Copper-Catalyzed Regioselective Intramolecular Electrophilic Sulfenoamination via Lewis Acid Activation of Disulfides under Aerobic Conditions

Article abstract of DOI:10.1021/acs.orglett.8b01803

The activation of disulfides by Cu(II) salts has been realized, which triggers a highly efficient electrophilic sulfenoamination of alkenes under aerobic conditions. Various sulfenyl N-heterocycles and their Selena counterparts were produced regioselectiv

Full text of DOI:10.1021/acs.orglett.8b01803

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper-Catalyzed Regioselective Intramolecular Electrophilic
Sulfenoamination via Lewis Acid Activation of Disulfides under
Aerobic Conditions
Yang Ni, Honghua Zuo, Yan Li, Yuzhou Wu, and Fangrui Zhong*
Hubei Key Laboratory of Bioinorganic Chemistry & Materia Medica, School of Chemistry and Chemical Engineering, Huazhong
University of Science and Technology (HUST), 1037 Luoyu Road, Wuhan 430074, China
S
* Supporting Information
ABSTRACT: The activation of disulfides by Cu(II) salts has
been realized, which triggers a highly efficient electrophilic
sulfenoamination of alkenes under aerobic conditions. Various
sulfenyl N-heterocycles and their Selena counterparts were
produced regioselectively, with no competing disulfidation
products detected. Mechanistic studies suggest a profound
influence of the counterions on the Lewis acidic copper
center, and the important roles of oxygen and DMSO as co-
oxidants for these cyclization processes.
rganosulfur compounds constitute an essential class of
mark et al. have described that addition of arylthiophthalimides
Osubstances for life, as manifested in their frequent generates thiiranium ions and further leads to various ring
systems upon capture by certain pendant nucleophiles (Scheme
1a).6a−e Such intermediates are conventionally accessed from
occurrence in nature and critical biochemical functions as
amino acids, vitamins, and cofactors (e.g., cysteine, biotin,
glutathione, etc.).1 The unique biological properties of these
molecules have inspired the innovation of a number of important
pharmaceutical agents such as antibiotic penicillin. Importantly,
a nitrogen-containing heterocycle motif is frequently found
adjacent to the sulfur unit in these molecular frameworks (Figure
1).2
Scheme 1. Strategies for Intramolecular Electrophilic Alkene
Sulfenoamination
Figure 1. Selected examples of bioactive sulfenylated nitrogen-
containing heterocycles.
In this context, synthetic methods allowing straightforward
assembly of sulfenylated N-heterocycles are in high demand.
Oxidativealkenesulfenofunctionalizationhasbeenestablishedas
a practical tool for the simultaneous introduction of sulfur and
other functionalities;3 however, direct sulfenoaminations are still
rare. The majority of the known studies have focused on
intermolecular acetamidosulfenylation via a Ritter-type reaction
using stoichiometric acids or oxidants.4 While other nitrogen
nucleophiles have also been sporadically documented,5 these
protocols could not be easily amended in intramolecular settings
for the preparation of sulfenylated N-heterocycles. In recent
years, electrophilic activation of alkenes has been utilized to
construct sulfenylated cyclic frameworks.6 For instance, Den-
reactive, but unstable sulfenyl halides,7 thus stimulating
researchers to seek alternative sulfur precursors that include
ease of handling.8 As such, the Li group recently disclosed an
elegantalkenesulfenoaminationreactionwithsulfenylfluoridein
situ generated from thiobenzimidazoles and selectfluor (Scheme
1b).8e Despite advantages in terms of stability, availability, and
ease of operation, drawbacks associated with these precursors,
Received: June 9, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01803
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
such as limited structural diversity and necessity of additional
oxidants, restrict the practical applications of these protocols.
Disulfides are attractive sulfenylating reagents featuring
modulable stability, ready availability, and biocompatibility.9
The polarizability of the S−S bond renders it susceptible to
scission by strong nucleophiles, as seen in thiol−disulfide
exchange in biological protein contexts.10 However, this
functional group is not sufficiently polar to directly undergo
electrophilic addition to alkenes, which requires activation by
stoichiometric oxidants (e.g., Pb(OAc)4, Mn(OAc)3).11 Funda-
mentally, coordination of Lewis acid to sulfur would enhance the
polarization of disulfide bonds and facilitate electrophilic alkene
sulfenoamination with nitrogen nucleophiles. Such a seemingly
simple strategy is, however, hampered by the competitive
disulfidation process and limited turnover of the metal catalyst
inhibited by sulfur and other heteroatoms in the reaction
mixture.12 On the basis of our recent report on Lewis acid
catalyzed synthesis of indolines via an oxidative [3 + 2]
cyclization,13 we reasoned that an appropriate selection of
metal catalysts and pendant nitrogen nucleophiles with weak
coordination properties might minimize poisoning of the Lewis
acid center. As a result, intramolecular sulfenoamination might
become possible that allows efficient assembly of valuable
sulfenylated N-heterocycles (Scheme 1c).
be highly effective, resulting in the isolation of indoline 3a in 63%
yield. The inability of Cu(OTf)2 and CuCl2 to mediate this
process indicates the profound influence of the counterions
(entries 8−10). CuBr and FeBr3 were also competent catalysts,
albeit less effective (entries 11−12). It is noteworthy that no
disulfidation adducts were detected; employing excess disulfide
2a was beneficial to reach complete consumption of 1a. Solvent
screening was subsequently performed, and DMSO was
identified as being superior to other mediums, deliveringproduct
3a in 89% yield.
Having identified the optimal reaction conditions, we
proceeded to explore the generality of this sulfenocyclization
reaction (Scheme 2). Pleasingly, a wide range of diarylsulfides
Scheme 2. Scope of CuBr2-Catalyzed Intramolecular
Sulfenoamination of Alkenylaniline 1 with Disulfide 2
a b
,
Our study began with the search for a suitable Lewis acid
catalyst for the model cyclization reaction of 2-alkenylaniline 1a
with disulfide 2a. Pleasingly, the performance of commonly used
Lewis acids, including Zn(OTf)2, Sc(OTf)3, AlCl3, InCl3,
AgOTf, and BF3·Et2O, indeed proved our hypothesis (Table 1,
entries1−5). Asubstantialamountofexocyclizedproduct3awas
regiospecifically produced (23%) with 10 mol % of InCl3 at 120
°C under air. Notably, no reaction occurred in the absence of a
catalyst (entry 7). Owing to the remarkable properties of copper
salts as Lewis acid catalysts in organic synthesis,14 various Cu(I)
and Cu(II) compounds were also evaluated. CuBr2 turned out to
a
Table 1. Optimization of the Sulfenoamination Reaction
b
entry
catalyst
solvent
toluene
yield (%)
1
2
3
4
5
6
7
8
Zn(OTf)2
Sc(OTf)3
AlCl3
<10
<10
12
23
11
<10
NR
0
63
trace
41
38
59
85
75
89
81
a
b
For reactions conditions, see Table 1, entry 16. Isolated yield.
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
P-xylene
DMF
with different electronic and steric substitution patterns could be
employed, and good to high yields (63−86%) were recorded for
the respective adducts (3b−o). Aliphatic disulfides were
tolerated as well, as seen in the effective production of indolines
3p−r bearing a cyclohexyl, n-butyl, or benzyl group in equally
good yields (64−71%). To the best of our knowledge, this case
represents the only method available for the synthesis of
alkylsulfenyl N-heterocycles in a single step. Apart from these,
substrates 1 with different substituents on their aromatic rings
were also readily processed to furnish the desired adducts 3s−v
(60−82%). Further efforts were made on the synthesis of N-
heterocycles other than indolines. To our delight, tetrahydro-
quinoline 3w was easily accessed (71%) as well by the same
protocol from an alkenylaniline with a longer tether. Reactions
with aliphatic sulfonamides also proceeded smoothly, leading to
the formation of sulfenylated pyrrolines and piperidines 3x−z
with equal efficiency. Importantly, in all the cases described
above, N-heterocycles were produced in a regiospecific fashion.
InCl3
AgOTf
BF3·Et2O
−
Cu(OTf)2
CuBr2
CuCl2
CuBr
9
10
11
12
13
14
15
16
17
FeBr3
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
DCE
DMSO
1,4-dioxane
a
Reactions were performed with 1a (0.2 mmol), 2a (0.2 mmol), and
catalyst (10 mol %) in solvent (2.5 mL) at 120 °C for 20 h in a sealed
tube under air. Isolated yield.
b
B
DOI: 10.1021/acs.orglett.8b01803
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
A scale-up preparation of compound 3b (1.26 g, 80%) has been
successfully performed, and we demonstrated the practicality of
this synthetic method.
Nevertheless, given that a 54% yield was obtained based on 0.5
equiv of 2a (entry 7), it seems safe to conclude that both sulfur
atoms of 2a are incorporated into product 3b in an atom-
economic fashion under aerobic conditions. On the other hand,
despite certain degrees of inhibition with BHT as an additive, the
isolated yield of 3b was, in reality, independent of the quantity of
this radical scavenger. These observations suggest that a radical
mechanism is not likely the case in the present catalytic system.
Collectively, we propose a plausible reaction mechanism
(Scheme 4). Complexation of copper with a sulfur atom
The success of the above-mentioned sulfenoamination
reactions encouraged us to attempt an analogous synthesis of
seleno-N-heterocycles owing to the strong bioactivity profiles of
this class of compounds.15 Gratifyingly, a quick examination of
cyclization with diselenide 4revealed that the desired selenylated
products 5, including indoline, tetrahydroquinoline, pyrroline,
and piperidine derivatives,16 could be efficiently prepared in
higher yields (73−93%) under identical reaction conditions in
comparison to their thia-counterparts (Scheme 3).
Scheme 4. Plausible Reaction Mechanism
a b
,
Scheme 3. Formation of Selenylated N-Heterocycles
polarizes the S−S bond of 2a and triggers an electrophilic
addition to the olefin moiety of 1b, and the resulting thiiranium
ion undergoes a regioselective ring-opening transformation to
afford product 3b and thiophenol. The latter is oxidized into
disulfide 2a to re-enter the catalytic cycle and is associated with
partial overoxidation into the side product sulfinic acid. The
thiophilic nature of copper and profound influence of the
counterions on its Lewis acidity might account for the superior
catalytic performance of CuBr2 over others,14 as showcased in
Table 1.19
The removal of the tosyl group was readily accomplished by
treating 3b with Red-Al, and indoline 6 was obtained in 68%
yield. The functionalized N-heterocycles produced herein are
not only of potential biological interest but also synthetically
useful (Scheme 5). For instance, compound 3b could be
a
b
For reactions conditions, see Table 1, entry 16. Isolated yield.
To gain more insight into the reaction mechanism, additional
controlled experiments were performed (Table 2). Strictly
a
Table 2. Controlled Experiments
Scheme 5. Synthetic Manipulations Using Adduct 3b as a
Precursor
b
entry
changes made to standard conditions
none
yield (%)
1
2
3
4
5
6
7
8
9
88
69
59
16
80
15
54
44
42
toluene was used instead of DMSO
in degassed DMSO under N2
in degassed toluene under N2
thiophenol was used instead of 2a
thiophenol was used instead of 2a in toluene
0.5 equiv of 2a was used
selectively oxidized into sulfoxide 7 (with separable 1:1
diastereoisomers) or sulfone 8 in excellent yields under specific
conditions. Moreover, upon treatment with DDQ in heated
dichloroethane, adduct 3b underwent a photochemical
desulfenylative aromatization to give indole 9 (79%).20 As
such, our method provides a highly practical two-step conversion
of alkenylaniline derivatives into indole-2-carboxaldehydes, a
class of versatile synthon in organic chemistry.
1.5 equiv of BHT was added
5.0 equiv of BHT was added
a
Reactions were performed with 1b (0.2 mmol), 2a (0.2 mmol), and
catalyst (10 mol %) in DMSO (2.5 mL) at 120 °C for 20 h in a sealed
tube under air. Isolated yield.
b
In summary, we have developed a highly efficient copper-
catalyzed intramolecular sulfenoamination reaction of alkenes.
Notably, this is the first time that Lewis acid activation of
disulfides has been realized successfully for in situ generation of
electrophilic thiiranium intermediates for aminofunctionaliza-
tion of alkenes. Diaryl and dialkyl sulfides as well as aryl and alkyl
sulfonamides are compatible reaction partners in this protocol,
allowing access to a broad range of synthetically and biologically
valuable sulfenyl N-heterocycles. Detailed mechanistic inves-
tigations and attempts to apply this novel Lewis acid catalyzed
deoxygenated reaction conditions resulted in substantially
decreased reactivity in both DMSO and toluene (entries 3−4).
However, the former still afforded 3b in 59% yield, suggesting an
oxidationprocessinvolvingbothmolecularoxygenandDMSOis
inoperation.17 Thisspeculation wasfurtherevidencedby the fact
that cyclization with thiophenol as a sulfur precursor also yielded
product 3b, and a higher yield was again recorded with DMSO
than toluene (entries 5−6). The necessity of using excess
disulfide might be attributable tothe generation of sulfinicacid.18
C
DOI: 10.1021/acs.orglett.8b01803
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01803.
■
S
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Experimental procedures, analytical data for all new
compounds, NMR spectra of the products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chemzfr@hust.edu.cn.
ORCID
(9) (a) Hunter, R.; Caira, M.; Stellenboom, N. J. Org. Chem. 2006, 71,
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8268. (b) Gongora-Benítez, M.; Tulla-Puche, J.; Albericio, F. Chem. Rev.
2014, 114, 901. (c) Maurya, C. K.; Mazumder, A.; Kumar, A.; Gupta, P.
K. Synlett 2016, 27, 409.
Fangrui Zhong: 0000-0003-2150-370X
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21602067) and Huazhong University of Science and Technol-
ogy (2016YXMS183) for financial support. We are also grateful
to the Analytical and Testing Centre of HUST, Analytical and
Testing Centre of the School of Chemistry and Chemical
Engineering (HUST) for access to their facilities.
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DOI: 10.1021/acs.orglett.8b01803
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