Copper-Mediated Sulfonylation of Aryl C(sp2)-H Bonds with Sodium and Lithium Sulfinates

Article abstract of DOI:10.1002/adsc.201500793

A copper-mediated direct sulfonylation of aryl C(sp²)-H bonds with sodium and lithium sulfinates is reported. Various aryl sulfones were synthesized in moderate to excellent yields with good functional group tolerance.

Full text of DOI:10.1002/adsc.201500793

UPDATES
DOI: 10.1002/adsc.201500793
2
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Copper-Mediated Sulfonylation of Aryl C(sp ) H Bonds with
Sodium and Lithium Sulfinates
Shuai Liang,a Nai-Wei Liu,a and Georg Manolikakesa,*
a
Department of Organic Chemistry and Chemical Biology, Goethe University Frankfurt, Max-von-Laue-Straße 7, 60438,
Frankfurt am Main, Germany
E-mail: g.manolikakes@chemie.uni-frankfurt.de
Received: August 24, 2015; Revised: October 12, 2015; Published online: December 17, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500793.
Abstract: A copper-mediated direct sulfonylation of
aryl C(sp ) H bonds with sodium and lithium sulfi-
nates is reported. Various aryl sulfones were synthe-
sized in moderate to excellent yields with good
functional group tolerance.
poor functional group compatibility and/or regioselec-
tivity issues.[1] In recent years several efficient reac-
tions of sodium sulfinates in metal-free[5] and metal-
catalyzed[6] processes have been reported. These
methods have been extended to three-component,
one-pot syntheses of sulfones with in situ generated
lithium, magnesium or zinc sulfinates.[7] However, one
common drawback of these methods is the utilization
of prefunctionalized coupling partners. The transition-
2
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À
Keywords: amide-oxazolines; C H activation;
copper; sulfinates; sulfonylation
À
metal catalyzed direct functionalization of C H
bonds has emerged as an attractive, atom-economic
alternative.[8] In 2009 Dong and co-workers reported
2
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Aryl sulfones are versatile intermediates in organic the first Pd-catalyzed C(sp ) H bond sulfonylation of
chemistry and important target structures in the syn- 2-arylpyridines with sulfonyl chlorides as an electro-
thesis of pharmaceuticals and functional materials.[1] phile.[9] Removal of the pyridine directing group is
Aryl sulfones are found in a variety of biologically not possible in this case and further improvements
active molecules such as Dapsone,[2] Casodex[3] or Py- would be highly desirable.[10] In the last 15 years, sig-
roxasulfone (Figure 1).[4]
nificant advances have been made in the field of oxi-
À
As a result of their interesting properties, efficient dative couplings of C H bonds for the construction of
À
À
and practical methods for the synthesis of sulfones C C and C X, so-called cross-dehydrogenative cou-
are in high demand. Traditional approaches, such as plings (CDC).[11] In this context several groups have
the oxidation of sulfides or the sulfonylation of arenes developed oxidative couplings of sodium sulfinates
in the presence of strong acids tend to suffer from with indoles.[12] Recently, the groups of Tan and Shi
2
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reported two copper-mediated/catalyzed C(sp ) H
sulfonylations of benzoic acids with sodium sulfinates
employing either the 8-aminoquinoline (AQ)[13] or 2-
pyridinyl isopropyl (PIP)[14] directing group. Herein
we wish to report a copper-mediated sulfonylation of
2
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aryl C(sp ) H bonds with sodium as well as lithium
sulfinates directed by the amide-oxazoline directing
group (Oxa).
Prompted by the work of Yu on Cu-mediated
ortho-functionalization using the amide-oxazoline di-
recting group,[15] we subjected amide 1a to various
conditions in the presence of sodium sulfinate 2a as
2
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coupling partner (Table 1). The aryl C(sp ) H sulfo-
nylation proceeded in various solvents in the presence
of 2 equiv. of TsNa, 1 equiv. of Cu(OAc)2·H2O and
2 equiv. of K2CO3 at 808C (entries 1–5) Notably, best
Figure 1. Biologically active aryl sulfones.
yields were obtained in trifluoroethanol (TFE).
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Shuai Liang et al.
Table 1. Optimization of the reaction.[a]
Entry
Cu salt [equiv.]
Base
Solvent Yield
[%][b]
1
2
3
4
5
6
7
8
Cu(OAc)2·H2O [1]
Cu(OAc)2·H2O [1]
Cu(OAc)2·H2O [1]
Cu(OAc)2·H2O [1]
Cu(OAc)2·H2O [1]
Cu(OAc)2·H2O [1]
Cu(OAc)2·H2O [1]
Cu(OAc)2·H2O [2]
Cu(OAc)2·H2O [0.5]
Cu(OAc)2·H2O [2]
Cu(OAc)2·H2O [2]
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMSO 34
DMF
THF
TFE
39
6
57
HFIP[c] 43
Na2CO3 TFE
28
54
61
52
69
74
<60
82
25
62
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
9
10[d]
11[d,e]
12[d,e]
13[d,e]
CuCl2, CuBr2, CuI [2] K2CO3
Cu(OAc)2 [2]
K2CO3
K2CO3
K2CO3
14[d,e,f] Cu(OAc)2 [2]
15[d,e,g] Cu(OAc)2 [2]
[a]
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), Cu
catalyst, base (0.4 mmol) in solvent (2 mL) at 808C for
20 h.
[b]
Yield determined by 1H NMR with CH2Br2 as internal
standard.
[c]
[d]
[e]
[f]
1,1,1,3,3,3-Hexafluoro-2-propanol (HFIP).
With 3 equiv.of TsNa.
Reaction performed in 1 mL of TFE.
Reaction performed at 608C.
Scheme 1. Scope of benzamides. Reaction conditions:
1 (0.2 mmol), 2a (0.6 mmol), Cu(OAc)2 (0.4 mmol), K2CO3
(0.4 mmol) in TFE (1 mL) at 808C for 20 h under air.
[g]
Reaction performed at 1008C.
Among various bases screened, K2CO3 gave the high- benzamides bearing a halogen (3f, 3g), trifluorometh-
est yields (entries 6 and 7). The yield increased to yl (3l), keto (3k) or nitro (3h) group proceeded
69% when 2 equiv. of Cu(OAc)2·H2O and 3 equiv. of smoothly, affording the desired diaryl sulfones in 48–
TsNa were employed (entries 8 and 10). Reducing the 82% yield. The method is somewhat sensitive to
amount of copper catalyst lead to a decreased yield steric hindrance. Reaction of benzamide 1b bearing
(entry 9). Further evaluation of the reaction condi- a methyl group in ortho positions (3b) required
tions revealed that the yield could be increased to higher temperatures of 1008C to obtain the sulfone in
82% by using anhydrous Cu(OAc)2 and performing 65% yield. In the case of meta-substituted benzamide
the reaction at higher concentrations (entries 11 and 3c, even higher temperatures were required to ach-
13). Other copper salts displayed reduced reactivity ieve reasonable conversion rates. Even so the sulfone
and changes of the temperature resulted in lower was obtained in only 46% yield. Heterocycles such as
yields (entries 12, 14, and 15).
pyridine (3m) or furan (3n) could also be sulfonylated
With the optimized conditions in hand, we explored albeit in lower yields (22–30%).
the reaction scope in terms of the benzamide compo-
Subsequently the scope of the sodium sulfinate
nent (Scheme 1). In general, both electron-withdraw- component was investigated (Scheme 2). A range of
ing and electron-donating substituents in the para-po- para-substituted arylsulfinic acids sodium salts deliv-
sition (3d–3l) were well tolerated. Reactions with ered the desired products in high yields. Sodium ben-
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Copper-Mediated Sulfonylation of Aryl C(sp ) H Bonds
zenesulfinates bearing fluoro (4c), chloro (4g), tri-
fluoromethyl (4f) or electron-donating (4d, 4e)
groups were well tolerated. Reaction with sodium
methyl sulfonate afforded alkyl aryl sulfone 4i in 55%
yield. In the cases of heterocyclic sulfones (4k, 4l) and
trifluoromethylsulfinate (4j), no desired products
could be obtained.
Although the scope of this oxidative coupling is
quite broad, this method is inherently limited by the
restricted access to the required sodium sulfinates.[16]
The group of Willis and we have shown that lithium,
magnesium or zinc sulfinates, generated from the re-
action of an organometallic reagent and an appropri-
ate sulfur dioxide source, are attractive and readily
available alternatives to sodium sulfinates and suit-
able reagents for a variety of transformations.[7]
Therefore we investigated the reaction with benzene-
sulfinic acid lithium salt 5a as sulfonylating reagent in
our transformation. The lithium salt was readily pre-
pared from commercial available phenyllithium and
sulfur dioxide. To our delight, the copper-mediated re-
action of the lithium sulfinate with benzamide 1a,
bearing the Oxa directing group, furnished the desired
sulfone 4b in 81% yield (Scheme 3).[17] Similar reac-
tions with benzamides bearing the AQ or PIP direct-
ing group and employing the reaction conditions re-
ported by Tan[13] and Shi[14] delivered the sulfonylated
Scheme 2. Scope of sulfinates. Reaction conditions: 1a
(0.2 mmol), sulfinate 2 (0.6 mmol), Cu(OAc)2 (0.4 mmol),
K2CO3 (0.4 mmol) in TFE (1 mL) at 808C for 20 h under
air.
Scheme 3. Sulfonylation of benzoic acids bearing different
directing groups with lithium sulfinates. Reaction conditions:
all reactions are carried out using conditions as reported in
ref.[13] (AQ), ref.[14] (PIP) and herein (Oxa).
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Shuai Liang et al.
well as lithium sulfinates are well tolerated. In combi-
nation with the generation of lithium sulfinates from
organolithium reagents and sulfur dioxide, this novel
methods allows the rapid construction of aryl sulfones
from readily available starting materials. Currently we
are investigating the extension of this strategy to
other organometallic compounds as well as the activa-
Scheme 4. Synthesis of diaryl sulfone 4b.
3
[19]
À
tion of C(sp ) H bonds.
products in only 27% and 18% yield (6b, 6c), high- Experimental Section
lighting the superior directing effect of the Oxa
group. The reaction of butanesulfinic acid lithium salt Typical Procedure for the Coupling of Sodium
5b, derived from n-BuLi, with benzamide 1a afforded Sulfinates
alkyl aryl sulfone 6d in 44% yield.
One of the most atom-economical routes to orga-
nolithium reagents is the direct deprotonation of
A sealed 10-mL screw cap glass vial was charged with a mag-
netic stirring bar, benzoic acid derivative 1 (1.0 equiv.,
0.2 mmol), sodium sulfinate
2
(3.0 equiv., 0.6 mmol),
[18]
À
acidic C H functionalities. In order to explore the
compatibility of our oxidative coupling with the in
situ generation of organolithium reagents, benzene
was deprotonated with n-BuLi/TMEDA (Scheme 4).
Reaction of the resulting organolithium compound
with sulfur dioxide furnished lithium benzenesulfi-
nate. After removal of solvents and excess sulfur di-
oxide, the crude sulfinate was subjected directly to
the copper-mediated coupling affording diaryl sulfone
in 61% yield. This three-step protocol allows the
Cu(OAc)2 (72.8 mg, 2.0 equiv., 0.4 mmol), K2CO3 (55 mg,
2.0 equiv., 0.4 mmol) and TFE (0.2M referred to benzoic
acid derivative, 1 mL). The vial was closed with a teflon-
lined screw cap and the resulting reaction mixture was
stirred at 808C for 20 h. After cooling down to room tem-
perature, ammonium hydroxide (1M, 10 mL) was added.
The aqueous layer was extracted with EtOAc (2”15 mL).
The combined organic layers were washed with saturated
aqueous NaCl (15 mL), dried over Na2SO4, and concentrat-
ed under reduced pressure. Purification of the crude residue
by column chromatography (Hexane/EtOAc) afforded the
analytically pure product.
direct synthesis of diaryl sulfones via stepwise func-
2
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tionalization of two aryl C(sp ) H bonds and should
find further application in the preparation of more
complex sulfones.
Finally, removal of the Oxa-directing group can be
Acknowledgements
achieved by
a standard deprotection procedure
(Scheme 5).[15b]
This work was financially supported by the Fonds der Che-
mischen Industrie (Liebig Fellowship to G. M.) and the pro-
gram of China Scholarships Council (PhD fellowship to S.
Liang, No. 201406240029). We would like to thank Prof. Mi-
chael Gçbel (Goethe University Frankfurt) for his support,
and BASF SE, Evonik Industries AG, and Rockwood Lithi-
um GmbH for the generous donation of chemicals.
In summary, we have developed an efficient
2
À
copper-mediated sulfonylation of aryl C(sp ) H
bonds assisted by an amide-oxazoline directing group.
The reaction scope is very broad and both sodium as
References
[1] a) S. Patai, C. Z. Rappoport, J. M. Stirling, The Chemis-
try of Sulfones and Sulfoxides, Wiley, New York, 1988;
b) N. S. Simpkins, Sulphones in Organic Synthesis, Per-
gamon Press, Oxford, 1993.
[2] R. L. Lopez de Compadre, R. A. Pearlstein, A. J. Hop-
finger, J. K. Seyde, J. Med. Chem. 1987, 30, 900.
[3] P. Iversen, C. J. Tyrrell, A. V. Kaisary, J. B. Anderson,
H. E. I. N. Van Poppel, T. L. Tammela, I. Melezinek, J.
Urol. 2000, 164, 1579.
[4] Y. Tanetani, K. Kaku, K. Kawai, T. Fujioka, T. Shimizu,
Pestic. Biochem. Physiol. 2009, 95, 47.
[5] a) Y. Yang, Z. Chen, Y. Rao, Chem. Commun. 2014, 50,
15037; b) S. K. Aithagani, K. R. Yempalla, G. Munaga-
la, R. A. Vishwakarma, P. P. Singh, RSC Adv. 2014, 4,
50208; c) V. G. Pandya, S. B. Mhaske, Org. Lett. 2014,
Scheme 5. Removal of the directing group.
162
asc.wiley-vch.de
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 159 – 163

2
À
UPDATES
Copper-Mediated Sulfonylation of Aryl C(sp ) H Bonds
16, 3836; d) N. Umierski, G. Manolikakes, Org. Lett.
133, 19298; b) Z.-Y. Wu, H.-Y. Song, X.-L. Cui, C. Pi,
W.-W. Du, Y.-J. Wu, Org. Lett. 2013, 15, 1270.
[11] a) C.-J. Li, Acc. Chem. Res. 2009, 42, 335; b) S. A.
Girard, T. Knauber, C.-J. Li, Angew. Chem. 2014, 126,
76; Angew. Chem. Int. Ed. 2014, 53, 74; c) R. Samanta,
K. Matcha, A. P. Antonchick, Eur. J. Org. Chem. 2013,
26, 5769.
[12] a) F. Xiao, H. Chen, H. Xie, S. Chen, L. Yang, G.-J.
Deng, Org. Lett. 2014, 16, 50; b) P. Katrun, C. Mueang-
kaew, M. Pohmakotr, V. Reutrakul, T. Jaipetch, D.
Soorukram, C. Kuhakarn, J. Org. Chem. 2014, 79, 1778;
c) A. M. A. Nassoy, P. Raubo, J. P. A. Harrity, Chem.
Commun. 2015, 51, 5914.
2013, 15, 188; e) S. Liang, R.-Y. Zhang, L.-Y. Xi, S. Y.
Chen, X.-Q. Yu, J. Org. Chem. 2013, 78, 11874; f) K. M.
Maloney, J. T. Kuethe, K. Linn, Org. Lett. 2011, 13,
102; g) R. Chawl, R. Kapoor, A. K. Singh, L. D. S.
Yadav, Green Chem. 2012, 14, 1308.
[6] For selected references, see: a) A. Kar, I. A. Sayyed,
W. F. Lo, H. M. Kaiser, M. Beller, M. K. Tse, Org. Lett.
2007, 9, 3405; b) J. M. Baskin, Z. Wang, Org. Lett.
2002, 4, 4423; c) W. Zhu, D. Ma, J. Org. Chem. 2005,
70, 2696; d) S. Cacchi, G. Fabrizi, A. Goggoamani,
L. M. Parisi, R. Bernini, J. Org. Chem. 2004, 69, 5608;
e) S. Cacchi, G. Fabrizi, A. Goggiamani, L. M. Parisi,
Org. Lett. 2002, 4, 4719; f) B. P. Bandgar, S. V. Bettigeri,
J. Phopase, Org. Lett. 2004, 6, 2105.
[13] J. Liu, L. Yu, S. Zhuang, Q. Gui, X. Chen, W. Wang, Z.
Tan, Chem. Commun. 2015, 51, 6418.
[14] W.-H. Rao, B.-F. Shi, Org. Lett. 2015, 17, 2784.
[15] a) M. Shang, S.-Z. Sun, H.-X. Dai, J.-Q. Yu, J. Am.
Chem. Soc. 2014, 136, 3354; b) M. Shang, H.-L. Wang,
S.-Z. Sun, H.-X. Dai, J.-Q. Yu, J. Am. Chem. Soc. 2014,
136, 11590; c) M. Shang, S.-Z. Sun, H.-L. Wang, B. N.
Laforteza, H.-X. Dai, J.-Q. Yu, Angew. Chem. 2014,
126, 10607; Angew. Chem. Int. Ed. 2014, 53, 10439;
d) M. Shang, S.-Z. Sun, H.-X. Dai, J.-Q. Yu, Org. Lett.
2014, 16, 5666; e) H.-L. Wang, M. Shang, S.-Z. Sun, Z.-
L. Zhou, B. N. Laforteza, H.-X. Dai, J.-Q. Yu, Org.
Lett. 2015, 17, 1228.
[16] Only a few sulfinic acid sodium salts are commercially
available. Most commonly the sodium salts have to be
prepared from the corresponding sulfonyl chlorides
(ref.[1]), which limits their applicability.
[17] Preparation of the lithium salt with the DABSO re-
agent (ref.[7c]), gave a low yield. We assume that the
formed DABCO reduces the reactivity of the copper
salt.
[7] a) E. J. Emmett, B. R. Hayter, M. C. Willis, Angew.
Chem. 2013, 125, 12911; Angew. Chem. Int. Ed. 2013,
52, 12679; b) B. N. Rocke, K. B. Bahnck, M. Herr, S.
Lavergne, V. Mascitti, C. Perreault, J. Polivkova, A.
Shavnya, Org. Lett. 2014, 16, 154; c) M. C. Willis, A. J.
Hennessy, C. J. Russell, A. S. Deeming, Org. Lett. 2014,
16, 150; d) N. Umierski, G. Manolikakes, Org. Lett.
2013, 15, 188; e) A. Shavnya, S. B. Coffey, A. C. Smith,
V. Mascitti, Org. Lett. 2013, 15, 6226.
[8] For selected reviews, see: a) D. Alberico, M. E. Scott,
M. Lautens, Chem. Rev. 2007, 107, 174; b) K. M. Engle,
T.-S. Mei, M. Wasa, J.-Q. Yu, Acc. Chem. Res. 2012, 45,
788; c) L. Ackermann, Chem. Rev. 2011, 111, 1315;
d) C. Shen, P. Zhang, Q. Sun, S. Bai, T. S. A. Hor, X.
Liu, Chem. Soc. Rev. 2015, 44, 291; e) I. P. Beletskaya,
V. P. Ananikov, Chem. Rev. 2011, 111, 1596; f) X. X.
Guo, D. W. Gu, Z. X. Wu, W. B. Zhang, Chem. Rev.
2015, 115, 1622.
´
[9] X. Zhao, E. Dimitrijevic, V. M. Dong, J. Am. Chem.
[18] J. Clayden, E. Baldwin, R. M. Willaims, Organolithium:
Soc. 2009, 131, 3466.
[10] For other examples of direct C H sulfonylation with
Selectivity for Synthesis, Pergamon, Oxford, 2002.
À
[19] Recently, Shi reported a Pd-catalyzed sulfonylation of
3
À
sulfonyl chlorides, see: a) O. Saidi, J. Marafie, A. E. W.
Ledger, P. M. Liu, M. F. Mahon, G. Kociok-Koehn,
M. K. Whittlesey, C. G. Frost, J. Am. Chem. Soc. 2011,
C(sp ) H bonds: W.-H. Rao, B.-B. Zhan, K. Chen, P.-
X. Ling, Z.-Z. Zhang, B.-F. Shi, Org. Lett. 2015, 17,
3552.
Adv. Synth. Catal. 2016, 358, 159 – 163
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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