Copper-Catalyzed Regioselective Borylfluoromethylation of Alkenes

Article abstract of DOI:10.1021/acscatal.9b01530

A copper-catalyzed borylfluoromethylation of alkenes with fluoromethyl iodide and diboron reagents was disclosed. This protocol afforded the previously unknown and synthetically useful borylfluoromethylated alkanes in good yields and excellent regioselectivity. Its synthetic application was illustrated through the derivatization of organoboron products and preparation of monofluorinated ibuprofen.

Full text of DOI:10.1021/acscatal.9b01530

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Letter
Copper-Catalyzed Regioselective Borylfluoromethylation of Alkenes
Nuo-Yi Wu, Xiu-Hua Xu, and Feng-Ling Qing
ACS Catal., Just Accepted Manuscript • Publication Date (Web): 23 May 2019
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ACS Catalysis
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Copper-Catalyzed Regioselective Borylfluoromethylation of
Alkenes
Nuo-Yi Wu,† Xiu-Hua Xu,‡ and Feng-Ling Qing†,‡,*
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†Key Laboratory of Science and Technology of Eco-Textiles, Ministry of Education, College of Chemistry, Chemical
Engineering and Biotechnology, Donghua University, 2999 North Renmin Lu, Shanghai 201620, China
‡Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of
Organic Chemistry, University of Chinese Academy of Science, Chinese Academy of Science, 345 Lingling Lu,
Shanghai 200032, China
CuCl or CuBr (10 mol %)
CH2F
ligand (12 mol %)
LiOt-Bu or NaOt-Bu
+ CH2FI
+ B2R'2
BR'
R
R
DMSO or DMAc, rt
R = COR'',
aryl, alkyl
R' = mpd,
pin
36 examples
up to 86% yield
ABSTRACT: A copper-catalyzed borylfluoromethylation of alkenes with fluoromethyl iodide and diboron reagents was
disclosed. This protocol afforded the previously unknown and synthetically useful borylfluoromethylated alkanes in good
yields and excellent regioselectivity. Its synthetic application was illustrated through the derivatization of organoboron
products and preparation of monofluorinated ibuprofen.
KEYWORDS: fluoromethylation, borylation, alkene, copper, regioselective
The presence of fluorine atom(s) in a group could affect
its electronic and physicochemical properties.1 For
instance, fluoromethyl group (CH2F) normally acts as a
metabolically stable bioisostere for methyl group (CH3).
Furthermore, the CH2F group is also considered as a
only three examples of fluoromethylation of alkenes have
been reported (Scheme 1a).12 In all these cases, the
addition of CH2F radical to electron-deficient alkenes
gave the linear fluoromethylated products.
CH2OH group mimic.2 As
fluoromethylated compounds
applications in agrochemicals, pharmaceuticals, and
materials.3
Conventionally, the fluoromethylated
a
consequence, the
have widespread
previous work
R'
CH2FSO2Cl
[R']
CH2F
or
(a)
(b)
+
R
R
CH2FSO2Na
linear
R = EWG
this work
compounds are prepared via C–H fluorination of CH3-
containing compounds4 or fluorination of functionalized
substrates.5 However, these methods have some
limitations, such as narrow substrate scope, low
regioselectivity, or prior installation of a functional group.
Alternatively, the method of choice for the preparation of
CH2F
CuCl (cat.)
+
CH2FI + B2R'2
BR'
branched
R
R
R = COR'',
CuX
aryl, alkyl

CuX
XCu BR'
FH2C
I
BR'
R
fluoromethylated
compounds
involves
indirect
Scheme 1. Regioselective fluoromethylation of
Alkenes
fluoromethylation using fluoromethylating agents bearing
a suitable auxiliary, followed by the removal of the
auxiliary.6 Compared to the indirect methods, the direct
fluoromethylation through electrophilic,7 nucleophilic,8
and radial pathways9 are more attractive due to the atom
and step economy. Recently, the groups of Zhang,10a Hu,10b
Wang,10c and Baran10d have also reported transition metal-
catalyzed direct fluoromethylation of aryl boronic acids
(esters), halides, and zinc reagents.
Organoboron compounds are versatile intermediates
for
difunctionalization of unsaturated carbon−carbon bonds
has emerged as powerful approach to highly
functionalized alkylboranes.13 Among them, copper-
catalyzed
arylborylation,14 alkylborylation,15
organic
synthesis.
Recently,
borylative
a
cyanoborylation,16 and aminoborylation17 of alkenes has
been extensively investigated. Inspired by these works,14-17
we envisioned that the borylcupration of alkenes,
followed by electrophilic fluoromethylation, might serve
as a novel method for fluoromethylation of alkenes.
Alkenes are prevalent chemical feedstocks in organic
synthesis. Recently, the difunctionalization of alkenes for
the incorporation of both fluoroalkyl and another
functional groups has been extensively studied for the
synthesis of fluorine-containing compounds.11 However,
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Herein, we disclose a copper-catalyzed regioselective
Page 2 of 7
including DMAc, DMF, and DMSO could promote this
reaction, and DMSO was optimal to provide 2a in 65%
yield (entries 2-5). The effect of the ligand was then
investigated. When nitrogen-based ligand phen or N-
heterocyclic carbene (NHC) ligand IMes was employed,
lower yields were obtained (entries 6 and 7). Other
bidentate phosphine ligands such as dppbz and XantPhos
were less effective (entries 8 and 9). In the cases of
monodentate phosphine ligands, JohnPhos improved the
yield to 70% (entry 10), whereas XPhos, PPh3, and PCy3
resulted in slightly lower yields (entries 11-13). The choice
of an inorganic base had strong influence on the reaction.
LiOt-Bu could slightly improve the yield to 78% (entry 15).
In contrast, the yield was diminished sharply when KOt-
Bu or LiOMe was used (entries 14 and 16). To our delight,
after further investigation of the diboron reagents (entries
17 and 18) and copper salts (entries 19 and 20), the yield of
2a was finally improved up to 93% when B2mpd2 and
CuBr were used as the boron reagent and catalyst,
respectively.
1
2
3
4
5
6
7
8
borylfluoromethylation of alkenes with fluoromethyl
iodide and diboron reagents for the formation of the
branched fluoromethylated compounds (Scheme 1b).18
Table 1. Optimization of Reaction Conditionsa
Me
N
Me CH2F
N
CuCl (10 mol%)
ligand (12 mol%)
BR
B R
+ CH2FI +
Ph
Ph
N
2
2
base
solvent, rt, 4 h
O
1a
O
9
2a
10
11
12
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60
N
PPh2
PPh2
N
N
phen
IMes
Binap
PCy2
Pt-Bu2
PPh2
i-Pr
i-Pr
O
PPh2
dppbz
PPh2
PPh2
i-Pr
XantPhos
XPhos
JohnPhos
CH2F
CuBr (10 mol%)
JohnPhos (12 mol%)
R
O
B
O
O
B
O
O
O
O
O
O
O
R
Bmpd
B mpd
+ CH2FI +
2
2
B
B
B
B
LiOt-Bu
DMSO, rt, 4 h
O
O
O
O
1
2
B2pin2
B2neo2
B2mpd2
Me CH2F
N
Me CH2F
N Bmpd
yield
entry ligand
base
solvent B2R2
Bmpd
R
(%)b
trace
0
O
O
1
2
3
4
5
6
Binap
Binap
Binap
Binap
Binap
phen
NaOt-Bu THF B2pin2
NaOt-Bu toluene B2pin2
NaOt-Bu DMAc B2pin2
R
b
2j
(R = Me), 75% (45:55) ;
b
2a
2b
2c
2d
2e
2f
2g
2h
2i
(R = H), 84% (45:55) ;
(R = Me), 85% (47:53) ;
(R = t-Bu), 80% (47:53) ;
(R = OMe), 86% (49:51) ;
(R = Ph), 76% (49:51) ;
(R = F), 63% (45:55) ;
(R = Cl), 61% (45:55) ;
(R = Br), 63% (45:55) ;
b
2k
(R = OMe), 74% (45:55)
b
41
61
b
Me CH2F
N
NaOt-Bu DMF
B2pin2
b
Bmpd
b
NaOt-Bu DMSO B2pin2
NaOt-Bu DMSO B2pin2
NaOt-Bu DMSO B2pin2
NaOt-Bu DMSO B2pin2
65
48
52
63
35
70
61
60
57
7
Me
O
b
R
b
b
2l
2m
2n
(R = H), 73% (43:57) ;
(R = OMe), 71% (43:57) ;
(R = F), 75% (43:57)
7
IMes
b
b
8
dppbz
b
b
(R = CO2Me), 52% (43:57)
9
10
11
XantPhos NaOt-Bu DMSO B2pin2
JohnPhos NaOt-Bu DMSO B2pin2
XPhos
PPh3
CH2F
Bn CH2F
O
O
t-BuO
Bmpd
N
Bmpd
NaOt-Bu DMSO B2pin2
NaOt-Bu DMSO B2pin2
NaOt-Bu DMSO B2pin2
B
Me
O
O
12
13
14
15
16
17
18
19c
20d
b
b
Bmpd
2p
, 47% (42:58)
2o
, 65% (43:57)
PCy3
JohnPhos KOt-Bu
JohnPhos LiOt-Bu
JohnPhos LiOMe
JohnPhos LiOt-Bu
JohnPhos LiOt-Bu
JohnPhos LiOt-Bu
JohnPhos LiOt-Bu
DMSO B2pin2
DMSO B2pin2
DMSO B2pin2
DMSO B2neo2
Scheme 2. Borylfluoromethylation of Acrylamidesa
aReaction conditions: 1 (0.2 mmol), B2mpd2 (0.3 mmol),
ICH2F (0.3 mmol), CuBr (0.02 mmol), JohnPhos (0.024
mmol), LiOt-Bu (0.36 mmol), DMSO (2.0 mL), rt, under N2, 4
78
0
72
b
DMSO B2mpd2 88
DMSO B2mpd2 93
DMSO B2mpd2 76
h, isolated yields. The diastereomer ratios were determined
by 19F NMR of the crude products (the Bmpd contains a
stereocenter).
aReaction conditions: 1a (0.2 mmol), B2R2 (0.3 mmol),
ICH2F (0.3 mmol), CuCl (0.02 mmol), ligand (0.024 mmol),
base (0.36 mmol), solvent (2.0 mL), rt, under N2, 4 h. bYields
determined by 19F NMR using fluorobenzene as an internal
standard. cCuBr (0.02 mmol). dCuI (0.02 mmol).
Under the optimal conditions (Table 1, entry 19), the
substrate scope of this reaction was then evaluated. As
shown in Scheme 2, a variety of α-fluoromethyl-β-boryl
carbonyl compounds (2a-p) were furnished in moderate
to high yields as mixtures of diastereomers. An array of
functionality including ether, ester, amide, fluoro, chloro,
and bromo were well tolerated. In general, the electron-
donating substitutions (1b-e) led to higher yields than the
We
commenced
our
studies
with
the
borylfluoromethylation of N-methyl-N-phenylacrylamide
(1a) with CH2FI and B2pin2 (Table 1). Only trace of the
desired product 2a was formed in the presence of CuCl,
Binap, and NaOt-Bu in THF (entry 1). Screening of
different solvents demonstrated that polar solvents
electron-withdrawing
substitutions
(1f-i).
Steric
hindrance of the substrates (1j,k) resulted in slightly
lower yields. Acrylamides 1l-o with methyl at the α-
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ACS Catalysis
carbon position were also suitable for this transformation.
Furthermore, the reaction of α,β-unsaturated ester 1p
proceeded smoothly to give product 2p in 47% yield.
NBS delivered compound 7 in 60% yield. Furthermore,
the cross-coupling of 4a and PhBr furnished arylated
product 8 in high yield. Additionally, β-fluoromethyl
alkylalcohol 9 was obtained in 91% yield after oxidation
by H2O2. The formation of brominated and iodinated
products was readily achieved by the reaction of 4a and n-
BuLi as well as NBS or NIS. Finally, silver-catalyzed
1
2
3
This borylfluoromethylation reaction was then
extended to other alkenes. However, only moderate yield
was observed when subjecting styrene 3a to the optimized
reaction conditions for acrylamides. After extensive
screening of reaction conditions (For details, see SI),
borylfluoromethylation of styrene 3a with CH2FI occurred
efficiently using B2pin2 as the boron reagent, CuCl as the
catalyst, IMes as the ligand, NaOt-Bu as the base, and
DMAc as the solvent. Under these optimized reaction
conditions, styrenes 3a-m bearing different substituents
were conveniently converted to borylfluoromethylated
products 4a-m (Scheme 3). 2-Thienyl (3n) and 2-naphthyl
(3o) substituted alkenes showed lower reactivity than
styrenes. The internal alkenes (3p,q) also provided the
desired products in a regioselective manner, albeit in low
yields. Notably, this reaction was easily scaled up to 8.0
mmol, providing 1.34 g of 4a in 64% yield. However, the
borylfluoromethylation of the unactivated alkenes 3r and
3s resulted in low yields.
4
5
6
7
8
9
fluorination
with
Selectfluor
delivered
novel
bis(fluoromethylated) product 12.
CH2FO
CH2F
10
11
12
13
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Ph
Ph
6
, 85%
7
, 60%
n-BuLi
NBS
THF
CH2F
CH2F
MgBr
I2, THF
O
Ph
Ph
Bpin
Ph
Pd2(dba)3
RuPhos
PhBr
toluene/H2O
8
, 67%
5
, 81%
ClCH2Br
THF
NaOt-Bu
n-BuLi
CH2F
Bpin
Ph
selectfluor
AgNO3
H3PO4
DCM/H2O
NaOH (aq)
H2O2
4a
TFA
CH2F
, 91%
CH2F
THF
OH
Ph
n-BuLi
NBS
THF
Ph
CH2F
, 82%
n-BuLi
THF
9
12
NIS
CuCl (10 mol%)
CH2F
IMes (12 mol%)
+
+
B2pin2
Bpin
CH2FI
R
CH2F
CH2F
NaOt-Bu
DMAc, rt, 20 h
R
4
3
I
Br
Ph
Ph
CH2F
Bpin
R
CH2F
CH2F
11
, 85%
10
, 90%
R
Bpin
Bpin
Scheme 4. Transformation of Compound 4a
R
4a
b
4g
4h
4i
4j
4k
4l
(R = Me), 66%;
(R = Me), 61%;
(R = OMe), 47%;
(R = Cl), 65%;
(R = Br), 51%;
(R = CF3), 68%
(R = H), 81% (64% );
(R = Me), 61%;
(R = t-Bu), 56%;
(R = CH2OBn), 48%;
(R = F), 55%;
(R = CO2Me), 44%
CH2F
CH2F
4m
(R = Cl), 72%
CH2FI, B2pin2
CuCl, IMes
4b
4c
4d
4e
4f
Bpin
CH2F
Bpin
NaOt-Bu
DMAc, rt, 20 h
S
4t
, 54%
3t
CH2F
OH
CH2F
CO2H
4n
, 36%
Jones
CH2F
Me
NaBO3•4H2O
THF/H2O
reagent
CH2F
Bpin
acetone
Bpin
4q
Bpin
13
, 95%
14
, 68%
monofluorinated ibuprofen
, 44%
(>99:1)c
c
4p
, 43% (>99:1)
4o
, 51%
O
Scheme 5. Preparation of Monofluorinated Ibuprofen
CH2F
CH2F
Bpin
Bpin
N
The synthetic utility of this protocol was further
highlighted through the preparation of monofluorinated
analogue of ibuprofen, an anti-inflammatory drug.19 As
shown in Scheme 5, the reaction of styrene 3t, CH2FI, and
B2pin2 under the standard conditions provided product 4t
in 54% yield. Compound 4t was easily converted to the
monofluorinated ibuprofen 146c,20 through sequential
oxidation with NaBO3·4H2O and Jones reagent (CrO3-
H2SO4-H2O).21
d
d
4r
4s
, 35%
, 23%
Scheme 3. Borylfluoromethylation of Alkenesa
aReaction conditions: 3 (0.2 mmol), B2pin2 (0.3 mmol), ICH2F
(0.3 mmol), CuCl (0.02 mmol), IMes (0.024 mmol), NaOt-Bu
(0.36 mmol), DMAc (2.0 mL), under N2, 20 h, isolated yields.
c
bReaction was performed in 8.0 mmol. The diastereomer
ratios were determined by 19F NMR of the crude products.
dXantPhos (0.024 mmol) was employed as the ligand.
Based on the literature data, a plausible mechanism for
borylfluoromethylation is illustrated in Scheme 6. Initially,
treatment of CuCl with NaOt-Bu and coordination of the
ligand generates (L)Cu–Ot-Bu.22 Then, (L)Cu–Ot-Bu
reacts with B2R2 to afford borylcopper species (L)Cu–BR.23
Subsequently, the insertion of the C–C double bond of
alkene (1,3) into the Cu–B bond gives borylcuprated
intermediate A,24 which is captured by CH2FI to furnish
To illustrate the application of this protocol, the further
transformations of the borylfluoromethylated product 4a
were surveyed (Scheme 4). Matteson homologation of 4a
with ClCH2Br and n-BuLi gave product 5 in 81% yield.
Treatment of 4a with vinylmagnesium bromide and I2
afforded vinylated product 6 in 85% yield. The similar
reaction of 4a and furan in the presence of n-BuLi and
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Page 4 of 7
borylfluoromethylated product (2,4).15-17 At the same time,
(L)Cu–I is formed and converted to (L)Cu–Ot-Bu for the
next catalytic cycle. However, the reason why two
different reaction systems are needed for acrylamides and
styrenes remains unclear.
330. (c) Wang, J.; Sánchez-Roselló, M.; Aceña, J. L.; del Pozo, C.;
Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H.
Fluorine in Pharmaceutical Industry: Fluorine-Containing Drugs
Introduced to the Market in the Last Decade (2001−2011). Chem.
Rev. 2014, 114, 2432-2506. (d) Gillis, E. P.; Eastman, K. J.; Hill, M.
D.; Donnelly, D. J.; Meanwell, N. A. Applications of Fluorine in
Medicinal Chemistry. J. Med. Chem. 2015, 58, 8315−8359.
(2) (a) Müller, K.; Faeh, C.; Diederich, F. Fluorine in
Pharmaceuticals: Looking Beyond Intuition. Science 2007, 317,
1881−1886. (b) Hu, J.; Zhang, W.; Wang, F. Selective
Difluoromethylation and Monofluoromethylation Reactions.
Chem. Commun. 2009, 7465-7478.
1
2
3
4
5
6
7
8
CuCl
L
NaOt-Bu
B2R2
NaI
(L)Cu Ot-Bu
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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(3) (a) Kollonitsch, J.; Perkins, L. M.; Patchett, A. A.;
Doldouras, G. A.; Marburg, S.; Duggan, D. E.; Maycock, A. L.;
Aster, S. D. Selective Inhibitors of Biosynthesis of Aminergic
Neurotransmitters. Nature 1978, 274, 906-908. (b) Silverman, R.
B.; Nanavati, S. M. Selective Inhibition of γ-Aminobutyric Acid
Aminotransferase by (3R,4R),(3S,4S)- and (3R,4S),(3S,4R)-4-
Amino-5-fluoro-3-phenylpentanoic Acids. J. Med. Chem. 1990, 33,
931-936. (c) Grunewald, G. L.; Caldwell, T. M.; Li, Q.; Slavica, M.;
Criscione, K. R.; Borchardt, R. T.; Wang, W. Synthesis and
RBOt-Bu
NaOt-Bu
(L)Cu
I
(L)Cu BR
CH2F
Bpin
R
R
Cu(L)
2 4
,
Biochemical Evaluation
tetrahydroisoquinolines as
of 3-Fluoromethyl-1,2,3,4-
Selective Inhibitors of
1 3
,
Bpin
R
CH2FI
Phenylethanolamine N-Methyltransferase versus the α2-
Adrenoceptor. J. Med. Chem. 1999, 42, 3588-3601. (d) Siméon, F.
G.; Brown, A. K.; Zoghbi, S. S.; Patterson, V. M.; Innis, R. B.; Pike,
V. W. Synthesis and Simple 18F-Labeling of 3-Fluoro-5-(2-(2-
A
Scheme 6. Proposed Catalytic Cycle
In summary, we have developed a copper-catalyzed
regioselective borylfluoromethylation of acrylamides,
styrenes, and unactivated alkenes with fluoromethyl iodide
and diboron reagents. This reaction proceeded smoothly to
deliver β-fluoromethyl alkylboronates in good yields. The
resulting products are useful synthetic intermediates for
various potentially valuable fluoromethylated compounds.
Efforts to explore Cu-catalyzed difunctionalization
reactions for the preparation of other fluoroalkylated
compounds are ongoing in our laboratory.
(fluoromethyl)thiazol-4-yl)ethynyl)benzonitrile as
a
High
Affinity Radioligand for Imaging Monkey Brain Metabotropic
Glutamate Subtype-5 Receptors with Positron Emission
Tomography. J. Med. Chem. 2007, 50, 3256-3266.
(4) For selected examples, see: (a) Bloom, S.; Pitts, C. R.;
Miller, D. C.; Haselton, N.; Holl, M. G.; Urheim, E.; Lectka, T. A
Polycomponent Metal-Catalyzed Aliphatic, Allylic, and Benzylic
Fluorination. Angew. Chem., Int. Ed. 2012, 51, 10580-10583. (b) Xia,
J.-B.; Zhu, C.; Chen, C. Visible Light-Promoted Metal-Free C−H
Activation: Diarylketone-Catalyzed Selective Benzylic Mono-
and Difluorination. J. Am. Chem. Soc. 2013, 135, 17494-17500. (c)
Huang, X.; Liu, W.; Ren, H.; Neelamegam, R.; Hooker, J. M.;
Groves, J. T. Late Stage Benzylic C−H Fluorination with
[18F]Fluoride for PET Imaging. J. Am. Chem. Soc. 2014, 136, 6842-
6845. (d) Groendyke, B. J.; AbuSalim, D. I.; Cook, S. P. Iron-
Catalyzed, Fluoroamide-Directed C−H Fluorination. J. Am. Chem.
Soc. 2016, 138, 12771-12774.
(5) For selected examples, see: (a) Sladojevich, F.; Arlow, S. I.;
Tang, P.-P.; Ritter, T. Late-Stage Deoxyfluorination of Alcohols
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2015, 137, 5654-5657. (d) Nielsen, M. K.; Ugaz, C. R.; Li, W.; Doyle,
AUTHOR INFORMATION
Corresponding Author
flq@mail.sioc.ac.cn
Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: XXX
Detailed experimental procedures, characterization data, and
copies of 1H, 19F and 13C NMR spectra.
A. G. PyFluor:
A
Low-Cost, Stable, and Selective
ACKNOWLEDGMENT
Deoxyfluorination Reagent. J. Am. Chem. Soc. 2015, 137, 9571-
9574. (e) Liu, J.-B.; Xu, X.-H.; Chen, Z.-H.; Qing, F.-L. Direct
Dehydroxytrifluoromethylthiolation of Alcohols Using Silver(I)
Trifluoromethanethiolate and Tetra-n-butylammonium Iodide.
Angew. Chem., Int. Ed. 2015, 54, 897-900. (f) Li, L.; Ni, C.; Wang,
F.; Hu, J. Deoxyfluorination of Alcohols with 3,3-Difluoro-1,2-
diarylcyclopropenes. Nat. Commun. 2016, 7, 13320. (g) Xu, P.;
Wang, F.; Fan, G.; Xu, X.; Tang. P. Hypervalent Iodine(III)-
Mediated Oxidative Fluorination of Alkylsilanes by Fluoride Ions.
Angew. Chem., Int. Ed. 2017, 56, 1101-1104. (h) Ma, X.; Diane, M.;
Ralph, G.; Chen, C.; Biscoe, M. R. Stereospecific Electrophilic
Fluorination of Alkylcarbastannatrane Reagents. Angew. Chem.,
Int. Ed. 2017, 56, 12663-12667.
National Natural Science Foundation of China (21421002,
21332010), Strategic Priority Research Program of the Chinese
Academy of Sciences (XDB20000000), and Youth Innovation
Promotion Association CAS (No. 2016234) are greatly
acknowledged for funding this work.
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CuCl or CuBr (10 mol %)
ligand (12 mol %)
LiOt-Bu or NaOt-Bu
CH2F
+ CH2FI
+ B2R'2
BR'
R
R
DMSO or DMAc, rt
R = COR'',
aryl, alkyl
R' = mpd,
pin
36 examples
up to 86% yield
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