Access to some angular aminochromeno[2,3-c]pyrazole Precursors by a domino knoevenagel-hetero-diels-alder reaction

Article abstract of DOI:10.1002/ejoc.201200751

A new, solvent-free tetrabutylammonium-hydrogensulfate-catalysed one-pot procedure to synthesise angular benzopyran-annulated pyrazoles, all of which incorporate a tertiary ring-junction carbon, has been demonstrated. A typical intermediate Knoevenagel he

Full text of DOI:10.1002/ejoc.201200751

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DOI: 10.1002/ejoc.201200751
Access to Some Angular Aminochromeno[2,3-c]pyrazole Precursors by a
Domino Knoevenagel–hetero-Diels–Alder Reaction
Narsidas J. Parmar,*[a] Bhavesh R. Pansuriya,[a] Balvantsingh M. Labana,[a]
Tushar R. Sutariya,[a] Rajni Kant,[b] and Vivek K. Gupta[b]
Keywords: Domino reactions / Oxygen heterocycles / Nitrogen heterocycles / Cyclization / One-pot reactions
A new, solvent-free tetrabutylammonium-hydrogensulfate-
catalysed one-pot procedure to synthesise angular benzopyr-
an-annulated pyrazoles, all of which incorporate a tertiary
ring-junction carbon, has been demonstrated. A typical inter-
mediate Knoevenagel heterodiene, formed by the reaction of
2-(alkenyloxy)- or 2-(alkynyloxy)acetophenones with pyraz-
olones smoothly underwent a subsequent hetero-Diels–Alder
reaction to give chromeno-fused pyrazoles in a highly stereo-
selective reaction. When nitro-containing DKHDA products
were treated further with Fe/HCl in tandem, they formed the
corresponding amino frameworks in a reduction step, which
highlights a new possibility for this cascade route to give
aminopolyheterocycles. The stereochemistry of all new terti-
ary ring-junction carbon-containing polyheterocycles was
confirmed by 2D NMR spectroscopy experiments, DQF-
COSY and NOESY, and single crystal X-ray diffraction data.
None of the products has had their biological profiled evalu-
ated before, and they are expected to have heterosteroidal
biological functions.
zinc oxide,[13] d-proline,[14] ionic liquids,[15] and pyridine,[16]
and has been used for the preparation of polyheterocycles
of pharmaceutical and photochromic interest.[17]
Introduction
Angularly fused polycyclic compounds are of interest
due to their significant roles in biological systems, which
ultimately make their various medicinal applications pos-
sible.[1,2] Compounds of interest from this family include
naturally occurring cannabicyclol,[3a] mahanimbine,[3b] ste-
roids[3c] and thyrsiferol.[1d] Analogues of thyrsiferol are
known to show cytotoxic, antiviral, and antitumor activi-
ties. Similarly, heterosteroids,[4] analogues of steroids, con-
taining a tertiary ring-junction carbon-like skeleton, have
shown significantly improved biological functions. Thus,
there is a great deal of research in this area, and more devel-
opment of such scaffolds is not only desired, but also re-
quired.
Tietze et al. have extensively studied this protocol.[18]
Many aldehyde substrates were used in this pioneering
work. By introducing tetrabutylammonium hydrogensulfate
(TBA-HS) as an efficient catalyst, our group has recently
extended this strategy further to cover some (aryldiazenyl)-
salicylaldehydes.[19] Other improvements like shorter reac-
tion times, highly regioselective and clean reactions, and fi-
nally the dispensability of a reaction solvent (as shown in
the solvent-free green approach described in this paper),
lead to a more economical and environmentally friendly re-
action. Moreover, our use in this study of alkenyl- and alk-
ynyl-ether-tethered ketones (instead of the more widely
studied aldehydes) extends the substrate scope of this strat-
egy. Work on activated ketones has been reported, but only
in an intermolecular hetero-Diels–Alder reaction.[20] TBA-
HS promoted a highly enantio- and regioselective catalytic
inverse-electron-demand cycloaddition with a dienophile to
form polyheterocyclic products, all incorporating a tertiary
ring-junction carbon, starting from the corresponding O-
allylated, prenylated, or propargylated 2-hydroxyacetophen-
ones and pyrazolones. This hetero-Diels–Alder sequence
could further be linked in tandem with another transforma-
tion i.e., reduction of nitro-substituted domino products, re-
sulting in the formation of aminobenzopyran-annulated py-
razolones in one pot. In the literature, 6-aminochromenes
are precursors to many bioactive compounds.[21] Moreover,
their salts are suitable for pharmaceutical purposes and
show drug activities. More interestingly, bridgehead methyl
The
domino
Knoevenagel–hetero-Diels–Alder
(DKHDA) reaction has contributed to the development of
polycyclic compounds, and it is still a vital part of the syn-
thetic repertoire, allowing access to diverse complex mole-
cules in modern synthetic organic chemistry.[5] To date, this
reaction, in which an olefin-ether-tethered aldehyde reacts
with a diketone, has been catalysed by Lewis acids,[6]
EDDA (ethylenediammonium diacetate),[7] copper(I) iod-
ide,[8] bismuth(III) chloride,[9] indium(III) chloride,[10] lith-
ium perchlorate,[11] triphenylphosphonium perchlorate,[12]
[a] Department of Chemistry, Sardar Patel University,
Vallabh Vidyanagar 388120, Dist. Anand, Gujarat, India
E-mail: njpchemdeptspu@yahoo.co.in
[b] Post-Graduate Department of Physics, University of Jammu,
Jammu Tawi 180006, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200751.
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N. J. Parmar et al.
FULL PAPER
attached to a pyranyl ring-junction carbon in all new po- Table 1. Optimizing the reaction conditions to assess model prod-
ucts 4a, 4d and 4o.
lyheterocycles may confer them with a new steroid-mimick-
ing biological function (Scheme 1).[4a,22]
Entry Solvent Catalyst
(reflux) [mol-%]
Product 4a Product 4d
Product 4o
Time Yield Time Yield Time Yield
[h]
[%]
[h]
[%]
[h]
[%]
1
2
3
4
5
6
7
8
MeCN
MeCN EDDA (25)
MeCN TBA-HS (25)
–
24
24
24
24
24
–
–
–
–
4
24
24
24
24
24
–
–
–
24
24
24
–
–
–
–
–
–
–
–
–
–
–
Scheme 1. Synthetic route to new angular polyheterocycles.
toluene
–
trace 24
7
8
61
62
65
79
78
toluene EDDA (25)
toluene TBA-HS (25)
24
24
24
6
24
[a]
Results and Discussion
–
5.0
4.0
3.5
3.5
3.5
60
58
63
75
73
4.0
4.0
3.5
3.0
3.0
5.0
5.0
5.0
5.0
5.0
[a]
TBA-HS (10)
TBA-HS (15)
TBA-HS (25)
TBA-HS (35)
[a]
Compounds that contain an aldehyde functionality to-
gether with suitably placed alkene or alkyne moieties are
widely studied substrates in the DKHDA protocol. Surpris-
9
10
11
[a]
[a]
ingly, the corresponding compounds based on the ketone [a] Solvent-free at 160 °C.
functionality have never been studied before. We therefore
set about studying 2-(allyloxy)-, 2-(prenyloxy)-, and 2-(pro-
pargyloxy)acetophenones 2a–i as a typical class of sub- yield of 4d starting from prenyl-based substrate 2d, could
strates. All are ketone-based substrates and all were formed be achieved using 25 mol-% of catalyst TBA-HS (Table 1,
in good yields by allylating, prenylating, or propargylating entry 6). In the absence of catalyst (Table 1, entry 4), only
2-hydroxyacetophenones using anhydrous potassium car- traces of product 4d were seen. Propargyl-based substrate
bonate in DMF at room temperature (Scheme 2),[19] as re- 2g showed no reactivity. Conventional heating, which took
ported elsewhere. All were isolated as oily products after 24 h to yield ca. 6% of 4a and 8% of 4d was thus inade-
extraction with ether.
quate to run the protocol. Next, we attempted a catalyst-
To optimise the DKHDA reaction conditions, we choose and solvent-free reaction at 160 °C (Table 1, entry 7), envis-
three model substrates to be coupled with pyrazolone 3a. aging that the higher temperature would activate the sub-
The O-allylated (2a), O-prenylated (2d), and O-proparg- strate. Under these conditions, all substrates formed oily
ylated 2-hydroxyacetophenones (2g) represent the three yellow Knoevenagel adducts with pyrazolone 3a. On heat-
classes of dienophile substrates. The effect of different cata- ing the reaction mass for 4–5 h, these adducts were trans-
lysts was examined, as summarised in Table 1. Ketone- formed into cyclised products, except that derived from sub-
based substrates 2a, 2d, and 2g seemed completely unreac- strate 2g. The Knoevenagel adduct derived from 2g failed
tive at temperatures below that of refluxing toluene, and to give the final cyclised product (i.e., 4o), which may be
even the formation of Knoevenagel adducts was not ob- due to the low reactivity of the propargyl dienophile. Thus,
served.
increasing the reaction temperature to 160 °C for substrates
We next heated an equimolar (0.3 mmol) mixture of 2a, 2a and 2d under catalyst- and solvent-free conditions, we
2d or 2g with pyrazolone 3a without catalyst in acetonitrile noticed that the reaction time decreased from 24 h taken at
at reflux (Table 1, entry 1). Here, no products formed from reflux temperature to 5 h for allyl-based substrate 2a
any substrate even after prolonged heating (24 h). When the (Table 1, entry 7), and to 4 h for prenyl-based substrate 2d
reactions were carried out in the presence of catalysts (Table 1, entry 7), yielding 60 and 61% of cyclised products
EDDA and TBA-HS (Table 1, entries 2–3), the formation 4a and 4d, respectively. No further improvement in the reac-
of a trace of the Knoevenagel condensation product was tion was seen above 160 °C. To improve the yields, we then
observed by TLC. Despite extended heating, however, it tried various amounts of the TBA-HS catalyst at this tem-
never transformed into cyclised products. On the other perature. With 10 mol-% TBA-HS, 2a gave 4a in 58% yield,
hand, in refluxing toluene (Table 1, entries 4–6), a 6% yield and 2d gave 4d in 62% yield after 4 h (Table 1, entry 8).
of 4a starting from allyl-based substrate 2a, and an 8% Increasing the catalyst loading (Table 1, entries 9–11) cer-
Scheme 2. Synthesis of O-allylated, prenylated, and propargylated 2-hydroxyacetophenones 2a–i: (a) allylation/prenylation, and (b) prop-
argylation.
2
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Domino Knoevenagel–hetero-Diels–Alder Reaction
tainly improved the yields and reaction times. This trend
was continued up to 25 mol-% catalyst loading, after which
no drastic changes were noted (Table 1, entries 9–11). The
optimal yields of representative products 4a and 4d were 75
and 79%, respectively (Table 1, entry 10). Therefore, run-
ning the reaction in the presence of 25 mol-% TBA-HS and
in the absence of solvent were the best conditions observed
so far and even more meritorious than our refluxing xylene
method reported elsewhere, which takes 12 h.[19] Other
compounds 4b–n were prepared under the optimised condi-
tions of Table 1, entry 10. All Knoevenagel adducts were
stable and isolable. Their structures were confirmed by IR
and NMR spectroscopic data.
To our surprise, none of the catalysts tested was effective
for the transformation of unreactive propargyl-based sub-
strate 2g into product 4o, except for ZnO, which resulted in
the formation of traces of products. Therefore, we worked
further with this result, and combined 25 mol-% ZnO with
varying amounts of TBA-HS Table 2. The yields of 4o were
improved when we performed the solvent-free reaction in
the presence of catalytic mixture containing 25 mol-% ZnO
and 25 mol-% TBA-HS (Table 2, entry 10). These optimised
conditions were used for the preparation of other heterocy-
cles 4o–u (Scheme 3). The yields of the products (Table 3)
were in the 65–73% range. The search to optimise the effi-
ciency of this method is ongoing.
Scheme 3. Synthesis of tetrahydro-5H-chromeno[4Ј,3Ј:4,5]pyrano-
[2,3-c]pyrazoles 4a–n, and dihydro-6H-chromeno[4Ј,3Ј:4,5]pyrano-
[2,3-c] pyrazoles 4o–u.
Table 3. Synthesis of tetrahydro-5H-chromeno[4Ј,3Ј:4,5]pyrano[2,3-
c]pyrazoles 4a–n, and dihydro-6H-chromeno [4Ј,3Ј:4,5]pyrano[2,3-
c] pyrazole 4o–u.
Entry Product
R
R1 R2 R3
M.p.
[°C]
Time Yield
[h]
[%]
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
H
H
CH3
CH3
CH3
H
H
H
CH3 NO2
CH3 NO2
CH3 NO2
H
CH3
–
–
–
–
–
H
H
H
H
H
H
NO2
NO2
NO2
NO2 Ph
172–174 3.5
196–198 3.5
208–210 3.5
232–234 3.0
208–210 2.5
238–240 2.0
162–164 3.0
218–220 3.5
224–226 3.0
220–222 2.5
224–226 2.5
218–220 2.0
152–154 2.5
170–172 2.0
170–173 5.0
218–220 5.5
203–205 5.0
182–184 5.5
206–208 6.0
196–197 5.0
156–158 4.0
75
79
76
79
72
78
81
78
80
78
74
71
78
76
65
71
73
67
65
70
72
NO2 3-ClC6H4
NO2 4-MeC6H4
NO2 Ph
NO2 3-ClC6H4
NO2 4-MeC6H4
Table 2. Optimizing the reaction conditions to access 4o.
H
H
H
H
H
H
H
H
Ph
Entry
Solvent
Catalytic mixture
Time Yield
3-ClC6H4
4-MeC6H4
Ph
3-ClC6H4
4-MeC6H4
Ph
ZnO [mol-%] TBA-HS [mol-%] [h]
[%]
9
1
2
3
4
5
6
7
8
xylene
toluene
xylene
toluene
–
–
–
–
25
25
–
–
–
15
25
35
24
24
24
24
24
10
7.5
7.5
6
–
–
8
10
11
12
13
14
15
16
17
18
19
20
21
4j
4k
4l
25
25
25
25
15
25
35
25
25
25
trace
11
34
57
59
59
65
67
4m
4n
4o
4p
4q
4r
4s
4t
H
H
H
H
xylene
Ph
[a]
NO2 Ph
NO2 3-ClC6H4
NO2 4-MeC6H4
[a]
[a]
[a]
[a]
[a]
H
9
10
11
NO2
NO2
NO2
H
H
H
H
H
Ph
5
5
3-ClC6H4
4-MeC6H4
Ph
–
–
4u
[a] Solvent-free at 160 °C.
Table 3 represents all the products formed using the op-
timised reaction conditions (i.e., those given in Table 1, en- sigmatropic rearrangement of the allylic ethers was detected
try 10 for 4a–h, and those given in Table 2, entry 10 for 4o– at higher temperature (160 °C), indicating that all of the
u). As expected, prenyl-based substrates generally require acetophenones are stable, and that all retained their original
less time than unreactive allyl-based ones. Substitution on carbonyl–dienophile skeleton to allow the DKHDA ap-
the phenyl ring attached to the 5-pyrazolone nitrogen N1 proach.
was also found to affect the reaction time. Methyl substitu-
A plausible mechanism is proposed in Scheme 4. The re-
ents in comparison with others reduced the reaction time action proceeds via a Knoevenagel adduct, the formation
1
in case of prenyl-based substrates (Table 3, entries 4–6, 10– of which was confirmed by H and 13C NMR and DEPT-
12), which may be due to a decrease in the HOMO–LUMO 135 spectroscopy. Because of angle strain, the formation of
energy gap. The same trend however, could not be clearly either endo-Z-anti or exo-E-anti geometries must be ruled
observed for the analogous O-allylated 2-hydroxyacetophe- out. Only less steric interaction between an ortho substitu-
none derivatives (Table 3, entries 1–3, 7–9). Finally, the ent and the carbonyl group favours the endo-E-syn transi-
presence of electron-withdrawing nitro groups has affected tion state. This was also supported by the X-ray crystal
the reaction time in case of O-propargylated acetophenone structure, in which the fused pyranyl ring-junction methyl
substrates, taking 5 h compared to 3.5 h in case of others, and hydrogen are orientated cis to each other. Thus it is
to react with pyrazolones. It is important to note that no inferred that endo-E-syn transition state favoured the ex-
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N. J. Parmar et al.
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clusive formation of cis products, even though two path-
ways are possible. Both allyl- and prenyl-based substrates
smoothly underwent a DKHDA reaction in the presence of
TBA-HS. This was not observed for the unreactive propar-
gyl-based substrate, which additionally required ZnO to
promote the DKHDA reaction to form 4o–u.
Figure 1. Characteristic nOe’s of 4a.
Scheme 4. Mechanism of TBA-HS catalysed DKHDA reaction 4a–
n.
Figure 2. Characteristic nOe’s of 5a.
The structures of all new polyheterocycles were deduced
from their spectroscopic data. The H NMR spectra of all-
1
β = 94.838(5)°, Z = 4. The crystal structure was solved by
direct methods[23] using single-crystal X-ray diffraction data
collected at room temperature, and refined by full-matrix
least-squares procedures to a final R value of 0.0651 for
1941 observed reflections. An ORTEP view with atomic
labelling is shown in Figure 3.[24]
yl- and propargyl-based products showed a singlet around
1.8 ppm, which was assigned to the bridgehead methyl pro-
tons attached to the ring-junction tertiary carbon. The cor-
responding protons in prenyl-based products could be seen
as a singlet at around 1.0 ppm. This upfield shift may be
due to the methyl group. From the 13C NMR spectrum, it
could also be observed that the methyl carbon that ap-
peared at ca. 28 ppm in allyl- and propargyl-based products
had shifted to ca. 22 ppm in prenyl-based products. The
ring-junction CH protons appeared as multiplets in allyl-
derived products and doublets (J = 4.0 Hz) in prenyl-de-
rived products in the 2.0–2.2 ppm range. In all products, a
ring-junction tertiary carbon appeared as a clear peak in
the 13C NMR spectrum in the 34–38 ppm range. To estab-
lish the stereochemistry of all new nitro-containing prod-
ucts, 2D NMR experiments were used. The nuclear Over-
hauser effect spectroscopy (NOESY) and double quantum
filtered correlation spectroscopy (DQF-COSY) data of ni-
tro derivative 4a support its proposed structure (Figure 1).
The NOESY data provided clear evidence for the vicinity
of the methyl group attached to the ring-junction carbon
with the pyrazolyl methyl protons, and also with the bridge-
head CH, and with the aromatic ring. For the aminobenzo-
pyrans, one more correlation could be added to these: the
amine protons correlated with the neighbouring ortho aro-
matic CH proton (Figure 2).
Figure 3. ORTEP view of compound 4m.
The structure was finally ascertained by single-crystal X-
ray diffraction data. Compound, 4m, crystallised in the mo-
The geometry of the molecule was calculated using the
noclinic space group P21/c with the following unit-cell pa- WinGX28 and PARST29 software packages.[25] The crystal-
rameters: a = 9.7115(5), b = 12.6094(6), c = 13.8066(8) Å, packing diagram is shown in Figure 4.
4
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Domino Knoevenagel–hetero-Diels–Alder Reaction
ethanol and water. A highest yield of 82% of model amino
product 5a was obtained under these conditions (Table 4,
entry 4). Other aminochromene-fused heterocycles 5a–f and
5g–l were prepared by the same method (Scheme 5,
Table 5). The structures of the reduced aminobenzopyran
derivatives were also confirmed by 2D NMR experiments,
which were consistent with the proposed structure shown
in Figure 2.
Table 5. Synthesis of tetrahydro-5H-chromeno[4Ј,3Ј:4,5]pyrano[2,3-
c]pyrazol-10-amines 5a–f and tetrahydro-5H-chromeno[4Ј,3Ј:4,5]-
pyrano[2,3-c]pyrazol-8-amines 5g–l.
Entry Product
R
R1
R2
R3
M.p. [°C] Yield [%]
118–120 72
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
H
H
H
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
NH2
NH2
NH2
NH2 Ph
NH2 3-ClC6H4 110–112 86
NH2 4-MeC6H4 98–100 75
NH2 Ph 162–164 89
NH2 3-ClC6H4 132–134 71
NH2 4-MeC6H4 143–145 73
H
H
H
H
H
H
Figure 4. Crystal-packing diagram of 4m.
7
8
9
5g
5h
5i
Ph
116–118 74
To derive potentially bioactive aminochromene-annu-
lated scaffolds, we treated all of the DKHDA nitro-contain-
ing products with various reducing agents under different
reaction conditions. These included: treatment with sodium
hydrogen sulfate in refluxing methanol or water; treatment
with Fe/HCl in refluxing methanol or in an ethanol/water
mixture; and treatment with SnCl2 in water at room tem-
perature and at reflux (Table 4). None of the methods gave
good results except for Fe/HCl in a refluxing mixture of
3-ClC6H4 138–140 82
4-MeC6H4 147–149 85
Ph
3-ClC6H4 152–154 70
4-MeC6H4 126–128 83
10
11
12
5j
5k
5l
CH3 NH2
CH3 NH2
CH3 NH2
115–117 73
Conclusions
In summary, we have described an intramolecular
DKHDA approach to assess some new tertiary carbon con-
taining polyheterocycles from three typical ketone-based
substrates O-allylated, O-prenylated, and O-propargylated
2-hydroxyacetophenones and pyrazolones by carrying out
the reaction in the presence of TBA-HS under solvent-free
conditions at high temperature. The reaction proceeded ef-
ficiently for all substrates except for the O-propargyl-based
substrate, which required the presence of ZnO as an ad-
ditional catalyst to proceed moderately. When the crude
DKHDA reaction products containing nitro groups were
treated further with Fe/HCl in tandem, they gave the corre-
sponding amino compounds in one pot. The compounds
are potential candidates for biological and photochromic
applications.
Table 4. Optimizing the reaction conditions to afford model amino
products 5a.
Entry
Refluxing medium
Catalyst
Yield [%]
1
2
3
4
5
6
MeOH[a]
acetone
H2O
H2O/EtOH
H2O/MeOH
MeOH
SnCl2/HCl
SnCl2·H2O
SnCl2/HCl
Fe/HCl
Fe/HCl
NaSH/MeOH
20
32
23
82
68
23
[a] Room temperature.
Experimental Section
General: All solvents and reagents were purified by standard tech-
niques or used as supplied from commercial sources as appropriate.
IR spectra were recorded using the KBr method with a Shimadzu
FTIR 8300 spectrometer, and are reported in wavenumbers (cm–1).
1H and 13C NMR spectra were recorded with a Bruker Avance 400
spectrometer operating at 400 MHz for 1H NMR and 100 MHz
for 13C NMR as solutions in CDCl3 or DMSO, unless otherwise
indicated. Chemical shifts are reported as parts per million (ppm,
δ) and are referenced to the residual protic solvent. Coupling con-
stants are reported in Hertz (Hz). Splitting patterns are designated
as s, singlet; d, doublet; t, triplet; q, quartet; br, broad; m, multiplet;
comp, complex multiplet. The degree of substitution (C, CH, CH2,
and CH3) was determined by the DEPT-135 method. Elemental
Scheme 5. Synthesis of tetrahydro-5H-chromeno[4Ј,3Ј:4,5]pyrano-
[2,3-c]pyrazol-10-amines 5a–f and tetrahydro-5H-chromeno-
[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazol-8-amines 5g–l.
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analysis was carried out with a Perkin–Elmer 2400 Series-II ele-
mental analyser. The ESI mass spectra were measured with a Shim-
adzu LCMS-2010 spectrometer. TLC was performed on Merck 60
F254 pre-coated silica plates, and spots were detected either by UV
(254 nm, 366 nm) or by dipping into permanganate [KMnO4 (3 g),
K2CO3 (20 g), NaOH (5 mL, 5% in H2O), H2O (300 mL)] or (2,4-
dinitrophenyl)hydrazine [2,4-DNP (12 g), conc. H2SO4 (6 mL),
water (8 mL), EtOH (20 mL)] solutions followed by heating. Single
crystal X-ray data were collected with a Bruker CCD area-detector
diffractometer equipped with graphite monochromated Mo-Kα ra-
diation (λ = 0.71073 Å). The structure was solved by direct meth-
ods using SHELXS97.[23] All non-hydrogen atoms of the molecule
were located in the best E-map.
CCDC-840897 contains the supplementary crystallographic data
for this paper.
General Procedure for the Synthesis of O-Allylated, Prenylated, and
Propargylated Acetophenones 2a–i: A solution of allyl or prenyl or
propargyl bromide (0.013 mol) in DMF (2 mL) was added drop-
wise to a stirred suspension of a 2-hydroxyacetophenone derivative
1a–c (0.01 mol) and anhydrous potassium carbonate (0.015 mol) in
DMF (10 mL). The resulting mixture was stirred at room tempera-
ture until completion of reaction as confirmed by the TLC (6–
12 h). It was then poured into ice (100 g) with constant stirring.
Solid products were filtered, washed with cold water (3ϫ 10 mL),
and then dried at room temperature. Oily products were extracted
with diethyl ether (3ϫ 25 mL). The combined ether extracts were
then dried with anhydrous sodium sulfate and evaporated to give
the pure products as colourless oils. The products were obtained in
93–97% of yields.
General Procedure for the Synthesis of 4a–n: A mixture of an O-
allylated/prenylated acetophenone 2a–f (3.0 mmol) and a 5-pyrazo-
lone derivative 3a–c (3.0 mmol) was heated with catalyst TBA-HS
(0.75 mmol, 25 mol-%) in a round-bottomed flask at 160 °C until
the reaction was complete, as monitored by TLC. The crude prod-
ucts obtained were purified by column chromatography to give the
products in good yields.
General Procedure for the Synthesis of 4o–u: An O-propargylated
acetophenone 2g–i (3.0 mmol), a 5-pyrazolone 3a–c (3.0 mmol),
and a catalytic mixture containing TBA-HS (0.75 mmol, 25 mol-
%) and zinc oxide (0.75 mmol, 25 mol-%) were heated in a round-
bottomed flask at 160 °C until the reaction was complete, as moni-
tored by TLC. The crude products obtained were purified by col-
umn chromatography to give the products in good yields.
(E)-4-{1-[2-(Allyloxy)phenyl]ethylidene}-3-methyl-1-phenyl-1H-pyr
azol-5(4H)-one (Intermediate I): Yellow oil, IR (KBr): ν = 2967,
˜
2926, 1689, 1629, 1500, 1232, 1119, 1048, 818, 755, 690 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 1.61 (s, 3 H, CH3), 2.84 (s, 3 H,
pyrazolone CH3), 4.60 (d, J = 4.0 Hz, 2 H, CH2), 5.28 (dd, J =
10.4, J = 1.2 Hz, 1 H, one methylene proton), 5.37 (dd, J = 17.2,
J = 1.6 Hz, 1 H, the other methylene proton), 5.99 (m, 1 H, CH),
6.98–7.99 (m, 9 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ =
16.62 (pyrazolone CH3), 22.21 (CH3), 69.00 (CH2), 112.46 (CH),
117.76 (methylene), 118.74, 118.80, 118.90, 120.76, 124.62, 126.66,
128.20, 128.74, 128.93, 130.41, 132.60, 138.46, 148.83, 154.17,
163.76 (C=N), 163.90 (C=O) (Ar-C) ppm. MS (ESI): m/z = 333.1
[M + H]+.
General Procedure for the Synthesis of 5a–l (Reduction of Nitro
Compounds): Water (10 mL) and concentrated hydrochloric acid
(1–2 drops) were added to the crude nitro compound 4a–l (1 equiv.)
that was formed in the DKHDA reaction as confirmed by TLC.
This was followed by the addition of Fe powder (6 equiv.) in eth-
anol. The mixture was then heated for 1–2 hat reflux. The progress
of the reaction was monitored by TLC, which indicated that re-
sulted amine products had formed cleanly in all cases. The crude
product was then obtained by chloroform extraction. The extracts
were dried with anhydrous MgSO4 and concentrated under reduced
pressure to give a solid residue. The residue was further purified
by column chromatography using hexane/ethyl acetate (6:4) as an
eluent.
(E)-4-{1-[2-(Prenyloxy)phenyl]ethylidene}-3-methyl-1-phenyl-1H-
pyrazol-5(4H)-one (Intermediate II): Yellow oil, IR (KBr): ν = 2972,
˜
2927, 1692, 1609, 1528, 1496, 1231, 1107, 1041, 823, 757, 688 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.62 (s, 3 H, acetyl CH3), 1.68
(s, 3 H, one prenyl CH3), 1.74 (s, 3 H, the other prenyl CH3), 2.85
(s, 3 H, pyrazolone CH3), 4.60 (d, J = 5.6 Hz, 2 H, CH2), 5.62 (t,
J = 6.7 Hz, 1 H, CH=), 7.00–7.96 (m, 9 H, Ar-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 17.11 (pyrazolone CH3), 23.08 (acetyl
Spectroscopic data of typical Knoevenagel alkene intermediates I,
II and III.
6
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Date: 17-09-12 16:57:23
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Domino Knoevenagel–hetero-Diels–Alder Reaction
CH3), 27.23 (one prenyl CH3), 31.30 (the other prenyl CH3), 68.67
= 392.12 [M + H]+. C22H21N3O4 (391.2): calcd. C 67.51, H 5.41,
(CH2), 114.64 (CH=), 117.76, 118.64, 118.87, 119.12, 121.03, N 10.74; found C 67.68, H 5.26, N 10.51.
124.85, 127.21, 128.36, 128.78, 129.21, 130.53, 132.71, 138.68,
(5aR,11bS)-1,5,5,11b-Tetramethyl-10-nitro-3-phenyl-3,5a,6,11b-
tetrahydro-5H-chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazole (4d): Iso-
lated yield (0.680 g, 79%) as white crystals, m.p. 232–234 °C. IR
148.56, 153.58, 164.14 (C=N), 165.63 (C=O) (Ar-C) ppm. MS
(ESI): m/z = 361.2 [M + H]+.
(E)-4-{1-[2-(Propargyloxy)phenyl]ethylidene}-3-methyl-1-phenyl-
(KBr): ν = 2981, 2929, 1598, 1512, 1444, 1339, 1250, 1089, 1041,
˜
832, 756, 694 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.08 (s, 3 H,
angular CH3), 1.67 (s, 3 H, 5-CH3), 1.79 (s, 3 H, 5Ј-CH3Ј), 2.05 (d,
J = 4.0, 1 H, 5a-H), 2.79 (s, 3 H, pyrazolone CH3), 4.58 (d, J =
13.2 Hz, 1 H, 6-H), 4.78 (dd, J = 13.0, J = 4.4 Hz, 1 H, 6Ј-H),
6.84–8.49 (m, 8 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ =
16.73 (pyrazolone CH3), 22.71 (angular CH3), 29.12 (CH3-5), 32.03
(CH3-5Ј), 33.77 (C-11b), 46.31 (C-5a), 62.75 (C-6), 82.21 (C-5),
99.99, 116.94, 120.79, 123.74, 124.24, 125.71, 128.88, 129.88,
138.50, 141.73, 146.36, 148.00, 158.04 ppm. MS (ESI): m/z =
406.15 [M + H]+. C23H23N3O4 (405.10): calcd. C 68.13, H 5.72, N
10.36; found C 68.41, H 5.40, N 10.42.
1H-pyrazol-5(4H)-one (Intermediate III): Yellow oil, IR (KBr): ν =
˜
2966, 2932, 2158, 1695, 1612, 1513, 1494, 1236, 1113, 1038, 815,
754, 691 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.62 (s, 3 H, acetyl
CH3), 1.68 (s, 3 H, one prenyl CH3), 2.43 (s, 1 H, CH), 4.90 (s, 2
H, CH2), 7.08–7.98 (m, 9 H, Ar-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 17.11 (pyrazolone CH3), 23.08 (acetyl CH3), 58.34
(CH2), 74.34 (CH), 79.02 (CCH), 116.22, 118.32, 118.68, 118.97,
120.85, 124.73, 127.46, 128.53, 128.65, 129.64, 130.35, 132.68,
138.46, 148.61, 154.12, 164.02 (C=N), 165.42 (C=O) (Ar-C) ppm.
MS (ESI): m/z = 331.0 [M + H]+.
Spectroscopic Data for Compounds 4a–u, and 5a–l
(5aR,11bS)-3-(3-Chlorophenyl)-1,5,5,11b-tetramethyl-10-nitro-
3,5a,6,11b-tetrahydro-5H-chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazole
(4e): Isolated yield (0.673 g, 72 %) as white crystals, m.p. 208–
(5aR,11bS)-1,11b-Dimethyl-10-nitro-3-phenyl-3,5a,6,11b-tetra-
hydro-5H-chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazole (4a): Isolated
yield (0.683 g, 75%) as white crystals, m.p. 172–174 °C. IR (KBr):
210 °C. IR (KBr): ν = 2972, 2931, 1604, 1516, 1498, 1437, 1336,
˜
ν = 2983, 2928, 1597, 1518, 1488, 1444, 1341, 1242, 1089, 1045,
˜
1233, 1091, 1039, 853, 764, 683 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 1.09 (s, 3 H, angular CH3), 1.67 (s, 3 H, 5-CH3), 1.78 (s, 3 H,
5Ј-CH3), 2.01 (d, J = 4.0, 1 H, 5a-H), 2.76 (s, 3 H, pyrazolone
CH3), 4.57 (d, J = 13.2 Hz, 1 H, 6-H), 4.78 (dd, J = 13.0, J = 4.4
Hz, 1 H, 6Ј-H), 6.78–8.46 (m, 7 H, Ar-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 17.13 (pyrazolone CH3), 22.56 (angular
CH3), 29.72 (CH3-5), 32.73 (CH3-5Ј), 33.76 (C-11b), 46.62 (C-5a),
63.31 (C-6), 82.29 (C-5), 100.55, 117.13, 120.43, 123.87, 128.65,
129.28, 129.64, 129.81, 130.54, 131.73, 136.24, 141.26, 148.01,
831, 757, 695 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.83 (s, 3 H,
angular CH3), 2.26 (m, 1 H, 5a-H), 2.66 (s, 3 H, pyrazolone CH3),
4.21 (t, J = 10.4 Hz, 1 H, 6-H), 4.38 (dd, J = 12.0, J = 3.6 Hz, 1
H, 5-H), 4.56 (dd, J = 11.2, J = 3.2 Hz, 1 H, 6Ј-H), 4.63 (dd, J =
12.0, J = 3.2 Hz, 1 H, 5Ј-H), 6.88–8.48 (m, 8 H, Ar-H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 16.34 (pyrazolone CH3), 29.38
(angular CH3), 34.26 (C-11b), 37.18 (C-5a), 62.78 (C-5), 68.49 (C-
6), 101.93, 117.87, 120.77, 123.77, 125.95, 126.36, 128.93, 129.51,
138.19, 141.73, 146.19, 148.29, 156.78 (Ar-C) ppm. MS (ESI): m/z
= 378.2 [M + H]+. C21H19N3O4 (378.1): calcd. C 66.83, H 5.07, N
11.13; found C 66.68, H 5.19, N 11.01.
149.77, 156.6 ppm. MS (ESI): m/z = 440.83 [M + H]+
.
C23H22ClN3O4 (439.12): calcd. C 62.80, H 5.04, N 9.55; found C
62.59, H 5.16, N 9.49.
(5aR,11bS)-3-(3-Chlorophenyl)-1,11b-dimethyl-10-nitro-3,5a,6,11b-
tetrahydro-5H-chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazole (4b): Iso-
lated yield (0.785 g, 79%) as white crystals, m.p. 196–198 °C. IR
(5aR,11bS)-1,5,5,11b-Tetramethyl-3-(4-methylphenyl)-10-nitro-
3,5a,6,11b-tetrahydro-5H-chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazole
(4f): Isolated yield (0.695 g, 78 %) as white crystals, m.p. 238–
(KBr): ν = 2978, 2923, 1594, 1518, 1482, 1432, 1339, 1240, 1089,
˜
1048, 849, 783, 742, 676 cm–1. 1H NMR (400 MHz, CDCl3): δ =
1.81 (s, 3 H, angular CH3), 2.24 (m, 1 H, 5a-H), 2.65 (s, 3 H,
pyrazolone CH3), 4.22 (t, J = 11.2 Hz, 1 H, 6-H), 4.38 (dd, J =
12.4, J = 3.6 Hz, 1 H, 5-H), 4.55 (dd, J = 12.0, J = 3.2 Hz, 1 H,
6Ј-H), 4.63 (dd, J = 12.0, J = 3.6 Hz, 1 H, 5Ј-H), 6.75–8.42 (m, 7
H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 16.10 (pyrazo-
lone CH3), 29.07 (angular CH3), 34.68 (C-11b), 37.86 (C-5a), 62.78
(C-5), 69.13 (C-6), 101.65, 116.78, 121.43, 124.02, 128.05, 129.21,
129.54, 129.79, 130.32, 131.54, 135.84, 141.13, 147.34, 149.43,
155.87 ppm. MS (ESI): m/z = 412.80 [M + H]+. C21H18ClN3O4
(411.10): calcd. C 61.24, H 4.41, N 10.20; found C 61.38, H 4.52,
N 10.08.
240 °C. IR (KBr): ν = 2977, 2930, 1597, 1518, 1496, 1445, 1341,
˜
1242, 1086, 1041, 863, 758, 688 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 1.09 (s, 3 H, angular CH3), 1.68 (s, 3 H, 5-CH3), 1.78 (s, 3 H,
5Ј-CH3), 1.99 (d, J = 3.6, 1 H, 5a-H), 2.37 (s, 3 H, CH3 of phenyl
ring), 2.78 (s, 3 H, pyrazolone CH3), 4.56 (d, J = 12.8 Hz, 1 H, 6-
H), 4.78 (dd, J = 12.4, J = 4.0 Hz, 1 H, 6Ј-H), 6.79–8.47 (m, 7 H,
Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 16.67 (pyrazolone
CH3), 20.01 (CH3 of phenyl ring), 22.75 (angular CH3), 29.65
(CH3-5), 32.87 (CH3-5Ј), 33.68 (C-11b), 47.34 (C-5a), 62.24 (C-6),
82.07 (C-5), 102.13, 116.35, 120.57, 123.61, 128.12, 129.72, 130.01,
135.64, 136.23, 141.86, 146.63, 149.20, 157.14 ppm. MS (ESI): m/z
= 420.47 [M + H]+. C24H25N3O4 (419.20): calcd. C 68.72, H 6.01,
N 10.02; found C 68.55, H 6.10, N 10.19.
(5aR,11bS)-1,11b-Dimethyl-3-(4-methylphenyl)-10-nitro-3,5a,6,11b-
tetrahydro-5H-chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazole (4c): Iso-
lated yield (0.717 g, 76%) as white crystals, m.p. 208–210 °C. IR
(5aR,11bS)-1,11b-Dimethyl-8-nitro-3-phenyl-3,5a,6,11b-tetra-
hydro-5H-chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazole (4g): Isolated
(KBr): ν = 2985, 2930, 1589, 1516, 1487, 1434, 1342, 1232, 1079, yield (0.738 g, 81%) as white crystals, m.p. 162–164 °C. IR (KBr):
˜
1038, 864, 757, 682 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.81 ν = 2983, 2928, 1597, 1518, 1488, 1444, 1340, 1242, 1089, 1045,
˜
(s, 3 H, angular CH3), 2.25 (m, 1 H, 5a-H), 2.39 (s, 3 H, CH3 of
phenyl ring), 2.66 (s, 3 H, pyrazolone CH3), 4.24 (t, J = 9.8 Hz, 1
H, 6-H), 4.39 (dd, J = 12.2, J = 3.6 Hz, 1 H, 5-H), 4.53 (dd, J =
11.2, J = 3.2 Hz, 1 H, 6Ј-H), 4.61 (dd, J = 12.4, J = 3.2 Hz, 1 H,
831, 757, 695 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.82 (s, 3 H,
angular CH3), 2.28 (m, 1 H, 5a-H), 2.60 (s, 3 H, pyrazolone CH3),
4.26 (t, J = 11.2 Hz, 1 H, 6-H), 4.44 (dd, J = 12.4, J = 3.2 Hz, 1
H, 5-H), 4.57 (dd, J = 11.6, J = 3.6 Hz, 1 H, 6Ј-H), 4.70 (dd, J =
5Ј-H), 6.78–8.46 (m, 7 H, Ar-H) ppm. 13C NMR (100 MHz, 12.0, J = 3.2 Hz, 1 H, 5Ј-H), 6.98–7.71 (m, 8 H, Ar-H) ppm. 13C
CDCl3): δ = 16.43 (pyrazolone CH3), 21.11 (CH3 of phenyl ring),
NMR (100 MHz, CDCl3): δ = 16.40 (pyrazolone CH3), 29.30
29.46 (angular CH3), 34.92 (C-11b), 37.54 (C-5a), 63.08 (C-5),
(angular CH3), 34.38 (C-11b), 37.00 (C-5a), 63.77 (C-5), 68.64 (C-
69.02 (C-6), 102.14, 117.32, 120.75, 123.67, 127.34, 129.43, 129.63, 6), 102.05, 120.09, 120.77, 123.96, 125.98, 128.96, 132.09, 134.21,
135.21, 135.96, 141.52, 146.32, 148.64, 156.54 ppm. MS (ESI): m/z 138.17, 139.44, 145.22, 146.10, 148.45 ppm. MS (ESI): m/z =
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Pages: 13
N. J. Parmar et al.
378.39 [M + H]+. C21H19N3O4 (377.16): calcd. C 66.83, H 5.07, N MS (ESI): m/z = 440.89 [M + H]+. C23H22ClN3O4 (439.15): calcd.
FULL PAPER
11.13; found C 66.68, H 5.19, N 11.01.
C 62.80, H 5.04, N 9.55; found C 62.67, H 5.16, N 9.29.
(5aR,11bS)-3-(3-Chlorophenyl)-1,11b-dimethyl-8-nitro-3,5a,6,11b-
tetrahydro-5H-chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazole (4h): Iso-
lated yield (0.775 g, 78%) as white crystals, m.p. 218–220 °C. IR
(5aR,11bS)-1,5,5,11b-Tetramethyl-3-(4-methylphenyl)-8-nitro-
3,5a,6,11b-tetrahydro-5H-chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazole
(4l): Isolated yield (0.633 g, 71 %) as white crystals, m.p. 218–
(KBr): ν = 2967, 2931, 1594, 1516, 1493, 1438, 1338, 1234, 1092, 220 °C. IR (KBr): ν = 2978, 2928, 1585, 1516, 1438, 1337, 1242,
˜
˜
1
1041, 864, 756, 685 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.84 1091, 1041, 864, 756, 686 cm–1. H NMR (400 MHz, CDCl3): δ =
(s, 3 H, angular CH3), 2.29 (m, 1 H, 5a-H), 2.63 (s, 3 H, pyrazolone 1.07 (s, 3 H, angular CH3), 1.66 (s, 3 H, 5-CH3), 1.79 (s, 3 H, 5Ј-
CH3), 4.28 (t, J = 11.6 Hz, 1 H, 6-H), 4.46 (dd, J = 12.0, J = CH3), 2.00 (d, J = 3.6, 1 H, 5a-H), 2.39 (s, 3 H, CH3 of phenyl
3.2 Hz, 1 H, 5-H), 4.59 (dd, J = 11.2, J = 3.2 Hz, 1 H, 6Ј-H), 4.73
ring), 2.80 (s, 3 H, pyrazolone CH3), 4.59 (d, J = 10.8 Hz, 1 H, 6-
(dd, J = 12.0, J = 3.6 Hz, 1 H, 5Ј-H), 6.82–7.76 (m, 7 H, Ar-H) H), 4.76 (dd, J = 12.0, J = 3.2 Hz, 1 H, 6Ј-H), 6.78–7.87 (m, 7 H,
ppm. 13C NMR (100 MHz, CDCl3): δ = 15.92 (pyrazolone CH3),
Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 17.46 (pyrazolone
29.16 (angular CH3), 34.63 (C-11b), 37.45 (C-5a), 63.41 (C-5),
CH3), 20.83 (CH3 of phenyl ring), 23.14 (angular CH3), 29.65
69.24 (C-6), 101.28, 120.15, 120.84, 121.65, 123.87, 125.41, 127.69, (CH3-5), 32.48 (CH3-5Ј), 33.42 (C-11b), 46.59 (C-5a), 61.94 (C-6),
129.52, 133.36, 134.97, 138.75, 139.44, 145.67, 146.76, 148.13 ppm.
MS (ESI): m/z = 412.24 [M + H]+. C21H18ClN3O4 (411.10): calcd.
C 61.24, H 4.41, N 10.20; found C 62.08, H 4.32, N 10.26.
81.76 (C-5), 101.48, 120.56, 121.17, 121.61, 123.73, 132.53, 134.42,
135.53, 135.91, 139.21, 145.32, 145.49, 148.75 ppm. MS (ESI): m/z
= 420.27 [M + H]+. C24H25N3O4 (419.18): calcd. C 68.72, H 6.01,
N 10.02; found C 68.51, H 6.26, N 10.13.
(5aR,11bS)-1,11b-Dimethyl-3-(4-methylphenyl)-8-nitro-3,5a,6,11b-
tetrahydro-5H-chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazole (4i): Iso-
lated yield (0.755 g, 80%) as white crystals, m.p. 224–226 °C. IR
(5aR,11bS)-1,11b-Dimethyl-3-phenyl-3,5a,6,11b-tetrahydro-5H-
chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazole (4m): Isolated yield
(KBr): ν = 2976, 2927, 1589, 1519, 1486, 1440, 1338, 1241, 1089, (0.735 g, 78%) as white crystals, m.p. 152–154 °C. IR (KBr): ν =
˜
˜
1032, 852, 758, 667 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.81 2957, 2927, 1595, 1516, 1485, 1442, 1227, 1093, 1048, 840, 756,
1
(s, 3 H, angular CH3), 2.29 (m, 1 H, 5a-H), 2.37 (s, 3 H, CH3 of
phenyl ring), 2.64 (s, 3 H, pyrazolone CH3), 4.30 (t, J = 10.8 Hz,
1 H, 6-H), 4.44 (dd, J = 12.4, J = 3.6 Hz, 1 H, 5-H), 4.56 (dd, J =
11.6, J = 3.2 Hz, 1 H, 6Ј-H), 4.74 (dd, J = 11.6, J = 3.2 Hz, 1 H,
692 cm–1. H NMR (400 MHz, CDCl3): δ = 1.81 (s, 3 H, angular
CH3), 2.16 (m, 1 H, 5a-H), 2.64 (s, 3 H, pyrazolone CH3), 4.27 (m,
2 H, 5-H and 6-H), 4.53 (dd, J = 11.2, J = 3.6 Hz, 1 H, 6Ј-H), 4.58
(dd, J = 12.0, J = 2.8 Hz, 1 H, 5Ј-H), 6.80–7.73 (m, 9 H, Ar-H)
5Ј-H), 6.89–7.79 (m, 7 H, Ar-H) ppm. 13C NMR (100 MHz, ppm. 13C NMR (100 MHz, CDCl3): δ = 16.47 (pyrazolone CH3),
CDCl3): δ = 16.72 (pyrazolone CH3), 21.53 (CH3 of phenyl ring),
29.35 (angular CH3), 34.56 (C-11b), 37.86 (C-5a), 63.18 (C-5),
29.64 (angular CH3), 34.07 (C-11b), 37.85 (C-5a), 62.86 (C-5),
69.07 (C-6), 103.15, 117.09, 120.71, 121.10, 125.68, 127.87, 128.89,
69.75 (C-6), 101.90, 120.43, 120.85, 121.07, 123.46, 132.19, 134.27, 129.09, 129.60, 138.45, 146.50, 148.51, 151.16 ppm. MS (ESI): m/z
135.47, 135.96, 139.64, 145.46, 146.14, 148.34 ppm. MS (ESI): m/z
= 392.42 [M + H]+. C22H21N3O4 (391.12): calcd. C 67.51, H 5.41,
N 10.74; found C 67.68, H 5.46, N 10.31.
= 333.20 [M + H]+. C21H20N2O2 (332.19): calcd. C 75.88, H 6.06,
N 8.43; found C 75.62, H 6.21, N 8.67.
(5aR,11bS)-1,5,5,11b-Tetramethyl-3-phenyl-3,5a,6,11b-tetrahydro-
(5aR,11bS)-1,5,5,11b-Tetramethyl-8-nitro-3-phenyl-3,5a,6,11b-tetra- 5H-chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazole (4n): Isolated yield
hydro-5H-chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazole (4j): Isolated (0.670 g, 76%) as white crystals, m.p. 170–172 °C. IR (KBr): ν =
˜
yield (0.672 g, 78%) as white crystals, m.p. 220–222 °C. IR (KBr):
2981, 2929, 1597, 1511, 1491, 1443, 1230, 1084, 1043, 838, 757,
1
ν = 2976, 2931, 1586, 1515, 1436, 1339, 1245, 1043, 1034, 848, 758,
673 cm–1. H NMR (400 MHz, CDCl3): δ = 1.09 (s, 3 H, angular
˜
1
668 cm–1. H NMR (400 MHz, CDCl3): δ = 1.10 (s, 3 H, angular
CH3), 1.64 (s, 3 H, 5-CH3), 1.77 (s, 3 H, 5Ј-CH3), 1.98 (d, J = 3.2,
1 H, 5a-H), 2.71 (s, 3 H, pyrazolone CH3), 4.43 (td, J = 12.8, J =
1.2 Hz, 1 H, 6-H), 4.72 (ddd, J = 12.6, J = 4.4, J = 2.0 Hz, 1 H,
CH3), 1.66 (s, 3 H, 5-CH3), 1.78 (s, 3 H, 5Ј-CH3), 2.02 (d, J = 3.6,
1 H, 5a-H), 2.76 (s, 3 H, pyrazolone CH3), 4.56 (d, J = 11.6 Hz, 1
H, 6-H), 4.77 (dd, J = 12.8, J = 4.0 Hz, 1 H, 6Ј-H), 6.72–7.78 (m, 6Ј-H), 6.76–7.78 (m, 9 H, Ar-H) ppm. 13C NMR (100 MHz,
8 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 16.24 (pyrazo-
lone CH3), 22.13 (angular CH3), 28.88 (CH3-5), 32.43 (CH3-5Ј), (CH3-5), 32.07 (CH3-5Ј), 33.64 (C-11b), 47.11 (C-5a), 61.95 (C-6),
34.06 (C-11b), 46.43 (C-5a), 62.65 (C-6), 82.64 (C-5), 101.56, 82.72 (C-5), 101.20, 116.29, 120.65, 120.99, 125.41, 127.50, 127.69,
CDCl3): δ = 16.78 (pyrazolone CH3), 22.75 (angular CH3), 29.21
120.26, 120.85, 123.67, 125.79, 128.36, 131.94, 134.46, 138.33, 128.83, 129.22, 138.75, 146.76, 148.13, 152.67 ppm. MS (ESI): m/z
139.87, 145.46, 146.57, 148.94 ppm. MS (ESI): m/z = 406.14 [M +
H]+. C23H23N3O4 (405.19): calcd. C 68.13, H 5.72, N 10.36; found
C 68.51, H 5.46, N 10.12.
= 361.24 [M + H]+. C23H24N2O2 (360.18): calcd. C 76.64, H 6.71,
N 7.77; found C 76.41, H 6.59, N 7.91.
(11bS)-1,11b-Dimethyl-10-nitro-3-phenyl-3,11b-dihydro-6H-
chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazole (4o): Isolated yield
(5aR,11bS)-3-(3-Chlorophenyl)-1,5,5,11b-tetramethyl-8-nitro-
3,5a,6,11b-tetrahydro-5H-chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazole
(0.561 g, 65%) as white crystals, m.p. 170–173 °C. IR (KBr): ν =
˜
(4k): Isolated yield (0.692 g, 74 %) as white crystals, m.p. 224– 2972, 2927, 1686, 1518, 1476, 1443, 1339, 1231, 1096, 1039, 856,
226 °C. IR (KBr): ν = 2983, 2933, 1593, 1517, 1443, 1342, 1239, 757, 683 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.85 (s, 3 H, angu-
˜
1084, 1037, 858, 757, 679 cm–1. 1H NMR(400 MHz, CDCl3): δ = lar CH3), 2.64 (s, 3 H, pyrazolone CH3), 4.64 (d, J = 12.0 Hz, 1 H,
1.09 (s, 3 H, angular CH3), 1.66 (s, 3 H, 5-CH3), 1.79 (s, 3 H, 5Ј-
CH3), 1.99 (d, J = 3.6, 1 H, 5a-H), 2.78 (s, 3 H, pyrazolone CH3),
4.58 (d, J = 10.8 Hz, 1 H, 6-H), 4.79 (dd, J = 12.4, J = 4.0 Hz, 1
H, 6Ј-H), 6.71–7.83 (m, 7 H, Ar-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 16.69 (pyrazolone CH3), 22.86 (angular CH3), 29.45
6-H), 5.14 (dd, J = 11.6, J = 1.2 Hz, 1 H, 6Ј-H), 6.55 (d, J = 1.2 Hz,
1 H, 5-H), 6.75–8.73 (m, 8 H, Ar-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 16.75 (pyrazolone CH3), 27.56 (angular CH3), 35.87
(C-11b), 65.89 (C-6), 101.23, 115.45, 117.54, 120.46, 123.34, 125.05,
126.43, 129.86, 131.42, 134.77, 138.85, 141.43, 146.42, 148.46,
(CH3-5), 32.64 (CH3-5Ј), 33.28 (C-11b), 46.83 (C-5a), 63.15 (C-6), 158.53 ppm. MS (ESI): m/z = 376.23 [M + H]+. C21H17N3O4
82.58 (C-5), 100.79, 120.54, 121.68, 121.98, 123.75, 125.69, 127.88, (375.12): calcd. C 67.19, H 4.56, N 11.19; found C 66.92, H 4.78,
129.62, 133.46, 134.76, 137.60, 139.16, 145.74, 146.93, 149.24 ppm.
N 11.01.
8
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20751
/KAP1
Date: 17-09-12 16:57:23
Pages: 13
Domino Knoevenagel–hetero-Diels–Alder Reaction
11bS)-3-(3-Chlorophenyl)-1,11b-dimethyl-10-nitro-3,11b-dihydro-
6H-chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazole (4p): Isolated yield
lar CH3), 2.34 (s, 3 H, CH3 of phenyl ring), 2.64 (s, 3 H, pyrazolone
CH3), 4.66 (d, J = 12.4 Hz, 1 H, 6-H), 5.20 (dd, J = 12.0, J =
(0.669 g, 71%) as white crystals, m.p. 218–220 °C. IR (KBr): ν = 1.2 Hz, 1 H, 6Ј-H), 6.58 (d, J = 1.2 Hz, 1 H, 5-H), 6.87–7.78 (m, 7
˜
2971, 2928, 1691, 1520, 1478, 1427, 1336, 1242, 1094, 1046, 868,
767, 691 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.86 (s, 3 H, angu-
lar CH3), 2.66 (s, 3 H, pyrazolone CH3), 4.65 (d, J = 12.0 Hz, 1 H,
6-H), 5.17 (dd, J = 11.2, J = 1.2 Hz, 1 H, 6Ј-H), 6.57 (d, J = 0.8 Hz,
H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 16.18 (pyrazo-
lone CH3), 20.23 (CH3 of phenyl ring), 27.64 (angular CH3), 36.68
(C-11b), 64.35 (C-6), 101.26, 115.16, 120.54, 121.34, 122.03, 123.46,
132.17, 134.56, 134.89, 135.64, 137.12, 139.65, 145.37, 146.87,
1 H, 5-H), 6.79–8.48 (m, 7 H, Ar-H) ppm. 13C NMR (100 MHz, 148.54 ppm. MS (ESI): m/z = 390.29 [M + H]+. C22H19N3O4
CDCl3): δ = 16.75 (pyrazolone CH3), 27.23 (angular CH3), 36.42
(389.20): calcd. C 67.86, H 4.92, N 10.79; found C 67.44, H 5.17,
(C-11b), 64.74 (C-6), 100.23, 115.68, 117.16, 120.43, 123.69, 128.71, N 11.03.
129.67, 129.93, 130.43, 130.92, 132.68, 134.35, 136.59, 142.12,
(11bS)-1,11b-Dimethyl-3-phenyl-3,11b-dihydro-6H-chromeno-
[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazole (4u): Isolated yield (0.683 g, 72%)
146.85, 149.56, 157.49 ppm. MS (ESI): m/z = 410.82 [M + H]+.
C21H16ClN3O4 (409.1): calcd. C 61.54, H 3.94, N, 10.25; found C
61.28, H, 4.17, N 10.02.
as white crystals, m.p. 156–158 °C. IR (KBr): ν = 2969, 2927, 1672,
˜
1595, 1518, 1488, 1451, 1227, 1109, 1039, 844, 753, 683 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 1.87 (s, 3 H, angular CH3), 2.66 (s,
3 H, pyrazolone CH3), 4.65 (d, J = 12.4 Hz, 1 H, 6-H), 5.17 (dd,
J = 12.0, J = 1.6 Hz, 1 H, 6Ј-H), 6.56 (d, J = 1.2 Hz, 1 H, 5-H),
6.87–7.73 (m, 9 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ =
16.10 (pyrazolone CH3), 27.67 (angular CH3), 36.05 (C-11b), 65.02
(C-6), 100.05, 115.01, 117.59, 120.75, 121.10, 125.19, 126.32,
(11bS)-1,11b-Dimethyl-3-(4-methylphenyl)-10-nitro-3,11b-dihydro-
6H-chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazole (4q): Isolated yield
(0.654 g, 73%) as white crystals, m.p. 203–205 °C. IR (KBr): ν =
˜
2968, 2927, 1681, 1517, 1473, 1433, 1339, 1229, 1084, 1039, 871,
758, 682 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.86 (s, 3 H, angu-
lar CH3), 2.36 (s, 3 H, CH3 of phenyl ring), 2.66 (s, 3 H, pyrazolone
CH3), 4.67 (d, J = 12.4 Hz, 1 H, 6Ј-H), 5.18 (dd, J = 12.8, J = 128.08, 129.07, 133.48, 134.02, 137.99, 145.55, 146.44, 152.78 ppm.
1.6 Hz, 1 H, 6-H), 6.62 (d, J = 1.2 Hz, 1 H, 5-H), 6.76–8.49 (m, 7
H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 16.43 (pyrazo-
lone CH3), 20.64 (CH3 of phenyl ring), 27.42 (angular CH3), 36.37
(C-11b), 64.59 (C-6), 101.12, 115.63, 117.56, 120.46, 124.65, 127.86,
129.87, 130.48, 134.73, 136.47, 137.24, 141.38, 146.79, 148.68,
157.82 ppm. MS (ESI): m/z = 390.20 [M + H]+. C22H19N3O4
(389.12): calcd. C 67.86, H 4.92, N 10.79; found C 67.49, H 4.67,
N 11.06.
MS (ESI): m/z = 331.38 [M + H]+. C21H18N2O2 (330.20): calcd. C
76.34, H 5.49, N 8.48; found C 76.05, H 5.76, N 8.28.
(5aR,11bS)-1,11b-Dimethyl-3-phenyl-3,5a,6,11b-tetrahydro-5H-
chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazol-10-amine (5a): Isolated
yield (0.565 g, 72%) as a pinkish white powder, m.p. 118–120 °C.
IR (KBr): ν = 3454, 3336, 2971, 2925, 1632, 1594, 1578, 1521,
˜
1
1497, 1443, 1227, 1095, 1049, 159, 681 cm–1. H NMR (400 MHz,
CDCl3): δ = 1.78 (s, 3 H, angular CH3), 2.12 (m, 1 H, 5a-H), 2.64
(s, 3 H, pyrazolone CH3), 4.28 (t, J = 10.4 Hz, 1 H, 6-H), 4.26 (dd,
J = 12.0, J = 3.6 Hz, 1 H, 5-H), 4.56 (dd, J = 11.2, J = 3.2 Hz, 1
H, 6Ј-H), 4.63 (dd, J = 12.0, J = 3.2 Hz, 1 H, 5Ј-H), 4.77 (s, 2 H,
NH2), 6.50–7.71 (m, 8 H, Ar-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 16.53 (pyrazolone CH3), 29.44 (angular CH3), 34.26
(11bS)-1,11b-Dimethyl-8-nitro-3-phenyl-3,11b-dihydro-6H-
chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazole (4r): Isolated yield
(0.579 g, 67%) as white crystals, m.p. 182–184 °C. IR (KBr): ν =
˜
2969, 2928, 1689, 1516, 1481, 1436, 1231, 1086, 1041, 856, 759,
1
690 cm–1. H NMR (400 MHz, CDCl3): δ = 1.85 (s, 3 H, angular
CH3), 2.65 (s, 3 H, pyrazolone CH3), 4.63 (d, J = 12.0 Hz, 1 H, 6Ј- (C-11b), 38.03 (C-5a), 62.67 (C-5), 69.34 (C-6), 103.18, 115.84,
H), 5.16 (dd, J = 12.4, J = 1.2 Hz, 1 H, 6-H), 6.57 (d, J = 1.2 Hz, 115.87, 117.66, 120.79, 125.72, 128.89, 129.89, 138.36, 139.95,
1 H, 5-H), 6.75–7.83 (m, 8 H, Ar-H) ppm. 13C NMR (100 MHz, 143.94, 146.41, 148.70 ppm. MS (ESI): m/z = 348.41 [M + H]+.
CDCl3): δ = 16.72 (pyrazolone CH3), 27.33 (angular CH3), 36.42 C21H21N3O2 (347.18): calcd. C 72.60, H 6.09, N 12.10; found C
(C-11b), 65.67 (C-6), 101.67, 115.42, 120.32, 120.94, 124.63, 125.87, 72.45, H 6.54, N 11.16.
129.32, 132.16, 134.21, 135.36, 138.74, 140.23, 145.63, 146.46,
(5aR,11bS)-3-(3-Chlorophenyl)-1,11b-dimethyl-3,5a,6,11b-tetra-
hydro-5H-chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazol-10-amine (5b):
Isolated yield (0.741 g, 86%) as an off-white powder, m.p. 110–
148.45 ppm. MS (ESI): m/z = 376.38 [M + H]+. C21H17N3O4
(375.18): calcd. C 67.19, H 4.56, N 11.19; found C 67.42, H 4.91,
N 11.41.
112 °C. IR (KBr): ν = 3387, 3336, 2971, 2924, 1615, 1593, 1526,
˜
1
(11bS)-3-(3-Chlorophenyl)-1,11b-dimethyl-8-nitro-3,11b-dihydro-
6H-chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazole (4s): Isolated yield
1497, 1443, 1395, 1228, 1097, 1044, 865, 759, 645 cm–1. H NMR
(400 MHz, [D6]DMSO): δ = 1.67 (s, 3 H, angular CH3), 2.10 (m,
1 H, 5a-H), 2.53 (s, 3 H, pyrazolone CH3), 4.02 (t, J = 10.4 Hz, 1
H, 6-H), 4.36 (dd, J = 12.0, J = 3.6 Hz, 1 H, 5-H), 4.58 (dd, J =
11.2, J = 3.2 Hz, 1 H, 6Ј-H), 4.62 (dd, J = 12.0, J = 3.2 Hz, 1 H,
(0.613 g, 65%) as white crystals, m.p. 206–208 °C. IR (KBr): ν =
˜
2967, 2925, 1691, 1517, 1483, 1428, 1231, 1075, 1037, 876, 767,
1
692 cm–1. H NMR (400 MHz, CDCl3): δ = 1.87 (s, 3 H, angular
CH3), 2.66 (s, 3 H, pyrazolone CH3), 4.62 (d, J = 12.0 Hz, 1 H, 6Ј- 5Ј-H), 4.94 (s, 2 H, NH2), 6.35–7.54 (m, 8 H, Ar-H) ppm. 13C
H), 5.18 (dd, J = 12.4, J = 1.2 Hz, 1 H, 6-H), 6.56 (d, J = 1.2 Hz,
1 H, 5-H), 6.74–7.78 (m, 7 H, Ar-H) ppm. 13C NMR (100 MHz, (angular CH3), 34.31 (C-11b), 38.09 (C-5a), 62.70 (C-5), 69.39 (C-
CDCl3): δ = 16.34 (pyrazolone CH3), 28.03 (angular CH3), 37.02 6), 103.21, 115.89, 115.92, 117.63, 120.76, 125.78, 128.86, 129.87,
NMR (100 MHz, [D6]DMSO): δ = 16.59 (pyrazolone CH3), 29.34
(C-11b), 65.39 (C-6), 101.43, 115.76, 120.46, 121.67, 122.43, 124.07, 138.38, 139.85, 143.91, 146.51, 148.76 ppm. MS (ESI): m/z =
125.49, 127.66, 129.64, 133.23, 134.52, 135.16, 138.48, 139.57, 382.86 [M + H]+. C21H20ClN3O2 (381.20): calcd. C 66.05, H 5.28,
145.73, 146.89, 148.46 ppm. MS (ESI): m/z = 410.22 [M + H]+.
C21H16ClN3O4 (409.13): calcd. C 61.54, H 3.94, N 10.25; found C
61.87, H 3.57, N 10.53.
N 11.00; found C 66.38, H 5.12, N 11.08.
(5aR,11bS)-1,11b-Dimethyl-3-(4-methylphenyl)-3,5a,6,11b-tetra-
hydro-5H-chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazol-10-amine (5c):
Isolated yield (0.613 g, 75%) as a white powder, m.p. 98–100 °C.
(11bS)-1,11b-Dimethyl-3-(4-methylphenyl)-8-nitro-3,11b-dihydro-
6H-chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazole (4t): Isolated yield
IR (KBr): ν = 3431, 3206, 2986, 2926, 1604, 1521, 1489, 1446, 1363,
˜
(0.627 g, 70%) as white crystals, m.p. 196–197 °C. IR (KBr): ν =
1246, 1091, 1046, 836, 753, 696 cm–1. 1H NMR (400 MHz, [D6]-
DMSO): δ = 1.79 (s, 3 H, angular CH3), 2.13 (m, 1 H, 5a-H), 2.65
(s, 3 H, pyrazolone CH3), 4.26 (t, J = 10.4 Hz, 1 H, 6-H), 4.23 (dd,
˜
2969, 2925, 1681, 1517, 1475, 1428, 1338, 1229, 1101, 1042, 870,
759, 682 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.85 (s, 3 H, angu-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O20751
/KAP1
Date: 17-09-12 16:57:23
Pages: 13
N. J. Parmar et al.
J = 12.0, J = 3.6 Hz, 1 H, 5-H), 4.57 (dd, J = 11.2, J = 3.2 Hz, 1 (0.581 g, 74%) as a white powder, m.p. 116–118 °C. IR (KBr): ν =
FULL PAPER
˜
H, 6Ј-H), 4.64 (dd, J = 12.0, J = 3.2 Hz, 1 H, 5Ј-H), 4.76 (s, 2 H,
3330, 3207, 2928, 1518, 1488, 1444, 1360, 1242, 1089, 1045, 831,
NH2), 6.51–7.72 (m, 8 H, Ar-H) ppm. 13C NMR (100 MHz, [D6] 757, 695 cm–1. H NMR (400 MHz, [D6]DMSO): δ = 1.83 (s, 3 H,
DMSO): δ = 16.56 (pyrazolone CH3), 29.39 (angular CH3), 34.36 angular CH3), 2.28 (m, 1 H, 5a-H), 2.60 (s, 3 H, pyrazolone CH3),
(C-11b), 38.09 (C-5a), 62.68 (C-5), 69.33 (C-6), 103.20, 115.84, 4.26 (t, J = 11.2 Hz, 1 H, 6-H), 4.44 (dd, J = 12.4, J = 3.2 Hz, 1
115.87, 117.66, 120.79, 125.74, 128.89, 129.89, 138.34, 139.91, H, 5-H), 4.57 (dd, J = 11.6, J = 3.6 Hz, 1 H, 6Ј-H), 4.70 (dd, J =
1
143.94, 146.48, 148.73 ppm. MS (ESI): m/z = 362.49 [M + H]+.
C22H23N3O2 (361.18): calcd. C 73.11, H 6.41, N 11.63; found C
73.21, H 6.38, N 11.56.
12.0, J = 3.2 Hz, 1 H, 5Ј-H), 4.73 (s, 2 H, NH2), 6.98–7.71 (m,
8 H, Ar-H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 16.40
(pyrazolone CH3), 29.30 (angular CH3), 34.38 (C-11b), 37.00 (C-
5a), 63.77 (C-5), 68.64 (C-6), 102.05, 120.09, 120.77, 123.96, 125.98,
128.96, 132.09, 134.21, 138.17, 139.44, 145.22, 146.10, 148.45 ppm.
MS (ESI): m/z = 348.23 [M + H]+. C21H21N3O2 (347.20): calcd. C
72.60, H 6.09, N 12.10; found C 72.68, H 5.99, N 12.19.
(5aR,11bS)-1,5,5,11b-Tetramethyl-3-phenyl-3,5a,6,11b-tetrahydro-
5H-chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazol-10-amine (5d): Isolated
yield (0.670 g, 89%) as a white powder, m.p. 162–164 °C. IR (KBr):
ν = 3432, 3215, 2984, 2930, 1523, 1488, 1447, 1361, 1241, 1088,
˜
1044, 839, 751, 693 cm–1. 1H NMR (400 MHz, [D6]DMSO): δ =
1.09 (s, 3 H, angular CH3), 1.68 (s, 3 H, 5-CH3), 1.78 (s, 3 H, 5Ј-
CH3), 1.99 (d, J = 3.4, 1 H, 5a-H), 2.37 (s, 3 H, CH3 of phenyl
ring), 2.78 (s, 3 H, pyrazolone CH3), 4.56 (d, J = 12.7 Hz, 1 H, 6-
H), 4.78 (dd, J = 12.6, J = 4.0 Hz, 1 H, 6Ј-H), 4.80 (s, 2 H, NH2),
6.79–8.47 (m, 7 H, Ar-H) ppm. 13C NMR (100 MHz, [D6]DMSO):
δ = 16.67 (pyrazolone CH3), 20.01 (CH3 of phenyl ring), 22.75
(angular CH3), 29.65 (CH3-5), 32.87 (CH3-5Ј), 33.68 (C-11b), 47.34
(C-5a), 62.24 (C-6), 82.07 (C-5), 102.13, 116.35, 120.57, 123.61,
128.12, 129.72, 130.01, 135.64, 136.23, 141.86, 146.63, 149.20,
157.14 ppm. MS (ESI): m/z = 376.49 [M + H]+. C23H25N3O
(375.15): calcd. C 73.57, H 6.71, N 11.19; found C 73.48, H 6.89,
N 11.28.
(5aR,11bS)-3-(3-Chlorophenyl)-1,11b-dimethyl-3,5a,6,11b-tetra-
hydro-5H-chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazol-8-amine (5h):
Isolated yield (0.706 g, 82%) as a pink powder, m.p. 138–140 °C.
IR (KBr): ν = 3335, 3210, 2931, 1516, 1438, 1360, 1338, 1234, 1092,
˜
1041, 864, 756, 685 cm–1. 1H NMR (400 MHz, [D6]DMSO): δ =
1.84 (s, 3 H, angular CH3), 2.26 (m, 1 H, 5a-H), 2.64 (s, 3 H,
pyrazolone CH3), 4.26 (t, J = 11.8 Hz, 1 H, 6-H), 4.46 (dd, J =
12.2, J = 3.1 Hz, 1 H, 5-H), 4.59 (dd, J = 11.2, J = 3.4 Hz, 1 H,
6Ј-H), 4.73 (dd, J = 12.1, J = 3.4 Hz, 1 H, 5Ј-H), 4.76 (s, 2 H,
NH2), 6.84–7.74 (m, 7 H, Ar-H) ppm. 13C NMR (100 MHz, [D6]
DMSO): δ = 15.93 (pyrazolone CH3), 29.21 (angular CH3), 34.66
(C-11b), 37.49 (C-5a), 63.51 (C-5), 69.30 (C-6), 101.29, 120.17,
120.90, 121.70, 123.86, 125.50, 127.71, 129.53, 133.37, 134.99,
138.79, 139.51, 145.59, 146.78, 148.20 ppm. MS (ESI): m/z =
382.86 [M + H]+. C21H20ClN3O2 (381.20): calcd. C 66.05, H 5.28,
N 11.00; found C 66.39, H 5.77, N 11.25.
(5aR,11bS)-3-(3-Chlorophenyl)-1,5,5,11b-tetramethyl-3,5a,6,11b-
tetrahydro-5H-chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazol-10-amine
(5e): Isolated yield (0.583 g, 71%) as a yellow powder, m.p. 132–
134 °C. IR (KBr): ν = 3430, 3204, 2986, 2930, 1521, 1485, 1443,
˜
(5aR,11bS)-1,11b-Dimethyl-3-(4-methylphenyl)-3,5a,6,11b-tetra-
hydro-5H-chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazol-8-amine (5i): Iso-
lated yield (0.694 g, 85%) as a white powder, m.p. 147–149 °C; IR
1362, 1243, 1085, 1036, 832, 732, 689 cm–1. 1H NMR (400 MHz,
[D6]DMSO): δ = 1.08 (s, 3 H, angular CH3), 1.66 (s, 3 H, 5-CH3),
1.76 (s, 3 H, 5Ј-CH3), 1.96 (d, J = 3.8, 1 H, 5a-H), 2.36 (s, 3 H,
CH3 of phenyl ring), 2.75 (s, 3 H, pyrazolone CH3), 4.53 (d, J =
12.7 Hz, 1 H, 6-H), 4.76 (dd, J = 12.6, J = 4.2 Hz, 1 H, 6Ј-H), 4.78
(s, 2 H, NH2), 6.78–8.46 (m, 7 H, Ar-H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 16.63 (pyrazolone CH3), 20.08 (CH3
of phenyl ring), 22.76 (angular CH3), 29.66 (CH3-5), 32.91 (CH3-
5Ј), 33.70 (C-11b), 47.36 (C-5a), 62.36 (C-6), 82.05 (C-5), 102.16,
116.30, 120.59, 123.59, 128.16, 129.80, 130.10, 135.70, 136.26,
141.89, 146.66, 149.28, 157.20 ppm. MS (ESI): m/z = 410.97 [M +
H]+. C23H24ClN3O2 (409.12): calcd. C 67.39, H 5.90, N 10.25;
found C 67.86, H 6.01, N 10.32.
(KBr): ν = 3334, 3201, 2978, 2927, 1486, 1440, 1338, 1241, 1089,
˜
1032, 852, 758, 667 cm–1. 1H NMR (400 MHz, [D6]DMSO): δ =
1.82 (s, 3 H, angular CH3), 2.28 (m, 1 H, 5a-H), 2.36 (s, 3 H, CH3
of phenyl ring), 2.65 (s, 3 H, pyrazolone CH3), 4.32 (t, J = 10.8 Hz,
1 H, 6-H), 4.46 (dd, J = 12.6, J = 3.4 Hz, 1 H, 5-H), 4.56 (dd, J =
11.4, J = 3.4 Hz, 1 H, 6Ј-H), 4.76 (dd, J = 11.6, J = 3.4 Hz, 1 H,
5Ј-H), 4.79 (s, 2 H, NH2), 6.86–7.76 (m, 7 H, Ar-H) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 16.76 (pyrazolone CH3), 21.60
(CH3 of phenyl ring), 29.38 (angular CH3), 34.58 (C-11b), 37.90
(C-5a), 63.19 (C-5), 69.79 (C-6), 101.96, 120.49, 120.86, 121.03,
123.66, 132.20, 134.26, 135.46, 135.99, 139.63, 145.49, 146.12,
148.40 ppm. MS (ESI): m/z = 362.34 [M + H]+. C22H23N3O2
(361.20): calcd. C 73.11, H 6.41, N 11.63; found C 73.07, H 6.86,
N 11.31.
(5aR,11bS)-1,5,5,11b-Tetramethyl-3-(4-methylphenyl)-3,5a,6,11b-
tetrahydro-5H-chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazol-10-amine
(5f): Isolated yield (0.571 g, 73%) as a white powder, m.p. 143–
145 °C. IR (KBr): ν = 3436, 3209, 2986, 2930, 1521, 1485, 1443,
˜
(5aR,11bS)-1,5,5,11b-Tetramethyl-3-phenyl-3,5a,6,11b-tetrahydro-
5H-chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazol-8-amine (5j): Isolated
yield (0.549 g, 73 %) as a brown powder, m.p. 115–117 °C. IR
1362, 1243, 1085, 1036, 832, 732, 689 cm–1. 1H NMR (400 MHz,
[D6]DMSO): δ = 1.06 (s, 3 H, angular CH3), 1.65 (s, 3 H, 5-CH3),
1.76 (s, 3 H, 5Ј-CH3), 1.98 (d, J = 3.6, 1 H, 5a-H), 2.38 (s, 3 H,
CH3 of phenyl ring), 2.76 (s, 3 H, pyrazolone CH3), 4.58 (d, J =
12.8 Hz, 1 H, 6-H), 4.76 (dd, J = 12.4, J = 4.0 Hz, 1 H, 6Ј-H), 4.79
(s, 2 H, NH2), 6.76–8.47 (m, 7 H, Ar-H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 16.65 (pyrazolone CH3), 20.20 (CH3
of phenyl ring), 22.70 (angular CH3), 29.63 (CH3-5), 32.86 (CH3-
5Ј), 33.70 (C-11b), 47.30 (C-5a), 62.28 (C-6), 82.11 (C-5), 102.12,
116.39 120.60, 123.66, 128.19, 129.69, 130.06, 135.69, 136.29,
141.91, 146.69, 149.27, 157.16 ppm. MS (ESI): m/z = 390.49 [M +
H]+. C24H27N3O2 (389.23): calcd. C 74.01, H 6.99, N 10.79; found
C 74.20, H 6.56, N 10.63.
(KBr): ν = 3328, 3211, 2973, 2926, 1486, 1440, 1338, 1241, 1089,
˜
1032, 852, 758, 667 cm–1. 1H NMR (400 MHz, [D6]DMSO): δ =
1.10 (s, 3 H, angular CH3), 1.66 (s, 3 H, 5-CH3), 1.78 (s, 3 H, 5Ј-
CH3), 2.02 (d, J = 3.6, 1 H, 5a-H), 2.76 (s, 3 H, pyrazolone CH3),
4.56 (d, J = 11.6 Hz, 1 H, 6-H), 4.77 (dd, J = 12.8, J = 4.0 Hz, 1
H, 6Ј-H), 4.80 (s, 2 H, NH2), 6.72–7.78 (m, 8 H, Ar-H) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 16.24 (pyrazolone CH3), 22.13
(angular CH3), 28.88 (CH3-5), 32.43 (CH3-5Ј), 34.06 (C-11b), 46.43
(C-5a), 62.65 (C-6), 82.64 (C-5), 101.56, 120.26, 120.85, 123.67,
125.79, 128.36, 131.94, 134.46, 138.33, 139.87, 145.46, 146.57,
148.94 ppm. MS (ESI): m/z = 376.46 [M + H]+. C23H25N3O2
(5aR,11bS)-1,11b-Dimethyl-3-phenyl-3,5a,6,11b-tetrahydro-5H- (375.21): calcd. C 73.57, H 6.71, N 11.19; found C 73.68, H 6.34,
chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazol-8-amine (5g): Isolated yield N 11.08.
10
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20751
/KAP1
Date: 17-09-12 16:57:23
Pages: 13
Domino Knoevenagel–hetero-Diels–Alder Reaction
M. Mori, T. Honda, Y. Mastsui, K. Wakabayashi, S. Hayashi,
(5aR,11bS)-3-(3-Chlorophenyl)-1,5,5,11b-tetramethyl-3,5a,6,11b-
tetrahydro-5H-chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazol-8-amine
(5k): Isolated yield (0.576 g, 70%) as a reddish powder, m.p. 152–
K. Avaki, J. Ohsumi, Bioorg. Med. Chem. Lett. 2012, 22, 1348–
1351; d) B. V. Subba Reddy, B. Divya, M. Swain, T. P. Rao, J. S.
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154 °C. IR (KBr): ν = 3331, 3205, 2978, 2930, 1484, 1442, 1341,
˜
1243, 1086, 1030, 859, 760, 681 cm–1. 1H NMR (400 MHz, [D6]
DMSO): δ = 1.08 (s, 3 H, angular CH3), 1.68 (s, 3 H, 5-CH3), 1.76
(s, 3 H, 5Ј-CH3), 1.98 (d, J = 3.6, 1 H, 5a-H), 2.76 (s, 3 H, pyrazo-
lone CH3), 4.56 (d, J = 10.8 Hz, 1 H, 6-H), 4.76 (s, 2 H, NH2),
4.79 (dd, J = 12.4, J = 4.0 Hz, 1 H, 6Ј-H), 6.72–7.84 (m, 7 H, Ar-
H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 16.70 (pyrazolone
CH3), 22.84 (angular CH3), 29.49 (CH3-5), 32.62 (CH3-5Ј), 33.30
(C-11b), 46.88 (C-5a), 63.20 (C-6), 82.56 (C-5), 100.60, 120.60,
121.71, 121.89, 123.80, 125.71, 127.86, 129.68, 133.56, 134.80,
137.68, 139.20, 145.78, 146.98, 149.30 ppm. MS (ESI): m/z =
410.99 [M + H]+. C23H24ClN3O2 (409.23): calcd. C 67.39, H 5.90,
N 10.25; found C 67.46, H 5.58, N 10.67.
[3]
[4]
[5]
(5aR,11bS)-1,5,5,11b-Tetramethyl-3-(4-methylphenyl)-3,5a,6,11b-
tetrahydro-5H-chromeno[4Ј,3Ј:4,5]pyrano[2,3-c]pyrazol-8-amine (5l):
Isolated yield (0.648 g, 83%) as a yellow powder, m.p. 126–128 °C.
IR (KBr): ν = 3331, 3204, 2978, 2930, 1484, 1442, 1341, 1243, 1086,
˜
1030, 859, 760, 681 cm–1. 1H NMR (400 MHz, [D6]DMSO): δ =
1.07 (s, 3 H, angular CH3), 1.66 (s, 3 H, 5-CH3), 1.79 (s, 3 H, 5Ј-
CH3), 2.00 (d, J = 3.6, 1 H, 5a-H), 2.39 (s, 3 H, CH3 of phenyl
ring), 2.80 (s, 3 H, pyrazolone CH3), 4.59 (d, J = 10.8 Hz, 1 H, 6-
H), 4.76 (dd, J = 12.0, J = 3.2 Hz, 1 H, 6Ј-H), 4.78 (s, 2 H, NH2),
6.78–7.87 (m, 7 H, Ar-H) ppm. 13C NMR (100 MHz, [D6]DMSO):
δ = 17.46 (pyrazolone CH3), 20.83 (CH3 of phenyl ring), 23.14
(angular CH3), 29.65 (CH3-5), 32.48 (CH3-5Ј), 33.42 (C-11b), 46.59
(C-5a), 61.94 (C-6), 81.76 (C-5), 101.48, 120.56, 121.17, 121.61,
123.73, 132.53, 134.42, 135.53, 135.91, 139.21, 145.32, 145.49,
148.75 ppm. MS (ESI): m/z = 390.50 [M + H]+. C24H27N3O2
(389.23): calcd. C 74.01, H 6.99, N 10.79; found C 74.51, H 6.56,
N 10.13.
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Acknowledgments
The authors express their sincere thanks to the head of the Depart-
ment of Chemistry, S. P. University for providing necessary re-
search facilities, to the University Grants Commission (UGC),
New Delhi for financial support under the UGC Scheme of Major
Research (project number 39-822/2010 (SR) dated 11.01.2011), and
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www.eurjoc.org
11

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/KAP1
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Pages: 13
N. J. Parmar et al.
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Published Online: ᭿
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20751
/KAP1
Date: 17-09-12 16:57:23
Pages: 13
Domino Knoevenagel–hetero-Diels–Alder Reaction
Heterocyclic Chemistry
N. J. Parmar,* B. R. Pansuriya,
B. M. Labana, T. R. Sutariya, R. Kant,
V. K. Gupta ..................................... 1–13
Access to Some Angular Aminochro-
meno[2,3-c]pyrazole Precursors by a Dom-
ino Knoevenagel–hetero-Diels–Alder Re-
action
Keywords: Domino reactions / Oxygen het-
erocycles / Nitrogen heterocycles / Cycli-
zation / One-pot reactions
A
solvent-free, tetrabutylammonium-hy-
taining DKHDA products were treated
further with Fe/HCl in tandem, they
drogensulfate-catalysed method to syn-
thesise angular aminobenzopyrano[2,3-c]-
pyrazole precursors by a domino Knoeven-
agel–hetero-Diels–Alder (DKHDA) reac-
tion has been developed. When nitro-con-
smoothly underwent
a subsequent re-
duction, facilitating access to aminobenzo-
pyran annulated products by this cascade
route.
Eur. J. Org. Chem. 0000, 0–0
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