Letter Cite This: Org. Lett. 2018, 20, 4950−4953
pubs.acs.org/OrgLett
Synthesis of Fluorescent Azafluorenones and Derivatives via a Ruthenium-Catalyzed [2 + 2 + 2] Cycloaddition Fei Ye,† Christine Tran,† Ludovic Jullien,‡ Thomas Le Saux,‡ Mansour Haddad,† Veŕ onique Michelet,*,† and Virginie Ratovelomanana-Vidal*,† †
PSL Research University, Chimie ParisTech - CNRS, Institut de Recherche de Chimie Paris, Paris 75005, France PASTEUR, Chemistry Department, É cole Normale Supérieure, PSL University, Sorbonne University, CNRS, Paris 75005, France
‡
Downloaded via KAOHSIUNG MEDICAL UNIV on August 17, 2018 at 17:14:24 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
S Supporting Information *
ABSTRACT: An original and mild synthetic route for the preparation of novel azafluorenones and derivatives via a rutheniummediated [2 + 2 + 2] cycloaddition of α,ω-diynes and cyanamides has been developed. This atom-economical catalytic process demonstrated remarkable regioselectivities to access fluorescent azafluorenone derivatives. The photophysical properties of azafluorenone derivatives have been evaluated, and photoluminescence phenomena at solid and liquid states have been highlighted.
A
zafluorenones, azafluorenols, and related compounds serve as privileged structures and constitute the central core of a variety of organic chemicals that have been found in natural products and biologically active molecules.1 Among them, aminoazafluorenones have received increasing interest in recent years. Synthetic and natural aminoazafluorenones display interesting properties and are present in a variety of pharmacophores. As depicted in Figure 1, 3-amino-2-azafluorenone A is an antagonist of the adenosine A2a receptor,2a piperazinyl-derived compound B exhibits an inhibitory effect on topoisomerase as a potent anti-breast cancer candidate,2b and isonicotinohydrazide derivative C has been evaluated as a
potential dual anti-tuberculosis and an anti-inflammatory drug candidate.2c Furthermore, azafluorenones are also found in some chromophores, although the properties and bioimaging applications have rarely been reported. Recent investigations demonstrated that aminoazafluorenones are potent, photoactivatable fluorescent probes because of the effective conjugative interaction of the nitrogen of the amino moiety with the 14-π-electron indenopyridine system that could be used for the lipid droplets (LDs)-specific live-cell imaging. 1Azafluorenone D was reported to be a nontoxic, highly selective, and stable dye for staining LDs in different cell lines;3d 2azafluorenone E also presented typical aggregation-induced emission (AIE) properties, compatible with LD in vitro imaging (Figure 1).3e Given the crucial importance of azafluorenone derivatives, the development of clean and flexible methods to access azafluorenone derivatives efficiently is highly desirable. Despite numerous strategies for the synthesis of azafluorenones,4 only a few examples have been reported for the construction of aminoazafluorenones including amination reactions,2c multicomponent heterocyclizations,3d,e oxidation of 1,2-dihydroazafluorenones,2a and Pd-catalyzed autotandem cyclizations.4i Alternatively, transition-metal-catalyzed [2 + 2 + 2] cycloaddition reactions are powerful methods to prepare heteroaromatic compounds.5 More particularly, [2 + 2 + 2] cycloadditions of alkynes with cyanamides have been extensively explored to access 2-aminopyridine derivatives based on Co,6 Rh,7 Ni,8 Fe,9 Ir,10 and Ru,11,12f,g catalysis. As a continuation of our recent investigations on transition-metal-catalyzed [2 + 2 +
Figure 1. Selected examples with azafluorenone units.
Received: July 3, 2018 Published: August 2, 2018
© 2018 American Chemical Society
4950
DOI: 10.1021/acs.orglett.8b02085 Org. Lett. 2018, 20, 4950−4953
Letter
Organic Letters 2] cyclization reactions,12 we hypothesized that novel azafluorenone and azafluorenol derivatives could be accessed through ruthenium-catalyzed [2 + 2 + 2] cycloadditions (Scheme 1). To the best of our knowledge, such an approach has not been reported so far.
Scheme 2. Ru-Catalyzed [2 + 2 + 2] Cycloaddition To Access 2-Azafluorenone and 3-Azafluorenone Derivativesa
Scheme 1. Our Strategy for the Construction of Azafluorenone(ol)s through [2 + 2 + 2] Cycloaddition
We initially studied the synthesis of 2-azafluorenones using benzoyl-bridged 1,6-diynes containing a substituent on the terminal position C1. The results are summarized in Scheme 2. The benzoyl-bridged diyne 1a reacted with cyanamide 2a in the presence of 2 mol % of Cp*Ru(CH3CN)3PF6 at room temperature under solvent-free conditions, affording 3-amino2-azafluorenone 3a in 87% yield with excellent regioselectivity. Screening different substituted cyanamides, such as morpholinyl (2b), piperidinyl (2c), and N-methyl/N-benzyl derivatives (2d) led to the desired 2-azafluorenones 3b−d in 78−92% yields with regioselectivities of >99/1. Both electron-donating and electronwithdrawing substituents, such as methoxy (1b) and fluoride (1c), could be introduced to evaluate the influence of the phenyl ring tether. Not only the alkyl groups, such as n-butyl and cyclopropyl, but also aromatic groups are compatible on the terminus of the diyne to deliver the corresponding cycloadducts 3i and 3j with high regioselectivities (for single-crystal X-ray diffraction of 3i, see the Supporting Information). However, TMS- and propenyl-substituted diynes (1d and 1e) provided the corresponding products with low yields. Furthermore, thienyl-based fluorenone 3k was obtained in 81% yield with complete regioselectivity from thiophene-bridged diyne 1h and pyrrolidine-1-carbonitrile 2a. In parallel to the synthesis of 2azafluorenones, exchanging the terminal position of the starting diynes, such as 1i, allowed the formation of the 2-amino-3azafluorenone 4 in 89% yield with 94:6 regioselectivity. The structure of the major product 4 was unambiguously confirmed by single-crystal X-ray diffraction (see the SI). Interestingly, we also found that the benzyl-bridged 1,6diynes containing a hydroxyl group were compatible with the reaction conditions, affording the cycloadducts in good to high yields with excellent regioselectivities (Scheme 3). Cyanamides 2a and 2b smoothly underwent the cycloaddition reactions to provide the corresponding 6a and 6b in 81% and 68% yields, respectively. Fluoride-substituted cycloadduct 6c was obtained in 77% yield by using the corresponding diyne 5b. Functional groups, such as TMS and propenyl, were all tolerated and gave the functionalized 2-azafluorenols 6d and 6e in good yields. Phenyl-substituted diynes 5e and 5f were successfully used in the reaction to afford 6f and 6g in 73% and 53% yields, respectively. Heteroaromatics, such as thienyl derivatives, were amenable with the reaction conditions to produce the corresponding product 6h in 87% yield. In addition to the monosubstituted diynes, disubstituted diyne 5i containing a
a Reaction conditions: 0.3−0.8 mmol of diyne 1, cyanamide 2 (2 equiv), and 2 or 5 mol % Cp*Ru(CH3CN)3PF6 were stirred in a screw-capped tube under solvent-free conditions and an argon atmosphere. Isolated yield. Regioselectivity was determined by crude 1H NMR analysis. b1.2 equiv of 2 was used, and CH2Cl2 was used as solvent. c1.2 equiv of 2 was used, DCE was used as solvent, and the reaction was stirred at 80 °C. dConversion = 53%. e50 °C.
bromide could also be used to afford 1-bromo-2-azafluorenol 6i in 69% yield with >99/1 regioselectivity. Similar to the synthesis of 3-azafluorenone 4, but starting from 1,6-diynes 5h and 5j, having substituents at position C7, the cyclizations furnished 3azafluorenols 7a and 7b in 71% and 78% yields, respectively, with 99/1 regioselectivities. Inspired by the efficient strategy to access azafluorenols described in Scheme 3, the synthesis of a complex derivative 9 was then explored (Scheme 4). Tetrayne 8 was converted into bis-azafluorenol 9 via a double Ru-catalyzed [2 + 2 + 2] cycloaddition reaction in the presence of cyanamide 2a. The expected product was obtained in 94% yield and >99/1 regioselectivity. Azafluorenones and azafluorenols 3a−k, 6g, and 9 possess attractive photophysical properties; these compounds exhibit UV spectra with an absorption maxima (λmax) in the 380−450 4951
DOI: 10.1021/acs.orglett.8b02085 Org. Lett. 2018, 20, 4950−4953
Letter
Organic Letters Scheme 3. Synthesis of 2-Azafluorenols and 3-Azafluorenolsa
a
Reaction conditions: 0.3 or 0.5 mmol of diyne 5, cyanamide 2 (2 equiv), and 2 or 5 mol % of Cp*Ru(CH3CN)3PF6 were stirred in a screw-capped tube under solvent-free conditions under an argon atmosphere. Isolated yield. Regioselectivity was determined by crude 1H NMR analysis. b1.2 equiv of 2 was used, and CH2Cl2 was used as solvent. c50 °C.
In conclusion, a straightforward unprecedented approach to access azafluorenones is described. This strategy involves the Ru-catalyzed [2 + 2 + 2] cycloaddition reaction of α,ω-diynes and cyanamides, which efficiently and regioselectively allows the construction of azafluorenone derivatives. An analogous method was also studied for the synthesis of azafluorenols catalyzed with Cp*Ru(CH3CN)3PF6. These results showed that the high regioselectivities mainly relied on the steric hindrance of the substituents on the terminus of the alkyne, which allowed the formation of less sterically hindered regioisomers. Moreover, photophysical properties of azafluorenones and some derivatives demonstrated that these compounds exhibited photoluminescence in the solid and liquid states with significant fluorescence quantum yields.
Scheme 4. Synthesis of Bis-azafluorenol Derivative 9
■
nm wavelength range and high molar absorption coefficients (εmax) at λmax around 15000 M−1·cm−1 in acetonitrile at 293 K. Additionally, all of these azafluorenones fluoresce in the 440− 570 nm wavelength range with quantum yields ranging from 0.1 to 0.5 (cf. the Supporting Information). Moreover, as depicted in Figure 2 for 3b, photoluminescence was observed in the solid state when these molecules were excited at 366 nm.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02085. Experimental procedures, Analytical data, and NMR spectra for all compounds are reported (PDF) Accession Codes
CCDC 1850884−1850885 contain 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.
■
AUTHOR INFORMATION
Corresponding Authors
Figure 2. Photoluminescence of 3b at 366 nm in MeCN and the solid state.
*E-mail:
[email protected]. 4952
DOI: 10.1021/acs.orglett.8b02085 Org. Lett. 2018, 20, 4950−4953
Letter
Organic Letters *E-mail:
[email protected].
2011, 40, 3430. (f) Hua, R.; Abrenica, M. V. A.; Wang, P. Curr. Org. Chem. 2011, 15, 712. (g) Weding, N.; Hapke, M. Chem. Soc. Rev. 2011, 40, 4525. (h) Broere, D. L.; Ruijter, E. Synthesis 2012, 44, 2639. (i) Tanaka, K. Heterocycles 2012, 85, 1017. (j) Wang, C.; Wan, B. Chin. Sci. Bull. 2012, 57, 2338. (k) Okamoto, S.; Sugiyama, Y. Synlett 2013, 24, 1044. (l) Satoh, Y.; Obora, Y. Eur. J. Org. Chem. 2015, 2015, 5041. (m) Jungk, P.; Täufer, T.; Thiel, I.; Hapke, M. Synthesis 2016, 48, 2026. (n) Babazadeh, M.; Soleimani-Amiri, S.; Vessally, E.; Hosseinian, A.; Edjlali, L. RSC Adv. 2017, 7, 43716. (6) (a) Bönnemann, H.; Brijoux, W.; Brinkmann, R.; Meurers, W. Helv. Chim. Acta 1984, 67, 1616. (b) Heller, B.; Reihsig, J.; Schulz, W.; Oehme, G. Appl. Organomet. Chem. 1993, 7, 641. (c) Fatland, A. W.; Eaton, B. E. Org. Lett. 2000, 2, 3131. (d) Heller, B.; Sundermann, B.; Buschmann, H.; Drexler, H.-J.; You, J.; Holzgrabe, U.; Heller, E.; Oehme, G. J. Org. Chem. 2002, 67, 4414. (e) Boñaga, L. V. R.; Zhang, H.-C.; Maryanoff, B. E. Chem. Commun. 2004, 2394. (f) Boñaga, L. V. R.; Zhang, H.-C.; Moretto, A. F.; Ye, H.; Gauthier, D. A.; Li, J.; Leo, G. C.; Maryanoff, B. E. J. Am. Chem. Soc. 2005, 127, 3473. (g) Zhang, H.C.; Boñaga, L. V. R.; Ye, H.; Derian, C. K.; Damiano, B. P.; Maryanoff, B. E. Bioorg. Med. Chem. Lett. 2007, 17, 2863. (h) Hapke, M.; Kral, K.; Fischer, C.; Spannenberg, A.; Gutnov, A.; Redkin, D.; Heller, B. J. Org. Chem. 2010, 75, 3993. (i) Nicolaus, N.; Schmalz, H.-G. Synlett 2010, 2010, 2071. (j) Garcia, P.; Evanno, Y.; George, P.; Sevrin, M.; Ricci, G.; Malacria, M.; Aubert, C.; Gandon, V. Org. Lett. 2011, 13, 2030. (k) Garcia, P.; Evanno, Y.; George, P.; Sevrin, M.; Ricci, G.; Malacria, M.; Aubert, C.; Gandon, V. Chem. - Eur. J. 2012, 18, 4337. (7) Tanaka, K.; Suzuki, N.; Nishida, G. Eur. J. Org. Chem. 2006, 2006, 3917. (8) (a) Kumar, P.; Prescher, S.; Louie, J. Angew. Chem., Int. Ed. 2011, 50, 10694. (b) Stolley, R. M.; Maczka, M. T.; Louie, J. Eur. J. Org. Chem. 2011, 2011, 3815. (c) Stolley, R. M.; Duong, H. A.; Louie, J. Organometallics 2013, 32, 4952. (d) Zhong, Y.; Spahn, N. A.; Stolley, R. M.; Nguyen, M. H.; Louie, J. Synlett 2015, 26, 307. (9) (a) Lane, T. K.; D’ Souza, B. R.; Louie, J. J. Org. Chem. 2012, 77, 7555. (b) Wang, C.; Wang, D.; Xu, F.; Pan, B.; Wan, B. J. Org. Chem. 2013, 78, 3065. (c) Spahn, N. A.; Nguyen, M. H.; Renner, J.; Lane, T. K.; Louie, J. J. Org. Chem. 2017, 82, 234. (10) (a) Hashimoto, T.; Ishii, S.; Yano, R.; Miura, H.; Sakata, K.; Takeuchi, R. Adv. Synth. Catal. 2015, 357, 3901. (b) Takeuchi, R.; Fujisawa, S.; Yoshida, Y.; Sagano, J.; Hashimoto, T.; Matsunami, A. J. Org. Chem. 2018, 83, 1852. (11) (a) Chowdhury, H.; Goswami, A. Adv. Synth. Catal. 2017, 359, 314. (b) Bhatt, D.; Patel, N.; Chowdhury, H.; Bharatam, P. V.; Goswami, A. Adv. Synth. Catal. 2018, 360, 1876. (c) Yamamoto, Y. Tetrahedron Lett. 2017, 58, 3787. (d) Chowdhury, H.; Goswami, A. Org. Biomol. Chem. 2017, 15, 5824. (12) (a) Auvinet, A.-L.; Ez-Zoubir, M.; Vitale, M. R.; Brown, J. A.; Michelet, V.; Ratovelomanana-Vidal, V. ChemSusChem 2012, 5, 1888. (b) Auvinet, A.-L.; Ez-Zoubir, M.; Bompard, S.; Vitale, M. R.; Brown, J. A.; Michelet, V.; Ratovelomanana-Vidal, V. ChemCatChem 2013, 5, 2389. (c) Auvinet, A.-L.; Michelet, V.; Ratovelomanana-Vidal, V. Synthesis 2013, 45, 2003. (d) Jacquet, J.; Auvinet, A.-L.; Mandadapu, A. K.; Haddad, M.; Ratovelomanana-Vidal, V.; Michelet, V. Adv. Synth. Catal. 2015, 357, 1387. (e) Ye, F.; Haddad, M.; Michelet, V.; Ratovelomanana-Vidal, V. Org. Lett. 2016, 18, 5612. (f) Ye, F.; Haddad, M.; Ratovelomanana-Vidal, V.; Michelet, V. Org. Lett. 2017, 19, 1104. (g) Ye, F.; Haddad, M.; Michelet, V.; Ratovelomanana-Vidal, V. Org. Chem. Front. 2017, 4, 1063. (h) Ye, F.; Boukattaya, F.; Haddad, M.; Ratovelomanana-Vidal, V.; Michelet, V. New J. Chem. 2018, 42, 3222.
ORCID
Véronique Michelet: 0000-0002-2217-9115 Virginie Ratovelomanana-Vidal: 0000-0003-1167-1195 Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS This work was supported by the Ministère de l’Education Nationale, de l’Enseignement Supérieur et de la Recherche (MENESR) and the Centre National de la Recherche Scientifique (CNRS). We gratefully acknowledge the China Scholarship Council (CSC) for a grant to F.Y. and warmly thank Dr. M.-N. Rager (Chimie ParisTech, Paris) for 2D NMR experiments and L.-M. Chamoreau and G. Gontard (IPCM, Université Pierre et Marie Curie, Paris) for X-ray analyses.
■
REFERENCES
(1) (a) Koyama, J.; Morita, I.; Kobayashi, N.; Osakai, T.; Usuki, Y.; Taniguchi, M. Bioorg. Med. Chem. Lett. 2005, 15, 1079. (b) Manpadi, M.; Uglinskii, P. Y.; Rastogi, S. K.; Cotter, K. M.; Wong, Y.-S. C.; Anderson, L. A.; Ortega, A. J.; Van Slambrouck, S.; Steelant, W. F. A.; Rogelj, S.; Tongwa, P.; Antipin, M. Y.; Magedov, I. V.; Kornienko, A. Org. Biomol. Chem. 2007, 5, 3865. (c) Mueller, D.; Davis, R. A.; Duffy, S.; Avery, V. M.; Camp, D.; Quinn, R. J. J. Nat. Prod. 2009, 72, 1538. (d) Prachayasittikul, S.; Manam, P.; Chinworrungsee, M.; IsarankuraNa-Ayudhya, C.; Ruchirawat, S.; Prachayasittikul, V. Molecules 2009, 14, 4414. (e) Pumsalid, K.; Thaisuchat, H.; Loetchutinat, C.; Nuntasaen, N.; Meepowpan, P.; Pompimon, W. Nat. Prod. Commun. 2010, 5, 1931. (f) Addla, D.; Sridhar, B.; Devi, A.; Kantevari, S. Bioorg. Med. Chem. Lett. 2012, 22, 7475. (g) Banjerdpongchai, R.; Khaw-On, P.; Ristee, C.; Pompimon, W. Asian Pacific. J. Cancer Prev. 2013, 14, 2637. (2) (a) Heintzelman, G. R.; Bullington, J. L.; Rupert, K. C. PCT Int. Appl. WO 2005042500 A1, May 12, 2005. (b) Chen, T.-C.; Yu, D.-S.; Chen, S.-J.; Chen, C.-L.; Lee, C.-C.; Hsieh, Y.-Y.; Chang, L.-C.; Guh, J.H.; Lin, J.-J.; Huang, H.-S. Arabian J. Chem. 2016, DOI: 10.1016/ j.arabjc.2016.06.014. (c) Tseng, C. H.; Tung, C. W.; Wu, C. H.; Tzeng, C. C.; Chen, Y. H.; Hwang, T. L.; Chen, Y. L. Molecules 2017, 22, 1001. (3) (a) Sharma, A.; Umar, S.; Kar, P.; Singh, K.; Sachdev, M.; Goel, A. Analyst 2016, 141, 137. (b) Gao, M.; Su, H.; Lin, Y.; Ling, X.; Li, S.; Qin, A.; Tang, B. Z. Chem. Sci. 2017, 8, 1763. (c) Landmesser, T.; Linden, A.; Hansen, H.-J. Helv. Chim. Acta 2008, 91, 265. (d) Sharma, A.; Umar, S.; Kar, P.; Singh, K.; Sachdev, M.; Goel, A. Analyst 2016, 141, 137. (e) Gao, M.; Su, H.; Lin, Y.; Ling, X.; Li, S.; Qin, A.; Tang, B. Z. Chem. Sci. 2017, 8, 1763. (4) (a) Kraus, G. A.; Kempema, A. J. Nat. Prod. 2010, 73, 1967. (b) Dhara, S.; Ahmed, A.; Nandi, S.; Baitalik, S.; Ray, J. K. Tetrahedron Lett. 2013, 54, 63. (c) Marquise, N.; Harford, P. J.; Chevallier, F.; Roisnel, T.; Dorcet, V.; Gagez, A. L.; Sablé, S.; Picot, L.; Thiéry, V.; Wheatley, A. E. H.; Gros, P. C.; Mongin, F. Tetrahedron 2013, 69, 10123. (d) Marquise, N.; Harford, P. J.; Chevallier, F.; Roisnel, T.; Wheatley, A. E. H.; Gros, P. C.; Mongin, F. Tetrahedron Lett. 2013, 54, 3154. (e) Marquise, N.; Dorcet, V.; Chevallier, F.; Mongin, F. Org. Biomol. Chem. 2014, 12, 8138. (f) Das, S.; Hong, D.; Chen, Z.-W.; She, Z.-G.; Hersh, W. H.; Subramaniam, G.; Chen, Y. Org. Lett. 2015, 17, 5578. (g) Laha, J. K.; Jethava, K. P.; Patel, S. Org. Lett. 2015, 17, 5890. (h) Zheng, M.; Chen, P.; Wu, W.; Jiang, H. Chem. Commun. 2016, 52, 84. (i) Marquise, N.; Chevallier, F.; Nassar, E.; Frédérich, M.; Ledoux, A.; Halauko, Y. S.; Ivashkevich, O. A.; Matulis, V. E.; Roisnel, T.; Dorcet, V.; Mongin, F. Tetrahedron 2016, 72, 825. (j) Laha, J. K.; Jethava, K. P.; Patel, S.; Patel, K. V. J. Org. Chem. 2017, 82, 76. (5) For selected reviews, see: (a) Heller, B.; Hapke, M. Chem. Soc. Rev. 2007, 36, 1085. (b) Tanaka, K. Synlett 2007, 2007, 1977. (c) Varela, J. A.; Saá, C. Synlett 2008, 2008, 2571. (d) Tanaka, K. Chem. - Asian J. 2009, 4, 508. (e) Domínguez, G.; Pérez-Castells, J. Chem. Soc. Rev. 4953
DOI: 10.1021/acs.orglett.8b02085 Org. Lett. 2018, 20, 4950−4953
