Advanced Synthetic Reaction

Advanced Synthetic Reactions
Metal mediated C-C and C-X coupling reactions

Coupling reaction
A coupling reaction in organic chemistry is a catch-all term for a variety of reactions where
two hydrocarbon fragments are coupled with the aid of a metal catalyst. In one important reaction type a
main group organometallic compound of the type RM (R = organic fragment, M = main group centre) reacts
with an organic halide of the type R'X with formation of a new carbon-carbon bond in the product R-R'
Broadly speaking, two types of coupling reactions are recognized:
Cross
couplings
involve
reactions
between
two
different
partners,
for
example bromobenzene (PhBr)and vinyl chloride to give styrene (PhCH=CH2).
Homocouplings couple two identical partners, for example, the conversion of iodobenzene (PhI)
to biphenyl (Ph-Ph).
Mechanism
The reaction mechanism usually begins with oxidative addition of one organic halide to the catalyst.
Subsequently, the second partner undergoes transmetallation, which places both coupling partners on the
same metal centre. The final step is reductive elimination of the two coupling fragments to regenerate the
catalyst and give the organic product. Unsaturated organic groups couple more easily in part because they
add readily. The intermediates are also less prone to beta-hydride elimination.
In one computational study, unsaturated organic groups were shown to undergo much easier coupling
reaction on the metal center. The rates for reductive elimination followed the following order: vinyl-vinyl >
phenyl-phenyl > alkynyl-alkynyl > alkyl-alkyl.
The activation barriers and the reaction energies for unsymmetrical R-R couplings were found to be close to
the averages of the corresponding values of the symmetrical R-R and R-R coupling reactions.
For example: vinyl-vinyl > vinyl-alkyl > alkyl-alkyl.
Another mechanistic approach proposes that specifically in aqueous solutions, coupling actually occurs via a
radical mechanism rather than a metal-assisted one.
Catalysts
The most popular metal catalyst is palladium, but some processes often use nickel and copper. A common
catalyst is Tetrakis(triphenylphosphine)palladium(0). Palladium catalysed reactions have several advantages
including functional group tolerance, low sensitivity of organopalladium compounds towards water and air.
Reviews have been written for example on cobalt, palladium and nickel mediated reactions and on
applications
Leaving groups
The leaving group X in the organic partner is usually bromide, iodide or triflate. Ideal leaving groups are
chloride, since organic chlorides are cheaper than related compounds. The main group metal in the
organometallic partner usually is tin, zinc, or boron.
Operating conditions
While many coupling reactions involve reagents that are extremely susceptible to presence of water or
oxygen, it is unreasonable to assume that all coupling reactions need to be performed with strict exclusion of
water. It is possible to perform palladium-based coupling reactions in aqueous solutions using the watersoluble sulfonated phosphines made by the reaction of triphenyl phosphine with sulfuric acid. Another
example of coupling in aqueous media, with the main reacting agent being trimolybdenum-alkylidyne
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clusters. In general, theoxygen in the air is more able to disrupt coupling reactions, because many of these
reactions occur via unsaturated metal complexes that do not have 18 valence electrons. For example,
in nickeland palladium cross couplings, a zerovalent complex with two vacant sites (or labile ligands) reacts
with the carbon halogen bond to form a metal halogen and a metal carbon bond. Such a zerovalent complex
with labile ligands or empty coordination sites is normally very reactive toward oxygen.
Some catalysts might be easily poisoned by heterocycles under prolonged reaction at elavated temperature.
To avoid this, chemists often use pressure reactors to accelerate reactions at high temperature and
pressure. Q-Tube and microwave synthesizer are available safe pressure reactors.
Coupling types
Coupling reactions include
Reaction
Reactant A
Reactant B
Homo
/Cros Catalyst Remark
s
Wurtz reaction
R-X
sp
R-X
homo
Glaser coupling
RCCH
sp
RCCH sp
homo Cu
O2 as H-acceptor
Ullmann reaction
Ar-X
sp
Ar-X
homo Cu
high temperatures
Gomberg-Bachmann
Ar-H
sp
Ar-N2X sp
homo
requires base
Cadiot-Chodkiewicz
RCCH
sp
RCCX sp
cross
Cu
Castro-Stephens
RCCH
sp
Ar-X
cross
Cu
Gilmanreagent coupling R2CuLi

Cassar reaction
Alkene
Kumada coupling
sp
sp
sp
R-X
requires base
cross
R-X
sp
cross
Pd
Ar-MgBr sp, sp
Ar-X
sp
cross
Pd or Ni
Heck reaction
alkene
sp
R-X
sp
cross
Pd
Sonogashira coupling
RCCH
sp
R-X
sp,sp cross
Pd
Cu
Negishi coupling
R-Zn-X
sp,sp,s
R-X
p
sp sp cross
Pd or Ni
Stille cross coupling
R-SnR3
sp,sp,s
R-X
p
sp sp cross
Pd
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sp
Na(stoich
iometric)
requires base
requires base
and
requires base
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Suzuki reaction
R-(OR)2
sp
R-X
sp sp cross
Pd
requires base
Hiyama coupling
R-SiR3
sp
R-X
sp sp cross
Pd
requires base
Buchwald-Hartwig
reaction
R2N-R
SnR3
sp
R-X
sp
cross
Pd
N-C coupling, second

generation free amine
Fukuyama coupling
R-Zn-I
sp3
RCO(SE 2
sp
t)
cross
Pd
LiebeskindSrogl
coupling
R-(OR)2
sp3, sp2
RCO(SE
t)
Ar- sp2
SMe
cross
Pd
requires CuTC
Miscellaneous reactions
One method for palladium-catalyzed cross-coupling reactions of aryl halides with fluorinated arenes was
reported by Keith Fagnou and co-workers. It is unusual in that it involves C-H functionalisation at
an electron deficient arene.
Applications
Many coupling reactions have found their way into pharmaceutical industry [17] and into conjugated organic
materials
1.
Suzuki reaction
The Suzuki reaction is the organic reaction of an aryl- or vinyl-boronic acid with an aryl- or vinylhalide catalyzed by a palladium(0) complex, which can also be in the form of ananomaterial-based catalyst.
It is widely used to synthesize poly-olefins, styrenes, and substituted biphenyls, and has been extended to
incorporate alkyl bromides.
The reaction also works with pseudohalides, such as triflates (OTf), instead of halides. Boronic
esters and organotrifluoroborate salts may be used instead of boronic acids.
Relative reactivity: R2I > R2OTf > R2Br >> R2Cl
The Suzuki reaction couples boronic acids (containing an organic substituent) to halides. The reaction relies
on a palladium catalyst such as tetrakis (triphenylphosphine)palladium(0) to effect part of the
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transformation. The palladium catalyst (more strictly a pre-catalyst) is 4-coordinate, and usually
involves phosphine supporting groups.
Reaction mechanismThe mechanism of the Suzuki reaction is best viewed from the perspective of the
palladium catalyst. The first step is the oxidative addition of palladium tothe halide 2 to form
the organopalladiumspecies 3. Reaction with base gives intermediate 4, which via transmetalation with the
boron-ate complex 6 forms the organopalladium species 8. Reductive elimination of the desired
product 9restores the original palladium catalyst 1.
Oxidative addition
Oxidative addition proceeds with retention of stereochemistry with vinyl halides, while
giving inversion of stereochemistry with allylic and benzylic halides.The oxidative addition initially
forms thecispalladium complex, which rapidly isomerizes to the trans-complex.
Reductive elimination
Using deuterium labelling,have shown the reductive elimination proceeds with retention of
stereochemistry. Relative reactivity of different metal complexes in the CC reductive elimination was
established: Pd(IV), Pd(II) > Pt(IV), Pt(II), Rh(III) > Ir(III), Ru(II), Os(II).
The Suzuki coupling has been frequently used in syntheses of complex compounds. The Suzuki
coupling has been used on a citronellal derivative for the synthesis of caparratriene, a natural product
that is highly active against leukemia
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Recent applications of the SuzukiMiyaura cross-coupling reaction in organic synthesis have been
summarized by Kotha and co-workers.[15] With a novel organophosphine ligand (SPhos), a catalyst
loading of down to 0.001 mol% has been reported:[16]
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 substituted alkene.This reaction was the first example of a
carbon-carbon bond-forming reaction that followed a Pd(0)/Pd(II) catalytic cycle, the same catalytic cycle
that is seen in other Pd(0)-catalyzed cross-coupling reactions. Together with other reactions in this class, the
Heck reaction is of great importance, as it allows one to do substitution reactions on planar sp2-hybridized
carbon centers.
The reaction is performed in the presence of an organopalladium catalyst. The halide (Br, Cl)or triflate is
an aryl, benzyl, or vinyl compound and the alkene contains at least one hydrogen and is often electrondeficient
such
as acrylate ester or
an acrylonitrile.The
catalyst
can
be tetrakis(triphenylphosphine)palladium(0), palladium
chloride or palladium(II)
acetate.
The ligand istriphenylphosphine, PHOX or BINAP.
carbonate or sodium acetate.
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The
base
is triethylamine, potassium
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Reaction mechanism
The catalytic cycle for the Heck reaction involves a series of transformations around the palladium catalyst.
The palladium (0) compound required in this cycle is generally prepared in situ from a palladium (II)
precursor.For instance, palladium (II) acetate is reduced by triphenylphosphine to
bis(triphenylphosphine)palladium(0) (1) and triphenylphosphine is oxidized to triphenylphosphine oxide.
Step A is anoxidative addition in which palladium inserts itself in the aryl to bromide bond. Palladium then
forms a complex with the alkene (3) and in step B the alkene inserts itself in the palladium - carbon bond
in a syn addition step. Then follows a torsional strain relieving rotation to the Trans isomer (not shown) and
step C is a beta-hydride elimination step with the formation of a new palladium - alkene complex (5). This
complex is destroyed in the next step. The palladium (0) compound is regenerated by reductive
elimination of the palladium (II) compound by potassium carbonate in the final step, D. In the course of the
reaction the carbonate is stoichiometrically consumed and palladium is truly a catalyst and used in catalytic
amounts. A similar palladium cycle but with different scenes and actors is observed in the Wacker process.
This cycle is not limited to vinyl compounds, in the Sonogashira coupling one of the reactants is
an alkyne and in the Suzuki coupling the alkene is replaced by an aryl boronic acid and in theStille
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reaction by an aryl stannane. The cycle also extends to the other group 10 element nickel for example in
the Negishi coupling between aryl halides and organozinc compounds. Platinum forms strong bonds with
carbon and does not have a catalytic activity in this type of reaction.
Stereoselectivity
This coupling reaction is stereoselective with a propensity for trans coupling as the palladium halide group
and the bulky organic residue move away from each other in the reaction sequence in a rotation step. The
Heck reaction is applied industrially in the production of naproxen and the sunscreen component octyl
methoxycinnamate.
The
naproxen
synthesis
includes
a
coupling
between
a
[14]
brominated naphthalene compound with ethylene:
Ionic liquid Heck reaction

In the presence of an ionic liquid a Heck reaction proceeds in absence of a phosphorus ligand. In one
modification palladium acetate and the ionic liquid (bmim)PF6 are immobilized inside the cavities of
reversed-phase silica gel.[15] In this way the reaction proceeds in water and the catalyst is re-usable.
Heck oxyarylation
In the Heck oxyarylation modification the palladium substituent in the syn-addition intermediate is
displaced by a hydroxyl group and the reaction product contains a tetrahydrofuran ring.
Amino-Heck reaction
In the amino-Heck reaction a nitrogen to carbon bond is formed. In one example, an oxime with a strongly
electron withdrawing group reacts intramolecularly with the terminal end of a dieneto a pyridine compound.
The catalyst is tetrakis(triphenylphosphine)palladium(0) and the base is triethylamine.
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Stille reaction
The Stille reaction (also known as Stille coupling) is a chemical reaction coupling an organotin
compound with a sp2-hybridized organic halide catalyzed by palladium.The reaction is widely used
in organic synthesis.
X is typically a halide, such as Cl, Br, I. Additionally, X can be a pseudohalide such as a triflate, C F3S O3-.
The reaction is usually performed under inert atmosphere using dehydrated and degassed solvent, as oxygen
causes the oxidation of the palladium catalyst and promotes homo-coupling of organic stannyl compounds,
and these side reactions lead to a decrease in the yield of the desired cross-coupling reaction.
As the organic tin compound, a trimethylstannyl or tributylstannyl compound is normally used. Although
trimethylstannyl compounds show higher reactivity compared with tributylstannyl compounds, the toxicity
of the former is about 1000 times larger than that of the latter. Therefore it is better to avoid using
trimethylstannyl compounds unless necessary.
Reaction mechanism
The reaction mechanism of the Stille reaction has been well studied. The first step in this catalytic cycle is
the reduction of the palladium catalyst (1) to the active Pd(0) species (2). Theoxidative addition of the
organohalide (3) gives a cis intermediate which rapidly isomerizes to the Trans
intermediate 4. Transmetalation with the organostannane (5) forms intermediate 7, which produces the
desired product (8) and the active Pd(0) species (2) after reductive elimination. The oxidative addition and
reductive elimination retain the stereochemical configuration of the respective reactants.
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Rate of transmetalation from tin:Alkynyl > alkenyl > aryl > allyl = benzyl > -alkoxyalkyl > alkyl
The low reactivity of alkyl stannanes is a serious drawback but can be remedied by the use of strongly
polar solvents such as HMPT, DMF or dioxane.
Variations
To improve the yield of the reaction, lithium chloride is often added to the reaction mixture. This reagent
stabilizes the intermediate complex formed by the oxidative addition of a catalyst and accelerates the
reaction.
Reactivity and specificity of the Stille reaction can be improved by the addition of stoichiometric
amounts of Cu(I) or Mn(II) salts.
The cross-coupling reaction can be inhibited by ligands of a high donor number.In the presence of Cu(I)
salts, palladium-on-carbon has been shown to be an effective catalyst.
In the realm of green chemistry a Stille reaction is reported taking place in a low melting and highly
polar mixture of a sugar such as mannitol, a urea such as dimethylurea and a salt such asammonium
chloride The catalyst system is tris(dibenzylideneacetone)dipalladium(0) with triphenylarsine:
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Sonogashira reaction
Sonogashira reaction is a cross-coupling reaction used in organic synthesis to form carboncarbon bonds.
It makes use of a palladium catalyst to form a carboncarbon bond between a terminal alkyne and
an aryl or vinyl halide.[1]
The Sonogashira cross-coupling reaction has been employed in a wide variety of areas, due to its usefulness
in the formation of carboncarbon bonds. The reaction can be carried out under mild conditions, such as at
room temperature, in aqueous media, and with a mild base, which has allowed for the use of the Sonogashira
cross-coupling reaction in the synthesis of complex molecules. Its applications include pharmaceuticals,
natural products, organic materials, and nanomaterials. Specific examples include its use in the synthesis
of tazarotene, which is a treatment for psoriasis and acne, and in the preparation of SIB-1508Y, also known
as Altinicline, which is a potential treatment for Parkinson's disease, Alzheimer's disease, Tourette
syndrome,schizophrenia, and attention deficit hyperactivity disorder (ADHD).
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Mechanism
The reaction mechanism is not clearly understood but the textbook mechanism revolves around a palladium
cycle and a copper cycle that is less well known.
Catalytic cycle for the Sonogashira reaction
The palladium cycle

The active palladium catalyst is the 14 electron compound Pd0L2, complex A, which reacts with
the aryl or vinylhalide in an oxidative addition to produce a PdII intermediate, complex B. This step
is believed to be the rate-limiting step of the reaction.
Complex B reacts in a transmetallation with the copper acetylide, complex F, which is produced in
the copper cycle, to give complex C, expelling the copper halide, complex G.
Both organic ligands are Trans oriented and convert to cis in a trans-cis isomerization to produce
complex D.
In the final step, complex D undergoes reductive elimination to produce the alkyne, with
regeneration of the palladium catalyst.
The copper cycle
It is suggested that the presence of base results in the formation of a pi-alkyne complex, complex E,
which makes the terminal proton on the alkyne more acidic, leading to the formation of the copper
acetylide, compound F.
Compound F continues to react with the palladium intermediate B, with regeneration of the copper
halide, G.
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Mechanistic studies suggest that these catalytic cycles represent the preferred reaction pathway; however
there is debate about the exact identity of some intermediates, which may depend upon reaction
conditions. For example, it has been shown that monoligated Pd0 (PR3) complexes (B) can be formed
when dealing with bulky phosphanes and have been suggested as possible catalytic species in coupling
reactions.In contrast, some results point to the formation of anionic palladium species, which would be
the real catalysts instead of the coordinatively unsaturated Pd0L2. Generally seen in the presence of
anions and halides, it is known that Pd0(PPh3)2 does not exist in solution when generated in the presence
of halide anions because they coordinate the Pd0 center to form anionic species of the type [L2Pd0Cl]which can participate in cross-coupling reactions.
Catalysts
Typically, two catalysts are needed for this reaction: a zerovalent palladium complex and a halide salt of
copper(I). Examples of such palladium catalysts include compounds in which palladium is ligated to
phosphines (Pd(PPh3)4). A common derivative is Pd(PPh3)2Cl2, but bidentate ligand catalysts, such as
Pd(dppe)Cl, Pd(dppp)Cl2, and Pd(dppf)Cl2have also been used. The drawback to such catalysts is the
need for high loadings of palladium (up to 5 mol %), along with a larger amount of a copper cocatalyst.PdII is often employed as a pre-catalyst since it exhibits greater stability than Pd0 over an
extended period of time and can be stored under normal laboratory conditions for months. The
Pd II catalyst is reduced to Pd0 in the reaction mixture by either anamine, a phosphine ligand, or a
reactant, allowing the reaction to proceed. The oxidation of triphenylphosphine to triphenylphosphine
oxide can
also
lead
to
the
formation
of
Pd0 in
situ when
catalysts
such
as bis(triphenylphosphine)palladium(II) chloride are used.
Copper(I) salts, such as copper iodide, react with the terminal alkyne and produce a copper(I) acetylide,
which acts as an activated species for the coupling reactions. Cu(I) is a co-catalyst in the reaction, and is
used to increase the rate of the reaction.
Reaction conditions
The Sonogashira reaction is typically run under mild conditions. The cross-coupling is carried out at
room temperature with a base, typically an amine, such as diethylamine,that also acts as the solvent. The
reaction medium must be basic to neutralize the hydrogen halide produced as the byproduct of this
coupling reaction, so alkylamine compounds such as triethylamine anddiethylamine are sometimes used
as solvents, but also DMF or ether can be used as solvent. Other bases such as potassium carbonate or
cesium carbonate are occasionally used. In addition, deaerated conditions are formally needed for
Sonogashira coupling reactions because the palladium(0) complexes are unstable in the air, and oxygen
promotes the formation of homocoupled acetylenes. Recently, development of air-stable
organopalladium catalysts enables this reaction to be conducted in the ambient atmosphere.
Depending on the sp2-carbon halide-or triflate used, these reaction conditions have varying results.
The rate of reaction of sp2 carbons.Vinyl iodide > vinyl triflate > vinyl bromide > vinyl chloride > aryl
iodide > aryl triflate > aryl bromide >>> aryl chloride.
Complications
Due to the crucial role of base, specific amines must be added in excess or as solvent for the reaction to
proceed. It has been discovered that secondary amines such as piperidine, morpholine, or
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diisopropylamine in particular can react efficiently and reversibly with trans-RPdX(PPh3)2 complexes
by substituting one PPh3 ligand. The equilibirium constant of this reaction is dependent on R, X, a factor
for basicity, and the amine's steric hindrance.[11] The result is competition between the amine and the
alkyne group for this ligand exchange, which is why the amine is generally added in excess to promote
preferential substitution.
Inverse Sonogashira Coupling
In an inverse Sonogashira coupling the reactants are an aryl or vinyl compound and an alkynyl halide.
Copper-free reaction
While a copper co-catalyst is added to the reaction to increase reactivity, the presence of copper can
result in the formation of alkyne dimers. This leads to what is known as the Glaser couplingreaction,
which is an undesired formation of homocoupling products of acetylene derivatives upon oxidation. As a
result, when running a Sonogashira reaction with a copper co-catalyst, it is necessary to run the reaction
in an inert atmosphere to avoid the unwanted dimerization. Copper-free variations to the Sonogashira
reaction have been developed to avoid the formation of the homocoupling products. [8][15] The exact
mechanism by which the copper-free reaction occurs is still under debate.[4] One mechanism seems to
indicate the following:
As in the original mechanism, oxidative addition of the aryl halide or triflate to the Pd(0) catalysts.
Since the amines associated with this reaction are not basic enough to deprotonate the reacting
alkyne, it is believed that complexation to the Pd(0) catalyst requires displacement of one ligand to
create an intermediate complex.
As a result, this new intermediate can then facilitate deprotonation of the terminal alkyne proton and
subsequent ligand exchange with the leaving group X.
Reductive elimination gives rise to the desired coupling product.
Proposed copper-free mechanism for Sonogashira Reaction

Due to mounting evidence that amines may also be involved in various steps exclusive of (via a new
mode of reactivity) and/or preceding deprotonation events, an alternate mechanism suggests the
following:
Amines can interfere with the oxidative addition through an accelerating effect brought upon to the
formation of more reactive [Pd(0)L(amine)] complexes.
As a result, they can also substitute one ligand in the complex formed after the addition.
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Depending on the rate of the competition between amine and alkyne in the substitution of one ligand
in this complex, an interplay between the original mechanism and the newer one seems likely.
Alternative copper-free mechanism

The crucial difference between the two mechanisms is that the former would be preferred if the amine is
a weaker ligand than the reacting alkyne, while the latter mechanism would be preferred if the amine
were a better ligand than the alkyne.[16]
Catalyst variations
Recently, a nickel-catalyzed Sonogashira coupling has been developed which allows for the coupling of
non-activated alkyl halides to acetylene without the use of palladium, although a copper co-catalyst is
still needed. It has also been reported that gold can be used as a heterogeneous catalyst, which was
demonstrated in the coupling of phenylacetylene and iodobenzene with an Au/CeO2 catalyst. In this
case, catalysis occurs heterogeneously on the Au nanoparticles,with Au(0) as the active
site.[21] Selectivity to the desirable cross coupling product was also found to be enhanced by supports
such as CeO2 and La2O3. Additionally, iron-catalyzed Sonogashira couplings have been investigated as
relatively cheap and non-toxic alternatives to palladium. Here, FeCl3 is proposed to act as the transitionmetal catalyst and Cs2CO3 as the base, thus theoretically proceeding through a palladium-free and
copper-free mechanism.
Suggested iron-catalyzed coupling reaction.

While the copper-free mechanism has been shown to be viable, attempts to incorporate the various
transition metals mentioned above as less expensive alternatives to palladium catalysts have shown a
poor track record of success due to contamination of the reagants with trace amounts of palladium,
suggesting that these theorized pathways are extremely unlikely, if not impossible, to achieve.
Palladium-nitrogen complexes
Pyridines and pyrimidines have shown good complexation properties
for palladium and have been employed in the formation of catalysts suitable
For Sonogashira couplings. The dipyrimidyl-palladium complex shown belo
has been employed in the copper-free coupling of iodo-, bromo-,
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and chlorobenzene with phenylacetylene using N-butylamineas base in THF solvent at 65 C.
Copper-free synthesis of dialkynylated benzene

Applications in Synthesis
Sonogashira couplings are employed in a wide array of synthetic reactions, primarily due to their
success in facilitating the following challenging transformations:
Alkynylation reactions
The coupling of a terminal alkyne and an aromatic ring is the pivotal reaction when talking about
applications of the copper-promoted or copper-free Sonogashira reaction. The list of cases where the
typical Sonogashira reaction using aryl halides has been employed is large, and choosing illustrative
examples is difficult. A recent use of this methodology is shown below for the coupling of iodinated
phenylalanine with a terminal alkyne derived from d-biotin using an in situ generated Pd(0) species as
catalyst, which allowed the preparation of alkynelinked phenylalanine derivative for bioanalytical
applications. There are also examples of the coupling partners both being attached to allyl resins, with
the Pd(0) catalyst effecting cleavage of the substrates and subsequent Sonogashira coupling in solution.
Alkynylation of phenylalanine.
Natural products
Many metabolites found in nature contain alkyne or enyne moieties, and therefore, the Sonogashira
reaction has found frequent utility in their syntheses.Several of the most recent and promising
applications of this coupling methodology toward the total synthesis of natural products exclusively
employed the typical copper-cocatalyzed reaction.
An example of the coupling of an aryl iodide to an aryl acetylene can be seen in the reaction of the
iodinated alcohol and the tris(isopropyl)silylacetylene, which gave alkyne, an intermediate in the total
synthesis of the benzindenoazepine alkaloid bulgaramine.
There are other recent examples of the use of aryl iodides for the preparation of intermediates under
typical Sonogashira conditions, which, after cyclization, yield natural products such as
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benzylisoquinoline or
indole
alkaloids. An
example
is
the
synthesis
of
the benzylisoquinoline alkaloids (+)-(S)-laudanosine and ()-(S)-xylopinine. The synthesis of these
natural products involved the use of Sonogashira cross-coupling to build the carbon backbone of each
molecule.
Natural products (+)-(S)-laudanosine and ()-(S)-xylopinine synthesized using the Sonogashira crosscoupling reaction.
Enynes andenediynes.
The 1, 3-enyne moiety is an important structural unit for biologically active and natural compounds. It is
derived from vinylic systems and terminal acetylenes by using a configuration-retention stereospecific
procedure such as the Sonogashira reaction. Vinyl iodides are the most reactive vinyl halides to
Pd0 oxidative addition, and their use is therefore most frequent for Sonogashira cross-coupling reactions
due to the usually milder conditions employed. Some examples include:
The coupling of 2-iodo-prop-2-enol with a wide range of acetylenes such as TMSA to give enynyl
alcohol, which can be oxidized to the corresponding R-alkynylated acroleins [38]
The preparation of an alk-2-ynylbuta-1,3-dienes from the cross-coupling of a diiodide and
phenylacetylene, as shown below.
Synthesis of an alk-2-ynylbuta-1,3,-diene accomplished by Sonogashira coupling.

Pharmaceuticals
The versatility of the Sonogashira reaction makes it a widely used reaction in the synthesis of a variety
of compounds. One such pharmaceutical application is in the synthesis of SIB-1508Y, which is more
commonly known as Altinicline. Altinicline is a nicotinic acetylcholine receptor agonist that has shown
potential in the treatment of Parkinsons disease, Alzheimers disease, Tourettes syndrome,
Schizophrenia, and attention deficit hyperactivity disorder (ADHD).As of 2008, Altinicline has
undergone Phase II clinical trials.
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Use of the Sonogashira cross-coupling reaction in the synthesis of SIB-1508Y.
BuchwaldHartwig amination
The BuchwaldHartwig amination is a chemical reaction used in organic chemistry for the synthesis
of carbonnitrogen bonds via the palladium-catalyzed cross-coupling of amines with aryl halides. The
reaction's synthetic utility stems primarily from the shortcomings of typical methods (nucleophilic
substitution,reductive amination, etc.) for the synthesis of aromatic CN bonds, with most methods suffering
from limited substrate scope and functional group tolerance. The development of the BuchwaldHartwig
reaction allowed for the facile synthesis of aryl amines, replacing to an extent harsher methods
(the Goldberg reaction, nucleophilic aromatic substitution, etc.) while significantly expanding the repertoire
of possible CN bond formation.
Over the course of its development, several 'generations' of catalyst systems have been developed, with each
system allowing greater scope in terms of coupling partners and milder conditions, allowing virtually any
amine to be coupled with a wide variety of aryl coupling partners. Because of the ubiquity of aryl C-N bonds
in pharmaceuticals and natural products, the reaction has gained wide use in synthetic organic chemistry,
finding application in many total syntheses and the industrial preparation of numerous pharmaceuticals.
The d10 complex Pd[P(o-Tolyl)3]2 was the active catalyst (with the corresponding chloride entering the
catalytic cycle via in situ reduction), and supported a catalytic cycle involving oxidative addition of the aryl
bromide.
Transamination of Bu3SnNEt2 followed byargon purge to remove the volatile diethylamine allowed
extension of the methodology to a variety of secondary amines (both cyclic and acyclic) and
primary anilines. Secondly, the yield for electron rich and electron poor arenes was improved via minor
S.Ahammad Kabeer
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modifications to the reaction procedure (higher catalyst loading, higher temperature, longer reaction time),
although no ortho-substituted aryl groups were included in this publication.
The couplings could be conducted with free amines in the presence of a bulky base (KOtBu ) allowing
for organotin-free coupling. Though these improved conditions proceeded at a faster rate, the substrate scope
was limited almost entirely to secondary amines due to competitive hydrodehalogenation of the
bromoarenes.
These results established the so-called "first generation" of BuchwaldHartwig catalyst systems. The
following years saw development of more sophisticated phosphine ligands that allowed extension to a larger
variety of amines and aryl groups. Aryl iodides, chlorides, and triflates eventually became suitable
substrates, and reactions run with weaker bases at room temperature were developed. These advances are
detailed in the Scope section below, and the extension to more complex systems remains an active area of
research.
Mechanism
The reaction mechanism for this reaction has been demonstrated to proceed through steps similar to those
known for palladium catalyzed C-C coupling reactions. Steps include oxidative additionof the aryl halide to
a Pd(0) species, addition of the amine to the oxidative addition complex, deprotonation followed
by reductive elimination. An unproductive side reaction can compete with reductive elimination wherein the
amide undergoes beta hydride elimination to yield the hydrodehalogenated arene and an imine product.
Over the course of the development of this reaction, there has been a great deal of work to determine the
exact palladium species responsible for each of these steps, with several mechanistic revisions occurr as
more data was garnered. These studies have revealed a divergent reaction pathways depending on
whether monodentate or chelating phosphine ligands are employed in the reaction, and a number of nuanced
influences have been revealed (especially concerning the dialkylbiarylphosphine ligands developed by
Buchwald).
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The catalytic cycle proceeds as follows:
For monodentate ligand systems, monophosphine palladium (0) species is believed to form before oxidative
addition, forming the palladium (II) species which is in equilibrium with the -halogen dimer. The stability
of this dimer decreases in the order of X = I > Br > Cl, and is thought to be responsible for the slow reaction
of aryl iodides with the first-generation catalyst system. Amine ligation followed by deprotonation by base
produces the palladium amide. (Chelating systems have been shown to undergo these two steps in reverse
order, with base complexation preceding amide formation.) This key intermediate reductively eliminates to
produce the product and regenerate the catalyst. However, a side reaction can occur wherein -hydride
elimination followed by reductive elimination produces the hydrodehalogenated arene and the
corresponding imine. Not shown are additional equilibria wherein various intermediates coordinate to
additional phosphine ligands at various stages in the catalytic cycle.
For chelating ligands, the monophosphine palladium species is not formed; oxidative addition, amide
formation and reductive elimination occur from L2Pd complexes. The Hartwig group found that "reductive
elimination can occur from either a four-coordinate bisphosphine or three-coordinate monophosphine
arylpalladium amido complex. Eliminations from the three-coordinate compounds are faster. Second, hydrogen elimination occurs from a three-coordinate intermediate. Therefore, -hydrogen elimination occurs
slowly from arylpalladium complexes containing chelating phosphines while reductive elimination can still
occur from these four-coordinate species.
First-generation catalyst system
The first generation (Pd[P(o-Tolyl)3]2) catalyst system was found to be effective for the coupling of both
cyclic and acyclic secondary amines bearing both alkyl and aryl functionality (though not diarylamines) with
a variety of aryl bromides. In general, these conditions were not able to couple primary amines due to
competitive hydrodehalogenation of the arene.[14][15]
Aryl iodides were found to be suitable substrates for the intramolecular variant of this reaction,[15] and
importantly, could be coupled intermolecularly only if dioxane was used in place of toluene as a solvent,
albeit with modest yields.[20]
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Bidentate phosphine ligands

The development of diphenylphosphinobinapthyl (BINAP) and diphenylphosphinoferrocene (DPPF) as
ligands for the BuchwaldHartwig amination provided the first reliable extension to primary amines and
allowed efficient coupling of aryl iodides and triflates. These ligands typically produce the coupled products
at higher rates and better yields than the first generation of catalysts. The initial reports of these ligands as
catalysts were somewhat unexpected given the mechanistic evidence for monoligated complexes serving as
the active catalysts in the first-generation system.
The chelation from these ligands is thought to suppress -hydride elimination by preventing an open
coordination site. In fact, -chiral amines were found not to racemize when chelating ligands were
employed, in contrast to the first-generation catalyst system.[24]
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Sterically hindered ligands
More recently, bulky tri- and di-alkyl phosphine ligands have been shown to be remarkably active catalysts,
allowing the coupling of a wide range of amines (primary, secondary, electron withdrawn, heteocyclic, etc.)
with aryl chlorides, bromides, iodides, and triflates. Additionally, reactions employing hydroxide, carbonate,
and phosphate bases in place of the traditional alkoxide and silylamide bases have been developed. The
Buchwald group has developed a wide range of dialkylbiarylphosphine ligands, while the Hartwig group has
focused on ferrocene-derived and trialkyl phosphine ligands.
The dramatic increase in activity seen with these ligands is attributed to their propensity to sterically favor
the monoligated palladium species at all stages of the catalytic cycle, dramatically increasing the rate of
oxidative addition, amide formation, and reductive elimination. Several of these ligands also seem to
enhance the rate of reductive elimination relative to -hydride elimination via the electron donating arenepalladium interaction.
Even electron withdrawn amines and heterocyclic substrates can be coupled under these conditions, despite
their tendency to deactivate the palladium catalyst.
Ammonia Equivalents
Despite progress made thus far, ammonia remains one of the most challenging coupling partners for
BuchwaldHartwig amination reactions due to its tight binding with palladium complexes; several strategies
have been developed to overcome this based on reagents that serve as ammonia equivalents. The use of
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a benzophenone imine or silylamide can overcome this limitation, with subsequent hydrolysis furnishing the
primary aniline.[33][34][35]
Notably, the Hartwig group has recently developed a catalyst system that can directly couple ammonia using
a Josiphos-type ligand.
Variations
Under similar conditions to those employed for amination, alcohols and can be coupled with aryl halides to
produce the corresponding aryl ethers. This serves as a convenient replacement for harsher analogues of this
process such as the Ullmann condensation.
Enolates and other similar carbon nucleophiles can also be coupled to produce -aryl ketones, malonates,
nitriles, etc. The scope of this transformation is similarly ligand-dependent and a number of systems have
been developed. Several enantioselective methods for this process have been developed.
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Several versions of the reaction employing complexes of copper and nickel rather than palladium have also
been developed.
Kumada coupling
In organic chemistry, the Kumada coupling is a type of cross coupling reaction, useful for
generating carboncarbon bonds by the reaction of a Grignard reagent and an organic halide. The procedure
uses transition metal catalysts, typically nickel or palladium, to couple combination of
two alkyl, aryl or vinyl groups.
Kumada coupling reaction
Mechanism
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Accepted catalytic cycle for Kumada cross coupling reaction

Palladium catalysis
According to the widely accepted mechanism, the palladium-catalyzed Kumada coupling is understood to be
analogous to palladium's role in other cross coupling reactions. The proposed catalytic cycle involves both
palladium(0) and palladium(II) oxidation states. Initially, the electron-rich Pd(0) catalyst (1) inserts into the
RX bond of the organic halide. This oxidative addition forms an organo-Pd(II)-complex (2). Subsequent
transmetalation with the Grignard reagent forms a hetero-organometallic complex (3). Before the next step,
isomerization is necessary to bring the organic ligands next to each other into mutually cis positions. Finally,
reductive elimination of (4) forms a carboncarbon bond and releases the cross coupled product while
regenerating the Pd(0) catalyst (1).[8] For palladium catalysts, the frequently rate-determining oxidative
addition occurs more slowly than with nickel catalyst systems.
Organic halides and pseudohalides
The Kumada coupling has been successfully demonstrated for a variety of aryl or vinyl halides. In place of
the halide reagent pseudohalides can also be used, and the coupling has been shown to be quite effective
using tosylate and triflate species in variety of conditions.
Despite broad success with aryl and vinyl couplings, the use of alkyl halides is less general due to several
complicating factors. Having no -electrons, alkyl halides require different oxidative addition mechanisms
than aryl or vinyl groups, and these processes are currently poorly understood. Additionally, the presence of
-hydrogens makes alkyl halides susceptible to competitiveelimination processes.
These issues have been circumvented by the presence of an activating group, such as the carbonyl in bromoketones that drives the reaction forward. However, Kumada couplings havealso been performed with
non-activated alkyl chains, often through the use of additional catalysts or reagents. For instance, with the
addition of 1, 3 -butadienes Kambe and coworkers demonstrated nickel catalyzed alkylalkyl couplings that
would otherwise be unreactive.
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Though poorly understood, the mechanism of this reaction is proposed to involve the formation of an
octadienyl nickel complex. This catalyst is proposed to undergo transmetalation with a Grignard reagent
first, prior to the reductive elimination of the halide, reducing the risk of -hydride elimination. However,
the presence of a Ni(IV) intermediate is contrary to mechanisms proposed for aryl or vinyl halide couplings.
Proposed Kumada coupling mechanism with addition of butadiene

Grignard reagent
Alkyl Grignard reagents can also be used without difficulty, as they do not suffer from -hydride elimination
processes. Although the Grignard reagent inherently has poor functional group tolerance, low-temperature
syntheses have been prepared with highly functionalized aryl groups.
Catalysts
Kumada couplings can be performed with a variety of nickel(II) or palladium(II) catalysts. The structures of
the catalytic precursors can be generally formulated as ML2X2, where L is a phosphine ligand.Common
choices for L2 include bidentate diphosphine ligands such as dppe and dppp among others.
Work by Frstner and coworkers on iron-based catalyts have shown reasonable yields. The catalytic species
in these reactions is proposed to be an "inorganic Grignard reagent" consisting of Fe(MgX)2.
Reaction condition
The reaction typically is carried out in tetrahydrofuran or diethyl ether as solvent. Such ethereal solvents are
convenient because these are typical solvents for generating the Grignard reagent.[2]Due to the high
reactivity of the Grignard reagent, Kumada couplings have limited functional group tolerance which can be
problematic in large syntheses. In particular, Grignard reagents are sensitive to protonolysis from even
mildly acidic groups such as alcohols. They also add to carbonyls and other oxidative groups.
As in many coupling reactions, the transition metal palladium catalyst is often air-sensitive, requiring an
inert Argon or nitrogen reaction environment.
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Stereoselectivity
Both cis- and trans-olefin halides promote the overall retention of geometric configuration when coupled
with alkyl Grignards. This observation is independent of other factors, including the choice of catalyst
ligands and vinylic subsituents.
Conversely, a Kumada coupling using vinylic Grignard reagents proceeds without stereospecificity to form a
mixture of cis- and trans-alkenes. The degree of isomerization is dependent on a variety of factors including
reagent ratios and the identity of the halide group. According to Kumada, this loss of stereochemistry is
attributable to side-reactions between two equivalents of the allylic Grignard reagent.
Enantioselectivity
Chiral ligands for enantioselective Kumada couplings. A: [Methoxyalkyl(ferrocenyl)] monophosphine B:

bis-oxazoline
Asymmetric Kumada couplings can be affected through the use of chiral ligands. Using planar
chiral ferrocene ligands, enantiomeric excesses (ee) upward of 95% have been observed in aryl
couplings.Enantioconvergent couplings of -bromoketones using catalysts based on bis-oxazoline ligands,
wherein the chiral catalyst converts a racemic mixture of starting material to one enantiomer of product with
up to 95% ee.The latter reaction is also significant for involving a traditionally inaccessible alkyl halide
coupling.
Enantioconvergent coupling of -bromoketones
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Chemoselectivity
Grignard reagents do not typically couple with chlorinated arenes. This low reactivity is the basis for
chemoselectivity for nickel insertion into the CBr bond of bromochlorobenzene using a NiCl2-based
catalyst.
NiCl2 catalyzed Kumada coupling shows haloselectivity on bromochlorobenzene.

Applications
Synthesis of Aliskiren
The Kumada coupling suitable for large-scale, industrial processes, such as drug synthesis. The reaction is
used to construct the carbon skeleton of aliskiren (trade name Tekturna), a treatment for hypertension.
Kumada coupling in the synthesis of aliskiren

Synthesis of polythiophenes
The Kumada coupling also shows promise in the synthesis of conjugated polymers, polymers such
as polyalkylthiophenes (PAT), which have a variety of potential applications in organic solar cells and lightemitting diodes.Synthesis of regioregular polyalkylthiophenes by utilizing the Kumada coupling scheme
pictured below, which requires subzero temperatures.
Synthesis of polythiophenes via Kumada coupling
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Negishi coupling
The Negishi coupling is a cross coupling reaction in organic chemistry involving an organozinc compound,
an organic halide and a nickel or palladium catalyst creating a new carboncarboncovalent bond:
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 or alkyl.
The metal M in the catalyst is nickel or palladium
The ligand L in the catalyst can be triphenylphosphine, dppe, BINAP or chiraphos
Palladium catalysts in general have higher chemical yields and higher functional group tolerance.
Reaction mechanism
The active catalyst in this reaction is zerovalent (M0) and the reaction in general proceeds through
an oxidative addition step of the organic halide followed by transmetalation with the zinc compound and
then 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
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reductive elimination to product while the latter gives the trans-adduct which has to go through a slow transcis isomerization first.
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:[4]
ArPdAr' + Ar'ZnX Ar'PdAr' + ArZnX
Ar'PdAr' Ar'Ar' + Pd(0) (homocoupling)
ArZnX + H2O ArH + HOZnX (reaction accompanied by dehalogenation)
Scope
The Negishi coupling has been applied in the synthesis of a 2,2'-bipyridine from 2-bromopyridine
with tetrakis(triphenylphosphine)palladium(0),the synthesis of a biphenyl from o-tolylzinc chloride
and o-iodotoluene and tetrakis(triphenylphosphine)palladium(0), the synthesis of 5,7-hexadecadiene
from 1-decyne and (Z)-1-hexenyl iodide.
Structure of hexaferrocenylbenzene, C6[(5-C5H4)Fe(5-C5H5)]6

Negishi coupling has been applied in the synthesis of hexaferrocenylbenzene
Withhexaiodidobenzene, 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-2phenylacetophenone 1 and the resulting palladium OPdCl complex then accepts both the organozinc
compound 2 and the organotin compound 3 in a double transmetalation:
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C-C formation reactions

Shapiro reaction
The Shapiro
reaction or tosylhydrazone
decomposition is
an organic
reaction in
which
a ketone or aldehyde is converted to an alkene through an intermediate hydrazone in the presence of 2
equivalents of strong base.
Reaction mechanism
In a prelude to the actual Shapiro reaction a ketone or an aldehyde is reacted with ptoluenesulfonylhydrazideto
a p-toluenesulfonylhydrazone
(or tosylhydrazone)
which
is
an imine orhydrazone. Two equivalents of a strong base, such as n-butyllithium, then abstract first
the proton from the hydrazone and then the less acidic proton to the hydrazone carbon, leaving acarbanion.
The carbanion proceeds in an elimination reaction to create the carboncarbon double bond. This step results
in expulsion of the tosyl group and formation of a diazonium anion. The anion then collapses, falling off as a
neutral nitrogen molecule. The result is a vinyllithium at the position where the nitrogen had been attached.
This organolithium carbon is both nucleophilic andbasic. It can be reacted with various electrophiles or
simply neutralized with water or an acid.
Scope
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The position of the alkene in the product is controlled by the site of deprotonation by the organolithium
base. In general, the kinetically favored, less substituted site of differentially substituted tosylhydrazones is
deprotonated selectively, leading to the less substituted vinyllithium intermediate. Although many secondary
reactions exist for the vinyllithium functional group, in the Shapiro reaction in particular water is added,
resulting in protonation to the alkene. Other reactions of vinyllithium compounds include alkylation
reactions with for instance alkyl halides.
Shapiro reactions starting from camphor (1) through the intermediate hydrazone (2) to the vinyllithium (3).
Addition of water (c) results in 2-bornene (4) and addition of an alkyl bromide (d) gives 5
Importantly, the Shapiro reaction cannot be used to synthesize 1-lithioalkenes (and the resulting
functionalized derivatives), as sulfonylhydrazones derived from aldehydes undergo exclusive addition of the
organolithium base to the carbon of the CN double bond.
BamfordStevens reaction
The BamfordStevens reaction is a chemical reaction whereby treatment of tosylhydrazones with strong
base gives alkenes. The usage of aprotic solvents gives predominantly Z-alkenes, while protic solvent gives
a mixture of E- and Z-alkenes.
The treatment of tosylhydrazones with alkyl lithium reagents is called the Shapiro reaction.
Reaction mechanism
The first step of the BamfordStevens reaction is the formation of the diazo compound 3.
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In protic solvents, the diazo compound 3 decomposes to the carbenium ion 5.
In aprotic solvents, the diazo compound 3 decomposes to the carbene 7.
McMurry reaction
The McMurry reaction is an organic reaction in which two ketone or aldehyde groups are coupled to
an alkene using titanium chloridecompound such as titanium(III) chloride and a reducing agent. McMurry
reaction originally involved the use of a mixture TiCl3 and LiAlH4, which produces the active reagent(s).
Related species have been developed involving the combination of TiCl3 or TiCl4 with various other
reducing agents, including potassium, zinc, andmagnesium. This reaction is related to the Pinacol coupling
reaction which also proceeds by reductive coupling of carbonyl compounds.
The McMurry reaction of benzophenone

Reaction mechanism
This reductive coupling can be viewed as involving two steps. First is the formation of a pinacolate (1,2diolate) complex, a step which is equivalent to the pinacol coupling reaction. The second step is
the deoxygenation of the pinacolate which yields the alkene. The second step exploits the oxophilicity of
titanium.
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A proposed mechanism when TiCl4 and Zn(Cu) are used for the coupling of benzophenone, as proposed in a
reference.[4] Note that the mechanism may vary when different conditions are used.
Julia olefination
The Julia
olefination (also
known
as
the JuliaLythgoe olefination)
is
the chemical
reaction of phenyl sulfones (1) with aldehydes (or ketones) to give alkenes (3) after alcohol functionalization
and reductive elimination using sodium amalgamor SmI2.
This transformation highly favors formation of the trans-alkene.

All four steps can be carried out in a single reaction vessel, and use of R 3X is optional. However,
purification of the sulfone intermediate 2 leads to higher yield and purity. Most often R 3 is acetyl orbenzoyl,
with acetic anhydride or benzoyl chloride used in the preparation of 2.
Reaction mechanism
The initial steps are straightforward. The phenyl sulfone anion (2) reacts with an aldehyde to form
the alkoxide 3. The alkoxide is functionalized with R3-X to give the stable intermediate 4. The exact
mechanism of the sodium amalgam reduction is unknown but has been shown to proceed through a vinylic
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radical species (5). Protonation of the vinylic radical gives the desired product (6).
The stereochemistry of the alkene (6) is independent of the stereochemistry of the sulfone intermediate 4. It
is thought that the radical intermediates are able to equilibrate so that the more thermodynamically stable
trans-olefin is produced most often.
Heteroaryl sulfones
The replacement of the phenyl sulfones with heteroaryl sulfones greatly alters the reaction pathway.The
most popular example is the benzothiazole sulfone. The reaction of the benzothiazole sulfone (1)
with lithium diisopropylamide (LDA) gives a metallated benzothiazolyl sulfone, which reacts quickly with
aldehydes (or ketones) to give an alkoxides intermediate (2). Unlike the phenyl sulfones, this alkoxide
intermediate (2) is unstable and will undergo a Smiles rearrangement to give the sulfinate salt 4. The
sulfinate salt (4) will spontaneously eliminate sulfur dioxide andlithium benzothiazolone (5) producing the
desired alkene (6).
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Since the benzothiazole variation of the Julia olefination does not involve equilibrating intermediates, the
stereochemical outcome is a result of the stereochemistry of the initial carbonyl addition. As a result, this
reaction often generates a mixture of alkene stereoisomers.
JuliaKocienski olefination:-In the JuliaKocienski olefination the alkylating agent is a tetrazole. It
proceeds with the same mechanism as the benzothiazole sulfone above. In one adaptation, with tbutyltetrazoylmethyl sulfone the reaction conditions are either sodium bis(trimethylsilyl)amide at 70 C
in tetrahydrofuran or caesium carbonate at +70 C.
Peterson olefination
The Peterson olefination (also called the Peterson reaction) is the chemical reaction of -silyl
carbanions 1 with ketones (or aldehydes) to form a -hydroxysilane 2 which eliminates to formalkenes 3.[1]
Reaction mechanism:-One attractive feature of the Peterson olefination is that it can be used to prepare
either cis- or trans-alkenes from the same -hydroxysilane. Treatment of the -hydroxysilane with acid will
yield one alkene, while treatment of the same -hydroxysilane with base will yield the alkene of opposite
stereochemistry.
Basic elimination:The action of base upon a -hydroxysilane 1 results in a concerted syn elimination of 2 or 3 to form the
desired alkene. The penta-coordinate silicate intermediate 3 is postulated, but no proof exists to date.
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Potassium alkoxides
eliminate
quickly,
while sodium alkoxides
generally
require
heating. Magnesium alkoxides only eliminate in extreme conditions. The order of reactivity of alkoxides, K
> Na >> Mg, is consistent with higher electron density on oxygen, hence increasing the alkoxide
nucleophilicity.
Acidic elimination
The treatment of the -hydroxysilane 1 with acid results in protonation and an anti elimination to form the
desired alkene.
Alkyl substituents
When
the
-silyl
carbanion
contains
only alkyl, hydrogen,
or electron-donating
substituents,
the stereochemical outcome of the Peterson olefination can be controlled, because at low temperature the
elimination is slow and the intermediate -hydroxysilane can be isolated.
Once isolated, the diastereomeric -hydroxysilanes are separated. One diastereomer is treated with acid,
while the other is treated with base, thus converted the material to an alkene with the required
stereochemistry.
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Electron-withdrawing substituents
When the -silyl carbanion contains electron-withdrawing substituents, the Peterson olefination directly
forms the alkene. The intermediate -hydroxysilane cannot be isolated as it eliminates in-situ. The basic
elimination pathway has been postulated in these cases.
Variations
Acidic elimination conditions are sometimes not feasible as the acid also promotes double
bond isomerization. Additionally, elimination using sodium or potassium hydride may not be feasible due to
incompatible functional groups. Chan et al. have found that acylation of the intermediate silylcarbinol with
either acetyl chloride or thionyl chloride gives a -silyl ester that will eliminate spontaneously at 25 C
giving the desired alkene.
Multi component reactions
Ugi reaction
The Ugi reaction is a multi-component reaction in organic chemistry involving a ketone or aldehyde,
an amine, an isocyanide and a carboxylic acid to form a bis-amide.
The Ugi reaction is exothermic and usually complete within minutes of adding the isocyanide. High
concentration (0.5M - 2.0M) of reactants give the highest yields. Polar, aprotic solvents, likeDMF, work
well. However, methanol and ethanol have also been used successfully. This uncatalyzed reaction has an
inherent high atom economy as only a molecule of water is lost and chemical yield in general are high.
Recent research has shown that the Ugi reaction is accelerated in water.
Reaction mechanism :-In the Ugi reaction, the initial reaction is the formation of an imine (1) from the
amine and the ketone. Subsequent reaction of the imine with the isocyanide and the carboxylic acid gives
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intermediate 2, which rearranges via an acyl transfer into the bis-amide 3. The exact mechanism of the
trimolecular reaction to form intermediate 2 is not known.
The reaction can also be performed with a pre-formed imine. This results in an increased yield.One
plausible reaction mechanism is depicted below
Amine 1 and ketone 2 form the imine 3 with loss of one equivalent of water. Proton exchange
with carboxylic acid 4 activates the iminium ion 5 for nucleophilic addition of the isocyanide 6 with its
terminal carbon atom to nitrilium ion 7. A second nucleophilic addition takes place at this intermediate with
the carboxylic acid anion to 8. The final step is a Mumm rearrangement with transfer of the R4 acyl group
from oxygen to nitrogen. Note that in the related Passerini reaction (lacking the amine) the isocyanide reacts
directly with the carbonyl group but other aspects of the reaction are the same. All reaction steps
are reversible except for the Mumm rearrangement, which drives the whole reaction sequence.
Combination of reaction components
The usage of bifunctional reaction components greatly increases the diversity of possible reaction products.
Likewise, several combinations lead to structurally interesting products. The Ugi reaction has been applied
in combination with an intramolecular Diels-Alder reaction [13] in an extended multistep reaction.
A reaction in its own right is the UgiSmiles reaction with the carboxylic acid component replaced by
a phenol. In this reaction the Mumm rearrangement in the final step is replaced by theSmiles
rearrangement.[14]
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UgiDielsAlder reaction
UgiSmiles reaction
Another combination (with separate workup of the Ugi intermediate) is one with the BuchwaldHartwig
reaction.[15] In the UgiHeck reaction a Heck aryl-aryl coupling takes place in a second step [16]
UgiBuchwaldHartwig reaction
UgiHeck reaction
Combination of amine and carboxylic acid

Several groups have used -amino acids in the Ugi reaction to prepare -lactams. This approach relies on
acyl transfer in the Mumm rearrangement to form the four-membered ring. The reaction proceeds in
moderate yield at room temperature in methanol with formaldehyde or a variety of aryl aldehydes. For
example, p-nitrobenzaldehyde reacts to form the -lactam shown in 71% yield as a 4:1 diastereomeric
mixture:
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Combination of carbonyl compound and carboxylic acid

Chemical libraries
The Ugi reaction is one of the first reactions to be exploited explicitly to develop chemical libraries. These
chemical libraries are sets of compounds that can be tested repeatedly. Using the principles of combinatorial
chemistry, the Ugi reaction offers the possibility to synthesize a great number of different compounds in one
reaction, by the reaction of various ketones (or aldehydes), amines, isocyanides and carboxylic acids. These
libraries can then be tested with enzymes or living organisms to find new active pharmaceutical substances.
One drawback is the lack of chemical diversity of the products. Using the Ugi reaction in combination with
other reactions enlarges the chemical diversity of possible products.
Examples of Ugi reaction combinations:Isoquinolines from Ugi and Heck reactions.
Passerini reaction
The Passerini reaction is a chemical reaction involving an isocyanide, an aldehyde (or ketone), and
a carboxylic acid to form a -acyloxy amide.
It is the first isocyanide based multi-component reaction developed, and currently plays a central role
incombinatorial chemistry.
Reaction mechanism
Two different reaction pathways have been hypothesized.
Ionic mechanism
In polar solvents such as methanol or water, the reaction proceeds by protonation of the carbonyl followed
by nucleophilic addition of the isocyanide to give the nitrilium ion 3. Addition of a carboxylate gives
intermediate 4. Acyl group transfer and amide tautomerization give the desired ester 5
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Concerted mechanism
In non-polar solvents and at high concentration a concerted mechanism is likely:[6]
This mechanism involves a trimolecular reaction between the isocyanide (RNC), the carboxylic acid, and
the carbonyl in a sequence of nucleophilic additions. The transition state TS# is depicted as a 5-membered
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ring with partial covalent or double bonding. The second step of the Passerini reaction is an acyl transfer to
the neighboring hydroxyl group. There is support for this reaction mechanism: the reaction proceeds in
relatively non-polar solvents (in line with transition state) and the reaction kinetics depend on all
three reactants. This reaction is a good example of aconvergent synthesis.
The Passerini reactions is used in many multicomponent reactions for instance one preceded by a HornerWadsworth-Emmons reaction and forming a depsipeptide:[7]
Passerini multicomponent reactions have found use in the preparation of polymers from renewable
materials.
Biginelli reaction
The Biginelli reaction is a multiple-component chemical reaction that creates 3,4-dihydropyrimidin-2(1H)ones 4 from ethyl acetoacetate 1, an aryl aldehyde (such as benzaldehyde 2), and urea3.
The reaction can be catalyzed by Brnsted acids and/or by Lewis acids such as copper(II) trifluoroacetate
hydrate and boron trifluoride.
Dihydropyrimidinones, the products of the Biginelli reaction, are widely used in the pharmaceutical industry
as calcium channel blockers, antihypertensive agents, and alpha-1-a-antagonists.
Reaction mechanism
The reaction mechanism of the Biginelli reaction is a series of bimolecular reactions leading to the desired
dihydropyrimidinone.
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According to a mechanism proposed by Sweet in 1973 the aldol condensation of ethylacetoacetate 1 and the
aryl aldehyde is the rate-limiting step leading to the carbenium ion 2. The nucleophilic addition of urea gives
the intermediate 4, which quickly dehydrates to give the desired product 5.
This mechanism is superseded by one by Kappe in 1997:
This scheme begins with rate determining nucleophilic addition by the urea to the aldehyde. The ensuing
condensation step is catalyzed by the addition of acid, resulting in the imine nitrogen. The -ketoester then
adds to the imine bond and consequently the ring is closed by the nucleophilic attack by the amine onto the
carbonyl group. This final step ensures a second condensation and results in the Biginelli compound.
Hantzsch pyridine synthesis
The Hantzsch pyridine synthesis or Hantzsch dihydropyridine synthesis is a multi-component organic
reaction between an aldehyde such as formaldehyde, 2 equivalents of a -keto estersuch as ethyl
acetoacetate and a nitrogen donor such as ammonium acetate or ammonia.[1] The initial reaction product is a
dihydropyridine which can be oxidized in a subsequent step to apyridine. The driving force for this second
reaction step is aromatization. A 1,4-dihydropyridine dicarboxylate is also called a 1,4-DHP compound or
a Hantzsch compound. These compounds are an important class of calcium channel blockers and as such
commercialized in for instance nifedipine, amlodipine or nimodipine.
The reaction has been demonstrated to proceed in water as reaction solvent and with direct aromatization
by ferric chloride or potassium permanganate in a one-pot synthesis.
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The Hantzsch dihydropyridine synthesis is found to benefit from microwave chemistry.

Mannich reaction
The Mannich reaction is an organic reaction which consists of an amino alkylation of an acidic proton
placed next to a carbonyl functional group with formaldehyde and ammonia or any primary or
secondary amine. The final product is a -amino-carbonyl compound also known as a Mannich
base.[1] Reactions between aldimines and -methylene carbonyls are also considered Mannich reactions
because these imines form between amines and aldehydes. The reaction is named after chemist Carl
Mannich.[2][3]
The Mannich reaction is an example of nucleophilic addition of an amine to a carbonyl group followed by
dehydration to the Schiff base. The Schiff base is an electrophile which reacts in the second step in
an electrophilic addition with a compound containing an acidic proton(which is, or had become an enol).
The Mannich reaction is also considered a condensation reaction.
In the Mannich reaction, ammonia or primary or secondary amines are employed for the activation
of formaldehyde. Tertiary amines lack an NH proton to form the intermediate enamine. -CH-acidic
compounds (nucleophiles) include carbonyl compounds, nitriles, acetylenes, aliphatic nitro compounds, alkyl-pyridines or imines. It is also possible to use activated phenyl groups and electron-rich heterocycles
such as furan, pyrrole, and thiophene. Indole is a particularly active substrate; the reaction
provides gramine derivatives.
Reaction mechanism
The mechanism of the Mannich reaction starts with the formation of an iminium ion from the amine and the
formaldehyde.
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The compound with the carbonyl functional group (in this case a ketone) can tautomerize to the enol form,
after which it can attack the iminium ion.
Asymmetric Mannich reactions

Progress has been made towards asymmetric Mannich reactions. When properly functionalized the newly
formed ethylene bridge in the Mannich adduct has two prochiral centers giving rise to two diastereomeric
pairs of enantiomers. The first asymmetric Mannich reaction with an unmodified aldehyde was carried
with (S)-proline as a naturally occurring chiral catalyst.
The reaction taking place is between a simple aldehyde such as propionaldehyde and an imine derived
from ethyl glyoxylate and p-methoxyaniline (PMP = paramethoxphenyl) catalyzed by (S)-proline
S.Ahammad Kabeer
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in dioxane at room temperature. The reaction product is diastereoselective with a preference for the synMannich reaction 3:1 when the alkyl substituent on the aldehyde is a methyl group or 19:1 when the alkyl
group the much larger pentyl group. Of the two possible syn adducts (S,S) or (R,R) the reaction is
also enantioselective with a preference for the (S,S) adduct withenantiomeric excess larger than 99%. This
stereoselectivity is explained in the scheme below.
Proline enters a catalytic cycle by reacting with the aldehyde to form an enamine. The two reactants (imine
and enamine) line up for the Mannich reaction with Si facial attack of the imine by the Si-face of the
enamine-aldehyde. Relief of steric strain dictates that the alkyl residue R of the enamine and the imine group
are antiperiplanar on approach which locks in the syn mode of addition. The enantioselectivity is further
controlled by hydrogen bonding between the proline carboxylic acid group and the imine. The transition
state for the addition is a nine-membered ring with chair conformation with partial single bonds and double
bonds. The proline group is converted back to the aldehyde and a single S,S isomer is formed.
By modification of the proline catalyst to it is also possible to obtain anti-Mannich adducts.
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An additional methyl group attached to proline forces a specific enamine approach and the transition state
now is a 10-membered ring with addition in anti-mode. The diastereoselectivity is at least anti:syn 95:5
regardless of alkyl group size and the S,R enantiomer is preferred with at least 97% ee.
Applications
The Mannich-Reaction is employed in the organic synthesis of natural compounds such
as peptides, nucleotides, antibiotics, and alkaloids (e.g. tropinone). Other applications are in agro chemicals
such as plant growth regulators,[6] paint- and polymer chemistry, catalysts and main mechanism of formalin
tissue crosslinking.
The Mannich reaction is also used in the synthesis of medicinal compounds e.g. rolitetracycline (Mannich
base of tetracycline), fluoxetine (antidepressant), tramadol, and tolmetin (anti-inflammatory drug)and
azacyclophanes,
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ClickChemistry
"Click chemistry" is a chemical philosophy introduced by K. Barry Sharpless in 2001 and describes
chemistry tailored to generate substances quickly and reliably by joining small units together. This is
inspired by the fact that nature also generates substances by joining small modular units.
In biochemistry, proteins are made from repeating amino acid units and sugars are made from repeating
monosaccharide units. The connecting units are based on carbon-hetero atom bonds C-X-C rather than
carbon-carbon bonds. In addition, enzymes ensure that chemical processes can overcome large enthalpy
hurdles by division into a series of reactions each with a small energy step. Mimicking nature in organic
synthesis of new pharmaceuticals is essential given the large number of possible structures.
In 1996 Guida calculated the size of the pool of drug candidates at 1063, based on the presumption that a
candidate consists of less than 30 non-hydrogen atoms, weighs less than 500 daltons, is made up of atoms of
hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine and bromine, and is stable at room
temperature and stable towards oxygen and water. Click chemistry in combination with combinatorial
chemistry, high-throughput screening and building chemical libraries speeds up new drug discoveries by
making each reaction in a multistep synthesis fast, efficient and predictable.
Click chemistry encourages the following criteria:
application modular and wide in scope

obtains high chemical yield
generates inoffensive byproducts
is stereospecific
simple reaction conditions
has readily available starting materials and reagents
no solvent involved or a benign solvent (preferably water)
easy product isolation by crystallisation or distillation but not preparative chromatography
physiologically stable
large thermodynamic driving force > 84 kJ/mol to favor a reaction with a single reaction product. A
distinct exothermic reaction makes a reactant "spring loaded".
high atom economy
Many of the criteria are subjective; and even if measurable and objective criteria could be agreed upon, it's
unlikely that any reaction will be perfect for every situation and application. However, several reactions
have been identified which fit the bill better than others:
The Huisgen 1,3-dipolar cycloaddition, in particular the Cu(I)-catalyzed stepwise variant, is often
referred to simply as the "click reaction". Fokin and Sharpless independently described it as a
reliable catalytic process offering "an unprecedented level of selectivity, reliability, and scope for
those organic synthesis endeavors which depend on the creation of covalent links between diverse
building blocks," firmly placing it among the most reliable processes fitting the click criteria.
other cycloadditions such as the Diels-Alder reaction
nucleophilic substitution especially to small strained rings like epoxy and aziridine compounds
carbonyl-chemistry-like formation of ureas but not reactions of the aldol type due to low
thermodynamic driving force.
Addition reactions to carbon-carbon double bonds like dihydroxylation.
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Azide-Alkyne Cycloaddition
In the azide-alkyne cycloaddition monosubstituted alkynes and organic azides under go cycloaddition
reaction selectively gives 1,2,3-triazoles.
Unfortunately, the thermal Huisgen 1,3-Dipolar Cycloaddition of alkynes to azides requires elevated
temperatures and often produces mixtures of the two regioisomers when using asymmetric alkynes. In this
respect, the classic 1,3-dipolar cycloaddition fails as a true click reaction. A copper-catalyzed variant that
follows a different mechanism can be conducted under aqueous conditions, even at room temperature.
Additionally, whereas the classic Huisgen 1,3-dipolar cycloaddition often gives mixtures of regioisomers,
the copper-catalyzed reaction allows the synthesis of the 1,4-disubstituted regioisomers specifically. By
contrast, a later developed ruthenium-catalyzed reaction gives the opposite regioselectivity with the
formation of 1,5-disubstituted triazoles. Thus, these catalyzed reactions comply fully with the definition of
click chemistry and have put a focus on azide-alkyne cycloaddition as a prototype click reaction.
Mechanism of the Copper-Catalyzed Azide-Alkyne Cycloaddition (CuAAC)

As one of the best click reactions to date, the copper-catalyzed azide-alkyne cycloaddition features an
enormous rate acceleration of 107 to 108 compared to the uncatalyzed 1,3-dipolar cycloaddition. It succeeds
over a broad temperature range, is insensitive to aqueous conditions and a pH range over 4 to 12, and
tolerates a broad range of functional groups. Pure products can be isolated by simple filtration or extraction
without the need for chromatography or recrystallization.
The active Cu(I) catalyst can be generated from Cu(I) salts or Cu(II) salts using sodium ascorbate as the
reducing agent. Addition of a slight excess of sodium ascorbate prevents the formation of oxidative
homocoupling products. Disproportionation of a Cu(II) salt in presence of a Cu wire can also be used to
form active Cu(I).
DFT calculations have shown that coordination of Cu(I) to the alkyne is slightly endothermic in MeCN, but
exothermic in water, which is in agreement with an observed rate acceleration in water. However,
coordination of Cu to the acetylene does not accelerate a 1,3-dipolar cycloaddition. Such a process has been
S.Ahammad Kabeer
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calculated to be even less favorable than the uncatalyzed 1,3-dipolar cycloaddition. Instead, a copper
acetylide forms, after which the azide displaces another ligand and binds to the copper. Then, an unusual
six-membered copper(III) metallacycle is formed. The barrier for this process has been calculated to be
considerably lower than the one for the uncatalyzed reaction. The calculated rate at room temperature is 1 s 1
, which is quite reasonable. Ring contraction to a triazolyl-copper derivative is followed by protonolysis
that delivers the triazole product and closes the catalytic cycle.
Mechanism of the Ruthenium-Catalyzed Azide-Alkyne Cycloaddition (RuAAC)

A search for catalysts revealed that pentamethylcyclopentadienyl ruthenium chloride [Cp*RuCl] complexes
are able to catalyze the cycloaddition of azides to terminal alkynes regioselectively leading to 1,5disubstituted 1,2,3-triazoles. In addition, RuAAC can also be used with internal alkynes, providing fully
substituted 1,2,3-triazoles, which contrasts with CuAAC.
The ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC) appears to proceed via oxidative coupling of
the azide and the alkyne to give a six-membered ruthenacycle, in which the first new carbon-nitrogen bond
is formed between the more electronegative carbon of the alkyne and the terminal, electrophilic nitrogen of
the azide. This step is followed by reductive elimination, which forms the triazole product. DFT calculations
support this mechanistic proposal and indicate that the reductive elimination step is rate-determining..
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Examples
A Novel Approach to 1-Monosubstituted 1,2,3-Triazoles by a Click Cycloaddition/Decarboxylation Process
The Use of Calcium Carbide in the Synthesis of 1-Monosubstituted Aryl 1,2,3-Triazole via Click Chemistry
Microwave Irradiation as an Effective Means of Synthesizing Unsubstituted N-Linked 1,2,3-Triazoles from

Vinyl Acetate and Azides
A Convenient Synthesis of 1-Substituted 1,2,3-Triazoles via CuI/Et3N Catalyzed Click Chemistry' from
Azides and Acetylene Gas
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Tandem Catalysis: From Alkynoic Acids and Aryl Iodides to 1,2,3-Triazoles in One Pot
CuI/DIPEA/HOAc is as a highly efficient catalytic system for CuAAC. In this novel acid-base jointly
promoted formation of 1,2,3-triazoles, HOAc was recognized to accelerate the conversions of the C-Cu
bond-containing intermediates and buffer the basicity of DIPEA. As a result, all drawbacks occurring in the
popular catalytic system CuI/NR3 were overcome easily.
[CuBr(PPh3)3] for Azide-Alkyne Cycloaddition Reactions under Strict Click Conditions
A Copper(I) Isonitrile Complex as a Heterogeneous Catalyst for Azide-Alkyne Cycloaddition in Water
An abnormal NHC complex of copper with 1,4-diphenyl-1,2,3-triazol-5-ylidene [CuCl(TPh)] efficiently

catalyzed click reactions of azides with alkynes to give 1,4-substituted 1,2,3-triazoles in excellent yields at
room temperature with short reaction times. CuCl(TPh) was particularly effective for the reaction between
sterically hindered azides and alkynes.
Carboxylic
Acid-Promoted
S.Ahammad Kabeer
Copper(I)-Catalyzed
Azide-Alkyne
Cycloaddition
Page52

Metathesis
Olefin metathesis is a metal-catalyzed transformation, which acts on carboncarbon double bonds and
rearranges them via cleavage and reassembly.1-5 While the reaction itself was discovered in the mid-1950s,
its now generally accepted mechanism was not proposed until 1971.6 According to this mechanism, first
introduced by Chauvin, the coordination of an olefin to a metal carbene catalytic species leads to the
reversible formation of a metallacyclobutane (Scheme 1.1). This intermediate then proceeds by
cycloreversion via either of the two possible paths: 1) non-productiveresulting in the re-formation of the
starting materials or 2) product-formingyielding an olefin that has exchanged a carbon with the catalysts
alkylidene. Since all of these processes are fully reversible (Scheme 1.1), only statistical mixtures of starting
materials as well as all of possible rearrangement products are produced in the absence of thermodynamic
driving force
Grubbs' Catalysts are a series of transition metal carbene complexes used as catalysts for olefin metathesis.
They are named after Robert H. Grubbs, the chemist who first synthesized them. There are two generations
of the catalyst, as shown on the right.[1][2] In contrast to other olefin metathesis catalysts, Grubbs' catalysts
tolerate other functional groups in the alkene, are air-tolerant and are compatible with a wide range of
solvents.For these reasons, Grubbs' catalysts have become popular in synthetic organic chemistry.
First generation catalyst
The first well-defined ruthenium catalyst for olefin metathesis was discovered in 1992.It was prepared from
RuCl2(PPh3)4 and diphenylcyclopropene.
This initial ruthenium catalyst was followed in 1995 by what is now known as the first generation Grubbs
catalyst. It is easily synthesized fromRuCl2(PPh3)3, phenyldiazomethane, and tricyclohexylphosphine in
a one-pot synthesis.
The first generation Grubbs catalyst, while largely replaced by the second generation catalyst in usage, was
not only the first catalyst to be developed other than those developed by Richard R. Schrock (Schrock
carbenes), but is also important as a precursor to all other Grubbs-type catalysts.
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Second generation catalyst
The second generation catalyst has the same uses in organic synthesis as the first generation catalyst, but
generally with higher activity. This catalyst is stable toward moisture and air, thus is easier to handle in the
lab.
Shortly before the discovery of the 2nd generation Grubbs' catalyst, a very similar catalyst based on
an unsaturated N-heterocyclic carbene (1,3-bis(2,4,6-trimethylphenyl)imidazole) was prepared by Grubbs
and reported the 2nd generation catalyst, based on a saturated N-heterocyclic carbene (1,3-bis(2,4,6trimethylphenyl)dihydroimidazole):
In both the saturated and unsaturated cases a phosphine ligand is replaced with an N-heterocyclic
carbene (NHC), which is characteristic of all 2ndgeneration type catalysts.
Both the 1st and 2nd generation catalysts are commercially available, along with many derivatives of the
2nd generation catalyst.
Applications
Olefin metathesis is a reaction between two molecules containing double bonds. The groups bonded to the
carbon atoms of the double bond are exchanged between molecules, to produce two new molecules
containing double bonds with swapped groups. Whether a cis isomer or trans isomer is formed in this type
of reaction is determined by the orientation the molecules assume when they coordinate to the catalyst, as
well as the sterics of the substituents on the double bond of the newly forming molecule.
Olefin metathesis
Olefin metathesis is an organic reaction that entails the redistribution of fragments of alkenes (olefins) by
the scission and regeneration of carbon-carbon double bonds.[1] Catalysts for this reaction have evolved
rapidly for the past few decades. Because of the relative simplicity of olefin metathesis it often creates fewer
undesired by-products and hazardous wastes than alternative organic reactions. Because of their elucidation
of the reaction mechanism and their discovery of a variety of highly efficient and selective catalysts, Yves
Chauvin, Robert H. Grubbs, and Richard R. Schrock were collectively awarded the 2005 Nobel Prize in
Chemistry.
Catalysts
The reaction is catalyzed by metal complexes. Traditional catalysts are prepared by a reaction of the metal
halides with alkylation agents, for example WCl6EtOHEtAlCl2. The traditional, industrial catalysts are illdefined
and
used
mainly
for Petroleum
products.
Modern
catalysts
are
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defined organometallic compounds that come in two main categories, commonly known as Schrock
catalysts and Grubbs' catalysts. Schrock catalysts are molybdenum(IV)- and tungsten(IV)-based, and are
examples of Schrock alkylidenes.[3]
Grubbs' catalysts, on the other hand, are ruthenium(II) carbenoid complexes.[4] Grubbs' catalysts are often
modified with a chelating isopropoxystyrene ligand to form the related HoveydaGrubbs catalyst.
Types of olefin metathesis process

Some important classes of olefin metathesis include:
Cross metathesis (CM)
Ring-opening metathesis (ROM)
Ring-closing metathesis (RCM)
Ring-opening metathesis polymerisation (ROMP)
Acyclic diene metathesis (ADMET)
Ethenolysis
Reaction mechanism
Hrisson and Chauvin first proposed the widely accepted mechanism of transition metal alkene
metathesis. The direct [2+2] cycloaddition of two alkenes is formally symmetry forbidden and thus has a
high activation energy. The Chauvin mechanism involves the [2+2] cycloaddition of an alkene double bond
to a transition metal alkylidene to form a metallacyclobutane intermediate. The metallacyclobutane
produced can then cyclorevert to give either the original species or a new alkene and alkylidene. Interaction
with the d-orbitals on the metal catalyst lowers the activation energy enough that the reaction can proceed
rapidly at modest temperatures.
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Like most chemical reactions, the metathesis pathway is driven by a thermodynamic imperative; that is, the
final products are determined by the energetics of the possible products, with a distribution of products
proportional to the exponential of their respective energy values. In olefin metathesis, however, this is
especially relevant since all the possible products have similar energy values (all of them contain an olefin).
Because of this the product mixture can be tuned by reaction conditions, such as gas pressure and substrate
concentration. In some cases a given reaction can be run in either direction to near completion.
Cross metathesis and Ring-closing metathesis are often driven by the entropically favored evolution
of ethylene or propylene, which are both gases. Because of this CM and RCM reactions often use alphaolefins. The reverse reaction of CM of two alpha-olefins, ethenolysis, can be favored but requires high
pressures of ethylene to increase ethylene concentration in solution. The reverse reaction of RCM, ringopening metathesis, can likewise be favored by a large excess of an alpha-olefin, often styrene. Ring
opening metathesis usually involves a strained alkene (often anorbornene) and the release of ring strain
drives the reaction. Ring-closing metathesis, conversely, usually involves the formation of a five- or sixmembered ring, which is energetically favorable; although these reactions tend to also evolve ethylene, as
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previously discussed. RCM has been used to close larger macrocycles, in which case the reaction may be
kinetically controlled by running the reaction at extreme dilutions. The same substrates that undergo RCM
can undergo acyclic diene metathesis, with ADMET favored at high concentrations. The ThorpeIngold
effectmay also be exploited to improve both reaction rates and product selectivity.
Cross-metathesis is synthetically equivalent to (and has replaced) a procedure of ozonolysis of an alkene to
two ketone fragments followed by the reaction of one of them with a Wittig reagent.
Ring-closing metathesis
Ring-closing metathesis or RCM is a variation on olefin metathesis that allows the closing of previously
hard to make rings (7-8 member rings in particular). RCM is simply an intramolecular olefin metathesis,
yielding the cycloalkene and a volatile alkene, in this example ethene.
Many metathesis reactions with ruthenium catalysts are hampered by unwanted isomerization of the newly
formed double bond and it is believed that ruthenium hydrides are responsible that form as a side reaction.
In one study it was found that isomerization is suppressed in the RCM reaction of diallyl ether with specific
additives capable of removing these hydrides . Without an additive, the reaction product is 2,3dihydrofuran and not the expected 2,5-dihydrofuran (together with the formation of ethylene gas). Radical
scavengers such as TEMPO or phenol as an additive show the same picture but with additives such as 1,4benzoquinone or acetic acid on the other hand isomerization is absent. Both additives are able to oxidize the
ruthenium hydrides which may explain their behaviour.
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Ring closing metathesis is important in total synthesis. One example is found in the synthesis of the
naturally occurring cyclophane floresolide (Scheme 3, R=H).[2]
Ring-opening metathesis polymerisation

Ring-opening metathesis polymerization (ROMP) is a type of olefin metathesis chain-growth
polymerization that produces industrially important products. The driving force of the reaction is relief
of ring strain in cyclic olefins (e.g. norbornene or cyclopentene) and a wide variety of catalysts have been
discovered. Research has shown that the addition of substituents to the monomer and the choice of solvent
can alter the molecular weight of the polymer produced.
Mechanism
The catalysts used in the ROMP reaction include a wide variety of metals and range from a simple
RuCl3/alcohol mixture to Grubbs' catalyst
The ROMP reaction is catalyzed primarily through the formation of metal-carbene complexes as first
reported by Nobel Prize winner Yves Chauvin and his colleague Jean-Louis Hrisson[3][4]although a hydride
mechanism has also been reported. The initiation of the carbene species occurs through numerous pathways;
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solvent interactions, substituent interactions, and co-catalysts all can contribute to the production of the
reactive catalytic species.
The ROMP catalytic cycle requires a strained cyclic structure because the driving force of the reaction is
relief of ring strain. After formation of the metal-carbene species, the carbene attacks the double bond in the
ring structure forming a highly strained metallacyclobutane intermediate. The ring then opens giving the
beginning of the polymer: a linear chain double bonded to the metal with a terminal double bond as well.
The new carbene reacts with the double bond on the next monomer, thus propagating the reaction
Solvent effects
The choice of solvent can play a vital role in the formation of the carbene species. One example of such
interactions was reported by Basset, et al. regarding RuCl3 and the effects of various alcohols on its
catalytic activity. Depending upon the alcohol used, the mechanistic pathway resulted in either a reactive
ruthenium-hydride species or the formation of a ruthenium-carbene. Experimental results demonstrated
that by altering the solvent, the molecular weight of the polymer produced was either increased or
decreased. This observation could result in increased diversity of the catalytic system enabling the
production of polymers of various strengths, as polymers with higher molecular weights are typically
stronger than polymers of low molecular weights. Drastic differences in the rate of the reaction were
also observed, thereby supporting the conclusion that the solvent plays a role in the formation of the
ruthenium-carbene.
Substituent Effects
As previously stated, ROMP catalysis is dependent on ring strain. Therefore, the best substrates are biand tri-cyclic rings; however, these reactions can lead to numerous products.The addition of substituents
to the ring system can result in more complex or more functional polymer products. Unfortunately,
substituents on the ring can react deleteriously with some of the most common catalysts. The first
Grubbs catalyst is poisoned by nitrile or amine groups. Many common molybdenum or tungsten
metathetical catalysts are affected by oxygenate or nitrogenous groups. Thus alternative catalysts, such
as ruthenium carbene complexes that are not affected by these functional groups are being researched.
The position of the substituent in the ring complex has a correlation to the poisoning effect on the
catalyst. However, in cases where it is non-poisoning, it also plays a role in determining the reactivity of
the substrate. Substituents cannot be placed on the carbon with the double bond or the reaction will not
take place. Slugovc, et al. tested the effect of numerous functional groups on the ROMP reaction using
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the Super-Grubbs catalyst, (H2IMes)(PCy3)(Cl)2Ru=CHPh. The experimental results show that the
addition of common substituents to the reaction mixture can be used to tune the molecular weight range
of the polymer produced.
Depending on the catalyst, some substituents can increase the rate of reaction. Norbornene epoxides
increase the rate of reaction when a ruthenium trichloride/alcohol mixture is used as the catalyst. Basset,
et al.contribute this rate increase to the production of a metallooxacyclobutane complex that, upon
metathetic opening, gives the active ruthenium carbene complex directly. It stands to reason that other
functional groups that can react with a similar mechanistic pathway will also increase the rate of
reaction.
Industrial Applications
Ring-opening metathesis polymerization of cycloalkenes can produce many important petrochemicals;
this is of particular importance in an industrial capacity because synthetic capabilities include linear
polymers from inexpensive monomers or polymers with special properties, thus compensating for an
additional expense. Some examples of polymers produced on an industrial level through ROMP
catalysis are Vestenamer or trans-polyoctenamer which is the metathetical polymer of cyclooctene;
Norsorex or polynorbornene is another important ROMP product on the market; Telene
and Metton are polydicyclopentadiene products produced in a side reaction of the polymerization of
norbornene.
The ROMP process is quite useful because a regular polymer with a regular amount of double bonds is
formed. The resulting product can be subjected to partial or total hydrogenation or can be functionalized
into more complex compounds.
BaylisHillman reaction
The BaylisHillman reaction is an organic reaction of an aldehyde and an ,-unsaturated electronwithdrawing group catalyzed by DABCO (1,4-diazabicyclo[2.2.2]octane) to give an allylicalcohol. This
reaction is also known as the MoritaBaylisHillman reaction or MBH reaction. The BaylisHillman
reaction, in the present day version, is an atom-economic carbon-carbon bond formation reaction.
In addition to DABCO, additional nucleophilic amines such as DMAP and DBU as well as phosphines have
been found to successfully catalyze this reaction.
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Reaction mechanism
The nucleophilic
addition of
DABCO 2 onto
the
,-unsaturated
ketone 1 gives
a zwitterionic intermediate 3, which will add to the electrophilic aldehyde producing the ketoalcohol 4. Elimination of the DABCO gives the desired allylic alcohol 5.
A simple relationship exists between pKa of the base (as its conjugate acids) and the reaction
rate with quinuclidine even
more
effective
than
DABCO. Protic additives
like methanol,triethanolamine, formamide, and water also accelerate the reaction.
An alternative mechanism, based on extensive rate data, has been proposed for some aldehydes.This
mechanism (figure below) takes into account experimentally determined second order kinetics for the
aldehyde and a substantial kinetic isotope effect for the enone alpha-proton. In it a second aldehyde
molecule reacts to form a hemiacetal (4) and this step is followed by arate-determining proton transfer step
to intermediate 5.
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In silico experiments confirm this mechanism and also explain how protic additives increase reaction rates
by facilitating the proton transfer step. Several of the key intermediates can also be detected experimentally
with ESI-MS
A related reaction actually predating the BaylisHillman reaction utilising phosphines and not DABCO is
the lesser known RauhutCurrier reaction.
Scope
The MBH reaction in general is any reaction of electron deficient alkenes and sp2 hybridized carbon
electrophiles such as aldehydes, ketones and aldimines catalyzed by a nucleophile. Under special reaction
conditions the reaction is also found to extend to alkyl halides as the electrophilic reagent. In this variation
amine nucleophiles are unsuitable and trialkyl phosphines are used instead. Under the given reaction
conditions these phosphines do not react directly with the alkyl halide. The added base in the second step of
this reaction promotes the elimination reaction to the enone.
In the aza-BaylisHillman reaction the electrophile is an imine.

Eschenmoser fragmentation
The Eschenmoser
fragmentation,the chemical
reaction of
with aryl sulfonylhydrazines (2) to give alkynes (3) and carbonyl compounds (4).
,-epoxyketones (1)
Reaction mechanism
The mechanism of the Eschenmoser fragmentation begins with the condensation of an ,-epoxyketone (1)
with an aryl sulfonylhydrazine (2) to afford the intermediate hydrazone (3). This hydrazone can either be
protonated at the expoxide oxgygen or deprotonated at the sulfonamide nitrogen to initiate the
fragmentation, and thus the fragmentation is catalyzed by acids or bases. Most common reaction conditions,
however, are treatment with acetic acid in dichloromethane. The proton transfer leads to intermediate 4,
which undergoes the key fragmentation to alkyne (6) and the corresponding carbonyl compound (7). Driving
force is the formation of molecular nitrogen.
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Besides this standard course, there is also a radical variant of this ,-enonealkynone fragmentation,
which employs 1,2-dibromo-5,5-dimethylhydantoin (DDH) in sec-butanol. Therefore, an epoxide is not
required. The ,-unsaturated hydrazone is brominated by DDH in allylic position at the sulfonamide
nitrogen, which constitutes the capto-dative stabilized radical position, and the bromide ion becomes the
leaving group in the following nucleophilic attack of an alcoholate ion.
Eschenmoser Fragmentation (Eschenmoser-Tanabe Fragmentation)
Mitsunobu reaction
The Mitsunobu reaction is an organic reaction that converts an alcohol into a variety of functional groups,
such
as
an ester,
using triphenylphosphine and
an
azodicarboxylate
such
as diethyl
[1]
azodicarboxylate (DEAD)
or diisopropyl
azodicarboxylate (DIAD). The
alcohol
undergoes
an inversion of stereochemistry. It was discovered by Oyo Mitsunobu (19342003).
Reaction mechanism
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The reaction mechanism of the Mitsunobu reaction is fairly complex. The identity of intermediates and the
roles they play has been the subject of debate.
Initially, the triphenyl phosphine (2) makes a nucleophilic attack upon diethyl azodicarboxylate (1)
producing a betaine intermediate 3, which deprotonates the carboxylic acid (4) to form the ion pair 5. DEAD
itself deprotonates the alcohol (6) forming an alkoxide that can form the key oxyphosphonium ion 8. The
ratio and interconversion of intermediates 811 depend on the carboxylic acid pKa and the solvent
polarity.[7][8][9] Although several phosphorus intermediates are present, the attack of the carboxylate anion
upon intermediate 8 is the only productive pathway forming the desired product 12 and triphenylphosphine
oxide (13).
Hughes et al. have found that the formation of the ion pair 5 is very fast. The formation of the
oxyphosphonium intermediate 8 is slow and facilitated by the alkoxide. Therefore, the overall rate of
reaction is controlled by carboxylate basicity and solvation.
Order of addition of reagents
The order of addition of the reagents of the Mitsunobu reaction can be important. Typically, one dissolves
the alcohol, the carboxylic acid, and triphenylphosphine in tetrahydrofuran or other suitable solvent
(e.g. diethyl ether), cool to 0 C using an ice-bath, slowly add the DEAD dissolved in THF, then stir at room
temperature for several hours. If this is unsuccessful, then preforming the betaine may give better results. To
preform the betaine, add DEAD to triphenylphosphine in tetrahydrofuran at 0 C, followed by the addition
of the alcohol and finally the acid.
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Other nucleophilic functional groups
Many other functional groups can serve as nucleophiles besides carboxylic acids. For the reaction to be
successful, the nucleophile must have a pKa less than 15.
Nucleophile
Product
hydrazoic acid alkyl azide

imide
substituted imide[12]
phenol
alkyl aryl ether
sulfonamide
substituted sulfonamide[13]
Modifications
Several modifications to the original reagent combination have been developed in order to simplify the
separation of the product and avoid production of so much chemical waste. One variation of the Mitsunobu
Reaction uses resin-bound triphenylphoshine and uses di-tert-butylazodicarboxylate instead of DEAD. The
oxidized triphenylphosphine resin can be removed by filtration, and the di-tert-butylazodicarboxylate
byproduct is removed by treatment with trifluoroacetic acid.[14] Bruce H. Lipshutz has developed an
alternative to DEAD, Di-(4-chlorobenzyl)azodicarboxylate (DCAD) where the hydrazine by-product can be
easily removed by filtration and recycled back to DCAD.
A modification has also been reported in which DEAD can be used in catalytic versus stoichiometric
quantities, however this procedure requires the use of stoichiometric (diacetoxyiodo)benzene to oxidise the
hydrazine by-product back to DEAD.
Phosphorane reagents[
(Cyanomethylene) trialkylphosphorane
Tsunoda et al. have shown that one can combine the triphenylphosphine and the diethyl azodicarboxylate
into one reagent: a phosphorane ylide. Both (cyanomethylene)trimethylphosphorane (CMMP, R = Me) and
(cyanomethylene)tributylphosphorane (CMBP, R = Bu) have proven particularly effective.
The ylide acts as both the reducing agent and the base. The byproducts are acetonitrile (6) and the
trialkylphosphine oxide (8).
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Uses
The Mitsunobu reaction has been applied in the synthesis of aryl ethers
With these particular reactants the conversion with DEAD fails because the phenol is only weakly acidic.
Instead the related 1,1'-(azodicarbonyl)dipiperidine (ADDP) is used of which the betaineintermediate is a
stronger base. The phosphine is a polymer-supported triphenylphosphine (PS-PPh3).
Stork enamine alkylation
The Stork enamine alkylation, involves the addition of an enamine to an alpha, beta-unsaturated carbonyl
acceptor in a process similar to the Michael reaction.[1] The product is then hydrolyzedby an aqueous acid to
produce a 1,5-dicarbonyl compound.
The process:
1. formation of an enamine from a ketone
2. addition of the enamine to an alpha, beta-unsaturated aldehyde or ketone
3. hydrolysis of the enamine back to a ketone
When the electrophile is an acyl halide, a 1,3-diketone is formed (Stork acylation).

In a special case of this reaction type it is also possible to alkylate ketones or aldehydes with alkyl halides as
less reactive electrophiles:[3]
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In this method a carbonyl compound is converted to an imine by alkylimino-de-oxo-bisubstitution with a

primary amine. The imine is then reacted with an Grignard reagent to the corresponding magnesium salt to
an intermediate capable of displacing a halide. Hydrolysis once again yields the alkylated ketone
Michael reaction
The Michael
reaction or Michael
addition is
the nucleophilic
addition of
a carbanion or
another nucleophile to an ,-unsaturated carbonyl compound. It belongs to the larger class ofconjugate
additions. This is one of the most useful methods for the mild formation of CC bonds.[4] Many asymmetric
variants exist.
In this scheme the R and R' substituents on the nucleophile (a Michael donor) are electron-withdrawing
groups such as acyl and cyano making the methylene hydrogen acidic forming the carbanion on reaction
with base B:. The substituent on the activated alkene, also called a Michael acceptor, is usually
a ketone making it an enone, but it can also be a nitro group.
Definition
The reaction is the addition of an enolate of a ketone or aldehyde to an ,-unsaturated carbonyl
compound at the carbon. A newer definition, proposed by Kohler, is the 1,4-addition of a doubly
stabilized carbon nucleophile to an ,-unsaturated carbonyl compound. Some examples of nucleophiles
include beta-ketoesters, malonates, and beta-cyanoesters. The resulting product contains a highly useful
1,5-dioxygenated pattern.
Classical examples of the Michael reaction are the reaction between diethyl malonate (Michael donor)
and diethyl fumarate (Michael acceptor),[10] that of mesityl oxide and diethyl malonate,that of diethyl
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malonate and methyl crotonate,[12] that of 2-nitropropane and methyl acrylate, that
phenylcyanoacetate and acrylonitrile[14] and that of nitropropane and methyl vinyl ketone.
of ethyl
The
Michael
addition
is
an
important atom-economical method
for diastereoselective and enantioselective CC bond formation. A classical tandem sequence of Michael
and aldol additions is theRobinson annulation.
Mechanism
The reaction mechanism is 1 (with R an alkoxy group) as the nucleophile
Deprotonation of 1 by base leads to carbanion 2 stabilized by its electron-withdrawing groups. Structures 2a

to 2c are three resonance structures that can be drawn for this species, two of which have enolate ions. This
nucleophile reacts with the electrophilic alkene 3 to form 4 in a conjugate addition reaction. Proton
abstraction from protonated base (or solvent) by the enolate 4 to 5 is the final step.
The course of the reaction is dominated by orbital, rather than electrostatic, considerations. The HOMO of
stabilized enolates has a large coefficient on the central carbon atom while the LUMO of many alpha, beta
unsaturated carbonyl compounds has a large coefficient on the beta carbon. Thus, both reactants can be
considered soft. These polarized frontier orbitals are of similar energy, and react efficiently to form a new
carboncarbon bond.
Like the aldol addition, the Michael reaction may proceed via an enol, silyl enol ether in the MukaiyamaMichael addition, or more usually, enolate nucleophile. In the latter case, the stabilized carbonyl compound
is deprotonated with a strong base (hard enolization) or with a Lewis acid and a weak base (soft enolization).
The resulting enolate attacks the activated olefin with 1,4-regioselectivity, forming a carboncarbon bond.
This also transfers the enolate to the electrophile. Since the electrophile is much less acidic than the
nucleophile, rapid proton transfer usually transfers the enolate back to the nucleophile if the product is
enolizable; however, one may take advantage of the new locus of nucleophilicity if a suitable electrophile is
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pendant. Depending on the relative acidities of the nucleophile and product, the reaction may be catalytic in
base. In most cases, the reaction is irreversible at low temperature.
Asymmetric Michael reaction
Recent research has focused on expanding the scope of asymmetric Michael additions. The most common
methods involve chiral phase transfer catalysis, involving chiral quaternary ammonium salts derived from
the Cinchona alkaloids, and organocatalysis, which uses enamine or iminium activation with chiral
secondary amines, usually derived from proline.
In the reaction between cyclohexanone and nitrostyrene sketched below, the base proline is derivatized and
works in conjunction with a protic acid such as p-toluenesulfonic acid:[16]
Syn addition is favored with 99% ee. In the transition state believed to be responsible for this selectivity,
the enamine (formed between the proline nitrogen and the cycloketone) and nitrostyrene are co-facial with
the nitro group hydrogen bonded to the protonated amine in the proline side group.
well-known
Michael
reaction
is
the
hydroxycoumarin and benzylideneacetone first reported by Link in 1944:
synthesis
of warfarin from 4-
[17]
Several asymmetric versions of this reaction exist using chiral catalysts.
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PausonKhand reaction
The PausonKhand reaction (or PKR or PK-type reaction) is a chemical reaction described as a
[2+2+1] cycloaddition between
an alkyne,
an alkene and carbon
monoxide to
form
a
,cyclopentenone. This reaction was originally mediated by stoichiometric amounts of dicobalt octacarbonyl,
but this has since been replaced by newer and more efficient catalyst systems.
With asymmetrical alkenes

with intramolecular reactions.
or
alkynes regioselectivity is
always
an
issue,
but
less
so
The reaction works with both terminal and internal alkynes although internal alkynes tend to give lower
yields. The order of reactivity for the alkene is strained cyclic alkene > terminal alkene > disubstituted
alkene > trisubstituted alkene. Unsuitable alkenes are tetrasubstituted alkenes and alkenes with
strongly electron withdrawing groups.
Mechanism of the Pauson-Khand Reaction
The following mechanism is postulated, although only the stable alkyne Co2(CO)6 complex has been
isolated.The stereochemistry of the complexation of the alkene at cobalt is guided by steric repulsions
between the R and R' groups, so that isomers 1 and 2 are favored.
The insertion of the alkene is followed by insertion of carbon monoxide and reductive elimination of one Co
unit:
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Dissociation of the second Co unit gives the resulting cyclopentenone product:
Variations
Wilkinson's catalyst, based on the transition metal rhodium, also effectively catalyses PK reactions but
requires silver triflate as a co-catalyst.
Molybdenum
hexacarbonyl is
a
carbon
monoxide
between allenes and alkynes with dimethyl sulfoxide in toluene.
donor
in
PK-type
reactions
Cyclobutadiene also lends itself to a [2+2+1] cycloaddition although this reactant is generated in situ from
decomplexation of stable cyclobutadiene iron tricarbonyl with CAN.
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Bergman cyclization
The Bergman
cyclization or Bergman
reaction or Bergman
cycloaromatization is
an organic
reaction and more specifically a rearrangement reaction taking place when an enediyne is heated in presence
of a suitable hydrogen donor (Scheme 1).[1] It is named for the American chemist Robert George Bergman
(b. 1942). The reaction product is a derivative of benzene.
The reaction proceeds by a thermal reaction or pyrolysis (above 200C) forming a short-lived and very
reactive para-benzyne biradical species. It will react with any hydrogen donor such as 1,4cyclohexadiene which converts to benzene. When quenched by tetrachloromethane the reaction product is
a 1,4-dichlorobenzene and with methanol the reaction product is benzyl alcohol.
When the enyne moiety is incorporated into a 10-membered hydrocarbon ring (e.g. cyclodeca-3-ene-1,5diyne in scheme 2) the reaction, taking advantage of increased ring strain in the reactant, is possible at the
much lower temperature of 37C.
Naturally occurring compounds such as calicheamicin contain the same 10-membered ring and are found to
be cytotoxic. These compounds generate the diradical intermediate described above which can cause single
and double stranded DNA cuts. There are novel drugs which attempt to make use of this property,
including monoclonal antibodies such as mylotarg.
A biradical mechanism is also proposed for the formation of certain biomolecules found in
marine sporolides that have a chlorobenzene unit as part of their structure. In this mechanism a halide salt
provides the halogen. A model reaction with the enediyene cyclodeca-1,5-diyn-3-ene, lithium bromide as
halogen source and acetic acid as hydrogen source in DMSO at 37C supports the theory:
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The reaction is found to be first-order in enediyne with the formation of p-benzyne A as the rate-limiting
step. The halide ion then donates its two electrons in the formation of a new Br-C bond and radical electron
involved is believed to shuttle over a transient C1-C4 bond forming the anion intermediate B. The anion is a
powerful base, stripping protons even from DMSO to final product. The dibromide or dihydrogen product
(tetralin) never form
Bergman Cyclization
Bergman Cycloaromatization
The Bergman Cyclization allows the construction of substituted arenes through the thermal or
photochemical cycloaromatization of enediynes in the presence of a H donor such as 1,4-cyclohexadiene.
Mechanism of the Bergman Cyclization

The cyclization is induced thermally or photochemically. Most cyclizations have a high activation energy
barrier and therefore temperatures around 200 C are needed for the cycloaromatization. The Bergman
Cyclization forms a 1,4-benzenediyl diradical - a highly reactive species, that reacts with a H donor to give
the corresponding arenes.
The interest in the Bergman Cyclization was somewhat low, due to its limited substrate scope and the
availability of alternative methods for the construction of substituted arenes. However, natural products that
contain the enediyne moiety have been discovered recently, and these compounds have cytotoxic activity.
An example is calicheamicin, which is able to form the reactive diradical species even under physiological
conditions. Here, the Bergman Cyclization is activated by a triggering reaction. A distinguishing property of
this diradical species is that it can effect a dual-strand cleavage of DNA:
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With the discovery of calicheamicin and similar natural products, interest in the Bergman Cyclization has
increased. Many enediynes can now be viewed as potential anticancer drugs. Thus, the development of
Bergman Cyclization precursors that can undergo cyclization at room temperature has attracted much
attention. Now, most publications on this topic deal with the parameters that control the kinetics of the
Bergman Cyclization.
For example, as shown by calicheamicin, cyclic enediynes have a lower activation barrier than acyclic
enediynes. As suggested by Nicolaou in 1988, the distance between the acetylenic carbons that form the
covalent bond influences the rate of cyclization. Another theory developed by Magnus and Snyder is based
on the molecular strain between ground state and transition state; this seems to be more general, especially
for strained cyclic systems. Often, as both the distance and the strain are not known, the development of
suitable precursors remains difficult, as exemplified by the following enediyne, in which a slight change
leads to a cycloaromatization:
In contrast to the Bergman Cyclization, the Myers-Saito Cyclization of allenyl enynes exhibits a much lower
activation temperature while following a similar pathway:
Cyclic enyne allenes are also reactive. Neocarzinostatin is a bacterial antibiotic that also shows antitumor
activity. Here, the occurrence of a Myers-Saito Cyclization sets the stage for the cleavage of DNA:
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For synthetic purposes, organometallic reagents can be used to generate a precursor to the Bergman
Cyclization in which the metal center forms a part of the cumulated unsaturated system; these cyclizations
occur at relatively low temperatures, as shown in the example reported by Finn (J. Am. Chem.
Soc. 1995, 117, 8045). Here the cyclization can be viewed as a Myers-Saito Cyclization that gives rise to a
metal-centered radical:
Photochemical and Thermal Bergman Cyclization of a Pyrimidine Enediynol and Enediyn
Nazarov cyclization reaction

The Nazarov cyclization reaction (often referred to as simply the Nazarov cyclization) is a chemical
reaction used in organic chemistry for the synthesis of cyclopentenones. The reaction is typically divided
into classical and modern variants, depending on the reagents and substrates employed.
As originally described, the Nazarov cyclization involves the activation of a divinyl ketone using
a stoichiometric Lewis acid or protic acid promoter. The key step of the reaction mechanism involves
a cationic 4-electrocyclic ring closure which forms the cyclopentenone product. As the reaction has been
developed, variants involving substrates other than divinyl ketones and promoters other than Lewis acids
have been subsumed under the name Nazarov cyclization provided that they follow a similar mechanistic
pathway.
Mechanism
The mechanism of the classical Nazarov cyclization reaction was first demonstrated experimentally by
Shoppe to be an intramolecular electrocyclization and is outlined below. Activation of theketone by the acid
catalyst
generates
a pentadienyl
cation which
undergoes
a
thermally
allowed
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4 conrotatory electrocyclization as dictated by the Woodward-Hoffman rules. This generates an oxyallyl
cation which undergoes an elimination reaction to lose a -hydrogen. Subsequent tautomerization of
the enolate produces the cyclopentenone product.
Mechanism of the classical Nazarov cyclization activated by Lewis acid catalyst. Note that - and substitution are not required for the reaction to occur and that more complex -substitution is also possible.
As noted above, variants that deviate from this template are known; what designates a Nazarov cyclization
in particular is the generation of the pentadienyl cation followed by electrocyclic ring closure to an oxyallyl
cation. In order to achieve this transformation, the molecule must be in the s-trans/s-trans conformation,
placing the vinyl groups in an appropriate orientation. The propensity of the system to enter this
conformation dramatically influences reaction rate, with -substituted substrates having an increased
population of the requisite conformer due to allylic strain. Coordination of an electron donating -substituent
by the catalyst can likewise increase the reaction rate by enforcing this conformation.
Relevant conformations for the Nazarov cyclization; Lewis-acid chelation in the s-cis conformer
Similarly, -substitution directed inward restricts the s-trans conformation so severely that EZ isomerization has been shown to occur in advance of cyclization on a wide range of substrates, yielding
the trans cyclopentenone regardless of initial configuration. In this way, the Nazarov cyclization is a rare
example of a stereoselective pericyclic reaction, whereas most electrocyclizationsare stereospecific. The
example below uses triethylsilyl hydride to trap the oxyallyl cation so that no elimination
occurs.[2] (See Interrupted cyclizations below)
Stereoselectivity in the Nazarov cyclization evident via reductive trapping

Along this same vein, allenyl vinyl ketones of the type studied extensively by Marcus Tius of the University
of Hawaii show dramatic rate acceleration due to the removal of -hydrogens, obviating a large amount of
steric strain in the s-cis conformer.
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Allene substrates for Nazarov cyclization with lowered steric interactions

Classical Nazarov cyclization
Though cyclizations following the general template above had been observed prior to Nazarov's
involvement, it was his study of the rearrangements of allyl vinyl ketones that marked the first major
examination of this process. Nazarov correctly reasoned that the allylic olefin isomerized in situ to form a
divinyl ketone before ring closure to the cyclopentenone product. The reaction shown below involves
an alkyne oxymercuration reaction to generate the requisite ketone.
Early investigation into the Nazarov cyclization

Research involving the reaction was relatively quiet in subsequent years, until in the mid-1980s when
several syntheses employing the Nazarov cyclization were published. Shown below are key steps in the
syntheses of Trichodiene and Nor-Sterepolide, the latter of which is thought to proceed via an
unusual alkyne-allene isomerization that generates the divinyl ketone.
Synthesis of Trichodiene using a classical Nazarov cyclization
Synthesis of Nor-Sterepolide using a classical Nazarov cyclization

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Shortcomings
The classical version of the Nazarov cyclization suffers from several drawbacks which modern variants
attempt to circumvent. The first two are not evident from the mechanism alone, but are indicative of the
barriers to cyclization; the last three stem from selectivity issues relating to elimination and protonation of
the intermediate.
1. Strong Lewis or protic acids are typically required for the reaction (e.g. TiCl4, BF3, MeSO3H). These
promoters are not compatible with sensitive functional groups, limiting the substrate scope.
2. Despite the mechanistic possibility for catalysis, multiple equivalents of the promoter are often
required in order to effect the reaction. This limits the atom economy of the reaction.
3. The elimination step is not regioselective; if multiple -hydrogens are available for elimination,
various products are often observed as mixtures. This is highly undesirable from an efficiency
standpoint as arduous separation is typically required.
4. Elimination destroys a potential stereocenter, decreasing the potential usefulness of the reaction.
5. Protonation of the enolate is sometimes not stereoselective, meaning that products can be formed as
mixtures of epimers.
Shortcomings of the Nazarov cyclization reaction
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Advanced Synthetic Reactions

Metal mediated C-C and C-X coupling reactions