Highly diastereoselective sulfonium ylide rearrangements to quaternary substituted indolines

Article abstract of DOI:10.1002/anie.200801336

(Chemical Equation Presented) Quat. centers: Sulfonium ylide intermediates generated from halogenated vinyl diazoacetates and 2-thioindoles in the presence of a Rh^II complex undergo highly diastereoselective [3,3] rearrangements to indolines having an asymmetric quaternary carbon center with an adjacent halogenated stereocenter (see scheme).

Full text of DOI:10.1002/anie.200801336

Communications
DOI: 10.1002/anie.200801336
Synthetic Methods
Highly Diastereoselective Sulfonium Ylide Rearrangements to
Quaternary Substituted Indolines**
Vyacheslav Boyarskikh, Abijah Nyong, and Jon D. Rainier*
The stereoselective generation of quaternary centers, includ-
ing quaternary centers at C3 of oxindoles and indolines,
remains a challenge for contemporary organic synthesis.[1] To
date, a list of the most successful methods addressing the
indoline/oxindole problem would include intra- and intermo-
lecular Mannich,[2] Heck,[3] and Mukaiyama aldol condensa-
tions,[4] as well as alkylation reactions,[5–7] cycloadditions,[8] p-
allyl couplings,[9] cyclopropane ring openings,[10] oxidative
couplings, and rearrangements.[11,12]
give 9 and 10, Scheme 2).[19] Because of the well-established
stability of sulfonium ylides, we presumed that RhII was
important in the generation and delivery of the carbenoid to
the thioether, but that it was absent during the subsequent
À
sequence leading to C C bond formation and 10 (cf. 7, R’’ = CC,
Scheme 2).[20]
In the course of our studies aimed at the use of 2-
thioindoles as precursors to substituted oxindoles and indo-
lines,[13–15] we became fascinated with the coupling of 2-thio-3-
alkylindoles with vinyl diazoacetates in the presence of RhII
salts because the reaction delivered structurally rich quater-
nary substituted indolines in high yield and the mechanism
was mechanistically interesting (Scheme 1).[16] We did not use
this reaction in total synthesis endeavors because it was only
modestly diastereoselective when monosubstituted vinyl
diazoacetates were used as the coupling partners.[17,18]
In terms of the mechanism for the transformation to 3 and
4, an abundance of indirect evidence suggested a [3,3] rear-
rangement of an intermediate sulfonium ylide (i.e. 7 or 8 to
Scheme 2. Working hypothesis for 2-thioindole RhII-vinyl carbenoid
couplings.
Our previous studies resulted in levels of diastereoselec-
tivity that were similar to those seen with 1, therefore we were
surprised when the reaction of bis(thioindole) 11[21] with 2
gave 12 in relatively high diastereoselectivity (Scheme 3). We
became intrigued by the generation of 12 and decided to
examine the reaction in more detail by exploring the effect of
thioindole substitution on diastereoselectivity. As an aside,
the importance of the thioether group in the reaction becomes
Scheme 1. 2-Thioindole RhII-vinyl carbenoid couplings.
[*] V. Boyarskikh, A. Nyong, Prof. J. D. Rainier
Department of Chemistry
University of Utah
315 South 1400 East, Salt Lake City, UT 84112 (USA)
Fax: (+1)801-581-8433
E-mail: rainier@chem.utah.edu
Homepage: http://www.chem.utah.edu/faculty/rainier/group.html
[**] We are grateful to the National Science Foundation (CHE-0650405)
for support of this work. We would like to thank the support staff at
the University of Utah and especially Dr. Charles Mayne (NMR) and
Dr. Jim Muller (mass spectrometry) for help in obtaining data as
well asProfessor Huw M. L. Davies(SUNY Buffalo) for the
generous donation of catalysts and for helpful discussions.
Supporting information for thisarticle isavailable on the WWW
under http://www.angewandte.org or from the author.
Scheme 3. Diastereo- and chemoselective bis(indole) vinyl carbenoid
couplings.
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Chemie
Table 2: The influence of thioaryl substitution on the diastereoselectivity
of the reactionswith 2 and 36.
clearer with this example; no products resulting from reaction
of the vinyl carbenoid with the indole lacking the thioether
unit were isolated.
To determine whether the substituent at C3 of the indole
ring was responsible for the enhanced diastereoselectivity
with 11, we examined the effect of a variety of C3 substituents
on the reaction (Table 1). Whereas 3-tert-butyl-2-thiophenyl-
Table 1: The influence of substitution at C3 on the diastereoselectivity.
Entry
Indole
Ar
Indoline
A/B
Yield
1
2
3
4
5
6
7
22
23
24
25
26
27
28
4-OMeC6H4
4-NO2C6H4
2-OMeC6H4
2-FC6H4
2-MeC6H4
2,6-dimethylphenyl
2-iPrC6H4
29
30
31
32
33
34
35
7:1
7:1
9:1
7:1
11:1
15:1
18:1
86%
74%
74%
81%
75%
96%
91%
Entry
Indole
R
Indoline
A/B
Yield
[a] Ratio of diastereomers determined by the integrations of the allylic
proton peak in the 1H NMR spectra of the crude reaction mixture.
1
2
3
4
5
11
14
15
16
17
3’-indole
Ph
Me
tBu
12
18
19
20
21
10:1[a]
8:1[a]
7:1[a]
76%
80%
75%
91%
88%
15:1[a]
8:1[b]
CH2CH2CO2Et
1
[a] Ratio of diastereomers determined by H NMR spectroscopy of the
crude reaction mixture. [b] Ratio of diastereomers determined by HPLC
analysis of the crude reaction mixture.
indole (16)[22] gave the highest selectivity (Table 1, entry 4),
more subtle structural modifications as exemplified by 14,[23]
15,[24] and 17[25] resulted in little to no change in diastereose-
lectivity (Table 1, entries 2, 3, and 5).
Scheme 4. (E)-Chlorovinyldiazoacetate coupling.
From our perspective the most interesting result from the
studies summarized in Table 1 was that 2-thiophenylethers
showed enhanced selectivity relative to 2-alkylthioethers
(compare Table 1, entry 5 with Scheme 1), implying that
substitution on the thioether group might influence the
reaction. We examined the effect of the substitution on the
thioarene unit to gain more insight (Table 2) into the
reaction.[26] Whereas para substitution resulted in selectivities
that were similar to those obtained with the parent thiophenyl
derivative (compare Table 2, entries 1 and 2 with Table 1,
entry 5), the reaction was significantly enhanced by substitu-
tion ortho to the thioether. The diastereoselectivity increased
to 11:1 with ortho-methyl thioether 26 (Table 2, entry 5) and
to 15:1 with 2,6-dimethylphenyl thioether 27 (Table 2,
entry 6). The highest selectivity in these studies was obtained
with ortho-isopropyl indole 28 giving indoline 35 with 18:1
diasteroselectivity. These results along with the lower selec-
tivities seen with ortho-methoxy and ortho-fluoro thiophenyl
ethers 24 and 25, respectively (Table 2, entries 3 and 4) imply
that steric, and not electronic effects are operative here.[27]
As would be expected for a reaction involving a concerted
rearrangement (cf. 8 to 9, Scheme 2), the reaction is
stereospecific; the reaction of 36 with (E)-vinylchloride 37
gave indoline 38, whose structure is analogous to the minor
isomer from the reaction of 17 with 2, as the major product in
88% yield as an 8:1 ratio of diastereomers (Scheme 4).
We next examined the influence of a chiral RhII complex
([Rh2(tbsp)4]; tbsp = tetrakis{1-[(4-tert-butylphenyl)sulfonyl]-
(2S-pyrrolidinecarboxylate}) on the reaction.[28] Although the
enantioselectivity was low (Table 3),[29] exposure of 2,6-
dimethylphenylthioindole 27 to 2 and [Rh2(tbsp)4] resulted
in an increased diastereoselectivity when compared to the
Table 3: Effect of [Rh2(tbsp)4] on the diastereoselective coupling reac-
tionsof 2 with 2-arylthioindoles.
Entry
Indole
Ar
Indoline
A/B[a]
Yield
1
2
22
27
4-OMeC6H4
2,6-dimethylphenyl
29
34
7:1[b]
94%
91%
>95:5[c]
[a] Ratio of diastereomers determined by integration of the of the allylic
proton in the 1H NMR spectrum of the crude reaction mixture. [b] e.r.=
62:38 asdetermined by chiral HPLC method.s [c] e.r.
determined by chiral HPLC methods.
=56:44 as
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analogous [Rh2(OAc)4] reaction (compare Table 2, entry 2
with entry 6). Interestingly, there was essentially no change in
selectivity for the reaction of p-methoxy derivative 22.
Although additional data is clearly needed, from these studies
we believe that the metal may be more involved in the
reaction than presumed previously. Our current speculation is
that it may be present at least up to the proton transfer step
(see 7, R’’ = RhÀ, Scheme 2).[30,31]
Of additional note is that the reaction is not limited to the
use of vinyl chlorides. In addition to the multitude of
substituted vinyl diazoacetates previously disclosed,[14,16,19]
bromovinyl diazoacetate 39 underwent a stereoselective
reaction with 2-arylthioindole 27 to give allylic bromide 40
as a single diastereomer in 78% yield (Scheme 5).
Scheme 7. Spirocyclopentane synthesis.
acetates and 2-thioindoles. These transformations led to the
synthesis of structurally interesting substrates that would be
difficult to prepare by using other methodologies. Current
efforts are focused on the control of the absolute stereo-
chemistry of the products and the application of the reaction
to non-indole aromatic thioether substrates.
Scheme 5. (Z)-Bromovinyldiazoacetate coupling.
Received: March 19, 2008
Revised: April 13, 2008
Published online: June 11, 2008
Based upon their wealth of interesting functionality, we
were hopeful that the products from the reactions outlined
above would be amenable to additional derivatization. Thus,
we were pleased to generate pyrroloindoline 43 in 95% yield
from the acid mediated cyclization of thioindoline 42 that
came from the reaction of 41 with 2 in the presence of
[Rh2((S)-tbsp)4] (Scheme 6).[32]
Keywords: allylic compounds· indole · rearrangement · sulfur ·
ylides
.
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