The Dark Side of Isocyanides: Visible-Light Photocatalytic Activity in the Oxidative Functionalization of C(sp³)–H Bonds

Abstract

The possibility to harness aromatic isocyanides as visible-light photocatalysts in the α-amino C(sp 3 )–H functionalization is herein presented. Actually, the three-component cross-dehydrogenative coupling of aromatic tertiary amines with isocyanides and water leads to amide products under very mild conditions in high yields and with a good substrate scope. While the reaction with aromatic isocyanides proceeds upon direct photoexcitation, aliphatic isocyanides are able to form a photoactive electron–donor–acceptor complex with aromatic amines. Moreover, the use of a catalytic loading of an aromatic isocyanide promotes the oxidative coupling of N -phenyl-1,2,3,4-tetrahydroisoquinoline with an array of different (pro)nucleophiles in good to excellent yields, thus providing the proof-of-concept for the development of a new highly tunable class of organic visible-light photocatalysts.

Visible-light photocatalytic metal-free multicomponent Ugi-like chemistry

“…Based on our recent findings 8 about the photocatalytic properties of both aromatic (direct photoexcitation) and aliphatic isocyanides (EDA complex with aromatic tertiary amines) we wondered if such (photo)reactivity could not only be preserved in the presence of different nucleophiles but also match with their ability to enable multicomponent processes (Fig. 2a).…”

“…23-7.20 (m, 2H), 6.94-6.92 (m, 4H), 6.77 (t, J = 7.3 Hz, 1H), 6.75 (d, J = 8.9 Hz, 2H), 6.64 (d, J = 8.2 Hz, 2H), 4.37 (s, 2H), 3.68 (s, 3H), 2.87 (s, 3H), 2.24 (s, 3H); 13 C NMR (176 MHz, CDCl 3 ) δ 176.0, 172. 1, 158.7, 148.7, 143.2, 131.2, 130.6, 130.0, 129.2, 128.9, 128.6, 117.8, 114.7, 112.6, 58.4, 55.4, 40.5, 21.6 (8). The crude material (reaction time: 48 h) was purified by column chromatography (n-hexane/ethyl acetate 99.5 : 0.5) to give the product as a pale-yellow sticky solid (33.0 mg, 95% yield).…”

“…3). Similarly, both aromatic and aliphatic carboxylic acids showed to be competent starting materials, including complex molecular architectures such as ibuprofen, biotin, indomethacin, and cholic acid (8)(9)(10)(11)Fig. 3).…”

“…7 Recently, we showed that aromatic isocyanides are able to absorb visible light and reach an electronically excited state to promote the oxidation of aromatic tertiary amines. 8 This finding provided a route to the exploitation of aromatic isocyanides as visible-light photocatalysts in different transformations such as Mannich, Strecker, aza-Henry, Michael addition, and phosphonylation reactions. On the other hand, we also observed that aliphatic isocyanides could induce the oxidation of tertiary aromatic amines as well via the formation of an electron donor-acceptor (EDA) complex.…”

Isocyanide‐Based Multicomponent Reactions Promoted by Visible Light Photoredox Catalysis

“…While investigating the possibility to perform some Ugi‐like MCRs starting from aromatic tertiary amines 58 , isocyanides 2 , and a third component we discovered that aromatic isocyanides could be harnessed as photocatalysts in the α‐amino C(sp 3 )−H functionalization (Scheme 27). [42] Accordingly, by mixing an aromatic isocyanide 2 and an N , N ‐dimethylaniline 58 in a MeCN/water mixture, at room temperature, under air and 30 W blue LEDs irradiation, in the presence of a 10 mol % loading of Yb(OTf) 3 , it was possible to obtain a wide range of amide derivatives 59 in good to excellent yields (up to 96 %). Both fluorescence and absorption experiments supported the ability of aromatic isocyanides 2 to reach an excited state upon visible light irradiation and to be quenched by an aromatic tertiary amine 58 , therefore indicating a possible SET event, which would trigger the formation of an amine radical cation I .…”