Nickel-Catalyzed Synthesis of Diaryl Sulfones from Aryl Halides and Sodium Sulfinates

Article abstract of DOI:10.1002/ejoc.201701478

A novel nickel-catalyzed cross-coupling of sulfinic acid salts with aryl halides is described. The reaction provides access to various diaryl sulfones in moderate to excellent yields. A broad range of functional groups and heteroaromatic compounds is tolerated under the reaction conditions.

Full text of DOI:10.1002/ejoc.201701478

DOI: 10.1002/ejoc.201701478
Communication
C–S Coupling
Nickel-Catalyzed Synthesis of Diaryl Sulfones from Aryl Halides
and Sodium Sulfinates
[
a]
[a]
[a]
[a,b]
Vanessa Luciano,[a]
Nai-Wei Liu, Shuai Liang, Natalie Margraf, Saad Shaaban,
[a]
[a]
Marcella Drost, and Georg Manolikakes*
Abstract: A novel nickel-catalyzed cross-coupling of sulfinic A broad range of functional groups and heteroaromatic com-
acid salts with aryl halides is described. The reaction provides pounds is tolerated under the reaction conditions.
access to various diaryl sulfones in moderate to excellent yields.
Introduction
(Table 1) and a number of nickel sources, ligands and solvents
were screened. Best results were achieved with 5 mol-%
NiBr ·3H O and 15 mol-% of the N-heterocyclic carbene (NHC)
Diaryl sulfones are useful building blocks in organic chemistry
and have found various applications as agrochemicals, active
pharmaceutical ingredients or functional materials.
have been shown to exhibit interesting biological properties,
such as antibacterial or antitumor activity or inhibition of the
HIV-1 reverse transcriptase. Common methods for the synthe-
sis of diaryl sulfones include oxidation of sulfides and electro-
2
2
ligand L1 together with 15 mol-% Et SiH in NMP at 105 °C
3
[
1–3]
They
(
entry 1). The addition of Et SiH is crucial for obtaining a high
3
yield (entry 2). We assume, that Et SiH serves as reducing agent
3
[
10]
for the generation of the active low-valent nickel catalyst.
[
4]
[
1,2,5]
philic sulfonylation of arenes with sulfonyl halides.
last years, sulfinic acid salts have emerged as useful building
In the
Table 1. Selected optimization data for the formation of sulfone 3a from the
[a]
cross-coupling of aryl bromide 1a and sulfinate 2a.
[
6]
blocks for the synthesis of diaryl sulfones. Palladium- or cop-
per-catalyzed cross-coupling of sulfinates with suitable cou-
pling partners provides a mild and regiospecific access to diaryl
[
7]
sulfones. Although there are two reports by Kambe and Song
2
on the nickel-catalyzed synthesis of sulfones via C(sp )–H-acti-
[
8]
vation, there has been, to the best of our knowledge, no ex-
ample on a nickel-catalyzed cross-coupling of sulfinic acid salts
with aryl or vinyl halides. This is quite surprising, considering
the tremendous advances in the field of homogeneous nickel
catalysis and nickel-catalyzed carbon–heteroatom bond forma-
Entry Variation from standard condition
Yield[b]
[
9]
1
2
3
4
5
6
7
8
9
none
no Et
89 % (77 %)[c]
tion. The unique properties of nickel-catalyst can offer an at-
tractive alternative to palladium- or copper-catalyzed reactions.
Herein, we wish to report the first nickel-catalyzed cross-cou-
pling of sodium sulfinates with aryl halides.
c]
3
SiH
41 % (38 %)[
8 %
Ni(COD)
NiCl , NiCl
Zn, Mn, PHMS instead of Et SiH
2
instead of NiBr
2
, no Et
3
SiH
2
2
(DME), Ni(acac)
2
instead of NiBr
2
34–50 %
2–65 %
19–88 %
55 %
64 %
5–20 %
3
PPh
with 10 mol-% of L1
DMSO instead of NMP
DMF, 1,4-dioxane, PhMe instead of NMP
3 3 4
, dppf, tBu P·HBF instead of L1
Results and Discussion
Initially the reaction of 4-bromotoluene (1a) with benzene-
sulfinic acid sodium salt (2a) was chosen as model system
[
[
a] Institute of Organic Chemistry and Chemical Biology, Goethe-University
Frankfurt,
Max-von-Laue-Str. 7, 60438 Frankfurt am Main, Germany
E-mail: g.manolikakes@chemie.uni-frankfurt.de
https://www.uni-frankfurt.de/53469467/Manolikakes
b] Organic Chemistry Division, Department of Chemistry, Faculty of Science,
Mansoura University,
[a] Standard reaction conditions: 1a (0.5 mmol, 1.0 equiv.), 2a (0.6 mmol,
1.2 equiv.), NiBr ·3H O (5 mol-%), L1 (15 mol-%), Et SiH (15 mol-%), NMP,
2
2
3
El-Gomhorya Street, 35516 Mansoura, Egypt
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201701478.
105 °C, 24 h under inert gas atmosphere. [b] GC Yields were determined by
GC using n-hexadecane as internal standard. [c] Isolated Yields are given in
brackets.
Eur. J. Org. Chem. 2018, 1208–1210
1208
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
The direct use of Ni(COD) as nickel(0)-precursor led to a very
Reactions with different aryl sulfinates did not proceed as
2
low yield (entry 3). Other common reducing agents in nickel- efficiently (Table 3). Aryl sulfinates bearing electron-donating,
catalyzed cross-coupling reactions, such as Zn, Mn or poly- electron-withdrawing or halide substituents were suitable cou-
methoxysiloxane (PMHS), afforded the desired sulfone in 3a up pling partners. In most cases the yields were obtained in 30–
to 65 % yield (entry 5). Among different phosphine or NHC- 50 %. However, heterocyclic as well as aliphatic sulfinates did
ligands evaluated, NHC-ligand L1 gave the best result (entries not afford the desired sulfones 4h–j at all.
1
and 6). An excess of the NHC-ligand was necessary in order
Table 3. Variation of the aryl bromide 1.[a]
to achieve high turnovers and yields (entries 1 and 7). Other
solvents proved to be less efficient. A yield of 64 % was ob-
tained in DMSO (entry 8), whereas in DMF or less polar solvents,
such as toluene, the isolated yields were very low (entry 9).
With the optimized reaction conditions established, the
scope and limitations of the nickel-catalyzed reaction were in-
vestigated. As shown in Table 2, a variety of electron-rich and
[
11]
electron-poor aryl bromides and one activated aryl chloride
could be coupled with benzenesulfinic acid sodium salt (2a) in
good to excellent yields. In general, electron-rich aryl bromides,
such as 4-bromoanisol 1d afforded the desired sulfones (3d)
in better yields than electron-poor aryl bromides, e.g. ethyl 4-
bromobenzoate 1f. The reaction tolerates various sensitive
functional groups (3f–h), such as an aldehyde or nitro function-
ality. More importantly, different heterocyclic aryl bromides
could be employed as coupling partners, affording the hetero-
arylsulfones 3o–s in 50–95 % yield. The reaction is sensitive to
steric hindrance on the aryl bromide. A substituent in the ortho-
position of the aryl bromide shuts down the reactivity com-
pletely (3m).
[
1
a] Standard reaction conditions: 1 (0.5 mmol, 1.0 equiv.), 2a (0.6 mmol,
2 2 3
.2 equiv.), NiBr ·3H O (5 mol-%), L1 (15 mol-%), Et SiH (15 mol-%), NMP,
1
05 °C, 24 h under inert gas atmosphere. Isolated yields, n.d. for not detected.
Table 2. Variation of the aryl bromide 1.[a]
Conclusions
In summary, we have reported a nickel-catalyzed cross-coupling
of aryl halides with sodium sulfinates. The reaction affords
diaryl sulfones as well as heteroarylsulfones in moderate to ex-
cellent yields. A variety of functional groups are tolerated under
the mild reaction conditions. Although the nickel-based catalyst
system does not offer any significant advantages compared re-
ported palladium- and copper-catalyzed reactions, this report
represents the first example of a nickel-catalyzed cross-coupling
reaction between sulfinic acid salts and aryl halides and might
open new opportunities in nickel catalysis. Studies to extend
the scope of this method and to increase the catalytic activity
are currently underway in our laboratory.
Experimental Section
Typical Procedure: A 10 mL Schlenk tube was charged with a stir-
ring bar, NiBr ·3H O (6.8 mg, 0.025 mmol, 5.0 mol-%), IPr·HCl (L1,
2
2
3
2 mg, 0.075 mmol, 15 mol-%), RSO Na (2, 0.60 mmol, 1.2 equiv.)
2
and 1 mL of dry NMP. Next Et SiH (12 μL, 8.7 mg, 15 mol-%) was
3
added dropwise to reaction mixture at ambient temperatures. The
resulting reaction mixture was stirred for 15 min. Then the aryl hal-
ide (1, 0.5 mmol, 1.0 equiv.) and another 1 mL of dry NMP were
added. The tube was placed into a preheated 105 °C oil bath and
heated for 24 h. After cooling to room temperature the mixture was
filtered through a short plug of silica gel and washed with EtOAc
to remove any insoluble solids. To the resulting organic solution
[
1
1
a] Standard reaction conditions: 1 (0.5 mmol, 1.0 equiv.), 2a (0.6 mmol,
2 2 3
.2 equiv.), NiBr ·3H O (5 mol-%), L1 (15 mol-%), Et SiH (15 mol-%), NMP,
05 °C, 24 h under shielding gas atmosphere. Isolated yields, n.d. for not
detected. [b] With 2-chloropyrazine as substrate.
Eur. J. Org. Chem. 2018, 1208–1210 www.eurjoc.org
1209
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
1
5 mL of H O and 15 mL of sat. aq. NaCl were added. The biphasic
Zhao, S. Sunder, T. R. Burke, R. J. Schultz, Y. Pommier, Antimicrob. Agents
Chemother. 1997, 41, 385.
5] a) S. Patai, Z. Rappoport, C. Stirling, Sulphones and Sulphoxides (1988),
John Wiley & Sons, Ltd, Chichester, UK, 1988; b) N.-W. Liu, S. Liang, G.
Manolikakes, Synthesis 2016, 48, 1939.
6] For a recent review on sulfinates, see: J. Aziz, S. Messaoudi, M. Alami, A.
Hamze, Org. Biomol. Chem. 2014, 12, 9743; For recent examples, see: a)
N. Margraf, G. Manolikakes, J. Org. Chem. 2015, 80, 2582; b) N. Umierski,
G. Manolikakes, Org. Lett. 2013, 15, 188; c) N. Umierski, G. Manolikakes,
Org. Lett. 2013, 15, 4972; d) V. G. Pandya, S. B. Mhaske, Org. Lett. 2014,
2
mixture was extracted three times with 25 mL of EtOAc. The com-
bined organic phases were washed three times with 25 mL of sat.
aq. NaCl, dried with Na SO and concentrated under reduced pres-
[
[
2
4
sure. Purification of the crude residue by column chromatography
n-hexane/EtOAc) afforded the analytically pure product.
(
Supporting Information (see footnote on the first page of this
article): Experimental procedures, characterization data, and copies
of the H NMR, C NMR and F NMR spectra.
1
13
19
1
6, 3836; e) A. S. Deeming, C. J. Russell, A. J. Hennessy, M. C. Willis, Org.
Lett. 2014, 16, 150; f) X. Liu, W. Li, D. Zheng, X. Fan, J. Wu, Tetrahedron
2
2
015, 71, 3359; g) D. Zheng, M. Chen, L. Yao, J. Wu, Org. Chem. Front.
016, 3, 985; h) G. C. Nandi, Synth. Commun. 2017, 47, 319; i) S. Liang,
Acknowledgments
We thank Prof. Michael Göbel for his support. Funding by the
Fonds der Chemischen Industrie (Liebig Fellowship to G. M.),
the Boehringer Ingelheim Foundation (Exploration Grant to
G. M.), the Deutsche Forschungsgemeinschaft (DFG), and the
program of China Scholarships Council (PhD fellowship to S. L.,
no. 201406240029) is gratefully acknowledged.
R.-Y. Zhang, L.-Y. Xi, S.-Y. Chen, X.-Q. Yu, J. Org. Chem. 2013, 78, 11874; j)
Y. Chen, M. C. Willis, Chem. Sci. 2017, 8, 3249; k) M. Wang, S. Chen, X.
Jiang, Org. Lett. 2017, 19, 4916.
7] a) F. Huang, R. A. Batey, Tetrahedron 2007, 63, 7667; b) J. M. Baskin, Z.
Wang, Org. Lett. 2002, 4, 4423; c) M. Yang, H. Shen, Y. Li, C. Shen, P.
Zhang, RSC Adv. 2014, 4, 26295; d) W. Zhu, D. Ma, J. Org. Chem. 2005,
[
7
0, 2696; e) G. Le Duc, E. Bernoud, G. Prestat, S. Cacchi, G. Fabrizi, A.
Iazzetti, D. Madec, G. Poli, Synlett 2011, 2011, 2943; f) S. Cacchi, G. Fabrizi,
A. Goggiamani, L. M. Parisi, Org. Lett. 2002, 4, 4719; g) S. Cacchi, G.
Fabrizi, A. Goggiamani, L. M. Parisi, R. Bernini, J. Org. Chem. 2004, 69,
Keywords: Earth-abundant metals · Nickel · Homogeneous
catalysis · Sulfones · Cross-coupling
5
608.
8] a) V. P. Reddy, R. Qui, T. Iwasaki, N. Kambe, Org. Biomol. Chem. 2015, 13,
803; b) S.-L. Liu, X.-H. Li, S.-S. Zhang, S.-K. Hou, G.-C. Yang, J.-F. Gong,
[
[
6
M.-P. Song, Adv. Synth. Catal. 2017, 359, 2241.
[
1] M. Feng, B. Tang, S. H. Liang, X. Jiang, Curr. Top. Med. Chem. 2016, 16,
200.
9] a) V. P. Ananikov, ACS Catal. 2015, 5, 1964; b) V. Ritleng, M. Henrion, M. J.
Chetcuti, ACS Catal. 2016, 6, 890; c) S. Z. Tasker, E. A. Standley, T. F.
Jamison, Nature 2014, 509, 299.
1
[
[
2] H. Liu, X. Jiang, Chem. Asian J. 2013, 8, 2546.
3] N. S. Simpkins, Sulphones in Organic Synthesis, Pergamon, Oxford
[
[
10] a) V. P. Ananikov, K. A. Gayduk, Z. A. Starikova, I. P. Beletskaya, Organome-
tallics 2010, 29, 5098; b) C. Desmarets, S. Kuhl, R. Schneider, Y. Fort,
Organometallics 2002, 21, 1554; c) J. Hashim, C. O. Kappe, Adv. Synth.
Catal. 2007, 349, 2353; d) X. Li, Z. Feng, Z.-X. Jiang, X. Zhang, Org. Lett.
[
England], New York, 1993.
[
4] a) T. R. Jones, S. E. Webber, M. D. Varney, M. R. Reddy, K. K. Lewis, V.
Kathardekar, H. Mazdiyasni, J. Deal, D. Nguyen, K. M. Welsh, S. Webber,
A. Johnston, D. A. Matthews, W. W. Smith, C. A. Janson, R. J. Bacquet, E. F.
Howland, C. L. J. Booth, S. M. Herrmann, R. W. Ward, J. White, C. A. Bart-
lett, C. A. Morse, J. Med. Chem. 1997, 40, 677; b) C. J. Dinsmore, T. M.
Williams, T. J. O'Neill, D. Liu, E. Rands, J. Culberson, R. B. Lobell, K. S.
Koblan, N. E. Kohl, J. B. Gibbs, A. I. Oliff, S. L. Graham, G. D. Hartman,
Bioorg. Med. Chem. Lett. 1999, 9, 3301; c) N. Neamati, A. Mazumder, H.
2015, 17, 5570; e) G. Manolikakes, A. Gavryushin, P. Knochel, J. Org.
Chem. 2008, 73, 1429.
11] Reactions with nonactivated aryl chlorides were unsuccessful.
Received: October 23, 2017
Eur. J. Org. Chem. 2018, 1208–1210
www.eurjoc.org
1210
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim