Research Article Cite This: ACS Catal. 2017, 7, 8324-8330
pubs.acs.org/acscatalysis
Radical Trifluoromethylative Dearomatization of Indoles and Furans with CO2 Jian-Heng Ye,†,§ Lei Zhu,‡,§ Si-Shun Yan,† Meng Miao,† Xin-Chi Zhang,† Wen-Jun Zhou,† Jing Li,† Yu Lan,*,‡ and Da-Gang Yu*,† †
Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, P. R. China ‡ School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400030, P. R. China S Supporting Information *
ABSTRACT: Disclosed herein is a versatile and practical strategy for catalytic radical dearomatization. By means of this strategy, we realized the trifluoromethylative dearomatization of indoles and furans with CO2 via Cu catalysis. We also demonstrated the dearomatization of indoles with C-3 C−O bond formation to generate spirocyclic indolines. A variety of important CF3-containing spirocyclic indolines and spiroacetals can be synthesized with atmospheric CO2 under mild reaction conditions. Moreover, these multicomponent reactions feature high selectivity, good functional group tolerance, broad substrate scope, and easy scalability. Further theoretical investigation indicates that this transformation starts with deprotonation of the amine and CO2 insertion, after which CF3· radical addition to the indole followed by intramolecular C−O coupling affords the oxazolidone product. KEYWORDS: carbon dioxide, dearomatization, radical, trifluoromethylation, spirocyclization
C
Scheme 1. Dearomatization of Indoles
arbon dioxide is considered to be an abundant, nontoxic, and recyclable building block in organic synthesis.1 Although significant effort has been exerted toward the conversion of CO2 into value-added chemicals, exploration of new transformations of CO2 under mild reaction conditions is a long-standing challenge. The dearomatization process is wellknown as a direct and economical way to construct architecturally complex molecules, particularly heterocyclic and spirocyclic skeletons, which represent important structural motifs in numerous natural products and pharmaceuticals.2 However, so far as we know, CO2 has rarely been used in dearomatization reactions.3 As part of our ongoing research exploring methodologies for the application of CO2 in organic synthesis,4 we wished to develop new strategy for catalytic dearomatization with incorporation of CO2. As one class of widely existing aromatic compounds, indoles have attracted significant attention and have been investigated systemically as starting materials for dearomatizations.5 Recently, You6 and others7 have contributed significantly to the synthesis of C-3 spirocyclic indolines by engineering an electrophilic side chain onto the nucleophilic C-3 position (Scheme 1A). However, all current methods in this area are confined to C−C and C−N bond formation events, and examples of C−O bond formation have not been reported.5−7 In addition, while radical chemistry is a powerful tool in organic synthesis, it is rare to utilize a radical pattern to construct C-3 spirocyclic indolines. We envisaged that the indole C-3 radical, generated by addition of a radical at the C-2 position of indole, © XXXX American Chemical Society
could further undergo cyclization with an internal carbamate, which could be generated in situ from an amine tethered to the C-3 side chain with CO2 (Scheme 1B). Moreover, in view of the importance of the trifluoromethyl group in medicinal chemistry because of its unique solubility, lipophilicity, Received: July 31, 2017 Revised: October 19, 2017
8324
DOI: 10.1021/acscatal.7b02533 ACS Catal. 2017, 7, 8324−8330
Research Article
ACS Catalysis bioavailability, and metabolic stability,8 the CF3 radical is a tantalizing radical to use in our hypothesis.9 Herein we report a three-component trifluoromethylation/dearomatization/spirocyclization reaction that affords functionalized C-3 spirocyclic indolines and 2-oxazolidones10 of pharmaceutical interest from simple building blocks. Moreover, this strategy can also be applied to the dearomatization of furans. Although our strategy has great potential to build C-3 spirocyclic indolines along with both C-2 functionalization and C-3 C−O bond formation in a convergent manner, the chemoselectivity between dearomatization and aromatization is a big challenge. The in situ-generated C-3 radical may be oxidized to the cation, which might undergo facile deprotonation/aromatization9q−t to give C-2 trifluoromethylated indoles instead of cyclization to afford spiroindolines. With this in mind, we began our study by examining the reaction of 1a and Togni’s reagent II with atmospheric CO2 in the presence of [Cu(MeCN)4]PF6 as a catalyst at room temperature. We tested a variety of bases and found that 1,5-diazobicyclo[4.3.0]non-5ene (DBN) was the best choice, giving the desired product 2a in 70% yield (Table 1, entries 1−9). Switching the solvent or
indolines arising from aminotrifluoromethylation or C-3 trifluoromethylation was detected under these reaction conditions, indicating the high chemo- and regioselectivity. With the optimized reaction conditions in hand, we investigated the substrate scope of the reaction (Table 2). A Table 2. Substrate Scope of Indolesa
Table 1. Optimization of the Reaction Conditionsa
entry
catalyst
base
solvent
yield (%)b
1 2 3 4 5 6 7 8c 9d 10 11 12 13 14 15 16 17
[Cu(MeCN)4]PF6 [Cu(MeCN)4]PF6 [Cu(MeCN)4]PF6 [Cu(MeCN)4]PF6 [Cu(MeCN)4]PF6 [Cu(MeCN)4]PF6 [Cu(MeCN)4]PF6 [Cu(MeCN)4]PF6 [Cu(MeCN)4]PF6 [Cu(MeCN)4]PF6 [Cu(MeCN)4]PF6 [Cu(MeCN)4]PF6 [Cu(MeCN)4]PF6 TcCu CuI CuCl −
K2CO3 K3PO4 Cs2CO3 TMG DABCO DBU DBN DBN DBN DBN DBN DBN DBN DBN DBN DBN DBN
MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN DCE DCM DMF DMSO MeCN MeCN MeCN MeCN
