Cobalt-Catalyzed Asymmetric Cross-Coupling Reaction of Fluorinated Secondary Benzyl Bromides with Lithium Aryl Boronates/ZnBr2

Article abstract of DOI:10.1021/acs.orglett.0c01363

A cobalt-catalyzed asymmetric cross-coupling of α-bromo-α-fluorotoluene derivatives with a variety of aryl zincates derived from lithium aryl n-butyl pinacol boronates and ZnBr2 under mild reaction conditions was described. In addition to mild reaction conditions, another advantage includes the compatibility of various common functional groups such as fluoride, chloride, bromide, cyano, or ester groups. Furthermore, this protocol was successfully applied to the enantioselective synthesis of three fluorinated derivatives of biologically active compounds or drug molecules.

Full text of DOI:10.1021/acs.orglett.0c01363

pubs.acs.org/OrgLett
Letter
Cobalt-Catalyzed Asymmetric Cross-Coupling Reaction of
Fluorinated Secondary Benzyl Bromides with Lithium Aryl
Boronates/ZnBr2
Weichen Huang, Xiaolong Wan, and Qilong Shen*
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ABSTRACT: A cobalt-catalyzed asymmetric cross-coupling of α-bromo-α-fluorotoluene derivatives with a variety of aryl zincates
derived from lithium aryl n-butyl pinacol boronates and ZnBr2 under mild reaction conditions was described. In addition to mild
reaction conditions, another advantage includes the compatibility of various common functional groups such as fluoride, chloride,
bromide, cyano, or ester groups. Furthermore, this protocol was successfully applied to the enantioselective synthesis of three
fluorinated derivatives of biologically active compounds or drug molecules.
n the past two decades, transition-metal-catalyzed asym-
metric cross-coupling reaction between a racemic secon-
Food and Drug Administration (FDA) in 2019 were
fluorinated.10 Consequently, development of an efficient
method for the strategic incorporation of fluorine into target
molecules, particularly in a stereoselective fashion, is of utmost
importance.11 More specifically, α-fluorinated diarylme-
thane,12 a potential pharmacophore for new drug discovery
as it is considered a metabolically more stable bioisostere of
diphenylmethanol,13 which is also known as benzhydrol, is a
key structural motif in a number of biologically active natural
occurring compounds14 and has thus attracted increasing
attention. Interestingly, while a few methods for the
preparation of racemic α-fluorinated diarylmethanes have
been reported previously,15 methods for the construction of
stereodefined α-fluorinated diarylmethanes are unknown and
remain an ongoing urgent challenge. In this respect, we
envisaged that an enantioselective coupling of a racemic
fluorinated secondary benzylic halide with an organometallic
nucleophile represents a potentially broadly applicable
approach for the preparation of these fluorinated drug-like
molecules.16
I
dary alkyl electrophile and an organometallic nucleophile has
emerged as a powerful strategy for the construction of
stereodefined tertiary carbon centers.1 The majority of
reported approaches typically employ a combination of a
nickel(II) precursor and a nitrogen based bidentate or
tridentate ligand as the catalyst to enable the high
enantioselectivity,2 owing largely to Fu and co-workers’
seminal discovery in 2005.3 Unlike nickel, even though cobalt
represents one of the earth abundant, first row transition
metals that are able to catalyze the cross-coupling of alkyl
halides,4−6 few cobalt-catalyzed asymmetric C(sp3)−C(sp2)
bond-forming cross-coupling reactions have been reported
previously (Figure 1). To the best of our knowledge, only two
Figure 1. Cobalt-asymmetric cross-coupling of fluorinated secondary
alkyl halides.
Nevertheless, to develop a cobalt-catalyzed asymmetric
cross-coupling reaction of fluorinated secondary benzylic
halides, we faced three formidable challenges: (1) As we
mentioned earlier, only two examples of such asymmetric
examples of cobalt catalysis in such asymmetric cross-coupling
reactions have been reported recently, wherein the substrates
of these reactions were limited to racemic α-bromoesters.7
Fluorinated organic compounds have been found to be of
enormous value in many fields, especially in the pharmaceut-
ical industry,8 mainly due to fluorine’s unique and “magical”
effect on the compound’s physical, chemical, and biological
properties.9 In fact, 18 out of 42 small-molecule drugs in
2018, as well as 11 out of 23 in 2019, approved by the US
Received: April 20, 2020
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reactions have been reported previously,7 which indicates that
the factors in controlling the enantioselectivity were largely
unknown and the choice of the suitable spectator ligand
remains something of an art. (2) It was reported that cobalt-
catalyzed coupling reaction of alkyl halides occurred quickly in
the absence of any added ligand.4 Consequently, this
background reaction may significantly decrease the enantio-
selectivity of the reaction. (3) The difference in the atomic
radius of the fluorine and hydrogen atoms is small. Thus, it is
difficult to differentiate the facial selectivity of the α-
fluorinated alkyl radical. Herein, we report that we have
now overcome these challenges and developed the first cobalt-
catalyzed asymmetric cross-coupling of easily available α-
bromo-α-fluorotoluene derivatives with a variety of aryl
pinacol boronates in the presence of zinc bromide with
excellent enantioselectivities. Furthermore, this protocol was
successfully applied to the enantioselective synthesis of three
fluorinated derivatives of biologically active compounds or
drug molecules.
Scheme 1. Optimization of the Conditions for Cobalt-
Catalyzed Asymmetric Coupling of 4-
a
(Bromofluoromethyl)benzoate 1a with Phenyl Zincate
We initially chose the reaction of methyl 4-(bromofluor-
omethyl) benzoate 1a with an organometallic nucleophile in
the presence of a combination of 20 mol % of CoBr2·DME
and 25 mol % of commercial bisoxazoline ligand L1 as a
model reaction to optimize the reaction conditions. Not
surprisingly, reactions using PhMgBr as the nucleophile
occurred after 24 h at 5 °C occurred sluggishly to give the
desired product in 26% yield with low enantioselectivity
(62:38 e.r.), while reactions of 1a with PhZnBr or Ph2Zn did
not take place at all. In contrast, when an “ate’ type
nucleophile phenyl zincate, in situ generated from a
combination of 3.0 equiv of lithium phenyl n-butyl pinacol
boronate and 1.0 equiv of ZnBr2 was used,17 the reaction
occurred to full conversion to give the desired coupled
product in 60% with 81:19 e.r. (eq 1). As a control, we also
studied the same reaction in the absence of ZnBr2. However,
the desired coupled product was not observed under
otherwise identical conditions (Figure 2).18
a
Reaction conditions: compound 1a (0.1 mmol), lithium phenyl n-
butyl boronic pinacol ester (0.3 mmol), additive (0.1 mmol), cobalt
precursor (20 mol %), ligand (25 mol %) for 24 h under conditions
Figure 2. Initial screening of cobalt-catalyzed asymmetric coupling of
4-(bromofluoromethyl) benzoate 1a with various nucleophiles using
L1 as the ligand.
b
otherwise indicated in the scheme. Yields were determined by 19F
NMR spectroscopy with 1-fluoronaphthlene as an internal standard.
c
d
e
0.5 equiv of ZnBr2 was used. 1.5 equiv of ZnBr2 was used. CoBr2·
With these initial results in hand, we then systematically
screened the reaction parameters to improve the yield and
enantioselectivity of the reaction, as summarized in Scheme 1.
A quick survey of the reaction conditions disclosed that the
choice of a suitable chiral ligand was crucial in delivering the
reaction’s high yields and enantioselectivity. Switching the
isopropyl group in bisoxazoline ligand to a benzyl (L2),
phenyl (L3), or tert-butyl group (L4) led to a decrease in
enantioselectivity (Scheme 1, entries 2−4). The enantiose-
lectivity was slightly improved when 4,5-diphenyl-substituted
bisoxazoline ligand L5 was used as the ligand, and reaction
using indene-derived ligand L6 gave much lower enantiose-
lectivity, while reaction with tridentate ligand L7 was not
DME (10 mol %), L8 (12.5 mol %).
effective at all (Scheme 1, entries 5−7). Considering that
ligand L1 was structurally more modifiable than ligand L6, we
chose to synthesize various L1 derivatives to improve the
enantioselectivity of the reaction. Notably, when the isopropyl
group in the bisoxazoline ligand was switched to more
sterically hindered ligand L8, the enantioselectivity was
significantly improved to 95:5 (Scheme 1, entry 8). Additional
studies showed that the smaller bite methylene group of the
bisoxazoline ligand resulted in a remarkable decrease in
enantioselectivity (Scheme 1, entries 9−11).
B
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Scheme 2. Scope of Cobalt-Catalyzed Asymmetric Coupling of α-Bromo-α-fluorotoluene Derivatives 1a−m with Lithium Aryl
a b
,
n-Butyl Boronic Pinacol Ester
a
Reaction conditions: compound 1 (0.3 mmol), aryl n-butyl boronic pinacol boronate 2 (0.9 mmol), CoBr2·DME (20 mol %), ligand L8 (25 mol
b
%), and ZnBr2 (0.3 mmol) in DME at 5 °C for 24 h. Isolated yields and e.r. were determined by chiral HPLC analysis.
Under the optimized conditions (Scheme 1, entry 8), we
next examined the generality of the cobalt-catalyzed
asymmetric coupling with a variety of lithium aryl n-butyl
pinacol boronates and different α-bromo-α-fluorotoluene
derivatives. As shown in Scheme 2, in general, α-bromo-α-
fluorotoluene derivatives with electron-poor substituents such
as the ester, cyano, trifluoromethyl group or weakly electron-
donating substituents such as chloride or bromide reacted
smoothly to give the corresponding products 3a−3ai in good
yields and good to excellent enantioselectivities. For examples,
reactions of both methyl 4-(bromofluoromethyl)benzoate 1a
and 4-(bromofluoromethyl)benzonitrile 1d with lithium
phenyl n-butyl boronate 2a gave the corresponding products
3a and 3q in 75% and 81% yields with 95:5 e.r., respectively
(Scheme 2, 3a and 3q). Nevertheless, α-bromo-α-fluoroto-
luene derivatives with strong electron-donating substituents
such as 1-(bromofluoromethyl)-4-methoxybenzene were un-
stable and easily underwent decomposition to give aldehydes.
Likewise, lithium aryl n-butyl boronates with electron-poor or
weakly electron-rich aryl groups reacted to give the desired
products in good to excellent enantioselectivities. For example,
lithium aryl n-butyl boronates with meta-methoxy, meta-
fluoride, or para-fluoride reacted with compound 1a to afford
the desired products in 66%, 72%, and 65% yields with 94:6,
95:5, and 93:3 e.r., respectively (Scheme 2, 3d−f). Reactions
of lithium aryl n-butyl boronates with electron-rich aryl
groups, however, gave the desired products in low yields,
mainly due to the unstable nature of those electron-rich
arylated products. Since no strong base was used in the
reaction, common functional groups such as esters (3a−j),
cyanos (3k−u), or halogens (3y−3ai) were compatible.
Notably, the reaction could be easily scaled up. Reaction of
5.0 mmol of compound 1a with lithium phenyl n-butyl
boronate 2a occurred to give the desired product in 68% yield
with 94:6 e.r. with a side product dimethyl 4,4′-(1,2-
difluoroethane-1,2-diyl)dibenzoate 3a′ in 15% yield19
(Scheme 2, 3a and 3a′). The absolute configuration of
compound 3q was determined to be S by X-ray diffraction of
its single crystals, and the configurations of the remaining
compounds were assigned based on the same mechanistic
assumption (Scheme 2, 3q).
C
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Figure 3. Preparation of fluorinated mimics of drug-like compounds. (i) LiOH, MeOH/H2O, rt, 24 h; (ii) (COCl)2, DMF (0.1 equiv), CH2Cl2,
rt, 3 h.
In general, cobalt-catalyzed coupling reaction of alkyl
halides was proposed to form an alkyl radical via single-
electron-transfer (SET) of an alkyl halide to the cobalt
complex.4 To probe whether a free alkyl radical was generated
in the current protocol, we conducted two sets of experiments
(eq 1). In the first experiment, the reaction of compound 1a
reaction via a benzylic radical intermediate, even though
further detailed mechanistic studies are required to further
elucidate the mechanism of the reaction.
Finally, to demonstrate the applicability of the current
protocol, we applied this methodology to synthesize a few
fluorine-substituted mimics of potentially drug-like com-
pounds (Figure 2). Compound 5, which is a fluorinated
mimic of an inhibitor for the histone lysine methyltransferase
enhancer of zeste homologue 2 (EZH2),20 was prepared in
53% overall yield with 95:5 e.r. via a four-step transformation
from easily available methyl 4-(bromofluoromethyl)benzoate
1a (eq 2 in Figure 3). Likewise, a fluoride-substituted
compound 6, which is a mimic of histamine H3 receptor,21
was synthesized from the same starting material after four
steps in 64% overall yield and 95:5 e.r. (eq 3 in Figure 3).
Furthermore, we applied this method to synthesize compound
7, a key intermediate of a fluoride-substituted analog of Lilly’s
mGlu2 receptor potentiators, a compound for the acute
treatment of migraine headaches,22 in 84% yield with 92:8 e.r.
(eq 4 in Figure 3). These examples clearly showed the
potential of the current protocol in the preparation of enantio-
enriched fluorinated drug analogs.
In summary, we developed a cobalt-catalyzed asymmetric
cross-coupling reaction of α-bromo-α-fluorotoluene deriva-
tives with a variety of aryl zincates that were in situ generated
from lithium aryl n-butyl pinacol boronates with ZnBr2 under
mild conditions, which may serve as a versatile, efficient, and
convenient approach for the rapid access of optically pure α-
fluorinated diarylmethane derivatives. Furthermore, this
reaction, which exhibits some advantages over nickel catalysis
in some respects, greatly strengthens the arsenal of the cobalt-
catalyzed asymmetric cross-coupling reactions of secondary
alkyl halides. Studies to extend this protocol to cobalt-
catalyzed asymmetric cross-coupling reactions of other
secondary alkyl halides and nucleophiles are currently
underway in our laboratory.
with lithium phenyl n-butyl boronate 2a was conducted in the
presence of 1.0 equiv of radical inhibitor (2,2,6,6-tetramethyl-
piperidin-1-yl)oxyl (TEMPO) or butylated hydroxytoluene
(BHT) under otherwise identical conditions. It was found that
reaction in the presence of TEMPO was completely shut
down, while the yield of the reaction in the presence of BHT
was decreased significantly to 20%. In addition, a doublet peak
at −104.80 ppm in 19F NMR spectroscopy showed up for the
reaction with TEMPO, which was further characterized by a
high resolution mass spectrometer (ESI) to be TEMPO-R
(MS(ESI): 324.4) wherein the R group was the benzylic
radical generated from compound 1a. In a second experiment,
the same reaction was conducted in the presence of 1.0 equiv
of an SET inhibitor 1,4-dinitrobenzene. Again, the reaction
was fully shut down. Furthermore, in several cases, the dimers
of the benzylic radical that was supposed to be generated from
the benzylic bromides were observed. These results suggest
that the cobalt-catalyzed asymmetric cross-coupling of the
fluorinated secondary benzylic bromides likely involves a free
alkyl radical intermediate.
To assess whether the enantioselectivity of the reaction
resulted from kinetic resolution of the α-bromo-α-fluoroto-
luene derivatives, we monitored the enantio-excess of
compound 1a at a different period of the reaction by
quenching an aliquot of the reaction mixture with an acid and
subsequently analyzing the organic layer by HPLC. It was
found that compound 1a remained racemic at 2.0, 5.0, or 12
h, respectively. These results clearly ruled out the possibility of
a kinetic resolution process.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01363.
The above-mentioned initial mechanistic experiments
indicate that the current cobalt-catalyzed asymmetric cross-
coupling reaction is a catalyst-controlled enantioselective
1H, 19F, 13C NMR and HPLC spectra of compounds
3a−3ai, 5−7; X-ray structure of 3q (PDF)
D
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Accession Codes
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Recent Advances in Cobalt-Catalyzed Csp2 and Csp3 Cross-
Couplings. Synthesis 2017, 49, 3887−3894.
CCDC 1983499 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(5) Selective examples for cobalt-catalyzed coupling of alkyl halides:
(a) Wakabayashi, K.; Yorimitsu, H.; Oshima, K. Cobalt-Catalyzed
Tandem Radical Cyclization and Cross-Coupling Reaction: Its
Application to Benzyl-Substituted Heterocycles. J. Am. Chem. Soc.
2001, 123, 5374−5375. (b) Ohmiya, H.; Yorimitsu, H.; Oshima, K.
Cobalt(diamine)-Catalyzed Cross-Coupling Reaction of Alkyl Hal-
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Arylated Asymmetric Carbons and Application to Total Synthesis of
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and Secondary Alkyl Halides and Aliphatic Grignard Reagents. Adv.
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Chemoselective Cobalt-Catalyzed Cross-Coupling of Aryl Grignard
Reagents with Primary and Secondary Alkyl Bromides. Org. Lett.
2009, 11, 277−280. (e) Nicolas, L.; Angibaud, P.; Stansfield, I.;
Bonnet, P.; Meerpoel, L.; Reymond, S.; Cossy, J. Diastereoselective
Metal-Catalyzed Synthesis of C-Aryl and C-Vinyl Glycosides. Angew.
Chem., Int. Ed. 2012, 51, 11101−11104. (f) Iwasaki, T.; Takagawa,
H.; Singh, S. P.; Kuniyasu, H.; Kambe, N. Co-Catalyzed Cross-
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AUTHOR INFORMATION
Corresponding Author
■
Qilong Shen − Key Laboratory of Organofluorine Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai Institute
of Organic Chemistry, University of Chinese Academy of
Sciences, Chinese Academy of Sciences, Shanghai 200032,
China; orcid.org/0000-0001-5622-153X; Email: shenql@
mail.sioc.ac.cn
Authors
Weichen Huang − Key Laboratory of Organofluorine
Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Sciences, Shanghai
200032, China
Xiaolong Wan − Key Laboratory of Organofluorine Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai
Institute of Organic Chemistry, University of Chinese Academy
of Sciences, Chinese Academy of Sciences, Shanghai 200032,
China
́
16, 6500−6503. (h) Gonnard, L.; Guerinot, A.; Cossy, J. Cobalt-
Catalyzed Cross-Coupling of 3- and 4-Iodopiperidines with Grignard
Reagents. Chem. - Eur. J. 2015, 21, 12797−12803. (i) Hammann, J.
M.; Haas, D.; Knochel, P. Cobalt-Catalyzed Negishi Cross-Coupling
Reactions of (Hetero)Arylzinc Reagents with Primary and Secondary
Alkyl Bromides and Iodides. Angew. Chem., Int. Ed. 2015, 54, 4478−
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01363
4481. (j) Hammann, J. M.; Haas, D.; Tullmann, C.-P.; Karaghiosoff,
̈
K.; Knochel, P. Diastereoselective Cobalt-Mediated Cross-Couplings
of Cycloalkyl Iodides with Alkynyl or (Hetero)Aryl Grignard
Reagents. Org. Lett. 2016, 18, 4778−4781. (k) Andersen, C.;
Notes
The authors declare no competing financial interest.
́
Ferey, V.; Daumas, M.; Bernardelli, P.; Guerinot, A.; Cossy, J.
ACKNOWLEDGMENTS
Introduction of Cyclopropyl and Cyclobutyl Ring on Alkyl Iodides
through Cobalt-Catalyzed Cross-Coupling. Org. Lett. 2019, 21,
2285−2289.
■
The authors gratefully acknowledge the financial support from
National Natural Science Foundation of China (21625206,
21632009, 21421002) and the Strategic Priority Research
Program of the Chinese Academy of Sciences
(XDB20000000).
(6) Three examples of cobalt-catalyzed cross-couplings of
fluoroalkyl halides have been reported previously: (a) Araki, K.;
Inoue, M. Cobalt-Catalyzed Cross-Coupling Reaction of Arylzinc
Reagents with Ethyl Bromodifluoroacetate. Tetrahedron 2013, 69,
3913−3918. (b) Ohtsuka, Y.; Yamakawa, T. Cobalt/Diamine-
Catalyzed 1,1-Difluoroethylationand 2,2,2-Trifluoroethylation of
Aryl Grignard Reagents with Corresponding Fluoroalkyl Halides. J.
Fluorine Chem. 2016, 185, 96−102. (c) Li, C.; Cao, Y.-X.; Wang, R.;
Wang, Y.-N.; Lan, Q.; Wang, X.-S. Cobalt-Catalyzed Difluoroalky-
lation of Tertiary Aryl Ketones for Facile Synthesis of Quaternary
Alkyl Difluorides. Nat. Commun. 2018, 9, 4951.
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