3904
A. E. Wahba et al. / Tetrahedron Letters 50 (2009) 3901–3904
6
NO2
3
6
instrumentation. Subagus Wahyuono at Gadjah Mada University is
6
1.6 eq. NaNO2
TFA
N
gratefully acknowledged for sample collections. We thank Shabana
Khan and John Trott for in vitro antimalarial evaluation. This work
was funded by NIH grants NCRR P20 RR021929 (Center of
Research Excellence in Natural Products Neuroscience); NIAID
5RO1AI1036596; and an NIH research facilities improvement grant
C06 RR-14503-01. A.E.W. gratefully thanks The Ministry of Higher
Education of Egypt for a predoctoral fellowship. Also A.E.W thanks
Triton BioPharma AG for a Triton fellowship.
N
N
N
H
N
H
N
H
+
8
8
8
NO2
CH3
CH3
CH3
(9)
(10)
43%
(8)
45%
Scheme 3. Nitration of harmane.
synthesized from 5 using the normal amidation reaction with a
very low yield (17%). Also, this analogue showed potent antimalar-
Supplementary data
ial activity in vitro with an IC50 of 0.032
lM against the D6 clone of
P. falciparum with no cytotoxicity up to 4.7
l
M. It was surprising
Supplementary data (detailed experimental information and
the spectral data as well as copies of the 1H NMR and 13C NMR
spectra for compounds 7, 9, 10 and (Table 2, entries 9 and 10)
are available) associated with this article can be found, in the on-
that the reductive amidation of 3 with cyclohexylcarbonyl chloride
(CCC) runs smoothly and quickly (10 min) without the addition of
Et3N and with a significant improvement in yield (56%). A reason-
able explanation is that nitromanzamines have two 3° amine
bases, which likely accelerate the amidation reaction.
To validate this rationale, we utilized harmane (8) as
a
precursor to the synthesis of the closely related model compounds
6-nitroharmane (9) and 8-nitroharmane (10). Harmane (8) was ni-
trated using exactly the same conditions as 1 (Scheme 3) which
gave 9 and 10 in 45% and 43% yields, respectively. Applying the
same reductive amidation conditions to 9 and 10 without the
addition of Et3N did not give the amide products, even after 12 h
of stirring. The amide products of 9 and 10 were obtained after
the addition of Et3N to the solution (Table 2, entries 9 and 10).
These results clearly validated our explanation regarding the built
in tertiary amine bases in manzamine alkaloids.
In conclusion, this is the first report of using 3° amine base in
the reduction step of the nitro compounds in addition to the acid
chloride in a one-pot approach to form the corresponding amide.
The yields of the amides are reasonable for the model compounds
however more significant is that the reaction conditions are very
mild well tolerated with 1 and showed significant improvement
in the yield of the amide analogues of 1. This reaction is certain
to have utility in the optimization studies of various natural prod-
uct heterocyclic systems.
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Acknowledgments
We thank Keith Hollis for valuable discussion and suggestions.
Desmond Slade for GCMS analysis and Mahmoud ElSohly for GCMS