Handbook of Functionalized Organometallics Applications in S

116
4 Polyfunctional Magnesium Organometallics for Organic Synthesis
I
CO 2Me
iPrMgBr
THF, –20 ºC
MgBr
18 19
CO 2Me
NC
CHO
-20 ºC, 0.5 h
c-HexCHO
-20 ºC, 0.5 h
MeO 2C
MeO 2C
Scheme 4.9 The reaction of ester containing arylmagnesium reagent 19 with aldehydes.
MeO
MeO
I
OMe
OTBS
TMS
1) iPrMgCl
O
O
O
MeO
MeO
OMe
O
OH
OH
OTBS
c-Hex
CN
20a: 83%
20b: 72%
I
1) iPrMgBr
THF, 25 ºC, 1 h
H2N CO2Et CO2Et 1) 2N LiOH
THF, rt, 2 h
H2N CO2H OMe
2) EtO2C EtO2C N 22
Boc
OMe
2) 1N HCl
50 ºC, 15 min
OMe
21
-78 ºC, 1 h
3) HCl, ether, rt
23: 79% 24: 81%
2)
THF, -25 ºC
TMS
25 HO O 26: 56%
Scheme 4.10 Reactions of electron-rich arylmagnesium reagents.
Schmalz showed in their synthesis of colchicine, [44] that even building block
25, possessing a very electron-rich aromatic system with three methoxy groups
and an additional alkyl chain, undergoes an I/Mg exchange reaction under very
mild conditions. Thus, the addition of iPrMgCl at ±25 C furnishes the magnesiated
intermediate that reacts with succinic anhydride leading to compound 26
in 56% yield (Scheme 4.10).
As already mentioned, the use of bromides would be advantageous, but the
Br/Mg-exchange reaction is significantly slower than the I/Mg-exchange. Using
iPrMgCl or iPrMgBr, the exchange is sufficiently fast below 0 C only for systems
bearing electron-withdrawing groups [45,46]. A few further examples are reported
in the literature, where aryl bromides are used as starting materials.
For example, Leazer from MerckProcess Research (USA) found the Br/Mgexchange
reaction the most reliable and safe method for the preparation of
Grignard reagent 27, a valuable building blockfor the synthesis of a new neurokin
1 receptor agonist (Scheme 4.11) [47]. It is known, that trifluoromethylphenyl