tion. It is suggested that this selectivity arises from the
formation of the more stable intermediate 5e′ (pathway A
having four conjugated double bonds, both endo and exo)
rather than intermediate 5e′′ (pathway B having only three
conjugated double bonds).
amine 6c (H2/Pd/C or Zn (1 equiv)/AcOH) was obtained,
whereas excess Zn (Zn (18 equiv)/AcOH) yielded the
monobromo 6d. Our postulated mechanism for this interest-
ing reductive elimination of bromine is depicted in Scheme
3. The postulated intermediate, leading to the 6-bromo-
In a recent paper by Gonza´lez et al., deoxygenation of a
series of N-heteroarene N-oxides was carried out utilizing
short C-chain alcohols as solvent in the presence of a base,
such as sodium alkoxide.5 The reaction conditions reported
were relatively harsh, requiring high temperature (120-160
°C). A deoxygenation reaction using 5% methanolic KOH
with heating to reflux (65 °C) for 30 min and then at room
temperature overnight was carried out. To our good surprise,
this method was successful in effecting both cyclization
3c,e f 4c,e and subsequent deoxgenation 4c,e f 5e,c in
quantitative yields. In contrast, these same reaction conditions
led to the cyclization of 3a,d f 4a,d but did not concomi-
tantly give reduced products 5a,d.
Scheme 3. Postulated Mechanism for the Formation of 6d
2-Amino-3-(2-nitroaryl)quinolines 3 offer a strategic route
toward the preparation of the natural product neocryptolepine
8a as well as the potential for preparing some of its derivatives
(8b,c). Although several pathways have been developed for the
synthesis of 8,6 they suffer from the use of sensitive catalysts,
low overall yields, or lengthy synthetic routes.
The key step in our preparation of 8 lies in reducing 3
(Zn/acetic acid, 10-15 min) to the corresponding 3-(2-
aminophenyl)quinolin-2-amines 6, in good to moderate yields
(Table 2). However, the reduction of 6,8-dibromo-3-(2-
substituted product 6d rather than the 8-bromo isomer, rests
upon the argument that this intermediate has three conjugated
double bonds in contrast to two for the alternative intermedi-
ate which would have led supposedly to the 8-bromo isomer.
This argument for selective debromination is analogous to
that, advanced above, for the formation of product 5e via
intermediate 5e′ (Scheme 2).
Cyclization of 6 under acidic conditions in the presence
of sodium nitrite afforded the 6H-indolo[2,3-b]quinoline
derivatives 7a-c. We assume that the more basic 2-amino
quinoline rather than the amino phenyl is the site of
diazotization (the pKa of the conjugate acid of 2-amino-
quinoline ) 7.2 compared to 5.2 for the conjugate acid of
aniline)7,8 although diazotization of either site can lead to 7.
The last step in the synthesis of neocryptolepine 8 is
methylation of its precursor, also known as norcryptotackie-
ine 7,9 by dimethylsulfate.10 This methylation occurs at N(5)
in view of the fact that the proton at N(6) is quite acidic and
therefore does not constitute a good nucleophilic site for
methylation.
Table 2. Route toward the Synthesis of 8
A chloro- or a bromo-substituent at position 2 of neoc-
ryptolepine results in enhanced potency,11 which prompted
us to synthesize such derivatives.6c Unfortunately, attempts
6
R1
R2
R3
7
yield (%)
8
yield(%)
(6) (a) Molina, P.; Alajar´ın, M.; Vidal, A. J. Nat. Prod. 1997, 60, 747.
(b) El Sayed, I.; Van der Veken, P.; Steert, K.; Dhooghe, L.; Hostyn, S.;
Van Baelen, G.; Lemie`re, G.; Maes, B. U. W.; Cos, P.; Maes, L.; Joossens,
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De Pauw-Gillet, M. C.; Van den Heuvel, H.; Claeys, M.; Lemie`re, F.;
Esmans, E. L.; Rozenski, J.; Quirijnen, L.; Maes, L.; Dommisse, R.;
Lemie`re, G.L. F.; Vlietinck, A.; Pieters, L. J. Med. Chem. 2002, 45, 3497.
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Schmittel, M.; Steffen, J. P.; Engels, B.; Lennartz, C.; Hanrath, M. Angew.
Chem., Int. Ed. 1998, 37, 2371.
a
b
c
H
H
H
H
H
H
H
Br
H
a
b
c
-
54
55
79
-
a
b
c
-
70
73
0
Cl
Br
Br
d
-
nitrophenyl)quinolin-2-amine 3d was rather intriguing as it
generated two reduced products depending on the reaction
conditions used: 3-(2-aminophenyl)-6,8-dibromoquinolin-2-
(7) Altun, Y. J. Solution Chem. 2004, 33, 479
(8) Kaljurand, I.; Kuett, A.; Soovaeli, L.; Rodima, T.; Maeemets, V.;
Leito, I.; Koppel, I. A. J. Org. Chem. 2005, 70, 1019
.
.
(9) Ho, T. L.; Jou, D. G. HelV. Chim. Acta 2002, 85, 3823.
(10) Guo, W.; Jiang, Q.-J.; Lu, F.; Yang, D.-Q. Chin. J. Synth. Chem.
2004, 12, 12.
(5) Bjørsvik, H.; Gambarotti, C.; Jensen, V. R.; Gonzalez, R. R. J. Org.
Chem. 2005, 70, 3218.
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Org. Lett., Vol. 12, No. 23, 2010