A facile access to the synthesis of functionalised unsymmetrical biaryls from 2H-pyran-2-ones through carbanion induced C-C bond formation

Article abstract of DOI:10.1039/b005572g

A convenient synthesis of highly functionalised biaryls 3 and 6 has been delineated through carbanion induced C-C bond formation from 6-aryl-3-cyano-4-substituted-2H-pyran-2-ones (1, 4) and acetone. Extension of this reaction, using aromatic ketones led to (4,6-diarylpyran-2-ylidene)acetonitrile (7) in lieu of the anticipated 2,4-diaryl-6-methylthiobenzonitrile (8). The structure of 2-methyl-6-methylthio-4-(3,4-methylenedioxyphenyl)benzonitrile (3f) was ascertained by single crystal X-ray diffraction analysis and displayed a variety of weak interactions, responsible for the stability and packing of the molecule in the crystalline state. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b005572g

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A facile access to the synthesis of functionalised unsymmetrical
biaryls from 2H-pyran-2-ones through carbanion induced C–C
bond formation†
1
Vishnu J. Ram,* Mahendra Nath, Pratibha Srivastava, Sanjay Sarkhel and Prakas R. Maulik‡
Divisions of Medicinal Chemistry and Membrane Biology, Central Drug Research Institute,
Lucknow 226001, India. E-mail: root@cscdri.ren.nic.in; Fax: ϩ91 522 223405
Received (in Cambridge, UK) 14th July 2000, Accepted 31st August 2000
First published as an Advance Article on the web 19th October 2000
A convenient synthesis of highly functionalised biaryls 3 and 6 has been delineated through carbanion induced C–C
bond formation from 6-aryl-3-cyano-4-substituted-2H-pyran-2-ones (1, 4) and acetone. Extension of this reaction,
using aromatic ketones led to (4,6-diarylpyran-2-ylidene)acetonitrile (7) in lieu of the anticipated 2,4-diaryl-6-
methylthiobenzonitrile (8). The structure of 2-methyl-6-methylthio-4-(3,4-methylenedioxyphenyl)benzonitrile (3f)
was ascertained by single crystal X-ray diffraction analysis and displayed a variety of weak interactions, responsible
for the stability and packing of the molecule in the crystalline state.
an electron withdrawing substituent at position 3 of the pyran
Introduction
ring. Reaction of 1 with the anion obtained from 2,2-dimethyl-
The biaryl system serves as a central building block in numer-
1,3-dioxane-4,6-dione (Meldrum’s acid) failed to provide the
ous natural products of biological significance. Besides diverse
anticipated product, 5-aryl-8-cyano-2,2-dimethyl-7-methylthio-
4H-1,3-benzodioxin-4-one (5). The products isolated were
assigned as 4-aryl-2-methyl-6-methylthiobenzonitrile (3) and 6-
aryl-3-cyano-4-dimethylamino-2H-pyran-2-one (4). The genesis
for compounds 3 and 4 is based on the reaction of 1 with
acetone and dimethylamine formed in situ from Meldrum’s acid
and DMF respectively from the reaction mixture (Scheme 1).
therapeutic potential, these compounds display interesting
properties as chiral reagents1 and crown ethers,2 as chiral host
molecules for inclusion compounds,3 as chiral phases for
chromatography4 and as chiral liquid crystals.5
Symmetrical biaryls have been synthesized earlier by coup-
ling of two aromatic moieties in the presence of different coup-
ling reagents.6–14 A highly versatile procedure, commonly used
in natural product synthesis, is based on palladium catalysed
cross coupling of electrophilic (R–X) species and arylboronic
acid.15 Unsymmetrical biaryls have been synthesized from
2H-pyran-2-one either by Diels–Alder reactions16 or by ring
transformation from Grignard reagents.17 Unsymmetrical
biaryls have been also obtained18 through dihydrooxazole-
mediated coupling reactions.
Results and discussion
We report here an alternative efficient and convenient synthesis
of unsymmetrical biaryls from 6-aryl-3-cyano-4-substituted-
2H-pyran-2-ones (1, 4) obtained from the reaction of ethyl
2-cyano-3,3-dimethylthioacrylate and an aromatic ketone19
using acetone as a source of carbanion, generated in situ or as a
reagent. This reaction is of high synthetic significance in terms
of (1) versatility and compatibility, (2) mild reaction conditions,
Scheme 1
(3) use of cost effective reagents, (4) easy work-up, and (5) no
use of catalyst. The only limitation of this reaction is that aro-
matic ketones do not follow the same course of reaction to yield
8, as enolization is favoured followed by cyclization to form
(4,6-diarylpyran-2-ylidene)acetonitrile (7).
The synthesis of biaryls is based on the carbanion induced
ring transformation of 6-aryl-3-cyano-4-substituted-2H-pyran-
Under similar reaction conditions no product analogous to
4 was obtained in the absence of Meldrum’s acid while in
the reaction without DMF neither compound 3 nor 4 was
isolated. These observations confirmed that DMF plays an
important role in the generation of acetone and dimethyl-
amine in situ from the reaction mixture. A change of solvent
from DMF to DMSO also failed to yield ring transformed
2-one (1, 4) with acetone. Pyran-2-ones (1 and 4) may be con-
product 3.
sidered to be a cyclic methylthioketene hemiacetal (1) and a
The structure of both the compounds (3, 4) was also
cyclic ketene hemiaminal (4) with three electrophilic centres
ascertained by their independent synthesis from the reaction
of 1 with acetone and dimethylamine. The formation of 3 is
presumed to occur through attack of the carbanion generated
C-2, C-4 and C-6 in which C-6 is highly vulnerable to nucleo-
philic attack due to extended conjugation and the presence of
from acetone in situ at C-6 in 1 with ring opening, followed
by decarboxylation and recyclization involving carbonyl and
methylene groups. A plausible mechanism for the reaction is
† CDRI communication No. 5981.
‡ For X-ray crystallography queries.
DOI: 10.1039/b005572g
J. Chem. Soc., Perkin Trans. 1, 2000, 3719–3723
This journal is © The Royal Society of Chemistry 2000
3719

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Fig. 1 Crystal structure of compound 3f.
Scheme 2
depicted in Scheme 2. The scope of this reaction was further
explored by subjecting 6-aryl-3-cyano-4-substituted-2H-pyran-
2-one (4) to ring transformation reactions from acetone
analogously. The product isolated in moderate yield from
this reaction was spectroscopically characterized as 4-aryl-2-
methyl-6-substituted-benzonitrile (6).
This reaction provided conclusive evidence that the SCH3
substituent at position 4 in 1 is not essential for the ring trans-
formation reactions. However the reaction of lactone 1 with
aromatic ketones did not follow the same course of reaction,
and failed to yield the anticipated 1,3-teraryl (8) as it favours
enolization followed by cyclization. In this reaction the anion
generated from the aromatic ketone attacks at the C-6 position
in 1 with ring opening followed by decarboxylation, enolization
and cyclization with elimination of methanethiol to yield (4,6-
diarylpyran-2-ylidene)acetonitrile (7). The configuration of
the isolated geometrical isomer 7 was ascertained by an NOE
experiment. Irradiation of vinylic proton at δ 6.45 showed
enhancement in the signal intensity of the H-3 proton by 25%
without any change in signal intensity of the H-5 proton, which
unambiguously confirmed the Z configuration of the isolated
product 7 (Scheme 3). The 6-aryl substituent in 1 plays a
pivotal role in the ring transformation reactions by either
increasing or maintaining the electrophilicity of the C-6 carbon
of the pyran ring but reduction in the electropositive character
of C-6 by the presence of an alkyl substituent, did not yield
desired compound. Thus the reaction of 3-cyano-6-methyl-4-
methylthio-2H-pyran-2-ones with acetone failed to yield a
compound analogous to 3 but led to recovery of starting
material.
Scheme 3
The structure of one of the biaryls (3f) was further con-
firmed by single crystal X-ray diffraction analysis. The crystal
structure of 3f (Fig. 1) showed that ring A is twisted with
respect to ring B by an angle of 30.7Њ.
The crystal packing revealed some interesting aspects of
weak, intermolecular non-covalent interactions. Weak hydro-
gen bonds of the nature of C–H ؒ ؒ ؒ O, C–H ؒ ؒ ؒ N and uncom-
mon C–H ؒ ؒ ؒ S interactions are present. The importance of
such interactions is currently being recognised in the stability
of nucleic acids,20 protein structures, molecular recognition
processes, crystal engineering21 and supramolecular design.
The important hydrogen bonding parameters are shown in
Table 1.
The observed C–H ؒ ؒ ؒ A (A = N, O and S) geometrical
parameters compare well with the literature values. There are
only a few previous reports of C–H ؒ ؒ ؒ S interactions.22
The four molecules in the unit cell (Fig. 2) show inter-
molecular aromatic π–π interactions (APPI). The molecules
3720
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Table 1 Intermolecular distances and angles for C–H ؒ ؒ ؒ A interactions in 3f
H-bond
H ؒ ؒ ؒ A/Å
C ؒ ؒ ؒ A/Å
C–H ؒ ؒ ؒ A/Њ
C9–H9C ؒ ؒ ؒ N1(X, 1 Ϫ Y, Ϫ1/2 ϩ Z )
2.880
2.804
2.638
3.191
3.289
3.817
3.702
3.591
3.882
4.131
165.5
162.5
171.6
132.7
151.7
C5Ј–H5Ј ؒ ؒ ؒ N1(Ϫ1/2 ϩ X, Ϫ1/2 ϩ Y, Ϫ1 ϩ Z )
C7–H7A ؒ ؒ ؒ O1(1/2 ϩ X, Ϫ1/2 ϩ Y, 1 ϩ Z )
C4–H4 ؒ ؒ ؒ S1(Ϫ1/2 ϩ X, 1/2 Ϫ Y, Ϫ1/2 ϩ Z )
C6–H6 ؒ ؒ ؒ S1(X, ϪY, Ϫ1/2 ϩ Z )
General procedure B. A mixture of 6-aryl-3-cyano-4-methyl-
thio-2H-pyran-2-one (1, 10 mmol), acetone (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 poured into ice–water with vigorous stirring
for half an hour, and thereafter acidified with 10% HCl. The
precipitate obtained was filtered, washed with water and puri-
fied on a silica gel column using chloroform–hexane (1:1) as
eluent.
The yields of the isolated products prepared by following
procedure B are given below.
4-(4-Fluorophenyl)-2-methyl-6-methylthiobenzonitrile
(3a).
Yield: 65%; mp: 106 ЊC; νmax/cmϪ1 2212 (CN); m/z (EI) 257
(Mϩ, 27%), 256 (100), 241 (3.5), 240 (9.6), 224 (34.1), 208 (15.6),
182 (12.2); δH (200 MHz, CDCl3) 2.59 (s, 3H, CH3), 2.60 (s, 3H,
SCH3), 7.23 (s, 1H, ArH), 7.25 (s, 1H, ArH), 7.26–7.28 (m, 2H,
ArH), 7.52–7.57 (m, 2H, ArH) (Found: C, 69.80; H, 4.92; N,
5.63. C15H12FNS requires: C, 70.01; H, 4.70; N, 5.44%).
Fig. 2 Crystal packing of compound 3f.
are stacked in pairs (along the a-axis), each with a symmetry-
translated molecule at an equivalent position. Phenyl rings (A)
and (B) overlap in an offset geometry. This is in accordance
with Hunter’s electrostatic model23–26 of APPI. The stacked
rings are separated by an average interplanar distance of 3.5 Å,
while the centre-to-centre distance measures 4.16 Å. The
stacked rings are almost parallel (angle between the planes
~7.6Њ) but are rotated almost by ~31Њ about the stacking axis.
This, thus presents an interesting example of the contribution
of these weak interactions towards the stability and packing of
the molecule 3f in the crystalline state.
4-(4-Chlorophenyl)-2-methyl-6-methylthiobenzonitrile (3b).
Yield: 68%; mp: 85 ЊC; νmax/cmϪ1 2210 (CN); m/z (EI) 273 (Mϩ,
21.3%), 272 (39.7), 269 (34.3), 239 (11.7), 189 (11.1); δH (300
MHz, CDCl3) 2.59 (s, 3H, CH3), 2.60 (s, 3H, SCH3), 7.23 (s, 1H,
ArH), 7.26 (d, 2H, J = 7.8 Hz, ArH), 7.27 (s, 1H, ArH), 7.45
(d, 2H, J = 7.8 Hz, ArH) (Found: C, 65.80; H, 4.42; N, 5.33.
C15H12ClNS requires: C, 65.79; H, 4.71; N, 5.11%).
Experimental
General
4-(4-Bromophenyl)-2-methyl-6-methylthiobenzonitrile
(3c).
Yield: 58%; mp: 132 ЊC; νmax/cmϪ1 2210 (CN); m/z (EI) 318
(Mϩ, 88.4%), 317 (100), 303 (4.5), 301 (3.4), 286 (19.3), 284
(16.9), 237 (5.3), 222 (16.2), 190 (52.0); δH (300 MHz, CDCl3)
2.59 (s, 3H, CH3), 2.60 (s, 3H, SCH3), 7.23 (s, 1H, ArH), 7.26 (s,
1H, ArH), 7.43 (d, 2H, J = 8.4 Hz, ArH), 7.6 (d, 2H, J = 8.4 Hz,
ArH) (Found: C, 56.48; H, 4.15; N, 4.58. C15H12BrNS requires:
C, 56.60; H, 3.80; N, 4.40%).
Mps were determined in an open capillary with a Büchi-530
melting point apparatus and are uncorrected. 1H NMR spectra
were recorded on a Bruker WM (400 MHz) spectrometer using
TMS as reference. IR spectra were obtained in KBr discs on a
Perkin-Elmer Ac-1 spectrophotometer. EI 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-
1108 elemental analyser. TLC was performed on 7 × 3 cm thin
layer analytical plates (SRL).
2-Methyl-6-methylthio-4-(4-nitrophenyl)benzonitrile
(3d).
Yield: 69%; mp: 193 ЊC; νmax/cmϪ1 2206 (CN); m/z (EI) 284
(Mϩ, 44.2%), 283 (100), 254 (14.6), 237 (42.3), 222 (17.5), 208
(20.1), 205 (22.2); δH (300 MHz, CDCl3) 2.62 (s, 3H, CH3), 2.63
(s, 3H, SCH3), 7.29 (s, 1H, ArH), 7.36 (s, 1H, ArH), 7.72 (d, 2H,
J = 9.3 Hz, ArH), 8.72 (d, 2H, J = 9.3 Hz, ArH) (Found: C,
63.52; H, 4.38; N, 10.21. C15H12N2O2S requires: C, 63.36; H,
4.26; N, 9.89%).
Precursors 1 and 4 were synthesized according to standard
procedures.19 The structure of the product 3f was assigned by
single crystal X-ray diffraction.
Synthesis of 4-aryl-2-methyl-6-methylthiobenzonitrile (3) and
6-aryl-3-cyano-4-dimethylamino-2H-pyran-2-one (4)
General procedure A. A mixture of 6-aryl-3-cyano-4-methyl-
4-(3,4-Dichlorophenyl)-2-methyl-6-methylthiobenzonitrile
(3e). Yield: 62%; mp: 100 ЊC; νmax/cmϪ1 2208 (CN); m/z (EI) 308
(Mϩ, 2.2%), 307 (5.4), 279 (3.3), 200 (57.5), 187 (37.2), 185
(100); δH (300 MHz, CDCl3) 2.57 (s, 3H, CH3), 2.58 (s, 3H,
SCH3), 7.2 (d, 1H, J = 8.4 Hz, ArH), 7.27 (s, 1H, ArH), 7.28
(s, 1H, ArH), 7.84 (d, 1H, J = 8.1 Hz, ArH), 7.92 (s, 1H, ArH)
(Found: C, 58.32; H, 4.86; N, 4.72. C15H11Cl2NS requires: C,
58.45; H, 4.58; N, 4.54%).
thio-2H-pyran-2-one (1,
1 mmol) and 2,2-dimethyl-1,3-
dioxane-4,6-dione (2, 1 mmol) in dry DMF (12 ml) contain-
ing powdered KOH (0.22 g, 4 mmol) was stirred under an
atmosphere of nitrogen at ambient temperature for 30 h. After
completion of the reaction, the mixture was poured into ice–
water and acidified with 10% HCl. The precipitate obtained was
collected and purified on a silica gel column using hexane as
eluent.
The two products isolated from the column were charac-
terized as 4-aryl-2-methyl-6-methylthiobenzonitrile (3) and
6-aryl-3-cyano-4-dimethylamino-2H-pyran-2-one (4).
Both compounds 3 and 4 were further independently
synthesized.
2-Methyl-4-(3,4-methylenedioxyphenyl)-6-methylthiobenzo-
nitrile (3f). Yield: 68%; mp: 142 ЊC; νmax/cmϪ1 2216 (CN); m/z
(EI) 283 (Mϩ, 100%), 281 (19.3), 253 (30.6), 250 (19.1), 210
(3.8); δH (300 MHz, CDCl3) 2.54 (s, 3H, CH3), 2.57 (s, 3H,
SCH3), 6.01 (s, 2H, CH), 6.88 (d, 1H, J = 8.4 Hz, ArH), 7.03 (d,
J. Chem. Soc., Perkin Trans. 1, 2000, 3719–3723
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1H, J = 8.6 Hz, ArH), 7.04 (s, 1H, ArH), 7.17 (s, 1H, ArH),
7.20 (s, 1H, ArH) (Found: C, 68.12; H, 4.83; N, 5.23.
C16H13NO2S requires: C, 67.82; H, 4.62; N, 4.94%).
2H, ArH) (Found: C, 68.93; H, 5.16; N, 8.73. C18H17FN2O2
requires: C, 69.22; H, 5.48; N, 8.97%).
3-Cyano-6-(4-chlorophenyl)-4-(4-methylpiperidino)-2H-
pyran-2-one (4h). Yield: 0.23 g (70%); mp: >280 ЊC; νmax/cmϪ1
1685 (CO), 2203 (CN); m/z (EI) 328 (Mϩ, 76.5%), 311 (12.2),
299 (18.3), 286 (34.5); δH (300 MHz, CDCl3) 1.03 (d, 3H, J = 6.3
Hz, CH3), 1.31–1.45 (m, 1H, CH), 1.76–1.81 (m, 2H, CH2),
1.82–1.93 (m, 2H, CH2), 3.22–3.31 (m, 2H, NCH2), 4.39 (t, 2H,
J = 7.8 Hz, NCH2), 6.43 (s, 1H, CH), 7.45 (d, 2H, J = 8.7 Hz,
ArH), 7.74 (d, 2H, J = 8.7 Hz, ArH) (Found: C, 65.56; H, 4.98;
N, 8.23. C18H17ClN2O2 requires: C, 65.75; H, 5.21; N, 8.52%).
6-Aryl-3-cyano-4-dimethylamino-2H-pyran-2-one (4a–f)
A mixture of 3-cyano-6-aryl-4-methylthio-2H-pyran-2-one (1,
0.26 g, 1 mmol), dimethylamine hydrochloride (0.12 g, 1.5
mmol) and potassium carbonate (0.21 g, 1.5 mmol) in acetone
was refluxed for 6 h. The solvent was removed under reduced
pressure and the residue was treated with water to remove the
inorganic material. The product thus obtained was crystallized
from methanol.
4-(4-Chlorophenyl)-2-dimethylamino-6-methylbenzonitrile (6b)
3-Cyano-4-dimethylamino-6-(4-fluorophenyl)-2H-pyran-2-one
(4a). Yield: 0.18 g (70%); mp: 230 ЊC; νmax/cmϪ1 1683 (CO),
2206 (CN); m/z (EI) 258 (Mϩ, 82%), 243 (25), 214 (20), δH (300
MHz, CDCl3) 3.45 (s, 6H, (CH3)2N), 6.36 (s, 1H, CH), 7.13–
7.19 (m, 2H, ArH), 7.82–7.85 (m, 2H, ArH) (Found: C, 65.32;
H, 4.51; N, 10.76. C14H11FN2O2 requires: C, 65.11; H, 4.26;
N, 10.85%).
Compound 6b was prepared by stirring a mixture of 6-(4-
chlorophenyl)-3-cyano-4-dimethylamino-2H-pyran-2-one (4b,
0.275 g, 1 mmol), dry acetone (0.5 mL, 7 mmol) and powdered
KOH (0.084 g, 1.5 mmol) in dry DMF (10 ml) at ambient tem-
perature under a nitrogen blanket for 35 h. The reaction mix-
ture was poured onto ice, stirred for 1 h and thereafter acidified
with 10% HCl. The precipitate thus obtained was filtered and
the crude product was purified on a silica gel column. Yield:
0.17 g (62.8%); mp: 110 ЊC; νmax/cmϪ1 2208 (CN); m/z (EI) 270
(Mϩ, 100%), 269 (88.2), 255 (24.1), 227 (7.7), 190 (17.0), 165
(15.8), 149 (40.5); δH (300 MHz, CDCl3) 2.59 (s, 3H, CH3), 3.15
(s, 6H, (CH3)2N), 7.12 (s, 1H, ArH), 7.32 (s, 1H, ArH), 7.44
(d, 2H, J = 9 Hz, ArH), 7.52 (d, 2H, J = 9 Hz, ArH) (Found: C,
71.21; H, 5.32; N, 10.56. C16H15ClN2 requires: C, 70.97; H, 5.58;
N, 10.35%).
6-(4-Chlorophenyl)-3-cyano-4-dimethylamino-2H-pyran-2-one
(4b). Yield: 0.20 g (73%); mp: 256 ЊC; νmax/cmϪ1 1683 (CO),
2202 (CN); m/z (EI) 276 (19.4), 274 (Mϩ, 56.7%), 246 (14.3),
183 (11.2), 163 (13.3), 139 (100), 111 (48); δH (300 MHz, CDCl3)
3.46 (s, 6H, (CH3)2N), 6.40 (s, 1H, CH), 7.45 (d, 2H, J = 8.7 Hz,
ArH), 7.75 (d, 2H, J = 8.7 Hz, ArH) (Found: C, 61.38; H, 4.32;
N, 10.42. C14H11ClN2O2 requires: C, 61.26; H, 4.00; N, 10.19%).
6-(4-Bromophenyl)-3-cyano-4-dimethylamino-2H-pyran-2-one
(4c). Yield: 0.22 g (70%); mp: 263 ЊC; νmax/cmϪ1 1683 (CO), 2203
(CN); m/z (EI) 319 (Mϩ, 75.0%), 304 (15.5), 293 (16.0), 291
(17.2), 186 (77.2), 184 (100); δH (300 MHz, CDCl3) 3.46 (s, 6H,
(CH3)2N), 6.41 (s, 1H, CH), 7.62 (d, 2H, J = 8.7 Hz, ArH), 7.68
(d, 2H, J = 8.7 Hz, ArH) (Found: C, 52.53; H, 3.56; N, 9.12.
C14H11BrN2O2 requires: C, 52.68; H, 3.47; N, 8.78%).
4-(3,4-Dichlorophenyl)-2-dimethylamino-6-methylbenzonitrile
(6e)
Compound 6e was obtained from the reaction of 3-cyano-
6-(3,4-dichlorophenyl)-4-dimethylamino-2H-pyran-2-one (4e,
0.31 g, 1 mmol), acetone (0.5 ml) and powdered KOH (0.084 g,
1.5 mmol) in dry DMF and isolated as described in the preced-
ing experiment. Yield: 0.15 g (50%); mp: 100 ЊC; νmax/cmϪ1 2208
(CN); m/z (EI) 305 (Mϩ, 58.5%), 304 (100), 291 (8.8), 290 (8.2),
3-Cyano-4-dimethylamino-6-(4-nitrophenyl)-2H-pyran-2-one
(4d). Yield: 0.2 g (70%); mp: 234 ЊC; νmax/cmϪ1 1687 (CO), 2206
(CN); m/z (EI) 285 (Mϩ, 38.7%), 150 (70); δH (300 MHz,
CDCl3) 3.45 (s, 6H, (CH3)2N), 6.36 (s, 1H, CH), 7.28 (d, 2H,
J = 8.5 Hz, ArH), 7.74 (d, 2H, J = 8.5 Hz, ArH) (Found: C,
59.21; H, 4.15; N, 14.85. C14H11N3O4 requires: C, 58.94; H,
3.89; N, 14.72%).
190 (14.0), 159 (10.7); δH
(300 MHz, CDCl3) 2.56 (s, 3H, CH3),
3.09 (s, 6H, (CH3
) N), 6.94 (s, 2H, ArH), 7.40 (d, 1H, J = 9 Hz,
2
ArH), 7.53 (d, 1H, J = 8.4 Hz, ArH), 7.64 (s, 1H, ArH) (Found:
C, 62.68; H, 4.38; N, 8.95. C16H14Cl2N2 requires: C, 62.96; H,
4.62; N, 9.18%).
4-(4-Fluorophenyl)-2-(4-methylpiperidino)-6-methylbenzonitrile
(6g)
3-Cyano-6-(3,4-dichlorophenyl)-4-dimethylamino-2H-pyran-
2-one (4e). Yield: 0.23 g (75%); mp: 240–242 ЊC; νmax/cmϪ1 1678
(CO), 2208 (CN); m/z (EI) 309 (Mϩ, 18.7%), 281 (16.4), 199
(55.7), 184 (100), 172 (59.8); δH (300 MHz, CDCl3) 3.49 (s, 6H,
(CH3)2N), 6.42 (s, 1H, CH), 7.55 (d, 1H, J = 8.4 Hz, ArH), 7.65
(d, 1H, J = 8.4 Hz, ArH), 7.92 (s, 1H, ArH) (Found: C, 54.62;
H, 3.52; N, 8.98. C14H10Cl2N2O2 requires: C, 54.39; H, 3.26; N,
9.06%).
Compound 6g was prepared by the reaction of 3-cyano-6-(4-
fluorophenyl)-4-(4-methylpiperidino)-2H-pyran-2-one (4g, 0.31
g, 1 mmol), acetone (0.5 ml) and powdered KOH (0.084 g, 1.5
mmol) in dry DMF and isolated as described in the preceding
experiment. Yield: 0.16 g (52%); mp: 115 ЊC; νmax/cmϪ1 2206
(CN); m/z (EI) 308 (Mϩ, 100%), 307 (93.5), 292 (20.2), 265
(18.9), 238 (26.3); δH (300 MHz, CDCl3) 0.96 (d, 3H, J = 6 Hz,
CH3), 1.12–1.14 (m, 1H, CH), 1.50–1.55 (m, 4H, CH2), 2.52 (s,
3H, CH3), 2.83 (t, 2H, J = 9 Hz, NCH2), 3.60 (t, 2H, J = 9 Hz,
NCH2), 6.99 (s, 1H, ArH), 7.01 (s, 1H, ArH), 7.10–7.16 (m, 2H,
ArH), 7.50–7.54 (m, 2H, ArH) (Found: C, 77.58; H, 6.49; N,
8.86. C20H21FN2 requires: C, 77.89; H, 6.86; N, 9.08%).
3-Cyano-4-dimethylamino-6-(3,4-methylenedioxyphenyl)-2H-
pyran-2-one (4f). Yield: 0.2 g (69.7%); mp: >280 ЊC; νmax/cmϪ1
1685 (CO), 2203 (CN); m/z (EI) 284 (Mϩ, 84%); δH (300 MHz,
CDCl3) 3.42 (s, 6H, (CH3)2N), 6.08 (s, 2H, CH), 6.31 (s, 1H,
CH), 6.89 (d, 1H, J = 8.6 Hz, ArH), 7.19 (s, 1H, ArH), 7.23
(d, 1H, J = 8.8 Hz, ArH) (Found: C, 63.25; H, 4.38; N, 9.56.
C15H12N2O4 requires: C, 63.37; H, 4.26; N, 9.86%).
4-(4-Chlorophenyl)-2-(4-methylpiperidino)-6-methylbenzonitrile
(6h)
3-Cyano-6-(4-fluorophenyl)-4-(4-methylpiperidino)-2H-pyran-
2-one (4g). Yield: 0.22 g (70.5%); mp: >280 ЊC; νmax/cmϪ1 1685
(CO), 2203 (CN); m/z (EI) 312 (Mϩ, 68.4%), 298 (18.0), 268
(19.5); δH (300 MHz, CDCl3) 1.03 (d, 3H, J = 6.5 Hz, CH3),
1.32–1.44 (m, 1H, CH), 1.75–1.81 (m, 2H, CH2), 1.83–1.92 (m,
2H, CH2), 3.22–3.27 (m, 2H, NCH2), 4.39 (t, 2H, J = 7.8 Hz,
NCH2), 6.4 (s, 1H, CH), 7.13–7.20 (m, 2H, ArH), 7.79–7.84 (m,
Compound 6h was prepared by the reaction of 3-cyano-6-
(4-chlorophenyl)-4-(4-methylpiperidino)-2H-pyran-2-one (4h,
0.32 g, 1 mmol), acetone (0.5 ml) and powdered KOH (0.084 g,
1.5 mmol) in dry DMF and isolated as described in the preced-
ing experiment. Yield: 0.18 g (55.6%); mp: 110 ЊC; νmax/cmϪ1
2200 (CN); m/z (EI) 324 (Mϩ, 48.9%), 323 (100), 322 (82.4), 308
(23.3); δH (200 MHz, CDCl3) 1.01 (d, 3H, J = 6 Hz, CH3), 1.47–
3722
J. Chem. Soc., Perkin Trans. 1, 2000, 3719–3723

View Article Online
9 M. F. Semmelhack, P. Helquist, L. D. Lones, L. Keller,
L. Mendelson, L. Speltz Ryono, J. Gorzynski Smith and R. D.
Stauffer, J. Am. Chem. Soc., 1981, 103, 6460.
10 (a) W. I. Taylor and A. R. Battersby, Oxidative Coupling of Phenols,
Dekker, New York, 1967; (b) D. H. R. Barton and T. Cohen, Prof.
A. Stoll, Festschrift Zum Siebzigsten Geburtstag [Script on 70th
birthday of Professor A. Stoll], Birkhanser, Basel, 1957.
11 R. A. Kjonaas and D. C. Shubert, J. Org. Chem., 1983, 48, 1924.
12 Y. Landais, A. Lebrun, V. Lenian and J.-P. Robin, Tetrahedron Lett.,
1987, 28, 5161.
1.56 (m, 1H, CH), 1.68–1.70 (m, 4H, CH2), 2.55 (s, 3H,
CH3), 2.81 (t, 2H, J = 9 Hz, NCH2), 3.44 (t, 2H, J = 9 Hz,
NCH2), 6.96 (s, 1H, ArH), 7.01 (s, 1H, ArH), 7.49 (d, 2H,
J = 8.8 Hz, ArH), 7.51 (d, 2H, J = 8.8 Hz, ArH) (Found: C,
73.56; H, 6.33; N, 8.28. C20H21ClN2 requires: C, 73.95; H, 6.51;
N, 8.62%).
[4,6-Bis(4-fluorophenyl)-2H-pyran-2-ylidene]acetonitrile (7)
13 Y. Landais, D. Rambault and J.-P. Robin, Tetrahedron Lett., 1987,
28, 543.
A mixture of 1a (0.26 g, 1 mmol), 4-fluoroacetophenone (0.74
g, 1 mmol) and powdered KOH (0.12 g, 2 mmol) in anhydrous
DMF (8 ml) was stirred at ambient temperature for 20 h. The
reaction mixture was poured into ice–water and acidified with
10% HCl. The precipitate obtained was purified on silica gel
column using CHCl3–hexane (1:1) as eluent. Yield: 0.1 g (30%);
mp: 149 ЊC; νmax/cmϪ1 2200 (CN); m/z (EI) 307 (Mϩ, 22%), 306
(100), 280 (41); δH (300 MHz, CDCl3) 6.45 (s, 1H, CH), 6.90 (s,
1H, ArH), 7.30 (s, 1H, ArH), 7.52 (d, 2H, J = 8 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, 3.6; N, 4.56%).
14 (a) D. C. Billington, Coupling Reactions Between sp3 Carbon Centers,
in Comprehensive Organic Synthesis, B. M. Trost and I. Fleming,
Eds., Pergamon Press, Oxford, 1991, vol. 3, ch. 2.1; (b) K. Tamao,
Coupling reactions Between sp3 Carbon Centers, in Comprehensive
Organic Synthesis, B. M. Trost and I. Fleming, Eds., Pergamon
Press, Oxford, 1991, vol. 3, ch. 2.2; (c) D. W. Knight, Coupling
Reactions Between sp2 Carbon Centers, in Comprehensive Organic
Synthesis, B. M. Trost and I. Fleming, Eds., Pergamon Press,
Oxford, 1991, vol. 3, ch. 2.3; (d) S. K. Taylor, S. G. Bennett,
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. Miyaura, K. Yamada, N. Suginome and A. Suzuki,
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1991, 63, 419; (d) A. Suzuki, Pure Appl. Chem., 1994, 66, 213;
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1994, 35, 3277; ( f ) T. I. Wallow and B. M. Novak, J. Org. Chem.,
1994, 59, 5034; (g) M. Moreno-Manas, F. Pajuelo and R. Pleixats,
J. Org. Chem., 1995, 60, 2396.
Crystal data for 3f
C16H13NO2S, monoclinic, space group Cc, a = 11.283(1) Å,
b = 13.226(1) Å, c = 9.239(1) Å, β = 98.35(1)Њ, V = 1364.1(2) Å3,
Z = 4, Mo-Kα, λ = 0.71073 Å, µ = 0.24 mmϪ1, Dc = 1.380 g cmϪ3
.
16 (a) K. Alder and H. Rickert, Ber., 1937, 70, 1354; (b) E. Wenkert,
D. B. R. Johnston and K. G. Dave, J. Org. Chem., 1964, 29, 2534;
(c) J. E. Reed, C. L. Strilling, R. F. Tarvin, Jr., T. A. Rettig and
J. K. Stille, J. Org. Chem., 1969, 34, 2188.
17 (a) R. Gompper and O. Christmann, Angew. Chem., 1959, 71, 32; (b)
R. Gompper and O. Christmann, Chem. Ber., 1961, 94, 1795.
18 (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.
19 Y. Tominaga, A. Ushirogochi and Y. Matsuda, J. Heterocycl. Chem.,
1987, 24, 1557.
20 G. A. Leonard, K. Metuley-Hecht, T. Brown and W. N. Hunter,
Acta Crystallogr., Sect. D, 1995, 51, 136.
21 G. R. Desiraju, Angew. Chem., Int. Ed. Engl., 1995, 34, 2311.
22 (a) G. R. Desiraju, Acc. Chem. Res., 1996, 29, 441; (b) T. Steiner,
Chem. Commun., 1997, 727; (c) B. Z. Yellin and L. Seiserowitz, Acta
Crystallogr., Sect. C, 1984, 40, 159.
23 (a) S. J. Narayanan, Sridevi, T. K. Chandrashekhar, A. Vij and
R. Roy, Angew. Chem., Int. Ed., 1998, 37, 3394; (b) M. Iwaoka and
S. Tomoda, J. Am. Chem. Soc., 1994, 116, 4463; (c) V. R. Pedireddi,
S. Chatterjee, A. Ranganathan and C. N. R. Rao, J. Am. Chem. Soc.,
1997, 119, 10867.
X-Ray data were collected on an Enraf-Nonius CAD4 dif-
fractometer (graphite monochromator, T = 293(2) K, θ = 25Њ).
The structure was solved by direct methods using SHELXS8627
and refined anisotropically on non-H atoms by full-matrix
least-squares method on F 2 using SHELXL9328 (1272 reflec-
tions and 183 parameters). All H-atoms were placed in geo-
metrically idealised positions and refined using the riding
model. Convergence was reached [(∆/σ)max = 0.000] at R =
0.0383 for 1228 reflections with I > 2σ(I) [wR2 = 0.1107, S =
0.767]. The final difference Fourier map showed no significant
peaks (∆ρmax,min = 0.17, Ϫ0.31 e ÅϪ3).
CCDC reference number 207/482. See http://www.rsc.org/
suppdata/p1/b0/b005572g/ for crystallographic files in .cif
format.
The ORTEP29 and view of the crystal packing (PLUTO29)
diagrams of 3f are shown in Fig. 1 and Fig. 2 respectively.
Acknowledgements
P. S. and S. S. are thankful to CSIR (India) for SRF.
24 (a) A. E. Alexander, J. Chem. Soc., 1937, 1813; (b) A. Hughes, Proc.
R. Soc. London, Ser. A, 1936, 155, 710; (c) R. J. Abraham, F. Eivazi,
H. Pearson and K. M. Smith, J. Chem. Soc., Chem. Commun., 1976,
699.
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