Synthesis of sulfonamides from azoles and sodium sulfinates at ambient temperature

Article abstract of DOI:10.1016/j.tet.2017.03.038

NBS or NIS mediated direct S[sbnd]N bond formation between azoles and sodium sulfinates is described. The reaction shows good substrate scope and tolerates a wide range of functionalities in both azoles and sodium sulfinate substrates. Pyrazoles are also suitable for this method, various 4-halopyrazoles derivatives were obtained by using N-halosuccinimide (NXS) as the halogen source.

Full text of DOI:10.1016/j.tet.2017.03.038

Accepted Manuscript
Synthesis of sulfonamides from azoles and sodium sulfinates at ambient temperature
Lili Fu, Xiaodong Bao, Shanshan Li, Lingtian Wang, Zhiguo Liu, Wanzhi Chen, Qinqin
Xia, Guang Liang
PII:
S0040-4020(17)30275-2
10.1016/j.tet.2017.03.038
TET 28544
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 27 December 2016
Revised Date: 3 March 2017
Accepted Date: 14 March 2017
Please cite this article as: Fu L, Bao X, Li S, Wang L, Liu Z, Chen W, Xia Q, Liang G, Synthesis of
sulfonamides from azoles and sodium sulfinates at ambient temperature, Tetrahedron (2017), doi:
10.1016/j.tet.2017.03.038.
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.

ACCEPTED MANUSCRIPT
Synthesis of Sulfonamides from Azoles and Sodium Sulfinates at
Ambient Temperature
Lili Fu, a, 1 Xiaodong Bao, a, 1 Shanshan Li, a Lingtian Wang, c Zhiguo Liu, a Wanzhi Chen,b Qinqin Xia,a* and
Guang Lianga
a
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
Corresponding Authors: zdxiaqinqin@163.com.
b Department of Chemistry, Zhejiang University, Hangzhou 310028, China.
c School of Medicine, Shandong University, Jinan 250012, China.
1 These authors contributed equally to this work.
Graphical Abstract：
2
2
R
O
R
1
R
S
N
NH
NH
O
N
N
O
NXS
+
S ONa
1
EtOAc or dioxane
25 °C, 12 h
R
X
O
N S
O
1
N
R
3
N
R
3
R
ABSTRACT. NBS or NIS mediated direct S-N bond formation between azoles and sodium sulfinates is
described. The reaction shows good substrate scope and tolerates a wide range of functionalities in both
azoles and sodium sulfinate substrates. Pyrazoles are also suitable for this method, various 4-halopyrazoles
derivatives were obtained by using N-halosuccinimide (NXS) as the halogen source.
1

Key words: Synthetic methods; Sodium sulfinates; azoles; sulfonylation; halogenation
ACCEPTED MANUSCRIPT
1. Introduction
Sulfonamides are important building blocks for pharmaceuticals and bioactive compounds, owing to their
well-known anticonvulsant, antibacterial, anticancer, antitumor, anti-inflammatory, and HIV protease
inhibitory activities.1 Sulfonamides are widely applicated in herbicides and dyes.2 Therefore, the
development of general methods for the synthesis of sulfonamides is consequently an important goal in
organic chemistry. Traditionally, sulfonamides are produced from the reaction of an amine and a sulfonyl
chloride in the presence of a base.3 Recently, a few examples have been reported on direct synthesis of the
sulfonamides from sulfinates and amines. Jiang and co-workers reported an elegant work for
CuBr2-catalyzed oxidative synthesis of sulfonamides from sodium sulfinatesand amines with DMSO or O2.4
It was found that sulfonamides could also be formed via oxidative amination of sodium sulfinate under
metal-free conditions later.5 Zeng and co-workers reported a protocol for the synthesis of sulfonamides via
the electrochemical oxidative amination of sodium sulfinates.6 These methods avoid the prefunctionalization
of the sulfonate component, therefore they are step and atom economical methods. To extend the application
scope of this methodology, we have developed a route for synthesis of sulfonamides by using NIS or NBS
as the oxidant.
Azoles are ubiquitous motifs in nature and exhibit potential biological activities and medicinal
significance.7 Thus the development of new synthetic methods for the functionalization of azoles is of great
interest.8 The N-alkylation and N-arylation of azoles present the most straightforward method for the
synthesis of azole derivatives. As a part of our continuous interest in the functionalization of azoles,8e,8f
herein, we report a metal-free sulfonamides formation between sodium sulfinates and azoles mediated by
NBS or NIS at room temperature.
2

2. Results and Discussion
ACCEPTED MANUSCRIPT
Benzimidazole (1a) and sodium p-tolylsulfinate (2a) was selected as the model substrates to establish
optimized reaction conditions, and selected results were summarized in Table 1. When the reaction of 1a
with 2a was carried out in the presence of I2 (1 equiv) under air in 1,2-dichloroethane (DCE) at room
temperature for 12 h, the product 3a could be obtained in 44% yield (Table 1, entry 1). Next, various
oxidants were screened, and different oxidants had distinct effects on the yield of 3a (entries 2-5). A
significant enhancement of the reaction yield (87%) was accomplished when NBS was used (entry 3). When
the amount of NBS was increased to 2 or 3 equiv, the yield of 3a was slightly decreased (entries 6 and 7).
Lower yields of product 3a were obtained and some unidentified byproducts were observed when the
temperature was increased to 50 and 90 °C (entries 8 and 9). The effect of solvents on the model reaction
was also surveyed (entries 10−18), and a significant enhancement of the reaction yield (93%) was
accomplished when 1,4-dioxane was used (entry 15). We also found that relatively lower yields were
obtained when the reaction took place in polar solvents such as DMSO, DMF and ethanol (entries 16-18).
We found that running reaction with 100 mg 4 Å MS did not enhance the reaction yield (entry 19). Other
oxidants such as N-Bromophthalimide and N-Bromoacetamide were also tested, the products was obtained
in 93% and 84% yields, respectively (entries 20 and 21).
Table 1. Optimization of Reaction Conditions a
O
H
N
ONa
S
oxidation
solvent
O
S
+
N
N
N
O
1a
2a
3a
Entry
Oxidant
I2
Temp (°C)
Solvent
Yield (%)
1
2
3
25
25
25
DCE
DCE
DCE
44
78
87
NIS
NBS
3

4
5
NCS
25
DCE
52
20
85
83
79
60
86
62
77
68
69
93
22
15
26
92
ACCEPTED MANUSCRIPT
TBHP
25
25
25
50
90
25
25
25
25
25
25
25
25
25
25
DCE
6 b
7 c
8
NBS
DCE
NBS
DCE
NBS
DCE
9
NBS
DCE
10
11
12
13
14
15
16
17
18
19 d
NBS
EtOAc
CH2Cl2
CH3CN
Tol
NBS
NBS
NBS
NBS
THF
NBS
1,4-dioxane
DMSO
DMF
NBS
NBS
NBS
C2H5OH
1,4-dioxane
NBS
N-Bromophth
alimide
N-Bromoacet
amide
20
21
25
25
1,4-dioxane
1,4-dioxane
93
84
a
Reaction conditions: 1a 0.5 mmol, 2a 1.0 mmol, oxidant 0.5
mmol, solvent 2 mL, 12 h, under air. b 1.0 mmol NBS was used.
c 1.5 mmol was used. d 4 Å MS (100 mg) was used.
Under the optimized reaction conditions, we next examined the scope of different azoles and sodium
sulfinates (Scheme 1). The reactions of sodium sulfinates 2b−2e bearing both electron-rich and
electron-deficient functional groups at the para-position of the aryl ring afforded the corresponding products
(3b−3e) in good yields. Moreover, sodium naphthalene-1-sulfinate 2f was successfully employed as the
substrate, and the desired product 3f was obtained with a moderate yield (65%). Sodium
2,5-dichloro-thiophene-3-sulfinate 2g was also a suitable substrate, and the expected product 3g was
obtained in 75% yield. To our delight, sodium methanesulfinate could also be used as substrates with
4

benzimidazole (1a) to afford the desired product 3h in 61% yield. The scope of azoles was also examined in
ACCEPTED MANUSCRIPT
this reaction. 2-Methyl-1H-benzoimidazole 2i and 5,6-dimethyl-1H-benzoimidazole 2j reacted with sodium
p-tolylsulfinate smoothly, and gave the corresponding products 3i and 3j in 82% and 91% yields,
respectivelty. Additionally, triazoles such as benzotriazole 2k and 1,2,4-triazole 2l were also tolerated in this
reaction leading to the products in moderate to good yields.
Scheme 1. Reactions of various azoles with sodium sulfinates a
R1
R1
NBS (1 equiv)
O
O
N S R2
O
Z
Y
Z
Y
R2 S ONa
NH
+
dioxane (2 mL)
25 , 12 h
X
X
X, Y, Z = C or N
3
2
1
NO2
O
F
O
Cl
O
S
O
S
S
N
N
S
N
N
O
N
O
N
O
N
O
N
3c, 87%
3d, 75%
3a, 93%
3b, 85%
Cl
O
O
O
O
S
O
S
N
S
N
S
S
N
N
Cl
O
N
O
N
O
N
O
N
3f, 65%
3g, 75%
3e, 88%
3h, 61%
O
O
O
O
S
S
N
N
N
N
S
O
S
N
N
N
O
N
O
N
O
N
3l, 55%
3i, 82%
3k, 95%
3j, 91%
a Reaction conditions: 1 0.5 mmol, 2 1.0 mmol, oxidant 0.5 mmol, 1,4-dioxane 2 mL, 12 h, under air.
Pyrazoles are essential skeletons of many biologically active organic compounds that have found wide
applications in pesticides, medicines, and functional materials.9 To further explore the potential of this
efficient reaction, various pyrazoles were examined as substrates to react with sodium sulfinates (Scheme 2).
However, an unexpected compound 4-iodo-1-tosyl-1H-pyrazole 5a was obtained instead of our desired
product. Clearly, 4-iodination of pyrazoles was carried out during the N-S bond formation reaction. NIS was
5

used as both oxidant and iodination reagent. 4-Halopyrazoles, which possess a useful functional handle at
ACCEPTED MANUSCRIPT
the 4-position, represent valuable intermediates toward the syntheses of these targets.10 A 85% yield of 5a
was obtained when NIS was increased to 3 equiv. NBS was also suitable for this transformation, generating
the corresponding bromination product 5b in 66% yield. In addition to sodium p-tolylsulfinate 2a, various
substituted sodium arenesulfinates were all favorable substrates to generate the corresponding halogenation
products in moderate to good yields (5c-5j). Additionally, sodium naphthalene-1-sulfinate was also tolerated
in this reaction leading to the iodination and bromination products in moderate yields (5k and 5l).
Subsequently, the scope of pyrazoles was investigated under the standard reaction conditions.
3-Substituted pyrazoles such as 3-Methyl-1H-pyrazole, 3-phenyl-1H-pyrazole, 3-bromo-1H-pyrazole and
2-(1H-Pyrazol-3-yl)-pyridine were effective substrates in this transformation furnishing the corresponding
products in good yields (5m, 5o, 5p, 5q, 5r, 5t and 5u). Pyrazole bearing an electron-withdrawing group
gave the corresponding product in 72% yield (5s). We further found that substitution was tolerated at both
the 3- and 5-positions (5n).
Scheme 2. Reactions of pyrazoles with sodium sulfinates a
6

R3
R3
NXS (3 equiv)
X
ACCOEPTED MANUSCRIPT
O
S R2
+
R2 S ONa
N
NH
EtOAc (2 mL)
N
N
O
25 °C, 12 h
4
2
5
I
I
O
I
O
S
Br
O
S
O
N
S
N
Cl
N
N
S
N
N
N
N
N
O
O
O
O
5c, 60%
5a, 85%
5b, 66%
5d, 84%
Br
Br
I
O
Br
O
O
I
O
N
S
Cl
N
S
O
N
S
F
N
S
O
F
N
N
N
N
O
O
O
5e, 85%
5h, 73%
5f, 71%
5g, 72%
Br
O
I
O
I
O
O
N
S
N
S
O
N
S
N
S
NO2
N
N
N
O
O
O
O
5i, 71%
5j, 62%
5k, 57%
5l, 52%
I
O
Br
O
S
I
Br
O
O
N
S
N
N
N
S
N
S
N
O
N
N
O
O
O
N
N
5m, 79%
5n, 62%
5o, 94%
5p, 98%
I
Br
Br
O
S
O
S
O
S
N
N
N
O
N
N
N
O
O
O
Br
Br
O
5s, 72%
5q, 87%
5r, 96%
I
Br
O
O
N
S
N
S
N
N
O
O
5t, 64%
5u, 91%
a Reaction conditions: 4 0.5 mmol, 2 1.0 mmol, oxidant 1.5 mmol, ethyl acetate 2 mL, 12 h, under air.
To investigate the reaction mechanism, several control experiments were conducted. A radical scavenger
was added to the reaction system, 71% and 76% of desired product 3aa was obtained in the presence of
TEMPO (2,2,6,6-tetramethylpiperidine-N-oxyl) and BHT (2,6-di-tert-butyl-4-methylphenol), respectively
(Scheme 3a). Therefore, we think that a radical-based reaction mechanism can be excluded. Treatment of
sodium p-tolylsulfinate 2a with 1 equiv of NBS at room temperature gave 4-methyl-benzenesulfonyl
bromide 6 in 52% yield (scheme 3b). Further reaction of benzoimidazole 1a with isolated 6 afforded 4c in
7

48% yield (scheme 3c). The result implies that sulfonyl bromide is a likely intermediate in the reaction. As
ACCEPTED MANUSCRIPT
we know, NIS or NBS was used both as the catalyst and halogen source. When the reaction of 4t with 2a
was carried out in the presence of
1
equiv of NIS, 4-Iodo-3-phenyl-1H-pyrazole 7,
3-Phenyl-1-(toluene-4-sulfonyl)-1H-pyrazole 8 and 4-Iodo-3-phenyl-1-(toluene-4-sulfonyl)-1H-pyrazole 5t
were obtained in 15%, 18% and 32% yields, respectively (Scheme 3d). Moreover, 3-Phenyl-1H-pyrazole 4t
could be converted to the corresponding 4-Iodo-3-phenyl-1H-pyrazole 5t in 85% yield under 1 equiv of NIS
(Scheme 3e). These results indicating that the halogenation and sulfonylation occurred simultaneously
during the reaction.
Scheme 3. Control experiments
8

ACCEPOT
S
EODNaMANUSCRIPT
NBS (1.0 equiv)
dioxane (2 mL)
H
N
O
S
(a)
+
N
N
N
25 , 12 h
O
radical inhibitors (1.0 equiv)
3a
1a
2a
TEMPO
BHT
71%
76%
1.0 mmol
0.5 mmol
O
S
Br
NBS (1.0 equiv)
O
S ONa
O
(b)
1,4-dioxane (2 mL)
25 , 12 h
2a
0.5 mmol
6 (52% )
O
S
H
N
Br
1,4-dioxane (2 mL)
O
(c)
O
+
N
25 , 12 h
S
N
N
O
3a (48%)
1a
6
1.0 mmol
0.5 mmol
I
NH
N
7 (15%)
+
O
S
O
S
ONa
NH
NIS (1.0 equiv)
N
(d)
+
N
N
O
EA (2 mL)
8 (18%)
>30% of 4t was recovered
2a
+
1.0 mmol
0.5 mmol
I
O
N
S
N
O
5t (32%)
I
NH
NIS (1.0 equiv)
NH
(f)
N
N
EA (2 mL)
4t
0.5 mmol
5t (85%)
A possible reaction pathway is proposed based on the control experiments. Initially, sodium sulfinate
interacted with NIS to generate sulfonyl iodide. Then, nucleophilic reaction of azoles with sulfonyl iodide
would form the product. The halogenation could occur before or after the sulfonylation during the reaction
(Scheme 4).
9

Scheme 4. Possible reaction pathway
ACCEPTED MANUSCRIPT
O
S ONa
O
S
I
NIS
O
O
S
I
O
I
O
O
N S
O
NIS
O
route 1
N S
O
NH
N
N
N
HI
NH
O
O
I
S
O
I
I
NIS
O
S
NH
route 2
NH
N
N
N
N
O
O
HI
NH
O
3. Conclusions
In summary, we have developed a new method of NIS or NBS-mediated direct N-sulfonylation of azoles
with sodium sulfinates. This protocol provides a simple and green approach for the preparation of
sulfonamides derivatives. The optimized method works successfully with diverse ranges of azoles and
sodium sulfinates. Moreover, the present method gives a diverse range of 4-Halopyrazoles that can be
explored for pharmacological applications and as intermediates in organic synthesis.
4. Experimental Section
4.1. General Procedures.
All of the reagents and solvents were purchased from commercial suppliers and used without further
purification. All experiments were carried out under air, and oven-dried glassware was used in all cases. 1H
13
1
13
and C NMR spectra were recorded at 500 and 125 MHz, respectively. H NMR and C NMR chemical
shifts are reported in ppm using tetramethylsilane (TMS) as an internal standard or residual nondeuterated
solvent peak as an internal standard. High-resolution mass spectra were recorded on an ESI-Q-TOF mass
spectrometer.
10

4.2. General procedure for the synthesis of products 3
ACCEPTED MANUSCRIPT
Azoles 1 (0.5 mmol), sodium sulfinate 2 (1.0 mmol) and NBS (0.5 mmol) were dissolved in 2 mL of
1,4-dioxane solvent. the reaction mixture was stirred at room temperature under air for 12 h. After the
reaction, the resulting mixture was extracted with EtOAc. The combined organic phase was dried over
anhydrous Na2SO4 and the solvent was then removed under vacuum. The residue was purified by flash
column chromatography on silica gel (petroleum ether/ethyl acetate, 3:1) to afford the corresponding
product.
1
1-Tosyl-1H-benzo[d]imidazole (3a).5d Light yellow oil (126 mg, 93% yield); H NMR (500 MHz,
CDCl3): δ 8.84 (s, 1H), 8.04 (d, J = 7.0 Hz, 2H), 7.88 (d, J = 6.5 Hz, 1H), 7.76 (d, J = 7.0 Hz, 1H),
7.45~7.38 (m, 4H), 2.33 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 146.5, 143.5, 142.4, 133.6, 130.6, 130.1,
127.3, 125.6, 124.9, 120.7, 112.4, 21.08.
1-((4-Chlorophenyl)sulfonyl)-1H-benzo[d]imidazole (3b).11 White solid (124 mg, 85% yield); Mp
122-123 °C; 1H NMR (500 MHz, CDCl3): δ 8.37 (s, 1H), 7.93 (d, J = 9.0 Hz, 2H), 7.84 (d, J = 7.5 Hz, 1H),
7.79 (d, J = 7.5 Hz, 1H), 7.49 (d, J = 9 Hz, 2H), 7.43~7.38 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 144.1,
141.7, 141.1, 136.0, 130.6, 130.1, 128.6, 125.8, 125.0, 121.3, 112.4.
1-((4-Fluorophenyl)sulfonyl)-1H-benzo[d]imidazole (3c). White solid (117 mg, 85% yield); Mp
135-138 °C; 1H NMR (500 MHz, CDCl3): δ 8.37 (s, 1H), 7.93 (d, J = 9.0 Hz, 2H), 7.84 (d, J = 7.5 Hz, 1H),
7.79 (d, J = 7.5 Hz, 1H), 7.49 (d, J = 9.0 Hz, 2H), 7.43~7.38 (m, 2H); 13C NMR (125MHz, CDCl3): δ 144.1,
141.7, 141.1, 136.0, 130.6, 130.1, 128.6, 125.8, 125.0, 121.3, 112.4; HRMS (ESI): m/z calcd for
C13H9FN2O2S [M + H]+: 277.0447. Found: 277.0443.
1-(4-Nitro-benzenesulfonyl)-1H-benzoimidazole (3d). Yellow solid (114 mg, 75% yield); Mp 155-158
°C; 1H NMR (500 MHz, CDCl3): δ 8.38 (s, 1H), 8.37 (d, J = 9.0 Hz, 2H), 8.19 (d, J = 9.0 Hz, 2H), 7.86 (d, J
= 8.0 Hz, 1H), 7.80 (d, J = 7.0 Hz, 2H), 7.46~7.39 (m, 2H); 13C NMR (125MHz, CDCl3): δ 151.2, 144.1,
142.9, 140.8, 130.5, 128.6, 126.2, 125.5, 125.0, 121.6, 112.2; HRMS (ESI): m/z calcd for C13H9N3O4S [M +
H]+: 304.0392. Found: 304.0395.
1-(4-Methoxy-benzenesulfonyl)-1H-benzoimidazole (3e).5d Colorless oil (127 mg, 88% yield); 1H NMR
(500 MHz, CDCl3): δ 8.39 (s, 1H), 7.93 (d, J = 9.0 Hz, 2H), 7.85 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.0 Hz,
1H), 7.40~7.33 (m, 2H), 6.94 (d, J = 9.0 Hz, 2H), 3.81 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 164.5, 144.0,
141.3, 130.7, 129.6, 128.7, 125.5, 124.7, 121.0, 114.9, 112.5, 55.8.
11

1-(Naphthalene-1-sulfonyl)-1H-benzoimidazole (3f). White solid (100 mg, 65% yield); Mp 137-140 °C;
ACCEPTED MANUSCRIPT
1H NMR (500 MHz, CDCl3): δ 8.66 (d, J = 9.0 Hz, 1H), 8.63 (s, 1H), 8.51 (d, J = 7.5 Hz, 1H), 8.13 (d, J =
8.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.74~7.72 (m, 1H), 7.68~7.56 (m, 4H), 7.31~7.26 (m, 2H); 13C NMR
(125 MHz, CDCl3): δ 143.9, 141.4, 136.8, 134.3, 132.2, 130.9, 129.5, 127.9, 127.6, 125.5, 124.7, 124.1,
123.1, 121.1, 112.3; HRMS (ESI): m/z calcd for C17H12N2O2S [M + H]+: 309.0698. Found: 309.0691.
1-((2,5-Dichlorothiophen-3-yl)sulfonyl)-1H-benzo[d]imidazole (3g). White solid (125 mg, 75% yield);
Mp 122-125 °C; 1H NMR (500 MHz, CDCl3): δ 8.43 (s, 1H), 7.83 (d, J = 9.0 Hz, 1H), 7.76 (d, J = 9.5 Hz,
1H), 7.43~7.41 (m, 2H), 7.30 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 144.1, 141.3, 133.9, 132.9, 130.6,
128.9, 125.9, 125.8, 125.2, 121.4, 112.3; HRMS (ESI): m/z calcd for C11H6Cl2N2O2S2 [M + H]+: 332.9326.
Found: 332.9330.
1
1-Methanesulfonyl-1H-benzoimidazole (3h).12 White solid (60 mg, 61% yield); Mp 121-124 ; H
NMR (500 MHz, CDCl3): δ 8.27 (s, 1H), 7.86~7.81 (m, 2H), 7.48~7.42 (m, 2H), 3.31 (s, 3H); 13C NMR
(125 MHz, CDCl3): δ 144.1, 141.0, 130.9, 125.9, 125.1, 121.4, 112.1, 42.3.
1
2-Methyl-1-tosyl-1H-benzo[d]imidazole (3i).13 White solid (117 mg, 82% yield); Mp 135-137 ; H
NMR (500 MHz, CDCl3): δ 8.02 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 7.0 Hz,1H),
7.36~7.28 (m, 4H), 2.81(s, 3H), 2.39 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 151.4, 146.0, 141.9, 135.5,
133.2, 130.3, 126.8, 124.7, 124.6, 119.7, 113.5, 21.6, 16.9.
1
5,6-Dimethyl-1-tosyl-1H-benzo[d]imidazole (3j). White solid (137 mg, 91% yiel); Mp 140-144 °C; H
NMR (500 MHz, CDCl3): δ8.26 (s, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.61 (s, 1H) 7.50 (s, 1H), 7.29 (d, J = 8.0
Hz,2H), 2.37(s, 6H), 2.33(s, 3H); 13C NMR (125 MHz, CDCl3): δ 145.9, 142.6, 140.5, 135.0, 134.9, 133.9,
130.3, 129.3, 127.1, 121.0, 112.7, 21.6, 20.6, 20.1; HRMS (ESI): m/z calcd for C16H16N2O2S [M + H]+:
301.1011. Found:301.1023.
1
1-Tosyl-1H-benzo[d][1,2,3]triazole (3k).14 White solid (130 mg, 95% yield); Mp 128-130 °C; H NMR
(500 MHz, CDCl3): δ 8.12~8.07 (m, 2H), 8.00 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.0
Hz, 1H), 7.32 (d, J = 8.5 Hz, 2H), 2.39 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 146.7, 145.5, 134.2, 131.7,
130.3, 128.0, 125.8, 120.6, 112.1, 21.7.
1
1-Tosyl-1H-1,2,4-triazole (3l).15 White solid (61 mg, 55% yield); Mp 99-102 °C; H NMR (500 MHz,
CDCl3): δ 8.75 (s, 1H), 8.02 (s, 1H), 7.97 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 2.46 (s, 3H); 13C
NMR (125 MHz, CDCl3): δ 154.2, 147.2, 144.5, 132.7, 130.4, 128.7, 21.8.
4.3. General procedure for the synthesis of products 5
12

Pyrazoles 4 (0.5 mmol), sodium sulfinate 2 (1.0 mmol) and NBS or NIS (1.5 mmol) were dissolved in 2
ACCEPTED MANUSCRIPT
mL of EtOAc solvent. the reaction mixture was stirred at room temperature under air for 12 h. After the
reaction, the resulting mixture was extracted with EtOAc. The combined organic phase was dried over
anhydrous Na2SO4 and the solvent was then removed under vacuum. The residue was purified by flash
column chromatography on silica gel (petroleum ether/ethyl acetate, 3:1) to afford the corresponding
product.
1
4-Iodo-1-(toluene-4-sulfonyl)-1H-pyrazole (5a).16 White solid (148 mg, 85% yield); Mp 85-87 °C; H
NMR (500 MHz, CDCl3): δ 8.14 (s, 1H), 7.89 (d, J = 7.0 Hz, 2H), 7.68 (s, 1H), 7.34 (d, J = 7Hz, 2H), 2.43
(s, 3H); 13C NMR (125 MHz, CDCl3): δ 149.8, 146.5, 134.9, 133.6, 130.3, 128.5, 61.3, 21.9; HRMS (ESI):
m/z calcd for C10H9IN2O2S [M + Na]+: 370.9327. Found: 370.9316.
4-Bromo-1-(toluene-4-sulfonyl)-1H-pyrazole (5b).17 White solid (99 mg, 66% yield); Mp 109-111 °C;
1H NMR (500 MHz, CDCl3): δ 8.10 (s, 1H), 7.89 (d, J = 8 Hz, 2H), 7.65 (s, 1H), 7.35 (d, J = 8 Hz, 2H); 13C
NMR (125 MHz, CDCl3): δ 146.4, 145.6, 133.5, 130.4, 130.2, 128.4, 97.4, 21.7; HRMS (ESI): m/z calcd for
C10H9BrN2O2S [M + Na]+: 322.9466. Found: 322.9462.
1
4-Iodo-1-(phenylsulfonyl)-1H-pyrazole (5c). White solid (100 mg, 60% yield); Mp 125-128 °C; H
NMR (500 MHz, CDCl3): δ 8.16 (s, 1H), 8.02 (d, J = 7.5 Hz, 2H), 7.70~7.66 (m, 2H), 7.563 (t, J = 8Hz,
2H); 13C NMR (125 MHz, CDCl3): δ 149.8, 136.6, 134.9, 134.8, 129.5, 128.3, 61.3; HRMS (ESI): m/z calcd
for C9H7IN2O2S [M + H]+: 334.9351. Found: 334.9343.
1-((4-Chlorophenyl)sulfonyl)-4-iodo-1H-pyrazole (5d). White solid (155 mg, 84% yield); Mp 120-123
°C; 1H NMR (500 MHz, CDCl3): δ 8.14 (s, 1H), 7.97 (d, J = 9.0 Hz, 2H), 7.71 (s, 1H), 7.53 (d, J = 9.0 Hz,
2H); 13C NMR (125 MHz, CDCl3): δ 150.1, 141.9, 134.9, 134.8, 129.9, 129.7, 61.6; HRMS (ESI): m/z calcd
for C9H6ClIN2O2S [M + H]+: 368.8961. Found: 368.8960.
4-Bromo-1-((4-chlorophenyl)sulfonyl)-1H-pyrazole (5e). White solid (136 mg, 85% yield); Mp
117-119°C; 1H NMR (500 MHz, CDCl3) : δ 8.11 (s, 1H), 7.96 (d, J = 9.0 Hz, 2H), 7.68 (s, 1H), 7.53 (d, J =
8.5 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ 146.1, 142.0, 134.9, 130.5, 129.7, 129.7, 97.9; HRMS (ESI):
m/z calcd for C9H6BrClN2O2S [M + H]+: 320.9100. Found: 320.9091.
1-((4-Fluorophenyl)sulfonyl)-4-iodo-1H-pyrazole (5f). White solid (125 mg, 71% yield); Light yellow
1
oil; H NMR (500 MHz, CDCl3): δ 8.15 (s, 1H), 8.07~8.04 (m, 2H), 7.71 (s, 1H), 7.26~7.22 (m, 2H); 13C
NMR (125 MHz, CDCl3): δ 166.5 (d, JC-F = 258.6 Hz), 150.0, 134.8, 132.5 (d, JC-F = 3.1 Hz), 131.4 (d, JC-F
13

= 9.9 Hz), 117.0 (d, JC-F = 23.4 Hz), 61.4; HRMS (ESI): m/z calcd for C9H6FIN2O2S [M + H]+: 352.9257.
ACCEPTED MANUSCRIPT
Found: 352.9258.
4-Bromo-1-((4-fluorophenyl)sulfonyl)-1H-pyrazole (5g). White solid (109 mg, 72% yield); Mp
1
106-107 °C; H NMR (500 MHz, CDCl3): δ 8.11 (s, 1H), 8.07~8.04 (m, 2H), 7.68 (s, 1H), 7.26~7.22 (m,
2H); 13C NMR (125 MHz, CDCl3): δ 166.5 (d, JC-F = 257.9 Hz), 146.0, 132.4 (d, JC-F = 3.6 Hz), 131.4 (d,
JC-F = 9.9 Hz), 130.5, 117.0 (d, JC-F = 23.3 Hz), 97.8; HRMS (ESI): m/z calcd for C9H6BrFN2O2S [M + H]+:
304.9396. Found: 304.9408.
1
4-Iodo-1-(4-methoxy-benzenesulfonyl)-1H-pyrazole (5h). Yellow oil (133 mg, 73% yield); H NMR
(500 MHz, CDCl3): δ 8.14 (s, 1H), 7.95 (d, J = 9.0 Hz, 2H), 7.68 (s, 1H), 7.00 (d, J = 9.0 Hz, 2H), 3.87 (s,
3H); 13C NMR (125 MHz, CDCl3): δ 164.8, 149.5, 134.6, 130.8, 127.5, 114.8, 60.9, 55.9; HRMS (ESI): m/z
calcd for C10H9IN2O3S [M + H]+: 364.9457. Found: 364.9458.
1
4-Bromo-1-(4-methoxy-benzenesulfonyl)-1H-pyrazole (5i). Colorless oil (112 mg, 71% yield); H
NMR (500 MHz, CDCl3): δ 8.10 (s, 1H), 7.95 (d, J = 8.5 Hz, 2H), 7.65 (s, 1H), 7.00 (d, J = 9.0 Hz, 2H),
3.87 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 164.8, 145.4, 130.8, 130.3, 127.4, 114.8, 97.2, 55.9; HRMS
(ESI): m/z calcd for C10H9BrN2O3S [M + H]+: 316.9595. Found: 316.9587.
4-Iodo-1-(4-nitro-benzenesulfonyl)-1H-pyrazole (5j). Yellow solid (117 mg, 62% yield); Mp 125-128
°C; 1H NMR (500 MHz, CDCl3): δ 8.40 (d, J = 9.0 Hz, 1H), 8.23 (d, J = 9.0 Hz, 2H), 8.18 (s, 1H), 7.75 (s,
1H); 13C NMR (125 MHz, CDCl3): δ 151.3, 150.8, 141.9, 135.1, 129.8, 124.7, 62.5; HRMS (ESI): m/z calcd
for C9H6IN3O4S [M + H]+: 379.9202. Found: 379.9208.
4-Iodo-1-(naphthalene-1-sulfonyl)-1H-pyrazole (5k). White solid (109 mg, 57% yield); Mp 165-168 °C;
1H NMR (500 MHz, CDCl3): δ 8.74 (d, J = 8.5 Hz, 1H), 8.52 (d, J = 8.0 Hz, 2H), 8.29 (s, 1H), 8.16 (d, J =
8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 8.5 Hz, 1H), 7.62-7.59 (m, 3H); 13C NMR (125 MHz,
CDCl3): δ 149.3, 137.0, 134.7, 134.2, 131.5, 129.3, 129.2, 128.3, 127.5, 124.3, 124.1, 61.1; HRMS (ESI):
m/z calcd for C13H9IN2O2S [M + H]+: 384.9508. Found: 384.9513.
1
4-Bromo-1-(naphthalene-1-sulfonyl)-1H-pyrazole (5l). Yellow oil (87 mg, 52% yield); H NMR (500
MHz, CDCl3): δ 8.74 (d, J = 9.0 Hz, 1H), 8.52 (d, J = 8.5 Hz, 2H), 8.26 (s, 1H), 8.18 (d, J = 8.5 Hz, 1H),
7.94 (d, J = 8.0 Hz, 1H), 7.71 (t, J = 8.5 Hz, 1H), 7.64-7.60 (m, 3H); 13C NMR (125 MHz, CDCl3): δ 145.2,
137.0, 134.2, 132.0, 131.5, 130.4, 129.3, 129.3, 128.3, 127.5, 124.3, 124.1, 97.4; HRMS (ESI): m/z calcd for
C13H9BrN2O2S [M + H]+: 336.9646. Found: 336.9635.
14

1
4-Iodo-3-methyl-1-tosyl-1H-pyrazole (5m). White solid (143 mg, 79% yield); Mp 97-100 °C; H NMR
ACCEPTED MANUSCRIPT
(500 MHz, CDCl3): δ 8.05 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 2.43 (s, 3H), 2.23 (s,
3H); 13C NMR (125 MHz, CDCl3): δ 157.0, 146.0, 135.6, 130.1, 128.2, 65.8, 21.7, 14.0; HRMS (ESI): m/z
calcd for C11H12IN2O2S [M + H]+: 362.9664. Found: 362.9660.
4-Bromo-3,5-dimethyl-1-tosyl-1H-pyrazole (5n).18 White solid (102 mg, 62% yield); Mp 127-130 °C;
1H NMR (500 MHz, CDCl3): δ 7.84 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 2.51 (s, 3H), 2.42 (s, 3H) ,
2.22 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 152.1, 145.6, 141.1, 134.9, 130.0, 127.8, 100.9, 21.7, 12.8,
12.2; HRMS (ESI): m/z calcd for C12H13BrN2O2S [M + H]+: 328.9959. Found: 328.9960.
1
2-(4-Iodo-1-tosyl-1H-pyrazol-3-yl)pyridine (5o). White solid (200 mg, 94% yield); Mp 120-124°C; H
NMR (500 MHz, CDCl3): δ 8.69 (d, J = 4.5 Hz, 1H), 8.25 (s, 1H) , 7.94~7.91 (m, 3H) , 7.75 (t, J = 7.5 Hz
,1H) , 7.34~7.30 (m,3H); 13C NMR (125 MHz, CDCl3): δ 154.7, 150.2, 148.9, 146.3, 137.6, 136.6, 133.6,
130.2, 128.4, 123.8, 122.9, 60.9, 21.7; HRMS (ESI): m/z calcd for C15H12IN3O2S [M + H]+: 425.9773.
Found: 425.9771.
2-(4-Bromo-1-tosyl-1H-pyrazol-3-yl)pyridine (5p). White solid (185 mg, 98% yield); Mp 104-107 °C;
1H NMR (500 MHz, CDCl3): δ 8.72~8.71 (m, 1H), 8.22 (s, 1H) , 7.94~7.91 (m, 3H) , 7.78~7.74 (m, 1H),
7.33~7.30 (m,3H), 2.40 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 152.6, 149.6, 149.2, 146.5, 136.8, 133.3,
132.3, 130.2, 128.4, 123.9, 123.2, 96.9, 21,7; HRMS (ESI): m/z calcd for C15H12BrN3O2S [M + H]+:
377.9912. Found: 377.9920.
3-Bromo-4-iodo-1-tosyl-1H-pyrazole (5q). White solid (185 mg, 87% yield); Mp 134-138 °C; 1H NMR
(500 MHz, CDCl3): δ 8.04 (s, 1H), 7.90 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 2.44 (s, 3H); 13C NMR
(125 MHz, CDCl3): δ 146.8, 139.4, 136.6, 132.9, 130.3, 128.6, 68.7, 21.8; HRMS (ESI): m/z calcd for
C10H8BrIN2O2S [M + H]+: 426.8613. Found: 426.8617.
1
3,4-Dibromo-1-tosyl-1H-pyrazole (5r).19 White solid (181 mg, 96% yield); Mp 116-119 °C; H NMR
(500 MHz, CDCl3): δ 8.05 (s, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 2.45 (s, 3H); 13C NMR
(125 MHz, CDCl3): δ 146.8, 135.2, 132.9, 131.8, 130.3, 128.6, 101.4, 21.8; HRMS (ESI): m/z calcd for
C10H8Br2N2O2S [M + Na]+: 400.8571. Found: 400.8562.
Ethyl 4-bromo-1-tosyl-1H-pyrazole-3-carboxylate (5s). White solid (134 mg, 72% yield); Mp 108-111
°C; 1H NMR (500 MHz, CDCl3): δ 8.17 (s, 1H), 7.94 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz ,2H), 4.39 (q, J
= 7.0 Hz, 2H), 2.44 (s, 3H), 1.38 (t, J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 160.0, 147.0, 145.4,
15

132.7, 132.5, 130.4, 128.7, 98.6, 61.9, 21.8, 14.2; HRMS (ESI): m/z calcd for C13H13BrN2O4S [M + H]+:
ACCEPTED MANUSCRIPT
372.9858. Found: 372.9875.
1
4-Iodo-3-phenyl-1-tosyl-1H-pyrazole (5t). White solid (136 mg, 64% yield); Mp 139-143 °C; H NMR
(500 MHz, CDCl3): δ 8.21 (s, 1H), 7.94 (d, J = 8.5 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.42~7.41 (m, 3H),
7.35 (d, J = 8.0 Hz, 2H), 2.43 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 156.9, 146.2, 137.0, 133.7, 131.0,
130.1, 129.3, 128.5, 128.4, 128.3, 62.0, 21.7; HRMS (ESI): m/z calcd for C16H13IN2O2S [M + Na]+:
446.9640. Found: 446.9645.
1
4-Bromo-3-phenyl-1-tosyl-1H-pyrazole (5u).18 White solid (184 mg, 98% yield); Mp 97-100 °C; H
NMR (500 MHz, CDCl3): δ 8.18 (s, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.85~7.84 (m, 2H), 7.42~7.40 (m, 3H),
7.35 (d, J = 8.0 Hz, 2H), 2.43 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 154.1, 146.3, 133.6, 132.3, 130.2,
130.1, 129.4, 128.7, 128.4, 128.3, 128.2, 96.7, 21.8; HRMS (ESI): m/z calcd for C16H13BrN2O2S [M + H]+:
376.9959. Found: 376.9961.
1
4-Methyl-benzenesulfonyl bromide (6).20 White solid (115 mg, 98% yield); Mp 94-97 °C; H NMR
(500 MHz, CDCl3): δ 7.88 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 2.49 (s, 3H); 13C NMR (125 MHz,
CDCl3): δ 146.7, 144.7, 130.1, 126.5, 21.8;
4-Iodo-3-phenyl-1H-pyrazole (7). White solid (20 mg, 15% yield); Mp 135-138 °C; 1H NMR (500 MHz,
CDCl3): δ 9.26 (br, 1H), 7.71 (dd, J 1= 8.0 Hz, J 2= 1.5 Hz, 2H), 7.58 (s, 1H), 7.47~7.42 (m, 3H); 13C NMR
(125 MHz, CDCl3): δ 147.5, 141.6, 130.3, 130.0, 128.7, 128.0, 57.2; HRMS (ESI): m/z calcd for C9H7IN2
[M + H]+: 270.9654. Found: 270.9652.
3-Phenyl-1-(toluene-4-sulfonyl)-1H-pyrazole (8).21 White solid (27 mg, 18% yield); Mp 130-133 °C; 1H
NMR (500 MHz, CDCl3): δ 8.12 (d, J = 2.5 Hz, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.81 (d, J = 8.0 Hz, 2H),
7.39~7.31 (m, 5H), 6.69 (d, J = 2.5 Hz, 1H), 2.40 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 156.9, 145.7,
134.3, 132.5, 131.5, 130.0, 129.2, 128.6, 128.2, 126.4, 106.4, 21.7;
Acknowledgment. The project is supported by National Natural Science Foundation of China (21602159,
80214004), Natural Science Foundation of Zhejiang Province (LQ15B020005), Funding for Scientific
Research of Wenzhou Medical University (QTJ14037), Zhejiang Province Xinmiao Talent Program
(2015R413075) and Public Welfare Science and Technology Project of Wenzhou (Y20160164).
16

References
ACCEPTED MANUSCRIPT
1.
(a) Banerjee, M.; Poddar, A.; Mitra, G.; Surolia, A.; Owa, T.; Bhattacharyya, B. J Med Chem. 2005,
48, 547-555; (b) Chohan, Z. H.; Youssoufi, M. H.; Jarrahpour, A.; Ben Hadda, T. Eur J Med Chem.
2010, 45, 1189-1199; (c) Mujumdar, P.; Poulsen, S. A. J Nat Prod. 2015, 78, 1470-1477.
(a) Jabusch, T. W.; Tjeerdema, R. S. J Agr Food Chem. 2005, 53, 7179-7183; (b) Zhang, S. F.;
Cheng, X. D.; Yang, J. Z. Dyes Pigments. 1999, 43, 167-172.
(a) Harmata, M.; Zheng, P. G.; Huang, C. F.; Gomes, M. G.; Ying, W. J.; Ranyanil, K. O.; Balan, G.;
Calkins, N. L. J Org Chem. 2007, 72, 683-685; (b) Sridhar, R.; Srinivas, B.; Kumar, V. P.; Narender,
M.; Rao, K. R. Adv Synth Catal. 2007, 349, 1873-1876; (c) Veisi, H.; Ghorbani-Vaghei, R.;
Hemmati, S.; Mahmoodi, J. Synlett 2011, 2315-2320.
2.
3.
4.
5.
Tang, X. D.; Huang, L. B.; Qi, C. R.; Wu, X.; Wu, W. Q.; Jiang, H. F. Chem Commun. 2013, 49,
6102-6104.
(a) Zhao, J. W.; Xu, J. X.; Chen, J. X.; Wang, X. Q.; He, M. H. Rsc Advances 2014, 4, 64698-64701;
(b) Buathongjan, C.; Beukeaw, D.; Yotphan, S. Eur J Org Chem. 2015, 1575-1582; (c) Wei, W.; Liu,
C. L.; Yang, D. S.; Wen, J. W.; You, J. M.; Wang, H. Adv Synth Catal. 2015, 357, 987-992; (d)
Yang, K.; Ke, M. L.; Lin, Y. G.; Song, Q. L. Green Chem. 2015, 17, 1395-1399.
6.
7.
Jiang, Y. Y.; Wang, Q. Q.; Liang, S.; Hu, L. M.; Little, R. D.; Zeng, C. C. J Org Chem. 2016, 81,
4713-4719.
(a) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem Rev. 2003, 103, 893-930; (b) Mckee, M. L.;
Kerwin, S. M. Bioorgan Med Chem. 2008, 16, 1775-1783; (c) Rossello, A.; Bertini, S.; Lapucci, A.;
Macchia, M.; Martinelli, A.; Rapposelli, S.; Herreros, E.; Macchia, B. J Med Chem. 2002, 45,
4903-4912; (d) Morphy, R.; Rankovic, Z. J Med Chem. 2005, 48, 6523-6543; (e) Gaba, M.; Singh,
D.; Singh, S.; Sharma, V.; Gaba, P. Eur J Med Chem. 2010, 45, 2245-2249.
8.
(a) Zhang, H. Z.; Damu, G. L. V.; Cai, G. X.; Zhou, C. H. Eur J Med Chem. 2013, 64, 329-344; (b)
Monnier, F.; Taillefer, M. Angew Chem Int Ed. 2009, 48, 6954-6971; (c) Pan, S. G.; Liu, J. H.; Li, H.
R.; Wang, Z. Y.; Guo, X. W.; Li, Z. P. Org Lett. 2010, 12, 1932-1935; (d) Xue, Q. C.; Xie, J.; Xu,
P.; Hu, K. D.; Cheng, Y. X.; Zhu, C. J. Acs Catal. 2013, 3, 1365-1368; (e) Xia, Q. Q.; Chen, W. Z.;
Qiu, H. Y. J Org Chem. 2011, 76, 7577-7582; (f) Xia, Q. Q.; Chen, W. Z. J Org Chem. 2012, 77,
9366-9373; (g) Xue, Q. C.; Xie, J.; Li, H. M.; Cheng, Y. X.; Zhu, C. J. Chem Commun. 2013, 49,
3700-3702; (h) Wang, L.; Zhu, K. Q.; Chen, Q.; He, M. Y. J Org Chem. 2014, 79, 11780-11786; (i)
Chen, W. L.; Yan, R. L.; Tang, D.; Guo, S. B.; Meng, X.; Chen, B. H. Tetrahedron 2012, 68,
7956-7959; (j) Aruri, H.; Singh, U.; Sharma, S.; Gudup, S.; Bhogal, M.; Kumar, S.; Singh, D.;
Gupta, V. K.; Kant, R.; Vishwakarma, R. A.; Singh, P. P. J Org Chem. 2015, 80, 1929-1936; (k)
Rajamanickam, S.; Majji, G.; Santra, S. K.; Patel, B. K. Org Lett. 2015, 17, 5586-5589; (l) Sun, J.
W.; Zhang, Y.; Mathan, S.; Wang, Y.; Pan, Y. J Org Chem. 2016, 81, 3380-3385; (m) Zhao, J. J.; Li,
P.; Xia, C. G.; Li, F. W. Chem Commun. 2014, 50, 4751-4754.
9.
(a) Mowbray, C. E.; Burt, C.; Corbau, R.; Gayton, S.; Hawes, M.; Perros, M.; Tran, I.; Price, D. A.;
Quinton, F. J.; Selby, M. D.; Stupple, P. A.; Webster, R.; Wood, A. Bioorganic & Medicinal
Chemistry Letters 2009, 19, 5857-5860; (b) Wyatt, P. G.; Woodhead, A. J.; Berdini, V.; Boulstridge,
J. A.; Carr, M. G.; Cross, D. M.; Davis, D. J.; Devine, L. A.; Early, T. R.; Feltell, R. E.; Lewis, E. J.;
McMenamin, R. L.; Navarro, E. F.; O'Brien, M. A.; O'Reilly, M.; Reule, M.; Saxty, G.; Seavers, L.
C. A.; Smith, D. M.; Squires, M. S.; Trewartha, G.; Walker, M. T.; Woolford, A. J. A. J Med Chem.
2008, 51, 4986-4999; (c) Chauhan, P.; Mahajan, S.; Enders, D. Chem Commun. 2015, 51,
17

12890-12907; (d) Koohshari, M.; Dabiri, M.; Salehi, P. Rsc Advances 2014, 4, 10669-10671; (e)
ACCEPTED MANUSCRIPT
Kuo, T. H.; Lin, T. H.; Yang, R. S.; Kuo, S. C.; Fu, W. M.; Hung, H. Y. J Med Chem. 2015, 58,
4954-4963.
10.
11.
(a) Rodriguez-Franco, M. I.; Dorronsoro, I.; Martinez, A. Synthesis-Stuttgart 2001, 1711-1715; (b)
Felding, J.; Kristensen, J.; Bjerregaard, T.; Sander, L.; Vedso, P.; Begtrup, M. J Org Chem. 1999, 64,
4196-4198; (c) Sammelson, R. E.; Casida, J. E. J Org Chem. 2003, 68, 8075-8079; (d) Nayak, M.;
Rastogi, N.; Batra, S. Eur J Org Chem. 2012, 1360-1366.
Abdireimov, K. B.; Mukhamedov, N. S.; Aiymbetov, M. Z.; Shakhidoyatov, K. M. Chemistry of
Heterocyclic Compounds 2010, 46, 941-946.
12.
13.
14.
15.
16.
17.
Morofuji, T.; Shimizu, A.; Yoshida, J. J Am Chem Soc. 2014, 136, 4496-4499.
Alla, S. K.; Kumar, R. K.; Sadhu, P.; Punniyamurthy, T. Org Lett. 2013, 15, 1334-1337.
Katritzky, A. R.; Rodriguez-Garcia, V.; Nair, S. K. J Org Chem. 2004, 69, 1849-1852.
Keith, J. M. J Org Chem. 2010, 75, 2722-2725.
Rakshit, S.; Patureau, F. W.; Glorius, F. J Am Chem Soc. 2010, 132, 9585-9587.
You, H.; Youn, H. S.; Im, I.; Bae, M. H.; Lee, S. K.; Ko, H.; Eom, S. H.; Kim, Y. C. Eur J Med
Chem. 2011, 46, 1153-1164.
18.
19.
20.
21.
Milner, P. J.; Yang, Y.; Buchwald, S. L. Organometallics 2015, 34, 4775-4780.
Holzer, W.; Jager, C.; Slatin, C. Heterocycles 1994, 38, 2433-2448.
Madabhushi, S.; Jillella, R.; Sriramoju, V.; Singh, R. Green Chem. 2014, 16, 3125-3131.
Xu, S. X.; Hao, L.; Wang, T.; Ding, Z. C.; Zhan, Z. P. Org Biomol Chem. 2013, 11, 294-298.
18