A highly efficient Cu-catalyzed S-transfer reaction: From amine to sulfide

Article abstract of DOI:10.1021/ol5009747

A highly efficient Cu-catalyzed dual C-S bonds formation reaction, proceeding in alcohol and water under air, is reported, in which inodorous stable Na₂S₂O₃ is used as a sulfurating reagent. This powerful strategy provides a practical and efficient approach to construct thioethers, using readily available aromatic amines and alkyl halides as starting materials. Sensitive and synthetic useful functional groups could be tolerated. Furthermore, pharmaceuticals, glucose, an amino acid, and a chiral ligand are successfully furnished by this late-stage sulfuration strategy.

Full text of DOI:10.1021/ol5009747

Letter
pubs.acs.org/OrgLett
A Highly Efficient Cu-Catalyzed S‑Transfer Reaction: From Amine to
Sulfide
Yiming Li,† Jiahua Pu,† and Xuefeng Jiang*,†,‡,§
†Shanghai Key Laboratory of Green Chemistry and Chemical Process, Department of Chemistry, East China Normal University,
Shanghai 200062, P. R. China
‡Beijing National Laboratory for Molecular Sciences (BNLMS), Beijing 100190, P. R. China
§State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P. R. China
S
* Supporting Information
ABSTRACT: A highly efficient Cu-catalyzed dual C−S bonds formation reaction, proceeding in alcohol and water under air, is
reported, in which inodorous stable Na2S2O3 is used as a sulfurating reagent. This powerful strategy provides a practical and
efficient approach to construct thioethers, using readily available aromatic amines and alkyl halides as starting materials. Sensitive
and synthetic useful functional groups could be tolerated. Furthermore, pharmaceuticals, glucose, an amino acid, and a chiral
ligand are successfully furnished by this late-stage sulfuration strategy.
arbon−sulfur bond formation1 is of strategic importance in
bonds. Despite this progress, there are still some drawbacks in
applications, such as odorous and expensive thiols, unavoidable
Csynthetic programs since thioether fragments widely exist
in pharmaceuticals,2 materials,3 and even kinds of food.4
over-oxidation, and sensitive substrate incompatibility.
To overcome the problems mentioned above, our group1a,7a,b
Furthermore, thioether derivatives in different oxidative states,
and Boehringer Ingelheim Pharmaceutials7c have developed
e.g., sulfone and sulfoxide, show divergent functions and
potencies as well.2 Large amounts of research being conducted
novel sulfur transfer methods using Na2S2O3 as a sulfurating
reagent. The corresponding Pd-catalyzed sulfuration, which used
and an enormous pharmaceutical market demand indicate that
highly effective and broadly tolerant C−S bond constructing
methods and late-stage sulfuration techniques are urgently
aryl halides as starting materials,7b has been achieved (Scheme 1,
eq 3). Meanwhile, we have been trying to implement the late-
stage sulfuration strategy in the modification of bioactive7b and
desired. Traditionally, some aryl alkyl thioethers could be
critical functional compounds. Aryl amines widely exist in
synthesized through thiol alkylation5 (Scheme 1, eq 1). Since the
significant pharmaceuticals2b and pesticides8 and could be used
in various conversions,9 which make the transformation from
first transition metal catalyzed thiol arylation (eq 2) developed by
Migita6a in 1980, different catalysts, such as Pd,6b−i Cu,6j−m
amine to sulfide important and promising for drug discovery.
Herein, we report an odorless, divergent, and practical dual C−S
bonds formation reaction that is convenient among aromatic
Fe,6n−q Rh,6r Ni,6s In,6t and Co,6u were tested to form sp2 C−S
Scheme 1. Strategies for Constructing Aryl-S-Alkyl
Compounds
amines, alkyl halides, and Na2S2O3 (eq 4).
We began our study by examining the reaction between 4-
methoxy aniline and benzyl chloride in the presence of Na2S2O3·
5H2O (Table 1). After the examination of different transition
metals, copper was found to be the only active catalyst species for
this transformation (entries 1−5). In view of the efficiency and
selectivity, Na2S2O3·5H2O, an alkyl chloride, a catalyst, a ligand,
and MeOH/H2O were stirred at 80 °C for 2 h and then cooled to
t
0 °C. After aniline and BuONO were added, the mixture was
stirred at rt for 10 h, which results in a 20% yield (entry 7). When
the temperature was raised to 80 °C, the desired product was
afforded in 45% yield (entry 9). Different ligands were estimated,
in which 2,2′-bipyridine (L3) was found to be the best choice
Received: April 2, 2014
Published: May 6, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
a
a
Table 1. Optimization of Reaction Conditions
Table 2. Diversity of Aryl Amines for Sulfuration
a
General procedure: To a Schlenk tube were added, Na2S2O3·5H2O
(1.0 mmol), alkyl chloride (1.0 mmol), catalyst (0.02 mmol), ligand
(0.02 mmol), and MeOH/H2O (1 mL/1 mL). The mixture was
stirred at 80 °C for 2 h, then cooled to 0 °C. After aniline (0.2 mmol)
and tBuONO (0.3 mmol) were added, the mixture was stirred at room
temperature for 10 min, then at a certain temperature for appointed
b
c
d
time. Isolated yields. All compounds were added in one step. BnCl
e
(1.4 mmol), Na2S2O3·5H2O (1.4 mmol). CuSO4·5H2O, bipy were
added in step 2. Without BnCl.
f
a
b
Standard conditions. Isolated yields are shown. Step 2, 80 °C, 24 h.
c
d
Step 2, rt, 24 h. Step 2, rt, 4.5 h.
withdrawing (26) anilines. Remarkably, substrates containing
active hydrogen, such as carboxyl acid (29), amide (30), and
hydroxyl (31−33), could be tolerated, which is a big challenge in
many coupling reactions. Moreover, sensitive coupling pre-
cursors such as Bpin (36) and diazo (37), Michael addition
precursor (38), and Cu-sensitive terminal alkyne (40) as well as
compounds bearing pyridine (41), indole (42), benzohetero-
cycle (43), and a benzo fused ring (44) could be transformed by
this method as well.
giving a 60% yield (entries 10−15). Following the transversion
through GC/MS, a reaction time of 4.5 h was found to be the
peak point (entry 16). The yield was further promoted to 99% by
increasing the amount of BnCl and Na2S2O3 to 7 equiv (entry
17). Yet, when the catalyst and ligand were added in step 2, the
yield decreased to 68% (entry 18). Remarkably, other S-sources,
such as Na2S, S8, BnSH, and BnSSBn (entries 19−22), could not
afford the transformation, showing the irreplaceability of
Na2S2O3 in this system.
Under the optimized conditions, we investigated the
sulfurating reaction with multifarious aryl amines. The results
in Table 2 showed the great functional group tolerance of the
protocol. Generally, the aniline derivatives, bearing both
electron-withdrawing and -donating groups in ortho-, meta-, or
para- positions of the amino group, afford moderate to excellent
yields (2−18). Halogen atoms are well tolerated, amazingly for
iodine (16), which should be highly reactive in coupling and
radical reactions. Notably, more sterically hindered groups, such
as 2,6-dimethyl and 2-isopropyl, could afford the desired
products (19, 20). Di- or multisubstituted thioethers could
also be obtained through this transformation (21−27), especially
for strongly electron-donating (25) and strongly electron-
After the high tolerance of aryl amine derivatives was
demonstrated, the diversity of alkyl halide partners for sulfuration
was examined. As shown in Table 3, in general, benzylic halides
with electron-withdrawing and -donating groups in different
positions could produce moderate to excellent yields (45−53).
Other activated halides, e.g., bromo acetonitrile (54), allyl
bromide (55), cinnamyl bromide (56), and 4-bromocrotonic
ethyl ester (57), could be a sulfurating partner as well.
Satisfactory results could also be achieved by using unactivated
alkyl halides (58−60).
Late-stage modification10 was considered as a valuable method
for screening drugs and constructing complex materials. Herein,
we present the late-stage sulfuration of functional aryl amines
through this protocol (Table 4). Sulfonamides11 show a broad
spectrum of antimicrobial properties and exhibit much activity
against Gram positive and Gram negative bacteria. Among these,
sulfonamide, sulfamethoxazole, and sulfadiazine were converted
to thiol ether analogues from amine substrates (61−63) in good
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Organic Letters
Letter
a
Showing the efficiency and practicability further, 4-methox-
yaniline was reacted on the gram scale to generate the desired
product 2 in 99% yield in a higher concentration. Furthermore,
the sulfide 2 could be easily transformed to sulfoxide 67 and
sulfone 68 by tuning the oxidants (Scheme 2).
Table 3. Diversity of Alkyl Halides for Sulfuration
Scheme 2. Gram Scale and Synthetic Transformations
To explore the reaction mechanism, first, benzyl thiosulfate,
which was prepared by BnCl and Na2S2O3, was used in this
reaction and a 76% yield was obtained (Scheme 3a). By adding
a
Standard conditions. Isolated yields are shown.
Scheme 3. Control Experiments
a
Table 4. Late-Stage Sulfuration of Functional Aryl Amines
additional NaCl, the yield was back to 99%, which showed that
the salt played a role in this system (see Supporting Information
(SI)). Second, a radical trapping experiment was performed
(Scheme 3). Compound 70 was obtained in 46% yield when
TEMPO was added after the addition of tBuONO. These results
indicated that a Cu-catalyzed aryl radical species existed in this
system. Meanwhile, the reaction could not proceed without
CuSO4 (Table 1, entry 6). It means that copper behaved critically
in the combination of the aryl radical and the unique sulfur
species, which contrasted with Na2S, S8, BnSH, and BnSSBn
(Table 1, entries 18−21). On the basis of the above results, we
proposed that the Cu-catalyzed thiolation reaction may proceed
through the mechanism in Scheme 4. The arene diazonium B,
which was generated in situ from aryl amine and tert-butyl nitrite,
a
b
Standard conditions, isolated yields are shown. CuSO4·5H2O (0.1
c
mmol), bipy (0.1 mmol), step 2, 80 °C, 24 h. CuSO4·5H2O (0.1
mmol), bipy (0.1 mmol). 0.1 mmol scale.
Scheme 4. Proposed Mechanism
d
yields. 62 was confirmed by X-ray crystallography analysis.12
Lenalidomide13 could significantly improve overall survival in
myeloma, which exhibits excellent reactivity producing thiol
analogue compound 64 in 93% yield. Glucose and amino acid
functional structures as essential components in a living body
could also be tolerated in our system and give desired products in
good yields (65, 66), which show the potential of this reaction in
a bioorthogonal reaction.14 A chiral aryl diamine ligand could
also be transferred into 2,2′-bis(benzylthio)-1,1′-binaphthalene
(67) without racemation, providing a convenient route to
construct corresponding chiral sulfur ligands.
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Organic Letters
Letter
(4) (a) Block, E. Angew. Chem. In. Ed. 1992, 31, 1135. (b) Lin, D. Y.;
Zhang, S. Z.; Block, E.; Katz, L. C. Nature 2005, 434, 470.
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produced Cu-intermediate C through oxidative addition with
Cu(I).15 On the other hand, alkyl halide and Na2S2O3 generated
special sulfurating reagent D.7b Then the ligands exchange
between C and D affording the Cu-intermediate E, which could
convert to intermediate F through releasing SO3. During this
step, the electron-withdrawing effect of the sulfonic acid group
weakened the strong coordinating properties from sulfur to
copper, which makes a difference from other sulfur sources. The
product emerged through reductive elimination of F, which was
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In summary, we have developed a cheap metal catalyzed sulfur
transfer reaction, which could be realized by free assembly
between aryl amines, alkyl halides, and Na2S2O3 in alcohol and
H2O under air. As a novel sulfur source, Na2S2O3 shows its
irreplaceability in this system. In contrast with organic thiols and
thiophenols, its intrinsic properties helped us accomplish this S-
atom transfer reaction efficiently and practicably. This reaction
functions under mild conditions, and various useful functional
groups are well tolerated. Most importantly, it possesses an
inspiring capability in functional compounds decoration. This
powerful late-stage sulfuration strategy will be bringing about
further profound applications in medicinal chemistry and
chemical biological studies. Further study on the mechanism
and additional applications is ongoing in our laboratory.
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ASSOCIATED CONTENT
* Supporting Information
■
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Experimental procedure, NMR spectra, and X-ray and analytical
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(9) (a) Dai, J.; Fang, C.; Xiao, B.; Yi, J.; Xu, J.; Liu, Z.; Lu, X.; Liu, L.; Fu,
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AUTHOR INFORMATION
Corresponding Author
■
Grunberg, M. F.; Gooßen, L. J. Angew. Chem., Int. Ed. 2013, 52, 7972.
̈
(c) Wang, X.; Xu, Y.; Mo, F.; Ji, G.; Qiu, D.; Feng, J.; Ye, Y.; Zhang, S. N.;
Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2013, 135, 10330. (d) Qiu, D.;
Meng, H.; Jin, L.; Wang, S.; Tang, S.; Wang, X.; Mo, F.; Zhang, Y.; Wang,
J. Angew. Chem., Int. Ed. 2013, 52, 11581. (e) Danoun, G.; Bayarmagnai,
*E-mail: xfjiang@chem.ecnu.edu.cn.
Notes
The authors declare no competing financial interest.
B.; Grunberg, M. F.; Gooßen, L. J. Chem. Sci. 2014, 5, 1312.
̈
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2013, 23, 369. (c) Lee, E.; Kamlet, A. S.; Powers, D. C.; Neumann, C. N.;
Boursalian, G. B.; Furuya, T.; Choi, D. C.; Hooker, J. M.; Ritter, T.
Science 2011, 334, 639. (d) Wang, D.; Yu, J. J. Am. Chem. Soc. 2011, 133,
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Curr. Med. Chem. 2003, 29, 925. (b) Supuran, C. T.; Casini, A.;
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ACKNOWLEDGMENTS
■
Financial support was provided by NSFC (21272075), NCET
(120178), DFMEC (20130076110023), Fok Ying Tung
Education Foundation (141011), “Shanghai Pujiang Program”
(12PJ1402500), the program for Professor of Special Appoint-
ment (Eastern Scholar) at Shanghai Institutions of Higher
Learning, and the program for the Changjiang Scholar and
Innovative Research Team in University.
(12) CCDC-983614 (62): C17H16N2O3S2, MW = 360.44, monoclinic,
space group P21/n, final R indices [I > 2σ(I)], R1 = 0.0418, wR2 = 0.0983,
R indices (all data), R1 = 0.0593, wR2 = 0.1102, a = 10.7362(5) Å, b =
14.1883(7) Å, c = 12.3716(6) Å, α = 90°, β = 108.855(2)°, γ = 90°, V =
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