Letter Cite This: Org. Lett. 2018, 20, 345−348
pubs.acs.org/OrgLett
Palladium-Catalyzed, Norbornene-Mediated, ortho-Amination ipsoAmidation: Sequential C−N Bond Formation Andrew Whyte, Maxwell E. Olson, and Mark Lautens* Davenport Research Laboratories, Department of Chemistry, University of Toronto, Toronto M5S 3H6, Canada S Supporting Information *
ABSTRACT: A palladium-catalyzed, norbornene-mediated ortho- and ipso-C−N bond-forming Catellani reaction is reported. This reaction proceeds through a sequential intermolecular amination followed by intramolecular cyclization of a tethered amide. The products, ortho-aminated dihydroquinolinones, were generated in moderate to good yields and are present in bioactive molecules. This work highlights the challenge of competing intra- vs intermolecular palladium-catalyzed processes.
T
Scheme 1. C−N Bond Formation in the Catellani Reaction
ransition-metal-catalyzed carbon−nitrogen bond-forming reactions are of continuing interest.1 Norbornenemediated, palladium-catalyzed reactions have provided efficient routes to create new carbon−nitrogen bonds in otherwise inaccessible positions.2 The Catellani reaction3 describes the polyfunctionalization of aryl iodides using norbornene (NBE) as a directing group to access the ortho-positions, creating up to three new carbon−carbon bonds to generate highly substituted aryl rings. Since its initial discovery in 1997, Catellani,4 our group,5 and others6 have further developed this method and expanded the scope beyond the traditional carbon−carbon bond-forming reactions (Scheme 1). The application of this reaction in divergent syntheses has been demonstrated by the production of various heterocyclic scaffolds.2 However, the production of these scaffolds has still generally relied on carbon−carbon bond formation, therefore limiting the scope of the potential heterocycles. Recently, major advances in the field of directed C−H functionalization have been made with significant contributions by Yu,7 Bach,8 and others9 using norbornene to access remote C−H bonds. Typically, this chemistry is limited to monofunctionalization of C−H bonds and requires preinstalled directing groups. In 2013, the Dong group reported the ortho-amination of aryl iodides with O-benzoylhydroxylamines.10 Since then, a variety of terminating steps have been reported including alkenylation,11 cyanation,12,13 alkynylation,14 arylation,15 N-tosylhydrazone insertion,16 methylation,17 α-arylation of acetone,18 and borylation.19 In the case of borylation, the carbon−boron bond could be transformed into a variety of carbon− heteroatom bonds. Recently, a cyclization strategy was reported by Luan through dearomatization of tethered phenols.20 Our objective in continuing to expand the scope of the Catellani reaction led us to investigate sequential carbon− © 2017 American Chemical Society
nitrogen bond formation. We sought to accomplish this through an intermolecular ortho-amination followed by an intramolecular ipso-amidation. However, this requires the orthofunctionalization step to outcompete the entropically favored, intramolecular cyclization, and previous attempts utilizing this strategy showed limited success.21 Poor to moderate yields were observed, and the major byproduct was the cyclized product. Herein, we report the ortho-amination/ipso-amidation of aryl halides, the first Catellani reaction to form ortho- and Received: November 17, 2017 Published: December 28, 2017 345
DOI: 10.1021/acs.orglett.7b03577 Org. Lett. 2018, 20, 345−348
Letter
Organic Letters ipso-carbon−nitrogen bonds. The product’s core structure is found in many bioactive compounds, thereby allowing access to a diverse array of useful molecles22 (Scheme 2).
Table 2. Optimization of Final Reaction Conditions
Scheme 2. Examples of Bioactive Molecules with orthoAminated Dihydroquinolinones Derived Scaffolds entry 1 2 3 4 5 6 7 8 9
We initiated our investigations with previously reported conditions10 for ortho-amination utilizing Pd(OAc)2 with tris(pmethoxyphenyl)phosphine. However, we were disappointed to find low yields of the desired product and a poor ratio between 2a and 2a′ (Table 1, entry 1). RuPhos, a common ligand for
variation from standard condition none dioxane instead of toluene MeCN instead of toluene 0.1 M 100 °C 2 equiv of NBE K2CO3 instead of Cs2CO3 1 equiv of KOtBu added 5 mol % Pd(PPh3)4
2a (%)a,b 82 (77) 56 20 40 50 53 13 38 52
b
2a′ (%)a 9 19 66 22 30 39 0 33 22
a
Yields were determined by 1H NMR spectroscopy analysis of crude reaction mixture using 1,3,5-trimethoxybenzene as an internal standard. bIsolated yields in parentheses.
Table 1. Optimization of Catalyst System
lower yield (Table 2, entries 7 and 8). Finally, lowering the catalyst loading resulted in a poorer result, providing 52% of the desired product (Table 2, entry 9). With the optimized conditions in hand, we explored amide substitution and its effect on the yield for the desired product (Scheme 3). We found that a methyl amide provided the best
entry
ligand
x (mol %)
2a (%)a
2a′ (%)a
1 2 3 4 5 6
(pCH3OC6H4)3P RuPhos PPh3 PPh3 PPh3 PPh3
25 25 30 40 50 60
28 8 51 64 76 62
14 92 12 8 7 25
Scheme 3. Substrate Scope, Variations on N-Substituenta
a
Yields were determined by 1H NMR spectroscopy analysis of crude reaction mixture using 1,3,5-trimethoxybenzene as an internal standard.
C−N coupling, reversed the selectivity and generated 2a′ in excellent yield (Table 1, entry 2). We found more promising results with PPh3, and a subsequent metal-to-ligand ratio screen revealed the ideal ratio as 1:5 (Table 1, entry 5). Exceeding the 1:5 ratio substantially increased the amount of 2a′ (Table 1, entry 6). This observation suggests that the intramolecular cyclization is favored by excess PPh3, which potentially explains lower product yields when less ligand is used (Table 1, entries 3 and 4). Due to the likely consumption of PPh3 in the reduction of Pd(OAc)2, the preformed Pd(PPh3)4 catalyst was employed and gave a 77% yield of 2a (Table 2, entry 1). We found the ideal conditions utilized Pd(PPh3)4 (10 mol %) with 2 equiv of the electrophilic nitrogen reagent, 4 equiv of norbornene, and 5 equiv of Cs2CO3 in toluene (0.05 M) at 110 °C. Notably, more polar solvents led to preferential formation of 2a′ in 66% yield (Table 2, entry 3). Increasing the concentration of the reaction or decreasing the temperature led to lower yields and selectivity (Table 2, entries 4 and 5). We found the equivalents of norbornene play a key role in reducing the amount of the cyclized byproduct 2a′. Whereas previous reports have utilized substoichiometric amounts of norbornene, we found that 4 equiv were necessary (Table 2, entry 6) to reduce 2a′ by promoting the intermolecular carbopalladation as opposed to the intramolecular cyclization. Modifications to the base such as using K2CO3 or the addition of KOtBu led to a
a b
Isolated yields of the ortho-aminated dihydroquinolinones are shown. Reaction done on 1 mmol scale.
yield, delivering the product in 77% yield, and the reaction was scaled to 1 mmol, giving a 65% yield. The primary amide (2b) performed significantly worse, showing only a 35% yield. A functionalized amide containing a tert-butyl glycine group (2c) provided a 62% yield of the desired product and was also scaled to 1 mmol at 55% yield. In an effort to generate the free secondary amide in the product with good yields, we explored removable groups such as benzyl (2d) and para-methoxybenzyl (2e), which returned a 64% and 44% yield, respectively. A similar substrate containing a para-trifluoromethylbenzyl group 2f performed similarly at 42% yield. A variety of aryl iodides were explored to generate functionalized nitrogenated dihydroquinolinones (Scheme 4). The major byproduct observed was the product lacking the ortho-amine resulting from intramolecular cyclization. Intro346
DOI: 10.1021/acs.orglett.7b03577 Org. Lett. 2018, 20, 345−348
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Organic Letters Scheme 4. Variations on Aryl Substituenta
Scheme 5. Variation of O-Benzoylhydroxylaminea
a b
Isolated yields of the ortho-aminated dihydroquinolinones are shown. Reaction done on 1 mmol scale.
6). The benzylamide product 2d could be deprotected to generate the free secondary amide (2b) in 82% yield. The BocScheme 6. Derivatization of the Products
a b
Isolated yields of the ortho-aminated dihydroquinolinones are shown. Reaction run at 120 °C.
duction of alkyl groups such as methyl (2g) were tolerated, giving a 73% yield. Fluorine at the para or meta position (2h or 2i) gave similar results (40% and 45% respectively); however, 2h required higher temperatures to reach full completion. Substrates bearing chlorine produced slightly better results, generating 2j and 2k at 50% and 57% yield, respectively. The introduction of electron-rich groups para with respect to the aryl iodide led to a decrease in yield as demonstrated by 2l (36% yield). When the electron-donating methoxy group was positioned meta to the iodide, the yields were restored, generating 2m in 60% yield. The reverse trend was observed with a strongly electron-withdrawing nitro group. Product 2n was obtained in 52% yield; however, 2o was only obtained in 26% yield. X-ray crystallography of 2n verified the structure of the product (see Supporting Information (SI) for details). Other electron-withdrawing groups such as trifluoromethyl (2p) and an ester (2q) provided the products in 54% and 78% yields, respectively. Other heteroaromatic structures could be produced as well, such as pyridine 2r or urea 2s. However, these products were generated in poor yields (25% and 30%). Substitution para relative to the tether was unsuccessful, likely due to the ortho hydrogen becoming more difficult to access (see SI for details). Next, the scope of O-benzoylhydroxylamines was explored (Scheme 5). The ketal-protected product 2t, which can be deprotected to obtain the primary aniline,19 was generated in 70% yield. The aryl piperazinyl product 2u, which allowed access to biologically relevant molecules, was generated in good yield (71%). Both 2t and 2u were scaled up to 1 mmol at 60% and 70% yield, respectively. The piperidine product 2v was obtained in 33% yield, and a similar product 2w was generated in 60% yield. Pyrrolidine and acyclic O-benzoylhydroxylamines were unsuccessful (see SI for details). We sought to demonstrate the versatility of the product through derivatization toward useful building blocks (Scheme
protected piperazine product (2u) could be readily deprotected to generate the free piperazinyl product (3a) in quantitative yield, allowing access to a variety of biologically relevant compounds. Finally, product 2c could be reduced to generate the tetrahydroquinoline core (3b) in 84% yield. In conclusion, we have developed an ortho-amination/ipsoamidation through an intermolecular reaction followed by an intramolecular cyclization. The reaction utilized Pd(PPh3)4 wherein the palladium-to-ligand ratio was key to cyclization of the tethered amide. Various optimizations aimed to reduce the major byproduct in the reaction, which was the cyclized product devoid of the ortho-amine. The functionalized dihydroquinolinones were readily diversified to generate useful building blocks to make bioactive molecules.
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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.7b03577. Procedures, characterization data, and 1H/13C NMR spectra (PDF) 347
DOI: 10.1021/acs.orglett.7b03577 Org. Lett. 2018, 20, 345−348
Letter
Organic Letters Accession Codes
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CCDC 1586135 contains 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_
[email protected], 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]. ORCID
Andrew Whyte: 0000-0001-7261-4309 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the University of Toronto, the Natural Science and Engineering Research Council (NSERC), and Alphora Inc. for financial support. A.W. thanks CREATE ChemNET and the Province of Ontario (OGS) for funding. M.O. thanks NSERC for a summer scholarship. We thank Alan Lough (University of Toronto) for X-ray crystallography of product 2n. We thank H. Yoon (University of Toronto) for fruitful discussions throughout the project and for proofreading the manuscript.
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DOI: 10.1021/acs.orglett.7b03577 Org. Lett. 2018, 20, 345−348
