Reassignment of the structures of condensation products of α-keto α′-formylarylhydrazones with ethyl cyanoacetate: A novel route to ethyl 5-arylazo-2-hydroxynicotinates

Article abstract of DOI:10.1016/j.tetlet.2010.10.127

The condensation of α-keto α′-formylarylhydrazones with ethyl cyanoacetate afforded ethyl 5-arylazo-2-hydroxy-6-aryl (or alkyl) nicotinates. The structures of the reaction products could be established based on X-ray crystal structure determination.

Full text of DOI:10.1016/j.tetlet.2010.10.127

Tetrahedron Letters 52 (2011) 202–204
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Tetrahedron Letters
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Reassignment of the structures of condensation products of a-keto
a0-formylarylhydrazones with ethyl cyanoacetate: a novel route to ethyl
5-arylazo-2-hydroxynicotinates
Saleh M. Al-Mousawi a, , Moustafa Sherief Moustafa a, , Ismail Abdelshafy Abdelhamid b,c
,
⇑
⇑
Mohamed Hilmy Elnagdi a
a Department of Chemistry, Faculty of Science, University of Kuwait, PO Box 12613, Safat 13060, Kuwait
b Institut für Organische Chemie der Universität Hannover, Schneiderberg 1B, 30167 Hannover, Germany
c Chemistry Department, Faculty of Science, Cairo University Giza, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
The condensation of
a
-keto a0-formylarylhydrazones with ethyl cyanoacetate afforded ethyl 5-arylazo-2-
Received 13 August 2010
Revised 8 October 2010
Accepted 22 October 2010
Available online 30 October 2010
hydroxy-6-aryl (or alkyl) nicotinates. The structures of the reaction products could be established based
on X-ray crystal structure determination.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Arylhydrazonals
Condensation
Ethyl cyanoacetate
Ethyl 5-arylazo-2-hydroxynicotinate
O
The considerable biological activities of nicotinic acid deriva-
tives have attracted significant interest in their synthesis.1–3
Despite the large number of nicotinates,4–6 to our knowledge, 5-
arylazonicotinates have not yet been synthesized. In continuation
of our programme aimed at re-inspecting the structure of products
resulting from the condensation of 2-arylhydrazonoketones 1 with
active methylene nitriles we have discovered a novel efficient
route to the above mentioned nicotinates. It has been reported
that7–12 condensation of 1a–c with ethyl cyanoacetate affords the
pyridazinones 2a–c. This is in contrast to the established formation
of pyridazine-6-imines 3d–g upon condensation of 1d–g (R = alkyl
or aryl) with the same reagent.13 This contradiction attracted our
interest as we are convinced that pyridazine-imines are highly
unstable and ought to hydrolyse to the corresponding pyridazinon-
es (Scheme 1). We have established that condensation of 1a–c with
ethyl cyanoacetate affords the previously reported pyridazinones
2a–c.14 Although the condensation of hydrazonals 1d–g (R1 =
CHO) with ethyl cyanoacetate affords products with the same
molecular formula as those obtained earlier, we noted in the 13C
NMR spectra, the lack of a carbonyl carbon resonance at d ꢀ 180.
R1
R
NCCH2CO2Et
+
N
NH
Ph
1a-h
reflux, 1-2 h
NH4OAc / AcOH
1a-c
1d-g
O
O
R
O
CN
O
EtO
R
OEt
N
N
N
N
NH
Ph
Ph
2a-c
3d-g
a: R= Me, R1= CO2Et; b: R= Et, R1= CO2Et;
c: R= Ph, R1= CO2Et; d: R= Me, R1= CHO;
e: R= Ph, R1= CHO; f: R= 4-ClC6H4, R1= CHO;
⇑
Corresponding authors. Tel.: +965 24987081; fax: +965 24816482.
E-mail addresses: salehalmousawi@hotmail.com (S.M. Al-Mousawi), mostafa_
g: R= 4-CH3OC6H4, R1= CHO; h: R= 2-thienyl, R1= CHO;
msm@hotmail.com (M.S. Moustafa).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.127

S. M. Al-Mousawi et al. / Tetrahedron Letters 52 (2011) 202–204
203
O
R1
R
NCCH2CO2Et
+
N
NH
Ph
1a-h
NH4OAc / AcOH
reflux, 1-2 h
O
O
O
CN
R
OEt
R
N
N
CO2Et
N
Ph
NH
NH
Ph
3d-h
4d-h
NH
CO2Et
O
R
N
N
O
Figure 1. X-ray structure of compound 7e.
O
N
5d-h
Ph
H2N
O
CO2Et
CO2Et
The reported value of d ꢀ 166 is too low for an aroylcarbonyl and
thus we became convinced that these products were not the
described pyridazine-6-imines 3d–g. Fortunately, the product of
the reaction of 1e with ethyl cyanoacetate afforded crystals
suitable for an X-ray crystal structure determination.15 The X-ray
crystal structure clearly revealed that the product is actually 7e
(Fig. 1).
HN
R= 2-thienyl
R
S
N
NH
Ph
N
6d-g
8h
Ph
In fact, the initial condensation of 1d–g with ethyl cyanoacetate
affords the intermediates 4d–g which cyclize into the pyran-2-
imine intermediates 5d–g. These readily undergo Dimroth type
rearrangement to give ethyl 5-arylazonicotinates 6d–g (Scheme
2).16 Although pyridones are believed to exist mainly in the keto
form 6d–g, the predominance of 7d–g (as indicated by the X-ray
analysis) is attributed to stabilization of the product by hydrogen
bonding.
In contrast to the observed behaviour of 1d–g towards ethyl
cyanoacetate, the hydrazonal 1h behaves differently affording
pyridazinone 9h. It is believed that in this case intermediate 5h
undergoes ring opening, through addition of water to yield 8h
which then cyclizes into 9h.17
O
O
H
O
N
O
NH2
S
N
OEt
N
N
O
R
Ph
N
9h
7d-g
Ph
Reduction of 7d–g with Zn in acetic acid gave the corresponding
ethyl 5-amino-2-hydroxynicotinates which could be diazotized
and coupled with different active methylene compounds.
In conclusion, we have established a new and efficient route to
ethyl 5-arylazo-2-hydroxy-6-aryl (or alkyl) nicotinates. Currently,
we are inspecting the behaviour of hydrazonals 1d–h towards
other active methylene nitriles.
Scheme 2.
References and notes
1. Skinner, P. J.; Cherrier, M. C.; Webb, P. J.; Sage, C. R.; Dang, H. T.; Pride, C. C.;
Chen, R.; Tamura, S. Y.; Richman, J. G.; Connolly, D. T. Bioorg. Med. Chem. Lett.
2007, 17, 6619.
2. Wise, A.; Foord, S. M.; Fraser, N. J.; Barnes, A. A.; Elshourbagy, N.; Eilert, M.;
Ignar, D. M.; Murdock, P. R.; Steplewski, K.; Green, A.; Brown, A. J.; Dowell, S. J.;
Szekeres, P. G.; Hassall, D. G.; Marshall, F. H.; Wilson, S.; Pike, N. B. J. Biol. Chem.
2003, 278, 9869.
3. Soga, T.; Kamohara, M.; Takasaki, J. M.; Shun-Ichiro, S.; Tetsu, O.; Takahide, H.;
Hideki, M. A.; Matsushime, H.; Furuichi, K. Biochem. Biophys. Res. Commun.
2003, 303, 364.
Acknowledgements
The authors are grateful to Kuwait University, College of Grad-
uate Studies for financial support of Mr. Moustafa Sherief’s master
degree. The use of analytical facilities provided by SAF projects No.
GS 01/05 and GS 03/01 are greatly appreciated.
4. Ferlin, M. G.; Di Marco, V. B.; Dean, A. Tetrahedron 2006, 62, 6222.

204
S. M. Al-Mousawi et al. / Tetrahedron Letters 52 (2011) 202–204
5. Hirota, K.; Kitade, Y.; Shimada, K.; Maki, Y. J. Org. Chem. 1985, 50, 1512.
6. Ghosez, L.; Jnoff, E.; Bayard, F.; Sainte, F.; Beaudegnies, R. Tetrahedron 1999, 55,
([Mꢁ2]+, 100), 317 (10), 241 (15), 213 (55), 196 (25), 168 (10), 140 (30), 115
(20), 104 (10), 77 (30).
3387.
Ethyl 6-(4-chlorophenyl)-2-hydroxy-5-(phenyldiazenyl)-nicotinate (7f): yield =
ꢁ89%; mp 193–195 °C. Anal. Calcd for C20H16ClN3O3 (381.82): C, 62.91; H,
4.22; N, 11.01. Found: C, 62.85; H, 4.21; N, 11.26; IR (cmꢁ1): 3417 (OH), 1688
(CO); 1H NMR (400 MHz, DMSO-d6): d, ppm = 1.35 (t, 3H, J = 8 Hz, CH3), 4.37 (q,
7. Elnagdi, M. H.; Erian, A. W.; Sadek, K. U.; Selim, M. A. J. Chem. Res. 1990, 5, 148.
8. Gewald, K.; Hain, U. Synthesis 1984, 62.
9. Al-Awadhi, H.; Al-Omran, F.; Elnagdi, M. H.; Infantes, L.; Foces-Foces, C.;
Jagerovic, N.; Elguero, J. Tetrahedron 1995, 51, 12745.
2H, J = 8, CH2), 7.47–7.84 (m, 9H, Ar-H), 8.05 (br s, 1H, OH), 8.57 (s, 1H, CH); 13
C
10. Abdelrazek, F. M.; Salah El-Din, A. M.; Mekky, A. E. Tetrahedron 2001, 57, 1813.
11. Al-Omran, F.; Abdel-Khalik, M. M.; Abou-Elkhair, A.; Elnagdi, M. H. Synthesis
1997, 1, 91.
12. Behbehani, H.; Abdel-Khalik, M. M.; Elnagdi, M. H. Org. Prep. Proceed Int. 1999,
31, 551.
13. Abdel-Khalik, M. M.; Agamy, S. M.; Elnagdi, M. H. Synthesis 2001, 1861.
14. General procedure for the synthesis 7e–g and 9h: A mixture of 1e–h (2.52 g,
0.01 mol) and ethyl cyanoacetate (1.13 g, 0.01 mol) in presence of NH4OAc
(2 g) and AcOH (20 mL) as a solvent was refluxed for 1–2 h. (monitored by TLC
using 1:1 EtOAc–petroleum ether as eluent). The reaction mixture was cooled
and then was poured onto ice-water. The solid, so formed, was collected by
filtration and crystallized from EtOH to give orange crystals.
15. CCDC 787021 contains the supplementary crystallographic data for compound
7e. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk.
16. Ethyl 2-hydroxy-6-phenyl-5-(phenyldiazenyl)nicotinate (7e): yield 87%; mp 188–
190 °C. Anal. Calcd for C20H17N3O3 (347.36): C, 69.15; H, 4.93; N, 12.10. Found:
C, 69.15; H, 4.82; N, 12.15; IR (cmꢁ1): 3406 (OH), 1693 (CO); 1H NMR
(400 MHz, DMSO-d6): d, ppm = 1.36 (t, 3H, J = 8 Hz, CH3), 4.38 (q, 2H, J = 8 Hz,
CH2), 7.48–7.80 (m, 10H, Ar-H), 7.81 (br s, 1H, OH), 8.57 (s, 1H, CH); 13C NMR
(100 MHz, DMSO-d6): d, ppm = 166.2, 161.7, 159.7, 152.3, 137.2, 136.5, 130.6,
130.5, 129.4, 129.3, 127.5, 127.3, 122.4, 105.0, 61.1, 14.2. MS: m/z (%) 345
NMR (100 MHz, DMSO-d6): d, ppm = 166.2, 160.3, 159.7, 153.6, 136.5, 136.0,
134.4, 132.7, 131.5, 130.7, 129.5, 127.4, 122.5, 105.3, 61.2, 14.2. MS: m/z (%)
336 ([Mꢁ45]+, 100), 321 (70), 263 (20), 203 (20), 176 (40), 127 (35), 100 (55),
91 (90), 81 (100).
Ethyl 2-hydroxy-6-(4-methoxyphenyl)-5-(phenyldiazen-yl)nicotinate (7g): yield
75%; mp 174–176 °C. Anal. Calcd for C21H19N3O4 (377.40): C, 66.83; H, 5.07; N,
11.13. Found: C, 66.62; H, 5.24; N, 11.06; IR (cmꢁ1): 3410 (OH), 1687 (CO); 1
H
NMR (400 MHz, DMSO-d6): d, ppm = 1.36 (t, 3H, J = 8 Hz, CH3), 3.35 (s, 3H,
CH3), 4.36 (q, 2H, J = 8 Hz, CH2), 7.05–7.83 (m, 9H, Ar-H), 7.88 (br s, 1H, OH),
8.54 (s, 1H, CH); 13C NMR (100 MHz, DMSO-d6): d, ppm = 166.3, 160.9, 160.7,
160.5, 159.6, 152.4, 136.5, 132.7, 130.5, 129.5, 127.4, 122.4, 113.1, 104.4, 61.0,
55.3, 14.2. MS: m/z (%) 377 (M+, 100), 361 (15), 347 (5), 271 (10), 243 (20), 225
(15), 198 (10), 170 (10), 145 (10), 134 (5), 77 (20).
17. 3-Oxo-2-phenyl-6-(thiophenylene-2-carbonyl)-2,3-dihydropyridazine-4-carboxamide
(9h): yield 73%; mp 261–263 °C. Anal. Calcd for C16H11N3O3S (325.34): C,
59.07; H, 3.41; N, 12.92; S, 9.85. Found: C, 59.24; H, 3.41; N, 13.01; S, 9.75; IR
(cmꢁ1): 3349, 3161 (NH2), 1700 (CO), 1667 (CO), 1640 (CO); 1H NMR
(400 MHz, DMSO-d6): d, ppm = 7.27–8.52 (m, 10H, Ar-H, NH2 D2O
exchangeable), 8.59 (s, 1H, CH); 13C NMR (100 MHz, DMSO-d6): d, ppm =
178.7, 162.0, 159.5, 141.9, 140.9, 138.4, 137.7, 136.9, 131.5, 131.2, 129.2, 129.0,
128.5, 126.2. MS: m/z (%) 325 (M+, 100), 280 (5), 237 (20), 197 (5), 174 (20),
121 (5), 111 (90), 83 (5), 77 (40).