Recent Progress in Metal-Catalyzed [2+2+2] Cycloaddition Reactions

Abstract

Metal-catalyzed [2+2+2] cycloaddition is a powerful tool that allows rapid construction of functionalized 6-membered carbo- and heterocycles in a single step through an atom-economical process with high functional group tolerance. The reaction is usually regio- and chemoselective although selectivity issues can still be challenging for intermolecular reactions involving the cross-[2+2+2] cycloaddition of two or three different alkynes and various strategies have been developed to attain high selectivities. Furthermore, enantioselective [2+2+2] cycloaddition is an efficient means to create central, axial, and planar chirality and a variety of chiral organometallic complexes can be used for asymmetric transition-metal-catalyzed inter- and intramolecular reactions. This review summarizes the recent advances in the field of [2+2+2] cycloaddition.1 Introduction2 Formation of Carbocycles2.1 Intermolecular Reactions2.1.1 Cyclotrimerization of Alkynes2.1.2 [2+2+2] Cycloaddition of Two Different Alkynes2.1.3 [2+2+2] Cycloaddition of Alkynes/Alkenes with Alkenes/Enamides2.2 Partially Intramolecular [2+2+2] Cycloaddition Reactions2.2.1 Rhodium-Catalyzed [2+2+2] Cycloaddition2.2.2 Molybdenum-Catalyzed [2+2+2] Cycloaddition2.2.3 Cobalt-Catalyzed [2+2+2] Cycloaddition2.2.4 Ruthenium-Catalyzed [2+2+2] Cycloaddition2.2.5 Other Metal-Catalyzed [2+2+2] Cycloaddition2.3 Totally Intramolecular [2+2+2] Cycloaddition Reactions3 Formation of Heterocycles3.1 Cycloaddition of Alkynes with Nitriles3.2 Cycloaddition of 1,6-Diynes with Cyanamides3.3 Cycloaddition of 1,6-Diynes with Selenocyanates3.4 Cycloaddition of Imines with Allenes or Alkenes3.5 Cycloaddition of (Thio)Cyanates and Isocyanates3.6 Cycloaddition of 1,3,5-Triazines with Allenes3.7 Cycloaddition of Aldehydes with Enynes or Allenes/Alkenes3.8 Totally Intramolecular [2+2+2] Cycloaddition Reactions4 Conclusion

Steric Parameterization Delivers a Reciprocally Predictive Model for Substrate Reactivity and Catalyst Turnover in Rh-Catalyzed Diyne-Alkyne [2 + 2 + 2] Cycloadditions

“…As noted above, the current understanding is that this reaction is governed by electronics, with electron-deficient alkynes proposed to be more reactive than electron-rich alkynes. This model has clear outliers, with examples of unactivated alkynes shown to be successful in the literature, − and contrasts with the electronic requirements of the Rh­(III) intermediate.…”

“…Approximately five (productive) turnovers were observed for this substrate regardless of Rh loading. Literature processes using terminal or electronically activated alkynes operate effectively with 5 mol % Rh or lower; − however, alkyne 13 is not electronically activated, which either indicated a requirement for electronic activation or a significant steric contribution or a combination of both as the cause of the observed low product yield.…”

“…Transition-metal-catalyzed alkyne [2 + 2 + 2] cycloadditions are broadly used to yield densely functionalized benzenes. − Significant contributions have been made in the implementation of [2 + 2 + 2] cycloaddition using several metal catalysts including cobalt, iridium, rhodium, and ruthenium. − The reaction has three general categories: [2 + 2 + 2] cyclo­(homo)­trimerization of a single alkyne, intramolecular [2 + 2 + 2] of a triyne, and the semi-intermolecular [2 + 2 + 2] of a diyne and an alkyne (Scheme a). Completely intermolecular cycloadditions using three different alkynes are very difficult, due to issues with simultaneous control of both chemo- and regioselectivity; however, tethering methods have offered a specific solution to this problem. , The diyne-alkyne process offers the most modular approach and has therefore seen significant interest in methodological development.…”

“…Completely intermolecular cycloadditions using three different alkynes are very difficult, due to issues with simultaneous control of both chemo- and regioselectivity; however, tethering methods have offered a specific solution to this problem. , The diyne-alkyne process offers the most modular approach and has therefore seen significant interest in methodological development. The related [2 + 2 + 2] cycloadditions involving nitriles (to yield pyridines) and alkenes (to yield cyclohexadienes) expand this overall area and enable access to an increased diversity of scaffolds. , Overall this general reaction class has been extensively deployed within the synthetic strategy, including natural product and pharmaceutical synthesis, and polymerization. − …”

“…The most broadly used alkynes are either terminal or internal with electron-withdrawing groupspropiolate ester derivatives are very common. − Comparatively fewer examples exist of Rh-catalyzed diyne-alkyne cycloadditions using unactivated internal alkynes (i.e., those that do not use electron-deficient alkynes or highly activated diynes). − Based on this observed reactivity, electronic arguments dominate the current understanding of this reaction: an electronic-deficient alkyne is often accepted to be essential for reaction efficiency but with little mechanistic data to underpin this argument. − Indeed, two observations indicate that the present understanding might require refinement: (1) terminal alkynes without electron-withdrawing groups are highly effective in general; − (2) Rh­(III) species 3 is electrophilic; thus, a preference for an electron-deficient alkyne seems counterintuitive. − Based on this, ambiguity remains over the determinants for reactivity in this otherwise very well-studied reaction.…”