Synthesis of some new optically active octahydro-6 H -pyrido[4,3- b ]-carbazole derivatives

Article abstract of DOI:10.1055/s-0029-1218007

An optically active octahydro-6H-pyrido[4.3-b]carbazole derivative was obtained by Fischer indolization of a decahydroisoquinolone with phenylhydrazine. The reaction proceeded with quantitative regioselectivity; no angular annulation products could be obs

Full text of DOI:10.1055/s-0029-1218007

3016
LETTER
Synthesis of Some New Optically Active Octahydro-6H-pyrido[4,3-b]-
carbazole Derivatives
Optically Active
O
i
ctahyd
n
ro-6
H
-pyrido
a
[4,3-b]carbazole
W
D
erivatives ache, Jens Christoffers*
Institut für Reine und Angewandte Chemie, Carl von Ossietzky-Universität Oldenburg, 26111 Oldenburg, Germany
Fax +49(441)7983873; E-mail: jens.christoffers@uni-oldenburg.de
Received 25 August 2009
purity (>98% ee and de) was confirmed by GLC on a
chiral phase, after conditions for appropriate baseline res-
olution was developed with the racemic material
(Scheme 2).
Abstract: An optically active octahydro-6H-pyrido[4.3-b]carba-
zole derivative was obtained by Fischer indolization of a decahy-
droisoquinolone with phenylhydrazine. The reaction proceeded
with quantitative regioselectivity; no angular annulation products
could be observed. The tetracyclic product was derivatized by sul-
fonamide, urea or carboxamide formation. Its linear constitution as
well as relative and absolute configuration were established by sin-
gle crystal X-ray crystallography of a derivative.
In initial attempts at Fischer indolization, we decided to
heat compound 1 in TFA–AcOH together with phenylhy-
drazine, in order to cleave the carbamate protective group
in situ. However, we obtained a mixture of materials,
which could be clearly identified as indoles by 1H NMR
of the crude reaction mixture, but showed molecular
masses of m/z = 284 (compound 2), m/z = 340 (three com-
pounds) and m/z = 396 (one compound) upon GC-MS
analysis. Obviously, isobutene generated by Boc-cleav-
age reacted with the indole moiety to generate several un-
specifically tert-butylated compounds (Dm/z = 56). For
this reason, we performed the conversion stepwise as in-
dicated in Scheme 2: The Boc-group was first cleaved
with TFA at elevated temperature, then AcOH and phe-
nylhydrazine were added to the reaction mixture. After
some optimization of reaction times and temperatures, py-
ridocarbazole 2 was isolated in 54% yield.8 By applying
H,H-COSY, HMBC and HMQC experiments, we were
able to assign almost all 1H and 13C resonances. The prod-
uct constitution is therefore in accordance with structural
formula 2. We were not able to detect any product with
angular constitution 3.
Key words: indoles, carbazoles, heterocycles, piperidines, amides
The indole ring system is a leading structural motif in drug
discovery.1 In most cases it appears annulated with other
heterocyclic rings. For example, the 6H-pyrido[4,3-b]car-
bazole skeleton is the structural motif of ellipticine2 and
related indole alkaloids.3 Octahydro-congeners like com-
pound 2 have been reported to be potent pharmaceuticals,
such as opioid receptor ligands4 and melanin-concentrat-
ing hormone antagonists.1a We have previously reported
on the preparation of building block 1 in optically active
form on a large scale by copper-catalyzed asymmetric
Michael reaction5 and it has since been used as a starting
material in medicinal chemistry.6 In this work, we have
used compound 1 as a starting material in Fischer indole
synthesis.7 We were expecting either linear octahydro-
6H-pyrido[4,3-b]carbazole derivative 2 or angular annu-
lation product 3 (Scheme 1).
Since we were planning to utilize the N-2 function for fur-
ther derivatization (sulfonamide, urea and carboxyamide
formation), we have prepared para-bromobenzene sul-
fonamide 5 (Scheme 3), which proceeded smoothly at
23 °C within two hours with triethylamine as an addition-
al base.9 As expected, we obtained compound 5 as a high-
ly crystalline material and were able to grow single
crystals that were suitable for a X-ray diffraction analysis.
In the Supporting Information the molecular structure is
shown, which confirms the linear annulation as already
indicated by the 2D-NMR experiments. trans-Annulation
of the two saturated six-membered rings is clearly visible.
Furthermore, the bromine and sulfur atom in this com-
pound allowed for anomalous dispersion giving the
(4aS,11aR)-configuration as shown in the Supporting
Information with an absolute structure parameter10 of
–0.0086(68).11
O
NH
HN
H
H
H
or
CO2Me
CO2Me
CO2Me
N
N
H
N
H
Boc
1
2 (linear)
3 (angular)
Scheme 1 Synthetic plan for an octahydro-6H-pyrido[4,3-b]carba-
zole derivative 2 from optically active building block 1
trans-Decahydroisoquinolone 1 was prepared in three
steps (copper-catalyzed Michael-reaction, aldol-cycliza-
tion and catalytic hydrogenation) from L-valine-derived
enaminoester 4 as reported before.5 The stereochemical
As mentioned, we were planning to prepare the urea and
carboxamide derivatives at N-2. Conversion of carbazole
derivative 2 with phenyl isocyanate proceeded slowly, but
smoothly at ambient temperature to give the correspond-
SYNLETT 2009, No. 18, pp 3016–3018
Advanced online publication: 02.10.2009
DOI: 10.1055/s-0029-1218007; Art ID: G27509ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
9

LETTER
Optically Active Octahydro-6H-pyrido[4,3-b]carbazole Derivatives
3017
H
O
N
CONEt2
NH
1. + TFA, 50 °C, 15 h
2. 100 °C, 6.5 h
i-Pr
H
H
3 steps
CO2Me
3. + AcOH, PhNHNH2
100 °C, 1 d
CO2Me
CO2Me
N
N
H
54%
N
Boc
Boc
(S)-4
(4aS,8aR)-1
(4aS,11aR)-2
Scheme 2 Regioselective Fischer-indolization of decahydroisoquinolone 1
H
N
H
H
H
N
N
N
PhNCO
BrC6H4SO2Cl
H
H
O
H
H
O
toluene
23 °C, 2.5 d
Et3N, CH2Cl2
23 °C, 2 h
CO2Me
CO2Me
CO2Me
CO2Me
75%
N
N
N
N
71%
H
H
S
NHPh
O
2
2
6
Br
5
H
H
N
N
Scheme 3 Preparation of sulfonamide 5 for the determination of
constitution as well as relative and absolute configuration
N-Boc-Npg-OH
H
H
O
DCC, HOBt
CH2Cl2, 80 °C, 1.5 d
ing urea derivative 6 (for experimental details see Sup-
porting Information) in good yield (Scheme 4).
Amidation at N-2 with N-Boc-protected neopentyl gly-
cine (Npg)12 was performed with DCC–HOBt. However,
high reaction temperature was required in order to achieve
full conversion of starting material 2; compound 7 was
obtained in satisfying yield (for experimental details see
Supporting Information). Its NMR spectra showed dou-
bled signal sets, presumably due to rotamers along the
amide C–N bond (ratio 2:1). Conversion of the a-quater-
nary N-Boc aminoisobutyric acid (Aib)13 under the same
conditions required longer reaction times. Furthermore,
the yield was low, because separation of product 8 from
dicyclohexyl urea required two-fold chromatography (for
experimental details see Supporting Information). At am-
bient temperature, the 1H and 13C NMR spectra show very
broad signals. Two partly doubled, though still broad, sig-
nal sets appear when the spectra are recorded at 60 °C.
CO2Me
CO2Me
N
H
N
63%
2
BocHN
7
H
H
N
N
N-Boc-Aib-OH
H
H
DCC, HOBt
CH2Cl2, 80 °C, 3 d
CO2Me
CO2Me
N
H
45%
N
O
2
NHBoc
8
Scheme 4 Synthesis of urea 6 and two carboxyamides 7 and 8 star-
ting from carbazole derivative 2
In summary, we conclude that Fischer indolization of iso-
quinolone derivative 1 proceeded with high regioselectiv-
ity to yield pyrido[4,3-b]carbazole derivative 2. Further
functionalization at N-2 by sulfonamide, urea, or carbox-
amide formation went smoothly.
References and Notes
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Wang, X.; Li, L.; Fan, P.; Chen, X.; Allgeier, A.; Burgos, A.;
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C.; Chakravorty, S.; Shyam, P. K.; Taher, A. Synthesis 2009,
403.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We are grateful to Wolfgang Saak and Detlev Haase for X-ray sin-
gle crystal structure analysis and to Dr. Herbert Frey for helping us
with the preparation of this manuscript.
Synlett 2009, No. 18, 3016–3018 © Thieme Stuttgart · New York

3018
N. Wache, J. Christoffers
LETTER
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Lockey, P.; Devos, R.; Wong, M.; Porres, S. S.; Bright,
C. P.; Jenkins, R. E.; Belanoff, J. Bioorg. Med. Chem. Lett.
2008, 18, 1312.
J = 15.7 Hz, 2 H, 3-H and 11-H), 3.56 (s, 3 H, OCH3), 3.60
(d, J = 12.4 Hz, 1 H, 1-H), 7.05–7.12 (m, 2 H, 8-H and 9-H),
7.23–7.26 (m, 1 H, 7-H), 7.42 (d, J = 7.0 Hz, 1 H, 10-H),
8.05 (s, 1 H, 6-NH). 13C{1H} NMR (CDCl3, 126 MHz):
d = 27.90 (CH2, C-4), 29.73 (CH2, C-5 or C-11), 30.26 (CH2,
C-11 or C-5), 40.13 (CH, C-4a), 46.89 (CH2, C-3), 47.14 (C,
C-11a), 51.66 (CH3), 56.75 (CH2, C-1), 107.17 (C, C-10b),
110.44 (CH, C-7), 117.66 (CH, C-10), 119.14 (CH, C-9),
121.16 (CH, C-8), 127.39 (C, C-10a), 133.26 (C, C-5a),
135.89 (C, C-6a), 174.72 (CO). IR (ATR): 3345 (m), 3140
(w), 3049 (w), 2922 (s), 2852 (m), 1705 (s), 1589 (m), 1451
(s), 1324 (m), 1194 (s), 741 (vs) cm–1. MS (EI, 70 eV):
m/z (%) = 284 (100) [M+], 252 (40), 241 (12), 225 (50),
208 (70), 194 (60), 180 (54), 167 (56), 157 (20), 143 (52).
HRMS (EI, 70 eV): m/z [M+] calcd for C17H20N2O2:
284.1525; found: 284.1523. [a]D20 +81 (c 1.3, CHCl3).
(9) (4aS,11aR)-Methyl 2-(4-bromobenzenesulfonyl)-
1,2,3,4,4a,5,11,11a-octahydro-6H-pyrido[4.3-b]carbazole-
11a-carboxylate (5). Et3N (57 mg, 0.56 mmol) and 4-
BrC6H4SO2Cl (142 mg, 0.56 mmol) were subsequently
added to a cooled (ice-water bath) solution of the carbazole
2 (79 mg, 0.28 mmol) in CH2Cl2 (0.6 mL). The resulting
mixture was stirred for 2 h at 23 °C and then diluted with
water (2 mL) and the layers were separated. The aqueous
layer was extracted with CH2Cl2 (3 × 1 mL). The combined
organic layers were dried (MgSO4) and the solvent was
evaporated after filtration. Two-fold chromatography of the
residue (SiO2; hexane–MTBE, 1:2; Rf = 0.36; then hexane–
EtOAc, 1:2) gave the title compound 5 (100 mg, 0.200
mmol, 71%) as a brown solid; mp 165–175 °C (dec.). Single
crystals were obtained by slow evaporation of a solution in
CHCl3. 1H NMR (CDCl3, 500 MHz): d = 1.72–1.82 (m, 2
H), 2.23 (d, J = 11.5 Hz, 1 H), 2.30–2.48 (m, 3 H), 2.64–2.70
(dd, J = 5.4 Hz, J = 16.0 Hz, 1 H), 3.18–3.39 (m, 2 H), 3.58
(s, 3 H), 3.90–3.94 (m, 1 H), 4.35 (dd, J = 1.7 Hz, J = 11.5
Hz, 1 H), 7.04–7.08 (m, 1 H), 7.08–7.13 (m, 1 H), 7.23–7.27
(m, 1 H), 7.39 (d, J = 7.8 Hz, 1 H), 7.63–7.66 (m, 2 H), 7.70–
7.71 (m, 2 H), 7.74 (s, 1 H). 13C{1H} NMR (CDCl3, 126
MHz): d = 27.05 (CH2), 28.35 (CH2), 29.91 (CH2), 39.27
(CH), 46.63 (C), 47.05 (CH2), 51.93 (CH3), 55.76 (CH2),
106.00 (C), 110.54 (CH), 117.55 (CH), 119.26 (CH), 121.39
(CH), 127.03 (C), 127.90 (C), 129.11 (2 × CH), 132.42
(2 × CH), 132.96 (C), 135.56 (C), 135.89 (C), 172.61 (C). IR
(ATR): 3370 (s), 2953 (w), 2915 (m), 2853 (m), 1719 (s),
1575 (m), 1469 (m), 1454 (m), 1389 (m), 1339 (s), 1324
(m), 1234 (vs), 1159 (vs), 1090 (s), 1011 (m), 943 (m), 916
(vs), 747 (vs), 732 (vs) cm–1. MS (EI, 70 eV): m/z (%) = 502
(42) [M+], 283 (69), 251 (100), 223 (29), 194 (58), 143 (38),
97 (27). HRMS (EI, 70 eV): m/z [M+] calcd for
(7) For a review, see: Humphrey, G. R.; Kuethe, J. T. Chem.
Rev. 2006, 106, 2875.
(8) (4aS,11aR)-Methyl 1,2,3,4,4a,5,11,11a-octahydro-6H-
pyrido[4.3-b]carbazole-11a-carboxylate (2). TFA (1.0 mL,
1.5 g, 14 mmol) was added dropwise to the cooled (ice-water
bath) isoquinolone 1 (347 mg, 1.11 mmol). The resulting
solution was stirred for 15 h at 50 °C and then for 6.5 h at
100 °C. After cooling to ambient temperature, glacial AcOH
(3 mL) and phenylhydrazine (240 mg, 2.22 mmol) were
added. The mixture was again heated for 30 h at 100 °C and
then poured onto ice (ca. 45 g). Aqueous KOH (5 mL, 50%)
was added to the mixture until pH 14. Subsequently, CH2Cl2
(100 mL) was added and the layers were separated. The
aqueous layer was extracted with CH2Cl2 (2 × 100 mL). The
combined organic layers were washed with water (100 mL)
and dried (MgSO4). After filtration, the solvent was
evaporated and the residue was purified by chromatography
(SiO2; CH2Cl2–MeOH, 2:1; Rf = 0.23) to yield the title
compound 2 (170 mg, 0.60 mmol, 54%) as a yellow solid;
mp 170–180 °C (dec.). 1H NMR (CDCl3, 300 MHz):
d = 1.64 (d, J = 12.5 Hz, 1 H, 4-H), 1.93–2.21 (m, 1 H, 4a-
H), 2.12 (dq, J = 4.5 Hz, J = 15.6 Hz, 2 H, 4-H and 2-NH),
2.47 (d, J = 15.7 Hz, 1 H, 11-H), 2.65 (d, J = 12.7 Hz, 2 H,
1-H and 5-H), 2.76 (dt, J = 12.3 Hz, J = 3.0 Hz, 1 H, 3-H),
3.08 (dd, J = 11.6 Hz, J = 14.9 Hz, 1 H, 5-H), 3.21 (d,
C23H23BrN2O4S: 502.0562; found: 502.0566. [a]D20 –46 (c
0.9, CH2Cl2).
(10) Bernardinelli, G.; Flack, H. D. Acta Crystallogr., Sect. A
1985, 41, 500.
(11) CCDC 742770 (5) contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting
The Cambridge Crystallographic Data Centre, 12, Union
Road, Cambridge CB2 1EZ, UK; fax: +44 (1223)336033
(12) Christoffers, J.; Schuster, K. Chirality 2003, 15, 777.
(13) Kondo, M.; Kimura, M.; Sato, K.-i.; Horimoto, H. Bull.
Chem. Soc. Jpn. 1987, 60, 1391.
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