Angewandte
Chemie
DOI: 10.1002/anie.201205465
Synthetic Methods
The ortho and meta Magnesiation of Functionalized Anilines and
Amino-Substituted Pyridines and Pyrazines at Room Temperature**
Gabriel Monzꢀn, Ilaria Tirotta, and Paul Knochel*
The directed lithiation[1] of anilines or aminopyridines is an
important method[2] for preparing functionalized amino-
substituted arenes and N-heterocycles. These scaffolds may
have pharmaceutical applications as antiviral agents[3] or
antibiotics.[4] Although directed ortho lithiations give access
to various aminated aromatics, the use of strong lithium bases
such as nBuLi or tBuLi is incompatible with standard
carbonyl functionalities, such as an ester or a nitrile, as well
as with sensitive heterocyclic moieties. Generally the amino
group was protected with a pivaloyl, a tert-butoxycarbonyl, or
a trifluoroacetyl group leading to substrates of type ArNH-
COR, which, after treatment with two equivalents of base,
afforded an ortho-lithiated bimetallic intermediate.[5] Low
temperatures were usually required for these lithiations.[6]
Also, the directed lithiation of trifluoroacetamides led to
extensive side products.[7] Recently, we have shown that aryl
magnesium reagents are readily prepared by metalation with
TMPMgCl·LiCl (1; TMP = 2,2,6,6-tetramethylpiperidyl)[8]
and that this magnesiation is compatible with sensitive
functional groups.[9] However, the magnesiation of anilines
proved to be sluggish and inefficient with most directing
groups. After extensive experimentation, we found that
trifluoroacetamides of type 2 are readily deprotonated with
MeMgCl (1.1 equiv) and ring-metalated at room temperature
with TMPMgCl·LiCl (1; 1.2 equiv), leading to dimagnesiated
intermediates of type 3, which were efficiently trapped with
a range of electrophiles (E) to provide substituted anilides of
type 4 (Scheme 1).
The trifluoroacetamides of type 2 are readily obtained
from the corresponding anilines in high yields and are easy-to-
handle crystalline solids.[10] Thus, the treatment of the
dichloroaniline derivative 2a (1.0 equiv) with MeMgCl
(1.1 equiv, THF, 08C, 10 min) followed by the addition of
TMPMgCl·LiCl (1; 1.2 equiv, 258C, 4 h) led to the expected
ortho-magnesiated intermediate of type 3, which was
quenched with various electrophiles such as iodine (Table 1,
entry 1), ethyl 2-(bromomethyl)acrylate[11] (entry 2), or
(BrCl2C)2 (entry 3) to afford the functionalized aniline
Scheme 1. The ortho magnesiation of trifluoroacetamides (3) and
reaction with electrophiles (E), leading to amides of type 4.
derivatives 4a–c in 68–72% yield. A further ortho metalation
of 4c was realized using the same procedure with a metalation
time of 4 h at 258C. After iodolysis, the tetrahalogenated
anilide 4d was obtained in 69% yield (entry 4). This double
ortho,ortho’ functionalization allows a versatile preparation
of pentasubstituted aniline derivatives. Thus, the quenching of
the bis(magnesiated) derivative of 2a with MeSSO2Me
produced the thioether 4e in 76% yield. Applying the same
metalation sequence (THF, 258C, 4 h) furnished a bis(magne-
sium) intermediate, which after transmetalation with CuCN·2
LiCl[12] (1.1 equiv) and acylation with 4-chlorobenzoyl chlo-
ride (À20 to 258C, 3 h) afforded, after work-up (aq. sat.
NH4Cl), directly the unprotected aniline 4 f in 81% yield
(Scheme 2).
Similarly, the bis(trifluoromethyl) trifluoroacetamide 2b
was metalated under these optimized conditions (258C, 4 h),
leading, after bromination, to the ortho-bromoanilide (4g) in
74% yield. Further magnesiation of 4g with MeMgCl and
TMPMgCl·LiCl (1; 1.2 equiv, 258C, 4 h) followed, after
transmetalation with ZnCl2 (1.2 equiv, 08C, 10 min), by
a
Negishi cross-coupling[13] (3% [Pd(dba)2], 5% P(o-
furyl)3,[14] 508C, 3 h) provided the biphenyl 4h in 78% yield
(Scheme 2). The use of a magnesium base (1) instead of
a strong lithium base[15] allows the presence of a cyano group
in the starting trifluoroacetamide. Thus, the magnesiation of
the benzonitrile 2c (258C, 2 h) with our base system gave
access to a room temperature stable magnesium intermediate,
which after Negishi cross-coupling[13] (258C, 3 h), led to the
biphenyl 4i in 65% yield (Table 1, entry 5). Similarly, the
aminonitrile 2d was magnesiated (258C, 3 h) and trapped
with various electrophiles, affording the expected products
4j–l in 72–85% yield (entries 6–8). The metalation of
trifluoroacetamides bearing less-electron-withdrawing sub-
stituents such as the chloro derivative 2e was best performed
using the combination of MeMgCl (1.1 equiv, 08C, 10 min)
and TMP2Mg·2LiCl[16] (5; 1.2 equiv, 258C, 5 h). Cross-cou-
pling or allylation of the intermediate magnesium reagent
furnished the desired products 4m,n in 65% yield (entries 9
and 10). Similarly, the chlorotrifluoromethyl trifluoroaceta-
mide 2 f was best magnesiated with this last base combination
[*] M. Sc. G. Monzꢀn, Dr. I. Tirotta, Prof. Dr. P. Knochel
Ludwig Maximilians-Universitꢁt Mꢂnchen
Department Chemie & Biochemie
Butenandtstrasse 5–13, Haus F, 81377 Mꢂnchen (Germany)
E-mail: Paul.Knochel@cup.uni-muenchen.de
[**] We thank the Fonds der Chemischen Industrie and the European
Research Council (ERC) for financial support. We also thank Evonik
Industries AG (Hanau), and BASF AG (Ludwigshafen) for generous
donations of chemicals.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!
Monzon, Gabriel
