A ruthenium-containingorganometallic catalyst for alkenemetathesis reactions. See Section24.5 for the structure of thiscatalyst and a discussion of thisreaction.

OUTLINE24.1 Carbon-Carbon Bond-

Forming Reactions fromEarlier Chapters

24.2 OrganometallicCompounds

24.3 OrganopalladiumReagents-The HeckReaction

24.4 OrganopalladiumReagents-The SuzukiCoupling

24.5 Alkene Metathesis24.6 The Diels-Alder Reaction24.7 Pericyclic Reactions

and Transition StateAromaticity

24.8 The Synthesis ofEnantiomerically PureTarget Molecules

Online homework for thischapter may be assignedin Organic OWL.

930

Organic chemists have learned over the course of the last one hundred twen-ty or so years how to synthesize amazingly complex molecules. In recentyears, particularly, they have focused on compounds of medicinal interest,and a large number of current pharmaceuticals are synthesized from simpler com-pounds. Many of these pharmaceuticals are natural products or their analogs, andothers are either simpler analogs or unrelated compounds that have been foundto be active against certain organisms or diseased cells, specific cellular receptors,or specific enzyme targets. A key development that has allowed synthesis of thesecompounds has been the discovery of many novel methods of carbon-carbon bondformation. It is now possible, using a combination of new and classical methods, tocarry out the synthesis of molecules with sensitive functionality and amazingly com-plex carbon skeletons from simple and inexpensive starting materials, often withexcellent stereo- and regiocontrol. In this chapter, we make a dramatic leap fromthe more classical organic reactions covered in previous chapters of this book tosurvey several particularly useful methods of carbon-carbon bond formation, someof which represent very recent developments. We have room for only a few repre-sentative examples out of the wealth of carbon-carbon bond forming reactions thatare now available to the modern synthetic chemist. Finally, a number of problemsbased on modern organic syntheses are given to illustrate the use of these reac-tions and their combination with other reactions.

24.1 Carbon-Carbon Bond-Forming Reactionsfrom Earlier Chapters

Let us list the methods of carbon-carbon bond formation that you have alreadystudied as a review. All these reactions should be available to you for syntheticproblems.

attack by nucleophiles or oxygen. Rather than being electron-deficient like mostcarbenes, these compounds are nucleophiles because of the strong electron dona-tion by the nitrogens. Because of their nucleophilicity, they are excellent ligands(resembling phosphines) for certain transition metals.

B. Ring-Closing Alkene Metathesis UsingNucleophilic Carbene Catalysts

These stable carbenes (and others that are less stable) provide ligands for cer-tain metals that are catalysts for the alkene metathesis reaction. As we saw at thebeginning of this section, this reaction is an equilibrium. However, it can be aneffective means of forming new carbon-carbon double bonds if the equilibriumcan be driven in the desired direction. For example, if the reaction involves two2,2-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 asproduct.

AXA BXB AXA ~J(~I + I ~ I + IH HH H B BH' H

Ethylene

A particularly useful variant of this reaction uses a starting material in which bothalkenes are in the same molecule. In this case, the product is a cycloalkene, andthe reaction is called ring-closing alkene metathesis. Ring sizes up to 26 and higherhave been prepared by ring-closing alkene metathesis. This reaction is amazinglygeneral and synthetically useful.

24.5 Alkene Metathesis 941

carbon atoms 1 and 4 of the conjugated system are close enough to react with thecarbon-carbon double or triple bond of the dienophile and to form a six-memberedring. In the !rtrans conformation, they are too far apart for this to happen.

The energy barrier for interconversion of the !rtrans and !rcis conformationsfor 1,3-butadiene is low, approximately 11.7 kJ (2.8 kcal)/mol; consequently, 1,3-butadiene can still be a reactive diene in Diels-Alder reactions.

~cis conformation(Higher in energy)~rransconfonnation

(Lower in energy)

(2Z,4Z)-2,4-Hexadiene is unreactive in Diels-Alder reactions because it is prevent-ed by steric hindrance from assuming the required !rcis conformation.

)Methyl groups would beforced closer than allowedby van der Waals radii

s-trans conformation(Lower in energy)

s-cis conformation(Higher in energy)

(2Z,4Z)-2,4-Hexadiene

Example 24.6Which molecules can function as dienes in Diels-Alder reactions?(b)WSolutionThe dienes in both (a) and (b) are fixed in the !rtrans conformation and, there-fore, are not capable of participation in Diels-Alder reactions. The diene in (c) isfixed in the His conformation and, therefore, has the proper orientation to par-ticipate in Diels-Alder reactions.

Problem 24.6Which molecules can function as dienes in Diels-Alder reactions?

(a) 0 (b) 0 (c) 024.6 The Diels Alder Reaction 945

group can be either electron-donating or -withdrawing depending on whether theoxygen or the carbonyl is attached to the double bond.

C. Diels-Alder Reactions Can Be Used toForm Bicyclic Systems

Conjugated cyclic dienes, in which the double bonds are of necessity held in ans-cis conformation, are highly reactive in Diels-Alder reactions. Two particularlyuseful dienes for this purpose are cyclopentadiene and 1,3-cyclohexadiene. Infact, cyclopentadiene is reactive both as a diene and as a dienophile, and, onstanding at room temperature, it forms a Diels-Alder self-adduct known by thecommon name dicyclopentadiene. When dicyclopentadiene is heated to 170C,a reverse Diels-Alder reaction takes place, and cyclopentadiene is reformed.

roomtemperature

,

H

OJH

Diene Dienophile Dicyclopentadiene(endo form)

From top From side

The terms "endo" and "exo" are used for bicyclic Diels-Alder adducts to describethe orientation of substituents of the dienophile in relation to the two-

( H3COOC1,+ lCOOCH3

Dimethyl trans-2-butenedioate(a trans dienophile)

Dimethyl trans-4-eyclohexene-1,2-dicarboxylate (racemic)

E. The Configuration at the Diene Is RetainedThe reaction is also completely stereospecific at the diene. Groups on the 1 and 4positions of the diene retain their relative orientation.

~o

+ ~o

--

A~D""BC/

o=Q=o

A picture of the transition state will help clarify the reason for this. Bondsbeing formed in the transition state are shown as dashed red lines; bonds beingbroken are shown as dashed blue lines. The groups that are inside on the dieneend up on the opposite side from the dienophile.

Aft...~D.. ..

... ..-

o~oTransition state Endo adduct

Side viewof

product

C

Front viewof

product

F. Mechanism-The Diels-Alder ReactionIs a Pericyclic Reaction

As chemists probed for details of the Diels-Alder reaction, they found no evi-dence for participation of either ionic or radical intermediates. Thus, the

948 Chapter 24 Carbon-Carbon Bond Formation and Synthesis

(endo)

The carbonylgroup on thedienophile is endo(tucked inside)

CD New bonds form Envelope flap

moves up

Hmovesto exo position;- C02CH3 movesto endo position

plane ofdienophile

Figure 24.1Mechanism of the Diels-Alderreaction. The diene anddienophile approach eachother in parallel planes, oneabove the other, with thesubstituents on the dienophileendo to the diene. There isoverlap of the 7r orbitals ofeach molecule and syn addi-tion of each molecule to theother. As (1) new CT bondsform in the transition state,(2) the -CH2- on the dienerotates upward, (3) the hydro-gen atom of the dienophilebecomes exo and the estergroup becomes endo.

Diels-Alder reaction is unlike any reaction we have studied thus far. To accountfor the stereoselectivity and the lack of evidence for either ionic or radi-cal intermediates, chemists have proposed that the reaction takes place in asingle step during which there is a cyclic redistribution of electrons. Duringthis cyclic redistribution, bond forming and bond breaking are concerted(simultaneous). Such reactions that take place in a single step, without inter-mediates, and involve a cyclic redistribution of bonding electrons are calledpericyclic reactions. We can envision a Diels-Alder reaction taking place asshown in Figure 24.1.

Example 24.7Complete the following Diels-Alder reaction, showing the stereochemistry of theproduct.

O (COOCH3+ I ----+~ COOCH3

Pericyclic reactionA reaction that takes place in asingle step, without intermediates,and involves a cyclic redistributionof bonding electrons.

24.6 The Diels Alder Reaction 949

SolutionReaction of cyclopentadiene with this dienophile forms a disubstituted bicyclicproduct. The two ester groups are cis in the dienophile, and, given the stereo-selectivity of the Diels-Alder reaction, they are cis and endo in the product.

~~H~"COOCH3COOCH3

Problem 24.7What diene and dienophile might you use to prepare the following racemic Diels-Alder adduct?

G. A Word of Caution About ElectronPushing

We developed a mechanism of the Diels-Alder reaction and used curved arrowsto show the flow of electrons that takes place in the process of bond breaking andbond forming. Diels-Alder reactions involve a four-carbon diene and a two-carbondienophile and are termed [4 + 2] cycloadditions. We can write similar electron-pushing mechanisms for the dimerization of ethylene by a [2 + 2] cycloadditionto form cyclobutane, and for the dimerization of butadiene by a [4 + 4] cycloaddi-tion to form 1,5-cyclooctadiene.

*Two moleculesof ethylene

not formed under~Diels-AlderL.:J conditions

Cyclobutane

*

not formed underr-xDielS-AlderU conditions

Two moleculesof butadiene

1,5-Cyclooctadiene

Although [2 + 2] and [4 + 4] cycloadditions bear a formal relationship to theDiels-Alder reaction, neither, in fact, takes place under the thermal conditionsrequired for Diels-Alder reactions. These cycloadditions do occur, but only underdifferent (and usually much more vigorous) experimental conditions and by quite

950 Chapter 24 Carbon-Carbon Bond Formation and Synthesis

Assignable in OWL

1% mol Pd(OAc)24% molPh3P

Online homework for this chapter may be assigned in Organic OWL. indicates problems assignable in Organic OWL.Red numbers indicate applied problems.

OH

"",-,""e ~

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

24.11 The following reaction involves two sequential Heck reactions. Draw structuralformulas for each organopalladium intermediate formed in the sequence and showhow the final product is formed. Note from the molecular formula given under eachstructural formula that this conversion corresponds to a loss of H and I from thestarting material. Acetonitrile, CH3CN, is the solvent.

24.12 Complete these Heck reactions.

The Heck Reaction

Chapter 24 Carbon-Carbon Bond Formation and Synthesis

6. The Cope Rearrangement: A Pericyclic Reaction (Section 24.781 The Cope rearrange-ment converts a 1,!H:liene to give an isomeric 1,5-diene. The reaction takes place in asingle step and involves the redistribution of six 7T electrons in a cyclic transition state.

5. The Claisen Rearrangement: A Pericyclic Reaction (Section 24.7AI The Claisen rear-rangement transforms an allyl phenyl ether to an ortho-substituted phenol. The reac-tion takes place in a single step and involves the redistribution of six 7T electrons in acyclic transition state.

PROBLEMS

960