1,3-Dipolar Cycloaddition of Alkyne-Tethered N-Tosylhydrazones: Synthesis of Fused Polycyclic Pyrazoles

Article abstract of DOI:10.1021/acs.joc.6b02076

A general and transition-metal-free access to the fused polycyclic pyrazoles via an intramolecular 1,3-dipolar cycloaddition reaction of alkyne-tethered tosylhydrazones has been reported. The pure solid products could be obtained without column chromatography in high to excellent yields, and the obtained products are useful bioactive molecules or could be used as the key intermediate for synthesis of these compounds in one or two steps. Additionally, a [3+2]-cycloaddition followed by a direct H-shift aromatization reaction mechanism was proposed, which is different from the previously reported aryl or alkyl sequential [1,5]-sigmatropic rearrangement pathway.

Full text of DOI:10.1021/acs.joc.6b02076

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Article
1,3-Dipolar Cycloaddition of Alkyne-Tethered N-
Tosylhydrazones: Synthesis of Fused Polycyclic Pyrazoles
Yang Zheng, Xiaolu Zhang, Ruwei Yao, Yuecheng Wen, Jingjing Huang, and Xinfang Xu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02076 • Publication Date (Web): 10 Oct 2016
Downloaded from http://pubs.acs.org on October 12, 2016
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1,3-Dipolar Cycloaddition of Alkyne-Tethered N-Tosylhydrazones:
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Synthesis of Fused Polycyclic Pyrazoles
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Yang Zheng, Xiaolu Zhang, Ruwei Yao, YueCheng Wen, Jingjing Huang,* and
Xinfang Xu*
† Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical
Engineering and Materials Science; Analysis and Testing Centre, Soochow University, Suzhou
215123, China
Email: xinfangxu@suda.edu.cn; jjhuang@suda.edu.cn
ABSTRACT: A general and transition-metal-free access to the fused polycyclic
pyrazoles via an intramolecular 1,3-dipolar cycloaddition reaction of alkyne-tethered
tosylhydrazones has been reported. The pure solid products could be obtained without
column chromatography in high to excellent yields, and the obtained products are
useful bioactive molecules or could be used as the key intermediate for synthesis of
these compounds in one or two steps. Additionally, a [3+2]-cycloaddition followed by
a direct H-shift aromatization reaction mechanism was proposed, which is different
from previously reported aryl or alkyl sequential [1,5]-sigmatropic rearrangement
pathway.
INTRODUCTION
The fused polycyclic pyrazole motif is a core structure in various important
heterocycles, which show broad bioactivities and are extensively applied in
pharmacology.1-4 For example, compound A is an important KDR kinase inhibitor,2a
and its also works as a vascular endothelial growth factor (VEGF);2b the ketone
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variant B shows anti-depression and antitumor activities;3 and molecule C works as
an effective benzodiazepine receptor (BZR) ligand (Figure 1).4 During the past
decades, methods are developed for the pyrazoles construction, especially for the
multi-substituted and fused polycyclic structure.5-11 Among these works, stepwise
condensation of 1,3-dicarbonyl compounds with hydrazines, which is known as Knorr
pyrazole synthesis, is a classic access to these library of compounds.5 Recently,
Joksović5e and Banerjee5f disclosed two eco-friendly processes of this transformation
by carrying out the reactions “in water” or “in one-pot” individually.
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Figure 1. Selected examples of bioactive fused polycyclic pyrazoles.
On the other hand, 1,3-dipolar cycloaddition of diazo compounds, hydrazones or
their equivalents, with C-C double or triple bonds is a complementary approach to the
pyrazole framework (Scheme 1).7-12 Breakthroughs have been disclosed recently in
this context, for example, 1,3-dipolar cycloaddition of diazo compounds to
electron-deficient alkynes were reported by Li7a and Legros7b, which were carried out
in water or under catalyst-free conditions individually. In addition, Valdés reported a
one-step approach with N-tosylhydrazones and alkynes, which broadly expended the
substrate scope of the 1,3-dipoles.8 Nevertheless, challenges remain in these reactions,
for example, the migration preference in the dipolar cycloaddition reaction (Scheme
1A, R1 vs R2 shift; and/or C→N vs C→C migration).8 Meanwhile, high temperature
o
(>100 C),8 or catalysts9 are inescapable to promote these transformations, and even
using transition-metal catalyst in some case.10 In addition, substrate limitation is
another shortcoming in this cycloaddition reaction. Although the diazo compound part
is extended via applying hydrazones as their stable precursor by Valdés in this
[3+2]-cycloaddition,8 only terminal alkynes8,9,10a,10b or alkynes with carbonyl
group10c,10d are reported in these transformations. And reaction with internal alkynes,
which have two different substitutions on each carbon, is rare.13 Additionally, direct
approaches to the fused polycyclic pyrazole frameworks are under development6
compared with the method to the multi-substituted pyrazoles. Inspired by these works,
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and in our continuing interest in bioactive fused polycyclic structure synthesis,14 we
disclose here a direct access to fused polycyclic pyrazoles via an intramolecular
[3+2]-cycloaddition reaction of alkyne-tethered tosylhydrazones under mild
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conditions (60 C, transition-metal-free) with high to excellent yields (Scheme 1B).
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Besides, it takes a few of steps to prepare these polycyclic bioactive molecules with
other methods.2-4
Scheme 1. [3+2]-Cycloaddition for the Pyrazole Synthesis
A) [3+2]-Cycloaddition of diazo compound with alkyne:
R2
N2
R2
R1
and/or
H
[3+2]
R1
R2
R3
R1
N
NH
High temp.
or with cat
+
R3
N
N
R3
C
N R1 shift
C
N H shift
H
R2
R1
N
R2
R1
[3+2]
C
C
H
H
R1 shift
N
N
R3
N
R3
B)This Work: Direct access to bioactive fused pyrazoles:
H
NNHTs
N
N
tBuOLi, 60 oC
H
R
R
Transition metal-free
Mild conditions, gram scale
No column chromatography
X
X
71~>95%
RESULTS AND DISCUSSION
The condition optimization is summarized in Table 1. Initially, substrate 1a was
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treated with lithium tert-butoxide (tBuOLi) in 1,4-dioxane at 50 C and the
corresponding fused prazole product 2a was obtained in 41% yield (Table 1, entry 1).
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Elevating the reaction temperature can promote the conversion and 60 C was found
to be the best temperature, which gave the product 2a in 95% yield (Table 1, entry 2).
The reaction also occurs at room temperature and much longer time is needed to get
full conversion. It should be noted that the pure product could be obtained in similar
yield without column chromatography (entry 2, in parentheses),15 and this is the first
example of intramolecular [3+2]-cycloaddition of hydrazones with unsymmetrical
internal alkynes with high selectivity control. Encouraged by these results, other bases
were also investigated, and only inferior results were obtained due to their solubility
and/or basicity under current conditions (Table 1, entries 4-7).16 Notably, the pure
solid product could be obtained via filtration and followed by washing with DCM
with comparable yield (entry 2, result in parentheses).
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Table 1. Optimization of Reaction Conditionsa
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Entry
Base
tBuOLi
tBuOLi
tBuOLi
CsF
Temp (oC)
Yield (%)b
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2
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7
50
60
70
60
60
60
60
41c
95 (94)d
87
70
NaOMe
NaOH
K2CO3
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50
a Reaction conditions: 1a (0.15 mmol), base (1.2 equiv) in 2.0 mL of 1,4-dioxane under
b
an atmosphere of argon at indicated temperature for 12 h. Isolated yields after
c
d
chromatography. Unreacted 1a was recovered. Yields after washing the filtered solid
product with DCM three times (3.0 mL× 3).
Under the optimized conditions, the substrate generality was tested, and the results
were shown in Table 2. The transformation proceeded smoothly with a wide range of
substrates and gave the desired products 2 in high to excellent yields. Higher yield is
obtained for substrates with para-substituted aryl at the terminal alkyne 2f) compared
to the ortho- or meta-substituted ones (2g-2h). The naphthyl-substituted compound 1i
and the substrates with fluorinated aryl linker are also well tolerated under these
conditions (2i-2k, >91% yields). The structure of this fused compound was confirmed
by the X-ray diffraction of its bromo-derivative 2e.17
Table 2. [3+2]-Cycloaddition for the Construction of 6,5,5-Tricyclic Pyrazolesa
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NNHTs
H
N
N
o
Ar
tBuOLi, 60 C, 12 h
R
R
N
Ar
Ar, 1,4-dioxane
2
1
H
N
H
N
N
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Ar
2i, 92%
2j, 91%
2a, Ar = Ph, 95%
H
N
F
2b, Ar = 4-CF3C6H4, >95%
2c, Ar = 4-FC6H4, 85%
2d, Ar = 4-ClC6H4, >95%
2e, Ar = 4-BrC6H4, >95%
2f, Ar = 4-MeC6H4, >95%
2g, Ar = 2-MeC6H4, 71%
2h, Ar = 3-MeC6H4,72%
N
Ph
H
N
N
F
Ph
2k, >95%
a Reaction conditions: 1 (0.15 mmol), tBuOLi (1.2 equiv, 14.4 mg) in
2.0 mL of 1,4-dioxane under an atmosphere of argon for 12 h.
To further explore the potential of this methodology, substrates using an
ether linker instead of methylene were also tested under the optimized conditions
(Table 3). In general, all the tested substrates gave the desired products in
excellent yields (>92% yields). Notably, substrate with terminal alkyne also
proceeded very well, and gave the corresponding product in >95% yield (4j). The
tautomers with the proton on the two different nitrogen-atoms were existing in
the products, which are inseparable by column chromatography.18 To distinguish
these two isomers, gram scale pure product 4a was prepared in >95% yield
without column chromatography under the standard conditions (Scheme 2). Then
the product was treated with p-toluenesulfonyl chloride (TsCl) under basic
1
conditions to give 5 and 5’ in 66:34 ratio (determined by H-NMR, and the ratio
is identical to 4a:4a’), which could be separated by column chromatography. The
structure of 5 was unambiguously determined by the X-ray diffraction, and the
structure of 4a could be deduced.17
Table 3. [3+2]-Cycloaddition for the Construction of 6,6,5-Tricyclic
Pyrazolesa
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H
N
N
R1
TsHN
R1
R1
+
HN
N
N
O
tBuOLi, 60 oC
R
1,4-dioxane
O
O
R
R
3
4
4'
N
N
N
H
N
H
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R1
R
O
O
R1 = 2-naphthyl, >95%, 4ib
R1 = H, >95%, 4jb
R = H, >95%, 4a:4a' = 34:66
R = Me, 95%, 4b:4b' = 31:69
R = OMe, >95%, 4c:4c' = 31:69
R = F, 92%, 4d:4d' = 37:63
R = Cl, >95%, 4e:4e' = 44:56
R = Br, >95%, 4f:4f' = 47:53
R = CF3, 93%, 4g:4g' = 58:42
R = COOMe, >95%, 4hb
N
N
H
R
O
R = 2-Me, >95%
4k:4k' = 35:65
R = 3-Me, >95%, 4lb
N
N
H
N
N
H
Cl
Cl
Ph
Br
Ph
O
O
>95%, 4m:4m' = 34:66
>95%, 4n:4n' = 37:63
a Reaction conditions: (0.15 mmol), tBuOLi (1.2 equiv, 14.4 mg) in 2.0
mL of 1,4-dioxane under an atmosphere of argon at 60 oC for 12 h.
b The ratio was not detected by 1H NMR.
3
Scheme 2.
Ts
N
N
N
TsCl, Bu4NHSO4
standard
Ph
Ts
O
O
NaOH (aq.)
DCM, rt
conditions
5
N
4a 4a'
:
3a
+
5.0 mmol
66:34
1.23 g, >95% yield
Ph
5'
5:5' = 66:34, 90% yield
In order to gain insight into the reaction mechanism, a control reaction was
carried out in an NMR tube with d8-dioxane as the solvent (Figure 2). A
corresponding proton signal of diazo compound intermediate D was detected at 5.43
ppm.19 Based on this observation and according to the previous reports,7-11, 19-20
a
plausible reaction mechanism is proposed in Scheme 3. First, the diazo compound D
was generated under basic conditions from N-tosylhydrazone.20 Then intramolecular
1,3-dipolar cycloaddition directly provided E. The desired products 2 or 4 were
formed via a direct H-shift aromatization (Scheme 2, path a), which was different
from previous aryl or alkyl [1,5]-sigmatropic rearrangement and aromatization
process reported by Valdés (Scheme 1A).8 In contrast, a stepwise pathway involving
base captured a proton from the hydrazone to generate anion A followed by addition
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with alkynyl and aromatization to give the final product could be totally ruled out so
far.21
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NNHTs
8
9
H
Ph
H
H
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1a
In NMR tube
tBuOLi 1.2 eq.
12 h, rt, D8-dioxane
N2
H
H
Ph
H
A
48 h
H
N
N
Ph
H
2a
H
Figure 2. Control experiments.
Scheme 3. Proposed Reaction Mechanism
In addition, product 2a was prepared on a gram scale under the optimization
condition in 90% yield without column chromatography (Scheme 4). And the utility
of this fused polycyclic pyrazole was demonstrated by various transformations to give
the corresponding derivatives. For example, the conversion of 2a to ketone 6 under
mild oxidative conditions proceeds in quantitative yield.3a Aza-Michael addition of 2a
with ethyl acrylate produced 7 in 90% yield in the presence of DBU.22 Besides,
compound 8 was reported to be synthesized from 2a in two steps, which is a
promising candidates in developing OAB drugs.23
Scheme 4. The Derivatization of 2a
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In conclusion, we have developed an intramolecular 1,3-dipolar cycloaddition
reaction of alkyne-tethered tosylhydrazones, which lead to a direct approach to the
selective synthesis of fused polycyclic pyrazoles in high to excellent yields. This
transition metal-free reaction is carried out under mild conditions and the pure
products are obtained without column chromatography. Notably, the reaction could be
carried out on gram scale with almost the same yields. The obtained polycyclic
products are very useful bioactive molecules, which take a few of steps to prepare by
other methods. And some of these could be used as a practical material to the
bioactive compounds in one or two steps.
EXPERIMENTAL SECTION
General. All reactions were carried out in oven-dried glassware under an atmosphere
of dry argon. Solvents were dried and degassed by the standard methods. Flash
column chromatography was performed using silica gel (300-400 mesh). Analytical
thin-layer chromatography was performed using glass plates pre-coated with 200-300
1
13
mesh silica gel impregnated with a fluorescent indicator (254 nm). H NMR and C
NMR spectra were recorded in CDCl3 on a 400 MHz spectrometer; chemical shifts
are reported in ppm with the solvent signals as reference, and coupling constants (J)
are given in Hertz. The peak information is described as: br = broad, s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, comp = composite. High-resolution
mass spectra (HRMS) were recorded on a commercial apparatus (ESI or CI Source).
General Procedure for the Synthesis of Alkyne-tethered N-Tosylhydrazones 1.
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Alkyne-tethered aldehydes were prepared from corresponding 2-bromobenzaldehyde
according to the procedures of the reported literature.24
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Synthesis of 1: To a 50-mL oven-dried flask containing a magnetic stirring bar,
alkyne-tethered aldehydes (3.0 mmol), p-toluenesulfonhydrazide (3.3 mmol, 613.8
mg) and methanol (15.0 mL) were added in sequence, and the reaction mixture was
stirred at 65 oC for 12 h. After the reaction was completed, the solvent was evaporated
and the residue was purified by column chromatography on silica gel
(Hexanes:EtOAc = 10:1~5:1) to provide the pure compound 1 as yellow solid
(80-90% yield).
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General Procedure for the Synthesis of Alkyne-tethered N-Tosylhydrazones 3.
Propargyl alcohol tethered aldehydes were prepared from corresponding
o-hydroxybenzaldehydes according to the procedures of the reported literature.25
Synthesis of 3: To a 50-mL oven-dried flask containing a magnetic stirring bar,
propargyl alcohol tethered aldehydes (3.0 mmol), p-toluenesulfonhydrazide (3.3
mmol, 613.8 mg) and methanol (15.0 mL) were added in sequence, and the mixture
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was stirred at 65 C for 12 h. After the reaction completed, half of the solvent was
evaporated and the residue was precipitated out from the cold methanol. The pure
compound 3 were obtained as white solid after filtration (> 90% yield).
4-Methyl-N'-[2-(3-phenylprop-2-yn-1-yl)benzylidene]benzenesulfonohydrazide (1a).
954.5 mg, 82% yield. Yellow solid, mp: 82.9-83.8 oC. 1H NMR (400 MHz, CDCl3) (δ,
ppm) δ 8.10 (s, 1 H), 7.90-7.87 (m, 2H), 7.63 (d, J = 7.3 Hz, 1H), 7.55 (d, J = 7.3 Hz,
1H), 7.40-7.25 (comp, 10H), 3.90 (s, 2H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3)
(δ, ppm) δ 146.9, 144.4, 135.7, 135.3, 131.7, 130.9, 130.3, 129.8, 129.5, 128.7, 128.3,
128.1, 128.0, 127.2, 123.5, 87.1, 83.7, 24.2, 21.7. HRMS (TOF MS CI+) calculated
for C23H21N2O2S [M+H]+: 389.1324, found 389.1319.
4-Methyl-N'-{2-[3-(4-(trifluoromethyl)phenyl]prop-2-yn-1-yl}benzylidene)benzenesulf
onohydrazide (1b). 1101.4 mg, 82% yield. White solid, mp: 124.0-125.9 oC. 1H NMR
(400 MHz, CDCl3) (δ, ppm) δ 8.07 (s, 1H), 7.98 (s, 1H), 7.88 (d, J = 8.3 Hz, 2H),
7.61 (d, J = 7.7 Hz, 1H), 7.55-7.47 (comp, 5H), 7.39-7.37 (m, 1H), 7.31-7.28 (comp,
3H), 3.94 (s, 2H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) (δ, ppm) δ 146.9, 144.5,
135.3, 135.2, 132.0, 131.0, 130.5, 129.9, 129.62, 129.57, 129.0, 128.1, 127.4, 125.4,
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125.2 (q, J = 3.7 Hz), 122.7, 89.9, 82.4, 24.4, 21.7. HRMS (TOF MS ESI+) calculated
for C24H20F3N2O2S [M+H]+: 457.1198, found 451.1189.
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N'-{2-[3-(4-Fluorophenyl)prop-2-yn-1-yl]benzylidene}-4-methylbenzenesulfonohydra
zide (1c). 974.4 mg, 80% yield. White solid, mp: 131.0-132.1 oC. 1H NMR (400 MHz,
CDCl3) (δ, ppm) δ 8.11 (s, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.60 (d, J = 7.6 Hz, 1H),
7.51 (d, J = 7.6 Hz, 1H), 7.37-7.31 (comp, 3H), 7.28-7.25 (comp, 4H), 6.95 (m, 2H),
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3.86 (s, 2H), 2.37 (s, 3H). C NMR (100 MHz, CDCl3) (δ, ppm) 162.2 (d, J = 250.1
Hz), 146.9, 144.4, 135.7, 135.3, 133.6 (d, J = 8.3 Hz), 131.0, 130.4, 129.8, 129.5,
128.7, 128.1, 127.2, 119.6 (d, J = 3.5 Hz), 115.5 (d, J =21.8 Hz), 86.8, 82.6, 24.2, 21.7.
HRMS (TOF MS CI+) calculated for C23H20FN2O2S [M+H]+: 407.1230, found
407.1229.
N'-{2-[3-(4-Chlorophenyl)prop-2-yn-1-yl]benzylidene}-4-methylbenzenesulfonohydra
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zide (1d). 1101.4 mg, 87% yield. White solid, mp: 118.4-119.8 C. H NMR (400
MHz, CDCl3) (δ, ppm) δ 8.40 (s, 1H), 8.10 (s, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.61 (d, J
= 7.4 Hz, 1H), 7.50 (d, J = 7.4 Hz, 1H), 7.35-7.29 (comp, 4H), 7.27-7.22 (comp, 4H),
3.88 (s, 2H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3) (δ, ppm) δ 146.9, 144.5,
135.5, 135.2, 133.9, 132.9, 131.0, 130.4, 129.8, 129.5, 128.8, 128.6, 128.1, 127.3,
122.0, 88.2, 82.6, 24.3, 21.7. HRMS (TOF MS ESI+) calculated for C23H20ClN2O2S
[M+H]+: 423.0934, found 423.0942.
N'-{2-[3-(4-bromophenyl)prop-2-yn-1-yl]benzylidene}-4-methylbenzenesulfonohydraz
ide (1e). 1202.3 mg, 86% yield. White solid, mp: 123.4-124.8 oC. 1H NMR (400 MHz,
CDCl3) (δ, ppm) δ 8.07 (s, 1H), 8.00 (s, 1H), 7.89-7.86 (m, 2H), 7.63-7.61 (m, 1H),
7.52-7.51 (m, 1H), 7.43-7.40 (m, 2H), 7.38-7.34 (m, 1H), 7.33-7.28 (comp, 3H),
7.25-7.23 (m, 2H), 3.89 (s, 2H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) (δ, ppm) δ
146.1, 143.9, 134.9, 134.7, 132.6, 131.0, 130.3, 129.9, 129.3, 129.1, 128.3, 128.2,
127.5, 126.8, 121.6, 87.1, 82.1, 23.8, 21.1. HRMS (TOF MS ESI+) calculated for
C23H20BrN2O2S [M+H]+: 467.3782, found 467.3785.
4-Methyl-N'-{2-[3-(p-tolyl)prop-2-yn-1-yl]benzylidene}benzenesulfonohydrazide (1f).
1025.1 mg, 85% yield. White solid, mp: 121.9-122.5 oC.1H NMR (400 MHz, CDCl3)
(δ, ppm) δ 8.15 (s, 1H), 8.10 (s, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 6.8 Hz, 1H),
7.54 (d, J = 6.8 Hz, 1H), 7.34 (m, 1H), 7.30-7.27 (comp, 5H), 7.09 (d, J = 8.3 Hz, 2H),
3.88 (s, 2H), 2.38 (s, 3H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3) (δ, ppm) δ 146.8,
144.5, 138.2, 136.0, 135.3, 131.6, 130.9, 130.5, 129.9, 129.7, 129.2, 128.7, 128.2,
127.2, 100.0, 86.2, 83.9, 24.3, 21.7, 21.6. HRMS (TOF MS ESI+) calculated for
C24H23N2O2S [M+H]+: 403.1480, found 403.1484.
4-Methyl-N'-{2-[3-(o-tolyl)prop-2-yn-1-yl]benzylidene}benzenesulfonohydrazide (1g).
976.9 mg, 81% yield. Yellow oil. 1H NMR (400 MHz, CDCl3) (δ, ppm) δ 8.12 (s, 1H),
7.89 (d, J = 8.3 Hz, 2H), 7.62-7.58 (m, 2H), 7.37-7.32 (comp, 3H), 7.28-7.25 (comp,
4H), 7.19-7.15 (m, 2H), 3.93 (s, 2H), 2.36 (comp, 6H). 13C NMR (100 MHz, CDCl3)
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(δ, ppm) δ 146.8, 144.5, 140.2, 136.0, 135.3, 132.0, 130.8, 130.5, 129.9, 129.6, 129.5,
128.8, 128.2, 128.1, 127.2, 125.6, 123.3, 90.9, 82.8, 24.5, 21.7, 20.9. HRMS (TOF
MS ESI+) calculated for C24H22N2NaO2S [M+Na]+: 425.1300, found 425.1288.
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988.9 mg, 82% yield. White solid, mp: 124.0-125.9 C. H NMR (400 MHz, CDCl3)
(δ, ppm) δ 8.43 (s, 1H), 8.14 (s, 1H), 7.93-7.91 (m, 2H), 7.64 (dd, J = 7.7, 1.3 Hz, 1H),
7.58 (d, J = 7.1 Hz, 1H), 7.39-7.36 (m, 2H), 7.32-7.28 (m, 4H), 7.22-7.18 (m, 2H),
7.14-7.12 (m, 1H), 3.91 (s, 2H), 2.41 (s, 3H), 2.34 (s, 3H). 13C NMR (100 MHz,
CDCl3) (δ, ppm) δ 146.8, 144.5, 138.1, 135.9, 135.3, 132.3, 130.9, 130.5, 129.9,
129.6, 129.0, 128.8, 128.7, 128.3, 128.2, 127.2, 123.3, 86.6, 86.4, 24.3, 21.7, 21.3.
HRMS (TOF MS ESI+) calculated for C24H23N2O2S [M+H]+: 403.1480, found
403.1486.
4-Methyl-N'-{2-[3-(naphthalen-1-yl)prop-2-yn-1-yl]benzylidene}benzenesulfonohydra
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zide (1i). 1182.6 mg, 90% yield. White solid, mp: 165.7-166.5 C. H NMR (400
MHz, DMSO) (δ, ppm) δ 11.62 (s, 1H), 8.33 (s, 1H), 8.15-8.13 (m, 1H), 7.95-7.90 (m,
2H), 7.75 (d, J = 8.1 Hz, 2H), 7.62 (t, J = 7.3 Hz, 2H), 7.55 (d, J = 6.1 Hz, 3H), 7.46
(t, J = 7.7 Hz, 1H), 7.40-7.36 (m, 1H), 7.32-7.29 (m, 3H), 4.08 (s, 2H), 2.26 (s, 3H);
13C NMR (100 MHz, DMSO) (δ, ppm) δ 145.3, 143.4, 136.2, 135.4, 132.8, 132.6,
131.4, 130.2, 130.1, 129.62, 129.60, 128.5, 128.4, 127.3, 127.2, 127.1, 127.0, 126.6,
125.48, 125.46, 120.3, 93.1, 80.5, 23.2, 20.9. HRMS (TOF MS ESI+) calculated for
C27H23N2O2S [M+H]+: 439.1480, found 439.1489.
N'-[2-Fluoro-6-(3-phenylprop-2-yn-1-yl)benzylidene]-4-methylbenzenesulfonohydrazi
de (1j). 1084.0 mg, 89% yield. White solid, mp: 114.1-115.0 oC. 1H NMR (400 MHz,
CDCl3) (δ, ppm) δ 8.13-8.12 (comp, 2H), 7.91 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 7.9 Hz,
1H), 7.46-7.44 (comp, 2H), 7.34-7.30 (m, 6H), 7.00-6.95 (m, 1H), 4.00 (s, 2H), 2.38
(s, 3H); 13C NMR (100 MHz, CDCl3) (δ, ppm) δ 162.2 (d, J = 250.1 Hz), 144.6, 141.8
(d, J = 8.1 Hz), 138.2, 135.1, 131.7, 131.1 (d, J = 9.7 Hz), 129.9, 128.4, 128.2, 128.0,
125.3 (d, J = 3.1 Hz), 123.7, 118.9 (d, J = 9.2 Hz), 114.0 (d, J = 22.1 Hz), 87.0, 83.8,
25.3, 21.7. HRMS (TOF MS ESI+) calculated for C23H20FN2O2S [M+H]+: 407.1230,
found 407.1227.
N'-[5-Fluoro-2-(3-phenylprop-2-yn-1-yl)benzylidene]-4-methylbenzenesulfonohydrazi
de (1k). 1084.0 mg, 89% yield. White solid, mp: 117.9-118.9 oC. 1H NMR (400 MHz,
CDCl3) (δ, ppm) δ 8.46 (s, 1H), 8.08 (d, J = 0.8 Hz, 1H), 7.89 (d, J = 8.3 Hz, 2H),
7.47 (dd, J = 8.5, 5.5 Hz, 1H), 7.39-7.36 (comp, 3H), 7.30-7.27 (comp, 5H), 7.03 (m,
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1H), 3.81 (s, 2H), 2.39 (s, 3H); C NMR (100 MHz, CDCl3) (δ, ppm) δ161.8 (d, J =
244.3 Hz), 144.81, 144.78, 144.7, 135.1, 132.8 (d, J = 7.7 Hz), 131.7, 131.5 (d, J =
3.0 Hz), 131.3 (d, J = 7.9 Hz), 129.9, 128.4, 128.1, 123.3, 117.3 (d, J = 21.4 Hz),
114.4 (d, J = 23.0 Hz), 86.7, 83.9, 23.5, 21.7. HRMS (TOF MS ESI+) calculated for
C23H20FN2O2S [M+H]+: 407.1230, found 407.1225.
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(3a). 1151.4 mg, 95% yield. White solid, mp: 125.1-126.5 C. H NMR (400 MHz,
CDCl3) (δ, ppm) δ 8.21 (s, 1H), 7.88-7.86 (comp, 4H), 7.41-7.28 (comp, 8H),
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7.05-6.97 (comp, 2H), 4.91 (s, 2H), 2.38 (s, 3H); C NMR (100 MHz, CDCl3) (δ,
ppm) δ 156.2, 144.2, 143.7, 135.5, 131.9, 131.7, 129.8, 129.0, 128.5, 128.1, 126.9,
122.5, 122.1, 121.8, 112.8, 87.8, 83.4, 57.3, 21.7. HRMS (TOF MS ESI+) calculated
for C23H21N2O3S [M+H]+: 405.1273, found 405.1268.
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(3b). 1203.8 mg, 96% yield. White solid, mp: 153.7-154.6 C. H NMR (400 MHz,
CDCl3) (δ, ppm) δ 8.20 (s, 1H), 7.88-7.85 (comp, 3H), 7.37-7.28 (comp, 5H), 7.10 (d,
J = 8.0 Hz, 2H), 7.05-6.97 (m, 2H), 4.90 (s, 2H), 2.39 (s, 3H), 2.34 (s, 3H); 13C NMR
(100 MHz, CDCl3) (δ, ppm) δ 156.3, 144.2, 143.7, 139.2, 135.5, 131.8, 131.7, 129.8,
129.2, 128.1, 126.8, 122.5, 121.73, 119.0, 112.9, 88.0, 82.7, 57.4, 21.7, 21.6. HRMS
(TOF MS ESI+) calculated for C24H23N2O3S [M+H]+: 419.1429, found 419.1411.
N'-{2-[(3-(4-Methoxyphenyl)prop-2-yn-1-yl)oxy]benzylidene}-4-methylbenzenesulfon
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ohydrazide (3c). 1276.0 mg, 98% yield. White solid, mp: 181.6-182.9 C. H NMR
(400 MHz, DMSO) (δ, ppm) δ 11.42 (s, 1H), 8.25 (s, 1H), 7.75(d, J = 8.2 Hz, 2H),
7.63 (d, J = 8.3 Hz, 1H), 7.41-7.36 (comp, 5H), 7.18 (d, J = 8.3 Hz, 1H), 7.00 (t, J =
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7.5 Hz, 1H), 6.93 (d, J = 8.2 Hz, 2H), 5.06 (s, 2H), 3.76 (s, 3H), 2.34 (s, 3H); C
NMR (100 MHz, DMSO) (δ, ppm) δ 159.8, 155.6, 143.4, 142.2, 136.2, 133.2, 131.4,
129.7, 127.2, 125.3, 122.3, 121.5, 114.4, 113.5, 113.3, 86.9, 83.0, 57.0, 55.3, 21.0.
HRMS (TOF MS ESI+) calculated for C24H23N2O4S [M+H]+: 435.1379, found
435.1380.
N'-{2-[(3-(4-Fluorophenyl)prop-2-yn-1-yl)oxy]benzylidene}-4-methylbenzenesulfonoh
ydrazide (3d). 1164.7 mg, 92% yield. White solid, mp: 163.8-164.9 oC. 1H NMR (400
MHz, CDCl3) (δ, ppm) δ 8.20 (s, 1H), 7.89-7.85 (comp, 4H), 7.40-7.35 (comp, 3H),
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7.29 (d, J = 8.0 Hz, 2H), 7.03-6.96 (comp, 4H), 4.89 (s, 2H), 2.39 (s, 3H); C NMR
(100 MHz, CDCl3) (δ, ppm) δ163.0 (d, J = 248.9 Hz), 156.2, 144.3, 143.6, 135.5,
133.9 (d, J = 8.5 Hz), 131.7, 129.8, 128.1, 126.9, 122.5, 121.9, 118.1 (d, J = 3.5 Hz),
115.8 (d, J = 21.9 Hz), 112.8, 86.8, 83.1, 57.3, 21.7. HRMS (TOF MS ESI+)
calculated for C23H20FN2O3S [M+H]+: 423.1179, found 423.1159.
N'-{2-[3-(4-Chlorophenyl)prop-2-yn-1-yl)oxy]benzylidene}-4-methylbenzenesulfonoh
ydrazide (3e). 1235.2 mg, 94% yield. White solid, mp: 177.0-178.9 oC. 1H NMR (400
MHz, CDCl3) (δ, ppm) δ 8.20 (s, 1H), 8.01 (s, 1H), 7.88-7.85 (m, 3H), 7.34-7.25 (m,
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7H), 7.02-6.97 (m, 2H), 4.89 (s, 2H), 2.38 (s, 3H); C NMR (100 MHz, CDCl3) (δ,
ppm) δ 156.2, 144.2, 143.7, 135.5, 135.1, 133.1, 131.7, 129.8, 128.8, 128.1, 126.9,
122.6, 121.9, 120.5, 112.8, 86.7, 84.4, 57.2, 21.7. HRMS (TOF MS ESI+) calculated
for C23H20ClN2O3S [M+H]+: 439.0883, found 439.0872.
N'-{2-[(3-(4-Bromophenyl)prop-2-yn-1-yl)oxy]benzylidene}-4-methylbenzenesulfonoh
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ydrazide (3f). 1344.8 mg, 93% yield. White solid, mp: 179.0-180.9 oC. 1H NMR (400
MHz, CDCl3) (δ, ppm) δ 8.19 (s, 1H), 7.87 (d, J = 8.4 Hz, 3H), 7.78 (s, 1H),
7.45-7.41 (m, 2H), 7.37-7.33 (m, 1H), 7.30 (d, J = 8.1 Hz, 2H), 7.24 (s, 1H),
7.03-6.98 (m, 2H), 4.89 (s, 2H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3) (δ, ppm) δ
156.2, 144.3, 143.6, 135.5, 133.3, 131.8, 131.7, 129.8, 128.1, 127.0, 123.4, 122.6,
121.9, 121.0, 112.8, 86.8, 84.6, 57.3, 21.7. HRMS (TOF MS ESI+) calculated for
C23H20BrN2O3S [M+H]+: 483.0378, found 483.0381.
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4-Methyl-N'-{2-[(3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-yl)oxy]benzylidene}benze
nesulfonohydrazide (3g). 1316.8 mg, 93% yield. White solid, mp: 160.6-161.9 oC. 1H
NMR (400 MHz, CDCl3) (δ, ppm) δ 8.22 (s, 1H), 7.87 (comp, 3H), 7.56 (d, J = 8.2
Hz, 2H), 7.50 (d, J = 8.2 Hz, 2H), 7.37 (t, J = 7.9 Hz, 1H), 7.30 (d, J = 8.2 Hz, 2H),
7.02 (m, 2H), 4.94 (s, 2H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3) (δ, ppm) δ
156.1, 144.3, 143.6, 135.5, 132.2, 131.7, 130.9, 130.6, 129.8, 128.1, 127.0, 125.9,
125.3 (q, J = 16.0 Hz), 122.6, 122.0, 112.8, 86.4, 85.8, 57.2, 21.7. HRMS (TOF MS
ESI+) calculated for C24H20F3N2O3S [M+H]+: 473.1147, found 473.1158.
4-Methyl-{3-[2-((2-tosylhydrazono)methyl)phenoxy]prop-1-yn-1-yl}benzoate
(3h).
1344.4 mg, 97% yield. White solid, mp: 202.8-203.1 oC. 1H NMR (400 MHz, CDCl3)
(δ, ppm) δ 8.20 (s, 1H), 7.97 (d, J = 8.5 Hz, 2H), 7.88-7.86 (comp, 3H), 7.76 (s, 1H),
7.45 (d, J = 8.4 Hz, 2H), 7.38-7.34 (m, 1H), 7.30 (d, J = 8.1 Hz, 2H), 7.04-6.99 (m,
2H), 4.93 (s, 2H), 3.91 (s, 3H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3) (δ, ppm) δ
166.5, 156.2, 144.3, 143.8, 135.5, 131.9, 131.8, 130.3, 129.8, 129.6, 128.1, 127.1,
126.7, 122.4, 122.0, 112.78, 87.0, 86.2, 57.2, 52.5, 21.7. HRMS (TOF MS ESI+)
calculated for C25H23N2O5S [M+H]+: 463.1328, found 463.1329.
4-Methyl-N'-{2-[(3-(naphthalen-1-yl)prop-2-yn-1-yl)oxy]benzylidene}benzenesulfono
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hydrazide (3i). 1297.0 mg, 95% yield. White solid, mp: 156.9-157.9 C. H NMR
(400 MHz, CDCl3) (δ, ppm) δ 8.25 (s, 1H), 8.15-8.12 (m, 1H), 7.90-7.82 (comp, 6H),
7.63 (d, J = 7.1 Hz, 1H), 7.51-7.49 (m, 2H), 7.42-7.36 (m, 2H), 7.27-7.25 (m, 2H),
7.15 (d, J = 8.3 Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 5.07 (s, 2H), 2.36 (s, 3H); 13C NMR
(100 MHz, CDCl3) (δ, ppm) δ 156.2, 144.2, 143.7, 135.5, 133.4, 133.2, 131.7, 131.0,
129.8, 129.5, 128.5, 128.1, 127.1, 126.9, 126.7, 126.0, 125.2, 122.7, 121.9, 119.7,
113.1, 88.2, 86.1, 57.5, 21.7. HRMS (TOF MS ESI+) calculated for C27H23N2O3S
[M+H]+: 455.1429, found 455.1421.
4-Methyl-N'-[2-(prop-2-yn-1-yloxy)benzylidene]benzenesulfonohydrazide (3j). 934.8
mg, 95% yield. White solid, mp: 89.9-91.2 oC. 1H NMR (400 MHz, CDCl3) (δ, ppm)
δ 8.16 (s, 1H), 7.88-7.84 (comp, 3H), 7.36-7.27 (comp, 3H), 7.01-6.95 (m, 2H), 4.69
(d, J = 2.4 Hz, 2H), 2.50 (t, J = 2.4 Hz, 1H), 2.40 (s, 3H); 13C NMR (100 MHz,
CDCl3) (δ, ppm) δ 155.9, 144.3, 143.5, 135.5, 131.6, 129.8, 128.1, 126.9, 122.6,
122.0, 112.7, 78.1, 76.2, 56.4, 21.7. HRMS (TOF MS ESI+) calculated for
C17H17N2O3S [M+H]+: 329.0960, found 329.0961.
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(3k). 1141.1 mg, 91% yield. White solid, mp: 162.7-163.2 C. H NMR (400 MHz,
CDCl3) (δ, ppm) δ 8.21 (s, 1H), 7.87 (comp, 3H), 7.37-7.33 (m, 2H), 7.29 (d, J = 8.1
Hz, 2H), 7.25-7.07 (comp, 5H), 7.00 (t, J = 7.6 Hz, 1H), 4.97 (s, 2H), 2.39 (s, 3H),
2.32 (s, 3H); 13C NMR (100 MHz, CDCl3) (δ, ppm) δ 156.2, 144.3, 143.7, 140.6,
135.5, 132.3, 131.7, 129.8, 129.6, 129.0, 128.1, 126.9, 125.7, 122.5, 121.9, 121.8,
113.0, 87.2, 86.9, 57.3, 21.7, 20.7. HRMS (TOF MS ESI+) calculated for
C24H23N2O3S [M+H]+: 419.1429, found 419.1409.
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e (3l). 1128.6 mg, 90% yield. White solid, mp: 134.7-135.4 C. H NMR (400 MHz,
CDCl3) (δ, ppm) δ 8.21 (s, 1H), 7.88-7.85 (comp, 3H), 7.37-7.33 (m, 1H), 7.29 (d, J =
8.0 Hz, 2H), 7.23-7.18 (comp, 3H), 7.15 (t, J = 7.0 Hz, 1H), 7.05-6.97 (m, 2H), 4.90
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(s, 2H), 2.39 (s, 3H), 2.31 (s, 3H); C NMR (100 MHz, CDCl3) (δ, ppm) δ 156.3,
144.3, 143.7, 138.2, 135.5, 132.5, 131.7, 129.9, 129.8, 129.0, 128.4, 128.1, 126.9,
122.5, 121.9, 121.8, 112.8, 88.0, 83.0, 57.4, 21.7, 21.3. HRMS (TOF MS ESI+)
calculated for C24H23N2O3S [M+H]+: 419.1429, found 419.1426.
N'-{4,5-Dichloro-2-[(3-phenylprop-2-yn-1-yl)oxy]benzylidene}-4-methylbenzenesulfo
nohydrazide (3m). 1359.4 mg, 96% yield. White solid, mp: 101.7-102.4 oC. 1H NMR
(400 MHz, CDCl3) (δ, ppm) δ 8.20 (s, 1H), 7.83 (d, J = 8.3 Hz, 2H), 7.78 (d, J = 2.6
Hz, 1H), 7.42 (d, J = 2.6 Hz, 1H), 7.36-7.28 (comp, 7H), 4.95 (s, 2H), 2.43 (s, 3H);
13C NMR (100 MHz, CDCl3) (δ, ppm) δ 150.7, 144.0, 141.1, 134.7, 131.1, 131.0,
130.3, 130.2, 129.3, 128.7, 128.6, 128.0, 127.4, 124.2, 121.0, 88.8, 82.3, 61.9, 21.2.
HRMS (TOF MS ESI+) calculated for C23H19Cl2N2O3S [M+H]+: 473.0493, found
473.0496.
N'-{5-Bromo-2-[(3-phenylprop-2-yn-1-yl)oxy]benzylidene}-4-methylbenzenesulfonohy
drazide (3n). 1359.2 mg, 94% yield. White solid, mp: 143.0-143.7 oC. 1H NMR (400
MHz, CDCl3) (δ, ppm) δ 8.11 (comp, 2H), 7.94 (d, J = 2.5 Hz, 1H), 7.87 (d, J = 8.3
Hz, 2H), 7.43-7.37 (comp, 3H), 7.33-7.29 (comp, 5H), 6.93 (d, J = 8.3 Hz, 1H), 4.89
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(s, 2H), 2.40 (s, 3H); C NMR (100 MHz, CDCl3) (δ, ppm) δ 155.1, 144.5, 142.0,
135.4, 134.0, 131.9, 129.9, 129.3, 129.1, 128.5, 128.1, 124.4, 121.8, 114.7, 114.5,
88.2, 82.9, 57.5, 21.7. HRMS (TOF MS ESI+) calculated for C23H20BrN2O3S [M+H]+:
483.0378, found 483.0382.
General Procedure for 1,3-Dipolar [3+2]-Cycloaddition Reactions. To a 10-mL
oven-dried vial containing a magnetic stirring bar, compound 1 (or 3, 0.15 mmol), the
base tBuOLi ( 1.2 equiv, 14.4 mg) and 1,4-dioxane (2.0 mL) were added in sequence
under an atmosphere of argon, and the mixture was stirred at 60 oC for 12 h. After the
reaction was completed, the mixture was quenched by the addition of saturated brine
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and extracted with EtOAc (3×10 mL). The combined organic phases were dried over
Na2SO4, filtered and concentrated in vacuo to provide a crude residue, which was
purified by washing with dichloromethane for three times (3.0 mL×3) to give the
pure product in high yields. Further purification is necessary in some cases by
recrystalization in DCM, including 2c, 2g and 2h (the crude product was dissolved in
5~10 mL of warm DCM, and after most of the solvent was volatilize under open air at
room temperature, about 1-2 mL left over, the pure product was obtained by
filtration).
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3-Phenyl-1, 4-dihydroindeno[1, 2-c]pyrazole (2a). 33.1 mg, 95% yield. Yellow solid,
o
mp: 238.9-241.9 C.26a 1H NMR (400 MHz, DMSO) (δ, ppm) δ 13.24 (s, 1H),
7.84-7.82 (m, 2H), 7.69-7.67 (m, 1H), 7.57-7.56 (m, 1H), 7.50 (t, J = 7.5 Hz, 2H),
7.38-7.33 (m, 2H), 7.31-7.27 (m, 1H), 3.86 (s, 2H); 13C NMR (100 MHz, DMSO) (δ,
ppm) δ 159.8, 148.3, 135.7, 134.8, 129.6, 129.1, 127.7, 126.9, 126.3, 126.1, 125.2,
120.6, 119.3, 29.2. HRMS (TOF MS ESI+) calculated for C16H13N2 [M+H]+: 233.1079,
found 233.1086.
3-[4-(Trifluoromethyl)phenyl]-1,4-dihydroindeno[1,2-c]pyrazole (2b). 44.1 mg, >95%
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yield. Yellow solid, mp: 278.5-279.6 C. H NMR (400 MHz, DMSO) (δ, ppm) δ
13.48 (s, 1H), 8.02 (s, 2H), 7.84 (s, 2H), 7.69 (s, 1H), 7.58-7.56 (m, 1H), 7.39-7.36 (m,
1H), 7.32-7.28 (m, 1H), 3.89 (s, 2H); 13C NMR (100 MHz, DMSO) (δ, ppm) δ 160.0,
148.2, 137.7, 134.5, 133.4, 131.3, 126.9, 126.5-125.7 (multi-C), 122.9, 122.0, 119.4,
118.9, 29.2. HRMS (TOF MS ESI+) calculated for C17H12F3N2 [M+H]+: 301.0953,
found 301.0963.
3-(4-Fluorophenyl)-1, 4-dihydroindeno[1, 2-c]pyrazole (2c). 31.9 mg, 85% yield.
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Yellow solid, mp: 239.7-242.3 C. H NMR (400 MHz, DMSO) (δ, ppm) δ 13.24 (s,
1H), 7.86 (s, 2H), 7.67 (s, 1H), 7.58-7.56 (m, 1H), 7.39-7.27 (comp, 4H), 3.85 (s, 2H);
13C NMR (100 MHz, DMSO) (δ, ppm) δ161.6 (d, J = 243.3 Hz), 159.8, 148.3, 134.8
(d, J = 10.6 Hz), 127.3, 127.2, 126.9, 126.3, 126.2, 126.1, 120.4 (d, J = 9.8 Hz), 119.3,
116.0 (d, J = 21.2 Hz), 29.1. HRMS (TOF MS ESI+) calculated for C16H12FN2
[M+H]+: 251.0985, found 251.0976.
3-(4-Chlorophenyl)-1, 4-dihydroindeno[1, 2-c]pyrazole (2d). 39.2 mg, >95% yield.
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Yellow solid, mp: 262.3-263.9 C. H NMR (400 MHz, DMSO) (δ, ppm) δ 13.29 (s,
1H), 7.83-7.81 (m, 2H), 7.70-7.56 (comp, 4H), 7.39-7.35 (m, 1H), 7.32-7.28 (m, 1H),
3.87 (s, 2H); 13C NMR (100 MHz, DMSO) (δ, ppm) δ 159.9, 148.2, 134.6, 132.2,
129.1, 128.8, 128.5, 126.9, 126.8, 126.4, 126.1, 121.0, 119.3, 29.1. HRMS (TOF MS
ESI+) calculated for C16H12ClN2 [M+H]+: 267.0689, found 267.0679.
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3-(4-Bromophenyl)-1, 4-dihydroindeno[1, 2-c]pyrazole (2e). 46.2 mg, >95% yield.
Yellow solid. 1H NMR (400 MHz, DMSO) (δ, ppm) δ 13.34 (s, 1H), 7.78-7.68 (comp,
5H), 7.57-7.56 (m, 1H), 7.39-7.35 (m, 1H), 7.31-7.27 (m, 1H), 3.85 (s, 2H); 13C NMR
(100 MHz, DMSO) (δ, ppm) δ 159.8, 148.2, 134.6, 132.0, 129.1, 128.8, 127.2, 126.9,
126.4, 126.1, 121.0, 120.7, 119.3, 29.1. HRMS (TOF MS ESI+) calculated for
C16H12BrN2 [M+H]+: 311.0184, found 311.0179.
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3-(p-Tolyl)-1, 4-dihydroindeno[1, 2-c]pyrazole (2f). 36.6 mg, >95% yield. Yellow
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solid, mp: 254.1-255.5 C.26b 1H NMR (400 MHz, DMSO) (δ, ppm) δ 13.14 (s, 1H),
7.71–7.67 (comp, 3H), 7.58-7.56 (m, 1H), 7.38-7.27 (comp, 4H), 3.85 (s, 2H), 2.35 (s,
3H); 13C NMR (100 MHz, DMSO) (δ, ppm) δ 159.7, 148.3, 137.2, 135.8, 134.8,
129.6, 126.9, 126.3, 126.1, 125.2, 125.1, 120.1, 119.3, 29.1, 20.9. HRMS (TOF MS
ESI+) calculated for C17H15N2 [M+H]+: 247.1235, found 247.1227.
3-(o-Tolyl)-1, 4-dihydroindeno[1, 2-c]pyrazole (2g). 26.2 mg, 71% yield. Yellow oil.
1H NMR (400 MHz, CDCl3) (δ, ppm) δ 7.77 (d, J = 7.4 Hz, 1H), 7.51-7.47 (m, 2H),
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7.38-7.28 (comp, 5H), 3.69 (s, 2H), 2.46 (s, 3H); C NMR (100 MHz, CDCl3) (δ,
ppm) δ 148.5, 136.5, 134.8, 131.13, 131.10, 129.9, 129.3, 128.9, 127.1, 126.9, 126.3,
125.9, 122.9, 120.4, 120.3, 30.0, 20.8. HRMS (TOF MS ESI+) calculated for
C17H15N2 [M+H]+: 247.1235, found 247.1248.
3-(m-Tolyl)-1, 4-dihydroindeno[1, 2-c]pyrazole (2h). 26.6 mg, 72% yield. Yellow
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solid, mp: 230.4-232.9 C. H NMR (400 MHz, DMSO) (δ, ppm) δ 13.17 (s, 1H),
7.65-7.56 (comp, 4H), 7.39-7.35 (m, 2H), 7.31-7.27 (m, 1H), 7.18-7.16 (m, 1H), 3.87
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(s, 2H), 2.39 (s, 3H); C NMR (100 MHz, DMSO) (δ, ppm) δ 159.7, 148.3, 138.2,
135.7, 134.8, 129.6, 128.9, 128.3, 126.9, 126.2, 126.1, 125.8, 122.3, 120.5, 119.2,
29.3, 21.2. HRMS (TOF MS ESI+) calculated for C17H15N2 [M+H]+: 247.1235, found
247.1236.
3-(Naphthalen-1-yl)-1,4-dihydroindeno[1,2-c]pyrazole (2i). 39.0 mg, 92% yield.
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Yellow solid, mp: 91.4-98.6 C. H NMR (400 MHz, CDCl3) (δ, ppm) δ 11.37 (br,
1H), 8.10 (d, J = 8.1 Hz, 1H), 7.93-7.88 (m, 2H), 7.65-7.63 (m, 1H), 7.55-7.44 (comp,
5H), 7.29-7.20 (m, 2H), 3.66 (s, 2H); 13C NMR (100 MHz, CDCl3) (δ, ppm) δ 159.0,
147.9, 136.6, 134.0, 133.3, 130.7, 128.7, 128.1, 127.8, 126.7, 126.4, 126.23, 126.16,
125.8, 125.3, 125.0, 124.9, 123.3, 119.7, 29.2. HRMS (TOF MS ESI+) calculated for
C20H15N2 [M+H]+: 283.1235, found 283.1244.
8-Fluoro-3-phenyl-1, 4-dihydroindeno[1, 2-c]pyrazole (2j). 34.2 mg, 91% yield.
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Yellow solid, mp: 272.1-273.6 C. H NMR (400 MHz, DMSO) (δ, ppm) δ 13.37 (s,
1H), 7.83-7.81 (m, 2H), 7.51-7.49 (m, 2H), 7.49-7.32 (comp, 3H), 7.22-7.18 (m, 1H),
3.96 (s, 2H); 13C NMR (100 MHz, DMSO) (δ, ppm) δ 166.9, 156.8, 151.5, 135.7,
131.7 (d, J = 14.4 Hz), 129.4, 129.1, 128.7, 128.1 (d, J = 28.8 Hz), 125.3, 122.3,
120.4, 113.8 (d, J = 19.0 Hz), 29.5. HRMS (TOF MS ESI+) calculated for C16H12FN2
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[M+H]+: 251.0985, found 251.0986.
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7-Fluoro-3-phenyl-1, 4-dihydroindeno[1, 2-c]pyrazole (2k). 37.2 mg, >95% yield.
Yellow solid, mp: 272.1-273.6. 1H NMR (400 MHz, DMSO) (δ, ppm) δ 13.36 (s, 1H),
7.83-7.81 (m, 2H), 7.59-7.56 (m, 1H), 7.53-7.45 (comp, 3H), 7.39-7.35 (m, 1H),
7.14-7.09 (m, 1H), 3.86 (s, 2H); 13C NMR (100 MHz, DMSO) (δ, ppm) δ161.8 (d, J =
239.2 Hz), 157.1, 144.0, 138.0, 136.5 (d, J = 9.4 Hz), 131.0, 129.0, 127.4, 127.2 ( d, J
= 9.1 Hz), 125.1, 122.3, 112.2 (d, J = 22.5 Hz), 106.0 (d, J = 23.8 Hz), 28.8. HRMS
(TOF MS ESI+) calculated for C16H12FN2 [M+H]+: 251.0985, found 251.0995.
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(4a+4a’)27 36.9 mg, >95% yield. White solid, mp: 254.4-256.1. 4a: 1H NMR (400
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MHz, DMSO) (δ, ppm) δ 13.39 (s, 1H), 7.66-6.95 (comp, 9H), 5.52 (s, 2H); 4a’: H
NMR (400 MHz, DMSO) (δ, ppm) δ 13.54, (s, 1H), 7.66-6.95 (comp, 9H), 5.52 (s,
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2H); C NMR (100 MHz, DMSO, + Cs2CO3) (δ, ppm) δ 152.9, 140.2 131.6 128.9
(2C), 128.6, 127.4, 126.0, 121.7, 121.5, 118.2, 116.6, 107.9, 64.6. HRMS (TOF MS
ESI+) calculated for C16H13N2O [M+H]+: 249.1082, found 249.1088.
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(4b+4b’). 37.4 mg, 95% yield. White solid, mp: 273.7-274.6 C. 4b: 1H NMR (400
MHz, DMSO) (δ, ppm) δ 13.30 (s, 1H), 7.66-6.95 (comp, 8H), 5.50 (s, 2H), 2.34 (s,
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3H); 4b’: H NMR (400 MHz, DMSO) (δ, ppm) δ 13.48 (s, 1H), 7.66-6.95 (comp,
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8H), 5.50 (s, 2H), 2.34 (s, 3H); C NMR (100 MHz, DMSO, + Cs2CO3) (δ, ppm) δ
153.0, 140.3, 137.0, 129.5, 128.7, 128.3, 125.9, 121.7, 121.5, 118.1, 116.7, 107.7,
64.45, 20.83. HRMS (TOF MS ESI+) calculated for C17H15N2O [M+H]+: 263.1184,
found 263.1183.
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(4c+4c’). 40.9 mg, >95% yield. White solid, mp: 228.1-229.7 C. 4c: 1H NMR (400
MHz, DMSO) (δ, ppm) δ 13.23 (s, 1H), 7.66-6.94 (comp, 8H), 5.47 (s, 2H), 3.80 (s,
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3H); 4c’: H NMR (400 MHz, DMSO) (δ, ppm) δ 13.44 (s, 1H), 7.66-6.94 (comp,
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8H), 5.55 (s, 2H), 3.80 (s, 3H); C NMR (100 MHz, DMSO, + Cs2CO3) (δ, ppm) δ
158.2, 152.6, 141.0, 140.4, 127.8, 127.1, 125.5, 121.5, 121.3, 119.4, 116.4, 114.2,
106.8, 65.10, 55.15. HRMS (TOF MS ESI+) calculated for C17H15N2O2 [M+H]+:
279.1134, found 279.1148.
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(4d+4d’). 36.7 mg, 92% yield. White solid, mp: 267.6-269.6 C. 4d: 1H NMR (400
MHz, DMSO) (δ, ppm) δ 13.35 (s, 1H), 7.62-6.95 (comp, 8H), 5.49 (s, 2H); 4d’: 1H
NMR (400 MHz, DMSO) (δ, ppm) δ 13.55 (s, 1H), 7.62-6.95 (comp, 8H), 5.56 (s,
2H); 13C NMR (100 MHz, DMSO, + Cs2CO3) (δ, ppm) δ161.8 (d, J = 243.9 Hz),
153.0, 144.0, 141.3, 129.3, 128.3 (d, J = 8.2 Hz), 123.8, 121.8, 121.6, 116.8, 116.0 (d,
J = 21.7 Hz), 108.1, 99.5, 64.1. HRMS (TOF MS ESI+) calculated for C16H12FN2O
[M+H]+: 267.0934, found 267.0948.
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(4e+4e’). 40.7 mg, >95% yield. White solid, mp: 262.1-267.9 C. 4e: 1H NMR (400
MHz, DMSO) (δ, ppm) δ 13.35 (s, 1H), 7.53-6.83 (comp, 8H), 5.41 (s, 2H); 4e’: 1H
NMR (400 MHz, DMSO) (δ, ppm) δ 13.55 (s, 1H), 7.53-6.83 (comp, 8H), 5.41 (s,
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2H); C NMR (100 MHz, DMSO, + Cs2CO3) (δ, ppm) δ 153.0, 140.0, 139.7, 132.5,
129.4, 129.0 (2C), 127.8, 124.1, 121.8, 121.6, 116.8, 108.4, 64.1. HRMS (TOF MS
ESI+) calculated for C16H12ClN2O [M+H]+: 283.0638, found 283.0646.
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(4f+4f’). 48.6 mg, >95% yield. White solid, mp: 275.7-277.8 C. 4f: 1H NMR (400
MHz, DMSO) (δ, ppm) δ 13.47 (s, 1H), 7.66-6.94 (comp, 8H), 5.49 (s, 2H); 4f’: 1H
NMR (400 MHz, DMSO) (δ, ppm) δ 13.70 (s, 1H), 7.66-6.94 (comp, 8H), 5.56 (s,
2H); C NMR (100 MHz, DMSO, + Cs2CO3) (δ, ppm) δ 152.9, 140.3, 139.5, 131.9,
130.8, 129.3, 129.2, 128.1, 121.8, 121.6, 120.9, 116.7, 108.3, 64.2. HRMS (TOF MS
ESI+) calculated for C16H12BrN2O [M+H]+: 327.0133, found 327.0139.
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(4g+4g’). 44.1 mg, 93% yield. White solid, mp: 237.7-246.5 C. 4g: 1H NMR (400
MHz, DMSO) (δ, ppm) δ 13.61 (s, 1H), 7.81-6.96 (comp, 8H), 5.60 (s, 2H); 4g’: 1H
NMR (400 MHz, DMSO) (δ, ppm) δ 13.75 (s, 1H), 7.81-6.96 (comp, 8H), 5.60 (s,
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2H); C NMR (100 MHz, DMSO, + Cs2CO3) (δ, ppm) δ 152.9, 140.4, 139.2, 135.4,
129.4, 128.0, 127.7, 126.7, 125.9-125.6 (multi-C), 125.6, 122.9, 121.8, 121.6, 116.8,
109.0, 64.3. HRMS (TOF MS ESI+) calculated for C17H12F3N2O [M+H]+: 317.0902,
found 317.0901.
(4h). 44.6 mg, >95% yield. White solid, mp: 263.3-264.9 C. 1H NMR (400 MHz,
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DMSO) (δ, ppm) δ 13.70 (br, 1H), 8.04-6.95 (comp, 8H), 5.58 (s, 2H), 3.86 (s, 3H);
13C NMR (100 MHz, DMSO, + Cs2CO3) (δ, ppm) δ 165.9, 152.9, 135.5, 129.9,
129.5-129.4 (3C), 128.6, 126.2, 121.9, 121.7, 116.8, 106.3, 94.8, 64.2, 52.2. HRMS
(TOF MS ESI+) calculated for C18H15N2O3 [M+H]+: 307.1083, found 307.1085.
(4i). 44.3 mg, >95% yield. White solid, mp: 97.3-101.0 C. 1H NMR (400 MHz,
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CDCl3) (δ, ppm) δ 10.75 (br, 1H), 7.87-6.75 (comp, 8H), 5.15 (s, 2H); 13C NMR (100
MHz, CDCl3) (δ, ppm) δ 154.1, 142.8, 138.7, 133.8, 131.2, 129.7, 129.6, 128.7, 127.7,
127.1, 127.0, 126.4, 125.3, 124.9, 122.6, 122.0, 117.8, 117.2, 111.2, 64.1. HRMS
(TOF MS ESI+) calculated for C20H15N2O [M+H]+: 299.1184, found 299.1185.
(4j). 25.6 mg, >95% yield. White solid, mp: 158.4-163.1 C. 1H NMR (400 MHz,
CDCl3) (δ, ppm) δ 7.68-6.95 (comp, 5H), 5.31 (s, 2H); C NMR (100 MHz, CDCl3)
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(δ, ppm) δ 154.1, 142.0, 129.6, 125.8, 122.3, 121.9, 117.8, 117.4, 111.7, 63.9. HRMS
(TOF MS ESI+) calculated for C10H9N2O [M+H]+: 173.0715, found 173.0718.
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(4k+4k’). 39.0 mg, >95% yield. White solid, mp: 221.0-222.9 C. 4k: 1H NMR (400
MHz, DMSO) (δ, ppm) δ 13.32 (s, 1H), 7.69-6.95 (comp, 8H), 5.50 (s, 2H), 2.37 (s,
3H); 4k’: 1H NMR (400 MHz, DMSO) (δ, ppm) δ 13.53 (s, 1H), 7.69-6.95 (comp,
8H), 5.59 (s, 2H), 2.37 (s, 3H); C NMR (100 MHz, DMSO, + Cs2CO3) (δ, ppm) δ
153.1, 140.3, 138.3, 129.2, 128.9, 128.7, 126.6, 126.4, 123.3, 121.8, 121.6, 116.8,
116.7, 108.2, 107.8, 64.2, 21.1. HRMS (TOF MS ESI+) calculated for C17H15N2O
[M+H]+: 263.1184, found 263.1196.
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(4l). 39.0 mg, >95% yield. White solid, mp: 103.7-105.2. 4l: 1H NMR (400 MHz,
CDCl3) (δ, ppm) δ 9.06 (br, 1H), 7.57-6.88 (comp, 8H), 5.22 (s, 2H), 2.29 (s, 3H); 13C
NMR (100 MHz, CDCl3) (δ, ppm) δ 154.1, 142.8, 139.4, 136.8, 130.9, 129.8, 129.7,
129.3, 128.9, 126.2, 122.6, 122.0, 118.0, 117.3, 110.5, 64.0, 20.0. HRMS (TOF MS
ESI+) calculated for C17H15N2O [M+H]+: 263.1184, found 263.1185.
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(4m+4m’). 47.1 mg, >95% yield. White solid, mp: 278.1-278.9 oC. 4m: 1H NMR (400
MHz, DMSO) (δ, ppm) δ 13.80 (s, 1H), 7.90-7.41 (comp, 8H), 5.67 (s, 2H); 4m’: 1H
NMR (400 MHz, DMSO) (δ, ppm) δ 14.10 (s, 1H), 7.90-7.41 (comp, 8H), 5.76 (s,
2H); C NMR (100 MHz, DMSO, + Cs2CO3) (δ, ppm) δ 147.5, 138.6, 129.6, 129.0,
128.3, 127.9, 127.8, 126.1, 125.2, 121.7, 120.7, 120.0, 108.1, 65.7. HRMS (TOF MS
ESI+) calculated for C16H11Cl2N2O [M+H]+: 317.0248, found 317.0240.
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(4n+4n’). 48.5 mg, >95% yield. White solid, mp: 275.7-277.8 C. 4n: 1H NMR (400
MHz, DMSO) (δ, ppm) δ 13.54 (s, 1H), 7.76-6.93 (comp, 8H), 5.55 (s, 2H); 4n’: 1H
NMR (400 MHz, DMSO) (δ, ppm) δ 13.59 (s, 1H), 7.76-6.93 (comp, 8H), 5.60 (s,
13
2H); C NMR (100 MHz, DMSO, + Cs2CO3) (δ, ppm) δ152.3, 139.5, 132.3, 131.0,
129.3, 127.7, 126.3, 124.2, 121.1, 119.2, 113.3, 108.3, 92.2, 65.5. HRMS (TOF MS
ESI+) calculated for C16H12BrN2O [M+H]+: 327.0133, found 327.0140.
Procedure for the Synthesis of 5 and 2bb:
The obtained products 2/4 (0.30 mmol) and tetrabutylammonium hydrogen sulfate
(0.03 mmol, 10 mol %) was dissolved in CH2Cl2 (5.0 mL), and 50% NaOH aqueous
solution (150 μL) was added to the above reaction mixture. After the mixture was
stirred for a few minutes, TsCl (0.45 mmol, 1.5 equiv) was added to the reaction
mixture and the solution was then stirred vigorously at room temperature. When the
reaction was completed (monitored by TLC plates), the solution was poured into
water and extracted with dichloromethane. The combined organic layers were dried
over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was
purified by silica gel flash chromatography to afford the N-Ts protected products.
1
3-Phenyl-1-tosyl-1,4-dihydrochromeno[4, 3-c]pyrazole (5). 71.7 mg, 60% yields. H
NMR (400 MHz, CDCl3) (δ, ppm) δ 8.36-8.34 (m, 1H), 7.78 (d, J = 8.4 Hz, 2H),
7.53-7.51 (m, 2H), 7.45-7.40 (comp, 3H), 7.33-7.29 (m, 1H), 7.25-7.23 (m, 2H),
7.16-7.12 (m, 1H), 7.04-7.02 (m, 1H), 5.21 (s, 2H), 2.36 (s, 3H); 13C NMR (100 MHz,
CDCl3) (δ, ppm) δ 153.7, 151.1, 145.2, 139.8, 133.9, 130.32, 130.30, 129.3, 128.9,
128.4, 127.5, 127.1, 126.7, 121.9, 117.1, 116.9, 115.6, 63.1, 21.2. HRMS (TOF MS
ESI+) calculated for C23H19N2O3S [M+H]+: 403.1116, found 403.1112.
1
3-Phenyl-2-tosyl-2,4-dihydrochromeno[4, 3-c]pyrazole (5’). 36.9 mg, 30% yields. H
NMR (400 MHz, CDCl3) (δ, ppm) δ 7.96-7.93 (m, 1H), 7.60 (d, J = 8.4 Hz, 2H),
7.51-7.46 (comp, 3H), 7.33-7.29 (m, 1H), 7.35-7.33 (m, 2H), 7.30-7.25 (m, 1H), 7.21
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(d, J = 8.4 Hz, 1H), 7.06-7.02 (m, 1H), 6.94-6.92 (m, 1H), 5.00 (s, 2H), 2.38 (s, 3H);
13C NMR (100 MHz, CDCl3) (δ, ppm) δ 157.4, 147.5, 144.9, 141.4, 134.2, 130.9,
129.4, 129.2, 127.71, 127.67, 127.5, 123.6, 121.7, 117.0, 116.1, 116.0, 62.2, 21.2.
HRMS (TOF MS ESI+) calculated for C23H19N2O3S [M+H]+: 403.1116, found
403.1119.
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1-tosyl-3-[4-(trifluoromethyl)phenyl]-1,4-dihydroindeno[1,2-c]pyrazole (2bb). 111.7
mg, 82% yields. 1H NMR (400 MHz, CDCl3) (δ, ppm) δ 8.46-8.45 (m, 1H), 8.06 (d, J
= 8.2 Hz, 2H), 8.01-7.99 (m, 2H), 7.79-7.77 (m, 1H), 7.73 (d, J = 8.2 Hz, 2H),
7.62-7.56 (m, 2H), 7.54-7.51 (m, 1H), 7.45-7.42 (m, 1H), 7.33-7.31 (m, 2H), 3.82 (s,
2H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3) (δ, ppm) δ 167.8, 152.4, 148.9, 148.8,
145.9, 134.7, 132.5, 131.3, 131.0, 130.1, 129.0, 128.4, 128.1, 127.8, 127.7, 127.0,
126.0, 125.6 (q, J = 3.8 Hz), 30.1, 21.8. HRMS (TOF MS ESI+) calculated for
C24H18F3N2O2S [M+H]+: 455.1041, found 455.1049.
General Procedure for Scale Up:
To a 50-mL oven-dried vial containing a magnetic stirring bar, compound 1a (5.0
mmol, 1.94 g), base tBuOLi ( 1.2 equiv, 480.0 mg) and 1,4-dioxane (50 mL) were
added in sequence under an atmosphere of argon, and the mixture was stirred at 60 oC
for 12 h. After the reaction was completed, the mixture was quenched by the addition
of saturated brine and extrated with EtOAc (3×80 mL). The combined organic
extracts were dried over Na2SO4, filtered and concentrated reduced pressure to
provide a crude residue which was purified by washing with dichloromethane for
three times (15 mL×3) to give the pure product 2a (1.05 g, 90% yield).
To a 50-mL oven-dried vial containing a magnetic stirring bar, compound 3a (5.0
mmol, 2.02 g), the base tBuOLi (1.2 equiv, 480.0 mg) and 1,4-dioxane (50 mL) were
added in sequence under an atmosphere of argon, and the mixture was stirred at 60 oC
for 12 h. After the reaction was completed, the mixture was quenched by the addition
of saturated brine and extracted with EtOAc (3×80 mL). The combined organic
extracts were dried over Na2SO4, filtered and concentrated in vacuo to provide a crude
residue which was purified by washing with dichloromethane for three times (15 mL
×3) to give the pure product 4 (4a and 4a’, 1.23 g, >95% yield).
Compound 6 was synthesized from 2a via reported procedure.3a
Procedure for the Synthesis of 7:
The obtained 2a (1.0 mmol, 232.3 mg) and methyl acrylate (1.5 mmol, 150.2 mg) was
dissolved in CH3CN (2.0 ml), and DBU (0.5 mmol) was added to the reaction mixture
at room temperature. After 6 h, the mixture was concentrated reduced pressure. The
resulting residue was purified by silica gel column chromatography, and the pure
product 7 was isolated in 90% yield (299.2 mg). 1H NMR (400 MHz, CDCl3) (δ, ppm)
δ 7.95-7.93 (m, 2H), 7.69 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.52-7.48 (m,
2H), 7.46-7.42 (m, 1H), 7.40-7.31 (m, 2H), 4.75 (t, J = 7.0 Hz, 2H), 4.19 (q, J = 7.1
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Hz, 2H), 3.80 (s, 2H), 3.13 (t, J = 7.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) (δ, ppm)
δ 171.0, 149.8, 149.1, 144.9, 133.7, 131.9, 128.7, 127.5, 126.9, 126.2, 126.1, 125.8,
123.5, 118.8, 60.9, 46.5, 35.1, 30.1, 14.2. HRMS (TOF MS ESI+) calculated for
C21H21N2O2 [M+H]+: 333.1603, found 333.1607.
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ASSOCIATED CONTENT
Supporting Information
1H, and 13C NMR spectra for all products. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
Email: xinfangxu@suda.edu.cn (X. X.).
Email: jjhuang@suda.edu.cn (J.H.).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the grants from the Priority Academic Program Development
(PAPD) of Jiangsu Higher Education Institutions; and NSFC of Jiangsu China
(BK20150315 and NSFC21602148).
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