Handbook of Functionalized Organometallics Applications in S

4.3 Further Applications of Functionalized Grignard Reagents
version of a Grignard reagent to either the corresponding phenol or the aniline
derivative using N,O-bis(trimethylsilyl)hydroxylamine 294 as reagent [143]. For
example, the direct reaction of magnesiated aryl derivative 295 with 294 provides
exclusively the corresponding aminophenol 296 in 64% yield (Scheme 4.62; see
also Scheme 4.17) [56].
NH 2
CN
I
1) PhMgCl
2) iPrMgCl
THF, -25 ºC
1h
NHMgCl
MgCl
Me3SiNHOSiMe3 294
NH2 OH
CN
THF, -30 ºC
1.5 h
CN
295 296: 64%
I
NH2 I 1) PhMgCl
I
NHMgCl
MgCl
1) CuCN·2LiCl
I
NH2 NH2 CN
2) iPrMgCl
THF, -25 ºC
1h
CN
69
2) Me3SiNHOSiMe3 294
THF, -30 ºC
1.5 h
CN
297: 65%
Scheme 4.62 Oxidation of Grignard reagents using N,O-bis(trimethylsilyl)hydroxylamine 294.
On the other hand, a transmetallation of Grignard reagent 69 to the corresponding
copper derivative with CuCN´2LiCl [49] leads to the formation of the
diamino derivative 297 in 65% yield (Scheme 4.62). Besides this, several other
reagents are known that allow the formal oxidation of a Grignard reagent to an
amino function and their use has been excellently reviewed elsewhere [144].
Diarylamines, often found in pharmaceuticals, are usually accessed by the reaction
of a nitrogen nucleophile with an aromatic halide following a S NAr mechanism.
Generally, activating groups are required together with a good leaving group
on the aromatic ring (pathway a, Scheme 4.63) [145]. More recently, various arylamines
were prepared by palladium-catalyzed cross-coupling reactions of amines
with aryl halides [146,147,148]. Other transition metals such as copper [149,150]
and nickel [151] have also allowed the performance of C(aryl)-N bond formation
reactions. Oxidative coupling procedures between arylboronic acids and aromatic
or heterocyclic amines mediated by Cu(II) salts proved to be effective as well [149].
In all these approaches, aromatic amines were used as precursors following pathway
a (Scheme 4.63).
On the other hand, one can envision the reaction of an electrophilic nitrogen
synthon with a carbon nucleophile such as a Grignard reagent. In this case, nitrogen
will act as an electrophile, resulting in an ªumpolungº of the reactivity (pathway
b, Scheme 4.63) [152]. The polarization of the nitro group would, in principle,
permit such a retrosynthetic analysis. Indeed, the reaction of nitroarenes with
Grignard reagents was first investigated in pioneering workby Wieland in
1903 [153]. Gilman and McCracken observed the formation of diarylamine, when
reacting a Grignard reagent with nitrosobenzene [154] and later Köbrich sug-
149