer (3s): 1H NMR (400 MHz, CDCl3) δ 8.34 (t, J =
8.8 Hz, 1H), 8.33 (d, J = 9.0 Hz, 1H), 8.25 (d, J = 8.8 Hz, 2H), 7.99 (d, J = 8.5 Hz, 3H), 7.64
(t, J = 7.3 Hz, 1H), 6.47 (s, 1H).
2. Gram-scale Synthesis of Product 2a
General Procedure: To a solution of substrates 1ab (6 mmol, 1.42 g) in DCE (15 mL) was
added BF3•Et2O (1 mmol, 123 μL) at room temperature. Then the mixture was stirred at 80
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 40
1
2
3
4
5
6
7
8
9
oC (temperature of oil bath) for 8 h. After the complete consumption of the substrate, the
resulting mixture was cooled to room temperature and purified by flash chromatography
using a mixture of 10-30% EtOAc/PE (V/V) as eluent to afford isochromenone 2a: 1.15 g,
86% yield.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
IV. Control experiment
General Procedure a: To a solution of substrate 1af (0.4 mmol, 125 mg) in DCE (4 mL)
was added BF3•Et2O (0.4 mmol, 50 μL) at room temperature. Then the mixture was stirred at
o
80 C (temperature of oil bath) for 2 h. Then the resulting mixture was cooled to room
temperature and purified by flash chromatography using a mixture of 10-30% EtOAc/PE
(V/V) as eluent to afford isochromenone product 2a and benzyl alcohol.
General Procedure b: A solution of substrate 1ab (0.4 mmol, 94 mg) in DCE (4 mL) was
put in a sealed tube under N2 protection. BF3•Et2O (0.4 mmol, 50 μL) was then added at
room temperature. The resultiung mixture was stirred at 80 oC (temperature of oil bath). After
stirring for 2 h, the resulting mixture was quenched with D2O (27.6 mmol, 0.5 mL) and
extracted with DCM (30 mL x 2). The combined organic extract was dried by anhydrous
Na2SO4, concentrated in vacco, and purified by flash chromatography using a mixture of
10-30% EtOAc/PE (V/V) as eluent to afford isochromenone product 2a' as a pale yellow
solid.
3-Phenyl-1H-isochromen-1-one-4-d (2a'). Following the general procedure b, 2a' was
purified by silica gel chromatography (10% EtOAc/PE). Yield: 77 mg, 86%, white solid, mp.
o
86-87 C. 1H NMR (600 MHz, CDCl3) δ 8.32 (d, J = 7.7 Hz, 1H), 7.89 (d, J = 7.2 Hz, 2H),
13
7.72 (t, J = 8.1 Hz, 1H), 7.53 – 7.42 (m, 5H). C {1H} NMR (150 MHz, CDCl3) δ 162.3,
ACS Paragon Plus Environment

Page 27 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
153.6, 137.5, 134.9, 131.0, 130.0, 129.7, 128.9, 128.2, 126.0, 125.3, 120.6, 101.8. HRMS
(ESI) calcd for C15H10DO2 [M + H]+ 224.0816, found 224.0817.
8
9
V. Synthesis of 4-Acyl Isochromenones 4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Procedure: To a solution of substrate 1a or 2a (1.0 mmol) in DCE (10 mL) was
added BF3•Et2O (1.0 mmol, 123 μL), acyl chloride 5 (1.2 mmol, 86 μL) or triphosgene (1.2
o
mmol, 356 mg) at room temperature. Then the mixture was stirred at 80 C (temperature of
oil bath). After stirring for 4 h to 24 h, the resulting mixture was cooled to room temperature
and purified by flash chromatography using a mixture of EtOAc/PE (35% for 4a, 5% for 4b-f)
as eluent to afford 4-acyl isochromenone derivatives 4 as light yellow solid.
4-Acetyl-3-phenyl-1H-isochromen-1-one (4a). Following the general procedure, 4a was
purified by silica gel chromatography (30% EtOAc/PE). Yield: 248 mg, 94%, white solid, mp.
o
o
1
127–129 C (lit46 126.5–129.5 C). H NMR (600 MHz, CDCl3) δ 8.39 (dd, J = 8.2, 1.2 Hz,
1H), 7.79 – 7.76 (m, 1H), 7.66 – 7.64 (m, 2H), 7.58 (dd, J = 7.5, 6.0 Hz, 2H), 7.53 (d, J = 7.2
Hz, 1H), 7.49 (dd, J = 11.4, 4.5 Hz, 2H), 2.14 (s, 3H).
3-Phenyl-4-propionyl-1H-isochromen-1-one (4b). Following the general procedure, 4b was
purified by silica gel chromatography (5% EtOAc/PE). Yield: 156 mg, 56%, white solid, mp.
o
1
110–111 C. H NMR (600 MHz, CDCl3) δ 8.39 (d, J = 8.0 Hz, 1H), 7.78 – 7.74 (m, 1H),
7.65 – 7.61 (m, 2H), 7.60 – 7.56 (m, 1H), 7.52 – 7.46 (m, 4H), 2.35 (q, J = 7.2 Hz, 2H), 1.01
(t, J = 7.2 Hz, 3H). 13C {1H} NMR (150 MHz, CDCl3) δ 205.5 (s), 161.3 (s), 152.7 (s), 135.3
(s), 134.7 (s), 132.2 (s), 131.0 (s), 130.1 (s), 129.0 (s), 128.8 (s), 128.6 (s), 123.9 (s), 120.2 (s),
+
118.2 (s), 38.4 (s), 8.3 (s). HRMS (ESI) calcd for C18H15O3 [M + H+] 279.1016, found
279.1015.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 40
1
2
3
4
5
4-Pentanoyl-3-phenyl-1H-isochromen-1-one (4c). Following the general procedure, 4c was
6
7
purified by silica gel chromatography (5% EtOAc/PE). Yield: 116 mg, 38%, white solid, mp.
8
9
o
1
96–97 C. H NMR (600 MHz, CDCl3) δ 8.39 (d, J = 8.0 Hz, 1H), 7.77 (t, J = 8.4 Hz, 1H),
7.65 – 7.61 (m, 2H), 7.58 (t, J = 8.4 Hz, 1H), 7.54 – 7.46 (m, 4H), 2.32 (t, J = 7.4 Hz, 2H),
1.50 (dt, J = 15.0, 7.4 Hz, 2H), 1.21 – 1.07 (m, 2H), 0.74 (t, J = 7.4 Hz, 3H). 13C {1H} NMR
(150 MHz, CDCl3) δ 205.0 (s), 161.4 (s), 152.9 (s), 135.3 (s), 134.8 (s), 132.2 (s), 131.0 (s),
130.1 (s), 129.0 (s), 128.8 (s), 128.7 (s), 123.9 (s), 120.2 (s), 118.3 (s), 44.8 (s), 26.1 (s), 21.9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
(s), 13.7 (s). HRMS (ESI) calcd for C20H18O3 [M + H+] 307.1329, found 307.1333.
3-Phenyl-4-(2-phenylacetyl)-1H-isochromen-1-one (4d). Following the general procedure,
4d was purified by silica gel chromatography (5% EtOAc/PE). Yield: 265 mg, 78%, white
o
1
solid, mp. 174–175 C. H NMR (600 MHz, CDCl3) δ 8.35 (d, J = 7.8 Hz, 1H), 7.71 – 7.65
(m, 3H), 7.60 – 7.56 (m, 1H), 7.55 – 7.52 (m, 3H), 7.35 (d, J = 7.8 Hz, 1H), 7.23 – 7.16 (m,
13
3H), 6.92 (d, J = 7.8 Hz, 2H), 3.61 (s, 2H). C {1H} NMR (150 MHz, CDCl3) δ 201.5 (s),
161.3 (s), 153.1 (s), 135.3 (s), 134.7 (s), 132.5 (s), 132.2 (s), 131.3 (s), 130.0 (s), 129.6 (s),
129.2 (s), 128.9 (s), 128.8 (s), 128.6 (s), 127.3 (s), 123.9 (s), 120.0 (s), 117.8 (s), 51.6 (s).
+
HRMS (ESI) calcd for C23H17O3 [M + H+] 341.1172, found 341.1172.
4-(4-Methoxybenzoyl)-3-phenyl-1H-isochromen-1-one (4e). Following the general
procedure, 4e was purified by silica gel chromatography (5% EtOAc/PE). Yield: 221 mg,
62%, white solid, mp. 146–147 oC. 1H {1H} NMR (600 MHz, CDCl3) δ 8.41 (d, J = 7.8 Hz,
1H), 7.85 (d, J = 9.0 Hz, 2H), 7.67 (t, J = 7.8 Hz, 1H), 7.62 (d, J = 6.4 Hz, 2H), 7.56 (t, J =
7.6 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.32-7.25 (m, 3H), 6.80 (d, J = 9.0 Hz, 2H), 3.80 (s,
3H). 13C NMR (150 MHz, CDCl3) δ 193.1 (s), 164.4 (s), 161.6 (s), 152.1 (s), 136.1 (s), 135.2
ACS Paragon Plus Environment

Page 29 of 40
The Journal of Organic Chemistry
1
2
3
4
5
(s), 132.2 (s), 132.0 (s), 130.4 (s), 130.0 (s), 129.9 (s), 128.8 (s), 128.5 (s), 128.4 (s), 124.6 (s),
6
7
+
120.2 (s), 115.8 (s), 114.1 (s), 55.5 (s). HRMS (ESI) calcd for C23H17O4 [M + H+] 357.1121,
8
9
found 357.1123.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-Cinnamoyl-3-phenyl-1H-isochromen-1-one (4f). Following the general procedure, 4f was
purified by silica gel chromatography (5% EtOAc/PE). Yield: 204 mg, 58%, white solid, mp.
145–146 oC. 1H NMR (600 MHz, CDCl3) δ 8.41 (d, J = 8.0 Hz, 1H), 7.75 (t, J = 7.8 Hz, 1H),
7.70 – 7.66 (m, 2H), 7.63 – 7.56 (m, 2H), 7.47 (d, J = 16.0 Hz, 1H), 7.42 – 7.38 (m, 3H), 7.36
13
– 7.33 (m, 1H), 7.32 – 7.30 (m, 4H), 6.66 (d, J = 16.0 Hz, 1H). C {1H} NMR (150 MHz,
CDCl3) δ 193.7 (s), 161.4 (s), 153.5 (s), 146.2 (s), 135.4 (s), 135.3 (s), 133.9 (s), 132.1 (s),
131.1 (s), 130.9 (s), 130.0 (s), 128.9 (s), 128.8 (s), 128.8 (s), 128.8(s), 128.5 (s), 127.5 (s),
+
124.5 (s), 120.2 (s), 116.5 (s). HRMS (ESI) calcd for C24H16O3 [M + H+] 353.1172, found
353.1173.
VI. Applications for the Construction of Compounds 6 and 7.
General Procedure:
Step a32: To a solution of compound 2l (1.0 mmol, 359 mg) in methanol (4 mL) was added 1
M NaOH aqueous solution (2 mL) at room temperature. Then the mixture was stirred at 40
oC (temperature of oil bath) for 4 h. After the complete consumption of the substrate, the
resulting mixture was cooled to room temperature and acidified with 1 M HCl solution to pH
3~5. Then the solution was extracted with EtOAc three times (3 × 30 mL). The organic phase
was combined, washed with brine, concentrated to give an acid intermediate 5l (340 mg,
99%).
Step b: To a solution of the acid intermediate (0.4 mmol, 138 mg) in DCM (4 mL) was added
ACS Paragon Plus Environment