Oxidative and Transition-Metal Catalyzed Cross-Coupling Reactions
Cross Coupling Reactions -...
Transcript of Cross Coupling Reactions -...
Cross Coupling Reactions
Stille Coupling ! ! !
• general principles
- Pd catalyzed reaction of aryl or vinyl halide with an aryl or vinyl stannane
R’ = aryl, vinyl X = I > OTf > Br >> Cl Pd cat: Pd(PPh3)4, Pd(OAc)2, Pd2(dba)3
solvent: DMF, dioxane, DMSO, THF, NMP
Pd(0) cat+R X R' SnR3 R' R'
Cross Coupling Reactions
Stille Coupling ! ! !
• general principles
- Pd catalyzed reaction of aryl or vinyl halide with a vinyl or aryl stannane
Cl
MeO Bu3Sn
OEtPd2(dba)3, P(tBu)3
CsF, dioxane, 100°C+
MeO
OEt
ISnBu3
HO+
Pd(PPh3)4DMF
OH
Cross Coupling Reactions
Stille Coupling ! ! !
• mechanism
Ln PdII
X
Ln Pd0Pd0 or PdII
complexes
oxidativeaddition
transmetallation
reductiveelimination
R'X
R'R
Bu3Sn
Bu3Sn X
Ln
PdII
R'
R
R'R
rate of group transfer: alkynyl > vinyl > aryl > allyl = benzyl >>>> alkyl
Cross Coupling Reactions
Stille Coupling ! ! !
• problems & solutions
- electron-rich and sterically hindered aryl halides undergo slower oxidative addition - electron-poor stannanes undergo slower transmetallation
- 1-substituted vinylstannanes can be poor substrates for the Stille reaction (steric)
Br
MeO
Pd2Cl2, P(tBu)3CuI, CsF, DMF, 45°C
+
MeOOMe
NO2
Bu3SnOMe
NO2
89%electron
richelectron
poor
ONfBu3Sn Me
OMOM
MeOH
Pd(PPh3)4, LiClCuCl, DMSO, 60°C Me
OMOM
MeOH92%
+
Nf = C4H9SO2
Cross Coupling Reactions
Stille Coupling ! ! !
• applications
OHO2C IH H
Bu3SnH
H
OHN
+ Pd(PPh3)4DMF
61%
H
H
OHN
OHO2CH H
indanomycin
O O
NH
HO OMe
O
HOMeO O
NH
IITIPSO OMe
MeO
TBSO
SnBu3Bu3Sn1. Pd(MeCN)cl2, iPr2NEt2. CAN, THF/H2O3. HF (aq), MeCN
(+)-mycotrienol
Cross Coupling Reactions
Stille Coupling ! ! !
• applications
Lett Tetrahedron Lett. 1992, 33, 777.
O
Cl
OTBSO
TBSO
HO
Bu3Sn OMOM
O+ Pd(MeCN)2Cl2
PPh3, DMF, Δ
HO
OMOM
OO
TBSO
TBSO
O
75%
HO
OH
O
OO O
H
monocillin I
Cross Coupling Reactions
Stille Coupling ! ! !
• sp2-sp3 coupling
O
O
Br
MeBu3Sn
OTHP
[(allyl)PdCl2]2, [HP(tBu)2Me]+BF4-
Me4NF, 3Å MS, THF, rt
O
O
Me
OTHP53%
+
EtO BrO
EtO
O OMe
Bu3Sn
OMe[(allyl)PdCl2]2, [PCy(pyrrolidinyl)2
Me4NF, 3Å MS, MTBE, rt
71%
Cross Coupling Reactions
Stille Coupling ! ! !
• sp2-sp3 coupling (2° alkyl halides)
tin free!
Br
Cl3SnNiCl2, 2,2'-bipyridine
KOtBu, tBuOH, iBuOH, 60°C
72%
+
Cross Coupling Reactions
Stille Coupling ! ! !
• related processes
- Stille reaction with acid chlorides
- Carbonylative cross coupling
R X R' SnBu3 R C R'
OPd0 catCO, ligand
Cl
O
H2N
Bu3Sn O
O
BnPdCl(PPh3)2CuI, THF, 50°C
93%H2N
O
O
O
Cross Coupling Reactions
Stille Coupling ! ! !
• applications – carbonylative coupling
N N
NI OMe
Me
OtBu
TIPSO
Bu3Sn+
OtBu
TIPSO
CO
N
N
N
OMe
Me
Pd2(dba)3, AsPh3CO, LiCl, NMP, Δ
80%
N
C
N
O
H
O Hstrychnime
O
O
OTfSnBu3
Pd(MeCN)2Cl2DMF, CO, LiCl; 13h
53%
O
O
CO
jatrophone
Cross Coupling Reactions
Stille Coupling ! ! !
• stannane prep
1-substituted vinyl stannanes
cis vinyl stannanes
Cross Coupling Reactions
Suzuki Coupling ! ! !
• Akira Suzuki: Nobel Prize 2010
For palladium-catalyzed cross couplings in organic synthesis. Shared Prize with Heck and Negishi
RBY2
BY2R
+
+
XR'
R'X
R
R
R'
R'Pd
Pd
Cross Coupling Reactions
Suzuki Coupling ! ! !
• general principles
- Pd catalyzed reaction of aryl or vinyl halide with an organoborane
X = I > OTf > Br >> Cl R’ = H, aryl, alkenyl, alkynyl, allyl, alkyl
Pd cat: Pd(PPh3)4, PdCl2(dppf)2, Pd2(dba)3, Pd(OAc)2, etc. base: Na2CO3, Ba(OH)2, K3PO4, Cs2CO3, KF, RONa, TlOEt, etc. solvent: MeCN, THF, EtOAc, benzene, DMF
Pd(0) cat+ R' BR2
X R'
base, ligand
R B R B
R BF3K
OH
OH
OiPr
OiPr
OBO
RO
BO
R
BR
Cross Coupling Reactions
Suzuki Coupling ! ! !
• general principles
- Pd catalyzed reaction of aryl or vinyl halide with an organoborane
Pd(PPh3)4NaOEt, EtOH, Δ
Ph Br Ph B(OR)2+ Ph Ph
B(OH)2 CHOBr+Pd(OAc)2, PPh3
Na2CO3, iPrOH/H2O, Δ CHO
Ph Br 69-BBN 6Ph+
PdCl2(dppf)NaOH, THF, Δ
85%
Cross Coupling Reactions
Suzuki Coupling ! ! !
• mechanism
Ln Pd0 Ln PdII
X
Ln PdII
OEtLn PdII
R
R
X
oxidativeaddition
transmetallation
reductiveelimination
R BR'2 R BR'2EtONa
EtONa
NaX
metathesis
L
OEtEtO BR'2
OEtL +
Cross Coupling Reactions
Suzuki Coupling ! ! !
• mechanism
- during oxidative addition
- during reductive elimination
isomerization
!
!
Cross Coupling Reactions
Suzuki Coupling ! ! !
• modifications
base temp time yield rel rate
KOH 50°C 30 min 87% 1
TlOH rt <30 sec 92% >60
Kishi J. Am. Chem. Soc. 1987, 109, 4756.
OTBSO
TBSOTBSO
OMe
OH
IH
OTBSO
TBSO
OHTBSO
OMe
H
OTBS
TBSO OTBSOTBS
Pd(PPh3)4base+ OTBS
TBSO OTBSOTBS
(HO)2B
Cross Coupling Reactions
Suzuki Coupling ! ! !
• modifications
Roush Org. Lett. 2000, 2, 2691.
TlX source reagent age yield TlOH (10% stock soln) 1 month 71%
TlOH (10% stock soln)* 5 months 50%
TlOH (fresh, from solid)* 12 months 52%
TlOEt --- 83%
* precipitate formed over time; removed by filtration
OTBS
I
TBSO
OOO
(HO)2B OH
OTBS
OTBS
TBSO
OOO
OH
OTBS
Pd(PPh3)4, TlX, THF, H2O
Cross Coupling Reactions
Suzuki Coupling ! ! !
• examples
BNH
OHI O
O
O+
Pd(OAc)2, TPPTSiPrNEt2, MeCN/H2O
OOH
myxalamide A
44% (2 steps)
Heathcock J. Org. Chem. 1999, 64, 23.
Cross Coupling Reactions
Suzuki Coupling ! ! !
• examples
OH O
OBn
OMOM
Br
OH
O
O
OBn
OMOM
BrBF3K
O
OOH OH
O
OOH OMOM
BnOHN
O NOMe
, BH3•DMS
Pd(PPh3)4, Cs2CO3THF/H2O, Δ, 20h
then H2Oi.
ii. KHF2
oximidine II
99%
42%
Molander J. Am. Chem. Soc. 2004, 126, 10313.
Cross Coupling Reactions
B-Alkyl Suzuki Coupling ! ! !
• sp2-sp3 coupling
O
IO OO
9-BBN; TlOEtPdCl2(dppf), AsPh3
THF, H2O
48%
O
O OO
CN9-BBN
CNR2B
O
Br
O
PdCl2(dppf), K2CO3DMF, THF, 50°C CN
81%
Cross Coupling Reactions
B-Alkyl Suzuki Coupling ! ! !
• examples
I
PMBO OTES
tBuLi (2 equiv), then
B OMeB
MeO
PMBO OTES
O O
PMP
ORI
OMOM
OR'
R = TBS; R' = MOM
K3PO4; A, DMF;PdCl2(dppf) O O
PMP
OR
OMOM
OR'
R = TBS; R' = MOM; R" = PMB
OR" OTES
A
O
OH
OH OH O
HO
O NH2
O
discodermolide
40%
Marshall J. Org. Chem. 1998, 63, 7885.
Cross Coupling Reactions
Suzuki Coupling ! ! !
• boronic ester prep
aryl boronic esters
trans vinyl organoborane derivatives
Cross Coupling Reactions
Suzuki Coupling ! ! !
• boronic ester prep
substituted vinyl boronic esters
cis vinyl boronic esters
Cross Coupling Reactions
Nozaki-Hiyama-Kishi (NHK) Reaction ! ! !
• general properties
R X2 CrCl2 R CrClX R' R"
R' R"
O
R OH
(CrII) (CrIII)
X = Cl, Br, I, OTf R = vinyl, aryl, alkynyl, allyl, propargyl R’, R” = H, aryl, alkenyl, alkyl solvent: DMF, DMSO, THF
O
CrCl3: LiAlH4 (2:1)Br
HO
78%
CHO
CrCl2, DMF
I
100%
OH
Cross Coupling Reactions
Nozaki-Hiyama-Kishi (NHK) Reaction ! ! !
• reaction features
- both inter- and intramolecular processes known - aldehydes react faster than ketones (selectivity if both FG present) - organochromium reagents show low basicity
CHO
OBr
CrCl2/NiCl2, THF
O
OH66%
OI
OMeMOMOH
O
CHOPMBOCrCl2/NiCl2DMSO
92%
PMBO
PMBO
OO
OMOM
OMe
H
Cross Coupling Reactions
Nozaki-Hiyama-Kishi (NHK) Reaction ! ! !
• reaction features
- allylic halides react to give SN2’ type products
- addition of crotyl chromium gives anti product, regardles of stereochem of starting crotyl halide
OBr
CrCl2/NiCl2
HO
BrPhCHO
CrCl2/NiCl2 BrPhCHO
CrCl2/NiCl2Ph
OH
Cross Coupling Reactions
Nozaki-Hiyama-Kishi (NHK) Reaction ! ! !
• reaction features
- favors Felkin product even with adjacent heteroatom
- variations catalytic in chromium are known
I
O
OO
O
OBnBnO OBn
OMeOHC
BnO O
OO
BnO
OHO
OBnBnO OBn
OMeCrCl2/NiCl2
82%
*
* dr = 5:1
OTf
O
OO
HCrCl2 (15mol%), NiCl2 (cat)
Mn (1.7 equiv), TMSCl (2.4 equiv)O
OOH
+
80%
Cross Coupling Reactions
Nozaki-Hiyama-Kishi (NHK) Reaction ! ! !
• mechanism
oxidativeaddition
transmetallation
reductiveelimination
CrIIINiII
NiIIX
X
CrIII 2 CrIII
2 CrII
Ni0
R R'OH R R'
O
Cross Coupling Reactions
Nozaki-Hiyama-Kishi (NHK) Reaction ! ! !
• examples
I
O
TBSOTBSO
O CHO
CrCl2/NiCl2
O
OH
O
TBSOTBSO
49%
O
O
OCHO
BrOTIPSO
Me
H
HMe
Me
CrCl3, LiAlH4
81%
O
O
O
OTIPSO
Me
H
HMe
Me
HO Me
O
OH
OO
CHO
MeO2CH
H
O
OH
OO
MeO2CH
HTMS
OH
Br TMS
CrCl2, NiCl2
81%
dr = 10:1
*
*
Cross Coupling Reactions
Negishi Coupling ! ! !
• Ei-ichi Negishi: Nobel Prize 2010
For palladium-catalyzed cross couplings in organic synthesis. Shared Prize with Heck and Suzuki
R ZnCl + XR' R
R'Pd
Cross Coupling Reactions
Negishi Coupling ! ! !
• general principles
- Pd (or Ni) catalyzed reaction of aryl or vinyl halide with an organozinc reagent
X = Cl, Br, I, OTf, OAc R = aryl, vinyl, allyl, benzyl, 1° alkyl Pd cat: Pd(PPh3)4, Pd2(dba)3, Cl2Pd(PPh3)2, etc.
Pd(0) cat+ R ZnXX R
Cross Coupling Reactions
Negishi Coupling ! ! !
• mechanism
oxidativeaddition
transmetallation
reductiveelimination
LnPd0X
PdL
LX
II
R ZnXZnX2
PdL
LR
II
R
Cross Coupling Reactions
Negishi Coupling ! ! !
• examples
O Me
O
TfO
Me
Me2ZnPd(PPh3)4
84%
O Me
O
Me
Me
OTHP
I tBuLi (2 equiv);then ZnCl2
OTHP
ClZn I
OSEM
OTBDPS
Pd(PPh3)4OTHP
SEMO OTBDPS
84%