One-pot synthesis of unsymmetrical biaryls from suitably functionalized 2H-pyran-2-ones through carbanion-induced ring-transformation reactions

Article abstract of DOI:10.1039/b009725j

An innovative synthesis of unsymmetrical biaryls (2,6) with electron-acceptor and electron-donor substituents through carbanion-induced C-C bond formation from 6-aryl-3-cyano-4-methylthio-2H-pyran-2-ones (1) and 4-sec-amino-6-aryl-2H-pyran-2-ones (5), using aliphatic ketones as a source of carbanion, is delineated and illustrated. However, a reaction of pyran-2-ones (1) with aromatic ketones failed to yield any desired product and in lieu a new compound isolated was characterized as the corresponding (4,6-diarylpyran-2-ylidene)acetonitrile (3). The structure of two representative compounds 5h and 6q has been confirmed by single-crystal X-ray diffraction analysis.

Full text of DOI:10.1039/b009725j

View Article Online / Journal Homepage / Table of Contents for this issue
One-pot synthesis of unsymmetrical biaryls from suitably
functionalized 2H-pyran-2-ones through carbanion-induced
ring-transformation reactions
1
Vishnu J. Ram,* Pratibha Srivastava, Nidhi Agarwal, Ashoke Sharon and Prakas R. Maulik†
Medicinal Chemistry and Molecular and Structural Biology Division,
Central Drug Research Institute, Lucknow, 226001, India. E-mail: root@cscdri.ren.nic.in;
Fax: 91-0522-223405/223938
Received (in Cambridge, UK) 5th December 2000, Accepted 20th June 2001
First published as an Advance Article on the web 31st July 2001
An innovative synthesis of unsymmetrical biaryls (2,6) with electron-acceptor and electron-donor substituents
through carbanion-induced C–C bond formation from 6-aryl-3-cyano-4-methylthio-2H-pyran-2-ones (1) and 4-sec-
amino-6-aryl-2H-pyran-2-ones (5), using aliphatic ketones as a source of carbanion, is delineated and illustrated.
However, a reaction of pyran-2-ones (1) with aromatic ketones failed to yield any desired product and in lieu a new
compound isolated was characterized as the corresponding (4,6-diarylpyran-2-ylidene)acetonitrile (3). The structure
of two representative compounds 5h and 6q has been confirmed by single-crystal X-ray diffraction analysis.
cyano-2H-pyran-2-ones 5 separately. The precursors 1 were
Introduction
prepared from base-catalyzed reaction of ethyl 2-cyano-3,3-
The synthesis of highly functionalized biaryl systems, particu-
bis(methylthio)acrylate and aryl ketones as described earlier.21
larly those with hindered rotation, is highly demanding not only
A further reaction of 1 with secondary amines such as piper-
idine, morpholine and piperazine, etc. at reflux temperature in
ethanol led to 4-sec-aminopyran-2-ones 5 (Schemes 1 and 2).
The structure of all the synthesized compounds was con-
firmed on the basis of spectroscopic data and elemental anal-
yses. The NMR spectrum of 5a showed two triplets at δ 3.42
in the construction of natural products and pharmaceuticals,
but also in the discovery of entities for asymmetric synthesis,1
crown ethers,2 chiral liquid crystals,3 chiral phases for chrom-
atography4 and preparation of materials for their nonlinear
optical properties.5
Historically, biaryls have been synthesized by coupling of
and 4.07 due to four methylene protons of the piperazinyl
two aromatic moieties in the presence of different coupling
moiety. A singlet at δ 6.42 was assigned as a characteristic peak
reagents.6–13 Recently, palladium-catalyzed cross-coupling
between electrophilic (Ar-X) and organometallic species pre-
for the C5 proton in the pyran-2-one (1 and 5a). Three multi-
plets at δ 6.85–6.95, 7.22–7.36 and 7.59–7.71 were designated
for aromatic protons. In all the compounds a characteristic
pared from Mg, Zn, Sn and B was found to be a versatile route
for C–C bond formation.14–16 Though palladium-catalyzed
peak for the C5 proton at δ ≈ 6.42 clearly indicated the presence
coupling between arylboronic acids and haloarenes is highly
of the lactone ring. In addition a peak at ν ≈ 1689 cmϪ1, due to
versatile for the synthesis of biaryls17 it suffered from certain
the carbonyl function in the IR spectrum, confirmed the pres-
ence of the lactone ring in compounds 5. The structure of 5h
was finally ascertained by single-crystal X-ray diffraction
analysis. The presence of the the piperazinyl moiety at C4 in the
crystal structure of 5h (Fig. 1) confirmed the nucleophilic sub-
stitution by piperazine only at the ‘soft’ electrophilic centre C4
of the lactone ring. The molecular structure of 5h (Fig. 1)
limitations due to coupling between the arylboronic acid with a
phenyl group of triphenylphosphine as well as self-coupling of
aryl groups of the arylboronic acid. However, initially, unsym-
metrical biaryls were synthesized18 by Diels–Alder reactions of
2H-pyran-2-ones with electron-rich and -poor dienophiles.
Further, Gompper and Christmann19 have also prepared
similar compounds from the reaction of 2H-pyran-2-one with
showed that the piperazine ring (B) adopts a chair conform-
aryl Grignard reagents. The recent efficient synthesis of
ation [deviations of N7 and N10 are Ϫ0.604(5) and 0.704(4) Å
unsymmetrical biaryls, through oxazoline-mediated coupling
from the mean plane defined by C8, C9, C11 and C12] and the
N7 and N10 substituents are in equatorial positions. The fluoro-
benzene rings (C and D) are separated from each other by an
reactions,20 though it acquired widespread popularity and
applications in natural-product synthesis has limitations with
respect to certain substitution in the phenyl ring and the dif-
angle of 107.9(2)Њ at C13. The chlorobenzene ring (E) is almost
ficulty in obtaining numerous Grignard reagents. The continu-
in the same plane as the lactone ring (A) [twist angle is 5.8(1)Њ].
ously growing demands for functionalized biaryls warrants an
efficient and convenient, innovative route for their synthesis.
There is an intramolecular H-bond, C31–H31 ؒ ؒ ؒ O1, with
H-bonding parameters C31–O1: 2.708(4) Å, H31 ؒ ؒ ؒ O1: 2.376
Å and C31–H31 ؒ ؒ ؒ O1: 101.4Њ.
The crystal packing (Fig. 2) revealed a network of various
weak intermolecular H-bonds and aromatic π–π interactions
Results and discussion
Our approach to the synthesis of unsymmetrical biaryls with
electron-donor and -acceptor substituents is based on the base-
catalyzed ring-transformation reactions of 6-aryl-3-cyano-
(APPIs). Currently the importance of these interactions is
being realized in crystal engineering22 and supramolecular
design.23 The weak H-bonding of the types C–H ؒ ؒ ؒ O,
C–H ؒ ؒ ؒ N and C–H ؒ ؒ ؒ F range in length from 3.243 to 3.799
Å (some of the H-bonds are shown in Fig. 2 by dotted lines).
Both the chlorobenzene (E) and lactone (A) rings are stacked in
4-methylthio-2H-pyran-2-ones
1 and 4-sec-amino-6-aryl-3-
† For X-ray crystallography queries.
DOI: 10.1039/b009725j
J. Chem. Soc., Perkin Trans. 1, 2001, 1953–1959
This journal is © The Royal Society of Chemistry 2001
1953

View Article Online
Scheme 1
Scheme 2
pairs due to APPI. The molecules are stacked in such a way that
ring A overlaps with ring B and vice-versa (as indicated by
shading in Fig. 2) along the b-axis direction. An approximate
interplanar distance of 3.8 Å separates the stacked rings. In
addition, one of the fluorobenzene rings, D, also shows APPI
(with an approximate stacking distance of 3.7 Å) in an offset
geometry with its symmetry-related counterpart (as indicated
by ↔ in Fig. 2). These π–π interactions are in accord with
Hunter’s electrostatic model.24 Thus the combination of
weak H-bonding and aromatic π–π interactions stabilizes the
molecule in the crystalline state.
Based on the topography of pyran-2-ones 1 and 5, they may
be considered as cyclic ketene hemithioacetals (1) and ketene
hemiaminals (5) with three electrophilic centres C2, C4 and C6
in which the last is highly susceptible to nucleophilic attack,
owing to extended conjugation and the presence of an electron-
withdrawing substituent at position 3 in the pyran ring. The
difference in electron density on various carbon centres led us
to exploit pyran-2-ones 1 and 5 as synthons for ring-
transformation reactions. Thus the carbanion generated in situ
from an aliphatic ketone by alkali in DMF attacks at C6 with
ring opening followed by decarboxylation and condensation–
cyclization involving both the keto group and C3 of the pyran
ring with elimination of water, affording products 2 and 6
(Schemes 1 and 3). This is a one-pot reaction in which an equi-
molar mixture of a pyran-2-one (1 or 5), aliphatic ketone, and
powdered KOH in DMF was stirred at ambient temperature for
35 h under an inert atmosphere. After pouring of the reaction
mixture into ice–water, the solution was neutralized with 10%
HCl to pH 7, the precipitate thus obtained was filtered off, and
the crude product was purified by column chromatography as
an unsymmetrical biaryl 2 or 6. This procedure not only pro-
vided a novel general route for preparing highly functionalized
unsymmetrical biaryls but also opens an alternative approach
to the synthesis of polyfunctionalized N,NЈ-diarylpiperazines
as drug intermediates.
A plausible mechanism of this reaction is depicted in Scheme
1
3. The H NMR spectrum of a biaryl, 4-(4-chlorophenyl)-2-
1954
J. Chem. Soc., Perkin Trans. 1, 2001, 1953–1959

View Article Online
Fig. 3 ORTEP diagram showing the molecular structure of 6q with
atomic labelling.
Fig. 1 ORTEP diagram showing the molecular structure of 5h with
atom labelling.
biaryls with respect to its (i) mild reaction conditions, (ii) use of
inexpensive reactants, (iii) no use of catalyst in the reaction, (iv)
versatility and compatibility, and (v) easy access to the synthesis
of 1,4-biarylpiperazines.
Exploring further the versatility of this reaction, alkyl
aromatic ketones were used as a source of carbanions but
failed to yield desired products, and instead a new compound
isolated from the reaction with p-fluoroacetophenone was iden-
tified as the (4,6-diarylpyran-2-ylidene)acetonitrile 3 through
enolization of the alkyl aryl ketone followed by cyclization
(Scheme 1).
Fig. 2 PLUTO diagram showing the crystal-packing interactions of
5h.
Experimental
Mps were determined in an open capillary Büchi-530 melting
point apparatus and are uncorrected. H NMR spectra were
methyl-6-(4-phenylpiperazinyl-1-yl)benzonitrile 6g, showed a
singlet at δ 2.59 for a methyl group and two triplets at δ 3.40 and
4.06 for piperazinyl protons. A singlet at δ 6.42 was assigned for
two aromatic protons. Three doublets at δ 6.96, 7.46 and 7.76
were assigned to two aromatic protons each while a multiplet at
δ 7.27–7.33 corresponded to 3 aromatic protons. The structure
of another representative compound, 6q, was confirmed by
single-crystal X-ray analysis. It is evident from its crystal struc-
ture (Fig. 3) that it has been formed by attack of a carbanion, a
‘hard’ base generated from the ketone, at the C6 position of the
lactone ring, followed by condensation. The crystal structure of
6q showed that the asymmetric unit contains two molecules of
similar conformations (not shown). The piperazine ring (C)
adopts a chair conformation [deviations of N16 and N19 are
0.600(4) and Ϫ0.699(4) Å from the mean plane defined by C17,
C18, C20 and C21 atoms in one molecule and those of N46 and
N49 are 0.716(4) and Ϫ0.568(4) Å from the mean plane defined
by C47, C48, C50 and C51 atoms in the other molecule]. The
structure further shows that ring B is twisted with respect to
ring A by an angle 36.6(1)Њ for one molecule and 38.1(1)Њ for the
other molecule in the asymmetric unit.
1
recorded on Bruker WM (400 MHz) and Bruker WM (200
MHz) spectrometers using SiMe4 as reference compound. IR
spectra were obtained in KBr discs on a Perkin-Elmer Ac-1
spectrophotometer. Electron-impact mass spectra were
obtained at 70 eV using a JEOL JMS-D 300 spectrometer.
Elemental analyses (C, H, N) were carried out on a Carlo Erba
EA-1108 elemental analyzer, within 0.5% of the theoretical
values. Thin layer chromatography (TLC) was performed on
7 × 3 cm precoated analytical plates (SRL).
General procedure for the synthesis of 2a–d and 3
A mixture of a 6-aryl-3-cyano-4-methylthio-2H-pyran-2-one 1
(10 mmol), ketone RCOCH3 (15 mmol) and potassium hydrox-
ide (15 mmol) in dry DMF was stirred at room temperature
under a nitrogen blanket for 30 h. The reaction mixture was
then poured into ice–water and vigorously stirred for 30 min
and thereafter acidified with 10% HCl. The precipitate obtained
was filtered off, washed with water, and purified on a silica gel
column, using chloroform–hexane (1 : 1) as eluent.
The crystal packing revealed the presence of weak intra- and
intermolecular C–H ؒ ؒ ؒ N and C–H ؒ ؒ ؒ π interactions that play
a fundamental role in three-dimensional organization of the
molecules in the solid state.25 The C–H ؒ ؒ ؒ N distances range
from 3.418 to 3.762 Å while the C–H ؒ ؒ ؒ π distances are
2.916(3) and 2.942(5) Å respectively.
2-Methyl-6-methylthio-4-[4-(4-phenylpiperazino)phenyl]-
benzonitrile 2a. Yield 60%; mp 210 ЊC; νmax/cmϪ1 2204 (CN);
m/z (EI) 399 (Mϩ, 100%), 384 (10.2), 307 (20.6); δH (200 MHz;
CDCl3) 1.89 (s, 3H, CH3), 2.56 (s, 3H, SCH3), 3.25–3.44 (m, 8H,
NCH2), 6.87 (s, 2H, CH), 6.97–7.10 (m, 5H, ArH), 7.25–7.34
(m, 4H, ArH) (Found: C, 75.29; H, 6.42; N, 10.39. C25H25N3S
requires C, 75.15; H, 6.31; N, 10.52%).
Our synthetic approach in many ways is superior to the exist-
ing procedures known for the construction of unsymmetrical
J. Chem. Soc., Perkin Trans. 1, 2001, 1953–1959
1955

View Article Online
Scheme 3
2-Cyclopropyl-4-(4-fluorophenyl)-6-(methylthio)benzonitrile
4-(4-Chlorophenyl)-2-ethyl-6-(methylthio)benzonitrile
2d.
Yield 54%; mp 108 ЊC; νmax/cmϪ1 2229 (CN); m/z (EI) 287 (Mϩ,
100%), 283 (11), 204 (46.7); δH (200 MHz, CDCl3) 1.22 (t, 3H, J
6.3 Hz, CH3), 2.56 (s, 3H, SCH3), 2.88 (q, 2H, J 5.4 Hz, CH2),
6.90 (s, 2H, CH), 7.19–7.25 (m, 2H, ArH), 7.36–7.43 (m, 2H,
ArH) (Found: C, 67.12; H, 4.82; N, 5.03. C16H14ClNS requires
C, 66.95; H, 4.91; N, 4.98%).
2b. Yield 38%; mp 115 ЊC; νmax/cmϪ1 2229 (CN); m/z (EI) 284
(Mϩ ϩ 1, 75%), 283 (Mϩ, 52.4), 154 (100); δH (200 MHz,
CDCl3) 0.84 (q, 2H, J 5.2 Hz, CH2), 1.15 (q, 2H, J 5.4 Hz,
CH2), 1.67–2.32 (m, 1H, CH), 2.60 (s, 3H, SCH3), 6.82 (s, 2H,
CH), 7.05–7.19 (m, 2H, ArH), 7.46–7.53 (m, 2H, ArH) (Found:
C, 71.56; H, 4.85; N, 4.99. C17H14FNS requires C, 71.89; H,
4.96; N, 4.94%).
[4,6-Bis(4-fluorophenyl)pyran-2-ylidene]acetonitrile 3. Yield
50%; mp 149 ЊC; νmax/cmϪ1 2229 (CN); m/z (EI) 307 (Mϩ,
92%), 306 (100), 280 (46.7); δH (200 MHz, CDCl3) 6.45 (s,
1H, CH), 6.90 (s, 1H, CH), 7.30 (s, 1H, CH), 7.52 (d, 2H, J 8.0
Hz, ArH), 7.58 (d, 2H, J 8.1 Hz, ArH), 7.72 (d, 2H, J 8.0
Hz, ArH), 7.86 (d, 2H, J 8.2 Hz, ArH) (Found: C, 74.35; H,
3.46; N, 4.25. C19H11F2NO requires C, 74.26; H, 3.60; N,
4.56%).
4-(4-Chlorophenyl)-2-cyclopropyl-6-(methylthio)benzonitrile
2c. Yield 58%; mp 122 ЊC; νmax/cmϪ1 2229 (CN); m/z (EI) 299
(Mϩ, 100%), 286 (60.2), 249 (43.1); δH (200 MHz, CDCl3) 0.83
(q, 2H, J 5.3 Hz, CH2), 1.17 (q, 2H, J 5.4 Hz, CH2), 1.59–2.30
(m, 1H, CH), 2.60 (s, 3H, SCH3), 6.72 (s, 2H, CH), 7.16–7.26
(m, 2H, ArH), 7.34–7.44 (m, 2H, ArH) (Found: C, 67.82; H,
5.06; N, 4.87. C17H14ClNS requires C, 68.28; H, 4.91; N, 4.68%).
1956
J. Chem. Soc., Perkin Trans. 1, 2001, 1953–1959

View Article Online
Table 1 Physical and spectral data of compounds 5a–o
Compd.
Yield (%)
69
Mp (θ/ЊC)a
νmaxb/cmϪ1
δH, J/Hzc
m/z (%)
5a
>260
1689, 2000
3.42 (t, 4H, J 6.2, NCH2), 4.07 (t, 4H, J 6.0,
NCH2), 6.42 (s, 1H, CH), 6.85–6.95 (m, 5H,
ArH), 7.22–7.36 (m, 2H, ArH), 7.59–7.71 (m,
2H, ArH)
3.27 (t, 4H, J 6.2, NCH2), 3.89 (s, 3H, OCH3),
4.06 (t, 4H, J 6.4, NCH2), 6.44 (s, 1H, CH),
6.89–6.95 (m, 4H, ArH), 7.17–7.26 (m, 2H,
ArH), 7.79–7.87 (m, 2H, ArH)
3.82 (t, 4H, J 6.3, NCH2), 4.05 (t, 4H, J 6.2,
NCH2), 6.43 (s, 1H, CH), 6.67–6.73 (m, 2H,
py), 7.14 (d, 1H, J 7.9, py), 7.21 (d, 1H, J 8.2,
py), 7.26–7.35 (m, 2H, ArH), 7.79–7.87 (m,
2H, ArH)
2.82 (t, 4H, J 5.8, NCH2), 3.88 (t, 4H, J 5.9,
NCH2), 4.19 (m, 1H, CH), 6.32 (s, 1H, CH),
7.16–7.35 (m, 9H, ArH), 7.74–7.87 (m, 4H,
ArH)
3.42 (t, 4H, J 6.0, NCH2), 4.07 (t, 4H, J 6.2,
NCH2), 6.43 (s, 1H, CH), 6.84–6.98 (m, 3H,
ArH), 7.13–7.35 (m, 3H, ArH), 7.80–7.87 (m,
2H, ArH)
2.72 (t, 4H, J 6.0, NCH2), 3.86 (t, 4H, J 6.4,
NCH2), 4.29 (m, 1H, CH), 6.94 (s, 1H, CH),
7.24–7.42 (m, 12H, ArH)
3.42 (t, 4H, J 6.2, NCH2), 4.07 (t, 4H, J 6.0,
NCH2), 6.46 (s, 1H, CH), 6.96 (d, 2H, J 7.4,
ArH), 7.27–7.31 (m, 3H, ArH), 7.45 (d, 2H,
J 8.2, ArH), 7.76 (d, 2H, J 8.0, ArH)
2.64 (t, 4H, J 6.0, NCH2), 3.88 (t, 4H, J 6.3,
NCH2), 4.30 (s, 1H, CH), 6.57 (s, 1H, CH),
7.32–7.40 (m, 6H, ArH), 7.67–7.81 (m, 6H,
ArH)
3.78 (t, 4H, J 6.2, NCH2), 3.90 (s, 3H, OCH3),
4.07 (t, 4H, J 6.4, NCH2), 6.47 (s, 1H, CH),
6.89–6.95 (m, 4H, ArH), 7.44–7.51 (m, 2H,
ArH), 7.74–7.84 (m, 2H, ArH)
3.82 (t, 4H, J 6.3, NCH2), 4.07 (t, 4H, J 6.2,
NCH2), 6.47 (s, 1H, CH), 6.62–6.76 (m, 2H,
py), 7.18 (d, 1H, J 7.9, py), 7.27 (d, 1H, J 8.0,
py), 7.29–7.35 (m, 2H, ArH), 7.59–7.77 (m,
2H, ArH)
3.43 (t, 4H, J 6.4, NCH2), 4.05 (t, 4H, J 6.6,
NCH2), 4.19 (s, 1H, CH), 6.60 (s, 1H, CH),
6.92 (d, 2H, J 8.8, ArH), 6.98 (d, 2H, J 9.0,
ArH), 7.35–7.53 (m, 5H, ArH), 7.63–7.69 (m,
4H, ArH)
2.64 (t, 4H, J 6.2, NCH2), 3.58 (s, 2H, CH2),
3.88 (t, 4H, J 6.4, NCH2), 6.40 (s, 1H, CH),
7.28–7.42 (m, 5H, ArH), 7.61–7.72 (m, 4H,
ArH)
3.43 (t, 4H, J 6.2, NCH2), 4.06 (t, 4H, J 6.0,
NCH2), 6.48 (s, 1H, CH), 6.94 (d, 2H, J 8.0,
ArH), 7.21–7.35 (m, 3H, ArH), 7.53–7.90 (m,
2H, ArH), 7.91 (s, 1H, ArH)
3.40 (t, 4H, J 6.1, NCH2), 3.87 (s, 3H, OCH3),
4.06 (t, 4H, J 6.2, NCH2), 6.66 (s, 1H, CH),
7.27–7.35 (m, 3H, ArH), 7.46–7.92 (m, 5H,
ArH)
2.56 (t, 4H, J 6.0, NCH2), 3.87 (t, 4H, J 6.3,
NCH2), 4.26 (s, 1H, CH), 6.36 (d, 2H, J 7.8,
CH, Furyl), 6.77 (d, 1H, J 7.9, Furyl), 6.88–
7.12 (m, 1H, Furyl), 7.32–7.40 (m, 4H, ArH),
7.67–7.81 (m, 4H, ArH)
376 (Mϩ ϩ 1, 100), 375 (Mϩ, 10.2)
405 (Mϩ, 61.2), 404 (57.5), 162 (100)
377 (Mϩ ϩ 1, 100), 376 (Mϩ, 57.5)
5b
5c
70
71
195
220
1693, 2206
1679, 2204
5d
5e
56
72
212
1701, 2206
1703, 2206
500 (Mϩ ϩ 1, 68.6), 499 (Mϩ, 100)
>260
393 (Mϩ, 93.8), 332 (12.5)
5f
62
89
200
220
1689, 2202
1695, 2213
518 (Mϩ ϩ 1, 81.6), 517 (Mϩ, 88.6)
5g
391 (Mϩ, 95.2), 375 (5.9)
5h
5i
5j
84
82
89
220
170
1684, 2210
1695, 2215
1685, 2202
520 (Mϩ, 93.6), 446 (12.3)
421 (Mϩ, 100), 277 (10.9)
>260
393 (Mϩ ϩ 1, 51.5), 392 (Mϩ, 83.1)
5k
68
260
1699, 2218
516 (Mϩ, 58.6), 460 (28.6)
5l
59
70
74
62
210
230
210
178
1681, 2208
1687, 2216
1705, 2205
1708, 2208
406 (Mϩ ϩ 1, 100), 405 (Mϩ, 68.9)
426 (Mϩ, 50.4), 425 (33.8)
5m
5n
5o
393 (Mϩ, 86.4), 307 (48.3)
474 (Mϩ ϩ 1, 50), 473 (Mϩ, 39.3), 461
(20.2)
a Uncorrected. b From KBr discs. c From CHCl3.
General procedure for the synthesis of 5a–o
General procedure for the synthesis of 6a–v
A mixture of a 6-aryl-3-cyano-4-methylthio-2H-pyran-2-one 1
(10 mmol) and N-substituted piperazine 4 (15 mmol) in meth-
anol was refluxed for 6 h on a boiling water-bath. After comple-
tion of the reaction, solvent was distilled off under reduced
pressure and the product obtained was filtered off and crystal-
lized from ethanol. Characterization data for all the synthesized
compounds are listed in Table 1.
A mixture of a 6-aryl-3-cyano-4-(NЈ-substituted piperazino)-
2H-pyran-2-one 5 (10 mmol), ketone RCOCH3 (15 mmol) and
potassium hydroxide (15 mmol) in dry DMF was stirred at
room temperature under a nitrogen blanket for 30 h. The reac-
tion mixture was then poured into ice–water, vigorously stirred
for 30 min, and thereafter acidified with 10% HCl. The precipi-
tate obtained was filtered off, washed with water, and purified
J. Chem. Soc., Perkin Trans. 1, 2001, 1953–1959
1957

View Article Online
Table 2 Physical and spectral data of compounds 6a–v
Compd.
Yield (%)
48
Mp (θ/ЊC)a
νmaxb/cmϪ1
δH, J/Hzc
m/z (%)
6a
145
2210
2.58 (s, 3H, CH3), 2.64 (t, 4H, J 6.2, NCH2), 3.41 (t, 4H, J 6.1, NCH2),
6.86–7.00 (m, 2H, CH), 7.11–7.19 (m, 5H, ArH), 7.51–7.57 (m, 4H,
ArH)
2.57 (s, 3H, CH3), 3.30 (t, 4H, J 5.8, NCH2), 3.46 (t, 4H, J 6.0, NCH2),
3.89 (s, 3H, OCH3), 6.87–7.02 (m, 2H, CH), 7.10–7.19 (m, 4H, ArH),
7.50–7.57 (m, 4H, ArH)
0.75–0.84 (m, 4H, CH2), 1.18–2.26 (m, 1H, CH), 3.26 (t, 4H, J 5.7,
NCH2), 3.39 (t, 4H, J 6.2, NCH2), 3.82 (s, 3H, OCH3), 6.87–7.02 (m,
2H, CH), 7.03–7.11 (m, 4H, ArH), 7.29–7.46 (m, 4H, ArH)
0.78–0.82 (m, 4H, CH2), 1.27–1.36 (m, 1H, CH), 3.31 (t, 4H, J 6.4,
NCH2), 3.94 (t, 4H, J 6.0, NCH2), 6.43–6.88 (m, 2H, CH), 6.99–7.03
(m, 2H, py), 7.14 (d, 1H, J 7.8, py), 7.23 (d, 1H, J 8.0, py), 7.26–7.35 (m,
2H, ArH), 7.61–7.81 (m, 2H, ArH)
2.53 (s, 3H, CH3), 2.61 (t, 4H, J 5.8, NCH2), 3.25 (t, 4H, J 6.4, NCH2),
4.30 (s, 1H, CH), 6.95 (s, 1H, CH), 7.03 (s, 1H, CH), 7.09–7.54 (m, 13H,
ArH)
1.25 (t, 3H, CH3), 2.07–2.54 (m, 2H, CH2), 3.38 (t, 4H, J 6.4, NCH2),
3.88 (t, 4H, J 6.0, NCH2), 6.52–6.73 (m, 2H, CH), 6.99–7.11 (m, 2H,
py), 7.24 (d, 1H, J 7.9, py), 7.34 (d, 1H, J 8.0, py), 7.35–7.50 (m, 2H,
ArH), 7.61–7.81 (m, 2H, ArH)
2.59 (s, 3H, CH3), 3.40 (t, 4H, J 6.1, NCH2), 4.06 (t, 4H, J 6.4, NCH2),
6.42 (s, 2H, CH), 6.96 (d, 2H, J 7.4, ArH), 7.27–7.33 (m, 3H, ArH), 7.46 (7.6)
(d, 2H, J 7.8, ArH), 7.76 (d, 2H, J 8.0, ArH)
2.53 (s, 3H, CH3), 2.72 (t, 4H, J 6.1, NCH2), 3.24 (t, 4H, J 6.2, NCH2),
4.30 (s, 1H, CH), 6.86 (s, 1H, CH), 6.95 (s, 1H, CH), 7.16–7.4 (m, 13H,
ArH)
2.47 (s, 3H, CH3), 2.53 (t, 4H, J 6.2, NCH2), 3.44 (t, 4H, J 6.0, NCH2),
4.24 (s, 1H, CH), 6.57 (s, 2H, CH), 6.87–6.98 (m, 6H, ArH), 7.30–7.42
(m, 6H, ArH)
2.55 (s, 3H, CH3), 3.32 (t, 4H, J 5.9, NCH2), 3.44 (t, 4H, J 6.1, NCH2),
3.89 (s, 3H, OCH3), 6.88–7.02 (m, 2H, CH), 7.10–7.19 (m, 4H, ArH),
7.35–7.48 (m, 4H, ArH)
2.58 (s, 3H, CH3), 3.35 (t, 4H, J 6.2, NCH2), 3.78 (t, 4H, J 6.1, NCH2),
6.64–6.73 (m, 2H, CH), 6.99–7.26 (m, 2H, py), 7.34 (d, 1H, J 7.8, py),
7.44 (d, 1H, J 8.0, py), 7.47–7.58 (m, 2H, ArH), 7.63–7.81 (m, 2H, ArH)
2.07–2.14 (m, 4H, CH2), 2.34 (t, 4H, J 5.8, NCH2), 3.22 (t, 4H, J 6.0,
NCH2), 3.83 (s, 3H, OCH3), 6.44 (s, 2H, CH), 6.74–6.97 (m, 4H, ArH),
7.10–7.19 (m, 4H, ArH), 7.35–7.48 (m, 5H, ArH)
0.68 (t, 3H, J 6.2, CH3), 1.10–1.28 (m, 4H, CH2), 1.30–1.40 (m, 4H,
CH2), 2.46 (t, 4H, J 6.2, NCH2), 3.08 (t, 4H, J 6.0, NCH2), 4.22 (s, 1H,
CH), 6.57 (s, 2H, CH), 7.07–7.18 (m, 6H, ArH), 7.25–7.34 (m, 6H,
ArH)
2.14–2.27 (m, 4H, CH2), 2.37 (t, 4H, J 5.9, NCH2), 3.13 (t, 4H, J 6.1,
NCH2), 4.30 (s, 1H, CH), 6.44 (s, 2H, CH), 6.85–6.98 (m, 4H, ArH),
7.16–7.23 (m, 8H, ArH), 7.30–7.40 (m, 5H, ArH)
0.75–0.84 (m, 4H, CH2), 2.26–2.33 (m, 1H, CH), 3.43 (t, 4H, J 5.9,
NCH2), 3.81 (t, 4H, J 6.2, NCH2), 3.89 (s, 3H, OCH3), 6.87–6.99 (m,
2H, CH), 7.03–7.11 (m, 4H, ArH), 7.29–7.44 (m, 4H, ArH)
0.75–0.83 (m, 4H, CH2), 2.24–2.67 (m, 1H, CH), 3.34 (t, 4H, J 5.9,
NCH2), 3.48 (t, 4H, J 6.0, NCH2), 3.67 (s, 2H, NCH2Ph), 6.88–7.02 (m,
2H, CH), 7.06–7.19 (m, 4H, ArH), 7.29–7.46 (m, 5H, ArH)
0.79–1.12 (m, 4H, CH2), 2.29–2.36 (m, 1H, CH), 3.36 (t, 4H, J 6.4,
NCH2), 3.79 (t, 4H, J 6.2, NCH2), 6.64–6.73 (m, 2H, CH), 6.99–7.26
(m, 2H, py), 7.36 (d, 1H, J 7.9, py), 7.43 (d, 1H, J 8.0, py), 7.47–7.58 (m,
2H, ArH), 7.71–7.85 (m, 2H, ArH)
371 (Mϩ, 100), 340
(10.8)
6b
6c
6d
56
58
64
147
158
190
2218
2216
2218
401 (Mϩ, 100), 238
(38.5)
427 (Mϩ, 80.2), 391
(42)
398 (Mϩ, 51.1), 167
(39)
6e
6f
60
52
140
148
2214
2220
495 (Mϩ, 50), 467
(10.2)
387 (Mϩ ϩ 1, 100),
386 (Mϩ, 55.3)
6g
6h
6i
65
53
56
68
67
39
36
140
160
176
170
168
142
oil
2200
2205
2210
2212
2214
2232
2228
387 (Mϩ, 92.2), 320
512 (Mϩ, 50.8), 460
(10.8)
513 (Mϩ, 88.8), 310
(31)
6j
417 (Mϩ, 100), 402
(20.2)
6k
6l
388 (Mϩ, 33.3), 282
(18.7)
508 (Mϩ ϩ 1, 80),
507 (Mϩ, 74.2)
6m
570 (Mϩ ϩ 1, 90),
569 (Mϩ, 62), 535
(70.5)
6n
6o
6p
6q
40
55
54
49
98
178
159
152
2214
2216
2214
2222
604 (Mϩ ϩ 1, 50),
603 (Mϩ, 22.2)
443 (Mϩ, 100), 279
(26.5)
427 (Mϩ, 88.2), 401
(33.5)
415 (Mϩ ϩ 1, 90),
414 (Mϩ, 58)
6r
50
126
2214
0.76–1.18 (m, 4H, CH2), 2.25–2.33 (m, 1H, CH), 2.60 (t, 4H, J 6.2,
NCH2), 3.25 (t, 4H, J 6.0, NCH2), 4.31 (s, 1H, CH), 6.57 (s, 2H, CH),
6.89–6.95 (m, 6H, ArH), 7.26–7.39 (m, 6H, ArH)
2.53 (s, 3H, CH3), 3.42 (t, 4H, J 6.0, NCH2), 4.01 (t, 4H, J 6.2, NCH2),
6.42 (s, 2H, CH), 6.86–7.01 (m, 3H, ArH), 7.29–7.41 (m, 5H, ArH)
2.50 (s, 3H, CH3), 2.60 (t, 4H, J 6.3, NCH2), 3.24 (t, 4H, J 6.4, NCH2),
4.21 (s, 1H, CH), 6.52 (s, 2H, CH), 6.60–6.75 (m, 4H, ArH), 7.03–7.17
(m, 4H, ArH), 7.26–7.36 (m, 1H, Furyl), 7.41 (d, 1H, J 8.0, Furyl), 7.49
(d, 1H, J 7.9, Furyl)
0.79–1.13 (m, 4H, CH2), 1.80–2.33 (m, 1H, CH), 2.60 (t, 4H, J 6.2,
NCH2), 3.24 (t, 4H, J 6.3, NCH2), 4.31 (s, 1H, CH), 6.52 (s, 2H, CH),
6.71–6.94 (m, 4H, ArH), 6.99–7.09 (m, 4H, ArH), 7.27–7.34 (m, 1 H,
Furyl), 7.39 (d, 1H, J 7.8, Furyl), 7.49 (d, 1H, J 7.9, Furyl)
2.61 (s, 3H, CH3), 3.31 (t, 4H, J 5.8, NCH2), 4.08 (t, 4H, J 6.1, NCH2),
7.04 (s, 1H, CH), 7.16 (s, 1H, CH), 7.36 (s, 1H, ArH), 7.85–7.90 (m, 4H,
ArH), 7.92 (s, 1H, ArH), 8.53 (d, 2H, J 8.4, ArH), 8.61 (s, 1H, ArH)
540 (Mϩ ϩ 1, 60),
539 (Mϩ, 38.8)
6s
6t
63
58
140
169
2218
2220
422 (Mϩ, 98.2), 421
(100)
469 (Mϩ, 73.1), 266
(69.5)
6u
6v
48
53
182
150
2208
2210
496 (Mϩ ϩ 1, 100),
495 (Mϩ, 52.8)
423 (Mϩ ϩ 1, 100),
422 (Mϩ, 50.6)
a Uncorrected. b From KBr discs. c From CHCl3.
1958
J. Chem. Soc., Perkin Trans. 1, 2001, 1953–1959

View Article Online
Table 3 Elemental analyses of compounds 5 and 6
both compounds were performed on a Bruker P4 diffract-
ometer at 293(2) K. Structure solutions by direct methods and
refinements by full-matrix least-squares methods on F 2. Pro-
grams: XSCANS26 (data collection and data processing),
SHELXTL-NT27 (structure determination and refinements)
and NRCVAX28 (molecular graphics).
Found (%) (Required)
Compound (Formula)
C
H
N
5a (C22H18FN3O2)
5b (C23H20FN3O3)
5c (C21H17FN4O2)
5d (C29H23ClFN3O2)
5e (C22H17F2N3O2)
5f (C29H22ClF2N3O2)
5g (C22H18ClN3O2)
5h (C29H22ClF2N3O2)
5i (C23H20ClN3O3)
5j (C21H17ClN4O2)
5k (C29H23Cl2N3O2)
5l (C23H20ClN3O2)
5m (C22H17Cl2N3O2)
5n (C22H20FN3O3)
5o (C27H21F2N3O3)
6a (C24H22FN3)
70.64 (70.39)
68.04 (68.12)
67.35 (67.07)
69.39 (69.66)
66.95 (67.16)
67.39 (67.25)
67.67 (67.48)
66.56 (66.97)
65.66 (65.61)
64.13 (64.33)
67.12 (67.45)
68.04 (68.20)
62.12 (61.98)
67.22 (67.16)
68.34 (68.55)
77.41 (77.60)
74.51 (74.87)
76.11 (75.94)
75.75 (75.43)
74.89 (75.06)
74.53 (74.67)
73.99 (74.30)
72.38 (72.65)
72.48 (72.57)
71.87 (72.00)
71.53 (71.19)
75.87 (75.80)
73.48 (73.87)
75.87 (75.68)
73.51 (73.19)
76.11 (76.40)
75.53 (75.24)
73.98 (73.53)
68.39 (68.25)
73.98 (74.26)
74.98 (75.21)
68.14 (68.23)
4.59 (4.83)
4.78 (4.97)
4.75 (4.55)
4.75 (4.63)
4.63 (4.35)
4.39 (4.28)
4.59 (4.63)
4.59 (4.26)
4.92 (4.78)
4.55 (4.37)
4.25 (4.48)
4.92 (4.97)
4.35 (4.02)
5.35 (5.12)
4.89 (5.11)
5.58 (5.97)
5.98 (6.03)
5.98 (6.13)
5.55 (5.82)
5.75 (5.48)
6.13 (6.00)
5.76 (5.71)
4.93 (5.31)
5.28 (5.10)
5.74 (5.80)
5.13 (5.45)
5.74 (5.96)
6.28 (6.02)
5.74 (5.34)
5.98 (5.91)
5.98 (6.07)
5.33 (5.60)
5.48 (5.23)
5.36 (5.01)
5.28 (5.37)
5.90 (5.49)
5.36 (5.25)
11.34 (11.19)
10.59 (10.36)
14.78 (14.90)
8.29 (8.40)
10.39 (10.68)
8.42 (8.11)
10.59 (10.62)
7.69 (8.08)
9.68 (9.98)
13.98 (14.29)
8.29 (8.13)
10.58 (10.37)
9.98 (9.86)
10.39 (10.68)
8.59 (8.88)
11.65 (11.31)
10.80 (10.67)
10.05 (9.84)
14.28 (14.07)
8.29 (8.47)
The ORTEP28 diagrams of 5h (Fig. 1) and 6q (Fig. 3) and
crystal packing (PLUTO28) of 5h (Fig. 2) are shown.
Acknowledgements
We are thankful to ICMR New Delhi for financial support.
References
1 R. Noyori, Chem. Soc. Rev., 1989, 18, 187.
2 D. Cram, J. Angew. Chem., Int. Ed. Engl., 1988, 27, 1009.
3 (a) K. Yamamura, S. Ono and I. Taushi, Tetrahedron Lett., 1988,
29, 1797; (b) K. Yamamura, S. Ono, H. Ogoshi, H. Masuda and
Y. Kuroda, Synlett, 1989, 18.
6b (C25H24FN3O)
6c (C27H26FN3O)
6d (C25H23FN4)
6e (C31H27ClFN3)
6f (C24H23FN4)
4 F. Mikes and G. Boshart, J. Chromatogr., 1978, 149, 455.
5 (a) D. S. Chemia and J. Zyss, Nonlinear Optical Properties of Organic
Molecules and Crystals, Academic Press, New York, 1987; (b) K.
Kobayashi, Nonlinear Optics of Organics and Semiconductors,
Springer-Verlag, Tokyo, 1989; (c) P. N. Prasad and D. J. Williams,
Introduction to Non-linear Optical Effects in Molecules and Polymers,
Wiley-Interscience, New York, 1991.
14.76 (14.51)
10.65 (10.83)
8.42 (8.20)
6g (C24H22ClN3)
6h (C31H27Cl2N3)
6i (C31H26ClF2N3)
6j (C25H24ClN3O)
6k (C23H21ClN4)
6l (C32H30ClN3O)
6m (C35H34ClF2N3)
6n (C38H32ClF2N3)
6o (C27H26ClN3O)
6p (C27H26ClN3)
6q (C25H23ClN4)
6r (C33H28ClF2N3)
6s (C24H21Cl2N3)
6t (C29H25F2N3O)
6u (C31H27F2N3O)
6v (C24H22N8)
8.59 (8.19)
6 F. Ullman and J. Bielecki, Ber. Dtsch. Chem. Ges., 1901, 34, 2174.
7 P. E. Fanta, Synthesis, 1974, 9.
9.87 (10.07)
14.76 (14.44)
8.87 (8.28)
7.59 (7.38)
6.87 (6.96)
8 E. Brown and J.-P. Robin, Tetrahedron, 1982, 38, 2569.
9 M. F. Semmelhack, P. Helquist, L. D. Lones, L. Keller,
L. Mendelson, L. S. Royono, J. Gorzynski Smith and R. D. Stauffer,
J. Am. Chem. Soc., 1981, 103, 6460.
10 W. I. Taylor and A. R. Battersby, in Oxidative Coupling of Phenols,
Marcel Dekker, New York, 1967, vol. 1.
11 R. A. Jonass and D. C. Shubert, J. Org. Chem., 1983, 48, 1924.
12 Y. Landais, A. Lebrum, U. Lenain and J.-P. Robin, Tetrahedron
Lett., 1987, 28, 5161.
13 Y. Landais, A. Lebrum, D. Rambault and J.-P. Robin, Tetrahedron
Lett., 1987, 28, 543.
9.05 (9.48)
10.05 (9.80)
13.96 (13.53)
8.09 (7.79)
9.63 (9.95)
7.59 (7.38)
8.09 (8.48)
26.28 (26.52)
14 S. K. Taylor, S. G. Bennet, K. J. Heinz and L. K. Lashley, J. Org.
Chem., 1981, 46, 2194.
15 (a) N. Miyaura, T. Yanagi and A. Suzuki, Synth. Commun., 1981, 11,
513; (b) N. Miyara, K. Yamada, H. Suginome and A. Suzuki, J. Am.
Chem. Soc., 1985, 107, 972; (c) A. Suzuki, Pure Appl. Chem., 1991,
63, 419.
16 A. Suzuki and N. Miyaura, Chem. Rev., 1995, 95, 2457.
17 (a) G. Marck, A. Villinger and R. Buchecker, Tetrahedron Lett.,
1994, 35, 3277; (b) T. I. Wallow and B. M. Novak, J. Org. Chem.,
1994, 59, 5034; (c) M. Moreno-Manas, F. Pajuelo and R. Pleixats,
J. Org. Chem., 1995, 60, 2396.
18 (a) K. Alder and H. Rickert, Ber. Dtsch. Chem. Ges., 1937, 70, 1354;
(b) E. Wenkert, D. B. R. Johnston and K. G. Dave, J. Org. Chem.,
1964, 29, 2534; (c) J. A. Reed, C. L. Shilling, R. F. Tarvin, Jr,
T. A. Rettig and J. K. Stille, J. Org. Chem., 1969, 34, 2188.
19 (a) R. Gompper and O. Christmann, Angew. Chem., 1959, 71,
32; (b) R. Gompper and O. Christmann, Chem. Ber., 1961, 94,
1795.
20 (a) A. I. Meyers and E. D. Mihelich, J. Am. Chem. Soc., 1975, 97,
7383; (b) A. I. Meyers, R. Gabel and E. D. Mihelich, J. Org. Chem.,
1978, 43, 1372; (c) A. M. Warshawsky and A. I. Meyers, J. Am.
Chem. Soc., 1990, 112, 8090; (d ) A. I. Meyers and D. J. Rawson,
Tetrahedron Lett., 1992, 33, 583.
on a silica gel column, using chloroform–hexane (1 : 1) as elu-
ent. Characterization data for all the synthesized compounds
are listed in Table 2. Elemental analyses of compounds 5 and 6
are listed in Table 3.
X-Ray crystallographic data‡
Crystal data for 5h. C29H22ClF2N3O2, M = 517.95, mono-
clinic, C2/c, a = 44.292(4) b = 7.662(1), c = 14.949(1) Å,
β = 92.71(0)Њ, V = 5067.5(9) Å3, Z = 8, Dc = 1.358 g cmϪ1
,
µ(Mo-Kα) = 0.198 mmϪ1, F(000) = 2144.0, yellowish plate crys-
tal, size 0.375 × 0.275 × 0.075 mm, 5759 reflections measured
(Rint = 0.033), 4445 unique, Rw = 0.124 for all data, con-
ventional R = 0.054 [(∆/σ)max = 0.000] on F-values of 2219
reflections with I > 2σ(I ), S = 1.006 for all data and 334 param-
eters. Final difference map between 0.172 and Ϫ0.297 e ÅϪ3
.
Crystal data for 6q. C25H23ClN4, M = 414.92, triclinic, P(Ϫ1),
a = 8.452(1), b = 12.398(1), c = 21.137(1) Å, α = 75.02(1),
β = 83.19(1), γ = 81.70(1)Њ, V = 2109.6(4) Å3, Z = 4, Dc = 1.307 g
21 (a) Y. Tominaga, A. Ushirogochi and Y. Matsuda, J. Heterocycl.
Chem., 1987, 24, 1557; (b) V. J. Ram, M. Verma, F. A. Hussaini and
A. Shoeb, J. Chem. Res (S), 1991, 98; (c) V. J. Ram, M. Verma,
F. A. Hussaini and A. Shoeb, Liebigs Ann. Chem., 1991, 1229.
22 M. Lehn, Angew. Chem., Int. Ed. Engl., 1990, 29, 1304.
23 G. R. Desiraju, Angew. Chem., Int. Ed. Engl., 1995, 34, 2311.
24 C. A. Hunter and J. K. M. Sanders, J. Am. Chem. Soc., 1990, 112,
5525.
cmϪ1
, , F(000) = 872.0, colourless
µ(Mo-Kα) = 0.201 mmϪ1
block crystal, size 0.425 × 0.352 × 0.200 mm, 8900 reflections
measured (Rint = 0.028), 7258 unique, Rw = 0.143 for all data,
conventional R = 0.055 [(∆/σ)max = 0.000] on F-values of 5254
reflections with I > 2σ(I ), S = 0.962 for all data and 542 param-
eters. Final difference map between 0.62 and Ϫ0.59 e ÅϪ3. Unit-
cell determination and intensity-data collection (2θ = 50Њ) for
25 D. Braga and F. Grepioni, Acc. Chem. Res., 1997, 30, 81.
26 XSCANS, Version 2.21, 1996, Siemens Analytical X-ray
Instruments Inc., Madison, Wisconsin, USA, 1996.
27 SHELXTL-NT, Version 5.1, Bruker AXS Inc., Madison,
Wisconsin, USA, 1997.
28 E. J. Gabe, Y. Le Page, J.-P. Charland, F. L. Lee and P. S. White,
J. Appl. Crystallogr., 1989, 22, 384.
‡ CCDC reference numbers 164198 and 164199. See http://www.rsc.org/
suppdata/p1/b0/b009725j/ for crystallographic files in .cif or other
electronic format.
J. Chem. Soc., Perkin Trans. 1, 2001, 1953–1959
1959