Enantioselective Intramolecular Copper-Catalyzed Borylacylation

Article abstract of DOI:10.1002/anie.201808460

An enantioselective copper-catalyzed intramolecular borylacylation is reported. The reaction proceeds through an initial enantioselective borylcupration of the styrene, followed by a nucleophilic attack on the tethered carbamoyl chloride. The products, chiral borylated 3,3-disubstituted oxindoles, were generated in excellent yields and enantioselectivities. The versatile carbon–boron bond provides a platform for a wide array of diversification.

Full text of DOI:10.1002/anie.201808460

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Title: Enantioselective Intramolecular Copper-Catalyzed Borylacylation
Authors: Andrew Whyte, Katherine Isabelle Burton, Jingli Zhang, and
Mark Lautens
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201808460
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10.1002/anie.201808460
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Enantioselective Intramolecular Copper-Catalyzed Borylacylation
Andrew Whyte[a], Katherine I. Burton[a], Jingli Zhang[a,b], and Mark Lautens*[a]
Abstract: An enantioselective copper-catalyzed intramolecular
In 2017, Brown reported preliminary results on
enantioselective borylacylation (shown in Scheme 1)[9]. Recent
efforts to further this methodology have focused on utilizing
different acylating reagents[10]. However, little attention has been
paid to development of enantioselective variants and amides are
yet to be introduced through copper-catalyzed borylacylation. We
envisioned tethering a reactive olefin to a carbamoyl chloride for
use in enantioselective borylacylation and subsequent
transformation into chiral borylated 3,3-disubstituted oxindoles
(shown in Scheme 1). The carbamoyl chloride moiety is a readily
accessible and easy to handle acylating source, which forges new
amide bonds. Previous work in our group applied an approach
through a proposed chloropalladation of an alkyne, followed by
borylacylation is reported. The reaction proceeds through an initial
enantioselective borylcupration of the styrene, followed by
a
nucleophilic attack on the tethered carbamoyl chloride. The products,
chiral borylated 3,3-disubstituted oxindoles, were generated in
excellent yields and enantioselectivities. The versatile carbon-boron
bond provides a platform for a wide array of diversification.
Enantioselective addition of a nucleophilic boron species to
double bonds represents a powerful strategy in organic chemistry,
as the carbon-boron bond readily facilitates further
functionalization. In recent years, copper has emerged as a cost-
effective catalyst to introduce boron in an asymmetric fashion[1].
These reactions often achieve a difunctionalization of the alkene
or alkyne, initiated by a borylcupration and terminated using an
electrophilic reagent. Significant recent contributions by Ito[2],
Brown[3], Hoveyda[4], Yun[5], and others[6] have established the
versatility in this process, typically utilizing an intermolecular
electrophilic termination. Although intramolecular termination has
been explored[7] there have been few examples in the synthesis
of heterocycles[8].
termination with
chlorinated methylene oxindoles[11]
enantioselective borylacylation using anhydrides[12]
Oxindoles exhibit a wide range of biological activities and
have become sought-after targets in medicinal chemistry[13]
a
tethered carbamoyl chloride to obtain
.
Recently, Meng disclosed
.
.
Borylated oxindoles have previously been synthesized by van der
Eycken in an achiral fashion[14]. Song recently reported an effort
to generate the same products using a dual copper/palladium
system but the dihydroquinolinones were obtained as a result of
protodemetallation[15]. Thus far, enantioenriched 3,3-disubstituted
borylated oxindoles have not been reported and represent a
valuable intermediate for the synthesis of bioactive products.
Table 1. Optimization of reaction conditions
Scheme 1. Selected examples of previous reports of copper-catalyzed
borylation and our work on enantioselective borylacylation.
Entry
Variation of Standard Condition
none
Yield [%]a
erb
1
2
3
4
5
6
7
>99 (94)
59
98:2
[a]
[b]
A. Whyte, K. I. Burton, Dr. J. Zhang, Prof. Dr. Mark Lautens
Davenport Research Laboratories, Department of Chemistry
University of Toronto
80 St. George Street, Toronto, Ontario M5S 3H6 (Canada)
E-mail: mlautens@chem.utoronto.ca
L2 instead of L1
70.5:29.5
87:13
38.5:61.5
97:3
L3 instead of L1
98
L4 instead of L1
68
Dr. J. Zhang
School of Chemistry, Chemical Engineering and Life Sciences
Wuhan University of Technology
122 Luoshi Road, Wuhan 430074 (China)
L5 instead of L1
77
LiOtBu instead of NaOtBu
KOtBu instead of NaOtBu
76
96:4
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
82
98:2
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10.1002/anie.201808460
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dioxane as
a
solvent were critical to restoring good
8
THF instead of Et2O
MTBE instead of Et2O
dioxane instead of Et2O
>99
86
97.5:2.5
97.5:2.5
97:3
enantioselectivities. The electron-withdrawing trifluoromethyl
moiety (2p) showed slightly lower yield and enantioselectivity
compared to the electron rich methyl (2q) and methoxy (2r). The
absolute stereochemistry was determined for 2p via X-ray
crystallography, while the configuration of all other products is
assigned by analogy. When a chloride was positioned ortho to the
nitrogen (2s), nearly identical results were observed in
comparison to 2k. Finally, the phenyl backbone could be replaced
with a heteroaromatic pyridine backbone (2t) while maintaining
good yield and enantioselectivity.
9
10
87
[a] NMR yield determined by using 1,3,5-trimethoxybenzene as standard,
isolated yield in parenthesis [b] determined by chiral HPLC using IA column
eluting with 10% IPA in hexanes
We began our investigations with conditions based on Xiong’s
hydroboration of 1,1-disubstituted olefins[16], obtaining the product
(2a) in both excellent yield and enantioselectivity. Further
evaluation of other bisphosphine ligands showed no improvement
(Table 1, Entries 2-4), however, SEGPHOS delivered the product
(2a) in 97:3 er (Table 1, Entry 5). Further, sodium tert-butoxide
and diethyl ether proved superior to other bases (Table 1, Entries
6-7) and ethereal solvents (Table 1, Entries 8-10) respectively.
Scheme 2. Reaction scope with varied nitrogen substitution (0.2 mmol scale).
All reported yields are after isolation, er determined by chiral HPLC.
We explored the scope of the reaction by varying the
substituent on the nitrogen (Scheme 2). Both the methylene
cyclopropane (2b) and cyclopentyl (2c) were tolerated providing
excellent enantioselectivities. A variety of benzyl substitutions (2d,
2e) including halides (2f) and heteroaromatics (2g) were also
produced with excellent enantioselectivities.
Scheme 3. Reaction scope with varied aryl substitution (0.2 mmol scale). All
[a]
reported yields are after isolation, er determined by chiral HPLC.
dioxane with 8 mol% ligand. [b] Reaction run for 48 h
Run in
We also examined the effect of varying the pendant aromatic
ring (Scheme 4). As observed in 2o, we found that product 2u led
to a large decrease in enantioselectivity, delivering the product as
a near racemate. Switching to dioxane and increasing the ligand
concentration did not have the same effect as was found with 2o.
Similarly, product 2v was obtained with low er which only saw
slight improvement using dioxane as a solvent. Other para
substitutions such as fluoride (2w) and methyl (2x) gave excellent
yields and enantioselectivities. The dioxolane group (2y) and
meta substitution (2z and 2aa) were both well tolerated.
Interestingly, a 2-substituted thiophene (2ab) were successful.
Finally, we explored alkyl substitution in place of the aryl rings.
While methyl substitution (2ac) performed satisfactorily, we were
We continued to probe the reaction by varying the substitution
of the backbone aromatic ring (Scheme 3). Substituents ortho to
the styrene (2h, 2i, 2j) on the substrate led to a substantial
decrease in the enantioselectivities likely due to steric effects in
the substrate. However, a smaller moiety (2i), showed moderate
enantioselectivity (88.5:11.5 er). meta-Substituted chloride (2k),
bromide (2l), and dimethoxy (2m) containing products were
obtained in good yields and excellent enantioselectivities.
Halogens positioned para to the styrene (2n and 2o) showed
large decreases in enantioselectivity and in the case of bromide
substitution, longer reaction times were required. Further
optimizations revealed higher ligand loading, and the use of
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10.1002/anie.201808460
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disappointed that introduction of a methoxy group on the aryl ring
(2ad) showed lower enantioselectivity. A butyl group (2ae) on the
alkene required longer reaction times and gave decreased
enantioselectivity.
Scheme 5. Scaled up reaction, see SI for details. Product derivatizations were
run on 0.2 mmol scale. All reported yields are after isolation, er determined by
chiral HPLC.
In conclusion, we have developed an enantioselective
copper-catalyzed
intramolecular
borylacylation
process,
successful in accessing chiral 3,3-disubstituted oxindoles. We
exploited a tethered carbamoyl chloride as an electrophilic trap for
the benzylic copper intermediate, generated from borylcupration.
A wide variety of substitution patterns afforded the products in
generally excellent yields and enantioselectivities. We also
demonstrated the versatility afforded by the carbon-boron bond to
generate a library of compounds that could serve as building
blocks towards medicinally relevant molecules. This method
represents the effectiveness of copper-catalyzed borylation in the
synthesis of chiral, functionalized heterocycles.
Scheme 4. Reaction scope with alkene substitution (0.2 mmol scale). All
[a]
reported yields are after isolation, er determined by chiral HPLC.
dioxane with 8 mol% ligand. [b] Reaction run for 48 h
Run in
To demonstrate the versatility of this methodology we
performed the reaction on a larger scale, utilizing 4 mmol of
substrate 1a to produce product 2a. Further, we dropped the
catalyst and ligand loading, switched to a safer solvent (MTBE),
used less base (1.5 equivalents), and increased the concentration
of the reaction to 0.1 M. The desired product, 2a, was obtained in
90% yield and 97:3 er, showing a slight decrease in yield and
enantioselectivity compared to the standard reaction conditions
(Scheme 5).
Acknowledgements
We thank the University of Toronto, the Natural Science and
Engineering Research Council (NSERC), and Alphora Research
Inc. for financial support. A.W. thanks the Province of Ontario
(OGS) and CREATE ChemNET for funding. J.Z. would like to
thank the China Scholarship Council, Wuhan University of
Technology, and the Fundamental Research Funds for the
Central Universities (WUT2018IB021). We thank Alan Lough
(University of Toronto) for X-ray crystallograhpy of 2ae. We thank
the Dr. Darcy Burns and Dr. Jack Sheng (University of Toronto)
for their assistance in NMR experiments.
We further aimed to diversify the carbon-boron bond, in order
to demonstrate the versatility of the borylated 3,3-disubstituted
oxindole scaffold (Scheme 5). Suzuki coupling was successfully
performed under conditions established by van der Eycken,[53]
delivering the arylated product (3a) in 48% yield with no change
in er. We then attempted to oxidize the carbon-boron bond using
hydrogen peroxide and sodium hydroxide but were surprised to
obtain the dealkylated alcohol (3b) in racemic form. We
hypothesize the basic and oxidizing reaction conditions trigger a
retro-aldol of the desired alcohol followed by oxidation of the
enolate to generate product 3b. By using a weaker base, we
obtained the oxidized product (3c) maintaining chirality in
excellent yield. Finally, we performed Matteson homologation
followed by oxidation to obtain the extended alcohol (3d) in 65%
yield with no loss in stereochemistry.
Keywords: copper • borylacylation • oxindoles • cyclization •
asymmetric catalysis
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10.1002/anie.201808460
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Andrew Whyte, Katherine I. Burton,
Jingli Zhang, and Mark Lautens*
Page No. – Page No.
Enantioselective Intramolecular
Copper-Catalyzed Borylacylation
Text for Table of Contents
The synthesis of chiral 3,3-disubstituted borylated oxindoles is reported in good
yields and enantioselectivities. The reaction employed a chiral copper catalyst
to perform an enantioselective borylcupration followed by intramolecular
acylation with a tethered carbamoyl chloride. The chiral oxindole products are
readily diversifiable to a range of substituted oxindole products.
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