24.2 Organometallic Compounds and Catalysis

Transcription

1 24.2 rganometallic Compounds and Catalysis We introduced organometallic compounds in Chapter 5. n the next few sections, we discuss several reactions of transition metals that are particularly useful for preparation of new carbon-carbon bonds. xidative addition ddition of a reagent to a metal center causing it to add two substituents and to increase its oxidation state by two. Reductive elimination Elimination of two substituents at a metal center, causing the oxidation state of the metal to decrease by two. Ligand Lewis base bonded to a metal atom in a coordination compound. t may bond strongly or weakly.. xidative ddition and Reductive Elimination Two extremely important reactions of transition metals and transition metal compounds are oxidative addition and its reverse reductive elimination. n oxidative addition, a reagent adds to a metal, causing its coordination to increase by two; reductive elimination is the opposite. These reactions are called oxidative or reductive because the formal charge of the metal changes by two during the reaction. xidative addition can occur with a metal coordinated with one or more ligands (L n, where n is the number); it can also occur with a free metal, M(0). aloalkanes, hydrogen, halogens, and many other types of compounds can take part in these reactions. The reactivity of different substrates depends greatly on the metal. ML n 2 oxidative addition reductive elimination ML n lthough there are numerous other reactions that are unique and essential to the action of organometallic catalysts, the key steps of the catalytic processes we discuss in this chapter involve oxidative additions and reductive eliminations. Thus, in an introductory chapter on catalytic C!C bond-forming reactions, we need go no deeper.. Key Features of the Utility of Catalytic C!C ond Formation The reactions and mechanisms covered in this chapter represent a growing modern trend in organic chemistry. rganometallic catalysts facilitate reactions that are otherwise 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 sequence. This decrease means that the chemical waste from an industrial process can be dramatically reduced. ntentionally designing a chemical procedure or process so as to decrease waste and toxic byproducts is now a whole chemical field in and of itself that is called green chemistry. t is a goal of green chemistry 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 the atoms involved. n ideal reaction would consist of the mass of the product equaling the mass of all the reactants used. n 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. ence, going green is permeating society in many ways, with the chemical industry recognizing and embracing the value of green The eck Reaction. The ature of the Reaction n the early 970s, Richard eck, at the ercules Company 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 eck reaction, is particularly valuable in synthetic organic chemistry because it is the only general method yet discovered for this type of substitution. 002 Chapter 24 Catalytic Carbon-Carbon ond Formation Copyright 200 Cengage Learning. ll Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eook and/or echapter(s).

2 R9 Pd catalyst eck reaction R 2 aloalkene or haloarene lkene ase Substituted alkene Conjugate acid of the base Substitution for a vinylic hydrogen by the eck reaction is highly regioselective; formation of the new carbon-carbon bond most commonly occurs at the less substituted carbon of the double bond. n addition, where an E or Z configuration is possible at the new carbon-carbon double bond of the product, the eck reaction is highly stereoselective, often giving almost exclusively the E configuration of the product. r C 2 "CCC 3 Pd catalyst eck reaction CC 3 romobenzene Methyl 2-propenoate (Methyl acrylate) Methyl (E)-3-phenyl-2-propenoate (Methyl cinnamate) n addition, the eck reaction is completely stereospecific with regard to the haloalkene; the configuration of the double bond in the haloalkene is preserved. Z Z Pd catalyst eck reaction (Z)-3-odo-3-hexene enylethene (Styrene) (E,3Z)-3-Ethyl--phenyl-,3-hexadiene E E Pd catalyst eck reaction (E)-3-odo-3-hexene enylethene (Styrene) (E,3E)-3-Ethyl--phenyl-,3-hexadiene Preparation of the Catalyst The form of the palladium catalyst most commonly added to the reaction medium is palladium() acetate, Pd(c) 2. This and other Pd() compounds are better termed precatalysts because the catalytically active form of the metal is a complex of Pd(0) formed in situ by reduction of Pd() to Pd(0). c Pd(c) 2 Pd 0 c Palladium() acetate n alkene (reductant) xidized alkene Reaction of Pd(0) with good ligands, L, gives the actual eck catalyst, PdL 2. Without the ligand, Pd(0) is insoluble. Pd 0 2 L PdL 2 Ligand The eck catalyst 24.3 The eck Reaction 003 Copyright 200 Cengage Learning. ll Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eook and/or echapter(s).

3 mong the most common ligands, L, used for coordination of the Pd(0) is triphenylphosphine, (C 6 5 ) 3 P. Many other ligands can be used as well, including chiral ones such as P (Section 6.7) that can lead to a significant excess of a single enantiomer in the case of chiral products. The aloalkane The most common halides used in eck reactions are aryl, heterocyclic, benzylic, and vinylic iodides and bromides, with iodides being generally most reactive. The reactivity of substrates with leaving groups on sp 2 carbons contrasts with nucleophilic substitution reactions, where such substrates are essentially unreactive. aloalkanes in which there is an acidic beta hydrogen are rarely used because of the ease with which they undergo b-elimination under conditions of the eck reaction to form alkenes. Triflates (trifluoromethanesulfonates, CF 3 S 2!), which are easily prepared by treating an alcohol with trifluoromethanesulfonyl chloride, are also excellent substrates. CF 3 S9Cl 9R CF 3 S9R Cl Trifluoromethanesulfonyl chloride lcohol trifluoromethanesulfonate (a triflate) The halide or triflate (R) reacts with PdL 2 by oxidative addition to give a square planar Pd() species, which is the reaction intermediate. R PdL 2 R L9Pd9 The eck catalyst L particular advantage of the eck reaction is the wide range of functional groups, including alcohols, ethers, aldehydes, ketones, and esters, that may be present elsewhere in the organic halogen compound or alkene without reacting themselves or affecting the eck reaction. The lkene The reactivity of the alkene is a function of steric crowding about the carboncarbon double bond. Ethylene and monosubstituted alkenes are the most reactive; the greater the degree of substitution on the double bond, the slower the reaction and the lower the 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 ase Commonly used bases are tertiary amines such as triethylamine, Et 3, sodium or potassium acetate, and sodium hydrogen carbonate. The Solvent Polar aprotic solvents (Section 9.3D) such as,-dimethylformamide (DMF), acetonitrile, and dimethyl sulfoxide (DMS) are commonly used. t is also possible to carry out some eck reactions in aqueous methanol. The polar solvents are needed to dissolve the Pd(c) 2 at the beginning of the reaction.. Mechanism of the Reaction The mechanism of the eck reaction is divided into two stages: formation of the eck catalyst and the catalytic cycle. s you study the catalytic cycle, note in particular 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 PdL Chapter 24 Catalytic Carbon-Carbon ond Formation Copyright 200 Cengage Learning. ll Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eook and/or echapter(s).

4 Mechanism The eck Reaction Stage : Formation of the eck Catalyst, PdL 2 two-electron reduction of Pd() to Pd(0) accompanied by its complex formation with two molecules of a ligand, L, gives the eck catalyst, PdL 2. common reducing agent is triethylamine or, as in the following example, the alkene itself. ecause the catalyst is present only in small amounts, an insignificant amount of the alkene is lost to this reaction. n the reaction shown here, L is triphenylphosphine, (C 6 5 ) 3 P. s 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. Pd(c) 2 c 2 3 P Pd(P 3 ) 2 c Palladium() acetate n alkene (reductant) Triphenylphosphine (ligand) Pd(0) complex (abbreviated PdL 2 ) xidized alkene Stage 2: The Catalytic Cycle The catalytic cycle of the eck reaction involves five steps. n Step, oxidative addition of the haloalkene or haloarene, R, to PdL 2 gives a tetracoordinated Pd() complex containing both R and groups bonded to Pd. Syn addition of the R and PdL 2 of this complex to the alkene gives an intermediate in which Pd is bonded to the more substituted carbon for steric reasons. ecause of the long Pd!C bond, the palladium is sterically less demanding than the organic group and, therefore, 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 and PdL 2 syn to each other. Syn elimination of and PdL 2 in Step 4 gives the new alkene and PdL 2. Reductive elimination in Step 5 releases the acid and regenerates the PdL 2 catalyst. is then neutralized by the added base. R 4 R 2 R 3 R 5 R9 reductive elimination The catalytic cycle of the eck reaction syn elimination 4 R 4 oxidative addition R R 2 3 R R syn addition R 4R3 R 4 R 3 R R 2 rotation about the C9C bond by 60 n this cycle, the alkene, haloalkane compound, and base are required in equimolar amounts; the Pd(0) species is required in only a catalytic amount. ote also the inversion of the configuration (R 2 and R 3 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. 3 2 R The eck Reaction 005 Copyright 200 Cengage Learning. ll Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eook and/or echapter(s).

5 to the double bond. Step 4 involves syn elimination of and the Pd() species to generate 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 geometry. dditions of boron hydrides (Section 6.4, hydroboration) and osmium tetroxide (Section 6.5) or ozone (Section 6.5) to alkenes are some examples of syn additions that you have already seen. Example 24. Complete these eck reactions. (a) Me cat. Pd(c) 2 3 P, K 2 C 3, DMF (b) cat. Pd(c) 2 3 P, K 2 C 3, DMF Solution n (a), -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 eck reaction is highly stereoselective, and this double bond has the more stable E configuration as well. n (b), the major product is (E)-,2-diphenylethene. (a) C 3 (b) Methyl (2E,4E)-2,4-nonadienoate (E)-,2-Diphenylethene (trans-stilbene) Problem 24. Show how you might prepare each compound by a eck reaction using methyl 2-propenoate as the starting alkene. C 2 "C9CC 3 (a) C 3 C 3 (b) C 3 Methyl 2-propenoate (Methyl acrylate) (the E isomer) (the 2E,4Z isomer) The usual pattern in a eck reaction of acyclic alkenes is replacement of one of the hydrogens on the double bond by an organo group. f the organopalladium group attacks the double bond so that the R group in the original R 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. ote that the product 006 Chapter 24 Catalytic Carbon-Carbon ond Formation Copyright 200 Cengage Learning. ll Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eook and/or echapter(s).

6 of the following reaction contains a chiral center, but, because it is formed from achiral reagents in an achiral environment, it is formed as a racemic mixture. Pd(c) 2 L, (C 2 5 ) 3 L 2 P PdL 2 Formed as a racemic mixture s mentioned earlier, a particularly valuable feature of the eck reaction is that, when used with a chiral ligand, it can give chiral products in significant enantiomeric excess (ee). n the following, the chirality is provided by the chiral ligand (R)-P (Section 6.7C). C 3 Pd complex C 3 C 3 0% (R)-P DMF This enantiomer is formed in 7% ee 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. ecause 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 diastereomers). 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. ote that this reaction is not a normal eck reaction in that it forms a carbon-carbon bond to the more substituted carbon, and the double bond shifts. ttack at the other carbon, because of the requirement for syn elimination, cannot lead to a normal eck product, and 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. C 3 ttack at more substituted carbon o here PdL 2 C 3 syn here L C 2 Pd 3 C 3 ttack at less substituted carbon o syn hydrogen here 24.3 The eck Reaction 007 Copyright 200 Cengage Learning. ll Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eook and/or echapter(s).

7 Example 24.2 eck 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. ccount for the formation of these two products. (E)-3-exene Pd(c) 2, 2 3 P C 6 5 C 6 5 r (C 3 C 2 ) 3 (Z )-3-enyl- 3-hexene C 6 5 (E )-4-enyl- 2-hexene Solution Syn addition gives the product shown. fter rotation, syn elimination of the 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-exene C 6 5 r Pd(c) 2, 2 3 P (C 3 C 2 ) 3 Syn elimination Rotate C 6 5 Pdr(c) 2 Pdr(c) 2 C 6 5 C 6 5 Pdr(c) 2 Syn elimination Problem 24.2 C 6 5 Give reagents and conditions for the following reaction. (Z )-3-enyl- 3-hexene C 6 5 (E )-4-enyl- 2-hexene (racemic) r r r r r r 24.4 Catalytic llylic lkylation Substitution mechanisms were covered in Chapter 9. t was noted that the S 2 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 008 Chapter 24 Catalytic Carbon-Carbon ond Formation Copyright 200 Cengage Learning. ll Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eook and/or echapter(s).

8 allylic, metals can catalyze the reaction, i.e., palladium, platinum, and rhodium, among others. uc 2 metal catalyst uc 2 Two of the most common catalysts for this reaction are Pd(L) 4 (frequently L is triphenylphosphine) and PdCl 2. Two examples of the reaction are given below. ne interesting feature is the retention of stereochemistry at the carbon with the leaving group. ote that this outcome is the opposite of what would occur in an S 2 mechanism. 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, sulfonates, and cyanides are some examples. The leaving groups can be halogens as with S 2 reactions, but this catalytic reaction is particularly useful with esters as the leaving group. cetate, written as c, is most commonly used (below in both examples). c C 3 2 C 3 a C 2 C 3 C 2 C 3 c 2 2 S 2 2 S 2 Example 24.3 Write the products of the following reactions. ac(c 2 C 3 ) 2 c C 2 C 3 ac(c 2 C 3 ) 2 c C 2 C 3 Solution s 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 Catalytic llylic lkylation 009 Copyright 200 Cengage Learning. ll Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eook and/or echapter(s).

9 c C 2 C 3 ac(c 2 C 3 ) 2 C 3 2 C C 2 C 3 C 2 C 3 c C 2 C 3 ac(c 2 C 3 ) 2 C 3 2 C C 2 C 3 C 2 C 3 Problem 24.3 Write the product(s) of the following reaction. ow many stereoisomers of the product are formed? c 2 2 S 2 lthough 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. lso acetate is not normally a good leaving group in an S 2 reaction. owever, the real primary advantage is in reversing the stereochemical outcome of the reaction as compared to S 2. efore examining the reason behind the stereochemistry of the reaction, let s first take a look at the mechanism involving one particularly common catalyst,.. The Mechanism of Catalytic llylic lkylation 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 addition occurs. The new step that occurs in catalytic allylic alkylation is nucleophilic attack on an allyl-ligand coordinated to a metal. Mechanism The Catalytic Cycle for llylic lkylation The catalytic cycle of allylic alkylation has several steps, six of which are shown below. The cycle is initiated by dissociation of a ligand (L 5 P 3, step ), followed in step 2 by coordination of the allylic species to make a p complex and another ligand loss (step 3). fter step 3, the Pd is in the zero oxidation state 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- 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. t is common in organometallic chemistry to represent the two contributing structures involved in an allyl complex with three carbons and an arc (see the figure on the next page). The interaction of three carbons to one metal is denoted by the prefix h 3 ; such a complex is called an h 3 -allyl complex (h is pronounced eta ). 00 Chapter 24 Catalytic Carbon-Carbon ond Formation Copyright 200 Cengage Learning. ll Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eook and/or echapter(s).

10 L 4 Pd uc L 3 Pd L uc 6 L 2 5 uc 2 L 3 Pd p complex 4 3 L Common representation of an h 3 allyl complex 2 fter 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.. Stereochemical and Regiochemical ssues 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 h 3 -allyl complex occurs from solution in an analogous fashion to an S 2 reaction, and therefore also occurs with clean inversion of stereochemistry. The net effect of two consecutive inversions of stereochemistry 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). 2 Pd(L) 4 Y Y c L Pd L Y Y The reaction is also very regioselective. ucleophilic attack occurs at the less substituted end of the of the h 3 -allyl complex regardless of the initial position of the leaving group Catalytic llylic lkylation 0 Copyright 200 Cengage Learning. ll Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eook and/or echapter(s).

11 C(C 2 C 3 ) 2 c ac(c 2 C 3 ) 2 dominant product C(C 2 C 3 ) 2 c ac(c 2 C 3 ) 2 dominant product 24.5 Palladium-Catalyzed Cross-Coupling Reactions Catalytic Cross-Coupling Reaction reaction wherein a C!C bond is formed in a catalytic fashion between alkyl, aryl, alkenyl, or alkynyl groups. Transmetallation nterchange of ligands between two metals or metalloids. rguably, the largest impact that organometallic chemistry has had on organic synthesis involves a series of reactions that are classified as cross-coupling reactions, many of which are catalyzed by palladium. cross-coupling reaction is defined as one that creates a C!C bond by coupling together two alkyl, aryl, alkenyl, or alkynyl groups, as we saw with the Gilman reaction in Section 5.2. Yet, the reactions we are now examining are catalytic. There are a large number of these reactions, most of which are named after the chemists primarily associated with their creation. We will examine three in this book: the Suzuki, Stille, and Sonogashira couplings. Cross-couplings reactions involve a transmetallation step. transmetallation is a pairwise interchange of ligands between two different metals or metalloids. n the case of palladium-catalyzed cross-coupling reactions, the other metal/metalloid is commonly Zr, Sn,, Zn, Cu, or Mg, which we designate as M in the following general example. R Pd R9 M R9 Pd R M. General Mechanism for Cross-Coupling Reactions n 200, Richard eck, Ei-ichi egishi, and kira Suzuki shared the obel Prize in Chemistry for their work on C!C coupling reactions. For simplicity sake, all the catalytic cross-coupling reactions can be represented by one general mechanism, even though each has subtle differences that we describe in the sections below. The catalytic cycle is so simple that it is presented here with only three steps. The differences between M, L, L9, and are what differentiate and classify a particular reaction. Mechanism The Catalytic Cycle of Cross-Coupling Various Pd(0) or Pd() species are used in the catalytic reactions. Step involves oxidative addition of one of the organic species to the palladium. transmetallation in step 2 results in the palladium having two carbon-based ligands. reductive elimination in step 3 couples the two carbon fragments together. The relative simplicity and variability of each component involves has made this catalytic cycle a very powerful one. R-R9 3 PdL n R- R-Pd(R9)L n R9-ML9 n 2 -ML9 n R-Pd()L n 02 Chapter 24 Catalytic Carbon-Carbon ond Formation Copyright 200 Cengage Learning. ll Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eook and/or echapter(s).

12 . The Suzuki Coupling The Suzuki coupling was developed by Professor kira Suzuki of okkaido University. The Suzuki coupling uses a boron compound (R9-Y 2 ) and an alkenyl, aryl, or alkynyl halide or triflate (R) as the carbon sources, with a palladium salt as the catalyst. romides and iodides are the most commonly used halides; chlorides are less reactive. lkyl halides can sometimes be used but are subject to elimination. base is also required. The boron compound can be a borane (R9 3 ), a borate ester (R9(R) 2 ), or a boric acid (R9() 2 ), where R9 is alkyl, alkenyl, or aryl. The general reaction is shown in the following scheme, where is halide or triflate and Y is alkyl, alkoxyl, or. list of the types of components that can be used is given in Table 24.. This reaction is one of the principal methods now used to prepare biaryls. R R'-Y 2 R-R' Y 2 PdL 4 ase oranes 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. (Sia) 2 (ydroboration) (Sia) 2 (Me) 3 LiMe Li (Me) 2 Following are three examples of the reaction that show its versatility. Pd( 3 P) 4 ame C 6 3 r (Sia) 2 C 6 3 () 2 r 2 Pd(c) 2, a 2 C 3 2 r Pd(c) 2 Et 3 (Me) Palladium-Catalyzed Cross-Coupling Reactions 03 Copyright 200 Cengage Learning. ll Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eook and/or echapter(s).

13 Table 24. rganoboron compounds Suzuki Coupling Components Where ne of the rganoboron Compounds Couples with ne of the Coupling Reagents Shown Coupling reagents 5 halide or triflate 9 9 RC"C9 RC"C! lkyl 9 RC"C! lkyl- (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. xidative addition and ligand exchange: orane activation: Reaction: PdL n R R R Pd R Pd R R R 3 R 3 R R Pd R R Pd R' R R' Pd 0 R R' Example 24.4 Show how the following penicillin analog can be prepared from the indicated starting material and any other necessary compounds. R R C CR Tf CR Solution R C R C CR Tf () 2 PdL 2 a CR 04 Chapter 24 Catalytic Carbon-Carbon ond Formation Copyright 200 Cengage Learning. ll Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eook and/or echapter(s).

14 Problem 24.4 Show how the following compound can be prepared from starting materials containing eight carbons or less. Me Me 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 not only with regioselectivity but also retains the stereochemistry from the reactants to the products. n-u 3 Sn Pd(0) n-u 3 Sn Pd(0) Many stannane reagents are commercially available, or they can be readily synthesized 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!S 2 CF 3 ) and a vinyl iodide. Vinyl triflates are prepared from the reaction of an enolate with -phenyl triflimide (Tf 2, Tf 5 S 2 CF 3 ). Cl-Mg n-u 3 SnCl n-u 3 Sn LD Li (S 2 CF 3 ) 2 Tf Example 24.5 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. ne reactant should be a vinyl iodide (or triflate) while the other reactant is a stannane Palladium-Catalyzed Cross-Coupling Reactions 05 Copyright 200 Cengage Learning. ll Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eook and/or echapter(s).

15 n-u 3 Sn Problem 24.5 What is the product of the following reaction? Tf n-u 3 Sn C 2 Et Pd(0) D. The Sonogashira Coupling The last Pd(0) catalyzed cross-coupling reaction covered in this chapter is the Sonogashira coupling. t involves transmetallation of an alkynyl-cu() species to Pd, followed by coupling to an aryl or vinyl iodide or triflate. The Cu() alkynyl complex is created in situ by the reaction of a terminal alkyne with Cu in the presence of triethylamine. The reaction is most commonly used to create diaryl alkynyl products. Cu Cu Et 3 Example 24.6 Two Sonogashira coupling reactions can be used to make unsymmetrical diaryl alkynes by first using trimethylsilyl acetylene. The trimethylsilyl protecting group can be removed by addition of fluoride (usually tetrabutyl ammonium fluoride, see Section.6). Show how such a sequence of reactions can be used to construct the following product when one reactant is phenyl iodide. S Solution Sonogashira coupling conditions using trimethylsilyl acetylene give phenyl acetylene after deprotection using fluoride. nother such coupling using the phenyl iodide reactant shown gives the product. Cu, Et 3 SiMe 3 u 4 F 2 SiMe 3 S Cu, Et 3 S 06 Chapter 24 Catalytic Carbon-Carbon ond Formation Copyright 200 Cengage Learning. ll Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eook and/or echapter(s).

16 Problem 24.6 What sequence of reactions will produce the following product if starting with trimethylsilyl acetylene and the appropriate two aryl iodides? 24.6 lkene Metathesis Recently, a novel catalytic reaction leading to alkene metathesis has been developed. Robert Grubbs of the California nstitute of Technology and Richard Schrock of the Massachusetts nstitute of Technology made major contributions to this chemistry. Together their work has provided a remarkably easy and general way to generate carbon-carbon double bonds, even in complex molecules. n an alkene metathesis reaction, two alkenes interchange the carbons attached to their double bonds. catalyst n 2005, Robert Grubbs, Richard Schrock, and Yves Chauvin shared the obel prize in chemistry for their work on metathesis reactions. lkene metathesis n an alkene metathesis reaction, two alkenes interchange the carbons attached to their double bonds.. Stable ucleophilic Carbenes We discussed carbenes and carbenoids (derivatives of divalent carbon) in Section 5.3, 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. n this case, the large 2,4,6-trimethylphenyl substituents protect the carbene from attack by nucleophiles or oxygen. Rather than being electron-deficient like most carbenes, these compounds are nucleophiles because of the strong electron donation by the nitrogens. ecause of their nucleophilicity, they are excellent ligands (resembling phosphines) for certain transition metals lkene Metathesis 07 Copyright 200 Cengage Learning. ll Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eook and/or echapter(s).

17 . Ring-Closing lkene Metathesis Using ucleophilic Carbene Catalysts These stable carbenes (and others that are less stable) provide ligands for certain metals that are catalysts for the alkene metathesis reaction. s we saw at the beginning of this section, this reaction is an equilibrium. owever, it can be an effective means of forming new carbon-carbon double bonds if the equilibrium can be driven in the desired direction. For example, if the reaction involves two 2,2-disubstituted alkenes of the type R 2 C"C 2, one of the products is ethylene. Loss of gaseous ethylene drives the reaction to the right, giving a single alkene as product. catalyst Ethylene particularly useful variant of this reaction uses a starting material in which both alkenes are in the same molecule. n this case, the product is a cycloalkene, and the reaction is called ring-closing alkene metathesis. Ring sizes up to 26 and higher have been prepared by ring-closing alkene metathesis. This reaction is amazingly general and synthetically useful. EtC CEt EtC CEt catalyst C 2 "C 2 Example 24.7 Show how the following compound can be prepared from an acyclic diene. Solution Ring-closing alkene metathesis gives the product in one step. 2 C catalyst 2 2 C C 2 "C 2 (racemic) (racemic) Problem 24.7 Show the product of the following reaction. nucleophilic carbene catalyst 08 Chapter 24 Catalytic Carbon-Carbon ond Formation Copyright 200 Cengage Learning. ll Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eook and/or echapter(s).