Synthesis of fused polycyclic nitrogen-containing heterocycles via cascade cyclization

Article abstract of DOI:10.1016/j.tetlet.2006.02.072

A novel strategy for the synthesis of fused polycyclic-nitrogen containing heterocycles via cascade cyclization is described. The methodology involves condensation of 1-(2-aminophenyl)-9H-β-carboline-3-carboxylic acid amide with isothiocyanates followed b

Full text of DOI:10.1016/j.tetlet.2006.02.072

Tetrahedron Letters 47 (2006) 2765–2769
Synthesis of fused polycyclic nitrogen-containing heterocycles
via cascade cyclizationI
Biswajit Saha,a Rishi Kumar,b Prakash R. Maulikb and Bijoy Kundua,*
aMedicinal Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India
bMolecular and Structural Biology Division, Central Drug Research Institute, Lucknow 226 001, India
Received 30 December 2005; revised 7 February 2006; accepted 14 February 2006
Available online 3 March 2006
Abstract—A novel strategy for the synthesis of fused polycyclic-nitrogen containing heterocycles via cascade cyclization is described.
The methodology involves condensation of 1-(2-aminophenyl)-9H-b-carboline-3-carboxylic acid amide with isothiocyanates fol-
lowed by in situ treatment of the resulting thioureas with HgCl2 for 1 h at rt. The one-pot cascade cyclization leads to interesting
changes in molecular structure and an increase in molecular complexity. A mechanistic rationale for the cascade cyclization is
discussed.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Natural products have had a profound impact upon
both chemical biology and drug discovery. One such
example is the tetrahydro-b-carbolines, which are found
abundantly in the plant and animal kingdom, and many
of them exhibit potent biological activities.1–5 This
group of indole alkaloids are widely distributed among
23 angiosperm plant families, the original source being
Peganum harmala.1 In addition to the diverse biological
activity of the naturally occurring compounds, synthe-
tically derived b-carbolines also exhibit significant bio-
activity.6 The reported effects of this class of compound
comprise antineoplastic (tubulin binding),6,7 anticonvul-
sive, hypnotic and anxiolytic (benzodiazepine receptor
ligands),8,9 antiviral,1 antimicrobial5 as well as topoiso-
merase-II inhibition10 and inhibition of cGMP-depen-
dent processes.11 In addition to this, the b-carboline
nucleus is also present in a variety of alkaloids isolated
both from terrestrial plants12 and marine organisms13
with antiplasmodial activity. Waldmann and co-work-
ers14 strongly advocate the need for staying close to nat-
ural products when it comes to designing small-molecule
chemical probes. The rationale behind this philosophy is
that natural products have gone through the evolution-
ary process, and thus serve as a useful guiding principle
for developing clinical candidates.
In view of our continued interest in the development of
novel antimalarial agents derived from natural prod-
ucts,15,16 we were interested in the synthesis and screen-
ing of b-carboline derivatives for which we required
intermediate Ia (Scheme 1). However, our attempts to
synthesize Ia led to fused polycyclic nitrogen-containing
heterocycles via cascade cyclizations. The details of our
findings are presented in this letter.
The synthesis of Ia was attempted by treating 1-(2-ami-
no-phenyl)-9H-b-carboline-3-carboxylic acid amide 1a
(1 equiv) with isothiocyanate (1.2 equiv) in DMSO at
room temperature (Scheme 1, route 1). The progress
of the reaction was monitored by both TLC and HPLC.
The reaction was found to be complete within 2 h and
the product was found to be a mixture of two compo-
nents with traces of unreacted isothiocyanate as the
third component. The HPLC exhibited a major peak
in 82% yield (area under the curve) and a minor compo-
nent in 8% yield. The reaction was worked-up by precipi-
tating the product with water followed by extraction
with ethyl acetate. The organic layer was dried over
Na2SO4 and during its evaporation on a rotavapor,
the foul smell of H2S was noted. This led us to reexam-
ine the purity of the crude product by TLC and HPLC,
which showed an increase in the concentration of the
minor component to 67% from 8% before work-up.
Keywords: b-Carbolines; Fused polycyclic indoles; Cyclodesulfuriza-
tion; Cascade cyclization.
q CDRI Communication No. 6898.
*
Corresponding author. Tel.: +91 522 2262411 18x4383; fax: +91 522
2623405; e-mail: bijoy_kundu@yahoo.com
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.072

2766
B. Saha et al. / Tetrahedron Letters 47 (2006) 2765–2769
O
N
R2
O
N
O
NH2
HN
NH2
N
N
N
+
N
a
N
H
NH2
H
N
R1
Route 1
R2
R1
IIa-g
S
R1
1a (R1 = H)
1b (R1 = 5-Cl)
I
Route 2
a, b
Scheme 1. Reagents and conditions: (a) R2NCS (1.2 equiv), DMSO, rt, 2 h; (b) HgCl2, Et3N, rt, 1 h.
Interestingly, the major peak observed before work-up
was now reduced to 23%. We envisaged that evapora-
tion of the solvent at 50 ꢁC may have triggered the trans-
formation. The two components were separated by
column chromatography and characterized by FAB
mass, NMR and X-ray diffraction crystallographic stud-
ies. One of the components with a lower Rf on TLC was
obtained in 16% isolated yield (mass of 450 Da) and was
found to be thiourea Ia (Scheme 1, route 1). The second
component with a higher Rf was obtained in 56% iso-
lated yield (mass of 400 Da) and was identified by X-
ray diffraction crystallographic studies as a fused poly-
cyclic nitrogen-containing heterocyclic compound IIa
(Scheme 1) probably derived from Ia via cascade cycli-
zation. Of these two, thiourea Ia had only moderate sta-
bility, because even after purification, it had a tendency
to undergo slow conversion to the cyclized product IIa.
The X-ray structure of IIa is depicted in Figure 1.17
A survey of the literature revealed IIa to be a new family
of indole based polycycles produced by sequential intra-
molecular guanylation via cyclodesulfurization followed
by transamidation/cyclization in one-pot. A plausible
mechanism for the formation of IIa from Ia is depicted
in Figure 2. The reaction commences with nucleophilic
attack on the thioureido carbon, which results in an
intermediate with a delocalized positive charge (repre-
sented by two canonical forms). This then triggers the
release of a proton from Na and allows the formation
of the quinazoline ring with the release of H2S. This is
then followed by a second cyclization between the car-
boxamide and the NH attached to the quinazoline ring
via transamidation with the release of NH3. Since by
HPLC we could not observe the quinazoline intermedi-
ate III (Fig. 2) arising from the first cyclization, this led
us to believe that intermediate III, though formed slowly
from Ia, appears to be highly reactive. The second cycli-
Figure 1. ORTEP plot of the molecular structure of compound IIa (at
30% probability level).
O
NH2
O
NH2
HN
O
NH2
HN
N
H
S
N
N
S
S
N
N
N
N
H
H
H
N
H
NH
N
H
Ia
O
N
O
NH2
HN
O
NH2
HN
N
N
N
-NH3
SH
H
N
N
N
-H2S
N
N
N
IIa
Figure 2. Proposed mechanism for the formation of IIa from Ia.
III

B. Saha et al. / Tetrahedron Letters 47 (2006) 2765–2769
Table 1. Optimization of IIa formation from 1a
2767
Entry
Reaction conditions
IIaa (%)
Iaa (%)
1
2
3
4
1a + o-Tolyl isothiocyanate, at 80 ꢁC, 12 h
68
70
82
93
26
20
12
0
1a + o-Tolyl isothiocyanate + HgCl2 (1 equiv) heating at 60 ꢁC, 6 h
1a + o-Tolyl isothiocyanate, 2 h then HgCl2 (1 equiv), rt, 6 h
1a o-Tolyl isothiocyanate, 2 h then HgCl2 (1 equiv), Et3N (2 equiv), rt, 1 h
a Based on HPLC of the crude reaction product.
zation furnishing the polycyclic framework II from III,
however, appears to be both easy and rapid. Polycyclic
indolic compounds are the targets of extensive synthetic
interest, partly because there are many biologically
active natural products of this type, and also because
the polycyclic frameworks lead to relatively rigid struc-
tures that might be expected to show substantial selec-
tivity in their interaction with enzymes or receptors.
This prompted us to develop a suitable strategy to effect
cascade cyclization in quantitative yields.
room temperature conditions in two steps (Table 1,
entry 4).
In the first step, 1a is allowed to react with isothiocya-
nate (1.2 equiv) at rt for 2 h and in the second step,
the resulting thiourea Ia is treated in situ with HgCl2
(1 equiv) and Et3N (2 equiv) for 1 h at rt (Scheme 1,
route 2).19 We were pleased to observe complete conver-
sion of thiourea Ia into IIa within 1 h, along with traces
of unreacted isothiocyanate. The crude product was
purified by silica gel column chromatography to give
IIa in 85% isolated yield. The scope and limitation of
the method was established by synthesizing six com-
pounds II by varying the isothiocyanates (aryl and alkyl)
and o-nitrobenzaldehydes (Table 2). Starting b-carbo-
lines 1 were synthesized (Scheme 2) by treating Trp-
amide with o-nitrobenzaldehydes under Pictet–Spengler
conditions.20 The resulting tetrahydro-b-carboline was
then oxidized with KMnO4 to give b-carbolines.21 Sub-
sequently, the nitro group was reduced to the amine by
hydrogenation in the presence of Pd/C to furnish 1. Sub-
stitution on the aryl aldehydes or isothiocyanates did
not have any affect on the yields and purities of II. Next,
we extended our methodology to tryptamine, as this
would result in compounds IV via single cyclization
(Scheme 3), again a class of b-carboline derived com-
pounds hitherto unknown. Interestingly, compounds
IV appear to structurally resemble the yohimbane/reser-
pine backbone.22 The precursor 1-(2-aminophenyl)-9H-
b-carboline 2 derived from tryptamine (Scheme 2) by
the literature procedure23 was treated with isothiocya-
nates in the presence of HgCl2 to furnish IV in high
yields (Scheme 3, Table 3).
In view of the slow and incomplete conversion of I to
III, we directed our efforts towards this cyclization
involving guanylation via cyclodesulfurization. In the
first instance, based on our initial observation that heat-
ing triggered the cascade cyclization, we treated 1a with
isothiocyanate at 80 ꢁC and monitored the progress of
the reaction by HPLC. Unfortunately, even after pro-
longed heating for 24 h, the final product IIa could still
only be obtained in 68% yield along with Ia (Table 1, en-
try 1). This led us to add reagents that are known to cat-
alyze guanylation via desulfurization and accordingly
we selected HgCl2 for this purpose.18 We carried out
the reaction of 1a with isothiocyanate (1.2 equiv) in
the presence of HgCl2 and monitored the progress of
reaction by HPLC. Optimization of the reaction led to
Table 2. Compounds (II) prepared via Scheme 1 (route 2)
Compound
R1
R2
Isolated yield
(%)
FAB
(M++1)
IIa
IIb
IIc
IId
IIe
IIf
H
H
H
5-Cl
5-Cl
5-Cl
H
2-CH3C6H4
C6H5
4-FC6H4CH2
2-CH3C6H4
C6H5
85
72
74
70
75
76
80
401
387
419
435
421
453
367
In summary, we have developed a mild and versatile ap-
proach for the synthesis of a structurally unique group
of fused polycyclic b-carboline based heterocycles in
high yield and purity. The one-pot cascade cyclization
4-FC6H4CH2
n-C4H9
IIg
CHO
X
NO2
X
X
X
N
b (when X = CONH2)
c (when X = H)
N
NH
d
N
H
N
N
H
NH2
NH2
H
NO2
NO2
N
a
H
R1
X = CONH2; Tryptophan
X = H; Tryptamine
R1
R1
1; X = CONH2
2; X= H
Scheme 2. Reagents and conditions: (a) 2% TFA in DCM, rt, 7 h; (b) KMnO4, THF, 0 ꢁC, 30 min; (c) S, DMSO, 100 ꢁC, 48 h; (d) 10% Pd/C,
MeOH, 30 psi, 2 h.

2768
B. Saha et al. / Tetrahedron Letters 47 (2006) 2765–2769
Houghton, P. J. Planta Med. 1999, 65, 690–694; (c) Johns,
R2
HN
S. R.; Lamberton, J. A.; Sioumis, A. A. Aust. J. Chem.
1970, 23, 629–634; (d) Pavanand, K.; Yongvanitchit, K.;
Webster, H. K.; Dechatiwongse, T.; Nutakul, W.; Jew-
vachdamrongkul, Y.; Bansiddhi, J. Phytother. Res. 1988,
2, 33–36.
N
N
a, b
N
N
H
NH2
N
R1
2 (R1 = H)
R1
IV a-d
13. Ang, K. K. H.; Holmes, M. J.; Higa, T.; Hamann, M. T.;
Kara, U. A. K. Antimicrob. Agents Chem. 2000, 1645–
1649.
Scheme 3. Reagents and conditions: (a) R2NCS (1.2 equiv), DMSO,
rt, 2 h; (b) HgCl2, Et3N, rt, 1 h.
14. Dekker, F. J.; Koch, M. A.; Waldmann, H. Curr. Opin.
Chem. Biol. 2005, 9, 232–239.
15. Srinivasan, T.; Srivastava, G. K.; Pathak, A.; Batra, S.;
Puri, S. K.; Raj, K.; Kundu, B. Bioorg. Med. Chem. Lett.
2002, 12, 2803–2806.
Table 3. Compounds (IV) prepared via Scheme 3
16. Pathak, A.; Singh, S. K.; Farooq Biabani, M. A.;
Srivastava, S.; Kulshreshtha, D. K.; Puri, S. K.; Kundu,
B. Comb. Chem. High Throughput Screening 2002, 5, 241–
248.
Compound
R1
R2
Isolated yield
(%)
FAB
(M++1)
IVa
IVb
IVc
IVd
H
H
H
H
2-CH3C6H4
C6H5
C6H5CH2–
n-C4H9
80
77
74
79
375
361
375
341
17. Crystal data for IIa: C26H16N4O, M = 400.43, mp >
300 ꢁC, triclinic, P1, a = 8.468(2), b = 11.229(2), c =
˚
11.557(2) A, a = 90.13(1), b = 109.67(1), c = 111.90(1)ꢁ,
3
À3
˚
V = 949.8(3) A , T = 293(2) K, Z = 2, Dc = 1.400 g cm
,
l = 0.88 mmÀ1
,
F(000) = 416,
k
(Mo Ka) = 0.71073 A,
˚
reddish block, crystal size 0.250 · 0.125 · 0.050 mm,
3069 reflections measured (Rint = 0.0676), 2325 unique,
R1 = 0.0677 for 819 Fo > 4r(Fo) and 0.2149 for all 2325
data, S = 0.919 for all data and 281 parameters. Unit cell
determinations and intensity data collection (2h = 44.16ꢁ)
were performed on a Bruker P4 diffractometer at 293(2) K.
Structure solutions by direct methods and refinements by
full-matrix-least-squares methods on F2. Programs:
XSCANS [(Siemens Analytical X-ray Instruments Inc.:
Madison, Wisconsin, USA 1996) were used for data
collection and data processing], SHELXTL-NT [(Bruker
AXS Inc.: Madison, Wisconsin, USA 1997) was used for
structure determination, refinements and molecular graph-
ics]. Further details of the crystal structure investigation
can be obtained from the Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK
(CCDC deposit No. 297367).
leads to interesting changes in molecular structure and
an increase in molecular complexity.
Acknowledgements
B.S. and R.K. are grateful to CSIR and DOD, New
Delhi, respectively, for financial support. The authors
also thank Dr. A. Arora, for providing 600 MHz
NMR facilities.
References and notes
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19. Representative procedure IIa/IVa: To a solution of 1a or 2
(0.33 mmol) in dry DMSO (5 mL) was added o-tolyl
phenylisothiocyanate (98 lL, 0.66 mmol) and the mixture
was stirred for 2 h. Then, triethylamine (91 lL,
0.66 mmol) and HgCl2 (90 mg, 0.33 mmol) were added
to the reaction mixture which was stirred for 1 h. To the
mixture was added EtOAc (5 mL) and stirring continued
for an additional 5 min. After this, the mixture was poured
in cold water and an additional amount of EtOAc (50 mL)
was added and the mixture filtered through a bed of
Celiteꢂ. The organic layer was separated, washed with
water and dried over Na2SO4. It was then evaporated to
dryness under reduced pressure and the crude red residue
so obtained was purified by column chromatography on
silica gel (100–200 mesh) using chloroform as an eluent to
afford IIa or IVa.
5. Molina, P.; Fresneda, P. M.; Zafra, G. S.; Almendros, P.
Tetrahedron Lett. 1994, 35, 8851–8854.
6. (a) Takasu, K.; Shimogama, T.; Saiin, C.; Kim, H. S.;
Wataya, Y.; Ihara, M. Bioorg. Med. Chem. Lett. 2004, 14,
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F.; Liao, X.; Cook, J. M. J. Org. Chem. 2003, 68, 7565–
7581; (b) Keawpradub, N.; Kirby, G. C.; Steele, J. C. P.;
Compound IIa: red solid; mp > 300 ꢁC; IR mmax (KBr)
1649 cmÀ1 1H NMR (600 MHz, DMSO): d = 8.68 (d,
;

B. Saha et al. / Tetrahedron Letters 47 (2006) 2765–2769
2769
J = 7.8 Hz, 1H, ArH), 8.14 (d, J = 8.4 Hz, 1H, ArH),
8.12–8.10 (overlapped, 2H, ArH), 8.08–8.06 (m, 2H, ArH),
7.72 (t, J = 7.2 Hz, 1H, ArH), 7.63 (d, J = 8.4 Hz, 1H,
ArH), 7.57–7.56 (overlapped, 3H, ArH), 7.50–7.48 (m, 1H,
ArH) 7.45 (t, J = 7.2 Hz, 1H, ArH), 2.30 (s, 3H, CH3).
Anal. Calcd for C26H16N4O: C, 77.99; H, 4.03; N, 13.99.
Found: C, 77.75; H, 4.27; N, 13.84.
ArH), 7.37 (t, J = 7.8 Hz, 1H, ArH), 7.34 (t, J = 7.2 Hz,
1H, ArH), 2.67 (s, 3H, CH3). Anal. Calcd for C25H18N4:
C, 80.19; H, 4.85; N, 14.96. Found: C, 80.55; H, 4.77; N,
14.84.
20. Cox, E. D.; Cook, J. Chem. Rev. 1995, 95, 1797–1842.
21. Tietze, L. F.; Zhou, Y.; Topken, E. Eur. J. Org. Chem.
2000, 2247–2252.
Compound IVa: brown solid; mp > 250 ꢁC; IR mmax (KBr)
22. Bailey, P. D.; Cochrane, P. J.; Forster, A. H.; Morgana,
K. M.; Pearson, D. P. J. Tetrahedron Lett. 1999, 40, 4597–
4600.
23. Zili, X.; Ren, W.; Mo; Angou, M.; Xipeng, J.; Fengyan, S.
Chin. Chem. Lett. 1991, 2, 677–680.
3426 cmÀ1 1H NMR (600 MHz, DMSO): d = 8.90 (d,
;
J = 6.6 Hz, 1H, ArH), 8.57 (d, J = 7.8 Hz, 1H, ArH), 8.02
(d, J = 8.4 Hz, 1H, ArH), 7.84–7.81 (m, 3H, ArH), 7.59
(br s, 1H, NH), 7.53–7.51 (m, 3H, ArH), 7.37–7.33 (m, 3H,