View source for Negishi coupling

{{Short description|Chemical reaction}}
{{Reactionbox
|Name = Negishi coupling
|Type = Coupling reaction
|NamedAfter = [[Ei-ichi Negishi]]
|Section3 = {{Reactionbox Identifiers
|OrganicChemistryNamed = negishi-coupling
|RSC_ontology_id = 0000088
}}
}}

The '''Negishi coupling''' is a widely employed [[transition metal]] catalyzed [[cross-coupling reaction]]. The reaction couples [[halocarbon|organic halides]] or [[Trifluoromethanesulfonate|triflates]] with [[organozinc compound]]s, forming  [[carbon-carbon bond]]s (C-C) in the process. A [[palladium]] (0) species is generally utilized as the [[catalyst]], though [[nickel]] is sometimes used.<ref>{{cite journal | first1 = Anthony O. | last1 = King | first2 = Nobuhisa | last2 = Okukado | first3 = Ei-ichi | last3 = Negishi | name-list-style = vanc | author-link3 = Ei-ichi Negishi |doi=10.1039/C39770000683 |title=Highly general stereo-, regio-, and chemo-selective synthesis of terminal and internal conjugated enynes by the Pd-catalysed reaction of alkynylzinc reagents with alkenyl halides |year=1977 |journal=Journal of the Chemical Society, Chemical Communications |pages=683 |issue=19}}</ref><ref>{{cite book|last1=Kürti|first1=László|last2=Czakó|first2=Barbara | name-list-style = vanc |title=Strategic applications of named reactions in organic synthesis : background and detailed mechanisms ; 250 named reactions |date=2007 |publisher=Elsevier Academic Press|location=Amsterdam|isbn=978-0-12-429785-2}}</ref> A variety of nickel catalysts in either Ni<sup>0</sup> or Ni<sup>II</sup> oxidation state can be employed in Negishi cross couplings such as Ni(PPh<sub>3</sub>)<sub>4</sub>, Ni(acac)<sub>2</sub>, Ni(COD)<sub>2</sub> etc.<ref>{{Cite journal|last1=Zhou|first1=Jianrong (Steve)|last2=Fu|first2=Gregory C.|date=December 2003|title=Cross-Couplings of Unactivated Secondary Alkyl Halides: Room-Temperature Nickel-Catalyzed Negishi Reactions of Alkyl Bromides and Iodides|url=https://pubs.acs.org/doi/10.1021/ja0389366|journal=Journal of the American Chemical Society|language=en|volume=125|issue=48|pages=14726–14727|doi=10.1021/ja0389366|pmid=14640646|issn=0002-7863}}</ref><ref>{{Cite journal|last1=Negishi|first1=Eiichi|last2=King|first2=Anthony O. |last3=Okukado |first3=Nobuhisa |date=1977-05-01 |title=Selective carbon-carbon bond formation via transition metal catalysis. 3. A highly selective synthesis of unsymmetrical biaryls and diarylmethanes by the nickel- or palladium-catalyzed reaction of aryl- and benzylzinc derivatives with aryl halides |url=https://doi.org/10.1021/jo00430a041 |journal=The Journal of Organic Chemistry|volume=42|issue=10|pages=1821–1823|doi=10.1021/jo00430a041|issn=0022-3263}}</ref><ref>{{Cite journal |last1=Gavryushin |first1=Andrei |last2=Kofink |first2=Christiane |last3=Manolikakes |first3=Georg |last4=Knochel |first4=Paul |date=2005-10-01 |title=Efficient Cross-Coupling of Functionalized Arylzinc Halides Catalyzed by a Nickel Chloride−Diethyl Phosphite System|url=https://doi.org/10.1021/ol051615+ |journal=Organic Letters |volume=7 |issue=22 |pages=4871–4874 |doi=10.1021/ol051615+ |pmid=16235910 |issn=1523-7060}}</ref> 

:[[File:NegishiScheme1.png|centre|343x343px]]
:* The leaving group '''X''' is usually [[chloride]], [[bromide]], or [[iodide]], but [[triflate]] and [[acetyloxy]] groups are feasible as well. '''X''' = Cl usually leads to slow reactions.
:* The organic residue '''R''' = [[alkenyl]], [[aryl]], [[allyl]], [[alkynyl]] or [[propargyl]].
:* The halide '''X'''' in the organozinc compound can be [[chloride]], [[bromine]] or [[iodine]] and the organic residue '''R'''' is [[alkenyl]], [[aryl]], [[allyl]], [[alkyl]], [[benzyl]], homoallyl, and homopropargyl.
:* The metal '''M''' in the catalyst is [[nickel]] or [[palladium]]
:* The [[ligand]] '''L''' in the catalyst can be [[triphenylphosphine]], [[dppe]], [[BINAP]], [[chiraphos]] or [[XPhos]].
Palladium catalysts in general have higher [[chemical yield]]s and higher [[functional group]] tolerance.

The Negishi coupling finds common use in the field of [[total synthesis]] as a method for selectively forming C-C bonds between complex synthetic intermediates. The reaction allows for the coupling of sp<sup>3</sup>, sp<sup>2</sup>, and sp carbon atoms, (see [[orbital hybridization]]) which make it somewhat unusual among the [[palladium-catalyzed coupling reactions]]. Organozincs are moisture and [[air sensitivity|air sensitive]], so the Negishi coupling must be performed in an [[oxygen]] and water free environment, a fact that has hindered its use relative to other cross-coupling reactions that require less robust conditions (i.e. Suzuki reaction). However, organozincs are more reactive than both organostannanes and organoborates which correlates to faster reaction times.

The reaction is named after [[Ei-ichi Negishi]] who was a co-recipient of the 2010 [[Nobel Prize in Chemistry]] for the discovery and development of this reaction.

Negishi and coworkers originally investigated the cross-coupling of [[organoaluminum chemistry|organoaluminum]] reagents in 1976 initially employing [[Nickel|Ni]] and [[Palladium|Pd]] as the transition metal catalysts, but noted that Ni resulted in the decay of [[stereospecifity]] whereas Pd did not.<ref>{{cite journal | vauthors = Baba S, Negishi E | author-link2 = Ei-ichi Negishi |title=A novel stereospecific alkenyl-alkenyl cross-coupling by a palladium- or nickel-catalyzed reaction of alkenylalanes with alkenyl halides |journal=Journal of the American Chemical Society |year=1976 |volume=98 |issue=21 |pages=6729–6731 |doi=10.1021/ja00437a067}}</ref> Transitioning from organoaluminum species to organozinc compounds Negishi and coworkers reported the use of Pd complexes in organozinc coupling reactions and carried out methods studies, eventually developing the reaction conditions into  those commonly utilized today.<ref>{{cite journal | vauthors = Negishi E, King AO, Okukado N | author-link1 = Ei-ichi Negishi |title=Selective carbon-carbon bond formation via transition metal catalysis. 3. A highly selective synthesis of unsymmetrical biaryls and diarylmethanes by the nickel- or palladium-catalyzed reaction of aryl- and benzylzinc derivatives with aryl halides |journal=The Journal of Organic Chemistry |year=1977 |volume=42 |issue=10 |pages=1821–1823 |doi=10.1021/jo00430a041}}</ref> Alongside [[Richard F. Heck]] and [[Akira Suzuki (chemist)|Akira Suzuki]], El-ichi Negishi was a co-recipient of the Nobel Prize in Chemistry in 2010, for his work on "palladium-catalyzed cross couplings in organic synthesis".

==Reaction mechanism==
The reaction mechanism is thought to proceed via a standard Pd catalyzed cross-coupling pathway, starting with a Pd(0) species, which is oxidized to Pd(II) in an oxidative addition step involving the organohalide species.<ref name="Kurti, L.; Czako, B. 2005">{{cite book | vauthors = Kurti L, Czako B | title = Strategic Applications of Named Reactions in Organic Synthesis |publisher=Elsevier Academic Press |location=New York |year=2005}}</ref> This step proceeds with aryl, vinyl, alkynyl, and acyl halides, acetates, or triflates, with substrates following standard [[oxidative addition]] relative rates (I>OTf>Br>>Cl).<ref>{{cite web| author = Andrew G Myers Research Group|title=Chemistry 115 Handouts | url = https://faculty.chemistry.harvard.edu/myers/pages/chem-215-handouts | publisher = Harvard University Department of Chemistry | location = Boston, Massachusetts }}</ref>
[[File:Scheme2Catcycle.png|centre|581x581px]]
The actual mechanism of oxidative addition is unresolved, though there are two likely pathways. One pathway is thought to proceed via an [[sn2|S<sub>N</sub>2]] like mechanism resulting in inverted stereochemistry. The other pathway proceeds via [[concerted reaction|concerted addition]] and retains stereochemistry. 
[[File:Scheme3oxadd.png|352x352px|Mechanisms of oxidative addition|centre]]
Though the additions are cis- the Pd(II) complex rapidly isomerizes to the trans- complex.<ref>{{cite journal | vauthors = Casado AL, Espinet P | title = On the Configuration Resulting from Oxidative Addition of RX to Pd(PPh3)4 and the Mechanism of the cis-to-trans Isomerization of [PdRX(PPh3)2] Complexes (R = Aryl, X = Halide) |journal=Organometallics |year=1998 |volume=17 |issue=5 |pages=954–959 |doi=10.1021/om9709502}}
</ref>
[[File:Scheme4cistrans.png|centre|291x291px]]
Next, the [[transmetalation]] step occurs where the organozinc reagent exchanges its organic substituent with the halide in the Pd(II) complex, generating the trans- Pd(II) complex and a zinc halide salt. The organozinc substrate can be aryl, vinyl, allyl, benzyl, homoallyl, or homopropargyl.<ref name="Kurti, L.; Czako, B. 2005"/> Transmetalation is usually [[rate limiting]] and a complete mechanistic understanding of this step has not yet been reached though several studies have shed light on this process. Alkylzinc species form higher-order zincate species prior to transmetalation whereas arylzinc species do not.<ref>{{cite journal | vauthors = McCann LC, Hunter HN, Clyburne JA, Organ MG | title = Higher-order zincates as transmetalators in alkyl-alkyl negishi cross-coupling | journal = Angewandte Chemie | volume = 51 | issue = 28 | pages = 7024–7 | date = July 2012 | pmid = 22685029 | doi = 10.1002/anie.201203547 }}</ref> ZnXR and ZnR<sub>2</sub> can both be used as reactive reagents, and Zn is known to prefer four coordinate complexes, which means solvent coordinated Zn complexes, such as {{chem2|ZnXR(solvent)2}} cannot be ruled out ''a priori''.<ref>{{cite journal | vauthors = García-Melchor M, Braga AA, Lledós A, Ujaque G, Maseras F | title = Computational perspective on Pd-catalyzed C-C cross-coupling reaction mechanisms | journal = Accounts of Chemical Research | volume = 46 | issue = 11 | pages = 2626–34 | date = November 2013 | pmid = 23848308 | doi = 10.1021/ar400080r }}</ref> Studies indicate competing equilibriums exist between cis- and trans- bis alkyl organopalladium complexes, but that the only productive intermediate is the cis complex.<ref name="Casares 2007">{{cite journal | vauthors = Casares JA, Espinet P, Fuentes B, Salas G | title = Insights into the mechanism of the Negishi reaction: ZnRX versus ZnR2 reagents | journal = Journal of the American Chemical Society | volume = 129 | issue = 12 | pages = 3508–9 | date = March 2007 | pmid = 17328551 | doi = 10.1021/ja070235b }}</ref><ref>{{cite journal | vauthors = Fuentes B, García-Melchor M, Lledós A, Maseras F, Casares JA, Ujaque G, Espinet P | title = Palladium round trip in the Negishi coupling of trans-[PdMeCl(PMePh2)2] with ZnMeCl: an experimental and DFT study of the transmetalation step | journal = Chemistry: A European Journal | volume = 16 | issue = 29 | pages = 8596–9 | date = August 2010 | pmid = 20623568 | doi = 10.1002/chem.201001332 }}</ref> 
	
[[File:Scheme5redelim.png|300px|Generation of active species via cis/trans isomerism|centre]]

The last step in the catalytic pathway of the Negishi coupling is [[reductive elimination]], which is thought to proceed via a three coordinate [[transition state]], yielding the coupled organic product and regenerating the Pd(0) catalyst. For this step to occur, the aforementioned cis- alkyl organopalladium complex must be formed.<ref>{{cite book | vauthors = Crabtree R |title=The Organometallic Chemistry of the Transition Metals |publisher=John Wiley and Sons Inc. |location=Hoboken, NJ |year=2005 |volume=4}}
</ref>[[File:Scheme6redelim2.png|450px|center|Mechanism of reductive elimination]]

Both organozinc halides and diorganozinc compounds can be used as starting materials. In one model system it was found that in the transmetalation step the former give the cis-adduct R-Pd-R' resulting in fast reductive elimination to product while the latter gives the trans-adduct which has to go through a slow [[trans-cis isomerization]] first.<ref name="Casares 2007" />

A common [[side reaction]] is homocoupling. In one Negishi model system the formation of homocoupling was found to be the result of a second transmetalation reaction between the diarylmetal intermediate and arylmetal halide:<ref>{{cite journal | vauthors = Liu Q, Lan Y, Liu J, Li G, Wu YD, Lei A | title = Revealing a second transmetalation step in the Negishi coupling and its competition with reductive elimination: improvement in the interpretation of the mechanism of biaryl syntheses | journal = Journal of the American Chemical Society | volume = 131 | issue = 29 | pages = 10201–10 | date = July 2009 | pmid = 19572717 | doi = 10.1021/ja903277d | s2cid = 58240 }}</ref>
: Ar–Pd–Ar' + Ar'–Zn–X  →  Ar'–Pd–Ar' + Ar–Zn–X
: Ar'–Pd–Ar' →  Ar'–Ar' + Pd(0) ''(homocoupling)''
: Ar–Zn–X + H<sub>2</sub>O → Ar–H + HO–Zn–X  ''(reaction accompanied by [[dehalogenation]])''


Nickel catalyzed systems can operate under different mechanisms depending on the coupling partners. Unlike palladium systems which involve only Pd<sup>0</sup> or Pd<sup>II</sup>, nickel catalyzed systems can involve nickel of different oxidation states.<ref>{{Cite journal|last1=Phapale|first1=Vilas B.|last2=Cárdenas|first2=Diego J.|date=2009-05-27|title=Nickel-catalysed Negishi cross-coupling reactions: scope and mechanisms|url=https://pubs.rsc.org/en/content/articlelanding/2009/cs/b805648j|journal=Chemical Society Reviews|language=en|volume=38|issue=6|pages=1598–1607|doi=10.1039/B805648J|pmid=19587955|issn=1460-4744}}</ref> Both systems are similar in that they involve similar elementary steps: oxidative addition, transmetalation, and reductive elimination. Both systems also have to address issues of β-hydride elimination and difficult oxidative addition of alkyl electrophiles.<ref>{{Cite journal|last1=Zhou|first1=Jianrong (Steve)|last2=Fu|first2=Gregory C.|date=December 2003|title=Cross-Couplings of Unactivated Secondary Alkyl Halides: Room-Temperature Nickel-Catalyzed Negishi Reactions of Alkyl Bromides and Iodides|url=https://pubs.acs.org/doi/10.1021/ja0389366|journal=Journal of the American Chemical Society|language=en|volume=125|issue=48|pages=14726–14727|doi=10.1021/ja0389366|pmid=14640646|issn=0002-7863}}</ref>

For unactivated alkyl electrophiles, one possible mechanism is a [[transmetalation]] first mechanism. In this mechanism, the alkyl zinc species would first transmetalate with the nickel catalyst.  Then the nickel would abstract the halide from the alkyl halide resulting in the alkyl radical and oxidation of nickel after addition of the radical.<ref>{{Cite journal|last1=Schley|first1=Nathan D.|last2=Fu|first2=Gregory C.|date=2014-11-26|title=Nickel-Catalyzed Negishi Arylations of Propargylic Bromides: A Mechanistic Investigation|url=https://doi.org/10.1021/ja508718m|journal=Journal of the American Chemical Society|volume=136|issue=47|pages=16588–16593|doi=10.1021/ja508718m|issn=0002-7863|pmc=4277758|pmid=25402209}}</ref>
[[File:NickelMechanism.png|center|frameless|373x373px]]

One important factor when contemplating the mechanism of a nickel catalyzed cross coupling is that reductive elimination is facile from Ni<sup>III</sup> species, but very difficult from Ni<sup>II</sup> species.  Kochi and Morrell provided evidence for this by isolating Ni<sup>II</sup> complex Ni(PEt<sub>3</sub>)<sub>2</sub>(Me)(''o''-tolyl), which did not undergo reductive elimination quickly enough to be involved in this elementary step.<ref>{{Cite journal|last1=Morrell|first1=Dennis G.|last2=Kochi|first2=Jay K.|date=1975-12-01|title=Mechanistic studies of nickel catalysis in the cross coupling of aryl halides with alkylmetals. Role of arylalkylnickel(II) species as intermediates|url=https://doi.org/10.1021/ja00858a011|journal=Journal of the American Chemical Society|volume=97|issue=25|pages=7262–7270|doi=10.1021/ja00858a011|issn=0002-7863}}</ref>

==Scope==
The Negishi coupling has been applied the following illustrative syntheses:
*unsymmetrical [[2,2'-bipyridine]]s from [[2-bromopyridine]] with [[tetrakis(triphenylphosphine)palladium(0)]],<ref>
{{OrgSynth |author=Adam P. Smith, Scott A. Savage, J. Christopher Love, and Cassandra L. Fraser |collvol=10 |collvolpages=517 |year=2004 |prep=v78p0051 |title=Synthesis of 4-, 5-, and 6-methyl-2,2'-bipyridine by a Negishi cross-coupling strategy: 5-methyl-2,2'-bipyridine}}</ref>
*[[biphenyl]] from ''o''-tolylzinc chloride and  ''o''-iodotoluene and tetrakis(triphenylphosphine)palladium(0),<ref>
{{OrgSynth |author=[[Ei-ichi Negishi]], Tamotsu Takahashi, and Anthony O. King |collvol=8 |collvolpages=430 |year=1993 |prep=cv8p0430 |title=Synthesis of biaryls via palladium-catalyzed cross-coupling: 2-methyl-4'-nitrobiphenyl}}
</ref>
*5,7-hexadecadiene from 1-decyne and (''Z'')-1-hexenyl iodide.<ref>
{{OrgSynth |author=[[Ei-ichi Negishi]], Tamotsu Takahashi, and Shigeru Baba |collvol=8 |collvolpages=295 |year=1993 |prep=cv8p0295 |title=Palladium-catalyzed synthesis of conjugated dienes}}
</ref>

[[Image:Hexaferrocenylbenzene-3D-sticks.png|200px|thumb|right|Structure of hexaferrocenylbenzene, C<sub>6</sub>[(η<sup>5</sup>-C<sub>5</sub>H<sub>4</sub>)Fe(η<sup>5</sup>-C<sub>5</sub>H<sub>5</sub>)]<sub>6</sub>]] Negishi coupling has been applied in the synthesis of [[hexaferrocenylbenzene]]:<ref>
{{cite journal | vauthors = Yu Y, Bond AD, Leonard PW, Lorenz UJ, Timofeeva TV, Vollhardt KP, Whitener GD, Yakovenko AA | title = Hexaferrocenylbenzene | journal = Chemical Communications | issue = 24 | pages = 2572–4 | date = June 2006 | pmid = 16779481 | doi = 10.1039/b604844g | url = https://zenodo.org/record/896672 }}
</ref>
:[[Image:Hexaferrocenylbenzene.png|400px|Hexaferrocenylbenzene]]
with hexaiodidobenzene, diferrocenylzinc and [[tris(dibenzylideneacetone)dipalladium(0)]] in [[tetrahydrofuran]]. The yield is only 4% signifying substantial crowding around the aryl core.

In a novel modification palladium is first oxidized by the [[haloketone]] ''2-chloro-2-phenylacetophenone'' '''1''' and the resulting palladium OPdCl complex then accepts both the [[organozinc compound]] '''2''' and the [[organotin compound]] '''3''' in a double [[transmetalation]]:<ref>
{{cite journal | vauthors = Zhao Y, Wang H, Hou X, Hu Y, Lei A, Zhang H, Zhu L | title = Oxidative cross-coupling through double transmetallation: surprisingly high selectivity for palladium-catalyzed cross-coupling of alkylzinc and alkynylstannanes | journal = Journal of the American Chemical Society | volume = 128 | issue = 47 | pages = 15048–9 | date = November 2006 | pmid = 17117830 | doi = 10.1021/ja0647351 }}
</ref>
:[[Image:DoubleTransmetallationcrosscoupling.png|400px|Double Transmetallation crosscoupling]]

Examples of nickel catalyzed Negishi couplings include sp<sup>2</sup>-sp<sup>2</sup>, sp<sup>2</sup>-sp<sup>3</sup>, and sp<sup>3</sup>-sp<sup>3</sup> systems.  In the system first studied by Negishi, aryl-aryl cross coupling was catalyzed by Ni(PPh<sub>3</sub>)<sub>4</sub> generated ''in situ'' through reduction of Ni(acac)<sub>2</sub> with PPh3 and (i-Bu)<sub>2</sub>AlH.<ref>{{Cite journal|last1=Negishi|first1=Eiichi|last2=King|first2=Anthony O.|last3=Okukado|first3=Nobuhisa|date=1977-05-01|title=Selective carbon-carbon bond formation via transition metal catalysis. 3. A highly selective synthesis of unsymmetrical biaryls and diarylmethanes by the nickel- or palladium-catalyzed reaction of aryl- and benzylzinc derivatives with aryl halides|url=https://doi.org/10.1021/jo00430a041|journal=The Journal of Organic Chemistry|volume=42|issue=10|pages=1821–1823|doi=10.1021/jo00430a041|issn=0022-3263}}</ref>
[[File:Picture1ArArCC.png|center|frameless|370x370px]]
Variations have also been developed to allow for the cross-coupling of aryl and alkenyl partners.  In the variation developed by Knochel et al, aryl zinc bromides were reacted with vinyl triflates and vinyl halides.<ref>{{Cite journal|last1=Gavryushin|first1=Andrei|last2=Kofink|first2=Christiane|last3=Manolikakes|first3=Georg|last4=Knochel|first4=Paul|date=2005-10-01|title=Efficient Cross-Coupling of Functionalized Arylzinc Halides Catalyzed by a Nickel Chloride−Diethyl Phosphite System|url=https://doi.org/10.1021/ol051615+|journal=Organic Letters|volume=7|issue=22|pages=4871–4874|doi=10.1021/ol051615+|pmid=16235910|issn=1523-7060}}</ref>

[[File:ArSP2CC.png|center|frameless|316x316px]]
Reactions between sp<sup>3</sup>-sp<sup>3</sup> centers are often more difficult;  however, adding an unsaturated ligand with an electron withdrawing group as a cocatalyst improved the yield in some systems.  It is believed that added coordination from the unsaturated ligand favors reductive elimination over β-hydride elimination.<ref>{{Cite journal|last1=Giovannini|first1=Riccardo|last2=Stüdemann|first2=Thomas|last3=Dussin|first3=Gaelle|last4=Knochel|first4=Paul|date=1998|title=An Efficient Nickel-Catalyzed Cross-Coupling Between sp3 Carbon Centers|url=https://onlinelibrary.wiley.com/doi/abs/10.1002/%28SICI%291521-3773%2819980918%2937%3A17%3C2387%3A%3AAID-ANIE2387%3E3.0.CO%3B2-M|journal=Angewandte Chemie International Edition|language=en|volume=37|issue=17|pages=2387–2390|doi=10.1002/(SICI)1521-3773(19980918)37:17<2387::AID-ANIE2387>3.0.CO;2-M|pmid=29710957|issn=1521-3773}}</ref><ref>{{Cite journal|last1=Jensen|first1=Anne Eeg|last2=Knochel|first2=Paul|date=2002-01-01|title=Nickel-Catalyzed Cross-Coupling between Functionalized Primary or Secondary Alkylzinc Halides and Primary Alkyl Halides|url=https://doi.org/10.1021/jo0105787|journal=The Journal of Organic Chemistry|volume=67|issue=1|pages=79–85|doi=10.1021/jo0105787|pmid=11777442|issn=0022-3263}}</ref> This also works in some alkyl-aryl systems.<ref>{{Cite journal|last1=Giovannini|first1=Riccardo|last2=Knochel|first2=Paul|date=1998-11-01|title=Ni(II)-Catalyzed Cross-Coupling between Polyfunctional Arylzinc Derivatives and Primary Alkyl Iodides|url=https://doi.org/10.1021/ja982520o|journal=Journal of the American Chemical Society|volume=120|issue=43|pages=11186–11187|doi=10.1021/ja982520o|issn=0002-7863}}</ref>

Several asymmetric variants exist and many utilize Pybox ligands.<ref>{{Cite journal|last1=Fischer|first1=Christian|last2=Fu|first2=Gregory C.|date=April 2005|title=Asymmetric Nickel-Catalyzed Negishi Cross-Couplings of Secondary α-Bromo Amides with Organozinc Reagents|url=https://pubs.acs.org/doi/10.1021/ja0506509|journal=Journal of the American Chemical Society|language=en|volume=127|issue=13|pages=4594–4595|doi=10.1021/ja0506509|pmid=15796523|issn=0002-7863}}</ref><ref>{{Cite journal|last1=Son|first1=Sunghee|last2=Fu|first2=Gregory C.|date=2008-03-01|title=Nickel-Catalyzed Asymmetric Negishi Cross-Couplings of Secondary Allylic Chlorides with Alkylzincs|url=https://pubs.acs.org/doi/10.1021/ja800103z|journal=Journal of the American Chemical Society|language=en|volume=130|issue=9|pages=2756–2757|doi=10.1021/ja800103z|pmid=18257579|issn=0002-7863}}</ref><ref>{{Cite journal|last1=Phapale|first1=Vilas B.|last2=Buñuel|first2=Elena|last3=García-Iglesias|first3=Miguel|last4=Cárdenas|first4=Diego J.|date=2007|title=Ni-Catalyzed Cascade Formation of C(sp3)C(sp3) Bonds by Cyclization and Cross-Coupling Reactions of Iodoalkanes with Alkyl Zinc Halides|url=https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.200702528|journal=Angewandte Chemie International Edition|volume=46|issue=46|pages=8790–8795|doi=10.1002/anie.200702528|pmid=17918274|issn=1521-3773}}</ref>

===Industrial applications===
The Negishi coupling is not employed as frequently in industrial applications as its cousins the [[Suzuki reaction]] and [[Heck reaction]], mostly as a result of the water and air sensitivity of the required aryl or alkyl zinc reagents.<ref>{{cite journal | vauthors = Johansson Seechurn CC, Kitching MO, Colacot TJ, Snieckus V | title = Palladium-catalyzed cross-coupling: a historical contextual perspective to the 2010 Nobel Prize | journal = Angewandte Chemie | volume = 51 | issue = 21 | pages = 5062–85 | date = May 2012 | pmid = 22573393 | doi = 10.1002/anie.201107017  }}</ref><ref>{{cite journal | vauthors = Sase S, Jaric M, Metzger A, Malakhov V, Knochel P | title = One-pot Negishi cross-coupling reactions of in situ generated zinc reagents with aryl chlorides, bromides, and triflates | journal = The Journal of Organic Chemistry | volume = 73 | issue = 18 | pages = 7380–2 | date = September 2008 | pmid = 18693766 | doi = 10.1021/jo801063c }}</ref> In 2003 [[Novartis]] employed a Negishi coupling in the manufacture of PDE472, a [[phosphodiesterase]] type 4D inhibitor, which was being investigated as a drug lead for the treatment of [[asthma]].<ref>{{cite journal | vauthors = Manley PW, Acemoglu M, Marterer W, Pachinger W |title=Large-Scale Negishi Coupling as Applied to the Synthesis of PDE472, an Inhibitor of Phosphodiesterase Type 4D |journal=Organic Process Research & Development |year=2003 |volume=7 |issue=3 |pages=436–445 |doi=10.1021/op025615q}}</ref> The Negishi coupling was used as an alternative to the Suzuki reaction providing improved yields, 73% on a 4.5&nbsp;kg scale, of the desired benzodioxazole synthetic intermediate.<ref>{{cite journal | vauthors = Torborg C, Beller M |title=Recent Applications of Palladium-Catalyzed Coupling Reactions in the Pharmaceutical, Agrochemical, and Fine Chemical Industries |journal=Advanced Synthesis & Catalysis |year=2009 |volume=351 |issue=18 |pages=3027–3043 |doi=10.1002/adsc.200900587}}</ref> 
:[[File:Scheme7natprod1.png|500px|Synthesis of benzodioxazole synthetic intermediate|centre]]

===Applications in total synthesis===
Where the Negishi coupling is rarely used in industrial chemistry, a result of the aforementioned water and oxygen sensitivity, it finds wide use in the field of [[natural product]]s total synthesis. The increased reactivity relative to other cross-coupling reactions makes the Negishi coupling ideal for joining complex intermediates in the synthesis of natural products.<ref name="Kurti, L.; Czako, B. 2005"/> Additionally, Zn is more environmentally friendly than other metals such as [[Tin|Sn]] used in the [[Stille coupling]]. The Negishi coupling historically is not used as much as the Stille or Suzuki coupling.  When it comes to fragment-coupling processes the Negishi coupling is particularly useful, especially when compared to the aforementioned Stille and Suzuki coupling reactions.<ref>{{cite journal | vauthors = Nicolaou KC, Bulger PG, Sarlah D | title = Palladium-catalyzed cross-coupling reactions in total synthesis | journal = Angewandte Chemie | volume = 44 | issue = 29 | pages = 4442–89 | date = July 2005 | pmid = 15991198 | doi = 10.1002/anie.200500368 }}</ref> The major drawback of the Negishi coupling, aside from its water and oxygen sensitivity, is its relative lack of [[functional group]] tolerance when compared to other cross-coupling reactions.<ref>{{cite journal | vauthors = Lessene G |title=Advances in the Negishi coupling |journal=Aust. J. Chem. |year=2004 |volume=57 |issue=1 |pages=107 |doi=10.1071/ch03225}}</ref>

(−)-stemoamide is a natural product found in the root extracts of ‘’Stemona tuberosa’’. These extracts have been used Japanese and Chinese [[folk medicine]] to treat respiratory disorders, and (−)-stemoamide is also an anthelminthic. Somfai and coworkers employed a Negishi coupling in their synthesis of (−)-stemoamide.<ref>{{cite journal | vauthors = Torssell S, Wanngren E, Somfai P | title = Total synthesis of (-)-stemoamide | journal = The Journal of Organic Chemistry | volume = 72 | issue = 11 | pages = 4246–9 | date = May 2007 | pmid = 17451274 | doi = 10.1021/jo070498o }}</ref> The reaction was implemented mid-synthesis, forming an sp<sup>3</sup>-sp<sup>2</sup> c-c bond between β,γ-unsaturated ester and an intermediate diene '''4''' with a 78% yield of product '''5'''. Somfai completed the stereoselective total synthesis of (−)-stemoamide in 12-steps with a 20% overall yield.

[[File:Scheme8natprod2.png|600px|centre|Synthesis of (−)-stemoamide]]

Kibayashi and coworkers utilized the Negishi coupling in the total synthesis of [[Pumiliotoxin]] B. Pumiliotoxin B is one of the major toxic [[alkaloids]] isolated from Dendrobates pumilio, a Panamanian poison frog. These toxic alkaloids display modulatory effects on voltage-dependent [[sodium channels]], resulting in cardiotonic and myotonic activity.<ref name="Gusovsky_1992">{{cite journal | vauthors = Gusovsky F, Padgett WL, Creveling CR, Daly JW | title = Interaction of pumiliotoxin B with an "alkaloid-binding domain" on the voltage-dependent sodium channel | journal = Molecular Pharmacology | volume = 42 | issue = 6 | pages = 1104–8 | date = December 1992 | pmid = 1336116 }}</ref> Kibayashi employed the Negishi coupling late stage in the synthesis of Pumiliotoxin B, coupling a homoallylic sp<sup>3</sup> carbon on the zinc alkylidene indolizidine '''6''' with the (E)-vinyl iodide '''7''' with a 51% yield. The natural product was then obtained after deprotection.<ref>{{cite journal | vauthors = Aoyagi S, Hirashima S, Saito K, Kibayashi C |title=Convergent Approach to Pumiliotoxin Alkaloids. Asymmetric Total Synthesis of (+)-Pumiliotoxins A, B, and 225F |journal=The Journal of Organic Chemistry |year=2002 |volume=67 |issue=16 |pages=5517–5526 |doi=10.1021/jo0200466|pmid=12153249}}</ref>

:[[File:Scheme9natprod3.png|600px|Synthesis of Pumiliotoxin B|centre]]

δ-trans-tocotrienoloic acid isolated from the plant, Chrysochlamys ulei, is a natural product shown to inhibit [[DNA polymerase]] β (pol β), which functions to repair DNA via base excision. Inhibition of pol B in conjunction with other [[chemotherapy]] drugs may increase the [[cytotoxicity]] of these chemotherapeutics, leading to lower effective dosages. The Negishi coupling was implemented in the synthesis of δ-trans-tocotrienoloic acid by Hecht and Maloney coupling the sp<sup>3</sup> homopropargyl zinc reagent '''8''' with sp<sup>2</sup> vinyl iodide '''9'''.<ref>
{{cite journal | vauthors = Maloney DJ, Hecht SM | title = A stereocontrolled synthesis of delta-trans-tocotrienoloic acid | journal = Organic Letters | volume = 7 | issue = 19 | pages = 4297–300 | date = September 2005 | pmid = 16146411 | doi = 10.1021/ol051849t}}
</ref> The reaction proceeded with quantitative yield, coupling fragments mid-synthesis en route to the stereoselectively synthesized natural product δ-trans-tocotrienoloic acid.

:[[File:Scheme10natprod4.png|center|800px|Synthesis of δ-trans-tocotrienoloic acid]]

Smith and Fu demonstrated that their method to couple secondary nucleophiles with secondary alkyl electrophiles could be applied to the formal synthesis of α-cembra-2,7,11-triene-4,6-diol, a target with antitumor activity.  They achieved a 61% yield on a gram scale using their method to install an ''iso''-propyl group.  This method would be highly adaptable in this application for diversification and installing other alkyl groups to enable structure-activbity relationship (SAR) studies.<ref>{{Cite journal|last1=Smith|first1=Sean W.|last2=Fu|first2=Gregory C. |date=2008 |title=Nickel-Catalyzed Negishi Cross-Couplings of Secondary Nucleophiles with Secondary Propargylic Electrophiles at Room Temperature|journal=Angewandte Chemie International Edition |volume=47 |issue=48 |pages=9334–9336 |doi=10.1002/anie.200802784 |issn=1521-3773|pmc=2790060|pmid=18972493}}</ref>[[File:Synth1.png|center|frameless|601x601px]]Kirschning and Schmidt applied nickel catalyzed negishi cross-coupling to the first total synthesis of carolactone. In this application, they achieved 82% yield and dr = 10:1.<ref>{{Cite journal|last1=Schmidt|first1=Thomas|last2=Kirschning|first2=Andreas|date=2012|title=Total Synthesis of Carolacton, a Highly Potent Biofilm Inhibitor|url=https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.201106762|journal=Angewandte Chemie International Edition |volume=51 |issue=4 |pages=1063–1066|doi=10.1002/anie.201106762|pmid=22162345|issn=1521-3773}}</ref>[[File:Synth2.png|center|frameless|614x614px]]

==Preparation of organozinc precursors==
Alkylzinc reagents can be accessed from the corresponding alkyl bromides using iodine in dimethylacetamide (DMAC).<ref>
{{cite journal | vauthors = Huo S | title = Highly efficient, general procedure for the preparation of alkylzinc reagents from unactivated alkyl bromides and chlorides | journal = Organic Letters | volume = 5 | issue = 4 | pages = 423–5 | date = February 2003 | pmid = 12583734 | doi = 10.1021/ol0272693}}</ref> The catalytic I<sub>2</sub> serves to activate the zinc towards nucleophilic addition.

:[[File:Scheme11alkylzinc.png|330x330px|Preparation of alkylzinc reagent]]

Aryl zincs can be synthesized using mild reaction conditions via a [[Grignard reagens|Grignard]] like intermediate.<ref>{{cite journal | vauthors = Giovannini R, Knochel P |title=Ni(II)-Catalyzed Cross-Coupling between Polyfunctional Arylzinc Derivatives and Primary Alkyl Iodides |journal=Journal of the American Chemical Society |year=1998 |volume=120 |issue=43 |pages=11186–11187 |doi=10.1021/ja982520o}}</ref>

:<math chem title="Preparation of arylzinc reagent">\begin{matrix} {}\\
\ce{Ar-I ->[\begin{matrix}\ce{iPrMgCl}\\\text{THF}\end{matrix}][\ce{ZnBr2}] Ar-ZnBr}
\end{matrix}</math>

Organozincs can also be generated in situ and used in a one pot procedure as demonstrated by Knochel et al.<ref>{{Cite journal|last1=Sase|first1=Shohei|last2=Jaric|first2=Milica|last3=Metzger|first3=Albrecht|last4=Malakhov|first4=Vladimir|last5=Knochel|first5=Paul|date=2008-09-19|title=One-Pot Negishi Cross-Coupling Reactions of In Situ Generated Zinc Reagents with Aryl Chlorides, Bromides, and Triflates|url=https://pubs.acs.org/doi/10.1021/jo801063c|journal=The Journal of Organic Chemistry|language=en|volume=73|issue=18|pages=7380–7382|doi=10.1021/jo801063c|pmid=18693766|issn=0022-3263}}</ref>

[[File:RZnXscheme.png|center|frameless|375x375px]]

==Further reading==
*{{cite journal | vauthors = McCann LC, Hunter HN, Clyburne JA, Organ MG | title = Higher-order zincates as transmetalators in alkyl-alkyl negishi cross-coupling | journal = Angewandte Chemie | volume = 51 | issue = 28 | pages = 7024–7 | date = July 2012 | pmid = 22685029 | doi = 10.1002/anie.201203547 }}
*{{cite journal | vauthors = Yang Y, Oldenhuis NJ, Buchwald SL | title = Mild and general conditions for negishi cross-coupling enabled by the use of palladacycle precatalysts | journal = Angewandte Chemie | volume = 52 | issue = 2 | pages = 615–9 | date = January 2013 | pmid = 23172689 | pmc = 3697109 | doi = 10.1002/anie.201207750 }}

== See also ==
* [[CPhos]]
* [[Heck reaction]]
* [[Suzuki reaction]]

== References ==
{{reflist|32em}}

== External links ==
* [https://www.organic-chemistry.org/namedreactions/negishi-coupling.shtm The Negishi coupling] at www.organic-chemistry.org

[[Category:Carbon-carbon bond forming reactions]]
[[Category:Condensation reactions]]
[[Category:Name reactions]]