Letter pubs.acs.org/OrgLett
Construction of Fused Polyheterocycles through Sequential [4 + 2] and [3 + 2] Cycloadditions Yadong Feng, Nian Tian, Yudong Li, Chunqi Jia, Xuening Li, Lianhui Wang, and Xiuling Cui* Engineering Research Center of Molecular Medicine, Ministry of Education, Key Laboratory of Xiamen Marine and Gene Drugs, Institute of Molecular Medicine and School of Biomedical Sciences, Huaqiao University, Xiamen 361021, China S Supporting Information *
ABSTRACT: A method for Pd-catalyzed aerobic oxidative reaction of quinazolinones and alkynes has been developed for sequential [4 + 2] and [3 + 2] cycloadditions to assemble a novel fused-polycyclic system containing tetrahydropyridine and dihydrofuran rings. The reaction process involves C−H and N−H bond functionalization for the formation of tetrahydropyridine and an oxygen radical cyclization for the dihydrofuran ring. This atom- and step-economical synthesis is highly efficient and has good substrate tolerance, which provides a new approach for the construction of polycyclic molecules with potential pharmaceutical interest.
F
used polyheterocycles have attracted considerable attention in the fields of electrochemistry, photochemistry, biochemistry, and advanced functional materials, with particular interest in condensed multiaryl heterocyclic compounds because of their stability, enhanced ability to transport charge, and fluorescent properties that are granted by the aryl groups.1 As a result, great progress has been made toward construction of various fused polyheterocycles,2 among which cycloaddition has played an increasingly important role3 because multiple C− C and C−X (X = N, O, S, etc.) bonds can be formed in a onepot manner with high regioselectivity and stereoselectivity. In the forward direction, various cycloaddition pathways have been developed for the synthesis of both small- and mediumsized heterocyclic compounds, with much attention having been paid to the formation of four-, five-, six-, and sevenmembered rings through [2 + 2],4 [3 + 2],5 [4 + 2],6 [4 + 3],7 and [5 + 2]8 cycloaddition reactions. Nonetheless, di- or monofunctionalized aromatic substrates, such as aryl halides and aryl boronates, were required and reduced the “greenness”. Recently, the combination of cyclization reactions with C−H bond activation has presented an attractive and powerful protocol to generate fused aromatic or heteroaromatic compounds.9 In particular, the oxidative cycloaddition of alkynes through C−H bond cleavage has lately set the stage for economically attractive, ecologically benign syntheses of fused polycyclic heteroarenes such as indoles, isoquinolines, benzothiazoles, and pyridines.10 On the other hand, polyheterocycles containing a furan unit are important structural motifs found in biologically active molecules, such as PARS inhibitors, 5-HT, MP470, and mGluR1 (Figure 1). Herein, we present sequential [4 + 2] and [3 + 2] cycloadditions of quinazolinones with alkynes to prepare fused polyheterocycles (Scheme 1), and such a structure is notably different from the current portfolio of coupling products of alkynes. This novel protocol features easy operation, inexpensive and easily available starting materials, © XXXX American Chemical Society
Figure 1. Biologically active compounds containing a furan ring.
Scheme 1. Sequential Cycloadditions of Quinazolinones with Alkynes
high efficiency, environmental friendliness, and tolerance of a broad range of substrates. Initially, the condensation of 2-phenylquinazolin-4(3H)-one (1a) with diphenylethyne (2a) was chosen as a model reaction to examine various parameters (Table 1). The results revealed that polysubstituted 4,5-dihydro-3aH-furo[2′,3′:5,6]pyrido[1,2a]pyrimidin-9(10aH)-one (3a) was obtained as a main product in 78% yield in DMF/DMA (v/v = 1:1) at 140 °C when Pd(CH3CN)2Cl2 (10 mol %) was used as a catalyst and CuBr Received: February 14, 2017
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DOI: 10.1021/acs.orglett.7b00452 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization of the Reaction Conditionsa
entry
Pd
Cu
1 2c 3d 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Pd(CH3CN)2Cl2 Pd(CH3CN)2Cl2 Pd(CH3CN)2Cl2
CuBr CuBr CuBr CuBr CuBr CuBr CuBr CuBr CuBr
Pd(OAc)2 PdCl2 Pd(PPh3)4 Pd(CF3COO)2 Pd2(dba)3 Pd(CH3CN)2Cl2 Pd(CH3CN)2Cl2 Pd(CH3CN)2Cl2 Pd(CH3CN)2Cl2 Pd(CH3CN)2Cl2 Pd(CH3CN)2Cl2 Pd(CH3CN)2Cl2 Pd(CH3CN)2Cl2 Pd(CH3CN)2Cl2 Pd(CH3CN)2Cl2 Pd(CH3CN)2Cl2 Pd(CH3CN)2Cl2 Pd(CH3CN)2Cl2 Pd(CH3CN)2Cl2 Pd(CH3CN)2Cl2 Pd(CH3CN)2Cl2
CuI CuCl CuBr CuBr CuBr CuBr CuBr CuBr CuBr CuBr CuBr CuBr CuBr CuBr CuBr
acid TFA TFA TFA TFA TFA TFA TFA TFA TFA TFA TFA TFA AcOH PivOH TFA TFA TFA TFA TFA TFA TFA TFA TFA TFA
solvent
temp (°C)
time (h)
yieldb (%)
DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMA DMSO DCE toluene NMP DMF/DMA DMF/DMA DMF/DMA DMF/DMA DMF/DMA
140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 150 130 140 140
2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 3.0 2.0
54 19 nd nd trace nd 35 nd trace nd trace trace nd nd nd 38 nd nd nd nd 78 58 62 68 65
a
Reaction conditions: 1a (0.10 mmol), 2a (0.30 mmol), Pd (10 mol %), Cu (0.5 equiv), Acid (4.0 equiv), solvent (1.0 mL), O2 (1 atm). bIsolated yields. cAir. dN2. nd = not detected.
yields, respectively, which indicated that the electron density on the moiety of the quinazolinones did not significantly influence the efficiency of the cycloaromatization. An F group at the ortho- and para-positions of 2-phenyl in 2-arylquinazolin4(3H)-one provided the corresponding products 3e,f in 51% and 72% yields, which indicated that the steric effect of the 2aryl groups slightly impacted this transformation. Other groups, such as Cl, Br, trifluoromethyl, methyl, tert-butyl, and methoxyl, could be well tolerated and gave the corresponding products in satisfactory yields (3g−l) (45−76%). 2-Phenylquinazolin4(3H)-one (1a) also reacted smoothly with substituted alkynes (2b−d) to give the desired products 3m−o in 38−63% yields. However, electron-rich diarylacetylenes (2b, 63%) exhibited higher reactivity than electron-deficient diarylacetylenes (2c and 2d, 50% and 38%, respectively). Moreover, the reaction of 6-methoxy-2-phenylquinazolin-4(3H)-one (1d) with 1,2-di-ptolylethyne (2b) proceeded smoothly under standard reaction conditions to give the corresponding products 3p in 52% yield. Meanwhile, the reaction of 2-(p-tolyl)quinazolin-4(3H)-one (1j) with 1,2-di-p-tolylethyne (2b) could afford the corresponding product 3q in 41% yield. However, other alkyenes, such as phenylacetylene, oct-4-yne, or diethyl but-2-ynedioate, could not give the desired products. The structure of 3j was confirmed by single-crystal X-ray diffraction analysis (see the Supporting Information, Figure S2). To clarify the reaction mechanism, control experiments were carried out (Scheme 2). First, no reaction occurred when 1a
(0.5 equiv) and CF3COOH (TFA) (4 equiv) were used as additives under O2 (1 atm) (Table 1, entry 21). The structure of the product 3a was confirmed by single-crystal X-ray diffraction (see the Supporting Information, Figure S1). Only 19% yield of the target product 3a was achieved when the reaction was carried out under air atmosphere, and no product was obtained under N2 protection (Table 1, entry 1 vs entries 2 and 3). Palladium salts, such as Pd(OAc)2, PdCl2, Pd(PPh3)4, Pd(CF3COO)2, and Pd2(dba)3, were screened, showing that Pd(CH3CN)2Cl2 gave the highest yield and the reaction did not proceed without a Pd catalyst (Table 1, entry 1 vs entries 4−9). Moreover, CuBr and CF3COOH were shown to favor this reaction to a greater extent than other Cu salts and acids (Table 1, entry 1 vs entries 10−15). A mixture of DMF and DMA (v/v = 1:1) was demonstrated to be better than other solvents, such as DMF, DMA, DMSO, DCE, toluene, and NMP (Table 1, entry 21 vs entries 1 and 16−20). In addition, the yield of 3a was decreased when the reaction temperature and reaction time were either increased or decreased (Table 1, entries 22−25). With the optimized reaction conditions in hand, the scope of the substrates was examined (Table 2). Diphenylethylene (2a) reacted smoothly with 2-phenylquinazolin-4(3H)-one (1a) and its derivatives (1b−l) to give desired products (3a−l) in moderate to good yields (45−82%). Halogen groups, such as F, Cl, and methoxy, at the 5- or 6-position of quinazolinones provided the corresponding products 3b−d in 63, 72, and 82% B
DOI: 10.1021/acs.orglett.7b00452 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 2. Scope of the Substratesa,b
On the basis of the results obtained, a plausible reaction mechanism for the direct coupling of 2-phenylquinazolin4(3H)-one with diphenylethyne was proposed and is shown in Scheme 3. First, the cyclopalladated complex A was formed Scheme 3. Proposed Reaction Mechanism
entry
1
2
3
yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
1a, R1 = H; R2 = H 1b, R1 = 5-F; R2 = H 1c, R1 = 6-Cl; R2 = H 1d, R1 = 6-OCH3; R2 = H 1e, R1 = H; R2 = 2-F 1f, R1 = H; R2 = 4-F 1g, R1 = H; R2 = 4-Cl 1h, R1 = H; R2 = 4-Br 1i, R1 = H; R2 = 4-CF3 1j, R1 = H; R2 = 4-CH3 1k, R1 = H; R2 = 4-t-Bu 1l, R1 = H; R2 = 4-OCH3 1a, R1 = H; R2 = H 1a, R1 = H; R2 = H 1a, R1 = H; R2 = H 1d, R1 = 6-OCH3; R2 = H 1j, R1 = H; R2 = 4-CH3
2a, R3 = Ph 2a, R3 = Ph 2a, R3 = Ph 2a, R3 = Ph 2a, R3 = Ph 2a, R3 = Ph 2a, R3 = Ph 2a, R3 = Ph 2a, R3 = Ph 2a, R3 = Ph 2a, R3 = Ph 2a, R3 = Ph 2b, R3 = 4-CH3Ph 2c, R3 = 4-FPh 2d, R3 = 4-ClPh 2b, R3 = 4-CH3Ph 2b, R3 = 4-CH3Ph
3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n 3o 3p 3q
78 63 72 82 51 72 45 63 62 63 76 58 63 50 38 52 41
a Reaction conditions: 1 (0.10 mmol), 2 (0.30 mmol), Pd (10 mol %), Cu (0.5 equiv), TFA (4.0 equiv), solvent (1.0 mL), under O2 (1 atm). b Isolated yields.
from 1a by coordination of the palladium atom to the NH and electrophilic attack of the palladium atom at the carbon atom of benzene ring.11 Then the coordination of Pd from A with 2a gave the intermediate B, which subsequently transformed into the intermediate C.12 Then the intermediate D was generated through elimination and coordinated with molecular oxygen to give E. After that, the intermediate E could be converted to intermediate F,13 and the two phenyl groups were in the cis form when the new five-membered ring was generated, which would explain why the [3 + 2] cycloaddition is stereospecific. Another molecule of 2a coupled with F to form the intermediate G. Subsequently, G could be converted into intermediate H, which afforded the radical I as well as Pd(0) species, and the radical I finally afforded the cis-isomer product 3a. Meanwhile, Pd(0) was oxidated into the active Pd(II) species for the next catalytic cycle. In summary, we have demonstrated the first palladiumcatalyzed reaction of quinazolinones with alkynes, leading to fused polyheterocycles. This transformation involves C−H bond activation, C−N bond coupling, and a unique furan ring formation through a radical pathway. The C−H/N−H bond functionalization proceeds well to construct two heterocycles simultaneously with high yields and a broad substrate scope tolerance. Reaction mechanism studies have demonstrated the formation of an oxygen radical species as a key intermediate, which might be responsible for the subsequent formation of the furan ring, and O2 (1 atm) was used as a green source of the oxygen atom in the furan ring. Moreover, this approach provided a fast-track strategy for atom-/step-economical syntheses of useful pharmaceutical molecules.
Scheme 2. Control Experiments
was treated with 2,3,4,5-tetraphenylfuran (4) under the optimized conditions (Scheme 2a). Additionally, 5,6-diphenyl8H-isoquinolino[1,2-b]quinazolin-8-one (5) could not react with 2a to give the expected product 3a (Scheme 2b). These results suggested that compounds 4 and 5 were both ruled out as key intermediates in this reaction. When the reaction of 1a with 2a was carried out under 18O2 instead of O2, the 18Olabeled product 3a-18O was provided, indicating that the oxygen of the furan ring originated from O2 (Scheme 2c) (Supporting Information, Figure S3). When a radical scavenger, TEMPO, was introduced into the reaction, the yield of 3a was largely decreased, and byproduct 6 was generated and detected by HRMS (Supporting Information, Figure S4), which suggested that a radical pathway was involved in this reaction (Scheme 2d). C
DOI: 10.1021/acs.orglett.7b00452 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
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(8) For selected examples, see: (a) Harmata, M. Chem. Commun. 2010, 46, 8886. (b) Harmata, M. Chem. Commun. 2010, 46, 8904. (c) Lohse, A. G.; Hsung, R. P. Chem. - Eur. J. 2011, 17, 3812. (d) Ylijoki, K. E. O.; Stryker, J. M. Chem. Rev. 2013, 113, 2244. (9) For selected examples, see: (a) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624. (b) Wencel-Delord, J.; Drcge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40, 4740. (c) Satoh, T.; Miura, M. Chem. - Eur. J. 2010, 16, 11212. (d) Song, G. Y.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651. (e) Li, B.-J.; Shi, Z.-J. Chem. Soc. Rev. 2012, 41, 5588. (f) Kuhl, N.; Schroder, N.; Glorius, F. Adv. Synth. Catal. 2014, 356, 1443. (g) Mo, J.; Wang, L.; Liu, Y.; Cui, X. Synthesis 2015, 47, 439. (10) For selected examples, see: (a) Ackermann, L.; Pospech, J. Org. Lett. 2011, 13, 4153. (b) Ueyama, T.; Mochida, S.; Fukutani, T.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2011, 13, 706−708. (c) Weissman, H.; Song, X.; Milstein, D. J. Am. Chem. Soc. 2001, 123, 337. (d) Wu, J.; Cui, X.; Mi, X.; Li, Y.; Wu, Y. Chem. Commun. 2010, 46, 6771. (e) Ackermann, L.; Wang, L.; Lygin, A. V. Chem. Sci. 2012, 3, 177. (11) (a) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172. (b) Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 8172. (c) Beck, E. M.; Hatley, R.; Gaunt, M. J. J. Am. Chem. Soc. 2006, 128, 2528. (d) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 9578. (e) Fujiwara, Y.; Moritani, I.; Danno, S.; Asano, R.; Teranishi, S. J. Am. Chem. Soc. 1969, 91, 7166. (f) Shi, Z.; Ding, S.; Cui, Y.; Jiao, N. Angew. Chem., Int. Ed. 2009, 48, 7895. (12) (a) Satoh, T.; Ogino, S.; Miura, M.; Nomura, M. Angew. Chem. 2004, 116, 5173; Angew. Chem., Int. Ed. 2004, 43, 5063. (b) Horiguchi, H.; Tsurugi, H.; Satoh, T.; Miura, M. Adv. Synth. Catal. 2008, 350, 509. (c) Horiguchi, H.; Hirano, K.; Satoh, T.; Miura, M. Adv. Synth. Catal. 2009, 351, 1431. (13) (a) Ishii, Y.; Sakaguchi, S.; Iwahama, T. Adv. Synth. Catal. 2001, 343, 393. (b) Sheldon, R. A.; Arends, I. W. C. E. Adv. Synth. Catal. 2004, 346, 1051. (c) Recupero, F.; Punta, C. Chem. Rev. 2007, 107, 3800. (d) Wan, C.; Zhang, J.; Wang, S.; Fan, J.; Wang, Z. Org. Lett. 2010, 12, 2338. (e) Wan, C.-F.; Gao, L.-F.; Wang, Q.; Zhang, J.-T.; Wang, Z.-Y. Org. Lett. 2010, 12, 3902. (f) Zhang, C.; Xu, Z.; Zhang, L.; Jiao, N. Angew. Chem. 2011, 123, 11284; Angew. Chem., Int. Ed. 2011, 50, 11088. (g) Zhang, C.; Xu, Z.; Shen, T.; Wu, G.; Zhang, L.; Jiao, N. Org. Lett. 2012, 14, 2362.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00452. General procedures, relevant NMR spectra, X-ray structures and catalytic experiments (PDF) X-ray data for compound 3a (CIF) X-ray data for compound 3j (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Xiuling Cui: 0000-0001-5759-766X Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the NSF of China (21572072), the Xiamen Southern Oceanographic Center (15PYY052SF01), the Science and Technology Bureau of Xiamen City (3502Z20150054), and Huaqiao University.
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DOI: 10.1021/acs.orglett.7b00452 Org. Lett. XXXX, XXX, XXX−XXX
