Highly diastereoselective one-pot synthesis of spirocyclic oxindoles through intramolecular Ullmann coupling and Claisen rearrangement

Article abstract of DOI:10.1002/anie.200504247

(Chemical Equation Presented) An efficient and convenient approach to the synthesis of spirocyclic oxindoles from iodoindoles involves a sequential intramolecular C-O Ullmann coupling reaction and Claisen rearrangement (see scheme). The one-pot procedure affords 3-spiro-2-oxindoles in good yield with excellent diastereoselectivities.

Full text of DOI:10.1002/anie.200504247

Communications
clinical pharmaceuticals.[1] Therefore, a number of synthetic
methods have been developed in pursuit of this structure,
including intermolecular alkylations,[2] palladium-catalyzed
reactions,[1c,3] cycloadditions,[4] and sigmatropic rearrange-
ments.[5] We recently developed the stereoselective synthesis
of spiro[4.5]decane frameworks through a Claisen rearrange-
ment of alkenyl bicyclic dihydropyrans.[6,7] On the basis of this
result, we envisioned that a Claisen rearrangement of alkenyl
pyranoindoles 2 would produce 3-spiro-2-oxindoles 3, which
are potential synthetic intermediates for indole alkaloids.
Pyranoindoles 2 might, in turn, be prepared by an intra-
molecular Ullmann coupling (IUC) of haloindoles 1 bearing
an allylic alcohol unit (Scheme 1).[8]
Scheme 1. General scheme for the construction of spirocyclic
oxindoles 3.
Domino Reactions
DOI: 10.1002/anie.200504247
Herein we report an efficient and convenient method for
the synthesis of spirocyclic oxindoles from haloindoles. The
most striking feature of this approach is that it is a one-pot
procedure in which the IUC of 1 and Claisen rearrangement
of 2 proceed successively to provide 3-spiro-2-oxindoles 3 in
good yields with high diastereoselectivities.[9]
Highly Diastereoselective One-Pot Synthesis of
Spirocyclic Oxindoles through Intramolecular
Ullmann Coupling and Claisen Rearrangement**
To our knowledge, few general procedures are available
for the preparation of 2, and considering the reported
properties of the unsubstituted pyranoindole, it was antici-
pated that 2 would be sensitive to acidic conditions.[10] Hence,
we decided to examine the transition-metal-catalyzed intra-
Hiroshi Miyamoto, Yoichiro Okawa, Atsuo Nakazaki,
and Susumu Kobayashi*
Oxindoles that incorporate a quaternary stereogenic center at
C3 are attractive targets in organic synthesis because of their
significant biological activities as well as wide-ranging utility
as synthetic intermediates for alkaloids, drug candidates, and
À
molecular C O coupling of 1 which is usually carried out
À
under basic conditions. For C O bond formation, the copper-
mediated Ullmann-type reaction was chosen owing to its ease
and lower cost.[11] Although several recent syntheses have
involved IUC, these examples are much rarer than the
intermolecular version.[12] As a preliminary survey, we
compared several known procedures in which various
2-haloindoles 1 (R1 = Me, SO2Ph, R2 = Me, nBu) were
employed. As a result, the Hauptman protocol (CuCl/2-
aminopyridine, NaOMe)[13] was found to be effective and
proceeds in moderate yield (up to 60%). However, direct
application of the original Hauptman method to our indole
substrates suffered from poor reproducibility. After many
trials with 1a, which can be readily prepared from commer-
cially available N-methylindole by a three-step sequence,[14]
we solved this problem with the following minor modifica-
tions: 1) Addition of a small amount of MeOH ( ꢀ 2%
v/v), and 2) more base (NaOMe). Under these optimized
[*] Y. Okawa, Dr. A. Nakazaki, Prof. Dr. S. Kobayashi
Faculty of Pharmaceutical Sciences
Tokyo University of Science
2641 Yamazaki, Noda-shi, Chiba 278-8510 (Japan)
Fax: (+81)4-7121-3671
E-mail: kobayash@rs.noda.tus.ac.jp
H. Miyamoto
Process Development Laboratories
Sankyo Co. Ltd.
1-12-1 Shinomiya, Hiratsuka-shi, Kanagawa 254-8560 (Japan)
[**] We thank Professor Takao Ikariya and Professor Shigeki Kuwata
(Tokyo Institute of Technology) for X-ray crystallographic analysis.
We also thank Shin-Etsu Chemical Co. Ltd. for a gift of silicone oil.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Angew. Chem. Int. Ed. 2006, 45, 2274 –2277

Angewandte
Chemie
conditions, the yield of 2a increased to 91% with good
reproducibility (Scheme 2). The IUC of 1a proceeded rapidly
and was completed within 10 min. Interestingly, neither
dehalogenated product A nor the product of cross-coupling
was required (Table 1, entry 3). An increase in the concen-
tration of 1a from 0.05 to 0.10 molLÀ1 resulted in a slightly
lower yield owing to side reactions during the IUC step
(Table 1, entry 4). In the absence of CuCl and 2-amino-
pyridine, the IUC was sluggish; the yield of 3a dropped to
6%, and 74% of 1a was recovered (Table 1, entry 5). This
result clearly indicates that CuCl and 2-aminopyridine
efficiently catalyze the IUC.
To study the effect of substituents on the Claisen
rearrangement, compounds 1 with a variety of substituents
on the allylic alcohol unit were explored next (Table 2).
Notably, all the indoles with trans-oriented substituents on the
allylic double bond afforded the corresponding oxindoles as a
single isomer, irrespective of the substituents (Table 2,
entries 1, 2, 6–11).[15] The relative configuration was assigned
on the basis of an X-ray crystal structure of oxindole 3h and
NOE experiments.[14] The configuration of these products
indicates that the Claisen rearrangement proceeds through a
boatlike transition state, analogously to previous results.[16] In
contrast, the reaction of the cis isomer 1c did not give the
desired product; instead decomposition of the initially formed
2c was observed (Table 2, entry 3). This result can be
rationalized by considering the unfavorable transition state
as a result of the steric repulsion between the cis-oriented
methyl group and the hydrogen atoms of the dihydropyran
ring.
Scheme 2. Stepwise synthesis of oxindole 3a. DME=1,2-dimethoxy-
ethane.
with NaOMe, B, was obtained. Finally, the isolated product 2a
underwent Claisen rearrangement, as expected, to afford the
desired oxindole 3a by heating in 1,2-dimethoxyethane
(DME) at 1508C.
As 2a is relatively unstable, especially under acidic
conditions, we next attempted a one-pot synthesis of 3a
(Table 1). When the reaction mixture was heated at 1008C for
24 h, 3a was obtained in 53% yield (Table 1, entry 1). On the
other hand, when the reaction temperature was increased to
1508C after complete formation of 2a (1008C, 10 min), the
rearrangement of 2a proceeded cleanly to afford 3a in 84%
yield (Table 1, entry 2). The IUC was completed with 5 mol%
of CuCl and 2-aminopyridine, although a longer reaction time
The rate of the Claisen rearrangement is strongly
dependent on the presence of substituents on the allylic
double bond. The reaction of substrates with an alkyl or aryl
substituent on the allylic double bond is fast (Table 2,
entries 1, 6, 8–10). In contrast, substrates with no substituent
on the allylic double bond react slowly (Table 1, entry 2).[7a]
In the case of bromoindole 4, although the reactivity in the
IUC is apparently lower than that of iodide 1b, the reaction
proceeded to afford oxindole 3b in 55% yield (Table 2,
entry 2). Notably, sterically hindered substrates such as 1e
and 1g gave the desired 3e and 3g, respectively, in good yields
(Table 2, entries 5, 7). The slow reaction of 1g could be
accelerated without any side reactions by increasing the
temperature. The fact that diol 1i gave 3i exclusively in 93%
yield indicates that the allylic hydroxy group reacts selectively
and that the IUC is tolerant of unprotected hydroxy groups
(Table 2, entry 9). The low yield observed for 1k, which bears
a silyl group, is due to the formation of the desilylated
products 3a and its double-bond isomer (Table 2, entry 11).
The synthetic utility of N-methylated oxindoles is rather
limited owing to the difficulty in the deprotection of the N-
Table 1: One-pot synthesis of oxindole 3a.[a]
Entry
CuCl
[mol%]
2-NH2Py
[mol%]
[1a]
Conditions
Yield of
[molLÀ1
]
3a [%][b]
1
2
10
10
10
10
0.05
0.05
1008C, 24 h
53[c]
1008C, 10 min
1508C, 12 h
84
3
4
5
5
10
0
5
10
0
0.05
0.10
0.05
1008C, 3 h
1508C, 12 h
80
72
6[d]
1008C, 10 min
1508C, 12 h
1008C, 24 h
[a] Reaction conditions: indole 1a (0.5 mmol), NaOMe/MeOH (25 wt%;
2.0 equiv), Ar, sealed tube. [b] Yield of isolated product. [c] 2a was also
obtained in 22% yield. [d] 1a was recovered (74%) along with 2a (10%).
Scheme 3. Preparation of oxindole 6a. Reagents and conditions:
a) TMSCl, NaI, CH3CN, 08C; then Et3N, MeOH, 558C, 81%.
MOM=methoxymethyl.
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Communications
Table 2: Synthesis of spirocyclic oxindoles.[a]
methyl group. Thus, we extended this
method to the synthesis of free (NH)
oxindoles. The unprotected iodoindole 5a
is not a suitable starting material for con-
version into 6a, as 5a readily decomposes.
Thus, several N-protected iodoindole sub-
strates were prepared and exposed to sim-
ilar conditions. N-TBS indole 5b afforded
the desired 6a in 57% yield (Scheme 3). In
this reaction, all of 5b was converted into 5a
upon heating to 1008C, as monitored by
HPLC analysis. However, the subsequent
IUC of 5a was rather slow, and the reaction
temperature had to be elevated to 1508C to
allow complete consumption of 5a. In
contrast, the methoxymethyl (MOM)
group was found to be a suitable protecting
group for the present transformation. The
IUC of 5c and Claisen rearrangement of the
resultant pyranoindole proceeded smoothly
to give 6c in 92% yield as a single isomer.
The MOM group was readily cleaved (81%
yield) by the Fukuyama procedure.[17]
In summary, we have developed a con-
venient and efficient method for the prep-
aration of spirocyclic oxindoles with vicinal
stereogenic centers from the corresponding
2-haloindoles by a one-pot IUC and Claisen
rearrangement. The IUC is a simple and
low-cost method for the preparation of the
rearrangement precursors, alkenyl pyra-
noindoles. The Claisen rearrangement of
the pyranoindoles proceeds smoothly to
give the desired oxindoles in good yields
with high diastereoselectivities. The Claisen
rearrangement is stereospecific in most
cases; hence this method is also applicable
to the enantioselective synthesis of spirocy-
clic oxindoles. Further applications of this
reaction to chiral nonracemic substrates and
the synthesis of natural products are under-
way.
Entry
Substrate
Product[b]
Conditions
Yield de
[%][c] [%][d]
1008C, 30 min
1508C, 1 h
1
89
>95
2
3
3b
1008C, 24 h
55[e]
>95
1008C, 1.5 h
1508C, 6 h
Complex
mixture
–
–
1008C, 4 h
1508C, 1 h
4
5
6
80
84
92
–
–
1308C, 21 h
1508C, 1 h
1008C, 1 h
1508C, 1 h
>95
1008C, 22 h
1208C, 11 h
89
90
>95
>95
7
8
1008C, 1 h
84
>95
>95
>95
>95
1008C, 30 min
1508C, 1 h
9
93
Received: November 30, 2005
Published online: March 3, 2006
1008C, 1 h
1508C, 40 min
Keywords: cyclization · domino reactions ·
10
11
66[f]
.
oxindoles · sigmatropic rearrangement · spiro
compounds
1008C, 5 h
1508C, 2 h
20[g]
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Angew. Chem. Int. Ed. 2006, 45, 2274 –2277

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À
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À
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