Table 1. Examples of 3,3-Disubstituted Oxindole Synthesis via
Table 2. Variation in Yield of 8 and 10 upon Attempted
Extended Pummerer Reaction of 2-(Phenylsulfinyl)indoles
Pummerer-Initiated Cyclization of Indole Allylsilane Sulfoxide 7
entry activator
base
temp (°C) solvent 8a (%) 10a (%)
1
2
3
4
5
6
7
TFAA
TFAA
Tf2O
Tf2O
Tf2O
Tf2O
Tf2O
i-Pr2NEt
DTBPb
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
DTBP
-40
-75
-75
-75
-75
-75
-75
CH2Cl2
CH2Cl2
toluene
Et2O
CH2Cl2
CH2Cl2
CH2Cl2
64
58
<5
42
30
56
82
19
2,6-lutidine
a Yields reported are for chromatographically pure, characterized material.
b DTBP ) 2,6-di-tert-butylpyridine.
temperature led to varying amounts of the desired spiro-
methylenecyclohexane 2-(phenylthio)indolenine 8, Table 2.
These optimization studies revealed that use of 2 equiv of
Tf2O and 3 equiv of 2,6-lutidine with 0.005 M substrate in
CH2Cl2 at -75 °C afforded the highest yield of the desired
spirocyclic product. Interestingly, use of TFAA as an
activator provided only the trifluoroacetate-trapped product,
isolated as the unstable alcohol 10 after SiO2-induced
trifluoroacetate hydrolysis or solvolysis upon attempted
chromatographic purification (Table 2, entries 1-2). It
appears that the electrophilicity at C(3) of the indole core
(cf. 3) is expressed under these conditions, but then the weak
nucleophile trifluoroacetate surprisingly out-competes the
pendant alkene nucleophile (allylsilane or propenyl; the
timing of TMS loss is not known) for this reactive intermedi-
ate. The hydrolysis of the thioimidate function of 8 proceeded
in higher yield using an oxidative protocol (CAN, H2O)4
rather than the standard Hg2+-promoted procedure.5 The
thioimidate within 10 lacks the sensitive exocyclic alkene,
and mercury-assisted hydrolysis cleanly provides the ex-
pected 3-hydroxyoxindole 11 without complication.
A second substrate of interest, 12, featured a silyl enol
ether nucleophilic trap (Table 1, entry b). Treatment of this
species under the conditions optimized for the allylsilane
analogue led to formation of the expected spirocyclohexa-
none product 13 in good yield. Unlike the related alkene-
bearing species 8, ketone 13 could be readily hydrolyzed
with Hg2+ assistance to provide the oxindole product 14 in
excellent yield.
A departure from C-C bond-forming nucleophiles fea-
tured ketone 15 (Table 1, entry c) as the Pummerer
cyclization substrate. In this instance, cyclization at oxygen
is readily accomplished, presumably via the derived enol.
The O-C over C-C bond-forming selectivity observed
within this putative enol-bearing Pummerer intermediate
might be attributed to the facility of 6-enol-exo cyclizations
over the alternative C-C bond-forming 6-enol-endo pathway.
a Conditions: 7, see Table 2; 12, 15, 17, Tf2O, 2,6-lutidine CH2Cl2, -75
°C; 20, Tf2O, 2,6-lutidine, indicated solvent/temperature. b Conditions: 9,
CAN, H2O; 10, 13, 18, HgCl2, H2O.
with (additive), nucleophilic attack. In either circumstance,
the transposition of “oxidation” results in electrophilic
activation at C(3) (cf. 1 f 2 or 3). This electrophilicity can
be quenched through internal trapping by a pendant nucleo-
philic atom to provide a thioimidate product 5 en route to
the ultimate spirocyclic oxindole product 6. Nucleophilic
addition at other accessible and conceivably electrophilic sites
in 2 or 3 such as C(2) or C(4) is likely to be dissuaded by
the loss of aromaticity upon bond formation. In this way,
the regiochemistry of nucleophile addition is assured.
A search to uncover carbon-based nucleophiles that would
tolerate both sulfoxide formation and subsequent Pummerer
reaction began with the allylsilane sulfoxide 7, Table 1.
Exposure of this sulfoxide to either of the two common
Pummerer activators, triflic anhydride (Tf2O) or trifluoro-
acetic anhydride (TFAA), in the presence of a variety of
bases in moderately polar to nonpolar solvents at low
The occurrence of several 3,3-disubstituted oxindole-
derived natural products formally originating from tryptamine6
provided the motivation to explore this Pummerer cyclization
chemistry of the tryptamine derivative 17 (Table 1, entry
(4) Ho, T.-L.; Ho, H.; Wong, C. M. J. Chem. Soc., Chem. Commun.
1972, 791.
(5) Satchell, D. P. N. Chem. Soc. ReV. 1977, 6, 345-371.
1870
Org. Lett., Vol. 6, No. 11, 2004