Synthesis of spiro[indoline-3,2′-pyrrolidine] derivatives from β-3-indolyl ketone oximes

Article abstract of DOI:10.1246/cl.2004.26

Spiro[indoline-3,2′-pyrrolidine] derivatives were prepared from β-3-indolyl ketone oximes by treatment with methanesulfonyl chloride and triethylamine via the bond formation between 3-position of the indole ring and oxime nitrogen. These diazaspirocycles

Full text of DOI:10.1246/cl.2004.26

26
Chemistry Letters Vol.33, No.1 (2004)
Synthesis of Spiro[indoline-3,20-pyrrolidine] Derivatives from ꢀ-3-Indolyl Ketone Oximes
Kenichi Tanaka, Yutaka Mori, and Koichi Narasakaꢀ
Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033
(Received October 6, 2003; CL-030937)
Spiro[indoline-3,20-pyrrolidine] derivatives were prepared
1) MsCl, Et3N
from ꢀ-3-indolyl ketone oximes by treatment with methanesul-
fonyl chloride and triethylamine via the bond formation between
3-position of the indole ring and oxime nitrogen. These diaza-
spirocycles were readily transformed to the corresponding spiro
oxindole derivatives.
Me
0 °C, 1 h
CH2Cl2
N
X
N
2
2) C6F5COCl
rt, 4 h
N
N
Me
H
O
C6F5
OH
1a
4a (X = Cl) 79%
5a (X = OH) 63%b
MsCl, Et3N
Spiro[indoline-3,20-pyrrolidine] derivatives have received
much attention in the development of pharmaceutically active
molecules. These diazaspirocyles are mostly synthesized by
the 1,3-dipoloar cycloaddition of azomethine ylides derived
from isatins and secondary amines or ꢁ-amino acids.1 Because
the dipolarophiles available for the cycloaddition are limited to
the activated alkenes, the alternative methods need to be devel-
oped for the preparation of a wide variety of the azaspiro indo-
lines. Although the cyclization of 3-(3-aminoalkyl)indoles
would be a candidate, there has been reported only one example
of such a cyclization by the oxidation of 3-(3-ethylaminopro-
pyl)indole, giving the low yield of the cyclized product.2
Recently, we have developed the intramolecular SN2-type
reaction at the oxime sp2 nitrogen to prepare azaheterocycles.3
For the latest instances, cyclic imines and quinolines are synthe-
sized form ꢂ,ꢃ-unsaturated and ꢀ-aryl ketone oximes.3g,h Since
the reaction of indoles and electrophiles normally takes place
at their 3-position,4 we expected that spiro[indoline-3,20-pyrroli-
dine]s would be obtained from ꢀ-3-indolyl ketone oximes by a
similar intramolecular SN2-type cyclization. In this paper is de-
scribed this transformation reaction briefly.
ꢀ-3-Indolyl ketone oximes were readily prepared by the In-
Cl3-catalyzed reaction of indole and enones,4c followed by the
oximation8 of the resulting ketones. The syn and anti isomers5
of the oximes are separated by column chromatography on silica
gel. Thus obtained 4-(3-indolyl)butan-2-one anti-oxime 1a was
treated with methanesulfonyl chloride (1.1 molar amounts) and
triethylamine (2.2 molar amounts) at 0 ꢁC (Scheme 1). A com-
plex reaction mixture was obtained and the desired indolenine
derivative 3a was not isolated, whereas the same reaction of
the syn isomer of 1a gave only the O-sulfonylated oxime in
95% yield. As the intramolecular cyclization product, spiro indo-
lenine 3a, might have been readily hydrolyzed, the isolation of
the cyclized product was attempted after the protection of an
imino group. When pentafluorobenzoyl chloride6 was added to
the reaction mixture, spirocyclic 2-chloroindoline 4a7 was ob-
tained in 79% yield. In addition, quenching the acylation mixture
with aqueous sodium bicarbonate in acetone for 20 h yielded the
corresponding 2-hydroxy derivative 5a.7
C6F5COCl
3
Et3N
Me
N
N
H
N
Me
N
OMs
2a
3a
a 1a:MsCl:Et3N:C6 F5COCl = 1:1.1:2.2:1.05.
b The reaction mixture was treated with NaHCO3 (aq.) in acetone
for 20 h after the pentafluorobenzoylation.
Scheme 1. Synthesis of diazaspirocycle 4a and 5a from anti-
oxime 1a.a
Some examples for the transformation of ꢀ-3-indolyl ketone
oxime to spiro[indoline-3,20-pyrrolidine] derivatives are shown
in Table 1. Oximes 1b and 1c having alkyl substituents at the
ꢁ- or ꢀ-position gave the 2-hydroxy cyclized products7 5b and
5c in moderate yields, respectively (Entries 2 and 3).
Table 1. Transformation of 4-(3-indolyl)butan-2-one oximes 1
to spiro-cyclic 2-hydroxyindolines 5a
2 R1
R
1) MsCl, Et3N
0 °C, 1 h
R3
R3 R2
R1
Me
CH2Cl2
N
N
2) C6F5COCl, rt, 4 h
3) NaHCO3 (aq.)
acetone, rt, 20 h
2
OH
N
N
Me
H
O
5
1
OH
C6F5
Entry
Oxime
R1
R2
R3
Product (Yield)
1b
2c
3b
1a
1b
1c
H
Me
H
H
H
Me
H
H
Me
5a (63%)
5b (72%)
5c (74%)
a
b
c
1:MsCl:Et3N:C6F5COCl = 1:1.1:2.2:1.05.
NaHCO3 (aq.) was added 4 h after the addition of C6F5COCl.
NaHCO3 (aq.) was added after the extraction of the product obtained by the
treatment of C6F5COCl.
When ꢀ-(2-methyl-3-indolyl) ketone oxime 1d was treated
with methanesulfonyl chloride and triethylamine, the cyclization
also proceeded smoothly to yield azaspirocyclic indolenine 3d,
which was stable enough to be isolated in 95% yield by a column
chromatography on Florisil (Table 2, Entry 1). Also in a similar
cyclization of oxime 1e having a tert-butoxycarbonyl group at
the ꢀ-position of the oxime, 68% yield of the corresponding bi-
simine 3e7 was obtained (Table 2, Entry 2).
The formation of the diazaspiro compounds 4a and 5a indi-
cates that the indole ring attacks the oxime nitrogen at the 3-po-
sition, affording unstable indolenine derivative 3a. 4a was ob-
tained by the N-pentafluorobenzoylation of 3a at the less
hindered aldimine nitrogen.
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.1 (2004)
27
Table 2. Conversion of 4-(3-indolyl)butan-2-one oximes 1 to
spiroindolenine 3
This work was supported by the Grant-in-Aid for Scientific
Research on Priority Areas (A) No. 412 ‘‘Exploitation of Multi-
Element Cyclic Molecules’’ and the Grant-in-Aid for The 21st
Century COE Program for Frontiers in Fundamental
Chemistry from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
OH
R3
R3
N
MsCl, Et3N
Me
Me
N
R4
CH2Cl2
0 °C, Time
R4
N
N
H
References and Notes
1
1
3
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For some recent examples, see: a) T. Okauchi, M. Itonaga, T.
Minami, T. Owa, K. Kitoh, and H. Yoshino, Org. Lett., 2, 1485
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In this manuscript, syn and anti isomer of oxime derivatives are
defined when the hydroxy group on the oxime nitrogen is ori-
ented syn and anti to the nucleophilic moiety, respectively.
Trapping of the 3a with other electrophiles such as acetyl chlo-
ride, trifluoroacetic anhydride, benzyloxycarbonyl chloride,
and p-toluenesulfonyl chloride gave the complex mixture of
products.
Entry Oxime Time
R3
R4 Product (Yield)
1
2
1d
1e
1 h
6 h
H
t-BuO2C
Me 3d (95%)b
H
3e (68%)b,c
a
b
c
1:MsCl:Et3N = 1:1.1:2.2.
Isolated by column chromatography on Florisil.
NMR yield (anthracene as an internal standard).
Spiro[pyrrolidine-2,30-oxindole] derivatives are reported to
have a antimicrobial and antifungal acitivity,1j and were readily
obtained from diazaspirocycles 5. As shown in Scheme 2, treat-
ment of 5a with Dess–Martin periodinane and the successive re-
moval of N-pentafluorobenzoyl group resulted in the formation
of oxindole 6a. In addition, it is noteworthy that 6a was synthe-
sized from oxime 1a in one-pot procedure. After oxime 1a was
treated with methanesulfonyl chloride and triethylamine, excess
manganese dioxide was added to the mixture, yielding 6a in 53%
yield.
2
3
Me
Me
N
(i), (ii)
N
N
OH
N
O
O
H
C6F5
5a
6a 66%
OH
Me
N
(iii)
6a 53%
N
H
1a
4
Reagents: (i) Dess-Martin periodinane, CH2Cl2; (ii) NaOMe,
MeOH, rt, 10 h; (iii) MsCl, 2Et3N, 0 °C, 1 h, CH2Cl2 then
MnO2 (15 molar amounts), rt, overnight.
Scheme 2. Synthesis of spiro[pyrrolidine-2,30-oxindole] deriv-
ative 6a from 1a or 5a.
General experimental procedure is as follows (Scheme 1):
To a dichloromethane (3 mL) solution of 4-(3-indolyl)butan-2-
one oxime (1a) (0.30 mmol) and triethylamine (0.65 mmol)
was added methanesulfonyl chloride (0.33 mmol) at 0 ꢁC. After
1 h at 0 ꢁC, the reaction mixture was treated with a dichlorome-
thane (2 mL) solution of pentafluorobenzoyl chloride
(0.31 mmol) and was stirred at room temperature for 4 h, fol-
lowed by the addition of aqueous sodium bicarbonate and ace-
tone. After 20 h with stirring, the organic materials were extract-
ed with dichloromethane and dried over sodium sulfate. The
solvent was removed in vacuo, and the crude products were
purified by thin-layer chromatography (silica gel deactivated
with triethylamine, hexane:ethyl acetate = 1:2) to afford 30,40-di-
hydro-2-hydroxy-50-methyl-1-pentafluorobenzoylspiro[indoline-
3,20-[2H]pyrrole] (5a) (75 mg, 63%).
5
6
7
8
Compound 4a, 5b, and 3e were obtained as a mixture of two
diastereomers, while compound 5a and 5c were obtained as
a single diastereomer. The stereochemistry of 5a–c has not
been determined.
Yields of the oximes 1a–e: 1a, 95% (anti:syn = 3:1). 1b, 92%
(anti:syn = 3:1). 1c, 96% (anti:syn = 4:1). 1d, 95% (anti:syn =
3:1). 1e, 95% (anti:syn = 7:2).
Published on the web (Advance View) December 15, 2003; DOI 10.1246/cl.2004.26