Divergent Synthesis of Fused Tricyclic Compounds via a Tandem

Nov 20, 2017 - Divergent Synthesis of Fused Tricyclic Compounds via a Tandem Reaction from Alkynyl-cyclohexadienones and Diazoesters. Guangyang Xu, Ka...
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Divergent Synthesis of Fused Tricyclic Compounds via a Tandem Reaction from Alkynyl-cyclohexadienones and Diazoesters Guangyang Xu, Kai Liu, and Jiangtao Sun* Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, School of Petrochemical Engineering, Changzhou University, Changzhou 213164, P. R. China S Supporting Information *

ABSTRACT: A distinct one-pot protocol toward several types of fused tricyclic scaffolds has been developed, by employing diazoesters and alkynyl-cyclohexadienones as starting materials, enabling rapid construction of diverse tricyclic compounds with multiple bonds formation in an operationally simple procedure. Typically, this controlled tandem sequence showcases the in situ formation of tetrasubstituted allenoates, an unprecedented aniontriggered annulation, and oxidative aromatization.

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On the other hand, metal-carbene initiated tandem reactions have been validated as powerful tools for diversity-oriented synthesis.3 Recently, we reported a tandem reaction to prepare chiral five-membered N-heterocycles using diazoesters with amino alkynes as the starting materials (Scheme 1a).4a This annulation proceeded through copper-catalyzed allenoate formation and sequential intramolecular Michael addition by an internal nucleophile under base-free conditions. To extend this strategy, we seek to introduce an external nucleophile with a view to constructing more complex molecules (Scheme 1b). We envisaged that as an excellent Michael acceptor tetrasubstituted allenoates 3 could undergo Michael addition at the β-position in the presence of an anionic nucleophile to yield intermediate I (3 could be prepared in one step from alkynyl-cyclohexadienones 1 and diazoesters 2, see SI for details).5 Then this intermediate would be followed by anion transfer, affording intermediate II, which might be trapped by an internal electrophile (carboxylate) to form fused tricyclic compounds 4 with newly formed contiguous stereogenic centers. Furthermore, upon oxidation, 4 could be converted to other types of aromatic tricyclic compounds. In continuation with our research interests in diazo chemistry, herein we report the divergent synthesis of fused tricyclic compounds from readily available alkynyl-cyclohexadienones and diazoesters in a one-pot manner. The initial investigation toward tricyclic compounds has been performed (Scheme 2, see SI for optimization and the full characterization of allenoates). Treatment of alkynyl-cyclohexadienone 1a and phenyl diazoacetate 2a with a catalytic amount of CuI (10 mol %) in acetonitrile at 40 °C for 5 h provided 87% yield of 3a in 4:1 dr ratio (Scheme 2A). The configuration of 3a (major isomer) was determined by X-ray analysis.6 Next, to a solution of 3a (mixture of two isomers) in

o develop efficient strategies for forging multiple bonds in a controllable sequence and thus allow rapidly assembling structurally complex molecules is a persistent pursuit in organic synthesis. Although many such processes have been achieved, methods with novel transformations are still in high demand for molecular complexity. For example, fused tricyclic scaffolds (Figure 1, types I to V) exist in numerous building blocks,

Figure 1. Representative examples of biologically active compounds bearing fused tricyclic rings.

naturally occurring products, and biologically active pharmaceuticals,1 thereby attracting considerable attention in the past decades. However, to access those compounds with such skeletons, quite different strategies and multistep synthesis are often required.2 Given the prevalence of those tricyclic structures, we pursue the design and further development of a distinct reaction sequence for their construction. © 2017 American Chemical Society

Received: October 27, 2017 Published: November 20, 2017 6440

DOI: 10.1021/acs.orglett.7b03356 Org. Lett. 2017, 19, 6440−6443

Letter

Organic Letters

sodium salts (Scheme 3). Generally, the use of aryl diazoacetates 2 or aryl phenate (ArYNa, Y = O or S) bearing

Scheme 1. Previous Report and Our New Design

Scheme 3. One-Pot Reaction Towards Tricyclic Compounds 4a,b

Scheme 2. Initial Studies

a

The reactions were carried out with 1 (0.5 mmol), diazoester 2 (0.6 mmol), and CuI (10 mol %) in MeCN (5 mL) at 40 °C for 5 h (for 4a−4e, 4g, 4l−4q) or 16 h (for 4f, 4h−4k, and 4r−4t), followed by addition of ArYNa (1.2 equiv) and stirred at 40 °C for another 5 h. b Yield of isolated products; dr values were determined by NMR analysis of crude products.

electron-donating substituents provided the corresponding tricyclic compounds in higher yields than the electron-deficient aryl substrates (4a to 4i). Even simple ethyl diazoacetate also reacted well to furnish 4j in 63% yield, whereas the use of alkyl diazoacetate provided the desired product 4k in 43% yield. For alkynyl-cyclohexadienones, the substrates with methyl group (R1 and R2) at the cyclohexadienone skeleton reacted well and delivered 4l and 4m in 82% and 75% yield, respectively. Next, various R3 groups of alkynes 1 were evaluated. The substituents such as methoxy, phenyl, alkyl, and methyl acetate were all tolerated, affording the corresponding products in moderate to high yields (4n to 4r). For N-linked cyclohexadienone, the final compound 4s was obtained as inseparable isomers in 1.2:1 ratio. The use of C-tethered alkyne furnished 4t in 32% yield. Importantly, PhSNa, p-Me-PhSNa, and PhSeNa were also amenable to the reaction and provided the corresponding products in acceptable yield (4u to 4x). It should be noted that

acetonitrile was added sodium phenoxide (1.2 equiv) at 40 °C and stirred for another 5 h. The tricyclic compound 4a was isolated as a single isomer in 95% yield (Scheme 2B). Furthermore, when 4a was subjected to DDQ (2,3-dicyano5,6-dichlorobenzoquinone) for 1 h in acetonitrile at room temperature, the fused tricyclic aromatic compound 5a was obtained in 90% yield (Scheme 2C). Notably, since the three steps (A, B, and C) were all performed in acetonitrile, the whole procedure can be completed in one pot without isolating the intermediates. 4a was cleanly isolated in 85% yield (Scheme 2D), whereas 5a could be obtained in 75% yield from one-pot reaction of 1a and 2a (Scheme 2E). With the one-pot reaction conditions for the preparation of 4a in hand, we set out to investigate the substrate scope for a range of alkynyl-cyclohexadienones 1, diazoesters 2, as well as 6441

DOI: 10.1021/acs.orglett.7b03356 Org. Lett. 2017, 19, 6440−6443

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Organic Letters most of the tricyclic compounds were obtained in excellent dr value (>20:1) except 4s. The structure of 4b and 4l was confirmed by X-ray analysis.6 Since 4a can be smoothly converted to 5a in the presence of DDQ, the one-pot reaction toward various aromatic tricyclic compounds 5 was further investigated without the isolation of the intermediates (Scheme 4). To our delight, most of the

Scheme 5. One-Pot Reaction Towards Aromatic Tricyclic Compounds 6a,b

Scheme 4. One-Pot Reaction Towards Aromatic Tricyclic Compounds 5a,b

a The reactions were carried out with 1 (0.5 mmol), diazoester 2 (0.6 mmol), and CuI (10 mol %) in MeCN (5 mL) at 40 °C for 5 to 16 h, followed by addition of ArYNa (1.2 equiv) and stirred at 40 °C for another 5 h. Then 1.5 equiv of DDQ was added and the mixture stirred at rt for 1 h. bYield of isolated products.

Further application of this one-pot protocol has been investigated (Scheme 6). The reaction of 4c with PhNTf2 in the presence of sodium hydride followed by Suzuki-coupling reaction with phenylboronic acid delivered 7 in 78% yield for two steps. Removing the TBS group of 5n with tetrabutylammonium fluoride gave the tetracyclic compound 8 in 65% yield. Moreover, hydrogenation of acetyl-protected 6f resulted in the formation of naphthalene tricyclic compound, which can a

The reactions were carried out with 1 (0.5 mmol), diazoester 2 (0.6 mmol), and CuI (10 mol %) in MeCN (5 mL) at 40 °C for 5 to 16 h, followed by addition of ArYNa (1.2 equiv) and stirred at 40 °C for another 5 h. Then 1.5 equiv of DDQ was added and the mixture stirred at rt for 1 h. bYield of isolated products.

Scheme 6. Synthetic Applications

alkynyl-cyclohexadienones 1, diazo substrates 2, and the sodium phenolates/thiophenolates used in Scheme 3 all proceeded well to give the corresponding products in moderate to high yields, but the use of sodium selenophenate resulted in the formation of 5s in 25% yield. Moreover, the structure of 5b was also determined by X-ray analysis.6 Notably, the use of substrate 1 baring the methoxy group at R3 delivered 5q in 30% yield. For the oxidative aromatization of tricyclic compunds 4 bearing a methoxy group adjacent to oxygen or nitrogen tethered alkynes 1, we observed the unexpected formation of 3,4-tethered benzofurans and indoles, indicating the oxidative aromatization occurred with the cleavage of a methoxy group. Thus, this method was extended to a range of substrates to prepare tricyclic benzofuran and indole derivatives (Scheme 5). Gratifyingly, all of the yields were acceptable for either tricyclic indoles or benzofurans. As a result, a distinct approach toward 3,4-substituted tricyclic benzofuran and indole has also been established. Furthermore, the configuration of 6b was determined by X-ray analysis.6 6442

DOI: 10.1021/acs.orglett.7b03356 Org. Lett. 2017, 19, 6440−6443

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Organic Letters

(c) Jauch, J. Angew. Chem., Int. Ed. 2008, 47, 34. (d) Hanessian, S.; Boyer, N.; Reddy, G. J.; Deschênes-Simard, B. Org. Lett. 2009, 11, 4640. (e) Hsu, D.-S.; Liao, C.-C. Org. Lett. 2003, 5, 4741. (f) Nicolaou, K. C.; Lim, Y. H.; Becker, J. Angew. Chem., Int. Ed. 2009, 48, 3444. (2) For selected examples, see: (a) Keilitz, J.; Newman, S. G.; Lautens, M. Org. Lett. 2013, 15, 1148. (b) Martín-Santos, C.; JaravaBarrera, C.; del Pozo, S.; Parra, A.; Díaz-Tendero, S.; Mas-Ballesté, R.; Cabrera, S.; Alemán, J. Angew. Chem., Int. Ed. 2014, 53, 8184. (c) He, Z.-T.; Tang, X.-Q.; Xie, L.-B.; Cheng, M.; Tian, P.; Lin, G.-Q. Angew. Chem., Int. Ed. 2015, 54, 14815. (d) Takizawa, S.; Kishi, K.; Yoshida, Y.; Mader, S.; Arteaga, F. A.; Lee, S.; Hoshino, M.; Rueping, M.; Fujita, M.; Sasai, H. Angew. Chem., Int. Ed. 2015, 54, 15511. (e) Murthy, A. S.; Donikela, S.; Reddy, C. S.; Chegondi, R. J. Org. Chem. 2015, 80, 5566. (f) Tan, S. M.; Willis, A. C.; Paddon-Row, M. N.; Sherburn, M. S. Angew. Chem., Int. Ed. 2016, 55, 3081. (g) Kumar, R.; Hoshimoto, Y.; Tamai, E.; Ohashi, M.; Ogoshi, S. Nat. Commun. 2017, DOI: 10.1038/ s41467-017-00068-8. (3) For selected representative examples for carbene-involved tandem reactions, see: (a) Jiang, J.; Xu, H.-D.; Xi, J.-B.; Ren, B.-Y.; Lv, F.-P.; Guo, X.; Jiang, L.-Q.; Zhang, Z.-Y.; Hu, W.-H. J. Am. Chem. Soc. 2011, 133, 8428. (b) Zhou, C.-Y.; Wang, J.-C.; Wei, J.; Xu, Z.-J.; Guo, Z.; Low, K.-H.; Che, C.-M. Angew. Chem., Int. Ed. 2012, 51, 11376. (c) Zhou, L.; Ye, F.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2010, 132, 13590. (d) Jansone-Popova, S.; May, J. A. J. Am. Chem. Soc. 2012, 134, 17877. (e) Jia, S.; Xing, D.; Zhang, D.; Hu, W. Angew. Chem., Int. Ed. 2014, 53, 13098. (f) González-Rodríguez, C.; Suárez, J. R.; Varela, J. A.; Saá, C. Angew. Chem., Int. Ed. 2015, 54, 2724. (g) Ye, F.; Qu, S.; Zhou, L.; Peng, C.; Wang, C.; Cheng, J.; Hossain, M. L.; Liu, Y.; Zhang, Y.; Wang, Z.-X.; Wang, J. J. Am. Chem. Soc. 2015, 137, 4435. (h) Pagar, V. V.; Liu, R.-S. Angew. Chem., Int. Ed. 2015, 54, 4923. (i) Jing, C.; Xing, D.; Gao, L.; Li, J.; Hu, W. Chem. - Eur. J. 2015, 21, 19202. (j) Alamsetti, S. K.; Spanka, M.; Schneider, C. Angew. Chem., Int. Ed. 2016, 55, 2392. (k) Nicolle, S. M.; Lewis, W.; Hayes, C. J.; Moody, C. J. Angew. Chem., Int. Ed. 2016, 55, 3749. (l) Day, J.; McKeever-Abbas, B.; Dowden, J. Angew. Chem., Int. Ed. 2016, 55, 5809. (4) (a) Liu, K.; Zhu, C.; Min, J.; Peng, S.; Xu, G.; Sun, J. Angew. Chem., Int. Ed. 2015, 54, 12962. For related works, see (b) Zhao, X.; Zhang, Y.; Wang, J. Chem. Commun. 2012, 48, 10162. (c) Wu, Y.-N.; Xu, T.; Fu, R.; Wang, N.-N.; Hao, W.-J.; Wang, S.-L.; Li, G.; Tu, S.-J.; Jiang, B. Chem. Commun. 2016, 52, 11943. (5) For the leading example on the formation of tetrasubstituted allenes from copper-catalyzed cross-coupling of alkynes and diazoesters, see: Ye, F.; Hossain, M. L.; Xu, Y.; Ma, X.; Xiao, Q.; Zhang, Y.; Wang, J. Chem. - Asian J. 2013, 8, 1404. (6) CCDC 1447631 (3a), CCDC 1448896 (4b), CCDC 1447629 (4l), CCDC 1479469 (5b), and CCDC 1514211 (6b). (7) Chen, P. H.; Xu, T.; Dong, G. Angew. Chem., Int. Ed. 2014, 53, 1674 and references therein. (8) Miyashita, K.; Sakai, T.; Imanishi, T. Org. Lett. 2003, 5, 2683.

be further converted to 9 by hydrogenation. This type of aromatic tricyclic scaffold can be found in many nature products and biologically active molecules.7 Next, treatment of 5r with Raney-Ni in ethanol yielded tricyclic compound 10 by removing the sulfide moiety, which is the core structure of spiroxin C.8 Treatment of 5r with PhNTf2 gave TfO-protected intermediate, which was followed by hydrogenation to remove the OTf and SPh moieties cleanly and generate 11 in 61% total yield. Moreover, copper-catalyzed addition of isopropenylmagnesium bromide to an enone moiety of the aryl triflate intermediate derived from 5r followed by hydrogenation with Raney-Ni delivered 12 in 33% total yield. In summary, we have developed a distinct protocol toward rapidly accessing several different types of tricyclic compounds by employing diazoesters and cyclohexadienone-tethered terminal alkynes as the starting materials. Importantly, upon rational design, after treatment of the in situ formed tetrasubstituted allenoates with sodium phenolate/thiophenolate/selenophenate, a novel annulation occurs through a formal anion relay process. Further oxidative aromatization results in the formation of aromatic tricyclic compounds, including 3,4tethered indoles and benzofurans. Typically, the sequential transformations can be simply manipulated in one pot.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03356. Experimental procedures along with characterizing data and copies of NMR spectra (PDF) Accession Codes

CCDC 1447629, 1447631, 1448896, 1479469, and 1514211 contain 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 data_request@ccdc. cam.ac.uk, 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 Author

*E-mail: [email protected] or [email protected]. ORCID

Jiangtao Sun: 0000-0003-2516-3466 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge the National Natural Science Foundation of China (21572024), the Natural Science Foundation of Jiangsu Province (BK20151184), Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology (BM2012110), and Advanced Catalysis & Green Manufacturing Collaborative Innovation Center for their financial support.

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REFERENCES

(1) For selected examples, see: (a) Leclaire, M.; Levet, R.; Péricaud, F.; Ricard, L.; Lallemand, J. Y. Tetrahedron 1996, 52, 7703. (b) Germain, J.; Deslongchamps, P. J. Org. Chem. 2002, 67, 5269. 6443

DOI: 10.1021/acs.orglett.7b03356 Org. Lett. 2017, 19, 6440−6443