One-Pot Synthesis of Spirocyclic or Fused Pyrazoles from Cyclic Ketones: Calcium Carbide as the Carbon Source in Ring Expansion

Article abstract of DOI:10.1021/acs.joc.7b01496

N-Tosylhydrazones generated in situ from cyclic ketones smoothly underwent a [3 + 2] cycloaddition to afford saturated spirocyclic pyrazoles and further transformed to the fused analogues via a ring expansion in certain cases. An inexpensive and renewable

Full text of DOI:10.1021/acs.joc.7b01496

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Article
One-Pot Synthesis of Spirocyclic or Fused Pyrazoles from Cyclic
Ketones: Calcium Carbide as the Carbon Source in Ring Expansion
Yue Yu, Yang Chen, Wei Huang, Wanqing Wu, and Huanfeng Jiang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01496 • Publication Date (Web): 23 Aug 2017
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One-Pot Synthesis of Spirocyclic or Fused
Pyrazoles from Cyclic Ketones: Calcium Carbide
as the Carbon Source in Ring Expansion
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Yue Yu, Yang Chen, Wei Huang, Wanqing Wu*, Huanfeng Jiang*
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of
Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640,
P. R. China
Fax: (+86) 20ꢀ87112906; Eꢀmail: jianghf@scut.edu.cn; cewuwq@scut.edu.cn
Abstract: NꢀTosylhydrazones generated in situ from cyclic ketones smoothly
underwent a [3+2] cycloaddition to afford saturated spirocyclic pyrazoles and further
transformed to the fused analogues via a ring expansion in certain cases. An
inexpensive and renewable resource, calcium carbide, was utilized as the carbon
source in the ring expansion. The salient features of this reaction include widely
available starting materials, convenient oneꢀpot/twoꢀstep procedure, great efficiency
and high regioselectivity. Remarkably, this reaction underwent [1,5]ꢀsigmatropic
rearrangement process, which was supported by deuteriumꢀlabeling experiments.
INTRODUCTION
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Owing to their convenient accessibility and structural diversity, cycloalkanone
derivatives have been widely used as raw materials for many total syntheses of natural
products or bioactive molecules.1ꢀ2 Ring expansion reactions of cycloalkanones rank
among the most strategically useful in the steps of these syntheses, since many natural
products consist of unavailable polycyclic networks. To date, there have been various
methods developed for the ring expansion of cycloalkanones,3 some of which have
even become name reactions. For examples, the Lewis acidꢀcatalyzed addition of
αꢀdiazoacetates or diazoalkanes to cyclohexanones has been known for more than half
a century as a practical strategy to synthesize sevenꢀmembered carbocyclic ketones
through the TiffeneauꢀDemjanov rearrangement intermediates (Scheme 1a).4 Another
wellꢀknown and efficient method is the DowdꢀBeckwith ring expansion reaction, in
which the 2ꢀoxocyclohexanecarboxylate compounds are transformed to mediumꢀsized
ring cyclic ketones. However, this process requires the addition of toxic or explosive
reagents such as AIBN and Bu3SnH, and environmentally unfriendly haloalkane
substrates are used as the carbon source (Scheme 1b).5
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In order to expand the richness of green ring expansion reactions, we tried to
hunt for other atomꢀeconomical and easyꢀtoꢀobtain carbon sources. It is known that
calcium carbide (CaC2) is thought to be a promising candidate for a safer and more
inexpensive alternative to acetylene gas that has become an important basic organic
chemical raw material.6 Therefore, the conversions of CaC2 to acetyleneꢀderived
compounds have received continuing attention in these years owing to their potential
to the preparation of 3ꢀsubstituted or 3,4ꢀdisubstituted 1Hꢀpyrazoles in industry field
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Scheme 1. Transitionꢀmetal free ring expansion reactions of cyclic ketones
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by using CaC2 as the source.7 The reaction pathways have been clarified that the
3Hꢀpyrazole intermediates were involved and spontaneously rearranged to the final
products. On the basis of this work and Valdés’s report8, we envisaged that the
3Hꢀpyrazole intermediate could be stably isolated as product by using symmetrical
cyclic ketones as substrates. In addition, asymmetrical cyclic ketones would undergo
the [3+2] cycloaddition/[1,5] rearrangement sequence to give the fused pyrazoles with
expansion of the carbocyclic ring. In this context, we report herein a new method for
utilizing CaC2 as both an acetylide source in the [3+2] annulation and the carbon
source in ring expansion to synthesize spirocyclic or fused pyrazoles (Scheme 1c).
Such saturated polycyclic pyrazole motifs were prevalent structural elements in
numerous compounds of significant biological/medicinal value for the applications in
dyes, agrochemicals and pharmaceuticals.8ꢀ11 However, their preparations were
typically challenging to achieve directly by using conventional methods.
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RESULTS AND DISCUSSION
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At the outset of our studies, we investigated this reaction for the synthesis of
spiroꢀheterocycles from 4ꢀphenylꢀcyclohexanone (1b) and calcium carbide. The
condensation reaction between ketones and tosylhydrazide can easily afford
Nꢀtosylhydrazones in situ without the need for chromatographic purification.12
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Therefore, a mixture of 1b and tosylhydrazide was first stirred at 70 C for 2 h in
methanol, followed by removal of the solvent. The remaining crude mixture was then
treated with excessive amounts of CaC2, H2O and equivalent amounts of bases in
appropriate solvents. To our delight, when the reaction was performed in DMSO at 80
oC for 6 h with the addition of Cs2CO3, the desired spirocyclic pyrazole 3b was
obtained in 51% isolated yield (Table 1, entry 1). Subsequent screening of other bases
such as K2CO3, KOH, tꢀBuOLi or MeONa did not improve the yield (Table 1, entries
2ꢀ5). Significantly, increasing the reaction temperature had a positive effect on the
yield. 110 oC was found to be optimal, affording the target product 3b in 87% isolated
yield (Table 1, entries 6ꢀ8). Different types of solvents were then investigated, while
no superior results were obtained (Table 1, entries 9ꢀ13). Furthermore, the molecular
structure of 3b was unambiguously determined by Xꢀray crystallographic analysis
(see Supporting Information for details).
Table 1. Optimization of Reaction Conditions a
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Xꢀray of 3b
entry
1
base
solvent
DMSO
DMSO
T (oC)
yield b(%)
54 (51)c
35
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Cs2CO3
K2CO3
80
80
2
KOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
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29
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3
tꢀBuOLi
MeONa
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
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4
80
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5
100
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6
92 (87)c
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90
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63
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1,4ꢀDioxane
DMA
86
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CH3CN
Toluene
trace
trace
a Reaction conditions: 1) 1 (0.5 mmol), TsNHNH2 (0.5 mmol), MeOH (2 mL) at 70 oC for 2 h; 2)
CaC2 (2 mmol), base (0.5 mmol), H2O (2.5 mmol) and 2.0 mL solvent heating for 6 h. b GC yield
with nꢀdodecane as internal standard. c Number in parentheses is the yield of isolated product.
With the optimized reaction conditions in hand, we turned our attention to the
generality of this transformation (Table 2). Initially, Nꢀtosylhydrazones generated
from cyclohexanone and 4ꢀsubstituted cyclohexanones were found to undergo [3+2]
annulations with CaC2 to give the corresponding spiroꢀheterocycles 3aꢀ3c in 73ꢀ87%
yields. Pleasingly, a series of 6ꢀmembered saturated oxygenꢀ, sulfurꢀ and
nitrogenꢀcontaining heterocyclic ketones were also suitable substrates for this
cyclization that the target products 3dꢀ3h were isolated in 61ꢀ89% yields. Concerning
the cycloalkanone ring size, cycloheptanone, cyclooctanone and adamantanone were
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next investigated, and the corresponding products (3iꢀ3k) were obtained in moderate
to good yields. Notably, when cyclopentanone 1l was examined, a 6ꢀmembered fused
pyrazole product 3l was afforded in 56% yield while the spirocyclic one was not
detected. We supposed that spontaneous rearrangement in this manner might occur,
based on the angle strain in the spirocyclic intermediate. Moreover, the temperature of
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this transformation should not be more than 100 C, otherwise 3l would further react
with another equivalent of acetylene via nucleophilic addition to form a Nꢀvinyl
pyrazole product instead. As for other cycloalkanones, cyclobutanone was found to be
in similar situation with cyclopentanone, albeit with too low yield that we only
detected the product by crude 1H NMR.
Table 2. Substrate scope for the synthesis of spirocyclic pyrazoles a
a Reaction conditions: 1) 1 (0.5 mmol), TsNHNH2 (0.5 mmol), MeOH (2 mL) at 70 oC for 2 h; 2)
CaC2 (2 mmol), base (0.5 mmol), H2O (2.5 mmol) and 2.0 mL DMSO at 110 oC for 6 h. b Nꢀvinyl
c
pyrazole product 3i’ was detected in 13% yield. Nꢀvinyl pyrazole product 3j’ was detected in
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16% yield. d 90 oC.
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The spirocyclic substrates that spontaneously rearranged to the fused analogues
prompted us to examine the synthesis of fused pyrazoles 4 directly from their parent
cyclic ketones. In addition to the angle strain, a rich electron density adjacent to the
carbonyl moiety was also anticipated to be an important influence factor for the
expansion of the carbocyclic ring in this reaction. Therefore, various examples were
tested under similar reaction conditions with a lower temperature, as shown in Table 3.
Indeed, [3+2] annulations between CaC2 and a series of Nꢀtosylhydrazones generated
from 5ꢀmembered cyclic ketenes or benzo ketones proceeded smoothly to give the
corresponding pyrazoles fused to a sixꢀmembered ring in moderate to good yields
(4aꢀ4g). Owing to the rich electron density of vinyl or aryl group, the
[1,5]ꢀsigmatropic rearrangement took place again in a regioselective manner, thus
giving rise exclusively to the ringꢀexpanded pyrazoles. Furthermore, a range of 6ꢀ and
7ꢀmembered saturated cyclic ketenes or benzo ketones were then investigated in the
reaction as well, and the corresponding 7ꢀ or 8ꢀmembered products were generated in
50ꢀ88% yields (4hꢀ4q). In general, ketones with electronꢀdonating substituents on the
phenyl ring furnished the desired products in higher yields than those with
electronꢀneutral or electronꢀwithdrawing groups.
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Table 3. Substrate scope of the cyclization/ring expansion a
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a Reaction conditions: 1) 2 (0.5 mmol), TsNHNH2 (0.5 mmol), MeOH (2 mL) at 70 oC for 2 h; 2)
CaC2 (2 mmol), base (0.5 mmol), H2O (2.5 mmol) and 2.0 mL DMSO at 80 oC for 6 h.
We then applied the present protocol to the functionalization of two biologically
active molecules. Under the standard conditions, (ꢀ)ꢀCarvone 5 and (+)ꢀNootkatone 7
could undergo further modification smoothly and the corresponding pyrazoles 6 and 8
were successfully obtained in moderate yields (Scheme 2). The practicality of this
ringꢀexpansion reaction using calcium carbide as a oneꢀcarbon unit should lead to
potential utilities in the synthesis of valuable polycyclic pyrazole derivatives.
Scheme 2. Further modification on biologically active molecules
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To validate the potential industrial applications of this strategy, two scaleꢀup
experiments were then carried out for 4ꢀphenylꢀcyclohexanone (1b) and
4,4ꢀdimethylcyclohexꢀ2ꢀenone (2i) (Scheme 3). The two reactions afforded the
corresponding spirocyclic pyrazole 3b or fused pyrazole 4i in gram scale, albeit in
diminished yields as compared with the smallꢀscale experiments (see Supporting
Information for details).
Scheme 3. Gramꢀscale experiments
To cast some light on the mechanism details for our reaction, deuteriumꢀlabeling
experiments were conducted. Initially, the reaction of CaC2 and Nꢀtosylhydrazone
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generated in situ from 2m was performed in dry DMSO at 80 C for 6 h with the
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addition of Cs2CO3 and D2O. It was found that the reaction afforded the
corresponding deuterated pyrazole [D2]ꢀ4m in 80% yield with 97% D (Scheme 4, eq
1). In order to confirm whether the deuteration occurred before or after the cyclization,
we tried to test the reaction of pyrazole 4m under the standard conditions in the
presence of Cs2CO3 and D2O, and the deuterated product [D2]ꢀ4m was not detected,
which suggested that the deuteration occurred before the [3+2] cyclization (Scheme 4,
eq 2). In view of the structure of [D2]ꢀ4m and our previous works7, we deduced that
the deuterium atom on N1 was shifted from C4 of the pyrazole ring through multiple
[1,5]ꢀH shifts during the process of aromatic isomerization. Before that, a migration
of phenyl group from C3 to C4 through [1,5]ꢀsigmatropic rearrangement should occur.
We also tried to cultivate single crystals of pyrazoles 4 while no direct experimental
result was obtained. We supposed that due to the prototropic tautomerism of
1Hꢀpyrazoles, the characters of 4 are either oils or amorphous powders. Since the
migrational principles of [1,5]ꢀsigmatropic rearrangement are clear, the structures of 4
are considered credible.
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Scheme 4. Deuteriumꢀlabeling experiments
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On the basis of the results of deuteriumꢀlabeling experiments and previous
works7, 8a, we tentatively proposed the reaction mechanism as outlined in Scheme 5.
Initially, in the presence of Cs2CO3, the cesium salt A was afforded by the
deprotonation of Nꢀtosylhydrazone 1’. In one possible way, reactive diazo compound
B was rapidly formed under the action of the base, followed by a [3+2] cycloaddition
with [D2]ꢀacetylene gas, affording deuterated spirocyclic pyrazole [D2]ꢀ3 (Path I).
Another possibility is that nucleophilic addition of the counter Nꢀanion of
intermediate A to [D2]ꢀacetylene gas followed by the elimination of Ts anion and
cesium ion led to the spirocyclic product [D2]ꢀ3 (Path II). The reactions of 6, 7 or
8ꢀmembered heterocyclic ketones resulted in spirocyclic products which would not
spontaneously occur rearrangement. While for 4 or 5ꢀmembered cyclic ketones with
strong angle strain, or substrates with rich electron density adjacent to the carbonyl
moiety, the nonaromatic spirocyclic pyrazole [D2]ꢀ3 have a trend to isomerize to the
aromatic fused analogues. Thus, a spontaneous [1,5]ꢀsigmatropic rearrangement from
[D2]ꢀ3 to E through the transition state D must be favored and the subsequent multiple
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[1,5]ꢀD shifts gave the final product [D2]ꢀ4.
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Scheme 5. Possible mechanism
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In summary, we present a convenient oneꢀpot/twoꢀstep procedure for transition
metalꢀfree coupling between calcium carbide and Nꢀtosylhydrazones generated in situ
from cyclic ketones, affording saturated spirocyclic pyrazoles via [3+2]
cycloadditions. In certain cases, the spirocyclic pyrazoles could undergo a ring
expansion to give the fused analogues, in which calcium carbide was used as the
carbon source. In addition, deuteriumꢀlabeling experiments have been conducted to
clarify the reaction pathway that multiple [1,5]ꢀsigmatropic rearrangements were
involved in the transformation. From a synthetic point of view, this ringꢀexpanded
reaction should lead to great utilities in formation of biologically active pyrazole
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scaffolds.
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EXPERIMENTAL SECTION
General Methods
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1H and 13C NMR spectra were recorded using a Bruker DRXꢀ400 spectrometer using
CDCl3 as solvent. The chemical shifts are referenced to signals at 7.26 and 77.0 ppm,
respectively. Mass spectra were recorded on a Thermo Scientific ISQ gas
chromatographꢀmass spectrometer. The data of HRMS was carried out on a
highꢀresolution mass spectrometer (LCMSꢀITꢀTOF). IR spectra were obtained either
as potassium bromide pellets or as liquid films between two potassium bromide
pellets with a Bruker TENSOR 27 spectrometer. Melting points were determined with
a Büchi Melting Point Bꢀ545 instrument.
General Procedure for the Preparation of 3 and 4
In a Schlenk tube, a mixture of cyclic ketone (0.5 mmol) and tosylhydrazide (0.5
o
mmol) was stirred at 70 C for 2 h in methanol (3 mL), followed by removal of the
solvent in vacuo. The remaining crude mixture was then treated with CaC2 (2 mmol),
Cs2CO3 (0.5 mmol), H2O (2.5 mmol, added by using a microliter syringe) and DMSO
o
o
(2 mL). The mixture was stirred at 110 C or 80 C for 6 h. After completion of the
reaction (monitored by TLC), water (10 mL) was added to the reaction mixture, and
the resulting mixture was extracted with ethyl acetate. The combined organic layers
were then dried over MgSO4, filtered, and then concentrated in vacuo. The residue
was purified by flash chromatography on silica gel to give 3 or 4.
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Procedure for the Preparation of 3b or 4i on a gram scale
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In a 200 mL roundꢀbottom flask with a reflux condenser, a mixture of 1b (1.74 g, 10
mmol)/2i (1.24 g, 10 mmol) and tosylhydrazide (1.86 g, 10 mmol) was first stirred at
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70 C for 2 h in methanol, followed by removal of the solvent. The remaining crude
mixture was then treated with CaC2 (2.56 g, 40 mmol), Cs2CO3 (3.26 g, 10 mmol) and
H2O (0.9 mL, 50 mmol) in DMSO (40 mL). The flask was then sealed with an
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uninflated balloon and the mixture was stirred at 110 C/80 C for 6 h. After
completion of the reaction (monitored by TLC), water (3 × 100 mL) was added to the
reaction mixture, and the resulting mixture was extracted with ethyl acetate for 3
times. The combined organic layers were then dried over MgSO4, filtered, and then
concentrated in vacuo. The residue was purified by flash chromatography on silica gel
to give 3b as a brown solid or 4i as a yellow oil.
1,2-Diazaspiro[4.5]deca-1,3-diene (3a)
The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 20:1), the product was
isolated as a black oil (57.9 mg, 85%); IR (KBr): 2930, 2858, 1670, 1444, 1048 cm−1;
1H NMR (400 MHz, CDCl3) δ ppm 7.56 (s, 1H), 7.13 (s, 1H), 2.08ꢀ2.01 (m, 2H), 1.92
(t, J = 11.2 Hz, 2H), 1.73ꢀ1.53 (m, 4H), 1.34ꢀ1.26 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ ppm 145.5, 142.6, 97.4, 30.5, 25.3, 24.5; MS (EI, 70 eV) m/z: 136.25,
108.22, 94.20, 84.04; HRMS ESI (m/z): calcd for C8H13N2 [M + H]+: 137.1073, found:
137.1074.
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8-Phenyl-1,2-diazaspiro[4.5]deca-1,3-diene (3b)
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The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 20:1), the product was
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isolated as a brown crystalline solid (92.3 mg, 87%), mp 110.5ꢀ111.9 C; IR (KBr):
3081, 2929, 1700, 1438, 690 cm−1; H NMR (400 MHz, CDCl3) δ ppm 7.60 (s, 1H),
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7.35 (t, J = 9.5 Hz, 4H), 7.22 (t, J = 6.9 Hz, 1H), 6.92 (s, 1H), 2.81 (t, J = 12.2 Hz,
1H), 2.54ꢀ2.42 (m, 2H), 2.06 (dd, J = 22.6, 12.3 Hz, 4H), 1.28 (d, J = 13.9 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ ppm 147.7, 146.5, 142.2, 128.3, 126.8, 126.1, 95.2,
43.5, 31.6, 31.4; MS (EI, 70 eV) m/z: 212.28, 134.25, 108.20, 94.21; HRMS ESI
(m/z): calcd for C14H16N2Na [M + Na]+: 235.1206, found: 235.1210.
9,12-Dioxaspiro-1,2-diazaspiro[4.5]deca-1,3-diene (3c)
The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 10:1), the product was
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isolated as a brown crystalline solid (70.9 mg, 73%), mp 127.8ꢀ128.9 C; IR (KBr):
3740, 3087, 1739, 1259, 952 cm−1; H NMR (400 MHz, CDCl3) δ ppm 7.61 (s, 1H),
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7.07 (s, 1H), 4.10ꢀ3.97 (m, 4H), 2.30 (t, J = 8.4 Hz, 2H), 1.88ꢀ1.70 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ ppm 145.5, 142.9, 108.0, 64.5, 64.5, 33.4, 28.6; MS (EI, 70 eV)
m/z: 194.26, 149.22, 107.20, 87.17; HRMS ESI (m/z): calcd for C10H14N2NaO2 [M +
Na]+: 217.0947, found: 217.0950.
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8-Oxa-1,2-diazaspiro[4.5]deca-1,3-diene (3d)
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The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 20:1), the product was
isolated as a brown oil (57.4 mg, 83%); IR (KBr): 3738, 2928, 1744, 1524, 1038, 883
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cm−1; H NMR (400 MHz, CDCl3) δ ppm 7.72ꢀ7.59 (m, 1H), 7.14ꢀ7.00 (m, 1H),
4.34ꢀ4.23 (m, 2H), 3.94ꢀ3.85 (m, 2H), 1.79ꢀ1.65 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ ppm 144.6, 143.4, 93.8, 65.8, 30.0; MS (EI, 70 eV) m/z: 138.36, 109.22,
95.17, 79.17; HRMS ESI (m/z): calcd for C7H11N2O [M + H]+: 139.0866, found:
139.0865.
8-Thia-1,2-diazaspiro[4.5]deca-1,3-diene (3e)
The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 20:1), the product was
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isolated as a brown amorphous solid (68.6 mg, 89%), mp 142.7ꢀ144.4 C; IR (KBr):
3740, 3089, 2924, 1427, 1254, 913 cm−1; 1H NMR (400 MHz, CDCl3) δ ppm 7.65 (d,
J = 3.2 Hz, 1H), 7.09 (d, J = 3.2 Hz, 1H), 3.33ꢀ3.23 (m, 2H), 2.79ꢀ2.71 (m, 2H),
2.01ꢀ1.94 (m, 2H), 1.82 (t, J = 11.1 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ ppm
145.1, 143.4, 95.4, 31.2, 26.5; MS (EI, 70 eV) m/z: 154.18, 111.15, 97.15, 79.19;
HRMS ESI (m/z): calcd for C7H11N2S [M + H]+: 155.0637, found: 155.0637.
8-Propyl-1,2,8-triazaspiro[4.5]deca-1,3-diene (3f)
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The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 10:1), the product was
isolated as a brown oil (56.5 mg, 61%); IR (KBr): 2935, 1740, 1454, 1250, 780 cm−1;
1H NMR (400 MHz, CDCl3) δ ppm 7.62 (d, J = 3.3 Hz, 1H), 7.08 (d, J = 2.9 Hz, 1H),
3.08ꢀ2.99 (m, 2H), 2.66 (d, J = 4.8 Hz, 2H), 2.52ꢀ2.46 (m, 2H), 1.86ꢀ1.73 (m, 4H),
1.59 (dd, J = 15.2, 7.5 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ ppm 145.1, 143.0, 95.1, 60.7, 51.8, 30.1, 20.1, 12.0; MS (EI, 70 eV) m/z: 179.32,
150.25, 122.22, 98.23; HRMS ESI (m/z): calcd for C10H18N3 [M + H]+: 180.1495,
found: 180.1494.
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8-Phenethyl-1,2,8-triazaspiro[4.5]deca-1,3-diene (3g)
The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 10:1), the product was
isolated as a brown oil (102.6 mg, 85%); IR (KBr): 3080, 2935, 1500, 1128, 763 cm−1;
1H NMR (400 MHz, CDCl3) δ ppm 7.63 (s, 1H), 7.30 (t, J = 7.3 Hz, 2H), 7.25ꢀ7.19
(m, 3H), 7.09 (s, 1H), 3.11 (t, J = 10.7 Hz, 2H), 2.94ꢀ2.86 (m, 2H), 2.80ꢀ2.74 (m, 4H),
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1.87ꢀ1.76 (m, 4H); C NMR (100 MHz, CDCl3) δ ppm 145.0, 143.0, 140.1, 128.6,
128.3, 126.0, 94.8, 60.4, 51.6, 33.6, 30.0; MS (EI, 70 eV) m/z: 241.32, 150.26, 121.21,
91.16; HRMS ESI (m/z): calcd for C15H20N3 [M + H]+: 242.1652, found: 242.1655.
Ethyl 1,2,8-Triazaspiro[4.5]deca-1,3-diene-8-carboxylate (3h)
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The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 5:1), the product was
isolated as a brown oil (79.5 mg, 76%); IR (KBr): 2936, 1692, 1435, 1246, 774 cm−1;
1H NMR (400 MHz, CDCl3) δ ppm 7.63 (s, 1H), 7.01 (s, 1H), 4.16 (q, J = 7.0 Hz, 2H),
3.95ꢀ3.79 (m, 4H), 1.73ꢀ1.65 (m, 2H), 1.57 (d, J = 13.5 Hz, 2H), 1.26 (t, J = 7.1 Hz,
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3H); C NMR (100 MHz, CDCl3) δ ppm 155.5, 144.5, 143.5, 94.5, 61.5, 42.3, 29.7,
14.6; MS (EI, 70 eV) m/z: 209.28, 180.24, 120.21, 108.20; HRMS ESI (m/z): calcd
for C10H15N3NaO2 [M + Na]+: 232.1056, found: 232.1055.
1,2-Diazaspiro[4.6]undeca-1,3-diene (3i)
The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 20:1), the product was
isolated as a black oil (42.8 mg, 57%); IR (KBr): 2924, 2857, 1692, 1450, 1246 cm−1;
1H NMR (400 MHz, CDCl3) δ ppm 7.46 (s, 1H), 7.08 (s, 1H), 2.08ꢀ1.97 (m, 4H),
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1.82ꢀ1.58 (m, 6H), 1.33 (dd, J = 14.5, 8.5 Hz, 2H); C NMR (100 MHz, CDCl3) δ
ppm 146.8, 142.0, 100.4, 32.1, 29.4, 25.6; MS (EI, 70 eV) m/z: 150.26, 121.20,
107.20, 94.21; HRMS ESI (m/z): calcd for C9H14N2Na [M + Na]+: 173.1049, found:
173.1042.
1,2-Diazaspiro[4.7]dodeca-1,3-diene (3j)
The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 20:1), the product was
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isolated as a brown oil (56.7 mg, 69%); IR (KBr): 3095, 2924, 1598, 1454, 774 cm−1;
1H NMR (400 MHz, CDCl3) δ ppm 7.54 (d, J = 1.9 Hz, 1H), 7.10 (d, J = 1.7 Hz, 1H),
2.05 (dd, J = 13.6, 8.8 Hz, 2H), 1.96 (dd, J = 13.7, 11.6 Hz, 2H), 1.87ꢀ1.58 (m, 8H),
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1.33 (dd, J = 14.8, 8.3 Hz, 2H); C NMR (100 MHz, CDCl3) δ ppm 146.9, 142.6,
100.3, 28.3, 28.2, 25.0, 24.9; MS (EI, 70 eV) m/z: 164.28, 135.24, 121.21, 107.18;
HRMS ESI (m/z): calcd for C10H16N2Na [M + Na]+: 187.1206, found: 187.1205.
(1r,3r,5r,7r)-Spiro[adamantane-2,3'-pyrazole] (3k)
The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 20:1), the product was
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isolated as a yellow crystalline solid (75.3 mg, 80%), mp 104.0ꢀ105.2 C; IR (KBr):
3093, 2901, 1738, 1446, 1241, 779 cm−1; 1H NMR (400 MHz, CDCl3) δ ppm 7.56 (s,
1H), 7.34 (s, 1H), 2.83 (d, J = 12.6 Hz, 2H), 2.10 (d, J = 45.4 Hz, 2H), 1.90 (dd, J =
13
36.2, 17.8 Hz, 8H), 1.33 (s, 2H); C NMR (100 MHz, CDCl3) δ ppm 145.6, 142.3,
102.0, 38.6, 37.7, 37.5, 35.7, 35.3, 35.2, 31.4, 27.3, 27.2; MS (EI, 70 eV) m/z: 188.28,
131.20, 117.23, 91.18; HRMS ESI (m/z): calcd for C12H16N2Na [M + Na]+: 211.1206,
found: 211.1210.
4,5,6,7-Tetrahydro-2H-indazole (3l)
The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 5:1), the product was
isolated as a yellow oil (34.2 mg, 56%); IR (KBr): 3163, 2930, 1445, 1157, 960 cm−1;
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1H NMR (400 MHz, CDCl3) δ ppm 7.61 (s, 1H), 7.29 (s, 1H), 2.66 (t, J = 6.0 Hz, 2H),
2.53 (t, J = 5.9 Hz, 2H), 1.84ꢀ1.70 (m, 4H); 13C NMR (100 MHz, CDCl3) δ ppm
143.2, 132.0, 115.0, 23.4, 23.1, 22.0, 20.4; MS (EI, 70 eV) m/z: 122.23, 119.20, 94.20,
67.18; HRMS ESI (m/z): calcd for C7H11N2 [M + H]+: 123.0917, found: 123.0914.
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4,5,6,7-Tetramethyl-6,7-dihydro-2H-indazole (4a)
The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 5:1), the product was
isolated as a yellow oil (45.0 mg, 51%); IR (KBr): 3217, 2963, 1728, 1376, 1058 cm−1;
1H NMR (400 MHz, CDCl3) δ 7.29 (s, 1H), 5.12 (dr, 1H), 2.81ꢀ2.68 (m, 1H),
2.12ꢀ1.81 (m, 1H), 1.91 (s, 3H), 1.81 (s, 3H), 1.10 (d, J = 7.1 Hz, 3H), 0.94 (d, J = 7.1
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ ppm 150.5, 129.1, 123.8, 118.1, 117.6, 44.4,
34.2, 20.8, 18.6, 18.0, 14.7; MS (EI, 70 eV) m/z: 176.30, 161.27, 146.23, 131.20;
HRMS ESI (m/z): calcd for C11H17N2 [M + H]+: 177.1386, found: 177.1379. Anal.
Calcd for C11H16N2: C, 74.96; H, 9.15; N, 15.89; Found: C, 75.10; H, 9.22; N, 15.68.
4,5-Dihydro-2H-benzo[e]indazole (4b)
The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 5:1), the product was
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isolated as a brown amorphous solid (57.8 mg, 68%), mp 127.1ꢀ128.0 C; IR (KBr):
3172, 2931, 1592, 1176, 761 cm−1; 1H NMR (400 MHz, CDCl3) δ 11.12 (dr, 1H), 7.78
(s, 1H), 7.39 (d, J = 7.4 Hz, 1H), 7.20 (t, J = 7.3 Hz, 2H), 7.10 (t, J = 7.3 Hz, 1H),
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2.97 (dd, J = 19.7, 6.5 Hz, 4H); C NMR (100 MHz, CDCl3) δ ppm 146.5, 134.1,
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130.3, 128.4, 126.8, 126.6, 125.8, 122.8, 117.2, 29.5, 21.2; MS (EI, 70 eV) m/z:
170.10, 142.08, 115.06, 84.10; HRMS ESI (m/z): calcd for C11H11N2 [M + H]+:
171.0917, found: 171.0914.
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8-Methyl-4,5-dihydro-2H-benzo[e]indazole (4c)
The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 5:1), the product was
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isolated as a brown amorphous solid (56.2 mg, 61%), mp 172.5ꢀ173.2 C; IR (KBr):
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3180, 2929, 1725, 1164, 810 cm−1; H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.23
(s, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 3.00ꢀ2.89 (m, 4H), 2.34 (s,
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3H); C NMR (100 MHz, CDCl3) δ ppm 146.8, 136.3, 131.1, 130.0, 129.5, 128.2,
126.5, 123.5, 117.3, 29.1, 21.3, 21.1; MS (EI, 70 eV) m/z: 184.26, 169.24, 142.22,
115.20; HRMS ESI (m/z): calcd for C12H13N2 [M + H]+: 185.1073, found: 185.1075.
8-Chloro-4,5-dihydro-2H-benzo[e]indazole (4d)
The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 5:1), the product was
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isolated as a brown amorphous solid (52.1 mg, 51%), mp 144.1ꢀ145.6 C; IR (KBr):
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3164, 2930, 1595, 1170, 805 cm−1; H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.37
(d, J = 2.0 Hz, 1H), 7.14 (d, J = 8.1 Hz, 1H), 7.10ꢀ6.90 (m, 2H), 3.06ꢀ2.84 (m, 4H);
13C NMR (100 MHz, CDCl3) δ ppm 147.1, 132.4, 132.4, 131.9, 129.6, 128.0, 125.6,
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ESI (m/z): calcd for C11H10ClN2 [M + H]+: 205.0527, found: 205.0525.
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7-Fluoro-4,5-dihydro-2H-benzo[e]indazole (4e)
The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 5:1), the product was
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isolated as a brown amorphous solid (48.9 mg, 52%), mp 76.2ꢀ77.3 C; IR (KBr):
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3180, 2931, 1579, 1243, 812 cm−1; H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.34
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(dd, J = 8.3, 5.6 Hz, 1H), 6.96ꢀ6.89 (m, 2H), 4.58 (dr, 1H), 3.11ꢀ2.84 (m, 4H); C
NMR (100 MHz, CDCl3) δ ppm 161.1 (J = 242.7 Hz), 146.3, 136.4 (J = 7.4 Hz),
126.4 (J = 2.8 Hz), 126.1, 124.0 (J = 8.1 Hz), 116.6, 115.4 (J = 21.5 Hz), 113.4 (J =
21.4 Hz), 29.7 (J = 1.2 Hz), 20.9; MS (EI, 70 eV) m/z: 188.24, 160.20, 133.20, 93.61;
HRMS ESI (m/z): calcd for C11H10FN2 [M + H]+: 189.0823, found: 189.0822. Anal.
Calcd for C11H9FN2: C, 70.20; H, 4.82; N, 14.88; Found: C, 70.41; H, 4.92; N, 14.71.
7-Bromo-4,5-dihydro-2H-benzo[e]indazole (4f)
The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 5:1), the product was
isolated as a white amorphous solid (69.5 mg, 56%), mp 103.4ꢀ105.1oC; IR (KBr):
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3181, 2933, 1726, 1066, 811 cm−1; H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H),
7.37ꢀ7.22 (m, 2H), 7.23ꢀ7.02 (m, 2H), 2.93ꢀ2.83 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ ppm 146.3, 136.1, 131.2, 129.7, 129.2, 126.7, 124.2, 118.9, 116.4, 29.3,
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20.9; MS (EI, 70 eV) m/z: 248.17, 169.24, 140.19, 115.20; HRMS ESI (m/z): calcd
for C11H10BrN2 [M + H]+: 249.0022, found: 249.0016. Anal. Calcd for C11H9BrN2: C,
53.04; H, 3.64; N, 11.25; Found: C, 53.19; H, 3.70; N, 11.13.
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4,5,8,10-Tetrahydro-2H-isobenzofuro[4,5-e]indazole (4g)
The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 3:1), the product was
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isolated as a brown amorphous solid (60.5 mg, 57%), mp 161.3ꢀ161.9 C; IR (KBr):
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3739, 2923, 1463, 1239, 807 cm−1; H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.00
(d, J = 8.0 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 5.89 (dr, 1H), 4.65 (t, J = 8.7 Hz, 2H),
3.28 (t, J = 8.6 Hz, 2H), 3.05ꢀ2.87 (m, 4H); 13C NMR (100 MHz, CDCl3) δ ppm
159.2, 147.6, 127.7, 127.7, 126.9, 126.2, 121.4, 116.3, 106.3, 30.0, 29.0, 21.8, 21.8;
MS (EI, 70 eV) m/z: 212.28, 184.24, 156.23, 91.18; HRMS ESI (m/z): calcd for
C13H13N2O [M + H]+: 213.1022, found: 213.1024.
2,6,7,8-Tetrahydrocyclohepta[c]pyrazole (4h)
The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 10:1), the product was
isolated as a brown oil (45.6 mg, 68%); IR (KBr): 3217, 2930, 1713, 1437, 1144, 807
cm−1; 1H NMR (400 MHz, CDCl3) δ 7.37 (s, 1H), 6.49 (dr, 1H), 6.22 (d, J = 11.5 Hz,
1H), 5.68ꢀ5.57 (m, 1H), 3.00ꢀ2.90 (m, 2H), 2.47ꢀ2.42 (m, 2H), 1.94 (dt, J = 11.4, 5.7
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ ppm 146.3, 129.9, 128.8, 127.2, 119.1, 31.2,
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28.1, 22.8; MS (EI, 70 eV) m/z: 134.25, 119.20, 92.18, 79.18; HRMS ESI (m/z): calcd
for C8H11N2 [M + H]+: 135.0917, found: 135.0910. Anal. Calcd for C8H10N2: C, 71.61;
H, 7.51; N, 20.88; Found: C, 71.87; H, 7.54; N, 20.59.
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6,6-Dimethyl-2,6,7,8-tetrahydrocyclohepta[c]pyrazole (4i)
The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 10:1), the product was
isolated as a yellow oil (64.1 mg, 79%); IR (KBr): 3649, 2934, 1727, 1457, 800 cm−1;
1H NMR (400 MHz, CDCl3) δ 10.49 (dr, 1H), 7.38 (s, 1H), 6.08 (d, J = 11.7 Hz, 1H),
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5.40 (d, J = 11.7 Hz, 1H), 2.97ꢀ2.87 (m, 2H), 1.79ꢀ1.69 (m, 2H), 1.09 (s, 6H); C
NMR (100 MHz, CDCl3) δ ppm 145.6, 137.2, 134.7, 116.9, 115.8, 36.8, 35.8, 30.1,
22.7; MS (EI, 70 eV) m/z: 162.26, 147.24, 19.20, 92.20; HRMS ESI (m/z): calcd for
C10H15N2 [M + H]+: 163.1230, found: 163.1230.
2,4,5,6-Tetrahydrobenzo[3,4]cyclohepta[1,2-c]pyrazole (4j)
The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 10:1), the product was
isolated as a black oil (60.7 mg, 66%); IR (KBr): 3066, 2935, 1601, 1440, 759 cm−1;
1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 3.3 Hz, 1H), 7.27ꢀ7.16 (m, 3H), 6.96 (t, J
= 7.4 Hz, 1H), 6.20 (d, J = 7.8 Hz, 1H), 3.11ꢀ2.96 (m, 2H), 2.45 (dt, J = 7.4, 6.5 Hz,
1H), 2.00 (dd, J = 14.7, 9.0 Hz, 2H), 1.79 (t, J = 10.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ ppm 147.6, 143.2, 137.6, 130.3, 128.2, 126.6, 126.0, 125.4, 98.6, 29.5, 29.5,
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21.9; MS (EI, 70 eV) m/z: 184.09, 169.06, 128.06, 115.07; HRMS ESI (m/z): calcd
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for C12H13N2 [M + H]+: 185.1073, found: 185.1070.
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9-Methoxy-2,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1,2-c]pyrazole (4k)
The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 5:1), the product was
isolated as a black oil (90.0 mg, 84%); IR (KBr): 3096, 2936, 1605, 1497, 1244, 1036
cm−1; 1H NMR (400 MHz, CDCl3) δ ppm 7.65 (d, J = 3.3 Hz, 1H), 7.16 (dd, J = 8.3,
5.9 Hz, 2H), 6.78 (dd, J = 8.5, 2.7 Hz, 1H), 5.71 (d, J = 2.6 Hz, 1H), 3.61 (s, 3H),
2.96 (tdd, J = 11.6, 9.2, 4.5 Hz, 2H), 2.46ꢀ2.37 (m, 1H), 2.05ꢀ1.94 (m, 2H), 1.77 (dd, J
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= 15.9, 5.9 Hz, 1H); C NMR (100 MHz, CDCl3) δ ppm 157.6, 147.6, 143.1, 131.1,
129.6, 127.4, 114.8, 109.7, 98.7, 55.1, 29.4, 28.7, 22.1; MS (EI, 70 eV) m/z: 214.30,
199.26, 183.25, 156.22; HRMS ESI (m/z): calcd for C13H15N2O [M + H]+: 215.1179,
found: 215.1178.
9-Chloro-2,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1,2-c]pyrazole (4l)
The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 10:1), the product was
isolated as a black oil (79.7 mg, 73%); IR (KBr): 3094, 2939, 1590, 1479, 807 cm−1;
1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 3.3 Hz, 1H), 7.15 (dd, J = 6.7, 3.2 Hz, 3H),
6.18 (s, 1H), 3.09ꢀ2.91 (m, 2H), 2.44 (dt, J = 17.6, 7.6 Hz, 1H), 2.03ꢀ1.96 (m, 2H),
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1.80 (dd, J = 18.3, 8.7 Hz, 1H); C NMR (100 MHz, CDCl3) δ ppm 147.0, 143.7,
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136.0, 131.5, 131.5, 128.4, 128.4, 125.3, 98.1, 29.2, 29.0, 21.7; MS (EI, 70 eV) m/z:
218.24, 183.27, 156.25, 127.20; HRMS ESI (m/z): calcd for C12H12ClN2 [M + H]+:
219.0684, found: 219.0682.
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8-Methoxy-2,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1,2-c]pyrazole (4m)
The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 5:1), the product was
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isolated as a black amorphous solid (84.6 mg, 79%), mp 150.3ꢀ151.2 C; IR (KBr):
2934, 1602, 1254, 1038, 822 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 3.3 Hz,
1H), 7.13 (d, J = 3.3 Hz, 1H), 6.75 (d, J = 2.5 Hz, 1H), 6.54 (dd, J = 8.6, 2.6 Hz, 1H),
6.14 (d, J = 8.6 Hz, 1H), 3.75 (s, 3H), 3.09ꢀ2.94 (m, 2H), 2.50ꢀ2.37 (m, 1H),
2.04ꢀ1.93 (m, 2H), 1.85ꢀ1.76 (m, 1H); 13C NMR (100 MHz, CDCl3) δ ppm 159.3,
147.6, 142.9, 139.1, 123.6, 118.5, 114.6, 112.5, 98.2, 55.1, 29.9, 29.5, 21.9; MS (EI,
70 eV) m/z: 214.28, 199.25, 171.23, 130.22; HRMS ESI (m/z): calcd for C13H15N2O
[M + H]+: 215.1179, found: 215.1175.
8,9-Dimethoxy-2,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1,2-c]pyrazole (4n)
The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 3:1), the product was
isolated as a brown oil (107.5 mg, 88%); IR (KBr): 3337, 2934, 1737, 1513, 1253,
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1034 cm−1; H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 3.3 Hz, 1H), 7.15 (d, J = 3.3
Hz, 1H), 6.69 (s, 1H), 5.62 (s, 1H), 3.84 (s, 3H), 3.62 (s, 3H), 3.04ꢀ2.88 (m, 2H),
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2.45ꢀ2.36 (m, 1H), 2.04ꢀ1.93 (m, 2H), 1.74 (dd, J = 13.1, 6.7 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ ppm 149.0, 147.8, 147.3, 142.9, 130.2, 118.0, 112.4, 107.6, 98.4, 55.7,
55.7, 29.4, 29.2, 22.1; MS (EI, 70 eV) m/z: 244.30, 229.28, 201.27, 160.23; HRMS
ESI (m/z): calcd for C14H17N2O2 [M + H]+: 245.1285, found: 245.1290.
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4-Methyl-2,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1,2-c]pyrazole (4o)
The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 10:1), the product was
isolated as a yellow oil (61.5 mg, 62%); IR (KBr): 3190, 2935, 1730, 1453, 949, 754
cm−1; 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.1 Hz, 1H), 7.45 (s, 1H), 7.21ꢀ7.12
(m, 3H), 6.28 (dr, 1H), 3.09ꢀ2.86 (m, 1H), 2.81ꢀ2.62 (m, 2H), 2.19ꢀ2.01 (m, 1H),
1.70ꢀ1.56 (m, 1H), 1.22 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ ppm
141.6, 136.0, 130.2, 129.5, 127.7, 127.0, 126.4, 125.9, 123.5, 36.3, 33.0, 30.3, 22.9;
MS (EI, 70 eV) m/z: 198.28, 183.27, 168.24, 115.21; HRMS ESI (m/z): calcd for
C13H15N2 [M + H]+: 199.1230, found: 199.1233.
4,5-Dihydro-2H-benzo[6,7]oxepino[4,5-c]pyrazole (4p)
The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 10:1), the product was
isolated as a black oil (49.4 mg, 53%); IR (KBr): 3093, 2962, 1486, 1228, 761 cm−1;
1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 3.3 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.12
(d, J = 3.3 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 6.72 (t, J = 7.5 Hz, 1H), 6.25 (d, J = 7.8
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Hz, 1H), 4.82 (td, J = 11.0, 2.4 Hz, 1H), 4.43 (ddd, J = 11.2, 4.9, 3.6 Hz, 1H), 2.23
(ddd, J = 13.8, 10.2, 3.4 Hz, 1H), 1.89 (ddd, J = 14.0, 5.1, 2.4 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ ppm 155.3, 145.4, 144.4, 130.1, 126.1, 120.6, 118.2, 112.8, 94.2, 61.5,
27.7; MS (EI, 70 eV) m/z: 186.26, 171.23, 128.21, 115.20; HRMS ESI (m/z): calcd
for C11H11N2O [M + H]+: 187.0866, found: 187.0866.
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4,5,6,7-Tetrahydro-2H-benzo[3,4]cycloocta[1,2-c]pyrazole (4q)
The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 10:1), the product was
isolated as a brown oil (49.5 mg, 50%); IR (KBr): 3320, 2922, 2861, 1732, 754 cm−1;
1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 3.3 Hz, 1H), 7.51 (d, J = 3.4 Hz, 1H),
7.21ꢀ7.13 (m, 2H), 7.01 (ddd, J = 19.0, 10.4, 5.1 Hz, 2H), 3.19 (ddd, J = 24.5, 14.5,
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9.1 Hz, 2H), 2.41ꢀ2.18 (m, 2H), 2.01ꢀ1.42 (m, 4H); C NMR (100 MHz, CDCl3) δ
ppm 144.0, 143.1, 142.1, 136.2, 130.9, 128.0, 126.4, 126.1, 102.5, 36.6, 34.4, 31.0,
27.8; MS (EI, 70 eV) m/z: 198.13, 183.12, 169.10, 142.10; HRMS ESI (m/z): calcd
for C13H15N2 [M + H]+: 199.1230, found: 199.1228.
(R)-8-Methyl-5-(prop-1-en-2-yl)-2,4,5,6-tetrahydrocyclohepta[c]pyrazole (6)
The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 10:1), the product was
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isolated as a brown oil (73.4 mg, 78%); IR (KBr): 2908, 1730, 1657, 1047 cm−1; H
NMR (400 MHz, CDCl3) δ 9.81 (dr, 1H), 7.45 (s, 1H), 5.46 (t, J = 5.3, 5.3 Hz, 1H),
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4.73 (s, 2H), 3.11ꢀ2.88 (m, 2H), 2.52 (ddd, J = 10.0, 7.8, 2.6 Hz, 1H), 2.48ꢀ2.38 (m,
2H), 2.01 (d, J = 1.2 Hz, 3H), 1.77 (s, 3H); 13C NMR (100 MHz, CDCl3) δ ppm 149.6,
144.3, 132.5, 126.2, 122.9, 119.4, 109.3, 41.2, 36.1, 33.4, 23.1, 20.5; MS (EI, 70 eV)
m/z: 188.30, 173.28, 147.24, 131.21; HRMS ESI (m/z): calcd for C12H17N2 [M + H]+:
189.1386, found: 189.1383. [α]D20 = 37.7 (c 0.945, CH2Cl2).
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(5S,5aR,7S)-5,5a-Dimethyl-7-(prop-1-en-2-yl)-2,4,5,5a,6,7,8,9-octahydrobenzo[5,6
]cyclohepta[1,2-c]pyrazole (8)
The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 10:1), the product was
isolated as a brown oil (57.6 mg, 45%); IR (KBr): 3164, 2933, 1733, 1447, 884 cm−1;
1H NMR (400 MHz, CDCl3) δ 8.81 (dr, 1H), 7.32 (s, 1H), 6.07 (s, 1H), 4.71 (s, 2H),
2.92ꢀ2.72 (m, 2H), 2.60ꢀ2.19 (m, 4H), 1.93ꢀ1.72 (m, 5H), 1.32ꢀ1.24 (m, 2H),
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1.14ꢀ0.98 (m, 6H); C NMR (100 MHz, CDCl3) δ ppm 150.2, 146.8, 143.6, 132.5,
116.9, 112.8, 108.7, 45.7, 43.3, 41.0, 40.9, 37.0, 33.6, 30.8, 20.8, 19.5, 17.6; MS (EI,
70 eV) m/z: 256.18, 213.15, 187.12, 145.10; HRMS ESI (m/z): calcd for C17H25N2 [M
+ H]+: 257.2012, found: 257.2011. Anal. Calcd for C17H24N2: C, 79.64; H, 9.44; N,
10.92; Found: C, 79.98; H, 9.34; N, 10.68. [α]D20 = 85.3 (c 0.842, CH2Cl2).
D2-4m
The title compound was prepared via the general procedure. After purification by
silica gel column chromatography (petroleum ether/EtOAc = 5:1), the product was
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