Letter Cite This: Org. Lett. 2017, 19, 6124-6127
pubs.acs.org/OrgLett
Indium-Catalyzed Intramolecular Hydroamidation of Alkynes: An Exo-Dig Cyclization for the Synthesis of Pyranoquinolines through Post-Transformational Reaction Saeed Balalaie,*,†,‡ Sattar Mirzaie,† Ali Nikbakht,† Fatima Hamdan,† Frank Rominger,§ Razieh Navari,† and Hamid Reza Bijanzadeh∥ †
Peptide Chemistry Research Center, K. N. Toosi University of Technology, P.O. Box 15875-4416, Tehran, Iran Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran § Organisch-Chemisches Institut der Universitaet Heidelberg, Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany ∥ Department of Biophysics, Tarbiat Modares University, Tehran, Iran ‡
S Supporting Information *
ABSTRACT: An efficient approach for the synthesis of pyranoquinolines through the indium-catalyzed activation of alkynes is reported. Intramolecular hydroamidation of alkynes can proceed through alkyne activation by indium(III) and then 6-exo-dig cyclization, leading to a fused pyran ring with high selectivity, high atom economy, and good to excellent yields. The cyclization was accomplished through the oxygen, not the nitrogen, of the amide functional group.
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catalyst can affect whether the endo- or exo-cyclization approach can occur, and to access the specified product there is a special catalyst. The choice of the metal catalyst also influences whether ring closure occurs via the nitrogen or oxygen of the amide functional group. Late transition metals often activate the amides by intermediate formation of metal−amido complexes, thereby increasing the reactivity of the nitrogen nucleophile toward the alkyne bond. Recently, Belmont reported an approach for the cyclization of O-alkynyl benzo hydroxamic acids through 5-exo-dig cyclization by means of the C−O bond formation using silver-catalysis.13 Indium(III) salts were used as a suitable catalyst for different cyclization reactions. This considerable attention is due to the water-tolerant and low-toxicity Lewis acid character of indium catalysts, which can be used for activation of CO and CN bonds.14 Selecting a suitable starting material and designing a posttransformation reaction can make way for the synthesis of different bioactive molecules. The combination of established isocyanide-based multicomponent reactions (IMCRs) with post-transformational reactions has become a useful approach to the synthesis of complex and diverse molecular libraries with novel properties.15 Thus, a wise choice of starting materials
he synthesis of biologically active molecules containing some heterocyclic skeletons is a fascinating issue of organic synthesis.1 The pyranoquinoline skeleton is a known heterocyclic moiety that is present in many alkaloid compounds and has a broad range of biological activities.2 There are some reports for the synthesis of these heterocyclic skeletons. Among the reported methods using o-alkynyl aldehydes, o-alkynyl esters, and o-alkynyl benzyl alcohols are general and known approaches.3 To achieve the desired cyclization, transitionmetal catalysts, electrophiles, and bases were used for the activation of the alkyne moiety.3j Furthermore, the choice of activation method has an essential role concerning the regioselectivity of the reaction. However, some of the reported methods for the synthesis of pyranoquinolinones are limited and have many drawbacks such as multistep reactions and poor availability of starting materials.4,5 In this intramolecular cyclization, different metal-catalysts, such as Pd,6 Ag salts,7,8 Au9 and Pt10 are used. O-Alkynyl amides are also suitable starting materials for the metal-catalyzed cyclization reaction of amides.11 Intramolecular hydroamidation of alkynes is known for the synthesis of N-heterocyclic skeletons and an easier approach compared to intermolecular versions. Different metal catalysts have been reported to promote such reactions.12 Most substrates appear to exhibit a preference for the formation of either exo- or endo cyclization products, and in some cases lead to a mixture of products. In several examples, however, the © 2017 American Chemical Society
Received: September 24, 2017 Published: October 31, 2017 6124
DOI: 10.1021/acs.orglett.7b02603 Org. Lett. 2017, 19, 6124−6127
Letter
Organic Letters
The attempts gave unsatisfactory results (entries 2−5) in which the reaction did not proceed with different silver salts or palladium acetate in toluene. We changed our approach, using indium(III) chloride as a catalyst and checking its effect by using different ratios. The reactions were carried out in different solvents such as toluene, acetonitrile, ethanol, and DMSO (entries 7−11). Decreasing the reaction mixture temperature reduced the yield (entry 8). On the basis of this data, the optimized reaction conditions were selected as carrying out the reaction, using 10% of InCl3 in toluene at 100 °C (entry 9). The influence of different catalysts was also explored as shown in Table 1. The spectroscopic data confirmed the formation of 6l. Compared to the Ugi-4CR product 5l, in the 1H NMR spectrum of 6l, the amide proton in the spectra was deleted, and a new peak at δ 4.00 ppm appeared, being related to the amine group. Meanwhile, in the 13C NMR spectra, there was only one peak in the region of the carbonyl amide (168 ppm), which confirmed that the oxygen of the amide functional group contributed to cyclization. The two benzylic hydrogens are diastereotopic hydrogens and resonated as two doublets at δ 4.20 and 5.50 ppm with J = 15.0 Hz, respectively. Meanwhile, in the 13C NMR spectra, there is only one amide carbon. These data are in agreement with the structure of product 6l. The Xray crystallographic data of compound 6d confirmed the structure of the product (Figure 1). Thus, these data confirmed
with suitable functional groups to access the alkynyl groups and the amide bonds has an essential role for further transformations and the construction of bioactive heterocyclic skeletons. In continuation of our interest in post-transformational reactions,16 we report the indium-catalyzed intramolecular hydroamidation reaction for the synthesis of functionalized pyranoquinolines through an Ugi post-transformational reaction (Scheme 1). Scheme 1. Synthesis of Functionalized Pyranoquinolines 6a−l through Ugi-4CR/Indium-Catalyzed Cyclization Reaction Sequences
In the beginning, 2-chloro-3-formylquinolone was prepared on the basis of a known method.17 We focused our initial studies on the preparation of the novel bifunctional precursor 2-alkynynylquinoline-3-carbaldehyde 1 using a previously reported synthetic procedure.18 Subjecting 2-phenylacetynylquinoline carbaldehyde 1a, benzylamine 2b, 4-methoxybenzoic acid 3d, and cyclohexyl isocyande 4b to stirring in methanol at room temperature for 24 h furnished the desired Ugi adduct (5l). The desired compound was separated, and its structure was confirmed on the basis of spectroscopic data. With this compound in hand, we next explored the optimum reaction conditions for the cyclization reaction of the pseudopeptide containing quinoline and alkyne moiety 6l. At the outset of this study, our efforts were focused on finding appropriate reaction conditions to perform the proposed reaction. Consequently, the model reaction was carried out in various solvents such as acetonitrile, toluene, ethanol, and DMSO. The results are summarized in Table 1. The reaction did not proceed without a catalyst.
Figure 1. ORTEP structure of 6d.
that cyclization was made through the oxygen of the amide functional group and not the nitrogen. A distinguishing point in the X-ray crystal structure is related to the conformation of the aryl group. It seems that π−π stacking has an important role in the orientation of the aryl group. Following these valuable results, we investigated the sequential process of Ugi−4CR/cyclization reaction. To achieve this goal, we filtered the precipitated Ugi−4CR product and used it for a further cyclization reaction. In this reaction condition, the yield was the same as before, and the results were validated. To examine the scope and generality of sequential reaction, other 2-chloro-3-formylquinolone, furfurylamine, tertbutyl isocyanide, and different carboxylic acid derivatives were examined. As illustrated in Figure 2, this sequential reaction proceeded very well for all starting materials and led to the expected products 6a−l in good to excellent yields. The reported yields are related to the sequential reaction obtained after purification of the final products. The meta-, para-substituted derivatives were obtained efficiently without significant influence by the nature of substitutive electron-withdrawing or electron-donating groups. From a mechanistic point of view, it seems that π-activation of the triple bond by using indium trichloride produces
Table 1. Optimization Reaction Conditions for the Synthesis of Compound 6la
entry 1 2 3 4 5 6 7 8 9 10 11 a
catalyst (mol %)
solvent
temp (°C)
AgNO3 (10) AgOTf (10) AgOAc (10) Pd(OAc)2 (10) InCl3 (10) InCl3 (5) InCl3 (10) InCl3 (10) InCl3 (10) InCl3 (10)
toluene toluene toluene toluene toluene CH3CN toluene toluene toluene EtOH DMSO
100 100 100 100 100 80 100 90 100 80 100
yield (%)
42 82 87 94
In all cyclization reactions, the time of the reaction was 16 h. 6125
DOI: 10.1021/acs.orglett.7b02603 Org. Lett. 2017, 19, 6124−6127
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Organic Letters
the internal carbon of the triple bond led to the formation of the complex. An interesting point in the cyclization is related to the contribution of the amide in cyclization through oxygen and the formation of pyranoquinoline derivatives. This reaction possesses highly atom-economical-character and requires only a catalytic amount of the appropriate indium(III) chloride and provides, with high selectivity, only the pyran ring. To confirm our claim about the role of nitrogen in cyclization reaction, 2-(phenylacetynyl)benzaldehyde was used as starting material in Ugi-4CR. The cyclization reaction of Ugi product 7 in the presence of InCl3 (10%) at 100 °C in toluene after 24 h did not proceed, and the starting material remained (Scheme 3). Scheme 3. Attempted Cyclization Study of 7
In conclusion, we have successfully established an efficient route toward the synthesis of a diverse array of pyranoquinolines through an expedient post-Ugi intramolecular cyclization reaction. We showed an interesting behavior of indium and the cyclization of the amide through oxygen, not nitrogen. This procedure provides several advantageous features including one-pot procedure, mild reaction conditions, the simplicity of operation, high atom-economy, and good to high yields.
Figure 2. Structures of synthesized pyranoquinolinones 6a−l (a) Reaction conditions: 5a−l (0.50 mmol), indium chloride (10% mol) in 10 mL of toluene, at 100 °C for 16 h.
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intermediate A. Meanwhile, the existence of the nitrogen in the structure of quinolone has an essential role in the stability and formation of the complex.9b Among the two cyclization approaches, the 6-exo-dig that led to the pyran ring is favored over the 7-endo-dig cyclization that gave oxepine ring (Scheme 2). Later, nucleophilic addition of the oxygen of the amide to
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02603. Detailed experimental procedure, 1H NMR and 13C NMR spectra, as well as X-ray data information (PDF) Crystallographic data for compound 6d (CIF)
Scheme 2. Proposed Mechanism for the Synthesis of Pyranoquinolines 6a−l through Post-Ugi Cyclization Reaction
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Tel: +98-21-23064226. Fax: +9821-22889403. ORCID
Saeed Balalaie: 0000-0002-5764-0442 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the Iran National Science Foundation (INSF, Grant No. 96003234) and the National Institute for Medical Research Development (NIMAD) for financial support.
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REFERENCES
(1) Cabrele, C.; Reiser, O. J. Org. Chem. 2016, 81, 10109−10125 and references cited therein. 6126
DOI: 10.1021/acs.orglett.7b02603 Org. Lett. 2017, 19, 6124−6127
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Organic Letters (2) (a) Verma, A. K.; Rustagi, V.; Aggarwal, T.; Singh, A. P. J. Org. Chem. 2010, 75, 7691−7703. (b) Verma, A. K.; Aggarwal, T.; Rustagi, V.; Larock, R. C. Chem. Commun. 2010, 46, 4064−4066. (c) Zhang, Q.; Zhang, Z.; Yan, Z.; Liu, Q.; Wang, T. Org. Lett. 2007, 9, 3651− 3653. (d) Michael, J. P. Nat. Prod. Rep. 2005, 22, 627−646. (e) Babu, G.; Perumal, P. T. Tetrahedron Lett. 1998, 39, 3225−3228. (3) (a) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079−3160. (b) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127−2198. (c) Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem., Int. Ed. 2004, 43, 3368−3398. (d) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285−2310. (e) Shen, H. C. Tetrahedron 2008, 64, 3885−3903. (f) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395−3442. (g) Asao, N.; Nogami, T.; Takahashi, K.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 764−765. (h) Cikotiene, I.; Buksnaitiene, R. Adv. Synth. Catal. 2012, 354, 2719−2726. (4) (a) Zhang, X.; Campo, M. A.; Yao, T.; Larock, R. C. Org. Lett. 2005, 7, 763. (b) Dhanabal, T.; Suresh, T.; Mohan, P. S. Indian J. Chem. 2006, 45B, 523. (5) (a) Ravindranath, N.; Ramesh, C.; Reddy, M. R.; Das, B. Chem. Lett. 2003, 32, 222−223. (b) Marco-Contelles, J.; León, R.; López, M. G.; García, A. G.; Villarroya, M. Eur. J. Med. Chem. 2006, 41, 1464− 1469. (c) Butenschon, I.; Möller, K.; Hansel, W. J. J. Med. Chem. 2001, 44, 1249−1256. (d) Kalita, K. P.; Baruah, B.; Bhuyan, P. J. Tetrahedron Lett. 2006, 47, 7779−7782. (6) (a) Li, Y.; Zhang, Q.; Wang, H.; Cheng, B.; Zhai, H. Org. Lett. 2017, 19, 4387−4390 and references cited therein. (b) Mondal, S.; Nogami, T.; Asao, N.; Yamamoto, Y. J. Org. Chem. 2003, 68, 9496− 9498. (c) Gulías, M.; Rodríguez, J. R.; Castedo, L.; Mascareñas, J. L. Org. Lett. 2003, 5, 1975−1977. (7) (a) Harmata, M.; Huang, C. Synlett 2008, 2008, 1399−1401. (b) Godet, T.; Vaxelaire, C.; Michel, C.; Milet, A.; Belmont, P. Chem. Eur. J. 2007, 13, 5632−5641. (c) Parker, E.; Leconte, N.; Godet, T.; Belmont, P. Chem. Commun. 2011, 47, 343−345. (8) (a) Verma, A. K.; Reddy Kotla, S. K.; Choudhary, D.; Patel, M.; Tiwari, R. K. J. Org. Chem. 2013, 78, 4386−4401. (b) Bontemps, A.; Mariaule, G.; Desbène-Finck, S.; Philippe Helissey, P.; Giorgi-Renault, S.; Michelet, V.; Belmon, P. Synthesis 2016, 48, 2178−2190. (9) (a) Tomás-Mendivil, E.; Starck, J.; Ortuno, J.-C.; Michelet, V. Org. Lett. 2015, 17, 6126−6129. (b) Tomás-Mendivil, E.; Heinrich, C. F.; Ortuno, J.-C.; Starck, J.; Michelet, V. ACS Catal. 2017, 7, 380−387. (10) (a) Girard, A.-L.; Enomoto, T.; Yokouchi, S.; Tsukano, C.; Takemoto, Y. Chem. - Asian J. 2011, 6, 1321−1324. (b) Tsukano, C.; Yokouchi, S.; Girard, A.-L.; Kuribayashi, T.; Sakamoto, S.; Enomoto, T.; Takemoto, Y. Org. Biomol. Chem. 2012, 10, 6074−6086. (11) (a) Obika, S.; Yasui, Y.; Yanada, R.; Takemoto, Y. J. Org. Chem. 2008, 73, 5206. (b) Zhang, L.; Ye, D.; Zhou, Y.; Liu, G.; Feng, E.; Jiang, H.; Liu, H. J. Org. Chem. 2010, 75, 3671. (c) Wu, J.; Jiang, Y.; Dai, W.-M. Synlett 2009, 2009, 1162. (d) Zhao, X.; Zhang, E.; Tu, Y.Q.; Zhang, Y.-Q.; Yuan, D.-Y.; Cao, K.; Fan, C.-A.; Zhang, F.-M. Org. Lett. 2009, 11, 4002. (12) Huang, L.; Arndt, M.; Gooßen, K.; Heydt, H.; Gooßen, L. J. Chem. Rev. 2015, 115, 2596−2697 and references cited therein. (13) Bantreil, X.; Bourderioux, A.; Mateo, P.; Hagerman, C. E.; Selkti, M.; Brachet, E.; Belmont, P. Org. Lett. 2016, 18, 4814−4817. (14) (a) Itoh, Y.; Tsuji, H.; Yamagata, K-i.; Endo, K.; Tanaka, I.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2008, 130, 17161− 17167. (b) Sakai, N.; Annaka, K.; Fujita, A.; Sato, A.; Konakahara, T. J. Org. Chem. 2008, 73, 4160−4165. (c) Patil, D. V.; Phun, L. H.; France, S. Org. Lett. 2010, 12, 5684−5687. (d) Surendra, K.; Qiu, W.; Corey, E. J. J. Am. Chem. Soc. 2011, 133, 9724−9726. (e) Tsuji, H.; Yamagata, K-i.; Itoh, Y.; Endo, K.; Nakamura, M.; Nakamura, E. Angew. Chem., Int. Ed. 2007, 46, 8060−8062. (f) Yadav, J. S.; Reddy, B. V. S.; Rao, K. V.; Raj, K. S.; Prasad, A. R.; Kumar, S. R.; Kunwar, A. C.; Jayaprakash, P.; Jagannath, B. Angew. Chem., Int. Ed. 2003, 42, 5198−5201. (g) Yanada, R.; Obika, S.; Kono, H.; Takemoto, Y. Angew. Chem., Int. Ed. 2006, 45, 3822−3825. (15) (a) Müller, T. J. J. In Synthesis of Heterocycles via Multicomponent Reactions II; Orru, R. V., Ruijter, E., Eds.; Springer: Berlin, 2010; Chapter 1, pp 25−94. (b) Koopmanschap, G.; Ruijter, E.; Orru, R. V.
Beilstein J. Org. Chem. 2014, 10, 544. (c) Zarganes-Tzitzikas, T.; Chandgude, A. L.; Dömling, A. Chem. Rec. 2015, 15, 981. (d) Sharma, U. K.; Sharma, N.; Vachhani, D. D.; Van der Eycken, E. V. Chem. Soc. Rev. 2015, 44, 1836. (16) (a) Balalaie, S.; Shamakli, M.; Nikbakht, A.; Alavijeh, N. S.; Rominger, F.; Rostamizadeh, S.; Bijanzadeh, H. R. Org. Biomol. Chem. 2017, 15, 5737−5742. (b) Ghabraie, E.; Balalaie, S.; Mehrparvar, S.; Rominger, F. J. Org. Chem. 2014, 79, 7926−7934. (c) Maghari, S.; Ramezanpour, S.; Balalaie, S.; Darvish, F.; Rominger, F.; Bijanzadeh, H. R. J. Org. Chem. 2013, 78, 6450−6456. (17) (a) Verma, A. K.; Aggarwal, T.; Rustagi, V.; Larock, R. C. Chem. Commun. 2010, 46, 4064. (b) Chandra, A.; Singh, B.; Upadhyay, S.; Singh, R. M. Tetrahedron 2008, 64, 11680. (18) Bontemps, A.; Mariaule, G.; Desbène-Fincka, S.; Helisseya, P.; Giorgi-Renault, S.; Michelet, V.; Belmon, P. Synthesis 2016, 48, 2178− 2190 and references cited therein.
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DOI: 10.1021/acs.orglett.7b02603 Org. Lett. 2017, 19, 6124−6127
