attempts.7 As exemplified with the chiral indole-2-sulfoxide
1, significant sulfur-to-carbon transfer of stereochemical
information is possible only if the intermediacy of an achiral
thionium ion 6 can be avoided. In earlier studies on other
systems, both concerted bond-breaking/bond-making schemes4
and, in independent work, tight ion pairs that preserve
(planar) chirality5,6 have been invoked as the means to steer
reaction away from an achiral thionium ion.
With unsaturated sulfoxide substrates, the course of the
Pummerer reaction embodies a mechanistic dichotomy: re-
arrangement via either an additiVe or a Vinylogous pathway,
as exemplified with the indole-2-sulfoxide substrate in
Scheme 1. The additive pathway offers an intrinsic conduit
for passing stereochemical information from sulfur to the
newly forming C-Nu1 bond (2f3), at least in principle (cf.
Marino’s work4). On the other hand, the vinylogous alterna-
tive can proceed either with loss of stereochemistry through
an achiral thionium ion 6 or with preservation of stereo-
chemical information via a planar chiral tight ion pair 5. In
the case of the indole-2-sulfoxides, the nucleophilic addition
products derived from either pathway are identical, prevent-
ing a simple assignment of mechanism based on the product
formed.
excesses of the ketone precursors to 9a/b were assayed at >
98% by the chiral shift reagent (S)-2,2,2-trifluoroanthryl
ethanol, as expected by the use of enantiopure 10.
The Pummerer chemistry commenced with the simple
allylsilane-bearing sulfoxide 7a, Table 1. Unfortunately, 1H
Table 1. Pummerer-Initiated Cyclization of the
Allylsilane-Bearing Chiral (S)-Indole-2-sulfoxide 10a
polaritya
(viscos)b
yield 13
(%)
eec
(%)
entry
solvent
T (°C)
1
2
3
4
5
6
7
8
CF3CH2OH
n-C5H11OH
C2H2Cl4
CH2Cl2
Et2O
toluene
toluene
Et2O
59.8 (2.0)
49.1 (25.4)
39.4 (3.7)
40.7 (0.73)
34.5 (0.28)
33.9 (1.2)
-40
-78
-40
-78
-78
-78
-90
-110
18
17
17
57
39
41
NR
NR
0
0
26
38
49
55
Six chiral indole-2-sulfoxides 7a/b, 8a/b, and 9a/b were
chosen to study the possibility of S f C chirality transfer,
Figure 1 (see the Supporting Information for syntheses). The
a ET(30) values (kcal/mol) from: Reichardt, C. Chem. ReV. 1994, 94,
2319-2358. b Centipoise, from: CRC Handbook of Chemistry and Physics,
85th ed.; Lide, D. R., Ed.; CRC Press: Boca Raton, 2004; 2004-2005.
c Average of two independent trials.
NMR chiral shift reagent studies with thioimidate 11 did not
lead to identification of a characteristic signal that permitted
differentiation of the enantiomers. Only upon conversion of
11 into 13 were the enantiomers distinguishable by use of
Eu(tfc)3 (see the Supporting Information), but the absolute
configuration of the newly formed quaternary stereogenic
center could not be assigned at this time.
Both yield and enantiomeric excess with 7a responded to
solvent variation, as the less polar solvents led to product in
both higher yield and greater ee. The alcohol solvents
performed poorly by any criteria, although the role of
competitive solvent sulfonylation in diverting the reaction
was not assessed. Switching to the non-hydroxylic and less
polar solvents C2H2Cl4 and CH2Cl2 provided the first glimpse
of success by delivering product in modest ee. By switching
to the slightly less polar but more viscous toluene as solvent,
the maximum ee (55%) was observed. Temperatures lower
than -78 °C did not lead to productive reaction for these
substrates.
Examination of 7b (R ) OCH3) was undertaken with the
expectation that the electronic character of R would have
little impact on a Pummerer reaction proceeding through an
additive Sn2′-like path but might exert some influence on
the reaction through the vinylogous Sn1-like path as a
consequence of a Hammond postulate-type argument. Greater
incursion of the vinylogous path from 7b might promote
reaction through achiral 6, leading to a drop in ee’s compared
Figure 1. Chiral indole-2-sulfoxide substrates for Pummerer-
mediated oxidative cyclization.
key transformation in each of these substrate syntheses
involved the sulfinylation of an indole C(2) anion with the
chiral sulfoxide transfer reagent 10 introduced by Evans,8
following the protocols described in the pioneering studies
of Marino.4 The enantiomeric excesses (>98%, detection
limit) of the chiral sulfoxides 7a/b were verified by chiral
shift reagent studies with Eu(tfc)3, whereas the enantiomeric
(4) (a) Marino, J. P.; Perez, A. D. J. Am. Chem. Soc. 1984, 106, 7643-
7644. (b) Marino, J. P.; Bogdan, S.; Kimura, K. J. Am. Chem. Soc. 1992,
114, 5566-5572.
(5) Kita, Y.; Shibata, N.; Fukui, S.; Masahiko, B.; Fujita, S. J. Chem.
Soc., Perkin Trans. 1 1997, 1763-1767.
(6) (a) Garc´ıa Ruano, J. L.; Alema´n, J.; Aranda, M. T.; Are´valo, M. J.;
Padwa, A. Org. Lett. 2005, 7, 19-22. (b) Garc´ıa Ruano, J. L.; Alema´n, J.;
Aranda, M. T.; Are´valo, M. J.; Padwa, A. Phosphorus, Sulfur, Silicon 2005,
180, 1497-1498. (c) Garc´ıa Ruano, J. L.; Alema´n, J.; Padwa, A. Org. Lett.
2004, 6, 1757-1760.
(7) Feldman, K. S. Tetrahedron 2006, 62, 5003-5034.
(8) Evans, D. A.; Faul, M. M.; Colombo, L.; Bisaha, J. J.; Clardy, J.;
Cherry, D. J. Am. Chem. Soc. 1992, 114, 5977-5985.
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Org. Lett., Vol. 8, No. 18, 2006