Construction of Quaternary Stereocenters by Nickel-Catalyzed Heck Cyclization Reactions

Article abstract of DOI:10.1002/anie.201606955

A nickel-catalyzed Heck cyclization for the construction of quaternary stereocenters is reported. This transformation is demonstrated in the synthesis of 3,3-disubstituted oxindoles, which are prevalent motifs seen in numerous biologically active molecules. The method shows broad scope, proceeds in synthetically useful yields, and provides a rare means to construct stereochemically complex frameworks by nonprecious-metal catalysis.

Full text of DOI:10.1002/anie.201606955

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201606955
German Edition: DOI: 10.1002/ange.201606955
Synthetic Methods
Construction of Quaternary Stereocenters by Nickel-Catalyzed Heck
Cyclization Reactions
Jean-Nicolas Desrosiers,* Liana Hie, Soumik Biswas, Olga V. Zatolochnaya, Sonia Rodriguez,
Heewon Lee, Nelu Grinberg, Nizar Haddad, Nathan K. Yee, Neil K. Garg, and
Chris H. Senanayake
Abstract: A nickel-catalyzed Heck cyclization for the con-
struction of quaternary stereocenters is reported. This trans-
formation is demonstrated in the synthesis of 3,3-disubstituted
oxindoles, which are prevalent motifs seen in numerous
biologically active molecules. The method shows broad
scope, proceeds in synthetically useful yields, and provides
a rare means to construct stereochemically complex frame-
works by nonprecious-metal catalysis.
I
n recent years, there has been tremendous interest in the
development of cross-coupling reactions facilitated by non-
precious-metal catalysis.[1] Reactions catalyzed by nickel, in
particular, have been highly sought after. In comparison to
palladium, the metal most frequently used in cross-coupling
reactions, nickel is significantly more abundant, much less
expensive, and also possesses a lower CO2 footprint.[1]
Contributions in the field of nickel-catalyzed cross-coupling
include arylation and amination reactions (Scheme 1a), and
coupling reactions that allow for the introduction of sp3-
hybridized carbon atoms.[1a]
Scheme 1. a) Common nickel-catalyzed coupling reactions and b) present
study of nickel-catalyzed Heck cyclization for quaternary-stereocenter for-
mation.
As a part of our efforts to incorporate the use of non-
precious-metal catalysis in the preparation of active pharma-
ceutical ingredients, we became interested in the use of nickel
catalysis to forge new rings and install quaternary stereocen-
ters. We targeted the Heck cyclization for this task, given the
success of the palladium-catalyzed variant.[2,3] Examples of
nickel-catalyzed Heck cyclization reactions have been
reported;[4] however, no methodological studies focused on
building quaternary stereocenters have been described.[5] In
fact, we are only aware of a single example of a nickel-
catalyzed Heck cyclization to build a quaternary stereocenter,
which proceeded in modest yield.[6] Encouraged by the
growing demonstrated versatility of nickel,[1] as well as the
arylcyanation methodologies described by Watson and Jacob-
sen[7a] and Nakao et al.[7b] for the construction of quaternary
centers, we sought to develop the first nickel-catalyzed Heck
cyclization methodology to construct quaternary stereocen-
ters. We report the success of these efforts, as demonstrated in
the synthesis of medicinally privileged 3,3-disubstituted
oxindole frameworks[8] (Scheme 1b). The reaction possesses
wide scope in terms of suitable substrates, proceeds in
synthetically useful yields, and provides a rare means to
construct stereocomplex frameworks by nonprecious-metal
catalysis.
Although analogous to the palladium-catalyzed Heck
cyclization, the nickel-catalyzed variant bears less precedent
and is complicated by several challenges. First, catalyst
regeneration from the nickel(II) hydride species back to Ni0
is more arduous than in the corresponding palladium-
catalyzed system.[9] The nickel(II) hydride resting-state spe-
cies can induce undesired side reactions, such as over-
reduction or isomerization.[10] Second, Guo and co-workers
demonstrated by DFT calculations that the energy barrier of
the b-hydride elimination step for Ni systems is higher than
for Pd systems by 8.7 kcalmolÀ1.[9] The organonickel inter-
mediate could then potentially undergo other transforma-
tions, such as protonolysis or dimerization, instead of the
productive b-H elimination.[10] In addition to the aforemen-
tioned challenges, the nickel-catalyzed Heck reaction for
[*] Dr. J.-N. Desrosiers, Dr. S. Biswas, Dr. O. V. Zatolochnaya,
Dr. S. Rodriguez, Dr. H. Lee, Dr. N. Grinberg, Dr. N. Haddad,
Dr. N. K. Yee, Dr. C. H. Senanayake
Department of Chemical Development US
Boehringer-Ingelheim Pharmaceuticals, Inc.
900 Ridgebury Road, Ridgefield, CT 06877 (USA)
E-mail: nick.desrosiers@boehringer-ingelheim.com
L. Hie, Prof. N. K. Garg
Department of Chemistry and Biochemistry
University of California, Los Angeles (USA)
Homepage: http://garg.chem.ucla.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201606955.
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quaternary-center formation is presumably difficult, given
that only a single example of such a process has been
reported previously.[6]
We selected 1 as a substrate for initial testing of the
nickel-catalyzed intramolecular Heck reaction[11] for qua-
ternary-stereocenter construction and surveyed various
bases and reducing agents in the presence of phenanthro-
line (phen), [NiCl2(dme)], and DBU (Table 1). Preliminary
results indicated the base-sensitivity of the starting material
(Table 1, entries 1–3). In these examples, decomposition
was observed. The use of carbonate bases, such as K2CO3,
afforded the desired spiroxindole 2 and reduced product 3
(Table 1, entry 4). Also, slight variations in the nickel/
phenanthroline ratio gave nonreproducible results. To
facilitate catalyst activation/regeneration and to ensure
the reproducibility of reaction yields, we tested several
external reducing agents.[12] In the presence of these
reducing agents, varying amounts of the reduced product
3 were observed. Among the reductants explored (Table 1,
entry 5–11), manganese gave the highest yields of 2. The
combination of manganese and a lower temperature was
found to be optimal (Table 1, entries 12 and 13).[13]
We carried out an extensive survey of ligands to
improve the reaction profile and yield (Figure 1). Most
phenanthroline derivatives provided no higher yield than
52% (L1–L7). The use of the N-heterocyclic carbenes IPr
and SIPr gave poor yields. The desired cyclized product
could be obtained in higher yields when bis(phosphines)
were employed; the best result was observed with dppe
(59% yield of 2). The use of monophosphine ligands (PPh3,
PCy3, PtBu3, PnBu3, PEt3) demonstrated that electron-rich
nonhindered ligands, such as PnBu3, led to a striking
improvement in the yield of 2, which was formed in the
Figure 1. Survey of ligands. Yields were determined by 1H NMR spectros-
copy with dimethyl fumarate as an external standard. SIPr=1,3-bis(2,6-
diisopropylphenyl)imidazolidin-2-ylidene, IPr=1,3-bis(2,6-diisopropyl-
phenyl)-1,3-dihydro-2H-imidazol-2-ylidene, binap=(2,2’-bis(diphenylphos-
phanyl)-1,1’-binaphthyl, diop=2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis-
(diphenylphosphanyl)butane.
Table 1: Optimization of the reaction conditions.[a]
presence of PnBu3 in 90% yield according to a 1H NMR assay
and isolated in 85% yield. Furthermore, it was discovered
that the air-stable precatalyst [NiCl2(PnBu3)2] could be used
in place of [NiCl2(dme)] and the ligand to give 2 in
comparable yield.[14]
Having optimized the reaction conditions,[15] we explored
the effects of the electrophile with substrates derived from
indene carboxylic acid (substrates 1 and 4–6), tiglic acid
(substrates 7–10), and angelic acid (substrate 11; Scheme 2).
Both the aryl bromide 1 and chloride 4 are competent
electrophiles and afforded spirooxindole 2 in good yield.
However, the cyclization proceeded in lower yield or
provided no oxindole when iodide 5 or methoxide 6 was
used as the electrophile. With substrates 7–10, similar
behavior was observed, and the bromide 7 and chloride 8
afforded oxindole 12 in the highest yields. Lower conversion
was observed for the triflate derivative 9, and the pivalate
substrate 10 did not give oxindole 12. The effect of the alkene
configuration on the formation of the quaternary center was
then studied. E and Z alkenes 7 and 11 afforded oxindole 12
in similar yields of 64 and 66%, respectively.
Entry Base
Additive
T [8C] Yield 2 [%][b] Yield 3 [%][b]
1
2
DBU
Et3N
none
none
none
none
120
120
120
120
80
3
0
0
0
0
0
0–15
0
3
4
5
6
7
8
9
10
11
12
13
KOAc
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
10–57
0
À
Ph B(OH)2
À
Ph B(pin)
80
0
0
PhSiH3
Et3SiH
Cr
80
0
0
80
80
80
80
60
60
36
14
53
77
79
81
64
0
47
23
12
6
Zn
Mn
Mn
Na2CO3 Mn
[a] Reaction conditions: [NiCl2(dme)] (10 mol%), phen (10 mol%),
additive (3.0 equiv), base (3.0 equiv), DMF (0.3m). [b] The yield was
determined by HPLC peak integration. DBU=1,8-diazabicyclo-
[5.4.0]undec-7-ene, dme=dimethoxyethane, DMF=N,N-dimethyl-
formamide.
The compatibility of the transformation with various
functional groups (alcohols, nitriles, esters, ketones, and
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Scheme 2. Influence of the source of the electrophile and the alkene
geometry. Piv=pivaloyl.
amides) was first evaluated in a robustness screening.[16] The
observations were then confirmed by subjecting a wide array
of substrates to the optimal reaction conditions (Scheme 3).
The reaction tolerates a variety of aryl substituents, such as
ether (products 14 and 15), nitrile (products 18 and 19), ketal
(products 16 and 21), fluoro (product 17), keto (product 22),
ester (product 23), trifluoromethyl, (product 20) and methyl
groups (product 13). A MOM-protected aniline, which can be
readily deprotected under acidic conditions, gave rise to the
desired cyclized product 25. An attempt to generate 24
containing a nitro substituent was not successful.
The alkene substitution pattern of the substrate was then
examined. A high yield was observed for the cyclization of
a substrate containing a propene side chain, which gave
oxindole 26 with exclusive formation of the E alkene. A
cyclopentene-derived substrate was also evaluated; intrigu-
ingly, in this case the iodo-substituted arene was required for
the generation of the desired product 27 in 70% yield.[17] In
contrast, the corresponding cyclohexyl-based substrate was
converted into 28 in only 12% yield. Notably, there are only
few examples of nickel-catalyzed Heck cyclization reactions
in the presence of basic nitrogen atoms.[4i,11b,18]
An asymmetric version of the nickel-catalyzed Heck
cyclization was then examined. When substrate 1 was treated
with the ligand catASium KtB, oxindole 2 was obtained in
enantiomerically enriched form in 37% yield with e.r.
70:30.[19] This result suggests that ligated nickel is involved
in the enantiodetermining migratory-insertion step. Despite
the modest yield, this preliminary result is promising for
a future comprehensive study on the enantioselective nickel-
catalyzed Heck cyclization.
With the objective to provide additional insight into the
mechanism of this transformation, we conducted control
experiments.[19] The presence of a cyclopropyl substituent as
a radical clock on the alkene did not provide a significant
amount of the cyclized product with ring opening. A radical-
induced cyclization is then not likely to be the major
mechanistic pathway. In the absence of Na2CO3, the reaction
gave oxindole 2 and 3 in 53 and 18% yield, respectively. This
result demonstrates the importance of combining manganese
and a base to attain high yields. When the reaction was
initiated with a catalytic amount of [Ni(cod)(PnBu3)2] (cod =
Scheme 3. Scope of the nickel-catalyzed Heck cyclization. Reaction
conditions: substrate (100.0 mg), [NiCl2(PnBu3)2] (10 mol%), Mn
(3.0 equiv), Na2CO3 (3.0 equiv), DMF (0.3m), 608C, 12 h. [a] Product
obtained from the corresponding aryl iodide. [b] The yield was deter-
mined by using 1H NMR analysis with dimethyl fumarate as an
external standard.
1,5-cyclooctadiene), the presence of 3 equivalents of manga-
nese were still required for high yields to be attained.[20]
A
stoichiometric amount of [Ni(cod)(PnBu3)2] produced 2 with
73% yield in the absence of manganese.[21]
In conclusion, we have reported a methodological study
on the first nickel-catalyzed intramolecular Heck reaction for
the synthesis of quaternary stereocenters. The transformation
was studied in the context of the synthesis of 3,3-disubstituted
oxindoles and gives products in synthetically useful yields
while tolerating various functional groups. The use of an air-
stable nickel precatalyst provides additional cost-efficiency
and makes the methodology experimentally convenient. This
method demonstrates the potential of Ni catalysis for the
construction of stereochemically complex polycyclic frame-
works. Optimization of the enantioselective version of this
transformation by the use of chiral ligands will be the subject
of future investigations.
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Acknowledgements
[5] Few nickel-catalyzed methods to build quaternary stereocenters
We thank the Boehringer-Ingelheim-Pfizer-Glaxo-Smith-
Kline-Abbvie Non-Precious Metal Catalysis Consortium for
general discussions in this area. We are grateful to Bristol-
Myers Squibb (L.H.), the ACS Division of Organic Chemistry
(L.H.), the Foote and Majeti-Alapati families (L.H.), and
UCLA for fellowship support.
À
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Keywords: cyclization · Heck reaction · heterocycles ·
homogeneous catalysis · nickel
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[13] When the amount of manganese was decreased to 1.0 equiv-
alent, only a slight decrease in the yield (71%) was observed.
With 0.5 equivalents, the yield of the reaction decreased
significantly to 13%.
[14] This reaction could be set up outside of a glovebox and gave
similar yields to those observed when a glovebox was used.
[15] Lowering of the nickel-catalyst loading to 5 mol% led to
a decrease in the yield of 2 to 42%.
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[17] The corresponding bromide substrate provided oxindole 27 in
20% yield at 608C and 27% yield at 808C.
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[19] See the Supporting Information for experimental details.
[20] Aworking hypothesis to explain this result is that manganese not
only reduces [NiCl2(PnBu3)2], but is also involved in the catalytic
cycle.
[21] On the basis of this result, a Ni0/NiII catalytic cycle could
hypothetically be responsible for the oxindole products
obtained.
Received: July 18, 2016
Published online: && &&, &&&&
4
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Communications
Synthetic Methods
J.-N. Desrosiers,* L. Hie, S. Biswas,
O. V. Zatolochnaya, S. Rodriguez, H. Lee,
N. Grinberg, N. Haddad, N. K. Yee,
N. K. Garg,
C. H. Senanayake
&&&& — &&&&
Affordable complexity: A nickel-catalyzed
Heck cyclization for the construction of
quaternary stereocenters was developed
in the context of the synthesis of 3,3-
disubstituted oxindoles (see scheme),
which are prevalent motifs in biologically
active molecules. The efficient reaction
Construction of Quaternary Stereocenters
by Nickel-Catalyzed Heck Cyclization
Reactions
shows broad scope and provides a rare
means to construct stereochemically
complex frameworks by catalysis with
nonprecious metals.
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These are not the final page numbers!