The remarkable effect of the 7-substituent in the diastereoselective oxidative rearrangement of indoles: Asymmetric synthesis of 3,3-disubstituted oxindoles

Article abstract of DOI:10.1039/b613716d

The nature of the 7-substituent has a remarkable effect on the diastereoselectivity of the oxidative rearrangement of indole-2-carboxamides derived from (S)-2-methoxymethylpyrrolidine into chiral 3,3-disubstituted oxindoles. The Royal Society of Chemistry.

Full text of DOI:10.1039/b613716d

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The remarkable effect of the 7-substituent in the diastereoselective
oxidative rearrangement of indoles: Asymmetric synthesis of
3,3-disubstituted oxindoles{
Mathilde Lachia,a Cyril Poriel,b Alexandra M. Z. Slawinc and Christopher J. Moody*ab
Received (in Cambridge, UK) 20th September 2006, Accepted 13th October 2006
First published as an Advance Article on the web 26th October 2006
DOI: 10.1039/b613716d
The nature of the 7-substituent has a remarkable effect on the
diastereoselectivity of the oxidative rearrangement of indole-2-
carboxamides derived from (S)-2-methoxymethylpyrrolidine
into chiral 3,3-disubstituted oxindoles.
The construction of all carbon quaternary centres in an
asymmetric manner remains a challenging problem in organic
chemistry, not least because the process requires the creation of a
new C–C bond at a hindered centre.1,2 A number of elegant
solutions to the problem have been advanced over the last few
years and these are well illustrated by recent approaches to the
synthesis of 3,3-disubstituted oxindoles. Such compounds are
widely distributed in nature, and also serve as starting points for
the synthesis of more complex indole alkaloids. Thus, for example,
approaches based on the construction of the oxindole ring itself
employing the asymmetric Heck reaction have been developed,3 as
have those that use an asymmetric functionalization of an existing
oxindole.4–8 Asymmetric variants on the Black rearrangement9
have also been used; these feature the rearrangement of a
3-substituted-2-alkoxycarbonyloxyindole catalyzed by a chiral
derivative of DMAP.10,11 We now report an alternative approach
to the asymmetric synthesis of 3,3-disubstituted oxindoles using an
oxidative rearrangement of an indole-2-carboxamide bearing a
chiral auxiliary, in which the nature of the substituent at the
apparently remote indole 7-position plays a major, but totally
Scheme 1
unexpected, role.
The oxidative rearrangement of indoles to oxindoles upon
In connection with our efforts directed towards the total
synthesis of diazonamide A (Fig. 1),18,19 we were attracted to the
oxidative rearrangement of indoles for the construction of the C-10
quaternary centre (diazonamide A numbering), and wondered if
an asymmetric variant could be developed by employing a chiral
treatment with electrophilic halogenating agents has long been
known. Although the reaction has been investigated in simple
indoles,12–14 it has also found use in indole alkaloids,15,16 and has
recently been elegantly employed in a biogenetically patterned
transformation of the Corynanthe skeleton into the Strychnos
system.17 The generally accepted mechanism is shown in Scheme 1
and involves conversion of the indole 1 into the 3-haloindolenine 2,
followed by protonation to give cation 3, possibly stabilized by the
cyclic halonium ion, attack of a nucleophile (water) and finally
migration of the R2-group with loss of halide and formation of the
oxindole 5.
aSchool of Chemistry, University of Nottingham, University Park,
Nottingham, UK NG7 2RD. E-mail: c.j.moody@nottingham.ac.uk
bDepartment of Chemistry, University of Exeter, Stocker Road, Exeter,
UK EX4 4QD
cSchool of Chemistry, University of St. Andrews, Fife, Scotland, UK
KY16 9ST
{ Electronic supplementary information (ESI) available: General experi-
mental details, characterization data for chiral oxindoles 8, X-ray crystal
structures of 8f and 8g. See DOI: 10.1039/b613716d
Fig. 1 Diazonamide A
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Scheme 2
Fig. 2 X-Ray crystal structure of oxindole 8b.
Table 1 Diastereoselective oxidative rearrangement of indoles 7 into
oxindoles 8
diastereoisomers of oxindoles 8f and 8g could again be isolated by
crystallization, and their stereochemistry confirmed by X-ray
analysis (see ESI{). Further evidence that the effect of the indole
7-position was purely steric was obtained in the oxidative
rearrangement of the 7-phenylindole 7h that gave an 11 : 1 ratio
of oxindole products 8h. Finally it was demonstrated that the effect
was not limited to 3-arylindoles, and the 7-bromo-3-methylindole
SMP-derivative 7i gave a 4 : 1 ratio of oxindoles 8i, a ratio that was
increased to 15 : 1 when the acid catalyzed rearrangement step was
carried out at 0 uC rather than at room temperature. Again the
major diastereoisomer of oxindole 8i was readily obtained by
crystallization, and X-ray analysis established its stereochemistry
(Fig. 3).21
6–8
X
Y
R
8 Yield (%) dr
a
b
c
d
e
f
g
h
i
H
H
H
H
Ph
Ph
82
83
1.3 : 1
Br
Br
H
H
Cl
F
8 : 1
9.5 : 1
1.4 : 1
1.4 : 1
6 : 1
2 : 1
11 : 1
4 : 1 (15 : 1 at 0 uC)
4-Cl–C6H4 82
93
Br 4-Cl–C6H4 90
Br Ph
H
H
H
H
Ph
Ph
Ph
Me
91
95
75
90 (65)
Ph
Br
auxiliary at the indole 2-position (1, R2 = chiral auxiliary). The
chiral auxiliary investigated was (S)-2-methoxymethylpyrrolidine
(SMP), one of the most generally useful auxiliaries that has been
used in a very wide range of different applications.20
Hence the presence of a large substituent at the indole 7-position
has a dramatic effect on the stereoselectivity of the oxidative
rearrangement of the indoles 7. The influence of a substituent at a
seemingly remote position on the stereochemical outcome of an
auxiliary mediated reaction is truly remarkable and extremely
unusual. Therefore we sought some evidence for the exact nature
of this process. It was clear from NMR spectroscopy that the
initial chlorination step was poorly stereoselective. Thus chlorina-
tion of both 7b and 7i at room temperature gave an isolable
Thus a range of indole-2-carboxylates 6, prepared by the Fischer
indole synthesis, was converted into the corresponding (S)-2-
methoxymethylpyrrolidinamides 7, which were subjected to
oxidative rearrangement using tert-butyl hypochlorite as the
halogen source and HCl in ethanol to initiate the rearrangement.14
The oxindoles 8 were obtained in good to excellent yield after
chromatography (Scheme 2, Table 1) as a mixture of two
diastereoisomers due to the presence of the new chiral quaternary
centre. The first result was disappointing, the oxindole 8a being
formed as a ca. 1.3 : 1 mixture. However, since our projected
diazonamide synthesis required a suitable substituent that would
enable formation of the rings E–D biaryl bond at a later stage, we
investigated the corresponding 7-bromoindole 7b. Gratifyingly, the
oxindole 8b was formed as a 8 : 1 mixture of diastereoisomers. The
major diastereoisomer was isolated by crystallization, and
subsequent X-ray crystallographic analysis allowed the configura-
tion of the new chiral centre to be assigned as (S) (Fig. 2).21 The
corresponding 4-chlorophenyl derivative 7c behaved similarly.
Hence the presence of the bromine substituent at the indole
7-position appears to have a dramatic effect on the stereochemical
course of the oxidative rearrangement. That it is the 7-position that
is important was established by studies on the 5-bromoindoles 7d,e
that gave the corresponding oxindoles with poor diastereoselec-
tivity (Table 1). Stereoselectivity was restored in the rearrangement
of the 7-chloro- and 7-fluoroindoles 7f and 7g, although the
levels of selectivity were more modest. Nevertheless the major
Fig. 3 X-Ray crystal structure of oxindole 8i.
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Notes and references
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12 R. M. Acheson, J. M. Vernon and R. W. Snaith, J. Chem. Soc., 1964,
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Scheme 3
13 J. M. Muchowski, Can. J. Chem., 1970, 48, 422.
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16 K. V. Lichman, J. Chem. Soc. C, 1971, 2539.
3-chloroindolenine intermediate 9 (X = Br, R = Ph or Me) as a
1.4 : 1 mixture of diastereoisomers. It is in this intermediate that we
assume that the 7-substituent plays a role by severely limiting the
conformational mobility of the 2-methoxymethylpyrrolidine
group. Inspection of molecular models suggests that the con-
formation depicted in Scheme 3 would minimize steric interaction
both with the newly introduced chlorine and the large substituent
at C-7. Protonation at nitrogen followed by auxiliary-controlled
attack of ethanol from the least hindered side would then lead to
intermediate 10, whereupon SN1 loss of chloride with concomitant
migration of the auxiliary across the a-face would give 2-ethoxy-
indolenine 11 in which the stereochemistry of the final product is
already established before hydrolysis to the oxindole 8 upon
chromatography. In accord with our proposal, in the case of the
oxidative rearrangement of 7-bromoindole 7b, we were able to
isolate the ethoxyindolenine 11 (X = Br, R = Ph) and ascertain
that it was an 8 : 1 mixture of diastereoisomers. An alternative
explanation is that the a- and b-chloro epimers of indolenine 9 are
in equilibrium via the N-chloroindole as has been suggested in
simpler systems,22 with the equilibration possibly being assisted by
the presence of a substituent X, and it is the b-chloro compound,
with the chloride anti to the migrating group, that reacts faster.
The applications of this remarkable effect of a remote
substituent in the asymmetric synthesis of a range of 3,3-
disubstituted oxindoles are under investigation.
17 M. Ito, C. W. Clark, M. Mortimore, J. B. Goh and S. F. Martin, J. Am.
Chem. Soc., 2001, 123, 8003.
18 J. R. Davies, P. D. Kane and C. J. Moody, J. Org. Chem., 2005, 70,
7305.
19 F. N. Palmer, F. Lach, C. Poriel, A. G. Pepper, M. C. Bagley,
A. M. Z. Slawin and C. J. Moody, Org. Biomol. Chem., 2005, 3, 3805.
20 D. Enders and M. Klatt, Synthesis, 1996, 1403.
21 Full hemisphere of data collected, corrected for Lorentz and polariza-
tion and for absorption, using multiple equivalent reflections.
Refinements on F2 using SHELXTL. Compound 8b (crystallizes with
two independent molecules in the asymmetric unit and with 0.5 mol
CHCl3): Rigaku MM007 high brilliance generator, confocal optic,
Saturn 92 detector, colourless needle 0.2 6 0.01 6 0.01 mm,
C21.5H21.5BrCl1.5N2O3, Mr = 488.99, monoclinic, space group P2(1),
˚
a = 9.64370(19), b = 12.4445(12), c = 18.3737(17) A, b = 102.099(3)u, V =
3
˚
˚
2156.1(3) A , Z = 4, 2hmax 136u , CuKa l = 1.54718 A, T = 173(2) K,
rcalcd = 1.506 g cm23, m = 4.520 mm21 (max, min transmission 1.00,
0.3940), 28203 reflections collected, 7217 unique [R(int) = 0.1652], R1 =
0.0858, wR2 = 0.1330 for 4900 observed reflections [(I) . 2s (I)], max.
and min. residual electron density 0.494, 20.481 e A23. Flack parameter
˚
0.01(3). Compound 8i Rigaku MM007 high brilliance generator,
confocal optics, Mercury detector, colourless prism 0.1 6 0.03 6
0.03 mm, C16H19Br1N2O3, Mr = 367.24, orthorhombic, space group
˚
P212121, a = 8.5669(14), b = 12.7503(16), c = 14.900(3) A, V =
3
˚
˚
1627.6(4) A , Z = 4, 2hmax 50.7u , MoKa l = 0.71073 A, T = 93(2) K,
rcalcd = 1.499 g cm23, m = 2.539 mm21 (max., min. transmission 1.00,
0.7533), 10 463 reflections collected, 2932 unique [R(int) = 0.0274], R1 =
0.0206, wR2 = 0.0468 for 2707 observed reflections [(I) . 2s(I)], max.
and min. residual electron density 0.589, 20.294 e A23. Flack parameter
˚
20.005(7). CCDC 609781–609784. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b613716d.
22 M. De Rosa and J. L. T. Alonso, J. Org. Chem., 1978, 43, 2639.
This work was supported by the EPSRC.
288 | Chem. Commun., 2007, 286–288
This journal is ß The Royal Society of Chemistry 2007