I2/TBHP Mediated C-N and C-H Bond Cleavage of Tertiary Amines toward Selective Synthesis of Sulfonamides and β-Arylsulfonyl Enamines: The Solvent Effect on Reaction

Article abstract of DOI:10.1021/acs.orglett.6b01412

A novel method toward synthesis of sulfonamides and β-arylsulfonyl enamines has been developed via I₂/TBHP mediated C-N and C-H bond cleavage of tertiary amines, which features highly selective formation of two different target products depending on the reaction solvent. The experimental results reveal that H₂O as the solvent could effectively achieve the C-N bond cleavage to produce sulfonamides due to H₂O participating in the reaction process where H₂O plays a dual role. Differing from H₂O, organic solvents (such as dimethyl sulfoxide) could promote the C-H bond cleavage of tertiary amines to yield β-arylsulfonyl enamines.

Full text of DOI:10.1021/acs.orglett.6b01412

Letter
pubs.acs.org/OrgLett
I2/TBHP Mediated C−N and C−H Bond Cleavage of Tertiary Amines
toward Selective Synthesis of Sulfonamides and β‑Arylsulfonyl
Enamines: The Solvent Effect on Reaction
Junyi Lai, Liming Chang, and Gaoqing Yuan*
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, P. R. China
S
* Supporting Information
ABSTRACT: A novel method toward synthesis of sulfona-
mides and β-arylsulfonyl enamines has been developed via I2/
TBHP mediated C−N and C−H bond cleavage of tertiary
amines, which features highly selective formation of two
different target products depending on the reaction solvent.
The experimental results reveal that H2O as the solvent could
effectively achieve the C−N bond cleavage to produce
sulfonamides due to H2O participating in the reaction process
where H2O plays a dual role. Differing from H2O, organic solvents (such as dimethyl sulfoxide) could promote the C−H bond
cleavage of tertiary amines to yield β-arylsulfonyl enamines.
Scheme 1. Synthesis of Sulfonamides and β-Arylsulfonyl
Enamines
he activation of C−N and C−H bonds plays an important
role in organic synthesis since these bonds are abundant
T
and unreactive in organic molecules. An efficient control over
cleavage of C−N and C−H bonds toward synthesis of target
products has been an active research area.1,2 However, previous
investigations mainly focused on transition−metal catalysis
processes. In contrast, nontransition metal catalysis for the
activation of C−N and C−H bonds has been rarely explored.
Only a few examples have been reported to date.3 Thus, it is
highly desirable to develop a new and efficient metal-free method
for realizing cleavage of C−N or C−H bonds.
The synthesis of sulfonamides and β-arylsulfonyl enamines has
attracted much attention due to their highly biological activities
such as anticancer, antithyroid, antiinflamatory, hypoglycemic,
and diuretic agents.4 Sulfonamides were typically synthesized by
the reaction of thiols or sulfonyl chlorides with amino
compounds and sulfonamides with organic halides, alcohols, or
hydrocarbons.5 Recently, Jiang and co-workers reported an
attractive process for the synthesis of sulfonamides from sodium
sulfinates and amines by CuBr2 catalyst.6 Very recently, Song and
our group further developed a green and sustainable method for
the synthesis of sulfonamides from sodium sulfinates and
primary/secondary amines via I2-mediated approach (Scheme
1a).7 Our previous investigation has revealed that the formation
of sulfonamides practically underwent a radical process via I2-
induced N−H bond cleavage. Following our continuous interest
in radical reactions, we found that the combination of I2 and t-
butyl hydroperoxide (TBHP) with H2O or dimethyl sulfoxide
(DMSO) as the reaction solvent could realize a selective cleavage
of C−N and C−H bonds of tertiary amines toward synthesis of
sulfonamides and β-arylsulfonyl enamines (Scheme 1b). Herein,
we report this interesting finding.
investigations. In the presence of iodine, the reaction was carried
out in H2O solvent at room temperature, affording the product
N,N-diethyl-4-methylbenzenesulfonamide (3a) related with the
C−N bond cleavage of 2a in 13% yield (Table 1, entry 1). When
I2 with TBHP was used as the inducer at the same time, the yield
of 3a was raised to 34% (Table 1, entry 2). In addition, reaction
temperature has a great impact on the formation of 3a (Table 1,
entries 2−5). At 80 °C, the yield of 3a was drastically improved,
up to 96% (entry 5). It is noteworthy that (E)-N,N-diethyl-2-
tosylethenamine (4a) corresponding to the C−H bond cleavage
of 2a was not observed at all in the H2O solvent case (Table 1,
entries 1−5). Surprisingly, it was found that 4a could be obtained
in moderate to high yields besides 3a if reaction medium H2O
was replaced by organic solvents such as N,N-dimethylforma-
mide (DMF), dimethylacetamide (DMA), CH3CN, toluene,
EtOH, and DMSO (Table 1, entries 12−17). These
The reaction of sodium 4-methylbenzenesulfinate (1a) with
Received: May 16, 2016
triethylamine (2a) was chosen as a model to initiate our
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01412
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
ab
,
Table 1. Optimization of Reaction Conditions
Scheme 2. Scope of Sodium Sulfinate Salts
b
I2
TBHP
(equiv)
temp
(°C)
yield
entry (equiv)
solvent
(3a/4a, %)
1
1
0
H2O
rt
13/0
2
1
3
H2O
rt
34/0
3
1
3
H2O
40
60
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
60
60
60
60/0
4
1
3
H2O
78/0
5
1
3
H2O
96/0
6
0.5
0.1
0
3
H2O
75/0
7
3
H2O
19/0
8
3
H2O
NR
9
1
5.5
1.5
0
H2O
95/0
10
11
12
13
14
15
16
17
18
19
20
21
22
1
H2O
84/0
1
H2O
27/0
1
3
DMF
DMA
CH3CN
toluene
EtOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
29/49
34/66
55/45
49/51
53/47
10/83
6/89
1
3
1
3
1
3
a
Reaction conditions: sodium sulfinate salts (0.6 mmol), 2a (0.5
1
3
mmol), I2 (1 equiv), TBHP (3 equiv), H2O (2 mL), and 8 h under air
0.5
0.5
0.5
0.5
0
3
b
in a sealed tube. Isolated yield.
4
5.5
5.5
5.5
0
trace/90
trace/90
trace/30
trace/32
addition, sodium naphthalene-1-sulfinate and sodium naphtha-
lene-2-sulfinate were proven to be good substrates for this
process (Scheme 2, 3l and 3m).
0.5
To determine whether other tertiary amines could be
applicable to this reaction process, various tertiary amines were
investigated under the optimized conditions. It was found that
both aliphatic and aromatic tertiary amines reacted smoothly
with sodium 4-methylbenzoate to afford the target products in
good yields (Scheme 3, 3p−3r). When the tertiary amine with
a
Reaction conditions: 1a (0.6 mmol), 2a (0.5 mmol), solvent (2 mL),
TBHP (70% in water), and 8 h under air in a sealed tube.
b
Determined by GC.
experimental results clearly indicate that solvents have a
remarkable effect on the C−N and C−H bond cleavage of 2a.
Further investigation demonstrated that the formation of 3a was
negligible and that 4a became almost a sole product when the
amount of TBHP was increased to 5.5 equiv in the DMSO
solvent case (Table 1, entries 19−21). Moreover, the yield of 3a
or 4a obviously declined in the absence of TBHP or I2 (Table 1,
entries 11, 21, and 22). This means that the combination of I2
with TBHP is very important for the formation of 3a and 4a. In
addition, only 19% yield of 3a was obtained when 0.1 equiv
(catalytic amount) of I2 was used (Table 1, entry 7), indicating
that I2 could not act as a catalyst in the present system.
a b
,
Scheme 3. Scope of Tertiary Amines
For the reaction of C−N bond cleavage of tertiary amines in
H2O solvent, we further investigated the substrate scope with
respect to sodium sulfinate salts. As shown in Scheme 2, a wide
range of sodium sulfinate salts with triethylamine (2a) could be
applicable to this reaction system under the optimized
conditions. The sodium sulfinate salts with electron-withdrawing
and electron-donating groups reacted with 2a to afford the
corresponding sulfonamides in good to excellent yields smoothly
(Scheme 2, 3a−3j). This process could tolerate various
functional groups such as halogen, −CN, and −OCH3 (Scheme
2, 3b−3e and 3j), which provided the possibility for further
functionalization. Moreover, the substituted group at different
positions on the phenyl ring of sodium sulfinates had no obvious
effect on the reaction (Scheme 2, 3a and 3k). Besides, the
substrates bearing two substituted groups (especially trifluor-
omethyl group) such as sodium 3-bromo-5-methylbenzenesulfi-
nate and sodium 4-chloro-3-(trifluoromethyl)benzenesulfinate
could smoothly perform as well (Scheme 2, 3n and 3o). In
a
b
Reaction conditions as shown in Scheme 2. Isolated yield.
different substituent groups like N,N-dimethylbutan-1-amine
was involved, the target product (3s) was also obtained in a high
yield. Delightfully, the reaction could afford the corresponding
products in excellent yields (Scheme 3, 3t−3v) when cyclic and
heterocyclic tertiary amines, such as 1-ethylpiperidine, 4-
ethylmorpholine, and 1-ethylpyrrolidine, were used as the
substrates.
B
DOI: 10.1021/acs.orglett.6b01412
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
For the activation of C−H bond of tertiary amines toward
synthesis of β-arylsulfonyl enamines in DMSO solvent, we
further investigated the reaction of various sodium sulfinate salts
with triethylamine (2a). As shown in Scheme 4, sodium sulfinate
Scheme 5. Control Experiments
a b
,
Scheme 4. Synthesis β-Arylsulfonyl Enamines
a
Reaction conditions: 1a (0.6 mmol), 2a (0.5 mmol), I2 (0.5 equiv),
TBHP (5.5 equiv), DMSO (2 mL), and 8 h under air in a sealed tube.
b
Isolated yield.
Scheme 6. Possible Mechanism
salts bearing electron-withdrawing and electron-donating groups
with 2a were well converted to the corresponding β-arylsulfonyl
enamine products in good yields. Using N,N-diisopropylethyl-
amine as the substrate, the reaction of sodium 4-methylbenze-
nesulfinate (1a) with N,N-diisopropylethylamine gave a mixture
of β-arylsulfonyl enamines in DMSO solvent, while the target
product sulfonamides were not obtained at all in H2O solvent
(Scheme S1, see the Supporting Information).
To gain further insight into the mechanism, a series of control
experiments were carried out. No desired product was detected
in the presence of the radical scavenger 2,2,6,6-tetramethylpiper-
idine-1-oxyl (TEMPO), indicating that the formation of 3a or 4a
presumably underwent a radical pathway (Scheme 5, eqs 1 and
2). In the absence of sodium 4-methylbenzoate (1a), tribenzyl-
amine was changed to dibenzylamine and benzaldehyde via the
C−N bond cleavage (Scheme 5, eq 3). Dibenzylamine with 1a
could be smoothly converted to sulfonamide 3r (Scheme 5, eq
4). In addition, benzaldehyde could also be detected during the
reaction of 1a with tribenzylamine for the synthesis of 3r under
the standard conditions (Scheme 3). Therefore, we deduce that
the formation of sulfonamide may involve the conversion of
tertiary amine to secondary amine. The C−N bond cleavage of
tertiary amine is contributed to H2O participating in this reaction
process. In the present system, H2O could serve not only as the
solvent but also as the reactant. In addition, we deduce that
enamine may be the intermediate product in the DMSO solvent
case. In order to confirm this point, N,N-diethylethenamine was
synthesized via the reaction of diethylamine with acetaldehyde by
using K2CO3 as the dehydrating agent at 40 °C for 4 h,8 followed
by the reaction with 1a without further purification. As shown in
Scheme 5 (eq 5), (E)-N,N-diethyl-2-tosylethenamine (4a) could
be obtained, which indicates that N,N-diethylethenamine may be
the intermediate product.
butylperoxyl radicals. Meanwhile, the sulfinic acid sodium is
activated by I2, providing a sulfonyl radical.9 tert-Butoxyl and tert-
butylperoxyl radicals then abstract hydrogen from the tertiary
amine to generate a radical A or B, followed by an electron
transfer to form intermediate C. Because of its instability, the
intermediate C is readily hydrolyzed to produce an aldehyde and
a secondary amine in water.10 Then, the sulfonyl radical attacks
the secondary amine to afford the target product 3.7 However,
the intermediate C is converted into enamine D by
deprotonation in DMSO solvent.11 Enamine D combines with
Based on our experimental results and previous publications, a
plausible mechanism is depicted in Scheme 6. Initially, I−/I2
redox cycle promotes TBHP to furnish tert-butoxyl and tert-
C
DOI: 10.1021/acs.orglett.6b01412
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Chen, H.; Luus, L.; Diercks, J.; Aktas, H.; Chorev, M.; Halperin, J. A. J.
Med. Chem. 2004, 47, 4979. (d) Gilbert, A. M.; Caltabiano, S.; Koehn, F.
E.; Chen, Z.; Francisco, G. D.; Ellingboe, J. W.; Kharode, Y.; Mangine, A.
M.; Francis, R.; TrailSmith, M.; Gralnick, D. J. Med. Chem. 2002, 45,
2342.
(5) (a) Katritzky, A. R.; Garcia, V. R.; Niar, S. K. J. Org. Chem. 2004, 69,
1849. (b) Kamal, A.; Reddy, J. S.; Bharathi, E. V.; Dastagiri, D.
Tetrahedron Lett. 2008, 49, 348. (c) Moore, J. D.; Herpel, R. H.;
Lichtsinn, J. R.; Flynn, D. L.; Hanson, P. R. Org. Lett. 2003, 5, 105.
(d) Gioiello, A.; Rosatelli, E.; Teofrasti, M.; Filipponi, P.; Pellicciari, R.
ACS Comb. Sci. 2013, 15, 235. (e) Shi, F.; Tse, M. K.; Zhou, S.; Pohl, M.
M.; Radnik, J.; Hubner, S.; Jahnisch, K.; Bruckner, A.; Beller, M. J. Am.
Chem. Soc. 2009, 131, 1775. (f) Burton, G.; Cao, P.; Li, G.; Rivero, R.
Org. Lett. 2003, 5, 4373.
a sulfonyl radical to give a radical E, followed by the reaction with
I2 to form intermediate product F. Finally, HI elimination from F
provides the target product 4.9c,12
In summary, the preparation of sulfonamides and β-
arylsulfonyl enamines via I2/TBHP-mediated reaction between
tertiary amines and sodium sulfinates has been achieved. In this
reaction system, the combination of I2 with TBHP induces a
radical reaction, and solvents have a great effect on the reaction.
H2O takes part in the reaction to result in the C−N bond
cleavage of tertiary amines so that sulfonamides could be formed.
In the DMSO solvent case, the C−H bond cleavage of tertiary
amines readily occurred to give β-arylsulfonyl enamines. The
present work provides a new strategy for the synthesis of
sulfonamides and β-arylsulfonyl enamines. The strategy is of
interest and has potential applications due to selective cleavage of
C−N and C−H bonds of tertiary amines for achieving desirable
synthetic purposes.
(6) Tang, X.; Huang, L.; Qi, C.; Wu, X.; Wu, W.; Jiang, H. Chem.
Commun. 2013, 49, 6102.
(7) (a) Yang, K.; Ke, M.; Lin, Y.; Song, Q. Green Chem. 2015, 17, 1395.
(b) Pan, X.; Gao, J.; Liu, J.; Lai, J.; Jiang, H.; Yuan, G. Green Chem. 2015,
17, 1400.
(8) (a) Curphey, T. J.; Hung, J. C. Y.; Chu, C. C. C. J. Org. Chem. 1975,
40, 607. (b) Hodgson, D. M.; Bray, C. D.; Kindon, N. D.; Reynolds, N.
J.; Coote, S. J.; Um, J. M.; Houk, K. N. J. Org. Chem. 2009, 74, 1019.
(9) (a) Liu, Z.; Zhang, J.; Chen, S.; Shi, E.; Xu, Y.; Wan, X. Angew.
Chem., Int. Ed. 2012, 51, 3231. (b) Tan, B.; Toda, N.; Barbas, C. F.
Angew. Chem., Int. Ed. 2012, 51, 12538. (c) Xiao, F.; Chen, H.; Xie, H.;
Chen, S.; Yang, L.; Deng, G. J. Org. Lett. 2014, 16, 50.
(10) (a) Tian, J. S.; Loh, T. P. Angew. Chem., Int. Ed. 2010, 49, 8417.
(b) Ling, Z.; Yun, L.; Liu, L.; Wu, B.; Fu, X. Chem. Commun. 2013, 49,
4214. (c) Guo, S.; Qian, B.; Xie, Y.; Xia, C.; Huang, H. Org. Lett. 2011,
13, 522.
(11) Huang, X.; Wang, J.; Ni, Z.; Wang, S.; Pan, Y. Org. Lett. 2015, 17,
5488.
(12) (a) Katrun, P.; Mueangkaew, C.; Pohmakotr, M.; Reutrakul, V.;
Jaipetch, T.; Soorukram, D.; Kuhakarn, C. J. Org. Chem. 2014, 79, 1778.
(b) Tang, S.; Wu, Y.; Liao, W.; Bai, R.; Liu, C.; Lei, A. Chem. Commun.
2014, 50, 4496.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01412.
■
S
Typical experimental procedure and characterization for
all products (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: gqyuan@scut.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of
China (21572070 and 21172079).
■
REFERENCES
■
(1) (a) Koreeda, T.; Kochi, T.; Kakiuchi, F. J. Am. Chem. Soc. 2009, 131,
7238. (b) Roglans, A.; Pla-Quintana, A.; Moreno-Manas, M. Chem. Rev.
2006, 106, 4622. (c) Patil, R. D.; Adimurthy, S. Adv. Synth. Catal. 2011,
353, 1695. (d) Wu, W.; Su, W. J. Am. Chem. Soc. 2011, 133, 11924.
(e) Zhu, M. K.; Zhao, J. F.; Loh, T. P. Org. Lett. 2011, 13, 6308. (f) Yang,
C. F.; Wang, J. Y.; Tian, S. K. Chem. Commun. 2011, 47, 8343. (g) Li, M.;
Wang, Y.; Tian, K. Angew. Chem., Int. Ed. 2012, 51, 2968. (h) Wang, Q.;
Su, Y.; Li, L.; Huang, H. Chem. Soc. Rev. 2016, 45, 1257.
(2) (a) Yang, Y.; Li, K.; Cheng, Y.; Wan, D.; Li, M.; You, J. Chem.
Commun. 2016, 52, 2872. (b) Zhang, Y.; Hu, G.; Ma, D.; Xu, P.; Gao, Y.;
Zhao. Chem. Commun. 2016, 52, 2815. (c) Liu, Y.; Yang, K.; Ge, H.
Chem. Sci. 2016, 7, 2804. (d) Meng, G.; Szostak, M. Org. Lett. 2016, 18,
796. (e) Shang, R.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc. 2015, 137,
7660. (f) Luo, C. Z.; Gandeepan, P.; Wu, Y. C.; Tsai, C. H.; Cheng, C. H.
ACS Catal. 2015, 5, 4837. (g) Dyker, G. Angew. Chem., Int. Ed. 1999, 38,
1698.
(3) (a) Ilangovan, A.; Satish, G. J. Org. Chem. 2014, 79, 4984. (b) Yan,
Y.; Zhang, Y.; Feng, C.; Zha, Z.; Wang, Z. Angew. Chem., Int. Ed. 2012,
51, 8077. (c) Yan, Y.; Xu, Y.; Niu, B.; Xie, H.; Liu, Y. J. Org. Chem. 2015,
80, 5581. (d) Shi, E.; Shao, Y.; Chen, S.; Hu, H.; Liu, Z.; Zhang, J.; Wan,
X. Org. Lett. 2012, 14, 3384. (e) Zhang, H.; Gu, Z.; Xu, P.; Hu, H.;
Cheng, Y.; Zhu, C. Chem. Commun. 2016, 52, 477. (f) Sharma, K. K.;
Patel, D. I.; Jain, R. Chem. Commun. 2015, 51, 15129.
(4) (a) Yoshino, H.; Ueda, N.; Niijima, J.; Sugumi, H.; Kotake, Y.;
Koyanagi, N.; Yoshimatsu, K.; Asada, M.; Watanabe, T. J. Med. Chem.
1992, 35, 2496. (b) Supuran, C. T.; Casini, A.; Scozzafava, A. Med. Res.
Rev. 2003, 23, 535. (c) Natarajan, A.; Guo, Y.; Harbinski, F.; Fan, Y.-H.;
D
DOI: 10.1021/acs.orglett.6b01412
Org. Lett. XXXX, XXX, XXX−XXX