Copper-catalyzed cascade reactions of N-(2-bromoallyl)amines with KHCO₃ as the C1 source: an efficient process for the synthesis of oxazolidin-2-ones

Abstract

A novel synthesis of oxazolidin-2-ones by carbamic acid formation and a subsequent copper-catalyzed intramolecular vinylation from N-(2-bromoallyl)amines and KHCO₃ was developed. KHCO₃ was used as a C1 source and base in this efficient and convenient cascade process.

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As an abundant, cheap and nontoxic C1 source for the production of organic chemicals, carbon dioxide is attractive to both industrial and academic scientists.¹ Extensive research has been conducted on the transformation of carbon dioxide into useful bulk products.² Nevertheless, the critical conditions regarding the transportation and storage of carbon dioxide as well as the safety factors associated with high-pressured batch reaction processes affect its utilization in scientific research and industrial production to some extent. Meanwhile, as a safe, cheap and commercially available carbon dioxide equivalent, inorganic carbonate is rarely used in organic synthesis as a C1 source, and its application is undoubtedly desirable.³

The classical copper-mediated Ullmann coupling reaction has been developed over one hundred years,⁴ and great achievements have been made in the copper-mediated C–N, C–O and C–C bond formation reactions in the past two decades.⁵ Although various ethers and oxygenated heterocycles can be constructed using a copper-mediated C–O formation reaction,⁶ to our knowledge results have rarely been reported on the copper-mediated vinylation of carboxylic acid.⁷ During the course of our continued research on the copper-catalyzed synthesis of heterocycles,⁸ we unexpectedly discovered a novel cascade reaction of N-(2-bromoallyl)amine with KHCO₃, in which KHCO₃ acted as a C1 source, leading to the formation of oxazolidin-2-ones in moderate to good yields. The resulting heterocycles are important ubiquitous substructural units which exist in many natural products and biologically active compounds,⁹ and can be obtained from CO₂ fixing reactions.¹⁰

Using 0.2 equivalent of CuI as the catalyst and 0.4 equivalent of L-proline as the ligand, N-(2-bromoallyl)benzylamine (1a) was treated with 2 equivalents of K₂CO₃ in DMSO at 120 °C for 2 hours. After analyzing the ¹³C-NMR and IR spectra of the final product, we surprisingly found that oxazolidin-2-one A (45% yield) was obtained instead of the expected aziridine B through a direct intramolecular Ullmann-type C–N formation (Scheme 1).

Scheme 1 The reaction of N-(2-bromoallyl)benzylamine with K₂CO₃.

This unexpected and interesting result prompted us to screen the reaction conditions (Table 1). Firstly, we set out to screen the ligands in this reaction, N,N-dimethyl-ethane-1,2-diamine was found to be the best choice among the ligands (Table 1, entry 3).

Table 1 Optimization of the reaction conditions for the formation of 2a^a

Entry	Base/equiv.	Ligand^b	Solvent	Yield^c (%)
a Reaction conditions: 1a (0.5 mmol), CuI (0.1 mmol), ligand (0.2 mmol), carbonate base (1.0 mmol), and 2 mL of solvent were sealed in a pressurized process vial at 120 °C for 4 h.b Ligand: A = L-proline, B = N,N-diethylglycine, C = N,N-dimethyl-ethane-1,2-diamine, D = 1,10-phenanthroline.c Isolated yield for 2a.d The temperature of the reaction was 110 °C.e The temperature of the reaction was 100 °C.
1	K2CO3/2.0	A	DMSO	45
2	K2CO3/2.0	B	DMSO	40
3	K2CO3/2.0	C	DMSO	48
4	K2CO3/2.0	D	DMSO	37
5	Cs2CO3/2.0	C	DMSO	Trace
6	KHCO3/2.0	C	DMSO	55
7	KHCO3/1.0	C	DMSO	68
	K2CO3/1.0
8	KHCO3/2.0	C	DMSO	74
	K2CO3/1.0
9	KHCO3/2.0	C	DMSO	74
	K2CO3/0.1
10	KHCO3/2.0	C	DMF	60
	K2CO3/0.1
11^d	KHCO3/2.0	C	DMSO	59
	K2CO3/0.1
12^e	KHCO3/2.0	C	DMSO	33
	K2CO3/0.1

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We then turned our attention to other C1 sources such as Cs₂CO₃ and KHCO₃. A higher yield was obtained when KHCO₃ was used (Table 1, entry 6). To our delight, the yields were improved when additional K₂CO₃ was used in the reaction (Table 1, entries 7 and 8). Finally, we found that the highest yield of 2a was obtained when a mixture of 2.0 equivalents of KHCO₃ and 0.1 equivalent of K₂CO₃ was used (Table 1, entry 9). Varying the solvent from DMSO to DMF did not enhance the yield of product (Table 1, entry 10). Lower yields were obtained when the reaction temperature was reduced to 110 °C or 100 °C (Table 1, entries 11 and 12).

With the optimal conditions established, various N-(2-bromoallyl)amines were tested to form the corresponding oxazolidin-2-ones 2 (Table 2). As shown in Table 2, the products corresponding to the alkylamine substrates were obtained in good yields (Table 2 2a–l), and it is noteworthy that even a strained cyclopropyl substituted amine could give a corresponding ring preserved product 2j. In contrast, the reactions of arylamines led to lower yields, probably due to the poor nucleophilicity of the arylamines (Table 2 2m and n). However, the yield could be improved when an electron donating group was introduced to the benzene ring (Table 2 2o). Importantly, this process could be extended to the reactions of internal alkenyl bromides, and modest yields of the products were obtained under identical reaction conditions (Table 2 2p–r).

Table 2 Synthesis of various oxazolidin-2-ones 2^a

a Reaction conditions: 1 (0.5 mmol), CuI (0.1 mmol), DMEDA (0.2 mmol), KHCO₃ (1.0 mmol), K₂CO₃ (0.05 mmol), and 2 mL of DMSO were sealed in a pressurized process vial at 120 °C for 4 h.

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According to the previous reports and results above,¹¹ a proposed mechanism for this oxazolidin-2-one formation process is described in Scheme 2. When KHCO₃ is heated, it produces CO₂ and K₂CO₃. The substrate 1a reacts with CO₂ in the presence of the base K₂CO₃ to form the carbamic acid salt X. The oxidative addition of X with the copper catalyst offers the intermediate Y. An intramolecular nucleophilic substitution in Y generates Z. The subsequent reductive elimination in Z readily affords the final product 2a and regenerates the copper species to fulfil the catalytic cycle.

Scheme 2 The proposed mechanism for the formation of 2a.

To further demonstrate the applicability and efficiency of this cascade methodology, a gram-scale reaction was performed. When 1.00 g (4.4 mmol) of 1a was used as the starting material, the reaction could readily offer 0.60 g of 2a (72%).

Conclusions

In conclusion, we have developed a novel protocol for the synthesis of oxazolidin-2-ones via a cascade process of carbamic acid formation and a sequential copper-catalyzed intramolecular vinylation of carboxylic acid. The utilization of KHCO₃ as the C1 source made this method efficient and convenient. Further applications of KHCO₃ as a C1 source are being investigated in our laboratory.

Acknowledgements

This work was supported by the Key Innovation Team of Science and Technology in Zhejiang Province (2010R50018) and Chemistry Experiment Demonstration Center of Zhejiang Province.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra02304h

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