Extending Pummerer reaction chemistry. Development of a strategy for the regio- and stereoselective oxidative cyclization of 3-(ω-nucleophile)- tethered indoles

Article abstract of DOI:10.1021/jo050896w

The brominative cyclization of diastereomeric β-silyloxy tryptophan derivatives proceeded with divergent regiochemistry (C(2) or C(3) addition), depending on the relative stereochemistry of the silyloxy substituent. This lack of C(2) vs C(3) regiochemical predictability led to the development of a new approach, which featured Pummerer-type chemistry on an indole C(2) sulfoxide or sulfide substrate, for steering nucleophilic addition to C(3) of the indole. Extension of this transformation from carboxylate nucleophiles to carbon analogues such as allylsilane, silyl enol ether, and silyl ketene iminal bearing substrates led to the formation of spirocyclic oxindole derivatives in good yields with complete regioselectivity for C(3) cyclization and with good diastereoselectivity where relevant.

Full text of DOI:10.1021/jo050896w

Extending Pummerer Reaction Chemistry. Development of a
Strategy for the Regio- and Stereoselective Oxidative Cyclization
of 3-(ω-Nucleophile)-Tethered Indoles
Ken S. Feldman,* Daniela Boneva Vidulova, and Andrew G. Karatjas
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802
ksf@chem.psu.edu
Received May 4, 2005
The brominative cyclization of diastereomeric â-silyloxy tryptophan derivatives proceeded with
divergent regiochemistry (C(2) or C(3) addition), depending on the relative stereochemistry of the
silyloxy substituent. This lack of C(2) vs C(3) regiochemical predictability led to the development
of a new approach, which featured Pummerer-type chemistry on an indole C(2) sulfoxide or sulfide
substrate, for steering nucleophilic addition to C(3) of the indole. Extension of this transformation
from carboxylate nucleophiles to carbon analogues such as allylsilane, silyl enol ether, and silyl
ketene iminal bearing substrates led to the formation of spirocyclic oxindole derivatives in good
yields with complete regioselectivity for C(3) cyclization and with good diastereoselectivity where
relevant.
SCHEME 1
The oxidative cyclization of tryptophan derivatives has
served as a workable strategy for synthesis efforts
directed toward members of the tryptoquivaline family
of mycotoxins.1 The scope and limitations of this process
are summarized by the conversions of 1 into the diaster-
eomeric products 2 and 3,1,2 Scheme 1. With the singular
exception shown in entry b,1a the diastereoselectivity is
typically quite modest. In addition to these discouraging
observations, further problems occasionally arise in the
form of either (1) product overoxidation3 or (2) a lack of
regiochemical control (C(3) vs C(2)) upon nucleophile
(1) (a) Bu¨chi, G.; DeShong, P. R.; Katsumura, S.; Sugimura, Y. J.
Am. Chem. Soc. 1979, 101, 5084-5086. (b) Ohnuma, T.; Kimura, Y.;
Ban, Y. Tetrahedron Lett. 1981, 22, 4969-4972. (c) Nakagawa, M.;
Taniguchi, M.; Sodeoka, M.; Ito, M.; Yamaguchi, K.; Hino, T. J. Am.
Chem. Soc. 1983, 105, 3709-3710. (d) Nakagawa, M.; Sodeoka, M.;
Yamaguchi, K.; Hino, T. Chem. Pharm. Bull. 1984, 32, 1373-1384.
(2) (a) Lawson, W. B.; Patchornik, A.; Witkop, B.J. Am. Chem. Soc.
1960, 82, 5918-5923. (b) Hinman, R. L.; Bauman, C. P. J. Org. Chem.
1964, 29, 1206-1214. (c) Hinman, R. L.; Bauman, C. P. J. Org. Chem.
1964, 29, 2431-2437. (d) Nagasaka, T.; Ohki, S. Chem. Pharm. Bull.
1971, 19, 603-611. (e) Palla, G.; Marchelli, R.; Casnati, G.; Dossena,
A. Gazz. Chim. Ital. 1982, 112, 535-536. (f) Ohnuma, T.; Kasuya, H.;
Kimura, Y.; Ban, Y. Heterocycles 1982, 17, 377-380. (g) Labroo, R. B.;
Labroo, V. M.; King, M. M.; Cohen, L. A. J. Org. Chem. 1991, 56, 3637-
3642.
addition to the oxidized, electrophilic indole unit.4 Despite
these potential shortcomings of tryptophan oxidative
(3) (a) Somei, M.; Noguchi, K.; Yamagami, R.; Kawada, Y.; Yamada,
K.; Yamada, F. Heterocycles 2000, 53, 7-10. (b) Wang, H.; Ganesan,
A. J. Org. Chem. 2000, 65, 4685-4693. (c) Irikawa, H.; Mutoh, S.;
Uehara, M.; Okumura, Y. Bull. Chem. Soc. Jpn. 1989, 62, 3031-3033.
(d) Gu¨ller, Borschberg, H.-J. Helv. Chim. Acta 1993, 76, 1847-1862.
(4) Braun, N. A.; Ousmer, M.; Bray, J. D.; Bouchu, D.; Peters, K.;
Peters, E.-M.; Ciufolini, M. A. J. Org. Chem. 2000, 65, 4397-4408.
10.1021/jo050896w CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/09/2005
J. Org. Chem. 2005, 70, 6429-6440
6429

Feldman et al.
SCHEME 2
cyclization chemistry, the recent discovery of the complex
20S proteosome inhibitor TMC-95A (4)5 provided motiva-
tion to revisit this transform with the goal of designing
a possibly biomimetic synthesis of the oxindole core 5 via
an oxidative cyclization of the â-oxygenated tryptophan
derivative 6. In this instance, the additional steric
interactions engendered between the peri-positioned
hydrogen Hp and the group at the â-carbon (Hâ vs OP)
might provide a bias for cyclization favoring the desired
stereochemistry at C(6) (TMC-95A numbering), vide
infra. An additional benefit of reaction through 6 might
stem from the Felkin-Ahn-type mixing between the now
electrophilic C(6) carbon and the adjacent, perpendicu-
larly disposed OP antibond, an electronic advantage not
shared with the possible diastereomeric transition state
featuring alignment between C(6) and Hâ. Although a
case for stereochemical control can be made in this
tryptophan oxidative cyclization substrate, other poten-
tial problems (overoxidation, regioselectivity of cycliza-
tion, yield) cannot be so readily addressed by a priori
argument.
A project on the oxidative cyclization of species related
to 6 was initiated to provide an experimental test of these
ideas, with the downstream aim of incorporating any
advances in tryptophan oxidative cyclization chemistry
into a synthesis of TMC-95A.6 As it transpired, the
cyclization of â-oxygenated tryptophan derivatives pro-
ceeded with mixed results (Scheme 2) using documented
protocols (cf. Scheme 1, 1 f 2/3). These disappointing
results provided the impetus to develop an alternative
approach to tryptophan, and more generally, indole,
oxidative cyclizations that proceeds in good-to-excellent
yields and without any evidence for product overoxidation
or undesired regiochemistry.7 This approach features an
advance in Pummerer reaction chemistry that serves to
formally transfer oxidation from sulfur positioned at C(2)
of the indole nucleus to C(3), thus enabling bond forma-
tion at that site. The details of both the brominative
cyclization attempts on â-oxygenated tryptophan deriva-
tives and the emerging Pummerer-triggered oxidative
cyclization chemistry are presented below.
at C(6). Based upon the results with 1, the stereochem-
istry at the amide-bearing carbon C(8) was not expected
to exert much influence on the diastereoselectivity of
cyclization, but examining both diastereomers 9 and 13
will test this assumption directly. The synthesis of both
cyclization substrates relied on Sharpless asymmetric
amidohydroxylation and dihydroxylation,8 respectively,
to set the relative and absolute stereochemistry. The
observed enantiomeric excesses for both reactions ex-
ceeded 99% (detection limit, HPLC with an OJ-H col-
umn). The synthesis of 9 was completed by hydroxyl
protection and ester hydrolysis, whereas the sequence
that converted diol 11 into the diastereomeric cyclization
precursor 13 was more indirect and exploited recent
advances from the Boger laboratory on R-azidation
chemistry.9
The initial foray into oxidative cyclization of â-oxygen-
ated tryptophan derivatives encompassed the two dia-
stereomeric species 9 and 13, Scheme 2. Substrate 13
has the correct relative stereochemistry at C(7) and C(8)
(TMC-95A numbering) for TMC-95A synthesis, whereas
9 would lead to a diastereomeric oxindole product. This
study focused on determining the relationship between
the C(7) substituents and the emerging stereochemistry
In the critical tests of this hypothesis, both 9 and 13
were subjected to a range of oxidative cyclization proce-
dures (cf. Scheme 1, 1 f 2/3), but it was only with NBS/
NaHCO3/t-BuOH/H2O that productive cyclization was
observed. The conversion of 9 into the butyrolactone 10
proceeded along orthodox lines, albeit in modest yield. A
single diastereomer of 10 was detected, and the stereo-
chemical outcome is nicely rationalized by reaction
through the construct 6. This stereochemical assignment
was based upon the observation of a nOe between the
hydrogen on C(7) and the peri-positioned aryl hydrogen.
It is noteworthy that only the N-tosyl substrates 9 and
13 participated in this cyclizationsprevious scouting
experiments with the N-H indole analogue of 13 failed
to provide cyclized product under any experimental
regimen examined.
(5) Isolation. (a) Kohno, J.; Koguchi, Y.; Nishio, M.; Nakao, K.;
Kuroda, M.; Shimizu, R.; Ohnuki, T.; Komatsubara, S. J. Org. Chem.
2000, 65, 990-995. Total synthesis. (b) Lin, S.; Danishefsky, S. J.
Angew. Chem., Int. Ed. 2002, 41, 512-515. (c) Albrecht, B. K.;
Williams, R. M. Org. Lett. 2003, 5, 197-200. (d) Inoue, M.; Sakazaki,
H.; Furuyama, H.; Hirama, M. Angew. Chem., Int. Ed. 2003, 42, 2654-
2657. Synthesis studies. (e) Ma, D.; Wu, Q. Tetrahedron Lett. 2000,
41, 9089-9093. (f) Ma, D.; Wu, Q. Tetrahedron Lett. 2001, 42, 5279-
5281. (g) Kaiser, M.; Siciliano, C.; Assfalg-Machleidt, I.; Groll, M.;
Milbradt, A. G.; Moroder, L. Org. Lett. 2003, 5, 3435-3437. (h)
Berthelot, A.; Piguel, S.; Le Dour, G.; Vidal, J. J. Org. Chem. 2003,
68, 9835-9838. (i) Yang, Z.-Q.; Kwok, B. H. B.; Lin, S.; Koldobskiy,
M. A.; Crews, C. M.; Danishefsky, S. J. ChemBioChem 2003, 4, 508-
513. (j) Lin, S.; Yang, Z.-Q,; Kwok, B. H. B.; Koldobskiy, M.; Crews, C.
M.; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 6347-6355.
(6) Feldman, K. S.; Karatjas, A. G. Org. Lett. 2004, 6, 2849-2852.
(7) (a) Feldman, K. S.; Vidulova, D. B. Org. Lett. 2004, 6, 1869-
1871. (b) Feldman, K. S.; Vidulova, D. B. Tetrahedron Lett. 2004, 45,
5035-5037.
The cyclization of the stereochemically “correct” isomer
13 was investigated next, and in light of the encouraging
(8) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483-2547. (b) Tao, B.; Schlingloff, G.; Sharpless, K.
B. Tetrahedron Lett. 1998, 39, 2507-2510.
(9) Boger, D. L.: Patane, M. A.; Zhou, J. J. Am. Chem. Soc. 1994,
116, 6, 8544-8556.
6430 J. Org. Chem., Vol. 70, No. 16, 2005

Extending Pummerer Reaction Chemistry
of H-X (termed the “vinylogous Pummerer reaction”10).
Cyclization of the carboxylate oxygen into C(3) rather
than the thionium ion at C(2), might be favored since it
would restore aromaticity, whereas the latter course
would not. This process would lead unambiguously to the
butyrolactone product 17, and subsequent hydrolysis of
the thioimidate moiety would deliver an oxindole product
appropriately functionalized for TMC-95A synthesis. A
mechanistic alternative to the vinylogous Pummerer
pathway from 15 to 17 may intervene. Termed the
“additive Pummerer reaction”,11 this sequence proceeds
with Sn2′-like displacement of X by the nucleophile in a
presumably concerted manner. As in the vinylogous
mechanism, carboxylate attack strictly at C(3) would be
expected based upon the construct 18. The thionium ion-
containing product 19 then can deprotonate to furnish
the same thioimidate 17. Irrespective of the mechanistic
intricacies, a developing steric interaction between OP1
and Hp in diastereomeric transition state 16b (or its
additive Pummerer equivalent) should enforce reaction
through 16a and afford the desired stereochemical result.
SCHEME 3
result with 9, formation of the TMC-95A-like diastere-
omer of 10 was expected. Indeed, exposure of 13 to the
successful NBS procedure did provide a single lactone
product in good yield, but an unusually low lactone IR
absorbance at 1764 cm-1 signaled problems (compare
1810 cm-1 for 10; ∼ 1800 cm-1 for 2/3). Further spectro-
scopic characterization pointed to the valerolactone struc-
ture 14, a species that presumably originates with
nucleophilic carboxylate attack at C(2) of the indole
system. The stereochemical relationship between the ring
fusion and the preexisting C(7) and C(8) centers was not
determined. This diversion of reactivity to C(2) has been
observed previously in indole oxidative cyclizations.1d It
appears that a lack of regiochemical control has thwarted
this approach to the TMC-95A oxindole core. The reasons
for the different behavior of 9 and 13 remain a matter of
speculation, but problems with eclipsing interactions
between the OTBS and NHCBz substituents in a forming
five-membered ring derived from 13 (absent with the
diastereomeric substrate 9) might play a role in directing
13 down an alternative path. In this scenario, a regioi-
someric six-membered ring transition state, which fea-
tures a less penalizing gauche-type interaction between
the C(7) and C(8) substituents, appears to be preferred.
Whatever the reason, it became clear that the bromina-
tive cyclization approach to the TMC-95A oxindole frag-
ment 5 was not going to reach fruition.
These discouraging results prompted a reevaluation of
the approach but not the overall strategy, as a biomimetic
oxidative cyclization theme still held its appeal. In
considering what might have gone wrong with 13, it
became apparent that incorporation of some additional
driving force might be necessary to overcome the bur-
geoning eclipsing interactions between OTBS and NH-
CBz and thereby favor the desired C(3) cyclization
pathway over the undesired C(2) alternative. Upon
evaluating options along these lines, the idea of coupling
C(3)-specific nucleophilic addition with rearomatization
of a transient indole-derived aza-orthoquinonedimethane
formed from oxidation was intriguing. One manifestation
of this strategy is detailed in Scheme 3, where Pummerer
chemistry originating with indole C(2) sulfoxide 15 might
lead to such an intermediate 16 via a base-promoted loss
The exploration of this Pummerer-based oxidative
cyclization strategy began, and nearly ended, with the
unrewarded attempts to utilize the model N-BOC tryp-
tophan derived substrate 22, Scheme 4. This sulfoxide
as a mixture of diastereomers was readily available from
N-BOC tryptophan in two well-precedented steps.12
Unfortunately, all attempts to engage this species in
Pummerer chemistry failed to deliver even trace amounts
of cyclized lactone product. Matters improved consider-
ably when the standard sulfoxide/acylation Pummerer
trigger was replaced with an alternative initiation com-
bination, the hypervalent iodine reagent PhI(CN)OTf and
sulfide 21. Use of this iodonium reagent, first introduced
by Stang and Zhdankin in 1991,13 provided the first
glimpse of success in these trials as the butyrolactone-
containing product 23 was obtained (1:1 mixture of
diastereomers) in encouraging yield. Why should the
(10) (a) Kosugi, H.; Uda, H.; Yamagiwa, S. J. Chem. Soc., Chem.
Commun. 1975, 192-193. (b) Jung, M. E.; Kim, C.; Bussche, L. v.d. J.
Org. Chem. 1994, 59, 3248-3249. (c) Jung, M. E.; Jachiet, D.; Khan,
S. I.; Kim, C. Tetrahedron Lett. 1995, 36, 361-364 (d) Kuethe, J. T.;
Cochran, J. E.; Padwa, A. J. Org. Chem. 1995, 60, 7082-7083. (e)
Padwa, A.; Kuethe, J. T. J. Org. Chem. 1998, 63, 4256-4268. (f) Akai,
S.; Morita, N.; Iio, K.; Nakamura, Y.; Kita, Y. Org. Lett. 2000, 2, 2279-
2282.
(11) (a) Kitchin, J.; Stoodley, R. J. J. Chem. Soc., Chem. Commun.
1972, 959-960. (b) Kosugi, H.; Uda, H.; Yamagawa, S. J. Chem. Soc.,
Chem Commun. 1976, 71-72. (c) Re´amonn, L. S. S.; O’Sullivan, W. I.
J. Chem. Soc., Chem. Commun. 1976, 642-643. (d) King, R. R. J. Org.
Chem. 1980, 45, 5347-5349. (e) Garcia, J.; Ortiz, C.; Greenhouse, R.
J. Org. Chem. 1988, 53, 2634-2637. (f) Marino, J. P.; Neisser, M. J.
Am. Chem. Soc. 1981, 103, 7687-7689. (g) Marino, J. P.; Perez, A. D.
J. Am. Chem. Soc. 1984, 106, 7643-7644. (h) Marino, J. P.; Ferna´ndez
de la Pradilla, R. Tetrahedron Lett. 1985, 26, 5381-5384. (i) Posner,
G. H.; Asirvatham, E.; Ali, S. F. J. Chem. Soc., Chem. Commun. 1985,
542-543. (j) Marino, J. P.; Ferna´ndez de la Pradilla, R.; Laborde, E.
Synthesis 1987, 1088-1091. (k) Kita, Y.; Tamura, O.; Itoh, F.; Yasuda,
H.; Miki, T.; Tamura, Y. Chem. Pharm. Bull. 1987, 35, 562-569. (l)
Kosugi, H.; Tagami, K.; Takahashi, A.; Kanna, H.; Uda, H. J. Chem.
Soc., Perkin Trans. 1 1989, 935-943. (m) Craig, D.; Daniels, K.
Tetrahedron Lett. 1990, 31, 6441-6444. (n) Craig, D.; Daniels, K.;
MacKenzie, A. R. Tetrahedron Lett. 1991, 32, 6973-6976. (o) Iwata,
C.; Maezaki, N.; Kurumada, T.; Fukuyama, H.; Sugiyama, K.;
Imanishi, T. J. Chem. Soc., Chem. Commun. 1991, 1408-1409. (p)
Marino, J. P.; Bogdan, S.; Kimura, K. J. Am. Chem. Soc. 1992, 114,
5566-5572. (q) Shibata, N.; Fujimori, C.; Fujita, S.; Kita, Y. Chem.
Pharm. Bull. 1996, 44, 892-894.
(12) Crich, D.; Davies, J. W. Tetrahedron Lett. 1989, 30, 4307-4308.
(13) Stang, P. J.; Williamson, B. L.; Zhdankin, V. V. J. Am. Chem.
Soc. 1991, 113, 5870-5871.
J. Org. Chem, Vol. 70, No. 16, 2005 6431

Feldman et al.
SCHEME 4
SCHEME 5
iodonium/sulfide initiation work whereas the sulfoxide
acylation chemistry failed? Speculation might focus on
the culpability of the acid function in 22, as formation of
a mixed anhydride upon exposure to acylation conditions
might compete with the desired sulfoxide acylation. This
mixed anhydride itself could then acylate the sulfoxide
to form a seven-membered ring product whose confor-
mational constraints might make attaining the necessary
stereoelectronic alignment between the C(3) p orbital and
the scissile S-O bond energetically prohibitive. The
sulfide/hypervalent iodonium system, on the other hand
would face no such competition, as these reagents do not
activate carboxylic acids for acylation. A test of this
hypothesis came with use of the sensitive silyl ester
sulfoxide substrate 24, formed by carboxylate silylation
and then sulfide oxidation within 21. Treatment of this
sulfoxide with trifluoroacetic anhydride and Hunig’s base
did furnish the same butyrolactone 23, again as a 1:1
mixture of diastereomers, in modest yield. No other
characterizable materials were isolated from this trans-
formation, and so it is not possible to determine what
other competing reactions intervene, although the insta-
bility of the TBS-ester may have played a role in the poor
yield of the transformation. Later studies with other
N-BOC substrates (vide infra) suggest that this carbam-
ate unit also serves as a locus of unwanted reactivity that
diverts starting material. Attempts to extend Pummerer
reactivity to alkyl ester substrates such as the methyl
ester 25 did not expand the scope of the transform
significantly. The desired butyrolactone product 23 (1:1
mixture of diastereomers) was formed in the typical 30%
yield, but in this instance a near equal amount of the
C(3)-hydroxylated species 26 was observed also. Presum-
ably, this product resulted from trifluoroacetate trapping
(followed by hydrolysis upon workup) of the Pummerer-
generated C(3) electrophile in competition with internal
delivery of the carboxylate nucleophile. These results,
taken together, lend support to the notion that this
Pummerer-based strategy for C(3) selective tryptophan
oxidative cyclization is indeed feasible. However, the
implementation of this idea is beset with a range of
competitive reactions that limit yield. Complete regiose-
lectivity for C(3) carboxylate addition is the most valuable
asset, although this selectivity has yet to be tested in the
more demanding â-oxygenated series of substrates rel-
evant to TMC-95A synthesis.
Extending these trials to the aforementioned â-oxygen-
ated substrates of interest for TMC-95A synthesis is
detailed in Scheme 5. The initial entry point is the C(2)
thiophenyl analogue of 13, compound 30. This cyclization
substrate was prepared via initial substitution of thio-
phenol for chloride within the known aldehyde 27.14,15
Emmons-Horner extension of the aldehyde within 28
afforded an unsaturated methyl ester that was processed
through the Sharpless/Boger chemistry (>99% ee in the
dihydroxylation, HPLC with an OH-J column) much like
the des-thiophenyl version (cf. Scheme 2). In this in-
(14) Hollis Showalter, H. D.; Sercel, A. D.; Leja, B. M.; Wolfangel,
C. D.; Ambroso, L. A.; Elliott, W. L.; Fry, D. W.; Kraker, A. J.; Howard,
C. T.; Lu, G. H.; Moore, C. W.; Nelson, J. M.; Roberts, B. J.; Vincent,
P. W.; Denny, W. A.; Thompson, A. M. J. Med. Chem. 1997, 40, 413-
426.
(15) Ruhland, T.; Pedersen, H.; Andersen, K. Synthesis 2003, 2236-
2240.
6432 J. Org. Chem., Vol. 70, No. 16, 2005

Extending Pummerer Reaction Chemistry
SCHEME 6
stance, however, the azide function was retained in the
cyclization substrate 30, as attempts to oxidatively cyclize
N-carbamate versions of 30 led to competitive participa-
tion of the carbamate carbonyl as a nucleophile (cf. 36
f 37). Examination of the PhI(CN)OTf-promoted Pum-
merer cyclization of 30 included optimization of yield with
respect to solvent, temperature, and base. Solvent polar-
ity played the largest role (see Table in Scheme 5), with
the best yields observed in the least polar solvents
toluene and CH2Cl2. Despite extensive exploration of
parameter space for this transformation, the yield could
not be coaxed above 40%. Cyclization attempts with the
sulfoxide derived from 30 were not successful, as antici-
pated from the results with 22. The product spirobuty-
rolactone 31 was formed as a single diastereomer whose
relative stereochemistry is in complete accord with the
expectations of cyclization through the model transition
state 16a (or its additive Pummerer equivalent 18). This
stereochemical assignment was based the observation of
the nOe signal shown with structure 32. This spirolac-
tone has the correct relative and absolute stereochemistry
for use in TMC-95A synthesis, and ceric ammonium
nitrate-mediated hydrolysis of the thioimidate function
within 31 delivered the expected oxindole product 32 in
moderate yield. Further attempts to identify structural
perturbations that might lead to improved yield of 31
included the tert-butyl esters 33 and 34. Both species did
perform with modest efficiency in the Pummerer process
upon exposure to the appropriate initiator (PhI(CN)OTf
with the sulfide 33 and Tf2O with the sulfoxide 34), but
overall, the use of esters in place of the carboxylic acid
reside in 30 did not extend the reaction in useful ways.
A reminder that competitive reactions are ever present
came with attempts to perform the oxidative cyclization
sequence on the N-BOC substrate 36, prepared by azide
reduction and in situ acylation within 35. In this case,
the only cyclized material isolated corresponded to C(3)-O
bond formation that originated with the carbamate’s
carbonyl function. As with the earlier substrates featur-
ing â-oxygenation, this material was formed as a single
(unassigned) stereoisomer. The contrasting reactions of
36 and its azide analogue 33 illustrate an apparent
limitation of this chemistry and suggests that nonpar-
ticipating nitrogen protecting groups are a valuable asset.
All successful Pummerer-initiated oxidative cycliza-
tions of tryptophan derivatives examined to date pro-
ceeded with complete regiochemical control for C-O bond
formation at C(3). This preference was observed even
with the â-silyloxy substrates 30, 33, and 34, where
eclipsing interactions between the OTBS and N3 units
might have been a cause for concern based on the
chemistry of 13. Nevertheless, these encouraging results
with carboxylate nucleophiles prompted exploration of
the scope of the oxidative cyclization transform through
the use of related carbon-based nucleophiles.
a result in sharp contrast to the base-mediated C(2)
sulfenylation recorded earlier with acid 20 (Scheme 4).
Resorting to acidic sulfenylation conditions did deliver
the requisite C(2)-thiophenyl product 39 in excellent
yield.17 Under no set of conditions did the electrophilic
sulfenylating agent initiate any detectable oxidative
cyclization of the pendant ester or acid moieties. Conver-
sion of ester 39 into allylsilane 40 followed the procedure
of Fuchs,18a with the modification of including CeCl3 in
the nucleophilic addition step.18b Omission of this media-
tor led only the R-trimethylsilyl ketone product (i.e.,
mono-addition), a result that presumably reflects the
ready enolization of that first-formed species. Silica gel-
assisted Peterson olefination completed the sequence and
delivered sulfide 40, from which sulfoxide 41 could be
derived. It is noteworthy that sulfur oxidation in the
presence of the allylsilane moiety did not present a
problem in this instance, a favorable chemoselectivity
that unfortunately was not borne out with subsequent
substrates.
Both iodonium-promoted oxidative cyclization of sulfide
40, and triflic anhydride initiated Pummerer reaction of
sulfoxide 41, were examined, Scheme 6. The sulfoxide
substrate, being the inaugural example of the carbon-
nucleophile series, was subjected to an extensive opti-
mization study during which temperature, concentration,
(16) (a) Patz, M.; Mayr, H.; Maruta, J.; Fukuzumi, S. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1225-1227. (b) Burfeindt, J.; Patz, M.; Mu¨ller,
M.; Mayr, H. J. Am. Chem. Soc. 1998, 120, 3629-3634. (c) Gotta, M.
F.; Mayr, H. J. Org. Chem. 1998, 63, 9769-9775. (d) Mayr, H.; Bug,
T.; Gotta, M. F.; Hering, N.; Irrgang, B.; Janker, B.; Kempf, B.; Loos,
R.; Ofial, A. R.; Remennikov, G.; Schimmel. H. J. Am. Chem. Soc. 2001,
123, 9500-9512. (e) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res.
2003, 36, 66-77. (f) Kempf, B.; Hampel, N.; Ofial, A. R.; Mayr, H.
Chem. Eur. J. 2003, 9, 2209-2218.
(17) Bhardari, P.; Crombie, L.; Harper, M. F.; Rossiter, J. T.;
Sanders, M.; Whiting, D. A. J. Chem. Soc., Perkin Trans. 1 1992, 1685-
1697.
(18) (a) Anderson, M. B.; Fuchs, P. L. Synth. Commun. 1987, 17,
621-635. (b) Lee, T. V.; Porter, J. R.; Roden, F. S. Tetrahedron Lett.
1988, 29, 5009-5012.
Preparation of the initial nucleophilic carbon-based
oxidative cyclization substrate 41 is shown in Scheme 6.
The allylsilane function of 41 was chosen for examination
first as it is a relatively poor nucleophile (Mayr N ) 1.8),16
and so it should provide a demanding probe of the degree
of electrophilicity generated at C(3) via the Pummerer
sequence. Curiously, attempted C(2) phenylsulfenylation
of ester 38 under basic conditions (PhSCl, Et3N) afforded
only the N-SPh product in essentially quantitative yield,
J. Org. Chem, Vol. 70, No. 16, 2005 6433

Feldman et al.
SCHEME 7
solvent, base and activator were varied. Select data from
this study are shown in Scheme 6. Consideration of these
results reveals that (1) a non-nucleophilic counterion is
essential for successful C-C bond formation (trifluoro-
acetate vs triflate) and (2) a sterically hindered pyridine
base struck the appropriate balance between basicity and
steric bulk. The reaction proceeded essentially instanta-
neously at -78 °C under the optimized conditions. The
exclusive formation of alcohol 42a from trifluoroacetic
anhydride initiation, followed by trifluoroacetate and
thioimidate hydrolysis, speaks to the concerns about
allylsilane nucleophilicity raised earlier. In this instance,
even the weakly nucleophilic trifluoroacetate anion ap-
parently is sufficient to win the competition for the C(3)
electrophilic center over the internal allylsilane nucleo-
phile. Of course, clouding this interpretation is the timing
of trimethylsilyl loss, an unknown at present. Ceric
ammonium nitrate (CAN)-mediated hydrolysis19 of the
thioimidate function within 42 proceeded smoothly to
furnish the oxindole-containing product 43 in excellent
yield.
The iodonium-initiated Pummerer transform that com-
menced with sulfide 40 provided the same thioimidate
42 in good but somewhat diminished yield compared with
the sulfoxide Pummerer variant. Product formation at
even this undistinguished level required extensive opti-
mization studies that highlighted an unexpected (and
unexplained) aspect of the hypervalent iodine chemis-
try: the PhI(CN)OTf reagent was consumed under the
reaction conditions in uncharacterized competitive pro-
cesses, and so the best product yields attended experi-
ments where a 4-fold molar excess of the iodonium
reagent was added portion-wise until TLC analysis
indicated consumption of starting sulfide. Since both the
starting material and the product of this reaction are
sulfides, product (over)oxidation was a concern. No such
product(s) were detected, and a control experiment
documented that 42 was unreactive to PhI(CN)OTf.
Apparently, there is a sufficient spread in reactivity
between the electron rich sulfide of 40 and the electron
deficient sulfide of 42 to allow discrimination with this
oxidant. A much stronger oxidant, CAN, is capable of
reaction with the sulfide within imidate 42. Attempts to
effect the oxidative cyclization of sulfide 40 with the more
common hypervalent iodine reagents PIDA (PhI(OAc)2)
or PIFA (PhI(OCOCF3)2)20 led to only trace amounts of
oxindole 42a following aqueous workup, although in
these trials the starting sulfide 40 was rapidly consumed.
The disparate results among the various hypervalent
iodine reagents is striking, and perhaps reflects the
differential acidic character of the iodonium ligand’s
conjugate acid (HCN vs HOAc vs HOCOCF3).
formation, as all attempts to oxidize the sulfur atom
within enol ether substrate 53 met with failure. Exposure
of sulfoxide 48 to the now optimized reaction conditions
(CH2Cl2 solvent) led to clean and high-yielding conversion
into the expected cyclohexanone-containing product 50.
The thioimidate moiety within 50 was converted ef-
ficiently into the oxindole of 51 using mercury-assisted
hydrolysis,21 a procedure that appeared to work better
with this substrate than the oxidative hydrolysis ap-
proach employed with 42. Interestingly, similar reaction
in the less polar solvent toluene afforded only a 37% yield
of the same ketone product 50, and new spirocycle-
containing compounds, the silyl enol ethers 49, were
formed in significant amounts. These product were
isolated as a 7:1 ratio of regioisomeric enol ethers, with
the minor species favoring enolization toward the qua-
ternary (spiro) ring junction. Both isomers were readily
converted into the ketone-containing product 50 upon
treatment with fluoride. A rationale for formation of this
silyl enol ether product in the less polar solvent is
provided by the constructs 52a and 52b, presumed
intermediates en route to 50 from 48. In the more polar
solvent CH2Cl2, formation of the highly charged zwitte-
rion 52b might be more favorable than in toluene, and
this intermediate should rapidly decompose to the ketone
The second substrate examined, TIPS enol ether sul-
foxide 48, presented the putative C(3) electrophile with
a more nucleophilic alkene (Mayr N ∼ 5.4),16 Scheme 7.
The synthesis of this substrate began with the com-
mercially available acid 44, and in a few steps both the
sulfide 46 and the sulfoxide 47 were accessed. The
formation of sulfoxide 47 had to precede silyl enol ether
(19) Ho, T.-L.; Ho, H.; Wong, C. M. J. Chem. Soc., Chem. Commun.
1972, 791.
(20) (a) Tamura, Y.; Yakura, T.; Shirouchi, Y.; Haruta, J.-i. Chem.
Pharm. Bull. 1986, 34, 1061-1066. (b) Wang, H.-M.; Lin, M.-C.; Chen,
L.-C. Heterocycles 1994, 38, 1519-1526.
(21) Satchell, D. P. N. Chem. Soc. Rev. 1977, 6, 345-371.
6434 J. Org. Chem., Vol. 70, No. 16, 2005

Extending Pummerer Reaction Chemistry
SCHEME 8
facile hydrolysis of an intermediate thionium ion (cf. 60)
upon aqueous workup. Tracking the conversion of either
55 or 56 through to common product 60 via the vinylo-
gous Pummerer intermediate 58 or the additive alterna-
tive 59 raises an interesting question about the relative
energies of these processes. The additive mechanism
proceeds through a transition state (modeled by 59) that
is not likely to be substantially different in energy from
the similar one posited for the des methyl series 40/41
f 42 (Scheme 4), with the possible exception of a more
pronounced steric perturbation introduced by the N-CH3
unit compared with the N-H lower homologue. The
vinylogous Pummerer mechanism, however, has no N-H
proton to lose, and so participation by the indole nitro-
gen’s lone pair in the ejection of X- would necessarily
deliver an iminium/thionium dicationic intermediate 58.
The energetic consequence of generating a species with
adjacent cationic charges is not readily estimated, but
this value is likely to bear heavily on the prospects for
proceeding through the vinylogous reaction channel from
55 or 56. The higher yield of 57 in the more polar solvent
is certainly consistent with enhanced stabilization of
more highly charged intermediates/transition states, but
that stabilization could be manifest at points other than
58 or 59 along either mechanistic pathway. Thus, the
most plausible explanation for the formation of 57 from
55 or 56 would seem to rely on the Sn2′-like additive
pathway, although the alternative vinylogous course
cannot be rigorously ruled out. Irrespective of this
mechanistic conundrum, acquisition of an oxindole prod-
uct directly from the oxidative cyclization transformation
avoids the discrete thioimidate hydrolysis step and
provides a more efficient route to N-methyloxindoles from
N-methylindole precursors.
product. In contrast, in the less polar solvent toluene,
the earlier intermediate 52a might be intercepted by base
to furnish the enol ether product in competition with
forming appreciable concentrations of 52b.
The use of the sulfide/iodonium Pummerer initiation
sequence with 53 proceeded in more modest yield than
the sulfoxide analogue, but in this instance, only the
ketone product 50 was formed. No other characterizable
products could be isolated from the reaction mixture, and
so the question of where the rest of 53 goes remains open.
The methyl ketones 46 and 47 themselves proved to
be competent substrates in this oxidative cyclization. The
sulfoxide 47 with Tf2O initiation and the sulfide 46 with
iodonium initiation led in each case to clean conversion,
and the sensitive enol ether product 54 was formed
uncontaminated by any detectable exocyclic alkene iso-
mer. No attempt was made to hydrolyze the thioimidate
function in the presence of the enol ether moiety. That
the initial oxidation chemistry is confined, at least in
large measure, to the sulfur function is a reminder of the
value of using the Pummerer strategy to effect selective
oxidation in a polyfunctional molecule. The precise
sequence of events that evolves from treating either 46
or 47 with their respective initiators is unknown, and so
speculation about the role of an enol nucleophile vs a
ketone version of same cannot be addressed directly.
Use of the N-methylated substrates 55 and 56 provided
some insight into the vinylogous/additive mechanistic
dichotomy discussed earlier, Scheme 8. Both the sulfide
55 and the sulfoxide 56 were prepared in good yield by
direct methylation of the precursors 40 and 41, respec-
tively. Treatment of either Pummerer precursor with its
appropriate initiator led to the same oxindole product 57
with distinctly different efficiencies. The sulfide/hyper-
valent iodine system provided product in a yield that
never could be improved beyond 46%, despite extensive
exploration of reaction parameters. The yield of 57 in the
sulfoxide/Tf2O case varied with solvent, and uniquely for
this study, the more polar solvent acetonitrile afforded
the highest yield (80%). Note that in all cases, the
oxindole product was isolated directly, presumably through
The final carbon-nucleophile substrate examined in
this study featured a very reactive silyl ketene iminal
(Mayr N > 10)16 as the partner for the C(3) electrophile,
Scheme 9. In addition, this example introduces an issue
of diastereoselectivity upon cyclization. Assembly of the
oxidative cyclization precursors 66 (sulfide) and 67
(sulfoxide) commenced with tryptamine (61) and passed
through the naphthylmethyl carbamate22-24-containing
species 63 en route to the silyl ketene iminal precursor
64. The use of this uncommon indole nitrogen protecting
group was indicated by the ready loss of the C(2) sulfur
moiety upon attempted hydrogenolysis of a CBz ana-
logue. The naphthyl unit within 63 is claimed to be a
much better ligand for the Pd catalyst’s surface than is
a simple phenyl ring, and so the rate of hydrogenolysis
of the carbamate should be enhanced compared with
other competitive processes relying on Pd-phenyl interac-
tions. Enolization and silylation proceeded smoothly from
sulfide 64 to afford the silyl ketene iminal product 66 as
a single (Z) geometrical isomer. The configurational
1
assignment is based upon comparison of the H and 13C
NMR spectra of this species with those of the sulfoxide-
derived analogue, a compound whose geometry was
secured by observation of an NOE between the alkene
proton and the hydrogens of the tert-butyl group. The
enolization/silylation sequence with the sulfoxide 65 was
troublesome, and typically equal parts of 67 and starting
(22) Papageorgiou, E. A.; Gaunt, M. J.; Yu, J.-q.; Spencer, J. B. Org.
Lett. 2000, 2, 1049-1051.
(23) Kim, C. M.; Cole, P. A. J. Med. Chem. 2001, 44, 2479-2485.
J. Org. Chem, Vol. 70, No. 16, 2005 6435

Feldman et al.
SCHEME 9
case carries through to product. Based upon this analysis,
the minor product 71 emerges from the alternative
transition state modeled by 69, where now the indole’s
aryl ring occupies the psuedoaxial position on the forming
six-membered ring, an arrangement that introduces a
serious steric clash between C(4)-H of the indole and
the axially disposed OTBS and C-H groups of the linking
tether. Control experiments indicated that the major and
minor isomers did not equilibrate under the reaction
conditions. The alternative Pummerer procedure stem-
ming from sulfide 66 treatment with PhI(CN)OTf fur-
nished the same mixture of thioimidate products 70 and
71, although both yield and diastereoselectivity were
compromised compared to the sulfoxide case. The drop
in yield appears characteristic of the iodonium/sulfide
chemistry relative to the sulfoxide/Tf2O protocol. How-
ever, the diminished diastereoselectivity was surprising,
and perhaps reflects a difference in steric demand
between -S(+)(OTf)Ph and -S(+)[I(CN)Ph]Ph in transi-
tion state model 68. The presumably larger iodonium-
appended species may disfavor 68 more than the sulfoxide-
derived alternative, and so reaction through 69 to furnish
71 may be more energetically competitive for the iodo-
nium-derived case.
The application of Pummerer chemistry to the oxida-
tive cyclization of C(3) indole derivatives has extended
this venerable transform in new directions. Species with
both carboxylate and activated alkene nucleophiles per-
form satisfactorily to furnish spirocyclic products at C(3)
of the indole core. The first-formed thioimidate products
can be readily converted to oxindoles. Both yields and
diastereoselectivity can be high with certain substrates.
Future directions for this work will include development
of an asymmetric version of the oxidative cyclization, and
applications of this chemistry toward cognate natural
products.
Experimental Section
General Procedure A for the Sulfoxide-Initiated Pum-
merer Rearrangement. Trifluoromethanesulfonic anhydride
(Tf2O) was added to a solution of the corresponding sulfoxide
and 2,6-lutidine in the relevant solvent at the indicated
temperature. Typically, the reaction was completed in 2 min
(TLC). Ice-cold water was added and the cooling bath was
removed, allowing the mixture to warm to room temperature.
The two layers were separated and the aqueous phase was
extracted with ethyl acetate (3 × 30 mL) unless otherwise
indicated. The combined organic layers were dried, filtered,
and concentrated in vacuo. The crude product was purified via
flash column chromatography, eluting with the indicated
solvent system.
General Procedure B for the Pummerer-like Reaction
Promoted by PhI(CN)OTf. Initially, a small amount of PhI-
(CN)OTf (about 0.3 equiv) was suspended in the indicated
solvent and cooled to the indicated temperature. 2,6-Lutidine
was added, and the reaction flask was removed from the
cooling bath for a few seconds to dissolve the base and then it
was brought again to the indicated temperature. The substrate
was dissolved in the indicated solvent and cannulated into the
reaction mixture in a dropwise fashion. Further amounts of
the iodonium reagent were added in small portions (0.3-0.5
equiv each) every 15 min until the starting material was fully
consumed (TLC). Cold water was added, and the bath was
removed, allowing the mixture to warm to room temperature.
The two layers were separated, and the aqueous phase was
extracted with EtOAc (3 × 25 mL). The combined organic
material 65 were isolated. The basis for the greater
sensitivity of sulfoxide 67 to workup/purification com-
pared with 66 is not clear. Subjection of sulfoxide 67 to
the optimized Pummerer conditions delivered the ex-
pected spirocyclic products 70 and 71 as a 6.8:1 mixture
of diastereomers in excellent yield. The stereochemical
assignment of the major isomer was discerned by NOE
as shown, whereas the minor isomer was assigned by
default. Mercury-assisted hydrolysis of the thioimidate
function within major isomer 70 was accompanied by
imide deprotection, and so amide oxindole 72 was formed
in good yield.
The observed diastereoselectivity of this transform can
be rationalized by citing major product formation through
cyclization of a six-membered chairlike transition state
modeled by the additive Pummerer construct 68. The aryl
portion of the indole nucleus occupies a pseudoequatorial
location on the forming cyclohexane ring, and so the
-S(X)Ph unit must then claim the more sterically
demanding psuedoaxial position. The (Z) alkene geometry
dictates the location of the phenyl ring in this transition
state model, and its pseudoequatorial disposition in this
6436 J. Org. Chem., Vol. 70, No. 16, 2005

Extending Pummerer Reaction Chemistry
layers were dried, filtered, and concentrated in vacuo. The
crude product was purified via flash column chromatography
using the indicated solvent system.
The methyl ester (330 mg, 0.77 mmol) was cooled to 0 °C in
CH2Cl2 (15 mL). m-Chloroperbenzoic acid (132 mg, 0.76 mmol)
was added, and the reaction solution was stirred at 0 °C for
90 min. The reaction solution was added to NaHCO3 (10 mL),
extracted with CH2Cl2 (3 × 10 mL), washed with water and
brine, dried over Na2SO4, filtered, and concentrated in vacuo.
The crude product was purified by flash chromatography using
4/1 ether/hexanes as the eluent to yield 240 mg (71%) of 25 as
a white solid (1:1 mixture of diastereomers): IR (CDCl3) 3439,
Oxindole 10. N-Bromosuccinimide (16 mg, 0.09 mmol) was
added to a solution of 9 (30 mg, 0.045 mmol) and sodium
bicarbonate (8 mg, 0.09 mmol) in t-BuOH (340 µL)/H2O (80
µL) and stirred for 15 h. The reaction solution was concen-
trated in vacuo, and the residue was purified by flash chro-
matography using 33% ether in hexanes as the eluent,
providing 10 mg (33%) of the product, as a white solid: mp
1
1741, 1708 cm-1; H NMR (360 MHz, CDCl3, 1:1 mixture of
diastereomers) δ 8.58 (s, 1H), 8.53 (s, 1H), 7.72 (m, 4H), 7.64
(m, 2H), 7.52 (m, 6H), 7.29 (m, 6H), 7.16 (m, 2H), 5.35 (d, J )
8.2 Hz, 1H), 5.24 (d, J ) 8.0 Hz, 1H), 4.73 (m, 2H), 3.74 (s,
3H), 3.64 (s, 3H), 3.59 (d, J ) 5.9 Hz, 1H), 3.50 (m, 3H), 1.46
(s, 9H), 1.37 (s, 9H); 13C NMR (100 MHz, CDCl3, 1:1 mixture
of diastereomers) δ 173.2, 172.2, 155.3, 155.1, 143.3, 143.2,
137.8, 137.7, 134, 133.7, 131.2, 129.6, 129.5, 127.3, 127.2,
125.5, 125.2, 120.7, 120.6, 120.3, 120.2, 116.3, 115.8, 112.7,
112.6, 80.2, 80.1, 54.3, 54.2, 52.7, 52.6, 28.5, 28.4, 14.3; ESI
m/z (relative intensity) 465.1 (M + Na, 100); HRMS calcd for
C23H26N2O5S 465.1460 (M + Na), found 465.1465.
82-85 °C (sublime); IR (CDCl3) 3452, 1810, 1772, 1725 cm-1
;
1H NMR (360 MHz, CDCl3) δ 7.97 (m, 3H), 7.53 (m, 2H), 7.42
(m, 1H), 7.36 (m, 7H), 5.50 (d, J ) 7.4 Hz, 1H), 5.35 (d, J ) 9
Hz, 1H), 5.22 (d, J ) 12 Hz, 1H), 5.09 (d, J ) 12 Hz, 1H), 4.61
(m, 1H), 2.42 (s, 3H), 0.84 (m, 21H); 13C NMR (100 MHz,
CDCl3) δ 174.5, 171.7, 156.0, 147.0, 146.6, 141.3, 136.0, 135.0,
132.7, 130.3, 129.0, 128.9, 128.3, 126.1, 125.9, 124.0, 114.3,
83.1, 78.4, 68.0, 57.9, 22.1, 17.9, 12.6; ESI m/z (relative
intensity) 679.2 (M + H, 35), 696.3 (M + NH4, 100), 701.2 (M
+ Na, 70); HRMS calcd for C35H42N2O8SSi (M + NH4)
696.2775, found 696.2778. Anal. Calcd for C35H42N2O8SSi: C,
61.92; H, 6.24; N, 4.13; S, 4.72. Found: C, 61.31; H, 6.13; N,
4.01; S, 4.68.
Methyl 2-tert-Butoxycarbonylamino-3-(3-hydroxy-2-
phenylsulfanyl-3H-indol-3-yl)propionate (26) and (23)
from 25. Diisopropylethylamine (86 µL, 0.49 mmol) was added
to a solution of 25 (88 mg, 0.20 mmol) in CH2Cl2 (8 mL) at
-78 °C and stirred for 5 min. Trifluoroacetic anhydride (36
µL, 0.26 mmol) was added, and the reaction solution was
slowly warmed to room temperature over 3 h and stirred there
for 15 h. Additional diisopropylethylamine (86 µL, 0.49 mmol)
and then trifluoroacetic anhydride (36 µL, 0.26 mmol) were
added, and the reaction solution was stirred for 48 h. The
reaction solution was added to water (10 mL), extracted with
CH2Cl2 (3 × 5 mL), dried over Na2SO4, filtered, and concen-
trated in vacuo. The crude product was purified by flash
chromatography using 1/1 ether/hexanes as the eluent to yield
52 mg (63%) of 23 as a white solid (1:1 mixture of diastereo-
mers) and 29 mg (33%) of 26 as a white solid (1:1 mixture of
diastereomers). 26: IR (CDCl3) 1745, 1714 cm-1; 1H NMR (400
MHz, CDCl3, 1:1 mixture of diastereomers) δ 8.00 (d, J ) 12.2
Hz, 1H), 7.72 (m, 4H), 7.46 (m, 7H), 7.33 (m, 4H), 7.17 (m,
2H), 5.35 (bs, 1H), 5.09 (bs, 1H), 4.57 (bs, 1H), 4.25 (bs, 1H),
3.68 (s, 3H), 3.65 (s, 3H), 2.71 (dd J ) 14.4, 5 Hz, 1H), 2.56
(dd, J ) 14.6, 9.4 Hz, 1H), 2.34 (dd J ) 14.4, 9.0 Hz, 1H), 2.26
(dd, J ) 14.7 Hz, 3.6 Hz, 1H), 1.44 (s, 9H), 1.39 (s, 9H); 13C
NMR (75 MHz, CDCl3, 1:1 mixture of diastereomers) δ 184.8,
172.4, 154.0, 153.9, 138.6, 134.8, 134.7 130.7, 130.5, 129.7,
129.6, 125.5, 125.3, 123.5, 123.0, 120.3, 86.6, 86.3, 80.8, 77.4,
52.8, 28.5 (2 carbons), 23.8; ESI m/z (relative intensity) 443.1
(M + H, 85), 465.1 (M + Na, 100); HRMS calcd for C23H26N2O5S
443.1641 (M + H), found 443.1644.
Benzyl [4a-Bromo-4-(tert-butyldimethylsilanyloxy)-2-
oxo-9-(toluene-4-sulfonyl)-2,3,4,4a,9,9a-hexahydropyrano-
[2,3-b]indol-3-yl]carboxylate (14). N-Bromosuccinimide (250
mg, 1.5 mmol) was added to a solution of 13 (200 mg, 0.32
mmol) and NaHCO3 (120 mg, 1.4 mmol) in t-BuOH (5.5 mL)/
H2O (1.3 mL) and stirred for 15 h. The reaction solution was
concentrated in vacuo and purified by flash chromatography
using 33% ether in hexanes as the eluent, providing 150 mg
(67%) of lactone 14, as a white solid: mp 92-95 °C; IR (CDCl3)
1
3426, 1764, 1718 cm-1; H NMR (300 MHz, CDCl3) δ 7.93 (d,
J ) 8.3 Hz, 2H), 7.53 (d, J ) 8.3 Hz, 2H), 7.42 (m, 9H), 6.62
(s, 1H), 5.61 (d, J ) 4.4 Hz, 1H), 5.23 (m, 3H), 4.32 (dd, J )
4.4, 1.4 Hz, 1H), 2.40 (s, 3H), 0.95 (s, 9H), 0.27 (s, 3H), 0.09 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 165.4, 155.6, 145.3, 139.9,
135.8, 135.2, 131.9, 130.3, 130.0, 128.8, 128.6, 128.3, 128.1,
125.8, 124.9, 115.2, 98.1, 74.1, 67.5, 63.5, 54.3, 26.1, 21.9, 18.6,
-3.5, -4.1; APCIMS m/z (relative intensity) 701.1 (M + H,
85), 703.1 (81Br, 100); HRMS calcd for C32H37BrN2O7SSi (M +
H) 701.1352, found 701.1373. Anal. Calcd for C32H37BrN2O7-
SSi: C, 54.77; H, 5.31; N, 3.99; S, 4.57. Found: C, 54.76; H,
5.30; N, 3.91; S, 4.57.
Lactone 23 from Sulfide 21. Sulfide 21 (500 mg, 1.21
mmol) was cooled to -78 °C in CH2Cl2 (40 mL). 2,6-Lutidine
(400 µL, 3.46 mmol) was added followed by PhI(CN)OTf (1.12
g, 2.96 mmol). The reaction solution was slowly warmed to
room temperature and stirred there for 15 h. The reaction
solution was added to water (25 mL), extracted with CH2Cl2
(3 × 25 mL), dried over Na2SO4, filtered, and concentrated in
vacuo. The crude product was purified by flash chromatogra-
phy using 2/1 hexanes/Et2O as the eluent to yield 190 mg (38%)
of 23 as a white solid (1:1 mixture of diastereomers).
Methyl 3-(2-Benzenesulfinyl-1H-indol-3-yl)-2-tert-bu-
toxycarbonylaminopropionate (25). Trimethylsilyldiaz-
omethane (2 M in hexanes, 808 µL, 1.62 mmol) was added to
acid 21 (500 mg, 1.21 mmol) in benzene (5 mL) and methanol
(5 mL). The reaction solution was stirred for 45 min and then
concentrated in vacuo. The crude product was purified by flash
chromatography using 1/2 ether/hexanes as the eluent to yield
330 mg (64%) of the methyl ester as a white solid: mp 104-
106 °C; IR (CDCl3) 3458, 1741, 1710 cm-1; 1H NMR (360 MHz,
CDCl3) δ 8.53 (s, 1H), 7.59 (d, J ) 7.9 Hz, 1H), 7.33 (m, 8H),
5.15 (d, J ) 8.0 Hz, 1H), 4.66 (m, 1H), 3.61 (s, 3H), 3.44 (dd,
J ) 14.3, 5.5 Hz), 3.31 (dd, J ) 14.3, 6.3 Hz, 1H), 1.36 (s, 9H);
13C NMR (90 MHz, CDCl3) δ 172.8, 155.3, 137.2, 136.6, 129.4,
128.1, 127.1, 126.3, 123.9, 123.8, 120.3, 119.5, 117.7, 111.2,
79.9, 54.3, 52.5, 28.4, 14.3; ESI m/z (relative intensity) 449.1
(M + Na, 100); HRMS calcd for C23H26N2O4S 449.1511 (M +
Na), found 449.1502.
Spiro Butyrolactone Thioimidate 31. A solution of 30
(20 mg, 0.043 mmol) in CH2Cl2 (1 mL) was cooled to -78 °C.
2,6-Lutidine (15 µL, 0.13 mmol) followed by PhI(CN)OTf (41
mg, 0.11 mmol) were added, and the reaction solution was
slowly warmed to room temperature over 45 min and stirred
there for 15 h. The reaction solution was added to water (3
mL), extracted with CH2Cl2 (3 × 5 mL), washed with water
and brine, dried over Na2SO4, filtered, and concentrated in
vacuo. The crude products were purified by flash chromatog-
raphy using 20% Et2O in hexanes as the eluent to yield 8 mg
(40%) of 31 as an orange oil: IR (CDCl3) 2116, 1803, 1524 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.68 (m, 2H), 7.49 (m, 3H), 7.34
(m, 2H), 7.22 (m, 2H), 5.03 (d, J ) 9.5 Hz, 1H), 4.56 (d, J )
9.5 Hz, 1H), 0.79 (s, 9H), 0.00 (s, 3H), -0.48 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 178.0, 169.8, 154.7, 134.5, 134.0, 132.0,
129.9, 129.6, 126.9, 125.7, 122.8, 120.2, 93.2, 79.2, 63.6, 25.3,
17.7, -5.2, -5.9; ESI m/z (relative intensity) 467.1 (M + H,
100); HRMS calcd for C23H26N4O3SSi (M + H) 467.1573, found
467.1591.
Oxindole 32. Cerium(IV) ammonium nitrate (42 mg, 0.077
mmol) was added to a solution of 31 (30 mg, 0.06 mmol) in
CH3CN/H2O (4.5 mL, 5/1) and stirred for 15 h. The reaction
J. Org. Chem, Vol. 70, No. 16, 2005 6437

Feldman et al.
solution was extracted with EtOAc (3 × 5 mL), dried over Na2-
SO4, filtered, and concentrated in vacuo. The crude product
was purified by flash chromatography using 1/1 hexanes/Et2O
as the eluent to yield 12 mg (50%) of 32 as a white solid: mp
128-130 °C; IR (CDCl3) 3432, 2117, 1807, 1752 cm-1; 1H NMR
(360 MHz, CDCl3) δ 7.50 (m, 2H), 7.41 (m, 1H), 7.15 (m, 1H),
6.91 (d, J ) 7.7 Hz, 1H), 4.93 (d, J ) 5.1 Hz, 1H), 4.51 (d, J )
5.1 Hz), 0.87 (s, 9H), -0.06 (s, 3H), -0.36 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 173.4, 170.1, 142.4, 132.1, 125.2, 123.9,
123.6, 110.8, 83.1, 79.9, 62.7, 25.4, 17.8, 0.2, -5.5; ESI m/z
(relative intensity) 392.2 (M + NH4, 100), 375.2 (M + H, 16);
HRMS calcd for C17H22N4O4Si (M + H) 375.1489, found
375.1454. Anal. Calcd for C17H22N4O4Si: C, 54.53; H, 5.92; N,
14.96. Found: C, 54.32; H, 5.94; N, 14.73.
tert-Butyl 2-Azido-3-(tert-butyldimethylsilanyloxy)-3-
(2-phenylsulfanyl-1H-indol-3-yl)propionate (33). N,N-
Dimethylformamide di-tert-butyl acetal (232 µL, 0.97 mmol)
was added to a solution of acid 30 (87 mg, 0.19 mmol) in
toluene (3 mL). The reaction solution was brought to 55 °C
and held there for 15 h. The reaction solution was added to
water (5 mL), extracted with ethyl acetate (3 × 5 mL), washed
with brine, dried over Na2SO4, filtered, and concentrated in
vacuo. The crude product was purified by flash chromatogra-
phy using 1/5 ether/hexanes as the eluent to yield 50 mg (52%)
of 33 as a colorless oil: IR (CDCl3) 3458, 2115, 1733 cm-1; 1H
NMR (300 MHz, CDCl3) δ 8.25 (s, 1H), 8.06 (d, J ) 7.7 Hz,
1H), 7.34 (m, 8H), 5.83 (d, J ) 4.4 Hz, 1H), 3.70 (m, 1H), 1.40
(s, 9H), 0.94 (s, 9H), 0.09 (s, 3H), -0.29 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 168.9, 137.2, 136.2, 129.8, 129.0, 127.6, 127.1,
124.0, 123.1, 121.9, 121.5, 121.0, 111.2, 83.1, 71.9, 69.0, 28.6,
26.2, 18.5, -4.3, -5.2; ESI m/z (relative intensity) 547.1 (M +
Na, 100); HRMS calcd for C27H36N4O3SSi 547.2175 (M + Na),
found 547.2162.
to -40 °C. A solution of Tf2O (17 µL, 0.10 mmol) in CH3CN (1
mL) was added, and the reaction solution was stirred for 36
h. The reaction solution was added to satd NaHCO3 (5 mL),
extracted with CH2Cl2 (3 × 5 mL), washed with water and
brine, dried over Na2SO4, filtered, and concentrated in vacuo.
The crude products were purified by flash chromatography
using 1/4 ether/hexanes as the eluent to yield 7 mg (37%) of
31 as an orange oil.
tert-Butyl 2-tert-Butoxycarbonylamino-3-(tert-butyldim-
ethylsilanyloxy)-3-(2-phenylsulfanyl-1H-indol-3-yl)pro-
pionate (36). Trimethylphosphine (0.95 mL, 1 M in THF, 0.95
mmol) was slowly added to a solution of 35 (200 mg, 0.32
mmol) in THF (4 mL), and stirring was continued for 45 min.
The reaction solution was cooled below -20 °C, BOC-ON (230
mg, 0.93 mmol) in THF (1 mL) was added, and the reaction
solution was warmed to room temperature and stirred for 15
h. The reaction mixture was added to water (10 mL), extracted
with CH2Cl2 (3 × 10 mL), washed with brine, dried over Na2-
SO4, filtered, and concentrated in vacuo. The crude product
was purified by flash chromatography using 20% ether in
hexanes as the eluent, providing 160 mg (72%) of the Boc
protected amine as a colorless oil: IR (CDCl3) 3550, 1743, 1710
1
cm-1; H NMR (300 MHz, CDCl3) δ 8.21 (d, J ) 8.3 Hz, 1H),
8.02 (d, J ) 7.8 Hz, 1H), 7.84 (m, 2H), 7.51 (m, 4H), 7.38 (m,
6H), 5.94 (d, J ) 2.6 Hz, 1H), 5.72 (d, J ) 9.8 Hz, 1H), 5.26 (s,
2H), 4.72 (dd, J ) 9.8, 2.3 Hz, 1H), 3.76 (s, 3H) 1.14 (s, 9H),
0.86 (s, 9H), -0.07 (s, 3H), -0.29 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 171.1, 155.5, 151.2, 138.1, 137.3, 134.7, 133.3, 131.2,
129.6, 129.2 (2 carbons), 128.9, 128.7, 128.5, 126.4, 126.1,
125.7, 123.0, 115.7, 80.5, 72.1, 69.2, 66.4, 52.7, 28.1, 25.8, 15.2,
-3.5, -4.7; ESI m/z (relative intensity) 713.2 (M + Na, 90);
HRMS calcd for C37H46N2O7SiS 713.2693 (M + Na), found
713.2673.
tert-Butyl 2-Azido-3-(2-benzenesulfinyl-1H-indol-3-yl)-
3-(tert-butyldimethylsilanyloxy)propionate (34). Sulfide
33 (153 mg, 0.29 mmol) was cooled to 0 °C in CH2Cl2 (9 mL).
m-Chloroperbenzoic acid (49 mg, 0.28 mmol) was added, and
the reaction solution was stirred at 0 °C for 20 min. The
reaction solution was added to satd NaHCO3 (10 mL), ex-
tracted with CH2Cl2 (3 × 10 mL), washed with water and
brine, dried over Na2SO4, filtered, and concentrated in vacuo.
The crude product was purified by flash chromatography using
2/1 ether/hexanes as the eluent to yield 107 mg (70%) of 34 as
a white solid (1:1 mixture of diastereomers) and 45 mg of
The Boc-protected amine (160 mg, 0.23 mmol) and LiOH‚
H2O (33 mg, 0.79 mmol) were stirred for 15 h in THF/H2O (15
mL, 4/1). The reaction mixture was acidified with 1 M HCl (5
mL), extracted with CH2Cl2 (3 × 5 mL), washed with water
and brine, dried over Na2SO4, filtered, and concentrated in
vacuo. The crude product was purified by flash chromatogra-
phy using 50% ether in hexanes as the eluent, providing 31
mg (25%) of the acid as a yellow solid.
N,N-Dimethylformamide di-tert-butyl acetal (72 µL, 0.30
mmol) was added to a solution of the acid from above (31 mg,
0.057 mmol) in toluene (2 mL). The reaction solution was
brought to 55 °C and held there for 15 h. The reaction solution
was added to water (5 mL), extracted with ethyl acetate (3 ×
5 mL), washed with brine, dried over Na2SO4, filtered, and
concentrated in vacuo. The crude product was purified by flash
chromatography using 1/5 ether/hexanes as the eluent to yield
50 mg (52%) of 36 as a colorless oil: IR (CDCl3) 3692, 3458,
recovered 33 (30%): IR (CDCl3) 3430, 2115, 1737 cm-1 1H
;
NMR (400 MHz, CDCl3, 1:1 mixture of diastereomers) δ 7.94
(d, J ) 8.0 Hz, 1H), 7.84 (m, 4H), 7.78 (d, J ) 2.0 Hz, 1H),
7.49 (m, 3H), 7.44 (m, 3H), 7.41 (m, 3H), 7.34 (m, 2H), 7.23
(m, 2H), 7.14 (m, 2H), 5.84 (d, J ) 3.6 Hz, 1H), 5.74 (d, J )
4.4 Hz, 1H), 3.57 (bs, 1H), 3.46 (bs, 1H), 0.94 (s, 18H), 0.94 (s,
9H), 0.86 (s, 9H), 0.17 (s, 3H), 0.07 (s, 3H), -0.01 (s, 3H), -0.33
(s, 3H); 13C NMR (100 MHz, CDCl3, 1:1 mixture of diastere-
omers) δ 167.6, 167.4, 143.8, 143.3, 137.6, 137.0, 136.8, 134.1,
132.4, 132.0, 131.8, 131.7, 129.7, 129.7, 128.8, 128.8, 126.6,
126.3, 126.3, 125.6, 125.2, 125.1, 121.1, 120.9, 119.4, 112.5,
83.5, 83.4, 70.3, 70.2, 68.7, 68.3, 28.1, 28.1, 18.4, 18.3, 0.2, -4.6,
-5.2, -5.3; ESI m/z (relative intensity) 563.2 (M + Na, 100);
HRMS calcd for C27H36N4O4SSi 563.2124 (M + Na), found
563.2133.
1
1712 cm-1; H NMR (300 MHz, CDCl3) δ 8.07 (s,1H), 7.89 (d,
J ) 7.8 Hz, 1H), 7.23 (m, 7H), 7.10 (m, 1H), 5.66 (d, J ) 3.1
Hz, 1H), 5.52 (d, J ) 10 Hz, 1H), 4.44 (dd, J ) 9.7, 3.1 Hz,
1H), 1.38 (s, 9H), 1.19 (s, 9H), 0.85 (s, 9H), -0.08 (s, 3H), -0.40
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 169.8, 155.2, 136.9, 131.2,
131.0, 129.2, 129.0, 127.9, 127.0, 126.4, 126.3, 123.1, 119.9,
110.5, 81.6, 79.2, 70.8, 61.0, 28.3, 28.1, 25.8, 18.0, -4.7, -5.7;
ESI m/z (relative intensity) 621.2 (M + Na, 100); HRMS calcd
for C32H46N2O5SiS 621.2794 (M + Na), found 621.2795.
Lactone 31 from 33. A solution of 33 (45 mg, 0.086 mmol)
in CH2Cl2 (2.5 mL) was cooled to -78 °C. 2,6-Lutidine (37 µL,
0.32 mmol) followed by PhI(CN)OTf (51 mg, 0.13 mmol) were
added, and the reaction solution was slowly warmed to room
temperature over 45 min and stirred there for 15 h. The
reaction solution was added to water (3 mL), extracted with
ethyl acetate (3 × 5 mL), washed with brine, dried over Na2-
SO4, filtered, and concentrated in vacuo. The crude products
were purified by flash chromatography using 10% Et2O in
hexanes as the eluent to yield 8 mg (20%) of 31 as an orange
oil.
Cyclic Carbamate 37. A solution of 36 (3 mg, 0.005 mmol)
in CH2Cl2 (1 mL) was cooled to -78 °C. 2,6-Lutidine (2 µL,
0.017 mmol) followed by PhI(CN)OTf (3 mg, 0.008 mmol) were
added,and the reaction solution was slowly warmed to room
temperature over 45 min and stirred there for 15 h. The
reaction solution was added to water (3 mL), extracted with
ethyl acetate (3 × 5 mL), washed with brine, dried over Na2-
SO4, filtered, and concentrated in vacuo. The crude products
were purified by flash chromatography using 50% Et2O in
hexanes as the eluent to yield 2 mg (74%) of 37 as a colorless
1
oil: IR (CDCl3) 3691, 1737 cm-1; H NMR (400 MHz, CDCl3)
Lactone 31 from 34. 2,6-Lutidine (17 µL, 0.15 mmol) was
added to 34 (22 mg, 0.041 mmol) in CH3CN (1 mL) and cooled
δ 7.73 (m, 2H), 7.54 (m, 3H), 7.39 (m, 3H), 7.12 (td J ) 7.1,
1.6 Hz, 1H), 5.93 (s, 1H), 4.71 (m, 1H), 4.68 (d, J ) 2.6 Hz,
6438 J. Org. Chem., Vol. 70, No. 16, 2005

Extending Pummerer Reaction Chemistry
1H), 1.60 (s, 9H), 0.80 (s, 9H), 0.00 (s, 3H), -0.69 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 179.4, 166.2, 154.2, 152.4, 135.8,
135.0, 131.1, 130.3, 129.9, 127.6, 127.0, 125.6, 120.2, 85.5, 77.6,
69.5, 58.3, 30.1, 26.3, 18.5, -4.0, -4.6; ESI m/z (relative
intensity) 604.1 (M + Na); HRMS calcd for C28H36N2O5SiS
563.2012 (M + Na), found 563.2018.
14.1, 1.6 Hz, 1H), 1.69 (m, 1H); 13C NMR (75 MHz, CDCl3) δ
208.6, 183.5, 154.1, 142.4, 134.6, 129.59, 129.56, 128.6, 128.2,
124.5, 122.9, 120.2, 61.6, 47.5, 40.9, 33.2, 22.7; APCIMS m/z
(relative intensity) 308.1 (M + H, 100); HRMS calcd for C19H17-
NOS (M + H) 308.1104, found 308.1095. Anal. Calcd for C19H17-
NOS: C, 74.23; H, 5.57; N, 4.56; S, 10.43. Found: C, 73.94;
H, 5.69; N, 4.47; S, 10.47.
2-(Phenylthio)indolenine 42 from Sulfoxide 41. Ac-
cording to general procedure A, trifluoromethanesulfonic
anhydride (52 µL, 0.309 mmol), allylsilane sulfoxide 41 (60.4
mg, 0.153 mmol), and 2,6-lutidine (54 µL, 0.464 mmol) in dry
CH2Cl2 (30 mL) at -75 °C were combined. A bright yellow color
was observed instantaneously, and the reaction was completed
in 2 min as evidenced by TLC. The residual material was
purified via flash column chromatography using 10% Et2O in
hexanes as eluent. The product indolenine 42, 38.4 mg of a
colorless oil that solidifies slowly upon standing, was isolated
in 82% yield: mp 95-98 °C; IR (thin film) 1515 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.74-7.66 (m, 2H), 7.53-7.43 (m, 5H),
7.29 (td, J ) 7.6, 1.2 Hz, 1H), 7.09 (td, J ) 7.5, 1.1 Hz, 1H),
4.98 (d, J ) 1.7 Hz, 1H), 4.71 (d, J ) 1.6 Hz, 1H), 2.73 (d, J )
13.1 Hz, 1H), 2.60 (d, J ) 13.4 Hz, 1H), 2.37-2.27 (m, 1H),
2.13 (d, J ) 13.2 Hz, 1H), 2.13-1.93 (m, 3H), 1.54 (d, J ) 13.4
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 186.0, 154.4, 143.81,
143.78, 134.6, 129.5, 129.3, 128.7, 127.9, 124.4, 123.6, 119.8,
111.6, 60.2, 41.8, 34.2, 34.1, 23.0; APCIMS m/z (relative
intensity) 306.1 (M + H, 100) 197.1 (M - PhS, 15); HRMS
calcd for C20H19NS (M + H) 306.1311, found 306.1296. Anal.
Calcd for C20H19NS: C, 78.65; H, 6.27; N, 4.59; S, 10.50.
Found: C, 78.78; H, 6.42; N, 4.62; S, 10.79.
2-(Phenylthio)indolenine 50 from Sulfide 53. Following
general procedure B, sulfide 53 (18.8 mg, 0.040 mmol) in 4
mL of CH3CN was added to a mixture of 2,6-lutidine (14 µL,
0.12 mmol) and PhI(CN)OTf (8.0 mg, 0.021 mmol) in 0.5 mL
of CH3CN at 0 °C. The remaining iodonium reagent (8.0 mg,
0.021 mmol) was added in a single portion. The product 50
was isolated via flash column chromatography, eluting with
20% Et2O in hexanes, 5.2 mg (42%).
2′-(Phenylsulfenyl)-3-(triisopropylsilanyloxy)spiro-
[cyclohex-3-ene-1,3′-indole] and 2′-(Phenylsulfenyl)-3-
(triisopropylsilanyloxy)spiro[cyclohex-2-ene-1,3′-in-
dole (49). Following general procedure A, Tf2O (15 µL, 0.09
mmol) was added dropwise to a solution of sulfoxide 48 (22.0
mg, 0.046 mmol) and 2,6-lutidine (16 µL, 0.14 mmol) in toluene
(4.6 mL) at -75 °C. A mixture of compounds was obtained and
separated via preparative TLC. The major product was indo-
lenine 50 (5.4 mg, 39%), which was isolated along with the
inseparable mixture of indolenines 49 (major and minor
components) in 17.5% and 2.5% yield, respectively, as revealed
by 1H NMR: IR (thin film) 2866, 1516 cm-1 1H NMR (300
;
MHz, CDCl3) δ 7.69 (m, 2H), 7.48-7.36 (m, 5H), 7.31-7.24
(m, 1H), 7.09 (td, J ) 7.5, 0.8 Hz, 1H), 5.12 (s, 1H, major),
4.47 (s, 1H, minor), 2.77 (d, J ) 17.2 Hz, 1H, major), 2.43-
2.33 (m, 2H, major; m, 2H, minor), 2.05-1.97 (m, 1H, major;
m, 4H, minor), 1.98 (d, J ) 17.2 Hz, 1H, major), 1.46 (d, J )
10.8 Hz, 1H, major), 1.21 (m, 3H), 1.11 (d, J ) 6.7 Hz, 18H);
13C NMR (75 MHz, CDCl3) δ 185.9, 154.3, 148.6, 144.1, 134.6,
129.5, 129.3, 128.6, 128.1, 124.3, 123.3, 119.7, 102.2, 58.6, 36.6,
30.2, 21.5, 18.3, 12.8; LRMS (APCI+) m/z (relative intensity)
464.3 (M + H, 100); HRMS calcd for C28H37NOSSi (M + H)
464.2438, found 464.2416. Anal. Calcd for C28H37NOSSi: C,
72.52; H, 8.04; N, 3.02; S, 6.91. Found: C, 72.47; H, 7.84; N,
3.13; S, 6.94.
2-(Phenylthio)indolenine 42 from Sulfide 40. Following
general procedure B, sulfide 40 (16.8 mg, 0.040 mmol) in 4
mL of CH2Cl2 was added to a mixture of 2,6-lutidine (14 µL,
0.12 mmol) and PhI(CN)OTf (5.0 mg, 0.013 mmol) in 0.9 mL
of CH2Cl2 at 0 °C. The remaining iodonium reagent (57 mg,
0.15 mmol) was added in small portions. The product 42 was
isolated via flash column chromatography, eluting with 10%
Et2O-hexanes as a white solid, 8.1 mg (67%).
Oxindole 43. Cerium(IV) ammonium nitrate (133 mg, 0.243
mmol) was added in one portion to a solution of phenylthio-
indolenine 42 (73.7 mg, 0.241 mmol) in 1:5 water-CH3CN (4.8
mL). The clear solution was stirred for 24 h, during which time
the color changed from bright yellow to orange and back to
yellow. The mixture was partitioned between water (10 mL)
and EtOAc (10 mL), and the aqueous phase was extracted with
EtOAc (3 × 5 mL). The combined organic fractions were dried
with MgSO4, filtered, and concentrated in vacuo. The yellow
oily residue obtained was purified with flash column chroma-
tography eluting with 50% Et2O in hexanes. The oxindole 43
as a white solid (47.9 mg, 93%) was recovered: mp 119-121
°C; IR (thin film) 3212, 1708 cm-1; 1H NMR (300 MHz, CDCl3)
δ 9.08 (br s, 1H), 7.42 (d, J ) 7.4 Hz, 1H), 7.22 (tdd, J ) 7.7,
1.2, 0.3 Hz, 1H), 6.98 (m, 2H), 4.91 (d, J ) 1.6 Hz, 1H), 4.67
(d, J ) 1.4 Hz, 1H), 2.66 (d, J ) 13.6 Hz, 1H), 2.52 (dt, J )
13.4, 3.6 Hz, 1H), 2.29 (td, J ) 12.3, 5.4 Hz, 1H), 2.16 (d, J )
13.3 Hz, 1H), 2.03 (td, J ) 12.2, 4.7 Hz, 1H), 1.90 (m, 2H),
1.62 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 182.9, 144.3, 140.2,
134.6, 127.8, 125.4, 121.9, 111.2, 110.1, 49.9, 40.6, 34.2, 33.0,
22.6; APCIMS m/z (relative intensity) 214.1 (M + H, 100).
Anal. Calcd for C14H15NO: C, 78.84; H, 7.09; N, 6.57; O, 7.50.
Found: C, 78.80; H, 7.19; N, 6.54.
2-(Phenylthio)indolenine 70 from Sulfoxide 67. Fol-
lowing general procedure A, trifluoromethanesulfonic anhy-
dride (19 µL, 0.113 mmol) was added to a solution of sulfoxide
67 (55% silyl ketene iminal, 61.9 mg, 0.055 mmol of silyl ketene
iminal) and 2,6-lutidine (20 µL, 0.172 mmol) in dry CH2Cl2
(5.9 mL) at -75 °C. After 5 min, ice-cold water was added,
and the cooling bath was removed, allowing the mixture to
warm to room temperature. The residual material was purified
via preparative thin-layer chromatography using 10% Et2O in
benzene as eluent. The desired product was obtained as a
mixture of diastereomers (24.5 mg, 92%, 6.8:1 ratio of 70 to
71). Major diastereomer 70 (white solid): mp 186-187 °C; IR
(thin film) 1770, 1717, 1509 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.57 (m, 2H), 7.46-7.35 (m, 4H), 7.18-7.02 (m, 8H), 4.62
(ddd, J ) 13.7, 6.8, 5.9 Hz, 1H), 4.22 (s, 1H), 3.99 (ddd, J )
13.6, 7.6, 5.7 Hz, 1H), 2.44 (m, 2H), 1.60 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 181.4, 169.4, 153.7, 153.1, 142.8, 134.2, 132.4,
130.7, 129.5 (two carbons), 128.7, 128.2, 127.8, 127.6, 124.9,
121.2, 119.8, 83.9, 62.8, 57.2, 42.4, 31.5, 28.3; APCIMS m/z
(relative intensity) 485.3 (M + H, 100); HRMS calcd for
C29H28N2O3S (M + H) 485.1893, found 485.1872.
tert-Butyl [1-(tert-Butyldimethylsilanyloxy)-2-phenylvi-
nyl]-[2-(2-phenylsulfenyl-1H-indol-3-yl)ethyl] Carbamate
(66). A mixture of sulfide 64 (259 mg, 0.532 mmol) and TBSCl
(277 mg, 1.84 mmol) was dissolved in THF (5.3 mL) and
treated with LiHMDS (1.0 M in THF, 4.25 mL, 4.25 mmol) at
-75 °C. The reaction mixture was slowly warmed to 0 °C (over
3 h), and the solution was poured into ice-cold water. The
aqueous phase was extracted with Et2O (3 × 20 mL), and the
combined organic layers were dried over MgSO4, filtered, and
concentrated under reduced pressure. Flash column chroma-
tography of the crude product using water-deactivated silica
2-(Phenylthio)indolenine 50 from Sulfoxide 48. Fol-
lowing general procedure A, trifluoromethanesulfonic anhy-
dride (82 µL, 0.49 mmol) was added to a solution of sulfoxide
48 (117 mg, 0.244 mmol) and 2,6-lutidine (85 µL, 0.73 mmol)
in dry CH2Cl2 (48 mL) at -75 °C. The residual material was
purified via flash column chromatography, eluting with 20%
Et2O in hexanes. The product 50, 56.9 mg (76%), was isolated
as a white solid: mp 140 °C; IR (thin film) 1719, 1515 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.69-7.65 (m, 2H), 7.50-7.41
(m, 4H), 7.28 (ddd, J ) 7.3, 1.3, 0.3 Hz, 1H), 7.18 (ddd, J )
7.5, 1.6, 0.7 Hz, 1H), 7.09 (ddd, J ) 7.2, 1.2, 0.4 Hz, 1H), 2.92
(d, J ) 14.0 Hz, 1H), 2.65 (m, 2H), 2.33 (m, 3H), 2.24 (dt, J )
J. Org. Chem, Vol. 70, No. 16, 2005 6439

Feldman et al.
(20 g water, 80 g silica) and eluting with 10% Et2O in hexanes
provided the desired product 66 as a yellow oil (240 mg, 75%)
as a Z-double bond isomer: IR (thin film) 3309 cm-1; 1H NMR
(400 MHz, CDCl3) δ 8.03 (br s, 1H), 7.75 (m, 1H), 7.40 (m, 2H),
7.32-7.21 (m, 4H), 7.20-7.07 (m, 5H), 7.07-7.02 (m, 2H), 5.30
(br s, 1H), 3.58 (m, 2H), 3.30 (m, 2H), 1.50 (s, 9H), 0.92 (s,
9H), 0.04 (s, 6H); LRMS (APCI+) m/z (relative intensity) 601.3
(M + H, 57), 545.2 (M + H - C4H8, 100), 501.2 (M + H -
C4H8 - CO2, 9).
2-(Phenylthio)indolenine 70 from Sulfide 66. Following
general procedure B, sulfide 66 (40.5 mg, 0.067 mmol) in 3.4
mL of CH2Cl2 was added to a mixture of 2,6-lutidine (47 µL,
0.40 mmol) and PhI(CN)OTf (13.0 mg, 0.034 mmol) in 1 mL
of CH2Cl2 at -78 °C. The remaining iodonium reagent (91 mg,
0.24 mmol) was added portionwise. The product was purified
via preparative TLC using 10% Et2O in benzene. The indo-
lenines 70/71 were recovered as an inseparable mixture of
diastereomers (17.9 mg, 55%, 3.2:1).
Acknowledgment. Financial support from the NIH/
GMSI through GM 35727 is gratefully acknowledged.
1
Supporting Information Available: Copies of H NMR
and 13C NMR spectra for compounds 8, 12, 13, 22-26, 30, 31,
33, 34, 36, 37, 42a, 51, 53, 56, 64, 66, 67, and 72 and full
experimental descriptions for the preparation of 8, 9, 11-13,
21-23, 28-30, 39-41, 42a, 46-48, 51, 53-57, 62-65, 67,
and 72. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO050896W
6440 J. Org. Chem., Vol. 70, No. 16, 2005