Copper-Mediated Cross-Coupling of Diazo Compounds with Sulfinates

Article abstract of DOI:10.1021/acs.orglett.1c02481

A copper-mediated cross-coupling reaction between a diazo compound and a sodium alkane(arene)sulfinate gives a sulfone as the product. This reaction proceeds under mild conditions and features excellent functional group compatibility. A wide range of sodium alkane(arene)sulfinates were successfully applied in this chemistry. Mechanistic studies revealed that the overall reaction efficiency of the sulfinates was in line with their nucleophilicity in this reaction.

Full text of DOI:10.1021/acs.orglett.1c02481

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Letter
Copper-Mediated Cross-Coupling of Diazo Compounds with
Sulfinates
Qian Wang, An Liu, Yan Wang, Chuanfa Ni, and Jinbo Hu*
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ABSTRACT: A copper-mediated cross-coupling reaction between
a diazo compound and a sodium alkane(arene)sulfinate gives a
sulfone as the product. This reaction proceeds under mild
conditions and features excellent functional group compatibility.
A wide range of sodium alkane(arene)sulfinates were successfully
applied in this chemistry. Mechanistic studies revealed that the overall reaction efficiency of the sulfinates was in line with their
nucleophilicity in this reaction.
sulfones involves three-component processes using two sulfur-
ulfones are a ubiquitous class of organic molecules that
Shave received much attention within the chemistry free building blocks and sulfur dioxide or a suitable surrogate,
community.1 They play a prominent role in a variety of
yet the toxic and corrosive nature of sulfur dioxide largely
limits the application of this protocol (path b).6,7 Alternatively,
those strategies involving the direct transfer of sulfonyl groups
using sulfonyl sources, which are usually readily available,
bench-stable, and nonodorous solids, are even more attractive
(path c).6
chemical transformations, such as Julia olefination,2 the
3
4
̈
Ramberg−Backlund reaction, and cross-coupling reactions.
Furthermore, interest in the synthesis of sulfones has also been
drawn by the widespread distribution of sulfone scaffolds in
many biologically active compounds in pharmaceuticals and
agrochemicals.1b,5 Consequently, a number of methods for the
synthesis of sulfones have been disclosed, which can be divided
into three types (Scheme 1a): the oxidation of sulfides, three-
component approaches, and the transfer of sulfonyl groups.6
The sulfone unit has historically been accessed through the
oxidation of the corresponding sulfides (path a).1,6a However,
the strong oxidizing condition may lead to scope limitations
and safety problems. Another strategy for the synthesis of
In this context, the transformation of sulfinates is currently
one of the most valuable research topics. As easily prepared
nucleophiles and radical precursors,8,9 sulfinates are versatile
reagents that can participate in various reactions, such as
nucleophilic reactions,6a,c,10 C−H bond functionalizations,6d,11
radical processes,6b,9,12 and transition-metal-catalyzed cross-
coupling reactions.6,13 Despite the elegance of the chemistry
previously mentioned, to the best of our knowledge, the
reaction of sulfinates with metal carbene remains elusive. In
2010, an elegant synthesis of sulfones from sulfonylhydrazones
was demonstrated by Yu and coworkers.14a Nevertheless, the
strategy is heavily based on prefunctionalized starting materials
and displays a narrow substrate scope. More recently, Wan and
coworkers reported a coupling reaction between sulfonyl
radicals and silver carbenes.14b However, the reaction mainly
focused on α-diazo carbonyl substrates. Therefore, the direct,
efficient, and mild synthesis of sulfones from the reaction of
sulfinates with metal carbene is still highly desirable.
Scheme 1. Strategies for the Synthesis of Sulfones
On the other hand, the recent decades have witnessed rapid
and significant advances in the alliance of diazo chemistry and
organofluorine chemistry.15,16 Since our pioneering develop-
Received: July 26, 2021
https://doi.org/10.1021/acs.orglett.1c02481
© XXXX American Chemical Society
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ment of the trifluoromethylation of diazo compounds,17 diazo
chemistry has been widely applied to versatile transformations
in organofluorine chemistry.18 As part of our ongoing
investigations dedicated to diazo chemistry, we explored the
reaction of sulfinates with diazo compounds, thus synthesizing
alkyl sulfones, which are usually difficult to access. Here we
present a direct copper-mediated cross-coupling of diazo
compounds with sulfinates, providing easy access to structur-
ally diverse sulfones in good yields under very mild reaction
conditions.
(Scheme 2). A range of diazo compounds bearing different
substituents on the aromatic ring, such as alkyls (3, 13), ethers
a b
,
Scheme 2. Scope of Diazo Compounds
To test our hypothesis, we investigated the reaction between
bis(4-methylphenyl)diazomethane (1a) and CH2FSO2Na (2b)
as a model reaction (Table 1). Considering the poor solubility
a
Table 1. Optimization of the Reaction Conditions
b
entry
CuX (x)
L (y)
solvent
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuCl (1.0)
CuBr (1.0)
CuTc (1.0)
CuI (0.2)
CuI (0.6)
CuI (1.0)
CuI (1.0)
CuI (1.0)
CH3CN
NMP
dioxane
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
46
77
65
84
55
64
69
54
20
57
c
a
Reaction was performed on a 0.4 mmol scale with 2, CuI (0.4 mmol,
d
1.0 equiv), phen (0.08 mmol, 0.2 equiv), DMF (4.0 mL), H2O (0.4
phen (0.2)
phen (0.5)
phen (1.0)
>99 (93 )
97
87
b
c
mL), room temperature, 10 h. Isolated yields. phen (1.0 equiv) was
d
used. Yields were determined by 19F NMR with PhOCF3 as an
internal standard.
a
Reaction conditions (unless otherwise specified): 1a (0.2 mmol, 1.0
equiv), 2b (0.3 mmol, 1.5 equiv), CuX, L, solvent (2.0 mL), H2O (0.2
b
mL), room temperature for 12 h. Yields were determined by 19F
(5, 7, 14), halogens (8−10, 12, 15−17), and trifluoromethyl
groups (11), were well accommodated, giving the desired
products in moderate to high isolated yields (62−97%). The
ortho-substituted diaryl diazomethane also worked well, as
shown in the case of 12 and 27. Of note, the C(sp2)−Br bonds
remained unreacted under our cross-coupling conditions (10,
17), providing a platform for further elaborations via
traditional cross-coupling strategies. Lower yields were
observed in the case of a strong electron-deficient substrate
(11), probably due to its lower reactivity with copper species.
Next, we were interested in extending this chemistry toward
the synthesis of difluoromethyl sulfones, which have led to the
development of various transformations.2b,c,4c,g Gratifyingly,
CF2HSO2Na (2c) could also react smoothly with all of the
previously mentioned diazo compounds, and the correspond-
ing products (18−32) were successfully obtained. It is worth
mentioning that compared with CH2FSO2Na (2b), lower
yields were obtained in most cases, which will be discussed in
detail in the mechanistic studies.
Subsequently, the sulfinate component was further varied
using 1a or 1c as the coupling partner (Scheme 3). Not
surprisingly, an array of commercially available alkyl sulfinates
(33−35) could be smoothly converted to target sulfones in
high yields (92−97%). The aryl sulfinates were also competent
coupling partners, and halogen atoms (F, Cl) or a
trifluoromethoxy group (OCF3) on the phenyl moiety of
sulfinates were well tolerated in the reaction, yielding the
c
NMR using PhOCF3 as an internal standard. In the absence of H2O.
d
Isolated yield.
of sulfinates in most organic solvents, we chose H2O as a
cosolvent, which also served as a proton source. CuI was
selected as the copper reagent for the initial screening of
solvents. Gratifyingly, the use of MeCN as the solvent formed
the desired product 3 in a moderate 19F NMR yield (entry 1).
Our further screening of solvents (entries 2−4) demonstrated
that dimethylformamide (DMF) was the best choice, providing
3 in 84% 19F NMR yield (entry 4). Notably, in the absence of
H2O, the yield decreased to 55%, implying that H2O played a
critical role in the reaction (entry 5). Using other copper
reagents, such as CuCl, CuBr, and CuTc, provided 3 in lower
yields (entries 6−8). Decreasing the loading amount of CuI
(entries 9 and 10) led to significant decreases in yields (20%
for 0.2 equiv of CuI; 57% for 0.6 equiv of CuI). These results
indicate that the copper species is presumably transformed to
unreactive Cu2O, making it unavailable for catalysis, which is
consistent with our previous findings.17 Finally, we were
pleased to find that the use of 1,10-phenanthroline (0.2 equiv)
delivered 3 in a nearly quantitative 19F NMR yield and a 93%
isolated yield (entry 11).
With the optimized conditions in hand, we explored the
generality of the reaction by first varying the scope of diazo
compounds using CH2FSO2Na (2b) as the coupling reagent
B
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a b
,
Scheme 3. Scope of Sulfinate Salts
Scheme 4. Competition Experiments
showed a higher reaction rate constant (k2) at inception (k2/k1
= 1.50). It should be emphasized that 2c seems to be more
“reactive” in the parallel experiments, which seemingly
contradicts the result of the previously described competition
experiments (Scheme 4c).
a
Unless otherwise mentioned, the reaction was performed on a 0.4
mmol scale with 2 (0.6 mmol, 1.5 equiv), CuI (0.4 mmol, 1.0 equiv),
phen (0.4 mmol, 1.0 equiv), DMF (4.0 mL), H2O (0.4 mL), room
b
temperature, 10 h. Isolated yields. Tol = p-tolyl, PMP = 4-
Therefore, to excavate more details, we carried out the N2
evolution experiments to investigate the formation rate of the
copper carbene species. (See Part 4.3 in the SI.) The volumes
of released N2 gas were measured in the reaction of
CH2FSO2Na (2b) and CF2HSO2Na (2c) under the standard
reaction conditions with 1f, respectively. As we can see from
Figure S3 (in the SI), the diazo compound 1f decomposed
more quickly during the reaction of 2c. Specifically, 10.7 mL of
N2 gas was generated within just 148 min during the reaction
of 2c, whereas 9.4 mL of N2 gas was generated within 660 min
during the reaction of 2b. (Theoretically, 11.2 mL of N2 gas
should be produced after the complete decomposition of the
diazo compound at standard temperature and pressure.) These
significant differences indicate that the sulfinate-coordinated
copper A (see Scheme 5a) was an active species to react with
the diazo compounds, and the electron-deficient species (2c)
was more “reactive” owing to its high electrophilicity toward
methoxyphenyl.
corresponding products with high efficiency (36−40). In
addition, substrates containing medicinally relevant hetero-
cycles, including pyridine (41), naphthalene (42, 43), and
benzothiazole (44), all proved to be effective coupling
partners.
To gain more insights into the mechanism, we carried out
some additional experiments. With our continuous interest in
probing the unique fluorine effects,9c,19,20 we started off with a
comparison of the overall reaction efficiencies of different
sodium sulfinates (Scheme 4). First, an intermolecular
competition experiment using equimolar amounts of
CH3SO2Na (2a), CH2FSO2Na (2b), CF2HSO2Na (2c), and
CF3SO2Na (2d) under the standard reaction conditions with
1c was carried out (Scheme 4a). The ratio of the
corresponding products was 100:45:7:0, which was in line
with the order of the nucleophilicity of sulfinates (2a−2d).
The following competition experiments were also consistent
with this result, giving ratios of 100:45, 100:22, and 100:3 for
2a/2b, 2b/2c, and 2c/2d, respectively (Scheme 4b−d). The
significant electronic preference found in these experiments
suggests that the overall efficiencies of these sodium sulfinates
in the reaction decrease with their decreasing nucleophilicity in
the following order: 2a > 2b > 2c> 2d.
Scheme 5. Proposed Mechanism
Subsequently, a parallel experiment was carried out to study
the kinetics of the reaction. Two separate reactions of
CH2FSO2Na (2b) and CF2HSO2Na (2c) under the standard
reaction conditions with phenyl (4-fluorophenyl)-diazome-
thane (1f) were conducted, and the rate constants of two
reactions (k1 and k2) were measured independently (see details
in the Supporting Information (SI)). Interestingly, it was found
that the reaction of the more nucleophilic 2b had a lower
reaction rate constant (k1). In contrast, the reaction of 2c
C
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Letter
diazo compounds. This is also consistent with the results from
parallel experiments. Furthermore, 19F NMR analysis of these
reactions revealed that both products were formed just after
the N2 evolution (85% for reaction of 2b at 660 min; 61% for
reaction of 2c at 148 min). We can thus conclude that the
generation of final products after the N2 evolution is relatively
faster, and the formation of a copper-carbene species is likely
the rate-determining step.
Academy of Sciences, Chinese Academy of Sciences, Shanghai
200032, China; orcid.org/0000-0003-3537-0207;
Email: jinbohu@sioc.ac.cn
Authors
Qian Wang − 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/0000-0001-5986-6595
An Liu − 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
Yan Wang − 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
Another particularly noteworthy result is that the more
“reactive” CF2HSO2Na (2c) provided lower yields compared
with CH2FSO2Na (2b), which was also observed during our
survey of the substrate scope (Scheme 2). We believe that the
main reason lies in the stronger binding forces between the
more electron-rich 2b and the copper-carbene species.
On the basis of the aforementioned mechanistic studies, a
possible mechanism is proposed in Scheme 5a. Rapid cation
exchange between sodium sulfinate and CuI forms the
sulfinate-coordinated copper species A.14,21,22 Subsequently,
A reacts with the diazo substrate to form the copper-carbene
species B, and this process is presumably the rate-determining
step. The migration insertion of B generates intermediate C.
Finally, the protonation of C delivers the final product and
CuOH, which is unstable and further decomposes into Cu2O
and H2O.17,23 On the basis of the above analysis, the
competition experiments can be well explained (Scheme 5b).
In the presence of different sulfinates, the more electron-
deficient sulfinate reacts faster with the diazo compound and is
therefore called the more “reactive” species; however, the
electron-rich sulfinate dominants the subsequent steps because
sulfinates are in rapid equilibrium via ligand exchange on
copper-carbene species.24
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
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02481
Notes
The authors declare no competing financial interest.
In conclusion, we have developed an effective protocol for
the synthesis of sulfones through the copper-mediated cross-
coupling of diazo compounds with sulfinates. Various readily
available sulfinates are directly utilized as sulfonyl group
sources through the migration insertion of copper carbene
species, enabling rapid access to an array of structurally diverse
sulfones. The reaction is also an interesting case where a more
“reactive” species does not necessarily result in higher reaction
efficiency. Further efforts in the efficient synthesis and new
applications of sulfones are currently underway in our lab.
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 Shanghai
Science and Technology Program (18JC1410601).
REFERENCES
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02481.
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Accession Codes
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