Sulfur ylide-initiated thio-claisen rearrangements. The synthesis of highly substituted indolines

Article abstract of DOI:10.1021/jo026582f

The coupling of rhodium carbenoids from vinyl diazoacetates with 2-thio-3-alkyl indoles was found to generate C(3) quaternary substituted indolines via a thionium ylide-initiated [3,3]-sigmatropic rearrangement.

Full text of DOI:10.1021/jo026582f

Su lfu r Ylid e-In itia ted Th io-Cla isen Rea r r a n gem en ts. Th e
Syn th esis of High ly Su bstitu ted In d olin es
Alexei V. Novikov,† Abigail R. Kennedy,‡ and J on D. Rainier*,†
Department of Chemistry, The University of Arizona, Tucson, Arizona 85721, and Department of
Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112
rainier@chem.utah.edu
Received October 18, 2002
The coupling of rhodium carbenoids from vinyl diazoacetates with 2-thio-3-alkyl indoles was found
to generate C(3) quaternary substituted indolines via a thionium ylide-initiated [3,3]-sigmatropic
rearrangement.
TABLE 1. Cou p lin g of 1 w ith Mon osu bstitu ted Vin yl
Dia zoa ceta tes
In tr od u ction
The presence of C(3) quaternary substitution in a wide
variety of interesting indoline-containing natural and
nonnatural products has inspired a number of groups,
including ours, to develop new and improved routes to
their synthesis.1-3 Our contributions to this area began
with the somewhat surprising result that was obtained
when we attempted to couple vinyl diazoacetate 2 with
2-thio-3-alkylindole 1 in the presence of rhodium acetate
(eq 1).4 Rather than the anticipated C-S insertion
product that had been observed with diazomalonates and
diazo-â-ketoesters, we isolated C(3) quaternary-substi-
tuted indoline 3.
entry diazo
R′
Me
R′′ conditionsa productb drc yield
1
2
3
4
4
5
6
7
H
H
H
Cl
A
A
B
B
8
2:1 95%
2:1 93%
1:1 95%
3:1 98%
CO2Et
Ph
H
9
10
11
a
b
A: PhH, reflux. B: CH2Cl2, rt. Relative stereochemistry of
the major diastereomer is shown. This assignment was based upon
the X-ray structural determination of 25 (Table 3 and Supporting
information). c Determined by 1H NMR.
cascades and C(10) fragmentation-coupling reactions,5
we felt that the 1 f 3 transformation might prove to be
useful in the synthesis of highly substituted indoline ring
systems. However, to achieve this goal it was clear to us
that we needed to have a better sense of the scope and
limitations of this reaction. Herein, we report the results
of these efforts.
Gen er a tion of In d olin es Ha vin g C(3) Qu a ter n a r y
Su bstitu tion . In addition to the reaction illustrated in
eq 1, our initial experiments had demonstrated that the
coupling of thioindole 1 with vinyldiazoacetates was
insensitive to methyl and carboxyethyl substitution on
the terminus of the vinyl diazoacetate (Table 1, entries
1 and 2).4 In an effort to gain a better understanding of
the range of monosubstituted olefins capable of undergo-
ing this transformation, we synthesized phenyl- and
chloro-substituted vinyl diazoacetates 66 and 7,6 respec-
tively, and examined their coupling with thioindole 1. To
When combined with our ability to generate 2-thio-3-
alkylindoles from the coupling of isonitrile-alkyne radical
† Current address: Department of Chemistry, University of Utah,
315 South 1400 East, Salt Lake City, UT 84112
‡ Current address: Exelixis, Inc., 170 Harbor Way, P.O. Box 511,
So. San Francisco, CA 94083-0511.
(1) For recent reviews of indole-containing natural products, see:
(a) Lounasmaa, M.; Tolvanen, A. Nat. Prod. Rep. 2000, 17, 175. (b)
Faulkner, D. J . Nat. Prod. Rep. 1999, 16, 155.
(2) For a recent review covering approaches to the synthesis of
indoles, see: Gribble, G. W. J . Chem. Soc., Perkin Trans. 1 2000, 1045.
(3) For representative examples of the synthesis of indolines having
quaternary substitution at C(3) see: (a) Overman, L. E.; Paone, D. V.;
Stearns, B. A. J . Am. Chem. Soc. 1999, 121, 7702. (b) Overman, L. E.;
Paone, D. V. J . Am. Chem. Soc. 2001, 123, 9465. (c) Marsden, S. P.;
Depew, K. M.; Danishefsky, S. J . J . Am. Chem. Soc. 1994, 116, 11143.
(d) Fischer, C.; Meyers, C.; Carreira, E. M. Helv. Chim. Acta 2000, 83,
1175. (e) Nakazawa, K.; Hayashi, M.; Tanaka, M.; Aso, M.; Suemune,
H. Tetrahedron: Asymmetry 2001, 12, 897. (f) Kawahara, M.; Nishida,
A.; Nakagawa, M. Org. Lett. 2000, 2, 675. (g) Fuji, K.; Kawabata, T.;
Ohmori, T. Heterocycles 1998, 47, 951. (h) Bruncko, M.; Crich, D.;
Samy, R. J . Org. Chem. 1994, 59, 5543. (i) Booker-Milburn, K. I.;
Fedouloff, M.; Paknoham, S. J .; Strachan, J . B.; Melville, J . L.; Voyle,
M. Tetrahedron Lett. 2000, 41, 4657.
(5) (a) Rainier, J . D.; Kennedy, A. R.; Chase, E. Tetrahedron Lett.
1999, 40, 6325. (b) Rainier, J . D.; Kennedy, A. R. J . Org. Chem. 2000,
65, 6213.
(4) Kennedy, A. R.; Taday, M. H.; Rainier, J . D. Org. Lett. 2001, 3,
2407.
(6) Bulugahapitiya, P.; Landais, Y.; Parra-Rapado, L.; Planchenault,
D.; Weber, V. J . Org. Chem. 1997, 62, 1630.
10.1021/jo026582f CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/24/2002
J . Org. Chem. 2003, 68, 993-996
993

Novikov et al.
TABLE 2. Cou p lin g of 1 w ith Disu bstitu ted Vin yl
our delight, when 6 and 7 were added to a solution of
Rh2(OAc)4, 1, and CH2Cl2 at room temperature, we
isolated 10 and 11 in 95 and 98% yields, respectively.
In addition to the overall efficiency of these transfor-
mations, three features are worthy of note. First, the
coupling results in the selective formation of the (E)-olefin
isomer.7 Second, these reactions are run in the absence
of protection on the indole nitrogen and proceed without
any evidence of NH insertion. Finally, the products result
from the selective coupling of the 3-position on the indole
with the vinyl terminus of the vinyl diazoacetate.
As a demonstration of the synthetic potential of thio-
imidates 8-11, we transformed one of the diastereomers
of thioimidate 10 into spirocycle 128 in 90% yield by
simply treating it with DBU (eq 2). The presence of the
spirocyclic framework of 12 in a number of intriguing
natural products speaks to the utility of these coupling
reactions.9
Dia zoa ceta tes
a
Formed as a 1.5:1 mixture of diastereomers as determined by
1H NMR integration.
In contrast to the results with 14 and 17, vinyl
diazoacetate 1911 underwent intramolecular C-H inser-
tion to generate indene 20 when exposed to Rh2(OAc)4
and 1 (eq 4). We observed no product resulting from the
coupling of 1 and 19. In the absence of thioindole, we
found that the conversion of 19 into 20 occurred in 88%
yield.12
Gen er a t ion of In d olin es Ha vin g C(3) Vicin a l
Qu a ter n a r y Su bstitu tion . Having demonstrated that
a variety of monosubstituted vinyldiazoacetates undergo
coupling with 1 in the presence of Rh2(OAc)4, we chose
to investigate disubstituted vinyl diazoacetates. These
experiments would not only give us a better understand-
ing of the reaction scope but also, if successful, enable
us to access a plethora of interesting indoline natural
products having C(3) vicinal quaternary substitution.10
With this in mind, we examined the coupling of
dimethyl vinyldiazoacetate 136 with thioindole 1 (Table
2). Slow addition of 13 to a solution of 1, Rh2(OAc)4, and
CH2Cl2 at room temperature resulted in the formation
of indoline 15 in 86% yield. As in the reactions of the
monosubstituted vinyl diazoacetates with 1, 15 was
formed exclusively as its (E)-olefin isomer. Similarly, the
coupling of vinyl diazoacetate 146 with 1 resulted in the
formation of thioimidate 16 in 96% yield. Clearly, these
experiments demonstrate that sterically encumbered
indolines can be obtained using this methodology.
When the size of the substituents on the terminus of
the vinyl diazoacetate was increased to diphenyl, the
reaction entered a new manifold (eq 3). That is, the
coupling of vinyl diazoacetate 176 with 1 led to the
formation of thioimidate 18 as a 1:1 mixture of diaster-
eomers in 71% yield. Overall, 18 results from the coupling
of 1 with 17 at the carbenoid-bearing carbon.
Ester a n d Th ioeth er Su bstitu en t Effects on Cou -
p lin g Rea ction s. The diastereoselectivity in the con-
densation between monosubstituted vinyl diazoacetates
and thioindoles was only marginally affected by substitu-
tion on the thioether (Table 3). When chloro-substituted
vinyl diazoacetate 7 was coupled with 2-isopropylthio-
indole 2113 in the presence of Rh2(OAc)4, thioimidate 25
was formed in 83% yield as a 3.4:1 mixture of diastereo-
mers (entry 1). A 3:1 ratio of diastereomers had been
observed when ethyl thioindole 1 was used (Table 1).
Similarly, the steric environment about the diazoester
had little influence on the diastereoselectivity of the
coupling reaction. For example, the coupling of tert-butyl
ester 23 with 21 resulted in the formation of 26 in
approximately the same diastereomeric ratio as the
corresponding ethyl ester (Table 3, entries 1 and 2).
(7) The corresponding (Z)-olefin isomer was not observed by 1H NMR
spectroscopy.
(8) Determined by 1NMR experiments. See Supporting Information
for details.
(11) Davies, H. M. L.; Clark, D. M.; Alligood, D. B.; Eiband, G. R.
Tetrahedron 1987, 43, 4265.
(9) For example, the paraherquamides contain spirofused oxindoles
analogous to 12. The Williams group has been at the forefront of the
synthetic studies towards these agents. See: Williams, R. M.; Cao, J .;
Tsujishima, H. Angew. Chem., Int. Ed. 2000, 39, 2540 and references
therein.
(10) Examples include paraherquamides (see ref 9) and a number
of dimeric indoles. The Overman group has been at the forefront of
efforts in this latter area. See ref 3b and references therein.
(12) There are numerous examples of related reactions. See: Doyle,
M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic
Synthesis with Diazo Compounds; Wiley & Sons: New York, 1998;
325-336.
(13) From the free radical cyclization of (2-isocyanophenylethynyl)
trimethylsilane with 2-propanethiol followed by fragmentation coupling
with dimethylmalonate. See Supporting Information and ref 5b.
994 J . Org. Chem., Vol. 68, No. 3, 2003

Synthesis of Highly Substituted Indolines
TABLE 3. Effect of Th ioeth er a n d Dia zoester
Su bstitu tion on th e Dia ster eoselectivity
SCHEME 1. Da vies’ Cou p lin g of En ol Eth er s w ith
Vin yl Dia zoa ceta te 2914
entry
indole
R
R′
R′′
Et
t-Bu
t-Bu
indoline
dra
yield
1
2
3
21
21
22
i-Pr
i-Pr
Ph
Cl
Cl
H
25
26
27
3.4:1
3.6:1
83%
79%
80%
SCHEME 2. P r op osed Mech a n ism for th e
Cou p lin g of Th ioin d oles w ith Vin yl Dia zoa ceta tes
a
Determined by integration of the vinyl protons in the crude
1H NMR spectra.
TABLE 4. Cou p lin g of Th ioin d oles w ith Vin yl
Dia zoa ceta tes
SCHEME 3. P r op osed Mech a n ism for th e
Gen er a tion of 18
Finally, phenyl thioether 22 underwent successful
coupling with vinyl diazoacetate 24, thus demonstrating
that the reaction is amenable to nonalkyl substitution
on the thioether.
The relative stereochemistry of chlorothioimidate 25
(major diastereomer) was determined through single
X-ray diffraction (See Supporting Information).
P r op osed Mech a n ism for Cou p lin g of 2-Th ioin -
d oles w ith Vin yl Dia zoa ceta tes. Davies and co-work-
ers observed phenomena similar to that presented here
when they attempted to couple pyrroles, enol ethers,
dihydrofurans, and cyclopentadienes with unsubstituted
vinyl diazoacetates in the presence of rhodium (Scheme
1).14 They reasoned that the products from these reac-
tions arose from the conjugate addition of the electron-
rich olefin with the vinyl terminus of the rhodium
carbenoid. Consistent with this notion, terminally sub-
stituted vinyl diazoacetates did not give conjugate addi-
tion products.
As has been described, we have found the coupling of
2-thioindoles with vinyl diazoacetates to also give con-
jugate addition products. However, in light of the pres-
ence of thioethers and our ability to utilize substituted
vinyl diazoacetates in these couplings, we believe that
2-thioindoles proceed through an entirely different mech-
anism (Scheme 2). As in the coupling of 1 with malonate
and â-ketoester rhodium carbenoids,4 it is reasonable to
assume that the reaction is initiated by the formation of
a sulfur ylide intermediate (i.e., 32 and/or 33, Scheme
2).15 After proton transer,16,17 the resulting allyl thionium
(15) For reviews on ylide-initiated cascades (rearrangements and
cycloadditions), see: (a) Padwa, A.; Weingarten, M. D. Chem. Rev.
1996, 96, 223. (b) Hodgson, D. M.; Pierard, F. Y. T. M.; Stupple, P. A.
Chem. Soc. Rev. 2001, 30, 50. (c) Doyle, M. P.; Forbes, D. C. Chem.
Rev. 1998, 98, 911.
(14) (a) Davies, H. M. L.; Saikali, E.; Young, W. B. J . Org. Chem.
1991, 56, 5696. (b) Davies, H. M. L.; Hu, B. Tetrahedron Lett. 1992,
33, 453. (c) Davies, H. M. L.; Hu, B.; Saikali, E.; Bruzinski, P. R. J .
Org. Chem. 1994, 59, 4535.
J . Org. Chem, Vol. 68, No. 3, 2003 995

Novikov et al.
ion 34 undergoes a [3,3]-sigmatropic rearrangement to
give indoline 35 after isomerization to the thioimidate.18-20
As was mentioned above (eq 3), the coupling of 1 with
diphenyl vinyl diazoacetate 17 results in the formation
of 18 from the coupling at the diazo-bearing carbon of
the vinyl diazoacetate with C(3) of the indole. Presum-
ably, this reaction also proceeds through an allyl thion-
ium ion (e.g., 36). However, rather than undergoing a
[3,3]-sigmatropic rearrangement as had been observed
in the other systems, the presence of the diphenyl
substituents on the alkene forces an overall [1,3]-sigma-
tropic rearrangement to give 18. Presumably, this occurs
an N-H insertion reaction with a [3,3]-rearrangement.
To test the viability of this hypothesis, we synthesized
allyl indole 39 and subjected it to our rearrangement
conditions. The quantitative recovery of starting material
from this experiment effectively rules out the N-H
insertion initiated pathway (eq 6).
21-23
via the intermediacy of ionic intermediate 37.
Consistent with the mechanism proposed in Scheme
2, we have found that N-methyl indole 3824 does not
undergo this process. That is, when 38 was subjected to
vinyldiazoacetate 2 and Rh2(OAc)4, no coupling occurred
and thioindole 38 was reisolated in quantitative yield
(eq 5).
Cou p lin g of C(3)-Su bstitu ted In d oles w ith Vin yl
Dia zoa ceta tes. Finally, to demonstrate that these reac-
tions can be carried out with indoles having substitution
other than malonate at C(3), cyclic acetal 40 and 2-thio-
tryptophan methyl ester 4125 were subjected to Rh2(OAc)4
and vinyl diazoacetates 2 and 13, respectively. These
couplings resulted in the isolation of indolines 42 and
43 in 75 and 82% yields, respectively.
Con clu sion
From the experiments that have been outlined here,
it is clear that 2-thioindoles show remarkable potential
as precursors to highly substituted indoline systems. This
work has described the generation of C(3) quaternary and
C(3) vicinal quaternary substitution via the coupling of
vinyl carbenoids with 3-alkyl-2-thioindoles. Our current
investigations are focused on optimizing the reactions
that we have discovered and, in the process, uncovering
more insight into the mechanism. Additionally, we are
currently utilizing asymmetric carbenoids in these reac-
tions and taking advantage of these transformations to
generate bioactive indoline-containing natural products.
An alternative mechanism that would be consistent
with all of the results presented thus far would couple
(16) For reports from other laboratories of proton transfer to ylide
intermediates, see: (a) Padwa, A.; Dean, D. C.; Zhi, L. J . Am. Chem.
Soc. 1992, 114, 593. (b) Padwa, A.; Dean, D. C.; Zhi, L. J . Am. Chem.
Soc. 1989, 111, 6451. (c) Mori, T.; Sawada, Y.; Oku, A. J . Org. Chem.
2000, 65, 3620.
(17) While we cannot rule it out at the present time, we disfavor
the rearrangement of 33 because it would lead to a highly energetic
vinyl anion.
(18) We are aware of three other examples of an ylide-initiated [3,3]-
sigmatropic rearrangement. See (a) Nakano, H.; Ibata, T. Bull. Chem.
Soc. J pn. 1995, 68, 1393. (b) Wood, J . L.; Moniz, G. A.; Pflum, D. A.;
Stoltz, B. M.; Holubec, A. A.; Dietrich, H.-J . J . Am. Chem. Soc. 1999,
121, 1748. (c) Wood, J . L.; Moniz, G. A. Org. Lett. 1999, 1, 371. (d)
May, J . A.; Stoltz, B. M. J . Am. Chem. Soc. 2002, 124, 12426.
(19) For examples of thio-Claisen rearrangements in indole systems,
see: (a) Bycroft, B. W.; Landon, W. J . Chem. Soc., Chem. Commun.
1970, 168. (b) Bycroft, B. W.; Landon, W. J . Chem. Soc., Chem.
Commun. 1970, 967.
Ack n ow led gm en t. We thank the National Insti-
tutes of Health, General Medical Sciences (GM61608),
for their generous funding of this work. Support of the
NMR facility in the Department of Chemistry at the
University of Arizona by the National Science Founda-
tion under Grant 9729350 is also gratefully acknowl-
edged. We thank Dr. Neil J acobsen and Dr. Arpad
Somagyi for help with NMR and mass spectra experi-
ments, respectively. Finally, we are indebted to our
friend and colleague Professor Michael P. Doyle for
many helpful discussions and the generous gift of the
Rh2(OAc)4 used in this work.
(20) For an example of the use of Claisen rearrangements in the
synthesis of oxindoles having quaternary substitution at C(3), see ref
3i.
(21) For examples of [1,3]sigmatropic rearrangements in allyl vinyl
ethers, see: (a) Grieco, P. A.; Clark, J . D.; J agoe, C. T. J . Am. Chem.
Soc. 1991, 113, 5488. (b) Danishefsky, S.; Funk, R. L.; Kerwin, J . F.,
J r. J . Am. Chem. Soc. 1980, 102, 6891. (c) Trost, B. M.; Runge, T. A.
J . Am. Chem. Soc. 1981, 103, 7559. (d) Nonoshita, K.; Banno, H.;
Maruoka, K.; Yamamoto, H. J . Am. Chem. Soc. 1990, 112, 316.
(22) Alternatively, cyclopropanation of the thioindole could be
followed by the in situ ring opening of the cyclopropane. Although this
mechanism would not be consistent with our results from reactions of
other rhodium carbenoids with 2-thioindoles (see ref 4), we cannot rule
it out at the present time.
(23) While we cannot rule out the possibility that 35 also comes from
an ion pair similar to 37, the recombination to form vicinal quaternary
substitution is not consistent with such a mechanism.
(24) Compound 38 comes from the reduction of malonate 2 with
LiAlH4 followed by acetonide formation and methylation.
Su p p or tin g In for m a tion Ava ila ble: Complete experi-
mental details and spetroscopic data for compounds 10-12,
15-27, and 38-43. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O026582F
(25) Compound 41 comes from the reaction of ClSPh with L-
tryptophan methyl ester. See: Crich, D.; Davies, J . W. Tetrahedron
Lett. 1989, 30, 4307.
996 J . Org. Chem., Vol. 68, No. 3, 2003