X-ray supramolecular structure, NMR spectroscopy and synthesis of 3-methyl-1-phenyl-1H-chromeno[4,3-c]pyrazol-4-ones formed by the unexpected cyclization of 3-[1-(phenylhydrazono)ethyl]-chromen-2-ones

Article abstract of DOI:10.3390/molecules16010915

The molecular structures of nine 3-methyl-1-phenyl-1H-chromeno[4,3-c] pyrazol-4-one isomers, obtained by the oxidative cyclization of the corresponding 1-phenylhydrazono chromen-2-ones with copper acetate as catalyst, are reported. The molecular and supra

Full text of DOI:10.3390/molecules16010915

Molecules 2011, 16, 915-932; doi:10.3390/molecules16010915
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
X-Ray Supramolecular Structure, NMR Spectroscopy and
Synthesis of 3-Methyl-1-phenyl-1H-chromeno[4,3-c]pyrazol-4-
ones Formed by the Unexpected Cyclization of 3-[1-(Phenyl-
hydrazono)ethyl]-chromen-2-ones
Itzia I. Padilla-Martinez 1, Irma Y. Flores-Larios 2, Efren V. García-Baez 1, Jorge Gonzalez 2,
Alejandro Cruz 1 and Francisco J. Martínez-Martinez 2,*
1
Unidad Profesional Interdisciplinaria de Biotecnología del Instituto Politécnico Nacional, Av.
Acueducto s/n, Barrio la Laguna Ticomán 07340, México D. F., Mexico;
E-Mail: ipadillamar@ipn.mx (I.I.P.-M.)
2
Facultad de Ciencias Químicas, Universidad de Colima, km 9 Carretera Coquimatlán-Colima,
Coquimatlán Colima 28400, Mexico
* Author to whom correspondence should be addressed; E-Mail: fjmartin@ucol.mx;
Tel.: +52-312-3161163.
Received: 16 December 2010; in revised form: 8 January 2011 / Accepted: 18 January 2011 /
Published: 21 January 2011
Abstract: The molecular structures of nine 3-methyl-1-phenyl-1H-chromeno[4,3-
c]pyrazol-4-one isomers, obtained by the oxidative cyclization of the corresponding 1-
phenylhydrazono chromen-2-ones with copper acetate as catalyst, are reported. The
molecular and supramolecular structures of the 8-chloro, 8-bromo- and 8-nitro isomers 2b-d,
were established by X-ray diffraction. The halogenated isomers 2b and 2c are isomorphs,
they crystallize as a triclinic system, space group P-1 with two molecules in the asymmetric
unit. Compound 2d crystallizes as a monoclinic system, space group P21/m with two
molecules in the unit cell. The 1-phenyl ring [Cg(4)] is almost perpendicularly positioned to
the chromene-pyrazole ring system. This conformation is in agreement with the anisotropic
NMR shielding effect exerted by the phenyl ring over H-9 in solution. The supramolecular
architecture is almost controlled by C―H···A (A = O, π) and face to face π-stacking
interactions. The observed π-stacking trend between chromene and pyrazole rings is given by
the overlapping between the best donor and acceptor rings in each compound.

Molecules 2011, 16
916
Keywords: oxidative cyclization; benzopyrano-arylhydrazone; benzopyrano-pyrazolone;
pi-stacking
1. Introduction
Pyrazole and its derivatives are shown to possess important biological and pharmaceutical
activities [1,2] such as antimicrobial [3,4], antiviral [5,6], anxiolytic [7,8] and anti-inflammatory [4,9]
activities. They are also useful in agrochemical industry as herbicides [10,11] and insecticides [12].
The 1-phenylchromeno[4,3-c]pyrazol-4-ones are important pyrazole derivatives which have been
used for the synthesis of inmunomodulatory drugs because of their interaction with the benzodiazepine
central receptor [13]. Several methods of synthesis have been reported starting from
arylidenechromones and hydrazine in basic media [14,15]; 3-CN-4-[(o-hydroxy)phenyl]-1-phenyl-3-
methylpyrazole in ethanediol [16]; 4-substituted with –OH and –Cl 1-(phenylhydrazono)-chromen-2-
ones by cyclization in acidic media [17]. To the best of our knowledge, this cyclization is not expected
in the absence of a 4-positioned good leaving group, and the closest reported approach is the
cyclization of 6-chloro-3-{1-[(2,4,6-trichlorophenyl)-hydrazono]-ethyl}-chromen-2-one in the
presence of equimolar quantities of SbCl5 to obtain a 3-methyl-1-(2,4,6-trichlorophenyl)-1H-
chromeno-[4,3-c]pyrazol-4-one similar to 2a in 86% yield [18] and the reaction of 1-(chloro(thiophen-
2-yl)methylene)-2-phenylhydrazine with coumarin at reflux in chloroform and triethylamine to yield 1-
phenyl-3-thiophen-2-yl-1H-chromeno[4,3-c]pyrazol-4-one [19]. In addition, it is worth mentioning
that there are six related structures deposited in the CSD (Version of November 2008) [20] but only
one discussed in the literature.
In this contribution the synthesis of 1-phenyl-chromeno[4,3-c]pyrazol-4-ones 2a-i through the
oxidative cyclization of 3-(phenyl-hydrazono)-chromen-2-ones 1a-i with copper acetate as catalyst is
reported (Scheme 1). The structures in solution by NMR as well as the molecular and supramolecular
structures in the solid state, by monocrystal X-ray diffraction, are discussed.
Scheme 1. Synthesis of 3-methyl-1-phenyl-1H-chromeno[4,3-c]pyrazol-4-ones 2a-i
starting form 3-[1-(phenyl-hydrazono)-ethyl]-chromen-2-ones 1a-i.
N
N
O
H
H
N
X
X
Cu(OAc)2
EtOH
N
O
O
O
Y
Y
2
1
a X = Y = H; b X = Cl, Y = H; c X = Br, Y = H; d Y = NO2, Y = H; e X = OMe, Y = H
f X = H, Y = OMe ; g X = Br, Y = OMe ; h X = Cl, Y = Br ; i X = Y = Cl

Molecules 2011, 16
917
2. Results and Discussion
2.1. Synthesis and Molecular Structure in Solution
In our efforts to crystallize hydrazone 1a from a saturated chloroform solution, crystals of 3-methyl-
1-phenyl-1H-chromeno[4,3-c]pyrazol-4-one 2a were spontaneously formed instead in 30% yield at
RT. It is worthy to note that the cyclization reaction of 1a is not expected, because of the absence of a
4-positioned good leaving group to allow pyrazole ring formation. To ascertain the scope and
limitation of this transformation, several 3-(phenyl-hydrazono)-chromen-2-ones 1b-i were tested but
cyclization did not proceed under the same conditions as for 1a. This result lead us to use
Cu(CH3COO)2·H2O as catalyst, since some examples of copper-catalyzed oxidative amination of
alkynes [21] and azoles [22] via CH and NH coupling have recently been reported. Then, compounds
2a-i were prepared in poor to good yields (50–83%), starting from the corresponding 3-[1-(phenyl-
hydrazono)-ethyl]-chromen-2-ones 1a-i, using Cu(CH3COO)2·H2O as catalyst in 20:1 weight ratio
under mild conditions. In comparison with reported methods, starting from 4-hydroxybenzopyrano-
arylhydrazones, the yields are lower or similar for 2a (76%) [17] and 2b (39%) [15], but in the case of
2c (78%) and 2d (83%) [23] they are significantly enhanced by the use of the copper catalyst.
The reaction should proceed by a simple intramolecular conjugate addition of the Ph-N to the α,β-
unsaturated–C=N+ system, through the intermediate A, and the subsequent oxidation of the resulting
dihydro-pyrazolone B (Scheme 2). This proposal is supported on similar reactions reported in acid
media [24,25]. The formation of the key intermediate A’ would be disfavored either by electro
withdrawing (W) or by electrodonating (D) substituents, which would explain the necessary aid of the
copper catalyst (Scheme 3).
Scheme 2. Proposed mechanism of reaction.
Ph
N
Ph
N
Ph
H
H
N
+
H
N
H
O
N
H
O
N
+
H
O
O
O
O
1
B
A
O
Ph
N
Ph
H
N
H
+
N
N
O
O
O
O
A'
2

Molecules 2011, 16
918
Scheme 3. Resonance structures of 6-substituted-3-[1-(phenyl-hydrazono)-ethyl]-chromen-
2-ones 1a-i with electrowithdrawing (W) or electrodonor (D) groups.
Ph
N
Ph
N
Ph
N
H
O
N
(-)
H
N
O
H
N
O
W
W
W
+
+
O
O
O
Ph
Ph
Ph
N
+
N
N
H
O
N
H
O
N
H
O
N
+
D
D
D
-
-
O
O
O
1
13
Several differences in the H- and C-NMR spectra appear as a consequence of the cyclization.
1
Selected NMR and IR data are listed in Tables 1 and 2 for 1a-i and 2a-i, respectively. The H-NMR
spectra of compounds 2a-i is characterized by the loss of the H-4 signal, usually appearing as a singlet
at δ 7.98–8.17, in the starting compounds 1a-i. In addition, the chemical shift of H-9 in 2a-i appears at
δ 6.62–8.02, more shielded than the former H-5 (δ 6.97–8.51) in 1a-i, because of the anisotropic NMR
shielding effect exerted by the phenyl group which should be almost perpendicular to the 1-phenyl-
chromeno[4,3-c]pyrazol-4-one ring system in compounds 2a-f. The 13C chemical shift of C-3a appears
at 106–107 ppm in compounds 2a-i, whereas the former C-3, in the starting hydrazones 1a-i, is at
127.8–130.6 ppm. Subtle shielding is also observed for C-9a (former C-10) by 7.0 ppm, in agreement
with the aromatic character of the newly formed pyrazole ring. The chemical shift of C-9b (former C-4)
remains almost the same even when in this position was performed the ring closure.
Table 1. Selected NMR and IR spectroscopic data for hydrazones 1a-i.
H
H
N
11
5
4
10
9
3
X
N
6
7
2
O1
O
8
Y
δ 1H
H-5
δ 13C
C-4
ν/cm−1
CO
Comp. H-4
C-2
C-3
C-10
1a
1b
1c
1d
1e
1f
8.16
8.17
8.15
8.40
7.98
8.02
7.95
7.95
7.96
7.81
7.97
8.08
8.84
6.97
7.06
7.34
7.51
7.41
160.2
159.2
159.1
159.2
160.9
160.2
156.3
159.2
159.0
127.9
128.2
128.3
130.6
127.9
127.9
128.8
129.2
129.7
139.8
137.8
137.7
137.7
139.7
140.0
138.3
137.6
137.6
119.9
119.5
116.1
119.9
120.1
120.4
116.9
121.6
121.6
1695, 1596
1703, 1598
1704, 1597
1726, 1604
1698, 1574
1700, 1601
1713, 1599
1707, 1530
1709, 1533
1g
1h
1i

Molecules 2011, 16
919
The saturation of the Me frequency in 1a (δ 2.20, s) gives a NOE effect on proton H-4 (δ 8.16, s)
and NH proton (δ 9.43, s), suggesting an E configuration for the C=N double bond and thus the
predominance in solution of the rotamer I (Scheme 4). Thus the transformation of 1a into 2a implies
the breaking of the double –C=N– bond to a single –C–N– to allow the location of the atoms in the
proper place for cyclization in agreement with the above mentioned copper-catalyzed
oxidative amination.
Table 2. Selected NMR and IR spectroscopic data for pyrazoles 2a-i.
2
N
1
N
9
3
9a
3a
8
X
9b
4
7
5a O5
O
6
Y
δ 1H
H-9
δ 13C
C-9a
ν/cm−1
CO
Comp.
2a
C-4
C-3a
C-9b
7.09
7.03
7.16
8.02
6.50
6.65
6.72
6.90
6.90
158.3
157.6
157.6
156.9
158.4
157.6
156.7
156.2
156.2
106.5
106.8
106.8
106.8
106.7
106.6
106.8
106.8
106.8
112.0
113.1
113.7
112.4
112.1
112.7
113.7
112.6
114.0
141.9
140.7
140.6
143.6
141.9
142.1
140.1
140.2
140.2
1726
1743
1742
1756
1734
1743
1744
1749
1750
2b
2c
2d
2e
2f
2g
2h
2i
Scheme 4. Rotamers I-IV in solution and isomerization from E to Z in acid media.
H
..
N
N
..
Ph
Ph
N
N
H
O
O
O
O
E (III)
E (IV)
Ph
Ph
..
N
+
N
H
N
..
N
..
H
N
H
H
H
+
N
Ph
O
O
O
O
O
O
E (I)
A
E (II)
Ph
Ph
Ph
N
..
N
H
N
..
+
N
..
N
N
..
H
H
H
..
H
H
+
+
O
O
O
O
O
O
A'
A'
Z

Molecules 2011, 16
920
2.2. Molecular and Supramolecular Structure in Solid State
1-Phenyl-chromeno[4,3-c]pyrazol-4-ones 2b-d were crystallized from saturated DMF solutions.
The halogenated isomers 2b,c crystallize as a triclinic system, space group P-1 with two molecules in
the asymmetric unit. Compound 2d crystallizes as a monoclinic system, space group P21/m with two
molecules in the unit cell. A summary of bond lengths and angles are listed in Table 3 and crystal data
and structure refinement for 2b-d are listed in Table 4. As in other coumarin derivatives, the
replacement of Cl by Br does not alter the crystal packing [26]. All the atoms of pyrazole and
chromenone rings lie in a single plane within the limits of experimental error. The 1-phenyl ring in
compounds 2b-d is sterically hindered and appears twisted by 71.9(2)º, 74.7(5)º and 92.1(2)º,
respectively, from the three ring fused coplanar chromeno[4,3-c]pyrazol-4-one system in agreement
with the conformation observed in solution (vide supra). The torsion angle between both planes is very
close to that observed for 1-phenyl-1H-chromeno[4,3-c]pyrazol-4-one of 73.1(6)º [27]. However, in
compound 2d the 1-phenyl ring [Cg(4)] is almost perpendicularly positioned, thus a symmetry plane
cut the molecule through its equatorial plane and only one half of the phenyl ring is observed. This
conformation is in agreement with the observed anisotropic NMR shielding effect exerted by the
phenyl ring over H-9 in solution.
The molecular structures of the three isomers are very similar and the major differences among
them arise from the nature of the 8-substituent, Figure 1. A brief comparison with the starting
coumarins points out the lengthening of C9a―C9b bond length to 1.439(5) Å (mean value of 2b-d),
from a mean reported value of 1.35 Å (C3―C4 in the former coumarins) [28], in agreement with a
delocalized electronic character of the pyrazole ring.
Figure 1. The molecular structures of 2b-d, from left to right, showing the atom-labelling
scheme. Displacement ellipsoids are drawn at the 30% probability level and H atoms are
shown as small spheres of arbitrary radii.
Because of the arrangement of the aromatic rings, the supramolecular architecture is almost
controlled by C―H···A (A = O, π) and face to face π-stacking interactions, whose geometrical
parameters are listed in Table 4. In the solid state C9―H9···Cg(4) and C9···Cg(4) distances, and
C9―H9··· Cg(4) angle, suggest an intramolecular C―H···π interaction S(6) in 2d, Figure 2. Even
when these geometric parameters are similar among 2a-d, only those corresponding to 2d lie are in the
proper range to be considered as such [29].

Molecules 2011, 16
Table 3. Selected bond lengths and angles from X-ray data of compounds 2b-d.
921
1
2
3
N
N
9
6
9b
X
9a
8
3a
7
5a
4
O
O
5
2b X = Cl
2c X = Br
2d X = NO2
Atoms
Bond lengths (Å)
X(8)―C(8)
1.732(2)
1.200(2)
1.385(2)
1.382(2)
1.376(2)
1.346(2)
1.433(2)
1.321(2)
1.408(3)
1.435(3)
1.384(2)
1.402(3)
1.437(3)
1.894(4)
1.197(6)
1.385(6)
1.379(5)
1.374(5)
1.353(5)
1.428(6)
1.315(6)
1.400(7)
1.441(6)
1.378(5)
1.389(6)
1.438(5)
1.466(2)
1.189(2)
1.404(2)
1.374(2)
1.379(2)
1.345(2)
1.433(2)
1.315(2)
1.408(3)
1.441(3)
1.380(2)
1.403(3)
1.442(2)
1.195(3)
1.204(2)
O(4)―C(4)
O(5)―C(4)
O(5)―C(5A)
N(1)―N(2)
N(1)―C(9B)
N(1)―C(10)
N(2)―C(3)
C(3)―C(3A)
C(3A)―C(4)
C(3A)―C(9B)
C(5A)―C(9A)
C(9A)―C(9B)
O(8B)―N(8)
O(8A)―N(8)
Bond angles (º)
C(4)―O(5)―C(5A)
N(2)―N(1)―C(9B)
N(2)―N(1)―C(10)
123.60(15)
111.82(14)
118.91(15)
123.8(4)
111.3(3)
119.8(4)
128.9(3)
105.9(4)
131.9(4)
106.5(4)
117.0(4)
114.5(4)
119.0(4)
105.9(3)
124.12(15)
111.53(12)
121.02(14)
127.44(14)
105.81(15)
132.13(14)
106.24(15)
115.98(18)
114.44(14)
119.30(18)
106.10(15)
C(9B)―N(1)―C(10) 129.18(15)
N(1)―N(2)―C(3)
C(3)―C(3A)―C(4)
105.86(15)
131.53(15)
C(3)―C(3A)―C(9B) 106.46(16)
O(4)―C(4)―O(5)
O(5)―C(4)―C(3A)
X(8)―C(8)―C(7)
116.68(17)
114.98(14)
119.13(15)
N(1)―C(9B)―C(3A) 105.87(15)

Molecules 2011, 16
922
Table 4. Geometric parameters associated with D―H···A (A = O, π) interactions for
compounds 2a–d.
Comp.
D―H···Aa (symmetry code)
H···A/Å
D···A/Å
D―H···A/º
2ab
2b
C6―H6···Cg(4) (x, y, 1 + z)
C9―H9···Cg(4) (x, y, z)
2.89
3.820(3)
3.825(3)
3.6659(18)
3.265(7)
3.443(6)
3.460(2)
3.535(2)
3.340(7)
3.450(6)
3.631(5)
3.633(5)
3.464(3)
3.6999(3)
3.632(3)
178
150(2)
157
155
157
161
136
161
156
167
137
179
171
152
2.99
C16―H16A···Cg(3) (−x, −½ + y, −z)
C13―H13···O4 (x, y, z − 1)
C15―H15···O5 (2 − x, 1 − y,1 − z)
C7―H7···Cg(4) (x, y − 1, z)
C16―H16C···Cg(3) (1 − x, 1 − y, −z)
C13―H13···O4 (x, y, z + 1)
C15―H15···O5 (−x, 1 − y, −z)
C7―H7···Cg(4) (x, 1 + y, z)
C16―H16B···Cg(3) (1 − x, 1 − y, −z)
C13―H13···O4 (x, y, z + 1)
C7―H7···Cg(4) (1 + x, y, z)
C9―H9···Cg(4)
2.75(3)
2.400
2.570
2.57
2.78
2c
2.450
2.580
2.72
2.87
2d
2.53
2.78
2.79
a Cg(3) the centroid of the benzenoid ring (C5AC9AC9C8C7C6C5A) and Cg(4) the centroid of the
phenyl ring (C10―C15); b From reference 32.
Figure 2. Supramolecular structure of compound 2d in the ac plane. S(6) intramolecular
ring and C(8) chain forming bifacial C―H···π interactions, C(12) chain and R5 (25) ring
4
motifs are also observed.

Molecules 2011, 16
923
The first dimension (1-D) is directed by C13—H13···O4C4 interactions, between an aromatic
hydrogen and the oxygen of the lactone group, developing C(10) chains along the direction of the c
axis in 2b-d. Molecules of 2b,c self assemble in the bc plane and 2d in the ac plane through
C7―H7···Cg(4) interactions forming C(8) chains. The 2-D assembly is thus described as a R5 (25)
4
ring, in agreement with the graph set notation conventions [30], Figure 2. 2-D assembled monolayers
of 2b,c and 2d are face-to-face π-stacked developing the 3-D along the a and the b axis, respectively.
A C(12) chain motif complements the 3-D in compounds 2b,c through the participation of
C15―H15···O5 and C16―H16B···Cg(3) contacts running along the direction of the a axis (Figure 3).
Figure 3. Intermolecular interactions for molecule 2c in the ac plane. C(12) chain motif is
observed through the participation of C15―H15···O5 and C16―H16B···Cg(3) contacts
running along the direction of the a axis.
The participation of the N-phenyl ring [Cg(4)] in π-stacking is restricted to C―H···π interactions
because of its disposition out of the plane. In contrast, the remaining pyrazole [Cg(1)], pyrone [Cg(2)]
and benzenoid [Cg(3)] rings are lying in the same plane and thus are appropriately positioned for π-
stacking. The geometric parameters associated with π-stacking interactions are listed in Table 5.
Pyrazole ring is stacked with pyrone ring in compound 2a [Cg(1)···Cg(2)] [31], it further appears
stacked with the Cl- or Br- substituted benzenoid ring [Cg(1)···Cg(3)] in compounds 2b and 2c. In both
compounds, the π-stacking between pyrone and benzenoid rings, typical of coumarins, is also observed
[Cg(2)···Cg(3)]. However, in the case of compound 2d only Cg(1) and Cg(3) are stacked, the EW
group 8-NO2 diminishes the charge transfer capability of the benzenoid ring, enabling the formation of
π-stacked centrosymmetric pairs with pirazole ring, the best charge transfer donor ring. In the other
hand, the donor-acceptor capabilities of the benzenoid ring changes on going from 2a to 2d, according
with the increase of the EW nature of the 8-substituent. Thus, the observed π-stacking trend between
the rings is given by the overlapping between the best donor and acceptor ring in each molecule. This
trend is consistent with those observed for other CCDC deposited structures [32], whose molecular and
supramolecular analysis is missing (LOLZER, LOLZOB, LOLZUH, LOMBAQ, LOMBEU).
Compounds 2a-2d are functional isomers but only 2b and 2c are isomorphous, however the

Molecules 2011, 16
924
supramolecular structure of all of them is almost the same, varying only in the π-stacked rings and the
propagating directions of the supramolecular motifs.
Table 5. Geometric parameters associated with π···π stacking interactions for compounds 2a–2d.
Intercentroid
distance/A°
Dihedral
angle/º
Interplanar
distance/A°
Comp.
Centroidsa (symmetry code)
2ab
2b
Cg(1)···Cg(2) (−x, −½ + y, −z)
Cg(1) · Cg(2) (1 − x, 1 − y, 1 − z)
Cg(1)···Cg(3) (2 − x, 1 − y, 1 − z)
Cg(2)···Cg(3) (2 − x, 1 − y, 1 − z)
Cg(1)···Cg(2) (1 − x, 1 − y, 1 − z)
Cg(1)···Cg(3) (−x, 1 − y, −z)
3.8508(9)
3.6117(10)
3.6664(11)
3.6345(11)
3.708(2)
0.000
3.4916(1)
3.3563(7)
3.3697(7)
3.4103(6)
3.4328(17)
3.4367(17)
3.4103(6)
3.5032(7)
0.30(8)
1.33(9)
1.23(8)
0.3(2)
2c
3.727(2)
1.0(2)
Cg(2)···Cg(3) (−x, 1 − y, −z)
3.6345(11)
3.8523(8)
1.23(8)
0.02(8)
2d
Cg(1)···Cg(3) (1 − x, −½ + y, −z)
a
Cg(1) is the centroid of the pyrazole ring (N1N2C3C3AC9B), Cg(2) the centroid of the pyrone
ring (O5C4C3AC9BC9AC5A), Cg(3) the centroid of the benzenoid ring (C5AC9AC9C8C7C6C5A)
and Cg(4) the centroid of the phenyl ring (C10-C15); b From reference 32 (LOLZUH).
It is noteworthy that in these compounds, neither –Cl, –Br or –NO2 substituents in the benzenoid ring
nor the lactone carbonyl, are involved in dipole-dipole interactions [33,34]. This observation contrasts
with most of the coumarins studied by our group, whose supramolecular architectures are strongly
influenced by the participation of these groups in multicentered interactions [35,36].
3. Experimental
3.1. Materials and Methods
All chemicals and solvents were of reagent grade and used as received. The starting coumarins were
synthesized as reported elsewhere [33]. Melting points were measured on an Electrothermal IA 9100
apparatus and were uncorrected. IR spectra were recorded neat using a Varian 3100 FT-IR
EXCALIBUR series spectrophotometer. 1H- and 13C-NMR spectra were recorded on a Varian Mercury
300 (1H, 300.08; 13C, 75.46 MHz) instrument in CDCl3 solutions, unless otherwise is specified,
chemical shifts are in ppm and coupling constants in Hz, measured with SiMe4 as internal reference.
Mass spectra were obtained in a GC-MS system (Saturn 2100T) with an electron ionization mode
(Hewlett-Packard 5972 series) using HP5. Elemental analyses were performed on a Perkin-Elmer 2400
elemental analyzer.
3.2. X-ray Data Collection and Structure Determination
Crystals suitable for X-ray analysis were obtained by slow crystallization from saturated DMF
solutions. Single-crystal X-ray diffraction data for molecules 2b-d were collected on a Bruker Apex II
area detector diffractometer at 293 K with Mo Kα radiation, λ = 0.71073 Å. A semiempirical absorption
correction was applied using SADABS [37], and the program SAINT [37] was used for integration of the
diffraction profiles. The structures were solved by direct methods using SHELXS97 [38] program of

Molecules 2011, 16
925
WinGX package [39]. The final refinement was performed by full-matrix least-squares methods on F2
with SHELXL97 program [37]. H atoms on C, N and O were positioned geometrically and treated as
riding atoms, with C―H = 0.93–0.98 Å, and with Uiso(H) = 1.2Ueq(C). Mercury was used for
visualization, molecular graphics and analysis of crystal structures [40], software used to prepare
material for publication was PLATON [41]. Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication CCDC numbers 766071 2b, 766070 2c, 766072 2d. Crystal data and details
concerning data collection and structure refinement are given in Table 6.
Table 6. Crystal data and structure refinement details for 2b-d.
2b
2c
2d
Chemical formula
Mw
C17H11N2O2Cl1
310.7
C17H11N2O2Br1
355.19
C17H11N3O4
321.2
Cell setting, Space group Triclinic, P-1
Triclinic, P-1
7.1681(8)
9.3210(11)
11.8449(14)
109.820(2)
97.016(2)
96.891(2)
727.83(15)
2
Monoclinic, P 21/m
a (A°)
7.1177 (8)
9.2540 (10)
11.7266(13)
110.450(2)
98.468(2)
97.748(2)
701.14(8)
2
9.4294(11)
b (A°)
7.0064(8)
c (A°)
12.0294(14)
α (º)
β (º)
90
112.826(2)
γ (º)
90
V (Å 3)
732.50(7)
Z
2
Density (mg cm−3)
μ (mm−1)
1.471
1.621
1.46
0.281
2.831
0.11
Crystal form, color
Crystal size (mm3)
No. of measured,
independent and
observed reflections
Rint
Block, pale yellow
0.48 × 0.22 × 0.19
6092
Block, colorless
0.40 × 0.20 × 0.20
7652
Block, pale yellow
0.45 × 0.33 × 0.30
4922
3160
2853
2514
2840
2013
2261
0.024
0.054
0.024
θ
max(°)
28.3
26.0
28.3
Refinement on
R[F2 > 2σ(F2)],
wR(F2),S
F2
F2
F2
0.048, 0.116, 1.089
0.057, 0.116, 1.029
0.043, 0.122, 1.056
No. of reflections
No. of parameters
Weighting scheme
3160
200
2853
200
2514
218
1/[σ2(Fo2) + (0.0542P)2 1/[σ2(Fo2) + (0.0542P)2 + 1/[σ2(Fo2) + (0.0576P)2
+ 0.2899P]
0.1266P]
+ 0.321P]
P = (Fo2 + 2Fc2)/3
0.411, −0.281
P = (Fo2 + 2Fc2)/3
0.670, −0.322
P = (Fo2 + 2Fc2)/3
0.194, −0.199
Δρmax, Δρmin (eÅ−3)

Molecules 2011, 16
926
3.3. General Methods of Synthesis
6-Substituted-3-[1-(phenylhydrazono)-ethyl]-chromen-2-ones 1a-i. were synthesized from phenyl-
hydrazine and 0.5 g of the corresponding coumarins, following standard procedures. The syntheses of
compounds 2a [15,17], 2b [15], 2c, 2d [23] have been reported elsewhere, albeit with lack of some
spectroscopic data, thus for completeness purposes they are included but elemental analysis was
performed only to the new compounds 2e-f.
3-[1-(Phenylhydrazono)-ethyl]-chromen-2-one (1a). Obtained from 3-acetyl-2H-1-benzopyran-2-one
(0.5 g, 2.66 mmol) and phenylhydrazine (0.26 mL, 2.66 mmol) as an orange solid in 85% yield (0.633 g,
2.26 mmol), mp = 193–196 °C, IR νneat (cm−1): 3295 (N-H), 1695 (OC=O), 1596 (C=O), 1255, 1155
1
(C-O). H-NMR (DMSO-d6) δ: 9.43 (s, 1H, NH), 8.16 (s, 1H, H-4), 7.81 (d, 1H, H-5, 3J = 7.7), 7.57
3
3
3
(dd, 1H, H-7, J = 8.0, 7.5), 7.38 (d, 1H, H-8, J = 8.3, J = 8.3), 7.33 (t, 1H, H-6, 3J = 8.0, 7.6,
4J = 2.2), 6.74–7.24 (m, 5H, Ph), 2.20 (s, 3H, CH3). 13C-NMR (DMSO-d6) δ: 160.2 (C-2), 153.6 (C-9),
146.2 (C-11), 139.8 (C-4), 139.2 (Ci), 132.2 (C-7), 129.5 (C-5), 129.5 (Cm), 127.9 (C-3), 125.2 (C-6),
120.0 (Cp), 116.4 (C-8), 119.9 (C-10), 113.7 (Co), 15.8 (Me). Anal. Calcd for C17H14N2O2; C, 73.37;
H, 5.07; N, 10.12. Found: C, 73.27; H, 4.91; N, 10.12. m/z = 277.1 (M, 22%), 77 (20%).
6-Chloro-3-[1-(phenylhydrazono)-ethyl]-chromen-2-one (1b). Obtained from 3-acetyl-6-cloro-2H-1-
benzopyran-2-one (0.5 g, 2.22 mmol) and phenylhydrazine (0.22 mL, 2.22 mmol) as an orange solid in
82% yield (0.578 g, 1.83 mmol), mp = 184–188 °C, IR νneat (cm−1): 3300 (N-H), 1703 (OC=O), 1598
1
(C=O), 1251, 1155 (C-O), 810 (C-Cl). H-NMR (DMSO-d6) δ: 9.49 (s, 1H, NH), 8.17 (s, 1H, H-4),
7.97 (d, 1H, H-5, 4J = 2.3), 7.57 (dd, 1H, H-7, 3J = 8.8, 4J = 2.3), 7.43 (d, 1H, H-8, 3J = 8.8), 6.75–7.25
(m, 5H, Ph), 2.20 (s, 3H, CH3). 13C-NMR (DMSO-d6) δ: 159.2 (C-2), 151.6 (C-9), 145.4 (C-11), 138.1
(Ci), 137.8 (C-4), 130.9 (C-7), 129.0 (C-6), 128.8 (Cm), 128.2 (C-3), 127.7 (C-5), 120.8 (Cp), 119.5
(C-10), 117.8 (C-8), 113.1 (Co), 15.0 (Me). m/z = 312 (M, 30%), 313 (8%), 240 (8%), 77 (28%).
6-Bromo-3-[1-(phenylhydrazono)-ethyl]-chromen-2-one (1c). Obtained from 3-acetyl-6-bromo-2H-1-
benzopyran-2-one (0.5 g, 1.87 mmol) and phenylhydrazine (0.18 mL, 1.87 mmol) as an orange solid in
67% yield, (0.451 g, 1.25 mmol), mp = 184–186 °C, IR νneat (cm−1): 3301 (N-H), 1704 (OC=O), 1597
1
(C=O), 1250, 1158 (C-O), 681 (C-Br). H-NMR (DMSO-d6) δ: 9.48 (s, 1H, NH), 8.15 (s, 1H, H-4),
4
3
4
8.08 (d, 1H, H-5, J = 2.3), 7.68 (dd, 1H, H-7, J = 8.8, J = 2.3), 7.35 (d, 1H, H-8,
3J = 8.8), 6.75–7.23 (m, 5H, Ph), 2.17 (s, 3H, CH3). C-NMR (DMSO-d6) δ: 159.1 (C-2), 152.0 (C-
13
9), 145.4 (C-11), 138.1 (Ci), 137.7 (C-4), 133.8 (C-7), 130.8 (C-5), 128.9 (Cm), 128.3 (C-3), 121.3 (C-
6), 119.5 (Cp), 118.1 (C-8), 116.1 (C-10), 113.1 (Co), 15.0 (Me). m/z = 356 (M, 100%), 358 (30%),
357 (20%), 278 (5%), 77 (27%).
6-Nitro-3-[1-(phenylhydrazono)-ethyl]-chromen-2-one (1d). Obtained from 3-acetyl-6-nitro-2H-1-
benzopyran-2-one (0.5 g, 2.14 mmol) and phenylhydrazine (0.21 mL, 2.14 mmol) as an orange solid in
53% yield (0.370 g, 1.14 mmol), mp = 204–206 °C, IR νneat (cm−1): 3328 (N-H), 1726 (OC=O), 1604
1
(C=O), 1516, 1340 (C-NO2), 1239, 1113 (C-O). H-NMR (DMSO-d6) δ: 9.55 (s, 1H, NH), 8.84 (d,
1H, H-5, 4J = 2.6), 8.35 (dd, 1H, H-7, 3J = 9.1, 4J = 2.6), 8.40 (s, 1H, H-4), 7.60 (d, 1H, H-8, 3J = 9.1),
6.76-7.78 (5H, -Ph), 2.20 (s, 3H, CH3). 13C-NMR (DMSO-d6) δ: 159.2 (C-2), 157.1 (C-9), 144.4 (C-11),

Molecules 2011, 16
927
144.2 (C-6), 137.7 (C-4), 137.5 (Ci), 130.6 (C-3), 129.6 (Cm), 126.1 (C-7), 124.2 (C-5), 121.5 (Cp),
119.9 (C-10), 117.7 (C-8), 113.6 (Co), 13.7 (Me). m/z = 322 (M, 20%), 246 (5%), 77 (15%).
6-Methoxy-3-[1-(phenylhydrazono)-ethyl]-chromen-2-one (1e). Obtained from 3-acetyl-6-methoxy-
2H-1-benzopyran-2-one (0.5 g, 2.29 mmol) and phenylhydrazine (0.23 mL, 2.29 mmol) as an orange
solid in 72% yield (0.512 g, 1.65 mmol), mp = 147–149 °C, IR νneat (cm−1): 3303 (N-H), 1698
(OC=O), 1574 (C=O), 1243, 1134 (C-O). 1H-NMR δ: 7.98 (s, 1H, H-4), 7.63 (s, 1H, NH), 7.24 (d, 1H,
3
3
4
H-8, J = 8.1), 7.05 (dd, 1H, H-7, J = 9.1, J = 2.1), 6.86–7.30 (m, 5H,-Ph), 6.97 (d, 1H, H-5,
4J = 2.4), 2.28 (s, 3H, CH3). 13C-NMR δ: 160.9 (C-2), 156.3 (C-6), 148.4 (C-9), 144.8 (C-11), 139.7 (C-4),
139.3 (Ci), 129.5 (Cm), 127.9 (C-3), 120.9 (Cp), 120.1 (C-10), 119.7 (C-7), 117.6 (C-8), 110.2 (C-5),
113.5 (Co), 14.1 (Me). m/z = 307 (M, 24%), 230 (5%), 77 (15%).
8-Methoxy-3-[1-(phenylhydrazono)-ethyl]-chromen-2-one (1f). Obtained from 3-acetyl-8-methoxy-
2H-1-benzopyran-2-one (0.5 g, 2.29 mmol) and phenylhydrazine (0.23 mL, 2.29 mmol) as an orange
solid in 91% yield (0.647 g, 2.09 mmol), mp = 152–156 °C, IR νneat (cm−1): 3306 (N-H), 1700
(OC=O), 1601 (C=O), 1263, 1160 (C-O). 1H-NMR δ: 8.02 (s, 1H, H-4), 7.59 (s, 1H, NH), 7.28 (d, 1H,
3
3
3
H-7, J = 7.7), 7.17 (t, 1H, H-6, J = 7.7), 7.06 (d, 1H, H-5, J = 7.7), 6.87-7.36 (m, 5H, Ph), 2.29 (s,
13
3H, CH3). C-NMR δ: 160.2 (C-2), 147.1 (C-8), 144.7 (C-11), 140.0 (C-4), 143.5 (C-9), 139.3 (Ci),
129.5 (Cm), 127.9 (C-3), 124.6 (C-5), 120.9 (C-6), 120.4 (C-10), 120.0 (Cp), 113.5 (Co), 113.4 (C-7),
14.1 (Me). m/z = 306.2 (M, 100%), 230 (5%), 77 (17%).
6-Bromo-8-methoxy-3-[1-(phenylhydrazono)-ethyl]-chromen-2-one (1g). Obtained from 3-acetyl-6-
bromo-8-methoxy-2H-1-benzopyran-2-one (0.5 g, 1.68 mmol) and phenylhydrazine (0.16 mL, 1.68
mmol) as an orange solid in 74% (0.485 g, 1.25 mmol), mp = 185–188 °C, IR νneat (cm−1) 3312 (N-H),
1713 (OC=O), 1599 (C=N), 1258 (C-O). 1H-NMR δ: 7.95 (s, 1H, H-4), 7.58 (s, 1H, NH), 7.34 (s, 1H,
13
H-5), 7.24 (s, 1H, H-7), 6.84–7.29 (m, 5H, Ph), 2.28 (s, 3H, CH3), 3.96 (s, 3H, OMe). C-NMR δ:
156.3 (C-2), 151.6 (C-8), 147.8 (C-9), 144.5 (C-11), 138.5 (C-13), 138.3 (C-4), 129.5 (Cm), 128.8 (C-
3), 121.1 (Cp), 122.0 (C-5), 121.4 (C-6), 116.9 (C-10), 116.5 (C-7), 113.5 (Co), 56.7 (MeO–), 13.8 (Me).
m/z = 386 (M, 100%), 308 (5%), 77 (20%).
8-Bromo-6-chloro-3-[1-(phenylhydrazono)-ethyl]-chromen-2-one (1h). Obtained from 3-acetyl-8-
bromo-6-chloro-2H-1-benzopyran-2-one (0.5 g, 1.66 mmol) and phenylhydrazine (0.16 mL, 1.66
mmol) as an orange solid in 84% yield (0.548 g, 1.39 mmol), mp = 199–201 °C, IR νneat (cm−1) 3312
(N-H), 1707 (OC=O), 1530 (C=N), 1248 (C-O). 1H-NMR δ: 7.95 (s, 1H, H-4), 7.62 (s, 1H, NH), 7.71
(d, 1H, H-7, 4J = 2.4), 7.51 (d, 1H, H-5, 4J = 2.4), 6.90-7.29 (m, 5H, Ph.), 2.29 (s, 3H, CH3). 13C-NMR
δ:159.2 (C-2), 144.3 (C-11), 140.2 (C-9), 137.8.5 (C-13), 137.6 (C-4), 134.2 (C-7), 130.1 (C-6), 129.6
(C-14), 129.2 (C-3), 126.9 (C-5), 121.6 (C-10), 113.5 (C-15), 110.7 (C-8), 13.8 (Me).
m/z = 390.1 (M, 100%), 391.1 (30%), 392.0 (25%), 315 (5%), 76.9 (30%).
6,8-Dichloro-3-[1-(phenylhydrazono)-ethyl]-chromen-2-one (1i). Obtained from 3-acetyl-6,8-dichloro-
2H-1-benzopyran-2-one (0.5 g, 1.95 mmol) and phenylhydrazine (0.19 mL, 1.95 mmol) as an orange
solid in 82% yield (0.557 mg, 1.60 mmol), mp = 196–198 °C, IR νneat (cm−1) 3311 (N-H), 1709
(OC=O), 1533 (C=N), 1162 (C-O). 1H-NMR δ: 7.96 (s, 1H, H-4), 7.62 (s, 1H, NH), 7.55 (d, 1H, H-7,

Molecules 2011, 16
928
4J = 2.2), 7.41 (2, 1H, H-5, 4J = 2.2), 6.94–7.30 (m, 5H, Ph), 2.29 (s, 3H, CH3). 13C-NMR δ: 159.0 (C-
2), 151.3 (C-9), 144.3 (C-11), 138.8 (C-13), 137.6 (C-4), 134.2 (C-6), 131.3 (C-7), 129.8 (Cm), 129.7
(C-3), 124.2 (C-8), 121.6 (C-10), 121.3 (Cp), 113.6 (Co), 13.8 (Me). m/z = 347 (M, 20%), 346.3
(55%), 274 (8%), 77 (30%).
3-Methyl-1-phenyl-1H-chromeno[4,3-c]pyrazol-4-one (2a). Cu(CH3COO)2·H2O (0.025 g, 0.125
mmol) was dissolved in ethyl alcohol (20 mL) and added to a solution of 1a (0.500 g, 1.78 mmol) and
ethyl alcohol (30 mL). The mixture was refluxed during 3 h, the resulting solid was filtered, washed
with cold ethyl alcohol (5 mL) and several times with distilled water, air dried and recrystallized from
ethyl acetate to obtain 0.372 mg (1.34 mmol) of 2a as a white powder in 76% yield, mp = 227–230 °C,
IR νneat (cm−1): 1726 (OC=O), 1272, 1202 (C-O). 1H-NMR δ: 7.44 (t, 1H, H-7, 3J = 8.6, 4J = 1.6 Hz),
7.40 (d, 1H, H-6, 3J = 8.1), 7.09 (d, 1H, H-9, 3J = 7.9), 7.02 (t, 1H, H-8, 3J = 7.9, 4J = 1.6), 7.52–7.62
13
(m, 5H, Ph), 2.67 (s, 3H, CH3). C-NMR δ: 158.3 (C-4), 153.4 (C-5a), 151.0 (C-3), 141.9 (C-9b),
139.5 (Ci), 131.3 (C-7), 130.4 (Cp), 130.1 (Co), 127.0 (Cm), 124.1 (C-8), 122.6 (C-9), 118.2 (C-6),
112.0 (C-9a), 106.5 (C-3a), 13.1 (Me). m/z = 276.2 (M, 100%), 247.3 (5%), 206.2 (14%), 77.0 (16%).
8-Chloro-3-methyl-1-phenyl-1H-chromeno[4,3-c]pyrazol-4-one (2b). Obtained as described for 2a
starting from 1b (0.500 g, 1.59 mmol) to give 2b (0.343 g, 1.10 mmol, 69% yield) as a pale yellow
1
powder, mp = 280–283 °C, IR νneat (cm−1): 1743 (OC=O), 1204 (C-O), 814 (C-Cl). H-NMR δ: 7.58
3
4
3
4
(dd, 1H, H-7 J = 8.8, J = 1.9), 7.35 (d, 1H, H-6 J = 8.8), 7.03 (d, 1H, H-9 J = 1.9), 7.38–7.65 (m,
13
5H, Ph), 2.68 (s, 3H, CH3). C-NMR δ: 157.6 (C-4), 151.8 (C-5a), 151.2 (C-3), 140.7 (C-9b), 139.0
(Ci), 131.2 (C-7), 130.8 (C-p), 130.2 (C-o), 129.5 (C-8), 126.9 (C-m), 122.3 (C-9), 119.6 (C-6), 113.1
(C-9a), 106.8 (C-3a), 13.1 (Me). m/z = 310.2 (M, 100%), 311.0 (70%), 309.3 (45%), 275.3 (5%), 77
(22%).
8-Bromo-3-methyl-1-phenyl-1H-chromeno[4,3-c]pyrazol-4-one (2c).. Obtained as described for 2a
starting from 1c (0.500 g, 1.39 mmol) to afford 2c (0.388 g, 1.09 mmol, 78% yield) as a white powder,
1
mp = 278–280 °C, IR νneat (cm−1): 1742 (OC=O), 1266, 1203 (C-O). H-NMR δ: 7.52 (dd, 1H, H-7),
7.28 (d, 1H, H-6, 3J = 8.9), 7.16 (d, 1H, H-9 4J = 2.4), 7.54–7.78 (m, 5H, Ph), 2.67 (s, 3H, CH3). 13C-
NMR δ: 157.6 (C-4), 152.3 (C-5a), 151.2 (C-3), 140.6 (C-9b), 139.0 (Ci), 134.0 (C-7), 130.8 (Cp),
130.3 (Co), 126.9 (Cm), 125.3 (C-9), 119.9 (C-8), 116.8 (C-6), 113.7 (C-9a), 106.8 (C-3a), 13.1
(Me).m/z = 354.3 (M, 80%), 356.1 (100%), 356.9 (35%), 358.0 (5%), 274.3 (5%), 77 (25).
3-Methyl-8-nitro-1-phenyl-1H-chromeno[4,3-c]pyrazol-4-one (2d). Obtained as described for 2a
starting from 1d (0.500 g, 1.54 mmol) to give 2d (0.412 g, 1.28 mmol, 83% yield) as a pale yellow
powder, mp = 248–254 °C, IR νneat (cm−1): 1756 (OC=O), 1259, 1207 (C-O), 1519 (C-NO2). 1H-NMR
δ: 8.31 (dd, 1H, H-7, 3J = 9.1, 4J = 2.6), 8.02 (d, 1H, H-9 4J = 2.6), 7.55 (d, 1H, H-6, 3J = 9.1), 7.56–
7.72 (m, 5H, Ph), 2.71 (s, 3H, CH3). 13C-NMR δ: 156.9 (C-4), 156.6 (C-5a), 151.5 (C-3), 143.6 (C-9b),
140.2 (C-8), 138.6 (Ci), 131.2 (Cp), 130.6 (Co), 126.7 (Cm), 126.0 (C-7), 119.3 (C-9), 118.8 (C-6),
112.4 (C-9a), 106.8 (C-3a), 13.1 (Me). m/z = 321.0 (M, 100%), 320.2 (25%), 322.9 (5%), 275.3 (10%),
77 (21%).

Molecules 2011, 16
929
8-Methoxy-3-methyl-1-phenyl-1H-chromeno[4,3-c]pyrazol-4-one (2e). Obtained as described for 2a
starting from 1e (0.500 g, 1.61 mmol) to obtain 2e (0.258 g, 0.84 mmol, 52% yield) as a white powder,
1
mp = 232–234 °C, IR νneat (cm−1): 1734 (OC=O), 1238, 1203 (C-O). H-NMR δ: 7.32 (d, 1H, H-6,
3J = 9.0), 6.98 (dd, 1H, H-7, 3J = 9.0, 4J = 3.1), 6.50 (d, 1H, H-9, 4J = 3.1), 7.63-7.54 (m, 5H, Ph), 2.68
13
(s, 3H, CH3). C-NMR δ: 158.4 (C-4), 155.6 (C-8), 151.0 (C-3), 147.9 (C-5a), 141.9 (C-9b), 139.5
(Ci), 130.5 (Co), 130.5 (Cp), 127.4 (Cm), 119.2 (C-7), 118.8 (C-6), 112.1 (C-9a), 106.7 (C-3a), 105.5
(C-9), 13.4 (Me). m/z = 306.1 (M, 100%), 291.3 (28%), 277 (3%), 77 (22%). Anal. Calcd. for
C18H14N2O3; C, 70.58; H, 4.61; N, 9.14. Found: C, 70.22; H, 4.50; N, 9.00.
6-Methoxy-3-methyl-1-phenyl-1H-chromeno[4,3-c]pyrazol-4-one (2f). Obtained as described for 2a
starting from 1f (0.500 g, 1.61 mmol) to give 2f (0.248 g, 0.806 mmol, 50% yield) as a white powder,
1
mp = 238–240 °C, IR νneat (cm−1): 1743 (OC=O), 1273, 1207 (C-O). H-NMR δ: 7.02 (dd, 1H, H-7,
3J = 8.2, 7.6), 6.97 (t, 1H, H-8, 3J = 7.6, 8.2), 6.65 (dd, 1H, H-9 3J = 7.6, 4J = 1.5), 7.54–7.62 (m, 5H,
Ph), 2.69 (s, 3H, CH3). 13C-NMR δ: 157.6 (C-4), 151.0 (C-3), 148.4 (C-6), 143.3 (C-5a), 142.1 (C-9b),
139.6 (Ci), 130.4 (Cp), 130.0 (Co), 127.2 (Cm), 123.9 (C-8), 114.1 (C-9), 112.9 (C-7), 112.7 (C-9a),
106.6 (C-3a), 13.2 (Me). m/z = 306.1 (M, 100%), 291.3 (5%), 277 (20%), 77 (22%). Anal. Calcd. for
C18H14N2O3; C, 70.58; H, 4.61; N, 9.14. Found: C, 70.83; H, 4.70; N, 9.00.
8-Bromo-3-methyl-6-methoxy-1H-chromeno[4,3-c]pyrazol-4-one (2g). Obtained as described for 2a
starting from 1g (0.500 g, 1.28 mmol) to obtain 2g (0.393 g, 1.01 mmol, 79% yield) as a pale yellow
powder, mp = 289–292 °C, IR νneat (cm−1): 1744 (OC=O), 1275, 1205 (C-O). 1H-NMR δ: 6.72 (s, 1H,
H-9), 7.06 (s, 1H, H-6), 7.51-7.62 (m, 5H, Ph), 2.67 (s, 3H, CH3). 13C-NMR δ: 156.7 (C-4), 151.1 (C-5a),
148.9 (C-3), 142.3 (C-6), 140.1 (C-9b), 139.0 (C-10), 130.7 (C-9), 130.1 (C-11), 127.0 (C-12), 123.9
(C-5), 123.3 (C-8), 116.5 (C-13), 116.1 (C-7), 113.7 (C-9a), 106.8 (C-3a), 13.1 (Me). m/z = 384.5 (M,
80%), 386.2 (100%), 385.5 (25%), 357.5 (10%), 290.5 (10%), 77.0 (25%). Anal. Calcd. for
C18H13N2O3Br; C, 56.13; H, 3.40; N, 7.27. Found: C, 55.88; H, 3.40; N, 7.20.
6-Bromo-8-Chloro-3-methyl-1H-chromeno[4,3-c]pyrazol-4-one (2h). Obtained as described for 2a
starting from 1h (0.5 g, 1.27 mmol) to obtain 2h (0.249 g, 0.64 mmol, 50% yield) as a pale yellow
powder, mp = 259–261 °C, IR νneat (cm−1): 1749 (OC=O), 1277, 1224 (C-O). 1H-NMR δ: 6.90 (s, 1H,
H-9), 7.82 (s, 1H, H-7), 7.53-7.65 (m, 5H, Ph), 2.65 (s, 3H, CH3). 13C-NMR δ: 156.2 (C-4), 151.1 (C-
5a), 148.2 (C-3), 140.2 (C-9b), 138.8 (C-10), 134.2 (C-7), 130.9 (C-9), 130.6 (C-11), 129.5 (C-8),
126.9 (C-12), 121.4 (C-13), 113.9 (C-6), 112.6 (C-9a), 106.8 (C-3a), 13.0 (Me). m/z = 390.0 (M,
100%), 389.5 (60%), 388.5 (62%), 310 (5%), 77(25%). Anal. Calcd. for C17H10N2O2BrCl; C, 52.40; H,
2.59; N, 7.19. Found: C, 52.70; H, 2.63; N, 7.00.
6,8-Dichloro-3-methyl-1H-chromeno[4,3-c]pyrazol-4-one (2i). Obtained as described for 2a starting from
1i (0.5 g, 1.43 mmol) to obtain 2i (0.259 g, 0.74 mmol, 52% yield) as a pale yellow powder,
mp = 224–226 °C, IR νneat (cm−1): 1750 (OC=O), 1225 (C-O). 1H-NMR δ: 6.90 (s, 1H, H-9), 7.47 (s, 1H,
H-7), 7.52-7.64 (m, 5H, Ph), 2.65 (s, 3H, CH3). 13C-NMR δ: 156.2 (C-4), 151.1 (C-5a), 147.8 (C-3), 140.2
(C-9b), 138.8 (C-10), 131.3 (C-7), 130.9 (C-9), 130.3 (C-11), 129.1 (C-8), 126.9 (C-12), 124.1 (C-6), 120.8
(C-13), 114.0 (C-9a), 106.8 (C-3a), 13.0 (Me). m/z = 344.5 (M, 100%), 346.2 (80%), 345.3 (68%), 308.5,
77 (22%). Anal. Calcd. for C17H10N2O2Cl2; C, 59.15; H, 2.92; N, 8.11. Found: C, 58.90; H, 2.89; N, 8.00.

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4. Conclusions
3-Methyl-1-phenyl-1H-chromeno[4,3-c]pyrazol-4-one (2a) spontaneously crystallizes from CHCl3
solutions of 3-[1-(phenyl-hydrazono)-ethyl]-chromen-2-one (1a) whereas the 6-substituted isomers 1b-i
failed to do so, requiring Cu(CH3COO)2·H2O as catalyst to yield the corresponding 1-phenyl-
chromeno[4,3-c]pyrazol-4-ones 2b-i in moderate to good yields (50–83%) under mild conditions. The
NMR data in solution and the X-ray data in the solid state are consistent with the N-phenyl ring almost
perpendicular to the three fused rings chromeno-pyrazole system. In the solid state this geometrical
arrangement of the aromatic rings determines the supramolecular architecture by C―H···A (A = O, π)
and face to face π-stacking interactions which are very similar among 2b-d, varying only in the nature
of the π-stacked rings and in the propagating direction. The observed π-stacking trend between
chromeno and pyrazole rings is given by the overlapping between the best donor and acceptor rings in
each molecule, modulated by the electronic character of the X and Y substituents.
Acknowledgements
Authors thanks to CONACYT project 83378, Secretaria de Investigación y Posgrado del Instituto
Politécnico Nacional and Fondos FRABA for financial support, and Centro de Investigaciones
Químicas de la Universidad Autónoma del Estado de Morelos for the CSD license.
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Sample Availability: Samples of the compounds 2e-i are available from the authors.
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