Stereoselective synthesis of indolines via organocatalytic thioester enolate addition reactions

Article abstract of DOI:10.1021/ol501936n

A straightforward stereoselective synthesis route to indolin-3-yl acetates has been developed using organocatalytic addition reactions of monothiomalonates to ortho-bromo nitrostyrenes as the key step. The addition products of this highly stereoselective one-pot addition-deprotection-decarboxylation sequence were easily further converted to the target indolin-3-yl acetates, via an intramolecular Buchwald-Hartwig coupling reaction. The route provided indolin-3-yl acetates bearing tertiary and exocyclic quarternary stereogenic centers in excellent stereoselectivities and overall yields of 34-83%.

Full text of DOI:10.1021/ol501936n

Letter
pubs.acs.org/OrgLett
Stereoselective Synthesis of Indolines via Organocatalytic Thioester
Enolate Addition Reactions
Andrej Kolarovic, Alexander Kaslin, and Helma Wennemers*
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ETH Zurich, Laboratorium fur Organische Chemie, Vladimir-Prelog-Weg 3, CH-8093 Zurich, Switzerland
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̈
̈
S
* Supporting Information
ABSTRACT: A straightforward stereoselective synthesis
route to indolin-3-yl acetates has been developed using
organocatalytic addition reactions of monothiomalonates to
ortho-bromo nitrostyrenes as the key step. The addition
products of this highly stereoselective one-pot addition−
deprotection−decarboxylation sequence were easily further
converted to the target indolin-3-yl acetates, via an intra-
molecular Buchwald−Hartwig coupling reaction. The route provided indolin-3-yl acetates bearing tertiary and exocyclic
quarternary stereogenic centers in excellent stereoselectivities and overall yields of 34−83%.
o-bromo-nitrostyrenes followed by an intramolecular Buch-
ndolines are common structural motifs in natural products
Iand therapeutically active compounds and are also valuable wald−Hartwig cyclization as key steps. The route offers access
to indolin-3-yl derivatives in high yields and stereoselectivities.
In addition, we present the first synthesis of an indoline bearing
an exocyclic all-carbon quaternary stereogenic center.
as organocatalysts and ligands for stereoselective synthesis
(Figure 1).1−3
Recently, we introduced monothiomalonates (MTMs) as
robust thioester enolate equivalents that allow for stereo-
selective addition reactions with electrophiles under mild
organocatalytic conditions.12−14 We showed that MTMs react
in the presence of catalytic amounts of cinchona alkaloid-urea
derivatives with nitroolefins or imines to provide access to γ-
nitrothioesters and β-aminothioesters, respectively, in high
yields and stereoselectivities (Scheme 1a).12−14 The efficiency
of these asymmetric reactions intrigued us to expand their
synthetic utility for organic synthesis. We envisioned that
Scheme 1. (a) One-Pot Conjugate Addition−Deprotection−
Decarboxylation with MTMs and (b) Retrosynthetic
Analysis towards Indolines
Figure 1. Examples of indolines and closely related derivatives.
The development of straightforward enantioselective syn-
thetic routes toward substituted indoline derivatives is therefore
important. Known stereoselective syntheses of indolines with
substituents at C(3) rely on either enantioselective catalytic
hydrogenations or hydrosilylations of indoles,4,5 enantioselec-
tive catalytic or stoichiometric intramolecular cyclizations of
aniline derivatives with chiral ligands,6,7 ring closure of
enantioenriched precursors by radical or metal-catalyzed
cyclizations,8,9 or diastereoselective conjugate additions.10,11
Whereas many of these approaches provide the target indolines
in good yields and stereoselectivities, the substrate scope and
the accessible substitution patterns are typically limited.
Alternative stereoselective routes to, e.g., functionalized
indolin-3-yl derivatives are therefore important. Herein we
present a method that relies on an organocatalytic, highly
enantioselective addition reaction of thioester enolates to
Received: July 3, 2014
© XXXX American Chemical Society
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1,4-addition reactions of MTMs with nitroolefins bearing an o-
Br-aryl functionality would furnish γ-nitrothioesters that could
be easily converted via a Buchwald−Hartwig cyclization to
indolin-3-yl acetates (Scheme 1b).
Scheme 3. (a) Synthetic Route towards Esters of Indolin-3-yl
acetic acids; (b) Overall Yields of Indolines 6a−g
To probe the value of the envisioned route we started by
preparing seven differently functionalized o-bromo-β-nitro-
styrenes (1a−g)15,16 and reacted them with MTM 2a in the
presence of cinchona alkaloid-urea derivatives under the
previously established conditions (Scheme 2).
Scheme 2. 1,4-Addition Reactions between Nitrostyrenes
1a−g and MTM 2a, Catalyzed by eQDTU
was obtained in an overall yield of 83% starting from nitroolefin
1a.
Also the other γ-nitrothioesters 3b−g were converted via this
synthetic route into the indolin-3-yl acetates 6b−g. They were
obtained in excellent overall yields of 53−80% starting from
nitroolefins 1b−g, which illustrates the efficiency of the
syntheses (Scheme 3b).
We were pleased to find that o-bromo-β-nitrostyrenes 1a−g
reacted smoothly with MTM 2a in the presence of as little as
1 mol % of epiquinidine thiourea catalyst (eQDTU)17 at
−50 °C. Also removal of the p-methoxylbenzyl (PMB)
protecting group followed by base-induced decarboxylation
proceeded cleanly. Regardless of the substitution pattern and
the nature of the substituent at the nitrostyrene, the
γ-nitrothioesters 3a−g were obtained in very high yields and
enantioselectivities (Scheme 2). These results underline that
this organocatalytic transformation of thioester enolate
equivalents is very robust and tolerates a broad range of
substitution patterns on the nitroolefin.
Next, the route from the γ-nitrothioesters 3a−g to indolin-3-
yl acetates 6a−g was explored. Scheme 3a exemplifies the route
that proved to be best for the synthesis of indoline 6a.
Reduction of the nitro group under traditional conditions using
zinc in acetic acid, followed by intermolecular cyclization to
lactam 4a, proved to be problematic due to the formation of
high amounts of the corresponding hydroxamic acid (30−
35%).18 We solved this issue by developing an efficient catalytic
system based on substoichiometric amounts of TiCl319 that was
concurrently regenerated by a small excess of zinc (3.3 equiv
with respect to the electron demand). These conditions
enabled the in situ reduction of the undesired hydroxamic
acid intermediate and formation of the lactams in excellent
yields of e.g. 91% for 4a. Activation of the lactam group by Boc-
protection facilitated a subsequent base-mediated ring opening
to furnish γ-amino acid derivative 5a. Finally, cyclization by an
intramolecular Buchwald−Hartwig coupling20 provided indo-
lin-3-yl acetic acid derivative 6a in an excellent yield of 96% and
uncompromised stereochemical integrity. Overall, indoline 6a
Finally we investigated whether the described method can be
expanded to the synthesis of indoline derivatives bearing an
exocyclic all-carbon quaternary stereogenic center. The
construction of such acyclic quaternary stereocenters under
mild conditions is challenging.21 Whereas several syntheses of
indolines and indolinones with C(2) or C(3) as quaternary
stereocenters have been accomplished, not a single example for
an enantioselective synthesis with an exocyclic all-carbon
quaternary stereogenic center has been reported.22 We were
therefore pleased when o-bromo-β-nitrostyrene 1a reacted
readily with a slight excess (1.2 equiv) of the α-methyl
substituted MTM 2b in the presence of 3 mol % of
epicinchonine urea catalyst eCNU (Scheme 4). Addition
product 7a with adjacent quaternary stereocenters was obtained
with a diastereoselectivity of 11:1 in favor of the syn product
and an excellent enantioselectivity of ≥98%.
The crude addition product 7a was sufficiently pure to be
directly reduced to the amine. Under the previously established
conditions (Zn/AcOH/TiCl3) the amine formed and cyclized
immediately to lactam 8a that was isolated in a yield of 86%
over three steps. Reduction of the p-methoxybenzyl ester with
LiBH4 yielded alcohol 9a, which was isolated after column
chromatographic purification as a single diastereoisomer. This
lactam proved to be significantly less reactive compared to the
analogues bearing a tertiary stereocenter. For example,
activation of the lactam by Boc-protection followed by base
mediated lactam ring opening was dismissed after numerous
unsuccessful attempts.23 Hydrolysis of the lactam was finally
achieved with concentrated hydrochloric acid, and the resulting
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Scheme 4. Synthesis of Indolin-3-yl Acetate 11a Bearing a
Quarternary Stereocenter
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indolin-3-yl acetate 11a that was obtained in an excellent
overall yield of 34% for 8 steps starting from nitroolefin 1a.
In conclusion, we have developed an efficient synthetic route
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diastereoselectivity. Key steps are an organocatalytic addition
reaction of monothiomalonates to o-bromo-nitrostyrene and an
intramolecular Buchwald−Hartwig cyclization. Both steps are
robust and furnished the indolines on gram scales in overall
yields of 34−83% starting from the nitrostyrenes. The route
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carbon quaternary stereogenic centers. The results also
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, analytical data, and 1H and 13C NMR
spectra for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(17) For original reports on cinchona alkaloid urea derivatives, see:
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: Helma.Wennemers@org.chem.ethz.ch.
Notes
(18) For another example of undesired hydroxamic acid formation,
see: Kimmel, K. L.; Weaver, J. D.; Lee, M.; Ellman, J. A. J. Am. Chem.
Soc. 2012, 134, 11828−11828.
The authors declare no competing financial interest.
(19) E°(TiO2+/Ti3+) = +0.10 V, E°(Zn2+/Zn0) = −0.76 V. For work
describing the reduction of hydroxamic acids with stoichiometric
amounts of TiCl3 (2 equiv), see: Mattingly, P. G.; Miller, M. J. J. Org.
Chem. 1980, 45, 410−415.
ACKNOWLEDGMENTS
■
A.K. is grateful to SCIEX for the postdoctoral fellowship
12.158.
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(20) (a) Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35−37. For
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(22) The only previously described example relies on chiral
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(23) For details, see the Supporting Information.
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