Non-cryogenic metalation of aryl bromides bearing proton donating groups: Formation of a stable magnesio-intermediate

Article abstract of DOI:10.1016/S0040-4039(02)01747-1

Bromine-metal exchange of o-bromobenzoic acid (1) with Bu₂Mg followed by n-BuLi was successfully carried out at non-cryogenic temperature (>-20°C), and gave a stabilized metal species which smoothly reacted with several electrophiles. This methodology expanded to several other bromides bearing proton donating groups (PDGs).

Full text of DOI:10.1016/S0040-4039(02)01747-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7315–7317
Non-cryogenic metalation of aryl bromides bearing proton
donating groups: formation of a stable magnesio-intermediate
Shinji Kato,* Nobuaki Nonoyama, Koji Tomimoto and Toshiaki Mase
Process Research, Process R&D, Laboratories for Technology Development, Banyu Pharmaceutical Co. Ltd.,
Kamimutsuna 3-Chome-9-1, Okazaki, Aichi 444-0858, Japan
Received 16 July 2002; revised 20 August 2002; accepted 21 August 2002
Abstract—Bromine–metal exchange of o-bromobenzoic acid (1) with Bu2Mg followed by n-BuLi was successfully carried out at
non-cryogenic temperature (>−20°C), and gave a stabilized metal species which smoothly reacted with several electrophiles. This
methodology expanded to several other bromides bearing proton donating groups (PDGs). © 2002 Elsevier Science Ltd. All rights
reserved.
The halogen–metal exchange reaction is a valuable
transformation for carbonꢀcarbon bond formation in
synthetic organic chemistry.1 However, this reaction is
normally conducted with an alkyllithium reagent at
cryogenic temperatures (−78°C) which limits its practi-
cality and economic feasibility for industrial scale oper-
ation. Recently, halogen–metal exchange reactions at
higher temperature ranges have been developed.2 (We
have also reported that magnesium ate complexes are
quite effective for this purpose.3) During the course of
our ongoing process development efforts, we required a
non-cryogenic metalation of o-bromobenzoic acid
(1).4,5 Although halogen–metal exchange reactions on
aryl halides bearing proton donating groups (PDGs)
have been successfully conducted with alkyllithiums at
−78°C, considerable amounts of the corresponding pro-
tonated products are also formed due to intermolecular
quenching.6 Hence, development of new methodology
which can simultaneously address these issues was quite
desirable. In this article, we wish to report a non-cryo-
genic metalation of aryl bromides bearing PDGs (which
involves formation of a stable magnesium species) and
their subsequent reactions with several electrophiles
under non-cryogenic temperature (>−20°C).
In this regard, magnesium and zinc organometallic
compounds appeared to be the most attractive candi-
dates.8 Knochel and co-workers have reported that
halogen–magnesium exchange reactions are mediated
by i-PrMgBr or i-Pr2Mg. However, these reagents have
been thus far limited to relatively reactive aryl halides
such as aryl iodides or electron deficient aryl bromides
Our initial concept involved quenching the carboxylic
acid with a base to prevent proton transfer and subse-
quent generation of a stable metalated intermediate
that would also have the appropriate reactivity to effect
a clean reaction in a higher temperature range.7
* Corresponding author. Tel.: +81-564-51-5668; fax: +81-564-51-7086;
e-mail: katousn@banyu.co.jp
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01747-1

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S. Kato et al. / Tetrahedron Letters 43 (2002) 7315–7317
due to sluggish exchange reactions with non-activated
aryl halides.1c Accordingly, the high reactivity of alkyl-
lithiums is fascinating although the resulting aryllithi-
ums are generally unstable at >–20°C. We envisioned
that immediate conversion of an unstable aryllithium,
under non-cryogenic conditions, to a stable aryl metal
species might address these problems. More specifically,
we proposed that treatment of 1 with 0.5 equiv. of a
dialkyl metal (M=Mg or Zn) would afford metal
dibenzoate 2, which would then undergo bromine–
metal exchange reaction directly with an alkyllithium
(or indirectly via an intramolecular ate complex) to
immediately form the more stable ate complexes 3b (via
3a). Consequently, two CꢀMg bonds might be formed
via these ate complexes to favorably generate a stable
diaryl metal bis-(lithium carboxylate) 3e (via 3d) in an
equilibrium under non-cryogenic temperatures (or 3b,
3d and 3e might exist as an equilibrium mixture
(Scheme 1)).
addition of benzaldehyde to the resulting yellowish
slurry followed by treatment of 2 M hydrochloric acid
afforded 3-phenylphthalide (4) in 88% yield (Scheme 2).
Only a few percent of benzoic acid was observed while
a similar reaction with n-BuLi (2 equiv.) produced a
significant amount of benzoic acid. The metalated inter-
mediate was fairly stable, giving 4 in 70–80% yield even
at 0°C or even after aging for 5 h. In contrast, the
reaction with 2.2 equiv. of n-BuLi in THF at −20°C for
1 h gave 4 in only 11% yield after subsequent addition
reaction and lactonization.4 The halogen–metal
exchange with i-PrMgCl was not completed even when
3 equiv. of the reagents were used at 20°C.10 It has not
yet been clarified whether some species exist in equi-
librium, or not, since all intermediates formed existed
as a slurry in THF throughout the reaction. However,
it is apparent that this protocol provides a stability–
reactivity balanced magnesium species under non-cryo-
genic conditions.
Reactions of the magnesio-intermediate generated
above with other electrophiles were next examined. The
results are summarized in Table 1. Reaction with N,N-
dimethylformamide (entry 1), aldehydes (entry 2) or
ketones at −20°C gave the corresponding phthalides in
good yields. Slightly lower yields were obtained with
2-butanone and cyclohexanone, probably due to a-pro-
ton abstraction of the ketones (entries 3 and 4). Also,
considerable amounts (22 and 21% yields) of benzoic
acid were produced. Reaction with alkyl halide needed
higher temperature. With methyl iodide, o-toluic acid
was obtained in reasonable yield (entry 5).
Based on the above hypothesis, 1 was treated with 0.52
equiv. of Bu2Mg in THF at −20°C to give 2 as colorless
precipitates.9 At this stage, benzoic acid was not
detected. To this slurry was added 1.1 equiv. of n-BuLi
at −20°C and the mixture was aged for 1 h. Finally,
We next examined the extension of this protocol to aryl
bromides bearing other PDGs. The results are summa-
rized in Table 2. Bromine–metal exchange of N-ethyl-o-
bromobenzamide (10) smoothly proceeded at −20°C
without any complications (as reported by Beak and
co-workers),6 to furnish the corresponding diaryl-
Scheme 2.
Table 1. Extension to several electrophiles
Table 2. Extension to other aryl bromides bearing proton
donating group
aTemperatures and aging times in reactions with electrophiles.
b1.2 equiv. of ketones were used.
aTemperatures and aging times in metalation reactions.

S. Kato et al. / Tetrahedron Letters 43 (2002) 7315–7317
7317
methanol 14 in 58% yield after reaction with benzalde-
hyde (entry 1).11 o-Bromobenzyl alcohol (11), lacking
electron withdrawing functionality, also showed good
result, but required higher reaction temperature in
order to complete the bromine–metal exchange (entry
2). Furthermore, we tried bromine–metal exchanges of
m- and p-bromobenzoic acids (12 and 13). Interest-
ingly, both bromine–metal exchanges were successfully
carried out at −20°C, giving 16 and 17 in 68 and 71%
yields, respectively. Intermolecular stabilization might
also be involved in these examples, but would probably
be less effective than intramolecular stabilization in
comparison with 1.
difficulties). Direct metalation of benzoic acid with sec-
BuLi/TMEDA at −90 to −78°C was also reported, see:
Mortier, J.; Moyroud, J.; Bennetau, B.; Cain, P. A. J.
Org. Chem. 1994, 59, 4042–4044. Direct method in a
higher temperature range is still to be challenged.
6. (a) Beak, P.; Musick, T. J.; Chen, C.-W. J. Am. Chem.
Soc. 1988, 110, 3538–3542; (b) Beak, P.; Musick, T. J.;
Liu, C.; Cooper, T.; Gallagher, D. J. J. Org. Chem. 1993,
58, 7330–7335.
7. Simple application of our ate complex protocol
(Bu3MgLi) for this case did not work well.
8. CrCl3-mediated additions of the arylzinc compound pre-
pared from methyl o-iodobenzoate to aldehydes at room
temperature were reported, see: Ogawa, Y.; Saiga, A.;
Mori, M.; Shibata, T.; Takagi, K. J. Org. Chem. 2000,
65, 1031–1036.
9. (a) Rathman, T. L. In Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed.; John Wiley &
Sons, 1995; Vol. 3, pp. 1612–1613; (b) Williams, A. W.;
Miller, M. J.; Rath, N. P. J. Org. Chem. 1991, 56,
1293–1296.
10. 9% of the substrate 1 remained unreacted although 51%
of the desired product 4 was obtained.
11. Considerable amount of protonated product (ca. 30%)
was formed probably due to incomplete formation of the
magnesium salt.
In summary, we have developed a novel halogen–metal
exchange reaction of aryl bromide bearing PDGs under
non-cryogenic conditions. This protocol obviates both
intermolecular quenching, observed in reactions with
alkyllithiums, and the necessity of cryogenic tempera-
ture ranges by providing a stable magnesio-intermedi-
ate. In addition, the appropriate reactivity of the
metalated intermediate allows one to effect clean subse-
quent transformations with several electrophiles. This
new methodology12 offers a significant advantage for
practical and large-scale synthesis of ortho-substituted
aryls bearing PDGs.
12. Typical experimental procedure: A solution of o-bromo-
benzoic acid (1, 1 g, 4.97 mmol) in THF (10 mL) was
cooled below −15°C under nitrogen atmosphere, and 1.0
M Bu2Mg in heptane (2.6 mL, 2.6 mmol, 0.52 equiv.) was
slowly added to the solution below −5°C. Then 1.56 M of
n-BuLi in hexane (3.4 mL, 5.30 mmol, 1.07 equiv.) was
slowly added to the slurry below −15°C over 20 min
under effective stirring. The solution became viscous
slurry during addition of Bu2Mg and then changed to less
viscous yellowish slurry gradually during addition of
n-BuLi. After stirring below −15°C for 1 h, a solution of
benzaldehyde (1.0 mL, 9.84 mmol, 2 equiv.) in heptane (3
mL) was added to the mixture below −15°C. After stir-
ring below −15°C for 1 h, the reaction was quenched with
2 M HCl (10 mL). The resulting mixture was stirred at
room temperature overnight. EtOAc (20 mL) was added
to the resulting mixture and the mixture was stirred for a
few minutes. The organic layer was separated and washed
with H2O (5 mL), 5% aqueous NaHCO3 (10 mL), H2O (5
mL) and saturated aqueous NaCl (5 mL) successively.
After drying over anhydrous Na2SO4, the solvent was
removed under reduced pressure, and the crude solid thus
obtained was purified with silica gel chromatography
(Wako gel™ C-300, EtOAc–heptane) to afford 3-
phenylphthalide (4, 919 mg) as colorless crystals in 88%
yield.
References
1. (a) Wakefield, B. J. Organolithium Method; Academic
Press: London, 1988; (b) Wakefield, B. J. Organomagne-
sium Methods in Organic Synthesis; Academic Press: Lon-
don, 1995; (c) Boudier, A.; Bromm, L. O.; Lotz, M.;
Knochel, P. Angew. Chem., Int. Ed. 2000, 39, 4414–4435.
2. (a) Tre´court, F.; Breton, G.; Bonnet, V.; Mongin, F.;
Marsais, F.; Que´guiner, G. Tetrahedron Lett. 1999, 40,
4339–4342; (b) Abarbi, M.; Dahmel, F.; Knochel, P.
Tetrahedron Lett. 1999, 40, 7449–7453; (c) Kitagawa, K.;
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4. Bromine–lithium exchange of 1 with n-BuLi at lower
temperature than −75°C was well studied by Parham and
co-workers, see: Parham, W. E.; Bradsher, C. K. Acc.
Chem. Res. 1982, 15, 300–305.
5. ortho-Metalation of benzamide with alkyllithium has
been conducted at −78°C. This protocol practically has
some drawbacks such as tedious amidation/deamidation
process and use of sec- or tert-BuLi (with handling