New Reagents for Lithium Assisted ... - Chemspec Events

Jens Röder – Business Development Lithium
© 2010 CHEMETALL GMBH - This document and all information contained herein is the proprietary information of CHEMETALL GMBH.
No intellectual property rights are granted by the delivery of this document or the disclosure of its content. This document shall not be
reproduced or disclosed to a third party without the express written consent of CHEMETALL GMBH. This document and its content shall
not be used for any purpose other than that for which it is supplied.

• Chemetall – The Lithium Company
• New Reagents for Lithium Assisted Addition
and Deprotonation Reactions:
- Improving Grignard-addition reactions -
LaCl 3 x LiCl
- Li-powered metalation reactions - New
Mg- and Zn-amide bases
2

Group Structure 2008
Net Sales: $ 3.380
Employees: 10.000
Specialty
Chemicals
(Chemetall)
Pigments &
Additivs
Advanced
Materials
Net Sales: $ 1.233 Net Sales: $ 1.370 Net Sales: $ 767
Rockwood – Global specialty chemicals and advanced materials company
3

Chemetall Group – At a glance 2008
1923 Lithium operations
started by Metallgesellschaft
1992 Dynamit Nobel-Group
1998 Acquisition Foote Corp.
2004 Rockwood Holdings
Chemetall-Group
Sales: 847 million €
Employees: 3008
Subsidiaries: More than 40
Production sites: 33
Fine Chemicals
Surface
Treatment
• Lithium
• Special Metals
• Metal Sulphides
• Automotive
Technologies
• Advanced
Technologies
• Performance
Products
• System
Technologies
4
4

Chemetall Lithium - Manufacturing Sites
La Porte, TX, USA
New Johnsonville, TN, USA
Langelsheim, Germany
Silver Peak, NV, USA
Taichung, Taiwan
Antofagasta, Chile
Kings Mountain, NC, USA
5

Lithium – Selected Applications
Key Products
Key Applications
Lithium
carbonate
Li-Ionen-Batteries
Glass ceramics
Cement
Aluminum
Lithium
hydroxide
Li-Ionen-Batterien
Grease
CO 2
Absorption
Mining
Lithium
metal
Lithium Batteries
Pharmaceuticals
Al - alloys
Butyllithium
Elastomers
Pharmaceuticals
Agrochemicals
Lithium
specialties
Electronic Materials
Pharmaceuticals
Agrochemicals
6
6

The “Lithium Tree”
Li-Acetylide
Li-
Peroxide
LiBOB
Li-
Perchlorate
Li-
Iodide
Methyllithium
Phenyllithium
Li-t-
Butoxide
Li-
Methoxide
LDA
LHS
Lithium
Metal
Li-
Hydride
Li-tri
(t-butoxy)-
alanate
Butyllithium
Li-
Alanate
Li-Tetraborate
Li-
Nitride
Li-
Amide
Sabalith
Li-
Silicate
Li-
Phosphate
Comments
• Providing lithium compounds
throughout all stages of the
value chain
• Constant expansion due to
new applications
• Optimization according to
customer needs
Li-
Salicylate
Li-
Fluoride
Foils
Lithium
Chloride
Li-
Nitrate
Li-
Citrate
Li-
Benzoate
Li-
Acetate
Li-
Bromide
Li-
Hydroxide
Anodes
Lithium
Carbonate
Li-
Zeolite
Li-
Sulphate
STB
STA STAB MTB
Sodium
Compounds
R-Zn-X
Grignards
Magnesium
Compounds
MDA
Potash
CO2-
Absorption
Products
Brines
Bischofite
Know
How
7

Application Areas
8

1,2-Addition Reactions with R-MgX
Most Grignard products are used for 1,2-addition reactions to carbonyl compounds:
OMgX
R 2 R 3
O
R 2
R 3
R 1 MgX
OMgX
R 2 +
R 3
R 1
enolisation
OMgX
side
reactions
R 2 R 3
reduction
Especially when bulky groups are present in the molecule side reactions take place
which
• lead to lower yields
• require extensive purification of the product
• sometimes inhibit the desired reaction
9

Soluble Lanthanoide Halides - LiCl Complexes
Reducing formation of by-products by Lewis-acid activation of the ketone:
State State of of the theart art solution solutionisisthe theuse useof
of
water waterfree freeCe Ce (III) (III) salts salts (Imamoto (Imamoto
method) method)
-Low -Low solubility solubilityof of CeCl CeCl 3 in process
3 in process
solvent solvent THF THF (0.6 (0.6 weight%) weight%) results results
in in inhomogeneous inhomogeneousreaction
mixtures mixtures
-Handling -Handling of of highly highlyhygroscopic
hygroscopic
CeCl CeCl 3 3
-Only -Onlyspecial specialgrades (pretreatment)
(pretreatment)
CeCl CeCl 3 result in good results
3 result in good results
Improved ImprovedChemetall solution solutionisisthe
the
use useof of LaCl LaCl 3 LiCl solution in
3 x 2 LiCl solution in
THF THF
+ High High solubility solubilityof of LaCl LaCl 3 due to
3 due to
addition additionof of LiCl LiCl
+ Ready Readyto to use useproduct
+ Easy Easy handling handlingand and dosing dosing
+ Low Low water watercontent
+ Lots Lots of of examples examplesdescribed describedin in the the
literature literature
10

LaCl 3 x LiCl - Examples
O
+
MgCl
OH
without additive
CeCl 3 (Imamoto, Dimitriov)
LnCl 3 *2 LiCl
3-5%
80%
>90%
O
+
MgCl*LiCl
OH
Ln = La, Ce, Nd
Ln = La, Ce, Nd
without additive
CeCl 3 (Imamoto, Dimitriov)
LnCl 3 *2 LiCl
4%
-
> 90%
O
+
MgCl
OH
without additive
CeCl 3 (Imamoto, Dimitriov)
LnCl 3 *2 LiCl
21%
-
> 90%
A. Krasovskiy, P. Knochel, Angew. Chem. Int. Ed. 2006, 45,497-500.
11

LaCl 3
x LiCl - Influence of Stoichiometry
MgBr·LiCl
+
Ph
O
Me
Ph HO Me
without additive: 33 %
LaCl 3
.
2 LiCl (30 mol%) 87 %
LaCl 3 . 2 LiCl (100 mol%) 93 %
O
i-PrMgCl + Ph Ph
Ph
OH
Ph
without additive: 3 %
LaCl 3
.
2 LiCl (30 mol%) 65 %
LaCl 3 . 2 LiCl (100 mol%) 86 %
A. Metzger, G. Gavryushin, P. Knochel, Synlett, 2009, 9, 1433
12

LaCl 3
x LiCl – Synthesis of Tryptamines
N
Boc
MeO
OMe
I
Boc
N
Me
1. iPrMgCl . LiCl;
2. LaCl . 3 2LiCl;
OH
O
Boc
3. MeO
N
N Boc
OMe Me
without isolation of intermediates
78%
NH 2
“An “An expedient strategy for for the the synthesis of of
tryptamines and and other other heterocycles…”
MeO
OMe
N
Me
key intermediate for aspidophytine
K. C. Nicolaou et al, Angew. Chem. Int. Ed 2008, 47, 4217.
13

LaCl 3
x LiCl – Industrial Interest
Challenge:
Suppression of side products generated by
enolization of ketone intermediate
Cl
N
OH
O
O
R
Method
Method
A:
A:
1
1
equiv.
equiv.
anhydrous
anhydrous
CeCl
CeCl 3 3
•
•
Special
Special
two
two
step
step
drying
drying
method
method
is
is
essential
essential
•
•
Special
Special
crystal
crystal
habit
habit
of
of
CeCl
CeCl 3
is critical
3
is critical
•
•
Tedious
Tedious
activation
activation
method
method
is
is
required
required
•
•
Low
Low
solubility
solubility
results
results
in
in
heterogenous
heterogenous
reaction
reaction
mixture
mixture
Adv.
Adv.
Synth.
Synth.
Catal.
Catal.
2004,
2004,
346,
346,
1307
1307
Cl
CH 3 -MgCl (5 equiv.)
N
OH
HO CH 3
CH 3
Method
Method
B:
B:
LaCl
LaCl 3
*2 LiCl – THF solution
3
*2 LiCl – THF solution
•
•
Highly
Highly
soluble,
soluble,
homogenous
homogenous
reaction
reaction
conditions
conditions
•
•
Water-free
Water-free
product
product
•
•
Lower
Lower
LaCl
LaCl 3
/ester ratios possible:
3
/ester ratios possible:
1.0
1.0
equiv.
equiv.
LaCl
LaCl 3
: 94,9% yield
3
: 94,9% yield
0.5
0.5
equiv.
equiv.
LaCl
LaCl 3
: 88,3% yield
3
: 88,3% yield
EP
EP
2
2
014
014
633
633
(Lonza
(Lonza
AG)
AG)
key intermediate in the synthesis of Montelukast
14

Application Areas
15

Directed ortho-Metalation (DOM) Reactions
DG
DG
DG
FG
H
Base
FG
M
E +
FG
E
DG = directing group
FG = functional group
Base= e.g. BuLi, LDA, MDA or other
M = Li (BuLi, TMPLi, LDA ..)
• High reactivity
• Low functional group tolerance
M = Mg, Zn
• Lower reactivity
• Higher selectivity and functional
group tolerance
16

Hauser Base with LiCl
N
MgCl/LiCl
(TMP- MgCl/LiCl)
• the combination of Mg and Li increases the deprotonation
power
• nevertheless selectivity and functional group tolerance remain
at a high level
• reagent exhibts excellent solubility and stability in THF
17

TMP-MgCl x LiCl – Crystal Structure
Source of powerful magnesiating ability:
• active basic ligand binds to Mg (not to Li)
• four-coordinate Mg center is coordinatively saturated, but has a labile
THF ligand geminal to TMPH
• bimetallic, ate („Li + MgR 3-
) constitution could be a key factor for the
enhanced magnesiating ability
P. Garcia-Alvarez, R. E. Mulvey, Angew. Chem.Int. Ed. 2008, 47, 8079-8081.
18

TMP-MgCl x LiCl - Examples
high functional group
tolerance…
DG
DG
H
MgCl/LiCl
TMPMgCl/LiCl
FG
FG
DG = OBoc, CO 2 R, COR.....
FG = CO 2 R, CN, COR,.... not FG = CHO, NO 2
LDA
THF, -78 °C
Br
Li
Br
Br
Br
N
…different selectivity
N
Br
Br
TMPMgCl . LiCl (1.1 eq)
THF, -25°C
N
MgCl . LiCl
19

TMP-MgCl x LiCl – Synthesis of Talnetant
CO 2 Et
1) TMPMgCl/LiCl
-10 °C, 3 h
2)
O
B
O
OEt
CO 2 Et
B
R R
N
92 %
Br
3) HCl, Et 2
O
N
71 %
Br
1) iPrMgCl/LiCl
-78°C,2h
2) NC-CO 2 Et
-78 °C to rt, 12 h
Br
O
Ph
NH
Et
OH
N
N
Br
Nadege Boudet, P. Knochel, Org. Lett., 2007,9, 5525-5528.
under research for treatment of schizophrenia
and as potential antipsychotic
20

TMP-MgCl x LiCl – Hexasubstituted Benzene
Multiple functionalization of 3-chlorobenzoate by successive magnesations:
CO 2 Et
1) TMPMgCl LiCl
1,2equiv,0°C,6h
CO 2 Et
CN
1) TMPMgCl LiCl
1,5equiv,-20°C,5h
CO 2 Et
CO 2 Et
CN
Cl
2) TsCN
Cl
2) EtOCOCN
Cl
76%
60%
1) TMPMgCl LiCl
1,2 equiv, -50 °C to -30 °C,
30 min
CO 2 Et
CO 2
Et
CN
1) TMPMgCl LiCl
1,2equiv,-50°C,1.5h
CO 2 Et
CO 2
Et
CN
2) ZnCl 2
3) Pd(PPh 3 ) 4 (2 mol%)
ElOCOCl (1.5 equiv)
CO 2
Et
83%
Cl
2) an electrophile
CO 2
Et
E
Cl
W. Lin, O. Baron, P. Knochel, Org. Lett. 2006, 8, 5673 - 5676
21

TMP-MgCl x LiCl – Magnesation of Chloropyrimidines
Lithiation of pyrimidines is difficult due to high reactivity of the ring
towards addition reactions therefore requiring low temperatures
S
N
N
Cl
TMP-MgCl LiCl
(1,1 equiv.)
THF, 25°C, 5 min
S
N
N
Cl
E
MgCl LiCl
Cl
N
N
S
TMP-MgCl LiCl
(1,1 equiv.)
THF, 25°C, 30 min
Cl
ClLi ClMg
N
N
S
E
Cl
Cl
M. Mosrin, P. Knochel, Chem. Eur. J. 2009, 15, 1468
22

Even higher functional group tolerance – Zn-Amides
In contrast to TMPMgCl/LiCl, TMP 2 Zn/2MgCl 2 /LiCl
• tolerates NO 2 and CHO functionalities
• as well as labile hetero-arenes
• both TMP-groups are active !!
23

Zn-amides - Examples
High functional group tolerance:
O 2 N
Cl
N
TMP 2 Zn (0.55 Eq.)
THF, -25 °C, 1.5 h
Cl
N
NO 2
2
Zn
Br
CuCN * 2 LiCl (5 mol%)
Cl
N
NO 2
80 %
N
CHO
TMP 2 Zn (0.55 eq.)
THF, 25 °C, 45 min
N
CHO
Br
Zn
2 CuCn * 2 LiCl (5 mol%)
CHO
N
Me
Me
Me
71 %
TMP 2 Zn = TMP 2 Zn/2MgCl 2 /2LiCl
S. Wunderlich, P. Knochel, Angew. Chem. Int. Ed. 2007, 46, 7685.
24

Zn-amides – increasing selectivity…..
N
ZnCl LiCl
• highly chemoselective deprotonation (zincation)
• of various sensitive aromatics and heteroaromatics
• even at room temperature (25°C)
M.Mosrin, P. Knochel, Org. Lett. 2009, 11, 1837
25

TMP-ZnCl/LiCl - Examples
Cl
N
N
Cl
Cl
N
N
Cl
• zincation of electron poor aromatics
• with highly sensitive functional group
• at 25°C !
Cl
N
Cl
N
TMPZnCl LiCl
1,1 equiv
25°C
I
Cl
I
I
N
Cl
N
NO 2
F
TMP-ZnCl LiCl
1,1 equiv.
25°C
NO 2
F
ZnCl LiCl
Cl
N
Cl
Cl
N
Cl
F
F
>95%
N
I
N
regio- and chemoselective
deprotonation of diazines at 25°C
M.Mosrin, P. Knochel, Org. Lett. 2009, 11, 1837
26

Chemetall Products – Mg- and Zn-amides
N
MgCl LiCl
20% solution in THF/toluene
reactivity
N Zn N
2LiCl2MgCl 2
15% solution in THF/toluene
N
ZnCl LiCl
20%solutioninTHF
selectivity
Chemetall offers:
• a tool box of bases for effective and selective deprotonation reactions
• with varying basicity and selectivity
• for the synthesis of (highly) substituted aromatics and heteroaromatics
• under reasonable reaction conditions
27

Thank you very much for your kind attention
© 2010 CHEMETALL GMBH - This document and all information contained herein is the proprietary information of CHEMETALL GMBH.
No intellectual property rights are granted by the delivery of this document or the disclosure of its content. This document shall not be
reproduced or disclosed to a third party without the express written consent of CHEMETALL GMBH. This document and its content shall
not be used for any purpose other than that for which it is supplied.