Aromatic enamide/ene metathesis toward substituted indoles and its application to the synthesis of indomethacins

Article abstract of DOI:10.1002/ejoc.200900520

A. steric and electronic effect: on enamide/ene metathesis, a novel preparation of 2-substituted indoles and 3-substituted indoles using enamide-ene metathesis as a key reaction, and its application to the synthesis of indoniethacin are described. Wiley-VCH Verlag GmbH & Co. KGaA.

Full text of DOI:10.1002/ejoc.200900520

FULL PAPER
DOI: 10.1002/ejoc.200900520
Aromatic Enamide/Ene Metathesis toward Substituted Indoles and Its
Application to the Synthesis of Indomethacins
Yayoi Kasaya,[a] Kosuke Hoshi,[a] Yukiyoshi Terada,[b] Atsushi Nishida,[b] Satoshi Shuto,*[a]
and Mitsuhiro Arisawa*[a,b]
Keywords: Heterocycles / Metathesis / Isomerization / Cyclization / Ruthenium / NSAID
A steric and electronic effect on enamide/ene metathesis, a
novel preparation of 2-substituted indoles and 3-substituted
indoles using enamide-ene metathesis as a key reaction, and
its application to the synthesis of indomethacin are de-
scribed.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
methods for preparing 4-siloxy-1,2-dihydroquinolines and
indoles, which are key compounds for the synthesis of bio-
logically active natural products and important pharmaceu-
ticals.
Introduction
Over the past 10 years, diene and enyne metathesis, such
as ring-closing metathesis (RCM), ring-opening metathesis
(ROM), and cross metathesis (CM) have been major tools
for the synthesis of complex molecules.[1] The product of
widely used diene metathesis is an olefin, which can be fur-
ther modified but only to a limited extent. Since the regiose-
lective transformation of the newly formed double bond is
generally difficult, the resulting olefin moiety usually either
remains in the final product without modification or un-
dergoes only simple chemical transformations in which re-
gioselectivity is not required (e.g. epoxidation, hydrogena-
tion, and dihydroxylation).
On the other hand, carbon–carbon double bonds substi-
tuted by a heteroatom, such as Si, O, N, P, S, B, or a halo-
gen, offer vast functionalization possibilities, and regiose-
lectivity in the transformation is no longer a problem.
Therefore, the metathesis of heteroatom-substituted ole-
fins, where the newly formed double bond can undergo ver-
satile chemical transformations, is a valuable process in or-
ganic synthesis.[2] We have been exploring a method for the
synthesis of N-containing heterocycles using RCM and
then applying them to the synthesis of biologically active
natural products.[3] In the course of our research, we have
reported several novel examples of heteroatom-substituted
olefin metathesis such as silyl enol ether/ene metathesis[3a]
and aromatic enamide/ene metathesis.[3b] These led to novel
Indole is a prominent and privileged structure widely
found in naturally occurring substances and biologically
active molecules of pharmaceutical importance.[4,5] Progress
in indole chemistry depends on efficient synthetic routes to
indole derivatives with various substitution patterns.[5] Al-
though many methodologies have been developed, the syn-
thesis of 2,3-disubstituted indoles with a substituent at a
desired position remains challenging. We previously devel-
oped an aromatic enamide/ene metathesis induced synthesis
of substituted indoles without a substituent at the 2- and/
or 3-positions on the indole ring.[3b,3d] However, enamide/
ene metathesis is in the middle of development,[3b,3f,6] and
has recently been highlighted.[7] An isomerization/RCM-
based strategy[8] and RCM/isomerization[9] have also been
reported. Therefore, we decided to explore our enamide/ene
metathesis in much more detail and establish a flexible
method for the synthesis of 2,3-disubstituted indoles with a
variety of substituents under mild conditions. In this article,
we report a novel method for preparing 2,3-disubstituted
indoles, including 2-substituted indoles and 3-substituted
indoles using enamide/ene metathesis as a key reaction, and
its application to the synthesis of indomethacin, a non-
steroid anti-inflammatory drug (NSAID), and its deriva-
tive. We also describe steric and electronic effects in
enamide/ene metathesis.
[a] Faculty of Pharmaceutical Sciences, Hokkaido University,
Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812, Japan
Fax: +81-11-706-3769
Results and Discussion
E-mail: arisawa@pharm.hokudai.ac.jp
Our one-pot method for preparing substituted indoles
consists of two reactions: the selective isomerization of an
N-allyl-amide to the corresponding aromatic enamide and
subsequent aromatic enamide/ene metathesis.
Shu@pharm.hokudai.ac.jp
[b] Graduate School of Pharmaceutical Sciences, Chiba University,
Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900520.
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Aromatic Enamide/Ene Metathesis toward Substituted Indoles
Before we investigated a novel synthetic method for pre- ing RCM products in higher yields (Table 1, Entries 3 and
paring 2,3-disubstituted indoles, we examined the prepara- 4) compared to the substrates with an electron-withdrawing
tion of 2- or 3-monosubstituted indoles by our indole syn- sulfonyl substituent (Table 1, Entries 1 and 2). To confirm
thesis procedure. We refluxed the 2nd-generation Grubbs these suppositions, we prepared the acetyl and trifluoroace-
catalyst (A, 5 mol-%) and enamide 2a, N-(but-2-en-2-yl)- tyl substrates 1f and 1g and subjected them to the same
N-(tolylsulfonyl)-2-vinylaniline (which was prepared in the one-pot reaction. As expected, we converted these into the
same flask by the RuH(CO)Cl(PPh3)3-induced[3f] isomeriza- desired cyclized products, 3f and 3g, in yields of 83% and
tion of 1a and subsequent concentration in 76% yield) in 21%, respectively (Table 1, Entries 5 and 6). Thus, it be-
toluene for 1 h, and obtained the corresponding 2-methylind- came clear that there is an electronic effect on aromatic en-
ole derivative 3a in 90% yield (Scheme 1), which was com- amide/ene metathesis. For the preparation of 3-substituted
parable to a simple indole synthesis.[3b] On the other hand, indole derivatives, an N substituent is very important, and
the selective isomerization of N-allyl-2-isopropenyl-N-(tol- acetyl gave the best results among all of the protecting
ylsulfonyl)aniline (1b) to give 2b proceeded quantitatively. groups we examined.
However, the subsequent aromatic enamide/ene metathesis
to form the 3-methylindole derivative 3b did not proceed at
all. In this reaction, we isolated the corresponding enamide
intermediate 2b in 59% yield instead (Table 1, Entry 1). If
we consider the reactivity of monosubstituted terminal ole-
fins, it is reasonable that the enamide/ene metathesis be-
tween a 1-monosubstituted olefin and a 1,1,2-trisubstituted
olefin to form a 2-substituted indole derivative such as 3a
proceeded much better than that of a 1,1-disubstituted ole-
fin and a 1,2-disubstituted olefin to form a 3-substituted
indole derivative like 3b. Based on these results, since we
sought to establish a method for preparing 3-substituted
indole derivatives by our indole synthesis procedure, we
Scheme 1. Synthesis of 2-methylindole.
Based on these results and with the goal of establishing
continued experiments by changing the N substituent and a novel method for the synthesis of 2,3-disubstituted in-
prepared N-substituted 2-isopropenylaniline derivatives 1c– doles with a variety of substituents on the benzene moiety
g. The same one-pot reaction of the less hindered N-(meth- (positions 4–7), we next designed a stepwise method, in
ylsulfonyl) substrate 1c gave the cyclized product 3c and which we introduced a substituent at position 3 by alkyl-
the intermediate 2c in yields of 13% and 78%, respectively ation of a 2-substituted indole, which would be prepared by
(Table 1, Entry 2). We converted the N-(tert-butoxycar- our indole synthesis procedure. Thus, we found that Bach’s
bonyl) substrate 1d and the methoxycarbonyl substrate 1e method is useful for the 3-alkylation of 2-substituted in-
into the cyclized products 3d and 3e in yields of 23% and doles by treating the zinc salt of the indole with a primary
64%, respectively (Table 1, Entries 3 and 4). These results alkyl halide.[10] When we stirred 2-methylindole (4a) and
suggest that there is a steric effect on the aromatic enamide/ ICH2CO2Bn at 0 °C to r.t. for 22 h in the presence of nBuLi
ene metathesis; a bulky N substituent on the substrate may and ZnCl2 in THF, we isolated the desired 2,3-disubstituted
suppress the cyclization. These results also seem to indicate product 5a in 81% yield (Scheme 2). Therefore, 2,3-disub-
the existence of an electronic effect on this reaction, since stituted indoles can be prepared by this stepwise method, a
substrates with a less electron-withdrawing alkoxycarbonyl combination of aromatic enamide/ene metathesis to form 2-
substituent on the aromatic amine formed the correspond- substituted indoles and subsequent 3-alkylation.
Table 1. Synthesis of 3-methylindole.
Entry
Substrate
Protecting group (Pg)
Yield [%, 2 steps][a]
1
2
3
1
2
3
4
5
6
b
c
d
e
f
pTs
Ms
Boc
MeOCO
Ac
CF3CO
59
78
62
23
11
44
0
13
23
64
83
21
g
[a] Isolated yields.
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FULL PAPER
tions of indomethacin in complexes with cyclooxygenase-1
(COX-1) and COX-2 are the s-trans[11] and s-cis forms,[12]
respectively (Figure 1), the introduction of substituents at
the 2- or 7-position of indomethacin may restrict its confor-
mation in the s-trans or s-cis form due to steric repulsion
of the substituent at the 2- or 7-position relative to the N-
acyl side chain. These conformationally restricted ana-
logues may be selectively active toward COX-1 or COX-2.
Thus, we set out to synthesize these indomethacin ana-
logues, which could not be prepared previously, because
methods for preparing substituted indomethacins has been
limited for these purposes.[13] Before such a medicinal chem-
ical study, we applied our method for preparing 2,3-disub-
stituted indoles to the synthesis of indomethacin (6). The
removal of the p-tolylsulfonyl group on the N atom of 3l,
the 3-alkylation of 4l, the N-acylation of 5l, and the deben-
zylation by using Pd/C led to 6 in 51% yield (4 steps,
Scheme 3). This new method can be applied to the synthesis
of a variety of indomethacin derivatives. One synthetic ex-
ample was shown in Scheme 3.
Scheme 2. 3-Alkylation of 2-methylindole.
We next sought to confirm that a variety of 2-substituted
indoles could be prepared by our method. Thus, we pre-
pared N-(alk-2-en-2-yl)-N-(tolylsulfonyl)-2-vinylanilines 1i
and 1j with a substituent at the allylic carbon atom and
subjected them to our two-step reaction (Table 2, Entries 1–
4). The results show that the 2-substituent of the resulting
indole had an effect on the reaction. We obtained the 2-
ethyl and -phenyl derivatives 3i and 3j from 1i and 1j in
yields of 91% and 84%, respectively.
We next examined a substituent effect on the benzene
ring in the resulting indole with the substrates 1k–1n, and
the results are shown in Table 2, Entries 5–8. The reactions
of 1k–1n, under the optimized conditions, gave the corre-
sponding enamides quantitatively. However, substitution at
the 3-position of the substrate 1k prevented cyclization to
give the corresponding indole (Table 2, Entry 2), probably
due to steric hindrance or chelation in the transition state.
We transformed other substrates, including the 4-methoxy
substrate 1l, the 5-methoxy substrate 1m, and the 6-meth-
oxy substrate 1n, into the corresponding indoles (i.e. the
RCM product) in good to excellent yields. Based on our
previous results,[3f] various 2-substituted indoles with a sub-
stituent on the aromatic ring, such as methyl or halogen,
can be prepared by this method.
Indomethacin (6) is a clinically useful non-steroid anti-
inflammatory drug (NSAID) with an indole structure. Al-
though it has been reported that the bioactive conforma- Figure 1. Bioactive conformations of indomethacin (6).
Table 2. Scope and limitations of the two-step preparation of substituted indoles.
Entry
Substrate
R
Yield [%, 2 steps][a]
1
RЈ
3
1
2
3
4
5
6
7
8
a
h
i
Me
H
Et
Ph
Me
Me
Me
Me
H
H
H
68[b]
94[c]
91
j
H
84
k
l
m
n
3-MeO
4-MeO
5-MeO
6-MeO
11 (55)[d]
73
98
92
[a] Isolated yields. [b] The same data is seen in Scheme 1. [c] Ref.[3c,3d] [d] 20 mol-% of A was used; 80% of 1k was recovered. The yield
in parentheses indicates the yield based on the recovered starting material.
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Eur. J. Org. Chem. 2009, 4606–4613

Aromatic Enamide/Ene Metathesis toward Substituted Indoles
132.82, 131.95, 131.90, 130.61, 29.39, 129.20, 129.10, 128.71,
128.84, 128.35, 128.00, 127.85, 127.80, 127.65, 127.48, 127.39,
125.96, 125.86, 124.88, 116.89, 116.47, 115.67, 115.19, 58.40, 58.32,
54.10, 21.51, 18.80, 18.69, 17.54 ppm. IR (neat): ν = 2980, 1598,
˜
1342, 1162 cm–1. LRMS (EI): m/z (%) = 172 (100), 327 (35) [M]+.
HRMS (FAB): calcd. for C19H22NO2S [M+ + H]+ 328.1371, found
328.1385.
1i: 95% yield from 2-ethenyl-N-(p-tolylsulfonyl)aniline[3e] and 1-
penten-3-ol as an inseparable mixture of 1i and 2-ethenyl-N-(pent-
2-en-1-yl)-N-(p-tolylsulfonyl)aniline (7:3); colorless oil. 1H NMR
(400 MHz, CDCl3): δ = 7.69 (dd, J = 1.4, 7.8 Hz, 0.5 H, aromatic),
7.63–7.67 (m, 0.5 H, aromatic), 7.59 (d, J = 8.2 Hz, 1 H, aromatic),
7.56 (d, J = 8.7 Hz, 1 H, aromatic), 7.09–7.34 (m, 4 H, aromatic),
7.06 (dd, J = 10.9, 17.8 Hz, 0.6 H, Ar-CH), 6.91 (dd, J = 10.9,
17.9 Hz, 0.4 H, Ar-CH), 6.63–6.67 (m, 1 H, aromatic), 5.74 (dd, J
= 0.9, 18.0 Hz, 0.6 H, Ar-CH=CH2), 5.64 (dd, J = 0.9, 17.8 Hz,
0.4 H, Ar-CH=CH2), 5.26–5.42 (m, 2 H, Ar-CH=CH2, NCHCH),
5.05–5.21 (m, 2 H, NCHCH=CH2), 4.52–4.28 (m, 0.6 H, NCH),
4.46–4.52 (m, 0.4 H, NCH), 2.40–2.42 (m, 3 H, pTs 4-CH3), 1.70–
1.80 (m, 0.6 H, NCHCH2), 1.56–1.66 (m, 0.4 H, NCHCH2), 1.31–
1.43 (m, 0.4 H, NCHCH2), 1.07–1.19 (m, 0.6 H, NCHCH2), 0.75–
0.82 (m, 3 H, CHCH3) ppm. 13C NMR (500 MHz, CDCl3): δ =
143.29, 143.03, 140.39, 139.70, 138.72, 138.25, 137.79, 137.42,
136.67, 136.36, 135.79, 135.45, 134.17, 133.77, 133.65, 132.90,
132.15, 132.05, 129.37, 129.30, 129.11, 129.01, 128.81, 128.73,
128.31, 128.14, 127.80, 127.77, 127.52, 127.28, 125.91, 125.84,
125.79, 122.56, 118.95, 118.57, 115.39, 114.86, 65.90, 65.58, 54.12,
26.34, 26.26, 25.00, 21.46, 13.00, 11.01, 10.94 ppm. LRMS (EI):
m/z (%) = 341 [M]+. HR-MS (EI): calcd. for C20H23NO2S
341.1449, found 341.1447 [M]+.
Scheme 3. Novel method for the synthesis of indomethacin (6) and
derivative 7.
Conclusions
We found that steric hindrance and an electron-with-
drawing effect influence aromatic enamide/ene metathesis
and developed a novel method for preparing 2-substituted
indoles and 3-substituted indoles, using enamide/ene me-
tathesis as a key reaction, which led to a novel synthetic
method of preparing substituted indomethacin derivatives.
1j: 66% yield from 2-ethenyl-N-(p-tolylsulfonyl)aniline[3e] and 1-
phenyl-2-propenol as an inseparable mixture of 1j and 2-ethenyl-
N-(3-phenylprop-2-en-1-yl)-N-(p-tolylsulfonyl)aniline (7:3); color-
Experimental Section
General: 1H NMR spectra were recorded in CDCl3 at 25 °C, unless
otherwise noted, at 400 or 500 MHz, with TMS as an internal stan-
dard. 13C NMR spectra were recorded in CDCl3 at 25 °C, unless
otherwise noted, at 400 or 500 MHz. Flash column chromatog-
raphy was performed with silica gel 60 (spherical, neutral, 40–
50 µm, Kanto Chemical Co., Inc.). A and RuH(CO)Cl(PPh3)3 were
obtained commercially. Compounds 1f,[3d] 1h,[3b] and 3h[3b] were
prepared according to reported procedures.
1
less oil. H NMR (400 MHz, [D6]DMSO): δ = 7.60–7.66 (m, 2 H,
aromatic), 7.19–7.49 (m, 9 H, aromatic), 6.98–7.03 (m, 2 H, aro-
matic, Ar-CH=CH2), 6.81 (d, J = 6.8 Hz, 1 H, aromatic), 6.16–
6.26 (m, 1 H, Ar-CH=CH2), 6.00–6.09 (m, 1 H, NCHCH), 5.78–
5.91 (m,
1 H, NCH), 5.26–5.45 (m, 2 H, Ar-CH=CH2,
NCHCH=CH2), 5.12–5.16 (m, 1 H, NCHCH=CH2), 2.42–2.45 (m,
3 H, pTs 4-CH3) ppm. 13C NMR (400 MHz, CDCl3): δ = 143.20,
143.05, 140.78, 136.86, 138.97, 137.75, 137.69, 137.61, 135.41,
134.88, 134.43, 133.69, 133.48, 133.04, 132.10, 131.93. 129.22,
129.08, 128.95, 128.88, 128.82, 128.19, 128.14, 128.00, 127.95,
127.85, 127.79, 127.32, 127.29, 125.72, 125.64, 118.88, 118.13,
115.24, 114.39, 67.43, 66.58, 21.54, 21.48 ppm. LRMS (EI): m/z =
389 [M]+. HR-MS (EI): calcd. for C24H23NO2S 389.1449, found
389.1448 [M]+.
General Procedure for the Preparation of Dienes 1a,i–n
1a: To
a
solution of 2-ethenyl-N-(p-tolylsulfonyl)aniline[3e]
(1.00 mmol, 273 mg), 3-buten-2-ol (1.00 mmol, 79.3 mg), and tri-
phenylphosphane (1.10 mmol, 289 mg) in THF (1.0 mL) was added
dropwise
a solution of diethyl azodicarboxylate (1.10 mmol,
0.17 mL) in THF (5.0 mL), and the mixture was stirred at r.t. for
2.5 h. After the solvent was removed, the residue was subjected to
column chromatography (hexane/AcOEt, 20:1) to give 1a (242 mg,
1k: 80% yield from 2-ethenyl-3-methoxy-N-(p-tolylsulfonyl)ani-
line[3f] and 1-buten-3-ol as an inseparable mixture of 1k and N-
74%) as a colorless oil. 1H NMR ([D6]DMSO, 150 °C): δ = 7.67 (but-2-en-1-yl)-2-ethenyl-3-methoxy-N-(p-tolylsulfonyl)aniline (4:1);
(d, J = 6.8 Hz, 1 H, aromatic), 7.59 (d, J = 8.2 Hz, 2 H, aromatic),
colorless oil. 1H NMR (500 MHz, [D6]DMSO): δ = 7.67 (d, J =
7.39–7.37 (m, 1 H, aromatic), 7.36 (d, J = 8.4 Hz, 2 H, aromatic), 8.0 Hz, 0.8 H, aromatic), 7.63 (d, J = 8.0 Hz, 1.2 H, aromatic), 7.46
7.23 (dd, J = 7.7, 7.7 Hz, 1 H, aromatic), 7.00–6.83 (m, 2 H, Ar- (d, J = 8.0 Hz, 0.8 H, aromatic), 7.43 (d, J = 8.0 Hz, 1.2 H, aro-
CH=CH2, aromatic), 5.76–5.69 (m, 1 H, NCHCH), 5.69 (d, J = matic), 7.25–7.17 (m, 1 H, aromatic), 7.14 (d, J = 8.6 Hz, 1 H,
17.4 Hz, 1 H, Ar-CH=CH2), 5.22 (d, J = 1.7 Hz, 1 H, Ar-
CH=CH2), 5.03 (d, J = 17.2 Hz, 1 H, NCHCH=CH2), 4.98 (d, J
= 10.4 Hz, 1 H, NCHCH=CH2), 4.77 (dq, J = 6.6, 6.6 Hz, 0.66 H,
NCH), 4.04 (d, J = 6.4 Hz, 0.34 H, NCH), 2.42 (s, 0.51 H, pTs 4-
CH3), 2.41 (s, 2.49 H, pTs 4-CH3), 1.49 (d, J = 5.9 Hz, 0.51 H,
NCHCH3), 1.13 (d, J = 6.7 Hz, 2.49 H, NCHCH3) ppm. 13C NMR
(400 MHz, CDCl3): δ = 143.35, 134.18, 143.14, 140.35, 139.90,
138.66, 138.07, 137.75, 137.68, 137.64, 133.85, 133.63, 133.56,
aromatic), 6.95 (dd, J = 18.0, 12.6 Hz, 0.6 H, Ar-CH), 6.83 (dd, J
= 18.0, 12.6 Hz, 0.4 H, Ar-CH), 6.43 (d, J = 8.0 Hz, 0.4 H, aro-
matic), 6.31 (d, J = 8.0 Hz, 0.6 H, aromatic), 6.15 (dd, J = 18.0,
2.2 Hz, 0.6 H, Ar-CH=CH2), 6.10 (dd, J = 18.0, 2.2 Hz, 0.4 H, Ar-
CH=CH2), 5.66–5.73 (m, 0.4 H, NCHCH), 5.47–5.56 (m, 0.6 H,
NCHCH), 5.49 (dd, J = 12.3, 2.2 Hz, 0.6 H, Ar-CH=CH2), 5.41
(dd, J = 12.3, 2.2 Hz, 0.4 H, Ar-CH=CH2), 4.98–5.08 (m, 2 H,
NCHCH=CH2), 4.81–4.87 (m, 1 H, NCH), 3.89 (s, 1.8 H, OCH3),
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FULL PAPER
3.88 (s, 1.2 H, OCH3), 2.45 (s, 1.8 H, pTs 4-CH3), 2.44 (s, 1.2 H,
pTs 4-CH3), 1.07 (d, J = 6.9 Hz, 1.8 H, NCHCH3), 1.00 (d, J =
H, aromatic), 7.66 (d, J = 8.6 Hz, 0.8 H, aromatic), 7.29–7.17 (m,
4.4 H, aromatic), 7.07 (dd, J = 10.9, 17.8 Hz, 0.6 H, aromatic),
6.9 Hz, 1.8 H, NCHCH3) ppm. 13C NMR (500 MHz, CDCl3): δ = 6.77–6.73 (m, 0.6 H, Ar-CH), 6.70 (dd, J = 2.3, 7.3 Hz, 0.4 H, Ar-
159.21, 159.14, 158.88, 143.22, 143.13, 143.07, 138.45, 138.12,
137.81, 173.71, 136.57, 135.82, 135.57, 130.60, 130.39, 130.34,
129.36, 129.33, 129.11, 128.79, 123.38, 128.15, 127.89, 127.86,
127.79, 127.58, 127.47, 127.27, 126.82, 126.71, 124.92, 124.08,
124.03, 121.32, 120.75, 120.43, 120.22, 116.68, 116.21, 111.61,
111.57, 111.01, 110.95, 58.74, 58.72, 55.52, 55.49, 54.05, 21.49,
18.79, 18.72, 17.54, 13.43 ppm. LRMS (EI): m/z = 357 [M]+. HR-
MS (EI): calcd. for C20H23NO3S 357.1399, found 357.1400 [M]+.
CH), 5.87–5.70 (m, 2 H, NCHCH, Ar-CH=CH2), 5.34 (dd, J =
1.4, 11.2 Hz, 0.4 H, Ar-CH=CH2), 5.26 (dd, J = 1.4, 11.2 Hz, 0.6
H, Ar-CH=CH2), 5.11 (d, J = 17.2 Hz, 0.6 H, NCHCH=CH2),
4.99–4.95 (m, 1 H, NCHCH=CH2), 4.86 (d, J = 10.0 Hz, 0.4 H,
NCHCH=CH2), 4.73–4.60 (m, 1 H, NCH), 3.47 (s, 1.8 H, OCH3),
3.33 (s, 1.2 H, OCH3), 2.42 (s, 1.8 H, pTs 4-CH3), 2.41 (s, 1.2 H,
pTs 4-CH3), 1.17 (d, J = 6.8 Hz, 1.2 H, NCHCH3), 1.08 (d, J =
6.8 Hz, 1.8 H, NCHCH3) ppm. 13C NMR (400 MHz, CDCl3): δ =
158.00, 157.68, 142.41, 142.30, 141.51, 141.17, 139.04, 138.98,
138.97, 134.18, 134.11, 129.23, 128.65, 128.49, 128.02 127.91,
124.00, 123.82, 117.36, 117.31, 115.66, 115.59, 115.47, 114.77,
110.20, 110.16, 60.22, 59.44, 54.55, 54.21, 21.34, 20.91, 18.88,
14.06 ppm. LRMS (EI): m/z = 357 [M]+. C20H23NO3S (357.47):
calcd. C 67.20, H 6.49, N 3.92; found C 67.21, H 6.40, N 3.94.
1l: 100% yield from 2-ethenyl-4-methoxy-N-(p-tolylsulfonyl)ani-
line[3f] and 1-buten-3-ol; colorless oil. 1H NMR (500 MHz, [D6]-
DMSO): δ = 7.64 (d, J = 8.0 Hz, 0.8 H, aromatic), 7.61 (d, J =
8.0 Hz, 1.2 H, aromatic), 7.45 (d, J = 8.0 Hz, 0.8 H, aromatic), 7.43
(d, J = 8.0 Hz, 1.2 H, aromatic), 7.30 (d, J = 2.9 Hz, 0.6 H, aro-
matic), 7.28 (d, J = 2.9 Hz, 0.4 H, aromatic), 7.01 (dd, J = 11.5,
17.8 Hz, 0.6 H, Ar-CH), 6.91–6.82 (m, 1.4 H, Ar-CH, aromatic),
6.72 (d, J = 8.6 Hz, 0.4 H, aromatic), 6.59 (d, J = 9.2 Hz, 0.6 H,
aromatic), 5.92 (d, J = 17.8 Hz, 0.6 H, Ar-CH=CH2), 5.86 (d, J =
11.5 Hz, 0.4 H, Ar-CH=CH2), 5.69–5.62 (m, 0.4 H, NCHCH),
5.58–5.51 (m, 0.6 H, NCHCH), 5.37 (d, J = 11.5 Hz, 0.6 H, Ar-
CH=CH2), 5.29 (d, J = 12.0 Hz, 0.4 H, Ar-CH=CH2), 5.09 (m, 2
H, NCHCH=CH2), 4.90–4.88 (m, 1 H, NCH), 3.82 (s, 3 H, OCH3),
2.45 (s, 1.2 H, pTs 4-CH3), 2.44 (s, 1.8 H, pTs 4-CH3), 1.05 (d, J =
General Procedure for the Isomerization of Terminal Olefins and
Subsequent RCM: To a solution of diene in toluene (0.04 ) was
added Ru(CO)HCl(PPh3)3 (10 mol-%) or 2nd-generation Grubbs
catalyst A (5 mol-%) and trimethyl(vinyloxy)silane (10 mol-%), and
the mixture was refluxed for 1 h. The reaction mixture was cooled,
more A (5 mol-%) was added, and the mixture was refluxed for 1 h.
The residue was subjected to column chromatography to give the
corresponding indole.
6.9 Hz, 1.8 H, NCHCH3), 1.02 (d, J = 6.9 Hz, 1.2 H, NCHCH3) 3a:[14] 68% from 1a; colorless prisms, m.p. 63–64 °C (MeOH),
ppm. 13C NMR (500 MHz, CDCl3): δ = 159.43, 159.40, 143.08, ref.[14] 66–67 °C. 1H NMR (500 MHz, CDCl3): δ = 8.15 (d, J =
143.04, 141.41, 140.95, 138.05, 137.80, 137.75, 137.64, 133.73,
132.93, 132.87, 129.35, 129.16, 127.93, 127.73, 127.57, 126.40,
126.40, 126.23, 116.78, 116.33, 115.44, 115.15, 113.32, 113.22,
110.32, 110.25, 58.22, 58.10, 55.28, 21.46, 18.71, 18.64 ppm. LRMS
(EI): m/z = 357 [M]+. C20H23NO3S (357.47): calcd. C 67.20, H 6.49,
N 3.92; found C 66.91, H 6.42, N 3.99.
8.2 Hz, 1 H, indole), 7.66 (d, J = 8.4 Hz, 2 H, aromatic), 7.40 (d,
J = 7.3 Hz, 1 H), 7.26 (ddd, J = 7.8, 7.8, 1.3 Hz, 1 H, indole), 7.20
(dd, J = 7.3, 1.3 Hz, 1 H, indole), 7.20 (d, J = 8.4 Hz, 2 H, aro-
matic), 6.34 (d, J = 0.9 Hz, 1 H, indole), 2.60 (s, 3 H, pTs 4-CH3),
2.34 (s, 3 H, indole-CH3) ppm. 13C NMR (400 MHz, CDCl3): δ =
144.65, 137.26, 136.91, 136.20, 129.80, 129.60, 126.24, 13.65,
123.33, 119.90, 114.40, 109.51, 21.48, 15.72 ppm. LRMS (EI): m/z
(%)= 130 (100), 285 (96) [M]+.
1m: 85% yield from 2-ethenyl-5-methoxy-N-(p-tolylsulfonyl)ani-
line[3f] and 1-buten-3-ol as an inseparable mixture of 1m and N-
(but-2-en-1-yl)-2-ethenyl-5-methoxy-N-(p-tolylsulfonyl)aniline (6:1);
colorless oil. 1H NMR (500 MHz, [D6]DMSO): δ = 7.76 (d, J =
9.2 Hz, 0.6 H, aromatic), 7.74 (d, J = 8.6 Hz, 0.4 H, aromatic), 7.68
(d, J = 8.0 Hz, 0.8 H, aromatic), 7.65 (d, J = 8.0 Hz, 1.2 H, aro-
matic), 7.47 (d, J = 8.0 Hz, 1.2 H, aromatic), 7.45 (d, J = 8.0 Hz,
0.8 H, aromatic), 7.04 (d, J = 9.2 Hz, 1 H, aromatic), 7.00 (dd, J
= 11.4, 17.8 Hz, 0.6 H, Ar-CH), 6.90 (dd, J = 11.4, 17.4 Hz, 0.4
3f:[15] 83% from 1f; colorless prisms, m.p. 64–65 °C (EtOH), ref.[15]
1
66–67 °C (hexane/AcOEt). H NMR (400 MHz, CDCl3): δ = 8.41
(br., 1 H, indole), 7.49 (d, J = 7.7 Hz, 1 H, indole), 7.27–7.37 (m,
2 H, indole), 7.17 (br., 1 H, indole), 2.59 (s, 3 H, COCH3), 2.28 (d,
J = 1.4 Hz, 3 H, indole-CH3) ppm. 13C NMR (500 MHz, CDCl3):
δ = 168.22, 135.73, 131.32, 125.04, 123.28, 122.13, 118.72, 118.26,
116.48, 23.88, 9.60 ppm. LRMS (EI): m/z = 173 [M]+.
H, Ar-CH), 6.26 (d, J = 2.3 Hz, 0.4 H, aromatic), 6.15 (d, J = 3i: 91% from 1i; colorless needles, m.p. 68–69 °C (EtOH). 1H NMR
2.9 Hz, 0.6 H, aromatic), 5.74 (d, J = 17.8 Hz, 0.6 H, Ar- (500 MHz, CDCl3): δ = 8.17 (d, J = 8.2 Hz, 1 H, indole), 7.62 (d,
CH=CH2), 5.69 (d, J = 17.1 Hz, 0.4 H, Ar-CH=CH2), 5.71–5.64 J = 8.6 Hz, 2 H, aromatic), 7.41 (d, J = 7.2 Hz, 1 H, indole), 7.27–
(m, 0.4 H, NCHCH), 5.61–5.54 (m, 0.6 H, NCHCH), 5.24 (d, J = 7.20 (m, 2 H, indole), 7.18 (d, J = 8.0 Hz, 2 H, aromatic), 6.39 (s,
10.9 Hz, 0.6 H, Ar-CH=CH2), 5.16 (d, J = 12.0 Hz, 0.4 H, Ar- 1 H, indole), 3.02 (q, J = 7.4 Hz, 2 H, indole-CH2), 2.33 (s, 3 H,
CH=CH2), 5.11–5.01 (m, 2 H, NCHCH=CH2), 4.91–4.85 (m, 1 H,
NCHCH=CH2), 3.69 (s, 1.2 H, OCH3), 3.65 (s, 1.8 H, OCH3), 2.46 (400 MHz, CDCl3): δ = 144.58, 143.78, 137.16, 136.18, 129.76,
pTs 4-CH3), 1.34 (t, J = 7.4 Hz, 3 H, CH2CH3) ppm. 13C NMR
(s, 1.2 H, pTs 4-CH3), 2.44 (s, 1.8 H, pTs 4-CH3), 1.07 (d, J =
129.73, 126.19, 123.74, 123.35, 120.04, 114.61, 107.65, 22.29, 21.49,
6.9 Hz, 1.8 H, NCHCH3), 1.04 (d, J = 6.9 Hz, 1.2 H, NCHCH3) 12.86 ppm. LRMS (EI): m/z = 299 [M]+. C17H17NO2S (299.39):
ppm. 13C NMR (400 MHz, CDCl3): δ = 158.59, 158.47, 143.36, calcd. C 68.20, H 5.72, N 4.68; found C 67.96, H 5.74, N 4.66.
143.23, 143.20, 138.01, 137.73, 137.62, 137.60, 134.67, 134.40,
133.03, 132.99, 132.93, 132.44, 132.20, 131.23, 130.71, 129.37,
129.16, 128.02, 127.82, 127.66, 126.61, 126.56, 126.46, 124.86,
117.13, 117.09, 116.96, 116.43, 114.79, 114.77, 114.59, 114.04,
113.25, 112.97, 58.41, 58.34, 55.23, 55.18, 54.08, 21.47, 18.88,
18.60, 17.54 ppm. LRMS (EI): m/z = 357 [M]+. HR-MS (EI): calcd.
for C20H23NO3S 357.1399, found 357.1399 [M]+.
3j:[16] 84% from 1j; colorless solid. 1H NMR (400 MHz, CDCl3): δ
= 8.31 (d, J = 8.2 Hz, 1 H, aromatic), 7.52–7.49 (m, 2 H, aromatic),
7.43–7.42 (m, 4 H, aromatic), 7.38–7.33 (m, 1 H, aromatic), 7.28–
7.25 (m, 3 H, aromatic), 7.04 (d, J = 8.2 Hz, 2 H, aromatic), 6.54
(s, 1 H, aromatic), 2.28 (s, 3 H, pTs 4-CH3) ppm. 13C NMR
(400 MHz, CDCl3): δ = 144.50, 142.10, 138.23, 134.58, 132.38,
130.53, 130.30, 1229.17, 128.63, 127.48, 126.77, 124.76, 124.29,
120.66, 116.64, 113.62, 21.51 ppm. LRMS (EI): m/z = 347 [M]+.
1n: 100% yield from 2-ethenyl-6-methoxy-N-(p-tolylsulfonyl)ani-
line[3f] and 1-buten-3-ol; yellow powder, m.p. 72.5–74.0 °C (hexane/
3k:[17] 11% from 1k, 80% of 1k was recovered; colorless oil. 1H
AcOEt). 1H NMR (400 MHz, CDCl3): δ = 7.69 (d, J = 8.6 Hz, 1.2 NMR (400 MHz, CDCl3): δ = 7.76 (d, J = 8.2 Hz, 1 H, indole),
4610
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4606–4613

Aromatic Enamide/Ene Metathesis toward Substituted Indoles
7.66 (d, J = 8.2 Hz, 2 H, aromatic), 7.15–7.21 (m, 3 H, indole, were extracted with AcOEt, and the combined organic layers were
aromatic), 6.65 (d, J = 7.7 Hz, 1 H, indole), 6.45 (s, 1 H, indole),
washed with HCl (1 ⁿ), saturated aqueous NaHCO3 and brine and
3.88 (s, 3 H, OCH3), 2.58 (s, 3 H, pTs 4-CH3), 2.34 (s, 3 H, indole- dried with Na2SO4. After the solvent was removed, the residue was
CH3) ppm. 13C NMR (400 MHz, CDCl3): δ = 152.07, 144.63,
138.15, 136.27, 135.77, 129.82, 126.30, 124.50, 119.79, 107.60,
106.30, 103.69, 55.36, 21.54, 15.78 ppm. LRMS (EI): m/z = 315
[M]+.
3l: 73% from 1l; colorless prisms, m.p. 80–82 °C (MeOH). 1H
NMR (400 MHz, CDCl3): δ = 8.04 (d, J = 10.4 Hz, 1 H, indole),
7.62 (d, J = 8.2 Hz, 2 H, aromatic), 7.18 (d, J = 8.2 Hz, 2 H, aro-
matic), 6.84–6.87 (m, 2 H, indole), 6.26 (s, 1 H, indole), 3.81 (s, 3
H, OCH3), 2.57 (d, J = 0.9 Hz, 3 H, pTs 4-CH3), 2.33 (s, 3 H,
indole-CH3) ppm. 13C NMR (400 MHz, CDCl3): δ = 156.33,
144.57, 138.05, 136.07, 131.50, 130.64, 29.77, 126.18, 115.28,
112.12, 109.72, 102.61, 55.50, 21.49, 15.75 ppm. LRMS (EI): m/z
= 315 [M]+. C17H17NO3S (315.38): calcd. C 64.74, H 5.43, N 4.44;
found C 64.40, H 5.44, N 4.35.
purified by column chromatography (hexane/AcOEt, 9:1) to give 5a
(134 mg, 81%); yellow solid, m.p. 84.0–85.0 °C (EtOH). H NMR
1
(500 MHz, CDCl3): δ = 7.84 (br., 1 H, NH), 7.52 (d, J = 7.4 Hz, 1
H, indole), 7.29–7.34 (m, 5 H, CH2-Ph), 7.25 (d, J = 7.1 Hz, 1 H,
indole), 7.06–7.13 (m, 2 H, indole), 5.11 (s, 2 H, CH2-Ph), 3.74 (s,
2 H, indole-CH2-CO), 2.38 (s, 3 H, indole-CH3) ppm. 13C NMR
(500 MHz, CDCl3): δ = 171.85, 135.99, 135.03, 132.69, 128.44,
128.40, 128.05, 121.19, 119.50, 118.06, 110.21, 104.35, 66.42, 30.37,
11.66 ppm. HRMS (EI): calcd. for C18H17NO2 [M]+ 279.1259;
found 279.1259. C18H17NO2·0.1H2O: calcd. C 76.90, H 6.17, N
4.98; found C 76.70, H 6.14, N 5.01.
Synthesis of Indomethacin (6)
4l: To a solution of 3l (35 mg, 0.11 mmol) in EtOH (1.0 mL) and
THF (0.1 mL) was added KOH (62 mg, 1.1 mmol), and the mixture
was refluxed for 6 h. The mixture was cooled and partitioned be-
tween HCl (1 ⁿ) and Et2O. The aqueous layers were combined with
saturated aqueous NaHCO3, and the organic compounds were ex-
tracted with AcOEt. The AcOEt layers were washed with brine and
dried with Na2SO4. After the solvent was removed, the residue was
purified by column chromatography (hexane/AcOEt, 24:1) to give
4l (16 mg, 92%); colorless prisms, m.p. 84–85 °C (Et2O/hexane),
1
3m:[17] 98% from 1m; colorless oil. H NMR (500 MHz, CDCl3):
δ = 7.74 (d, J = 1.7 Hz, 1 H, indole H-7), 7.64 (d, J = 8.6 Hz, 2 H,
aromatic), 7.26 (d, J = 8.6 Hz, 1 H, indole H-4), 7.20 (d, J = 8.0 Hz,
2 H, aromatic), 6.79 (dd, J = 8.0, 2.3 Hz, 1 H, indole H-5), 6.25 (s,
1 H, indole H-3), 3.88 (s, 3 H, OCH3), 2.55 (d, J = 1.1 Hz, 3 H,
pTs 4-CH3), 2.34 (s, 3 H, indole-CH3) ppm. 13C NMR (400 MHz,
CDCl3): δ = 157.17, 144.64, 137.91, 136.24, 135.96, 129.82, 126.19,
123.37, 120.24, 112.14, 109.25, 99.30, 55.74, 21.52, 15.75 ppm.
LRMS (EI): m/z = 315 [M]+. C17H17NO3S (315.39): calcd. C 64.74,
H 5.43, N 4.44; found C 64.58, H 5.47, N 4.35.
1
ref.[19] 86–88 °C (Et2O/hexane). H NMR (500 MHz, CDCl3): δ =
7.74 (br., 1 H, NH), 7.16 (d, J = 9.2 Hz, 1 H, indole 7-H), 6.99 (d,
J = 2.3 Hz, 1 H, indole 6-H), 6.76 (dd, J = 8.6, 2.3 Hz, 1 H, indole
5-H), 6.15 (s, 1 H, indole 3-H), 3.84 (s, 3 H, OCH3), 2.42 (s, 3 H,
indole-CH3) ppm. 13C NMR (400 MHz, CDCl3): δ = 153.92,
135.93, 131.06, 129.39, 110.83, 110.52, 101.77, 100.13, 55.79,
13.63 ppm. LRMS (EI): m/z = 161 [M]+.
3n: 92% from 1n; colorless prisms, m.p. 108.0–109.5 °C (MeOH).
1H NMR (400 MHz, CDCl3): δ = 7.70 (d, J = 8.6 Hz, 2 H, aro-
matic), 7.26 (d, J = 8.2 Hz, 2 H, aromatic), 7.10–7.01 (m, 2 H,
indole), 6.63 (d, J = 7.7 Hz, 1 H, indole), 6.37 (d, J = 0.9 Hz, 1 H,
indole H-3), 3.61 (s, 3 H, OCH3), 2.73 (d, J = 0.9 Hz, 3 H, pTs 4-
CH3), 2.39 (s, 3 H, indole-CH3) ppm. 13C NMR (500 MHz,
CDCl3): δ = 147.36, 143.46, 140.58, 138.95, 132.1, 129.20, 126.53,
126.32, 124.14, 112.77, 109.40, 107.22, 55.52, 21.54, 17.14 ppm.
LRMS (EI): m/z = 315 [M]+. C17H17NO3S (315.39): calcd. C 64.74,
H 5.43, N 4.44; found C 64.91, H 5.40, N 4.43.
5l: To a solution of 4l (430 mg, 2.5 mmol) in THF (15.0 mL) was
added dropwise a solution of nBuLi in hexane (1.61  solution,
3.0 mmol, 1.8 mL) at 0 °C. The reaction mixture was stirred at am-
bient temperature for 1 h, and to the mixture was added a solution
of ZnCl2 in Et2O (1.0  solution, 2.5 mmol, 2.5 mL). The mixture
was stirred at r.t. for 30 min. To the mixture, a solution of benzyl
iodoacetate (3.0 mmol, 828 mg) in THF (3.5 mL) was cannulated,
and the mixture was stirred at r.t. for 17 h. The reaction was
quenched with saturated aqueous NH4Cl. The organic compounds
were extracted with AcOEt, and the combined organic layers were
washed with HCl (1 ⁿ), saturated aqueous NaHCO3, and brine and
dried with Na2SO4. After the solvent was removed, the residue was
purified by column chromatography (hexane/AcOEt, 8:1) to give 5l
Preparation of 4a: To a solution of 3a (28 mg, 0.098 mmol) in
EtOH (1.0 mL) was added KOH (56 mg, 1.0 mmol), and the mix-
ture was refluxed for 7 h. The mixture was cooled and partitioned
between HCl (1 ⁿ) and Et2O. The aqueous layers were combined
with saturated aqueous NaHCO3, and the organic compounds
were extracted with AcOEt. The AcOEt layers were washed with
brine and dried with Na2SO4. After the solvent was removed, the
residue was purified by column chromatography (hexane/AcOEt,
24:1) to give 4a (12 mg, 90%); red prisms, m.p. 55–56 °C (EtOH/
H2O), ref.[18] 59–60 °C (EtOH/H2O). 1H NMR (500 MHz, CDCl3):
δ = 7.82 (br., 1 H, NH), 7.51 (d, J = 8.0 Hz, 1 H, indole), 7.27 (d,
J = 8.0 Hz, 1 H, indole), 7.04–7.12 (m, 2 H, indole), 6.21 (d, J =
1.1 Hz, 1 H, indole 3-H), 2.44 (d, J = 1.1 Hz, 3 H, indole) ppm.
13C NMR (400 MHz, CDCl3): δ = 135.81, 135.17, 128.76, 120.68,
119.44, 110.32, 99.94, 13.27 ppm. LRMS (EI): m/z = 131 [M]+.
1
(510 mg, 67%); yellow oil. H NMR (500 MHz, CDCl3): δ = 7.77
(br. s, 1 H, NH), 7.21–7.29 (m, 5 H, CH2-Ph), 7.07 (d, J = 8.6 Hz,
1 H, indole 7-H), 6.95 (d, J = 2.3 Hz, 1 H, indole 4-H), 6.75 (dd,
J = 8.6, 2.3 Hz, 1 H, indole 6-H), 5.10 (s, 2 H, CH2-Ph), 3.76 (s, 3
H, OCH3), 3.69 (s, 2 H, indole-CH2CO), 2.30 (s, 3 H, indole-CH3)
ppm. 13C NMR (400 MHz, CDCl3): δ = 171.87, 154.00, 135.94,
133.55, 130.06, 128.77, 128.43, 128.07, 128.04, 110.99, 110.96,
104.13, 100.18, 66.43, 55.73, 30.48, 11.69 ppm. LRMS (EI): m/z =
309 [M]+. C19H19NO3 (309.36): calcd. C 73.77, H 6.19, N 4.53;
found C 73.63, H 6.29, N 4.53.
C-3 Alkylation of 4a To Give 5a: To a solution of 4a (77 mg,
0.59 mmol) in THF (2.0 mL) was added dropwise a solution of
nBuLi in hexane (1.65  solution, 0.62 mmol, 0.38 mL) at 0 °C.
The reaction mixture was stirred at ambient temperature for
30 min, and to the mixture was added a solution of ZnCl2 in Et2O
(1.0  solution, 0.60 mmol, 0.60 mL). The mixture was stirred at
r.t. for 25 min. To the mixture, a solution of benzyl iodoacetate
6: To a solution of 5l (51 mg, 0.16 mmol) in THF (1.5 mL) was
added a solution of tBuOK in THF (1.0  solution, 0.2 mL,
0.20 mmol) at –78 °C, and the mixture was stirred for 30 min. To
the mixture,
a solution of p-chlorobenzoyl chloride (25 µL,
0.20 mmol) in THF (1.0 mL) was added dropwise, and the mixture
(1.10 mmol, 303 mg) in THF (1.0 mL) was cannulated over 3 min, was stirred for 2 h. The reaction was quenched with saturated aque-
and the mixture was stirred at r.t. for 22 h. The reaction was
quenched with saturated aqueous NH4Cl. The organic compounds
ous NH4Cl. The organic compounds were extracted with AcOEt,
and the combined organic layers were washed with saturated aque-
Eur. J. Org. Chem. 2009, 4606–4613
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4611

Y. Kasaya, K. Hoshi, Y. Terada, A. Nishida, S. Shuto, M. Arisawa
FULL PAPER
ous NaHCO3, H2O, and brine and dried with Na2SO4. After the
solvent was removed, the residue was purified by column
chromatography (hexane/AcOEt, 24:1) to give indomethacin benzyl
ester (66 mg, 92%); colorless needles, m.p. 89–90 °C (EtOH). 1H
NMR (400 MHz, CDCl3): δ = 7.64 (d, J = 8.6 Hz, 2 H, benzoyl),
7.54 (d, J = 8.6 Hz, 2 H, benzoyl), 7.29–7.34 (m, 5 H, CH2-Ph),
6.93 (d, J = 2.3 Hz, 1 H, indole 4-H), 6.67 (dd, J = 9.1, 2.7 Hz, 1
H, indole 7-H), 6.63 (d, J = 9.1 Hz, 1 H, indole 6-H), 5.14 (s, 2 H,
CH2-Ph), 3.76 (s, 3 H, OCH3), 3.71 (s, 2 H, indole-CH2CO), 2.36
(s, 3 H, indole-CH3) ppm. 13C NMR (400 MHz, CDCl3): δ =
170.61, 168.20, 155.93, 139.15, 135.84, 135.64, 133.79, 131.10,
130.68, 130.49, 129.03, 128.48, 128.23, 128.09, 114.90, 112.42,
111.78, 101.03, 66.72, 55.52, 30.32, 13.34, 0.98 ppm. LRMS (EI):
m/z = 447 [M]+. C26H22ClNO4 (447.91): calcd. C 69.72, H 4.93, N
3.12; found C 69.43, H 4.93, N 3.12. To a solution of indomethacin
benzyl ester (45 mg, 0.10 mmol) in AcOEt (2.0 mL) was added Pd/
C (10%, 20 mg), and the mixture was stirred under H2 for 40 min.
The mixture was filtered through Celite 545. After the solvent was
removed, the residue was purified by column chromatography
(CHCl3) to give 6 (30 mg, 84%); pale yellow solid, m.p. 152–153 °C
(s, 3 H, indole-CH3) ppm. 13C NMR (500 MHz, CDCl3): δ =
171.90, 155.82, 135.95, 135.74, 131.34, 128.42, 128.04, 122.79,
118.62, 108.82, 103.97, 94.46, 66.39, 55.66, 30.42, 11.52 ppm.
HRMS (EI): calcd. for C19H19NO3 [M]+ 309.1365; found 309.1365.
C19H19NO3·0.1H2O: calcd. C 73.34, H 6.22, N 4.50; found C 73.25,
H 6.48, N 4.40.
7: To a solution of 5m (40 mg, 0.13 mmol) in THF (1.0 mL) was
added a solution of tBuOK in THF (1.0  solution, 156 µL,
0.16 mmol) at –78 °C, and the mixture was stirred for 30 min. To
the mixture,
a solution of p-chlorobenzoyl chloride (20 µL,
0.16 mmol) in THF (1.0 mL) was added dropwise, and the mixture
was stirred for 2 h. The reaction was quenched with saturated aque-
ous NH4Cl. The organic compounds were extracted with AcOEt,
and the combined organic layers were washed with brine and dried
with Na2SO4. After the solvent was removed, the residue was puri-
fied by column chromatography (hexane/AcOEt, 20:1) to give an
N-acylated compound (56 mg, 97%); yellow needles, m.p. 92–93 °C
1
(EtOH). H NMR (500 MHz, CDCl3): δ = 7.65 (d, J = 8.3 Hz, 2
H, benzoyl), 7.46 (d, J = 8.3 Hz, 2 H, benzoyl), 7.29–7.37 (m, 6 H,
CH2-Ph, indole 4-H), 6.82 (dd, J = 8.6, 2.0 Hz, 1 H, indole 5-H),
6.72 (d, J = 2.0 Hz, 1 H, indole 7-H), 5.13 (s, 2 H, CH2-Ph), 3.70
(s, 3 H, OCH3), 3.67 (s, 2 H, indole-CH2CO), 2.26 (s, 3 H, indole-
CH3) ppm. 13C NMR (500 MHz, CDCl3): δ = 170.69, 168.58,
156.99, 139.27, 137.05, 135.70, 133.82, 133.30, 131.13, 129.08,
128.50, 128.23, 128.11, 123.51, 118.81, 112.33, 111.35, 99.21, 66.71,
55.49, 30.38, 13.40 ppm. HRMS (EI): calcd. for C26H22ClNO4
[M]+ 447.1237; found 447.1238. To a solution of the above N-acyl-
ated compound (39 mg, 87 µmol) in AcOEt (1.0 mL) was added
Pd/C (10%, 13 mg), and the mixture was stirred under H2 for 3 h.
The mixture was filtered through Celite 545. After the solvent was
removed, the residue was purified by column chromatography (hex-
ane/AcOEt, 2:1) to give 7 (78 mg, 90%); pale yellow solid, m.p.
145–146 °C (50% aq. EtOH). 1H NMR (500 MHz, CDCl3): δ =
7.67 (d, 2 H, J = 8.6 Hz, benzoyl): δ = 7.45 (d, J = 8.6 Hz, 2 H,
benzoyl), 7.37 (d, J = 8.6 Hz, 1 H, indole 4-H), 6.85 (dd, J = 8.6,
2.3 Hz, 1 H, indole 5-H), 6.68 (d, J = 2.3 Hz, 1 H, indole 7-H),
3.68 (s, 3 H, OCH3), 3.66 (s, 2 H, indole-CH2CO), 2.29 (s, 3 H,
indole-CH3) ppm. 13C NMR (500 MHz, CDCl3): δ = 176.61,
168.61, 157.05, 139.41, 137.05, 133.73, 133.63, 131.18, 129.15,
123.38, 118.69, 111.67, 111.40, 99.33, 55.53, 30.00, 13.30 ppm.
HRMS (EI): calcd. for C19H16ClNO4 [M]+ 357.0768; found
357.0768.
1
(50% aq. EtOH), ref.[20] 153–154 °C (50% aq. alcohol). H NMR
(500 MHz, CDCl3): δ = 7.66 (d, J = 8.6 Hz, 2 H, benzoyl), 7.46 (d,
J = 8.6 Hz, 2 H, benzoyl), 6.94 (d, J = 2.9 Hz, 1 H, indole 4-H),
6.85 (d, J = 9.2 Hz, 1 H, indole 7-H), 6.67 (dd, J = 8.9, 2.9 Hz, 1
H, indole 6-H), 3.82 (s, 3 H, OCH3), 3.69 (s, 2 H, indole-CH2CO),
2.38 (s, 3 H, indole-CH3) ppm. 13C NMR (500 MHz, CDCl3): δ =
176.78, 168.28, 156.03, 139.32, 136.24, 133.74, 131.18, 130.74,
130.42, 129.13, 114.99, 111.78, 111.67, 101.19, 55.70, 30.00,
13.29 ppm. LRMS (EI): m/z = 357 [M]+.
Synthesis of Indomethacin Derivative 7
4m: To a solution of 3m (424 mg, 1.34 mmol) in EtOH (13 mL)
was added KOH (2.3 g, 40.3 mmol), and the mixture was refluxed
for 4 h. The mixture was cooled and partitioned between water and
CH2Cl2. The combined organic layers were washed with water and
dried with Na2SO4. After the solvent was removed, the residue was
purified by column chromatography (hexane/AcOEt, 15:1) to give
4m (151 mg, 70%); colorless prisms, m.p. 100–101 °C (Et2O/hex-
ane), ref.[21] 103–104 °C. 1H NMR (500 MHz, CDCl3): δ = 7.72
(br., 1 H, NH), 7.37 (d, J = 8.6 Hz, 1 H, indole 4-H), 6.80 (d, J =
2.3 Hz, 1 H, indole 7-H), 6.74 (dd, J = 8.6, 2.3 Hz, 1 H, indole 5-
H), 6.13 (s, 1 H, indole 3-H), 3.83 (s, 3 H, OCH3), 2.40 (s, 3 H,
indole-CH3) ppm. 13C NMR (400 MHz, CDCl3): δ = 155.58,
136.67, 133.80, 123.23, 120.03, 108.93, 99.93, 94.40, 55.68,
13.64 ppm. LRMS (EI): m/z = 161 [M]+.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of 1a,i–n, 3a, 3f,i–n, 4a, 4l, 4m, 5a,
5l, 5m, 6, and 7.
5m: To a solution of 4m (70 mg, 0.43 mmol) in THF (2.0 mL) was
added dropwise a solution of nBuLi in hexane (1.59  solution,
0.65 mmol, 0.41 mL) at 0 °C. The reaction mixture was stirred at
ambient temperature for 50 min, and to the mixture was added a
solution of ZnCl2 in Et2O (1.0  solution, 0.52 mmol, 0.52 mL).
The mixture was stirred at r.t. for 50 min. To the mixture, a solution
of benzyl iodoacetate (178 mg, 0.65 mmol) in THF (1.5 mL) was
cannulated over 3 min, and the mixture was stirred at r.t. for 17 h.
The reaction was quenched with saturated aqueous NH4Cl. The
organic compounds were extracted with AcOEt, and the combined
organic layers were washed with saturated aqueous NH4Cl and
brine and dried with Na2SO4. After the solvent was removed, the
residue was purified by column chromatography (hexane/AcOEt,
5:1) to give 5m (48 mg, 36%); yellow oil. 1H NMR (400 MHz,
CDCl3): δ = 7.75 (br., 1 H, NH), 7.54 (d, J = 8.6 Hz, 1 H, indole
4-H), 7.26–7.34 (m, 5 H, CH2-Ph), 6.73 (dd, J = 8.6, 2.3 Hz, 1 H,
indole 5-H), 6.67 (d, J = 2.3 Hz, 1 H, indole 7-H), 5.09 (s, 2 H,
CH2-Ph), 3.78 (s, 3 H, OCH3), 3.68 (s, 2 H, indole-CH2CO), 2.25
Acknowledgments
This research was supported by Grants-in-Aid from the Ministry
of Education, Culture, Sports, Science and Technology, Japan. We
also thank the Akiyama Foundation and Mitsubishi Chemical Cor-
poration Fund for financial support.
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Received: May 9, 2009
Published Online: August 10, 2009
Eur. J. Org. Chem. 2009, 4606–4613
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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