A comparative study of Cu(II)-assisted vs Cu(II)-free chalcogenation on benzyl and 2°/3°-cycloalkyl moieties

Article abstract of DOI:10.1007/s12039-015-0981-0

A relative synthetic strategy toward intermolecular oxidative C -Chalcogen bond formation of alkanes has been illustrated using both Cu(II) assisted vs Cu(II) free conditions. This led to construction of a comparative study of hydrocarbon benzylic and 2°/ 3°-cycloalkyl moieties bond sulfenylation and selenation protocol by the chalcogen sources, particularly sulfur and selenium, respectively. In addition, this protocol disclosed the auspicious formation of sp³ C-S coupling products over leading the sp³ C-N coupling products by using 2-mercaptobenzothiazole (MBT) substrates.

Full text of DOI:10.1007/s12039-015-0981-0

c
J. Chem. Sci. Vol. 127, No. 12, December 2015, pp. 2151–2157. ꢀ Indian Academy of Sciences.
DOI 10.1007/s12039-015-0981-0
A comparative study of Cu(II)-assisted vs Cu(II)-free chalcogenation
on benzyl and 2◦/3◦-cycloalkyl moieties
SANTOSH K SAHOO∗
Department of Chemistry, Indian Institute of Technology - Bombay, Powai, Mumbai 400 076, India
e-mail: santoshsahoo.iit@gmail.com
MS received 18 May 2015; revised 13 August 2015; accepted 14 August 2015
Abstract. A relative synthetic strategy toward intermolecular oxidative C−Chalcogen bond formation of
alkanes has been illustrated using both Cu(II) assisted vs Cu(II) free conditions. This led to construction of a
comparative study of hydrocarbon benzylic and 2◦/3◦-cycloalkyl moieties bond sulfenylation and selenation
protocol by the chalcogen sources, particularly sulfur and selenium, respectively. In addition, this protocol
disclosed the auspicious formation of sp3C−S coupling products over leading the sp3C−N coupling products
by using 2-mercaptobenzothiazole (MBT) substrates.
Keywords. C-H functionalization; C-Chalcogen bond formation; metal vs. metal free condition
1. Introduction
scope of substrates and tolerant to a wide range of
functional groups, would be of prime synthetic value.
To the best of knowledge, in literature till now,
there are very few examples of benzylic and 2◦/3◦-
cycloalkyl moieties have been reported.9c,d,e It is wor-
thy to note that in literature,9e the toluene deriva-
tives are over oxidized to give carbonyl derivative ben-
zoylic sp2 C-S coupling products, however herein only
benzylic sp3 C-S coupling products are exclusively
observed.
From earlier observations, the reaction was believed
to undergo via a radical alkyl species, which then
reacted with chalcogen to afford the desired products.
The fact that alkanes could be easily converted into
the corresponding alkyl radicals in the presence of
peroxides10 was a motivation to try the direct coupling
of alkanes with chalcogens in a novel C−H chalco-
genation reaction. However, very few reactions are
reported recently using DTBP (di-tertiary butyl per-
oxide) under metal free condition. The earlier report
was also completely silent about toluene derivative
moiety (benzyl radical). Keeping this observation in
view, a comparative investigation is disclosed herein for
thio- and seleno-ether formation via both metal-assisted
and metal-free conditions, which also envisaged that
chalcogen source is utilized as a stoichiometric reactant
for the chalcogenation of alkanes.
Chalcogen containing molecules are important motifs
found in organic synthesis,1 biological chemistry,2 and
materials science.3 However, the direct C−H function-
alization of simple hydrocarbons has emerged as a
research topic of great interest in recent years due to the
potential opportunity of developing novel methodolo-
gies in synthesis and chemical processes.4 The selective
activation of benzylic C−H bonds in toluene deriva-
tives is significant since the catalytic functionalization
of toluene can yield industrially important chemicals
such as benzyl alcohols, benzaldehydes, and benzoic
acids. However, it is more difficult to achieve the
benzylic C−H bond functionalization5 because of the
existence of both sp2 as well as sp3 C−H bonds.
Notably, copper salts have been used as a catalyst for
the oxidation of certain types of hydrocarbons to give
alcohols, ketones, or carboxylic acids.6 Further, inter-
molecular heteroatom-based functionalization is very
rare.7
In the area of C−H bond functionalization, much
attention has been paid to C−C, C−O, and C−N
bond-forming reactions.8 In contrast, only a few meth-
ods for C−H bond sulfenylation and selenation have
been published recently.9 Therefore, the development
of a general alkyl C−H thio and seleno etherification
reaction that enables the selective preparation of valu-
able alkyl thioethers, and is compatible with a broad
2. Experimental
∗For correspondence
Working hypothesis is given in scheme 1.
2151

2152
Santosh K Sahoo
Previous Works
Metal Free
Table 2. Scope of thiol/diaryldidulfides for sulfenylation
Alkyl XR
of sp3 C−H bond.a
Aliphatic Alkanes
X = S, Se
Alkyl
+
RX XR
Condition A
Condition B
H
Alkyl H
+
Alkyl SAr
(4aa-4od)
ArS SAr
This Work
(1a 1o)
(2a-3f)
Alkyl XR
N
S
S
Tolune Derivatives,
Aliphatic Alkanes
Metal vs. Metal Free
CH3
N
S
SH
H3C
H3C
4aa, A, 83%,
B, 65%
1a
2a
Scheme 1. Reactions of chalcogens with alkyl halides or
B
alkanes.
Cl
N
Cl
S
N
3. Results and Discussion
S
SH
H3C
S
4ab, A, 75%,
B, 62%
2b
3.1 Reactions and Yields
N
S
N
O
O
SH
H3C
To test our hypothesis on the intermolecular S-
alkylation of simple alkanes, 2-mercaptobenzothiazole
(MBT, 2a) was initially employed to react with p-
xylene using catalytic amount of various Cu salts and
ditertiary butyl peroxide (DTBP) oxidant under various
conditions (table 1). Gratifyingly, the desired product
(4aa) formed with a complete conversion was obtained
at 120◦C using 10% of Cu(OAc)2.H2O salt and 3 equiv.
of DTBP (entry 5). The loading of reduced amounts of
oxidant resulted in lower conversion (entry 7). How-
ever, it is interesting to see that, in the absence of metal
catalyst the oxidant also afford the expected product
in moderate yield. With initial observations in hand,
the protocol was treated with various solvents sources
(CH3CN, DCE, DMSO, DMF, EtOH, benzene) and
found that the solvent is ineffective for this reaction.
The other oxidant candidates (TBHP, T-HYDRO, DCP)
4ac, A, 48%,
B, 43%
2c
S
H3C
S
S
4ad, A, 48%,
B, 55%
3d
S
CH3
H3C
H3C
Cl
S
S
3e
CH3
Cl
4ae, A, 56%,
B, 33%
S
Cl
H3C
S
S
4af, A, 58%
B, 56%
3f
N
S
CH3
S
4ba, A, 45%,
B, 70%
1b
2a
N
S
S
H3C
CH3
H3C
CH3
CH3
4ca, A, 76%,
B, 83%
1c
2a
2a
N
S
S
Table 1. Selected list for the Optimized Conditionsa.
CH3
H3CO
H3CO
CH3
4da, A, 64%,
B, 81%
N
S
N
S
Conditions
1d
S
+
SH
H3C
H3C
MBT
S
N
1a
4aa
2a
S
Entry
Metal Salt
Oxidant
NMR Yield%
CH3
H3C
4ea, A, 71%,
B, 26%
1e
2a
3d
3d
1
2
3
4
5
6
7
8
CuI
CuBr
CuBr2
DTBP (3)
DTBP (3)
DTBP (3)
DTBP (3)
33
36
44
74
85
82
65
12
21
S
CH3
CH3
CH3
Cu(OAc)2
4fd, A, 52%,
Cu(OAc)2.H2O DTBP (3)
Cu(OAc)2.H2O DTBP (4)
Cu(OAc)2.H2O DTBP (2)
Cu(OAc)2.H2O
Cu(OAc)2.H2O T-HYDRO (3)
1f
B, 59%
H3C
H3C
S
H3C
CH3
TBHP(3)
4gd, A, 51%,
B, 60%
9
1g
10
11
12
13
14
Cu(OAc)2.H2O
DCP (3)
DTBP(2)
DTBP(3)
DTBP(4)
-
45
22
S
-
-
-
-
69(65)b
64
CH3
4cd, A, 42%,
B, 55%
N.D
1c
3d
3d
ap-Xylene 10 mmol, metal salt 10% compared to MBT, MBT
S
0.3 mmol, Temp. 120◦C, Time 18 h. C2H2Cl4 (TCE) used
Cl
CH3
b
as an internal standard. N.D. = Not detected. In bracket
4hd, A, 38%,
B, 20%
1h
Cl
isolated yield.

Study of Cu(II)-assisted vs Cu(II)-free Chalcogenation
2153
Table 2. (continued)
Condition A
Condition B
Alkyl H
+
ArS SAr
Alkyl SAr
(4aa-4od)
(1a 1o)
(2a-3f)
S
CH3
4id, A, 48%,
B, 61%
1i
3d
S
4jd, A, 65%,
B, 86%
1j
3d
3d
3d
S
Figure 1. ORTEP diagram of compound 4da.
4kd, A, 68%,
B, 89%
1k
1l
S
With the newly developed protocol of intermolecu-
lar C−H sulfenylation, a variety of thiol sources were
next subjected to the optimized conditions (table 2).
Mercapto thiol derivatives such as (2a, 2b, 2c) were
still facile reactants albeit with moderate to good yield.
In these cases, Cu(II) catalyst was ineffective to pro-
mote the reaction to get good yield compared to metal
free condition. A good yield of product was observed
as well from the diaryldisulfide moieties with alkane
derivatives (4aa, 4ba, 4ca). The toluene derivatives
such as toluene (1b), mesitylene (1c), p-methylanisole
(1d) aslo provided corresponding their C−S coupling
product (4ba, 4ca, 4da) in good to excellent yields.
However, metal free condition provided better chem-
ical yield compared to metal free condition for these
moieties. Although for MBT moiety there is a chance
also to couple on nitrogen site to form 4da’ prod-
uct, interestingly that it regioselectively was giving sin-
gle C−S coupled isomer (scheme 2) which is further
confirmed by X-ray crystallographic analysis (depicted
in figure 1, H atom omitted for clarity). Surpris-
ingly, ethylbenzene (1e) gave a poor yield (4ea) in the
absence of Cu(II) salt. Perhaps, it is due to presence
of methyl group at the alpha position which makes it
difficult to form free radical in the absence of metal
salt.
4ld, A, 61%,
B, 95%
S
4md, A, 53%,
B, 88%
1m
3d
S
4nd, A, 57%,
B, 75%
1n
3d
3d
S
4od, A, 62%,
B, 52%
1o
Condition A: Alkane10 mmol, (ArS)2 0.15 mmol or RSH
0.3 mmol, Cu(OAc)2.H2O 10 mol%, DTBP 0.9 mmol. Con-
dition B: Alkane 10 mmol, (ArS)2 0.15 mmol or RSH 0.3
mmol, DTBP 0.9 mmol. aIsolated yield. bAdamantane (1o)
2.5 equiv. used compared to (PhS)2 and benzene 1mL used
as solvent. cTemp.120 oC, Time 18 h.
were also found to be ineffective for this transforma-
tion. However, 18 h is the optimum reaction time to
afford good yield of the desired product. It is worthy
to observe that 120◦C is optimum temperature for
this protocol for both metal free and Cu(II) catalyzed
reaction.
S
S
HS
S
N
H
N
S
N
H
Condition A
S
+
H
H
or
S
Condition B
H3CO
H3CO
S
H3CO
N
H
1d
4da
Observed
4da'
Not Observed
2a
Scheme 2. A comparative observation for C−S bond formation.

2154
Santosh K Sahoo
The optimized imitation procedure was subsequently carbon to give exclusively C−S coupled product, which
was further confirmed by X−ray crystallographic
applied to a range of simple alkanes like mesitylene
analysis (4od, depicted in figure 2, H atom omitted for
clarity). From this observation, it is clear that particu-
larly aliphatic alkanes in presence of Cu(II) salts poison
the formation of C−S coupling product and metal free
condition is more facile.
(1c), o-xylene (1f), m-xylene (1g), using a phenyl disul-
fide source under both metal and metal free conditions
(table 2). Stimulatingly, metal free condition gave bet-
ter yield (4cd, 4fd, 4gd) compared to Cu(II) assisted
reaction. However, in the case of p-Cl toluene (1h) poor
yield (4hd) was obtained in metal free condition. Poly-
cyclic aromatic ring like 1-methyl naphthalene (1i) also
provided corresponding C−S coupling product (4id)
in good yield in metal free condition. After seeing
these observations, the reaction condition was shifted
to aliphatic alkane derivatives like cyclopentane (1j),
cyclohexane (1k), cycloheptane (1l), cyclooctane (1m),
cyclododecane (1n) and adamantane (1o) yielding good
to excellent yield of corresponding C−S coupled prod-
ucts (4jd−4od) under metal free condition. It was also
observed that, adamantane (1o) tertiary carbon is more
favorable to form free radical compared to secondary
From the mentioned observations, aim was to find
out the reactivity of same family chalcogen deriva-
tive selenide substrates (table 3). Likewise, C−S bond
formation of p-xylene (1a), mesytilene (1c) afforded
their corresponding sp3 C−Se coupling product in bet-
ter yield under metal free condition. Further, 1-methyl
naphthalene (1i) reacted with diphenylselenide (3g)
moderately to provide (4ig) product. However, from the
Table 3. Scope of various alkanes for selenation of sp3
C−H bond.a
Condition A
Alkyl SePh
Alkyl H
+
PhSe
SePh
Condition B
(4ag-4ng)
3g
(1a,1c,1i, 1k-1n)
Se
H3C
Se Se
4ag, A, 66%,
B, 75%
3g
1a
1c
H3C
Se
CH3
4cg, A, 59%,
B, 81%
3g
3g
Se
4ig, A, 46%,
B, 36%
1i
Se
4kg, A, 71%,
B, 96%
1k
1l
3g
3g
3g
Se
4lg, A, 69%,
B, 89%
Se
4mg, A, 90%,
B, 79%
1m
Se
4ng, A, 63%,
B, 78%
1n
3g
Condition A: Alkane 10 mmol, (PhSe)2 0.15 mmol,
Cu(OAc)2.H2O 10 mol%, DTBP 1.2 mmol.
Condition B: Alkane 10 mmol, (ArSe)2 0.15 mmol, DTBP
1.2 mmol. aIsolated yield. bTemp. 120◦C, Time 18 h.
Figure 2. ORTEP diagram of compound 4od.

Study of Cu(II)-assisted vs Cu(II)-free Chalcogenation
2155
Table 4. Effect of Radical Inhibitors on the Reaction
3.2 Mechanism
Efficiencya.
Based on the above experimental data, a plausi-
ble pathway for the formation of sulfenylated prod-
uct is proposed in scheme 3. Our proposed mecha-
nism begins with the thio-Cu(II) complexation. Subse-
quently, decomposition of (tBuO)2 to produce a tert-
butoxy radical which supports to abstract a hydrogen
atom from an alkane to form an alkyl radical, fol-
lowed by a potential intermediate containing a Cu(III)
complex species. The next step plausibly, undergo-
ing reductive elimination route to generate the desired
sulfenylated product.
Condition A,
N
S
CH3
Radical Scavenger
N
S
+
SH
Condition B,
Radical Scavenger
S
H3C
H3C
1a
MBT 2a
4aa
Entry Radical Scavenger Condition A % Condition B %
1
2
3
None
TEMPO
BHT
85
27
05
35
65
15
02
08
DPE
Condition: 1 equiv. radical scavenger was added compared to
MBT (both in condition A and B).
Perhaps, the reaction of thiol with tBuOOtBu in the
presence of Cu leads to rapid oxidation of thiol to
exclusive formation of thioanisole derivated product, in
which the methyl radical is derived from tert-butoxy
radical by β-Me scission.10b Second, copper partici-
pates in the event after the turnover-limiting step of
C−H functionalization by tert-butoxy radical to form
the S-alkyl product. However, it is possible that the for-
mation of O-alkylated product as a side derivative via
the insertion of t-butoxy radical to the Cu salt, followed
by reductive elimination of Cu(III) species. Further, the
oxidative dimerised product of alkane substituents has
also been isolated as a side product which is generated
during the course of reaction and fully characterized
(scheme 4).9,10
From the observed reaction conditions, it is clear
that in the absence of metal salt also the product is
formed and in most cases with a better yield compared
to Cu(II) assisted protocol. These results led us to pro-
pose that a single electron transfer oxidation pathway
might be engaged in the generation of an alkyl radical
X, which is further oxidized to a cationic species Y, and
experimental observation it was found that in the pres-
ence of metal salt (4ig) gave good yield whereas
(4id) gave poor yield. Notably, aliphatic cycloalka-
nes like cyclohexane (1k), cycloheptane (1l), cyclooc-
tane (1m) and cyclododecane (1n) provided their cor-
responding C−Se coupling products (4kg, 4lg, 4mg,
4ng) in excellent yields under metal free condition.
From this observation, it seems to be that Cu(II)
salts poison the yield of aliphatic alkane derived
substrates.
A radical inhibition test was next carried out in
order to get insight into whether the reaction proceeds
via radical intermediates. When TEMPO, 2,6-di-tert-
butyl-4-methylphenol (BHT) or 1,1-diphenylethylene
(DPE), which are well known to be active radical scav-
engers, was added to the reaction mixture, the reaction
progress was significantly decreased under either the
Cu-assisted or Cu-free conditions. Poor product yields
were obtained, suggesting that present intermolecular
sp3 C−S bond-forming reaction involves radical inter-
mediates (table 4).
RSH
+
Cu(OAc)2.H2O
O2
Cu(OAc)
(tBuO)2
RS
Cu(OAc)
SR
RS
OAc
Cu
+ tBuOH + tBuO
Target product
Scheme 3. Proposed mechanistic pathway.

2156
Santosh K Sahoo
OtBu
O
O
+ CH3
tBuO
Cu(II)
S
R
RSH
+ CH3
Isolated
Scheme 4. Possible formation of side product.
tBu
O
O
tBu
r.d.s
X
tBuO
SET
tBuO
tBuOH + tBuO
Side products
OtBu
SR
R
SH
_
Y
tBuO
tBuOH
Scheme 5. Proposed mechanistic pathway in the absence of metal catalyst.
then subsequent nucleophilic attack of thiol moiety pro- Acknowledgements
vides the product, being sulfenylated at the alkyl site
Author thanks IITB for fellowship. The author dedicates
this paper to Prof. Bhisma K Patel on the eve of his 49th
birthday.
(scheme 5).9,10
4. Conclusions
References
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C−H chalcogenation of alkanes with thiol and selenide
derivatives using peroxide (DTBP) as oxidant as well as
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assisted conditions have been developed. A broad range
of substrates are selectively chalcogenated at the ben-
zyl or alkyl position. Although detailed mechanistic
descriptions and development of milder reaction con-
ditions are still desirable, it is believed that in forth-
coming period this new protocol will be offering a new
avenue for a more practical and selective construction
of C−chalcogen bond from the unactivated sp3 C−H
bonds.
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Supplementary Information
CCDC 1058940, 1058941 contain the supplementary
crystallographic data for the compound 4da and 4od.
These data can be obtained free of charge via www.
ccdc.cam.ac.uk/datarequest/cif. The NMR spectra and
figures (1H and 13C), are available at www.ias.ac.in/
chemsci.

Study of Cu(II)-assisted vs Cu(II)-free Chalcogenation
2157
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