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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed Cyclocarbonylation of Pyridinylated Vinylogous Amides and Ureas to Generate Ring-Fused Pyridopyrimidinones Gang Yan and Jennifer E. Golden* Department of Pharmaceutical Sciences, School of Pharmacy, University of WisconsinMadison, Madison, Wisconsin 53705-2222, United States
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S Supporting Information *
ABSTRACT: As part of a program aimed at generating new heterocyclic frameworks for medicinal chemistry exploration, an efficient approach to the assembly of novel ring-fused pyridopyrimidinones was undertaken. Specifically, a collection of 11H-pyrido[2,1-b]quinazoline-1,11(2H)-diones and 2,3-dihydropyrido[1,2-a]pyrrolo[3,4-d]pyrimidine-1,10-diones was generated via a palladium-catalyzed, pyridine-directed, cyclocarbonylation of 2-pyridyl-linked vinylogous amides and ureas in yields of up to 90%.
T
Scheme 1. General Approaches to Pyridopyrimidinones
he pyridopyrimidinone core is a privileged scaffold with diverse pharmacological activity depending on its functionalization (Figure 1, red highlighting). For instance,
coupling partners that are devoid of a bridging carbonyl group. As a result, pyridine-directed CO insertions of metal-activated C−H bonds have emerged as a powerful means to construct similar heterocycles.16,17 For instance, CO insertion chemistry was reported18 to form quinazolinones 13 or incognito pyridopyrimidinones featuring an annulated phenyl ring (B, Scheme 1). This precedent is considered along with the suggestion that the cyclocarbonylation of a C(sp2)−H of a vinylogous system affixed to a pyridyl moiety (C, Scheme 1) might lead to differentiated scaffolds if suitable reaction conditions can be identified. To initiate this study, vinylogous substrates were prepared by treating 2-aminopyridines with 1,3-cyclic diones under acidcatalyzed conditions (Supporting Information (SI)).19 With substrates in hand, parameters were screened to promote the cyclocarbonylation (Table 1). A pilot reaction using vinylogous amide 14a was attempted using palladium acetate-mediated conditions reported by Zhu18 for the generation of quinazolinones 13; however, product 15a was not obtained, presumably due to vinylogous substrate instability in the harsh acidic
Figure 1. Pharmacological and structural diversity of derivatized pyridopyrimidinones and prospective template opportunities.
the structural motif is exemplified by allergy drug Pemirolast1,2 1, antidepressant3 Lusaperidone 2, antihypertensive4 Seganserin 3, antiviral compound 4,5 antiulcer agent 5,6 and antiproliferative probe 6,7 just to name a few (Figure 1).8 Consequently, we envisioned using this privileged template to design new frameworks for medicinal chemistry optimization, as pyridopyrimidinone-embedded structures 7 and 8 have yet to be reported. As such, we explored strategies to efficiently construct and diversify these scaffolds. With the exception of compound 6, prepared by an unusual naphthaquinone rearrangement,7 known compounds in Figure 1 were generally assembled by the condensation of 2-aminopyridines with β-keto esters,9,10 ethyl cyanoacetate,11 or other carbonyl-containing partners3 as the key step (A, Scheme 1).12 However, the development of metal-catalyzed C−H activation chemistry13−15 has opened up the possibility of employing © XXXX American Chemical Society
Received: April 22, 2018
A
DOI: 10.1021/acs.orglett.8b01275 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Table 1. Vinylogous Amide Cyclocarbonylation Optimizationa
entry
catalyst (10 mol %)
1c 2 3 4 5 6 7 8 9 10 11 12 13 14h 15i
Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 PdCl2(PPh3)2 PdCl2(PhCN)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(OAc)2 Pd(OAc)2
Scheme 2. Survey of Substituted 2-Aminopyridyl Substrates with an Appended NH-Cycloalkenonea,b
ligand (20 mol %)
oxidant (3 equiv)
solvent
yield (%)b
PPh3 PPh3 PPh3 dpppd tdmppe tbtfmppf CH3PPh2 PPh3 PPh3 PPh3 PPh3 PPh3 PPh3
K2S2O8 K2S2O8 K2S2O8 K2S2O8 K2S2O8 K2S2O8 K2S2O8 K2S2O8 K2S2O8 Cu(OAc)2 airg K2S2O8 K2S2O8 K2S2O8 K2S2O8
TFA dioxane dioxane dioxane dioxane dioxane dioxane dioxane dioxane dioxane dioxane toluene DMF CH3CN CH3CN
0 10 48 0 trace 14 36 22 trace 12 41 11 24 75 90
a
Reaction conditions: 14a (0.3 mmol), Pd catalyst (10 mol %), ligand (20 mol %), oxidant (3 equiv), CO balloon (1 atm), solvent (2 mL), 100 °C, 15 h. bIsolated yield of 15a. c70 °C, 3 h. ddppp: 1,3bis(diphenylphosphino)propane. etdmpp: tris(2,6-dimethoxyphenyl)phosphine. ftbtfmpp = tris[3,5-bis(trifluoromethyl)phenyl]phosphine. g Air/CO = 1:1. h80 °C. i80 °C, 3 h, CH3CN (1 mL).
environment (entry 1). Encouragingly, the replacement of TFA in this reaction with 1,4-dioxane afforded a modest 10% yield of pyridopyrimidinone 15a, along with a substantial amount of recovered starting material (entry 2). As solvents and the catalyst loading were screened, the effect of adding PPh3 as a potential ligand was examined. To our delight, a 48% yield of 15a was obtained with a combination of PPh3 (20 mol %), Pd(OAc)2 (10 mol %), and potassium persulfate (3 equiv) as an oxidant in 1,4-dioxane at 100 °C for 15 h (entry 3). The exchange of triphenylphosphine for triphenylphosphine oxide was examined to assess the role of the latter as an in-situ-generated oxidant;20 however, product conversion was poor (SI). Changing the palladium catalyst (entries 4 and 5), the phosphine ligands bearing electron-donating or electronwithdrawing substituents (entries 6−9), or the identity or equivalency of the oxidant (entries 10 and 11 and SI) was less effective. While toluene and DMF were inferior to the use of 1,4dioxane, switching to acetonitrile afforded 15a in 75% yield after 15 h at a lower temperature (80 °C) and with full conversion based on TLC (entry 14). Monitoring the reactions by TLC revealed that full conversion to the product occurred after only 3 h, affording isolated 15a with an optimized 90% yield (entry 15). Notably, the solubility of the persulfate oxidant in acetonitrile was better than in dioxane or other solvents, likely contributing to the improved outcome. Performing the reaction on a 10 mmol (1.88 g) scale afforded a 68% yield of 15a after 4 h under the same conditions. With an optimized protocol in hand, we assessed the performance of substrates bearing different pyridine ring substitutions of 2-aminopyridyl-NH-cyclohexenones 14a−r and 2-aminopyridyl-NH-cycloalkenones 14s−y (Scheme 2). Reactions were worked up after the starting material was consumed, as judged by TLC. Unsubstituted pyridyl substrates
a
Reaction conditions: 14a−y (0.3 mmol), Pd(OAc)2 (10 mol %), PPh3 (20 mol %), K2S2O8 (3 equiv), CO balloon (1 atm), CH3CN (1 mL), 80 °C. bEach yield is averaged from n ≥ 2 reactions.
or those bearing a methyl group at any one of the C3−C6 2aminopyridyl ring positions afforded moderate to good yields of the corresponding pyridopyrimidinone products (15a−e). While the C6-methyl pyridyl substrate performed well to afford pyridopyrimidinone 15e (67%), substrates with a C6−F or C6− OCH3 group were unreactive under these conditions. It is reasoned that the electron-withdrawing fluorine atom sufficiently attenuates the coordinating ability of the adjacent pyridine nitrogen such that the reaction is not fruitful. While the C6−OCH3 substituent has an opposing resonance effect, it appears that the inductive effect of the ortho-methoxy group prevails. The importance of the coordinating capability of the pyridine nitrogen in this reaction is supported by the failure of reactions using pyrazines in place of the pyridyl group, as the additional ring nitrogen inductively draws electron density away from the coordinating nitrogen, which is speculated to be integral to the key cyclization event. (See the proposed mechanism in Scheme 6.) Product yields were not generally influenced by varying the electronic character of the aminopyridyl C5 substituent. For example, 2-aminopyridyl substrates with C5-methyl (14d), C5B
DOI: 10.1021/acs.orglett.8b01275 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
Scheme 4. Attempted Synthesis of an N-Benzyl PyridoneFused Pyridopyrimidinone
methoxy (14h), C5-phenyl (14j), C5-halides (14m−o), C5ester (14f), or a C5-CF3 group (14r) were successfully converted to the desired products in 51−84% yields. Comparatively, the C4 position was more sensitive to substitution, affording the corresponding C8-substituted products, methyl (15c), methoxy (15g), and phenyl (15k) derivatives, in yields of 44−68%. Nonetheless, a reasonable tolerance for C4/C5-disubstitution was observed with the formation of ring-fused pyridoisoquinolinone 15l (47%). Substrates bearing C3 substitution were synthetically more challenging to obtain; however, a few examples were explored. Pyridopyrimidinones with methyl (15b), benzyloxy (15i), and fluorine (15p) substituents were obtained in yields of 32−75%, and a 3,5-difluorinated substrate was also cyclocarbonylated in good yield (15q, 68%). Augmentation of the unsaturated carbonyl partner appended to the 2-aminopyridyl directing group was also investigated. A cyclopentanone-fused pyridopyrimidonone (15s) was obtained in 85% yield, while the yield of a seven-membered ring fused analog (15t) was diminished, presumably due to increased steric congestion adjacent to the C−H inactivation site. Several 2-aminopyridyl substrates with NH-appended C3-substituted cyclohexenones were transformed to the corresponding products (15u−y) in 49−63% yields. Given the tolerance of the reaction for a variety of vinylogous amide substrates, we also examined the productivity of the reaction using a vinylogous urea (Scheme 3). A reported
Mechanistic insights were gleaned by synthesizing deuteriumlabeled 3-(pyridin-2-ylamino)cyclohex-2-enone 14a-D5 and executing experiments with nonisotopically labeled substrate 14a to enable a determination of the kinetic isotope effects (Scheme 5).24 An intermolecular competition experiment was Scheme 5. Evaluation of Kinetic Isotope Effects
Scheme 3. Synthesis of NH-Pyridyl Vinylogous Ureas
carried out in which a 1:1 mixture of nonisotopically labeled 14a and deuterated 14a-D5 was submitted to the standard reaction conditions. After 15 min, examination by 1H NMR showed a 1.99:1 ratio of 15a to 15a-D4. Parallel experiments were also performed in which 14a or 14a-D5 was individually subjected to the optimized conditions and 1H NMR data were taken at three time points (5, 10, and 15 min) to calculate a kH/kD value of 1.76. These combined results indicate that the C−H bond activation step might be the turnover-determining step or C−H activation might be a reversible step that occurs beforehand.24 A possible mechanism using the conversion of 14a to 15a that takes into account the observations from this work (Scheme 6) is shown. As first proposed by Zhu,18 it is reasoned that the basic
procedure was adapted to prepare N-benzyl- or N-4fluorobenzylpyrrolidine-2,4-diones 17a,b.21,22 These substrates were then independently treated with 2-aminopyridine to afford requisite vinylogous ureas 14z and 14aa. Submission of each to the optimized conditions smoothly afforded corresponding pyrrolidinone-fused pyridopyrimidinones 15z and 15aa in 80 and 58% yields, respectively. While five-membered vinylogous ureas 14z-aa were successfully transformed to the desired products, six-membered variants did not fare as well. To explore this reaction, 1-benzylpiperidine2,4-dione 18 was prepared by a four-step protocol23 and subsequently converted to vinylogous urea 14bb (Scheme 4). After 30 min of reaction time under the standard conditions described herein, the starting material was consumed, only trace amounts of desired product 15bb could be detected by 1H NMR, and oxidized vinylogous urea 14bb was isolated in 53% yield. Interestingly, cyclocarbonylated product 15cc, expected from 14cc, was not detected, even after prolonging the reaction for 5 h, and 15bb was not generated in any greater quantity. Isolation of 14cc from the reaction and resubmission to the reaction conditions resulted in the isolation of 15cc in 18% yield after 4 h. Prolonging the reaction time and/or adding additional catalyst and/or oxidant did not enhance the outcome.
Scheme 6. Mechanistic Rationale for Pyridopyrimidinone Formation
C
DOI: 10.1021/acs.orglett.8b01275 Org. Lett. XXXX, XXX, XXX−XXX
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(3) Kennis, L. E. J.; Bischoff, F. P.; Mertens, C. J.; Love, C. J.; Van den Keybus, F. A. F.; Pieters, S.; Braeken, M.; Megens, A. A. H. P.; Leysen, J. E. Bioorg. Med. Chem. Lett. 2000, 10, 71. (4) Pettersson, A.; Gradin, K.; Hedner, T.; Persson, B. NaunynSchmiedeberg's Arch. Pharmacol. 1985, 329, 394. (5) Hajimahdi, Z.; Zarghi, A.; Zabihollahi, R.; Aghasadeghi, M. R. Med. Chem. Res. 2013, 22, 2467. (6) Harriman, G. C. B.; Chi, S.; Zhang, M.; Crowe, A.; Bennett, R. A.; Parsons, I. Tetrahedron Lett. 2003, 44, 3659. (7) Tsanakopoulou, M.; Cottin, T.; Buttner, A.; Sarli, V.; MalamidouXenikaki, E.; Spyroudis, S.; Giannis, A. ChemMedChem 2008, 3, 429. (8) Mane, U. R.; Li, H.; Huang, J.; Gupta, R. C.; Nadkarni, S. S.; Giridhar, R.; Naik, P. P.; Yadav, M. R. Bioorg. Med. Chem. 2012, 20, 6296. (9) Roslan, I. I.; Lim, Q.-X.; Han, A.; Chuah, G.-K.; Jaenicke, S. Eur. J. Org. Chem. 2015, 2015, 2351. (10) Hermecz, I.; Vasvari-Debreczy, L.; Horvath, A.; Balogh, M.; Kokosi, J.; DeVos, C.; Rodriguez, L. J. Med. Chem. 1987, 30, 1543. (11) Zou, P.; Xie, M. H.; Luo, S. N.; He, Y. J.; Liu, Y. L. Chin. J. Pharm. 2002, 33, 215. (12) Ferrarini, P. L.; Mori, C.; Livi, O.; Biagi, G.; Marini, A. M. J. Heterocycl. Chem. 1983, 20, 1053. (13) Brennführer, A.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2009, 48, 4114. (14) Wu, X.-F.; Neumann, H.; Beller, M. Chem. Soc. Rev. 2011, 40, 4986. (15) Wu, X.-F.; Neumann, H.; Beller, M. Chem. Rev. 2013, 113, 1. (16) Xie, Y.; Chen, T.; Fu, S.; Jiang, H.; Zeng, W. Chem. Commun. 2015, 51, 9377. (17) Chen, J.; Natte, K.; Wu, X.-F. Tetrahedron Lett. 2015, 56, 6413. (18) Liang, D.; He, Y.; Zhu, Q. Org. Lett. 2014, 16, 2748. (19) Liu, J.; Wei, W.; Zhao, T.; Liu, X.; Wu, J.; Yu, W.; Chang, J. J. Org. Chem. 2016, 81, 9326. (20) Risley, J. M.; Van Etten, R. L. Int. J. Chem. Kinet. 1984, 16, 1167. (21) Issa, F.; Fischer, J.; Turner, P.; Coster, M. J. J. Org. Chem. 2006, 71, 4703. (22) Heinicke, G. W.; Morella, A. M.; Orban, J.; Prager, R. H.; Ward, A. D. Aust. J. Chem. 1985, 38, 1847. (23) Gupta, V.; Yang, J.; Liebler, D. C.; Carroll, K. S. J. Am. Chem. Soc. 2017, 139, 5588. (24) Simmons, E. M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51, 3066. (25) Würtz, S.; Rakshit, S.; Neumann, J. J.; Dröge, T.; Glorius, F. Angew. Chem., Int. Ed. 2008, 47, 7230. (26) Maleckis, A.; Kampf, J. W.; Sanford, M. S. J. Am. Chem. Soc. 2013, 135, 6618. (27) Gray, A.; Tsybizova, A.; Roithova, J. Chem. Sci. 2015, 6, 5544.
pyridyl nitrogen of 14a coordinates to Pd(II) and subsequent ligand exchange of acetate with CO forms complex A. Insertion of the palladium metal into the C(sp2)−H of the appended vinylogous moiety25 with a concomitant loss of acetic acid leads to intermediate B formation. After migratory insertion of CO to form intermediate C, reductive elimination affords product 15a along with Pd(0), the latter of which is oxidized by K2S2O8 to regenerate the Pd(II) catalyst. It is notable that other palladium catalysts that lacked the acetate ligand were not functional in promoting the reaction, an observation that may implicate acetate as part of a critical carboxylate-assisted C−H cleavage (not pictured).26,27 Advancements in metal-catalyzed C−H activation not only have enabled efficient heterocycle construction but also have facilitated the assembly of challenging chemical architecture. Herein, we described the synthesis of two unprecedented frameworks that feature a common, privileged pyridopyrimidine scaffold. The transformation leverages a pendant pyridyl group to direct the palladium-mediated cyclocarbonylation of vinylogous amides and ureas, which are bidirectionally diversified. Notably, the substrates did not require the intermediacy of a vinylic halogen to afford the product, and the transformation was carried out in a few hours with catalytic quantities of palladium acetate and with atmospheric CO pressure. Over 25 substrates were exemplified under these conditions with yields of up to 90%. Furthermore, most of the pyridopyrimidinones contain a ketone moiety that is readily derivatized. These products and their functionalized analogs, along with the pyrrolidinone-fused pyridopyrimidinones, have been collectively submitted to a broad-spectrum screening effort that will survey the library for valuable biological activity that can be optimized as part of a traditional medicinal chemistry program.
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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.8b01275. Experimental procedures and full analytical data (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected] ORCID
Jennifer E. Golden: 0000-0002-6813-3710 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS J.E.G. acknowledges institutional support from the Office of the Vice Chancellor for Research and Graduate Education at the University of WisconsinMadison with funding from the Wisconsin Alumni Research Foundation (WARF): UW2020 infrastructure grant (JEG, PI). This work made use of the instrumentation at the UW−Madison Medicinal Chemistry Center, funded by the UW School of Pharmacy.
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REFERENCES
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DOI: 10.1021/acs.orglett.8b01275 Org. Lett. XXXX, XXX, XXX−XXX
