One pot synthesis of phenanthridines using a palladium-catalyzed cyclization of aromatic ketoximes with aryl iodides via Beckmann rearrangement

Abstract

The catalytic reaction of ketoximes with aryl iodides via a Beckmann rearrangement in the presence of a catalytic amount of Pd(OAc)₂, Ag₂O and ZnBr₂ gave substituted phenanthridines in good to excellent yield. In the reaction, aromatic ketoximes converted first to acetanilides in the presence of ZnBr₂/TFA via a Beckmann rearrangement followed by arylation in the presence of palladium complex. Furthermore, ortho-arylated acetanilides were converted to phenanthridine derivatives in the presence of a Hendrickson reagent.

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Phenanthridines and their derivatives are the important core structures of many hetero cyclic compounds naturally occurring and biologically active molecules. They have many clinical applications, including antiprotozoal, antibacterial, anticancer agents, pharmaceutically and optoelectronic properties.¹ Several methods have been reported for the syntheses of phenanthridine skeleton such as radical,² one pot cascade,³ benzyne-mediated,⁴ photochemical,⁵ hypervalent iodine-promoted,⁶ photocyclized,⁷ microwave assisted⁸ and transition-metal-catalyzed.⁹ Palladium-catalyzed C–C bond-forming reactions involving direct C–H bond activation is a powerful method for the synthesis of complex polycyclic heterocyclic structures.¹⁰ In 2009, Fagnou group reported a simple catalytic method for a direct intramolecular arylation reaction for the synthesis of six- and five-membered ring biaryls.¹¹ Recently, Lautens described a palladium-catalyzed reaction involving ligand-mediated C–H activation and cross-coupling for the preparation of substituted phenanthridine derivatives (Fig. 1).¹² Fensterbank et al. demonstrated a palladium catalyzed reaction for the most efficient synthesis of phenanthridines from benzylamines and aryl iodides through oxidative dehydrogenative coupling by a palladium and norbornene mediated domino reaction.¹³

Fig. 1 Synthesis of phenanthridines.

More recently, Bin Li described a direct and efficient method for the synthesis of phenanthridines using a palladium-catalyzed C–H activation and C–C bond forming intramolecular reaction of N-(2-haloaryl)-imines.¹⁴ Although a number of useful synthetic methods are available for the synthesis of phenanthridine core structures, there are many limitations, such as multi step synthetic methods, limited substrate scope and in some cases, harsh reaction conditions. Therefore, the development of milder, general and convenient methods from easily available starting materials is needed for the synthesis of phenanthridine ring structures. Herein, we report the one pot synthesis of phenanthridines in the presence of a palladium catalyst. The catalytic reaction was also compatible with various functional groups such as electron-rich, electron-deficient and halogen group substituted aromatic oximes and substituted iodo benzenes. In addition, ortho-arylated anilides were converted to useful heteroaromatics such as phenanthridines in the presence of Ph₃PO and Tf₂O.¹⁵

The oxidative cyclization of 3-bromo acetophenone oxime 1a with iodobenzene 2a in the presence of Pd(OAc)₂ (5 mol%), Ag₂O (1.5 equiv.), and ZnBr₂ (0.5 equiv.) in TFA at 110 °C for 16 h obtained 3-bromo-6-methylphenanthridine 4a in 87% isolated yield (Scheme 1). In the reaction, 3-bromo acetophenone oxime 1a converted first to acetanilide via a Beckmann rearrangement in the presence of ZnBr₂ and TFA followed by the subsequent ortho-arylation of acetanilide in presence of Pd(OAc)₂ and Ag₂O. Furthermore, ortho-arylated acetanilides 3a were converted to 3-bromo-6-methylphenanthridine 4a in 87% yield in the presence of a Hendrickson reagent.

Scheme 1 Phenanthridine synthesis of 4a.

In the beginning of the project, our aim was to synthesize phenanthridines from the cyclization reaction of ketoximes with aryl iodides. For this strategy, we started our optimization studies. The cyclization reaction of 3-bromo acetophenone oxime 1a, iodobenzene 2a was examined in the presence of Pd(OAc)₂ (5 mol%) and AgOAc (1.5 equiv.) in AcOH at 110 °C for 16 h. However, in the reaction, no cyclization product 4a was observed; only a minor amount of ortho-arylated anilide 3a was found. The catalytic reaction was also tested with various solvents, such as TFA and TfOH, which provided ortho-arylated anilide 3a in 50% and 28% yield, respectively. In the presence of acidic solvents, ketoxime was converted to acetanilide via a Beckmann rearrangement followed by ortho-arylation in the presence of a palladium complex.

To increase the yield of 3a, initially, the reaction was studied with different types of solvents, such as AcOH, TfOH and TFA, with AgOAc (Table 1, entry 1–3). Among these TFA provided ortho-arylated anilide compound 3a in 50% yield (entry 3) and TfOH was less effective, obtaining 28% yield (entry 2). AcOH was totally inactive for the arylation reaction (entry 1). The catalytic reaction was also tested with various oxidants such as Ag₂O, AgOTf, AgOCOCF₃, AgF, and Ag₂CO₃ (Table 1, entry 4–8). The ortho-arylated anilide 3a was produced in the presence of Ag₂O in 65% yield (entry 4); AgOTf, AgOCOCF₃, AgF, and Ag₂CO₃ were less effective for obtaining 3a in 30%, 10%, 5%, and 3% yield, respectively (entry 5–8). The reaction was tested without a palladium catalyst and only in the presence of Ag₂O and TFA. In addition, the catalytic reaction was also tested without Ag₂O but with palladium and TFA. In both reactions, no ortho-arylated anilide product 3a was observed (entry 9 and 10). The catalytic reaction was also studied with various acids, such as TfOH, ZnBr₂, ZnCl₂ and p-TsCl (entry 11–14). Among them, ZnBr₂ is the best for the Beckmann rearrangement for providing the ortho-arylated anilide 3a in excellent 89% yield (entry 12); TfOH, ZnCl₂, and p-TsCl produced ortho-arylated anilide 3a in 30%, 43% and 65% yield, respectively (entry 11, 13 and 14). The catalytic reaction was also studied with Lewis acids, such as AlCl₃ and PCl₅, under the same optimized conditions in the reaction, no arylation compound 3a was observed, only a minor amount of 3-bromo acetanilide 7a was obtained (entry 15 and 16). The yield of product 3a was determined by ¹H NMR integration methods using mesitylene as an internal standard. These results clearly showed that both palladium and oxidant such as Ag₂O are crucial for the ortho-arylation reaction. The intra-molecular cyclization reaction for the synthesis of phenanthridine was also tested with 3-bromo acetophenone oxime 1a under the optimized reaction conditions and TFAA; in the reaction, the cyclization compound 4a was observed in only 35% yield. When the cyclization reaction was performed in the presence of Hendrickson reagent instead of TFAA, 3-bromo-6-methylphenanthridine 4a was observed in 83% yield.

Table 1 Optimization studies^a

Entry	Pd cat.	Oxidant	Acid	Solvent	Yield^b (%)
a All reactions were carried out using 1a (1.0 mmol), iodo benzene 2a (3.0 mmol), oxidant (1.5 mmol), acid (0.5 mmol) and Pd(OAc)2 (5 mol%) in solvent (2.0 mL) at 110 °C for 16 h.b Yields were determined by the ^1H NMR integration method using mesitylene as an internal standard.
1	Pd	AgOAc	—	AcOH	nr
2	Pd	AgOAc	—	TfOH	28
3	Pd	AgOAc	—	TFA	50
4	Pd	Ag2O	—	TFA	65
5	Pd	AgOTf	—	TFA	30
6	Pd	AgOCOCF3	—	TFA	10
7	Pd	AgF	—	TFA	5
8	Pd	Ag2CO3	—	TFA	3
9	Pd	—	—	TFA	nr
10	—	Ag2O	—	TFA	nr
11	Pd	Ag2O	TfOH	TFA	30
12	Pd	Ag2O	ZnBr2	TFA	89
13	Pd	Ag2O	ZnCl2	TFA	43
14	Pd	Ag2O	p-TsCl	TFA	65
15	Pd	Ag2O	AlCl3	TFA	nr
16	Pd	Ag2O	PCl5	TFA	nr

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Under similar reaction conditions, the catalytic reaction was examined with various substituted ketoximes 1a–e. Therefore, 3-bromo 1a, 3-methoxy 1b, 2-chloro 1c, 1-naptho 1d, 3,4-dimethoxy 1e substituted ketoximes with aryl iodides 2a–e underwent cyclization reaction selectively at the less hindered ortho C–H bond, yielding the corresponding 6-methyl phenanthridines 4b–i in good to excellent yields (Scheme 2). The cyclization reaction of 3-bromo acetophenone oxime 1a with 4-methyl 2b, 4-methoxy 2c, 4-bromo 2d, 4-CO₂Me 2e obtained the corresponding 6-methyl phenanthridines 4b–e in excellent 80%, 73%, 78% and 68% yield, respectively. Furthermore, the cyclization reaction of 3-methoxy acetophenone oxime 1b with iodo benzene 2a and 2-chloro acetophenone oxime 1c with 4-methyl iodo benzene 2b afforded the corresponding 6-methylphenanthridines 4f and 4g in 79% and 65% yield, respectively. 1-Naptho 1d, 3,4-dimethoxy 1e acetophenone oximes with iodo benzene 2a also proceeded smoothly under similar reaction conditions, providing the 6-methylphenanthridines 4h and 4i in 70% and 79% yield, respectively.

Scheme 2 Scope of the aromatic oximes.

Furthermore, the scope of the cyclization reaction of substituted symmetrical acetophenone oximes was examined under the optimized reaction conditions (Scheme 3). Initially, the reaction was tested with 4-chloro acetophenone oxime 1f with iodo benzene 2a in the reaction. Two types of cyclization products were observed, mono arylated 4ja and di arylated 4jb in 64% and 13% yield, respectively. The cyclization reaction was tested with O-methyl 4-chloro ketoxime 5a and iodo benzene 2a under similar reaction conditions, forming mono arylated 4ja and di arylated 4jb in 47% and 39% yield, respectively. The catalytic reaction was also tested with O-acyl 4-chloro ketoxime 6a, cyclization with iodo benzene 2a, under the optimized reaction conditions providing mono arylated 4ja and di arylated 4jb in 40% and 18% yield, respectively. The cyclization of 4-methoxy ketoxime 1g, with 4-methoxy iodo benzene 2c, obtained 4ka and 4kb in 47% and 39% yield, respectively; 4-methoxy ketoxime 1g, with 4-methyl iodo benzene 2b, obtained 4la and 4lb in 60% and 23% yield, respectively. The cyclization of 4-methyl ketoxime 1h with iodo benzene 2a also provided 4ma and 4mb in 55% and 21% yield, respectively. The cyclization reaction of acetophenone oxime 1i with iodo benzene 2a in the reaction produced 6-methylphenanthridine 4na and 4nb in 49% and 32% yield, respectively. The reaction was tested with propiophenone oxime 1j and 4-methyl iodo benzene 2b; 6-ethylphenanthridines 4oa and 4ob were observed in 57% and 31% yield, respectively. The reaction of isobutero acetophenone oxime 1k, with iodo benzene 2a, obtained 6-isopropyl phenanthridines 4pa and 4pb in 53% and 22% yield, respectively.

Scheme 3 Scope of the symmetrical oximes.

The catalytic reaction was also tested with unsymmetrical iodo benzenes, such as 3-methyl 2f and 3-fluoro 2g, iodo benzenes with 3-bromo acetophenone oxime 1a; in this reaction, there are two ortho C–H bonds for cyclization. In both reactions, two types of 3-bromo phenanthridines cyclization products were observed 4qa, 4qb in 61% and 15%, and 4ra and 4rb in 60% and 13% yield, respectively (Scheme 4).

Scheme 4 Scope of the unsymmetrical iodo benzenes.

The Beckmann rearrangement of 3-bromo acetophenone oxime 1a in the presence of ZnBr₂/TFA provided 3-bromo acetanilide 7a in 95% yield. The catalytic reaction was also studied with 3-bromo acetanilide 7a with iodo benzene 2a in the presence of palladium catalyst and Ag₂O obtained ortho-arylated 3-bromo acetanilide 3a in 86% yield. Furthermore, ortho-arylated 3-bromo acetanilide 3a was converted to phenanthridine derivatives using Hendrickson reagent in 83% yield (Scheme 5).

Scheme 5 Phenanthridine synthesis.

A possible reaction mechanism was explained for the catalytic reaction in Scheme 6.^9,16 The catalytic reaction first converted ketoxime 1 to acetanilide 7 in the presence of ZnBr₂/TFA via a Beckman rearrangement. Acetanilide 7 oxygen chelating with a palladium complex followed by the ortho metalation of aromatics provided intermediate 8. The trans metalation of palladium to the aryl iodide 2 bond in the presence of Ag₂O provided the intermediate 9. Furthermore, the reductive elimination of intermediate 9 in the presence of AcOH or TFA produced ortho-arylated acetanilide 3 and regenerated the active catalyst for the next catalytic reaction. Furthermore, ortho-arylated acetanilides 3 were converted to phenanthridine derivatives 4 in the presence of Hendrickson reagent (Ph₃PO and Tf₂O) (Scheme 6).

Scheme 6 Proposed mechanism.

Conclusions

The palladium-catalyzed synthesis of phenanthridine derivatives from the catalytic reaction of substituted aromatic ketoximes with aryl iodides was developed. The present catalytic reaction is highly regioselective in the case of unsymmetrical oximes, yielding substituted phenanthridines in good to excellent yield. In the reaction, meta-substituted ketoximes cyclization occurs quite selectively at the less hindered aromatic C–H bond and also the reaction oxime moiety is converted to the anilide moiety. In addition, substituted arylated anilides were converted to phenanthridine derivatives in the presence of a Hendrickson reagent.

Acknowledgements

Gajula Raju is thankful to the Head, Department of Chemistry, Osmania University, Hyderabad, India for providing the research facilities.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra07423e

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