C-H Imidation and Dual C-H Bond Aminobromination of Five-Membered Heterocycles

Article abstract of DOI:10.1021/acs.joc.9b02941

Here, we report a practical C-H imidation of five-membered heterocycles under metal-free conditions. We also report the first dual C-H bond aminobromination of thiophenes, with benzotriazole, saccharin, 1,2,4-triazole, benzimidazole, pyrazole, 4-bromopyra

Full text of DOI:10.1021/acs.joc.9b02941

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Article
C-H Imidation and Dual C-H Bond
Aminobromination of Five-Membered Heterocycles
Kai Sun, Yali Li, Ranran Feng, Shiqiang Mu, Xin Wang, and Bing Zhang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02941 • Publication Date (Web): 24 Dec 2019
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C−H Imidation and Dual C−H Bond
Aminobromination of Five-Membered
Heterocycles
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Kai Sun,*† Yali Li,† Ranran Feng,† Shiqiang Mu,† Xin Wang,†‡ and Bing Zhang†‡
†College of Chemistry and Chemical Engineering, Anyang Normal University,
‡
Anyang 455000, P. R. China
College of Chemistry and Energy, Zhengzhou University, Zhengzhou 450001, P. R.
China.
Corresponding author: sunk468@nenu.edu.cn
H
H
DCDMH
NBS
X
+
NR1R2
NR1R2
H
Br
X
X
X = S
H NR1R2
X = N, O, S
Useful skeletons
Metal free conditions
Simple operation
C-H Imidation and the first dual C-H bond aminobromination
ABSTRACT: Here, we report a practical C−H imidation of five-membered
heterocycles under metal free conditions. We also report the first dual C−H bond
aminobromination of thiophenes, with benzotriazole, saccharin, 1,2,4-triazole,
benzimidazole,
pyrazole,
4-bromopyrazole,
5-methyltetrazole,
and
dibenzenesulfonimides as effective amine sources. Mechanistic studies support the
radical pathway of the imidation and aminobromination reactions.
INTRODUCTION
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Structures containing amino groups are prevalent in natural products,
pharmaceutical agents, synthetic intermediates, and materials.1 The development of
convenient and direct strategies for the construction of C–N bonds has become a
fascinating topic in synthetic chemistry. Transition metal-catalyzed direct C−H
aminations have emerged as a step- and atom-economical synthetic route and have
made impressive achievements during recent years.2 Site-selectivity in C–H
aminations is a crucial problem to be solved because of the similarity of C–H bonds in
organic molecules. Besides, several disadvantages also still exist, such as (1) the
installation and elimination of directing-groups, (2) limited substrate scope, especially
for 5-membered heterocycles without acidic C–H bond,3 (3) the need preactivated
amino precursors,4 and (4) the inevitable metal residue, which restricts use for
pharmaceutical chemistry applications. Therefore, there is a great demand for the
establishment of sustainable new strategies to functionalize specific C–H bonds, and
the development of C−H aminations under metal-free conditions is one of
complementary avenues to established methods.
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Five-membered heterocycles bearing an amine group are commonly found in
natural products, bioactive compounds, and pharmaceuticals.5 For example,
2-aminothiophenes are widely used as inhibitors of APE 1 and tubulin
polymerization.6 Zyprexa (Olanzapine), which contains a 2-aminothiophene core, is
ranked as one of the world’s top 200 drugs in terms of sales. The dehydrogenative
C–H amination of five-membered heterocycles is one of the most reliable and
atom-economical approaches for nitrogen atom incorporation. In 2009, Mori et al.,
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Schreiber et al., and Chang et al. successfully reported the metal-catalyzed C−H
amination of azoles bearing a relatively active acidic C−H bond (Scheme 1a).7 In
2015, Itami et al. described an elegant copper-catalyzed regioselective α-position
C−H imidation of substituted thiophenes with N-fluorobenzenesulfonimide.8 The
substrate scope of these reactions was wide enough to cover a variety of 5-membered
heteroarenes, including materials and biology-oriented aromatics. Subsequently, Pan
et al. and our group described the copper-catalyzed imidation of heterocycles such as
thiophene, furan, and pyrrole.9 Recently, the Lei group, Itoh group, and Itami group
expanded their C–H imidation chemistry with photoredox technology suitable for
producing a thiophene radical cation or imidyl radical for the dehydrogenative
imidation of five-membered heterocycles (Scheme 1b).10 Our interest in
metal-catalyzed11 and organocatalyst enabled C−H aminations12 inspired us to explore
new amination strategies of five-membered heterocycles involed nitrogen radicals13
with suitable amination reagents and halogenides under metal-free conditions. Dual
C−H bond functionalization, such as both C−H halogenation and amination of
five-membered heterocycles, may be achieved simultaneously (Scheme 1c).
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Scheme 1. C2 Amination of five-membered heterocycles
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Previous works:
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(a) Metal-Catalyzed C2 Amination of Azoles
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X
X
N
Cu, Ag salts
H NR1R2
NR1R2
H
+
ref. 7
N
X = O, S
(b) Visible-Lighe-Mediated C2 Amination of Heteroarenes
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R1
N
R
R
DDQ, TBN, Blue LEDs
Lei's work, ref. 10a
H NR1R2
+
H
S
S
R2
Ru(bpy)2, IBB
Blue LEDs
Itami's work, ref. 10b
Y
X
Y
H NR1R2
H
NR1R2
+
X
X, Y = C, O, S, N
This study:
(c) C-H Imidation and Dual C-H Bonds Aminobromination
of Five-Membered Heterocycles
H
H
DCDMH
NBS
X
+
NR1R2
X = N, O, S
NR1R2
H
Br
X
X
X = S
H NR1R2
RESULTS AND DISCUSSION
To probe the feasibility of the proposed nitrogen radicals involed C−H
functionalization strategy under metal-free conditions, we initially chose thiophene 1a
as a model substrate. A mixture of N-bromosuccinimide (NBS, 2.0 equiv) and
dibenzenesulfonimide N1 (1.0 equiv) in 1,2-dichloroethane (DCE, 2.0 mL) were
added to the thiophene 1a. When the reaction proceeded at 90 °C for 12 h, the desired
C−H imidation product 2a was obtained in 76% yield (Table 1, entry 1). Reducing the
amount of NBS to 1.0 equivalent significantly decreased the yield of 2a to 44%
(Table 1, entry 2). Further amino source screenings revealed that phthalimide N2,
saccharin N3, and 1,2,4-triazole N4 were not suitable amino sources, and no C−H
imidation occurred (Table 1, entries 3−5). Using 5-phenyltetrazole N5 as an amino
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source resulted in the desired product 2b in 62% yield (Table 1, entry 6).
Benzotriazole N6 produced only trace amounts of the C−H imidation product, while
simultaneous dual C−H bond functionalization formed the aminobromination product
3a in 74% yield (Table 1, entry 7). To our knowledge, this is the first example of a
simultaneous dual C−H bond aminobromination of thiophene. Inspired by this result,
we studied the effect of different halogen reagents, such as N-chlorosuccinimide
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(NCS),
N-iodosuccinimide
(NIS),
molecular
bromine
B1,
1,3-dibromo-5,5-dimethylhydantoin (DCDMH, B2), and tetrabutylammonium
tribromide B3, with dibenzenesulfonimide N1 on aminohalogenation. Screening
results revealed that only C−H imidation occurred when using NCS, NIS, and B1. No
reaction occurred at all with B3 added (Table 1, entries 8−12). B2 afforded a 79%
yield of the desired aminobromination product 3b (Table 1, entry 11). No significant
improvement of product yield was found by increasing the reaction temperature to
120 °C. The yield of 3a decreased to 39% when the reaction was carried out at 60 °C
(Table 1, entries 13 and 14).
Table 1. Survey of the Reaction Conditionsa
conditions
H NR1R2
+
NR1R2
NR1R2
+
Br
N
S
S
S
1a
2
3
O
O
O
H
S
N
N
Ph
NH
NH
N
HN(SO2Ph)2
N
NH
N NH
N
N
O
O
N1
N2
N3
N4
N5
N6
entry
halogen reagent amino source temp (oC) yields of 2/3(%) b
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1
2c
3
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NCS
NIS
B1
N1
N1
N2
N3
N4
N5
N6
N1
N1
N1
N1
N1
N1
N1
90
90
90
90
90
90
90
90
90
90
90
90
120
60
76/0
44/0
0/0
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4
0/0
5
0/0
6
62/0
7
trace/74
71/0
8
9
55/0
10
11
12
13d
14e
41/0
B2
trace/79
0/0
B3
B2
Trace/77
trace/39
B2
aReactions were carried out with 1a (0.3 mmol), halogen reagent (2.0 equiv) and
amino source (1.0 equiv) in DCE (2.0 mL) under an air atmosphere at 90 °C for 12 h.
bYield of the isolated product. c1.0 equiv NBS was added. dReactions were performed
at 120 °C. eReactions were performed at 60 °C.
With standard conditions established, we evaluated the scope of C−H imidation
using different five-membered heterocycles and dibenzenesulfonimides as substrates.
As shown in Scheme 2, thiophenes (1a) bearing the electron-withdrawing Cl or Br
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were well tolerated under the current reaction conditions and delivered the desired 2c
and 2d in good yields (71% and 53%). However, no desired products were obtained
when thiophene bearing electron-donating substituents, such as 2-methylthiophene
and 3-methoxythiophene, were employed as substrates. The regioselective C–H
imidation of thiophene 1a with N1 type dibenzenesulfonimides bearing different
electron-donating and electron-withdrawing substituents on the benzene ring occurred
at the 2-position, affording 2f–2h in high yields (69%−81%). Furthermore,
benzothiophene, and benzofuran also reacted with dibenzenesulfonimide N1 and
5-phenyltetrazole N5 to successfully give the desired 2i–2n in good yields
(74%−85%). It should be noted that although dual C−H bond aminobromination
occurred when benzotriazole N6 was tested with thiophene 1a, benzotriazole N6
produced only C2 imidation products 2o and 2p (74% and 67%), with pyrrole and
furan, respectively. As expected, benzothiophene was also suitable substrates with
benzotriazole N6 and gave the desired product 2q in 83% yield.
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Scheme 2. C–H imidation of five-membered heterocycles and derivativesa,b
NBS
DCE, 90 oC
+
H NR1R2
NR1R2
H
X
X
X = O, NH, S
1
2
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N
N
N
N
S
Br
N(SO2Ph)2
N(SO2Ph)2
, 76%
S
S
Ph
2b
2a
2c
, 62%
Br
, 71%
Ts
Cl
Br
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N
S
N(SO2Ph)2
, 53%
N(SO2Ph)2
S
S
Ts
, 81%
2d
2e
2f
, 78%
O2
S
O2
S
N
N
S
S
N(SO2Ph)2
Cl
F
S
Ts
Ts
, 69%
2g
2h
2i
, 74%
, 76%
O2
S
Ts
Ts
N
N
N
S
O
S
F
Ts
Ts
Ts
2j
2k
2l
, 83%
, 85%
, 81%
N
N
N
O2
S
N
O
N
N
S
N
O
N
F
Ts
Ph
, 78%
2m
2n
2o
, 74%
, 75%
N
N
N
N
N
N
N
S
H
2p
2q
, 83%
, 67%
aReaction conditions: 1 (0.3 mmol), NBS (2.0 equiv) and amino source (1.0 equiv) in
b
DCE (2.0 mL) under an air atmosphere at 90 °C for 12 h. The percentage yields
represent the isolated yields.
To enrich the dual C−H bonds aminobromination strategy, we further examined
and explored the scope of amino sources under the optimized reaction conditions. As
shown in Scheme 3, saccharin N3 and 1,2,4-triazole N4, which were not suitable for
C−H imidation reactions, performed well during the dual C−H bond
aminobromination process. The desired difunctionalized products 3c−3e were
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produced in good yields (67%−81%). Because azoles are structural motifs in many
antibacterial, anticancer, antidepressant, antifungal, and antimalarial compounds,14
benzimidazole, 5-methyltetrazole and 4-bromopyrazole were examined as potential
nitrogen radical precursors. Benzimidazole, 5-methyltetrazole and 4- bromopyrazole
were well tolerated and afforded the corresponding aminobromination products 3f–3h
in moderate to high yields (46%–80%). Imidazole and purine were not compatible
with this catalytic system, and no difunctionalization occurred under the optimized
conditions. The current methodology is also applicable for dibenzenesulfonimide
derivatives, affording the corresponding 3i and 3j in good yields (83% and 78%).
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Finally,
thiophene
derivatives,
such
as
3-methylthiophene
and
thieno[3,4-d][1,3]dioxole, were tested and produced the desired products 3k and 3l in
moderate yields (48% and 69%). No aminobromination occurred with
3-chlorothiophene and 3,4-dibromothiophene as the substrates.
Scheme 3. Dual C−H bonds aminobromination of thiophenesa,b
B2
H NR1R2
NR1R2
+
H
H
Br
DCE, 90 oC
S
S
1
3
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O O
S
N
N
N
Br
S
Br
N
S
N(SO2Ph)2
Br
S
O
3a
3b
3c
, 74%
, 79%
, 81%
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O O
S
Cl
N
N
Br
N
S
Br
N
S
N
Br
S
N
O
3d
3e
3f
, 67%
, 80%
, 80%
N
N
N
Ts
N
N
N
Br
N
Br
S
Br
S
S
Ts
Br
3g
3h
3i
, 63%
, 46%
, 83%
O
O2
S
O
Ts
N
Br
S
N
Br
Cl
S
N(SO2Ph)2
3l
, 69%
Br
Ts
S
Ts
3j
3k
, 78%
, 48%
Br
Cl
Br
Br
Ts
N
Br
S
N(SO2Ph)2
S
0%
Ts
0%
aReaction conditions: 1 (1.8 mmol), benzimidazoles 2 (0.3 mmol), DBDMH (1.0
equiv) at 90 °C in DCE (2.0 mL). bYield of isolated product.
Control experiments were carried out to acquire mechanistic insights into the
reaction pathway (Scheme 4). When radical scavengers such as
2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO,
2.0
equiv),
2,6-di-tert-butyl-4-methylphenol (BHT, 2.0 equiv), and p-benzoquinone (BQ, 2.0
equiv) were added to the optimized imidation reaction, the reaction was markedly
inhibited,
and
the
adduct
4
between
benzotriazole
and
2,6-di-tert-butyl-4-methylphenol (see SI) was detected
via GC-MS analysis
(Scheme 4a). Similar results were observed when TEMPO, BHT, and BQ were added
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to the optimized aminobromination reaction, and only trace amounts of 3b were
detected (Scheme 4b). These observations imply that nitrogen radical species may
involved in the reaction. To identify the possible intermediate in the
aminobromination reaction, control experiments with 2-bromothiophene 1c and 2a
were examined as the substrates, separately. As described, 3b could be isolated with a
71% yield when 2-bromothiophene 1c was tested, while a 24% yield of the desired 3b
was obtained with 2a as the substrate (Scheme 4c and 4d). To provide further
evidence regarding the possible intermediate, we prepared the N-Br reagent 5
according to a previous literature report.15 When the reaction between 1a and 5 was
performed in DCE, 3b could be isolated in 53% yield (Scheme 4e).
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Scheme 4. Reactions determining the mechanism
NBS
2a
TEMPO, , 27%
2a
BHT, , trace
2a
BQ, , trace
radical scavengers
HN(SO2Ph)2
+
(a)
DCE, 90 oC
S
1a
N1
, 0.3 mmol
B2
3b
TEMPO, , trace
3b
BHT, , trace
3b
BQ, , trace
radical scavengers
+
HN(SO2Ph)2
(b)
(c)
(d)
DCE, 90 oC
S
1a
N1
, 0.3 mmol
B2
HN(SO2Ph)2
+
N(SO2Ph)2
, 71%
Br
DCE, 90 oC
Br
S
, 0.3 mmol
S
3b
1c
N1
B2
DCE, 90 oC
N(SO2Ph)2
, 0.3 mmol
N(SO2Ph)2
Br
S
S
2a
3b
, 24%
N(SO2Ph)
Br
(PhO2S)2N Br
2 (e)
+
S
DCE, 90 oC
S
1a
5
3b
, 53%
, 0.3 mmol
, 0.3 mmol
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Although further studies are still needed to fully uncover the precise mechanism of
the C−H imidation and aminobromination, the possible mechanism was proposed
based on the present findings and previous reports,16 as shown in Scheme 5. For the
imidation mechanism (path a), the initial interaction between the amino source and
NBS would generate the corresponding nitrogen-centered radical A, which undergoes
electrophilic addition with 1a to deliver the radical intermediate B. Subsequently,
single electron oxidation and hydrogen proton trap processes led to the final product 2.
For the aminobromination mechanism (path b), the interaction between the amino
source and B2 would generate the corresponding 5 and D. Compared with NBS, the
electron-deficiency of D is prone to electrophilic addition with 1a to generate the
intermediate E. Then, a hydrogen proton trap process gave the 2-bromothiophene 1c.
Subsequently, similar single electron oxidation and hydrogen proton trap processes
led to the final product 3.
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Scheme 5. Proposed reaction mechanism
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Path a: Imidation mechanism
- e-
- H+
HBr
5
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8
NBS
1a
R2R1N
R2R1NH
2
NR1R2
NR1R2
O
S
S
A
B
C
Br-
+
Br
NH
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O
Path b: Aminobromination mechanism
H
O
N
- H+
1a
B
DCDMH,
2
R2R1NH
O
1c
Br
N
S
Br
N-
O
H
E
Br NR1R2
O
D
N
O
5
O
HN
HN
- e-
Br-
- H+
HBr
5
NR1R2
NR1R2
NR1R2
Br
Br
Br
S
S
S
3
CONCLUSIONS
In summary, we have presented a practical and economical regioselective
C−H imidation of five-membered heterocycles. This synthetic technique does
not require additional treatments process to remove metal residues. We also
achieved the first dual C−H bond aminobromination of thiophenes, with
benzotriazole, saccharins, 1,2,4-triazole, pyrazole, benzimidazole, tetrazole and
dibenzenesulfonimides
as
effective
amine
sources
and
1,3-dibromo-5,5-dimethylhydantoin as the bromination reagent. The possible
radical mechanism was proposed to explain the imidation and
aminobromination process based on control experiments. Further mechanistic
studies and applications of this strategy to more complicated materials and drug
candidates are underway in our laboratory.
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Experimental Section
General Information. All reagents were purchased from commercial sources and
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used without further purification. H NMR and C NMR spectra were recorded on a
Bruker Ascend™ 400 spectrometer in deuterated solvents containing TMS as an
internal reference standard. High-resolution mass spectrometry (HRMS) analyses
were conducted on a Waters LCT Premier/XE. Melting points were measured on a
melting point apparatus equipped with a thermometer and were uncorrected. All the
reactions were conducted in oil bath and monitored by thin-layer chromatography
(TLC) using GF254 silica gel-coated TLC plates. Purification by flash column
chromatography was performed over SiO2 (silica gel 200−300 mesh).
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General procedure:
Synthesis procedure for compounds 2:
To a reaction tube equipped with a stir bar was sequentially added 1 (0.3 mmol), NBS
(0.6 mmol, 2.0 equiv) and amino source (0.3 mmol, 1.0 equiv) in DCE (2.0 mL) under
an air atmosphere. Then the reaction mixture was stirred at 90 °C in an oil bath. Upon
completion of the reaction (as monitored by TLC), the mixture was cooled to room
temperature and quenched with water before being extracted with dichloromethane (5
× 3 mL). The combined organic layers were dried over anhydrous Na2SO4 and
concentrated under reduced pressure to give a residue, which was purified by flash
column chromatography to give the desired product 2.
Synthesis procedure for compounds 3:
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To a reaction tube equipped with a stir bar was sequentially added 1 (0.3 mmol),
1,3-dibromo-5,5-dimethylhydantoin (B2, 0.6 mmol, 2.0 equiv) and amino source (0.3
mmol, 1.0 equiv) in DCE (2.0 mL) under an air atmosphere. Then the reaction
mixture was stirred at 90 °C in an oil bath. Upon completion of the reaction (as
monitored by TLC), the mixture was cooled to room temperature and quenched with
water before being extracted with dichloromethane (5 × 3 mL). The combined organic
layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to
give a residue, which was purified by flash column chromatography to give the
desired product 3.
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N-(phenylsulfonyl)-N-(thiophen-2-yl)benzenesulfonamide (2a). The product was
purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 5:1),
white solid (76%, 86.4 mg), melting point: 130-131 oC; 1H NMR (400 MHz; CDCl3):
δ = 6.75 (dd, J1 = 1.2, J2 = 4.0, 1H), 6.95 (q, J = 4.0, 1H), 7.38 (dd, J1 = 1.2, J2 = 4.0,
1H), 7.56-7.59 (m, 4H), 7.70 (t, J = 7.2, 2H), 8.00 (m, 4H). 13C{1H} NMR (100 MHz;
CDCl3): δ = 125.6, 128.7, 128.8, 129.0, 131.3, 133.9, 134.2, 138.7. HRMS (ESI-TOF)
Calcd for C16H14NO4S3, [M+H]+ 380.0085; Found 380.0091.
5-phenyl-1-(thiophen-2-yl)-1H-tetrazole (2b). The product was purified by column
chromatography on silica gel (petroleum ether/ethyl acetate = 7:1), white solid (62%,
42.4 mg), melting point: 153-154 oC; 1H NMR (400 MHz; CDCl3): δ = 7.11 (q, J = 4.0,
1H), 7.31 (q J = 4.0, 1H), 7.52-5.54 (m, 3H), 7.71 (dd, J1 = 1.6, J2 = 4.0, 1H), 8.23 (t, J
= 3.2, 2H). 13C{1H} NMR (100 MHz; CDCl3): δ = 119.0, 119.1, 123.6, 126.5, 126.7,
127.1, 128.9, 130.6, 165.1. HRMS (ESI-TOF) Calcd for C11H9SN4, [M+H]+ 229.0548;
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Found 229.0552.
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N-(5-bromothiophen-2-yl)-N-(phenylsulfonyl)benzenesulfonamide
(2c).
The
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product was purified by column chromatography on silica gel (petroleum ether/ethyl
o
acetate = 4:1), white solid (71%, 97.6 mg), melting point: 93-94 C; 1H NMR (400
MHz; CDCl3): δ = 6.51 (d, J = 4.0, 1H), 6.94 (d, J = 4.4, 1H), 7.59 (t, J = 8.0, 4H),
7.70-7.38 (m, 2H), 8.00 (d, J = 8.0, 4H). 13C{1H} NMR (100 MHz; CDCl3): δ = 115.7,
128.7, 128.8, 129.1, 130.8, 132.1, 134.3, 134.4, 138.5, 139.1. HRMS (ESI-TOF)
Calcd for C16H13NBrO4S3, [M+H]+ 457.9192; Found 457.9195.
N-(4-chlorothiophen-2-yl)-N-(phenylsulfonyl)benzenesulfonamide
(2d).
The
product was purified by column chromatography on silica gel (petroleum ether/ethyl
acetate = 4:1), white solid (53%, 65.8 mg), melting point: 201-202 oC; 1H NMR (400
MHz; CDCl3): δ = 6.67 (d, J = 1.6, 1H), 7.17 (d, J = 1.6, 1H), 7.59 (t, J = 8.0, 4H),
13
7.72 (d, J = 7.6, 2H), 8.02 (d, J = 7.6, 4H). C{1H} NMR (100 MHz; CDCl3): δ =
123.4, 124.0, 128.7, 129.2, 131.2, 134.2, 134.4, 138.4. HRMS (ESI-TOF) Calcd for
C16H13NClO4S3, [M+H]+ 413.9695; Found 413.9691.
N-(3,4-dibromothiophen-2-yl)-N-(phenylsulfonyl)benzenesulfonamide (2e). The
product was purified by column chromatography on silica gel (petroleum ether/ethyl
acetate = 4:1), white solid (78%, 125.1 mg), melting point: 182-183 oC; 1H NMR (400
MHz; CDCl3): δ = 7.49 (s, 1H), 7.58 (t, J = 8.0, 4H), 7.71 (d, J = 7.6, 2H), 8.03 (d, J =
13
7.6, 4H). C{1H} NMR (100 MHz; CDCl3): δ = 113.4, 121.0, 126.0, 129.2, 130.4,
134.6, 138.7. HRMS (ESI-TOF) Calcd for C16H12NBr2O4S3, [M+H]+ 535.8297;
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Found 535.8301.
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4-methyl-N-(thiophen-2-yl)-N-tosylbenzenesulfonamide (2f). The product was
purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 5:1),
white solid (81%, 99.0 mg), melting point: 180-181 oC; 1H NMR (400 MHz; CDCl3):
δ = 6.74 (dd, J1 = 1.2, J2 = 3.6, 1H), 6.94 (q, J = 4.0, 1H), 7.34-7.38 (m, 5H), 7.86 (d, J
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= 8.4, 4H). C{1H} NMR (100 MHz; CDCl3): δ = 21.7, 125.6, 128.6, 128.7, 129.6,
131.1, 134.2, 135.8, 145.3. HRMS (ESI-TOF) Calcd for C18H18NO4S3, [M+H]+
408.0398; Found 408.0393.
4-fluoro-N-(thiophen-2-yl)-N-tosylbenzenesulfonamide (2g). The product was
purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 5:1),
white solid (69%, 85.2 mg), melting point: 142-143 oC; 1H NMR (400 MHz; CDCl3):
δ = 6.75 (dd, J1 = 1.2, J2 = 3.6, 1H), 6.96 (d, J = 4.0, 1H), 7.24 (d, J = 7.6, 2H), 7.38 (q,
13
J = 8.8, 3H), 7.86 (d, J = 8.4, 2H), 8.02 (q, J = 5.2, 2H). C{1H} NMR (100 MHz;
CDCl3): δ = 166.16 (d, J = 257.4 Hz), 145.71, 135.82, 134.92 (d, J = 3.0 Hz), 134.07,
131.86 (d, J = 9.6 Hz), 131.38, 129.85, 129.00, 128.93, 125.86, 116.51 (d, J = 22.8
Hz), 21.88. HRMS (ESI-TOF) Calcd for C17H15NFO4S3, [M+H]+ 412.0148; Found
412.0152.
4-chloro-N-(thiophen-2-yl)-N-tosylbenzenesulfonamide (2h). The product was
purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 4:1),
white solid (76%, 97.6 mg), melting point: 168-169 oC; 1H NMR (400 MHz; CDCl3):
δ = 6.76 (dd, J1 = 1.2, J2 = 4.0, 1H), 6.95 (q, J = 3.6, 1H), 7.38 (d, J = 8.4, 3H), 7.53 (d,
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J = 8.4, 2H), 7.86-7.95 (m, 4H). C{1H} NMR (100 MHz; CDCl3): δ = 21.7, 125.7,
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128.8, 128.9, 129.3, 129.7, 130.1, 131.2, 133.8, 135.5, 137.2, 140.9, 145.6. HRMS
(ESI-TOF) Calcd for C17H15NClO4S3, [M+H]+ 427.9852; Found 427.9857.
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N-(benzo[b]thiophen-2-yl)-N-(phenylsulfonyl)benzenesulfonamide
(2i).
The
product was purified by column chromatography on silica gel (petroleum ether/ethyl
acetate = 4:1), white solid (74%, 95.3 mg), melting point: 161-162 oC; 1H NMR (400
MHz; CDCl3): δ = 7.03 (s, 1H), 7.38-7.42 (m, 2H), 7.59 (d, J = 8.0, 4H), 7.71-7.74 (m,
4H), 8.05 (d, J = 7.6, 4H). 13C{1H} NMR (100 MHz; CDCl3): δ = 122.4, 124.7, 126.1,
128.7, 128.8, 129.1, 134.2, 134.3, 136.7, 138.7, 140.3. HRMS (ESI-TOF) Calcd for
C20H16NO4S3, [M+H]+ 430.0240; Found 430.0247.
N-(benzo[b]thiophen-2-yl)-4-methyl-N-tosylbenzenesulfonamide (2j). The product
was purified by column chromatography on silica gel (petroleum ether/ethyl acetate =
o
7:1), white solid (85%, 116.7 mg), melting point: 206-207 C; 1H NMR (400 MHz;
CDCl3): δ = 2.50 (s, 6H), 7.04 (s, 1H), 7.36-7.41 (m, 6H), 7.75 (t, J = 8.0, 2H), 7.92 (d,
J = 8.4, 4H). 13C{1H} NMR (100 MHz; CDCl3): δ = 21.7, 122.3, 124.6, 124.7, 125.9,
128.5, 128.8, 129.6, 134.5, 135.9, 136.8, 140.3, 145.4. HRMS (ESI-TOF) Calcd for
C22H20NO4S3, [M+H]+ 458.0554; Found 458.0561.
N-(benzo[b]thiophen-2-yl)-4-fluoro-N-tosylbenzenesulfonamide (2k). The product
was purified by column chromatography on silica gel (petroleum ether/ethyl acetate =
o
4:1), white solid (81%, 112.1 mg), melting point: 193-194 C; 1H NMR (400 MHz;
CDCl3): δ = 2.50 (s, 3H), 7.05 (s, 1H), 7.24 (t, J = 8.8, 2H), 7.40 (t, J = 8.8, 4H), 7.76
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(t, J = 7.6, 2H), 7.94 (d, J = 8.4, 2H), 8.07-8.10 (m, 2H). C{1H} NMR (100 MHz;
CDCl3): δ = 166.23 (d, J = 257.6 Hz), 145.84, 140.42, 136.90, 135.88, 134.96 (d, J =
2.9 Hz), 134.34, 131.95 (d, J = 9.8 Hz), 129.91, 129.01, 128.80, 126.27, 124.95,
124.91, 122.55, 116.57 (d, J = 22.8 Hz), 21.90. HRMS (ESI-TOF) Calcd for
C21H17NFO4S3, [M+H]+ 462.0304; Found 462.0308.
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N-(benzofuran-2-yl)-4-methyl-N-tosylbenzenesulfonamide (2l). The product was
purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 6:1),
white solid (83%, 109.9 mg), melting point: 167-168 oC; 1H NMR (400 MHz; CDCl3):
δ = 2.47 (s, 6H), 7.06 (d, J = 7.6, 1H), 7.15 (d, J = 7.2, 1H), 7.32-7.34 (m, 4H), 7.38 (d,
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J = 8.0, 1H), 7.50 (t, J = 4.8, 2H), 7.86 (d, J = 8.0, 4H). C{1H} NMR (100 MHz;
CDCl3): δ = 21.7, 116.3, 116.5, 122.4, 124.8, 126.1, 128.6, 128.8, 129.7, 131.7, 131.8,
134.2, 134.8, 135.7, 136.7, 140.2, 145.7, 164.8, 167.3. HRMS (ESI-TOF) Calcd for
C22H20NO5S2, [M+H]+ 442.0783; Found 442.0788.
N-(benzofuran-2-yl)-4-fluoro-N-tosylbenzenesulfonamide (2m). The product was
purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 6:1),
white solid (75%, 100.2 mg), melting point: 157-158 oC; 1H NMR (400 MHz; CDCl3):
δ = 2.48 (s, 3H), 6.62 (s, 1H), 7.04-7.23 (m, 6H), 7.33 (d, J = 8.0, 1H), 7.51 (d, J = 8.4,
1H), 7.88 (d, J = 8.4, 2H), 8.02 (d, J = 5.2, 2H). 13C{1H} NMR (100 MHz; CDCl3): δ
= 166.15 (d, J = 257.5 Hz), 154.65, 146.17, 145.68, 136.21, 135.34 (d, J = 3.0 Hz),
131.69 (d, J = 9.9 Hz), 129.86, 128.76, 125.49, 125.18, 123.94, 119.62, 117.30,
116.51 (d, J = 22.8 Hz), 112.27, 21.84. HRMS (ESI-TOF) Calcd for C21H17NFO5S2,
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[M+H]+ 446.0533; Found 446.0539.
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1-(benzo[b]thiophen-2-yl)-5-phenyl-1H-tetrazole (2n). The product was purified by
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column chromatography on silica gel (petroleum ether/ethyl acetate = 6:1), white
o
solid (78%, 65.1 mg), melting point: 132-133 C; 1H NMR (400 MHz; CDCl3): δ =
7.45 (t, J = 4.0, 2H), 7.54 (dd, J1 = 2.0, J2 = 5.2, 3H), 7.86 (dd, J1 = 2.0, J2 = 5.2, 2H),
7.95 (s, 1H), 8.26 (dd, J1 = 2.0, J2 = 8.0, 2H). 13C{1H} NMR (100 MHz; CDCl3): δ =
114.9, 122.4, 124.7, 125.5, 126.0, 126.6, 127.2, 128.9, 130.8, 136.7, 137.0, 137.6,
165.4. HRMS (ESI-TOF) Calcd for C15H11N4S, [M+H]+ 279.0703; Found 279.0706.
1-(furan-2-yl)-1H-benzo[d][1,2,3]triazole (2o). The product was purified by column
chromatography on silica gel (petroleum ether/ethyl acetate = 4:1), white solid (74%,
41.1 mg), melting point: 117-119 oC; 1H NMR (400 MHz; CDCl3): δ = 6.65 (t, J = 3.2,
1H), 6.70 (d, J = 3.2, 1H), 7.46-7.61 (m, 3H), 7.79 (d, J = 8.0, 1H), 8.12 (d, J = 8.4,
1H). 13C{1H} NMR (100 MHz; CDCl3): δ = 100.6, 110.7, 111.9, 120.2, 124.7, 128.8,
132.3, 140.4, 143.7, 145.5. HRMS (ESI-TOF) Calcd for C10H8N3O, [M+H]+ 186.0667;
Found 186.0662.
1-(1H-pyrrol-2-yl)-1H-benzo[d][1,2,3]triazole (2p). The product was purified by
column chromatography on silica gel (petroleum ether/ethyl acetate = 4:1), white
o
solid (67%, 37.0 mg), melting point: 111-112 C; 1H NMR (400 MHz; CDCl3): δ =
6.39 (d, J = 3.2, 1H), 6.48 (s, 1H), 6.90 (d, J = 1.2, 1H), 7.43 (t, J = 7.6, 1H), 7.57 (t, J
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= 7.2, 1H), 7.73 (d, J = 8.4, 1H), 8.09 (d, J = 8.4, 1H), 9.36 (s, 1H). C{1H} NMR
(100 MHz; CDCl3): δ = 99.3, 109.0, 110.5, 116.7, 120.1, 124.6, 125.0, 128.4, 131.9,
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145.7. HRMS (ESI-TOF) Calcd for C10H9N4, [M+H]+ 185.0827; Found 185.0825.
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1-(benzo[b]thiophen-2-yl)-1H-benzo[d][1,2,3]triazole (2q). The product was
purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 5:1),
white solid (83%, 62.6 mg), melting point: 146-147 oC; 1H NMR (400 MHz; CDCl3):
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δ = 7.47-7.64 (m, 6H), 7.88-7.96 (m, 2H), 7.98 (d, J = 7.2, 1H). C{1H} NMR (100
MHz; CDCl3): δ = 106.6, 110.8, 120.4, 122.7, 124.3, 124.7, 125.3, 126.0, 127.1,
128.8, 133.8, 136.3, 136.6, 145.6. HRMS (ESI-TOF) Calcd for C14H10N3S, [M+H]+
252.0595; Found 252.0599.
1-(5-bromothiophen-2-yl)-1H-benzo[d][1,2,3]triazole (3a). The product was
purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 5:1),
white solid (74%, 62.2 mg), melting point: 104-105 oC; 1H NMR (400 MHz; CDCl3):
δ = 7.12 (q, J = 4.0, 2H), 7.46 (d, J = 8.0, 1H), 7.58 (q, J = 7.2, 1H), 7.68 (d, J = 8.4,
1H), 8.10 (d, J = 8.4, 1H). 13C{1H} NMR (100 MHz; CDCl3): δ = 109.9, 110.6, 119.9,
120.5, 124.9, 129.0, 132.4, 137.7, 146.0. HRMS (ESI-TOF) Calcd for C10H7N3SBr,
[M+H]+ 279.9544; Found 279.9541.
N-(5-bromothiophen-2-yl)-N-(phenylsulfonyl)benzenesulfonamide (3b). The
product was purified by column chromatography on silica gel (petroleum ether/ethyl
o
acetate = 5:1), white solid (79%, 108.5 mg), melting point: 93-94 C; 1H NMR (400
MHz; CDCl3): δ = 6.51 (d, J = 4.0, 1H), 6.94 (d, J = 4.4, 1H), 7.59 (t, J = 8.0, 4H),
7.70-7.38 (m, 2H), 8.00 (d, J = 8.0, 4H). 13C{1H} NMR (100 MHz; CDCl3): δ = 115.7,
128.7, 128.8, 129.1, 130.8, 132.1, 134.3, 134.4, 138.5, 139.1. HRMS (ESI-TOF)
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Calcd for C16H13NBrO4S3, [M+H]+ 457.9192; Found 457.9195.
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2-(5-bromothiophen-2-yl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (3c). The
product was purified by column chromatography on silica gel (petroleum ether/ethyl
acetate = 4:1), white solid (81%, 83.6 mg), melting point: 133-134 oC; 1H NMR (400
MHz; CDCl3): δ = 7.10 (q, J = 4.0, 2H), 7.91-8.02 (m, 3H), 8.16 (d, J = 7.2, 1H).
13C{1H} NMR (100 MHz; CDCl3): δ = 114.0, 121.5, 126.5, 127.2, 127.5, 128.9, 134.7,
135.5, 137.3, 157.6. HRMS (ESI-TOF) Calcd for C11H7NBrO3S2, [M+H]+ 343.9051;
Found 343.9055.
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2-(5-bromothiophen-2-yl)-5-(4-chlorophenyl)-4-methylisothiazol-3(2H)-one
1,1-dioxide (3d). The product was purified by column chromatography on silica gel
(petroleum ether/ethyl acetate = 5:1), white solid (67%, 84.2 mg), melting point:
145-146 oC; 1H NMR (400 MHz; CDCl3): δ = 2.26 (s, 3H), 7.03 (d, J = 4.0, 1H), 7.09
(d, J = 4.0, 1H), 7.55 (d, J = 8.4, 2H), 7.64 (d, J = 8.4, 2H). 13C{1H} NMR (100 MHz;
CDCl3): δ = 10.5, 113.7, 122.7, 126.8, 127.4, 128.9, 129.9, 130.4, 132.8, 138.3, 144.0,
159.4. HRMS (ESI-TOF) Calcd for C14H10NBrClO3S2, [M+H]+ 417.8975; Found
417.8981.
1-(5-bromothiophen-2-yl)-1H-1,2,4-triazole (3e). The product was purified by
column chromatography on silica gel (petroleum ether/ethyl acetate = 5:1), white
solid (80%, 55.2 mg), melting point: 88-89 oC; 1H NMR (400 MHz; CDCl3): δ = 6.96
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(d, J = 4.0, 1H), 7.01 (d, J = 4.0, 1H), 8.08 (s, 1H), 8.43 (s, 1H). C{1H} NMR (100
MHz; CDCl3): δ = 110.2, 117.8, 124.5, 128.8, 141.6, 152.5. HRMS (ESI-TOF) Calcd
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for C6H5N3BrS, [M+H]+ 229.9388; Found 229.9392.
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1-(5-bromothiophen-2-yl)-1H-benzo[d]imidazole (3f). The product was purified by
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column chromatography on silica gel (petroleum ether/ethyl acetate = 5:1), white
o
solid (80%, 66.9 mg), melting point: 144-146 C; 1H NMR (400 MHz; CDCl3): δ =
6.94 (d, J = 4.0, 1H), 7.10 (d, J = 3.6, 1H), 7.37 (q, J = 4.0, 1H), 7.46 (dd, J1 = 2.0, J2 =
8.4, 2H), 7.51-7.65 (m, 1H), 7.70 (d, J = 8.4, 1H). 13C{1H} NMR (100 MHz; CDCl3):
δ = 110.2, 113.4, 120.6, 122.8, 123.4, 123.5, 124.4, 126.9, 129.1, 143.4. HRMS
(ESI-TOF) Calcd for C11H8N2BrS, [M+H]+ 278.9592; Found 278.9597.
1-(5-bromothiophen-2-yl)-5-methyl-1H-tetrazole (3g). The product was purified by
column chromatography on silica gel (petroleum ether/ethyl acetate = 6:1), white
solid (63%, 46.3 mg), melting point: 71-73 oC; 1H NMR (400 MHz; CDCl3): δ = 2.61
(s, 3H), 7.05 (d, J = 4.0, 1H), 7.35 (d, J = 4.0, 1H). 13C{1H} NMR (100 MHz; CDCl3):
δ = 10.8, 111.2, 118.6, 129.2, 163.3. HRMS (ESI-TOF) Calcd for C6H6N4BrS,
[M+H]+ 244.9497; Found 244.9503.
4-bromo-1-(5-bromothiophen-2-yl)-1H-pyrazole (3h). The product was purified by
column chromatography on silica gel (petroleum ether/ethyl acetate = 6:1), white
solid (46%, 42.5 mg), melting point: 87-88 oC; 1H NMR (400 MHz; CDCl3): δ = 6.77
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(d, J = 4.0, 1H), 6.93 (d, J = 4.0, 1H), 7.61 (s, 1H), 7.77 (s, 1H). C{1H} NMR (100
MHz; CDCl3): δ = 96.1, 108.1, 114.4, 127.7, 128.6, 141.8, 143.0. HRMS (ESI-TOF)
Calcd for C7H5N2Br2S, [M+H]+ 306.8540; Found 306.8543.
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N-(5-bromothiophen-2-yl)-4-methyl-N-tosylbenzenesulfonamide (3i). The product
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was purified by column chromatography on silica gel (petroleum ether/ethyl acetate =
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o
6:1), white solid (83%, 121.0 mg), melting point: 183-184 C; 1H NMR (400 MHz;
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CDCl3): δ = 6.49 (d, J = 4.0, 1H), 6.93 (d, J = 4.0, 1H), 7.36 (d, J = 8.0, 4H), 7.86 (d, J
13
= 8.4, 4H). C{1H} NMR (100 MHz; CDCl3): δ = 21.7, 125.5, 128.6, 129.6, 131.1,
134.2, 135.8, 145.3. HRMS (ESI-TOF) Calcd for C18H17NBrO4S3, [M+H]+ 485.9503;
Found 485.9509.
N-(5-bromothiophen-2-yl)-4-chloro-N-tosylbenzenesulfonamide (3j). The product
was purified by column chromatography on silica gel (petroleum ether/ethyl acetate =
o
4:1), white solid (78%, 118.6 mg), melting point: 166-167 C; 1H NMR (400 MHz;
CDCl3): δ = 6.51 (d, J = 4.0, 1H), 6.95 (d, J = 4.0, 1H), 7.37 (d, J = 8.4, 2H), 7.55 (d, J
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= 8.8, 2H), 7.86 (d, J = 8.0, 2H), 7.93 (d, J = 8.8, 2H). C{1H} NMR (100 MHz;
CDCl3): δ = 115.7, 128.7, 129.4, 129.8, 130.1, 132.1, 134.0, 135.3, 136.9, 141.1,
145.8. HRMS (ESI-TOF) Calcd for C17H14NClBrO4S3, [M+H]+ 505.8957; Found
505.8954.
N-(5-bromo-4-methylthiophen-2-yl)-4-methyl-N-tosylbenzenesulfonamide (3k).
The product was purified by column chromatography on silica gel (petroleum
o
ether/ethyl acetate = 4:1), white solid (48%, 72.1 mg), melting point: 162-164 C; 1H
NMR (400 MHz; CDCl3): δ = 1.84 (s, 3H), 2.48 (s, 6H), 6.61 (s, 1H), 7.35 (d, J = 8.4,
13
4H), 8.82 (d, J = 8.8, 4H). C{1H} NMR (100 MHz; CDCl3): δ = 12.5, 21.7, 107.3,
127.3, 128.0, 128.5, 129.5, 129.6, 130.3, 136.4, 144.6, 145.3. HRMS (ESI-TOF)
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Calcd for C19H19NBrO4S3, [M+H]+ 499.9660; Found 499.9667.
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N-(7-bromo-2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)-N-(phenylsulfonyl)benzene
sulfonamide (3l). The product was purified by column chromatography on silica gel
(petroleum ether/ethyl acetate = 6:1), white solid (69%, 106.9 mg), melting point:
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182-184 C; 1H NMR (400 MHz; CDCl3): δ = 3.86-3.88 (m, 2H), 4.15-4.17 (m, 2H),
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7.56 (t, J = 7.6, 4H), 7.69 (t, J = 7.2, 2H), 8.02 (d, J = 8.0, 4H). C{1H} NMR (100
MHz; CDCl3): δ = 64.5, 64.6, 90.4, 108.0, 128.8, 134.1, 138.5, 139.1, 141.5. HRMS
(ESI-TOF) Calcd for C18H15NBrO6S3, [M+H]+ 515.9245; Found 515.9251.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications
1
13
website at DOI: xxx. Copies of H and C NMR spectra for Compounds 2, 3 and 4
(PDF).
ACKNOWLEDGMENTS
This work was supported by the National Natural Science Foundation of China
(21801007), the Program for Innovative Research Team of Science and Technology
in the University of Henan Province (18IRTSTHN004 and 18HASTIT006), the
Science and Technology Plan Projects of Henan Province (19A150015) and the Jilin
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Province Key Laboratory of Organic Functional Molecular Design & Synthesis
(130028911).
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References and Notes
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