The use of sulfur ylides in the synthesis of substituted indoles.

Article abstract of DOI:10.1021/ol0162320

[reaction: see text] This letter describes the insertion of rhodium carbenoids into thioindoles. C-10 thioindoles undergo fragmentation-coupling reactions when exposed to rhodium carbenoids. In an analogous fashion, ketoester- and malonate-substituted car

Full text of DOI:10.1021/ol0162320

ORGANIC
LETTERS
2001
Vol. 3, No. 15
2407-2409
The Use of Sulfur Ylides in the
Synthesis of Substituted Indoles
Abigail R. Kennedy, Michael H. Taday, and Jon D. Rainier*
Department of Chemistry, The UniVersity of Arizona, Tucson, Arizona 85721
rainier@u.arizona.edu
Received June 6, 2001
ABSTRACT
This letter describes the insertion of rhodium carbenoids into thioindoles. C-10 thioindoles undergo fragmentation−coupling reactions when
exposed to rhodium carbenoids. In an analogous fashion, ketoester- and malonate-substituted carbenoids have been found to insert into C-2
thioindoles. In contrast, vinylogous carbenoids were found to alkylate C-2 thioindoles at C-3.
The presence of highly substituted indoles in a number of
architecturally and biologically interesting natural and non-
natural products1 continues to inspire chemists to develop
new and improved routes to their synthesis.2 Our contribution
to this area has been the synthesis of 2,10-dithioindoles from
aryl isonitrile free radical cyclizations.3
interested in other thioether coupling protocols.5 Among the
possibilities, the selective formation of a sulfur ylide (e.g.,
3 or 4) seemed appealing, as it might lead to the insertion
of a carbon atom into the C-S bond.6,7 The possibility of
generating the ylide using metal carbenoid chemistry made
this proposal all the more attractive to us, as it presented us
with the possibility of carrying out these transformations in
an asymmetric fashion.8,9 Described herein are our investiga-
tions laying the foundation for the use of dithioindoles in
sulfur ylide rearrangement reactions.
We became fascinated with the notion that dithioindoles
(2) might serve as versatile precursors to highly function-
alized indole ring systems. As an illustration of this, we
recently described the use of 2 in fragmentation-coupling
reactions with active hydrogen compounds.4 In an effort to
further demonstrate the synthetic potential of 2, we became
To simplify our initial investigations we opted to focus
our efforts on the intramolecular ylide chemistry of a
(5) We have recently utilized KF and 18-C-6 to couple dithioindoles
with active hydrogen compounds. Rainier, J. D.; Kennedy, A. R.,
unpublished work.
(6) Doyle, M. P.; McKervey, M. A.; Ye, T. In Modern Catalytic Methods
for the Synthesis with Diazo Compounds; Wiley: New York, 1998.
(7) Padwa, A.; Weingarten, M. D. Chem. ReV. 1996, 96, 223.
(8) Doyle, M. P.; Forbes, D. C. Chem. ReV. 1998, 98, 911.
(9) Davies, H. M. L. Eur. J. Org. Chem 1999, 2459.
(1) (a) Lounasmaa, M.; Tolvanen, A. Nat. Prod. Rep. 2000, 17, 175. (b)
Faulkner, D. J. Nat. Prod. Rep. 1999, 16, 155.
(2) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045.
(3) Rainier, J. D.; Kennedy, A. R.; Chase, E. Tetrahedron Lett. 1999,
40, 6325.
(4) Rainier, J. D.; Kennedy, A. R. J. Org. Chem. 2000, 65, 6213.
10.1021/ol0162320 CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/03/2001

substrate lacking the C-2 thioether and settled upon 6.
Diazoketoester 6 was generated from the coupling of
methylated gramine with thiol 510 by employing KF and 18-
C-6. Exposure of 6 to Rh2(OAc)4 resulted in diazo decom-
to 10 and Rh2(OAc)4, we isolated coupled product 14a in
an unoptimized 58% yield. In an analogous fashion, we
isolated 14b in 50% yield when sulfonamide 13 was exposed
to 10 and Rh2(OAc)4.
position and the formation of coupled product 7 in 70% yield.
Presumably 7 is the result of the intramolecular formation
of sulfur ylide 8 followed by a subsequent elimination-
coupling reaction. Alternatively, 7 could result from a
Stevens-type [1,2]-shift of 8.11
Similarly, we isolated indole 15 in 71% yield when 13
was subjected to TMS diazomethane and Rh2(OAc)4. These
experiments clearly demonstrate that unactivated C-10 thio-
indoles are amenable to fragmentation-coupling reactions
when sulfur ylides are involved.
With the success of our experiments with the C-10
thioindoles, we turned our attention to 2,10-dithioindoles.
We synthesized dithioindole 16 with the notion that the C-2
thioether would be much less reactive than the corresponding
C-10 thioether in intermolecular ylide forming reactions.16
That is, since the lone pairs on the C-2 sulfur are conjugated
with both the indole and the phenyl group, we reasoned that
they should be less available for attack onto the Rh carbenoid.
Therefore, we were surprised to isolate the C-2 insertion
product 17 in 47% yield as the only identifiable product when
16 was exposed to diazo-â-ketoester 10 and Rh2(OAc)4.
Presumably, 17 results from the formation of sulfur ylide
18 followed by a subsequent Stevens-type [1,2]-alkyl shift.
Having demonstrated the feasibility of our approach in
an intramolecular sense, we decided to pursue the analogous
intermolecular reactions. As 3-ethylthiomethylindole had
been found to be immune to traditional fragmentation-
coupling conditions,12 the success of these experiments would
allow us and others to utilize indoles other than gramine and
methylated gramine in fragmentation-coupling reactions.13
In the event, exposure of C-10 thioether 9 to diazoketoester
1014 and Rh2(OAc)4 resulted in a low yield of the C-7 C-H
insertion product 11.15
From the notion that the indole nitrogen was interfering
with the formation of a C-10 sulfur ylide, we synthesized
the corresponding N-methylindole 12. When 12 was exposed
To illustrate the potential that these reactions and substrates
bring to the synthesis of substituted indoles, we carried out
an elimination-coupling reaction on 17 with dimethyl
malonate using our KF, 18-C-6 conditions. This resulted in
the formation of the highly substituted indole 19.
(10) Moyer, M. P.; Feldman, P. L.; Rappaport, H. J. Org. Chem. 1985,
50, 5223.
(11) Moody, C. J.; Taylor, R. J. Tetrahedron Lett. 1988, 29, 6005.
(12) Poppelsdorf, F.; Holt, S. J. J. Chem. Soc. 1954, 4094.
(13) Somei, M.; Karasawa, Y.; Kaneko, C. Heterocycles 1981, 16, 941.
(14) Baum, J. S.; Shook, D. A.; Davies, H. M. L.; Smith, H. D. Synth.
Commun. 1987, 17, 1709.
(15) The remainder of the identifiable material from the reaction consisted
of starting material (47%) and what we have tentatively assigned as the
C-2 C-H insertion product (ca. 3%).
(16) Compound 16 comes from the coupling of EtSH with the corre-
sponding 2-thiophenyl-3-phenylthiomethylindole.
2408
Org. Lett., Vol. 3, No. 15, 2001

into bioactive indoles containing quaternary substitution at
C-3 (e.g., amouramine, spirotryprostatins).
Scheme 2
As the generation of 17 and 19 represents a novel and
potentially important entry into 2,3-disubstituted indoles, we
decided to further examine the C-2 thioether insertion
chemistry. To best utilize both the C-2 and C-10 thioethers,
we decided to reverse the order of the C-C bond-forming
reactions. The coupling of 2 with dimethyl malonate using
KF and 18-C-6 resulted in the formation of 20 in 98% yield.
As an aside, this experiment illustrates the importance of
the C-2 thioether in elimination-coupling reactions. The
reaction of 17 with dimethyl malonate using the same
conditions was much less efficient. Thioether 20 was exposed
to diazocarbonyls 10 and 2114 in the presence of Rh2(OAc)4.
In both instances sulfur ylide formation was followed by a
Stevens-type [1,2] shift to provide C-S insertion products
22 and 23 respectively.
Presumably, 27-29 result from either the conjugate
addition of 20 onto the respective rhodium carbenoids19 or
from the formation of an intermediate sulfur ylide followed
by a [3,3]-sigmatropic rearrangement. These transformations
are reminiscent of the vinylogous rhodium carbenoid cou-
plings with electron-rich olefins that have emanated from
the Davies laboratories.20
From the experiments that have been outlined in this
manuscript, it is clear that thioindoles are valuable substrates
in synthetic chemistry. We had previously demonstrated this
through novel elimination-coupling reactions. This letter has
described a continuation of these studies and several interest-
ing transformations. These include the use of C-2 and C-10
thioethers in C-S insertion reactions with rhodium car-
benoids. We have also found that C-2 thioethers undergo
alkylation reactions at C-3 with vinylogous rhodium car-
benoids. Our current investigations in this area are focused
on optimizing the reactions that we have discovered, utilizing
asymmetric carbenoids in these reactions, and using the
products of these transformations in the synthesis of bioactive
indole-containing natural products.
Scheme 1
Acknowledgment. We gratefully acknowledge the Na-
tional Institutes of Health (GM56677) for support of this
work. M.H.T. thanks ACRE for an undergraduate research
fellowship. The authors would like to thank Professor
Michael P. Doyle (University of Arizona), Professor Huw
M. L. Davies (SUNY Buffalo), and Dr. Bruce E. Maryanoff
(R. W. Johnson Pharmaceutical Research Institute) for
helpful discussions. We would also like to thank Dr. Arpad
Somagyi and Dr. Neil Jacobsen for help with mass spectra
and NMR experiments, respectively.
In addition to ketoester- and malonate-substituted diazo
compounds, we have examined the reactions of vinyl
diazoacetates 24,17 25,20 and 2618 with 20. Interestingly, when
decomposed with Rh2(OAc)4 these provided thioimidates 27,
28, and 29, respectively. Thioimidates 28 and 29 were both
formed as a 2:1 mixture of diastereomers. These reactions
caught our attention as they might represent a novel entry
(17) Davies, H. M. L.; Hougland, P. W.; Cantrell, W. R., Jr. Synth.
Commun. 1992, 22, 971.
(18) Davies, H. M. L.; Clark, D. M.; Alligood, D. B.; Eiband, G. R.
Tetrahedron 1987, 43, 4265.
(19) We quantitatively reisolated starting material when 20 was subjected
to unsubstituted vinyl diazoester 24 in the absence of Rh2(OAc)4.
(20) (a) Davies, H. M. L.; Hu, B.; Saikali, E.; Bruzinski, P. R. J. Org.
Chem. 1994, 59, 4535. (b) Davies, H. M. L.; Saikali, E.; Young, W. B. J.
Org. Chem. 1991, 56, 5696.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0162320
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2409