Switchable Ring-Contractive Extrusion Reactions of 2,5-Dihydro-1,4,5-thiadiazepine S-Oxides: Entries to Pyridazines or Pyrazoles

Article abstract of DOI:10.1021/acs.joc.9b03003

Switchable ring-contractive extrusion reactions of 2,5-dihydro-1,4,5-thiadiazepine S-oxides are described, which allow expedient access to pyridazines under thermal conditions or pyrazoles under Lewis acid-mediated conditions.

Full text of DOI:10.1021/acs.joc.9b03003

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Article
Switchable Ring-Contractive Extrusion Reactions of 2,5-Dihydro-1,4,5-
thiadiazepine S-Oxides: Entries to Pyridazines or Pyrazoles
Bin Cheng, Yuntong Li, Hui Li, Xinping Zhang, Taimin Wang, Yun Li, and Hongbin Zhai
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03003 • Publication Date (Web): 19 Dec 2019
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The Journal of Organic Chemistry
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Switchable Ring-Contractive Extrusion Reactions of 2,5-Dihydro-
1,4,5-thiadiazepine S-Oxides: Entries to Pyridazines or Pyrazoles
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Bin Cheng,*,†,‡ Yuntong Li,‡, ⊥ Hui Li,‡, ⊥ Xinping Zhang,‡ Taimin Wang,† Yun Li,‡ and Hongbin
Zhai*,†,‡,§
† Institute of Marine Biomedicine, Shenzhen Polytechnic, Shenzhen 518055, China
‡ State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University,
Lanzhou 730000, China
§ State Key Laboratory of Chemical Oncogenomics, Shenzhen Engineering Laboratory of Nano Drug Slow-Release, Peking
University Shenzhen Graduate School, Shenzhen 518055, China
Supporting Information Placeholder
R2
ABSTRACT: Switchable ring-contractive extrusion reactions
of 2,5-dihydro-1,4,5-thiadiazepine S-oxides are described,
which allow expedient access to pyridazines under thermal
conditions or pyrazoles under Lewis acid-mediated conditions,
respectively.
CO2R3
CO2R3
ZnBr2
DCM
DMSO
80 o
N
N
CO2R3
CO2R3
N
HN
R1
CO2R3
N
C
N
R1
R1
– CH2SO
R2 = Boc
– SO
S
CO2R3
O
R2 = Boc, Ac
Scheme 1. Previous work for the synthesis of 2,5-dihydro-
1,4,5-thiadiazepine S-oxides and this work.
Previous work
INTRODUCTION
Ring-contraction reactions have been developed as important
alternative solutions to access small ring compounds which are
inaccessible via direct cyclization reactions from acyclic
precursors in modern organic chemistry and great advances
had been made by organic chemists in the past decades.1
Moreover, extrusion reactions (i.e., expulsion of atoms or a
group of atoms and reformation of a new bond between the
two parts disconnected) are common phenomena in chalcogen
and organometallic chemistry, for example, the well-known
Ramberg–Bäcklund olefination reaction.2 As for ring-
contractive extrusion reactions, they sometimes could enable
the formation of challenging structures (e.g., sterically bulky
bonds or strained rings) and have been demonstrated as a kind
of useful strategies in synthetic chemistry.3 For example,
Nicolaou had adopted the Ramberg–Bäcklund olefination
reaction to access an unusual 13-membered ring in the total
synthesis of hirsutellone B.4a Corey had disclosed an azo
decomposition strategy to construct rare ladderane moiety in
the first-generation synthesis of pentacycloanammoxic acid
methyl ester.4b Thus, to develop new ring-contractive
extrusion reactions is highly desired.
R2
NHR2
+
R2
N
CO2R3
CO2R3
CO2R3
CO2R3
N
m-CPBA
DCM
Na2CO3
DCM
N
N
(a)
N
N
R1
S
R3O2C
R1
[3+4]
selective
[O]
S
X
R1
S
CO2R3
O
O
This work
R2
N
CO2R3
CO2R3
ZnBr2
DMSO
80 o
N
CO2R3
CO2R3
N
HN
DCM
– CH2SO
R2 = Boc
CO2R3
N
C
N
(b)
R1
R1
R1
S
– SO
R2 = Boc, Ac
CO2R3
O
RESULTS AND DISCUSSION
At first, when we checked the spectra of 2,5-dihydro-1,4,5-
thiadiazepine S-oxides, a serendipitous discovery evoked our
great interest. When the samples of sulfoxide 1 were kept in
CDCl3 or d6-DMSO overtime, they would deteriorate
apparently and new substances were formed as detected on
TLC (thin layer chromatography) and 1H-NMR. The structures
of these new substances were finally determined to be 2 after
comprehensive identifications including X-ray diffraction
analysis of 2a (Table 1).6 Pyridazines (2) were generated from
a ring-contraction reaction via SO extrusion, which was a
common phenomenon in chalcogen chemistry.7 However, this
kind of desulfuration transformations only sporadically
appeared in the literature for the synthesis of heterocyclic
compounds (e.g., indoles, isoquinolines, and so on), owing to
the difficulties in preparing ring-contraction precursors.
Pyridazines were one of the privileged structural units often
recurring in natural products and pharmaceuticals with wide
spectrum of bioactive and pharmaceutical applications.8 After
simple optimization of the solvents and temperatures, we
Recently we reported the synthesis of 2,5-dihydro-1,4,5-
thiadiazepines from pyridinium 1,4-zwitterionic thiolates with
1,2-diaza-1,3-dienes and their S-oxides (i.e., sulfoxides and
sulfones) via subsequent selective oxidation (eq a, Scheme 1).5
During our studies, we accidentally discovered two kinds of
novel ring-contractive extrusion reactions of 2,5-dihydro-
1,4,5-thiadiazepine S-oxides, which allow expedient access to
pyridazines under thermal conditions or pyrazoles under
Lewis acid-mediated conditions (eq b, Scheme 1). Herein we
would describe our detailed results on these two interesting
transformations.
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found that a series of sulfoxide analogues prepared according
Page 2 of 6
Ac
CO2Me
CO2Me
Ac
DMSO
140 o
DMSO
140 o
CO2Me
CO2Me
N
CO2Me
CO2Me
N
to the reported method5 could be transformed into
functionalized pyridazines (2a−i) in DMSO at 80 oC with good
yields (Table 1). Among them, electron-withdrawing
substituents on the benzene ring induced slightly lower yields
(entries 4 and 5). Heteroaryl, alkyl, and alkenyl substituted
substrates were all applicable to this transformation (entries 6–
8). The N-Ac sulfoxide performed well as the N-Boc substrate
and afforded a comparable yield (see, 2a). However, when
thioether 4a or sulfone 5a was examined under thermal
conditions, even at 140 oC, the desired pyridazine 2a was only
obtained in low yields. Indeed, these results were in
accordance with the empirical extrusion order (SO >
SO2 >S).7a
N
N
1
2
3
4
5
6
7
8
N
C
C
N
20%
– S
34%
Ph
S
Ph
O
S
Ph
– SO2
O
4ac
2a
5ac
a Reaction conditions: ring-contraction precursor (0.3 mmol),
DMSO (3 mL), 80 °C unless otherwise noted. Isolated yield. b The
yield was obtained from the corresponding N-Ac analogue.
c140 °C was employed instead.
9
To elucidate the mechanism of our unexpected discovery,
we attempted to get the N-free analogues of 1. To our surprise,
upon treatment of 1a with ZnBr2 in DCM at room temperature,
the expected N-Boc deprotection product was not obtained and
pyrazole 3a was gained instead as the major product via
CH2SO extrusion (entry 1, Table 2). The exact structure of 3a
was subsequently confirmed by analogy with 3g.6 This
accidental discovery offered a novel synthetic approach to
access pyrazoles, which demonstrated a curious and entirely
distinct ring-contraction pathway from the identical sulfoxide
precursors. Pyrazoles were another fundamentally important
class of heterocycles and of great value in organic and
medicinal chemistry.9 By following this Lewis acid-mediated
ring-contraction protocol, a library of pyrazoles (3a−i) with
diverse functional groups were obtained in moderate to good
yields. In addition, this ring-contractive extrusion reaction
could be scaled up to gram with only a slight loss of the yield
(see, 3a). However, as for thioether 4b and sulfone 5b in
different oxidant states, 4b delivered pyrazole 3a in a low
yield of 22%, while 5b could not afford the extrusion product,
even in refluxing DCM.
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Table 1. Ring-contraction reaction of sulfoxides 1 under
thermal conditions a
Boc
CO2R3
DMSO
N
CO2R3
CO2R3
N
80 o
C
N
N
CO2R3
S
R1
R1
– SO
O
2
1
R1 = Aryl, Heteroaryl, Alkyl, Alkenyl; R3 = Me, Et
entry
1
Product (yield)
entry
5
Product (yield)
N
CO2Me
CO2Me
N
CO2Me
CO2Me
N
N
F
Table 2. Ring-contraction reaction of sulfoxides 1 under
Lewis-acid mediated conditions a
2e, 59%
Boc
CO2R3
ZnBr2
N
CO2Me
CO2Me
N
N
N
DCM
HN
R1
CO2R3
N
CO2R3
6
7
8
9
– CH2SO
R1
S
CO2R3
O
O
3
1
R1 = Aryl, Heteroaryl, Alkyl, Alkenyl; R3 = Me, Et
2a, 78% (70%)b
2f, 57%
N
CO2Me
N
CO2Me
CO2Me
N
entry
1
Product (yield)
entry
6
Product (yield)
N
CO2Me
2
3
4
N
N
MeO
HN
HN
CO2Me
CO2Me
CO2Me
CO2Me
O
2b, 81%
2g, 42%
N
N
CO2Me
CO2Me
3a, 92% (86%)b
3f, 37%
N
CO2Me
CO2Me
N
Ph
N
N
HN
HN
Me
CO2Me
CO2Me
CO2Me
2
3
7
CO2Me
2c, 72%
2h, 68%
MeO
N
N
CO2Me
CO2Me
3b, 85%
N
CO2Et
CO2Et
N
Ph
N
HN
F3C
CO2Me
CO2Me
2d, 65%
2i, 74%
Me
3c, 78%
3g, 78%
2
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The Journal of Organic Chemistry
sulfur sometimes could be adopted as a traceless linker to
N
HN
1
2
3
4
5
6
7
8
promote bond-forming and then disappear without a trace.
N
CO2Me
HN
CO2Me
CO2Me
4
5
8
9
Ph
CO2Me
F3C
EXPERIMENTAL SECTION
General Information. All isolated compounds were
characterized on Bruker 400 and JEOL 400 spectrometers in
CDCl3. Chemical shifts were reported as δ values relative to
internal chloroform (δ 7.26 for 1H NMR and 77.00 for 13C NMR).
High-resolution mass spectra (HRMS) were obtained on a 4G
mass spectrometer by using electrospray ionization (ESI)
analyzed by quadrupole time-of-flight (QTof). All melting points
were measured with the samples after column chromatography
and uncorrected. Column chromatography was performed on
silica gel. Anhydrous THF and PhMe were distilled over sodium
benzophenone ketyl under Ar. All other solvents and reagents
were used as obtained from commercial sources without further
3d, 81%
3h, 63%
N
HN
N
HN
CO2Me
CO2Et
Ph
CO2Me
CO2Et
F
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3e, 76%
3i, 91%
Boc
CO2Me
CO2Me
Boc
ZnBr2
DCM
CO2Me
ZnBr2
DCM
N
N
HN
Ph
N
N
CO2Me
N
CO2Me
22%
50 o
C
S
O
Ph
O
S
Ph
CO2Me
– CH2S
4b
3a
5bc
purification.
a Reaction conditions: ring-contraction precursor (0.3 mmol),
ZnBr2 (1.0 equiv), RT (25 oC) unless otherwise noted. Isolated
yield. b The reaction was conducted in gram-scale. c 50 oC was
employed instead.
General Procedure for the Preparation of 2,5-Dihydro-
1,4,5-thiadiazepines and Their S-Oxides. Compounds (1a−i, 4a,
4b, 5a, and 5b) are all known. They were prepared according to
the literature.5
General Procedure for the Synthesis of Pyridazine (2). A
solution of sulfoxide (1, 0.3 mmol) in DMSO (3 mL) was heated
at 80 °C (oil bath). After completion as monitored by TLC, the
mixture was diluted with H2O and extracted with Et2O for three
times. The combined organic layers were dried over anhydrous
Na2SO4. After evaporation of solvent, the residue was purified by
silica gel column chromatography to get the corresponding
pyridazine 2.
General Procedure for the Synthesis of Pyrazole (3). To a
solution of sulfoxide (1, 0.3 mmol) in DCM (3 mL) was added
ZnBr2 (0.3 mmol, 1.0 equiv) at room temperature. After
completion as monitored by TLC, the solvent was removed in
vacuo and the crude product was purified by silica gel column
chromatography to give the corresponding pyrazole 3.
Scale-up Experiment for 3a. To a solution of sulfoxide 1a
(2.00 g, 4.73 mmol) in DCM (47 mL) was added ZnBr2 (1.06 g,
4.73 mmol), and the resulting solution was stirred at room
temperature for 2 h. After removal of the solvent under reduced
pressure, the resulting residue was purified by silica gel column
chromatography to give 3a (1.06 g, 86%) as a yellow oil.
Characterization Data of Compounds 2a−i.
Based on the previous reports and our experimental results,
we proposed plausible reaction mechanisms for the switchable
ring-contraction reactions as shown in Scheme 2. (a) Initially,
sulfoxide 1a undergoes a deprotection of N-Boc under thermal
conditions.10 Then a 1,3-H shift and an intramolecular
nucleophilic addition of enamine to activated α,β-unsaturated
ester occur to form a 6/3 fused system. After SO extrusion
followed by oxidation,11 pyridazine 2a is formed (eq a).
Whereas, after removal of N-Boc assisted with ZnBr2, an
intramolecular addition of enamine to imine activated by
ZnBr2 furnishes a 5/4 fused system, then CH2SO extrusion12
and isomerization occur to afford pyrazole 3a (eq b).
Scheme 2. Proposed mechanisms for the switchable ring-
contraction reactions
Boc
CO2Me
CO2Me
H
N
CO2Me
CO2Me
H
CO2Me
CO2Me
N
N
N

N
HN
Ph
DMSO
S
Ph
S
Ph
S
O
O
O
1a
(a)
Dimethyl 6-phenylpyridazine-3,4-dicarboxylate. Compound 2a
(64 mg, 78%, Rf = 0.40 (PE:EA = 2:1)) was isolated as a yellow
H
H
N
N
CO2Me
CO2Me
N
CO2Me
CO2Me
CO2Me
CO2Me
N
N
 SO
N
[O]
1
Ph
solid; mp 97.1−98.0 °C. H NMR (400 MHz, CDCl3) δ 8.19 (s,
Ph
Ph
S
O
2a
1H), 8.17–8.11 (m, 2H), 7.58–7.52 (m, 3H), 4.07 (s, 3H), 4.00 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 165.0, 164.5, 160.6, 149.4,
134.4, 131.2, 129.8, 129.2, 127.4, 122.9, 53.6, 53.5; HRMS (ESI)
m/z: [M + H]+ Calcd for C14H13N2O4 273.0870, Found 273.0869.
H
N
Boc
H
CO2Me
CO2Me
CO2Me
O
Zn+2
Ph
N
N
ZnBr2
CO2Me DCM
N
N
CO2Me
N
Ph
Dimethyl
6-(4-methoxyphenyl)pyridazine-3,4-dicarboxylate.
S
Ph
CO2Me
S
S
O
Compound 2b (73 mg, Y = 81%, Rf = 0.65 (PE:EA = 1:1)) was
O
(b)
1a
1
isolated as a yellow solid; mp 102.6−103.3 °C. H NMR (400
H
H
N
N
N
N
MHz, CDCl3) δ 8.13 (d, J = 9.2 Hz, 2H), 8.10 (s, 1H), 7.05 (d, J =
8.8 Hz, 1H), 4.06 (s, 3H), 3.99 (s, 3H), 3.88 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 165.0, 164.8, 162.2, 160.0, 148.6, 130.0,
129.0, 126.8, 121.9, 114.6, 55.4, 53.5, 53.4; HRMS (ESI) m/z: [M
+ H]+ Calcd for C15H15N2O5 303.0975, Found 303.0975.
CO2Me
CO2Me

CH2SO
Ph
Ph
CO2Me
CO2Me
3a
CONCLUSIONS
Dimethyl 6-(p-tolyl)pyridazine-3,4-dicarboxylate. Compound 2c
(62 mg, Y = 72%, Rf = 0.49 (PE:EA = 2:1)) was isolated as a
In summary, two bonuses of the ring-contraction reactions
of 2,5-dihydro-1,4,5-thiadiazepine S-oxides under thermal or
acidic conditions via the extrusion of small molecules
highlight the utility of sulfur in synthetic chemistry, wherein
1
yellow solid; mp 88.2−89.0 °C. H NMR (400 MHz, CDCl3) δ
8.16 (s, 1H), 8.06 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H),
4.07 (s, 3H), 4.00 (s, 3H), 2.44 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 165.1, 164.7, 160.5, 149.1, 141.8, 131.7, 130.0, 129.9,
3
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127.3, 122.5, 53.6, 53.5, 21.5; HRMS (ESI) m/z: [M + H]+ Calcd
for C15H15N2O4 287.1026, Found 287.1025.
129.5, 120.1, 114.1, 112.4, 55.3, 52.4, 52.3; HRMS (ESI) m/z: [M
+ H]+ Calcd for C14H15N2O5 291.0975, Found 291.0973.
1
2
3
4
5
6
7
8
Dimethyl
6-(4-(trifluoromethyl)phenyl)pyridazine-3,4-
Dimethyl 3-(p-tolyl)-1H-pyrazole-4,5-dicarboxylate. Compound
3c (64 mg, Y = 78%, Rf = 0.23 (PE:EA = 2:1)) was isolated as a
yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.0 Hz, 2H),
7.17 (d, J = 7.6 Hz, 2H), 3.81 (s, 3H), 3.74 (s, 3H), 2.35 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 164.3, 161.3, 146.2, 141.4, 139.6,
129.3, 127.8, 125.1, 112.6, 52.3, 52.2, 21.2; HRMS (ESI) m/z: [M
+ H]+ Calcd for C14H15N2O4 275.1026, Found 275.1027.
dicarboxylate. Compound 2d (66 mg, Y = 65%, Rf = 0.52 (PE:EA
= 2:1)) was isolated as a yellow solid; mp 85.2−86.2 °C. 1H NMR
(400 MHz, CDCl3) δ 8.25 (d, J = 8.4 Hz, 2H), 8.24 (s, 1H), 7.78
(d, J = 8.4 Hz, 2H), 4.04 (s, 3H), 3.98 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 164.7, 164.1, 159.3, 150.2, 137.8,132.7 (q, J =
32.6 Hz), 129.7, 127.8, 126.1 (q, J = 3.7 Hz),123.6 (q, J = 270.8
Hz), 123.3, 53.6, 53.5; HRMS (ESI) m/z [M + Na]+ Calcd for
C15H11F3N2O4Na 363.0563, Found 363.0562.
Dimethyl
3-(4-(trifluoromethyl)phenyl)-1H-pyrazole-4,5-
dicarboxylate. Compound 3d (80 mg, Y = 81%, Rf = 0.56 (PE:EA
9
1
Dimethyl
6-(4-fluorophenyl)pyridazine-3,4-dicarboxylate.
= 2:1)) was isolated as a yellow oil. H NMR (400 MHz, CDCl3)
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Compound 2e (51 mg, Y = 59%, Rf = 0.48 (PE:EA = 2:1)) was
isolated as a yellow solid; mp 82.3−82.9 °C. 1H NMR (400 MHz,
CDCl3) δ 8.18–8.12 (m, 3H), 7.26–7.19 (m, 2H), 4.06 (s, 3H),
3.98 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.9, 164.8 (d, J =
251.1 Hz), 164.4, 159.5, 149.4, 130.6 (d, J = 3.1 Hz), 129.9, 129.5
(d, J = 8.8 Hz), 122.5, 116.4 (d, J = 21.8 Hz), 53.6, 53.4; HRMS
(ESI) m/z: [M + H]+ Calcd for C14H12FN2O4 291.0776, Found
291.0774.
Dimethyl 6-(furan-2-yl)pyridazine-3,4-dicarboxylate. Compound
2f (45 mg, Y = 57%, Rf = 0.56 (PE:EA = 1:1)) was isolated as a
red solid; mp 149.3−149.6 °C. 1H NMR (400 MHz, CDCl3) δ 8.08
(s, 1H), 7.65 (d, J = 1.2 Hz, 1H), 7.48 (d, J = 3.6 Hz, 1H), 6.62
(dd, J = 3.6, 1.6 Hz, 1H), 4.03 (s, 3H), 3.97 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 164.8, 164.4, 153.2, 149.4, 148.5, 145.8,
130.0, 120.5, 113.1, 113.0, 53.5, 53.4; HRMS (ESI) m/z: [M +
H]+ Calcd for C12H11N2O5 263.0662, Found 263.0661.
δ, 7.70 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 3.84 (s, 3H),
3.80 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.0, 160.4, 146.1,
139.6, 132.3, 131.3 (q, J = 32.5 Hz), 128.3, 125.6 (q, J = 3.7 Hz),
123.8 (q, J = 270.6 Hz), 113.8, 52.6, (1C missing); HRMS (ESI)
m/z: [M + Na]+ Calcd for C14H11F3N2O4Na 351.0563, Found
351.0562.
Dimethyl
3-(4-fluorophenyl)-1H-pyrazole-4,5-dicarboxylate.
Compound 3e (63 mg, Y = 76%, Rf = 0.21 (PE:EA = 2:1)) was
isolated as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.58–7.52
(m, 2H), 7.06 (t, J = 8.8 Hz, 2H), 3.82 (s, 3H), 3.74 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 164.1, 163.4 (d, J = 248.6 Hz), 161.0,
145.7, 140.8, 130.1 (d, J = 8.4 Hz), 124.4 (d, J = 3.1 Hz), 115.8 (d,
J = 21.7 Hz), 112.8, 52.4 (2C); HRMS (ESI) m/z: [M + Na]+
Calcd for C13H11FN2O4Na 301.0595, Found 301.0593.
Dimethyl
3-(furan-2-yl)-1H-pyrazole-4,5-dicarboxylate.
Compound 3f (28 mg, Y = 37%, Rf = 0.26 (PE:EA = 2:1)) was
1
Dimethyl 6-(tert-butyl)pyridazine-3,4-dicarboxylate. Compound
2g (32 mg, Y = 42%, Rf = 0.52 (PE:EA = 2:1)) was isolated as a
isolated as a yellow oil. H NMR (400 MHz, CDCl3) δ 7.50 (d, J
= 1.2 Hz, 1H), 7.24 (d, J = 3.2 Hz, 1H), 6.53 (dd, J = 3.2, 1.6 Hz,
1H), 3.93 (s, 3H), 3.93 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
163.2, 161.6, 143.5, 142.9, 142.6, 137.7, 112.6, 112.2, 110.1, 52.6,
52.2; HRMS (ESI) m/z: [M + Na]+ Calcd for C11H10N2O5Na
273.0482, Found 273.0481.
1
yellow oil. H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 4.04 (s,
3H), 3.97 (s, 3H), 1.48 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
172.4, 165.3, 164.8, 149.1, 129.2, 122.3, 53.4, 53.3, 37.5, 29.8;
HRMS (ESI) m/z: [M + H]+ Calcd for C12H17N2O4 253.1183,
Found 253.1183.
Dimethyl
3-(tert-Butyl)-1H-pyrazole-4,5-dicarboxylate.
Dimethyl (E)-6-styrylpyridazine-3,4-dicarboxylate. Compound 2h
(61 mg, Y = 68%, Rf = 0.40 (PE:EA = 2:1)) was isolated as a
Compound 3g (56 mg, Y = 78%, Rf = 0.24 (PE:EA = 2:1)) was
1
isolated as a white solid; mp 117−118 °C. H NMR (400 MHz,
yellow solid; mp 149.3−149.6 °C. H NMR (400 MHz, CDCl3) δ
CDCl3) δ 3.90 (s, 3H), 3.88 (s, 3H), 1.40 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 165.6, 161.7, 153.3, 141.5, 112.7, 52.3, 52.1, 32.4,
29.0; HRMS (ESI) m/z: [M + Na]+ Calcd for C11H16N2O4Na
263.1002, Found 263.1001.
1
7.93 (s, 1H), 7.80 (d, J = 16.4 Hz, 1H), 7.62 (d, J = 6.8 Hz, 2H),
7.46–7.37 (m, 4H), 4.05 (s, 3H), 3.99 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 164.9, 164.6, 159.7, 148.8, 138.0, 135.2, 129.8,
129.7, 128.9, 127.7, 123.5, 122.9, 53.5, 53.4; HRMS (ESI) m/z:
[M + H]+ Calcd for C16H15N2O4 299.1026, Found 299.1025.
Diethyl 6-phenylpyridazine-3,4-dicarboxylate. Compound 2i (67
mg, Y = 74%, Rf = 0.45 (PE:EA = 2:1)) was isolated as a yellow
solid; mp 149.3−149.6 °C. 1H NMR (400 MHz, CDCl3) δ 8.18 (s,
1H), 8.17–8.10 (m, 2H), 7.58–7.50 (m, 3H), 4.53 (q, J = 7.2 Hz,
2H), 4.45 (q, J = 7.2 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H), 1.40 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 164.6, 164.0, 160.5,
150.0, 134.7, 131.1, 129.8, 129.2, 127.4, 122.9, 62.9, 62.7, 14.0,
13.9; HRMS (ESI) m/z: [M + H]+ Calcd for C16H17N2O4
301.1183, Found 301.1181.
(E)-dimethyl 3-styryl-1H-pyrazole-4,5-dicarboxylate. Compound
3h (54 mg, Y = 63%, Rf = 0.20 (PE:EA = 2:1)) was isolated as a
1
white solid; mp 117.5−118.3 °C. H NMR (400 MHz, CDCl3) δ
7.48 (d, J = 7.2 Hz, 2H), 7.40–7.28 (m, 5H), 3.93 (s, 3H), 3.70 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 163.2, 161.7, 145.1, 142.8,
135.6, 134.3, 129.0, 128.7, 127.1, 113.7, 111.5, 52.4, 52.0; HRMS
(ESI) m/z: [M + Na]+ Calcd for C15H14N2O4Na 309.0846, Found
309.0845.
Diethyl 3-phenyl-1H-pyrazole-4,5-dicarboxylate. Compound 3i
(79 mg, Y = 91%, Rf = 0.30 (PE:EA = 2:1)) was isolated as a
1
yellow oil. H NMR (400 MHz, CDCl3) δ 7.60–7.52 (m, 2H),
7.39–7.33 (m, 3H), 4.29 (q, J = 7.2 Hz, 2H), 4.18 (q, J = 7.2 Hz,
2H), 1.26 (t, J = 7.2 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 163.8, 160.7, 146.1, 141.0, 129.3, 128.5,
128.4, 127.9, 113.3, 61.4, 61.3, 13.9 (2C); HRMS (ESI) m/z: [M
+ Na]+ Calcd for C15H16N2O4Na 311.1002, Found 311.1002.
Characterization Data of Compounds 3a−i.
Dimethyl 3-phenyl-1H-pyrazole-4,5-dicarboxylate. Compound 3a
(72 mg, Y = 92%, Rf = 0.29 (PE:EA = 3:1)) was isolated as a
1
yellow oil. H NMR (400 MHz, CDCl3) δ 7.57–7.51 (m, 2H),
7.37–7.32 (m, 3H), 3.81 (s, 3H), 3.63 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 164.2, 161.1, 146.6, 141.0, 129.6, 128.7, 128.3,
128.0, 113.1, 52.4, 52.4; HRMS (ESI) m/z: [M + Na]+ Calcd for
C13H12N2O4Na 283.0689, Found 283.0688.
ASSOCIATED CONTENT
Supporting Information
Dimethyl
3-(4-methoxyphenyl)-1H-pyrazole-4,5-dicarboxylate.
Compound 3b (74 mg, Y = 85%, Rf = 0.33 (PE:EA = 1:1)) was
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
Copies of 1H and 13C NMR spectra for all new compounds (PDF),
1
isolated as a yellow oil. H NMR (400 MHz, CDCl3) δ 7.50 (d, J
= 7.6 Hz, 2H), 6.90 (d, J = 7.6 Hz, 2H), 3.81 (s, 6H), 3.78 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 164.1, 161.4, 160.7, 146.2, 141.6,
Crystallographic information for 2a and 3g (CIF)
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some representative examples, see: (c) Rabet, P. T. G.; Boyd, S.;
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AUTHOR INFORMATION
Corresponding Author
*E-mail: chengbin@szpt.edu.cn.
*E-mail: zhaihb@pkusz.edu.cn.
into
indolo[2,3-b][1,4]benzothiazepines
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Author Contributions
⊥Those authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
We thank NSFC (21971092, 21901014, 21472072, and
21672017), Program for Changjiang Scholars and Innovative
Research Team in University (PCSIRT: IRT_15R28), and
FRFCU (lzujbky-2019-50, lzujbky-2017-90) for financial support.
We thank Dr. Hanwei Hu for assistance in polishing the
manuscript.
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