Scheme 2. Selective Halogenation and Protection of
Para-Functionalized Anilines of Type 5 Followed by Negishi
Cross-Coupling
Scheme 3. One-Pot Procedure for the Polyfunctionalization
and Deprotection of Aniline Derivative 3a
6c (88%). Additional nitrogen protection using the protecting
group (ClMe2SiCH2)2 (1.0 equiv, -60 °C)10 in the presence
of TMPMgCl‚LiCl (magnesium 2,2,6,6-tetramethylpiperidides
lithium chloride, 2.0 equiv, -60 °C, 1 h) provided the
Scheme 4. Polyfunctionalization and Deprotection of
p-Fluoro-Substituted Aniline 3b
Thus, the sequential halogenation of para-substituted
anilines 5 first, with NCS9 (1-chloro-2,5-pyrrolidinedione,
1.0 equiv, 90 °C, 2-5 h) followed by iodine in the presence
of silver sulfate7a (1.0 equiv, rt, 1.3 h), led to the corre-
sponding 2-chloro-6-iodoanilines bearing functional groups
such as an ester 6a (83%), a fluoride 6b (65%), or a nitrile
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expected building blocks 4a (83%), 4b (81%), and 4c (98%)
(Scheme 2). The Negishi cross-couplings of alkynylzinc
chlorides (R ) Ph, Bu)11 with an aryl iodide of type 4 [Pd-
(PPh3)4 (2-4 mol %), 60 °C, 17 h] afforded the expected
o-alkynylanilines 3a (97%), 3b (96%), and 3c (70%). These
protected anilines 3 undergo smoothly successive metalations
using TMPMgCl‚LiCl and provide after trapping with
different electrophiles fully functionalized anilines of type
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(11) The corresponding alkynylzinc chlorides (R ) Ph, Bu) were prepared
by first metalation with i-PrMgCl‚LiCl or n-BuLi (21 °C, 0.5 - 1 h)
followed by a transmetalation reaction with ZnCl2 (1.0 equiv, c ) 1.0 mol/L
in THF, -30 °C, 30 min); see the Supporting Information.
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