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. They are the elements that can ...
catalyzed
cross-coupling reaction In organic chemistry, a cross-coupling reaction is a reaction where two fragments are joined together with the aid of a metal catalyst. In one important reaction type, a main group organometallic compound of the type R-M (R = organic fragment, M = ...
. The reaction couples organic halides or
triflates In organic chemistry, triflate (systematic name: trifluoromethanesulfonate), is a functional group with the formula and structure . The triflate group is often represented by , as opposed to −Tf, which is the triflyl group, . For example, ' ...
with
organozinc compound Organozinc compounds in organic chemistry contain carbon (C) to zinc (Zn) chemical bonds. Organozinc chemistry is the science of organozinc compounds describing their physical properties, synthesis and reactions.The Chemistry of Organozinc Compoun ...
s, forming carbon-carbon bonds (C-C) in the process. A
palladium Palladium is a chemical element with the symbol Pd and atomic number 46. It is a rare and lustrous silvery-white metal discovered in 1803 by the English chemist William Hyde Wollaston. He named it after the asteroid Pallas, which was itself na ...
(0) species is generally utilized as the metal
catalyst Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
, though
nickel Nickel is a chemical element with 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 slow to ...
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. : :* The leaving group X is usually
chloride The chloride ion is the anion (negatively charged ion) Cl−. It is formed when the element chlorine (a halogen) gains an electron or when a compound such as hydrogen chloride is dissolved in water or other polar solvents. Chloride salts ...
,
bromide A bromide ion is the negatively charged form (Br−) of the element bromine, a member of the halogens group on the periodic table. Most bromides are colorless. Bromides have many practical roles, being found in anticonvulsants, flame-retardant ...
, or
iodide An iodide ion is the ion I−. Compounds with iodine in formal oxidation state −1 are called iodides. In everyday life, iodide is most commonly encountered as a component of iodized salt, which many governments mandate. Worldwide, iodine defic ...
, but
triflate In organic chemistry, triflate (systematic name: trifluoromethanesulfonate), is a functional group with the formula and structure . The triflate group is often represented by , as opposed to −Tf, which is the triflyl group, . For example, ' ...
and acetyloxy groups are feasible as well. X = Cl usually leads to slow reactions. :* The organic residue R =
alkenyl In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond. Alkene is often used as synonym of olefin, that is, any hydrocarbon containing one or more double bonds.H. Stephen Stoker (2015): General, Organic, an ...
,
aryl In organic chemistry, an aryl is any functional group or substituent derived from an aromatic ring, usually an aromatic hydrocarbon, such as phenyl and naphthyl. "Aryl" is used for the sake of abbreviation or generalization, and "Ar" is used as ...
,
allyl In organic chemistry, an allyl group is a substituent with the structural formula , where R is the rest of the molecule. It consists of a methylene bridge () attached to a vinyl group (). The name is derived from the scientific name for garlic, ...
,
alkynyl \ce \ce Acetylene \ce \ce \ce Propyne \ce \ce \ce \ce 1-Butyne In organic chemistry, an alkyne is an unsaturated hydrocarbon containing at least one carbon—carbon triple bond. The simplest acyclic alkynes with only one triple bond and no ...
or
propargyl In organic chemistry, the propargyl group is a functional group of 2-propynyl with the structure . It is an alkyl group derived from propyne (). The term propargylic refers to a saturated position ( ''sp''3-hybridized) on a molecular framework n ...
. :* The halide X' in the organozinc compound can be
chloride The chloride ion is the anion (negatively charged ion) Cl−. It is formed when the element chlorine (a halogen) gains an electron or when a compound such as hydrogen chloride is dissolved in water or other polar solvents. Chloride salts ...
,
bromine Bromine is a chemical element with the symbol Br and atomic number 35. It is the third-lightest element in group 17 of the periodic table (halogens) and is a volatile red-brown liquid at room temperature that evaporates readily to form a simila ...
or
iodine Iodine is a chemical element with the symbol I and atomic number 53. The heaviest of the stable halogens, it exists as a semi-lustrous, non-metallic solid at standard conditions that melts to form a deep violet liquid at , and boils to a vi ...
and the organic residue R' is
alkenyl In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond. Alkene is often used as synonym of olefin, that is, any hydrocarbon containing one or more double bonds.H. Stephen Stoker (2015): General, Organic, an ...
,
aryl In organic chemistry, an aryl is any functional group or substituent derived from an aromatic ring, usually an aromatic hydrocarbon, such as phenyl and naphthyl. "Aryl" is used for the sake of abbreviation or generalization, and "Ar" is used as ...
,
allyl In organic chemistry, an allyl group is a substituent with the structural formula , where R is the rest of the molecule. It consists of a methylene bridge () attached to a vinyl group (). The name is derived from the scientific name for garlic, ...
,
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 is derived from a cycloalk ...
,
benzyl In organic chemistry, benzyl is the substituent or molecular fragment possessing the structure . Benzyl features a benzene ring () attached to a methylene group () group. Nomenclature In IUPAC nomenclature, the prefix benzyl refers to a substi ...
, homoallyl, and homopropargyl. :* The metal M in the catalyst is
nickel Nickel is a chemical element with 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 slow to ...
or
palladium Palladium is a chemical element with the symbol Pd and atomic number 46. It is a rare and lustrous silvery-white metal discovered in 1803 by the English chemist William Hyde Wollaston. He named it after the asteroid Pallas, which was itself na ...
:* The
ligand In coordination chemistry, a ligand is an ion or molecule (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 electr ...
L in the catalyst can be
triphenylphosphine Triphenylphosphine (IUPAC name: triphenylphosphane) is a common organophosphorus compound with the formula P(C6H5)3 and often abbreviated to P Ph3 or Ph3P. It is widely used in the synthesis of organic and organometallic compounds. PPh3 exists a ...
,
dppe 1,2-Bis(diphenylphosphino)ethane (dppe) is an organophosphorus compound with the formula (PhPCH) (Ph = phenyl). It is a commonly used bidentate ligand in coordination chemistry. It is a white solid that is soluble in organic solvents. Preparation ...
,
BINAP BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) is an organophosphorus compound. This chiral diphosphine ligand is widely used in asymmetric synthesis. It consists of a pair of 2-diphenylphosphinonaphthyl groups linked at the 1 and 1â ...
or
chiraphos Chiraphos is a chiral diphosphine employed as a ligand in organometallic chemistry. This bidentate ligand chelates metals via the two phosphine groups. Its name is derived from its description — being both ''chiral'' and a ''phosphine''. As ...
Palladium catalysts in general have higher
chemical yield In chemistry, yield, also referred to as reaction yield, is a measure of the quantity of moles of a product formed in relation to the reactant consumed, obtained in a chemical reaction, usually expressed as a percentage. Yield is one of the pr ...
s and higher
functional group In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the rest ...
tolerance. The Negishi coupling finds common use in the field of
total synthesis Total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially-available precursors. It usually refers to a process not involving the aid of biological processes, which distinguishes ...
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 In chemistry, orbital hybridisation (or hybridization) is the concept of mixing atomic orbitals to form new ''hybrid orbitals'' (with different energies, shapes, etc., than the component atomic orbitals) suitable for the pairing of electrons to f ...
) which make it somewhat unusual among the
palladium-catalyzed coupling reactions In organic chemistry, a cross-coupling reaction is a reaction where two fragments are joined together with the aid of a metal catalyst. In one important reaction type, a main group organometallic compound of the type R-M (R = organic fragment, M = ...
. 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 the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as wel ...
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 was a Japanese chemist who was best known for his discovery of the Negishi coupling. He spent most of his career at Purdue University in the United States, where he was the Herbert C. Brown Distinguished Professor and the director of the Negis ...
who was a co-recipient of the 2010
Nobel Prize in Chemistry ) , image = Nobel Prize.png , alt = A golden medallion with an embossed image of a bearded man facing left in profile. To the left of the man is the text "ALFR•" then "NOBEL", and on the right, the text (smaller) "NAT•" then "M ...
for the discovery and development of this reaction. Negishi and coworkers originally investigated the cross-coupling of
organoaluminum Organoaluminium chemistry is the study of compounds containing bonds between carbon and aluminium. It is one of the major themes within organometallic chemistry. Illustrative organoaluminium compounds are the dimer trimethylaluminium, the monome ...
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 Oxidative addition and reductive elimination are two important and related classes of reactions in organometallic chemistry. Oxidative addition is a process that increases both the oxidation state and coordination number of a metal centre. Oxidat ...
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 Transmetalation (alt. spelling: transmetallation) is a type of organometallic reaction that involves the transfer of ligands from one metal to another. It has the general form: :M1–R + M2–R′ → M1–R′ + M2–R where R and R′ can be, but ...
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 In computer networks, rate limiting is used to control the rate of requests sent or received by a network interface controller. It can be used to prevent DoS attacks and limit web scraping. Research indicates flooding rates for one zombie machine ...
and a complete mechanistic understanding of this step has not yet been reached though several studies have shed light on this process. It was recently determined that alkylzinc species must go on to form a 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 Reductive elimination is an elementary step in organometallic chemistry in which the oxidation state of the metal center decreases while forming a new covalent bond between two ligands. It is the microscopic reverse of oxidative addition, and is ...
, 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 wi ...
, 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 of main product is reduced: : + B ->[] P1 : + C ->[] P2 P1 is th ...
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 In organic chemistry, dehalogenation is a set of chemical reactions that involve the cleavage of carbon- halogen bonds; as such, it is the inverse reaction of halogenation. Dehalogenations come in many varieties, including defluorination (remov ...
)'' 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 Transmetalation (alt. spelling: transmetallation) is a type of organometallic reaction that involves the transfer of ligands from one metal to another. It has the general form: :M1–R + M2–R′ → M1–R′ + M2–R where R and R′ can be, but ...
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'-bipyridine The comma is a punctuation mark that appears in several variants in different languages. It has the same shape as an apostrophe or single closing quotation mark () in many typefaces, but it differs from them in being placed on the baseline o ...
s from 2-bromopyridine with
tetrakis(triphenylphosphine)palladium(0) Tetrakis(triphenylphosphine)palladium(0) (sometimes called quatrotriphenylphosphine palladium) is the chemical compound d(P(C6H5)3)4 often abbreviated Pd( PPh3)4, or rarely PdP4. It is a bright yellow crystalline solid that becomes brown upon de ...
, *
biphenyl Biphenyl (also known as diphenyl, phenylbenzene, 1,1′-biphenyl, lemonene or BP) is an organic compound that forms colorless crystals. Particularly in older literature, compounds containing the functional group consisting of biphenyl less one ...
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) Tris(dibenzylideneacetone)dipalladium(0) or d2(dba)3is an organopalladium compound. The compound is a complex of palladium(0) with dibenzylideneacetone (dba). It is a dark-purple/brown solid, which is modestly soluble in organic solvents. Becau ...
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 ma ...
. The yield is only 4% signifying substantial crowding around the aryl core. In a novel modification palladium is first oxidized by the
haloketone In organic chemistry, an α-haloketone is a functional group consisting of a ketone group or more generally a carbonyl group with an α-halogen substituent. α-haloketones are alkylating agents. Prominent α-haloketones include phenacyl bromide ...
''2-chloro-2-phenylacetophenone'' 1 and the resulting palladium OPdCl complex then accepts both the
organozinc compound Organozinc compounds in organic chemistry contain carbon (C) to zinc (Zn) chemical bonds. Organozinc chemistry is the science of organozinc compounds describing their physical properties, synthesis and reactions.The Chemistry of Organozinc Compoun ...
2 and the
organotin compound Organotin compounds or stannanes are chemical compounds based on tin with hydrocarbon substituents. Organotin chemistry is part of the wider field of organometallic chemistry. The first organotin compound was diethyltin diiodide (), discovered by ...
3 in a double
transmetalation Transmetalation (alt. spelling: transmetallation) is a type of organometallic reaction that involves the transfer of ligands from one metal to another. It has the general form: :M1–R + M2–R′ → M1–R′ + M2–R where R and R′ can be, but ...
: : Recent conditions for the Negishi reaction have demonstrated extremely broad scope and tolerance of a broad range of functional groups and heteroaromatic nuclei and proceed at or near room temperature. 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. 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 The Suzuki reaction is an organic reaction, classified as a cross-coupling reaction, where the coupling partners are a boronic acid and an organohalide and the catalyst is a palladium(0) complex. It was first published in 1979 by Akira Suzuki, ...
and
Heck reaction The Heck reaction (also called the Mizoroki–Heck reaction) is the chemical reaction of an unsaturated halide (or triflate) with an alkene in the presence of a base and a palladium catalyst (or palladium nanomaterial-based catalyst) to form a s ...
, 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-American multinational pharmaceutical corporation based in Basel, Switzerland and Cambridge, Massachusetts, United States (global research).name="novartis.com">https://www.novartis.com/research-development/research-loc ...
employed a Negishi coupling in the manufacture of PDE472, a
phosphodiesterase A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, ''phosphodiesterase'' refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many oth ...
type 4D inhibitor, which was being investigated as a drug lead for the treatment of
asthma Asthma is a 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 wheezing, cou ...
. 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 syn ...
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 Stille reaction is a chemical reaction widely used in organic synthesis. The reaction involves the coupling of two organic groups, one of which is carried as an organotin compound (also known as organostannanes). A variety of organic electroph ...
. Though the Negishi coupling historically has not been used as much as the Stille or Suzuki coupling, recent years have seen the Negishi coupling gain a foothold in the field of
synthetic chemistry As a topic of chemistry, chemical synthesis (or combination) is the artificial execution of chemical reactions to obtain one or several products. This occurs by physical and chemical manipulations usually involving one or more reactions. In mod ...
, so much so that it has become the cross-coupling method of choice for select synthetic tasks. 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 a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the rest ...
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) comprises medical aspects of traditional knowledge that developed over generations within the folk beliefs of various societies, including indigenous peoples, before the ...
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 Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar st ...
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 and can be classified according to the trigger that opens the chann ...
, 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 ...
β (pol β), which functions to repair DNA via base excision. Inhibition of pol B in conjunction with other
chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...
drugs may increase the
cytotoxicity Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (''Bitis arietans'') or brown recluse spider (''Loxosceles reclusa''). Cell physiology Treating cells ...
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 carolactone. 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.


See also

* CPhos *
Heck reaction The Heck reaction (also called the Mizoroki–Heck reaction) is the chemical reaction of an unsaturated halide (or triflate) with an alkene in the presence of a base and a palladium catalyst (or palladium nanomaterial-based catalyst) to form a s ...
*
Suzuki reaction The Suzuki reaction is an organic reaction, classified as a cross-coupling reaction, where the coupling partners are a boronic acid and an organohalide and the catalyst is a palladium(0) complex. It was first published in 1979 by Akira Suzuki, ...


References

{{reflist, 32em


External links


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