An efficient and greener approach to the synthesis of 3,5-dicyanopyridin- 2(1H)-one derivatives in aqueous media under microwave irradiation conditions

Article abstract of DOI:10.1002/jhet.5570440533

(Chemical Equation Presented) A facile and greener synthesis of a series of 3,5-dicyanopyridin-2(1H)-one derivatives was accomplished via the one-pot reaction of aldehyde, malononitrile and sodium hydroxide in aqueous media under microwave irradiation. Th

Full text of DOI:10.1002/jhet.5570440533

Sep-Oct 2007
1177
An Efficient and Greener Approach to the Synthesis of 3,5-
Dicyanopyridin-2(1H)-one Derivatives in Aqueous Media under
Microwave Irradiation Conditions
Runhong Jia [a,b], Shujiang Tu* [b], Yan Zhang [b], Bo Jiang [b], Junyong Zhang [b],
Changsheng Yao [b], Feng Shi [b]
[a] Lianyungang Teachers’ College, Lianyungang, Jiangsu, 222006, P. R. China
[b] College of Chemistry and Chemical Engineering, Xuzhou Normal University,
Xuzhou, Jiangsu, 221116, P. R. China
Received October 24, 2006
R
CN
NC
O
CN NaOH, H2O
+
2
RCHO
MWI
CN
NH2
N
H
1
2
3
A facile and greener synthesis of a series of 3,5-dicyanopyridin-2(1H)-one derivatives was accomplished
via the one-pot reaction of aldehyde, malononitrile and sodium hydroxide in aqueous media under
microwave irradiation. This method had several advantages such as shorter route and time, lower cost,
reduced environmental impact.
J. Heterocyclic Chem., 44, 1177 (2007).
greener synthesis of a series of 6-amino-4-aryl-1,2-
dihydro-2-oxopyridine-3,5-dicarbonitrile in aqueous media
by a one-pot reaction under MWI (Scheme 1).
INTRODUCTION
In recent years, amino-substituted 2-pyridones have
attracted attention due to their promising features as an
important core structure for the development of biologi-
cally active molecules [1]. Pharmaceuticals with the 2-
pyridone skeleton have emerged as antitumor [2], anti-
fungal [3], antibacterial [4], antiviral [5], antithrombotic
[6] agents. Meanwhile it is well-known that the 2-pyri-
done ring system is a valuable building block in natural
product synthesis [7]. On the other hand, pyridine
dicarbonitriles have been exhibited as potential novel
prion disease therapeutics [8]. Therefore design and
synthesis of these compounds has been challenging.
Many synthetic methods for the preparation of 3,5-
dicyanopyridin-2(1H)-one derivatives have been reported
[9], analysis of these literatures reveals that the published
approaches involve multi-step procedure, longer reaction
time and use of organic solvents. To the best of our
knowledge, the synthesis of 3,5-dicyanopyridin-2(1H)-
one derivatives in aqueous media has seldom been
reported [10]. For the stringent and growing environ-
mental regulations, organic chemists are requested to
develop environmentally benign synthetic methodologies.
The most promising approaches are to perform organic
reactions in aqueous media and use the raw material.
The microwave assisted organic synthesis has been a
topic of continued studies as it could lead to easier opera-
tion and shorter reaction time as compared to the tradi-
tional heating methods [11]. Use of microwave irradiation
(MWI) for the formation of carbon-heteroatom, especially
carbon-nitrogen bonds, has been reported [12].
Scheme 1
R
CN
NC
O
CN NaOH, H2O
+
2
RCHO
MWI
CN
NH2
N
H
1
2
3
The products were synthesized by aldehyde (1 mmol),
malononitrile (2 mmol) and sodium hydroxide (10%) in
aqueous media under microwave irradiation (Scheme 1).
After irradiation for 2-3 min, the 6-amino-4-aryl-1,2-
dihydro-2-oxo-pyridine-3,5-dicarbonitrile derivatives were
obtained.
RESULTS AND DISCUSSION
In an effort to search the suitable base, six reactions
were carried out in parallel, with water as solvent. Several
organic bases and inorganic bases have been employed
instead of NaOH, it was shown that the reaction using
NaOH (entry 6 of Table 1) gave the highest yield and the
reaction time was the shortest. Therefore, NaOH was
chosen as the optimum base.
To optimize the reaction conditions, the effects of
different reaction temperature, concentrations of sodium
hydroxide and microwave irradiation power were
investigated in the synthesis of 3a. To optimize the reac-
tion temperature, the reaction of 4-chlorobenzaldehyde 1a
(1 mmol), malononitrile 2 (2 mmol) in the presence of
sodium hydroxide (10%) was carried out in water at
In continuation of our recent interest in the synthesis of
2-pyridone derivatives [13], we herein developed a

1178
R. Jia, S. Tu, Y. Zhang, B. Jiang, J. Zhang, C. Yao, F. Shi
Vol 44
temperatures ranging from 70 to 130 °C in an increments
of 10 °C each time. The results showed that the yield of
product 3a was improved and the reaction time was
shortened as the temperature was increased from 70 to
100 °C. The yield levelled off when the temperature was
further increased to 110 and 130 °C. Therefore, 100 °C
groups or electron-donating groups, but also for hetero-
cyclic and aliphatic aldehydes.
This reaction of aldehydes, malonitrile and sodium
hydroxide may occur via a mechanism of condensation,
Michael addition, cyclization and elimination. The
condensation between aldehyde 1 and malonitrile 2 gives
the intermediate 4 which further undergoes in situ
Michael addition reaction with another malononitrile 2 to
yield intermediate 5, followed by the nucleophilic attack
of OH to CN group to afford compound 6, which
undergoes intramolecular cyclization, isomerisation,
dehydrogenization, to finally afford 3 (Scheme 2).
Table 1
Investigation of bases in the synthesis of 3a [a]
Entry
Base
Time (min)
Yield (%)
1
2
3
4
5
6
DMAP[b]
Pyridine
Et3N
8
8
10
12
4
20
18
25
30
32
48
NH3ꢀH2O
K2CO3
NaOH
Scheme 2
2
R
NC
[a] The product 3a was synthesized under MWI in 100 °C and the
power of MWI was 150W. [b] DMPA = N,N-dimethylamino-
pyridine.
CN
CN
CN
2
-
NC
NC
NC
NC
RCHO
OH-
CHR
C
CN
C
1
N
2
4
5
was chosen for all further reactions. Furthermore, the
concentration of NaOH was found to be important as
well. The same reaction was tested in different concen-
trations of NaOH at 100 °C under microwave irradiation
conditions. When 10% NaOH was used, the yield was the
highest. In addition, the power of MWI was optimized by
carrying out the same reaction at 100, 150, 200 and 250
W, respectively, at 100 °C. The results showed that MWI
at 150 W gave the highest yield.
R
R
R
NC
CN
NC
HN
CN
NC
N
CN
O
C
..
CN
C
N
H
O
H2N
OH
HN
6
7
8
R
R
NC
NC
CN
O
-H2
CN
O
Under these optimized reaction conditions, we synthe-
sized a series of products 6-amino-4-aryl-1,2-dihydro-2-
oxopyridine-3,5-dicarbonitrile 3 (Table 2).
H2N
N
H
H2N
N
H
9
3
Table 2
The synthesis of 3 under MWI
Moreover, we performed the synthesis of 3 under both
MWI and classical heating conditions at 100 °C. The
reactions were efficiently promoted by MWI and the
reaction time was strikingly shortened to 2ꢀ3 min from
2ꢀ3 h required under traditional heating conditions and
the yields were increased to 40ꢀ49% from 25ꢀ37%.
Therefore, microwave irradiation exhibited several
advantages over the conventional heating by significantly
reducing the reaction time and dramatically improving the
reaction yield owing to a specific nonthermal microwave
effect.
All the products were characterized by IR, 1H NMR and
elemental analysis. Furthermore, the structure of 3a was
established by an X-ray crystallographic analysis [14]
(Figure 1).
Yield Mp
(%)
(°C)
Product
R
Time(min)
(lit.)[a]
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
4-ClC6H4
4-BrC6H4
4-FC6H4
4-CH3C6H4
3,4-(CH3O)2C6H3
3, 4-OCH2OC6H3
4-CH3OC6H4
3,4,5-(CH3O)3C6H2
3-CH3O-4-OHC6H4
4-N(CH3)2C6H4
3-NO2C6H4
C6H5
2
2
2
3
3
3
3
3
3
3
2
3
3
3
3
48
49
49
45
43
43
44
41
41
47
44
42
46
41
40
>300(>320)[b]
>300
>300
>300(>320)[b]
>300
>300
>300(290)[b]
>300
>300
>300
>300
>300(>320)[b]
>300
2-C4H3S
CH3(CH2)3
CH3(CH2)2
>300
>300
In conclusion, we developed a greener synthesis of
amino-substituted 3,5-dicyanopyridone using raw
material. This method not only afforded a new method for
the synthesis of 3,5-dicyanopyridone derivatives but also
avoided using the organic solvent reducing environmental
impact.
[a] Melting points are uncorrected; [b] Known compounds (3a, 3d, 3g,
3l, ref. 12(i).
We found that this protocol can be applied not only for
the aromatic aldehydes with either electron-withdrawing

Sep-Oct 2007
An Efficient and Greener Approach to the Synthesis
1179
of 3,5-Dicyanopyridin-2(1H)-one Derivatives
6-Amino-1,2-dihydro-2-oxo-4-p-tolylpyridine-3,5-dicarbo-
nitrile (3d). This compound was obtained according to above
general procedure; ir (potassium bromide): 3445, 3326, 3208,
1
2218, 1681, 1588, 1483, 1376, 1267, 1165, 840, 685 cm-1; H
nmr (DMSO-d6): ꢀ 2.40 (s, 3H, CH3), 7.40 (t, 2H, ArH, J = 8.8
Hz), 7.57 (t, 2H, ArH, J = 8.8 Hz), 8.00 (brs, 2H, NH2), 11.88 (s,
1H, NH). Anal. Calcd. for C14H10N4O: C, 67.19; H, 4.03; N,
22.39. Found: C, 67.23; H, 4.14; N, 22.51.
6-Amino-1,2-dihydro-4-(3,4-dimethoxyphenyl)-2-oxopyri-
dine-3,5-dicarbonitrile (3e). This compound was obtained
according to above general procedure; ir (potassium bromide):
3530, 3321, 3211, 2217, 1672, 1552, 1482, 1332, 1270, 1148,
1023, 870, 682 cm-1; 1H nmr (DMSO-d6): ꢀ 3.80 (s, 3H, OCH3),
3.84 (s, 3H, OCH3), 7.06–7.13 (m, 3H, ArH), 7.61 (brs, 2H,
NH2), 11.90 (s, 1H, NH). Anal. Calcd. for C15H12N4O3: C,
60.81; H, 4.08; N, 18.91. Found: C, 60.93; H, 4.04; N, 18.98.
6-Amino-1,2-dihydro-4-(3,4-methylenedioxylphenyl)-2-
oxopyridine-3,5-dicarbonitrile (3f). This compound was
obtained according to above general procedure; ir (potassium
bromide): 3450, 3324, 3114, 2217, 1678, 1570, 1484, 1343,
Figure 1
EXPERIMENTAL
All reactions were performed in a monomodal EmrysTM
Creator from Personal Chemistry, Uppsala, Sweden. Melting
points were determined in open capillaries and are uncorrected.
IR spectra were recorded on a FT-IR-tensor 27 spectrometer. 1H
NMR spectra were measured on a DPX 400 MHz spectrometer
using TMS as an internal standard and DMSO-d6 as solvent.
Elemental analysis was determined by using a Perkin-Elmer
240c elemental analysis instrument.
General Procedure for preparation of 6-amino-4-
substituted-1,2-dihydro-2-oxopyridine-3,5-dicarbonitrile (3).
A solution of the appropriate aldehyde (1 mmol), malononitrile
(2 mmol), sodium hydroxide (10%) and water (2 mL) was
irradiated for 2-3 min (TLC) at 100°C with power 150 W. The
reaction mixture was cooled to room temperature, neutralized
with HOAc and then washed out with water until neutral pH was
obtained, filtered to give the crude product, which was further
purified by recrystallization from EtOH-DMF (3a-3o). All the
products were characterized by IR, 1H NMR and elemental
analysis.
6-Amino-4-(4-chlorophenyl)-1,2-dihydro-2-oxopyridine-
3,5-dicarbonitrile (3a). This compound was obtained according
to above general procedure; ir (potassium bromide): 3450, 3317,
3205, 2216, 1669, 1590, 1484, 1378, 1267, 1094, 1015, 831, 679
cm-1; H nmr (DMSO-d6): ꢀ 7.53 (d, 2H, ArH, J = 8.4 Hz), 7.64
(d, 2H, ArH, J = 8.4 Hz), 7.72 (brs, 2H, NH2), 11.94 (s, 1H,
NH). Anal. Calcd. for C13H7ClN4O: C, 57.69; H, 2.61; N, 20.70.
Found: C, 57.75; H, 2.54; N, 20.63.
1
1260, 1161, 1041, 927, 810, 686 cm-1; H nmr (DMSO-d6): ꢀ
6.15 (s, 2H, OCH2O), 6.98 (dd, 1H, J1 = 8.0 Hz, J2 = 1.6 Hz,
ArH), 7.07-7.09 (m, 2H, ArH), 7.78 (brs, 2H, NH2), 11.92 (s,
1H, NH). Anal. Calcd. for C14H8N4O3: C, 60.00; H, 2.88; N,
19.99. Found: C, 60.08; H, 2.79; N, 19.89.
6-Amino-1,2-dihydro-4-(4-methoxyphenyl)-2-oxopyridine-
3,5-dicarbonitrile (3g). This compound was obtained according
to above general procedure; ir (potassium bromide): 3566, 3329,
3189, 2232, 2217, 1678, 1590, 1484, 1304, 1266, 1190, 1029,
1
833, 687 cm-1; H nmr (DMSO-d6): ꢀ 3.84 (s, 3H, OCH3), 7.09
(d, 2H, J = 8.8 Hz, ArH), 7.45 (d, 2H, J = 8.8 Hz, ArH), 7.78
(brs, 2H, NH2), 11.87 (s, 1H, NH). Anal. Calcd. for C14H10N4O2:
C, 63.15; H, 3.79; N, 21.04. Found: C, 63.22; H, 3.83; N, 21.12.
6-Amino-1,2-dihydro-4-(3,4,5-trimethoxyphenyl)-2-oxo-
pyridine-3,5-dicarbonitrile (3h). This compound was obtained
according to above general procedure; ir (potassium bromide):
3418, 3330, 3189, 2213, 1680, 1594, 1513, 1414, 1323, 1253,
1
1131, 995, 850, 671 cm-1; H nmr (DMSO-d6): ꢀ 3.74 (s, 3H,
OCH3), 3.82 (s, 6H, 2OCH3), 6.83 (s, 2H, ArH), 7.94 (brs, 2H,
NH2), 11.88 (s, 1H, NH). Anal. Calcd. for C16H14N4O4: C, 58.89;
H, 4.32; N, 17.17. Found: C, 58.95; H, 4.26; N, 17.26.
6-Amino-1,2-dihydro-4-(4-hydroxy-3-methoxyphenyl)-2-
oxopyridine-3,5-dicarbonitrile (3i). This compound was
obtained according to above general procedure; ir (potassium
bromide): 3450, 3329, 3173, 2214, 1687, 1604, 1549, 1444,
1
1
1281, 1215, 1137, 878, 818, 667 cm-1; H nmr (DMSO-d6): ꢀ
6-Amino-4-(4-bromophenyl)-1,2-dihydro-2-oxopyridine-
3,5-dicarbonitrile (3b). This compound was obtained according
to above general procedure; ir (potassium bromide): 3450, 3320,
3206, 2216, 1668, 1590, 1484, 1392, 1265, 1042, 1011, 823, 671
3.80 (s, 3H, OCH3), 6.87-6.93 (m, 2H, ArH), 7.06 (s, 1H, ArH),
7.70 (brs, 2H, NH2), 9.53 (s, 1H, OH), 11.87 (s, 1H, NH). Anal.
Calcd. for C14H10N4O3: C, 59.57; H, 3.57; N, 19.85. Found: C,
59.67; H, 3.45; N, 19.99.
1
cm-1; H nmr (DMSO-d6): ꢀ 7.46 (d, 2H, ArH, J = 8.8 Hz), 7.77
6-Amino-4-(4-(dimethylamino)phenyl)-1,2-dihydro-2-oxo-
pyridine-3,5-dicarbonitrile (3j). This compound was obtained
according to above general procedure; ir (potassium bromide):
3440, 3330, 3201, 2214, 1685, 1587, 1531, 1478, 1371, 1205,
(d, 2H, ArH, J = 8.4 Hz), 7.95 (brs, 2H, NH2), 11.98 (s, 1H,
NH). Anal. Calcd. for C13H7BrN4O: C, 49.55; H, 2.24; N, 17.78.
Found: C, 49.63; H, 2.17; N, 17.82.
1
1168, 946, 819, 684 cm-1; H nmr (DMSO-d6): ꢀ 3.00 (s, 6H,
6-Amino-4-(4-fluorophenyl)-1,2-dihydro-2-oxopyridine-
3,5-dicarbonitrile (3c). This compound was obtained according
to above general procedure; ir (potassium bromide): 3445, 3326,
3208, 2218, 1681, 1588, 1483, 1376, 1267, 1165, 840, 685 cm-1;
1H nmr (DMSO-d6): ꢀ 7.40 (t, 2H, ArH, J = 8.8 Hz), 7.57 (t, 2H,
ArH, J = 8.8 Hz), 8.00 (brs, 2H, NH2), 11.88 (s, 1H, NH). Anal.
Calcd. for C13H7FN4O: C, 61.42; H, 2.78; N, 22.04. Found: C,
61.55; H, 2.59; N, 22.12.
2CH3), 6.80 (d, 2H, J = 8.8 Hz, ArH), 7.37 (d, 2H, J = 8.8 Hz,
ArH), 7.62 (brs, 2H, NH2), 11.66 (s, 1H, NH). Anal. Calcd. for
C15H13N5O: C, 64.51; H, 4.69; N, 25.07. Found: C, 64.66; H,
4.61; N, 25.16.
6-Amino-1,2-dihydro-4-(3-nitrophenyl)-2-oxopyridine-3,
5-dicarbonitrile (3k). This compound was obtained according
to above general procedure; ir (potassium bromide): 3546, 3338,

1180
R. Jia, S. Tu, Y. Zhang, B. Jiang, J. Zhang, C. Yao, F. Shi
Vol 44
Microwaves in Organic Synthesis; Loupy, A., Ed.; Wiley-VCH:
Weinheim, Germany, 2002, pp253-293.
3189, 2214, 1670, 1646, 1529, 1479, 1353, 1269, 1092, 840,
1
785, 669 cm-1; H nmr (DMSO-d6): ꢀ 7.88-8.01 (m, 4H, ArH),
[3] Parlow, J. J.; Kurumbail, R. G.; Stegeman, R. A.; Stevens, A.
M.; Stallings, W. C. and South, M. S. J. Med. Chem. 2003, 46, 4696.
[4] Hasvold, L. A.; Wang, W.; Gwaltney, S. L.; Rockway, T. W.;
Nelson, L. T. J.; Mantei, R. A.; Fakhoury, S. A.; Sullivan, G. M.; Li, Q.;
Lin, N.-H.; Wang, L.; Zhang, H.; Cohen, J.; Gu, W.-Z.; Marsh, K.;
Bauch, J.; Rosenberg, S. and Sham, H. L. Bioorg. Med. Chem. Lett.
2003, 13, 4001.
7.87 (brs, 2H, NH2), 11.85 (s, 1H, NH). Anal. Calcd. for
C13H7N5O3: C, 55.52; H, 2.51; N, 24.90. Found: C, 55.66; H,
2.43; N, 24.84.
6-Amino-1,2-dihydro-2-oxo-4-phenylpyridine-3,5-dicarbo-
nitrile (3l). This compound was obtained according to above
general procedure; ir (potassium bromide): 3460, 3311, 3110,
2218, 1675, 1635, 1540, 1486, 1440, 1266, 1043, 874, 718, 649
[5] Cox, R. J. and O’Hagan, D. J. Chem. Soc., Perkin Trans.1
1991, 10, 2537.
1
cm-1; H nmr (DMSO-d6): ꢀ 7.47-7.50 (m, 2H, ArH), 7.52-7.56
[6] Li, Q.; Mitscher, L. A. and Shen, L. L. Med. Res. Rev. 2000,
20, 231.
(m, 3H, ArH), 7.81 (brs, 2H, NH2), 11.90 (s, 1H, NH). Anal.
Calcd. for C13H8N4O: C, 66.10; H, 3.41; N, 23.72. Found: C,
66.03; H, 3.38; N, 23.66.
[7] Dragovich, P. S.; Prins, T. J.; Zhou, R.; Brown, E. L.;
Maldonado, F. C.; Fuhrman, S. A.; Zalman, L. S.; Tuntland, T.; Lee, C.
A.; Patick, A. K.; Matthews, D. A.; Hendrickson, T. F.; Kosa, M. B.;
Liu, B.; Batugo, M. R.; Gleeson, J.-P. R.; Sakata, S. K.; Chen, L.;
Guzman, M. C.; Meador, J. W. III; Ferre, R. A. and Worland, S. T. J.
Med. Chem. 2002, 45, 1607.
6-Amino-1,2-dihydro-2-oxo-4-(thiophen-2-yl)pyridine-3,5-
dicarbonitrile (3m). This compound was obtained according to
above general procedure; ir (potassium bromide): 3443, 3309,
3228, 2213, 1680, 1634, 1540, 1477, 1427, 1240, 1042, 862,
719, 683 cm-1; 1H nmr (DMSO-d6): ꢀ 7.25-7.28 (m, 1H,
thiophenyl-H), 7.53-7.53 (m, 1H, thiophenyl-H), 7.81 (brs, 2H,
NH2), 7.92-7.94 (m, 1H, thiophenyl-H), 11.90 (s, 1H, NH). Anal.
Calcd. for C11H6N4OS: C, 54.54; H, 2.50; N, 23.13; S, 13.24.
Found: C, 54.46; H, 2.63; N, 23.26; S, 13.31.
[8] (a) Mederski, W. W. K. R.; Lefort, M.; Germann, M. and
Kux, D. Tetrahedron 1999, 55, 12757; (b) Sanderson, P. E. J.; Lyle, T.
A.; Cutrona, K. J.; Dyer, D. L.; Dorsey, B. D.; McDonough, C. M.;
Naylor-Olsen, A. M.; Chen, I.-W.; Chen, Z.; Cook, J. J.; Cooper, C. M.;
Gardell, S. J.; Hare, T. R.; Krueger, J. A.; Lewis, S. D.; Lin, J. H.; Lucas
B. J., Jr.; Lyle, E. A.; Lynch, J. J.; Stranieri, M. T.; Vastag, K.; Yan, Y.;
Shafer, J. A. and Vacca, J. P. J. Med. Chem. 1998, 41, 4466.
[9] Comins, D. L.; Hong, H.; Saha, J. K. and Jianhua, G. J. Org.
Chem. 1994, 59, 5120; (b) Comins, D. L.; Hong, H. and Jianhua, G.
Tetrahedron Lett. 1994, 35, 5331; (c) Bernstein, P. R.; Gomes, B. C.;
Kosmider, B. J.; Vacek, E. P. and Williams, J. C. J. Med. Chem. 1995,
38, 212; (d) Kozikowski, A. P.; Campiani, G.; Sun, L.-Q.; Wang, S.;
Saxena, A.; Doctor, B. P. J. Am. Chem. Soc. 1996, 118, 11357; (e)
Williams, D. R.; Lowder; P. D.; Gu, Y.-G. Tetrahedron Lett. 1997, 38,
327.
6-Amino-4-butyl-1,2-dihydro-2-oxopyridine-3,5-dicarbo-
nitrile (3n). This compound was obtained according to above
general procedure; ir (potassium bromide): 3440, 3326, 3203,
2216, 1672, 1634, 1589, 1494, 1374, 1270, 1166, 853, 720, 667
1
cm-1; H nmr (DMSO-d6): ꢀ 0.92 (t, 3H, J = 7.2 Hz, CH3), 1.35-
1.40 (m, 2H, CH2), 1.55-1.59 (m, 2H, CH2), 2.61 (t, 2H, J = 7.6
Hz, CH2), 7.71 (brs, 2H, NH2), 11.68 (s, 1H, NH). Anal. Calcd.
for C11H12N4O: C, 61.10; H, 5.59; N, 25.91. Found: C, 61.22; H,
5.61; N, 25.99.
[10] Akiyama, T.; Takaya, J.; Kagoshima, H. Tetrahedron Lett.
1999, 40, 7831.
[11] Reddy, T. R. K.; Mutter, R.; Heal, W.; Guo, K.; Gillet, V. J.;
Pratt, S. and Chen, B. J. Med. Chem. 2006, 49, 607.
6-Amino-1,2-dihydro-2-oxo-4-propylpyridine-3,5-dicarbo-
nitrile (3o). This compound was obtained according to above
general procedure; ir (potassium bromide): 3445, 3325, 3201,
2217, 1672, 1635, 1589, 1494, 1374, 1272, 1167, 835, 704, 669
[12] Elgemeie, G. E. H.; Sallam, M. M. M.; Sherif, S. M.;
Elnagdi, M. H. Heterocycles 1985, 23, 3107; (b) Attia, A. M. E. and
Ismail, A. E.-H. A. A. Tetrahedron 2003, 59, 1749; (c) Ghozlan, S. A. S.
and Hassanien, A. Z. A. Tetrahedron 2002, 58, 9423; (d) Sadek, K. U.
and Elnagdi, M. H. Synthesis 1988, 6, 483; (e) Alberola, A.; Antolin, L.
F.; Gonzalez, A. M.; Laguna, M. A. and Pulido, F. J. Heterocycles
1987, 25, 393; (f) Lorente, A. and Soto, J. L. Afinidad 1978, 35, 138; (g)
Seoane, C.; Soto, J. L.; Zamorano, P. and Quinteiro, M. J. Heterocycl.
Chem. 1981, 18, 309; (h) Rudorf, W. D. and Augustin, M. Synthesis
1980, 12, 1022; (i) Soto, J. L.; Seoane, C.; Zamorano, P. and Cuadrado,
F. J. Synthesis 1981, 7, 529; (j) Seoane, C.; Soto, J. L. and Zamorano, M.
P. Heterocycles 1980, 14, 639; (k) Linstead, R. P. and Willams, L. T. D.
J. Chem. Soc.1926, 2735.
1
cm-1; H nmr (DMSO-d6): ꢀ 0.97 (t, 3H, J = 7.6 Hz, CH3), 1.61-
1.67 (m, 2H, CH2), 2.60 (t, 2H, J = 7.2 Hz, CH2), 7.70 (brs, 2H,
NH2), 11.69 (s, 1H, NH). Anal. Calcd. for C10H10N4O: C, 59.40;
H, 4.98; N, 27.71. Found: C, 59.55; H, 4.87; N, 27.88.
Acknowledgement. We are grateful for financial support
from the National Science Foundation of China (No. 20672090)
and Natural Science Foundation of the Jiangsu Province (No.
BK2006033), Six Kinds of Professional Elite Foundation of the
Jiangsu Province (No. 06-A-039).
[13] Tu, S.; Zhu, X.; Zhang, J.; Xu, J.; Zhang, Y.; Wang, Q.; Jia,
R.; Jiang, B.; Zhang, J. and Yao, C. Bioorg. Med. Chem. Lett. 2006, 16,
2925; (b) Tu, S.; Zhang, J.; Zhu, X.; Xu, J.; Zhang, Y.; Jia, R.; Jiang, B.
and Zhang, J. Bioorg. Med. Chem. Lett., 2006, 16, 3578.
[14] The single-crystal growth was carried out in ethanol at room
temperature. X-ray crystallographic analysis was performed with a
Siemens SMART CCD and a Siemens P4 diffractometer. Crystal data
for 3a: C13H7ClN4OꢀC2H5OH, yellow, crystal dimension 0.14 x 0.09 x
0.03mm, Triclinic, space group P-1, a = 6.779 (15) Å, b = 10.43 (2) Å, c
= 11.29 (2) Å, ꢀ = 88.63 (4)°,ꢁ = 84.64 (5)°, ꢂ = 81.70 (5) °, V = 786
(3) Å3, Mr = 316.74, Z = 2, Dc = 1.338 g/cm3, ꢃ = 0.71073 Å, μ (Mokꢀ)
= 0.255 mm-1, F(000) = 328, S = 1.001, R1 = 0.0580, wR2 = 0.1258.
REFERENCES AND NOTES
[1] (a) Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250; (b)
Varma, R. S. Green Chem. 1999, 1, 43; (c) Bose, A. K.; Manhas, M. S.;
Ganguly, S. N.; Sharma, A. H. and Banik, B. K. Synthesis 2002, 1578;
(d) Mingos, D. M. P. and Baghurst, D. R. Chem. Soc. Rev. 1991, 20, 1.
[2] (a) Varma, R. S. J. Heterocycl. Chem. 1999, 36, 1565; (b)
Shi, L.; Wang, M.; Fan, C.-A.; Zhang F.-M. and Tu, Y.-Q. Org. Lett.
2003, 5, 3515; (c) Shi, L.; Tu, Y.-Q.; Wang, M.; Zhang F.-M. and Fan,
C.-A. Org. Lett. 2004, 6, 1001; (d) Wu, X.; Larhed, M. Org. Lett. 2005,
7, 3327; (e) Hamelin, J.; Bazureau, J.-P.; Texier-Boullet, F. In