Copper-catalyzed methylative difunctionalization of alkenes

Trifluoromethylative difunctionalization and hydrofunctionalization of unactivated alkenes have been developed into powerful synthetic methodologies. On the other hand, methylative difunctionalization of olefins remains an unexplored research field. We report in this paper the Cu-catalyzed alkoxy methylation, azido methylation of alkenes using dicumyl peroxide (DCP), and di-tert-butyl peroxide (DTBP) as methyl sources. Using functionalized alkenes bearing a tethered nucleophile (alcohol, carboxylic acid, and sulfonamide), methylative cycloetherification, lactonization, and cycloamination processes are subsequently developed for the construction of important heterocycles such as 2,2-disubstituted tetrahydrofurans, tetrahydropyrans, γ-lactones, and pyrrolidines with concurrent generation of a quaternary carbon center. The results of control experiments suggest that the 1,2-alkoxy methylation of alkenes goes through a radical-cation crossover mechanism, whereas the 1,2-azido methylation proceeds via a radical addition and Cu-mediated azide transfer process.

T he so-called magic methyl effect has long been known in medicinal chemistry and has been frequently used to optimize the biological and pharmacological properties of a drug candidate 1 . In addition to traditional nucleophilic substitution reaction, transition metal-catalyzed cross-coupling reaction has recently been developed into a powerful tool for the methylation of (hetero)aromatics 2,3 . However, in comparison to the recent advances in the field of trifluoromethylation of organic compounds 4,5 , progress on the development of new methylation protocols has been much slower. While the importance of the CF 3 group in pharmaceuticals and crop science is undeniable, the CH 3 group deserved certainly equal attention. In fact, it was estimated that over 67% of 200 top-selling drugs bore at least one CH 3 group, while <5% of the small molecule drugs in the same list contained a CF 3 group 6 .
Most of the trifluoromethylative difunctionalization of alkenes involved the generation of electrophilic CF 3 radical from the hypervalent iodine reagents 7 followed by its addition to the electron-rich alkenes (Fig. 1a) 3 . Similarly, metal-catalyzed hydrofunctionalization of alkenes, pioneered by Mukaiyama in 1980s 8 , has been extensively investigated (Fig. 1b) [9][10][11][12][13][14][15][16] . By choosing an appropriate radical acceptor, Baran and co-workers developed a protocol for the hydromethylation of unactivated alkenes for the one-pot conversion of alkenes to alkanes (Fig. 1c) 15 . Interestingly, in spite of the known magic methyl effect in medicinal chemistry and its utility in natural product synthesis, the related methylative difunctionalization of unactivated olefins was, to the best of our knowledge, far less developed and a multistep sequence was generally needed to accomplish this endeavor. As illustrated in Fig. 1d, five steps were needed to convert alkene I to hydroxymethylated derivative II, an advanced intermediate on the way to vinigrol 17,18 .
Peroxides undergo homolytic cleavage of the O-O bond to generate acyloxy or alkoxy radicals, which can act as oxidants and radical initiators. These oxygen-centered radicals can also undergo further fragmentation to produce the alkyl radicals 19 . The groups of Kawazoe 20 and Wong 21 demonstrated in 1970s that the methyl radical generated from tert-butyl hydroperoxide and tert-butyl peracetate can methylate the protonated nucleobases via homolytic aromatic substitution (HAS) reaction. These pioneering studies, akin to Minisci reaction 22 , is in line with the nucleophilic nature of the methyl radical. Since then, conditions allowing the methylation of (hetero)arenes [23][24][25][26] , amides/carboxylic acids [27][28][29][30] , and isocyanides [31][32][33][34] have been exploited. In addition, methylation of electron-deficient olefins such as Narylacrylamides have also been developed [35][36][37][38] . In this latter case, the resulting electrophilic radical adduct underwent rapid intramolecular HAS with the tethered aromatic ring to afford 2,2disubstituted oxindoles. On the other hand, methylative difunctionalization of unactivated double bonds using peroxide as methyl source has, to the best of our knowledge, not been reported 39 . This was probably due to the perception that methyl radical is nucleophilic, therefore, its addition to electron-rich alkenes would be polarity mismatched process [40][41][42][43] . We report herein the realization of this endeavor by developing threecomponent 1,2-alkoxy methylation, 1,2-azido methylation, and methylative cycloetherification, lactonization, cycloamination of unactivated alkenes (Fig. 1e). The results of control experiments suggested that the 1,2-alkoxy methylation of alkenes went through a radical-cation crossover mechanism, whereas the azido methylation proceeded via a radical addition and Cu-mediated redox azide transfer process.

Results
Three-component 1,2-alkoxy methylation of alkenes. Examples of alkoxy alkylation of unactivated alkenes are rare. Wang and coworkers reported a rhenium-catalyzed 1,2-acetoxy methylation of styrene derivatives using phenyliodine diacetate (PIDA) as both the methyl and the acetoxy sources 44 , while Glorius 45 and Bao 46,47 reported the alkoxy alkylation of alkenes via decarboxylative generation of alkyl radicals.
We began our studies by examining the 1,2-alkoxy methylation of α-methylstyrene (1a). After extensive survey of the reaction parameters varying the Cu sources, the ligands, the Cu/ligand ratio, the peroxides, the bases, the solvents, the concentration, and the reaction temperature, the optimum conditions found consisted of heating a MeOH solution of 1a (c 0.1 M) in a sealed tube in the presence of a catalytic amount of Cu(BF 4 ) 2 •6H 2 O (0.2 equiv), 4,4-dimethoxy-2,2'-bipyridine (L1, 0.3 equiv) and Na 2 HPO 4 (0.2 equiv) at 120°C for 4 h. Under these conditions, 2a was isolated in 96% yield. We note that reaction using  The scope of this 1,2-alkoxy methylation of alkenes is shown in Fig. 2. Electron-donating (Me and OMe) and electronwithdrawing (F and Cl) substituents at different positions of the phenyl ring of the α-methylstyrene derivatives were transformed into the corresponding methylated ethers (2b-2i) in excellent yields. Different alkyl groups (Et, iPr, and CH 2 CH 2 Ph) at the αposition of styrene were compatible (2j-2l) and the 1,1diarylethylenes were similarly difunctionalized to afford the desired products (2m-2q) regardless of the electronic nature of the substituents on the aromatic ring. 2-Vinylnaphthalene and 1methylene-1,2,3,4-tetrahydronaphthalene took part in the reaction to afford the three-component adducts without event (2r, 2s). However, styrene failed to give the desired 1,2-methoxy methylation product under standard conditions. Performing the reaction of 1a in ethanol and isopropanol under otherwise standard conditions afforded the ethyl ether (2t) and the isopropyl ether (2u), respectively. A gram scale experiment converted 1a to the three-component adduct 2a in 93% isolated yield.
Methylative cycloetherification. Metal-catalyzed arylative cycloetherification and cycloamination has been well developed for the synthesis of functionalized oxa-and aza-heterocycles 54,55 . The alkylation-induced heterocyclization is, on the other hand, poorly documented. For instance, only few examples of alkylative cycloetherification have been reported in the literature 56 .
Methylative cycloamination. While trifluoromethylative cycloamination of alkenes have been reported recently 65,66 , the methylative counterpart is to the best of our knowledge unknown. We therefore set out to examine this reaction using sulfonamide as internal nucleophile. Optimum conditions found for the methylative cycloamination of 8a with DTBP (4.0 equiv) consisted of heating a solution of 8a in tBuOH (c 0.1 M) in the presence of Cu(OAc) 2 (0.2 equiv), 1,10-Phen (L2) and Na 3 PO 4 (0.2 equiv) at 120°C. Under these conditions, the pyrrolidine 9a was isolated in 71% yield. As it is shown in Fig. 4c, electrondonating (Me, OMe, Ph, and iPr) and electron-withdrawing groups (F, Br, Cl, and CN) on the phenyl ring of the α-methyl styrene derivatives were well tolerated leading to 2,2-disubstituted pyrrolidines (9a-9k) in good yields.
Mechanistic studies. Possible reaction pathways for the 1,2alkoxy methylation and 1,2-azido methylation of alkenes are depicted in Fig. 5a. Reduction of peroxide (DCP or DTBP) by the in situ generated Cu(I)X salt A would produce the tert-alkoxy radical B and Cu(II) salt C. Alternatively, thermal decomposition of peroxide would generate two molecules of alkoxy radical B. β-Scission of B would generate ketone D and methyl radical E. Addition of E to the alkene would produce the benzyl radical F which would be oxidized by Cu(II) salt C to the carbenium G with the concurrent regeneration of the Cu(I)X salt. Trapping of the carbenium G by nucleophile would then afford the observed products (route a). Alternatively, radical F could be directly converted to the adduct via a Cu-centered redox transfer process (route b) or via radical rebound of F with C followed by reductive elimination of the resulting Cu(III) species H (route c) 64 .
In accordance with the aforementioned reaction manifolds, 1,2-methoxy methylation of 1-methyl-1-(4-nitrophenyl)ethylene (21) under standard conditions afforded a significant amount of dimer 22 and only a trace amount of the desired methoxy methylation product (Fig. 6a). The presence of the strong electron-withdrawing nitro group on the phenyl ring might significantly reduce the rate of the oxidation of benzyl radical 23 to carbenium, blocking therefore the methoxylation process. It underwent instead the dimerization to afford 22. On the other hand, treatment of 21 under standard azido methylation conditions afforded the three-component adduct 3f in 78% yield together with a small amount of dimer 22 (Fig. 6b). The result supported the notion that oxidation of radical to cation is not involved in the azidation step and the azido group was transferred directly to the radical 23 via presumably a Cu-mediated redox transfer process. The azide transfer reaction was apparently faster than the dimerization process under our optimized azido methylation conditions. It is also worth noting that dimer was rarely observed under the optimized methoxy methylation of alkenes due presumably to the rapid oxidation of benzyl radical to benzyl cation (except for 21), while it was very often observed as a side product in the azido methylation process due to the relatively long-lived benzyl radical species. Finally, performing the azidomethylation of α-methylstyrene (1a) in MeOH and tBuOH/MeOH (v/v = 4:1) under otherwise standard conditions afforded the desired product 3a in yields of 46 and 62%, respectively. The potential competitive reaction leading to the 1,2methoxy methylated product 2a was not observed. This result reinforced the hypothesis that benzyl cation might not be involved in the azidomethylation of alkenes.
At the outset of this research, we were concerned about the hydrogen abstraction of MeOH by tert-alkoxy radical B to generate the hydroxymethyl radical I (route d, Fig. 5a). This process has indeed been exploited in the difunctionalization of activated alkenes 69,70 . Two pathways, namely, thermal decomposition and reduction by Cu(I) salt, may contribute to the generation of the radical B from the peroxide. The formal process generates two molecules of alkoxy radical B, while the latter produces one molecule of B and one molecule of copper tertbutoxide C. Therefore, it was difficult to quantify the ratio of βscission of B (generating Me•) vs H-abstraction of MeOH by B (leading to •CH 2 OH) based on the ratio of acetophenone (D) vs 2phenylpropan-2-ol (J). Nevertheless, the high J/D ratio (3/1) we obtained for the methylative methoxylation of α-methylstyrene (1a) indicated that route d, a thermodynamically favorable process (BDE of H-CH 2 OH: 96.06 ± 0.15 kcal/mol; tBuO-H: 106.3 ± 0.7 kcal/mol), was indeed occurring in parallel. However, the sogenerated hydroxymethyl radical I did not interfere with the methylation process probably due to the pronounced nucleophilic nature of this radical or its rapid oxidation to formaldehyde.
In summary, we reported the Cu-catalyzed carboalkoxylation, carboazidation, carbocycloetherification, carbolactonization, and carbocycloamination of alkenes using dicumyl peroxide (DCP) or di-tert-butyl peroxide (DTBP) as methyl sources. A diverse set of   styrene derivatives were converted to the methylated ethers, azides, tetrahydrofurans, tetrahydropyrans, γ-lactones, and pyrrolidines with concurrent generation of a quaternary carbon in good to excellent yields. The results of control experiments suggested that the 1,2-alkoxy methylation of alkenes went through a radicalcation crossover mechanism, whereas the azido methylation proceeded via a radical addition and Cu-mediated redox azide transfer process. This mechanistic insight would serve as a guideline in our searching for new alkene difunctionalization protocols.
Three-component 1,2-azido methylation of alkenes. A screw cap tube was charged with CuSO 4 (0.32 mg, 0.002 mmol, 0.01 equiv), 1,10-phenanthroline L2 (1.08 mg, 0.003 mmol, 0.03 equiv) and tBuOH (2.0 mL). The mixture was stirred at 40°C for 30 min, then cooled to room temperature. Substrate 1 (0.2 mmol, 1.0 equiv), LiN 3 (20% w/w, 0.12 mL, 2.5 equiv) and DTBP (0.15 mL, 4.0 equiv) were added to the above mixture, and the reaction mixture was stirred at 120°C for 8 h under N 2 atmosphere. The reaction was quenched with water and the aqueous phase was extracted with EtOAc. The organic extracts were washed with brine, dried over Na 2 SO 4 . The solvent was removed under reduced pressure. The residue was purified by flash chromatography to give 3.
Methylative cycloetherification. A screw cap tube was charged with Cu(OTf) 2 (14.5 mg, 0.04 mmol, 0.2 equiv), L1 (13.0 mg, 0.06 mmol, 0.03 equiv) and CF 3 CH 2 OH (2.0 mL). The mixture was stirred at room temperature for 30 min. Substrate 4 (0.2 mmol, 1.0 equiv), Na 3 PO 4 (6.5 mg, 0.04 mmol, 0.2 equiv) and DTBP (0.15 mL, 4.0 equiv) were added to the above mixture, and the reaction mixture was stirred at 120°C for 6 h under N 2 atmosphere. The reaction was quenched with water, and the aqueous phase was extracted with EtOAc. The organic extracts were washed with brine, dried over Na 2 SO 4 . The solvent was removed under reduced pressure. The residue was purified by flash chromatography to give 5.
Methylative lactonization. A screw cap tube was charged with CuSO 4 (6.4 mg, 0.04 mmol, 0.2 equiv), 1,10-phenanthroline L2 (10.8 mg, 0.06 mmol, 0.03 equiv) and CF 3 CH 2 OH (2.0 mL). The mixture was stirred at room temperature for 30 min. Substrate 6 (0.2 mmol, 1.0 equiv), Na 3 PO 4 (9.8 mg, 0.06 mmol, 0.3 equiv) and DTBP (0.15 mL, 4.0 equiv) were added to the above mixture, and the reaction mixture was stirred at 120°C for 6 h under N 2 atmosphere. The reaction was quenched with water and extracted with EtOAc. The organic extracts were washed with brine, dried over Na 2 SO 4 . The solvent was removed under reduced pressure. The residue was purified by flash chromatography to give 7.
Methylative cycloamination. A screw cap tube was charged with Cu(OAc) 2 (7.3 mg, 0.04 mmol, 0.2 equiv), 1,10-phenanthroline L2 (10.8 mg, 0.06 mmol, 0.03 equiv), and tBuOH (2.0 mL). The mixture was stirred at room temperature for 30 min. Substrate 8 (0.2 mmol, 1.0 equiv), Na 3 PO 4 (6.5 mg, 0.04 mmol, 0.2 equiv) and DTBP (0.15 mL, 4.0 equiv) were added to the above mixture, and the reaction mixture was stirred at 120°C for 3 h under N 2 atmosphere. The reaction was quenched with water and the mixture was extracted with EtOAc. The organic extracts were washed with brine, dried over Na 2 SO 4 . The solvent was removed under reduced pressure. The residue was purified by flash chromatography to give 9.