Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
2H‑Azirines as C−C Annulation Reagents in Cu-Catalyzed Synthesis of Furo[3,2‑c]quinolone Derivatives Pavel A. Sakharov,† Nikolai V. Rostovskii,† Alexander F. Khlebnikov,† Taras L. Panikorovskii,†,‡ and Mikhail S. Novikov*,† †
St. Petersburg State University, Institute of Chemistry, 7/9 Universitetskaya nab., St. Petersburg 199034, Russia Kola Science Centre, Russian Academy of Sciences, 14 Fersman str., Apatity 184200, Russia
‡
Org. Lett. Downloaded from pubs.acs.org by BOSTON COLG on 05/07/19. For personal use only.
S Supporting Information *
ABSTRACT: A method of furo-annulation of 4-hydroxy-2oxoquinoline-3-carboxylates with 3-arylazirines under Cu(II) catalysis was developed to synthesize a variety of 2,3dihydrofuro[3,2-c]quinolones bearing a carbamate group at the C2 position. The reaction involves an azirine ring opening across the N−C2 bond and formation of a dihydrofuran ring with the inclusion of two azirine carbon atoms, accompanied by a shift of the ester group to the nitrogen. The discovered reaction is the first example of the use of 2H-azirines for furo-annulation. Scheme 1. Azirines as Building Blocks for Annulation Reactions
2H-azirines are a unique class of strained compounds generating increasing interest as flexible building blocks for the synthesis of various nitrogen heterocycles.1 An azirine strategy was used for the straightforward synthesis of 5- and 6membered heterocycles of pyrrole, isoxazole, oxazole, pyridine, pyrazine, 1,3- and 1,4-oxazine families, and others. Azirine ringexpansion reactions, leading to 4- and 7-membered heterocycles as well as to ortho-fused systems, are found to a much lesser extent in the literature. Almost all the intermolecular reactions of azirines leading to ortho-fused heterocycles are the annulation reactions of an aromatic 5- or 6-membered ring to the aromatic benzene or pyridine system (Scheme 1, reactions 1−3).2−4 Only two reactions of 2H-azirines, resulting in the fusion of a nonaromatic ring, namely the dihydropyrazine5 ring (reaction 4) and 3H-azepine ring (reaction 5),6 with aromatic systems, are known. In all of these processes, azirines undergo a ring opening across the N−C2 or N−C3 bond, usually under metal catalysis, and allow the incorporation of a three-atom C−C−N fragment into the target heterocycle. The annulation reactions of synthetically available nonaromatic cyclic systems with azirines are of particular interest because they can provide an easy access to ortho-fused lactones, thiolactones, lactams, and other systems with active functional groups. For example, recently we described the stereoselective (2 + 3)-annulation of five-membered cyclic enols with 3-aryl-2H-azirines under Cu(I) catalysis (Scheme 1, reaction 6).7 3-Arylazirines 2 in the presence of the Cu(I)− NHC complex cycloadd to 5-membered cyclic enols 1 across the CC bond via N−C2 azirine bond cleavage. To the best of our knowledge, ortho-annulation reactions of nonaromatic 6membered cyclic systems with 2H-azirines are unknown. In this regard, 2-quinolone derivatives would appear to be attractive nonaromatic partners for azirines in the annulation reactions. Compounds containing an ortho-fused 2-quinolone © XXXX American Chemical Society
fragment can be found in natural alkaloids and unnatural compounds exhibiting a wide range of biological activities such as SRS-A antagonistic,8 cytotoxic,9 antibacterial, and others.10 We speculated that the annulation of the synthetically available quinolone-based enols (4-hydroxyquinoline-2(1H)-ones) with azirines could open a route to new ortho-fused quinolone Received: March 25, 2019
A
DOI: 10.1021/acs.orglett.9b01043 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
reaction did not proceed in 1,2-dichloroethane, 1,4-dioxane, and toluene (entries 10−12). As a result, the following reaction conditions, Cu(acac)2 (5 mol %) in MeOH at 100 °C, were used for further experiments. Next, we explored the scope of the reaction using variously substituted quinolones 4a−j and 3-arylazirines 2a−g (Scheme 2). The reaction occurred with all of the selected substrates
derivatives, which could be of interest for medicine and material science. Herein, we report the unprecedented Cu(II)-catalyzed furoannulation reaction of methyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylates 4 with 2H-azirines 2 as a route to 2,3dihydrofuro[3,2-c]quinolones 5 (Scheme 1, reaction 7). For initial experiments, we used the readily available quinolone-based enol 4a11 and 3-(p-tolyl)-2H-azirine (2a).12 The reaction of 4a with 2a did not proceed in MeOH or 1,2dichloroethane (DCE) at room temperature or under heating (Table 1). At elevated temperatures, only azirine decom-
Scheme 2. Synthesis of Dihydrofuroquinolones 5a,b
Table 1. Optimization of 5a Synthesisa
entry
catalyst
solvent
yield of 5ab (%)
1 2 3 4 5 6 7c 8d 9 10 11 12
Cu(OAc)2·H2O Cu(acac)2 Cu(hfacac)2 Cu(tfacac)2 IPrCuCl Cu(acac)2 Cu(acac)2 Cu(acac)2 Cu(acac)2 Cu(acac)2 Cu(acac)2
MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeCN 1,4-dioxane DCE toluene
0 60 77 73 76 65 40 75 27 0 0 0
a
Reaction conditions: 4a (0.08 mmol), 2a (0.13 mmol), catalyst (0.004 mmol), solvent (1.0 mL), 100 °C, 30 min, in sealed tube. b Yields were determined by 1H NMR spectroscopy. c1.2 equiv of azirine 2a was used. d3.2 equiv of azirine 2a was used at 60 °C.
position products were detected. Several Cu(I) and Cu(II) compounds were tested as catalysts. Unexpectedly, heating a solution of quinolone 4a, azirine 2a (1.6 equiv), and Cu(OAc)2·H2O (5 mol %) at 100 °C in MeOH gave dihydrofuroquinolone 5a in 55% isolated yield. This reaction is the first example of using azirines for the formation of not only furan-type systems but also nitrogen-free rings at all. The uniqueness of the transformation is that an azirine transfers a two-atom carbon−carbon fragment into a new heterocycle. The only known reaction of this type is the synthesis of 2phenyl-1-(pyrid-2-yl)indole in 39% yield by the Pd(II)catalyzed reaction of 3-phenyl-2H-azirine with N-phenylpyridin-2-amine.13 Hydrogenated furan structures are often encountered in natural compounds14 and biologically active synthetic products.15 Taking all this into account, we decided to investigate the furo-annulation of 4-hydroxyquinolones with azirines in more detail. We initiated this study with the optimization of the reaction conditions using 1H NMR spectroscopy to estimate the yield of compound 5a (Table 1). It was found that exchanging copper acetate for copper acetylacetonates leads to an increase in the yield of 5a by 13− 17% (entries 3−5). The use of Cu(I)−NHC complex, IPrCuCl, did not improve the product yield (entry 6). The reaction is solvent sensitive. The yield of 5a dropped to 27% when MeOH was replaced by acetonitrile (entry 9), and the
a
Reaction conditions: quinolone 4 (0.2 mmol, 1.0 equiv), azirine 2 (0.32 mmol, 1.6 equiv), Cu(acac)2 (0.01 mmol), MeOH (3.0 mL), 100 °C, 20−30 min, in sealed tube. bIsolated yields.
4a−j and provided good yields of dihydrofuroquinolones 5 in almost all cases. Steric hindrance created by a substituent at the peri position to the hydroxyl in the quinolone did not affect the reaction efficiency (compound 5b). However, the product yield was significantly reduced when the quinolone contained the nitro group at position 7 (compound 5h). NH-Quinolone 4j also tolerated the reaction conditions, affording 5unsubstituted dihydrofuroquinolone 5j in moderate yield. Azirines with both electron-donating and electron-withdrawing aryl groups gave good yields of the products (5k−p). The introduction of an ortho-substituent in the phenyl ring of the azirine did not reduce the yield of the product (compound 5m). The scalability of the reaction was demonstrated by 0.2 mmol scale (45 mg, 60% yield) and 1.25 mmol scale (308 mg, B
DOI: 10.1021/acs.orglett.9b01043 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 4. Synthesis of Furoquinolones 8a,b
65% yield) syntheses of dihydrofuroquinolones 5f. It was also found that quinolones 4 are inactive toward 2-methyl-3phenyl-2H-azirine and 2,2-dimethyl-3-phenyl-2H-azirine under the standard conditions. Compounds 5 have the carbamate group at C2, which could be used for further structural modification of the molecule. In particular, they can be considered as potential precursors of furoquinolones, which are known to display various bioactivity16 and can be applied in analytical chemistry.17 It was found that compounds 5 undergo dihydrofuran ring opening across the O−C2 bond under basic conditions. Thus, treatment of compounds 5c,e with Et3N in the presence of catalytic amounts of DMAP afforded 3-(2-aminovinyl)substituted quinolones 6a,b in high yields (Scheme 3, reaction Scheme 3. Transformations of Dihydrofuroquinolones 5
a
Reaction conditions: carbamate 5 (0.2 mmol), anhydrous TsOH (0.02 mmol), o-xylene (4.0 mL), 144 °C, 30−60 min. bIsolated yields.
Scheme 5. Plausible Reaction Mechanism
1). Under acidic conditions (HCl−H2O−MeOH−dioxane), the ring opening in 5a,c was accompanied by hydrolysis providing ketones 7a,b (reaction 2). Heating a toluene solution of compound 5a and TsOH hydrate (10 mol %) under reflux afforded the desired furoquinolone 8a and ketone 7a in ca. 2:1 ratio (reaction 3). The structure of 8a was confirmed by X-ray diffraction analysis. The optimization of the reaction conditions showed that an increase in temperature favors the formation of the target furoquinolone 8a, which was obtained in 85% yield after heating of 5a and anhydrous TsOH under reflux in o-xylene solution (Supporting Information, Table S1). Under the same conditions variously substituted furoquinolones 8b−j were prepared in good yields (Scheme 4). Furoquinolones 8a−j are luminescent in solutions. Emission maximums in the fluorescence spectra of these compounds in acetonitrile solutions lie within 360−390 nm. The fluorescence quantum yields reach 86% (for compound 8i) (Supporting Information, Table S3). The data of emission spectra for compounds 8a−j are listed in Table S4. A plausible mechanism for the formation of dihydrofuroquinolones 5 is shown in Scheme 5. The first step is the generation of enolate A from enol 4 and the Cu(II) catalyst. Its reaction with azirine 2 affords radical intermediate B, which rearranges to imine−copper(II) intermediate C. The N-attack onto the ester group leads to the spiro-fused intermediate D, which undergoes ring cleavage across the C−C bond to give Cu(II) enolate E. Further cyclization via the formation of
intermediate F finally leads to carbamate 5. The cyclization in intermediate C through the attack onto the less electrophilic ester carbonyl, rather than the ketone carbonyl, can be explained by the reversible character of the latter process. The proposed mechanism does not contradict the results of the reaction of enol 4a with azirine 2a carried out in the presence of TEMPO as a radical scavenger. When 55 mol % of TEMPO was added to the reaction mixture, the yield of carbamate 5a decreased from 80 to 14%. Such a dramatic decrease in yield can be an argument in favor of the formation of radical intermediates, for example, intermediate B, during the reaction. According to this mechanism, an increase in the electrophilicity of the C2 atom of the cyclic enols could lead to the appearance of another competitive transformation pathway of the intermediate C, namely, N-attack on the atom C2 and subsequent the 6-membered ring cleavage. To test this hypothesis, 4-hydroxycoumarins 9a,b, which are lactone-type analogues of enols 4, were synthesized according to the known procedures.18 The reaction of azirine 2a with enols 9a or 9b in C
DOI: 10.1021/acs.orglett.9b01043 Org. Lett. XXXX, XXX, XXX−XXX
Organic Letters
■
MeOH produced complex mixtures of products in both cases whatever catalyst was used (Cu(acac)2, Cu(OAc)2·H2O or IPrCuCl). A complex mixture of compounds was also observed in the reaction of 9a with these catalysts in DCE at 100 °C, but when 9b was treated with IPrCuCl under these conditions, only one product, pyrrolinone 11a, was isolated in high yield (Scheme 6). The reaction of coumarin 9b also smoothly
Letter
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Pavel A. Sakharov: 0000-0001-7746-7387 Nikolai V. Rostovskii: 0000-0002-8925-794X Alexander F. Khlebnikov: 0000-0002-6100-0309 Taras L. Panikorovskii: 0000-0002-2323-1413 Mikhail S. Novikov: 0000-0001-5106-4723
Scheme 6. Synthesis of Pyrrolinones 11a−d
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS We gratefully acknowledge the financial support of the Russian Science Foundation (17-13-01078). This research used resources of the Magnetic Resonance Research Centre, Chemical Analysis and Materials Research Centre, Centre for X-ray Diffraction Studies, Centre for Optical and Laser Materials Research, and Chemistry Educational Centre of the Research Park of St. Petersburg State University.
occurred with 3-aryl-2H-azirines having both a donor or acceptor substituent in the aryl group providing good yields of pyrrolinones 11b−d. The mechanism of the formation of compounds 11 is likely similar to those presented in Scheme 5 and involves the formation of Cu(I)−alcoholates 10 which after pyran ring cleavage produce 11. These results serve as a strong argument in favor of the above proposed mechanism involving the N-nucleophilic cyclization in intermediate C. It is very likely that the reported earlier Mn(OAc)2-catalyzed reaction of 4-hydroxycoumarin with vinyl azides as precursors of azirines, resulting in the formation of spiropyrrolinones, occurs through a similar cyclization stage.19 In conclusion, an effective method of furo-annulation of methyl 4-hydroxy-2-oxoquinoline-3-carboxylates at the C3−C4 bond with 3-aryl-2H-azirines under Cu(II) catalysis was developed to synthesize a variety of 2,3-dihydrofuro[3,2c]quinolones. The reaction proceeds via the azirine ring opening across the N−C2 bond resulting in the incorporation of two azirine carbons in the dihydrofuran cycle and transfer of the ester group to the nitrogen to form the carbamate C2substituent. This reaction is the first example of the use of 2Hazirines for the furo-annulation of carbo- and heterocyclic systems. The presence of the methoxycarbonylamino leaving group at the C2 atom makes these compounds convenient precursors of luminescent furo[3,2-c]quinolin-4(5H)-ones.
■
■
REFERENCES
(1) For recent reviews on azirine chemistry, see: (a) Khlebnikov, A. F.; Novikov, M. S.; Rostovskii, N. V. Tetrahedron 2019, 75, 2555− 2624. (b) Zhou, H.; Shen, M.-H.; Xu, H.-D. Synlett 2016, 27, 2171− 2177. (c) Khlebnikov, A. F.; Novikov, M. S. Top. Heterocycl. Chem. 2015, 41, 143−232. (d) Huang, C.-Y.; Doyle, A. G. Chem. Rev. 2014, 114, 8153−8198. (e) Khlebnikov, A. F.; Novikov, M. S. Tetrahedron 2013, 69, 3363−3401. For recent examples on synthesis of heterocycles, see: (f) Zhao, M.-N.; Ren, Z.-H.; Yang, D.-S.; Guan, Z.-H. Org. Lett. 2018, 20, 1287−1290. (g) Sujatha, C.; Bhatt, C. S.; Ravva, M. K.; Suresh, A. K.; Namitharan, K. Org. Lett. 2018, 20, 3241−3244. (h) Peng, Q.; Zhang, B.; Xie, Y.; Wang, J. Org. Lett. 2018, 20, 7641−7644. (i) Agafonova, A. V.; Smetanin, I. A.; Rostovskii, N. V.; Khlebnikov, A. F.; Novikov, M. S. Org. Chem. Front. 2018, 5, 3396−3401. (2) (a) Borra, S.; Chandrasekhar, D.; Newar, U. D.; Maurya, R. A. J. Org. Chem. 2019, 84, 1042. (b) Thangaraj, M.; Bhojgude, S. S.; Jain, S.; Gonnade, R. G.; Biju, A. T. J. Org. Chem. 2016, 81, 8604−8611. (c) Candito, D. A.; Lautens, M. Org. Lett. 2010, 12, 3312−3315. (3) (a) Adiyala, P. R.; Sastry, K. N. V.; Kovvuri, J.; Nagarajan, A.; Reddy, V. G.; Sayeed, I. B.; Nayak, V. L.; Maurya, R. A.; Kamal, A. ChemistrySelect 2017, 2, 8158−8161. (b) Adiyala, P. R.; Mani, G. S.; Nanubolu, J. B.; Shekar, K. C.; Maurya, R. A. Org. Lett. 2015, 17, 4308−4311. (c) Donthiri, R. R.; Pappula, V.; Reddy, N. N. K.; Bairagi, D.; Adimurthy, S. J. Org. Chem. 2014, 79, 11277−11284. (d) Baek, Y.; Kim, J.; Kim, H.; Jung, S. J.; Ryu, H.; Kim, S.; Son, J.-Y.; Um, K.; Han, S. H.; Seo, H. J.; Heo, J.; Lee, K.; Baik, M.-H.; Lee, P. H. Chem. Sci. 2019, 10, 2678−2686. (4) Zhu, Z.; Tang, X.; Li, X.; Wu, W.; Deng, G.; Jiang, H. J. Org. Chem. 2016, 81, 1401−1409. (5) (a) Baek, Y.; Maeng, C.; Kim, H.; Lee, P. H. J. Org. Chem. 2018, 83, 2349−2360. (b) Ruvinskaya, J. O.; Rostovskii, N. V.; Filippov, I. P.; Khlebnikov, A. F.; Novikov, M. S. Org. Biomol. Chem. 2018, 16, 38−42. (c) Ding, H.; Wang, Z.; Bai, S.; Lu, P.; Wang, Y. Org. Lett. 2017, 19, 6514−6517. (6) Pawar, S. K.; Sahani, L.; Liu, R.-S. Chem. - Eur. J. 2015, 21, 10843−10850. (7) (a) Sakharov, P. A.; Rostovskii, N. V.; Khlebnikov, A. F.; Novikov, M. S. Tetrahedron 2017, 73, 4663−4670. (b) Rostovskii, N. V.; Sakharov, P. A.; Novikov, M. S.; Khlebnikov, A. F.; Starova, G. L. Org. Lett. 2015, 17, 4148−4151. (8) Kamikawa, T.; Hanaoka, Y.; Fujie, S.; Saito, K.; Yamagiwa, Y.; Fukuhara, K.; Kubo, I. Bioorg. Med. Chem. 1996, 4, 1317−1320.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01043. Experimental procedures, characterization data, X-ray structure of compound 8a, and 1H and 13C NMR spectra (PDF) Accession Codes
CCDC 1900721 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. D
DOI: 10.1021/acs.orglett.9b01043 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters (9) Chen, I. S.; Wu, S. J.; Tsai, I. L.; Wu, T. S.; Pezzuto, J. M.; Lu, M. C.; Chai, H.; Suh, N.; Teng, C. M. J. Nat. Prod. 1994, 57, 1206−1211. (10) Audisio, D.; Messaoudi, S.; Cojean, S.; Peyrat, J. F.; Brion, J. D.; Bories, C.; Huteau, F.; Loiseau, P. M.; Alami, M. Eur. J. Med. Chem. 2012, 52, 44−50. (11) Pudlo, M.; Luzet, V.; Ismaïli, L.; Tomassoli, I.; Iutzeler, A.; Refouvelet, B. Bioorg. Med. Chem. 2014, 22, 2496−2507. (12) Hortmann, A.; Robertson, D.; Gillard, B. J. Org. Chem. 1972, 37, 322−324. (13) Jie, L.; Wang, L.; Xiong, D.; Yang, Z.; Zhao, D.; Cui, X. J. Org. Chem. 2018, 83, 10974−10984. (14) (a) Igwe, O. U.; Okwu, D. E. Der Pharma Chemica 2013, 5, 39−44. (b) Feng, W.-S.; Zang, X.-Y.; Zheng, X.-K.; Wang, Y.-Z.; Chen, H.; Li, Z. J. J. Asian Nat. Prod. Res. 2010, 12, 557−561. (c) Xiang, W.-J.; Ma, L.; Hu, L.-H. Fitoterapia 2010, 81, 1228−1231. (d) Trost, B. M.; Thiel, O. R.; Tsui, H.-C. J. Am. Chem. Soc. 2003, 125, 13155−13164. (15) (a) Manna, S. K.; Bose, J. S.; Gangan, V.; Raviprakash, N.; Navaneetha, T.; Raghavendra, P. B.; Babajan, B.; Kumar, C. S.; Jain, S. K. J. Biol. Chem. 2010, 285, 22318−22327. (b) Pieters, L.; Van Dyck, S.; Gao, M.; Bai, R.; Hamel, E.; Vlietinck, A.; Lemière, G. J. Med. Chem. 1999, 42, 5475−5481. (16) (a) Guo, T.; Wei, X.-N.; Wang, H.-Y.; Zhao, B. Synth. Commun. 2018, 48, 761−767. (b) O’Donnell, F.; Smyth, T. J. P.; Ramachandran, V. N.; Smyth, W. F. Int. J. Antimicrob. Agents 2010, 35, 30−38. (c) Butenschön, I.; Möller, K.; Hänsel, W. J. Med. Chem. 2001, 44, 1249−1256. (17) Kumar, M.; Kumawat, L. K.; Gupta, V. K.; Sharma, A. RSC Adv. 2015, 5, 106030−106037. (18) (a) Xi, G.-L.; Liu, Z.-Q. J. Agric. Food Chem. 2014, 62, 5636− 5642. (b) Stefanou, V.; Matiadis, D.; Melagraki, G.; Afantitis, A.; Athanasellis, G.; Igglessi-Markopoulou, O.; McKee, V.; Markopoulos, J. Molecules 2011, 16, 384−402. (19) Guo, S.; Chen, B.; Zhao, D.; Chen, W.; Zhang, G. Adv. Synth. Catal. 2016, 358, 3010−3014.
E
DOI: 10.1021/acs.orglett.9b01043 Org. Lett. XXXX, XXX, XXX−XXX
