Nickel-Catalyzed Oxidative Decarboxylative Annulation for the Synthesis of Heterocycle-Containing Phenanthridinones

Abstract

A nickel-catalyzed oxidative decarboxylative annulation reaction of simple benzamides and (hetero)aromatic carboxylates has been developed. This reaction provides access to a large array of phenanthridinones and their heterocyclic analogues, highlighting the utility and versatility of oxidative decarboxylative coupling strategies for C-C bond formation.

Graphical abstract

Phenanthridinones are key structures found in a variety of natural products and biologically active compounds¹ including antiviral and anticancer therapeutics², aurora kinase³ and polymerase (PARP) inhibitors⁴ as well as serve as important building blocks toward complex polycyclic targets.⁵ The corresponding heterocycle-containing phenanthridinones, however, are less-explored due, in part, to a shortage of efficient synthetic routes to these compounds. Because of the prevalence of heterocycles with important biological properties,⁶ the ability to access such heterocycle-containing phenanthridinones could provide new libraries of compounds with novel properties and activities.

Typically, construction of these scaffolds^7,8 relies on traditional cross-coupling reactions,³ such as Suzuki-Miyaura coupling (Scheme 1, eq 1) or Buchwald-Hartwig amination reactions.⁹ These methods, however, require prefunctionalized aryl halide and arylboronic ester or acid coupling partners. Alternatively, oxidative C-H arylation routes enable the utilization of simple arenes as coupling partners,¹⁰ yet we are aware of only a single report in which efficient incorporation of heteroarenes into phenanthridinone structures is achieved (Scheme 1, eq 2). ^10f Baidya and coworkers have reported the copper-mediated dehydrogenative annulation of amides with fluorinated arenes in which 3,5-difluoropyridine is also a competent coupling partner (Scheme 1, eq 2).

Scheme 1.

Selected Examples of Synthetic Routes to Phenanthridinones.

More recently, transition-metal catalyzed oxidative decarboxylative coupling (ODC) reactions¹¹ have been applied to the synthesis of phenanthridinones. Wang and coworkers reported the synthesis of phenanthridinones utilizing a Pd-catalyzed ODC strategy to effect the coupling of aryl acyl peroxides in fair yields.¹² Similarly, Miura¹³ and coworkers reported an analogous copper-mediated ODC reaction for the synthesis of phenanthridinones from ortho-nitrobenzoates (Scheme 1, eq 3) Unfortunately, both catalyst systems are limited to select benzoic acids, and heteroaryl carboxylates are ineffective coupling partners under these reported conditions. We have recently developed a new nickel catalyst system for the efficient ODC reactions of a large scope of heteroaryl carboxylates.¹⁴ In this work, we highlight the utility of a related nickel-catalyzed oxidative decarboxylative annulation strategy for the synthesis of heterocycle-containing phenanthridinones (Scheme 1, eq 4).

During the course of our previous studies, we observed the formation of the oxidative decarboxylative annulation product 3 in low yields when ortho-fluoro substituted (hetero)aromatic carboxylates 2 were employed as coupling partners. Following this initial discovery, we focused our attention on optimizing the conditions for the coupling of quinolinylbenzamide 1a¹⁵ with the 2-fluoronicotinic carboxylate 2a (Table 1). Ni(OAc)₂ 4H₂O was identified to be the most efficient precatalyst generating 3a in 25% yield (Table 1, entry 4), while all other Ni salts tested provided only low yields of the product (<10%, Table S1). Replacing Ag₂CO₃ with AgNO₃ was found to dramatically increase the yield of 3a to 72% (Table 1, entry 8). Finally, increasing the loading of 2a to 2 equivalents led to an increase in yield of 3a to 81% (Table 1, entry 9). No coupled product 3a was observed when either nickel or silver was omitted from the reaction (entries 10 and 11, respectively). Therefore, the optimized reaction conditions employ 20 mol % Ni(OAc)₂ 4H₂O, AgNO₃ (4.0 equivalents), and Na₂CO₃ (4.0 equivalents) in DMA at 130 °C for 24 h.

Table 1. Optimization of Reaction Conditions^a.

entry	[Ni]	oxidantb	yield 3a (%)c
1	Ni(acac)2	Ag2CO3	4
2	Ni(OTf)2	Ag2CO3	3
3	NiCl2	Ag2CO3	5
4	Ni(OAc)2·4H2O	Ag2CO3	25
5	Ni(OAc)2·4H2O	AgOPiv	63
6	Ni(OAc)2·4H2O	AgOAc	51
7	Ni(OAc)2·4H2O	Ag3PO4	35
8	Ni(OAc)2·4H2O	AgNO3	72
9d	Ni(OAc)2·4H2O	AgNO3	81 (80)e
10d	—	AgNO3	0
11d	Ni(OAc)2·4H2O	—	0

^aReaction conditions: 1a (0.2 mmol), 2a (0.3 mmol) in DMA (2 mL). Q = quinolyl

^b4.0 equiv Ag was used in all reactions (0.4 mmol Ag₂CO₃, 0.8 mmol AgOPiv and AgNO₃, and 0.26 mmol. Ag₃PO₄).

^c1H NMR yield with 1,3,5-trimethoxybenzene as an internal standard.

^d2a (0.4 mmol).

^eIsolated yield.

With the optimized reaction conditions in hand, we turned our attention to the heteroaromatic carboxylate coupling partners (Scheme 2). The reaction is compatible with both electron-withdrawing (2d, 2e, 2g) and electron-donating (2b, 2c, 2f) substituents on the nicotinic carboxylate. Substitution in the 6-position (2c-2e) resulted in slightly lower yields than that obtained with the parent (2a) nicotinate, while substitution in the 5-position was better-tolerated (2f and 2g). This reaction system also tolerates bromo-and chloro-substitution allowing for further functionalization of the cyclized products 3e and 3g. We focused our attention on halide-substituted 2-fluoronicotinic carboxylates because they are the most accessible from existing synthetic routes.¹⁶ Quinoline and thiophene scaffolds are found in pharmacologically active compounds¹⁷ and material sciences¹⁸ and the corresponding carboxylates 2h-2j also proved to be competent coupling partners under these catalytic conditions. Finally, this protocol could also be conducted on a 1 mmol scale without a significant reduction in yield (75% of 3a).

Scheme 2. Scope of Heteroaromatic Carboxylate Coupling Partners in the Ni-Catalyzed Oxidative Decarboxylative Annulation Reaction.^a.

^aIsolated yields. Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol) in DMA (2 mL). Q =quinolyl. ^b130 °C for 8 h then 170 °C for 16 h ^c170 °C.

We then examined the scope of the substituted benzoate coupling partners (Scheme 3). The decarboxylative annulation of ortho-fluorobenzoates proceeded smoothly at 170 °C when a variety of electron-donating (2m, 2n) and electron-withdrawing substituents (2l, 2o, 2p) were included. Unfortunately, the di-ortho-substituted benzoate 2q was an ineffective coupling partner under these reaction conditions (Chart S1).

Scheme 3. Scope of Benzoate Coupling Partners in the Ni-Catalyzed Oxidative Decarboxylative Annulation Reaction.^a.

^aIsolated yields. Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol) in DMA (2 mL). Q = quinolyl.

Finally, we explored the scope of substituted benzamide coupling partners (Scheme 4). Although other directing groups have proven valuable in related catalytic coupling reactions,¹⁹ this decarboxylative annulation reaction appears to be limited to the 8-aminoquinoline directing group (Chart S1), which can be removed under oxidizing conditions.²⁰ Substrates with electron-donating groups para to the benzamide functionality (1r, 1s) afforded higher yields (75% and 71%, respectively) than those bearing electron-withdrawing groups (1t, 63%). Similarly, substrates with electron-donating groups in the meta-position (1u, 1v) provided higher yields (70% and 54% respectively) than those with electron-withdrawing functionalities (1w, 31% yield). It should be mentioned that the absence of ortho-substitution resulted in a lower yield (1x, 48%). This new catalyst system also tolerates heterocyclic benzamide 1y providing the opportunity to access additional classes of substituted phenanthridinones with this methodology.

Scheme 4. Scope of Benzamide Coupling Partners in the Ni-Catalyzed Oxidative Decarboxylative Annulation Reaction.^a.

^aIsolated yields. Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol) in DMA (2 mL). Q =quinolyl.

We hypothesized that this new decarboxylative annulation reaction likely proceeds via an initial oxidative decarboxylative heteroarylation step,¹⁴ followed by an S_NAr-type ring closing reaction^10f,13,21 (Scheme 5). To explore the possibility of such a pathway, we conducted a series of control experiments. First, we performed the standard reaction in the presence of common radical trapping reagents. The reaction of 1a and 2a in the presence of 1.0 equivalent of TEMPO or 9,10-dihydroanthracence resulted in only a slight decrease in the yields (74 and 78% respectively, Table S6) These data are consistent with the absence of trappable radical intermediates.²²

Scheme 5. Proposed Pathway for the Ni-Catalyzed Oxidative Decarboxylative Annulation Reaction.^a.

^aQ = quinolyl.

Next, to gain insight into the C-H activation step, we carried out a pair of deuterium-exchange and kinetic isotope effect (KIE) experiments (Scheme 6). First, we measured the KIE from an intermolecular competition experiment. The reaction of an equimolar mixture of 1a and 1a-d₇ was treated under the standard reaction conditions. After 30 min, the product was obtained as a mixture of 3a and 3a-d₆ in 16% and 4% yields, respectively, giving a KIE of 4.5. We then carried out a hydrogen-deuterium exchange experiment of the deuterated benzamide 1a-d₇. When the standard reaction is conducted with 1a-d₇ for 30 min, less than 1% H incorporation is observed. These combined data suggest that the cleavage of the C-H bond is an irreversible process, similar to that observed in our prior studies of the Ni-catalyzed ODC reaction.¹⁴

Scheme 6. Kinetic Isotope Effect in the Ni-Catalyzed Oxidative Decarboxylative Annulation Reaction.^a.

^aQ = quinolyl.

Finally, we explored the C-N bond-forming step. Treatment of independently synthesized fluorinated biaryl benzamide 1z with 4.0 equivalents of sodium carbonate in the absence of both silver and nickel resulted in the formation of the cyclized product 3k in nearly quantitative yield (>95%, Scheme 7). Taken together, these data are consistent with a pathway involving initial Ni-catalyzed oxidative decarboxylative arylation followed by a based-promoted ring closing reaction as proposed in Scheme 5.

Scheme 7. Base-Promoted S_NAr-Type Cyclization.^a.

^aQ = quinolyl.

In conclusion, we have developed the first nickel-catalyzed oxidative decarboxylative annulation reaction for the synthesis of heterocycle-containing phenanthridinones. This new method is effective not only for the coupling of heteroaromatic carboxylates but also for that of ortho-fluorobenzoates. As a result, this reaction allows access to a series of new heterocycle-containing phenanthridinones of potential biological importance.