Synthesis of 2,3-disubstituted indoles by a rhodium-catalyzed aromatic amino-claisen rearrangement of N-propargyl anilines

Article abstract of DOI:10.1002/anie.200605162

(Chemical Equation Presented) Give me a ring! A cationic Rh^I catalyst promotes the formation of fused arenes containing a five-membered ring (see scheme) by an aromatic amino-Claisen rearrangement of N-propargyl aniline derivatives in refluxing

Full text of DOI:10.1002/anie.200605162

Angewandte
Chemie
DOI: 10.1002/anie.200605162
Heterocycle Synthesis
Synthesis of 2,3-Disubstituted Indoles by a Rhodium-Catalyzed
Aromatic Amino-Claisen Rearrangement of N-Propargyl Anilines**
Akio Saito,* Ayumi Kanno, and Yuji Hanzawa*
Table 1: RhI catalysts investigated for the cyclization of 1a.
Transition-metal-catalyzed intramolecular reactions of heter-
oatom-tethered substrates are attractive methods for the
synthesis of heterocyclic compounds.[1] In particular, regiose-
lective annulations of N-propargyl aniline derivatives by
intramolecular hydroarylation are diverse methods for pre-
paring quinoline or indole ring systems (6-endo or 5-exo).
Intramolecular hydroarylation is catalyzed by various metal-
containing catalysts,[2] and the reactions of N-propargyl
anilines give 1,2-dihydroquinolines in a 6-endo manner
(path b, Scheme 1).[3] Amino-Claisen rearrangements[4,5] of
Entry
Catalyst
Ligand[a]
t [h]
Yield [%][b]
2a
3
1a
1
2
3
4
5
6
7
8
[Rh(cod)2]OTf
[Rh(cod)2]OTf
[Rh(cod)2]OTf
[Rh(cod)2]OTf
[Rh(cod)2]OTf
[Rh(cod)2]OTf
[Rh(cod)2]BF4
[{Rh(cod)Cl}2]/
AgSbF6[d]
dppp (10)
dppp (15)
dppe (10)
dppb (10)
5
18
5
5
5
5
5
1
90
97
32
25
60
–
–
–
–
–
–
65
58
–
64
77
8
6
[c]
PCy3 (20)
10
12
-
–
dppp (10)
dppp (10)
8
12
34
9[e]
10
[Rh(cod)2]OTf
dppp (10)
–
–
5
5
5
26
–
–
19
–
–
–
99
94
HOTf[f]
11[g]
–
[a] Amount used [mol%] given in parentheses. [b] The yield was
determined by 1H NMR analysis using toluene as internal standard.
[c] Cy=cyclohexyl. [d] 5 mol% [{Rh(cod)Cl}2] and 13 mol% AgSbF6.
[e] The reaction mixture was refluxed in trifluoroethanol. [f] 20 mol%
CF3SO3H. [g] The reaction mixture was refluxed in HFIP in the absence of
RhI and ligand.
Scheme 1. Possible routes for the cyclization of N-propargyl anilines
(see text for details).
N-propargyl aniline derivatives, which open up an alternative
route to quinoline ring systems, proceed via o-allenylaniline
under thermal[6] or copper-promoted condition[7,8] (path a’,
Scheme 1). Although a few indoles have been synthesized by
the thermal rearrangement of N-propargyl anilines, these
procedures require extremely high temperatures (240–2608C)
and products were only obtained in low yields.[6a] Herein, we
describe the mild formation of indoles by an amino-Claisen
rearrangement of N-propargyl anilines catalyzed by cationic
RhI complexes.[9]
absence of such a ligand (entry 6, Table 1). Thus, in the
presence of 10 mol% [Rh(cod)2]OTf (cod = 1,5-cycloocta-
diene; Tf = trifluoromethanesulfonyl) and 10 mol% 1,3-bis(-
diphenylphosphanyl)propane (dppp) in hexafluoro-2-propa-
nol (HFIP), 1a was consumed within five hours at reflux
(808C) to give indole 2a in 90% yield. Although the use of
15 mol% dppp required a prolonged reaction time, the yield
of 2a increased up to 97% (entry 2, Table 1). Other cationic
RhI complexes, such as [Rh(cod)2]BF4 and [{Rh(cod)Cl}2]/
AgSbF6 ,[10] and the use of trifluoroethanol as solvent were not
effective (entries 7–9, Table 1). The reaction in other solvents
(2-propanol, 1,2-dichloroethane, toluene, THF, acetone, and
acetonitrile) gave no cyclized product. Although Lewis acids
(AlCl3, ZnCl2, and BF3·OEt2)[11] and CuCl[7] have often been
employed in the aromatic amino-Claisen rearrangement,
these reagents did not promote the formation of the indole
product here. The Brønsted acid that might be generated
during the reaction does not take part in the reaction
(entry 10, Table 1), and the absence of the catalyst leads to
the complete recovery of 1a (entry 11, Table 1).
Evaluation of the rhodium catalysts was conducted for the
reaction with N-propargyl aniline (1a). It turns out that
phosphine ligands are very important for the formation of 2a
(entries 1–5, Table 1); no cyclized product was obtained in the
[*] Dr. A. Saito, A. Kanno, Prof. Dr. Y. Hanzawa
Laboratory of Organic Reaction Chemistry
Showa Pharmaceutical University
3-3165 Higashi-tamagawagakuen, Machida, Tokyo 194-8543
(Japan)
Fax: (+81) 42-721-1569
E-mail: akio-sai@ac.shoyaku.ac.jp
hanzaway@ac.shoyaku.ac.jp
The efficiency of [Rh(cod)2]OTf encouraged us to exam-
ine the effect of the alkyne substituent of the substrate. It
turned out that the present catalytic system can also be
applied to the reaction of compounds containing an internal
alkyne (Table 2). Thus, the n-pentyl compound 1b gives rise
[**] This work was supported by a Grant-in-Aid for Young Scientists (B)
from MEXT, Japan (grant No. 17790021). A generous donation of
HFIP by Central Glass Co., Ltd. is gratefully acknowledged.
Supporting Information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 2: RhI-catalyzed reaction of various alkynes.
Table 3: RhI-catalyzed reaction of various arenes.[a]
Entry
Substrate
Product
Yield
[%][b]
1
92
Entry
1
R
Phosphane[a]
t [h]
Yield [%][b]
2
4
1
2
3
4
5
6
1a
1a
1b
1c
1c
1d
Me
Me
n-C5H11
Ph
Ph
H
dppp (10)
dppp (15)
dppp (15)
dppp (15)
dppe (15)
dppp (15)
5
18
13
18
18
21
87
93
82
–
–
–
3
26
–
50
(p-11)
+
19
(o-11)
55
(p-11)
+
26
5[c]
2
34[d]
0[e]
3[c]
[a] Amount used [mol%] given in parentheses. [b] Yield of isolated
product. [c] Yield of 3: 22%. [d] Yield of 3: 9%. [e] Yield of 3: 19%; 1d
recovered: 40%.
(o-11)
to the corresponding indole 2b in 82% yield in refluxing
HFIP in the presence of [Rh(cod)2]OTf and dppp (entry 3,
Table 2). In the case of phenyl derivative 1c, 1,2-bis(di-
phenylphosphanyl)ethane (dppe) was superior to dppp,
with indole 3c being obtained in 34% yield along with
tetrahydroquinoline 4c in 26% yield (entry 5, Table 2).[12]
It is noteworthy that aniline 1e leads to the formation of
conjugated diene 5 (Scheme 2). This result suggests that
12a
(R=OMe)
12b
(R=H)
12c
(R=Br)
12d
4
5
87 (13a)
93
(13b)
92 (13c)
6
7
89
(13d)
(R=F)
8
89
25 (17)
+
9
25 (18)
[a] All reactions were carried out in the presence of 10 mol% [Rh(cod)2]OTf and
10 mol% dppp in refluxing HFIP for 2–5 h. [b] Yield of isolated product.
[c] 15 mol% dppp. [d] Yield of N-benzyl-3,5-difluoroaniline: 26%.
Scheme 2. Formation of a diene or an indole.
the initially formed o-allenylaniline 6e isomerizes to form a
1,3-dienyl side chain.[13] Support for this assumption comes
from the reaction of 1 f, which has no migrating hydrogen in
the assumed phenyl allene intermediate 6 f and therefore
gives indole 7 under the present conditions (Scheme 2).[14]
The effect of the substituent on the arene ring is shown in
Table 3. Regardless of whether an o-, m-, or p-OMe-
substituted aniline derivative (12a, 10, and 8, respectively)
is used, the reaction in the presence of [Rh(cod)2]OTf and
dppp gives the corresponding indole products in good yields
(entries 1–4, Table 3). In the case of meta-substituted aniline
10, attack at the position para to the OMe group is preferable
to that at the ortho position (entries 2 and 3, Table 3).
Substrates 12c and 12d, both of which have electron-with-
drawing halogen substituents, also gave good results (entries 6
and 7, Table 3). The reaction of difluorinated compounds 16,
however, afforded a 1:1 mixture of indole 17 and the
tetrahydroquinoline compound 18 (entry 9).[12]
To gain a better understanding of how the aromatic
amino-Claisen rearrangement occurs under these conditions,
we attempted the cyclization of o-allenylaniline 20
(Scheme 3), which was considered to be an intermediate in
the reaction with 12b. Thus, 20 was generated independently
by treatment of 19 with CuCN·2LiCl and MeMgBr at 08C for
15 min (yield of 20: 84%; 13b: 4%). Since 20 is sensitive to air
and proved to be difficult to separate from 13b, it was used as
a mixture with 13b after being passed through a short
chromatography column packed with silica gel. Under similar
conditions to those used previously for the reaction with 12b
(entry 5, Table 3), the cyclization of 20 gave 13b in 74% yield
(with respect to 19). Thus, taking into consideration the
formation of diene 5 and indole 7 from 1e and 1 f,
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Scheme 3. Cyclization of o-allenylaniline. a) [Rh(cod)2]OTf (10 mol%),
dppp (10 mol%), HFIP, reflux, 3 h, 74% yield. b) No catalyst, HFIP,
reflux, 3 h, 51% yield. c) No catalyst, 1,2-dichloroethane, reflux, 3 h,
53% yield.
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of an initial Rh-catalyzed amino-Claisen rearrangement of N-
propargyl aniline[15] and the subsequent cyclization of o-
allenylaniline by path a in Scheme 1. Since heating 20 in HFIP
or 1,2-dichloroethane gave 13b in moderate yield, cyclization
of the o-allenylaniline intermediate is induced by both the Rh
catalyst and by heating.
In summary, we have reported the facile formation of
indoles by an aromatic amino-Claisen rearrangement of N-
propargyl aniline derivatives in the presence of a [Rh-
(cod)2]OTf/dppp catalyst in HFIP. We believe that these
findings raise new possibilities for the formation of 2,3-
disubstituted indoles under mild conditions. Investigation of
the synthetic applications and detailed mechanistic studies of
this reaction are underway.
Received: December 21, 2006
Revised: January 23, 2007
Published online: April 11, 2007
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[12] Although the formation mechanism of 4c and 18 remains
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dihydroquinoline derivative formed from 1c or 16 according to
Scheme 1. However, the corresponding quinoline compounds,
which are considered to be oxidized products, were not detected.
See also: T. P. Forrest, G. A. Dauphinee, S. A. Deraniyagala,
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[13] A similar observation has been reported in the Brønsted acid-
catalyzed rearrangement of N-propargyl anilines. See referen-
ce [5c].
Keywords: alkynes · cyclization · heterocycles · rearrangement ·
rhodium
.
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