Visible-Light-Promoted Cross-Coupling Reactions of 4-Alkyl-1,4-dihydropyridines with Thiosulfonate or Selenium Sulfonate: A Unified Approach to Sulfides, Selenides, and Sulfoxides

Article abstract of DOI:10.1021/acs.orglett.0c01776

In this paper, a visible-light-promoted cross-coupling of 4-alkyl-1,4-dihydropyridines with thio-/selenium sulfonates under transition-metal-free conditions is described. This strategy features easily available substrates, mild reaction conditions, high yields, and high chemoselectivity. A novel synthetic route for the construction of a sulfide or selenide Csp3-S or Csp3-Se bond under transition-metal-free conditions without an additive oxidant or base is developed. This method is well extended to the synthesis of a class of thiolated or selenylated glycosides that has not been explored before. Sulfoxides were also successfully chemoselectively observed via a facile variation of the atmosphere under photocatalyzed conditions.

Full text of DOI:10.1021/acs.orglett.0c01776

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Letter
Visible-Light-Promoted Cross-Coupling Reactions of 4‑Alkyl-1,4-
dihydropyridines with Thiosulfonate or Selenium Sulfonate: A
Unified Approach to Sulfides, Selenides, and Sulfoxides
Jian Li, Xin-Er Yang, Shan-Le Wang, Long-Long Zhang, Xiao-Zhou Zhou, Shun-Yi Wang,*
and Shun-Jun Ji*
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ABSTRACT: In this paper, a visible-light-promoted cross-
coupling of 4-alkyl-1,4-dihydropyridines with thio-/selenium
sulfonates under transition-metal-free conditions is described.
This strategy features easily available substrates, mild reaction
conditions, high yields, and high chemoselectivity. A novel
synthetic route for the construction of a sulfide or selenide Csp3
−
S or Csp3−Se bond under transition-metal-free conditions without
an additive oxidant or base is developed. This method is well
extended to the synthesis of a class of thiolated or selenylated
glycosides that has not been explored before. Sulfoxides were also successfully chemoselectively observed via a facile variation of the
atmosphere under photocatalyzed conditions.
rganosulfur compounds are widely used in chemical
Obiology, medicinal chemistry, and pharmaceuticals. The
development of new approaches for the construction of a C−S
bond has attracted considerable attention.1 The traditional
method for the construction of C−S bond is the substitution
reaction of organic halides and RSH (or RSSR).2 However,
these reactions have several drawbacks such as the unpleasant
odor of sulfuration reagents, alkaline reaction conditions, high
temperature, and expensive transition-metal catalysts. Devel-
oping efficient and mild methodologies for the construction of
a C−S bond continues to be highly desirable. As a clean,
efficient, and accessible strategy, photoredox catalysis has been
recognized as a useful tool for the direct coupling of two
electrophiles under mild conditions during the past decade.3
Recently, the Fu and Miyake groups achieved the representa-
tive visible-light photoredox construction of Csp2−S bonds
(Figure 1, a).4 While the visible-light mediated photoredox
reactions to construct Csp2−S bonds have been well developed,
the construction of Csp3−S bonds in this field are less reported.
Wang, Xu, and Fu’s groups successively reported the Csp3−S
construction reaction under visible-light conditions. However,
these reactions often require equivalent amounts of base or
oxidant with limited substrates (Figure 1, b).5 Therefore, it is
still very challenging to develop novel strategies to construct
Csp3−S bonds under visible-light conditions.
Figure 1. Visible-light photoredox construction of C−S bonds.
Cl, Br, I)10 bonds. In addition, Melchiorre’s group recently
reported a visible-light-mediated strategy that successfully
Received: May 26, 2020
4-Alkyl-1,4-dihydropyridines (DHPs) can be readily pre-
pared from aldehydes in one step with high functionalization
levels. Since the pioneering work of Nishibayashi,6 C−C bond
cleavage of DHPs has emerged as an effective strategy to
8
construct Csp3−Csp2,7 Csp3−Csp Csp3−N,9 and Csp3−X (X =
https://dx.doi.org/10.1021/acs.orglett.0c01776
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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couples symmetrical anhydrides and DHPs to afford
enantioenriched α-substituted ketones under mild condi-
tions.11 To the best of our knowledge, in such an active
field, the use of DHPs to construct Csp3−S or Csp3−Se bonds
has not been achieved. Very recently, our group has achieved a
nickel-catalyzed reductive thiolation and selenylation of
unactivated alkyl bromides12 and a nickel-catalyzed defluor-
inative reductive cross-coupling of gem-difluoroalkenes with
thio-/selenosulfonates.13 As a novel sulfuration reagent,
benzenesulfonothioate14 has some advantages compared to
other sulfuration agents (thiols, disulfides, sulfenyl halides,
sulfonium salts, N-thioimide quinone mono O,S-acetals, p-
toluenesulfonyl hydrazide S-acetals, arylsulfonyl chlorides,
sulfinic acids, and p-tolylsulfinate)15 such as being stable to
air, without unpleasant odors, and easy to prepare. Based on
our previous investigation of the thio-/selenosulfonates, we
wonder whether thio-/selenosulfonates might trap the radicals
generated by DHPs. If so, construction of Csp3−S bonds would
be accessible under photocatalyzed conditions. Herein, we
reported a visible-light-promoted cross-coupling of 4-alkyl-1,4-
dihydropyridines with thio-/selenosulfonates (Figure 1, c).
This protocol provided a novel synthetic route for the
construction of Csp3−S bonds or Csp3−Se bonds under
metal-free conditions. No metal, alkali, or oxidant involvement
is required compared to previous reports.
entries 4−6). Next, we screened reaction solvents. When DMF
was applied to the reaction, 3 was observed in 53% yield
(Table 1, entry 7). It should be noted that the reaction of 1a
and 2a in DCE gave 3 in 85% yield (Table 1, entry 8). After
carefully studying the reaction concentration, it was found that
2 mL of DCE was the ideal amount for this reaction and the
yield of 3 was increased to 99% (Table 1, entries 9 and 10).
Notably, by only altering the atmosphere to air, 1-(cyclo-
hexylsulfinyl)-4-methylbenzene 3′ was obtained in 95%
isolated yield (Table 1, entry 11).
With the optimized conditions in hand, we evaluated the
synthetic potential of this photomediated reaction (Table 1).
First, we focused our attention on radical precursors (Scheme
1). Importantly, secondary alkyl radicals such as cyclohexyl
Scheme 1. Substrate Scope of Various DHPs,
a b
,
Thiosulfonates, and Selenosulfonates
Initially, we studied the model reaction of cyclohexyl-DHP
(1a) with S-(p-tolyl) benzenesulfonothioate (2a) in MeCN
catalyzed by fac-Ir(ppy)3 under irradiation of 40 W blue LED
light. To our delight, it was found that the desired
cyclohexyl(p-tolyl)sulfane 3 was obtained in 77% isolated
yield (Table 1, entry 1). No desired product was detected in
a
Table 1. Screening of Reaction Conditions
b
yield (%)
entry
P.C.
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
[Ir(dtbbpy)(ppy)2][PF6]
EosinY
4-CzIPN
4-CzIPN
4-CzIPN
4-CzIPN
solvent
3
3′
0
0
0
0
0
0
0
0
1
2
3
MeCN (1)
MeCN (1)
MeCN (1)
MeCN (1)
MeCN (1)
MeCN (1)
DMF(1)
DCE (1)
DCE (1.5)
DCE (2)
77
0
0
c
4
5
6
7
8
9
64
76
81
53
85
91
99
0
a
Standard conditions: 1 (0.6 mmol), 2a (0.2 mmol), 4-CzIPN (3 mol
b
%), DCE (4 mL), 40 W LED, rt under N2 for 24 h. Isolated yields.
0
0
95
radical, cyclopentyl radical, and isopropyl radical are tolerated
well in this transformation (3-5). A pyran-derived DHP could
likewise be used, and the resulting sulfide was isolated in 88%
yield (6). Diethyl 4-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-
yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate was
also tolerated under this transformation (7). More interest-
ingly, alkyl radicals bearing distal alkenes were compatible with
such mild reaction conditions (8). α-Nitrogen radicals were
also tested, and a series of N,S-acetal derivatives were furnished
in excellent yields (9−12). Similar results were achieved for
primary alkyl radical (13). α-Oxygen radicals could also be
employed, which brought about the introduction of dioxolane
motif (14).
10
11
4-CzIPN
4-CzIPN
d
DCE (2)
a
Reaction conditions: diethyl 4-cyclohexyl-2,6-dimethyl-1,4-dihydro-
pyridine-3,5-dicarboxylate (1a, 0.30 mmol), S-(p-tolyl) benzenesulfo-
nothioate (2a, 0.10 mmol), P.C. (3 mol %), in solvent at room
temperature for 24 h under N2, 40 W LED. Yields were determined
b
c
d
by GC. In the dark. Under air.
the absence of photocatalyst or in the dark (Table 1, entries 2
and 3). These results indicate that both photocatalyst and
visible-light irradiation are absolute requirements for this
reaction. We further examined the effect of other photo-
catalysts ([Ir(dtbbpy)(ppy)2][PF6], EosinY and 4-CzIPN). 4-
CzIPN ($6.01/g) is the best choice for this reaction (Table 1,
Next, we turned our attention to investigate whether other
sulfonothioates can be employed as radical receptors using
B
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diethyl 4-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)-2,6-di-
methyl-1,4-dihydropyridine-3,5-dicarboxylate as a radical pre-
cursor (Scheme 1). For S-aryl benzenesulfonothioates, both
electron-donating (OMe) and electron-withdrawing (NO2)
substituents were well tolerated in the meta and para positions
so that products 15 and 16 could be isolated in 78% and 53%
yields. When S-(Het) benzenesulfonothioate was used for the
reaction, the desired product 17 could be obtained in 53%
yield. Subsequently, a series of S-alkyl benzenesulfonothioates
were investigated, and the corresponding alkyl−alkyl sulfides
18−23 could be obtained under standard conditions. It should
be noted that the use of DHPs allowed a room temperature set
of reaction conditions, in contrast with previous reports that
generally require 60−100 °C.12,13 It is worth mentioning that
substituents bearing functionalized groups such as chlorine,
indole, and thiophene could also be accommodated under the
mild reaction conditions to afford the desired products 24−26
in moderate to good yields. Furthermore, the reactions of
various Se- primary aryl benzenesulfonoselenoates could be
successfully coupled with DHPs (adducts 27−28). Se-
Secondary alkyl benzenesulfonoselenoates were also inves-
tigated in the reactions with DHPs, and we could obtain the
cyclobutyl and cyclohexyl (29−30) selenides in high yields.
Glycosyl thioacetals, as versatile glycosyl donors, have
emerged as a class of important fragments because of their
numerous synthetic applications.16 Our protocol provides a
simple strategy to directly prepare a range of glycosyl
thioacetals from the corresponding DHPs under the mild
conditions (Scheme 2). Upon treating furanose DHP with S-
performed equally well (34). The furanose DHPs with ortho-
and para- groups on the aromatic rings were tested, and all of
them reacted smoothly with S-aryl benzenesulfonothioates,
yielding the desired products with high efficiency (35 and 36).
Moreover, pyranose DHP could work well in the reactions
with S-(p-tolyl) benzenesulfonothioate. We could obtain the
corresponding product 37 in 45% yield with excellent 18:1 dr
selectivity.
On the other hand, by altering the atmosphere to air, a range
of sulfoxides were efficiently obtained in high isolated yields
(38−40) (Scheme 3). Moreover, electronic effects of
substituents on both the DHPs and S-aryl benzenesulfono-
thioates did not affect the efficiency (41 and 42).
a b
,
Scheme 3. Scope of Thiosulfonate
a
Standard conditions: 1c (0.6 mmol), 2 (0.2 mmol), 4-CzIPN (3 mol
b
%), DCE (4 mL), 40 W LED, rt under air for 24 h. Isolated yields.
a−c
Scheme 2. Scope with Respect to Monosaccharides
To evaluate the application of this visible-light-promoted
cross-coupling reaction, the gram-scale reaction of 1a (10
mmol) with 2a (5 mmol) in the presence of only 1 mol % of 4-
CzIPN was investigated (as shown in Scheme 4, a). The
Scheme 4. Gram-Scale Reaction and Control Experiments
a
Standard conditions: 1 (0.4 mmol), 2 (0.2 mmol), 4-CzIPN (3 mol
b
%), DCE (4 mL), 40 W LED, rt under N2 for 24 h. Isolated yields
c
1
The dr selectivity was determined by H NMR spectra.
aryl benzenesulfonothioates under the standard reaction
conditions, the nontraditional C-sulfenylated glycoside was
isolated in 75% yield with excellent diastereoselectivity (31). S-
Benzyl benzenesulfonothioates and Se-aryl benzenesulfonose-
lenoates are also amenable to this visible-light-promoted
reaction (32−33). Less sterically constrainted furanose DHP
C
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desired product 3 could also be obtained in 98% yield with
lower catalyst loading. Subsequently, to preliminarily probe
into the mechanism of the reaction, several control experi-
ments were conducted (Scheme 4, b). When 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) as radical scavenger
was added in this reaction system, a trace amount of adduct 3
was detected (Scheme 4, b, I), which revealed that a radical
mechanism was involved in this transformation. The use of
PhSSPh in place of 2a resulted in only <5% yield of product 3.
This result indicates that PhSSPh was not the intermediate of
this reaction (Scheme 4, b, II). Recenty, Loh’s group reported
a water-catalyzed reaction of sulfonic acid and allyl alcohol.17
Encouraged by these interesting results, we added 1,3-
diphenyl-2-enol and 1 mL of water to the reaction system
directly without separation and then reacted the system for an
additional 24 h. The formation of cyclohexyl(p-tolyl)sulfane
(3) and (3-(phenylsulfonyl)prop-1-ene-1,3-diyl)dibenzene
(43) was observed, indicating the formation of benzenesulfinic
acid (Scheme 4, b, III). Addionally, through this novel strategy,
we can improve the atomic economy of this strategy.
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01776.
Detailed experimental procedures (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Shun-Yi Wang − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science and Collaborative Innovation Center of
Suzhou Nano Science and Technology, Soochow University,
Suzhou 215123, China; orcid.org/0000-0002-8985-8753;
Email: shunyi@suda.edu.cn
Shun-Jun Ji − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science and Collaborative Innovation Center of
Suzhou Nano Science and Technology, Soochow University,
Suzhou 215123, China; orcid.org/0000-0002-4299-3528;
Email: shunjun@suda.edu.cn
On the basis of the above results and literature reports,7−10
a
plausible reaction mechanism was proposed in Scheme 5. The
Scheme 5. Proposed Mechanism
Authors
Jian Li − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science and Collaborative Innovation Center of
Suzhou Nano Science and Technology, Soochow University,
Suzhou 215123, China
Xin-Er Yang − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science and Collaborative Innovation Center of
Suzhou Nano Science and Technology, Soochow University,
Suzhou 215123, China
Shan-Le Wang − Key Laboratory of Organic Synthesis of
Jiangsu Province, College of Chemistry, Chemical Engineering
and Materials Science and Collaborative Innovation Center of
Suzhou Nano Science and Technology, Soochow University,
Suzhou 215123, China
Long-Long Zhang − Key Laboratory of Organic Synthesis of
Jiangsu Province, College of Chemistry, Chemical Engineering
and Materials Science and Collaborative Innovation Center of
Suzhou Nano Science and Technology, Soochow University,
Suzhou 215123, China
Xiao-Zhou Zhou − Suzhou High School of Jiangsu Province,
Suzhou 215000, China
photocatalyst 4-CzIPN assists the single electron transfer of the
DHPs to generate an alkyl radical and pyridine A.
Subsequently, alkyl radical reacts with sulfonothioates to afford
a sulfone radical intermediate.18 Then reductive SET of sulfone
radical furnishes benzosulfinic acid anion. Subsequent
protonation of benzosulfinic acid anion affords the benzo-
sulfinic acid. On the other hand, 1O2 can be generated from an
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01776
energy-transfer process19 between O2 and 4-CzIPN*, which
3
Notes
The authors declare no competing financial interest.
can oxidize the sulfide to the corresponding sulfoxide.
In summary, we have developed a visible-light-promoted
cross-coupling of 4-alkyl-1,4-dihydropyridines with thio-/
selenium sulfonates. This strategy realized the construction
of a Csp3−S bond or Csp3−Se bond under metal-free, oxidant-
free, and base-free conditions, enabling access to thiolated or
selenylated glycosides that has been underexplored until now.
Moreover, sulfoxides were successfully tuned via a facile
variation of the atmosphere under photocatalyzed conditions
without any additional oxidant.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Natural Science
Foundation of China (21971174, 21772137, 21542015, and
21672157), PAPD, the project of scientific and technologic
infrastructure of Suzhou (SZS201708), and the Major Basic
Research Project of the Natural Science Foundation of the
Jiangsu Higher Education Institutions (16KJA150002),
Soochow University.
D
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(5) (a) Zhu, X.; Xie, X.; Li, P.; Guo, J.; Wang, L. Visible-Light-
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