Tributylmagnesium ate complex-mediated bromine-magnesium exchange of bromoquinolines: A convenient access to functionalized quinolines

Article abstract of DOI:10.1016/S0040-4039(03)00183-7

2-, 3- and 4-bromoquinolines were converted to the corresponding lithium tri(quinolyl)magnesates at -10°C by treatment with Bu₃MgLi in THF or toluene. The resulting organomagnesium derivatives were quenched by various electrophiles to afford functionalized quinolines.

Full text of DOI:10.1016/S0040-4039(03)00183-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2033–2035
Tributylmagnesium ate complex-mediated bromine–magnesium
exchange of bromoquinolines: a convenient access to
functionalized quinolines
Sylvain Dumouchel, Florence Mongin,* Franc¸ois Tre´court and Guy Que´guiner
Laboratoire de Chimie Organique Fine et He´te´rocyclique, UMR 6014, IRCOF, Place E. Blondel, BP 08,
76131 Mont-Saint-Aignan Ce´dex, France
Received 20 November 2002; revised 18 January 2003; accepted 20 January 2003
Abstract—2-, 3- and 4-bromoquinolines were converted to the corresponding lithium tri(quinolyl)magnesates at −10°C by
treatment with Bu3MgLi in THF or toluene. The resulting organomagnesium derivatives were quenched by various electrophiles
to afford functionalized quinolines. © 2003 Elsevier Science Ltd. All rights reserved.
The preparation of functional heterocycles is an impor-
tant synthetic goal because of the multiple applications
of these molecules.1 Among the methods developed,
lithiation is convenient to allow a number of polyfunc-
tional azines (pyridines, quinolines...) and diazines syn-
tions of magnesate reagents remained unexplored until
very recently.8 In 2001, the first halogen–magnesium
exchanges via organomagnesium ate complexes were
published by Oshima in the benzene, pyridine and
thiophene series.8i,l The same year, the mono-exchange
of dibromobenzenes and dibromoheteroarenes (pyri-
dine and thiophene series) was reported by Iida and
Mase using lithium tributylmagnesate.8m
theses since lithiated derivatives display
a high
reactivity towards many electrophilic functions.2 Never-
theless, this methodology often requires low tempera-
tures, which can be difficult to realize on an industrial
scale. Moreover, halogen–lithium exchange is very sen-
sitive to reaction temperature,3 particularly in the quino-
line series where derivatives are more prone to nucleo-
philic addition due to their lower LUMO levels.
Herein, we describe the bromine–magnesium exchange
of 2-, 3- and 4-bromoquinolines using lithium
tributylmagnesate.
Preliminary experiments on 3-bromoquinoline showed
that reagents such as isopropylmagnesium chloride,
tert-butylmagnesium chloride, di(isopropyl)magnesium,
and isopropyl(2,2,6,6-tetramethyl-piperido)magnesium9
could not be used to generate the corresponding 3-
quinolylmagnesium derivatives, as observed in the case
of pyridylmagnesium derivatives.5c,f,g,i Due to its lower
LUMO level, quinoline is more prone to nucleophilic
attack: addition of the base to the quinoline ring was
favored over exchange reaction. So, we turned our
attention to magnesium ate complexes.
Grignard reagents are of great importance, and numer-
ous reports for the preparation of various organomag-
nesium compounds through direct metalation of
organic halides with metallic magnesium, deprotona-
tion, transmetallation, or halogen–magnesium exchange
have been published.4 We have been interested in the
development of quinolylmagnesium reagents via
bromine–magnesium exchange that could be subse-
quently involved in either electrophilic trapping or cou-
pling reactions.5
Since a magnesium ate complex (R3MgLi) was first
published in 1951,6 several investigations on its struc-
ture have been reported.7 However, synthetic applica-
First experiments were conducted on 3-bromoquinoline
using lithium tributylmagnesate in toluene at −10°C, as
described for the bromine–magnesium exchange of 2,6-
dibromopyridine.8m Trapping the corresponding
lithium tri(quinolyl)magnesate with benzaldehyde,
dimethylformamide, iodine and diphenyl disulfide
afforded alcohol 1a,3d aldehyde 1b,10 iodide 1c11 and
sulfide 1d,12 in medium to good yields (Scheme 1).
Keywords: quinoline; Grignard reagents; exchange reaction; ate com-
plexes.
* Corresponding author. Tel.: +33 (0) 2 35 52 29 00; fax: +33 (0) 2 35
52 29 62; e-mail: florence.mongin@insa-rouen.fr
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00183-7

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S. Dumouchel et al. / Tetrahedron Letters 44 (2003) 2033–2035
Scheme 1.
Note that the yields largely depend on the amount of
magnesate used: 0% of 1a with 1 equiv. of Bu3MgLi,
5–10% with 0.66 equiv. and 65% with 0.35 equiv.!
Butylated products obtained in the first and second
cases could be formed through addition of the residual
butylmagnesium species to the quinoline ring.
afforded iodide 2c16 and sulfide 2d,12 in low to medium
yields (Scheme 3).
As previously observed in the pyridine series,5i,8i,l,m the
bromine–magnesium exchange at C2 of the quinoline
ring seems to be more difficult than the reaction at C3.
Moreover, the lithium tri(2-quinolyl)magnesate could
be less reactive than its 3-quinolyl analogue since the
yields observed increase with the reactivity of the
electrophile.
Since the main by-product is quinoline, the yields seem
to depend on the trapping step with the electrophiles.
Various polar solvents, such as tetrahydrofuran (THF),
methyl-tert-butyl ether (MTBE) and diethyl ether
(DEE), were then tested in order to optimize the reac-
tion. THF was found to be the best solvent when
benzaldehyde was used (Scheme 2).
Bromine–magnesium exchange reaction was likewise
observed with 4-bromoquinoline,13 and the magnesate
formed could be intercepted to produce the expected
alcohol 3a,17 iodide 3b,11 sulfide 3c18 and carboxylic
acid 3d10 in medium yields (Scheme 4).
The bromine–magnesium exchange reaction was then
applied to 2-bromoquinoline13 using THF as a solvent,
under the same conditions. Reaction with benzaldehyde
provided the alcohol 2a14 in 39% yield, the remaining
61% being a mixture of butylated quinolines, 2-bromo-
quinoline and 2,2%-biquinoline. In the case of enolizable
3-pentanone, a moderate yield of alcohol 2b15 was
obtained. Trapping with iodine and diphenyl disulfide
In conclusion, 2-, 3- and 4-substituted quinolines could
be prepared from the corresponding bromo derivatives
by bromine–magnesium exchange reaction. The main
advantage of this methodology is the relative stability
of these organometallic species: bromine–lithium
exchange has to be performed at low temperature in
Scheme 2.
Scheme 3.

S. Dumouchel et al. / Tetrahedron Letters 44 (2003) 2033–2035
2035
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Scheme 4.
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Bromine–magnesium exchange; typical procedure: BuLi
(1.6 M in hexanes, 1.3 mmol) was added to a solution
of BuMgCl (2.0 M in ether, 0.65 mmol) in toluene (2
mL) at −10°C. After stirring for 1 h at −10°C, a
solution of 3-bromoquinoline (0.23 mL, 1.7 mmol) in
toluene (2 mL) was introduced at −30°C. After 2.5 h at
−10°C, benzaldehyde (0.17 mL, 1.7 mmol) and, 1 h
later, water (0.5 mL) were added. Dilution with AcOEt
(50 mL), drying over MgSO4 and column chromatogra-
phy using CH2Cl2/AcOEt (80:20) as an eluent afforded
alcohol 1a (65% yield).
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