- Email: [email protected]
Four component DHARMA-synthesis of some densely functionalized 1,8-naphthyridines
Tetrahedron Letters 56 (2015) 5434–5436
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Four component DHARMA-synthesis of some densely functionalized 1,8-naphthyridines Ivan N. Bardasov ⇑, Anastasiya U. Alekseeva, Oleg V. Ershov, Mikhail Yu. Belikov Ulyanov Chuvash State University, Moskovsky pr. 15, Cheboksary 428015, Russia
a r t i c l e
i n f o
Article history: Received 6 May 2015 Revised 18 June 2015 Accepted 7 August 2015 Available online 12 August 2015
a b s t r a c t We report the one-pot synthesis of the triethylammonium salts of 5,7-diamino-4-aryl-2-(dicyanomethyl)-1,4-dihydro-1,8-naphthyridine-3,6-dicarbonitriles from the reaction of aromatic aldehydes, a malononitrile dimer and triethylamine. Ó 2015 Elsevier Ltd. All rights reserved.
Keywords: One-pot reactions 1,8-Naphthyridines Double heteroannulation reactions Knoevenagel condensation Michael addition
Cascade reactions of cyano-containing poly- and heterofunctional compounds are a highly effective strategy for the synthesis of aza-heterocycles. The cyano group of the acyclic substrate, in most cases, is involved in the construction of a pyrrole or pyridine ring.1–3 This is due to its ability to form an iminium anion after the attack of nucleophilic reagents, which then reacts with the electrophilic center of the molecule, forming an azaheterocycle. This strategy permits the synthesis of mono and polycyclic compounds in a single step (see Scheme 1). We have previously described a convenient one-step process for the preparation of heterocyclic compounds using arylmethylidene derivatives of malononitrile dimers (AMD) 1 as starting materials.2 The presence of enamine-carbonitrile moieties and a highly reactive double-bond make them promising for cascade reactions. The reactions of compounds 1 with active phenols, cyclic 1,3-dicarbonyl compounds, or their enamine derivatives have led to the formation of chromeno[2,3-b]pyridines and 1,8-naphthyridines via double heteroannulation reactions of Michael adducts (DHARMA) involving the hydroxy, amino, and cyano groups.2a–e,3 In this Letter, we describe a new one-pot approach to 1,8-naphthyridine derivatives, which are well-known compounds as a consequence of their varied biological activities.4 Examples include cytotoxic,4a inflammatory,4b–d antibacterial,4e and neuroprotective activities, which have the potential for the treatment of Alzheimer’s disease.4i,4j The new method reported herein, involves
the one-pot reaction of aromatic aldehydes 2a–e, a malononitrile dimer 3 and triethylamine. A series of intramolecular transformations led to the formation of the triethylammonium salts of 5,7-diamino-4-aryl-2-(dicyanomethyl)-1,4-dihydro-1,8-naphthyridine3,6-dicarbonitriles 4a–e in 75–89% yields (Scheme 2 and Table 1).5 Knoevenagel condensation of aromatic aldehydes 2a–e with the malononitrile dimer 3 leads to the formation of AMD compounds 1a–e (Scheme 3). Further reaction of malononitrile dimer 3 via Michael addition to compound 1a–e resulted in the formation of intermediate A. The close proximity of the amino and cyano groups leads to formation of pyridine B. Finally, a second cyclization of the generated amino group to a further cyano group resulted in the formation of 1,8-naphthyridines 4a–e.
Ar
NH2 + XH
Ar CN
X = O, NR
CN
1 Ar
E-mail address: [email protected] (I.N. Bardasov). http://dx.doi.org/10.1016/j.tetlet.2015.08.013 0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
CN CN XH Ar
NH2
CN X
CN
Michael adducts
NH2 CN NH2
first heteroannulation
⇑ Corresponding author. Tel.: +7 9083030163; fax: +7 8352450279.
NH2
CN
CN X
N
NH 2
second heteroannulation
Scheme 1. Double heteroannulation reactions of Michael adducts (DHARMA) using AMD 1.
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Ar H O 2a-e +
NC NC
NH2 CN
NEt3
3
Ar
NH 2
NHEt3
CN CN
- H 2O
CN
CN
NC CN
3
NH2
NC N H
N
NH2
4a-e
Scheme 2. One-pot synthesis of the triethylammonium salts of 5,7-diamino-4-aryl-2-(dicyanomethyl)-1,4-dihydro-1,8-naphthyridine-3,6-dicarbonitriles 4a–e.
Table 1 One-pot synthesis of the triethylammonium salts of 5,7-diamino-4-aryl-2-(dicyanomethyl)-1,4-dihydro-1,8-naphthyridine-3,6-dicarbonitriles 4a–e. Entry
Ar
1
2
Product
Yielda (%)
4a
78
4b
82
4c
75
Acknowledgement This research was supported by the Russian Foundation for Basic Research (Project No. 15-33-21087 mol_a_ved). Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.08. 013.
Cl 3
References and notes
O 2N
a
4
F
4d
88
5
H 3C
4e
89
1. (a) Villemin, D.; Belhadj, Z.; Cheikh, N.; Choukchou-Braham, N.; Bar, N.; Lohier, J.-F. Tetrahedron Lett. 2013, 54, 1664–1668; (b) Elinson, M. N.; Gorbunov, S. V.; Vereshchagin, A. N.; Nasybullin, R. F.; Goloveshkin, A. S.; Bushmarinov, I. S.; Egorov, M. P. Tetrahedron 2014, 70, 8559–8563; (c) Bahrami, K.; Khodaei, M. M.; Naali, F.; Yousefi, B. H. Tetrahedron Lett. 2013, 54, 5293–5298; (d) Fedoseev, S. V.; Ershov, O. V.; Belikov, M. Yu.; Lipin, K. V.; Bardasov, I. N.; Nasakin, O. E.; Tafeenko, V. A. Tetrahedron Lett. 2013, 54, 2143–2145. 2. (a) Bardasov, I. N.; Alekseeva, A. U.; Mihailov, D. L.; Ershov, O. V.; Grishanov, D. A. Tetrahedron Lett. 2015, 56, 1830–1832; (b) Alekseeva, A. Yu.; Mikhailov, D. L.; Bardasov, I. N.; Ershov, O. V.; Nasakin, O. E. Russ. J. Org. Chem. 2013, 49, 1715– 1717; (c) Alekseeva, A. Yu.; Mikhailov, D. L.; Bardasov, I. N.; Ershov, O. V.; Nasakin, O. E.; Lyshchikov, A. N. Russ. J. Org. Chem. 2014, 50, 244–250; (d) Melekhin, E. A.; Bardasov, I. N.; Ershov, O. V.; Eremkin, A. V.; Kayukov, Ya. S.; Nasakin, O. E. Russ. J. Org. Chem. 2006, 42, 622–623; (e) Ershov, O. V.; Melekhin, E. A.; Bardasov, I. N.; Kayukov, Ya. S.; Eremkin, A. V.; Nasakin, O. E. Russ. J. Org. Chem. 2006, 42, 1380–1382; (f) Bardasov, I. N.; Alekseeva, A. U.; Mihailov, D. L.; Ershov, O. V.; Nasakin, O. E.; Tafeenko, V. A. Tetrahedron Lett. 2014, 55, 2730– 2733; (g) Bardasov, I. N.; Mihailov, D. L.; Alekseeva, A. U.; Ershov, O. V.; Nasakin, O. E. Tetrahedron Lett. 2013, 54, 21–22. 3. (a) Li, J.; Yu, Y.; Tu, M.-S.; Jiang, B.; Wang, S.-L.; Tu, S.-J. Org. Biomol. Chem. 2012, 10, 5361–5365; (b) Anderson, D. R.; Hegde, S.; Reinhard, E.; Gomez, L.; Vernier, W. F.; Lee, L.; Liu, S.; Sambandam, A.; Snider, P. A.; Masih, L. Bioorg. Med. Chem. Lett. 2005, 15, 1587–1590; (c) Davis, T.; Bagley, M. C.; Dix, M. C.; Murziani, P. G. S.; Rokicki, M. J.; Widdowson, C. S.; Zayed, J. M.; Bachler, M. A.; Kipling, D. Bioorg. Med. Chem. Lett. 2007, 17, 6832–6835; (d) Svetlik, J.; Turecek, F.; Hanus, V. J. Chem. Soc., Perkin Trans. 1 1988, 2053–2058; (e) Roman, S. V.; Dyachenko, D. V.; Litvinov, V. P. Chem. Heterocycl. Compd. 1999, 35, 1253. 4. (a) Willemann, C.; Grünert, R.; Bednarski, P. J.; Troschütz, R. Bioorg. Med. Chem. 2009, 17, 4406–4419; (b) Blum, Ch. A.; Caldwell, T.; Zheng, X.; Bakthavatchalam,
Yield of isolated product.
Formation of the AMD 1a–e was confirmed by the reaction of isolated 1a–e with the malononitrile dimer 3 under the same conditions, which also led to the formation of 1,8-naphthyridines 4a–e.6 The structures of compounds 4a–e were confirmed by IR, NMR spectroscopy, and mass spectrometry.7 In conclusion, the triethylammonium salts of 5,7-diamino-4aryl-2-(dicyanomethyl)-1,4-dihydro-1,8-naphthyridine-3,6-dicarbonitriles 4a–e have been obtained for the first time as a result of the double heteroannulation reactions of Michael adducts (DHARMA) using a malononitrile dimer. The structures of the products contain a biologically important 1,8-naphthyridine fragment.
NH2
H Ar
O
CN
+ CN
2a-e
CN
NEt 3 - H 2O
NH2 CN
Ar CN
3
NH2
+
NEt3
CN
NHEt3
NC
CN 3
Ar
NH2
NHEt3 NC NC
NC
NC NC
CN 1a-e
CN CN NH2
NH2
CN
A
CN
Ar NC CN
Ar
NH2
NHEt3 NC
CN N H
N 4a-e
NH2
NHEt3
NC
NC CN
Scheme 3. Proposed mechanism for the synthesis of compounds 4a–e.
NH2 CN
N H B
CN NH2
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R.; Capitosti, S.; Brielmann, H.; De Lombaert, S.; Kershaw, M. T.; Matson, D.; Krause, J. E.; Cortright, D.; Crandall, M.; Martin, W. J.; Murphy, B. A.; Boyce, S.; Jones, A. B.; Mason, G.; Rycroft, W.; Perrett, H.; Conley, R.; Burnaby-Davies, N.; Chenard, B. L.; Hodgetts, K. J. J. Med. Chem. 2010, 53, 3330–3348; (c) Hodgetts, K. J.; Blum, Ch. A.; Caldwell, T.; Bakthavatchalam, R.; Zheng, X.; Capitosti, S.; Krause, J. E.; Cortright, D.; Crandall, M.; Murphy, B. A.; Boyce, S.; Jones, A. B.; Chenard, B. L. Bioorg. Med. Chem. Lett. 2010, 20, 4359–4363; (d) Roma, G.; Di Braccio, M.; Grossi, G.; Piras, D.; Ballabeni, V.; Tognolini, M.; Bertoni, S.; Barocelli, E. Eur. J. Med. Chem. 2010, 45, 352–366; (e) Surivet, J.-Ph.; Lange, R.; Hubschwerlen, Ch.; Keck, W.; Specklin, J.-L.; Ritz, D.; Bur, D.; Locher, H.; Seiler, P.; Strasser, D. S.; Prade, L.; Kohl, Ch.; Schmitt, Ch.; Chapoux, G.; Ilhan, E.; Ekambaram, N.; Athanasiou, A.; Knezevic, A.; Sabato, D.; Chambovey, A.; Gaertner, M.; Enderlin, M.; Boehme, M.; Sippel, V.; Wyss, P. Bioorg. Med. Chem. Lett. 2012, 22, 6705–6711; (f) Samadi, A.; Valderas, C.; de los Ríos, C.; Bastida, A.; Chioua, M.; Gonzalez-Lafuente, L.; Colmena, I.; Gandía, L.; Romero, A.; del Barrio, L.; Martín-de-Saavedra, M. D.; Lopez, M. G.; Villarroya, M.; Marco-Contelles, J. Bioorg. Med. Chem. 2011, 19, 122–133; (g) Leon, R.; Marco-Contelles, J.; García, A. G.; Villarroya, M. Bioorg. Med. Chem. 2005, 13, 1167–1175; (h) Soriano, E.; Samadi, A.; Chioua, M.; De los Ríos, C.; Marco-Contelles, J. Bioorg. Med. Chem. Lett. 2010, 20, 2950–2953; (i) Samadi, A.; de los Ríos, C.; Bolea, I.; Chioua, M.; Iriepa, I.; Moraleda, I.; Bartolini, M.; Andrisano, V.; Galvez, E.; Valderas, C.; Unzeta, M.; Marco-Contelles, J. Eur. J. Med. Chem. 2012, 52, 251–262; (j) de los Ríos, C.; Egea, J.; Marco-Contelles, J.; Leon, R.; Samadi, A.; Iriepa, I.; Moraleda, I.;
Galvez, E.; García, A. G.; Lopez, M. G.; Villarroya, M.; Romero, A. J. Med. Chem. 2010, 53, 5129–5143. 5. Typical one-pot procedure for the preparation of triethylammonium salts of 5,7-diamino-4-aryl-2-(dicyanomethyl)-1,4-dihydro-1,8-naphthyridine-3,6dicarbonitriles 4. A mixture of aromatic aldehyde (2) (10 mmol), malononitrile dimer (3) (20 mmol) and Et3N (10 mmol) in EtOH (20 mL) was heated at reflux for 3–4 h. After cooling, the resulting precipitate was filtered and washed with EtOH. 6. Typical procedure for the preparation of triethylammonium salts of 5,7-diamino-4aryl-2-(dicyanomethyl)-1,4-dihydro-1,8-naphthyridine-3,6-dicarbonitriles 4. A mixture of 2-amino-4-arylbuta-1,3-diene-1,1,3-tricarbonitrile (1) (10 mmol), malononitrile dimer (3) (10 mmol) and Et3N (10 mmol) in EtOH (20 mL) was heated at reflux for 3–4 h. After cooling, the resulting precipitate was filtered and washed with EtOH. 7. Compound 4a. mp 246–247 °C (dec); 1H NMR (500.13 MHz, DMSO-d6): d 1.16 (9H, t, J = 7.3 Hz, 3CH3), 2.93 (6H, q, J = 7.3 Hz, 3CH2), 4.43 (1H, s, CH), 6.08 (2H, s, NH2), 6.11 (2H, s, NH2), 7.04 (1H, s, NH), 7.13–7.18 (3H, m, C6H5), 7.23 (2H, t, J = 7.5 Hz, C6H5), 8.15 (1H, br s, NH). 13C NMR (125.76 MHz, DMSO-d6): 8.82 0 (CH3), 29.46 (C(CN)2), 39.97 (C4), 45.35 (CH2), 64.74, 67.47 (C3, C6), 91.01 (C4 ), 116.56, 121.30, 121.82 (CN), 126.16, 126.63, 128.08, 144.91 (C6H5), 145.98, 0 146.52 (C2, C8 ), 157.93, 159.56 (C5, C7). IR (mineral oil, cm1): 3314–3200 (NH2), 3160 (NH), 2200, 2179 (CN). MS (EI, 70 eV): m/z (%) 352 [M101]+ (19). Anal. Calcd for C25H27N9: C, 66.20; H, 6.00; N, 27.79. Found: C, 65.92; H, 6.13; N, 27.85.
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Four component DHARMA-synthesis of some densely functionalized 1,8-naphthyridines Ivan N. Bardasov ⇑, Anastasiya U. Alekseeva, Oleg V. Ershov, Mikhail Yu. Belikov Ulyanov Chuvash State University, Moskovsky pr. 15, Cheboksary 428015, Russia
a r t i c l e
i n f o
Article history: Received 6 May 2015 Revised 18 June 2015 Accepted 7 August 2015 Available online 12 August 2015
a b s t r a c t We report the one-pot synthesis of the triethylammonium salts of 5,7-diamino-4-aryl-2-(dicyanomethyl)-1,4-dihydro-1,8-naphthyridine-3,6-dicarbonitriles from the reaction of aromatic aldehydes, a malononitrile dimer and triethylamine. Ó 2015 Elsevier Ltd. All rights reserved.
Keywords: One-pot reactions 1,8-Naphthyridines Double heteroannulation reactions Knoevenagel condensation Michael addition
Cascade reactions of cyano-containing poly- and heterofunctional compounds are a highly effective strategy for the synthesis of aza-heterocycles. The cyano group of the acyclic substrate, in most cases, is involved in the construction of a pyrrole or pyridine ring.1–3 This is due to its ability to form an iminium anion after the attack of nucleophilic reagents, which then reacts with the electrophilic center of the molecule, forming an azaheterocycle. This strategy permits the synthesis of mono and polycyclic compounds in a single step (see Scheme 1). We have previously described a convenient one-step process for the preparation of heterocyclic compounds using arylmethylidene derivatives of malononitrile dimers (AMD) 1 as starting materials.2 The presence of enamine-carbonitrile moieties and a highly reactive double-bond make them promising for cascade reactions. The reactions of compounds 1 with active phenols, cyclic 1,3-dicarbonyl compounds, or their enamine derivatives have led to the formation of chromeno[2,3-b]pyridines and 1,8-naphthyridines via double heteroannulation reactions of Michael adducts (DHARMA) involving the hydroxy, amino, and cyano groups.2a–e,3 In this Letter, we describe a new one-pot approach to 1,8-naphthyridine derivatives, which are well-known compounds as a consequence of their varied biological activities.4 Examples include cytotoxic,4a inflammatory,4b–d antibacterial,4e and neuroprotective activities, which have the potential for the treatment of Alzheimer’s disease.4i,4j The new method reported herein, involves
the one-pot reaction of aromatic aldehydes 2a–e, a malononitrile dimer 3 and triethylamine. A series of intramolecular transformations led to the formation of the triethylammonium salts of 5,7-diamino-4-aryl-2-(dicyanomethyl)-1,4-dihydro-1,8-naphthyridine3,6-dicarbonitriles 4a–e in 75–89% yields (Scheme 2 and Table 1).5 Knoevenagel condensation of aromatic aldehydes 2a–e with the malononitrile dimer 3 leads to the formation of AMD compounds 1a–e (Scheme 3). Further reaction of malononitrile dimer 3 via Michael addition to compound 1a–e resulted in the formation of intermediate A. The close proximity of the amino and cyano groups leads to formation of pyridine B. Finally, a second cyclization of the generated amino group to a further cyano group resulted in the formation of 1,8-naphthyridines 4a–e.
Ar
NH2 + XH
Ar CN
X = O, NR
CN
1 Ar
E-mail address: [email protected] (I.N. Bardasov). http://dx.doi.org/10.1016/j.tetlet.2015.08.013 0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
CN CN XH Ar
NH2
CN X
CN
Michael adducts
NH2 CN NH2
first heteroannulation
⇑ Corresponding author. Tel.: +7 9083030163; fax: +7 8352450279.
NH2
CN
CN X
N
NH 2
second heteroannulation
Scheme 1. Double heteroannulation reactions of Michael adducts (DHARMA) using AMD 1.
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Ar H O 2a-e +
NC NC
NH2 CN
NEt3
3
Ar
NH 2
NHEt3
CN CN
- H 2O
CN
CN
NC CN
3
NH2
NC N H
N
NH2
4a-e
Scheme 2. One-pot synthesis of the triethylammonium salts of 5,7-diamino-4-aryl-2-(dicyanomethyl)-1,4-dihydro-1,8-naphthyridine-3,6-dicarbonitriles 4a–e.
Table 1 One-pot synthesis of the triethylammonium salts of 5,7-diamino-4-aryl-2-(dicyanomethyl)-1,4-dihydro-1,8-naphthyridine-3,6-dicarbonitriles 4a–e. Entry
Ar
1
2
Product
Yielda (%)
4a
78
4b
82
4c
75
Acknowledgement This research was supported by the Russian Foundation for Basic Research (Project No. 15-33-21087 mol_a_ved). Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.08. 013.
Cl 3
References and notes
O 2N
a
4
F
4d
88
5
H 3C
4e
89
1. (a) Villemin, D.; Belhadj, Z.; Cheikh, N.; Choukchou-Braham, N.; Bar, N.; Lohier, J.-F. Tetrahedron Lett. 2013, 54, 1664–1668; (b) Elinson, M. N.; Gorbunov, S. V.; Vereshchagin, A. N.; Nasybullin, R. F.; Goloveshkin, A. S.; Bushmarinov, I. S.; Egorov, M. P. Tetrahedron 2014, 70, 8559–8563; (c) Bahrami, K.; Khodaei, M. M.; Naali, F.; Yousefi, B. H. Tetrahedron Lett. 2013, 54, 5293–5298; (d) Fedoseev, S. V.; Ershov, O. V.; Belikov, M. Yu.; Lipin, K. V.; Bardasov, I. N.; Nasakin, O. E.; Tafeenko, V. A. Tetrahedron Lett. 2013, 54, 2143–2145. 2. (a) Bardasov, I. N.; Alekseeva, A. U.; Mihailov, D. L.; Ershov, O. V.; Grishanov, D. A. Tetrahedron Lett. 2015, 56, 1830–1832; (b) Alekseeva, A. Yu.; Mikhailov, D. L.; Bardasov, I. N.; Ershov, O. V.; Nasakin, O. E. Russ. J. Org. Chem. 2013, 49, 1715– 1717; (c) Alekseeva, A. Yu.; Mikhailov, D. L.; Bardasov, I. N.; Ershov, O. V.; Nasakin, O. E.; Lyshchikov, A. N. Russ. J. Org. Chem. 2014, 50, 244–250; (d) Melekhin, E. A.; Bardasov, I. N.; Ershov, O. V.; Eremkin, A. V.; Kayukov, Ya. S.; Nasakin, O. E. Russ. J. Org. Chem. 2006, 42, 622–623; (e) Ershov, O. V.; Melekhin, E. A.; Bardasov, I. N.; Kayukov, Ya. S.; Eremkin, A. V.; Nasakin, O. E. Russ. J. Org. Chem. 2006, 42, 1380–1382; (f) Bardasov, I. N.; Alekseeva, A. U.; Mihailov, D. L.; Ershov, O. V.; Nasakin, O. E.; Tafeenko, V. A. Tetrahedron Lett. 2014, 55, 2730– 2733; (g) Bardasov, I. N.; Mihailov, D. L.; Alekseeva, A. U.; Ershov, O. V.; Nasakin, O. E. Tetrahedron Lett. 2013, 54, 21–22. 3. (a) Li, J.; Yu, Y.; Tu, M.-S.; Jiang, B.; Wang, S.-L.; Tu, S.-J. Org. Biomol. Chem. 2012, 10, 5361–5365; (b) Anderson, D. R.; Hegde, S.; Reinhard, E.; Gomez, L.; Vernier, W. F.; Lee, L.; Liu, S.; Sambandam, A.; Snider, P. A.; Masih, L. Bioorg. Med. Chem. Lett. 2005, 15, 1587–1590; (c) Davis, T.; Bagley, M. C.; Dix, M. C.; Murziani, P. G. S.; Rokicki, M. J.; Widdowson, C. S.; Zayed, J. M.; Bachler, M. A.; Kipling, D. Bioorg. Med. Chem. Lett. 2007, 17, 6832–6835; (d) Svetlik, J.; Turecek, F.; Hanus, V. J. Chem. Soc., Perkin Trans. 1 1988, 2053–2058; (e) Roman, S. V.; Dyachenko, D. V.; Litvinov, V. P. Chem. Heterocycl. Compd. 1999, 35, 1253. 4. (a) Willemann, C.; Grünert, R.; Bednarski, P. J.; Troschütz, R. Bioorg. Med. Chem. 2009, 17, 4406–4419; (b) Blum, Ch. A.; Caldwell, T.; Zheng, X.; Bakthavatchalam,
Yield of isolated product.
Formation of the AMD 1a–e was confirmed by the reaction of isolated 1a–e with the malononitrile dimer 3 under the same conditions, which also led to the formation of 1,8-naphthyridines 4a–e.6 The structures of compounds 4a–e were confirmed by IR, NMR spectroscopy, and mass spectrometry.7 In conclusion, the triethylammonium salts of 5,7-diamino-4aryl-2-(dicyanomethyl)-1,4-dihydro-1,8-naphthyridine-3,6-dicarbonitriles 4a–e have been obtained for the first time as a result of the double heteroannulation reactions of Michael adducts (DHARMA) using a malononitrile dimer. The structures of the products contain a biologically important 1,8-naphthyridine fragment.
NH2
H Ar
O
CN
+ CN
2a-e
CN
NEt 3 - H 2O
NH2 CN
Ar CN
3
NH2
+
NEt3
CN
NHEt3
NC
CN 3
Ar
NH2
NHEt3 NC NC
NC
NC NC
CN 1a-e
CN CN NH2
NH2
CN
A
CN
Ar NC CN
Ar
NH2
NHEt3 NC
CN N H
N 4a-e
NH2
NHEt3
NC
NC CN
Scheme 3. Proposed mechanism for the synthesis of compounds 4a–e.
NH2 CN
N H B
CN NH2
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Galvez, E.; García, A. G.; Lopez, M. G.; Villarroya, M.; Romero, A. J. Med. Chem. 2010, 53, 5129–5143. 5. Typical one-pot procedure for the preparation of triethylammonium salts of 5,7-diamino-4-aryl-2-(dicyanomethyl)-1,4-dihydro-1,8-naphthyridine-3,6dicarbonitriles 4. A mixture of aromatic aldehyde (2) (10 mmol), malononitrile dimer (3) (20 mmol) and Et3N (10 mmol) in EtOH (20 mL) was heated at reflux for 3–4 h. After cooling, the resulting precipitate was filtered and washed with EtOH. 6. Typical procedure for the preparation of triethylammonium salts of 5,7-diamino-4aryl-2-(dicyanomethyl)-1,4-dihydro-1,8-naphthyridine-3,6-dicarbonitriles 4. A mixture of 2-amino-4-arylbuta-1,3-diene-1,1,3-tricarbonitrile (1) (10 mmol), malononitrile dimer (3) (10 mmol) and Et3N (10 mmol) in EtOH (20 mL) was heated at reflux for 3–4 h. After cooling, the resulting precipitate was filtered and washed with EtOH. 7. Compound 4a. mp 246–247 °C (dec); 1H NMR (500.13 MHz, DMSO-d6): d 1.16 (9H, t, J = 7.3 Hz, 3CH3), 2.93 (6H, q, J = 7.3 Hz, 3CH2), 4.43 (1H, s, CH), 6.08 (2H, s, NH2), 6.11 (2H, s, NH2), 7.04 (1H, s, NH), 7.13–7.18 (3H, m, C6H5), 7.23 (2H, t, J = 7.5 Hz, C6H5), 8.15 (1H, br s, NH). 13C NMR (125.76 MHz, DMSO-d6): 8.82 0 (CH3), 29.46 (C(CN)2), 39.97 (C4), 45.35 (CH2), 64.74, 67.47 (C3, C6), 91.01 (C4 ), 116.56, 121.30, 121.82 (CN), 126.16, 126.63, 128.08, 144.91 (C6H5), 145.98, 0 146.52 (C2, C8 ), 157.93, 159.56 (C5, C7). IR (mineral oil, cm1): 3314–3200 (NH2), 3160 (NH), 2200, 2179 (CN). MS (EI, 70 eV): m/z (%) 352 [M101]+ (19). Anal. Calcd for C25H27N9: C, 66.20; H, 6.00; N, 27.79. Found: C, 65.92; H, 6.13; N, 27.85.