Synthesis of 2,3-disubstituted benzofurans and indoles by π-Lewis acidic transition metal-catalyzed cyclization of ortho-alkynylphenyl O,O- and N,O-acetals

Article abstract of DOI:10.1016/j.tet.2007.03.039

The PtCl₂-catalyzed cyclization reaction of ortho-alkynylphenyl acetals 1 in the presence of COD (1,5-cyclooctadiene) produces 3-(α-alkoxyalkyl)benzofurans 2 in good to high yields. For example, the reaction of acetaldehyde ethyl 2-(1-octynyl)phenyl acetal (1a), acetaldehyde ethyl 2-(cyclohexylethynyl)phenyl acetal (1c), and acetaldehyde ethyl 2-(phenylethynyl)phenyl acetal (1f) in the presence of 2 mol % of platinum(II) chloride and 8 mol % of 1,5-cycloocatadiene in toluene at 30 °C gave the corresponding 2,3-disubstituted benzofurans 2a, 2c, and 2f in 91, 94, and 88% yields, respectively. Moreover, the reaction of N-methoxymethyl-2-alkynylanilines 3 was catalyzed by PdBr₂, affording the corresponding 2,3-disubstituted indoles 4 in moderate yields. For example, the reaction of N-methoxymethyl-2-(1-pentynyl)-N-tosylaniline (3a) and N-methoxymethyl-2-(phenylethynyl)-N-tosylaniline (3b) in the presence of 10 mol % of PdBr₂ in toluene at 80 °C gave 3-methoxymethyl-2-propyl-1-tosylindole (4a) and 3-methoxymethyl-2-phenyl-1-tosylindole (4b) in 33 and 33% yields, respectively.

Full text of DOI:10.1016/j.tet.2007.03.039

Tetrahedron 63 (2007) 8670–8676
Synthesis of 2,3-disubstituted benzofurans and indoles by
p-Lewis acidic transition metal-catalyzed cyclization
of ortho-alkynylphenyl O,O- and N,O-acetals
*
Itaru Nakamura, Yuya Mizushima, Uichiro Yamagishi and Yoshinori Yamamoto
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Received 25 January 2007; revised 1 March 2007; accepted 2 March 2007
Available online 12 March 2007
Dedicated to Professor Hisashi Yamamoto in honor of his receipt of the Tetrahedron Prize
Abstract—The PtCl2-catalyzed cyclization reaction of ortho-alkynylphenyl acetals 1 in the presence of COD (1,5-cyclooctadiene) produces
3-(a-alkoxyalkyl)benzofurans 2 in good to high yields. For example, the reaction of acetaldehyde ethyl 2-(1-octynyl)phenyl acetal (1a), acet-
aldehyde ethyl 2-(cyclohexylethynyl)phenyl acetal (1c), and acetaldehyde ethyl 2-(phenylethynyl)phenyl acetal (1f) in the presence of
2 mol % of platinum(II) chloride and 8 mol % of 1,5-cycloocatadiene in toluene at 30 ꢀC gave the corresponding 2,3-disubstituted benzo-
furans 2a, 2c, and 2f in 91, 94, and 88% yields, respectively. Moreover, the reaction of N-methoxymethyl-2-alkynylanilines 3 was catalyzed
by PdBr2, affording the corresponding 2,3-disubstituted indoles 4 in moderate yields. For example, the reaction of N-methoxymethyl-2-(1-
pentynyl)-N-tosylaniline (3a) and N-methoxymethyl-2-(phenylethynyl)-N-tosylaniline (3b) in the presence of 10 mol % of PdBr2 in toluene
at 80 ꢀC gave 3-methoxymethyl-2-propyl-1-tosylindole (4a) and 3-methoxymethyl-2-phenyl-1-tosylindole (4b) in 33 and 33% yields, respec-
tively.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
group. More recently, we disclosed that the PtCl2-catalyzed
cyclization reaction of ortho-alkynylphenyl acetals 1 in the
presence of COD (1,5-cyclooctadiene) produces 3-(a-alk-
oxyalkyl)benzofurans 2 in good to high yields (Eq. 4).8 This
reaction proceeds through formal addition of a carbon–oxygen
bond to triple bond, so-called carboalkoxylation.9 Now, we
report the detailed study of the platinum-catalyzed carbo-
alkoxylation of the O,O-acetals 1, together with the palladium-
catalyzed cyclization of the N,O-acetal analogues 3, which
produces 2,3-disubstituted indoles 4 (Eq. 5).
Transition metal-catalyzed annulation of ortho-alkynylaryl
amines and alcohols has been widely investigated as a syn-
thetic method of the corresponding mono-substituted hetero-
cycles (Eq. 1).1 Furthermore, it is becoming popular that the
2,3-disubstituted indoles and benzofurans shown in Eq. 2
can be synthesized from ortho-alkynylanilines and phenols,
through the external addition of organopalladium species to
the triple bond (Eq. 2).2 Recently, the intramolecular annula-
tion accompanied with the migration of the functional group
(E) on the heteroatom (Y) has been noted as a synthetic
method for disubstituted heterocycles (Eq. 3).3–6 This type
of formal sequential addition of the two functional groups
to the triple bond is important from synthetic point of
view, since the structural framework of a,b-disubstituted in-
doles and benzofurans is often found in biologically active
compounds.7 Allyl,3 propargyl,4 acyl,5 and methoxyphenyl-
methyl (MPM) groups6 have been utilized as a migrating
R1
H
H
R1
cat. Pd, Au, Cu, Mo
Y
n
Y
ð1Þ
ð2Þ
n
Y = NR2, O
n = 0-2
R1
R3
R3-X, cat. Pd(0)
Base
Keywords: Platinum catalysts; Benzofuran; Acetal; Cyclization; Indole.
* Corresponding author. Tel.: +81 22 795 6754; fax: +81 22 795 6784;
e-mail addresses: itaru-n@mail.tains.tohoku.ac.jp; yoshi@mail.tains.
tohoku.ac.jp
R1
H
Y
Y
Y = NR2, O
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.039

I. Nakamura et al. / Tetrahedron 63 (2007) 8670–8676
8671
R1
E
Table 2. Platinum-catalyzed carboalkoxylation of ortho-alkynylphenyl
O,O-acetals 1a
E
R1
cat. Pd, Pt
Entry
1
R1
R2
R3 Time (h)
2
Yieldb (%)
Y
Y
ð3Þ
n
n
1
2
3
4
5
6
7
1a n-Hex
Et
Et
Et
Et
Me
Me
Me 2.5
Me 24
Me 24
1
1
2a 91
2b 92
2c 94
2d Trace
2e 90
2f 88
2g 61
2h 92
2i 73
2j 94
2k 83
2l 61
Y = NR2, O
n = 0,1
E = allyl, propargyl, acyl, MPM
1b (CH2)4Cl
1c Cyclohexyl
1d t-Bu
1e p-(MeO)C6H4 Et
1f Ph
1g p-(CF3)C6H4
1h n-Pr
1i Ph
1j n-Pr
1k Ph
1l Ph
Et
Et
Me
Me 4 days
3
R3
8c
9c
10d
11d
12e
Me
Me
Bn
Bn
TBS
H
H
H
H
H
22
24
20
48
R1
OR2
R1
cat. PtCl2 / COD
toluene, 30 °C
R3
ð4Þ
ð5Þ
O
OR2
O
2
4 days
1
a
The reaction of 1 was carried out in the presence of 2 mol % of PtCl2 and
8 mol % of COD in toluene at 30 ꢀC.
Isolated yield.
20 mol % of PtCl2 and 80 mol % of COD were used.
10 mol % of PtCl2 and 40 mol % of COD were used.
100 mol % of PtCl2 and 80 mol % of COD were used.
b
c
d
e
R
OMe
R
cat. PdBr2
N
Ts
N
Ts
3
OMe
4
of 1. The results are summarized in Table 2. The reaction
of substrates bearing 4-chlorobutyl (1b) and cyclohexyl
group (1c) at the alkynyl terminus proceeded very smoothly,
while the reaction of 1d having a tert-butyl group was slug-
gish (entries 2–4). The reaction of 1e, which had an electron-
rich aromatic group at R1 position, gave the desired product
in a high yield, while the reaction of 1g, which had an electron-
deficient aromatic group, proceeded slowly, producing
2g in a moderate yield (entries 5–7). The reaction of sub-
strates without any substituents at R3 required higher cata-
lyst loading. For example, the reaction of the MOM ethers
(1h and 1i) and the BOM ethers (1j and 1k) proceeded
smoothly using slightly higher amounts of platinum cata-
lysts (entries 8–11); the reaction of 1h using 2 mol % of
PtCl2 and 8 mol % of COD proceeded very slowly and it
took 5 days, giving 2h in 50% yield along with 50% yield
of recovered 1h. The reaction of TBS ether 1l was promoted
by the use of a stoichiometric amount of the platinum
catalyst (entry 12).
2. Results and discussion
The reaction of acetaldehyde ortho-(1-octynyl)phenyl ethyl
acetal 1a in the presence of 2 mol % of PtCl2 and 8 mol % of
COD in toluene proceeded at 30 ꢀC, and 1 h later 3-(1-eth-
oxyethyl)-2-hexylbenzofuran 2a was produced in 91% yield
(Table 1, entry 1). The use of COD as an additive is very im-
portant for facilitating this migration as shown in Table 1.
The reaction in the absence of COD gave 2a in 24% yield
(entry 2). The reaction using 1-hexene or cyclooctene, in-
stead of COD, gave 2a in a similar yield (entries 3 and 4),
while the use of b-pinene, norbornadiene, or styrene resulted
in lower yields (entries 5–7). Interestingly, PtCl2(cod) did not
promote the reaction at all (entry 8). Other transition metal
complexes, such as PtBr2, PtI2, K2PtCl4, PdCl2, NiCl2,
Yb(OTf)3, [RhCl(cod)]2, and Pd(PPh3)4, did not promote
the reaction at all. The reaction of 1a under the same reaction
conditions using acetonitrile as solvent produced 2a in 60%
yield along with a small amount of unknown byproducts.
We found that the reaction of the substrate 1m having a THP
group did not proceed under the standard reaction condi-
tions; the substrate 1m was quantitatively recovered (Eq. 6).
This result indicates that the bulky THP group interfered
the cyclization step even though the substrate had a substitu-
ent at R3; it is unlikely that cleavage of the acetal carbon–
oxygen bond occurs prior to cyclization. To find out if the
reaction proceeds in an intramolecular or intermolecular
fashion, we carried out a crossover experiment (Eq. 7). The
reaction of a 1:1 mixture of 1h and 1k in the presence of
20 mol % of PtCl2 and 80 mol % of COD afforded the prod-
ucts 2h and 2k deriving from 1h and 1k, respectively; the
crossover products, such as 2i and 2j, were not detected by
GC–MS and NMR. This result clearly indicates that the
present reaction proceeds in an intramolecular manner.
We applied the optimal conditions (2 mol % of PtCl2 and
8 mol % of COD in toluene at 30 ꢀC) to various substrates
Table 1. Carboalkoxylation of 1a catalyzed by platinum–olefin systema
Entry
Pt
Olefin (mol %)
Yield of
Recovery
2ab (%)
of 1ab (%)
1
2
3
4
5
6
7
8
PtCl2
PtCl2
PtCl2
PtCl2
PtCl2
PtCl2
PtCl2
PtCl2(cod)
COD (8)
None
93 (91)c
—
68
Trace
16
48
50
60
Quant.
24
90
84
51
50
40
0
1-Hexene (16)
Cyclooctene (16)
b-Pinene (16)
Norbornadiene (8)
Styrene (16)
None
a
n-Pr
The reaction of 1a (0.3 mmol) was carried out in the presence of 2 mol %
of PtCl2 and olefin in toluene at 30 ꢀC for 1 h.
The yield was determined by H NMR using 1,4-dioxane as an internal
standard.
Isolated yield in parenthesis.
no reaction
cat. PtCl2 / COD
1
b
c
ð6Þ
(1m was recovered
quantitatively)
O
1m
O

8672
I. Nakamura et al. / Tetrahedron 63 (2007) 8670–8676
OTBS
Ph
n-Pr
Ph
OH
Ph
TBAF
88%
+
ð9Þ
O
O
1h
OMe
O
1k
OBn
O
9
2l
OMe
OBn
Ph
20 mol% PtCl2
80 mol% COD
We applied the present reaction for the synthesis of vibsanol
10, which was isolated from Viburnum awabuki (Scheme 2).
It is well known that 10 works as an inhibitor for lipid per-
oxidation.11,12 The precursor of carboalkoxylation, ortho-
alkynylaryl benzyl acetal 12, was synthesized from the
ortho-iodophenol 11, prepared from iodovaniline according
to the reported procedures.12 The carboalkoxylation of 12
proceeded smoothly, giving the desired vibsanol precursor
13 in 76% yield.13
+
n-Pr
toluene, 30 °C
O
2h
O
ð7Þ
2k
(83%)
(92%)
not detected
OMe
Ph
OBn
n-Pr
O
O
2j
2i
OH
OMe
OH
Based on these results, we propose the reaction mechanism
for the platinum-catalyzed reaction of 1 as illustrated in
Scheme 1. Platinum chloride coordinates to the triple bond
of the substrate 1. Nucleophilic attack of the oxygen atom
of the phenyl acetal moiety of 5 would give the cyclized in-
termediate 6. Migration of a-alkoxyalkyl group of 6 to the
carbon atom bonded to platinum atom would produce the
intermediate 7. Elimination of platinum chloride from 7 gives
the product 2. COD probably works as an activating agent to
disconnect Pt–Cl bonds of polymeric platinum chloride and
to generate a reactive platinum catalyst.10 However, since
PtCl2(cod) itself did not promote the present reaction at
all, a real active species might be a platinum oligomer (Table
1, entry 8).
HO
O
OH
10 vibsanol
I
OHC
I
Ref. 12
EEO
OH
OH
OEE
OMe
11
OEE
OMe
a,b
EEO
O
OBn
R1
OEE
12
R3
OR2
PtCl2
OBn
O
R1
c
EEO
R3
OR2
O
OEE
1
2
O
OMe
OEE
13
R3
R1
Cl2Pt
Cl2Pt
OR2
R1
Scheme 2. Synthesis of vibsanol precursor 13 via carboalkoxylation. (a)
BOMCl, NaH, 0 ꢀC, quantitative; (b) [4-(1-ethoxyethyl)-3-methoxyphen-
yl]acetylene, Pd(PPh3)4, CuI, Et3N, THF, room temperature, 64%; (c)
20 mol % PtCl2, 80 mol % COD, toluene, 30 ꢀC, 76%.
O
O
7
R3
OR2
PtCl2
R1
5
O
It is interesting to know whether or not the present
methodology for the O,O-acetals can be extended to the
N,O-acetal analogues, since 2,3-disubstituted indoles can
be synthesized through the carboamination of alkynes. The
reaction of N-methoxymethyl-2-(1-pentynyl)-N-tosylaniline
3a in the presence of 10 mol % of PdBr2 in toluene at 80 ꢀC
gave 3-methoxymethyl-1-methyl-2-propylindole 4a in 33%
yield (Eq. 10). The use of Pd(NO3)2, instead of PdBr2,
afforded 4a in 26% yield and other catalyst systems, such
as PtCl2–COD, PtCl2, and PdCl2 did not show the cata-
lytic activity. The reaction of 3b bearing a phenyl group
at the alkynyl moiety gave the desired product 4b in 33%
yield. The structure of 4a was unambiguously determined
by X-ray crystallographic analysis as shown in Figure 1.14
In contrast, the reaction of N-acetyl-N-methoxymethyl-
2-(1-pentynyl)aniline 3c proceeded through migration of
the acetyl group, affording the 3-acetylindole 14 in
OR2
R3
6
Scheme 1. Mechanism of the carboalkoxylation of 1.
The benzyl ether 2k was converted to 3-(2-phenylbenzo-
furan)carbaldehyde 8 by treatment with 4 equiv of DDQ.
The reaction of the TBS ether 2l with TBAF afforded the
3-(2-phenylbenzofuran)carbinol 9 in 88% yield (Eq. 9).
O
OBn
Ph
H
Ph
4 equiv DDQ
96%
ð8Þ
O
O
2k
8

I. Nakamura et al. / Tetrahedron 63 (2007) 8670–8676
8673
4. Experimental
4.1. General
Spectroscopic measurements were carried out by the use
of following instruments: JEOL JNM AL 400 (1H and 13C
NMR), JASCO FTIR-460 plus (FTIR), HITACHI M-2500s
(HRMS). PtCl2 was purchased from WAKO Co. Ltd. The
starting materials 1 were prepared from 2-iodophenol
through acetalization and Sonogashira coupling. Chromato-
graphy was performed using Kanto Chemical silica gel 60N
(spherical, neutral, 100–210 mm) or Fuji Silysia silica gel
BW-300 (200–400 mesh).
4.2. General procedure for platinum-catalyzed cycliza-
tion of 2-alkynylphenyl acetals
To PtCl2 (1.6 mg, 0.006 mmol) and 1,5-cyclooctadiene
(2.9 mL, 0.024 mmol) in toluene (0.5 ml) was added the ace-
tal 1 (0.3 mmol) in toluene (0.7 ml) under Ar atmosphere in
a pressure vial. After heating at 30 ꢀC for 1–24 h, the reac-
tion mixture was filtered through a short silica gel column
using ethyl acetate as an eluant. Separation by silica gel
column chromatography using hexane/EtOAc (30:1) as an
eluant afforded the products 2.
4.2.1. 3-(1-Ethoxyethyl)-2-hexylbenzofuran (2a). IR
1
(neat) 3055, 2975–2860, 1622, 1370, 1101, 746 cmꢁ1. H
Figure 1. ORTEP drawing of 4a.
NMR (400 MHz, CDCl3) d 0.88 (t, J¼7.0 Hz, 3H), 1.16 (t,
J¼7.2 Hz, 3H), 1.26–1.40 (m, 6H), 1.58 (d, J¼6.8 Hz,
3H), 1.72 (quint, J¼7.3 Hz, 2H), 2.74 (td, J¼7.3, 3.1 Hz,
2H), 3.30–3.41 (m, 2H), 4.66 (q, J¼6.8 Hz, 1H), 7.15–
7.22 (m, 2H), 7.39 (dd, J¼7.4, 1.4 Hz, 1H), 7.71 (d,
J¼7.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) d 14.08,
15.43, 22.42, 22.60, 26.60, 28.45, 29.02, 31.60, 63.58,
70.17, 110.59, 116.03, 120.38, 122.06, 123.09, 127.47,
154.01, 155.01. Anal. Calcd for C18H26O2 (274.40): C,
78.79; H, 9.55. Found: C, 79.05; H, 9.73. HRMS (ESI)
calcd for C18H26O2 (M+Na)+: m/z 297.1825. Found: m/z
297.1825.
52% yield (Eq. 11).5 It is noteworthy that acetyl group is
transferred more easily in comparison with methoxymethyl
group.
R
OMe
R
10 mol% PdBr2
toluene, 80 °C
N
Ts
N
Ts
3
OMe
ð10Þ
ð11Þ
4
4.2.2. 2-(4-Chlorobutyl)-3-(1-ethoxyethyl)benzofuran
(2b). IR (neat) 3055, 2975–2867, 1622, 1455, 1370, 1089,
3a (R = n-Pr)
3b (R = Ph)
4a (R = n-Pr)
4b (R = Ph)
33%
33%
1
1012, 940, 849, 748 cmꢁ1. H NMR (400 MHz, CDCl3)
d 1.17 (t, J¼7.0 Hz, 3H), 1.58 (d, J¼6.8 Hz, 3H), 1.81–
1.93 (m, 4H), 2.75–2.85 (m, 2H), 3.33–3.40 (m, 2H), 3.56
(t, J¼6.2 Hz, 2H), 4.66 (q, J¼6.8 Hz, 1H), 7.17–7.25 (m,
2H), 7.39 (dd, J¼7.0, 1.0 Hz, 1H), 7.71 (dd, J¼7.0,
1.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) d 15.4, 22.4,
25.7, 25.8, 32.0, 44.5, 63.6, 70.1, 110.6, 116.5, 120.3,
122.1, 123.3, 127.3, 153.8, 153.9. Anal. Calcd for
C16H21ClO2 (280.79): C, 68.44; H, 7.54; Cl, 12.63. Found:
C, 68.47; H, 7.67; Cl, 12.52. HRMS (ESI) calcd for
C16H21ClO2 (M+Na)+: m/z 303.1122. Found: m/z 303.1123.
n-Pr
Ac
10 mol% PdBr2
toluene, 80 °C
n-Pr
N
N
Ac
OMe
MeO
14 (52%)
3c
3. Conclusions
4.2.3. 2-Cyclohexyl-3-(1-ethoxyethyl)benzofuran (2c). IR
(neat) 3087–2857, 1963, 1786, 1621, 1446, 943, 845,
We are in a position to synthesize 3-(a-alkoxyalkyl)-2-
substituted benzofurans and indoles in an efficient and
atom economic manner. The present result suggests that
a cation stabilizing group E may undergo the transition
metal-catalyzed intramolecular 1,3-transfer from the hetero-
atom to C-3 position of the heterocycles containing E
(Eq. 3).
756 cmꢁ1
.
1H NMR (400 MHz, CDCl3) d 1.16 (t,
J¼7.2 Hz, 3H), 1.29–1.44 (m, 3H), 1.58 (d, J¼6.4 Hz,
3H), 1.77–1.89 (m, 7H), 2.80–2.88 (m, 1H), 3.30–3.39 (m,
2H), 4.71 (q, J¼6.4 Hz, 1H), 7.14–7.23 (m, 2H), 7.39 (dd,
J¼7.2, 1.2 Hz, 1H), 7.71 (d, J¼6.9 Hz, 1H). 13C NMR
(100 MHz, CDCl3) d 15.4, 22.6, 25.8, 26.37, 26.38, 31.4,

8674
I. Nakamura et al. / Tetrahedron 63 (2007) 8670–8676
31.7, 36.5, 63.5, 69.9, 110.6, 114.4, 120.4, 121.9, 122.9,
127.4, 153.8, 158.7. Anal. Calcd for C18H24O2 (272.38):
C, 79.37; H, 8.88. Found: C, 79.11; H, 8.91. HRMS (ESI)
calcd for C18H24O2 (M+Na)+: m/z 295.1669. Found: m/z
295.1669.
1H), 7.47–7.53 (m, 3H), 7.69–7.71 (m, 1H), 7.83–7.86 (m,
1H). 13C NMR (100 MHz, CDCl3) d 57.9, 64.6, 111.0,
112.4, 119.6, 122.7, 124.4, 127.3, 128.57, 128.64, 129.8,
130.2, 153.8, 153.9. Anal. Calcd for C16H14O2 (238.28):
C, 80.65; H, 5.92. Found: C, 80.42; H, 6.18. HRMS (ESI)
calcd for C16H14O2 (M+Na)+: m/z 261.0886. Found: m/z
261.0885.
4.2.4. 3-(1-Ethoxyethyl)-2-(4-methoxyphenyl)benzo-
furan (2e). IR (neat) 3226, 3049–2843, 2042, 1604, 1508,
1449, 1257, 1176–1087, 1026, 937, 833, 749 cmꢁ1
.
1H
4.2.9. 3-Benzyloxymethyl-2-propylbenzofuran (2j). IR
(neat) 3087–2871, 1626, 1455, 1175, 1072, 1028,
NMR (400 MHz, CDCl3) d 1.12 (t, J¼7.0 Hz, 3H), 1.70
(d, J¼6.4 Hz, 3H), 3.27–3.39 (m, 2H), 3.87 (s, 3H), 4.97
(q, J¼6.4 Hz, 1H), 7.00–7.03 (m, 2H), 7.22 (ddd, J¼7.4,
7.4, 1.1 Hz, 1H), 7.28 (ddd, J¼8.0, 7.2, 1.6 Hz, 1H), 7.48
(d, J¼8.0 Hz, 1H), 7.64–7.68 (m, 2H), 7.87 (dd, J¼7.8,
1.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) d 15.4, 22.0,
55.4, 63.7, 70.3, 110.9, 114.1, 116.7, 121.3, 122.4, 123.3,
123.9, 128.2, 129.1, 151.6, 153.9, 159.8. Anal. Calcd for
C19H20O3 (296.36): C, 77.00; H, 6.80. Found: C, 76.83; H,
6.87. HRMS (ESI) calcd for C19H20O3 (M+Na)+: m/z
319.1305. Found: m/z 319.1305.
746 cmꢁ1
.
1H NMR (400 MHz, CDCl3) d 0.96 (t,
J¼7.6 Hz, 3H), 1.75 (sext, J¼7.6 Hz, 2H), 2.73 (t,
J¼7.6 Hz, 2H), 4.55 (s, 2H), 4.64 (s, 2H), 7.21–7.24 (m,
2H), 7.28–7.33 (m, 1H), 7.34–7.36 (m, 4H), 7.41 (dd,
J¼6.4, 2.4 Hz, 1H), 7.57–7.60 (m, 1H). 13C NMR
(100 MHz, CDCl3) d 13.8, 21.8, 28.5, 62.1, 71.7, 110.6,
111.6, 119.4, 122.4, 123.4, 127.6, 127.8, 128.3, 128.9,
138.2, 153.9, 157.1. Anal. Calcd for C19H20O2 (280.36):
C, 81.40; H, 7.19. Found: C, 81.60; H, 7.15. HRMS (ESI)
calcd for C19H20O2 (M+Na)+: m/z 303.1356. Found: m/z
303.1358.
4.2.5. 3-(1-Ethoxyethyl)-2-phenylbenzofuran (2f). IR
(neat) 3057–2870, 1590, 1493, 1454, 1371, 1256, 1210,
4.2.10. 3-Benzyloxymethyl-2-phenylbenzofuran (2k). IR
(neat) 3084–3033, 2925–2858, 1591, 1496, 1454, 1352,
1
1125–1062, 936, 746 cmꢁ1. H NMR (400 MHz, CDCl3)
1
d 1.12 (t, J¼7.2 Hz, 3H), 1.72 (d, J¼6.4 Hz, 3H), 3.28–
3.39 (m, 2H), 5.01 (q, J¼6.4 Hz, 1H), 7.24 (ddd, J¼7.5,
7.5, 1.1 Hz, 1H), 7.30 (ddd, J¼7.5, 7.5, 1.1 Hz, 1H), 7.37–
7.41 (m, 1H), 7.46–7.51 (m, 3H), 7.72 (dd, J¼8.6, 1.4 Hz,
1H), 7.91 (d, J¼7.8 Hz, 1H). 13C NMR (100 MHz, CDCl3)
d 15.3, 22.0, 63.7, 70.2, 110.9, 118.1, 121.5, 122.4, 124.5,
127.6, 128.4, 128.5, 130.6, 151.3, 154.1. Anal. Calcd for
C18H18O2 (266.33): C, 81.17; H, 6.81. Found: C, 81.25; H,
6.94. HRMS (ESI) calcd for C18H18O2 (M+Na)+: m/z
289.1199. Found: m/z 289.1199.
1252, 1202, 1065, 744 cmꢁ1. H NMR (400 MHz, CDCl3)
d 4.64 (s, 2H), 4.82 (s, 2H), 7.23–7.41 (m, 8H), 7.43–7.47
(m, 2H), 7.51 (dd, J¼8.2, 0.6 Hz, 1H), 7.64 (d, J¼8.0 Hz,
1H), 7.82–7.84 (m, 2H). 13C NMR (100 MHz, CDCl3)
d 62.2, 72.2, 111.1, 112.5, 119.8, 122.8, 124.5, 127.4,
127.7, 128.0, 128.4, 128.6, 128.7, 129.8, 130.3, 137.9,
153.9, 154.0. Anal. Calcd for C22H18O2 (314.38): C,
84.05; H, 5.77. Found: C, 84.19; H, 6.00. HRMS (ESI)
calcd for C22H18O2 (M+Na)+: m/z 337.1199. Found: m/z
337.1198.
4.2.6. 3-(1-Ethoxyethyl)-2-(4-trifluoromethylphenyl)-
benzofuran (2g). IR (neat) 3059–2883, 1625, 1448, 1408,
4.2.11. tert-Butyldimethyl-(2-phenylbenzofuran-3-yl-
methoxy)silane (2l). IR (neat) 3062–2854, 1876, 1757,
1322, 1164–1070, 936, 847, 755 cmꢁ1
.
1H NMR
1594, 1455, 1362, 850, 764 cmꢁ1 1H NMR (400 MHz,
.
(400 MHz, CDCl3) d 1.13 (t, J¼7.2 Hz, 3H), 1.72 (d,
J¼6.6 Hz, 3H), 3.30 (m, 2H), 5.02 (q, J¼6.6 Hz, 1H),
7.25–7.29 (m, 1H), 7.35 (ddd, J¼8.0, 7.2, 1.2 Hz, 1H),
7.52 (d, J¼7.6 Hz, 1H), 7.73–7.75 (m, 2H), 7.87–7.93 (m,
3H). 13C NMR (100 MHz, CDCl3) d Anal. Calcd for
C19H17F3O2 (334.33): C, 68.26; H, 5.13; F, 17.05. Found:
C, 68.19; H, 5.17; F, 16.88. HRMS (ESI) calcd for
C19H17F3O2 (M+Na)+: m/z 357.1073. Found: m/z 357.1074.
CDCl3) d 0.12 (s, 6H), 0.93 (s, 9H), 4.97 (s, 2H), 7.24–
7.32 (m, 2H), 7.38–7.42 (m, 1H), 7.46–7.52 (m, 3H), 7.69
(d, J¼7.9 Hz, 1H), 7.82 (d, J¼7.2 Hz, 1H). 13C NMR
(100 MHz, CDCl3) d ꢁ5.1, 18.5, 26.0, 56.1, 111.1, 115.2,
120.0, 122.6, 124.3, 127.4, 128.5, 129.6, 130.5, 152.9,
153.9. Anal. Calcd for C21H26O2Si (338.52): C, 74.51;
H, 7.74. Found: C, 74.59; H, 7.80. HRMS (ESI) calcd
for C21H26O2Si (M+Na)+: m/z 361.1594. Found: m/z
361.1596.
4.2.7. 3-Methoxymethyl-2-propylbenzofuran (2h). IR
(neat) 3056, 2962–2816, 1627, 1455, 1174, 1094, 910,
4.2.12. ortho-Alkynylphenyl benzyloxymethyl ether 12.
(a) To a suspension of NaH (1.5 mmol, prewashed by hex-
ane) in THF (2.5 ml) at 0 ꢀC was added 9 (1.0 mmol) in
THF (0.5 ml). After stirring for 1 h at 0 ꢀC, to the resulting
mixture at 0 ꢀC was added benzyl chloromethyl ether
(4 mmol). After stirring at room temperature for 5 h, the
reaction mixture was quenched with Et3N (0.2 ml). The
mixture was diluted by ether and washed with water. The
organic layer was washed with brine and dried over
Na2SO4. Purification by silica gel column chromatography
using hexane/ethyl acetate (2:1) gave BOM ether quantita-
747 cmꢁ1
.
1H NMR (400 MHz, CDCl3) d 0.98 (t,
J¼7.4 Hz, 3H), 1.77 (sext, J¼7.4 Hz, 2H), 3.36 (s, 3H),
4.56 (s, 2H), 7.18–7.24 (m, 2H), 7.37–7.41 (m, 1H), 7.57–
7.59 (m, 1H). 13C NMR (100 MHz, CDCl3) d 13.8, 21.8,
28.5, 57.7, 64.6, 110.6, 111.6, 119.3, 122.4, 123.4, 128.8,
153.9, 157.0. Anal. Calcd for C13H16O2 (204.26): C,
76.44; H, 7.90. Found: C, 76.16; H, 7.92. HRMS (ESI) calcd
for C13H16O2 (M+Na)+: m/z 227.1043. Found: m/z
227.1044.
1
4.2.8. 3-Methoxymethyl-2-phenylbenzofuran (2i). IR
(neat) 3061–2817, 1592, 1455, 1255, 1190, 1088, 949,
tively. IR (neat) 2977–2934, 1737, 1572, 1509 cmꢁ1. H
NMR (400 MHz, CDCl3) d 1.13–1.24 (m, 6H), 1.36 (d,
J¼5.6 Hz, 3H), 1.48 (d, J¼5.2 Hz, 3H), 3.50–3.54 (m,
2H), 3.65–3.75 (m, 2H), 4.15 (dd, J¼4.8, 6.0 Hz, 1H),
745 cmꢁ1 1H NMR (400 MHz, CDCl3) d 3.47 (s, 3H),
.
4.74 (s, 2H), 7.25–7.33 (m, 2H), 7.41 (tt, J¼7.2, 1.5 Hz,

I. Nakamura et al. / Tetrahedron 63 (2007) 8670–8676
8675
4.24 (m, 1H), 4.79 (q, J¼5.2 Hz, 1H), 4.96 (s, 2H), 5.40 (s,
2H), 5.36 (q, J¼5.6 Hz), 6.18 (m, 1H), 6.46 (d, J¼15.6 Hz),
7.11 (s, 1H), 7.28–7.39 (m, 5H), 7.48 (s, 1H). 13C NMR
(100 MHz, CDCl3) d 15.3, 15.4, 19.9, 20.3, 60.7, 61.8,
71.9, 77.2, 92.7, 96.7, 99.2, 100.8, 116.5, 126.9, 127.7,
127.9, 128.3, 129.6, 130.5, 135.0, 146.8, 149.1. HRMS
(ESI) calcd C25H33IO6 (M+Na)+: m/z 579.1214. Found:
m/z 579.1216.
gel column chromatography using hexane/EtOAc (30:1) as
an eluant afforded the products 4.
4.3.1. 3-Methoxymethyl-2-propyl-1-tosylindole (4a). IR
(neat) 2961–2854, 1519, 1458, 1300, 1260, 1113 cmꢁ1. 1H
NMR (399.65 MHz, CDCl3) d 2.32 (3H, s), 3.12 (3H, s)
5.19 (2H, s), 7.10 (2H, d, J¼8.0 Hz), 7.33–7.38 (4H,
m), 7.46–7.57 (6H, m), 8.32–8.35 (1H, m). 13C NMR
(149.40 MHz, CDCl3) d 21.4, 56.1, 74.8, 110.8, 115.5,
120.9, 123.1, 124.1, 125.1, 126.6, 127.6, 127.8, 127.9,
128.5, 129.2, 129.9, 131.2, 135.6, 140.8, 143.0, 144.1.
HRMS (ESI) calcd C20H23NO3S (M+Na)+: m/z 380.1296.
Found: m/z 380.1291.
(b) To a mixture of Pd(PPh3)4 (0.1 mmol), CuI (0.2 mmol),
and Et3N (3 mmol) in THF (2.5 ml) were added the BOM
ether (1 mmol) and 4-(1-ethoxyethyl)-3-methoxyphenyl-
acetylene (1.3 mmol) at room temperature. After stirring
for 2 h at room temperature, the reaction mixture was diluted
with ether. The ethereal solution was washed with a saturated
NH4Cl aqueous solution and water, dried over Na2SO4, and
concentrated. The crude product was purified by silica gel
column chromatography using hexane/ethyl acetate (5:1)
as an eluant to give 12 in 64% yield. IR (neat) 2977–2934,
4.3.2. 3-Methoxymethyl-2-phenyl-1-tosylindole (4b). IR
(neat) 3055–2824, 1733, 1456, 1379, 1321, 1143,
1
1077 cmꢁ1. H NMR (399.65 MHz, CDCl3) d 1.07 (3H, t,
J¼7.6 Hz), 1.62–1.71 (2H, m), 2.35 (3H, s), 3.17–3.21
(2H, m), 3.28 (3H, s), 5.44 (2H, s), 7.10–7.21 (4H, m),
7.33–7.37 (1H, m), 7.79 (2H, d, J¼8.4 Hz), 7.99–8.03
(1H, m). 13C NMR (100.40 MHz, CDCl3) d 14.4, 21.5,
23.9, 26.8, 56.3, 74.1, 110.0, 112.8, 120.1, 122.3, 122.6,
125.0, 126.2, 129.4, 136.2, 141.2, 143.1, 146.3. HRMS
(ESI) calcd C23H21NO3S (M+Na)+: m/z 414.1140. Found:
m/z 414.1134.
2210, 1737, 1572, 1509 cmꢁ1
.
1H NMR (400 MHz,
CDCl3) d 1.07–1.15 (m, 9H), 1.28 (d, J¼5.2 Hz, 3H),
1.42–1.43 (m, 6H), 3.43–3.49 (m, 4H), 3.50–3.57 (m, 2H),
3.59–3.74 (m, 2H), 3.59 (s, 3H), 4.72 (q, J¼5.2 Hz, 1H),
4.91 (s, 2H), 5.29–5.34 (m, 2H), 5.33 (s, 2H), 6.17 (m,
1H), 6.44 (d, J¼16.0 Hz, 1H), 6.91–6.96 (m, 3H), 7.06 (s,
1H), 7.14–7.25 (m, 6H). 13C NMR (100 MHz, CDCl3)
d 15.15, 15.24, 15.4, 19.9, 20.3, 20.4, 55.8, 60.6, 61.7,
62.0, 65.5, 71.0, 84.8, 93.4, 96.4, 99.1, 100.8, 101.0,
114.9, 116.7, 117.1, 118.6, 118.7, 124.6, 124.8, 126.4,
127.5, 127.9, 128.2, 130.5, 133.0, 137.5, 146.4, 147.6,
149.6, 150.3. HRMS (ESI) calcd for C38H48O9 (M+Na)+:
m/z 671.3191. Found: m/z 671.3188.
4.3.3. 3-Acetyl-1-methoxymethyl-2-propylindole (14). IR
(neat) 2964–2828, 1632, 1510, 1459, 1122, 1104 cmꢁ1. 1H
NMR (270.05 MHz, CDCl3) d 1.04 (3H, t, J¼7.6 Hz), 1.68
(2H, m), 2.70 (3H, s), 3.20 (2H, m), 3.30 (3H, s), 5.50
(2H, s), 7.24–7.34 (2H, m), 7.46–7.52 (1H, m), 7.94–8.00
(1H, s). 13C NMR (67.80 MHz, CDCl3) d 14.3, 23.1, 27.8,
31.8, 73.6, 110.1, 114.9, 120.8, 122.3, 122.5, 126.4, 136.7,
149.4, 194.7. HRMS (ESI) calcd C15H19NO2 (M+Na)+:
m/z 268.1313. Found: m/z 268.1308.
4.2.13. Vibsanol precursor 13. To a mixture of PtCl2
(20 mol %) and 1,5-cyclooctadiene (80 mol %) in toluene
(0.5 ml) was added 12 in toluene (0.3 ml) at room tempera-
ture. After stirring at 30 ꢀC for 1 h, the reaction mixture was
filtered through a short silica gel column using ethyl acetate
as an eluant. Purification by silica gel column chromato-
graphy using hexane/EtOAc (2:1) as an eluant afforded 13
in 76% yield. IR (neat) 2977–2934, 2247, 1737, 1596,
Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.03.039.
1509, 1466 cmꢁ1 1H NMR (400 MHz, CDCl3) d 1.20–
.
1.27 (m, 9H), 1.39 (d, J¼5.2 Hz, 3H), 1.55 (d, J¼5.2 Hz,
3H), 1.61 (d, J¼4.8 Hz, 3H), 3.55–3.71 (m, 4H), 3.86 (s,
3H), 3.87–4.01 (m, 2H), 4.65 (s, 2H), 4.77 (s, 2H), 4.83 (q,
J¼5.6 Hz, 1H), 5.44 (q, J¼5.2 Hz, 1H), 5.64 (q, J¼5.6 Hz,
1H), 6.28 (m, 1H), 6.67 (d, J¼16.0 Hz, 1H), 7.09 (d,
J¼1.6 Hz, 1H), 7.14–7.45 (m, 9H). 13C NMR (100 MHz,
CDCl3) d 15.2, 15.3, 15.4, 20.0, 20.3, 20.9, 55.9, 60.6,
62.0, 62.1, 62.8, 65.9, 72.1, 99.1, 101.0, 101.7, 111.2,
111.7, 112.0, 112.3, 118.8, 120.3, 124.6, 125.2, 127.7,
127.9, 128.3, 132.2, 133.0, 137.9, 141.6, 144.1, 146.6,
150.7, 154.9. HRMS (ESI) calcd for C38H48O9 (M+Na)+:
m/z 671.3191. Found: m/z 671.3187.
References and notes
1. For a review: (a) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004,
104, 2127; (b) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104,
2258 and references therein.
2. For a review: (a) Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Eur.
J. Org. Chem. 2002, 2671; (b) Cacchi, S.; Fabrizi, G.;
Goggiomani, A. Heterocycles 2002, 56, 613; (c) Balme, G.;
Bouyssi, D.; Lomberget, T.; Monteiro, N. Synthesis 2003, 14,
2115.
3. For cyclization of allylic amines: (a) Cacchi, S.; Fabrizi, G.;
Pace, P. J. Org. Chem. 1998, 63, 1001; (b) Arcadi, A.;
Cacchi, S.; Rosario, M. D.; Fabrizi, G.; Marinelli, F. J. Org.
Chem. 1996, 61, 9280; Palladium(0)-catalyzed endo-cycliza-
tion of allylic ethers: (c) Cacchi, S.; Fabrizi, G.; Moro, L.
Synlett 1998, 741; (d) Monterio, N.; Balme, G. Synlett 1998,
746; For PtCl2-catalyzed exo-cyclization of allylic ethers: (e)
F€urstner, A.; Szillat, H.; Stelzer, F. J. Am. Chem. Soc. 2000,
4.3. General procedure for palladium-catalyzed
cyclization of N,O-acetals 3
To PdBr2 (0.03 mmol) in toluene (0.5 ml) was added the
N,O-acetal 3 (0.3 mmol) in toluene (0.7 ml) under Ar atmo-
sphere in a pressure vial. After heating at 80 ꢀC for 18 h, the
reaction mixture was filtered through a short silica gel col-
umn using ethyl acetate as an eluant. Separation by silica
€
122, 6785; (f) Furstner, A.; Stelzer, F.; Szillat, H. J. Am.
Chem. Soc. 2001, 123, 11863.

8676
I. Nakamura et al. / Tetrahedron 63 (2007) 8670–8676
4. Cacchi, S.; Fabrizi, G.; Moro, L. Tetrahedron Lett. 1998, 39,
5101.
Yamamoto, Y. Chem. Lett. 2005, 34, 174; (d) Dube, P.; Toste,
F. D. J. Am. Chem. Soc. 2006, 128, 12062.
5. Shimada, T.; Nakamura, I.; Yamamoto, Y. J. Am. Chem. Soc.
2004, 126, 10546.
10. (a) Nakamura, I.; Bajracharya, G. B.; Wu, H.; Oishi, K.;
Mizushima, Y.; Gridnev, I. D.; Yamamoto, Y. J. Am. Chem.
Soc. 2004, 126, 15423; (b) Pujanauski, B. G.; Prasad,
B. A. B.; Sarpong, R. J. Am. Chem. Soc. 2006, 128, 6786.
11. Fukuyama, Y.; Nakahara, M.; Minami, H.; Kodama, M. Chem.
Pharm. Bull. 1996, 44, 1418.
12. (a) Sakai, A.; Aoyama, T.; Shioiri, T. Tetrahedron Lett. 1999,
40, 4211; (b) Sakai, A.; Aoyama, T.; Shioiri, T. Heterocycles
2000, 52, 643.
6. F€urstner, A.; Davies, P. W. J. Am. Chem. Soc. 2005, 127, 15024.
7. For a recent report: (a) Gfesser, G. A.; Faghih, R.; Bennani,
Y. L.; Curtis, M. P.; Esbenshade, T. A.; Hancock, A. A.;
Cowart, M. D. Bioorg. Med. Chem. Lett. 2005, 15, 2559; (b)
Locuson, C. W., II; Suzuki, H.; Rettie, A. E.; Jones, J. P.
J. Med. Chem. 2004, 47, 6768; (c) Abele, E.; Abele, R.;
Dzenitis, O.; Lukevics, E. Chem. Heterocycl. Comp. 2003,
39, 3.
8. (a) Nakamura, I.; Mizushima, Y.; Yamamoto, Y. J. Am. Chem.
Soc. 2005, 127, 15022. F€urstner’s group independently reported
the same reaction using PtCl2 as a catalyst under CO atmo-
sphere. See, Ref. 6.
13. Our preliminary attempts to deprotect the BOM group of 13
failed.
14. Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication nos. CCDC-629327. Copies of the data can be ob-
tained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK, (fax: +44 (0)1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk).
9. (a) Nakamura, I.; Bajracharya, G. B.; Mizushima, Y.;
Yamamoto, Y. Angew. Chem., Int. Ed. 2002, 41, 4328; (b)
Nakamura, I.; Kamada, M.; Yamamoto, Y. Tetrahedron Lett.
2004, 45, 2903; (c) Nakamura, I.; Bajracharya, G. B.;