Bischalcones - Synthons for a new class of bis(heterocycles)

Article abstract of DOI:10.1039/b409968k

Novel oxo-linked bis(heterocycles) containing two different heterocyclic rings, viz. pyrroles in combination with pyrazolines and isoxazolines, are synthesized.

Full text of DOI:10.1039/b409968k

View Article Online / Journal Homepage / Table of Contents for this issue
P A P E R
Bischalcones—synthons for a new class of bis(heterocycles)
Venkatapuram Padmavathi,* B. Jagan Mohan Reddy and D. R. C. Venkata Subbaiah
Department of Chemistry, Sri Venkateswara University, Tirupati, 517 502 India.
E-mail: vkpuram2001@yahoo.com; Fax: +91-877-2261825
Received (in Toulouse, France) 30th June 2004, Accepted 10th September 2004
First published as an Advance Article on the web 15th November 2004
Novel oxo-linked bis(heterocycles) containing two different heterocyclic rings, viz. pyrroles in combination
with pyrazolines and isoxazolines, are synthesized.
Introduction
Results and discussion
Amongst five-membered heterocycles, pyrroles, pyrazolines
and isoxazolines represent a class of compounds of great
importance in heterocyclic chemistry. These compounds have
intrinsic biological activities and constitute the structural
feature of many bioactive compounds. As constituents of
cytotoxic drugs (such as netrospin and distamycin), 4-amino-
pyrrole-2-carboxylates have been used as the main compounds
in the construction of a diverse series of DNA-binding ligands
exhibiting antibiotic, antiviral and oncolytic properties.1
The related 3-aminopyrroles also exhibit anticonvulsant activ-
ity by blocking sodium channels.2 In addition, pyrazolines
and isoxazolines have gained importance due to their various
chemotherapeutic properties. In fact, Celecoxib, a pyrazole
derivative, and Valdecoxib, an isoxazole derivative, are
now widely used in the market as anti-inflammatory drugs.3
Hence, it is considered worthwhile to prepare molecules
having both pyrrole and pyrazole/isoxazole rings. In the
literature, multistep synthetic routes to 3,4-disubstituted
pyrroles have been reported either by coupling imines and
nitroalkanes or by using Friedel–Crafts acylation in the pre-
sence of an electron-withdrawing group on the pyrrole nitro-
gen or on 3,4-silylated precursors.4 However, these synthetic
routes are often complicated and limited to only some sub-
stituents.
Previously, 3,4-disubstituted pyrroles have also been synthe-
sized from Michael acceptors and tosyl methyl isocyanide
(TosMIC).5 Following this synthetic methodology, we re-
ported recently a new regioselective one-step procedure using
TosMIC, leading to a series of 3,4-disubstituted pyrroles in
good yields.6 Similarly, pyrazolines and isoxazolines have been
synthesized by 1,3-dipolar cycloaddition of an ylide to an
alkene involving the 3 + 2 principle.7 Among the ylides,
diazomethane, nitrile imines and nitrile oxides have been used
extensively as reactive intermediates. These nitrile imines and
nitrile oxides can be generated by the dehydrogenation of
araldehyde phenylhydrazones and araldoximes with lead tetra-
acetate,8 mercury acetate,9 1-chlorobenzotriazole,10 chlora-
mine-T,11 etc. Use of the latter for in situ generation of
dipolar reagents has enthused many organic chemists. In
fact, we ourselves have reported in the past the 1,3-dipolar
cycloaddition reaction of chloramine-T catalysed dipolar re-
agents with a variety of activated mono and bis(olefins).12 The
present communication deals with the synthesis of hitherto
unknown oxo-linked bis(heterocycles) having pyrrole together
with pyrazole or isoxazole units, from 1,3-dipolar cycloaddi-
tion of TosMIC, nitrile imines and nitrile oxides to activated
olefins.
The general synthetic pathway discussed hereafter is de-
picted in Scheme 1. Experimental data and spectroscopic
analyses of compounds 2–9 are compiled in Tables 1 and 2.
When bischalcone 1 is treated with TosMIC in the presence of
sodium hydride in a solvent mixture of ether and DMSO, a
solid is obtained and identified by NMR spectroscopy as 30-
aryl-10-(4-aryl-1H-pyrrol-3-yl)-prop-20-enone 2. Compound 2a
exhibits two singlets at d 6.80 and 6.96 ppm, assigned to H-2
and H-5 pyrrole ring protons. Two doublets are observed at d
7.08 and 7.65 ppm corresponding to olefinic protons, in addi-
tion to the signals of aromatic protons. Thus, the formation of
2 indicates that the reaction is regiospecific. Attempts to
prepare bis-(4-aryl-1H-pyrrol-3-yl)methanone 3 by refluxing 1
with 2 equiv. of TosMIC were not successful. However, 3 can
be obtained by treating 2 with 1 equiv. of TosMIC, as
confirmed by NMR spectroscopy. Compound 3a presents
two sharp singlets at d 6.84 and 6.97 ppm corresponding to
H-2,20 and H-5,50. This indicates that the molecule is highly
symmetrical.
The olefinic group in 2 is used to develop different hetero-
cyclic rings such as pyrazoles and isoxazoles. Treatment of 2
with diazomethane at ꢀ15 1C for 48 h gives a solid identified as
(40-aryl-40,50-dihydro-10H-pyrazol-30-yl)-(4-aryl-1H-pyrrol-3-yl)
methanone 4 by spectral analysis. The 1H NMR spectrum of 4a
shows an AMX splitting pattern for the pyrazoline ring
protons at d 4.53 (HA), 3.64 (HM) and 3.58 (HX) ppm,
respectively, in addition to the signals of the pyrrole ring
protons. The observed coupling constant values JAM = 12.6,
JAX = 5.5 and JMX = 10.0 Hz indicate that HA and HM are
cis, HA and HX are trans and HM and HX are geminal
(see Table 2). Similarly, 1,3-dipolar cycloaddition of nitrile
imines and nitrile oxides (generated from araldehyde phenyl-
hydrazones and araldoximes, respectively) to 2 results in
(4-aryl-1H-pyrrol-3-yl)-(10,30,50- triaryl-40,50-dihydro-10H-pyra-
zol-40-yl)methanone 5 and (30,50-diaryl-40,50-dihydroisoxazol-
40-yl)-(4-aryl-1H-pyrrol-3-yl)methanone 6, respectively. The
1H NMR spectra of 5a and 6a display two doublets at d
5.23, 5.61 ppm and 5.20, 5.65 ppm, respectively, which are
assigned to H-4 and H-5, that is, the two methine protons of
the pyrazoline and isoxazoline rings. The J values show that
they are in a trans geometry (see Table 2). Compounds 4a, 5a
and 6a, upon oxidation with chloranil in xylene, give the
corresponding pyrazoles and isoxazoles 7a, 8a and 9a. The
disappearance of the two doublets from the pyrazoline/isoxa-
zoline ring protons in the 1H NMR spectra confirms their
formation. The structures of 2–9 were further confirmed by 13
C
NMR spectroscopy (Table 2).
T h i s j o u r n a l i s & T h e R o y a l S o c i e t y o f C h e m i s t r y a n d t h e
C e n t r e N a t i o n a l d e l a R e c h e r c h e S c i e n t i f i q u e 2 0 0 4
N e w J . C h e m . , 2 0 0 4 , 2 8 , 1 4 7 9 – 1 4 8 3
1479

View Article Online
Scheme 1
Compounds 3–6 were further tested for antimicrobial activ-
ity at three different concentrations (25, 75 and 100 mg per
disc). The antibacterial activity was screened against the fol-
lowing microorganisms: Staphylococcus aureus, Bacillus subtilis
(Gram-positive bacteria) and Escherichia coli, Klebsiella pneu-
moniae (Gram-negative bacteria), on nutrient agar plates at
37 1C for 24 h using Gentamycin as a reference drug. The
compounds were also evaluated for their antifungal activity
Table 1 Experimental and IR spectroscopy data of compounds 2–9
Anal. calcd. (found)/wt %
IR n/cmꢀ1
NH
% Yield M.p./1C Molecular formula (MW/g molꢀ1
2a 74 201–202 C19H15NO (273.33)
)
C
H
N
C
O
C
C
C
N
Q
Q
Q
83.49 (83.56) 5.53 (5.50)
75.66 (75.52) 5.74 (5.69)
66.68 (66.53) 3.83 (3.80)
80.75 (80.81) 5.16 (5.12)
74.18 (74.11) 5.41 (5.38)
66.16 (66.24) 3.70 (3.75)
5.12 (5.17)
3169 1664
3172 1658
3170 1665
3180 1673
3175 1678
3178 1669
1636
1629
1628
—
—
—
—
—
—
—
2b 71
2c 68
3a 78
3b 82
3c 79
4a 69
4b 72
4c 66
5a 71
5b 66
5c 69
5d 72
6a 70
6b 68
6c 72
6d 74
7a 68
8a 64
9a 67
212–214 21H19NO3 (333.38)
C
4.20 (4.27)
4.09 (4.18)
8.97 (9.04)
7.52 (7.59)
7.35 (7.41)
236–238 C19H13Cl2NO (342.22)
209–211 C21H16N2O (312.36)
203–205 C23H20N2O3 (372.42)
243–245 C21H14Cl2N2O (381.25)
—
—
225–227
C
20H17N3O (315.37)
217–219 C22H21N3O3 (375.42)
76.17 (76.10) 5.43 (5.40) 13.32 (13.41) 3182 1685
70.38 (70.32) 5.64 (5.68) 11.19 (11.24) 3174 1681
62.51 (62.44) 3.93 (3.88) 10.94 (10.99) 3169 1676
—
—
1568
1571
1570
1572
1569
1558
1562
1581
1573
1571
1562
1572
1560
1559
248–250
289–281
C
C
20H15Cl2N3O (384.26)
32H25N3O (467.56)
—
—
82.20 (82.29) 5.39 (5.42)
77.40 (77.51) 5.54 (5.50)
76.56 (76.68) 4.82 (4.87)
67.32 (67.24) 3.88 (3.92)
79.57 (79.43) 5.14 (5.19)
74.32 (74.41) 5.35 (5.14)
73.15 (73.28) 4.49 (4.43)
62.99 (62.81) 3.46 (3.51)
8.99 (9.04)
7.96 (8.00)
8.37 (8.43)
7.36 (7.42)
7.14 (7.19)
6.19 (6.27)
6.56 (6.64)
5.65 (5.62)
3174 1680
3180 1682
3184 1685
3172 1680
3168 1679
3175 1684
3180 1677
3182 1678
277–279 C34H29N3O3 (527.61)
—
—
285–287
298–300
C
C
32H24ClN3O (502.01)
32H22Cl3N3O (570.89)
—
—
269–271 C26H20N2O2 (392.45)
255–257 C28H24N2O4 (452.50)
249–251 C26H19ClN2O2 (426.89)
271–273 C26H17Cl3N2O2 (495.78)
—
—
—
268–270
C
20H15N3O (313.35)
76.66 (76.75) 4.82 (4.76) 13.41 (13.57) 3204 1664
82.56 (82.64) 4.98 (4.88)
79.98 (80.08) 4.65 (4.72)
1628
1622
1632
292–294 C32H23N3O (465.54)
284–286 C26H18N2O2 (390.43)
9.03 (9.12)
7.17 (7.24)
3196 1656
3188 1655
1480
N e w J . C h e m . , 2 0 0 4 , 2 8 , 1 4 7 9 – 1 4 8 3

View Article Online
N e w J . C h e m . , 2 0 0 4 , 2 8 , 1 4 7 9 – 1 4 8 3
1481

View Article Online
against Fusarium solani, Curvularia lunata, Aspergillus niger
and Cunninghemella elegans, using Nystatin (25 mg per disc) as
a standard drug. Fungal cultures were grown on potato
dextrose broth (PDA) at 25 1C for 3 days, then the spore
suspension was adjusted to 106 pores mlꢀ1 (fungi) at a mg mlꢀ1
concentration by the Vincent and Vincent method.13
All test compounds were found to display moderate anti-
microbial activity towards both Gram-positive and Gram-
negative bacteria as well as antifungal activity towards all
fungi. Compounds 4 and 5, which have both pyrrole and
pyrazoline rings, exhibit a relatively higher activity than the
others. Further bioassay studies on these compounds are in
progress.
(1 mmol), araldehyde phenylhydrazone (2 mmol) and chlor-
amine-T (2 mmol) in methanol (20 ml) is refluxed for 18–20 h
over a water bath. The precipitated inorganic salts are filtered
off. The filtrate is concentrated and the residue is extracted with
dichloromethane. The organic phase is washed with water,
brine and dried over anhydrous Na2SO4. The solvent is
removed under reduced pressure. Recrystallization of the crude
product from ethanol resulted in pure 5.
(30,50-Diaryl-40,50-dihydroisoxazol-40-yl)-(4-aryl-1H-pyrrol-3-
yl)methanone 6: general procedure. A mixture of 2 (1 mmol),
araldoxime (2 mmol) and chloramine-T (2 mmol) in methanol
(20 ml) is refluxed for 18–20 h over a water bath. The
precipitated inorganic salts are filtered off. The filtrate is
concentrated and the residue is extracted with dichloro-
methane. The organic phase is washed with water, brine and
dried over anhydrous Na2SO4. The solvent is removed under
reduced pressure. Recrystallization of the crude product from
ethanol resulted in pure 6.
In conclusion, novel oxo-linked bis(heterocycles) containing
two different heterocyclic rings were developed from a simple
substrate, bischalcone, by an elegant and well-versed metho-
dology.
Experimental
Melting points were determined in open capillaries on a Mel-
Temp apparatus and are uncorrected. The purity of the
compounds was checked by TLC (silica gel H, BDH, 3 : 1 ethyl
acetate–hexane). The IR spectra were recorded on KBr pellets
on a Perkin–Elmer grating infrared spectrophotometer, model
337. 1H NMR spectra were recorded in CDCl3–DMSO-d6 on a
300 MHz Varian EM-360 spectrophotometer. 13C NMR spec-
tra were recorded in CDCl3–DMSO-d6 on a Varian VXR
spectrometer operating at 75.5 MHz. All chemical shifts are
reported in ppm from TMS as an internal standard. Mass
spectra were recorded on a Joel JMS-D 300 instrument at
70 eV. Elemental analyses were performed at Punjab Univer-
sity, Chandigarh, India. Starting materials, bischalcones, ara-
ldehyde phenylhydrazones and araldoximes, were prepared by
standard procedures.14
(40-Phenyl-10H-pyrazol-30-yl)-(4-phenyl-1H-pyrrol-3-yl)metha-
none 7a; (4-phenyl-1H-pyrrol-3-yl)-(10,30,50-triphenyl-10H-pyra-
zol-40-yl)methanone 8a; (30,50-diphenylisoxazol-40-yl) (4-phenyl-
1H-pyrrol-3-yl)methanone 9a: general procedure. A solution of
4a or 5a or 6a (1 mmol) and chloranil (1.04 mmol) in xylene
(10 ml) is refluxed for 24–32 h. Then the reaction mixture is
treated with a 5% NaOH solution. The organic layer is sepa-
rated and repeatedly washed with water, dried over anhydrous
Na2SO4 and the solvent is removed on a rotary evaporator. The
solid obtained is purified by recrystallization in 2-propanol to
give pure 7a, 8a or 9a, respectively.
References
1
(a) C. C. C. Wang and P. B. Dervan, J. Am. Chem. Soc., 2001, 123,
8657; (b) B. Wellenzohn, W. Flader, R. H. Winger, A. Hallbruck-
er, E. Mayer and K. R. Liedl, J. Am. Chem. Soc., 2001, 123, 5044
and references 1–33 therein; (c) S. K. Sharma, M. Tandon and
J. W. Lown, J. Org. Chem., 2001, 66, 1030; (d) N. R. Wurtz, J. M.
Turner, E. E. Baird and P. B. Dervan, Org. Lett., 2001, 3(8), 1201;
(e) N. B. Dyatkina, C. D. Roberts, J. D. Keicher, Y. Dai, J. P.
Nadherny, W. Zhang, U. Schmitz, A. Kongpachith, K. Fung,
A. A. Nokikov, L. Lou, M. Velligan, A. A. Khorlin and M. S.
Chen, J. Med. Chem., 2002, 45, 805.
Synthesis
30-Aryl-10-(4-aryl-1H-pyrrol-3-yl)-prop-20-enone 2: general
procedure. A mixture of TosMIC (5 mmol) and bischalcone 1
(5 mmol) in Et2O–DMSO (2 : 1) is added dropwise under
stirring to a suspension of NaH (50 mg) in Et2O (10 ml) at
room temperature. Stirring is continued for about 5 h. Then,
water is added and the product is extracted with Et2O. The
ethereal fraction is dried over anhydrous Na2SO4. The solvent
is removed in vacuo. The resulting solid is purified by recrys-
tallization from methanol.
2
K. Unverferth, J. Engel, N. Hofgen, A. Rostock, R. Gunther,
H. J. Lankau, M. Menzer, A. Rolfs, J. Liebscher, B. Muller and
H. J. Hofmann, J. Med. Chem., 1998, 41, 63.
3
4
G. Dannahardt, W. Kiefer, G. Kramer, S. Maehrlein, U. Nowe
and B. Fiebich, Eur. J. Med. Chem., 2000, 35, 499.
Bis(4-aryl-1H-pyrrol-3-yl)methanone 3: general procedure. A
mixture of TosMIC (5 mmol) and 30-aryl-10-(4-aryl-1H-pyrrol-
3-yl)-prop-20-enone 2 (5 mmol) in Et2O–DMSO (2 : 1) is added
dropwise under stirring to a suspension of NaH (50 mg) in
Et2O (10 ml) at room temperature. Stirring is continued for
about 5 h. Then, water is added and the product is extracted
with Et2O; the ethereal fraction is dried over anhydrous
Na2SO4. The solvent is removed in vacuo. The resulting solid
is purified by column chromatography [hexane–ethyl acetate
(1 : 4)].
(a) H. Shiraishi, T. Nishitani, T. Nishihara, S. Sakaguchi and
Y. Ishii, Tetrahedron, 1999, 55, 13957; (b) A. Zelikin, V. R. Shastri
and R. Langer, J. Org. Chem., 1999, 64, 3379; (c) J. H. Liu,
H. W. Chan and H. N. C. Wong, J. Org. Chem., 2000, 65
3274.
(a) A. M. van Leusen, H. Siderius, B. E. Hoogenboom and D. van
Leusen, Tetrahedron Lett., 1972, 5337; (b) N. P. Pavri and
M. L. Trudell, J. Org. Chem., 1997, 62, 2649.
V. Padmavathi, B. Jagan Mohan Reddy, M. Rajagopala Sarma
and P. Thriveni, J. Chem. Res. (S), 2004, 79.
(a) A. G. Lee, Synthesis, 1982, 508; (b) Z. Bao-Xiang, Yu. Yang
and E. Shoji, Tetrahedron, 1996, 52, 12049.
G. Just and K. Dahl, Tetrahedron, 1968, 24, 5251.
5
6
7
8
9
(40-Aryl-40,50-dihydro-10H-pyrazol-30-yl)-(4-aryl-1H-pyrrol-3-
yl)methanone 4: general procedure. To a cooled solution of 2 (5
mmol) in dichloromethane (20 m), an ethereal solution of
diazomethane (40 ml, 0.4 M) and triethylamine (0.12 g) is
added. The reaction mixture is kept at ꢀ20 to ꢀ15 1C for 40–48 h.
The solvent is removed under reduced pressure. The resulting
solid is purified by recrystallization from methanol.
K. M. Lokanath Rai, N. Liganna, A. Hassner and C. A. Murthy,
Org. Prep. Proced. Int., 1992, 24, 91.
10 J. N. Khim and E. K. Ryu, Synth. Commun., 1990, 20, 1373.
11 (a) K. M. Lokanath Rai and A. Hassner, Indian J. Chem., Sect. B:
Org. Chem. Incl. Med. Chem., 1997, 36, 242; (b) K. M. Lokanath
Rai and A. Hassner, Synth. Commun., 1997, 27, 467; (c) A.
Hassner and K. M. Lokanath Rai, Synthesis, 1989, 57; (d) K.
M. Lokanath Rai and A. Hassner, Synth. Commun., 1989, 19,
2799.
12 (a) V. Padmavathi, A. V. Bhaskar Reddy, R. P. Sumathi and D.
Bhaskar Reddy, Indian J. Chem., Sect. B: Org. Chem. Incl. Med.
Chem., 1998, 37, 1286; (b) V. Padmavathi, R. P. Sumathi,
(4-Aryl-1H-pyrrol-3-yl)-(10,30,50-triaryl-40,50-dihydro-10H-py-
razol-40-yl)methanone 5: general procedure. A mixture of 2
1482
N e w J . C h e m . , 2 0 0 4 , 2 8 , 1 4 7 9 – 1 4 8 3

View Article Online
N. Chandrasekhar Babu and D. Bhaskar Reddy, J.Chem. Res.
(S), 1999, 2, 610; (c) V. Padmavathi, R. P. Sumathi, K. Venugo-
pal Reddy, A. Somasekhar Reddy and D. Bhaskar Reddy, Synth.
Commun., 2000, 30, 4007; (d) V. Padmavathi, K. Venugopal
Reddy, A. Padmaja and D. Bhaskar Reddy, Synth. Commun.,
2002, 32, 1227; (e) V. Padmavathi, K. Venugopal Reddy, A.
Balaiah, T. V. Ramana Reddy and D. Bhaskar Reddy, Heteroat.
Chem., 2002, 13, 677.
13 J. C. Vincent and H. W. Vincent, Proc. Soc. Exp. Biol. Med., 1944,
55, 162.
14 A. I. Vogel, A Text Book of Practical of Organic Chemistry,
Longman’s Green & Co., Ltd, London, 5th edn.,1989.
N e w J . C h e m . , 2 0 0 4 , 2 8 , 1 4 7 9 – 1 4 8 3
1483