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C6dex, France.
Abstract: The synthesis of new 3-substituted a-carbolines is described and these products were
subjected to ortho-lithiation
experiments. 3-pivalamido and 3-carboxamido derivatives are
cleanly lithiated at 4position. The results are correlated with MNDO calculations. Various
3,4-disubstituted a-carbolines are obtained in excellent yields.
Our group has been interested for a long time in the metalation of x-deficient heterocycles. Good results
were obtained in the pyridine and diazines series. 1 Nowadays, the association
cross-coupling
methods affording
2,3- or 3,4-disubstituted
between metalation
reactions has become a powerful tool to obtain a large variety of natural producta
structures
possessing
and
We
1 or -2,3
the
acid 1
COOH
3s: R, = H, R, = tBu
3b:R1=Rz=iPr
a) (PhO)zPONflEt,;
CH
3
d)CICOtBu/IHF/NEt,;
4099
4100
carboxamides,
of 1 with
tert-butylalcohol
diphenylphosphoryl
ax&,
pivalamido
and N-(tert-butyloxycarbonylamino)
the intermediate
carbonyl
axide was
refluxed
with
leading to the carbamate 2a in a 70 % overall yield,s or was heated in acidic water, and
leading to carboxamide
the carboxamido
derivative8
Zb in a 72 % overall yield .*
or
in 80 % and 90 96 yields
respectively.*
Metal&ion
of amine
derivatives 2a-b:
NHCOzBu t
NHCOBu t
Q--&S
Q--g
kH3
&Hs
2b
2a
n-BuLi
set-BuLi
1) tert-BuLi
2) E+, Hz0
I
&t-B&i
&
NHCOzBu t
\;
4a RI = n-Bu
4b RI = set-Bu
4c Rl = tert-Bu
R,
N
kH3
NHCOBu t
Sa
\ 5
E=D
Sb E=I
SC E=CHO
CHs
Scheme 2
We first studied the metalation reaction of carbamate 2a (Scheme 2), with various alkyllithiums
conditions
The aromatization
and compound8
of the intermediate
between
consequence
2-position.
2,2,6,6+ztramethylpiperidide
order to rationalize
derivative
of the H, hydrogen
not be introduced
were
performed
in the 4-position
with
occurred
during the
group could
only mixture8 of
experiments
Some
isolated
dihydropyridine
a tert-butyl
under
methyl
ring (the
softwares).
and addition
lithium
As a
occured
or
in
lithium
these surprising
derivatives
concerning
structures
respectively
2a-b
(Table I).
from N-H
4101
Ar
2b: R = tBu
Ar
38
Computed
Lstructure
hl
Emo(ev)
& = 3-carboline
ELUMO(ev)
Ar = 3-pytidyl
2a
1.7
4.3
4.4
2b
2.7
3a
2.1
3.3
3b
-0.56
-0.47
iPr
A
Ar (
Pr
The calculation
conformation
3b
Table 1
results on carbolioe and pyridioe derivatives depend at a small extent oo the actual
of the 3-substituent.
addition reactions .4 However, the difference is smaller in the case of pivalamide 2b (intermediate 2b) and
we decided to carry out the metalation experiments with this compound. With n-BuLi (-70C or -20C) or
set-BuIi
(-4OC), only
observed. However, with tert-BuLi in THF at -70C. with a reaction time of 6 hours and quenching with
EtOD (Scheme 2) we observed the formation of a deuterated compound 5a in good yield (80 %, with five
equivalents
unambigously
but
reaction, we
quenched the reaction medium with iodine or ethyl formate and obtained an iodo derivative Sb and a
fbrmyl derivative SC.*
Metalation of carboxamide derivatives 3a-b:
While metalatioo
experiments
CH,CHO
6e
Scheme 3
on compound 3a always afforded mixtures of additioo product and
lithiated at carbon C4
4102
These experimental
be rationalized
the difference
carboxamides
MNDO
calculations.9
As can be seen
After metalation
The regioselectivity
of the metalation
in
with
reaction
3b and rather
was confirmed
deshielding of proton H-5 in the NMR spectra of compounds 6b-e t3 and nuclear Overhauser experiments.
Acid hydrolysis of the carboxamide 6e gave the lactone 7 with a non-optimized
REFERENCES
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yield of 50 %.14
AND NOTES