Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Radical Promoted C(sp2)−S Formation and C(sp3)−S Bond Cleavage: Access to 2‑Substituted Thiochromones Jian Xu, Fan Zhang, Shifan Zhang, Li Zhang, Xiaoxia Yu, Jianxiang Yan, and Qiuling Song* Institute of Next Generation Matter Transformation, College of Chemical Engineering and College of Material Sciences Engineering at Huaqiao University, 668 Jimei Boulevard, Xiamen, Fujian 361021, P. R. China
Org. Lett. Downloaded from pubs.acs.org by EASTERN KENTUCKY UNIV on 01/28/19. For personal use only.
S Supporting Information *
ABSTRACT: A radical-promoted cyclization of methylthiolated alkynones with diverse radical precursors has been developed. This strategy occurred via a C(sp2)−S bond formation and C(sp3)−S cleavage sequence and allows an efficient synthesis of a variety of phosphoryl-, sulfenyl-, CF2COOEt-, and acyl-containing thiochromone derivatives in moderate to good yields under mild conditions.
T
pendently reported a more general approach to access thiochromones starting from sodium sulfide and appropriate alkynones; i.e., the addition of sodium sulfide with alkynones gave sulfide carbinols followed by intramolecular cyclization reaction (Scheme 1d). More recently, Wu and co-workers improved this method by developing a palladium-catalyzed carbonylative four-component reaction (Scheme 1e).12 The advantages of this work lie in the commercially available starting materials and non-preinstalled alkynones. Despite these great advances, synthesis of diversely functionalized thiochromones, especially 2-functionalized thiochromones which were not easily prepared via the above approaches, is still highly desirable. Recently, with the advantages of easily prepared starting materials, simple reaction conditions, and step- economy, the radical cascade reaction has emerged as a powerful strategy for the construction of complex compounds.13 One of the most challenging tasks in radical-involved reaction is developing new radical partners. Alkynone is a well-developed radical acceptor, and a variety of heterocyclic compounds including indenones, 14a−d naphthoquinones, 14d,e 4-quinolone, 14f and spiro[5.5]trienones14g had been successfully achieved via the addition of radical to alkynone. These results suggested that the vinyl radical is the key intermediate. Based on the reported works with methylthio as radical acceptor,15 we envisioned that thiochromones can be constructed by a radical addition reaction to methylthio-substituted alkynones followed by an intramolecular radical cyclization reaction. We initiated this study with 1-(2-(methylthio)phenyl)-3phenylprop-2-yn-1-one (1a) and diphenylphosphine oxide (2a) as model substrates (1a/2a = 1:2). To our delight, the desired product 3a was obtained in 51% yield in the presence of AgNO3 (100 mol %) at 100 °C for 12 h (entry 1, Table 1). The structure of 3a was confirmed by X-ray analysis (see the SI
hiochromones are prevalent structures in various natural products, potent drug candidates, and biologically active molecules. They are known as antimicrobial and antifungal,1 antibiotic,2 antibacterial,3 anticarcinogenic,4 and antimalaria agents.5 Furthermore, the oxidized products of thiochromones have shown activity against the human cytomegalovirus protease.6 However, reported methods for the synthesis of thiochromones are very limited.7 Conventional methods for the construction of thiochromones include the polyphosphoric acid mediated condensation reaction of β-keto esters with thiophenols (Scheme 1a)8 and the intramolecular cyclization Scheme 1. Strategies for the Core of the Thiochromone Ring
of β-substituted cinnamates prepared from propiolates and thiophenols (Scheme 1b).9 Recently, synthesis of thiochromones from alkynones has been well studied. Larock developed an ICl-induced cyclization of methylthio-substituted alkynones, affording an efficient approach to various 3iodochromones (Scheme 1c).10 Müller11a and Fu11b inde© XXXX American Chemical Society
Received: January 3, 2019
A
DOI: 10.1021/acs.orglett.9b00023 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization of Reaction Conditionsa
Scheme 2. Scope of Alkynonesa
entry
catalyst (mol %)
additive
solvent
yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13b 14c
AgNO3 (100) AgNO3 (20) AgOTf (20) Ag2CO3 (20) AgBF4 (20) Ag2O (20) AgOAc (20) Ag2CO3 (20) Ag2CO3 (20) Ag2CO3 (20) Ag2CO3 (20) Ag2CO3 (10) Ag2CO3 (10) Ag2CO3 (10)
Mg(NO3)2·6H2O Mg(NO3)2·6H2O Mg(NO3)2·6H2O Mg(NO3)2·6H2O Mg(NO3)2·6H2O Mg(NO3)2·6H2O Mg(NO3)2·6H2O Mg(NO3)2·6H2O Mg(NO3)2·6H2O Zn(NO3)2·6H2O Zn(NO3)2·6H2O Zn(NO3)2·6H2O Zn(NO3)2·6H2O
CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN THF toluene DCE CH3CN CH3CN CH3CN CH3CN
51 58 67 80 60 57 74 60 65 70 84 90 81 75
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), additive (0.12 mmol) in solvent (2 mL), stirring at 100 °C under argon for 12 h. Yield of the isolated product. b110 °C. c80 °C.
for details). Decreasing the loading of AgNO3 to 20 mol % and adding Mg(NO3)2·6H2O as an oxidant did not affect the yield of 3a (entry 2, Table 1). Then different Ag salts were screened, including AgOTf, Ag2CO3, AgBF4, Ag2O, and AgOAc (entries 3−7), and Ag2CO3 proved to be the most efficient catalyst and gave the desired product 3a in 80% yield (entry 4). Replacing CH3CN with other solvents, such as THF, toluene, and DCE (entries 8−10), only led to inferior results. After surveying various oxidants [e.g., Zn(NO3)2·6H2O, Fe(NO3)2·6H2O], Zn(NO3)2·6H2O was found to be the best choice. The yield was increased to 90% when the catalyst loading was reduced to 10 mol % (entry 12). Increasing or decreasing the temperature did not provide better results. The scope of this radical annulation reaction was examined by using the optimized conditions (Scheme 2). The R3 group on the benzene ring of alkynones was first investigated. Different aliphatic substituents at the para- and meta-positions of the right aryl ring presented similar reactivities, and the corresponding products 3b−d were obtained in 84−95% yields. Halogen substituents including F, Cl, and Br on the aromatic ring also had no influence on the outcome of the reactions and delivered the desired products 3e−j with excellent yields (80−92%). Electron-withdrawing group CF3 also could be tolerated under these conditions, giving 3k in 84% yield. Nevertheless, the electron-donating group OMe had a negative influence on this reaction, and corresponding product 3l was obtained in only 78% yield. Substituents such as Br and OMe on the left aromatic ring were also compatible with the reaction, affording 3m and 3n in 65% and 70% yields, respectively. However, no reaction took place when the right aromatic ring was changed to alkyl (3o), presumably due to the unstable alkenyl radical intermediate. Furthermore, diphenylphosphine oxides with different substituents such as p-Me, 3,4-di-Me, and p-F on the phenyl ring delivered the desired products 3p−r in satisfactory yields. To our delight, diethyl H-phosphonate also gave the desired product 3s albeit with a relatively low yield (45%). Gratifyingly, methylselanylalkynones were also suitable substances under the standard
a
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), Ag2CO3 (10 mol %), Zn(NO3)2·6H2O (60 mol %) in CH3CN (2 mL), stirring under argon at 100 °C for 12 h.
reaction conditions, gave the corresponding products 3t and 3u in 75% and 72% yields. To explore the generality of this radical annulation reaction, the scope was then examined by using other radical precursors instead of 2. Gratifyingly, the reaction of 1a with thiophenol in the presence of TBHP in CH3CN at 80 °C delivered sulfurized thiochromone 5a in 88% yield. Further scope expansion showed that various substituted thiophenols are all well tolerated under the oxidant conditions, yielding the desired products 5b−k in 75−90% yields (Scheme 3). Since BrCF2CO2Et has been widely used as source of CF2CO2Et radical under photoredox catalysis conditions, this reagent was also a suitable reaction partner in our radicalcyclization process and produced the corresponding productd 5l−s in 71−80% yields. In addition to the above radicals, the successful reaction of benzaldehydes with substrate 1 provided the desired acyl-containing thiochromones 5t−y in 51−65% yields, demonstrating the compatibility of this protocol with the acyl radicals. A series of control experiments were performed to interpret the reaction pathway as shown in Scheme 4. When the model B
DOI: 10.1021/acs.orglett.9b00023 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
On the basis of the above experiments and precedent reports,15 a rational mechanism of this radical-promoted cyclization reaction is described in Scheme 5. To initiate the
Scheme 3. Scope of Other Radical Precursors
Scheme 5. Proposed Mechanism
process, the R radical is first in situ generated from the corresponding conditions. Then the C−C triple bond in 1a is attacked by radical R to afford a vinyl radical A, which follows 6-exo-trig cyclization with the SMe moiety to give the desired product along with the release of methyl radical. In conclusion, we have developed a novel and efficient method for diversity-oriented synthesis of C2-substituted thiochromones through a cascade radical addition and cyclization of alkynones with diverse radical precursors. This protocol exhibits a broad substrate scope, good functional group tolerance, and the compatibility of diverse radical precursors including H-phosphorus oxides, arylthiols, BrCF2COOEt, and aryl aldehydes.
a
Reaction conditions:1 (0.2 mmol), ArSH (0.24 mmol), TBHP (0.3 mmol), CH3CN (2 mL), 80 °C, 12 h, N2. bReaction conditions:1 (0.2 mmol), BrCF2COOEt (0.4 mmol), Ir(ppy)3 (2 mol %), K2HPO4 (0.4 mmol), DMF (2 mL), rt, 12 h, 10 W blue LED, N2. cReaction conditions:1 (0.2 mmol), ArC(O)H (0.4 mmol), TBAB (0.2 mmol), K2S2O8 (0.4 mmol), DCE (2 mL), 90 °C, 12 h, N2.
■
ASSOCIATED CONTENT
* Supporting Information S
Scheme 4. Control Experiments
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00023. Experimental procedure, characterization data, and copies of 1H, 13C and 19F NMR spectra (PDF) Accession Codes
CCDC 1887370 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
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
■
AUTHOR INFORMATION
Corresponding Author
*Fax: 86-592-6162990. E-mail:
[email protected]. ORCID
Qiuling Song: 0000-0002-9836-8860
reaction was carried out in the absence of radical precusors, no cyclization product was observed, suggesting that the product was not formed via radical addition to thiochromone (eq 1, Scheme 4). When radical scavengers TEMPO or BHT were used as additives, the model reactions were completely inhibited, and the TEMPO−CF2COOEt was determined by HRMS analysis, indicating that a radical process might be involved in this transformation (eq 2, Scheme 4). When 6 as a well-known radical partner was added to the standard conditions, radical cyclization products 7−9 were determined by HR-MS (eq 3, Scheme 4), implying the involvement of phosphorus and methyl radical intermediates (see the SI for details).
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS We gratefully acknowledge the National Natural Science Foundation of China (21602065 and 21772046). We also thank the Instrumental Analysis Center of Huaqiao University for analysis support.
■
REFERENCES
(1) Nakazumi, H.; Ueyama, T.; Kitao, T. J. Heterocycl. Chem. 1984, 21, 193.
C
DOI: 10.1021/acs.orglett.9b00023 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters (2) Couquelet, J.; Tronche, P.; Niviere, P.; Andraud, G. Trav. Soc. Pharm. Montpellier 1963, 23, 214. (3) Nakazumi, H.; Ueyama, T.; Kitao, T. J. J. Heterocycl. Chem. 1984, 21, 193. (4) Holshouser, M. H.; Loeffler, L. J.; Hall, I. H. J. Med. Chem. 1981, 24, 853. (5) Razdan, R. K.; Bruni, R. J.; Mehta, A. C.; Weinhardt, K. K.; Papanastassiou, Z. B. J. Med. Chem. 1978, 21, 643. (6) Dhanak, D.; Keenan, R. M.; Burton, G.; Kaura, A.; Darcy, M. G. D.; Shah, H.; Ridgers, L. H.; Breen, A.; Lavery, P.; Tew, D. G.; West, A. Bioorg. Med. Chem. Lett. 1998, 8, 3677. (7) (a) Sangeetha, S.; Sekar, G. Org. Lett. 2019, 21, 75. (b) Zhu, F.; Wu, X.-F. J. Org. Chem. 2018, 83, 13612. (c) Kim, H. Y.; Song, E.; Oh, K. Org. Lett. 2017, 19, 312. (8) (a) Schneller, S. W. Adv. Heterocycl. Chem. 1975, 18, 59. (b) Nakazumi, H.; Watanabe, S.; Kitaguchi, T.; Kitao, T. Bull. Chem. Soc. Jpn. 1990, 63, 847. (9) (a) Razdan, R. K.; Bruni, R. J.; Mehta, A. C.; Weinhardt, K. K.; Papanastassiou, Z. B. J. Med. Chem. 1978, 21, 643. (b) Buggle, K.; Delahunty, J. J.; Philbin, E. M.; Ryan, N. D. J. Chem. Soc. C 1971, 3168. (10) Zhou, C.; Dubrovsky, A. V.; Larock, R. C. J. Org. Chem. 2006, 71, 1626. (11) (a) Willy, B.; Frank, W.; Müller, T. J. Org. Biomol. Chem. 2010, 8, 90. (b) Yang, X.-B.; Li, S.-F.; Liu, H.-X.; Jiang, Y.-Y.; Fu, H. RSC Adv. 2012, 2, 6549. (12) Shen, C.-R.; Spannenberg, A.; Wu, X.-F. Angew. Chem., Int. Ed. 2016, 55, 5067. (13) For selected reviews for radical cascade reactions, see: (a) Wille, U. Chem. Rev. 2013, 113, 813. (b) Zard, S. Z. Radical Reactions. In Organic Synthesis; Oxford University Press: Oxford, UK, 2003. (c) Chen, Z.-M.; Zhang, X.-M.; Tu, Y.-Q. Chem. Soc. Rev. 2015, 44, 5220. (d) Zhang, B.; Studer, A. Chem. Soc. Rev. 2015, 44, 3505. (e) Chen, J.-R.; Hu, X.-Q.; Lu, L.-Q.; Xiao, W.-J. Chem. Soc. Rev. 2016, 45, 2044. (f) Staveness, D.; Bosque, I.; Stephenson, C. R. Acc. Chem. Res. 2016, 49, 2295. (g) Huang, M.-H.; Hao, W.-J.; Li, G.-G.; Tu, S.-J.; Jiang, B. Chem. Commun. 2018, 54, 10791. (14) (a) Pan, X.-Q.; Zou, J.-P.; Zhang, G.-L.; Zhang, W. Chem. Commun. 2010, 46, 1721. (b) Yan, Z.-F.; Xie, J.; Zhu, C.-J. Adv. Synth. Catal. 2017, 359, 4153. (c) Pan, C.-D.; Huang, B.-F.; Hu, W.-M.; Feng, X.-M.; Yu, J.-T. J. Org. Chem. 2016, 81, 2087. (d) Zhang, Y.; Ye, S.-Y.; Ji, M.-M.; Li, L.-S.; Guo, D.-M.; Zhu, G.-G. J. Org. Chem. 2017, 82, 6811. (e) Zhang, Y.; Guo, D.-M.; Ye, S.-Y.; Liu, Z.-C.; Zhu, G.-G. Org. Lett. 2017, 19, 1302. (f) Zhou, N.-N.; Yan, Z.-F.; Zhang, H.-L.; Wu, Z.-K.; Zhu, C.-J. J. Org. Chem. 2016, 81, 12181. (g) Zhang, Y.; Zhang, J.-H.; Hu, B.-Y.; Ji, M.-M.; Ye, S.-Y.; Zhu, G.-G. Org. Lett. 2018, 20, 2988. (15) (a) Hari, D. P.; Hering, T.; Köning, B. Org. Lett. 2012, 14, 5334. (b) Staples, M. K.; Grange, R. L.; Angus, J. A.; Ziogas, J.; Tan, N. P. H.; Taylor, K. T.; Schiesser, C. H. Org. Biomol. Chem. 2011, 9, 473. (c) McDonald, F. E.; Burova, S. A.; Huffman, L. G., Jr. Synthesis 2000, 970. (d) Zang, H.; Sun, J. G.; Dong, X.; Li, P.; Zhang, B. Adv. Synth. Catal. 2016, 358, 1746. (e) Yang, W.-C.; Wei, K.; Sun, X.; Zhu, J.; Wu, L. Org. Lett. 2018, 20, 3144. (f) Xu, J.; Yu, X.-X.; Yan, J.-X.; Song, Q. Org. Lett. 2017, 19, 6292. (g) Gao, Y.-Z.; Zhang, P.-B.; Li, G.; Zhao, Y.-F. J. Org. Chem. 2018, 83, 13726. (h) Yan, J.-X.; Xu, J.; Zhou, Y.; Chen, J.; Song, Q. Org. Chem. Front. 2018, 5, 1483. (i) Liu, W.; Hu, Y.-Q.; Hong, X.-Y.; Li, G.-X.; Huang, X.-B.; Gao, W.-X.; Liu, M.-C.; Xia, Y.; Zhou, Y.-B.; Wu, H.-Y. Chem. Commun. 2018, 54, 14148.
D
DOI: 10.1021/acs.orglett.9b00023 Org. Lett. XXXX, XXX, XXX−XXX
