lanthanides in organic synthesis - princeton university - home
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HeH
Li Be B C N O F Ne
Na
K
Mg
Ca
Al Si SP Cl
Kr
Sn
Br
I
At
Xe
Rn
Fr
Rb Sr
Cs Ba
Ra
Ar
Sc
Y
Ti
Zr
Hf
V
Nb
Ta
Cr
Mo
W
Mn
Tc Ru
Re
Fe
Os
Co
Rh
Ir
Ni
Pd
Pt
Cu
Ag
Au
Zn
Cd
Hg
Ga
In
Tl
Ge
Pb
As
Sb
Bi
Se
Te
Po
La Ce Pr Nd Pm Sm Eu Gd Tb Dy Ho Er Tm Yb Lu
Ac Th Pa U Np Pu Am Cm Bk Cf Es Fm Md No Lr
Lanthanides in Organic SynthesisHeathcock / MacMillan Seminar
Feb. 22, 2000
Tristan Lambert
I. Properties of the lanthanidesII. Lanthanide metalsIII. Divalent lanthanidesIV. Trivalent lanthanidesV. Tetravalent lanthanidesVI. Enantioselective processes
Reviews: Molander Chem. Rev. 1992, 92, 29
Imamoto, Lanthanides in Organic Synthesis, 1994.
Oxidation States of the Lanthanides
Most stable oxidation state of the lanthanides is +3
For dipositive lanthanides Sm2+ (f6, nearly half-filled), Eu2+ (f7, half-filled), and
Yb2+ (f14, filled) are known with relative stability in H2O being
Ce4+ (f0) is the only tetrapositive lanthanide stable in water
La
Ce
Pr
Nd
Pm
Sm
Eu
Gd
Tb
Dy
Ho
Er
Tm
Yb
Lu
5d16s2
4f15d16s2
4f36s2
4f46s2
4f66s2
4f56s2
4f76s2
4f96s2
4f106s2
4f116s2
4f126s2
4f136s2
4f146s2
4f75d16s2
4f145d16s2
Ionization Energies for Lanthanides
0
1000
2000
3000
4000
5000
6000
La Ce Pr Nd Pm Sm Eu Gd Tb Dy Ho Er Th Yb Lu
KJ/
mol
4+
3+
2+
1+
Ionization energies reflect relative energies of the 4f, 5d, 6s
orbitals
6s electrons are removed first, hence first two ionization
energies for all lanthanides are essentially the same
Third ionization usually results from removal of an electron
from the 5d orbital
Fourth ionization energy reflects successive electron
occupation of 4f orbitals
Eu2+ >> Yb2+ >> Sm2+
Rf Db Sg Bh Hs Mt
OH Me OH
Sm(Hg), ICH2Cl
H
H
O
R
R1 R2
CH2
SmI
H
I
Me3C Me
OH
CH2I2
Sm
Me3C Me
OH
Me
OH
CH2I2
Sm
Me
OHMe3C Me3C
OH OHH
H
Me
Lanthanide Metals: Sm0
Cyclopropanation of Allylic Alcohols
THF, -78 oC to rt
98%
d.r. >200:1
d.r. >200:1
Exo: Endo
Sm / CH3CHI2
Et2Zn / CH3CHI2
5:1
1.6:1
Using samarium, only olefin with allylic hydroxyl group is cyclopropanated
Samarium offers enhanced diastereoselectivity over conventional reagents
99%
99%
EvansChem. Rev. 1993, 93, 1307.
Molander J. Org. Chem. 1989, 54, 3525.
Lanthanide Metals: Reductions
Dissolving Metal Reductions Using Yb
OMe
OMe
OMe
O1. Yb, NH3-THF-tBuOH
2. aq. NH4OH
80%
C3H7 C3H7
Yb, NH3-THF-tBuOH
85%
C3H7C3H7
Similar to Birch reduction with alkali metal, however avoids strongly basic hydroxide upon workup
White J. Org. Chem. 1978, 43, 4555.
Hydrogenation Using Lanthanide Alloys
S
CHOLaNi5H6
THF-MeOH
93%
S
OH
CHO LaNi5H6
THF-MeOH
95%
OH
Reduces alkynes, alkenes, aldehydes, ketones
nitriles, imines, and nitro compounds
Not poisoned by amino or halogen containing
compounds
Imamoto J. Org. Chem. 1987, 52, 5695.
O
MeO
MeO
OCH2OMe
H
SmI2
O
OCH2OMe
H
O
Me
OH
HMeMe
H
O
Me
H
HMeMe
HSmI2
C5H11 H
H COCH3O SmI2
HO
CH2COCH3
C5H11
H
Divalent Lanthanides: Samarium IodideReduction of !-Substituted Ketones and Esters
THF-MeOH, -78 oC
92%
THF-tBuOH, 25 oC
87%
Tetrahedron Lett. 1991,32, 6583
White J. Am. Chem. Soc. 1987,109, 4424
!-Halo, sulfoxides, sulfones, and !-oxygenated ketones are reduced
Primary iodides, esters, and ketones are unaffectedJ. Org. Chem. 1986,51, 1135
THF-MeOH, -90 oC
94% J. Org. Chem. 1986,51, 2596
Reduction of optically active epoxy ketones gives "-hydroxy ketones without loss of optical purity
Divalent Lanthanides: Samarium IodideIntramolecular Barbier Reactions
O
H
HO2 eq. SmI2, cat. Fe(DMB)3
THF / -78 oC to rt
80%
O
H
HO
2 eq. SmI2, cat. Fe(DMB)3
THF / -78 oC to rt
80%
IO
H
I
100:0 d.s.
1:1 d.s.
O
H
I
Method overcomes difficulties associated with using Mg, Li, Na
O
Me
I
2 eq. SmI2, cat. Fe(DMB)3
THF / -78 oC to rt
OH
Me
75%
Synthetically useful for substrates which allow for control of diastereoselectivity
Molander J. Org. Chem. 1991, 56, 4112.
I
O
R6O
O
Br
O
R1
R3 R2
R5
R4
O
R2
R3R4
R5
R1
O
R6
Sm(III)O
R2
R4
R5
R3
OHR1
R6
O
O
Me
O
Br
O
O
H
OHH
Me
O
Ph H Me H H H
tBu H Me H H H
Et H Me H H H
Divalent Lanthanides: Samarium IodideIntramolecular Reformatsky Reactions
-78 oC / THF
-78 oC / THF>200:1 d.r.
nn
n yield d.r.
0
1
73
68 29:1
yield d.r.
76 >200:1
85 >200:1
85 3:1
Large substituent in the R1 position usually results in high diastereoselectivity
Reactions to form bicyclic systems proceed with very high diastereoselectivities although yields are sometimes moderate to low
Molander J. Am. Chem. Soc. 1991, 113, 8036.
Divalent Lanthanides: Samarium IodideRadical Carbonyl-Alkene Couplings
R1 R2
OSmI2
R1 R2
OSmI2
EWG R1
R2 OSmI2
EWG SmI2, ROHR1
R2 OSmI2
EWG
Mechanism
EWG = CO2R, CN
Fukuzawa J. Chem. Soc., Chem. Comm. 1986, 624.
CHO
O
Me
OMeCO2Me
SmI2, iPrOH, THF71% >20:1
HMPA 96% 1:1
additive yield d.r.
none
time
4 h
1 min
O
Me
Me
CO2Me
SmI2, iPrOH, THF
O
MeMe
O
57% 1.3:1
HMPA 89% 4.9:1
additive yield d.r.
none
time
4 h
1 min
HMPA dramatically improves reaction rate and yield.
Diastereoselectivity is improved when !-disubstituted lactones are formed
Inanaga Tetrahedron Lett. 1986, 27, 5763.
2 SmI2
2 SmI2
R1 R2 R3 R4 R5 R6
ROSmI2
NaBH4
CeCl3
MeO- B- H C O H OR C OHH
ONaBH4
MeOH
OH OH
with CeCl3
O
Me
Me
H
Me Me
Me
Me
H
Me Me
NaBH4-CeCl3
MeOH
OHH
Trivalent Lanthanides: Luche ReductionSelective 1,2 Reduction of !-Enones
Mechanism
BH-4-n(OR)n
Ln3+
Sodium borohydride is rapidly converted to an alkoxide species
Carbonyl is activated through hydrogen bonding by a
lanthanide-bound molecule solvent
Hard borohydride preferentially attacks the hard carbonyl carbon
Luche J. Am. Chem. Soc. 1981, 103, 5454.
5 min.
without
97% 3%
0% 100% Luche J. Am. Chem. Soc. 1978, 100, 2226.
rt
97%
Paquette J. Am. Chem. Soc. 1987, 109, 3025.
Trivalent Lanthanides: Reduction of KetonesSelective Reduction of Ketones in the Presence of Aldehydes
O CHO OH CHO1.5 eq. NaBH4,CeCl3
1.5:1 EtOH:H2O
78%
Eliminates need for three step protection-reduction-deprotection scheme
Rationale
R
O
H R H
HO OHLnCl3
R
O
R R R
HO OH
LnCl3
In the presence of lanthanide (III) salts
aldehydes yield hydrates
Ketones remain unaffected
Hemiketal or Ketal formation is ruled out because similar results (within 5%) were obtained with MeOH and iPrOH
Luche J. Am. Chem. Soc. 1979, 101, 5848.
7H2O
ROH
6H2O
O
O
O
H
Me
HPMBO
Me
Me
TBDSO
H
Et
O
O
OH
H
Me
HPMBO
Me
Me
TBDSO
H
Et
H
O OH
La
Ce
Sm
Gd
Yb
Trivalent Lanthanides: Reduction of KetonesMeerwein-Ponndorf-Verley / Oppenauer Reactions
SmI2 (15 mol%), Me2CHOH (10 equiv.)
THF, 25 oC, 18 h
99%
97% de
Evans J. Org. Chem., 1990, 55, 6260
Ln(OiPr)3
iPrOH (4-20 eq)
Ln mol % h yield
5
10
10
2
5
80 oC
18
24
18
2
24
>98
95
>98
85
40
Gd(OiPr)3 is 103 times more reactive than Al(OiPr)3
Kagan, H. B. et al Tetrahedron Lett., 1991, 32, 2355.
Konishi, H. Chem. Lett., 1987, 181.
H
Trivalent Lanthanides: Reduction of KetonesEvans-Tischenko Reduction
R1
Me
Me
OOH
15% SmI2
HR1
O O
R2
Me2HC
SmR1
Me
Me
OHOR2
O
Evans J. Am. Chem. Soc., 1990, 112, 6447.
R1 = n-hexyl, iPr; R2 = Me, iPr, Ph anti:syn >99:1
Asymmetric induction by !-hydroxy stereocenter dominates "-methyl stereocenter
MeMe
Me
O
Me
OH
Me Me
OTBS
MeCHO
40% SmI2
1.5 h
MeMe
Me
O
Me
OH
Me Me
OTBS
89%
>99:1
O
CHO
Me
Me
Me
TBDMSO
OBn
O
Me
Me
Me
TBDMSO
OBn
Ocat. SmI2(OtBu)
THF, rt89%
Intramolecular Tischenko Reaction
Uenishi Tetrahedron Lett., 1991, 32, 5097.
R2CHO
OTMS
MeO
OMeH
O
Ph
O
O
MeO Ph
CH2Cl2, rt, 48 h
OMe
Me
TMSO
Me
Me
O
H
OMe
TMSO
H
H
H MeMe
OMe
TMSO
Me OMe
Me O
Me
H
Eu3+
R
HEtO O
H
H
OEt
R
O Me
O
Me MeF F
FF
F
F
F
O
Trivalent Lanthanides: Hetero-Diels-Alder
+Eu(fod)3, 1.7 mol %
84%
CastellinoTetrahedron Lett., 1984, 25, 4059.Exclusive carbonyl addition
+
Eu(fod)3 (0.5 mol %)
CDCl3, rt
66%
One isomer
Midland J. Am. Chem. Soc., 1984, 106, 4294.
R = Me, Ph
Yb(fod)3 (5 mol %)
neat, rt, 2h
60-80%
+
Reactions proceed with high endo selectivity
Bulky catalyst prefers to occupy exo position
fod = (6,6,7,7,8,8,8-heptafluoro-2,2-
dimethyl-3,5-octanedionato-
Inverse Demand
endo product
H
Trivalent Lanthanides: Reduction of KetonesEvans-Tischenko Reduction
R1
Me
Me
OOH
15% SmI2
HR1
O O
R2
Me2HC
SmR1
Me
Me
OHOR2
O
Evans J. Am. Chem. Soc., 1990, 112, 6447.
R1 = n-hexyl, iPr; R2 = Me, iPr, Ph anti:syn >99:1
Asymmetric induction by !-hydroxy stereocenter dominates "-methyl stereocenter
MeMe
Me
O
Me
OH
Me Me
OTBS
MeCHO
40% SmI2
1.5 h
MeMe
Me
O
Me
OH
Me Me
OTBS
89%
>99:1
O
CHO
Me
Me
Me
TBDMSO
OBn
O
Me
Me
Me
TBDMSO
OBn
Ocat. SmI2(OtBu)
THF, rt89%
Intramolecular Tischenko Reaction
Uenishi Tetrahedron Lett., 1991, 32, 5097.
R2CHO
OH
OH
O
OH
OMe
OMe
NH
OMe
OR
MeO
Me
MeO
Me Me
O
O
OMe
OR
MeO
Me
MeO
Me Me
OMe OMeCAN
MeCN-H2O
R1 R2
NO2
R1 R2
N+TMSO O-
R1 R2
OTMSCl, Li2S
CeO3N
O3N NO3
NO3
NH4
NH4
Tetravalent Lanthanides: Oxidations
Selective Secondary Alcohol Oxidation
CAN (10 mol %), NaBrO3
MeCN-H2O, 80 oC, 0.5 h
89%
Oshima Bull. Chem. Soc. Jpn., 1986, 59, 105
Oxidation of Phenol Ethers
R = TBS
71%
Evans J. Org. Chem, 1992, 57, 1067
Oxidation of Nitro Compounds to Ketones
25 oC, 6-8 h
CAN, 25 oC
5 min.
CAN =
Ceric Ammonium Nitrate
Olah Sythesis, 1980, 44
Enantioselective ReactionsEuropium(III) Hfc Promoted Hetero-Diels-Alder
OtBu
Me
TMSO
R
H Ph
O Eu(hfc)3, (1 mol %)
neat, -10 oC
O
TMSO
Me
R
Ph
OtBu
+
O
OMe OH
R
Ph
R = H 58% ee
R = Me 55% ee
4 steps
Danishefsky, Tetrahedron Lett. 1983, 24, 3451.
Danishefsky, J. Am. Chem. Soc. 1983, 105, 3716.
Me Me
Me
CF2CF2CF3
O
OEu *
*
Eu(hfc)3
OMe
H
O
CO2tBu
O
OMe
CO2tBu
Eu(hfc)3 (5 mol %)
rt
+
trans cis
yield
ee
79
19
39 %
64%
Jankowski, J. Chem. Soc. , Chem. Comm. 1987, 676.
Larger C1 alkoxy substituents gave increased ee
Me
O
N O
O
H
Me
OXn
Yb(OTf)3 NMe Me
Me
MS 4Å
CH2Cl2
O
O YbO
TfO O
OTf
N
O
R
HMe
Me Me
N
Me
Me
Me
H
+
Yb-BINOL-amine catalyst
CH2Cl2, -78 to 0 oC
20 mol %
94%
endo:exo 86:14
90% ee
Enantioselective ReactionsYb(III) BINOL Hetero-Diels-Alder
+ + (R)-BINOL
1 mmol
2.4 mmol
1.2 mmol0 oC, 30 min
Chiral Catalyst
Reaction proceeds only very slowly without BINOL
amine not interacting with metal
Larger amines typically give higher ee
Spectroscopic evidence for amine-BINOL H-bonding
Kobayashi J. Org. Chem. 1994, 59, 3758.
Kobayashi Tetrahedron Lett. 1993, 34, 4535.
Me
Me
N
Me H
Enantioselective ReactionsYb(III) BINOL Hetero-Diels-Alder: Reversal of Enantioselectivity
R
O
N O
O
+H
R
20 mol % catalyst
CH2Cl2, 0 oC
MS 4Å
20 mol % additive
R
H+
O Xn
O Xn
Me
O
N O
O
Me
O
Ph
O
Meadditive
Me
nPr
% yield endo:exo 2S, 3R 2R, 3S
2S, 3R 2R, 3S
77
81
89:11
80:20
98 2
93 8
% yield endo:exo 2S, 3R 2R, 3S
83
81
93:7
91:9
9 91
10 90
O
O YbO
TfO O
OTf
N
O
R
HMe
Me Me
N
Me
Me
Me
HO
OYb
O
OO
O
Me
Me
N
Me
Me
Me
H
N
O
R
O
ON
O
Me
Site A
Site B
Kobayashi Tetrahedron Lett., 1994, 35, 6325 Kobayashi J. Am. Chem. Soc, 1994, 116, 4083
R
O
Ln
O
O
O
O
O O M
M
M
R2NO2R1
R2
OH
NO2
R1
HR2
N+
HO
LiO
Ln
O
R1
HH
N+
R2
O
LiO
Ln
R1
H
OR2
N+
HO
LiO
Ln
R1
H
OH
N+
R2
O
LiO
Ln
OH
R1
HR2
NO2
H
R1R2
OH
NO2
Enantioselective ReactionsHeterobimetallic Catalysis
Ln = Lanthanide
M = Alkali Metal
Nitroaldol
1 equiv
+
10 equiv
3-10 mol % cat
THF, -40 oC
78-97 % yield
66-97 % ee
Shibasaki Tetrahedron Lett. 1993, 34, 2657.
Review: Shibasaki ACIE, 1997, 36, 1236.
Catalyst acts as Lewis acid and Lewis Base
74:27 to 93:7 syn:antiShibasaki J. Org. Chem. 1995, 60, 7388.
Explanation of syn selectivity
syn
anti
Shibasaki J. Org. Chem. 1995, 60, 7388.
Enantioselective ReactionsHeterobimetallic Catalysis
Michael Reaction
La
O
O
O
O
O O Na
Na
Na
La
O
O
O
O
O OH
Na
Na
La
O
O
O
O
O OH
M
M
Na
O
O
OMe
OMeO O
NaO
O
OMe
OMe
O
CO2Me
CO2Me
=
O O
O
Me CO2Bn
CO2Bn
Me
CO2Bn
CO2BnCO2Me
CO2Me
Ph
Ph
CO2Me
CO2Me
O O O
Yield
% ee
89
72
91
92
98
83
93
77
Li and K catalysts gave poor ee
OMeO
MeO
O
O
Metal free La-BINOL complex provides
almost no enantioselectivity
Shibasaki J. Am. Chem. Soc., 1995, 117, 6195
O O
R1CHO
Me
Ph
MeMe
Ph
Sm
Cl
Cl
(Et2O)2Sm Me
Me
MeMe
Si
Me
Me
R*
H2
O
O
SmI2OH
O
H
N
H
HO
MeO
Rh(PPh3)3Cl
Ru(H)(Cl)(PPh3)3
Enantioselective ReactionsMiscellaneous Reactions
Olefin Hydrogenation
96% ee
H2 (1 atm), catalyst
heptane, -78 oC
100% R* = (-)-menthyl
catalyst =
Marks, T. J. J. Am. Chem. Soc., 1992, 114, 2761.
Lanthanide hydrogenation catalysts are highly reactive
MLn
Ketone Reduction
THF-HMPA, rt, 30 min
56% ee
200 mol% quinidine
quinidine
MLn Nt (turnover number)
((C5Me5)2LuH)2
Ru(COD)(PPh3)2PF6
120,000 h-1
650 h-1
3,000 h-1
4,000 h-1
Takeuchi Chem. Lett. 1988, 403.
Marks, T. J. J. Am. Chem. Soc., 1985, 107, 8111.
=
Summary
Lanthanide metals are useful for reduction of functional groups and for carbon-carbon bond forming reactions
Europium, Samarium, and Ytterbium can form relatively stable divalent states. Europium is stable enough to exist in water.
SmI2 is the most widely employed Ln(II) and is used for one electron reductive reactions
Trivalent lanthanides are hard Lewis acids with high oxophilicity and as such are employed in several highly selective reactions
(Luche reduction, hetero-Diels-Alder)
f-orbital electrons are imperfect shielders and so Ln(III) have their f-orbitals greatly contracted towards the nucleus.
This effectively eliminates covalent bonding interactions with ligands and therefore lanthanide-ligand geometries
are largely determined by steric considerations. Asymmetric lanthanide promoted processes are therefore less straight-
forward than those using main group or d-block elements
Ce(IV) is the only tetrapositive lanthanide which is stable in water and to date is the only synthetically useful Ln(IV)
with applications in the oxidation of functional groups such as alcohols and phenol ethers.
Note: Scandium (3d1) and Yttrium (4d1) have similar properties to those of the lanthanides and are often treated as lanthanides