Metal-free synthesis of sulfonylated amides through radical aryl migration-desulfonylation

Article abstract of DOI:10.1016/j.tetlet.2016.04.073

A metal-free arylsulfonyl radical-triggered desulfonylation of N-aryl-N-arylsulfonyl-acrylamides under mild conditions for the facile synthesis of a series of sulfonylated amides has been described. The radical transformation simultaneously installs C-S a

Full text of DOI:10.1016/j.tetlet.2016.04.073

Accepted Manuscript
Metal-free synthesis of sulfonylated amides through radical aryl migration-de-
sulfonylation
Jiang-Kai Qiu, Wen-Juan Hao, Li-Fang Kong, Wei Ping, Shu-Jiang Tu, Bo Jiang
PII:
S0040-4039(16)30448-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.04.073
TETL 47573
Reference:
Tetrahedron Letters
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18 April 2016
20 April 2016
Please cite this article as: Qiu, J-K., Hao, W-J., Kong, L-F., Ping, W., Tu, S-J., Jiang, B., Metal-free synthesis of
sulfonylated amides through radical aryl migration-desulfonylation, Tetrahedron Letters (2016), doi: http://
dx.doi.org/10.1016/j.tetlet.2016.04.073
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Tetrahedron Letters
Metal-free synthesis of sulfonylated amides through radical aryl migration-
desulfonylation
Jiang-Kai Qiu,a,b Wen-Juan Hao,a Li-Fang Kong,c Wei Ping,b,* Shu-Jiang Tu,a Bo Jianga,*
a School of Chemistry and Chemical Engineering, and Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal
University, Xuzhou, 221116, P. R. China, E-mail: jiangchem@jsnu.edu.cn; bBiotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing,
210009, Jiangsu, P. R. China, E-mail: weiping@njtech.edu.cn,; c Department of Basic Teaching, Air Force Logistic Academy, Xuzhou, Jiangsu, P. R. China
AR TIC LE INF O
ABS TR AC T
A
metal-free arylsulfonyl radical-triggered desulfonylation of N-aryl-N-arylsulfonyl-
Article history:
Received
Received in revised form
Accepted
acrylamides under mild conditions for the facile synthesis of a series of sulfonylated amides
has been described. The radical transformation simultaneously installs C-S and C-C bonds
with concomitant cleavage of N-S and C-S bonds through continuous 5-exo-trig cyclization,
desulfonylation and aryl migration sequence.
Available online
Keywords:
Desulfonylation
Metal-free synthesis
Sulfonylated amides
2016 Elsevier Ltd. All rights reserved.
Desulfonylation reactions have taken an important position in the
total synthesis of many natural products and in medicinal
chemistry, because these reactions could realize direct
functionalization of the desired bioactive molecules by functional
group transformations (FGTs).1 Traditional desulfonylations
demand a two-step process including i) introduction of sulfone
functionality into reagents to modify molecular polarity and
activate reaction site; ii) after the completion of the required
operation, the sulfone moiety has to be removed by using
reductive, alkylative and oxidative desulfonylation, etc.2
However, these desulfonylations suffer from the shortcomings
such as the use of strong bases, transition-metal catalysts and
toxic metal salts peroxides. Recently, Nevado, Zhu and co-
workers independently reported radical-triggered aryl migration
and desulfonylation reactions of N-arylsulfonyl-acrylamides,
3,4
leading to C-C and/or C-N bond formation (Schemes 1a).
Later, Kuang et al. developed a similar radical protocol toward
sulfonated oxindoles from copper-catalyzed reaction of N-
methyl-N-arylsulfonyl-acrylamides with sulfonyl hydrazides
using K2S2O8 as an oxidant (Scheme 1b).5 Very recently, we
presented a new tetrabutylammonium iodide (TBAI)/t-butyl
Scheme 1. Desulfonylation-involved radical reactions
sulfonhydrazides could be achieved under TBAI/TBHP-mediated
conditions, delivering a wide range of sulfonylated amides with
structural diversity, (Scheme 1d). The success of this reaction is
based on the factors that in the presence of TBAI/TBHP, aryl
sulfonhydrazides could be converted into the arylsulfonyl
radicals,8 which is quickly intercepted by radical acceptors such
as activated olefins.9 Herein, we would like to report this metal-
free radical method for the synthesis of sulfonylated amides.
We began our study with N-aryl-N-arylsulfonyl-acrylamides 1a
and p-toluenesulfonyl hydrazide (2a) by using TBAI/TBHP
hydroperoxide
(TBHP)-mediated
1,7-enyne-bicyclization,
providing densely functionalized benzo[j]phenanthridines. In this
reaction, metal-free radical desulfonylation was successfully
realized (Scheme 1c).6 Based on aforementioned studies and our
interest in radical chemistry7 and considering the difference of N-
nucleophilicity between alkylamines and arylamines, we
reasoned that with replacement of methyl group with aryl
counterpart at the N-substituent (Scheme 1b), a metal-free
desulfonylation of N-aryl-N-arylsulfonyl-acrylamides with aryl

2
Tetrahedron Letters
aryl-N-arylsulfonyl-acrylamides with aryl sulfonhydrazides. As
system in CH3CN at room temperature under air conditions for
shown in Scheme 2, we firstly used N-(p-tolyl)-N-
tosylmethacrylamide (1a) to react with a wide range of sulfonyl
hydrazides 2 under the oxidative conditions. It was found that the
sulfonyl hydrazides with substituents at meta or para-position on
the phenyl group were all successfully engaged in the
transformation and gave the corresponding sulfonylated amides
3a-3i in 52%-78% yields. The electronic nature of substituents
exerted a slight influence on the reaction efficiency and the
obtainable yields. For instance, electron-donating groups on the
phenyl ring, such as CH3, and OCH3, showed higher reactivity
and gave higher yields than those with electron-withdrawing
substituents like Cl, Br or NO2 (3a and 3b vs. 3e-3i). Similarly,
phenyl and 2-naphthyl counterparts were also proved to be
effective substrates, resulting in the corresponding products 3c
and 3d in 77% and 72% yields, respectively. Unluckily, sulfonyl
hydrazides with ortho substituents on the phenyl ring gave a
complex mixture and a trace amount of product 3j (or 3k) was
observed (Scheme 2), which may be caused by their large steric
effect. The similar result was observed when benzyl counterpart
was used (Scheme 2, 3l), which may be ascribed to the relative
instability of the benzyl sulfonyl radical generated in situ. In
view of these results, we then varied substituents of
methacrylamides 1 to further expand their synthetic utility of this
methodology. As we had expected, methacrylamides 1 bearing
electron-donating, -neutral, or -withdrawing groups on the
arylsulfonyl (Ar1) moiety were successfully engaged in the
current TBAI/TBHP-mediated reactions with 2a, affording the
desired sulfonylated amides 3m-3p with yields ranging from
60% to 80% yields. With the tosyl group (Ar1) on the amine
anchor, the variant of substituents on the aryl (Ar2) moiety was
compatible with the catalytic oxidation system. Functional
groups like methyl, methoxy, chloro and bromo could be
accommodated, thus confirming the reaction efficiency, as 3q-3v
was generated in 60%-74% yields.
12 h (Table1, entry1). The reaction proceeded to give the desired
sulfonylated amides 3a, albeit with a relatively low 23% yield.
An increase of the reaction temperature resulted in the
remarkable improvement of the reaction efficiency (entries 2-3).
A higher 78% chemical yield was obtained when the reaction
temperature was increased to 70 oC. However, the higher reaction
o
temperature (90 C) is not beneficial to the chemical yield (entry
4). Next, different solvents, such as DMSO, DMF, EtOH,
CH2Cl2, 1,2-dichloroethane (DCE), toluene and water, were
conducted to examine the solvent effects (entries 5-11). It was
found that the reaction in DMSO did not work at all and the
starting materials remained completely unconsumed (entry 5),
whereas the use of other solvents, including DMF, EtOH,
CH2Cl2, 1,2-dichloroethane (DCE), toluene and water, all led to
the formation of product 3a, but gave inferior results compared
with CH3CN (entries 6-12). Afterword, the loading of TBAI was
evaluated. Increasing or decreasing the loading of TBAI did not
improve the reaction efficiency (entries 13-14). Then, we
adjusted other reaction parameters including catalysts and
oxidants. Replacing TBAI with iodine or potassium iodide, the
reaction resulted in slightly lower yield of 3a (entries 15-16),
whereas the reaction completed suppressed in copper catalysis
(entries 17-18). Without TBAI, no product 3a was observed
(entry 19). Screening followed by various oxidants showed that
the oxidants like benzoyl peroxide (BPO), tert-butyl
peroxybenzoate (TBPB) and H2O2 as well as m-
chloroperoxybenzoic acid (m-CPBA) all gave unsatisfactory
outcomes compared with TBHP in terms of
Table 1. Optimization of conditions for the product 3aa
Entry
1
2
3
4
5
6
7
8
Oxidant
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
BPO
Cat. (mol %)
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (10)
TBAI (50)
I2 (20)
KI (20)
CuI (20)
CuBr (20)
-
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
Solvent
CH3CN
CH3CN
CH3CN
CH3CN
DMSO
DMF
EtOH
CH2Cl2
DCE
T / °C Yield / %b
rt
23
40
70
90
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
36
78
50
NDc
37
46
52
64
37
57
62
71
76
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
toluene
1,4-dioxane
H2O
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
70
66
NDc
NDc
NDc
60
TBPB
H2O2
m-CPBA
DTBP
O2
42
65
27
trace
NDc
a Reaction conditions: 1a (0.25 mmol), 2a (0.50 mmol), catalyst, oxidant (2
equiv.), solvent (2.5 mL), 70 oC, 12 h, under air conditions. bIsolated yield
based on 1a. cNot detected (ND). TBHP (70% solution in water).
Scheme 2. The scope of metal-free cascade reaction. Reaction
conditions: 1 (0.25 mmol), 2 (0.50 mmol), catalyst (20 mol%), oxidant (2
equiv.), CH3CN (2.5 mL), 70 oC, 12 h, under air conditions. Isolated yield
based on 1.
reaction yields (entries 19-23). The reaction did not proceed in
the presence of di-tert-butyl peroxide (DTBP) or O2 (entries 24-
25).
With the optimized reaction conditions in hand, the scope of this
metal-free radical desulfonylation was examined by treating N-
To understand the mechanism, the following control reactions
were conducted. Firstly, methacrylamides 1a was subjected to
reaction with 2a in the presence of 2,2,6,6-tetramethylpiperidine

oxide (TEMPO)10 radical inhibitor under the standard conditions,
and a trace amount of 3a was detected (Scheme 3a). Without
TBHP, no conversion to the desired product 3a was observed and
starting materials 1a and 2a were recovered (Scheme 3b) these
experimental results supported the present reaction involving a
radical pathway under TBAI/TBHP system.
References and notes
(1) For selected examples, sees: (a) Mori, Y.; Yaegashi, K.; Furukawa, H.
J. Am. Chem. Soc. 1997, 119, 4557. (b) Thomas, G.; Michael, D.;
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Kwon, O. J. Am. Chem. Soc. 2009, 131, 6318. (d) Ota, K.; Sugata,N.;
Ohshiro, Y.; Kawashima, E.; Miyaoka, H.; Chem. Eur. J. 2012, 18,
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H.; Kayano, A.; Tagami, K. Org. Lett. 2015, 17, 3158.
(2) For selected examples, sees: (a) Kigoshi, H.; Ojika, M.; Ishigaki, T.;
Suenaga, K.; Mutou, T.; Sakakura, A.; Ogawa, T.; Yamada, K. J. Am.
Chem. Soc. 1994, 116, 7443. (b) Oikawa, M.; Ueno, T.; Oikawa, H.;
Ichihara, A. J. Org. Chem. 1995, 60, 5048. (c) Lautens, M.; Ren, Y. J.
Am. Chem. Soc, 1996, 118, 10668. (d) Trost, B. M.; Calkins, T. L.;
Bochet, C. G. Angew. Chem, Int. Ed. 1997, 36, 2632. (e) Pettus, T. R. R.;
Chen, X. T.; Danishefsky, S. J. J. Am. Chem. Soc. 1998, 120, 12684. (f)
Thomas, G.; Michael, D. Org. Lett. 2002, 4, 1779. (g) Mizuta, S.;
Shibata, N.; Goto, Y.; Furukawa, T.; Nakamura, S.; Toru, T. J. Am.
Chem. Soc. 2007, 129, 6394.
(3) (a) Kong, W.; Casimiro, M.; Merino, E.; Nevado, C. J. Am. Chem. Soc.
2013, 135, 14480. (b) Fuentes, N.; Kong, W.; Fernandez-Sanchez, L.;
Merino, E.; Nevado, C. J. Am. Chem. Soc. 2015, 137, 964. (c) Kong, W.;
Casimiro, M.; Fuentes, N.; Merino, E.; Nevado,C. Angew. Chem., Int.
Ed. 2013, 52, 13086.
Scheme 3. Control Experiments
Based on the above experiments and literature reports,11
a
plausible mechanism is proposed in Scheme 4. Acrylamides 1
first capture sulfonyl radicals, generated in situ from the
oxidative decomposition of sulfonyl hydrazides mediated by
(4) Zhang, H.; Pan, C.; Jin, N.; Gu, Z.; Hu, H.; Zhu, C. Chem. Commun.
2015, 51, 1320.
TBAI and TBHP,12 to give
A
via radical addition.
(5) Tian, Q.; He, C.; Kuang, P. Org. Biomol. Chem., 2014, 12, 6349.
(6) Zhu, Y.-L.; Jiang, B.; Hao, W.-J.; Qiu, J.-K.; Sun, J.; Wang, D.-C.; Wei,
P.; Wang, A.-F.; Li, G.; Tu, S.-J. Org. Lett. 2015, 17, 6078.
(7) (a) Wang, A.-F.; Zhu, Y.-L.; Wang, S.-L.; Hao, W.-J.; Li, G.; Tu, S.-J.;
Jiang, B. J. Org. Chem. 2016, 81, 1099. (b) Wang, N.-N.; Hao, W.-J.;
Zhang, T.-S.; Li, G.; Wu, Y.-N.; Tu, S.-J.; Jiang, B. Chem. Commun.
2016, 52, 5144. (c) Zhu, Y.-L.; Wang, D.-C.; Jiang, B.; Hao, W.-J.;
Wei, P.; Wang, A.-F.; Qiu, J.-K.; Tu, S.-J. Org. Chem. Front. 2016, 3,
385. (d) Fan, W.; Li, Q.; Li, Y.; Sun, H.; Jiang, B.; Li, G. Org. Lett.
2016, 18, 1258.
Intermediates
A
undergo 5-exo-trig cyclization and
desulfonylation to access amide radicals C, which are
converted into sulfonylated amides 3 through hydrogen
abstraction with TBHP.
(8) (a) Zhang, J.; Shao, Y.; Wang, H.; Luo, Q.; Chen, J.; Xu, D.; Wan, X.
Org. Lett. 2014, 16, 3312. (b) Tang, Y.; Fan, Y.; Gao, H.; Li, X.; Xu, X.
Tetrahedron Lett. 2015, 56, 5616. (c) Yu, W.; Hu, P.; Fan, Y.; Yu, C.;
Yan, X.; Li, X.; Xu, X. Org. Biomol. Chem. 2015, 13, 3308. (d) Zhang,
M.; Xie, P.; Zhao, W.; Niu, B.; Wu, W.; Bian, Z.; Pittman, C. U.; Zhou,
A. J. Org. Chem. 2015, 80, 4176.
(9) (a) Wang, S.; Huang, X.; Wang, Q.; Ge, Z.; Wang, X.; Li, R. RSC Adv.
2016, 6, 11754. (b) Wei, W.; Liu, C.; Yang, D.; Wen, J.; You, J.; Suo,
Y.; Wang, H. Chem. Commun. 2013, 49, 10239. (c) Li, X.; Xu, X.; Hu,
P.; Xiao, X.; Zhou, C. J. Org. Chem. 2013, 78, 7343. (d) Li, X.; Xu, X.;
Zhou, C. Chem. Commun. 2012, 48, 1224. (e) Taniguchi, T.; Idota, A.;
Ishibashi, H. Org. Biomol. Chem. 2011, 9, 3151. (f) Yu, W.; Hu, P.;
Fan, Y.; Yu, C.; Yan, X.; Li, X.; Xu, X. Org. Biomol. Chem. 2015, 13,
3308.
(10) (a) Qiu, J.-K.; Jiang, B.; Zhu, Y.-L.; Hao, W.-J.; Wang, D.-C.; Sun, J.;
Wei, P.; Tu, S.-J.; Li, G. J. Am. Chem. Soc. 2015, 137, 892. (b) Rong,
G.; Mao, J.; Yan, H.; Zheng Y.; Zhang, G. J. Org. Chem. 2015, 80,
4697. (c) Chen, Z.-Z.; Liu, S.; Xu, G.; Wu, S.; Miao, J.-N.; Jiang, B.;
Hao, W.-J.; Wang, S.-L.; Tu, S.-J.; Li, G. Chem. Sci. 2015, 6, 6654. (d)
Tang, S.; Wu, Y.; Liao, W.; Bai, R.; Liu, C.; Lei, A. Chem. Commun.
2014, 50, 4496. (e) Wei, W.; Liu, C.; Yang, D.; Wen, J.; You, J.; Suo,
Y.; Wang, H. Chem. Commun. 2013, 49, 10239. (f) Taniguchi, T.;
Sugiura Y.; Zaimoku, H.; Ishibashi, H. Angew. Chem., Int. Ed. 2010,
49, 10154.
Scheme 4. The proposed mechanism
In summary, we have reported a metal-free sulfonylation
reaction of N-aryl-N-arylsulfonyl-acrylamides under catalytic
oxidation conditions. The addition of sulfonyl radicals to the
double bond of acrylamides can trigger a domino 5-exo-trig
cyclization, desulfonylation and aryl migration sequence,
giving access to a series of sulfonylated amides in C–S/C–C
bond-forming process with concomitant cleavage of N-S and
C-S bonds. We hope this protocol will find applications in the
synthesis of functionalized sulfones of potential usefulness.
(11) (a) Zhang, J.; Shao, Y.; Wang, H.; Luo, Q.; Chen, J.; Xu, D.; Wan, X.
Org. Lett. 2014, 16, 3312. (b) Liu, Z.; Zhang, J.; Chen, S.; Shi, E.; Xu,
Y.; Wan, X. Angew. Chem., Int. Ed., 2012, 51, 3231. (c) Wu, X.-F.;
Gong, J.-L.; Qi, X. Org. Biomol. Chem., 2014, 12, 5807.
Acknowledgments
(12) (a) Zhu, Y.-L.; Jiang, B.; Hao, W.-J.; Wang, A.-F.; Qiu, J.-K.; Wei, P.;
Wang, D.-C.; Li, G.; Tu, S.-J. Chem. Commun. 2016, 52, 1907. (b)
Yang, Z.; Hao, W.-J.; Wang, S.-L.; Zhang, J.-P.; Jiang, B.; Li, G.; Tu,
S.-J. J. Org. Chem. 2015, 80, 9224. (c) Qiu, J.-K.; Hao, W.-J.; Wang,
D.-C.; Wei, P.; Sun, J.; Jiang, B.; Tu, S.-J. Chem. Commun. 2014, 5094,
14782.
We are grateful for financial support from the NSFC (No. 21232004
and 21472071), PAPD of Jiangsu Higher Education Institutions, the
Outstanding Youth Fund of JSNU (YQ2015003), and NSF of
Jiangsu Province (BK20151163)
(13) General procedure for the synthesis of compounds 3a: To a stirred
mixture of N-aryl-N-arylsulfonyl-acrylamides 1a (82.2mg, 0.25 mmol)
and p-toluenesulfonyl hydrazide 2a (93 mg, 0.5 mmol) in CH3CN (2.5
ml) and then the TBAI (18.5 mg, 0.05 mmol) TBHP (70% solution in
water) (64.2 mg, 0.5mmol) were successively added. Then the reaction
mixture was immersed in a 70 °C oil bath and stirred overnight. The
mixture was cooled to room temperature, and then quenched by water
and extracted with Et2O. The combined organic layers were washed
with brine, dried over Na2SO4, filtered, and concentrated. After
Supplementary Material
Supplementary data (experimental details and spectroscopic
characterization of all compounds along with 1H NMR, IR and
mass spectra) associated with this article can be found, in the
online version, at doi:

4
Tetrahedron Letters
purification by flash column chromatography on silica gel
(Hexane/EtOAc = 50/1-20/1 as eluent), compound 3a was obtained as a
white solid. 2-methyl-N,2-di-p-tolyl-3-tosylpropanamide (3a): White
solid; mp 176-177 °C; IR (KBr, v, cm-1): 3368, 2920, 2360, 1910, 1676,
1597, 1521, 1453, 1400, 1312, 1298, 1239, 1208, 1146, 1128, 1084,
1058, 921, 867, 818, 750, 710, 627, 553, 512. 1H NMR (400 MHz,
CDCl3) δ 7.54 (d, J = 8.0 Hz, 2H), 7.20 (m, 6H), 7.13 – 7.02 (m, 4H),
6.86 (s, 1H), 4.15 (d, J = 14.8 Hz, 1H), 3.85 (d, J = 14.8 Hz, 1H), 2.41 (s,
3H), 2.34 (s, 3H), 2.30 (s, 3H), 2.12 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 172.8, 143.9, 138.2, 137.9, 136.3, 134.8, 134.3, 129.6, 129.5,
129.4, 127.6, 127.0, 120.2, 64.1, 50.0, 22.7, 21.6, 21.0, 20.9. HRMS
(ESI) m/z: calcd for C25H27NO3S: 406.1471[M-H]-; found: 406.1479.

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Metal-free synthesis of sulfonylated amides
through radical aryl migration-
desulfonylation
Jiang-Kai Qiu, Wen-Juan Hao, Li-Fang Kong, Wei Ping, Shu-Jiang Tu, Bo Jiang

6
Tetrahedron Letters
1. A metal-free desulfonylation of N-aryl-N-
arylsulfonyl-acrylamides is developed
2. The mechanism involves 5-exo-trig cyclization,
desulfonylation and aryl migration.
3. This method installs C-S and C-C bonds with
cleavage of N-S and C-S bonds.