Completely Stereoselective Synthesis of Sulfonated 1,3-Dihydroisobenzofurans via Radical Multicomponent Reactions

Article abstract of DOI:10.1021/acs.joc.9b01918

Two types of new oxidant-free radical multicomponent reactions of β-alkynyl ketones, aryldiazonium salts, and DABCO·(SO₂)₂ (DABSO) were established, leading to the tunable generation of two class of sulfonated 1,3-dihydroisobenzofurans with moderate to good yields and complete stereoselectivity under the mild conditions. The radical-induced scission/recombination of the C(sp³)-C(sp³) bond enabled direct 1,8-halosulfonylation of β-alkynyl ketones, giving 1,3-dimethylene-substituted (1Z,3Z)-1,3-dihydroisobenzofurans with substituent diversity by p-nitrobenzyl bromide (PNBB) or p-nitrobenzyl chloride (PNBC) as the halo source. Fine-tuning substituents to strong electron-withdrawing ones, such as nitro, cyano, and trifluoromethyl, linked to aryldiazonium tetrafluoroborates allowed a different annulation/1,5-azosulfonylation process to access sulfonated (Z)-1,3-dihydroisobenzofurans with one quaternary carbon-amino functionality.

Full text of DOI:10.1021/acs.joc.9b01918

Subscriber access provided by UNIV OF NEW ENGLAND ARMIDALE
Article
Completely Stereoselective Synthesis of Sulfonated 1,3-
Dihydroisobenzofurans via Radical Multicomponent Reactions
Hao-Nan Shi, Min-Hua Huang, Chun-Lan He, Hai-Ping Lu,
Wen-Juan Hao, Xing-Chao Tu, Shu-Jiang Tu, and Bo Jiang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01918 • Publication Date (Web): 23 Sep 2019
Downloaded from pubs.acs.org on September 26, 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 31
The Journal of Organic Chemistry
1
2
3
Completely Stereoselective Synthesis of Sulfonated 1,3-Dihydroisobenzofurans via
4
5
6
7
Radical Multicomponent Reactions
8
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
Hao-Nan Shi,a,1 Min-Hua Huang,a,b,1 Chun-Lan He,a Hai-Ping Lu,a Wen-Juan Hao,a,* Xing-Chao Tu,a,*
Shu-Jiang Tu,a Bo Jianga,*
a School of Chemistry & Materials Science, Jiangsu Key Laboratory of Green Synthetic Chemistry for
Functional Materials, Jiangsu Normal University, Xuzhou 221116, P. R. China.
b
Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, 210009, Jiangsu,
P. R. China.
1These authors contributed equally.
E-mail: wjhao@jsnu.edu.cn(WJH); tuxingchao@jsnu.edu.cn(XCT), jiangchem@jsnu.edu.cn(BJ);
RECEIVED DATE
O
X
ArN2BF4
R2
R2
or
O
PNBB PNBC
+
DCE, 85 o
C
Ar
O
R1
S
R1
DABCO (SO2)2
X = Br, Cl
O
29 examples
Ar
N
N
DCE, 85 o
C
O
-
Ar = 4-F, 4 CF3, 4-NO2
and 4-CNC6H4
Ar
O
S
O
R1
7 examples
ABSTRACT. Two types of new oxidant-free radical multicomponent reactions of β-alkynyl ketones,
aryldiazonium salts and DABCO•(SO2)2 (DABSO) were established, leading to the tunable generation
of two class of sulfonated 1,3-dihydroisobenzofurans with moderate to good yields and complete
stereoselectivity under the mild conditions. The radical-induced scission/recombination of C(sp3)–
C(sp3) bond enabled direct 1,8-halosulfonylation of β-alkynyl ketones, giving 1,3-dimethylene-
substituted (1Z,3Z)-1,3-dihydroisobenzofurans with a substituent diversity by p-nitrobenzyl bromide
(PNBB) or p-nitrobenzyl chloride (PNBC) as the halo source. Fine-tuning substituents to strong
ACS Paragon Plus Environment
1

The Journal of Organic Chemistry
Page 2 of 31
electron-withdrawing ones, such as nitro, cyano and trifluoromethyl, linked to aryldiazonium
tetrafluoroborates allowed a different annulation/1,5-azosulfonylation process to access sulfonated (Z)-
1,3-dihydroisobenzofurans with one quaternary carbon-amino functionality.
1
2
3
4
5
6
7
8
9
Introduction
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
Multicomponentreactions (MCRs) represent one of attractive and powerful strategies in building
complex molecular architectures under usually mild conditions.1 Such reactions enable the assembly of
the fragments of the starting materials into the final molecular skeletons in an extremely convergent
manner by merging two or more distinct transformations into a one-pot manipulation.2 Accordingly,
MCRs feature high atom-utilization, bond forming efficiency and high levels of structural complexity
and diversity as well as the minimum generation of waste.3 Specifically, radical-triggered
multicomponent reactions, standing at the intersection of both radical and multicomponent
transformations, constitute a unique reaction category which enables to assemble significant compounds
not available from other methods.4 Despite great achievements have made in this field, it remains
formidably challenging to design new radical multicomponent reactions for the collection of bioactive
molecules due to the inherent difficulty in the control of reaction selectivities and radicals’ behavior,
especially for the latter when trapped in the selection of radical acceptors.
Meanwhile, 1,3-disubstituted isobenzofurans are privileged structural units that have been shown to
exhibit a broad spectrum of biological activities, such as anti-inflammatory,5 antihistam inic,6 and anti-
HIV activity,7 etc. Over the past few years, various synthetic approaches toward 1,3-disubstituted
isobenzofurans have been developed, including traditional iodocyclization of o-alkynyl benzylic
alcohols,8 photocatalytic lactonization,9 nucleophilic ring-opening of epoxides,10 Rh-catalyzed triazole
denitrogenation,11 Michael addition of chalcones,12 catalytic oxo-cyclization of o-alkynyl arones,13 and
transition-metal-catalyzed annulations of o-bromobenzyl alcohols.14 Very recently, we disclosed a
palladium(II)-catalyzed cyclization-radical addition cascade of β-alkynyl ketones, aryl diazonium salts
ACS Paragon Plus Environment
2

Page 3 of 31
The Journal of Organic Chemistry
and DABCO•bis(sulfur dioxide) (DABSO), leading to the stereoselective formation of sulfonated 1,3-
disubstituted isobenzofurans via a SO2 insertion process (Scheme 1a).15 To continue our interest in the
oxo-cyclization of β-alkynyl ketones16 and SO2 insertion,17 we introduced cyclopropyl functionality into
the β-alkynyl ketone unit to synthesize cyclopropane-containing β-alkynyl ketones and employed them
to react with aryldiazonium tetrafluoroborates and DABSO in the presence of p-nitrobenzyl bromide
(PNBB). This multicomponent reaction proceeded in an unexpected direction to access 1,3-
dimethylene-substituted (1Z,3Z)-isobenzofurans with the complete stereoselectivity via radical-induced
multiple σ-bond breaking events including C(sp3)-C(sp3), C(sp3)-halogen and C(sp2)-nitrogen bonds
(Scheme 1b). Alternatively, p-nitrobenzyl chloride (PNBC) as a chloro source was also suitable for this
radical transformation. Interestingly, the presence of strong electron-withdrawing groups, such as nitro,
cyano and trifluoromethyl, linked to aryldiazonium tetrafluoroborates gave sulfonated (Z)-
isobenzofurans with one quaternary carbon-amino functionality and complete stereoselectivity through a
different catalyst- and oxidant-free 1,5-azosulfonylation of β-alkynyl ketones (Scheme 1c). Herein, we
elaborate this substrate-controlled divergent synthesis of structurally diverse sulfonated
dihydroisobenzofurans through radical enabled site-specific annulation /1,n-bifunctionalization of β-
alkynyl ketones.
1
2
3
4
5
6
7
8
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
Scheme 1. Synthesis of 1,3-Dihydroisobenzofuran Derivatives
our previous work
O
S
O
ArN2BF4
Me
Ar
Pd(OAc)2
R2
(a)
O
O
R2
+
MeCN, 60 oC, air
DABCO (SO2)2
R1
R1
Ar
this work
O
X
ArN2BF4
R2
R2
or
2
O
PNBB PNBC
(b)
+
DCE, 85 o
X = Br, Cl
C
Ar
R1
S
R1
DABCO (SO2)2
3
1
O
O
4
Ar
N
N
DCE, 85 o
C
O
(c)
-
Ar
O
Ar = 4 CF3, 4-NO2
and 4-CNC6H4
S
R1
5
O
Results and Discussion
Recent combination of aryldiazonium salts with DABSO has proven to be a reliable method to
generate arylsulfonyl radicals, which can be trapped by unsaturated systems to form skeletally diverse
ACS Paragon Plus Environment
3

The Journal of Organic Chemistry
Page 4 of 31
sulfones.18 In view of these successfully reports, we initially adopted 4-(tert-butyl)phenyldiazonium
tetrafluoroborate (2a) and DABSO (3) as a combined sulfonyl radical precursor to react with β-alkynyl
ketone 1a in the presence of a suitable bromo source. The reaction of 1a with 2a and 3 in 1:2:2 mol ratio
in 1,2-dichloroethane (DCE) worked sluggishly, generating 1,8-halosulfonylation product 3a in very
low yield (25%) when 1.0 equivalent of benzyl bromide (BB) was acted as the bromo source (Table 1,
entry 1). These preliminary results prompted us to further optimize the reaction condition to realize the
improvements in the yield of the desired products. The following screening of bromo sources, such as p-
nitrobenzyl bromide (PNBB), p-cyanobenzyl bromide (PCBB), N-bromosuccinimide (NBS), and
tetrabuylammonium bromide (TBAB), showed that the former two could make this reaction work more
efficiently (entries 2-3), in which PNBB was the best choice (35%, entry 2) whereas the latter two
completely suppressed the transformation into product 4a and resulted in a messy system (entries 4-5).
Consequently, PNBB was selected as the bromo sources for next optimization. Due to the incomplete
consumption of substrate 1a was observed in the reaction system, we simultaneously increased the
amount of 2a, 3 and PNBB and found that it was beneficial for this radical transformation (entries 6-9).
The yield of 73% was obtained when their mol ratio was increased to 1:4:4:4 (entry 9). The solvent
effect was next investigated (entries 10-11). The representative solvents such as 1,4-dioxane and
tetrahydrofuran (THF) were evaluated, and it is found that both gave relatively poor results as compared
with DCE (entries 10-11 vs entry 9). The lower conversion was observed if the reaction was carried out
at 70 °C (entry 12), whereas a slightly lower yield was obtained with increase in temperature to 100 °C
(entry 13).
1
2
3
4
5
6
7
8
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
Table 1. Optimization of the Reaction Conditionsa
O
N2BF4
4-tBuC6H4
Br
2a
O
Br
-source
+
4-tBuC6H4
solvent, temp
Ph
DABSO
3
S
O
1a
Ph
O
4a
entry
solvent
Br sources
t (oC)
yield (%)b
ACS Paragon Plus Environment
4

Page 5 of 31
The Journal of Organic Chemistry
1
2
DCE
DCE
BB
85
85
85
85
85
85
85
85
85
85
85
70
100
25
35
30
NR
NR
45
50
58
75
62
58
60
71
1
2
3
4
5
6
7
8
PNBB
PCBB
NBS
3
DCE
4
DCE
9
5
DCE
TBAB
PNBB
PNBB
PNBB
PNBB
PNBB
PNBB
PNBB
PNBB
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
6c
7d
8e
9f
DCE
DCE
DCE
DCE
10f
11f
12f
13f
1,4-dioxane
THF
DCE
DCE
aReaction conditions: β-alkynyl ketone 1a (0.2 mmol), 4-tertbutylphenyldiazonium tetrafluoroborate 2a (2.0 equiv), DABSO (2.0 equiv), Br-source (1.0
equiv), solvent (2.0 mL) under Ar conditions at 85 oC for 15 min. bIsolated yield based on 1a. cMol ratio of 1a with 2a, 3 and PBNN in 1:3:3:1. dMol ratio of
1a with 2a, 3 and PBNN in 1:3:3:2. eMol ratio of 1a with 2a, 3 and PBNN in 1:3:3:3. fMol ratio of 1a with 2a, 3 and PBNN in 1:4:4:4. (NR = no reaction)
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
With these optimized conditions in hand, we next explored the reaction scope of this radical
multicomponent reaction by examining β-alkynyl ketones and aryldiazonium tetrafluoroborate
components. The result is presented in Scheme 2. β-Alkynyl ketones with diverse electronic properties
were first investigated in combination with aryldiazonium tetrafluoroborate 2a under standard
conditions. Both electron-rich and electron-poor groups at the para-position of the arylalkynyl moiety
(R1) could completely orient the stereoselectivity to generate the corresponding sulfonated (Z,Z)-1,3-
ACS Paragon Plus Environment
5

The Journal of Organic Chemistry
Page 6 of 31
1
2
3
Scheme 2. Substrate Scope for 1,8-Bromosulfonylation Products
4
5
6
7
8
O
Br
ArN2BF4
R2
R2
O
2
+
PNBB
DCE, 85 o
C
Ar
O
R1
S
R1
4
DABSO
3
1
O
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
Br
Br
Br
O
O
O
4-tBuC6H4
2-MeC6H4
Ph
S
S
S
R1
Ph
4-MeC6H4
O
O
O
O
O
4a-4g
O
4h
(61%)
4i
(57%)
, R1 = Ph (73%)
4a
4b
4c
4d
4e
4f
Br
Br
, R1 = 4-MeC6H4 (59%)
, R1 = 4-EtC6H4 (68%)
, R1 = 4-tBuC6H4 (71%)
, R1 = 4-MeOC6H4 (88%)
, R1 = 4-ClC6H4 (58%)
, R1 = 2-thienyl (45%)
O
O
S
Me
4-tBuC6H4
Me
Ar
O
S
4-ClC6H4
4-MeC6H4
O
O
O
4j-4m
4n
(65%)
4g
t
4j
, Ar = 4- BuC6H4 (61%)
Br
4k
, Ar = 2-ClC6H4 (59%)
, Ar = 3-ClC6H4 (67%)
Br
O
4l
O
Cl
4-tBuC6H4
4m
, Ar = 3,4-Cl2C6H3 (62%)
F
4-tBuC6H4
S
4-tBuC6H4
Br
S
O
O
F
Ph
O
O
4p
O
(69%)
4o
(61%)
4-tBuC6H4
Br
S
Cl
Br
4-MeC6H4
O
Me
O
O
O
4r
(67%)
4-tBuC6H4
4-tBuC6H4
S
Br
Ph
Cl
O
S
O
4-ClC6H4
O
O
O
4s
(62%)
4q
(66%)
4-tBuC6H4
S
R1
, R1 = 4-MeC6H4 (66%)
4t
, R1 = 4-ClC6H4 (77%)
O
O
4u
4t 4u
-
dihydroisobenzofurans 4b–4f in 58%–88% yields. It is obvious that the current system would be
compatible with various substituents, such as methyl (1b), ethyl (1c), tert-butyl (1d), methoxy (1e), and
chloro (1f). Similarly, 2-thienyl analogue 1g still showed a good reactivity profile, enabling its
conversion into product 4g as a sole (Z,Z)-isomer with 45% yield. Next, the scope regarding the
aryldiazonium tetrafluoroborates was briefly studied. Various aryldiazonium tetrafluoroborates 2b-2f
having electronically rich (Me, 2b), neutral (H, 2c) and poor (Cl, 2d-2f) groups at different positions of
the arene ring, delivering (Z,Z)-1,3-dihydroisobenzofurans 4h–4m as single stereoisomers with
acceptable yields. The potential variations in the internal arene ring of β-alkynyl ketones 1 were
subsequently evaluated by adopting aryldiazonium tetrafluoroborate 2a as a representative partner. The
reaction worked well under standard conditions to exclusively access (Z,Z)-1,3-dihydroisobenzofurans
4n–4u with 62-77% yields and complete stereoselectivity (Scheme 2). The electronic nature of
ACS Paragon Plus Environment
6

Page 7 of 31
The Journal of Organic Chemistry
substituents at C4 or C5 position on the internal aromatic ring of 1 had no impact on the
stereoselectivity and limited influence on the obtainable yields.
1
2
3
4
5
6
7
8
9
To expand the utility of this methodology, we made our next efforts to investigate the feasibility of
annulation/1,8-chlorosulfonylation17 of β-alkynyl ketones 1 by using PNBC as the chloro source. As
anticipated, the reaction of β-alkynyl ketones 1 with 2 and 3 in the presence of PNBC enabled a
completely stereoselective access to furnish flexibly decorated (Z,Z)- 1,3-dihydroisobenzofurans 4v–4cc
with moderate to good yields (Scheme 3). β-Alkynyl ketones 1 bearing either electronically rich,
neutral, or poor groups attached by both phenyl rings were accommodated. Obviously, the current SO2
insertion-based multicomponent cyclization can be perfectly compatible with structurally diverse
substrates with a different electronic nature, which renders a highly stereoselective approach for
constructing vinyl aryl sulfones with generally good yields, all of which were obtained with complete
stereoselectivity.18
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. Substrate Scope for 1,8-Chlorosulfonylation Products
O
Cl
ArN2BF4
R2
R2
O
2
PNBC
+
DCE, 85 o
C
Ar
O
R1
S
R1
DABSO
3
1
O
4v-4cc
Cl
Cl
Cl
O
O
O
4-tBuC6H4
Me
4-tBuC6H4
4-tBuC6H4
S
S
S
Ph
4v
4-ClC6H4
4-ClC6H4
O
O
O
O
O
O
4w
(52%)
4x
(75%)
(64%)
Cl
Cl
Cl
F
O
O
O
Cl
Me
Cl
4-tBuC6H4
4-tBuC6H4
4-BrC6H4
S
S
S
4-ClC6H4
4-MeC6H4
4-MeC6H4
O
O
O
O
O
O
4y
(64%)
4z
(72%)
4aa
(65%)
Cl
Cl
MeO
O
O
4-tBuC6H4
4-tBuC6H4
S
S
4-ClC6H4
Ph
O
O
O
O
4bb
(61%)
4cc
(63%)
ACS Paragon Plus Environment
7

The Journal of Organic Chemistry
Page 8 of 31
1
2
3
Scheme 4. Substrate Scope for 1,5-Azosulfonylation Products
4
5
6
7
8
9
O
Ar
ArN2BF4
N
N
R2
DCE, 85 o
C
2
R2
O
+
Ar
R1
DABCO (SO2)2
3
S
1
R1
O
O
5
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-O2NC6H4
4-FC6H4
4-O2NC6H4
N
N
N
N
N
N
O
O
O
Cl
Me
4-FC6H4
4-O2NC6H4
4-O2NC6H4
S
S
S
4-tBuC6H4
5c
C6H4
4-ClC6H4
O
O
O
O
O
O
5a
5b
(52%)
(45%)
(67%)
4-CNC6H4
4-CNC6H4
4-O2NC6H4
N
O
N
N
N
N
N
MeO
MeO
O
O
Cl
4-tBuC6H4
4-O2NC6H4
4-CNC6H4
4-CNC6H4
S
S
S
4-ClC6H4
5f
4-ClC6H4
5d
O
O
O
O
O
O
(64%)
5e
(62%)
(74%)
4-F3CC6H4
N
N
O
Cl
4-F3CC6H4
S
4-ClC6H4
O
O
5g
(58%)
Interestingly, when aryldiazonium tetrafluoroborates possessed strong electron-withdrawing groups,
such as fluoro, nitro, cyano and trifluoromethyl, the above reaction occurred in an unexpected 1,5-
azosulfonylation pathway to generate sulfonated (Z)-1,3-dihydroisobenzofurans 5a-5f with one
quaternary carbon-amino functionality without any catalyst and oxidant (Scheme 4). In this
transformation, aryldiazonium salts play dual roles as arylsulfonyl source as well as azo functionality,
both of which was installed into the molecular frameworks. The structures of products 4 and 5 were
identified by NMR spectroscopy and HRMS. Furthermore, in cases of 4r (CCDC 1952517) and 5a
(CCDC 1952518), their stereo-structures were confirmed by carrying out single-crystal X-ray
diffraction analysis (see the Supporting Information).
Subsequently, the control experiment was performed to gain more insights into the reaction
mechanism. The radical scavenger of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) (4.0 equiv) was
added to the reaction system under standard reaction conditions (Scheme 5). As expected, the reaction
process was completely suppressed and the desired product 4a was not detected.
ACS Paragon Plus Environment
8

Page 9 of 31
The Journal of Organic Chemistry
1
2
3
Scheme 5. Preliminary Mechanism Study
4
O
5
6
7
8
Br
2a
O
PCBB
DCE, 85 oC
+
4-tBuC6H4
Ph
DABSO
3
S
TEMPO
1a
Ph
4a
9
O
O
10
11
12
13
14
(trace)
Based on the above observations and literature reports,17,19 reasonable mechanisms for selectively
forming products 4 and 5 were proposed in Scheme 6. In the former, the interaction between
aryldiazonium cations and DABSO is believed to generate the radical cation A, SO2, and the aryl radical
by homolytic cleavage of the N–S bond via a SET process.19 Then, aryl radical is trapped by SO2 to give
arylsulfonyl radical, followed by radical addition of β-alkynyl ketones 1 to yield vinyl radical (Z)-B, due
to (E)-B possesses strong steric hindrance, which undergoes 5-endo-trig cyclization to give radical
intermediate C. Subsequently, ring opening of cyclopropyl group occurs to the primary carbon radical
(Z)-D as (E)-D also possesses strong steric hindrance (path a). (Z)-D reacts with PNBB to give the final
(1Z,3Z)-products 4 together with PNB radical. PNB radical is captured by arylsulfonyl radical and
radical cation A, respectively, transforming into by-products of alkyl aryl sulfone and quaternary
ammonium salt, which are detected by LC-MS. When aryldiazonium salts with strong electron-
withdrawing groups are employed, radical intermediate C is intercepted by aryldiazonium cations to
afford radical cations E, which is reduced to the final (Z)-product 5 via our previous proposed
pathway.17a,b
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
ACS Paragon Plus Environment
9

The Journal of Organic Chemistry
Page 10 of 31
1
2
3
4
5
Scheme 6. Proposed Mechanism
6
7
8
O
O
N
N
Ar
S
SO2
+ Ar
DABSO
3
Ar
N
N2
+
A
R
R
R
9
Ar
Ar
+
N
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
N
N
N
Ref 17a
N
N Ar
O
path b
Ar
Ar
O
S
S
R1
5
R1
E
O
O
O
O
O
O
S
O
S
Ar
5-endo-trig
O
Ar
O
R1
1
Ar
S
R1
B
R1
C
O
O
O
X
path a
X
PNB
PNB
O
O
Ar
Ar
S
O
S
R1
R1
4
O
O
O
D
O
O
S
O
S
R
Ar
A
R
N
PNB
PNB
R
O
detected by LCMS
detected by LCMS
R1
O
H
E
H
Ar
S
O
O
O
Ar
O
S
R1
-B
O
(E)
-D
(E)
In summary, by combining aryldiazonium salts with DABSO as sulfonyl radical precursors, we have
established two types of new oxidant-free radical-induced addition-cyclization of β-alkynyl ketones,
from which a wide range of functionalized sulfone-containing 1,3-dimethylene-substituted 1,3-
dihydroisobenzofurans with complete stereoselectivity were synthesized. In the former, radical-induced
annulation/1,8-halosulfonylation of β-alkynyl ketones via cleavage/recombination of C(sp3)-C(sp3) bond
was realized, enabling a completely stereoselective access to functionalized sulfonylated 1,3-
dimethylene-substituted (Z,Z)-isobenzofuran derivatives with generally good yields by using PNBB and
PNCB as the halo source. The latter allowed annulation/1,5-azosulfonylation of β-alkynyl ketones to
construct another new type of sulfonylated (Z)-isobenzofurans under the oxidant- and metal-free
conditions, in which aryl diazonium tetrafluoroborates could serve both initiator and terminator for this
ACS Paragon Plus Environment
10

Page 11 of 31
The Journal of Organic Chemistry
radical transformation. Further investigations on its mechanism and application are underway in our
laboratory.
1
2
3
4
5
6
Experimental Section
7
8
General Information.
9
All melting points are uncorrected. The NMR spectra were recorded in CDCl3 or DMSO-d6 on a 400
MHz instrument with TMS as internal standard. Chemical shifts (δ) were reported in ppm with respect
to TMS. Data are represented as follows: chemical shift, mutiplicity (s = singlet, d = doublet, t = triplet,
m = multiplet), coupling constant (J, Hz) and integration. HRMS analyses were carried out using a
TOF-MS instrument with an ESI source. X-ray crystallographic analysis was performed with a SMART
CCD and a P4 diffractometer.
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 for the Preparation of Compounds 1 (Known).20
PdCl2(PPh3)2 (0.12 mmol, 0.02 equiv) and CuI (0.29 mmol, 0.05 equiv) were added to a solution of 2-
bromobenzaldehyde (5.8 mmol, 1.0 equiv), phenylacetylene (6 mmol, 1.05 equiv), and Et3N (5 mL, 1.0
M). The mixture was heated at oil bath 60 °C under N2. The system was filtered by a short silica
column, the solvent was evaporated under reduced pressure, and the residue was purified by flash
chromatography with petroleum to afford β-alkynyl aldehydes I. Yields of the β-alkynyl aldehydes I
ranged from 65% to 89%.
β-Alkynyl aldehydes I (10 mmol, 1.0 equiv) and THF (10 mL) were added to a flame-dried flask
equipped with a magnetic stir bar. After that, 25 mL (1 M, 2.5 equiv) cyclopropylmagnesium bromide
o
solution was added into the reaction system by dropwise at -10 C and stirred for 10 min. Then, the
mixture was moved to room temperature for another 6 hours. The resulting mixture was stirred until
TLC indicated complete consumption of the compound I. Subsequently, the mixture was quenched by
saturated ammonium chloride solution at -10 oC and extracted with 20 mL ethyl acetate for three times
at room temperature. The organic phase was concentrated and evaporated on a rotary evaporator. The
crude product was purified by chromatography on silica gel with petroleum ether/ethyl acetate (50:1) as
the eluent to afford compound II (90-94% yield).
ACS Paragon Plus Environment
11

The Journal of Organic Chemistry
Page 12 of 31
Under argon conditions, Dess-Martin periodinane (12.0 mmol, 1.5 equiv) and CH2Cl2 (15 mL) were
added into a dried flask. Then, the mixture was cooled down to 0 °C. Next, compound II (8.0 mmol, 1.0
equiv) was dropwise. After stirring at this temperature for 2.0 h, and it was quenched by saturated
aqueous NaHCO3. Then the mixture was extracted with DCM and concentrated under vacuum. The
residue was purified by flash column chromatography on silica gel (200-300 mesh) using mixtures of
petroleum ether/ethyl acetate (50:1, v/v) afforded substrates 1 (90%-95% yield). Total yields of β-
alkynyl ketones 1a-1r ranged from 50% to 74% yield.
1
2
3
4
5
6
7
8
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
General Procedure for the Preparation of Aryldiazonium Salts 2a−2j (Known).21
Aniline 1 (10 mmol, 1.0 equiv) was added to a mixture of 50% fluoroboric acid (3 mL) and distilled
water (3 mL) in an ice bath. To this solution was added an ice-cold solution of sodium nitrite (10.2
mmol, 1.2 equiv) in distilled water (3 mL). After stirring for 30 min, the precipitate was collected on a
Hirch funnel and washed with small amount of ice-cold distilled water. The solid was dissolved in
acetone and precipitated with slow addition of ethyl ether. White crystalline solids were obtained after
repeated trituration two or three times. Yields of the aryldiazonium salts 2 ranged from 72% to 85%.
General Procedure for the Synthesis of 4a-4u.
Example for the Synthesis of 4a. A mixture of cyclopropyl(2-(phenylethynyl)phenyl)methanone (1a,
49.2 mg, 0.2 mmol), 4-tertbutylbenzenediazonium tetrafluoroborate (2a, 198.4 mg, 0.8 mmol), DABSO
(3, 176.0 mg, 0.8 mmol), PNBB (172.8 mg, 0.8 mmol) and DCE (2.0 mL) were added in a Schlenk
o
tube. The mixture was stirred in oil bath at 85 C for about 2 hours. After the reaction was completed
(detected by TLC, petroleum ether/ethyl acetate = 4:1), the reaction mixture was concentrated by
vacuum distillation and was purified by flash column chromatography to afford the desired pure product
(4a, 43 mg, 75% yield) as a light yellow solid.
Amplification Reaction of 4a.
A mixture of cyclopropyl(2-(phenylethynyl)phenyl)methanone (1a, 468 mg, 1.8 mmol), 4-
tertbutylbenzenediazonium tetrafluoroborate (2a, 1113.75 mg, 4.5 mmol), DABSO (3, 990 mg, 4.5
mmol), PNBB (976.5 mg, 4.5 mmol) and DCE (15 mL) were added in a Schlenk tube. The mixture was
ACS Paragon Plus Environment
12

Page 13 of 31
The Journal of Organic Chemistry
o
stirred in oil bath at 85 C for about 2 hours. After the reaction was completed (detected by TLC,
petroleum ether/ethyl acetate = 4:1), the reaction mixture was concentrated by vacuum distillation and
was purified by flash column chromatography to afford the desired pure product (4a, 667 mg, 71%
yield) as a light yellow solid.
1
2
3
4
5
6
7
8
9
(1Z,3Z)-1-(3-bromopropylidene)-3-(((4-(tert-butyl)phenyl)sulfonyl)(phenyl)methylene)-1,3-
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
o
1
dihydroisobenzofuran (4a). Yield 43 mg, 75%, as a light yellow solid; mp 178-179 C; H NMR (400
MHz, CDCl3; δ, ppm) 7.95 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.52-7.49 (m, 4H), 7.40 (d, J =
6.4 Hz, 2H), 7.37-7.33 (m, 1H), 7.04-7.00 (m, 1H), 6.09 (d, J = 8.0 Hz, 1H), 5.49-5.45 (m, 1H), 3.53-
3.52 (m, 2H), 3.14-3.08 (m, 2H), 1.34 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3; δ, ppm) 156.7, 156.3,
152.4, 132.2, 131.4, 129.5, 129.3, 127.7, 125.9, 124.8, 119.7, 100.6, 35.2, 31.9, 31.1, 29.4; IR (KBr, ν,
cm-1): 2962, 1616, 1316, 1152, 1123, 1104, 1079, 862, 752; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
for C28H27BrO3SNa 545.0762, Found 545.0766.
(1Z,3Z)-1-(3-bromopropylidene)-3-(((4-(tert-butyl)phenyl)sulfonyl)(p-tolyl)methylene)-1,3-
o
1
dihydroisobenzofuran (4b) Yield 63 mg, 59%, as a light yellow solid; mp 161-162 C; H NMR (400
MHz, CDCl3; δ, ppm) 7.98 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 6.8 Hz, 1H), 7.40-
7.29 (m, 6H), 7.09-7.05 (m, 1H), 6.21 (d, J = 8.0 Hz, 1H), 5.50-5.46 (m, 1H), 3.57-3.53 (m, 2H), 3.15-
3.10 (m, 2H), 2.49 (s, 3H), 1.37 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3; δ, ppm) 156.6, 156.2, 152.4,
131.9, 131.3, 130.1, 129.2, 127.6, 125.8, 124.9, 119.7, 100.5, 35.2, 31.9, 31.2, 29.4, 21.6; IR (KBr, ν,
cm-1): 2955, 1627, 1472, 1310, 1145, 1106, 1078, 868, 755; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
for C29H29BrO3SNa 559.0918, Found 559.0944.
(1Z,3Z)-1-(3-bromopropylidene)-3-(((4-(tert-butyl)phenyl)sulfonyl)(4-ethylphenyl)methylene)-1,3-
o
1
dihydroisobenzofuran (4c) Yield 78 mg, 71%, as a light yellow solid; mp 152-153 C; H NMR (400
MHz, CDCl3; δ, ppm) 7.97-7.95 (m, 2H), 7.57-7.55 (m, 2H), 7.49 (d, J = 7.6 Hz, 1H), 7.37-7.29 (m,
5H), 7.06-7.02 (m, 1H), 6.15 (d, J = 8.0 Hz, 1H), 5.48-5.44 (m, 1H), 3.54-3.51 (m, 2H), 3.13-3.07 (m,
2H), 2.80-2.74 (m, 2H), 1.34 (s, 9H), 1.32 (d, J = 7.6 Hz, 3H); C{1H} NMR (100 MHz, CDCl3; δ,
13
ppm) 156.6, 152.4, 145.7, 140.0, 134.6, 131.9, 131.3, 129.2, 128.8, 128.2, 127.7, 125.8, 124.9, 119.7,
ACS Paragon Plus Environment
13

The Journal of Organic Chemistry
Page 14 of 31
116.1, 100.4, 35.2, 31.9, 31.2, 29.4, 28.8, 15.3; IR (KBr, ν, cm-1): 2963, 1628, 1303, 1146, 1106, 1079,
1059, 852, 756; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C30H31BrO3SNa 573.1075, Found
573.1094.
1
2
3
4
5
6
7
8
(1Z,3Z)-1-(3-bromopropylidene)-3-((4-(tert-butyl)phenyl)((4-(tert-butyl)phenyl)sulfonyl)methylene)-1,3-
9
o
1
dihydroisobenzofuran (4d) Yield 79 mg, 68%, as a light yellow solid; mp 207-208 C; H NMR (400
MHz, CDCl3; δ, ppm) 7.97 (d, J = 8.4 Hz, 2H), 7.57-7.52 (m, 3H), 7.50-7.48 (m, 2H), 7.37-7.31 (m,
3H), 7.04-7.00 (m, 1H), 6.10 (d, J = 8.0 Hz, 1H), 5.47-5.44 (m, 1H), 3.54-3.50 (m, 2H), 3.12-3.07 (m,
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
2H), 1.40 (s, 9H), 1.34 (s, 9H); C{1H} NMR (100 MHz, CDCl3; δ, ppm) 156.6, 156.2, 152.6, 152.4,
13
131.9, 131.7, 129.2, 127.7, 126.2, 125.8, 124.8, 119.7, 100.4, 35.2, 34.9, 31.9, 31.4, 31.2, 29.4; IR (KBr,
ν, cm-1): 2961, 1616, 1472, 1317, 1168, 1107, 1080, 874, 753; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
for C32H35BrO3SNa 601.1388, Found 601.1391.
(1Z,3Z)-1-(3-bromopropylidene)-3-(((4-(tert-butyl)phenyl)sulfonyl)(4-methoxyphenyl)methylene)-1,3-
o
1
dihydroisobenzofuran (4e) Yield 97 mg, 88%, as a light yellow solid; mp 130-131 C; H NMR (400
MHz, CDCl3; δ, ppm) 7.94 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.0 Hz, 1H), 7.36-
7.30 (m, 3H), 7.08-7.02 (m, 3H), 6.22 (d, J = 8.0 Hz, 1H), 5.48-5.44 (m, 1H), 3.90 (s, 3H), 3.54-3.51
(m, 2H), 3.12-3.07 (m, 2H), 1.34 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3; δ, ppm) 160.5, 156.6,
156.3, 152.5, 133.4, 131.3, 129.3, 127.6, 125.8, 124.9, 119.7, 114.7, 100.5, 55.4, 35.2, 31.9, 31.2, 29.4;
IR (KBr, ν, cm-1): 2965, 1618, 1508, 1316, 1173, 1105, 1058, 868, 753; HRMS (ESI-TOF) m/z: [M +
Na]+ Calcd for C29H29BrO4SNa 575.0868, Found 575.0868.
(1Z,3Z)-1-(3-bromopropylidene)-3-(((4-(tert-butyl)phenyl)sulfonyl)(4-chlorophenyl)methylene)-1,3-
o
1
dihydroisobenzofuran (4f) Yield 67 mg, 60%, as a light yellow solid; mp 144-145 C; H NMR (400
MHz, CDCl3; δ, ppm) 7.94 (d, J = 8.4 Hz, 2H), 7.56-7.46 (m, 6H), 7.38-7.36(m, 2H), 6.99-6.97 (m,
1H), 5.98 (d, J = 8.4 Hz, 1H), 5.50-5.46 (m, 1H), 3.55-3.51 (m, 2H), 3.14-3.08 (m, 2H), 1.34 (s, 9H);
13C{1H} NMR (100 MHz, CDCl3; δ, ppm) 156.9, 155.4, 151.3, 139.6, 132.0, 130.9, 129.7, 129.7, 129.4,
127.7, 125.9, 125.9, 119.8, 102.0, 35.2, 31.7, 31.1, 29.3; IR (KBr, ν, cm-1): 2961, 1773, 1718, 1654,
ACS Paragon Plus Environment
14

Page 15 of 31
The Journal of Organic Chemistry
1541, 1490, 1322, 1106, 754, 675; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C28H26BrClO3SNa
579.0372, Found 579.0377.
1
2
3
4
5
6
(1Z,3Z)-1-(3-bromopropylidene)-3-(((4-(tert-butyl)phenyl)sulfonyl)(thiophen-2-yl)methylene)-1,3-
o
1
7
dihydroisobenzofuran (4g) Yield 48 mg, 45%, as a light yellow solid; mp 210-211 C; H NMR (400
MHz, CDCl3; δ, ppm) 7.99 (d, J = 8.8 Hz, 2H), 7.59-7.51 (m, 5H), 7.43-7.40 (m, 1H), 7.21-7.19 (m,
1H), 6.31 (d, J = 8.0 Hz, 1H), 5.54-5.50 (m, 1H), 3.55-3.51 (m, 2H), 3.15-3.10 (m, 2H), 1.34 (s, 9H);
13C{1H} NMR (100 MHz, CDCl3; δ, ppm) 158.2, 156.9, 152.4, 139.5, 131.8, 129.5, 129.5, 127.9, 127.8,
125.9, 125.1, 119.7, 108.5, 101.7, 35.3, 31.8, 31.2, 29.4; IR (KBr, ν, cm-1): 2965, 1616, 1573, 1490,
1384, 1315, 1281, 1077, 763, 607; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C26H26BrO3S2Na
552.0404, Found 552.0408.
8
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
(1Z,3Z)-1-(3-bromopropylidene)-3-(phenyl(o-tolylsulfonyl)methylene)-1,3-dihydroisobenzofuran (4h)
o
1
Yield 60 mg, 63%, as a light yellow solid; mp 147-148 C; H NMR (400 MHz, CDCl3; δ, ppm) 8.19-
8.16 (m, 1H), 7.51-7.27(m, 10H), 7.06-7.02 (m, 1H), 6.15 (d, J = 8.0 Hz, 1H), 5.43-5.39 (m, 1H), 3.43-
3.40 (m, 2H), 2.83-2.79 (m, 2H), 2.64 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3; δ, ppm) 155.4, 152.1,
137.9, 134.7, 132.9, 132.6, 132.2, 130.3, 129.6, 129.2, 126.1, 124.8, 119.7, 100.6, 32.0, 28.9, 20.6; IR
(KBr, ν, cm-1): 2966, 1625, 1305, 1146, 1105, 1092, 1079, 826, 720; HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C25H21BrO3SNa 503.0292, Found 503.0284.
(1Z,3Z)-1-(3-bromopropylidene)-3-(((4-(tert-butyl)phenyl)sulfonyl)(p-tolyl)methylene)-1,3-
o
1
dihydroisobenzofuran (4i) Yield 56 mg, 58%, as a light yellow solid; mp 99-100 C; H NMR (400
MHz, CDCl3; δ, ppm) 8.02 (d, J = 7.2 Hz, 2H), 7.58-7.48 (m, 5H), 7.37-7.34 (m, 1H), 7.30 (d, J = 8.0
Hz, 2H), 7.25 (d, J = 4.8 Hz, 2H), 7.06-7.02 (m, 1H), 6.17 (d, J = 8.0 Hz, 1H), 5.48-5.44 (m, 1H), 3.55-
3.51 (m, 2H), 3.11-3.06 (m, 2H), 2.46 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3; δ, ppm) 156.4, 152.4,
142.9, 139.6, 134.6, 132.8, 131.9, 131.7, 131.4, 130.0, 129.2, 128.8, 127.8, 124.9, 119.7, 115.6, 100.7,
31.9, 29.3, 21.6; IR (KBr, ν, cm-1): 3026, 1614, 1317, 1152, 1119, 1078, 1058, 872, 753; HRMS (ESI-
TOF) m/z: [M + Na]+ Calcd for C25H21BrO3SNa 503.0292, Found 503.0299.
ACS Paragon Plus Environment
15

The Journal of Organic Chemistry
Page 16 of 31
(1Z,3Z)-1-(3-bromopropylidene)-3-(((4-(tert-butyl)phenyl)sulfonyl)(p-tolyl)methylene)-5-methyl-1,3-
1
2
3
4
5
6
7
8
9
o
1
dihydroisobenzofuran (4j) Yield 67 mg, 61%, as a light yellow solid; mp149-150 C; H NMR (400
MHz, CDCl3; δ, ppm) 7.95 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.38-7.28 (m, 6H), 7.17 (d, J =
8.4 Hz, 1H), 5.93 (s, 1H), 5.39-5.36 (m, 1H), 3.53-3.49 (m, 2H), 3.06 (d, J = 7.2 Hz, 2H), 2.47 (s, 3H),
2.08 (s, 3H), 1.34 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3; δ, ppm) 156.5, 156.3, 152.4, 139.4, 132.6,
132.0, 129.9, 127.6, 125.8, 124.9, 119.4, 99.5, 35.2, 32.0, 31.2, 31.1, 29.3, 21.7, 21.5; IR (KBr, ν, cm-1):
2960, 1623, 1312, 1145, 1134, 1107, 1079, 826, 721; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C30H31BrO3SNa 573.0750, Found 573.0785.
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
(1Z,3Z)-1-(3-bromopropylidene)-3-(((2-chlorophenyl)sulfonyl)(p-tolyl)methylene)-5-methyl-1,3-
o
1
dihydroisobenzofuran (4k) Yield 62 mg, 59%, as a light yellow solid; mp 126-127 C; H NMR (400
MHz, CDCl3; δ, ppm) 8.45-8.43 (m, 1H), 7.61-7.58 (m, 2H), 7.57-7.55 (m, 1H), 7.51 (d, J = 8.0 Hz,
2H), 7.42 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 1H), 6.14 (s, 1H), 5.34-5.30
(m, 1H), 3.39-3.35 (m, 2H), 2.70-2.51 (m, 2H), 2.51 (s, 3H), 2.17 (s, 3H); C{1H} NMR (100 MHz,
13
CDCl3; δ, ppm) 152.2, 139.7, 139.6, 133.8, 132.7, 132.6, 131.8, 131.5, 129.8, 127.1, 125.0, 119.4, 99.4,
31.8, 29.0, 21.7, 21.6; IR (KBr, ν, cm-1): 2962, 1654, 1625, 1612, 1570, 1347, 1323, 1212, 858, 632,
579; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C26H22BrClO3SNa 551.0059, Found 551.0059.
(1Z,3Z)-1-(3-bromopropylidene)-3-(((3-chlorophenyl)sulfonyl)(p-tolyl)methylene)-5-methyl-1,3-
o
1
dihydroisobenzofuran (4l) Yield 67 mg, 63%, as a light yellow solid; mp 124-125 C; H NMR (400
MHz, DMSO-d6; δ, ppm) 7.95 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.73-7.67 (m,
2H), 7.40-7.35 (m, 3H), 7.28 (d, J = 7.2 Hz, 2H), 5.81 (s, 1H), 5.74-5.70 (m, 1H), 3.70-3.66 (m, 2H),
2.97-2.92 (m, 2H), 2.45 (s, 3H), 2.03 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 156.7,
151.8, 144.8, 139.9, 139.8, 134.2, 133.8, 132.4, 131.9, 131.1, 130.4, 127.5, 127.1, 126.3, 124.5, 120.8,
114.5, 102.1, 33.4, 29.5, 21.7, 21.5; IR (KBr, ν, cm-1): 2965, 1685, 1654, 1616, 1570, 1541, 1308, 1082,
817, 695; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C26H22BrClO3SNa 551.0059, Found 551.0060.
(1Z,3Z)-1-(3-bromopropylidene)-3-(((3,4-dichlorophenyl)sulfonyl)(p-tolyl)methylene)-5-methyl-1,3-
o
1
dihydroisobenzofuran (4m) Yield 72 mg, 64%, as a light yellow solid; mp 130-131 C; H NMR (400
ACS Paragon Plus Environment
16

Page 17 of 31
The Journal of Organic Chemistry
MHz, DMSO-d6; δ, ppm) 8.24-8.22 (m, 2H), 8.11 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.8 Hz,
1H), 7.72 (s, 2H), 7.40-7.38 (m, 1H), 7.31 (s, 1H), 5.82 (s, 1H), 5.75-5.71 (m, 1H), 3.70-3.66 (m, 2H),
2.96-2.94 (m, 2H), 2.45 (s, 3H), 2.03 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 156.9,
151.8, 147.6, 146.1, 143.2, 139.9, 137.0, 134.1, 132.4, 131.0, 130.4, 129.2, 127.7, 127.4, 124.3, 120.8,
114.1, 102.3, 32.6, 29.5, 21.7, 21.5; IR (KBr, ν, cm-1):2962, 1625, 1611, 1483, 1451, 1308, 1146, 1030,
858, 683, 632; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C26H21BrCl2O3SNa 584.9670, Found
584.9681.
1
2
3
4
5
6
7
8
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
(1Z,3Z)-1-(3-bromopropylidene)-3-(((4-(tert-butyl)phenyl)sulfonyl)(4-chlorophenyl)methylene)-5-
o
1
methyl-1,3-dihydroisobenzofuran (4n) Yield 74 mg, 65%, as a light yellow solid; mp 122-123 C; H
NMR (400 MHz, CDCl3; δ, ppm) 7.92 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.4 Hz,
2H), 7.40 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 7.6 Hz, 1H), 5.97 (s, 1H), 5.44-5.40
13
(m, 1H), 3.53-3.50 (m, 2H), 3.12-3.06 (m, 2H), 2.12 (s, 3H), 1.34 (s, 9H); C{1H} NMR (100 MHz,
CDCl3; δ, ppm) 156.8, 152.3, 139.8, 135.7, 133.6, 132.9, 129.5, 127.6, 125.9, 124.7, 119.6, 100.2, 35.2,
31.9, 31.1, 29.4, 21.8; IR (KBr, ν, cm-1):2965, 1615, 1508, 1317, 1305, 1151, 1119, 1079, 998, 872,
753; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C29H28BrClO3SNa 593.0529, Found 593.0534.
(1Z,3Z)-1-(3-bromopropylidene)-3-(((4-(tert-butyl)phenyl)sulfonyl)(phenyl)methylene)-5-fluoro-1,3-
o
1
dihydroisobenzofuran (4o) Yield 70 mg, 65%, as a light yellow solid; mp 159-160 C; H NMR (400
MHz, CDCl3; δ, ppm) 7.95 (d, J = 8.4 Hz, 2H), 7.59-7.53 (m, 3H), 7.42-7.38 (m, 3H), 7.25-7.21 (m,
2H), 7.12-7.08 (m, 1H), 6.18 (d, J = 8.0 Hz, 1H), 5.53-5.50 (m, 1H), 3.58-3.54 (m, 2H), 3.17-3.11 (m,
2H), 1.37 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3; δ, ppm) 164.7(1JCF = 248.4 Hz), 162.3, 156.8,
152.3, 134.7, 134.2(3JCF = 8.4 Hz), 131.6, 131.5, 129.3, 127.6, 127.2(4JCF = 3.4 Hz), 125.9, 124.6,
119.8, 116.6(2JCF = 21.5 Hz), 116.3, 100.9, 35.2, 31.8, 31.1, 29.3; IR (KBr, ν, cm-1): 2965, 1625, 1303,
1201, 1145, 1106, 1079, 869, 755; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C28H26BrFO3SNa
563.0668, Found 563.0665.
(1Z,3Z)-1-(3-bromopropylidene)-3-((4-(tert-butyl)phenyl)((4-(tert-butyl)phenyl)sulfonyl)methylene)-5-
o
1
chloro-1,3-dihydroisobenzofuran (4p) Yield 82 mg, 67%, as a light yellow solid; mp 223-224 C; H
ACS Paragon Plus Environment
17

The Journal of Organic Chemistry
Page 18 of 31
NMR (400 MHz, CDCl3; δ, ppm) 7.95 (d, J = 8.4 Hz, 2H), 7.57-7.53 (m, 5H), 7.40 (d, J = 8.4 Hz, 1H),
7.31-7.29 (m, 2H), 5.78 (d, J = 1.6 Hz, 1H), 5.46-5.42 (m, 1H), 3.53 (m, 2H), 3.09 (m, 2H), 1.40 (s,
10H), 1.35 (s, 10H) 13C{1H} NMR (100 MHz, CDCl3; δ, ppm) 156.8, 155.0, 153.2, 151.8, 139.7, 135.1,
131. 5, 127.7, 126.4, 125.9, 124.9, 120.7, 101.2, 35.2, 34.9, 31.8, 31.3, 31.1, 29.3; IR (KBr, ν, cm-1):
2964, 1627, 1303, 1197, 1131, 1105, 1079, 822, 753; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C32H34BrClO3SNa 635.0998, Found 635.0111.
1
2
3
4
5
6
7
8
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
(1Z,3Z)-3-(3-bromopropylidene)-1-(((4-(tert-butyl)phenyl)sulfonyl)(4-chlorophenyl)methylene)-5-
o
1
methyl-1,3-dihydroisobenzofuran (4q) Yield 74 mg, 65%, as a light yellow solid; mp 132-133 C; H
NMR (400 MHz, CDCl3; δ, ppm) 7.93 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 8.4 Hz,
2H), 7.41-7.35 (m, 3H), 6.91 (d, J = 8.0 Hz, 1H), 6.10 (d, J = 8.4 Hz, 1H), 5.47-5.44 (m, 1H), 3.54-3.51
(m, 2H), 3.13-3.08 (m, 2H), 2.40 (s, 3H), 1.34 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3; δ, ppm) 156.8,
156.7, 152.3, 142.6, 135.7, 133.7, 130.8, .129.9, 129.6, 129.1, 127.6, 125.9, 124.4, 120.0, 100.8, 35.3,
31.9, 31.2, 29.3, 21.7; IR (KBr, ν, cm-1): 2965, 1624, 1487, 1315, 1144, 1124, 1080, 868, 755; HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C29H28BrClO3SNa 593.0529, Found 593.0545.
(1Z,3Z)-3-(3-bromopropylidene)-1-(((4-(tert-butyl)phenyl)sulfonyl)(p-tolyl)methylene)-5-fluoro-1,3-
o
1
dihydroisobenzofuran (4r) Yield 78 mg, 70%, as a light yellow solid; mp 136-137 C; H NMR (400
MHz, CDCl3; δ, ppm) 7.93 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.32-7. 26(m, 3H), 7.25 (s,
1H), 7.15-7.12 (m, 1H), 6.78-6.73 (m, 1H), 6.14-6.11 (m, 1H), 5.47-5.43 (m, 1H), 3.54-3.51 (m, 2H),
13
3.13-3.07 (m, 2H), 2.46 (s, 3H), 1.34 (s, 9H); C{1H} NMR (100 MHz, CDCl3; δ, ppm) 165.8 (1JCF
=
251.6 Hz), 163.3, 156.7, 155.4, 151.6, 151.6, 139.8 (3JCF = 17.9 Hz), 131.8, 130.2, 127.9(4JCF = 7.5 Hz),
127.6, 125.8, 117.5(2JCF = 23.9 Hz), 117.3, 106.5, 106.3, 101.8, 35.2, 31.7, 31.1, 29.3, 21.6; IR (KBr, ν,
cm-1): 2962, 1634, 1299, 1182, 1118, 1105, 1080, 833, 752; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
for C29H28BrFO3SNa 577.0824, Found 577.0844.
(1Z,3Z)-3-(3-bromopropylidene)-1-(((4-(tert-butyl)phenyl)sulfonyl)(phenyl)methylene)-5-chloro-1,3-
o
1
dihydroisobenzofuran (4s) Yield 69 mg, 62%, as a light yellow solid; mp 139-140 C; H NMR (400
MHz, CDCl3; δ, ppm) 7.93 (d, J = 8.4 Hz, 2H), 7.56-7.46 (m, 6H), 7.38-7.35 (m, 2H), 6.98-6.97 (m,
ACS Paragon Plus Environment
18

Page 19 of 31
The Journal of Organic Chemistry
1H), 5.98 (d, J = 8.4 Hz, 1H), 5.49-5.46 (m, 1H), 3.55-3.51 (m, 2H), 3.14-3.08 (m, 2H), 1.34 (s, 9H),
13C{1H} NMR (100 MHz, CDCl3; δ, ppm) 156.9, 155.3, 151.4, 139.7, 137.9, 136.2, 132.0, 130.9, 1,
129.7, 129.7, 129.3, 127.7, 125.9, 119.8, 101.1, 43.6, 35.2, 31.1, 29.2; IR (KBr, ν, cm-1): 2962, 1625,
1302, 1147, 1130, 1103, 1080, 824, 758; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C28H26BrClO3SNa 579.0372, Found 579.0376.
1
2
3
4
5
6
7
8
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
(1Z,3Z)-3-(3-bromopropylidene)-1-(((4-(tert-butyl)phenyl)sulfonyl)(p-tolyl)methylene)-5-chloro-1,3-
o
1
dihydroisobenzofuran (4t) Yield 76 mg, 66%, as a light yellow solid; mp 145-146 C; H NMR (400
MHz, CDCl3; δ, ppm) 7.95 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.49 (s, 1H), 7.33 (d, J = 7.6
Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.04-7.02 (m, 1H), 6.09 (d, J = 8.8 Hz, 1H), 5.50-5.47 (m, 1H), 3.57-
3.53 (m, 2H), 3.15-3.09 (m, 2H), 2.49 (s, 3H), 1.37 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3; δ, ppm)
156.8, 155.2, 151.4, 139.8, 131.8, 130.1, 129.7, 127.7, 126.0, 125.9, 119.7, 101.8, 35.2, 31.7, 31.1, 29.3,
21.6; IR (KBr, ν, cm-1): 2965, 1615, 1509, 1399, 1290, 1194, 1182, 1080, 955, 753. HRMS (ESI-TOF)
m/z: [M + Na]+ Calcd for C29H28BrClO3SNa 593.0529, Found 593.0530.
(1Z,3Z)-3-(3-bromopropylidene)-1-(((4-(tert-butyl)phenyl)sulfonyl)(4-chlorophenyl)methylene)-5-
o
1
chloro-1,3-dihydroisobenzofuran (4u) Yield 91 mg, 77%, as a light yellow solid; mp 166-167 C; H
NMR (400 MHz, CDCl3; δ, ppm) 7.90 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.8 Hz, 2H), 7.50-7.48 (m, 3H),
7.31 (d, J = 8.4 Hz, 2H), 7.06-7.03 (m, 1H), 6.11 (d, J = 8.8 Hz, 1H), 5.52-5.48 (m, 1H), 3.55-3.51 (m,
13
2H), 3.14-3.08 (m, 2H), 1.34 (s, 9H); C{1H} NMR (100 MHz, CDCl3; δ, ppm) 157.1, 155.6, 151.2,
139.4, 133.4, 129.9, 129.7, 127.6, 126.0, 125.7, 119.9, 102.5, 35.3, 31.6, 31.1, 29.3; IR (KBr, ν, cm-1):
2963, 1624, 1303, 1290, 1148, 1089, 1079, 824, 755; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C28H25BrCl2O3SNa 612.9983, Found 612.9980.
General Procedure for the Synthesis of 4v-4cc.
Example for the Synthesis of 4v. A mixture of cyclopropyl(2-(phenylethynyl)phenyl)methanone (1a,
0.2 mmol, 49.2 mg), 4- tertbutylbenzenediazonium tetrafluoroborate (2, 0.8 mmol, 198.4 mg), DABSO
(3, 0.8 mmol, 176.0 mg), PNBC (0.8 mmol, 136.8 mg) and DCE (2.0 mL) were added in a Schlenk
o
tube. The mixture was stirred in oil bath at 85 C for about 2 hours. After the reaction was completed
ACS Paragon Plus Environment
19

The Journal of Organic Chemistry
Page 20 of 31
(detected by TLC, petroleum ether/ethyl acetate = 4:1), the reaction mixture was concentrated by
vacuum distillation and was purified by flash column chromatography to afford the desired pure product
4v as a light yellow solid.
1
2
3
4
5
6
7
8
(1Z,3Z)-1-(((4-(tert-butyl)phenyl)sulfonyl)(phenyl)methylene)-3-(3-chloropropylidene)-1,3-
9
o
1
dihydroisobenzofuran (4v) Yield 72 mg, 75%, as a light yellow solid; mp 204-205 C; H NMR (400
MHz, CDCl3; δ, ppm) 7.95 (d, J = 8.4 Hz, 2H), 7.56-7.48 (m, 6H), 7.41-7.33 (m, 3H), 7.04-7.00 (m,
1H), 6.09 (d, J = 8.0 Hz, 1H), 5.51-5.47 (m, 1H), 3.70-3.67 (m, 2H), 3.02-3.00 (m, 2H), 1.34 (s, 9H);
13C{1H} NMR (100 MHz, CDCl3; δ, ppm) 156.7, 152.5, 132.2, 131.4, 131.2, 129.5, 129.3, 127.7, 125.8,
124.8, 119.7, 99.7, 43.8, 35.2, 31.1, 29.3; IR (KBr, ν, cm-1): 2957, 1616, 1593, 1317, 1155, 1107, 1074,
857, 756; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C28H27ClO3SNa 501.1267, Found 501.1287.
(1Z,3Z)-1-(((4-(tert-butyl)phenyl)sulfonyl)(4-chlorophenyl)methylene)-3-(3-chloropropylidene)-1,3-
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
o
1
dihydroisobenzofuran (4w) Yield 53 mg, 52%, as a light yellow solid; mp 137-138 C; H NMR (400
MHz, CDCl3; δ, ppm) 7.93 (d, J = 8.8 Hz, 2H), 7.57-7.44 (m, 6H), 7.38-7.36 (m, 2H), 6.99-6.96 (m,
1H), 5.97 (d, J = 8.4 Hz, 1H), 5.41-5.48 (m, 1H), 3.70-3.69 (m, 2H), 3.01-2.98 (m, 2H), 1.34 (s, 9H).
13C{1H} NMR (100 MHz, CDCl3; δ, ppm) 156.9, 155.4, 151.4, 139.6, 137.9, 136.2, 132.0, 130.9, 129.7,
129.7, 129.4, 127.7, 125.9, 119.8, 101.1, 43.6, 35.2, 31.1, 29.2, IR (KBr, ν, cm-1):2967, 1623, 1590,
1474, 1307, 1278, 1149, 1091, 858, 735; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C28H26Cl2O3SNa
535.0877, Found 535.0879.
(1Z,3Z)-3-(((4-(tert-butyl)phenyl)sulfonyl)(4-chlorophenyl)methylene)-1-(3-chloropropylidene)-5-
o
1
methyl-1,3-dihydroisobenzofuran (4x) Yield 67 mg, 64%, as a light yellow solid; mp 203-204 C; H
NMR (400 MHz, CDCl3; δ, ppm) 7.92 (d, J = 8.8 Hz, 2H), 7.55-7.48 (m, 4H), 7.39 (d, J = 8.0 Hz, 1H),
7.34 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.0 Hz, 1H), 5.97 (s, 1H), 5.46-5.42 (m, 1H), 3.69-3.65 (t, m, 2H),
3.02-2.97 (m, 2H), 2.12 (s, 3H), 1.34 (s, 9H); C{1H} NMR (100 MHz, CDCl3; δ, ppm) 156.8, 152.4,
13
139.8, 135.7, 133.6, 132.9, 132.5, 131.7, 129.8, 129.5, 127.6, 125.9, 124.7, 119.6, 99.3, 43.8, 35.2, 31.1,
29.3, 21.7; IR (KBr, ν, cm-1): 2964, 1624, 1590, 1311, 1145, 1108, 1080, 911, 754; HRMS (ESI-TOF)
m/z: [M + Na]+ Calcd for C29H28Cl2O3SNa 549.1034, Found 549.1007.
ACS Paragon Plus Environment
20

Page 21 of 31
The Journal of Organic Chemistry
(1Z,3Z)-3-(((4-bromophenyl)sulfonyl)(p-tolyl)methylene)-1-(3-chloropropylidene)-5-methyl-1,3-
1
2
3
4
5
6
7
8
9
o
11
dihydroisobenzofuran (4y) Yield 67 mg, 64%, as a light yellow solid; mp 125-126 C; H NMR (400
MHz, DMSO-d6; δ, ppm) 7.87 (s, 3H), 7.73 (d, J = 8.0 Hz, 1H), 7.39-7.36 (m, 3H), 7.26 (d, J = 7.6 Hz,
2H), 5.80 (s, 1H), 5.73-5.69 (m, 1H), 3.67-3.63 (m, 2H), 2.96-2.91 (m, 2H), 2.45 (s, 3H), 2.04 (s, 3H);
13C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 156.4, 151.8, 142.3, 139.8, 133.9, 132.8, 132.3, 131.2,
130.3, 129.6, 127.7, 120.8, 104.4, 102.0, 99.9, 33.5, 29.5, 21.8, 21.5; IR (KBr, ν, cm-1): 2965, 1633,
1488, 1394, 1278, 1200, 1123, 1010, 821, 716; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C26H22BrClO3SNa 551.0059, Found 551.0066.
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
(1Z,3Z)-3-(((4-(tert-butyl)phenyl)sulfonyl)(4-chlorophenyl)methylene)-5-chloro-1-(3-
chloropropylidene)-1,3-dihydroisobenzofuran (4z) Yield 79 mg, 72%, as a light yellow solid; mp 145-
146 oC; 1H NMR (400 MHz, CDCl3; δ, ppm) 7.90 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 8.8 Hz, 2H), 7.51 (d,
J = 8.4 Hz, 2H), 7.45 (d, J = 8.0 Hz, 1H), 7.36-7.30 (m, 3H), 6.13 (d, J = 1.6 Hz, 1H), 5.51-5.47 (m,
1H), 3.55-3.51 (m, 2H), 3.13-3.07 (m, 2H), 1.34 (s, 9H); C{1H} NMR (100 MHz, CDCl3; δ, ppm)
13
157.1, 155.1, 151.6, 139.3, 133.3, 132.0, 129.7, 127.7, 126.0, 124.4, 120.9, 101.8, 35.3, 31.6, 31.1, 29.3;
IR (KBr, ν, cm-1): 2933, 1720, 1604, 1505, 1470, 1384, 1331, 1260, 1151, 1086, 1028, 812; HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C28H25Cl3O3SNa 569.0488, Found 569.0497.
(1Z,3Z)-1-(((4-(tert-butyl)phenyl)sulfonyl)(p-tolyl)methylene)-3-(3-chloropropylidene)-5-fluoro-1,3-
o
1
dihydroisobenzofuran (4aa) Yield 66 mg, 65%, as a light yellow solid; mp 124-125 C; H NMR (400
MHz, CDCl3; δ, ppm) 7.93 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.14-
7.12 (m, 1H), 6.77-6.72 (m, 1H), 6.14-6.11 (m, 1H), 5.48-5.45 (m, 1H), 3.70-3.66 (m, 2H), 3.03-2.98
(m, 2H), 2.46 (s, 3H), 1.34 (s, 9H); C{1H} NMR (100 MHz, CDCl3; δ, ppm) 165.8(1JCF = 251.8 Hz),
13
156.7, 155.4, 151.7, 139.9(3JCF = 18.7 Hz), 131.8, 130.2, 127.8, 127.7, 125.8, 117.5(2JCF = 23.9 Hz),
117.2, 106.3(4JCF = 2.4 Hz), 106.2, 100.9, 99.9, 43.6, 35.2, 31.1, 29.2, 21.6; IR (KBr, ν, cm-1): 2961,
1629, 1300, 1144, 1124, 1105, 1078, 821, 753; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C29H28ClFO3SNa 533.1329, Found 533.1302.
ACS Paragon Plus Environment
21

The Journal of Organic Chemistry
Page 22 of 31
(1Z,3Z)-1-(((4-(tert-butyl)phenyl)sulfonyl)(phenyl)methylene)-5-chloro-3-(3-chloropropylidene)-1,3-
1
2
3
4
5
6
7
8
9
o
1
dihydroisobenzofuran (4bb) Yield 63 mg, 61%, as a light yellow solid; mp 150-151 C; H NMR (400
MHz, CDCl3; δ, ppm) 7.92 (d, J = 8.4 Hz, 2H), 7.55-7.46 (m, 6H), 7.37-7.35 (m, 2H), 6.99-6.97 (m,
1H), 5.97 (d, J = 8.4 Hz, 1H), 5.51-5.47 (m, 1H), 3.70-3.67 (m, 2H), 3.03-2.99 (m, 2H), 1.34 (s, 9H),
13C{1H} NMR (100 MHz, CDCl3; δ, ppm) 156.9, 155.3, 151.3, 139.7, 137.9, 136.2, 132.0, 130.9, 129.7,
129.4, 127.7, 125.9, 119.8, 101.9, 35.2, 31.7, 31.1, 29.3; IR (KBr, ν, cm-1): 2962, 1626, 1302, 1148,
1131, 1104, 108, HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C28H26Cl2O3SNa 535.0877, Found
535.0883.
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
(1Z,3Z)-1-(((4-(tert-butyl)phenyl)sulfonyl)(4-chlorophenyl)methylene)-3-(3-chloropropylidene)-5-
methoxy-1,3-dihydroisobenzofuran (4cc) Yield 68 mg, 63%, as a light yellow solid; mp 147-148 oC; 1H
NMR (400 MHz, CDCl3; δ, ppm) 7.91 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.4 Hz,
2H), 7.32 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 2.0 Hz, 1H), 6.65-6.63 (m, 1H), 6.10 (d, J = 8.8 Hz, 1H),
5.50-5.47 (m, 1H), 3.80 (s, 3H), 3.70-3.67 (m, 2H), 3.04-2.98 (m, 2H), 1.34 (s, 9H); 13C{1H} NMR (100
MHz, CDCl3; δ, ppm) 162.7, 156.7, 156.6, 152.3, 140.0, 136.9, 135.6, 133.8, 130.0, 129.5, 127.5, 125.9,
124.2, 117.7, 112.7, 102.8, 100.3, 55.7, 43.8, 35.2, 31.1, 29.2; IR (KBr, ν, cm-1): 3026, 1614, 1317,
1152, 1119, 1078, 1058, 872, 753; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C29H28Cl2O4SNa
565.0983, Found 565.0963.
General Procedure for the Synthesis of 5a-5g. Example for the Synthesis of 5b. A mixture of (2-((4-
chlorophenyl)ethynyl)-5-methylphenyl)(cyclopropyl)methanone (1k, 0.2 mmol, 58.8 mg), 4-
nitrobenzenediazonium tetrafluoroborate (2, 0.8 mmol, 189.6 mg), DABSO (3, 0.8 mmol, 176.0 mg)
and DCE (2.0 mL) were added in a Schlenk tube. The mixture was stirred in oil bath at 85 oC for about
2 hours. After the reaction was completed (detected by TLC, petroleum ether/ethyl acetate = 4:1), the
reaction mixture was concentrated by vacuum distillation and was purified by flash column
chromatography to afford the desired pure product 5b as a light yellow solid.
1-((Z)-1-cyclopropyl-3-(((4-fluorophenyl)sulfonyl)(phenyl)methylene)-1,3-dihydroisobenzofuran-1-yl)-
o
1
2-(4-fluorophenyl)diazene (5a) Yield 48 mg, 45%, as a light yellow solid; mp 124-125 C; H NMR
ACS Paragon Plus Environment
22

Page 23 of 31
The Journal of Organic Chemistry
(400 MHz, DMSO; δ, ppm) 8.05-8.01 (m, 2H), 7.71-7.64 (m, 3H), 7.60-7.46 (m, 5H), 7.43-7.37 (m,
3H), 7.33 (d, J = 7.2 Hz, 1H), 7.24-7.20 (m, 1H), 5.97 (d, J = 8.0 Hz, 1H), 1.99-1.94 (m, 1H), 0.81-0.78
(m, 1H), 0.69-0.63 (m, 1H), 0.57-0.53 (m, 1H), 0.36-0.33 (m, 1H).13C{1H} NMR (100 MHz, DMSO; δ,
ppm) 158.9, 147.7, 143.0, 139.4, 132.9(1JCF = 251.6 Hz), 132.2, 131.1(4JCF = 4 Hz), 130.3, 130.0, 129.9,
125.4 (3JCF = 9.4 Hz), 124.6, 123.8, 117.0, 116.8, 116.7(2JCF = 22.7 Hz), 115.4, 110.0, 17.9, 1.9, 0.9;
19F NMR ( 376 MHz, DMSO; δ, ppm) 106.1, 108.1. IR (KBr, ν, cm-1): 2964, 1614, 1572,
1456, 1107, 1045, 1009, 976, 845, 759; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C30H22F2N2NaO3S
551.1217, Found 551.1221.
1
2
3
4
5
6
7
8
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
1-((Z)-3-((4-chlorophenyl)((4-nitrophenyl)sulfonyl)methylene)-1-cyclopropyl-5-methyl-1,3-
dihydroisobenzofuran-1-yl)-2-(4-nitrophenyl)diazene (5b) Yield 66 mg, 52%, as a light yellow solid;
o
1
mp 155-156 C; H NMR (400 MHz, CDCl3; δ, ppm) 8.91 (s, 1H), 8.32-8.28 (m, 2H), 8.24 (d, J = 8.8
Hz, 2H), 7.88 (d, J = 8.8 Hz, 2H), 7.77-7.74 (m, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H),
7.31 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 2.53 (s, 3H), 1.83 (m, 1H), 0.51-0.45 (m, 2H), 0.41-
0.35 (m, 1H), 0.25-0.19 (m, 1H), 13C{1H} NMR (100 MHz, CDCl3; δ, ppm) 163.6, 154.3, 150.1, 149.2,
147.3, 141.7, 140.8, 134.7, 133.7, 133.0, 131.0, 129.2, 128.9, 128.7, 128.7, 124.7, 123.9, 123.5, 122.6,
114.3, 108.5, 77.4, 77.2, 77.0, 76.7, 21.9, 17.4, 1.5, 0.8, IR (KBr, ν, cm-1): 2958, 1613, 1573, 1397,
1200, 1175, 1079, 947, 895, 759; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C31H23ClN4O7SNa
653.0874, Found 653.0883.
1-((Z)-3-((4-(tert-butyl)phenyl)((4-nitrophenyl)sulfonyl)methylene)-5-chloro-1-cyclopropyl-1,3-
dihydroisobenzofuran-1-yl)-2-(4-nitrophenyl)diazene (5c) Yield 92 mg, 67%, as a light yellow solid; mp
o
1
167-168 C; H NMR (400 MHz, CDCl3; δ, ppm) 8.38-8.34 (m, 4H), 8.30-8.26 (m, 2H), 7.74-7.71 (m,
2H), 7.62-7.61 (m, 1H), 7.54-7.51 (m, 2H), 7.43-7.42 (m, 1H), 7.39-7.37 (m, 1H), 7.15-7.12 (m, 1H),
5.83 (d, J = 1.6 Hz, 1H), 1.87-1.85 (m, 1H), 1.43 (s, 9H), 1.06-1.03 (m, 1H), 0.76-0.74 (m, 1H), 0.67-
0.52 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3; δ, ppm) 158.7, 154.1, 153.7, 150.2, 149.4, 148.2, 140.6,
136.1, 133.1, 132.1, 132.1, 131.1, 129.6, 126.8, 126.5, 125.4, 124.8, 124.0, 123.7, 123.3, 115.6, 110.9,
ACS Paragon Plus Environment
23

The Journal of Organic Chemistry
Page 24 of 31
34.9, 31.3, 18.1, 2.7, 1.1, IR (KBr, ν, cm-1): 3056, 1625, 1605, 1574, 1299, 1277, 1108, 1023, 820, 741;
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C34H29ClN4NaO7S 695.1343, Found 695.1342.
1-((Z)-3-((4-chlorophenyl)((4-nitrophenyl)sulfonyl)methylene)-1-cyclopropyl-6-methoxy-1,3-
dihydroisobenzofuran-1-yl)-2-(4-nitrophenyl)diazene (5d) Yield 96 mg, 74%, as a light yellow solid;
1
2
3
4
5
6
7
8
9
o
1
mp 154-155 C; H NMR (400 MHz, CDCl3; δ, ppm) 8.37 (m, 4H), 8.28-8.16 (m, 2H), 7.78-7.66 (m,
2H), 7.57-7.55 (m, 1H), 7.51-7.45 (m, 2H), 7.19-7.17 (m, 1H), 7.07 (d, J = 2.0 Hz, 1H), 6.72-6.69 (m,
1H), 6.18 (d, J = 8.8 Hz, 1H), 3.83 (s, 3H), 1.95-1.88 (m, 1H), 1.09-1.01 (m, 1H), 0.78-0.72 (m, 1H),
0.68-0.50 (m, 2H), 13C{1H} NMR (100 MHz, CDCl3; δ, ppm) 163.2, 160.7, 154.1, 150.0, 149.3, 148.6,
145.1, 136.0, 134.4, 133.3, 129.9, 129.4, 126.6, 124.8, 123.7, 123.3, 116.5, 111.1, 110.7, 107.9, 55.9,
18.1, 2.1, 1.1, IR (KBr, ν, cm-1): 2961, 1619, 1459, 1308, 1271, 1200, 1149, 1124, 1064, 1001, 827;
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C31H23ClN4O8SNa 669.0823, Found 669.0824.
4-(((Z)-3-((4-(tert-butyl)phenyl)((4-cyanophenyl)sulfonyl)methylene)-5-chloro-1-cyclopropyl-1,3-
dihydroisobenzofuran-1-yl)diazenyl)benzonitrile (5e) Yield 78 mg, 62%, as a light yellow solid; mp
135-136 oC; 1H NMR (400 MHz, CDCl3; δ, ppm) 8.18 (d, J = 8.4 Hz, 2H), 7.83-7.77 (m, 4H), 7.68-7.65
(m, 2H), 7.58-7.57 (m, 1H), 7.48-7.47 (m, 2H), 7.39-7.37 (m, 1H), 7.35-7.33 (m 1H), 7.11-7.09 (m,
1H), 5.79 (d, J = 1.6 Hz, 1H), 1.85-1.78 (m, 1H), 1.39 (s, 9H), 1.03-0.94 (m, 1H), 0.73-0.67 (m, 1H),
0.62-0.56 (m, 1H), 0.54-0.46 (m, 1H), 13C{1H} NMR (100 MHz, CDCl3; δ, ppm) 158.6, 153.6, 152.9,
146.8, 140.6, 135.9, 133.4, 133.1, 132.4, 132.0, 131.1, 128.9, 126.8, 126.7, 126.5, 125.4, 124.0, 123.2,
117.9, 117.6, 116.3, 115.5, 115.3, 110.7, 34.9, 31.3, 18.1, 2.0, 1.0, IR (KBr, ν, cm-1): 2964, 1613, 1414,
1323, 1172, 1131, 1063, 1013, 880, 757; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C36H29ClN4O3SNa 655.1547, Found 655.1553.
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-(((Z)-3-((4-chlorophenyl)((4-cyanophenyl)sulfonyl)methylene)-1-cyclopropyl-6-methoxy-1,3-
dihydroisobenzofuran-1-yl)diazenyl)benzonitrile (5f) Yield 78 mg, 64%, as a light yellow solid; mp
o
1
176-177 C; H NMR (400 MHz, CDCl3; δ, ppm) 8.17-8.11 (m, 2H), 7.87-7.84 (m, 1H), 7.87-7.83 (m,
2H), 7.82-7.75 (m, 2H), 7.73-7.65 (m, 2H), 7.57-7.54 (m, 1H), 7.49-7.44 (m, 2H), 7.19-7.16 (m, 1H),
7.05 (d, J = 2.4 Hz, 1H), 6.71-6.68 (mz, 1H), 6.17 (d, J = 8.8 Hz, 1H), 3.83 (s, 3H), 1.91-1.87 (m, 1H),
ACS Paragon Plus Environment
24

Page 25 of 31
The Journal of Organic Chemistry
1.03-1.00 (m, 1H), 0.74-0.71 (m, 1H), 0.63-0.58 (m, 1H), 0.57-0.50 (m, 1H), 13C{1H} NMR (100 MHz,
CDCl3; δ, ppm) 163.2, 160.6, 152.9, 147.2, 145.2, 135.9, 134.4, 133.4, 132.9, 132.3, 131.2, 129.6,
129.3, 128.7, 126.5, 124.9, 123.2, 117.6, 116.5, 115.2, 110.5, 107.9, 55.89, 18.1, 2.0, 1.1, IR (KBr, ν,
cm-1): 2965, 1621, 1572, 1488, 1293, 1139, 1121, 1062, 1019, 900, 748; HRMS (ESI-TOF) m/z: [M +
Na]+ Calcd for C33H23ClN4O4SNa 629.1026, Found 629.1033.
1
2
3
4
5
6
7
8
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
1-((Z)-3-((4-(tert-butyl)phenyl)((4-(trifluoromethyl)phenyl)sulfonyl)methylene)-5-chloro-1-cyclopropyl-
1,3-dihydroisobenzofuran-1-yl)-2-(4-(trifluoromethyl)phenyl)diazene (5g) Yield 83 mg, 58%, as a light
yellow solid; mp 144-145 oC; 1H NMR (400 MHz, CDCl3; δ, ppm) 8.22 (d, J = 8.4 Hz, 2H), 7.77-7.71
(m, 4H), 7.66-7.58 (m, 3H), 7.51-7.44 (m, 3H), 7.33-7.32 (m, 1H), 7.15-7.12 (m, 1H), 5.80 (d, J = 1.6
Hz, 1H), 1.86-1.82 (m, 1H), 1.40 (s, 9H), 1.05-1.00 (m, 1H), 0.75-0.68 (m, 1H), 0.62-0.51 (m, 2H),
13C{1H} NMR (100 MHz, CDCl3; δ, ppm) 158.4, 153.4, 152.8, 146.2, 140.9, 135.8(1JCF = 251.6 Hz),
134.7, 134.4, 134.1, 133.7, 133.4(2JCF = 32.5 Hz), 133.3, 133.1, 132.1(3JCF = 31.3 Hz), 131.8, 131.9,
128.9, 127.1, 126.7, 126.4(6JCF = 3.7 Hz), 126.4, 126.3, 126.3, 125.6, 125.6, 125.6, 125.3, 124.9(5JCF
=
20.0 Hz), 124.8, 123.9, 122.9, 122.3(4JCF = 20.4 Hz), 122.1, 115.8, 110.5, 34.9, 31.3, 17.9, 1.9, 0.9; IR
(KBr, ν, cm-1): 2960, 1629, 1488, 1309, 1174, 1090, 1011, 875, 755, 664; HRMS (ESI-TOF) m/z: [M +
Na]+ Calcd for C36H29ClF6N2O3SNa 741.1389, Found 741.1390.
ASSOCIATED CONTENT
Supporting Information
1H and 13C NMR spectra for all pure products and X-ray crystal data in CIF format for 4r and 5a. This
material is available free of charge via the Internet at http//pubs.acs.org.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
ACS Paragon Plus Environment
25

The Journal of Organic Chemistry
Page 26 of 31
We are grateful for financial support from the NSFC (Nos. 21602087, 21871112 and 21971090),
1
2
3
NSF of Jiangsu Province (BK20160212).
4
5
6
REFERENCES
7
8
9
[1]
For selected reviews, see: (a) Dömling, A.; Wang, W.; Wang, K. Chemistry and Biology of Multicomponent
Reactions. Chem. Rev. 2012, 112, 3083-3135. (b) Jiang, B.; Rajale, T.; Wever, W.; Tu, S.-J.; Li, G. Multicomponent
Reactions for the Synthesis of Heterocycles. Chem. - Asian J. 2010, 5, 2318-2335. (c) skoopmanschap, G.; Ruijter, E.;
Orru, R.-V. Beilstein Phenylation of Some Hydrocarbons with a Phenyl Halide Activated by an Alkali Amide. J. Org.
Chem. 1945, 10, 544-550. (d) Vlaar, T.; Maes, B.-U.; Ruijter, E.; Orru, R. V. Palladium-Catalyzed Migratory Insertion
of Isocyanides: an Emerging Platform in Cross-Coupling Chemistry. Angew. Chem., Int. Ed. 2013, 52, 7084-7097. (e)
Rotstein, B.-H.; Zaretsky, S.; Rai, V.; Yudin, A. K. Small Heterocycles in Multicomponent Reactions. Chem. Rev. 2014,
114, 8323-8359. (f) Brauch, S.; Van Berkel, S.-S.; Westermann, B. Higher-order multicomponent reactions: beyond four
reactants. Chem. Soc. Rev. 2013, 42, 4948-4962.
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
[2]
For selected examples, see: (a) Tian, Y.; Tian, L.; He, X.; Li, C.-J.; Jia, X.; Li, J. Indium(III) Chloride-Catalyzed
Isocyanide Insertion Reaction to Construct Complex Spirooxindole. Org. Lett. 2015, 17, 4874-4877. (b) Jia, S.; Su, S.;
Li, C.; Jia, X.; Li, J. Multicomponent Cascade Cycloaddition Involving Tropone, Allenoate, and Isocyanide: a Rapid
Access to a 7,6,5-Fused Tricyclic Skeleton. Org. Lett. 2014, 16, 5604-5607. (c) Su, S.; Li, C.; Jia, X.; Li, J. Isocyanide-
Based Multicomponent Reactions: Concise Synthesis of Spirocyclic Oxindoles with Molecular Complexity by Using a
[1,5]-Hydrogen Shift as the Key Step. Chem. -Eur. J. 2014, 20, 5905-5909. (d) Wu, C.; Lu, L.-H.; Peng, A.-Z.; Jia, G.-
K.; Peng, C.; Cao, Z.; Tang, Z.; He, W.-M.; Xu, X. Ultrasound-promoted Brønsted acid ionic liquid-catalyzed
hydrothiocyanation of activated alkynes under minimal solvent conditions. Green Chem. 2018, 20, 3683-3688. (e) Yuan,
H.; Tang, C.; Su, S.; Cui, L.; Jia, X.; Li, C.; Li, J. A bicyclization reaction with two molecular allenyl ketones and
isocyanides: synthesis of a lactone-containing azaspirocycle derivative. Chem. Commun., 2019, 55, 7231-7234. (f) Bao,
W.-H.; He, M.; Wang, J.-T.; Peng, X.; Sung, M.; Tang, Z.; Jiang, S.; Cao, Z.; He, W.-M. Iodine-Catalyzed Odorless
Synthesis of S-Thiocarbamates with Sulfonyl Chlorides as a Sulfur Source. J. Org. Chem. 2019, 84, 6065-6071. (g) Wu,
C.; Xiao, H.-J.; Wang, S.-W.; Tang, M.-S.; Tang, Z.-L.; Xia, W.; Li, W.-F.; Cao, Z.; He, W.-M. Natural Deep Eutectic
Solvent-Catalyzed Selenocyanation of Activated Alkynes via an Intermolecular H-Bonding Activation Process. ACS
Sustainable Chem. Eng. 2019, 7, 2169-2175.
ACS Paragon Plus Environment
26

Page 27 of 31
The Journal of Organic Chemistry
[3]
For selected reviews, see: (a) Neochoritis, C. G.; Zhao, T.; Doemling, A. Tetrazoles via Multicomponent Reactions.
Chem. Rev. 2019, 119, 1970-2042; (b) Cherian, R. M.; Harry, N. A.; Saranya, S.; Rohit, K. R.; Anilkumar, G. Copper-
Catalysed Multicomponent Syntheses of Heterocycles. Chem.-Asian J. 2019, 8, 197-233. (c) Preeti, S.; Krishna, N.;
Multicomponent reactions: a sustainable tool to 1,2- and 1,3-azoles, Org. Biomol. Chem. 2018, 16, 9084-9116; (d) da
Silveira Pinto, L. S.; Couri, M. R. C.; de Souza, M. V. N. Multicomponent Reactions in the Synthesis of Complex Fused
Coumarin Derivatives. Curr. Org. Synth. 2018, 15, 21-37. (e) Ibarra, I. A.; Islas, J. A.; Gonzalez, Z. E. Synthesis of
polyheterocycles via multicomponent reactions. Org. Biomol. Chem. 2018, 16, 1402-1418.
1
2
3
4
5
6
7
8
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
[4]
For selected reviews, see: (a) Huang, M.-H.; Hao, W.-J.; Jiang, B.; Recent Advances in Radical ‐ Enabled
Bicyclization and Annulation/1,n-Bifunctionalization Reactions. Chem. – Asian J. 2018, 13, 2958-2977. (b)Wang, F.;
Chen, P.; Liu, G.; Copper-Catalyzed Radical Relay for Asymmetric Radical Transformations. Acc. Chem. Res. 2018, 51,
2036-2046. (c) Chu, X.-Q. Ge, D.; Shen, Z.-L.; Loh, T.-P. Recent Advances in Radical-Initiated C(sp3)–H Bond
Oxidative Functionalization of Alkyl Nitriles. ACS Catal. 2018, 8, 258-271; (d) Qiu, G.; Zhou, K.; Gao, L.; Wu, J.
Insertion of sulfur dioxide via a radical process: an efficient route to sulfonyl compounds. Org. Chem. Front. 2018, 5,
691-705. (e) Qiu, G.; Lai, L.; Cheng, J.; Wu, J. Recent advances in the sulfonylation of alkenes with the insertion of
sulfur dioxide via radical reactions. Chem. Commun. 2018, 54, 10405-10414. (f) Qiu, G.; Zhou, K.; Wu, J. Recent
advances in the sulfonylation of C–H bonds with the insertion of sulfur dioxide. Chem. Commun. 2018, 54, 12561-
12569. (g) Huang, M.-H.; Hao, W.-J.; Li, G.; Tu, S.-J.; Jiang, B. Recent advances in radical transformations of internal
alkynes. Chem. Commun. 2018, 54, 10791-10811
[5]
(a) Goezler, B.; Goezler, T.; Shamma, M. Egenine: a possible intermediate in phthalideisoquinoline biogenesis.
Tetrahedron. 1983, 39, 577−580. (b) Jing, L.; Wenzao, L.; Guoshi, T. Two phthalideisoquinoline hemiacetal alkaloids
from Corydalis decumbens. Planta Med. 1994, 60, 486−487.
[6]
Coote, S. J.; Davies, S. G.; Middlemiss, D.; Naylor, A. Stereoselective synthesis of cis-1,3-disubstituted 1,3-
dihydroisobenzofurans via arenechromium tricarbonyl methodology. J. Organomet. Chem. 1989, 379, 81−88.
[7]
Len, C.; Selouane, A.; Postel, D.; Villa, P.; Aubertin, A. M.; Egron, D.; Gosselin, G.; Périgaud, C. Synthesis
Stability and Biological Evaluation of 1,3-Dihydrobenzo[c]furan Analogue of d4T and Its SATE Pronucleotide.
Nucleosides. Nucleos. Nucleot. Nucl. 2003, 22, 943−945.
[8]
Mancuso, R.; Mehta, S.; Gabriele, B.; Salerno, G.; Jenks, W. S.; Larock, R. C. A Simple and Mild Synthesis of 1H-
Isochromenes and (Z)-1-Alkylidene-1,3-dihydroisobenzofurans by the Iodocyclization of 2-(1-Alkynyl)benzylic
Alcohols. J. Org. Chem. 2010, 75, 897−901.
ACS Paragon Plus Environment
27

The Journal of Organic Chemistry
Page 28 of 31
[9]
(a) Sha, W.; Ni, S.; Han, J.; Pan, Y. Access to Alkyl-Substituted Lactone via Photoredox-Catalyzed
Alkylation/Lactonization of Unsaturated Carboxylic Acids. Org. Lett. 2017, 19, 5900−5903. (b) Sha, W.; Zhang, W.; Ni,
S.; Mei, H.; Han, J.; Pan, Y. Photoredox-Catalyzed Cascade Difluoroalkylation and Intramolecular Cyclization for
Construction of Fluorinated γ-Butyrolactones. J. Org. Chem. 2017, 82, 9824−9831.
1
2
3
4
5
6
7
8
9
[10] Capriati, V.; Florio, S.; Luisi, R.; Perna, F. M.; Salomone, A. Synthesis of 1,3-Dihydrobenzo[c]furans from Ortho-
Lithiated Aryloxiranes. J. Org. Chem. 2006, 71, 3984−3987.
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
[11] (a) Shen, H.; Fu, J.; Gong, J.; Yang, Z. Tunable and Chemoselective Syntheses of Dihydroisobenzofuransand
Indanones via Rhodium-Catalyzed Tandem Reactions of 2-Triazole-benzaldehydes and 2-Triazole-alkylaryl Ketones.
Org. Lett. 2014, 16, 5588-5591. (b) Yuan, H.; Gong, J.; Yang, Z. Stereoselective Synthesis of
Oxabicyclo[2.2.1]heptenes via a Tandem Dirhodium(II)-Catalyzed Triazole Denitrogenation and [3 + 2] Cycloaddition.
Org. Lett. 2016, 18, 5500-5503.
[12] (a) Maity, S.; Saha, M.; Hazra, G.; Ghorai, P. Switchable Chemoselectivity for Organocatalytic, Asymmetric
Malononitrile Addition to ortho-Formyl Chalcones. Org. Lett. 2017, 19, 5872−5875. (b) Yang, X.; Pang, S.; Cheng, F.;
Zhang, Y.; Lin, Y.-W.; Yuan, Q.; Zhang, F.-L.; Huang, Y.-Y. Enantioselective Synthesis of 1,3-Disubstituted 1,3-
Dihydroisobenzofurans via a Cascade Allylboration/Oxo-Michael Reaction of o-Formyl Chalcones Catalyzed by a
Chiral Phosphoric Acid. J. Org. Chem. 2017, 82, 10388−10397.
[13] (a) Bantreil, X.; Bourderioux, A.; Mateo, P.; Hagerman, C. E.; Selkti, M.; Brachet, E.; Belmont, P. Phosphine-
Triggered Selectivity Switch in Silver-Catalyzed o-Alkynylbenzohydroxamic Acid Cycloisomerizations. Org. Lett.
2016, 18, 4814−4817. (b) Mehta, S.; Yao, T.; Larock, R. C. Regio- and Stereoselective Synthesis of Cyclic Imidates via
Electrophilic Cyclization of 2-(1-Alkynyl)benzamides. A Correction. J. Org. Chem. 2012, 77, 10938−10944. (c)
Jithunsa, M.; Ueda, M.; Miyata, O. Copper(II) Chloride-Mediated Cyclization Reaction of N-Alkoxy-ortho-
alkynylbenzamides. Org. Lett. 2011, 13, 518−521. (d) Sekine, K.; Takayanagi, A.; Kikuchi, S.; Yamada, T. Silver-
catalyzed C-C bond formation with carbon dioxide: significant synthesis of dihydroisobenzofurans. Chem. Commun.
2013, 49, 11320−11322. (e) Zhang, W.-Z.; Yang, M.-W.; Yang, X.-T.; Shi, L.-L.; Wang, H.-B.; Lu, X.-B. Double
carboxylation of o-alkynyl acetophenone with carbon dioxide. Org. Chem. Front. 2016, 3, 217−221.
[14] (a) Mahendar, L.; Satyanarayana, G. Domino [Pd]-Catalysis: One-Pot Synthesis of Isobenzofuran-1(3H)-ones. J.
Org. Chem. 2016, 81, 7685−7691. (b) Mahendar, L.; Satyanarayana, G. Domino One-Pot Process for the Synthesis of
Isobenzofuran-1(3H)-ones via [Cu]-Catalysis Using Water as the Green Solvent. J. Org. Chem. 2015, 80, 7089−7098.
ACS Paragon Plus Environment
28

Page 29 of 31
The Journal of Organic Chemistry
[15] Liu, S.; Chen, K.; Hao, W.-J.; Tu, X.-C.; Tu, S.-J.; Jiang, B. Generation of 1,3-dimethylene-substituted
isobenzofurans via Pd(II)-catalyzed selective oxo-cyclization/SO2 insertion ascade of β-alkynyl ketones. J. Org. Chem.
2019, 84, 1964-1971.
1
2
3
4
5
6
7
8
9
[16] (a) Liu, S.; Chen, K.; Lan, X.-C.; Hao, W.-J.; Li, G.; Tu, S.-J.; Jiang, B. Synergistic silver/scandium catalysis for
divergent synthesis of skeletally diverse chromene derivatives. Chem. Commun. 2017, 53, 10692-10695. (b) Wang, D.;
Liu, S.; Lan, X.-C. Armando, P.; Hao, W.-J.; Li, G.; Tu, S.-J.; Jiang, B. Tunable dimerization and trimerization of β-
alkynyl ketones via silver catalysis for accessing spiro and dispiro compounds containing 1H-isochromene. Adv. Synth.
Catal. 2017, 359, 3186-3193. (c) Liu, S.; Lan, X.-C.; Chen, K.; Hao, W.-J.; Li, G.; Tu, S.-J.; Jiang, B. Ag/Brønsted acid
co-catalyzed spiroketalization of b-alkynyl ketones towards spiro[chromane-2,1'-isochromene] derivatives. Org. Lett.
2017, 19, 3831-3834. (d) Ji, C.-L.; Pan, Y.; Geng, F.-Z.; Hao, W.-J.; Tu, S.-J.; Jiang, B. Synergistic silver/scandium
catalytic spiroketalization of β-alkynyl ketones for the atom economical synthesis of skeletally diverse spirocyclic
isochromenes. Org. Chem. Front. 2019, 6, 474-479.
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
[17] (a) Liu, F.; Wang, J.-Y.; Zhou, P.; W.-J.; Li, G.; Tu, S.-J.; Jiang, B. Merging [2 + 2] cycloaddition with radical 1,4-
addition: Metal-free access to functionalized cyclobuta[a]naphthalen-4-ols. Angew. Chem., Int. Ed. 2017, 56, 15570-
15574. (b) Shen, Z.-J.; Wu, Y.-N.; He, C.-L.; He, L.; Hao, W.-J.; Wang, A.-F.; Tu, S.-J.; Jiang, B. Stereoselective
synthesis of sulfonated 1-indenones via radical-triggered multi-component cyclization of β-alkynyl propenones. Chem.
Commun. 2018, 54, 445-448. (c) Wang, A.-F.; Hao, W.-J.; Zhu, Y.-L.; Li, G.; Zhou, P.; Tu, S.-J.; Jiang, B. Double SO2
insertion into 1,7-diynes leading to functionalized naphtho[1,2-c]thiophene 2,2-dioxides. ACS Omega 2018, 3, 1482-
1491. (d) Gong, X.; Wang, M.; Ye, S.; Wu, J. Synthesis of 3-(Methylsulfonyl)benzo[b]thiophenes from Methyl(2-
alkynylphenyl)sulfanes and Sodium Metabisulfite via a Radical Relay Strategy. Org. Lett. 2019, 21, 1156-1160. (e) Ye,
S.; Qiu, G.; Wu, J. Inorganic sulfites as the sulfur dioxide surrogates in sulfonylation reactions. Chem. Commun. 2019,
55, 1013-1019. (f) Ye, S.; Zheng, D.; Wu, J.; Qiu, G. Photoredox-catalyzed sulfonylation of alkyl iodides, sulfur
dioxide, and electron-deficient alkenes. Chem. Commun. 2019, 55, 2214-2217. (g) Ye, S.; Li, Y.; Wu, J.; Li, Z. Thiourea
dioxide as a source of sulfonyl groups: photoredox generation of sulfones and sulfonamides from heteroaryl/aryl halides.
Chem. Commun. 2019, 55, 2489-2492. (h) Gong, X.; Li, X.; Xie, W.; Wu, J.; Ye, S. An unexpected reaction of
aryldiazonium tetrafluoroborates, sodium metabisulfite, and thiourea under photoinduced conditions. Org. Chem. Front.
2019, 6, 1863-1867. (i) Zhang, J.; Xie, W.; Ye, S.; Wu, J. Synthesis of β-hydroxysulfones through a copper(II)-catalyzed
multicomponent reaction with the insertion of sulfur dioxide. Org. Chem. Front. 2019, 6, 2254-2259. (j) Ye, S.; Xiang,
T.; Li, X.; Wu, J. Metal-catalyzed radical-type transformation of unactivated alkyl halides with C–C bond formation
under photoinduced conditions. Org. Chem. Front. 2019, 6, 2183-2199, and references cited therein.
ACS Paragon Plus Environment
29