Cocondensation Reactions of Five-Membered Heterocycles with Lithium Atoms at 77 K
FULL PAPER
1-methylpyrrole, 2,5-dimethylfuran, 2,5-dimethylthiophene, 1,2,5-
trimethylpyrrole, 2-methoxyfuran and oxazole were dried and dis-
tilled from calcium dihydride under argon. All solvents were then
degassed by three freeze-pump-thaw cycles. Celite was stored in an
oven at 120 °C overnight and was dried under vacuum for three
hours before use. For each filtration, a plug of approximately 6 cm
of Celite was used and each filtration was performed under the
Scheme 8. Reaction of oxazole with lithium atoms in the presence
of THF
1
vigorous exclusion of air and moisture. H and 13C NMR spectra
Scheme 8, is the governing factor here. The first intermedi-
ate is characterised by the nitrogen, which is able to stabilise
the LiϪLi cluster more than the oxygen η1-complex. How-
ever, no π-complex was found as a stable intermediate.
Once the first CϪH activation has occurred, the mono-
lithiated oxazole is still able to react further. As Scheme 8
shows, this second lithium is also observed in an ortho posi-
tion with respect to the oxygen.
From the calculated LUMO energies of the reactants
(Table 2), a comparison can be made in relation to the dili-
thiated species. The calculation of LUMO energies of the
monolithiated compounds was carried out considering sol-
vent interaction with the lithium. For this purpose, three
molecules of ammonia were taken to fill the coordination
were obtained with either a Varian 300 MHz or a Varian 500 MHz
NMR machine. All chemical shifts are reported in ppm and are
referenced to TMS. All GC-MS samples were run as liquid samples
in ethyl acetate on a Finnigan Trace GC-MS, equipped with an
RTX-5MS 15 m column.
A Typical Cocondensation Experiment: Lithium metal (0.53 g,
0.076 mol) was vapourised from an alumina crucible protected by
a stainless-steel inlet at around 800 °C over 90 minutes and cocon-
densed with a mixture of the aromatic compound (15 mL) and
THF (80 mL, 1.12 mol). The solution was filtered through a plug
of Celite in order to remove the solid lithium hydride by-product
and unchanged lithium metal. After removal of the solvent mixture
in vacuo, a solid was isolated and washed with THF (20 mL). The
lithiated aromatic compound was identified by derivatisation with
sphere of lithium instead of THF, in order to simplify the Me3SiCl.
process. The calculated LUMO energies for the mono-
A Typical Derivatisation of the Lithiated Aromatic with Me3SiCl:
lithiated species 2-lithiooxazole and 5-lithiooxazole are 0.21
and 0.12 eV respectively. These LUMO energies can be con-
sidered within the range of species that can be activated. It
follows that a further activation with addition of lithium to
the lithiated oxazole can readily occur during the coconden-
sation reaction.
Me3SiCl in THF solution was added dropwise with vigorous stir-
ring to a solution of the lithiated aromatic compound (about
0.25 g) in THF (20 mL) at room temperature. The reaction was
judged to be finished when a colour change from dark red-yellow
to pale yellow occurred. Water (10 mL) was added to this solution,
and the organic phase was separated. The aqueous phase was
washed three times with dichloromethane (10 mL). The combined
organic extracts were dried with MgSO4 and then the solvent was
removed under reduced pressure, affording the derivative. GC-MS,
1H and 13C NMR were used to identify the product.
Conclusion
Lithium atoms are able to activate heterocyclic aromatic
compounds like furan and thiophene, which have a rela-
tively low-lying LUMO energy. The only product of this
selective CϪH-activation process is 2-lithiofuran or 2-lithio-
thiophene. If the LUMO energy is considerably higher as
in pyrrole, no CϪH activation can be observed. If the nor-
Theoretical Methods Used in This Study: DFT calculations were
performed with B3LYP and the 6Ϫ31G** basis set for C, H, O, N,
S, and Li. For this purpose the program GAUSSIAN 98[19] was
used on a Dell workstation running Red Hat Linux. Harmonic
vibrational frequencies, calculated at the same level, characterised
stationary points and gave the zero-point energy. The difference in
mally activated ortho position is blocked, as in 2,5-dimeth- the sum of the electronic and the zero-point energies were inter-
preted as reaction enthalpies at 0 Kelvin. LUMO energies for each
aromatic compound were obtained from geometry-optimised struc-
tures using B3LYP/6-31G**.
ylfuran or thiophene, the cocondensation reaction in the
presence of THF leads to a selective monolithiation at the
meta position. The corresponding 1,2,5-trimethylpyrrole
fails to react because of its high-lying LUMO energy. Inter-
estingly, oxazole cocondensed with lithium atoms results in
2,5-dilithiooxazole in a novel reaction variation, but the ex-
act mechanism of the dilithiation of oxazole remains un-
2,5-Dimethyl-3-(trimethylsilyl)furan: The general procedure applied
to 2,5-dimethylfuran gave 3-lithio-2,5-dimethylfuran (red) in 25%
yield (0.8 g), identified as its TMS derivative. 1H NMR (CDCl3):
δ ϭ 5.7 (s), 2.1 (s) ppm. 13C NMR (CDCl3): δ ϭ 151.0, 106.9, 99.8,
clear. For all the furans in this study and the oxazole, an 14.5, 12.1, 2.9 ppm.
η1-complex was calculated to be the most stable intermedi-
ate in the early phase of the CϪH activation reaction, while
thiophenes preferred π-complexes with the intermediate di-
lithium cluster.
2,5-Dimethyl-3-(trimethylsilyl)thiophene: The general procedure ap-
plied to 2,5-dimethylthiophene gave 3-lithio-2,5-dimethylthiophene
(brown) in 45% yield (5.8 g), identified as its TMS derivative. 1H
NMR (CDCl3): δ ϭ 6.5 (s), 2.4 (s) ppm. 13C NMR (CDCl3): δ ϭ
137.0, 126.0, 123.7, 14.2, 13.0, 2.1 ppm.
Experimental Section
2-Methoxy-3-(trimethylsilyl)furan: The general procedure applied
to 2-methoxyfuran gave 3-lithio-2-methoxyfuran (red) in 35% yield
(2.7 g), identified as its TMS derivative. 1H NMR (CDCl3): δ ϭ 7.5
(d, J ϭ 5.3 Hz), 6.1 (d, J ϭ 5.3 Hz), 3.7 (s) ppm. 13C NMR
(CDCl3): δ ϭ 172.7, 151.8, 120.6, 98.0, 67.0, 0.9 ppm.
General: All experimental procedures were performed using stand-
ard Schlenk techniques under dry argon. THF was dried and dis-
tilled from sodium/benzophenone under argon. Furan, thiophene,
Eur. J. Inorg. Chem. 2004, 4525Ϫ4532
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4531