Synthesis of fused oxazole-containing coumarin derivatives via oxidative cross coupling reaction using a combination of CuCl₂ and TBHP

Abstract

Various fused oxazoles containing coumarin derivatives were synthesized via an oxidative cross coupling reaction by employing 20 mol% CuCl₂ as the catalyst and TBHP as an oxidant. The reaction proceeds through functionalization of a C–H bond by a cross-dehydrogenative coupling (CDC) pathway to produce various oxazole derivatives. The reaction protocol gives easy access to a number of oxazole derivatives containing the coumarin moiety at room temperature from various 3-(benzylamino)-2H-chromen-2-one derivatives.

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Coumarins are biologically active compounds widely distributed in nature. Many biologically important fused coumarin derivatives have been reported by our research groups as well as by others.¹ Also, a number of naturally occurring fused coumarin derivatives with the oxazole moiety exhibit interesting biological properties such as anticancer, antifungal, and antiviral activity, and these are shown in Fig. 1.² Many methods have been reported for the synthesis of various oxazole derivatives in the literature.³ But, a very few methodologies are available for the synthesis of fused oxazoles containing coumarin derivatives except some classical methods (Scheme 1).⁴ Therefore, there is a scope to synthesize these compounds by a simpler approach avoiding harsh reaction condition.

Fig. 1 Some biologically active oxazole derivatives.^2a,d

Scheme 1 Methods for synthesis of various coumarin fused oxazoles.

Transition metal catalysed oxidative coupling reactions have been widely explored for functionalization of C–H bond.⁵ These methodologies are being used for formation of diverse heterocyclic molecular entities in recent time.⁶ Functionalization of a sp³ C–H bond through cross dehydrogenative coupling reaction adjacent to a nitrogen atom is an interesting approach to access various molecular transformations.⁷ Literature survey reveals that a number of oxidants have been employed for oxidative coupling reaction to avoid the use of stoichiometric amount of the catalyst.⁸ TBHP has been extensively used as a useful oxidant for oxidative cross coupling reactions.⁹ Li et al. have reported the use of TBHP and a copper salt to achieve various C–C bond formation adjacent to a nitrogen atom.¹⁰

The present protocol gives access to various oxazoles derivatives of coumarin through cross dehydrogenative coupling at room temperature. Initially, 3-(benzylamino)-2H-chromen-2-one (1a) was synthesized using 3-aminocoumarin and benzyl bromide in presence of K₂CO₃ in DMF at 100 °C by a previously reported method by our group (ref. 1a). The substrate 1a was treated with 10 mol% CuI and TBHP in DCM at room temperature and the desired the product 2a was obtained in 50% yield (entry 1, Table 1). The product was characterized by ¹H NMR, ¹³C NMR and HRMS spectra. Further, the structure of 2a was also established from single XRD data (Fig. 2).

Table 1 Optimization of reaction condition^a

Entry	Catalyst (mol%)	Solvent	Oxidant	Time/h	Yield^b (%)
a Unless otherwise stated all the reactions were carried out with 0.3 mmol of 1a, 3 equiv. of oxidant, in 3 mL of solvent at RT.b Isolated yield.
1	CuI (10)	DCM	TBHP	18	50
2	CuBr (10)	DCM	TBHP	18	50
3	CuBr2 (10)	DCM	TBHP	20	52
4	Cu(AcO)2·H2O (10)	DCM	TBHP	24	10
5	CuCl2 (10)	DCM	TBHP	18	64
6	CuCl2 (15)	DCM	TBHP	18	66
7	CuCl2 (20)	DCM	TBHP	20	72
8	CuCl2 (5)	DCM	TBHP	18	61
9	CuCl (10)	DCM	TBHP	12	58
10	Cu(NO2)2 (10)	DCM	TBHP	20	60
11	CuSO4 (10)	DCM	TBHP	20	57
12	CuCl2 (10)	DCE	TBHP	14	62
13	CuCl2 (20)	DCE	TBHP	14	69
14	CuCl2 (10)	CH3CN	TBHP	24	45
15	CuCl2 (10)	CHCl3	TBHP	32	45
16	CuCl2 (10)	DMF	TBHP	32	NR
17	CuCl2 (10)	DMSO	TBHP	32	NR
18	FeCl2 (10)	DCM	TBHP	24	NR
19	FeCl3 (10)	DCM	TBHP	24	NR
20	CuCl2 (10)	DCM	—	24	NR
21	—	DCM	TBHP	24	NR
22	CuCl2 (10)	DCM	H2O2	24	NR
23	CuCl2 (10)	DCM	(PhCO)2O2	24	NR

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Fig. 2 ORTEP diagram of 2a (CCDC number 1405370).

To find out the optimal reaction condition, a number of reactions were executed using different copper salts like CuBr, CuBr₂, Cu(OAc)₂·H₂O, CuCl₂, CuCl, Cu(NO₂)₂, CuSO₄ as the catalyst and TBHP as the oxidant in DCM at room temperature. The desired product 2a was obtained from moderate to good yields (entries 2–5 and 9–11). Among various copper salts, CuCl₂ was found to be the optimized catalyst for the reaction. The desired product 2a was obtained in 64%, 66% and 72% yield with 10 mol%, 15 mol% and 20 mol% of CuCl₂ respectively employing 3 equivalent of TBHP as oxidant in DCM at room temperature (entry 5–7). Lowering the amount of catalyst from 10 mol% to 5 mol%, yield of desired product was decreased to 61% (entry 8). Apart from DCM, the desired oxazole product was also obtained in 1,2-dichloroethane (DCE), acetonitrile and chloroform (entries 12–15) whereas no product was formed in DMF or DMSO (entry 16 and 17). Furthermore, iron salts like FeCl₂ and FeCl₃ were found ineffective to produce the desired product (18 and 19). Also, the reaction was unsuccessful without any catalyst or oxidant (entry 20 and 21) indicating that both are crucial for the formation of product. The reaction was not feasible with other oxidants like H₂O₂ and benzoyl peroxide (entry 22 and 23).

A number of 3-(benzylamino)-2H-chromen-2-one derivatives were synthesized using various 3-aminocoumarin and benzyl bromide derivatives and was examined to evaluate the substrates scope of the present protocol. At first, the group tolerance on the benzyl moiety was studied. Interestingly, the desired oxazole derivatives of coumarin were afforded in good yield with both electron donating-(2b, 2e, 2h and 2i, Scheme 2) and withdrawing substituents (2c, 2d, 2f and 2g). Product 2j was obtained in 68% yield containing a heteroatom in the benzyl ring. Whereas replacing benzyl moiety with naphthyl moiety, the desired product 2k were obtained in significant yield, but in lesser time compared to the benzyl derivatives under the optimized condition. The yield was comparable with substituent at the meta- and para position of the benzyl group indicating no significant role of steric hindrance for the formation of products (2e, 2f, 2g and 2h).

Scheme 2 Synthesis of various oxazole derivatives via oxidative cross coupling reaction. All the reaction were carried out with 0.3 mmol of 1, 3 equiv. of TBHP, 20 mol% of the CuCl₂ in 3 mL of DCM at RT. Isolated yield.

Notably, no product was obtained on replacing benzyl moiety with alkyl moiety.

Similarly, 3-(benzylamino)-2H-chromen-2-one with substituents on the coumarin moiety such as 7-MeO, 8-MeO and 8-EtO were also examined and the desired products 2l–u were isolated in satisfactory yield (Scheme 2). Unfortunately, the present protocol is not feasible with electron withdrawing substituents like 6-NO₂, 6-Cl and 6-Br on the coumarin moiety.

From literature survey¹¹ and our experimental results, a plausible mechanism is presented for the formation of 2 from 1. Initially an iminium ion A (Scheme 3) might be formed from 1 with the help of TBHP/CuCl₂ and then another molecule of TBHP attacks the electrophilic centre of A to form intermediate B. Intermediate B cyclizes to intermediate D through C and finally D on aerial oxidation provides the desired product 2.

Scheme 3 Plausible reaction mechanism.

Conclusions

In conclusion we have demonstrated a novel approach for the construction of various fused oxazole containing coumarin derivatives under mild reaction conditions. We do hope that the synthesized compounds may exhibit interesting biological activity.

Acknowledgements

M. B. is thankful to IIT Guwahati for his research fellowship. A. T. K. is thankful to CSIR, New Delhi for research grant no. 02(0181)/14/EMR-II for financial support. The authors are grateful to the Department of Science and Technology, New Delhi for financial assistance for creating single XRD facility in the Department of Chemistry under FIST programme. We are thankful to the referees' for their valuable comments and suggestions.

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Footnote

† Electronic supplementary information (ESI) available: ¹H NMR, ¹³C NMR and HRMS spectra for all compounds. CCDC 1405370. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra27993c

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