One-pot formation of functionalised 2-piperidinones from arylidenecyanoacetates and methanolic ammonia via tandem reactions

Article abstract of DOI:10.3987/COM-07-S(U)59

Aryl aldehydes react with ethyl cyanoacetate in methanolic ammonium acetate to expeditiously furnish, besides high yields of arylidenecyanoacetates, 4,6-diaryl-3,5-dicyano-5-ethoxycarbonyl-2-piperidinonesinlow yields. But preformed arylidenecyanoacetates

Full text of DOI:10.3987/COM-07-S(U)59

HETEROCYCLES, Vol. 73, 2007
795
HETEROCYCLES, Vol. 73, 2007, pp. 795 - 804. © The Japan Institute of Heterocyclic Chemistry
Received, 3rd August, 2007, Accepted, 13th September, 2007, Published online, 18th September, 2007. COM-07-S(U)59
ONE-POT FORMATION OF FUNCTIONALISED 2-PIPERIDINONES
FROM ARYLIDENECYANOACETATES AND METHANOLIC
AMMONIA VIA TANDEM REACTIONS
Manas Chakrabarty,a∗ Sulakshana Karmakar,a Shiho Arima,b and Yoshihiro
Harigayab
aDepartment of Chemistry, Bose Institute, 93/1, A.P.C. Road, Kolkata 700009,
India
E-mail:chakmanas@yahoo.co.in
bSchool of Pharmaceutical Sciences, Kitasato University, Minato-ku, Tokyo 108,
Japan
Abstract – Aryl aldehydes react with ethyl cyanoacetate in methanolic ammonium
acetate to expeditiously furnish, besides high yields of arylidenecyanoacetates,
4,6-diaryl-3,5-dicyano-5-ethoxycarbonyl-2-piperidinones in low yields. But
preformed arylidenecyanoacetates react with methanolic ammonia to furnish the
same functionalised 2-piperidinones in much better yields. The actual
stereostructure of one of the products was determined by single crystal X-ray
diffraction analysis, and novel tandem reactions occurring in one pot are proposed
for the formation of the products.
INTRODUCTION
The importance of heterocyclic compounds as drugs is well documented.1 Our ongoing interest in the
development of newer synthetic routes to heterocyclic molecules having proven and/or potential
bioactivity2 drew our attention to substituted 3-cyanopyridin-2(1H)-ones since they exhibit plant growth
inhibitory, cardiotonic, hypoglycemic and antiviral properties.3 In fact, three such compounds are available
commercially.4 This class of compounds are mainly prepared by the reaction of β-diketones, β-ketoesters,
conjugated enones or enals with cyanoacetamide using a variety of bases, phase transfer catalysts, resins or
enzymes as the catalysts.5 But most of these methods have their own disadvantages, for which newer
synthetic routes to this class of compounds continue to be developed.6
In response to this continuing need, we planned to develop a new synthetic route to functionalised 3-cyano-

796
HETEROCYCLES, Vol. 73, 2007
2-pyridones by the reaction of aryl aldehydes, ethyl cyanoacetate, a methyl ketone and ammonium acetate
in methanol – a modification of a recent report.7 Accordingly, benzaldehyde and isobutyl methyl ketone
were used in the above mentioned reaction. It furnished, apart from the corresponding Knoevenagel
condensate as the major product, a minor product which was not the target molecule, which did not involve
the ketone at all and whose formation could not be explained by any straightforward mechanism. The
product was identified as 3,5-dicyano-4,6-dipheyl-5-ethoxycarbonyl-2-piperidinone. A rational follow-up
of this observation led to development of a better, general route to the formation of similarly substituted
2-piperidinones from arylidenecyanoacetates. We propose a sequence of tandem reactions occurring in one
pot for their formation. Our findings, since mechanistically significant, are presented briefly in this paper.
RESULTS AND DISCUSSION
As stated above, initially benzaldehyde (1a) was treated with equimolar amounts of ethyl cyanoacetate (2),
isobutyl methyl ketone and ammonium acetate in methanol at room temperature. The reaction, complete in
five minutes, resulted in the formation of two products (TLC). The major (42%), less polar product was
identified spectroscopically as the Knoevenagel condensate, E-ethyl 2-cyanocinnamate (3a). The minor
(14%), more polar product, C22H19N3O3 (HR EI-MS), was unambiguously identified as 3,5-dicyano-
4,6-diphenyl-5-ethoxycarbonyl-2-piperidinone (4a) by combined spectroscopic analysis. The depicted
stereostructure of 4a was ascertained from its single crystal X-ray diffraction analysis,8 and the ORTEP
diagram of 4a is shown in Figure 1. The reactions along with the expected and isolated products are shown
in Scheme 1.
This unexpected observation prompted us to check the generality of the reaction before looking into its
mode of formation. Accordingly, the reaction was repeated with each of eight benzaldehydes (1a-f, h, i)
Figure 1: The ORTEP diagram of compound 4a

HETEROCYCLES, Vol. 73, 2007
797
Ph
CN
i
Pr
O
N
H
H3C
PhCHO
(expected)
1a
+
i
BuCOMe
Ph
NH4OAc
MeOH, rt
EtO2C
CN
O
NCCH2CO2Et
E
CN
+
PhCH C
2
NC
Ph
2
CO2Et
3a (42%)
Scheme 1
N
H
4a (14%)
and 2-naphthaldehyde (1g), but without using the ketone. All the reactions were complete within five
minutes, furnishing single product from each of 1h and 1i and two products - one major and one minor -
from each of the rest of the substrates. The major products (52-81%) from 1a-g and the only products from
1h (82%) and 1i (79%) were identified as the corresponding Knoevenagel condensates, i.e. the
corresponding E-arylidenecyanoacetates (3a-i) from their 1H NMR spectra and by comparing their melting
points with those reported in the literature (vide Experimental). The minor products (2-15%) from 1a-g
were identified spectroscopically as the respective 4,6-diaryl-3,5-dicyano-5-ethoxycarbonyl-
2-piperidinones (4a-g). The depicted stereostructures of 4b-g were assumed from the similarity of their
mainly NMR spectroscopic data to those of 4a. Noticeably, 4-nitrobenzaldehyde (1h) and veratraldehyde
(1i) did not furnish the respective 2-piperidinones. The reactions are presented in Scheme 2 and the results
in Table 1.
A survey of the literature at this stage revealed that Nagai et al. had previously prepared the 2-piperidinones
4a (38.4%) and 4f (15.5%) from the same substrates (viz. 1a and 1f) as ours but by using ethanolic
ammonia (instead of methanolic ammonium acetate, used by us) and by keeping these solutions in fridge
for ten days.9 They also subjected 1b and 1h separately to similar reaction conditions, but none of them
furnished either the Knoevenagel condensates (3b/3h) or the corresponding 2-piperidinones (4b/4h). Since
Nagai’s work lacked generality (involved only two 2-piperidinones) and the reactions required ten days, we
Ar
CN
EtO2C
CN
E
CN
NH4OAc
+
ArCHO +
ArCH C
H2C
NC
Ar
MeOH, rt, 5 min
CO2Et
CO2Et
O
N
H
1a-i
2
3a-i (52-82%)
4a-d (11-15%)
4e-g (2-4%)
Scheme 2

798
HETEROCYCLES, Vol. 73, 2007
Table 1. Reactions of ArCHO with NCCH2CO2Et and NH4OAc-MeOH
Entry
(1)
Yield (%)
Yield (%)
Overall
Ar = 4-R-C6H4
(for a-f, h)
a: R = H
of (3)a
of (4)b
Yield (%)
1
2
3
4
5
6
7
8
9
58
52
69
62
73
81
69
82
79
15
13
11
14
4
73
65
80
76
77
83
73
82
79
b: R = Cl
c: R = Br
d: R = CN
e: R = Me
f: R = OMe
g: 2-naphthyl
h: R = NO2
2
4
⎯
⎯
i: veratryl
aIdentified by 1H NMR and mps; bIdentified by spectroscopic (IR, 1H and 13C NMR,
DEPT 135, LR/HR EI/FAB/ESI-MS) and elemental analysis.
went ahead with our study.
We envisaged the following sequence of tandem reactions to explain the formation of 4. We believed, the
initially formed Knoevenagel condensates (3) are the actual substrates. They then undergo Michael attack
by one molecule of ammonia, formed in situ from ammonium acetate, to result in the formation of the
unisolated β-aminoesters (3′). The derived anion, formed by ammonia as the base, triggers a second
Michael addition at the β-position of another molecule of 3 to form the δ-aminoester (with respect to the
terminal ethoxycarbonyl group) (3″). Finally, cyclocondensation with the loss of one molecule of ethanol
furnishes the substituted 2-piperidinones (4) (Scheme 3).
Since the Knoevenagel condensates (3) were considered by us to be the initial products, each of 3a and 3b,
as representative molecules, was separately treated with ammonium acetate in methanol at room
temperature. In each case, the starting 3 remained partly unconsumed even after a prolonged reaction
period (5 h), leading, however, to the isolation of 4a and 4b in better yields, viz. 24% and 35%,
respectively. This observation thus lent support to the proposed mechanism.
Since the yields of the isolated 2-piperidinones 4a and 4b obtained from the respective Knoevenagel
condensates 3a and 3b and methanolic ammonium acetate were still not satisfactory, a number of
preformed arylidenecyanoacetates (3a-i) were treated separately with methanolic ammonia, instead of
methanolic ammonium acetate, at room temperature, in order to obtain better yields of the 2-piperidinones.
The reaction with the anisylidene derivative (3f) was inordinately sluggish (18 h) and furnished 4f in only

HETEROCYCLES, Vol. 73, 2007
799
CN
ArCH CH
NH2
CN
β
E
CN
NH3
(from NH4OAc)
ArCHO +
ArCH C
H2C
CO2Et
CO2Et
CO2Et
1
2
3
3'
(i) NH3 (base)
(ii) 3
Ar
Ar
CN
NC
EtO2C
Ar
EtO2C
NC
_
CN
- EtOH
4
CO2Et
NH2
δ
CO2Et
Ar
NH2
3"
Scheme 3
5% yield, whereas 3h and 3i did not react at all. For the rest of the substrates, the reactions were complete
within 20-60 minutes, furnishing the respective 2-piperidinones (4a-e, g) in even better (than for the
reactions of aryl aldehydes or arylidenecyanoacetates with methanolic ammonium acetate) yields, viz.
30-69% (except for 4f, 5%). These reactions are presented in Scheme 4 and the results in Table 2.
That the reactions with 3h and 3i did not produce any 2-piperidinone and that 3f furnished 4f in extremely
low yield, constitutes an evidence in support of the proposed mechanism, since the presence of either a
strong electron-withdrawing group (as in 3h) or strong electron-donating groups (as in 3f and 3i) render
these molecules weaker Michael acceptors.
Pertinently, some of these functionalised 2-piperidinones, viz. 4a, b, f have been recently reported to be
formed by the reaction of the preformed arylimines and ethyl cyanoacetate using sodium ethoxide in
ethanol10 and have been shown to display antibacterial property.11
In conclusion, while trying to develop a new route to substituted 3-cyano-2-pyridones, we have found out
that (i) the arylidenecyanoacetates (3), i.e. the Knoevenagel condensates are better substrates (than the aryl
aldehydes themselves) for the preparation of the functionalised 2-piperidinones (4), specially if the aryl
aldehydes do not bear a strong electron-donating group (e.g. 1f, i) or electron-withdrawing group (e.g. 1h),
Ar
CN
O
EtO2C
CN
E
30% aq. NH3
MeOH, rt
NC
Ar
ArCH C
CO2Et
N
H
3a-i
4a-e, g (30-69%)
4f (5%)
Scheme 4

800
HETEROCYCLES, Vol. 73, 2007
Table 2. Reactions of arylidenecyanoacetates (3) with NH3-MeOH
Entry
(3): Ar = 4-R-C6H4
(for a-f, h)
Time
Yield (%)a
of (4)b
1
2
3
4
5
6
7
8
9
a: R = H
b: R = Cl
20 min
20 min
20 min
60 min
35 min
18 h
30
48
60
50
69
5
c: R = Br
d: R = CN
e: R = Me
f: R = MeO
g: 2-naphthyl
h: R = NO2
i: veratryl
30 min
⎯
35
⎯
⎯
⎯
aRefer to isolated, pure products; bIdentified by spectroscopic (IR, 1H and 13C NMR,
DEPT 135, LR/HR EI/FAB/ESI-MS) and elemental analysis.
and (ii) methanolic ammonia at room temperature brings about the reactions (of 3) much faster (20-60
min) than does ethanolic ammonia (10 days in fridge) for the aryl aldehydes (1). We have also established
for the first time the actual stereostructure of 4 by single crystal X-ray diffraction analysis (of 4a), which
renders the stereostructures suggested for 4 by Nagai (based on Dreiding model) and by Rai (based on
assumption) invalid.
In view of the fact that the last decade witnessed a large number of functionalised piperidines entering
preclinical and clinical trials,12 our present work assumes importance since these δ-lactams can be
reduced chemoselectively to the corresponding piperidines in the presence of other reducible groups.13
Moreover, these δ-lactams contain cyanide and ethoxycarbonyl groups and a carbanion-generating centre
(CH-3), all of which can be used as handles for various chemical transformations.14 The δ-lactams as well
as their transformation products are likely to have bioactive potential, which, though not yet explored,
adds to the importance of the present work.
EXPERIMENTAL
Mps were determined on a Toshniwal apparatus and are uncorrected. IR spectra (nujol) were recorded in
1
13
a Nicolet Impact 410 FT-IR spectrophotometer, and H (500 MHz) and C (125 MHz) NMR spectra,
both 1D and 2D, including DEPT 135, in a Bruker DRX 500 NMR spectrometer. The LR EI/FAB-MS,
HR EI/FAB-MS (using m-nitrobenzyl alcohol as the liquid matrix) and HR ESI-MS were recorded in
JEOL JMS-AX505HA, JEOL JMS-700 MStation and Qtof Micro YA263 mass spectrometers,

HETEROCYCLES, Vol. 73, 2007
801
respectively. Column Chromatography (CC) was carried out over silica gel (60-120 mesh, Qualigens,
India). PE refers to petroleum ether, bp 60-80 °C.
General experimental procedure. Reactions of aryl aldehydes (1) with NH4OAc/MeOH. To a
solution of NH4OAc (3 mmol) in MeOH (8-10 mL) were added successively 1 (2 mmol) and 2 (2 mmol),
and the resulting solution was stirred at rt until the reaction was complete (TLC). Water (5 mL) was then
added to the reaction mixture and the solution extracted with EtOAc (3×15 mL). The combined solvent
extracts were washed with water, dried (Na2SO4) and the solvent removed. The resulting residue was
purified by CC to furnish 3 and 4 in 3-5% and 15-25% EtOAc/PE eluates, respectively.
Reactions of 3 with 30% aq. NH3/MeOH. To a solution of 3 (1 mmol) in MeOH (10 mL) was added
30% aq. NH3 (2 mL), and the resulting solution was stirred at rt. After the reaction was complete (TLC),
the reaction mixture was heated on steam-bath to remove both NH3 and MeOH. The resulting residue was
purified by CC, as before, to furnish 4a-g.
Mps of compounds 3: 3a: oil (lit.,15 49-50 °C); 3b: 90-91 °C (PE-EtOAC) (lit.,16 91-92 °C); 3c: 95-96 °C
(PE-EtOAc) (lit.,17 96 °C); 3d: 170-171 °C (PE-CH2Cl2) (lit.,18 168.5-168.9 °C); 3e: 90-91 °C
(PE-EtOAc) (lit.,19 90 °C); 3f: 88-89 °C (PE-EtOAc) (lit.,20 89-90 °C); 3g: 124-125 °C (PE-EtOAc) (lit.,21
125-126 °C); 3h: 168-169 °C (EtOAc) (lit.,20 169-170 °C); 3i: 155-157 °C (EtOAc) (lit.,20 157 °C).
Spectroscopic data of the known piperidinones (4a, b, f) are not furnished here. Their mps: 4a: 180-181
°C (PE-EtOAc) (lit.,10 171-173 °C); 4b: 188-190 °C (PE-CH2Cl2) (lit.,10 192-194 °C); 4f: 207-210 °C
(decomp) (PE-EtOAc) (lit.,9 211-214 °C).
4,6-Bis(4-bromophenyl)-3,5-dicyano-5-ethoxycarbonyl-2-piperidinone (4c): mp 244-246 °C (PE-
EtOAc); IR: 3354, 2249, 1744, 1681, 1490, 1249, 1075, 1010, 844, 824, 764 cm-1; 1H NMR (DMSO-d6):
δ 0.83 (3H, t, J=7 Hz), 3.85 (1H, dq, J1=11 Hz, J2=7 Hz), 3.89 (1H, dq, J1=11 Hz, J2=7 Hz), 4.59 (1H, d,
J=13 Hz), 5.06 (1H, d, J=13 Hz), 5.34 (1H, s), 7.23 (2H, d, J=8.5 Hz), 7.41 (2H, d, J=8.5 Hz), 7.62 (2H,
13
d, J=8 Hz), 7.63 (2H, d, J=8 Hz), 8.97 (1H, s); C NMR : δ 14.1 (CH3), 64.2 (CH2), 39.1, 47.0, 60.7,
130.5, 131.5, 132.5, 132.8 (all CH), 58.9, 114.6, 117.1, 123.6, 123.7, 134.1, 134.7, 163.7, 164.7 (all C);
EI-MS: m/z (%) 533 (M++4, <5), 531 (M++2, <5), 529 (M+, <5), 281 (71), 279 (62), 252 (83), 251 (100),
250 (81), 249 (59), 236 (39), 234 (54), 209 (15), 208 (21), 207 (28), 206 (23), 200 (19), 182 (19), 180
79
(21), 171 (33), 155 (38), 127 (67), 100 (16), 44 (26); HRMS (FAB+): calcd for C22H18N3O3 Br81Br,
531.9694 (M++H); found 531.9682; Anal. Calcd for C22H17N3O379+81Br2: C, 49.71; H, 3.20; N, 7.91.
Found: C, 49.75; H, 3.21; N, 7.93.

802
HETEROCYCLES, Vol. 73, 2007
4,6-Bis(4-cyanophenyl)-3,5-dicyano-5-ethoxycarbonyl-2-piperidinone (4d): mp 188-190 °C (PE-
EtOAc); IR: 3257, 2223, 1738, 1686, 1609, 1276, 1083, 1001, 844, 724 cm-1; 1H NMR (DMSO-d6): δ
0.80 (3H, t, J=7 Hz), 3.84 (1H, dq, J1=11 Hz, J2=7 Hz), 3.87 (1H, dq, J1=11 Hz, J2 = 7 Hz), 4.76 (1H, d,
J=13 Hz), 5.22 (1H, d, J=13 Hz), 5.46 (1H, s), 7.47 (2H, d, J=8.5 Hz), 7.67 (2H, d, J=8.5 Hz), 7.91 (2H,
13
d, J=8.5 Hz), 7.94 (2H, d, J=8.5 Hz), 9.09 (1H, br s); C NMR: δ 14.1 (CH3), 64.5 (CH2), 38.8, 47.4,
60.9, 129.6, 130.5, 133.5, 133.8 (all CH), 58.4, 113.2, 113.3, 114.3, 116.9, 119.02, 119.04, 139.8, 140.3,
163.6, 164.4 (all C); LR FAB-MS (+): m/z 424 (M++H), 447 (M++Na); HRMS (FAB+): calcd for
C24H18N5O3, 424.1409 (M++H); found 424.1418; Anal. Calcd for C24H17N5O3: C, 68.08; H, 4.02; N,
16.55. Found: C, 68.13; H, 4.01; N, 16.58.
4,6-Bis(4-tolyl)-3,5-dicyano-5-ethoxycarbonyl-2-piperidinone (4e): mp 184-186 °C (PE-EtOAc); IR:
3200, 2249, 1735, 1676, 1513, 1252, 1096, 1063, 1019, 813, 718 cm-1; 1H NMR (DMSO-d6): δ 0.83 (3H,
t, J=7 Hz), 2.29 (3H, s), ca. 2.3 (3H, s), 3.83 (1H, dq, J1=14 Hz, J2=7 Hz), 3.84 (1H, dq, J1=14 Hz, J2=7
Hz), 4.49 (1H, d, J=13 Hz), 4.93 (1H, d, J=13 Hz), 5.31 (1H, s), 7.19 (2H, d, J=8 Hz), 7.20 (2H, d, J=9.5
13
Hz), 7.21 (2H, d, J=9.5 Hz), 7.33 (2H, d, J=8 Hz), 8.87 (1H, br s); C NMR: δ 14.2, 21.54, 21.57 (all
CH3), 63.8 (CH2), 39.3, 47.3, 61.0, 128.2, 129.1, 129.9, 130.2 (all CH), 59.6, 115.1, 117.4, 131.9, 132.5,
139.4, 139.8, 163.9, 164.9 (all C); FAB-MS (+): m/z 402 (M++H); HRMS (FAB+): calcd for C24H24N3O3,
402.1818 (M++H); found 402.1812; Anal. Calcd for C24H23N3O3: C, 71.82; H, 5.73; N, 10.47. Found: C,
71.86; H, 5.72; N, 10.49.
4,6-Bis(2-naphthyl)-3,5-dicyano-5-ethoxycarbonyl-2-piperidinone (4g): mp 199-200 °C (PE-EtOAc);
1
IR: 3184, 2256, 2223, 1759, 1686, 1600, 1255, 1222, 1089, 1009, 870, 817, 758 cm-1; H NMR
(DMSO-d6): δ 0.67 (3H, t, J=7 Hz), 3.79 (1H, dq, J1=14 Hz, J2=7 Hz), 3.81 (1H, dq, J1=14 Hz, J2=7 Hz),
4.83 (1H, d, J=13 Hz), 5.22 (1H, d, J=13 Hz), 5.61 (1H, s), 7.46 (1H, d, J=8 Hz), 7.53-7.58 (4H, m), 7.63
(1H, d, J=8 Hz), 7.87 (1H, s), 7.93 (2H, d, J=8 Hz), 7.97 (4H, dd, J1=8 Hz, J2=2.5 Hz), 8.04 (1H, s), 9.12
13
(1H, s); C NMR: δ 14.1 (CH3), 63.9 (CH2), 39.4, 47.8, 61.5, 125.54, 125.55, 127.5, 127.6, 127.81,
127.84, 128.2, 128.4, 128.6, 129.0, 129.1, 129.7, 129.8, 130.0 (all CH), 59.6, 115.1, 117.4, 133.0, 133.25,
133.28, 133.5, 134.1, 135.4, 163.9, 165.0 (all C); FAB-MS (+): m/z 474 (M++H); HRMS (FAB+): calcd
for C30H24N3O3, 474.1818 (M++H); found 474.1815; Anal. Calcd for C30H23N3O3: C, 76.11; H, 4.86; N,
8.88. Found: C, 76.18; H, 4.85; N, 8.89.
ACKNOWLEDGEMENTS
The authors express their sincere thanks to the Director, Bose Institute for providing laboratory facilities,
Dr. Tomoyasu Hirose, The Kitasato Institute, Tokyo for undertaking the single crystal X-ray diffraction

HETEROCYCLES, Vol. 73, 2007
803
studies of a 2-piperidinone, the C.S.I.R., Govt. of India for providing a Fellowship (S.K.), Mr. B. Majumder
and Mr. P. Dey, both of Bose Institute, for recording the NMR and the IR spectra, respectively.
REFERENCES AND NOTES
1. ‘A. M. A. Drugs Evaluations,’ John Wiley and Sons, New York, 1980, pp. 1409-1426; A. F.
Pozharskii, A. T. Soldatenkov, and A. R. Katritzky, ‘Heterocycles in Life and Society,’ John Wiley
and Sons, Chichester, U.K., 1997.
2. M. Chakrabarty, R. Basak, Y. Harigaya, and H. Takayanagi, Tetrahedron, 2005, 61, 1793; M.
Chakrabarty, T. Kundu, S. Arima, and Y. Harigaya, Tetrahedron Lett., 2005, 46, 2865; M.
Chakrabarty, A. Mukherji, S. Karmakar, S. Arima, and Y. Harigaya, Heterocycles, 2006, 68, 331; M.
Chakrabarty, S. Karmakar, A. Mukherji, S. Arima, and Y. Harigaya, Heterocycles, 2006, 68, 967; M.
Chakrabarty, R. Mukherjee, M. Chakrabarty, S. Arima, and Y. Harigaya, Lett. Org. Chem., 2006, 3,
868.
3. Plant growth inhibition: M. C. Siedel, K. L. Viste, and R. Y. Yih, U.S. Patent 3,761,240, Sept. 25,
1973; cardiotonic: N. F. Tsoi and M. E. Konshin, Deposited Documents, 1983, VINITI, 3802, 7 pp
(Russ.); B. Sing and G. Y. Lesher, U.S. Patent 4,451,469, 1984; N. Odo, K. Otsuka, M. Maruyama, Y.
Kamiya, T. Kitano, T. Nakono, and T. Ito, Jpn. Kokai Tokkyo Koho, JPN 60, 146 873 [85,146,872]
1985; hypoglycemic: G. A. Youngdale and T. F. Oglia, J. Med. Chem., 1985, 28, 1790; antiviral: V. G.
Kulnevich, E. A. Kaigorodova, I. S. Arustamova, L. V. Korobchenko, G. V. Vladyko, and E. I. Boreko,
Khim. Pharm. Zh., 1990, 24, 132.
4. ‘International Drug Discovery,’ Swiss Pharmaceutical Society, Ed., Medfarm, Stuttgart, 1994/1995, p.
71, 805, 1062.
5. R. P. Mariella, Org. Synth. Coll. Vol. 4, 1963, 210; V. S. Hawaldar and S. V. Sunthankar, Indian. J.
Chem., 1980, 19B, 151; M. Radojkovic-Velickovic, M. Misic-Vukovic, and S. Jovanovic, 6th
European Symposium on Organic Chemistry (ESOC VI), Belgrade, Yugoslavia, 1989, AP-261, 307; D.
Mijin, D. G. Antonovic, and M. Misic-Vukovic, Indian. J. Chem., 1994, 33B, 309; R. Jain, F.
Roschangar, and M. A. Ciufolini, Tetrahedron Lett., 1995, 36, 3307; M. Misic-Vukovic, D. Mijin, M.
Radojkovic-Velickovic, N. Valentic, and V. Krstic, J. Serb. Chem. Soc., 1998, 63, 585 and references
cited therein.
6. C. G. Dave, D. A. Shah, and Y. K. Agrawal, Indian. J. Chem., 2004, 43B, 885; D. Mijin and A.
Marinkovic, Synth. Commun., 2006, 36, 193.
7. F. Shi, S. Tu, F. Fang, and T. Li, ARKIVOC, 2005, (i), 137.
8. Crystal data for 4a: C22H19N3O3, FW = 373.41, colourless, crystal dimension 0.25 × 0.25 × 0.30 mm,
monoclinic, space group P21/n (#14), a = 6.132(2) Å, b = 20.905(4) Å, c = 16.083(2) Å, α = β = γ =

804
HETEROCYCLES, Vol. 73, 2007
90.0000°, V = 2061.8(8) Å3, Z = 4, dc = 1.203 g/cm3, λ = 1.54178 Å, µ(Mo Kα) = 0.665 mm-1,
F(000) = 784.00, 2θmax = 145.3°, R = 0.102, wR2 = 0.153. Crystallographic data (excluding structure
factors) for 4a, reported in this paper, have been deposited with the Cambridge Crystallographic
Data Center as supplementary publication no. CCDC-639606. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, [fax:
+44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
9. W. Nagai, Y. Hirata, and T. Miwa, J. Org. Chem., 1974, 39, 3735.
10. K. Ajay Kumar and K. M. Lokanatha Rai, Bulg. Chem. Commun., 2006, 38, 93.
11. K. Ajay Kumar, K. M. Lokanatha Rai, and K. B. Umesha, J. Pharm. Biomed. Anal., 2002, 27, 837.
12. P. S. Watson, B. Jiang, and B. Scott, Org. Lett., 2000, 2, 3679.
13. C. Pedregal, J. Ezquerra, A. Escribano, M. C. Carreno, and J. L. G. G. Ruano, Tetrahedron Lett.,
1994, 35, 2053.
14. M. B. Smith and J. March, ‘March’s Advanced Organic Chemistry,’ John Wiley and Sons, New
York, 2001; W. D. Rounds, J. T. Eaton, J. H. Urbanowicz, and G. W. Gribble, Tetrahedron Lett.,
1988, 29, 6557; Reference 586, p. 1551 of March’s Book, referred to above.
15. Y. Lu, Z. Ren, W. Cao, W. Tong, and M. Gao, Synth. Commun., 2004, 34, 2047.
16. S.-X. Wang, J.-T. Li, W.-Z. Yang, Y.-H. Yin, and Z.-H. Xie, Synth. Commun., 2004, 34, 829.
17. J. Zabicky, J. Chem. Soc., 1961, 683.
18. D. T. Mowry, J. Am. Chem. Soc., 1943, 65, 992.
19. J. A. Cabello, J. M. Campelo, A. Garcia, D. Luna, and J. M. Marinas, J. Org. Chem., 1984, 49, 5195.
20. K. Mogilaiah, M. Prashanthi, G. R. Reddy, C. S. Reddy, and N. V. Reddy, Synth. Commun., 2003,
33, 2309.
21. J. D. Fulton, R. Robinson, J. W. H. Oldham, and A. R. Ubbelohde, J. Chem. Soc., 1939, 200.