View source for Chemistry:Nazarov cyclization reaction

{{Short description|Chemical reaction used in organic chemistry}}
{{Reactionbox
|Name = Nazarov cyclization
|Type = Ring forming reaction
|NamedAfter = Ivan Nikolaevich Nazarov
|Section3 = {{Reactionbox Identifiers
| OrganicChemistryNamed = nazarov-cyclization
| RSC_ontology_id = 0000209
}}
}}
The '''Nazarov cyclization reaction''' (often referred to as simply the '''Nazarov cyclization''') is a [[Chemistry:Chemical reaction|chemical reaction]] used in [[Chemistry:Organic chemistry|organic chemistry]] for the synthesis of [[Chemistry:Cyclopentenone|cyclopentenone]]s. The reaction is typically divided into ''classical'' and ''modern'' variants, depending on the [[Biology:Reagent|reagent]]s and [[Chemistry:Substrate|substrate]]s employed. It was originally discovered by Ivan Nikolaevich Nazarov (1906–1957) in 1941 while studying the rearrangements of allyl vinyl ketones.<ref name=Nazarov>{{citation|author1=Nazarov, I.N. |author2=Zaretskaya, I.I. |journal= Izv. Akad. Nauk. SSSR, Ser. Khim|year= 1941|pages=211–224}}</ref>

[[File:Nazarov cyclization.png|center|320px|The Nazarov cyclization reaction]]

As originally described, the Nazarov cyclization involves the activation of a [[Chemistry:Enone|divinyl ketone]] using a stoichiometric [[Chemistry:Lewis acid|Lewis acid]] or protic acid promoter. The key step of the reaction mechanism involves a cationic 4π-[[Chemistry:Electrocyclic reaction|electrocyclic ring closure]] which forms the cyclopentenone product (See [[Chemistry:Nazarov cyclization reaction#Mechanism|Mechanism]] below). As the reaction has been developed, variants involving substrates other than divinyl ketones and promoters other than Lewis acids have been subsumed under the name Nazarov cyclization provided that they follow a similar [[Physics:Reaction mechanism|mechanistic pathway]].

The success of the Nazarov cyclization as a tool in organic synthesis stems from the utility and ubiquity of [[Chemistry:Cyclopentenone|cyclopentenone]]s as both motifs in [[Chemistry:Natural product|natural product]]s (including [[Chemistry:Jasmone|jasmone]], the [[Chemistry:Aflatoxin|aflatoxin]]s, and a subclass of prostaglandins) and as useful synthetic intermediates for [[Chemistry:Total synthesis|total synthesis]]. The reaction has been used in several total syntheses and several reviews have been published.<ref name="Frontier">{{citation|author1=Frontier, A. J. |author2=Collison, C. |title=The Nazarov cyclization in organic synthesis. Recent advances.|journal=Tetrahedron|year=2005|volume=61|issue=32 |pages=7577–7606|doi= 10.1016/j.tet.2005.05.019}}</ref><ref name="Santelli">{{citation|author1=Santelli-Rouvier, C. |author2=Santelli, M. |title=The Nazarov Cyclization|journal=Synthesis|year=1983|volume=1983|issue=6 |pages=429–442|doi=10.1055/s-1983-30367}}</ref><ref name="OrgReact">{{citation|title=The Nazarov Cyclization|author1=Denmark, S.E. |author2=Habermas, K.L. |author3=Jones, T. K. | journal= [[Chemistry:Organic Reactions|Organic Reactions]]|year= 1994|volume= 45|pages= 1–158}}</ref><ref name="CompSynth">{{citation|title=The Nazarov and Related Cationic Cyclizations|author=Denmark, S.E.|journal=Comprehensive Organic Synthesis|volume= 5|editor= Paquette, L.A.|publisher= Pergamon Press|location=Oxford|year=1991|pages=751–784|doi=10.1016/b978-0-08-052349-1.00138-4|isbn=9780080523491}}</ref><ref name="Tius">{{citation|author=Tius, M. A.|title=Some New Nazarov Chemistry|journal=Eur. J. Org. Chem.|year=2005|issue=11|doi=10.1002/ejoc.200500005|volume=2005|pages=2193–2206}}</ref><ref name="Pellissier">{{citation|title=Recent developments in the Nazarov process|author=Pellissier, Hélène|journal=Tetrahedron|volume=61|issue=27|pages=6479–6517|doi=10.1016/j.tet.2005.04.014|year=2005}}</ref>

==Mechanism==
The mechanism of the classical Nazarov cyclization reaction was first demonstrated experimentally by [[Biography:Charles Shoppee|Charles Shoppee]] to be an [[Chemistry:Intramolecular reaction|intramolecular]] [[Chemistry:Electrocyclic reaction|electrocyclization]] and is outlined below. Activation of the [[Chemistry:Ketone|ketone]] by the acid catalyst generates a [[Chemistry:Pentadienyl|pentadienyl]] cation, which undergoes a thermally allowed 4π [[Chemistry:Conrotatory and disrotatory|conrotatory]] electrocyclization as dictated by the Woodward-Hoffman rules. This generates an '''oxyallyl cation''' which undergoes an [[Chemistry:Elimination reaction|elimination reaction]] to lose a β-hydrogen. Subsequent tautomerization of the [[Chemistry:Enolate|enolate]] produces the cyclopentenone product.<ref name="Mech1">{{citation|title=Intramolecular electrocyclic reactions. Part I. Structure of 'bromohydroxyphorone': 3-bromo-5-hydroxy-4,4,5,5-tetramethylcyclopent-2-enone|author1=Shoppee, C. W. |author2=Lack, R. E. |journal=Journal of the Chemical Society C: Organic|issue=10 |year=1969|pages=1346–1349|doi=10.1039/J39690001346 }}</ref><ref name="Mech2">{{citation|title=Intramolecular electrocyclic reactions. Part II. Reactions of 1,5-di-phenylpenta-1,4-dien-3-one|author1=Shoppee, C. W. |author1-link= Charles Shoppee |author2= Cooke, B. J. A. |journal=Journal of the Chemical Society, Perkin Transactions 1|year=1972|pages=2271|doi=10.1039/p19720002271 }}</ref>

[[File:Nazarov reaction mechanism.png|thumb|center|650px|Mechanism of the classical Nazarov cyclization activated by Lewis acid catalyst. Note that α- and β-substitution are not required for the reaction to occur and that more complex α-substitution is also possible.]]

As noted above, variants that deviate from this template are known; what designates a Nazarov cyclization in particular is the generation of the pentadienyl cation followed by electrocyclic ring closure to an oxyallyl cation. In order to achieve this transformation, the molecule must be in the s-trans/s-trans conformation, placing the [[Chemistry:Alkene|vinyl]] groups in an appropriate orientation. The propensity of the system to enter this conformation dramatically influences [[Physics:Reaction rate|reaction rate]], with α-substituted substrates having an increased population of the requisite conformer due to [[Chemistry:Allylic strain|allylic strain]]. Coordination of an electron donating α-substituent by the catalyst can likewise increase the reaction rate by enforcing this conformation.<ref name="Frontier"/>

[[File:Nazarov conformation.png|thumb|center|570px|Relevant conformations for the Nazarov cyclization; Lewis-acid chelation in the s-cis conformer]]

Similarly, β-substitution directed inward restricts the s-trans conformation so severely that E-Z [[Chemistry:Isomerization|isomerization]] has been shown to occur in advance of cyclization on a wide range of substrates, yielding the trans cyclopentenone regardless of initial configuration. In this way, the Nazarov cyclization is a rare example of a stereoselective [[Chemistry:Pericyclic reaction|pericyclic reaction]], whereas most electrocyclizations are stereospecific. The example below uses [[Chemistry:Triethylsilane|triethylsilane]] to trap the oxyallyl cation so that no elimination occurs.<ref name="Frontier"/> (See [[Chemistry:Nazarov cyclization reaction#Interrupted cyclization|Interrupted cyclizations]] below)

[[File:Nazarovselective.png|thumb|center|450px|Stereoselectivity in the Nazarov cyclization evident via reductive trapping]]

Along this same vein, allenyl vinyl ketones of the type studied extensively by Marcus Tius of the [[Organization:University of Hawaii|University of Hawaii]] show dramatic rate acceleration due to the removal of β-hydrogens, obviating a large amount of steric strain in the s-cis conformer.<ref name="Tius"/>

[[File:Tiusallene.png|thumb|center|250px|Allene substrates for Nazarov cyclization with lowered steric interactions]]

==Classical Nazarov cyclizations==
Though cyclizations following the general template above had been observed prior to Nazarov's involvement, it was his study of the rearrangements of allyl vinyl [[Chemistry:Ketone|ketone]]s that marked the first major examination of this process. Nazarov correctly reasoned that the allylic olefin isomerized ''[[Biology:In situ#Chemistry and chemical engineering|in situ]]'' to form a divinyl ketone before ring closure to the cyclopentenone product. The reaction shown below involves an [[Chemistry:Alkyne|alkyne]] [[Chemistry:Oxymercuration reaction|oxymercuration reaction]] to generate the requisite ketone.<ref name="Strategy">{{Cite book |author1=Kürti, L. |author2=Czakó, B. |title=Strategic Applications of Named Reactions in Organic Synthesis|edition=1|publisher=Elsevier Academic Press|year=2005|location=Burlington, MA|pages=304–305|url=https://books.google.com/books?id=mjpJmiZ9OZ8C&pg=PA304|isbn=9780124297852 }}</ref>

[[File:NazarovOriginal.png|thumb|center|500px|Early investigation into the Nazarov cyclization]]

Research involving the reaction was relatively quiet in subsequent years, until in the mid-1980s when several syntheses employing the Nazarov cyclization were published. Shown below are key steps in the syntheses of Trichodiene and Nor-Sterepolide, the latter of which is thought to proceed via an unusual [[Chemistry:Alkyne|alkyne]]-allene isomerization that generates the divinyl ketone.<ref name="Trichodiene">{{citation|title=A Highly Stereoselective, Convergent Synthesis of (±)-Trichodiene|author1=Harding, K. E. |author2=Clement, K. S. |journal=The Journal of Organic Chemistry|year=1984|volume=49|issue=20 |pages=3870–3871|doi=10.1021/jo00194a054}}</ref><ref name="NorSterepolide">{{citation|title=Synthesis of(±)-Nor-Sterepolide|author1=Arai, Y. |author2=Takeda, K. |author3=Masuda, K. |author4=Koizumi, T. |journal=[[Chemistry:Chemistry Letters|Chemistry Letters]]|volume=14|issue=10|year=1985|pages=1531–1534|doi=10.1246/cl.1985.1531}}</ref>

[[File:NazarovTrichodiene.png|thumb|center|500px|Synthesis of Trichodiene using a classical Nazarov cyclization]]
[[File:Nazarovnorsterepolide.png|thumb|center|600px|Synthesis of Nor-Sterepolide using a classical Nazarov cyclization]]

===Shortcomings===
The classical version of the Nazarov cyclization suffers from several drawbacks which modern variants attempt to circumvent. The first two are not evident from the mechanism alone, but are indicative of the barriers to cyclization; the last three stem from selectivity issues relating to elimination and protonation of the intermediate.<ref name="Frontier"/>
# Strong Lewis or protic acids are typically required for the reaction (e.g. [[Chemistry:Titanium tetrachloride|TiCl<sub>4</sub>]], BF<sub>3</sub>, [[Chemistry:Methanesulfonic acid|MeSO<sub>3</sub>H]]). These promoters are not compatible with sensitive functional groups, limiting the substrate scope.
# Despite the mechanistic possibility for [[Chemistry:Catalysis|catalysis]], multiple [[Chemistry:Equivalent|equivalent]]s of the promoter are often required in order to effect the reaction. This limits the [[Chemistry:Atom economy|atom economy]] of the reaction.
# The elimination step is not regioselective; if multiple β-hydrogens are available for elimination, various products are often observed as mixtures. This is highly undesirable from an efficiency standpoint as arduous [[Chemistry:Separation process|separation]] is typically required.
# Elimination destroys a potential [[Chemistry:Stereocenter|stereocenter]], decreasing the potential usefulness of the reaction.
# Protonation of the enolate is sometimes not stereoselective, meaning that products can be formed as mixtures of [[Chemistry:Epimer|epimer]]s.

[[File:Nazarovunselective.png|thumb|center|600px|Shortcomings of the Nazarov cyclization reaction]]

==Modern variants==
The shortcomings noted above limit the usefulness of the Nazarov cyclization reaction in its canonical form. However, modifications to the reaction focused on remedying its issues continue to be an active area of academic research. In particular, the research has focused on a few key areas: rendering the reaction catalytic in the promoter, effecting the reaction with more mild promoters to improve [[Chemistry:Functional group|functional group]] tolerance, directing the [[Chemistry:Regioselectivity|regioselectivity]] of the elimination step, and improving the overall [[Chemistry:Stereoselectivity|stereoselectivity]]. These have been successful to varying degrees.

Additionally, modifications focused on altering the progress of the reaction, either by generating the pentadienyl cation in an unorthodox fashion or by having the oxyallyl cation "intercepted" in various ways. Furthermore, enantioselective variants of various kinds have been developed. The sheer volume of literature on the subject prevents a comprehensive examination of this field; key examples are given below.

===Silicon-directed cyclization===
The earliest efforts to improve the selectivity of the Nazarov cyclization took advantage of the β-silicon effect in order to direct the regioselectivity of the elimination step. This chemistry was developed most extensively by Professor Scott Denmark of the University of Illinois, Urbana-Champaign in the mid-1980s and utilizes stoichiometric amounts of iron trichloride to promote the reaction. With [[Physics:Bicyclic molecule|bicyclic]] products, the cis isomer was selected for to varying degrees.<ref name="Silicon">{{citation|author1=Denmark, S.E. |author2=Jones, T.K. |title=Silicon-Directed Nazarov Cyclization|journal=J. Am. Chem. Soc.|year=1982|volume=104|issue=9 |pages=2642–2645|doi=10.1021/ja00373a055}}</ref>

[[File:Siliconnazarov.png|thumb|center|500px|Silicon-directed Nazarov cyclization]]

The silicon-directed Nazarov cyclization reaction was subsequently employed in the synthesis of the natural product Silphinene, shown below. The cyclization takes place before elimination of the [[Chemistry:Benzyl alcohol|benzyl alcohol]] moiety, so that the resulting [[Chemistry:Stereochemistry|stereochemistry]] of the newly formed ring arises from approach of the silyl alkene ''anti'' to the ether.<ref name="Strategy"/>

[[File:Silphinenenazarov.png|thumb|center|550px|Synthesis of Silphinene using Nazarov cyclization]]

===Polarization===
Drawing on the substituent effects compiled over various trials of the reaction, Professor Alison Frontier of the [[Organization:University of Rochester|University of Rochester]] developed a paradigm for "polarized" Nazarov cyclizations in which [[Chemistry:Polar effect|electron donating]] and electron withdrawing groups are used to improve the overall selectivity of the reaction. Creation of an effective [[Chemistry:Vinyl group|vinyl]] [[Chemistry:Nucleophile|nucleophile]] and vinyl [[Chemistry:Electrophile|electrophile]] in the substrate allows catalytic activation with copper triflate and regioselective elimination. In addition,  the electron withdrawing group increases the acidity of the α-proton, allowing selective formation of the trans-α-epimer via equilibration.<ref name="polarize">{{citation|title=Polarizing the Nazarov Cyclization: Efficient Catalysis under Mild Conditions|author1=He, W. |author2=Sun, X. |author3=Frontier, A.J. |journal=J. Am. Chem. Soc.|year=2003|volume=125|issue=47|pages=14278–14279|doi=10.1021/ja037910b|pmid=14624567 }}</ref>

[[File:Polarized Nazarov.png|thumb|center|600px|Polarized Nazarov cyclization]]

It is often possible to achieve catalytic activation using a donating or withdrawing group alone, although the efficiency of the reaction (yield, reaction time, etc.) is typically lower.

===Alternative cation generation===
By extension, any pentadienyl cation regardless of its origin is capable of undergoing a Nazarov cyclization. There have been a large number of examples published where the requisite cation is arrived at by a variety of rearrangements.<ref name="Frontier"/> One such example involves the silver catalyzed cationic ring opening of allylic dichloro cylopropanes. The silver salt facilitates loss of chloride via precipitation of insoluble [[Chemistry:Silver chloride|silver chloride]].<ref name="West1">{{citation|title=A New Approach to the Nazarov Reaction via Sequential Electrocyclic Ring Opening and Ring Closure|author1=Grant, T.N.  |author2=West, F.G. |name-list-style=amp |journal= J. Am. Chem. Soc.|year=2006|volume= 128|issue=29|pages=9348–9349|doi=10.1021/ja063421a|pmid=16848467 }}</ref>

[[File:Westchloro.png|thumb|center|550px|Nazarov cyclization initiated by dichlorocyclopropane rearrangement]]

In the [[Chemistry:Total synthesis|total synthesis]] of rocaglamide, epoxidation of a vinyl alkoxyallenyl stannane likewise generates a pentadienyl cation via ring opening of the resultant [[Chemistry:Epoxide|epoxide]].<ref name="rocag">{{citation|title=Nazarov Cyclization Initiated by Peracid Oxidation: The Total Synthesis of (±)-Rocaglamide|author1=Malona, J.A. |author2=Cariou, K. |author3=Frontier, A.J. |journal=J. Am. Chem. Soc.|year=2009|volume=131|issue=22|pages=7560–7561|doi=10.1021/ja9029736 |pmid=19445456 |pmc=2732401}}</ref>

[[File:Rocaglamidenazarov.png|thumb|center|600px|Nazarov cyclization initiated by oxidation]]

===Interrupted cyclization===
Once the cyclization has occurred, an oxyallyl cation is formed. As discussed extensively above, the typical course for this intermediate is [[Chemistry:Elimination reaction|elimination]] followed by [[Chemistry:Enolate|enolate]] tautomerization. However, these two steps can be interrupted by various [[Chemistry:Nucleophile|nucleophile]]s and [[Chemistry:Electrophile|electrophile]]s, respectively. Oxyallyl cation trapping has been developed extensively by Fredrick G. West of the University of Alberta and his review covers the field.<ref name="West2">{{citation|title=Interrupting the Nazarov reaction: domino and cascade processes utilizing cyclopentenyl cations|author1=Grant, T.N. |author2=Rieder, C.J. |author3=West, F.G. |year= 2009|pages=5676–5688|journal=Chem. Commun.|issue=38|doi=10.1039/B908515G|pmid=19774236 }}</ref> The oxyallyl cation can be trapped with [[Chemistry:Heteroatom|heteroatom]] and carbon [[Chemistry:Nucleophile|nucleophile]]s and can also undergo cationic [[Chemistry:Cycloaddition|cycloaddition]]s with various tethered partners. Shown below is a cascade reaction in which successive cation trapping generates a pentacyclic core in one step with complete diastereoselectivity.<ref name="West3">{{citation|title=Nazarov-Initiated Diastereoselective Cascade Polycyclization of Aryltrienones|author1=Bender, J.A. |author2=Arif, A.M. |author3=West, F.G. |journal=J. Am. Chem. Soc.|year=1999|volume=121|issue=32 |pages=7443–7444|doi=10.1021/ja991215f}}</ref>

[[File:Westcascade.png|thumb|center|730px|Nazarov cyclization cationic cascade]]

Enolate trapping with various [[Chemistry:Electrophile|electrophile]]s is decidedly less common. In one study, the Nazarov cyclization is paired with a [[Chemistry:Michael reaction|Michael reaction]] using an iridium catalyst to initiate [[Chemistry:Nucleophilic conjugate addition|nucleophilic conjugate addition]] of the enolate to [[Chemistry:Beta-Nitrostyrene|β-nitrostyrene]]. In this tandem reaction the [[Chemistry:Iridium|iridium]] [[Chemistry:Catalyst|catalyst]] is required for both conversions: it acts as the [[Chemistry:Lewis acid|Lewis acid]] in the Nazarov cyclization and in the next step the [[Chemistry:Nitro compound|nitro]] group of nitrostyrene first coordinates to iridium in a ligand exchange with the carbonyl ester oxygen atom before the actual Michael addition takes place to the opposite face of the R-group.<ref name="Michael">{{citation|title=Tandem Nazarov Cyclization-Michael Addition Sequence Catalyzed by an Ir(III) Complex|author1=Janka, M. |author2=He, W. |author3=Haedicke, I.E. |author4=Fronczek, F.R. |author5=Frontier, A.J. |author6=Eisenberg, R. |journal= J. Am. Chem. Soc.|year=2006|volume= 128|issue=16|pages=5312–5313|doi=10.1021/ja058772o|pmid=16620081 }}</ref>

[[File:NazarovMichaelTandem.png|thumb|center|600px|Tandem Nazarov cyclization and Michael reaction]]

===Enantioselective variants===
The development of an enantioselective Nazarov cyclization is a desirable addition to the repertoire of Nazarov cyclization reactions. To that end, several variations have been developed utilizing chiral auxiliaries and chiral catalysts. Diastereoselective cyclizations are also known, in which extant [[Chemistry:Stereocenter|stereocenter]]s direct the cyclization. Almost all of the attempts are based on the idea of [[Chemistry:Torquoselectivity|torquoselectivity]]; selecting one direction for the vinyl groups to "rotate" in turn sets the stereochemistry as shown below.<ref name="Frontier"/>

[[File:Torquoselectivity.png|thumb|center|600px|Torquoselectivity in the Nazarov cyclization]]

Silicon-directed Nazarov cyclizations can exhibit induced diastereoselectivity in this way. In the example below, the silyl-group acts to direct the cyclization by preventing the distant alkene from rotating "towards" it via unfavorable steric interaction. In this way the silicon acts as a traceless [[Chemistry:Chiral auxiliary|auxiliary]]. (The starting material is not enantiopure but the retention of [[Chemistry:Enantiomeric excess|enantiomeric excess]] suggests that the auxiliary directs the cyclization.)<ref name="Frontier"/>

[[File:NazarovSiliconauxilliary.png|thumb|center|300px|Silicon as a chiral auxiliary for the Nazarov cyclization]]

Tius's allenyl substrates can exhibit axial to tetrahedral chirality transfer if enantiopure allenes are used. The example below generates a chiral diosphenpol in 64% yield and 95% [[Chemistry:Enantiomeric excess|enantiomeric excess]].<ref name="Frontier"/>

[[File:Axialtotetrahedral transfer.png|thumb|center|800px|Axial to tetrahedral chirality transfer in the Nazarov cyclization of allenyl vinyl ketones]]

Tius has additionally developed a [[Chemistry:Camphor|camphor]]-based auxiliary for achiral allenes that was employed in the first asymmetric synthesis of [[Chemistry:Roseophilin|roseophilin]]. The key step employs an unusual mixture of [[Chemistry:Hexafluoro-2-propanol|hexafluoro-2-propanol]] and trifluoroethanol as solvent.<ref name="Frontier"/><ref name="roseophilin">{{citation|title=A Formal Total Synthesis of Roseophilin: Cyclopentannelation Approach to the Macrocyclic Core|author1=Harrington, P.E. |author2=Tius, M.A. |journal=Org. Lett.|year=1999|volume=1|issue=4|pages=649–652|doi=10.1021/ol990124k|pmid=10823195 }}</ref>

[[File:Tiusroseophilin.png|thumb|center|600px|Synthesis of roseophilin using asymmetric Nazarov cyclization]]

The first chiral Lewis acid promoted asymmetric Nazarov cyclization was reported by [[Biography:Varinder Aggarwal|Varinder Aggarwal]] and utilized copper (II) [[Chemistry:Bisoxazoline ligand|bisoxazoline ligand]] complexes with up to 98% ee. The enantiomeric excess was unaffected by use of 50&nbsp;mol% of the copper complex but the yield was significantly decreased.<ref name="Frontier"/>

[[File:Aggarwalnazarov.png|thumb|center|400 px|Lewis-acid mediated asymmetric Nazarov cyclization]]

==Related Reactions==
Extensions of the Nazarov cyclization are generally also subsumed under the same name. For example, an α-β, γ-δ unsaturated [[Chemistry:Ketone|ketone]] can undergo a similar cationic conrotatory cyclization that is typically referred to as an '''iso-Nazarov cyclization reaction'''.<ref name="Iso">{{citation |title=Unprecedented Rearrangement of a 4-Alkoxy-5-bromoalk-2-en-1-ol to a Cyclopentenone via an Iso-Nazarov Cyclization Process|author1=Jung, M. E. |author2=Yoo, D. |journal=The Journal of Organic Chemistry|year=2007|volume=72|issue=22 |pages=8565–8568|doi=10.1021/jo071104w|pmid=17910498 }}</ref> Other such extensions have been given similar names, including '''[[Chemistry:Homologous series|homo]]-Nazarov cyclizations''' and '''vinylogous Nazarov cyclizations.'''<ref name="Homo">{{citation |title=Catalytic Formal Homo-Nazarov Cyclization|author1=De Simone, F. |author2=Andrès, J. |author3=Torosantucci, R. |author4=Waser, J. r. m. |journal=[[Chemistry:Organic Letters|Organic Letters]]|year=2009|volume=11|issue=4 |pages=1023–1026|doi=10.1021/ol802970g|pmid=19199774 |url=http://infoscience.epfl.ch/record/134233 }}</ref><ref name="Vinyl">{{citation |title=Cyclization of Cross-Conjugated Trienes: The Vinylogous Nazarov Reaction|author1=Rieder, C. J. |author2=Winberg, K. J. |author3=West, F. G. |journal=[[Organization:Journal of the American Chemical Society|Journal of the American Chemical Society]]|year=2009|volume=131|issue=22 |pages=7504–7505|doi=10.1021/ja9023226|pmid=19435345 }}</ref>

===Retro-Nazarov reaction===
Because they overstabilize the pentadienyl cation, β-electron donating substituents often severely impede Nazarov cyclization. Building from this, several electrocyclic ring openings of β-alkoxy cyclopentanes have been reported. These are typically referred to as '''retro-Nazarov cyclization reactions'''.<ref name="Frontier"/>

[[File:Retronazarov.png|thumb|center|500px|Retro-Nazarov reaction]]

===Imino-Nazarov reaction===
Nitrogen analogues of the Nazarov cyclization reaction (known as '''imino-Nazarov cyclization reactions''') have few instances; there is one example of a generalized imino-Nazarov cyclization reported (shown below),<ref name="Imino">{{citation|title=An imino Nazarov cyclization|author1=Tius, M. A. |author2=Chu, C. C. |author3=Nieves-Colberg, R. |journal=[[Chemistry:Tetrahedron Letters|Tetrahedron Letters]]|year=2001|volume=42|issue=13 |pages=2419–2422|doi= 10.1016/s0040-4039(01)00201-5}}</ref> and several iso-imino-Nazarov reactions in the literature.<ref name="Cha">{{citation |title=Synthetic Studies Toward caphalotaxine: Functionalization of Tertiary N-Acylhemiaminals by Nazarov Cyclization|author1=Kim, S.-H. |author2=Cha, J. K. |journal=Synthesis|year=2000|volume=2000|issue=14 |pages=2113–2116|doi=10.1055/s-2000-8711}}</ref><ref name="Larini">{{citation|author1=Larini, P. |author2=Guarna, A. |author3=Occhiato, E. G. |journal=Org. Lett.|year=2006|volume=8|issue=4 |pages=781–784|title=The Lewis Acid-Catalyzed Nazarov Reaction of 2-(N-Methoxycarbonylamino)-1,4-pentadien-3-ones|doi=10.1021/ol053071h|pmid=16468766 }}</ref> Even these tend to suffer from poor stereoselectivity, poor yields, or narrow scope. The difficulty stems from the relative over-stabilization of the pentadienyl cation by electron donation, impeding cyclization.<ref name="Smith">{{citation|author1=Smith, D. A. |author2=Ulmer, C. W. |title=Effects of Substituents in the 3-Position on the [2 + 2] Pentadienyl Cation Electrocyclization|journal=The Journal of Organic Chemistry|year=1997|volume=62|issue=15 |pages=5110–5115|doi=10.1021/jo9703313}}</ref>

[[File:Iminonazarov.png|thumb|center|600px|Imino-Nazarov cyclization]]

==See also==
{{colbegin}}
* [[Chemistry:Pauson–Khand reaction|Pauson–Khand reaction]]
* Electrocyclization
* [[Chemistry:Cyclopentenone|Cyclopentenone]]
* [[Chemistry:Merrilactone A|Merrilactone A]]
{{colend}}

==References==
{{Reflist|2}}

[[Category:Rearrangement reactions]]
[[Category:Name reactions]]

{{Sourceattribution|Nazarov cyclization reaction}}