C549R.M. Williams

Organometallic Coupling Reactions

The Heck ReactionThe Heck reaction involves the use of Pd(0) catalysts that mediate the net insertion of nucleophiles into

metal carbon s-bonds which are produced by oxidative addition processes. The most synthetically usefultransformations involves the insertion of CO and alkenes into metal carbon s-bonds. This reaction is generallylimited to organic substrates lacking b-hydrogen atoms since, reductive elimination is a facile process whichusually occurs under the conditions for oxidative addition. The catalytic cycle for the Heck reaction, involvingCO insertion is shown below.

R-XPd(0)

R-Pd(II)-X

R Pd(II)-XO CO

(insertion)

(oxidative addition)

H-Pd(II)-X

HX

R NuO

(reductiveelimination)

Nu-H

Examples of the CO insertion process are given below.

OTf

OO H

Me

Me

MeMe

Pd(OAc)2, Ph3P

CO, MeOH, Et3N

CO2Me

OO H

Me

Me

MeMe

NHBn

Br

Pd(OAc)2, Ph3P

CO, Et3N NBnO63%

75%

The olefin insertion process is similar and involves coordination of the olefin p-system to the Pd(II)intermediate followed by insertion and b-H-elimination. Typical catalysts used are: ((Ph)3P)4Pd, *Pd(dba)2,PdCl2L2 + DIBAH; Pd(OAc) 2 + reducing agent (such as Ph3P).*Note Pd)dba)2 :

O OPd = Pd(dba)2

R-XPd(0)

R-Pd(II)-X

R Pd(II)-X(coordination)

(oxidative addition)

H-Pd(II)-X

HX(reductiveelimination)

Z

Z = H, R, Ph, CN, CO2R, OMe, OAc, NHAcZ

(less substituted)

PdX

Z

R

H H

ZR

b-H-elimination (cis)

An elegant example of the olefin insertion reaction was published by Rawal in the total synthesis ofstrychnine as shown below:

N

N

O

I OTBS

N

N

O

OHH

1. Pd(OAc)2, K2CO3

Bu4NCl, DMF2. 2N HCl, THF

71%isostrychnine

Rawal, V.H.; Iwasa, S., J.Org.Chem., 1994, 59, 2685~2686

The Stille Cross-Coupling Reaction

A major advance in the field of Pd-catalyzed cross-coupling reactions was developed by J.K Stille andco-workers and involves the use of vinyl and aryl stannanes with activated vinylic or aryl halides or triflates.The catalytic cycle for the Stille reaction is shown below:

Pd(II)R1Sn(R2)3

R1-R1Pd(0)Ln

R3-Pd(II)Ln-X

R3-X

R1Sn(R2)3XSn(R2)3

R3-Pd(II)Ln-R1

R1-R3

Several examples of the Stille reaction cast in complex polyfunctional molecules are illustrated below:

O

SnBu3TfO

Me Me

Pd(PPh3)4

LiCl75%

+ O Me Me

pleraplysillin-1

Scott, W.J.; Crisp, G.T.; Stille, J.K., J.Am.Chem.Soc., 1984, 106, 4630~4632

Stille and co-workers published an impressive demonstration of the Stille coupling reaction in a totalsynthesis of D9(12)-capnellene. This synthesis also features two sequential Nazarov cyclization reactions toconstruct the fused five-membered rings.

Me Me

O

Me

Tf2O

base85%

Me Me

OTf

Me

Me3SnSiMe3

CO, Pd(PPh3)4

Me Me

Me

O

SiMe3

BF3-OEt2

tol., D

Me MeO

Me(Nazarov)

1. L-selectride

2. Tf2NPh

76%70%87%

Me MeOTf

Me

Me3SnSiMe3

CO, Pd(PPh3)4

86%

Me Me

Me

O

SiMe3BF3-OEt2

tol., D(Nazarov)

80%

Me Me

Me

O

H

H Me Me

Me H

H1. H2, Pd/C

2. Ph3P=CH2

D9(12)-capnellene

Crisp, G.T.; Scott, W.J.; Stille, J.K., J.Am.Chem.Soc., 1984, 106, 750~7506

O

O Me

MeMe

SnBu3TfO Me

Me CO, Pd(MeCN)2Cl2

LiCl, DMF

O

O Me

MeMe

Me

Me

O

Gyorkos, A.C.; Stille, J.K.; Hegedus, L.S., J.Am.Chem.Soc., 1990, 112, 8465~8472

24%

jatrophone

When the halide is allylic, coupling occurs from the least hindered termini as shown by the twoexamples below:

Me Me

Me

Cl

allylic halides (typically Cl) couple at the least hindered termini:

Pd(dba)2, P(Ph)3

PhSnBu3

Me Me

Me

90%

Me

MeCHO

Cl

Pd(dba)2, P(Ph)3

(p-OMe)PhSnBu3

87%Me

MeCHO

OMe

Alkenyl chlorides are generally not used in the Stille coupling reaction due to low reactivity, whereasalkenyl bromides and iodides are very useful coupling partners. Some examples are illustrated below:

Pd(PPh3)2Cl2, THF

PhSnMe3

80%

Me Br

O

Ph

I

Me Br

O

Ph

n-Bu IBu3Sn OH

+Pd(MeCN)2Cl2 n-Bu

OH

78%

O

O SiMe2Ph

OMOM

OTBS

O

O SiMe2Ph

Br OMOM

OTBS

SnBu3 Pd(AsPh3)2Cl2

80%

Perhaps one of the most spectacular illustrations of the Stille coupling reaction can be found in the totalsynthesis of rapamycin reported by Nicolaou and co-workers as shown below. This reaction involves a daringdouble Stille cross-coupling and macrocyclization directly providing the natural product.

O

I

MeOMe

Me

O

O N

O H

OH

OMe

Me

Me

OMe Me

OH

MeO

O

I

Me

Me

Bu3Sn SnBu3

Pd(MeCN)2Cl2i-Pr2NEt, DMF, THF

OMe

OMe

Me

O

O N

O H

OH

OMe

Me

Me

OMe Me

OH

MeO

O

Me

Me

Nicolaou, K.C.; et al., J.Am.Chem.Soc., 1993, 115, 4419

~ 46%

rapamycin

Biaryl couplings. The Stille reaction is a very powerful method to prepare biaryl cross-coupling reactions. Theease of preparation of the aryl triflates from the corresponding phenol, make this a very useful method. Someof the examples below illustrate this.

OH

NO2

+ Tf2Opyridine

OTf

NO2

MgBr

OMe

+ Bu3SnClTHF

SnBu3

OMe

PdCl2(PPh3)2

LiCl, DMF

OMe

NO2

Stille, J.K.; Echavarren, A.M.; Williams, R.M.; Hendrix, J.A., Org.Syn., 1992, 71, 97~106.

OO

O

O

Me NH3+OH

MeHO

HOHO

O O

NO

NH

H

ONH

ON

OHH

O

Me

Me

NHMeH

HH

OHOH

NO

HHO2C

H

NO

Cl

Cl

H2NO

HO

HOH H

HH HH

HOHO OH

H2N CO2HH2N CO2H

HH

7

5

ACTINOIDIC ACID

7

5

6 4 2

VANCOMYCIN

CHO

BrOMe

1. KCN, NaHSO3, MeOH, H2O2. conc. HCl, diox., 16 h

3. SOCl2, MeOH; then NaHCO34. Pb(OAc)4, MeOH, CH2Cl25. aq. HCl, MeOH, rt., 16 h6. (BOC)2O

Ph

NH2

OHH

OMeBr

tBOCHNH

CO2Me

(96% er)

0.4 eq. Pd(PPh3)4 , 0.4 eq. CuBrdiox., D

CHOMe3Sn

OMeMeO

44-51%44% overall

MeO

tBOCHNH

CO2Me

CHO

OMeMeO

1.

MeOH, rt.; 2 eq. TMSCN2. conc. HCl, diox., rt. 16 h 3. SOCl2, MeOH4. (BOC)2O, NaHCO3, H2O CHCl3

Ph

NH2

OHH

50%

MeO

tBOCHNH

CO2Me

OMeMeO

MeO2C NH

OHPh

H

H

+

MeO

tBOCHNH

CO2Me

OMeMeO

MeO2C NH

OHPh

H

H

1. Pb(OAc)4 , CH2Cl2 MeOH

2. conc. HCl, D76%

MeO

H2NH

CO2H

OMeMeO

HO2C NH2H

1. 48% HBr, D, 12h2. Dowex-50

40%

OH

H2NH

CO2H

OHHO

HO2C NH2H

Actinoidic Acid

(atropisomer mixture)

(atropisomer mixture)

(atropisomer mixture)

Williams, R.M.; Amino, Y. (unpublished)

Acyl halide couplings. Acid chlorides tend to couple with stannanes in the presence of a palladium catalystand few limitations are apparently associated with this reaction. There are also examples of this reaction inthe absence of apalladium (and in some cases the yields are higher than in the presence of Pd!). Two examplesare shown below:

acyl halide couplings:

COCl

COCl+

SnMe3

SnMe3

BnPd(PPh3)2Cl

THF62%

O

O

Degl'Innocenti, A., et al., Synthesis, 1991, 267

O Cln-C5H11

SnBu3

n-Bu

O

Pd(PPh3)4

THF, D O

On-Bu

n-C5H11

Linderman, et al., J. Am. Chem. Soc., 1990, 112, 7438

77%

The Suzuki Coupling

Suzuki has brought a major advance to the field of Pd-mediated coupling reactions through thedemonstration that alkylboranes can serve as organic donors provided base is used in the reaction. Mostsignificantly, aqueous base can be used and this constitutes one of the few synthetically useful C-C couplingreactions mediated by transition metals that can be conducted in water.

R1 BY2 + R2XPd(0)

baseR1 R2

BY2 = B(OR)2, 9-BBN, B(CHCH3CH(CH3)2)2X = Cl, Br, I, OTfbase = Na2CO3, NaOEt, TEA, K3PO4

R'-XPd(0)

R'-Pd(II)-X

R' Pd(II)-OR

(oxidative addition)

R'R

NaOR

NaX

BR

Pd-R'R

RO B

Examples of this reaction are shown below.

Me

MeMe

Me

B(sia)2BrMe

MeMe

Me

BrH

HB(sia)2 Pd(PPh3)4

NaOH, PhH, D

Me

Me

MeMe

humulene32%

Miyaura, N.; Suginome, H.; Suzuki, A., Tetrahedron Lett., 1984, 25, 761~764

One of the most impressive demonstrations of the utility of the Suzuki diene synthesis can be found inthe dauntingly complex coupling of two large segments in the total synthesis of palytoxin reported by Kishiand co-workers.

A significant advance of the Suzuki coupling is the capacity to transfer alkyl groups whereas the Heckand Stille coupling reactions are limited to vinyl and aryl couplings.

O

O

O Me

Me

OO

O

TBSO

HNO

OTMS

TBSOOTBS

OTBS

OTBS

TBSOTBSO

Me

OTBS

TBSO

OTBS

BO

O

OAcI

O

OTBS

OTBS

OTBS

OTBS

TBSO

O

OTBS

OTBS

TBSO

MeO2C OTBS

+Pd(Ph3P)4, TlOH

H2O, hexanes

O

O

O Me

Me

OO

O

TBSO

HNO

OTMS

TBSOOTBS

OTBS

OTBS

TBSOTBSO

Me

OTBS

TBSO

OTBS

OAc

O

OTBS

OTBS

OTBS

OTBS

TBSO

O

OTBS

OTBS

TBSO

MeO2C OTBS

Kishi, et al., J.Am.Chem.Soc., 1989, 111, 7525~7530Kishi, et al., J.Am.Chem.Soc., 1987, 109, 4756~4758

The Castro-Stephens Coupling

The Castro-Stephens cross-coupling reaction involves the reaction of a vinyl halide with a terminalalkyne to give eneynes (see: Castro, C.E.; Stephens, R.D., J.Org.Chem., 1963, 28 , 2163). This reactions hasrecently attracted a great deal of attention due to the direct applicability to construct the enediynesubstructures of the calicheamicin/esperamicin family of antitumor antibiotics. One application is shownbelow in Nicolaou’s total synthesis of calicheamicinone.

R'HCl

R+

Pd(0) R'

R

ON

OO

H

TESO

CO2Me

SiMe3

Cl

Pd(PPh3)4, CuIBuNH2, PhH, 0oC

ON

OO

TESO

CO2MeSiMe391%

OH

SSSMeO

HO

NHCO2Me

calicheamicinone

Smith, A.L.; Hwang, C.-K.; Pitsinos, E.; Scarlato, G.R.; Nicolaou, K.C., J.Am.Chem.Soc., 1992, 114, 3134~3136

The Nicholas ReactionThe reaction of cobalt-complexed propargyl alcohols and derivatives with a Lewis acid generates a

cobalt-stabilized propargylic cation which can suffer nucleophilic addition to give, after oxidative removal ofthe dicobalt hexacarbonyl ligand, substituted alkynes. The general reaction is shown below.

R

R'O

Co2(CO)8R Co(CO)3

R'O

Lewis Acid

R

Nu

Co2(CO)6

-2 CO

Co(CO)3R Co(CO)3

Co(CO)3

1. Nu:

2. [ox]

R

R'O

The Pauson-Khand ReactionWhen heated in the presence of olefins, dicobalt hexacarbonyl complexes of alkynes undergo a

synthetically useful and interesting [2+2+1] cycloaddition resulting in cyclopentenones as shown below.

Rs

RLCo2(CO)8

RL

RsCo(CO)3

-2 CO

Co(CO)3

R" RL

RsCo(CO)3

Co(CO)2- CO

R

RL

RsCo(CO)3

Co(CO)3

R

CO

RL

RsCo(CO)3

Co(CO)3

CO

R OOR

Rs

RL

Co(CO)3Co(CO)3

OR

Rs

RL

A nice illustration of the Pauson-Khand reaction is shown below in Takano’s approach to dendrobine:

Me

Me

NMeO2C

HCo2(CO)8

R3NO

MeO2CN O

Me

Me HH

dendrobine

70%

Takano, S.; Inomata, K.; Ogasawara, K., Chem. Lett., 1992, 443

MeN

Me

Me HH

H

MeO O

Schreiber, et al., have cleverly coupled the Nicholas and Pauson-Khand reactions to build up rapidmolecular complexity from relatively simple substrates as shown below (Schreiber, S.L.; Sammakia, T.; Crowe,W.E., J.Am.Chem.Soc., 1986, 108, 3128~3130):

Co(CO)3Co(CO)3

O

TMS

BF3-OEt2

CH2Cl2

67%Co(CO)3

Co(CO)3

O O CO

PhH

85%

O

O

Schreiber, S.L.; Sammakia, T.; Crowe, W.E., J.Am.Chem.Soc., 1986, 108, 3128~3130):

O MeMe

MeMe

H

H

H

epoxydictymene

The Cadiot-Chodkiewicz Coupling

Coupling of 1-bromo alkynes with terminal alkynes in the presence of copper(I) salts is a syntheticallyuseful process for preparing unsymmetrical conjugated diynes as shown below (see: Alami, M.; Ferri, F.,Tetrahedron Lett., 1996, 37, 2763~2766).

RX R'H+10% CuI

pyrrolidine, 20oCR'R

X = Br, I

Sonagashira Coupling

The cross-coupling of terminal alkynes and vinyl iodides and related substrates proceeds in theporesence of CuI and a palladium catalyst.

OI 5 mol% Pd2Cl2(PPh3)2

10mol% CuI

i-Pr2NH, THF, 0oC

HMe

O

89%

Me

Miller, M.W.; Johnson, C.R., J. Org. Chem. , 1997, 62, 1582~1583

original reference: Sonagashira, K.; Tohda, Y.; Hagihara, N., Tetrahedron Lett., 1975, 4467