Simultaneous C-and N-alkylation of 2-oxo-4,6-diaryl-1,2,3,4- tetrahydropyridine-3-carbonitrile under solid-liquid phase-transfer conditions

Article abstract of DOI:10.1080/00397910903003474

The alkylation of 2-oxo-4,6-diaryl-1,2,3,4-tetrahydropyridine-3- carbonitrile 1 has been carried out using different alkyl/arylating agents in solid-liquid phase-transfer catalysis conditions. The aim was to study the effect of steric hindrance offered by

Full text of DOI:10.1080/00397910903003474

This article was downloaded by: [University of York]
On: 15 October 2014, At: 09:47
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Simultaneous C- and N-Alkylation
of 2-Oxo-4,6-diaryl-1,2,3,4-
tetrahydropyridine-3-carbonitrile Under
Solid–Liquid Phase-Transfer Conditions
Hetal C. Shah a , Vaishali H. Shah a & Nirmal D. Desai b
a Organic Synthesis Laboratory , M. G. Science Institute ,
Navrangpura, Ahmedabad, India
b Loyola Center for Research and Development , St. Xavier's
College , Navrangpura, Ahmedabad, India
Published online: 03 Feb 2010.
To cite this article: Hetal C. Shah , Vaishali H. Shah & Nirmal D. Desai (2010) Simultaneous C- and
N-Alkylation of 2-Oxo-4,6-diaryl-1,2,3,4-tetrahydropyridine-3-carbonitrile Under Solid–Liquid Phase-
Transfer Conditions, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 40:4, 540-550, DOI: 10.1080/00397910903003474
To link to this article: http://dx.doi.org/10.1080/00397910903003474
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,

systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &
Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Synthetic Communications1, 40: 540–550, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903003474
SIMULTANEOUS C- AND N-ALKYLATION OF
2-OXO-4,6-DIARYL-1,2,3,4-TETRAHYDROPYRIDINE-
3-CARBONITRILE UNDER SOLID–LIQUID
PHASE-TRANSFER CONDITIONS
Hetal C. Shah,1 Vaishali H. Shah,1 and Nirmal D. Desai2
1Organic Synthesis Laboratory, M. G. Science Institute, Navrangpura,
Ahmedabad, India
2Loyola Center for Research and Development, St. Xavier’s College,
Navrangpura, Ahmedabad, India
The alkylation of 2-oxo-4,6-diaryl-1,2,3,4-tetrahydropyridine-3-carbonitrile 1 has been
carried out using different alkyl/arylating agents in solid–liquid phase-transfer catalysis con-
ditions. The aim was to study the effect of steric hindrance offered by the aryl group in the
sixth position of the pyridine ring on the ambient N- vs. O-alkylation ratio. Simultaneous
C- and N-alkylation was encountered and confirmed by x-ray crystallography. Our study
to gain exclusive regiocontrol for simultaneous alkylation was carried out. An alternative
route for CꢀC bond formation was also established by the removal of the cyano functionality.
Keywords: N- vs. O-alkylation; simultaneous C- and N-alkylation; solid–liquid phase-transfer conditions
INTRODUCTION
2-Pyridones are important intermediates in the synthesis of polycyclic com-
pounds of biological significance, as illustrated by the recent synthetic approaches
toward the camptothecin family of antitumor agents.[1] They are also structural sub-
units of naturally occurring products such as the heterocycle annelated pyridone
alkaloid cerpegin, which has analgesic, antiulcer, and anti-inflammatory activities,[2]
or the antibiotic 4-hydroxypyridone funiculosine, which possesses fungicidal proper-
ties.[3] Moreover, pharmaceuticals with the 2-pyridone skeleton have emerged as
specific nonnucleoside reverse transcriptase inhibitors of human immunodeficiency
virus 1 (HIV-1),[4] multiple sclerosis immunomodulators,[5] and antibacterial[6] and
anticancer[7] agents. Such diverse biological activity has fueled the development of
an important core structure, 2-pyridone.[8]
As a part of our ongoing program on application of phase-transfer catalyst,[9]
herein we report the alkylation of 2-oxo-4,6-diaryl-1,2,3,4-tetrahydropyridine-3-
carbonitrile 1 using solid–liquid phase-transfer catalysis condition to get a novel
Received February 25, 2009.
Dedicated to the memory of Dr. Chaitanya G. Dave.
Address correspondence to Nirmal D. Desai, Loyola Center for Research and Development,
St. Xavier’s College, Navrangpura, Ahmedabad 380 009, India. E-mail: nirmal.desai@yahoo.com
540

SIMULTANEOUS C- AND N-ALKYLATION
541
heterocyclic compound involving a 2-pyridone scaffold. It was envisioned that the
target involves an ambident anion and can be expected to yield a mixture of
N- and O-alkylated products; however, C- and N-alkylation took place simul-
taneously. This was used to gain advantage; nitrile functionality was removed by
hydrolysis. This may be an ideal surrogate that imparts a C-C coupling reaction
to molecules.
Alkylation of an ambident anion such as 2-pyridone is generally performed by
treating the corresponding metal salt (SE2cB mechanism) with an alkyl halide. N- vs.
O-alkylation of 2-pyridone[10] has been extensively investigated. Selectivity depends on
solvent, cation, alkylating agent, and catalyst. In the case of 2-pyridone,[10a] alkylation
using the sodium salt in dimethylformamide (DMF) leads to selective N-alkylation
(97:3), whereas using the silver salt in benzene leads exclusively to the O-alkylated pro-
duct. Phase-transfer conditions are often employed in such alkylations and have been
reported to favor the formation of N-alkylated products (and, in certain cases, only
N-alkylation is observed).[10b] Alkylation of 2-pyridone using liquid–liquid phase-transfer
conditions was found to result in preferential N-alkylation[10c] (N=O ¼ 4:1) Selective
O-alkylation of 2-pyridone has been achieved using Mitsunobu conditions.[10d]
RESULTS AND DISCUSSION
Starting material 2-oxo-4,6-diaryl-1,2,3,4-tetrahydropyridine-3-carbonitrile 1
was obtained according to the procedure prescribed in literature.[11] It had two ambi-
dent sites, the first on the nitrogen of pyridine and the second on the oxygen atom at
position 2 of the pyridine ring. 2-Oxo-4,6-diaryl-1,2,3,4-tetrahydropyridine-3-
carbonitrile 1 was alkylated with alkyl=aryl halides in the presence of powdered
potassium hydroxide (KOH) at 60–70ꢁC in toluene, and Aliquat 336 was employed
as phase-transfer catalyst (Scheme 1). As only one product was obtained as determ-
ined by thin-layer chromatography (TLC), the hypothesis was that it could be an
O-alkylated product with steady increases with the increase in chain length of alky-
lating agent and the steric hindrance offered by unsubstituted or unsubstituted aryl
ring present at position 6 of the pyridine ring.
Elemental analytical data proved that derivatives 2a, 2b, and 2c had empirical
formulas C20H18N2O, C22H22N2O, and C32H26N2O, respectively (Table 1). 1H
NMR of compound 2a showed two singlets of 3H each at 1.84 and 3.16, proving
the presence of two (ꢀCH3) groups. Compound 2b exhibited two triplets integrating
for 3H at 1.04–1.08 and 1.19–1.24 and multiplets integrating for 2H at 1.94–2.26 and
3.69–3.80, indicating the presence of two (ꢀCH2CH3) groups. Proton integration
Scheme 1. Synthesis of 2-oxo-4,6-diaryl-1,2,3,4-tetrahydropyridine-3-carbonitrile 1.

542
H. C. SHAH, V. H. SHAH, AND N. D. DESAI
Table 1. 1,3-Alkyl=aryl-2-oxo-4,6-diaryl-1,2,3,4-tetrahydropyridine-3-carbonitrile 2a–i
Entry Compound
Ra
R1
R2
Time (min) Yieldb (%) Mp (ꢁC)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
CH3
CH2CH3
CH2C6H5
CH3
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
60
65
60
50
55
55
65
50
55
85
86
89
75
80
90
77
74
85
137–138
123–124
140–141
142–143
117–118
151–152
108–109
134–135
165–167
C6H5
C6H5
4-OCH3C6H4
4-OCH3C6H4
4-OCH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
CH2CH3
CH2C6H5
CH3
C6H5
4-OCH3C6H4
2g
2h
2i
CH2CH3 4-OCH3C6H4
CH2C6H5 4-OCH3C6H4
aAlkyl=arylating agents, methyl iodide, ethyl bromide, benzyl chloride.
bIsolated yields.
for compound 2c showed two (-CH2C6H5). Further investigation using x-ray
crystallography data suggested that C- and N-alkylation took place simultaneously;
hence, structures 2a, 2b, and 2c were 1,3-dimethyl-2-oxo-4,6-diphenyl-1,2,3,4-tetra-
hydropyridine-3-carbonitrile, 1,3-diethyl-2-oxo-4,6-diphenyl-1,2,3,4-tetrahydropyri-
dine-3-carbonitrile, and 1,3-dibenzyl-2-oxo-4,6-diphenyl-1,2,3,4-tetrahydropyridine-
3-carbonitrile, respectively (Scheme 1). Similar conclusions were also drawn for
compounds 2d–i. This was in line with elemental and spectral data. The ortep dia-
grams of compound 2a[12a] (Fig. 1), 2b[12b] (Fig. 2), and 2c[12c] (Fig. 3) are shown.
Our attention turned next to scope and limitations of this novel simultaneous
C- and N-alkylation. The strategy was to optimize the simultaneous alkylation by
using different phase-transfer catalysts in solid–liquid phase-transfer conditions. Thus,
alkyl=aryl halides were reacted with 2-oxo-4,6-diaryl-1,2,3,4-tetrahydropyridine-3-
carbonitrile 1 at 70ꢁC using different phase-transfer catalysts in increasing order of
Figure 1. ORTEP diagram of 1,3-dimethyl-2-oxo-4,6-diphenyl-1,2,3,4-tetrahydropyridine-3-carbonitrile 2a.

SIMULTANEOUS C- AND N-ALKYLATION
543
Figure 2. ORTEP diagram of 1,3-diethyl-2-oxo-4,6-diphenyl-1,2,3,4-tetrahydropyridine-3-carbonitrile 2b.
carbon atoms possessed by them. The results are tabulated in Table 2. The data indi-
cated that for smaller and more hydrophilic cations tetramethylammonium chloride
(entry 1) and tetraethylammonium chloride (entry 2), the reaction could not give good
yields, and therefore it was not an ideal catalyst for this type of reaction. Triethylben-
zylammonium chloride (TEBA, entry 3), on the other hand, provides enough organic
structure to the reactant anions, enabling the reaction to proceed to completion.
As the number of carbon atoms increases in the catalyst, the most lipophilic quats
[cetyltrimethyl ammonium chloride (entry 5) and Aliquat 336 (entry 6)], simultaneous
C- and N-alkylation also increases.
Figure 3. ORTEP diagram of 1,3-dibenzyl-2-oxo-4,6-diphenyl-1,2,3,4-tetrahydropyridine-3-carbonitrile 2c.

544
H. C. SHAH, V. H. SHAH, AND N. D. DESAI
Table 2. Optimizing 1,3-alkyl=aryl-2-oxo-4,6-diaryl-1,2,3,4-tetrahydropyridine-3-carbonitrile 2a–i using
various phase-transfer catalysts
Type of catalysta
(no. of carbon
atoms in catalyst)
Yield (%) of compound 2 C- and N-alkylation
Entry
2a
12
2b
2c
2d
2e
2f
2g
2h
2i
1
2
3
4
5
(CH3)4NþClꢀ (4)
(C2H5)4NþBrꢀ(8)
TEBA (13)
—
—
18
55
70
—
—
22
41
63
10
11
18
45
68
—
—
15
48
62
—
—
19
40
66
12
14
16
50
71
—
—
10
43
58
—
—
20
45
60
15
20
50
65
TBAB (16)
Cetyltrimethyl ammonium
chloride (19)
Aliquat 336 (22)
6
85
86
89
75
80
90
77
74
85
aTEBA, triethylbenzylammonium chloride; TBAB, tetrabutylammonium bromide; Aliquat 336,
tricaprylmethylammonium chloride.
Scheme 2. Synthesis of 1,3-alkyl-4,6-diaryl-3,4-dihydropyridin-2(1H)-one 3.
Nickel-catalyzed cross-coupling of aryl nitriles and Grignard reagents provides
an efficient method for the preparation of styrene and alkyl arene derivatives via acti-
vation of the CꢀCꢂN bond.[13] Following the success of simultaneous alkylation, our
attention next turned to provide an alternative for CꢀC coupling reaction by cleaving
the CꢀCꢂN bond. To achieve the goal, compound 2 was subjected to hydrolysis and
decarboxylation with 85% phosphoric acid to remove nitrile at position 3 of pyridine
and to afford 1,3-alkyl-4,6-diaryl-3,4-dihydropyridin-2(1H)-one 3 (Scheme 2).
CONCLUSION
In conclusion, during the study of N- vs. O-alkylation using solid–liquid
phase-transfer condition, simultaneous C- and N-alkylation was encountered and
has been optimized using various phase-transfer catalysts. To the best of our knowl-
edge, this is the first reported method of preparing simultaneous C- and N-alkylation
using phase-transfer conditions. We have also established an alternative and practi-
cal procedure for the CꢀC bond formation by hydrolysis of ꢀCꢂN functionality.
EXPERIMENTAL
General
Melting points were determined using an electrothermal method in open capil-
lary tubes and are uncorrected. The infrared (IR) spectra were recorded in

SIMULTANEOUS C- AND N-ALKYLATION
545
centimetersꢀ1 for KBr pellets on a Buck 500 spectrophotometer. The 1H NMR spec-
tra were recorded on Varian 300- and 400-MHz spectrophotometers in CDCl3 or
dimethylsulfoxide (DMSO-d6), using tetramethylsilane (TMS) as internal standard,
and the chemical shifts are expressed in d ppm. Mass spectra (MS) were recorded
on a Jeol SX-102 mass spectrophotometer under electron-impact (EI) ionization.
Elemental analyses were performed on a Carlo Erba 1108 microanalyzer or Elemen-
tar’s Vario EL III microanalyzer. The completion of reaction was checked by TLC
using silica gel G, and spots were exposed to iodine vapor.
Compound 1 was obtained according to procedures published in the litera-
ture.[11] All the other starting materials were obtained from commercial suppliers
and were used without further purification.
Synthesis of 1,3-Dialkyl/aryl-2-oxo-4,6-diaryl-1,2,3,4-
tetrahydropyridine-3-carbonitrile 2a–i
Alkyl=aryl halide (7 mmol) was added dropwise to a well-stirred mixture of
powdered potassium hydroxide (0.7 g, 12.5 mmol), tricaprylmethylammonium
chloride (Aliquat 336) (0.5 mmol, 0.202 g), and 2-oxo-4,6-diaryl-1,2,3,4-
tetrahydropyridine-3-carbonitrile 1 (5 mmol) in toluene (25 mL). The reaction
mixture was heated up to 60–70ꢁC. After the completion of the reaction (ca. 1 h,
TLC), water (25 mL) was added to the reaction mixture and stirring was continued
for 5 min. The organic layer was separated, and the aqueous layer was washed with
toluene (15 mL). The combined organic layer was dried over anhydrous magnesium
sulfate; the solvent was removed in vacuo. The solid thus obtained was filtered,
washed with chilled methanol, dried, and crystallized from ethanol.
Selected Data
1,3-Dimethyl-2-oxo-4,6-diphenyl-1,2,3,4-tetrahydropyridine-3-carbonitrile
1
(2a). IR (KBr): n ¼ 3060, 3010, 2228, 1680, 1616, 1540 cmꢀ1; H NMR (300 MHz,
CDCl3): d ¼ 1.84 (s, J ¼ 7.34 Hz, 3H, CH3), 3.16 (s, J ¼ 7.12 Hz 3H, N-CH3), 3.83
(d, 1H), 5.66 (d, 1H), 7.22–7.52 (m, 10H, Ar-H); MS: m=z ¼ 302 (Mþ). Anal. calcd.
for C20H18N2O (302.37): C, 79.44; H, 6.00; N, 9.26. Found: C, 79.60; H, 5.98;
N, 9.30%.
1,3-Diethyl-2-oxo-4,6-diphenyl-1,2,3,4-tetrahydropyridine-3-carbonitrile
1
(2b). IR (KBr): n ¼ 3050, 3010, 2232, 1684, 1624, 1524 cmꢀ1; H NMR (300 MHz,
CDCl3): d ¼ 1.04–1.08 (t, J ¼ 7.34 Hz, 3H, CH2CH3), 1.19–1.24 (t, J ¼ 7.19, 3H,
N-CH2CH3), 1.94–2.26 (q, J ¼ 7.29, 2H, CH2CH3), 3.45–3.80 (m, J ¼ 7.08 Hz,
1H þ 2H, H at C4, N-CH2CH3), 5.49 (d, 1H), 7.26–7.43 (m, 10H, Ar-H); MS:
m=z ¼ 330 (Mþ). Anal. calcd. for C22H22N2O (330.42): C, 79.97; H, 6.71; N, 8.48.
Found: C, 79.92; H, 6.75; N, 8.34%.
1,3-Dibenzyl-2-oxo-4,6-diphenyl-1,2,3,4-tetrahydropyridine-3-carbonitrile
1
(2c). IR (KBr): n ¼ 3090, 3000, 2220, 1676, 1612, 1500 cmꢀ1; H NMR (300 MHz,
CDCl3): d ¼ 3.24 (m, 1H), 3.54 (m, 1H), 3.91 (d, 1H), 4.90 (s, 2H), 6.12 (d, 1H),
7.20–8.34 (m, 20H, Ar-H); MS: m=z ¼ 454 (Mþ). Anal. calcd. for C32H26N2O
(454.56): C, 84.55; H, 5.77; N, 6.16. Found: C, 84.74; H, 5.92; N, 6.01%.

546
H. C. SHAH, V. H. SHAH, AND N. D. DESAI
6-(4-Methoxyphenyl)-1,3-dimethyl-2-oxo-4-phenyl-1,2,3,4-tetrahydro-
pyridine-3-carbonitrile (2d). IR (KBr): n ¼ 3070, 3010, 2216, 1672, 1604,
1
1512 cmꢀ1; H NMR (300 MHz, CDCl3): d ¼ 1.80 (s, J ¼ 7.34 Hz, 3H, CH3), 3.11
(s, J ¼ 7.12 Hz, 3H, N-CH3), 3.71 (d, 1H), 3.98 (s, 3H, OCH3), 5.56 (d, 1H),
7.21–7.50 (m, 9H, Ar-H); MS: m=z ¼ 332 (Mþ). Anal. calcd. for C21H20N2O2
(332.40): C, 75.88; H, 6.06; N, 8.43. Found: C, 75.67; H, 6.23; N, 8.22%.
1,3-Diethyl-6-(4-methoxyphenyl)-2-oxo-4-phenyl-1,2,3,4-tetrahydropyr-
idine-3-carbonitrile (2e). IR (KBr): n ¼ 3060, 2990, 2224, 1684, 1616, 1520 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d ¼ 0.97–1.02 (t, J ¼ 7.34 Hz, 3H, CH2CH3),
1.10–1.16 (t, J ¼ 7.20, 3H, N-CH2CH3), 1.99–2.28 (q, J ¼ 7.26, 2H, CH2CH3),
3.40–3.77 (m, J ¼ 7.12 Hz, 1H þ 2H, H at C4, N-CH2CH3), 4.03 (s, 3H, OCH3),
5.76 (d, 1H), 7.20–7.41 (m, 9H, Ar-H); MS: m=z ¼ 360 (Mþ). Anal. calcd. for
C23H24N2O2 (360.45): C, 76.64; H, 6.71; N, 7.77. Found: C, 76.72; H, 6.75; N, 7.64%.
1,3-Dibenzyl-6-(4-methoxyphenyl)-2-oxo-4-phenyl-1,2,3,4-tetrahydropyr-
idine-3-carbonitrile (2f). IR (KBr): n ¼ 3120, 3000, 2230, 1680, 1600, 1512 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d ¼ 3.20 (m, 1H), 3.49 (m, 1H), 3.87 (d, 1H), 4.00
(s, 3H, OCH3), 4.87 (s, 2H), 5.90 (d, 1H), 7.25–8.32 (m, 19H, Ar-H); MS:
m=z ¼ 484 (Mþ). Anal. calcd. for C33H28N2O2 (484.59): C, 81.79; H, 5.82; N, 5.78.
Found: C, 81.74; H, 5.92; N, 5.88%.
4-(4-Methoxyphenyl)-1,3-dimethyl-2-oxo-6-p-tolyl-1,2,3,4-tetrahydro-
pyridine-3-carbonitrile (2g). IR (KBr): n ¼ 3050, 3000, 2224, 1682, 1612,
1
1500 cmꢀ1; H NMR (300 MHz, CDCl3): d ¼ 1.80 (s, J ¼ 7.34 Hz, 3H, CH3), 2.47
(s, 3H, CH3), 3.15 (s, J ¼ 7.12 Hz, 3H, N-CH3), 3.78 (d, 1H), 4.04 (s, 3H, OCH3),
5.67 (d, 1H), 7.19–7.67 (m, 8H, Ar-H); MS: m=z ¼ 346 (Mþ). Anal. calcd. for
C22H22N2O2 (346.42): C, 76.28; H, 6.40; N, 8.09. Found: C, 76.34; H, 6.33; N, 8.02%.
1,3-Diethyl-4-(4-methoxyphenyl)-2-oxo-6-p-tolyl-1,2,3,4-tetrahydropyri-
dine-3-carbonitrile (2h). IR (KBr): n ¼ 3090, 3000, 2228, 1680, 1620, 1516 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d ¼ 1.02–1.07 (t, J ¼ 7.29 Hz, 3H, CH2CH3),
1.19–1.26 (t, J ¼ 7.17, 3H, N-CH2CH3), 1.90–2.18 (m, J ¼ 7.29, 2H, CH2CH3),
2.42 (s, 3H, CH3), 3.96 (s, 3H, OCH3), 3.53–3.86 (m, J ¼ 7.08 Hz, 1H þ 2H, H at
C4, N-CH2CH3), 5.80 (d, 1H), 7.23–7.43 (m, 8H, Ar-H); MS: m=z ¼ 374 (Mþ). Anal.
calcd. for C24H26N2O2(374.48): C, 76.98; H, 7.00; N, 7.48. Found: C, 76.72; H, 7.05;
N, 7.38%.
1,3-Dibenzyl-4-(4-methoxyphenyl)-2-oxo-6-p-tolyl-1,2,3,4-tetrahydropyr-
idine-3-carbonitrile (2i). IR (KBr): n ¼ 2990, 3020, 2210, 1674, 1608, 1500 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d ¼ 2.39 (s, 3H, CH3), 3.26 (m, 1H), 3.59 (m, 1H),
3.98 (d, 1H), 4.06 (s, 3H, OCH3), 4.88 (s, 2H), 5.83 (d, 1H), 7.22–8.45 (m, 18H,
Ar-H); MS: m=z ¼ 498 (Mþ). Anal. calcd. for C34H30N2O2 (498.61): C, 81.90; H,
6.06; N, 5.62. Found: C, 81.80; H, 5.98; N, 5.78%.
Synthesis of 1,3-Alkyl/aryl-4,6-diaryl-3,4-dihydropyridin-2(1H)-one 3a–i
Compound 1,3-dialkyl=aryl-2-oxo-4,6-diaryl-1,2,3,4-tetrahydropyridine-3-
carbonitrile 2 (1 g) and 85% phosphoric acid (15 mL) were refluxed with stirring

SIMULTANEOUS C- AND N-ALKYLATION
547
for 18–20 h, allowed to cool, and poured onto crushed ice. The aqueous mixture was
alkaline with 6 N NH4OH, and the resulting precipitates (ppts) were filtered, washed
with water, dried in vacuo at 60ꢁC, and crystallized from dimethyl formamide.
Selected Data
1,3-Dimethyl-4,6-diphenyl-3,4-dihydropyridin-2(1H)-one
(3a). Mp
245–247ꢁC; IR (KBr): n ¼ 3050, 2970, 1688, 1620, 1540 cmꢀ1; H NMR (300 MHz,
DMSO-d6): d ¼ 1.31–1.40 (m, 3H, CH3), 3.16 (s, 3H, N-CH3), 3.28–3.40 (m, 1H),
4.75 (m, 1H), 6.08 (d, 1H), 7.28–7.64 (m, 10H, Ar-H); MS: m=z ¼ 277 (Mþ). Anal.
calcd. for C19H19NO (277.36): C, 82.28; H, 6.90; N, 5.05. Found: C, 82.30;
H, 7.01; N, 5.10%.
1
1,3-Diethyl-4,6-diphenyl-3,4-dihydropyridin-2(1H)-one (3b). Mp 220–222ꢁC;
1
IR (KBr): n ¼ 3040, 2860, 1676, 1600, 1540 cmꢀ1; H NMR (300 MHz, DMSO-d6):
d ¼ 1.01–1.05 (t, J ¼ 7.31 Hz, 3H, CH2CH3), 1.15–1.20 (t, J ¼ 7.22 Hz, 3H, N-CH2-
CH3), 1.92–2.23 (m, J ¼ 7.26 Hz, 2H, CH2CH3), 3.48–3.79 (q, J ¼ 7.12 Hz, 2H,
N-CH2CH3), 3.90 (m, 1H), 4.39 (m, 1H), 5.98 (d, 1H), 7.12–7.56 (m, 10H, Ar-H);
MS: m=z ¼ 305 (Mþ). Anal. calcd. for C21H23NO (305.41): C, 82.58; H, 7.59;
N, 4.59. Found: C, 82.49; H, 7.67; N, 4.70%.
1,3-Dibenzyl-4,6-diphenyl-3,4-dihydropyridin-2(1H)-one (3c). Mp
1
200–202ꢁC; IR (KBr): n ¼ 3020, 2900, 1680, 1616, 1524 cmꢀ1; H NMR (300 MHz,
DMSO-d6): d ¼ 2.93 (m, 1H), 3.35 (m, 1H), 3.90 (m, 1H), 4.39 (m, 1H), 4.89 (s,
2H), 6.20 (d, 1H), 7.12–7.66 (m, 20H, Ar-H); MS: m=z ¼ 429 (Mþ). Anal. calcd.
for C31H27NO (429.55): C, 86.68; H, 6.34; N, 3.26. Found: C, 86.70; H, 6.45;
N, 3.44%.
6-(4-Methoxyphenyl)-1,3-dimethyl-4-phenyl-3,4-dihydropyridin-2(1H)-
one (3d). Mp 267–268ꢁC; IR (KBr): n ¼ 3070, 2990, 1680, 1616, 1530 cmꢀ1
;
1H NMR (300 MHz, DMSO-d6): d ¼ 1.33–1.41 (m, 3H, CH3), 3.10 (s, 3H,
N-CH3), 3.34–3.47 (m, 1H), 4.70 (m, 1H), 3.97 (s, 3H, OCH3), 6.08 (d, 1H),
7.35–7.59 (m, 9H, Ar-H); MS: m=z ¼ 307 (Mþ). Anal. calcd. for C20H21NO2
(307.39): C, 78.15; H, 6.89; N, 4.56. Found: C, 78.30; H, 7.01; N, 4.39%.
1,3-Diethyl-6-(4-methoxyphenyl)-4-phenyl-3,4-dihydropyridin-2(1H)-
one (3e). Mp 254–256ꢁC; IR (KBr): n ¼ 3020, 2880, 1676, 1604, 1520 cmꢀ1
;
1H NMR (300 MHz, DMSO-d6): d ¼ 0.92–1.00 (t, J ¼ 7. 25 Hz, 3H, CH2CH3),
1.14–1.20 (t, J ¼ 7.33 Hz, 3H, N-CH2CH3), 1.89–2.21 (m, J ¼ 7.33 Hz, 2H, CH2CH3),
3.39–3.70 (q, J ¼ 7.08 Hz, 2H, N-CH2CH3), 3.98 (s, 3H, OCH3), 4.09 (m, 1H), 4.44
(m, 1H), 6.01 (d, 1H), 7.10–7.50 (m, 9H, Ar-H); MS: m=z ¼ 335 (Mþ). Anal. calcd.
for C22H25NO2 (335.44): C, 78.77; H, 7.51; N, 4.18. Found: C, 78.54; H, 7.60;
N, 4.22%.
1,3-Dibenzyl-6-(4-methoxyphenyl)-4-phenyl-3,4-dihydropyridin-2(1H)-
one (3f). Mp 180–181ꢁC; IR (KBr): n ¼ 3010, 2980, 1684, 1604, 1500 cmꢀ1
;
1H NMR (300 MHz, DMSO-d6): d ¼ 3.24 (m, 1H), 3.54 (m, 1H), 3.86 (m, 1H),
4.00 (s, 3H, OCH3), 4.52 (m, 1H), 4.90 (s, 2H), 5.99 (s, 1H), 7.25–8.32 (m, 19H,

548
H. C. SHAH, V. H. SHAH, AND N. D. DESAI
Ar-H); MS: m=z ¼ 459 (Mþ). Anal. calcd. for C32H29NO2 (459.58): C, 83.63; H, 6.36;
N, 3.05. Found: C, 83.74; H, 6.21; N, 3.00%.
4-(4-Methoxyphenyl)-1,3-dimethyl-6-p-tolyl-3,4-dihydropyridin-2(1H)-
1
one (3g). Mp 267–268ꢁC; IR (KBr): n ¼ 3040, 2980, 1672, 1608, 1520 cmꢀ1; H
NMR (300 MHz, DMSO-d6): d ¼ 1.29–1.38 (m, 3H, CH3), 2.39 (s, 3H, CH3), 3.10
(s, 3H, N-CH3), 3.30–3.45 (m, 1H), 3.97 (s, 3H, OCH3), 4.70 (m, 1H), 6.08
(d, 1H), 7.23–7.55 (m, 8H, Ar-H); MS: m=z ¼ 321 (Mþ). Anal. calcd. for
C21H23NO2 (321.41): C, 78.47; H, 7.21; N, 4.36. Found: C, 78.44; H, 7.23; N, 4.39%.
1,3-Diethyl-4-(4-methoxyphenyl)-6-p-tolyl-3,4-dihydropyridin-2(1H)-
1
one (3h). Mp 273–275ꢁC; IR (KBr): n ¼ 3010, 2910, 1674, 1608, 1512 cmꢀ1; H
NMR (300 MHz, DMSO-d6): d ¼ 0.93–1.02 (t, J ¼ 7.27 Hz, 3H, CH2CH3),
1.18–1.22 (t, J ¼ 7.31 Hz, 3H, N-CH2CH3), 1.88–2.15 (m, J ¼ 7.36 Hz, 2H, CH2CH3),
2.46 (s, 3H, CH3), 3.99 (s, 3H, OCH3), 3.42–3.76 (q, J ¼ 7.16 Hz, 2H, N-CH2CH3),
4.05 (m, 1H), 4.32 (m, 1H), 6.05 (d, 1H), 7.08–7.45 (m, 8H, Ar-H); MS: m=z ¼ 349
(Mþ). Anal. calcd. for C23H27NO2 (349.47): C, 79.05; H, 7.79; N, 4.01. Found: C,
79.19; H, 7.68; N, 4.14%.
1,3-Dibenzyl-4-(4-methoxyphenyl)-6-p-tolyl-3,4-dihydropyridin-2(1H)-
1
one (3i). Mp ¼ 253–241ꢁC; IR (KBr): n ¼ 3020, 2950, 1670, 1600, 1508 cmꢀ1; H
NMR (300 MHz, DMSO-d6): d ¼ 2.53 (s, 3H, CH3), 3.28 (m, 1H), 3.55 (m, 1H),
3.95 (m, 1H), 4.10 (s, 3H, OCH3), 4.41 (m, 1H), 4.90 (s, 2H), 5.80 (d, 1H),
7.22–8.45 (m, 18H, Ar-H); MS: m=z ¼ 473 (Mþ). Anal. calcd. for C33H31NO2
(473.60): C, 83.69; H, 6.60; N, 2.96. Found: C, 83.80; H, 6.68; N, 2.88%.
ACKNOWLEDGMENTS
We thank the Regional Sophisticated Instrumentation Center, Central Drug
Research Institute, Lucknow and Chandigarh, India, for 1H NMR and mass spectral
analysis and Dishman Pharmaceuticals and Chemicals Ltd. for their support.
REFERENCES
1. (a) Josein, H.; Ko, S.-B.; Bom, D.; Curran, D. P. A general synthetic approach to the
(20S)-camptothecin family of antitumor agents by a regiocontrolled cascade radical cycli-
zation of aryl Isonitriles. Chem. Eur. J. 1998, 4, 67–83; (b) Comins, D. L.; Saha, J. K.
Concise synthesis of mappicine ketone and (ꢃ)-mappicine. J. Org. Chem. 1996, 61,
9623–9624; (c) Comins, D. L.; Nolan, J. M. A practical six-step synthesis of
(S)-camptothecin. Org. Lett. 2001, 3, 4255–4257.
2. (a) Villemin, D.; Liao, L. One-pot three-step synthesis of cerpegin. Tetrahedron Lett. 1996,
37, 8733–8734; (b) Lazaar, J.; Hoarau, C.; Mongin, F.; Tre
Queguiner, G.; Marsais, F. One-pot four-step synthesis of cerpegin. Tetrahedron Lett.
2005, 46, 3811–3813.
´
court, F.; Godard, A.;
´
3. Buck, J.; Madeley, J. P.; Pattenden, G. Lithiation of 4-methoxy-2-pyridones: Synthetic
entry to tenellin and funiculosin, and related natural 3,5-disubstituted 4-oxy-2-pyridones.
J. Chem. Soc., Perkin Trans. 1 1992, 1, 67–77.
4. (a) Dolle, R. E.; Nicolaou, K. C. Total synthesis of elfamycins: Aurodox and efrotomycin,
2: Coupling of key intermediates and completion of the synthesis. J. Am. Chem. Soc. 1985,

SIMULTANEOUS C- AND N-ALKYLATION
549
107, 1695–1698; (b) Vogeley, L.; Palm, G. J.; Mesters, J. R.; Hilgenfeld, R. Conforma-
tional change of elongation factor Tu (EF-Tu) induced by antibiotic binding. J. Biol.
Chem. 2001, 276, 17149–17155; (c) Parreira, R. L. T.; Abrahao, O.; Galembeck, S. E.
Conformational preferences of non-nucleoside HIV-1 reverse transcriptase inhibitors.
Tetrahedron 2001, 57, 3243–3253.
5. Sorbera, L. A.; Castaner, J. Laquinimod. Drugs Future 2003, 28, 1059.
6. Li, Q.; Mitscher, L. A.; Shen, L. L. The 2-pyridone antibacterial agents: Bacterial
topoisomerase inhibitors. Med. Res. Rev. 2000, 20, 231.
7. (a) Dias, N.; Vezin, H.; Lansiaux, H.; Lansiaux, A.; Bailly, C. Topoisomerase inhibitors of
marine origin and their potential use as anticancer agents. Top. Curr. Chem. 2005, 253, 89;
(b) Doll, R. J.; Kirschmeier, P.; Bishop, W. R. Farnesyltransferase inhibitors as anticancer
agents: Critical crossroads. Curr. Opin. Drug. Disc. Dev. 2004, 7, 478.
8. Torres, M.; Gil, S.; Parra, M. New synthetic methods to 2-pyridone rings. Curr. Org.
Chem. 2005, 9, 1757–1779.
9. (a) Desai, N. D.; Shah, R. D. Improved protocol for thorpe reaction: Synthesis of
4-amino-1-arylpyrazole using solid–liqiud phase-transfer conditions. Synth. Commun.
2008, 38, 309–315; (b) Desai, N. D.; Shah, R. D. Improved synthesis and efficient
chemoselective reduction of fused tetrazoles under phase-transfer conditions. Synthesis
2006, 3275–3279.
10. (a) Hopkins, G.; Jonak, J. P.; Minnemeyer, H. J.; Tieckelmann, H. Alkylations of
heterocyclic ambident anions II: Alkylation of 2-pyridone salts. J. Org. Chem. 1967, 32,
4040–4044; (b) Gallo, R. J.; Makosza, M.; Dou, H. J. M.; Hassanaly, P. Applications of
phase-transfer catalysis in heterocyclic chemistry. Adv. Heterocycl. Chem. 1984, 36, 175–
234; (c) Dou, H. J. M.; Hassanaly, P.; Metzger, J. Alkylation d’anions ambidents en catalyse
par transfert de phase: Cas des hydroxypyridines. J. Heterocycl. Chem. 1977, 14, 321–323;
(d) Comins, D.; Jianhua, G. N- vs. O-Alkylation in the mitsunobu reaction of 2-pyridone.
Tetrahedron Lett. 1994, 35, 2819–2822; (e) Rico, I.; Halvorsen, K.; Dubrule, C.; Lattes, A.
Effect of micelles on cyclization reactions: The use of N-hexadecyl-2-chloropyridinium
iodide as an amphiphilic carboxyl-activating agent in lactonization and lactamization. J.
Org. Chem. 1994, 59, 415–420; (f) Liu, H.; Ko, S. B.; Josien, H.; Curran, D. P. Selective
N-functionalization of 6-substituted-2-pyridones. Tetrahedron Lett. 1995, 36, 8917–8920;
(g) Koppe, T.; Mederski, R. K. W.; Osswald, M.; Schwarz, M. On the regiochemistry of
the alkylation of tert-butyl N-[6-butyl-1,2-dihydro-2-oxo-3-pyridylmethyl]carbamate:
Precursor of a series of potent angiotensin II receptor antagonists. Tetrahedron Lett.
1995, 36, 377–380; (h) Almena, I.; Diaz-Ortiz, A.; Diez-Barra, E.; de la Hoz, A.; Loupy, A.
Solvent-free benzylations of 2-pyridone: Regiospecific N- or C-alkylation. Chem. Lett.
1996, 5, 333–334; (i) Sato, T.; Yoshimatsu, K.; Otera, J. CsF in organic synthesis: Tuning
of N- or O-alkylation of 2-pyridone. Synlett. 1995, 845–846; (j) Bowman, W. R.; Bridge,
C. F. Regioselective synthesis of N-alkyl pyridones. Synth. Commun. 1999, 29, 4051–
4059; (k) Nadin, A.; Harrison, T. Synthesis of tricyclic pyridones by radical cyclization.
Tetrahedron Lett. 1999, 40, 4073–4076; (l) Sugahara, M.; Moritani, Y.; Kuroda, T.; Kondo,
K.; Shimadzu, H.; Ukita, T. An efficient synthesis of the anti-asthmatic agent T-440: A
selective N-alkylation of 2-pyridone. Chem. Pharm. Bull. 2000, 48, 589–591; (m) Janin,
Y. L.; Huel, C.; Flad, G.; Thirot, S. Methyl orthocarboxylates as methylating agents of
heterocycles. Eur. J. Org. Chem. 2002, 1763–1769; (n) Ruda, M. C.; Bergman, J.; Wu, J.
Preparation of N-alkylated pyridones via selective N-alkylation of 2-alkoxypyridines on
solid phase. J. Comb. Chem. 2002, 4, 530–535; (o) Olaf, R. L.; Chris, M. Synthesis of carbo-
cyclic pyrimidine nucleosides using the Mitsunobu reaction, part II: Influence of the solvent
on N1- versus O2-alkylation. Synlett. 2006, 324–326.
´
11. (a) Bomika, Z. A.; Andaburskaya, M. B.; Pelcher, Y. E.; Dubur, G. Y. 2-Oxopyridine
derivatives. Khim. Geterotsikl. Soedin 1975, 8, 1108–1111; (b) Kuthan, J.; Nesvadba, P.;

550
H. C. SHAH, V. H. SHAH, AND N. D. DESAI
Donnerova, Z.; Trska, P. Contribution to the study of cyclocondensations of cyanoacetic
acid derivatives with benzylideneacetophenone. Coll. Czech. Chem. Commun. 1977, 42,
2152–2160.
12. (a) Crystallographic Data Centre as supplementary publication numbers CCDC 183036:
copies of the data can be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge, CB2 1EZ, UK (fax: þ44-1223-336033 or e-mail: deposit@ccdc.cam.
ac.uk): Patel, U. H.; Dave, C. G.; Jotani, M. M.; Shah, H. C. 1,3-Dimethyl-2-
oxo-4,6-diphenyl-1,2,3,4-tetrahydropyridine-3-carbonitrile. Acta Cryst. 2002, C58, o191;
(b) CCDC 294954: Patel, U. H.; Jotani, M. M.; Shah, H. C. Crystal and molecular struc-
ture of 1,3-diethyl-2-oxo-4,6-diphenyl-1,2,3,4-tetrahydropyridine-3-carbonitrile. Anal. Sci.
2006, 22, 109; (c) CCDC 187605: Patel, U. H.; Dave, C. G.; Jotani, M. M.; Shah, H. C.
Crystal structure of 1,3-dibenzyl-2-oxo-4,6-diphenyl-1,2,3,4-tetrahydropyridine-3-carbo-
nitrile, C32H26N2O. Z. Kristallogr.-New Cryst. Struct. 2002, 217, 29.
13. Miller, J. A.; Dankwardt, J. W. Nickel-catalyzed cross-coupling of modified alkyl and
alkenyl Grignard reagents with aryl- and heteroaryl nitriles: Activation of the CꢀCN
bond. Tetrahedron Lett. 2003, 44, 1907–1910.