Cu-catalyzed dehydrogenative olefinsulfonation of Alkyl arenes

Article abstract of DOI:10.1021/acs.orglett.0c03146

A copper-catalyzed reaction protocol for the dehydrogenation of ethylbenzenes into styrene derivatives has been developed. This reaction procedure proceeded well under mild reaction conditions, providing a practical and efficient strategy for the rapid assembly of biologically and pharmaceutically significant molecules, such as vinyl sulfone. Simple alkyl arenes were functionalized via consecutive β-elimination in the presence of N-sulfonylbenzo[d]imidazole with broad substrate scope and good functional group tolerance.

Full text of DOI:10.1021/acs.orglett.0c03146

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Letter
Cu-Catalyzed Dehydrogenative Olefinsulfonation of Alkyl Arenes
Fangfang Li,§ Guang’an Zhang,§ Yingguo Liu, Bingke Zhu, Yuting Leng,* and Junliang Wu*
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ABSTRACT: A copper-catalyzed reaction protocol for the dehydro-
genation of ethylbenzenes into styrene derivatives has been developed.
This reaction procedure proceeded well under mild reaction conditions,
providing a practical and efficient strategy for the rapid assembly of
biologically and pharmaceutically significant molecules, such as vinyl
sulfone. Simple alkyl arenes were functionalized via consecutive β-
elimination in the presence of N-sulfonylbenzo[d]imidazole with broad
substrate scope and good functional group tolerance.
β-Elimination happens as an important dehydrogenative event
during many organometallic transformations.1 It plays a vital
role as a step or a side reaction toward alkenes, which shapes β-
elimination in a metal-mediated process into the major
synthetic tool for diverse olefin scaffolds.2 The most well-
known β-elimination takes place in the Heck reaction and its
modified versions.3 They have been extensively employed for
the construction of functionalized alkenes in current industrial
manufacturing. During such an event, the metal hydride olefin
species generates from the metal alkyl complex and
subsequently releases modified alkene derivatives (Figure
1a). This reaction pattern has been broadly investigated, and
2-alkenyl heteroarenes.1e Huo and co-workers also reported
the elegant dehydrogenation of ethylbenzene with glycine
derivatives into quinoline-2-carboxylates and demonstrated
that the reaction could be applicable in 10 g scale synthesis of a
medicinally important motif.6 Despite these important
contributions, construction of functionalized styrene deriva-
tives through one-pot consecutive dehydrogenation has not
been reported yet.7
Herein, we disclose a Cu(I)-catalyzed sulfonation of
ethylbenzene (EB) 1 with N-sulfonylbenzo[d]imidazole 2,
which features an unprecedented simultaneous dehydrogen-
ation and functionalization process of ethylbenzene involving
two successive metal-mediated β-hydride elimination steps.
Vinylsulfone 3 is subsequently delivered in a trans form. The
catalyzed process can be rationalized in terms of a [Cu-
(OTf)]2·toluene-mediated consecutive dehydrogenation of the
benzylic metal species, accompanied by radical addition
between the sulfone radical and the in situ generated styrene.8
This approach applies to a variety of ethyl arenes and
numerous N-sulfonylbenzo[d]imidazoles, affording the corre-
sponding vinyl sulfones in good yields under mild conditions.
We began our investigation using ethylbenzene 1a as a
model substrate for dehydrogenative transformation. N-
Sulfonylbenzo[d]imidazole 2a was used as a mild sulfonating
reagent, which was different from traditional reagents and new
sulfonating reagents developed by other groups such as
sulfonyl chloride and tosyl hydrazide.9 Key optimization
results from the extensive screening (Tables S1−S13, including
catalysts, ligands, solvents, additives, molecule sieves, etc.) are
shown in Table 1. Several copper catalysts were tested initially
Figure 1. β-Elimination via metal hydride species for olefin scaffolds.
many elegant methodologies have been developed.4 Despite
these signs of progress, during the metal-mediated radical
process, the metal alkyl complex’s generation from the alkanes
is still very challenging in synthetic chemistry (Figure 1b). In
particular, dehydrogenation of ethylbenzene into styrene has
been massively utilized in industrial production. But these
manufacturing processes require a harsh temperature of 500−
600°C.5 The further optimization of them into a mild and
effective synthetic method for the formation of functionalized
olefin derivatives is rare. Impressive progress on the
dehydrogenation of alkanes was made by Newhouse and co-
workers, who revealed arylnickel-catalyzed benzylic dehydro-
genation of electron-deficient heteroarenes for the synthesis of
Received: September 18, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03146
© XXXX American Chemical Society
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A

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a
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst (mol %)
co-catalyst
additive
yield (%)
1
2
3
4
5
6
CuCl
Cu(OTf)2
trace
trace
11
[Cu(OTf)]2·toluene
[Cu(OTf)]2·toluene
[Cu(OTf)]2·toluene
[Cu(OTf)]2·toluene
[Cu(OTf)]2·toluene
[Cu(OTf)]2·toluene
[Cu(OTf)]2·toluene
[Cu(OTf)]2·toluene
[Cu(OTf)]2·toluene
[Cu(OTf)]2·toluene
[Cu(OTf)]2·toluene
[Cu(OTf)]2·toluene
NCS
3 Å MS
6
trace
trace
34
40
52
37
70
70
75
TBAB
TBAB
KBr
LiBr
FeBr3
FeBr3+ LiBr
Fe(ClO4)3·xH2O+ LiBr
Fe(ClO4)3·xH2O+ LiBr
Fe(ClO4)3·xH2O+ LiBr
c
7
8
NCS + 3 Å MS
NCS + 3 Å MS
NCS + 3 Å MS
NCS + 3 Å MS
NCS + 3 Å MS
NCS + 3 Å MS
NCS + 3 Å MS
3 Å MS
d
9
10
11
12
13
14
e
e
f
f
34
a
Reaction conditions: 1a (1.4 mmol), 2a (0.2 mmol), [Cu] (10 mol %), DTBP (0.4 mmol), L1 (6 mol %), NCS (1.2 equiv), Fe(ClO4)3·H2O (10
b
c
d
e
mol %), LiBr (2 equiv), 3 Å MS (25 mg), toluene (1.0 mL), 120 °C, 36 h, Argon. Isolated yield. TBAB (0.5 equiv). KBr (2 equiv). FeBr3 (10
mol %). L1 = 3,4,7,8-tetramethyl-1,10-phenantholine, TBAB = tetrabutylammonium bromide, NCS = N-chlorosuccinimide. Li2CO3 (2 equiv).
f
in the presence of di-tert-butyl peroxide (DTBP) in toluene
under argon. It was observed that these catalysts could catalyze
the transformation, but most of them led to a trace amount of
product 3aa, such as CuCl and Cu(OTf)2 (entries 1 and 2),
when using [Cu(OTf)]2·toluene complex as a catalyst, and the
desired dehydrogenative olefinsulfonation proceeded to afford
the expected product 3aa in 11% isolated yield (entry 3). A
decline in the yield of 3aa was observed when N-
chlorosuccinimide (NCS) or tetrabutylammonium bromide
(TBAB) was used as the additive (entries 4−6), respectively.
To our delight, the accidental addition of both NCS and TBAB
into the reaction led to a higher yield (20%) (see Table S5,
entry 4). Enlightened by this, we added a combination of
TBAB, NCS, and 3 Å MS into our present reaction
simultaneously, and the product was obtained with a slightly
but consistently improved yield (34%, entry 7). These results
indicated that suitable bromide salts may be critical reagents
for the optimal reaction conditions. Consistent amelioration in
the yield of 3aa was achieved when KBr or LiBr was used
instead of tetrabutylammonium bromide (TBAB) (entries 8
and 9, Table S9). Afterward, iron salts with LiBr were found to
promote the desired transformation more effectively. An
obvious improvement in yield was found when the catalytic
amount of FeBr3 or Fe(ClO4)3·xH2O served as the co-catalyst
(entries 10−12, Tables S9 and S11). This may be attributed to
the fact that combination of iron salts with LiBr could always
leave the FeBr3 species in the reaction system, and FeBr3 might
help generate suitable benzylic radical species during DTBP-
initiated reactions (Table S11).10 This speculation was in
accordance with the control experiments that were carried out
to figure out the functions of co-catalyst and additives (see
entry 14, Tables S1−S13, and Mechanistic Studies in the
Supporting Information) for the reaction proceeding and its
high yields. However, considering FeBr3 is sticky and not easy
to handle, Fe(ClO4)3·xH2O was chosen as the iron source for
in situ generation of FeBr3 in the final reaction conditions.
Further reaction optimization found that 75% yield of 3aa
could be realized using [Cu(OTf)]2·toluene as a catalyst,
Fe(ClO4)3·xH2O as co-catalyst with a combination of LiBr,
NCS, and Li2CO3 as additives (entry 13). We also investigated
NBS (N-bromosuccinimide) instead of the combination of
Fe(ClO4)3·xH2O, LiBr and NCS; unfortunately, messy results
were acquired.
The scope of the dehydrogenative olefinsulfonation of alkyl
arenes was summarized in Scheme 1. For substituted
ethylbenzenes, both electron-withdrawing groups, such as
chloro, bromo, and iodo, and electron-donating groups, such as
amyl ether, could be tolerated and proceeded smoothly to
Scheme 1. Substrate Scope for Alkyl Arenes
a
Reaction conditions: 1a (1.4 mmol), 2a (0.2 mmol), [Cu(OTf)]2·
toluene (10 mol %), DTBP (0.4 mmol), L1 (6 mol %), NCS (1.2
equiv), Fe(ClO4)3·H2O (10 mol %), LiBr (2 equiv), 3 Å MS (25 mg),
Li2CO3 (2 equiv), toluene (1.0 mL), 120 °C, 36 h, argon.
B
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afford the desired vinyl sulfones 3aa−3fa in moderate to good
yields (54−75%) with exclusive trans-stereoselectivity. Specif-
ically, vinyl sulfone 3aa was successfully prepared on a 1 mmol
scale with 60% yield, and the stereochemistry was
unambiguously confirmed by X-ray crystallographic analysis
of 3ba. Interestingly, 1,4-diethylbenzene underwent exclusive
dehydrogenative olefinsulfonation on only one of the ethyl
moieties even in the presence of excess N-sulfonylbenzo[d]-
imidazole to afford 3ea. However, the dehydrogenative
olefinsulfonation became inefficient with those substrates
bearing trimethylsilyethynyl and allyloxy (3ga and 3ha) groups
due to decomposition under the reaction conditions. Using the
present method, (E)-1-(2-tosylvinyl)naphthalene 3ia was
obtained in good yield by employing ethyl naphthalene as
substrate. It was noteworthy that alkyl heteroarenes were also
amenable to this methodology, producing vinyl sulfones 3ja
and 3la in moderate yields. The dehydrogenative olefinsulfo-
nation can also occur on cycloalkenes. Tetrahydronaphthalene
was used to furnish 3-tosyl-1,2-dihydronaphthalene 3ka and 3-
(cyclopropylsulfonyl)-1,2-dihydronaphthalene 3kt in good
yields with different sulfonation reagents, respectively.
However, 4-ethylpyridine failed to participate in the reaction,
and no desired product 3ma was observed.
tolerated, the reaction was not efficient with a bulky
substituent (3ao, 34%). 1-Naphthyl and 2-naphthyl N-
sulfonylbenzo[d]imidazoles were amenable to our strategy in
good yields (3ap, 74% and 3aq, 61%). In addition, heterocyclic
substituents behaved differently in our reactions. Sulfonation
reagent with pyridyl group led to a very low yield (3ar, 10%),
while the thiofurylsulfonation reagent could still offer a good
yield (3as, 56%). This might be due to pyridine’s susceptibility
to the radical process. Thus, the present reaction pathway was
interrupted. We also tested alkyl-substituted N-sulfonylbenzo-
[d]imidazoles such as 1-(cyclopropylsulfonyl)-1H-benzo[d]-
imidazole and 1-(butylsulfonyl)-1H-benzo[d]imidazole, and
olefinsulfonation products 3at and 3au were obtained in 70%
and 30% yield, respectively.
To gain insight into the present reaction process, a radical
scavenger TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) was
added into the reaction systems in Scheme 3a. Although
Scheme 3. Mechanistic Investigation
Next, the dehydrogenative olefinsulfonation of 1a with
diverse N-sulfonylbenzo[d]imidazoles were examined. A
variety of alkyl and aryl N-sulfonylbenzo[d]imidazoles took
part in the present reaction to afford the corresponding vinyl
sulfones 3ab−3au in moderate to good yields. Evaluation of
substituted N-sulfonylbenzo[d]imidazoles revealed that both
electron-deficient and electron-rich derivatives were effective in
the dehydrogenative olefinsulfonation. This transformation was
compatible with fluoro (3ae), chloro (3af, 3am and 3an),
bromo (3ag), alkyl (3ad, 3al), alkoxy (3ac, 3ah), trifluor-
omethyl (3ai), and cyano (3aj) functional groups summarized
in Scheme 2. Although both electron-donating and electron-
withdrawing groups on N-sulfonylbenzo[d]imidazole could be
TEMPO-trapped products were not detected, the formation of
3aa was suppressed substantially, which was indicated that a
single-electron-transfer radical process may be involved. To
validate the radical process, another radical scavenger, 2,6-di-
tert-butyl-4-methylphenol (BHT), was added to the reaction
under standard reaction conditions in Scheme 3b. No desired
product 3aa was found. To further clarify the reaction pathway
of the dehydrogenative olefinsulfonation, experiments with
styrene (the proposed intermediate C) instead of ethylbenzene
were carried out under the standard conditions in Scheme 3c.
Sulfonation product 3aa was then obtained in 67% isolated
yield, which may be indicated that the in situ generated styrene
was one of the key intermediates during the dehydrogenative
olefinsulfonation process.
Scheme 2. Substrate Scope for N-
Sulfonylbenzo[d]imidazole
On the basis of the above results and previous reports, a
possible mechanism was illustrated in Scheme 4, though it
might be controversial.11 Initially, N-sulfonylbenzo[d]-
imidazole is reduced by Cu(I) via a single-electron-transfer
(SET) process to generate tosyl radical and Cu(II) complex
A.12 While benzylic radical is generated by a radical transfer
process initiated by decomposition of DTBP.13 Subsequently,
metal alkyl complex B is formed via a Cu(II)-mediated SET
oxidation process.14 β-Hydride elimination of intermediate B
releases the styrene C and Cu(I) species.12b,15 This metal
hydride species is then oxidized into the Cu(II) catalyst by N-
sulfonylbenzo[d]imidazole or DTBP to close the first catalytic
cycle. The second catalytic circle is continued with the styrene
C and the tosyl radical generated before. The in situ generated
a
Reaction conditions: 1a (1.4 mmol), 2a (0.2 mmol), [Cu(OTf)]2·
toluene (10 mol %), DTBP (0.4 mmol), L1 (6 mol %), NCS (1.2
equiv), Fe(ClO4)3·H2O (10 mol %), LiBr (2 equiv), 3 Å MS (25 mg),
Li2CO3 (2 equiv), toluene (1.0 mL), 120 °C, 36 h, argon.
C
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Scheme 4. Possible Mechanism for the Dehydrogenative
Olefinsulfonation
AUTHOR INFORMATION
Corresponding Authors
■
Yuting Leng − Green Catalysis Center, and College of
Chemisty, Zhengzhou University, Zhengzhou 450001, P.R.
China; Email: yutingleng@zzu.edu.cn
Junliang Wu − Green Catalysis Center, and College of
Chemisty, Zhengzhou University, Zhengzhou 450001, P.R.
China; orcid.org/0000-0001-5123-5051; Email: wujl@
zzu.edu.cn
Authors
Fangfang Li − Green Catalysis Center, and College of
Chemisty, Zhengzhou University, Zhengzhou 450001, P.R.
China
Guang’an Zhang − Green Catalysis Center, and College of
Chemisty, Zhengzhou University, Zhengzhou 450001, P.R.
China
Yingguo Liu − Division of Molecular Catalysis & Synthesis,
Henan Institute of Advanced Technology, Zhengzhou
University, Zhengzhou 450001, P.R. China
Bingke Zhu − Green Catalysis Center, and College of
Chemisty, Zhengzhou University, Zhengzhou 450001, P.R.
China
styrene traps the tosyl radical to form the functionalized
intermediate D. The final product is delivered via a Cu(II)-
mediated SET oxidative process followed by a second β-
hydride elimination step. Cu(I) complex is also formed during
this step and then oxidized into Cu(II) catalysis, completing
the second catalytic cycle. The addition of Fe(III) species leads
to a significant improvement of yield, but this reaction can
occur smoothly in moderate yields without Fe(ClO4)3·xH2O.
We speculate that it might bring some benefits to the
generation of benzylic radicals as reported.9 Detailed
investigations into their roles are shown in the Supporting
Information (see Tables S1−S13 and Mechanistic Studies).
In conclusion, we report an efficient copper-catalyzed
dehydrogenative coupling reaction of enthylbenzene with N-
sulfonylbenzo[d]imidazole under mild conditions, featuring
two successive β-elimination steps along with radical
sulfonation. A series of E-vinyl sulfones have been prepared
in moderate to good yields. Further studies to clearly
understand the detailed mechanism as well as applications in
natural product synthesis are currently underway.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03146
Author Contributions
§F.L. and G.Z. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by grants from the Top Youth Talent
Fund of Zhengzhou University and The State Key Laboratory
of Bio-organic and Natural Products Chemistry, CAS
(SKLBNPC18440).
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03146.
Experimental procedures, full spectroscopic data, and 1H
and 13C NMR spectra of all compounds (PDF)
Accession Codes
CCDC 2033227 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
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