Palladium-Catalyzed Monofluoromethylation of Arylboronic Esters with Fluoromethyl Iodide

Article abstract of DOI:10.1021/acs.orglett.5b01361

The first palladium-catalyzed direct monofluoromethylation of arylboronic esters to produce monofluoromethyl arenes is reported. The reaction is typically carried out at room temperature within 4 h and has a good functional group tolerance. The monofluoromethylating agent, CH₂FI, was readily prepared via a halogen-exchange process.

Full text of DOI:10.1021/acs.orglett.5b01361

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Monofluoromethylation of Arylboronic Esters
with Fluoromethyl Iodide
Jingyu Hu, Bing Gao, Lingchun Li, Chuanfa Ni, and Jinbo Hu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Ling-Ling
Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: The first palladium-catalyzed direct monofluor-
omethylation of arylboronic esters to produce monofluor-
omethyl arenes is reported. The reaction is typically carried out
at room temperature within 4 h and has a good functional
group tolerance. The monofluoromethylating agent, CH2FI,
was readily prepared via a halogen-exchange process.
Scheme 1. Transition-Metal-Participated Cross-Coupling
ecent years have witnessed rapidly increasing demand for
Monofluoromethylation Reactions
R
organofluorine compounds. Properties of organic mole-
cules, such as lipophilicity, metabolic stability, and bioavail-
ability, can be significantly altered by the introduction of
fluorinated moieties.1 Therefore, organofluorine compounds
have become regular candidates for agrochemicals and
pharmaceuticals.2 In contrast to the prosperous progress of
the transition-metal-catalyzed tri-3 and difluoromethylation4 of
arenes during the past years, the incorporation of the
monofluoromethyl (CH2F) group into arenes has been studied
to a much lesser extent.5 Conventionally, monofluoromethyl
arenes (benzylic fluorides) are prepared via nucleophilic
fluorination of benzylic alcohols, their derivatives, and benzylic
halides.6 Although this well- and long-known fluorination
method is efficient and convenient for the preparation of many
benzylic fluorides, it is not suitable for the late-stage
monofluoromethylation of complex molecules due to the
limited availability of the corresponding benzylic precursors.7
Considering that many biologically active molecules, such as
afloqulone, fluticasone propionate, and the anesthetic sevofur-
ane, contain the CH2F group as the crucial motif,8 the
modification of complex molecules with the CH2F group is
potentially useful to improve their bioactivities. However,
following Olah’s report on monofluoromethylation of arenes
with fluoromethanol,9 it is only in 2009 that the Suzuki group
reported the second example of direct monofluoromethylation
of arenes.10 In Suzuki’s report, a large excess amount of
pinacolphenylboronate (40 equiv) was treated with [18F]CH2FI
as the limiting reactant using a stoichiometric amount of
palladium and the yield was modest (57%, Scheme 1).10 As an
alternative, indirect monofluoromethylation of arenes assisted
by removable activation groups have also appeared in recent
years.11,12In 2013, our group reported a copper-catalyzed
debenzoylative monofluoromethylation of aryl iodides using
fluoromethyl 2-pyridyl sulfone reagents.12a,b More recently,
Wang and co-workers reported the nickel-catalyzed mono-
fluoromethylation of arylboronic acids, using fluoromethylating
agents bearing either a phenylsulfonyl or ethoxycarbonyl
moiety.12c However, the reaction conditions of the cross-
coupling step were relatively harsh, and the demand for
Na(Hg) amalgam for reductive desulfonylation may limit the
compatibility of the substrates.12c Herein, we report a facile
synthesis of CH2FI and its use in the first example of palladium-
catalyzed direct monofluoromethylation of the arylboronic
esters.
We surmised that a palladium-catalyzed monofluoro-
methylation using fluoromethyl iodide (CH2FI) and boronate
esters could be realized under carefully optimized reaction
conditions. However, there are only a few methods to prepare
CH2FI, which use highly toxic reagents (such as HgF2), and the
purification is usually difficult.13 We commenced our study with
a halogen-exchange process (Finkelstein reaction)14 to prepare
Received: May 10, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01361
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
CH2FI. We chose acetone (200 mL) as the solvent and NaI as
the iodination reagent (390 mmol) to exchange the chlorine
atom of CH2FCl (195 mmol) with iodine. After purification, we
obtained CH2FI in 53% isolated yield (Scheme 2).
Table 1. Survey of Reaction Conditions
b
entry ligand
[Pd]
base
H2O (equiv) yield (%)
Scheme 2. Novel Method to Prepare CH2FI Reagent
c
1
2
3
4
5
6
7
8
9
L7
L7
L7
L7
L7
L7
L1
L2
L3
L4
L5
L6
L8
L7
L7
L7
L7
L7
L7
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(dppf)Cl2
Pd(OAc)2
Pd(PPh3)4
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
K2CO3
−
−
20
22
15
57
64
74
0
c
c
c
d
Cs2CO3
K2CO3
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
5.0
5.0
5.0
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Having CH2FI in hand, we chose air-stable biphenylboronic
ester (2a) as model substrate to survey reaction conditions. In
the presence of a catalytic amount of [Pd2(dba)3] (5 mol %) in
DMF at 50 °C, with K2CO3 as the base and tris(o-
tolyl)phosphine (L7, Scheme 3) as the ligand, the desired
e
e
e
0
0
e
10
11
12
13
14
15
16
17
18
19
0
58
66
73
68
46
39
83
87
85 (83)
Scheme 3. Various Ligands Used in Pd-Catalyzed Cross-
Coupling Reactions
e
f
f
f
g
h
a
Reaction conditions (unless otherwise noted): 2a (0.15 mmol, 1.0
equiv), CH2FI (1.1 equiv), [Pd] (5 mol %), ligand (20 mol %), base
(1.5 equiv), DMF/CH2Cl2 = 1:1 (1 mL in total), 50 °C, 3 h.
b
Determined by 19F NMR spectroscopy using benzotrifluoride as an
internal standard, and yield within parentheses is that of the isolated
c
d
e
product. DMF (1 mL). CH2Cl2 (1 mL). Ligand (10 mol %) was
f
g
used. 10 mol % [Pd] was used. 2a (0.15 mmol, 1.0 equiv), room
temperature, 4 h. 2a (0.50 mmol, 1.0 equiv), room temperature, 4 h.
h
monofluoromethylated product 3a was obtained in 20% yield
(Table 1, entry 1). Thereafter, a survey of bases (see Table S1
in the Supporting Information) was conducted, which indicated
that Cs2CO3 showed better activity (Table 1, entry 2). Similar
to many other Suzuki cross-coupling reactions, the addition of
water plays an important role in our reaction. With 1 equiv of
water added, the yield increased to 57% (Table 1, entry 4).
Finally, the optimal yield of 3a (74%) was obtained when the
reaction was carried out with CH2Cl2 and DMF as cosolvent
(Table 1, entry 6; for details of the survey of solvents, see
Tables S2 in the Supporting Information).
Using the optimized reaction conditions (Table 1, entry 6) as
standard, we next investigated the influence of the ligands and
palladium source. The nature of the phosphine ligand has a
strong influence on the reaction outcome (Table 1, entries 6−
13). Flexible bidentate phosphine ligands (L1 and L2) and rigid
bidenate phosphine ligand dppf (L3)15 were ineffective in the
current reaction (Table 1, entries 7−9). XantPhos (L4), a
bidentate phosphine ligand with a wide bite angle,16 was found
to be ineffective as well (Table 1, entry 10). The dialkylbiaryl
phosphine ligands developed by Buchwald and co-workers17
were also examined, but neither of them gave a high yield (see
Table S3 in the Supporting Information). Other meta or para
substituted triarylphosphine ligands gave only a trace amount of
the desired product (see Table S3 in the Supporting
Information), which indicates that the steric nature (rather
than the electronic effect) plays an important role in this
reaction. The tris(2-methoxyphenyl)phosphine (L5) and tri(1-
naphthyl)phosphine (L6) performed almost as effectively as
tri(o-tolyl)phosphine (L7) (Table 1, entries 6 and 11−12) .
The phosphine ligand PAd2(n-Bu)·HI (L8), which was used by
the Zhang group in their heteroaryldifluoromethylation
reaction recently,18 also worked well in our reaction (Table 1,
entry 13). Considering the cost efficiency, we finally chose
tri(o-tolyl)phosphine as the supporting ligand. A survey of
palladium sources showed that Pd2(dba)3 was optimal, followed
by Pd(dppf)Cl2, giving a 68% yield (Table 1, entry 14; for
details, see Table S4 in the Supporting Information). Increasing
the amount of CH2FI did not improve the product yield (see
Table S8 in the Supporting Information). Adjusting the amount
of added water to 5 equiv improved the yield to 83% (Table 1,
entry 17; for details, see Table S5 in the Supporting
Information). Finally, we decreased the reaction temperature
to room temperature and prolonged the reaction time to 4 h,
and the 4-fluoromethyl-1,1′-biphenyl (3a) was isolated in 83%
yield (Table 1, entry 19).
With the optimized reaction conditions (Table 1, entry 19)
as standard, we examined the scope of this palladium-catalyzed
monofluoromethylation of arylboronic pinacol esters (2). As
shown in Scheme 4, both electron-neutral and electron-rich aryl
boronates are compatible with this reaction, giving the
corresponding products in high yields. According to the
previous study,4h the benzylic fluorides of anisyl and phenolic
substrates are not stable because of their highly electron-rich
properties. During our study, we also found the electron-rich
products, such as 3h and 3l, decomposed during the
purification process. In contrast to electron-rich and electron-
neutral substrates, the reactions of electron-deficient aryl
boronate esters gave low yields, with the homocoupling
B
DOI: 10.1021/acs.orglett.5b01361
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 4. Monofluoromethylation of Arylboronate Esters
Scheme 5. Monofluoromethylation of Biologically Active
Estrone (4)
a
a
(a) Tf2O (1.1 equiv), DIPEA (1.1 equiv), 87%; (b) [Pd(dppf)Cl2] (4
mol %), (Bpin)2 (2.0 equiv), KOAc (3.0 equiv), 69%; (c) [Pd2(dba)3]
(5 mol %), P(o-toluene)3 (20 mol %), CH2FI (1.1 equiv), Cs2CO3
(1.5 equiv), 73%.
Under mild conditions, both electron-rich and electron-
deficient arylboronic esters could be monofluoromethylated
in good yields. It can be easily anticipated that aryl halides and
phenols are promising substrates for borylation and subsequent
monofluoromethylation reactions. We also demonstrated the
late-stage monofluoromethylation of a biologically active
molecule using our monofluoro-methylation protocol (Scheme
5). Considering the mild conditions of this method and the
high potential of monofluoromethyl-containing compounds as
biologically active agents, this protocol promises to find more
applications in the life-science-related fields. Further exploita-
tion of CH2FI-based chemistry is underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization data for prod-
ucts. The Supporting Information is available free of charge on
the ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01361.
AUTHOR INFORMATION
Corresponding Author
a
■
Reaction conditions (unless otherwise noted): 2 (0.5 mmol, 1.0
equiv), CH2FI (1.1 equiv), P(o-toluene)3 (20 mol %), Cs2CO3 (1.5
equiv), DMF/CH2Cl2 = 1:1 (3 mL in total), room temperature, 4 h.
* Emial: jinbohu@sioc.ac.cn.
Notes
b
c
For conditions A: Pd2(dba)3 (5 mol %). For conditions B:
d
Pd(dppf)Cl2 (10 mol %). Determined by 19F NMR spectroscopy
using benzotrifluoride as an internal standard. Yield of the isolated
e
The authors declare no competing financial interest.
product.
ACKNOWLEDGMENTS
■
This work was supported by the National Basic Research
Program of China (2015CB931900, 2012CB821600), the
National Natural Science Foundation of China (21372246,
21421002, 21402227), Shanghai City (13QH1402400 and
15XD1504400), and the Chinese Academy of Sciences.
product being formed as major byproducts when we used
Pd2(dba)3 as the catalyst. To our delight, changing the
palladium catalyst from Pd2(dba)3 (5 mol %) to Pd(dppf)Cl2
(10 mol %) significantly improved the product yields.
Therefore, various boronic esters containing an electron-
withdrawing group, such as sulfonyl (3n), cyano (3o), acetyl
(3t), ester (3u), nitro (3w), and amides (3x), afforded the
desired products in good yields (Scheme 4).
To demonstrate further the synthetic application of our
monofluoromethylation protocol, we applied this method to
the late-stage monofluoromethylation of biologically active
compounds. Estrone-derived arylboronate ester was prepared
in two steps from estrone by a palladium-catalyzed borylation
reaction of the corresponding triflate.19 We carried out the
monofluoromethylation under the optimized reaction con-
ditions, and 3-monofluoromethyl-3-dehydroxyestrone (5) was
obtained in 73% yield (Scheme 5).
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