Chiral bromine-lithium exchange
catalysed by diamines
Jezabel Praz, Quentin Perron, Alexandre Alexakis*
University of Geneva, Departement of Organic Chemistry, 30 Quai Ernest Ansermet, CH-1211
Geneva, Switzerland
Abstract - We report one of the first chiral halogen-lithium exchange.[1,2] Different classes of prochiral polybromides compounds have been tested in a
chiral bromine-lithium exchange in presence of different diamines with enantiomeric excess up to 63%.[2] The first catalytic desymmetrisation of the
2,2’,6,6’-tetrabromobiphenyl 1 and analogues was described by the bromine -lithium exchange catalyzed by 0.5 eq. of either diamines or diether
derivatives.[3]
Br
Achiral molecules
Br
Br
1
Chiral Br-Li
exchange
Sub-stoichiometric
4 eq RLi
0.5 eq Diamine
2 eq of E+
Br
Br
Chiral molecules
X
PG
X = O or N
Stoichiometric
2 eq RLi
2 eq Diamine
2 eq of E+
1 eq RLi
1 eq Diamine
1 eq of E+
Enantioselective
step
Br
E
E
X
PG
Axial chirality
Br
Br
1) Diamine,RLi,
toluene, -78°C
Central chirality
O
Br
Br
2) DMF
E
Central chirality
Axial chirality
Br
Br
Br
Br
Br
Br
X
PG
Br
1) Diamine 1eq, RLi,
toluene, -80°C, 20 min
O
1
Br
X
PG
2) MeOH
2
X= O, PG= 3 H
4 Me
5 TMS
6 TBDPS
7 MOM
8 MEM
X= N, PG= 9 Boc
Catalysts screening
Stoichiometric reaction : Diamine 2eq., n-BuLi 2eq., 20 min
Substrates and Catalysts studies
N
N
100% conv.
-50% ee
N
N
N
N
100% conv.
29% ee
N
H
O
N
N
89% conv.
-50% ee
100% conv.
60% ee
O
N
N
N
N
100% conv.
-24% ee
-58% ee (with s-BuLi)
100% conv.
-22% ee
Sub-stoichiometric reaction : Diamine 0.5eq., n-BuLi 4eq., 2h
N
N
100% conv.
60% ee
N
N
100% conv.
20% ee
Substrate
ligand
RLi
Time
Conv
1
3
TMEDA
n-BuLi
1h30
4%
ee
-
2
4
(-)-sparteine
n-BuLi
45min
73%
16%
3
5
(-)-sparteine
n-BuLi
2h30
15%
10%
4
6
(-)-sparteine
n-BuLi
2h
nd
6%
n-BuLi
2h
nd
7%
n-BuLi
1h30
45%
29%
n-BuLi
2h
55%
4%
n-BuLi
2h
65%
6%
n-BuLi
2h
58%
9%
n-BuLi
2h
50%
14%
N
H
(-)-sparteine
100% conv.
66% ee
Entry
N
N
100% conv.
72% ee
N
5
6
6
7
7
7
8
8
9
8
10
9
N
N
(-)-sparteine
N
N
(-)-sparteine
N
100% conv.
62% ee
N
N
(-)-sparteine
References - [1] a) Fan, C.-A.; Ferber, B.; Kagan , H., B.; Lafon, O.; Lesot, P.
N
N
100% conv.
55% ee
N
N
100% conv.
37% ee
OMe OMe
OMe OMe
100% conv.
80% ee
100% conv.
-54% ee
Tetrahedron: Asymmetry 2008, 19, 2666–2677; b) Brückner et
al.,Chem.Eur.J., 2009, 15, 6688-6703
[2] Perron, Q.; Praz, J.; Alexakis, A. Tetrahedron: Asymmetry
2009, 20, 1004-100
[3] Perron, Q.; Alexakis, A. Unpublished results 2010
Acknowledgments - We thank the Swiss National Science Foundation (No. 200020-113332) for financial support and Chemetall GmbH for
generous gift of i-PrMgCl.LiCl.