Chapter 24

Catalytic Carbon-Carbon Bond Formation

Ch-24 !

0 !

Carbon-Carbon Bond Formation

Nucleophilic substitution by a carbon nucleophile (:Nu) displacing a leaving group (Lv). :Nu = organometallic compound (RMgX, RLi, R2CuLi); Lv = O in epoxide (Ch 15.1C). :Nu = RCC:, :NC:; Lv = O in epoxide (Ch 11.9B). :Nu = Enolate anion (-C of acetoacetic ester, malonic ester) in acetoacetic ester (AAE), malonic ester (ME) syntheses; Lv = X in alkylX (alkyl halide, alkyl tosylate, methyl sulfate) (Ch 19). :Nu = Enamine in enamine alkylation; Lv = X in alkylX (alkyl halide, alkyl tosylate, methyl sulfate) (Ch 19).
Ch-24 ! 1 !

Carbon-Carbon Bond Formation

Nucleophilic addition of a carbon nucleophile (:Nu) adding to a carbonyl group in an aldehyde, ketone, or in carboxylic acid derivatives. :Nu = organometallic compound (RMgX, RLi, R2CuLi) (Ch 16.5A, B; Ch 18.9). :Nu = RCC:, :NC: (Ch 16.5C, D). :Nu = Enolate anion (-C of aldehyde, ketone) in aldol reaction (Ch 19.2). :Nu = Enolate anion (-C of ester) in Claisen, Dieckmann reaction; AAE and ME syntheses (Ch 19.3, 6, 7). :Nu = Enamine in enamine acylation (Ch 19.5). . :Nu = Phosphonium ylide in Wittig reactions (Ch 16.6).
Ch-24 ! 2 !

Carbon-Carbon Bond Formation

Conjugate nucleophilic addition (= 1,4-addition, = Michael addition) of carbon nucleophile, :Nu adding to an ,-unsaturated carbonyl compound (in aldehyde, ketone, ester, amide); an ,-unsaturated nitrile, or an ,-unsaturated nitro compound: (Ch 19.8; Ch 19.9). :Nu = enolate anion (-C of -diketone, -ketoester, -ketonitrile, -diester) (Ch 19.6, 19.7; Ch 19.9). :Nu = enamine (Ch 19.8). [also, :Nu = ammonia or amine (1, 2) in Michael addition reactions -amino carbonyl compound (Ch 19.8)].
Ch-24 ! 3 !

Carbon-Carbon Bond Formation

Pericyclic Reactions Diels Alder reaction (Ch 20.5). Claisen rearrangement (Ch 20.6). Cope rearrangement (Ch 20.6). Carbene / carbenoid addition (Simmons-Smith reaction) (Ch 15.3). Electrophilic Aromatic Substitution (Ch 22.1). :Nu = ArH; E = R in Friedel-Crafts alkylation, E = RC=O in Friedel-Crafts acylation. Substitution of aromatic diazonium ion (Ch 23.8E). :Nu = :NC:; E = ArNN in Sandmeyer reactions.
Ch-24 ! 4 !

Organometallic Compounds
Following are two extremely important reactions of metals and organometallic compounds; Metal M (also free metal, M0) is coordinated with ligands L, M0Ln (n = number of ligands) Oxidative addition: Addition of a reagent to a metal center; adds two substituents, the oxidation state of the metal increases by two. Reductive elimination: Elimination of two substituents at a metal center; the oxidation state of the metal decreases by two.
MLn + RX Oxidative addition R X MLn Reductive elimination
Ch-24 !

5 !

Heck Reaction
Heck Reaction: A palladium-catalyzed reaction, in which the carbon group of a haloalkene or haloarene (or haloalkane) is substituted for a vinylic H of an alkene. (:B = base).
Haloalkene X or H Pd0 catalyst R H or Ar Substituted alkene
Ch-24 ! 6 !

+ B

ArX Haloarene

H H Alkene

+ HB

Heck Reaction
The catalyst: most common precatalyst Pd(II) acetate, Pd(OCOCH3)2 = Pd(OAc)2; Pd(II) is reduced in situ to Pd(0) = Pd0.
Pd(OAc)2 Palladium(II) acetate

Pd0

AcO

HOAc

Alkene

Oxidized alkene

Ch-24 !

7 !

Heck Reaction
The ligand L: Reaction of Pd(0) with good ligands L gives PdL2 or PdL4.
Pd0

+ 2L
Ligand

Pd0L2 Heck catalyst

Triphenylphosphine, PPh3 is one of the most common ligands: e.g., Pd0(PPh3)2 or Pd0(PPh3)4.

Ch-24 !

8 !

Heck Reaction
The organic halogen compound: X = halogen, I, Cl, Br; or triflate, CF3SO2O-. Ar = aryl, heterocyclic; alkenyl group; alkyl = benzyl,.
ArX Haloarene X ArCH2X Haloalkene Benzyl halides

(Alkyl halides with a -hydrogen are rarely used because they undergo -elimination to give alkenes). OH groups and the C=O groups of aldehydes, ketones, and esters are unreactive under Heck conditions.

Ch-24 !

9 !

Heck Reaction
The alkene: The less crowding on the alkene, the more reactive it is. (best is a vinyl group CH=CH2). Also, electron withdrawing groups attached to the alkene work very well, e.g., H2C=CHCOOMe, H2C=CHCN. The base: Et3N, NaOAc, KOAc, and NaHCO3 are most common bases. The solvent: Polar aprotic solvents such as DMF, acetonitrile, DMSO. Aqueous methanol may also be used.

Ch-24 !

10 !

Heck Reaction Mechanism

Ch-24 !

11 !

Heck Reaction
With respect to the alkene: Substitution is highly regioselective; most commonly at the less substituted carbon of the double bond. Substitution is highly stereoselective; where E,Z isomerism is possible in the product, the E configuration is often formed almost exclusively.

Base" The haloarene The alkene"

Ch-24 !

12 !

Heck Reaction
With respect to the haloalkene: The reaction is stereospecific; the configuration of the double bond in the haloalkene is preserved.

Haloalkene"

The alkene"

Ch-24 !

13 !

Heck Reaction
The usual pattern of acyclic compounds is: replacement of a hydrogen of the double bond with an R group. If attack of the organopalladium group on the double bond occurs in such a way that the R group has no syn H for syn elimination, then the double bond may shift.
Pd(OAc)2I, Et3N

H H

H Pd(OAc)2I H Ph

H H
Ch-24 !

H Pd(OAc)2I H
14 !

Pd-Catalyzed Cross-Coupling
Cross-coupling reactions forming CC bonds by coupling together two alkyl, aryl, alkenyl or alkynyl groups (cf. Gilman reactions, Ch. 15.2). Mostly Pd-catalyzed. Cross-coupling reactions involve a transmetallation step, the interchange of ligands / groups between two metals M = Zn, Sn, Zr, Cu, Mg, or metalloids (e.g., M = B) with Pd.
RPd

R'M

R'Pd

RM

Ch-24 !

15 !

Pd-Catalyzed Cross-Coupling
Catalytic cycle of cross-coupling, general mechanism.
Reductive elimination ( coupling R and R; restoring the catalyst) Oxidative addition (= insertion of PdLn in between RX)

Transmetallation ( Pd with two C groups R and R)

Suzuki coupling! Stille coupling! Sonogashira coupling!

Pd-catalyzed cross-coupling" reactions differentiated by M, L, L, and X utilized. "

Ch-24 ! 16 !

Suzuki Coupling
Suzuki coupling: A palladium-catalyzed reaction of an organoborane (RBY2) with an alkenyl, aryl, or alkynyl halide RX or triflate ROSO2CF3 in the presence of a base.
R'X

+ R"BY2

PdL4 NaOMe

R'R"

+ XBY2

Ch-24 !

17 !

Suzuki Coupling
Boranes are easily prepared from alkenes or alkynes by hydroboration.
H

(sia)2BH H

B(sia)2

Borates are prepared from alkyl or aryl lithium compounds and trimethylborate."
Li

+ B(OMe)3

B(OMe)2

+ LiOMe

Ch-24 !

18 !

Suzuki Coupling
These examples illustrate the versatility of the reaction.
H B(sia)2 + Br H C6H13 Pd(PPh3)4 NaOMe H H

C6H13

Ch-24 !

19 !

Suzuki Coupling
Step 1: Oxidative addition ( RPd(L2)X) followed by ligand exchange: loss of 2 L ( RPdX) and treatment with base MeO Na+ to replace X ( RPdOMe).
R'X Pd0L2 R' PdL2 X 2L R'PdX MeO X R'PdOMe

Step 2: Borane activation: reaction of the borane R3B (a Lewis acid) with MeO (a Lewis base)." MeO
R"3B

R"3BOMe

Step 3: Coupling: transmetallation followed by reductive elimination ( CC bond in RR). " R' R" + Pd0 R'PdR" R'Pd OMe
R" R" B OMe R" R" MeO B OMe Ch-24 ! R"

20 !

Stille Coupling
Pd(0)-catalyzed CC-bond formation using vinyl- or aryl-Sn reactants (= stannanes) for transmetallation, followed by reaction with alkenyl- or aryl halides conjugated dienes or alkenylarenes, respectively. The reaction is regioselective with retention of the stereochemistry of the reactants in the product (= stereospecific).

Ch-24 !

21 !

Stille Coupling
Preparation of stannanes from a Grignard reagent and tributylchlorostannane (= tributyltin chloride).

The stannane undergoes transmetallation and reacts with an aryl halide or an alkenyl iodide or an alkenyl triate; the latter is prepared from an enolate with N-phenyl triimide."

Ch-24 !

22 !

Sonogashira Coupling
Pd(0)-catalyzed CC-bond formation involving the transmetallation of an alkynyl-Cu(I) species followed by coupling to an aryl iodide (or an alkynyl iodide) commonly providing diaryl alkynes.

The Cu(I) alkynyl compound is formed in situ from a terminal alkyne with CuI in the presence of Et3N."
Ch-24 ! 23 !

Alkene Metathesis
Robert M. Grubbs and Richard R Schrock." Alkene metathesis: A reaction in which two alkenes interchange carbons on their double bonds.

If the reaction involves 2,2-disubstituted alkenes, ethylene is lost to give a single alkene product."

Ch-24 !

24 !

Alkene Metathesis
A useful variant of this reaction uses a starting material in which both alkenes are in the same molecule, and the product is a cycloalkene.

Catalysts for these reactions are a class of compounds called stable nucleophilic carbenes."

Ch-24 !

25 !

Stable Nucleophilic Carbenes

Carbenes and carbenoids (Chapter 15) provide the best route to three membered carbon rings. Most carbenes are highly reactive electrophiles. Carbenes with strongly electron-donating atoms, however, for example nitrogen atoms, are particularly stable. Rather than being electron deficient, these carbenes are nucleophiles because of the strong electron donation by the nitrogens: Nucleophilic carbenes. Because of their nucleophilicity, they are excellent ligands (resembling phosphines) for certain transition metals.

Ch-24 !

26 !

Nucleophilic Carbene
A stable nucleophilic carbene.

Ch-24 !

27 !

Alkene Metathesis Catalyst

A particularly useful alkene methathesis catalyst consists of ruthenium, Ru, complexed with nucleophilic carbenes and another carbenoid ligand. In this example, the other carbenoid ligand is a benzylidene group.

Ch-24 !

28 !

End of Chapter 24

Catalytic Carbon-Carbon Bond Formation

Ch-24 !

29 !