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. 2019 Feb 26;10(14):3987-3993.
doi: 10.1039/c9sc00545e. eCollection 2019 Apr 14.

Rhodium(iii)-catalyzed diverse [4 + 1] annulation of arenes with 1,3-enynes via sp3/sp2 C-H activation and 1,4-rhodium migration

Dachang Bai  1 , Jintao Xia  2   3 , Fangfang Song  1 , Xueyan Li  1 , Bingxian Liu  1 , Lihong Liu  1 , Guangfan Zheng  4 , Xifa Yang  2 , Jiaqiong Sun  4 , Xingwei Li  1   2   4
Affiliations

Rhodium(iii)-catalyzed diverse [4 + 1] annulation of arenes with 1,3-enynes via sp3/sp2 C-H activation and 1,4-rhodium migration

Dachang Bai et al. Chem Sci. .

Abstract

Nitrogen-rich heterocyclic compounds have a profound impact on human health. Despite the numerous synthetic methods, diversified, step-economic, and general synthesis of heterocycles remains limited. C-H bond functionalization catalyzed by rhodium(iii) cyclopentadienyls has proven to be a powerful strategy in the synthesis of diversified heterocycles. Herein we describe rhodium(iii)-catalyzed sp2 and sp3 C-H activation-oxidative annulations between aromatic substrates and 1,3-enynes, where alkenyl-to-allyl 1,4-rhodium(iii) migration enabled the generation of electrophilic rhodium(iii) π-allyls via remote C-H functionalization. Subsequent nucleophilic trapping of these species by various sp2-hybridized N-nucleophiles delivered three classes (external salts, inner salts, and neutral azacycles) of five-membered azacycles bearing a tetrasubstituted saturated carbon center, as a result of [4 + 1] annulation with the alkyne being a one-carbon synthon. All the reactions proceeded under relatively mild conditions with broad substrate scope, high efficiency, and excellent regioselectivity. The synthetic applications of this protocol have also been demonstrated, and experimental studies have been performed to support the proposed mechanism.

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Figures

Scheme 1
Scheme 1. Rh(iii)-catalyzed oxidative annulation of 1,3-enynes or alkynes. (a) Some drugs with isoindoline or the quaternary ammonium motif. (b) Quaternary ammonium salts formed via coupling with alkynes. (c) Synthesis of diversified heterocycles bearing a quaternary carbon center via coupling of arenes and 1,3-enynes.
Scheme 2
Scheme 2. Scope of the coupling of 2-phenylpyridines with 1,3-enynes. Reaction conditions: arene 1 or 2 (0.2 mmol), enyne 3 (0.22 mmol), [Cp*Rh(OAc)2] (8 mol%), Cu(OAc)2 (50 mol%), and KPF6 (0.5 mmol) in CF3CH2OH (2.0 mL) under air, 50 °C, monitored by TLC, isolated yields. See general procedure A.
Scheme 3
Scheme 3. Scope of the coupling of 8-methylquinolines with 1,3-enynes. Reaction conditions: 6 (0.2 mmol), 3 (0.3 mmol), [Cp*Rh(OAc)2] (8 mol%), AgSbF6 (0.2 mmol), AgOAc (0.3 mmol), DCE (2.0 mL), monitored by TLC, isolated yields. see general procedure B.
Scheme 4
Scheme 4. Scope of the coupling of oximes with 1,3-enynes.a,b aReaction conditions A: 8 (0.20 mmol), 3 (0.22 mmol), [Rh*CpCl2]2 (4.0 mol%), Cu(OAc)2 (2.1 equiv.), MeOH (2 mL) at 40 °C under N2 for 10 h. bIsolated yields. cReaction was performed with 4 mmol of 8 at 2.5 mol% catalyst loading. dIsoquinoline 9ib′, a [4 + 2] annulation product, was also isolated in 10% yield (see ESI†). eregioselectivity. See general procedure C.
Scheme 5
Scheme 5. Oxidative annulation of ketimines with 1,3-enynes and sequential hydrogenation. Reaction conditions: imine 10 (0.20 mmol), enyne 3 (0.22 mmol), [RhCp*Cl2]2 (4.0 mol%), AgOAc (2.1 equiv.), HFIP (2 mL) at 100 °C under N2 for 10 h; NaBH(OAc)3 (2.5 equiv.)/HOAc (20 equiv.) was sequentially added and was kept for 30 min at room temperature, followed by quenching with NaOH solution. Isolated yields. See general procedure D.
Scheme 6
Scheme 6. Applications of the coupling reaction. (a) Reaction on a gram scale. (b) Derivations of a coupled product through chemoselective reduction, Diels–Alder reaction and oxidative cleavage.
Scheme 7
Scheme 7. Mechanistic studies. (a) Catalytic reactivity of a rhodacyclic intermediate. (b) Kinetic isotope effect. (c) Competition experiment. (d) Reaction with deuterio-enyne [D]6-3b. (e) Control experiment.
Scheme 8
Scheme 8. Proposed mechanism.
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