Metal- And Base-Free C(sp2)-H Arylsulfonylation of Enamides for Synthesis of (E)-β-Amidovinyl Sulfones via the Insertion of Sulfur Dioxide

Article abstract of DOI:10.1021/acs.orglett.1c01419

A metal- and base-free C(sp2)-H direct arylsulfonylation of secondary and tertiary enamides with aryldiazonium salts and ex situ generated SO2 (from SOgen) is presented. This method runs smoothly to produce β-amidovinyl sulfones with excellent stereoselectivities in moderate to excellent yields. Moreover, this strategy features good functional group tolerance and environmentally benign reaction conditions. Mechanistic experiments indicate that this sulfonylation may proceed in a radical pathway.

Full text of DOI:10.1021/acs.orglett.1c01419

pubs.acs.org/OrgLett
Letter
Metal- and Base-Free C(sp2)−H Arylsulfonylation of Enamides for
Synthesis of (E)‑β-Amidovinyl Sulfones via the Insertion of Sulfur
Dioxide
Lei Chen, Mi Zhou, Lin Shen, Xiaochun He, Xiong Li, Xuemei Zhang,* and Zhong Lian*
Cite This: Org. Lett. 2021, 23, 4991−4996
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ABSTRACT: A metal- and base-free C(sp2)−H direct arylsulfonylation of secondary and tertiary enamides with aryldiazonium salts
and ex situ generated SO2 (from SOgen) is presented. This method runs smoothly to produce β-amidovinyl sulfones with excellent
stereoselectivities in moderate to excellent yields. Moreover, this strategy features good functional group tolerance and
environmentally benign reaction conditions. Mechanistic experiments indicate that this sulfonylation may proceed in a radical
pathway.
β-Amido sulfones are very important building blocks existing in
many natural products and biologically active compounds.1
Many methods have been explored for the preparation of β-
amido sulfones.2 Among them, hydrogenation of β-amidovinyl
sulfones is recognized as an efficient way to synthesize β-amido
sulfones.3 It is therefore encouraging to develop efficient and
straightforward approaches for the synthesis of β-amidovinyl
sulfones.
In the past decade, efforts have been made for the synthesis of
β-amidovinyl sulfones through C(sp2)−H sulfonylation of
enamides.4 In 2013, Loh reported C−H sulfonylation of
indenyl-derived enamides with sulfonyl chlorides under
palladium catalysis5 (Figure 1a, top). In the same year, Yu
described a mild, environmentally friendly method involving
direct C−H arylsulfonylation of enamides with arylsulfonyl
chlorides via visible-light photoredox catalysis6 (Figure 1a,
bottom). In 2018, in the absence of transition metals, Zhang
managed to prepare β-amidovinyl sulfones through visible light
induced oxidative cross-coupling of sodium sulfinates with
secondary enamides7 (Figure 1b, top). More recently,
Manolikakes reported a Mn(OAc)3-mediated oxidative C-
(sp2)−H sulfonylation of secondary enamides with sodium or
lithium sulfinates8 (Figure 1b, bottom). However, limited
accessibility of sulfonyl chlorides and metal sulfinates has greatly
restricted substrate scope and applications of the methods
above.
In 2019, Loh and Zhao developed a copper(II) triflate
mediated C−H sulfonylation of tertiary enamides with DABSO,
leading to the formation of (E)-β-amidovinyl sulfones.11 Then
they adopted an iridium-catalyst in the similar system and
successfully made β-amidovinyl sulfones12 (Figure 1c). Despite
progress made in these studies, transition metals are necessarily
added as promotors or catalysts in most cases. Therefore, it is
interesting to explore direct C−H sulfonylation of enamides in
transition-metal-free systems to produce β-amidovinyl sulfones.
Recently, our group designed a cheap, solid, and bench-stable
SO2 surrogate (SOgen) which was successfully applied in Pd-
catalyzed direct aminosulfonylation of aryl iodides and amines.13
Herein, we demonstrate a transition-metal- and base-free
C(sp2)−H direct arylsulfonylation of secondary and tertiary
enamides with aryl diazonium salts and SOgen (Figure 1d) This
method proceeds smoothly and exhibits excellent stereo-
selectivities to produce geometrically defined (E)-β-amidovinyl
sulfones in moderate to good yields.
We started our research by investigating direct C(sp2)−H
sulfonylation of N-(1-phenylvinyl)acetamide 1a with 4-methyl-
benzenediazonium tetrafluoroborate 2a and ex situ generated
Received: April 28, 2021
Published: June 11, 2021
Synthesis of sulfonyl compounds through sulfur dioxide
insertion is an attractive and ideal strategy since it features easily
available starting materials and broad substrate scope.9,10
https://doi.org/10.1021/acs.orglett.1c01419
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4991−4996
4991

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a
Table 1. Optimization of Reaction Conditions
b
e
entry
1
variation from std conditions
yield of 3a (%)
E/Z
c
86 (81)
>99:1
23:77
63:37
69:31
d
2
DABSO instead of SO2
Na2S2O5 instead of SO2
K2S2O5 instead of SO2
HOCH2SO2Na·2H2O instead of SO2
DCE instead of DMA
DMSO instead of DMA
MeCN instead of DMA
toluene instead of DMA
MeOH instead of DMA
dioxane instead of DMA
H2O instead of DMA
air instead of Ar
84
59
51
0
trace
72
0
0
0
0
0
d
3
d
4
d
5
6
7
8
9
10
11
12
13
14
15
82:18
61
71
60
>99:1
>99:1
>99:1
2.0 equiv of SO2
1.5 equiv of SO2
a
Standard conditions: chamber A, 1a (0.2 mmol, 1.0 equiv), 2a (0.28
mmol, 1.4 equiv), DMA (1.0 mL), at room temperature for 8 h under
argon atmosphere; chamber B, SOgen (0.51 mmol), 1-methyl-4-
vinylbenzene (0.5 mmol), tetradecane (1.0 mL), at 100 °C for 10
b
min. Yields were determined by 1H NMR analysis using 1,3,5-
c
trimethoxybenzene as an internal standard. Isolated yield in
d
e
parentheses. The reaction was set up in a 4 mL vial. E/Z ratio
1
was determined by H NMR analysis.
Figure 1. Sulfonylation reactions of enamides.
SO2 gas (from SOgen)13 under metal- and base-free conditions
(Table 1). Pleasingly, when the reaction was carried out in DMA
at room temperature for 8 h, desired product 3a was successfully
obtained in 86% yield with excellent stereoselectivity (Table 1,
entry 1). The configuration of compound 3a was confirmed by
X-ray crystallography. Next, other sulfur dioxide surrogates were
examined. Interestingly, when DABSO was employed as the SO2
surrogate, the stereoselectivity was converse, with the Z-isomer
as the major product14 (Table 1, entry 2). The use of inorganic
SO2 surrogates (Na2S2O5 and K2S2O5) could lead to the
formation of 3a with lower yields and poorer stereoselectivity,
while Rongalite reagent would hamper the sulfonylation (Table
1, entries 3−5). Subsequently, we screened other commercially
available solvents such as DCE, DMSO, MeCN, toluene,
MeOH, and dioxane, which did not lead to better results (Table
1, entries 6−11). Green solvent H2O would hinder the reaction
(Table 1, entry 12). Although this sulfonylation was adapted to
air atmosphere, argon atmosphere is more beneficial for this
transformation (Table 1, entry 13). Lastly, screening the amount
of SO2 employed suggested that 2.5 equiv of SO2 gave the
highest yield (Table 1, entries 14 and 15)
Having decided the optimized reaction conditions, we then
began to explore the substrate scope of this direct sulfonylation
of enamides with diazonium salts, and the results are
summarized in Scheme 1. It was found that the electronic
variation (electron-donating or electron-withdrawing) and
steric effects of secondary enamides were both amenable to
this transformation, affording products 3b−3j in good yields
(55−82%). When the R3 group is α-naphthyl and β-naphthyl,
the reactions could proceed smoothly to generate corresponding
products 3k and 3l in around 80% yields. It is worth noting that
enamide bearing a heterocycle was well tolerated under standard
conditions, giving the expected product 3m in 41% yield. More
importantly, alkyl (tert-butyl and adamantyl)-substituted
enamides could also produce the desired products 3n and 3o
in 71% and 69% yields, respectively. In the methods previously
reported,11,12 however, the alkyl substituted enamides were not
adapted for the conditions of direct C(sp2)−H sulfonylation via
insertion of sulfur dioxide. Encouraged by these results, we then
applied our strategy on a wide variety of enamides. Various
benzamide-derived enamides bearing methoxy, phenyl, and
trifluoromethyl groups were able to provide (E)-β-amidovinyl
sulfones 3p−3s in 56−87% yields. Reactions of α-naphthyl and
β-naphthyl derivatives produced compounds 3t and 3u in
excellent yields. Alkenyl- or pyridyl-substituents in the enamide
side chain could afford the corresponding products 3v and 3w in
88% and 94% yields, respectively. Furthermore, alkyl enamide
derivatives were adapted to the system, giving corresponding
products (3x and 3y) in good yields. Moreover, enamides
containing cyclic alkanes (3z and 3aa) were also suitable for the
sulfonylation conditions. When a Cbz protecting group was
introduced in the enamide, corresponding product 3ab was
formed in 78% yield. Encouragingly, more complicated
substrates derived from L-menthol, pregnenolone, and choles-
terol also worked under the standard conditions to give the
desired products 3ac−3ae in moderate yields.
We then investigated the effect of employing different
aryldiazonium salts on this sulfonylation. Benzenediazonium
tetrafluoroborates bearing a methoxy or phenyl group reacted
with 1a smoothly to give target products 3af−3aj in moderate
yields. A substrate bearing a fluorine atom also gave 3ah in 60%
yield. Disubstituted and trisubstituted benzenediazonium salts
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a
Scheme 1. Substrate Scope for Arylsulfonylation of Enamides
a
Reaction conditions: Chamber A, 1 (0.2 mmol, 1.0 equiv), 2 (0.28 mmol, 1.4 equiv), DMA (1.0 mL), at room temperature for 8 h under argon
atmosphere; Chamber B, SOgen (0.51 mmol), 1-methyl-4-vinylbenzene (0.5 mmol), tetradecane (1.0 mL), at 100 °C for 10 min. E/Z > 99:1
b
unless otherwise noted. 1.0 mmol scale.
were also effective substrates, attaining the expected products
3ai and 3aj in the same yield (84%).
We then explored the direct C(sp2)−H sulfonylation with
different tertiary enamides. N-Vinyl lactams with different ring
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Letter
sizes could also be employed as coupling partners to deliver the
corresponding products 3ak and 3al in excellent yields. Acyclic
and phenyl-substituted tertiary enamides were also suitable
substrates for this transformation to afford desired products 3am
and 3ao in excellent yields. In the same way, we investigated the
sulfonylation reaction between N-vinyl lactams with different
aryldiazonium salts. Substrates bearing functional groups such as
phenyl, methoxy, fluorine, and ester were compatible with the
optimized conditions (3ap−3as). The naphthyl group on the
diazonium salt side was also tolerated in this reaction, affording
sulfonylation product 3at in 56% yield. To our delight, the N−
H-unprotected sulfonamide moiety was adapted to this
transformation as well, affording desired product 3au in 91%
yield. Moreover, substrates containing two methyl or three
methoxy groups were well tolerated, attaining desired products
3av and 3aw in outstanding yields.
was detected by LC−MS (Scheme 4a). Second, when a milder
radical scavenger (1,1-diphenylethylene) was applied, the
Scheme 4. Control Experiments and Proposed Mechanism
To further simplify the operation process, we carried out a
one-pot straightforward synthesis of (E)-β-amidovinyl sulfones
directly from anilines. As illustrated in Scheme 2, anilines
Scheme 2. One-Pot Synthesis of (E)-β-Amidovinyl Sulfones
from Anilines
sulfonylation was hampered to some extent (Scheme 4b).
These results suggested that a radical intermediate might be
involved in this transformation.
On the basis of the control experiments above and related
literatures,10−12 a plausible reaction mechanism is proposed
(Scheme 4c). First, complex A is generated by mixing enamide
(1ak), aryldiazonium salt (2a), and SO2.10a After release of one
molecular N2, complex A is transferred to arylsulfonyl radical C
and cationic intermediate B. Then the addition of arylsulfonyl
radical C into intermediate B produces intermediate D which
has an equilibrium with E. Finally, the desired product 3ak is
produced via tautomerization from E.
bearing methyl or phenyl substituents proceeded smoothly to
give the corresponding products 3ak and 3ap in moderate yields.
Likewise, 3,4-dimethylaniline could provide the desired product
3av in moderate yield.
To illustrate synthetic utility of this methodology, β-
acetylamino acrylosulfone (3a), as a typical example, was
applied in subsequent transformations. In the presence of
hydrochloric acid, compound 3a was hydrolyzed to correspond-
ing ketone (5) in 99% yield (Scheme 3, top). Furthermore, in
the presence of 10 mol % Wilkinson’s catalyst, the hydro-
genation of 3p provided β-amido sulfones (6) in85% yield
(Scheme 3, bottom).
To understand reaction mechanism of this transformation,
some preliminary control experiments with radical scavengers
were carried out. Two types of radical scavengers were tested in
the reactions. First, in the presence of 3.0 equiv of TEMPO, the
sulfonylation was completely suppressed and TEMPO adduct 7
In conclusion, a metal- and base-free direct C(sp2)−H
sulfonylation of secondary and tertiary enamides with
aryldiazonium tetrafluoroborates has been developed. This
strategy could tolerate a variety of functional groups and give
corresponding geometrically defined (E)-β-amidovinyl sulfones
in good to excellent yields. Furthermore, one-pot synthesis of β-
amidovinyl sulfones directly from anilines has also been realized.
Preliminary mechanistic studies suggest that a radical process
may be involved in the reaction.
ASSOCIATED CONTENT
* Supporting Information
Scheme 3. Transformations of β-Acetylamino Acrylosulfones
■
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01419.
Experimental procedures, characterization data, and
copies of 1H, 13C and 19F NMR spectra (PDF)
Accession Codes
CCDC 2045557 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 Cambridge
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Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Xuemei Zhang − Department of Dermatology, State Key
Laboratory of Biotherapy and Cancer Center, National
Clinical Research Center for Geriatrics, West China Hospital,
and West China School of Pharmacy, Sichuan University,
Chengdu 610041, P.R. China; Email: xuemeizhang@
scu.edu.cn
Zhong Lian − Department of Dermatology, State Key
Laboratory of Biotherapy and Cancer Center, National
Clinical Research Center for Geriatrics, West China Hospital,
and West China School of Pharmacy, Sichuan University,
Chengdu 610041, P.R. China; orcid.org/0000-0003-
2533-3066; Email: lianzhong@scu.edu.cn
Authors
Lei Chen − Department of Dermatology, State Key Laboratory
of Biotherapy and Cancer Center, National Clinical Research
Center for Geriatrics, West China Hospital, and West China
School of Pharmacy, Sichuan University, Chengdu 610041,
P.R. China
Mi Zhou − Department of Dermatology, State Key Laboratory
of Biotherapy and Cancer Center, National Clinical Research
Center for Geriatrics, West China Hospital, and West China
School of Pharmacy, Sichuan University, Chengdu 610041,
P.R. China
Lin Shen − Department of Dermatology, State Key Laboratory
of Biotherapy and Cancer Center, National Clinical Research
Center for Geriatrics, West China Hospital, and West China
School of Pharmacy, Sichuan University, Chengdu 610041,
P.R. China
Xiaochun He − Department of Dermatology, State Key
Laboratory of Biotherapy and Cancer Center, National
Clinical Research Center for Geriatrics, West China Hospital,
and West China School of Pharmacy, Sichuan University,
Chengdu 610041, P.R. China
Xiong Li − Department of Dermatology, State Key Laboratory
of Biotherapy and Cancer Center, National Clinical Research
Center for Geriatrics, West China Hospital, and West China
School of Pharmacy, Sichuan University, Chengdu 610041,
P.R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01419
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is supported by the National Natural Science
Foundation of China (21901168), “1000-Youth Talents Plan”,
Sichuan Science and Technology Program (2021YJ0395), and
“1.3.5 project for disciplines of excellence, West China Hospital,
Sichuan University”.
(11) Zhu, T.-H.; Zhang, X.-C.; Zhao, K.; Loh, T.-P. Cu(OTf)2-
Mediated C(sp2)−H Arylsulfonylation of Enamides via the Insertion of
Sulfur Dioxide. Org. Chem. Front. 2019, 6, 94−98.
(12) Zhu, T.-H.; Zhang, X.-C.; Cui, X.-L.; Zhang, Z.-Y.; Jiang, H.; Sun,
S.-S.; Zhao, L.-L.; Zhao, K.; Loh, T.-P. Direct C(sp2)−H
Arylsulfonylation of Enamides via Iridium(III)-Catalyzed Insertion of
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