synthesis of 1,1-disubstituted olefins via catalytic ...ccc.chem.pitt.edu/wipf/current...
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Anthony Sabarre and Jennifer Love*University of British Columbia
Synthesis of 1,1-Disubstituted Olefinsvia Catalytic Alkyne Hydrothiolation/
Kumada Cross Coupling
Org. Lett., ASAP
Amol Kulkarni @ Wipf Group Page 1 of 12 9/7/2008
1,1-Disubstituted Alkenes
J. Am. Chem. Soc. 1997,119, 12425-12431.
Org. Lett. 2008,10, 1711-1714.
J. Am. Chem. Soc. 2000,122, 11027-11028.
Antitumor agent CNS stimulant Microtubulestabilizer
Neurotoxin
J. Am. Chem. Soc. 1998,120, 7647-7648.
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Synthesis of 1,1-Disubstituted Alkenes
Wittig reaction
Tetrahedron Lett. 2008, 49, 2013
Julia Olefination
J. Am. Chem. Soc. 2000,122, 11027-11028.
J. Am. Chem. Soc. 1997,119, 12425-12431.
SN2 reaction
OPMB
TBSO
OHSO2Ph
Me
O
OTBSOPMB
TBSO
Me
O
OTBS
1. PhCOCl, Et3N, DMAP
2. Na(Hg), Na2HPO4, MeOH, -20 ˚C
5 6
MeO2C O MeO2CPPh3CH3Br, n-BuLi,
THF, 0 ˚C, 66 %3 4
I
H
TBDPSO
H
TBDPSO
Br
t-BuLi, CuI
-30 ˚C to 0 ˚C
97 %
dysidiolide
1 2
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Synthesis of 1,1-Disubstituted Alkenes Negishi Coupling
Tetrahedron 2006, 62,7521-7533.
Suzuki Coupling
Eur. J. Org. Chem. 2007, 3, 437-444.
ZnBr
+
Br
OAcNi(PPh3)4
THF, rt, 12 h
81 %
OAc
1 2 3
Alkyne Carbometallation/H+
OTIPSCp2ZrCl2, AlMe3
1,2-DCE, rt
then HCl
OTIPS
6 7
J. Am. Chem.Soc. 2006, 128, 15396-15398
MeO
HN
Br
O+ PhB(OH)2
Pd(PPh3)4, K2CO3
DMF, 48 h, 63 %MeO
HN
Ph
O
4 5
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Kumada CouplingRMgX + R'X
Ni(dppb)Cl2 or
Pd(PPh3)4
R-R' R’ = aryl, vinylR = aryl, vinyl, alkyl
+ RMgBr Ar-RNiLn
- BrMgSR1
ArSR1
Kumada Coupling using aryl sulfides
NiLn
ArLnNi SR1
Ar-SR1
BrMgSR1
ArLnNi R
RMgBr
Ar-R
• low functional group tolerance
The catalytic cycle
Takei et al.
Tetrahedron Lett. 1979, 20, 43-46.
PhS Ph
Z+ PhMgBr
NiCl2(PPh3)2
THF, reflux, 6 h
97 %
Ph Ph
Z
SMe + MgClMe
Ni(dppp)Cl2
benzene, reflux
97 %PhMe
Wenkert et al.
Chem. Commun. 1979, 637-638.
AB
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Alkyne Hydrothiolation Addition of aromatic thiols to terminal alkynes
RArSH
Pd(OAc)2 R
ArSJ. Am. Chem. Soc. 1992,114, 5902-5903.
55-86 %
• wide range of functional groups tolerated
Proposed catalytic cycle
A
B
C
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Addition of Aliphatic Thiols to Alkynes
A = rt; B = 0 ˚C to rt
Rh-pyrazolylborate
J. Am. Chem. Soc. 2005,127, 17614-17615.
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1,1-Disubstituted Vinyl Sulfides Sulfide partner: • efficient cross coupling• low mol. wt. to minimize waste
Use of n-PrSH: • excellent reactivity• mass comparable to Br-, typical leaving group
• Electron-rich aryl alkynes well-tolerated
• Electron-poor aryl alkynes: significantly reduced yields
• Aliphatic aldehydes well-tolerated
Sabarre and Love, Org. Lett., ASAP
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Kumada Cross Coupling
Sabarre and Love, Org. Lett., ASAP
Salient Features:
• moderate to good yield of the product
• competing grignard reagent homocoupling
• n-BuMgCl and vinylmagnesium bromide
did not give the desired product
• cross-coupling products from ethynyl
cyclohexene: potential Diels-Alder precursors
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One-Pot Hydrothiolation/Kumada Coupling
Sabarre and Love, Org. Lett., ASAP
(51)
(61)(43)(38)(60)
(55)(41)(37)(81)
(51)
• Yields comparable or superior compared to the two-step protocol
• Greatly improved efficiency in the cross-coupling reactions
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Conclusions
• Authors demonstrated Tp*Rh(PPh3)2 catalyzed hydrothiolation using n-PrSH with aliphatic and aryl alkynes.
• The resulting vinyl sulfides underwent Ni-catalyzed Kumada cross coupling with Grignard reagents; synthesis of 1,1- disubstituted alkenes.
• One-pot hydrothiolation/Kumada coupling protocol has been developed.
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Catalytic CycleMLn
R'LnM X
R'-X
BrMgX
R'LnM R
R-R'
RMgBr
Heck Reaction
J. Org. Chem. 1992, 57, 1481-1486.On-Bu +
OTfPd(OAc)2, Et3N
dppp, DMF
100 ˚C, 30 min
n-BuO
H+
O
1 2 3 (91 %)
Amol Kulkarni @ Wipf Group Page 12 of 12 9/7/2008