Letter Cite This: Org. Lett. 2019, 21, 124−128
pubs.acs.org/OrgLett
Direct Synthesis of Benzo[f ]indazoles from Sulfonyl Hydrazines and 1,3-Enynes by Copper-Catalyzed Annulation Biao Yao, Tao Miao,*,† Pinhua Li,† and Lei Wang*,†,‡ †
Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000, P. R. China State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 200032, P. R. China
‡
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S Supporting Information *
ABSTRACT: A novel and efficient strategy for the direct synthesis of benzo[f ]indazoles via copper-catalyzed cascade reaction of sulfonyl hydrazides with 1,3-enynes under mild conditions has been developed. This method achieves the formation of two C−N bonds and one C−C bond in one pot, providing a series of benzo[f ]indazoles in moderate to good yields with good functional group tolerance and remarkable regioselectivity.
T
he indazole moiety is a privileged N-heterocyclic structure in medicinal chemistry due to its pronounced biological and therapeutic activities,1 and in particular, tricyclic 1H-benzoindazole plays an increasingly important role in drug discovery.2 For example, benzo[f ]indazole I is the lead compound for both antifungal and antibacterial activities,2a and II, as an antiproliferative agent, has been chosen in preclinical antitumor evaluation.2b Their analogue III, a selective ligand of the human glucocorticoid receptor,2c shows highly efficacious IL-6 inhibition (Scheme 1). In the
Scheme 2. Synthetic Routes to Benzo[f ]indazoles
Scheme 1. Bioactive Benzoindazole Analogues
It is well-known that cascade cyclizations, particularly those involving a radical process, are reliable and powerful synthetic strategies for the straightforward construction of cyclic molecules with unique chemical and biological importance.6 To date, the majority of work in this field has been focused on the radical addition to unsaturated chemical bonds followed by intramolecular cyclization to access cyclic skeletons.7 On the other hand, 1,3-enynes are versatile building blocks for the specific domino cyclization and have been widely applied in numerous intriguing preparation via synergistic cascade processes across CC and CC bonds of substrates in a one-pot fashion.8 However, the radical cascade cyclization of 1,3-enynes is a particularly challenging transformation owing to the inherent difficulty of controlling reaction reactivity and regio- and chemo-selectivity. Herein, we wish to report a copper-catalyzed synthesis of 1H-benzo[f ]indazoles from
past few decades, a number of impressive methods have been reported for the construction of indazole frameworks,3 yet synthetic protocols to benzo[f ]indazole are severely scarce, which have hampered their biomedical applications. Recently, a synthetic reaction of 1,1-dialkylhydrazones with o(trimethylsilyl)naphthyl triflates via aryne annulation provided a direct route to 1-alkylbenzo[f ]indazoles (Scheme 2a).4 Subsequently, the RhIII/CuII-cocatalyzed method for the synthesis of 1H-indazoles through C−H amidation and N− N bond formation was developed, generating the substituted benzo[f ]indazole from naphthylimidate and organo azides (Scheme 2b).5 However, some limitations including harsh reaction conditions with high temperature, expensive starting materials and catalysts, or limited substrate scope (naphthalene derivatives) remain in the above methods. Therefore, the development of novel and efficient method for the direct synthesis of 1H-benzo[f ]indazoles with a variety of functional groups under mild conditions is highly desirable. © 2018 American Chemical Society
Received: November 7, 2018 Published: December 21, 2018 124
DOI: 10.1021/acs.orglett.8b03564 Org. Lett. 2019, 21, 124−128
Letter
Organic Letters
40−52% yields when PAA (peracetic acid), CHP (cumyl hydroperoxide), and m-CPBA (3-chloroperbenzoic acid) were employed as oxidants (Table 1, entries 14−16). However, other oxidants including tert-butyl peroxybenzoate (TBPB), ditert-butyl peroxide (DTBP), dicumyl peroxide (DCP), and H2O2 exhibited negative efficiency to the model reaction (Table 1, entries 17−20). In addition, the reaction could not work in an O2 atmosphere. It was found that CuI was not involved in this reaction and still deposited at the bottom of reaction tube (Table 1, entry 21). Furthermore, increasing the amount of 1a to 1.5 equiv did not enhance the yield of 3a (Table 1, entry 22). It is important to note that Cu catalyst and TBHP showed a significant impact on the reaction, and no desired product 3a was detected in the absence of either the catalyst or oxidant (Table 1, entries 23 and 24). With the optimized reaction conditions in hand, we first investigated the scope of sulfonyl hydrazides, and the results are listed in Scheme 3. A variety of arylsulfonyl hydrazides with
easily available sulfonyl hydrazides and (E)-2-benzylidene-4arylbut-3-ynals via a radical domino annulation in one pot. The reaction proceeded smoothly to generate the corresponding benzo[f ]indazoles in good yields with excellent selectivity under mild conditions (Scheme 2c). Initially, 4-toluenesulfonyl hydrazide (1a) and (E)-2benzylidene-4-phenylbut-3-ynal (2a) were selected as the model substrates to optimize the reaction conditions (Table 1). To our delight, when the model reaction of 1a and 2a was Table 1. Optimization of the Reaction Conditionsa
entry
catalyst
oxidant
solvent
yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuCl CuBr Cu(OAc)2 CuI CuI CuI CuI CuI CuI CuI CuI CuI
TBHP TBHP TBHP TBHP TBHP TBHP TBHP TBHP TBHP TBHP TBHP TBHP TBHP PAA CHP m-CPBA TBPB DTBP DCP H2O2 O2 TBHP TBHP
DCM DCE CHCl3 DMF DMSO toluene 1,4-dioxane CH3CN THF MeOH DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE
55 79 60 32 23 45 18 trace 0 0 55 64 67 40 52 47 0 0 0 0 0c 77d 0 0
CuI
Scheme 3. Scope of Sulfonyl Hydrazidesa,b
a
Reaction conditions: 4-toluenesulfonyl hydrazide (1a, 0.30 mmol), (E)-2-benzylidene-4-phenylbut-3-ynal (2a, 0.25 mmol), Cu-catalyst (10 mol %), oxidant (0.50 mmol), solvent (2.0 mL), 40 °C, N2, 5 h. b Isolated yield based on 2a. cO2 balloon was used. d1a (1.5 equiv) was used.
conducted in dichloromethane (DCM) under N2 atmosphere at 40 °C for 5 h by using CuI as a catalyst and TBHP (70% in water) as an oxidant, the cascade cyclization afforded product 9-phenyl-1-tosyl-1H-benzo[f ]indazole (3a) in 55% yield (Table 1, entry 1). The structure of 3a was confirmed unambiguously by X-ray crystal analysis.9 Further exploration of a variety solvents indicated that 1,2-dichloroethane (DCE) was the most efficient, and 79% yield of 3a was obtained (Table 1, entry 2). Other solvents including CHCl3, DMF, DMSO, toluene, and 1,4-dioxane were less effective and gave 3a in 18−60% yields (Table 1, entries 3−7). Solvents CH3CN, THF, and methanol were not suitable, and the model reaction was almost prohibited (Table 1, entries 8−10). Next, a range of copper sources such as CuCl, CuBr, and Cu(OAc)2 were evaluated, leading to the desired 3a with inferior results (Table 1, entries 11−13). Subsequently, the effect of the oxidants on the model reaction was examined. Product 3a was isolated in
a Reaction conditions: sulfonyl hydrazide (1, 0.30 mmol), 2a (0.25 mmol), CuI (10 mol %), TBHP (0.50 mmol), DCE (2.0 mL), 40 °C, N2, 5 h. bIsolated yield based on 2a.
an electron-donating group (MeO, Me, t-Bu) or an electronwithdrawing group (F, Cl, Br, CF3, CN, Ph) on the aryl rings reacted efficiently with 2a to give the corresponding products 3a−p in good yields. The sterically hindered o-methylsubstituted benzenesulfonyl hydrazide was a suitable substrate in this process, giving the corresponding product 3d in 65% 125
DOI: 10.1021/acs.orglett.8b03564 Org. Lett. 2019, 21, 124−128
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Organic Letters
removed by reduction to afford 4 in excellent yield, which can be used for the further functionalization of the benzo[f ]indazoles (Supporting Information). To gain insight into the reaction mechanism, some control experiments were conducted, as shown in Scheme 5. First,
yield. Notably, arylsulfonyl hydrazides bearing a trifluoromethyl group (CF3), as a useful structural motif in biologically active molecules,10 reacted with 2a to generate the anticipated products 3k and 3l in good yields. High yields were obtained with the bulkier 1,1′-biphenyl- and 2-naphthylsulfonyl hydrazides as substrates. On the other hand, multisubstituted arylsulfonyl hydrazides were also well tolerated in this transformation, affording the products 3o and 3p in 70% and 84% yields, respectively. Furthermore, 2-thienylsulfonyl hydrazide was also suitable for this protocol, which gave the desired product 3q in 58% yield. Importantly, aliphatic sulfonyl hydrazides, as a case study of n-butylsulfonyl hydrazide, worked well with 2a, producing the product 3r in good yield. However, when phenylhydrazine and benzhydrazide were employed as starting materials to react with 2a under the optimized conditions, no desired product was obtained. We then turned our attention to explore the scope of 1,3enynes by reacting with a number of arylsulfonyl hydrazides, and the results were shown in Scheme 4. This radical domino
Scheme 5. Control Experiments
Scheme 4. Scope of 1,3-Enynesa,b
when 1a was treated with 2a in DCE at 40 °C in the absence of catalyst and oxidant for 5 h, a condensation product hydrazone (A) was formed in 92% yield (Scheme 5a). In a further experiment, hydrazone (A) was subjected the reaction under the standard conditions, affording 3a in 85% yield (Scheme 5b). Meanwhile, the reaction of obtained A by using Cu(OAc)2 as catalyst in the O2 generated 3a in 65% yield (Scheme 5c). Nevertheless, no desired 3a was obtained when a well-known radical scavenger, TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl, 2.0 equiv), was added in the reaction system of A (Scheme 5d). Furthermore, when BHT (butylated hydroxytoluene, 2.0 equiv) was added to the reaction of A, the yield of 3a was decreased to 18%. More importantly, a possible vinyl radical formed in situ were trapped by BHT through the formation of radical adduct 5, which was determined by HPLC−HRMS analysis (Scheme 5e, and Supporting Information). The above observations clearly suggest that a Cu(II) initiated radical pathway was involved in the reaction. On the basis of control experiments and previous literature survey,7,8,11 a plausible mechanism is proposed in Scheme 6. Initially, a hydrazone A was formed from the condensation of 1a and 2a. Then the intramolecular aminocupration of A occurred upon alkyne activation by a copper(II) via intermediate B to form vinylcopper complex C. Subsequently,
a
Reaction conditions: arylsulfonyl hydrazide (1, 0.30 mmol), 1,3enyne (2, 0.25 mmol), CuI (10 mol %), TBHP (0.50 mmol), DCE (2.0 mL), 40 °C, N2, 5 h. bIsolated yield based on 2.
reaction was not sensitive to the nature of the substituted group on the 1,3-enyne moiety, as evidenced by the moderate to good yields of 3s−ag. It is noteworthy that halogen and dimethylamino substituents on the benzylidene moiety were tolerated, thus facilitating further modifications toward the synthesis of structural diverse benzo[f ]indazoles. In particular, this transformation was not limited to phenyl 1,3-enynes; other aromatic ring and aliphatic substituents, e.g., thienyl, cyclopropyl, and propyl, could also be compatible to afford the expected benzo[f ]indazoles (3ah, 3ai, and 3aj) in 76%, 74%, and 64% yields, respectively. The developed radical annulation could be performed on a gram scale, giving 3a in 72% yield (Supporting Information). In addition, the N-sulfonyl group of 3a could be easily
Scheme 6. Proposed Mechanism
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DOI: 10.1021/acs.orglett.8b03564 Org. Lett. 2019, 21, 124−128
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(2) (a) Tandon, V. K.; Yadav, D. B.; Chaturvedi, A. K.; Shukla, P. K. Bioorg. Med. Chem. Lett. 2005, 15, 3288. (b) Pinna, G. A.; Pirisi, M. A.; Mussinu, J.-M.; Murineddu, G.; Loriga, G.; Pau, A.; Grella, G. E. Il Farmaco 2003, 58, 749. (c) Shah, N.; Scanlan, T. S. Bioorg. Med. Chem. Lett. 2004, 14, 5199. (d) Hashem, M. M.; Berlin, K. D.; Chesnut, R. W.; Durham, N. N. J. Med. Chem. 1976, 19, 229. (3) For metal-free examples, see: (a) Caron, S.; Vazquez, E. Synthesis 1999, 1999, 588. (b) Lukin, K.; Hsu, M. C.; Fernando, D.; Leanna, M. R. J. Org. Chem. 2006, 71, 8166. (c) Spiteri, C.; Keeling, S.; Moses, J. E. Org. Lett. 2010, 12, 3368. (d) Li, P.; Zhao, J.; Wu, C.; Larock, R. C.; Shi, F. Org. Lett. 2011, 13, 3340. For transition-metal-catalyzed examples, see: (e) Gao, M.; Liu, X.; Wang, X.; Cai, Q.; Ding, K. Chin. J. Chem. 2011, 29, 1199. (f) Xiong, X.; Jiang, Y.; Ma, D. Org. Lett. 2012, 14, 2552. (g) Inamoto, K.; Saito, T.; Katsuno, M.; Sakamoto, T.; Hiroya, K. Org. Lett. 2007, 9, 2931. (h) Zhang, T.; Bao, W. J. Org. Chem. 2013, 78, 1317. (i) Li, X.; He, L.; Chen, H.; Wu, W.; Jiang, H. J. Org. Chem. 2013, 78, 3636. (j) Deng, G.-B.; Li, H.-B.; Yang, X.-H.; Song, R.-J.; Hu, M.; Li, J.-H. Org. Lett. 2016, 18, 2012. (4) (a) Jin, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2007, 46, 3323. (b) Markina, N. A.; Dubrovskiy, A. V.; Larock, R. C. Org. Biomol. Chem. 2012, 10, 2409. (5) Yu, D.-G.; Suri, M.; Glorius, F. J. Am. Chem. Soc. 2013, 135, 8802. (6) (a) Dhimane, A.-L.; Fensterhank, L.; Malacria, M. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2008; pp 350−382. (b) Snider, B. B. Chem. Rev. 1996, 96, 339. (c) Yi, H.; Zhang, G.; Wang, H.; Huang, Z.; Wang, J.; Singh, A. K.; Lei, A. Chem. Rev. 2017, 117, 9016. (d) Miyabe, H.; Kawashima, A.; Yoshioka, E.; Kohtani, S. Chem. - Eur. J. 2017, 23, 6225. (e) Chen, J.-R.; Hu, X.-Q.; Lu, L.-Q.; Xiao, W.-J. Acc. Chem. Res. 2016, 49, 1911. (f) Studer, A.; Curran, D. P. Angew. Chem., Int. Ed. 2016, 55, 58. (g) Alpers, D.; Gallhof, M.; Witt, J.; Hoffmann, F.; Brasholz, M. Angew. Chem., Int. Ed. 2017, 56, 1402. (h) Huang, L.; Ye, L.; Li, X.-H.; Li, Z.-L.; Lin, J.-S.; Liu, X.-Y. Org. Lett. 2016, 18, 5284. (7) For selected reviews and examples, see: (a) Clark, A. J. Chem. Soc. Rev. 2002, 31, 1. (b) Yu, J.-T.; Pan, C. Chem. Commun. 2016, 52, 2220. (c) Wille, U. Chem. Rev. 2013, 113, 813. (d) Hu, M.; Fan, J.-H.; Liu, Y.; Ouyang, X.-H.; Song, R.-J.; Li, J.-H. Angew. Chem., Int. Ed. 2015, 54, 9577. (e) Kong, W.; Fuentes, N.; García-Domínguez, A.; Merino, E.; Nevado, C. Angew. Chem., Int. Ed. 2015, 54, 2487. (f) Fuentes, N.; Kong, W.; Fernández-Sánchez, L.; Merino, E.; Nevado, C. J. Am. Chem. Soc. 2015, 137, 964. (g) Liu, F.; Wang, J.-Y.; Zhou, P.; Li, G.; Hao, W.-J.; Tu, S.-J.; Jiang, B. Angew. Chem., Int. Ed. 2017, 56, 15570. (8) For selective examples, see: (a) O’Connor, J. M.; Friese, S. J.; Rodgers, B. L. J. Am. Chem. Soc. 2005, 127, 16342. (b) Michelet, V.; Toullec, P. Y.; Genêt, J.-P. Angew. Chem., Int. Ed. 2008, 47, 4268. (c) Kinoshita, H.; Ueda, A.; Fukumoto, H.; Miura, K. Org. Lett. 2017, 19, 882. (d) Chun, Y. S.; Lee, J. H.; Kim, J. H.; Ko, Y. O.; Lee, S. Org. Lett. 2011, 13, 6390. (e) Aguilar, E.; Sanz, R.; Fernández-Rodríguez, M. A.; García-García, P. Chem. Rev. 2016, 116, 8256. (f) Barday, M.; Ho, K. Y. T.; Halsall, C. T.; Aïssa, C. Org. Lett. 2016, 18, 1756. (g) Bharathiraja, G.; Sakthivel, S.; Sengoden, M.; Punniyamurthy, T. Org. Lett. 2013, 15, 4996. (h) Zhou, X.; Huang, C.; Zeng, Y.; Xiong, J.; Xiao, Y.; Zhang, J. Chem. Commun. 2017, 53, 1084. (i) Partridge, B. M.; Callingham, M.; Lewis, W.; Lam, H. W. Angew. Chem., Int. Ed. 2017, 56, 7227. (j) Xuan, J.; Studer, A. Chem. Soc. Rev. 2017, 46, 4329. (9) X-Ray crystal structure of 3a.
the homolysis of complex C afforded the copper(I) and a vinyl radical D, followed by an intramolecular cyclization with phenyl ring, generating aryl radical E. Intermediate E underwent a SET (single electron transfer) oxidation and a deprotonation process to provide the product 3a. Finally, Cu(I) could be oxidized by TBHP to regenerate Cu(II) for the next run. In summary, we have developed a facile and efficient method for the synthesis of substituted benzo[f ]indazoles from easily available sulfonyl hydrazides and (E)-2-benzylidene-4-arylbut3-ynals through copper-catalyzed two C−N bonds and one C− C bond formation in one pot. Mechanistic investigation to elucidate the reaction involved a condensation of two reaction partners followed by a Cu(II)-initiated radical tandem annulation. The corresponding products benzo[f ]indazoles were obtained in moderate to high yields with good functional group tolerance under mild reaction conditions. Further scope and mechanism studies of the reaction are currently in progress in our laboratory.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03564. Full experimental details and characterization data for all products (PDF) Accession Codes
CCDC 1874385 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.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Lei Wang: 0000-0001-6580-7671 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We gratefully acknowledge the National Natural Science Foundation of China (21772062, 21602072, 21572078) and the National Science Foundation of Anhui Education Department (KJ2016A643) for financial support of this work.
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REFERENCES
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DOI: 10.1021/acs.orglett.8b03564 Org. Lett. 2019, 21, 124−128
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