Diastereoselective synthesis of tetrasubstituted-octahydro-3,6- diazacarbazoles and tetrasubstituted-3,6-diazacarbazoles via double Pictet-Spengler reaction

Article abstract of DOI:10.1016/j.tetlet.2011.03.060

Pictet-Spengler condensation of 2,5-bis(2-phenyl-1-aminoethyl)pyrrole using glacial acetic acid afforded only one diastereomer of unreported tetrasubstituted-octahydro-3,6-diazacarbazoles. These were readily dehydrogenated to tetrasubstituted-3,6-diazacar

Full text of DOI:10.1016/j.tetlet.2011.03.060

Tetrahedron Letters 52 (2011) 2661–2663
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Tetrahedron Letters
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Diastereoselective synthesis of tetrasubstituted-octahydro-3,
6-diazacarbazoles and tetrasubstituted-3,6-diazacarbazoles via
double Pictet–Spengler reaction
Abdullah M. A. Shumaila a, Vedavati G. Puranik b, Radhika S. Kusurkar a,
⇑
a Department of Chemistry, University of Pune, Pune 411007, Maharashtra, India
b Center for Materials Characterization, National Chemical Laboratory, Pune 411008, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Pictet–Spengler condensation of 2,5-bis(2-phenyl-1-aminoethyl)pyrrole using glacial acetic acid afforded
only one diastereomer of unreported tetrasubstituted-octahydro-3,6-diazacarbazoles. These were readily
dehydrogenated to tetrasubstituted-3,6-diazacarbazoles. The stereoselectivity in the Pictet–Spengler
reaction has been demonstrated using single crystal X-ray analysis.
Received 20 January 2011
Revised 10 March 2011
Accepted 14 March 2011
Available online 21 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Tetrasubstituted-octahydro-3,6-
diazacarbazoles
Diasteroselective Pictet–Spengler reaction
2,5-Bis(2-phenyl-1-aminoethyl)pyrrole
Tetrasubstituted-3,6-diazacarbazoles
Glacial acetic acid
Diazacarbazole is a ring system obtained by substituting two
carbons of carbazole skeleton by two nitrogen atoms. They are
frequently exploited as carbazole bioisosteres in the design of
biologically interesting molecules.1 Many of these compounds
show diverse biological activities, such as Sarcoma 180 inhibitor,2,3
potential antineoplastic4 and cytotoxic activities towards L1210
leukaemia cells.5
In the earlier work, silica gel has been used as a solid catalyst for
Michael addition reactions where monoalkylated pyrroles were
obtained selectively along with little amount of dialkylated pyr-
roles in some cases.14 To achieve the exclusive formation of dialky-
lated pyrroles, the above reactions were carried out at 150 °C using
excess amounts of nitro-olefins.
Thus, pyrrole 1 and nitro-olefin 2a (in 1:3 ratio) were loaded on
silica gel and heated at 150 °C for 15 min. This reaction furnished
exclusively the expected dialkylated pyrrole 3a in 91% yield as
shown in Scheme 1. Subsequently, the same reaction was carried
out using other nitro-olefins 2b–e resulting in dialkylated products
3b–e (Scheme 1, Table 1). All dialkylated pyrroles were character-
ised by comparing the spectral data with the reported values.14,15
Thus a new method for an exclusive formation of dialkylated pyr-
roles was developed by using excess of nitro-olefins and heating at
150 °C. These products could serve as important intermediates for
the synthesis of biologically active compounds.
After generalizing the conjugate addition of pyrrole, the nitro
compound 3a was reduced using freshly prepared Raney Nickel
in methanol to obtain a new amino compound 4 as a diastereo-
meric mixture in the ratio of 1:1 (Scheme 2).
Further, treatment of amine 4 with benzaldehyde in the pres-
ence of glacial acetic acid in dichloromethane furnished tetra-
phenyl-octahydro-3,6-diazacarbazole 5a melting at 229–231 °C
in 43% yield as shown in Scheme 2. The product 5a was a single
diastereomer which was revealed from 1H and 13C NMR.16 In
The Pictet–Spengler reaction6 has been shown to be useful and
important for the synthesis of tetrahydro-isoquinoline, tetrahydro-
b-carboline and tetrahydro-azaindole ring systems, which are
present in numerous natural and synthetic organic compounds
possessing various biological activities.7–9 There are a few re-
ports3,5,10–12 available in the literature for the synthesis of substi-
tuted 3,6-diazacarbazoles and only one report for the synthesis
of disubstituted-octahydro-3,6-diazacarbazoles using Pictet–
Spengler condensation in HCl.13 Considering the biological
importance there is a need of good synthetic routes towards these
compounds. In continuation with our earlier7d,8b work in diaste-
reoselective Pictet–Spengler reactions using glacial acetic acid,
we herein describe these reactions for the synthesis of new tetra-
substituted-octahydro-3,6-diazacarbazoles and their further dehy-
drogenation to 3,6-diazacarbazoles.
⇑
Corresponding author. Tel.: +91 20 25601400; fax: +91 20 25691728.
E-mail address: rsk@chem.unipune.ac.in (R.S. Kusurkar).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.060

2662
A. M. A. Shumaila et al. / Tetrahedron Letters 52 (2011) 2661–2663
NO2
Ar
NO2
Ar
silica gel
150 oC
NO2
+
Ar
N
H
N
H
1
2a-2e
3a-3e
2a, 3a. Ar = Phenyl; 2b, 3b. Ar = 4-Methoxyphenyl; 2c, 3c. Ar = 3,4-
Dimethoxyphenyl; 2d, 3d. Ar = 2-Furyl; 2e, 3e. Ar = 2-Thienyl.
HN
NH
N
H
Scheme 1. Reaction of pyrrole with nitro-olefin.
5a
Table 1
Time and yield for Michael adducts 3a–e
Compd no.
Ar
Time (min)
Yielda (%)
3a
3b
3c
3d
3e
Phenyl
15
20
20
15
15
91
89
88
90
91
4-Methoxyphenyl
3,4-Dimethoxyphenyl
2-Furyl
Figure 1. ORTEP diagram of compound 5a ellipsoids is drawn at 50% probability.
2-Thienyl
a
Products 3a–e are mixture of diastereomers.
diazacarbazole 6a. The structure was confirmed using analytical
and spectral data.19
After getting a successful diastereoselective reaction using ace-
tic acid as a catalyst, it was decided to generalize the stereoselec-
tivity in these reactions. Thus, condensation of the amine 4 with
benzaldehydes having electron donating (4-methoxybenzalde-
hyde) and electron withdrawing (4-nitrobenzaldehyde) substitu-
NO2
Ph
NO2
Ph
NH2
N
NH2
Ph
Raney Nickel
H2, MeOH
N
H
H
Ph
4
3a
ents afforded new compounds 5b and c, respectively, in
a
ArCHO, DCM
diastereoselective manner (Scheme 2). Since the X-ray revealed
the geometry of compound 5a to be as shown in Figure 1, it was
presumed that the compounds 5b and c should have the similar
geometry.
AcOH, rt
2-4 d
Ar
Ar
NH
Ar
Ar
In the last step, dehydrogenation of tetrasubstituted-octahydro-
3,6-diazacarbazoles 5b and c furnished tetrasubstituted-3,6-dia-
zacarbazole 6b and c, respectively. During the Pictet–Spengler
condensation step compounds 6a and b were also obtained in very
minor amounts. The presence of them was confirmed by TLC.
A diastereoselective method was established for the synthesis
of octahydro-3,6-diazacarbazoles using Pictet–Spengler condensa-
tion in glacial acetic acid. This method was used for synthesizing
three new tetrasubstituted-octahydro-3,6-diazacarbazoles 5a, b
and c which were dehydrogenated to tetrasubstituted-3,6-diazac-
arbazoles 6a, b and c. The structure and stereochemistry of com-
pound 5a were unambiguously established as S, R, S and R at C1,
C4, C5 and C8, respectively, using single crystal X-ray analysis.
The importance of new tetrasubstituted-3,6-diazacarbazoles lies
in their structural similarity with biphenyls and thus may exhibit
atropisomerism.
Pd/C (5%), xylene
HN
N
N
N
N
seal tube
H
H
Ph
Ph
Ph
Ph
6a-6c
5a-5c
5a, 6a. Ar = Phenyl; 5b, 6b. Ar = 4-Methoxyphenyl; 5c, 6c. Ar = 4-
Nitrophenyl.
Scheme 2.
addition to this product, one diastereomer of starting amino com-
pounds was recovered from the original reaction mixture in 33%
yield which was confirmed by 1H NMR. In the starting amino com-
pound 4 (diastereomeric mixture), there were two singlets at 5.84
and 5.87 ppm with equal intensity where as in the recovered
product only one singlet was observed at 5.83 ppm. The other re-
gions in the 1H NMR spectrum also indicated simplification of
the signals consistent with the recovered product being a single
diastereomer.17
To investigate the stereochemistry of the diastereomer 5a, a
single crystal was prepared and X-ray analysis was carried out
which unambiguously showed that the diastereomer of 5a has S,
R, S and R relative configurations at C1, C4, C5 and C8, respectively,
as shown in Figure 1.18
Acknowledgements
We are grateful to Professor M.S. Wadia for helpful discussion,
B.S. Kalshetti for IR spectra, J.P. Choudhary for NMR spectra and
D.S. Shishupal for GCMS. A.M.A.S. is thankful to MOHE in Yemen
for the award of a fellowship.
Supplementary data
This indicated trans geometry at C1 and C4 and at C5 and C8 and
cis geometry at C1 and C8 and at C4 and C5. From this observation it
is revealed that amongst the mixture of two diastereomers of the
starting amino compound, only one isomer reacted and other
was recovered from the Pictet–Spengler condensation. The diaste-
reoselectivity obtained in the above mentioned reaction can be
attributed to slow and selective reaction in the presence of glacial
acetic acid.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.03.060.
References and notes
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(2 ꢁ carbons), 47.9 (2 ꢁ carbons), 40.3 (2 ꢁ carbons); m/z 481 [M+], 452
(100%), 423, 404, 91, 77; Anal. Calcd for C34H31N3 requires: C, 84.79; H, 6.49;
N, 8.72. Found: C, 84.98; H, 6.74; N, 8.48.
17. 2,5-Bis(2-phenyl-1-aminoethyl)pyrrol 4 (diastereomeric mixture): 92%, brown
solid, mp 77–79 °C; vmax (KBr) 3319 (br), 3286 (br) cmꢀ1; dH (300 MHz, CDCl3)
9.39 (1H, br s, NH exchangeable with D2O), 9.29 (1H, br s, NH exchangeable with
D2O), 7.31–7.11 (20H, m, ArH), 5.87 (2H, s, ArH), 5.84 (2H, s, ArH), 3.87 (4H, dd, J
6.6, 12.6 Hz, C2H), 3.17 (4H, dd, J 7.1, 12.4 Hz, C1H), 3.07 (4H, dd, J 6.6, 12.4 Hz,
C1H), 1.64 (8H, br s, NH2 exchangeable with D2O); dC (75 MHz, CDCl3) 142.0
(2 ꢁ carbons), 141.9 (2 ꢁ carbons), 132.4 (2 ꢁ carbons), 132.3 (2 ꢁ carbons),
128.49 (4 ꢁ carbons), 128.47 (4 ꢁ carbons), 128.1 (8 ꢁ carbons), 126.7
(4 ꢁ carbons), 105.0 (2 ꢁ carbons), 104.9 (2 ꢁ carbons), 47.7 (2 ꢁ carbons),
47.6 (2 ꢁ carbons), 47.2 (2 ꢁ carbons), 47.1 (2 ꢁ carbons); m/z 305 [M+], 275,
259, 246 (100%), 156, 141, 91, 77. The 1H NMR spectrum of recovered amino
product: dH (300 MHz, CDCl3) 10.48 (1H, br s, NH exchangeable with D2O),
7.29–7.06 (10H, m, ArH), 5.83 (2H, s, ArH), 4.09 (2H, t, J 5.1 Hz, C2H), 3.93 (4H, br
s, 2 ꢁ NH2 exchangeable with D2O), 3.27 (2H, dd, J 5.1, 12.2 Hz, C1H), 3.08 (2H,
dd, J 6.6, 12.2 Hz, C1H).
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18. Crystallographic data in this paper have been deposited with the Cambridge
Crystallographic Data Centre. Deposition number is CCDC 808489 for 5a. Copy
of the data can be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK (fax: +44 1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk).
16. 1,4,5,8-Tetraphenyl-1,2,3,4,5,6,7,8-octahydro-9H-dipyrido-[4,3-b;30,40-d]pyrrole
5a: 43%, colourless crystals; mp 229–231 °C; Rf 0.41 (50% EtOAc/hexane); vmax
19. 1,4,5,8-Tetraphenyl-9H-dipyrido-[4,3-b;30,40-d]pyrrole 6a: 35%, white solid; mp
197–199 °C; Rf 0.29 (30% EtOAc/hexane); vmax (KBr) 3421 cmꢀ1; dH (300 MHz,
DMSO-d6) 11.73 (1H, br s, NH exchangeable with D2O), 8.57 (2H, s, C2H,C7H),
7.76 (4H, d, J 7.0 Hz, ArH), 7.65–7.21 (10H, m, ArH), 7.06–6.91 (6H, m, ArH); dC
(75 MHz, DMSO-d6) 148.5 (2 ꢁ carbons), 141.5 (2 ꢁ carbons), 137.4
(2 ꢁ carbons), 135.9 (2 ꢁ carbons), 135.5 (2 ꢁ carbons), 132.7 (2 ꢁ carbons),
129.2 (8 ꢁ carbons), 127.7 (4 ꢁ carbons), 127.6 (4 ꢁ carbons), 126.1
(2 ꢁ carbons), 125.9 (2 ꢁ carbons), 121.0 (2 ꢁ carbons); m/z 473 [M+], 446,
396, 91 (100%), 77; Anal. Calcd for C34H23N3 requires: C, 86.23; H, 4.90; N, 8.87.
Found: C, 86.51; H, 4.63; N, 8.59.
(KBr) 3308, 3217, 3140 cmꢀ1
; dH (300 MHz, CDCl3) 7.41 (1H, br s, NH
exchangeable with D2O), 7.29–7.2 (4H, m, ArH), 7.17 (2H, t, J 7.4 Hz, ArH),
7.07 (4H, d, J 7.3 Hz, ArH), 6.86 (10H, strong br s, ArH), 4.89 (2H, s, C4H,C5H), 4.0
(2H, t, J 5.0 Hz, C1H,C8H), 3.36 (2H, dd, J 5.5, 12.7 Hz, C2H,C7H), 2.75 (2H, dd, J
5.0, 12.7 Hz, C2H,C7H), 1.72 (2H, br s, 2>NH exchangeable with D2O); dC
(75 MHz, DMSO-d6) 145.6 (2 ꢁ carbons), 143.2 (2 ꢁ carbons), 128.1
(8 ꢁ carbons), 127.8 (4 ꢁ carbons), 126.7 (4 ꢁ carbons), 126.5 (2 ꢁ carbons),
125.8 (2 ꢁ carbons), 125.6 (2 ꢁ carbons), 115.2 (2 ꢁ carbons), 55.7