Direct cross-coupling of aryl alkynyliodines with arylsulfinic acids leading to alkynyl sulfones under catalyst-free conditions

Article abstract of DOI:10.1016/j.tetlet.2017.11.029

A facile and efficient one-pot method has been developed for the construction of alkynyl sulfones via direct cross-coupling reaction of aryl alkynyliodines and arylsulfinic acids. The present transformation could be accomplished under catalyst- and additive-free conditions, providing a series of alkynyl sulfones in moderate to good yields with favorable functional group tolerance.

Full text of DOI:10.1016/j.tetlet.2017.11.029

Accepted Manuscript
Direct cross-coupling of aryl alkynyliodines with arylsulfinic acids leading to
alkynyl sulfones under catalyst-free conditions
Leilei Wang, Wei Wei, Daoshan Yang, Huanhuan Cui, Huilan Yue, Hua Wang
PII:
S0040-4039(17)31432-6
https://doi.org/10.1016/j.tetlet.2017.11.029
TETL 49472
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 September 2017
10 November 2017
14 November 2017
Please cite this article as: Wang, L., Wei, W., Yang, D., Cui, H., Yue, H., Wang, H., Direct cross-coupling of aryl
alkynyliodines with arylsulfinic acids leading to alkynyl sulfones under catalyst-free conditions, Tetrahedron
Letters (2017), doi: https://doi.org/10.1016/j.tetlet.2017.11.029
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Direct cross-coupling of aryl alkynyliodines with aryl Leave this area blank for abstract info.
sulfinic acids leading to alkynyl sulfones under
catalyst-free conditions
Leilei Wang, Wei Wei, Daoshan Yang, Huanhuan Cui, Huilan Yue, Hua Wang
Direct coupling of aryl alkynyliodines with arylsulfinic acids to access alkynyl sulfones has been
accomplished under catalyst- and additive-free conditions.

1
Tetrahedron Letters
journal homepage: www.els evier.com
Direct cross-coupling of aryl alkynyliodines with arylsulfinic acids leading to alkynyl
sulfones under catalyst-free conditions
Leilei Wanga, Wei Wei a,b,*, Daoshan Yanga, Huanhuan Cuia, Huilan Yueb, Hua Wang a,∗
a Institute of Medicine and Material Applied Technologies, Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, School of
Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, Shandong, China.
b Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Qinghai 810008, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
A facile and efficient one-pot method has been developed for the construction of alkynyl
sulfones via direct cross-coupling reaction of aryl alkynyliodines and arylsulfinic acids. The
present transformation could be accomplished under catalyst- and additive-free conditions,
providing a series of alkynyl sulfones in moderate to good yields with favorable functional
group tolerance.
Received in revised form
Accepted
Available online
Keywords:
Alkynyliodines
Sulfinic acids
Alkynyl sulfones
Additive-free
Catalyst-free
2016 Elsevier Ltd. All rights reserved.
Sulfone-containing compounds have shown various interesting
biological activities and constitute primary components of
clinical pharmaceuticals and drug candidates.1 Furthermore, they
can also serve as versatile building blocks in diverse range of
synthetically useful transformations.2 In particular, alkynyl
sulfones are an important class of sulfone-containing molecules,
which exhibit widespread applications in organic synthesis
because sulfonyl group acts not only as an activator to enhance
the reactivity of the triple bond but also as an easily removable
protective motif.3,4 In general, conventional methods for the
synthesis of alkynylsulfones involve the oxidation of the alkynyl
sulfides,5 sulfonylation of alkynylsilanes,6 and elimination
reactions from β-keto sulfones,7 α,β-unsaturated sulfones,8 or 5-
amino-4-isoxazolyl sulfones.9 Alternative methods such as the
sulfonylation reaction of alkynyl(aryl)iodonium salts by addition
of arylsulfinate salts,10 the coupling of alkynyl halides with
copper sulfinates,11 the addition of aryl sulfinates to
ethynylbenzio-doxolone derivatives (R-EBX),12 and the
sulfonylation of arylacetylenic acids and arylacetylenes with
sodium sulfinates13 have also been developed. However, almost
all of these methods might suffer from certain limitations such as
the tedious work-up procedures, unstable or toxic starting
materials, and complex reaction mixtures or low selectivity.
Therefore, the development of direct and more efficient methods
to access alkynyl sulfones in terms of operational simplicity,
availability of starting materials and environmental sustainability
is still in constant demand in the synthetic chemistry.
With our continued interest in the construction of sulfone-
containing compounds,14 herein, we wish to present a simple and
efficient method for the construction of alkynyl sulfones through
the direct cross-coupling of aryl alkynyliodines and arylsulfinic
acids under catalyst- and additive-free conditions (Scheme 1).
Scheme 1. Direct cross-coupling of alkynyliodines with sulfinic acids to
access alkynyl sulfones.
The initial exploration of this reaction was carried out
using (iodoethynyl)benzene 1a and 4-methylbenzenesulfinic
acid 2a as coupling partners to determine the optimal
reaction conditions. When the model reaction was conducted
in DME at room temperature under catalyst- and additive-
free conditions, the desired product 3a was isolated in 34%
yield (Table 1, entry 1). To our delight, the reaction
efficiency was significantly improved along with the
increase of reaction temperature, and the highest yield (86%)
was obtained when the reaction was carried out at 100oC
(Table 1, entry 4). Then, the solvent effect was investigated.
The reaction performed in DME gave higher yield than in
other ether solvent such as THF or 1,4-dioxane (Table 1,
entries 4, 7, 8). When reaction was conducted in DCE,
CH3CN or EtOH, the corresponding product 3a was
obtained in moderate yields (Table 1, entries 9-11).
Nevertheless, low yields or none of the desired product was
∗ Corresponding author.
E-mail address: weiweiqfnu@163.com, huawang_qfnu@126.com.

2
Tetrahedron Letters
Table 2. Catalyst-free cross-coupling of aryl alkynyliodines with arylsulfinic
acids to access alkynyl sulfonesa,b
detected when toluene, DMF, or DMSO was used alone as
the solvent (Table 1, entries 12-14). Also, the reaction
efficiency was obviously low with the decreasing of 2a
loading (Table 1, entries 15 and 16). The highest yield was
provided when the ratio of 1a:2a is 1:2 (Table 1, entry 4). A
further increase in the quantity of 2a did not improve the
reaction efficiency (Table 1, entry 17). As a consequence,
the reaction conditions used in entry 4 were determined to
be the optimized conditions.
Table 1. Optimization of reaction conditionsa
Entry
1
T(oC)
25
Solvent
DME
DME
Yield (%)b
34
51
2
60
80
3
DME
DME
65
86
4
100
110
120
100
100
100
100
100
100
100
100
100
100
100
5
6
DME
DME
THF
82
77
7
56
8
1,4-dioxane
DCE
40
68
9
10
11
12
13
14
15
16
17
CH3CN
EtOH
Toluene
DMF
59
58
17
Trace
0
56c
61d
85e
DMSO
DME
DME
DME
a Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), DME (2 mL), 100oC,
12h.
b Isolated yields based on 1a.
c 1a (0.1 mmol), 2a (0.1 mmol).
d 1a (0.1 mmol), 2a (0.15 mmol).
e 1a (0.1 mmol), 2a (0.3 mmol).
a Reaction conditions:1 (0.1 mmol), 2 (0.2 mmol), DME (2 mL), 100oC, 12h.
b Isolated yields based on 1.
phenylacetylene 4a with 4-methylbenzenesulfinic acid 2a
was conducted under the optimized conditions (Scheme 2
(a)). Furthermore, when the preformed β-iodovinyl sulfone
5a was subjected separately under the standard conditions,
the desired product 3a was also not observed (Scheme 2 (b)).
The above results suggested alkyne and β-iodovinyl sulfone
should not be the key intermediates in the present reaction
system. Next, the model reaction was significantly inhibited
when 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), a well
known radical-capturing species, was added into reaction
With the optimal reaction conditions in hand, the substrate
scope of this coupling reaction was tested (Table 2).
Generally, aromatic alkynyliodines with a wide range of aryl
substituents including electron-rich substituents and
electron-poor substituents all successfully delivered the
desired products in satisfactory yields (3b-3l). In addition, 1-
(iodoethynyl)naphthalene could undergo the transformation
smoothly, furnishing its corresponding product (3m) in good
yield. Remarkably, heteroaryl alkynyliodine such as 3-
(iodoethynyl)thiophene was also suitable for this reaction,
affording the desired product 3n in 79% yield. Next, we also
examined the scope of various sulfinic acids as the coupling
partners. Both electron-donating (Me, OMe) and electron-
withdrawing substituents (Cl, Br, CF3) on the aryl groups of
sulfinic acids were well tolerated in this process to give the
desired products (3q-3v) in moderate to good yields. The
ortho substituted sulfinic acids could also effectively react
with (iodoethynyl)benzene leading to the product 3w in
good yield. Moreover, naphthalene-1-sulfinic acid was
compatible with the standard conditions to provide the
desired product 3x in 88% yield.
Several control experiments were carried out to elucidate
the possible reaction mechanism. Initially, none of the
alkynyl sulfone 3a was detected when the reaction of
Scheme 2. Preliminary mechanistic studies

3
Soc., 2008, 130, 9238; (c) Desrosiers, J. N.; Charette, A. B. Angew.
system, indicating that the possible involvement of a radical
process in the present transformation (Scheme 2, (c)). Moreover,
in addition to product 3a, the homocoupling diyne was also
detected by GC-MS in the model reaction (see SI), which
indicated an alkynyl and iodine radical might involve in this
reaction system (Scheme 2, (d)).15
Chem., Int. Ed., 2007, 46, 5955; (d) Kotha, S.; Chavan, A. S. J. Org.
Chem., 2010, 75, 4319; (e) Kumar, A.; Muthyala, M. K. Tetrahedron
Lett., 2011, 22, 1287 and references in.
3. Selected reviews: (a) Back, T. G.; Clary K. N.; Gao, D. Chem. Rev. 2010,
110, 4498; (b) Garcia Ruano, J. L.; Aleman, J.; Parra, J.; Marzo, L. Eur.
J. Org. Chem. 2014, 1577.
4. Selected examples: (a) Huang, D. F.; Shen, T. Y. Tetrahedron Lett.
1993, 34, 4477; (b) Hlasta, D. J.; Ackerman, J. H. J. Org. Chem. 1994,
59, 6184; (c) Spencer, J.; Pfeffer, M.; DeCian, A.; Fischer, J. J. Org.
Chem. 1995, 60, 1005; (d) Riddell, N.; Tam, W. J. Org. Chem. 2006, 71,
1934; (e) Takeda, T.; Ando, M.; Sugita, T.; Tsubouchi, A. Org. Lett.
2007, 9, 2875; (f) Li, J.; Tian, H.; Jiang, M.; Yang, H.; Zhao, Y.; Fu, H.
Chem. Commun. 2016, 52, 8862.
On the basis of these results, a possible reaction pathway
for this coupling reaction was proposed as shown in Scheme
3. Firstly, sulfinic acid 2a gave the sulfonyl radical 6a with
the help of iodine radical, which was generated in situ from
homocoupling of alkynliodine. Then, the selective addition
of sulfonyl radical 6a to alkynyliodine 1a would lead to
formation of alkenyl radical 7a. Finally, 7a underwent β-
fragmentation of an iodine radical that then abstracted a H-
atom from the sulfinic acid 2a to sustain the chain and
produce the desired alkynyl sulfone 3a. Nevertheless,
another possible pathway involving the cross-coupling of
sulfonyl radical with alkyne radical that generated in situ
from alkynyliodine might also be involved in this reaction
5. (a) Truce, W. E.; Hill, H. E.; Boudakian, M. M. J. Am. Chem. Soc. 1956,
78, 2760; (b) Miller, S. I.; Orzech, C. E.; Welch, C. A.; Ziegler, G. R.;
Dickstein, J. I. J. Am. Chem. Soc. 1962, 84, 2020.
6. Waykole, L.; Paquette, L. A. Org. Synth. 1989, 67, 149.
7.
(a) Lee, J. W.; Oh, D. Y. Synlett 1990, 290; (b) Clasby, M. C.; Craig, D.
Synlett 1992, 825.
8. (a) Miura, T.; Kobayashi, M. J. Chem. Soc., Chem. Commun. 1982, 438;
(b) Waykole, L.; Paquette, L. A. Org. Synth. 1989, 67, 149; (c) Back, T.
G.; Collins S.; Kerr, R. G. J. Org. Chem. 1983, 48, 3077; (d) Iwata, N.;
Morioka, T.; Kobayashi, T.; Asada, T.; Kinoshita H.; Inomata, K. Bull.
Chem. Soc. Jpn. 1992, 65, 1379; (e) Lee, J. W.; Kim, T. H.; Oh, D. Y.
Synth. Commun. 1989, 19, 2633; (f) Rajakumar, P.; Kannan, A. J. Chem.
Soc., Chem. Commun. 1989, 154; (g) Back, T. G.; Krishna, M. V. J. Org.
Chem. 1987, 52, 4265.
system 15
.
9. Beccaili, E. M.; Manfredi, A.; Marchesini, A. J. Org. Chem. 1985, 50,
2372.
10. (a) Tykwinski, R. R.; Williamson, B. L.; Fischer, D. R.; Stang, P. J.; Arif,
A. M. J. Org. Chem. 1993, 58, 5235; (b) Liu Z.-D.; Chen, Z.-C. Synth.
Commun. 1992, 22, 1997; (c) Hamnett, D. J.; Moran, W. J. Org. Biomol.
Chem. 2014, 12, 4156; (d) Rodríguez, A.; Moran, W. J. J. Org. Chem.
2016, 81, 2543.
11. Suzuki, H.; Abe, H. Tetrahedron Lett, 1996, 37, 3717.
12. Chen, C. C.; Waser, J. Org. Lett. 2015, 17, 736.
13. Meesin, J.; Katrun, P.; Pareseecharoen, C.; Pohmakotr, M.; Reutrakul,
V.; Soorukram, D.; Kuhakarn, C. J. Org. Chem. 2016, 81, 2744.
14. (a) Wei, W.; Liu, C.; Yang, D.; Wen, J.; You, J.; Suo, Y.; Wang, H.
Chem. Commun., 2013, 49, 10239; (b) Wei, W.; J, Wen, Yang, D.; Du,
J.; You, J.; Wang, H. Green Chem., 2014, 16, 2988; (c) Wei, W.; Wen,
J.; Yang, D.; Guo, M.; Wang, Y.; You, J.; Wang, H. Chem. Commun.,
2015, 51, 768; (d) Wei, W.; Liu, C.; Yang, D.; Wen, J.; You, J.; Wang,
H. Adv. Synth. Catal., 2015, 357, 987; (e) Wen, J.; Wei, W.; Xue, S.;
Yang, D.; Lou, Y.; Gao C.; Wang, H. J. Org. Chem., 2015, 80, 4966;
(f) Wei, W.; Li, J.; Yang, D.; Wen, J.; Jiao, Y.; You, J.; Wang, H. Org.
Biomol. Chem. 2014, 12, 1861; (g) Wei, W.; Wen, J.; Yang, D.; Wu, M.;
You, J.; Wang, H. Org. Biomol. Chem. 2014, 12, 7678; (h) Wei, W.;
Wen, J.; Yang, D.; Jing, H.; You J.; Wang, H. RSC Adv.,2015, 5, 4416;
(i) Wei, W.; Cui, H.; Yang, D.; Liu, X.; He, C.; Dai, S.; Wang, H. Org.
Chem. Front., 2017, 4, 26.
Scheme 3. Possible reaction pathway
In summary, we have successfully developed a convenient and
efficient catalyst-free method for the construction of alkynyl
sulfones through the direct cross-coupling of aryl alkynyliodines
and arylsulfinic acids. The present protocol, which utilizes
readily available starting materials, simple operation, and
environmentally benign conditions, provides a highly attractive
approach to various alkynyl sulfones in moderate to good yields.
Preliminary mechanistic studies indicated that a radical process
might be involved in the present reaction. Further investigation of
the detailed reaction mechanism and synthetic application are
ongoing in our lab.
15. (a) Xie, J.; Shi, S.; Zhang, T.; Mehrkens, N.; Rudolph, M.; Hashmi, A. S.
K. Angew. Chem., Int. Ed. 2015, 54, 6046; (b) Huang, H-Y.; Cheng, L.;
Liu, J-J.; Wang, D.; Liu, L.; Li, C-J. J. Org. Chem., 2017, 82, 2656; (c)
Gu, X.; Guo, Y.; Zhang, F.; Mebel, A. M.; Kaiser, R. I. Chem. Phys. Lett.
2007, 436, 7.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (No. 21302109, 21302110, and 21675099),
the Natural Science Foundation of Shandong Province
(ZR2015JL004 and ZR2016JL012), the Open Projects Program
of the Key Laboratory of Tibetan Medicine Research, Chinese
Academy of Sciences and International Cooperation Project of
Qinghai Province (2017-HZ-806).
References and notes
1. (a) Artico, M.; Silvestri, R. Pagnozzi, E.; Bruno, B.; Novellino, E.;
Greco, G.; Massa, S.; Ettorre, A.; Giulia Loi, A.; Scintu, F.; Colla, P. La.
J. Med. Chem. 2000, 43, 1886; (b) Lopez de Compadre, R. L.; Pearlstein,
R. A.; Hopfinger, A. J.; Seyde, J. K. J. Med. Chem. 1987, 30, 900; (c)
Petrov, K. G.; Zhang, Y.; Carter, M.; Cockerill, G. S.; Dickerson, S.;
Gauthier, C. A.; Guo, Y.; Mook, R. A.; Rusnak, D. W.; Walker, A. L.;
Wood, E. R.; Lackey, K. E. Bioorg. Med. Chem. Lett., 2006, 16, 4686.
2. (a) Simpkins, N. S.; Sulfones in Organic Synthesis, Pergamon Press,
Oxford, 1993; (b) Yang, H.; Carter, R. G.; Zakharov, L. N. J. Am.Chem.

4
Tetrahedron Letters
•
Direct coupling of aryl alkynyliodines with
arylsulfinic acids to access alkynyl sulfones
Catalyst- and additive free method
•
•
A radical process is proposed