Synthesis of benzo[1,3]oxazines via copper(I)-catalyzed cascade annulation of nitriles, aldehydes and diaryliodonium salts

Abstract

A copper(I)-catalyzed one-pot [2 + 2 + 2] cascade annulation reaction of diaryliodoniums, nitriles, and aldehydes has been developed for the efficient synthesis of 2,4-substituted benzoxazine derivatives.

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Benzoxazine I, a heterocycle containing two heteroatoms (N,O), is an important backbone in a large variety of derivatives used as antifungal, antiobiotic, and anti-inflammatory agents, as well as C 1r serine protease inhibitors, anticonvulsants, and DNA-binding antitumor agents.¹ Furthermore, 2,4-substituted benzoxazine skeletons II show great significance in many pharmaceutical molecules and biologically active natural products (Fig. 1).² For example, etifoxine, a non-benzodiazepine anticonvulsant drug, is used for the treatment of psychiatric illnesses with great therapeutic efficiency and less toxicity. Therefore, how to synthesize the benzoxazines and their analogues efficiently received large attention and interest among organic chemists. As a result, new elegant methodologies to prepare 2,4-substituted benzoxazines have been developed rapidly in the recent decades.³ However, most of these reactions are intramolecular cyclization initiated by radicals or cations with vinyl amide (or alkynyl amide) and their derivatives as starting materials.⁴ Herein, we would like to report an intermolecular annulation reaction to synthetize benzo[d][1,3]oxazine derivatives by using readily available substrates including diaryliodonium salts, nitriles and aldehydes. The reaction proceeded smoothly with copper catalysts through the formation of the C–N bond, C–O bond and C–C bond in cascade annulation reactions (Scheme 1).

Fig. 1 Benzoxazine ring I and 2,4-substituted benzoxazine II.

Scheme 1 Synthesis of benzoxazine by diaryliodonium salts, nitriles and aldehydes.

C–N bond and C–O bond formation reactions are developed fleetly and maturely with transition metal catalysts in the past few decades.⁵ Moreover, the utilization of the C–N bond and C–O bond formation reactions to construct heterocycles is rapidly realized.⁶ However, to the best of our knowledge, there are few reports to build N and O contained heterocycles from two different substrates in the cascade annulation reaction. Thus, the development of simple and efficient methods to build several heteroatoms containing heterocycles by the formation of the C–N and C–O bonds is highly attractive.⁷ For this goal, we exploited diaryliodoniums, simple nitriles and aldehydes as reactants to build up the benzoxazine backbone.^8,9

Our study was stemmed with di-p-tolyliodonium triflate (1a), benzonitrile (2a) and benzaldehyde (3a) (Table 1) in the presence of 10% Cu(OTf)₂ as a catalyst in DCE (entry 2). Delightfully, we detected 6-methyl-2,4-diphenyl-4H-benzo[d][1,3]oxazine (4aaa) in 56% GC yield. The screening of copper-catalysts showed that CuBr was the most efficient for this transformation (entries 2–6). No copper catalyst or FeCl₃ catalyst didn't work for this reaction. To improve the yield of 4aaa, we adjusted the temperature and found that 4aaa was obtained in 90% yield (isolated in 81%) at 120 °C.

Table 1 Optimization studies of the formation of 4aaa ^a

Entry	Cat. [10%]	Temp. [°C]	Yield^b [%]
a Unless otherwise noted, reactions were performed with 1a (0.3 mmol), 2a (0.3 mmol), 3a (0.3 mmol), and catalyst (10 mol%), in the solvent DCE (1.5 ml) at the preceding temperature. b GC-MS yield using dodecane as an internal standard. c Isolated yield.
1	No	100	6
2	Cu(OTf)2	100	56
3	CuBr	100	69
4	CuI	100	60
5	CuCl	100	67
6	CuCl2	100	51
7	FeCl3	100	0
8	CuBr	100	87
9	CuBr	80	57
10	CuBr	60	42
11	CuBr	120	90 (81 )
12	CuBr	130	87
13	CuBr	140	86

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Under the optimal conditions, a range of functionalized diaryliodoniums were examined in this reaction (Scheme 2). To our delight, diaryliodoniums with a range of substituents involving 2- and 4-methyl, 2,4- and 2,5-dimethyl, 4-methoxyl, 4-t-butyl, 4-phenyl and benzo groups all worked well with benzonitrile and 4-fluorobenzaldehyde. Disappointingly, diaryliodoniums with electron-withdrawing, such as 4-CF₃ and 4-Cl, did not undergo the benzoxazine annulation. When the unsymmetrical diaryliodonium salt 4-methyl-4′-methoxycarbonyl diaryliodonium was used, only 4aab was obtained in 54% GC yield.¹⁰ The above results show that the electronic effect strongly affected this reaction.

Scheme 2 Scope of the synthesis of benzoxazines by investigating diaryliodoniums. Reactions performed under conditions: CuBr (0.05 mmol), 1 (0.5 mmol), 2a (0.5 mmol), 3b (0.5 mmol) in DCE (2.5 mL) under a N₂ atmosphere, % isolated yield.

Next, a series of aromatic nitriles, including 4-cyano, 4-nitro, and 4-iodo were examined and in all cases 2,4-substituted benzoxazine was obtained in good yields except for anisonitrile isolated in 23% yields (Scheme 3). The structure of 4aeb was further confirmed by XRD of its single crystal (Fig. 2). Strangely, the use of aliphatic nitriles like valeronitrile only supplied trace amounts of the product, accompanied by quinazoline as the side-product.^9c

Scheme 3 Scope of the synthesis of benzoxazine by investigating nitriles. Reactions performed under conditions: CuBr (0.05 mmol), 1 (0.5 mmol), 2a (0.5 mmol), 3b (0.5 mmol) in DCE (2.5 mL) under a N₂ atmosphere, % isolated yield.

Fig. 2 X-ray structure of 4aeb.¹¹

To further broaden the scope of this transformation, a series of aldehydes were examined (Scheme 4). Encouragingly, aromatic aldehydes with a large variety of substituents including the electron-withdrawing and electron-donating groups such as 2-napth, 4-methoxyl and 4-nitro were fit for this reaction. It is worth mentioning that p-phthalaldehyde underwent cyclization once to give the product 4aaq in 71%.

Scheme 4 Scope of the synthesis of benzoxazine by investigating aldehydes. Reactions performed under conditions: CuBr (0.05 mmol), 1a (0.5 mmol), 2a (0.5 mmol), 3 (0.5 mmol) in DCE(2.5 mL) under a N₂ atmosphere, % isolated yield.  ^aThe reaction was performed for 48 h.

Besides, multiple substituted benzaldehydes like 2-bromo-4,5-methylenedioxybenzaldehyde, 2,4-dichloro-benzaldehyde and 2,5-dimethoxybenzaldehyde proceeded well to give the product in 76%, 95% and 54% yields.

Based on the previous reports, a preliminary mechanism suggested that an Ar–Cu(III) species is involved as shown in Scheme 5.¹² Firstly, oxidative addition to CuBr by the diaryliodonium salt (exemplified as Ph₂I⁺) gives a Ph–Cu(III) species, which transferred the phenyl group to the nitrile to give the N-phenylnitrilium intermediate A.^9a,c Then N-phenylnitrilium species A is quickly attacked by the benzaldehyde to give the intermediate B, which undergoes an electrophilic substitution on the aryl ring to give the benzoxazine product.

Scheme 5 Proposed mechanism for the formation of benzoxazine.

Conclusions

In summary, an one-pot approach to multiply substituted benzoxazines with diaryliodonium salts 1, simple nitriles 2 and aldehydes 3 has been presented. This reaction provided efficient and practical access to diversely functionalized benzoxazine derivatives which could realize the flexible control of the substituents on benzoxazines. The facile construction of the benzoxazine skeleton and simple manipulation might be useful for the design and generation of a benzoxazines’ library.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1420993. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6qo00012f

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