Enantioselective Construction of Trifluoromethoxylated Stereogenic Centers by a Nickel-Catalyzed Asymmetric Suzuki–Miyaura Coupling of Secondary Benzyl Bromides

Article abstract of DOI:10.1002/anie.201706868

Trifluoromethoxy-substituted stereogenic centers can be constructed with high enantioselectivity by a nickel-catalyzed Suzuki–Miyaura coupling of readily available α-bromobenzyl trifluoromethyl ethers with a variety of aryl pinacol boronates. The coupling proceeds under mild reaction conditions, and a variety of common functional groups, such as fluoride, chloride, bromide, ester, enolizable ketone, nitro, cyano, amino, and vinyl moieties, were well tolerated. Furthermore, the reaction can be easily scaled up to gram quantities without a decrease in enantioselectivity.

Full text of DOI:10.1002/anie.201706868

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
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Accepted Article
Title: Enantioselective Construction of Trifluoromethoxylated
Stereogenic Centers by Nickel-Catalyzed Asymmetric Suzuki-
Miyaura Coupling of Secondary Benzyl Bromides
Authors: Weichen Huang, Xiaolong Wan, and Qilong Shen
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201706868
Angew. Chem. 10.1002/ange.201706868
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10.1002/anie.201706868
Angewandte Chemie International Edition
COMMUNICATION
Enantioselective
Construction
of
Trifluoromethoxylated
Stereogenic Centers by Nickel-Catalyzed Asymmetric Suzuki-
Miyaura Coupling of Secondary Benzyl Bromides
Weichen Huang,[a] Xiaolong Wan and Qilong Shen*[a]
Abstract:
A
method for the construction of trifluoromethoxy-
variety of nucleophiles,[9-12] we envisaged that if a nickel-
catalyzed asymmetric cross-coupling of racemic
containing stereogenic centers with high enantiometric excess via
nickel-catalyzed Suzuki-Miyaura coupling of easily available -
bromobenzyl trifluoromethylethers 1a-f with a variety of aryl pinacol
boronates was described. The reaction conditions were mild and a
variety of common functional groups such as fluoride, chloride,
bromide, ester, enolizable ketone, nitro, cyano, amino and vinyl
group were well tolerated. Furthermore, the reaction can be easily
scaled up to gram quantities without erosion of the enantioselectivity.
trifluoromethoxy-substituted secondary alkyl bromide such as
compound 1 can be developed (Eq. 1), a general method for the
formation of trifluoromethoxy-bearing stereogenic carbon
centers could be provided for the medicinal chemists in search
of high performance drug candidates. To achieve such a
transformation, we are facing several formidable challenges: 1)
Nickel-catalyzed Negishi asymmetric cross-couplings of benzylic
bromides have previously been reported.[13] Analogous studies
on asymmetric Suzuki-coupling reactions, however, has not be
described; 2) -Bromobenzyl methylethers were known to be
unstable and easily underwent decomposition to form
aldehydes;[14] while the electron-withdrawing trifluoromethyl
group may increase the stability of -bromobenzyl
trifluoromethylethers, the stability of these compounds and the
final products in the presence of Lewis acidic reagents or
catalyst are questionable; 3) It has been reported previously that
in the presence of a nickel catalyst, benzylic ethers underwent
carbon-oxygen activation and further transformations.[15] In
addition, since trifluoromethoxy group is considered as a
“pseudo halogen”, the selective activation of carbon-bromide
bond over carbon-oxygen bond is not an easy task. Herein, we
report that we have now developed a nickel catalyst that
overcomes these challenges to catalyze the coupling of
compounds 1a-f with a variety of readily available aryl pinacol
boronates with high enantiometric excess under mild conditions.
Nowadays, it is generally accepted that fluorine and fluoroalkyl
groups
such
as
trifluoromethyl,
difluoromethyl
or
trifluoromethylthio group have a “magic effect” in facilitating the
search of lead compounds for new drug discovery in the fields of
pharmaceutical and agrochemical industry.[1] Compared to these
well-recognized fluoroalkyl groups, the trifluoromethoxy group (-
OCF3), however, is perhaps the least well understood,[2] even
though it is commonly referred as “pseudo halogen”.[3]
Nevertheless, recently, this particular fluoroalkyl group has
gained considerable attention because of its beneficial
properties, which may improve the drug molecule’s
pharmacokinetics and efficacy, such as high lipophicicity
(Hansch’s hydrophobicity parameter π = 1.04) which is higher
than that of trifluoromethyl group (π = 0.88),[4] and strong
electron-withdrawing nature (inductive effect σI = +0.40).[5]
Consequently, various stragegies that can access to the
trifluoromethoxylated compounds have been actively pursued
and a few elegant methods for the formation of alkyl or aryl
trifluoromethylethers have been reported.[6,7]
Despite these tremendous achievements, methods that can
build the CF3O-containing stereogenic centers with high
enantioselectivity remain extremely rare. To the best of our
knowledge, up until now, only one method has been reported by
Tang and co-workers for the construction of the CF3O-containing
stereogenic centers, whereas moderate enantioselectivities
were observed.[8] Thus, development of new efficient protocol for
the construction of tertiary stereogenic carbon centers bearing a
trifluoromethoxy group with high enantioselectivity is urgently
needed.
We began our investigation by optimizing the conditions of
the nickel-catalyzed coupling reaction of compound 1a, which
was prepared by bromination of 4-methoxycarbonylbenzyl
trifluoromethylether[16] using NBS. During the preparation of
compound 1a, we found that an electron-withdrawing
substitution such as ester, ketone, cyano or nitro group
stabilizes -bromobenzyl trifluoromethylethers, while substrates
with an electron-donating group such as methoxy or
dimethylamino easily underwent decomposition to give the
corresponding aldehydes. After initial considerable investigation,
it was discovered that in the presence of 20 mol% NiBr2•DME
and 25 mol% pyridine-oxazoline ligand L1, reaction of 1a with
PhMgBr or Ph2Zn occurred smoothly in full conversion after 12 h
at 0 oC to give the coupled compound 2a with a good
enantioselectivity (91:9 e.r.). However, the yields for both
reactions were low (38% and 15%, respectively). It was soon
determined that the low yields were due to the side reaction of
compound 2a with aryl Grignard or Zinc reagent. These
observations confirmed our previous speculation about the
Inspired by the pioneer work from Fu’s group on nickel-
catalyzed asymmetric coupling of secondary alkyl halides with a
[a]
W. Huang, X. Wang and Prof. Dr. Q. Shen
Key Laboratory of Organofluorine Chemistry
Shanghai Institute of Organic Chemistry
University of Chinese Academy of Sciences
Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032
shenql@sioc.ac.cn
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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10.1002/anie.201706868
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Scheme 1. Optimization of the conditions for nickel-catalyzed asymmetric
Suzuki-coupling of -bromo-4-methoxycarbonylbenzyl trifluoromethylether 1a
with phenylboronic pinacol ester. [a] Reaction conditions: compound 1a (0.1
mmol), phenylboronic pinacol ester (0.15 mmol), nickel precursor (20 mol%),
ligand (25 mol%) under conditions indicated in the scheme; [b] Yields were
determined by 19F NMR spectroscopy with trifluorotoluene as an internal
standard; [c] 1.0 equivalent of 1a was used; [d] 2.0 equivalents of 1a was
used; [e] MeLi was used; [f] The formation of homocoupling side product from
compound 1a was observed in 8% yield.
stability of the product in the presence of Lewis acidic reagents.
To circumvent the use of Lewis acidic Grignard or Zinc reagents,
we studied the reaction of 1a with aryl boronic acid in the
presence of a base. To our delight, when PhB(OH)2 was
employed as the nucleophile and K2CO3 was used as the base,
the yield of the coupling reaction was improved to 81% when the
reaction was conducted at 60 oC.[17] However, the
enantioselectivity of the reaction decreased to 84:16 e.r.. To
improve the enantioselectivity, we studied the reaction at lower
temperature. Nevertheless, less than 10% conversion was
observed when the reaction was conducted at 30 oC for 8 h.
It was postulated that sluggish reaction with aryl boronic acid
at low temperature is because of the slow transmetallation step
in the catalytic cycle. To facilitate the transmetallation, we
studied the reaction of 1a with lithium organoborate which was
formed in situ by mixing phenylboronic acid pinacol ester with
nBuLi.[18] Indeed, it was found that the reaction of 1a with lithium
organoborate in THF occurred smoothly in full conversion after
5.0 h at 0 oC to give the corresponding coupled product 2a in 81%
yield with 93:7 e.r. (Scheme 1, entry 1). The same reactions in
Scheme 2. Scope of nickel-catalyzed asymmetric Suzuki-coupling of -bromo-
benzyl trifluoromethylether 1a-e with arylboronic pinacol ester. [a] Reaction
conditions: compound 1a (0.5 mmol), phenylboronic pinacol ester (0.75 mmol),
nBuLi (0.75 mmol, 0.3 mL, 2.5 M in hexane), NiBr2•DME ( 0.1 mmol), ligand
L3 (0.125 mmol) at 10 oC for 5 h ; Isolated yields; [b] Reactions conducted at 0
oC for 5 h; [c] Reactions conducted at 30 oC for 8 h; [d] Yields were determined
by 19F NMR spectroscopy with trifluorotoluene as an internal standard.
other etheric solvents such as DME, dioxane, diglyme or
triglyme were much less effective in terms of yields and
enantioselectivities (Scheme 1, entries 2-5). The nickel catalyst
precursor was important for the reaction. While the reaction
catalyzed by a combination of NiCl2•DME with ligand L1
occurred in lower yield with comparable enantioselectivity,
reaction using Ni(OAc)2 as the catalyst precursor was
completely ineffective at all (Scheme 1, entries 6-7). Further
optimization in term of the reaction temperature and
stoichiometry of the reagents disclosed that reactions conducted
o
at 0 C with 1.5 equivalents of lithium organoborate occurred in
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10.1002/anie.201706868
Angewandte Chemie International Edition
COMMUNICATION
high yields with good enantioselectivity (Scheme 1, entries 8-12).
On the other hand, replacement of nBuLi with MeLi led to
decrease both in yield and enantioselectivity (Scheme 1, entry
13). To further improve the enantioselectivity of the reaction, we
evaluated the effects of the other dinitrogen ligand L2-6.[19] The
enantioselectivity decreased when the ligand was switched from
(1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol-derived ligand L1 to
pyridine-oxazoline ligand L2 (Scheme 1, entry 14). Instead,
increasing the steric hindrance at 3-position of the pyridyl moiety
led to an increase in enantioselectivity (Scheme 1, entry 15).
However, replacement of the methyl group in L3 by an electron-
withdrawing trifluoromethyl group led to a slight decrease in
enantioselectivity (Scheme 1, entry 17). Finally, bisoxazoline
ligands L5-6 were completely ineffective at all (Scheme 1,
To demonstrate the applicability of nickel-catalyzed
asymmetric Suzuki-coupling reaction for the construction of the
CF3O-containing stereogenic centers, we applied this method to
synthesize a trifluoromethoxy-substituted mimic of an inhibitor
for the histone lysine methyltransferase enhancer of Zeste
Homolog 2 (EZH2).[20] As shown in Figure 1, compound 3 was
formed in 58% yield with 95:5 e.r. after recrystallization from
Et2O/CH2Cl2 via four step transformations from easily available
-bromo-4-tert-butoxybenzyl trifluoromethylether.
o
entries 18-19). Nevertheless, reaction conducted at 10 C gave
slightly higher yields with similar enantioselectivity (Scheme 1,
entry 16). Under these conditions, the main side product was the
homocoupling compound of 1a which was formed in 8% yield
(Scheme 1, entry 16).
Under the optimized conditions of entry 15 or 16 in Scheme
1, we next examined the generality of the nickel-catalyzed
asymmetric Suzuki-coupling of a variety of aryl boronic acid
pinacol esters, as summarized in Scheme 2. In general, aryl
boronic pinacol esters with both electron-rich and electron-poor
groups at mata- or para-substituted positions reacted smoothly
to give the corresponding compounds 2a-x in good yields and
high enantioselectivities. For example, reaction of -bromo-4-
Figure 1. Preparation of trifluoromethoxylated derivatives of drug candidates.
In summary, we developed a nickel-catalyzed Suzuki-
Miyaura coupling of easily available
-bromobenzyl
methoxycarbonylbenzyl trifluoromethylether
1a with 4-
trifluoromethylethers 1a-f with a variety of aryl pinacol boronates
with high enantiometric excess. The reactions were conducted
under mild conditions that a variety of common functional groups
such as fluoride, chloride, bromide, ester, enolizable ketone,
nitro, cyano, amino and vinyl group were well tolerated.
Furthermore, the reaction can be easily scaled up to gram
quantities without erosion of the enantioselectivity. Studies to
extend this method to the construction of CF3O-containing
quaternary stereogenic centers are currently undergoing in our
laboratory.
bromophenyl boronic pinacol ester gave compound 2b in 71%
yield with 94:6 e.r., while the same reaction with 3-methylphenyl
boronic pinacol ester afforded the corresponding product 2j in 91%
yield with 93:7 e.r. (Scheme 2, 2b and 2j). Nevertheless,
reactions of aryl boronic pinacol esters bearing a meta-fluoro,
chloro or bromo substituent occurred in lower yields but with
good enantioselectivities (Scheme 2, 2c, 2f, 2k-l). In these
cases, the homocoupling products were formed in roughly 20-30%
yields. On the other hand, -bromobenzyl trifluoromethylether
(1b-d) with electron-withdrawing substituted groups such as
ketone, cyano or nitro group reacted with various aryl boronic
acid pinacol esters to afford the coupled products 2p-x in high
yields and high enantioselectivities (Scheme 2, 2p-x). For
Acknowledgements
example,
trifluoromethylether
reactions
of
both
and
-bromo-4-nitrobenzyl
-bromo-4-cyanobenzyl
The authors gratefully acknowledge the financial support from
National Natural Science Foundation of China (21625206,
21632009, 21372247, 21572258, 21572259, 21421002) and the
Strategic Priority Research Program of the Chinese Academy of
Sciences (XDB20000000). We thank Mr. Xiaoge Li of Shanghai
Institute of Organic Chemistry for determining the absolute
configuration of compound 2s.
1c
trifluoromethylether 1d with phenyl boronic pinacol ester under
the optimized conditions to give the corresponding products in
56% and 71% yields, respectively, with excellent
enantioselectivities (95:5 e.r.) (Scheme 2, 2s and 2v). Because
of the mild conditions, a variety of common functional groups
such as fluoride (2f), chloride (2c, 2k and 2u), bromide (2b, 2l
and 2x), ester (2a-o), enolizable ketone (2p-r), nitro (2s-u),
cyano (2v-w), amino (2m) and vinyl group (2g) were compatible.
Finally, the reaction can be conducted at gram-scale quantities
with comparable yield and enantioselectivity (Eq. 2).
Keywords: Fluorine • trifluoromethoxy • nickel • asymmetric•
cross-coupling
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COMMUNICATION
Weichen Huang, Xiaolong Wan, Qilong
Shen*
Page No. – Page No.
Enantioselective Construction
Trifluoromethoxylated Stereogenic
Centers by Nickel-Catalyzed
Asymmetric Suzuki-Miyaura Coupling
of Secondary Benzyl Bromides
of
A general method for the construction of trifluoromethoxy-containing stereogenic
centers with high enantiometric excess via nickel-catalyzed Suzuki-Miyaura
coupling of easily available -bromobenzyl trifluoromethylethers 1a-f with a variety
of aryl pinacol boronates was described. The reaction conditions were mild and a
variety of common functional groups such as fluoride, chloride, bromide, ester,
enolizable ketone, nitro, cyano, amino and vinyl group were well tolerated.
This article is protected by copyright. All rights reserved.