COMMUNICATION
Halogen–magnesium exchange on unprotected aromatic and
heteroaromatic carboxylic acids{
Felix Kopp, Stefan Wunderlich and Paul Knochel*
Received (in Cambridge, UK) 2nd January 2007, Accepted 17th January 2007
First published as an Advance Article on the web 22nd February 2007
DOI: 10.1039/b618923g
Grignard reagents show a good reactivity towards electrophiles
The magnesiation of halogenated aromatic and heteroaromatic
carboxylic acids is accomplished by their treatment with
MeMgCl in the presence of LiCl and subsequent reaction with
i-PrMgCl?LiCl; the resulting double-magnesiated species react
with a variety of electrophiles in up to 97% yield.
like cyclohexane carbaldehyde, 4-bromobenzaldehyde or allyl
bromide. The desired products 3f–h have been isolated in 69–
91% yield (entries 6, 7, 8). The reaction of the organomagnesium
reagent 2e with TsCN gives rise to the benzonitrile 3i in 55% (entry
9). Also, an ethyl ester (1f) or a sensitive pivalate like 1g are
appropriate substrates. The desired products from the reactions
with pivaldehyde and anthraldehyde, 3j and 3k, are isolated in 70
and 67%, respectively (entries 10 and 11). Finally, a sterically
hindered substrate like 1h reacts smoothly under the usual reaction
conditions; subsequent treatment with p-bromobenzoyl chloride
affords the ketoacid 3l in 81% yield (entry 12).
The preparation of functionalized Grignard reagents is an
important goal, since these organometallics represent unique tools
for the construction of complex molecules.1 The halogen–
magnesium exchange is a broadly applicable and convenient
method for the generation of polyfunctional Grignard reagents,
recently being extended by the use of LiCl as an additive.2 Besides
increasing the reactivity of Grignard reagents,3 we have found that
LiCl dramatically improves the solubility of organometallics.4 A
double-magnesiation strategy5 allows the generation of Grignard
reagents derived from iodophenols without the need of a
protecting group. A similar approach would be very useful for
the functionalization of carboxylic acid derivatives.6 The use of
mixed Li/Mg-reagents, as investigated by Mase is not applicable to
a broad range of functionalized substrates. Indeed, the high
reactivity of lithium reagents precludes the presence of many
functional groups.7
Highly activated heteroaromatic acids like 5-bromo-2-furoic
acid (4), 5-bromothiophene-2-carboxylic acid (5), or 4,5-dibro-
mothiophene-2-carboxylic acid (6) react rapidly (220 uC to rt)
(Scheme 2). Thus, 5-bromo-2-furoic acid (4) is magnesiated in only
30 min and its reactions with allyl bromide and 4-(trifluoro-
methyl)benzaldehyde lead to the expected products 7a and 7b in 92
and 88% yield. Analogously, the corresponding thiophene
carboxylic acid 5 was metallated and reacted with MeSSO2Me
to give the thioether 8a in 93% yield. Transmetallation of the same
Grignard reagent with ZnCl2 followed by a Pd-catalyzed cross-
coupling9 with 4-iodo-N,N-dimethylaniline employing Pd(dba)2
(5.0 mol%) and tri-2-furylphosphine (10 mol%) as a catalyst
system, affords the functionalized 2-arylated thiophene 8b in 95%
yield. 4,5-Dibromothiophene-2-carboxylic acid (6) can be selec-
tively magnesiated in the 5-position (220 uC, 1 h).10 The resulting
Grignard reagent was reacted with allyl bromide providing the
desired product 9a in 97% yield. The reaction with ethyl
chloroformate gives, after recrystallization, the 5-carbethoxythio-
phene derivative 9b (56%).
Thus, 4-iodobenzoic acid was reacted with MeMgCl (1.0 equiv.)
in the presence of LiCl (1.0 equiv.) at 220 uC, and subsequently
i-PrMgCl?LiCl (1.1 equiv.) was added to perform the iodine–
magnesium exchange. The reaction mixture was allowed to warm
up to room temperature. After 0.5 h, a full conversion to the
desired magnesium reagent was observed. The reactions with
typical electrophiles like benzaldehyde or benzoyl chloride afforded
the desired products 3a and 3b in 95 and 71% isolated yield
(Table 1, entries 1, 2). By applying a mild acidic workup using
citric acid, even a sensitive boronic ester can be installed by a
sequential reaction with B(Oi-Pr)3 and 2,2-dimethylpropane-1,3-
diol, yielding the desired boronic ester (3c) in 50% yield (entry 3).
Also meta- and ortho- positions can be easily functionalized
using this protocol. Using ethyl 2-(bromomethyl)acrylate,8 the
expected allylated product 3d is produced in 78% yield (entry 4).
The lactone 3e is obtained by the reaction with cyclohexane
carbaldehyde in 87% yield (entry 5). Several functionalized
substrates can be used. Halides like a bromide (1d) or an
additional iodide (1e) are tolerated and the corresponding
Department Chemie, Ludwig-Maximilians-Universita¨t Mu¨nchen,
Butenandtstr. 5-13, Haus F, 81377 Mu¨nchen, Germany.
E-mail: Paul.Knochel@cup.uni-muenchen.de;
Fax: (+49)-89-2180-77680; Tel: (+49)-89-2180-77681
{ Electronic supplementary information (ESI) available: experimental
procedures for the starting materials and products as well as the
characterization of all compounds. See DOI: 10.1039/b618923g
Scheme 1
This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 2075–2077 | 2075
Kopp, Felix
