Oxidative magnesiation of halogenopyridines: Introduction of electrophilic substituents to the pyridine moiety under the Barbier condition

Article abstract of DOI:10.1016/S0040-4039(02)00513-0

Oxidative magnesiation of halogenopyridines was carried out using active magnesium prepared by the reduction of magnesium chloride, to give pyridinylmagnesium halides, which were treated with electrophiles to afford the corresponding pyridine derivatives.

Full text of DOI:10.1016/S0040-4039(02)00513-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3355–3357
Oxidative magnesiation of halogenopyridines: introduction of
electrophilic substituents to the pyridine moiety under the
Barbier condition
Osamu Sugimoto,* Shigeru Yamada and Ken-ichi Tanji*
Laboratory of Organic Chemistry, School of Food and Nutritional Sciences, University of Shizuoka, 52-1 Yada,
Shizuoka 422-8526, Japan
Received 5 January 2002; revised 12 March 2002; accepted 13 March 2002
Abstract—Oxidative magnesiation of halogenopyridines was carried out using active magnesium prepared by the reduction of
magnesium chloride, to give pyridinylmagnesium halides, which were treated with electrophiles to afford the corresponding
pyridine derivatives. © 2002 Elsevier Science Ltd. All rights reserved.
Metalation of organic compounds is a useful method to
introduce an electrophilic substituent. Because nitro-
gen-containing six-membered heteroaromatics (abbrevi-
ated as heteroaromatics), such as pyridine, are usually
inert to electrophiles, metalation of heteroaromatics is
an important synthetic technique.
(1538 mg, 12.0 mmol), magnesium dichloride (571 mg,
6.00 mmol) and dry THF (30 ml) was stirred at room
temperature until lithium was completely consumed
(4–5 h) to give a pale green suspension of Mg* (about
0.2 M). The amount of these reagents may be used in
proportion to that of the substrate.
Lithiation of halogenopyridines is accomplished by
At first the reaction of 2-chloro-, 2-bromo-, or 2-
iodopyridine with Mg* was carried out as shown in
Table 1. The oxidative magnesiation of 2-iodopyridine
with Mg* in the presence of pivalaldehyde as an elec-
trophile proceeded at 0–35°C to give 2,2-dimethyl-1-(2-
pyridinyl)-1-propanol in 55–67% yield (entries 4–6).
The oxidative magnesiation was inhibited when excess
aldehyde compared to Mg* was used (entry 7). When
2-chloro- or 2-bromopyridine was used as a substrate,
the magnesiation at 20–30°C hardly proceeded, and the
reaction under reflux gave the product in low yield
1
,2
3,4
using alkyllithium or lithium naphthalenide as a
lithiating reagent, but these reactions require low tem-
perature (e.g. −78°C). On the contrary, magnesiopyridi-
nes are stable enough compared to lithiopyridines to be
prepared at room temperature. However, magnesiopy-
ridines are usually prepared by the reaction of
halogenopyridines with alkylmagnesium halide (the
5
–10
halogen–magnesium exchange reaction),
and only
1
1
one report about the oxidative magnesiation of 3-bro-
mopyridines using a magnesium metal is known.
(
entries 1–3). Both 3- and 4-iodopyridine were magnesi-
In recent years, the chemistry of active magnesium
ated to afford the product (entries 8, 9).
(
indicated as Mg*), which is prepared by the reduction
of magnesium halide using alkali metal, has been inves-
The experiment proceeded as follows: To a suspension
of Mg* (6.00 mmol) in dry THF (30 ml) at an appro-
priate temperature inside, pivalaldehyde (4.50 mmol)
was added in one portion. A solution of halogenopy-
ridine (1.50 mmol) in THF (10 ml) was added dropwise
1
2
tigated. So, we examined the synthesis of a pyridine
Grignard reagent from the corresponding halogenopy-
ridine and Mg*.
Preparation of Mg*: Under an argon atmosphere, a
mixture of lithium (83.3 mg, 12.0 mmol), naphthalene
(
for 5–10 min) so as to keep the appropriate tempera-
ture. The mixture was stirred for 30 min, quenched with
aqueous HCl and extracted with ethyl acetate. The
organic layer was dried over Na SO , and treated with
2
4
silica gel chromatography (eluted with hexane–ethyl
acetate (2:1)) to give 2,2-dimethyl-1-(2-pyridinyl)-1-
propanol.
*
Corresponding authors. Tel.: +81-54-264-5542; fax: +81-54-264-
099; e-mail: osamu@smail.u-shizuoka-ken.ac.jp; tanji@
smail.u-shizuoka-ken.ac.jp
5
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00513-0

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O. Sugimoto et al. / Tetrahedron Letters 43 (2002) 3355–3357
Table 1. Magnesiation of 2-halogenopyridines under the Barbier condition
t
Mg* / BuCH=O
t
X
CH(OH) Bu
THF / Condition
N
N
(added dropwise)
Entry
X
Reagents
Conditions
Yield (%)
t
Mg* (equiv.)
BuCHꢀO (equiv.)
1
2
3
4
5
6
7
8
9
2-Cl
2-Cl
2-Br
2-I
2-I
2-I
2-I
3-I
4-I
3
3
4
4
4
4
4
4
4
2
25–30°C, 24 h
Reflux, 2 h
0
21
Trace
67
65
55
42
73
64
2
3
3
3
3
5
3
3
20°C, 30 min
0°C, 30 min
20°C, 30 min
35°C, 30 min
20°C, 30 min
20°C, 30 min
20°C, 30 min
Table 2. Reaction of 2-pyridinylmagnesium iodide with
some electrophiles
Lithiation of quinoxaline derivatives using a tellurium–
lithium exchange reaction followed by addition of
13
pivalaldehyde was already reported, but the Wurtz-
type coupling reaction proceeded to give the 2,2%-
quinoxaline dimmer even at −78°C because the
quinoxaline ring is highly reactive with nucleophiles.
So, the Barbier reaction was applied to the magnesia-
tion of 2-chloroquinoxaline and the desired product
was obtained as shown in Table 3. It should be noted
that the chloro compound, which is regarded as an
inert substrate for the metalation, can be magnesiated
without requiring low temperature.
Mg* (4 eq) / Electrophile (3 eq)
THF / 20 °C, 30 min
N
I
N
E
(
added dropwise)
Entry
Electrophile
-E
Yield (%)
t
t
1
2
3
4
BuCHꢀO
E CꢀO
-CH(OH) Bu
-C(OH)Et2
65
50
35
17
2
PhMeCHCHꢀO -CH(OH)CHPhMe
PhCHꢀO -CH(OH)Ph
In conclusion, we have accomplished the oxidative
magnesiation of halogenopyridines using Mg*. As the
Barbier reaction enables the magnesio derivatives to be
trapped with electrophiles quickly, it may make it possi-
ble to magnesiate many nitrogen-containing halogeno-
heteroaromatics under mild conditions.
Table 3. Magnesiation of 2-chloroquinoxaline under the
Barbier condition
N
N
i), ii)
t
N
Cl
N
CH(OH) Bu
(
added dropwise)
t
References
Reagents and conditions: (i) Mg* (4 equiv.)/ BuCHꢀO (3
equiv.) THF/condition; (ii) H O .
+
3
1
2
3
4
5
6
7
. Peterson, M. A.; Mitchell, J. R. J. Org. Chem. 1997, 62,
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