Nathan Wilde
Unused Elements in Organic Synthesis: Thallium, Tellurium, Lead
Introduction
January 2014
The elements:
Tellurium: Discovered in 1782 as a gold telluride mineral. Named from tellus, the Latin word
for "earth." The percent of relative elemental abundance for the universe is far higher than that
on Earth, partly because Te forms TeH2, which is volatile so it escapes the Earth. Te has no
biological function, but some fungi can incorporate it into peptides in the place of S or Se.
Thallium: Discovered in 1861. It produced a green spectral line by flame spectroscopy, so it
is named after thallos, the Greek word for "a green shoot or twig." It is usually at the +1 or +3
oxidation state. Tl+ ions are similar to Ag+ and K+ in size, and in vivo they are pumped into
cells through potassium channels, and once inside the cell thallium binds to sulfur in cystein
residues and ferrodoxins. Tl3+ ions resemble softer versions of boron and aluminum Lewis
acids, and are also a potent oxidants.
Lead: Discovered roughly 9000 years ago in the middle east. In atomic physics, 208Pb is
"double magic" because it has 82 protons and 126 neutrons, making it excpetionally stable to
radioactive decay. In animals, lead accumulates in the tissues and bones, as well as attacks
the nervous system.
Why are they not used?
Tellurium: Not very toxic, but relatively rare and expensive. Humans exposed to as little as
0.01 mg/m3 or less of Te metal in air exude a foul garlic-like odor known as 'tellurium breath'"
(Wikipedia: "Tellurium"). Most organisms metabolize tellurium to dimethyl telluride, the source
of the smell. Other organo tellurides do not smell bad. Mostly perception is why it's not used.
Thallium: Crazy toxic. "Poisoner's poison": Tl(I) salts are tasteless and odor-free. Also,
symptoms of thallium poisoning are similar to other illnesses, so physicians are often
confused. Unlike mercury and lead, however, thallium is not a bioaccumulative poison.
Tellurium
Lead: Toxic, but not as toxic as public perception leads you to believe. By weight, palladium is
more toxic than lead, and some authors in the literature claim palladium is ten times more
toxic. Lead is abundant and has many industrial applications, so you're more likely to be
affected by it. Pb tends to have high ligand coordination numbers (4-7, even as high as 8 or
9), so making as using well-defined organoplumbanes can be difficult.
Relative abundance in the earth's crust
Element ppm
Oral LD50 for rat (Sigma Aldrich's MSDS's)
Lead
14
Pb(OAc)2: 4665 mg/kg
2.2
Tin
Pd(OAc)2: 2100 mg/kg
Thallium 0.6
TlCl: 24 mg/kg
Iodine
0.14
TeO2: > 5000 mg/kg Note: Diarrhea
Tellurium 0.005
Platinum 0.003
SeO2: 68.1 mg/kg
Gold
0.0011
Lead
Thallium
Main Sources:
"Main Group Metals in Organic Synthesis",
2004, edited by H. Yamamoto and K. Oshima.
Chapters 9, 13, and 15.
Reviews:
Te: Synthesis 1991, 793 & 897. Tetrahedron
2005, 1613. Chem. Rev. 2006, 1032.
Tl: Synthesis 2010, 1059. Synthesis 1999,
2001. Acc. Chem. Res. 1970, 338.
Pb: Tetrahedron 2001, 5683.
Tellurium reagents and making C-Te bonds
Al2Te3 + 3H2O
See book chapter
Homogeneous production of Ti(III) species in inert solvents
3H2Te + Al2O3
Ph
Na/NH3
Na2Te (or Na2Te2)
NaBH4/EtOH
$1/g (Strem)
RM + Te
RTeM
Na2Te
RX
Na2Te2
R = alkyl
I
O2
I
(RTe)2
R2Te
ArX + Na2Te
Ar2Te
X = I, or N2BF4 (requires heat)
(RTe)2
Ph
H
Ph
H
D2Te
(from Al2Te3 + D2O)
$5/g
(Aldrich)
Cl
OH
Ph
Works on aliphatic aldehydes and
ketones too, but with lower yields.
OD
Ph
D
D2O is a cheap way to reductively
deauterate things.
100%
O
Ph
H
CO2Et
Other reactions with similar mechanisms: Reformatsky-type, epoxides
with an -LG give allylic alcohols, dealkylation of quaternary ammonium
salts, removal of nitro groups, removal of sulfones, and more. See the
above review.
JOC 1992, 6598
Telluronium Ylides ... do the same things as sulfonium ylides
ACIE 1980, 1009
H2Te
(from Al2Te3 + H2O)
CO2Et
TeCl4 +
RTeX3
100%
O
(PhTe)2
NaBH4
53%
Reduction
O
Bull. Chem. Soc. Jpn. 1986, 3013
TePh
RTeR'
TeCl3
(RTe)2 + X2
OH
Only diasteromer. With aqueous
TiCl3 they get a mixture of this
and the meso isomer.
99%
Dehalogenation
R'X
Ph
Ph
DCM, rt
H
Chem. Lett. 1986, 1339
NaTeH
M = Li, Na, MgX
OH
iBu2Te, TiCl4
O
$25/g (Materion)
Te
Tellurium
January 2014
Unused Elements in Organic Synthesis: Thallium, Tellurium, Lead
Nathan Wilde
H2Te
(from Al2Te3 + H2O)
O
Ph
89%
H
Other reductions possible with Te reagents (such as NaTeH, PhTeSiMe3):
aryl alkenes, enemines and imines, nitrones, thio carbonyls, nitro groups, N-oxides, azides. See
the reviews, especially Synthesis 1991, 793.
LiTMP
Te(iBu)2
O
Te(iBu)2
THF, -78°C
TMS
, -unsaturated esters and ketones can also
undergo cyclopropanation.
Ar
H
TMS
O
Ar
TMS
H
Tet. Lett. 1983, 2599
If your HWE isn't working, telluronium ylides can do that too.
R
CO2Et
KOtBu
Br
CO2Et
then RR'CO
Te(nBu)2
CO2Et
Te(nBu)2
R'
Note: stabilized sulfonium ylides such as these are inert to carbonyl groups.
Or even a Julia-olefination-type dimerization
JOC 1984, 3559
Ar
Ar
nBuLi
SO2Ph then cat. Te
TeLi
Ar
Halotelluration of alkynes
R
Ar
Ar
SO2Ph
Te
SO2Ph
-LiO2SPh
TeCl4
Ar
Li
Br
SO2Ph
Hydrotelluration of alkynes
R
H
M = Al, B, Zr
M
R
Ar
Ar
EtOH
Br
Br
R
TeBr2Ar
So what do you do with all these fancy tellurides you can make?
Metal-tellurium exchange and direct cross-coupling!
R
BuLi
Ph
EtOH
Te Bu
Ph
75%
R
R3
Te Bu 77%
OTBS
TenBu
72%
This method also works great for Michael-addition on alkynes bearing an EWG. You can even trap
with an electrophile stereospecifically, opening possibilities for stereodefined tetrasubstituted olefins.
R
R
TeR'
Pd(0),
R2M
HO
Ph
AlEt3
R3
R
Ph
OTBS
Me2CuCNLi2
Pd(0),
n
Ph
CuCNLi2
88%
n
TenBu
Ph
OH
R
Li
TeR'
(nBuTe)2, NaBH4
Ph
TeAr
TeR'
R
Ph
R
‡
EtO H
H M
Br
TeBr2Ar
NaBH4
anti-addition
‡
TeBr2Ar
‡
ArBr2
Te
‡
Br
R
R
anti-addition
R
Ar
H
(R'Te)2, NaBH4
syn-addition
R
MeOH
syn-addition
R
see Chem. Rev. 2006, 1032
M H
R
TeBr2Ar benzene
Br
ArTeBr3
Te
-Te
CHCl3, reflux Ar
ArTeBr3
Li
-LiO2SPh
Ar
Tellurium
January 2014
Unused Elements in Organic Synthesis: Thallium, Tellurium, Lead
Nathan Wilde
R2
M = SnR3, ZnR, Cu, B(OH)2
ZnEt2
R
ZnEt
AlEt2
Syntheses using telluride chemistry
Romo's gymnodimine synthesis
Me
OPMB
Me
H
SnBu3
O
H
Me
O
H
O
HO
HN
OTBS
( )-gymnodimine
I
O
+
O
OH
M
OTBS
OTIPS
Me
H
OH
O
N
Me
Marino's macrolactin A synthesis. JACS 2002, 1664
H
Me
H
O
Tellurium
January 2014
Unused Elements in Organic Synthesis: Thallium, Tellurium, Lead
Nathan Wilde
Me
CO2H
Me
Me
Me
HO
( )-macrolactin A
Me
OTBS
O
O
O
Me
PhO2S
Me
Me
O
TeBu
nBuLi,
(BuTe)2
Me
TBSO
O
Me
NaBH4
Me
>19:1 Z:E
Me
O
O
S
Cl
OEt
TBSO
O
pTol Cl
O
S
pTol
ZnCl2,
DIBAL
Me
MeN Me
OMe
TBSO
Me
OH
O
Cl
S
O
CsF
OH
O
S
pTol
pTol
epoxide
OTBS
NaHMDS
Et2AlCl,
Me
O
O
TsN
OTBS
TsN
TBSOTf
TBSO
(BuTe)2
Me
They got the same
diastereomer using either
olefin geometry,
Me suggesting a stepwise DA.
Me
NaBH4
Barbier-type
macrocyclization
R
N
Me
H
O
O
H
NHK
O coupling
Vinylogous
Mukaiyama
aldol coupling O
O
M
OTBS
TeBu
[Cu]
OTBS
OTBS
M
Me
OTBS BuCuCN(2-Th)Li2
Me
Me
ACIE 2009, 7402. Org. Lett. 2005, 5127. Org. Lett. 2000, 763
O
1. Me2C(OMe)2
2. TFAA
3. Ph3PCHCHO
epoxide
Me
HO
HO
O
O
S
pTol
Me
Me
O
O
Not covered
Miscellaneous telluride applications from Li-Te exchange
Acyl anions
JACS 1990, 455
O
O
nBuLi
R
TeBu
Li
tBu
Me
tBu
Many more ways to make C-Te bonds!
Allylic oxidations
Telluroxide eliminations
Tellurolactonization
Not much on tellurium heterocycles
O
O
R
R
HO Me
R = Ph, 85%
Acyl stannanes or selenoesters don't do this.
Thallium
Butenolide synthesis
R
Tetrahedron 2012, 10601
R
1. BuTeLi
TeBu
Me
O
OH
2. NaBH4
nBuLi,
then CO2,
then H3O+
O
BuTe
TeBu
Standard
Hg(II)
Pd(II)
Tl(III)
Cr2O72Pb(IV)
MnO4-
O
R
R
O
Me
O
HO
Me
Tellurophene synthesis
Me
Tetrahedron 1997, 4199
nBuLi
BuTe
Li
Synthesis 1999, 2001
E+
Bases in Suzuki coupling
Li
Li
TBSO
Org. Lett. 2013, 5122
Me
Me
O
Et3B, O2
O
TePh
OAc
Ph
O
O
H
O
Ph
O H
Me
H
Me
HO
O
AcO
AcO
HO Me
O
Ph
OAc
OBz trigohownin A
OTBS
OTBS
OAc
OTBS
OTBS
O
Pd(PPh3)4
(0.25 eq)
base
TBSO
TBSO
O
OTBS
THF/H2O
OAc
OTBS
(HO)2B
OTBS
OMe
single isomer
Me
Me
OTBS
OTBS
OH
OAc
DCM
87%
No reaction with the selenium acetal.
OH
TBSO
I
E
Te
Radical-polar crossover reaction
electrode potentials
Hg(0) = +0.91 V
Pd(0) = +0.915 V
Tl(I) = +1.25 V
2Cr(III)= +1.33 V
Pb(II) = +1.69 V
Mn(II) = +1.70 V
Li
Te
nBuLi
O
O
Tellurium
January 2014
Unused Elements in Organic Synthesis: Thallium, Tellurium, Lead
Nathan Wilde
Ph
O
B
O
O
Et
O
H
Et
O
‡
Base
Time
KOH
2 hr
TlOH <<30 s
TlOEt 30 min
Ag2O
5 min
JACS 1987, 4756.
Yield
86%
Kishi's palytoxin
92%
substrates
74%
92%
See also Org. Lett. 2000, 2691.
O
OTBS
OMe
These Tl(I) salts also seems to be very capable of alkylating and acylating 1,3-dicarbonyls and
phenols. See Acc. Chem. Res. 1970, 338.
Tl(III) Oxidative Rearrangements
R
OH
Tl(NO3)3
R
Ar
-NO3
R
Ar
(O3N)2Tl
Me
Me
MeOH
-[O] of ketones is also
possible by this
mechanism, but I won't MeO
show any examples.
O
MeO
R
Ar
R
Tl(NO3)2
OMe O
1. H2, Pd/C
2. KOH, MeOH
3. MeLi
Me
Me
Me
O
CO2Me
1. PhI(OAc)2,
KOH
2. HO2CCF3
76%
Ring contraction
MeO2C
Me
H
O
H
Me
Me
O
Me
Me
Ph3P=CH2
O
O
H
H
( )-bakkenolide A
Me
Tl(NO3)3•3H2O
O
H
CO2H
DCM, rt, 24 hr
Me
To shift or to eliminate?
H
90%
O
OH
Me
(III)
Tl
Me
Tl(III)
Me
Me
Me
Me
O
O
-Tl(I) Me
OH
O
Ph
O
O
Tl(OTs)3
OH
Ph
Tl(OAc)2
AcOH, reflux
O
H
Ph
O
TsOH, reflux
Tl(III)
OH
CO2H
Ph
OH
Me
H
Tl(OAc)3
O
H2O
Me
J. Chem. Soc., Perkin Trans. 1 1992, 2565
O
Me
Me
Me
Me
Me
O
JOC 1998, 1716
Me
1. HMDS, TMSI
2. MeLi, then
NCCO2Me
O
Me
HC(OMe)3
MeOH
Me
59%
single diastereomer
Tl(NO3)3
Et
Iodine(III) reagents
gave a 1:1 mixture
of diastereomers
and 40% overall
yield
HC(OMe)3/
MeO2C
MeOH (7:3)
O
Synth. Commun. 1995, 3931
O
Me
Me
Tl(NO3)3
OH
Ar
-TlNO3
-NO3
-aryl esters from aryl ketones
OMe O
JOC 2010, 2877
An example in synthesis of ( )-bakkenolide A
OH
O
Ar
Thallium
January 2014
Unused Elements in Organic Synthesis: Thallium, Tellurium, Lead
Nathan Wilde
Ph
Tl(OTs)2
O
Aryl shift doesn't work with
electron-poor arenes.
O
Ring expansion
Tet. Lett. 1996, 3865
Olefins and alkynes react with Tl(III) with and without rearrangement, much
like other pi-acids. Here is a one-pot synthesis of coumarins.
O
TMSO
HO
Tl(O2CCF3)3
82%
Ph
MeCN
Ph
CO2H
O
O
Tl(OAc)3
Ph
O
O
Tl(O2CCF3)3
74%
MeCN
Ph
TMSO
HO
CO2H
OH
CO2H
(AcO)2Tl
OH
O
Ph
Tl(O2CCF3)3
H O P R
cis:trans = 9:1
70%
MeCN
J. Chem. Res. 1998, 392
OH
Phenol oxidation.
JOC 1994, 5439
Estrone semisynthesis
Me
H
H
MeO
AcO
Br
PhI(O2CCF3) does not activate the olefin, but it does do the other oxidation.
Evans: JACS 1997, 3419 and refs.
Completed Vancomycin w/o Tl(III): ACIE 1998, 2700
OH
Zn
Tl(NO3)3
O
AcO
AcO
R
O
O
I
Tl(NO3)3
R
I
Tl(NO3)2
HOAr
R
OAr
R OMe
R
Me O
3 steps
AcO
R
OAr
80%
H
H
HO
estrone
H
R
Yamamura: Tetrahedron Lett. 1996,
8791 and refs.
CrCl2
one-pot
MeOH
OH
OH
AcO
O
Ar
OH
Vancomycin syntheses
H2O
-CH2O
-TlNO3
-NO3
MeO
OMe
H
Ar
O
Tl(NO3)3
MeOH
HO
Br
O
Pb(OAc)4
HOBr
AcO
O
JOC 1995, 6499
OH
Me O
Me
O P R
Tl(OAc)2
Tl(OAc)2
O
Ph
HO
OH
polyphosphoric acid
Ph
TMSO
AcO
Thallium
January 2014
Unused Elements in Organic Synthesis: Thallium, Tellurium, Lead
Nathan Wilde
R OMe
Thallium
January 2014
Unused Elements in Organic Synthesis: Thallium, Tellurium, Lead
Nathan Wilde
Aromatic thallation
OMe
CHO
Tl(O2CCF3)2
CHO
Tl(O2CCF3)3
SnBu3
Cl
HO2CCF3
N
H
Lead
OMe
CHO
Pd(PPh3)4
Cl
N
H
Cl
N
H
Synlett 1996, 609
Making lead reagents and making C-Pb bonds
For R = vinyl or alkynyl, M = Hg, Sn.
For R = aryl, M = Si, Zn, B(OH)2 are
Pb(OAc)4 + RM
RPb(OAc)3
also used. Note: transfer with B(OH)2
requires Hg(OAc)2 as catalyst.
ArH + PbX4
ArPbX3 + HX
X = OAc, O2CCF3
Ar must be electron-rich
Thallation then halogenation
Tl(O2CCF3)3
Ar
H
Tet. Lett. 1969, 2427
Arylation and vinylation of enolates
KI
Ar
HO2CCF3
(or MeCN)
Tl(O2CCF3)2
Ar
I
CO2Bn
H2O
O
BocHN
Yield
96%
70%
98%
75%
96%
98%
OH
+
BocHN
OBn
DCM, rt
O
O
Tl(O2CCF3)3
CO2Bn
NHTr
Na
Substrate
Product
benzene
iodobenzene
fluorobenzene
o:p = 11:89
o-xylene
4-iodo-o-xylene
anisole
o:p = 17:83
benzoic acid
ortho only
2-methylthiophene 2-methyl-5-iodothiophene
Synlett 1996, 609. Tetrahedron 2001, 5683.
OBn
O
MeO
Pb(OAc)3
MeO
Br
O
O
40%
unoptimized
single diastereomer
Towards diazonamide.
JACS 1984, 5274
Thallation then Pd-coupling
O
OH
Tl(O2CCF3)2
styrene
PdCl2
Enantioselective arylation of phenols
O
OLi
O
MeCN
80%
Ph
+
Me
Me
R
Pb(OAc)3
N
H
MeO
MeO
N H
O
brucine
toluene
-20°C
R = iPr
R = Ph
H
O
H
Me
Br
Yamamoto: JACS 1999, 8943
OH
brucine
Or you can do it with
Ru, Cu, and alkynes:
Org. Lett. 2012, 930.
Not covered
One-electron aryl-aryl coupling
Triorganothallium and tetraorganothallate
Reductions with Tl0
NHTr
O
R
Me
Me
R
99%, >99% de, 61% ee
68%, >99% de, 83% ee
Me
Ph
O Pb
L L
N*
Attempts to make the same C-C bonds, much less enantioselectively, gave lower yields for
Pd-catalysis and no triaryl for Ni-catalysis.
Enolate vinylation towards CP-263,114
nHex
O
O
Pb(OAc)4
CO2Me
O
H
R
(AcO)3Pb
nHex
O
H
H
CO2H
(+)-CP-263,114
SnMe3
O
O
OAc
R = CH2CH2OTBDPS
H
SnMe3
Shair did finish the molecule. Although they didn't use
the organolead vinylation, they did use the same oxyCope strategy. JACS 2000, 7424.
Bioorg. Med. Chem. 2001, 347
OMe Me
More functionalization through radical intermediates
Carbonylation of saturated alcohols
O
H
R
Pb(OAc)4,
CO
benzene
OH
R
JACS 1998, 8692
Me
Me
O
R
O
63%
OMe Me
Me
Me
Pb(OAc)4,
Cu(OAc)2,
quinoline
CO2H
H
Me Me
9%
Pb(OAc)4,
CaCO3
H
H
O
O
Me
5
H
O
SnMe3
2
O
HO
O
O
Me
Tet. Lett. 2000, 9655
H
O
BF3•OEt2
64%
O
O
HO
O
1) LiSnMe 3
2)
BrMg
51%
H
Oxidative cleavage of C-C bonds
R
Bu3Sn
OMe
OO
Shair: JACS 1998, 10784
O
nHex
O
Lead
January 2014
Unused Elements in Organic Synthesis: Thallium, Tellurium, Lead
Nathan Wilde
H
Me Me
[O]
O
H
R
O
R
OH CO R
O
OH [O] R
Tet. Lett. 1966, 1017
OH
O
-oxidation of carbonyls
N
Me
CO2Bn
O
O
O
O
AcO
toluene, reflux
N
Me
via:
O
H2,
Pd/C
Pb(OAc)4
O
CO2Bn
N
CO2Bn
Me
O
O
O
(OAc)2
Pb
Me
h
O
Tet. Lett. 1998, 5693
O
Pb(OAc)4
O
CO2H
CO2H
basketene!
O
+
Na2CO3
Nathan Wilde
Unused Elements in Organic Synthesis: Thallium, Tellurium, Lead
It should be pointed out that more effective structural design of lead species would be
possible if one could control the number of coordination sites and complex ligand exchange.
Carboxylate ligands are labile and rapidly undergo intermolecular exchange. In connection
with this undesirable equilibrium, concomitant formation of oligomeric or polymeric
structures as a result of complex intermolecular interactions imposes significant limitations
on further development in this area of research.
-Taichi Kano and Susumu Saito, 2004
Not covered
Pb(II) as a Lewis acid.
N-arylation (lead version of a Buchwald reaction)
Olefin aziridination
Carbon radicals from organolead species
Alkylation of aldehydes with tetraorganolead species
Allylic and benzylic acetoxylation
Pb(0) reductions
Lead
January 2014