Examples of thermal VCP [5+2] cycloaddition are relatively rare, but still feasible in certain cases.[1] However, vinylcyclopropanes readily undergo formal [5+2] processes catalyzed by transition metal complexes. Since the initial report of a
rhodium-catalyzed VCP [5+2] cycloaddition from
Paul A. Wender's research group,[2] other reaction protocols have been developed with transition metal complexes of rhodium,[3] ruthenium,[3] iron,[4] nickel,[5] iridium[6] and other metals.
Mechanism
Thermal reactions
Vinylcyclopropanes can undergo formal [5+2] cycloadditions with highly activated
dienophiles such as tetracyanoethylene (TCNE).[1] The proposed reaction mechanism involves an initial
[2+2] cycloaddition between the vinylcyclopropane and TCNE, followed by rearrangement to furnish the seven-membered ring in the product. Evidences have shown that depending on the reaction conditions, the rearrangement step can occur via either radical or ionic intermediates.[7]
Facile [5+2] cycloaddition is also observed when the vinylcyclopropane moiety is part of a strained heterobicyclic system. A
zwitterionic intermediate is proposed for this reaction.[8]
Metal-Catalyzed reactions
Rhodium-catalyzed reactions
In his initial disclosure, Paul Wender proposed a
cyclometalation mechanism for Rh-catalyzed VCP [5+2] cycloaddition,[2] which is similar to Trost's mechanistic proposal for Ru-catalyzed reactions (see next section). However, DFT calculation studies by
Kendall Houk and co-workers suggested a different mode of action in intermolecular cases.[9][10][11] The Rh-VCP complex first undergoes a C-C bond activation event to form a rhodium
π-allyl complex, a process that can be best visualized as the conceptual equivalent of
cyclometalation with a diene. Subsequent alkyne coordination followed by 1,2-
migratory insertion and
reductive elimination affords the heptadiene product.
Ruthenium-catalyzed reactions
Barry M. Trost and co-workers proposed a mechanism for Ru-catalyzed VCP [5+2] cycloaddition that is slightly different from its rhodium counterpart.[12]Cyclometalation of the ruthenium complex with the
enyne takes place first to form a ruthenacyclopentene intermediate with a pendant cyclopropane ring. Subsequent C-C bond activation, which can be viewed as conceptually analogous to
tautomerization of metal
π-allyl complexes, and reductive elimination afford the final product.
Reaction scope
Intramolecular [5+2] cycloaddition of VCP with a tethered alkyne,[2] alkene,[13] or allene[14] have been reported.
Examples of intermolecular VCP cycloaddition with alkynes were also reported. However, a heteroatom substituent (e.g. a siloxy group)[15] or a sterically bulky group[16] on the vinylcyclopropane is usually required.
Other variants
Asymmetric [5+2] cycloaddition
An enantioselective version of the reaction was reported by Wender et al in 2005, featuring a Rh-BINAP catalyst that induces up to >99%
enantiomeric excess.[17]
Bridged [5+2] cycloaddition
Yu and co-workers reported a unique variant of the reaction that preferentially forms bridged bicyclic compounds.[18]
Tandem allylic alkylation/[5+2] cycloaddition
Martin and co-workers developed an allylic alkylation/[5+2] cycloaddition sequence that forms the enyne precursor in situ with
Tsuji-Trost allylic substitution chemistry.[19][20]
Applications in total syntheses
Metal-catalyzed VCP [5+2] cycloaddition has found applications in the total syntheses of a variety of molecules such as (+)-dictamnol,[21] (+)-aphanamol I,[22] (+)-allocyathin B2[23] (–)-pseudolaric acid B,[24][25] and (+)-frondosin A.[26]
^
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abYlijoki KE, Stryker JM (March 2013). "[5 + 2] cycloaddition reactions in organic and natural product synthesis". Chemical Reviews. 113 (3): 2244–66.
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^Fürstner A, Majima K, Martín R, Krause H, Kattnig E, Goddard R, Lehmann CW (February 2008). "A cheap metal for a "noble" task: preparative and mechanistic aspects of cycloisomerization and cycloaddition reactions catalyzed by low-valent iron complexes". Journal of the American Chemical Society. 130 (6): 1992–2004.
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^Zuo G, Louie J (April 2005). "Selectivity in nickel-catalyzed rearrangements of cyclopropylen-ynes". Journal of the American Chemical Society. 127 (16): 5798–9.
doi:
10.1021/ja043253r.
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^Melcher MC, von Wachenfeldt H, Sundin A, Strand D (January 2015). "Iridium catalyzed carbocyclizations: efficient (5+2) cycloadditions of vinylcyclopropanes and alkynes". Chemistry: A European Journal. 21 (2): 531–5.
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^Herges R, Ugi I (1985). "Synthesis of Seven-Membered Rings by [(?2+?2)+?2] Cycloaddition to Homodienes". Angewandte Chemie International Edition in English. 24 (7): 594–596.
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^Yu ZX, Wender PA, Houk KN (August 2004). "On the mechanism of [Rh(CO)2Cl]2-catalyzed intermolecular (5 + 2) reactions between vinylcyclopropanes and alkynes". Journal of the American Chemical Society. 126 (30): 9154–5.
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^Yu ZX, Cheong PH, Liu P, Legault CY, Wender PA, Houk KN (February 2008). "Origins of differences in reactivities of alkenes, alkynes, and allenes in [Rh(CO)2Cl]2-catalyzed (5 + 2) cycloaddition reactions with vinylcyclopropanes". Journal of the American Chemical Society. 130 (8): 2378–9.
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^Wender PA, Husfeld CO, Langkopf E, Love JA (1998). "First Studies of the Transition Metal-Catalyzed [5+2] Cycloadditions of Alkenes and Vinylcyclopropanes: Scope and Stereochemistry". Journal of the American Chemical Society. 120 (8): 1940–1941.
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^Wender PA, Glorius F, Husfeld CO, Langkopf E, Love JA (1999). "Transition Metal-Catalyzed [5 + 2] Cycloadditions of Allenes and Vinylcyclopropanes: First Studies of Endo−Exo Selectivity, Chemoselectivity, Relative Stereochemistry, and Chirality Transfer". Journal of the American Chemical Society. 121 (22): 5348–5349.
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^Wender PA, Rieck H, Fuji M (1998). "The Transition Metal-Catalyzed Intermolecular [5+2] Cycloaddition: The Homologous Diels−Alder Reaction". Journal of the American Chemical Society. 120 (42): 10976–10977.
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^Wender PA, Barzilay CM, Dyckman AJ (2001). "The First Intermolecular Transition Metal-Catalyzed [5+2] Cycloadditions with Simple, Unactivated, Vinylcyclopropanes". Journal of the American Chemical Society. 123 (1): 179–180.
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^Wender PA, Haustedt LO, Lim J, Love JA, Williams TJ, Yoon JY (May 2006). "Asymmetric catalysis of the [5 + 2] cycloaddition reaction of vinylcyclopropanes and pi-systems". Journal of the American Chemical Society. 128 (19): 6302–3.
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^Liu CH, Yu ZX (July 2017). "Rhodium(I)-Catalyzed Bridged [5+2] Cycloaddition of cis-Allene-vinylcyclopropanes to Synthesize the Bicyclo[4.3.1]decane Skeleton". Angewandte Chemie. 56 (30): 8667–8671.
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^Ashfeld BL, Miller KA, Smith AJ, Tran K, Martin SF (April 2005). "[Rh(CO)2Cl]2-catalyzed domino reactions involving allylic substitution and subsequent carbocyclization reactions". Organic Letters. 7 (8): 1661–3.
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^Wender PA, Zhang L (2000). "Asymmetric Total Synthesis of (+)-Aphanamol I Based on the Transition Metal Catalyzed [5 + 2] Cycloaddition of Allenes and Vinylcyclopropanes". Organic Letters. 2 (15): 2323–2326.
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^Trost BM, Hu Y, Horne DB (September 2007). "Total synthesis of (+)-frondosin A. Application of the Ru-catalyzed [5+2] cycloaddition". Journal of the American Chemical Society. 129 (38): 11781–90.
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