Alkylation of Nonacidic C(sp³)–H Bonds by Photoinduced Catalytic Michael-Type Radical Addition

Abstract

Photoinduced catalytic Michael-type radical addition was achieved via olefin insertion into a nonacidic C(sp)-H bond, utilizing 2-chloroanthraquinone as a C-H bond-cleaving catalyst and 1,1-bis(phenylsulfonyl)ethylene as an olefinic substrate. The present radical protocol allows carbon chain extension stemming from nonacidic C-H bonds, which complements alkylation at acidic C-H bonds under ionic conditions and installs the active methine site that acts as a versatile synthetic handle for further transformations.

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

“…This work opened the floodgates for the development of photoredox α‐amino functionalization methodologies applicable to morpholines, either by using iridium catalysts alone or in conjunction with another catalyst which can be a transition state metal or an organocatalyst, as elaborated in representative examples shown in Figure ; The a‐amino functionalization of morpholines by a radical‐mediated photo‐induced coupling, was initially developed via another strategy by the Hoffmann group and then applied further by Inoue, Kamijo et al (Figure ). These reactions proceed with use of either catalytic (Figure A, B and C, yields 70%, 60%, and 48%, respectively) or stoichiometric (Figure D; 98% yield) amounts of the photoactive reagent. While useful and unique, these transformations have a significant drawback, which is the need for 5 to 8 equivalents of the morpholine coupling partner, impeding their potential wider use for morpholine functionalization in drug discovery projects.…”

“…Other photoredox α‐amino functionalization methodologies. [Conditions: (a) 4,4’‐dimethoxybenzophenone (10 mol%), hv (350 nm), dithiocarbamate, MeCN; (b) 5,7,12,14‐pentacenetetrone (5 mol%), hv (365 nm LED lamp), K 2 CO 3 , rt, 24 hours; (c) 2‐chloroanthraquinone (10 mol%), hv (365 nm Hg lamp), CH 2 Cl 2 , rt, 4 hours; (d) Ph 2 CO (1 equiv), hv (medium pressure Hg lamp), t ‐BuOH, rt, 1 hour]…”

Morpholine As a Scaffold in Medicinal Chemistry: An Update on Synthetic Strategies

“…The α‐amino functionalization of morpholines via a radical mediated photo‐induced coupling, was initially developed by the Hoffmann group and then explored further by Kamijo and co‐workers. These reactions require the photoactive reagent either in catalytic (Scheme B−D) or stoichiometric (Scheme E) amounts. However, the need for 5 to 8 equivalents of the morpholine coupling partner is the main disadvantage of these methods, limiting their potential wider use in drug discovery projects.…”

“… A direct photo‐catalyzed C−H vinylation ( A ) and examples of photoredox α‐amino functionalization methodologies ( B – E ). Reagents and conditions : a) Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1 mol %), CsOAc, DCE, 26 W fluorescent light, rt (yield: 79 %); b) 4,4’‐dimethoxybenzophenone (10 mol %), hv (350 nm), dithiocarbamate, MeCN (yield: 70 %); c) 5,7,12,14‐pentacenetetrone (5 mol %), hv (365 nm LED lamp), K 2 CO 3 , rt, 24 h (yield: 60 %); d) 2‐chloroanthraquinone (10 mol %), hv (365 nm Hg lamp), DCM, rt, 4 h (yield: 48 %); e) Ph 2 CO (1 equiv), hv (medium pressure Hg lamp), t ‐BuOH, rt, 1 h (yield: 98 %)]; (Bn: benzene).…”

“…After the abovementioned studies, a number of groups further researched the development of photoredox α-amino functionalization methodologies applicable to morpholines, by using iridium catalysts alone (Scheme 26A), [81] or in conjunction with another catalyst such as a transition state metal [82][83] or an organocatalyst, [84] as demonstrated in representative examples shown in Scheme 26BÀ E. The α-amino functionalization of morpholines via a radical mediated photo-induced coupling, was initially developed by the Hoffmann group and then explored further by Kamijo and co-workers. These reactions require the photoactive reagent either in catalytic (Scheme 26BÀ D) [85][86][87] or stoichiometric (Scheme 26E) [88] amounts. However, the need for 5 to 8 equivalents of the morpholine coupling partner is the main disadvantage of these methods, limiting their potential wider use in drug discovery projects.…”