Direct synthesis of unsymmetrical bis-heterocycles from 2-heterosubstituted 6-lithiopyridines

Article abstract of DOI:10.1039/a807161f

Unsymmetrical bis-heteroaromatic compounds have been synthesized by nucleophilic coupling of C-6 lithiated 2-heterosubstituted pyridines with various heterocycles.

Full text of DOI:10.1039/a807161f

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Direct synthesis of unsymmetrical bis-heterocycles from
2-heterosubstituted 6-lithiopyridines
Philippe Gros and Yves Fort*
Synthèse Organique et Réactivité, ERS-634, Université de Nancy-1, Faculté des Sciences,
BP239, F-54506 Vandoeuvre-Les-Nancy, France
Received (in Cambridge) 14th September 1998, Accepted 22nd September 1998
Table 1 Coupling of pyridines 1a and 1b with heteroaromatic
Unsymmetrical bis-heteroaromatic compounds have been
synthesized by nucleophilic coupling of C-6 lithiated 2-
heterosubstituted pyridines with various heterocycles.
compoundsa
Substrate HetArH
Product
Yield (%)b
Bis-heterocyclic compounds have been the focus of a great deal
of attention. They have found numerous applications as elec-
trical materials,1 biologically active molecules,2 chelating agents
and metal ligands.3
Two major synthetic methods are generally used to prepare
these compounds. The palladium- or nickel-catalyzed homo-
coupling of heteroaryl halides leads to symmetrical products,4
while the use of intermediate organotin or organozinc species
allows the preparation of unsymmetrical compounds.5 The
main drawbacks of these processes are generally the cost and
availability of halogenated heterocycles as well as the formation
of side-products.
In this context, the nucleophilic addition of a lithiated hetero-
cycle to an electrophilic substrate appeared promising.6 How-
ever, this route has been scarcely used since there is a lack of
selective methods for the direct lithiation of heteroaromatics.
Indeed, alkyllithiums lead mainly to nucleophilic addition
products7 and a prior halogen–metal exchange step is often
necessary.
Recently,8 we have shown that the basicity/nucleophilicity
ratio of BuLi was considerably increased by association with
lithium 2-dimethylaminoethanolate (LiDMAE). As a con-
sequence, the newly formed base BuLi–LiDMAE8a allowed an
unusual and regioselective metallation of 2-heterosubstituted
pyridines (1a,b) at their C-6 position, affording the correspond-
ing C-6 substituted 2-heterosubstituted pyridines in good yields
(Scheme 1).
Scheme 1
In the course of our ongoing research on coupling reac-
tions,5c,9 we decided to attempt to perform the nucleophilic
addition of the C-6 lithiated 2-heterosubstituted pyridines to
heterocyclic compounds (Scheme 2).
a Reaction performed on 4 mmol of substrate; metallation: 4 equiv.
of BuLi–Me2N(CH2)2OLi, hexane, 0 ЊC, 1 h; coupling: 4 equiv. of
HetArH in THF, 0 ЊC to RT, 2 h. b Isolated yields after purification
(flash chromatography or Chromatotron). c 50% of 2,2Ј-bipyridine was
isolated. d 42% of 2,2Ј-bipyridine was isolated.
Scheme 2
2-methoxy-6,6Ј-bipyridine 2a in good yield. The above deter-
mined conditions were used to perform reactions starting
from 2-methoxypyridine 1a and 2-methylthiopyridine 1b
(Table 1).
The obtained results show that the methoxy and methylthio
substituted bis-heterocycles were obtained in acceptable to
After a preliminary study performed with 2-methoxypyridine
as substrate and pyridine as an electrophile, we found that
four equivalents10 of the base BuLi–LiDMAE as well as THF
as trapping co-solvent were necessary to obtain the expected
J. Chem. Soc., Perkin Trans. 1, 1998, 3515–3516
3515

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good yields. It is worthy of note that it is not necessary to carry
out an oxidation step6 to obtain products since the dihydro
intermediates aromatized readily in the reaction medium or
upon aqueous work-up.
In these reactions, pyridine displayed particularly interesting
behavior. Whatever the conditions used (unreported here),
2,2Ј-bipyridine was obtained as a by-product. This side-
reaction could be expected according to our previous work.8b
Indeed, the reaction of BuLi–LiDMAE with pyridine at 0 ЊC
gave 82% of 2,2Ј-bipyridine after addition of THF. However,
2,2Ј-bipyridine was easily separated from 2a and 2b by classical
flash-chromatography.
On the other hand, quinoline which is known to be very
sensitive to nucleophilic attack by BuLi7a led surprisingly to the
lowest yields. This may be interpreted as a consequence of a
strong complexation of lithiopyridines by the formed com-
pounds 3a and 3b, weakening their nucleophilicity.6a
Finally, the method was also successful in the preparation
of symmetrical products leading to 6,6Ј-dimethoxy-2,2Ј-
bipyridine 6a in 58% yield. This result is far better than those
obtained in our previous work. Indeed, 6a was obtained in 30%
yield after addition of THF in a mixture of BuLi–LiDMAE
with 2-methoxypyridine.8a
In conclusion, we have shown that the direct conden-
sation of heterocycles with 2-heterosubstituted 6-lithiopyridines
is an efficient and simple method and has to be considered
for the synthesis of new and not easily accessible bis-hetero-
cycles.
Selected data
2b: δH 2.69 (s, 3H), 7.15 (d, J 8, 1H), 7.25 (dt, J 5 and 2, 1H),
7.57 (t, J 8, 1H), 7.75 (dt, J 8 and 2, 1H), 8.07 (d, J 8, 1H),
8.42 (d, J 8, 1H), 8.62 (d, J 4, 1H); δC 13.6, 117.1, 121.2,
121.3, 132.1, 136.5, 148.8, 155.3, 156.0, 157.1; m/z (CI) 203
(M ϩ Hϩ) (C11H10N2S requires C, 65.32; H, 4.98; N, 13.85.
Found: C, 65.45; H, 5.02; N, 14.16%); 3b: δH 2.69 (s, 3H), 7.32
(d, J 8, 1H), 7.68 (t, J 7.5, 1H), 8.21 (d, J 7.5, 1H), 8.40 (d, J 4.5,
1H), 8.87 (d, J 4.5, 1H), 9.30 (s, 1H); δC 13.6, 117.5, 117.8,
124.0, 137.2, 153.6, 158.3, 159.1, 160.3, 162.9; m/z (CI)
204 (M ϩ Hϩ) (C10H9N3S requires C, 59.09; H, 4.46; N, 20.67.
Found: C, 59.16; H, 4.73; N, 20.32%); 4b: δH 2.65 (s, 3H), 7.26
(d, J 8, 1H), 7.63 (t, J 7.5, 1H), 8.05 (d, J 7.5, 1H), 8.59 (br
s, 2H), 9.68 (s, 1H); δC 13.5, 116.6, 122.9, 137.1, 143.7, 143.9,
144.8, 151.2, 154.0, 160.0; m/z (CI) 204 (M ϩ Hϩ) (C10H9N3S
requires C, 59.09; H, 4.46; N, 20.67. Found: C, 59.36; H,
4.61; N, 20.43%). 6b: δH 2.57 (s, 3H), 4.18 (s, 3H), 6.50 (dd, J 8
and 1, 1H), 6.85 (dd, J 7.5 and 1, 1H), 7.45 (t, J 7, 1H), 7.46 (t,
J 8 and 2, 1H), 8.30 (dd, J 7.5 and 1, 1H), 8.40 (dd, J 7.2 and 1,
1H); δC 12.3, 54.4, 113.1, 117.1, 120.5, 125.4, 132.8, 135.6,
153.4, 155.9, 156.3, 161.3; m/z (CI) 233 (M ϩ Hϩ) (C12H12N2OS
requires C, 62.07; H, 5.15; N, 12.07. Found: C, 62.36; H, 4.97;
N, 12.18%).
References
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Experimental
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All new compounds have been satisfactorily characterized [1H
NMR (400 MHz), 13C NMR (100 MHz), MS and elemental
analysis].
Typical experimental procedure
To a solution of 2-dimethylaminoethanol (720 mg, 16 mmol) in
hexane (10 mL) cooled at 0 ЊC, was added dropwise BuLi (1.6
M solution in hexane, 20 mL, 32 mmol). After 15 min, a solu-
tion of 2-methoxypyridine (436 mg, 4 mmol) in hexane (10 mL)
was added dropwise (10 min) and the reaction mixture stirred at
0 ЊC for 1 h. The orange solution was cooled at Ϫ20 ЊC and a
solution of pyrimidine (1.28 g, 16 mmol) in THF (40 mL) was
added dropwise, and the mixture stirred for 1 h at 0 ЊC and 1 h
at room temperature. Hydrolysis was performed at 0 ЊC with
water (20 mL). After aqueous work-up, the organic layer was
dried (MgSO4) and the solvents evaporated. The residue was
purified on a Chromatotron (AcOEt–hexane, 5:95), yielding
463 mg (62%) of 3a. δH 4.06 (s, 3H), 6.88 (d, J 8, 1H), 7.74 (t,
J 7.5, 1H), 8.11 (d, J 7.5, 1H), 8.33 (d, J 5, 1H), 8.84 (d, J 5, 1H),
9.26 (s, 1H); δC 53.8, 113.9, 115.1, 117.6, 139.9, 151.5, 158.0,
158.9, 163.1, 164.1; m/z (CI) 188 (M ϩ Hϩ) (C10H9N3O requires
C, 64.16; H, 4.85; N, 22.45. Found: C, 64.25; H, 5.17; N,
22.12%).
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Y. Fort, Tetrahedron Lett., 1998, 39, 5359.
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Communication 8/07161F
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J. Chem. Soc., Perkin Trans. 1, 1998, 3515–3516