Aryne-induced dearomatized phosphonylation of electron-deficient azaarenes

Abstract

An aryne-induced dearomatized phosphonylation reaction has been developed. Electron-deficient azaarenes such as quinolines, isoquinolines, phenanthroline and acridine undergo multicomponent reaction with arynes and dialkylphosphites to afford the corresponding dearomatized phosphonylated heterocycles in 50–90% yields.

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Introduction

The quinoline and isoquinoline skeletons are found in a large number of biologically active natural products and pharmaceutically active compounds.¹ Moreover, these nitrogen-containing heterocycles serve as versatile building blocks in organic synthesis. Therefore, considerable efforts have been exerted to develop new protocols for the synthesis and transformation of these ubiquitous structural motifs.² On the other hand, α-aminophosphoric acids and their esters are important subunits found in many compounds possessing vital biological properties.³ We envisaged that nitrogen-containing heterocycles with a phosphonylated carbon centre will have interesting bioactivities, which prompted us to develop an efficient method to prepare these valuable compounds.

Recently, dearomatization reactions⁴ provide a powerful strategy for the construction and functionalization of aromatics. For electron-deficient azaarenes,⁵ N-acylations or N-alkylations are generally required in order to improve their electrophilicity. Arynes⁶ are highly active intermediates that can be readily attacked by various nucleophiles to generate zwitterionic species and initiate different reactions. In line with our continued interest of aryne chemistry,⁷ we hypothesized that electron-deficient nitrogen-containing azaarenes can undergo N-arylation with arynes to form zwitterionic species I,⁸ and after the following proton transfer and nucleophilic addition will furnish dearomatized phosphonylated nitrogen-containing heterocycles (Scheme 1).

Scheme 1 Aryne induced dearomatization of quinoline.

Results and discussion

With this idea in mind, we began our studies with the commercially available aryne precursor 1a,⁹ quinoline 2a and dimethyl phosphite 3a. With 2.0 equiv. CsF as fluoride source, this dearomatized phosphonylation reaction smoothly proceeded in THF at ambient temperature to produce phosphonylated dihydroquinoline 4a (ref. 10) in 44% yield (Table 1, entry 1). Encouraged by this result, other fluorides were subsequently tested for the reaction. TBAT can promote this three-component reaction in moderate yield, while KF, TBAF and TMAF are inefficient for the reaction (Table 1, entries 2–5). Fortunately, with 2.0 equiv. 18-crown-6 as coadditive, both KF and CsF can promote the dearomatization with dramatically increased efficiency, producing the desired product in high yield (Table 1, entries 6 and 7). A brief evaluation of the reaction media revealed that THF is the best choice in terms of the reaction yield (Table 1, entries 8–11). Reduction the additive loading to 1.0 equiv. resulted in decreased reaction yield (Table 1, entry 12).

Table 1 Evaluation of reaction conditions^a

Entry	Additives	Solvent	Yield^b (%)
a Reaction conditions: 1a (1.5 equiv.), 2a (1.0 equiv.), 3a (1.5 equiv.), room temperature.b Isolated yield.
1	CsF (2 equiv.)	THF	44
2	TBAT (2 equiv.)	THF	52%
3	KF (2 equiv.)	THF	12
4	TBAF (2 equiv.)	THF	<10
5	TMAF (2 equiv.)	THF	<10
6	KF (2 equiv.) 18-crow-6 (2 equiv.)	THF	89
7	CsF (2 equiv.) 18-crow-6 (2 equiv.)	THF	75
8	KF (2 equiv.) 18-crow-6 (2 equiv.)	Toluene	72
9	KF (2 equiv.) 18-crow-6 (2 equiv.)	DMF	<10
10	KF (2 equiv.) 18-crow-6 (2 equiv.)	DCM	38
11	KF (2 equiv.) 18-crow-6 (2 equiv.)	CH3CN	47
12	KF (1 equiv.) 18-crow-6 (1 equiv.)	THF	56

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Under the optimal reaction conditions (Table 1, entry 6), we next examined the generality of these dearomatized phosphonylation reaction and the results are summarized in Table 2. Different dialkyl phosphites can trap the quinoline-aryne zwitterionic intermediate I, producing dearomatized products in good yields (Table 2, entries 1–4). However, owing to the relatively low nucleophilicity, diphenyl phosphite can not undergo the reaction (Table 2, entry 5). Both electron-donating and electron-withdrawing groups substituted quinolines efficiently underwent the multicomponent reaction to furnish the corresponding products in high yields (Table 2, entries 6–10). C-3 and C-4 substituted quinolines produced the phosphonylated dihydroquinolines in relatively low yields (Table 2, entries 11 and 12). Similar as quinolines, isoquinolines were proved to be good reactants for the reaction, affording 1-phosphite substituted 1,2-dihydro isoquinolines in moderate to high yields, with complete regioselectivities (Table 2, entries 13–15). Interestingly, 1,10-phenanthroline underwent the reaction, leading to monophosphonylated product in 70% yield, and no bisphosphonylated product was obtained (Table 2, entry 16). Notably, the symmetrical naphthalene performed very well, producing the corresponding dearomatized heterocycle in high yield (Table 2, entries 17 and 18). Intriguingly, when unsymmetrical 3-methoxyaryne was used for the reaction, the desired product can be formed in high yield with excellent regioselectivities (Table 2, entries 19 and 20).¹¹ However, 6-methyl-2-trimethylsilylphenyl triflate provided two inseparable isomers in 50 : 50 ratios, albeit in high yield (Table 2, entry 21).

Table 2 Evaluation of substrates scope^a

Entry	Time	Product 4	Yield^b (%)
a Reaction conditions: 1 (1.5 equiv.), 2 (1.0 equiv.), 3 (1.5 equiv.), KF (1.5 equiv.), 18-crown-6 (1.5 equiv.) in the THF at room temperature.b Isolated yield.
1	14		89
2	14		70
3	13		75
4	15		71
5	18		<10
6	16		72
7	16		67
8	15		72
9	15		78
10	15		75
11	16		60
12	16		55
13	14		83
14	14		77
15	14		50
16	16		70
17	14		82
18	13		88
19	15		86
20	14		90
21	16		80

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The present protocol can be further extended to acridine.¹² Under the same reaction conditions, acridine underwent this dearomatized phosphonylation via 1,4-addition, producing 4v in 55% yield, and no 1,2-addition product was detected (Scheme 2).

Scheme 2 Aryne induced dearomatization of acridine.

Conclusions

In conclusion, we have demonstrated an efficient approach for the synthesis of phosphonylated nitrogen-containing heterocycles via an aryne-induced dearomatized phosphonylation of electron-deficient azaarenes. The simple procedure and mild conditions provide an interesting methodology for dearomatization of azaarenes. Further study of the substrate scope and the applications of this method are ongoing in our laboratory.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 21462034) and the Distinguished Young Scientist Program of Shihezi University (No. 2012ZRKXJQ06).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra02128j

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