Synthetic Applications of Fluorous Molecules Stewart Hart Michigan State University October 20, 2004 “It is ironic that organic synthesis and separation science are separate disciplines because synthesis and separation are inseparable.” Dennis Curran
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Synthetic Applications of Fluorous Molecules
Stewart Hart
Michigan State University
October 20, 2004
“It is ironic that organic synthesis and separation science are separate disciplines because synthesis and separation are inseparable.”
Dennis Curran
Fluorous Seminar Outline• Section I: General Fluorous Information
– What is a fluorous compound (history, properties)?– Why fluorous molecules are immiscible with aqueous
solution?– Why fluorous molecules are immiscible with organic
Yao, Q.; Zhang, Y. J. Am. Chem. Soc. 2004, 126, 74
E EE = CO2Et
E E
NTs
NTs
S SO
O
OO
OBz OBz
NTs N
Ts
SO
OS
Ph
Ph OO
Batch A 1 h >98 [2], 98 [2], 95, 93, 92
Batch B 3 h >98 (94)
Batch B 1.5 h >98 (90)
Batch B 1.5 h >98 (94)
Batch B 1.5 h >98 (96)
Batch B 3 h >98 (91)
Cat. Batch Time % Conv.(%Yield)Substrate / Product Mol % of Cat.
2
2
2
2
2
5
Further Activity of Fluorous Ru-Catalyst
Yao, Q.; Zhang, Y. J. Am. Chem. Soc. 2004, 126, 74
O OPh Ph
OO
Ph
Ph
Ph
O
O
O
O
SOOPh
SPh
OO
NTs
NTs
SOO S OO
Batch C 2 h >98 (95)
Batch C 5 h 89 (85)
Batch C 5 h 80 (74)
Batch D
6 h 43 (39)
Batch E36 h 51 (50)
Cat. Batch Time % Conv.(%Yield)Substrate / Product
16 h 94 (93)
2.5 h 96 (96)
Mol % of Cat.
2
2
5
2
5
5
2
Fluorous Metathesis Advantages
• Easily separated by liquid extraction• Extremely reusable• Using one batch of catalyst for different
substrates is effective• Tetrasubstituted products are accessible
with small condition modifications
Mizoroki-Heck Reaction
Pd(0) R X
R Pd(II) X
R Pd(II) X
Z
Pd
Z
HR
H
X
H Pd X
ZR
Z
OxidativeAddition
CoordinationInsertion(cis)
cis-β-Elimination
Li, J. J. Name Reactions 2nd Ed.; Springer: Ann Arbor, MI, 2003; p 179
R XPd(0)
ZR
Z
X = I, Br, OTf, etc.Z = H, R, Ar, Cn, CO2R, OR, OAc, NHAc, etc.
A Fluorous Mizoroki-Heck
ABeforeHeating
BWhile
Heating
CAfter
Reaction
N N
PdPh3P Cl
Cl
C10F21
Fluorous Pd Catalyst
Ryu, I.; Fukuyama, T.; Arai, M.; Matsubara, H. J. Org. Chem. ASAP, DOI jo04928
I
COOH
COOHFluorous Pd Catalyst
NPr3, F-626120 οC, 2 h
+
Reusability of Fluorous Pd Catalyst
Run 1 Run 2 Run 3 Run 4 Run 5 Run 6
Product 88% 85% 83% 84% 78% 83%
F-626 98% 97% 93% 96% 95% 94%
Ryu, I.; Fukuyama, T.; Arai, M.; Matsubara, H. J. Org. Chem. ASAP, DOI jo04928
I
COOH
COOHFluorous Pd Catalyst
NPr3, F-626120 οC, 2 h
+
Filtration
F-626 solution containing fluorous Pd catalyst
Reuse
C6F13 OF-626
Scope of Fluorous Mizoroki-Heck
Ryu, I.; Fukuyama, T.; Arai, M.; Matsubara, H. J. Org. Chem. ASAP, DOI jo04928
I
MeO MeO
COOH
ICOOH
I
MeO
COOH
MeO
COOH
COOH
COOH
I
MeO
COOH
MeOCOOH
Yield (%) F-626 (%)
98 96
56E/Z = 93:7 97
47E/Z =94/6 98
74 95
ProductHalide Olefin
The Ideal Transesterification
• Quantitative yields• Atom economical (1:1 ester to alcohol ratio)• Mild, recyclable catalyst• Easy removal of co-product alcohol• Large variety of substrates• Non-equilibrium process
RCOOR' + R''OH RCOOR''+ R'OH
Distannoxane Catalyst in Transesterification
Sn
Cl Sn
O
O
Sn
Sn
Cl
Cl
ClR
R
R
R
R
R
R
R
Sn
O Sn
O
O
Sn
Sn
O
Cl
ClR
R
R
R
R
R
R
RR1
R1
R1OH
O
Sn
Sn
O
Cl
R
R
R
R
R1
O
R2
OR3R1OH
R2COOR1R3OH R2COOR3
Solubility of the Distannoxane Catalyst
Distannoxane
Organic Shell
A "reverse micelle"
Sn
Cl Sn
O
O
Sn
Sn
Cl
Cl
ClBu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Nonpolar Soluble Distannoxane
How Ideal is the Distannoxane Transesterification
• Requires 2 equivalents of alcohol• Sensitive to steric bulk at the α-carbon of the
ester• Near quantitative yields for non-sterically
hindered substrates• Co-product alcohol removed by biphasic
system (benzene and small alcohols are partially miscible)
• Mild conditions, but not recyclable
Reasons for the Steric Problems of the Distannoxane Catalyst