Palladium-catalyzed three-component coupling reactions of 2-(cyanomethyl)phenol, aryl halides, and carbon monoxide

Article abstract of DOI:10.1016/j.tet.2015.04.049

Three-component coupling reactions of 2-(cyanomethyl)phenol, aryl halides, and carbon monoxide (CO) in orthogonal-tandem catalysis were investigated. In the reactions, 2-(cyanomethyl)phenyl esters, which are produced through Pd(PPh₃)₄-catalyzed alkoxycarbonylation of aryl halides with 2-(cyanomethyl)phenol, undergo cycloisomerization in situ catalyzed by Pd(PCy₃)₂ as a co-catalyst to give 3-acyl-2-aminobenzofurans. Palladium species with homoleptic tertiary phosphines, such as Pd(PPh₃)₄ and Pd(PCy₃)₂, can catalyze the mechanistically distinct reactions in an orthogonal-tandem manner without interference. By switching the base used in this reaction, 3-acyl-2-(N-acylamino)benzofurans were obtained as major products instead of 3-acyl-2-aminobenzofurans. Given that 2-(cyanomethyl)phenols can be synthesized from commercially available salicylic acid derivatives in two steps, the present method thus provides facile access to synthetically useful 3-acyl-2-aminobenzofurans.

Full text of DOI:10.1016/j.tet.2015.04.049

Accepted Manuscript
Palladium-catalyzed three-component coupling reactions of 2-(cyanomethyl)phenol,
aryl halides, and carbon monoxide
Masahito Murai, Kazuhiro Okamoto, Koji Miki, Kouichi Ohe
PII:
S0040-4020(15)00548-7
10.1016/j.tet.2015.04.049
TET 26652
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 5 February 2015
Revised Date: 13 April 2015
Accepted Date: 17 April 2015
Please cite this article as: Murai M, Okamoto K, Miki K, Ohe K, Palladium-catalyzed three-component
coupling reactions of 2-(cyanomethyl)phenol, aryl halides, and carbon monoxide, Tetrahedron (2015),
doi: 10.1016/j.tet.2015.04.049.
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Palladium-catalyzed three-component coupling
reactions of 2-(cyanomethyl)phenol, aryl halides,
and carbon monoxide
Leave this area blank for abstract info.
Masahito Murai, Kazuhiro Okamoto, Koji Miki, and Kouichi Ohe*
Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University
Katsura, Nishikyo-ku, Kyoto 615-8510, Japan

1
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Tetrahedron
journal homepage: www.elsevier.com
Palladium-catalyzed three-component coupling reactions of 2-
(cyanomethyl)phenol, aryl halides, and carbon monoxide
Masahito Murai†, Kazuhiro Okamoto , Koji Miki , and Kouichi Ohe
aDepartment of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Three-component coupling reactions of 2-(cyanomethyl)phenol, aryl halides, and carbon
monoxide (CO) in orthogonal–tandem catalysis were investigated. In the reactions, 2-
Received in revised form
Accepted
Available online
(cyanomethyl)phenyl
esters,
which
are
produced
through
Pd(PPh3)4-catalyzed
alkoxycarbonylation of aryl halides with 2-(cyanomethyl)phenol, undergo cycloisomerization in
situ catalyzed by Pd(PCy3)2 as a co-catalyst to give 3-acyl-2-aminobenzofurans. Palladium
species with homoleptic tertiary phosphines, such as Pd(PPh3)4 and Pd(PCy3)2, can catalyze the
mechanistically distinct reactions in an orthogonal–tandem manner without interference. By
switching the base used in this reaction, 3-acyl-2-(N-acylamino)benzofurans were obtained as
major products instead of 3-acyl-2-aminobenzofurans. Given that 2-(cyanomethyl)phenols can
be synthesized from commercially available salicylic acid derivatives in two steps, the present
method thus provides facile access to synthetically useful 3-acyl-2-aminobenzofurans.
Keywords:
Tandem Catalysis
Carbonylation
Cycloisomerization
3-Acyl-2-aminobenzofuran
2009 Elsevier Ltd. All rights reserved.
1. Introduction
Cascade and tandem reactions provide efficient access to
structurally complex molecules from simple and readily available
starting materials.1 Almost all such reactions involve both inter-
and intramolecular multibond-forming processes and they are
usually straightforward to perform. Ideally, these approaches can
minimize the amount of reagent, cost, byproduct formation, time,
and complexity of separation processes required for a desired
transformation. The development of step-economic processes
through the use of tandem reactions involving different types of
reactions promoted by more than two catalysts is a challenging
subject.2 In this context, we have developed a number of
transition metal-catalyzed cascade reactions.3,4 We have recently
reported the one-pot synthesis of hetero α,α’-dimers of
heterocycles involving the Sonogashira reaction of acyclic
coupling partners and subsequent cycloisomerization reactions
catalyzed by Pd and Cu species.3 These examples represent a
strategy that has been classified as orthogonal–tandem catalysis
(Scheme 1).2d We have also developed palladium-catalyzed
Scheme 2. Palladium-catalyzed cycloisomerization (the downstream
reaction) and carbonylation (the upstream reaction).
cycloisomerization reactions for the short step synthesis of 3-
acyl-2-aminobenzofurans 2. Ideally, the mechanistically discrete
reaction cascade could be catalyzed by a single catalyst;
however, when more than two catalysts are required, it is
essential for efficient operation that there is no interference
between catalysts. Here, we wish to report an efficient and
cycloisomerization
reactions
based
on
intramolecular
oxypalladation to a C–N triple bond of 2-(cyanomethyl)phenyl
esters
1
leading to 3-acyl-2-aminobenzofurans 25 (the
downstream reaction presented in Scheme 2).6 In the course of
our studies, we envisioned that the carbonylation reaction of aryl
halides with 2-cyanomethylphenols 3 (the upstream reaction
presented in Scheme 2) could be combined with such
———
†Present Address: Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, 3-1-1
Tsushimanaka, Kita-ku, Okayama 700-8530, Japan. Corresponding author. Tel.: +81-75-383-2495; fax: +81-75-383-2499; e-mail:
ohe@scl.kyoto-u.ac.jp (K. Ohe).

2
Tetrahedron
ACCEPTED MANUSCRIPT
straightforward synthesis of 3-acyl-2-aminobenzofurans 2 by
employing three-component
catalysts are effective for the three-component synthesis of 3-
acyl-2-aminobenzofuran, we then optimized the reaction
conditions by using 4-bromotoluene with 3a and CO.
Gratifyingly, we found that the three-component coupling
reaction led to the formation of 2a in 52% yield in the presence
of palladium catalysts, Pd(PPh3)4 (2 mol%) and Pd(PCy3)2 (8
mol%).9
coupling reactions of 2-(cyanomethyl)phenol derivatives 3, aryl
halides, and CO, catalyzed by two homoleptic tertiary phosphine-
ligated palladium(0) species (Scheme 2). Because 3-acyl-2-
aminobenzofurans have both an amino and a carbonyl group,
they are useful building blocks for the synthesis of a range of
benzofuran-fused heterocycles.
Under the optimized reaction conditions [aryl bromide (1.5
equiv), Pd(PPh3)4 (2 mol %), Pd(PCy3)2 (8 mol %), and Et3N (1.5
equiv) in DMF at 100 °C under 1 atm CO], the substrate scope of
the reaction was examined by using a range of aryl halides. The
results are summarized in Table 1. The reactions with aryl
bromides having an electron-withdrawing group, such as a
trifluoromethyl or a chloro group at the para-position, afforded
the corresponding 3-acyl-2-aminobenzofurans 2b and 2c in 84
and 74% yields, respectively (entries 1 and 2). The presence of a
substituent such as a chloro group at an ortho-position was also
tolerated in the reaction (entry 3). The three-component cascade
reaction was also applicable to aryl halides having either
2. Results and discussion
Initially, the palladium-catalyzed, three-component coupling
reaction of 2-(cyanomethyl)phenol 3a and 4-bromotoluene (1.5
equiv) in the presence of Et3N (1.5 equiv) in DMF at 100 °C
under a CO atmosphere (1 atm) for 40 h was examined.7
Although Pd(PCy3)2 was effective for the cycloisomerization of
2-(cyanomethyl)phenyl ester 1a into 3-acyl-2-aminobenzofuran
2a,5 it was ineffective in the three-component coupling reaction
even in the presence of Zn(OAc)2 (10 mol%) as an additive
(Scheme 3). The use of Pd(PPh3)4 (5 mol%) led to the selective
formation of 1a (94%) with none of 2a.8 However, when the
reaction was carried out in the presence of both Pd(PCy3)2 and
Pd(PPh3)4 (5 mol% each), 2a was obtained in 28% yield along
with 1a (42% yield). Having found that two types of palladium
moderately
electron-withdrawing
or
electron-donating
substituents, although extended reaction times were required for
these reactions to reach completion (entries 4–6). The reaction
using 4-bromoanisole was sluggish, giving a small amount of 3-
acyl-2-aminobenzofuran 2h, whereas the reaction using 4-
iodoanisole afforded 2h in 42% yield (entries 7 and 8).10
The substrate scope of the reaction with respect to variation
of 2-(cyanomethyl)phenols was also examined. As shown in
Table 2, 2-(cyanomethyl)phenols 3 possessing a range of
substituents participated in the cascade reactions to give the
corresponding 3-acyl-2-aminobenzofuran derivatives 2i–l in
moderate to good yield (entries 1–4). It should be noted that a
remote ester group of 2m remained intact under the reaction
conditions (entry 5). Silyloxy and methoxymethyloxy groups
were compatible with the reaction conditions, affording 2n and
2o in 70 and 72% yields, respectively (entries 6 and 7).11
Scheme 3. Palladium-catalyzed three-component coupling.
Table 1. Pd-catalyzed three-component coupling reactions using aryl halides, 3a, and CO leading to 3-acyl-2-aminobenzofurans
2a
Entry
Ar
X
Time
20 h
Product
Yieldb
84%
2b
1
2
3
4
5
6
7
8
4-CF3C6H4
4-ClC6H4
2-ClC6H4
4-FC6H4
2-Naph
Br
Br
Br
Br
Br
Br
Br
I
30 h
30 h
40 h
40 h
40 h
40 h
40 h
2c
2d
2e
2f
74%
71%
60%
71%
57%
7%
Ph
2g
2h
2h
4-MeOC6H4
4-MeOC6H4
42%
aReaction conditions: 3a (0.30 mmol), ArX (0.45 mmol), Et3N (0.45 mmol), Pd(PPh3)4 (0.006 mmol), and Pd(PCy3)2 (0.024 mmol) in DMF (1.2 mL) under CO
(1 atm).

3
bIsolated yield
ACCEPTED MANUSCRIPT
Table 2. Pd-catalyzed three-component coupling reactions
(cycle A).7 The latter then participates in a second catalytic
cycle, and is converted into 3-acyl-2-aminobenzofuran 2 through
cycloisomerization catalyzed by Pd(PCy3)2 (cycle B).5 We
propose that the mechanistically distinct cascade reactions can be
catalyzed by two different types of catalyst with homoleptic
tertiary phosphines.12
leading to 3-acyl-2-aminobenzofurans 2a
Pd(PPh3)4 (2 mol%)
R
OH
Pd(PCy3)2 (8 mol%)
ArBr
2
CO
CN
Et3N (1.5 equiv)
DMF, 100 ºC
1 atm, 40 h
3
When the reaction was carried out by using K2CO3 or NaOEt
as
a
base and Pd(PPh3)4 as
a
catalyst, 3-acyl-2-(N-
2
Product ( )
Entry
Yieldb
55%
acylamino)benzofuran 4a was obtained in 9 and 4% yields,
respectively, together with ester 1a. The yield of 4a increased to
73%, when Pd(OAc)2, PPh3 (Pd/P ratio 1:2), 4-bromotoluene (3
equiv), and K2CO3 were used, as shown in Table 3. Under these
conditions, a variety of aryl halides afforded the corresponding 3-
acyl-2-(N-acylamino)benzofurans 4b–g in moderate to good
yields (entries 2–7). In none of the cases was 3-acyl-2-
aminobenzofuran 2 obtained. These results show that the
reactions leading to 2 or 4 proceed through different pathways
and that the course of the reaction is determined by the nature of
the base used.
Me
O
2i
NH2
1
O
Ph
Me
O
2j
2
3
(Ar = 4-CF3C6H4)
(Ar = Ph)
NH2
86%
71%
2k
O
Ar
Cl
O
NH2
To gain insight into the reaction mechanism, we carried out
the reaction of 2a with 4-bromotoluene in the presence of a
palladium catalyst and K2CO3 under CO. However, 4a was not
obtained even in the presence of an excess of 4-bromotoluene (eq
1). This result clearly shows that the conversion of 3a into 4a did
not proceed via 2a.
2l
66%
4
O
Ph
O
2m
5
6
7
(R = OBz)
54%
NH2
2n
2o
(R = OTBDMS)
(OMOM)
70%
72%
R
O
Ph
aReaction conditions: 3 (0.30 mmol), ArBr (0.45 mmol), Et3N (0.45 mmol),
Pd(PPh3)4 (0.006 mmol), and Pd(PCy3)2 (0.024 mmol) in DMF (1.2 mL)
under CO (1 atm).
bIsolated yields.
Based on these results, we propose a reaction mechanism
leading to 4 as shown in Scheme 4. The reaction proceeds
through acylation of 3a followed by a 1,4-benzoyl shift to afford
intermediate X. Direct attack of a phenolate anion of X to the
nitrile moiety followed by a second acylation of the resulting
iminyl anion Y gives cyclic intermediate Z, which leads to the
The most plausible catalytic cycle leading to 3-acyl-2-
aminobenzofurans 2 is shown in Figure 1. The Pd(PPh3)4-
catalyzed alkoxycarbonylation of an aryl halide, CO, and 2-
cyanomethylphenol 3a produces 2-(cyanomethyl)phenyl ester 1
formation of the 3-acyl-2-(N-acylamino)benzofuran
4 by
prototropy. 13

4
Tetrahedron
ACCEPTED MANUSCRIPT
Table 3. Pd-catalyzed three-component coupling reactions in the
presence of K2CO3 leading to 3-acyl-2-(N-acylamino)-
benzofurans 4a
3. Conclusion
We have demonstrated
a
palladium-catalyzed, three-
component cascade reaction of 2-(cyanomethyl)phenols, aryl
halides, and CO, leading to 3-acyl-2-aminobenzofuran
derivatives. A diverse array of functional groups is tolerated in
the orthogonal–tandem catalysis. The present transformation is
composed of two types of mechanistically discrete reactions
catalyzed by independent palladium complexes: (i) Pd(PPh3)4-
catalyzed alkoxycarbonylation of aryl halides with 2-
(cyanomethyl)phenols,
cycloisomerization leading to 3-acyl-2-aminobenzofurans. In the
synthesis of 3-acyl-2-aminobenzofuran and 3-acyl-2-(N-
acylamino)benzofuran
substrates serve as scaffolds for the carbonylative carbon–carbon
and carbon–nitrogen bond-forming reactions. The present
method using 2-(cyanomethyl)phenols, which can be easily
prepared from commercially available salicylic acids, thus
provides facile access to 3-acyl-2-aminobenzofuran derivatives.
O
Ar
Pd(OAc)2 (10 mol%)
PPh3 (20 mol%)
O
NH
3a
ArX
CO
K2CO3 (3.0 equiv)
O
Ar
DMF, 100 ºC, 12 h
4
Entry Ar
X
Product
4a
Yieldb
73%
91%
63%
82%
88%
41%
68%
and
(ii)
Pd(PCy3)2-catalyzed
1
2
3
4
5
6
7
4-MeC6H4
4-CF3C6H4
4-ClC6H4
Ph
Br
Br
Br
Br
Br
I
4b
derivatives,
2-(cyanomethyl)phenol
4c
4d
2-Naph
4e
4-MeOC6H4
2-MeC6H4
4f
I
4g
aReaction conditions: 3a (0.30 mmol), ArX (0.90 mmol), K2CO3 (0.90 mmol),
4. Experimental section
4.1. General Information
Pd(OAc)2 (0.03 mmol), and PPh3 (0.06 mmol) in DMF (1.2 mL) under CO (1
atm).
Unless otherwise noted, chemicals obtained from commercial
suppliers were used without further purification. CO gas (purity
99.97%) was purchased from Sumitomo Seika Co. Solvents
were dried by the usual methods and distilled before use. Unless
otherwise noted, reactions were carried out under nitrogen
atmosphere. NMR spectra were measured for solutions in CDCl3
or acetone-d6 with tetramethylsilane as an internal standard (1H
and 13C): the following abbreviations are used; br s: broad
singlet, s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet.
IR spectra were recorded with an FT-IR spectrometer. Melting
points (mp) are uncorrected. Element analyses were performed
at Microanalytical Center of Kyoto University. High-resolution
mass spectra (HRMS) were measured with JEOL JMX-SX 102A
spectrometer.
bIsolated yields.
Benzofurans obtained from the present palladium-catalyzed,
three-component reactions possess both an amino and a carbonyl
group; therefore, they can serve as key intermediates for the
synthesis
of
benzofuran-fused,
nitrogen-containing
heterocycles.14 For example, 3-acyl-2-aminobenzofuran 2g was
converted into the corresponding benzofuro[2,3-d]pyrimidine
derivative 5 in 97% yield by simply heating with formamide in
the presence of 3 mol% Sc(OTf)3 (eq 2).
4.2. General procedure of palladium-catalyzed three-
component coupling reactions leading to 3-acyl-2-
aminobenzofurans.

5
A flame dried Schlenk flask was charged with Pd(PCy3)2 (16.1
4.2.5. 2-Amino-3-benzoyl-5-(tert-butyldimethylsilyl)oxybenzo-
ACCEPTED MANUSCRIPT
mg, 0.024 mmol), Pd(PPh3)4 (6.9 mg, 0.006 mmol), 2-
(cyanomethyl)phenols 3a (0.30 mmol), aryl halides (0.45 mmol),
Et3N (0.063 mL, 0.45 mmol), and DMF (1.2 mL). The flask was
then flushed with CO, and the system was closed. After the
reaction mixture was stirred at 100 °C for the time specified in
Scheme 3 and Tables 1 and 2, it was diluted with Et2O and
filtered through a short silica gel pad. The filtrate was washed
with brine, and the aqueous layer was extracted with Et2O (10
mL×3). The combined organic layer was dried over MgSO4,
and then filtered. The organic solvent was removed under
reduced pressure and the residue was subjected to flash column
chromatography on silica gel with hexane/AcOEt (v/v = 7/1-2/1)
as eluents to afford the corresponding 3-acyl-2-
aminobenzofurans 2.
[b]furan (2n): A yellow solid; mp 147.8-148.8 °C. IR (KBr):
752, 852, 920, 1073, 1156, 1232, 1364, 1438, 1479, 1590, 1655
(C=O), 3112, 3326 cm-1. 1H NMR (400 MHz, CDCl3):
δ 0.06 (s,
6H), 0.91 (s, 9H), 6.29 (d, J = 2.9 Hz, 1H), 6.52 (dd, J = 2.9, 8.6
Hz, 1H), 7.04 (d, J = 8.6 Hz, 1H), 7.19 (br s, 2H), 7.45-7.55 (m,
3H), 7.67 (d, J = 6.6 Hz, 2H). 13C NMR (100 MHz, CDCl3):
δ -
4.64, 18.1, 25.6, 94.6, 110.0, 110.1, 113.9, 127.0, 127.1, 128.3,
130.6, 140.9, 144.2, 152.1, 167.2, 190.7. HRMS (FAB) calcd for
M+H+ of C21H25NO3Si 368.1682, found 368.1682.
4.2.6. 2-Amino-3-benzoyl-4-(methoxymethyloxy)benzo[b]furan
(2o): A yellow solid; mp 118.9-119.7 °C. IR (KBr): 756, 797,
920, 1023, 1079, 1152, 1175, 1246, 1342, 1480, 1593,
1651(C=O), 2942, 3111, 3325 cm-1. 1H NMR (400 MHz,
CDCl3):
δ 3.40 (s, 3H), 4.98 (s, 2H), 6.55 (d, J = 2.5 Hz, 1H),
4.2.1. 2-Amino-3-benzoyl-7-methylbenzo[b]furan (2i): A yellow
solid; mp 153.8-154.7 °C. IR (KBr): 749, 772, 849, 920, 1062,
1170, 1281, 1340, 1477, 1645 (C=O), 3198, 3366 cm-1. 1H NMR
6.74 (dd, J = 2.5, 8.8 Hz, 1H), 7.06 (br s, 2H), 7.11 (d, J = 8.8
Hz, 1H), 7.49 (d, J = 6.8 Hz, 1H), 7.49-7.55 (m, 2H), 7.69 (d, J =
6.8 Hz, 2H). 13C NMR (100 MHz, CDCl3):
δ 55.8, 94.7, 95.4,
(400 MHz, CDCl3):
δ
2.40 (s, 3H), 6.70 (d, J = 7.3 Hz, 1H), 6.84
107.6, 110.2, 110.7, 127.2, 127.4, 128.3, 130.9, 140.7, 144.8,
154.0, 167.1, 190.7. Anal. calcd for C17H15NO4: C, 68.68; H,
5.09. Found: C, 68.61; H, 5.11.
(d, J = 6.8 Hz, 1H), 6.89 (t, J = 7.3 Hz, 1H), 7.11 (br s, 2H), 7.44-
7.54 (m, 3H), 7.70 (d, J = 6.8 Hz, 2H). 13C NMR (100 MHz,
CDCl3):
δ 14.7, 94.7, 116.5, 120.1, 123.3, 123.6, 125.8, 127.4,
128.3, 130.8, 140.9, 147.9, 166.4, 190.9. Anal. calcd for
C16H13NO2: C, 76.48; H, 5.21. Found: C, 76.38; H, 5.50.
4.3. General Procedure of Palladium-Catalyzed Three-
component Coupling Reactions Leading to 3-Acyl-2-(N-
acylamino)benzofurans.
4.2.2. 2-Amino-6-methyl-3-(4’-trifluoromethylbenzoyl)benzo[b]-
furan (2j): A yellow solid; mp 126.8-127.3 °C. IR (KBr): 782,
810, 859, 904, 980, 1018, 1067, 1109, 1125, 1173, 1250, 1323,
1475, 1589, 1656 (C=O), 3165, 3351 cm-1. 1H NMR (400 MHz,
A flame dried Schlenk flask was charged with Pd(OAc)2 (6.7
mg, 0.03 mmol), PPh3 (15.7 mg, 0.06 mmol), 2-
(cyanomethyl)phenol 3a (39.9 mg, 0.30 mmol), aryl halides (0.9
mmol), K2CO3 (124 mg, 0.9 mmol), and DMF (1.2 mL). The
flask was then flushed with CO, and the system was closed.
After the reaction mixture was stirred at 100 °C for the time
specified in Table 3, it was diluted with Et2O and filtered through
a short silica gel pad. The filtrate was washed with brine, and the
aqueous layer was extracted with Et2O (10 mL ×3). The
combined organic layer was dried over MgSO4, and then filtered.
The organic solvent was removed under reduced pressure and the
residue was subjected to flash column chromatography on silica
gel with hexane/AcOEt = 7/1-2/1 as eluents to afford the
corresponding 3-acyl-2-(N-acylamino)benzofurans 4.
CDCl3):
Hz, 1H), 7.03 (s, 1H), 7.25 (br s, 2H), 7.74 (d, J = 8.3 Hz, 2H),
7.79 (d, J = 8.3 Hz, 2H). 13C NMR (100 MHz, CDCl3):
21.2,
δ 2.35 (s, 3H), 6.64 (d, J = 8.3 Hz, 1H), 6.83 (d, J = 8.3
δ
94.2, 110.7, 118.2, 123.0, 123.8 (q, J = 271.9 Hz), 124.8, 125.4
(q, J = 3.3 Hz), 127.8, 132.4 (q, J = 32.2 Hz), 132.5, 144.1,
149.6, 166.9, 188.7.
HRMS (FAB) calcd for M+H+ of
C17H12F3NO2 320.0898, found 320.0891.
4.2.3. 2-Amino3-benzoyl-6-chlorobenzo[b]furan (2l): A pale
yellow solid; mp 121.3-122.5 °C. IR (KBr): 759, 799, 858, 920,
993, 1073, 1177, 1242, 1347, 1435, 1478, 1589, 1658 (C=O),
3110, 3325 cm-1. 1H NMR (400 MHz, CDCl3):
δ 6.84 (d, J = 2.0
4.3.1. N-[3-(4’-Methylbenzoyl)-2-benzo[b]furyl]-4’-methylbenz-
amide (4a): A yellow solid; mp 157.1-157.7 °C. IR (KBr): 745,
773, 828, 932, 1016, 1061, 1285, 1324, 1461, 1557, 1614 (C=O),
Hz, 1H), 6.99 (dd, J = 2.0, 8.8 Hz, 1H), 7.09 (br s, 2H), 7.13 (d, J
= 8.8 Hz, 1H), 7.52 (d, J = 7.3 Hz, 2H), 7.49-7.59 (m, 1H), 7.67
(d, J = 7.3 Hz, 2H). 13C NMR (100 MHz, CDCl3):
δ 94.0, 110.9,
1712 (C=O), 2921, 3027 cm-1. 1H NMR (400 MHz, CDCl3):
δ
118.8, 121.7, 127.3, 127.9, 128.5, 129.4, 131.3, 140.4, 147.5,
167.0, 190.7. Anal. calcd for C15H10ClNO2: C, 66.31; H, 3.71.
Found: C, 66.34; H, 3.53.
2.43 (s, 3H), 2.46 (s, 3H), 7.11-7.15 (m, 2H), 7.20-7.25 (m, 1H),
7.32 (d, J = 2.4 Hz, 2H), 7.33 (d, J = 2.4 Hz, 2H), 7.58 (d, J = 8.3
Hz, 1H), 7.71 (d, J = 7.8 Hz, 2H), 8.01 (d, J = 8.3 Hz, 2H), 12.2
(s, 1H). 13C NMR (100 MHz, CDCl3):
δ 21.5, 21.6, 100.0, 111.6,
120.2, 123.7, 123.8, 124.0, 124.2, 127.9, 128.2, 129.1, 129.6,
136.8, 142.8, 143.9, 150.7, 158.9, 163.1, 192.6. HRMS (FAB)
calcd for M+H+ of C24H19NO3 370.1443, found 370.1449.
4.2.4. 5-(2-Amino-3-benzoylbenzo[b]furyl) benzoate (2m): A
yellow solid; mp 145.4-146.3 °C. IR (KBr): 757, 800, 873, 923,
1004, 1065 1165, 1266, 1450, 1479, 1593, 1656 (C=O), 1722
(C=O), 3096, 3329 cm-1. 1H NMR (400 MHz, CDCl3):
δ 6.72 (d,
J = 2.0 Hz, 1H), 6.86 (dd, J = 2.0, 8.3 Hz, 1H), 7.17 (br s, 2H),
7.22 (d, J = 8.8 Hz, 1H), 7.46-7.50 (m, 5H), 7.61 (t, J = 7.3 Hz,
1H), 7.71 (d, J = 7.3 Hz, 2H), 8.14 (d, J = 8.3 Hz, 2H). 13C NMR
4.3.2. N-[3-(4’-Trifluoromethylbenzoyl)-2-benzo[b]furyl]-4’-
trifluoromethylbenzamide (4b): A yellow solid; mp 176.2-176.9
°C. IR (KBr): 677, 751, 785, 855, 1014, 1068, 1124, 1170, 1287,
1326, 1462, 1558, 1617, 1718, 2361, 3077 cm-1. 1H NMR (400
(100 MHz, CDCl3):
δ 94.4, 110.4, 112.3, 115.2, 127.4, 127.5,
128.4, 128.5, 129.5, 130.1, 131.1, 133.5, 140.5, 146.7, 147.3,
165.5, 167.3, 190.5. Anal. calcd for C22H15NO4: C, 73.94; H,
4.23. Found: C, 73.77; H, 4.18.
MHz, CDCl3):
δ 7.01 (d, J = 7.8 Hz, 1H), 7.19 (t, J = 7.8 Hz,
1H), 7.29 (t, J = 7.3 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.83 (d, J
= 8.3 Hz, 4H), 7.91(d, J = 8.3 Hz, 2H), 8.21 (d, J = 7.8 Hz, 2H),

6
Tetrahedron
ACCEPTED MANUSCRIPT
12.3 (s, 1H). 13C NMR (100 MHz, CDCl3):
δ
100.3, 111.9,
4.3.7. N-[3-(2’-Methylbenzoyl)-2-benzo[b]furyl]-2’-methylbenz-
amide (4g): A yellow solid; mp 169.7-170.3 °C. IR (KBr): 738,
763, 929, 1054, 1174, 1221, 1284, 1322, 1434, 1461, 1558, 1592,
119.9, 123.1, 123.4 (q, J = 272.3 Hz), 123.6 (q, J = 272.3 Hz),
124.6, 124.8, 125.7 (q, J = 3.3 Hz), 126.2 (q, J = 3.3 Hz), 128.3,
128.4, 133.8 (q, J = 32.3 Hz), 134.8 (q, J = 32.3 Hz), 135.4,
142.4, 150.8, 159.0, 161.9, 191.6. HRMS (FAB) calcd for M+H+
of C24H13F6NO3 478.0878, found: 478.0884.
1621, 1708, 3063 cm-1. 1H NMR (400 MHz, CDCl3):
δ 2.33 (s,
3H), 2.67 (s, 3H), 6.47 (d, J = 7.8 Hz, 1H) 7.06 (t, J = 8.3 Hz,
1H), 7.21 (t, J = 8.3 Hz, 1H), 7.30-7.37 (m, 5H), 7.42-7.47 (m,
2H), 7.58 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 11.8 (s,
1H). 13C NMR (100 MHz, CDCl3):
δ 19.1, 20.7, 100.8, 111.6,
119.4, 123.7, 123.9, 124.6, 126.0, 126.3, 126.4, 127.7, 130.2,
130.9, 131.7, 132.0, 133.2, 134.7, 138.7, 140.1, 150.7, 158.3,
165.5, 194.7. HRMS (FAB) calcd for M+H+ of C24H19NO3
370.1443, found 370.1444.
4.3.3. N-[3-(4’-Chlorobenzoyl)-2-benzo[b]furyl]-4’-chlorobenz
amide (4c): A yellow solid; mp 181.2-181.9 °C. IR (KBr): 668,
742, 774, 845, 934, 1011, 1060, 1091, 1285, 1323, 1430, 1458,
1558, 1615, 1714, 2342, 2359. 3032 cm-1. 1H NMR (400 MHz,
CDCl3):
δ 7.11 (d, J = 7.6 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.27
(t, J = 7.6 Hz 1H), 7.52 (d, J = 8.3 Hz, 4H), 7.60 (d, J = 8.3 Hz,
1H), 7.75 (d, J = 8.3 Hz, 2H), 8.04 (d, J = 8.3 Hz, 2H), 12.2 (s,
4.4. Synthesis of 4-Phenylbenzofuro[2,3-d]pyrimidine (5).
1H). 13C NMR (100 MHz, CDCl3):
δ
100.1, 111.9, 120.1, 123.5,
To a solution of 2-amino-3-benzoylbenzo[b]furan 2g (94.9
mg, 0.40 mmol) in formamide (0.8 mL) was added Sc(OTf)3 (5.9
mg, 0.012 mmol), and the resulting mixture was stirred at 140 °C
for 3 h. The reaction mixture was washed with water and brine,
and then dried over MgSO4. The organic solvent was removed
under reduced pressure and the residue was subjected to flash
column chromatography on silica gel with hexane/AcOEt = 4/1
as eluents to afford 4-phenylbenzofuro[2,3-d]pyrimidine 5 as a
white solid (95.5 mg, 0.39 mmol, 97% yield) as a white solid.
mp 120.2-120.8 °C. IR (KBr): 750, 765, 816, 849, 930, 941,
1128, 1201, 1248, 1315, 1368, 1431, 1462, 1478, 1552, 1585,
124.3, 124.6, 128.9, 129.3, 129.4, 129.6, 130.7, 137.6, 138.6,
139.8, 150.8, 159.0, 162.1, 191.6. HRMS (FAB) calcd for M+H+
of C22H13Cl2NO3 410.0351, found 410.0344.
4.3.4. N-(3-Benzoyl-2-benzo[b]furyl)benzamide (4d): A yellow
solid; mp 162.4-163.0 °C. IR (KBr): 622, 698, 749, 860, 982,
1178, 1282, 1451, 1487, 1504, 1523, 1610, 1625, 1662, 2953,
3036, 3285 cm-1. 1H NMR (400 MHz, CDCl3):
δ 7.11 (t, J = 7.8
Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 7.26 (t, J = 8.8 Hz, 1H), 7.52-
7.65 (m, 7H), 7.81 (d, J = 6.8 Hz, 2H), 8.13 (d, J = 7.3 Hz, 2H),
3023, 3071 cm-1. 1H NMR (400 MHz, CDCl3):
δ 7.30 (t, J = 7.3
12.3 (s, 1H). 13C NMR (100 MHz, CDCl3):
δ 100.2, 111.8, 120.2,
Hz, 1H), 7.53 (t, J = 8.3 Hz, 1H), 7.60-7.68 (m, 4H), 7.91 (d, J =
7.8 Hz, 1H), 7.96-8.00 (m, 2H), 9.10 (s, 1H). 13C NMR (100
123.9, 124.0, 124.4, 128.0, 128.1, 128.5, 129.1, 132.2, 132.4,
133.2, 139.5, 150.8, 159.0, 163.3, 193.0. HRMS (FAB) calcd for
M+H+ of C22H15NO3 342.1130, found 342.1131.
MHz, CDCl3):
δ 112.2, 112.3, 120.2, 122.8, 124.0, 128.7, 128.8,
129.2, 130.7, 137.1, 153.7, 155.4, 161.6, 168.9. Anal. calcd for
C16H10N2O: C, 78.03; H, 4.09. Found: C, 78.05; H, 4.37.
4.3.5.
N-[3-(2’-Naphtoyl)-2-benzo[b]furyl]-2’-naphthalene-
carboxamide (4e): A yellow solid; mp 184.0-184.5 °C. IR
(KBr): 698, 749, 806, 932, 1060, 1125, 1198, 1224, 1286, 1318,
1435, 1457, 1473, 1558, 1607, 1704, 2258, 3027 cm-1. 1H NMR
Acknowledgments
This work was financially supported by Nissan Chemical
Industries, Ltd. and Grants-in-Aid for Scientific Research from
the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
(400 MHz, CDCl3):
δ 7.12-7.13 (m, 2H), 7.25-7.29 (m, 1H),
7.57-7.67 (m, 5H), 7.88-7.91 (dd, J = 1.5, 8.3 Hz, 1H), 7.93-7.97
(m, 3H), 8.00 (d, J = 8.8 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 8.07
(d, J = 7.8 Hz, 1H), 8.17 (dd, J = 1.5, 8.3 Hz, 1H), 8.38 (s, 1H),
8.67 (s, 1H), 12.5 (br s, 1H). 13C NMR (100 MHz, CDCl3):
δ
References and notes
100.4, 111.8, 120.3, 123.6, 123.9, 124.0, 124.4, 126.9, 127.0,
127.8, 127.9, 128.1, 128.5, 128.6, 129.0, 129.1, 129.2, 129.3,
129.4, 129.5, 129.6, 132.4, 132.5, 135.1, 135.4, 136.7, 150.8,
1. (a) Tietze, L. F. Ed. Domino Reactions; Wiley-VCH: Weinheim,
Germany, 2014. (b) Ashikari, Y.; Kiuchi, Y.; Takeuchi, T.; Ueoka,
K.; Suga, S.; Yoshida, J.-i. Chem. Lett. 2014, 43, 210. (c)
Pellissier, H. Chem. Rev. 2013, 113, 442. (d) Lu, L.-Q.; Chen, J.-
R.; Xiao, W.-J. Acc. Chem. Res. 2012, 45, 1278. (e) Yoshida, J.-
i.; Saito, K.; Nokami, T.; Nagaki, A. Synlett 2011, 1189.
159.0, 163.3, 192.8.
HRMS (FAB) calcd for M+H+ of
C30H19NO3 442.1443, found 442.1440.
2. For reviews on cascade reactions catalyzed by more than two
metal species, see: (a) Lee, J. M.; Na, Y.; Han, H.; Chang, S.
Chem. Soc. Rev. 2004, 33, 302. (b) Wasilke, J.-C.; Obrey, S. J.;
Baker, R. T.; Bazan, G. C. Chem. Rev. 2005, 105, 1001. (c)
Wang, C.; Xi, Z. Chem. Soc. Rev. 2007, 36, 1395. (d) Shindoh,
N.; Takemoto, Y.; Takasu, K. Chem. Eur. J. 2009, 15, 12168. (e)
Ambrosini, L. M.; Lambert, T. H. ChemCatChem 2010, 2, 1373.
3. For Pd- and Cu-catalysis, see: Murata, T.; Murai, M.; Ikeda, Y.;
Miki, K.; Ohe K. Org. Lett. 2012, 14, 2296.
4. For Au-catalyzed-isomerization of alkynylpyridine N-oxides and
cycloisomerization, see: Murai, M.; Kitabata, S.; Okamoto, K.;
Ohe, K. Chem. Commun. 2012, 48, 7622.
5. Murai, M.; Miki, K.; Ohe, K. Chem. Commun. 2009, 3466.
6. For selected catalytic reactions involving carbo-metalation to a
cyano moiety, see: (a) Yang, C.-C.; Tai, H.-M.; Sun, P.-J. J.
Chem. Soc. Perkin Trans. 1 1997, 2843. (b) Luo, F.-H.; Chu, C.-
I.; Cheng, C.-H. Organometallics 1998, 17, 1025. (c) Larock, R.
4.3.6. N-[3-(4’-Methoxybenzoyl)-2-benzo[b]furyl]-4’-methoxy-
benzamide (4f): A yellow solid; mp 202.9-203.7 °C. IR (KBr):
749, 780, 840, 933, 1032, 1063, 1174, 1192, 1246, 1286, 1328,
1430, 1463, 1558, 1576, 1615, 1698, 3040 cm-1. 1H NMR (400
MHz, CDCl3):
δ 3.90 (s, 3H), 3.93 (s, 3H), 7.03 (dd, J = 1.5, 8.8
Hz, 4H), 7.18 (d, J = 7.3 Hz, 1H), 7.24 (d, J =7.3 Hz, 1H), 7.26-
7.27 (m, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 6.8 Hz, 2H),
8.09 (d, J = 8.8 Hz, 2H), 12.2 (br s, 1H). 13C NMR (100 MHz,
CDCl3):
124.1, 124.2, 124.8, 130.1, 130.6, 132.0, 150.8, 159.0, 162.8,
163.0, 163.6, 191.7.
HRMS (FAB) calcd for M+H+ of
C24H19NO5 402.1341, found 402.1344.
δ 55.4, 55.5, 100.0, 111.8, 113.7, 114.3, 120.3, 123.7,

7
C.; Tian, Q.; Pletnev, A. A. J. Am. Chem. Soc. 1999, 121, 3238.
ACCEPTED MANUSCRIPT
(d) Zhao, L.; Lu, X. Angew. Chem. Int. Ed. 2002, 41, 4343. (e)
Pletnev, A. A.; Tian, Q.; Larock, R. C. J. Org. Chem. 2002, 67,
9428. (f) Tian, Q.; Pletnev, A. A.; Larock, R. C. J. Org. Chem.
2003, 68, 339. (g) Miura, T.; Nakazawa, H.; Murakami, M. Chem.
Commun. 2005, 2855. (h) Miura, T.; Murakami, M. Org. Lett.
2005, 7, 3339. (i) Zhao, B.; Lu, X. Org. Lett. 2006, 8, 5987. (j)
Miura, T.; Murakami, M. Org. Lett. 2007, 9, 741. (k) Ju, Y.; Liu,
F.; Li, C. Org. Lett. 2009, 11, 3582. (l) Tsui, G. C.; Glenadel, Q.;
Lau, C.; Lautens, M. Org. Lett. 2011, 13, 208. (m) Xia, G.; Han,
X.; Lu, X. Adv. Synth. Catal. 2012, 354, 2701. (n) Xia, G.; Han,
X.; Lu, X. Org. Lett. 2014, 16, 2058.
7. For palladium-catalyzed alkoxycarbonylation reactions of aryl
halides with phenol derivatives, see: (a) Colquhoun, H. M.;
Thompson, D. J.; Twigg, M. V. Carbonylation: Direct Synthesis
of Carbonyl Compounds; Plenum Press: New York and London,
1991. (b) Nikitin, K. V.; Andryukhova, N. P.; Bumagin, N. A.;
Beletskaya, I. P. Mendeleev Commun. 1991, 1, 129. (c) Satoh, T.;
Kokubo, K.; Miura, M.; Nomura, M. Organometallics 1994, 13,
4431. (d) Wu, X.-F.; Neumann, H.; Beller, M. ChemCatChem
2010, 2, 509.
8. Conditions for phenoxycarbonylation of p-TolBr have been
optimized. For details, see: Supplementary material.
9. When Pd(OAc)2 10 mol%) as a precatalyst with PCy3 and PPh3
(Pd:PCy3:PPh3 = 1:1:1) was used instead of Pd(PCy3)2 and
Pd(PPh3)4, the yield of 2a deteriorated to 19% with 1a (69%) as a
major component.
10. In entry 7, almost all compounds 3a and 4-MeOC6H4Br were
recovered intact.
11. The present reaction is applicable to a scale-up experiment (up to
2 mmol) without defect on the chemical yield.
12. The formation of heteroleptic phosphine–palladium(0 or II)
complexes as active catalysts cannot be ruled out although it was
demonstrated that each palladium(0) species acts independently as
reactive catalysts for the discrete reactions. For ligand exchange
of phosphine-ligated Pd(II) species generating heteroleptic
phosphine-palladium complexes, see: (a) Tkach, V. S.; Suslov, D.
S.; Myagmarsuren, G.; Ratovskii, G. V.; Rohin, A. V.; Felix, T.;
Shmidt, F. K. J. Organomet. Chem. 2008, 693, 2069. (b) Mitchell,
E. A.; Baird, M. C. Organometallics 2007, 26, 5230. (c) Kong,
K.-C.; Cheng, C.-H. J. Am. Chem. Soc. 1991, 113, 6313. (d)
Wada, M.; Nishiwaki, K. J. Chem. Soc., Dalton Trans. 1983, 1841.
(e) Verstuyft, A. W.; Redfield, D. A.; Cary, L. W.; Nelson, J. H.
Inorg. Chem. 1976, 15, 1128.
13. Differences in pKb values of Et3N (10.7 in DMSO) and K2CO3
(11.6 in DMSO) in DMF might alter the reaction pathway to
mono- or double-acylation.
14. Benzofuran-fused nitrogen-containing heterocycles are common
structural motifs in biologically active natural products and drug
candidates. See: (a) Zili, X.; Norman, C. W.; Cassandra, L. W.;
Zhiyu, L.; Pui-Kai L. Bioorg. Med. Chem. Lett. 2001, 11, 2875.
(b) Voigt, B.; Meijer, L.; Lozach, O.; Schächtele, C.; Totzke, F.;
Hilgeroth, A. Bioorg. Med. Chem. Lett. 2005, 15, 823. (c) Zhang,
Y.; Lee, Y. S.; Rothman, R. B.; Dersch, C. M.; Deschamps, J. R.;
Jacobson, A. E.; Rice, K. C. J. Med. Chem. 2009, 14, 2462. (d)
Tripathy, R.; McHugh, R. J.; Bacon, E. R.; Salvino, J. M.; Morton,
G. C.; Aimone, L. D.; Huang, Z.; Mathiasen, J. R.; DiCamillo, A.;
Huffman, M. J.; McKenna, B. A.; Kopec, K.; Lu, L. D.; Qian, J.;
Angeles, T. S.; Connors, T.; Spais, C.; Holskin, B.; Duzic, E.;
Schaffhauser, H.; Rossé, G. C. Bioorg. Med. Chem. Lett. 2012, 22,
1421.
Supplementary Material
Supplementary data associated with this article can be found
in online version at doi:10.1016/j.tet.2015.xx.xxx.

ACCEPTED MANUSCRIPT
Supplementary Material
Palladium-catalyzed Three-component Coupling Reactions of
2-(Cyanomethyl)phenol, Aryl Halides, and Carbon Monoxide
Masahito Murai, Kazuhiro Okamoto, Koji Miki, and Kouichi Ohe*
Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering,
Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
e-mail: ohe@scl.kyoto-u.ac.jp
Table of Contents
1. General Methods
S2
S2
S4
S6
2. Preparation of 2-(Cyanomethyl)phenols 3
3. Phenoxycarbonylation of p-TolBr using 2-(Cyanomethyl)phenols 3a
4. 1H NMR and 13C-NMR Spectra of New Compounds
S1

ACCEPTED MANUSCRIPT
1. General Method. All reactions were carried out in dry solvent under an argon
atmosphere. Unless otherwise noted, other chemicals obtained from commercial suppliers
were used without further purification. CO gas (purity 99.97%) was purchased from
Sumitomo Seika Co. Solvents were dried by the usual methods and distilled before use.
Unless otherwise noted, reactions were carried out under nitrogen atmosphere. Proton
chemical shifts are reported in ppm based on the solvent resonance resulting from incomplete
deuteration (CDCl3 at 7.26 ppm and acetone-d6 at 2.05 ppm) as the internal standard. 13C
NMR was recorded with complete proton decoupling and the chemical shifts are reported
relative to CDCl3 at 77.00 ppm and acetone-d6 at 29.8 ppm. The following abbreviations are
used; br s: broad singlet, s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet. IR spectra
were recorded with an FT-IR spectrometer. Melting points (mp) were measured on a Yanaco
micromelting point apparatus and are uncorrected. Element analyses were performed at
Microanalytical Center of Kyoto University. High-resolution mass spectra (HRMS) was
measured with JEOL JMX-SX 102A spectrometer.
The analytical data for 3m,
3-acyl-2-aminobenzofurans 2a-2h, and 2k were reported previously by this group (Murai, M.;
Miki, K.; Ohe, K. Chem. Commun. 2009, 3466).
2. Preparation of 2-(Cyanomethyl)phenols 3
2-(Cyanomethyl)phenol (3a): To a solution of LiAlH4 (2.1 g, 55 mmol) in
THF (100 mL) was added salicylic acid (6.9 g, 50 mmol) at 0 °C, and stirred
at 60 °C overnight. The reaction mixture was cooled to 0 °C, and then
degassed water (2.0 mL), 15 wt% NaOH aqueous solution (2.0 mL), and water (6.0 mL) were
successively added. After stirring at room temperature for 1 h, the mixture was filtered and
washed with Et2O (50 mL×3). The combined organic layer was washed with brine and
dried over MgSO4. The organic solvent was removed under reduced pressure to afford
2-hydroxymethyl phenol (4.5 g, 33.5 mmol, 67% yield) as a colorless oil. 1H NMR (400
MHz, CDCl3):  (br s, 1H), 4.86 (s, 2H), 6.84 (t, J = 7.3 Hz, 1H), 6.88 (d, J = 6.8 Hz,
1H), 7.04 (d, J = 6.8 Hz, 1H), 7.21 (t, J = 7.3 Hz, 1H). A solution of 2-hydroxymethyl
phenol (3.9 g, 30 mmol) in DMF(30 mL) was added to sodium cyanide (2.9 g, 60 mmol), and
the resulting mixture was stirred at 100 °C for 12 h. After the resulting solution was cooled
to room temperature, it was poured into 10% HCl aqueous solution (30 mL), and extracted
with Et2O (30 mL×3). The combined organic layer was dried over MgSO4, and the organic
solvent was removed under reduced pressure. The residue was filtered through a short silica
S2

ACCEPTED MANUSCRIPT
gel pad followed by recrystallization from hexane / CHCl3 to furnish 2-(cyanomethyl)phenol
3a (3.2 g, 24 mmol, 80% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): 3.72
(s, 2H), 5.05 (br s, 1H), 6.80 (d, J = 7.9 Hz, 1H), 6.95 (t, J = 7.9 Hz, 1H), 7.20 (t, J = 7.9 Hz,
1H), 7.33 (d, J = 7.9 Hz, 1H).
2-Cyanomethyl-6-methylphenol (3i): A yellow solid; mp 103.5-104.3 °C.
IR (KBr / cm-1): 762, 883, 958, 1097, 1160, 1193, 1216, 1333, 1411, 1472,
1595, 2255 (CN), 2926, 3422 (OH). 1H NMR (400 MHz, acetone-d6): 2.15
(s, 3H), 3.67 (s, 2H), 6.69 (t, J = 7.3 Hz, 1H), 6.98 (d, J = 7.3 Hz, 1H), 7.05 (d, J = 7.3 Hz,
1H). 13C NMR (100 MHz, acetone-d6): 16.4, 18.8, 118.9, 119.0, 120.9, 125.3, 127.8,
131.4, 153.4. HRMS (FAB) calcd for M+H+ of C9H9NO 148.0762, found 148.0758.
2-Cyanomethyl-5-methylphenol (3j):
A
yellow solid; mp
107.2-108.3 °C. IR (KBr / cm-1): 734, 813, 858, 957, 1114, 1157, 1195,
1233, 1287, 1353, 1425, 1523, 1593, 1618, 2262 (CN), 2907, 2957, 3332
(OH). 1H NMR (400 MHz, CDCl3): 2.28 (s, 3H), 3.68 (s, 2H), 5.40 (br s, 1H), 6.60 (s,
1H), 6.75 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): 18.1,
21.1, 113.8, 116.1, 118.2, 121.9, 129.4, 139.8, 153.0. HRMS (FAB) calcd for M+H+ of
C9H9NO 148.0762, found 148.0760.
5-Chloro-2-(cyanomethyl)phenol (3l): An orange solid;
mp
108.7-109.5 °C. IR (KBr / cm-1): 724, 822, 870, 910, 1086, 1119, 1228,
1284, 1351, 1426, 1505, 1607, 2268 (CN), 2914, 2974, 3328 (OH). 1H
NMR (400 MHz, acetone-d6):  3.76 (s, 2H), 6.90 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 8.8 Hz,
1H), 7.31 (s, 1H). 13C NMR (100 MHz, acetone-d6): 18.4, 117.4, 118.4, 120.8, 124.7,
129.7, 129.9, 154.6. HRMS (FAB) calcd for M+H+ of C8H6ClNO 168.0216, found
168.0210.
4-(tert-Butyldimethylsilyloxy)-2-(cyanomethyl)phenol (3n): A
yellow solid; mp 69.7-70.4 °C. IR (KBr / cm-1): 780, 813, 912,
985, 1093, 1151, 1206, 1270, 1362, 1438, 1511, 1614, 2277 (CN),
2856, 2892, 2927, 2957, 3325 (OH). 1H NMR (400 MHz, CDCl3): 0.17 (s, 6H), 0.97 (s,
9H), 3.67 (s, 2H), 5.73 (br s, 1H), 6.65-6.66 (m, 2H), 6.82 (s, 1H). 13C NMR (100 MHz,
S3

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CDCl3): -4.5, 18.1, 18.5, 25.6, 116.1, 117.5, 118.0, 120.4 (overlapped), 147.6, 149.3.
HRMS (FAB) calcd for M+H+ of C14H21NO2Si 264.1420, found 264.1428.
2-Cyanomethyl-4-(methoxymethoxy)phenol (3o): A yellow oil;
IR (neat / cm-1): 733, 810, 872, 1112, 1188, 1262, 1351, 1452, 1612,
2259 (CN), 2824, 2957, 3328 (OH). 1H NMR (400 MHz,
CDCl3): 3.48 (s, 3H), 3.66 (s, 2H), 5.10 (br s, 1H), 6.69 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8
Hz, 1H), 7.00 (s, 1H). 13C NMR (100 MHz, CDCl3): 18.5, 55.8, 95.2, 116.0, 117.5, 117.6,
117.9, 118.0, 148.7, 150.7. HRMS (FAB) calcd for M+H+ of C10H11NO3 194.0817, found
194.0812.
3. Phenoxycarbonylation of p-TolBr using 2-(Cyanomethyl)phenols 3
The reaction conditions for alkoxycarbonylation by using 4-bromotoluene with 3a and CO
were optimized; the results are summarized in Table S1.
When carbonylation of 4-bromotoluene with 3a and CO was carried out by using 5 mol%
Pd(OAc)2 and 10 mol% PPh3 as catalyst, 1a was obtained in 91% yield (Table S1, entry 1).
Although replacing PPh3 by more sterically hindered P(o-Tol)3 or basic PtBu3 was detrimental
to the carbonylation reaction, the use of bidentate ligands such as dppf and DPEphos gave 1a
in 82 and 92% yields, respectively (entries 2–5). Among the catalysts screened, Pd(PPh3)4
showed the best catalytic activity for the alkoxycarbonylation; the use of this catalyst afforded
1a in 94% yield (entry 6). The reaction was then examined with a range of bases and
Pd(PPh3)4 as catalyst. Whereas iPr2EtN was comparably effective, affording 1a in 94%
yield, pyridine, K2CO3, and NaOEt were less effective, affording 1a in moderate yields
(entries 7–10). Interestingly, when inorganic bases such as K2CO3 or NaOEt were used, a
small amount of 3-acyl-2-(N-acylamino)benzofuran 4a was obtained together with 1a (entries
9 and 10). However, the formation of 3-benzoyl-2-aminobenzofuran 2a was not observed
under any of the conditions listed in Table S1. These results show that the combination of
Pd(PPh3)4 as a catalyst and Et3N as a base is most effective for the alkoxycarbonylation, with
2a remaining untouched under these conditions. The alkoxycarbonylation proceeded even
when the loading of Pd(PPh3)4 was decreased to 2 mol% (entry 11).
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Table S1. Pd-catalyzed alkoxycarbonylation of 4-bromotoluene with 3a and COa
Entry
1
Catalyst
Base
Et3N
Conversionb
100%
Yield of 1ac
Yield of 4ac
Pd(OAc)2/PPh3 (1:2)
91%
0%
2
Pd(OAc)2/P(o-Tol)3 (1:2)
Pd(OAc)2/PtBu3 (1:2)
Pd(OAc)2/dppf (1:1)
Pd(OAc)2/DPEphos (1:1)
Pd(PPh3)4
Et3N
68%
6%
34%
0%
0%
0%
0%
0%
0%
0%
0%
9%
4%
0%
3
Et3N
4
Et3N
100%
100%
100%
100%
89%
82%
92%
94%
94%
63%
68%
79%
94%
5
Et3N
6
Et3N
7
Pd(PPh3)4
iPr2EtN
pyridine
K2CO3
NaOEt
Et3N
8
Pd(PPh3)4
9
Pd(PPh3)4
83%
10
11d
Pd(PPh3)4
100%
100%
Pd(PPh3)4
aReaction conditions: 3a (0.20 mmol), p-TolBr (0.30 mmol), base (0.30 mmol), catalyst (0.01 mmol) in DMF (0.8 mL) under CO (1 atm).
bDetermined by 1H NMR.
cIsolated yields.
dPd(PPh3)4 (0.004 mmol).
dppf = diphenylphosphinoferrocene. DPEphos = 2,2’-bis(diphenylphosphino)diphenyl ether.
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13
4. H NMR and C NMR Spectra of New Compounds
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