24

Catalytic Carbon-Carbon
Bond Formation

A ruthenium-
Outline
containing
organometallic 24.1 Carbon-Carbon Bond-Forming Reactions from Earlier Chapters
catalyst for
alkene metathesis
24.2 Organometallic Compounds and Catalysis
reactions. See 24.3 The Heck Reaction
Section 24.6 for 24.4 Catalytic Allylic Alkylation
the structure of
this catalyst and 24.5 Palladium-Catalyzed Cross-Coupling Reactions
a discussion of 24.6 Alkene Metathesis
this reaction.

Over the course of the last 120 years, chemists have learned how to synthesize amaz-
ingly complex molecules. In recent years particularly, they have focused on com-
pounds of medicinal interest, and a large number of current pharmaceuticals are
synthesized from simpler compounds. Many of these pharmaceuticals are natural
products or their analogs, and others are either simpler analogs or unrelated com-
pounds that have been found to be active against certain organisms or diseased
cells, specific cellular receptors, or specific enzyme targets. A key development that
has allowed synthesis of these compounds has been the discovery of many catalytic
methods of carbon-carbon bond formation. It is now possible, using a combination
of new and classical methods, to carry out the synthesis of molecules with sensitive
functionality and amazingly complex carbon skeletons from simple and inexpensive
starting materials, often with excellent stereo- and regiocontrol. In this chapter, we
make a dramatic leap from the more classical organic reactions covered in previous
chapters of this book to survey several particularly useful catalytic methods of carbon-
carbon bond formation, some of which represent very recent developments. Further,
the catalytic methods we present are part of a thrust in industry to move to green
chemistry, in which less chemical waste is generated. We have room for only a few

1095

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1096  Chapter 24: Catalytic Carbon-Carbon Bond Formation

representative examples out of the wealth of carbon-carbon bond forming reactions

that are now available to the modern synthetic chemist. Finally, a number of problems
based on modern organic syntheses are given to illustrate the use of these reactions
and their combination with other reactions.

24.1 Carbon-Carbon Bond-Forming Reactions

from Earlier Chapters
As a review, let us list the methods of carbon-carbon bond formation you have
already studied. All these reactions should be available to you for synthetic
problems.
Nucleophilic displacement of a leaving group by a carbon nucleophile
●● Gilman (organocuprate) reagents (Section 15.2C) if the leaving group is a halogen
atom or tosylate.
●● Grignard reagents, organolithium reagents (Section 15.1C) and Gilman reagents if
the leaving group is the oxygen of an epoxide.
●● Alkyne (Sections 7.5 and 9.1) and cyanide (Section 9.1) anions. The leaving group
can be the oxygen of an epoxide (Section 11.9B).
●● Enolate anion alkylations, acetoacetic ester synthesis and malonic ester synthesis
(Sections 19.6 and 19.7).
●● Enamine alkylations (Section 19.5).
Nucleophilic addition to a carbonyl or a carboxyl group
●● Grignard reagents (Sections 16.5A and 18.9A), organolithium reagents (Sections
16.5B and 18.9B), and Gilman reagents (Section 18.9C).
●● Alkyne (Section 16.5C) and cyanide (Section 16.5D) anions.
●● Aldol reactions (Section 19.2).
●● Claisen (Section 19.3A) and Dieckmann (Section 19.3B) condensations.
●● Enamine acylations (Section 19.5B).
●● Wittig reaction (Section 16.6 for C"C double bonds).
Conjugate addition to a,b-unsaturated carbonyl compounds
●● Michael reaction (Section 19.8A).
Pericyclic reactions
●● Diels-Alder reaction (Section 20.5).
●● Claisen rearrangement (Section 20.6).
●● Cope rearrangement (Section 20.6).
Carbene/carbenoid additions (Section 15.3).
Aromatic substitution
●● Friedel-Crafts alkylation and acylation of aromatics (Section 22.1C).
●● Reaction of cyanide with aromatic diazonium compounds (Section 23.8E).
This list already includes many different reactions, but you will find that the new reac-
tions in this chapter are of somewhat different character.
None of the C!C bond-forming reactions summarized above are catalytic. R ­ ecall
that a catalyst is a species that becomes involved in the mechanism of a reaction and
lowers the barrier to that reaction, thereby accelerating the reaction rate. Catalysts do
not change the thermodynamics of a reaction; instead, they alter the kinetics. Further,
a catalyst is regenerated at the end of the reaction in the same form as at the start of
the reaction; hence, a catalyst is available to be used over and over!a property often
referred to as “turnover.”

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 24.2 Organometallic Compounds and Catalysis   1097

This chapter focuses on catalytic C!C bond-forming reactions. In other words, a

chemical (the catalyst) is added to the reaction vessel and causes C!C bond forma-
tion in a manner that is faster than would occur in the absence of the catalyst. In fact,
most of the reactions we examine in this chapter (particularly those of Section 24.5)
would essentially never occur without the catalyst. Consequently, we start the chapter
with a brief overview of the key reactions performed by organometallic compounds.

24.2 Organometallic Compounds and Catalysis

We introduced organometallic compounds in Chapter 15. In the next few sections,
we discuss several reactions of transition metals that are particularly useful for the
preparation of new carbon-carbon bonds.

A. Oxidative Addition and Reductive Elimination

Two extremely important reactions of transition metals and transition metal com-
pounds are oxidative addition and its reverse, reductive elimination. In oxidative Oxidative addition
addition, a reagent adds to a metal, causing its coordination to increase by two; re- Addition of a reagent to a
ductive elimination is the opposite. These reactions are called oxidative or reductive metal center causing it to
because the formal charge of the metal changes by two during the reaction. Oxidative add two substituents and to
addition can occur with a metal coordinated with one or more ligands (Ln, where increase its oxidation state
n is the number); it can also occur with a free metal, M(0). Haloalkanes, hydrogen, by two.
halogens, and many other types of compounds can take part in these reactions. The Reductive elimination
reactivity of different substrates depends greatly on the metal.
Elimination of two
substituents at a metal center,
causing the oxidation state of
n 1 n
the metal to decrease by two.
Ligand
Although numerous other reactions are unique and essential to the action of A Lewis base bonded to a
­organometallic catalysts, the key steps of the catalytic processes we discuss in this metal atom in a coordination
chapter involve oxidative additions and reductive eliminations. Thus, in an introduc- compound. It may bond
tory chapter on catalytic C!C bond-forming reactions, we need go no deeper. strongly or weakly.

B. Key Features of the Utility of Catalytic C—C Bond Formation

The reactions and mechanisms covered in this chapter represent a growing modern
trend in organic chemistry. Organometallic catalysts facilitate reactions that are oth-
erwise ­impossible, are very difficult, or would require many synthetic steps in order
to accomplish. The use of these catalysts causes a net decrease in the number and
quantity of reagents, solvents, and purifications necessary in an overall synthetic se-
quence. This decrease means that the chemical waste from an industrial process can
be dramatically reduced. Intentionally designing a chemical procedure or process to
decrease waste and toxic byproducts is now a whole chemical field in and of itself that
is called green chemistry.
A goal of green chemistry is to use effectively each of the atoms involved in a
reaction so that atoms are not “thrown away” by being incorporated into byproducts
of the reactions. This concept is called atom economy, which describes the efficiency
of a chemical process in terms of all atoms involved. An ideal reaction would con-
sist of the mass of the product equaling the mass of all the reactants used. In such a
case, each atom of the reactants would be completely incorporated into the product
and no waste would be generated. Such reactions are rare, but the goal of achieving
the highest atom economy clearly has both an environmental and economic benefit.
Hence, “going green” is permeating society in many ways, with the chemical industry
recognizing and embracing the value of green.

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1098  Chapter 24: Catalytic Carbon-Carbon Bond Formation

Watch a video explanation

24.3 The Heck Reaction
A. The Nature of the Reaction
In the early 1970s, Richard Heck, at Hercules, Inc. and later at the University of
­Delaware, discovered a palladium-catalyzed reaction in which the carbon group of a
haloalkene or haloarene is substituted for a hydrogen on the carbon-carbon double
bond (a vinylic hydrogen) of an alkene. This reaction, now known as the Heck
reaction, is particularly valuable in synthetic organic chemistry because it is the only
general method yet discovered for this type of substitution.

9 1 1 1 1 2

Substitution for a vinylic hydrogen by the Heck reaction is highly regioselec-

tive; formation of the new carbon-carbon bond most commonly occurs at the less
substituted carbon of the double bond. In addition, where an E or Z configuration is
possible at the double bond of the product, the Heck reaction is highly s­ tereoselective,
often giving almost exclusively the E configuration of the product.

1 "

Bromobenzene Methyl 2-propenoate Methyl (E)-3-phenyl-2-propenoate

(Methyl acrylate) (Methyl cinnamate)

In addition, the Heck reaction is completely stereospecific with regard to the haloal-
kene; the configuration of the double bond in the haloalkene is preserved.

Z Z

(Z)-3-Iodo-3-hexene Phenylethene (1E,3Z)-3-Ethyl-1-phenyl-1,3-hexadiene

(Styrene)

E E

(E )-3-Iodo-3-hexene Phenylethene (1E,3E )-3-Ethyl-1-phenyl-1,3-hexadiene

(Styrene)

Preparation of the Catalyst

The form of the palladium catalyst most commonly added to the reaction medium is
palladium(II) acetate, Pd(OAc)2. This and other Pd(II) compounds are better termed

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 24.3 The Heck Reaction   1099

precatalysts because the catalytically active form of the metal is a complex of Pd(0)
formed in situ by reduction of Pd(II) to Pd(0).

Palladium(II)
acetate

Reaction of Pd(0) with good ligands, L, gives the actual Heck catalyst, PdL2. Without
the ligand, Pd(0) is insoluble.

Among the most common ligands, L, used for coordination of the Pd(0) is tri-
phenylphosphine, (C6H5)3P. Many other ligands can be used as well, including chiral
ones such as BINAP (Section 6.7) that can lead to a significant excess of a single en-
antiomer in the case of chiral products.

The Haloalkane
The most common halides used in Heck reactions are aryl, heterocyclic, benzylic,
and vinylic iodides and bromides, with iodides generally being most reactive. The
reactivity of substrates with leaving groups on sp2 carbons contrasts with nucleo-
philic substitution reactions, where such substrates are essentially unreactive.
Haloalkanes in which there is an acidic b-hydrogen are rarely used because of the
ease with which they undergo b-elimination under conditions of the Heck reaction
to form alkenes. Triflates (trifluoromethanesulfonates, CF 3SO2O!), which are eas-
ily prepared by treating an alcohol with trifluoromethanesulfonyl chloride, are also
excellent substrates.

9 1 9 9 1

Trifluoromethanesulfonyl chloride

The halide or triflate (RX) reacts with PdL2 by oxidative addition to give a square
planar Pd(II) species, which is the reaction intermediate.

9 9

A particular advantage of the Heck reaction is the wide range of functional groups,
including alcohols, ethers, aldehydes, ketones, and esters, that may be present else-
where in the organic halogen compound or alkene without reacting themselves or
affecting the Heck reaction.

The Alkene
The reactivity of the alkene is a function of steric crowding about the carbon-carbon
double bond. Ethylene and monosubstituted alkenes are most reactive; the greater the
degree of substitution on the double bond, the slower the reaction and the lower the

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1100  Chapter 24: Catalytic Carbon-Carbon Bond Formation

yield of product. These steric effects also control the regiochemistry of the ­addition,
with the alkyl group adding to the less hindered carbon of the alkene.

The Base
Commonly used bases are tertiary amines such as triethylamine, Et 3N, sodium or
­ otassium acetate, and sodium hydrogen carbonate.
p

The Solvent
Polar aprotic solvents (Section 9.3D) such as N,N-dimethylformamide (DMF), ace-
tonitrile, and dimethyl sulfoxide (DMSO) are commonly used. It is also possible to
carry out some Heck reactions in aqueous methanol. The polar solvents are needed to
dissolve the Pd(OAc)2 at the beginning of the reaction.

B. Mechanism of the Reaction

The mechanism of the Heck reaction is divided into two stages: formation of the
Heck catalyst and the catalytic cycle. As you study the catalytic cycle, note in particu-
lar that both Steps 2 and 4 are syn stereoselective; reaction will not proceed if these
syn relationships cannot be obtained. Step 2 involves syn addition of R and PdL2X to
the double bond. Step 4 involves syn elimination of H and the Pd(II) species to gen-
erate a new double bond. These syn additions and eliminations contrast with most
of the addition and elimination reactions we have seen, which prefer the anti geom-
etry. Additions of boron hydrides (Section 6.4, hydroboration) and osmium tetroxide
(Section 6.5A) or ozone (Section 6.5B) to alkenes are some examples of syn additions
that you have already seen.

Mechanism 24.1

The Heck Reaction

Stage 1: Formation of the Heck Catalyst, PdL2

A two-electron reduction of Pd(II) to Pd(0) accompanied by its complex formation with two molecules of a ligand,
L, gives the Heck catalyst, PdL2. A common reducing agent is triethylamine or, as in the following example, the
alkene itself. Because the catalyst is present only in small amounts, an insignificant amount of the alkene is lost
to this reaction. In the reaction shown here, L is triphenylphosphine, (C6H5)3P. As mentioned previously, this is
actually a two-step reaction: reduction of the palladium followed by reaction of the palladium with the ligand. We
show the two steps combined here for simplicity.

1 1 1 1

Palladium(II) Triphenylphosphine
acetate

Stage 2: The Catalytic Cycle

The catalytic cycle of the Heck reaction involves five steps. In Step 1, oxidative addition of the haloalkene or
haloarene, RX, to PdL2 gives a tetracoordinated Pd(II) complex containing both R and X groups bonded to Pd.
Syn addition of the R and PdL2X of this complex to the alkene gives an intermediate in which Pd is bonded to
the more substituted carbon for steric reasons. Because of the long Pd!C bond, the palladium is sterically less
demanding than the organic group; therefore, it ends up on the more hindered carbon. This intermediate must
undergo internal rotation about the central carbon-carbon single bond in Step 3 to place H and PdL2X syn to

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 24.3 The Heck Reaction   1101

each other. Syn elimination of H and PdL2X in Step 4 gives the new alkene and HPdL2X. Reductive elimination
in Step 5 releases the acid HX and regenerates the PdL2 catalyst. HX is then neutralized by the added base.

9
1

The catalytic
cycle of the
Heck reaction

9 8

In this cycle, the alkene, haloalkane compound, and base are required in equimolar amounts; the Pd(0) species is
required in only a catalytic amount. Note also the inversion of the configuration (R2 and R3 are originally cis to each
other but in the product are trans). This inversion is a consequence of the consecutive syn addition and elimination steps.
The complete mechanism for this reaction has additional intermediates (involving p complexes of the alkene with the
palladium), but those shown here are the important ones for understanding the reaction and its stereochemistry.

Example 24.1 Heck Reaction I

Complete these Heck reactions.
(a)

(b) 1

Solution
In (a), 1-iodohexene has the E configuration, and this double bond retains its
configuration in the product. Furthermore, the carbon-carbon double bond
adjacent to the ester in the product now has the possibility for cis,trans isomerism.
The Heck reaction is highly stereoselective, and this double bond has the more
stable E configuration as well. In (b), the major product is (E)-1,2-diphenylethene.

(a) (b)

Methyl (2E,4E )-2,4-nonadienoate (E)-1,2-Diphenylethene

(trans-Stilbene)

(Continued)

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1102  Chapter 24: Catalytic Carbon-Carbon Bond Formation

Problem 24.1
Show how you might prepare each compound by a Heck reaction using methyl
2-propenoate as the starting alkene.

" 9 (a) (b)

Methyl 2-propenoate E E Z
(Methyl acrylate)

The usual pattern in a Heck reaction of acyclic alkenes is replacement of one of

the hydrogens on the double bond by an organo group. If the organopalladium group
attacks the double bond so that the R-group in the original RX is bonded to a carbon
that lacks a hydrogen (or if the only syn hydrogen is on a neighboring carbon), the
double bond shifts away from the original position. Note that the product of the fol-
lowing reaction contains a chiral center, but because it is formed from achiral reagents
in an achiral environment, it is formed as a racemic mixture.

1 1

As mentioned earlier, a particularly valuable feature of the Heck reaction is that,

when used with a chiral ligand, it can give chiral products in significant enantiomeric
excess (ee). In the following, the chirality is provided by the chiral ligand (R)-BINAP
(Section 6.7C).

R
1

For this reaction to yield a chiral product, the hydrogen eliminated cannot be on the
carbon that subsequently obtains the aryl substituent because if this were the case,
the substituent would be attached to a double bond and the product would be achiral.
Because of the chiral ligand, the activation energy for the transition state in the syn
addition to the alkene (Step 2 of the catalytic cycle) is different depending on which
side of the alkene the metal complex approaches (the two transition states are diaste-
reomers). This difference in activation energy means that approach to one side of the
alkene is favored and results in an excess of one enantiomer of the product. Note that
this reaction is not a normal Heck reaction in that it forms a carbon-carbon bond to
the more substituted carbon and the double bond shifts. Attack at the other carbon,
because of the requirement for syn elimination, cannot lead to a normal Heck product;
therefore, the reaction reverses. The attack takes place at the more substituted carbon
less often, but in this case, there is a hydrogen that can undergo elimination.

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 24.3 The Heck Reaction   1103

Example 24.2 Heck Reaction II

Heck reaction of bromobenzene and (E)-3-hexene gives a mixture of (Z)-3-
phenyl-3-hexene and (E)-4-phenyl-2-hexene in roughly equal amounts. Account
for the formation of these two products.

(E)-3-Hexene
(Z )-3-Phenyl- (E )-4-Phenyl-
3-hexene 2-hexene

Solution
Syn addition gives the product shown. After rotation, syn elimination
of the H on the original double bond gives (Z)-3-phenyl-3-hexene; syn
elimination on the neighboring carbon (in its most stable conformation) gives
(E)-4-phenyl-2-hexene.

(E)-3-Hexene

(Z )-3-Phenyl- (E )-4-Phenyl-
3-hexene 2-hexene

(Continued)

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1104  Chapter 24: Catalytic Carbon-Carbon Bond Formation

Problem 24.2
Give reagents and conditions for the following reaction.

24.4 Catalytic Allylic Alkylation

Substitution mechanisms were covered in Chapter 9. It was noted that the S N2
mechanism occurs by a single-step process wherein a leaving group (often a
halogen) on an alkyl group is replaced with a nucleophile. When the alkyl group
is allylic, metals can catalyze the reaction (i.e., palladium, platinum, and rhodium,
among others).

2
2
1

Two of the most common catalysts for this reaction are PdL 4 (frequently, L
is triphenylphosphine) and PdCl2. Two examples of the reaction are given below.
One interesting feature is the retention of stereochemistry at the carbon with the
leaving group. Note that this outcome is the opposite of what would occur in an
SN2 mechanism. A particularly useful feature of the reaction is the ability to use
enolates as the nucleophile, thus resulting in C!C bond formation. The enolates
most commonly used are those derived by deprotonation of a hydrogen that is
alpha to two electron-withdrawing groups; ketones, aldehydes, nitro, esters, sul-
fonates, and cyanides are some examples. The leaving groups can be halogens
as with SN2 reactions, but this catalytic reaction is particularly useful with esters
as the leaving group. Acetate, written as OAc, is most commonly used (below in
both examples).

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 24.4 Catalytic Allylic Alkylation   1105

Example 24.3 Allylic Alkylation

Write the products of the following reactions.

Solution
As stated above, the reaction occurs with retention of stereochemical configuration
at the carbon with the acetate leaving group. Consequently, in order to write the
products, we simply replace the acetate with the enolate, writing a C!C bond
between the enolate carbon and the carbon that bears the acetate.

Problem 24.3 Watch a video explanation

Write the product(s) of the following reaction. How many stereoisomers of the
product are formed?

Although allylic alkylation with halogens as the leaving group occurs readily
without a catalyst with enolate nucleophiles, several advantages exist in having the
reaction be catalytic. There is, of course, the advantage of having the reaction occur
faster and potentially under milder conditions. Also, acetate is not normally a good
leaving group in an SN2 reaction. However, the real primary advantage is in reversing
the stereochemical outcome of the reaction as compared to SN2. Before examining
the reason behind the stereochemistry of the reaction, let’s first take a look at the
mechanism involving one particularly common catalyst, Pd(PPh3)4.

A. The Mechanism of Catalytic Allylic Alkylation

The mechanism of the reaction is a combination of the simple steps we have seen
before. The phosphine ligands reversibly dissociate and associate, and an oxidative

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1106  Chapter 24: Catalytic Carbon-Carbon Bond Formation

addition occurs. The new step that occurs in catalytic allylic alkylation is nucleophilic
attack on an allyl ligand coordinated to a metal.

Mechanism 24.2

The Catalytic Cycle for Allylic Alkylation

The catalytic cycle of allylic alkylation has several steps, six of which are shown below. The cycle is initiated by
dissociation of a ligand (L5PPh3, Step 1), followed in Step 2 by coordination of the allylic species to make a p
complex and another ligand loss (Step 3). After Step 3, the Pd has a vacant coordination site and can undergo
oxidative addition of the coordinated allylic species. The oxidative addition leads to expulsion of the leaving group
and replacement of the allyl-X bond with an allyl-Pd bond. This newly formed complex has two contributing
structures in which either terminal carbon of the allyl group can be envisioned as having the Pd-C bond with the
remaining two carbons involved in a p complex. It is common in organometallic chemistry to represent the two
contributing structures involved in an allyl complex with three carbons and an arc (see the following figure). The
interaction of three carbons to one metal is denoted by the prefix h3; such a complex is called an h3-allyl complex
(h is pronounced “eta”).

1 1

2
1

After the oxidative addition, the coordinated allyl group is susceptible to nucleophilic attack from solution (Step 5).
This attack completes the substitution, and all that is left to start the cycle again would be coordination of a
phosphine ligand (L) and loss of the organic product.

B. Stereochemical and Regiochemical Issues

Several steps in the catalytic cycle are stereoselective and therefore result in the
ability to control the configuration at chiral carbons. First, the oxidative addition of
the allylic-LG species occurs with clean inversion of configuration (Step 4 of the
mechanism). The nucleophilic attack on the h3-allyl complex occurs from solution

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 24.5 Palladium-Catalyzed Cross-Coupling Reactions   1107

in an analogous fashion to an S N 2 reaction and therefore occurs with clean

­inversion of stereochemistry. The net effect of two consecutive inversions of stereo-
chemistry is overall retention of stereochemistry. The following example highlights
the stereochemistry of the two steps that we are considering (Y is an electron-
withdrawing group).

The reaction is also very regioselective. Nucleophilic attack occurs at the less
substituted end of the h3-allyl complex regardless of the initial position of the leaving
group.

24.5 Palladium-Catalyzed Cross-Coupling
Reactions
Arguably, the largest impact that organometallic chemistry has had on organic
synthesis involves a series of reactions that are classified as cross-coupling Catalytic cross-coupling
reactions, many of which are catalyzed by palladium. A cross-coupling reaction is reaction
defined as a reaction that creates a C!C bond by coupling together two alkyl, aryl, A reaction wherein a C!C
alkenyl, or alkynyl groups, as we saw with the Gilman reaction in Section 15.2. Yet, bond is formed in a catalytic
the reactions we are now examining are catalytic. There are a large number of fashion between alkyl, aryl,
these reactions, most of which are named after the chemists primarily associated alkenyl, or alkynyl groups.
with their creation. We will examine three in this book: the Suzuki, Stille, and
Sonogashira couplings.
Cross-coupling reactions involve a transmetallation step. A transmetallation is Transmetallation
a pairwise interchange of ligands between two different metals or metalloids. In the Interchange of ligands
case of palladium-catalyzed cross-coupling reactions, the other metal/metalloid is between two metals or
commonly Zr, Sn, B, Zn, Cu, or Mg, which we designate as M in the following gen- metalloids.
eral example.

R!Pd 1 R9!M h R9!Pd 1 R!M

A. General Mechanism for Cross-Coupling Reactions

For the sake of simplicity, all the catalytic cross-coupling reactions can be represented In 2010, Richard Heck, Ei-ichi
by one general mechanism, even though each has subtle differences that we describe Negishi, and Akira Suzuki
in following sections. The catalytic cycle is so simple that it is presented here with shared the Nobel Prize in
only three steps. The differences between M, L, L9, and X are what differentiate and Chemistry for their work on
classify a particular reaction. C!C coupling reactions.

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1108  Chapter 24: Catalytic Carbon-Carbon Bond Formation

Mechanism 24.3

The Catalytic Cycle of Cross-Coupling

Various Pd(0) or Pd(II) species are used in the catalytic reactions. Step 1 involves o
­ xidative addition of one of the
organic species to the palladium. A transmetallation in step 2 results in the palladium having two carbon-based
ligands. A reductive elimination in Step 3 couples the two carbon fragments together. The relative simplicity and
variability of each component involved has made this catalytic cycle a very powerful one.
9 n

9 9n
9 n n

9n

B. The Suzuki Coupling

The Suzuki coupling was developed by Professor Akira Suzuki of Hokkaido Uni-
versity. The Suzuki coupling uses a boron compound (R-BY 2) and an alkenyl,
aryl, or alkynyl halide or triflate (RX) as the carbon sources, with a palladium
salt as the catalyst. Bromides and iodides are the most commonly used halides;
chlorides are less reactive. Haloalkanes can sometimes be used but are subject to
elimination. A base is also required. The boron compound can be a borane (R93B),
a borate ester (R9B(OR)2), or a boric acid (R9B(OH)2), where R9 is alkyl, alkenyl,
or aryl. The general reaction is shown in the following scheme, where X is halide
or triflate and Y is alkyl, alkoxyl, or OH. A list of the types of components that can
be used is given in Table 24.1. This reaction is one of the principal methods now
used to prepare biaryls.

9 9

Boranes are easily prepared from alkenes or alkynes by hydroboration

(Section 6.4); borates are made from aryl or alkyl lithium compounds and trimethyl
borate, among other routes.

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 24.5 Palladium-Catalyzed Cross-Coupling Reactions   1109

Following are three examples of the reaction that show its versatility.

Table 24.1  uzuki Coupling Components Where One of the

S
Organoboron Compounds Couples with One of
the Coupling Reagents Shown

Coupling Reagents
Organoboron Compounds X 5 halide or triflate

9 9

" 9 RCH"CH!X

9 RC"CH!X
Alkyl-X (Difficult)

The mechanism of the reaction starts with an oxidative addition, followed by a

transmetallation in which the substituent on the borane replaces the ligand on the
palladium, concluding with a reductive elimination of the palladium to form the new
C!C bond. The base may serve as a new, labile ligand for the palladium, or the base
may activate the borane by coordination.
Oxidative addition and ligand exchange:
n

Borane activation:
2

Reaction:

9 9

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1110  Chapter 24: Catalytic Carbon-Carbon Bond Formation

Example 24.4 Suzuki Coupling

Show how the following penicillin analog can be prepared from the indicated
starting material and any other necessary compounds.

Solution

Problem 24.4
Show how the following compound can be prepared from starting materials
containing eight carbons or less.

C. The Stille Coupling

The second Pd(0)-catalyzed cross-coupling reaction we cover is the Stille
coupling, which involves the use of vinyl or aryl tin reagents (called stannanes)
as the transmetallating agents. Coupling with another vinyl or aryl group leads
to the creation of conjugated dienes or an alkenylarene. The coupling occurs
with regioselectivity and retains the stereochemistry from the reactants to the
products.

Many stannane reagents are commercially available, or they can be readily syn-
thesized via reaction between a Grignard reagent and tri-n-butyl tin chloride. The
reactants that most commonly react with the transmetallated group are a vinyl triflate
(C"C!OSO2CF3) and a vinyl iodide. Vinyl triflates are prepared from the reaction of
an enolate with N-phenyl triflimide (PhNTf2, Tf 5 SO2CF3).

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 24.5 Palladium-Catalyzed Cross-Coupling Reactions   1111

n
n

Example 24.5 Stille Coupling

When a conjugated diene is the desired product in a reaction, a Stille coupling
is a logical choice to invoke during the synthesis. Write the correct stannane
starting material and a vinyl iodide reactant that would couple with Pd(0) to
give the following product.

Solution
To consider the proper starting materials for a Stille coupling, dissect the central
C!C bond of the diene into two parts in a retrosynthetic fashion. One reactant
should be a vinyl iodide (or triflate) and the other reactant a stannane.

Problem 24.5
What is the product of the following reaction?

D. The Sonogashira Coupling

The last Pd(0)-catalyzed cross-coupling reaction covered in this chapter is the Sono-
gashira coupling. It involves transmetallation of an alkynyl-Cu(I) species to Pd fol-
lowed by coupling to an aryl or vinyl iodide or triflate. The Cu(I) alkynyl complex is
created in situ by the reaction of a terminal alkyne with CuI in the presence of trieth-
ylamine. The reaction is most commonly used to create diaryl alkynyl products.

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1112  Chapter 24: Catalytic Carbon-Carbon Bond Formation

Example 24.6 Sonogashira Coupling

Two Sonogashira coupling reactions can be used to make unsymmetrical diaryl
alkynes by first using trimethylsilylacetylene. The trimethylsilyl protecting
group can be removed by addition of fluoride (usually tetrabutylammonium
fluoride, see Section 11.6). Show how such a sequence of reactions can be used
to construct the following product when one reactant is phenyl iodide.

Solution
Sonogashira coupling conditions using trimethylsilylacetylene give phenyl
­acetylene after deprotection using fluoride. Another such coupling using the
­aryl iodide reactant shown gives the product.
1 2

Problem 24.6
What sequence of reactions will produce the following product if starting with
trimethylsilylacetylene and the appropriate two aryl iodides?

In 2005, Robert Grubbs, 24.6 Alkene Metathesis

Richard Schrock, and Yves
Chauvin shared the Nobel A novel catalytic reaction leading to alkene metathesis has been developed.
Prize in Chemistry for Robert Grubbs of the California Institute of Technology and Richard Schrock
their work on metathesis of the Massachusetts Institute of Technology made major contributions to this
reactions. chemistry. Together their work has provided a remarkably easy and general way
to generate carbon-carbon double bonds, even in complex molecules. In an
Alkene metathesis alkene metathesis reaction, two alkenes interchange the carbons attached to
In an alkene metathesis their double bonds.
reaction, two alkenes
interchange the carbons
attached to their double 1 1
bonds.

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 24.6 Alkene Metathesis   1113

A. Stable Nucleophilic Carbenes Watch a video explanation

We discussed carbenes and carbenoids (derivatives of divalent carbon) in Section

15.3, where we saw that these compounds provide one of the best routes to three-
membered rings, making two C!C bonds in the process. Certain carbenes with
strongly electron-donating substituents are particularly stable. Their stability can be
enhanced further by adding sterically bulky substituents that hinder self-reactions.
For example, the following cyclic carbene is stable enough to isolate. In this case, the
large 2,4,6-trimethylphenyl substituents protect the carbene from attack by electro-
philes or oxygen. Rather than ­being electron deficient like most carbenes, these com-
pounds are nucleophiles because of the strong electron donation by the nitrogens.
Because of their nucleophilicity, they are excellent ligands (resembling phosphines)
for certain transition metals.

N N+ N
..

..

– –
..

..

..

N N N+
..

..

B. Ring-Closing Alkene Metathesis Using

Nucleophilic Carbene Catalysts
These stable carbenes (and others that are less stable) provide ligands for certain met-
als that are catalysts for the alkene metathesis reaction. As we saw at the beginning of
this section, this reaction is an equilibrium. However, it can be an effective means of
forming new carbon-carbon double bonds if the equilibrium can be driven in the de-
sired direction. For example, if the reaction involves two 2,2-disubstituted alkenes of
the type R2C"CH2, one of the products is ethylene. Loss of gaseous ethylene drives
the reaction to the right, giving a single alkene as product.

1 1

Ethylene

A particularly useful variant of this reaction uses a starting material in which both
alkenes are in the same molecule. In this case, the product is a cycloalkene and the
reaction is called ring-closing alkene metathesis. Ring sizes up to 26 and higher have

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1114  Chapter 24: Catalytic Carbon-Carbon Bond Formation

been prepared by ring-closing alkene metathesis. This reaction is amazingly general

and synthetically useful.

1 "

Example 24.7 Ring-Closing Metathesis

Show how the following compound can be prepared from an acyclic diene.

Solution
Ring-closing alkene metathesis gives the product in one step.

1 "

Problem 24.7
Show the product of the following reaction.

Particularly useful alkene metathesis catalysts consist of ruthenium complexes

with a nucleophilic carbene and another carbenoid ligand, C6H5CH"[M], where [M]
is the metal with its ligands.
For a model of the catalyst
shown here, see the opening 9 9
page of this chapter

9 9

C. Mechanism of the Metathesis Reaction

The mechanism of the alkene metathesis reaction also involves a catalytic cycle. A key
step involves addition of the metallocarbenoid to the alkene to give a four-membered
metallacycle. This metallacycle is unstable and can either revert to starting material
or eliminate an alkene in the opposite direction to give a new alkene. Addition is not

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 Study Guide   1115

regioselective; consequently, all possible combinations of R1 and R2 result. In this

scheme, the catalyst is R1CH"[M].

1 1

cis trans

In this section, we have concentrated on the use of transition-metal nucleophilic-

carbene catalysts to bring about ring-closing alkene metathesis reactions. These same
types of compounds can also be used to catalyze a remarkable reaction called ring-
opening alkene metathesis polymerization (ROMP). A special value of ROMP is that
it can be used to prepare highly unsaturated polymers. For a discussion of ROMP
techniques, see Section 29.6E.

Study Guide
24.1 Carbon-Carbon Bond-Forming Reactions from Earlier Chapters
●●
The classical methods for making carbon-carbon bonds during synthesis can be grouped broadly into
these categories:
– Displacement of a leaving group by a carbon nucleophile (Gilman reagents, a­ lkyne anions, enolate
anions, and enamine alkylations)
– Nucleophilic addition to a carbonyl or a carboxyl group, usually involving enolate nucleophiles
(Grignard, alkyne anion, cyanide, aldol, Claisen, enamine, and Wittig)
– Conjugate addition to an a,b-unsaturated compound (Michael reaction)
– Aromatic substitution (Friedel-Crafts)

24.2 Organometallic Compounds and Catalysis

●●
Two important reactions of transition metals and their compounds are oxidative addition and its
complement, reductive elimination.
– Oxidative addition occurs when a reagent adds to a metal, causing its coordination to increase by
two ligands, and reductive elimination is the reverse.
– The terms oxidative and reductive refer to the change in formal charge on the metal that occurs
during these reactions.
– Reagents such as organohalogen, hydrogen, halogens, and many others can react with metals in
these ways.
●●
The catalytic properties of transition metals are manipulated by adding different ligands, which are
Lewis bases that coordinate to the metal.
– Ligands can be used to modify the electronic properties, steric crowding, and even chirality around
the metal in some situations.

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1116  Chapter 24: Catalytic Carbon-Carbon Bond Formation

●●
Green chemistry and atom economy are relatively new thrusts in the chemical industry
worldwide; their goals are well complemented by organometallic catalytic reactions.

24.3 The Heck Reaction

●●
In the Heck reaction, the H atom on an alkene (vinylic hydrogen) is substituted by a haloalkene or
haloarene in the presence of base and a small amount of Pd catalyst.
– When there is a difference, the substitution occurs at the less substituted carbon of the alkene,
and is often stereoselective for the E product.
– The configuration of the haloalkene (when appropriate) is conserved.
– A significant advantage of the Heck reaction is that alcohol, ether, aldehyde, ketone, and ester
functional groups are compatible with the reaction.
– The organohalogen, alkene, and base are used in stoichiometric amounts, and the Pd catalyst is
used in small amounts.
– When there is no syn hydrogen from the original alkene double bond that can eliminate in the
last step of the reaction, the double bond shifts away from the original position so that a syn
elimination of an H atom can take place.

P 24.1, 24.2, 24.8–24.18

The Heck Reaction

Key Reactions
1. The Heck Reaction (Section 24.3) In a palladium(0)-catalyzed reaction, the carbon group of
a haloalkene (a vinylic halide) or haloarene is substituted for a hydrogen on a carbon-carbon
double bond (a vinylic hydrogen) of an alkene. Reaction generally proceeds with a high
degree of both stereoselectivity and regioselectivity. The small amount of palladium catalyst
is generally introduced as a precatalyst in the form of Pd(OAc)2, which is Pd(II), and is
reduced in the reaction to Pd(0) by reaction with the alkene (only a small amount of which
is lost because the catalyst is used in small amounts) or a reagent such as triethylamine. The
Pd(0) then reacts with two ligands, generally phosphine ligands (L), to create the active
catalyst PdL2. The phosphine ligands can be chiral, such as BINAP, so that single enantiomer
products are possible for reactions that create new chiral centers.
The catalytic cycle involves five steps, the most important of which are oxidative addition of the
organohalogen to the catalyst, syn addition of the alkene, syn elimination of the new alkene product,
and reductive elimination of HX (neutralized by the added base) to regenerate the catalyst.

9
9 1 "

24.4 Catalytic Allylic Alkylation

●●
In catalytic allylic alkylation, a nucleophile, commonly an enolate of a doubly a­ ctivated a-carbon,
replaces an allylic leaving group, commonly a carboxylate such as acetate. The reaction occurs in the
presence of a catalytic amount of Pd(0).
– In contrast to SN 2 allylic alkylation, stereochemistry at the alkylated carbon is retained.

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 Study Guide   1117

– The mechanism consists of a multistep cycle involving h3-allyl Pd complexes.

– The reaction is regioselective with allylation occurring preferentially at the less substituted end of
the h3-allyl complex irrespective of the initial position of the leaving group.

P 24.3, 24.19–24.22

Problem 24.3

Key Reactions
2. Catalytic Allylic Alkylation (Section 24.4) Catalytic allylic alkylation commonly takes allyl acetate
species and substitutes the acetate with a nucleophile. Some of the most useful nucleophiles
are enolates derived from methylenes that are flanked by two electron-withdrawing groups. The
mechanism of the reaction involves the oxidative addition of the allyl acetate to palladium and
results in the intermediacy of h3-allyl complexes that give inversion of configuration at the carbon
with the acetate leaving group. Attack by the nucleophile from solution gives a second inversion
of configuration and, by virtue of having two SN2-like reactions, results in overall retention of
configuration. The regiochemistry in the reaction is also highly selective, with nucleophilic attack from
solution being preferential at the least substituted carbon of the h3-allyl complex.

24.5 Palladium-Catalyzed Cross-Coupling Reactions

●●
Cross-coupling reactions all have very similar mechanisms. The first step is oxidative addition to Pd of
an R-X species, followed by transmetallation of an R9 group from an R9-metal/metalloid species.
Reductive elimination of R-R9 from palladium completes the cycle.
●●
The Suzuki coupling uses a boron reagent (R9-BY2) with an alkenyl, aryl, or alkynyl halide (usually
Br or I) or triflate with a palladium salt to give a new carbon-carbon bond.
– The boron compound can be a borane (R93B), a borate ester (R9-B(OR)2), or a boric
acid (R9-B(OH)2), where R9 is an alkyl, alkenyl, or aryl group. Boranes are made using
hydroboration of alkenes or alkynes. Borates are made from aryl or alkyl lithium compounds
and trimethyl borate.
– The Suzuki reaction is particularly good for the construction of biaryl compounds.

P 24.3, 24.23, 24.24, 24.38

Key Reactions
3. The Suzuki Coupling (Section 24.5B) The Suzuki coupling reaction is a palladium-catalyzed reaction
of an organoboron compound with an organic halide or triflate. The mechanism involves transmetallation,
in which the substituent on the borane replaces a ligand on palladium, followed by reductive elimination
to form the new C!C bond.

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1118  Chapter 24: Catalytic Carbon-Carbon Bond Formation

●●
The Stille coupling uses a tin reagent (Bu3Sn-R) in which the R-group is commonly a vinyl species with
an alkenyl, aryl, or alkynyl halide (often iodide or triflate) with palladium to give a new carbon-carbon bond.
– The tin reagent (a stannane) is created from a Grignard reagent of the R-group and n-Bu3SnCl,
and the triflates are often derived from enolates.
– The Stille coupling is most commonly used to make conjugated dienes or alkenyl aryl systems.

P 24.5, 24.25–24.31

Key Reactions
4. The Stille Coupling (Section 24.5C) The Stille coupling is the palladium-catalyzed reaction of a vinyl
tin reagent with an organic halide or triflate. The mechanism involves oxidative addition of the organic
halide/triflate, transmetallation of the vinyl group on Sn to Pd, and reductive elimination to form the
new C!C bond.

1 n

●●
The Sonogashira coupling starts with a terminal alkyne with CuI and triethylamine to create a Cu-
alkyne complex. This undergoes reaction with vinyl or aryl iodides.
– This coupling is routinely used to create diaryl alkynes, aryl alkenyl alkynes, or dialkenyl alkynes.
– It is common to use trimethylsilylacetylene with two sequential Sonogashira reactions when
unsymmetrical alkynes are desired as the final products.

P 24.6, 24.25–24.28, 24.31

Alkene Metathesis

Key Reactions
5. The Sonogashira Coupling (Section 24.5D) The Sonogashira coupling is the palladium-catalyzed
reaction of a Cu(I)-alkynyl complex with a vinyl or aryl iodide. The Cu(I)-alkynyl compound is
created by the reaction of a terminal alkyne with CuI in the presence of an amine base. The coupling
mechanism involves oxidative addition of the organic iodide to Pd, transmetallation of the alkynyl
group to Pd from Cu, and reductive elimination to form the new C!C bond.

24.6 Alkene Metathesis

●●
In an alkene metathesis reaction, two alkenes interchange the carbons attached to their double bonds.
●●
The catalyst is a transition metal complex such as Ru complexes of stable nucleophilic carbenes (highly
sterically hindered nitrogen heterocycles).

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 Problems   1119

●●
The metathesis reaction is usually an equilibrium process driven to completion by using two terminal
alkenes that give gaseous ethylene as a product, which bubbles out of the reaction.
– A particularly useful version of the metathesis reaction, called ring-closing alkene metathesis,
involves two terminal alkenes on the same molecule, leading to an intramolecular reaction that
creates a cycloalkene product.
– Ring-closing alkene metathesis has been used to construct very large ring sizes that are hard to
make in other ways.

P 24.4, 24.32–24.34

Key Reactions
6. Alkene Metathesis (Section 24.6) The alkene metathesis reaction is an o­ rganometallic-catalyzed
reaction in which two alkenes exchange carbons of their double bonds. In a ring-closing alkene
metathesis reaction, both alkenes are in the same molecule and the product is a cycloalkene. Catalysts
with Ru are often used; a nucleophilic carbene complex of Ru is particularly useful. The catalytic cycle
involves reaction of the metal catalyst with the alkenes to form a four-membered ring metallacycle, which
decomposes to give starting materials or, by elimination in the opposite direction, to give a new alkene.

1 "

Problems
Red numbers indicate applied problems.

The Heck Reaction

24.8 As has been demonstrated in the text, when the starting alkene has CH2 as its terminal
group, the Heck reaction is highly stereoselective for formation of the E isomer. Here,
the benzene ring is abbreviated C6H5!. Show how the mechanism proposed in the text
allows you to account for this stereoselectivity.

" 9 1

24.9 The following reaction involves two sequential Heck reactions. Draw structural formu-
las for each organopalladium intermediate formed in the sequence and show how the
final product is formed. Note from the molecular formula given under each structural
formula that this conversion corresponds to a loss of H and I from the starting material.
Acetonitrile, CH3CN, is the solvent.

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1120  Chapter 24: Catalytic Carbon-Carbon Bond Formation

24.10 Complete these Heck reactions.

(a) " 1

(b) " 1

24.11 Treatment of cyclohexene with iodobenzene under the conditions of the Heck reac-
tion might be expected to give 1-phenylcyclohexene. The exclusive product, however, is
3-phenylcyclohexene. Account for the formation of this product.

1 1

3-Phenylcyclohexene 1-Phenylcyclohexene

24.12 Account for the formation of the product and for the cis stereochemistry of its ring junc-
tion. (The function of silver carbonate is to enhance the rate of reaction.)

24.13 Account for the formation of the following product, including the cis stereochemistry at
the ring junction.

24.14 The aryl diene undergoes sequential Heck reactions to give a product with the molecu-
lar formula C15H18. Propose a structural formula for this product.

24.15 Heck reactions take place with alkynes as well as alkenes. The following conversion in-
volves an intramolecular Heck reaction followed by an intermolecular Heck. Propose
structural formulas for the palladium-containing intermediates involved in this reaction.

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 Problems   1121

24.16 The following conversion involves sequential Heck reactions. Propose structural formu-
las for the palladium-containing intermediates involved in this reaction.

24.17 The following transformation involves a series of four consecutive Heck reactions and the
formation of the four-ring steroid nucleus (Section 26.4) as a racemic mixture. Propose
structural formulas for the palladium-containing intermediates involved in this reaction.

24.18 Show the sequence of Heck reactions by which the following conversion takes place.
Note from the molecular formula given under each structural formula that this conver-
sion corresponds to a loss of H and I from the starting material.

Catalytic Allylic Alkylation

24.19 Write the product of the following reaction and account for the regiochemistry that
you predict.

24.20 Write the steps that are critical in the following reaction in order to explain the stereo-
chemical outcome at the carbon marked with the asterisk.

24.21 One of the most useful aspects of Pd(0)-catalyzed allylic alkylation is the ability to take
racemic mixtures of reactants and create preferred chirality in the product by the ad-
dition of a chiral ligand for the Pd metal. Draw the h3-allylic complex created in the
catalytic cycle of the following reactant with PdL4. Describe why chirality in a ligand L
would influence the stereochemistry of nucleophilic attack.

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1122  Chapter 24: Catalytic Carbon-Carbon Bond Formation

24.22 Another useful aspect of Pd(0)-catalyzed allylic alkylation is the ability to take reactants
that are meso and desymmetrize them in the resulting products through the addition
of a chiral ligand for the Pd metal. Draw the two h3-allylic complexes formed in this
reaction of the following reactant with PdL4. Describe why chirality in a ligand L would
influence the preference for one of these complexes over the other.

Palladium-Catalyzed Cross-Coupling Reactions

24.23 Suggest reagents and the other fragment that could be used to carry out the indicated
conversion.

24.24 Show how the following compound could be prepared by a Suzuki reaction
(Bn 5 benzyl).

24.25 It is typically very difficult to do a substitution reaction on an aromatic ring when the
leaving group is flanked by two other bulky substituents. Moreover, in Section 22.3, we
found that nucleophilic aromatic substitution requires strongly electron-withdrawing
groups on the benzene ring. However, Pd-catalyzed coupling allows entry into such
products. As examples, write the products of the following reactions and state which
coupling reaction is being utilized.

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 Problems   1123

24.26 The compound eutypine is an antibacterial agent isolated from the fungus Eutypa lata.
This fungus results in a disease common to vineyards called eutyposis. Give a sequence
of reactions that will take the following reactant and give eutypine when the other reac-
tants used in the sequence are acetylene and acetone.

24.27 When the Pd(0)-catalyzed reactions covered in this chapter are run with a slight pres-
sure of carbon monoxide, a ketone is often created as the product. For ­example, the
following Stille coupling conditions with added CO give the product shown. Write a
mechanism for how this reaction could occur using the organometallic mechanistic
steps introduced in this chapter, along with new steps that would be required in this
transformation. Hint: CO can coordinate to Pd and ­insert into Pd-C bonds.

24.28 Many of the cross-coupling reactions described in this chapter have been used to make
fascinating polymeric materials, as covered in Chapter 29. Give the proper reactants to
create the following polymers and name the coupling reaction involved.

n n

24.29 b-Lactams are amides in four-membered rings and are common elements found in
­antibiotics. Show what reagents would be involved in creating the following series of
b-lactams using a common vinyl triflate in each case.

24.30 The creation of very large ring systems is often difficult and challenging. The following
macrocyclic ring was created using one of the coupling reactions described in this chap-
ter. Which one was used? What was the starting material?

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1124  Chapter 24: Catalytic Carbon-Carbon Bond Formation

24.31 As presented in the chapter, the Sonogashira coupling reaction is commonly used to
create diaryl alkynyl structures. However, it can also be used to create divinyl alkynyl
structures. The following sequence of reactions creates such a product. Write possible
reactants that would be placed in the boxes in the sequence.

Olefin Metathesis
24.32 The cyclic ester (lactone) Exaltolide has a musk-like fragrance and is used as a fixative in
perfumery. Show how this compound could be synthesized from the indicated starting
material. Give the structure of R.

Exaltolide

24.33 Predict the product of each alkene metathesis reaction using a Ru-nucleophilic carbene
catalyst.

(a)
8

(b)
8

24.34 The following transformation can be accomplished by reactions we have studied in this
chapter and Chapter 20. Name the type of reaction used in each step.

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 Problems   1125

Synthesis
The following problems are based on relatively recent total syntheses of important natu-
ral products. Many such syntheses are outlined in compendia of synthetic reactions. Particu-
larly valuable in preparing these problems were Classics in Total Synthesis, K. C. Nicolaou and
E. J. Sorensen, Wiley-VCH, Weinheim, New York, Basel, Cambridge, Tokyo, 1996; Classics in
­Total Synthesis II, K. C. Nicolaou and S. A. Snyder, Wiley-VCH Verlag GmbH, Weinheim (2003).
24.35 Following is an outline of the stereospecific synthesis of the “Corey lactone.” Professor E. J.
Corey (Harvard University) describes it this way.“The first general synthetic route to all the
known prostaglandins was developed by way of bicycloheptene intermediates. The design
was guided by the requirements that the route be versatile enough to allow the synthesis
of many analogs and also allow early resolution. This synthesis has been used on a large
scale and in laboratories throughout the world; it has been applied to the production of
countless prostaglandin analogs.” Corey was awarded the 1990 Nobel Prize in Chemistry
for the development of retrosynthetic analysis for synthetic production of complex mol-
ecules. See E. J. Corey and Xue-Min Cheng, The Logic of Chemical Synthesis, John Wiley &
Sons, New York, 1989, p. 255. For the structure of the prostaglandins, see Section 26.3. Note:
The wavy lines in compound C indicate that the stereochemistry of !Cl and !CN groups
was not determined. [The conversion of (D) to (E) involves an oxidation of the ketone
group to a lactone by the Baeyer-Villiger reaction, which we have not studied in this text.]

(A) (B) (C) (D)

(E) (F) (G)

(H) (I) (J) (K)

(a) What is the function of sodium hydride, NaH, in the first step? What is the pK a of
cyclopentadiene? How do you account for its remarkable acidity?
(b) By what type of reaction is (B) converted to (C)?

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1126  Chapter 24: Catalytic Carbon-Carbon Bond Formation

(c) What is the function of the carbon dioxide added to the reaction mixture in Step 2
of the conversion of (E) to (F)? Hint: What happens when carbon dioxide is dis-
solved in water? Why not just use HCl?
(d) The tributyltin hydride, Bu3SnH, used in the conversion of (H) to (I) reacts via a
radical chain reaction; the first step involves a reaction with a radical initiator to
form Bu3Sn?. Suggest a mechanism for the rest of the reaction.
(e) The Corey lactone contains four chiral centers with the relative configurations
shown. In what step or steps in this synthesis is the configuration of each chiral
center determined? Propose a mechanism to account for the observed stereospeci-
ficity of the relevant steps.
(f) Compound (F) was resolved using (1)-ephedrine. Following is the structure of
(2)-ephedrine, the naturally occurring stereoisomer. What is meant by “resolu-
tion”? What is the rationale for using a chiral, enantiomerically pure amine for the
resolution of (F)?

Ephedrine

(Note: By resolving at this stage, one-half of the material is discarded. A more efficient

route would be to have an earlier resolution; in fact, Corey later solved this prob-
lem in an elegant way by using an enantioselective Diels-Alder reaction with the
alkene in the form of an acrylate ester of enantiomerically pure 8-phenylmenthol.
Asymmetric ­induction gave a product with a diastereoselectivity of 97:3. So rather
than resolving, he was able to get the correct stereoisomer directly.)
(g) You have not studied the Baeyer-Villiger reaction (D to E). The mechanism involves
nucleophilic reaction of the peroxyacid with the carbonyl followed by a rearrange-
ment much like that involved in the hydroboration reaction (Section 6.4). Write a
mechanism for this reaction.
24.36 Chapman’s (O. L. Chapman, then at Iowa State and later at UCLA) classic total synthe-
sis of (6)-carpanone is so remarkably simple that it is used as an undergraduate labora-
tory preparation. It is modeled on a possible biosynthetic route for this lignan-derived
natural product. Phenol oxidations figure prominently in many such biosyntheses of
natural products. In one step, this reaction creates no less than five contiguous chiral
centers, all in the correct relative configuration.
tert

(6)-Carpanone

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 Problems   1127

(a) Give a mechanism for the first step of the reaction and explain why it goes in the
direction it does.
(b) The oxidation step uses a palladium salt. Suggest a mechanism for this coupling,
which you have not encountered. Hint: Do not concern yourself with the role of the
metal except as an acceptor of electrons.
(c) The third step is spontaneous. Give a mechanism for this reaction and show how it
accounts for the stereochemistry of the final product.
(d) Would you expect the product to be racemic or a single enantiomer?
24.37 Gilvocarcin M is isolated from Streptomyces strains and has strong antitumor activity.

Gilvocarcin M

Suzuki and coworkers were able to carry out the total synthesis of naturally o ­ ccurring
(2)-gilvocarcin M. Their synthesis included the following steps. (The wavy line means
that stereochemistry is unspecified or is a mixture.) The stereochemistry of the product
appears to be counterintuitive (apparent attack from the more hindered side). The rea-
son is that the reaction involves initial O-alkylation followed by a rearrangement that
need not concern us.

(A) (B)

(a) This reaction gives both high regioselectivity and stereoselectivity. What other
products might have been expected?
The next step involves triflation and treatment with butyl lithium.

i 8
(C) (D)

(B)

(b) Give a structure for (C).

(c) 
Give a structure for (D). This reaction requires that you know that lithium reagents
can interchange with haloarenes:

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1128  Chapter 24: Catalytic Carbon-Carbon Bond Formation

Recall that OTf is an excellent leaving group. You may wish to review Section 24.3A.
The reaction yielding (D) is carried out in the presence of 2-methoxyfuran.
(D) decomposes under the conditions to a compound (E) that instantly reacts with
the furan to give (F).
(d) Give a structure for (E) and the mechanism of (D) to (E).
(e) Give a mechanism for (E) to (F).

8 8
(D) (E)

2-Methoxyfuran (F)

Compound (F) is unstable and undergoes ring opening upon workup to give (G).

(F)
(G)

(f) Give a mechanism for (F) to (G).

The next step involves conversion of (G) to (H).

(G) )H(

(g) Give reagents and conditions required for (G) to (H).

Formation of the final tetracyclic ring involves conversion of (H) to (I).

)H( (I)

(h) Give reagents and conditions required for (H) to (I).

(I) is then is converted to (2)-gilvocarcin M, the natural enantiomer.

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 Problems   1129

(I)

Gilvocarcin M

(i) What reagents could be used for this reaction?

(j) Comment on the probable source of the chiral centers in this synthesis. Note that
the chirality was not created in any of the reaction steps. You can find a possible
readily available and inexpensive source (see Chapter 25,“Carbohydrates”).
(k) Given reactions that are later in the sequence, why is it necessary to protect some of
the OH groups as the benzyl ether? What side reactions would occur without this
protection? Starting with OH groups, how would you add these protecting groups?
24.38 Vancomycin is an important antibiotic. It is isolated from the bacterium Streptomyces
orientalis and functions by inhibiting bacterial mucopeptide synthesis. It is a last line of
defense against the resistant Staph organisms that are now common in hospitals.

Vancomycin aglycon

In 1999, Professor Dale Boger (The Scripps Research Institute) reported a synthesis of
vancomycin aglycon (aglycon 5 lacking a sugar) involving the following steps, among Aglycon
others. Compound (I) was prepared from simple starting materials by a series of steps
Lacking a sugar.
involving forming amide bonds.
(a) Suggest reasonable precursors and show how the bonds could be formed (the
­actual reagents used have not been introduced, but they work in a similar way to
those you know).

(I)

Compound (I) was then converted into (II).

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1130  Chapter 24: Catalytic Carbon-Carbon Bond Formation

(b) Give reagents for this reaction and suggest the mechanism.

(II)

One of the interesting features of this synthesis is that ring C in compound (II) (and subse-
quent compounds in this synthesis) has extremely hindered rotation. As a result, compound
(II) exists as two atropisomers (Section 3.2) that are interconverted only at 140°C.
(c) Show these two isomers.
(II) was then converted to (III).
(d) Suggest reagents to accomplish this transformation.

(III)

Compound (III) was then converted to (IV).
(e) Suggest reagents and the ring A fragment that could be used for this reaction.

(IV)

Closure of an amide link between the amine on ring A (after removal of the protecting
group) and the carbomethoxy group above it led to a precursor of vancomycin.
(f) Show the ring closure reaction of the deprotected free amino group and its mechanism.
Another interesting feature of this synthesis is that rings A and B also form atropisomers.
These can be converted into a 3:1 mixture of the desired and undesired atropisomers on
heating at 120°C.

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 Problems   1131

(g) Draw these atropisomers and show that only one can be converted to vancomy-
cin. The synthesis of the aglycon was completed by functional manipulation and
addition of ring E by chemistry similar to that detailed earlier. Yet, another set of
atropisomers (this time of ring E) was formed! However, this one was more easily
equilibrated than the others; model studies had shown that the activation barrier
for this set of atropisomers should be lower than that of the others.
24.39 E
 . J. Corey’s 1964 total synthesis of a-caryophyllene (essence of cloves) solves a number
of problems of construction of unusual-sized rings.

-Caryophyllene

The first step uses an efficient photochemical [2 1 2] reaction. The desired stereochem-
istry and regiochemistry had been predicted based on model reactions.

(a) 
[2 1 2] Reactions are quite common in photochemical reactions. Would this reac-
tion be predicted to occur in the ground state?
The next steps follow. Basic alumina is a chromatography support that will often act as a
base catalyst.

(b) What is the mechanism of the first step?

(c) What is the mechanism of the second step?
(d) Look at later steps in the synthesis. Does the stereochemistry of the added carbo-
methoxy group matter?
The next steps are shown here.

(A)

(e) What is the structure of compound (A)?

(f) Give a mechanism for the formation of the cyclized product.

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1132  Chapter 24: Catalytic Carbon-Carbon Bond Formation

Here are the next steps.

(B)

(g) Give a mechanism for the first step. Hint: Attack on the lactone carbonyl may be the
first step.
(h) Give a structure for product (B).
The following two steps are next.

(B)

(i) Show the reactions of (B).

(j) Write a mechanism for the ring-opening reaction. Hint: Note the presence of an
acidic proton and a good leaving group in the molecule.
The synthesis was completed by the following steps.

(C)

(k) What is (C)?

(l) What reagents would you use for these transformations?
24.40 O
 ver the past several decades, chemists have developed a number of synthetic meth-
odologies for the synthesis of steroid hormones. One of these, developed by Lutz
Tietze at the Institut für Organische Chemie der Georg-August-Universität, Göttin-
gen, Germany, used a double Heck reaction to create ring B of the steroid nucleus. As
shown in the following retrosynthetic analysis, a key intermediate in his synthesis is
compound (1). Two Heck reaction disconnects of this intermediate give compounds
(2) and (3). Compound (2) contains the aromatic ring that becomes ring A of estrone.
Compound (3) contains the fused five- and six-membered rings that become rings C
and D of estrone.

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 Problems   1133

(2) (3)

Estrone (1)

(a) Name the types of functional groups in estrone.

(b) How many chiral centers are present in estrone?
(c) Propose structural formulas for compounds (2) and (3).
(d) Show how your proposals for compounds (2) and (3) can be converted to c­ ompound
(1). (Note: In the course of developing this synthesis, Tietze discovered that vinylic
bromides and iodides are more reactive in Heck reactions than are aryl bromides
and iodides.)
(e)  In the course of the double Heck reactions, two new chiral centers are created.
­Assume in compound (3), the precursor to rings C and D of estrone, that the fusion
of rings C and D is trans and that the angular methyl group is above the plane
of the ring. Given this stereochemistry, predict the stereochemistry of compound
(1) formed by the double Heck reaction.
(f) To convert (1) to estrone, the tert-butyl ether on ring D must be converted to a
­ketone. How might this transformation be accomplished?

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25
Carbohydrates

Outline Foxglove (Digitalis

purpurea), an
25.1 Monosaccharides ornamental flower­
ing plant, is the
25.2 The Cyclic Structure of Monosaccharides source of digitoxin
25.3 Reactions of Monosaccharides and digitalis,
25.4 Disaccharides and Oligosaccharides medicines used
in cardiology
25.5 Polysaccharides to reduce pulse
25.6 Glucosaminoglycans rate, regularize
heart rhythm,
and strengthen
heartbeat. Inset:
Carbohydrates are the most abundant organic compounds in the plant world. They digitoxose, a
act as storehouses of chemical energy (glucose, starch, and glycogen); are compo- monosaccharide
obtained on hydro­
nents of supportive structures in plants (cellulose), crustacean shells (chitin), and lysis of digitoxin.
connective tissues in animals (glucosaminoglycans); and are essential components of See Problem 25.15.
(Gary K Smith/Alamy
nucleic acids (d-ribose and 2-deoxy-d-ribose). Carbohydrates make up about three- Stock Photo)
fourths of the dry weight of plants. Animals (including humans) get their carbohy-
drates by eating plants, but they do not store much of what they consume. Less than
1% of the body weight of animals is made up of carbohydrates.
The name carbohydrate means hydrate of carbon and derives from the formula
Cn(H2O)m. Following are two examples of carbohydrates with molecular formulas
that can be written alternatively as hydrates of carbon.
Glucose (blood sugar): C6H12O6, or alternatively C6(H2O)6
Sucrose (table sugar): C12H22O11, or alternatively C12(H2O)11

Not all carbohydrates, however, have this general formula. Some contain too few
oxygen atoms to fit this formula, and others contain too many oxygens. Some also
contain nitrogen. The term carbohydrate has become so firmly rooted in chemical

1134

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