A General Strategy for the Construction of Functionalized Azaindolines

Letter pubs.acs.org/OrgLett

A General Strategy for the Construction of Functionalized Azaindolines via Domino Palladium-Catalyzed Heck Cyclization/ Suzuki Coupling Tabitha T. Schempp, Blake E. Daniels, Steven T. Staben, and Craig E. Stivala* Discovery Chemistry Group, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States S Supporting Information *

ABSTRACT: The preparation of substituted azaindolines utilizing a domino palladium-catalyzed Heck cyclization/Suzuki coupling is described. The approach is amenable for the construction of all four azaindoline isomers. A range of functional groups such as esters, amides, ketones, sulfones, amines, and nitriles are all tolerated under the reaction conditions.

T

Scheme 1. Strategies to Access Functionalized Azaindolines

he preparation of substituted heterocycles remains a fundamental challenge in organic synthesis. The construction of indolines and azaindolines is of particular interest due to their prominence in natural products and drug discovery programs (see Figure 1 for representative examples).1−4 As a result, considerable effort has been dedicated toward developing new strategies and methodologies that enable access to these important heterocycles.5 Despite the numerous methods that exist for the preparation of 3,3′-disubstituted indolines (Scheme 1),6 comparable studies with azaindolines are scarce. Many commonly employed strategies, such as the Fischer indole synthesis7 and the Friedel−Crafts reaction,8 are often unsuccessful with azaindolines due to subtle electronic perturbations. While methods to prepare 7-azaindolines,9 6-azaindolines,10 5-azaindolines,6j,11 and 4-azaindolines exist,10a,12 only a handful can be used in a general sense to access all four isomers.13 To the best of our knowledge, a general strategy for the construction of 3,3′disubstituted azaindolines has yet to be reported. During the course of a drug discovery program, we required access to these types of heterocyclic scaffolds. A six-step

synthesis involving sequential alkylations of an azaoxindole was sufficient for the preparation of simple analogues; however, due to the necessity of reducing the azaoxindole to the corresponding azaindoline, it was difficult to generate analogues that were highly functionalized. It became necessary to develop a complementary synthetic route that would minimize steps, oxidation state adjustments, and protecting group use. We were drawn to redox-neutral transformations involving anionic, radical, and metal-catalyzed cyclizations onto pendent olefins. These approaches are particularly attractive because in situ Figure 1. Substituted 3,3- or 3,3′-indolines and azaindolines featured in various drug discovery programs. © 2017 American Chemical Society

Received: May 27, 2017 Published: June 27, 2017 3616

DOI: 10.1021/acs.orglett.7b01606 Org. Lett. 2017, 19, 3616−3619

Letter

Organic Letters Table 1. Optimization of Reaction Conditions

Scheme 3. Scope of the Domino Heck Cyclization/Suzuki Coupling with Unprotected Substratesa

entrya

catalyst

ligand

3 conv (%)b

4 conv (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14

Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(CF3CO2)2 Pd(PPh3)2Cl2 Pd(PPh3)4 Pd2(dba)3 Pd(dppf)Cl2

PPh3 P(o-Tol)3 PCy3 P(t-Bu)3 XPhos SPhos DavePhos JohnPhos − PPh3 − − − −

100 100 85 100 100 100 100 100 100 100 100 100 100 (87%)c 100

83 100 64 83 58 68 70 100 88 87 88 75 100 (67%)c 100

a

All reactions were performed on a 0.20 mmol scale (0.1 M) using Pd (5 mol %), ligand (10 mol %), K2CO3 (2 equiv), and phenylboronic acid (2 equiv) and heated at 100 °C for 18 h. bConversion was determined by 1H NMR. cIsolated yield

a All reactions were performed on 0.25−1.00 mmol scales (0.1 M) using Pd (5 mol %), K2CO3 (2 equiv), and phenylboronic acid (2 equiv) and heated at 100 °C for 18 h. b4-Iodo-N-(2-methylallyl)pyridin-3-amine was used as the starting material.

generated reactive intermediates can be used in domino processes.14 Palladium-catalyzed domino processes have been extensively studied for the preparation of substituted indolines and are known to be robust toward a broad range of functional groups. Previously,15 Grigg described a tandem Pd-catalyzed Heck cyclization/Suzuki coupling that provides access to function-

alized benzofurans, protected indolines, and oxindoles. However, to the best of our knowledge, this methodology has not been applied to the preparation of substituted azaindolines. Herein, we describe our efforts in further developing this reaction and demonstrating its general utility for the construction of functionalized azaindolines.

Scheme 2. Scope of the Domino Heck Cyclization/Suzuki Coupling with Protected Substratesa

a All reactions were performed on 0.50−1.00 mmol scales (0.1 M) using Pd (5 mol %), K2CO3 (2 equiv), and phenylboronic acid (2 equiv) and heated at 100 °C for 18 h. bN-(5-Bromo-4-chloro-3-iodopyridin-2-yl)-4-methyl-N-(2-methylallyl)benzenesulfonamide was used as the starting material. NR = No Reaction.

3617

DOI: 10.1021/acs.orglett.7b01606 Org. Lett. 2017, 19, 3616−3619

Letter

Organic Letters

lower compared to their protected variants, this approach provides direct access to free azaindolines and eliminates a potentially challenging deprotection step. We were able to demonstrate the generality of this approach by successfully preparing each unprotected azaindoline isomer (31−33) with yields ranging from 30−75%. For azaindole 33, the low yield is a result of a competitive direct cross-coupling that occurs.17 To the best of our knowledge, this is the only general approach that enables access to all four unprotected 3,3′- azaindoline isomers. Azole heterocycles were also examined (Scheme 4). Pyrazoles 35 and 34 were isolated in low to moderate yields (11% and 53% respectively) whereas the unprotected isoxazole 36 decomposed under the reaction conditions. These results demonstrate just one of the many possible ways the scope of this transformation could be extended beyond what is presented in this manuscript.18 Since enantioselective variants of the 5-exo-trig Heck cyclization are known,19 we decided to screen a number of chiral phosphines in an attempt to render the reaction asymmetric.17 Unfortunately, all attempts yielded racemic material. This result is not surprising given the lack of phosphine dependence we observed during our optimization studies. Others in the field have reported similar results in their pursuit of tandem enantioselective processes.16a It has been suggested that the lack of stereocontrol might be the result of a “ligandless” Pd species involved in the stereodetermining step.20 In summary, we have described a general and efficient protocol for the domino Heck cyclization/Suzuki coupling that is amenable for the preparation of 3,3′-azaindolines. This unified approach can be used to construct all four 3,3′azaindoline isomers. The reaction has broad functional group compatibility and overcomes many challenges inherent to a traditional multistep approach.

Scheme 4. Scope of the Domino Heck Cyclzation/Suzuki Coupling with other Heterocyclesa

a

All reactions were performed on 0.50 mmol scales (0.1 M) using Pd (5 mol %), K2CO3 (2 equiv), and phenylboronic acid (2 equiv) and heated at 100 °C for 18 h.

We began our screening efforts by investigating the influence of different phosphine ligands in combination with palladium acetate, phenylboronic acid, and potassium carbonate in DMF (Table 1). Using tosyl-protected aminopyridine 1, we discovered that most reactions were generally insensitive toward the choice of phosphine ligand, as most proceeded with high levels of conversion. Furthermore, in the absence of a phosphine ligand, complete conversion to azaindoline 3 was still observed. This trend was maintained with a number of other palladium catalysts that were also screened in the reaction (Table 1, entries 10−14). Several transition-metal-catalyzed domino Heck/C−H functionalization reactions have been reported; in several cases unprotected nitrogen atoms often suppress reactivity.16 As a result, we wanted to explore if azaindoline 2 could be used in the reaction cascade (Table 1). In this case, reactions that used P(o-Tol)3 and JohnPhos maintained high levels of conversion (Table 1, entries 2 and 8), whereas other phosphine ligands were generally less effective. Once again, Pd2(dba)3 and Pd(dppf)Cl2 (Table 1, entries 13 and 14) successfully promoted the cascade in the absence of any exogenous phosphine ligand and maintained high conversion. Azaindoline 4 was isolated in 67% yield. Since reactions that employed Pd2(dba)3 as a catalyst were typically easier to purify, the scope (Scheme 2) of the cascade was next examined using this optimal set of reaction conditions (Table 1, entry 13). Substrates containing substitution at the ortho, meta, and para positions proceeded smoothly to provide azaindolines 5−7 in high yields (81−95%). Pyridines with electron-withdrawing groups suppressed reactivity. While 8 could be isolated in 30% yield, 9 failed to react under our optimized conditions. In addition to tosyl-protected substrates, a benzyl-protected aminopyridine underwent efficient cyclization and coupling to deliver 10 in 94% yield. Next, we tested the functional group tolerance of multiple aryl boronic acid coupling partners. Sulfones (11), nitriles (12 and 13), esters (14), ketones (15), and amides (16−18) could all be utilized, delivering products in moderate to high yields. Indazoles (19), biaryls (20), and other substituted aryl analogues (21−25) were also compatible and further highlight the breadth of functionality that can be incorporated into the 7azaindoline scaffold. We also investigated a series of unprotected azaindolines (Scheme 3). Once again, we observed excellent functional group compatibility (26−30). While yields were marginally

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01606. Experimental procedures, characterization, and spectral data for all new compounds (PDF)

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Craig E. Stivala: 0000-0002-5024-6346 Notes

The authors declare no competing financial interest.

■ ■

ACKNOWLEDGMENTS The authors would like to thank Baiwei Lin and Kewei Xu for HRMS data. REFERENCES

(1) Lounasmaa, M.; Tolvanen, A. Nat. Prod. Rep. 2000, 17, 175. (2) Gonzalez-Lopez De Turiso, F.; Shin, Y.; Brown, M.; Cardozo, M.; Chen, Y.; Fong, D.; Hao, X.; He, X.; Henne, K.; Hu, Y. L.; Johnson, M. G.; Kohn, T.; Lohman, J.; McBride, H. J.; McGee, L. R.; Medina, J. C.; 3618

DOI: 10.1021/acs.orglett.7b01606 Org. Lett. 2017, 19, 3616−3619

Letter

Organic Letters

Ravishankar, T.; Thornton-Pett, M. Tetrahedron Lett. 1994, 35, 2753. (e) de Meijere, A.; Bräse, S. J. Organomet. Chem. 1999, 576, 88. (f) Liu, X.; Ma, X.; Huang, Y.; Gu, Z. Org. Lett. 2013, 15, 4814. (g) Liu, X.; Gu, Z. Org. Chem. Front. 2015, 2, 778. (15) (a) Grigg, R.; Loganathan, V.; Sridharan, V.; Stevenson, P.; Sukirthalingam, S.; Worakun, T. Tetrahedron 1996, 52, 11479. (b) Grigg, R.; Mariani, E.; Sridharan, V. Tetrahedron Lett. 2001, 42, 8677. (16) (a) Piou, T.; Neuville, L.; Zhu, J. Org. Lett. 2012, 14, 3760. (b) Wu, X. X.; Chen, W. L.; Shen, Y.; Chen, S.; Xu, P. F.; Liang, Y. M. Org. Lett. 2016, 18, 1784. (17) See the Supporting Information (18) Five-membered heterosubstituted boronic acids were also screened; however, of those tested (4-pyrazoleboronic acid, 1methylpyrazole-4-boronic acid, and (1-methyl-1H-imidazol-2-yl) bornic acid) all failed to participate in the tandem reaction process. (19) (a) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945. (b) Quasdorf, K. W.; Overman, L. E. Nature 2014, 516, 181. (c) Steven, A.; Overman, L. E. Angew. Chem., Int. Ed. 2007, 46, 5488. (d) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 5363. (e) Shibasaki, M.; Vogl, E. M.; Ohshima, T. Adv. Synth. Catal. 2004, 346, 1533. (f) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388. (g) Tietze, L. F.; Ila, H.; Bell, H. P. Chem. Rev. 2004, 104, 3453. (20) Carrow, B. P.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 79.

Metz, D.; Miner, K.; Mohn, D.; Pattaropong, V.; Seganish, J.; Simard, J. L.; Wannberg, S.; Whittington, D. A.; Yu, G.; Cushing, T. D. J. Med. Chem. 2012, 55, 7667. (3) Vu, A. T.; Cohn, S. T.; Zhang, P.; Kim, C. Y.; Mahaney, P. E.; Bray, J. A.; Johnston, G. H.; Koury, E. J.; Cosmi, S. A.; Deecher, D. C.; Smith, V. A.; Harrison, J. E.; Leventhal, L.; Whiteside, G. T.; Kennedy, J. D.; Trybulski, E. J. J. Med. Chem. 2010, 53, 2051. (4) Yang, W.; Wang, Y.; Lai, A.; Qiao, J. X.; Wang, T. C.; Hua, J.; Price, L. A.; Shen, H.; Chen, X. Q.; Wong, P.; Crain, E.; Watson, C.; Huang, C. S.; Seiffert, D. A.; Rehfuss, R.; Wexler, R. R.; Lam, P. Y. S. J. Med. Chem. 2014, 57, 6150. (5) Liu, D.; Zhao, G.; Xiang, L. Eur. J. Org. Chem. 2010, 2010, 3975. (6) (a) Newman, S. G.; Lautens, M. J. Am. Chem. Soc. 2011, 133, 1778. (b) Liu, P.; Huang, L.; Lu, Y.; Dilmeghani, M.; Baum, J.; Xiang, T.; Adams, J.; Tasker, A.; Larsen, R.; Faul, M. M. Tetrahedron Lett. 2007, 48, 2307. (c) Zhu, Q.; Lu, Y. Angew. Chem., Int. Ed. 2010, 49, 7753. (d) Murphy, J. A.; Rasheed, F.; Gastaldi, S.; Ravishanker, T.; Lewis, N. J. Chem. Soc., Perkin Trans. 1 1997, 1549. (e) Kurono, N.; Honda, E.; Komatsu, F.; Orito, K.; Tokuda, M. Tetrahedron 2004, 60, 1791. (f) Leroi, C.; Bertin, D.; Dufils, P. E.; Gigmes, D.; Marque, S.; Tordo, P.; Couturier, J. L.; Guerret, O.; Ciufolini, M. A. Org. Lett. 2003, 5, 4943. (g) Yip, K.-T.; Yang, M.; Law, K.-L.; Zhu, N.-Y.; Yang, D. J. Am. Chem. Soc. 2006, 128, 3130. (h) Larock, R. C.; Babu, S. Tetrahedron Lett. 1987, 28, 5291. (i) Ibrahim-Ouali, M.; Sinibaldi, MÉ.; Troin, Y.; Guillaume, D.; Gramain, J. C. Tetrahedron 1997, 53, 16083. (j) Wipf, P.; Maciejewski, J. P. Org. Lett. 2008, 10, 4383. (k) René, O.; Lapointe, D.; Fagnou, K. Org. Lett. 2009, 11, 4560. (l) Groth, U.; Köttgen, P.; Langenbach, P.; Lindenmaier, A.; Schütz, T.; Wiegand, M. Synlett 2008, 2008, 1301. (m) Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira, E. M. Science 2013, 340, 1065. (n) Yao, T.; He, D. Org. Lett. 2017, 19, 842. (7) Liu, K. G.; Lo, J. R.; Robichaud, A. J. Tetrahedron 2010, 66, 573. (8) Ni, J.; Wang, H.; Reisman, S. E. Tetrahedron 2013, 69, 5622. (9) (a) Johnston, J. N.; Plotkin, M. A.; Viswanathan, R.; Prabhakaran, E. N. Org. Lett. 2001, 3, 1009. (b) Viswanathan, R.; Mutnick, D.; Johnston, J. N. J. Am. Chem. Soc. 2003, 125, 7266. (c) Srinivasan, J. M.; Burks, H. E.; Smith, C. R.; Viswanathan, R.; Johnston, J. N. Synthesis 2005, 2005, 330. (d) Ly, T.-M.; Quiclet-Sire, B.; Sortais, B.; Zard, S. Z. Tetrahedron Lett. 1999, 40, 2533. (e) Bacqué, E.; El Qacemi, M.; Zard, S. Z. Org. Lett. 2004, 6, 3671. (f) Liu, Z.; Qin, L.; Zard, S. Z. Org. Lett. 2014, 16, 2704. (g) Davies, A. J.; Brands, K. M. J.; Cowden, C. J.; Dolling, U.-H.; Lieberman, D. R. Tetrahedron Lett. 2004, 45, 1721. (h) Nguyen, H. N.; Wang, Z. J. Tetrahedron Lett. 2007, 48, 7460. (i) Desarbre, E.; Mérour, J.-Y. Tetrahedron Lett. 1996, 37, 43. (j) Moss, T. A.; Hayter, B. R.; Hollingsworth, I. A.; Nowak, T. Synlett 2012, 23, 2408. (10) (a) Badland, M.; Devillers, I.; Durand, C.; Fasquelle, V.; Gaudillire, B.; Jacobelli, H.; Manage, A. C.; Pevet, I.; Puaud, J.; Shorter, A. J.; Wrigglesworth, R. Tetrahedron Lett. 2011, 52, 5292. (b) De Bie, D. A.; Ostrowica, A.; Geurtsen, G.; Van Der Plas, H. C. Tetrahedron 1988, 44, 2977. (c) Fayol, A.; Zhu, J. Org. Lett. 2005, 7, 239. (11) (a) Yakhontov, L. N.; Azimov, V. A.; Lapan, E. I. Tetrahedron Lett. 1969, 10, 1909. (b) Spivey, A. C.; Fekner, T.; Adams, H. Tetrahedron Lett. 1998, 39, 8919. (c) Spivey, A. C.; Fekner, T.; spey, S. E.; Adams, H. J. Org. Chem. 1999, 64, 9430. (d) Laot, Y.; Petit, L.; Zard, S. Z. Org. Lett. 2010, 12, 3426. (12) (a) Bordi, S.; Starr, J. T. Org. Lett. 2017, 19, 2290. (b) Donati, D.; Fusi, S.; Ponticelli, F. Eur. J. Org. Chem. 2002, 2002, 4211. (c) Leroi, C.; Bertin, D.; Dufils, P. E.; Gigmes, D.; Marque, S.; Tordo, P.; Couturier, J. L.; Guerret, O.; Ciufolini, M. A. Org. Lett. 2003, 5, 4943. (13) (a) Danneman, M. W.; Hong, K. B.; Johnston, J. N. Org. Lett. 2015, 17, 3806. (b) Bailey, W. F.; Salgaonkar, P. D.; Brubaker, J. D.; Sharma, V. Org. Lett. 2008, 10, 1071. (c) Day, J.; Frederickson, M.; Hogg, C.; Johnson, C.; Meek, A.; Northern, J.; Reader, M.; Reid, G. Synlett 2015, 26, 2570. (14) (a) Tietze, L. F. Chem. Rev. 1996, 96, 115. (b) Copéret, C.; Negishi, E. Org. Lett. 1999, 1, 165. (c) Grigg, R.; Sridharan, V. Tetrahedron Lett. 1993, 34, 7471. (d) Brown, A.; Grigg, R.; 3619

DOI: 10.1021/acs.orglett.7b01606 Org. Lett. 2017, 19, 3616−3619