View source for Vinylcyclopropane (5+2) cycloaddition

{{Short description|Chemical reaction}}
'''Vinylcyclopropane (5+2) cycloaddition''' is a type of [[cycloaddition]] between a [[vinylcyclopropane]] (VCP) and an [[olefin]] or [[alkyne]] to form a seven-membered ring.
[[File:VCP 5+2 TOC.png|center|394x394px]]
Examples of thermal VCP (5+2) cycloaddition are relatively rare, but still feasible in certain cases.<ref name=":0" /> 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 Wender|Paul A. Wender]]'s research group,<ref name=":1">{{Cite journal|last1=Wender|first1=Paul A.|last2=Takahashi|first2=Hisashi|last3=Witulski|first3=Bernhard | name-list-style = vanc |date=1995|title=Transition Metal Catalyzed [5 + 2] Cycloadditions of Vinylcyclopropanes and Alkynes: A Homolog of the Diels-Alder Reaction for the Synthesis of Seven-Membered Rings|journal=Journal of the American Chemical Society|language=en|volume=117|issue=16|pages=4720–4721|doi=10.1021/ja00121a036|issn=0002-7863}}</ref> other reaction protocols have been developed with transition metal complexes of rhodium,<ref name=":2">{{cite journal | vauthors = Ylijoki KE, Stryker JM | title = [5 + 2] cycloaddition reactions in organic and natural product synthesis | journal = Chemical Reviews | volume = 113 | issue = 3 | pages = 2244–66 | date = March 2013 | pmid = 23153111 | doi = 10.1021/cr300087g }}</ref> ruthenium,<ref name=":2" /> iron,<ref>{{cite journal | vauthors = Fürstner A, Majima K, Martín R, Krause H, Kattnig E, Goddard R, Lehmann CW | title = A cheap metal for a "noble" task: preparative and mechanistic aspects of cycloisomerization and cycloaddition reactions catalyzed by low-valent iron complexes | journal = Journal of the American Chemical Society | volume = 130 | issue = 6 | pages = 1992–2004 | date = February 2008 | pmid = 18197669 | doi = 10.1021/ja0777180 | hdl = 11858/00-001M-0000-0024-C2BF-2 | hdl-access = free }}</ref> nickel,<ref>{{cite journal | vauthors = Zuo G, Louie J | title = Selectivity in nickel-catalyzed rearrangements of cyclopropylen-ynes | journal = Journal of the American Chemical Society | volume = 127 | issue = 16 | pages = 5798–9 | date = April 2005 | pmid = 15839672 | doi = 10.1021/ja043253r }}</ref> iridium<ref>{{cite journal | vauthors = Melcher MC, von Wachenfeldt H, Sundin A, Strand D | title = Iridium catalyzed carbocyclizations: efficient (5+2) cycloadditions of vinylcyclopropanes and alkynes | journal = Chemistry: A European Journal | volume = 21 | issue = 2 | pages = 531–5 | date = January 2015 | pmid = 25413863 | doi = 10.1002/chem.201405729 }}</ref> and other metals.
== Mechanism ==
=== Thermal reactions ===
Vinylcyclopropanes can undergo formal (5+2) cycloadditions with highly activated [[dienophile]]s such as tetracyanoethylene (TCNE).<ref name=":0">{{Cite journal|last1=Sarel|first1=Shalorn|last2=Felzenstein|first2=Abraham|last3=Yovell|first3=Joseph| name-list-style = vanc |date=1973|title=Alternative modes of addition of dienophiles to vinylcyclopropane systems|url=http://xlink.rsc.org/?DOI=c39730000859|journal=Journal of the Chemical Society, Chemical Communications|language=en|issue=22|pages=859–860|doi=10.1039/c39730000859|issn=0022-4936}}</ref> The proposed reaction mechanism involves an initial [[2+2 Cycloaddition|[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.<ref>{{Cite journal|last1=Felzenstein|first1=Avraham|last2=Sarel|first2=Shalom|last3=Yovell|first3=Joseph| name-list-style = vanc |date=1975|title=Uncatalysed olefin metathesis reaction|url=http://xlink.rsc.org/?DOI=c39750000918|journal=Journal of the Chemical Society, Chemical Communications|language=en|issue=22|pages=918–919|doi=10.1039/c39750000918|issn=0022-4936}}</ref>
[[File:1._Thermal_TCNE_5+2.png|alt=|center|451x451px]]
Facile (5+2) cycloaddition is also observed when the vinylcyclopropane moiety is part of a strained heterobicyclic system. A [[zwitterion]]ic intermediate is proposed for this reaction.<ref>{{Cite journal|last1=Herges|first1=Rainer|last2=Ugi|first2=Ivar| name-list-style = vanc |date=1985|title=Synthesis of Seven-Membered Rings by [(?2+?2)+?2] Cycloaddition to Homodienes|journal=Angewandte Chemie International Edition in English|language=en|volume=24|issue=7|pages=594–596|doi=10.1002/anie.198505941|issn=0570-0833}}</ref>
[[File:Bicyclic thermal 5+2.png|center|374x374px]]
=== Metal-Catalyzed reactions===
==== Rhodium-catalyzed reactions ====
In his initial disclosure, Paul Wender proposed a [[cyclometalation]] mechanism for Rh-catalyzed VCP (5+2) cycloaddition,<ref name=":1" /> 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.<ref>{{cite journal | vauthors = Yu ZX, Wender PA, Houk KN | title = On the mechanism of [Rh(CO)2Cl]2-catalyzed intermolecular (5 + 2) reactions between vinylcyclopropanes and alkynes | journal = Journal of the American Chemical Society | volume = 126 | issue = 30 | pages = 9154–5 | date = August 2004 | pmid = 15281784 | doi = 10.1021/ja048739m }}</ref><ref>{{cite journal | vauthors = Yu ZX, Cheong PH, Liu P, Legault CY, Wender PA, Houk KN | title = Origins of differences in reactivities of alkenes, alkynes, and allenes in [Rh(CO)2Cl]2-catalyzed (5 + 2) cycloaddition reactions with vinylcyclopropanes | journal = Journal of the American Chemical Society | volume = 130 | issue = 8 | pages = 2378–9 | date = February 2008 | pmid = 18251468 | doi = 10.1021/ja076444d }}</ref><ref>{{cite journal | vauthors = Liu P, Cheong PH, Yu ZX, Wender PA, Houk KN | title = Substituent effects, reactant preorganization, and ligand exchange control the reactivity in Rh(I)-catalyzed (5+2) cycloadditions between vinylcyclopropanes and alkynes | journal = Angewandte Chemie | volume = 47 | issue = 21 | pages = 3939–41 | date = 2008-05-13 | pmid = 18412215 | doi = 10.1002/anie.200800420 | doi-access = free }}</ref> The Rh-VCP complex first undergoes a C-C bond activation event to form a rhodium [[Allyl complex|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.
[[File:Rh cycle.png|center|772x772px]]
==== Ruthenium-catalyzed reactions ====
[[Barry Trost|Barry M. Trost]] and co-workers proposed a mechanism for Ru-catalyzed VCP (5+2) cycloaddition that is slightly different from its rhodium counterpart.<ref>{{Cite journal|last1=Trost|first1=Barry M.|last2=Toste|first2=F. Dean|last3=Shen|first3=Hong| name-list-style = vanc |date=2000|title=Ruthenium-Catalyzed Intramolecular [5 + 2] Cycloadditions|journal=Journal of the American Chemical Society|language=en|volume=122|issue=10|pages=2379–2380|doi=10.1021/ja993400z|issn=0002-7863}}</ref> [[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 [[Allyl complex|π-allyl complexes]], and reductive elimination afford the final product.
[[File:Ru VCP cycle.png|center|658x658px]]
== Reaction scope ==
Intramolecular (5+2) cycloaddition of VCP with a tethered alkyne,<ref name=":1" /> alkene,<ref>{{Cite journal|last1=Wender|first1=Paul A.|last2=Husfeld|first2=Craig O.|last3=Langkopf|first3=Elke|last4=Love|first4=Jennifer A.| name-list-style = vanc |date=1998|title=First Studies of the Transition Metal-Catalyzed [5+2] Cycloadditions of Alkenes and Vinylcyclopropanes: Scope and Stereochemistry|journal=Journal of the American Chemical Society|language=en|volume=120|issue=8|pages=1940–1941|doi=10.1021/ja973650k|issn=0002-7863}}</ref> or allene<ref>{{Cite journal|last1=Wender|first1=Paul A.|last2=Glorius|first2=Frank|last3=Husfeld|first3=Craig O.|last4=Langkopf|first4=Elke|last5=Love|first5=Jennifer A.| name-list-style = vanc |date=1999|title=Transition Metal-Catalyzed [5 + 2] Cycloadditions of Allenes and Vinylcyclopropanes: First Studies of Endo−Exo Selectivity, Chemoselectivity, Relative Stereochemistry, and Chirality Transfer|journal=Journal of the American Chemical Society|language=en|volume=121|issue=22|pages=5348–5349|doi=10.1021/ja9903072|issn=0002-7863}}</ref> have been reported.
[[File:5+2 Reaction scope.png|center|386x386px]]
Examples of intermolecular VCP cycloaddition with alkynes were also reported. However, a heteroatom substituent (e.g. a siloxy group)<ref>{{Cite journal|last1=Wender|first1=Paul A.|last2=Rieck|first2=Heiko|last3=Fuji|first3=Masahiro| name-list-style = vanc |date=1998|title=The Transition Metal-Catalyzed Intermolecular [5+2] Cycloaddition: The Homologous Diels−Alder Reaction|journal=Journal of the American Chemical Society|language=en|volume=120|issue=42|pages=10976–10977|doi=10.1021/ja982196x|issn=0002-7863}}</ref> or a sterically bulky group<ref>{{Cite journal|last1=Wender|first1=Paul A.|last2=Barzilay|first2=Claudia M.|last3=Dyckman|first3=Alaric J.| name-list-style = vanc |date=2001|title=The First Intermolecular Transition Metal-Catalyzed [5+2] Cycloadditions with Simple, Unactivated, Vinylcyclopropanes|journal=Journal of the American Chemical Society|language=en|volume=123|issue=1|pages=179–180|doi=10.1021/ja0021159|pmid=11273617|issn=0002-7863}}</ref> on the vinylcyclopropane is usually required.
[[File:Intermolecular reaction scope.png|center|450x450px]]
== 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]].<ref>{{cite journal | vauthors = Wender PA, Haustedt LO, Lim J, Love JA, Williams TJ, Yoon JY | title = Asymmetric catalysis of the [5 + 2] cycloaddition reaction of vinylcyclopropanes and pi-systems | journal = Journal of the American Chemical Society | volume = 128 | issue = 19 | pages = 6302–3 | date = May 2006 | pmid = 16683779 | doi = 10.1021/ja058590u | s2cid = 197039161 }}</ref>
[[File:Asymmetric 5+2.png|center|398x398px]]
=== Bridged (5+2) cycloaddition ===
Yu and co-workers reported a unique variant of the reaction that preferentially forms bridged bicyclic compounds.<ref>{{cite journal | vauthors = Liu CH, Yu ZX | title = Rhodium(I)-Catalyzed Bridged [5+2] Cycloaddition of cis-Allene-vinylcyclopropanes to Synthesize the Bicyclo[4.3.1]decane Skeleton | journal = Angewandte Chemie | volume = 56 | issue = 30 | pages = 8667–8671 | date = July 2017 | pmid = 28643412 | doi = 10.1002/anie.201702288 }}</ref>
[[File:Bridged VCP 5+2.png|center|352x352px]]
=== 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 reaction|Tsuji-Trost allylic substitution]] chemistry.<ref>{{cite journal | vauthors = Ashfeld BL, Miller KA, Smith AJ, Tran K, Martin SF | title = [Rh(CO)2Cl]2-catalyzed domino reactions involving allylic substitution and subsequent carbocyclization reactions | journal = Organic Letters | volume = 7 | issue = 8 | pages = 1661–3 | date = April 2005 | pmid = 15816777 | doi = 10.1021/ol0504300 }}</ref><ref>{{cite journal | vauthors = Ashfeld BL, Miller KA, Smith AJ, Tran K, Martin SF | title = Features and applications of [Rh(CO)(2)Cl](2)-catalyzed alkylations of unsymmetrical allylic substrates | journal = The Journal of Organic Chemistry | volume = 72 | issue = 24 | pages = 9018–31 | date = November 2007 | pmid = 17973524 | doi = 10.1021/jo701290b | s2cid = 22154209 }}</ref>
[[File:Tandem allylation 5+2.png|center|720x720px]]
== 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,<ref>{{Cite journal|last1=Wender|first1=Paul A.|last2=Fuji|first2=Masahiro|last3=Husfeld|first3=Craig O.|last4=Love|first4=Jennifer A.| name-list-style = vanc |date=1999|title=Rhodium-Catalyzed [5 + 2] Cycloadditions of Allenes and Vinylcyclopropanes: Asymmetric Total Synthesis of (+)-Dictamnol|journal=Organic Letters|language=en|volume=1|issue=1|pages=137–140|doi=10.1021/ol990599b|issn=1523-7060}}</ref> (+)-aphanamol I,<ref>{{Cite journal|last1=Wender|first1=Paul A.|last2=Zhang|first2=Lei| name-list-style = vanc |date=2000|title=Asymmetric Total Synthesis of (+)-Aphanamol I Based on the Transition Metal Catalyzed [5 + 2] Cycloaddition of Allenes and Vinylcyclopropanes|journal=Organic Letters|language=en|volume=2|issue=15|pages=2323–2326|doi=10.1021/ol006085q|pmid=10930274|issn=1523-7060}}</ref> (+)-allocyathin B<sub>2</sub><ref>{{Cite journal|last1=Wender|first1=Paul A.|last2=Bi|first2=F. Christopher|last3=Brodney|first3=Michael A.|last4=Gosselin|first4=Francis| name-list-style = vanc |date=2001|title=Asymmetric Synthesis of the Tricyclic Core of NGF-Inducing Cyathane Diterpenes via a Transition-Metal-Catalyzed [5 + 2] Cycloaddition|journal=Organic Letters|language=en|volume=3|issue=13|pages=2105–2108|doi=10.1021/ol0160699|pmid=11418060|issn=1523-7060}}</ref> (–)-pseudolaric acid B,<ref>{{cite journal | vauthors = Trost BM, Waser J, Meyer A | title = Total synthesis of (-)-pseudolaric acid B | journal = Journal of the American Chemical Society | volume = 129 | issue = 47 | pages = 14556–7 | date = November 2007 | pmid = 17985906 | pmc = 2535803 | doi = 10.1021/ja076165q }}</ref><ref>{{cite journal | vauthors = Trost BM, Waser J, Meyer A | title = Total synthesis of (-)-pseudolaric acid B | journal = Journal of the American Chemical Society | volume = 130 | issue = 48 | pages = 16424–34 | date = December 2008 | pmid = 18998641 | pmc = 2698933 | doi = 10.1021/ja806724x }}</ref> and (+)-frondosin A.<ref>{{cite journal | vauthors = Trost BM, Hu Y, Horne DB | title = Total synthesis of (+)-frondosin A. Application of the Ru-catalyzed [5+2] cycloaddition | journal = Journal of the American Chemical Society | volume = 129 | issue = 38 | pages = 11781–90 | date = September 2007 | pmid = 17760442 | doi = 10.1021/ja073272b }}</ref>
[[File:VCP 5+2 Total Synthesis Application.png|center|742x742px]]
== See also ==
* [[Cycloaddition]]
*[[Cyclopropane]]
* [[Vinylcyclopropane rearrangement]]
== References ==
{{Reflist}}
[[Category:Cycloadditions]]