Copper(II)-catalyzed cleavage of carbon–carbon triple bond to synthesize 1,2,3-triesterindolizines

Abstract

An efficient Cu(II)-catalyzed carbon–carbon triple bond cleavage protocol for the synthesis of 1,2,3-triesterindolizines via the reaction of pyridines with butynedioates has been developed. This reaction has perfect atom economy and both fragments from the cleaved alkyne are successively incorporated into the products.

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Cleavage of carbon–carbon bonds is a useful transformation in organic synthesis.¹ In sharp contrast to carbon–carbon single and double bond cleavage reactions,^2,3 the cleavage of carbon–carbon triple bonds is particularly difficult owing to its high bond dissociation energy.⁴ Apart from alkyne metathesis,⁵ early work on carbon–carbon triple bond cleavage mainly relied on stoichiometric organometallic reactions.⁶ Later on, some metal-catalyzed cleavage of C–C triple bonds was reported,⁷ however, the limited examples usually used expensive and toxic metals such as rhodium,^7a ruthenium,^7b,c gold,^7d or palladium.^7e–g Therefore, there have great demands for carbon–carbon triple bond cleavage using eco-friendly and cheap metal as the catalyst.

On the other hand, as an important class of N-heterocycles, indolizines have found various pharmaceutical applications as anti-HIV,⁸ anti-inflammatory,⁹ H3 receptor antagonist,¹⁰ and MPtpA/MPtpB phosphatases inhibitors.¹¹ Moreover, the indolizines constitute the core structure of many naturally occurring alkaloids.¹² Consequently, synthesis of indolizines continues to attract the attention of chemists.¹³ Recently, a domino synthesis of 1,2,3-triaryolindolizines from methyl ketones and pyridines in the presence of iodine had been reported.¹⁴ Following our interest in copper-catalyzed reaction¹⁵ and as a complementary to the synthesis of 1,2,3-trisubstituted indolizines, we reported herein copper(II)-catalyzed carbon–carbon triple bond cleavage reaction to synthesize 1,2,3-triesterindolizines.

Recently, we have reported the first example of copper(II)-catalyzed carbon–carbon triple bond cleavage via the reaction of naphthoquinone, butynedioates, and pyridines.^15a On the basis of this, we tried to use open chain unsaturated compounds in place of naphthoquinone to undergo this reaction. To our delight, we found that an additional amount of butynedioate itself may serve as an electrophile to take part in the reaction with butynedioate and pyridine under copper(II)-catalysis, leading to the efficient carbon–carbon triple bond cleavage (Scheme 1).

Scheme 1 Cleavage of carbon–carbon triple bond.

Encouraged by this result, we optimized the reaction conditions using dimethyl butynedioate 2a and pyridine 1a as the model compounds. Solvents were first screened and acetonitrile was confirmed to be most promising (entry 1–5, Table 1). Regarding the copper(II) salts, copper(II) chloride led to higher yield than other copper(II) salts (entry 5–9, Table 1). Subsequently, we screened the amount of copper(II) chloride in this reaction. Without copper(II) salt but in the air, only small amount of target product 3a was formed (entry 10, Table 1).¹⁶ When the reaction was carried out in oxygen atmosphere, the amount of copper(II) chloride can be decreased to 0.1 mmol (entry 11, Table 1). Finally, we optimized the reaction temperature under 1 atm O₂, and found refluxing was the best choice (entry 12, Table 1). Therefore, the optimized reaction condition was refluxing the reaction mixture in acetonitrile for 12 h under 1 atm O₂ using 10 mol% copper(II) chloride as catalyst.

Table 1 Optimization of the reaction condition^a

Entry	Solvent	Copper (mmol)	Temp (°C)	Yield^b (%)
a Reaction condition: the mixture of pyridine 1a (2.0 mmol), dimethyl butyndioate 2a (1.5 mmol) and copper(II) salt was heated in the solvent for 12 h in the air.b Isolated yield.c Heated in oxygen atmosphere.
1	DMF	CuCl2 (0.3)	80	86
2	C2H5OH	CuCl2 (0.3)	Reflux	22
3	C6H6	CuCl2 (0.3)	Reflux	75
4	Toluene	CuCl2 (0.3)	80	78
5	CH3CN	CuCl2 (0.3)	Reflux	89
6	CH3CN	CuBr2 (0.3)	Reflux	83
7	CH3CN	Cu(OAc)2 (0.3)	Reflux	87
8	CH3CN	CuSO4 (0.3)	Reflux	80
9	CH3CN	Cu(OTf)2 (0.3)	Reflux	82
10	CH3CN	None	Reflux	15
11	CH3CN	CuCl2 (0.1)^c	Reflux	89
12	CH3CN	CuCl2 (0.1)^c	60	52

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With the optimized reaction conditions in hand, the substrate scope for this transformation was investigated. Firstly, we used butynedioates 2a–f to react with pyridine 1a under the optimal reaction condition, and found various butynedioates possessing different ester groups underwent this reaction smoothly, leading to corresponding indolizines 3a–f in good to excellent yields (Table 2).

Table 2 Reactions of 1a with 2^a

Entry	2 R	3	Yield^b (%)
a The mixture of pyridine 1a (2.0 mmol), butynedioates 2a–f (1.5 mmol) and copper(II) chloride (0.1 mmol) was refluxed in acetonitrile for 12 h in oxygen atmosphere.b Isolated yield.
1	2a R = Me	3a	89
2	2b R = Et	3b	86
3	2c R = n-Pr	3c	85
4	2d R = i-Pr	3d	85
5	2e R = n-Bu	3e	83
6	2f R = t-Bu	3f	82

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The generality of this reaction was further examined by employing p-substituted pyridines as the substrates. As we expected, pyridines including either electron-withdrawing groups (CO₂Me, CO₂Et, CN) or electron-donating group (phenyl, tert-butyl) could be converted to the desired products 4a–o well, in 72% to 93% yield. All products are fully characterized by analytical and spectral data and the structure of 4d was unambiguously established by X-ray crystallography (see ESI†) (Table 3).

Table 3 Reactions of 1b–f with 2^a

Entry	1 R′	2 R	4	Yield^b (%)
a Refluxing the mixture of pyridine 1b–f (2.0 mmol), butynedioates 2 (1.5 mmol), and copper(II) chloride (0.1 mmol) in acetonitrile for 12 h in oxygen atmosphere.b Isolated yield.
1	1b R′ = CO2Me	2a R = Me	4a	91
2	1b R′ = CO2Me	2b R = Et	4b	88
3	1b R′ = CO2Me	2c R = n-Pr	4c	86
4	1c R′ = CO2Et	2a R = Me	4d	92
5	1c R′ = CO2Et	2b R = Et	4e	90
6	1c R′ = CO2Et	2c R = n-Pr	4f	87
7	1c R′ = CO2Et	2d R = i-Pr	4g	88
8	1d R′ = CN	2a R = Me	4h	76
9	1d R′ = CN	2b R = Et	4i	72
10	1e R′ = Ph	2a R = Me	4j	93
11	1e R′ = Ph	2b R = Et	4k	90
12	1f R′ = t-Bu	2a R = Me	4l	88
13	1f R′ = t-Bu	2b R = Et	4m	86
14	1f R′ = t-Bu	2c R = n-Pr	4n	85
15	1f R′ = t-Bu	2d R = i-Pr	4o	85

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The regioselectivity in the reaction of 3-substituted pyridines 1g with butynedioates 2 was then studied (Scheme 2). After refluxing methyl nicotinate 1g (2.0 mmol) with diethyl butynedioate 2b (1.5 mmol) and copper(II) chloride (0.1 mmol) in CH₃CN for 12 h under 1 atm O₂, two regioisomers 4p and 4q were generated simultaneously.

Scheme 2 Reaction of 3-susbstituted pyridine.

In order to expand the substrate scope further, we used isoquinoline 5a or quinoline 5b to carry out this reaction for the synthesis of annulated indolizines. It is found that isoquinoline 5a could react with butynedioates 2a–d under the optimal condition to generate the desire products 6a–d in 88% to 92% yields. Noteworthy, quinoline 5b could also react with butynedioates 2a–d to give 7a–d with excellent yields, which indicated the steric hindrance caused by the C(8)–H bond in quinoline has very little effect in this reaction (Table 4).

Table 4 The reaction condition of 5 with 2^a

a Refluxing the mixture of isoquinoline 5a or quinoline 5b (2.0 mmol), butynedioates 2 (1.5 mmol), and copper(II) chloride (0.1 mmol) in acetonitrile for 12 h in oxygen atmosphere.

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On the basis of the above experimental results, a possible reaction mechanism was proposed. Initially, the reaction of pyridine with dimethyl butynedioate 2a generated intermediate I,¹⁷ which dimerized to form intermediate II. Intramolecular 5-exo-trig cyclization of II followed by proton transfer and loss of pyridinium ylide III led to product 3a (pathway a, Scheme 3). The eliminated pyridinium ylide III could then take part in reaction with the intermediate I, via nucleophilic addition, subsequent intramolecular cyclization and oxidative aromatization, also leading to 3a (path b, Scheme 3). According to the proposed mechanism, it is seen that both fragments of cleaved butynedioate eventually go into the products via pathway a and b, resulting in a perfect atom economy.

Scheme 3 Proposed mechanism.

Conclusions

In summary, an effective copper(II)-catalyzed cleavage of carbon–carbon triple bond for the synthesis of 1,2,3-triesterindolizines has been developed. This reaction has perfect atom economy and both fragments from the cleaved alkyne are successively incorporated into the products.

Experimental

General procedure

Pyridine 1a (2.0 mmol), butynedioates 2 (1.5 mmol), and hydrated copper(II) chloride (0.1 mmol) were mixed in 15 mL acetonitrile and refluxed for 12 h under 1 atm of oxygen. After completion of the reaction, the reaction mixture was allowed to cool to room temperature. Chromatographic separation of the reaction mixture (ethyl acetate–petroleum ether, 1 : 6) after removal of the solvent gave product 3.

Acknowledgements

The authors gratefully acknowledge National Natural Science Foundation of China (NSFC 21172188, 21202058), the Key Project of Natural Science Research of Universities in Jiangsu Province (14KJA430003), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) for financial support of this work.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedure, characterization data, ¹H and ¹³C NMR spectra of compounds. CCDC 1000659. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra06048b

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