Highly Diastereo- and Enantioselective CuH-Catalyzed Synthesis of 2,3-Disubstituted Indolines

Article abstract of DOI:10.1021/jacs.5b02316

A diastereo- and enantioselective CuHcatalyzed method for the preparation of highly functionalized indolines is reported. The mild reaction conditions and high degree of functional group compatibility as demonstrated with substrates bearing heterocycles,

Full text of DOI:10.1021/jacs.5b02316

Communication
pubs.acs.org/JACS
Highly Diastereo- and Enantioselective CuH-Catalyzed Synthesis
of 2,3-Disubstituted Indolines
Erhad Ascic and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
S
* Supporting Information
ABSTRACT: A diastereo- and enantioselective CuH-
catalyzed method for the preparation of highly function-
alized indolines is reported. The mild reaction conditions
and high degree of functional group compatibility as
demonstrated with substrates bearing heterocycles, olefins,
and substituted aromatic groups, renders this technique
highly valuable for the synthesis of a variety of cis-2,3-
disubstituted indolines in high yield and enantioeselectivity.
ptically active 2,3-disubstituted indolines are of consid-
Oerable interest in both synthetic and medicinal chemistry
due to the numerous natural products and pharmaceuticals
whose structures incorporate this heterocyclic framework.1
They also serve as key building blocks for drug discovery, as
exemplified in various natural product-like chemical libraries
based on the indoline framework.2
rapid and synthetically valuable approach to enantioenriched
indolines with two contiguous chiral centers could be realized in
two steps from readily available aminostyrene and aromatic
aldehyde derivatives (eq 2).
Consequently, a wide range of strategies have been developed
for the asymmetric synthesis of these structures.3 Among these
methods, the Brønsted acid-activated asymmetric hydrogenation
of functionalized indoles is perhaps the most important strategy
to their synthesis.4 Despite its attractiveness, the need to employ
acidic reaction conditions, high pressure, and the lack of broad
functional group compatibility manifested, have prevented
the more widespread application of this approach. Other
notable methods, such as the kinetic resolution of indolines,5
the Pd-catalyzed asymmetric intramolecular coupling reactions,6
tandem AN/SNAr processes,7 and asymmetric sparteine-
mediated reactions,8 have also been developed. Despite these
advances, the harsh reaction conditions,6,8 multistep synthesis,5
and modest to poor yields,6a,7 limits their synthetic applications.
To date, no direct asymmetric approach is available to access
2,3-disubstituted indolines bearing a wide variety of functional
groups. In particular, incorporation of pharmaceutically im-
portant heterocycles (e.g., indoles, quinolines, pyridines) with
indolines in an asymmetric fashion is not well-known. Herein,
we report a straightforward approach to the synthesis of 2,3-
disubstituted indolines in high diastereo- and enantioselectivities
through a CuH-based strategy. This protocol tolerates a broad
range of functional groups, including heteroarenes and olefins.
Recently, we and Miura and Hirano have independently
reported the enantioselective CuH-catalyzed Markovnikov
hydroamination of styrenes.9 Bearing in mind that these reac-
tions proceed via organocopper intermediates that undergo
amination with electrophilic hydroxylamine esters (eq 1), we
questioned whether these species could be trapped intra-
molecularly with tethered imine electrophiles. In this manner a
A scheme of our proposed strategy is illustrated in Figure 1.
Based on literature precedent for related CuH-based sys-
tems,9−14 the active L*CuH species A could be formed by
reacting Cu(OAc)2 with a chiral ligand and a stoichiometric
amount of a hydrosilane.9a,10a,b The olefinic moiety of 1a could
then readily insert into Cu−H bond of A. Based on previous
Figure 1. Proposed catalytic cycle for CuH-catalyzed synthesis of
2,3-disubstituted indolines.
Received: March 4, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b02316
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Journal of the American Chemical Society
Communication
results we would expect this to occur in a highly enantioselective
and in a Markovnikov fashion to form the alkylcopper interme-
diate B.9,10c−f Intermediate B could then undergo an unprece-
dented cyclization with the adjacent imine to form C.11 Sub-
sequent protonation of C with t-BuOH would then provide the
desired indoline 2a, and generate [L*CuOt-Bu] species D, which
is an ideal precursor for rapid regeneration of the active L*CuH
A.12 In order for this approach to be successful, it is necessary that
A react chemoselectively with the olefin over the imine.13 It is
also necessary that the cyclization (B to C) is faster than the
undesired protonation of B to 3.14
yield, while the enantioselectivity was unchanged (entry 2). We
attributed the improvement in catalyst turnover to the protonation
of [L*Cu−N-indoline] C with t-BuOH (Figure 1), bypassing the
slow transmetalation between C and R3Si−H needed for
regenerationofL*CuH.15 We nextexamined several commercially
available chiral bisphosphine ligands (entries 2−7), and we found
that (S,S)-Ph-BPE proved to be best in terms of reactivity and
enantioselectivity (84% yield, 84% ee, entry 7). Screening of
solvents revealed that a mixture of MTBE/THF (19:1) was the
best choice, leading to an enhanced yield and enantioselectivity
(92% yield, 90% ee, entry 8).
We found that the choice of alcohol was important for the
yield. For example, when using t-BuOH (entry 8) the reduced
styrene side product 3 could be detected in 3% yield. Examining
the use of i-PrOH, EtOH, MeOH, and 2-trifluoromethyl-2-
propanol, afforded the desired product 2a in lower yields (29−
88%, entries 9−12), while observing an increase in yield of the
side product 3 in 5%, 15%, 36%, and 55%, respectively. When t-
BuOD was used in lieu of t-BuOH, only a trace amount of 3
(<1%) could be detected, and a slight increase in yield of 2a was
obtained (96%, entry 13) compared to t-BuOH (92%, entry 8).
We attribute this to a deuterium isotope effect; i.e., the pro-
tonolysis of B to 3 is slower with t-BuOD than with t-BuOH.16
Lipshutz, in related CuH-catalyzed systems, has shown that
addition of triphenylphosphine as a secondary ligand, signifi-
cantly improves the catalyst turnover number.17 Applying this
strategy to our method, further improved the yield that could be
achieved without any erosion in enantioselectivity (entry 14).
With the optimized conditions in hand, we examined the
reaction scope using a variety of stable 2-alkenylimine precursors
1a−w. These were obtained in good to excellent yields from
readily available 2-alkenylanilines and aromatic aldehydes (Table 2).
Generally, the reaction displayed good functional group tolerance,
and in all cases (except for product 2i), the resulting indolines
were obtained exclusively as the cis-diastereomers.18 The reason
for the observed diastereoselectivitiy is not clear and remains to
be elucidated.
To test the viability of our proposed method, we examined
styrene 1a as our model substrate. We begun using our reported
conditions for the hydroamination of styrene9a (Table 1, entry 1).
Table 1. Reaction Optimization
It was found that electron-neutral and -rich substitutents on
the phenyl ring could be transformed, thus giving cis-indolines
2a−c,h in high yields and in good to excellent enantio-
selectivities. Electron-deficient substituents (2d−g) also gave
satisfactory results but with slightly lower levels of enantio-
selectivity. For these examples, the yield was higher if the reaction
was run in the absence of triphenylphosphine. The applicability
of this method to access indolines bearing a phenol (2c), aryl
bromide (2d), benzonitrile (2f), or methyl benzoate (2g) group
is important, as these functional groups can be used as synthetic
handles for further transformations. Moreover, the compatibility
of a vinyl group, which is a valuable feature that can be prob-
lematic in methods using asymmetric hydrogenation,4 furnishes
the resultant indoline 2i in good yield and enantioselectivity.
This method also tolerates a variety of hetereoarenes. As illus-
trated in Table 2, five-membered (2j−l), six-membered (2m),
and fused heterocycles (2n−q) could all be accommodated in
good yields with excellent levels of enantioselectivity.
We next turned our attention to substrates bearing
substituents on the aryl ring of styrene. We found that excellent
enantioselectivites were obtained for indolines 2r−u.19 However,
indoline 2r, with a methyl group at the 4-position displayed lower
reactivity (33% yield), with 30% of the reduced imine could be
also detected. We rationalize that the CuH insertion step is
slower due to steric encumbrance of the methyl group in the
4-position.
a
1
Yields were determined by H NMR analysis of the crude reaction
mixture using 1,1,2,2-tetrachloroethane as an internal standard.
b
Enantioselectivites were determined by chiral HPLC analysis.
ND = not determined. DEMS = (EtO)2MeSiH.
The reaction afforded the desired indoline 2a in 9% yield and 27%
ee, as a single cis-diastereomer. However, when a stoichiometric
amount of t-BuOH was added, the yield was improved to 67%
B
DOI: 10.1021/jacs.5b02316
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Journal of the American Chemical Society
Communication
a b
,
Table 2. Substrate Scope
a
b
c
Isolated yield on 1 mmol scale (average of two runs). Enantioselectivities were determined by chiral HPLC analysis. 3 equiv of DEMS was used.
d
e
f
Reaction performed in the absence of PPh3. Isolated as a 11:1 diastereoselective ratio. Cu(OAc)2 (8 mol%) and (S,S)-Ph-BPE (8.8 mol%) were
used.
We also briefly examined the extension of this method to
ACKNOWLEDGMENTS
■
β-substituted styrenes and found that indolines 2v,w could be
obtained in high yield and excellent enantioselectivities. In these
cases, 8 mol% catalyst loading was needed and best results were
observed in the absence of triphenylphosphine.
In conclusion, we have developed a mild, Cu-catalyzed strategy
for the highly diastereo- and enantioselective synthesis of a broad
range of cis-2,3-disubstituted indolines. Due to the generality
of the method and mild conditions employed, we believe this
method will see considerable use in both academic and industrial
settings.
Research reported in this publication was supported by the
National Institutes of Health under award no. GM46059. E.A.
thanks the Danish Council for Independent Research,
Technology and Production Sciences for a postdoctoral
fellowship. We thank Dr. Michael Pirnot and Dr. Yiming Wang
for their advice on the preparation of this manuscript.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
■
Corresponding Author
*sbuchwal@mit.edu
Notes
The authors declare no competing financial interest.
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Journal of the American Chemical Society
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D
DOI: 10.1021/jacs.5b02316
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