Iron-Catalyzed Difluoromethylation of Arylzincs with Difluoromethyl 2-Pyridyl Sulfone

Article abstract of DOI:10.1021/jacs.7b11976

We report the first iron-catalyzed difluoromethylation of arylzincs with difluoromethyl 2-pyridyl sulfone via selective C-S bond cleavage. This method employs the readily available, bench-stable fluoroalkyl sulfone reagent and inexpensive iron catalyst, allowing facile access to structurally diverse difluoromethylated arenes at low temperatures. The experiment employing a radical clock indicates the involvement of radical species in this iron-catalyzed difluoromethylation process.

Full text of DOI:10.1021/jacs.7b11976

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Communication
Iron-Catalyzed Difluoromethylation of
Arylzincs with Difluoromethyl 2-Pyridyl Sulfone
Wenjun Miao, Yanchuan Zhao, Chuanfa Ni, Bing Gao, Wei Zhang, and Jinbo Hu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b11976 • Publication Date (Web): 26 Dec 2017
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Iron-Catalyzed Difluoromethylation of Arylzincs with Difluoromethyl
2-Pyridyl Sulfone
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Wenjun Miao, Yanchuan Zhao, Chuanfa Ni, Bing Gao, Wei Zhang, and Jinbo Hu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Ling-Ling Road, Shanghai 200032, China
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Supporting Information Placeholder
metal (palladium, nickel, cobalt, or iron)-catalyzed CC bond for-
mation via CS bond cleavage.14 We have developed a bench-stable,
readily available and cost-effective reagent, difluoromethyl difluo-
romethyl 2-pyridyl sulfone (2-PySO2CF2H, 1), and established that
1 can accomplish gem-difluoroolefination15
Abstract: We report the first iron-catalyzed difluoromethylation of
arylzincs with difluoromethyl 2-pyridyl sulfone via selective CS
bond cleavage. This method employs the readily available, bench-
stable fluoroalkyl sulfone reagent and inexpensive iron catalyst,
allowing facile access to structurally diverse difluoromethylated
arenes at low temperatures. The experiment employing a radical
clock indicates the involvement of radical species in this iron-
catalyzed difluoromethylation process.
Scheme 1. Transition-Metal Catalyzed Reactions to Access
Difluoromethyl Arenes
There has been an increasing awareness of the use of fluorine at-
om(s) to alter the biological properties of organic molecules. The
fluorinated molecules often possess superior lipophilicity, bioavail-
ability, and metabolic stability (compared to the their nonfluorinated
counterparts) and therefore have great potentials in the areas of
pharmaceuticals, agrochemicals, and life sciences.1 As a result of the
extensive presence of hydrogen bonding in biological systems and
their indispensable role in achieving various physiological functions,
the use of the difluoromethyl group (CF2H) as a structural mimic to
the hydroxyl group in bioactive molecules attracts considerable
attentions.2, 3
However, methods for direct introduction of a difluoromethyl
group onto arenes are limited4 and often suffers from harsh reaction
conditions, and poor functional group compatibility.5 Several radical
strategies have been developed to incorporate CF2H group, such as
radical difluoromethylation of heteroarenes,6 difluorination of ben-
and formal nucleophilic halodifluoromethylation of carbonyl com-
pounds.16 Inspired by recent success by using difluoromethyl heter-
ocyclic sulfones as a precursor to generate difluoromethyl radical
through CS bond cleavage,17 we attempted the cross-coupling be-
tween 2-PySO2CF2H and arylmetal reagents catalyzed by the inex-
pensive and environmentally benign iron catalyst.18 Although iron-
catalyzed C(sp2)C(sp3) cross coupling using aryl Grignard reagents
or arylzinc reagents with alkyl electrophiles has been known,13,19 to
the best of our knowledge, the iron-catalyzed aromatic difluoro-
methylation has never been previously reported.
zylic CH bonds7 and decarboxylative fluorination of
-
fluoroarylacetic acids.8 Recently, transition-metal-mediated difluo-
romethylation reactions have been demonstrated as a viable ap-
proach for direct difluoromethylation.4,9,10 Most of the reported reac-
tion modes feature a cross-coupling between aryl halides with
difluoromethyl
trimethylsilane
(Me3SiCF2H),9a,9c,9d,9e
tribu-
tyl(difluoromethyl)stannane9b or various difluoromethyl metal rea-
gents (LnMCF2H, M = Zn and Ag) (Scheme 1a).10a,10d-f In contrast,
its complementary approach employing arylmetal reagents (ArM)
and XCF2H (X = heteroatom) has been scarcely explored,10g,10h
probably as a result of the low boiling point and limited accessibility
of XCF2H (X = I, Br, Cl).11 Furthermore, XCF2H (X = I, Br, Cl) are
known to be readily deprotonated and produce difluorocarbene spe-
cies, which add additional uncertainty to the desired reaction path-
way.10g,12 Herein, we report a new strategy for the aromatic difluo-
romethylation through the cross-coupling between difluoromethyl 2-
pyridyl sulfone (2-PySO2CF2H) and arylzinc reagents via CS bond
cleavage (Scheme 1b).
Our study began with the iron-catalyzed difluoromethylation us-
ing phenylmagnesium bromide as a model substrate, and the results
are shown in Table 1. It was quickly identified that the use of
Fe(acac)3 as the catalyst and N,N,N’,N’-tetramethylethane-1,2-
diamine (TMEDA) as the ligand allowed the difluoromethylation of
phenylmagnesium bromide (Table 1, entry 1). The control experi-
ment established that the iron catalyst is required to achieve the
desired difluoromethylarene 2a (entry 2). Higher yields were ob-
tained by slow addition of phenylmagenesium bromide to a solution
of 2-PySO2CF2H and Fe(acac)3 at 40 oC (entry 3). The effect of the
reaction temperature was also briefly investigated (entries 3-5).
Other iron salts and diamine-based ligands are less efficient for the
current transformation (entries 6-9). Although the use of anisole as
the solvent and the addition of substoichiometric amounts of N,N,
N’,N’-tetramethylbutane-1,4-diamine (TMBDA) improved the yield
to 44% (entry 10), attempts to further increase the yield were unsuc-
cessful (for details, see Supporting Information (SI)). As a result of
the highly reactive nature of Grignard reagents, a consumption of 2-
The cross-couplings via the activation of CS bond are challeng-
ing as a result of the inertness of the CS bond to engage in the oxi-
dation addition by transition metals.13 In addition, the regioselectivi-
tive cleavage of CS bonds of unsymmetrical sulfones is challeng-
ing. Recently, progresses have been made in the field of transition-
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PySO2CF2H was observed even in absence of iron catalyst with the
heterocyclic sulfone reagents that we examined provided inferior
1
2
3
4
attack of Grignard reagents to 2-PySO2CF2H, which explains the
low efficiency of the overall process. We then turned our attention
to the milder arylzinc reagents to diminish the undesired reaction
pathways.
yields under the same reaction conditions (see SI). Under our opti-
mized conditions, the desired difluormethylated product 2a was
obtained in 95% yield with 20 mol% Fe(acac)3 and 2.0 equiv
TMEDA.
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To demonstrate the substrate scope of this iron-catalyzed difluo-
romethyaltion protocol, a range of arylzincs were coupled with 2-
PySO2CF2H under the optimal conditions (Table 3). Arylzincs with
ortho-substituent gave inferior yields (2d and 2e),
Table 1. Optimization of the Reaction Conditionsa
9
Table 3. Scope of Iron-Catalyzed Cross-Coupling of Arylzinc
Reagents with 2-PySO2CF2Ha,b
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entry
1c
2c
3
4d
5e
6
catalyst
Fe(acac)3
-
ligand (equiv)
TMEDA (8.0)
TMEDA (8.0)
TMEDA (2.0)
TMEDA (2.0)
TMEDA (2.0)
TMEDA (2.0)
TMEDA (2.0)
TMEDA (2.0)
TMBDA (2.0)
TMBDA (0.4)
2a, yield (%)b
trace
0
Fe(acac)3
Fe(acac)3
Fe(acac)3
FeBr3
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16
trace
0
7
FeCl3
0
8
FeBr2
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44
9
10f
Fe(acac)3
Fe(acac)3
aReaction conditions: 1 (0.3 mmol), PhMgBr (0.45 mmol), catalyst
(20 mol%), CPME (cyclopentyl methyl ether) (2.0 mL), 40 oC to rt,
8 h. bYields were determined by 19F NMR with PhCF3 as an internal
standard. crt. d40 oC. e0 oC to rt. fAnisole(2.0 mL) was used as sol-
vent.
It turned out that the use of diphenyl zinc (Ph2Zn) in the current
Fe(acac)3-catalyzed difluoromethylation gave much better results
(Table 2). Varying the amounts of TMEDA proved to have a re-
markable influence on the reaction efficiency, as indicated in entries
1-6. TMEDA has proved to be an effective ligand in the iron-
catalyzed cross-coupling reactions, and the requirement of excess
amount of TMEDA (2.0 equiv) is likely owing to the coordination
of TMEDA to iron species and Zn reagents.19a,20 The reaction time
can be shortened to 2 h (entry 6), without substantially decreasing
product formation. It is noteworthy that other difluoromethyl
Table 2. Screening of the Reaction Conditionsa
entry
catalyst
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
ligand (equiv)
TMEDA (1.5)
TMEDA (0)
2a, yield (%)b
1
2
61
0
3
TMEDA (0.4)
TMEDA (1.0)
TMEDA (2.0)
TMEDA (2.0)
21
48
94
95
4
5
6c
aReaction condition: 1 (0.8 mmol), Ar2Zn (1.2 mmol, 1.5 equiv),
o
b
Fe(acac)3 (20 mol%), THF, 40 C to rt, 2 h, isolated yield. Yields
aReaction conditions: 1 (0.3 mmol), Ph2Zn (0.45 mmol), catalyst (20
mol%), THF (2.0 mL), 40 oC to rt, 8 h. bYields were determined by
19F NMR with PhCF3 as an internal standard. c2 h.
were determined by 19F NMR with PhCF3 as an internal standard.
d
cAr2Zn (1.6 mmol, 2.0 equiv). 8.0 mmol scale, isolated yields are
shown in parentheses.
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whereas reactions with meta- and para-substituted arylzincs gave
Scheme 3. The catalytic cycle commences with the formation of a
reduced iron species A, which is generated from the reduction of the
Fe(acac)3 precatalyst with an arylzinc reagent in the presence of
TMEDA. Electron transfer between the catalytically active iron
species A and 2-PySO2CF2H affords the radical anion B,
1
2
3
4
5
6
7
8
excellent yields (2b and 2c, 2f-2i). We found that electron-neutral
(2e-2h), -rich (2j-2n), and -poor (2n-2s) arylzinc reagents were all
viable in the current iron-catalyzed difluoromethylation. 1,3-
Propanediol acetal-bearing substrate was also successfully difluo-
romethylated to give product 2t in moderate yield. Furthermore,
aryzinc reagent bearing C=C double bond (2u) are also amena-
ble to this reaction. The cross-coupling reaction proceeds smoothly
with substrates bearing a range of heterocyclic motifs, such as pyri-
dine (2v-2x), morpholine (2x), benzofuran (2y), thiophene (2z),
carbazole (2aa), and indole (2ab). This method can also be used for
difluoromethylation of L-menthol derivative (2ac). It is notable that
this iron-catalyzed difluoromethylation reaction performs efficiently
in gram-scale experiments. We have conducted the iron-catalyzed
difluoromethylation on an 8.0-mmol scale without obvious decrease
of product yield, affording the corresponding difluoromethylated
product in good yields (2m, 2n, 2v). This additional advantage
makes the present method more attractive for large-scale preparation
of difluoromethylated arenes.
Scheme 3. Proposed Mechanism
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To gain more mechanistic insights into the current iron-catalyzed
difluoromethylation reaction, the radical inhibiting experiments
were performed. It was found that the reaction is completely sup-
pressed by the addition of 2,2,6,6-tetramethylpiperidin-1-oxyl
(TEMPO) and 1,4-benzoquinone (BQ), and the addition of 1,4-
dinitrobenzene, a single electron transfer (SET) inhibitor, led to the
substantial inhibition (Scheme 2a), which suggests that the involve-
ment of a SET process and radical intermediates is likely during the
reaction. The radical clock experiment employing 1b as a substrate
produced cyclized product 3b in 47% yield (Scheme 2b). The reac-
tion of Ph2Zn with 2-PySO2CF2D generated the deuterated (difluo-
romethyl)benzene 2a', without deuterium scrambling (Scheme 2c).
This result suggests that an alternative mechanism involves deproto-
nation and reductive desulfonylation is unlikely. Taken together,
these results suggest that carbon-centered radicals are generated by a
SET pathway.
the fragmentation of which produces a difluoromethyl radical that
undergoes recombination with iron complex C to produce the inter-
mediate D. The subsequent reductive elimination delivers the de-
sired product E and rendered the low-valent iron species F. The
catalytically active iron species A is then regenerated through the
transmetallation between F and Ar2Zn to close the catalytic cycle.
In summary, we have developed the first iron-catalyzed difluoro-
methylation of arylzincs with 2-PySO2CF2H. This new approach
employs bench-stable and readily available fluoroalkylation reagent
allows the difluoromethylation to proceed under mild reaction con-
ditions with the cost-effective iron catalyst. The current method is
complementary to the well-established difluoromethylation of aryl
halides and represents a valuable addition to the synthetic toolbox
for organofluorine chemistry. Our study not only provides a new
aromatic difluoromethylation protocol, it also gives new insights
into the new reactivity of fluoroalkyl sulfones under transition metal
catalysis. Further study in this direction is underway in our laborato-
ry.
Scheme 2. Mechanistic Investigations
ASSOCIATED CONTENT
SUPPORTING INFORMATION
The Supporting Information is available free of charge on the ACS
Publications website.
Experimental procedures and characterization for all new
compounds. (PDF)
AUTHOR INFORMATION
Corresponding Author
jinbohu@sioc.ac.cn
ACKNOWLEDGMENT
This work was supported by the National Key Research and
Development
Program
of
China
(2015CB931900,
Although the exact mechanism of the reaction remains elusive, on
the basis of previous investigation18,19b,21 and the above observations,
an outline of a possible mechanism for iron-catalyzed difluorometh-
ylation of arylzinc reagents with 2-PySO2CF2H is illustrated in
2016YFB0101200), the National Natural Science Foundation of
China (21632009, 21421002, 21372246, 21302206), Shanghai
Science and Technology program (15XD1504400 and
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16QA1404600), Youth Innovation Promotion Association CAS
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