Letter Cite This: Org. Lett. 2018, 20, 5228−5232
pubs.acs.org/OrgLett
Synthesis of Benzo[1,6]naphthyridinones Using the Catellani Reaction Mohamed S. A. Elsayed,† Brittany Griggs,† and Mark Cushman*,† †
Org. Lett. 2018.20:5228-5232. Downloaded from pubs.acs.org by UNIV OF CALIFORNIA SANTA BARBARA on 09/08/18. For personal use only.
Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and The Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, United States S Supporting Information *
ABSTRACT: An intramolecular version of the Catellani reaction was optimized for one-step synthesis of bulky Nsubstituted benzo[1,6]naphthyridinones with good to excellent yields. The optimized reaction of N-substituted o-bromobenzamides with 4-bromoquinolines features a wide substrate scope and yields of up to 98%. The employment of aryl bromides under carefully optimized conditions instead of the usual aryl iodides enhances the scope of the reaction.
T
Scheme 1. Most Common Literature Methodologies for the Synthesis of Benzo[1,6]napthyridinone Derivatives
he biological activities of compounds having the benzo[1,6]naphthyridinone scaffold have been extensively studied. This class of compounds includes cytotoxic and antiviral agents, as well as protein kinase inhibitors. LaVoie and his colleagues developed a class of noncamptothecin topoisomerase I poisons based on the dibenzo[c,h][1,6]naphthyridin-6(5H)-one framework, and one of these derivatives (topovale, 1) (Figure 1) advanced to clinical trials for the treatment of solid tumors.1−5 More recently, our group developed other derivatives from the dibenzo[c,h][1,6]naphthyridinedione class (e.g., compound 2) having excellent cytotoxicity profiles and moderate topoisomerase I inhibitory
activities (Figure 1).6 On the other hand, Nakamura et al. synthesized some derivatives of the benzo[1,6]naphthyridinone system (e.g., compound 3) as anti-HCV agents. 7 Incyte Corporation used the benzo[1,6]naphthyridinone scaffold to provide key intermediates in the synthesis of potent tetracyclic Janus kinase inhibitors.8 Nathaniel Gray at the Dana Farber Cancer Institute developed a closely related class of compounds as potent and selective mTOR kinase inhibitors with anticancer activity (e.g., compound 4).9 Later on, the same group utilized the scaffold for the discovery of a potent covalent inhibitor of BTK Figure 1. Structures of biologically active compounds and natural products with the [1,6]naphthyridine scaffold. © 2018 American Chemical Society
Received: July 12, 2018 Published: August 13, 2018 5228
DOI: 10.1021/acs.orglett.8b02171 Org. Lett. 2018, 20, 5228−5232
Letter
Organic Letters Scheme 2. One-Step Synthesis of Benzo[1,6]naphthyridinones
Figure 3. Exploration of the side chain and the yields of the isolated compounds. Figure 2. Examples of polycyclic compounds synthesized using the Catellani reaction.
analogues are present in numerous marine alkaloids such as nakijinamine C (7), suberitine, and aaptamine (8).12,13 The [1,6]naphthyridine scaffold itself also has an attractive biological activity profile.14,15 The literature methodologies reported for the synthesis of N-substituted benzo[1,6]naphthyridinones are summarized in Scheme 1. Only multistep processes that are dependent on the formation of the secondary amides (12) or the tertiary amides (13) in the first step, followed by Pd-catalyzed arylation chemistry, have been reported for the construction of this scaffold. Alternatively, the framework is constructed first (compound 14), and then the amide nitrogen is functionalized via SN1 or SN2 reactions. If the secondary amide is formed first, the amide nitrogen is functionalized by SN1 or SN2 reactions to form the tertiary amide. On the other hand, the tertiary amide can be synthesized directly from the reaction between an acid
Scheme 3. Catellani Synthesis of Phenanthridines
kinase for the treatment of B-cell lymphoma (compound 5).10 Finally, screening for antiviral compounds within the same class revealed the wide spectrum antiviral activity of the scaffold with minor modifications (e.g., compound 6).11 Moreover, the [1,6]naphthyridines and their benzo-fused
Table 1. Optimization of Catellani Reaction for the Synthesis of Benzo[1,6]naphthyridinonea
Reaction Conditions entry
catalyst
ligand
base
solvent
additive
temperature (°C)
time (h)
yielda (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
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 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd2(dba)3 Pd(TFA)2 Pd(TFA)2
TFP TFP TFP TFP TFP TFP TFP TFP TFP xantphos PCy3 SPhos XPhos XPhos XPhos XPhos
K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 Cs2CO3 t-BuOK Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3
CH3CN DMF CH3CN DMA THF dioxane toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene
NBE NBE NBE NBE NBE NBE NBE NBE NBE NBE NBE NBE NBE NBE NBE
85 105 100 130 70 100 110 110 110 110 110 110 110 110 110 110
18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18
14 22 20 4 25 21 60 73 68 18 57 32 90 58 95
