Metal-free oxidative C(sp3)-H bond thiolation of ethers with disulfides

Article abstract of DOI:10.1021/ol402281f

A novel method for the preparation of alkyl aryl sulfides through direct oxidation thiolation of commercial ethers with diaryl disulfides using di-tert-butyl peroxide (DTBP) as the oxidant without a metal catalyst was established. The C(sp³)-H

Full text of DOI:10.1021/ol402281f

ORGANIC
LETTERS
Metal-Free Oxidative C(sp3)ꢀH Bond
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Vol. XX, No. XX
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Thiolation of Ethers with Disulfides
Sheng-rong Guo,†,‡ Yan-qin Yuan,*,† and Jian-nan Xiang*,‡
Department of Chemistry, Lishui University, Lishui, 323000, China, and
College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082,
P.R. of China
yuanyq5474@lsu.edu.cn; jnxiang@hnu.edu.cn
Received July 1, 2013
ABSTRACT
A novel method for the preparation of alkyl aryl sulfides through direct oxidation thiolation of commercial ethers with diaryl disulfides using di-tert-butyl
peroxide (DTBP) as the oxidant without a metal catalyst was established. The C(sp3)ꢀH bond in various ethers was successfully converted into a CꢀS
bond, and the corresponding sulfides were achieved with moderate to high yields.
CꢀH bond functionalization to form CꢀC and CꢀX
(X = O, S, N, P, etc.) catalyzed by transition metals has
attracted significant interest and has become an alternative
to traditional Ullmann and other cross-coupling reactions
during the past decades.1 However, the direct thiolation of
the CꢀH bond has gained less attention. In 2006, Yu et al.2
first reported a C(sp2)ꢀH bond direct thiolation of the
2-aryl pyridine with aryl thiols catalyzed by a copper salt.
Subsequently, Fukuzawa3 and Cheng4 also described the
direct copper-catalyzed thiolation of the C(sp2)ꢀH bond
with disulfides respectively. Recently, our group demon-
strated a molecular-sieve-promoted TBHP-mediated thiol-
ation of a C(sp3)ꢀH bond in the amide with disulfides.5
Althouth the above progress has been made, the formation of
CꢀS bonds through CꢀH functionalization under metal-
free conditions also has been less explored.6
Transformation of an unactivated C(sp3)ꢀH bond into
more usable compounds has attracted much attention.7 In
particular, great progress has been achieved in the functio-
nalization of CꢀH bonds of ethers.8 Li et al. reported the
N-alkylation of azoles with ethers catalyzed by iron using
TBHP as an oxidant in DCE at 80 °C.9 Later, Reddy et al.
demonstrated a novel CꢀO bond formation protocol in
the reaction of ethers and β-ketoesters using Cu(OAc)2 as
the catalyst.10 Very recently, Lei et al. observed a CꢀC
bond formation reaction of arylboronic acids and cy-
cloethers using DTBP as the oxidant catalyzed by nickel.11
Moreover, the oxidative functionalization of C(sp3)ꢀH
† Lishui University.
‡ Hunan University.
(1) For reviews on transition-metal-catalyzed CꢀH functionaliza-
tion, see: (a) Scheuermann, C. J. Chem.;Asian J. 2010, 5, 436. (b) Sun,
C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293. (c) Yeung, C. S.;
Dong, V. M. Chem. Rev. 2011, 111, 1215. (d) Liu, C.; Zhang, H.; Shi, W.;
Lei, A. Chem. Rev. 2011, 111, 1780. (e) Lyons, T. W.; Sanford, M. S.
Chem. Rev. 2010, 110, 1147. (f) Li, C.-J. Acc. Chem. Res. 2009, 42, 335.
(g) Chen, X.; Engle, K. M.; Wang, D.; Yu, J. Angew. Chem., Int. Ed.
2009, 48, 5094. (h) Mkhalid, I.; Barnard, J.; Marder, T.; Murphy, J.;
Hartwig, J. Chem. Rev. 2010, 110, 890. (i) Ackermann, L.; Vicente, R.;
Kapdi, A. Angew. Chem., Int. Ed. 2009, 48, 9792. (j) Daugulis, O.; Do,
H. Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074.
(2) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem.
Soc. 2006, 128, 6790.
(3) Fukuzawa, S.-I.; Shimizu, S.-I.; Atsuumi, Y.; Haga, M.; Ogata,
K. Tetrahedron Lett. 2009, 50, 2374.
(4) Zhang, S.; Qian, P.; Zhang, M.; Hu, M.; Cheng, J. J. Org. Chem.
2010, 75, 6732.
(5) Tang, R.; Xie, Y.; Xie, Y.; Xiang, J .; Li, J. Chem. Commun. 2011,
47, 12867.
(6) (a) Zhu, Y. P.; Lian, M.; Jia, F. C.; Liu, M. C.; Yuan, J. J.; Gao,
Q. H.; Wu, A. X. Chem. Commun. 2012, 48, 9086. (b) Wu, Q.; Zhao, D.;
Qin, X.; Lan, J.; You, J. Chem. Commun. 2011, 47, 9188. (c) Yang, F.;
Tian, S. Angew. Chem., Int. Ed. 2013, 52, 4929.
(7) Baudoin, O. Chem. Soc. Rev. 2011, 40, 4902.
(8) Zhang, S.; Zhang, F.; Tu, Y. Chem. Soc. Rev. 2011, 40, 1937.
(9) Pan, S.; Liu, J.; Li, H.; Wang, Z.; Guo, X.; Li, Z. Org. Lett. 2010,
12, 1932.
(10) Kumar, G. S.; Pieber, B.; Reddy, K. R.; Kappe, C. O. Chem.;
Eur. J. 2012, 18, 6124.
(11) Liu, D.; Liu, C.; Li, H.; Lei, A. Angew. Chem., Int. Ed. 2013, 52,
4453.
(12) (a) Campos, K. R. Chem. Soc. Rev. 2007, 36, 1069. (b) Olivier, B.;
Li, C. Green Chem. 2007, 9, 1047. (c) Shu, X.; Xia, X.; Yang, Y.; Ji, K.;
Liu, X.; Liang, Y. J. Org. Chem. 2009, 74, 7464. (d) Li, Z.; Li, C. J. Am.
Chem. Soc. 2004, 126, 11810. (e) Yuan, Y.; Guo, S.; Xiang, J. Synlett
2013, 24, 443.
r
10.1021/ol402281f
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bonds adjacent to nitrogen atoms has also been demon-
strated in recent years.12 Moreover, to the best of our
knowledge, no reports of metal-free oxidative C(sp3)ꢀH
bond thiolation of ethers with disulfides or thiols are
known and the discovery of an metal-free CꢀH transfor-
mation would be of great value.13 Herein, we reported a
novel protocol to construct R-arylthio ethers by using
DTBP as an oxidant without the aid of a transition-metal
catalyst (Scheme 1).
(Table 1, entries 3ꢀ8). With respect to the amount of
oxidant, 4 equiv of DTBP based on thiols (1 mmol of
disulfides equivalent to 2 mmol of thiol) were found to be
optimal, the model reaction was not completed with less
than 4 equiv of DTBP (Table 1, entries 9ꢀ10), and no
significant increase in yield of 3aa was observed with more
than 4 equiv of DTBP (Table 1, entries 11). The reac-
tion yield was also affected by the reaction temperature:
67% yield at 100 °C (Table 1, entry 12) and 83% yield at
130 °C (Table 1, entry 13). Notably, the addition of some
˚
additives such as 4 A MS (50 mg), Pd(OAc)2 (10 mol %),
Cu(OAc)2 (10 mol %), and FeF2 (10 mol %) suppressed
the transformation slightly and the yield reduced (Table 1,
entries 13ꢀ17).
Scheme 1. CꢀX (X = C, N, O, S) Bond Formation via C(sp3)ꢀH
Activation of Ethers
Table 1. Optimization of the Reaction Conditionsa
Our initial investigation focused on examining the cou-
pling of diphenyldisulfide (1a, 0.5 mmol) with benzalde-
hyde (1.0 mmol) using 4 equiv of tert-butyl hydroperoxide
(TBHP, 4.0 mmol) as an oxidant in 1,4-dioxane (2 mL) at
120 °C with stirring for 12 h. Surprisingly, the expected
product S-phenyl benzothioate was not observed. Instead,
we found that the diphenyldisulfide coupled with 1,4-
dioxane directly, giving an unexpected alkyl aryl sulfide
product of 2-(phenylthio)-1,4-dioxane (3aa) with 18%
isolated yield (Table 1, entry 1). Given that alkyl aryl
sulfides and its derivatives are valuable synthetic inter-
mediates and important structural units found in numer-
ous biological and pharmaceutically active compounds,14
efforts were then made to improve the yield of this novel
direct arylthiolation reaction. From a wide range of can-
didates, the DTBP was found to be particularly effective.
Obviously the choice of oxidant was very important to the
reaction according to the results of Table 1. Replacing
TBHP with DTBP, the yield dramatically increased with-
out the metal catalyst or other additives (Table 1, entry 2).
But the formation of the desired product halted when the
other oxidants, such as CAN, NH4S2O8, PhI(OAc)2,
H2O2, NaClO, and DDQ, were added in this reaction
a Reaction conditions: 1a (0.5 mmol equal to 1.0 mmol thiophenol),
2a (2 mL), heated at 120 °C for 12 h under different amounts of DTBP.
b Isolated yield. c Not detected by GC-MS. d Reaction at 100 °C. e Reac-
tion at 130 °C. f 1a (0.5 mmol), 2a (20.0 equiv), solvent (2 mL), heated at
120 °C for 12 h. g 1a (0.5 mmol), 2a (5.0 mmol), solvent (2 mL), heated at
120 °C for 12 h.
The effect of solvent on the model reaction was also
examined. Moderate yields of the oxidative product 3aa
were obtained using chlorobenzene, benzene, CH3CN, or
DCE as a solvent; i-PrOH, DMSO, and toluene were not
suitable for the reaction, which afforded no products
(Table 1, entries 18ꢀ24). Gratifyingly, the reaction was also
achieved with moderate yields in the presence of 5.0 equiv of
(13) Chen, L.; Shi, E.; Liu, Z.; Chen, S.; Wei, W.; Li, H.; Xu, K.; Wan,
X. Chem.;Eur. J. 2011, 17, 4085.
(14) For recent reviews on this topic, see: (a) Bichler, P.; Jennifer,
A. L. Top. Organomet. Chem. 2010, 31, 39. (b) Dvorak, C. A.; Schmitz,
W. D.; Poon, D. J. Angew. Chem., Int. Ed. 2000, 39, 1664. (c) Herradura,
P. S.; Pendola, K. A.; Guy, R. K. Org. Lett. 2000, 2, 2019. (d) Ham, J.;
Yang, I.; Kang, H. J. Org. Chem. 2004, 69, 3236.
B
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2a using 2 mL of benzene or water as solvent (Table 1,
entries 25ꢀ26). But it should be noted that an excess amount
of dioxane as well as one of the substrate, was the most
suitable reaction media for the model reaction.
Scheme 2. Thiolation of 1,4-Dioxane with Disulfidesa,b
Having identified the optimal reaction conditions, this
approach was then applied to the coupling of 1,4-dioxane
to a variety of diaryl disulfides, the results of which are
shown in Scheme 2. In general, the electronic effects of the
substituents on the aromatic ring of disulfides or thiols
hardly influenced the reaction reactivity; both electron-
rich and -deficient disulfides are reactive, giving desired
products in good to excellent yields (entries 1ꢀ10). Ortho-
substituted diaryl disulfides were all tolerated, but the
steric effects of the disulfides had a slight impact on the
yields (entries 6 and 11ꢀ14). In addition, the commonly
used thiols such as 4-trifluoromethyl thiophenol, β-thio-
naphthaleneol, or thiophene-2-thiol, which surely would
be oxidated into disulfides first, were also tested in this
reaction, and the desired products were obtained with
moderate to good yields without any differences when
compared with disulfides (entries 7ꢀ9). Notably, the pre-
sence of the hydroxy on the phenyl ring of disulfides did
not interfere with the CꢀH transformation process (entry
10). Disappointingly, the reaction did not work when
disulfides containing a nitro or benzyl group was used as
a substrate (entry 15).
a Reaction were acrried out using 1 (0.5 mmol or thiols 1.0 mmol), 2a
(2 mL), DTBP (4 mmol) at 120 °C for 12 h. b Isolated yield based on 1.
Subsequently, other target ethers were examined for to
extend the application scope. As shown in Scheme 3, it was
gratifying to find that a variety of ethers including cyclic
and unsymmetrical linear ethers could couple with diverse
disulfides with satisfactory yields. The CꢀH bond of
tetrahydrofuran (THF), similar to 1,4-dioxane, was found
to be highly effective with different kinds of disulfides or
thiols, and the corresponding products were obtained in
moderate togoodyields(entries 1ꢀ5). The steric hindrance
of disulfides has little influence on the yield of the reaction,
and the reaction of 2,20-dimethyl diphenyldisulfide with
THF also proceeded well with a 81% yield (entry 6).
Surprisingly, methyl tert-butyl ether (MTBE), a very
stable compound, which has only one CH3 group adjacent
to the oxygen atom and a large steric hindrance group, also
led to the desired products with moderate yields (entries
7ꢀ12). Obviously, the sterically hindered effect of tert-
butyl and the ortho-substituted disulfides effected the
reaction; for example, it only resulted in a trace yield when
the 2,20-dimethoxy diphenyl disulfide reacted with MTBE,
and we assumed that the trace yield was due to the large
steric effects. Unfortunately, n-Bu2O, Et2O, and PhOCH3
remained completely unreactive under the optimal reac-
tion conditions.
Scheme 3. Thiolation of Ethers and Amidesa,b
Furthermore, under the optimal reaction conditions,
this protocol could also be applied to the oxidative thiola-
tion of the C(sp3)ꢀH bond adjacent to a nitrogen atom
such as N,N-dimethylacetamide (DMA, entries 13ꢀ15).
The disulfides bearing a strong electron-withdrawing
group, such as p-CF3, were also perfectly tolerated with
DMA, offering the product with good yields.
a Reactions were carried out using 1 (0.5 mmol, or thiols 1.0 mmol), 2
(2 mL), DTBP (4 mmol) at 120 °C for 12 h. b Isolated yield based on 1. c 1
(0.5 mmol), DMA (2 mL), DTBP (4 mmol) at 120 °C for 6 h.
reactions (Scheme 4). It was not the CH2 group but the
CH3 group that tended to be thiolated when 1,2-dimethox-
yethane (DME) reacted with 4,40-dimethyl diphenyldisul-
fide. Although only the major regioisomer was isolated
Lastly, in order to address the regioselectivity of the
reaction, we explored a series of intramolecular competition
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Regioselectivity Studies of Thiolation
Scheme 6. A Plausible Reaction Mechanism
Scheme 5. Mechanism Studies of Thiolation
was added into the reaction (Scheme 5). The formation of
desired product 3ba was suppressed, thus revealing that the
initial steps of the transformation probably were caused by a
radical process9,11 (see the Supporting Information).
On the basis of the above results and previous
publications,8ꢀ11,13,15 a plausible catalytic mechanism
was presented (Scheme 6). The DTBP decomposed to
form tert-butoxyl radicals under heating conditions, the
tert-butoxyl radical can abstract hydrogen from the ether
to generate the corresponding alkoxy radical intermediate,
and then the radical intermediate reacted with ArSSAr
affording the product and the ArS• free radical which
would be trapped by another alkoxy radical.
In conclusion, this work described the first example of
direct CꢀS bond formation via oxidative thiolation of
commercial ethers under metal-free conditions. A high
yielding, efficient, green methodology for the synthesis of
alkyl aryl sulfide compounds was developed; moreover,
this direct thiolation method is a new protocol for the
construction of CꢀS bonds, which might be very valuable
and attractive in sulfur chemistry and radical chemistry.
from the reaction mixture in 83% yield, a trace amount of
another regioisomer was observed from crude NMR ana-
lysis and the ratio of the two regioisomers was 90%:10%
(entry 1). We also found that the para-substitued diaryl
disulfides embodied better regioselectivities than the ortho-
substituted diaryl disulfides. 2-Methyltetrahydrofuran (2-
methyl THF) showed low reactivity with good regioselec-
tivity. The ratio of the two regioisomers was 92%:8%, and
the main product yield was only 35% when 2-methyl THF
reacted with diphenyldisulfide (entry2). The reaction ofN-
dimethylformamide (DMF) with diphenyldisulfides led to
two regioisomers with a ratio of 82%:18% (entry 3), and
the two regioisomers were obtained with a 93% combined
yield. It demonstrated that the regioselectivity toward the
acyl C(sp2)ꢀH bond was superior to the C(sp3)ꢀH bond
adjacent to nitrogen (see the Supporting Information).
To investigate the possible radical mechanism of the
present transformation, a series of radical-trapping experi-
ments were carried out. TEMPO, a radical-trapping reagent,
Acknowledgment. This work was supported by the
Natural Science Foundation of Zhejiang Province P.R.
China (No. Y407240) and Normal Foundation of Zhe-
jiang Education Department.
(15) (a) Kumar, G. S.; Maheswari, C. U.; Kumar, R. A.; Kantam,
M. L.; Reddy, K. R. Angew. Chem., Int. Ed. 2011, 50, 11748. (b) He, T.;
Li, H.; Li, P.; Wang, L. Chem. Commun. 2011, 47, 8946. (c) Liu, Z.;
Zhang, J.; Chen, S.; Shi, E.; Xu, Y.; Wan, X. Angew. Chem., Int. Ed.
2012, 51, 3231. (d) Xie, J.; Huang, Z. Angew. Chem., Int. Ed. 2010, 49,
10181. (e) Dai, C.; Xu, Z.; Huang, F.; Yu, Z.; Gao, Y. J. Org. Chem.
2012, 77, 4414. (f) Shi, E.; Shao, Y.; Chen, S.; Hu, H.; Liu, Z.; Zhang, J.;
Wan, X. Org. Lett. 2012, 14, 3384. (g) Wei, W.; Zhang, C.; Xu, Y.; Wan,
X. Chem. Commun. 2011, 47, 10827.
Supporting Information Available. Experimental de-
tails, 1H and 13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
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