Convenient magnesiation of aromatic and heterocyclic rings bearing a
hydroxy group in presence of LiCl{
Felix Kopp, Arkady Krasovskiy and Paul Knochel*
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: (149)-89-2180-77680;
Tel: (149)-89-2180-77681
Received (in Cambridge, UK) 25th June 2004, Accepted 26th July 2004
First published as an Advance Article on the web 26th August 2004
The reaction of various iodophenols with MeMgCl in
pivaldehyde furnish the corresponding alcohols in good yields
(entries 6 and 10). After transmetallation to the zinc species,
the Grignard reagent 2c can also be successfully used in a
palladium-catalyzed cross-coupling reaction7 with ethyl 4-iodo-
benzoate to give the functionalized biaryl 3h in 71% yield (entry 8).
Interestingly, our method allows us to functionalize selectively 2,6-
diiodophenols with two different electrophiles in the 2- and
6-positions. Thus, the phenol 1c was first converted to 3g (entry 7).
Subsequent conversion of 3g to the corresponding Grignard
reagent 2e and reaction with pivaldehyde provided the 2,6-
difunctionalized phenol derivative 3j (entry 10). Acylation reactions
can be problematic due to competitive acylation of the phenolate.
Thus, the acylation of the Grignard reagent 2c with benzoyl
chloride in presence of substoichiometric amounts of CuCN?2LiCl
(0.3 equiv.) affords the desired product only in 27% yield. The
product of O-acylation, benzoic acid 4-cyano-2-iodo-phenyl ester is
also isolated in 25% yield. Our method can be successfully extended
to several heterocyclic systems. Thus, 3-hydroxy-2-iodopyridine
was converted under similar conditions to the corresponding
dimagnesiated species 4. The reaction with benzaldehyde and
butyraldehyde gave the expected secondary pyridyl alcohols 5a–b
in 70% yield. Allylation with allyl bromide provided the product 5c
in 74% yield (Scheme 2). Similarly, 5,7-diiodo-8-hydroxy-quinoline
was regioselectively converted to the 5-magnesiated species 6. It
afforded after allylation only the 5-allylated product whereas the
reaction with MeSSO2Me led to the 5-thiomethyl-quinoline 7b
(Scheme 2).
In summary, we have shown that the in situ protection of the
hydroxy function of aryl and heteroaryl iodides with MeMgCl in
presence of LiCl produces soluble magnesium phenolates which
undergo rapidly an I/Mg-exchange with i-PrMgCl. Further
applications of this procedure are currently underway in our
laboratories.
We thank the Fonds der Chemischen Industrie, the
G.I.F. (German-Israeli Foundation for Scientific Research and
Development) for a fellowship to F.K. (I-693-7.5/01). We are
grateful to Chemetall GmbH (Frankfurt) and BASF AG
(Ludwigshafen) for generous gifts of chemicals.
presence of LiCl followed by the addition of i-PrMgCl
provides the corresponding magnesiated magnesium
phenolates as THF soluble reagents; this approach can be
extended to heterocyclic compounds bearing a hydroxy group
like pyridines and quinolines.
The preparation of polyfunctional Grignard reagents is an
important task since these organometallics undergo readily bond
formation with a broad range of electrophiles.1 Functionalized
aryl- and heteroaryl-magnesium compounds are best prepared
via an I/Mg-exchange reaction using i-PrMgCl. The reaction is very
general and applies to a wide range of aromatic and heteroaromatic
iodides.2 Unfortunately, the corresponding aryl bromides are much
less prone to undergo the exchange reaction and require often
higher reaction temperatures which are not compatible with
the presence of functional groups.3 Recently, we have found that
the mixed organometallic i-PrMgCl?LiCl allows the performance
of a Br/Mg-exchange with numerous aromatic and heteroaromatic
bromides under exceedingly mild conditions.4 The addition of
LiCl to i-PrMgCl gives an ate-character to the mixed organome-
tallic (i-PrMgCl22Li1). Furthermore, we noticed that also the
resulting arylmagnesium species are generally both more soluble
and more reactive due to the presence of LiCl. Herein, we wish to
report that various polyfunctional iodophenols and related
heterocyclic iodides of type 1 are readily protected in situ as
soluble magnesium alcoholates and smoothly converted to the
dimagnesiated species of type 2 by addition of i-PrMgCl.5 These
bimetallics react with standard electrophiles leading to products of
type 3 in good yields (Scheme 1 and Table 1). Thus, the reaction
of 4-bromo-2,6-diiodophenol (1a) with MeMgCl (1.0 equiv.) in a
THF solution of LiCl (1 equiv.) at 230 uC followed by the addition
of i-PrMgCl (1.1 equiv.) produced the Grignard reagent 2a as
a slightly opalescent solution within 20 min reaction time. After
addition of benzaldehyde (1.2 equiv.), the desired alcohol 3a was
isolated in 84% yield (entry 1 of Table 1). By adding only 0.5 equiv.
of LiCl, the exchange reaction was longer (35 min) and the yield of
3a was only 79%. In the absence of LiCl, the I/Mg-exchange
was sluggish, required 1 h for completion and the yield of 3a
was 69%. The allylation of 2a with ethyl 2-(bromomethyl)acrylate6
furnished the unsaturated ester 3b in 62% yield (entry 2). A range of
functional groups like trifluoromethyl (entries 3 and 4), cyano
(entries 5–10) and ester (entries 11–14) are perfectly tolerated. In the
cases where diiodophenol derivatives were used, a mono-exchange
was always observed. This can be expected since the exchange
rate is inversely proportional to the electron density of the aromatic
ring. After the first exchange, the formed C–Mg bond increases
the ring electron-density and therefore the second exchange is
disfavoured. Both aliphatic and aromatic aldehydes react with
similar yields (entries 3 and 4). Sterically hindered aldehydes like
{ Electronic supplementary information (ESI) available: experimental
Scheme 1
2 2 8 8
C h e m . C o m m u n . , 2 0 0 4 , 2 2 8 8 – 2 2 8 9
T h i s j o u r n a l i s ß T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
Kopp, Felix
