Synthesis of fully substituted pyrano[2,3-c]pyrazole derivatives via a multicomponent reaction of isocyanides

Article abstract of DOI:10.1016/j.tet.2009.02.035

The three-component reaction of the zwitterions generated from dialkyl acetylenedicarboxylate and isocyanides with 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one is described. The reaction afforded the corresponding special type of fully substituted pyrano[2,3-c]

Full text of DOI:10.1016/j.tet.2009.02.035

Tetrahedron 65 (2009) 3492–3495
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of fully substituted pyrano[2,3-c]pyrazole derivatives
via a multicomponent reaction of isocyanides
*
Ahmad Shaabani , Afshin Sarvary, Ali Hossein Rezayan, Sajjad Keshipour
Department of Chemistry, Shahid Beheshti University, PO Box 19396-4716, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
The three-component reaction of the zwitterions generated from dialkyl acetylenedicarboxylate and
isocyanides with 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one is described. The reaction afforded the cor-
responding special type of fully substituted pyrano[2,3-c]pyrazole derivatives in good yields without
using any catalyst and activation.
Received 4 November 2008
Received in revised form 25 January 2009
Accepted 13 February 2009
Available online 24 February 2009
Ó 2009 Published by Elsevier Ltd.
Keywords:
Multicomponent reaction
Isocyanide
Pyranopyrazole derivatives
1. Introduction
synthesize of these substances was undertaken by Otto,16 in
which he initiated the reaction sequence by the base-catalyzed
Multicomponent reactions (MCRs) are special types of syn-
thetically useful organic reactions in which three or more differ-
ent starting materials react to a final product in an onepot
procedure.1 Such reactions are atom-efficient processes by
incorporating the essential parts of the starting materials into the
final product. MCRs are powerful tools in the modern drug
discovery process and allow the fast, automated, and high-
throughput generation of organic compounds.2 In the past years
the pharmaceutical industry has focused more and more on
diversity-oriented and biased combinatorial libraries.3,4 Further-
more, the discovery of novel MCRs can be considered as an in-
teresting topic for academic research that also satisfies a practical
interest of applied science.5–9
Dihydropyrano[2,3-c]pyrazoles play an essential role in bi-
ologically active compounds and therefore represent an interesting
template for medicinal chemistry. They have been widely used as
medicine intermediates due to their useful biological and phar-
macological properties, such as antimicrobial,10 insecticidal,11 and
anti-inflammatory.12 Furthermore dihydropyrano[2,3-c]pyrazoles
showed molluscicidal activity13,14 and was identified as a screening
hit for Chk1 kinase inhibitor.15
cyclization of 4-aryliden-5-pyrazolone. In a further report, this
same group showed that weak bases can also be used for a
Michael-type cyclization.17
Extending the work of Otto, Klokol and colleagues performed
the direct conversion of 3-methyl-3-pyrazolin-5-one with malo-
nonitrile in the presence of a weak base.18 Recent methods for the
synthesis of 1,4-dihydropyrano[2,3-c]pyrazoles include synthesis
based on the procedure of Klokol,19 water or ethanol media,20–25
under microwave irradiation,26 and under solvent-free
conditions.27
As part of our continuing interest in the development of new
synthetic methods in heterocyclic chemistry and our interest in
isocyanide based multicomponent reactions,28–33 herein we de-
scribe an efficient synthesis of fully substituted pyrano[2,3-c]pyr-
azoles 4 via the reaction of an isocyanide 1 with an dialkyl
acetylenedicarboxylate
2
and 3-methyl-1-phenyl-1H-pyrazol-
5(4H)-one 3 in high yields without using any catalyst at ambient
temperature (Scheme 1).
CO2R2
CO2R2
CO2R2
Over the last years, the chemistry of dihydropyrano[2,3-c]-
pyrazoles has received great interest. The first approach to
CH3CN
C
C
R1
N
C
+
N
+
N
O
r.t., 12 h
N
N
Ph
NH
R1
O
CO2R2
Ph
1
2
3
4a-l
* Corresponding author. Fax: þ98 21 22403041.
Scheme 1. Synthesis of pyrano[2,3-c]pyrazoles via a three-component reaction.
E-mail address: a-shaabani@cc.sbu.ac.ir (A. Shaabani).
0040-4020/$ – see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tet.2009.02.035

A. Shaabani et al. / Tetrahedron 65 (2009) 3492–3495
3493
2. Results and discussion
Although the mechanism of this reaction has not been estab-
lished experimentally, the formation of these heterocycles can be
rationalized by initial Michael-type vinylisonitrilium cation 5.28,34–36
Then, the positively charged ion might be attacked by the anion
of the phenyl-1H-pyrazol-5(4H)-one to give the keteneimine 7.
Such an addition product may isomerize under the reaction con-
ditions employed to produce the fused heterocyclic system 4a–l
(Scheme 2).
As indicated in Table 1, isocyanides 1 with dialkyl acetylenedi-
carboxylate
2 and 1-phenyl-1H-pyrazol-5(4H)-one 3 undergo
a smooth 1:1:1 addition reaction in CH3CNat ambient temperature to
produce pyrano[2,3-c]pyrazole 4. The structures of the products were
deduced from their IR, mass, 1H NMR, and 13C NMR spectra. The mass
spectra of these compounds displayed molecular ion peaks at the
appropriate m/z values. The 1H NMR spectrum of 4a consisted of
a multiplet for the cyclohexyl ring (
methyl group (
¼2.30 ppm), multiplet for the NH–CH cyclohexyl
proton ( ¼3.66 ppm
¼3.62 ppm), two singlet for methoxy groups (
and
for the aromatic protons (
aromatic proton (
matic protons (
d
¼1.28–2.15 ppm), a singlet for
CO2R2
R1
d
N
C
d
d
C
3
R1
N
C
CO2R2
CO2R2
5
C
d
¼3.70 ppm), a singlet for the CH–CO2Me ( ¼4.57 ppm), a triplet
d
CO2R2
d
¼7.27 ppm, 3JHH¼7.2 Hz), a triplet for the
3
d
¼7.42 ppm, JHH¼7.3 Hz), a doublet for the aro-
R2O2C
CO2R2
d
¼7.55 ppm, 3JHH¼7.4 Hz), and a broad singlet for NH
CO2R2
¼8.87 ppm) protons. The 1H decoupled 13C NMR spectrum of 4a
N
N
N
N
(d
H
C
N
CO2R2
showed 21 distinct resonances, partial assignment of these reso-
nances is given in the Experimental section.
Ph
Ph
R1
O
C
O
6
7
N
The reaction did not require any optimization, and we explored
the use of various alkyl and aryl isocyanides with phenyl-1H-pyr-
azol-5(4H)-one in CH3CN at ambient temperature, which led to the
formation of the corresponding pyrano[2,3-c]pyrazole derivatives
in high yields.
CO2R2
R1
CO2R2
N
N
Ph
O
4a-l
NH
R1
The reaction proceeds under mild conditions and is compatible
with a wide range of functional groups. Owing to the great diversity
of substitution patterns, this reaction may be used in the pro-
duction of combinatorial libraries (Table 1).
Scheme 2. Proposed mechanism.
3. Conclusion
Table 1
In conclusion, we have developed a new and efficient approach
to the synthesis of fully substituted pyrano[2,3-c]pyrazole de-
rivatives from various isocyanides and dialkyl acetylenedicarboxy-
lates in the presence of phenyl-1H-pyrazol-5(4H)-one in absence of
any catalyst. The reaction has been shown to display relatively good
functional group tolerance and is high yielding and product
isolation is very straightforward. We hope that this approach may
be of value to others seeking novel synthetic fragments with unique
properties for medicinal chemistry.
Synthesis of pyrano[2,3-c]pyrazole derivatives
Me
O
Me
O
Me
O
Me
O
O
O
O
Me
O
O
Me
O
O
Me
O
Me
O
O
O
O
O
N
N
N
N
N
N
N
N
NH
O
O
NH
O
NH
O
NH
Ph
Ph
Ph
Ph
O
4a
4b
4d
4c
O
Me
O
Et
O
Et
O
Et
O
O
Me
O
Et
Et
O
O
Et
O
O
O
O
O
4. Experimental
4.1. General
O
O
N
N
N
N
N
N
Ph
N
O
NH
O
NH
N
Ph
O
NH
O
4f
NH
Ph
Ph
4e
4g
4h
Melting points were measured on an Electrothermal 9100 ap-
paratus and are uncorrected. Mass spectra were recorded on
a FINNIGAN-MAT 8430 mass spectrometer operating at an ioniza-
tion potential of 70 eV. IR spectra were recorded on a Shimadzu IR-
470 spectrometer. 1H and 13C NMR spectra were recorded on
Et
O
Et
O
O
Et
O
O
Et
O
O
O
O
O
O
O
O
O
N
N
O
O
a
BRUKER DRX-300 AVANCE spectrometer at 300.13 and
N
N
N
Ph
N
Ph
O
NH
O
NH
N
Ph
N
Ph
O
NH
75.47 MHz. NMR spectra were obtained on solution in CDCl3 using
TMS as internal standard. The chemicals used in this work were
purchased from Merck and Fluka Chemical Companies.
O
NH
4j
4k
4l
4i
4.1.1. Typical procedure for preparation of dimethyl 6-(cyclo-
hexylamino)-1,4-dihydro-3-methyl-1-phenylpyrano[2,3-
c]pyrazole-4,5-dicarboxylate (4a)
Entry
R1
R2
Product
Yield (%)
1
2
3
4
5
6
7
8
Cyclohexyl
Me
Me
Me
Me
Me
Et
Et
Et
Et
4a
4b
4c
4d
4e
4f
4g
4h
4i
79
75
58
64
70
75
72
74
76
69
74
58
1,1,3,3-Tetramethyl-butyl
Ethoxycarbonylmethyl
2,6-Dimethyl-phenyl
Benzyl
tert-Butyl
1,1,3,3-Tetramethyl-butyl
Cyclohexyl
2,6-Dimethyl-phenyl
Benzyl
Cyclohexyl
To a magnetically stirred solution of phenyl-1H-pyrazol-5(4H)-one
(0.17 g, 1.0 mmol) and dimethyl acetylenedicarboxylate (0.14 g,
1.0 mmol) in CH3CN (10 mL) was added dropwise a solution of
cyclohexyl isocyanide (0.11 g, 1 mmol) in CH3CN (2 mL) at room
temperature over 10 min. The mixture was finally stirred for 12 h. The
solvent was removed under vacuum and the residue was crystallized
from n-hexane/dichloromethane (2:1) mixture and washed with
ether (3ꢀ5 mL) and the product 4a was obtained. White crystals
(0.34 g, yield 79%). Mp 136–138 ꢁC. IR (KBr) (nmax/cmꢂ1): 2937, 2856,
9
10
11
12
Et
4j
4k
4l
tBu
tBu
2,6-Dimethyl-phenyl

3494
A. Shaabani et al. / Tetrahedron 65 (2009) 3492–3495
1743, 1681, 1633. MS, m/z (%): 426 (Mþþ1, 10), 372 (25), 354 (100), 289
(90), 252 (30), 185 (10), 77 (20), 57 (30). 1H NMR (300 MHz, CDCl3): dH
(ppm) 1.28–2.15 (10H, m, 5CH2 of cyclohexyl), 2.30 (3H, s, CH3), 3.62
(1H, br s, CH–NH), 3.66 (3H, s, O–CH3), 3.70 (3H, s, O–CH3), 4.57 (1H, s,
(ppm) 12.92 (CH3), 37.27 (CH–CO2Me), 45.04 (CH2 of benzyl), 51.34,
52.25 (2O–CH3), 73.01, 95.08, 121.03, 126.60, 126.64, 127.53, 128.80,
129.19, 137.42, 137.98, 144.06, 146.33, 160.18 (C-alkene, C–Ar), 170.06,
173.54 (2C]O). Anal. Calcd for C24H23N3O5: C, 66.50; H, 5.35; N,
9.69%. Found: C, 66.16; H, 5.39; N, 9.54%.
3
CH–CO2Me), 7.27 (1H, t, JHH¼7.2 Hz, arom), 7.42 (2H, t, 3JHH¼7.3 Hz,
arom), 7.55 (2H, d, 3JHH¼7.4 Hz, arom), 8.87 (1H, br s, CH–NH).13C NMR
(75 MHz, CDCl3): dC (ppm) 12.82 (CH3), 24.63, 24.71, 25.38, 33.51, 33.78
(C-cyclohexyl), 37.22 (CH–CO2Me), 50.77 (CH–NH), 51.15, 52.17 (2O–
CH3), 71.67, 95.11, 120.50, 126.46, 129.15, 137.67, 144.28, 146.41, 159.68
(C-alkene, C–Ar),170.05,173.68 (2C]O). Anal. Calcd for C23H27N3O5: C,
64.93; H, 6.40; N, 9.88%. Found: C, 64.97; H, 6.33; N, 9.93%.
4.1.6. Diethyl 6-(tert-butylamino)-1,4-dihydro-3-methyl-1-
phenylpyrano[2,3-c]pyrazole-4,5-dicarboxylate (4f)
White crystals (0.32 g, 75%). Mp 137–140 ꢁC. IR (KBr) (nmax
/
cmꢂ1): 2935, 2847, 1783, 1745, 1673. MS, m/z (%): 427 (Mþ, 2), 426
(Mþꢂ1, 5), 366 (100), 252 (30), 185 (10), 77 (20), 55 (20). 1H NMR
(300 MHz, CDCl3): dH¼1.21–1.29 (6H, m, 2CH3), 1.33 (9H, s,
C(CH3)3), 2.31 (3H, s, CH3), 4.05–4.23 (4H, m, 2OCH2), 4.56 (1H, s,
CH–CO2Et), 7.29 (1H, t, 3JHH¼7.1 Hz, arom), 7.41 (2H, t, 3JHH¼8.0 Hz,
arom), 7.57 (2H, d, 3JHH¼7.7 Hz, arom), 9.15 (1H, br s, NH). 13C NMR
(75 MHz, CDCl3): dC¼12.99, 14.28, 14.39 (3CH3), 30.29 (C(CH3)3),
37.40 (CH–CO2Et), 52.61 (C(CH3)3), 59.68, 60.94 (2OCH2), 72.87,
94.94, 122.72, 127.26, 129.03, 137.19, 144.35, 146.35, 169.99 (C-al-
kene, C–Ar), 169.86, 173.46 (2C]O). Anal. Calcd for C23H29N3O5: C,
64.62; H, 6.84; N, 9.83%. Found: C, 64.58; H, 6.80; N, 9.77%.
4.1.2. Dimethyl 6-(1,1,3,3-tetramethylpentylamino)-1,4-dihydro-3-
methyl-1-phenylpyrano[2,3-c]pyrazole-4,5-dicarboxylate (4b)
White crystals (0.34 g, yield 75%). Mp 143–146 ꢁC. IR (KBr) (nmax
/
cmꢂ1): 2951, 2867, 1748, 1670, 1637, 1603. MS, m/z (%): 456 (Mþþ1,
5), 396 (50), 344 (30), 284 (100), 252 (40), 77 (35), 55 (65), 57 (70).
1H NMR (300 MHz, CDCl3): dH (ppm) 0.88 (9H, s, C(CH3)3), 1.34 (3H,
s, CH3),1.36 (3H, s, CH3), 1.61 (2H, s, CH2), 2.29 (3H, s, CH3), 3.67 (3H,
s, O–CH3), 3.68 (3H, s, O–CH3), 4.58 (1H, s, CH–CO2Me), 7.31 (1H, t,
3
3JHH¼7.2 Hz, arom), 7.42 (2H, t, JHH¼7.8 Hz, arom), 7.55 (2H, d,
3JHH¼7.9 Hz, arom), 9.19 (1H, br s, NH). 13C NMR (75 MHz, CDCl3): dC
(ppm) 12.82 (CH3), 30.94, 31.14 (2CH3), 31.24 (C(CH3)3), 31.48 (CH2),
37.17 (CH–CO2Me), 51.15, 52.10 (2O–CH3), 52.71 (C–NH), 56.30,
72.38, 94.96, 123.11, 127.47, 129.08, 137.09, 144.34, 146.39, 161.00 (C-
alkene, C–Ar),170.25,173.70 (2C]O). Anal. Calcd for C25H33N3O5: C,
65.91; H, 7.30; N, 9.22%. Found: C, 65.83; H, 7.26; N, 9.25%.
4.1.7. Diethyl 6-(1,1,3,3-tetramethylpentylamino)-1,4-dihydro-3-
methyl-1-phenylpyrano[2,3-c]pyrazole-4,5-dicarboxylate (4g)
White crystals (0.35 g, 72%). Mp 144–147 ꢁC. IR (KBr) (nmax
/
cmꢂ1): 2951, 2784, 1738, 1673, 1601. MS, m/z (%): 411 (Mþꢂ72, 10),
410 (60), 372 (15), 298 (90), 252 (25), 215 (60), 199 (95), 174 (70), 91
(45), 77 (100), 57 (50). 1H NMR (300 MHz, CDCl3): dH (ppm) 0.90
(9H, s, C(CH3)3), 1.21–1.28 (6H, m, 2OCH2CH3), 1.34 (3H, s, CH3), 1.40
2
4.1.3. Dimethyl 6-((ethoxycarbonyl)methylamino)-1,4-dihydro-1-
phenylpyrano[2,3-c]pyrazole-4,5-dicarboxylate (4c)
(3H, s, CH3), 1.60 (1H, AB-q, JHH¼8.2 Hz, CHAHB), 1.65 (1H, AB-q,
2JHH¼8.2 Hz, CHAHB), 2.32 (3H, s, CH3), 4.11–4.18 (4H, m,
2OCH2CH3), 4.57 (CH–CO2Et), 7.27–7.58 (5H, m, arom), 9.20 (1H, br
s, NH). 13C NMR (75 MHz, CDCl3): dC (ppm) 12.97, 14.27, 14.40
(3CH3), 31.03, 31.14 (2CH3), 31.27 (C(CH3)3), 31.50 (CH2), 37.42 (CH–
CO2Et), 52.71 (C(CH3)3), 56.22 (C–NH), 59.62, 60.90 (2O–CH2),
72.57, 95.01, 123.12, 127.43, 129.07, 137.13, 144.38, 146.43, 160.89 (C-
alkene, C–Ar),169.93,173.44 (2C]O). Anal. Calcd for C27H37N3O5: C,
67.06; H, 7.71; N, 8.69%. Found: C, 68.91; H, 6.96; N, 11.53%.
White crystals (0.25 g, yield 58%). Mp 140–143 ꢁC. IR (KBr) (nmax
/
cmꢂ1): 2989, 2949, 1734, 1680, 1636. MS, m/z (%): 430 (Mþþ1, 3),
292 (100), 210 (65), 178 (70), 88 (25), 59 (30), 55 (65), 41 (60). 1H
3
NMR (300 MHz, CDCl3): dH (ppm) 1.21 (3H, t, s, JHH¼7.1 Hz,
CH2CH3), 2.31 (3H, s, CH3), 3.71 (3H, s, O–CH3), 3.72 (3H, s, O–CH3),
4.01–4.20 (4H, m, CH2CH3, HNCH2), 4.60 (1H, s, CH–CO2Me), 7.28
(1H, t, 3JHH¼7.2 Hz, arom), 7.43 (2H, t, 3JHH¼7.9 Hz, arom), 7.56 (2H,
3
d, JHH¼7.7 Hz, arom), 9.15 (1H, br s, CH2–NH). 13C NMR (75 MHz,
CDCl3): dC (ppm) 12.91, 14.09 (2CH3), 37.28 (CH–CO2Me), 43.09
(CH2–NH), 51.46, 52.26 (2O–CH3), 61.67 (OCH2CH3), 74.19, 95.18,
120.89, 126.64, 129.24, 137.49, 143.90, 146.42, 159.63 (C-alkene, C–
Ar), 169.63, 169.74, 173.28 (3C]O). Anal. Calcd for C21H23N3O7: C,
58.74; H, 5.40; N, 9.79%. Found: C, 58.64; H, 5.33; N, 9.73%.
4.1.8. Diethyl 6-(cyclohexylamino)-1,4-dihydro-3-methyl-1-
phenylpyrano[2,3-c]pyrazole-4,5-dicarboxylate (4h)
White crystals (0.41 g, 74%). Mp 139–141 ꢁC. IR (KBr) (nmax
/
cmꢂ1): 2937, 2856, 1743, 1681, 1633. MS, m/z (%): 553 (Mþþ1, 3),
292 (100), 210 (65), 178 (70), 88 (25), 59 (30), 55 (65), 41 (60). 1H
NMR (300 MHz, CDCl3): dH (ppm) 1.22–2.29 (16H, m, 5CH2 of
cyclohexyl, 2OCH2CH3), 2.33 (3H, s, CH3), 3.66 (1H, br s, CH–NH),
4.09–4.24 (4H, m, 2OCH2CH3), 4.58 (1H, s, CH–CO2Me), 7.26–7.68
(5H, m, arom), 8.88 (1H, d, 3J¼6.5 Hz, CH–NH). 13C NMR (75 MHz,
CDCl3): dC (ppm) 13.08, 14.31, 14.44 (3CH3), 24.68, 24.75, 25.51,
33.54, 33.83 (C-cyclohexyl), 37.43 (CH–CO2Et), 50.75 (CH–NH),
59.63, 60.99 (2OCH2CH3), 71.86, 95.19, 120.53, 126.44, 129.15,
137.71, 144.35, 146.42, 159.62 (C-alkene, C–Ar), 169.73, 173.46
(2C]O). Anal. Calcd for C25H31N3O5: C, 66.21; H, 6.89; N, 9.27%.
Found: C, 65.69; H, 6.81; N, 9.13%.
4.1.4. Dimethyl 6-(2,6-dimethylphenylamino)-1,4-dihydro-3-
methyl-1-phenylpyrano[2,3-c]pyrazole-4,5-dicarboxylate (4d)
White crystals (0.29 g, 64%). Mp 193–195 ꢁC. IR (KBr) (nmax
/
cmꢂ1): 2971, 2898, 1734, 1676, 1630. MS, m/z (%): 448 (Mþþ1, 3),
447 (Mþ, 2), 388 (100), 356 (20), 273 (10), 105 (5), 77 (25). 1H NMR
(300 MHz, CDCl3): dH (ppm) 2.21 (3H, s, CH3), 2.32 (3H, s, CH3), 2.34
(3H, s, CH3), 3.75 (3H, s, O–CH3), 3.80 (3H, s, O–CH3), 4.68 (1H, s,
CH–CO2Me), 7.07–7.21 (8H, m, arom), 10.02 (1H, br s, NH). 13C NMR
(75 MHz, CDCl3): dC (ppm) 12.93, 18.34, 18.43 (3CH3), 37.33 (CH–
CO2Me), 51.50, 52.31 (2O–CH3), 73.74, 95.25, 118.23, 125.62, 127.51,
128.21, 128.90, 134.26, 137.57, 144.32, 146.15, 159.38 (C-alkene, C–
Ar), 170.11, 173.32 (2C]O). Anal. Calcd for C25H25N3O5: C, 67.10; H,
5.63; N, 9.39%. Found: C, 66.53; H, 5.53; N, 9.34%.
4.1.9. Diethyl 6-(2,6-dimethylphenylamino)-1,4-dihydro-3-methyl-
1-phenylpyrano[2,3-c]pyrazole-4,5-dicarboxylate (4i)
White crystals (0.36 g, 76%). Mp 166–168 ꢁC. IR (KBr) (nmax
/
cmꢂ1): 2975, 2897,1729,1677,1644. MS, m/z (%): 476 (Mþþ1, 5), 475
(Mþ, 3), 402 (100), 356 (50), 302 (20), 185 (5), 77 (20). 1H NMR
(300 MHz, CDCl3): dH (ppm) 1.28–1.34 (6H, m, 2OCH2CH3), 2.15 (3H,
s, CH3), 2.21 (3H, s, CH3), 3.34 (3H, s, CH3), 4.14–4.31 (4H, m,
2OCH2CH3), 4.67 (1H, s, CH–CO2Et), 7.07–7.24 (8H, m, arom), 10.04
(1H, br s, NH). 13C NMR (75 MHz, CDCl3): dC (ppm) 13.05, 14.27,
14.41, 18.35 (4CH3), 37.56 (CH–CO2Et), 60.02, 61.09 (2OCH2CH3),
73.97, 95.30, 118.69, 125.55, 127.43, 128.23, 128.87, 134.39, 136.44,
136.82, 137.64, 144.35, 146.13, 159.25 (C-alkene, C–Ar), 169.75,
4.1.5. Dimethyl 6-(benzylamino)-1,4-dihydro-3-methyl-1-
phenylpyrano[2,3-c]pyrazole-4,5-dicarboxylate (4e)
White crystals (0.30 g, 70%). Mp 174–176 ꢁC. IR (KBr) (nmax/cmꢂ1):
2944, 2891,1738,1680,1637. MS, m/z (%): 434 (Mþþ1, 5), 433 (Mþ, 2),
374 (80), 251 (10), 185 (10), 91 (100), 77 (20), 65 (10). 1H NMR
(300 MHz, CDCl3): dH (ppm) 2.31 (3H, s, CH3), 3.73 (3H, s, O–CH3), 3.82
(3H, s, O–CH3), 4.55–4.62 (3H, m, CH2 of benzyl, CH–CO2Me), 7.29–
7.43 (10H, m, arom), 9.38 (1H, br s, NH). 13C NMR (75 MHz, CDCl3): dC

A. Shaabani et al. / Tetrahedron 65 (2009) 3492–3495
3495
172.99 (2C]O). Anal. Calcd for C27H29N3O5: C, 68.19; H, 6.15; N,
Supplementary data
8.84%. Found: C, 67.83; H, 6.07; N, 8.82%.
Experimental procedures, IR, Mass, 1H NMR, and 13C NMR
spectra and also elemental analysis for compounds 4a–l are pro-
vided. This material is available via the Internet at http://www.
elsevier.com. Supplementary data associated with this article can
be found in the online version, at doi:10.1016/j.tet.2009.02.035.
4.1.10. Diethyl 6-(benzylamino)-1,4-dihydro-3-methyl-1-
phenylpyrano[2,3-c]pyrazole-4,5-dicarboxylate (4j)
White crystals (0.32 g, 69%). Mp 128–129 ꢁC. IR (KBr) (nmax/cmꢂ1):
2980, 2952, 2929,1734,1677,1639. MS, m/z (%): 461 (Mþꢂ86,10), 410
(60), 372 (15), 298 (90), 252 (25), 215 (60), 199 (95), 174 (70), 91 (45),
77 (100), 57 (50). 1H NMR (300 MHz, CDCl3): dH (ppm) 1.26–1.34 (6H,
m, 2OCH2CH3), 2.33 (3H, s, CH3), 4.14–4.24 (4H, m, 2OCH2CH3), 4.24–
4.61 (3H, m, CH2 of benzyl, CH–CO2Me), 7.27–7.43 (10H, m, arom),
9.32 (1H, br s, NH). 13C NMR (75 MHz, CDCl3): dC (ppm) 13.05, 14.31,
14.40 (3CH3), 37.47 (CH–CO2Me), 45.00 (CH2 of benzyl), 59.86, 61.07
(2OCH2CH3), 73.20, 95.14,121.01,126.54,126.62,127.47,128.78,129.17,
137.46, 138.11, 144.10, 146.32, 160.09 (C-alkene, C–Ar), 169.74, 173.29
(2C]O). Anal. Calcd for C26H27N3O5: C, 67.66; H, 5.90; N, 9.10%.
Found: C, 67.00; H, 5.81; N, 9.06%.
References and notes
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phenylpyrano[2,3-c]pyrazole-4,5-dicarboxylate (4k)
White crystals (0.38 g, 74%). Mp 155–158 ꢁC. IR (KBr) (nmax
/
cmꢂ1): 2978, 2952, 2854, 1740, 1673, 1636. MS, m/z (%): 510 (Mþꢂ1,
5), 408 (25), 352 (100), 252 (20), 226 (15), 77 (20), 57 (45). 1H NMR
(300 MHz, CDCl3): dH (ppm) 1.27–2.04 (28H, m, 5CH2 of cyclohexyl,
2OC(CH3)3), 2.36 (3H, s, CH3), 3.59 (br s,1H, CH–NH), 4.40 (1H, s,
t
CH–CO2 Bu), 7.23–7.70 (5H, m, arom), 8.79 (1H, br s, CH–NH). 13C
NMR (75 MHz, CDCl3): dC (ppm) 13.22 (CH3), 24.92, 24.99, 25.45,
33.76, 33.96 (C-cyclohexyl), 28.12, 28.56 (2OC(CH3)3), 38.61 (CH–
t
CO2 Bu), 50.86 (CH–NH), 73.41, 79.55, 80.76 (2OC(CH3)3), 95.88,
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120.31, 126.22, 129.09, 137.85, 144.53, 146.22, 159.47 (C-alkene, C–
Ar), 169.52, 172.73 (2C]O). Anal. Calcd for C29H39N3O5: C, 68.34; H,
7.71; N, 8.25%. Found: C, 68.07; H, 7.65; N, 8.09%.
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methyl-1-phenylpyrano[2,3-c]pyrazole-4,5-dicarboxylate (4l)
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White crystals (0.31 g, 58%). Mp 166–168 ꢁC. IR (KBr) (nmax
/
22. Peng, Y.; Song, G.; Dou, R. Green Chem. 2006, 8, 573–575.
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cmꢂ1): 2975, 2926, 1738, 1676, 1635. MS, m/z (%): 531 (Mþþ1, 2),
373 (Mþ, 3), 314 (100), 282 (20), 254 (20), 226 (10), 143 (10), 111
(90), 77 (20), 59 (25), 39 (60). 1H NMR (300 MHz, CDCl3): dH (ppm)
1.48 (9H, s, OC(CH3)3), 1.56 (9H, s, OC(CH3)3), 2.20 (3H, s, CH3), 2.35
t
(3H, s, CH3), 2.37 (3H, s, CH3), 4.50 (1H, s, CH–CO2 Bu), 7.08–7.18
(8H, m, arom), 10.03 (1H, br s, NH). 13C NMR (75 MHz, CDCl3): dC
(ppm) 13.17, 18.36, 18.52 (3CH3), 28.07, 28.54 (2OC(CH3)3), 39.01
t
(CH–CO2 Bu), 75.48 (C-alkene), 80.28, 80.78 (2OC(CH3)3), 95.82,
118.55, 125.38, 127.21, 128.13, 128.85, 134.72, 136.48, 136.88, 137.79,
144.48, 146.07, 158.94 (C-alkene, C–Ar), 169.58, 172.03 (2C]O).
Anal. Calcd for C31H37N3O5: C, 70.03; H, 7.01; N, 7.90%. Found: C,
69.81; H, 6.93; N, 7.63%.
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8409–8412.
Acknowledgements
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36. Nair, V.; Vinod, A. U.; Ramesh, R.; Menon, R. S.; Varma, R. L.; Mathew, S.;
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We gratefully acknowledge financial support from the Research
Council of Shahid Beheshti University.