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Mild and efficient organocatalytic method for the synthesis of flavones
Tetrahedron Letters 57 (2016) 3841–3843
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Mild and efficient organocatalytic method for the synthesis of flavones Filip Stanek, Maciej Stodulski ⇑ Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
a r t i c l e
i n f o
Article history: Received 17 May 2016 Revised 29 June 2016 Accepted 12 July 2016 Available online 16 July 2016
a b s t r a c t A convenient and efficient organocatalytic procedure for the selective cyclization of 1,3-diketones to give aromatic substituted 4H-chromen-4-ones under mild reaction conditions using N-triflyl phosphoramide is described. Application of the described conditions is presented in a formal synthesis of (S)-flavanone. Ó 2016 Elsevier Ltd. All rights reserved.
Keywords: Brønsted acid Chromone Flavone N-Triflyl amide Organocatalysis
Flavonoids are plant metabolites that constitute a broad range of natural products (Fig. 1).1 In Nature flavonoids play many important roles e.g., plant pigmentation, UV filtration, symbiotic nitrogen fixation, floral pigmentation, and various physiological regulations.2 Moreover, these compounds exhibit a broad range of pharmacological activities including anticancer, antibacterial, antiviral, antioxidant, antiinflammatory, antiallergic, and estrogenic, or antiestrogenic properties.3 As a consequence of these physiological activities, significant efforts have been devoted to their isolation from plants and synthesis in the laboratory.4 The chromone ring (4H-chromen-4-one) constitutes a core subunit of flavones; therefore a broad range of studies have been related to the synthesis of novel, more diverse and complex bioactive chromone derivatives and the development of mild synthetic methods that can be applied to the synthesis of chromone derivatives.5 Various derivatives have been characterized as potent anticancer agents e.g., flavopirydol 4,6 or flavone-8-acetic acid 6.7 Cromolyn 5, and flavoxate 1 were already introduced for medicinal use (Fig. 1).8,9 The synthesis of the chromone skeleton and flavones possessing substituents at the C2 position are broadly described in the literature. The main synthetic routes relate to the use of ortho-hydroxyarylketones through the Claisen, Baker-Venkataraman or Kostanecki-Robinson cyclizations, benzopyrylium salts or the Vilsmeier–Haack reaction.5 Other methods have also been developed
⇑ Corresponding author. Tel.: +48 (22) 343 2130; fax: +48 (22) 632 6681. E-mail address: [email protected] (M. Stodulski). http://dx.doi.org/10.1016/j.tetlet.2016.07.042 0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
and are widely described.5 Historically, the most common method for chromone preparation involves the Baker-Venkataraman rearrangement and is related to the cyclization of 1-(o-hydroxyphenyl)-1,3-diketones in the presence of strong acids, anhydrides or bases.10 Other reagents have also been developed, e.g., CoIII(ligand)OH,11 FeCl3,12 Br2/CHCl3,13 or ionic liquids.14 Unfortunately, most of these methods require harsh reaction conditions, high temperatures, or stoichiometric use of reagents or metal catalysts. Despite the various methods reported, the efficient synthesis of chromone derivatives with aromatic substituents at the C2 position under mild and metal-free reaction conditions using the Baker-Venkataraman rearrangement is limited. As part of our efforts to develop a more practical catalytic system for the intramolecular cyclization of aromatic 1-(o-hydroxyphenyl)-1,3 diketones to give chromones as a method to access the flavone skeleton under mild and metal-free conditions; herein, we present novel reaction conditions that facilitate cyclization using catalytic N-triflyl phosphoramide. With the goal to develop mild, organocatalytic conditions, we developed a synthetic route utilizing aromatic diketones 8 as starting materials, which were easily prepared according to literature protocols11 (Scheme 1). We began our study by testing various Brønsted acids with the model substrate 8 (Table 1). We observed that treatment of compound 8 with p-TsOH or diphenyl phosphate (DPP) led to the formation of chromone 10a in 15% and 25%, respectively (Entries 3 and 4). It was noted, that the model reaction without catalyst gave no product (Entries 1 and 2). However, reaction with N-triflyl phos-
3842
F. Stanek, M. Stodulski / Tetrahedron Letters 57 (2016) 3841–3843
O
OH
O
OH
O
OH O CO2 R
HO
OH
O
HO
O
OH
1 Flavoxate
OH
O glucose
OH
2 Quercetin
3 Kampferol-3- O-glucoside
O
O O
O
O
OH HO HO
H
O
O HO2C
Cl
O
O
CO2H
CO2 H
N 4 Flavopirydol
5 Cromolyn
6 Flavone-8-acetic acid
Figure 1. Representative examples of natural and synthetic products containing the chromone framework.
O
1. ArCO 2H, DCC, DCM, DMAP, R 2 rt, 24 h
OH
1
R
7
O
2. tBuONa, DMF, rt, 1 h R1 42-68% yield
R OH 8
O PhO O F P F PhO HN S F O 9
O 2
Ar
O R2
Ar = Ph, 4-MePh, 4-OMePh, O Ar 1 4-ClPh, 4-CF 3Ph, 1-Naphthyl R 10 1 R = Cl, Br, OMe up to 89% yield R2 = H, Me, CH 2Ph
Scheme 1. Synthesis of ring substituted flavones.
Table 1 Optimization of the reaction conditionsa
O
O
O Cat., solvent, 40 °C sealed tube
O
OH 8
a
10a
Entry
Cat.
Solvent
Temp. (°C)
Yield (%)
1 2 3 4 5 6 7 8 9 10 11
— — p-TsOH (20 mol %) DPP (20 mol %) 9 (20 mol %) 9 (20 mol %) 9 (20 mol %) 9 (20 mol %) 9 (20 mol %) 9 (20 mol %) 9 (20 mol %)
DCM DCM DCM DCM DCM THF Dioxane Toluene MeCN AcOEt MeOH
rt 40 40 40 40 40 40 40 40 40 40
0 0 15 25 76 13 16 18 67 22 85
To examine the scope of the methodology, various starting materials (Table 2, entries 1–16) were used. This revealed that a broad spectrum of substrates containing electron donating or electron withdrawing groups can be used. Substituents in the metaposition or more sterically demanding groups such as 1-naphthylwere successful in this transformation. The reactivity of 8 was slightly dependent on the substituent in the para-position of the aromatic ring. Strongly electron withdrawing groups such as CF3 led to lower yields than other functional groups. Cyclization of
Table 2 Substrate scope
R5
R OH
R3
R5
O 6
R1
conditions a
R6
R3
O R2
R 8
a
O
R4
2
8 0.20 mmol, solvent (2 mL), 16 h, isolated yields; DPP: diphenyl phosphate.
phoramide afforded the desired flavone in 76% yield (Entry 5). These results were strongly correlated with the pKa of the Brønsted acids, where the stronger acid gave higher yields. Further optimization and solvent screening revealed that the best results were obtained in methanol using 5 mol % catalyst. In this case chromone 10a was obtained in 85% yield. Polar protic solvents favor formation of the chromone scaffold due to solvatation and stabilization of the forming ions. These experiments showed that N-triflyl phosphoroamide 9 actively promoted the cyclization reaction and constitutes an excellent alternative to known methods which give poor results in the case of aromatic substituted diketones. Moreover, it should be stressed that the reaction conditions are much milder than known acidic procedures where heating in a mixture of concentrated AcOH/HCl is required.10
O
R4
R1
10a-j
Entry
Product 10
R1
R2
R3
R4
R5
R6
Yield (%)
1 2 3 4 5 6 7 8 9 10 11 12 13
a b c d e f g h i j k l m
H H H H H H H H H H H H H
H H H H H H H H Me Cl H MeO MeO
H H H H H H H Me H H Br H H
H H H H H H H H H H H MeO MeO
H H H H H H H H H H H H H
85 86 86 79 77 89 68 67 79 71 60 61 55
14 15 16
n o p
Ph 4-ClPh 3-ClPh 1-Naphtyl 3-MeOPh 4-MeOPh 4-CF3Ph Ph Ph Ph Ph Ph 3,4MeOPh Ph Ph Ph
H H H
H H H
H H Br
H H H
Me CH2Ph Me
20 16 8
8 0.20 mmol, 9 (20 mol%), MeOH (2 mL), 40 °C, 16 h, sealed tube, isolated yields.
F. Stanek, M. Stodulski / Tetrahedron Letters 57 (2016) 3841–3843 Table 3 Comparison to literature methods
References and notes
Entry
Conditions
Yield of 10a (%)
Ref.
1 2 3 4 5 6 7 8
N-Tf-phosphoroamide (5 mol %), 40 °C AcOH/H2SO4, 100 °C KHSO4, 120 °C Gallium(III) triflate, MeCN, 80 °C CuBr2, CHCl3, AcOEt, reflux CuCl2, EtOH, 80 °C, MW Co(III)salen(OH), 60 °C [EtNH3]NO3, MW
85 76 98 97 79 98 94 81
10a 10o 10p 10q 10r 11 14
O
O ref. 15 O
3843
O 89% 78% ee
Scheme 2. Formal synthesis of (S)-flavone.
diketones 8 containing additional substituents (methyl and benzyl) on the methylene group between the two ketones were also investigated (Entries 14–16). Unfortunately, in these cases the desired chromones were only obtained in 8–20% yield. In comparison to other reports in the literature for the construction of related chromone derivatives using the Baker-Venkataraman rearrangement, the proposed procedure can be considered as particularly convenient in terms of mild, organocatalytic reaction conditions and efficiency for the synthesis of chromones 10 containing aromatic substituents (Table 3). Moreover, the presented protocol can be applied to the formal synthesis of (S)-flavone, which has been described by Glorious and co-workers (Scheme 2).15 This sequence involves stereoselective reduction of the double bond and oxidation of the hydroxyl group. Additional functionalization of the double bond in the aposition to the carbonyl group also can be applied to the synthesis of various oxygen-substituted flavone analogues.5 In conclusion, we report an efficient approach for the organocatalytic dehydrative cyclization of 1,3-diaryl diketones to give a variety of substituted flavones. The simple and straightforward cyclization can be performed under mild, metal-free, moisture, and air tolerant conditions. Taking into account the mild conditions and simple steps that do not require special preparative procedures, the presented methodology offers advantages over literature procedures. In most cases the flavones containing aromatic substituents were obtained in good yields in the presence of catalytic N-triflyl phosphoramide. Acknowledgment The authors gratefully acknowledge financial support from the Polish National Science Centre (DEC-2012/07/D/ST5/02313). Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.07. 042.
1. (a) McNaught, A. D.; Wilkinson, A. IUPAC. Compendium of Chemical Terminology, 2nd ed. (the ‘Gold Book’); Wiley Blackwell; 2nd Revised edition edition.; (b) Grotewold, E. The Science of Flavonoids; Springer Science + Business Media: New York, 2006. 2. Galeotti, F.; Barile, E.; Curir, P.; Dolci, M.; Lanzotti, V. Phytochem. Lett. 2008, 1, 44. 3. (a) Hollman, P. C. H.; Hertog, M. G. L.; Katan, M. B. Biochem. Soc. Trans. 1996, 24, 785; (b) Rice-Evans, C. A.; Miller, N. J. Biochem. Soc. Trans. 1996, 24, 790; (c) Manthey, J. A.; Guthrie, N.; Grohmann, K. Curr. Med. Chem. 2001, 8, 135; (d) Prasad, S.; Phromnoi, K.; Yadav, V. R.; Chaturvedi, M. M.; Aggarwal, B. B. Planta Med. 2010, 76, 1044. 4. (a) Tanaka, K.; Sugino, T. Green Chem. 2001, 3, 133; (b) Saravanamurugan, S.; Palanichamy, M.; Arabindoo, B.; Murugesan, V. J. Mol. Catal. A: Chem. 2004, 218, 101; (c) Marais, J. P. J.; Ferreira, D.; Slade, D. Phytochemistry 2005, 66, 2145; (d) Nibbs, A. E.; Scheidt, K. A. Eur. J. Org. Chem. 2012, 2012, 449. 5. (a) Gaspar, A.; Matos, M. J.; Garrido, J.; Uriarte, E.; Borges, F. Chem. Rev. 2014, 114, 4960; (b) Keri, R. S.; Budagumpi, S.; Pai, R. K.; Balakrishna, R. G. Eur. J. Med. Chem. 2014, 78, 340. 6. (a) Bible, K. C.; Kaufmann, S. H. Cancer Res. 1996, 56, 4856; (b) Thomas, J. P.; Tutsch, K. D.; Cleary, J. F.; Bailey, H. H.; Arzoomanian, R.; Alberti, D.; Simon, K.; Feierabend, C.; Binger, K.; Marnocha, R.; Dresen, A.; Wilding, G. Cancer Chemother. Pharm. 2002, 50, 465; (c) Aklilu, M.; Kindler, H. L.; Donehower, R. C.; Mani, S.; Vokes, E. E. Ann. Oncol. 2003, 14, 1270; (d) Hida, T.; Tamiya, M.; Nishio, M.; Yamamoto, N.; Hirashima, T.; Horai, T.; Tanii, H.; Shi, M. M.; Kobayashi, K.; Horio, Y. Cancer Sci. 2011, 102, 845. 7. (a) Kerr, D. J.; Maughan, T.; Newlands, E.; Rustin, G.; Bleehen, N. M.; Lewis, C.; Kaye, S. B. Br. J. Cancer 1989, 60, 104; (b) Bauvois, B.; Puiffe, M. L.; Bongui, J. B.; Paillat, S.; Monneret, C.; Dauzonne, D. J. Med. Chem. 2003, 46, 3900; (c) Gobbi, S.; Rampa, A.; Bisi, A.; Belluti, F.; Piazzi, L.; Valenti, P.; Caputo, A.; Zampiron, A.; Carrara, M. J. Med. Chem. 2003, 46, 3662. 8. (a) Miyatake, A.; Fujita, M.; Nagasaka, Y.; Fujita, K.; Tamari, M.; Watanabe, D.; Nakano, N.; Hidari, K. I.; Suzuki, Y. Allergol. Int. 2007, 56, 231; (b) Anderson, S. D.; Brannan, J. D.; Perry, C. P.; Caillaud, C.; Seale, P. J. Asthma 2010, 47, 429; (c) Yang, Y. H.; Lu, J. Y. L.; Wu, X. S.; Summer, S.; Whoriskey, J.; Saris, C.; Reagan, J. D. Pharmacology 2010, 86, 1. 9. (a) Bradley, D. V.; Cazort, R. J. Clin. Pharmacol. J. New Drugs 1970, 10, 65; (b) Chapple, C. R.; Parkhouse, H.; Gardener, C.; Milroy, E. J. G. Br. J. Urol. 1990, 66, 491; (c) Fehrmann-Zumpe, P.; Karbe, K.; Blessman, G. Int. Urogynecol. J. Pelvic Floor Dysfunct. 1999, 10, 91. 10. (a) Banerji, A.; Goomer, N. C. Synthesis 1980, 874; (b) Hoshino, Y.; Takeno, N. Bull. Chem. Soc. Jpn. 1987, 60, 1919; (c) Verma, R. S.; Saini, R. K.; Kumar, D. J. Chem. Res. 1998, 348; (d) Kumar, P. E.; Prashad, K. J. R.; Indian, J. Med. Chem. 1999, 1277; (e) Jung, J.-C.; Min, J.-P.; Park, O.-S. Synth. Commun. 2001, 31, 1837; (f) Tsukayama, M.; Kawamura, Y.; Ishizuka, T.; Hayashi, S.; Torii, F. Heterocycles 2003, 60, 2775; (g) Kucukislamoglu, M.; Nebioglu, M.; Zengin, M.; Arslan, M.; Yayli, N. J. Chem. Res. 2005, 556; (h) Ullah Mughal, E.; Ayaz, M.; Hussain, Z.; Hasan, A.; Sadiq, A.; Riaz, M.; Malik, A.; Hussain, S.; Choudhary, M. I. Bioorg. Med. Chem. 2006, 14, 4704; (i) Pathak, V. N.; Varshney, B.; Gupta, R. J. Heterocycl. Chem. 2008, 45, 589; (j) Stubbing, L. A.; Li, F. F.; Furkert, D. P.; Caprio, V. E.; Brimble, M. A. Tetrahedron 2012, 68, 6948; (k) Gray, C. A.; Kaye, P. T.; Nchinda, A. T. J. Nat. Prod. 2003, 66, 1144; (l) Irgashev, R. A.; Sosnovskikh, V. Y.; Kalinovich, N.; Kazakova, O.; Röschenthaler, G.-V. Tetrahedron Lett. 2009, 50, 4903; (m) Li, N.-G.; Shi, Z.-H.; Tang, Y.-P.; Ma, H.-Y.; Yang, J.-P.; Li, B.-Q.; Wang, Z.-J.; Song, S.-L.; Duan, J.-A. J. Heterocycl. Chem. 2010, 47, 785; (n) Chen, Y.; Liu, H. R.; Liu, H. S.; Cheng, M.; Xia, P.; Qian, K.; Wu, P. C.; Lai, C. Y.; Xia, Y.; Yang, Z. Y.; Morris-Natschke, S. L.; Lee, K. H. Eur. J. Med. Chem. 2012, 49, 74; (o) Pérez, M.; Ruiz, D.; Autino, J.; Sathicq, A.; Romanelli, G. C. R. Chim. 2016, 19, 551; (p) Jin, C.; He, F.; Wu, H.; Chen, J.; Su, W. J. Chem. Res. 2009, 27; (q) Miyake, H.; Nishino, S.; Nishimura, A.; Sasaki, M. Chem. Lett. 2007, 36, 522; (r) Kabalka, G. W.; Mereddy, A. R. Tetrahedron Lett. 2005, 46, 6315. 11. Nishinaga, A.; Ando, H.; Maruyama, K.; Mashino, T. Synthesis 1992, 839. 12. Zubaidha, P. K.; Hashmi, A. M.; Bhosale, R. S. Heterocycl. Commun. 2005, 11, 97. 13. (a) Garg, S.; Ishar, M. P. S.; Sarin, R.; Gandhi, R. P. Ind. J. Chem., Sect. B 1994, 1123; (b) Silva, A. M.; Santos, C. M.; Cavaleiro, J. A. Synlett 2005, 3095. 14. (a) Bhosale, R. S.; Sarda, S. R.; Giram, R. P.; Raut, D. S.; Parwe, S. P.; Ardhapure, S. S.; Pawar, R. P. J. Iran. Chem. Soc. 2005, 6, 519; (b) Bhosale, R. S.; Sarda, S. R.; Giram, R. P.; Raut, D. S.; Parwe, S. P.; Ardhapure, S. S.; Pawar, R. P. J. Iran. Chem. Soc. 2009, 6, 519. 15. Zhao, D.; Beiring, B.; Glorius, F. Angew. Chem., Int. Ed. 2013, 52, 8454.
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Mild and efficient organocatalytic method for the synthesis of flavones Filip Stanek, Maciej Stodulski ⇑ Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
a r t i c l e
i n f o
Article history: Received 17 May 2016 Revised 29 June 2016 Accepted 12 July 2016 Available online 16 July 2016
a b s t r a c t A convenient and efficient organocatalytic procedure for the selective cyclization of 1,3-diketones to give aromatic substituted 4H-chromen-4-ones under mild reaction conditions using N-triflyl phosphoramide is described. Application of the described conditions is presented in a formal synthesis of (S)-flavanone. Ó 2016 Elsevier Ltd. All rights reserved.
Keywords: Brønsted acid Chromone Flavone N-Triflyl amide Organocatalysis
Flavonoids are plant metabolites that constitute a broad range of natural products (Fig. 1).1 In Nature flavonoids play many important roles e.g., plant pigmentation, UV filtration, symbiotic nitrogen fixation, floral pigmentation, and various physiological regulations.2 Moreover, these compounds exhibit a broad range of pharmacological activities including anticancer, antibacterial, antiviral, antioxidant, antiinflammatory, antiallergic, and estrogenic, or antiestrogenic properties.3 As a consequence of these physiological activities, significant efforts have been devoted to their isolation from plants and synthesis in the laboratory.4 The chromone ring (4H-chromen-4-one) constitutes a core subunit of flavones; therefore a broad range of studies have been related to the synthesis of novel, more diverse and complex bioactive chromone derivatives and the development of mild synthetic methods that can be applied to the synthesis of chromone derivatives.5 Various derivatives have been characterized as potent anticancer agents e.g., flavopirydol 4,6 or flavone-8-acetic acid 6.7 Cromolyn 5, and flavoxate 1 were already introduced for medicinal use (Fig. 1).8,9 The synthesis of the chromone skeleton and flavones possessing substituents at the C2 position are broadly described in the literature. The main synthetic routes relate to the use of ortho-hydroxyarylketones through the Claisen, Baker-Venkataraman or Kostanecki-Robinson cyclizations, benzopyrylium salts or the Vilsmeier–Haack reaction.5 Other methods have also been developed
⇑ Corresponding author. Tel.: +48 (22) 343 2130; fax: +48 (22) 632 6681. E-mail address: [email protected] (M. Stodulski). http://dx.doi.org/10.1016/j.tetlet.2016.07.042 0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
and are widely described.5 Historically, the most common method for chromone preparation involves the Baker-Venkataraman rearrangement and is related to the cyclization of 1-(o-hydroxyphenyl)-1,3-diketones in the presence of strong acids, anhydrides or bases.10 Other reagents have also been developed, e.g., CoIII(ligand)OH,11 FeCl3,12 Br2/CHCl3,13 or ionic liquids.14 Unfortunately, most of these methods require harsh reaction conditions, high temperatures, or stoichiometric use of reagents or metal catalysts. Despite the various methods reported, the efficient synthesis of chromone derivatives with aromatic substituents at the C2 position under mild and metal-free reaction conditions using the Baker-Venkataraman rearrangement is limited. As part of our efforts to develop a more practical catalytic system for the intramolecular cyclization of aromatic 1-(o-hydroxyphenyl)-1,3 diketones to give chromones as a method to access the flavone skeleton under mild and metal-free conditions; herein, we present novel reaction conditions that facilitate cyclization using catalytic N-triflyl phosphoramide. With the goal to develop mild, organocatalytic conditions, we developed a synthetic route utilizing aromatic diketones 8 as starting materials, which were easily prepared according to literature protocols11 (Scheme 1). We began our study by testing various Brønsted acids with the model substrate 8 (Table 1). We observed that treatment of compound 8 with p-TsOH or diphenyl phosphate (DPP) led to the formation of chromone 10a in 15% and 25%, respectively (Entries 3 and 4). It was noted, that the model reaction without catalyst gave no product (Entries 1 and 2). However, reaction with N-triflyl phos-
3842
F. Stanek, M. Stodulski / Tetrahedron Letters 57 (2016) 3841–3843
O
OH
O
OH
O
OH O CO2 R
HO
OH
O
HO
O
OH
1 Flavoxate
OH
O glucose
OH
2 Quercetin
3 Kampferol-3- O-glucoside
O
O O
O
O
OH HO HO
H
O
O HO2C
Cl
O
O
CO2H
CO2 H
N 4 Flavopirydol
5 Cromolyn
6 Flavone-8-acetic acid
Figure 1. Representative examples of natural and synthetic products containing the chromone framework.
O
1. ArCO 2H, DCC, DCM, DMAP, R 2 rt, 24 h
OH
1
R
7
O
2. tBuONa, DMF, rt, 1 h R1 42-68% yield
R OH 8
O PhO O F P F PhO HN S F O 9
O 2
Ar
O R2
Ar = Ph, 4-MePh, 4-OMePh, O Ar 1 4-ClPh, 4-CF 3Ph, 1-Naphthyl R 10 1 R = Cl, Br, OMe up to 89% yield R2 = H, Me, CH 2Ph
Scheme 1. Synthesis of ring substituted flavones.
Table 1 Optimization of the reaction conditionsa
O
O
O Cat., solvent, 40 °C sealed tube
O
OH 8
a
10a
Entry
Cat.
Solvent
Temp. (°C)
Yield (%)
1 2 3 4 5 6 7 8 9 10 11
— — p-TsOH (20 mol %) DPP (20 mol %) 9 (20 mol %) 9 (20 mol %) 9 (20 mol %) 9 (20 mol %) 9 (20 mol %) 9 (20 mol %) 9 (20 mol %)
DCM DCM DCM DCM DCM THF Dioxane Toluene MeCN AcOEt MeOH
rt 40 40 40 40 40 40 40 40 40 40
0 0 15 25 76 13 16 18 67 22 85
To examine the scope of the methodology, various starting materials (Table 2, entries 1–16) were used. This revealed that a broad spectrum of substrates containing electron donating or electron withdrawing groups can be used. Substituents in the metaposition or more sterically demanding groups such as 1-naphthylwere successful in this transformation. The reactivity of 8 was slightly dependent on the substituent in the para-position of the aromatic ring. Strongly electron withdrawing groups such as CF3 led to lower yields than other functional groups. Cyclization of
Table 2 Substrate scope
R5
R OH
R3
R5
O 6
R1
conditions a
R6
R3
O R2
R 8
a
O
R4
2
8 0.20 mmol, solvent (2 mL), 16 h, isolated yields; DPP: diphenyl phosphate.
phoramide afforded the desired flavone in 76% yield (Entry 5). These results were strongly correlated with the pKa of the Brønsted acids, where the stronger acid gave higher yields. Further optimization and solvent screening revealed that the best results were obtained in methanol using 5 mol % catalyst. In this case chromone 10a was obtained in 85% yield. Polar protic solvents favor formation of the chromone scaffold due to solvatation and stabilization of the forming ions. These experiments showed that N-triflyl phosphoroamide 9 actively promoted the cyclization reaction and constitutes an excellent alternative to known methods which give poor results in the case of aromatic substituted diketones. Moreover, it should be stressed that the reaction conditions are much milder than known acidic procedures where heating in a mixture of concentrated AcOH/HCl is required.10
O
R4
R1
10a-j
Entry
Product 10
R1
R2
R3
R4
R5
R6
Yield (%)
1 2 3 4 5 6 7 8 9 10 11 12 13
a b c d e f g h i j k l m
H H H H H H H H H H H H H
H H H H H H H H Me Cl H MeO MeO
H H H H H H H Me H H Br H H
H H H H H H H H H H H MeO MeO
H H H H H H H H H H H H H
85 86 86 79 77 89 68 67 79 71 60 61 55
14 15 16
n o p
Ph 4-ClPh 3-ClPh 1-Naphtyl 3-MeOPh 4-MeOPh 4-CF3Ph Ph Ph Ph Ph Ph 3,4MeOPh Ph Ph Ph
H H H
H H H
H H Br
H H H
Me CH2Ph Me
20 16 8
8 0.20 mmol, 9 (20 mol%), MeOH (2 mL), 40 °C, 16 h, sealed tube, isolated yields.
F. Stanek, M. Stodulski / Tetrahedron Letters 57 (2016) 3841–3843 Table 3 Comparison to literature methods
References and notes
Entry
Conditions
Yield of 10a (%)
Ref.
1 2 3 4 5 6 7 8
N-Tf-phosphoroamide (5 mol %), 40 °C AcOH/H2SO4, 100 °C KHSO4, 120 °C Gallium(III) triflate, MeCN, 80 °C CuBr2, CHCl3, AcOEt, reflux CuCl2, EtOH, 80 °C, MW Co(III)salen(OH), 60 °C [EtNH3]NO3, MW
85 76 98 97 79 98 94 81
10a 10o 10p 10q 10r 11 14
O
O ref. 15 O
3843
O 89% 78% ee
Scheme 2. Formal synthesis of (S)-flavone.
diketones 8 containing additional substituents (methyl and benzyl) on the methylene group between the two ketones were also investigated (Entries 14–16). Unfortunately, in these cases the desired chromones were only obtained in 8–20% yield. In comparison to other reports in the literature for the construction of related chromone derivatives using the Baker-Venkataraman rearrangement, the proposed procedure can be considered as particularly convenient in terms of mild, organocatalytic reaction conditions and efficiency for the synthesis of chromones 10 containing aromatic substituents (Table 3). Moreover, the presented protocol can be applied to the formal synthesis of (S)-flavone, which has been described by Glorious and co-workers (Scheme 2).15 This sequence involves stereoselective reduction of the double bond and oxidation of the hydroxyl group. Additional functionalization of the double bond in the aposition to the carbonyl group also can be applied to the synthesis of various oxygen-substituted flavone analogues.5 In conclusion, we report an efficient approach for the organocatalytic dehydrative cyclization of 1,3-diaryl diketones to give a variety of substituted flavones. The simple and straightforward cyclization can be performed under mild, metal-free, moisture, and air tolerant conditions. Taking into account the mild conditions and simple steps that do not require special preparative procedures, the presented methodology offers advantages over literature procedures. In most cases the flavones containing aromatic substituents were obtained in good yields in the presence of catalytic N-triflyl phosphoramide. Acknowledgment The authors gratefully acknowledge financial support from the Polish National Science Centre (DEC-2012/07/D/ST5/02313). Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.07. 042.
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