Pictet-Spengler synthesis of some thiophene[c]-fused β-carbolines

Article abstract of DOI:10.1007/s00706-007-0763-6

5-(Substituted) thieno[2′,3′:5,6]pyrido[3,4-b]indoles were synthesized via cyclocondensation of 3-(3-aminothien-2-yl)indole with the appropriate aldehyde in the presence of boron trifluoride etherate under Pictet-Spengler reaction conditions. The constitu

Full text of DOI:10.1007/s00706-007-0763-6

Monatshefte fu¨r Chemie 139, 147–151 (2008)
DOI 10.1007/s00706-007-0763-6
Printed in The Netherlands
Pictet-Spengler Synthesis of Some Thiophene[c]-Fused b-Carbolines
Kayed A. Abu Safieh1, Basem A. Moosa2, Mustafa M. El-Abadelah2,
Salim S. Sabri3, and Wolfgang Voelter4;ꢀ
1
Chemistry Department, Faculty of Science, Hashemite University, Zarqa, Jordan
2
Chemistry Department, Faculty of Science, The University of Jordan, Amman, Jordan
3
University of Sharjah, Sharjah, United Arab Emirates
4
¨ ¨
¨ ¨ ¨
Interfakultares Institut fur Biochemie, Universitat Tubingen, Tubingen, Germany
Received June 20, 2007; accepted July 5, 2007; published online November 16, 2007
# Springer-Verlag 2007
Summary. 5-(Substituted) thieno[20,30:5,6]pyrido[3,4-b]in-
We became interested in thiophene-fused carbo-
doles were synthesized via cyclocondensation of 3-(3-ami-
nothien-2-yl)indole with the appropriate aldehyde in the
presence of boron trifluoride etherate under Pictet-Spengler
reaction conditions. The constitution of the new compounds
is evidenced from analytical and spectral (NMR and MS) data.
lines for which limited data were cited in literature.
Reports on synthetic thienopyridoindoles are con-
fined to tetrahydropyrido[4,3-b]thieno[3,2-e]indoles
in which the thiophene ring is condensed with the
indole moiety. Such compounds showed antidepres-
sant activity (e.g., 3) [6] or constitute useful central
nervous system agents (e.g., 4) [7], while others are
topical compounds for cosmetic and medical treat-
ment of skin disorders such as psoriasis (e.g., 5,
Fig. 1) [8].
Keywords. 3-(3-Aminothien-2-yl)indole; Pictet-Spengler
reaction; Thieno[2,3-c]-ꢀ-carbolines.
Introduction
The ꢀ-carboline ring system (e.g., in the Harmala
alkaloids: harman (1) and norharman (2), Fig. 1)
is among the most commonly encountered alkaloid
frameworks in the terrestrial environment [1, 2].
Recently, there is a wealth of research work oriented
toward the synthesis and bioassay of variant deriva-
tized ꢀ-carbolines [3]. On the other hand, thieno-
pyridines have been evaluated as calcium regulators,
5-lipoxygenase inhibitors, and as carbonic anhydrase
inhibitors [4]. The pharmacological interest in thie-
nopyridine systems stemmed from their potential
bioisosterism with quinoline and isoquinoline enti-
ties. In this respect, notable replacement of benzene
nucleus by thiophene in chemical mimic was re-
viewed [5].
However, thienopyridoindoles in which the thio-
phene ring is condensed with the pyridine moiety
(e.g., 6, Fig. 2) are hitherto undescribed in literature.
The latter ring system 6 is isosteric with that of
synthetic ‘‘isoneocryptolepine’’ (7) which has quite
recently been described as an interesting lead com-
pound in the search for new antiplasmodial drugs
[9]. Noteworthy is that 7 is isomeric with the closely
related naturally occurring indoloquinoline alkaloids
(cryptolepines 8–10, Fig. 3) isolated from the roots of
the West African shrub Cryptolepis sanguiolenta [10]
and used in African folk medicine as antiviral, antitu-
mor, antibacterial, and antimalarial agents [11, 12].
Accordingly, the present study deals with the
synthesis and properties of model tetracyclics in
which thienopyridine is condensed with indole,
namely, thieno[20,30:5,6]pyrido[3,4-b]indoles (15a–
15c, Scheme 1).
ꢀ
tuebingen.de
Corresponding author. E-mail: wolfgang.voelter@uni-

148
K. A. Abu Safieh et al.
Fig. 1. Formulae of Harmala alkaloids and their derivatives
latter intermediates, enhanced by the Lewis acid cat-
alyst, provides the driving force for attack of the
indolic C2–C3 double bond and consequent cycliza-
tion. Aromatization of the resulting tetracyclic in-
termediates 14a–14c, via air-oxidation, yielded the
respective target molecules 15a–15c as the final prod-
ucts. This result is in accordance with the estab-
lished pathway for Pictet-Spengler type reactions
[13–15].
Fig. 2. Comparison of isosteric ring structures of thienopyr-
idoindole and indolo[2,3-c]quinoline
The MS and NMR spectral data are in conformity
with the assigned structures 15a–15c, and are given
in the Experimental section. Thus, their MS spectra
display the correct molecular ions for which the m=z
data are in agreement with the calculated values.
Assignments of the 1H NMR signals to the different
protons are straightforward, and 13C signal assign-
ments are based on DEPT and 2D (COSY, HMBC,
HMQC) experiments; these experiments showed dif-
ferent correlations that helped in the full assignments
of the different hydrogens and carbons. It is worth
noting that the doublet, belonging to H-2 of the in-
Results and Discussion
The synthesis of 5-(substituted) thieno[20,30:5,6]py-
rido[3,4-b]indoles (15a–15c) was achieved through
cyclocondensation of freshly prepared 3-(3-amino-
thien-2-yl)indole (11) with the appropriate aldehyde
(Ar-CHO) in the presence of boron trifluoride ether-
ate under Pictet-Spengler reaction conditions as
depicted in Scheme 1. In this reaction, the main iso-
lable products were identified as the respective thie-
no[20,30:5,6]pyrido[3,4-b]indoles (15a–15c) on the
basis of their analytical and spectral data (vide in-
fra). The formation of 15a–15c implies the interme-
diacy of the corresponding imino derivatives 12B;
the electrophilic nature of the imino carbon in the
1
dole ring, is absent in the H NMR spectra of the
cyclized products. Furthermore, a long-range corre-
lation between C-5 of the ꢀ-carboline nucleus and
H-20=H-60 is observed in the HMBC spectrum of
15a. Collectively, these data indicate that ring clo-
sure has taken place at C-2 of the indole nucleus.
Fig. 3. Structures of naturally occurring indoloquinoline alkaloids

Pictet-Spengler Synthesis
149
Scheme 1
Laboratory-Inorganic Chemistry Department, Tu¨bingen Uni-
versity, Germany, and the results were found to be in good
agreement (ꢂ0.4%) with the calculated values.
It is worth noting that 3-(3-carboxamidothien-
2-yl)indoles, under Bischler-Napieralski reaction
conditions, underwent regioselective intramolecular
cyclization at the benzenoid C-4 of the indole nucle-
us (rather than the pyrrolic C-2) to deliver the cor-
responding thieno[20,30:5,6]azepino[5,4,3-cd]indoles
[16]. Under similar cyclization conditions, this mode
of site-selectivity reversal (occurring at the C-4
locus) has also been reported for the related 3-(4-
carboxamidopyrazol-5-yl)indoles [17].
3-(3-Aminothien-2-yl)indole (11)
This compound is prepared according to a reported procedure
[13] that involves reduction of the corresponding 3-(3-
nitrothien-2-yl)indole which, in turn, is accessible via coupling
of indolylzinc chloride with 2-chloro-3-nitrothiophene [13].
Due to the instability of 11, in the form of free amino group,
it was freshly prepared and immediately used in the next
condensation step.
5-(4-Chlorophenyl)-6H-thieno[20,30:5,6]pyrido[3,4-b]-
indole (15a, C19H11ClN2S)
Experimental
2-Chloro-3-nitrothiophene was purchased from Apollo Scien-
tific Ltd (UK) and aryl aldehydes were purchased from Acros.
Melting points were determined on an SMP2 Stuart Melting
point apparatus. 1H and 13C NMR spectra were measured on a
Bruker DPX-300 instrument with TMS as internal reference.
Electron-impact mass spectra were obtained using a Finnigan
MAT TSQ-70 spectrometer at 70 eVand at ion source temper-
ature of 200ꢁC. IR spectra were recorded as KBr discs on a
Nicolet Impact-400 FT-IR spectrophotometer. Elemental anal-
yses (C, H, N, and S) were preformed at the Microanalytical
A solution of 0.5g 11 (2.2mmol) and 0.17g p-chlorobenzal-
dehyde (2.2mmol) in 30 cm3 dry benzene was stirred at 60ꢁC
for 2 h. Thereafter, 2.0 cm3 borontrifluoride etherate were
added, whereby the solution acquired an immediate orange
color that changed to deep red. The resulting mixture were
refluxed for 3 h, and then benzene was removed in vacuo.
The solid residue was soaked with aqueous sodium hydroxide
(5%) and water (2ꢃ20cm3), collected, dried, and recrystal-
lized from methanol=diethyl ether. Yield of pure product:
0.34g (55%), mp>270ꢁC (dec); MS-EI: m=z (% rel int)¼

150
K. A. Abu Safieh et al.
334 (Mþ, 100), 298 (30), 167 (8), 149 (75), 127 (8), 99 (5);
1H NMR (300 MHz, DMSO-d6): ꢁ ¼ 7.37 (dd, 1H, J ¼ 7.3,
7.7 Hz, H-9), 7.60 (dd, 1H, J ¼ 7.3, 8.2 Hz, H-8), 7.68 (d,
2H, J ¼ 8.4 Hz, H-30=H-50), 7.72 (d, 1H, J ¼ 8.2 Hz, H-7),
7.75 (d, 1H, J ¼ 5.3 Hz, H-3), 7.95 (d, 1H, J ¼ 5.3 Hz, H-2),
8.08 (d, 2H, J ¼ 8.4Hz, H-20=H-60), 8.18 (d, 1H, J ¼ 7.7 Hz,
H-10), 11.8 (s, 1H, N(6)-H) ppm; 13C NMR (75 MHz, DMSO-
d6): ꢁ ¼ 113.3 (C-7), 120.1 (C-10a), 120.8 (C-9), 122.1 (C-10),
123.1 (C-10b), 124.8 (C-3a), 125.6 (C-3), 127.1 (C-2), 128.5
(C-8), 129.3 (C-30=C-50), 130.3 (C-5), 131.0 (C-20=C60),
134.0 (C-40), 137.5 (C-10), 141.1 (C-6a), 141.2 (C-5a), 148.8
(C-10c) ppm.
1H, J ¼ 8.1 Hz, H-7), 7.95 (d, 1H, J ¼ 5.4 Hz, H-2), 8.15 (d,
1H, J ¼ 7.8 Hz, H-10), 11.8 (s, 1H, N(6)-H) ppm; 13C NMR
(75 MHz, DMSO-d6): ꢁ ¼ 56.0, 56.2 (30OCH3=40–OCH3),
112.4 (C-20), 112.6 (C-50), 113.4 (C-7), 120.2 (C-10a),
120.6 (C-9), 121.7 (C-60), 122.0 (C-10), 122.7 (C-10b),
124.0 (C-3a), 125.6 (C-3), 126.6 (C-2), 128.2 (C-8), 130.3
(C-5), 131.2 (C-10), 141.0 (C-6a), 142.6 (C-5a), 148.6 (C-
10c), 149.4, 150.0 (C-30=C-40) ppm.
Acknowledgements
We thank the Internationales Bu¨ro of BMBF, Forschungs-
zentrum Ju¨lich (Bonn, Germany) and the Deanships of Scien-
tific Research at the University of Jordan (Amman) and
Hashemite University (Zarqa-Jordan) for financial support.
5-(4-Fluorophenyl)-6H-thieno[20,30:5,6]pyrido[3,4-b]indole
(15b, C19H11FN2S)
A solution of 0.5 g 11 (2.2 mmol) and 0.31 g p-fluorobenz-
aldehyde (2.2 mmol) in 30 cm3 dry benzene was stirred at
60ꢁC for 2 h. Thereafter, 2.0 cm3 borontrifluoride etherate
were added, whereby the solution acquired an immediate
orange color that changed to deep red. The resulting mix-
ture was refluxed for 3 h, and benzene was removed
in vacuo. The solid residue was soaked with aqueous sodi-
um hydroxide (5%) and 20 cm3 water, collected, dried, and
recrystallized from methanol=diethyl ether. Yield of pure
product: 0.34 g (45%), mp 268–270ꢁC; MS-EI: m=z (%
rel int) ¼ 318 (Mþ, 100), 281 (20), 159 (23), 149 (35),
137 (19); 1H NMR (300 MHz, DMSO-d6): ꢁ ¼ 7.45 (dd,
1H, J ¼ 6.9, 7.5 Hz, H-9), 7.60 (dd, 2H, J ¼ 6.2, 8.1 Hz,
H-20=H-60), 7.75 (dd, 2H, J ¼ 8.1, 8.2 Hz, H-30=H-50), 7.85
(d, 1H, J ¼ 5.5 Hz, H-3), 8.05 (d, 1H, J ¼ 8.4 Hz, H-7), 8.05
(dd, 1H, J ¼ 6.9, 8.4 Hz, H-8), 8.20 (d, 2H, J ¼ 7.5 Hz, H-
10), 8.34 (d, 1H, J ¼ 5.5 Hz, H-2), 12.5 (s, 1H, N(6)-H)
ppm; 13C NMR (75 MHz, DMSO-d6): ꢁ ¼ 113.8 (C-7),
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