Sulfoxidation of alkenes and alkynes with NFSI as a radical initiator and selective oxidant

Article abstract of DOI:10.1039/C6CC08631D

Sulfoxides are important functional molecules. We develop a short-route (one-pot) synthesis of this class of molecules by reacting thiols with alkenes or alkynes under mild and metal-free conditions. N-Fluorobenzenesulfonimide (NFSI) is used to play dual roles: as a radical initiator for a thiol-ene/-yne reaction to form sulfide adducts, and as efficient oxidant for conversion of the sulfides formed in situ to sulfoxides. Over-oxidation of the sulfoxides to sulfones is avoided in our approach.

Full text of DOI:10.1039/C6CC08631D

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DOI: 10.1039/C6CC08631D
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Sulfoxidation of Alkenes and Alkynes with NFSI as a Radical
Initiator and Selective Oxidant
Yuexia Zhang,a+ Zeng Rong Wong,a+ Xingxing Wu,a Sherman J. L. Lauw,a Xuan Huang,a Richard D.
Received 00th January 20xx,
Accepted 00th January 20xx
Webstera and Yonggui Robin Chi*ab
DOI: 10.1039/x0xx00000x
www.rsc.org/
Sulfoxides are important functional molecules. We develop a short- fluorinating agent,12 aminating reagent,13 or a combined amino
route (one-pot) synthesis of this class of molecules by reacting and fluorine source.14 In radical reactions (SET reactions), it can
thiols with alkenes or alkynes under mild and metal-free conditions. generate aminyl radical for Cu-catalyzed radical amination of
N-fluorobenzenesulfonimide (NFSI) is used to play dual roles: as a olefins, as reported by Kanai,15 Zhang16 and Studer.17 Zhang and
radical initiator for a thiol-ene/-yne reaction to form sulfide co-workers also developed radical aminofluorination of
adducts, and as efficient oxidant for conversion of the sulfides styrenes using NFSI.18 In addition, Ritter reported Pd-catalyzed
formed in situ to sulfoxides. Over-oxidation of the sulfoxides to direct radical arene amination with NFSI,19 and Studer
sulfones is avoided in our approach.
developed radical aminooxygenation of alkenes with NFSI in
combination with TEMPONa.20
The sulfoxide moiety is a functional group often found in
pharmaceuticals and natural products, such as Esomeprazole,1
Armodafinil2 and Alliin.3 Sulfoxides are also used as ligands for
metal catalysts with applications in a large set of reactions,
including Pummerer4 and Mislow-Evans rearrangements.5 To
date, the synthesis of sulfoxides typically involves oxidation of
sulfides using peroxides6 and hypervalent iodine reagent7 as the
oxidants with the assistance of transition metal catalysts.8 One
challenge of this otherwise widely used two-step protocol lies Figure 1 Our strategy of NFSI-enabled selective one-pot access to
with over-oxidation of sulfoxides to sulfones.6 Here we report a sulfoxides from alkenes/alkynes and thiols
new method that selectively converts alkenes and alkynes to
sulfoxides in a one-pot metal-free operation (Figure 1). N-
fluorobenzenesulfonimide (NFSI), a shelf-stable reagent,9 is
Our initial design was to combine NFSI and thiol to generate
used as a radical initiator and a selective oxidant. No over- thiyl and aminyl radicals for aminosulfidation of alkenes. We
oxidation of sulfoxides to sulfones was observed (Figure 1). first studied reactions between alkene 1a and thiol 2a with NFSI
Notably, Yadav10 and Lei11 have recently reported reactions as a potential radical generator in the presence of K2CO3 or
of alkenes and thiols under dioxygen to form -keto sulfoxides K3PO4 as the base (Table 1, entry 1). The expected alkene
and -oxy sulfoxides. In their reactions, oxidation of the alkene aminosulfidation adduct was not formed. Instead, we found
b
b
carbon by oxygen occurred concurrently. The NFSI reagent used alkene sulfoxidation adduct 3a as the product in 11% yield
in our reactions has often been employed as electrophilic (entry 1). Additional evaluation of the base effects (Table 1,
entries 2-6) indicated that 1,8-diazabicycloundec-7-ene (DBU)
performed the best, giving 3a in 72% yield (Table 1, entry 6).
Several other solvents studied here did not work as well as
toluene (Table 1, entries 7-10). The yield of 3a (based on 1a
)
could be further improved by increasing the loadings of thiol 2a
and NFSI (Table 1, entry 11).
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Table 1 Screening of reaction conditions for the reaction of 1a with 2a in the
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DOI: 10.1039/C6CC08631D
presence of NFSI.a
H
O
S
NFSI (130 mol%)
Base (50 mol%)
Solvent
Ph
PhSH
+
H3C
H3C
degassed, N2, RT
2a
1a
3a
(120 mol%)
Entry
Base
Solvent
Yield [%]b
11
1
2
K2CO3 or K3PO4
KOMe
NaOtBu
DIPEA
DABCO
DBU
toluene
toluene
toluene
toluene
toluene
toluene
THF
23
3
29
4
43
5
66
6
72
7
DBU
52
8
DBU
dioxane
CH3CN
EA
31
9
DBU
26
10
11c
DBU
48
DBU
toluene
87
a Conditions: 1a (0.2 mmol, 1.0 equiv.), 2a (0.24 mmol, 1.2 equiv.), NFSI (130
mol%) and base (50 mol%) in 3.0 mL of solvent at rt for 2~5 h; b Isolated yield
based on 1a. c 2a (0.4 mmol, 2.0 equiv.), NFSI (0.36 mmol, 1.8 equiv.).
With an acceptable condition (Table 1, entry 11) on hand, we
proceeded to explore the scope of the reaction (Table 2). We
first examined the reaction between various alkenes and thiol
a Conditions as in Table 1, entry 11; yields (after SiO2 chromatography
purification) were based on olefin 1
. bDiastereoselective ratio (d.r.) was
2a
patterns on the phenyl ring worked effectively (3a
alkenes, such as indene (3m), 1,2-dihydronaphthalene (3n),
trans- -methylstyrene (3o) were also effective substrates.
(
3a
-
3p). Styrenes with different substituents or substitution
determined via 1H NMR analysis of the product mixture.
-
3l). Internal
b
The proposed reaction pathway is illustrated in Scheme 1.
Notably, no sulfoxidation products were obtained when
aliphatic alkenes were used. Substituents (e.g., CH3 and Br)
Initially, removal of one electron from thiol 2a by oxidant
NFSI12a,12b generates radical cation
A
that can be subsequently
after a proton transfer (Scheme
1a). Thereafter, addition of radical to alkene forms radical
intermediate . A hydrogen atom transfer (HAT) from a
molecule of 2a converts to sulfide with the regeneration of
the thiyl radical intermediate which returns back into the
propagation step (scheme 1b). Finally, the sulfide is oxidized
to sulfoxide by NFSI. One possible pathway (see SI for another
possibility) for the oxidation of sulfide involves nucleophilic
addition of the sulfide to the electrophilic fluorine atom of NFSI
to afford intermediate (Scheme 1c). Substitution of the
fluorine atom of by water forms that then transforms to
sulfoxide after a proton transfer process.
could be placed on the phenyl unit of thiol 2a
napthyl thiol (3s) was also tolerated.
(3q, 3r), while 2-
transformed to thiyl radical
B
B
1
We next found that alkynes could be used as substrates (to
replace alkenes) under the same condition, affording
unsaturated sulfoxides as the products (Table 3). The reactions
proceeded smoothly for aryl alkynes with either electron-
withdrawing or electron-donating substituents present on the
C
C
D
B
D
3
aromatic ring (4a-4e) to afford the desired products (5a
-5e) in
D
moderate to excellent yields. Alkyl alkynes (4f 4i-j) and alkynes
,
bearing an ester (4g) or silyl (4h) moiety were also effective
E
substrates.21 The structures of two vinylsulfoxide products (E-
E
G
5a
,
E-5d
)
were unambiguously assigned via X-ray
3
crystallography.
Table 3 Substrate scope for reactions of alkynes with thiols in the presence of
NFSI. a
Table 2 Substrate scope for reactions of alkenes with thiols in the presence of
NFSI.a
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Adducts 7, 8 and 9 (89% of combined yields based on thiol 2a)
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DOI: 10.1039/C6CC08631D
were previously reported by Greci and co-workers in a study on
the reaction between 2a and TEMPO.22 The use of diphenyl
disulfide
7 in place of thiophenol 2a did not lead to desired
product 3a (Scheme 2b), suggesting that under the oxidative
condition of NSFI the disulphide adduct did not convert to thiol.
The oxygen atom in the sulfoxide product came from the trace
amount of H2O present in the solvent, as suggested by an 18O
isotope labelling experiment (Scheme 2c). Additional
experiments by adjusting the loadings of NFSI (Scheme 2d)
suggest that both the thiol-ene reaction and oxidation reaction
are enabled by NFSI. When 30 mol % of NFSI was added, only
sulfide adduct 10 was observed. Sulfide 10 could then be
transformed under standard conditions to sulfoxide 3a 23
. These
experiments (Scheme 2a, b) support the formation of radical
intermediate as proposed in Scheme 1a and 1b. The results
(Scheme 2c, d) showed that the formation of sulfide (
1c) and its oxidation occurs in a stepwise process.
D, scheme
a Alkyne (0.2 mmol), 2a (0.4 mmol), NFSI (0.36 mmol) and DBU (50 mol%), in
toluene (3 mL) at rt for 16h; yields (after SiO2 chromatography purification)
b
were based on alkyne. The ratio of E/Z was determined by the weight of
isolated E and Z products.
Scheme 1 Proposed reaction pathway.
To investigate the reaction mechanism, we performed
multiple experiments (Scheme 2). The addition of TEMPO
inhibited the formation of 3a (Scheme 2a). In the presence of
150 mol% TEMPO, the formation of sulfoxide product 3a was
Scheme 2 Experiments to probe mechanism.
completely suppressed. The aminooxygenation adduct
6
previously reported by Studer20 was observed in about 5% yield.
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12 (a) X. Dong, W. Yang, W. Hu, J. Sun, Angew. Chem. Int. Ed.
In summary, we have developed a facile synthesis of
sulfoxides from alkenes and alkynes in the presence of NFSI.
Sulfoxides are useful structural moieties for construction of
natural products and other functional molecules. Our approach
provides a metal-free and concise synthesis of this class of
molecules. The substrates and reagents used in our approach
are either inexpensive or readily available with reasonable cost.
NFSI is used as a radical initiator (to initiate the sulfide
formation) and a selective oxidant (to transform sulfides to
sulfoxides). The oxygen atom in the sulfoxide products was
determined to originate from trace water in the reaction
mixture, providing a simple way for the incorporation of 18O
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2015, 54, 660-663; (b) N. Kuhl, M. N.DHOoI:p1k0i.n10s3o9n/,CJ6.CWC0e8n6c3e1Dl-
Delord, F. Glorius, Angew. Chem. Int. Ed. 2012, 51, 10236-
10254; (c) D. D. Steiner, N. Mase, C. F. Barbas, 3rd, Angew.
Chem. Int. Ed. 2005, 44, 3706-3710; (d) T. D. Beeson, D. W. C.
MacMillan, J. Am. Chem. Soc. 2005, 127, 8826-8828.
13 (a) K. Sun, Y. Li, T. Xiong, J. Zhang, Q. Zhang, J. Am. Chem. Soc.
2011, 133, 1694-1697; (b) J. Trenner, C. Depken, T. Weber, A.
Breder, Angew. Chem. Int. Ed. 2013, 52, 8952-8956; (c) T.
Xiong, Y. Li, Y. Lv, Q. Zhang, Chem. Commun. 2010, 46, 6831-
6833.
14 (a) Y. Li, N. Lou, L. Gan, Org. Lett. 2015, 17, 524-527; (b) S. Qiu,
T. Xu, J. Zhou, Y. Guo, G. Liu, J. Am. Chem. Soc. 2010, 132
2856-2857.
,
15 K. Kaneko, T. Yoshino, S. Matsunaga, M. Kanai, Org. Lett. 2013,
15, 2502-2505.
isotope
to
sulfoxide-containing
molecules.
Further
development of related radical reactions, including catalytic
versions mediated by carbene organic catalysts, is in progress.
16 J. Sun, G. Zheng, T. Xiong, Q. Zhang, J. Zhao, Y. Li, Q. Zhang,
ACS Catal. 2016, 6, 3674-3678.
17 B. Zhang, A. Studer, Org. Lett. 2014, 16, 1790-1793.
18 H. Zhang, Y. Song, J. Zhao, J. Zhang, Q. Zhang, Angew. Chem.
Int. Ed. 2014, 53, 11079-11083.
19 G. B. Boursalian, M. Y. Ngai, K. N. Hojczyk, T. Ritter, J. Am.
Chem. Soc. 2013, 135, 13278-13281.
20 Y. Li, M. Hartmann, C. G. Daniliuc, A. Studer, Chem. Commun.
2015, 51, 5706-5709.
21 When internal alkyne 4k was used as the substrate, product
5k was isolated in low yield
Acknowledgements
We thank Dr. Yongxin Li (NTU) and Dr. Rakesh Ganguly for
assistance with X-ray structure analysis; We acknowledge
financial support by the Singapore National Research
Foundation (NRF-NRFI2016-06), the Ministry of Education of
Singapore (MOE2013-T2-2-003), Nanyang Technological
University (NTU, Singapore), China’s Ministry of Education,
National Key program for Basic Research (No. 2010CB 126105),
Thousand Talent Plan (700059143302), National Natural
Science Foundation of China (No. 21132003; No. 21472028).
Guizhou Province Returned Oversea Student Science and
Technology Activity Program, Science and Technology of
Guizhou Province, and Guizhou University.
22 P. Carloni, E. Damiani, M. Iacussi, L. Greci, P. Stipa, D. Cauzi, C.
Rizzoli, P. Sgarabotto, Tetrahedron 1995, 51, 12445-12452.
23 When
the
electron-deficient
aryl
thiol
2,3,5,6-
tetrafluorobenzenethiol was used, no desired sulfoxide was
isolated, instead sulfide 3u was isolated in 98% yield. This
might be due to the electron-deficient sulfide not being easy
to oxidize.
Notes and references
1
2
C. M. Spencer, D. Faulds, Drugs. 2000, 60, 321-329.
K. P. Garnock-Jones, S. Dhillon, L. J. Scott, CNS Drugs. 2009, 23
793-803.
,
3
4
A. Stoll, E. Seebeck, Advances in Enzymology and Related
Areas of Molecular Biology, Volume 11. 2006, 377-400.
For selected reviews on Pummer rearrangments, see (a) S. K.
Bur, A. Padwa, Chem. Rev. (Washington, DC, U. S.) 2004, 104
,
2401-2432; (b) K. S. Feldman, Tetrahedron 2006, 62, 5003-
5034; (c) L. H. Smith, S. C. Coote, H. F. Sneddon, D. J. Procter,
Angew. Chem. Int. Ed. 2010, 49, 5832-5844.
C. M. Rojas, in Molecular Rearrangements in Organic
Synthesis, John Wiley & Sons, Inc, 2015, pp. 569-626.
See the review: K. Kaczorowska, Z. Kolarska, K. Mitka, P.
Kowalski, Tetrahedron 2005, 61, 8315-8327.
5
6
7
(a) M. Xia, Z. C. Chen, Synth. Commun. 1997, 27, 1315-1320;
(b) B. Yu, C. X. Guo, C. L. Zhong, Z. F. Diao, L. N. He,
Tetrahedron Lett. 2014, 55, 1818-1821.
8
(a) M. Matteucci, G. Bhalay, M. Bradley, Org. Lett. 2003, 5,
235-237; (b) W. Dai, J. Li, B. Chen, G. Li, Y. Lv, L. Wang, S. Gao,
Org. Lett. 2013, 15, 5658-5661; (c) X. F. Wu, Tetrahedron Lett.
2012, 53, 4328-4331; (d) M. Bagherzadeh, M. M. Haghdoost,
A. Shahbazirad, J. Coord. Chem. 2012, 65, 591-601.
X. Yang, T. Wu, R. J. Phipps, F. D. Toste, Chem. Rev.
(Washington, DC, U. S.). 2015, 115, 826-870.
9
10 T. Keshari, V. K. Yadav, V. P. Srivastava, L. D. S. Yadav, Green.
Chem. 2014, 16, 3986-3992.
11 H. Wang, Q. Lu, C. Qian, C. Liu, W. Liu, K. Chen, A. Lei, Angew.
Chem. Int. Ed. 2016, 55, 1094-1097.
4 | J. Name., 2012, 00, 1-3
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