One-Pot Synthesis of Substituted Benzo[b]furans and Indoles from Dichlorophenols/Dichloroanilines Using a Palladium-Dihydroxyterphenylphosphine Catalyst

Article abstract of DOI:10.1021/acs.joc.6b00824

Disubstituted benzo[b]furans were synthesized by ortho-selective Sonogashira coupling of dichlorophenols and terminal alkynes, followed by cyclization and Suzuki-Miyaura coupling in one pot, using a palladium-dihydroxyterphenylphosphine (Cy-DHTP) catalyst. The use of substoichiometric amounts of tetrabutylammonium chloride was effective in accelerating the Suzuki-Miyaura coupling. This protocol was also successfully applied to the one-pot synthesis of disubstituted indoles from dichloroaniline derivatives.

Full text of DOI:10.1021/acs.joc.6b00824

Subscriber access provided by - Access paid by the | UCSB Libraries
Article
One-Pot Synthesis of Substituted Benzo[b]furans and
Indoles from Dichlorophenols/Dichloroanilines Using
a Palladium-Dihydroxyterphenylphosphine Catalyst
Miyuki Yamaguchi, Tomoyo Akiyama, Hirohisa Sasou, Haruka Katsumata, and Kei Manabe
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00824 • Publication Date (Web): 06 Jun 2016
Downloaded from http://pubs.acs.org on June 12, 2016
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 free 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 accessible to all
readers and 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.
The Journal of Organic Chemistry 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 55
The Journal of Organic Chemistry
1
One-Pot
Synthesis
of
Substituted
Benzo[b]furans
and
Indoles
from
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Dichlorophenols/Dichloroanilines Using a Palladium−Dihydroxyterphenylphosphine Catalyst
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Miyuki Yamaguchi, Tomoyo Akiyama, Hirohisa Sasou, Haruka Katsumata, and Kei Manabe*
School of Pharmaceutical Sciences, University of Shizuoka, 52ꢀ1 Yada, Surugaꢀku, Shizuoka 422ꢀ8526,
Japan
Corresponding Author
manabe@uꢀshizuokaꢀken.ac.jp
ABSTRACT: Disubstituted benzo[b]furans were synthesized by orthoꢀselective Sonogashira coupling
of dichlorophenols and terminal alkynes, followed by cyclization and Suzuki−Miyaura coupling in one
pot, using a palladium−dihydroxyterphenylphosphine (CyꢀDHTP) catalyst. The use of substoichiometric
amounts of tetrabutylammonium chloride (TBAC) was effective in accelerating the Suzuki−Miyaura
coupling. This protocol was also successfully applied to the oneꢀpot synthesis of disubstituted indoles
from dichloroaniline derivatives.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 55
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Introduction
Benzoꢀfused fiveꢀmembered heterocyclic compounds have attracted considerable interest from synthetic
1
ꢀ6
organic chemists due to their importance as frameworks in natural products and pharmaceuticals.
Benzo[b]furan is one such framework, with various synthetic methods being developed over the years to
7
ꢀ9
obtain the desired derivatives. Furthermore, considerable effort has been devoted to the synthesis of
7
, 9ꢀ13
14ꢀ16
indoles,
including palladiumꢀcatalyzed crossꢀcoupling.
Among these methods, the Sonogashira
coupling of 2ꢀhalophenols or 2ꢀhaloanilines with terminal alkynes followed by cyclization has been
17ꢀ27
17ꢀ19, 22, 24, 27ꢀ33
used to construct 2ꢀsubstituted benzo[b]furans
and indoles
(Scheme 1). However, in
general, iodoꢀ or bromoꢀsubstituted substrates were employed, with only a few examples using the less
3
4ꢀ36
37
reactive 2ꢀchlorophenols
or 2ꢀchloroanilines being reported. As these chloro compounds are
generally cheaper and more readily available, the development of efficient synthetic methods towards
benzo[b]furans and indoles from chloroꢀsubstituted substrates is highly desirable.
ACS Paragon Plus Environment

Page 3 of 55
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 1. Synthesis of 2-Substituted Benzo[b]furans/Indoles by Sonogashira Coupling and
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Subsequent Cyclization.
We previously reported the syntheses of benzo[b]furans from 2ꢀchlorophenols using a catalyst derived
38, 39
from palladium and terphenylphosphine ligands bearing hydroxy groups (Figure 1a).
This catalyst
remarkably accelerates oxidative addition of the C−Cl bond ortho to the substrate hydroxy group,
allowing the Sonogashira coupling of 2ꢀchlorophenols with terminal alkynes to take place. This catalyst
also enables the orthoꢀselective Sonogashira coupling of dichlorophenols, and so chlorobenzo[b]furan
was easily obtained from dichlorophenols by employing this catalyst. We assume that the origin of this
rateꢀacceleration and orthoꢀselectivity is based on heteroaggregate formation between lithium
phenoxides of both the ligand and the substrate (Figure 1b). In our previous studies, we found that
4
0ꢀ42
dihydroxyterphenylphosphine (CyꢀDHTP)
bearing two hydroxy groups is more effective in the
4
3ꢀ47
Sonogashira coupling than hydroxyterphenylphosphine (CyꢀHTP),
group.
which bears a single hydroxy
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 55
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 1. (a) Hydroxyterphenylphosphines and (b) assumed heteroaggregates.
The Pd–CyꢀDHTP system was further applied to the sequential oneꢀpot synthesis of disubstituted
4
8
benzo[b]furans by conducting Suzuki−Miyaura coupling reactions with boronic acids following
3
9
chlorobenzo[b]furan
formation
(Scheme
2a).
However,
the
use
of
XPhos
4
9
(
2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl) in addition to CyꢀDHTP was necessary to
obtain the Suzuki−Miyaura coupling products in good yield. In addition, substrate scope was limited as
a number of boronic acids afforded the desired products only in very low yield, even in the presence of
XPhos. These drawbacks prompted us to investigate a more efficient catalytic system for the synthesis
of a wide range of disubstituted benzo[b]furans. In addition, we envisaged that this oneꢀpot procedure
would also be applicable to the preparation of disubstituted indoles from dichloroaniline derivatives.
Here, we report the effects of tetrabutylammonium chloride (TBAC) addition on the Suzuki−Miyaura
coupling reaction to improve the oneꢀpot sequential synthesis of disubstituted benzo[b]furans from
dichlorophenols (Scheme 2b). Application of this protocol to the sequential oneꢀpot synthesis of
5
0
disubstituted indoles from Nꢀtosylꢀdichloroanilines is also presented in detail.
ACS Paragon Plus Environment

Page 5 of 55
The Journal of Organic Chemistry
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
2.
One-pot
Synthesis
of
Disubstituted
Benzo[b]furans/Indoles
from
Dichlorophenols/Dichloroanilines using a Pd–Cy-DHTP Catalyst.
Results and Discussion
Effect of Quaternary Ammonium Salts in the One-pot Synthesis of Disubstituted Benzo[b]furans
3
9
from Dichlorophenols. The previously reported oneꢀpot synthesis (see Scheme 2a) of disubstituted
5
1, 52
benzo[b]furans via a Suzuki−Miyaura coupling following chlorobenzo[b]furan formation
required
two ligands, namely CyꢀDHTP and XPhos. To carry out the oneꢀpot synthesis using a Pd–CyꢀDHTP
catalyst in the absence of XPhos, we investigated the effect of various quaternary ammonium salts in the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 55
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Suzuki−Miyaura coupling (Table 1), as it is well known that quaternary ammonium salts enhance
53ꢀ55
Suzuki−Miyaura coupling.
The synthesis of 2ꢀdecylꢀ5ꢀ(4ꢀmethoxyphenyl)benzo[b]furan (3) was
56
selected as our model reaction, which employed the HBF salt of CyꢀDHTP (CyꢀDHTP‧HBF ). Thus,
4
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
for the initial Sonogashira coupling step between 2,4ꢀdichlorophenol (1) and 1ꢀdodecyne (2) and for the
following cyclization, the previously reported reaction conditions for benzo[b]furan synthesis were
3
9
applied. Following chlorobenzo[b]furan formation, the Suzuki−Miyaura coupling was performed with
the addition of 4ꢀmethoxyphenylboronic acid, K PO as base, and a quaternary ammonium salt. Without
3
4
the addition of a quaternary ammonium salt, the Suzuki−Miyaura coupling did not reach completion and
a significant amount of chlorobenzo[b]furan 4 was recovered (entry 1). However, the reaction proceeded
smoothly in the presence of 2 equiv. of tetrabutylammonium chloride (TBAC), and the desired 3 was
obtained in good yield (71%, entry 2). Changing the counterion of TBA from chloride to either bromide
(TBAB) or hydroxide (TBAOH) resulted in lower yield (68%, entry 3 and 47%, entry 4). The use of
tetramethylammonium bromide was ineffective (27%, entry 5). TBAC was therefore selected as the
optimal salt for the reaction, with 0.5 equiv. being found to afford the highest yield of product (entries 6
and 7), with the desired product being obtained in good yield (78%) in the absence of XPhos as a second
ligand. We therefore assumed that the TBA salt works as a phase transfer catalyst, transporting boronic
acid from the aqueous phase to the organic phase, thus accelerating the Suzuki−Miyaura coupling step.
Table 1. Optimization of Reaction Conditions for the Synthesis of 2,5-Disubstituted Benzo[b]furan
ACS Paragon Plus Environment

Page 7 of 55
The Journal of Organic Chemistry
1
3
from 2,4-Dichlorophenol
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
a
quaternary
yield (%)
entry
ammonium salt
(equiv.)
3
4
1
2
3
none
31
71
68
47
27
65
78
41
TBAC (2)
TBAB (2)
TBAOH (2)
<12
<6
b
4
<17
<26
<15
trace
5
6
7
Me NBr (2)
4
TBAC (1)
TBAC (0.5)
a
b
Isolated yield. Without K PO .
3
4
Substrate Scope of the One-pot Syntheses of Disubstituted Benzo[b]furans from Dichlorophenols.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 55
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
With the optimized conditions in hand, substrate generality was examined for the syntheses of
disubstituted benzo[b]furans (Table 2). Initially, 2,5ꢀdisubstituted benzo[b]furans were prepared using
2
,4ꢀdichlorophenol (1), terminal alkynes, and a range of boronic acids. Boronic acids bearing either
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
electronꢀdonating (entries 1 and 2) or electronꢀwithdrawing groups (entries 3 and 4) reacted smoothly
with 5ꢀchlorobenzo[b]furan under the optimized conditions, and the corresponding disubstituted
benzo[b]furans 3 and 5ꢀ7 were obtained in high yields (74ꢀ82%). For the synthesis of benzo[b]furan 5,
reduction of the catalyst loading to 1 mol% gave an improved yield (89%, entry 2). 3ꢀThienyl (entry 5)
and alkenyl (entry 6) groups were also successfully introduced to give compounds 8 and 9, respectively.
Furthermore, 3ꢀ(hydroxymethyl)phenylboronic acid reacted smoothly to give the desired product 10 in
good yield (72%, entry 7). However, the Suzuki−Miyaura coupling did not proceed efficiently under the
optimized conditions when transꢀ2ꢀphenylvinylboronic acid was employed (<23% 11, entry 8). In
addition, the use of 3ꢀpyridylboronic acid and 2ꢀfurylboronic acid resulted in moderate yields (37% 12,
entry 9, and 42% 13, entry 10). The introduction of a 3ꢀhydroxyphenyl group was also not successful,
although a slightly higher yield of 14 was obtained using TBAOH (31%) rather than TBAC and K PO
3
4
(22%, entry 11).
The optimized reaction conditions were also applicable to the synthesis of 2,4ꢀdisubstituted
benzo[b]furans from 2,3ꢀdichlorophenol. A 4ꢀmethoxyphenyl group was successfully introduced at the
4ꢀposition of the benzo[b]furan, giving the desired product 15 in high yields (83ꢀ85%, entry 12).
ACS Paragon Plus Environment

Page 9 of 55
The Journal of Organic Chemistry
1
Surprisingly, 4ꢀnitrophenylboronic acid, which gave a poor result in the synthesis of 2,5ꢀdisubstituted
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
benzo[b]furans (data not shown), reacted smoothly with 4ꢀchlorobenzo[b]furan to afford the desired
2
,4ꢀdisubstituted product 16 in moderate yield (76%, entry 13). Furthermore, the reactions with
ꢀhydroxyphenyl and 3ꢀpyridyl groups were also successful, giving the desired products 17 and 18 in
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
good yields (71%, entry 14, and 87%, entry 15). We therefore assumed that these intermediates, i.e., the
4
2
ꢀchlorobenzo[b]furans, were more reactive than the 5ꢀchlorobenzo[b]furans. The reactions of 2,5ꢀ and
,6ꢀdichlorophenols also gave the desired products, albeit in lower yields (entries 16 and 17).
Table 2. One-pot Benzo[b]furan Synthesis from Dichlorophenols, Alkynes, and Boronic acids
a
entry product
yield (%)
78
1
2
b
82 (89)
c
3
74
81
d
4
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 55
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5
6
7
8
9
1
73
53
72
<23
37
42
c
e
e
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
e
0
f
11
22 (31)
g
1
2
3
85 (83)
1
76
71
f
14
1
1
5
6
87
32
c
c
1
7
32
a
b
c
d
Isolated yield. Pd 1 mol%. Suzuki−Miyaura coupling 8 h. Suzuki−Miyaura coupling 10 h.
e
f
g
Suzuki−Miyaura coupling 20 h. TBAOH (2 equiv.) instead of TBAC and K PO . 2 mmol scale.
3
4
ACS Paragon Plus Environment

Page 11 of 55
The Journal of Organic Chemistry
1
2
3
4
As shown above, the Suzuki−Miyaura coupling of 5ꢀchlorobenzo[b]furans with a number of different
boronic acids afforded the desired products in low yields (<50%, entries 8–11, Table 2). To accelerate
the reaction with these boronic acids, we revisited the effect of XPhos as a second ligand in the
Suzuki−Miyaura coupling (Table 3). Among the conditions tested, use of XPhos and CyꢀDHTP as
ligands and the addition of 0.5 equiv. of TBAC gave optimal results, with a significant improvement in
yields of the desired 2,5ꢀdisubstituted benzo[b]furans being observed. In the case of
transꢀ2ꢀphenylvinylboronic acid, the corresponding benzo[b]furan 11 was obtained in good yield (68%,
entry 1). Although the reason is unclear, the procedure in which XPhos was added together with the
boronic acid, TBAC, and K PO in the Suzuki−Miyaura coupling step resulted in lower yield (36%,
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
4
entry 1). The 3ꢀpyridyl and 2ꢀfuryl groups were also successfully introduced with the addition of XPhos
84%, entry 2, and 64%, entry 3). Coupling with 3ꢀhydroxyphenylboronic acid resulted in a moderate
(
yield only (57%, entry 4). In this case, the use of TBAOH rather than TBAC gave a higher yield (71%,
entry 4). However, in the absence of TBAC and TBAOH, the Suzuki−Miyaura coupling reaction did not
take place, and chlorobenzo[b]furan was recovered (entry 5). This result indicates that both XPhos and a
TBA salt are required to obtain the products in good yields.
Table 3. One-pot Benzo[b]furan Synthesis Using XPhos as a Secondary Ligand
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 55
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
entry product
yield (%)
b
1
2
3
68 (36)
84
64
c
d
e
4
57 (71)
c
f
5
0
a
b
Isolated yield. Sonogashira coupling was conducted without XPhos, which was added together with
c
d
TBAC and K PO in the Suzuki−Miyaura coupling step Suzuki−Miyaura coupling 6 h. TBAC
3
4
.
e
f
(
2 equiv.). TBAOH (2 equiv.) instead of TBAC and K PO . In the absence of TBAC.
3 4
Optimization of the Synthesis of Monosubstituted Indoles from Monochloroaniline Derivatives.
We then turned our attention to the synthesis of indoles, which are also important targets in synthetic
organic chemistry. We expected that the reaction conditions for the synthesis of benzo[b]furan using the
Pd–CyꢀDHTP catalyst could also be applied for the oneꢀpot synthesis of disubstituted indoles from
dichloroanilines and terminal alkynes. To confirm this hypothesis, we first investigated the synthesis of
ACS Paragon Plus Environment

Page 13 of 55
The Journal of Organic Chemistry
1
monosubstituted indoles from monochloroanilines. The Sonogashira coupling of 2ꢀchloroanilines 21a-g
with ethynylbenzene (22) and subsequent cyclization, were tested using the Pd–CyꢀDHTP catalyst
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(Table 4). Fortunately, with only a slight modification of the reaction conditions optimized for the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
benzo[b]furan synthesis, the Pd–CyꢀDHTP system was applicable to the synthesis of Nꢀtosylindole from
5
7
Nꢀtosylꢀ2ꢀchloroaniline (21a) and alkyne 22 (Table 4, entry 1). In this case, the catalyst allowed the
Sonogashira coupling to take place at the less reactive and sterically hindered 2ꢀchloro group. Following
the Sonogashira coupling, the addition of water was necessary to cyclize the alkynylaniline to afford the
desired 2ꢀsubstituted indole 23a (entry 1 vs. entry 2), as in the benzo[b]furan synthesis. Methanol was
not suitable as coꢀsolvent for this reaction (entry 3). Furthermore, the use of tꢀBuOLi as a base was key
in promoting the Sonogashira coupling, with other lithium salts (entries 4 and 5) and potassium salts
(entries 6ꢀ8) failing to yield the desired product. When DMF was used as a solvent instead of toluene,
the reaction did not proceed at all (entry 9). Monohydroxylated terphenylphosphine CyꢀHTP (Figure 1a)
was also ineffective (entry 10). We then screened several Nꢀprotecting groups. In the case of
2
ꢀchloroaniline (21b), neither the desired indole 24 nor the alkynylaniline 25b were obtained (entry 11).
NꢀAcetylated 21c afforded the deacylated indole 24 along with the Sonogashira coupling product 25c
entry 12). In the absence of water following the Sonogashira coupling of 21c and 22, 25c was obtained
(
in moderate yield (65%, entry 13), suggesting that the cyclization of 25c was problematic under these
conditions. Finally, 2ꢀchloroanilines bearing other protecting groups, such as trifluoroacetyl,
tꢀbutyloxycarbonyl (Boc), mesyl, and 2ꢀnitrobenzenesulfonyl (Ns), failed to yield the desired products
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 55
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
5d-g (entries 14ꢀ17).
Table 4. Optimization of Reaction Conditions for Indole Synthesis from 2-Chloroaniline
Derivatives
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
entry
variation from the standard conditions
yield (%)
23
24
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
25
nd
38
b
b
b
b
b
b
b
b
b
b
b
1
2
3
4
5
6
7
8
9
none
68
tꢀBuOLi (3.6 equiv.), without H O addition, 19 h
trace
25
2
MeOH instead of H O
trace
2
b
LiOH instead of tꢀBuOLi
Li PO instead of tꢀBuOLi
trace
trace
nd
b
nd
3
4
b
b
tꢀBuOK instead of tꢀBuOLi
K CO instead of tꢀBuOLi
nd
nd
b
b
nd
nd
2
3
b
b
K PO instead of tꢀBuOLi
nd
nd
3
4
b
b
DMF instead of toluene
nd
nd
b
1
0
CyꢀHTP‧HBF instead of CyꢀDHTP‧HBF
11
nd
4
4
ACS Paragon Plus Environment

Page 15 of 55
The Journal of Organic Chemistry
b
b
1
1
1
21b instead of 21a
21c instead of 21a
ꢀ
nd
12
nd
nd
nd
nd
nd
nd
23
65
23
nd
nd
nd
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
b
b
b
b
12
13
14
15
16
17
nd
nd
nd
nd
b
b
b
b
b
21c instead of 21a, without H O addition, 6 h.
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
c
b
b
b
21d instead of 21a
21e instead of 21a
21f instead of 21a
21g instead of 21a
trace
b
nd
a
b
c
Isolated yield. Not detected. 25b was obtained instead of 25d.
Substrate Scope for Indole Synthesis from 2-Chloroaniline Derivatives. The optimized reaction
conditions were then applied to the syntheses of a range of 2ꢀsubstituted indoles from 2ꢀchloroaniline
derivatives (Table 5). Initially, various Nꢀtosylꢀ2ꢀchloroanilines 26ꢀ34 were prepared from their
corresponding 2ꢀchloroanilines and tosyl chloride. Reaction of 21a with 1ꢀdodecyne (2) afforded
2
ꢀdecyl substituted indole 35 in high yield (82%, entry 1), while the 4ꢀmethylꢀsubstituted substrate gave
the corresponding 5ꢀmethylindoles 36ꢀ39 in moderate to good yields (60ꢀ72%, entries 2ꢀ5). Both
aliphatic (entries 2 and 3) and aromatic (entries 4 and 5) alkynes reacted smoothly. Furthermore, the
electronꢀwithdrawing fluoro group was successfully introduced using the 4ꢀfluoroꢀsubstituted substrate
27 to give the desired products 40 and 41 (entries 6 and 7). Trifluoromethylꢀsubstituted indole 42 was
also obtained by this method (entry 8). In addition, the 5ꢀmethoxyꢀsubstituted substrate afforded
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 55
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
ꢀmethoxyindoles 43 and 44 (entries
9
and 10), while the reaction of tosylated
3
ꢀaminoꢀ2ꢀchloropyridine and proceeded efficiently and gave the corresponding
2
pyrrolo[3,2ꢀb]pyridine 45 (entry 11). Similarly, pyrrolo[2,3ꢀb]pyridine 46 was obtained from tosylated
ꢀaminoꢀ3ꢀchloropyridine in moderate yield (64%, entry 12). The high orthoꢀselectivity in this
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
Sonogashira coupling reaction also enabled the preparation of various 2ꢀsubstituted chloroindoles 47ꢀ52
from the dichloroaniline derivatives (entries 13ꢀ18), with the second Sonogashira coupling being almost
completely suppressed even in the presence of an excess amount of alkyne. These results indicate the
effectiveness of the Pd–CyꢀDHTP system for the orthoꢀselective crossꢀcoupling.
Table 5. Indole Synthesis from 2-Chloroaniline Derivatives
a
entry
1
Nꢀtosylaniline product
yield (%)
82
72
64
60
64
b
2
c
3
4
5
ACS Paragon Plus Environment

Page 17 of 55
The Journal of Organic Chemistry
c
1
2
3
6
66
73
70
47
75
67
64
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
c
7
8
9
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
c
c
0
1
1
1
1
2
3
83
88
1
4
1
1
1
1
5
6
7
8
83
67
37
d
57
a
b
c
d
Isolated yield. Sonogashira coupling 5 h. Sonogashira coupling 6 h. Alkyne 1.05 equiv., mesitylene
instead of toluene, 140 °C, 2 h; H O, reflux, 1.5 h.
2
One-pot Synthesis of Disubstituted Indoles from Dichloroaniline Derivatives. We then conducted
the
oneꢀpot
synthesis
of
disubstituted
indoles
through
a
Sonogashira
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 55
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
coupling/cyclization/Suzuki−Miyaura coupling sequence using the Pd–CyꢀDHTP system (Table 6).
2
,4ꢀDisubstituted indoles were selected as synthetic targets due to the synthetic difficulty of
58ꢀ67
functionalizing at the 4ꢀposition using conventional methods.
As a result, various 2,4ꢀdisubstituted
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
indoles were successfully synthesized (53–68) from Nꢀtosylꢀ2,3ꢀdichloroaniline (32) using the Pd–
CyꢀDHTP catalyst (entries 1ꢀ16). In these reactions, the addition of a substoichiometric amount of
TBAC was also found to be effective in promoting the Suzuki−Miyaura coupling of 4ꢀchloroindoles and
boronic acids. Phenylboronic acids bearing not only electronꢀdonating but also electronꢀwithdrawing
groups afforded the desired products (entries 1ꢀ4, 6ꢀ13, and 16). Furthermore, 3ꢀthienyl (entries 5 and
14) and alkenyl groups (entry 15) were also successfully introduced. This method was applicable to the
synthesis of various disubstituted indoles bearing substituents at different positions; namely
2
,5ꢀdisubstituted indoles 69ꢀ71 (entries 17ꢀ19) and 2,6ꢀdisubstituted indoles 72ꢀ74 (entries 20ꢀ22),
which were obtained in moderate yields (36ꢀ63%).
Table 6. One-pot Indole Synthesis from Dichloroaniline Derivatives
a
entry product
yield (%)
ACS Paragon Plus Environment

Page 19 of 55
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
2
3
4
5
6
7
8
69
38
28
42
31
47
49
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
S
b
5
7
N
Ts
c
c
d
87 (73)
9
55
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 55
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
c
10
48
c
11
72
58
58
64
36
56
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
c
1
1
1
1
2
c
c
c
3
4
5
16
1
7
62
54
63
18
1
9
ACS Paragon Plus Environment

Page 21 of 55
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
20
44
e
2
1
2
53
36
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
a
b
c
Isolated yield. Boronic acid (3 equiv.), K PO (4.5 equiv.), Suzuki–Miyaura coupling 20 h. Alkyne
3
4
d
e
1
.05 equiv. 2 mmol scale. Suzuki−Miyaura coupling 20 h.
Mechanistic Study Using ESI-TOF-MS. We previously conducted electrospray ionization timeꢀof
flight mass spectrometry (ESIꢀTOFꢀMS) on the mixture of CyꢀDHTP and 2ꢀchlorophenol in the
presence of tꢀBuOLi, allowing the observation of complex formation between the lithium phenoxides of
3
9
CyꢀDHTP and 2ꢀchlorophenol. The obtained results support our hypothesis regarding the formation of
a heteroaggregate between the Pd–CyꢀDHTP catalyst and 2ꢀchlorophenols, which leads to acceleration
of the Sonogashira coupling reaction at the orthoꢀposition. We then turned our attention to the reaction
mechanism in the preparation of indoles from Nꢀtosylꢀchloroanilines. Based on the abovementioned
results and previous examples of single crystal Xꢀray structure determination for lithium salts of
6
8, 69
sulfonamides shown to form dimers via N–Li–O linkages,
heteroaggregates, such as structures A and B, with Nꢀtosylꢀ2ꢀchloroanilines in the presence of tꢀBuOLi
Scheme 3). We performed ESIꢀTOFꢀMS on the mixture of CyꢀDHTP and 21a with tꢀBuOLi. Under an
Pd–CyꢀDHTP was expected to form
(
argon atmosphere, 21a, CyꢀDHTP (40 mol%), and tꢀBuOLi (1.4 equiv.) were dissolved in toluene, and
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 55
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
stirred for 30 min at room temperature. An aliquot was then taken, diluted with acetonitrile, and
analyzed by ESIꢀTOFꢀMS in the negative ion mode.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 3. Formation of the Proposed Intermediate between Lithium Salts of Pd–Cy-DHTP and
2
1a.
As a result, a signal corresponding to the 1:1 complex between the CyꢀDHTP monophenoxide and the
lithium salt of 21a was observed at m/z 744 in the negative ion mode (Figure 2a). The observed isotopic
distribution of the signal is consistent with the theoretical isotopic pattern of the complex (Figures 2b
and 2c). We assume the structure of the complex as shown in Figure 3. Signals corresponding to the 1:2
and 1:3 complexes between the CyꢀDHTP phenoxide and the lithium salt of 21a were observed at m/z
1
031 and m/z 1320, respectively (Figure S2). In addition, signals corresponding to the aggregates of the
lithium salt of 21a were also observed at m/z 856 (trimer), 1143 (tetramer), and 1430 (pentamer) (Figure
ACS Paragon Plus Environment

Page 23 of 55
The Journal of Organic Chemistry
1
S3). These results indicate that CyꢀDHTP has the ability to form complexes with
Nꢀtosylꢀ2ꢀchloroanilines in the presence of t-BuOLi, and is consistent with our hypothesis regarding
heteroaggregate formation, as shown in Scheme 3.
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 2. Complex formation between 21a and CyꢀDHTP (0.4 equiv.) in the presence of tꢀBuOLi
(1.4 equiv.) as observed by ESIꢀTOFꢀMS in the negative ion mode. (a) ESIꢀTOF mass spectrum
obtained following stirring for 30 min. Detailed view of (b) the observed isotopic distribution compared
to (c) the theoretical isotopic pattern of the complex shown in Figure 3.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 55
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Figure 3. Assumed structure of the complex observed at m/z 744 in ESIꢀTOFꢀMS, as shown in Figure 2.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Conclusion
A oneꢀpot synthesis for the preparation of disubstituted benzo[b]furans from dichlorophenols, terminal
alkynes, and boronic acids was established using an orthoꢀselective Sonogashira coupling followed by
cyclization and Suzuki−Miyaura coupling. TBAC was found to play an important role in improving the
Suzuki−Miyaura coupling step. Furthermore, the novel protocol was also successfully applied in the
oneꢀpot synthesis of disubstituted indoles from Nꢀtosyldichloroanilines. Mechanistic studies using
ESIꢀTOFꢀMS suggested complex formation between the lithium salts of CyꢀDHTP and the
Nꢀtosyldichloroanilines, which is similar to the mechanism determined for 2ꢀchlorophenols. These
synthetic methods are expected to be useful in the preparation of benzo[b]furan and indole derivatives
bearing a range of substituent patterns.
Experimental
1
All reactions were performed under an argon atmosphere. For H NMR spectroscopic analysis,
1
3
tetramethylsilane (TMS) (δ = 0) in CDCl served as an internal standard. For C NMR spectroscopic
3
1
9
analysis, CDCl (δ = 77.0) served as an internal standard. For F NMR spectroscopic analysis, CFCl (δ
3
3
ACS Paragon Plus Environment

Page 25 of 55
The Journal of Organic Chemistry
1
=
0) served as an external standard. For IR spectroscopic analysis, ZnSe was used as an ATR crystal.
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
DARTꢀTOF mass spectrometric analyses were conducted using glass rods, which were dipped in the
sample solution (dissolved in dichloromethane or methanol) and placed in the open gap between the
DART source and the orifice of the API interface. Melting points were uncorrected. All reagents were
purchased from commercial suppliers and used without further purification. Anhydrous solvents were
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
2
also
purchased
from
commercial
suppliers.
CyꢀDHTP·HBF4,
7
0, 71
72, 73
76,
Nꢀ(2ꢀchlorophenyl)ꢀ4ꢀmethylbenzenesulfonamide (21a),
Nꢀ(2ꢀchlorophenyl)acetamide (21c),
7
4, 75
Nꢀ(2ꢀchlorophenyl)ꢀ2,2,2ꢀtrifluoroacetamide (21d),
Nꢀ(2ꢀchlorophenyl)methanesulfonamide (21e),
7
7
78, 79
Nꢀ(2ꢀchlorophenyl)ꢀ2ꢀnitrobenzenesulfonamide (21f),
tertꢀbutyl (2ꢀchlorophenyl)carbamate
8
0,
81
50,
82
(21g),
Nꢀ(2,3ꢀdichlorophenyl)ꢀ4ꢀmethylbenzenesulfonamide
(32),
5
0,
83
Nꢀ(2,4ꢀdichlorophenyl)ꢀ4ꢀmethylbenzenesulfonamide
(33),
and
5
0
Nꢀ(2,5ꢀdichlorophenyl)ꢀ4ꢀmethylbenzenesulfonamide (34) were prepared according to reported
procedures.
Typical experimental procedure for the synthesis of disubstituted benzo[b]furans (Method A,
39
Table 1, Entry 7). 2-Decyl-5-(4-methoxyphenyl)benzo[b]furan (3). Toluene (1.0 mL) was added to
PdCl (CH CN) (2.6 mg, 0.01 mmol), CyꢀDHTP·HBF (10.6 mg, 0.02 mmol), tꢀBuOLi (144 mg,
2
3
2
4
1
.20 mmol), and 1 (82.0 mg, 0.50 mmol) in a twoꢀneck flask under argon. The reaction mixture was
stirred at rt for 15 min, after which time 2 (112 ꢁL, 0.53 mmol) was added. The reaction mixture was
then stirred at reflux for 45 min. After cooling to rt, degassed water (1 mL) was added, and the reaction
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 55
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
mixture stirred at reflux for 2 h. After cooling to rt, 4ꢀmethoxyphenylboronic acid (114 mg, 0.75 mmol),
K PO (213 mg, 1.0 mmol), and tetrabutylammonium chloride (71.7 mg. 0.26 mmol) were added, and
3
4
the reaction mixture stirred at reflux for 6 h. The resulting suspension was quenched with 1 M aq. HCl
6 mL) at rt and extracted using ethyl acetate (2 × 20 mL). The combined organic layers were then dried
over anhydrous Na SO and concentrated in vacuo, and the resulting residue was purified by preparative
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
2
4
TLC (PTLC) (SiO , hexanes/dichloromethane = 4/1) to give 3 (142 mg, 78%) as a white solid.
2
3
9
5
-Chloro-2-decylbenzo[b]furan (4, Table 1, Entry 1). A paleꢀyellow solid (60 mg, 41%).
3
9
5-(4-Methylphenyl)-2-phenylbenzo[b]furan (5). Prepared from 1, 22, and 4ꢀmethylphenylboronic
acid following the typical procedure (Method A). Purification by column chromatography (SiO2,
hexanes/dichloromethane = 6/1) afforded 5 as colorless needles (116 mg, 82%).
3
9
2
-Phenyl-5-(4-trifluoromethylphenyl)benzo[b]furan (6).
Prepared from 1, 22, and
4
ꢀtrifluoromethylphenylboronic acid following the typical procedure (Method A).. Purification by PTLC
(
SiO , hexanes/dichloromethane = 6/1) afforded 6 as a pale yellow solid (126 mg, 74 %).
2
39
5
-(4-Fluorophenyl)-2-phenylbenzo[b]furan (7). Prepared from 1, 22, and 4ꢀfluorophenylboronic
acid following the typical procedure (Method A). Purification by column chromatography (SiO2,
hexanes/dichloromethane = 10/1) afforded 7 as yellow plates (117 mg, 81%).
3
9
2
-Phenyl-5-(thiophene-3-yl)benzo[b]furan (8). Prepared from 1, 22, and 3ꢀthiopheneboronic acid
following the typical procedure (Method A). Purification by column chromatography (SiO2,
hexanes/dichloromethane = 10/1) afforded 8 as colorless cubes (101 mg, 73%).
ACS Paragon Plus Environment

Page 27 of 55
The Journal of Organic Chemistry
1
39
(E)-5-(Octo-1-en-1-yl)-2-phenylbenzo[b]furan
(9).
Prepared
from
1,
22,
and
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
transꢀ1ꢀoctenꢀ1ꢀylboronic acid following the typical procedure (Method A). Purification by column
chromatography (SiO , hexanes/dichloromethane = 20/1) afforded 9 as a white solid (81 mg, 53%).
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(3-(2-Phenylbenzo[b]furan-5-yl)phenyl)methanol
(10).
Prepared
from
1,
22,
and
(3ꢀ(hydroxymethyl)phenyl)boronic acid following the typical procedure (Method A). Purification by
column chromatography (SiO , hexane/EtOAc = 2/1) afforded 10 (113 mg, 72%) as a yellow solid. Mp.
2
1
1
34.5–136.0 °C. H NMR (400 MHz, CDCl ): δ 7.85 (2H, dd, J = 7.2, 1.6 Hz), 7.72 (1H, d, J = 1.5 Hz),
3
7.59 (1H, s), 7.54–7.52 (2H, m), 7.47 (1H, dd, J = 8.5, 1.7 Hz), 7.45–7.39 (3H, m), 7.32 (2H, dd, J =
1
3
1
16.8, 7.6 Hz), 6.99 (1H, s), 4.72 (2H, s), 2.08 (1H, s). C{ H} NMR (125 MHz, CDCl ): δ 156.6, 154.5,
3
141.9, 141.3, 136.3, 130.3, 129.7, 128.9, 128.8, 128.6, 126.6, 126.0, 125.4, 124.9, 123.9, 119.3, 111.2,
ꢀ1
1
01.4, 65.3. IR (ATR) cm : 3447, 3422, 1464, 1441, 1269, 1177, 1152, 1126, 1072, 1038, 1023. HRMS
+
(
DART-TOF) m/z: calcd for C H O ([M+H] ), 301.1229; found, 301.1221.
2
1
17
2
Typical experimental procedure for the synthesis of disubstituted benzo[b]furans (Method B,
Table 3, Entry 1). (E)-2-Phenyl-5-styrylbenzo[b]furan (11). Toluene (1.0 mL) was added to
PdCl (CH CN) (2.6 mg, 0.01 mmol), CyꢀDHTP·HBF (10.6 mg, 0.02 mmol), XPhos (9.5 mg, 0.02
2
3
2
4
mmol), tꢀBuOLi (144 mg, 1.20 mmol), and 1 (81.6 mg, 0.50 mmol) in a twoꢀneck flask under argon.
The reaction mixture was stirred at rt for 15 min, after which time 22 (58 ꢁL, 0.53 mmol) was added.
The reaction mixture was then stirred at reflux for 45 min. After cooling to rt, degassed water (1 mL)
was added, and the reaction mixture stirred at reflux for 2 h. After cooling to rt,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 55
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
transꢀ2ꢀphenylvinylboronic acid (149 mg, 1.01 mmol), K PO
(318 mg, 1.5 mmol), and
3
4
tetrabutylammonium chloride (70.7 mg, 0.25 mmol) were added, and the reaction mixture stirred at
reflux for 20 h. The resulting suspension was quenched with 1 M aq. HCl (6 mL) at rt and extracted
using ethyl acetate (2 × 20 mL). The combined organic layers were then dried over anhydrous Na SO
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
4
and concentrated in vacuo, and the resulting residue was purified by preparative TLC (PTLC) (SiO2,
1
hexanes/dichloromethane = 4/1) to give 11 (101 mg, 68%) as a white solid. Mp. 211.4–211.9 °C. H
NMR (500 MHz, CDCl ): δ 7.87 (2H, d, J = 7.4 Hz), 7.70 (1H, s), 7.53 (2H, t, J = 7.4 Hz), 7.49 (2H, t, J
3
= 1.7 Hz), 7.45 (2H, t, J = 7.7 Hz), 7.38ꢀ7.35 (3H, m), 7.26 (1H, t, J = 7.5 Hz), 7.21 (1H, d, J = 16.0 Hz),
13
1
7.10 (1H, d, J = 16.4 Hz), 7.02 (1H, s). C{ H} NMR (125 MHz, CDCl ): δ 154.7, 137.6, 132.7, 130.3,
3
129.7, 129.0, 128.8, 128.7, 127.8, 127.4, 126.4, 124.9, 123.1, 118.8, 111.3, 101.3, 99.9 (one carbon
ꢀ1
signal is overlapped). IR (ATR) cm : 1489, 1466, 1449, 1271, 1254, 1119, 1072, 1038, 1018. HRMS
+
(
DART-TOF) m/z: calcd for C H O ([M+H] ), 297.1274; found, 297.1294.
2
2
17
2
-Phenyl-5-(pyridine-3-yl)benzo[b]furan (12, Table 3, Entry 2). Prepared from 1, 22, and
3
ꢀpyridineboronic acid following the typical procedure (Method B). Purification by column
chromatography (SiO , hexane/dichloromethane = 1/5) afforded 12 (114 mg, 84%) as a yellow solid.
2
1
Mp. 159.7–160.0 °C. H NMR (400 MHz, CDCl ): δ 8.90 (1H, d, J = 2.0 Hz), 8.59 (1H, dd, J = 4.9,
3
1
.5 Hz), 7.91 (3H, dt, J = 10.4, 3.0 Hz), 7.77 (1H, d, J = 2.0 Hz), 7.62 (1H, d, J = 8.3 Hz), 7.50–7.45
1
3
1
(
3H, m), 7.40–7.36 (2H, m), 7.08 (1H, s). C{ H} NMR (100 MHz, CDCl ): δ 157.0, 154.9, 148.5,
3
148.1, 137.1, 134.5, 133.1, 130.2, 130.0, 128.8, 125.0, 123.7, 123.5, 119.5, 111.6, 101.3 (one carbon
ACS Paragon Plus Environment

Page 29 of 55
The Journal of Organic Chemistry
ꢀ1
1
signal is overlapped). IR (ATR) cm : 3028, 1566, 1491, 1445, 1406, 1267, 1246, 1155, 1123, 1105.
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
HRMS (DART-TOF) m/z: calcd for C H NO ([M+H] ), 272.1075; found, 272.1065.
1
9
14
5
-(Furan-2-yl)-2-phenylbenzo[b]furan (13, Table 3, Entry 3). Prepared from 1, 22, and
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
ꢀfurylboronic acid following the typical procedure (Method B). Purification was by column
chromatography (SiO , hexane/dichloromethane = 5/1) afforded 13 (84 mg, 64%) as an orange solid.
2
1
Mp. 134 °C (decomposed). H NMR (400 MHz, CDCl ): δ 7.82 (3H, d, J = 9.3 Hz), 7.58 (1H, dd, J =
3
8
.8, 1.5 Hz), 7.43 (4H, m), 7.32 (1H, t, J = 7.3 Hz), 6.95 (1H, s), 6.59 (1H, d, J = 3.4 Hz), 6.45 (1H, dd,
13
1
J = 2.0, 0.8 Hz). C{ H} NMR (125 MHz, CDCl ): δ 156.7, 154.41, 154.36, 141.7, 130.3, 129.6, 128.8,
3
ꢀ1
128.6, 126.4, 124.9, 120.9, 116.1, 111.6, 111.3, 104.1, 101.4. IR (ATR) cm : 3109, 3057, 1489, 1458,
1445, 1431, 1269, 1240, 1213, 1163, 1038, 1011. HRMS (DART-TOF) m/z: calcd for C H O
2
1
8
13
+
(
[M+H] ), 261.0916; found, 261.0915.
5
-(3-Hydroxyphenyl)-2-phenylbenzo[b]furan (14, Table 3, Entry 4). Prepared from 1, 22, and
3
ꢀhydroxyphenylboronic acid following the typical procedure (Method B), except the use of TBAOH
(
2 equiv.) instead of TBAC and K PO . Purification was by column chromatography (SiO ,
3
4
2
1
hexanes/dichloromethane = 1/4) afforded 14 (102 mg, 71%) as yellow plates. Mp. 171.8–172.8 °C. H
NMR (400 MHz, CDCl ): δ 7.89 (2H, dd, J = 3.6, 1.6 Hz), 7.75 (1H, d, J = 2.0 Hz), 7.56 (1H, d, J =
3
8
.3 Hz), 7.50–7.45 (3H, m), 7.39–7.34 (1H, m), 7.31 (1H, d, J = 7.8 Hz), 7.21 (1H, d, J = 7.8 Hz), 7.10
1
3
1
(
1H, t, J = 2.2 Hz), 7.06 (1H, s), 6.82 (1H, ddd, J = 8.2, 2.8, 1.0 Hz), 4.80 (1H, s). C{ H} NMR
(100 MHz, acetoneꢀd ): δ 158.6, 157.2, 155.3, 143.7, 137.4, 131.1, 130.68, 130.66, 129.7, 129.5, 125.6,
6
ACS Paragon Plus Environment