One-pot synthesis of substituted benzo[b]furans from mono- and dichlorophenols using palladium catalysts bearing dihydroxyterphenylphosphine

Article abstract of DOI:10.1021/jo401503t

A dihydroxyterphenylphosphine bearing cyclohexyl groups on the phosphorus atom (Cy-DHTP) was found to be a powerful ligand for the palladium-catalyzed one-pot synthesis of substituted benzo[b]furans from 2-chlorophenols and terminal alkynes. This catalyst

Full text of DOI:10.1021/jo401503t

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Article
One-Pot Synthesis of Substituted Benzo[b]furans
from Mono- and Dichlorophenols Using Palladium
Catalysts Bearing Dihydroxyterphenylphosphine
Miyuki Yamaguchi, Haruka Katsumata, and Kei Manabe
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo401503t • Publication Date (Web): 16 Aug 2013
Downloaded from http://pubs.acs.org on August 17, 2013
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One-Pot Synthesis of Substituted Benzo[b]furans from Mono- and Dichlorophenols Using
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Palladium Catalysts Bearing Dihydroxyterphenylphosphine
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Miyuki Yamaguchi, Haruka Katsumata, and Kei Manabe*
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526,
Japan
Corresponding Author
manabe@u-shizuoka-ken.ac.jp
ABSTRACT: Dihydroxyterphenylphosphine bearing cyclohexyl groups on the phosphorous atom
(Cy-DHTP) was found to be a powerful ligand for the palladium-catalyzed one-pot synthesis of
substituted benzo[b]furans from 2-chlorophenols and terminal alkynes. This catalyst system was also
applicable to the sequential one-pot synthesis of disubstituted benzo[b]furans from dichlorophenols via
the Suzuki-Miyaura cross-coupling of chlorobenzo[b]furan with boronic acids. The use of two ligands,
Cy-DHTP and XPhos, is the key to promote the reactions. Mechanistic studies suggest that the Pd–
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Cy-DHTP catalyst is the active species in the Sonogashira cross-coupling step, while the Pd–XPhos
catalyst accelerates the Suzuki-Miyaura cross-coupling step.
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Introduction
Benzo[b]furan is a ubiquitous framework found in many natural products and pharmaceuticals.1 The
biological activity of this class of compounds has received considerable attention and many synthetic
methodologies have been developed for obtaining these compounds.2 Palladium-catalyzed
cross-coupling reactions are one of the powerful method for constructing the benzo[b]furan backbone.3
The palladium-catalyzed Sonogashira cross-coupling of 2-halophenols and terminal alkynes followed by
cyclization has been widely used for synthesizing 2-substituted benzo[b]furans (Scheme 1).4 These
reactions commonly employ 2-iodo- and 2-bromophenols as substrates. On the other hand, there are a
few reports5,6 using 2-chlorophenols, which are less expensive and more readily available than 2-iodo or
2-bromophenols, as the starting material. However, in one such attempt, the desired product was
obtained in less than 10% yield.5
Scheme 1. One-Pot Benzo[b]furan Synthesis from 2-Halophenols and Terminal Alkynes
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We have previously reported the one-pot synthesis of benzo[b]furan from 2-chlorophenols and terminal
alkynes using palladium catalysts bearing hydroxyterphenylposphine (HTP)7 with cyclohexyl groups on
the phosphorous atom (Cy-HTP, Figure 1a).8 Cy-HTP works as a bifunctional ligand in the presence of
palladium and t-BuOLi. We hypothesize that the phosphine moiety of Cy-HTP binds to Pd while the
hydroxy group is deprotonated by t-BuOLi and the resulting lithium phenoxide moiety act as a binding
site for the substrate, which also forms the lithium phenoxide. These lithium phenoxides are in
equilibrium with the heteroaggregate in which the 2-chloro group is in close proximity to the palladium
atom (Figure 1b). Therefore, the oxidative addition of C–Cl at the position ortho to the Pd atom is
accelerated. However, the above reaction suffers from drawbacks such as long reaction times, narrow
substrate scope, and the necessity of having to use a sealed tube for the reaction.
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Figure 1. (a) Hydroxyterphenylphosphines. (b) Formation of the proposed intermediate in the
Pd-HTP-catalyzed benzo[b]furan synthesis.
We have previously shown that dihydroxyterphenylphosphine (DHTP, Figure 1a) ligands are more
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effective than HTP for the ortho-selective, palladium-catalyzed cross-coupling of dihaloarenes and
Grignard reagents.9 Introduction of the second hydroxy group in terphenylphosphine dramatically
improved its catalytic efficiency and expanded the scope of the reaction. Therefore, we expected that the
use of DHTP would improve the catalytic efficiency and broaden the substrate scope of benzo[b]furan
synthesis. The expected high reactivity of DHTP can be explained by a conformational effect depicted
in Figure 2. The assumed catalytic species have flexibility in rotation of the C–C single bonds. In the
case of HTP, the conformation in which the lithium phenoxide moiety is close to palladium is in
equilibrium with that in which they are on the opposite side of the terphenyl group (Figure 2a). On the
other hand, in the case of DHTP, the lithium phenoxide moiety and the Pd atom are always located on
the same side of the terphenyl structure (Figure 2b). This results in a more effective cooperation
between palladium and the lithium phenoxide moieties affording higher reactivities in the Sonogashira
coupling step.
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Figure 2. C-C bond rotation for the assumed intermediates from (a) HTP and (b) DHTP.
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To afford multisubstituted benzo[b]furans, efficient synthetic methods need to be developed.10
Halogenated benzo[b]furans, which can be easily converted to other functional groups by
cross-coupling, are one of the versatile intermediates for multisubstituted benzo[b]furan syntheses
(Scheme 2).4h, 11 Thus, various methods to obtain halogenated benzo[b]furans12 have been developed.
These include the palladium-catalyzed Sonogashira coupling of dihalophenols and terminal alkynes
followed by cyclization.4h,13 However, substrates are limited to dihalophenols bearing different halogen
atoms (X1 ≠ X2) to achieve site-selective Sonogashira cross-coupling. In addition, the presence of a
bromo or an iodo group at the C2-position is crucial to achieving high reactivities. On the other hand, by
using the Pd–Cy-HTP catalyst, we obtained benzo[b]furans containing a chloro-group at different
positions from various dichlorophenols (X1 = X2 = Cl), which are inexpensive and easily available.8
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This preliminary success was realized because Cy-HTP promoted ortho-selective Sonogashira coupling
presumably through formation of heteroaggregate (Figure 1b) in which the chloro-group ortho to the
oxido group is placed close to the Pd. Therefore, we hypothesized that the Pd–DHTP catalyst would
further improve the reactivity and selectivity of chlorobenzo[b]furan synthesis from dichlorophenols
and terminal alkynes. In addition, we expected that various disubstituted benzo[b]furans would also be
synthesized via chlorobenzo[b]furans starting from dichlorophenols instead of using 2-bromo- or
2-iodophenols.
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Scheme 2. One-Pot Synthesis of Disubstituted Benzo[b]furan from Dihalophenols and Terminal
Alkynes
Due to increasing demand for development of rapid and environmentally friendly synthetic methods,
one-pot synthesis has been considered to be an attractive choice.14,15 Palladium-catalyzed reactions have
been widely applied to the one-pot synthesis because they generally show high chemo-, regio-, and
stereoselectivity along with high functional-group tolerance.15 Therefore, we hypothesized that the
synthesis of disubstituted benzo[b]furans from dichlorophenols would be performed sequentially in a
one-pot reaction (Scheme 2) by using Pd–DHTP as the catalyst.
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Herein, we present the palladium-catalyzed one-pot synthesis of substituted benzo[b]furans from
2-chlorophenols and terminal alkynes, using DHTP as the ligand. We further applied this catalyst
system to the sequential one-pot synthesis of disubstituted benzo[b]furans from dichlorophenols via the
Suzuki-Miyaura cross coupling of chlorobenzo[b]furan with boronic acids (Scheme 2, M = B(OH)2).
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Results and Discussion
Synthesis of Benzo[b]furans from Monochlorophenols. First, we investigated the synthesis of
benzo[b]furans from monochlorophenols. We determined the best reaction conditions to obtain
2-decylbenzo[b]furan (3) from 2-chlorophenol (1) and 1-dodecyne (2) using the catalyst derived from
Cy-DHTP·HBF4 and PdCl2(CH3CN)2. The choice of using Cy-DHTP·HBF4, which has a
dicyclohexylphosphine moiety (Figure 1a), over Ph-DHTP was based on our previous study8 using
Cy-HTP·HBF4 as the ligand. During optimization studies, we found that the addition of a polar
cosolvent after the Sonogashira cross-coupling step promoted the subsequent cyclization reaction, which
proceeds through base catalysis.16 Among the solvents and the cosolvents tested, the combination of
toluene as the solvent and MeOH as the cosolvent resulted in the highest yields of the desired
benzo[b]furan 3 (Table 1, entry 1). Compared to our previous attempts with the catalyst derived from
Cy-HTP·HBF4, this reaction proceeded much faster, indicating the high reactivity and effectiveness of
Cy-DHTP. In this case, the first Sonogashira cross-coupling step was completed within 45 min and the
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second cyclization step reached completion within one hour. In addition, no sealed-tube was necessary
in this case. Water was also found to be an effective cosolvent in promoting cyclization, although longer
reaction times were required (entry 2). On the other hand, the use of t-BuOH and CF3CH2OH as
cosolvents resulted in lowered yields of 3 and significant amounts of the Sonogashira cross-coupling
product 4 (entries 3 and 4). In the absence of a cosolvent, the cyclization of 4 proceeded slowly and did
not reach completion (entry 5). The importance of adding the cosolvent after the Sonogashira
cross-coupling step was evident when the use of MeOH or a mixture of MeOH/toluene as the solvent
did not give the desired product 3 (entries 6 and 7). When t-BuOH or DMF was used as the solvent in
the absence of a cosolvent, 3 was obtained in lower yields (entries 8 and 9). As for ligands, Ph-DHTP9
was found to be ineffective for this reaction (entry 10). Cy-HTP·HBF4 afforded the product in moderate
yields under the same conditions (entry 11). These results also show the effectiveness of Cy-DHTP.
Other commonly used phosphines for the cross-coupling of chloroarenes such as XPhos,17 PCy3,
P(t-Bu)3·HBF4,18 and DPPF did not work well (entries 12–15). Finally, various bases were tested.
However, none of them worked as well as t-BuOLi (entries 16–19).
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Table 1. Optimization of Reaction Conditions for Benzo[b]furan Synthesis from 2-Chlorophenol
and 1-Dodecyne
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yield (%)a
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4
entry
ligand
base
solvent
cosolvent
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9
1
Cy-DHTP·HBF4
Cy-DHTP·HBF4
Cy-DHTP·HBF4
Cy-DHTP·HBF4
Cy-DHTP·HBF4
Cy-DHTP·HBF4
Cy-DHTP·HBF4
Cy-DHTP·HBF4
Cy-DHTP·HBF4
Ph-DHTP
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
Li3PO4
toluene
toluene
toluene
toluene
toluene
MeOH
MeOH
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71
38
34
59
0
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2b
H2O
trace
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44
24
3c
t-BuOH
CF3CH2OH
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5 d, e
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-
f
f
-
No reaction
No reaction
f
7
toluene/MeOH
t-BuOH
DMF
-
8d, g
9d, h
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17
-
42
23
f
f
-
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trace
0
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
trace
40
Cy-HTP·HBF4
XPhos
16
0
PCy3
No reaction
No reaction
P(t-Bu)3·HBF4
DPPF
trace
0
Cy-DHTP·HBF4
Cy-DHTP·HBF4
No reaction
LiOH
0
0
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Cy-DHTP·HBF4
Cy-DHTP·HBF4
t-BuOK
toluene
toluene
MeOH
MeOH
No reaction
K3PO4
0
0
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7
8
9
aIsolated yield. bAfter H2O addition, reflux for 2 h. cAfter t-BuOH addition, reflux for 7 h. dAlkyne (1.5
equiv) used. eReflux for 1 h. fWithout cosolvent, additional reflux was not conducted. g110 °C for 23 h.
h110 °C for 1 h.
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Next, various other substrates were tested under these optimized reaction conditions. A variety of
terminal alkynes reacted with 1 to afford the corresponding benzo[b]furans (Table 2). When aliphatic
alkynes were used, products 3, 5, and 6 were obtained in moderate to good yields (entries 1–3).
Aromatic alkynes also gave the products 7–10 in moderate to high yields (entries 4–7). Substituents on
the phenyl ring significantly affected the yield; 4-fluoro group slowed down Sonogashira cross-coupling
more than electron-donating 4-methoxy group. Notably, the chloro-containing benzo[b]furan 8 was
obtained in good yields (entry 5), even though the chloro-group of 3-chloroethynylbenzene is generally
expected to be more reactive than that of 2-chlorophenol. These results show the high ortho-selectivity
of the Pd–Cy-DHTP catalyst.
Table 2. Benzo[b]furan Synthesis Using 2-Chlorophenol and Various Alkynes
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yield (%)a
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2
entry
R
3
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7
1b
C10H21 (3)
Ph-CH2CH2 (5)
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3
Cl-CH2CH2CH2 (6) 58
4c, d
5d, e
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Ph (7)
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97
3-Cl-C6H4 (8)
4-F-C6H4 (9)
7c, d
4-MeO-C6H4 (10)
aIsolated yield. Toluene reflux: 45 min and MeOH reflux: 1 h. Toluene reflux: 45 min and MeOH
b
c
reflux: 7 h. dAlkyne (1.5 equiv) used. eMeOH reflux: 3 h.
We also carried out reactions between various 2-chlorophenols and terminal alkyne 2 (Table 3).
Chlorophenols bearing electron-donating methoxy or methyl groups gave the corresponding
benzo[b]furans 11 and 13 in good yields (entries 1 and 3), while methyl 3-chloro-4-hydroxybenzoate
afforded the product 12 in moderate yield (entry 2). 2-Chloro-3-hydroxypyridine also reacted well with
the desired terminal alkyne to form product 14 in modest yield (entry 4). This catalyst system was also
used to synthesize chlorobenzo[b]furans from various 2-dichorophenols (entries 5–7). The use of
2,3-dichlorophenol or 2,4-dichlorophenol resulted in high yields of the corresponding
chlorobenzo[b]furans 15 and 16 (entries 5 and 6). However, when 2,5-dichlorophenol was used, product
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17 was obtained only in moderate yields along with the formation of byproducts such as overreacted
6-(1-dodecynyl)-1-decylbenzo[b]furan (entry 7).
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Table 3. Benzo[b]furan Synthesis Using Various 2-Chlorophenols and 1-Dodecyne
entry
product
yield (%)a
1b
2
78
37
82
53
77
80
37
3 b, c
4
5
6
7
aIsolated yield. bAlkyne (1.5 equiv) used. cToluene reflux 90 min and MeOH reflux 2 h.
One-Pot Sequential Synthesis of Disubstituted Benzo[b]furans from Dichlorophenols. To further
apply our catalyst system, we attempted the sequential one-pot synthesis of disubstituted benzo[b]furans
from dichlorophenols via the Suzuki-Miyaura cross-coupling between chlorobenzo[b]furans and
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boronic acids (Scheme 3).11b, 19
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Scheme 3. One-Pot Substituted Benzo[b]furan Synthesis from Dichlorophenols, Terminal Alkynes,
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and Boronic Acids
In the one-pot procedure depicted above, we expected the Pd–Cy-DHTP catalyst to promote both the
Sonogashira and Suzuki-Miyaura cross-coupling reactions. The reaction was carried out using
2,4-dichlorophenol, alkyne 2, and 4-methoxyphenylboronic acid as model substrates. Optimization
studies showed that the use of the second ligand and the additional base was necessary to promote the
Suzuki-Miyaura cross-coupling reaction. Thus, the use of Cy-DHTP·HBF4 and XPhos17 as the ligands,
H2O as the cosolvent, and K3PO4 as the additional base resulted in high yields of the desired
2,5-disubstituted benzo[b]furan 18 with trace amounts of 5-chlorobenzo[b]furan 16 (Table 4, entry 1).
We found that the presence of XPhos did not affect the first Sonogashira cross-coupling step, and it
could therefore be present in the initial reaction mixture along with Cy-DHTP·HBF4, thereby
simplifying the process. Boronic acid and the additional base could only be added after
chlorobenzo[b]furan formation. When they were added with cosolvent, the Suzuki-Miyaura
cross-coupling reaction did not proceed smoothly, and large amounts of biaryls were obtained as a
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byproduct resulting from the homocoupling between arylboronic acids. The use of MeOH as a cosolvent
was not suitable for this reaction (entry 2). Increasing the amount of t-BuOLi in the reaction
significantly affected the efficiency of the Suzuki-Miyaura cross-coupling (entry 3), and 2.4 equivalents
of the base was found to be optimum. The Suzuki-Miyaura cross-coupling reaction did not proceed well
in the absence of K3PO4 (entry 4). The use of two ligands is important in promoting the one-pot
sequential reaction. Use of 8 mol% of Cy-DHTP·HBF4 formed product 18 in low yields (entry 5).
Decreasing the amount of Cy-DHTP·HBF4 to 4 mol% (entry 6), resulted in better yields of 16 and 18
than those of entry 5, indicating the higher amount of Cy-DHTP had adverse effects on the reaction. On
the other hand, the conditions in entry 6 slowed down the Suzuki-Miyaura cross-coupling reaction in
comparison to the reaction in presence of Cy-DHTP/XPhos, although the Sonogashira cross-coupling
step proceeded smoothly. From these results, we conclude that the Pd-Cy-DHTP catalyst is less reactive
than the Pd–XPhos catalyst in Suzuki-Miyaura cross-coupling reactions. When only XPhos was used as
the ligand, no Sonogashira cross-coupling was observed (entry 7). Decreasing the amount of both
ligands to 2 mol% resulted in slightly lower yields of the product 18 (entry 8).
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40
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42
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 4. Optimization of Reaction Conditions for the One-pot Synthesis of 2,5-Disubstituted
Benzo[b]furan
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entry ligand (mol%)
t-BuOLi cosolvent K3PO4 time yield (%)a
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52
53
54
55
56
57
58
59
60
(equiv)
2.4
( h)
6
18
73
23
18
12
13
31
-
16
1
Cy-DHTP·HBF4 (4)/XPhos (4)
Cy-DHTP·HBF4 (4)/XPhos (4)
Cy-DHTP·HBF4 (4)/XPhos (4)
Cy-DHTP·HBF4 (4)/XPhos (4)
Cy-DHTP·HBF4 (8)
H2O
MeOH
H2O
H2O
H2O
H2O
H2O
H2O
+
+
+
-
trace
49
2 e
3
2.4
23
24
26
6
3.6
43
4
3.6
58
5
2.4
+
+
+
+
trace
41
6
Cy-DHTP·HBF4 (4)
2.4
6
7
XPhos (4)
2.4
-
n. d.c
trace
8
Cy-DHTP·HBF4 (2)/XPhos (2)
2.4
15
65
aIsolated yield. bMeOH reflux for 1 h. cNot detected.
To further understand the role of the two ligands in the Suzuki-Miyaura cross-coupling,
5-chlorobenzo[b]furan 16 was tested for the reaction with 4-methoxyphenylboronic acid in the presence
of PdCl2(MeCN)2 and using Cy-DHTP·HBF4 and/or XPhos as ligands (Table 5). As expected, the
combination of Cy-DHTP·HBF4 and XPhos formed the desired product 18 in high yields (entry 1).
When only XPhos was used, the reaction also proceeded smoothly (entry 2). On the other hand, use of
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only Cy-DHTP·HBF4 resulted in moderate yields of 18 and large amounts of 16 (entry 3). In this case,
even longer reaction times did not improve the yields (data not shown). These results support our
finding that the second ligand XPhos is necessary to promote the Suzuki-Miyaura cross-coupling
reaction shown in Table 4.
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Table 5. Suzuki-Miyaura Cross-coupling of 5-Chlorobenzo[b]furan and 4-Methoxyphenylboronic
Acid
entry
ligand (mol%)
yield (%)a
1
2
3
Cy-DHTP·HBF4 (4)/XPhos (4) 85
XPhos (4)
91
43
Cy-DHTP·HBF4 (4)
aIsolated yield.
Based on these results, we propose the following reaction mechanism for the one-pot sequential
synthesis of disubstituted benzo[b]furans from dichlorophenols, terminal alkynes, and boronic acids as
shown in Scheme 3. During the Sonogashira cross-coupling of dichlorophenols and terminal alkynes,
Pd–Cy-DHTP works as the active species. It seems that Pd–XPhos neither catalyzes nor affects the
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above reaction. Following cyclization catalyzed by the base, the Suzuki-Miyaura cross-coupling of
chlorobenzo[b]furans with boronic acid seems to be accelerated mainly by the Pd–XPhos catalyst,
although we cannot deny the possibility that Pd–Cy-DHTP also catalyzes the reaction to a lesser extent.
In this manner, the use of two ligands in the reaction makes it possible to sequentially carry out
benzo[b]furan formation and Suzuki-Miyaura cross-coupling in one-pot. Interestingly, both these
catalysts show specificity towards one of the two reactions, although both ligands have the same
2-dicyclohexylphosphinobiphenyl substructure.20
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60
Scheme 4. Proposed Reaction Mechanism
We then applied this catalyst in the synthesis of various 2,5-disubstituted benzo[b]furans from
2,4-dichlorophenol (Table 6). Both alkyl and aryl alkynes could be used in this reaction, and the
corresponding disubstituted benzo[b]furans 18–20 were obtained in high yields (entries 1–3). Next,
various boronic acids were utilized to introduce substituents at the C(5) position. Arylboronic acids
bearing a methoxy group at different positions reacted efficiently to afford products 20–22 in high
yields (entries 3–5). Reactions using arylboronic acids bearing either an electron-donating methyl group
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or an electron withdrawing trifluoromethyl or fluoro group also formed the corresponding products 23–
25 in good yields (entries 6–8). The 3-thienyl group could be successfully introduced at the C(5)
position to yield product 26 (entry 9). The use of alkenylboronic acid resulted in moderate yields of
product 27 (entry 10).
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Table 6. Synthesis of 2,5-Disubstituted Benzo[b]furan Using Various Alkynes and Boronic Acids
entry
product
yield
(%)a
73
1b
2
82
3
78
4
81
5
84
6
94
7c
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9
10
b
c
aIsolated yield. Boronic acid (1.5 equiv) and K3PO4 (2.0 equiv) were used. 8 h for Suzuki-Miyaura
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56
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coupling. d10 h for Suzuki-Miyaura coupling.
Then, disubstituted benzo[b]furans bearing substituents at different positions were prepared from
various dichlorophenols by using this catalyst system (Table 7). When 2,3-dichlorophenol was used, the
corresponding 2,4-disubstituted benzo[b]furans 28–30 were obtained in good yields (entries 1–3).
Notably, introduction of the aryl group at the more sterically hindered C(4) position still allowed the
reaction to proceed smoothly to completion via the Suzuki-Miyaura cross-coupling step. On the other
hand, 2,5-dichlorophenol gave the 2,6-disubstituted benzo[b]furan 31 only in moderate yields (entry 4).
This could be due to low yields of the 6-chlorobenzo[b]furan intermediate, as shown in Table 3. We
also applied this catalyst in the synthesis of 2,7-disubstituted benzo[b]furans from 2,6-dichlorophenol.
The use of ethynylbenzene resulted in low yields of the desired product 32 and the formation of many
byproducts (entry 5), while 4-ethynylanisole afforded the corresponding 2,7-disubstituted benzo[b]furan
33 in modest yields (entry 6).
Table 7. Synthesis of Disubstituted Benzo[b]furan Using Various Dichlorophenols
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entry
1
product
yield (%)a
73
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2
3
73
62
4
5
44
28
6
56
aIsolated yield.
Finally, we used this sequential one-pot method to synthesize precursor 34 of a biologically active
compound (Scheme 5). Tetrahydroxylated 2,5-diarylbenzofuran 35 and related compounds have been
recently reported to inhibit amyloid beta (Aβ) aggregation and cause dissociation of Aβ fibrils.21 We
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synthesized
its
precursor
34
from
2,4-dichlorophenol,
4-ethynylanisole,
and
3
4
5
6
7
8
9
3,4,5-trimethoxyphenylboronic acid using the one-pot procedure. The desired product 34 was
successfully obtained in 85% yield. Unlike the previous attempt21 in which compound 35 was prepared
in three steps from 5-bromo-2-hydroxybenzyl alcohol, we could obtain compound 35 from
commercially available substrates using a one-pot reaction. This shows the effectiveness and utility of
our method in constructing more complex, multi-substituted structures.
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Scheme 5. Synthesis of the Precursor of the Bioactive Compound
Mechanistic Study Using ESI-MS. As discussed above, the mechanism of the acceleration by
Cy-DHTP for the Sonogashira coupling step can be explained as follows: (1) both the two hydroxy
groups of Cy-DHTP and 2-chlorophenol 1 are deprotonated to generate lithium phenoxides under the
reaction conditions, and (2) these lithium phenoxides are in equilibrium with a heteroaggregate A and B
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(Scheme 6) in which the 2-chloro group is easily accessed by the Pd atom located nearby. This
heteroaggregate formation between the lithium phenoxides is responsible for the observed acceleration
in reaction rates and the ortho-selectivity of Cy-DHTP. To confirm the formation of a heteroaggregate
between Cy-DHTP and 2-chlorophenol, we performed electrospray ionization-mass spectrometry
(ESI-MS) analyses of these mixtures in the presence of t-BuOLi.
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60
Scheme 6. Formation of the Proposed Intermediate
2-Chlorophenol (1) and 40 mol % of Cy-DHTP were dissolved in toluene with 1 equivalent of
t-BuOLi22 and the resulting solution was stirred at room temperature for 30 min. The resulting solution
was injected into the ESI-MS after diluting with acetonitrile. A signal corresponding to the 1:1 complex
between lithium phenoxides of Cy-DHTP and 2-chlorophenol (1) (Figure 3c) was detected at m/z 591 in
the negative ion mode (Figure 3a). The observed isotopic distribution of the signal is consistent with the
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theoretical isotopic pattern of the complex (Figure 3b). Signals corresponding to the 1:2 and 1:3
complex between lithium phenoxides of Cy-DHTP and 2-chlorophenol (1) were also observed at m/z
725 and m/z 861, respectively (Figure S1). In addition, the signals whose isotopic distribution
correspond to the aggregates of lithium 2-chlorophenoxide were also observed at m/z 665 and 799
(Figure S2).23 This suggests that lithium 2-chlorophenoxide can form aggregates in the presence of
t-BuOLi. On the other hand, no complex formation between XPhos and lithium 2-chlorophenoxide was
observed when XPhos was used as the ligand instead of Cy-DHTP (data not shown). However, when a
1:1 mixture of Cy-DHTP (40 mol %) and XPhos (40 mol %) in the presence of lithium
2-chlorophenoxide was used, a spectrum similar to Figure 3a was observed, with the peak
corresponding to the 1:1 complex appearing at m/z 591 (Figure S3). These results show that Cy-DHTP
has the ability to form complexes with 2-chlorophenols in the presence of t-BuOLi while XPhos cannot.
This supports our hypothesis about the formation of the heteroaggregate A shown in Scheme 6 and the
subsequent acceleration of the Sonogashira coupling at the ortho-position. In addition, it also seems that
XPhos does not affect the formation of the complex between Cy-DHTP and 2-chlorophenols, which is
consistent with the results of the one-pot reaction using these two ligands.
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Figure 3. Complex formation between 2-chlorophenol and Cy-DHTP (0.4 equiv) in the presence of
t-BuOLi (1 equiv) studied by ESI-MS in the negative ion mode. (a) ESI-mass spectrum obtained after
stirring for 30 min. (b) A detailed view of the observed isotopic distribution (i) compared to the
theoretical isotopic patterns of the complex shown in Figure 3c (ii). (c) Assumed structure of the
complex observed at m/z 591.
Conclusion
In summary, dihydroxyterphenylphosphine bearing cyclohexyl groups on the phosphorous atom
(Cy-DHTP) has been shown to be a powerful ligand for the palladium-catalyzed one-pot synthesis of
2-substituted benzo[b]furans from 2-chlorophenols and terminal alkynes. The Pd–Cy-DHTP catalyst
can also be used in the sequential one-pot synthesis of disubstituted benzo[b]furans from
dichlorophenols, terminal alkynes, and boronic acids. In this strategy, use of XPhos as the second ligand
and the additional base is instrumental in promoting the Suzuki-Miyaura cross-coupling reaction. The
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use of this catalyst enabled the one-pot formation of chlorobenzo[b]furan from dichlorophenols and
terminal alkynes and the subsequent Suzuki-Miyaura cross-coupling with boronic acids. Both catalysts
were found to work independently, with Pd–Cy-DHTP catalyzing the Sonogashira cross coupling and
the Pd–XPhos catalyst accelerating the Suzuki-Miyaura cross-coupling reaction. The results of the
ESI-MS study provided strong evidence for the formation of heteroaggregates between lithium
phenoxides of 2-chlorophenol and Cy-DHTP in which the 2-chloro group is easily accessible to the Pd
atom located nearby. We hope that this catalyst system will not only provide various multi-substituted
benzo[b]furan derivatives but also lead to the development of new synthetic methods using chloroarenes
in the field of cross-coupling chemistry.
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Experimental Section
All reactions were performed under argon atmosphere. For 1H NMR, tetramethylsilane (TMS) (δ= 0) in
CDCl3 served as an internal standard. For 13C NMR, CDCl3 (δ= 77.0) served as an internal standard.
Melting points were uncorrected. All the reagents and anhydrous solvents (except for t-BuOH) were
purchased from commercial suppliers and used without further purification. t-BuOH was distilled from
Mg metal under argon. Cy-DHTP·HBF4 and Ph-DHTP were prepared according to the reported
procedure.7e
Typical experimental procedure for the synthesis of 2-substituted benzo[b]furans (Table 1, Entry
1). Toluene (1.0 mL) was added to PdCl2(CH3CN)2 (2.6 mg, 0.01 mmol), Cy-DHTP·HBF4 (10.6 mg,
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0.02 mmol), t-BuOLi (144 mg, 1.8 mmol), and 2-chlorophenol (64.3 mg, 0.50 mmol) in a two-neck
flask under argon. The reaction mixture was stirred at rt for 30 min, and then 1-dodecyne (112 µL, 0.53
mmol) was added. The reaction mixture was stirred at reflux for 45 min. After cooling down, methanol
(1 mL) was added, and the reaction mixture was stirred at reflux for 1 h. The resulting suspension was
quenched with aq. NH4Cl (5 mL) at rt and extracted with ethyl acetate (20 mL × 2). The combined
organic layers were dried over anhydrous Na2SO4 and concentrated, and then the residue was purified
by preparative TLC (hexanes) to give 2-decylbenzofuran 3 (102 mg, 79%) as a yellow oil.
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2-Decylbenzofuran (3)24: Prepared from 2-chlorophenol and 1-dodecyne. Purification by preparative
TLC (hexanes) afforded 3 (102 mg, 79%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.47 (1H, dd, J
= 7.2, 2.8 Hz), 7.40 (1H, d, J = 8.0 Hz), 7.21-7.15 (2H, m), 6.36 (1H, s), 2.75 (2H, t, J = 7.6 Hz),
13
1.77-1.70 (2H, m), 1.37-1.26 (14H, m), 0.88 (3H, t, J = 6.0 Hz); C NMR (100 MHz, CDCl3) δ 159.74,
159.67, 154.6, 129.0, 123.0, 122.3, 120.1, 110.7, 101.7, 31.9, 29.6, 29.5, 29.4, 29.3, 29.2, 28.4, 27.7,
22.7, 14.1; HRMS (DART) m/z calcd for C18H27O ([M+H]+) 259.2056, found 259.2062; IR (ATR) 2922,
2853, 1454, 1252, 748, 739.
1
2-(1-Dodecyn-1-yl)phenol (4): A yellow oil: H NMR (400 MHz, CDCl3) δ 7.30-7.26 (1H, m),
7.21-7.17 (1H, m), 6.92 (1H, d, J = 7.3 Hz), 5.81 (1H, s), 2.47 (2H, t, J = 7.1 Hz), 167-1.58 (2H, m),
13
1.46-1.27 (14H, m), 0.88 (3H, t, J = 6.8 Hz); C NMR (100 MHz, CDCl3) δ 156.5, 131.4, 129.5, 120.1,
114.3, 110.3, 98.1, 31.9, 29.6, 29.5, 29.3, 29.1, 29.0, 28.7, 22.7, 19.6, 14.1; HRMS (DART) m/z calcd
for C18H27O ([M+H]+) 259.2056, found 259.2058; IR (ATR) 2922, 2853, 1576, 1485, 1462, 1286, 1234,
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2-(2-Phenylethyl)-1-benzofuran (5)25: Prepared from 2-chlorophenol and 4-phenyl-1-butyne.
Purification by preparative TLC (hexanes) afforded 5 (91.1 mg, 82%) as a yellow solid: Mp.
46.7-48.7 °C; 1H NMR (400 MHz, CDCl3) δ 7.45 (2H, dd, J = 15.2 Hz, 6.4 Hz), 7.31-7.16 (7H, m), 6.36
(1H, s), 3.08 (4H, s); 13C NMR (100 MHz, CDCl3) δ 158.4, 154.6, 140.9, 128.9, 128.4, 128.3, 126.2,
123.2, 122.4, 120.3, 110.7, 102.3, 33.9, 30.3; HRMS (DART) m/z calcd for C16H15O ([M+H]+)
223.1117, found 223.1117; IR (ATR) 3109, 3061, 2934, 2857, 1601, 1495, 1452, 1427, 1254, 1167,
1101, 1001, 951, 808, 739, 700.
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59
60
2-(3-Chloropropyl)-1-benzofuran (6)26: Prepared from 2-chlorophenol and 5-chloro-1-pentyne.
1
Purification by preparative TLC (hexanes) afforded 6 (56.2 mg, 58%) as a yellow oil: H NMR (400
MHz, CDCl3) δ 7.48 (1H, d, J = 6.8 Hz), 7.40 (1H, d, J = 8.0 Hz), 7.23-7.18 (2H, m), 6.43 (1H, s), 3.59
13
(2H, t, J = 7.7 Hz), 2.95 (2H, t, J = 7.2 Hz), 2.24-2.19 (2H, quint, J = 10.1 Hz); C NMR (126 MHz,
CDCl3) δ 157.4, 154.7, 128.7, 123.4, 122.5, 120.33, 120.32, 110.76, 110.75, 102.8, 44.0, 30.5, 25.6;
HRMS (DART) m/z calcd for C11H12ClO ([M+H]+) 195.0571, found 195.0587; IR (ATR) 2846, 2326,
1585, 1454, 1250, 748.
2-Phenylbenzofuran (7)27: Prepared from 2-chlorophenol and ethylnylbenzene. Purification by
preparative TLC (hexanes/ethyl acetate, 10% ethyl acetate) afforded 7 (50.7 mg, 52%) as a white solid:
1
Mp. 117.1-118.1 °C; H NMR(400 MHz, CDCl3) δ 7.87 (2H, d, J = 8.4 Hz), 7.58 (1H, d, J = 6.8 Hz),
7.52 (1H, d, J = 8.4 Hz), 7.45 (2H, t, J = 7.6 Hz), 7.35 (1H, t, J = 7.4 Hz), 7.30-7.21 (2H, m), 7.03 (1H,
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s);13C NMR (100 MHz, CDCl3) δ 155.9, 154.9, 130.5, 129.2, 128.8, 128.5, 124.9, 124.2, 122.9, 120.8,
111.2, 101.3; HRMS (DART) m/z calcd for C14H11O ([M+H]+) 195.0804, found 195.0831; IR (ATR)
3105, 3051, 3034, 2955, 2930, 2855, 2648, 2610, 2494, 1441, 1258, 1020, 918, 806, 739, 689.
2-(3-Chlorophenyl)-1-benzofuran (8)28: Prepared from 2-chlorophenol and 3-chloro-1-ethynylbenzene.
Purification by preparative TLC (hexanes) afforded 8 (73.1 mg , 64% yield) as a yellow solid: Mp.
87.3-88.2 °C; 1H NMR (400 MHz, CDCl3) δ 7.85 (1H, t, J = 1.6 Hz), 7.73 (1H, d, J = 7.6 Hz), 7.59 (1H,
d, J = 8.4 Hz), 7.52 (1H, d, J = 8.4 Hz), 7.39-7.22 (4H, m), 7.04 (1H, s); 13C NMR (100 MHz, CDCl3) δ
154.9, 154.2, 134.8, 132.1, 130.0, 128.9, 128.3, 124.8, 124.7, 123.1, 122.9, 121.1, 111.2, 102.3; HRMS
(DART) m/z calcd for C14H10ClO ([M+H]+) 229.0415, found 229.0414; IR (ATR) 3109, 3067, 3040,
2957, 2930, 2870, 1603, 1558, 1452, 1408, 1258, 1038, 739, 662.
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2-(4-Fluorophenyl)-1-benzofuran (9)13d: Prepared from 2-chlorophenol and 1-ethynyl-4-fluorobenzene.
Purification by preparative TLC (hexanes/ethyl acetate, 10% ethyl acetate) afforded 9 (34.8 mg, 33%)
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as a yellow solid: Mp. 120.2-122.5 °C; H NMR (400 MHz, CDCl3) δ 7.84-7.80 (2H, m), 7.56 (1H, d, J
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= 7.6 Hz), 7.50 (1H, d, J = 8.4 Hz), 7.29-7.20 (2H, m), 7.12 (2H, t, J = 8.8 Hz), 6.93 (1H, s); C NMR
(100 MHz, CDCl3) δ 164.1, 161.7, 155.0, 154.9, 129.2, 126.8, 126.7, 124.3, 123.0, 120.9, 116.0, 115.8,
111.1, 101.01, 101.0; HRMS (DART) m/z calcd for C14H10FO ([M+H]+) 213.0710, found 213.0705; IR
(ATR) 3046, 1599, 1499, 1450, 1223, 1206, 1157, 1098, 839, 800.
2-(4-Methoxyphenyl)-1-benzofuran (10)29: Prepared from 2-chlorophenol and 4-ethynylanisole.
Purification by preparative TLC (hexanes/ethyl acetate, 10% ethyl acetate) afforded 10 (109 mg, 97%)
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The Journal of Organic Chemistry
as a brown solid: Mp. 142.6-144.7 °C; 1H NMR (400 MHz, CDCl3) δ 7.78 (2H, d, J = 8.0 Hz), 7.55 (1H,
d, J = 7.2 Hz), 7.49 (1H, d, J = 7.6 Hz), 7.24-7.20 (2H, m), 6.96 (2H, d, J = 8.8 Hz), 6.87 (1H, s), 3.84
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(3H, s); C NMR (100 MHz, CDCl3) δ 159.9, 156.0, 154.7, 129.5, 126.4, 123.7, 123.3, 122.8, 120.5,
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114.2, 110.9, 99.6, 55.2; HRMS (DART) m/z calcd for C15H13O2 ([M+H]+) 225.0910, found 225.0911;
IR (ATR) 3121, 3007, 2961, 2837, 1503, 1244, 1169, 741.
2-Decyl-5-methoxybenzofuran (11): Prepared from 2-chloro-4-methoxyphenol and 1-dodecyne.
Purification by preparative TLC (hexanes) afforded 11 (111.8 mg, 78%) as a yellow solid: Mp.
41.2-42.5 °C; 1H NMR (400 MHz, CDCl3) δ 7.27 (1H, d, J = 8.8 Hz), 6.94 (1H, d, J = 2.4 Hz), 6.78 (1H,
dd, J = 8.4, 2.4 Hz), 6.29 (1H, s), 3.81 (3H, s), 2.7 (2H, t, J = 7.6 Hz), 1.73-1.67 (2H, quint, J = 5.5 Hz),
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1.26 (14H, br s), 0.87 (3H, t, J = 6.8 Hz); C NMR (100 MHz, CDCl3) δ 160.6, 155.7, 149.6, 129.5,
111.2, 110.9, 103.0, 101.9, 55.7, 31.9, 29.6, 29.5, 29.34, 29.31, 28.5, 27.6, 22.7, 14.1; HRMS (DART)
m/z calcd for C19H29O2 ([M+H]+) 289.2162, found 289.2151; IR (ATR) 2914, 2847, 1614, 1464, 1452,
1207, 1180, 1153, 1136, 1030, 949, 939, 845, 806, 766, 721.
2-Decylbenzofuran-5-carboxylate (12):
Prepared from methyl-3-chloro-4-hydroxybenzoate and 1-dodecyne. Purification by preparative TLC
(hexanes/ethyl acetate, 10% ethyl acetate) afforded 12 (58.3 mg, 37%) as a yellow solid: Mp.
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39.0-39.2 °C; H NMR (500 MHz, CDCl3) δ 8.21 (1H, d, J = 1.7 Hz), 7.94 (1H, dd, J = 1.7, 8.5 Hz),
7.42 (1H, d, J = 8.5 Hz), 6.43 (1H, s), 3.93 (3H, s), 2.77 (2H, t, J = 7.4 Hz), 1.77-1.70 (2H, quint, J =
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7.5 Hz), 1.36-1.26 (14H, m), 0.88 (3H, t, J = 6.6 Hz); C NMR (126 MHz, CDCl3) δ 167.5, 161.4,
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