Syntheses of sulfides and selenides through direct oxidative functionalization of C(sp3)-H bond

Article abstract of DOI:10.1021/ol5011449

A new protocol for C-S and C-Se bond formation by the direct functionalization of the C(sp³)-H bond of alkanes under metal-free conditions was developed. Using ^tBuOO^tBu as the oxidant, the reaction of disulfides or diselenides with alkanes gave sulfides or selenides in moderate to good yields. The method was very simple and atom-economical.

Full text of DOI:10.1021/ol5011449

Letter
pubs.acs.org/OrgLett
Syntheses of Sulfides and Selenides through Direct Oxidative
Functionalization of C(sp3)−H Bond
Bingnan Du,† Bo Jin,† and Peipei Sun*,†,‡
†Jiangsu Key Laboratory of Biofunctional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing
210097, China
‡Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Nanjing 210023, China
S
* Supporting Information
ABSTRACT: A new protocol for C−S and C−Se bond formation by the
direct functionalization of the C(sp3)−H bond of alkanes under metal-free
conditions was developed. Using tBuOOtBu as the oxidant, the reaction of
disulfides or diselenides with alkanes gave sulfides or selenides in
moderate to good yields. The method was very simple and atom-
economical.
Scheme 1. Oxidative Functionalization of C(sp3)−H Bonds
he functionalization of C(sp3)−H bonds has been an
Textremely remarkable project in recent years because of
the atom-economics and the environmental sustainability.1
Direct functionalization of saturated C−H bonds to form C−C
or C−heteroatom bonds via metal-catalyzed atom/group
transfer reactions is becoming an appealing methodology in
modern organic synthesis.2 One of the most attractive
approaches on the functionalization of the C(sp3)−H bond is
the activation of purely isolated and unactivated C(sp3)−H
bonds of alkanes under the oxidation conditions.3 By this
strategy, vast lowcost feedstock of hydrocarbons could be
turned into synthetically useful compounds. Several oxidative
cross-couplings of simple alkanes with C(sp2) of arenes,
heteroarenes, or olefins by the C(sp3)−H bond activation to
form the C−C bond were reported recently.4 Moreover, a
series of encouraging progresses on oxidative functionalization
of C(sp3)−H bonds of simple alkanes to form C(sp3)−
heteroatom bonds also have been achieved in recent years. For
example, the peroxide-mediated amination with nitroarenes,5
Cu-catalyzed C−H amination/amidation with aromatic
amines/amides,6 Fe-catalyzed C−H amination with hypervalent
iodides,7 direct amination of alkanes by hypervalent bromides,8
direct azidation of alkanes by azidobenziodoxoles,9 Fe-catalyzed
C−H hydroxylation of alkanes,10 Cu-catalyzed C−H ether-
of Simple Alkanes
of sulfides is an important and challenging task because of the
significance of such compounds. In particular, the reactions
under metal-free conditions are desired in the pharmaceutical
synthesis. We report here the straightforward, mild, and
convenient protocol for the syntheses of sulfides and selenides
through the direct oxidative cross-couplings of simple alkanes
with disulfides or diselenides in the absence of a transition
metal.
We began our investigations by using diphenyl disulfide 1a
and cyclohexane 2a as the substrates to optimize the reaction
conditions (Table 1). The copper salt was initially employed as
the catalyst for this oxidative coupling reaction. We were
pleased to find that in argon atmosphere and using 2.0 equiv of
tert-butyl peroxide (TBP) as the oxidant, this reaction provided
the desired product 3aa in the yields of 46−71% after 18 h at
100 °C in the presence of 10 mol % various copper salts
(entries 1−6). We also noticed that without any catalyst, the
reaction still gave a 55% yield (entry 7). So we decided to carry
out the reaction under metal-free conditions. To our delight,
when the reaction temperature was increased to 120 °C, a yield
of 81% was obtained only in the presence of 2.0 equiv of TBP
(entry 8). Further increasing the amount of oxidant TBP to 3.0
equiv brought a yield of 88% (entry 9). When other oxidants,
such as dicumyl peroxide (DCP), tert-butyl hydroperoxide
(TBHP) and benzoyl peroxide (BPO) were used instead of
11
t
ification with BuOOtBu, etc. Until now, the oxidative
functionalization of C(sp3)−H bonds of simple alkanes mainly
focused on the formation of C−C, C−N, and C−O bonds
(Scheme 1). Thus, it would be highly desirable if this strategy
could be expanded to the construction of various C(sp3)−
heteroatom bonds.
The importance of organosulfur compounds in general
organic synthesis, in the pharmaceutical industry, in food
chemistry, as well as in material science is well-known.12 The
most striking development on the construction of the C−S
bond is transition metal-catalyzed cross-coupling reactions in
recent years except the traditional methods.13 To develop new,
efficient, and environmentally benign routes for the syntheses
Received: April 21, 2014
© XXXX American Chemical Society
A
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Letter
Table 1. Selected Results for Screening the Optimized
Reaction Conditions
Scheme 2. Results of Oxidative Coupling Reaction of
a
a
Alkanes with Disulfides
b
e
entry
additive (mol %)
oxidant (equiv) temp (°C) yield (%)
1
Cu(OTf)2 (10)
Cu(OAc)2 (10)
CuO (10)
TBP (2)
TBP (2)
TBP (2)
TBP (2)
TBP (2)
TBP (2)
TBP (2)
TBP (2)
TBP (3)
DCP (3)
TBHP (3)
BPO (3)
BQ (3)
100
100
100
100
100
100
100
120
120
120
120
120
120
120
120
120
120
120
47
54
46
65
71
63
55
81
88
59
17
35
0
2
3
4
CuI (10)
5
CuBr (10)
6
CuCl (10)
7
8
9
10
11
12
13
14
15
16
H2O2 (3)
K2S2O8 (3)
O2 (1 atm)
TBP (3)
TBP (3)
0
0
0
c
17
23
64
d
18
a
Reaction conditions: 1a (0.2 mmol), 2a (1.0 mL) and the oxidant, in
b
a sealed tube under Ar for 18 h. TBP: tert-butyl peroxide, DCP:
Dicumyl peroxide, TBHP: tert-butyl hydroperoxide 70% in water,
BPO: benzoyl peroxide, BQ: 1,4-benzoquinone. Under O2 atmos-
c
d
e
phere. Under air atmosphere. Isolated yield.
TBP, the reaction gave the poor yields (entries 10−12). And
also, the reaction could not take place at all if 1,4-benzoquinone
(BQ), H2O2, K2S2O8, or O2 was employed as the oxidant
(entries 13−16). Furthermore, O2 and air showed significant
inhibition to the reaction. When the reaction was performed
under O2 or air atmosphere, the lower yield of 23% or 64% was
obtained, respectively (entries 17−18).
a
Reaction conditions: 1 (0.2 mmol), 2 (1.0 mL) and TBP (3.0 equiv),
b
c
in a sealed tube under Ar at 120 °C for 18 h. Isolated yields. 2 (3.0
equiv) in benzene (1.0 mL). Determined by H NMR analysis.
d
1
With the optimized reaction conditions in hand, a series of
other disulfides and alkanes as the substrates were investigated
(Scheme 2). Aryl disulfides bearing both electron-donating
groups (R = Me, OMe) and electron-withdrawing groups (R =
Br, Cl) reacted with cyclohexane to give the desired sulfides in
moderate to good yields (3ba−ga), and the connection
position of substituent on the benzene ring had no significant
influence on the reaction (3ea−ga). It is worth noting that this
protocol is also applicable to a range of heterocyclic aromatics
such as benzothiazole, thiophene and pyridine (3ha−ja). Next
we employed a round of cycloalkanes, including cyclopentane,
cycloheptane, cyclooctane, cyclododecane and adamantane as
the coupling partner, and the results did not show evident
difference compared with the reaction of cyclohexane (3ab−
af). Finally, open chain compounds were also investigated, and
the corresponding oxidative coupling products were obtained
(3ag−ai). It is interesting that the reactions showed evident
regioselectivity, in which tertiary C−H of alkane had a higher
reactivity than secondary C−H (3af), and secondary C−H was
more active than primary C−H (3ag, 3ai), which is consistent
with the stability order of the radicals.
activities.14 Barton et al.15 reported a Fe-mediated phenyl-
selenation of saturated hydrocarbons to generate phenyseleno-
cyclohexane, in which saturated hydrocarbons were oxidized
synergistically with H2S and O2 in the presence of Fe.
Encouraged by the successful synthesis of sulfides under the
metal-free oxidation conditions above, we decided to expend
this strategy to the synthesis of selenides (Scheme 3). Under
the same reaction conditions, the oxidative coupling of
diselenide with alkanes gave the corresponding products
phenylselenides in yields of 57−93% (3ka−kf).
For understanding the pathway of the present reaction, an
intermolecular kinetic isotope experiment was carried out
(Scheme 4).4c,g,h The results showed that when equivalent
cyclohexane (2a) and [D12]cyclohexane ([D]12-2a) were
employed to react with diphenyl disulfide (1a) under the
standard reaction conditions for several reaction times a
significant isotopic effect could be observed (Scheme 4),
which indicated that the C(sp3)−H bond cleavage should be
the rate-determining step in this transformation. In addition,
only 3aa and [D]11-3aa were observed as the products, which
revealed that the process of C(sp3)−H bond cleavage is
irreversible. When 2.0 equiv of 2,2,6,6-tetramethyl-1-piperidi-
nyloxy (TEMPO, a radical-trapping reagent) was added, the
Organoselenium compounds are also attractive synthetic
targets not only owing to their chemo-, regio-, and stereo-
selective reactions but also because of their biological
B
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Scheme 3. Results of Oxidative Coupling Reaction of
Alkanes with Diselenide
AUTHOR INFORMATION
■
a
Corresponding Author
*E-mail: sunpeipei@njnu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Project 21272117 and 20972068) and
the Priority Academic Program Development of Jiangsu Higher
Education Institutions.
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Scheme 4. KIE Study
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a
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Scheme 5. Proposed Reaction Mechanism
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tert-butoxyl radical then abstracted hydrogen from the C−H
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