Auto-oxidative hydroxysulfenylation of alkenes

Article abstract of DOI:10.1039/c6cc01937d

One-pot auto-oxidation mediated hydroxysulfenylation of electron-deficient and electron-rich olefins with phenthiols was explored. The method illustrates a selective and convenient synthesis of complex β-hydroxysulfides using O₂ as both the oxidant and the oxygen source under mild transition-metal-free conditions. The application of this new methodology to the gram-scale synthesis of anti-cancer drug bicalutamide has been accomplished in a two-step sequence with 71% overall yield. A plausible radical involved mechanism is proposed.

Full text of DOI:10.1039/c6cc01937d

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Auto-Oxidative Hydroxysulfenylation of Alkenes
Congde Huo,* Yajun Wang, Yong Yuan, Fengjuan Chen, Jing Tang
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
deficient alkenes in such a reaction still remain an huge challenge
50 for selectivity reasons.13,14 As far as we know, until now, there
have been only two successful examples. In 2008, Naito et al.
creatively developed an Et3B promoted hydroxysulfenylation
reaction of specific -unsaturated imines under aerobic
conditions.13 Last year in 2015, Li et al. presented an elegant
55 hydroxysulfenylation reaction of simple -unsaturated
esters/amides using Cu(OAc)2/PhCOOH/O2 catalytic system.14
Herein we describe our recent progress in one-pot auto-oxidative
hydroxysulfenylation of electron-deficient and electron-rich
alkenes with thiols, which illustrates an convenient method
60 towards the synthesis of complex tertiary and secondary -
hydroxysulfides using simple chemical materials under mild
transition-metal-free conditions. Air is the oxidant and air is the
oxygen source as well in this transformation.
5
One-pot auto-oxidation mediated hydroxysulfenylation of
electron-deficient and electron-rich olefins with phenthiols
was explored. The method illustrates
a selective and
convenient synthesis of complex -hydroxysulfides using O2
as the oxidant and the oxygen source as well under mild
10 transition-metal-free conditions. The application of this new
methodology to the gram-scale synthesis of anti-cancer drug
bicalutamide has been accomplished in a two-step sequence
with 71% overall yield.
mechanism is proposed.
A plausible radical involved
15 O2 is one of the most environmentally benign and sustainable
oxidant. It's also an ideal oxygen source for the functionalization
of organic molecules.1 In recent years, the development of auto-
oxidation involved novel transformations has captured growing
attention by organic chemists and a few interesting progresses
20 have been developed.2-9 Since 2010, Klussmann et al. have
performed studies on auto-oxidation and the following
functionalization of benzylic C-H bonds of xanthene, acridane
and isochromane derivatives with nucleophilic carbonyl
compounds.2 Soon afterwards, Jiao et al. developed an
25 organocatalytic asymmetric version of benzylic C-H bond auto-
oxidation in 2011.3 Four years later in 2014, Similar strategy has
also been extended to the reaction of tetrahydroisoquinolines with
a range of nucleophiles by Tokuyama et al.4 In 2010, Caddick et
al. achieved the hydroacylation of -unsaturated esters using
30 the auto-oxidation of aldehydes.5 In the same year, Alexanian et
al. developed an aerobic dioxygenation method of alkenes.6 In
2013, Lei et al. reported an attractive auto-oxidation induced
intermolecular oxysulfonylation reaction of alkenes.7 In 2014, we
present the unprecedented auto-oxidative coupling reaction
35 between glycine derivatives and indoles, as well as the auto-
oxidative Povarov/aromatization tandem reaction of glycine
derivatives with olefins.8 This year, Liu et al. delivered an
efficient auto-oxidation-aldol tandem reaction between 2-
oxindoles and Ketones.9
Scheme 1. Screening of Reaction Conditions[a,b]
65
[a]
Standard reaction conditions: 1a (1.0 mmol), 2a (0.5 mmol),
[b]
solvent (10 mL), air (open flask), rt.
All experiments were
[c]
repeated three times and the mean values are given. Reaction
[d]
time before PPh3 was added.
Isolated Yields of the isolated
70 products after PPh3 workup. DCE=1,2-dichloroethane.
40 Radical mediated hydroxysulfenylation of alkenes was first
discovered by Kharasch et al. in the 1950s, which is also called
Recently, we observed the highly efficient auto-oxidation of
glycine derivatives in acetonitrile (MeCN) and dichloroethane
(DCE) as mixed reaction solvent. The interesting results
encouraged us to find more new auto-oxidation reactions to
75 broaden the application of this solvent system. Vicinal
difunctionalization reactions have become powerful tools in
organic synthesis as mentioned above, so we paid our attention to
investigating the auto-oxidative hydroxysulfenylation reactions of
thiol-oxygen
co-oxidation
reaction.10
This
vicinal
difunctionalization reaction has gained significant notice because
the produced -hydroxysulfides are important intermediates for
45 the preparation of natural products, fine chemicals and
pharmaceuticals.11 Although electron-rich alkenes such as
styrenes have been normally applied as radical acceptors in
hydroxysulfenylation reactions,12 the applications of electron-
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electron-deficient alkenes. Our investigation commenced with the
groups at the para-, meta-, and ortho-position of the phenyl ring
reaction of p-toluenethiol 1a with methyl methacrylate 2a as
shown in Scheme 1. To our delight, the desired -hydroxysulfide
product 3aa was formed in 32% yield without any catalyst and
could furnish to the desired -hydroxysulfides in high yields
(Scheme 2, 3aa−3ka). These results inDdiOcIa:t1e0d.10t3h9a/tC6nCeCit0h1e9r37D
electronic effect or steric hindrance of phenthiols show
View Article Online
5
additive in MeCN/DCE (5:1) in two hours at room temperature. 40 significant influence on the efficiency of this method. Halogen
The other major product was identified as the corresponding -
hydroxysulfoxide (58%). Trace amount of 1,2-di-p-tolyldisulfane
could be isolated too. Very gratifyingly, The formation of
substituents such as F, Cl, and Br were all well tolerated (Scheme
2, 3ga−3ia), which made this methodology more useful for
further transformations. Multiple substituted phenthiols also
delivered the desired compounds in excellent yields (Scheme 2,
hydroxysulfoxide
10 triphenylphosphine
could
(PPh3) workup
be
totally
prevented
and the
after
desired 45 3ja, 3ka). Moreover, the corresponding product 3la could be
hydroxysulfide product 3aa could be isolated in 96% yield
(Scheme 1, entry 1). Encouraged by this result, various reaction
parameters were screened to optimize the reaction conditions.
Different solvents were examined and MeCN/DCE (5:1) was
achieved in moderate yield using thionaphthol 1l as substrates.
However, aliphatic thiols such as phenylmethanethiol and
ethanethiol could not be used under the these reaction conditions.
As shown in Scheme 3, the scope of the electron-deficient
15 found to be the best choice of this reaction (Scheme 1, entries 1– 50 alkenes in this reaction has also been evaluated by the use of p-
12). Both increasing and decreasing the temperature resulted in
slight lower yields (Scheme 1, entries 13-14). No improvement of
the transformation was observed when pure oxygen gas was used
instead of air (Scheme 1, entry 15). Furthermore, the reaction of
toluenethiol 1a as a test substrate. various -unsaturated esters
and amides were effective substrates in this system (Scheme 3,
3aa−3al). Active functional groups of alkenes, such as allyl,
hydroxy, were well tolerated (Scheme 4, 3ac, 3ad). The
20 1a with 2a in an argon atmosphere (in the absence of molecular 55 secondary and tertiary amides all reacted well (Scheme 3,
oxygen) furnished no product, indicating that molecular oxygen
is definitely crucial for the reaction (Table 1, entry 16).
3ah−3al). It is worth noting that substrate 2e derived from
stigmasterol and substrate 2f derived from trans-
dehydroandrosterone were also suitable substrates for the reaction
under the standard conditions, affording the desired product 3ae
60 and 3af in 71% and 80% isolated yield, respectively. These
products may have potential applications in pharmaceutical
chemistry. The structure of 3af was confirmed by single crystal
X-ray diffraction as shown in Scheme 3.15
Scheme 2. Reactions of thiophenols 1 with methyl methacrylate
2a[a,b,c]
Scheme 3. Reactions of p-toluenethiol 1a with -unsaturated
65 esters/amides 2[a,b,c]
3aa-3al
Ar
R1
air, rt
S
R2
R2
+
SH
O
O
MeCN/DCE (5:1), PPh3
O
HO
R1
S
2
1a
S
O
S
O
O
O
O
HO
HO
OH
3aa (96%)
3ab (49%)
3ac (93%)
OH
H
S
O
H
H
S
O
O
HO
O
3ae (71%)
HO
O
3ad (72%)
H
H
H
S
O
O
3af (80%)
HO
25
[a]
Standard reaction conditions: 1 (1.0 mmol), 2a (0.5 mmol),
S
O
S
NH
S
NH
[b]
MeCN/DCE (5:1, 10 mL), air (open flusk), rt, 1.5-6.5 h.
experiments were repeated three times and the mean values are
given.
30 workup.
All
O
O
O
HO
HO
OH
[c]
3ag (59%)
3ah (48%)
3ai (63%)
Isolated Yields of the isolated products after PPh3
Br
CN
CF3
With optimized reaction conditions in hand, we examined various
phenthiols (Scheme 2) and electron-deficient alkenes (Scheme 3)
so as to gauge the scope of this auto-oxidative
hydroxysulfenylation reaction. As shown in Scheme 2, phenthiols
35 bearing both electron-donating groups and electron withdrawing
S
NH
S
NH
S
N
O
O
O
HO
HO
HO
3aj (61%)
3ak (60%)
3al (73%)
2
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[a]
Standard reaction conditions: 1a (1.0 mmol), 2 (0.5 mmol),
substrate. As shown in Scheme 5, styrenes with electron-donating
[b]
MeCN/DCE (5:1, 10 mL), air (open flusk), rt, 1.5-9 h.
experiments were repeated three times and the mean values are
given.
All
substituents and with electron-withdrawing substituents were all
well tolerant of the standard reaction conditions. VTiehweArstitcylerOennleinse
[c]
DOI: 10.1039/C6CC01937D
Isolated Yields of the isolated products after PPh3
30 with ortho, meta or para substituents all delivered the
corresponding secondary -hydroxysulfides in high yields
(Scheme 5, 3ah−3ak), illustrating again that steric hindrance
played a poor role to the reaction. Internal alkene 2l led to the
desired product 5al in good yield under the same reaction
35 conditions. -Methylstyrene and 1,1-Diphenylethylene gave good
yields of the corresponding tertiary -hydroxysulfides in high
yields too (Scheme 5, 3am, 3an). It is worth noting that product
5ao was achieved in moderate yield using 2-methyl-1,3-butadiene
(2o, a conjugated diene) as substrate.
5
workup. Thermal ellipsoids shown at 50% probability.
Scheme 4. Gram scale synthesis of anti-cancer drug bicalutamide.
40 To have a better understanding of this transformation, a radical
trapping
experiment
was
conducted
(Scheme
6).
To demonstrate the efficiency and practicality of this
transformation, a scaled up reaction was performed between
Tetramethylpiperidin-1-oxyl (TEMPO), a well known radical
scavenger, were added in the reaction of 1a with 2a. No desired
hydroxysulfenylation product was observed in the reaction.
10 thiophenol 1g and -unsaturated esters 2k. Gram-scale
synthesis of -hydroxysulfide 3gk was achieved in 79% yield.
Subsequently, the anti-cancer drug bicalutamide (the brand name
Casodex)16 was completed in one additional step from compound
3gk to demonstrate the utility of this methodology (Scheme 4, 71%
15 overall yield).
45 However, 2,2,6,6-tetramethyl-1-((phenylthio)oxy)-piperidine
6
formed from the reaction of TEMPO and thiophenyl radical was
isolated in 25% yield. This result suggests that the reaction
includes a radical process and is initiated by a thiyl radical which
generated by auto-oxidation. Moreover, no reaction occurred
50 between 1,2-di-p-tolyldisulfane and 2a under the standard
reaction conditions. This result indicate that disulfides are not
intermediates of this transformation.
Scheme 5. Reactions of p-toluenethiol 1a with electron-rich
alkenes 4[a,b,c]
5aa-5ao
S
air, rt
R2
R2
R3
Scheme 6. Radical trapping experiment and proposed mechanism
R3
HO
+
R1
1a
R1
MeCN/DCE (5:1), PPh3
SH
4
S
S
S
OH
OH
OH
5aa (91%)
5ab (79%)
5ac (65%)
O
Br
F
S
S
S
OH
OH
OH
5ad (91%)
5ae (86%)
5af (86%)
5ai (87%)
5al (58%)
Cl
S
S
S
S
Cl
OH
OH
OH Cl
5ag (75%)
5ah (29%)
N
NO2
S
S
55 On the basis of the results obtained and previous works, a
tentative mechanism of the auto-oxidative hydroxysulfenylation
reactions was proposed as shown in Scheme 6. The thiophenol 1a
was first auto-oxidized and went through the following homolytic
cleavage of the S-O bond to form the thiyl radical A. The radical
60 addition of A to methyl methacrylate 2a affords carbon-centered
radical B. Intermediate B can react with dioxygen to provide the
peroxide radical C, which then abstracts a hydrogen atom from
substrate 1a to form the hydroperoxide D and radical A. Chain
propagation continues until all substrate 2a is consumed. Finally,
65 reductive workup by PPh3 result in the desired -hydroxysulfide
3aa.17
OH
OH
S
OH
5aj (96%)
5ak (97%)
S
S
HO
HO
5am (83%)
OH
5ao (32%)
Ph
5an (85%)
[a]
Standard reaction conditions: 1a (1.0 mmol), 4 (0.5 mmol),
[b]
20 MeCN/DCE (5:1, 10 mL), air (open flusk), rt, 1-2 h.
experiments were repeated three times and the mean values are
given.
workup.
All
[c]
Isolated Yields of the isolated products after PPh3
In summary, we have developed a sustainable and practical auto-
oxidative hydroxysulfenylation reaction of electron-deficient
alkenes and also electron-rich alkenes which leads to complex -
To develop a more general and useful method, we also
25 investigated the auto-oxidative hydroxysulfenylation reaction of
various electron-rich alkenes using p-toluenethiol 1a as a test
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Bickley, J. Davies, M. D. Bachi, P. A. Stocks, Org. Lett. 2004, 6,
3035–3038.
hydroxysulfide derivatives in a simple mixed organic solvent
under mild reaction conditions. This difunctionalization reaction
showed highly functional groups tolerance, and the construction
of C-S and C-O bond in one-pot process. This method represents
the powerful potential to construct complex bioactive and
medicinal organic frameworks. The application of this method to
the gram-scale synthesis of an anti-cancer drug bicalutamide has
been accomplished in a 2-step sequence. Further studies on the
mechanism details and synthetic applications of this methodology
View Article Online
13 M. Ueda, H. Miyabe, H. Shimizu, H. Sugino, O. Miyata, T. Naito,
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Angew. Chem. Int. Ed. 2008, 47, 5600–5604.
14
H. Xi, B. Deng, Z. Zong, S. Lu, Z. Li, Org. Lett. 2015, 17,
1180−1183.
5
15 The X-ray crystal data (excluding structure factors) of compound 3af
have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication no CCDC 1445507. Copy of
the data can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK (fax: t44 (0) 1223
336033 or e-mail: deposit@ccdc.cam.ac.uk).
70
10 are underway in our laboratory.
16 (a) N. B. Bhise, D. G. Sathe, T. Radhakrishanan, R. Deore, Synth.
Commun. 2009, 39, 1516–1526. (b) B. Chen, R. Zhao, S. Gove, B.
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17 The remove of the generated Ph3PO is a classical bench problem. To
overcome it, we tried sodium triphenylphosphine-m-sulfonate
(TPPMS) as an ion-tagged phosphine ragent to facilitate this reaction.
In the following reaction of 1a and 2a, the separation of the ion-
tagged phosphine oxide (TPPMSO) was simply carried out by
precipitation with ether after completion of the reaction. No further
purification by column chromatography is needed. The recovered
TPPMSO can be recycled back to the TPPMS by reference method,
see: C. Huo, X. He, T. H. Chan, J. Org. Chem. 2008, 73, 8583 – 8586.
Acknowledgements
75
80
85
We thank the National Natural Science Foundation of China
(21262029, 21562037) and the Natural Science Foundation of
Gansu Province (1506RJZA122) for financially supporting this
15 work.
Notes and references
a
Key Laboratory of Eco-Environment-Related Polymer Materials
Ministry of Education; College of Chemistry and Chemical Engineering,
Northwest Normal University, Lanzhou, Gansu 730070, China. E-mail:
20 huocongde1978@hotmail.com
† Electronic Supplementary Information (ESI) available: [Experimental
procedures and characterization data]. See DOI: 10.1039/b000000x/
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