A short synthesis of the hexahydropyrido[4,3-b]carbazole core structure for the synthesis of aspidosperma alkaloids

Article abstract of DOI:10.1002/jhet.5570440306

(Chemical Equation Presented) A short synthesis of the hexahydropyrido[4,3- b]carbazole derivative 8 which is important for the preparation of aspidosperma alkaloids was described. Construction of the tetracyclic structure was achieved via a short synthetic route and some new carbazolone derivatives (4, 5, 6 and 7) were synthesized.

Full text of DOI:10.1002/jhet.5570440306

May-Jun 2007
539
A Short Synthesis of the Hexahydropyrido[4,3-b]carbazole Core
Structure For the Synthesis of Aspidosperma Alkaloids
Yavuz Ergun
Dokuz Eylul University, Faculty of Arts and Sciences, Department of Chemistry,
Kaynaklar Campus, 35160 Buca, Izmir-TURKEY
Received March 9, 2006
N
CO2C2H5
N
CH3
N
H
3
8
A short synthesis of the hexahydropyrido[4,3-b]carbazole derivative 8 which is important for the
preparation of aspidosperma alkaloids was described. Construction of the tetracyclic structure was
achieved via a short synthetic route and some new carbazolone derivatives (4, 5, 6 and 7) were
synthesized.
J. Heterocyclic Chem., 44, 539 (2007).
Herein, we have synthesized hexahydropyrido[4,3-b]-
carbazole core structure in five steps with 15 % overall
yield (Scheme 1). For this purpose we selected a tetra-
hydrocarbazole ester derivative 3 as the starting material,
which was synthesized from ethyl 4-oxocyclohexane-
carboxylate and phenylhydrazine in one step via the
Fischer-indol method previously described [15].
Compound 3 was selectively oxidized at position 4 with
2,3-dichloro-5,6-dicyano-p-benzoquinone in tetrahydro-
furan (90%) at -5 ºC to yield the carbazolone ester 4 [16].
Later we protected the indole nitrogen atom of 4 using
tetrabutylammonium hydrogen sulfate and methyl iodide
The Aspidosperma alkaloids constitute a large family of
natural products. Over the last three decades, aspidosperma
alkaloids have caught the attention of synthetic chemists
due to the unique structural features of many of their
members and because of their important biological
properties [1]. Aspidospermidine and deethylaspidosperm-
idine (1a, 1b), which are parent structures have been the
primary target molecules toward aspidosperma alkaloids
and many creative and useful synthetic strategies have been
developed [2-12]. Among these strategies, Stork’s Fischer
indol approach, Harley-Mason’s indoloquinolizidine
rearrangement approach, Overman’s aza-Cope
rearrangement, Buchi, Kuehne, Magnus and Wenkert’s
Diels-Alder approach and Urritia, d’Angelo and Gramain’s
carbazolone-cyclization approach have considerably
enriched the chemistry of aspidosperma alkaloids.
Scheme 1
O
CO2C2H5
CO2C2H5
i
ii
In the synthetic approaches, the [ABCD] type tetra-
cycles (2), so-called hexahydropyrido[4,3-b]carbazoles,
have been elaborated in the penultimate stage for the
synthesis of aspidosperma alkaloids. Especially in the
Urritia and d’Angelo’s studies, the [ABCD] type
tetracycles have been stereo selectively synthesized in
many steps and elaborated. These [ABCD] type tetra-
cycles are not only subunits of pentacyclic aspidosperma
alkaloids but also hexacyclic indole alkaloid kopsijasmine
and the heptacyclic indole alkaloid kopsine [13,14].
N
H
N
H
3
4
CN
O
O
CO2C2H5
iii
iv
CO2C2H5
N
N
CH3
CH3
5
6
2
1
N
O
3
N
N
H
CN
D
11
11c
v
4
11a 11b
10
9
4a
C
A
B
N
N
R
5
7N
7a
N
H
6a
6
8
CH3
CH3
H
8
H
7
1a R = C2H5
1b R = H
2
Reagents and conditions: i) DDQ, THF (90%), -5 ºC, 10 min., 33%; ii) TBAHS,
NaOH (50%), CH2Cl2, CH3I, 0 ºC, 1h, 91%; iii) Cs2CO3, tert-ButOH, acrylonitrile,
reflux, 5h, 94%; iv) KOH, H2O-(CH3)2CHOH, rt, 4h, 72%; v) NiCl2.6H2O,
NaBH4, NH2NH2.H2O, N2, stirred, 80 ºC, 5h, 76%.
Figure 1

540
Y. Ergun
Vol 44
and the mixture was stirred for 1 hour at 0 ºC, washed with 50
mL 10% hydrochloric acid, and the organic layer was dried with
anhydrous magnesium sulfate. The solvent was evaporated
under reduced pressure and the resulting residue was
chromatographed using silica gel and ethyl acetate-hexane (1:1).
The solvent was removed and then the product was
recrystallized from ether to afford 2.4 g (91%) of 5, mp 120-121
ºC; rf: 0.45 (ethyl acetate); ir (potassium bromide): ꢀ 2957 (CH),
1727 (C=O, ester), 1635 (C=O, ketone) cm-1; 1H nmr
(deuteriochloroform): ꢁ 1.23 (t, 3H, J= 7.16 Hz, CH2CH3), 2.32-
2.43 (m, 1H, CH), 2.56-2.62 (m, 1H, CH), 2.82-2.89 (m, 1H,
CH), 3.12 (dt, 1H, J= 17.53 and 5.52 Hz, C1H), 3.52 (dd, 1H, J=
8.90 and 4.6, C3H), 3.64 (s, 3H, N-CH3), 4.16 (q, 2H, J=7.13 Hz,
CH2CH3), 7.12-7.28 (m, 3H, aromatic protons), 8.16 (m,1H,
aromatic proton); 13C nmr (deuteriochloroform): ꢁ 14.62, 29.11,
30.25, 32.14, 60.41, 71.17, 109.12, 115.29, 120.86, 122.41,
124.70, 125.22, 137.43, 154.49, 170.41, 190.27; ms: m/z
272(2.3) [M+1]+, 270(12.3) [M-H]+, 255(6.2) [M-CH4]+,
228(3.3) [M-C3H7]+, 127(100) [M-C7H12O3]+. Anal. Calcd. for
C16H17NO3: C, 70.85; H, 6.27; N, 5.17. Found: C, 70.83; H,
6.25; N, 5.23.
which resulted in compound 5 [17]. Cyanoethylation of
compound 5 utilizing cesium carbonate in tert-butyl
alcohol gave the Michael adduct compound 6 [18].
Compound 7 was obtained by hydrolysis and following
decarboxylation of 6 with potassium hydroxide [19].
Finally, the reduction of the nitrile to amino group in
compound 7 was carried out with nickel boride as
catalyst, which was prepared in situ by reduction of
nickel(II) chloride hexahydrate with sodium borohydride
in ethanol, using hydrazine hydrate as the hydrogen
generator [20,21]. During the reduction of the nitrile
group, an intramolecular condensation occurred and gave
hexahydropyrido[4,3-b]carbazole 8. From 8, octahydro-
pyrido[3,2-c]carbazole and pentacyclic aspidosperma
alkaloids can be easily synthesized in a queue.
EXPERIMENTAL
All melting points were measured in sealed tubes using an
electro thermal digital melting point apparatus (Gallenkamp) and
uncorrected. Infrared spectra were recorded on a Hitachi 270-30
Ethyl-3-(cyanoethyl)-4-oxo-1,2,3,4-tetrahydro-9-methyl-
carbazole-3-carboxylate (6). A mixture of 2 g (7.4 mmoles) of
5, 2.5 g (7.7 mmoles) of cesium carbonate and 0.41 g (7.7
mmoles) of acrylonitrile in 50 ml of tert-butyl alcohol was
refluxed for 5 hours under a nitrogen atmosphere. The reaction
mixture was poured into 50 mL of 5% hydrochloric acid
solution and extracted with ethyl acetate. The solvent was
evaporated under reduced pressure and the resulting residue was
chromatographed using silica gel and ethyl acetate-hexane (1:1).
The solvent was removed and then the product was
recrystallized from methanol to afford 2.25 g (94%) of 6, mp
110-111 ºC; rf: 0.42 (ethyl acetate); ir (potassium bromide): ꢀ
2970 (CH), 2245 (CN), 1717 (C=O, ester), 1648 (C=O, ketone)
1
infrared spectrometer. H nmr and 13C nmr spectra were obtained
on a Bruker WH-400 NMR spectrometer with tetramethylsilane as
an internal standard. Mass spectra were determined with a
Micromass UK Platform II LC-MS spectrometer and a combined
5980 gas chromatography-HP 5971 mass system. Combustion
analysis of compounds was performed on a CHNS-932-LECO.
Analytical and preparative thin layer chromatographies were
carried out using silica gel 60 HF-254 (Merck). Column
chromatography was carried out by using 70-230 mesh silica gel
(0.063-0.2 mm, Merck) and neutral aluminum oxide (Merck).
Ethyl-4-oxo-1,2,3,4-tetrahydro-9H-carbazole-3-carbox-
ylate (4). To a solution of 5 g (20.60 mmoles) of 3 in 50 mL of
tetrahydrofuran (90%), a solution of 9.36 g (41.20 mmoles) of
2,3-dichloro-5,6-dicyano-p-benzoquinone in 20 mL of tetra-
hydrofuran was added dropwise at -5 ºC. The reaction mixture
was stirred for 10 minutes at -5 ºC then the solution was pored
into 500 mL of 10% sodium hydroxide and extracted with ethyl
acetate. The organic layer was dried with anhydrous magnesium
sulfate, and the solvent was removed. The residue was purified
by chromatography using silica gel and ethyl acetate. After the
solvent was evaporated, the product was recrystallized from
ether to afford 1.75 g (33%) of 4, mp 123-124 ºC; rf: 0.39 (ethyl
acetate); ir (potassium bromide): ꢀ 3284 (NH), 2980 (CH), 1703
(C=O, ester), 1633 (C=O, ketone) cm-1; 1H nmr (deuteriochloro-
form): ꢁ 1.27 (t, 3H, J= 7.14 Hz, CH2CH3), 2.37-2.49 (m, 1H,
CH), 2.55-2.66 (m, 1H, CH), 2.93-3.06 (m, 1H, CH), 3.20 (dt,
1H, J= 17.57 and 5.52 Hz, C1H), 3.63 (dd, 1H, J= 8.95 and 4.7,
C3H), 4.23 (q, 2H, J=7.12 Hz, CH2CH3), 7.19-7.33 (m, 2H,
aromatic protons), 7.40 (m, 1H, aromatic proton), 8.20 (m, 1H,
aromatic proton), 9.43 (s, 1H, NH); 13C nmr (deuteriochloro-
form): ꢁ 14.21, 30.14, 32.21, 62.15, 70.43, 110.04, 112.41,
120.36, 124.28, 124.82, 125.72, 144.36, 150.27, 172.63, 187.58;
ms: m/z 257(7.3) [M]+, 256(100) [M-H]+, 229(17.4) [M-C2H4]+,
210(4.3) [M-C2H7O]+. Anal. Calcd. for C15H15NO3: C, 70.03; H,
5.84; N, 5.45. Found: C, 69.95; H, 5.87; N, 5.48.
1
cm-1; H nmr (deuteriochloroform): ꢁ 1.26 (t, 3H, J= 7.13 Hz,
CH2CH3), 2.24-2.45 (m, 3H, CH and CH2), 2.56-2.72 (m, 2H,
CH2), 2.78-2.81 (m, 1H, CH), 3.02 (dt, 1H, J= 17.54 and 5.50
Hz, C1H), 3.14-3.22 (m, 1H, CH), 3.73 (s, 3H, CH3), 4.22 (q,
2H, J=7.14 Hz, CH2CH3), 7.29-7.37 (m, 3H, aromatic protons),
8.23 (m, 1H, aromatic proton); 13C nmr (deuteriochloroform): ꢁ
13.46, 14.08, 19.07, 29.91, 29.98, 31.27, 56.15, 61.77, 109.32,
111.55, 119.80, 121.82, 123.11, 123.62, 124.26, 140.17, 151.81,
171.25, 188.58; ms: m/z 323(27.4) [M-H]+, 309(14) [M-CH3]+,
249(46) [M-C3H7O2]+, 201(100) [M-C4H13NO3]+, 127(35.4) [M-
C10H15NO3]+. Anal. Calcd. for C19H20N2O3: C, 70.37; H, 6.17;
N, 8.64. Found: C, 70.48; H, 6.15; N, 8.58
3-(Cyanoethyl)-4-oxo-1,2,3,4-tetrahydro-9-methyl-carba-
zole (7). A 100 mL solution of 0.5 M potassium hydroxide in
water-isopropyl alcohol (1:5) was added to 2.5 g (7.7 mmoles)
of 6 and the reaction mixture was stirred for 4 hours. Then the
mixture was poured into 100 mL of cold water and extracted
with ether. The organic layer was dried with anhydrous
magnesium sulfate, and the solvent was evaporated under
reduced pressure. The residue was chromatographed on silica
gel using ethyl acetate-hexane. After the solvent was evaporated,
a yield of 1.40 g (72%) of 7, mp 164-165 ºC, rf: 0.36 (ethyl
acetate) was obtained; ir (potassium bromide): ꢀ 2940 (CH),
1
2245 (CN), 1645 (C=O) cm-1; H nmr (deuteriochloroform): ꢁ
Ethyl-4-oxo-1,2,3,4-tetrahydro-9-methyl-carbazole-3-
carboxylate (5). A solution of 2.5 g (9.7 mmoles) of 4 in 25 mL
of dichloromethane was cooled to 0ºC. After that, 5 mL of 50%
sodium hydroxide, 100 mg of tetrabutylammonium hydrogen
sulfate and 1.42 g (10 mmoles) of methyl iodide were added,
2.18-2.22 (m, 1H, CH), 2.24-2.34 (m, 2H, CH2), 2.52-2.64 (m,
2H, CH2), 2.70-2.76(m, 1H, CH), 2.92 (dt, 1H, J= 17.22 and
5.43 Hz, C1H), 3.07-3.16 (m, 1H, CH), 3.30-3.42 (m, 1H, C3H),
3.52 (s, 3H, CH3), 7.14-7.25 (m, 2H, aromatic protons), 7.30 (d,

May-Jun 2007
A Short Synthesis of the Hexahydropyrido[4,3-b]carbazole
541
C6H9N]+. Anal. Calcd. for C16H18N2: C, 80.67; H, 7.56; N,
11.76. Found; C, 80.61; H, 7.59; N, 11.72.
1H, J= 8.25 Hz, aromatic proton), 7.92 (d, 1H, J=8.17 Hz,
aromatic proton); 13C nmr (deuteriochloroform): ꢀ 13.86, 19.27,
28.21, 29.83, 30.23, 49.90, 110.04, 111.38, 118.41, 120.62,
122.35, 122.88, 124.81, 141.67, 150.72, 190.02; ms: m/z
253(1.9) [M+1]+, 252(7.2) [M]+, 212(10.1) [M-C2H2N]+,
184(61) [M-C4H6N]+, 129(100) [M-C7H9NO]+. Anal. Calcd. for
C16H16N2O: C, 76.19; H, 6.35; N, 11.11. Found; C, 76.25; H,
6.38; N, 11.06.
REFERENCES
[1] Saxton, J. E. In The Alkaloids; Cordel, G. A., Ed.; Academic
Press: New York, 1998, Vol. 51, Chapter 1.
[2] Stork, G.; Dolfini, J. E. J. Am. Chem Soc. 1963, 85, 2872.
[3] Harley-Mason, J.; Kaplan, M. J. J. Chem. Soc. Chem.
Commun. 1967 915.
2,3,4,4a,5,6-hexahydro-7-methyl-pyrido[4,3-b]carbazole
(8). To a solution of 2.73 g (11.5 mmoles) of nickel(II) chloride
hexahydrate in 5 mL of ethanol, under nitrogen atmosphere at 0
ºC, were successively dropped a solution of 23 mL (1 M, 23
mmoles) of sodium borohydride in ethanol and a solution of 23
mL (0.1 M) of sodium hydroxide in ethanol and the mixture was
stirred for 30 minutes at room temperature. Then, a solution of 1
g (3.97 mmoles) of 7 in ethanol was added, and the mixture was
heated to 80 ºC and then 3.80 mL (79.2 mmoles) of hydrazine
hydrate was added and stirred at 80 ºC for 5 hours. The residual
catalyst was filtered, and the solvent was removed. The residue
was hydrolyzed with 25 mL of 10% acetic acid and the mixture
was neutralized with sodium carbonate and extracted with
chloroform. The organic layer was dried with anhydrous
magnesium sulfate, and the solvent was evaporated under
reduced pressure. Then the residue was chromatographed with
neutral aluminum oxide using ethyl acetate-hexane (2:1). The
solvent was removed and then the product was recrystallized
from ether to afford 720 mg (76%) of hexahydropyrido[4,3-
b]carbazoles 8, mp 116-117 ºC; ir (potassium bromide): ꢁ 2953
(CH), 1605 (C=C) cm-1; 1H nmr (dimethyl sulfoxide-d6): ꢀ 1.56-
1.68 (m, 1H, CH), 1.75-1.80 (m, 2H, CH2), 1.94-2.06 (m, 2H,
CH2), 2.66-2.74 (m, 2H, CH2), 2.84-3.30 (m, 4H, 2xCH2), 3.72
(s, 3H, CH3), 7.15-7.38 (m, 2H, aromatic protons), 7.52 (d, 1H,
J= 7.83 Hz, aromatic proton) 7.96 (d, 1H, J=7.39 Hz, aromatic
proton); 13C nmr (dimethyl sulfoxide-d6): ꢀ 21.41, 22.63, 30.73,
32.61, 34.22, 35.03, 48.14, 109.83, 111.94, 119.35, 120.56,
121.27, 125.38, 137.02, 142.61, 169.62; ms: m/z 239(5.4)
[M+1]+, 238(27) [M]+, 168(100) [M-C4H8N]+, 143(100) [M-
[4] Overman, L. E.; Sworin, M.; Burk, R. M. J. Org. Chem.
1983, 48, 2685.
[5] Büchi, G.; Matsumoto, K. E. J. Am. Chem. Soc. 1971, 93,
3299.
[6] Kuehne, M. E.; Podhorez, D. E.; Moursounidis, J. J. Am.
Chem. Soc. 1987, 109, 2469.
[7] Magnus, P.; Cairns, M.P. J. Am. Chem. Soc. 1986, 108, 217.
[8] Le Menez, P.; Kunesch, N.; Lui, S.; Wenkert, E. J. Org.
Chem. 1991, 56, 2915.
[9] Urritia, A.; Rodriquez, J. G. Tetrahedron 1999, 55, 11095.
[10] d’Angelo, J.; Desmaele, D. Tetrahedron Lett. 1990, 31, 879.
[11] d’Angelo, J.; Desmaele, D. Tetrahedron Lett. 1990, 31, 883.
[12] Benchekroun, N.; Dugat, D.; Gramain, J. C. Tetrahedron
Lett. 1992, 33, 4001.
[13] Magnus, P.; MatMathews, I. R.; Schultz, J.; Waditschatka,
R.; Huffman, J. C. J. Org. Chem. 1988, 53, 5772.
[14] Magnus, P.; Katoh, T.; MatMathews, I. R.; Huffman, J. C. J.
Am. Chem. Soc. 1989, 111, 6707.
[15] Ergun, Y.; Patir, S.; Okay, G. Synt. Commun. 2004, 34, 435.
[16] Oikawa, Y.; Yonemitsu, O. J Org. Chem. 1977, 42, 1213.
[17] Magnus, P.; Sear, N. L.; Kim, C. S.; Vicker, N. J. Org.
Chem. 1992, 57, 70.
[18] Ergun, Y.; Patir, S.; Okay, G. J. Heterocycl. Chem. 2002, 39, 315.
[19] Toczko, M. A.; Heathcock, C. H. J. Org. Chem. 2000, 65,
2642.
[20] Lloyd, D. H.; Nichols, D. E. J. Org. Chem. 1986, 51, 4294.
[21] Backvall, Jan-E.; Plobeck, N. A. J. Org. Chem. 1990, 55,
4528.