Room temperature synthesis of isoquino[2,1-a][3,1]oxazine and isoquino[2,1-a]pyrimidine derivatives via visible light photoredox catalysis

Abstract

A novel and efficient construction of isoquino[2,1-a][3,1]oxazine and isoquino[2,1-a]pyrimidine frameworks has been realized by means of visible light photocatalytic reactions using air as the oxidant at room temperature. This strategy offers a direct and rapid access to two kinds of biologically important fused heterocycles in good to excellent yields.

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Nitrogen- and oxygen-containing fused heterocycles are widely found in natural products as well as in pharmaceuticals and other fine chemicals.¹ Among those compounds, the isoquino[2,1-a][3,1]oxazine and isoquino[2,1-a]pyrimidine derivatives have received much attention and such architectures have been considered as “privileged structures” for drug discovery.² For instance, PD 102807 is an efficient selective M₄ muscarinic receptor antagonist,^2c,d whilst compound A has proven to be a selective acetylcholinesterase inhibitor with an IC₅₀ (AChE) of 12 μM (Fig. 1).^2e Driven by their rich biological activities, the development of efficient methods for the construction of these fused heterocyclic compounds is of widespread interest in synthetic organic chemistry. These unique structures are typically constructed by means of domino reactions and oxidative cyclization reactions.³ These processes either required a high reaction temperature^3a,b or needed specific oxidants,^3c–e and therefore have shown limited generality. Recently, the Seidel group disclosed an elegant method to synthesise isoquino[2,1-a]pyrimidine derivatives through an α-functionalization reaction of cyclic amines.⁴ Furthermore, Che and co-workers reported an intramolecular amination of sp² and sp³ C–H bonds with aryl azides as the nitrogen source,⁵ providing an alternative route to these important heterocycles. Despite advances, the development of a versatile method, which can be applied to the construction of both isoquino[2,1-a][3,1]oxazine and isoquino[2,1-a]pyrimidine systems under benign conditions, is highly desirable and remains a challenge.

Fig. 1 Examples of biologically important molecules containing isoquino[2,1-a][3,1]oxazine and isoquino[2,1-a]pyrimidine motifs.

With inherent “green chemistry” features, the use of visible light to initiate organic transformations has attracted more and more attention.⁶ Various chemical reactions have been elegantly carried out under the irradiation of visible light.^7–10 Among these transformations, the oxidation of tertiary amines to highly reactive iminium ions followed by further functionalizations has been well established.¹¹ As part of our ongoing project on the synthesis of heterocyclic structures by visible light photoredox catalysis,¹² we describe herein a new route to construct isoquino[2,1-a][3,1]oxazine and isoquino[2,1-a]pyrimidine frameworks through a photocatalytic oxidation/functionalization sequence (Scheme 1).

Scheme 1 Photocatalytic oxidation/functionalization sequence.

Our studies began with the reaction of (2-(3,4-dihydroisoquinolin-2(1H)-yl)phenyl)methanol (1a) in the presence of 5.0 mol% Ir(ppy)₂(dtb–bpy)PF₆ under 36 W fluorescent light irradiation. As summarized in Table 1, the solvent investigation revealed that the reaction media had a pronounced effect on the reaction efficiency. DMF, DMSO, and CH₃CN have been widely used in visible light photocatalytic transformation,^7–12 but surprisingly they did not work well in our model reaction. The yield of the desired product 2a was basically less than 40% (Table 1, entries 1–3). Other solvents such as acetone (Table 1, entry 4), THF (Table 1, entry 5) and MeOH (Table 1, entry 6) have been examined. To our delight, 62% yield was achieved in the case of MeOH as the reaction media (Table 1, entry 6). When the reaction was performed in EtOH, it took longer to reach completion and gave a relatively lower efficiency (Table 1, entry 7, 58% yield). A significant improvement was observed when the concentration of the substrate was increased from 0.1 M to 0.3 M (62% to 73%, Table 1, entries 6 and 8), which might be attributed to the poor solubility of the product in MeOH. Further optimization showed that the catalyst loading could be decreased to 0.5 mol% without loss in the reaction yield (Table 1, entry 9).

Table 1 Optimisation of reaction conditions^a

Entry	Solvent	Time (h)	Yield (%)^b
a Reaction conditions: 1a (0.3 mmol) and Ir(ppy)2(dtb–bpy)PF6 (5.0 mol%), solvent (3.0 mL), air and 36 W fluorescent light irradiation. b Yield of the isolated product. c 1.0 mL MeOH was used. d 0.5 mol% catalyst was used.
1	DMF	8	16
2	DMSO	3	37
3	CH3CN	8	20
4	acetone	10	38
5	THF	4	19
6	MeOH	7	62
7	EtOH	24	58
8^c	MeOH	12	73
9^d	MeOH	13	72

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After the optimal reaction conditions were established, we then investigated the scope of this photocatalytic oxidation/functionalization cascade. As highlighted in Table 2, this reaction appeared to be quite general with respect to structural variation of both aryl groups in the substrate. Incorporation of one or more alkyl and alkoxyl substituents at different positions on the substrate (e.g.1b–1f) revealed that electronic and steric modification of the substrate can be accomplished, and the reaction gave the corresponding products in 52–65% yields. As revealed in the reaction of 1g, we have successfully used an electron-deficient nucleophilic component, (2-(3,4-dihydroisoquinolin-2(1H)-yl)-5-nitrophenyl)methanol. Moreover, the reaction appears tolerant with respect to the steric contribution near the –OH group. Incorporation of a methyl group at the α position to the hydroxyl group can be realized (e.g.1h). It was noteworthy that the less reactive tertiary amine 1i was also a promising substrate to give the desired fused heterocycle in moderate yield (2i, 50%). Significantly, this methodology could be successfully extended to construct the isoquino[2,1-a]pyrimidine framework. The reactions of 1j–1m furnished the corresponding products in relatively high yield probably due to the higher nucleophilicity of –NHTs in the presence of ^tBuOK. Furthermore, the structure of product 2a was unambiguously established by X-ray crystallographic analysis.¹³

Table 2 Substrates scope examination^ab

a Reaction conditions: 1a–1i (0.3 mmol), Ir(ppy)₂(dtb–bpy)PF₆ (0.5 mol%), MeOH (1 mL), air and 36 W fluorescent light irradiation; 1j–1m (0.2 mmol), Ir(ppy)₂(dtb–bpy)PF₆ (0.5 mol%), ^tBuOK (2.0 equiv.), MeOH/DCM (1 mL + 1 mL), air and 36 W fluorescent light irradiation. b Yields given are of the isolated product. c determined by ¹H NMR.

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In order to demonstrate the preparative utility of this methodology, the reaction of 1k (1.02 g) was performed on a gram scale in the presence of 0.5 mol% of Ir(ppy)₂(dtb–bpy)PF₆ (Scheme 2, eqn 1). The reaction proceeded smoothly to afford the corresponding fused heterocycle 2k in 82% yield after 36 h. Perhaps more importantly, the metal catalyst could be successfully replaced by an inexpensive organic dye catalyst without loss on the reaction efficiency (Scheme 2, eqn 2).

Scheme 2 Gram scale and metal-free reactions.

The reaction of substrate 1n was performed under the standard conditions in an effort to synthesize structurally more complex fused heterocycle 2n, assuming the formation of two carbon–nitrogen bonds in a one-pot procedure. However, only one oxidation/functionalization product 2o was obtained in 56% yield after 64 h (Scheme 3).

Scheme 3 The reaction of substrate 1n.

Conclusions

In summary, we have developed a novel and efficient procedure to construct both isoquino[2,1-a][3,1]oxazine and isoquino[2,1-a]pyrimidine frameworks in good to excellent yields by means of a visible light photoredox catalysis strategy. It should be noted that the reaction features simple experimental procedures under very mild conditions. The application of this photoredox catalysis strategy to the synthesis of other biologically important heterocycles is currently underway in our laboratory.

Experimental section

General procedure for photocatalytic synthesis of isoquino[2,1-a][3,1]oxazine derivatives 2a–2i

To a 5.0 mL flask equipped with a magnetic stir bar was added substrates 1a–i (0.3 mmol), 0.5 mol% Ir(ppy)₂(dtb–bpy)PF₆ (1.37 mg, 0.0015 mmol) and MeOH (1.0 mL). After this, the solution was stirred in the open air at a distance of ∼5 cm from a 36 W fluorescent lamp at room temperature. The reaction was stopped at the indicated time (TLC) and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (silica: 200–300; eluant: petroleum ether/ethyl acetate (10 : 1–5 : 1)) to provide pure products.

General procedure for photocatalytic synthesis of isoquino[2,1-a]pyrimidine derivatives 2j–m, 2o

To a 5.0 mL flask equipped with a magnetic stir bar was added substrates 1j–n (0.2 mmol), 0.5 mol% Ir(ppy)₂(dtb–bpy)PF₆ (0.913 mg, 0.001 mmol), ^tBuOK (44.8 mg, 0.4 mmol) and solvent (2.0 mL). After this, the solution was stirred in the open air at a distance of ∼5 cm from a 36 W fluorescent lamp at room temperature. Upon the completion of the reaction monitored by TLC, the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (silica: 200–300; eluant: petroleum ether/ethyl acetate (10 : 1–5 : 1)) to provide pure products.

Acknowledgements

We are grateful to the National Science Foundation of China (21072069 and 21002036) and the National Basic Research Program of China (2011CB808600) for support of this research.

References

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13. X-Ray crystal data for 2a CCDC 848932†: C₁₆H₁₅NO, M = 237.29, monoclinic, P21/c, P2ybc, a = 10.7911(19) Å, b = 8.3666(15) Å, c = 6.8985(12) Å, α = 90.00, β = 93.084(3), γ = 90.00, V = 621.93(19) ų, Z = 2, T = 296(2), F000 = 264, final R indices [I > 2σ(I)]: R₁ = 0.0595, wR₂ = 0.1796, R indices (all data): R₁ = 0.0637, wR₂ = 0.1854.

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Footnote

† Electronic supplementary information (ESI) available: Substrates preparation, experimental procedures and compound characterisation data. CCDC reference number 848932. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c2ra20403g

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