A study on the metalation of alkoxydibromobenzenes

Article abstract of DOI:10.1016/j.tetlet.2005.04.065

The metalation of (quasi)alkoxy-substituted dibromobenzenes C ₆H₃(OR)Br₂ with lithium diisopropylamide (LDA) has been investigated. For 1-(quasi)alkoxy-3,5-dibromobenzenes (R = Me, TMS), different selectivities were observ

Full text of DOI:10.1016/j.tetlet.2005.04.065

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4175–4178
A study on the metalation of alkoxydibromobenzenes
*
´
Marek Da˛browski, Joanna Kubicka, Sergiusz Lulinski and Janusz Serwatowski
Warsaw University of Technology, Faculty of Chemistry, Noakowskiego 3, 00-664 Warsaw, Poland
Received 23 February 2005; revised 11 April 2005; accepted 14 April 2005
Available online 29 April 2005
Abstract—The metalation of (quasi)alkoxy-substituted dibromobenzenes C6H3(OR)Br2 with lithium diisopropylamide (LDA) has
been investigated. For 1-(quasi)alkoxy-3,5-dibromobenzenes (R = Me, TMS), different selectivities were observed depending on
reaction conditions and the size of the alkoxy group. The methoxy group was an effective ortho-director whereas this was not
the case for the bulky trimethylsilyloxy group. The metalation of related 2,5-dibromoanisole was also examined showing a signifi-
cant meta-directing effect by the methoxy group. The thermal stability of aryllithium intermediates is significantly lower when
lithium is flanked by a bromine and a methoxy group, whereas 4-(quasi)alkoxy-2,6-dibromoaryllithiums are less labile.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
methoxybenzyne, which was trapped with furan as a
Diels–Alder adduct.9 Our study focused on the reactiv-
ity of related alkoxydibromobenzenes and is an exten-
sion of our recent investigations on the metalation and
functionalization of various bromobenzenes.10 We
attempted to use an internal TMSCl quench to trap the
labile 2-bromo-6-methoxyphenyllithium at À70 and
À90 °C, however, we obtained only a low yield (ca.
10%) of impure 3-bromo-2-(trimethylsilyl)anisole.
3-Methoxy-N,N-diisopropylaniline derived from the
addition of diisopropylamine to 3-methoxybenzyne
was formed as the main product. Recently, Schlosser
and Castagnetti demonstrated that 2-bromo-6-(trifluoro-
methoxy)phenyllithium generated from 1-bromo-3-(tri-
fluoromethoxy)benzene is stable at À78 °C.11
Directed ortho-metalation of substituted arenes has been
thoroughly investigated for many years and nowadays it
is a powerful method for the diverse functionalization of
aromatic systems.1 However, bromine has been ranked
as a relatively weakly ortho-directing group and hence
metalation of bromoarenes has not been the subject of
many studies. To effect ortho-directed deprotonation,
nonnucleophilic strong bases such as LDA must be used
as bromine–lithium exchange predominates when
alkyllithium bases are employed. The aryllithium inter-
mediates thus generated are usually very labile and
may readily isomerize2 or release the corresponding ary-
nes.3 This latter reaction has found numerous synthetic
applications,4 for example, in the synthesis of polycyclic
systems.5,6 Due to the limited stability of ortho-bromo-
aryllithium species, their subsequent trapping is fre-
quently difficult. An internal quench with an
appropriate electrophile may often be the only alterna-
tive.7 The metalation of simple bromoanisoles was
investigated showing 2- and 4-bromoanisole to be resis-
tant to LDA-mediated deprotonation under cryogenic
conditions.8 However, the metalation of 3-bromoanisole
proceeded readily between the two substituents reflect-
ing their enhanced activating effect, but the resultant
aryllithium decomposed instantaneously to form 3-
2. Results and discussion
We investigated the metalation of other compounds re-
lated to the parent 3-bromoanisole, namely, 1-alkoxy-
3,5-dibromo- and 1-alkoxy-2,5-dibromobenzenes. The
metalation of 3,5-dibromoanisole was thoroughly exam-
ined (Scheme 1). It is known that the position between
two bromine atoms can be readily deprotonated with
LDA due to their cooperating acidifying effect.12 How-
ever, we observed that the position flanked by bromine
and the methoxy group was deprotonated rather than
that between the two bromines, thus resembling the
s-BuLi promoted lithiation of 3,5-dichloroanisole.13 The
resultant aryllithium species was not stable on the mac-
roscopic time scale at around À70 °C and decomposed
Keywords: ortho-Metalation; Dibromobenzenes; Silylation.
*
Corresponding author. Tel.: +48 22 660 7575; fax: +48 22 628
2741; e-mail: serwat@ch.pw.edu.pl
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.065

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M. Da˛browski et al. / Tetrahedron Letters 46 (2005) 4175–4178
OMe
OMe
OMe
OMe
Br2
SiMe3
Br
HN(i-Pr)2
LDA / THF
LDA / TMSCl
–
70 °C, THF
–70 °C, LiBr
Br
Br
Br
N(i-Pr)2
Br
Br
Br
LDA
– 85 °C, THF
0 °C, CHCl3
OMe
OMe
OMe
OMe
OMe
Br
Br
Li
Br
CHO
+
1. DMF
2. H3O+
+
Br
Br
Br
Br
Br
Br
Br
CHO
Li
1a (45%)
1b (31%)
1c
Scheme 1. LDA-mediated metalation of 3,5-dibromoanisole.
via the corresponding aryne to form 3-bromo-5-meth-
oxy-N,N-diisopropylaniline as the major product in
ca. 50% yield. On the other hand, it could be effectively
trapped in situ with TMSCl to give 3,5-dibromo-2-(tri-
methylsilyl)anisole, contaminated with some impurities
but not with its regioisomeric analogue. This compound
was resistant to subsequent metalation/silylation and
underwent easy desilylation with bromine to produce
2,3,5-tribromoanisole 1a.14 We found that it was possi-
ble to generate 2,4-dibromo-6-methoxyphenyllithium
in the absence of the trapping electrophile at a tempera-
ture around À85 °C without instantaneous decomposi-
tion. Thus, the slight structural modification of placing
a bromine at the 4-position had a remarkable positive
effect on the thermal stability of the 2-bromo-6-meth-
oxyphenyllithium system. However, under these condi-
tions the lithiation was not regioselective as a mixture
of 3,5-dibromo-2-(trimethylsilyl)anisole and 3,5-di-
bromo-4-(trimethylsilyl)anisole in a ratio of 85:15 was
formed after subsequent TMSCl quench, and a substan-
tial amount of 3,5-dibromoanisole was recovered. Simi-
larly, 2,4-dibromo-6-methoxybenzaldehyde 1b and the
isomeric 2,6-dibromo-4-methoxybenzaldehyde 1c were
obtained in 55% overall yield and in a comparable ratio
with DMF as the electrophile, the major product 1b
being isolated in 31% yield. DMF is known to react
reversibly with some aryllithiums and the composition
of the reaction mixture might not reflect the real propor-
tion of aryllithium isomers before trapping.15 However,
the self-consistency with in situ silylation suggests that
this is not the case here. The selectivity of the reaction
is time dependent: when the lithiation was carried out
for 2 h prior to the DMF quench, the mixture of 1b
and 1c was formed in a ratio of 70:30. These results sug-
gest that the lithiation of 3,5-dibromoanisole at the
2-position is kinetically favored but the resultant aryl-
lithium isomerizes slowly to form 2,6-dibromo-4-
methoxyphenyllithium.
In the case of 1,3-dibromo-5-(trimethylsilyloxy)benzene
the bulky substituent completely protects the neighbor-
ing hydrogen atoms against attack by LDA. Thus, the
position between the two bromine atoms is selectively
deprotonated as shown in Scheme 2. The resultant aryl-
lithium species is stable at a temperature around
À70 °C. Apparently, the stabilization by the second bro-
mine is better than that provided by the methoxy group.
The trimethylsilyloxy group was readily cleaved during
aqueous workup to liberate the hydroxyl group, which
offers synthetic potential for subsequent transform-
ations. For example, treatment with DMF afforded
2,6-dibromo-4-hydroxybenzaldehyde 2a in good yield.
Similarly, an iodine quench followed by hydrolysis gave
3,5-dibromo-4-iodophenol and subsequent Williamson
methylation afforded 3,5-dibromo-4-iodoanisole 2b.
This compound was subjected to iodine–lithium ex-
OH
OSiMe3
OSiMe3
Br
LDA
—70 °C, THF
1. DMF
2. H3O+
Br
Br
Br
Br
Li
Br
CHO
2a (68%)
1) I2
2) H3O+
3) Me2SO4, OH—
OMe
OMe
OMe
CHO
1. DMF
2. H3O+
n-BuLi
—80 °C, THF
Br
Br
2b (57%)
Scheme 2. LDA-mediated metalation of 1,3-dibromo-5-(trimethylsilyloxy)benzene.
Br
Br
Br
Br
I
Li
1c (78%)

M. Da˛browski et al. / Tetrahedron Letters 46 (2005) 4175–4178
4177
change producing an aryllithium that was stable at
temperatures around À80 °C and could be successfully
trapped with DMF as shown in Scheme 2 to give a good
yield of 1c—the by-product of the direct lithiation of
3,5-dibromoanisole. It should be noted that attempted
isomerization of this aryllithium by the addition of
diisopropylamine prior to addition of DMF failed and
again pure 1c was isolated. To summarize, a selective
and diverse functionalization of 3,5-dibromophenol at
the 4-position can be achieved using an O-silylation/
metalation sequence.
Attempted in situ disilylation of 1,4-dibromo-2,5-
dimethoxybenzene using stoichiometric amounts of
LDA and TMSCl gave a product, which X-ray analysis
revealed to be an intermolecular 1:1 compound 4a
consisting of the starting material and the disilylation
product 4b. Conformational restrictions imposed by
methoxy groups did not prevent subsequent metala-
tion/silylation but significantly decreased the reactivity:
1,4-bis(trimethylsilyl)-2,5-dibromo-3,6-dimethoxybenzene
4b was isolated in good yield when a 2.5-fold excess (i.e.,
5:1) of LDA and TMSCl was used (Scheme 3).
The metalation of 2,5-dibromoanisole was performed
using 2 equiv of LDA followed by an internal TMSCl
quench (Scheme 3). According to GC/MS analysis,
2,5-dibromo-3,6-bis(trimethylsilyl)anisole was the major
product (43%), accompanied by substantial amounts of
2,5-dibromo-3-(trimethylsilyl)anisole (22%) and 3,6-di-
bromo-2-(trimethylsilyl)anisole (6%) as well as unreacted
starting material (14%). Thus, in contrast to 3,5-di-
bromoanisole, the metalation is not preferentially ortho-
directed by the methoxy group. In another experiment,
lithiation at around À85 °C followed by a DMF quench
afforded 2,5-dibromo-3-methoxybenzaldehyde 3a in
moderate yield. The regiochemistry of metalation is
clearly controlled primarily by the bromine. Deproton-
ation at the 3-position suggests that the long-range
inductive effect of the methoxy group is responsible for
the preferred orientation. We believe that the relatively
weak susceptibility of the angular position (the position
between two substituents) to undergo metalation can be
rationalized in terms of steric interactions between the
bromine and the methoxy group. Due to these inter-
actions, the methoxy group becomes anti-oriented with
respect to the neighboring bromine, and this conformation
provides, in turn, significant steric hindrance in the
vicinity of the neighboring hydrogen, which results in
its decreased reactivity.
In addition, the metalation of 3-bromo-5-fluoroanisole
with LDA was investigated to probe the relative
ortho-directing ability by bromine versus methoxy in
the presence of strongly acidifying fluorine.16,17
According to our earlier findings,10 disilylation was effi-
cient at both positions adjacent to fluorine, to give
2,4-bis(trimethylsilyl)-5-bromo-3-fluoroanisole
5
in
84% yield (Scheme 4). The introduction of a third
TMS group was not possible, presumably reflecting a
strong buttressing effect of the two TMS groups in 5.
Lithiation followed by a DMF quench afforded a
mixture of 4-bromo-2-fluoro-6-methoxybenzaldehyde
and 2-bromo-6-fluoro-4-methoxybenzaldehyde (40:60).
Hence, in this case bromine revealed a slightly stronger
ortho-directing power in comparison with a methoxy
group.
In conclusion, metalation of alkoxydibromobenzenes
with LDA proceeds with varying regioselectivity. Bro-
mine is able to compete with methoxy as the effective
ortho-director to a significant extent. Bulky trimethyl-
silyloxy groups prevent ortho-lithiation and this property
facilitates regioselective functionalization of alkoxydi-
bromobenzenes. In addition, the regioselectivity of the
metalation is strongly influenced by a combination of
steric (conformational) factors with distinct long-range
OMe
OMe
OMe
OMe
OMe
OMe
Br
Br
Br
Li
Br
SiMe3
Me3Si
Br
Br
Me3Si
Br
Br
1. DMF
2. H3O+
2 x LDA / 2 x TMSCl
70 C, THF
LDA
+
+
°
—
°
— 85 C, THF
Br
CHO
Br
Br
Br
SiMe3
3a (47%)
(22%)
(6%)
(43%)
OMe
OMe
OMe
OMe
OMe
Br
Me3Si
Br
Br
SiMe3
Br
Me3Si
Br
Br
5 x LDA / 5 x TMSCl
2 x LDA / 2 x TMSCl
*
°
°
—
70 C, THF
—
70 C, THF
Br
Br
SiMe3
OMe
OMe
OMe
4a (96%)
4b (86%)
Scheme 3. LDA-mediated metalation of 2,5-dibromoanisole and 1,4-dibromo-2,5-dimethoxybenzene.
OMe
OMe
OMe
OMe
OMe
Li
OMe
Li
OHC
Me3Si
F
1. DMF
2. H3O+
LDA
70 °C, THF
2 x LDA / 2 x TMSCl
–70 °C, THF
+
+
–
F
Br
F
Br
F
Br
F
Br
F
Br
Br
CHO
SiMe3
(40%)
(60%)
5a (84%)
Scheme 4. LDA-mediated metalation of 3-bromo-5-fluoroanisole.

4178
M. Da˛browski et al. / Tetrahedron Letters 46 (2005) 4175–4178
interactions as demonstrated by the behavior of 2,5-
dibromoanisole.
graphic data (excluding structure factors) for the
structure in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication numbers CCDC 264395. Copies of the
data can be obtained free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[fax: +44 (0)1223 336033 or e-mail: deposit@ccdc.cam.
ac.uk]. Supplementary data associated with this article
can be found in the online version, at doi:10.1016/
j.tetlet.2005.04.065.
3. A typical procedure for metalation of alkoxydi-
bromobenzenes
In a typical lithiation, LDA freshly prepared from diiso-
propylamine (2.42 g, 24 mmol) and n-BuLi (10 M solu-
tion in hexanes, 2.4 mL, 24 mmol) in THF (15 mL) at
À70 °C was added dropwise (ca. 15 min) to a solution
of 3,5-dibromoanisole (6.48 g, 20 mmol) in THF
(30 mL) at À85 °C. The resultant solution was stirred
for 15 min followed by slow addition of DMF (1.80 g,
24 mmol). The mixture was stirred for 15 min and then
hydrolyzed with dilute aq H2SO4. The organic phase
was separated and the water phase was extracted with
ether (10 mL). Evaporation of the combined organic
solutions left a solid that was washed with water and
recrystallized from toluene (5 mL) to give 1b as colorless
crystals, mp 128–130 °C. Yield: 1.8 g (31%). Evapora-
tion of the mother liquor followed by washing of the res-
idue with hexane (5 mL) afforded a mixture of 1b and
the isomeric by-product 1c (1.0 g, ca. 70:30). Character-
ization of 1b: 1H NMR (400 MHz, CDCl3): d 10.33 (1H,
s, CHO), 7.43 (1H, d, J 1.5 Hz, Ph), 7.11 (1H, d, J
1.5 Hz, Ph), 3.93 (3H, s, OMe); 13C{1H} NMR
(100.6 MHz, CDCl3): d 189.5, 162.1, 129.3, 129.0,
125.6, 122.4, 115.0, 56.7. Anal. Calcd for C8H6Br2O2:
C, 32.69; H, 2.06. Found C, 32.55; H, 2.16.
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This work was supported by the Warsaw University of
Technology. The X-ray measurements of compound 4a
were undertaken in the Crystallographic Unit of the
Physical Chemistry Laboratory at the Chemistry
Department of the University of Warsaw. Support by
the Aldrich Chemical Company, Milwaukee, WI,
USA, through donation of chemicals and equipment is
gratefully acknowledged.
Supplementary data
Selected synthetic experimental data, copies of the 13C
NMR spectra of all new compounds and X-ray experi-
mental data of compound 4a are included. Crystallo-