Mechanisms of the InCl₃‑Catalyzed Type-I, II, and III Cycloisomerizations of 1,6-Enynes

InCl₃-catalyzed cycloisomerizations of 1,6-enynes can give either type-I dienes and cyclohexenes (type-III dienes), or type-II dienes, depending on the substitutions in the substrates. Previously, we studied how the type-II diene products were generated and found that the real catalytic species for the cycloisomerizations is InCl₂⁺ (<i>J. Org. Chem</i>. <b>2012</b>, <i>77</i>, 8527–8540). In the present paper, we used density functional theory (DFT) calculations to reveal how the type-I and type-III dienes were generated. A unified model to explain how substituents affect the regiochemistry of type-I, II, and III cycloisomerizations has been provided. Experimental and computational investigation of the InCl₃-catalyzed cycloisomerization of 1,6-enynes with both substituents at the alkyne and alkene parts has also been reported in the present study

DFT and Experimental Exploration of the Mechanism of InCl₃‑Catalyzed Type II Cycloisomerization of 1,6-Enynes: Identifying InCl₂⁺ as the Catalytic Species and Answering Why Nonconjugated Dienes Are Generated

InCl₃ and other In­(III) species have been widely applied as catalysts in many reactions. However, what are the real catalytic species of these reactions? Through DFT calculations and experimental investigation of the mechanism and regioselectivity of InCl₃-catalyzed cycloisomerization reactions of 1,6-enynes (here all discussed 1,6-enynes are ene-internal-alkyne molecules), we propose that the catalytic species of this reaction is the in situ generated InCl₂⁺. Further electrospray ionization high-resolution mass spectroscopy (ESI-HRMS) supported the existence of InCl₂⁺ in acetonitrile solution. This finding of InCl₂⁺ as the catalytic species suggests that other reactions catalyzed by In­(III) species could also have cationic In­(III) species as the real catalysts. DFT calculations revealed that the catalytic cycle of the cycloisomerization of 1,6-enynes catalyzed by InCl₃ starts from InCl₂⁺ coordination to the alkyne of the substrate, generating a vinyl cation. Then nonclassical cyclopropanation of the vinyl cation to the alkene part of the substrate gives a homoallylic cation, which undergoes a novel homoallylic cation rearrangement involving a [1,3]-carbon shift to give the more stable homoallylic cation <b>15</b>. Finally InCl₂⁺ cation coordination assisted nonconjugated [1,2]-hydride shifts deliver the final nonconjugated diene products. The preference of generating nonconjugated dienes instead of conjugated dienes in the cycloisomerization reaction is mainly due to two reasons: coordination of the InCl₂⁺ to the alkene part in [1,2]-H shift transition states disfavors the conjugated [1,2]-H shifts that generate cations adjacent to the positively charged alkene, and coordination of InCl₂⁺ to the nonconjugated diene product is stronger than coordination to the conjugated diene, making nonconjugated [1,2]-H shift transition states lower in energy than conjugated [1,2]-H shift transition states, on the basis of the Hammond postulate. DFT calculations predicted that the conjugated [1,2]-H shifts could become favored if the electron-donating methyl substituent in the alkyne moiety of the 1,6-enyne is replaced by a H atom. This prediction of producing a conjugated diene has been verified experimentally. Rationalization about why type II rather than type I products were obtained using InCl₃ as the catalyst in the cycloisomerization of 1,6-enynes has also been investigated computationally

Rh(I)-Catalyzed [(3 + 2) + 1] Cycloaddition of 1-Yne/Ene-vinylcyclopropanes and CO: Homologous Pauson−Khand Reaction and Total Synthesis of (±)-α-Agarofuran

A novel Rh(I)-catalyzed [(3 + 2) + 1] cycloaddition, which can be regarded as a homologous Pauson−Khand reaction, was developed to synthesize bicyclic cyclohexenones and cyclohexanones, enabling a new approach for synthesis of six-membered carbocycles ubiquitously found in natural products and pharmaceutics. The significance of the Rh-catalyzed [(3 + 2) + 1] cycloaddition has been demonstrated by the total synthesis of a furanoid sesquiterpene natural product, α-agarofuran, in which the bicyclic skeleton was constructed by the [(3 + 2) + 1] reaction of 1-yne-VCP and CO

Rh(I)-Catalyzed [(3 + 2) + 1] Cycloaddition of 1-Yne/Ene-vinylcyclopropanes and CO: Homologous Pauson−Khand Reaction and Total Synthesis of (±)-α-Agarofuran

A novel Rh(I)-catalyzed [(3 + 2) + 1] cycloaddition, which can be regarded as a homologous Pauson−Khand reaction, was developed to synthesize bicyclic cyclohexenones and cyclohexanones, enabling a new approach for synthesis of six-membered carbocycles ubiquitously found in natural products and pharmaceutics. The significance of the Rh-catalyzed [(3 + 2) + 1] cycloaddition has been demonstrated by the total synthesis of a furanoid sesquiterpene natural product, α-agarofuran, in which the bicyclic skeleton was constructed by the [(3 + 2) + 1] reaction of 1-yne-VCP and CO

Synthesis of <i>Z</i>‑Alkenes from Rh(I)-Catalyzed Olefin Isomerization of β,γ-Unsaturated Ketones

Developing olefin isomerization reactions to reach kinetically controlled <i>Z</i>-alkenes is challenging because formation of <i>trans</i>-alkenes is thermodynamically favored under the traditional catalytic conditions using acids, bases, or transition metals as the catalysts. A new synthesis of <i>Z</i>-alkenes from Rh(I)-catalyzed olefin isomerization of β,γ-unsaturated ketones to α,β-unsaturated ketones was developed, providing an easy and efficient way to access various <i>Z</i>-enones

Mild-Condition Synthesis of Allenes from Alkynes and Aldehydes Mediated by Tetrahydroisoquinoline (THIQ)

A practical 1,2,3,4-tetrahydroisoquinoline (THIQ)-mediated synthesis of 1,3-disubstituted allenes from terminal alkynes and aldehydes under mild conditions in the presence of CuBr first and then ZnI₂ was reported. This telescoped allene synthesis reaction includes three consecutive steps and two reactions: first, a room-temperature CuBr-catalyzed synthesis of propargylamines, <i>exo</i>-yne-THIQs, from terminal alkynes, aldehydes, and THIQ, then filtration of the CuBr catalyst, and finally the ZnI₂-mediated allene synthesis from the generated <i>exo</i>-yne-THIQs under mild conditions (either at room temperature or heating at 50 or 75 °C). A wide range of aliphatic or aromatic aldehydes and terminal alkynes are tolerated, affording the allene products in up to 92% yield. Especially, temperature-sensitive aldehydes can be used in the reaction system. Preliminary exploration of the asymmetric allene synthesis has also been conducted, and a moderate enantioselectivity has been achieved. Finally, the relative reactivities of several secondary amines were compared with THIQ, showing that THIQ is the best of these amines in the synthesis of allenes under mild reaction conditions

Highly Enantioselective Hydrogenation of Quinolines Using Phosphine-Free Chiral Cationic Ruthenium Catalysts: Scope, Mechanism, and Origin of Enantioselectivity

Asymmetric hydrogenation of quinolines catalyzed by chiral cationic η6-arene–N-tosylethylenediamine–Ru(II) complexes have been investigated. A wide range of quinoline derivatives, including 2-alkylquinolines, 2-arylquinolines, and 2-functionalized and 2,3-disubstituted quinoline derivatives, were efficiently hydrogenated to give 1,2,3,4-tetrahydroquinolines with up to >99% ee and full conversions. This catalytic protocol is applicable to the gram-scale synthesis of some biologically active tetrahydroquinolines, such as (−)-angustureine, and 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline, a key intermediate for the preparation of the antibacterial agent (S)-flumequine. The catalytic pathway of this reaction has been investigated in detail using a combination of stoichiometric reaction, intermediate characterization, and isotope labeling patterns. The evidence obtained from these experiments revealed that quinoline is reduced via an ionic and cascade reaction pathway, including 1,4-hydride addition, isomerization, and 1,2-hydride addition, and hydrogen addition undergoes a stepwise H+/H– transfer process outside the coordination sphere rather than a concerted mechanism. In addition, DFT calculations indicate that the enantioselectivity originates from the CH/π attraction between the η6-arene ligand in the Ru-complex and the fused phenyl ring of dihydroquinoline via a 10-membered ring transition state with the participation of TfO– anion

Highly Enantioselective Hydrogenation of Quinolines Using Phosphine-Free Chiral Cationic Ruthenium Catalysts: Scope, Mechanism, and Origin of Enantioselectivity

Asymmetric hydrogenation of quinolines catalyzed by chiral cationic η6-arene–N-tosylethylenediamine–Ru(II) complexes have been investigated. A wide range of quinoline derivatives, including 2-alkylquinolines, 2-arylquinolines, and 2-functionalized and 2,3-disubstituted quinoline derivatives, were efficiently hydrogenated to give 1,2,3,4-tetrahydroquinolines with up to >99% ee and full conversions. This catalytic protocol is applicable to the gram-scale synthesis of some biologically active tetrahydroquinolines, such as (−)-angustureine, and 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline, a key intermediate for the preparation of the antibacterial agent (S)-flumequine. The catalytic pathway of this reaction has been investigated in detail using a combination of stoichiometric reaction, intermediate characterization, and isotope labeling patterns. The evidence obtained from these experiments revealed that quinoline is reduced via an ionic and cascade reaction pathway, including 1,4-hydride addition, isomerization, and 1,2-hydride addition, and hydrogen addition undergoes a stepwise H+/H– transfer process outside the coordination sphere rather than a concerted mechanism. In addition, DFT calculations indicate that the enantioselectivity originates from the CH/π attraction between the η6-arene ligand in the Ru-complex and the fused phenyl ring of dihydroquinoline via a 10-membered ring transition state with the participation of TfO– anion