Iron(III) chloride catalysed three-component Grieco condensation: Synthesis of tetrahydropyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidines/quinazolines

Article abstract of DOI:10.1016/j.jfluchem.2006.06.017

Three-component Grieco condensation reaction of 3-aminopyrazolo[3,4-b]pyridine, formaldehyde/benzaldehyde and electron rich alkenes in presence of iron(III) chloride gave tetrahydropyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidines/quinazolines in single pot. The sequence of reactions is formation of di-azadiene in situ and the subsequent regioselective addition of alkenes in aza-Diels Alder type reaction. The structure and stereochemistry of the products were confirmed by spectral data and single crystal X-ray crystallography.

Full text of DOI:10.1016/j.jfluchem.2006.06.017

Journal of Fluorine Chemistry 127 (2006) 1211–1221
www.elsevier.com/locate/fluor
Iron(III) chloride catalysed three-component Grieco condensation:
Synthesis of tetrahydropyrido[20,30:3,4]pyrazolo
[1,5-a]pyrimidines/quinazolines
S. Ravi Kanth a, G. Venkat Reddy a, D. Maitraie a, B. Narsaiah a,
*
,
P. Shanthan Rao a, K. Ravi Kumar b, B. Sridhar b
a Fluoroorganic Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Laboratory of X-ray crystallography, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 1 March 2006; received in revised form 30 May 2006; accepted 1 June 2006
Available online 27 June 2006
Abstract
Three-component Grieco condensation reaction of 3-aminopyrazolo[3,4-b]pyridine, formaldehyde/benzaldehyde and electron rich alkenes in
presence of iron(III) chloride gave tetrahydropyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidines/quinazolines in single pot. The sequence of reactions is
formation of di-azadiene in situ and the subsequent regioselective addition of alkenes in aza-Diels Alder type reaction. The structure and
stereochemistry of the products were confirmed by spectral data and single crystal X-ray crystallography.
# 2006 Elsevier B.V. All rights reserved.
Keywords: Pyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidines/quinazolines; Aza-Diels Alder reaction; Regioselective; Electron rich alkenes and dehydrogenation
1. Introduction
aminoheterocycles in single step, viz., synthesis of azasteroids
[10] from aminotetralones, polycyclic quinines [11] from
aminoanthraquinones, 3,4-dihydro-2H-pyrido[1,2-a]pyrimi-
dines [12] from 2-aminopyridines and cyclic amidines [13]
from aminoheterocycles. These reports have established with
different electron rich alkenes that the reaction proceeds via a
multi-step pathway. However 3-aminopyrazolo[3,4-b]pyri-
dines have not been exploited so far as starting materials for
aza-Diels Alder type reactions. Due to our continued interest
[14–17] in synthesis of novel ring systems, we report here for
the first time synthesis of new pyrido[20,30:3,4]pyrazolo[1,5-
a]pyrimidines/quinazolines by formal aza-Diels Alder type
reaction of 3-aminopyrazolo[3,4-b]pyridine with formalde-
hyde/benzaldehyde and various electron rich alkenes.
Pyrazole fused pyridines and pyrimidines are known to
possess a wide range of biological activity. Specifically
pyrazolo pyridines exhibit antitubercular [1], anxiolytic [2]
and potent vasodilating activity due to their calcium blocking
effect [3], whereas pyrazolo pyrimidines [4,5] are considered to
be selective inhibitors of cyclic 30,50-adenosine monophosphate
(cAMP) phosphodiesterases. The combination pyridine, pyr-
azole and pyrimidine ring system to form pyrido pyrazolo
pyrimidines and their influence on activity is of current interest.
Earlier reports on synthesis of pyrido[20,30:3,4]pyrazolo[1,5-
a]pyrimidines are mainly by reactions of 3-aminopyrazolo[3,4-
b]pyridines with symmetrical and unsymmetrical 1,3-diketones
[6], b-keto esters [7] and 1,1,1-trifluoro-3-(isobutoxymethy-
lene)-2-propanones.[8] Further Grieco and Bahsas [9] first
reported that cyclopentadiene and formaldehyde react with
anilines to give tetrahydroquinolines. The same methodology
has been applied to build many heterocyclic skeletons from
2. Results and discussion
The 6-phenyl-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyri-
din-3-amine (1), was reacted with formaldehyde/benzaldehyde
followed byelectron rich alkene in acetonitrile in presence of one
equivalentofFeCl3 underN2 atmosphereatroomtemperaturefor
30–60 min, to result tetrahydropyrido[20,30:3,4]pyrazolo[1,5-
a]pyrimidines/quinazolines in single pot. The reaction mixture
* Corresponding author. Tel.: +91 40 27193630;
fax: +91 40 27160387/27160757.
E-mail address: narsaiah@iict.res.in (B. Narsaiah).
0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2006.06.017

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S.R. Kanth et al. / Journal of Fluorine Chemistry 127 (2006) 1211–1221
Scheme 1.
after aqueous workup, extraction with dichloromethane and
column chromatography gave the corresponding adducts (2a–
2o) in good to excellent yields without side products. The yields
of the products with formaldehyde were higher compared to
benzaldehyde. This may be attributed to the steric factors. The
sequence of reaction is shown in Scheme 1. In case of reaction of
compound 1 with benzaldehyde followed by alkenes, the
formation of single product unlike the anticipated mixture of
regioisomers observed in aza-Diels Alder reactions, indicates
that the cyclisation is regioselective.
The mode of reaction is mainly formation of Schiff’s base in
situwhichactsasadiazadieneandiron(III)chlorideiscomplexed
with Schiff’s base double bond followed by regioselective
cyclisation with various electron rich alkenes leading to the
corresponding adducts. The regioselectivity in the reaction with
benzaldehyde may be due to formation of exclusively one stereo
isomer of the Schiff’s base, out of the possible E and Z isomers,
which undergoes cyclisation with the alkene. It may also be
attributed to the steric hindrance of the phenyl group in Schiff’s
base. The probable mechanism is given in Scheme 2.
Scheme 2.

S.R. Kanth et al. / Journal of Fluorine Chemistry 127 (2006) 1211–1221
1213
Scheme 3.
Fig. 1. X-ray crystal structure of 2l. Displacement ellipsoids are drawn at 30% probability level and H atoms are shown as small spheres of arbitrary radii.
In order to support the mechanism, compound 1 was reacted
with benzaldehyde in acetonitrile at room temperature and
isolated Schiff’s base 1a. The Schiffs base thus formed was
further reacted with styrene in presence of FeCl3 and obtained
compound 2b in 88% yield with stereochemistry identical to
the product formed by in situ reaction. Also there were no
intermediates isolated in the reaction. This indicates the
reaction probably proceeds by concerted mechanism. The
reaction is schematically drawn in Scheme 3.
adducts are formed. In case of compound 2d coupling constant
J (3a–4) = 16 Hz indicates anti-reciprocal or trans orientation
of H-3a and H-4 protons. Single X-ray crystal structure of 2l
(Fig. 1) shows anti-reciprocal or trans orientation of the 5 and
4a protons as indicated by the large coupling constant
(J = 18 Hz). This is possible only when the cyclohexane ring
and the phenyl ring are on the opposite sides of the pyrido
pyrazolo pyrimidine ring. Reaction of compound 1 with
aldehydes and electron deficient alkenes like DMAD or methyl
vinyl ketone under similar conditions did not give any product.
Other examples of the present cyclisation is summarized in
Table 1.
The structure and stereochemistry of all the products were
unambiguously confirmed based on 1H NMR, IR, mass spectra
and crystal data. The small coupling constant J (3a–
11a) = 7.3 Hz of the ring junction protons in 2c indicates a
cis ring junction, supported by crystal structure, is in
agreement with earlier reports [12,13]. Similarly regioselec-
tivity in cyclisation is observed whereby only cis ring fused
Finally the adducts were dehydrogenated using active MnO2
at room temperature to give the corresponding pyri-
do[20,30:3,4]pyrazolo[1,5-a]pyrimidine/quinazolines (3a–j).
1
The dehydrogenated product was characterized based on H
Table 1
Reaction of compound 1 with formaldehyde/benzaldehyde and alkenes
Substrates
Alkenes
Product
Yield (%)
1 + HCHO
90

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S.R. Kanth et al. / Journal of Fluorine Chemistry 127 (2006) 1211–1221
Table 1 (Continued )
Substrates
Alkenes
Product
Yield (%)
1 + PhCHO
82
1 + HCHO
94
1 + PhCHO
80
1 + HCHO
89
1 + PhCHO
81
1 + HCHO
85
1 + PhCHO
76
1 + HCHO
80

S.R. Kanth et al. / Journal of Fluorine Chemistry 127 (2006) 1211–1221
1215
Table 1 (Continued )
Substrates
Alkenes
Product
Yield (%)
1 + PhCHO
1 + HCHO
1 + PhCHO
68
87
82
1 + HCHO
1 + PhCHO
1 + HCHO
89
65
72
Table 2
Dehydrogenation of compound 2 with active MnO2
Substrate
Product
Yield (%)
85
78

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S.R. Kanth et al. / Journal of Fluorine Chemistry 127 (2006) 1211–1221
Table 2 (Continued )
Substrate
Product
Yield (%)
80
72
88
79
77
67
89
66

S.R. Kanth et al. / Journal of Fluorine Chemistry 127 (2006) 1211–1221
1217
NMR data and mass spectra. Disappearance of NH and
methylene protons and appearance of protons in aromatic
region established the products structure. The number of
compounds synthesized are tabulated in Table 2.
atmosphere at room temperature. Acetonitrile was removed
under vacuo and the reaction mixture was diluted with water,
extracted with dichloromethane and dried over sodium
sulphate. The dichloromethane extract was concentrated to
give the crude product which was purified by column
chromatography using 60–120 mesh silica gel and desired
product was eluted with 20% EtOAc/hexane mixture.
Yield: 0.73 g (88%); bright yellow coloured solid; mp
203 8C. IR (KBr) (cmꢀ1): 3356 (N–H), 1610 (C N). 1H NMR
(200 MHz, CDCl3), d = 2.45–2.65 (2H, m, CH2), 4.85 (1H, d, J
20 Hz, NHCHPh), 5.4 (1H, br, s, NH), 5.7 (1H, q, J 8.5 Hz, N–
CH–Ph), 7.2–7.4 (7H, m, Ar–H), 7.4–7.6 (6H, m, Ar–H), 8.0–
8.1 (3H, m, Ar–H), LSIMS; m/z: 471 (MH+). Anal. Calcd. for
C28H21F3N4: C, 71.84%; H, 4.50%; N, 11.91%. Found: C,
71.55%; H, 4.28%; N, 11.66%.
3. Conclusion
In conclusion novel pyrido[20,30:3,4]pyrazolo[1,5-a]pyrimi-
dines/quinazolines were synthesized from 3-aminopyra-
zolo[3,4-b]pyridine in presence of iron(III) chloride in a
single pot through aza-Diels Alder type reaction at room
temperature in good to excellent yields.
4. Experimental
Melting points were recorded on Casia-siamia (VMP-AM)
melting point apparatus and are uncorrected. IR spectra were
recorded on a Perkin-Elmer FT-IR 240 C spectro photometer
4.2. General procedure
1
using KBr disks. H NMR spectra were recorded on Gemini
4.2.1. Preparation of
tetrahydropyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidines
(2a–o)
varian 200 MHz, Bruker AV 300 MHz and Unity 400 MHz
spectro meter in CDCl3 using TMS as an internal standard.
LSIMS mass spectra were recorded on a VG 7070 H instrument
at 70 eV. All reactions were monitored by thin layer
chromatography (TLC) on precoated silicagel 60 F254 (mesh);
spots were visualized with UV light. Merck silicagel (60–120
mesh) was used for chromatography. CHN analyses were
recorded on a Vario EL analyser.
To a solution of 6-phenyl-4-(trifluoromethyl)-1H-pyra-
zolo[3,4-b]pyridin-3-amine (1) (0.5 g, 1.8 mmol) in acetoni-
trile (8 mL), 40% formaldehyde solution (3 mL) or
benzaldehyde (0.29 g, 2.7 mmol) was added and the reaction
mixture was stirred for 15–20 min under N2 atmosphere at
room temperature. The solution was cooled to 0 8C and FeCl3
(0.3 g, 1.8 mmol) was added followed by the addition of
corresponding alkene (2 equiv.). The total mixture was stirred
for 30–60 min, under N2 atmosphere at room temperature.
Acetonitrile was removed under vacuo and the reaction
mixture was diluted with water, extracted with dichloro-
methane and dried over sodium sulphate. The dichloromethane
extract was concentrated to give the crude product which was
purified by column chromatography using 60–120 mesh silica
gel and desired product was eluted with 20% EtOAc/hexane
mixture.
4.1. General procedure
4.1.1. Preparation of N-[1-phenylmethylidene]-N-[6-
phenyl-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-3-
yl]amine (1a)
To a solution of 6-phenyl-4-(trifluoromethyl)-1H-pyra-
zolo[3,4-b]pyridin-3-amine (1) (1.0 g, 3.6 mmol) in acetoni-
trile (8 mL), benzaldehyde (0.58 g, 5.47 mmol) and catalytic
amount of acetic acid was added and the reaction mixture was
stirred for 20 min, at room temperature. Acetonitrile was
removed under vacuum and the reaction mixture was diluted
with cold water. The separated solid was collected by filtration,
washed with water and dried. The crude product was purified
by column chromatography using 60–120 mesh silica gel and
the desired product was eluted with 50% CHCl3/hexane
mixture.
4.2.2. 4,8-Diphenyl-10-(trifluoromethyl)-1,2,3,4-
tetrahydropyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidine (2a)
Yield: 0.63 g (90%); bright yellow coloured solid; mp
166 8C. 1H NMR (200 MHz, CDCl3), d = 2.2–2.3 (2H, m,
CH2), 2.5–2.6 (2 H, m, CH2–N), 5.7 (1H, br, s, NH), 5.8 (1H, t,
J 8.2 Hz, CH–Ph), 7.0 (2H, d, J 17 Hz, Ar–H), 7.2–7.3 (3H, m,
Ar–H), 7.4–7.5 (4H, m, Ar–H), 8.05 (2H, m, Ar–H). IR (KBr)
(cmꢀ1): 3469 (N–H), 1607 (C N). LSIMS; m/z: 395 (MH+),
291 (M+ꢀCH2Ph). Anal. Calcd. for C22H17F3N4: C, 67.31%; H,
4.34%; N, 14.21%. Found: C, 67.52%; H, 4.58%; N, 14.41%.
Yield: 1.18 g (90%); reddish brown coloured solid; mp
172 8C. 1H NMR (200 MHz, CDCl3), d = 7.4–7.6 (6H, m, Ar–
H), 7.9 (1H, s, Ar–H), 8.0–8.2 (4H, m, Ar–H), 9.2 (1H, s,
HC N). IR (KBr) (cmꢀ1): 3469 (N–H), 1607 (C N). LSIMS;
m/z: 367 (MH+). Anal. Calcd. for C20H13F3N4: C, 65.75%; H,
3.58%; N, 15.29%. Found: C, 65.53%; H, 3.39%; N, 15.44%.
4.2.3. (2R)-2,4,8-Triphenyl-10-(trifluoromethyl)-1,2,3,4-
tetrahydropyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidine (2b)
Yield: 0.69 g (82%); bright yellow coloured solid; mp
4.1.2. Preparation of (2R)-2,4,8-triphenyl-10-
1
(trifluoromethyl)-1,2,3,4-
203 8C. H NMR (200 MHz, CDCl3), d = 2.45–2.65 (2H, m,
tetrahydropyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidine (2b)
To cooled solution of 1a (0.5 g, 1.36 mmol) in acetonitirile,
FeCl3 (0.22 g, 1.36 mmol) and styrene (0.28 g, 2.7 mmol) were
added and the reaction mixture was stirred for 1 h under N2
CH2), 4.85 (1H, d, J 16 Hz, NHCHPh), 5.4 (1H, br, s, NH), 5.7
(1H, q, J 8.5 Hz, N–CH–Ph), 7.2–7.4 (7H, m, Ar–H), 7.4–7.6
(6H, m, Ar–H), 8.0–8.1 (3H, m, Ar–H). IR (KBr) (cmꢀ1): 3356
(N–H), 1610 (C N). LSIMS; m/z: 471 (MH+), 367

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S.R. Kanth et al. / Journal of Fluorine Chemistry 127 (2006) 1211–1221
(M+ꢀCH2Ph). Anal. Calcd. for C28H21F3N4: C, 71.84%; H,
4.2.8. (6aS,11bR)-2-Phenyl-4-(trifluoromethyl)-
6,6a,7,11b-tetrahydro-5H-indeno[2,1-
e]pyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidine (2g)
4.50%; N, 11.91%. Found: C, 71.62%; H, 4.31%; N, 11.72%.
4.2.4. (3aS,11aS)-8-Phenyl-6-(trifluoromethyl)-3a,4,5,11a-
tetrahydro-3H-cyclopenta[e]pyrido[20,30:3,4]pyrazolo[1,5-
a]pyrimidine (2c)
Yield: 0.62 g (85%); bright yellow coloured solid; mp
159 8C. 1H NMR (200 MHz, CDCl3), d = 2.95–3.3
(2H + 1H + 1H, m, CH2, CH, CH2–N), 3.5–3.6 (1H, m,
CH2–N), 5.5 (1H, br, s, NH), 5.8 (1H, d, J 8.8 Hz, HC–N),
7.1–7.3 (3H, m, Ar–H), 7.35–7.5 (4H, m, Ar–H), 7.95 (1H, m,
Ar–H), 8.1–8.2 (2H, m, Ar–H). IR (KBr) (cmꢀ1): 3358 (N–H),
1605 (C N), 2926 (C–H). LSIMS; m/z: 407 (MH+). Anal.
Calcd. for C23H17F3N4: C, 67.97%; H, 4.22%; N, 13.79%.
Found: C, 67.74%; H, 4.46%; N, 13.93%.
1
Yield: 0.6 g (94%); yellow coloured solid; mp 217 8C. H
NMR (200 MHz, CDCl3), d = 2.4–2.9 (2H, m, CH2), 3.2–3.5
(3H, m, CH2–N and CH), 5.4 (1H, d, J 7.3 Hz, HC–N), 5.65
(1H, br, s, NH), 6.0 (1H, d, J 17.3 Hz, HC=CH), 6.25 (1H, d, J
17.3 Hz, HC CH), 7.6–7.7 (4H, m, Ar–H), 8.1–8.2 (2H, m,
Ar–H). IR (KBr) (cmꢀ1): 3352 (N–H), 1605 (C N), 2926 (C–
H). LSIMS; m/z: 357 (MH+), 291 (M+ꢀC5H4). Anal. Calcd. for
C19H15F3N4: C, 64.04%; H, 4.24%; N, 15.72%. Found: C,
64.24%; H, 4.43%; N, 15.54%.
4.2.9. (6R,6aS,11bR)-2,6-Diphenyl-4-(trifluoromethyl)-
6,6a,7,11b-tetrahydro-5H-indeno[2,1-
e]pyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidine (2h)
Yield: 0.66 g (76%); bright yellow coloured solid; mp
4.2.5. (3aS,4R,11aS)-4,8-Diphenyl-6-(trifluoromethyl)-
3a,4,5,11a-tetrahydro-3H-cyclo
1
192 8C. H NMR (200 MHz, CDCl3), d = 3.25–3.35 (2H, dd,
penta[e]pyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidine (2d)
Yield: 0.62 g (80%); bright yellow coloured solid; mp
249 8C. 1H NMR (200 MHz, CDCl3), d = 1.8–2.0 (1H, m,
CH2), 2.5–2.7 (1H, m, CH2), 3.05–3.15 (1H, m, CH), 5.0 (1H, d,
J 16 Hz, HC–Ph), 5.1 (1H, br, s, NH), 5.45 (1H, d, J 8.2 Hz,
CH–N), 6.0 (1H, d, J 18 Hz, HC CH), 6.25 (1H, d, J 17.3 Hz,
HC CH), 7.3–7.5 (9H, m, Ar–H), 8.0–8.1 (2H, m, Ar–H). IR
(KBr) (cmꢀ1): 3355 (N–H), 1605 (C N), 2926 (C–H). LSIMS;
m/z: 433 (MH+), 367 (M+ꢀC5H4). Anal. Calcd. for
C25H19F3N4: C, 69.44%; H, 4.43%; N, 12.96%. Found: C,
69.21%; H, 4.25%; N, 12.72%.
CH2), 3.9–3.95 (1H, m, CH–C), 5.45 (1H, br, s, NH), 5.6 (1H,
m, N–CHPh), 6.05 (1H, d, J 8.8 Hz, HC–N), 6.9–7.25 (7H, m,
Ar–H), 7.3–7.45 (6H, m, Ar–H), 8.4–8.45 (2H, m, Ar–H). IR
(KBr) (cmꢀ1): 3352 (N–H), 1602 (C N), 2926 (C–H). LSIMS;
m/z: 483 (MH+). Anal. Calcd. for C29H21F3N4: C, 72.19%; H,
4.39%; N, 11.61%. Found: C, 72.38%; H, 4.58%; N, 11.40%.
4.2.10. (4aS,12aS)-9-Phenyl-7-(trifluoromethyl)-
3,4,4a,5,6,12a-hexahydro-2H-pyrano[3,2-
e]pyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidine (2i)
Yield: 0.54 g (80%); yellow coloured solid; mp 202 8C. 1H
NMR (200 MHz, CDCl3), d = 1.55–1.6 (1H, m, OCH2CH2),
1.9–2.1 (1H + 2H, m, OCH2CH2, CH2–CH), 2.3–2.4 (1H, m,
CH), 3.3–3.4 (1H, m, CH2–N), 3.6–3.8 (1H + 2H, m, CH2–O,
CH2–N), 3.9–4.0 (1H, m, CH2–O), 5.6 (1H, d, J 9.6 Hz, HC–O),
5.85 (1H, br, s, NH), 7.35–7.5 (4H, m, Ar–H), 8.0–8.1 (2H, m,
Ar–H). IR (KBr) (cmꢀ1): 3381 (N–H), 1607 (C N), 2933 (C–
H). LSIMS; m/z: 375 (MH+), 291 (M+ꢀC6H7). Anal. Calcd. for
C19H17F3N4O: C, 60.96%; H, 4.58%; N, 14.97%. Found: C,
60.71%; H, 4.79%; N, 14.69%.
4.2.6. (4aS,12aS)-9-Phenyl-7-(trifluoromethyl)-
1,2,4a,5,6,12a-hexahydropyrido[20,30:3,4]pyrazolo[1,5-
a]quinazoline (2e)
Yield: 0.59 g (89%); yellow coloured solid; mp 188 8C. 1H
NMR (200 MHz, CDCl3), d = 1.9–2.0 (2H, m, CH2–CH2–
HC CH), 2.15–2.3 (2H, m, CH2–HC CH), 2.5–2.6 (1H, m,
CH), 3.4–3.5 (2H, m, CH2–N), 5.1 (1H, s, HC–N), 5.5 (1H, br,
s, NH), 5.9 (1H, d, J 18 Hz, HC CH), 6.25 (1H, d, J 17 Hz,
HC=CH), 7.4–7.5 (4H, m, Ar–H), 8.1–8.2 (2H, m, Ar–H). IR
(KBr) (cmꢀ1): 3406 (N–H), 1607 (C N), 2932 (C–H).
LSIMS; m/z: 371 (MH+). Anal. Calcd. for C20H17F3N4: C,
64.86%; H, 4.63%; N, 15.13%. Found: C, 64.63%; H, 4.41%;
N, 15.35%.
4.2.11. (4aS,5R,12aS)-5,9-Diphenyl-7-(trifluoromethyl)-
3,4,4a,5,6,12a-hexahydro-2H-pyrano[3,2-
e]pyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidine (2j)
1
Yield: 0.55 g (68%); yellow coloured solid; mp 228 8C. H
NMR(200 MHz, CDCl3), d = 1.2–1.3 (1H, m, CH2CH2–O), 1.6–
1.8 (2H + 1H, m, HC–CH2, CH2CH2–O), 2.4–2.5 (1H, m, CH),
3.4–3.65 (1H, m, CH2–O), 3.8 (1H, m, CH2–O), 4.8 (1H, d, J
16 Hz, HC–Ph), 5.1 (1H, br, s, NH), 6.3 (1H, s, HC–O), 7.25–7.6
(8H, m, Ar–H), 8.05–8.15(3H, m, Ar–H). IR(KBr)(cmꢀ1):3388
(N–H), 1600 (C N), 2930 (C–H). LSIMS; m/z: 451 (MH+), 367
(M+ꢀC6H7). Anal. Calcd. for C25H21F3N4O: C, 66.66%; H,
4.70%; N, 12.44%. Found: C, 66.42%; H, 4.51%; N, 12.67%.
4.2.7. (4aS,5R,12aS)-5,9-Diphenyl-7-(trifluoromethyl)-
1,2,4a,5,6,12a-hexahydropyrido[20,30:3,4]pyrazolo[1,5-
a]quinazoline (2f)
Yield: 0.65 g (81%); yellow coloured solid; mp 218 8C. 1H
NMR (200 MHz, CDCl3), d = 1.4–1.5 (2H, m, CH2–CH2–
HC CH), 1.9–2.05 (2H, m, CH2–HC CH), 2.35–2.4 (1H, m,
CH), 5.0 (1H, m, HC–Ph), 5.1 (1H, br, s, NH), 5.2 (1H, t, J
9.2 Hz, HC–N), 6.0 (1H, d, J 18 Hz, HC CH), 6.5 (1H, d, J
18 Hz, HC CH), 7.2–7.5 (9H, m, Ar–H), 8.0–8.1 (2H, m, Ar–
H). IR (KBr) (cmꢀ1): 3437 (N–H), 1607 (C N), 2932 (C–H).
LSIMS; m/z: 447 (MH+). Anal. Calcd. for C26H21F3N4: C,
69.94%; H, 4.74%; N, 12.55%. Found: C, 69.72%; H, 4.55%;
N, 12.32%.
4.2.12. (4aS,12aS)-9,12a-Diphenyl-7-(trifluoromethyl)-
1,2,3,4,4a,5,6,12a-octahydropyrido[20,30:3,4]pyrazolo[1,5-
a]quinazoline (2k)
Yield: 0.7 g (87%); bright yellow coloured solid; mp 237 8C.
1H NMR (200 MHz, CDCl3), d = 1.5–1.6 (2H + 1H, m,

S.R. Kanth et al. / Journal of Fluorine Chemistry 127 (2006) 1211–1221
1219
CH2CH2–CH, CH2CH2–CPh), 1.7–1.85 (2H + 1H, m, CH2–
HC, CH2CH2–CPh), 1.95–2.05 (1H, m, CH2–CPh), 2.55 (1H, d,
J 16 Hz, CH), 3.0–3.1 (1H, m, CH2–CPh), 3.2–3.4 (2H, m,
CH2–N), 4.8 (1H, br, s, NH), 6.75–6.8 (2H, m, Ar–H), 7.2–7.3
(3H, m, Ar–H), 7.4–7.5 (4H, m, Ar–H), 8.2–8.3 (2H, m, Ar–H).
IR (KBr) (cmꢀ1): 3322 (N–H), 1601 (C N), 2932 (C–H).
LSIMS; m/z: 449 (MH+). Anal. Calcd. for C26H23F3N4: C,
69.63%; H, 5.17%; N, 12.38%. Found: C, 69.88%; H, 5.37%;
N, 12.65%.
7.1 (2H, m, Ar–H), 7.15–7.25 (3H, m, Ar–H), 7.3–7.4 (5H, m,
Ar–H), 7.5–7.65 (4H, m, Ar–H), 8.25–8.4 (2H, m, Ar–H). IR
(KBr) (cmꢀ1): 3422 (N–H), 1601 (C N), 2930 (C–H). ESI
MS; m/z: 485 (MH+). Anal. Calcd. for C29H23F3N4: C, 71.89%;
H, 4.78%; N, 11.56%. Found: C, 71.65%; H, 4.52%; N,
11.77%.
4.2.17. 4-Methyl-8-phenyl-10-(trifluoromethyl)-4-vinyl-
1,2,3,4-tetrahydropyrido[20,30:3,4]pyrazolo[1,5-
a]pyrimidine (2o)
4.2.13. (4aS,5R,12aS)-5,9,12a-Triphenyl-7-
(trifluoromethyl)-1,2,3,4,4a,5,6,12a-octahydro
Yield: 0.46 g (72%); yellow coloured solid; mp 213 8C. 1H
NMR (200 MHz, CDCl3), d = 1.9 (3H, s, CH3–C), 2.1–2.3 (2H,
m, CH2), 3.5–3.6 (2H, m, CH2–NH), 4.75 (1H, d, J 18 Hz,
HC CH2), 5.2 (1H, d, J 18 Hz, HC CH2), 5.4 (1H, br, s, NH),
5.95–6.15 (1H, m, HC CH2), 7.4–7.6 (4H, m, Ar–H), 8.1–8.2
(2H, m, Ar–H). IR (KBr) (cmꢀ1): 3396 (N–H), 1608 (C N),
2930 (C–H). LSIMS; m/z: 359 (MH+). Anal. Calcd. for
C19H17F3N4: C, 63.68%; H, 4.78%; N, 15.63%. Found: C,
63.85%; H, 4.92%; N, 15.81%.
pyrido[20,30:3,4]pyrazolo[1,5-a]quinazoline (2l)
Yield: 0.77 g (82%); yellow coloured solid; mp 283 8C. 1H
NMR (200 MHz, CDCl3), d = 1.6–1.7 (2H + 1H, m, CH2CH2
CH, CH2CH2CPh), 1.75–1.9 (1H + 2H, m, CH2CH2CPh, CH2–
CH), 2.05–2.15 (1H, m, CH2–CPh), 2.65 (1H, d, J 14 Hz, CH),
3.1–3.2 (1H, m, CH2–CPh), 4.7 (1H, br, s, NH), 5.3 (1H, d, J
18 Hz N–CHPh), 6.4–6.5 (2H, m, Ar–H), 6.7–6.9 (8H, m, Ar–
H), 7.5–7.6 (4H, m, Ar–H), 8.2–8.3 (2H, m, Ar–H). IR (KBr)
(cmꢀ1): 3482 (N–H), 1612 (C N), 2938 (C–H). LSIMS; m/z:
525 (MH+). Anal. Calcd. for C32H27F3N4: C, 72.27%; H,
5.19%; N, 10.68%. Found: C, 72.42%; H, 5.33%; N, 10.87%.
4.3. Procedure for the preparation of
pyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidines (3a–j)
4.2.14. Crystal data for (4aS,5R,12aS)-5,9,12a-triphenyl-
7-(trifluoromethyl)-1,2,3,4,4a,5,6,12a-
octahydropyrido[20,30:3,4]pyrazolo[1,5-a]quinazoline (2l)
C32H27F3N4: Mw = 524.58, colorless needle crystal 0.19 mm
Tetrahydropyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidines
(0.35 g) and 10-fold excess of active MnO2 were taken in
dichloromethane and the reaction mixture was stirred at for 12–
24 h under N2 atmosphere at room temperature. The reaction
mixture was diluted with dichloromethane and MnO2 was
separated by filteration using Celite filtration aid. The filtrate
was concentrated under vacuo to give crude product which was
purified by column chromatography using 60–120 mesh silica
gel and desired product was eluted 30% CHCl3 in hexane
mixture.
˚
˚
ꢁ 0.11 mm ꢁ 0.09 mm, a = 9.1338(7) A, b = 13.2004(10) A,
3
˚
˚
c = 22.0747(16) A, b = 101.659(1)8, V = 2606.6(3) A , mono-
clinic, space group P21/c, rcalc = 1.337 mg mꢀ3, l = 0.71073 A,
˚
m(Mo Ka) = 0.095 mmꢀ1, F0 0 0 = 1096, T = 273(2) K. Data
collection yielded 24,529 reflection resulting in 4581 unique,
averaged reflection, 3897 with I > 2s(I), u range: 1.81–25.008.
Full-matrix least-squares refinement led to a final R = 0.0512,
Rw = 0.1370 and GOF = 1.026. Intensity data were measured on
Bruker Smart Apex with CCD area detector. CCDC 283727
contains supplementary crystallographic data forthe structure 2l.
4.3.1. 4,8-Diphenyl-10-
(trifluoromethyl)pyrido[20,30:3,4]pyrazolo[1,5-
a]pyrimidine (3a)
1
4.2.15. 4-Methyl-4,8-diphenyl-10-(trifluoromethyl)-
1,2,3,4-tetrahydropyrido[20,30:3,4]pyrazolo[1,5-
a]pyrimidine (2m)
Yield: 0.3 g (85%); green coloured solid; mp 232 8C. H
NMR (200 MHz, CDCl3), d = 7.4–7.6 (7H, m, Ar–H), 7.95–
8.05 (2H, m, Ar–H), 8.2–8.3 (3H, m, Ar–H), 8.9 (1H, d,
HC N). IR (KBr) (cmꢀ1): 1605 (C C), 1590 (C N).
LSIMS; m/z: 391 (MH+). Anal. Calcd. for C22H13F3N4: C,
67.69%; H, 3.36%; N, 14.35%. Found: C, 67.45%; H, 3.13%;
N, 14.52%.
1
Yield : 0.6 g (89%); yellow coloured solid; mp 167 8C. H
NMR (200 MHz, CDCl3), d = 2.2 (3H, s, CH3), 2.4–2.65 (2H,
m, C–CH2), 3.1–3.25 (1H, m, CH2–N), 3.3–3.4 (1H, m, CH2–
N), 4.85 (1H, br, s, NH), 6.8–6.9 (2H, m, Ar–H), 7.2–7.3 (3H,
m, Ar–H), 7.4–7.6 (4H, m, Ar–H), 8.15–8.25 (2H, m, Ar–H). IR
(KBr) (cmꢀ1): 3396 (N–H), 1606 (C N). ESIMS; m/z: 409
(MH+). Anal. Calcd. for C23H19F3N4: C, 67.64%; H, 4.69%; N,
13.72%. Found: C, 67.87%; H, 4.85%; N, 13.95%.
4.3.2. 2,4,8-Triphenyl-10-
(trifluoromethyl)pyrido[20,30:3,4]pyrazolo[1,5-
a]pyrimidine (3b)
4.2.16. (2R)-4-Methyl-2,4,8-triphenyl-10-(trifluoromethyl)-
1,2,3,4-tetrahydropyrido[20,30:3,4]pyrazolo[1,5-
a]pyrimidine (2n)
Yield: 0.56 g (65%); yellow coloured solid; mp 227 8C. 1H
NMR (200 MHz, CDCl3), d = 2.3 (3H, s, CH3), 2.5–2.6 (2H, m,
C–CH2), 4.6–4.65 (1H, m, HC–Ph), 4.85 (1H, br, s, NH), 6.9–
Yield: 0.27 g (78%); pale green coloured solid; mp 254 8C.
1H NMR (200 MHz, CDCl3), d = 7.5–7.7 (9H, m, Ar–H), 8.0–
8.1 (2H, m, Ar–H), 8.25–8.4 (6H, m, Ar–H). IR (KBr) (cmꢀ1):
1622 (C C), 1595 (C N). LSIMS; m/z: 467 (MH+). Anal.
Calcd. for C28H17F3N4: C, 72.10%; H, 3.67%; N, 12.01%.
Found: C, 72.34%; H, 3.73%; N, 12.23%.

1220
S.R. Kanth et al. / Journal of Fluorine Chemistry 127 (2006) 1211–1221
4.3.3. 8-Phenyl-6-(trifluoromethyl)-1H-
cyclopenta[e]pyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidine
(3c)
Yield: 0.28 g (80%); pale green coloured solid; mp 226 8C.
1H NMR (200 MHz, CDCl3), d = 3.95–4.2 (2H, m, CH2), 6.75
(1H, d, J 18 Hz, HC CH), 7.35 (1H, d, HC CH), 7.25–7.4 (4H,
m, Ar–H), 8.2–8.35 (2H, m, Ar–H), 9.05 (1H, s, HC N). IR
(KBr) (cmꢀ1): 1588 (C N). LSIMS; m/z: 353 (MH+). Anal.
Calcd. for C19H11F3N4: C, 64.77%; H, 3.15%; N, 15.90%.
Found: C, 64.94%; H, 3.37%; N, 15.72%.
7.4 (2H, m, Ar–H), 7.45–7.65 (7H, m, Ar–H), 7.7–7.8 (4H, m,
Ar–H), 8.2–8.3 (2H, m, Ar–H). IR (KBr) (cmꢀ1): 1594 (C N).
LSIMS; m/z: 479 (MH+). Anal. Calcd. for C29H17F3N4: C,
72.51%; H, 3.43%; N, 11.89%. Found: C, 72.72%; H, 3.66%;
N, 11.65%.
4.3.9. 9,12a-Diphenyl-7-(trifluoromethyl)-1,2,3,4,4a,12a-
hexadropyrido[20,30:3,4]pyrazolo[1,5-a]quinazoline (3i)
Yield: 0.31 g (89%); pale green coloured solid; mp 222 8C.
1H NMR (200 MHz, CDCl3), d = 1.51–1.65 (2H + 1H, m,
CH2–CH2–CH, CH2–CH2–CPh), 1.8–1.85 (1H + 2H, m,
CH2–CH2–CPh, CH2–CH2–CH), 1.90–2.0 (1H, m, CH2–
CPh), 3.2 (1H + 1H, m, CH2–CPh, CH), 6.95–7.05 (2H, m,
Ar–H), 7.2–7.3 (2H, m, Ar–H), 7.4–7.7 (4H, m, Ar–H), 8.2–
8.3 (3H, m, Ar–H), 8.7 (1H, s, HC N). IR (KBr) (cmꢀ1): 1590
(C N). LSIMS; m/z: 447 (MH+). Anal. Calcd. for
C26H21F3N4: C, 69.61%; H, 4.83%; N, 12.46%. Found: C,
69.83%; H, 4.61%; N, 12.69%.
4.3.4. 4,8-Diphenyl-6-(trifluoromethyl)-1H-
cyclopenta[e]pyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidine
(3d)
1
Yield: 0.25 g (72%); green coloured solid; mp 248 8C. H
NMR (200 MHz, CDCl3), d = 3.9–4.15 (2H, m, CH2), 6.6 (1H,
d, J 19 Hz, HC CH), 7.25 (1H, d, J 19 Hz, HC CH), 7.3–7.6
(7H, m, Ar–H), 7.85–7.95 (2H, m, Ar–H), 8.2–8.4 (2H, m, Ar–
H). IR (KBr) (cmꢀ1): 1592 (C N). LSIMS; m/z: 429 (MH+).
Anal. Calcd. for C25H15F3N4: C, 70.09%; H, 3.53%; N,
13.08%. Found: C, 70.27%; H, 3.36%; N, 13.22%.
4.3.10. 4-Methyl-4,8-diphenyl-10-(trifluoromethyl)-3,4-
dihydropyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidine (3j)
1
Yield: 0.23 g (66%); green coloured solid; mp 276 8C. H
4.3.5. 9-Phenyl-7-(trifluoromethyl)-1,4-
NMR (200 MHz, CDCl3), d = 2.15 (3H, s, CH3), 2.6–2.65
(2H, m, CH2), 6.9–7.0 (2H, m, Ar–H), 7.2–7.35 (3H, m, Ar–
H), 7.5–7.7 (4H, m, Ar–H), 8.2–8.3 (2H, m, Ar–H), 8.6 (1H,
s, HC N). IR (KBr) (cmꢀ1): 1596 (C N). LSIMS; m/z: 407
(MH+). Anal. Calcd. for C23H17F3N4: C, 67.61%; H, 3.59%;
N, 13.41%. Found: C, 67.85%; H, 3.38%; N, 13.63%.
dihydropyrido[20,30:3,4]pyrazolo[1,5-a]quinazoline (3e)
Yield: 0.3 g (88%); pale green coloured solid; mp 262 8C. 1H
(200 MHz, CDCl3), d = 2.6–2.8 (2H, m, CH2), 3.0–3.2 (2H, m,
CH2), 6.8–6.9 (1H, m, HC CH), 7.4–7.6 (3H, m, Ar–H), 7.7
(1H, d, J 19 Hz, HC CH), 8.0 (1H, s, Ar–H), 8.2–8.3 (2H, m,
Ar–H), 8.6 (1H, s, HC N). IR (KBr) (cmꢀ1): 1588 (C N).
LSIMS; m/z: 367 (MH+). Anal. Calcd. for C20H13F3N4: C,
66.57%; H, 3.58%; N, 15.22%. Found: C, 66.32%; H, 3.77%;
N, 15.45%.
Acknowledgements
The authors are thankful to Dr. J.S. Yadav, Director, IICT,
Hyderabad, Shri S. Narayan Reddy, Head, Fluoroorganics
division, IICT for their constant encouragement and SRK is
grateful to CSIR, New Delhi for grant of senior research
fellowship.
4.3.6. 5,9-Diphenyl-7-(trifluoromethyl)-1,4-
dihydropyrido[20,30:3,4]pyrazolo[1,5-a]quinazoline (3f)
1
Yield: 0.27 g (79%); green coloured solid; mp 227 8C. H
NMR (200 MHz, CDCl3), d = 3.0–3.15 (4H, m, CH2), 6.7–6.75
(1H, m, HC CH), 7.3–7.45 (6H, m, Ar–H), 7.55 (1H, d, J
17 Hz, HC CH), 7.8–8.1 (5H, m, Ar–H). IR (KBr) (cmꢀ1):
1598 (C N). LSIMS; m/z: 443 (MH+). Anal. Calcd. for
C26H17F3N4: C, 70.58%; H, 3.87%; N, 12.68%. Found: C,
70.32%; H, 3.61%; N, 12.43%.
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1
Yield: 0.26 g (77%); green coloured solid; mp 189 8C. H
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(3H, m, Ar–H), 7.25–7.5 (4H, m, Ar–H), 8.2–8.3 (3H, m, Ar–
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68.66%; H, 3.26%; N, 13.92%. Found: C, 68.83%; H, 3.47%;
N, 13.71%.
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e]pyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidine (3h)
Yield: 0.23 g (67%); pale green coloured solid; mp 194 8C.
1H NMR (200 MHz, CDCl3), d = 4.15–4.25 (2H, m, CH2), 7.3–
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1221
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