Editing Enamine (section)

==Reactions==
===Alkylation===
Even though enamines are more nucleophilic than their enol counterparts, they can still react selectively, rendering them useful for alkylation reactions. The enamine nucleophile can attack [[haloalkanes]] to form the alkylated [[iminium]] salt intermediate which then hydrolyzes to regenerate a ketone (a starting material in enamine synthesis). This reaction was pioneered by [[Gilbert Stork]], and is sometimes referred to by the name of its inventor (the [[Stork enamine alkylation]]). Analogously, this reaction can be used as an effective means of [[acylation]]. A variety of alkylating and acylating agents including benzylic, allylic halides can be used in this reaction.<ref>{{cite book|last1=Wade|first1=L.G.|title=Organic Chemistry|url=https://archive.org/details/organicchemistry00wade_1|url-access=registration|date=1999|publisher=Prentice Hall|location=Saddle River, NJ|pages=[https://archive.org/details/organicchemistry00wade_1/page/1019 1019]|isbn=9780139227417}}</ref>
:{{chem2|R2N\sCH\dCHR' +  R"X -> [R2N+\dCH\sCHR'R"]X-}}  (alkylation of enamine)
:{{chem2|[R2N+\dCH\sCHR'R"]+X-  + H2O ->  R2NH  + R'R"CHCHO}}  (hydrolysis of the resulting iminium salt, giving a 2-alkylated aldehyde)

===Acylation===

In a reaction much similar to the enamine alkylation, enamines can be acylated to form a final [[dicarbonyl]] product. The enamine starting material undergoes a nucleophilic addition to [[acyl halides]] forming the iminium salt intermediate which can hydrolyze in the presence of acid.<ref name="chemwiki_Enamine_Reactions"/>
:{{chem2|R2N\sCH\dCHR' +  R"COCl -> [R2N+\dCH\sCHR'C(O)R"]Cl-}}  (acylation of enamine)
:{{chem2|[R2N+\dCH\sCHR'C(O)R"]+Cl  + H2O ->  R2NH  + O\dC(H)CH(R')CR"\dO}}  (hydrolysis of the resulting acyl iminium salt, giving a C-acylated aldehyde)

===Metalloenamines===

Strong bases such as [[Lithium amide#Other lithium amides|LiNR<sub>2</sub>]] can be used to deprotonate imines and form metalloenamines.  Metalloenamines can prove synthetically useful due to their nucleophilicity (they are more nucleophilic than enolates). Thus they are better able to react with weaker electrophiles (for example, they can be used to open [[Epoxide|epoxides]].<ref>{{cite web|last1=Evans|first1=D.|title=Enolates and Metalloenamines II|url=http://isites.harvard.edu/fs/docs/icb.topic93502.files/Lectures_and_Handouts/25-Enolates-2.pdf|access-date=10 December 2014}}{{Dead link|date=August 2019 |bot=InternetArchiveBot |fix-attempted=yes }}</ref>)  Most prominently, these reactions have allowed for [[Asymmetric synthesis|asymmetric]] alkylations of ketones through transformation to chiral intermediate metalloenamines.<ref>{{cite journal|last1=Meyers|first1=A. I.|last2=Williams|first2=Donald R.|title=Asymmetric alkylation of acyclic ketones via chiral metallo enamines. Effect of kinetic vs. thermodynamic metalations.|journal=The Journal of Organic Chemistry|date=August 1978|volume=43|issue=16|pages=3245–3247|doi=10.1021/jo00410a034}}</ref>

===Halogenation===
[[Chlorination reaction|Chlorination]] of enamines followed by hydrolysis gives α-halo derivatives:
:{{chem2|R2NCH\dCHR' +  Cl2 -> [R2N+\dCH\sCHR'CCl]Cl-}}  (chlorination of enamine)
:{{chem2|[R2N+\dCH\sCHR'Cl]Cl-  + H2O ->  R2NH  + R'CH(Cl)CHO}}  (hydrolysis of chloroiminium, giving a chloroaldehyde)
In addition to chlorination, bromination and even iodination have been demonstrated.<ref>{{cite journal|last1=Seufert|first1=Walter|last2=Eiffenberger|first2=Franz|title=Zur Halogenierung von Enaminen — Darstellung von β-Halogen-iminium-halogeniden|journal=Chemische Berichte|date=1979|volume=112|issue=5|pages=1670–1676|doi=10.1002/cber.19791120517}}</ref> 

===Oxidative coupling===
Enamines can be efficiently [[Cross-coupling reaction|cross-coupled]] with enol silanes through treatment with [[ceric ammonium nitrate]].<ref>{{cite journal|last1=Jang|first1=HY|last2=Hong|first2=JB|last3=MacMillan|first3=DWC|title=Enantioselective organocatalytic singly occupied molecular orbital activation: the enantioselective alpha-enolation of aldehydes.|journal=J. Am. Chem. Soc.|date=2007|volume=129|issue=22|pages=7004–7005|doi=10.1021/ja0719428|pmid=17497866|url=https://authors.library.caltech.edu/76937/2/ja0719428si20070430_050938.pdf}}<!--|access-date=30 November 2014--></ref> Oxidative dimerization of aldehydes in the presence of amines proceeds through the formation of an enamine followed by a final [[pyrrole]] formation.<ref>{{cite journal|last1=Li|first1=Q|last2=Fan|first2=A|last3=Lu|first3=Z|last4=Cui|first4=Y|last5=Lin|first5=W|last6=Jia|first6=Y|title=One-pot AgOAc-mediated synthesis of polysubstituted pyrroles from primary amines and aldehydes: application to the total synthesis of purpurone|journal=Organic Letters|date=2010|volume=12|issue=18|pages=4066–4069|doi=10.1021/ol101644g|pmid=20734981}}</ref> This method for symmetric pyrrole synthesis was developed in 2010 by the Jia group, as a valuable new pathway for the synthesis of pyrrole-containing natural products.<ref>{{cite journal|last1=Guo|first1=Fenghai|last2=Clift|first2=Michael D.|last3=Thomson|first3=Regan J.|title=Oxidative Coupling of Enolates, Enol Silanes, and Enamines: Methods and Natural Product Synthesis|journal=European Journal of Organic Chemistry|date=September 2012|volume=2012|issue=26|pages=4881–4896|doi=10.1002/ejoc.201200665|pmid=23471479|pmc=3586739}}</ref>

===Annulation===

Enamines chemistry has been implemented for the purposes of producing a one-pot enantioselective version of the [[Robinson annulation]]. The Robinson annulation, published by Robert Robinson in 1935, is a base-catalyzed reaction that combines a ketone and a [[methyl vinyl ketone]] (commonly abbreviated to MVK) to form a [[cyclohexenone]] fused ring system. This reaction may be catalyzed by [[proline]] to proceed through chiral enamine intermediates which allow for good stereoselectivity.<ref>{{cite journal|last1=List|first1=Benjamin|title=Proline-catalyzed asymmetric reactions|journal=Tetrahedron|date=2002|volume=58|issue=28|pages=5573–5590|doi=10.1016/s0040-4020(02)00516-1}}<!--|access-date=29 November 2014--></ref> This is important, in particular in the field of natural product synthesis, for example, for the synthesis of the [[Wieland–Miescher ketone|Wieland-Miescher ketone]] – a vital building block for more complex biologically active molecules.<ref>{{cite journal|last1=Bui|first1=Tommy|last2=Barbas|title=A proline-catalyzed asymmetric Robinson Annulation|journal=Tetrahedron Letters|date=2000|volume=41|issue=36|pages=6951–6954|doi=10.1016/s0040-4039(00)01180-1}}<!--|access-date=29 November 2014--></ref><ref>{{cite web|last1=Wiener|first1=Jake|title=Enantioselective Organic Catalysis:Non-MacMillan Approaches|url=https://www.princeton.edu/chemistry/macmillan/group-meetings/jjmw-orgcats.pdf|access-date=29 November 2014|archive-url=https://web.archive.org/web/20171026175935/http://www.princeton.edu/chemistry/macmillan/group-meetings/jjmw-orgcats.pdf|archive-date=26 October 2017|url-status=dead}}</ref>