Advanced Synthesis and Catalysis ─ Carbene
Free carbene
Carbenes can exist in either singlet or triplet state whereas the
ground state of nitrene is always singlet. If there is a large gap
between the σ and p orbitals of the carbene, the ground state
will be singlet due to the relatively lower energy cost in electron
pairing. Carbenes with a p-donor atom (N, O, or halogen) can
also promote electron pairing.
Chen
Carbenes can be generated by α-elimination or decomposition
of ketene, diazo, or diazirine compounds. Carbenes can also
be generated by thermolysis. Flash vacuum pyrolysis (FVP)
allows heating the reactant at very high temperature for a short
period of time, typically > 500 ºC for 0.01 s in gas phase.
Carbene is normally unstable and undergoes rearrangement
readily.
Carbenes can also be formed by Bamford–Stevens reaction in
aprotic solvents. In protic solvents, the carbenium ion is formed
instead. This reaction is mechanistically similar to the Shapiro
reaction that generates vinyl carbanion.
In Wolff rearrangement and the Arndt–Eistert homologation,
carbene is generated by decomposition of diazoketone
promoted by photolysis or Ag(I) or Cu(II) catalysts.
Chen
The Corey–Fuch reaction is also a one-carbon homologatioin
reaction that generates terminal alkyne from aldehyde through
a vinylidene–acetylene rearrangement. The Seyferth–Gilbert
reaction can be viewed as the Horner–Emmons version of the
Wittig-type Corey–Fuch reaction. The Bestmann-Ohira
reaction is a modified Seyferth–Gilbert reaction with the
generation of the diazo nucleophile by deacetylation under
milder conditions.
Advanced Synthesis and Catalysis ─ Carbene
Skattebøl rearrangement generates a carbene from
dibromocyclopropane. Subsequent rearrangement yields
allene. When an adjacent olefin is present, cyclopentadiene is
formed.
Buchner reaction is a method for seven-membered ring
synthesis via ring-expansion. Cyclopropanation of a six-
membered aromatic ring with diazo compounds followed by a
rearrangement gives cycloheptatrienes.
Chen
Thiamine (vitamine B1) is a N-heterocyclic carbene (NHC) that
catalyzes benzoin condensation. This organocatalysis reaction
was first documented more than six decades ago, and the
mechanism of this umpolung reaction was established by
Breslow.
Advanced Synthesis and Catalysis ─ Carbene
Various NHC catalysts, including chiral versions, have been
developed. The scope of this carbonyl umpolung reaction has
also been explored extensively. Stetter demonstrated in 1976
that thiazolium-catalyzed nucleophilc addition also work with
Michael acceptors. Both intra- and intermolecular variants of
the Stetter reaction have been reported. Glorius also found
that cross-condensation of aldehydes/imines with enals gives
γ- or β-lactones depending on the reaction conditions.
Chen
Bode reported the use of NHC to catalyze internal redox of
epoxyaldehyde to generate activated carboxylate for
esterification. He has further shown that NHC can catalyze
asymmetric Diels-Alder reaction of azadienes and electron-
deficient enals.
Advanced Synthesis and Catalysis ─ Carbene
Advanced Synthesis and Catalysis ─ Carbene
Metal carbenoid
The reactivity of metal carbenoids is largely determined by the
π-donor ability of the carbene ligand. Metal carbenoids with
substituents capable of π-interactions, for example, N, O, Cl,
and Ph, are call Fischer carbenes. These electrophilic
complexes react with nucleophiles through the coordinating
carbon of the singlet carbene ligand. Metal carbenoids without
these substitutions, for example, methylene and alkylidene,
require substantial π-donation from the meal are called
Schrock carbene. These nucleophilic complexes react with
electrophiles through the coordinating carbon of the triplet
carbene ligand. However, reversed reactivity has been
observed. For example, methylene ligands on a positively
charged metal complex can be electrophilic.
Chen
Fischer carbenes are typically prepared by electrophilic O-
alkylation of acyl complexes that was synthesized by
nucleophilic alkylation of carbonyl complexes. Cationic
carbenoids can be prepared by alkylation or protonation of
neutral acyl complexes.
Schrock carbenes are typically prepared by removal of an α
hydrogen from an alkyl ligand. The loss of the α hydrogen
atom can be induced by steric crowding or α-elimination. They
can also be prepared by alkylidene transfer from phosphoranes
or other metals.
Advanced Synthesis and Catalysis ─ Carbene
Dötz discovered in 1975 that Fischer carbenes can react with
alkyne to give naphthols. Increasing the electrophilicity of the
carbenoids leads to more reactive complexes. The order of
reactivity is :CPh2 > :C(OR)Ph > :C(NR2)Ph and CO >> PR3,
but the reactivity is suppressed when performing the reaction in
the presence of excess CO. Terminal alkynes react to yield 2-
substituted naphtols selectively whereas internal alkynes react
with low regioselectivity.
Chen
Wulff has extended the scope of Dötz reaction to vinyl Fischer
carbenes. Vinyl and alkynyl Fischer carbenes are also good
dienophiles. The Diels–Alder reaction product of alkynyl
Fischer carbenes is a vinyl Fischer carbene that can participate
in Dötz reaction.
Advanced Synthesis and Catalysis ─ Carbene
In addition to participating in Dötz reaction, Fischer carbenes
can react with alkynes to give indenes, enones, or pyrones.
Chen
Fischer carbenes can also react with C=X groups through
ketene-type chemistry under photolytic conditions and enolate-
type chemistry under thermal conditions. Vinyl Fisher carbenes
undergo conjugate addition with hindered enolates and 1,2-
addition with unhindered enolates.
Advanced Synthesis and Catalysis ─ Carbene
Schrock carbenes can be viewed as the metal version of Wittig
reagents but much more reactive because of the oxophilicity of
the metal. In addition to aldehydes, they also react with esters
and amides to give enol ethers and enamides. The most useful
carbene for this type of reaction is the Tebbe’s reagent
Cp2TiCH2ClAlMe2. In the presence of pyridine, Tebbe’s
reagent is synthetically equivalent to Cp2Ti=CH2.
Chen
Tebbe’s reagent is also very reactive toward olefins, forming
stable metallacylces in the presences of base. These
metallacycles readily exchange with other olefins via
metathesis to give new metallacycles.
Fischer carbenes can react with olefins to form cyclopropanes
but the efficiency is low. Electrophilic, cationic iron carbenes,
however, are exceptionally efficient cyclopropanating agents as
first demonstrated by Helquist and Brookhart. Carreira has
recently shown that Fe(TPP)Cl catalyzes cyclopropanation in
6 M KOH with in situ generation of diazomethane.
Simmons–Smith cyclopropanation reaction can be directed by
polar functional groups. The generally accepted mechanism,
however, does not involve copper that consists up to 10% of
the alloy. The activation of Zn by Cu possibly at the surface of
the alloy is essential to this reaction. The use of Et2Zn/CH2I2 to
generate the carbenoid suppresses polymerization. Various
chiral auxiliaries and additives have been developed to effect
asymmetric cyclopropanation.
Chen
Copper(I), cobalt(II), palladium(II), irridium(III), ruthenium(II) and
rhodium(0/II) complexes can all catalyze the decomposition of
diazo compounds to give carbenoids that cyclopropanate
olefins. Doyle has demonstrated the intermediacy of metal
carbenoid and the coordination of olefin to metal. One or two
electron-withdrawing or vinyl/aryl groups are typically used to
stabilize the diazo compounds. Asymmetric cyclopropanation
was first achieved by Evans using the Cu-BOX catalyst system.
In addition to diazos, phenyliodonium ylides can also be used
as the carbene source.
Advanced Synthesis and Catalysis ─ Carbene
Advanced Synthesis and Catalysis ─ Carbene
In addition to cyclopropanation, metal carbenoids are also
highly reactive toward C–H and X–H insertion. The distribution
of the products can be controlled by the catalyst ligands.
Intramolecular C–H insertion generally gives five-membered
ring products. Researchers at Merck successfully applied the
rhodium-catalyzed N–H insertion to the synthesis of
thienamycin.
Chen
Doyle and Davies have each developed a chiral rhodium
catalyst system for asymmetric C–H insertion reactions.
Davies has also coupled C–H insertion with sigmatropic
rearrangement to establish allylic quaternary centers.
Ibata found in 1974 that decomposition of diazo compounds in
the presence of a nearby carbonyl group gives carbonyl ylides
that undergo 1,3-dipolar cycloaddition. This type of chemistry
was later studied by Padwa extensively.
Chen Advanced Synthesis and Catalysis ─ Carbene
Decomposition of diazo compounds in the presence of an
allylic sulfide, halide, amine, or ether gives hetero ylides that
undergo sigmatropic rearrangement to give C–X insertion
products. Early studies under photo or thermal conditions
leads to considerable cyclopropanation products. Krimse found
in 1968 that copper carbenoids favor the nucleophilic addition
of the heteroatom. The scope of this reaction was expanded by
Doyle and later by Wood.
Advanced Synthesis and Catalysis ─ Carbene
Nitrene
Breslow showed in 1982 that inter- and intramolecular C–H
amination can be catalyzed by Mn(III)-tetraphenylporphyrin
(TPP), Fe(III)-TPP, or Rh2(OAc)4.
Du Bois found in 2001 that both 1,2- and 1,3- functionalization
can be achieved to form oxazolidinones and oxathiazinanes.
Chen
Du Bois later developed nitrene insertion chemistry for the
synthesis of cyclic ureas and guanidines. Bridged ligands were
introduced as mechanistic studies indicated that ligand
dissociation is the major pathway for catalyst decomposition.
Intermolecular nitrene C–H insertion at the benzylic and tertiary
positions and catalytic asymmetric C–H amination with good
levels of enantioselectivity have also been achieved.
Advanced Synthesis and Catalysis ─ Carbene
Metathesis
In addition to cyclopropanation and C–H insertion, metathesis
is another important metal carbenoid-catalyzed reaction that
has found wide applications in synthetic, macromolecular and
biological chemistry. First observed as a thermodynamic
disproportionation reaction of olefins in 1956, Eleuterio at
DuPont reported that passing propylene over a molybdenum-
on-aluminum catalyst gave a mixture of propylene, ethylene
and 1-butene that polymerize into a propylene-ethylene
copolymer. Furthermore, the polymer obtained from
cyclopentene “looked like somebody took a pair of scissors,
opened up cyclopentene, and neatly sewed it up again.”
Meanwhile, Peters and Evering at Standard Oil found that
propylene combined with molybdenum oxide on alumina
treated with triisobutyl aluminum yields ethylene and butene.
Banks and Bailey at Phillips Petroleum later reported the
disproportionation of propylene to ethylene and butene using
molybdenum hexacarbonyl supported on alumina in 1964.
Natta also found in 1964 that cyclopentene polymerize in the
presence of tungsten or molybdenum halides.
Chen
Calderon at Goodyear Tire & Rubber discovered that internal
olefins exposed to tungsten hexachloride, ethylaluminum
dichloride and ethanol would undergo an interchange process.
For example, the reaction of 2-pentene gives a mixture of 2-
butene, 2-pentene and 3-hexene. Based on this observation,
Calderon concluded that one carbon of the double bond of one
olefin, along with everything attached to it, exchanges place
with one carbon of the double bond of the other olefin, along
with everything attached to it. Further experiments with butene
and 2-butene-d8 as well as 2-pentene and 6-dodecene
confirmed this conclusion. Mol also independently reached the
same conclusion by studying the metathesis products of 14C-
labeled propene.
Calderon coined the term “metathesis“, and proposed in 1968 a
three-step mechanism involving the formation of a metal-
coordinated cyclobutane. Petti suggested the formation of a
tetramethylene complex intermediate in 1971, and Grubbs a
metallacyclopentane intermediate in 1972.
Advanced Synthesis and Catalysis ─ Carbene
Chauvin at the French Petroleum Institute proposed in 1971
that olefin metathesis is initiated by a metal carbenoid that
reacts with an olefin to form a metallacyclobutane. This
intermediate then breaks apart to form a new olefin and a new
metal carbenoid that propagates the reaction. This mechanism
was inspired by the report of carbenoid (CO)5W=C(CH3)(OCH3)
by Fischer, ring-opening polymerization of cyclopentene by
Natta, and disproportionation of propylene by Banks all in 1964.
Chen
The Chauvin mechanism involves the formation of a
“nonstabilized”, electron-rich metal carbenoid intermediate with
an α-hydrogen on the carbene ligand. Schrock demonstrated
in 1974 that this type of complexes can be stable.
Casey found in 1974 during studying cyclopropanation that
(CO)5W=CPh2 can react with isobutene to give 1,1-
diphenylethene and 1-methoxy-1-phenylethylene. These
experiments provided the key evidence for the metathesis
reactivity of metal carbenoids.
Advanced Synthesis and Catalysis ─ Carbene
Katz studied in 1975 the kinetics of the Mo(PPh3)2Cl2(NO)2-
catalyzed metathesis of cyclooctene, trans-2-butene and trans-
4-octene in the presence of Me3Al2Cl3. Extrapolation of the
product distribution to time zero suggest that the C14 product
was formed directly from the starting materials. This
experiment rules out the mechanisms proposed by Calderon,
Petti and Grubbs wherein the C14 diene would be a secondary
product derived from the direct metathesis products.
At the same time, Grubbs used deuterium labeled olefins to
track the exchange pattern of olefinic groups in metathesis.
They found that the product distribution agrees with the
Chauvin mechanism instead of the pairwise-type mechanism.
Chen
Katz showed in 1976 that the Casey carbene (CO)5W=CPh2 is
a well-defined catalyst for metathesis. No Lewis acid activator
is needed. He also delineated the “directional specificity”, i.e.,
regioselectivity of metathesis of unsymmetrical olefins.
It has been known since 1970s that Fischer carbenes catalyze
polymerization of acetylenes and Katz predicted the feasibility
of alkyne metathesis. Schrock reported in 1981 the first metal
alkylidyne complex-catalyzed alkyne metathesis. Katz later
reported the first ene-yne metathesis in 1985.
Advanced Synthesis and Catalysis ─ Carbene
Whereas sterically crowded high oxidation state “homoleptic” or
“peralkyl” metal complexes lacking a β-hydrogen atom, for
example, M[CH2Si(CH3)3]4, M(CH2C6H5)4, and M[CH2C(CH3)3]4
(M = Ti, Zr, or Hf) are relatively stable as expected, it is
intriguing that W(CH3)6 prepared by Wilkinson, unlike M(CH3)4
(M = Ti, Zr, or Hf), is also stable. At the same time, Schrock
studied the chemistry of high oxidation state peralkyl tantalum
complexes that is relatively stable in its highest possible
oxidation state. He found that Ta(CH3)3Cl2 reacts with MeLi to
give volatile, yellow, crystalline Ta(CH3)5. While much less
stable than W(CH3)6, this unhindered, highly electron-deficient
10-electron complex is much more stable than Hf(CH3)4,
decomposing above 0 ºC bimolecularly.
Inspired by Wilkinson’s report of a carbyne-bridged tantalum
dimer, Schrock probed the limit of steric crowding with the
neopentyl ligand. Surprisingly, an orange, crystalline, and
thermally stable carbene complex was formed in quantitative
yield instead.
Chen
The tantalum neopentylidene (Me3CCH2)3Ta=CHCMe3 is the
first example of a stable transition metal carbenoid of the
M=CHR type. The exact mechanism for the unprecedented
intramolecular hydrogen abstraction remains unclear, but it is
likely that one α-hydrogen is activated by agostic interaction
with the metal. This Schrock carbene, unlike Fischer carbenes,
is highly electron-deficient and polarize in the way opposite to
that of the Fischer carbenes. Further deprotonation gives the
neopentylidyne complex [(Me3CCH2)3Ta≡CCMe3]–. The metal-
methylene species Cp2Ta=CH2(CH3) can also be prepared
through deprotonation. This 18-electron complex decomposes
slowly at 25 ºC through a bimolecular pathway.
Electron deficient tantalum and niobium alkylidenes react with
olefins readily to give metalacyclobutane intermediates that
rearrange via a β-hydride process. The alkylidene chain
reaction never started thus giving no metathesis products.
Advanced Synthesis and Catalysis ─ Carbene
Schrock later found that replacing the chloride ligand(s) with t-
butoxide gives catalytically active metathesis niobium and
tantalum complexes. He also showed that an 18-electron oxo
neopentylidene complex of tungsten generated from ligand
transfer gives an active metathesis complex, especially in the
presence of a trace amount of AlCl3.
Based on these observations, Schrock determined that an
isolable metathesis catalyst should have a neopentylidene
ligand and two oxide ligands. Using hexafluoro-tert-butoxide
dramatically increases the electrophilicity of the metal and thus
the rate of the reaction of the metal complex with an olefin.
Further replacement of the oxo ligand with an imido ligand that
is sterically protected by a large R group prevents bimolecular
decomposition.
Chen
Extending the alkoxide and neopentyl chemistry, Schrock
successfully prepared stable metal-alkylidyne complexes and
demonstrated the catalytic activity toward alkyne metathesis.
The metallocyclbutadiene intermediate has been isolated and
characterized by X-ray. He further showed that W≡W species
undergo metathesis with alkyne and nitrile but not dinitrogen.
Grubbs has also characterized by NMR and studied the
reactivity of the metallocyclobutane obtained from reacting
Tebbe’s reagent with isopentene or neohexene.
Advanced Synthesis and Catalysis ─ Carbene
Schrock has also demonstrated that deprotonation of the amido
ligand and protonation of the metal neopentylidyne yields imido
neopentylidene complexes. X-ray analysis reveals that the
anti-isomer with tert-butyl group pointing toward the imido
ligand is favored. This reaction allows for easy introduction of
different imido ligands.
Regarding the cleavage of dinitrogen, certain bacteria catalyze
nitrogen fixation by a two-component metalloprotein system
consisting an iron (Fe)-protein coupling hydrolysis of ATP to
electron transfer and a molybdenum-iron (MoFe)-protein
binding to dinitrogen. Shilov found several transition metal
systems promoting the reduction of dinitrogen, and Cummins
reported in 1995 a triamido molybdenum species that cleaves
N≡N effectively to give N≡Mo through a bimetallic reaction.
Chen
Because Mo–L is generally weaker than W–L, replacing
tungsten with molybdenum solves issues associated with slow
release of olefin from unsubstituted tungstenacyclobutane. The
metathesis reaction favored by the syn or anti isomer is case-
dependent, and the rotation barrier of the alkylidene ligand can
be tuned by the electronic properities of the alkoxide ligand (by
a factor of 106). The rotation is faster with tert-butoxide and
slower with hexafluoro-tert-butoxide. Consequently, the
metathesis rate and stereoselectivity can be tuned by varying
the alkoxide and the imido groups. Chiral Schrock catalysts
with biaryl ligands have also been developed.
Advanced Synthesis and Catalysis ─ Carbene
During the synthesis of polymeric ionophores by ring-opening
metathesis polymerization (ROMP) of 7-oxo-norbornenes,
Grubbs found that ruthenium salts have better functional group
tolerance than the Schrock tungsten alkylidenes. Based on this
observation, he developed the first class of metathesis
catalysts stable to protic solvents and compatible with aldehyde
and ketone groups. Switching the triphenylphosphine ligands
to electron-rich trialkylphosphines significantly improved the
reactivity and air-stability (days vs. minutes in the solid state).
Because the rate of propagation is much faster than the rate of
initiation, the resulting polymer has high molecular weight with
broad distribution.
Chen
To enable the large-scale synthesis of ruthenium metathesis
catalyst, Grubbs developed a new method based on the use of
a diazo precursor and reported in 1995 the first air-stable,
“bench-top” catalyst. This “first generation” Grubbs catalyst is
highly reactive and decomposes in solution within several
hours through biomolecular reactions.
The affinity of electron-rich ruthenium center toward soft Lewis
base (olefin) over hard Lewis base (oxygen) is responsible for
its high tolerance to air and water. Strongly electron-donating
ligands increase the activity of the Grubbs catalyst whereas the
opposite is true for Schrock catalyst. Dissociation of one
phosphine ligand is required to give the catalytically active 14-
electron species, making bulky, basic trialkylphosphine ligands
more effective than triphenylphosphine.
Advanced Synthesis and Catalysis ─ Carbene
The first generation Grubbs catalysts, while good for promoting
ROMP, ring-closing metathesis (RCM) of disubstituted olefins,
cross-metathesis (CM) of terminal olefins, and enyne
metathesis, are much less active than the Schrock catalysts, in
particular, for hindered substrates. Based on Herrmann’s work
in 1998, Grubbs developed the “second generation” Grubbs
catalyst with a NHC ligand that is highly active. Although the
initiation step is slower than the first generation catalyst, it has
significantly greater affinity toward π-acidic olefins. Additionally,
the strongly σ-donating NHC ligand stabilizes the Ru(IV)
intermediate. The Hoveyda-Grubbs catalyst also has slow
initiation rate but excellent stability. Replacing the phosphine
ligand with a pyridine ligand leads to extremely fast initiation.
This “third generation” Grubbs catalyst is particularly useful for
living polymerization to give polymers with low polydispersity.
Chen
Grubbs found in 1998 that Ru(H)(H2)Cl(PCy3)2 can be made
easily from Ru(cod)Cl2 and PCy3 under a hydrogen atmosphere,
and this hydrido complex reacts rapidly with propargylic halides
to give ruthenium vinylcarbenes. Werner later optimized this
reaction to synthesize metathesis catalysts in one pot. Fürstner
further used this method to prepare ruthenium indenylidene
complexes that has good metathesis activities.
Advanced Synthesis and Catalysis ─ Carbene
Schrock and Grubbs together showed in 1987 that the Schrock
carbene W(CHtBu)(NAr)[OCMe(CF3)3] initiated rapidly living
polymerization of norbornene. Schrock later showed that
ROMP of 2,3-bis(trifluoromethyl)norbonadiene catalyzed by a
chiral Schrock catalyst with a 2,6-dimethyl substituted
phenylimido ligand gave a highly regular cis,isotactic polymer.
In addition, the cis,isotactic structure could be formed through
enantiomorphic site control, and the trans,syndiotactic structure
through chain-end control.
Schrock also showed in 1994 that living copolymerization of
diethyldipropargylmalonate (DEDPM) can proceed with two
types of propagation mechanisms. The ratio of head-to-tail and
tail-to-tail cyclopolymerization can be controlled by the choice
of the catalyst.
Chen
Fu and Grubbs expanded the synthetic utility of metathesis to
small-molecule synthesis in 1994. Since then, RCM coupling
with hydrogenation has since been a popular way to make
cyclic molecules of various sizes. The scope of RCM in small-
molecule synthesis has further been extended to alkyne
substrates. Fürstner demonstrated in 1998 that alkyne RCM
coupled with partial hydrogenation offers expedient entry to
macrocycles with (Z)-olefins. He also found that the active
catalyst can be generated in situ by reacting Ar3Mo=NtBu with
CH2Cl2, and noted that terminal alkynes are not compatible with
the Schrock catalysts.
Advanced Synthesis and Catalysis ─ Carbene
With the development of highly active and tolerant catalysts,
olefin metathesis has been used widely to synthesize complex
small-molecules. In particular, RCM has joined Wittig reaction
and macrolactonization to become a “standard” method for
macrolide synthesis.
Chen
Boehringer Ingelheim has used RCM to produce its HCV
protease inhibitor BILN 2061. Their first-generation process
employing the Hoveyda–Grubbs catalyst has allowed for the
production of >400 kg active pharmaceutical ingredient (API) by
RCM performed at 20 kg per batch scale giving no trace
amount of the (E)-product.
In their second-generation process using Grela’s catalyst, the
turnover frequency (TOF) is ~1000 times higher and the
turnover number (TON) ~100 times higher. Performing this
reaction at higher temperature suppresses dimerization due to
favored reaction entropy change. This RCM reaction can be
carried out at normal concentrations without scrupulous
degassing. With a much lower catalyst loading, a silica pad
and charcoal filtration is not needed to remove the dissolved
ruthenium. The E-factor, the amount of waste for each unit of
useful product obtained, is reduced from 370 to 52.
Advanced Synthesis and Catalysis ─ Carbene
In addition to olefin and alkyne metathesis, ene-yne metathesis
has also been used to create macrocyles as exemplified in
Shair’s biomimetic synthesis of longithorone A. Common and
medium sized rings can also be constructed easily by RCM.
Phillps has also developed an elegant ROM/RCM strategy for
natural product synthesis.
Chen
Grubbs has systematically compared the reactivity and
functional group tolerance of different metathesis catalysts.
The selectivity rules of CM have also been outlined by Grubbs.
Selective cross metathesis can be achieved with a wide variety
of electron-rich, electron-deficient, and sterically bulky olefins
when using a catalyst with appropriate activity.
When an olefin with high reactivity reacts with an olefin with
lower reactivity (sterically bulky or electron-deficient olefins),
selective cross metathesis can be achieved using feedstock
stoichiometry as low as 1:1. By employing a metathesis
catalyst with appropriate activity, selective cross metathesis
can be achieved with a wide variety of electron-rich, electron-
deficient, and sterically bulky olefins.
CM with two type I olefins gives a statistical mixture of products
because the rates of homodimerization are similar, and the
reactivities of both the homodimers and the cross products
toward secondary metathesis are high. For example, CM
reaction of allylbenzene with two equivalents cis-2-butene-1,4-
diacetate gives the cross product in 80% yield with the first and
second generation of Grubbs catalyst. As a homodimerization
product of allyl acetate, cis-2-butene-1,4-diacetate provides two
allyl acetate in CM. The higher (E/Z) ratio provided by the
second generation Grubbs catalyst is presumably due to
secondary metathesis.
Advanced Synthesis and Catalysis ─ Carbene
Simple modification of the steric or electronic properties such
as changing a nearby protecting groups of an olefin often alters
its reactivity and lead to selective CM. The reactivity of various
olefins toward the first and second generation Grubbs catalysts
and the Schrock catalyst has been summarized by Grubbs.
Chen
The homodimerization of quaternary allylic olefins (type III) is
negligible, but there is a background homodimerization of the
unprotected tertiary alcohol substrates (type II) resulting in the
reduced CM yield.
CM between type II and type III olefins is selective but the yield
is low because homodimerization of the type II olefins leads to
a unreactive dimer. Differential reactivity of olefins allows for
chemo- and regioselective CM, as well as three-component CM.
Advanced Synthesis and Catalysis ─ Carbene
Selective CM occurs when a type I olefin reacts with a type II or
type III olefin that has a significantly lower homodimerization
rate. The homodimerization product of the type I olefin can
undergo secondary metathesis with the type II/III olefin to give
the cross-product; however, the cross-product will not undergo
secondary metathesis to give an equilibrium mixture of
products. The reaction of a type I and a type III olefin gives (E)-
products exclusively.
Chen
Advanced Synthesis and Catalysis ─ Carbene
Hoveyda and Schrock reported in 2009 the first (Z)-selective
olefin metathesis catalyst. The free rotation around the Mo–O
bond serves as the basis for high (Z)-selectivity. The flexibility
of a sterically demanding aryloxide ligand in combination with
a smaller imido ligand renders the reaction proceeding through
the syn alkylidene isomer and the all-cis metallacyclobutane
intermediate. They first used this Mo-chirogenic catalyst to
achieve (Z)- and enantioselective ring-opening/cross
metathesis (ROCM) and later direct CM.
Chen
Grubbs found in 2011 that C–H insertion of the NHC ligand
leads to a series of highly active and (Z)-selective catalysts.
The use of a nitrate instead of a carboxylate as the X-ligand
results in significantly improved activity (~1000 TON) and
selectivity. The chelation of the NHC ligand leads to olefin
side-bound instead of the traditional bottom-bound mechanism.
Resolution of the Ru-chirogenic complexes for enantioselective
metathesis was achieved by using a chiral carboxylate ligand.
Performing RCM in the presence of ethylene promotes
ethenolysis of the (Z)-macrocyclic products to give pure (E)-
products. Jensen and Hoveyda have both developed other (Z)-
selective ruthenium metathesis catalysts.
Advanced Synthesis and Catalysis ─ Carbene
The first asymmetric metathesis was reported by Grubbs in
1996 despite low krel in kinetic resolution of dienes by RCM.
Hoveyda later developed new chiral catalysts to achieve high
krel in kinetic resolution and high ee in desymmetrization.
Chen
Grubbs reported the first chiral ruthenium metathesis catalyst in
2001 using a C2-diphenylethylenediamine-derived NHC ligand.
Subsequently, Hoveyda introduced chiral biaryl NHC-alkoxide
system in 2002. Blechert reported a new chiral NHC-ruthenium
catalyst that offers excellent E selectivity and enantioselectivity
in asymmetric ring-opening cross metathesis in 2010.
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