Synthesis of 4-vinylindoles using ruthenium-catalyzed ring-closing enyne metathesis

Article abstract of DOI:10.1021/jo400099x

The selective synthesis of substituted 4-vinylindoles by the ring-closing enyne metathesis (RCEM)/dehydration sequence is reported. In contrast with many known methods in which a pyrrole ring is constructed onto a functionalized benzene precursor, this method enables the construction of a benzene ring onto a pyrrole precursor. The RCEM/tautomerization sequence for the synthesis of 7-hydroxy-4-vinylindole is also presented as an application of this method.

Full text of DOI:10.1021/jo400099x

Note
pubs.acs.org/joc
Synthesis of 4‑Vinylindoles Using Ruthenium-Catalyzed Ring-Closing
Enyne Metathesis
Kazushi Hayashi, Kazuhiro Yoshida,* and Akira Yanagisawa*
Department of Chemistry, Graduate School of Science, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
S
* Supporting Information
ABSTRACT: The selective synthesis of substituted 4-vinyl-
indoles by the ring-closing enyne metathesis (RCEM)/
dehydration sequence is reported. In contrast with many
known methods in which a pyrrole ring is constructed onto
a functionalized benzene precursor, this method enables the
construction of a benzene ring onto a pyrrole precursor.
The RCEM/tautomerization sequence for the synthesis of 7-hydroxy-4-vinylindole is also presented as an application of
this method.
Scheme 1. Retrosynthetic Analysis of Substrates 1
he construction of aromatic rings using ruthenium-
catalyzed ring-closing metathesis1,2 has recently emerged
T
as a powerful method for the preparation of aromatic
compounds.3−6 During the course of our study on this field,7
we reported in 2011 a new method for the synthesis of
substituted indoles, which are important nuclei for a variety of
natural products and medicinal agents,8 by using the ring-closing
olefin metathesis (RCM)/dehydration sequence (eq 1).7c The
5. In fact, cross-coupling 3 with 4, followed by allylation of the
resulting products with 5, yielded 1 successfully.12
With the desired precursors 1 in hand, we examined the
synthesis of 4-vinylindoles 2 by the RCEM/dehydration
sequence using Grubbs second-generation catalyst 613 (Table 1).
As our previous work on styrene ring formation revealed that
RCEM proceeded more smoothly under ethylene gas than under
nitrogen gas,7b we carried out the reaction of 1a under ethylene
atmosphere. As a result, 2a was obtained in 99% yield (entry 1).
In contrast, the reaction of 1a under nitrogen atmosphere gave 2a
in only 59% yield (entry 2). Lowering the catalyst loading from
7.5 mol % to 1 mol % decreased the product yield slightly, but it
was still sufficiently high (86% yield) (entry 1 vs 3). Under the
same reaction conditions as those for entry 1, substrates 1b and
1c having the same substitution pattern as 1a were converted into
corresponding 4-vinylindoles 2b and 2c, respectively, in good
yields (entries 4 and 5). The introduction of additional
substituents at the R6 or R7 position was also accomplished,
and various indoles 2d−g were obtained in moderate to good
yields (entries 6−9). It was, however, found that RCEM of 1h,
which had a methyl group at R5 position, did not occur at all
(entry 10).14 As an application of the RCEM/dehydration
sequence, we next examined the construction of two or three
benzene rings simultaneously. As a result, 2i and 2j were
successfully formed from 1i and 1j, respectively (entries 11
and 12). Furthermore, the RCEM/dehydration of 1k, an indole
most common method for the construction of the indole
skeleton involves pyrrole ring formation from a benzene
precursor.9 It is, however, quite rare to construct the benzene
ring of indole from a pyrrole precursor, similar to our method
mentioned above.10 Considering the product variations between
the two approaches, enriching this rare approach will be of great
value.
Herein, we report the synthesis of substituted 4-vinylindoles 2
from new pyrrole precursors 1 using the ring-closing enyne
metathesis (RCEM)/dehydration sequence (eq 2). The employ-
ment of RCEM enables not only the formation of the carbocyclic
six-membered ring but also the concurrent introduction of a vinyl
group to the ring. As vinyl groups can be easily converted into
other functional groups, products 2 are considered to be
attractive intermediates for various indole derivatives.
As shown in Scheme 1, our retrosynthetic analysis revealed
that precursors 1 could be prepared from three basic parts,
namely pyrroles 3,11 terminal alkynes 4, and allylic metal reagents
Received: January 29, 2013
Published: February 19, 2013
© 2013 American Chemical Society
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Note
a
Table 1. Synthesis of Substituted 4-Vinylindoles 2 by RCEM/Dehydration Sequence
a
Ring-closing enyne metathesis was carried out with 1 and ruthenium catalyst (6, 7.5 mol %) in toluene under ethylene atmosphere (1 atm). The
b
c
reaction mixture was treated with p-toluenesulfonic acid (10 mol %) at rt for 1 h. Isolated yield by silica gel chromatography. The reaction was
carried out under N2 atmosphere. The reaction was carried out with 1 mol % of 6. Because of the presence of a trace impurity with 1d, 2a was also
obtained in 2% yield (see the Supporting Information for details). Because of the presence of a trace impurity with 1e, 4-(5-chloropent-1-en-2-yl)-1-
(phenylsulfonyl)-1H-indole was obtained in 3% yield (see the Supporting Information for details). A mixture of 1f and its positional isomer (1/
0.014) was used as the starting material (see the Supporting Information for details). 1h was recovered in 35% yield. The reaction was carried out
with 15 mol % of 6. A high temperature (80 °C) was required for the dehydration step with p-toluenesulfonic acid.
d
e
f
g
h
i
j
derivative, gave the corresponding unsymmetrical carbazole 2k
quantitatively (entry 13).15
are particularly useful building blocks because the vinyl
and phenolic hydroxyl groups can be converted in many
ways.
In conclusion, we have presented a new method for the
selective synthesis of substituted 4-vinylindoles that uses RCEM.
As the method employs a rare approach by which the carbocyclic
rings of indoles are constructed, it provides novel access to
unique indoles.
Finally, we applied the RCEM/tautomerization sequence to 7,
which was prepared by the IBX oxidation of 1a. As a result, the
desired 7-hydroxy-4-vinylindole 8 was obtained in good yield
(Scheme 2). As the transformation of 7 into 8 involves no
elimination step, the RCEM/tautomerization sequence is a 100%
atom-economical process. Moreover, 7-hydroxy-4-vinylindoles
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Note
(125 MHz, CDCl3) δ 41.3, 57.8, 66.8, 71.6, 79.5, 90.2, 108.6, 115.2,
118.1, 122.7, 126.8, 127.9, 128.0, 128.4, 129.6, 133.8, 134.3, 137.3, 138.8,
139.6; HRMS (ESI) calcd for C24H23NNaO4S (M+ + Na) 444.1240,
found 444.1233.
Scheme 2. Synthetic Sequence for 7-Hydroxy-4-vinylindole 8
2-Methyl-1-(3-(phenylethynyl)-1-(phenylsulfonyl)-1H-pyrrol-2-yl)-
but-3-en-1-ol (1d). General procedure A (3a, 4a, hexane/toluene = 1/3
to toluene), C: diastereomeric mixture of 1d (0.58/0.42); pale brown
solid (205 mg, 83% yield); 1H NMR (500 MHz, CDCl3) δ 0.88 (d, J =
6.9 Hz, 3H (minor)), 1.23 (d, J = 6.9 Hz, 3H (major)), 2.69 (d, J = 8.0
Hz, 1H (minor)), 2.82 (d, J = 9.4 Hz, 1H (major)), 3.09 (sextet, J = 7.7
Hz, 1H (major)), 3.15 (sextet, J = 8.0 Hz, 1H (minor)), 4.80 (ddd, J =
10.4, 1.7, 0.9 Hz, 1H (major)), 4.90 (ddd, J = 17.2, 1.7, 1.1 Hz, 1H
(major)), 4.98 (t, J = 8.8 Hz, 1H (major), 1H (minor)), 5.17−5.23 (m,
2H (minor)), 5.51 (ddd, J = 17.2, 10.3, 8.0 Hz, 1H (major)), 5.92 (ddd,
J = 17.2, 10.4, 8.1 Hz, 1H (minor)), 6.37 (d, J = 6.8 Hz, 1H (major)),
6.40 (d, J = 3.5 Hz, 1H (minor)), 7.20 (d, J = 3.4 Hz, 1H (major)), 7.25
(d, J = 3.4 Hz, 1H (minor)), 7.30−7.35 (m, 3H (major), 3H (minor)),
7.41−7.46 (m, 2H (major), 2H (minor)), 7.50−7.55 (m, 2H (major),
2H (minor)), 7.59−7.65 (m, 1H (major), 1H (minor)), 7.82−7.87
(m, 2H (major), 2H (minor)); 13C NMR (125 MHz, CDCl3) δ 16.66,
16.69, 44.5, 44.6, 70.8, 71.5, 82.4, 82.5, 94.0, 94.1, 109.5, 109.8, 115.0,
115.1, 116.7, 122.77, 122.87, 122.95, 123.1, 126.77, 126.82, 128.39,
128.42, 129.49, 129.53, 131.18, 131.22, 134.15, 134.19, 138.9, 139.0,
139.6, 140.5; HRMS (ESI) calcd for C23H21NNaO3S (M+ + Na)
414.1134, found 414.1134.
1-(3-(5-Chloropent-1-yn-1-yl)-1-(phenylsulfonyl)-1H-pyrrol-2-yl)-
2-methylbut-3-en-1-ol (1e). General procedure A (3a, 5-chloro-1-
pentyne 4d), C: diastereomeric mixture of 1e (0.56/0.44); yellowish-
brown oil (219 mg, 92% yield); 1H NMR (500 MHz, CDCl3) δ 0.82 (d,
J = 6.9 Hz, 3H (minor)), 1.19 (d, J = 6.9 Hz, 3H (major)), 2.00 (quintet,
J = 6.6 Hz, 2H (minor)), 2.01 (quintet, J = 6.6 Hz, 2H (major)), 2.58 (t,
J = 6.6 Hz, 2H (minor)), 2.58 (t, J = 6.8 Hz, 2H (major)), 2.65 (d, J =
8.0 Hz, 1H (minor)), 2.80 (d, J = 9.5 Hz, 1H (major)), 2.99 (sextet, J =
7.4 Hz, 1H (major)), 3.05 (sextet, J = 7.8 Hz, 1H (minor)), 3.67 (t,
J = 6.3 Hz, 2H (minor)), 3.67 (t, J = 6.3 Hz, 2H (major)), 4.78 (ddd, J =
10.3, 1.7, 0.5 Hz, 1H (major)), 4.86 (ddd, J = 17.2, 1.7, 1.1 Hz, 1H
(major)), 4.89 (t, J = 8.9 Hz, 1H (major), 1H (minor)), 5.15−5.21 (m,
2H (minor)), 5.46 (ddd, J = 17.2, 10.3, 8.0 Hz, 1H (major)), 5.88 (ddd,
J = 17.2, 10.4, 7.7 Hz, 1H (minor)), 6.24 (d, J = 3.4 Hz, 1H (major)) 6.27
(d, J = 3.4 Hz,.1H (minor)), 7.14 (d, J = 3.5 Hz, 1H (major)), 7.19 (d, J =
3.4 Hz, 1H (minor)), 7.49−7.54 (m, 2H (major), 2H (minor)), 7.59−
7.64 (m, 1H (major), 1H (minor)), 7.78−7.84 (m, 2H (major), 2H
(minor)); 13C NMR (125 MHz, CDCl3) δ 16.5, 16.6, 16.9, 31.1, 43.6,
44.3, 44.4, 70.7, 71.5, 74.5, 74.6, 92.9, 93.1, 109.8, 110.1, 114.9, 115.19,
115.22, 116.5, 122.5, 122.8, 126.7, 126.8, 129.45, 129.49, 134.08, 134.13,
138.5, 138.99, 139.02, 139.2, 139.6, 140.6; HRMS (ESI) calcd for
C20H22ClNNaO3S (M+ + Na) 414.0901, found 414.0899.
EXPERIMENTAL SECTION
Unless otherwise noted, silica gel column chromatography or PTLC was
performed with hexane/EtOAc (1.5/1−4.5/1).
■
General Procedure A: Sonogashira Coupling. To a mixture of
PdCl2(PPh3)2 (5 mol %) and 3-bromo-1-(phenylsulfonyl)-1H-pyrrole-
2-carbaldehyde (3a) or 3-iodo-1-tosyl-1H-indole-2-carbaldehyde (3b)
in THF (1/7 M for 3) was added NEt3 (3 equiv). After the mixture was
stirred for 10 min at rt, terminal acetylene 4 (1.3 equiv) and CuI (5 mol %)
were added. After being stirred overnight (ca. 16 h), the reaction mixture
was diluted with saturated aqueous NH4Cl, extracted with EtOAc,
washed with brine, dried over Na2SO4, and evaporated. Purification
by silica gel column chromatography gave the corresponding
3-ethynylpyrrole-2-carbaldehydes or 3-ethynylindole-2-carbaldehyde 9.
General Procedure B: Allylation with Allyltrifluoroborate.
The reaction was performed according to the reported procedure.16
Purification by silica gel column chromatography gave 1.
General Procedure C: Allylation with Indium and 1-Bromo-2-
butene. The reaction was performed according to the reported
procedure.17 Purification by silica gel column chromatography gave 1.
General Procedure D: Alkylation with Grignard Reagent. To a
solution of carbonyl compound in THF (0.033−0.05 M) was added
Grignard reagent (1.5 equiv) at −80 °C. After being stirred for 1.4−3 h,
the mixture was quenched by saturated aqueous NH4Cl at the same
temperature, warmed to rt, extracted with EtOAc, washed with brine,
dried over Na2SO4, and evaporated. Purification by silica gel column
chromatography gave corresponding alcohols.
1-(3-(Phenylethynyl)-1-(phenylsulfonyl)-1H-pyrrol-2-yl)but-3-en-
1-ol (1a). General procedure A (3a, phenylacetylene 4a, hexane/toluene =
1/3 to toluene), B: orange gum (99.1 mg, 97% yield); 1H NMR (400
MHz, CDCl3) δ 2.73−2.90 (m, 3H), 5.01−5.12 (m, 2H), 5.25 (td, J =
8.2, 6.2 Hz, 1H), 5.76 (ddt, J = 17.4, 10.3, 7.1 Hz, 1H), 6.39 (d, J =
3.4 Hz, 1H), 7.25 (d, J = 3.4 Hz, 1H), 7.30−7.35 (m, 3H), 7.42−7.46 (m,
2H), 7.53 (t, J = 8.1 Hz, 2H), 7.64 (tt, J = 7.6, 1.2 Hz, 1H), 7.84 (dd, J =
8.2, 1.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 41.3, 66.8, 82.3, 94.1,
109.2, 115.0, 118.1, 122.8, 122.9, 126.8, 128.37, 128.41, 129.6, 131.2,
133.8, 134.2, 138.9, 139.2; HRMS (ESI) calcd for C22H19NNaO3S
(M+ + Na) 400.0978, found 400.0971.
Methyl 2-((3-((4-Ethoxyphenyl)ethynyl)-1-(phenylsulfonyl)-1H-
pyrrol-2-yl)(hydroxy)methyl)but-3-enoate (1f). General procedure A
(3a, 4-ethoxyphenylacetylene 4e, substantial amount of CH2Cl2 was
used for loading the crude product on silica gel). The allylation with
methyl 4-bromocrotonate 11 was performed according to the reported
procedure (reaction time: 18 h).18 Purification by silica gel column
chromatography (CH2Cl2 to CH2Cl2/EtOAc = 100/1−50/1−30/1−
15/1) gave a diastereomeric mixture of 1f (0.64/0.36) with trace of
inseparable byproducts such as isomerized product or α-adduct, which
are tentatively assigned by 1H NMR: yellowish-brown oil (379 mg, 93%
1-(1-(Phenylsulfonyl)-3-(thiophene-2-ylethynyl)-1H-pyrrol-2-yl)-
but-3-en-1-ol (1b). General procedure A (3a, 2-ethynylthiophene 4b),
B: yellowish brown oil (217 mg, 93% yield); H NMR (500 MHz,
1
CDCl3) δ 2.74 (dddt, J = 14.1, 7.2, 6.0, 1.1 Hz, 1H), 2.79 (d, J = 8.3 Hz,
1H), 2.83 (dddt, J = 14.3, 8.1, 6.9, 1.1 Hz, 1H), 5.03−5.06 (m, 1H), 5.09
(dq, J = 17.2, 1.5 Hz, 1H), 5.22 (td, J = 8.1, 6.9 Hz, 1H), 5.74 (ddt, J =
17.2, 10.0, 7.2 Hz, 1H), 6.38 (d, J = 3.5 Hz, 1H), 6.99 (dd, J = 5.2, 3.7 Hz,
1H), 7.20 (dd, J = 3.7, 1.1 Hz, 1H), 7.24 (d, J = 3.4 Hz, 1H), 7.28 (dd, J =
5.1, 1.1 Hz, 1H), 7.51−7.56 (m, 2H), 7.64 (tt, J = 7.4, 1.2 Hz, 1H), 7.81−
7.85 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 41.2, 66.7, 85.9, 87.2,
109.0, 114.9, 118.2, 122.9, 126.8, 127.1, 127.4, 129.6, 131.8, 133.8, 134.3,
138.8, 139.3; HRMS (ESI) calcd for C20H17NNaO3S2 (M+ + Na)
406.0542, found 406.0533.
1
yield; ca. 95% purity estimated by H NMR analysis). Further puri-
fication was performed by recycling gel permeation chromatography
before use for the next step: 1H NMR (500 MHz, CDCl3) δ 1.41 (t, J =
6.9 Hz, 3H (major), 3H (minor)), 3.19 (d, J = 8.3 Hz, 1H (major)), 3.20
(d, J = 8.3 Hz, 1H (minor)), 3.57 (s, 3H (major)), 3.76 (s, 3H (minor)),
4.03 (q, J = 7.1 Hz, 2H (major)), 4.03 (q, J = 6.9 Hz, 2H (minor)), 4.08
(t, J = 8.6 Hz, 1H (major)), 4.22 (t, J = 9.4 Hz, 1H (minor)), 4.91 (dd, J =
10.3, 1.1 Hz, 1H (minor)), 5.03 (dt, J = 16.8, 1.2 Hz, 1H (minor)), 5.24
(dt, J = 17.1, 0.9 Hz, 1H (major)), 5.32 (dd, J = 10.0, 1.2 Hz, 1H
(major)), 5.46−5.62 (m, 1H (major), 2H (minor)), 6.09 (ddd, J = 17.2,
10.1, 9.2 Hz, 1H (major)), 6.34 (d, J = 3.4 Hz, 1H (major)), 6.35 (d, J =
3.4 Hz, 1H (minor)), 6.82−6.87 (m, 2H (major), 2H (minor)), 7.22 (d,
J = 3.4 Hz, 1H (major)), 7.24 (d, J = 3.4 Hz, 1H (minor)), 7.37−7.44
1-(3-(3-(Benzyloxy)prop-1-yn-1-yl)-1-(phenylsulfonyl)-1H-pyrrol-
2-yl)but-3-en-1-ol (1c). General procedure A (3a, 3-phenoxy-1-
propyne 4c, first: hexane/EtOAc = 3/1, second: hexane/toluene =
10/1 to toluene to toluene/Et2O = 15/1), B: yellow oil (104 mg, 92%
1
yield); H NMR (500 MHz, CDCl3) δ 2.69 (quint, J = 6.9 Hz, 1H),
2.75−2.84 (m, 2H), 4.35 (s, 2H), 4.62 (s, 2H), 5.00−5.08 (m, 2H), 5.19
(q, J = 6.6 Hz, 1H), 7.52 (ddt, J = 17.2, 10.4, 6.8 Hz, 1H), 6.32 (d, J = 3.5
Hz, 1H), 7.21 (d, J = 3.4 Hz, 1H), 7.27−7.36 (m, 5H), 7.52 (t, J = 7.8 Hz,
2H), 7.63 (t, J = 7.7 Hz, 1H), 7.81 (d, J = 8.0 Hz, 2H); 13C NMR
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Note
(m, 2H (major), 2H (minor)), 7.52 (t, J = 8.3 Hz, 2H (major), 2H
(minor)), 7.60−7.64 (m, 1H (major), 1H (minor)), 7.84−7.89 (m, 2H
(major), 2H (minor)); 13C NMR (125 MHz, CDCl3) δ 14.7, 52.0, 52.2,
55.9, 56.3, 63.5, 67.6, 67.8, 80.5, 94.2, 94.7, 110.9, 114.3, 114.51, 114.54,
114.6, 114.7, 114.8, 115.2, 119.5, 120.6, 123.1, 123.4, 126.8, 127.0, 129.5,
131.2, 132.4, 132.70, 132.73, 134.19, 134.22, 135.9, 136.4, 138.7, 138.8,
159.1, 159.2, 171.3, 172.7; HRMS (ESI) calcd for C26H25NNaO6S
(M+ + Na) 502.1295, found 502.1296.
1-(3-(Phenylethynyl)-1-tosyl-1H-indol-2-yl)but-3-en-1-ol (1k).
General procedure A (3b, 4a, hexane/toluene = 1/4−1/6), B: orange
oil (110 mg, 90% yield); 1H NMR (500 MHz, CDCl3) δ 2.32 (s, 3H),
2.93−3.06 (m, 2H), 3.63 (d, J = 10.3 Hz, 1H), 5.08−5.12 (m, 1H), 5.19
(dq, J = 17.2, 1.7 Hz, 1H), 5.64 (ddd, J = 10.3, 7.4, 6.3 Hz, 1H), 5.87
(ddt, J = 17.2, 10.0, 6.8 Hz, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.28−7.40 (m,
5H), 7.52−7.57 (m, 2H), 7.64−7.68 (m, 1H), 7.74 (dt, J = 8.6, 1.8 Hz,
2H), 8.10 (d, J = 8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 21.6, 41.9,
68.3, 80.3, 97.8, 106.4, 115.0, 118.3, 120.2, 122.8, 124.3, 125.9, 126.6,
128.5, 128.7, 129.7, 129.9, 131.4, 133.8, 135.0, 136.1, 144.8, 145.3;
HRMS (ESI) calcd for C27H23NNaO3S (M+ + Na) 464.1291, found
464.1284.
General Procedure E: RCEM/Dehydration. To a solution of 1 in
toluene (0.01 M) was added catalyst 6 (7.5 mol %) under nitrogen, and
then the system was evacuated carefully and filled with ethylene gas in
three cycles. The reaction mixture was stirred for 12 h at 80 °C.
After being cooled to rt, the reaction mixture was treated with p-TsOH
(10 mol %) and stirred for 1 h at rt. The mixture was concentrated under
reduced pressure and purified by PTLC on silica gel to give 2.
1-(Phenylsulfonyl)-4-(1-phenylvinyl)-1H-indole (2a). General pro-
cedure E: yellow oil (38.1 mg, 99% yield); 1H NMR (400 MHz, CDCl3)
δ 5.39 (d, J = 1.1 Hz, 1H), 5.68 (d, J = 1.4 Hz, 1H), 6.28 (d, J = 3.6 Hz,
1H), 7.19 (dd, J = 7.6, 0.7 Hz, 1H), 7.22−7.32 (m, 6H), 7.40−7.46 (m,
3H), 7.52 (t, J = 7.3 Hz, 1H), 7.86−7.91 (m, 2H), 7.97 (d, J = 8.5 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 108.9, 112.8, 116.1, 124.0, 124.5,
125.9, 126.8, 127.5, 127.8, 128.3, 129.2, 129.6, 133.8, 134.9, 135.2, 138.2,
141.0, 148.0; HRMS (ESI) calcd for C22H17NNaO2S (M+ + Na)
382.0872, found 382.0870.
2-(3-(Phenylethynyl)-1-(phenylsulfonyl)-1H-pyrrol-2-yl)pent-4-
en-2-ol (1g). General procedure A (3a, 4a), D (MeMgBr (3.0 M in
Et2O)). MnO2 (230 mg, 2.65 mmol, 40 equiv) was added to a solution of
the alcohol (23.2 mg, 0.0660 mmol) in CH2Cl2 (1.3 mL) at rt under air.
After being stirred at 50 °C with a coldfinger condenser for 3 h, the
mixture was cooled to rt and filtered through Celite. The residual solid
was washed thoroughly with CH2Cl2, and the filtrate was evaporated.
Silica gel column chromatography gave corresponding ketone (20.5 mg,
89% yield). General procedure D (allylmagnesium bromide 5b (0.52 M
1
in Et2O)): yellowish-brown oil (22.6 mg, 95% yield); H NMR (500
MHz, CDCl3) δ 1.63 (s, 3H), 2.53 (dd, J = 13.8, 8.0 Hz, 1H), 3.21 (dd,
J = 13.8, 6.5 Hz, 1H), 3.56 (s, 1H), 5.00−5.09 (m, 2H), 5.55 (dddd, J =
17.2, 10.1, 8.1, 6.6 Hz, 1H), 6.41 (d, J = 3.7 Hz, 1H), 7.29−7.35 (m, 3H),
7.41−7.46 (m, 3H), 7.49 (t, J = 7.5 Hz, 2H), 7.59 (tt, J = 7.5, 1.1 Hz, 1H),
7.72 (dd, J = 8.3, 0.9 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 28.8,
47.2, 73.1, 83.9, 94.1, 108.2, 114.4, 119.3, 123.2, 124.3, 126.4, 128.3,
128.4, 129.0, 131.0, 133.1, 133.5, 140.5, 143.4; HRMS (ESI) calcd for
C23H21NNaO3S (M+ + Na) 414.1134, found 414.1131.
1-(3-Ethynyl-1-(phenylsulfonyl)-1H-pyrrol-2-yl)-3-methylbut-3-
en-1-ol (1h). General procedure A (3a, trimethylsilylacetylene 4f), D
((2-methylallyl)magnesium chloride 5e (0.67 M in THF)). To a
solution of the corresponding 3-((trimethylsilyl)ethynyl)pyrrole (113
mg, 0.290 mmol) in degassed methanol (5.8 mL) was added K2CO3
(100 mg, 0.726 mmol, 2.5 equiv). After being stirred for 1 h at rt, the
mixture was diluted with water at 0 °C, extracted with CH2Cl2, dried
over Na2SO4, and evaporated. Silica gel column chromatography
followed by further purification by recycling gel permeation
chromatography (CHCl3) gave 1h: yellow oil (61.6 mg, 67% yield);
1H NMR (400 MHz, CDCl3) δ 1.76 (s, 3H), 2.56 (dd, J = 13.9, 4.8 Hz,
1H), 2.68 (d, J = 7.9 Hz, 1H), 2.78 (ddd, J = 14.1, 9.2, 0.7 Hz, 1H), 3.24
(s, 1H), 4.76 (d, J = 0.9 Hz, 1H), 4.84 (t, J = 1.3 Hz, 1H), 5.31 (ddd, J =
9.3, 7.9, 4.9 Hz, 1H), 6.34 (d, J = 3.4 Hz, 1H), 7.20 (d, J = 3.4 Hz, 1H),
7.53 (t, J = 8.2 Hz, 2H), 7.64 (tt, J = 7.5, 1.2 Hz, 1H), 7.81−7.85 (m,
2H); 13C NMR (125 MHz, CDCl3) δ 22.1, 45.1, 65.1, 76.8, 82.4, 107.8,
113.9, 115.2, 122.5, 126.8, 129.6, 134.3, 138.8, 141.0, 141.7; HRMS
(ESI) calcd for C17H17NNaO3S (M+ + Na) 338.0821, found 338.0817.
1,1′-(3,3′-(1,4-Phenylenebis(ethyne-2,1-diyl))bis(1-(phenylsulfon-
yl)-1H-pyrrole-3,2-diyl))bis(but-3-en-1-ol) (1i). General procedure A
(3a, 1,4-diethynylbenzene 4g, CH2Cl2/EtOAc = 99/1−50/1), B
(CH2Cl2/EtOAc = 80/1−35/1−10/1): diastereomeric mixture of 1i;
yellow solid (47.5 mg, 87% yield); 1H NMR (500 MHz, CDCl3) δ 2.73−
2.88 (m, 6H), 5.02−5.05 (m, 2H), 5.07 (dd, J = 17.2, 1.7 Hz, 2H), 5.24
(t, J = 6.9 Hz, 2H), 5.73 (ddt, J = 17.2, 10.1, 6.9 Hz, 2H), 6.39 (d, J = 3.4
Hz, 2H), 7.25 (d, J = 3.4 Hz, 2H), 7.38 (s, 4H), 7.54 (t, J = 8.3 Hz, 4H),
7.64 (tt, J = 7.5, 1.1 Hz, 2H), 7.84 (dd, J = 8.3, 1.1 Hz, 4H); 13C NMR
(125 MHz, CDCl3) δ 41.2, 66.7, 84.3, 93.6, 109.0, 115.0, 118.2, 122.8,
126.8, 129.6, 131.1, 133.7, 134.3, 138.8, 139.3; HRMS (ESI) calcd for
C38H32N2NaO6S2 (M+ + Na) 699.1594, found 699.1585.
1,1′,1″-(3,3′,3″-(Benzene-1,3,5-triyltris(ethyne-2,1-diyl))tris(1-
(phenylsulfonyl)-1H-pyrrole-3,2-diyl))tris(but-3-en-1-ol) (1j). General
procedure A (3a, 1,3,5-triethynylbenzene 4g, first: CHCl3 to CHCl3/
EtOAc = 100/1, second: CHCl3, third: CH2Cl2 to CH2Cl2/EtOAc =
100/1), B (CH2Cl2/EtOAc = 20/1): diastereomeric mixture of 1j; beige
solid (130 mg, 69% yield); 1H NMR (500 MHz, CDCl3) δ 2.72−2.86
(m, 9H), 5.00−5.04 (m, 3H), 5.06 (dq, J = 17.2, 1.7 Hz, 3H), 5.23 (q, J =
6.6 Hz, 3H), 5.71 (ddt, J = 17.2, 10.3, 7.2 Hz, 3H), 6.38 (d, J = 3.4 Hz,
3H), 7.25 (d, J = 3.5 Hz, 3H), 7.42 (s, 3H), 7.53 (tt, J = 7.4, 1.7 Hz, 6H),
7.64 (tt, J = 7.4, 1.1 Hz, 3H), 7.81−7.85 (m, 6H); 13C NMR (125 MHz,
CDCl3) δ 41.2, 66.7, 83.9, 92.1, 108.7, 115.0, 118.2, 122.9, 123.9, 126.8,
129.6, 133.2, 133.6, 134.3, 138.8, 139.6; HRMS (ESI) calcd for
C54H45N3NaO9S3 (M+ + Na) 998.2210, found 998.2228.
1-(Phenylsulfonyl)-4-(1-(thiophene-2-yl)vinyl)-1H-indole (2b).
1
General procedure E: dark blue-green oil (36.1 mg, 98% yield); H
NMR (500 MHz, CDCl3) δ 5.20 (s, 1H), 5.75 (d, J = 0.5 Hz, 1H), 6.49
(dd, J = 3.7, 0.8 Hz, 1H), 6.69 (dd, J = 3.7, 1.1 Hz, 1H), 6.89 (dd, J = 5.2,
3.7 Hz, 1H), 7.20 (dd, J = 5.1, 1.1 Hz, 1H), 7.25 (dd, J = 7.5, 1.1 Hz, 1H),
7.32 (t, J = 7.4 Hz, 1H), 7.43−7.48 (m, 2H), 7.51 (d, J = 3.7 Hz, 1H),
7.55 (tt, J = 7.4, 1.5 Hz, 1H), 7.88−7.92 (m, 2H), 7.99 (dt, J = 8.3, 0.8
Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 108.7, 113.1, 114.8, 123.7,
124.5, 125.1, 126.0, 126.5, 126.8, 127.3, 129.3, 129.6, 133.8, 134.4, 134.9,
138.2, 141.1, 144.5; HRMS (ESI) calcd for C20H15NNaO2S2 (M+ + Na)
388.0436, found 388.0430.
4-(3-(Benzyloxy)prop-1-en-2-yl)-1-(phenylsulfonyl)-1H-indole
(2c). General procedure E (first: hexane/EtOAc = 3/1, second: toluene):
yellowish-brown oil (26.1 mg, 74% yield); 1H NMR (500 MHz, CDCl3)
δ 4.36 (t, J = 1.2 Hz, 2H), 4.55 (s, 2H), 5.40−5.42 (m, 1H), 5.60 (q, J =
1.4 Hz, 1H), 6.81 (dd, J = 3.8, 0.9 Hz, 1H), 7.17 (dd, J = 7.7, 0.9 Hz, 1H),
7.24−7.32 (m, 6H), 7.44 (tt, J = 8.0, 1.5 Hz, 2H), 7.54 (tt, J = 7.5, 1.1 Hz,
1H), 7.58 (d, J = 3.8 Hz, 1H), 7.88−7.91 (m, 2H), 7.93 (dt, J = 8.3, 0.9
Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 72.3, 72.6, 108.6, 112.8, 116.9,
122.0, 124.6, 126.3, 126.9, 127.7, 127.8, 128.5, 129.1, 129.4, 133.6, 134.0,
135.2, 138.1, 138.3, 143.7; HRMS (ESI) calcd for C24H20NO3S (M− − H)
402.1169, found 402.1180.
6-Methyl-1-(phenylsulfonyl)-4-(1-phenylvinyl)-1H-indole (2d).
General procedure E: pale green solid; mixture of 2d (31.4 mg, 85%
yield) and 2a (0.81 mg, 2% yield). The byproduct 2a which was assigned
by 1H NMR might be derived from trace of impurity with 1d (see the
Supporting Information): 1H NMR (400 MHz, CDCl3) δ 2.47 (s, 3H),
5.37 (d, J = 1.4 Hz, 1H), 5.66 (d, J = 1.4 Hz, 1H), 6.21 (d, J = 3.9 Hz,
1H), 7.03 (s, 1H), 7.23−7.30 (m, 5H), 7.37 (d, J = 3.6 Hz, 1H), 7.44 (t,
J = 8.0 Hz, 2H), 7.54 (tt, J = 7.6, 1.8 Hz, 1H), 7.79 (s, 1H), 7.85−7.90
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 21.9, 108.8, 113.0, 115.9,
125.2, 125.5, 126.8, 127.4, 127.5, 127.8, 128.2, 129.2, 133.7, 134.65,
134.74, 135.3, 138.4, 141.1, 148.0; HRMS (ESI) calcd for C23H19NNaO2S
(M+ + Na) 396.1029, found 396.1028.
4-(5-Chloropent-1-en-2-yl)-6-methyl-1-(phenylsulfonyl)-1H-in-
dole (2e). General procedure E: yellowish-brown oil; mixture of 2e
(29.9 mg, 82% yield) and 4-(5-chloropent-1-en-2-yl)-1-(phenyl-
sulfonyl)-1H-indole (0.98 mg, 3% yield). The byproduct which was
assigned by 1H NMR might be derived from trace of impurity with 1e
(see the Supporting Information); 1H NMR (500 MHz, CDCl3) δ 1.81
(quint, J = 7.1 Hz, 2H), 2.46 (s, 3H), 2.66 (t, J = 7.1 Hz, 2H), 3.49 (t,
J = 6.6 Hz, 2H), 5.17 (d, J = 1.7 Hz, 1H), 5.29 (d, J = 1.7 Hz, 1H), 6.71
3467
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Note
(dd, J = 3.7, 0.6 Hz, 1H), 6.94 (s, 1H), 7.45 (t, J = 8.0 Hz, 2H), 7.50 (d,
J = 3.7 Hz, 1H), 7.54 (tt, J = 7.8, 1.1 Hz, 1H), 7.73 (s, 1H), 7.89 (dd, J =
8.3, 1.5 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 21.9, 30.7, 33.9, 44.4,
108.3, 112.5, 115.8, 123.1, 125.5, 126.6, 126.8, 129.3, 133.8, 134.6, 135.0,
135.4, 138.3, 145.9; HRMS (ESI) calcd for C20H20ClNNaO2S (M+ +
Na) 396.0795, found 396.0793.
Methyl 4-(1-(4-Ethoxyphenyl)vinyl)-1-(phenylsulfonyl)-1H-indole-
6-carboxylate (2f). General procedure E (CH2Cl2): mixture of 1f and
its positional isomer (1/0.014) (1f: 71.4 mg, 0.149 mmol, dr = 0.65/
0.35) was used; pale yellow solid (45.9 mg, 67% yield); mp 141−144 °C;
1H NMR (500 MHz, CDCl3) δ 1.40 (t, J = 6.9 Hz, 3H), 3.95 (s, 3H),
4.02 (q, J = 6.9 Hz, 2H), 5.31 (d, J = 1.2 Hz, 1H), 5.64 (d, J = 1.2 Hz,
1H), 6.29 (dd, J = 3.7, 0.8 Hz, 1H), 6.79 (dt, J = 8.6, 2.0 Hz, 2H), 7.15
(dt, J = 8.9, 2.3 Hz, 2H), 7.47 (t, J = 8.3 Hz, 2H), 7.54−7.59 (m, 2H),
7.91−7.94 (m, 3H), 8.67 (t, J = 1.1 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 14.8, 52.3, 63.4, 108.9, 114.2, 114.4, 115.0, 124.8, 126.6, 126.9,
128.57, 128.59, 129.4, 132.9, 133.3, 134.1, 134.4, 135.5, 138.0, 146.7,
158.9, 167.2; HRMS (ESI) calcd for C26H23NNaO5S (M+ + Na)
484.1189, found 484.1188.
CDCl3) δ 5.30 (d, J = 1.5 Hz, 1H), 5.61 (d, J = 1.4 Hz, 1H), 6.29 (d, J =
3.7 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.18−7.29
(m, 5H), 7.32 (d, J = 3.7 Hz, 1H), 7.46 (tt, J = 7.4, 1.7 Hz, 2H), 7.56 (tt,
J = 7.5, 1.2 Hz, 1H), 7.78−7.82 (m, 2H), 8.75 (s, 1H); 13C NMR (125
MHz, CDCl3) δ 111.7, 113.6, 115.3, 122.8, 126.7, 126.9, 127.2, 127.4,
127.5, 127.8, 128.2, 129.5, 133.2, 134.1, 137.0, 141.4, 144.1, 147.6;
HRMS (ESI) calcd for C22H16NO3S (M− − H) 374.0856, found
374.0865.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
General and additional information about materials and H
NMR and 13C NMR spectra of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: kyoshida@faculty.chiba-u.jp, ayanagi@faculty.chiba-u.jp.
■
7-Methyl-1-(phenylsulfonyl)-4-(1-phenylvinyl)-1H-indole (2g).
1
Notes
General procedure E: blue-green oil (25.3 mg, 97% yield); H NMR
(500 MHz, CDCl3) δ 2.54 (s, 3H), 5.37 (d, J = 1.4 Hz, 1H), 5.72 (d, J =
1.1 Hz, 1H), 6.34 (d, J = 4.0 Hz, 1H), 7.02 (d, J = 7.5 Hz, 1H), 7.09 (d,
J = 7.4 Hz, 1H), 7.23−7.30 (m, 5H), 7.42−7.47 (m, 2H), 7.56 (tt, J = 7.4,
1.1 Hz, 1H), 7.64 (d, J = 3.7 Hz, 1H), 7.67 (dd, J = 8.6, 1.1 Hz, 2H); 13C
NMR (125 MHz, CDCl3) δ 21.7, 108.8, 115.8, 124.4, 124.6, 126.4,
127.4, 127.8, 128.1, 128.3, 129.2, 129.4, 131.8, 133.0, 133.5, 134.9, 139.8,
141.1, 147.8; HRMS (ESI) calcd for C23H20NO2S (M+ + H) 374.1209,
found 374.1208.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We appreciate financial support in the form of a Grant-in-Aid for
Scientific Research (KIBAN C-22550029) from the Ministry of
Education, Culture, Sports, Science and Technology, Japan. We
also gratefully acknowledge financial support from the Iodine
Research Project at Chiba University headed by Professor Hideo
Togo.
1,4-Bis(1-(1-(phenylsulfonyl)-1H-indol-4-yl)vinyl)benzene (2i).
General procedure E (first: hexane/EtOAc = 2/1, second: CH2Cl2/
EtOAc = 100/1): 6 (15 mol %) was used; pale yellow-green solid
(22.1 mg, 94% yield); mp 219−222 °C; 1H NMR (500 MHz, CDCl3) δ
5.39 (d, J = 1.1 Hz, 2H), 5.72 (d, J = 1.1 Hz, 2H), 6.31 (dd, J = 3.7, 0.6
Hz, 2H), 7.18 (s, 4H), 7.19 (dd, J = 7.8, 0.9 Hz, 2H), 7.31 (t, J = 8.3 Hz,
2H), 7.46 (t, J = 7.5 Hz, 4H), 7.47 (d, J = 3.7 Hz, 2H), 7.55 (tt, J = 7.4,
1.2 Hz, 2H), 7.88−7.92 (m, 4H), 7.97 (d, J = 8.3 Hz, 2H); 13C NMR
(125 MHz, CDCl3) δ 108.8, 112.9, 116.2, 123.9, 124.5, 125.8, 126.8,
127.4, 129.3, 129.6, 133.9, 134.8, 135.0, 138.2, 140.4, 147.4; HRMS
(ESI) calcd for C38H28N2NaO4S2 (M+ + Na) 663.1383, found 663.1378.
1,3,5-Tris(1-(1-(phenylsulfonyl)-1H-indol-4-yl)vinyl)benzene (2j).
General procedure E: 6 (15 mol %) was used; pale brown solid (29.5 mg,
78% yield); mp 101−104 °C; 1H NMR (400 MHz, CDCl3) δ 5.30 (d,
J = 0.9 Hz, 3H), 5.39 (d, J = 0.9 Hz, 3H), 6.23 (dd, J = 3.6, 0.7 Hz, 3H),
7.05 (s, 3H), 7.10 (dd, J = 7.5, 0.7 Hz, 3H), 7.21 (t, J = 8.2 Hz, 3H), 7.40
(t, J = 8.2 Hz, 6H), 7.47 (d, J = 3.8 Hz, 3H), 7.51 (tt, J = 7.3, 1.2 Hz, 3H),
7.84−7.88 (m, 6H), 7.92 (d, J = 8.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 109.0, 113.0, 116.5, 123.9, 124.5, 125.8, 126.5, 126.7, 129.27,
129.33, 133.8, 134.6, 135.0, 138.2, 141.4, 147.6; HRMS (APCI) calcd for
C54H40N3O6S3 (M+ + H) 922.2074, found 922.2083.
4-(1-Phenylvinyl)-9-tosyl-9H-carbazole (2k). General procedure E:
yellow gum (35.3 mg, 99% yield); 1H NMR (500 MHz, CDCl3) δ 2.28
(s, 3H), 5.37 (d, J = 0.8 Hz, 1H), 6.02 (d, J = 0.8 Hz, 1H), 7.06−7.11 (m,
1H), 7.11 (d, J = 8.0 Hz, 2H), 7.19−7.23 (m, 4H), 7.26−7.30 (m, 2H),
7.36 (ddd, J = 8.6, 7.2, 1.4 Hz, 1H), 7.49 (dd, J = 8.3, 7.4 Hz, 1H), 7.69−
7.74 (m, 3H), 8.31 (d, J = 8.6 Hz, 1H), 8.38 (dd, J = 8.3, 0.6 Hz, 1H); 13C
NMR (125 MHz, CDCl3) δ 21.5, 114.1, 114.7, 115.4, 122.9, 123.5,
124.1, 125.8, 125.9, 126.3, 126.5, 126.9, 128.0, 128.5, 129.6, 135.0, 136.7,
138.5, 138.6, 139.0, 144.8, 147.4; HRMS (ESI) calcd for C27H22NO2S
(M+ + H) 424.1366, found 424.1360.
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