Nickel-Catalyzed Reductive 2-Pyridination of Aryl Iodides with Difluoromethyl 2-Pyridyl Sulfone

Article abstract of DOI:10.1021/acs.orglett.0c03939

A novel nickel-catalyzed reductive cross-coupling between aryl iodides and difluoromethyl 2-pyridyl sulfone (2-PySO2CF2H) enables C(sp2)-C(sp2) bond formation through selective C(sp2)-S bond cleavage, which demonstrates the new reactivity of 2-PySO2CF2H reagent. This method employs readily available nickel catalyst and sulfones as cross-electrophile coupling partners, providing facile access to biaryls under mild reaction conditions without pregeneration of arylmetal reagents.

Full text of DOI:10.1021/acs.orglett.0c03939

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Letter
Nickel-Catalyzed Reductive 2‑Pyridination of Aryl Iodides with
Difluoromethyl 2‑Pyridyl Sulfone
Wenjun Miao, Chuanfa Ni, Pan Xiao, Rulong Jia, Wei Zhang, and Jinbo Hu*
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ABSTRACT: A novel nickel-catalyzed reductive cross-coupling between aryl iodides and difluoromethyl 2-pyridyl sulfone (2-
PySO2CF2H) enables C(sp2)−C(sp2) bond formation through selective C(sp2)−S bond cleavage, which demonstrates the new
reactivity of 2-PySO2CF2H reagent. This method employs readily available nickel catalyst and sulfones as cross-electrophile coupling
partners, providing facile access to biaryls under mild reaction conditions without pregeneration of arylmetal reagents.
ransition-metal-catalyzed C−C and C−heteroatom bond-
Scheme 1. Transition-Metal-Catalyzed Cross-Coupling of 2-
PySO2CF2H via Regioselective C−S Bond Cleavage
T
forming reactions are among the most widely used
transformations in modern synthetic organic chemistry.1
Transition-metal-catalyzed cross-coupling reactions of organic
electrophiles and organometallic reagents have emerged as
powerful synthetic tools, and a variety of such reactions have
been developed, including the Suzuki, Negishi, Hiyama,
Kumada, and Stille coupling reactions. Aside from traditional
cross-coupling between a nucleophile and an electrophile,
reductive cross-coupling of two different electrophiles
represents an alternative reaction type, which typically occurs
in the presence of a transition-metal catalyst (Ni, Co, Pd, or
Fe) and a suitable metallic reductant (Zn, Mn, or Mg).2 The
advantage of this strategy lies in avoiding the use of preformed
organometallic reagents, which are unstable and require special
care to exclude water and dioxygen, whereas most electrophilic
coupling partners can be easily stored and handled. In addition,
reductive cross-coupling reactions possess excellent functional
group compatibility because no stoichiometric amount of
strong base or nucleophile is needed. Despite the fact that
extensive studies have been done on the reductive cross-
coupling of aryl halides with alkyl electrophiles,3 the reductive
cross-coupling between aryl halides and (hetero)aryl electro-
philes remains underdeveloped.4
On the other hand, sulfones have served as the electrophilic
coupling partners in transition-metal-catalyzed cross-coupling
reactions. However, the majority of the research on such
transformations has focused on the nickel- or iron-catalyzed
cross-coupling of sulfones with Grignard reagents for C−C
bond formation.5,6 In 2018, we reported the first iron-catalyzed
difluoromethylation of arylzincs with difluoromethyl 2-pyridyl
sulfone (2-PySO2CF2H) via selective C(sp3)−S bond cleavage
(Scheme 1a).7,8 The Baran group developed a nickel-catalyzed
cross-coupling between aryl zinc reagents and alkyl heteroaryl
sulfones to form C(sp3)−C(sp2) bonds.9 To the best of our
knowledge, however, the transition-metal-catalyzed cross-
coupling of sulfones with aryl halides has been much less
investigated under reductive reaction conditions.10 Herein we
report our recent success in a nickel-catalyzed reductive cross-
coupling of aryl iodides with 2-PySO2CF2H to forge C(sp2)−
C(sp2) bonds via selective C(sp2)−S bond cleavage, which was
different from our previous work (Scheme 1b).
Our study commenced with the nickel-catalyzed reductive
cross-coupling of 4-iodotoluene (1a) with 2-PySO2CF2H (2a).
Initially, when we employed 10 mol % of NiCl2, 10 mol % of
4,4′-di-tert-butyl-2,2′-bipyridine (dtbbpy), 2.0 equiv of zinc
Received: November 28, 2020
Published: January 8, 2021
https://dx.doi.org/10.1021/acs.orglett.0c03939
© 2021 American Chemical Society
Org. Lett. 2021, 23, 711−715
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powder, DMF as the reaction solvent, and stirring for 8 h at 80
°C, a full consumption of 2a led to the formation of the desired
biaryl 3a (detected by GC-MS) in 18% NMR yield, with the
formation of the difluoromethanesulfinate as the only
detectable fluorinated side product (Table 1, entry 1). A
obtained when the combination of 10 mol % of NiCl2, 10 mol
% of dppp, and 2.0 equiv of zinc in DMF at 80 °C was used
(Table 1, entry 6). It is worth noting that no C(sp3)−C(sp2)
coupling product, namely, Ar−CF2H was detected, which is in
sharp contrast with our previous report on the iron-catalyzed
cross-coupling reaction between arylzincs and 2-Py-
SO2CF2H.7a
a
Table 1. Optimization of the Reaction Conditions
Having established the standard conditions for the reductive
cross-coupling reaction (Table 1, entry 6), we next assessed the
scope of the nickel-catalyzed reductive cross-coupling of aryl
iodides with 2-PySO2CF2H (Scheme 2). It turned out that the
b
entry
ligand
reductant (equiv)
T (°C)
3a, yield (%)
Scheme 2. Scope of Ni-Catalyzed Reductive Cross-Coupling
of Aryl Iodides with 2-PySO2CF2H
1
2
3
4
5
dtbbbpy
2,2′-bipy
1,10-Phen
PPh3
dppp
dppp
dppp
dppp
dppp
dppp
Zn (2.0)
Zn (2.0)
Zn (2.0)
Zn (2.0)
Zn (2.0)
Zn (2.0)
Zn (2.0)
Zn (2.0)
Zn (2.0)
Mn (2.0)
Fe (2.0)
Mg (2.0)
Cu (2.0)
Zn (2.0)
Zn (2.0)
80
80
80
80
80
80
rt
50
110
80
80
80
80
80
80
80
18
40
51
41
56 (51 )
87 (82 )
a b
,
c
d
c
6
d
7
0
0
d
8
d
9
72
50
trace
trace
6
trace
0
0
d
10
11
12
13
14
15
16
d
dppp
dppp
dppp
d
d
d
de
,
dppp
dppp
d
a
Reaction condition: 1a (0.5 mmol, 1.0 equiv), 2a (0.75 mmol, 1.5
equiv), NiCl2 (10 mol %), ligand (10 mol %), reductant (1.0 mmol,
b
2.0 equiv), solvent (3.0 mL), 80 °C, 8 h. Yields were determined by
c
1H NMR using 4-iodoanisole as the internal standard. Isolated yield.
d
e
16 h. NiCl2 (0 mol %).
further improvement in yield was observed when using other
bidentate nitrogen ligands (Table 1, entries 2 and 3). Then,
phosphorus ligands were evaluated to improve the reaction
efficiency (Table 1, entries 4−16). It was found that the
monodentate phosphine ligand triphenylphosphane (PPh3)
provided a 41% yield of the desired product 3a (Table 1, entry
4), whereas the bidentate phosphine ligand 1,3-bis-
(diphenylphosphino)propane (dppp) delivered 3a in 56%
NMR yield (51% isolated yield) (Table 1, entry 5). In these
two cases, there still remain substantial amounts of 1a and 2a.
We found that the reductive cross-coupling reaction with dppp
as the ligand proceeded smoothly to give biaryl 3a in 82%
isolated yield when the reaction time was extended to 16 h
(Table 1, entry 6). However, when the reaction proceeded at
room temperature or 50 °C for 16 h, no desired biaryl 3a was
detected (Table 1, entries 7 and 8). Increasing the temperature
to 110 °C led to a lower yield (Table 1, entry 9). Manganese
powder could also be used as reductant, giving a moderate
yield, as did zinc powder (Table 1, entry 10). Iron, magnesium
and copper metals, in contrast, were found to be ineffective
(Table 1, entries 11−13). Additionally, we noted that the
variation of the amounts of zinc powder proved to have an
influence on the reaction efficiency. (See the SI.) In the
absence of a ligand, only a trace amount of product 3a was
detected (entry 14). Control experiments showed that a nickel
catalyst, ligand, and reductant were essential for this trans-
formation (entries 14−16). After a brief screening of the
choices of nickel catalyst, ligand, reductant, solvent, and
temperature, the optimal isolated yield of 3a (82%) was
a
Reaction conditions: 1 (0.8 mmol, 1.0 equiv), 2a (1.2 mmol, 1.5
equiv), NiCl2 (10 mol %), dppp (10 mol %), Zn (1.6 mmol, 2.0
equiv), DMF (5.0 mL), 80 °C, 16 h. Isolated yield. Isolated yield of
the reaction performed on a 1.2 mmol scale is given in parentheses.
b
c
reaction was compatible not only with electron-poor (3f−r)
and electron-rich (3s and 3t) aryl iodides but also with aryl
iodides bearing a variety of functional groups (3u−x). As
shown in Scheme 2, in general, a variety of aryl iodides with
electron-withdrawing substituents (such as fluorine (3f),
chlorine (3g, 3h), cyano (3i and 3j), trifluoromethyl (3k
and 3l), ketone (3m−o), ester (3p), sulfone (3q), and
trifluoromethoxy (3r) groups) reacted with 2-PySO2CF2H
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smoothly to afford the desired biaryl products in good to
excellent yields (46−90%), whereas the substrates bearing
electron-donating groups (3s and 3t) gave inferior yields (68
and 50%, respectively). The cross-coupling reaction proceeded
smoothly with substrates bearing a range of heterocyclic
motifs, such as pyrrole (3u, 60%), carbazole (3v, 73%),
pyrimidine (3w, 39%), and pyrazole (3x, 55%). Vinyl iodides
(3w and 3x) were also able to couple to 2-PySO2CF2H.
However, substrates with an acidic proton (such as free alcohol
and acid) were not viable in the current nickel-catalyzed
reductive 2-pyridination (3ya, 3yb, and 3yc).
methyl 2-pyridyl sulfone (2d, 2-PySO2CH3) provided only a
trace amount of 3d under the standard reaction conditions.
To gain mechanistic insights into this nickel-catalyzed
reductive cross-coupling reaction with zinc, we conducted
several preliminary mechanistic experiments (Scheme 5). First,
Scheme 5. Mechanistic Investigation
In addition to 2-PySO2CF2H, 2-(methylsulfonyl)pyridine
(2-PySO2CH3) and its derivatives were also employed to
examine their reactivity in nickel-catalyzed reductive cross-
coupling with aryl iodides. As shown in Scheme 3, these
a b
,
Scheme 3. Substrate Scope of 2-PySO2CH3 Derivatives
we performed nickel-catalyzed cross-coupling of 2-Py-
SO2CF2H with preformed phenylzinc iodide, which gave the
product 3c in 70% yield, suggesting that an arylzinc reagent
might be engaged in this nickel-catalyzed cross-electrophile
coupling process. Furthermore, difluoromethanesulfinate salt
was observed as a byproduct via 19F NMR in 82% yield under
the standard reaction conditions, which suggests that the
generation of a difluoromethyl radical from 2-PySO2CF2H (as
a major pathway) is unlikely during the reaction. Furthermore,
the detection of 1,1′-biphenyl in this reaction (via GC-MS)
also supports the involvement of arylzinc. Although the exact
mechanism remains unclear, on the basis of these experiments
and the previous investigation, we propose a plausible
mechanism for the present nickel-catalyzed cross-electrophile
coupling reaction (Scheme 6). The catalytic cycle may be
a
Reaction conditions: 1 (0.8 mmol, 1.0 equiv), 2 (1.2 mmol, 1.5
equiv), NiCl2 (10 mol %), dppp (10 mol %), Zn (1.6 mmol, 2.0
equiv), DMF (5.0 mL), 80 °C, 16 h. Isolated yield.
b
electron-withdrawing group-substituted methyl sulfones under-
went reductive cross-coupling reactions, giving the correspond-
ing products 3aa−ae in moderate yields. Moreover, we also
found that electron-deficient aryl iodides showed better
reactivity in this reaction. Finally, we investigated the reactivity
of different fluoroalkylated 2-pyridyl sulfones under the
standard reaction conditions (Scheme 4) and found that the
Scheme 6. Proposed Mechanism
Scheme 4. Cross-Coupling with Different Fluoroalkyl 2-
a b
,
Pyridyl Sulfones
initiated by the reduction of NiCl2(dppp)n to Ni(0) species A
by Zn(0). The oxidative addition of 2-PySO2CF2H to Ni(0)
species A affords an arylnickel(II) species B.11 The subsequent
transmetalation of the arylnickel(II) species B with the arylzinc
reagent, which is in situ generated from aryl iodides and
Zn(0),12 furnishes Ni(II) species C. Finally, the reductive
elimination from C delivers the desired product D and
regenerates the catalytically active Ni(0) species A.13
a
Reaction conditions: 4-iodobiphenyl (0.8 mmol, 1.0 equiv), 2 (1.2
mmol, 1.5 equiv), NiCl2 (10 mol %), dppp (10 mol %), Zn (1.6
mmol, 2.0 equiv), DMF (5.0 mL), 80 °C, 16 h. Isolated yield.
b
In summary, we have developed a novel nickel-catalyzed
reductive cross-coupling reaction of 2-PySO2CF2H with aryl
iodides to forge C(sp2)−C(sp2) bonds via selective C(sp2)−S
bond cleavage. This synthetic protocol employs readily
available starting materials and reagents, proceeds under mild
conditions, and tolerates a range of functional groups and
reductive cross-coupling of 2-PySO2CF2H (2a) and fluoro-
methyl 2-pyridyl sulfone (2b, 2-PySO2CFH2) with 4-
iodobiphenyl proceeded smoothly to deliver the desired biaryl
3d in 83 and 62% yield, respectively. However, the reactions
with trifluoromethyl 2-pyridyl sulfone (2c, 2-PySO2CF3) and
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Notes
heterocycles. Moreover, this method avoids the need for the
pregeneration of arylmetal reagents, which is a notable
advantage for synthetic applications. Unlike our previous
work on iron-catalyzed reactions (Scheme 1a),7a the present
work not only provides a new strategy for the formation of
biaryls but also gives new insights into the new reactivity of
fluoroalkyl sulfones. Compared with results previously
reported by us7a and others,9,10 we conclude that the selectivity
of the cross-coupling reaction of heteroaryl sulfones is
influenced by both the transition-metal catalyst and the type
of the heteroaryl substituent of the sulfone. Further studies on
the transition-metal-catalyzed coupling reactions using sulfones
are underway in our laboratory.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Key Research and
Development Program of China (2016YFB0101200), the
National Natural Science Foundation of China (21632009),
the Key Programs of the Chinese Academy of Sciences
(KGZD-EW-T08), the Key Research Program of Frontier
Sciences of CAS (QYZDJ-SSW-SLH049), and the Shanghai
Science and Technology Program (18JC1410601).
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03939.
Experimental procedures and characterization data for
products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Jinbo Hu − 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/0000-0003-3537-0207;
Email: jinbohu@sioc.ac.cn
̈
Gartner, D.; Corpet, M.; Gosmini, C.; Jacobi von Wangelin, A.
Authors
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Wenjun Miao − 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; College of Basic Medicine, Chongqing
Medical University, Chongqing 400016, China
Chuanfa Ni − 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
Pan Xiao − 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
Rulong Jia − 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
Wei Zhang − 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
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