Ruthenium-Catalyzed Cycloisomerization of 2-Alkynylanilides: Synthesis of 3-Substituted Indoles by 1,2-Carbon Migration

Article abstract of DOI:10.1021/jacs.7b04564

We developed ruthenium-catalyzed cycloisomerization of alkynylanilides that gave 3-substituted indoles in high yields. The reaction proceeded via the disubstituted vinylidene ruthenium complex that was formed by the 1,2-carbon migration.

Full text of DOI:10.1021/jacs.7b04564

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Ruthenium-Catalyzed Cycloisomerization of 2-Alkynylanilides:
Synthesis of 3-Substituted Indoles by 1,2-Carbon Migration
Takuma Watanabe, Yuichiro Mutoh, and Shinichi Saito
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 24 May 2017
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Ruthenium-Catalyzed Cycloisomerization of 2-
Alkynylanilides: Synthesis of 3-Substituted Indoles by 1,2-
Carbon Migration
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Takuma Watanabe, Yuichiro Mutoh,* and Shinichi Saito*
Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku, Tokyo 162-8601, Japan
Supporting Information Placeholder
When a solution of 1a, [CpRuCl(dppe)] (3 mol %), and NaB-
ABSTRACT: We developed ruthenium-catalyzed cycloisomeri-
ArF ·3H2O (3.6 mol %) was heated at 110 °C for 4 h in chloro-
4
zation of alkynylanilides which gave 3-substituted indoles in high
benzene, two indoles (2a and 3a) were formed in 11% and 20%
yields, respectively (Table 1, entry 1). The yields of the products
increased when the reaction time was extended to 24 h (entry 2).
We assumed that the formation of 2a was accelerated by the high
nucleophilicity of the amino group. When we examined the reac-
tion of a benzoylated substrate (1b), the selective formation of the
3-substituted indole was observed (entry 3). We screened the
reaction of a series of protected anilines and found that the acety-
lated substrate (1c) was selectively converted to the 3-substituted
indole in high yield (entry 4).12,13
yields. The reaction proceeded via the disubstituted vinylidene
ruthenium complex which was formed by the 1,2-carbon migra-
tion.
Indole skeleton is found in a large number of natural products
and many of them have unique biological activity. Consequently,
the indole synthesis has been a very important issue in organic
chemistry.1 The cycloisomerization of 2-alkynylanilines is an
efficient method for the synthesis of 2-substituted indoles.2,3 In
the Lewis acid-catalyzed reaction, the cyclization proceeded by
the nucleophilic attack of the amino group to the activated alkynyl
moiety (Scheme 1a). Alternatively, the formation of the indole
skeleton was achieved via the vinylidene intermediate (Scheme
1b).4,5 In the reaction, the migrating group was limited to hydro-
gen atom or a silyl group, and no catalytic process which involve
the formation of the vinylidene intermediate by the 1,2-carbon
migration has been reported. Since the heterolytic cleavage of the
C-C bond occurs less readily than the C-Si bond,6 the 1,2-carbon
migration has been considered as a more challenging process.
Table 1. Ruthenium-Catalyzed Cycloisomerization of 2-
Aminodiphenylacetylene Derivativesa
entry
substrate
time (h)
product (yield, %)
2a (11), 3a (20)a
2a (26), 3a (63)
3b (34)b
1
2
3
4
1a (R = H)
1a (R = H)
1b (R = Bz)
1c (R = Ac)
4
24
4
The formation of the vinylidene complex from an alkyne by the
alkyne-to-vinylidene rearrangement is a well-known reaction in
organometallic chemistry.7-9 The migration of aryl, alkyl, and acyl
group, however, has been far less explored.10 Herein we report the
first ruthenium-catalyzed cycloisomerization of alkynylanilides
which gave 3-substituted indoles by 1,2-carbon migration
(Scheme 1c).11
4
3c (97)
aThe yield of 2a and the recovery of 1a (62%) were determined
by the 1H NMR analysis. bThe recovery of 1b (59%) was ob-
served.
Scheme 1. Metal-Catalyzed Cycloisomerization of 2-
Alkynylanilines
We studied the scope and limitation of this reaction (Table 2).
The reaction of a substrate with 4’-methoxy group (1d) completed
in 2 h and 2d was isolated in 96% yield (entry 2). The reaction of
4’-bromo derivative (1e) gave 3e (83% yield, entry 3). Compared
to these substrates, the reaction of 4’-ethoxycarbonyl derivative
(1f) was sluggish (entry 4).
Next, we examined the effect of the substituent introduced to the
benzene ring bound to the N-acetylamino group (entries 5-7). The
reaction of a substrate with 4-methoxy group (1g) was sluggish
compared to that of 1c, and 3g, together with the 2-substituted
indole (2g), was isolated (entry 5). The reactivity of the chloride
(1h) was similar to that of 1g (entry 6). Though the reactivity of
the ethoxycarbonyl derivative (1i) was very low, the product (3i)
was obtained in high yield (entry 7).
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H
N
H
N
The scope of this reaction was further explored using sterically
congested alkynes. Compared to the reaction of 1c, harsh condi-
tions (145 °C, 10 mol % of the Ru complex) were required for the
reaction of 2’-methylphenyl derivative (1j, entry 8). The reaction
of 2’,6’-dimethylphenyl derivative (1k) gave the 3-xylylindole
(3k) together with 1k (entry 9).
1
2
3
4
NHAc
N
Ac
16i 1r
90 °C, 1.5 h
3r (92)
5
6
7
8
We next studied the reactions of the substrates with non-
aromatic groups bound to the alkynyl group. Though the reaction
of a 2-hexynyl derivative (1l) completed in the presence of 10
mol % of [CpRuCl(dppbz)] (145 °C, 2 h), the selectivity of the
reaction was low (entry 10). The reaction proceeded selectively
when an N-benzoylaniline (1m) was employed as the substrate
(entry 11). The reaction of the cyclopentyl derivative (1n) gave
the corresponding 3-substituted indole (3n), while the reaction of
t-butyl derivative (1o) failed (entries 12 and 13). The 2-
benzoylethynyl derivative (1p) was highly reactive (entry 14).
The reaction of an ester (1q) gave the corresponding 3-substituted
indole (3q) in 79% yield (entry 15).
9
17h 1s
145 °C, 2.5 h 3s (95)
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aReaction conditions: 1 (0.5 mmol, [1] = 0.2 M, in PhCl),
[CpRuCl(dppe)] (3.0 mol %), NaBArF ·3H2O (3.6 mol %). bI-
4
solated yields. A trace amount of 2 was detected in the crude mix-
c
ture in some reactions. 2-Substituted indole (2g) was isolated in
13% yield. d[CpRuCl(dppe)] (10 mol %), NaBArF ·3H2O (12
4
mol %). eThe recovery of 1k (35%) was observed.
g
f[CpRuCl(dppbz)] (10 mol %), NaBArF ·3H2O (12 mol %). N-
4
Table 2. Synthesis of 3-Substituted Indoles through 1,2-
Carbon Migrationa
Acetyl-2-butylindole (2l) was isolated in 33% yield.
i
h[CpRuCl(dppe)] (5 mol %), NaBArF ·3H2O (6 mol %). [1r] =
4
0.13 M. dppbz = 1,2-bis(diphenylphosphino)benzene.
We further studied the reactions of the substrates bearing a het-
erocyclic component. The reaction of the 5-indolyl derivative (1r)
gave 3r (entry 16). Unexpectedly, the reaction of an aminocouma-
rin derivative (1s) proceeded selectively and a pyrrolocoumarin
derivative (3s) was isolated (entry 17).
substrate
temp, time
product
(yield, %)b
en-
try
To gain a mechanistic insight, we studied the stoichiometric re-
action of 1b (Scheme 2). When a mixture of 1b, [CpRuCl(dppe)],
and NaBArF ·3H2O was heated at 100 °C for 0.5 h, the vinylidene
4
complex 4 was isolated in 79% yield.10d,14 When a solution of 4
was heated at 110 °C for 1 h, 3b was isolated in 87% yield. The
formation of 3b from 4 supports the idea that the vinylidene com-
plex 4 would be the key intermediate.
1
2
3
4
1c (R3 = H)
1d (R3 = OMe)
1e (R3 = Br)
110 °C, 4 h
110 °C, 2 h
110 °C, 6 h
3c (97)
3d (96)
3e (83)
Scheme 2. Synthesis and Reaction of Vinylidene Complex 4
1f (R3 = CO2Et)
110 °C, 12 h 3f (91)
The proposed catalytic cycle of this reaction is shown in
Scheme 3. A cationic ruthenium complex would react with 1 to
yield π-alkyne complex X. The cyclization reaction would pro-
ceed when the amino group was bound to the benzene ring, and
the 2-substituted indole 2 would be isolated (path A). Alternative-
ly, the 1,2-carbon migration10c,f,g,i would yield the vinylidene
complex Y, which would undergo cyclization (path B). When a
less nucleophilic N-acylamino group was present, the reaction
would proceed preferentially via path B. Finally, 3-substituted
indole 3 would be isolated by the protonolysis of Z.
5
6
7
1g (R2 = OMe)
1h (R2 = Cl)
1i (R2 = CO2Et)
110 °C, 8.5 h 3g (84)c
110 °C, 8.5 h 3h (88)
145 °C, 9.5 h 3i (90)
8d
9d
1j (R1, R = 2’-MeC6H4, Ac) 145 °C, 2.5 h 3j (93)
145 °C, 24 h 3k (54)e
1k (R1, R = 2’,6’-Me2C6H3,
In summary, we developed a new ruthenium-catalyzed cycloi-
somerization of internal alkynes. This reaction is the first example
of the catalytic process which proceeded via the ruthenium vinyli-
dene intermediate formed by 1,2-carbon migration. Further devel-
opment of the reactions which involve the carbon migration is on
going.
Ac)
10f 1l (R1, R = n-Bu, Ac)
11f 1m (R1, R = n-Bu, Bz)
145 °C, 2.5 h 3l (60)g
145 °C, 2 h
3m (87)
12f
145 °C, 2.5 h 3n (92)
1n (R1, R = cyclopentyl,
Bz)
13f 1o (R1, R = t-Bu, Bz)
14
1p (R1, R = COPh, Ac)
15h 1q (R1, R = CO2Et, Ac)
145 °C, 6 h
no reaction
110 °C, 1.5 h 3p (93)
145 °C, 1 h
3q (79)
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures and characterization data (PDF)
Crystallographic data for 3g, 3k, 3p, and 3s (CIF)
(5) Kanno, H.; Nakamura, K.; Noguchi, K.; Shibata, Y.; Tanaka, K.
Org. Lett. 2016, 18, 1654–1657.
(6) Pawlenko, S. Ogranosilicon Chemistry; Walter De Gruyter Inc.:
Berlin, 1986; pp 7-12.
AUTHOR INFORMATION
Corresponding Authors
ymutoh@rs.tus.ac.jp
ssaito@rs.kagu.tus.ac.jp
Notes
The authors declare no competing financial interest.
ORCID
Yuichiro Mutoh: 0000-0002-5254-9383
Shinichi Saito: 0000-0001-8520-1116
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ACKNOWLEDGMENT
This research was supported in part by MEXT KAKENHI Grant
Numbers JP23105543, JP25105747 (Y. M.) and by Taisho Phar-
maceutical Co., Ltd. Award in Synthetic Organic Chemistry, Ja-
pan (Y. M.).
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(11) For the 1,2-migration of aryl groups in the synthesis of indole de-
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K.; Liu, S.; Bec, P. M.; Driver, T. G. Angew. Chem., Int. Ed. 2011, 50,
1702–1706. (c) Youn, S. W.; Lee, S. R Org. Biomol. Chem. 2015, 13,
4652–4656. (d) Youn, S. W.; Ko, T. Y.; Jang, M. J.; Jang, S. S. Adv. Synth.
Catal. 2015, 357, 227–234. (e) Youn, S. W.; Lee, S. R.; Kim, Y. A.; Kang,
D. Y.; Jang, M. J. ChemistrySelect 2016, 1, 5749–5757.
(12) The reactions of other aniline derivatives (trifluoroacetyl, Ts, PMB,
or Boc group) were unsuccessful.
(13) For the results of the screening of the ruthenium complexes, see
Supporting Information.
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(14) We assume that compound 4 was isolated because the introduction
of the benzoyl group reduced the rate of the cyclization of 4.
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R1
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R2
R1
R2
cat. Ru
Carbon Migration
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NHR3
R1 = aryl, alkyl, acyl
N
R3
R1
R2
up to 97% yield
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Ru
NHR3
Vinylidene Intermediate
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