Rh(III)-Catalyzed Regio- and Chemoselective [4 + 1]-Annulation of

May 17, 2017 - A Rh(III)-catalyzed tandem C–H alkylation/intramolecular decarboxylative cyclization of azoxy compounds with diazoesters for the synt...
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Rh(III)-Catalyzed Regio- and Chemoselective [4 + 1]-Annulation of Azoxy Compounds with Diazoesters for the Synthesis of 2H‑Indazoles: Roles of the Azoxy Oxygen Atom Zhen Long, Zhigang Wang, Danni Zhou, Danyang Wan, and Jingsong You* Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, Sichuan University, 29 Wangjiang Road, Chengdu 610064, P.R. China S Supporting Information *

ABSTRACT: A Rh(III)-catalyzed tandem C−H alkylation/intramolecular decarboxylative cyclization of azoxy compounds with diazoesters for the synthesis of 3-acyl-2H-indazoles is disclosed. The azoxy instead of the azo group enables a distinct approach for cyclative capture, leading to a [4 + 1]-annulation rather than a classic [4 + 2] manner. The azoxy oxygen atom is traceless after annulation, and further removal from the product is not required. This reaction features a complete regioselectivity for unsymmetrical azoxybenzenes and a compatibility of monoaryldiazene oxides.

T

Scheme 1. Annulations of Azo and Azoxy Compounds

he indazole backbone has been recognized as one of the most privileged structures found in natural products, pharmaceuticals, and bioactive compounds.1 Among these heterocyclic structures, 2H-indazoles, especially 3-acyl-2Hindazoles, are not only crucial pharmacophores (Figure 1)2 but

Figure 1. Selected biologically active 3-acyl-2H-indazoles.

also valuable synthetic intermediates that can be transformed into useful molecules.3 Although numerous efficient methods have been well developed for the synthesis of 1H-indazoles,1,4 only a limited number of reports have documented the regioselective synthesis of 2H-indazoles.5,6 In particular, the known routes toward 3-acyl-2H-indazoles often suffer from multistep synthetic precursors, harsh reaction conditions, and/or limited substrate scope. Thus, it is highly desirable to develop concise and regioselective strategies for preparing 3-acyl-2Hindazoles from readily accessible starting materials. During the past two decades, transition-metal-catalyzed C−H bond activation and subsequent functionalization have emerged as powerful tools to construct heterocycles.7 Recently, the azo group has attracted interest as an incorporated directing group to build heteroaromatic backbones. Pd-, Rh-, Co-, or Re-catalyzed C−H annulations of azobenzenes with aldehydes have been developed for the synthesis of 2H-indazoles (Scheme 1, eq 1).8 However, unsymmetrical azobenzenes as the reaction substrate may suffer from site-selectivity problems due to the competitive coordination of two electronically similar nitrogen atoms to the metal center. The incorporation of the oxygen atom into the azo group to form the azoxy unit could avoid such a competitive © 2017 American Chemical Society

coordination. Although two kinds of potentially reactive C−H bonds still exist, the electronically distinctly different nitrogen and oxygen atoms are capable of selectively coordinating to the metal center.9 Recent examples on the palladium-catalyzed C−H functionalization of azoxybenzenes demonstrated that the nitrogen atom in the azoxy group is a stronger coordinating atom than the O atom.10 Thus, the azoxy group could be an ideal incorporated directing group to implement both regio- and chemoselective C−H annulations. Diazo compounds as carbine precursors play a prominent role in transition-metal-catalyzed C−H coupling or cyclization due to Received: March 1, 2017 Published: May 17, 2017 2777

DOI: 10.1021/acs.orglett.7b00631 Org. Lett. 2017, 19, 2777−2780

Letter

Organic Letters their easy preparation and high reactivity.11 Recently, Lee and Kim independently disclosed the Rh(III)-catalyzed C−H bond alkylation/cyclization of azobenzenes with cyclic diazotized Meldrum’s acid, delivering six-membered cinnolin-3(2H)-ones through a [4 + 2]-annulation (Scheme 1, eq 2).12 Acyclic αdiazoesters could not fully accomplish the cyclization and tended to remain in the alkylation step. Thus, we supposed that the reaction of azoxybenzenes with α-diazo compounds could enable five-membered 2H-indazoles for the following reasons. The incorporated strongly electronegative oxygen atom significantly decreases electron density on the reaction site, N atom, and thus increases its electrophilic ability toward the α-C(sp3) of the alkylated intermediate. In other words, the incorporation of the oxygen atom enables to reverse the electrophilic/nucleophilic properties of the reactive N atom that determine the [4 + 1]- or [4 + 2]-annulation (Scheme 1, eq 3). Although the azoxy groups have recently been employed as the directing group for the o-C−H bond functionalization of azoxybenzenes (mainly the palladium-catalyzed acylation), the investigated substrate scope is mostly limited to symmetrical azoxybenzenes and the merged oxygen atom remained in the products.10,13 Following our continuous interest in the rhodiumcatalyzed C−H functionalization of N-oxides,14 we herein report the azoxy group as an incorporated directing group for a tandem C−H alkylation/cyclization for the synthesis of 3-acyl-2Hindazoles from easily available symmetrical and unsymmetrical di- and monoaryldiazene oxides (see section II in the SI for synthetic details). Initially, we found that azoxybenzenes could smoothly react with [Cp*RhCl2]2 in methanol in the presence of NaOAc at 80 °C for 24 h (eqs S4 and S5). The X-ray crystallographic analysis of isolated complexes I and II (64% and 40% yields, respectively) disclosed the five-membered rhodacycle complex (Figure 2). For

and PivOH (1.0 equiv) in a 1:1 mixture of DCE/dioxane (1:1, v/ v) at 130 °C for 24 h (Table S1, entry 18). Subsequently, we explored the substrate scope. The reactivity of diazoesters was investigated first (3aa−ar) (Scheme 2). Scheme 2. Scope of Diazoesters and Symmetrical Azoxybenzenesa

a

Reaction conditions: 1 (0.2 mmol) and 2 (1.5 equiv) in 1.0 mL of DCE/dioxane (1:1, v/v) at 130 °C for 24 h under N2. For the R2 group details, see the SI. b1.0 mmol scale. cDi-tert-butyl 2diazomalonate was used. d1.0 mL of DCE at 140 °C.

Gratifyingly, a wide range of diazoesters smoothly reacted with 3,3′-azoxytoluene 1a. First, various α-diazomalonates were tested, all of which proceeded smoothly in good yields. For example, diisopropyl 2-diazomalonate (2c) reacted with 1a to afford 3ac in an 80% yield. Interestingly, when the R2 group is tBu, the decarboxylated 3af was isolated as the sole product in a 34% yield, probably because of the easy hydrolysis of tert-butyl ester under the acidic conditions.15 In addition to αdiazomalonates, α-diazo-β-keto esters could also undergo the cyclization. The carbon−carbon single bond cleavage of α-diazoβ-keto esters involved a decarboxylation rather than a deacylation, affording the corresponding 3-acyl-2H-indazoles 3ag−ar in satisfactory yields. To our delight, both α-diazo-β-alkyl keto esters and α-diazo-β-(hetero)aryl keto esters underwent the cyclization. N-Heterocycle-containing diazoesters such as methyl 2-diazo-3-oxo-3-(pyridin-2-yl)propanoate (2t), methyl 2-diazo2-(pyridin-2-yl)acetate (2u), and methyl 2-(benzo[d]thiazol-2yl)-2-diazoacetate (2v) failed to undergo this annulation. Other diazo reagents such as EtCO2CHN2 (2w), EtCO2C(CH3)N2 (2x), EtCO2CPhN2 (2y), and EtCO2C(CF3)N2 (2z) did not deliver the desired products. We next investigated the scope of symmetrical azoxybenzenes (3ba−oa) (Scheme 2). Ortho-, meta-, and para-substituted azoxybenzenes were all compatible with the optimal conditions, but ortho-substituted azoxybenzenes gave a relatively low yield

Figure 2. ORTEP diagrams of complexes I and II. Thermal ellipsoids are shown at the 50% probability level.

both symmetrical azoxybenzene 1f and unsymmetrical azoxybenzene 1p, the rhodium(III) center coordinates to the nitrogen atom rather than the oxygen atom, which would lead to a 2H-indazole backbone rather than a benzo[c]isoxazole. Subsequently, we performed the reaction of 3,3′-azoxytoluene 1a with dimethyl 2-diazomalonate 2a for the reaction condition optimization (Table S1). Gratifyingly, the desired 2H-indazole 3aa was obtained in a 11% yield in the presence of [Cp*RhCl2]2 in combination with AgSbF6 and KOAc in 1,2-dichloroethane (DCE) at 120 °C for 24 h (Table S1, entry 1). When PivOH and AcOH were used as the additive instead of KOAc, the yield increased to 71% and 67%, respectively (Table S1, entries 2 and 3). However, only a trace amount of 3aa was obtained in the absence of PivOH, AcOH, and KOAc (Table S1, entry 6). These results indicated that the acidic nature of additives had a more significant effect than the type of carboxylates (pivalate and acetate). Dioxane proved to be superior to DCE, methanol, THF, and toluene (Table S1, entries 2 and 9−13). The best result was obtained using [Cp*RhCl2]2 (2.5 mol %)/AgSbF6 (10 mol %) 2778

DOI: 10.1021/acs.orglett.7b00631 Org. Lett. 2017, 19, 2777−2780

Letter

Organic Letters possibly due to steric congestion. Meta-substituted azoxybenzenes with either electron-donating or electron-withdrawing groups all gave an exclusively regioselective product at the less sterically hindered position. Most importantly, the current protocol was suitable for unsymmetrical azoxybenzenes and monoaryldiazene oxides. These azoxy compounds were easily prepared from the reaction of 1-aryl-2-(tosyloxy)diazene 1-oxide with Grignard reagent (for details, see section II in the SI), thus enabling a diversified library of 3-acyl-2H-indazoles (Scheme 3). Notably, in contrast to

Scheme 4. Investigation of Mechanism

Scheme 3. Scope of Unsymmetrical Azoxybenzenes and Monoaryldiazene Oxidesa annulated product 3fa in an almost quantitative yield. In contrast, the isolated decarboxylative molecule 5 could not afford any desired 3fa (Scheme 4, eq 2). Unlike the alkylated azoxybenzene 4, the alkylated azobenzene 6 could not enable a [4 + 1]annulation but led to a [4 + 2] manner to form the six-membered cinnolin-3(2H)-one 7 (Scheme 4, eq 3), indicating a pivotal function of the azoxy oxygen atom in cyclative capture. These results suggest that an alkylated azoxybenzene might be involved in the intermediate process. On the basis of the above experimental results and previous reports,12 a plausible reaction mechanism is depicted in Scheme 5. First, the active [Cp*Rh(III)] species A is generated by the Scheme 5. Proposed Pathway to 3-Acyl-2H-indazole

a b

The reaction was run under the same conditions shown in Scheme 2. 1.0 mL of DCE at 140 °C.

unsymmetrical azobenzenes,12a unsymmetrical azoxybenzenes bearing two electronically highly similar aromatic rings could afford an exclusive regioselectivity (3qa, 3ra, and 3qg) (Scheme 3). A thiophene-yl-containing azoxy compound was also a suitable substrate (3va). Furthermore, monoaryldiazene oxides efficiently coupled with both α-diazomalonates and α-diazo-βketo esters to give 2H-indazoles (3wa, 3xa, 3wg, and 3xg) (Scheme 3). To gain insight into the mechanism, a series of experiments were carried out. First, the hydrogen−deuterium exchange experiments were performed. Treatment of azoxybenzene 1f with PivOD led to significant deuterium scrambling (eq S1), thus indicating that the cleavage of the ortho C−H bond is a reversible process. Then kinetic isotope effect (KIE) experiments were run with the reactions of 1f and/or [D 10 ]-1f with ethyl diazoacetoacetate 2g. The KIE values for the parallel and intermolecular competitive reactions were detected to be 2.3 and 2.6, respectively (eqs S2 and S3). We next investigated the stoichiometric and catalytic reactivity of the rhodacycle complexes I and II (eqs S6−S8). Complexes I and II could efficiently catalyze the cyclization of 1f and 1p to furnish the expected products 3fg and 3pa in 55% and 64% yields, respectively. A stoichiometric amount of complex II could also react with 2a to afford 3pa in a 53% yield. These observations suggest that the five-membered cyclometalated complex is probably the intermediacy in the catalytic cycle. Fortunately, the reaction of 1f with 2a at a lower temperature (90 °C) led to the alkylated product 4 in a 53% yield (Scheme 4, eq 1). Surprisingly, only in a mixture solvent of DCE/dioxane (1:1, v/v) was 4 heated at 130 °C for 24 h to produce the

anion exchange of AgSbF6 with [Cp*RhCl2]2. The electrophilic [Cp*Rh(III)] species coordinates to the azoxy group and then undergoes a directed reversible C−H bond cleavage to form the five-membered rhodacycle intermediate B, followed by coordination to a diazoester to form the diazonium intermediate C. Subsequently, the reaction undergoes two possible pathways. In pathway a, the metal−carbene intermediate D is formed with the extrusion of nitrogen gas from C, followed by a migratory insertion of the carbene into the rhodium−carbon bond to form the six-membered rhodacycle species E. In pathway b, a direct intramolecular 1,2-migratory insertion of the aryl group affords E. The protonation of E next produces the alkylated intermediate F and regenerates the active rhodium species A. Finally, F could undergo intramolecular nucleophilic attack of the malonate ester by oxygen of azoxy, followed by CO2 extrusion and intramolecular cyclization to deliver 3pa with the release alcohol 2779

DOI: 10.1021/acs.orglett.7b00631 Org. Lett. 2017, 19, 2777−2780

Organic Letters

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(confirmed by GC−MS). In contrast, without the help of an extra electron-drawing ester group, 5 difficultly undergoes the intramolecular nucleophilic attack and subsequent decarboxylation. Finally, using 3fa as a representative example, we investigated the synthetic potential of the reaction. As shown in Scheme 6,

treatment of 3fa with KOH/EtOH and subsequent decarboxylation provided 2-phenyl-2H-indazole 8 in a 90% yield. Next, 8 reacted with dimethyl acetylenedicarboxylate (DMAD) and furan-2-carbaldehyde to deliver the 4-aminoquinoline derivative 93c and the Indazo-Fluor fluorophore 10,3d respectively. The quaternization of 3fa with dimethyl sulfate and subsequent hydrolysis produced the indazolium-3-carboxylate 11, which can in situ generate a N-heterocyclic carbene by thermal decarboxylation.3a In summary, we have developed a Rh(III)-catalyzed regioselective tandem C−H alkylation/cyclization of azoxy compounds with diazoesters to afford 3-acyl-2H-indazole derivatives. The azoxy group instead of the azo group enables a [4 + 1]-annulation rather than a conventional [4 + 2] manner. This reaction shows a broad functional group tolerance, a complete regioselectivity for unsymmetrical azoxybenzenes and a compatibility of monoaryldiazene oxides. The azoxy group has been disclosed as an incorporated directing group, which could have pronounced implications in future work and eventually lead to new, valuable synthetic reactions.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00631. Detailed experimental procedures, characterization data, and 1H and 13C NMR spectra of key intermediates and final products (PDF) X-ray crystallogrphic data for complex I (CIF) X-ray crystallogrphic data for complex II (CIF)

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REFERENCES

(1) (a) Elguero, J. Pyrazoles and their Benzo Derivatives. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon: New York, 1984; Vol. 5, pp 167−303. (b) Cerecetto, H.; Gerpe, A.; González, M.; Arán, V. J.; de Ocáriz, C. O. Mini-Rev. Med. Chem. 2005, 5, 869. (c) Schmidt, A.; Beutler, A.; Snovydovych, B. Eur. J. Org. Chem. 2008, 2008, 4073. (d) Haddadin, M. J.; Conrad, W. E.; Kurth, M. J. Mini-Rev. Med. Chem. 2012, 12, 1293. (2) (a) Halim, R.; Harding, M.; Hufton, R.; Morton, C. J.; Jahangiri, S.; Pool, B. R.; Jeynes, T. P.; Draffan, A. G.; Lilly, M. J.; Frey, B. WO 2012/ 051659 A1, 2012. (b) Steffan, R. J.; Matelan, E. M. WO 2006/050006 A2, 2006. (c) Aman, W.; Lee, J.; Kim, M.; Yang, S.; Jung, H.; Hah, J.-M. Bioorg. Med. Chem. Lett. 2016, 26, 1188. (3) (a) Schmidt, A.; Merkel, L.; Eisfeld, W. Eur. J. Org. Chem. 2005, 2005, 2124. (b) Zhou, Y.; Liu, Q.; Lv, W.; Pang, Q.; Ben, R.; Qian, Y.; Zhao, J. Organometallics 2013, 32, 3753. (c) Vidyacharan, S.; Sagar, A.; Sharada, D. S. Org. Biomol. Chem. 2015, 13, 7614. (d) Cheng, Y.; Li, G.; Liu, Y.; Shi, Y.; Gao, G.; Wu, D.; Lan, J.; You, J. J. Am. Chem. Soc. 2016, 138, 4730. (4) (a) Inamoto, K.; Saito, T.; Katsuno, M.; Sakamoto, T.; Hiroya, K. Org. Lett. 2007, 9, 2931. (b) Yu, D.-G.; Suri, M.; Glorius, F. J. Am. Chem. Soc. 2013, 135, 8802. (c) Chen, C.-Y.; Tang, G.; He, F.; Wang, Z.; Jing, H.; Faessler, R. Org. Lett. 2016, 18, 1690. (d) Wang, Q.; Li, X. Org. Lett. 2016, 18, 2102. (5) For selected examples, see: (a) Halland, N.; Nazaré, M.; R’kyek, O.; Alonso, J.; Urmann, M.; Lindenschmidt, A. Angew. Chem., Int. Ed. 2009, 48, 6879. (b) Wu, C.; Fang, Y.; Larock, R. C.; Shi, F. Org. Lett. 2010, 12, 2234. (c) Kumar, M. R.; Park, A.; Park, N.; Lee, S. Org. Lett. 2011, 13, 3542. (d) Genung, N. E.; Wei, L.; Aspnes, G. E. Org. Lett. 2014, 16, 3114. (6) For the synthesis of 3-acyl-2H-indazoles, see: (a) Luo, G.; Chen, L.; Dubowchik, G. J. Org. Chem. 2006, 71, 5392. (b) Bunnell, A.; O’Yang, C.; Petrica, A.; Soth, M. J. Synth. Commun. 2006, 36, 285. (c) Unsinn, A.; Knochel, P. Chem. Commun. 2012, 48, 2680. (d) Wang, C.-D.; Liu, R.-S. Org. Biomol. Chem. 2012, 10, 8948. (e) Yong, W.-S.; Park, S.; Yun, H.; Lee, P. H. Adv. Synth. Catal. 2016, 358, 1958. (7) (a) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem., Int. Ed. 2012, 51, 8960. (b) Ackermann, L. Acc. Chem. Res. 2014, 47, 281. (c) Huang, H.; Ji, X.; Wu, W.; Jiang, H. Chem. Soc. Rev. 2015, 44, 1155. (d) Song, G.; Li, X. Acc. Chem. Res. 2015, 48, 1007. (8) (a) Li, H.; Li, P.; Wang, L. Org. Lett. 2013, 15, 620. (b) Lian, Y.; Bergman, R. G.; Lavis, L. D.; Ellman, J. A. J. Am. Chem. Soc. 2013, 135, 7122. (c) Hummel, J. R.; Ellman, J. A. J. Am. Chem. Soc. 2015, 137, 490. (d) Geng, X.; Wang, C. Org. Lett. 2015, 17, 2434. (e) Jeong, T.; Han, S. H.; Han, S.; Sharma, S.; Park, J.; Lee, J. S.; Kwak, J. H.; Jung, Y. H.; Kim, I. S. Org. Lett. 2016, 18, 232. (9) Balch, A. L.; Petridis, D. Inorg. Chem. 1969, 8, 2247. (10) (a) Li, H.; Li, P.; Zhao, Q.; Wang, L. Chem. Commun. 2013, 49, 9170. (b) Sun, M.; Hou, L.-K.; Chen, X.-X.; Yang, X.-J.; Sun, W.; Zang, Y.-S. Adv. Synth. Catal. 2014, 356, 3789. (c) Zhang, D.; Cui, X.; Yang, F.; Zhang, Q.; Zhu, Y.; Wu, Y. Org. Chem. Front. 2015, 2, 951. (11) (a) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417. (b) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704. (c) Xiao, Q.; Zhang, Y.; Wang, J. Acc. Chem. Res. 2013, 46, 236. (d) Hu, F.; Xia, Y.; Ma, C.; Zhang, Y.; Wang, J. Chem. Commun. 2015, 51, 7986. (12) (a) Son, J.-Y.; Kim, S.; Jeon, W. H.; Lee, P. H. Org. Lett. 2015, 17, 2518. (b) Sharma, S.; Han, S. H.; Han, S.; Ji, W.; Oh, J.; Lee, S.-Y.; Oh, J. S.; Jung, Y. H.; Kim, I. S. Org. Lett. 2015, 17, 2852. (13) (a) Li, H.; Xie, X.; Wang, L. Chem. Commun. 2014, 50, 4218. (b) Xu, N.; Li, P.; Xie, Z.; Wang, L. Chem. - Eur. J. 2016, 22, 2236. (14) (a) Huang, X.; Huang, J.; Du, C.; Zhang, X.; Song, F.; You, J. Angew. Chem., Int. Ed. 2013, 52, 12970. (b) Huang, X.; Liang, W.; Shi, Y.; You, J. Chem. Commun. 2016, 52, 6253. (15) Xia, Y.; Liu, Z.; Feng, S.; Zhang, Y.; Wang, J. J. Org. Chem. 2015, 80, 223.

Scheme 6. Transformations of 3fa to Functional Molecules

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Letter

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Jingsong You: 0000-0002-0493-2388 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by grants from the National NSF of China (No. 21432005). 2780

DOI: 10.1021/acs.orglett.7b00631 Org. Lett. 2017, 19, 2777−2780