C549 R.M. Williams Organometallic Coupling Reactions The Heck Reaction The 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 useful transformations involves the insertion of CO and alkenes into metal carbon s-bonds. This reaction is generally limited to organic substrates lacking b-hydrogen atoms since, reductive elimination is a facile process which usually occurs under the conditions for oxidative addition. The catalytic cycle for the Heck reaction, involving CO insertion is shown below. R-X Pd(0) R-Pd(II)-X R Pd(II)-X O CO (insertion) (oxidative addition) H-Pd(II)-X HX R Nu O (reductive elimination) Nu-H Examples of the CO insertion process are given below. OTf O O H Me Me Me Me Pd(OAc) 2 , Ph 3 P CO, MeOH, Et 3 N CO 2 Me O O H Me Me Me Me NHBn Br Pd(OAc) 2 , Ph 3 P CO, Et 3 N NBn O 63% 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) 3 P) 4 Pd, *Pd(dba) 2 , PdCl 2 L 2 + DIBAH; Pd(OAc) 2 + reducing agent (such as Ph 3 P). *Note Pd)dba)2 : O O Pd = Pd(dba) 2
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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:
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:
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.
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.
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.
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.
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):
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.