Dual Nickel- And Photoredox-Catalyzed Reductive Cross-Coupling of Aryl Halides with Dichloromethane via a Radical Process

Article abstract of DOI:10.1021/acs.orglett.0c03248

The first catalytic strategy to harness a new chloromethane radical from dichloromethane under dual Ni/photoredox catalytic conditions has been developed. Compared with traditional two-electron reductive process associated with metallic reductants, this method via a single-electron approach can proceed under exceptionally mild conditions (visible light, ambient temperature, no strong base) and exhibits complementary reactivity patterns. It affords a broad scope of many functional groups, including alkenyl, which suffers cyclopropanation in previous routes. The diarylmethane-d2 compounds can be readily available with this transformation.

Full text of DOI:10.1021/acs.orglett.0c03248

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Dual Nickel- and Photoredox-Catalyzed Reductive Cross-Coupling of
Aryl Halides with Dichloromethane via a Radical Process
Wenhao Xu,∇ Purui Zheng,∇ and Tao XU*
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ABSTRACT: The first catalytic strategy to harness a new chloromethane
radical from dichloromethane under dual Ni/photoredox catalytic conditions
has been developed. Compared with traditional two-electron reductive process
associated with metallic reductants, this method via a single-electron approach
can proceed under exceptionally mild conditions (visible light, ambient
temperature, no strong base) and exhibits complementary reactivity patterns. It
affords a broad scope of many functional groups, including alkenyl, which
suffers cyclopropanation in previous routes. The diarylmethane-d2 compounds
can be readily available with this transformation.
ichloromethane (DCM), as the simplest geminal
chloride alkane, is an ideal methylene source, because
is involved, which can enable new reactivity and reactions
(Scheme 1a). Indeed, from the density functional theory
(DFT) calculation results, we can see that, although the C−Cl
bond dissociation energy (BDE) via homogeneous splitting is
extremely high, the process via a single electron reduction is
considerably favorable, thus providing a possibility to convert
the C−Cl bond under very mild conditions (Scheme 1b).
Herein, we first reported the dual nickel- and photoredox-
catalyzed reductive cross-coupling of aryl halides with DCM
via a radical mechanism. The generated benzyl chlorides could
further react with another aryl halide to access the diaryl-
methane products (Scheme 1c).
To test our hypothesis, 4-tert-butyl-iodobenzene (1) in the
DCM solvent with dual nickel catalyst and organic photo-
catalyst (4CzIPN) under blue LED conditions was examined.
With 4,4′-di-tert-butyl-2,2′-bipyridyl (dtbbpy, L1) as a ligand,
triethylamine (Et3N) as a reductant, the bicoupling product 2
was obtained in 63% GC yield (Table 1, entry 1). The electron
property of the ligand obviously affected this transformation, as
shown with the less-electron-rich bipyridine ligand (L2) or
electron-poor ligand (L3), as well as the steric effect, as
demonstrated with ligand L4 (Table 1, entries 2−4).
Surprisingly, other metallic photocatalysts (Ir or Ru) cannot
give any products under these conditions (Table 1, entries 5
and 6). Replacement of Et3N with other reductants, such as
diisopropylethylamine (DIPEA), diisopropylamine (DIPA), or
Hantzsch ester (HEH), led to lower yields (Table 1, entries 7−
D
of its abundance, low cost, and nontoxicity.1 However, more
often, its high stability allows it to be a general solvent. Instead,
the much more active diiodomethane is needed as the
methylene source, especially on the C−C bond formation.2
One of the famous processes is Simmons−Smith cyclo-
propanation via an organometallic carbenoid with the
stoichiometric metal reductants such as zinc (via IZnCH2I),
which was first reported in 1958.3 Recently, the Uyeda group
greatly promoted this process with DCM as well as 1,1-
dichloroalkene by employing well-designed dinuclear nickel
complexes.4 Meanwhile, a tridentate cobalt catalyst has also
proved its catalytic efficiency on this transformation.5 Although
a few literature reports have been presented on the cross-
coupling reaction involving DCM, the Grignard reagents and
transition metals with multidentate ligands were engaged. In
2008, Hu and co-workers demonstrated an impressive coupling
n
of DCM and BuMgCl to form two C−C bonds with the
nickamine catalyst developed by their group.6 Since that,
several complexes have shown their abilities, with regard to this
type of Kumada reaction.7 However, the development of a new
active mode to use DCM efficiently as a methylene source is of
high demand.
Generally, the unactivated C−Cl bond could be completely
inert in the reductive cross-coupling reactions with zinc or
manganese as reductants.8 The dual transition-metal- and
photoredox-catalyzed system has recently achieved consid-
erable developments in C−C bond formations.9 We envisioned
that the C−Cl bond in DCM would be efficiently promoted to
form a new chloromethane radical via a single-electron
reduction under photoredox-catalyzed conditions, which can
be subsequently trapped with a transition-metal catalyst,
followed by the generation of C−C bonds. With this novel
active mode, the radical intermediate rather than the carbeniod
Received: September 28, 2020
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© XXXX American Chemical Society
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the optimized conditions (Table 1, entry 11). In addition, a
trace amount of the product was formed when Zn or Mn was
used as a reductant (Table 1, entry 12), thus showing the huge
distinction between this single-electron reduction and the
traditional two-electron reductive process.
Scheme 1. New Reactivity Mode Enabled by Dual Catalysis:
(a) Novel Radicals Enable New Reactivity, (b) BDE
Calculation of the C−Cl Bond, and (c) Nickel/Photoredox-
Catalyzed Process
With the optimized conditions in hand, the dual nickel/
photoredox-catalyzed method was first applied for the
reactions with various aryl halides (Table 2). Generally, the
aryl halides with either electron-donating or electron-with-
drawing functional groups on the ortho-, meta-, and para-
positions reacted smoothly to give the corresponding products
in moderate to excellent yields, in an effort to showcase the
mild nature of this method. For example, substrates bearing
ether substituents were tolerated without significant reduction
in yield (3, 11). The alkyl substitutions in the benzene ring had
no influence on the high yields (4, 8). Selective cross-coupling
was observed in compounds with multiple electrophilic
handles (10, 23); both aryl chloride and fluoride bonds in
this system can survive (5, 13, 14). In addition, ketone (9)
could be embedded within substrates to afford products in
good yield.
Note that no reaction of olefin, which usually has a tendency
to be cyclopropanated in the Simmons−Smith reaction, with
DCM was detected under these conditions, and only the
bicoupling products were isolated (12, 21), hence serving to
highlight the mechanistic differences between the traditional
two-electron reduction process and this single-electron
reduction strategy described herein. Identically, the substrate
bearing alkynyl group was also tolerant (15). Besides the
phenyl iodide, the 2-iodothiophene (16) and 2-iodonaph-
thalene (17) could be also employed to produce the products
with moderate yields, thus demonstrating the application of
9). Although the direct homocoupling of substrate 1 was the
main side product, here, reducing the volume of DCM had no
obvious effect on the yield (Table 1, entry 10). Meanwhile,
increasing the loading of the nickel catalyst, ligand, and
reductant promoted the yield to 87%, which were selected as
a
Table 1. Optimization Conditions
b
b
entry
ligand
photocatalyst, PC
4CzIPN
4CzIPN
4CzIPN
4CzIPN
[Ir(dFCF3ppy)2dtbbpy]PF6
Ru(bpy)3Cl2·6H2O
4CzIPN
4CzIPN
4CzIPN
reductant
conversion (%)
yield (%)
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L1
L1
L1
L1
L1
L1
L1
L1
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
DIPEA
DIPA
HEH
Et3N
Et3N
Zn/Mn
73
53
20
0
16
0
10
50
43
75
100
<10
63
41
9
0
0
0
5
32
30
65
87
<5
c
10
cd
4CzIPN
4CzIPN
−
,
11
12
ce
,
a
Reaction conditions: 1 (0.1 mmol), Ni(cod)2 (5 mol %), ligand (6 mol %), photocatalyst (1 mol %), reductant (4 equiv), DCM (4 mL), blue LED
b
c
lamp (30 W), room temperature, 20 h. The conversions and yields were determined by GC, with dodecane as an internal standard. DCM (2
mL). Ni(cod)2 (10 mol %), L1 (12 mol %), TEA (8 equiv). Ni(cod)2 (10 mol %), L1 (12 mol %), Zn or Mn (2 equiv).
d
e
B
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a
Table 2. Scopes of Dual Ni/Photoredox-Catalyzed Cross-Coupling
a
Reaction conditions: aryl halide (0.2 mmol), Ni(cod)2 (10 mol %), L1 (12 mol %), photocatalyst (1 mol %), Et3N (8 equiv), DCM (4 mL), blue
LED lamp (30 W), room temperature, 20 h. Isolated yields were given. bDCM (8 mL). c1,10-phenanthroline (12 mol %) was used as ligand. LiBr
(1.5 equiv) was added. dDCM (16 mL). e1,10-phenanthroline (12 mol %) was used as ligand. KI (3 equiv) was added. fThe reaction was conducted
on 0.1 mmol in DCM-d2 (1.5 mL).
this methodology in the heterocyclic partners. The reaction
also exhibited comparable efficiency on a larger scale, as the
product was isolated in good yield on a 1 mmol scale. In
addition to aryl iodides, the aryl bromide components can also
work well (18−23); those bromides bearing the trifluor-
omethyl (18, 22), cyan (19), ester (20), and other groups
were all readily converted under the current conditions.
The method was applied for the vinyl halides substrates to
further study the scope of this transformation (24−28). This
dual catalytic method not only permits the cyclic alkenyl
bromides or iodides, but also suits the acyclic substrates, as
evidenced by isolation of the corresponding products in
moderate to high yields.
Considering the important application of molecules
containing deuterium in organic synthesis, mechanistic studies,
pharmaceutical discoveries, and developments,10 this method
was efficiently employed with dichloromethane-d2 to form the
diarylmethane-d2 products, which were relatively difficult to
synthesize using other known pathways. The synthesis of
deuterated diarylmethane often needs deprotonation or
dehalogenation with strong base.11 It is convenient to
introduce single deuterium with this route but not for the
germinal ones. However, with our transformation, this d2-
products can be formed in high yields under strong base-free
conditions as shown with the compounds 2-D and 25-D, thus
strengthening the high superiority of this dual nickel/
photoredox-catalyzed method. However, for the DCM with
C
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substituents, such as chloroform or 1,2-dichloroalkane, they
could not give any products via this route.
Scheme 3. Derivatives of Diarylmethanes
To give some insights into the mechanism of the coupling,
some experiments using probes were performed. In the
presence of 1 equiv of 2,2,6,6-tetramethylpiperidinooxy
(TEMPO), the product was obtained in 43% yield, which
was lower than that observed under the standard conditions.
Meanwhile, the alkylated TEMPO was also detected by MS
(see Scheme 2, top). Because of the excess chloromethane (as
Scheme 2. Mechanistic Experiments
amination product 36 was produced in high yield under Mn-
catalyzed conditions.
In summary, a dual nickle/photoredox-catalyzed coupling of
aryl halides with DCM via a single electron reduction was
reported. The differential reactivity between the two-electron
and single-electron processes enables this transformation under
very mild conditions with no need of Grignard reagents or
stoichiometric metallic reductants. The reaction accommo-
dates a broad palette of aryl iodides, aryl bromides, and alkenyl
halide architectures. Considering the readily available of
deuterated DCM, this strategy provides a convenient route
to form diarylmethane-d2 compounds.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03248.
Experimental procedures, DFT calculation, and spectro-
scopic data for new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Tao XU − Shanghai Key Laboratory of Chemical Assessment
and Sustainability, School of Chemical Science and Engineering,
Tongji University, Shanghai 200092, People’s Republic of
China; orcid.org/0000-0002-4228-4895; Email: taoxu@
tongji.edu.cn
solvent), it was still reasonable for the formation of the
products. When 1,1-diphenylethylene (29) was used, it
afforded the products 30 and 31 in 31% and 25% yield,
respectively, while trace cyclopropanation product was
detected (Scheme 2, bottom).12 This results suggest that the
chloromethane radical was indeed generated via a single
electron reductive process in this system.13 In addition, when
the benzyl chloride was employed as a cosubstrate, the cross-
coupling product 32 was also formed in 20% yield besides the
compound 2 obtained.14 Identically, three diarylmethanes
including the cross-coupling product 32 were detected in the
presence of iodobenzene and 4-tert-butyl-iodobenzene. These
results also suggest the benzyl chloride is an intermediate
under these optimized conditions, which followed second
cross-coupling with another aryl halide, thus further proving
our hypothesis.
Finally, the synthetic utility of this transformation was
demonstrated via a series of further functionalization of the
products (Scheme 3). The methylene can be oxidized with
TBHP to ketone in 88% yield (33). It can also proceed via
hydroxylation to give the product 34 in 71% yield. After
deprotonation, allylic bromide can be employed to introduce
an olefin group to the diarylmethane (35). In addition, the
Authors
Wenhao Xu − Shanghai Key Laboratory of Chemical Assessment
and Sustainability, School of Chemical Science and Engineering,
Tongji University, Shanghai 200092, People’s Republic of
China
Purui Zheng − Shanghai Key Laboratory of Chemical
Assessment and Sustainability, School of Chemical Science and
Engineering and Department of Polymeric Materials, School of
Materials Science and Engineering, Tongji University, Shanghai
200092, People’s Republic of China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03248
Author Contributions
∇These authors contributed equally.
Notes
The authors declare no competing financial interest.
D
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(13) The luminescence quenching experiments indicated that Et3N
is more likely to quench the excited state of 4CzIPN. For details and a
proposed catalytic cycle, see the Supporting Information. For
additional literature, see: Wang, Z.-S.; Chen, Y.-B.; Zhang, H.-W.;
Sun, Z.; Zhu, C.; Ye, L.-W. J. Am. Chem. Soc. 2020, 142, 3636.
(14) When this reaction was conducted with Zn/Mn as a reductant
under the Ni-catalyzed conditions in DCM solvent, it did not give any
conversion, thus demonstrating that the dual Ni/photoredox-
catalyzed system is also crucial for the second process in this
transformation.
ACKNOWLEDGMENTS
■
We thank NFS of China (Grant No. 21801188), Shanghai
Pujiang Program, the “1000 Youth Talents Plan”, and Tongji
University for financial support. We thank Ms. Feng Zheng
from Tongji University for the helpful discussion on the
computational experiments.
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E
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