Lanthanides in Organic Synthesis Heathcock / MacMillan Seminar Feb. 22, 2000 Tristan Lambert I. II. III. IV. V. VI.
Properties of the lanthanides Lanthanide metals Divalent lanthanides Trivalent lanthanides Tetravalent lanthanides Enantioselective processes He
H Li
Be
B
C
N
O
F
Ne
Na
Mg
Al
Si
P
S
Cl
Ar
K
Ca
Sc
Ti
V
Cr
Mn
Fe
Co
Ni
Cu
Zn
Ga
Ge
As
Se
Br
Kr
Rb
Sr
Y
Zr
Nb
Mo
Tc
Ru
Rh
Pd
Ag
Cd
In
Sn
Sb
Te
I
Xe
Cs
Ba
Hf
Ta
W
Re
Os
Ir
Pt
Au
Hg
Tl
Pb
Bi
Po
At
Rn
Fr
Ra
Rf
Db
Sg
Bh
Hs
Mt
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
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 Eu2+ >> Yb2+ >> Sm2+ Ce4+ (f0) is the only tetrapositive lanthanide stable in water Ionization Energies for Lanthanides 6000
5000
4+
4000
La Ce
5d16s2
Pr
4f36s2
4f15d16s2
Nd
4f46s2
Pm
4f56s2
Sm
4f66s2
Eu
4f76s2
Gd Tb Dy
4f96s2
4f75d16s2
Ho Er
4f106s2 4f116s2 4f126s2
Tm
4f136s2
Yb
4f146s2
Lu
4f145d16s2
Ionization energies reflect relative energies of the 4f, 5d, 6s
KJ/mol
orbitals
3000
6s electrons are removed first, hence first two ionization
2000
3+
energies for all lanthanides are essentially the same
2+
1000
1+ 0 La
Ce
Pr
Nd Pm Sm Eu
Gd
Tb Dy
Ho
Er
Th
Yb
Third ionization usually results from removal of an electron from the 5d orbital
Lu
Fourth ionization energy reflects successive electron occupation of 4f orbitals
Lanthanide Metals: Sm0 Cyclopropanation of Allylic Alcohols
Sm(Hg), ICH2Cl H
THF, -78 oC to rt 98%
OH
Me
OH
Using samarium, only olefin with allylic hydroxyl group is cyclopropanated
Me3C
CH2I2
Me
Me3C
Me
Sm
OH
R1
OH
99%
d.r. >200:1 CH2I2
Me Me3C
R
O
Me
Sm
OH
Me3C
99%
OH
I
SmI
H
OH
Molander J. Org. Chem. 1989, 54, 3525.
d.r. >200:1
OH
R2 H CH2
Exo: Endo
H
Sm / CH3CHI2
Me
5:1
Et2Zn / CH3CHI2
H
1.6:1
Samarium offers enhanced diastereoselectivity over conventional reagents EvansChem. Rev. 1993, 93, 1307.
Lanthanide Metals: Reductions Dissolving Metal Reductions Using Yb OMe
OMe OMe
1. Yb, NH3-THF-tBuOH
O
2. aq. NH4OH 80%
C3H7
C3H7
Yb, NH3-THF-tBuOH
C3H7
85%
C3H7
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 CHO
THF-MeOH
S
OH
LaNi5H6
Reduces alkynes, alkenes, aldehydes, ketones S
nitriles, imines, and nitro compounds
93% Not poisoned by amino or halogen containing CHO
LaNi5H6
OH
compounds
THF-MeOH 95%
Imamoto J. Org. Chem. 1987, 52, 5695.
Divalent Lanthanides: Samarium Iodide Reduction of !-Substituted Ketones and Esters H
H MeO
SmI2
OCH2OMe
MeO
OCH2OMe
THF-MeOH, -78
O
oC
Tetrahedron Lett. 1991,32, 6583
O
92%
H Me OH Me
O
Me
THF-tBuOH, 25 oC
H
87%
H
Me
H
SmI2
Me
O
H
Me
White J. Am. Chem. Soc. 1987,109, 4424
!-Halo, sulfoxides, sulfones, and !-oxygenated ketones are reduced Primary iodides, esters, and ketones are unaffected J. Org. Chem. 1986,51, 1135
H C5H11
O
SmI2
COCH3
THF-MeOH, -90 oC
H
H
C5H11
CH2COCH3
HO
94%
J. Org. Chem. 1986,51, 2596
Reduction of optically active epoxy ketones gives "-hydroxy ketones without loss of optical purity
Divalent Lanthanides: Samarium Iodide Intramolecular Barbier Reactions O HO
2 eq. SmI2, cat. Fe(DMB)3
I
O H
H
THF / -78 oC to rt 80%
I
100:0 d.s. O HO
2 eq. SmI2, cat. Fe(DMB)3
I
I O
H
THF / -78 oC to rt 80%
H
1:1 d.s. Method overcomes difficulties associated with using Mg, Li, Na Synthetically useful for substrates which allow for control of diastereoselectivity O
2 eq. SmI2, cat. Fe(DMB)3 Me
THF / -78 I
oC
to rt
OH Me
75% Molander J. Org. Chem. 1991, 56, 4112.
Divalent Lanthanides: Samarium Iodide Intramolecular Reformatsky Reactions O R6 Br
O
R5
R R4 3
-78 oC / THF
R1
R4
R2
2 SmI2
O
R6
O O R5
R3 R2
R2
R1
R6
R3
Sm(III)
O
R1 OH
R4 R5
O
O
R1
R2
R3
R4
R5
R6
yield
d.r.
Ph
H
Me
H
H
H
>200:1
tBu
H
Me
H
H
H
76 85
Et
H
Me
H
H
H
85
3:1
>200:1
Large substituent in the R1 position usually results in high diastereoselectivity O Br
O O
2 SmI2
Me
H
O
Me
n
yield
d.r.
OH
0
73
>200:1 d.r.
1
68
29:1
-78 oC / THF H
O
n
n
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 Iodide Radical Carbonyl-Alkene Couplings Mechanism O R1
O
SmI2 R2
R1
SmI2 EWG R2
R1
EWG = CO2R, CN
EWG
R2
SmI2, ROH
OSmI2
R2
EWG OSmI2
ROSmI2
Fukuzawa J. Chem. Soc., Chem. Comm. 1986, 624.
CO2Me
Me
R1
O
O
CHO
SmI2, iPrOH, THF Me
additive
time
yield
d.r.
none
4h
71%
>20:1
HMPA
1 min
96%
1:1
additive
time
yield
d.r.
none
4h
57%
1.3:1
HMPA
1 min
89%
4.9:1
Me Me
CO2Me
O
O
O
SmI2, iPrOH, THF Me
Me
Inanaga Tetrahedron Lett. 1986, 27, 5763.
HMPA dramatically improves reaction rate and yield. Diastereoselectivity is improved when !-disubstituted lactones are formed
Trivalent Lanthanides: Luche Reduction Selective 1,2 Reduction of !-Enones Mechanism
NaBH4
CeCl3 7H2O
BH-4-n(OR)n
Sodium borohydride is rapidly converted to an alkoxide species
ROH Carbonyl is activated through hydrogen bonding by a MeO-
B- H
C O
H OR
H
C
lanthanide-bound molecule solvent
OH
Hard borohydride preferentially attacks the hard carbonyl carbon
Ln3+
Luche J. Am. Chem. Soc. 1981, 103, 5454.
O
NaBH4
OH
OH
97%
3%
0%
100%
MeOH 5 min. with CeCl3 without
Luche J. Am. Chem. Soc. 1978, 100, 2226.
Me
Me H
O
OH
NaBH4-CeCl3
H
MeOH rt 97%
Me Me
H
Me
Me Me
Me
Paquette J. Am. Chem. Soc. 1987, 109, 3025.
Trivalent Lanthanides: Reduction of Ketones Selective Reduction of Ketones in the Presence of Aldehydes
O
CHO
1.5 eq. NaBH4,CeCl3 6H2O
OH
CHO
1.5:1 EtOH:H2O 78% Eliminates need for three step protection-reduction-deprotection scheme
Rationale LnCl3
O R
H
O R
R
LnCl3
HO
OH
R
H
HO
OH
R
R
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.
H
99%
PMBO
O
H Et
OH
Me
Evans J. Org. Chem., 1990, 55, 6260
97% de
Lanthanides: Reduction of Ketones Evans-Tischenko Reduction O
R2CHO 15% SmI2
Me2HC R1
H H
R2
R2
O
OH
Me
O Sm O
R1 Me
anti:syn >99:1
Pr, Ph
c induction by !-hydroxy stereocenter dominates "-methyl stereocenter
OTBS
OH Me
Me
MeCHO 40% SmI2 1.5 h
O
OTBS
Me
Me
89% >99:1
Me
Me
Me
Me
Evans J. Am. Chem. Soc., 1990, 112, 6447.
ction
OBn
Me
CHO O
OBn
cat. SmI2(OtBu) THF, rt
Me
O
Me O
TBDMSO
89%
Me Uenishi Tetrahedron Lett., 1991, 32, 5097.
Trivalent Lanthanides: Hetero-Diels-Alder O
OTMS O
Eu(fod)3, 1.7 mol %
+
OMe
H
O
CH2Cl2, rt, 48 h
Ph
MeO
MeO
84%
Exclusive carbonyl addition
CastellinoTetrahedron Lett., 1984, 25, 4059.
OMe
H O
Me
+
Me
Ph
Me
Eu(fod)3 (0.5 mol %) H
O
TMSO
66%
Me
Me
H
Me
Me
H
Bulky catalyst prefers to occupy exo position
Midland J. Am. Chem. Soc., 1984, 106, 4294.
Inverse Demand
F
O
+
EtO
O
Yb(fod)3 (5 mol %) neat, rt, 2h 60-80%
R
Eu3+
O
Me Me
One isomer
Reactions proceed with high endo selectivity
H
OMe
TMSO
H
CDCl3, rt
TMSO
OMe
H
R = Me, Ph
OEt
F
H
F
O
F
O Me
F
F
F
Me Me
fod = (6,6,7,7,8,8,8-heptafluoro-2,2dimethyl-3,5-octanedionato-
R
endo product
Trivalent Lanthanides: Reduction of Ketones Evans-Tischenko Reduction O OH
O
Me
R2CHO
R1
15% SmI2
Me
Me2HC R1
H H O Sm O
R2
R2
O
OH
Me
R1 Me
anti:syn >99:1
R1 = n-hexyl, iPr; R2 = Me, iPr, Ph
Asymmetric induction by !-hydroxy stereocenter dominates "-methyl stereocenter
OH
O
OTBS
Me
OH Me
Me
Me
Me
Me
MeCHO 40% SmI2 1.5 h
O
OTBS
Me
Me
89% >99:1
Me
Me
Me
Me
Evans J. Am. Chem. Soc., 1990, 112, 6447.
Intramolecular Tischenko Reaction OBn Me CHO
Me
O
TBDMSO Me
OBn
cat. SmI2(OtBu) THF, rt
Me
O
Me O
TBDMSO
89%
Me Uenishi Tetrahedron Lett., 1991, 32, 5097.
Tetravalent Lanthanides: Oxidations O 3N
CAN =
O3N
Selective Secondary Alcohol Oxidation OH
NH4 NO3
Ce
NO3 NH4
Ceric Ammonium Nitrate
O
CAN (10 mol %), NaBrO3 MeCN-H2O, 80 oC, 0.5 h OH
OH
89%
Oshima Bull. Chem. Soc. Jpn., 1986, 59, 105
Oxidation of Phenol Ethers Me
Me
Me
MeO
Me
MeO OR
OMe Me
O OMe
Me
MeO
Me
MeCN-H2O
NH
OR
OMe
CAN 71%
O
O
Me
MeO
R = TBS OMe
O Evans J. Org. Chem, 1992, 57, 1067
Oxidation of Nitro Compounds to Ketones
NO2 R1
TMSO
TMSCl, Li2S 25 oC, 6-8 h
R2
N+
O-
R1
5 min.
R2
R1
O
CAN, 25 oC
R2
Olah Sythesis, 1980, 44
Enantioselective Reactions
Me
Me
CF2CF2CF3 O
Europium(III) Hfc Promoted Hetero-Diels-Alder Me
Eu
*
O
* Eu(hfc)3 OtBu
OtBu
Me
O
Eu(hfc)3, (1 mol %)
+ H
TMSO
Ph
neat, -10 oC
4 steps
Me
TMSO
R
OMe OH
O Ph
O
Ph R
R
Danishefsky, Tetrahedron Lett. 1983, 24, 3451.
R=H
58% ee
Danishefsky, J. Am. Chem. Soc. 1983, 105, 3716.
R = Me 55% ee
Larger C1 alkoxy substituents gave increased ee
OMe
OMe O
Eu(hfc)3 (5 mol %)
+ H
CO2tBu
rt
yield
O CO2tBu
ee
trans 79
cis 39 %
19
64%
Jankowski, J. Chem. Soc. , Chem. Comm. 1987, 676.
Enantioselective Reactions Yb(III) BINOL Hetero-Diels-Alder O
O Me
N
Yb-BINOL-amine catalyst 20 mol %
+
O
Me H
CH2Cl2, -78 to 0 oC
Yb(OTf)3
+
Me
N
1 mmol
+
Me
Me
(R)-BINOL
MS 4Å
1.2 mmol
CH2Cl2 0 oC, 30 min
2.4 mmol
Chiral Catalyst
amine not interacting with metal
Me N O H O O O Yb Me N O TfO H Me OTf Me
Xn
Reaction proceeds only very slowly without BINOL
Me
Me
90% ee
O
94%
endo:exo 86:14
Larger amines typically give higher ee Spectroscopic evidence for amine-BINOL H-bonding
R Kobayashi Tetrahedron Lett. 1993, 34, 4535. Kobayashi J. Org. Chem. 1994, 59, 3758.
Enantioselective Reactions Yb(III) BINOL Hetero-Diels-Alder: Reversal of Enantioselectivity
R
20 mol % catalyst 20 mol % additive
O
O N
O
+
MS 4Å CH2Cl2, 0 oC
Me
additive
2S, 3R
O
O N
R
2R, 3S O
O
Me
O
H
+
Xn
O O
Me Ph
endo:exo 2S, 3R
2R, 3S
R
% yield
endo:exo
2S, 3R
2R, 3S
% yield
Me
77
89:11
98
2
83
93:7
9
91
nPr
81
80:20
93
8
81
91:9
10
90
Kobayashi J. Am. Chem. Soc, 1994, 116, 4083
Kobayashi Tetrahedron Lett., 1994, 35, 6325
Me Me N O H O O Yb O Me N O TfO H Me OTf Me
R H
Me
R
Site A O O
O N Me
Site B
O Me R
Me H O
Me Me N O H O Yb O Me O
N Me
N O
Me Me
Xn
Enantioselective Reactions Heterobimetallic Catalysis Review: Shibasaki ACIE, 1997, 36, 1236.
M O
Nitroaldol +
R1CHO 1 equiv
OH
3-10 mol % cat
R2NO2
THF, -40 oC
Shibasaki J. Org. Chem. 1995, 60, 7388.
Explanation of syn selectivity
syn
H
R1
H
O
anti
H
Catalyst acts as Lewis acid and Lewis Base
H
O
H
O
NO2 OH
H
O N+
O
R2
H
R1
Ln
R1
Li
Li O
O
H
O
R2
O N+
Ln
R1
R2
M = Alkali Metal
R1
Li
N+
H
Ln = Lanthanide
66-97 % ee
R2
O N+
H
78-97 % yield 74:27 to 93:7 syn:anti
Shibasaki J. Org. Chem. 1995, 60, 7388.
Ln
O
M
NO2
Shibasaki Tetrahedron Lett. 1993, 34, 2657.
R2
O O R2
R1
10 equiv
O M
O Ln O
NO2
Li
R1
O Ln
R2 OH
Enantioselective Reactions Heterobimetallic Catalysis O
Michael Reaction
O
=
O O
Na O
MeO
O
Na
O La O
O
O
O O
O
CO2Me
Na
O
CO2Me
MeO
Li and K catalysts gave poor ee Na O
OH
O
O La O
Na
O O
O
M O
OMe
O La O
Metal free La-BINOL complex provides almost no enantioselectivity
O Na
OMe O
O O
O
Na
OH
M
OMe
Shibasaki J. Am. Chem. Soc., 1995, 117, 6195
O OMe
O
O
O
O Ph
CO2Bn Me CO2Bn
Yield % ee
CO2Me
CO2Bn Me
CO2Bn
CO2Me
CO2Me
Ph
CO2Me
89
91
98
93
72
92
83
77
Enantioselective Reactions Miscellaneous Reactions Olefin Hydrogenation
Me Me
H2 (1 atm), catalyst
Me Ph
heptane, -78 oC
Me
Me
catalyst = (Et2O)2Sm
Sm Me
Me
R* = (-)-menthyl
96% ee
Me
Si
Cl
Ph
100%
Me
Cl
R*
Marks, T. J. J. Am. Chem. Soc., 1992, 114, 2761.
Nt (turnover number)
MLn ((C5Me5)2LuH)2 Rh(PPh3)3Cl Ru(H)(Cl)(PPh3)3 Ru(COD)(PPh3)2PF6
120,000 h-1 650
Lanthanide hydrogenation catalysts are highly reactive
h-1
H2
3,000 h-1 4,000
MLn
h-1
Marks, T. J. J. Am. Chem. Soc., 1985, 107, 8111.
H
Ketone Reduction N
O
OH
SmI2 O
quinidine
H
MeO
THF-HMPA, rt, 30 min O
200 mol% quinidine Takeuchi Chem. Lett. 1988, 403.
HO
=
56% ee
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 straightforward 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
