Behavior of 3(2-pyridinylmethylene)-5-aryl-2(3H)-furanones and 3(3-pyridinylmethylene)-5-aryl-2(3H)-furanones as alkylating agents: A comparative study

Article abstract of DOI:10.1002/jhet.709

3(2-pyridinylmethylene)-5-aryl-2(3H)-furanones and 3(3-pyridinylmethylene)- 5-aryl-2(3H)-furanones were prepared as a mixture of (E) and (Z) stereoisomers by condensing pyridine-2-carboxaldehyde and pyridine-3-carboxaldehyde with 3-aroylpropionic acids. T

Full text of DOI:10.1002/jhet.709

November 2011
Behavior of 3(2-Pyridinylmethylene)-5-aryl-2(3H)-furanones and
3(3-Pyridinylmethylene)-5-aryl-2(3H)-furanones as Alkylating
Agents: A Comparative Study
1361
Wael S. I. Abou Elmagd*
Department of Chemistry, Faculty of Science, Ain Shams University, Abassia, 11566 Cairo, Egypt
*E-mail: waelmagd97@yahoo.com
Received July 4, 2010
DOI 10.1002/jhet.709
Published online 30 June 2011 in Wiley Online Library (wileyonlinelibrary.com).
3(2-pyridinylmethylene)-5-aryl-2(3H)-furanones and 3(3-pyridinylmethylene)-5-aryl-2(3H)-furanones
were prepared as a mixture of (E) and (Z) stereoisomers by condensing pyridine-2-carboxaldehyde and
pyridine-3-carboxaldehyde with 3-aroylpropionic acids. The reaction of the furanones 6 and 7 with an-
hydrous aluminium chloride in benzene led to the formation of 4,4-diaryl-1-(2-pyridinyl)but-1,3-diene
(8) and 4,4-diaryl-1-(3-pyridinyl)but-1,3-diene (9) as mixtures of geometrical (E,E- and E,Z-) stereoiso-
mers via an intermolecular alkylation mode. When the reaction was carried out in tetrachloroethane as a
solvent, the reaction of 6 gave 5-arylquinoline-7-carboxylic acid via intramolecular alkylation mode.
This may be considered as a novel method for the synthesis of quinoline derivatives.
J. Heterocyclic Chem., 48, 1361 (2011).
INTRODUCTION
were obtained as the products of intramolecular alkyla-
tion [5]. However, using toluene or anisole as solvents
changed the mode of the reaction from intra- to intermo-
lecular with the formation of the corresponding butadie-
necarboxylic acids 5a [6].
It was of interest to the author to investigate the
behavior of two newly synthesized 2(3H)-furanones
namely 5-aryl-3(2-pyridinylmethylene)-2(3H)-furanones
6 and 5-aryl-3-(3-pyridinylmethylene)-2(3H)-furanones 7
to verify the possibility of intramolecular alkylation
mode at positions 2 and 3 of the pyridine nucleus.
Our research group was interested in studying the
behavior of 2(3H)-furanones 1 as alkylating agents. It
was found that the Lewis acid, AlCl3, affects carbon-ox-
ygen bond breaking of the furanone ring to give a reso-
nance stabilized carbocation 2. The reaction is com-
pleted through two distinct routes: either the carbocation
formed attacks the o-position (*) of X group situated at
position 3 intramolecularly or the solvent attacks the
carbocation to give the intermolecular reaction product.
It was found that the reaction course is affected by two
main factors namely: (a) the nature of X group; thus
when X was 2-furyl or 2-thienyl, the corresponding ben-
zofuran [1] and benzothiophene [2] carboxylic acids 3
were formed, respectively. However, when X was pyraz-
olyl [3] or indolyl [4] groups, the products of intermo-
lecular alkylations, butadienecarboxylic acids 5d and e,
were formed exclusively. (b) The nucleophilicity of the
solvent, thus when X was fluorenyl and the reaction was
conducted in benzene, fluoranthene carboxylic acids 4
RESULTS AND DISCUSSION
In this investigation, some 2(3H)-furanones bearing 2-
pyridinyl and 3-pyridinyl groups at position 3 were syn-
thesized with a study of their behavior as alkylating
agents. Thus, pyridine-2-carboxaldehyde and pyridine-3-
carboxaldehyde condense with 3-aroylpropionic acids
applying the procedure described by Khan and Rastogi
C
V
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1362
W. S. I. Abou Elmagd
Vol 48
[7], to give the corresponding furanones 6 and 7. The
structures of the furanones were inferred from their ana-
lytical and spectral data (cf., Experimental section). The
infrared spectra of these products show mC¼O at 1775
cmꢀ1 characteristic of the carbonyl moiety of 2(3H)-fur-
anones. The 1H-NMR spectra of compounds 6 and 7
showed two singlets for the olefinic proton Ha and two
singlets for OCH3 protons in case of 6c and 7c. This
showed that compounds 6 and 7 were formed as a mix-
ture of two geometrical (E- and Z-) isomers in which
the E-isomers predominates. The furnaones 6 and 7
reacted with AlCl3 in excess benzene to give the buta-
dienecarboxylic acids 8a–f via intermolecular alkylation
mode in which the solvent benzene undergoes nucleo-
philic attack on the intermediate carbocation (Scheme 1).
This may be attributed to the small charge density on
pyridinyl group compared with the solvent(benzene).
The structure of these acids was inferred from their
analytical and spectral data (c.f., Experimental section).
The analytical and mass spectroscopic data indicate the
incorporation of phenyl group.
The 1H-NMR spectra of compound 8b,c,e,f showed
two singlets for the olefinic protons and two singlets for
OCH3 protons in case of 8c,f. This showed that com-
pounds 8b,c,e,f exist as a mixture of two geometrical
(E,E) and (E,Z) stereoisomers in which the latter pre-
dominates due to steric factor. The deshielding of the
olefinic proton Hb in case of (E,E)-isomers when
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November 2011 Behavior of 3(2-Pyridinylmethylene)-5-aryl-2(3H)-furanones and
3(3-Pyridinylmethylene)-5-aryl-2(3H)-furanones as Alkylating Agents: A Comparative Study
1363
Scheme 1
compared with the (E,Z)-counterpart can be rationalized
in terms of the ring current of the more activated aryl
groups.
cosuric drug [8]. These reports initiated the interest of
the author to conduct the above reaction in tetrachloro-
ethane as solvent. Thus, when the reaction of furanones
6 and 7 with aluminium chloride was carried out in tet-
rachloroethane as solvent, 5-arylquinoline-7-carboxylic
acids 9a–c were isolated in case of 6. The formation of 9
may be rationalized on the basis of attack of the carbo-
cation intermediate on position 3 of the pyridine moiety.
Among the compounds of a quinoline series quinoli-
necarboxylic acids attract the attention of researchers
because of their close structure resemblance to alkaloids.
Cinchophen (2-phenylquinoline-4-carboxylic acid) was
introduced in 1910 as an analgesic, antipyretic, and uri-
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W. S. I. Abou Elmagd
Vol 48
(C¼¼N), 1610 (C¼¼C).1H-NMR (DMSO-d6) (E-form, 60%) d
6.02–7.63 (m, 9H, ArH), 8.80 (s, 1H, Ha); (Z-form, 40%) d 8.77
(s, 1H, Ha). MS: m/z (%) 285 (1.1), 283 (Mþ, 3.1), 141 (35),
193 (100), 93 (14), 75 (12). Anal. Calcd. for C16H10ClNO2: C,
67.74; H, 3.55; N, 4.94. Found: C, 67.59; H, 3.27; N, 5.02.
5-(4-Methoxyphenyl)-3-(2-pyridinylmethylene)-2(3H)-fura-
none (6c). 90% yield, m.p. 225–227ꢁC. IR: mmax 1753
(C¼¼O),1645 (C¼¼N), 1605 (C¼¼C).1H-NMR (DMSO-d6) (E-form,
70%) d 3.02 (s, 3H, OCH3), 6.37–8.01 (m, 9H, ArH), 8.62 (s, 1H,
Ha); (Z-form, 30%) d 8.59 (s, 1H, Ha). MS: m/z (%) 279 (Mþ, 6),
141 (20), 139 (58), 135 (100), 93 (8), 77 (14). Anal. Calcd. for
C17H13NO3: C, 73.11; H, 4.69; N, 5.02. Found: C, 74.01; H, 4.40;
N, 5.31.
This reaction may be considered as a versatile route for
the synthesis of quinolinecarboxylic acid derivatives.
However in case of 7, the reaction failed and the
unreacted furanones were isolated. The failure of 7 to
give the intramolecular products, quinolinecarboxylic
acids is not unexpected. It is well established that posi-
tion 2 in the pyridine nucleus is less susceptible to
attack by electrophilic reagents than position 3.The
structures of 9a–c were inferred from their analytical
and spectral data (c.f., Experimental section).
5-Phenyl-3-(3-pyridinylmethylene)-2(3H)-furanone (7a). 87%
yield, m.p. 186–187ꢁC. IR: mmax 1775 (C¼¼O), 1625 (C¼¼N),
1599 (C¼¼C).1H-NMR (DMSO-d6) (E-form, 60%) d ¼ 6.22–
7.30 (m, 10H, ArH), 8.98 (s, 1H, Ha); (Z-form, 40%) d ¼ 8.94
(s, 1H, Ha). MS: m/z 249 (Mþ, 4), 193 (6), 144 (67), 105
(100), 77 (39), 51 (12). Anal. Calcd. for C16H11NO2: C, 77.10;
H, 4.45; N, 5.62. Found: C, 76.89; H, 5.01; N, 5.74.
5-(4-Chlorophenyl)-3-(3-pyridinylmethylene)-2(3H)-furanone
(7b). 85% yield, m.p. 244–246ꢁC. IR: mmax 1762 (C¼¼O), 1643
(C¼¼N), 1597 (C¼¼C).1H-NMR (DMSO-d6) (E-form, 60%) d ¼
6.90–7.89 (m, 9H, ArH), 8.39 (s, 1H, Ha); (Z-form, 40%) d ¼
8.30 (s, 1H, Ha). MS: m/z 285 (0.45), 283 (Mþ, 1.1), 144 (79),
139 (100), 93 (14), 75 (11). Anal. Calcd. for C16H10ClNO2: C,
67.74; H, 3.55; N, 4.94. Found: C, 67.43; H, 3.20; N, 5.19.
5-(4-Methoxyphenyl)-3-(3-pyridinylmethylene)-2(3H)-fura-
none (7c). 80% yield, m.p. 198–200ꢁC. IR: mmax 1760 (C¼¼O),
1624 (C¼¼N), 1596 (C¼¼C).1H-NMR (DMSO-d6) (E-form,
78%) d ¼ 3.89 (s, 3H, OCH3), 6.62–8.27 (m, 9H, ArH), 8.78
(s, 1H, Ha); (Z-form, 22%) d ¼ 8.73 (s, 1H, Ha). MS: m/z 279
(Mþ, 3), 144 (36), 135 (100), 77 (14). Anal. Calcd. for
C17H13NO3: C, 73.11; H, 4.69; N, 5.02. Found: C, 73.65; H,
4.32; N, 5.39.
EXPERIMENTAL
Melting points were measured on an electrothermal melting
point apparatus. Elemental analyses were carried out at the
Microanalytical unit, Cairo University. IR spectra were measured
on a Unicam SP-1200 spectrometer using KBr wafer technique.
1H-NMR spectra were measured in DMSO-d6 on a Varian plus
instrument (300 MHz). Mass spectra were recorded on a
Shimadzu GC-MS QP1000 EX instrument operating at 70 eV.
General procedure for the preparation of 5-aryl-3-(2-
pyridinylmethylene)-2(3H)-furanones 6a–c and 5-aryl-3-(3-
pyridinylmethylene)-2(3H)-furanones 7a–c.
i. (Chlorosulfinyloxy)-N,N-dimethylmethaniminium chlo-
ride (the cyclodehydrating agent): Into a 25-mL drop-
ping funnel containing benzene (5 mL) and N,N-
dimethylformamide (1 mL, 10.2 mmol), followed by
thionyl chloride (0.8 mL, 11 mmol). After 5 min, the
two phases were separated, and the reagent (lower
layer) was used in the next step.
ii. To a stirred solution of 3-aroylpropionic acid (10
mmol) in dichloromethane (25 mL) at 0ꢁC, the cyclo-
dehydrating agent (10 mmol) prepared in step (i) was
added. Stirring was continued for 15 min. Pyridine-2-
carboxaldehyde or pyridine-3-carboxaldehyde (10
mmol) was added followed by triethylamine (30
mmol) in dichloromethane (15 mL). The resulting
mixture was stirred at room temperature for 5 h. The
organic layer was washed with water (2 ꢂ 50 mL)
and dried over anhydrous sodium sulfate. Removal of
the solvent left a residue that formed golden yellow
crystals, which were recrystallized from ethanol to
give 5-aryl-3-(2-pyridinylmethylene)-2(3H)-furanone
6 or 5-aryl-3-(3-pyridinylmethylene)-2(3H)-furanone
7, respectively.
General procedure for the preparation of 4,4-diaryl-1-(2-
pyridinyl)but-1,3-diene-2-carboxylic acids (8a–c) and 4,4-dia-
ryl-1-(3-pyridinyl)but-1,3-diene-2-carboxylic acids (8d–f). To
a stirred mixture of anhydrous AlCl3 (0.03 mole) in dry ben-
zene (100 mL), a solution of the furanone 6 or 7 in benzene
was added dropwise at 10–20ꢁC. After complete addition, the
reaction mixture was stirred at room temperature for an addi-
tional 15 h. The complex formed was decomposed with 15%
aqueous HCl and then steam-distilled to remove the excess of
benzene. The solid remaining was filtered off, dissolved in
aqueous sodium carbonate (25 mL, 20%), cooled well, and
reprecipitated by dropwise addition of conc. HCl. The solid
product obtained was recrystallized from benzene/ethanol to
give 4,4-diaryl-1-(2-pyridinyl)but-1,3-diene-2-carboxylic acids
(8a–c) in case of 6 and 4,4-diaryl-1-(3-pyridinyl)but-1,3-diene-
2-carboxylic acids (8d–f) in case of 7.
4,4-Diphenyl-1-(2-pyridinyl)but-1,3-diene-2-carboxylic acid
(8a). Yellowish-white (30% yield), m.p. 260–261ꢁC. IR: mmax
3200–3500 (OH), 1698 (C¼¼O), 1653 (C¼¼N), 1590 (C¼¼C)
5-Phenyl-3-(2-pyridinylmethylene)-2(3H)-furanone (6a). 90%
yield, m.p. 218–219ꢁC.IR: mmax 1770 (C¼¼O), 1650 (C¼¼N),
1600 (C¼¼C).1H-NMR (DMSO-d6) (E-form, 55%) d 6.53–7.94
(m, 10H, ArH), 8.60 (s, 1H, Ha); (Z-form, 45%) d 8.56 (s, 1H,
Ha). MS: m/z (%) 249 (Mþ, 3), 161 (30), 106 (9), 105 (100),
77(26), 51 (9). Anal. Calcd. for C16H11NO2: C, 77.10; H,
4.45; N, 5.62. Found: C, 77.39; H, 4.01; N, 5.94.
1
cmꢀ1. H-NMR (DMSO-d6): d 6.97 (s, 1H, Ha), 7.14–7.96 (m,
14H, ArH), 8.60 (s, 1H, Hb), 12.82 (br.s, 1H, OH, exchange-
able). MS: m/z (%) 327 (Mþ, 12), 284 (52), 240 (30), 210
(46), 143 (35), 78 (100). Anal. Calcd. for C22H17NO2: C,
80.71; H, 5.23; N, 4.28. Found: C, 80.23; H, 5.71; N, 4.47.
4-Phenyl-4-(4-chlorophenyl)-1-(2-pyridinyl)but-1,3-diene-2-
carboxylic acid (8b). Yellowish white crystals (35% yield),
5-(4-Chlorophenyl)-3-(2-pyridinylmethylene)-2(3H)-furanone
(6b). 83% yield, m.p. 230–231ꢁC. IR: mmax 1769 (C¼¼O),1650
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1365
m.p. 279–280ꢁC. IR: mmax 2900–3450 (OH), 1692 (C¼¼O),
Anal. Calcd. for C23H19NO3: C, 77.29; H, 5.36; N, 3.92.
Found: C, 78.01; H, 4.99; N, 3.69.
1630 (C¼¼N), 1610 (C¼¼C) cmꢀ1
.
1H-NMR (DMSO-d6) (E,Z-
form 55%): d 6.37 (s, 1H, Ha), 7.02–7.98 (m, 13H, ArH), 8.37
(s, 1H, Hb), 12.20 (br.s, 1H, OH, exchangeable). (E,E-form,
45%), d 8.34 (s, 1H, Hb). MS: m/z (%) 363 (7), 361 (Mþ, 18),
163 (25), 185 (17), 130 (67), 78 (100). Anal. Calcd. for
C22H16ClNO2: C, 73.03; H, 4.46; N, 3.87. Found: C, 72.81; H,
4.03; N, 3.52.
General procedure for the reaction of the furanones 6
and 7 with anhydrous AlCl3 in tetrachloroethane. The reac-
tion was carried out as described in the previous experiment
by using tetrachloroethane instead of benzene. The product in
case of 7 was shown by direct comparison (m.p, mixed m.p
and TLC) to be the unreacted furanones but in case of 6 gave
5-arylquinonline-7-carboxylic acids 9.
4-Phenyl-4-(4-methoxyphenyl)-1-(2-pyridinyl)but-1,3-diene-
2- carboxylic acid (8c). Yellow crystals (30% yield), m.p.
320–321ꢁC. IR: mmax 3150–3420 (OH), 1702 (C¼¼O), 1645
5-Phenylquinonline-7-carboxylic acid (9a). Yellow crystals
(35% yield), m.p. 250–252ꢁC. IR: mmax 3300–3500 (OH), 1703
(C¼¼O), 1640 (C¼¼N), 1605 (C¼¼C). 1H-NMR 7.22–8.98 (m,
10H, ArH), 13.2 (br.s, 1H, OH, exchangeable). MS: m/z (%)
(C¼¼N), 1602 (C¼¼C) cmꢀ1
.
1H-NMR (DMSO-d6) (E,Z-form
57%): d 3.90 (s, 3H, OCH3), 6.62 (s, 1H, Ha), 6.82–7.91 (m,
13H, ArH), 8.21 (s, 1H, Hb), 12.50 (br.s, 1H, OH, exchange-
able). (E,E-form, 43%), d 3.92 (s, 3H, OCH3), 8.24 (s, 1H,
Hb). MS: m/z (%) 357 (Mþ, 27), 340 (30), 250 (30), 180
(12), 141 (42), 130 (54), 78 (100). Anal. Calcd. for
C23H19NO3: C, 77.29; H, 5.36; N, 3.92. Found: C, 77.81; H,
5.60; N, 3.48.
249
(Mþ,17),
237(23),232(45),205(40),172(15)128(100),
77(32). Anal. Calcd. for C16H11NO2: C, 77.10; H, 4.45; N,
5.62. Found: C, 77.73; H, 4.90; N, 5.81.
5-(4-Chlorophenyl)quinonline-7-carboxylic acid (9b). Yellow
crystals, (35% yield), m.p. 289–290ꢁC. IR: mmax 3350–3500
(OH), 1695 (C¼¼O), 1628 (C¼¼N), 1600 (C¼¼C). 1H-NMR d
6.98–7.82 (m, 9H, ArH), 13.25 (br.s, 1H, OH, exchangeable).
MS: m/z (%) 285(5.3), 283(Mþ,14.9),266(30),238(19),
128(100)120(37). Anal. Calcd. for C16H10ClNO2: C, 67.74; H,
3.55; N, 4.94. Found: C, 67.39; H, 3.90; N, 4.65.
5-(4-Methoxyphenyl)quinonline-7-carboxylic acid (9c). Yellow
crystals (30% yield), m.p. 280–282ꢁC. IR: mmax 3250–3400
(OH), 1698 (C¼¼O), 1650 (C¼¼N), 1598 (C¼¼C). 1H-NMR d
3.92 (s, 3H, OCH3), 7.10–8.32 (m, 9H, ArH), 12.95 (br.s, 1H,
OH,exchangeable). MS: m/z(%) 279(Mþ,7),262(40), 248(15),
235(18), 128(100),77(56). Anal. Calcd. for C17H13NO3: C,
73.11; H, 4.69; N, 5.02. Found: C, 72.90; H, 5.01; N, 5.21.
4,4-Diphenyl-1-(3-pyridinyl)but-1,3-diene-2-carboxylic acid
(8d). Yellowish white crystals (32% yield), m.p. 354–355ꢁC.
IR: mmax 3250–3445 (OH), 1701 (C¼¼O), 1630 (C¼¼N), 1600
1
(C¼¼C) cmꢀ1. H-NMR (DMSO-d6): d 6.83 (s, 1H, Ha), 6.93–
8.07 (m, 14H, ArH), 8.35 (s, 1H, Hb), 12.57 (br.s, 1H, OH,
exchangeable). MS: m/z (%) 327 (Mþ, 70), 291 (31), 276 (25),
253 (70), 210 (20), 78 (100). Anal. Calcd. for C22H17NO2: C,
80.71; H, 5.23; N, 4.28. Found: C, 79.93; H, 5.49; N, 3.95.
4-Phenyl-4-(4-chlorophenyl)-1-(3-pyridinyl)but-1,3-diene-2-
carboxylic acid (8e). Yellow crystals (35% yield), m.p. 327–
328ꢁC. IR: mmax 3290–3510 (OH), 1705 (C¼¼O), 1650 (C¼¼N),
1600 (C¼¼C) cmꢀ1
.
1H-NMR (DMSO-d6) (E,Z-form 60%): d
6.29 (s, 1H, Ha), 6.98–7.87 (m, 13H, ArH), 8.19 (s, 1H, Hb),
12.59 (br.s, 1H, OH, exchangeable). (E,E-form, 40%), d 8.17
(s, 1H, Hb). MS: m/z (%) 363 (20), 361 (Mþ, 55), 212
(40),167 (20), 173 (30), 130 (70), 78 (100). Anal. Calcd. for
C22H16ClNO2: C, 73.03; H, 4.46; N, 3.87. Found: C, 73.41; H,
4.63; N, 4.07.
REFERENCES AND NOTES
[1] Hashem, A. I. J Prakt Chem 1977, 319, 689.
[2] Hashem, A. I.; Elkousy, S. M.; ElTorgoman, A. M.;
El-Basiouny, A. E. Int J Chem 1991, 2, 87.
[3] Hashem, A. I.; Kandeel, K. A.; Youssef, A. S. A.;
Abou-Elmagd, W. S. I. J Chem Res 2006, 315.
4-Phenyl-4-(4-methoxyphenyl)-1-(3-pyridinyl)but-1,3-diene-
2-carboxylic acid (8f). Yellow crystals (25% yield), m.p. 301–
303ꢁC. IR: mmax 3210–3490 (OH), 1705 (C¼¼O), 1647 (C¼¼N),
[4] Abou-Elmagd, W. S. I. J Chem Res 2007, 305.
[5] Hashem, A. I.; Ismail, Z. M. Indian J Chem 1974, 12, 902.
[6] Hashem, A. I.; Eid, E. E. Indian J Chem 1978, 16(B), 502.
[7] Khan, R. H.; Rastogi, R. C. J Chem Res 1991, 260.
[8] http://en.wikipedia.org/wiki/Cinchophen (accessed Decem-
ber 2010).
1595 (C¼¼C) cmꢀ1
.
1H-NMR (DMSO-d6) (E,Z-form 53%): d
3.90 (s, 3H, OCH3), 6.70 (s, 1H, Ha), 6.92–8.10 (m, 13H,
ArH), 8.23 (s, 1H, Hb), 12.53 (br.s, 1H, OH, exchangeable).
(E,E-form, 47%), d 3.93 (s, 3H, OCH3), 8.25 (s, 1H, Hb).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet