Communication Cite This: J. Am. Chem. Soc. 2018, 140, 8629−8633
pubs.acs.org/JACS
Copper-Catalyzed Domino [1,3]/[1,2] Rearrangement for the Efficient Synthesis of Multisubstituted ortho-Anisidines Yasuhiro Ishida,† Itaru Nakamura,*,‡ and Masahiro Terada† †
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
‡
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S Supporting Information *
Scheme 1. Cu-Catalyzed Rearrangement of NAlkoxyanilines
ABSTRACT: Multisubstituted ortho-anisidines were efficiently synthesized via cationic N-heterocyclic carbeneCu-catalyzed domino rearrangement of N-methoxyanilines that possess an electron-donating functional group, such as an alkyl or an aryl group, at the ortho position. The reaction proceeded first through a [1,3]-rearrangement of the methoxy group to the ortho position bound to the electron-donating substituent, followed by a semipinacol type [1,2]-rearrangement of the electron-donating group from the ortho to the meta position. Mechanistic studies suggest that both rearrangement reactions are promoted by a cationic Cu catalyst.
M
ultisubstituted anilines, which are frequently encountered in fields such as pharmaceutical and materials science,1 are typically synthesized via electrophilic substitution of anilines or nitration of aromatic compounds under strongly acidic conditions. Such methods, however, suffer from both low ortho/para selectivity and low reactivity due to electronwithdrawing functional groups. Recently, directed C−H functionalizations involving transition metal catalysts have been extensively investigated as an efficient and selective methodology to functionalize anilines under mild reaction conditions.2 In spite of tremendous progress, however, it remains a challenge to sequentially arrange more than three functional groups on the aromatic ring in an efficient manner with high functional group tolerance, because the efficiency and selectivity of such intermolecular functionalization reactions are often influenced by steric effects of the neighboring substituents.3 To overcome the aforementioned problems, we propose a “domino rearrangement reaction”, which features an initial rearrangement reaction on the aromatic ring that subsequently induces a second rearrangement (Scheme 1).4 Recently, we have reported on the efficient [1,3]-alkoxy rearrangement of N-alkoxyanilines that involve cationic Cu catalysts ligated to an N-heterocyclic carbene (NHC) ligand,5 to afford the corresponding ortho-alkoxyanilines with high functional group compatibility (Scheme 1a).6,7 Mechanistic studies suggest that the reaction proceeds via C−O bond formation between the Cu alkoxide and the positively charged arenium moiety of intermediate A. Accordingly, we envisioned that the [1,3]-rearrangement of the alkoxy group would preferentially occur at the substituted side because of stabilization of positively charged ortho position with the © 2018 American Chemical Society
electron-donating group (R1) (Scheme 1b). Consequently, intermediate B′ would undergo a semipinacol [1,2]-rearrangement8,9 of R1, which would be driven by the donation of electrons from the migrated alkoxy group, to afford the orthoanisidines with the sequential substitution of the amino, methoxy, and R1 groups. Herein, we report on the cationic NHC-Cu catalyzed domino [1,3]/[1,2]-rearrangement of Nmethoxyanilines 1, having an alkyl or aryl group at the ortho position, to afford the corresponding 3-substituted-2-anisidines 2 in good to high yields (eq 1). Initially, 1a, which possesses a methyl group at the ortho position and a para-trifluorobenzoyl group on the nitrogen atom, was treated with catalytic amounts of IPrCuBr [IPr: N,N′-bis(2,6-diisopropylphenyl)-imidazol-2-ylidene] and AgBF4 in chlorobenzene at 90 °C for 20 h. The reaction afforded the corresponding 3-methyl-2-anisidine derivative 2a in 63% yield, along with a small amount of 3a (16%), which was derived from the [1,3]-rearrangement on the nonsubstituted ortho position (Table 1, entry 1). Notably, the Received: April 5, 2018 Published: June 19, 2018 8629
DOI: 10.1021/jacs.8b03669 J. Am. Chem. Soc. 2018, 140, 8629−8633
Communication
Journal of the American Chemical Society Table 1. Reaction Conditionsa
d
1 2d 3d 4d 5 6e 7f 8 9 10 11g 12
Scheme 2. Cu-Catalyzed Reaction of 1i-ua
1
Catalyst
2 (%)b
3 (%)c
1 (%)c
1a 1a 1a 1a 1a 1b 1c 1d 1e 1f 1g 1h
IPrCuBr, AgBF4 SIPrCuCl, AgBF4 IPrCuBr, AgSbF6 IPrCuBr, AgNTf2 IPrCuBr, AgBF4 IPrCuBr, AgBF4 IPrCuBr, AgBF4 IPrCuBr, AgBF4 IPrCuBr, AgBF4 IPrCuBr, AgBF4 IPrCuBr, AgBF4 IPrCuBr, AgBF4
2a (63) 2a (13)c 2a (58)c 2a (18)c 2a (72) 2b (33)c 2c (76) 2d (51) 2e (86) 2f (63) 2g (82)
