Nickel-Catalyzed Intramolecular Arylcyanation for the Synthesis of 3,3-Disubstituted Oxindoles

Article abstract of DOI:10.1021/acs.orglett.8b01772

A nickel-catalyzed arylcyanation reaction for the synthesis of 3,3-disubstituted oxindoles has been developed. This method features a bench-stable precatalyst system and serves as an economical alternative to the existing palladium-catalyzed arylcyanations described to date. A wide scope of oxindole products were accessible in moderate to good yields, and the rich chemistry of the newly installed nitrile functional group was demonstrated in the synthesis of various oxindole derivatives.

Full text of DOI:10.1021/acs.orglett.8b01772

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Nickel-Catalyzed Intramolecular Arylcyanation for the Synthesis of
3,3-Disubstituted Oxindoles
Andy Yen and Mark Lautens*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada
S
* Supporting Information
ABSTRACT: A nickel-catalyzed arylcyanation reaction for the synthesis of 3,3-disubstituted oxindoles has been developed.
This method features a bench-stable precatalyst system and serves as an economical alternative to the existing palladium-
catalyzed arylcyanations described to date. A wide scope of oxindole products were accessible in moderate to good yields, and
the rich chemistry of the newly installed nitrile functional group was demonstrated in the synthesis of various oxindole
derivatives.
Scheme 1. Palladium-Catalyzed Methods for Accessing 3-
Cyanomethyl Oxindoles
ickel catalysis is playing an increasingly important role in
1
Nmodern organic synthesis. The high cost of noble metals
that dominate the landscape of catalytic C−C bond formation
has led synthetic chemists to seek out viable alternatives.
Accordingly, adopting the use of nonprecious and earth-
abundant base metals is attractive for reasons of cost and
sustainability. The widely practiced Heck reaction,2 which
traditionally employs palladium as the catalyst of choice, is one
such transformation that stands to benefit tremendously from a
switch to nickel.3
Figure 1. Domino Heck-cyanide capture cascade.
The domino Heck-anion capture cascade is a variation of the
classic Heck reaction wherein a persistent σ-alkylpalladium(II)
species is generated from an intramolecular Heck cyclization
before undergoing successive halide-for-nucleophile exchange
then reductive elimination to deliver the products of alkene
vicinal difunctionalization (Figure 1).4 This reaction is
exemplified by the palladium-catalyzed alkene arylcyanation
that was first disclosed by Grigg5 (Scheme 1a), and it remains a
topic of contemporary interest in our group.6 Inspired by the
recent reports of Garg,7 Kong,8 Zhou9 and others10 on nickel-
catalyzed Heck methods and in continuation of our work on this
reaction, we became interested in the pursuit of an analogous
nickel-catalyzed alkene arylcyanation.11
Received: June 6, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01772
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
We observed that a particular emphasis had been placed on
accessing the 3,3-disubstituted oxindole motif,12 which is a
privileged pharmacophore.12a,13 In fact, an examination of the
literature revealed a preponderance of palladium catalysis in the
synthesis of 3,3-disubstituted oxindoles via Heck cyclization of
acetanilides, and to a lesser extent, enolate α-arylation.14
Although benzylic all-carbon quaternary centers15 could be
forged in many instances, the α-substituent that serves to block
β-hydride elimination in the domino Heck reaction is often
relegated to a methyl group for ease of method development.
This lack of functional group content and subsequent anion
capture with a carbon nucleophile, that is itself typically devoid
of functionality, limits further elaboration at the 3-position. Due
to the rich chemistry of the nitrile functional group,16 we
envisioned that installation of a cyanomethyl group at the 3-
position via an alkene arylcyanation would address this
limitation.17
Table 1. Effect of Deviations from the Standard Conditions
b
entry
deviation from the standard conditions
yield (%) 2a
c
1
2
3
none (X = Br, 1a)
DPPF
DPPB
no reductant
85
68
39
0
4
5
6
7
8
9
10
Mn0 as reductant
1 h 30 min instead of 14 h
80 °C
1a-Cl (X = Cl) instead of 1a
1a-I (X = I) instead of 1a
1a-OTf (X = OTf) instead of 1a
0
61
81
13
64
11
In addition to Grigg’s seminal work, direct precedence in this
area comes from Zhu’s report on the palladium-catalyzed
synthesis of 3,3-disubstituted cyanomethyl oxindoles using
K4[Fe(CN6)] as the cyanide source (Scheme 1b).18 Modest
enantioselectivities for select examples were also disclosed.
Takemoto had also previously disclosed the enantioselective
synthesis of 3,3-disubstituted oxindoles via a palladium-
catalyzed intramolecular cyanoamidation of styrene derivatives
employing Feringa’s phosphoramidite19 as the chiral ligand
(Scheme 1c).20 The related nickel-catalyzed, Lewis acid-assisted
carbocyanations21 that involve C−CN bond activation from the
groups of Jacobsen22 and Hiyama23 also help to establish
feasibility for the desired carbonickelation and reductive
elimination steps. Recent contributions from Liu24 and Beller25
serve to complete the background literature for our proposed
transformation by demonstrating the use of the less toxic
a
b
Reactions were conducted on a 0.2 mmol scale. Determined by 1H
NMR analysis of the crude reaction mixture unless otherwise stated.
c
Isolated yield representing an average of 2 runs.
catalysis gave poor to moderate yields of the racemic product.30
This observation may stem in part from stringent structural and
electronic requirements for the challenging C−CN reductive
elimination, for which electron-rich chiral bisphosphines are
poorly suited.31
26
Zn(CN)2 as a cyanide source in a nickel-catalyzed process.
Herein, we report a practical alternative to the existing
palladium-based methods for the synthesis of 3,3-disubstituted
oxindoles via a nickel-catalyzed arylcyanation.
(S,S)-DIOP32 (Table 1) gave the best yields of the desired
oxindole 2a, albeit with minimal enantioselectivity. This is
presumably due to the nonrigid, fluxional nature of the
isopropylidene linker, which results in weak asymmetric
induction.33 Minor adjustments to reach the optimal conditions
included lowering the zinc dust loading to 11 mol % as well as
the Zn(CN)2 equivalents (to 0.67 equiv). Under these
conditions, oxindole 2a could now be synthesized in 85%
yield. This product could also be isolated in comparable yield at
a decreased catalyst and ligand loading when the reaction was
conducted on a 1.0 mmol (315 mg) scale. With the optimal
conditions and a scalable process in hand, we set out to examine
the scope of the nickel-catalyzed arylcyanation (Scheme 2).
Substitution on the aryl halide was shown to be generally well-
tolerated. Electron-rich aryl bromides such as 1b−d, 1g, and 1j
were excellent substrates for the arylcyanation reaction,
affording the corresponding oxindoles 2b−d, 2g, and 2j in
moderate to good yields. The methylated substrate 1i required a
higher loading of Zn(CN)2 (1.05 equiv) to achieve a moderate
yield of 2i.
An alternative to the air-sensitive Ni(cod)2 would be ideal, as
it would allow a user-friendly setup. Remarkable advances in
reductive nickel catalysis have demonstrated the practicality of a
Ni/Zn redox couple.27 Indeed, on heating model substrate 1a
with a combination of NiCl2(glyme) (10 mol %), DPPF (12 mol
%), activated zinc dust (20 mol %) and Zn(CN)2 (1.0 equiv),
the desired oxindole 2a was isolated in 68% yield along with
minor amounts of the 6-endo cyclization product (Table 1, entry
2).28 The zinc reductant was necessary, as no reaction occurred
in its absence (Table 1, entry 4). Interestingly, metallic
manganese powder was ineffective at serving as the reductant,
and this may point to an additional role for the generated zinc
salts that cannot be fulfilled by manganese salts (Table 1, entry
5).
Preliminary optimization experiments focused on 1a-Cl
(Table 1, entry 8) as the model substrate in the hopes of
using the less costly aryl chloride derivatives. However, a greater
tendency toward the 6-endo mode of cyclization as well as
inferior overall yields deterred further study of these
substrates.28 The aryl triflate derivative 1a-OTf (Table 1,
entry 10) was also tested to access a cationic Heck pathway,2a,29
although low yields were similarly observed.
Fluorinated and chlorinated aryl bromides such as 1e, 1f, 1h,
1k, and 1l were also tolerated. Drastic differences in reactivity
were observed when the para-substituents on the acrylamide
aryl moiety were electronically varied, as exemplified by 2m and
2n. An electron-donating p-OMe substituent is expected to
reverse the normal polarity of the acrylamide moiety in 1m,
thereby favoring the desired 5-exo mode of cyclization. In
contrast, substrate 1n, bearing the p-CF3 substituent, should see
We sought to make the nickel-catalyzed arylcyanation
enantioselective by screening various members of privileged
ligand families. Unfortunately, our screening revealed that
previously successful ligands utilized in asymmetric nickel
B
DOI: 10.1021/acs.orglett.8b01772
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
oxindole 2q being isolated in a comparably low yield, although a
disfavored conjugation-breaking migratory insertion with the
naphthyl group emerges as an equally likely contributor to this
outcome.
Scheme 2. Scope of the Nickel-Catalyzed Intramolecular
Arylcyanation
a,b
Figure 2. Observation of remote cyanation for substrate 1u.
Alkyl groups at the benzylic position were well-tolerated, as
was demonstrated by examples 2r through 2t. An interesting
observation arises when preparing 2u. The corresponding o-
bromoanilide 1u, derived from tiglic acid, bears a second methyl
group toward which β-hydride elimination can occur to initiate
chain-walking.34 The putative hydridonickel(II) cyanide com-
a,b
Scheme 3. Derivatization Studies of 2a
a
Reactions were conducted on a 0.2 mmol scale unless otherwise
b
c
stated. All yields shown are isolated yields. Reaction was conducted
on a 1.0 mmol scale. 1.05 equiv of Zn(CN)2 was used. Remaining
mass balance consists of unreacted substrate. Remaining mass
balance consists of unidentified side products. See Figure 2 for the
d
e
f
g
structure of 1u or refer to the Supporting Information.
the normal polarity of the alkene reinforced, disfavoring the 5-
exo migratory insertion.
Ortho substitution also proved to be limiting, as oxindoles 2o
and 2p were isolated in diminished yields. Notably, the o-OMe
group in 1o is expected to polarize the alkene in analogy to 1m;
however, this did not promote efficient product formation.
Combined with the observation that 1p bearing an o-Cl
substituent (which should also favor 5-exo migratory insertion)
led to low yields of 2p, this suggests that steric effects dominate
the insertion step. A similar argument may be invoked for
a
b
Reactions were conducted on a 0.2 mmol scale. All yields shown are
isolated yields. t-BuOAc = tert-butyl acetate; THF = tetrahydrofuran;
DMF = N,N-dimethylformamide; PhMe = toluene.
C
DOI: 10.1021/acs.orglett.8b01772
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
plex can undergo reinsertion followed by reductive elimination
to effect remote C−H cyanation at the γ position as was
previously observed by Hiyama (Figure 2).35
Examples 2v and 2w demonstrate that heteroarylcyanations
were also possible. To the best of our knowledge, these are the
first examples under nickel catalysis. However, the 2-thiophene
moiety in 1x provided low yields of 2x.
To demonstrate the value of the nitrile functional group, we
set out to diversify 2a. The anticipated versatility of the
cyanomethyl functional handle was fully displayed in a series of
successful derivatization experiments (Scheme 3).
Mark Lautens: 0000-0002-0179-2914
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Natural Science and Engineering Research
Council (NSERC), the University of Toronto (U of T), and
Alphora Research Inc. for financial support. A.Y. thanks the
Ontario Graduate Scholarship (OGS) for financial support. A.Y.
thanks H. Yoon (U of T) for helpful discussions in the initial
stages of this project. A.Y thanks Y. J. Jang (U of T) and E. Larin
(U of T) for providing substrates 1a−1x, H. Yoon for providing
1a-I, and A. H. Pham (U of T) for the synthesis of 1a-OTf. A.Y.
thanks Dr. I. Franzoni (U of T) and Y. J. Jang for proofreading
the manuscript. Dr. Alan Lough (U of T) is thanked for single-
crystal X-ray structural analysis of 2a, 3a, and 3e.42
An excess of the Reformatsky enolate36 derived from methyl
bromoacetate (5.0 equiv) was used in the Blaise reaction37 to
synthesize β-enamino ester 3a in moderate yield. Notably, the
possibility of further C−C bond construction starting from 3a is
appealing. A modified Ritter reaction38 led to the formation of
N-tert-butylated acetamide 3b in essentially quantitative yield.
Reductive cyclization by treating 2a with LiAlH418b,23b followed
by a brief period of reflux afforded tricyclic pyrroloindoline 3c,
presumably through the cyclization of a transient metal-
loimine.39 A [3 + 2] azide-nitrile cycloaddition furnished
tetrazole 3d in quantitative yield.40 An interesting fusion of
heterocycles was realized through a modification of the Witte-
Seeliger oxazoline synthesis,41 affording 3e in 60% yield. The
straightforward synthesis of 3a−3e from easily accessible 2a thus
demonstrates the ease with which diverse oxindole derivatives
can be accessed.
In conclusion, a nickel-catalyzed arylcyanation for the
synthesis of 3,3-disubstituted oxindoles has been developed.
Operational simplicity is achieved by employing a low-cost, air-
stable precatalyst and bench-stable reagents with accessible
starting materials. In addition, an assortment of novel hetero-
cycles can be readily synthesized from the cyanomethyl
functional handle, thereby demonstrating its exceptional
synthetic versatility. Further studies to identify an appropriate
chiral ligand to render this transformation asymmetric are
underway in our laboratories.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01772.
Optimization tables, experimental procedures, analytical
data, copies of the 1H, 13C, and 19F NMR spectra for all
new compounds (1o, 1p, 1q, 1s−1u, 1a-Cl, 2a−2x, and
3a−3e), and X-ray crystallographic data for 2a, 3a, and 3e
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Corresponding Author
*E-mail: mlautens@chem.utoronto.ca.
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E
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Org. Lett. XXXX, XXX, XXX−XXX