Palladium-catalyzed intermolecular coupling of 3-substituted propargylic carbonates with phenols: Synthesis of 2-substituted benzofuran derivatives

Article abstract of DOI:10.1016/j.tetlet.2017.06.023

We accomplished the synthesis of 2-substituted benzofuran derivatives by the palladium-catalyzed reaction of 3-substituted propargylic carbonates with phenols. The 2-substituted benzofuran derivatives were obtained through the intermolecular coupling of t

Full text of DOI:10.1016/j.tetlet.2017.06.023

Accepted Manuscript
Palladium-catalyzed intermolecular coupling of 3-substituted propargylic car-
bonates with phenols: Synthesis of 2-substituted benzofuran derivatives
Hirotaka Watanabe, Masataka Okubo, Kouichi Watanabe, Takumi Udagawa,
Motoi Kawatsura
PII:
S0040-4039(17)30745-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.06.023
TETL 49015
Reference:
Tetrahedron Letters
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10 May 2017
3 June 2017
9 June 2017
Please cite this article as: Watanabe, H., Okubo, M., Watanabe, K., Udagawa, T., Kawatsura, M., Palladium-
catalyzed intermolecular coupling of 3-substituted propargylic carbonates with phenols: Synthesis of 2-substituted
benzofuran derivatives, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.06.023
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Tetrahedron Letters
jo u r n a l h o m e p a g e : w w w . e ls e v i e r . c o m
Palladium-catalyzed intermolecular coupling of 3-substituted propargylic carbonates
with phenols: Synthesis of 2-substituted benzofuran derivatives
Hirotaka Watanabe, Masataka Okubo, Kouichi Watanabe, Takumi Udagawa, Motoi Kawatsura*
Department of Chemistry, College of Humanities & Sciences, Nihon University, Sakurajosui, Setagaya-ku, Tokyo 156-8550, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We accomplished the synthesis of 2-substituted benzofuran derivatives by the palladium-
catalyzed reaction of 3-substituted propargylic carbonates with phenols. The 2-substituted
benzofuran derivatives were obtained through the intermolecular coupling of the 3-substituted
propargylic carbonates with phenols, and sequential intramolecular cyclization reaction.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
Benzofuran
Phenol
Propargylic compound
Cyclization
Benzofuran is an important scaffold in several biologically-
active organic compounds, and development of an efficient
method to construct it and its derivatives is one of the major
topics in organic synthesis. Although several methods have been
reported to construct benzofuran derivatives involving the
transition metal catalyzed reaction,1 most of them are achieved
by the annulation reaction of prefunctionalized substrates,2–4 but
there are only limited examples of the construction of benzofuran
derivatives by the intermolecular coupling using simple phenols
and the sequential cyclization reaction. To the best of our
knowledge, alkynes,5 alkenes,6 or -keto esters7 were used as the
coupling partner for the transition metal catalyzed construction of
benzofuran derivatives with simple phenols. Furthermore, we
have studied the palladium-catalyzed double substitution
reactions of 2-haloallylic esters,8 and during the course of these
studies, we also succeeded in constructing the benzofuran
derivatives by the palladium-catalyzed intermolecular coupling
reaction of 2-fluoroallylic acetates with simple phenols.9
derivatives through the intermolecular attack of the phenoxide
anion and sequential intermolecular cyclization.
Table 1. Palladium-catalyzed reaction of propargylic ester 1a
with phenol 2aa
entry
[Pd/L] (mol %)
base
solvent
yieldb (%)
3aa
4aa
71
27
65
0
1
2
3
4
5
Pd(PPh3)4 (10)
Pd(PPh3)4 (10)
Pd(PPh3)4 (10)
Pd(PPh3)4 (10)
Pd(OAc)2 (10)/
P(PPh3)4 (20)
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
toluene
dioxane
DMF
0
6
6
On the other hand, there are several reports of palladium-
catalyzed coupling reactions of propargylic compounds,10-18 and
the palladium catalyzed reaction of propargylic esters with
nucleophiles generally provides doubly substituted products or
cyclized products. Furthermore, several groups have developed
the palladium-catalyzed reactions of several types of propargylic
compounds with phenols.5c,5f,19-23 For example, Koizumi reported
the palladium-catalyzed double substitution of propargylic
carbonates with phenols,19 and Sinou demonstrated the
construction of 2,3-dihydro-1,4-benzodioxines by the palladium-
catalyzed reaction of propargylic carbonates with catechols.20
Based on this background and our previous study,8,9 we expect
that the palladium-catalyzed reaction of propargylic compounds
with simple phenols provides 2-substituted benzofuran
DMSO
DMSO
27
25
5
6
7
Pd(OAc)2 (10)/
P(4-FC6H4)3 (20)
Pd(OAc)2 (10)/
P(4-MeOC6H4)3 (20)
Pd(OAc)2 (10)/
DPPE (20)
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMSO
DMSO
DMSO
DMSO
DMSO
22
39
0
9
0
8
49
16
22
9
Pd(OAc)2 (10)/
DPPF (20)
26
45
10
[Pd(C3H5)Cl]2 (5)/

2
Tetrahedron
P(4-MeOC6H4)3 (20)
[Pd (C3H5)Cl]2 (5)/
P(4-MeOC6H4)3 (20)
[Pd(C3H5)Cl]2 (5)/
P(4-MeOC6H4)3 (20)
11c
Cs2CO3
CsOAc
DMSO
DMSO
63
0
5
17
18
12c
90 (87)d
0
a Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), [Pd] (5 or 10 mol%), L
(20 mol%), and base (0.24 mmol) in solvent (2.8 mL) at 100 ˚C for 16 h.
6
7
b Yields are determined by 1H NMR of crude materials using internal standard
(trioxane).
c LiCl (10 mol%) was added.
19
dIsolated yield is shown in parentheses.
To realize the construction of benzofuran derivatives by the
palladium-catalyzed intermolecular reaction of propargylic
compounds with simple phenols, we examined the reaction of
methyl (3-phenylprop-2-yn-1-yl) carbonate (1a), which is a 3-
substituted propargylic carbonate, with phenol (2a). As shown
in Table 1, the reactions by Pd(PPh3)4 in the presence of Cs2CO3
in toluene, dioxane or DMF produced no or low product yields,
and doubly substituted product 4aa8,19b as a major product (Table
1, entries 1–3). However, when DMSO was used as the solvent,
we detected the formation of the benzofuran derivative 3aa in
27% NMR yield without formation of 4aa (entry 4). To increase
the yield of 3aa, we investigated the reactions by Pd(OAc)2
using several phosphine ligands, such as PPh3, P(4-FC6H4)3, P(4-
MeOC6H4)3, DPPE, and DPPF, and confirmed that P(4-
MeOC6H4)3 produced a better result (39% NMR yield) compared
to the other phosphine ligands (entries 5–9). These results
indicate that, in the reactions by Pd(OAc)2 with monophosphine
ligands, P(4-MeOC6H4)3 accelerated the oxidative addition of 1
to Pd(0). Changing the Pd(OAc)2 to [Pd(C3H5)Cl]2 was also
effective in increasing the yield (entry 10), and the addition of
LiCl (10 mol%) realized the higher yield (63% NMR yield)
(entry 11). To our delight, the highest yield (90% NMR yield,
87% isolated yield) was obtained when the base was changed
from Cs2CO3 to CsOAc (entry 12).
8
9
20
21
22
10
11
12
23
24
aReaction conditions: 1a (0.2 mmol), 2b–y (0.3 mmol), [Pd(C3H5)Cl]2 (5
mol%), P(4-MeOC6H4)3 (20 mol%), CsOAc (0.24 mmol), and LiCl (10
mol%) in DMSO (2.8 mL) at 100 ˚C for 16 h
Table 2. Palladium-catalyzed reaction of 1a with phenols 2b–ya
b Regioselectivity ratio was determined by 1H NMR of crude materials.
Based on this initial result, we examined the reaction of 1a
with several phenols 2b–y, and the results are summarized in
Table 2. The reactions with phenols 2b and 2c, which possess an
alkyl group at the para-position, smoothly proceeded, and the
intended 2-substituted benzofuran derivatives 3ab and 3ac were
produced in 79% and 82%, respectively (Table 2, entries 1 and
2). The reaction with m-cresole (2d) afforded a product in 77%
yield as a mixture of two regioisomers, and we confirmed that the
major product was 2-benzyl-6-methylbenzofuran (3ad) (entry 3).
This result indicated that the cyclization occurred at the sterically
less hindered site of 2d. Furthermore, the reaction of the ortho-
substituted phenols 2e and 2f provided the desired products 3ae
and 3af in 81% yields, respectively (entries 4 and 5). The
reactions with the dimethyl phenols 2g–i also gave the
corresponding benzofuran derivatives 3ag–ai in the range of 72–
82% yields (entries 6–8), respectively. We next demonstrated the
reactions of 1a with methoxyphenols 2j–m, and succeeded in
obtaining the desired products 3aj–am in good yields (entries 9–
12). The reactions with fluoro- or chlorophenols, such as 2n–r,
also afforded the 2-benzylbenzofuran derivatives in moderate to
good yields (entries 13–17), but the reaction with p-bromophenol
(2s) resulted in a low yield (38%) (entry 18). We further
investigated the reactions of the trifluoromethylphenols 2t and
2u, and obtained the intended benzofuran derivatives 3at and 3au
in 66% and 70% yields, respectively (entries 19 and 20). For the
reaction of 2u, we also confirmed that 3au was obtained as a
entry
1
Isolated yield (%)b of 3
entry
13
Isolated yield (%)b of 3
2
3
4
14
15
16

single regioisomer (entry 20). The reactions of 1a with naphthols
2v and 2w also occurred in good yields (entries 21 and 22), but
the regioselectivity for the reaction of 2v was low (entry 21).
Furthermore, we conducted the reactions with p-cyanophenol
(2x) or p-nitrophenol (2y) and confirmed that these reactions
provide 3ax and 3ay in 83% and 54% yields, respectively
(entries 23 and 24).
of 1 with Pd(0) initially generates an allenylpalladium
intermediate A. Attack of the phenoxide anion on the central
carbon of A provides the -allylpalladium complex C through the
-allylpalladium complex B. Although the details are unclear,
the regioselective cyclization of C proceeded at the sterically less
hindered site and the thermodynamically stable 2-substituted
benzofuran 3 was formed.
We next investigated the reactions of several aryl group
substituted carbonates 1b–k with phenol (2a). As shown in
Table 3, most of the reactions smoothly proceeded and provided
the intended 2-substituted benzofuran derivatives in moderate to
good yields. For example, the reactions of the carbonates 1b–h
with 2a gave the desired products 3ba–ha in the range of 71–
94% yields, respectively (Table 3, entries 1–7). We confirmed
that the reaction of 1i, which has a 1-naphthyl group at the C-3
position, also afforded the corresponding product 3ia in 74%
yield (entry 8). Furthermore, we succeeded in proceeding the
reaction of the thienyl group substituted carbonate 1j, and
obtained 3ja in 61% yield (entry 9). Unfortunately, we also
examined the reaction of 1k, which possessed an alkyl group
instead of an aryl group, but the reaction did not afford any
intended benzofuran derivative (entry 10).
Table 3. Palladium-catalyzed reaction of 1b–k with phenol (2a)a
Scheme 1. Possible reaction mechanism.
In conclusion, we demonstrated the palladium-catalyzed
reaction of 3-substituted propargylic carbonates with simple
phenols, and succeeded in obtaining the 2-substituted benzofuran
derivatives through the intermolecular coupling of the 3-
substituted propargylic carbonates with phenols, and sequential
intramolecular cyclization reaction.
1 (Ar = )
Isolated yield (%) of 3
75 (3ba)
entry
1
Acknowledgments
This work was supported by the Individual Research Expense
of College of Humanities and Sciences at Nihon University.
77 (3ca)
71 (3da)
2
3
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(b) Yoshida, M.; Higuchi, M.; Shishido, K.

5
Highlights
• Synthesis of 2-substituted benzofuran derivatives.
• The palladium-catalyzed intermolecular coupling, and
sequential intramolecular cyclization.
• One step synthesis of 2-substituted benzofuran derivatives
by the coupling of 3-substituted propargylic carbonates with
simple phenols.

6
Tetrahedron
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Palladium-catalyzed intermolecular coupling
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of 3-substituted propargylic carbonates with
phenols: Synthesis of 2-substituted
benzofuran derivatives
Hirotaka Watanabe, Masataka Okubo, Kouichi Watanabe, Takumi Udagawa, Motoi Kawatsura*