Metal free, facile sulfenylation of ketene dithioacetals catalyzed by an HBr-DMSO system

Article abstract of DOI:10.1039/C9NJ00925F

A transition metal free, highly efficient, sulfenylation of ketene dithioacetals catalyzed by an HBr-DMSO system is achieved. This strategy employs inexpensive and readily available HBr and DMSO to provide a direct C-H bond sulfenylation with a broad rang

Full text of DOI:10.1039/C9NJ00925F

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Metal free, facile sulfenylation of ketene
dithioacetals catalyzed by an HBr–DMSO system†
Cite this:DOI: 10.1039/c9nj00925f
Ganesh Shivayogappa Sorabad
and Mahagundappa Rachappa Maddani
*
A transition metal free, highly efficient, sulfenylation of ketene dithioacetals catalyzed by an HBr–DMSO
system is achieved. This strategy employs inexpensive and readily available HBr and DMSO to provide a
direct C–H bond sulfenylation with a broad range of aryl thiols. Highlights of the present strategy are
convenient, straightforward approach, metal free, short reaction time and excellent yields. This sulfenylated
product is also successfully transformed for the synthesis of pyrazole derivatives in excellent yields.
Received 21st February 2019,
Accepted 12th March 2019
DOI: 10.1039/c9nj00925f
rsc.li/njc
been utilized for in situ generation and it turned out to be a safer
alternative to toxic bromine.
Introduction
Metal mediated reactions are not acceptable, as the contamination
On the other hand, the a-oxo ketene dithioacetals containing
of metal is a serious issue in pharmaceutical industries. Due to an a donor–acceptor system have been found to be valuable three
increased emergence of atom economy and user-friendly strategies, carbon synthons in organic synthesis7 for the construction of
a variety of metal free synthetic methods have been developed for C–C and C–hetero bonds. Carbonyl groups, alkenes and S atoms
the construction of various C–C and C–hetero bonds via cross are the reactive sites, which makes ketene dithioacetals a more
coupling reactions. Among them, the formation of a C–S bond is admirable skeleton. In spite of huge popularity of aroylketene
fundamentally challenging in modern organic synthesis and of dithioacetals as powerful building blocks in the synthesis of a
paramount importance owing to the presence of aryl sulfides in a variety of important heterocyclic molecules,8 their utility in
variety of medicinally and biologically active molecules.1 Direct C–H a C(sp2)–H functionalization is not well explored. Although,
functionalization for the synthesis of aryl sulfides under metal-free metal9 mediated and few metal free10 C–H functionalizations
conditions is more viable and economical. In order to find are available, the C–H sulfenylation reactions under metal free
environmentally benign protocols, chemists have devoted much conditions are limited (Scheme 1). Recently, R. K. Peddinti’s11
attention in recent years to examining various non-metallic group has shown very few examples on sulfenylation of ketene
reagents2 and catalysts3 for the sulfenylation reactions.
dithioacetals using a catalytic I2/DMSO system. Yunyun Liu12
The HBr–DMSO system has drawn special attention in recent has also reported similar sulfenylation using I2 (3 eq.) in 12 h
years as inexpensive, non-metallic, and readily available for with moderate to good yields. Due to the importance of ketene
affording various organic transformations.4 It is well known in dithioacetals, it is a challenging task to develop an efficient, metal
the literature that the HBr–DMSO system works on the principle free and environmentally benign sulfenylation directly from thiols.
of oxidation5 of a halide ion by DMSO to generate molecular
bromine. Except iodine, all other halogens are quite dangerous;
hence, it is necessary to develop in situ preparative methods
followed by their use in organic synthesis. Although, several
oxidants6 have been reported for oxidation of halide ions, there
is a need of developing more safer and greener approaches in
this field. Interestingly, this inexpensive HBr–DMSO system has
Department of Postgraduate Studies and Research in Chemistry,
Mangalore University, Mangalgangothri-574199, Karnataka, India.
E-mail: mahagundappa@mangaloreuniversity.ac.in, mahagundappa@gmail.com
† Electronic supplementary information (ESI) available: Experimental procedure,
characterization details and 1H & 13C NMR spectra of unknown compounds. See
Scheme 1 Synthesis of sulfenylated ketene dithioacetals.
DOI: 10.1039/c9nj00925f
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In continuation of our success on the utility of HBr–DMSO in After optimization experiments, entry 9 of Table 1 has been
bromination13 and sulfenylation,14 herein, we wish to report a facile selected as the optimal reaction conditions, as HBr is easier to
direct C–H bond sulfenylation using a catalytic amount of inexpen- handle and DMSO is a green solvent over other organic solvents.
sive, environmentally benign HBr–DMSO as an oxidation system.
We then successfully investigated the substrate scope of the
present sulfenylation reaction as shown in Table 2 and it was
satisfying to find that a variety of substituted ketene dithioacetals
and thiols were coupled under the optimized conditions to afford
excellent yields in a short period of time. In the beginning, we
employed substituted ketene dithioacetals with fixed aryl thiol.
Thus, the reaction of ketene dithioacetals containing electron
donating groups 1b and 1c with 2a led to the formation of
the corresponding products 3ba and 3ca each in an excellent
yield (99%). This remarkable sulfenylation was indeed found to
be general and the reaction of halogen substituted ketene
dithioacetals underwent smooth sulfenylation with 2a to furnish
their sulfenylated products 3da–3fa in very high yields (98, 99 and
99% respectively).
Results and discussion
We began optimization experiments by the reaction of ketene
dithioacetal (1a) with aryl thiol (2a) in the presence of a catalytic
amount of HBr using DMSO as an oxidant for 2 h of reaction
time (Table 1). The reaction of 1a with thiol 2a in the presence
of 47%, aq. HBr (0.3 equiv.) in DMSO : CHCl3 (1 : 1, 3 ml) at
80 1C resulted in the formation of the corresponding sulfenylated
product 3a in very good yield of 92% (Table 1, entry 1). Other
chlorinated solvents such as CCl4 and DCE were not effective and
produced the product 3a in yields of 65% and 23% respectively
(Table 1, entries 2 and 3). Similarly, acetonitrile (ACN), t-BuOH
and toluene as solvents were unsuccessful and gave the corres-
ponding sulfenylated product 3a in 40, 35 and 62% yield
respectively (Table 1, entries 4–6). The reaction in water as a
solvent did not occur and the starting materials were isolated
unaffected (Table 1, entry 7). We attribute the unsuccessfulness in
aqueous medium to the insolubility of the reactants. Our efforts in
using DMSO as both the oxidant and the solvent furnished the
product 3a in 85% yield at 100 1C (Table 1, entry 8). Interestingly,
the reaction of 1a and 2a with catalytic HBr in DMSO : CHCl3 (1 : 1)
at 100 1C was highly successful, and furnished the desired
product 3a in 99% yield (Table 1, entry 9). We also examined
the reactivity of aq. HCl (35%) and aq. HI (57%) towards the
present sulfenylation and observed the formation of product 3a
in 60 and 76% yield, respectively (Table 1, entries 10 and 11).
Reactions using aq. H2O2, aq. TBHP and m-CPBA as oxidizing
agents failed to provide the product 3a (Table 1, entries 12–14).
Table 2 Substrate scope of dithioacetals on sulfenylationa
Table 1 Optimization on the reaction conditionsa
Entry Halo acid (0.3 eq.) Oxidant : solvent (1 : 1) 3 ml T (1C) Yieldb (%)
1
2
3
4
5
6
7
8
HBr
HBr
HBr
HBr
HBr
HBr
HBr
HBr
HBr
HCl
HI
DMSO : CHCl3
DMSO : CCl4
DMSO : DCE
DMSO : ACN
DMSO : t-BuOH
DMSO : toluene
DMSO : H2O
DMSO
DMSO : CHCl3
DMSO : CHCl3
DMSO : CHCl3
H2O2 : CHCl3
TBHP : CHCl3
mCPBA : CHCl3
80 92
80 65
80 23
80 40
80 35
100 62
80 NR
100 85
100 99
100 60
100 76
100 NR
100 NR
100 NR
9
10
11
12
13
14
HBr
HBr
HBr
a
a
All reactions were carried out by using 1a (1.0 equiv./0.44 mmol), 2a
All reactions were carried out by using 1a–o (100 mg, 1.0 equiv.), 2a–h
b
(1.0 equiv./0.44 mmol), and 47% aq. HBr (30 mol%). Isolated yield (1.0 equiv.) and 47% aq. HBr (30 mol%) in DMSO : CHCl3 (1 : 1, v/v 2 ml)
based on ketene dithioacetals 1a.
at 100 1C for 2 h.
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Similarly, a-naphthoyl and a-furoyl ketene dithioacetals also
Paper
Thus, the reaction of b-naphthol (4a) with p-tolyl thiol,
furnished their sulfenylated products 3ga and 3ha in high yields. p-bromo phenyl thiol and b-naphthyl thiol under the optimized
We then focused on the use of substituted thiols with 1a for a conditions furnished the corresponding products 5ac, 5ae and
sulfenylation reaction. Accordingly, the reaction of 1a with 5af in very high yields. Interestingly, 4a also coupled with
p-methoxyphenyl thiol and p-tolyl thiol resulted in the formation benzo[d]-thiazole-2-thiol to give the desired product 5ag in very
of the corresponding sulfenylated products 3ab and 3ac in excellent high yield.
yields (each in 99%). Additionally, 1a also furnished the sulfenylated
We then changed our focus on monitoring the efficiency of
products 3ad (99%) and 3ae (98%) in very high yields on reacting the present methodology by scaling it up as shown in Scheme 2.
with p-fluorophenyl thiol and p-bromophenyl thiol respectively Thus, the reaction of 1.5 g of 1a under the optimized conditions
under the optimized conditions. Similarly, b-naphthyl thiol coupled produced 2.15 g of the desired product 3a with a yield of 97%
with 1a to obtain the desired products 3af in high yield. It is indicating practicality or a large-scale of sulfenylation reaction.
noteworthy that, the aliphatic thiols such as p-methoxybenzyl thiol
and cyclohexyl thiol were also employed to furnish sulfenylated into substituted pyrazole as shown in Scheme 3. In the beginning,
products 3ag (97%) and 3ah (99%) in high yields. 1a was converted into the product 3ac using the optimized reaction
We also successfully transformed the sulfenylated product
Further investigations revealed that the present method is conditions and then product 3ac was reacted with hydrazine
versatile and a variety of ketene cyclic dithioacetals are also sulfeny- hydrate in ethanol at reflux temperature to obtain 5-(methylthio)-
lated with various thiols. These cyclic dithioacetals coupled smoothly 3-phenyl-4-(p-tolylthio)-1H-pyrazole (6) in excellent yield of 98%.
with p-tolyl thiol and halogen substituted aryl thiols under standard
To find the possible mechanism, we performed several
conditions to yield the desired products 3ic and 3ie in excellent controlled experiments as shown in Scheme 4. In the absence of
yields (99% in each case). A similar reaction with a-naphthyl thiol 1a, the reaction of phenyl thiol (2a) under the optimized conditions
also led to the formation of product 3if in 98% yield. p-Methoxy aryl led to the formation of the corresponding disulfide (7) (eqn (i)). In
ketene cyclic dithioacetal produced sulfenylated products 3ja, the absence of both 1a and HBr, the reaction produced disulfide in
3jb and 3jf in excellent yields on reacting with phenyl thiol, low yield (eqn (ii)). These experiments suggest that disulfides
p-methoxyphenyl thiol and p-flurophenylthiol respectively. In
addition, p-tolyl cyclic dithioacetal afforded the corresponding pro-
duct 3ka in a very high yield. In the same way, halogenated aryl cyclic
dithioacetals also led to the formation of the desired sulfenylated
products 3la, 3ld, 3lf, and 3ma–mc in admirable yields. The
a-naphthyl cyclic dithioacetal also gave the products 3na and
3nd in very good yields under the optimized reaction conditions.
We also examined the reactivity of hetero aryl ketene cyclic dithio-
acetal for sulfenylation, and thus the cyclic dithioacetal containing a
Scheme 2 Gram scale reaction.
furoyl moiety on reaction with thiol and p-bromophenyl thiol
furnished the desired sulfenylated products 3oa and 3oe in 99%
and 98% yields.
All of the above successful results encouraged us to extend
this protocol for naphthol under the present oxidative sulfenylation
reaction. In this context, we chose b-naphthol for the present
sulfenylation reaction with substituted thiols (Table 3).
Scheme 3 Synthetic transformation of a sulfenylated product.
Table 3 Extension of this sulfenylation to b-naphthola
a
All reactions were carried out by using 4a (100 mg, 1.0 equiv.), 2c, e, f and g
(1.0 equiv.) and 47% aq. HBr (30 mol%) in DMSO : CHCl3 (1 : 1, v/v 2 ml) at
100 1C for 2 h.
Scheme 4 Control experiments.
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are prepared more efficiently with the HBr–DMSO system via Conclusions
oxidation of a bromide ion by DMSO than direct oxidation of
In summary, a metal free facile sulfenylation of ketene dithioacetals
has been demonstrated. This sulfenylation is achieved by the use of
a catalytic amount of inexpensive HBr–DMSO combination with
excellent yields. Various substituted sulfenylated products are
obtained in a short period of time. This sulfenylation strategy
represents considerable advancement over previously reported
sulfenylations and is a straightforward approach for large-scale
preparations without the use of toxic molecular bromine. Sulfeny-
lated b-naphthols are also achieved in excellent yields using the
present method. This method is also applied for the synthesis
of substituted pyrazole in excellent yield. Similar C–H functio-
nalizations using the HX–DMSO combination are underway in
our research group.
thiols by DMSO alone, which is in agreement with previous
reports.15 To confirm the role of DMSO as an oxidant, a reaction
was performed with 1a and 2a in the absence of DMSO, which
failed to furnish the product 3a suggesting the role of DMSO
as an oxidant (eqn (iii)). Furthermore, the obtained disulfide 7
was reacted with ketene dithioacetal under the optimized
conditions, which resulted in the formation of product 3a in
85% yield (eqn (iv)). This experiment clearly supports the
intermediacy of disulfide in the reaction. However, the reaction
of 1a with 2a in the absence of HBr was not successful and
product 3a was obtained in a very low yield of 15% (eqn (v)). This
experiment clearly supports the requirement of HBr for an
efficient sulfenylation. Additionally, the possibility of a free
radical mechanism was ruled out based on the outcome of the
reaction of 1a and 2a in the presence of 2,2,6,6-tetramethylpiperidin-
1-oxyl (TEMPO) (eqn (vi)). This experiment with TEMPO did
not give any radical trapped species, and 3a was obtained in
95% yield.
Experimental
General procedure
For the synthesis of sulfenylated ketene dithioacetals. To a
solution of ketene dithioacetal (0.44 mmol), arylthiol 2a (0.44 mmol)
in a mixture of DMSO : CHCl3 (1 : 1, 3 mL), was added 47% of aq.
hydrobromic acid (HBr) (30 mol%). The resulting mixture was
stirred at 100 1C for 2 h. Progress of the reaction was monitored
by thin layer chromatography (TLC). After completion of the
reaction, 5 mL of water was added to the reaction mixture
followed by extraction of the product by ethyl acetate (3 Â 10 mL).
The organic phases were combined and washed with a brine
solution (1 Â 10 mL). Organic phases were dried over anhydrous
Na2SO4 and the solvent was evaporated under reduced pressure
to obtain a crude product. The resulting crude product was
then purified by column chromatography using petroleum
ether and ethyl acetate (v/v = 92/8) to obtain the desired product
in a pure form.
Thus, based on these experiments and literature precedence,16
a tentative mechanism is proposed (Scheme 5). The present
sulfenylation reaction is catalyzed by the formation of molecular
bromine via oxidation of a bromide ion by DMSO during the
course of the reaction. Bromine then converts the thiol into
disulfide, which further reacts with ketene dithioacetals and
b-naphthols to produce the corresponding sulfenylated products.
The above procedure was also employed for sulfenylation of
b-naphthol.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We gratefully acknowledge DST-SERB (No. DST-SERB-2016-
ECR-172) New Delhi, India for the financial support. Authors
also thank Prof. K. R. Prabhu, IISc for the kind support and
encouragement.
Notes and references
1 (a) J. Dumas, D. Brittelli, J. Chen, B. Dixon, H. H. Mokdad,
G. Konig, R. Sibley, J. Witowsky and S. Wong, Bioorg. Med.
Chem. Lett., 1999, 9, 2531; (b) W. Huang and G. Fu Yang,
Bioorg. Med. Chem., 2006, 14, 8280; (c) L. Zhang, J. Fan, K. Vu,
K. Hong, J. Le Brazidec, J. Shi, M. Biamonte, D. J. Busch,
R. E. Lough, R. Grecko, Y. Ran, J. L. Sensintaffar, A. Kamal,
Scheme 5 Tentative reaction mechanism.
New J. Chem.
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K. Lundgren, F. J. Burrows, R. Mansfield, G. A. Timony, E. H.
Paper
7 (a) R. K. Dieter, Tetrahedron, 1986, 42, 3029; (b) M. Kolb,
Synthesis, 1990, 171.
Ulm, S. R. Kasibhatla and M. F. Boehm, J. Med. Chem., 2006,
49, 5352.
8 (a) H. Junjappa, H. Ila and C. V. Asokan, Tetrahedron, 1990,
46, 5423; (b) P. Dhanalakshmi, S. Thimmarayaperumal and
S. Shanmugam, RSC Adv., 2014, 4, 12028; (c) L. Pan, X. Bi and
Q. Liu, Chem. Soc. Rev., 2013, 42, 1251; (d) C. S. Pradeepa
Kumara, G. Byre Gowda, K. S. Vinay Kumar, N. Ramesh,
M. P. Sadashiva and H. Junjappa, Tetrahedron Lett., 2016,
57, 4302; (e) X. Yang, F. Hu, H. Di, X. Cheng, D. Li, X. Kan,
X. Zoua and Q. Zhang, Org. Biomol. Chem., 2014, 12, 8947;
( f ) T. Wu, L. Pan, X. Xu and Q. Liu, Chem. Commun., 2014,
50, 1797.
9 (a) Z. Liu, F. Huang, J. Lou, Q. Wang and Z. Yu, Org. Biomol.
Chem., 2017, 15, 5535; (b) J. W. Wen, F. Zhang, W. Y. Shi and
A. W. Lei, Chem. – Eur. J., 2017, 23, 8814; (c) Q. Wang, J. Lou,
P. Wu, K. Wu and Z. Yu, Adv. Synth. Catal., 2017, 359, 2981;
(d) D. Liang, M. Wang, Y. Dong, Y. Guo and Q. Liu, RSC Adv.,
2014, 4, 6564; (e) S. Tian, X. Song, D. Zhu and M. Wang, Adv.
Synth. Catal., 2018, 360, 1414; ( f ) H. Yu, W. Jin, C. Sun,
J. Chen, W. Du, S. He and Z. Yu, Angew. Chem., Int. Ed., 2010,
49, 5792.
2 (a) Y. Ding, W. Wu, W. Zhao, Y. Li, P. Xie, Y. Huang, Yu. Liu
and A. Zhou, Org. Biomol. Chem., 2016, 14, 1428; (b) Y. Chen,
C. H. Cho and R. C. Larock, Org. Lett., 2009, 11(1), 173;
(c) D. Y. Huang, J. X. Chen, W. X. Dan, J. C. Ding, M. C. Liu
and H. Y. Wu, Adv. Synth. Catal., 2012, 354, 2123.
3 (a) R. Jamal, S. Sumbal, R. Alex, S. F. M. Symara and
L. B. Antonio, ACS Omega, 2017, 2, 2280; (b) X. Fuhong,
X. Hao, L. Saiwen and G. J. Deng, Adv. Synth. Catal., 2014,
356, 364; (c) Y. Siddaraju and K. R. Prabhu, J. Org. Chem.,
2016, 81, 7838; (d) M. A. Hiebel and S. B. Raboina, Green
Chem., 2015, 17, 937; (e) S. Yi, M. Li, W. Mo, X. Hu, B. Hu,
N. Sun, L. Jin and Z. Shen, Tetrahedron Lett., 2016, 57, 1912;
( f ) C. Xu, S. Yi, M. Li, X. Hu, N. Sun, L. Jin, B. Hu and
Z. Shen, Synlett, 2018, 1914; (g) H. Zhang, X. Bao, Y. Song,
J. Qu and B. Wang, Tetrahedron, 2015, 71, 8885.
4 (a) M. Karki and J. Magolan, J. Org. Chem., 2015, 7(80), 3701;
(b) S. Song, X. Huang, Y. F. Liang, C. Tang, X. Lia and N. Jiao,
Green Chem., 2015, 1(17), 2727; (c) S. Song, X. Sun, X. Li, Y. Yuan
and N. Jiao, Org. Lett., 2015, 17, 2886; (d) G. Majetich, R. Hicks 10 (a) L. Zhu, H. Yu, Q. Guo, Q. Chen, Z. Xu and R. Wang, Org.
and S. Reister, J. Org. Chem., 1997, 13(62), 4321; (e) M. Inagaki,
S. Matsumoto and T. Tsuri, J. Org. Chem., 2003, 3(68), 1128;
Lett., 2015, 17, 1978; (b) E. R. Anabha and C. V. Asokan,
Synthesis, 2006, 151.
( f ) Z. Cao, D. Shi, Y. Qu, C. Tao, W. Liu and G. Yao, Molecules, 11 S. K. R. Parumala and R. K. Peddinti, Green Chem., 2015,
2013, 18, 15717; (g) D. P. Bauer and R. S. Macomber, J. Org.
Chem., 1975, 13(40), 1990.
17, 4068.
12 L. Deng and Y. Liu, ACS Omega, 2018, 3, 11890.
5 (a) E. Shipper, M. Cinnamon, L. Rascher, Y. H. Chiang and 13 G. S. Sorabad and M. R. Maddani, Metal-Free, Green and
W. Oroshnik, Tetrahedron Lett., 1968, 59, 6201; (b) T. Aida,
T. Akasaka, N. Furukawa and S. Oae, Bull. Chem. Soc. Jpn.,
1976, 49, 1117.
6 (a) A. Podgorsek, M. Eissen, J. Fleckenstein, S. Stavber, M. Zupan
and J. Iskra, Green Chem., 2009, 11, 120; (b) K. Yonehara,
Efficient Oxidative Functionalization: Halo acid DMSO for
a-C–H Halogenation of Enaminones, manuscript submitted.
14 G. S. Sorabad and M. R. Maddani, HBr–DMSO Catalyzed
Metal Free, Facile Access to Sulfenylated Chromones and
Indoles via C(sp2)–H functionalization, manuscript submitted.
K. Kamata, K. Yamaguchi and N. Mizuno, Chem. Commun., 15 (a) P. Natarajan, H. Sharma, M. Kaur and P. Sharma, Tetrahedron
2011, 6(47), 1692; (c) V. Kavala, S. Naik and B. K. Patel, J. Org.
Chem., 2005, 70, 4267; (d) C. Ye and J. N. M. Shreeve, J. Org.
Lett., 2015, 56, 5578; (b) Y. Siddaraju and K. R. Prabhu, J. Org.
Chem., 2017, 82, 3084.
Chem., 2004, 69, 8561; (e) M. Inagaki, S. Matsumoto and 16 (a) V. Venkateswarlu, K. A. A. Kumar, S. Gupta, D. Singh,
T. Tsuri, J. Org. Chem., 2003, 3(68), 1128; ( f ) D. P. Bauer and
R. S. Macomber, J. Org. Chem., 1975, 13(40), 1990; (g) B. Sels,
D. De Vos, M. Buntinx, F. Pierard, A. K. Mesmaeker and
P. Jacobs, Nature, 1999, 400, 855.
R. A. Vishwakarma and S. D. Sawant, Org. Biomol. Chem.,
2015, 13, 7973; (b) W. W. Epstein and F. W. Sweat, Chem.
Rev., 1967, 67, 247; (c) T. Aida, T. Akasaka, N. Furukawa and
S. Oae, Bull. Chem. Soc. Jpn., 1976, 49, 1117.
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