Negishi Coupling
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The Negishi coupling is a widely employed
transition metal In chemistry, a transition metal (or transition element) is a chemical element in the d-block of the periodic table (groups 3 to 12), though the elements of group 12 (and less often group 3) are sometimes excluded. The lanthanide and actinid ...
catalyzed
cross-coupling reaction In organic chemistry, a cross-coupling reaction is a reaction where two different fragments are joined. Cross-couplings are a subset of the more general coupling reactions. Often cross-coupling reactions require metal catalysts. One important re ...
. The reaction couples organic halides or triflates with organozinc compounds, forming
carbon–carbon bond A carbon–carbon bond is a covalent bond between two carbon atoms. The most common form is the single bond: a bond composed of two electrons, one from each of the two atoms. The carbon–carbon single bond is a sigma bond and is formed between on ...
s (C–C) in the process. A
palladium Palladium is a chemical element; it has symbol Pd and atomic number 46. It is a rare and lustrous silvery-white metal discovered in 1802 by the English chemist William Hyde Wollaston. He named it after the asteroid Pallas (formally 2 Pallas), ...
(0) species is generally utilized as the
catalyst Catalysis () is the increase in rate of a chemical reaction due to an added substance known as a catalyst (). Catalysts are not consumed by the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recycles quick ...
, though
nickel Nickel is a chemical element; it has symbol Ni and atomic number 28. It is a silvery-white lustrous metal with a slight golden tinge. Nickel is a hard and ductile transition metal. Pure nickel is chemically reactive, but large pieces are slo ...
is sometimes used. A variety of nickel catalysts in either Ni0 or NiII oxidation state can be employed in Negishi cross couplings such as Ni(PPh3)4, Ni(acac)2, Ni(COD)2 etc. \begin \\ + \ce \ \ce \ \end :* The leaving group X is usually
chloride The term chloride refers to a compound or molecule that contains either a chlorine anion (), which is a negatively charged chlorine atom, or a non-charged chlorine atom covalently bonded to the rest of the molecule by a single bond (). The pr ...
, 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 In organic chemistry, an allyl group is a substituent with the structural formula . It consists of a methylene bridge () attached to a vinyl group (). The name is derived from the scientific name for garlic, . In 1844, Theodor Wertheim isolated a ...
, alkynyl or propargyl. :* The halide X′ in the organozinc compound can be
chloride The term chloride refers to a compound or molecule that contains either a chlorine anion (), which is a negatively charged chlorine atom, or a non-charged chlorine atom covalently bonded to the rest of the molecule by a single bond (). The pr ...
,
bromine Bromine is a chemical element; it has chemical symbol, symbol Br and atomic number 35. It is a volatile red-brown liquid at room temperature that evaporates readily to form a similarly coloured vapour. Its properties are intermediate between th ...
or
iodine Iodine is a chemical element; it has symbol I and atomic number 53. The heaviest of the stable halogens, it exists at standard conditions as a semi-lustrous, non-metallic solid that melts to form a deep violet liquid at , and boils to a vi ...
and the organic residue R′ is alkenyl, aryl,
allyl In organic chemistry, an allyl group is a substituent with the structural formula . It consists of a methylene bridge () attached to a vinyl group (). The name is derived from the scientific name for garlic, . In 1844, Theodor Wertheim isolated a ...
,
alkyl In organic chemistry, an alkyl group is an alkane missing one hydrogen. The term ''alkyl'' is intentionally unspecific to include many possible substitutions. An acyclic alkyl has the general formula of . A cycloalkyl group is derived from a cy ...
, benzyl, homoallyl, and homopropargyl. :* The metal M in the catalyst is
nickel Nickel is a chemical element; it has symbol Ni and atomic number 28. It is a silvery-white lustrous metal with a slight golden tinge. Nickel is a hard and ductile transition metal. Pure nickel is chemically reactive, but large pieces are slo ...
or
palladium Palladium is a chemical element; it has symbol Pd and atomic number 46. It is a rare and lustrous silvery-white metal discovered in 1802 by the English chemist William Hyde Wollaston. He named it after the asteroid Pallas (formally 2 Pallas), ...
:* The
ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...
L in the catalyst can be triphenylphosphine, dppe, BINAP, chiraphos or XPhos. Palladium catalysts in general have higher
chemical yield In chemistry, yield, also known as reaction yield or chemical yield, refers to the amount of product obtained in a chemical reaction. Yield is one of the primary factors that scientists must consider in organic and inorganic chemical synthesis ...
s and higher
functional group In organic chemistry, a functional group is any substituent or moiety (chemistry), moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions r ...
tolerance. The Negishi coupling finds common use in the field of
total synthesis Total synthesis, a specialized area within organic chemistry, focuses on constructing complex organic compounds, especially those found in nature, using laboratory methods. It often involves synthesizing natural products from basic, commercially ...
as a method for selectively forming C-C bonds between complex synthetic intermediates. The reaction allows for the coupling of sp3, sp2, and sp carbon atoms, (see orbital hybridization) which make it somewhat unusual among the palladium-catalyzed coupling reactions. Organozincs are moisture and
air sensitive Air sensitivity is a term used, particularly in chemistry, to denote the reactivity of chemical compounds with some constituent of air. Most often, reactions occur with atmospheric oxygen (O2) or water vapor (H2O), although reactions with the other ...
, so the Negishi coupling must be performed in an
oxygen Oxygen is a chemical element; it has chemical symbol, symbol O and atomic number 8. It is a member of the chalcogen group (periodic table), group in the periodic table, a highly reactivity (chemistry), reactive nonmetal (chemistry), non ...
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 The Nobel Prize in Chemistry () is awarded annually by the Royal Swedish Academy of Sciences to scientists in the various fields of chemistry. It is one of the five Nobel Prizes established by the will of Alfred Nobel in 1895, awarded for outst ...
for the discovery and development of this reaction. Negishi and coworkers originally investigated the cross-coupling of organoaluminum reagents in 1976 initially employing Ni and Pd as the transition metal catalysts, but noted that Ni resulted in the decay of stereospecifity whereas Pd did not. 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. Alongside Richard F. Heck and 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. 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). The actual mechanism of oxidative addition is unresolved, though there are two likely pathways. One pathway is thought to proceed via an SN2 like mechanism resulting in inverted stereochemistry. The other pathway proceeds via concerted addition and retains stereochemistry. Though the additions are cis- the Pd(II) complex rapidly isomerizes to the trans- complex. 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. 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. ZnXR and ZnR2 can both be used as reactive reagents, and Zn is known to prefer four coordinate complexes, which means solvent coordinated Zn complexes, such as cannot be ruled out ''a priori''. Studies indicate competing equilibriums exist between cis- and trans- bis alkyl organopalladium complexes, but that the only productive intermediate is the cis complex. 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 In chemistry, the transition state of a chemical reaction is a particular configuration along the reaction coordinate. It is defined as the state corresponding to the highest potential energy along this reaction coordinate. It is often marked w ...
, 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. 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. A common
side reaction A side reaction is a chemical reaction that occurs at the same time as the actual main reaction, but to a lesser extent. It leads to the formation of by-product, so that the Yield (chemistry), yield of main product is reduced: : + B ->[] P1 : + C ...
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: : Ar–Pd–Ar′ + Ar′–Zn–X → Ar′–Pd–Ar′ + Ar–Zn–X : Ar′–Pd–Ar′ → Ar′–Ar′ + Pd(0) ''(homocoupling)'' : Ar–Zn–X + H2O → 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 Pd0 or PdII, nickel catalyzed systems can involve nickel of different oxidation states. 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. 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. One important factor when contemplating the mechanism of a nickel catalyzed cross coupling is that reductive elimination is facile from NiIII species, but very difficult from NiII species.  Kochi and Morrell provided evidence for this by isolating NiII complex Ni(PEt3)2(Me)(''o''-tolyl), which did not undergo reductive elimination quickly enough to be involved in this elementary step.


Scope

The Negishi coupling has been applied the following illustrative syntheses: *unsymmetrical 2,2'-bipyridines from 2-bromopyridine with tetrakis(triphenylphosphine)palladium(0), * biphenyl from ''o''-tolylzinc chloride and ''o''-iodotoluene and tetrakis(triphenylphosphine)palladium(0), *5,7-hexadecadiene from 1-decyne and (''Z'')-1-hexenyl iodide. Negishi coupling has been applied in the synthesis of hexaferrocenylbenzene: : with hexaiodidobenzene, diferrocenylzinc and tris(dibenzylideneacetone)dipalladium(0) in
tetrahydrofuran Tetrahydrofuran (THF), or oxolane, is an organic compound with the formula (CH2)4O. The compound is classified as heterocyclic compound, specifically a cyclic ether. It is a colorless, water- miscible organic liquid with low viscosity. It is ...
. 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 Organotin chemistry is the scientific study of the synthesis and properties of organotin compounds or stannanes, which are organometallic compounds containing tin–carbon bonds. The first organotin compound was diethyltin diiodide (), discovered ...
3 in a double transmetalation: : Examples of nickel catalyzed Negishi couplings include sp2-sp2, sp2-sp3, and sp3-sp3 systems.  In the system first studied by Negishi, aryl-aryl cross coupling was catalyzed by Ni(PPh3)4 generated ''in situ'' through reduction of Ni(acac)2 with PPh3 and (i-Bu)2AlH. :\ce 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. Reactions between sp3-sp3 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. This also works in some alkyl-aryl systems. Several asymmetric variants exist and many utilize Pybox ligands.


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. In 2003
Novartis Novartis AG is a Swiss multinational corporation, multinational pharmaceutical company, pharmaceutical corporation based in Basel, Switzerland. Novartis is one of the largest pharmaceutical companies in the world and was the eighth largest by re ...
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 Asthma is a common long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wh ...
. The Negishi coupling was used as an alternative to the Suzuki reaction providing improved yields, 73% on a 4.5 kg scale, of the desired benzodioxazole synthetic intermediate. :


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 A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical s ...
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. Additionally, Zn is more environmentally friendly than other metals such as 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. The major drawback of the Negishi coupling, aside from its water and oxygen sensitivity, is its relative lack of
functional group In organic chemistry, a functional group is any substituent or moiety (chemistry), moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions r ...
tolerance when compared to other cross-coupling reactions. (−)-stemoamide is a natural product found in the root extracts of ‘’Stemona tuberosa’’. These extracts have been used Japanese and Chinese
folk medicine Traditional medicine (also known as indigenous medicine or folk medicine) refers to the knowledge, skills, and practices rooted in the cultural beliefs of various societies, especially Indigenous groups, used for maintaining health and treatin ...
to treat respiratory disorders, and (−)-stemoamide is also an anthelminthic. Somfai and coworkers employed a Negishi coupling in their synthesis of (−)-stemoamide. The reaction was implemented mid-synthesis, forming an sp3-sp2 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. 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 Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels. Classification They are classified into 2 types: Function In e ...
, resulting in cardiotonic and myotonic activity. Kibayashi employed the Negishi coupling late stage in the synthesis of Pumiliotoxin B, coupling a homoallylic sp3 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. : δ-trans-tocotrienoloic acid isolated from the plant, Chrysochlamys ulei, is a natural product shown to inhibit
DNA polymerase A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create t ...
β (pol β), which functions to repair DNA via base excision. Inhibition of pol B in conjunction with other
chemotherapy Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...
drugs may increase the
cytotoxicity Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are toxic metals, toxic chemicals, microbe neurotoxins, radiation particles and even specific neurotransmitters when the system is out of balance. Also some types of d ...
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 sp3 homopropargyl zinc reagent 8 with sp2 vinyl iodide 9. The reaction proceeded with quantitative yield, coupling fragments mid-synthesis en route to the stereoselectively synthesized natural product 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.Kirschning and Schmidt applied nickel catalyzed negishi cross-coupling to the first total synthesis of carolacton. In this application, they achieved 82% yield and dr = 10:1.


Preparation of organozinc precursors

Alkylzinc reagents can be accessed from the corresponding alkyl bromides using iodine in dimethylacetamide (DMAC). The catalytic I2 serves to activate the zinc towards nucleophilic addition. : Aryl zincs can be synthesized using mild reaction conditions via a Grignard like intermediate. :\begin \\ \ce \end Organozincs can also be generated in situ and used in a one pot procedure as demonstrated by Knochel et al. :\begin\\ \ce \end


Further reading

* *


See also

* CPhos * Heck reaction * Suzuki reaction


References

{{reflist, 32em


External links


The Negishi coupling
at www.organic-chemistry.org Carbon-carbon bond forming reactions Condensation reactions Name reactions