Syntheses of indolizinones from an intramolecular one-pot process of gem-dibromoolefins

Abstract

Transition-metal-catalyzed C–H activation has recently emerged as a powerful tool for the syntheses of natural products and bioactive compounds. We developed an efficient sequential one-pot intramolecular C–N bond formation and direct C–H arylation method to construct a series of unusual indolizinone scaffolds using gem-dibromoolefins in moderate to good yields under mild conditions.

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Transition-metal-catalyzed C–H activation has emerged as a powerful tool for the formation of carbon–carbon and carbon–heteroatom bonds.¹ A C–H activation strategy has been successfully applied for the syntheses of natural products and bioactive compounds.² With selective C–H activation in the aromatic and heteroaromatic compounds, some complex polycyclic heterocycles have been constructed efficiently.³ One-pot C–H activation coupling with other reactions would be more efficient and useful for the construction of many structurally interesting motifs.⁴

gem-Dibromoolefins, as bidentate electrophiles, have been found to be versatile intermediates in constructing various heterocyclic motifs.⁵ With catalyzed inter- or intramolecular nucleophilic reactions, such as Heck,⁶ Ullmann,⁷ Sonogashira,⁸ Suzuki⁹ and Buchwald¹⁰ reactions, two new C–C and/or C–N bonds can be formed in one step by using gem-dibromoolefins as the building block. Many facile methods for the formation of polycyclic heteroaromatics have been developed from gem-dibromoolefins.^{5a,d–f,6–10} In conjunction with our study of gem-dibromoolefins for the syntheses of heterocycles,¹¹ we have developed a facile and efficient method to construct indolizinone compounds via an intramolecular one-pot amination and C–H activation process with gem-dibromoolefins through an unexpected cyclization mode. Most of the compounds obtained are novel polycyclic heterocycles, and may be of great interest in drug discovery.

We initiated our investigation aiming for construction of the camptothecin framework by employing pyridinyl compound (1a) as the precursor for the synthesis of indolizinone 6. As the C–H functionalization of pyridines moiety is often hampered by its poor electron density of the aromatic ring,¹² we used the pyridine N-oxides in order to activate the o-H of pyridines to facilitate the subsequent C–H insertion step (Scheme 1).¹³ We first studied the reaction conditions with substrate 1b to investigate the effects of different catalysts, ligands, bases, solvents and temperatures for the preparation of 5 and subsequently 6 upon reduction of the N-oxides. The results are shown in Table 1.

Scheme 1 Planned for the synthesis of pyridine-fused indolizinone derivatives.

Table 1 Reaction condition optimization^a

Entry	Catalyst	Ligand	Base	Solvent	Yield^c [%]
a Reaction were carried out under an argon atmosphere.b Catalyst (10 mol%), ligand (20 mol%), 120 °C.c Yields of compound 2b, determined by NMR adding mesitylene as the internal standard.d Yield of isolated product.e Without catalyst and ligand and react in the air.
1^b	Pd(OAc)2	PtBu3–HBF4	K2CO3	Toluene	Trace
2^b	Pd(OAc)2	PCy3	Cs2CO3	Toluene	Trace
3^b	Pd2(dba)3	P(2-MeOPh)3	Cs2CO3	Toluene	Trace
4	CuI	Phen	Cs2CO3	Toluene	54
5	CuI	Phen	K3PO4	Toluene	73
6	CuI	Phen	K2CO3	Toluene	77^d
7	CuI	L-Proline	K2CO3	Toluene	6.5
8	CuCl	Phen	K2CO3	Toluene	65
9	CuBr	Phen	K2CO3	Toluene	45
10	CuI	Phen	K2CO3	THF	42
11	CuI	Phen	K2CO3	1,4-Dioxane	64
12	CuI	Phen	K2CO3	CH3CN	17
13^e			K2CO3	Toluene	99^d

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After an extensive survey of reaction conditions, we couldn't obtain the desired product by using various Pd or Cu catalysts. Quite surprisingly, compound 2b rather than the expected compound 2c was formed in moderate yield (Table 1, entry 6) and the structure of this intermediate was confirmed by two-dimensional NMR NOE spectroscopy experiment. Later, we found that the yield of 2b increased significantly when only base was added to the reaction (entry 13). Although the desired indolizinone compound 5 couldn't be afforded in this condition, a trace amount of another structurally rare type of indolizinone structure 3b was obtained instead when Pd catalysts were present. We then started to investigate the reaction conditions of transforming 2b into the indolizinone compound 3b separately and the results are summarized in Table 2. After we screened several reaction parameters, the reaction system with Pd(OAc)₂ (10 mol%), P(2-MeOPh)₃ (20 mol%), and K₂CO₃ (3.0 equiv.) in toluene was found to be most efficient (Table 2, entry 5). Finally we combined these two steps into a one-pot process. After the intramolecular amination addition reaction completed with mild base under 70 °C, we added catalyst and ligand into the reaction mixture for the direct arylation while raising the temperature to 120 °C for the C–H insertion reaction. The desired compound 3b was afforded in good yield through this sequential one-pot process. 3b was hydrogenated by Raney Ni to afford compound 3a in excellent yield (Scheme 2).

Table 2 Optimization of C–H activation conditions^a

Entry	Catalyst	Ligand	Base	Yield^b [%]
a Reactions were carried out under an argon atmosphere.b Yields were determined by NMR adding mesitylene as the internal standard.c Yield of isolated product.d 1 equiv. of Bu4NBr was added.
1	Pd(OAc)2	PCy3	K2CO3	54
2	Pd(OAc)2	PCy3	Cs2CO3	37
3	Pd(OAc)2	PCy3	K3PO4	61
4	Pd(OAc)2	PtBu3·HBF4	K2CO3	11
5	Pd(OAc)2	P(2-MeOPh)3	K2CO3	91^c
6	Pd(OAc)2	Diethyl phosphite	K2CO3	8
7	Pd(OAc)2	P(2-MeOPh)3	K2CO3	0^d
8	Pd(OAc)2	PPh3	K2CO3	79
9	Pd(OAc)2	JohnPhos	K2CO3	39
10	Pd(OAc)2	P(2-MeOPh)3	K3PO4	74
11	Pd2(dba)3	P(2-MeOPh)3	K2CO3	40

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Scheme 2 Reduction of indolizinone N-oxide.

With this optimized reaction conditions in hand, we set to investigate the generality of this one-pot reaction for various pyridinyl heterocycles (Table 3). In the case of unoxidized pyridinyl substrate, the reaction underwent smoothly but two isomers 3a and 4 from o and p insertions were obtained in 30% and 60% of yields respectively. We started by introducing substitutions on pyridine to study the substitution effects. Methyl substituted pyridinyl compounds were well tolerated (3c, 3d). We extended the linker between the pyridine and the nitrogen atom, and the pyridine-fused six-membered ring was formed in 63% under this standard condition (3e). A limitation of this protocol was observed for substrate 1f, as the m-H of the pyridine couldn't be activated under the standard conditions with only the intermediate 2f obtained.

Table 3 Synthesis of pyridine-fused indolizinone compounds^a

a Yield of isolated product.

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We then expanded the method to other aromatics. Benzene and substituted benzenes were chosen as the substrates first. We found that the reaction was sluggish in the amination addition step and complete conversion could not be reached even after several days. We reasoned that it may due to the lack of basicity of K₂CO₃. We then added 1 eq. of KOtBu to the reaction mixture, the amination addition step was finished in about one hour and the desired products were afforded readily. Benzene with various of functional group substitutions were well tolerated including both electron-donating and electron-withdrawing groups. Besides benzene aromatics, other aromatic rings including furan, thiophene, indol, quinolone, naphthalene moieties were applied to the reaction and the desired product were obtained in moderate to good yields. The results were summarized in Table 4.

Table 4 Synthesis of various indolizinone compounds^a

a Yield of isolated product.

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A tentative mechanism of the reaction is depicted in Scheme 3. The first step involves a simple elimination reaction to form the acetylene bromide followed by a 5-exo intramolecular N-nucleophilic addition as previously reported.¹⁴ The monobromo olefinic compound intermediate 2b was isolated and its structure was confirmed. This monobromo intermediate undergoes C–Br bond insertion with Pd followed by intramolecular C–H activation and insertion to give the indolidizines.¹⁵

Scheme 3 A proposed mechanism for this sequential addition and cross-coupling process.

In summary, we have developed an efficient and practical intramolecular N-nucleophilic addition and direct C–H arylation process using gem-dibromoolefins for the synthesis of uncommon indolizinone scaffold. This reaction process is applicable to various aromatic rings with various substitutions, and a series of novel indolizinone compounds were obtained in good yields. The method provides an entry into the efficient preparations of uncommon indolizinone structures.

Typical experimental process

3-((2-(2,2-Dibromovinyl)benzamido)methyl)pyridine N1-oxide (1b, 100 mg, 0.24 mmol, 1.0 equiv.) was dissolved in toluene and K₂CO₃ (100 mg, 0.74 mmol, 3.0 equiv.) was added. The mixture was stirred at 70 °C for 5 h. Then Pd(OAc)₂ (5.4 mg, 0.024 mmol, 10 mol%) and P(2-MeOPh)₃ (17 mg, 0.048 mmol, 20 mol%) were added. The reaction mixture was stirred under an argon atmosphere at 120 °C for 12 h. The resulting mixture was concentrated in vacuo and purified by column chromatography on silica gel to give the product 3b (55 mg, 90%).

Acknowledgements

The research was supported in part by Foshan municipal funds for scientific and technological innovation projects (2013HK100012), Guangzhou Science and Technology Project (2014J4100222), Chinese NSFC grant (nos 21402205).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: General procedures, spectral data. See DOI: 10.1039/c4ra09206f

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