Cu(I)-catalyzed multicomponent cascade reactions of terminal alkynes, unactivated primary alkyl bromides, CO₂ and NaN₃

Abstract

A multicomponent synthesis of a variety of triazolo-fused dihydrooxazinones was realized via the carboxylative coupling/cycloaddition of alkynes, unactivated primary alkyl bromides, carbon dioxide and sodium azide. This transformation was catalyzed by CuCl/PPh₃.

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Carbon dioxide (CO₂) causes global warming and a consequent series of environmental problems,¹ meanwhile, is an attractive, abundant, inexpensive, and nontoxic one-carbon source.² Indeed, the eliminations and applications of carbon dioxide continue to drive the interest in the development of new approaches to transform carbon dioxide into high-value chemicals. Among them, the most commonly used method is the well-known incorporation of carbon dioxide into alkyne derivatives in the presence of transition-metal catalysts to produce propiolic acids,³ which has been used to synthesise various heterocyclic compounds.⁴ Additionally, CO₂ has also been transformed into α,β-unsaturated carboxylic acids,⁵ 2-oxazolidinones,⁶ allylic 2-alkynoates,⁷ cyclic carbonates,⁸ heteroaromatic carboxylic acid derivatives,⁹ lactones,¹⁰ acids¹¹ and so on. Although these reported methods have proved useful in the eliminations and applications of carbon dioxide, the transformations of the carboxylation products into functionalization commodity chemicals have emerged as an attractive and challenging goal.

1,2,3-Triazoles are important N-heterocycles¹² which have received much attention for their unique properties in agrochemicals and industrial applications and biological activities (Fig. 1).¹³ In particularly, triazolo-fused dihydrooxazinones with privileged polyheterocycles, which dramatically enhances the expandability of their molecular diversity.¹⁴ To date, 1,2,3-triazoles can be accessible from azides and alkynes in good to excellent yields under mild conditions.¹⁵ While, to the best of our knowledge, there have been no reports of preparation of triazolo-fused dihydrooxazinones from alkynes, unactivated primary alkyl bromides, carbon dioxide and sodium azide. As our continuous efforts in the capture CO₂ into valuable chemicals¹⁶ and the development of efficient methods for the preparation of N-heterocycles,¹⁷ herein we report an efficient, one-pot and multicomponent synthesis of triazolo-fused dihydrooxazinones from alkynes, unactivated primary alkyl bromides, carbon dioxide and sodium azide via a carboxylative coupling/cycloaddition process.

Fig. 1 Representative examples of biologically active molecules containing 1,2,3-triazoles.

The carboxylative coupling reaction of ethynylbenzene (1a), 1,2-dibromoethane (2a) and CO₂ was chosen as a model reaction to identify an effective catalytic system and optimize the reaction conditions (Table 1). Initially, the reaction was carried out in the presence of CuCl (10 mol%), PPh₃ (10 mol%), in DMF at 60 °C for 12 h, and monitored periodically by TLC. Upon completion and after cooling, NaN₃ (1 equiv.) was added to the reaction mixture at r.t. and stirring for another 3 h to afford the desired product 4a in 65% yield (Table 1, entry 1). An increase in the temperature from 60 °C to 80 °C resulted in the desired product in higher yields, but when we raised the temperature to 90 °C, only 41% of 4a was isolated (Table 1, entries 1–4). To further optimize the conditions, we adjusted PPh₃ to 20 mol% and 30 mol%, but no obvious improvement in yields could be observed (Table 1, entries 5 and 6). A variety of copper catalysts, such as CuI, CuBr, and Cu₂O, were also screened; however, no superior yields were obtained and that CuCl was optimal (Table 1, entry 3 vs. entries 7–9). Subsequently, a solvent screening study indicated that DMF was the most suitable solvent for this transformation (Table 1, entry 3 vs. entries 10–12). Moreover, the control experiments indicated that a combination of CuCl and PPh₃ was indispensable in this reaction (Table 1, entries 13 and 14). Therefore, the optimal conditions for this transformation are CuCl (10 mol%) and PPh₃ (10 mol%), in DMF at 80 °C for 12 h, then NaN₃ (1 equiv.) was added to the reaction mixture at r.t. and stirring for another 3 h.

Table 1 Optimization of reaction conditions^a

Entry	[Cu]	PPh3 (mol%)	Solvent	Temperature (°C)	Yield^b (%)
a Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), [Cu] (10 mol%), PPh3 (10 mol%), Cs2CO3 (1.2 equiv.), NaN3 (0.4 mmol), solvent (2 mL), 12 h.b Isolated yields (based on NaN3).
1	CuCl	10	DMF	60	65
2	CuCl	10	DMF	70	70
3	CuCl	10	DMF	80	80
4	CuCl	10	DMF	90	41
5	CuCl	20	DMF	80	82
6	CuCl	30	DMF	80	81
7	CuI	10	DMF	80	70
8	CuBr	10	DMF	80	63
9	Cu2O	10	DMF	80	45
10	CuCl	10	Toluene	80	Trace
11	CuCl	10	CH3CN	80	Trace
12	CuCl	10	DMA	80	13
13	CuCl	—	DMF	80	0
14	—	10	DMF	80	0

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With the optimal conditions in hand, we next extensively evaluated the substrate scope and functional group tolerance of this reaction (Table 2). Gratifyingly, it was observed that a wide range of ethynylbenzenes were well tolerated, providing the corresponding triazolo-fused dihydrooxazinones in good to excellent yields. Electron-rich ethynylbenzenes facilitated the reaction with excellent yields (4b–4g). When 1d was used, the side-product ethane-1,2-diyl bis(3-(4-propylphenyl)propiolate) (3d) was detected by TLC (see ESI†). Ethynylbenzenes bearing electron-withdrawing substituents on the aryl ring were also found to be suitable substrates for this reaction with high yields (4h and 4i). As the above results shown, both the electron-rich ethynylbenzenes and electron-poor ethynylbenzenes are work rapidly under the standard conditions to form the corresponding products in good to excellent yields. To our delight, the ethynylbenzenes 1j and 1k possessing an electron-donating group at the meta-position of phenyl ring reacted readily to afford the desired products 4j and 4k in 84% and 90% yield, respectively. The structure of 4k was confirmed unambiguously by X-ray diffraction analysis (Fig. 2). However, a substrate with steric hindrance (o-CH₃), only a trace amount of 4l was detected under the standard conditions. In addition, 2-ethynylnaphthalene and heterocyclic substrates participated well and furnished the corresponding products 4m and 4n in good yields. It is noted that aliphatic alkynes (1o) also work smoothly to produce the desired product 4o in 82% yield.

Table 2 Synthesis of triazolo-fused dihydrooxazinones^a,b

a Reaction conditions: 1 (0.5 mmol), 2a (0.6 mmol), CuCl (10 mol%), PPh₃ (10 mol%), Cs₂CO₃ (1.2 equiv.), NaN₃ (0.4 mmol), DMF (2 mL), at 80 °C, 12 h.b Isolated yields (based on NaN₃).c The by-product was 3d (18%) (based on 1d) (see ESI).

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Fig. 2 X-ray crystal structure of triazolo-fused dihydrooxazinone 4k. (CCDC 1479362 contains the supplementary crystallographic data for this paper†).

Next, we focused our attention on a more challenging scenario dealing with a longer chain structure, such as 1,3-dibromopropane (Scheme 1). Unfortunately, when 1,3-dibromopropane (2b) was used as a reaction partner, only a trace amount of 4p was detected under the standard conditions.

Scheme 1 Copper(I)/phosphine-catalyzed carboxylative coupling/cycloaddition of ethynylbenzene, 1,3-dibromopropane, CO₂ and NaN₃.

To investigate the reaction mechanism, control experiments were performed and the results are presented in Scheme 2. The reaction of ethynylbenzene (1a), 1,2-dibromoethane (2a) and CO₂ in the presence of CuCl (10 mol%) and PPh₃ (10 mol%), in DMF at 80 °C for 12 h afforded the product of 3a in 86% isolated yield. Subsequently, 3a reacted with NaN₃ (1 equiv.) in DMF at r.t. for 3 h and provided 4a in 93% yield.¹⁸ While, the reaction of ethynylbenzene (1a) with 1,2-dibromoethane (2a) in the atmosphere of Ar instead of CO₂ could not afford the desired product 3a under the standard conditions, which confirmed that CO₂ has been incorporated into ethynylbenzene.

Scheme 2 Control experiments.

On the basis of above results, a plausible mechanism is proposed in Scheme 3. At first, the incorporation of CO₂ into terminal alkyne (1a) promoted by the CuCl/PPh₃, followed by, coupled with 1,2-dibromoethane (2a) and delivered propiolic acid ester 3a. The subsequent reaction of propiolic acid ester 3a with NaN₃ affording organic azide 7. Finally, a [3 + 2] cycloaddition reaction of the intermediate organic azide 7 resulted in the formation of the desired product 4a.

Scheme 3 Plausible mechanism.

In conclusion, we have developed a mild, robust, and multicomponent cascade reaction for the synthesis of triazolo-fused dihydrooxazinones via carboxylative coupling/[3 + 2] cycloaddition of terminal alkynes, unactivated primary alkyl bromides, carbon dioxide and sodium azide. This transformation features good yields, easily available starting materials, a broad range of substrates and multi-component cascade reactions, thus enabling the formation of triazolo-fused dihydrooxazinones that cannot be accessed effectively by other means. Moreover, the incorporation of CO₂ into terminal alkynes was carried out at 1 atm of CO₂ by balloon. Further studies on the applications of triazolo-fused dihydrooxazinones in drug discovery are currently ongoing in our laboratory.

Acknowledgements

We would like to thank the National Natural Science Foundation of China (21362002, 41465009 and 81260472), Guangxi Natural Science Foundation of China (2014GXNSFDA118007), State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (CMEMR2014-A02 and CMEMR2012-A20), Guangxi's Medicine Talented Persons Small Highland Foundation (1306), and The Fund of Guangxi Key Laboratory of Functional Phytochemicals Research and Utilization (FPRU2015-2) for financial support.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 1479362. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra13080a

‡ These authors contributed equally to this work.

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