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Cite this: Org. Biomol. Chem., 2014, 12, 9786 Received 6th October 2014, Accepted 23rd October 2014
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Highly efficient modular metal-free synthesis of 3-substituted 2-quinolones† Alexander V. Aksenov,*a Alexander N. Smirnov,a Nicolai A. Aksenov,a Inna V. Aksenova,a Asiyat S. Bijievaa and Michael Rubin*a,b
DOI: 10.1039/c4ob02131b www.rsc.org/obc
A modular approach to 3-substituted 2-quinolones via a cascade annulation reaction between 4-nitroketones and hydrazines has been developed.
We have recently communicated a novel metal-free transannulation reaction of 2-substituted indoles 3 with nitroalkenes 4 to produce 3-substituted 2-quinolones in polyphosphoric acid (Scheme 1).1 This reaction was also shown to proceed efficiently in one pot with the Fisher indole synthesis, starting from
readily available hydrazines 1 (Scheme 1). The mechanism of this cascade transformation involves electrophilic substitution at C-3 of indole triggered by addition of nitroalkene 4. The resulting isolable intermediate, hydroxamic acid 6 undergoes 5 → 6 ANRORC-type ring expansion with simultaneous extrusion of carboxamide 8, to afford 2-quinolone 7 (Scheme 2).1 The modular nature of this chemistry and rich biological profile of the products2–4 stimulated us to search for alternate precursors, which could offer practical advantages for rapid synthesis of 2-quinolone libraries. Thus, in the original protocol, the key intermediate 6 was derived from the corresponding nitroalkenes 4,5 which are not always easily accessible via the Henry reaction, particularly when R3 ≠ Ar (Scheme 1).6
Scheme 1
a Department of Chemistry, North Caucasus Federal University, 1a Pushkin St., Stavropol 355009, Russian Federation. E-mail: [email protected]; Tel: +7 (918) 743 0255 b Department of Chemistry, University of Kansas, 1251 Wescoe Hall Dr., Lawrence, KS 66045-7582, USA. E-mail: [email protected]; Fax: +1 (785) 864-5396; Tel: +1 (785) 864-5071 † Electronic supplementary information (ESI) available: Experimental procedures, physico-chemical and spectral data. See DOI: 10.1039/c4ob02131b
9786 | Org. Biomol. Chem., 2014, 12, 9786–9788
Scheme 2
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Table 1 Synthesis of 2-quinolones in reaction between 4-nitroketones and hydrazines
Scheme 3
Furthermore, the one-pot transformation required three different temperature regimens, to ensure efficient and complete: (a) indole formation (100–110 °C); (b) electrophilic addition of the nitroalkene and formation of hydroxamic acid 6 (80–85 °C); and (c) transannulation of hydroxamic acid to give 2-quinolone (95–100 °C, Scheme 1). To eliminate these issues, we envisioned that hydroxamic acid 6 could also be accessed alternatively via the Fisher reaction between hydrazines 1 and 4-nitroketones 9, which are, in turn, readily available via conjugate additions (Scheme 3).7 It should be mentioned that the nature of the sacrificial R2-group is not important since, according to the proposed scheme, it will not be incorporated into the structure of target quinolone 6. We reasoned that, among inexpensive groups, phenyl would be most convenient from the practical standpoint, as it would provide solid alkylideneacetophenones 10 and 4-nitroketones 9 (R2 = Ph) that can be easily purified by crystallization. To test this idea, an equimolar mixture of 4-nitro-1,3-diphenylbutan-1-one (9a) and phenylhydrazine (1a) was exposed to 80% PPA at 100–110 °C. We were pleased to find that all anticipated steps of this transformation proceeded uneventfully, affording the corresponding quinolone 7aa in good yield. (Table 1, entry 1). The reaction was found to be quite general and allows for both electron-donating and electron-withdrawing substituents at C3, including aryl and alkyl groups (entries 2–7), as well as C3-unsubstituted quinolones 7ah (R3 = H, entry 6). Possibility for diversification at C6 was also examined on a series of para-substituted aryl 1b–d with 4-nitroketone 9a (entries 7–9). No significant dependence of the product yield on substitution pattern of hydrazine was observed. It should be mentioned that in all tested reactions the corresponding 2-quinolones were obtained cleanly, as sole products.8 In all cases routine extraction followed by a filtration through a short pad of silica gel to remove insoluble byproducts was sufficient to obtain nearly quantitative yields of >95% pure materials. Analytically pure samples were obtained by a simple crystallization,9 and the corresponding yields are reported in Table 1.
This journal is © The Royal Society of Chemistry 2014
Entry
1
R1
9
R3
7
Yielda (%)
1 2 3 4 5 6 7 8 9 10 11
1a 1a 1a 1a 1a 1a 1a 1a 1b 1c 1d
H H H H H H H H Me MeO Cl
9a 9b 9c 9d 9e 9f 9g 9h 9a 9a 9a
Ph 4-MeOC6H5 4-(i-Pr)C6H5 4-FC6H5 3-BrC6H5 3,4-(MeO)2C6H3 n-Pr H Ph Ph Ph
7aa 7ab 7ac 7ad 7ae 7af 7ag 7ah 7ba 7ca 7da
78 64 73 76 76 68 57 67 79 71 75
a
Isolated yields of recrystallized products.
Conclusions We have designed an efficient, modular approach to 2-quinolones unsubstituted at C4, which are not easily available by alternative methods. This synthetic strategy combines Fisher indole synthesis and unusual ANRORC ring expansion, previously discovered in our laboratories. This methodology offers a very simple reaction setup and product isolation routine, and allows for rapid assembly of heterocyclic products from readily available acyclic precursors in excellent yields. This work is supported by the Russian Science Foundation (grant #14-23-00068).
Notes and references 1 A. V. Aksenov, A. N. Smirnov, N. A. Aksenov, I. V. Aksenova, L. V. Frolova, A. Kornienko, I. V. Magedov and M. Rubin, Chem. Commun., 2013, 49, 9305. 2 For recent reviews on biological studies of 2-quinolones, see: (a) C. B. M. Poulie and L. Bunch, ChemMedChem, 2013, 8, 205; (b) S. Heeb, M. P. Fletcher, S. R. Chhabra, S. P. Diggle, P. Williams and M. Camara, FEMS Microbiol. Rev., 2011, 35, 247. 3 For recent examples on medicinal activities of 2-quinolones, see: (a) D. A. Sabbah, N. A. Simms, W. Wang, Y. Dong, E. L. Ezell, M. G. Brattain, J. L. Vennerstrom and H. A. Zhong, Bioorg. Med. Chem., 2012, 20, 7175; (b) N. Kumar, V. P. Raj, B. S. Jayshree, S. S. Kar, A. Anandam, S. Thomas, P. Jain, A. Rai and C. M. Rao, Chem. Biol. Drug Des., 2012, 80, 291; (c) D. Beattie, D. Beer, M. E. Bradley, I. Bruce, S. J. Charlton, B. M. Cuenoud, R. A. Fairhurst, D. Farr, J. R. Fozard, D. Janus, E. M. Rosethorne, D. A. Sandham, D. A. Sykes, A. Trifilieff, K. L. Turner and E. Wissler, Bioorg. Med. Chem.
Org. Biomol. Chem., 2014, 12, 9786–9788 | 9787
View Article Online
Published on 30 October 2014. Downloaded by University of Florida Libraries on 07/12/2016 16:58:03.
Communication
Lett., 2012, 22, 6280; (d) A. Doléans-Jordheim, J. B. Veron, O. Fendrich, E. Bergeron, A. Montagut-Romans, Y. S. Wong, B. Furdui, J. Freney, C. Dumontet and A. Boumendjel, ChemMedChem, 2013, 8, 652; (e) S. E. Wolkenberg, Z. Zhao, C. Thut, J. W. Maxwell, T. P. McDonald, F. Kinose, M. Reilly, C. W. Lindsley and G. D. Hartman, J. Med. Chem., 2011, 54, 2351; (f ) P. V. Chaturvedula, S. E. Mercer, S. S. Pin, G. Thalody, C. Xu, C. M. Conway, D. Keavy, L. Signor, G. H. Cantor, N. Mathias, P. Moench, R. Denton, R. Macci, R. Schartman, V. Whiterock, C. Davis, J. E. Macor and G. M. Dubowchik, Bioorg. Med. Chem. Lett., 2013, 23, 3157; (g) B. Joseph, F. Darro, A. Behard, B. Lesur, F. Collignon, C. Decaestecker, A. Frydman, G. Guillaumet and R. J. Kiss, J. Med. Chem., 2002, 45, 2543. 4 For examples on medicinal activities of hydroxamic acids, see: (a) K. KrennHrubec, B. L. Marshall, M. Hedgin, E. Verdin and S. M. Ulrich, Bioorg. Med. Chem. Lett., 2007, 17, 2874; (b) P. Tessier, D. V. Smil, A. Wanhab, S. Leit, J. Rahil, Z. Li, R. Deziel and J. M. Besterman, Bioorg. Med. Chem. Lett., 2009, 19, 5684.
9788 | Org. Biomol. Chem., 2014, 12, 9786–9788
Organic & Biomolecular Chemistry
5 For alkylation of arenes with nitrostyrenes to form hydroxamic acids see: A. D. Grebenyuk and A. K. Tashmukhamedova, Chem. Heterocycl. Compd., 2006, 42, 732. 6 (a) C. Palomo, M. Oiarbide and A. Laso, Eur. J. Org. Chem., 2007, 2561; (b) F. A. Luzzio, Tetrahedron, 2001, 57, 915. 7 See, for example: (a) D. Wu and D. F. O’Shea, Org. Lett., 2013, 15, 3392; (b) L. P. Jameson and S. V. Dzyuba, Bioorg. Med. Chem. Lett., 2013, 23, 1732; (c) M. J. Hall, S. O. McDonnell, J. Killoran and D. F. O’Shea, J. Org. Chem., 2005, 70, 5571. 8 General procedure: The mixture of arylhydrazine 1 (1.0 mmol), 4-nitroketone 9 (1.0 mmol) and 80% PPA (2–3 g) was stirred at 100–110 °C for 1.5 h. When TLC analysis indicated complete conversion, the mixture was cooled to room temperature, poured into cold water (50 ml) and neutralized by aqueous ammonia. Product 7 was extracted with chloroform (2 × 20 mL) and filtered through a short pad of Silica gel. The solvent was removed in vacuum and the crude product was purified by recrystallization. 9 See ESI† for details.
This journal is © The Royal Society of Chemistry 2014
Published on 30 October 2014. Downloaded by University of Florida Libraries on 07/12/2016 16:58:03.
COMMUNICATION
Cite this: Org. Biomol. Chem., 2014, 12, 9786 Received 6th October 2014, Accepted 23rd October 2014
View Journal | View Issue
Highly efficient modular metal-free synthesis of 3-substituted 2-quinolones† Alexander V. Aksenov,*a Alexander N. Smirnov,a Nicolai A. Aksenov,a Inna V. Aksenova,a Asiyat S. Bijievaa and Michael Rubin*a,b
DOI: 10.1039/c4ob02131b www.rsc.org/obc
A modular approach to 3-substituted 2-quinolones via a cascade annulation reaction between 4-nitroketones and hydrazines has been developed.
We have recently communicated a novel metal-free transannulation reaction of 2-substituted indoles 3 with nitroalkenes 4 to produce 3-substituted 2-quinolones in polyphosphoric acid (Scheme 1).1 This reaction was also shown to proceed efficiently in one pot with the Fisher indole synthesis, starting from
readily available hydrazines 1 (Scheme 1). The mechanism of this cascade transformation involves electrophilic substitution at C-3 of indole triggered by addition of nitroalkene 4. The resulting isolable intermediate, hydroxamic acid 6 undergoes 5 → 6 ANRORC-type ring expansion with simultaneous extrusion of carboxamide 8, to afford 2-quinolone 7 (Scheme 2).1 The modular nature of this chemistry and rich biological profile of the products2–4 stimulated us to search for alternate precursors, which could offer practical advantages for rapid synthesis of 2-quinolone libraries. Thus, in the original protocol, the key intermediate 6 was derived from the corresponding nitroalkenes 4,5 which are not always easily accessible via the Henry reaction, particularly when R3 ≠ Ar (Scheme 1).6
Scheme 1
a Department of Chemistry, North Caucasus Federal University, 1a Pushkin St., Stavropol 355009, Russian Federation. E-mail: [email protected]; Tel: +7 (918) 743 0255 b Department of Chemistry, University of Kansas, 1251 Wescoe Hall Dr., Lawrence, KS 66045-7582, USA. E-mail: [email protected]; Fax: +1 (785) 864-5396; Tel: +1 (785) 864-5071 † Electronic supplementary information (ESI) available: Experimental procedures, physico-chemical and spectral data. See DOI: 10.1039/c4ob02131b
9786 | Org. Biomol. Chem., 2014, 12, 9786–9788
Scheme 2
This journal is © The Royal Society of Chemistry 2014
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Table 1 Synthesis of 2-quinolones in reaction between 4-nitroketones and hydrazines
Scheme 3
Furthermore, the one-pot transformation required three different temperature regimens, to ensure efficient and complete: (a) indole formation (100–110 °C); (b) electrophilic addition of the nitroalkene and formation of hydroxamic acid 6 (80–85 °C); and (c) transannulation of hydroxamic acid to give 2-quinolone (95–100 °C, Scheme 1). To eliminate these issues, we envisioned that hydroxamic acid 6 could also be accessed alternatively via the Fisher reaction between hydrazines 1 and 4-nitroketones 9, which are, in turn, readily available via conjugate additions (Scheme 3).7 It should be mentioned that the nature of the sacrificial R2-group is not important since, according to the proposed scheme, it will not be incorporated into the structure of target quinolone 6. We reasoned that, among inexpensive groups, phenyl would be most convenient from the practical standpoint, as it would provide solid alkylideneacetophenones 10 and 4-nitroketones 9 (R2 = Ph) that can be easily purified by crystallization. To test this idea, an equimolar mixture of 4-nitro-1,3-diphenylbutan-1-one (9a) and phenylhydrazine (1a) was exposed to 80% PPA at 100–110 °C. We were pleased to find that all anticipated steps of this transformation proceeded uneventfully, affording the corresponding quinolone 7aa in good yield. (Table 1, entry 1). The reaction was found to be quite general and allows for both electron-donating and electron-withdrawing substituents at C3, including aryl and alkyl groups (entries 2–7), as well as C3-unsubstituted quinolones 7ah (R3 = H, entry 6). Possibility for diversification at C6 was also examined on a series of para-substituted aryl 1b–d with 4-nitroketone 9a (entries 7–9). No significant dependence of the product yield on substitution pattern of hydrazine was observed. It should be mentioned that in all tested reactions the corresponding 2-quinolones were obtained cleanly, as sole products.8 In all cases routine extraction followed by a filtration through a short pad of silica gel to remove insoluble byproducts was sufficient to obtain nearly quantitative yields of >95% pure materials. Analytically pure samples were obtained by a simple crystallization,9 and the corresponding yields are reported in Table 1.
This journal is © The Royal Society of Chemistry 2014
Entry
1
R1
9
R3
7
Yielda (%)
1 2 3 4 5 6 7 8 9 10 11
1a 1a 1a 1a 1a 1a 1a 1a 1b 1c 1d
H H H H H H H H Me MeO Cl
9a 9b 9c 9d 9e 9f 9g 9h 9a 9a 9a
Ph 4-MeOC6H5 4-(i-Pr)C6H5 4-FC6H5 3-BrC6H5 3,4-(MeO)2C6H3 n-Pr H Ph Ph Ph
7aa 7ab 7ac 7ad 7ae 7af 7ag 7ah 7ba 7ca 7da
78 64 73 76 76 68 57 67 79 71 75
a
Isolated yields of recrystallized products.
Conclusions We have designed an efficient, modular approach to 2-quinolones unsubstituted at C4, which are not easily available by alternative methods. This synthetic strategy combines Fisher indole synthesis and unusual ANRORC ring expansion, previously discovered in our laboratories. This methodology offers a very simple reaction setup and product isolation routine, and allows for rapid assembly of heterocyclic products from readily available acyclic precursors in excellent yields. This work is supported by the Russian Science Foundation (grant #14-23-00068).
Notes and references 1 A. V. Aksenov, A. N. Smirnov, N. A. Aksenov, I. V. Aksenova, L. V. Frolova, A. Kornienko, I. V. Magedov and M. Rubin, Chem. Commun., 2013, 49, 9305. 2 For recent reviews on biological studies of 2-quinolones, see: (a) C. B. M. Poulie and L. Bunch, ChemMedChem, 2013, 8, 205; (b) S. Heeb, M. P. Fletcher, S. R. Chhabra, S. P. Diggle, P. Williams and M. Camara, FEMS Microbiol. Rev., 2011, 35, 247. 3 For recent examples on medicinal activities of 2-quinolones, see: (a) D. A. Sabbah, N. A. Simms, W. Wang, Y. Dong, E. L. Ezell, M. G. Brattain, J. L. Vennerstrom and H. A. Zhong, Bioorg. Med. Chem., 2012, 20, 7175; (b) N. Kumar, V. P. Raj, B. S. Jayshree, S. S. Kar, A. Anandam, S. Thomas, P. Jain, A. Rai and C. M. Rao, Chem. Biol. Drug Des., 2012, 80, 291; (c) D. Beattie, D. Beer, M. E. Bradley, I. Bruce, S. J. Charlton, B. M. Cuenoud, R. A. Fairhurst, D. Farr, J. R. Fozard, D. Janus, E. M. Rosethorne, D. A. Sandham, D. A. Sykes, A. Trifilieff, K. L. Turner and E. Wissler, Bioorg. Med. Chem.
Org. Biomol. Chem., 2014, 12, 9786–9788 | 9787
View Article Online
Published on 30 October 2014. Downloaded by University of Florida Libraries on 07/12/2016 16:58:03.
Communication
Lett., 2012, 22, 6280; (d) A. Doléans-Jordheim, J. B. Veron, O. Fendrich, E. Bergeron, A. Montagut-Romans, Y. S. Wong, B. Furdui, J. Freney, C. Dumontet and A. Boumendjel, ChemMedChem, 2013, 8, 652; (e) S. E. Wolkenberg, Z. Zhao, C. Thut, J. W. Maxwell, T. P. McDonald, F. Kinose, M. Reilly, C. W. Lindsley and G. D. Hartman, J. Med. Chem., 2011, 54, 2351; (f ) P. V. Chaturvedula, S. E. Mercer, S. S. Pin, G. Thalody, C. Xu, C. M. Conway, D. Keavy, L. Signor, G. H. Cantor, N. Mathias, P. Moench, R. Denton, R. Macci, R. Schartman, V. Whiterock, C. Davis, J. E. Macor and G. M. Dubowchik, Bioorg. Med. Chem. Lett., 2013, 23, 3157; (g) B. Joseph, F. Darro, A. Behard, B. Lesur, F. Collignon, C. Decaestecker, A. Frydman, G. Guillaumet and R. J. Kiss, J. Med. Chem., 2002, 45, 2543. 4 For examples on medicinal activities of hydroxamic acids, see: (a) K. KrennHrubec, B. L. Marshall, M. Hedgin, E. Verdin and S. M. Ulrich, Bioorg. Med. Chem. Lett., 2007, 17, 2874; (b) P. Tessier, D. V. Smil, A. Wanhab, S. Leit, J. Rahil, Z. Li, R. Deziel and J. M. Besterman, Bioorg. Med. Chem. Lett., 2009, 19, 5684.
9788 | Org. Biomol. Chem., 2014, 12, 9786–9788
Organic & Biomolecular Chemistry
5 For alkylation of arenes with nitrostyrenes to form hydroxamic acids see: A. D. Grebenyuk and A. K. Tashmukhamedova, Chem. Heterocycl. Compd., 2006, 42, 732. 6 (a) C. Palomo, M. Oiarbide and A. Laso, Eur. J. Org. Chem., 2007, 2561; (b) F. A. Luzzio, Tetrahedron, 2001, 57, 915. 7 See, for example: (a) D. Wu and D. F. O’Shea, Org. Lett., 2013, 15, 3392; (b) L. P. Jameson and S. V. Dzyuba, Bioorg. Med. Chem. Lett., 2013, 23, 1732; (c) M. J. Hall, S. O. McDonnell, J. Killoran and D. F. O’Shea, J. Org. Chem., 2005, 70, 5571. 8 General procedure: The mixture of arylhydrazine 1 (1.0 mmol), 4-nitroketone 9 (1.0 mmol) and 80% PPA (2–3 g) was stirred at 100–110 °C for 1.5 h. When TLC analysis indicated complete conversion, the mixture was cooled to room temperature, poured into cold water (50 ml) and neutralized by aqueous ammonia. Product 7 was extracted with chloroform (2 × 20 mL) and filtered through a short pad of Silica gel. The solvent was removed in vacuum and the crude product was purified by recrystallization. 9 See ESI† for details.
This journal is © The Royal Society of Chemistry 2014
