Letter Cite This: Org. Lett. 2018, 20, 7388−7391
pubs.acs.org/OrgLett
Catalyst-Free Phosphorylation of Acridine with Secondary Phosphine Chalcogenides: Nucleophilic Addition vs SNHAr Reaction Pavel A. Volkov, Kseniya O. Khrapova, Anton A. Telezhkin, Nina I. Ivanova, Alexander I. Albanov, Nina K. Gusarova, and Boris A. Trofimov* A.E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, 1 Favorsky St., Irkutsk 664033, Russian Federation
Org. Lett. 2018.20:7388-7391. Downloaded from pubs.acs.org by UNIV OF WINNIPEG on 12/19/18. For personal use only.
S Supporting Information *
ABSTRACT: Acridine adds secondary phosphine chalcogenides HP(X)R2 (X = O, S, Se; R = Ar, ArAlk) under catalystfree conditions at 70−75 °C (both in the presence and absence of the electron-deficient acetylenes) to give 9chalcogenophosphoryl-9,10-dihydroacridines in 61−94% yields. This contrasts with pyridines, which under similar conditions undergo an SNHAr reaction, wherein electron-deficient acetylenes play the role of oxidants. For acridine, the SNHAr step has been accomplished by the oxidation of the intermediate 9phosphoryl-9,10-dihydroacridines (X = O) with chloranil.
F
Scheme 1
unctionalized acridines have a great diversity of applications including pharmaceutics,1 catalysis,2 optoelectronics,3 and the development of advanced materials.4 However, comparatively few phosphorylated acridines are the focus of researchers, partially, due to the lack of reliable methods for their synthesis. Among these is nucleophilic substitution of the fluorine atom in 4,5-difluoroacridine by potassium secondary phosphine to produce the corresponding bis-4,5-phosphinoacridine designed for metal complex catalysts.5 Some other phosphorylated acridines were synthesized by the reaction of 9-haloacridines with phosphorus-centered nucleophiles6 as well as Arbuzov-type rearrangements of trialkylphosphites with acridinium salts.7 Attempting to make further contributions to the chemistry of phosphorylated acridines, we have tried to transfer the recently found cross-coupling of pyridines with secondary phosphine chalcogenides,8 a novel type of SNHAr reaction triggered and promoted by electron-deficient acetylenes as oxidants, which are consequently reduced to alkenes (Scheme 1). However, to our surprise, instead of the expected SNHAr reaction, which could lead to the corresponding aromatic phosphorylated derivatives, we have encountered a facile addition of secondary phosphine chalcogenides 1a−h to the 9,10-positions of acridine to give 9-chalcogenophosphoryl9,10-dihydroacridines 2a−h, while acetylene, the supposed oxidant, remained intact (Scheme 1). The major results and inferences of this study are summarized in the present letter. As follows from Scheme 2, the phosphorylation of acridine with diverse secondary phosphine chalcogenides proceeds as a facile catalyst-free reaction to form adducts 2a−h in good to excellent yields (61−94%). The reaction is implemented as a solvent-free version or in MeCN solution (for solid reactants). In the former case, the process requires a shorter time (1−5 h instead of 2−8 h) and © 2018 American Chemical Society
provides slightly higher yields. The yields and reaction time considerably depend on the substituent structure and nature of chalcogen in phosphine chalcogenides; bulkier substituents, lower yields, and longer reaction times are observed (Scheme 2, 2d,g), and the reaction efficiency (yields and time) decreases in the order Se > S > O (Scheme 2, 2b,e,h). Since the acidity of phosphine chalcogenides 1 decreases in the same order, it implies that proton renders an accelerating effect on the addition process. The results obtained provide evidence that the straightforward stereoselective addition of secondary phosphine chalcogenides to acridine opens up an easy expedient access to a novel family of phosphorylated acridines. Received: September 25, 2018 Published: November 16, 2018 7388
DOI: 10.1021/acs.orglett.8b03061 Org. Lett. 2018, 20, 7388−7391
Letter
Organic Letters
The target SNHAr reaction has been eventually accomplished by oxidation of the corresponding dihydroacridines 2a−d (which are actually intermediates in the expected SNHAr reaction) with chloranil to furnish aromatized products, 9phosphorylacridines 4a−d in almost quantitative yields (Scheme 4).
Scheme 2. Addition of Secondary Phosphine Chalcogenides to Acridine: Synthesis of 9-Chalcogenophosphoryl-9,10dihydroacridinesa
Scheme 4. Oxidative Aromatization of 9Chalcogenophosphoryl-9,10-dihydroacridines with Chloranila
a
Reagents and conditions: acridine (1.0 mmol), secondary phosphine chalcogenide 1a−h (1.0 mmol), MeCN (3 mL), 70−75 °C. bWithout solvent.
The scope of the addition step is extendable over dialkyl phosphonates as exemplified by Scheme 3 (for experimental details, see the Supporting Information).
a
Scheme 3. Addition of Dipropyl Phosphonate to Acridine
Only phosphoryl derivatives (X = O) appeared to be tolerant of this reaction, while sulfur or selenium analogues (X = S, Se) gave, under the same conditions, mixtures of products that were difficult to identify. In any case, completion of the SNHAr reaction for phosphoryl chalcogenides (X = O) can be considered a novel synthetically and fundamentally useful result. Similar to the reaction mechanism, the resistance of acridine to a one-step SNHAr reaction in the presence of electrondeficient acetylenes (stopping this reaction at the addition stage) may be understood in terms of steric hindrance to the approach of the acetylene molecule to the nitrogen atom of two neighboring benzene rings. At the same time, a proton, as a competitive electrophile, can easily attack the electron lone pair of the acridine nitrogen. Therefore, the addition of phosphine chalcogenides to acridines is likely initiated by equilibrium formation of a salt-like intermediate in which the positive charge on the nitrogen atom is partially translated to the position 9 in the resonance structure (Scheme 5). The chalcogenophosphoryl anion, generated by dissociation of this intermediate, attacks cationic position 9, to form the final adducts. The key role of the proton in this mechanism is evidenced by the experiments (Scheme 2) showing that the reaction efficiency (yields and the process duration) improves for more
Reagents and conditions: 9-chalcogenophosphoryl-9,10-dihydroacridine 2a−d (1.0 mmol), chloranil (1.2 mmol), toluene (4 mL), 80−85 °C.
Unlike pyridines, which under similar conditions in the presence of electron-deficient acetylenes undergo catalyst-free cross-coupling with secondary phosphine chalcogenides, i.e., a SNHAr reaction, wherein acetylene acts as an oxidant that is reduced to the corresponding alkene,8 acridine is not oxidized to its aromatic phosphorylated derivatives, even when heated with benzoylphenylacetylene at 160 °C for 20 h. According to the 1H NMR spectrum of the reaction mixture, elimination of bis(2-phenylethyl)phosphine sulfide 1e from dihydroacridine 2e took place under these conditions to restore acridine and to form an adduct of phosphine sulfide 1e to benzoylphenylacetylene. An attempt to aromatize dihydroacridines 2a−h by oxidation with air oxygen (80 °C, toluene, 8 h) led to a complex mixture of products, among which acridine was detected (1H NMR). 7389
DOI: 10.1021/acs.orglett.8b03061 Org. Lett. 2018, 20, 7388−7391
Letter
Organic Letters Scheme 5. Plausible Mechanism of Nucleophilic Addition
Scheme 7. Plausible Mechanism of 2a−d Oxidative Aromatization
acidic phosphine chalcogenides, as noted above. The carbon analogue of acridine, anthracene, which is not able to be protonated under the above conditions, did not add phosphine sulfide 1e as checked experimentally. The importance of steric requirements for the attack of secondary phosphine chalcogenides at the position 9 that follows from the mechanism proposed (Scheme 5) is also confirmed by the experimental results. In fact, higher yields and a shorter reaction time are observed for less voluminous diphenyl phosphine chalcogenides and otherwise (Scheme 2). Remarkably, for presumably less sterically demanding and more electrophilic acetylene carboxylates, the nucleophilic attack of the acridine nitrogen at the triple bond to generate carbanionic zwitterions is, in some cases, possible, as it was mentioned in earlier publications, wherein the threecomponent adducts with methanol or nitromethane were formed in 81%9 and 1−8%10 yields, respectively (Scheme 6).
efficiency in both the presence and absence of electrondeficient acetylene that essentially differs from the pyridine, which in the presence of the above acetylene as the oxidant under the same conditions affords SNHAr products in a one-pot procedure. For acridine, the SNHAr reaction has been accomplished (almost quantitatively) by oxidation of the intermediate 9-phosphoryl-9,10-dihydroacridines with chloranil instead of electron-deficient acetylenes which prove to be weaker oxidants in this case. The reactions developed make two new families of phosphorylated acridines easily accessible: 9-chalcogenophosphoryl-9,10-dihydroacridines (intermediates of SNHAr reaction) and 9-phosphorylacridines (final products of SNHAr reaction), which are new prospective ligands for the design of metal complex catalysts, precursors of pharmaceuticals and building blocks for advanced materials.
Scheme 6. Three-Component Reaction between Acridine, Acetylene Carboxylates, and Methanol or Nitromethane
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03061. Experimental procedures, characterization and NMR spectral data (PDF)
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ASSOCIATED CONTENT
* Supporting Information S
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AUTHOR INFORMATION
Corresponding Author
*E-mail: boris_trofi
[email protected]. ORCID
Apparently, in these reactions, acetylenes become competitive over protons due to the lower acidity of methanol or nitromethane as compared to phosphine chalcogenides 111 (pKa 29.9 and 17.2 for MeOH and MeNO2,12 respectively). The completion of the SNHAr step (Scheme 4) likely occurs as a single electron transfer (SET) from intermediate 9phosphoryl-9,10-dihydroacridines 2a−d to the oxidant (chloranil) to give a radical ion pair, which is further transformed to the final products 4a−d after the proton and hydrogen radical transfers between the phosphoryl radical cation and chloranil radical anion moieties (Scheme 7). In an agreement with the proposed mechanism, the most facile oxidation is observed for dihydroacridine 2d, which has a stronger electron-donating substituent (compared to other substituents), PhCH(Me)CH2, at the phosphorus atom that should facilitate the SET process. In conclusion, acridine undergoes a facile catalyst-free phosphorylation with secondary phosphine chalcogenides to form 9-chalcogenophosphoryl-9,10-dihydroacridines in good to excellent yields. This nucleophilic addition, which represents the first step of the SNHAr reaction, proceeds with the same
Boris A. Trofimov: 0000-0002-0430-3215 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the Russian Scientific Foundation (Grant No. 18-73-10080). The main results were obtained using the equipment of the Baikal Analytical Center of Collective using SB RAS.
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REFERENCES
(1) For example papers, see: (a) Ramesh, K. B.; Pasha, M. A. Bioorg. Med. Chem. Lett. 2014, 24, 3907. (b) Schmidt, A.; Liu, M. Adv. Heterocycl. Chem. 2015, 115, 287. (c) Pérez, S. A.; de Haro, C.; Vicente, C.; Donaire, A.; Zamora, A.; Zajac, J.; Kostrhunova, H.; Brabec, V.; Bautista, D.; Ruiz, J. ACS Chem. Biol. 2017, 12, 1524. (d) Matsheku, A. C.; Chen, M. Y.-H.; Jordaan, S.; Prince, S.; Smith, G. S.; Makhubela, B. C. E. Appl. Organomet. Chem. 2017, 31, e3852. (e) Li, Z.; Liu, R.; Tan, Z.; He, L.; Lu, Z.; Gong, B. ACS Sensors 2017, 2, 501. (f) Bragagni, M.; Carta, F.; Osman, S. M.; AlOthman, Z.; 7390
DOI: 10.1021/acs.orglett.8b03061 Org. Lett. 2018, 20, 7388−7391
Letter
Organic Letters Supuran, C. T. J. J. Enzyme Inhib. Med. Chem. 2017, 32, 701. (g) Kusuzaki, K.; Matsubara, T.; Murata, H.; Logozzi, M.; Iessi, E.; Di Raimo, R.; Carta, F.; Supuran, C. T.; Fais, S. J. J. Enzyme Inhib. Med. Chem. 2017, 32, 908. (h) Aday, B.; Ulus, R.; Tanç, M.; Kaya, M.; Supuran, C. T. Bioorg. Chem. 2018, 77, 101. (2) For example papers, see: (a) Gunanathan, C.; Milstein, D. Angew. Chem., Int. Ed. 2008, 47, 8661. (b) Srimani, D.; Diskin-Posner, Y.; Ben-David, Y.; Milstein, D. Angew. Chem., Int. Ed. 2013, 52, 14131. (c) Gigant, N.; Bäckvall, J.-E. Org. Lett. 2014, 16, 4432. (d) Ye, X.; Plessow, P. N.; Brinks, M. K.; Schelwies, M.; Schaub, T.; Rominger, F.; Paciello, R.; Limbach, M.; Hofmann, P. J. Am. Chem. Soc. 2014, 136, 5923. (e) Zhu, R.-Y.; He, J.; Wang, X.-C.; Yu, J.-Q. J. Am. Chem. Soc. 2014, 136, 13194. (3) For example papers, see: (a) Zhang, Y.-X.; Zhang, L.; Cui, L.-S.; Gao, C.-H.; Chen, H.; Li, Q.; Jiang, Z.-Q.; Liao, L.-S. Org. Lett. 2014, 16, 3748. (b) Chen, X.; Zhang, Y.; Chen, Y.; Zhang, J.; Chen, J.; Li, M.; Cao, W.; Chen, J. Eur. J. Org. Chem. 2014, 2014, 4170. (c) Cui, Y.; Liu, J. Tetrahedron Lett. 2017, 58, 1579. (d) Zhao, B.; Miao, Y.; Wang, Z.; Wang, K.; Wang, H.; Hao, Y.; Xu, B.; Li, W. Nanophotonics 2017, 6, 1133. (e) Wang, S.; Cheng, Z.; Song, X.; Yan, X.; Ye, K.; Liu, Y.; Yang, G.; Wang, Y. ACS Appl. Mater. Interfaces 2017, 9, 9892. (4) For example papers, see: (a) Chowdhury, M. A. H.; Rahman, M. S.; Islam, M. R.; Rajbangshi, S.; Ghosh, S.; Hogarth, G.; Tocher, D. A.; Yang, L.; Richmond, M. G.; Kabir, S. E. J. Organomet. Chem. 2016, 805, 34. (b) Manoryk, P. A.; Lampeka, Ya. D.; Ermokhina, N. I.; Tsymbal, L. V.; Telbiz, G. M.; Gurtovyi, R. I. Theor. Exp. Chem. 2017, 53, 349. (c) Zhang, M.; Wang, G.; Zhao, D.; Huang, C.; Cao, H.; Chen, M. Chem. Sci. 2017, 8, 7807. (d) Cho, A.-N.; Chakravarthi, N.; Kranthiraja, K.; Reddy, S. S.; Kim, H.-S.; Jin, S.-H.; Park, N.-G. J. Mater. Chem. A 2017, 5, 7603. (e) Wang, M.; Fan, Q.; Jiang, X. Org. Lett. 2018, 20, 216. (5) Hillebrand, S.; Bartkowska, B.; Bruckmann, J.; Krüger, C.; Haenel, M. W. Tetrahedron Lett. 1998, 39, 813. (6) (a) Issleib, K.; Brüsehaber, L. Z. Z. Naturforsch., B: J. Chem. Sci. 1965, 20, 181. (b) Srinivas, V.; Swamy, K. C. K. ARKIVOC 2009, xii, 31. (c) Zhang, H.-Y.; Sun, M.; Ma, Y.-N.; Tian, Q.-P.; Yang, S.-D. Org. Biomol. Chem. 2012, 10, 9627. (7) (a) Ishikawa, K.; Akiba, K.; Inamoto, N. Bull. Chem. Soc. Jpn. 1978, 51, 2684. (b) Motoyoshiya, J.; Ikeda, T.; Tsuboi, S.; Kusaura, T.; Takeuchi, Y.; Hayashi, S.; Yoshioka, S.; Takaguchi, Y.; Aoyama, H. J. Org. Chem. 2003, 68, 5950. (c) de Blieck, A.; Masschelein, K. G. R.; Dhaene, F.; Rozycka-Sokolowska, E.; Marciniak, B.; Drabowicz, J.; Stevens, C. V. Chem. Commun. 2010, 46, 258. (8) Trofimov, B. A.; Volkov, P. A.; Khrapova, K. O.; Telezhkin, A. A.; Ivanova, N. I.; Albanov, A. I.; Gusarova, N. K.; Chupakhin, O. N. Chem. Commun. 2018, 54, 3371. (9) Acheson, R. M.; Burstall, M. L. J. Chem. Soc. 1954, 3240. (10) Acheson, R. M.; Woollard, J. J. Chem. Soc., Perkin Trans. 1 1975, 438. (11) Semenzin, D.; Etemad-Moghadam, G.; Albouy, D.; Diallo, O.; Koenig, M. J. Org. Chem. 1997, 62, 2414. (12) (a) Matthews, W. S.; Bares, J. E.; Bartmess, J. E.; Bordwell, F. G.; Cornforth, F. J.; Drucker, G. E.; Margolin, Z.; McCallum, R. J.; McCollum, G. J.; Vanier, N. R. J. Am. Chem. Soc. 1975, 97, 7006. (b) Olmstead, W. N.; Margolin, Z.; Bordwell, F. G. J. Org. Chem. 1980, 45, 3295.
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DOI: 10.1021/acs.orglett.8b03061 Org. Lett. 2018, 20, 7388−7391
