Access to benzo-fused nine-membered heterocyclic alkenes with a trifluoromethyl carbinol moiety via a double decarboxylative formal ring-expansion process under palladium catalysis

Direct access to benzo-fused nine-membered heterocyclic alkenes with a trifluoromethyl carbinol moiety was achieved via a palladium-catalysis.


Introduction
Fluoro-functionalized heterocycles with diverse ring sizes and ring systems have been well studied in pharmaceuticals and agrochemicals. 1 Thus, a remarkable number of publications have been dedicated to the development of efficient synthetic methods to construct uoro-functionalized heterocycles. 1,2 In particular, heterocyclic molecules with a triuoromethyl carbinol moiety, i.e., CF 3 C(OR 1 )R 2 R 3 , have gathered much attention 3-6 on account of their promising biological properties. Efavirenz 4 (anti-HIV), triuoromethylated artemisinins 5 (antimalarial), and uralaner 6 (insecticide and acaricide) are representative examples (Fig. 1).
In this context, our group has been engaged in the development of novel synthetic methodologies for uorinecontaining heterocycles for decades. 7 Including our reports, 7 the present synthetic strategies for uorinated heterocyclic molecules are mostly limited to the construction of veand sixmembered ring systems, 1,2,7 while the synthesis of medium-to large-sized uoro-functionalized heterocycles such as derivatives of benzo-oxazepine 8 and macrosphelide A 9 (Fig. 1) is extremely rare, despite the pharmaceutical importance of medium-sized heterocyclic compounds (non-uorinated) 10 and biologically active natural products. 11 Very recently, Liu and coworkers reported an elegant method for the construction of uoroalkyl-functionalized medium-/large-sized carbocyclic alkenes via an intramolecular radical triuoromethylationcyclization process. 12 Recently, Zhao and co-workers successfully reported the palladium-catalyzed [5 + 4] and [6 + 4] cycloaddition reactions of azadienes with vinylethylene carbonates and vinyl oxetanes respectively in good yields and selectivities. 13 We disclose herein the rst synthesis of benzo-fused ninemembered heterocyclic alkenes 3 with a triuoromethyl carbinol moiety and vinylethylene carbonates 2 14 (Scheme 1). The resulting triuoromethylated heterocycles 3 have a benzo[c] [1,5]oxazonine skeleton, and are not only medicinally attractive uorine-containing heterocycles, 1 but also expanded variants of well-known [1,4]oxazepine pharmaceuticals. 15 Synthesis of the titled nine-membered compounds 3 were achieved from previously unknown triuoromethylated benzoxazinanones 1 (six-membered ring) via a formal ringexpansion pathway under palladium catalysis. The reaction proceeded via the double decarboxylation (DDC) 16 of 1 and vinylethylene carbonates 2 followed by a [5 + 4] cycloaddition reaction. The formation of Pd-complex I as an intermediate was proposed by LC-MS spectrometric analysis. This method provides an expedient access to triuoromethylated benzo[c] [1,5]oxazonines 3 with diverse functional groups in the aromatic moiety, including electron-donating, electron-decient, and halogenic groups. Moreover, the alkene moiety in products 3 was further functionalized by conventional chemical transformations such as epoxidation to 4 and reduction to 5 (Scheme 1) with high diastereoselectivities which make this novel triuoromethylated nine-membered skeleton more attractive as a template for drug discovery research. The presence of a triuoromethyl group on 1 plays a pivotal role for their successful transformation to 3 based on comparative studies using non-CF 3 -varients of 1.

Results and discussion
We started a preliminary investigation with the reaction of tri-uoromethyl (CF 3 ) benzoxazinanone 1a and phenyl vinylethylene carbonate 2a in the presence of suitable palladium precursors and/or phosphine ligands (Table 1). We rst attempted our reaction of 1a using similar Pd 2 (dba) 3 $CHCl 3 conditions in the presence or absence of phosphine ligands, but the results were disappointing (entries 1-4). Moving on to Pd(PPh 3 ) 4 as a palladium precursor at 50 C in THF furnished exclusively a nine-membered ring in good yield of 70% (entry 5). Motivated by this result, further optimization was carried out in different solvents. In toluene, a slight decrease in yield was observed, at 66% (entry 6), while in dichloroethane yield improved to 79% (entry 7). Lowering the temperature to room temperature (rt) furnished good yield (70%), but 40 hours were required to complete the reaction (entry 8). An excellent yield of 91% (89%) was observed by increasing the temperature to 80 C (entry 9). Increasing the temperature further decreased yield dramatically (entry 10, see ESI for more details †).
Based on the optimized reaction conditions, the exibility of the DDC reaction was scrutinized by using a broad array of vinylethylene carbonates (VECs) 2a-m with 1a. The results are summarized in Table 2. Both electron-withdrawing and electron-donating groups on the phenyl ring of 2 furnished Scheme 1 Direct access to benzo-fused nine-membered heterocyclic alkenes 3 with a trifluoromethyl carbinol moiety from sixmembered oxazinones 1 and vinylethylene carbonates 2 via palladium-catalyzed double decarboxylative cycloaddition and the further diastereoselective chemical transformations of 3. good to excellent yields. VECs 2b-c, which have electrondonating groups (Me and OMe) at the p-position, reacted efficiently to afford the desired products 3 in excellent yields (3ab: 83%; 3ac: 78%) whereas VEC 2g, which contains an electronwithdrawing group (CF 3 ) at the p-position, furnished moderate yield (3ag: 56%). Furthermore, halogen-substituted VECs (2d: F; 2e: Cl; 2f: Br) also underwent the DDC reaction very smoothly to furnish good to excellent yields (3ad: 69%; 3ae: 86%; 3af: 91%). Similarly, a highly electronegative atom (2h: F) and an electron-donating group (2i: OMe) at the o-position afforded excellent yields (3ah: 84% and 3ai: 88%). Noticeably, substrates bearing an electron-withdrawing group (F) and an electron-donating group (OMe) at the o-position furnished higher yields than p-substituted substrates. Moreover, the scope of VECs 2 was extended to heteroaryl systems (2j: 2-furyl; 2k: 2thiophenyl) and the reaction proceeded smoothly to afford the desired products 3 in good yields (3aj: 76%; 3ak: 79%). Gratifyingly, non-aromatic substituent VEC 2l and extended p conjugate naphthalene-derived VEC 2m also underwent the cycloaddition reaction to furnish 3al and 3am in moderate to good yield (53% and 65%, respectively), thus signicantly broadening the scope of substrate 2 of this DDC system (Table 2). Spurred by this interesting result, a range of differently substituted CF 3 -benzoxazinanones 1b-e were further examined to better understand the DDC reaction (Table 3). Substituents on 1 with electronically dissimilar properties at different positions on the benzene ring were well tolerated to provide 3 in moderate to good yields. The substrate-bearing electrondonating methyl group on the benzene ring, 1b produced CF 3tetrahydrobenzoxazonine 3ba in 81% yield. The halogensubstituted CF 3 -benzoxazinanones 1c and 1e (F and Br) produced DDC products 3 in moderate to good yields (3ca: 69% and 3ea: 78%) (Table 3).
To ensure the effect of the CF 3 group at the C-4 position, next we examined the reaction of benzoxazinanones 6, which contain different substituents at the C-4 position, with 2a (Scheme 2). In recent years, palladium-catalyzed cyclization reactions using vinyl benzoxazinanone 6a with a variety of substrates have been actively investigated by several groups. 17 We thus rst attempted the reaction of 6a with 2a. Interestingly, substrate 6a with a vinyl at the C-4 position produced a very different result. Under our best conditions, a vinyl-substituted benzoxazinanone 6a was converted to an intramolecular cyclization product 7 in 29% yield but no desired nine-membered cyclized product was observed (Scheme 2a). We next examined the reaction using 6b with a methyl group at the C-4 position instead, but were unable to furnish the desired product and the starting material 6b remained (Scheme 2b). Similar no conversion was obtained when we carried out the reaction of 6c having protected N-benzyl group (Scheme 2c). Although the reasons for the high reactivity of 1a are not clear, it might be due to the higher electrophilicity value of 1a induced by the strong electronegativity of the CF 3 group (group electronegativity of CF 3 is 3.45). 18 To ensure the effect of the CF 3 group at the C-4 position of 1a, we performed a DFT calculation. The electrophilic value of 1a having CF 3 at the C-4 position was estimated to be 3.67 (u Table 2 Scope of vinylethylene carbonates (VECs) 2 a a Experiments were performed with 1a (0.1 mmol), 2a-m (0.15 mmol), Pd(PPh 3 ) 4 (0.05 mmol) in 1.0 mL dry DCE with stirring at 80 C for 12-16 h. Yields are isolated yields and 19 F NMR yields with internal standard PhCF 3 also shown in parentheses. 3aa: CCDC 1575063; 3aj: CCDC 1575065. b 0.20 mmol of 2j was used. c 0.20 mmol of 2k was used. Table 3 Scope of benzoxazinanones 1 a a Unless noted otherwise, the reaction was performed with 0.10 mmol of 1b-e as mentioned in Table 1. Yields are isolated yields and 19 F NMR yields with internal standard (PhCF 3 ) also shown in parentheses.
Scheme 2 Reaction of benzoxazinanones 6a-c which contain different substituents at the C-4 position and N-protected group, with 2a under optimized conditions gave different results.
Interestingly, the X-ray crystallographic analysis of starting substrate 1a revealed that 1a has a sterically unfavourable cis-conguration between CF 3 and tosyl groups (Fig. 2). Although the reasons for the stabilization of 1a in this conguration are not sure, 19 the steric repulsion might be the additional factor for the high reactivity of 1a for decarboxylation reaction.
To demonstrate the synthetic applicability of CF 3 -substituted tetrahydrobenzoxazonines 3, epoxidation and hydrogenation reactions were carried out as displayed in Scheme 3 based on the classical work of Still and Hoveyda. 20 By using the Zhao's condition 13a we performed the epoxidation of 3aa in the presence of m-CPBA at 0 C to rt successfully transformed to epoxide 4 with 67% yield and >20 : 1 diastereoselectivity through the peripheral attack. The X-ray crystallographic structure of 4 (CCDC 1589030 †) suggested that epoxidation proceeded via a less hindered convex approach. Hydrogenation of 3aa with H 2 in the presence of Pd-C at rt furnished the desired product 5 (5 : 1 dr) in 74% yield (isolated as a single isomer) (Scheme 3).
A plausible reaction mechanism of the palladium-catalyzed DDC reaction of 1a with 2a to 3aa is portrayed in Scheme 4. The catalytic cycle is rst initiated by the oxidative addition of Pd(0) with 2 followed by decarboxylation, which generates the p-allyl-Pd(II) complex II. The extremely nucleophilic nature of the alkoxide oxygen of II attacks the most electrophilic carbon atom attached to the CF 3 group of 1a which triggers the opening of benzoxazinanone ring to generate reactive species III. Due to its highly reactive nature, species III immediately transforms into Pd-complex I via decarboxylation. Recently, Kleij et al. disclosed the similar kind of six membered Pd-complex with the support of DFT calculations. 21 In our case, the formation of Pdcomplex I was conrmed by LC-MS spectrometry (Fig. S2 in ESI for detail †) but we could not detect it by NMR (Fig. S3, in ESI for detail †).
From complex I, there might be two possible pathways for the formation of two different cyclized products. Attack at the terminal position of the Pd-complex (path A) would generate the [5 + 4] cycloaddition product 3aa while internal attack (i.e., path B) of Pd-complex could result in [4 + 3] cycloaddition to furnish a seven-membered heterocycle 8. However, we did not obtain the [4 + 3] cycloaddition adduct 8. This may be attributed to steric hindrance of 8, i.e., the NTs group as well as the tetrasubstituted tertiary carbon center on 8.

Conclusions
In conclusion, we have established a novel and highly efficient methodology for the synthesis of benzo-fused nine-membered heterocyclic alkenes with a triuoromethyl carbinol moiety through a palladium-catalyzed double decarboxylative formal ring expansion process. A combination of triuoromethylated six-membered benzoxazinanones with vinylethylene carbonates resulted in direct access to previously unknown triuoromethylfunctionalized nine-membered heterocycles. The tri-uoromethyl substituent at the C-4 position of benzoxazinanones plays an important role in this transformation. Diastereoselective transformations of the benzo-fused ninemembered heterocyclic alkene were also achieved to demonstrate the synthetic utility of the products. Investigation of the formation of other medium-sized rings as well as enantioselective variants of the reaction are presently under way in our laboratory.

Conflicts of interest
There are no conicts to declare.

Acknowledgements
This work was supported by JSPS KAKENHI Grant Number JP 16H01142 in the Middle Molecular Strategy, and the Advanced