About the reaction of β-dimethylamino-α,β-enones with active methylene nitriles

Article abstract of DOI:10.1002/jhet.181

(Chemical Equation Presented) The reaction of 3-dimethylamino-1- arylpropenone derivatives with active methylene nitriles was reinvestigated and a plausible mechanism to account for the results is suggested. X-ray crystallographic study supported the sugg

Full text of DOI:10.1002/jhet.181

September 2009
About the Reaction of b-Dimethylamino-a,b-enones with Active
Methylene Nitriles
949
Fathy M. Abdelrazek* and Akram N. Elsayed
Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt
*E-mail: prof.fmrazek@gmail.com
Received February 18, 2009
DOI 10.1002/jhet.181
Published online 3 September 2009 in Wiley InterScience (www.interscience.wiley.com).
The reaction of 3-dimethylamino-1-arylpropenone derivatives with active methylene nitriles was rein-
vestigated and a plausible mechanism to account for the results is suggested. X-ray crystallographic
study supported the suggested mechanism. Based on these findings, the reaction of 3-acetylamino-4-
dimethylaminobut-3-en-2-one with malononitrile was also reinvestigated and the correct structures
verified.
J. Heterocyclic Chem., 46, 949 (2009).
INTRODUCTION
do nothing with the products of 2b to afford the amides
3a–c [13]. Then, compounds 3a–c were cyclized to afford
the 2-1H-pyridones 4a–c. These assumptions attracted
our attention and raised our doubt in the structures of
these products. The NMe2 group is a very good leaving
group and the active methylene reagent must substitute it
easier and faster than to condense with the carbonyl
group. Furthermore, the hydrolysis of a cyano group by
the traces of water present in the solvent (ethanol and few
drops of piperidine as catalyst), or that resulting from the
condensation seemed far unlikely to occur. On the basis
of these reservations, we decided to reinvestigate this
reaction.
In the past 2 decades, we have been involved in a pro-
gram aiming to develop new simple routes for the synthe-
sis of heterocyclic compounds of biological interest to be
evaluated as biodegradable agrochemicals [1–5]. Pyri-
dines and pyridones represent an important class of these
compounds because of their pharmaceutical applications
[6–8]. The reaction of enaminones with active methylene
nitriles represents one of the strategies for the preparation
of 2-1H-pyridone [9–11]. 3-Dimethylamino-1-arylprope-
nones 1a–c have been extensively used in the last years
by Elnagdi and coworkers for the synthesis of pyridones
[12–14]. The reaction of 1a–c with active methylene
nitriles (namely malononitrile 2a and cyanoacetamide
2b; Scheme 1) in all these and other publications was
based on the idea of a Knoevenagel condensation of the
active methylene in 2a or 2b with the carbonyl groups of
1a–c. In one article, it was assumed that malononitrile 2a
is first hydrolyzed to cyanoacetamide by the water pres-
ent in the solvent [12], which then condenses with the
carbonyl group of 1a–c to afford 3a–c. In the other arti-
cle, it was assumed that the condensation takes place first
and then the water resulting from the condensation hydro-
lyzes one of the cyano groups in the products of 2a but
RESULTS AND DISCUSSION
Thus, the enaminone compounds 1a–c were prepared
and allowed to react with the active methylene com-
pounds 2a,b according to the method and under the
same reaction conditions reported by Elnagdi and
coworkers [12]. In our hands, we could isolate the 2-
cyano-5-dimethylamino-5-arylpenta-2,4-dienoic
amide
derivatives 8a–c from the reaction of 1a–c with malono-
nitrile 2a. The mass spectra of these compounds showed
C
V
2009 HeteroCorporation

950
F. M. Abdelrazek and A. N. Elsayed
Vol 46
Scheme 1
m/z ¼ 241, 231, and 247, respectively. These masses
reveal that 1:1 adducts were obtained and correspond to
molecular formulae C14H15N3O, C12H13N3O2, and
C12H13N3OS, respectively, as reported previously [12].
However, the cyclization of these compounds upon
reflux in acetic acid led to the 2-1H-pyridone derivatives
The formation of the enaminones 8a–c from the reac-
tion of 1a–c with 2a is assumed to take place via the
sequence depicted in Scheme 1. The active methylene
group of malononitrile undergoes addition to the double
bond of 1 to give the intermediate 5, followed by elimi-
nation of dimethyl amine to afford 2-(3-oxo-3-aryl-pro-
penyl)-malononitrile 6, which directly undergoes ring
closure via its enolized form to afford the iminopyran 7.
This newly born iminopyran is attacked by the dimethyl
amine (which is still present in the reaction medium)
and undergoes ring opening to afford the isolated 2-
cyano-5-dimethylamino-5-arylpenta-2,4-dienoic amides
8a–c. The ring opening of iminopyran under the effec-
tive ammonia and amines is well established in the
literature [10]. Elemental analyses and spectral data are
1
9a–c. The H NMR spectrum of 9a revealed two dou-
blets; each integrated for 1H at d ¼ 6.72 and 8.20 with
equal j value of 8 Hz, which could be attributed to the
pyridone 9a H-5 and H-4, respectively. A pyridone
structure like the claimed 4a should have revealed these
proton signals for H-5 and H-6 at slightly up field val-
ues d ꢀ 5.8 and 7.3 ppm. Thus, structures 9a–c were
assigned to these reaction products rather than 4a–c
(cf. Experimental).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2009
About the Reaction of b-Dimethylamino-a,b-enones with
Active Methylene Nitriles
951
2-cyano-5-oxo-5-arylpent-3-enoic acid amide 10 (analo-
gous to 6 in the above sequence), which undergoes
directly the cyclization via elimination of water without
passing through the step of the iminopyran, since the
amide group is initially present. The identity of the
products obtained from the reactions of 1a–c with either
2a or 2b was deduced from the typical melting points
and spectral data. It should be also clear that Elnagdi
and coworkers [12] have reported that they obtained the
same products from the reaction of 2b with 1a–c.
Furthermore, Elnagdi and coworkers [13] have
reported the reaction of 3-acetylamino-4-dimethylamino-
but-3-en-2-one 11 (obtained from the reaction of acety-
laminoacetone with DMFDMA) with malononitrile 2a
and assumed the same scenario of condensation to give
12, which is cyclized to 13 (Scheme 2).
Figure 1. Crystal structure of compound 8a. [Color figure can be
viewed in the online issue, which is available at www.interscience.
wiley.com.]
Reinvestigation of this reaction showed that it follows
the same mechanistic way shown in Scheme 1. Malono-
nitrile substitutes the dimethylamnino group to give the
intermediate 14 followed by cyclization and ring open-
ing of the formed iminopyran to afford 15, which read-
ily eliminates dimethylamine to afford the final isolable
2-1H-pyridinone derivative 16 (in a Dimroth-type rear-
rangement). Although the claimed structure 13 and our
structure 16 have almost the same elemental and spec-
tral data, however, the d value given by Elnagdi and
coworkers [13] to the pyridinone H is 7.95 ppm, which
better fits to the H-4 rather than the H-6. A structure
like 13 would have revealed this H-6 signal much up
field at ꢀ6–7 ppm. The 13C NMR data given in [13] are
wrongly interpreted. They assigned the value 116.64
ppm to the C-4, which points out that no methyl group
is attached to this carbon, because attached methyl
group at the fourth position would have shifted this
in complete agreement with structures 8a–c (cf.
Experimental).
The X-ray crystallographic picture [15] afforded
an unambiguous evidence of structure 8a (Fig. 1; cf. exper-
imental). It shows that the N(Me)2 attached to the same
carbon atom (C7) carrying the phenyl group and the other
terminus carrying the cyano and the amide group on (C2)
as shown in Figure 1 and Scheme 1, which affords a
conclusive evidence to the pyridone structures 9.
These compounds could be readily cyclized upon reflux
in acetic acid to afford the 2-1H-pyridinone derivatives
9a–c, respectively, via elimination of dimethyl amine.
The reaction of 1a–c with cyanoacetamide 2b
afforded the same 2-1H-pyridinones 9a–c, respectively,
which represents further evidence to this suggested
mechanism. It is apparent that 2b followed the same
addition elimination sequence to afford the intermediate
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

952
F. M. Abdelrazek and A. N. Elsayed
Vol 46
´
3
a[ꢁ]
¼
90.00, b[ꢁ]
¼
90.00, c[ꢁ]
¼
90.00; V[A
]
˚
value dramatically low field (>150 ppm); and the same
words can be said on the value given to C-6 d ¼
148.54, which is too much down field value to a simple
CH (ꢀ90–100 ppm) and this means that the methyl
group is attached to this carbon (C-6).
¼
1324.45(11). Z ¼ 4, Dx ¼ 1.210 Mg mꢂ3, l(Mo Ka) ¼ 0.08
nmꢂ1; fine-focus sealed tube. Data were collected using Kap-
paCCD. T[ꢁK] ¼ 298, with graphite monochromator with Mo
´
˚
Ka radiation (k ¼ 0.71073 A) min. 91.5%; max 98.2%. Meas-
ured reflections 2646, total independent reflections are 1898
were counted with observed reflections 582. Rint ¼ 0.024.
R(all) ¼ 0.218, R(gt) ¼ 0.101, wR(ref) ¼ 0.197 and wR(all) ¼
0.224.
Finally, this confusion of the structures can be excused
based on the similarity of analyses and the tiny differen-
ces in the spectral interpretation. However, the claim that
the pyridinone obtained from this reaction underwent a
Michael addition with ylidenemalononitriles to afford
diaminoisoquinolines [13] requires revision.
Anal. Calcd. for C14H15N3O: (241.12): C, 69.69; H, 6.27;
N, 17.41. Found: C, 69.55; H, 6.10; N, 17.30.
2-Cyano-5-dimethylamino-5-furan-2-yl-penta-2,4-dienoic acid
amide 8b. Reddish brown crystals, yield (1.75 g, 76%); mp
243–244ꢁC (Dioxan) (Lit 238–240 [12]); tmax ¼ 3330 and
3290 (NH2), 2187 (CN) and 1665 cmꢂ1 (C¼¼O); MS: m/z ¼
231 [Mþ]; dH ¼ 2.95 (s, 6H, 2 CH3), 5.6 (d, j ¼ 12.62 Hz,
1H, CH), 6.72 (d, 1H, furan H), 6.78 (d, 1H, furan H), 6.9
(br.s., 2H, NH2), 7.55 (d, j ¼ 12.62 Hz, 1H, CH), 7.75 (dd,
1H, furan H).
CONCLUSION
Thus, we could suggest a conceivable mechanism that
explains the behavior of active methylene nitriles with
enaminones and could correct some literature wrong
structures.
Anal. Calcd. for C12H13N3O2: (231.25): C, 62.33; H, 5.67;
N, 18.17. Found: C, 62.10; H, 5.60; N, 18.20.
2-Cyano-5-dimethylamino-5-thiophen-2-yl-penta-2,4-dienoic
acid amide 8c. Yellow crystals, yield (1.9 g, 78%); mp 253–
254ꢁC (Dioxan) (Lit. 250–252 [12]; tmax ¼ 3403 and 3328
(NH2), 2196 (CN) and 1669 cmꢂ1 (CO); MS: m/z ¼ 247
[Mþ]; dH ¼ 2.96 (s, 6H, 2 CH3), 5.65 (d, j ¼ 12.65 Hz, 1H,
CH), 6.90 (br.s., 2H, NH2), 7.15 (d, 1H, thiophene H), 7.25
(dd, 1H, thiophene H), 7.35 (d, 12.65 Hz, 1H, CH), 7.85
(d,1H, thiophene H).
Anal. Calcd. for C12H13N3OS: (247.32): C, 58.28; H, 5.30;
N, 16.99; S, 12.97. Found: C, 58.25; H, 5.35; N, 16.85; S,
12.85.
Cyclization of compounds 8a–c: Synthesis of the 2-1H-
pyridones 9a–c. Each of compounds 8a–c (10 mmol) was
refluxed in glacial acetic acid (15 mL) for 30 min. The solvent
was reduced to one-third of its volume under reduced pressure
and left to cool overnight. The solid precipitates that appeared
were collected by filtration and crystallized from the proper
solvent.
EXPERIMENTAL
Melting points were measured on an Electrothermal (9100)
apparatus and are uncorrected. IR spectra were recorded as KBr
pellets on a Perkin Elmer 1430 spectrophotometer. The 1H
NMR and 13C NMR spectra were taken on a Varian Gemini
300 MHz spectrometer in DMSO-d6 using TMS as an internal
standard and chemical shifts are expressed in d ppm values.
Mass spectra were taken on a Shimadzu GCMS-GB 1000 PX
(70 eV). Elemental analyses were carried out at the Microana-
lytical Center at Cairo University. X-ray data [15] were col-
lected using KappaCCD on a Bruker Nonius apparatus. The
structure was solved by direct methods and expanded using
Fourier technique SIR92 [16]. The structure was refined using
maXus [17]. Nonhydrogen atoms are refined anisotropically and
the hydrogen atoms were refined according to the theoretical
models.
Reaction of the enaminones 1a–c with malononitrile 2a:
Preparation of compounds 8a–c. To a mixture of each of
enaminone 1a–c (10 mmol) and malononitrile (0.66 g;
10 mmol) in ethanol (15 mL) was added few drops of piperi-
dine, which acts as catalyst. The reaction mixture was refluxed
for 2 h and then left to cool to room temperature. The solid
products thus precipitated were collected by filtration and
crystallized from the proper solvent.
2-Oxo-6-phenyl-1,2-dihydropyridine-3-carbonitrile 9a. Pale
yellow crystals, yield (1.7 g, 87%); mp 291–292ꢁC (AcOH)
(Lit. 158ꢁC [12]); tmax ¼ 3220, 3151 (NH), 2222 (CN) and
1662 cmꢂ1 (CO); MS: m/z ¼ 196 [Mþ]; dH ¼ 6.72 (d, j ¼
8.57 Hz, 1H, Pyr. H-5), 7.50–7.80 (m, 5H, Ph), 8.20 (d, j ¼
8.57 Hz, 1H, Pyr. H-4), 12.80 (s, 1H, NH).
Anal. Calcd. for C12H8N2O: (196.20): C, 73.46; H, 4.11; N,
14.28. Found: C, 73.35; H, 4.00; N, 14.20.
6-(Furan-2-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile
9b. Pale brownish crystals, yield (1.67 g, 90%); mp 298–
300ꢁC (AcOH) (Lit. 314ꢁC [12]); tmax ¼ 3215, 3160 (NH),
2-Cyano-5-dimethylamino-5-phenylpenta-2,4-dienoic acid
amide 8a. Canary yellow crystals, yield (1.8 g, 75%); mp
260–262ꢁC (Dioxan) (Lit. 254–256 [12]); tmax ¼ 3435 and
3284 (NH2), 2193 (CN) and 1665 cmꢂ1 (CO); MS: m/z ¼ 241
[Mþ]; dH ¼ 2.92 (s, 6H, 2 CH3), 5.65 (d, j ¼ 12.75 Hz, 1H,
CH), 6.77 (s, 2H, NH2), 7.13 (d, j ¼ 12.75 Hz, 1H, CH),
7.24–7.55 (m, 5H, Ph). dC ¼ 165.08 (s)(amide CO), 164.58
(d)(C-3), 153.26 (s)(C-5), [133.98(s), 129.56(d), 128.76(d),
128.72(d); Phenyl C’s], 118.90(s)(CN), 96.91 (s)(C-2),
87.57(d)(C-4), 41.92 (q).
2225 (CN) and 1659 cmꢂ1 (CO); MS: m/z ¼ 186 [Mþ]; dH
¼
6.71 (d, j ¼ 12.5 Hz, 1H, Pyr. H-5), 6.77 (t, 1H, Fur. H-4),
7.61 (d, 1H, Fur. H-3), 7.85 (d, 1H, Fur. H-5), 8.15 (d, j ¼
12.5 Hz, 1H, Pyr. H-4), 12.80 (s, 1H, NH).
Anal. Calcd. for C10H6N2O2: (186.17): C, 64.52; H, 3.25;
N, 15.05. Found: C, 64.50; H, 3.15; N, 15.10.
2-Oxo-6-(thiophen-2-yl)-1,2-dihydropyridine-3-carbonitrile
9c. Pale yellowish crystals, yield (1.87 g, 93%); mp 295–
296ꢁC (AcOH) (Lit. 288ꢁC [12]); tmax ¼ 3215, 3145 (NH),
X-ray crystallographic data using SIR92 [16] program to
solve structure: pale yellow crystals, C14H15N3O (Mr
¼
´
˚
2228 (CN) and 1655 cmꢂ1 (CO); MS: m/z ¼ 202 [Mþ]; dH
¼
241.294 g molꢂ1), orthorhombic prismatic, space group Pna-
´
´
˚
˚
2(1), a ¼ 10.0108(5) A
6.65 (d, j ¼ 12.55 Hz, 1H, Pyr. H-5), 7.23 (t, 1H, thienyl H),
, b ¼ 18.4003(9) A, c ¼ 7.1902(3) A,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2009
About the Reaction of b-Dimethylamino-a,b-enones with
Active Methylene Nitriles
953
[2] Abdelrazek, F. M. Synth Commun 2005, 35, 2251.
[3] Abdelrazek, F. M.; Metwally, N. H. Synth Commun 2006,
36, 83.
7.85 (d, 1H, thienyl H), 7.95 (d, 1H, thienyl H), 8.10 (d, j ¼
12.55 Hz, 1H, Pyr. H-4), 12.80 (s, 1H, NH).
Anal. Calcd. for C10H6N2OS: (202.23): C, 59.39; H, 2.99; N,
13.85; S, 15.86. Found: C, 59.35; H, 3.15; N, 13.90; S, 15.70.
N-(5-Cyano-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-acet-
amide 16. To a mixture of 11 (1.7g, 10 mmol; prepared
according to the literature method [13]) and malononitrile
2a (0.66 g, 10 mmol) in ethanol (20 mL) was added a cata-
lytic amount (five drops) of piperidine. The reaction mixture
was refluxed for 6 h and then left to cool to room tempera-
ture. The contents of the flask were poured into ice-cold
water and acidified with few drops of conc. HCl till just
neutral (pH paper). The precipitated solid product was fil-
tered off, washed thoroughly with cold water, dried, and
recrystallized from ethanol/DMF (4:1) to give 16 as lustrous
brown crystals, yield (1.5 g, 78%); mp. 215–217ꢁC (Lit.
200–220ꢁC [13]); tmax ¼ 3340, 3220 (NH), 2195 (CN) and
1655 cmꢂ1 (CO); MS: m/z ¼ 191 [Mþ]; dH ¼ 1.99 (s, 3H,
CH3), 2.15 (s, 3H, CH3), 7.95 (s, 1H, H-4), 9.3 (br.s., 1H,
NH), 12.25 (br.s., 1H, NH). dC ¼ 169.5 (s), 159.96 (s),
149.75 (d), 148.5 (s), 116.65 (s), 116.05 (s), 99.56 (s),
23.05 (q), 16.43 (q).
[4] Abdelrazek, F. M.; Metz, P.; Metwally, N. H.; El-Mah-
rouky, S. F. Arch Pharm Chem Life Sci (Weinheim) 2006, 339, 456.
[5] Abdelrazek, F. M.; Metz, P.; Kataeva, O.; Jaeger, A.; El-Mah-
rouky, S. F. Arch Pharm Chem Life Sci (Weinheim) 2007, 340, 543.
[6] Meyer, H.; Sitt, R.; Thomas, G.; Kaurse, H. Ger. Offen.
3015 219 (1980), Chem Abstr 1982, 96, 6604d.
[7] Deshang, P.; Cipolina, J. A.; Lowmoster, N. K. J Org Chem
1988, 53, 1356.
[8] Worbel, J.; Li, Z.; Dietrich, A.; McCaleb, M.; Mihan, B.;
Serdy, J.; Sullivan, D. J Med Chem 1998, 41, 1084.
[9] Torres, M.; Gil, S.; Parra, M. Curr Org Chem 2005, 9, 1757
(Review).
[10] Abdelrazek, F. M.; Michael, F. A. J Heterocycl Chem 2006,
43, 7.
[11] Yermolayev, S. A.; Gorobets, N. Yu.; Lukinova, E. V.;
Shishkin, O. V.; Shishkina, S. V.; Desenko, S. M. Tetrahedron 2008,
64, 4649.
[12] Al-Omran, F.; Al-Awadhi, N.; Abdelkhalik, M. M.; Kaul,
K.; Abu El-Khair, A.; Elnagdi, M. H. J Chem Res (S) 1997, 84/85,
(M) 601.
[13] Al-Omran, F.; Abu El-Khair, A.; Elnagdi, M. H. J Chem
Res (S) 1998, 798.
Anal. Calcd. for C9H9N3O2: (191.19): C, 56.54; H, 4.74; N,
21.98. Found: C, 56.35; H, 4.90; N, 21.90.
[14] Abdelkhalik, M. M.; Eltoukhy, A. M.; Agamy, S. M.;
Elnagdi, M. H. J Heterocycl Chem 2004, 41, 431.
Acknowledgments. F. M. Abdelrazek thanks the Alexander von
Humboldt-Foundation (Germany) for granting a research fellow-
ship, the continuous help and support, and Professor Peter Metz,
Institut fu¨r Organische Chemie, TU Dresden, for his kind
hospitality.
[15] Crystallographic data (excluding structure factors) for the
structure 8a reported in this paper have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary publication no.
CCDC-722543. Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax:
(internat.) þ 44 1223/336-033; e-mail: deposit@ccdc.cam.ac.uk].
[16] Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.;
Burl, M. C.; Polidori, G.; Camalli, M. J Appl Crystallogr 1994, 27, 435.
[17] Mackay, S.; Gilmore, C. J.; Edwards, C.; Stewart, N.;
Shankland, K. maXus Computer Program for the Solution and Refine-
ment of Crystal Structures; MacScience, Japan/The University of Glas-
gow: Bruker Nonius, The Netherlands, 1999.
REFERENCES AND NOTES
[1] (a) Abdelrazek, F. M.; Salah El-Din, A. M.; Mekky, A. E.
Tetrahedron 2001, 57, 1813; (b) Abdelrazek, F. M.; Salah El-Din, A.
M.; Mekky, A. E. Tetrahedron 2001, 57, 6787.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet