Handbook of Functionalized Organometallics Applications in S

4.2Methods of Preparation of Grignard Reagents and their Uncatalyzed Reactions
tageous from an economical point of view. For instance, the exchange reaction of
1-chloro-2,3,4,5,6-tetrafluorobenzene (14a) with EtMgBr, requires 1 h at room temperature
to reach complete conversion to the Grignard reagent, whereas the corresponding
bromo- and iodo-congeners 14b and 14c react already at 0 C within
1 min to compound 15 (Scheme 4.8).
F
F
F
F
F
F
F
X
14a: X=Cl
14b: X=Br
14c: X=I
Br
Br
F
F
EtMgBr
X=Cl; rt, 1 h
X=Br; 0 ºC, 1 min
X=I; 0 ºC, 1 min
EtMgBr
-78 ºC, 15 min
F
F
F
F
F
15
F
F
MgBr
F
F
MgBr
16 17: 93%
Scheme 4.8 Preparation of polyhalogenated Grignard reagents 15 and 17.
MgBr
It was shown that 1,4-dibromo-2,3,5,6-tetrafluorobenzene (16) is readily converted
to the corresponding 1,4-dimagnesium species 17 with EtMgBr
(Scheme 4.8). Similarly, Furukawa showed that 2-iodopyridine leads to the corresponding
Grignard reagent within 0.5 h by reaction with EtMgBr at 25 C [38].
These early results indicate the synthetic potential of the halogen±magnesium
exchange reaction and recent developments will be discussed in the following
chapters [39].
4.2.3.2 The Preparation of Functionalized Arylmagnesium Reagents
Functionalized aryl iodides react readily with iPrMgBr or iPrMgCl in THF below
0 C leading to a range of functionalized arylmagnesium iodides [40]. Sensitive
carbonyl group derivatives like nitriles, esters or amides are well tolerated. Typically,
the treatment of methyl 4-iodobenzoate (18) with iPrMgBr in THF at ±20 C for
30 min produces the functionalized Grignard reagent 19, which is stable for several
hours below 0 C and reacts smoothly with aldehydes at ±20 C leading to the
expected alcohols 20a and b in 72±83% yield (Scheme 4.9) [41].
Aromatic iodides bearing electron-donating groups, such as compound 21,
undergo the iodine±magnesium exchange as well, but usually higher temperatures
(25 C) and elongated reaction times are necessary [40,42]. The addition of
the resulting arylmagnesium species to diethyl N-Boc-iminomalonate 22 [43] furnishes
adduct 23 in 79% yield. Saponification followed by decarboxylation leads to
a-amino-acid 24 in 81% yield (Scheme 4.10) [42].
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