Thermal [3+2] cycloaddition reaction of azomethine imines with allenoates for dinitrogen-fused heterocycles

Article abstract of DOI:10.1016/j.tet.2012.01.029

The thermal [3+2] cycloaddition reactions of two classes of azomethine imines with allenoates have been investigated. The reactions are operationally simple and proceed smoothly under mild reaction conditions to provide a variety of dinitrogen-fused heter

Full text of DOI:10.1016/j.tet.2012.01.029

Tetrahedron 68 (2012) 2349e2356
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Thermal [3þ2] cycloaddition reaction of azomethine imines with allenoates
for dinitrogen-fused heterocycles
,
Risong Na a, Honglei Liu a, Zhen Li a, Bo Wang a, Jun Liu a b, Ming-An Wang a, Min Wang a,
,
Jiangchun Zhong a, Hongchao Guo a
*
a Department of Applied Chemistry, China Agricultural University, 2 West Yuanmingyuan Road, Beijing 100193, PR China
b Chemical Industry Press, 13 Qingnianhu South St., Beijing 100011, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The thermal [3þ2] cycloaddition reactions of two classes of azomethine imines with allenoates have
been investigated. The reactions are operationally simple and proceed smoothly under mild reaction
conditions to provide a variety of dinitrogen-fused heterocycles in moderate to excellent yields.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 15 November 2011
Received in revised form 29 December 2011
Accepted 13 January 2012
Available online 20 January 2012
Keywords:
Azomethine imine
[3þ2] Cycloaddition
Allenoate
Thermal
Dinitrogen-fused heterocycle
1. Introduction
fused heterocycles, such as tetrahydropyrazolo-pyrazolone,
-pyridazinone, -diazepinone, and -diazocinone,5 which are key
1,3-Dipolar cycloaddition reaction has emerged as one of the
most powerful tools for the construction of a variety of hetero-
cycles from simpler starting materials.1 Various 1,3-dipoles such
as nitrone, azomethine ylide, azomethine imine, nitrile oxide,
carbonyl ylide, azide, nitrile imine, carbonyl oxide, diazoalkane,
and diazoacetate have been used for all kinds of target hetero-
cycles.1 Among these 1,3-dipoles, azomethine imine is a highly
attractive one due to its salient features such as easy preparation,
stability, and the potential application of the corresponding
cycloadduct.2 It has been employed as efficient 1,3-dipole in
various thermal, metal-catalyzed, and organocatalytic cycload-
ditions.2,3 Various dipolarophiles such as alkenes and alkynes
could undergo [3þ2] cycloaddition with azomethine imines to
furnish the useful heterocycles.2,3 Although the allenes have
similar reaction mode as alkenes and alkynes and have been
extensively studied in the cycloaddition reactions with numerous
1,3-dipoles,4 the cycloaddition of allenoates with azomethines
has been overlooked for so many years. Most recently, we re-
ported first phosphine-catalyzed [3þ2], [3þ3], [4þ3], and
[3þ2þ3] annulation reactions of allenoates with azomethine
imines, providing generally applicable routes toward dinitrogen-
units in or building blocks of many pharmaceuticals, agrochem-
icals, biologically active compounds, and other useful chemicals.6
In the study of the phosphine-catalyzed cycloadditions, when the
reaction temperature was higher than room temperature, the
thermal cycloaddition product was often observed and isolated
as side-product. It prompted us to investigate thermal cycload-
dition reaction of azomethine imines with allenoates in detail.
Herein, we describe first thermal [3þ2] cycloaddition of azome-
thine imines with allenoates to furnish functionalized
dinitrogen-fused heterocycles (Scheme 1).
2. Results and discussion
The two classes of azomethine imines, C,N-cyclic azomethine
imines 1 and N,N0-cyclic azomethine imines 2, were investigated in
our research and prepared according to the reported procedur-
e.3j,m,n,cc,7 We first tried the reaction of C,N-cyclic azomethine imine
1a with the allenoate 2a in dichloromethane at room temperature.
The reaction was sluggish to give the corresponding annulation
product as a diastereomeric mixture of 4aa and 40aa in 40% yield,
which couldn’t be separated by silica gel chromatography (Table 1,
entry 1).8 Using the NMR spectroscopy and X-ray crystallography9
(Fig. 1), the structures of 4aa and 40aa were established to be
[3þ2] cycloaddition products, and the product 4aa was the major
* Corresponding author. Tel.: þ86 10 62731356; fax: þ86 10 62820325; e-mail
address: hchguo@cau.edu.cn (H. Guo).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.029

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R. Na et al. / Tetrahedron 68 (2012) 2349e2356
isomer. Considering the efficiency of thermal cycloaddition re-
action depends on the reaction temperature, the temperature was
increased to 40 ꢀC from room temperature, and accordingly the
yield was improved to 65% (entry 2). Next, the reactions were
performed at 80 ꢀC in several high boiling solvents such as 1,2-
dichloroethane, isopropanol, toluene, and N,N-dimethylforma-
mide. In these cases, a significant solvent effect was observed. The
isopropanol proved to be the optimal solvent to give 86% yield
(entry 4). In contrast, 1,2-dichloroethane and toluene afford 66%
and 79% yields, respectively, and N,N-dimethylformamide only
provided poor 42% yield (entries 3, 5, 6).
Allenes bear quite useful 1,2-propadiene system. Both C]C
bonds are active positions for dipolar attack, which can proceed
with two opposite orientations, especially, allenes possessing
electron-withdrawing substituents are very active to undergo di-
polar cycloaddition. Therefore, the cycloaddition reaction of azo-
methine imine 1a with the allenoate 2a might follow three possible
reaction pathways (Scheme 2). However, the cycloaddition product
5 and 50 hadn’t been observed. The cycloaddition reaction of azo-
methine imine with allenoate was highly regioselective to afford
the 2-exo methylene isomer as sole regioisomer, which possessed
two chiral carbons and was isolated as the diastereomeric mixture
(4aa and 40aa). It is quite interesting that a quaternary carbon
center was incorporated into the molecular skeleton of the prod-
ucts 4aa and 40aa.
Scheme 1. The thermal [3þ2] cycloaddition of azomethine imines with allenoates.
Table 1
The thermal cycloaddition of
a-benzyl allenoate 3a with C,N-cyclic azomethine
imines 1aa
Ph
CO2Et
+
N
Bz
N
1a
3a
Entry
Temp (ꢀC)
Solvent
Productb
Yieldc (%)
1
2
3
4
5
6
25
40
80
80
80
80
CH2Cl2
CH2Cl2
ClCH2CH2Cl
i-PrOH
Toluene
DMF
4aaþ40aa
4aaþ40aa
4aaþ40aa
4aaþ40aa
4aaþ40aa
4aaþ40aa
44
65
N
N
N
Bz
Ph
Bz
Bz
N
N
N
66
EtO2C
86d
79
EtO2C
Ph
42
Ph
EtO2C
a
Allenoate (1.2 equiv) was used. The reaction time was 48 h.
b
c
The 4aa/40aa ratios were not determined, except the case in entry 4.
Isolated yields.
d
The 4aa/40aa ratio was 90:10, based on integration of signals in the 1H NMR
spectrum.
N
N
N
Bz
Bz
N
N
Bz
N
H
EtO2C
EtO2C
EtO2C
Ph
Ph
4aa 4'aa
Ph
5
5'
+
Scheme 2. The possible reaction pathways of thermal [3þ2] cycloaddition of azome-
thine imines with allenoates.
Under the optimal reaction conditions (in isopropanol at 80 ꢀC),
the reactions of a range of distinctly substituted allenoates 3 with
the azomethine imine 1a were carried out for 48 h, giving the de-
rivatives of ethyl 3-benzoyl-2-methylene-1,2,3,5,6,10b-hexahy-
dropyrazolo[5,1-a]isoquinoline-1-carboxylate 4 and 40 as a mixture
of diastereomers in moderate to excellent yields with high dia-
stereoselectivity (Table 2). Although the R in allenoate is far away
from the reacted double bond, it still exerted certain influence on
the course of the reaction. A variety of
b
0-aryl-substituted alle-
noates underwent the cycloaddition reaction smoothly, providing
the corresponding product in good to excellent yields (entries 1e9).
Fig. 1. The X-ray structure of 4aa.

R. Na et al. / Tetrahedron 68 (2012) 2349e2356
2351
Table 2
Table 3
The thermal cycloaddition of
a
-substituted allenoate 3 with C,N-cyclic azomethine
The thermal cycloaddition of
a
-benzyl allenoate 3a with C,N-cyclic azomethine
imine 1aa
imines 1a
Entry
R
Product
Yieldb (%)
Ratio (4/40)c
Entry
R
Product
Yieldb (%)
Ratio (4/40)c
1
2
3
4
5
6
7
8
Ph (3a)
4aaþ40aa
4abþ40ab
4acþ40ac
4adþ40ad
4aeþ40ae
4afþ40af
4agþ40ag
4ahþ40ah
4aiþ40ai
86
85
80
62
83
93
84
87
91
48
67
76
49
52
90:10
89:11
90:10
81:19
87:13
87:13
83:17
86:14
86:14
88:12
83:17
88:12
88:12
92:8
1
2
3
4
5
7-Cl (1b)
7-Br (1c)
6-Br (1d)
5-Me (1e)
7-Me (1f)
4baþ40ba
4caþ40ca
4daþ40da
4eaþ40ea
4faþ40fa
78
77
80
77
89
85:15
85:15
85:15
85:15
85:15
3-ClC6H4 (3b)
4-ClC6H4 (3c)
2-BrC6H4 (3d)
3-BrC6H4 (3e)
4-BrC6H4 (3f)
2-MeC6H4 (3g)
3-MeC6H4 (3h)
4-MeC6H4 (3i)
Vinyl (3j)
a
Allenoate (1.2 equiv) was used.
Isolated yields.
b
c
Based on integration of signals in the 1H NMR spectrum.
9
10
11
12
13
14
4ajþ40aj
Styryl (3k)
CO2Et (3l)
H (3m)
4akþ40ak
4alþ40al
Table 4
4amþ40am
4anþ40an
The thermal cycloaddition of
g
-substituted allenoates 3 with C,N-cyclic azomethine
imine 1aa
Et (3n)
a
Allenoate (1.2 equiv) was used.
Isolated yields.
b
c
Based on integration of signals in the 1H NMR spectrum.
Allenoates featuring aryl groups with electron-withdrawing
worked very well as those substrates with electron-donating sub-
stituents under otherwise identical conditions. The reaction of b0
-
b
0-ethoxycarbonyl-substituted allenoates gave slightly
Entry
R
Product
Yieldb (%)
styryl- and
lower yields of the cycloaddition products (entries 11 and 12). In
comparison, the reactions of
0-vinyl-, 0-hydrogen-, and 0-ethyl-
1
2
3
4
5
Me (3o)
Et (3p)
i-Pr (3q)
t-Bu (3r)
Ph (3s)
4ao
4ap
4aq
4ar
4as
71
60
65
41
35
b
b
b
substituted allenoates were relative sluggish, affording their cor-
responding products in moderate yields (entries 10, 13, and 14). In
all cases, the diastereoselectivities ranged in narrow scope from
81:19 to 92:8. The diastereomeric mixture couldn’t be separated by
flash silica gel column. In particular, by recrystallizing the mixture
in methanol and dichloromethane, the product 4ak could be ob-
tained as a single diastereomer.
a
Allenoate (1.2 equiv) was used.
Isolated yields.
b
reaction was monitored using TLC, several spots could be observed,
but the amount of some products was too small to be isolated.
After the completion of the investigation on the reaction of C,N-
cyclic azomethine imines 1 with allenoates, the reaction of N,N0-
cyclic azomethine imines 2 with allenoates was examined. Com-
The reactions of several azomethine imines 1 bearing different
substituents on the benzene ring with a-benzyl allenoate 3a also
worked efficiently in isopropanol at 80 ꢀC to provide the corre-
sponding [3þ2] cycloaddition products in high yields and with
uniformly high diastereoselectivities (Table 3, entries 1e5). It seems
the substituents on the benzene ring of the azomethine imines 1
didn’t essentially influence the reaction process and diaster-
eoselectivity. Electron-donating alkyl substituted imines provided
similar yields as those with electron-withdrawing group did (en-
tries 4 and 5 vs entries 1e3).
pared with the imine 1, the imine 2 is not very active. Those
substituted allenoates and -substituted allenoates gave complex
a-
g
mixture in the cycloaddition reactions with 2 and most of imines
couldn’t completely convert even at 110 ꢀC. Only ethyl 2,3-
butadienoate (3t) could carry out the cycloaddition reaction in
1,2-dichloroethane at 80 ꢀC to give the derivatives of ethyl 3-
methyl-5-oxo-1,5,6,7-tetrahydropyrazolo[1,2-a]pyrazole-2-carbox
ylate in good to excellent yields (Table 5). The structure of 6 was
determined to be a [3þ2] cycloaddition product by NMR spectra
and the X-ray crystallography9 (Fig. 2). Interestingly, a remarkable
electronic effect related to the stability of [3þ2] cycloaddition
product was observed. The products from the annulation reaction
Besides
3oe3s had been studied in the cycloaddition reaction too. Com-
pared with the former, the reactions of -substituted allenoates
with azomethine imine 1a were lethargic, affording the corre-
sponding product in moderate to good yield (Table 4). The -alkyl-
a-substituted allenoates, g-substituted allenoates
g
g
substituted allenoates underwent the reaction to give fair yields of
of aromatic azomethine imines
2 bearing strong electron-
the cycloaddition products (entries 1e3), but the bulky tert-butyl
resulted in the low 41% yield (entry 4). The reaction of g-phenyl-
substituted allenoate only afforded poor yield of the corresponding
product (entry 5). Although a single diastereoisomer 4 was isolated
on the basis of NMR and 2D NMR data, it couldn’t be excluded that
other diastereomer or regiomer hadn’t been generated. When the
withdrawing groups (2ae2c) were very stable and could be
stored at room temperature for a couple of weeks. Thephenylimine
and those aromatic imines containing weak electron-withdrawing or
electron-donating groups also carried out the annulation reaction
with high conversion, but the corresponding products were not very
stable and decomposed easily in the solution in 24 h.

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R. Na et al. / Tetrahedron 68 (2012) 2349e2356
Table 5
based diffractometer equipped with a low-temperature apparatus
operated at 100 K.
The thermal cycloaddition of allenoate 3t with N,N0-cyclic azomethine imines 2a
4.2. General procedure for the [3D2] annulations products of
azomethine imines and allenoates
A solution of azomethine imine 1 or 2 (0.125 mmol) and the
allenoate (0.15 mmol) in 5 mL of solvent (isopropanol for the imine
1, 1,2-dichloroethane for the imine 2) was stirred at 80 ꢀC for 48 h
and then concentrated. The residue was purified through flash
column chromatography (EtOAc/hexane) to afford the corre-
sponding cycloaddition product.
Entry
R
Product
Yieldb (%)
1
2
3
4
5
2-NO2C6H4 (2a)
3-NO2C6H4 (2b)
4-NO2C6H4 (2c)
2-ClC6H4 (2d)
2-BrC6H4 (2e)
6at
6bt
6ct
6dt
6et
73
77
82
90
92
4.3. Characterization data for the [3D2] annulation products
4 and 6
a
Allenoate (1.2 equiv) was used.
Isolated yield.
b
Although some annulation products (4 and 40 in Tables 1e3)
were the diastereomeric mixture, which couldn’t be separated by
the flash silica gel column, the NMR signals of the product 4 could
be clearly read and picked out from the NMR spectra of the di-
astereomeric mixture. For the products in Tables 1e3, the IR data
and HRMS data were collected by using the diastereomeric mixture
of 4 and 40.
4.3.1. Ethyl 3-benzoyl-1-benzyl-2-methylene-1,2,3,5,6,10b-hexahy-
dro-pyrazolo[5,1-a]isoquinoline-1-carboxylate (4aa). Yield 86%,
a foam-like white solid. IR (neat) nmax 508, 634, 666, 702, 738, 760,
784, 863, 908, 949, 1011, 1046, 1077, 1106, 1200, 1231, 1283, 1340,
1383, 1446, 1454, 1495, 1580, 1602, 1636, 1663, 1728, 2893, 2981,
3027, 3062 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 7.52e7.00 (m, 14H),
6.15 (s, 1H), 5.06 (d, J¼1.1 Hz, 1H), 4.84 (s, 1H), 3.83e3.44 (m, 5H),
2.78e2.48 (m, 3H), 0.76 (t, J¼7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d
171.6, 167.3, 145.9, 135.8, 135.4, 133.7, 132.6, 131.0, 130.0, 128.5,
128.2, 127.8, 127.4, 127.2, 127.1, 126.0, 125.7, 100.5, 64.9, 61.6, 61.2,
48.5, 44.8, 28.6, 13.3; HRMS (EI) calcd for C29H29N2Oþ3 [MþH]þ
453.2173, found 453.2172.
Fig. 2. The X-ray structure of 6ct.
4.3.2. Ethyl 3-benzoyl-1-(3-chlorobenzyl)-2-methylene-1,2,3,5,6,10b-
hexahydropyrazolo[5,1-a]isoquinoline-1-carboxylate
(4ab). Yield
3. Conclusions
85%, a foam-like white solid. IR (neat) nmax 636, 667, 702, 738, 761,
788, 866, 908, 949, 1012, 1046, 1080, 1104, 1200, 1232, 1283, 1339,
1382, 1428, 1446, 1476, 1495, 1573, 1598, 1663, 1728, 2898, 2989,
In summary, the thermal [3þ2] cycloaddition reactions of two
classes of azomethine imines with allenoates have been explored.
To the best of our knowledge, this is first time to employ allenoate
as dipolarophile in thermal 1,3-dipolar cycloaddition of azomethine
imines. The reactions are operationally simple and work efficiently
to afford a broad range of dinitrogen-fused heterocycles in mod-
erate to excellent yield.
3027, 3063 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 7.50e6.95 (m, 13H),
6.14 (s, 1H), 5.02 (d, J¼1.2 Hz, 1H), 4.78 (s, 1H), 3.81e3.42 (m, 5H),
2.84e2.36 (m, 3H), 0.76 (t, J¼7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d
171.3, 167.2, 145.5, 137.9, 135.1, 134.2, 133.7, 132.2, 131.0, 130.1,
129.7, 129.1, 128.3, 127.8, 127.6, 127.5, 127.3, 127.2, 126.1, 125.7, 101.0,
64.8, 62.2, 61.3, 48.5, 44.4, 28.6, 13.3; HRMS (EI) calcd for
C29H28ClN2Oþ3 [MþH]þ 487.1783, found 487.1783.
4. Experimental
4.1. General
4.3.3. Ethyl 3-benzoyl-1-(4-chlorobenzyl)-2-methylene-1,2,3,5,6,10b-
hexahydropyrazolo[5,1-a]isoquinoline-1-carboxylate
(4ac). Yield
80%, a foam-like white solid. IR (neat) nmax 479, 515, 597, 635, 666,
701, 738, 762, 787, 832, 864, 908, 928, 950, 1015, 1045, 1078, 1096,
1200, 1232, 1283, 1339, 1382, 1446, 1493, 1579, 1600, 1635, 1662,
Unless otherwise stated, all reagents were purchased from
commercial suppliers and used without further purification. Or-
ganic solutions were concentrated under reduced pressure using
a rotary evaporator or oil pump. Reactions were monitored through
thin-layer chromatography (TLC) on silica gel-precoated glass
plates. Chromatograms were visualized by fluorescence quenching
under UV light at 254 nm. Flash column chromatography was
performed using Qingdao Haiyang flash silica gel (200e300 mesh).
Infrared spectra were recorded using a Bruker Optics TENSOR 27
instrument. 1H and 13C NMR spectra were recorded using a Bruker-
300 spectrometer. Accurate mass measurements were performed
using an Agilent instrument with the ESI-MS technique. X-ray
crystallographic data were collected using a Bruker SMART CCD-
1728, 2902, 2934, 2980, 3028, 3062 cmꢁ1 1H NMR (300 MHz,
;
CDCl3)
d
7.42e7.02 (m, 13H), 6.14 (s, 1H), 5.01 (d, J¼1.2 Hz, 1H), 4.75
(s, 1H), 3.83e3.66 (m, 2H), 3.66e3.45 (m, 3H), 2.79e2.55 (m, 3H),
0.76 (t, J¼7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 171.3, 167.4, 145.5,
135.1, 134.3, 133.7, 133.5, 132.3, 132.2, 130.2, 128.6, 128.5, 128.3,
127.7, 127.52, 127.48, 127.36, 127.2, 126.0, 125.7, 101.0, 64.8, 62.1,
61.3, 48.5, 44.1, 28.6, 13.3; HRMS (EI) calcd for C29H28ClN2O3þ
[MþH]þ 487.1783, found 487.1783.
4.3.4. Ethyl 3-benzoyl-1-(2-bromobenzyl)-2-methylene-1,2,3,5,6,10b
-hexahydropyrazolo[5,1-a]isoquinoline-1-carboxylate (4ad). Yield

R. Na et al. / Tetrahedron 68 (2012) 2349e2356
2353
62%, a foam-like white solid. IR (neat) nmax 516, 584, 635, 666, 701,
737, 759, 783, 865, 908, 928, 950, 1030, 1043, 1078, 1105, 1178, 1231,
1266, 1283, 1313, 1336, 1382, 1446, 1471, 1496,1579, 1601, 1635,
126.0, 125.6, 100.3, 64.8, 61.4, 61.2, 48.5, 44.6, 28.6, 21.2, 13.3;
HRMS (EI) calcd for
467.2329.
C
30H31N2Oþ3 [MþH]þ 467.2329, found
1662, 1728, 2900, 2938, 2981, 3060 cmꢁ1 1H NMR (300 MHz,
;
CDCl3)
d
7.73 (dd, J¼7.8, 1.5 Hz, 1H), 7.61 (dd, J¼8.0, 1.2 Hz, 1H),
4.3.9. Ethyl 3-benzoyl-1-(4-methylbenzyl)-2-methylene-1,2,3,5,6,10b-
hexahydropyrazolo[5,1-a]isoquinoline-1-carboxylate (4ai). Yield
7.55e7.27 (m, 3H), 7.25e7.08 (m, 6H), 7.08e6.99 (m, 2H), 6.15 (s,
1H), 5.07 (s, 1H), 4.84 (s, 1H), 4.17 (d, J¼14.4 Hz, 1H), 3.80e3.59 (m,
2H), 3.56e3.27 (m, 2H), 3.12e2.44 (m, 3H), 0.73 (t, J¼7.1 Hz, 3H);
91%, a foam-like white solid. IR (neat) nmax 494, 521, 598, 633, 667,
701, 737, 762, 787, 817, 864, 908, 950, 1012, 1045, 1077, 1106, 1200,
1231, 1283, 1340, 1383, 1446, 1495, 1515, 1580, 1601, 1634, 1663,
13C NMR (75 MHz, CDCl3)
d 171.3, 167.0, 145.9, 135.3, 135.0, 133.7,
132.8,132.7,132.4, 130.1,129.0,128.3, 128.0, 127.9,127.7,127.5,127.2,
127.1, 126.9, 126.4, 126.0, 100.8, 65.5, 61.9, 61.3, 48.8, 42.9, 28.7, 13.2;
HRMS (EI) calcd for C29H28BrN2Oþ3 [MþH]þ 531.1278, found
531.1271.
1728, 2953, 2980, 3026, 3057 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
d
7.39e6.96 (m, 13H), 6.13 (s, 1H), 5.04 (d, J¼1.2 Hz, 1H), 4.83 (s,
1H), 3.80e3.64 (m, 2H), 3.63e3.42 (m, 3H), 2.79e2.46 (m, 3H), 2.23
(s, 3H), 0.75 (t, J¼7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 171.7,
167.4, 146.0, 137.0, 135.4, 133.6, 132.6, 130.8, 129.9, 129.1, 128.2,
127.8, 127.2, 127.0, 126.0, 125.7, 100.3, 64.9, 61.4, 61.2, 48.5, 44.4,
28.6, 20.9, 13.3; HRMS (EI) calcd for C30H31N2Oþ3 [MþH]þ 467.2329,
found 467.2329.
4.3.5. Ethyl 3-benzoyl-1-(3-bromobenzyl)-2-methylene-1,2,3,5,6,10b-
hexahydropyrazolo[5,1-a]isoquinoline-1-carboxylate
(4ae). Yield
83%, a foam-like white solid. IR (neat) nmax 636, 667, 701, 738, 761,
788, 865, 908, 949, 1012, 1046, 1075, 1105, 1200, 1232, 1283, 1339,
1382, 1426, 1446, 1475, 1495, 1567, 1600, 1637, 1663, 1728, 2892,
4.3.10. Ethyl 1-allyl-3-benzoyl-2-methylene-1,2,3,5,6,10b-hexahydro-
pyrazolo[5,1-a]isoquinoline-1-carboxylate (4aj). Yield 48%, a foam-
like white solid. IR (neat) nmax 666, 701, 740, 762, 788, 861, 909,
941, 1027, 1098, 1187, 1232, 1284, 1382, 1447, 1495, 1579, 1601, 1662,
2981, 3061 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 7.59 (s,1H), 7.44e7.00
(m, 12H), 6.14 (s, 1H), 5.02 (s, 1H), 4.78 (s, 1H), 3.83e3.41 (m, 5H),
2.82e2.33 (m, 3H), 0.77 (t, J¼7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d
171.3, 167.2, 145.4, 138.2, 135.1, 133.9, 133.7, 132.2, 130.5, 130.1,
1731, 2901, 2982 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 7.78 e 7.68 (m,
130.0, 129.6, 128.3, 127.8, 127.3, 127.2, 126.1, 125.7, 122.4, 101.0, 64.8,
62.2, 61.4, 48.5, 44.3, 28.6, 13.3; HRMS (EI) calcd for C29H28BrN2O3þ
[MþH]þ 531.1278, found 531.1278.
2H), 7.49 e 7.32 (m, 3H), 7.22 e 7.10 (m, 3H), 7.12 e 7.01 (m, 1H),
6.08 (s,1H), 5.99 e 5.82 (m,1H), 5.40 (s,1H), 5.32 (d, J ¼ 11.5 Hz,1H),
4.93 (d, J ¼ 1.2 Hz, 1H), 4.80 (s, 1H), 3.78 e 3.53 (m, 3H), 3.14 e 2.71
(m, 4H), 2.65 e 2.53 (m, 1H), 0.77 (t, J ¼ 7.1 Hz, 3H); 13C NMR
4.3.6. Ethyl 3-benzoyl-1-(4-bromobenzyl)-2-methylene-1,2,3,5,6,10b-
(75 MHz, CDCl3) d 171.6,167.4,145.3,135.4,133.6,133.0,132.0,130.4,
hexahydropyrazolo[5,1-a]isoquinoline-1-carboxylate
(4af). Yield
128.4, 128.2, 127.5, 127.2, 126.2, 125.8, 120.8, 99.9, 63.6, 63.2, 61.1,
48.3, 43.9, 28.6, 13.3; HRMS (EI) calcd for C25H27N2Oþ3 [MþH]þ
403.2016, found 403.2023.
93%, a foam-like white solid. IR (neat) nmax 513, 596, 626, 667, 702,
738, 762, 787, 811, 829, 862, 908, 950, 1012, 1044, 1108, 1201, 1231,
1283, 1339, 1383, 1446, 1489, 1579, 1601, 1634, 1661, 1728, 2898,
2981, 3027, 3062 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
7.51e7.08 (m,
4.3.11. Ethyl 3-benzoyl-1-cinnamyl-2-methylene-1,2,3,5,6,10b-hex-
ahydropyrazolo[5,1-a]isoquinoline-1-carboxylate (4ak). Yield 67%,
a foam-like white solid. IR (neat) nmax 637, 667, 699, 739, 762, 788,
861, 925, 1015, 1047, 1104, 1179, 1211, 1230, 1284, 1339, 1365, 1382,
1446, 1495, 1579, 1601, 1638, 1661, 1728, 2898, 2980, 3027,
12H), 7.03 (d, J¼5.7 Hz, 1H), 6.12 (s, 1H), 5.00 (d, J¼1.2 Hz, 1H), 4.73
(s, 1H), 3.78e3.43 (m, 5H), 2.86e2.43 (m, 3H), 0.75 (t, J¼7.1 Hz, 3H);
13C NMR (75 MHz, CDCl3)
d 171.3, 167.4, 145.5, 135.2, 134.8, 133.7,
132.7, 132.2, 131.5, 130.2, 128.3, 127.7, 127.4, 127.2, 126.0, 125.7, 121.6,
101.0, 64.8, 62.1, 61.3, 48.5, 44.2, 28.6, 13.3; HRMS (EI) calcd for
C29H28BrN2Oþ3 [MþH]þ 531.1278, found 531.1271.
3066 cmꢁ1
; d 7.65e7.54 (m, 1H),
1H NMR (300 MHz, CDCl3)
7.44e7.01 (m, 13H), 6.69 (d, J¼16.1 Hz, 1H), 6.39e6.21 (m, 1H), 6.07
(s, 1H), 5.01 (d, J¼1.1 Hz, 1H), 4.83 (s, 1H), 3.80e3.55 (m, 3H),
3.32e3.03 (m, 2H), 2.95e2.85 (m, 1H), 2.85e2.69 (m, 1H),
2.65e2.52 (m, 1H), 0.78 (t, J¼7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
4.3.7. Ethyl 3-benzoyl-1-(2-methylbenzyl)-2-methylene-1,2,3,5,6,10b-
hexahydropyrazolo[5,1-a]isoquinoline-1-carboxylate
(4ag). Yield
84%, a foam-like white solid. IR (neat) nmax 514.8, 593.8, 636,
666, 701, 738, 784, 866, 908, 951, 1010, 1059, 1077, 1112, 1208,
1230, 1283, 1383, 1446, 1493, 1579, 1602, 1635, 1662, 1728, 2901,
d 171.6, 167.9, 145.5, 136.7, 135.9, 135.4, 133.6, 132.1, 130.2, 128.6,
128.2, 128.1, 127.6, 127.5, 127.3, 126.3, 126.2, 125.9, 124.4, 100.5, 64.0,
63.7, 61.2, 48.3, 43.5, 28.6, 13.4; HRMS (EI) calcd for C31H31N2O3þ
[MþH]þ 479.2329, found 479.2334.
2980, 3026, 3060 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 7.56 (dd,
J¼7.4, 1.5 Hz, 1H), 7.61e6.99 (m, 12H), 6.09 (d, J¼0.8 Hz, 1H), 4.95
(d, J¼1.2 Hz, 1H), 4.70 (s, 1H), 3.84e3.35 (m, 5H), 2.78e2.56 (m,
3H), 2.48 (d, J¼6.3 Hz, 3H), 0.72 (t, J¼7.1 Hz, 3H); 13C NMR
4.3.12. Ethyl 3-benzoyl-1-(2-ethoxy-2-oxoethyl)-2-methylene-1,2,3,
5,6,10b-hexahydropyrazolo[5,1-a]isoquinoline-1-carboxylate
(4al). Yield 76%, a foam-like white solid. IR (neat) nmax 506, 598,
635, 667, 696, 717, 739, 784, 862, 907, 950, 976, 1013, 1028, 1047,
1084, 1105, 1231, 1283, 1338, 1381, 1447, 1495, 1578, 1600, 1662,
(75 MHz, CDCl3)
d 171.8, 167.2, 145.7, 137.6, 135.3, 134.3, 133.8,
132.8, 130.7, 130.6, 130.0, 128.30, 128.26, 127.9, 127.3, 127.2, 127.0,
126.3, 126.0, 125.7, 100.9, 65.4, 62.8, 61.2, 48.6, 40.6, 28.8, 21.0,
13.2; HRMS (EI) calcd for C30H31N2Oþ3 [MþH]þ 467.2329, found
467.2329.
1727, 2900, 2981, 3027, 3059 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
d
7.83e7.74 (m, 2H), 7.43e7.28 (m, 3H), 7.19e7.11 (m, 3H), 7.05 (dd,
J¼7.5, 4.7 Hz, 1H), 6.06 (s, 1H), 5.13 (s, 1H), 5.07 (d, J¼1.3 Hz, 1H),
4.25e4.04 (m, 2H), 3.77e3.52 (m, 3H), 3.29 (dd, J¼48.0, 16.4 Hz,
2H), 3.01e2.67 (m, 2H), 2.58 (dd, J¼16.1, 2.4 Hz, 1H), 1.23 (t,
J¼7.1 Hz, 3H), 0.76 (t, J¼7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
4.3.8. Ethyl 3-benzoyl-1-(3-methylbenzyl)-2-methylene-1,2,3,5,6,10b-
hexahydropyrazolo[5,1-a]isoquinoline-1-carboxylate
(4ah). Yield
87%, a foam-like white solid. IR (neat) nmax 525, 604, 636, 666, 702,
737, 762, 788, 861, 908, 927, 950, 1011, 1046, 1077, 1105, 1178, 1203,
1231, 1266, 1283, 1340, 1383, 1446, 1494, 1580, 1603, 1635, 1663,
d
170.9, 169.9, 167.7, 145.1, 135.6, 133.6, 131.3, 130.2, 128.5, 128.34,
128.26, 127.52, 127.48, 127.4, 126.6, 125.7, 100.8, 64.8, 61.8, 61.4,
60.9, 48.0, 43.3, 28.5, 14.1, 13.3. HRMS (EI) calcd for C26H29N2O5þ
[MþH]þ 449.2071, found 449.2070.
1728, 2954, 2980, 3027, 3058 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
d
7.34e6.95 (m, 13H), 6.13 (s, 1H), 5.07 (d, J¼1.1 Hz, 1H), 4.83 (s,
1H), 3.80e3.66 (m, 2H), 3.56 (dd, J¼25.9, 14.0 Hz, 3H), 2.78e2.43
(m, 3H), 2.23 (s, 3H), 0.75 (t, J¼7.1 Hz, 3H); 13C NMR (75 MHz,
4.3.13. Ethyl 3-benzoyl-1-methyl-2-methylene-1,2,3,5,6,10b-hexahy-
dropyrazolo[5,1-a]isoquinoline-1-carboxylate (4am). Yield 49%,
a foam-like white solid. IR (neat) nmax 668, 701, 739, 764, 788, 862,
CDCl3)
d 171.6, 167.2, 146.0, 138.2, 135.7, 135.4, 133.6, 132.6, 131.4,
129.8, 128.31, 128.25, 128.15, 128.1, 128.0, 127.6, 127.4, 127.2, 127.0,

2354
R. Na et al. / Tetrahedron 68 (2012) 2349e2356
908, 954, 1020, 1115, 1179, 1211, 1234, 1283, 1337, 1382, 1446, 1496,
1578, 1601, 1634, 1660, 1728, 2892, 2982, 3027, 3062 cmꢁ1; 1H NMR
23.2, 22.4, 13.6; HRMS (EI) calcd for C25H29N2Oþ3 [MþH]þ 405.2173,
found 405.2179.
(300 MHz, CDCl3) d 7.92e7.74 (m, 2H), 7.49e7.30 (m, 3H), 7.24e7.02
(m, 4H), 6.05 (s, 1H), 4.86 (d, J¼1.2 Hz, 1H), 4.56 (s, 1H), 3.78e3.51
4.3.18. trans-(E)-Ethyl 3-benzoyl-2-(2,2-dimethylpropylidene)-1,2,3,
5,6, 10b-hexahydropyrazolo[5,1-a]isoquinoline-1-carboxylate
(4ar). Yield 41%, a foam-like white solid. IR (neat) nmax 662, 676,
697, 742, 761, 849, 869, 935, 986, 1029, 1086, 1124, 1174, 1211, 1244,
1274, 1336, 1364, 1386, 1427, 1446, 1476, 1579, 1657, 1706, 1733,
(m, 3H), 2.90e2.70 (m, 2H), 2.64e2.51 (m, 1H), 1.88 (s, 3H), 0.77 (t,
J¼7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 172.1, 167.5, 148.3, 135.4,
133.5, 131.6, 130.5, 128.5, 128.3, 127.5, 127.4, 126.3, 125.9, 98.4, 68.5,
61.1, 60.6, 47.7, 28.65, 28.60, 13.4; HRMS (EI) calcd for C23H25N2O3þ
[MþH]þ 377.1860, found 377.1860.
2904, 2958, 3027, 3061 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
7.70e7.61 (m, 2H), 7.41e7.27 (m, 3H), 7.25e7.09 (m, 3H),
4.3.14. Ethyl 3-benzoyl-2-methylene-1-propyl-1,2,3,5,6,10b-hexahy-
dropyrazolo[5,1-a]isoquinoline-1-carboxylate (4an). Yield 52%,
a foam-like white solid. IR (neat) nmax 667, 701, 737, 763, 788, 859,
907, 938, 1039, 1112, 1178, 1211,1229, 1282, 1382, 1447, 1494, 1579,
7.09e6.96 (m, 1H), 6.84 (d, J¼2.0 Hz,1H), 4.80 (d, J¼9.1 Hz,1H), 4.45
(dd, J¼9.1, 2.1 Hz, 1H), 3.82e3.63 (m, 2H), 3.56 (dq, J¼10.8, 7.1 Hz,
1H), 2.89 (ddd, J¼10.3, 5.6, 1.7 Hz, 1H), 2.73 (ddd, J¼17.7, 12.3,
5.7 Hz, 1H), 2.56 (dd, J¼16.5, 2.0 Hz, 1H), 1.14 (s, 9H), 0.85 (t,
1601, 1660, 1727, 2874, 2961, 3028, 3062 cmꢁ1
;
1H NMR
J¼7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 171.9, 169.0, 136.9, 134.0,
(300 MHz, CDCl3)
d
7.78 (dd, J¼8.2, 1.3 Hz, 2H), 7.47e7.30 (m, 3H),
132.0, 130.4, 129.7, 129.05, 129.03, 128.2, 127.8, 127.43, 127.39, 125.3,
62.7, 60.8, 53.1, 47.1, 33.1, 30.3, 28.5, 13.5; HRMS (EI) calcd for
C26H31N2Oþ3 [MþH]þ 419.2329, found 419.2334.
7.22e7.11 (m, 3H), 7.13e7.00 (m, 1H), 6.02 (s, 1H), 4.87 (d,
J¼0.9 Hz, 1H), 4.71 (s, 1H), 3.72e3.48 (m, 3H), 2.99e2.72 (m, 2H),
2.70e2.54 (m, 1H), 2.23e2.12 (m, 2H), 1.78e1.45 (m, 2H), 1.05 (t,
J¼7.2 Hz, 3H), 0.76 (t, J¼7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
4.3.19. trans-(E)-Ethyl 3-benzoyl-2-benzylidene-1,2,3,5,6,10b-hexah
ydropyrazolo[5,1-a]isoquinoline-1-carboxylate (4as). Yield 35%,
a foam-like white solid. IR (neat) nmax 667, 696, 750, 764, 1019, 1179,
1261, 1276, 1364, 1390, 1494, 1661, 1730, 1811, 3006 cmꢁ1; 1H NMR
d
172.0, 167.2, 145.5, 135.4, 133.5, 132.0, 130.4, 128.4, 128.2, 127.5,
127.2, 126.5, 125.8, 100.1, 64.5, 64.4, 60.9, 48.1, 41.5, 28.6, 17.2,
14.6, 13.3; HRMS (EI) calcd for C25H29N2Oþ3 [MþH]þ 405.2173,
found 405.2173.
(300 MHz, CDCl3)
d 7.84e7.75 (m, 3H), 7.46e7.12 (m, 11H),
7.08e7.00 (m, 1H), 4.99 (d, J¼9.4 Hz, 1H), 4.75 (dd, J¼9.4, 2.3 Hz,
1H), 3.76e3.58 (m, 1H), 3.56e3.32 (m, 2H), 2.99e2.90 (m, 1H),
2.86e2.69 (m, 1H), 2.59 (d, J¼15.2 Hz, 1H), 0.73 (t, J¼7.1 Hz, 3H); 13C
4.3.15. trans-(E)-Ethyl 3-benzoyl-2-ethylidene-1,2,3,5,6,10b-hexahy-
dropyrazolo[5,1-a]isoquinoline-1-carboxylate
a foam-like white solid. IR (neat) nmax 730, 1095, 1231, 1346, 1456,
1641, 1662, 1702, 1733, 1811, 2875, 2936 cmꢁ1 1H NMR (300 MHz,
CDCl3) 7.76e7.69 (m, 2H), 7.43e7.27 (m, 3H), 7.24e7.10 (m, 3H),
(4ao). Yield
71%,
NMR (75 MHz, CDCl3) d 169.8, 168.1, 136.5, 136.2, 135.9, 133.9, 130.3,
;
128.5, 128.32, 128.28, 128.24, 127.51, 127.46, 126.7, 125.5, 118.5, 62.4,
60.6, 54.5, 48.0, 28.5, 13.4; HRMS (EI) calcd for C28H27N2Oþ3 [MþH]þ
439.2016, found 439.2016.
d
7.09e6.99 (m, 1H), 6.72 (qd, J¼7.2, 2.3 Hz, 1H), 4.90 (d, J¼9.3 Hz,
1H), 4.44e4.30 (m, 1H), 3.88e3.58 (m, 3H), 2.95e2.67 (m, 2H),
2.65e2.49 (m, 1H), 1.72 (dd, J¼7.2, 1.4 Hz, 3H), 0.90 (t, J¼7.1 Hz, 3H);
4.3.20. Ethyl 3-benzoyl-1-benzyl-9-chloro-2-methylene-1,2,3,5,6,10b-
13C NMR (75 MHz, CDCl3)
d
170.7, 167.9, 136.1, 136.0, 134.0, 130.6,
hexahydropyrazolo[5,1-a]isoquinoline-1-carboxylate
(4ba). Yield
130.0, 128.3, 128.2, 127.43, 127.38, 125.6, 112.6, 61.8, 60.9, 54.1, 47.9,
28.6, 14.5, 13.7; HRMS (EI) calcd for C23H25N2Oþ3 [MþH]þ 377.1860,
found 377.1860.
78%, a foam-like white solid. IR (neat) nmax 510, 635, 666, 702, 736,
760, 787, 816, 866, 908, 929, 946, 1011, 1045, 1097, 1132, 1198, 1228,
1274,1296, 1332,1379,1414,1446,1489,1578,1601, 1637, 1665,1729,
2901, 2980, 3027, 3060 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 7.47e7.42
4.3.16. trans-(E)-Ethyl
3-benzoyl-2-propylidene-1,2,3,5,6,10b-hex-
(m, 2H), 7.37e7.07 (m, 10H), 6.97 (d, J¼8.1 Hz, 1H), 6.15 (s, 1H), 5.09
(d, J¼1.3 Hz, 1H), 4.77 (s, 1H), 3.91e3.75 (m, 2H), 3.67e3.43 (m, 3H),
2.73e2.35 (m, 3H), 0.87 (t, J¼7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
ahydropyrazolo[5,1-a]isoquinoline-1-carboxylate (4ap). Yield 60%,
a foam-like white solid. IR (neat) nmax 620, 633, 664, 698, 761, 787,
858, 918, 961, 990, 1032, 1068, 1097, 1121, 1174, 1232, 1273, 1338,
1368, 1392, 1446, 1456, 1494, 1578, 1601, 1641, 1662, 1733, 2875,
d
171.3, 167.3, 145.6, 135.5, 135.2, 134.4, 132.3, 131.7, 131.0, 130.0,
129.5, 128.6, 127.7, 127.6, 127.3, 127.2, 125.7, 100.9, 64.8, 61.4, 48.3,
44.7, 28.2, 13.4; HRMS (EI) calcd for C29H28ClN2Oþ3 [MþH]þ
487.1783, found 487.1783.
2935, 2965, 3027, 3059 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 7.72
(dd, J¼8.3, 6.7 Hz, 2H), 7.44e7.26 (m, 3H), 7.22e7.10 (m, 3H),
7.10e7.00 (m, 1H), 6.66 (td, J¼7.7, 2.1 Hz, 1H), 4.90 (d, J¼9.3 Hz,
1H), 4.37 (dd, J¼9.3, 1.1 Hz, 1H), 3.85e3.58 (m, 3H), 2.94e2.66 (m,
2H), 2.57 (dd, J¼16.3, 1.7 Hz, 1H), 2.19e1.91 (m, 2H), 1.05 (t,
J¼7.5 Hz, 3H), 0.89 (t, J¼7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
4.3.21. Ethyl 3-benzoyl-1-benzyl-9-bromo-2-methylene-1,2,3,5,6,10b-
hexahydropyrazolo[5,1-a]isoquinoline-1-carboxylate
(4ca). Yield
77%, a foam-like white solid. IR (neat) nmax 510, 621, 645, 667, 702,
736, 760, 785, 813, 845, 865, 908, 927, 945, 1045, 1078, 1108, 1133,
1198,1228, 1274,1294, 1331, 1378,1409,1446,1487, 1578,1600,1637,
1665,1728, 2899, 2980, 3027, 3060 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
170.9, 167.8, 136.1, 134.6, 134.0, 130.6, 130.0, 128.24, 128.20,
127.41, 127.36, 125.6, 119.5, 61.7, 60.9, 54.1, 47.8, 28.6, 23.1, 13.8,
13.6; HRMS (EI) calcd for C24H27N2Oþ3 [MþH]þ 391.2016, found
391.2017.
d
7.50e7.07 (m, 12H), 6.90 (d, J¼8.2 Hz, 1H), 6.14 (s, 1H), 5.08 (d,
J¼1.3 Hz, 1H), 4.76 (d, J¼4.4 Hz, 1H), 3.94e3.70 (m, 2H), 3.68e3.41
(m, 3H), 2.73 (ddd, J¼9.8, 4.9, 2.3 Hz,1H), 2.65e2.42 (m, 2H), 0.87 (t,
4.3.17. trans-(E)-Ethyl 3-benzoyl-2-(2-methylpropylidene)-1,2,3,5,6,
10b-hexahydropyrazolo[5,1-a]isoquinoline-1-carboxylate
(4aq). Yield 65%, a foam-like white solid. IR (neat) nmax 662, 697,
744, 761, 787, 864, 918, 990, 1030, 1069, 1109, 1174, 1272, 1338, 1366,
J¼7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 171.3, 167.3, 145.6, 135.5,
135.2, 134.8, 132.8, 131.0, 130.1, 130.0, 129.8, 128.65, 128.57, 127.7,
127.6, 127.3, 119.5, 100.9, 64.9, 61.45, 61.38, 48.2, 44.7, 28.2, 13.4;
HRMS (EI) calcd for C29H28BrN2Oþ3 [MþH]þ 531.1278, found
531.1271.
1391, 1446, 1577, 1642, 1662, 1735, 2870, 2959 cmꢁ1
;
1H NMR
(300 MHz, CDCl3)
d 7.79e7.71 (m, 2H), 7.44e7.27 (m, 3H), 7.23e7.09
(m, 3H), 7.09e6.96 (m, 1H), 6.54 (dd, J¼10.6, 1.9 Hz, 1H), 4.92 (d,
J¼9.3 Hz, 1H), 4.47e4.29 (m, 1H), 3.90e3.58 (m, 3H), 2.93e2.64 (m,
2H), 2.64e2.46 (m, 1H), 2.35e2.12 (m, 1H), 1.10 (d, J¼6.5 Hz, 3H),
0.98 (d, J¼6.6 Hz, 3H), 0.88 (t, J¼7.1 Hz, 3H); 13C NMR (75 MHz,
4.3.22. Ethyl 3-benzoyl-1-benzyl-8-bromo-2-methylene-1,2,3,5,6,10b-
hexahydropyrazolo[5,1-a]isoquinoline-1-carboxylate
(4da). Yield
80%, a foam-like white solid. IR (neat) nmax 665, 702, 734, 761, 786,
806, 865, 908, 946, 1013, 1046, 1077, 1111, 1200, 1230, 1278, 1327,
1382, 1446, 1488, 1600, 1664, 1728, 2981, 3028, 3060 cmꢁ1; 1H NMR
CDCl3)
d 171.0, 167.7, 136.2, 134.0, 133.1, 130.7, 130.0, 128.3, 128.24,
128.19, 127.40, 127.36, 125.6, 124.7, 61.6, 60.9, 54.0, 47.8, 30.2, 28.6,

R. Na et al. / Tetrahedron 68 (2012) 2349e2356
2355
(300 MHz, CDCl3)
d
7.49e6.96 (m,13H), 6.14 (s,1H), 5.07 (d, J¼1.3 Hz,
1722, 2927 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
8.21 (d, J¼8.7 Hz,
1H), 4.76 (s, 1H), 3.88e3.39 (m, 5H), 2.79e2.42 (m, 3H), 0.84 (t,
2H), 7.60 (d, J¼8.7 Hz, 2H), 5.12 (d, J¼1.0 Hz, 1H), 4.02 (qq, J¼10.9,
7.1 Hz, 2H), 3.49e3.37 (m, 1H), 3.00 (dddd, J¼19.9, 16.3, 12.1, 7.6 Hz,
2H), 2.74 (ddd, J¼13.1, 7.8, 5.7 Hz, 1H), 2.66 (d, J¼1.1 Hz, 3H), 1.08 (t,
J¼7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 171.4, 167.3, 145.6, 136.1,
135.6, 135.3, 131.7, 131.0, 130.9, 130.1, 129.1, 128.6, 128.3, 127.7, 127.6,
127.3, 120.9, 100.7, 64.8, 61.43, 61.37, 48.1, 44.7, 28.5, 13.4; HRMS (EI)
calcd for C29H28BrN2Oþ3 [MþH]þ 531.1278, found 531.1278.
J¼7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 165.3, 164.1, 147.7, 147.5,
144.4, 129.3, 123.4, 112.0, 73.3, 60.1, 51.8, 36.3, 14.0, 11.3; HRMS (EI)
calcd for C16H17N3Oþ5 [M]þ 331.1163, found 331.1163.
4.3.23. Ethyl 3-benzoyl-1-benzyl-7-methyl-2-methylene-1,2,3,5,6,10b-
hexahydropyrazolo[5,1-a]isoquinoline-1-carboxylate (4ea). Yield 77%,
a foam-like white solid. IR (neat) nmax 512, 619, 653, 667, 702, 735,
767, 787, 864, 909, 928, 973,1028,1049, 1078, 1120,1222,1236,1268,
1298,1336,1366,1386,1446,1475,1495,1580,1601,1636,1662,1728,
4.3.28. Ethyl 1-(2-chlorophenyl)-3-methyl-5-oxo-1,5,6,7-tetrahydro-
pyrazolo[1,2-a]pyrazole-2-carboxylate (6dt). Yield 90%, a foam-like
white solid. IR (neat) nmax 675, 681, 686, 711, 719, 728, 743, 763,
788, 841, 914, 949, 1019, 1040, 1064, 1104, 1144, 1171, 1208, 1230,
1324, 1363, 1385, 1443, 1475, 1488, 1548, 1573, 1626, 1708,
2980, 3028, 3060 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 7.47e6.98 (m,
13H), 6.18 (s, 1H), 5.09 (d, J¼1.1 Hz, 1H), 4.83 (s, 1H), 3.85e3.45 (m,
2982 cmꢁ1; 1H NMR (300 MHz, CD2Cl2)
d 7.45e7.14 (m, 4H), 5.68 (d,
5H), 2.79 (ddd, J¼9.9, 5.7, 1.8 Hz, 1H), 2.62e2.30 (m, 2H), 2.15 (s, 3H),
J¼1.3 Hz, 1H), 4.10e3.85 (m, 2H), 3.37e3.23 (m, 1H), 3.15 (ddd,
0.76 (t, J¼7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 171.6, 167.3, 145.9,
J¼10.1, 8.7, 7.8 Hz, 1H), 2.87e2.66 (m, 2H), 2.64 (d, J¼1.4 Hz, 3H),
135.82, 135.75, 135.4, 132.4, 132.2, 131.0, 129.9, 128.43, 128.38,
128.33, 127.8, 127.4, 127.2, 125.8, 123.5, 100.7, 64.8, 61.8, 61.2, 48.4,
44.9, 25.9, 19.3, 13.3; HRMS (EI) calcd for C30H31N2Oþ3 [MþH]þ
467.2329, found 467.2329.
1.01 (t, J¼7.1 Hz, 3H); 13C NMR (75 MHz, CD2Cl2)
d 165.5, 164.1,
144.6, 137.1, 134.1, 129.7, 129.3, 129.0, 127.0, 111.9, 68.4, 59.7, 51.2,
36.5, 13.6, 11.0; HRMS (EI) calcd for C16H17ClN2Oþ3 [M]þ 320.0922,
found 320.0921.
4.3.24. Ethyl 3-benzoyl-1-benzyl-9-methyl-2-methylene-1,2,3,5,6,10b-
hexahydropyrazolo[5,1-a]isoquinoline-1-carboxylate (4fa). Yield 89%,
a foam-like white solid. IR (neat) nmax 511, 644, 666, 702, 736,
762,786, 799, 811, 865, 909, 929, 959, 1011, 1046, 1078, 1108, 1161,
1223, 1242, 1281, 1300, 1335, 1380, 1446, 1495, 1508, 1580, 1602,
1636, 1663, 1728, 2935, 2980, 3026, 3059 cmꢁ1; 1H NMR (300 MHz,
4.3.29. Ethyl 1-(2-bromophenyl)-3-methyl-5-oxo-1,5,6,7-tetrahydro-
pyrazolo[1,2-a]pyrazole-2-carboxylate (6et). Yield 92%, a foam-like
white solid. IR (neat) nmax 676, 681, 688, 737, 762, 788, 801, 820,
1023,1064,1103,1171,1208,1230,1323,1363,1386,1441,1487,1627,
1708, 2977 cmꢁ1
;
1H NMR (300 MHz, CD2Cl2)
d
7.57 (dd, J¼8.0,
1.2 Hz, 1H), 7.42e7.28 (m, 2H), 7.23e6.99 (m, 1H), 5.68 (d, J¼1.2 Hz,
1H), 4.12e3.80 (m, 2H), 3.36e3.25 (m, 1H), 3.18 (ddd, J¼10.0, 8.7,
7.9 Hz, 1H), 2.87e2.66 (m, 2H), 2.63 (d, J¼1.4 Hz, 3H), 1.00 (t,
CDCl3)
d 7.50e7.40 (m, 2H), 7.36e7.09 (m, 8H), 7.01e6.88 (m, 3H),
6.14 (s, 1H), 5.06 (d, J¼1.1 Hz, 1H), 4.81 (s, 1H), 3.81e3.70 (m, 2H),
3.60 (d, J¼2.9 Hz, 2H), 3.56e3.43 (m, 1H), 2.79e2.44 (m, 3H), 2.33
J¼7.1 Hz, 3H); 13C NMR (75 MHz, CD2Cl2)
d 165.5, 164.1, 144.6, 138.7,
(s, 3H), 0.77 (t, J¼7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d
171.6,
132.6, 130.0, 129.4, 127.6, 124.5,112.2, 70.9, 59.7, 51.1, 36.5, 13.6,11.0;
167.3, 146.0, 135.8, 135.5, 135.3, 132.4, 131.0, 130.6, 129.9, 128.4,
128.3, 128.1, 127.9, 127.8, 127.4, 127.2, 126.1, 100.4, 64.8, 61.6, 61.2,
48.6, 44.8, 28.2, 21.1, 13.3; HRMS (EI) calcd for C30H31N2Oþ3 [MþH]þ
467.2329, found 467.2329.
HRMS (EI) calcd for C16H17BrN2Oþ3 [M]þ 364.0417, found 364.0411.
Acknowledgements
This study was supported by the National Natural Science
Foundation of China (No. 21172253), the National Scientific and
Technology Supporting Program of China (No. 2011BAE06B05-5),
Chinese Universities Scientific Fund (No. 2011JS029 and 2011JS031),
the Key Technologies R&D Program of China (No. 2012BAK25B03),
the startup research funding from China Agricultural University,
and Nutrichem Company.
4.3.25. Ethyl 3-methyl-1-(2-nitrophenyl)-5-oxo-1,5,6,7-tetrahydro-
pyrazolo[1,2-a]pyrazole-2-carboxylate (6at). Yield 73%, a foam-like
yellow solid. IR (neat) nmax 675, 678, 685, 693, 717, 733, 757, 786,
838, 913, 1019, 1063, 1079, 1102, 1136, 1170, 1207, 1229, 1323, 1385,
1527, 1623, 1690, 1723, 2980 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 7.81
(dd, J¼8.1,1.0 Hz,1H), 7.72e7.58 (m, 2H), 7.44 (ddd, J¼8.1, 7.2,1.6 Hz,
1H), 5.73 (d, J¼1.3 Hz, 1H), 4.05e3.81 (m, 2H), 3.57 (ddd, J¼8.9, 7.9,
2.6 Hz, 1H), 3.28 (ddd, J¼11.7, 9.0, 7.5 Hz, 1H), 3.00e2.70 (m, 2H),
2.67 (d, J¼1.4 Hz, 3H), 0.94 (t, J¼7.1 Hz, 3H); 13C NMR (75 MHz,
Supplementary data
CDCl3)
d 165.9, 163.8, 150.2, 145.0, 135.1, 132.8, 130.4, 128.6, 123.6,
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.01.029.
112.1, 67.0, 59.9, 52.1, 36.4, 13.7, 11.2.; HRMS (EI) calcd for
C16H17N3Oþ5 [M]þ 331.1163, found 331.1174.
References and notes
4.3.26. Ethyl 3-methyl-1-(3-nitrophenyl)-5-oxo-1,5,6,7-tetrahydro-
pyrazolo[1,2-a]pyrazole-2-carboxylate (6bt). Yield 77%, a foam-like
yellow solid. IR (neat) nmax 678, 683, 690, 696, 705, 721, 743, 751,
765, 785, 810, 829, 843, 907, 933, 1020, 1164, 1117, 1171, 1210, 1230,
1326, 1348, 1362, 1385, 1529, 1618, 1689, 1724, 2983 cmꢁ1; 1H NMR
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8.37e8.32 (m, 1H), 8.20 (ddd, J¼8.2, 2.3, 1.1 Hz,
1H), 7.90e7.79 (m, 1H), 7.59 (t, J¼7.9 Hz, 1H), 5.19 (d, J¼1.3 Hz, 1H),
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804943. These data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting
The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2
1EZ, UK; fax: þ44 1223 336033.