Efficient one-pot synthesis of anti-HIV and anti-tumour β-carbolines

Article abstract of DOI:10.1016/j.tet.2004.04.079

Thermal electrocyclisation of the azahexatriene system has been used as a key step for the synthesis of anti-HIV and anti-tumour compounds, harman, derivatives of harman and 1-aryl-β-carbolines. A one-pot reaction sequence was used to furnish these compounds in good yield.

Full text of DOI:10.1016/j.tet.2004.04.079

Tetrahedron 60 (2004) 5315–5318
Efficient one-pot synthesis of anti-HIV
and anti-tumour b-carbolines
*
Radhika S. Kusurkar and Shailesh K. Goswami
Department of Chemistry, University of Pune, Pune 411007, India
Received 17 February 2004; revised 5 April 2004; accepted 29 April 2004
Abstract—Thermal electrocyclisation of the azahexatriene system has been used as a key step for the synthesis of anti-HIV and anti-tumour
compounds, harman, derivatives of harman and 1-aryl-b-carbolines. A one-pot reaction sequence was used to furnish these compounds in
good yield.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Thus, indole was formylated7 using the Vilsmeier Haack
reaction to give 3-formyl indole. N-Protection was carried
out with benzenesulphonyl chloride using the reported5a
procedure. The protected aldehyde 1 was converted8 into
3-vinyl indole 7a using methylenetriphenylphosphorane. To
functionalise the indole ring at 2-position, compound 7a
was lithiated using LDA/THF at 278 8C and then treated
with N,N-dimethylacetamide. After work-up and washing
with hexane to remove the unreacted starting materials, the
reaction mixture, without further purification was treated
with hydroxylamine hydrochloride and sodium acetate and
refluxed in o-dichlorobenzene for 8 h to furnish b-carboline
alkaloid harman 11, in 46% yield starting from 7a. It was
characterized using 1H, 13C NMR spectroscopy and GC-MS
spectral data, which were consistent with the reported9 data.
Thus, in this sequence, four steps, oxime formation,
electrocyclisation and aromatization with deprotection
occurred in a one-pot reaction sequence. Efforts to isolate
the intermediate 2-keto compounds were unsuccessful due
to its rapid decomposition. The protected indole-3-aldehyde
1 was converted10 to 3-vinylindole 7b and to 3-(b-
nitrovinyl)indole 7c using nitromethane and ammonium
acetate. Treatment of 7b and 7c with LDA/THF at 278 8C,
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 hydrochloride and sodium acetate and
refluxed in o-dichlorobenzene. Both of these reactions
furnished harman 11 in 53 and 45% yields from 7b and 7c,
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.11 Furthermore, by
using N-methyl and N-methoxymethylindole-3-aldehydes 2
and 3, the same sequence of reactions was followed.
The b-carboline ring system is present in many naturally
occurring alkaloids which exhibit1 interesting biological
activities. Harman 11 has been reported2 to show mutagenic
and co-mutagenic properties and to inhibit topoisomerase
I. Harmine 14 showed2 significant anti- tumour activity.
Recently harman, harmine and their derivatives were
shown3 to possess potent anti-HIV activity. Numerous
alkaloids of b-carboline series, with various substituents at
a-position, display important biological properties.4
Amongst the variety of methods available for the synthesis
of b-carboline alkaloids, the most extensively used1 are the
Pictet Spengler and Bischler-Napieralski condensations.
However, there are a few routes in which electrocyclisation
reactions have been used5 for the synthesis. Recently, we
reported6 a preliminary communication, presenting the use
of electrocyclisation reaction, of monoazahexatriene system
as a key step, for the synthesis of harman and substituted
harmans. We describe here, in full, details of the synthesis
of harman, derivatives of harman and 1-aryl-b-carbolines.
2. Results and discussion
The key intermediate for the electrocyclization step was the
azatriene X. The synthesis of X was envisioned as involving
functionalising the indole ring at the 3-position initially and
subsequently at the 2-position as shown in Scheme 1.
Keywords: Harman; Harmine; b-Carboline; Electrocyclisation; 1-Aryl-b-
carboline.
*
Corresponding author. Tel.: þ91-20-25601202; fax: þ91-20-25691728;
e-mail address: rsk@chem.unipune.ernet.in
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.04.079

5316
R. S. Kusurkar, S. K. Goswami / Tetrahedron 60 (2004) 5315–5318
Scheme 1. Reagents: (i) (Ph)3PCH3I, t-BuOK, THF; (ii) (Ph)3PCH2OCH3Cl, t-BuOK, THF (iii) CH3NO2, AcOH, AcONa; (iv) LDA, THF, N,N-dimethyl
acetamide (for 7a, 7b, 7c, 9a, 9b, 9c, 10a, 10b and 10c); (v) n-BuLi, THF, N,N-dimethylacetamide (for 8a, 8b and 8c); (vi) NH2OH·HCl, AcONa,
o-dichlorobenzene.
Reactions using 3-vinylindoles 8a, 8b and 8c afforded
N-methylharman 12 in 45–46% overall yields and using 9a,
9b and 9c afforded N-methoxymethyl harman 13 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 consistent with that
reported.9
using the same one-pot strategy involving electrocyclisation
reaction. Thus starting from 6-methoxy-3-vinylindoles 10a,
10b and 10c (Scheme 1) harmine, N-ethylharmine and
N-butylharmine were synthesized in good yield.
In all these reactions, efforts were made to isolate the
intermediate 2-keto compounds, however, all of them were
shown to be unstable and light sensitive.
The presence of intermediate compounds was confirmed by
analogy with the reaction sequence used in the synthesis of
N-methylnorharman reported in our earlier communi-
cation.6
Recently in an activity evaluation report3 of harmine and its
derivatives, it was found that N-butylharmine was the most
potent compound and possessed a good therapeutic index.
N-ethylharmine was also potent and showed moderate
therapeutic index. Introduction of methoxy group at the
seven position methyl group at one position and alkylation
of indole nitrogen of norharman led to the enhanced anti-
HIV activity. N-Butylharmine was shown to be more active
than N-ethylharmine, indicating that the length of the alkyl
chain at this position is important to activity.
As 1-substituted-b-carbolines posses various biological
activities, it was envisaged to use our one-pot strategy for
the synthesis of 1-aryl-b-carbolines by changing the
electrophile, used in the lithiation reaction. Initially, the
use of N,N-dimethylbenzamide or N,N-dimethyl-2-furamide
as an electrophile gave a complex mixture. Then nitrile was
used as an electrophile in the lithiation reaction. There are a
few reports12 of the use of nitrile as an electrophile in
lithiation reaction. Benzonitrile was then used as an electro-
phile expecting a formation of 2-imino or 2-keto-3-vinyl
In view of the above report, the synthesis of other anti-
tumour and anti-HIV active b-carbolines; harmine 14,
N-ethyl harmine 15 and N-butylharmine 16 was carried out
Scheme 2. Reagents and conditions: (i) LDA/THF; (ii) ArCN; (iii) H2O; (iv) NH2OH·HCl, CH3COONa, o-dichlorobenzene.

R. S. Kusurkar, S. K. Goswami / Tetrahedron 60 (2004) 5315–5318
5317
indoles as shown in Scheme 2. Attempts13 to isolate these
intermediates gave rapid decomposition. Thus the reaction
mixture was stirred at 210 8C and after work-up, without
purification, was treated with hydroxylamine hydrochloride
and sodium acetate and refluxed in o-dichlorobenzene to
furnish 1-phenyl-b-carboline 17. Similar reaction sequence
was used for the synthesis of 1-(2-furyl)-b-carboline 18 and
1-(p-methoxyphenyl)-b-carboline 19 in which furan-2-carbo-
nitrile and p-methoxybenzonitrile were used as electrophiles
respectively. The formation of the b-carbolines was explained
as shown in Scheme 2. The imine produced in the lithiation
reaction might be hydrolysed to keto compound. Treatment of
thiscompoundwithhydroxylaminehydrochlorideandsodium
acetate gave an azatriene system. Further electrocyclisation,
aromatization and deprotection furnished 1-substituted-b-
carbolines.
distilled N,N-dimethylacetamide/aryl nitrile (0.002 mol) in
anhydrous THF (10 mL) was added to this solution at
278 8C. The mixture was further stirred for 1 h. The
temperature was allowed to rise up to 210 8C and it was
stirred for another 3 h. After work up with brine, the mixture
was extracted with ethyl acetate. The extract was washed
with water, dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The residue was washed with
hexane and without further purification treated with
hydroxylamine hydrochloride (0.04 mol) and NaOAc
(0.04 mol) and refluxed for 8 h in o-dichlorobenzene.
After removal of solvent the residue was chromatographed
on neutral alumina using hexane and ethyl acetate (90/10 to
80/20) to give corresponding b-carbolines.
3.2.1. Harman (11). Mp 235–236 8C (Lit.9 Mp 235–
238 8C); (Found: C, 79.24; H, 5.45. C12H10N2 requires C,
79.10; H, 5.53); nmax (nujol) 1663 cm21; dH (DMSO-d6)
2.85 (3H, s, ArCH3), 7.21 (1H, td, J¼7.5, 1.1 Hz, C6–H),
7.51 (1H, td, J¼7.1, 1.1 Hz, C7–H), 7.58 (1H, d, J¼7.9 Hz,
C8–H), 7.81 (1H, d, J¼5.2 Hz, C4–H), 8.07 (1H, d,
J¼8.0 Hz, C5–H), 8.21 (1H, d, J¼5.2 Hz, C3–H), 11.31
(1H, bs, exchange with D2O, NH); dC (DMSO-d6) 18.71,
110.09, 110.68, 117.28, 119.27, 119.62, 125.24, 125.81,
132.78, 135.44, 138.65, 140.20.
By the analogy3 to the anti HIV activity of N-substituted
and 1-substituted-b-carbolines, the newly synthesized
N-methoxymethylharman, and 1-phenyl, 1-(2-furyl) and
1-(p-methoxyphenyl)-b-carbolines, are expected to show
anti-HIV activity.
In summary, some biologically important anti-tumour
and anti-HIV active b-carboline alkaloids, harman 11,
N-methylharman 12, N-methoxymethylharman 13, harmine
14, N-ethylharmine 15 and N-butylharmine 16, were
synthesized in a one-pot reaction sequence using electro-
cyclisation reactions in good yields. In addition, use of aryl
nitrile as an electrophile in the lithiation reaction and a
further one-pot sequence of the reactions furnished
1-phenyl-b-carboline 17, 1-(2-furyl)-b-carboline 18 and
1-(p-methoxyphenyl)-b-carboline 19.
3.2.2. N-Methylharman (12). Mp 104–105 8C (Lit.9 Mp
102–104 8C); (Found: C, 79.67, H, 6.25. C13H12N2 requires
C, 79.56; H, 6.16); nmax (nujol) 1668 cm21; dH (DMSO-d6)
3.11 (3H, s, ArCH3), 4.14 (3H, s, NCH3), 7.1 (1H, t,
J¼7.5 Hz, C6–H), 7.47 (1H, d, J¼8.2 Hz, C8–H), 7.63 (1H,
t, J¼7.1 Hz, C7–H), 7.86 (1H, d, J¼4.4 Hz, C4–H), 8.15
(1H, d, J¼7.7 Hz, C5–H), 8.31 (1H, d, J¼4.4 Hz, C3–H);
dC (DMSO-d6) 22.93, 32.0, 110.03, 112.89, 119.29, 120.01,
121.35, 127.70, 128.1, 134.94, 136.64, 141.56.
3. Experimental
3.1. General
3.2.3. N-Methoxymethyl harman (13). Mp 152–154 8C;
(Found: C, 74.47; H, 6.45. C14H14N2O requires C, 74.31; H,
6.24); nmax (nujol) 1660 cm21; dH (DMSO-d6) 3.06 (3H, s,
ArCH3), 3.32 (3H, s, OCH3), 5.79 (2H, s, NCH2O), 7.26
(1H, t, J¼7.4 Hz, C6–H), 7.9 (1H, d, J¼8.7 Hz, C8–H),
7.60 (1H, m, C7–H), 8.27 (2H, bd, J¼5.2 Hz, C4–H and
C5–H), 8.42 (1H, d, J¼5.8 Hz, C3–H); dC (DMSO-d6)
20.30, 55.20, 82.80, 94.56, 109.10, 111.97, 114.82, 122.62,
127.25, 134.55, 137.73, 141.28, 141.97,160.10.
All recorded melting points are uncorrected. IR spectra (n,
cm21) were recorded on a Perkin–Elmer 1600 FTIR
spectrophotometer as a thin film or in nujol mull. NMR
spectra were recorded on a Varian Mercury instrument
1
(300 MHz for H and 75 MHz for 13C) with reference to
TMS as an internal standard. Elemental analyses were
carried out in a Hosli C, H-analyzer. As and when required
the reactions were carried out in oven-dried glassware under
dry N2. N-Protected indole aldehydes were prepared5a from
indole-3-aldehyde.Vinyl indoles 7a, 7b, 8a, 8b, 9a, 9b, 10a,
10b and 10c were prepared8,10 using Wittig reactions and
b-nitrovinyl indoles 7c, 8c and 9c were prepared using
nitromethane and ammonium acetate.
3.2.4. Harmine (14). Mp 262–263 8C (Lit.14 Mp 262 8C);
(Found: C, 73.40; H, 5.84. C13H12N2O requires C, 73.57; H,
5.70); nmax (nujol) 1665 cm21; dH (DMSO-d6) 2.59 (3H, s,
ArCH3), 3.73 (3H, s, OCH3), 6.67 (1H, dd, J¼2.2, 8.5 Hz,
C6–H), 6.88 (1H, d, J¼2.2 Hz, C8–H), 7.66 (1H, d,
J¼5.2 Hz, C4–H), 7.90 (1H, d, J¼8.8 Hz, C5–H), 8.01
(1H, d, J¼5.2 Hz, C3–H), 11.32 (1H, bs, exchange with
D2O, NH); dC (DMSO-d6) 20.32, 55.26, 94.56, 109.10,
111.97, 114.82, 122.62, 127.25, 134.55, 137.73, 141.28,
141.97, 160.09.
3.2. General procedure for one-pot synthesis of
b-carbolines
A solution of N-protected-3-vinyl indoles 7a, 7b, 7c, 9a, 9b,
9c, 10a, 10b and 10c (0.002 mol) in freshly distilled
anhydrous THF (5 mL) was added to freshly prepared LDA
(0.004 mol) solution in THF at 278 8C and n-BuLi (2.3 M,
0.004 mol) in hexane was added to the solution of
vinylindoles 8a, 8b and 8c in THF at 278 8C. The resulting
orange colored solution was stirred for 1 h and freshly
3.2.5. N-Ethyl harmine (15). Mp 251–252 8C; (Found: C,
74.87; H, 6.71. C15H16N2O requires C, 74.97; H, 6.71); nmax
(nujol) 1640 cm21; dH (CDCl3) 1.43 (3H, t, J¼7.2 Hz,
N-CH2CH3), 3.01 (3H, s, ArCH3), 3.97 (3H, s, OCH3), 4.51
(2H,q, J¼6.9 Hz, N-CH2CH3), 6.85 (2H, bd, J¼9.2 Hz,
C6–H and C8–H), 7.70 (1H, d, J¼4.7 Hz, C4–H), 7.94 (1H,

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R. S. Kusurkar, S. K. Goswami / Tetrahedron 60 (2004) 5315–5318
d, J¼8.2 Hz, C5–H), 8.25 (1H, d, J¼5.2 Hz, C3–H); dC
(CDCl3) 15.36, 23.01, 39.18, 55.44, 92.44, 108.48, 111.82,
114.87, 122.0, 128.97, 134.63, 137.73, 140.11, 142.22,
160.48.
Chaudhari for NMR spectra and Mr. Vishal Koske for
GC-MS.
References and notes
3.2.6. N-Butyl harmine (16). Mp 221–222 8C; (Found: C,
76.20; H, 7.71. C17H20N2O requires C, 76.09; H, 7.51); nmax
(nujol) 1663 cm21; dH (CDCl3) 0.95 (3H, t, J¼7.4 Hz,
N-CH2CH2CH2CH3), 1.45 (2H, m, N-CH2CH2CH2CH3),
1.80 (2H, m, N-CH2CH2CH2CH3), 3.01 (3H, s, ArCH3),
3.94 (3H, s, OCH3), 4.45 (2H,t, J¼7.9 Hz, N-CH2CH2CH2-
CH3), 6.86 (2H, bd, J¼9.9 Hz, C6–H and C8–H), 7.71 (1H,
d, J¼4.4 Hz, C4–H), 7.95 (1H, d, J¼9.9 Hz, C5-H), 8.25
(1H, d, J¼4.4 Hz, C3–H); dC (CDCl3) 13.98, 20.27, 23.51,
32.78, 44.70, 55.68, 93.39, 108.39, 112.13, 115.13, 122.22,
129.17, 135.19, 138.10, 140.45, 142.91, 160.59.
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3.2.7. 1-Phenyl-b-carboline (17). Mp 245–246 8C (Lit.15
Mp 246–247 8C); (Found: C, 83.40; H, 4.82. C17H12N2
requires C, 83.58; H, 4.95); nmax (nujol) 1660 cm21; dH
(DMSO-d6) 7.14 (1H, m, C6-H), 7.36–7.51 (5H, m, ArH),
7.88 (2H, d, J¼7.3 Hz, C7-H and C8–H), 7.97 (1H, d,
J¼5.3 Hz, C4-H), 8.10 (1H, d, J¼8.0 Hz, C5–H), 8.30 (1H,
d, J¼5.3 Hz, C3–H), 11.43 (1H, bs, exchange with D2O,
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C15H10N2O requires C, 76.91; H, 4.30); nmax (nujol)
1665 cm21; dH (DMSO-d6) 6.70 (1H, d, J¼1.8 Hz, C4–H
of furan), 7.18 (2H, bs, C3–H of furan and C6–H) 7.49 (1H,
t, J¼7.1 Hz, C7-H), 7.67 (1H, d, J¼7.9 Hz, C8–H) 7.90 (1H,
bs, C5–H of furan), 8.0 (1H, bd, J¼5.1 Hz, C4–H), 8.27
(1H, d, J¼7.9 Hz, C5–H), 8.29 (1H, bd, J¼5.1 Hz, C3–H),
11.43 (1H, bs, exchange with D2O, NH).
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C18H14N2O requires C, 78.81; H, 5.14); nmax (nujol)
1668 cm21; dH (DMSO-d6) 3.0–3.8 (3Hþ, bs, OCH3þ
DMSO-d6), 6.70 (2H, d, J¼8.5 Hz, ArH), 6.87 (1H, m, C6–
H), 7.19 (2H, m, C7–H and C8–H), 7.37 (2H, d, J¼8.5 Hz,
ArH), 7.87 (2H, d, J¼7.6 Hz, C4–H and C5–H), 7.99 (1H,
d, J¼6.1 Hz, C3–H), 12.19 (1H, bs, exchange with D2O,
NH).
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Acknowledgements
We are grateful to Mr. A. P. Gadgil for IR spectra, Mrs. J. P.