1
878
S. Kii et al. / Tetrahedron Letters 47 (2006) 1877–1879
n
for example, deprotonation, addition of BuLi to the
substrate, and b-elimination of an anion to form ben-
zyne (52%, entry 1). The use of aggregate base of BuLi
and LiOMe, which possesses moderate basicity, was also
produced less than the optimal results (32%). It has
been reported that pyridylmagnesium halides could be
prepared by a halogen–magnesium exchange of halo-
pyridines with PrMgCl or Pr Mg.
protocol to the preparation of metalated 2-picoline,
but the exchange yield was low (entry 3).
Table 3. Picolylmagnesium complex: trapping with various electro-
philes
n
n
i
Bu PrMgLi
2
Br
E
H+
(
0.50 eq.)
Electrophiles
0 ˚C, ~2 h
4
N
N
3a-I
a
THF, -10 ˚C
1
i
i
1f–1l
We applied this
2
Entry Electrophile
E
3
Yield (%)
1
2
3
4
5
6
PhCHO
PhCOCl
CH(OH)Ph
C(O)Ph
3a 93
b
3b 52
3c 57
3d 85
3e 92
3f 89
(CH
(CH
3
)
)
3
COCl
NCHO
C(O)C(CH
CHO
3
)
3
We recently demonstrated that magnesium complexes
are efficient reagents for the regioselective mono-halo-
gen–metal exchange of dibromoarenes (benzene, pyri-
dine, and thiophene).
complexes (R MgLi) exhibited both basic and nucleo-
philic properties, they could potentially generate metal-
ated 2-picolines without proton transfer from the C-2
methyl group. Additionally, this protocol could offer
c
3
2
CH
2
@CHCH
NC(S)SSC(S)N Pr
2
Br
CH
SC(S)N Pr
2 2
CH@CH
i
c
i
i
Pr
2
2
2
5
a
Because these magnesium
a
Yields were determined by HPLC or GC analysis.
Inverse addition: picolylmagnesium complex was added to the solu-
tion of the electrophile.
3
b
5
c
After quenching with aq acid.
6
a significant advantage for large-scale syntheses because
it can be carried out under noncryogenic conditions.
Thus, we applied the bromine–magnesium exchange
method to 5-bromo-2-picoline (1) with our magnesium
(
52%, entry 2; 57%, entry 3) due to side reactions, for
example, over-arylation. The reaction with thiuram
disulfide furnished the corresponding thiuram aryl sul-
fide 3f in 89% yield (entry 6).
n
i
7
complex ( Bu PrMgLi, 0.33 equiv). The desired 5-
2
iodo-2-picoline (2) was obtained in 90% yield (entry 4).
Furthermore, the transmetalation went to completion
In conclusion, we have demonstrated that the magne-
n
i
n
i
when 0.50 equiv of Bu PrMgLi was employed (entry
2
sium complex, Bu PrMgLi, is an efficient reagent for
2
8
5
).
the preparation of metalated picolines under noncryo-
genic conditions. The prepared picolylmagnesium com-
plex reacts efficiently with various electrophiles in good
yields. This is a quite general method for the preparation
of functionalized picolines.
We next examined the stability of the metalated species.
We found that the picolylmagnesium intermediate was
stable in THF at À10 °C, giving 2 in 96% yield, even
after aging for 2 h before treatment with iodine (Table
2
). In contrast, the lithiated intermediate was unstable
even under cryogenic conditions (À78 °C).
Acknowledgements
We then examined the reaction with various electro-
philes of the magnesium complex. These were generated
We thank Dr. T. Nemoto and Mr. M. Ishikawa, for
HRMS analysis.
n
i
with 0.50 equiv of Bu PrMgLi via a halogen–magne-
2
sium exchange reaction of 5-bromo-2-picoline (1) (Table
3
). The magnesium complex showed excellent nucleo-
References and notes
philicity. Reaction with benzaldehyde, DMF, and allyl
bromide afforded alcohol 3a, aldehyde 3d, and propene
1. [Li] (a) Qu e´ guiner, G.; Marsais, F.; Snieckus, V.; Epsztajn,
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3
e in 85–93% yields (entries 1, 4, and 5). The reaction of
the picolylmagnesium complex with acid chlorides pro-
vided ketones 3b and 3c, but the yields were moderate
3
7, 2537; (c) Peterson, M. A.; Mitchell, J. R. J. Org. Chem.
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Table 2. Stabilities of metalating reagents prepared from 5-bromo-2-
picoline (1)
Br
I
metalating reagent*
aging time
I
N
N
1
2
* nBu PrMgLi (0.50 equiv) ; -10 ˚C
i
2
nBuLi (1.0 equiv) ; -78 ˚C
a
Aging time (h)
Yield of 2 (%)
n
Bu
i
n
2
PrMgLi (0.50 equiv)
BuLi (1.0 equiv)
2
004, 7, 4905; (l) Krasovskiy, A.; Knochel, P. Angew.
0
0
2
.25
.5
—
>99
96
52
16
13
Chem., Int. Ed. 2004, 43, 3333.
2
. (a) Kaiser, E. M. Tetrahedron 1983, 39, 2055; (b) Pasquinet,
E.; Rocca, P.; Marsais, F.; Godard, A.; Qu e´ guiner, G.
Tetrahedron 1998, 54, 8771.
a
Yields were determined by HPLC analysis of reaction aliquots.