Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Synthesis of Quinolizinium-Type Heteroaromatics via a Carbene Intermediate Feng Li, Jihee Cho, Shenpeng Tan, and Sanghee Kim* College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Korea S Supporting Information *
ABSTRACT: An efficient synthesis of quinolizinium-type heteroaromatics by Pt(II)-catalyzed cyclization of 2-arylpyridine propargyl alcohol has been developed. The presence of a protic acid is crucial for the success of the reaction. Mechanistic studies disclosed that the reaction proceeds via a platinum−carbene intermediate. Additionally, the fluorescence properties of the synthesized heteroaromatics were investigated to provide perspectives for potential applications.
Q
Scheme 1. Construction of Polycyclic Aromatics
uinolizinium is a positively charged aromatic compound with a quaternary bridgehead nitrogen. Quinolizinium is a key structural motif in many natural alkaloids and biologically active compounds.1 In addition, quinolizinium-type polycyclic aromatic nitrogen cations have several potential applications in many fields and can be used as fluorescent dyes, nonlinear optical materials, and ionic liquids.2 Consequently, various methods of synthesis have been devised for these compounds.3 Most classical methods involve either N-alkylation or aromatization steps or both; these steps require rather harsh conditions. Thus, these methods often suffer from the lack of general applicability and low functional group tolerance. Recently, transition-metalcatalyzed C−H activation and annulation approaches have received attention as superlative methods for quinolizinium synthesis.3a,4 Although these methods are efficient, stoichiometric or excess amounts of oxidants are generally needed to complete the catalytic cycle, leading to low atom economy. Thus, the development of simple and effective methods for the construction of quinolizinium compounds with structural diversity is still in demand. As part of our continuing interest in the synthesis of polycyclic aromatic compounds via metal-catalyzed cyclization, we became interested in developing a new method for the preparation of quinolizinium scaffold containing heteroaromatic molecules via nucleophilic attack by pyridine nitrogens on alkyne groups. Although the intramolecular reactions between pyridine nitrogens and the metal-activated alkynes have been reported for the synthesis of five-membered ring products such as indolizines,5 there is no precedent for the use of these reactions for sixmembered ring annulation that leads to the formation of quinolizinium-type systems. Moreover, there exists no previous report for the synthesis of quinoliziniums through metal− carbene intermediates. We have previously reported a platinum-catalyzed synthesis of phenanthrenes from biphenyl propargyl alcohol substrates (1, Scheme 1) via a carbene intermediate 2.6 In light of this precedent, we envisioned that substrates such as 4, which contains a pyridine moiety, could provide quinolizinium scaffolds without the need for oxidation. Herein, we report our results on © XXXX American Chemical Society
the formation of quinolizinium-type heteroaromatic systems by a metal-catalyzed intramolecular cyclization reaction between a pyridine and a propargyl alcohol, with water as the only byproduct. Mechanistic studies disclosed that the reaction proceeds via a carbene intermediate. In addition, we present a brief study on the fluorescent properties of the obtained quinolizinium derivatives to provide a better understanding of these systems as fluorophores. The initial investigation was carried out using easily accessible 2-phenylpyridine propargyl alcohol 4a as a model substrate for the formation of the quinolizinium motif (Table 1). From the outset, we were aware that our envisioned reaction would face some challenges. The N-cyclization could proceed along three competing pathways, namely, 5-exo-tet, 6-exo-dig, and 7-endo-dig, which are all favored by Baldwin’s rules. Another main challenge is the deactivation of catalysts by the coordination of the pyridine nitrogen. With these in mind, several alkynophilic metal catalysts (10 mol %), such as AuCl3,7d,e,8d AgOTf,7c,8b Pd(OAc)2,7g,8c [RhCp*Cl2]2,7a,8a InBr3,7b and PtCl2,7f were screened in toluene (0.1 M) at 80 °C (oil bath). No product was observed, and the starting material was mostly recovered. Even in the presence of a typical counter-anionic source such as NaOTf or KPF6, the Received: December 21, 2017
A
DOI: 10.1021/acs.orglett.7b03964 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization of Reaction Conditionsa
With the optimized reaction conditions in hand, we next explored the scope of this transformation. In general, diversely fused quinolizinium-type heteroaromatics were afforded at satisfactory yields (Scheme 2). At first, we examined substrates Scheme 2. Substrate Scope of the Reaction
entry 1 2 3 4 5 6 7 8 9 10 11c 12 13 14 15 16 17
catalyst PtCl2 PtCl2 PtCl2 PtCl2 PtCl2 PtCl2 AuCl3 Pd(OAc)2 [RhCp*Cl2]2 AgOTf Cu(OTf)2 PtCl4 PtBr2 PtCl2(PPh3)2 PtCl2(PPh3)2 PtCl2(PPh3)2
additive (MX or HX) NaOTf KPF6 TfOH HCl TsOH TFA TfOH TfOH TfOH TfOH TfOH TfOH TfOH TfOH TfOH TfOH TfOH
solvent toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene DCE toluene/ MeOHd
time (h)
yieldb (%)
12 12 1 6 1 2 1 1 1 7 0.5 1 1 1 6 1 1.5
0 0 5a (81) 5a (72) 5a (70) 5a (63) messy 5a (40) 5a (24) 5a (27) 6 (78) 6 (32) 5a (57) 5a (84) 5a (92) 5a (83) 5a (95)
a Reaction conditions: 4a (0.1 mmol), additive (0.1 mmol), and metal catalyst (0.01 mmol, 10 mol %) in solvent (1 mL). bIsolated yield. c Reaction was conducted at rt. dToluene/MeOH (10:1, v/v).
reaction was not successful (entries 1 and 2). On the other hand, when the reaction was performed in the presence of a protic acid, the desired cyclization product 5a was obtained. For example, in the reaction with PtCl2 in the presence of 1 equiv of TfOH, the 6exo-dig cyclized product 5a was obtained in 81% yield (entry 3). Products derived from 5-exo-tet and 7-endo-dig cyclization were not observed. The molecular structure of 5a containing an OTf anion was confirmed by X-ray crystallography.9 The above results implied that the presence of a proton donor, not the effect of counteranion, was critical to the success of the reaction (entries 1 and 2 vs entry 3). Other protic acids, such as HCl, TsOH, and TFA, also successfully promoted the reaction with PtCl2 to yield 5a, albeit in lower yields (entries 4−6). Without the metal catalyst, acid alone resulted in a complex mixture without any noticeable amount of 5a (entry 7). In the presence of TfOH, some other alkynophilic metal ions, such as Au, Pd, and Rh, also provided the cyclized product 5a, but in much lower yields (entries 8−10). On the other hand, the use of AgOTf or Cu(OTf)2 led to the formation of quaternary pyridinium salt 6 without the formation of 5a (entries 11 and 12).10 The quaternary pyridinium salt 6 is also a 6-exo-dig product, but the hydroxyl group remained intact. Heating of the isolated 6 at 80 °C for 12 h, even in the presence of TfOH, did not result in the formation of 5a, suggesting that the reaction mechanism may differ from that observed with platinum. Further investigation of the platinum catalyst revealed that Pt(II) was more effective than Pt(IV) (entry 3 vs entry 13). The best results were achieved using PtCl2(PPh3)2. With respect to reaction rate and yield, the most effective solvent system for the PtCl2(PPh3)2catalyzed reaction was 10% methanolic toluene, which furnished 5a in 95% yield in 1.5 h (entry 17).
a Reaction conditions: 4 (0.1 mmol), TfOH (0.1 mmol), and PtCl2(PPh3)2 (0.01 mmol, 10 mol %) in toluene/MeOH (10:1, v/v, 1 mL).
bearing various functional groups at the alkyne moiety. The substrates with aliphatic groups, such as isopropyl and n-butyl, underwent smooth cyclization to afford 5b and 5c in 93 and 86% yields, respectively. The product 5c is a mixture of Z and E isomers in a 1:1.8 ratio. The benzyl-substituted alkynes 4d−f (R1 = Me or H, R2 = Ph) also successfully yielded quinolinium salts 5d−f but without appreciable Z/E selectivity. Our next investigation was focused on the alteration of the biaryl system of 4a. Changes to the electronic nature of the phenyl ring of biaryl 4a did not affect the reaction efficiency (5g− i). Introduction of fluoro, trifluoromethyl, or methyl substituents on the upper pyridinyl ring also resulted in satisfactory yields of the products 5j−l. In addition to 2-phenylpyridine substrates, other biaryl systems were also effective Pt-catalyzed cyclization substrates and enriched the structural diversity of the products. The 2-(naphthalen-2-yl)pyridine substrate underwent smooth cyclization to afford the corresponding product 5m, while low efficiency was observed for the synthesis of 5n. The reaction of the benzo[h]quinoline substrate proceeded smoothly to yield 5o at a high yield. The 2-(thiophene-2-yl)pyridine substrate also provided the product 5p in good yield. It is noteworthy that other N-heteroaromatics, such as pyrazole and thiazole groups, were also suitable for this transformation (5q and 5r). To elucidate the reaction mechanism, a few experiments were performed (Scheme 3). The reaction of substrate 7 with a tertbutyl group, in which a 1,2-hydride shift is unrealizable, yielded a B
DOI: 10.1021/acs.orglett.7b03964 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 3. 1,2-Methyl Shift and C−H Insertion of Platinum Carbene Complexes
Scheme 5. Plausible Mechanism
a
Yield in parentheses refers to the result obtained by using PtBr2 (10 mol %) instead of PtCl2(PPh3)2.
platinum carbene intermediate III. Finally, the intermediate III undergoes 1,2-H migration to yield the final product 5a, with regeneration of the active catalyst. The fluorescence properties of the obtained heteroaromatic compounds were studied (Figure 1a and Figures S2−S4). The
tetrasubstituted vinyl product 8. This compound might arise from a 1,2-shift of one of the methyl groups.11 When substrate 9, with a benzyloxyphenyl substituent attached to the alkyne, was subjected to the standard reaction conditions, a complex mixture was obtained. However, when TfOH was replaced with TsOH, the C−H insertion12 product 10 was formed in 31% yield. Further studies showed that the product 10 was formed in 60% yield when changing the catalyst to PtBr2. Since 1,2-alkyl shift and C−H insertion are characteristic features of carbene species,13 these experiments clearly suggest that the present reaction proceeds through a platinum carbene intermediate. In the reaction process, the role of protic acids is obviously as a source of counteranions to quinolizinium. Other possible roles include attenuation of the metal coordination ability of the pyridine nitrogen by protonation to allow the Pt catalyst to preferentially interact with the alkyne functionality for activation. This hypothesis might be plausible; we have previously observed6 that when PtCl2 was used as a catalyst the biphenyl propargyl alcohol substrate 11 was readily transformed to vinylphenanthrene 12 in the absence of a protic acid (Scheme 4a). When we conducted the same experiment in the presence of
Figure 1. (a) Fluorescence spectra of the selected compound 5 (5 μM) in 10 mM Tris−HCl buffer (10% MeOH) at pH 7.5. (b) Changes in the fluorescence of 5o (5 μM) with various anions (50 equiv) and ct DNA (30 equiv) in 10 mM Tris−HCl buffer (10% MeOH) at pH 7.5 (excitation at 282 nm).
fluorescence intensity and maximum emission wavelength (λmax) varied markedly by substituent and type of aromatic backbone. The examined compounds showed emission wavelengths in the blue to green region (λem: 380−510 nm). The maximum emission of 5m was more red-shifted than that of others. Among the compounds prepared, the strongest fluorescence intensity was shown by 5o (Figure S4). The fluorescence intensities of some compounds (e.g., 5d, 5l, and 5q) were very weak, although the structures of these compounds are not very different from those with strong fluorescence. For example, compound 5a exhibited high fluorescence intensity,15 while 5l, which differs only by one methyl group, showed very low fluorescence intensity. This is an interesting observation and deserves more systematic investigation to fully understand the relationship between the chemical structures of quinolizinium-type heteroaromatics and their fluorescence properties. Additionally, taking 5o as a representative probe, the changes in fluorescence in the presence of various anions were examined in aqueous solution at pH 7.5 (Figure 1b). As shown in Figure 1b, 5o did not display significant changes in fluorescence with various inorganic anions, such as F−, Cl−, Br−, I−, H2PO4−, or HSO4−. On the other hand, mononucleotides (AMP, ADP, and ATP) exhibited modest fluorescence-quenching effects. This result encouraged us to examine the changes in fluorescence caused by polynucleotide DNA. Calf thymus DNA (ct DNA) exhibited a large and selective fluorescence-quenching effect on compound 5o in a concentration-dependent manner (Figure S5). This fluorescence-quenching property is comparable to that of the proven DNA-intercalating agent proflavine16,17a and can
Scheme 4. Control Experiments
a stoichiometric amount of pyridine, no product was formed (Scheme 4b). When a stoichiometric amount of TfOH was added to the above reaction mixture, the reaction resumed and product 12 was formed, albeit in lower yield (36%). These results suggested that the pyridine moiety in substrate 4 captures a metal ion, leading to the inhibition of the alkyne activation. Thus, protonation of the pyridine nitrogen is an important component of the reaction. A plausible mechanism involving protonation of the pyridine moiety and formation of a metal carbene intermediate is outlined in Scheme 5.14 The first stage is protonation of the pyridine nitrogen by a protic acid, which enables the coordination of the alkyne moiety to the platinum catalyst. The intermediate I then undergoes intramolecular cyclization to generate the vinylplatinum intermediate II. Subsequent elimination of the hydroxyl group affords a quinolizinium scaffold with the C
DOI: 10.1021/acs.orglett.7b03964 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters be utilized as a fluorescent sensor for monitoring DNA-related biological functions, such as the action of DNase17 and photoinduced DNA damage.18 In conclusion, the construction of quinolizinium-type systems was achieved via intramolecular C−N bond formation between the pyridine nitrogen and metal-activated alkynes. The Pt catalyst and protic acid efficiently induced the desired cyclization and subsequent dehydration. The reaction proceeds via a carbene intermediate, which paves the way for synthesis of more sophisticated polycyclic compounds. This new and convenient synthetic protocol for securing functionalized quinoliziniums might be applied to the synthesis of related heteroaromatics with a positively charged nitrogen atom.
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(4) For a recent review, see: Gandeepan, P.; Cheng, C.-H. Chem. Asian J. 2016, 11, 448. (5) (a) Oh, K. H.; Kim, S. M.; Park, S. Y.; Park, J. K. Org. Lett. 2016, 18, 2204. (b) Xu, T.; Alper, H. Org. Lett. 2015, 17, 4526. (c) Smith, C. R.; Bunnelle, E. M.; Rhodes, A. J.; Sarpong, R. Org. Lett. 2007, 9, 1169. (d) Yan, B.; Liu, Y. Org. Lett. 2007, 9, 4323. (6) Kwon, Y.; Kim, I.; Kim, S. Org. Lett. 2014, 16, 4936. (7) (a) Kumaran, E.; Leong, W. K. Organometallics 2012, 31, 1068. (b) Sakai, N.; Annaka, K.; Konakahara, T. Tetrahedron Lett. 2006, 47, 631. (c) Asao, N.; Yudha, S. S.; Nogami, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2005, 44, 5526. (d) Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. J. Am. Chem. Soc. 2000, 122, 11553. (e) Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew. Chem., Int. Ed. 2000, 39, 2285. (f) Chatani, N.; Furukawa, N.; Sakurai, H.; Murai, S. Organometallics 1996, 15, 901. (g) Luo, F.-T.; Schreuder, I.; Wang, R.-T. J. Org. Chem. 1992, 57, 2213. (8) For recent reviews on the metal-catalyzed activation of C−C multiple bonds, see: (a) Yang, Y.; Li, K.; Cheng, Y.; Wan, D.; Li, M.; You, J. Chem. Commun. 2016, 52, 2872. (b) Fang, G.; Bi, X. Chem. Soc. Rev. 2015, 44, 8124. (c) Chinchilla, R.; Nájera, C. Chem. Rev. 2014, 114, 1783. (d) Corma, A.; Leyva-Pérez, A.; Sabater, M. J. Chem. Rev. 2011, 111, 1657. (9) See the Supporting Information for details. (10) With stoichiometric amounts of AgOTf or Cu(OTf)2 alone, the reaction also yielded 6 in 87 and 79% yields, respectively. (11) (a) Lauterbach, T.; Higuchi, T.; Hussong, M. W.; Rudolph, M.; Rominger, F.; Mashima, K.; Hashmi, A. S. K. Adv. Synth. Catal. 2015, 357, 775. (b) Lauterbach, T.; Gatzweiler, S.; Nösel, P.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Adv. Synth. Catal. 2013, 355, 2481. (12) For recent reviews of catalytic carbene insertion into C−H bonds, see: (a) Santiago, J. V.; Machado, A. H. L. Beilstein J. Org. Chem. 2016, 12, 882. (b) Gillingham, D.; Fei, N. Chem. Soc. Rev. 2013, 42, 4918. (c) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704. (13) For selected reviews of metal carbenes, see: (a) Jia, M.; Ma, S. Angew. Chem., Int. Ed. 2016, 55, 9134. (b) Zhang, Z.; Wang, J. Tetrahedron 2008, 64, 6577. (c) Bourissou, D.; Guerret, O.; Gabbaï, F. P.; Bertrand, G. Chem. Rev. 2000, 100, 39. (14) Another possible mechanism that involves the protonation of the vinylplatinum intermediate II was excluded, based on the observation that deuterium was not incorporated into the product 5a when the reaction of 4a was conducted with TfOD instead of TfOH. See the Supporting Information for details. (15) The quantum yield of 5a was determined as 0.36. For quantum yield determination, anthracene was used as a reference material (Φ = 0.27). See the Supporting Information for details. (16) Steiner, R. F. Excited States of Biopolymers; Plenum: New York, 1983. (17) (a) Kim, H. N.; Lim, J.; Lee, H. N.; Ryu, J.-W.; Kim, M. J.; Lee, J.; Lee, D.-U.; Kim, Y.; Kim, S.-J.; Lee, K. D.; Lee, H.-S.; Yoon, J. Org. Lett. 2011, 13, 1314. (b) Chang, Y.; Jin, L.; Duan, J.; Zhang, Q.; Wang, J.; Lu, Y. RSC Adv. 2015, 5, 103358. (18) (a) Barbafina, A.; Amelia, M.; Latterini, L.; Aloisi, G. G.; Elisei, F. J. Phys. Chem. A 2009, 113, 14514. (b) Ihmels, H.; Faulhaber, K.; Wissel, K.; Bringmann, G.; Messer, K.; Viola, G.; Vedaldi, D. Eur. J. Org. Chem. 2001, 2001, 1157.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03964. Experimental procedures and copies of spectra (PDF) Accession Codes
CCDC 1811500 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 data_
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Sanghee Kim: 0000-0001-9125-9541 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the Mid-Career Researcher Program (No. 2016R1A2A1A05005375) of the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP).
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REFERENCES
(1) (a) Zou, K.; Li, Z.; Zhang, Y.; Zhang, H.; Li, B.; Zhu, W.; Shi, J.; Jia, Q.; Li, Y. Acta Pharmacol. Sin. 2017, 38, 157. (b) Jortzik, E.; Zocher, K.; Isernhagen, A.; Mailu, B. M.; Rahlfs, S.; Viola, G.; Wittlin, S.; Hunt, N. H.; Ihmels, H.; Becker, K. Antimicrob. Agents Chemother. 2016, 60, 115. (c) Bhadra, K.; Kumar, G. S. Med. Res. Rev. 2011, 31, 821. (2) (a) Zacharioudakis, E.; Cañeque, T.; Custodio, R.; Müller, S.; Cuadro, A. M.; Vaquero, J. J.; Rodriguez, R. Bioorg. Med. Chem. Lett. 2017, 27, 203. (b) Seferoğlu, Z. Org. Prep. Proced. Int. 2017, 49, 293. (c) Goossens, K.; Lava, K.; Bielawski, C. W.; Binnemans, K. Chem. Rev. 2016, 116, 4643. (d) Marcelo, G.; Pinto, S.; Cañeque, T.; Mariz, I. F. A.; Cuadro, A. M.; Vaquero, J. J.; Martinho, J. M. G.; Macôas, E. M. S. J. Phys. Chem. A 2015, 119, 2351. (3) For reviews on the synthesis of quinolizinium-type heterocyclics, see: (a) Sucunza, D.; Cuadro, A. M.; Alvarez-Builla, J.; Vaquero, J. J. J. Org. Chem. 2016, 81, 10126. (b) Vaquero, J. J.; Alvarez-Builla, J. In Modern Heterocyclic Chemistry; Alvarez-Builla, J., Vaquero, J. J., Barluenga, J., Eds.; Wiley-VCH: Weinheim, Germany, 2011; Vol. 4, Chapter 22, pp 1989−2070. (c) Arai, S.; Hida, M. Adv. Heterocycl. Chem. 1992, 55, 261. D
DOI: 10.1021/acs.orglett.7b03964 Org. Lett. XXXX, XXX, XXX−XXX
