Download Solid-Supported Reagents for Organic Synthesis Advantages and

Solid-Supported Reagents for Organic Synthesis
Catharine Larsen
MacMillan Group Meeting
December 6, 2001
· A recent review on functionalized polymers with an emphasis on chiral catalysts: Synthesis 1997,
1217-1239.
· Main text references:
Solid Supports and Catalysts in Organic Synthesis; Smith, K., Ed.; Ellis Horwood and
PTR Prentice Hall: New York, 1992.
Polymer-Supported Reactions in Organic Synthesis; Hodge, P. and Sherrington,
D.C., Ed.; John Wiley & Sons: New York, 1980.
Solid-Phase Organic Synthesis; Burgess, K., Ed.; Wiley-Interscience: New York,
2000.
Solid-Phase Synthesis: a Practical Guide; Kates, S. A. and Albericio, F.; Marcel
Dekker, Inc.: New York, 2000.
Advantages and Disavantages of Solid-Support Reagents
! Advantages
· Solid-supported reagents are easily removed from reactions by filtration.
· Excess reagents can be used to drive reactions to completion without introducing difficulties in purification.
· Recycling of recovered reagents is economical, enivironmentally-sound, and efficient.
· Ease of handling is especially important when dealing with expensive or time-intensive catalysts which can
be incorporated into flow reactors and automated processes.
· Finely tune chemical properties by altering choice of support and its preparation
· Toxic, explosive, and noxious reagents are often more safely handled when contained on solid support.
· Reagents on solid-support react differently, mostly more selectively, than their unbound counterparts.
! Disadvantages
· Some reagents may not interact well with solid support.
· Ability to recycle reagents on solid support is not assured.
· Reactions may run more slowly due to diffusional constraints.
· Polymeric support materials can be very expensive to prepare.
· Stability of the support material can be poor under harsher reaction conditions.
· Side reactions with the polymer support itself may occur.
Synthesis 1997, 1217-1239.
Solid Supports and Catalysts in Organic Synthesis; Smith, K., Ed.; Ellis Horwood and PTR Prentice Hall: New York, 1992.
Inorganic Supports: Alumina
! Alumina — Al2O3·(H2O)n, n=0-3
· thermally-stable, high-surface-area forms lead to use as acid or base catalysis or as supports for other catalytic
materials (e.g. metals, oxides, sulphides, etc.)
· composition depends on precursors, temperature, and mode of heating, thermolysis combines hydroxyls to
generate water which is driven from the solids
· formed from Al(OH)3 [Al2O3·(H2O)3] and AlO(OH) [Al2O3·(H2O)] to give 3 surface species: OH-, O-2, and Al+3
· dehydrated and hydrated forms
· used as a drying agent, catalyst, catalyst support, and for column choromatography among other applications
OH-
OH-
OH- OH-
Al3+
Al3+
Al3+
O2-2H2O
Al3+
Al3+
O2Al3+
Al3+
Al3+
Tetrahedron 1997, 53, 7999-8065.
Solid Supports and Catalysts in Organic Synthesis; Smith, K., Ed.; Ellis Horwood and PTR Prentice Hall: New York, 1992.
Some Common Reagents on Alumina
· CuBr2/Al2O3: alternative to traditional halolactonization
Me
O
O
Me
CuBr2/Al2O3
HO
Me
CO2H
CHCl3, 3h, 65 °C
HO
Br
Me
O
O
97%
Tetrahedron 1997, 53, 799-8065.
· KF/neutral-Al2O3 as a heterogeneous base for Pd-catalyzed allylic alkylations of carbon acids with 5 < pKa < 13
and for Michael reactions of nitroalkanes
(note: compares favorably with TEA and DBU but does not cause decarboxylation as DBU does)
O
NO2
Ph
Ph
Me
CO2Me
KF/neutral-Al2O3
80 °C, 15 h
O
NO2
Ph
CO2Me
91% yield
Me
Me
O
Ph
Ph
SO2Ph
KF/neutral-Al2O3
80 °C, 15 h
Me
SO2Ph
91% yield
Me
Me
O
Ph
Solid Supports and Catalysts in Organic Synthesis; Smith, K., Ed.; Ellis Horwood and PTR Prentice Hall: New York, 1992.
More Common Reagents on Alumina
· NaBH4/Al2O3 for selective reductions
· Al2O3: Diels-Alder; sigmatropic rearrangements; epoxide ring-opening with amines, allyl alcohols etc.
· KF/Al2O3 for mild (compared to NaNH2, for example) N-alkylation of carboxamides, lactams, and other N-heterocycles with
alkyl halides or dialkyl sulfates; appears to be catalytic for N-alkylation of 2° amides, N,N-dialkylation of 1° amides
· KOH/Al2O3 for selective monoalkylation of 1° amides
O
Me
NH2
Ph
O
Br
Me
KOH/Al2O3
O
nBuBr
O
NH2
71% yield (96.8% monoalkylation)
N
H
60% yield (99.5% monoalkylation)
Ph
KOH/Al2O3
NHBu
Solid Supports and Catalysts in Organic Synthesis; Smith, K., Ed.; Ellis Horwood and PTR Prentice Hall: New York, 1992.
Selective Esterification on Alumina
· Chromatographic alumina and EtOAc for the transesterification of 1° ROH of base-sensitive compounds
· Monoesters of dicarboxylic acids using neutral alumina and dimethyl sulfate or diazomethane
CO2H
CO2Me
CH2N2
+ N2
DMF, 30°C
O
O
O
Al2O3
O
Al2O3
Selective Monomethyl Esterification of Dicarboxylic
Acids using Alumina and Dimethyl Sulfate
% yield of
mono-Me
% yield of
di-Me
C6H4-1,4-(CO2H)2
72
12
C6H4-1,3-(CO2H)2
63
19
80
8
93
7
99
0
97
3
Substrate
C6H4-1,2-(CO2H)2
HO2C(CH2)4CO2H
HO2C(CH2)6CO2H
HO2C(CH2)10CO2H
Solid Supports and Catalysts in Organic Synthesis; Smith, K., Ed.; Ellis Horwood and PTR Prentice Hall: New York, 1992.
Nitrogen Heterocycles from Alumina Reagents
· AlPO4-Al2O3: epoxide ring-opening with alcohols, carboxylic acids, and MeCN to give a !-acetamido moiety
Me
O
Me
CO2Et
+
MeCN
AlPO4-Al2O3
N
Me
Me
H3COCHN
hydrolysis
O
Me
CO2Et
Me
Me
CO2Et
OH
85% overall
Solid Supports and Catalysts in Organic Synthesis; Smith, K., Ed.; Ellis Horwood and PTR Prentice Hall: New York, 1992.
· Al2O3: formation of enamines, pyrroles, and pyrazoles
Ph
O
N
O
O
NH2CH2CN
N
Me
Me
Me
Al2O3
Me
Me
NH2CH2CN
NHCH2CN
Al2O3
90%
95%
CH2Ph
O
Me
Me
O
NH2CH2Ph
N
Me
Me
Al2O3
99%
Tetrahedron 1997, 53, 799-8065.
Selective Reductions on Alumina
! NaBH4/Al2O3 is more selective and less acidic than its non-alumina counterparts.
· NaBH4, NaBH4·AlCl3, DIBAL, and NaBH3CN/acid all reduced aldehyde and the ",!-double bond, but the
chromone was inert to homogenous Meerwein-Pondorf-Verley (MPV) conditions using Al(Oi-Pr)3.
CHO
OH
O
O
O
i-PrOH/Al2O3
OMe
CCl4, 25 °C
2h
O
OMe
O
OMe
O
OMe
J. Org. Chem. 1977, 42, 1202-1208.
· Under normal NaBH4 conditions, the enol acetate undergoes rapid hydrolysis.
Me O
Me
Me OH
Me
NaBH4/Al2O3
AcO
AcO
Solid Supports and Catalysts in Organic Synthesis; Smith, K., Ed.; Ellis Horwood and PTR Prentice Hall: New York, 1992.
! Pyridine-borane/Al2O3 selectively reduces aldehydes in the presence of ketones.
O
O
H
Me
+
OH
Me
Pyridine-borane/Al2O3
1/3 eq.
OH
H
+
Me
Me
>95%
J. Org. Chem. 1977, 42, 1202-1208.
<2%
Oxidants on Silica
! Magnesium monoperoxyphthalate on wet SiO2 oxidizes sulfides to sulfoxides without !-hydroxylating ketones.
· First examples of oxidation of sulfides with a carbonyl group with MMPP in aqueous media without Baeyer-Villiger reaction
Me
Me
Me 60 min
S
O
Me
Me
Me
S
O
90 min
PhS
PhS
HOCH2PhSMe
O
45 min
HOCH2PhSMe
89%
94%
92%
all yields in paper 89-100%
· MMPP normally extremely insoluble, limiting its utility
· Better than most sulfide oxidation reagents, which are expensive, toxic, or rare and difficult to prepare
Synthesis 1997, 764-768.
! Oxidative coupling of phenols and phenol ethers using FeCl3/SiO2.
· FeCl3/SiO2 acts as an electron-transfer oxidant for intermolecular and intramolecular couplings.
OMe
EtO
Me
OMe
OMe
HO
formed by electron-transfer oxidation and
C-C coupling papa to the methoxy group
followed by rearrangement
FeCl3/SiO2
O
OMe
EtO
Me
J. Org. Chem. 1980, 749-751.
FeIII-Catalyzed Epoxide Ring Opening on Silica
! FeCl3/SiO2 for ring opening of epoxides:
· Iron is abundant, cheap, and non-toxic.
FeCl3/SiO2, cat.
r.t. or heat
O
Nu
R
Nu: Cl-, Br-, NO3-, MeOH,
EtOH, n-PrOH, i-PrOH,
t-BuOH, H2O, AcOH
R
HO
R
OH
O
R = Ph
Nu
R = CH2Cl, CH2OCH2CH=CH2,
CH2Oi-Pr, OPh
O
O
yields: 86-95% for ROH; 78-96% for Cl-, 78-92% for Br-,
51-54% for NO3-, 79-89% for H2O, 78-91% for AcOH
· If the halide or nitrate epoxide opening is attempted with BF·OEt2, SnCl4, or anhydrous FeCl3, which have been
reported for the alcoholysis of epoxides, there is no halide or nitrate addition.
O
H
Ph
H
H
FeCl3/SiO2
H
Ph
MeOH
HOMe
OH
H
H
Lewis Acid
FeCl3/SiO2
SnCl4
TiCl4
AlCl3
ZnCl2
BF·OEt2
Synthesis 1996, 1473-1476.
Temp. (°C) Yield (%)
0
-30
-30
0
-20
-30
94
88
80
45
0
92
ee (%)
93
95
90
58
75
Inorganic Supports: Clays
! Clay Minerals
· Occurence of high surface areaclay minerals is ubiquitous.
· Comprise a large family of fine-grained crystalline sheet silicates
· Sorptive and ion exchange properties due to composition and structure
! Functions in Solid Catalysis
· Catalytically active, generally as solid acids
· Bifunctional or 'inert' supports; e.g. for highly dispersed metals, metal complexes, enzymes, etc.
· Fillers to give solid catalysts required physical properties; e.g. attrition resistance, density, specific heat capacity
! Montmorillonite
· Most versatile intermediate charge clay (high layer or low layer charge minerals do not swell much)
· High cation exchange capacity and good swelling properties allow a wide variety of catalytically active forms to be
prepared: acidic cations, metal complexes, photocatalytically active cations, etc.
· Ideal formula: M+x[Si8tet(M3+4-xM2+x)octO20(OH)4]x· Interlayer
species: Na+, K+, Ca2+, Mg2+ used to fine-tune catalyst selectivity; exchangeable cations: H+, Al3+, Cr3+,
Fe3+
Solid Supports and Catalysts in Organic Synthesis; Smith, K., Ed.; Ellis Horwood and PTR Prentice Hall: New York, 1992.
Selective Bromination Using Solid-Support Reagents
! NBS on K-10 Montmorillonite
O
O
Br
NBS
Me
Me
NHR
K-10/MeOH
Me
Me
NHR
yields = 60-74%
R = H, Me, i-Pr, Ph, Bn, allyl
· Conventional methods (NBS/MeOH, Br2/CCl4 or BrCN) give a mix of !-bromination, allylic di-bromination, and salts
· Isolation is simplified because the succinimide formed during the reaction is adsorbed onto the support
· Decreased reaction time of 5 h
Synthesis 2001, 1935-1937.
! Br2 on Zeolite
NH2
Me
Br2 pre-adsorbed
on CaA zeolite
0 °C, CCl4
lutidine
NH2
Me
Br
94%
· Selectivity is attributed to aniline being to large to enter the pore cavities of CaA and the controlled release of
bromine from the pore system
· Irreversible damage to wet zeolites by wet hydrogen halides limits zeolite lifetime
Solid Supports and Catalysts in Organic Synthesis; Smith, K., Ed.; Ellis Horwood and PTR Prentice Hall: New York, 1992.
Effect of Support Material Chosen for Permanganate
! On acidic media such as alumina, KMnO4 affords cleavage of aryl-substituted olefins to aldehydes.
O
KMnO4, alumina
C
H
X
C Y
H
X
CH2Cl2
· Other good supports : Amberlite and Rexyn 101 (H)
CH
· Among poor supports: molecular sieves, CuSO4·5H2O,
X = MeO, OH, Br, Cl, CF3, CO2Me, H, Me
· Substrate-dependent : Amberlite (sodium form),
Florisil, and SiO2
Y = H, COMe, CO2H, Me
Synthesis 2001, 1645-1648.
! On neutral media such as CuSO4·5H2O, KMnO4 converts olefins to !"hydroxy ketones and !"diketones.
Me
O
0.5 h
Me
O
OH
59% yield
2h
79% yield
Me
Me
6h
O
O
Me
OH
(CH2)10
58% yield
O
(CH2)10
O
Me
· Epoxidation (steroidal substrate) and cleavage (bis-aryl-substituted) not as common as with free KMnO4, but still present
J. Org. Chem. 1989, 54, 5182-5184.
! On SiO2, KMnO4 easily oxidatively cleaves olefins with 1-3 substituents, including electron-withdrawing groups.
OAc
OAc
Me
KMnO4/SiO2
Me
Me
Me CO2H
Me
CO2H
· Conveniently performed by elution of a benzene
solution through a short column of MnO4/SiO2
· Traditional methods failed in this example: KMnO4/acid
or base; KMnO4/MgSO4,KMnO4/NaIO4.
O
Me
O
Solid Supports and Catalysts in Organic Synthesis; Smith, K., Ed.; Ellis Horwood and PTR Prentice Hall: New York, 1992.
Organic Supports: Polymeric Resins
! Functionalized Polymers
· In addition to the construction of new compounds on polymer supports, functionalized polymers have long
been used as stoichiometric reagents, catalysts, and reaction purifiers.1
· Reactions are easily monitored by TLC.
· Cross-linked polymeric species can be recycled many times without appreciable loss of reactivity.
! Reagents
· Highly-enantioselective insoluble polymer bound (IPB) catalysts: Sharpless dihydroxylation , oxazaborolidine
reduction, oxazaborolidine Diels-Alder, N-butylnorephedrine for diethylzinc additions to aldehydes,2 polybinapthols
for diethylzinc additions to aldehydes,3 dihydroxylation using Cinchona alkaloid ligands,4
· Not nearly as many soluble polymer bound (SPB) catalysts: Janda's (PHQD)2PHAL for catalytic asymmetric
dihydroxylations2
· Polymer-supported chiral auxiliaries: Leznoff's primary amine for asymmetric synthesis of 2-alkylcyclohexanones,
Evans' oxazolidinone on Merrifield resin5
· Oxidants: poly(vinylpyridinium chlorochromate), poly(vinylpyridinium dichromate), CrIII and CeIV on resin
1. Solid Supports and Catalysts in Organic Synthesis; Smith, K., Ed.; Ellis Horwood and PTR Prentice Hall: New York, 1992.
2. Synthesis 1997, 1217-1239.
3. J. Am. Chem. Soc. 1997, 119, 4313-4314.
4. J. Am. Chem. Soc. 1997, 119, 6929-6930.
5. Tetrahedron Let. 1996, 36, 8023.
Synthesis of Polymeric Supports
! In 1963, Merrifield unveiled the original cross-linked polystyrene-divinylbenzene polymer.
· Merrifield resin is an addition polymer prepared by free radical initiated suspension copolymerization of styrene and 1%
divinylbenzene as cross-linkage. It is sold commercially in Aldrich for $4 / g .
n
Procedure: The comonomer mixture is suspended in a excess of an immiscible solvent which acts as an efficient heat
transfer agent. Hydrophobic monomers like styrene are suspended in water with vigorous stirring and with suspension
stabilizers such as polyvinylalcohol and calcium phosphate. During polymerization, spherical liquid monomer/comonomer
droplets are converted into spherical solid droplets, often referred to as 'beads' or 'pearls'. The beads are collected by
filtration, washed free of stabilizer and other contaminants, and dried for use.
Polymer-Supported Reactions in Organic Synthesis; Hodge, P. and Sherrington, D.C., Ed.; John Wiley & Sons: New York, 1980.
! Nafion 511
! Nafion NR-50—Sc
(F2C—F2C)m
F F2
C C
(F2C—F2C)m
n
O
F F2
C C
n
O
CF2
CF2
F3C C
F
OCF2CF2
F3C C
F
SO3K
x
OCF2CF2
SO3Sc
x
Synthesis 1997, 1217-1239
Polymer-Supported Scandium
· Few examples of polymer-supported Lewis acids are known
· Sc(OTf)3 can catalyze reactions in both organic solvents and water
· Compounds that would not undergo nucleophilic attack under general Lewis acid conditions do react with the
nucleophile when Sc—Nafion is used
Sc—Nafion-Catalyzed Allylation Reactions
O
R1
H
Sc—Nafion
(allyl)4Sn
OH
R1
r.t.
Sc—Nafion reagent preparation:
3 eq. Nafion beads (NR-50, $8 / g) were
treated with ScCl3·6H2O in MeCN under reflux.
After 40 h, 96% of ScCl3·6H2O was
consumed, and the polymer contained 1.3%
Sc.
N
R1
Ph CH2CH2Ph CH=CHPh
yield(%) 91
solvent A, B
O
R2
R2
Me
83
A,B
98
B
Sc—Nafion
(allyl)4Sn
Me
78
A
PhCHO
+ Sn
run
yield(%)
57
87
95
84
solvent
A, B
A,B
B
A
1
2
3
4
yield
75
93
84
84
J. Org. Chem. 1996, 61, 2256-2257.
OH
Nafion-Sc
4
R2
60 °C
B: MeCN
Nafion—Sc-Catalyzed Allylation Using a Flow System
OH
Ph CH2CH2Ph CH=CHPh CO2Me
A: H2O/THF (1:9)
Sc—Nafion recovery:
Filtered and washed with suitable solvent.
Activity is comparable to that of fresh catalyst.
MeCN, r.t.
Ph
Procedure:
Nafion—Sc (2 g) and sea sand (2 g, 15-20
mesh were combined, and the mixture was
packed in a 6 mm glass tube. A carbonyl
compound (0.5 mmol) and tetraallyltin (0.5)
mmol) were dissolved in MeCN (4 mL) and
passed through the column using a peristaltic
pump.
Oxidants on Polymeric Resins
! Poly(vinylpyridinium dichromate) (PVPDC) for the non-acidic oxidation of alcohols
· PVPDC used in 1.1 eq. to oxidize 1° and 2° aliphatic, benzylic, and allylic alcohols to the corresponding aldehyde
or ketone without overoxidation even at longer reaction times (1.7 was used for faster reaction times).
OH
O
PVPDC
24h, C6H12
94% (on 113 g scale)
· Poly(vinylpyridine) resin is treated with a slight excess of CrO3 in water at r.t. and washed with water before use.
PVPDC may also be dried to a yellow-brown powder for prolonged storage.
J. Org. Chem, 1981, 1728-1730.
! CrIII or CeIV impregnated perfluorinated resin-sulfonic acid catalyst for alcohol oxidation
· t-BuOOH oxidizes alcohols to the corresponding carbonyl compounds effectively with CrIII or CeIV impregnated
Nafion 511 (Nafion SAC-13, 10-20% fluorosulfonic acid with Nafion polymer on amorphous silica, $8/g).
· Cr/NAFK and Ce/NAFK catalysts are reusable after simple washing with EtOAc.
· Cr/NAFK gives 81-98% yields; Ce/NAFK gives 71-98% yields
· Oxidations are selective for 2° alcohols; 1° alcohols give complex mixtures of products
· NaBrO3 in AcOH can also be used as a co-oxidant.
NaBrO3
HO
CH2OH
O
CH2OH
Ce/NAFK
Tetrahedron Let., 1984, 3317-3320.
Synthesis of Polystyrene-Bound Chiral Co(Salen) Complex
H
H
O
HO
O
H
OH
H
H2N
t-Bu
ratio:
t-Bu
HO
NH2
t-Bu
1
:
2
:
3
1) CH2Cl2, 24h
t-Bu
expected
stat. ratio:
t-Bu
9
t-Bu
HO
:
HO
6
:
OH
1
O
2)
O
O
NO2
3) Co(OAc)2, MeOH/PhMe
4) Rinse with 9:1 PhMe in air
· Resin capture synthesis of Co(Salen)
complex showed no apparent reactivity or
selectivity differences from resin-bound
catalyst synthesized from purified ligand
H
O
H
N
N
Co
O
O
O
O
OAc
t-Bu
t-Bu
(R,R)-1
J. Am. Chem. Soc. 1999, 121, 4147-4154.
t-Bu