A simple synthesis of 6-phenylpyrano[2,3-c]pyrazol-4(1H)-ones

Article abstract of DOI:10.1055/s-2005-872078

A novel synthesis of substituted 6-phenylpyrano[2,3-c]pyrazol-4(1H)-ones via reaction of various 2-substituted or 2,5-disubstituted 2,4-dihydro-3H- pyrazol-3-ones with phenylpropynoyl chloride using calcium hydroxide in refluxing 1,4-dioxane is described.

Full text of DOI:10.1055/s-2005-872078

PAPER
2583
A Simple Synthesis of 6-Phenylpyrano[2,3-c]pyrazol-4(1H)-ones
6
-Phenylpyrano[2,3-
c
]p
i
yrazol-
l
4(1
H
)-
f
ones ried Becker, Gernot A. Eller, Wolfgang Holzer*
Department of Drug Synthesis, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria
Fax +43(1)42779556; E-mail: wolfgang.holzer@univie.ac.at
Received 14 February 2005; revised 4 April 2005
Abstract: A novel synthesis of substituted 6-phenylpyrano[2,3-
c]pyrazol-4(1H)-ones via reaction of various 2-substituted or 2,5-
disubstituted 2,4-dihydro-3H-pyrazol-3-ones with phenylpropyn-
oyl chloride using calcium hydroxide in refluxing 1,4-dioxane is de-
scribed. N-Unsubstituted representatives were obtained by
treatment of 4-methoxybenzyl-protected congeners with trifluoro-
acetic acid.
Key words: pyrazolones, acylations, cyclizations, fused-ring sys-
tems, PMB protecting group
Figure 1
The 6-phenylpyrano[2,3-c]pyrazol-4(1H)-one moiety 1 is and 1y have been obtained by acid-catalyzed cyclization
an interesting heterocyclic system as it represents a pyra- of 1,3-diketones 4,3–7 the latter being available either from
zole analogue of flavone (2-phenyl-4H-chromen-4-one), 2-pyrazolin-5-ones 2 by acetylation and subsequent Clais-
the latter being the parent system for a large variety of nat- en condensation4,7 [or treatment with lithium bis(trimeth-
ural products which play important roles in numerous bi- ylsilyl)amide/benzoyl chloride]3,6 or via ring-
ological processes (Figure 1).1 Few representatives of transformation of phenylhydrazone 6 derived from 3-
type 1 are hitherto known (for instance 1b,2 1g,3 1h,4–7 acetyl-4-hydroxy-6-phenyl-2H-pyran-2-one (5).5,6 Alter-
1x,7 1y5); reported pathways for their synthesis are dis- natively, reaction of 4-cinnamoyl-5-hydroxypyrazoles 7
played in Scheme 1. Accordingly, derivatives 1g, 1h, 1x, with bromine followed by treatment of the resulting bro-
Scheme 1 Known methods for the synthesis of the title compounds 1
SYNTHESIS 2005, No. 15, pp 2583–2589
x
x.
x
x
.
2
0
0
5
Advanced online publication: 20.07.2005
DOI: 10.1055/s-2005-872078; Art ID: T01805SS
© Georg Thieme Verlag Stuttgart · New York

2584
W. Becker et al.
PAPER
mo compounds 8 with DBU afforded 1b2 and 1h,6 respec-
tively. However, these traditional preparations are multi-
step reactions characterized by poor overall yields.
In the benzene series, an interesting strategy for the syn-
thesis of substituted flavones 11 consists of a base-
catalyzed 6-endo-dig cyclization of o-phenylpropyn-
oylphenols 10.8–11 Strongly dependent on the reaction
conditions, the formation of 5-exo-dig product 11a (au-
rones) is also possible.8,11 The starting phenylpropynoyl
compounds 10 are available, for instance, by photo-Fries
rearrangement of aryl phenylpropynoates 9 (Scheme 2).8,9
Scheme 3 Novel one-pot synthesis of 6-phenylpyrano[2,3-c]pyra-
zol-4(1H)-ones
bond – into the isomeric 3-hydroxy-2,6-diphenylpyra-
no[2,3-c]pyrazol-4(2H)-one (13; Scheme 4). Isomers 1i
and 13 are difficult to discriminate on the basis of their
spectroscopic properties. However, NOE-difference ex-
periments and NOESY spectra unambiguously revealed
the structure of 1i as the isolated reaction product. Ac-
cordingly, a clear NOE on the signal of NPh-H-2,6 pro-
tons upon irradiation of the CPh-H-2,6 transition (and,
reversely, on the signal of CPh-H-2,6 upon disturbing the
NPh-H-2,6 transition) provides proof of the spatial prox-
imity of the two phenyl rings and thus the 4(1H)-one
structure (Scheme 4). In contrast, the corresponding phe-
nyl protons in 13 are too far apart for an NOE to be detect-
ed.
Scheme 2 Synthesis of flavones by cyclization of ortho-phenylpro-
pynoylphenols
We herein, wish to report a straightforward synthesis of
various 6-phenylpyrano[2,3-c]pyrazol-4(1H)-ones 1 fol-
lowing a related approach. It includes acylation of pyrazo-
lones 2 with phenylpropynoyl chloride following the
general procedure described by Jensen [RCOCl, Ca(OH)2,
refluxing dioxane]12 in order to obtain the corresponding
4-phenylpropynoyl-substituted 5-hydroxypyrazoles of
type 12. Subsequently, the latter could be cyclized into
target compounds 1 (Scheme 3).
However, it turned out that even under the acylation con-
ditions pyran ring-closure into 1 occurred. For this reason,
apparent intermediates 12 were not isolated and cycliza-
tion was completed with prolonged reaction times (six
hours instead of two hours for a ‘normal’ Jensen-acyla-
tion). After reaction of N-methylpyrazolone 2b with phe-
nylpropynoyl chloride the crude product still contained
50% of non cyclized intermediate 12b. Nevertheless, cy-
clization to 1b could be obtained smoothly, by subsequent
treatment of this mixture with potassium carbonate in an-
hydrous acetone. Although yields are average, the pre-
sented approach leads to the desired 6-phenylpyrano[2,3-
c]pyrazol-4(1H)-ones 1 in a quick and simple reaction and
thus seems to be superior and much more convenient than
those hitherto used syntheses.
Scheme 4
Reaction of pyrazolone 2i with phenylpropynoyl chloride
represents a special case: the intermediate 3,5-dihydroxy-
4-phenylpropynoylpyrazole (12i) can either cyclize into
the 3-hydroxy-1,6-diphenylpyrano[2,3-c]pyrazol-4(1H)-
one (1i) or – upon attack of 3-OH on the alkyne triple
Recently, we presented the application of the 4-methoxy-
benzyl (PMB) protecting group in the synthesis of N-un-
substituted 4-acylpyrazolones.13 This protecting group
resists the conditions of primary pyrazolone ring synthesis
Synthesis 2005, No. 15, 2583–2589 © Thieme Stuttgart · New York

PAPER
6-Phenylpyrano[2,3-c]pyrazol-4(1H)-ones
2585
as well as those of 4-acylation under the ‘Jensen’ condi- ‘fixed’ 1-phenylpyrazole the pyrazole C-4 atom is in-
tions and, moreover, it can be conveniently removed by volved in two different geminal couplings [2J(C-4,H-
the action of trifluoroacetic acid. Similarly, i.e. by treat- 3) = 10.3 Hz, 2J(C-4,H-5) = 8.1 Hz] (Figure 2).17
ment of 1-PMB-substituted compounds 1e and 1f with tri-
Moreover, an NOE on the signal of H-3 upon irradiation
fluoroacetic acid, the N-unsubstituted bicyclic target
of the NH transition additionally hints at a contribution of
compounds 14e and 14f were easily available (Scheme 5).
the 2H-form B to the structure of 14e (Figure 2).
Compound 14e represents the ‘parent’ pyrazole analogue
of flavone.
Scheme 5
Detailed NMR spectroscopic investigations in DMSO-d6
solution revealed 14e to be involved in prototropic tau-
tomerism resulting in an equilibrium between the 1H-
form A and 2H-form B (Figure 2). This mainly follows
from the magnitude of the geminal spin-coupling constant
2J(C-3a,H-3). Corresponding coupling constants have
Figure 2 Prototropic tautomerism in pyrazole and in 14e
been shown to be sensitive probes for discrimination be-
tween forms having an ‘intact’ lone-pair at N-2 and those
Detailed NMR analyses for all prepared compounds were
characterized by an N2-H (N2-R) substructure.14 In the
undertaken, considering also characteristic 13C,1H spin-
case of 14e this coupling (2J = 8.6 Hz) is significantly re-
coupling constants as well as 15N NMR chemical shifts.
duced compared to 2J(C-3a,H-3) in the corresponding N-
Owing to their low solubility in CDCl3, the spectra of
1 substituted 3-H congeners 1a, 1c, 1e, and 1g (10.1–10.5
compounds 1i, 14e, and 14f were recorded in DMSO-d6
Hz). This situation closely resembles that of pyrazole,
solutions. The data obtained show a high degree of consis-
where – due to fast prototropic exchange – the observed
tency and are summarized in Table 1 (1H NMR), Table 2
geminal 13C,1H coupling (2J = 9.9 Hz, in CDCl3) repre-
(13C NMR chemical shifts), Table 3 (13C,1H coupling con-
2
sents a mean value between the larger J(C-4,H-3) cou-
stants), and Table 4 (15N NMR chemical shifts).
pling and the smaller J(C-4,H-5) one,15,16 whereas in
2
Table 1 1H NMR Data of Compounds 1a–j and 14e,f
Compd
1a
Solvent
CDCl3
H of R1
H of R3
H-5
H of 6-Ph
4.00 (Me)
7.96 (H-3)
2.55 (Me)
8.02 (H-3)
2.58 (Me)
7.99 (H-3)
2.57 (Me)
8.18 (H-3)
2.66 (Me)
11.53 (OH)
4.13 (OMe)
8.45 (H-3)
2.53 (Me)
6.66
6.59
6.65
6.59
6.64
6.59
6.77
6.77
6.83
6.70
6.75
6.66
7.81 (2,6), 7.53 (3,4,5)
7.79 (2,6), 7.51 (3,4,5)
7.71 (2,6), 7.51 (3,4,5)
7.69 (2,6), 7.50 (3,4,5)
7.73 (2,6), 7.53 (3,4,5)
7.71 (2,6), 7.51 (3,4,5)
7.82 (2,6), 7.53 (3,4,5)
7.80 (2,6), 7.53 (3,4,5)
7.94 (2,6), 7.57 (3,4,5)
7.78 (2,6), 7.53 (3,4,5)
7.99 (2,6), 7.56 (3,4,5)
7.95 (2,6), 7.53 (3,4,5)
1b
CDCl3
3.90 (Me)
1c
CDCl3
7.38 (Ph-2,3,4,5,6), 5.48 (NCH2)
7.36 (Ph-2,3,4,5,6), 5.39 (NCH2)
7.33 (Ph-2,6), 6.90 (Ph-3,5), 5.41 (NCH2), 3.79 (OMe)
7.31 (Ph-2,6), 6.89 (Ph-3,5), 5.32 (NCH2), 3.78 (OMe)
7.89 (Ph-2,6), 7.59 (Ph-3,5), 7.45 (Ph-4)
7.86 (Ph-2,6), 7.56 (Ph-3,5), 7.40 (Ph-4)
7.83 (Ph-2,6), 7.60 (Ph-3,5), 7.39 (Ph-4)
7.85 (Ph-2,6), 7.55 (Ph-3,5), 7.36 (Ph-4)
13.80 (NH)
1d
CDCl3
1e
CDCl3
1f
CDCl3
1g
CDCl3
1h
CDCl3
1i
DMSO-d6
CDCl3
1j
14e
14f
DMSO-d6
DMSO-d6
13.40 (NH)
Synthesis 2005, No. 15, 2583–2589 © Thieme Stuttgart · New York

2586
W. Becker et al.
PAPER
Table 2 13C NMR Chemical Shifts of Compounds 1a–j and 14e,f (Solvents as in Table 1)
Compd C-3
C-3a
C-4
C-5
C-6
C-7a
C of 6-Ph
C-1 C-2,6 C-3,5 C-4
C of R1
C of R3
1a
1b
1c
134.3 107.4 174.8 109.4 160.0 153.9 130.7 126.0 129.2 131.5 34.3 (Me)
145.4 105.5 175.6 109.6 159.7 154.1 130.9 125.9 129.1 131.1 33.8 (Me)
–
13.8 (Me)
–
134.6 107.8 174.8 109.5 160.1 153.8 130.8 126.0 129.1 131.5 52.1 (NCH2), Ph: 134.7
(1), 129.0 (3,5), 128.6 (4),
127.9 (2,6)
1d
1e
1f
145.8 105.9 175.6 109.7 159.8 154.0 130.9 125.9 129.1 131.3 51.7 (NCH2), Ph: 135.0
13.9 (Me)
–
(1), 129.0 (3,5), 128.4 (4),
127.8 (2,6)
134.5 107.7 174.8 109.4 160.0 153.6 130.8 126.0 129.1 131.5 55.3 (OMe), 51.7 (NCH2),
Ph: 159.8 (4), 129.4 (2,6),
126.7 (1), 114.4 (3,5)
145.7 105.9 175.6 109.7 159.7 153.8 131.0 125.9 129.1 131.3 55.3 (OMe), 51.2 (NCH2),
13.9 (Me)
Ph: 159.6 (4), 129.3 (2,6),
127.1 (1), 114.3 (3,5)
1g
1h
1i
135.7 108.9 174.8 109.8 160.5 153.1 130.7 126.1 129.3 131.7 Ph: 137.0 (1), 129.6 (3,5),
127.9 (4), 121.3 (2,6)
–
147.0 107.0 175.6 109.9 160.4 153.3 130.8 126.0 129.2 131.5 Ph: 137.0 (1), 129.5 (3,5),
127.5 (4), 121.1 (2,6)
13.9 (Me)
–
151.8 96.4
173.2 109.3 159.3 156.1 130.4 126.0 129.2 131.4 Ph: 136.6 (1), 129.6 (3,5),
126.7 (4), 120.6 (2,6)
1j
157.8 97.1
174.0 110.0 160.1 152.5 130.7 125.9 129.3 131.5 Ph: 137.1 (1), 129.5 (3,5),
126.9 (4), 120.6 (2,6)
56.2
(OMe)
14e
14f
127.1 107.1 175.9 107.2 161.2 161.6 131.3 126.3 129.2 131.5
138.6 104.6 176.7 107.1 161.0 161.6 131.3 126.1 129.0 131.3
–
–
–
10.9 (Me)
In conclusion, we have presented a simple and straightfor- Moreover, detailed NMR data material concerning 6-phe-
ward one-pot synthesis for the title compounds which is nylpyrano[2,3-c]pyrazol-4(1H)-ones was provided.
advantageous compared to the hitherto used methods.
Table 3 Selected 13C,1H Spin-Coupling Constants (Hz) of 1a–j and 14e,f (Solvents as in Table 1)
Compd
1J(C-3,H-3)
1J(3-Me)
4J(C-3,H-5)
2J(C-3a,H-3) 3J(C-3a,H-5) 2J(C-4,H-5)
3J(C-3a,3-Me)
1J(C-5,H-5)
Other Couplings
1a
1b
194.3
129.0
1.4
1.5
10.1
2.8
4.1
4.2
2.0
2.1
165.5
164.9
1J(NMe) = 141.6
1J(NMe) = 141.3, 2J(C-3,3-
Me) = 7.1, 3J(C-7a,NMe) = 2.3
1c
194.5
129.0
1.3
1.5
10.5
2.6
4.3
4.1
2.0
2.1
165.4
165.0
1J(NCH2) = 141.2
1d
1J(NCH2) = 140.5,
2J(C3,3-Me) = 7.1,
3J(C-7a,NCH2) = 2.6
1e
194.1
1.5
10.1
4.3
2.1
165.4
1J(NCH2) = 140.8, 3J(C-
7a,NCH2) = 2.5, 3J(C-7a,H-
3) = 5.2, 1J(OMe) = 143.9
Synthesis 2005, No. 15, 2583–2589 © Thieme Stuttgart · New York

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6-Phenylpyrano[2,3-c]pyrazol-4(1H)-ones
2587
Table 3 Selected 13C,1H Spin-Coupling Constants (Hz) of 1a–j and 14e,f (Solvents as in Table 1) (continued)
Compd
1J(C-3,H-3)
1J(3-Me)
4J(C-3,H-5)
2J(C-3a,H-3) 3J(C-3a,H-5) 2J(C-4,H-5)
3J(C-3a,3-Me)
1J(C-5,H-5)
Other Couplings
1f
128.9
1.5
2.8
4.2
2.1
165.0
1J(NCH2) = 140.5, 2J(C-3,3-
Me) = 7.1, 3J(C-7a,NCH2) = 2.5,
1J(OMe) = 144.0
1g
1h
1i
194.9
129.2
–
1.5
10.3
2.8
–
4.4
4.0
4.0
4.3
2.1
2.0
1.9
2.0
165.8
165.6
166.7
166.1
3J(C-7a,H-3) = 5.0
2J(C-3,3-Me) = 7.1
1.4
<0.5
1.4
1j
–
–
1J(OMe) = 146.9, 3J(C-
3,OMe) = 4.0, 3J(C-6,H-
5) = 7.4, 3J(Ph-C1,H-5) = 2.6
14e
14f
194.5
130.1
8.6
2.9
4.5
4.5
1.8
1.8
165.5
165.4
3J(C-7a,H-3) = 8.5, 2J(C-6,H-
5) = 6.6, 3J(Ph-C1,H-5) = 2.9
2J(C-3,3-Me) = 7.1, 2J(C-6,H-
5) = 6.7, 3J(Ph-C1,H-5) = 2.9
Table 4 15N NMR Chemical Shifts of 1a–j
Compd
1a
Solvent
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
N-1
N-2
Compd
Solvent
N-1
N-2
–205.1
–211.9
–193.5
–200.2
–191.7
–85.9
–92.9
–86.5
–93.2
–86.7
1f
1g
1h
1i
CDCl3
–198.5
–186.4
–192.5
–211.3
–210.1
–93.4
1b
CDCl3
–88.0
1c
CDCl3
–94.7
1d
DMSO-d6
CDCl3
not found
not found
1e
1j
Melting points were determined on a Reichert–Kofler hot-stage mi-
croscope and are uncorrected. Mass spectra were obtained on a Shi-
madzu QP 1000 instrument (EI, 70 eV). IR spectra were recorded
on a Perkin-Elmer FTIR 1605 spectrophotometer. 1H and 13C NMR
spectra were recorded on a Varian UnityPlus 300 spectrometer
(299.95 MHz for 1H, 75.43 MHz for 13C) at 28 °C. The center of the
solvent signal was used as an internal standard which was related to
TMS with d = 7.26 ppm (1H in CDCl3), d = 2.49 ppm (1H in DMSO-
d6), d = 77.0 ppm (13C in CDCl3), and d = 39.5 ppm (13C in DMSO-
d6). 15N NMR spectra were obtained on a Bruker Avance 500 instru-
ment with a ‘directly’ detecting broadband observe probe and were
referenced against external nitromethane (coaxial capillary). Full
and unambiguous assignment for all NMR signals was achieved by
combined application of standard NMR techniques such as fully 1H-
coupled 13C NMR (gated decoupling), APT, 1D-TOCSY, NOE-dif-
ference, NOESY, HMQC, gs-HSQC, gs-HMBC, and selective
long-range INEPT in a 1D and a 2D version.16 The following com-
mercially non available pyrazolones were prepared according to the
literature: 2a,18 2b,19 2c,3 2d,20 2e,13 2g,21 2i,22 2j.23 Yields of prod-
ucts 1 were not optimized.
Bp 76–78 °C/1.3 mbar.
1H NMR (CDCl3): d = 7.64 (m, 2 H, Ph-2,6), 7.56 (m, 1 H, Ph-4),
7.43 (m, 2 H, Ph-3,5).
13C NMR (CDCl3): d = 149.5 (C=O), 133.7 (Ph-2,6), 132.2 (Ph-4),
128.9 (Ph-3,5), 118.0 (Ph-1), 94.1 (PhC≡), 84.1 (≡CCO).
2-(4-Methoxybenzyl)-5-methyl-2,4-dihydro-3H-pyrazol-3-one
(2f)25
Under cooling with an ice bath, 4-methoxybenzylhydrazine (1.52 g,
10 mmol) (prepared according to literature procedures13) was added
slowly to ethyl acetoacetate (1.30 g, 10 mmol). After stirring for 30
min at 0 °C, the mixture was suction filtered and the remaining solid
was washed with cold Et2O (3 mL) to afford 1.64 g (75%) of a col-
orless powder.
Mp 128–130 °C.
1H NMR (CDCl3): d = 7.27 (m, 2 H, Ph-2,6), 6.85 (m, 2 H, Ph-3,5),
4.72 (s, 2 H, NCH2), 3.78 (s, 3 H, OMe), 3.18 (s, 2 H, pyrazole H-
4), 2.05 (s, 3 H, 5-Me).
13C NMR (CDCl3): d = 171.9 [pyrazole C-3, 2J(C-3,H-4) = 5.1 Hz,
3J(C-3,NCH2) = 2.1 Hz], 159.1 (Ph-4), 155.6 [pyrazole C-5,
2J(C-5,5-Me) = 7.6 Hz), 2J(C-5,H-4) = 5.2 Hz], 129.6 (Ph-2,6),
3-Phenylprop-2-ynoyl Chloride24
Under anhyd conditions, to a soln of phenylpropiolic acid (10.0 g,
68.4 mmol) in CH2Cl2 (260 mL) was added SOCl2 (24.4 g, 205
mmol) and the resulting mixture was stirred at 40 °C for 16 h. Then
the solvent and excess SOCl2 were removed under reduced pressure
and the oily residue was subjected to vacuum distillation to afford
9.0 g (80%) of a colorless oil.
1
128.8 (Ph-1), 114.0 (Ph-3,5), 55.2 (OMe, J = 143.7 Hz), 47.2
(NCH2, 1J = 138.9 Hz), 41.6 [pyrazole C-4, 1J = 133.0 Hz,
3J(C-4,5-Me) = 2.9 Hz], 17.0 (5-Me, 1J = 128.9 Hz).
15N NMR (CDCl3): d = –55.7 (N-1), –192.4 (N-2).
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W. Becker et al.
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6-Phenylpyrano[2,3-c]pyrazol-4(1H)-ones 1; General Proce-
dure
IR (KBr): 1639 cm–1 (C=O)
MS: m/z (%) = 332 (M+, 4), 240 (43), 138 (100), 70 (20), 69 (25),
A solution of phenylpropynoyl chloride (823 mg, 5 mmol) in anhyd
1,4-dioxane (3 mL) was added dropwise to a mixture of the appro-
priate pyrazolone 2 (5 mmol), Ca(OH)2 (741 mg, 10 mmol), and an-
hyd 1,4-dioxane (10 mL). The resulting mixture was heated at
reflux for 6 h. After cooling to r.t., the mixture was treated with 2 N
HCl (20 mL) and then stirred for 1 h before it was poured onto H2O
(50 mL). After 30 min, the mixture was suction filtered, the remain-
ing solid was repeatedly washed with H2O, and purified as outlined
below. It should be mentioned that the crude products in most cases
were accompanied by small amounts of highly colored by-products.
67 (19), 43 (20).
Anal. Calcd for C20H16N2O3 (332.35): C, 72.28; H, 4.85; N, 8.43.
Found: C, 72.00; H, 4.88; N, 8.38.
1-(4-Methoxybenzyl)-3-methyl-6-phenylpyrano[2,3-c]pyrazol-
4(1H)-one (1f)
Recrystallization (EtOH–H2O) afforded 800 mg (46%) of pale pink
crystals.
Mp 188 °C.
IR (KBr): 1647 cm–1 (C=O).
MS: m/z (%) = 346 (M+, 26), 121 (100).
1-Methyl-6-phenylpyrano[2,3-c]pyrazol-4(1H)-one (1a)
The crude product (416 mg) was subjected to flash chromatography
(silica gel, EtOAc) and subsequently recrystallized (EtOH–H2O) to
afford 166 mg (15%) of a brownish solid.
Anal. Calcd for C21H18N2O3 (346.38): C, 72.82; H, 5.24; N, 8.09.
Found: C, 72.55; H, 5.05; N, 8.36.
Mp 165 °C.
IR (KBr): 1643 cm–1 (C=O).
MS: m/z (%) = 227 (M+ + 1, 10), 226 (M+, 57), 124 (100), 102 (21),
53 (16), 43 (15).
1,6-Diphenylpyrano[2,3-c]pyrazol-4(1H)-one (1g)
Recrystallization (EtOH) afforded 878 mg (61%) of beige crystals.
Mp 189 °C (Lit.3 190 °C).
Anal. Calcd for C13H10N2O2 (226.23): C, 69.02; H, 4.46; N, 12.38.
Found: C, 68.77; H, 4.66; N, 12.16.
3-Methyl-1,6-diphenylpyrano[2,3-c]pyrazol-4(1H)-one (1h)
Recrystallization (EtOH–H2O) afforded 854 mg (57%) of tan-col-
ored crystals.
1,3-Dimethyl-6-phenylpyrano[2,3-c]pyrazol-4(1H)-one (1b)
The crude product (793 mg) consisted of a 1:1 mixture of 1b and
12b.
Mp 208–209 °C (Lit.4 210–211 °C, Lit.5 209–210 °C).
MS: m/z (%) = 303 (M+ + 1, 11), 302 (M+, 52), 201 (15), 200 (100),
132 (27), 91 (43), 77 (13), 51 (11), 43 (15).
To the crude product was added K2CO3 (235 mg, 1.7 mmol) and an-
hyd acetone (60 mL) and the suspension was refluxed for 3.5 h with
stirring. After filtration, the filtrate was evaporated under reduced
pressure to afford 789 mg (66%) of 1b as a yellowish powder (pure
according to NMR analysis).
3-Hydroxy-1,6-diphenylpyrano[2,3-c]pyrazol-4(1H)-one (1i)
Recrystallization (EtOH–H2O) afforded 377 mg (25%) of beige
crystals.
Mp 241–244 °C.
IR (KBr): 3400–2400 (OH), 1666, 1647 cm–1 (C=O).
In another run the crude product was recrystallized (EtOH–H2O) af-
fording 204 mg (17%) of 1b as yellow crystals.
MS: m/z (%) = 304 (M+, 0.5), 240 (26), 226 (49), 138 (50), 124
Mp 197 °C (Lit.2 197–198 °C).
(100), 102 (22).
1-Benzyl-6-phenylpyrano[2,3-c]pyrazol-4(1H)-one (1c)
Recrystallization (EtOH–H2O) afforded 333 mg (22%) of brownish
crystals.
Anal. Calcd for C18H12N2O3 (304.30): C, 71.05; H, 3.97; N, 9.21.
Found: C, 70.80; H, 3.98; N, 9.06.
3-Methoxy-1,6-diphenylpyrano[2,3-c]pyrazol-4(1H)-one (1j)
Mp 178–179 °C.
Recrystallization (EtOH) afforded 778 mg (49%) of beige crystals.
IR (KBr): 1634 cm–1 (C=O).
Mp 208–209 °C.
IR (KBr): 1661 cm–1 (C=O).
MS: m/z (%) = 303 (M+ + 1, 13), 302 (M+, 77), 172 (54), 144 (52),
91 (100), 65 (31).
MS: m/z (%) = 319 (M+ + 1, 15), 318 (M+, 57), 317 (45), 290 (29),
289 (100), 217 (18), 216 (98), 187 (18), 133 (22), 105 (36), 102
(28), 91 (29), 83 (33), 77 (83), 51 (34).
Anal. Calcd for C19H14N2O2 (302.30): C, 75.48; H, 4.67; N, 9.27.
Found: C, 75.20; H, 4.58; N, 9.26.
1-Benzyl-3-methyl-6-phenylpyrano[2,3-c]pyrazol-4(1H)-one
(1d)
Recrystallization (EtOH–H2O) afforded 554 mg (35%) of brownish
crystals.
Anal. Calcd for C19H14N2O3 (318.33)·0.2 H2O: C, 70.89; H, 4.51; N,
8.70. Found: C, 70.72; H, 4.56; N, 8.74.
Compounds 14e and 14f; General Procedure
To the PMB-protected 6-phenylpyrano[2,3-c]pyrazol-4(1H)-one
(1e or 1f, 1 mmol) was added TFA (2.85 g, 25 mmol) and the mix-
ture was stirred at 70–75 °C for 24 h. After removal of excess TFA
under reduced pressure, the residue was washed with cold acetone
to afford a nearly colorless powder.
Mp 189–190 °C.
IR (KBr): 1653 cm–1 (C=O).
MS: m/z (%) = 317 (M+ + 1, 19), 316 (M+, 81), 225 (37), 186 (22),
158 (27), 91 (100), 67 (23), 65 (25).
Anal. Calcd for C20H16N2O2 (316.35): C, 75.93; H, 5.10; N, 8.85.
Found: C, 75.73; H, 5.15; N, 8.78.
6-Phenylpyrano[2,3-c]pyrazol-4(1H)-one (14e)
Yield: 133 mg (63%); mp 309–310 °C.
IR (KBr): 3125, 3070 (NH), 1630 cm–1 (C=O).
1-(4-Methoxybenzyl)-6-phenylpyrano[2,3-c]pyrazol-4(1H)-one
(1e)
Recrystallization (EtOH) afforded 376 mg (23%) of pink crystals.
MS: m/z (%) = 213 (M+ + 1, 15), 212 (M+, 69), 121 (28), 110 (67),
97 (22), 83 (20), 81 (26), 69 (52), 57 (48), 55 (53), 53 (21), 45 (22),
44 (34), 43 (100).
Mp 220 °C.
Synthesis 2005, No. 15, 2583–2589 © Thieme Stuttgart · New York

PAPER
6-Phenylpyrano[2,3-c]pyrazol-4(1H)-ones
2589
Anal. Calcd for C12H8N2O2 (212.21)·0.2H2O: C, 66.79; H, 3.92; N,
12.98. Found: C, 66.67; H, 3.98; N, 12.61.
(6) Colotta, V.; Catarzi, D.; Varano, F.; Melani, F.; Filacchioni,
G.; Cecchi, L.; Trincavelli, L.; Martini, C.; Lucacchini, A.
Farmaco 1998, 53, 189.
3-Methyl-6-phenylpyrano[2,3-c]pyrazol-4(1H)-one (14f)
Yield: 174 mg (77%); mp 314–315 °C.
(7) Khan, M. A.; Ellis, G. P.; Pagotto, M. C. J. Heterocycl.
Chem. 2001, 38, 193.
(8) Garcia, H.; Iborra, S.; Primo, J.; Miranda, M. A. J. Org.
Chem. 1986, 51, 4432.
(9) McGarry, L. W.; Detty, M. R. J. Org. Chem. 1990, 55, 4349.
(10) Bhat, A. S.; Whetstone, J. L.; Brueggemeier, R. W.
Tetrahedron Lett. 1999, 40, 2469.
(11) Hepworth, J. D.; Gabbutt, C. D.; Heron, B. M. In
Comprehensive Heterocyclic Chemistry II, Vol. 5;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Elsevier: Oxford, 1996, 431.
IR (KBr): 3152 (NH), 1643 cm–1 (C=O).
MS: m/z (%) = 227 (M+ + 1, 24), 226 (M+, 100), 124 (80), 102 (15),
67 (35).
Anal. Calcd for C13H10N2O2 (226.23): C, 69.02; H, 4.46; N, 12.38.
Found: C, 68.76; H, 4.72; N, 12.11.
1-(5-Hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)-3-phenylprop-2-
yn-1-one (12b)
(12) Jensen, B. S. Acta Chem. Scand. 1959, 13, 1668.
(13) Eller, G. A.; Holzer, W. Heterocycles 2004, 63, 2537.
(14) Holzer, W.; Kautsch, C.; Laggner, C.; Claramunt, R. M.;
Pérez-Torralba, M.; Alkorta, I.; Elguero, J. Tetrahedron
2004, 60, 6791.
(15) Begtrup, M.; Boyer, G.; Cabildo, P.; Cativiela, C.;
Claramunt, R. M.; Elguero, J.; Garcia, J. I.; Toiron, C.;
Vedsø, P. Magn. Reson. Chem. 1993, 31, 107.
(16) Braun, S.; Kalinowski, H.-O.; Berger, S. 150 and More
Basic NMR Experiments; Wiley-VCH: Weinheim, 1998.
(17) Bruix, M.; Claramunt, R. M.; Elguero, J.; de Mendoza, J.;
Pascual, C. Spectrosc. Lett. 1984, 17, 757.
(18) Tietze, L. F.; Brumby, T.; Pretor, M.; Remberg, G. J. Org.
Chem. 1988, 53, 810.
(19) Veibel, S.; Eggersen, K.; Linholt, S. C. Acta Chem. Scand.
1954, 8, 768.
(20) Curtius, T. J. Prakt. Chem. 1912, 85, 37.
(21) Michaelis, A. Justus Liebigs Ann. Chem. 1911, 385, 1.
(22) Weissberger, A.; Porter, H. D. J. Am. Chem. Soc. 1943, 65,
52.
(23) Molinari, A.; Oliva, A. J. Heterocycl. Chem. 1996, 33, 479.
(24) Bergmann, F.; Haskelberg, L. J. Am. Chem. Soc. 1941, 63,
2243.
From the mixture 1b/12b the following NMR data for 12b were un-
ambiguously extracted:
1H NMR (CDCl3): d = 9.25 (br s, 1 H, OH), 7.61 (m, 2 H, Ph-2,6),
7.48 (m, 1 H, Ph-4), 7.41 (m, 2 H, Ph-3,5), 3.60 (s, 3 H, NMe), 2.54
(s, 3 H, 3-Me).
13C NMR (CDCl3): d = 172.1 (C=O), 159.2 (pyrazole C-5), 147.8
(pyrazole C-3), 132.7 (Ph-2,6), 130.8 (Ph-4), 128.7 (Ph-3,5), 119.9
(Ph-1), 104.6 (pyrazole C-4), 94.7 (PhC≡), 86.5 (≡CCO), 32.5
(NMe), 14.1 (3-Me).
References
(1) The Flavonoids – Advances in Research Since 1986;
Harborne, J. B., Ed.; Chapman and Hall: London, 1994.
(2) Heinisch, G.; Hollub, C.; Holzer, W. J. Heterocycl. Chem.
1991, 28, 1047.
(3) Holzer, W.; Krca, I. Heterocycles 2003, 60, 2323.
(4) Khan, M. A.; Pagotto, M. C.; Ellis, G. P. Heterocycles 1977,
6, 983.
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4078.
(25) Aroyan, A. A.; Iradyan, N. S. Arm. Khim. Zh. 1971, 24, 338;
Chem. Abstr. 1971, 75, 118088.
Synthesis 2005, No. 15, 2583–2589 © Thieme Stuttgart · New York