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involving functionalizing the indole ring at the 3-posi-
tion initially and subsequently at the 2-position as
shown in Scheme 1.
45–46% overall yields and using 7a, 7b and 7c
afforded N-methoxymethyl harman 11 in 37–47%
overall yields (Scheme 1). In all these reactions, the
methoxy and the nitro groups were eliminated during
the one-pot reaction sequence. The vinyl compounds
and the b-carbolines were characterized using spectral
data. The NMR data of N-methylharman was consis-
tent with that reported.7
Thus, indole was formylated5 using the Vilsmeier–
Haack reaction to give 3-formyl indole. N-Protection
was carried out with benzenesulphonyl chloride using
the reported4a procedure. The protected aldehyde 1
was converted6 into 3-vinyl indole 5a using methylene-
triphenyl phosphorane. Compounds 1 and 5a were
characterized using spectral data. To functionalize the
indole ring at the 2-position, compound 5a was lithi-
ated using LDA/THF at −70°C and then treated with
N,N-dimethylacetamide. After work-up and washing
with hexane to remove the unreacted starting materi-
als, the reaction mixture, without further purification
was treated with hydroxylamine hydrochloride and
sodium acetate and was refluxed in o-dichlorobenzene
for 8 h to furnish b-carboline alkaloid harman 9 in
46% overall yield starting from 5a. It was character-
ized using 1H, 13C NMR and GC–MS spectral data
which were consistent with the reported7 data. Thus,
in this sequence, four steps, oxime formation, electro-
cyclization and aromatization with deprotection
occurred in a one-pot reaction sequence. Efforts to
isolate the intermediate 2-keto compound were unsuc-
cessful due to its rapid decomposition. The protected
indole-3-aldehyde 1 was converted8 to 3-vinylindole
5b and to 3-(b-nitrovinyl) indole 5c using
nitromethane and ammonium acetate. The com-
pounds 5b and 5c were characterized using spectral
data. Treatment of 5b and 5c with LDA/THF at
−70°C, followed by N,N-dimethylacetamide furnished
two oily liquids. After washing with hexane to
remove unreacted starting materials, the two oily
compounds were treated with hydroxylamine hydro-
chloride and sodium acetate and refluxed in o-
dichlorobenzene. Both of these reactions furnished
harman 9 in 53 and 45% overall yields from 5b and
5c, respectively (Scheme 1). It was observed that the
methoxy and nitro groups were eliminated during the
reaction sequence, probably during the aromatization
step. A similar observation has been reported earlier.9
Using the same strategy, another antitumor and anti-
HIV active b-carboline, harmine 12 was synthesized
in 56% overall yield starting from 6-methoxy-3-
vinylindole 8 (Scheme 1). The formation of the
harmine 12 was confirmed by comparing the spectral
data with that reported.10
Thus, harman, its derivatives and harmine were syn-
thesized in good overall yields in a one-pot reaction
sequence. In all these reactions, efforts were made to
isolate the intermediate 2-keto compounds, however,
all were shown to be unstable and light sensitive.
The presence of intermediate compounds was con-
firmed by analogy with the reaction sequence used
(Scheme 2) in the synthesis of N-methylnorharman
17. In this route, all the intermediates were isolated
and characterized by 1H NMR. Thus, lithiation of
3-vinylindole 6a with n-BuLi in hexane and 7c with
t-BuLi in pentane, then treatment with DMF
afforded the aldehydes 13 and 14, respectively, which
were converted to oximes 15 and 16. Electrocycliza-
tion of 15 by refluxing in o-dichlorobenzene furnished
N-methylnorharman 17 in poor yield as a 1:1 mixture
along with the starting oxime. Moreover, electrocy-
clization of 16 and the one-pot reaction on 13, failed
to produce the desired product. Compounds 13, 14,
1
15, 16 and 17 were characterized using H NMR. The
poor yields are probably due to the instability and
light sensitivity of the intermediates.
In summary, biologically important, antitumor and
anti-HIV b-carboline alkaloids, harman, N-methylhar-
man, N-methoxymethyl harman and harmine were
synthesized in a one-pot reaction sequence using elec-
trocyclization reactions in good overall yields. Appli-
cation of this strategy to other biologically important
b-carboline alkaloids is in progress.
Further, using N-methyl and N-methoxymethyl
indole-3-aldehydes 2 and 3, the same sequence of
reactions was followed. Reactions using 3-vinyl
indoles 6a, 6b and 6c afforded N-methylharman 10 in
Scheme 2. Reagents: (i) n-BuLi, THF, DMF; (ii) t-BuLi, THF, DMF; (iii) NH2OH·HCl, AcONa, MeOH; (iv) o-dichlorobenzene.
Kusurkar, Radhika S.
