Synthesis of Tetra-Substituted Trifluoromethyl-3,1-Benzoxazines by Transition-Metal-Catalyzed Decarboxylative Cyclization of N-Benzoyl Benzoxazinones.

Efficient synthesis of N,O-heterocyclic tetra-substituted trifluoromethyl-3,1-benzoxazines via a transition-metal-catalyzed decarboxylative intramolecular cyclization was achieved. The decarboxylation of N-benzoyl trifluoromethyl-benzoxazinones generated the amide oxygen nucleophile, allowing a selective internal C1 -attack on Pd- or Cu-coordinated zwitterions, affording medicinally attractive tetra-substituted vinyl- or ethynyl-trifluoromethyl-3,1-benzoxazines. This protocol can be applied to the synthesis of perfluoroalkyl- and non-fluorinated 3,1-benzoxazines.

Fluorinated N‐heterocyclic compounds have been in a promising position of drug development in pharmaceuticals or agrochemicals since the discovery of fluorinated quinolones. In particular, trifluoromethylated N,O‐containing six‐membered heterocycles have become primary synthetic targets in recent drug discovery due to their great market success. A representative example is the anti‐HIV drug, efavirenz, which has an N,O‐heterocyclic 3,1‐benzoxazine structure with a tetra‐substituted trifluoromethyl Csp3 center (Figure 1). Thus, the development of an efficient synthetic methodology for trifluoromethylated N,O‐heterocyclic compounds is highly desirable. Besides, N,O‐heterocyclic 3,1‐benzoxazines with a tetra‐substituted Csp3 center are privileged structures of biologically active molecules (Figure 1). In this context, many chemists have focused on the development of efficient synthetic methods to synthesize N,O‐heterocyclic 3,1‐benzoxazine structures with a tetra‐substituted Csp3 center. However, the synthesis of a N,O‐heterocyclic 3,1‐benzoxazine structure with a tetra‐substituted trifluoromethyl Csp3 center remains a challenge.

Figure 1

Bioactive N,O‐heterocyclic 3,1‐benzoxazines.

In the last few decades, the transition‐metal‐catalyzed cycloaddition reaction of zwitterion intermediates has emerged as a powerful method for constructing various N‐heterocyclic compounds. N‐Toluene sulfonyl (tosyl) 4‐vinyl benzoxazinones and N‐tosyl 4‐ethynyl benzoxazinones are two representative substrates in this area that have been widely used for many types of annulation reactions under metal catalysis, Pd for 4‐vinyl and Cu for 4‐ethynyl substrates. The decarboxylative generation of zwitterionic π‐allyl‐Pd or Cu‐allenylidene intermediates, which serve as crucial reactive species for the annulation reactions, are promptly trapped intermolecularly by a variety of interceptors.[ , , ] N‐Tosyl 4‐trifluoromethyl‐benzoxazinones have recently joined this research area (Scheme 1a), and a couple of novel annulation reactions have been disclosed under Pd‐catalysis. π‐Benzyl‐Pd zwitterionic intermediates generated via decarboxylation have been suggested as reactive species,[ , ] and unique trifluoromethylated N‐heterocycles are synthesized in good to high yields. In 2019, we revealed that medicinally attractive trifluoromethyl‐dihydroquinoline derivatives are obtained in good yields by the decarboxylative intramolecular annulation of N‐tosyl 4‐vinyl‐4‐trifluoromethyl benzoxazinones in the presence of Pd‐catalysts (Scheme 1b). The intramolecular C3‐attack by tosyl amide‐nitrogen is the key to the cyclization reaction. During the decarboxylative annulation reactions,[ , , ] we noticed the critical role of the N‐tosyl‐moiety in a series of benzoxazinones for annulation reactions, while N‐benzoyl‐variants furnished completely different products. In a seminal paper by Tunge in 2009, a single example of 3,1‐benzoxazine synthesis from N‐benzoyl 4‐vinyl benzoxazinone under Pd‐catalysis was shown. However, the substrate scope and generality were entirely unexplored, despite their potential applications. Herein, we report the efficient synthesis of N,O‐heterocyclic tetra‐substituted trifluoromethyl‐3,1‐benzoxazines by the transition‐metal‐catalyzed decarboxylative intramolecular cyclization of 4‐vinyl or 4‐ethynyl 4‐trifluoromethyl‐benzoxazinones in good to high yields. Independent of the substitution of the 4‐vinyl or the 4‐ethynyl group, the amide oxygen of the benzoyl moiety attacks at the C1‐position of trifluoromethyl‐substituted Pd‐π‐allyl or Cu‐allenylidene zwitterions to generate a tetra‐substituted trifluoromethyl Csp3‐stereogenic center in the N,O‐heterocyclic skeleton. While there is much effort on synthesizing N,O‐heterocyclic 3,1‐benzoxazine structures,[ , ] no general method for the synthesis of trifluoromethylated 3,1‐benzoxazines with a tetra‐substituted stereogenic center has appeared. Only a handful of corresponding compounds are registered in the SciFinder®.[ , ] Moreover, this strategy applies to the synthesis of a variety of tetra‐substituted 3,1‐benzoxazines, including perfluoroalkyl and non‐fluorinated derivatives, in high yields.

Scheme 1

Synthesis of heterocycles from benzoxazinones: a) Three benzoxazinone derivatives for annulation reactions. b) Annulation reaction of N‐tosyl 4‐vinyl‐4‐trifluoromethyl benzoxazinones under Pd‐catalysis (previous work). c) Annulation reaction of N‐benzoyl 4‐vinyl‐4‐trifluoromethyl benzoxazinones under Pd‐catalysis (this work). d) Annulation reaction of N‐benzoyl 4‐ethynyl‐4‐trifluoromethyl benzoxazinones under Cu‐catalysis (this work).

We initiated our investigation with the reaction of 4‐vinyl 4‐trifluoromethyl benzoxazinone 1 a under Pd(PPh3)4 catalyst in CH2Cl2. As expected, decarboxylative intramolecular cyclization proceeded to furnish tetra‐substituted 3,1‐benzoxazine 2 a in 99 % yield (Table 1, entry 1). Prompted by this result, we optimized the reaction conditions by examining the effect of ligand and solvent. Another monodentate ligand, PCy3, provided only a trace amount of 2 a after 20 h (entry 2). Although bidentate phosphine ligands such as DPEPhos and dppe also gave product 2 a in high yield, a prolonged reaction time was required (entries 3–4). Thus, with the optimal Pd(PPh3)4 catalyst, we screened solvents (entries 5–7). Even though other solvents such as toluene, THF, or DMF allowed the reaction to successfully proceed, CH2Cl2 gave the best result.

Table 1

Optimization of reaction conditions for vinyl‐benzoxazinones.[a]

Entry	[Pd]	Ligand	Solvent	Time	Yield/%[b]
1	Pd(PPh3)4	–	CH2Cl2	10 min	99
2	Pd2(dba)3⋅CHCl3	PCy3	CH2Cl2	20 h	8
3	Pd2(dba)3⋅CHCl3	DPEPhos	CH2Cl2	20 h	98
4	Pd2(dba)3⋅CHCl3	dppe	CH2Cl2	20 h	88
5	Pd(PPh3)4	–	Toluene	17.5 h	98
6	Pd(PPh3)4	–	THF	4.5 h	96
7	Pd(PPh3)4	–	DMF	10 min	96

[a] Reaction was carried out with 1 a (0.05 mmol), [Pd] (5 mol %), ligand (10 mol %) in CH2Cl2 (0.5 mL) at room temperature. [b] Determined by 19F NMR in crude using PhCF3 as an internal standard.

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With the optimal conditions in hand, the substrate generality of the Pd‐catalyzed decarboxylative cyclization was examined using a broad array of substituted N‐benzoyl benzoxazinones 1 a–o (Scheme 2). As shown in Scheme 2, a range of N‐benzoyl benzoxazinones containing both electron‐donating and electron‐withdrawing groups on the benzene rings furnished the desired tetra‐substituted 3,1‐benzoxazines 2 quickly in high yields. Benzoxazinone 1 b with an electron‐donating alkyl group on benzoyl gave 2 b in 92 % yield. Even with halogen‐substitution, including of the extremely electronegative fluorine atom, on the benzoyl group, the reaction proceeded efficiently to furnish high yields regardless of the ortho‐, meta, or para‐position (2 c: 86 %; 2 d: 90 %; 2 e: 86 %). Furthermore, the hetero‐aryl ring and π‐extended naphthyl substitution were tolerated in this reaction (2 f: 96 %; 2 g: 91 %). We further explored the effect of substitution on the benzene rings of benzoxazinones. Regardless the electronic nature and substitution position, the desired products were successfully obtained with a benzoyl group (2 h: 99 %; 2 i: 96 %; 2 j: 95 %; 2 k: 80 %) and a 4‐tBu‐benzoyl group (2 l: 98 %; 2 m: 86 %; 2 n: 83 %). It is noteworthy that 4‐vinyl 4‐pentafluoroethyl benzoxazinone 1 o also underwent the reaction to provide 2 o in 40 % yield when heated.

Scheme 2

The substrate scope of tetra‐substituted vinyl 3,1‐benzoxazines. Isolated yield values are shown. (a) 40 °C and 1.5 h.

Next, we attempted to expand this transformation to the Cu‐catalyzed decarboxylative intramolecular cyclization of 4‐ethynyl 4‐trifluoromethyl benzoxazinone 3 a (Table 2). As a result, the reaction with 3 a, [Cu(MeCN)4]PF6 catalyst and rac‐iPr‐PyBOX ligand in MeOH solvent allowed decarboxylation to proceed followed by an intramolecular C1‐attack to afford tetra‐substituted 3,1‐benzoxazine 4 a in 72 % yield (entry 1). Encouraged by this initial result, we investigated the optimization of reaction conditions. While the rac‐tBu‐PyBOX ligand resulted in low yield, rac‐Ph‐PyBOX increased yield to 86 % (entries 2–3). A copper(II) catalyst, Cu(OTf)2, gave lower yield (76 %, entry 4). After solvent screening with the optimal catalyst (entries 5–8), the reaction proceeded efficiently with EtOH to furnish 94 % yield.

Table 2

Optimization of reaction conditions for ethynyl‐benzoxazinones.[a]

Entry	[Cu]	Ligand	Solvent	Time/h	Yield/%[b]
1	[Cu(MeCN)4]PF6	L1	MeOH	2	72
2	[Cu(MeCN)4]PF6	L2	MeOH	19	11
3	[Cu(MeCN)4]PF6	L3	MeOH	2	86
4	Cu(OTf)2	L3	MeOH	2	76
5	[Cu(MeCN)4]PF6	L3	EtOH	2	94
6	[Cu(MeCN)4]PF6	L3	MeCN	2	84
7	[Cu(MeCN)4]PF6	L3	THF	18	89
8	[Cu(MeCN)4]PF6	L3	CH2Cl2	18	88

[a] Reaction was carried out with 3 a (0.05 mmol), [Cu] (5 mol%), ligand (racemic, 10 mol%), DIPEA (1.2 equiv) in solvent (1.0 mL) at room temperature. [b] Determined by 19F NMR in crude using PhCF3 as an internal standard.

Subsequently, we examined the substrate scope using a range of substituted 4‐ethynyl 4‐trifluoromethyl benzoxazinones, 3 a–3 l, with varying substitution patterns of benzene rings (Scheme 3). The desired trifluoromethyl‐ethynyl‐3,1‐benzoxazines 4 a–4 l were obtained in good yield, regardless of the substitution effects. The electron‐donating groups at para‐, ortho‐, and meta‐positions were tolerated in this reaction to give 4 b, 4 e, and 4 f (92 %, 87 %, and 79 %, respectively). The halogen substitution on the benzoyl ring also furnished the products in good to excellent yields (4 c: 74 %; 4 d: 95 %). Similarly, π‐extended naphthyl and hetero‐aryl substituted benzoxazinones 3 g–h afforded 4 g in 91 % yield and 4 h in 90 % yield, respectively. The benzoxazinones 3 i–l, which have a methyl group on the phenyl ring, provided the desired products regardless of the substitution on the benzoyl group (4 i: 83 %; 4 j: 93 %; 4 k: 92 %; 4 l: 86 %). Furthermore, 4‐ethynyl 4‐pentafluoroethyl benzoxazinone 3 m also underwent the reaction to give corresponding product 4 m in 73 % yield.

Scheme 3

The substrate scope of tetra‐substituted ethynyl 3,1‐benzoxazines. Yield values shown are for isolated.

To further investigate the potential of this method for the synthesis of tetra‐substituted 3,1‐benzoxazines, we attempted the reaction using 1 x and 3 x with 4‐methyl substitution instead of the trifluoromethyl group (Scheme 4a). In the case of both 4‐vinyl and 4‐ethynyl substrates, decarboxylation followed by the C1‐attack of amide oxygen proceeded under the optimized conditions to provide the corresponding non‐fluorinated methyl‐3,1‐benzoxazines 2 x and 4 x (83 % and 90 %, respectively). The obtained products 4, tetra‐substituted ethynyl 3,1‐benzoxazines, were derivatized to 5 by the Huisgen cycloaddition using TsN3 under Cu‐catalysis (Scheme 4b, 5 a: 99 %; 5 x: 86 %).

Scheme 4

a) Synthesis of non‐fluorinated derivatives. b) Derivatization of products.

A plausible reaction mechanism was proposed based on previous works.[ , , , ] As shown in Scheme 5, in both cases, the coordination of metal‐catalysts caused the decarboxylation of 1 a and 3 a to form zwitterionic intermediates I or II. The less steric amide oxygen nucleophile attacks at the C1‐position via intramolecular cyclization gave tetra‐substituted benzoxazines 2 a and 4 a.

Scheme 5

Plausible reaction mechanisms.

In conclusion, we disclose herein that N‐benzoyl 4‐trifluoromethyl benzoxazinones are efficient synthons for constructing tetra‐substituted 3,1‐benzoxazines via an intramolecular cyclization reaction. Whereas N‐tosyl protected 4‐vinyl or 4‐ethynyl trifluoromethyl‐benzoxazinones resulted in a C3‐attack product,[ , ] N‐benzoyl protection allowed selective C1‐attack by the amide oxygen nucleophile to generate a tetra‐substituted trifluoromethyl stereogenic carbon center. The enantioselective variants of this reaction are currently being assessed in our laboratory.

Conflict of interest

The authors declare no conflict of interest.

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