Synthesis of the azocino[4,3-b]indole core structure for the synthesis of strychnos alkaloids

Article abstract of DOI:10.1002/jhet.5570390212

The synthesis of compound 12 which has a hexahydro-1,5-methanoazocino[4,3-b]indole structure for the synthesis of pentacyclic strychnos type alkaloids (tubifolin and tubifolidine) is described. Many new compounds 5-12 have also been synthesized.

Full text of DOI:10.1002/jhet.5570390212

Mar-Apr 2002
315
Synthesis of the Azocino[4,3-b]indole Core Structure for the Synthesis
of Strychnos Alkaloids
Yavuz Ergün , Süleyman Patir and Gürol Okay *
a
b
a
a
Department of Chemistry, Faculty of Science, Hacettepe University, 06532-Beytepe-Ankara, Turkey
Department of Science, Faculty of Education, Hacettepe University, 06532-Beytepe-Ankara, Turkey
Received August 17, 2001
b
The synthesis of compound 12 which has a hexahydro-1,5-methanoazocino[4,3-b]indole structure
for the synthesis of pentacyclic strychnos type alkaloids (tubifolin and tubifolidine) is described. Many new
compounds 5-12 have also been synthesized.
J. Heterocyclic Chem., 39, 315 (2002).
The tetracyclic structure hexahydro-1,5-methanoazo-
cino[4,3-b]indole (1) is the core structure for the synthesis
of pentacyclic strychnos type of alkaloids such as tubifolin
(2) and tubifolidine (3) [1,2,3]. Therefore, many chemists
have tried to synthesize this tetracyclic ring system [4,5,6].
Reagents and Conditions: (i) CH CH CHCNCO C H , NaOEt/EtOH,
In this work we have succesfully obtained compound
12 which has a hexahydro-1,5-methanoazocino[4,3-
b]indole structure. In the first part of the work a new
cyclohexanone derivative 5 was obtained by the reac-
tion of 2-cyclohexenone with ethyl 2-cyano butanoate
by a Michael reaction [7]. Reaction of compound 5 with
phenyl hydrazine by Fischer indol reaction gave the
tetrahydrocarbazole derivative 6 [8]. Compound 7 which
was obtained by deesterification of 6 at high tempera-
ture, was oxidized using 2,3-dichloro-5,6-dicyano-p-
benzoquinone yielding compound 8 [9]. Subsequent
hydrolysis of 8 with boron fluoride in aqueous acetic
acid afforded compound 9 [10]. We also tried to obtain
amide 9 from nitrile 8 using hydrogen peroxide-sodium
hydroxide [11]. Unfortunately the trial was unsuccess-
ful. Later we protected the indol nitrogen using tetra-
butyl ammonium hydrogen sulfate and benzene sulfonyl
chloride, which resulted in compound 10, which was
reacted with sodium borohydride to yield intermediate
11 [6]. Finally, hexahydro-1,5-methanoazocino[4,3-
b]indole structure 12 was synthesized by ring closure of
11 using trifluoro acetic acid [6].
3
2
2 2 5
0¡, 15 min, then rt, 16h, 66%; (ii) PhNHNH , AcOH, N , reflux, 5h, 57%;
2
2
(iii) DMSO, NaCl, H O, 160°, 18h, 68%; (iv) DDQ, THF (90%), rt, 5h,
2
52%; (v) BF .Et O, AcOH-H O, reflux, 72h, 75%; (vi) TBAHS, NaOH
3
2
2
(50%), CH Cl , PhSO Cl, rt, 1h, 84%; (vii) NaBH , THF-MeOH, rt, 2h,
2
2
2
4
86%; (viii) CF CO H, CH Cl , 0¡ then rt, 12h, 36%.
3
2
2
2
EXPERIMENTAL
All melting points were measured in sealed tubes using an
electrothermal digital melting point apparatus (Gallenkamp) and
are uncorrected. Infrared spectra were recorded on a Hitachi 270-
1
30 infrared spectrometer. H-nmr spectra were obtained on a high
resolution fourier transform Bruker WH-400 NMR spectrometer
with tetramethylsilane as an internal stantard. Mass spectra were
recorded on a Micromass UK Platform II LC-MS spectrometer.
Analytical and preparative thin layer chromatography (TLC) was
carried out using silica gel 60 HF-254 (Merck). Column chro-
matography was carried out by using 70-230 mesh silica gel
(0.063-0.2 mm, Merck).
Ethyl 2-Cyano-2-(3-oxo-cyclohexyl)-butanoate (5).
To a solution of a catalytic amount of sodium ethylate in
ethanol (prepared by adding 1 g of metallic sodium to 50 ml of
absolute ethanol at 0°) were added 20 g (14 mmoles) of ethyl

316
Y. Ergün, S. Patir and G. Okay
Vol. 39
2-cyano butanoate, and the solution was stirred for 15 minutes at
0°. To this solution were added dropwise 12.5 g (13 mmoles) of
2-cyclohexene-1-one at the same temperature. The reaction mix-
ture was stirred for 16 hours at room temperature. The solution
was acidified with acetic acid, then diluted with water. The com-
pound was extracted with ether, and the extract was dried with
anhydrous magnesium sulfate. The solvent was evaporated under
reduced pressure, and destillation of the residue gave 20.5 g
(66%) of 5, bp: 135-145° (5 mmHg); ir (potassium bromide): ν
1.13 (3H, t, J = 7.3 Hz, CH CH ), 1.46-1.80 (4H, m, 2xCH ),
2 3 2
1.85-2.05 (2H, m, CH ) 2.59-2.66 (1H, m, CH), 2.74-2.82 (2H,
2
m, CH ), 2.98 (1H, m, CH), 7.12 (1H, m, J = 7.5 Hz, aromatic
2
proton), 7.23 (1H, m, J = 7.6 Hz, aromatic proton), 7.35 (1H, d, J
= 8.1 Hz, aromatic proton), 7.54 (1H, d, J = 8.1 Hz, aromatic pro-
+
ton), 8.14 (1H, s, NH); ms: m/z 240(5) [M+2] , 239(25.5)
+
+
+
[M+1] , 238(3) [M] , 210(2.78) [M-C H ] , 207(1.78) [M-
2
4
+
+
+
C H ] , 170(9.55) [M-C H N] , 169(9.46) [M-C H N] ,
2
7
4
6
4
7
+
+
168(29) [M-C H N] , 167(20.14) [M-C H N] , 117(5.38) [M-
C H N] , 115(19) [M-C H N] , 77(11) [M-C H N ] .
4
8
4 9
-1
1
+
+
+
2965 (CH), 2250 (CN), 1740 (C=O) 1685 (C=O) cm ; H nmr
8
11
8
13
10 13 2
(deuteriochloroform): δ 1.11 (3H, t, J = 7.4 Hz, CH CH ), 1.33
Anal. Calcd. for C
H
N : C, 80.68; H, 7.56; N, 11.76.
2
3
16 18
2
(3H, t, J = 7.2 Hz, OCH CH ), 1.60-1.80 (2H, m, CH ), 1.90 (2H,
Found: C, 80.60; H, 7.58; N, 11.79.
2
3
2
q, J = 7.4 Hz, CH CH ), 1.95-2.10 (2H, m, CH ), 2.30-2.42 (5H,
2
3
2
2-(1, 2, 3, 4-Tetrahydrocarbazol-4-oxo-2yl)-butyronitrile (8).
m, CH and 2xCH ), 4.25 (2H, q, J = 7.1 Hz, OCH CH ); ms: m/z
2
2
3
+
+
+
238(1.5) [M+1] , 237(1.1) [M] , 210(1.15) [M-HCN] ,
182(1.50) [M-C H N] , 181(1.60) [M-C H N] , 153(1.64) [M-
To a solution of 5 g (21 mmoles) of 7 in 50 ml of tetrahydrofu-
rane (90%) were added dropwise 9.54 g (42 mmoles) of 2,3-
dichloro-5,6-dicyano-p-benzoquinone in 15 ml of tetrahydrofu-
rane at 0°. The reaction mixture was stirred for 5 hours at room
temperature then the solution was poured into 500 ml of 10%
sodium hydroxide and extracted with ethyl acetate. The organic
layer was dried with anhydrous magnesium sulfate, and the sol-
vent was removed. The residue was purified by chromatography
using silica gel and ethyl acetate. After the solvent was evapo-
rated, the product was recrystallized from ether to afford 2.75 g
(52%) of 8, mp: 224-225°; rf: 0.32 (ethyl acetate); ir (potassium
bromide): ν 3300 (NH), 2980 (CH), 2250 (CN), 1645 (C=O)
+
+
3
5
3 6
+
+
+
C H N] , 141(22) [M-C H O] , 113(28) [M-C H O] , 97(82)
3
10
6
9
8 12
+
+
[M-C H NO ] , 96(100) [M-C H NO ] , 69(67) [M-
7
10
2
7
11
2
+
+
C H O ] , 68(100) [M-C H O ] .
9
11
3
9 12 3
Anal. Calcd. for C
H NO : C, 65.82; H, 8.02; N, 5.91.
13 19 3
Found: C, 65.75; H, 8.06; N, 5.85.
Ethyl 2-Cyano-2-(1, 2, 3, 4-tetrahydrocarbazol-2-yl)-butanoate
(6).
A solution of 10 g (42.2 mmoles) of 5 and 4.6 g (42.5 mmoles)
of phenyl hydrazine in 250 ml of acetic acid was refluxed for 5
-1
1
hours under N and then cooled to room temperature. The reaction
cm ; H nmr (deuteriochloroform): δ 1.17 (3H, t, J = 7.3 Hz,
CH ), 1.76 (2H, m, CH ), 2.58-2.75 (4H, m, 2xCH ), 3.03 (1H,
2
mixture was poured into 500 ml of cold water and extracted with
ether. The organic layer was washed with 100 ml of 10%
hydrochloric acid and then 100 ml of 10% sodium carbonate. The
organic layer was dried with anhydrous magnesium sulfate, and
the solvent was evaporated under reduced pressure. The crude
product was dissolved in chloroform and chromatographed using
silica gel and ethyl acetate. The solvent was evaporated and the
residue was recrystallized from methanol to yield 7.5 g (57%) of
6, mp: 158-159°; rf: 0.64 (ethyl acetate); ir (potassium bromide): ν
3
2
2
m, CH), 3.25 (1H, m, CH), 7.28 (2H, m, aromatic protons), 7.37
(1H, d, J = 8.8 Hz, aromatic proton), 8.21 (1H, d, J = 8.7 Hz, aro-
matic proton), 8.65 (1H, s, NH); ms: m/z 254(7.35) [M+2] ,
+
+
+
+
253(36) [M+1] , 252(12) [M] , 185(4.10) [M-C H N] , 184(25)
4
5
+
+
+
[M-C H N] , 183(5.78) [M-C H N] , 158(13) [M-C H NO] ,
4
6
4
7
5 4
+
+
157(100) [M-C H NO] , 156(31) [M-C H NO] , 131(6.93) [M-
5
5
5 6
+
+
+
C H NO] , 130(54.5) [M-C H NO] , 129(23) [M-C H NO] ,
7
7
7
8
7 9
+
+
128(42.5) [M-C H NO] , 117(3.83) [M-C H NO] , 104(1.94)
7
10
8 9
-1
1
+
+
3415 (NH), 2940 (CH), 2250 (CN) 1745 (C=O) cm ; H nmr
[M-C H N O] , 103(13.5) [M-C H N O] , 102(48.5) [M-
8
8
2
8 9 2
+
+
(deuteriochloroform): δ 1.11 (3H, t, J = 7.4 Hz, CH CH ), 1.35
C H N O] , 77(21) [M-C H N O] .
2
3
8
10
2
10 11 2
(3H, t, J = 7.1 Hz, OCH CH ), 1.90-2.80 (9H, m, CH and 4xCH ),
Anal. Calcd. for C H N O: C, 76.19; H, 6.35; N, 11.11.
2
3
2
16 16
2
4.25-4.35 (2H, q, J = 7.1 Hz, OCH CH ), 7.05-7.12 (2H, m, aro-
Found: C, 76.23; H, 6.37; N, 11.15.
2
3
matic protons), 7.20 (1H, d, J = 8.1 Hz, aromatic proton), 7.45
(1H, d, J = 7.5 Hz, aromatic proton), 7.80 (1H, s, NH); ms: m/z
2-(1, 2, 3, 4-Tetrahydrocarbazol-4-oxo-2yl)-butanamide (9).
+
+
+
311(5) [M+1] , 310(22) [M] , 265(4) [M-OC H ] , 238(4) [M-
A solution of 1.5 g (5.95 mmoles) of 8, 4.22 g (29.75 mmoles)
of boron trifluoride-diethyl ether complex and 0.10 g (5.59
mmoles) of water in 50 ml of acetic acid was refluxed for 72
hours. Then the mixture was poured into 10% sodium hydroxide
solution and extracted with ethyl acetate. The organic layer was
dried with anhydrous magnesium sulfate and the solvent was
removed under reduced pressure. The residue was chro-
matographed on silica gel using ethyl acetate. After the solvent
was evaporated, the product was recrystallized from methanol to
yield 1.20 g (75%) of 9, mp: 192-193°; rf: 0.41 (ethyl acetate); ir
(potassium bromide): ν 3405 (NH), 3395 (NH), 2980 (CH), 1690
2
5
+
+
+
CO C H ] , 237(3) [M-CO C H ] , 170(59) [M-C H NO ] ,
169(75) [M-C H NO ] , 143(100) [M-C H NO ] , 69(31) [M-
2
2
4
2
2
5
7
10
2
+
+
7
11
2
9
13
2
+
+
C H NO ] , 68(26.5) [M-C H NO ] .
15 15
2
15 16
2
Anal. Calcd. for C H N O : C, 73.55; H, 7.10; N, 9.03.
19 22
2 2
Found: C, 73.61; H, 7.02; N, 9.15.
2-(1, 2, 3, 4-Tetrahydrocarbazol-2yl)-butyronitrile (7).
A solution of 7 g (22.6 mmoles) of 6, 3.96 g (67.74 mmoles) of
sodium chloride and 1.22 g (67.74 mmoles) of water in 100 ml of
dimethyl sulfoxide was stirred for 18 hours at 160°. Then the
mixture was poured into 250 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. After the solvent was evaporated, the product was recrys-
tallized from methanol to yield 3.65 g (68%) of 7, mp: 167-168°;
rf: 0.60 (ethyl acetate); ir (potassium bromide): ν 3400 (NH),
-1
1
(C=O), 1665 (C=O) cm ; H nmr (deuteriochloroform): δ 1.20
(3H, t, J = 7.3 Hz, CH ), 1.80 (2H, m, CH ), 2.60-2.80 (4H, m,
3
2
2xCH ), 3.05 (1H, m, CH), 3.30 (1H, m, CH), 5.40 (1H, s, NH),
2
7.32 (2H, m, aromatic protons), 7.42 (1H, d, J = 9.0 Hz, aromatic
proton), 8.24 (1H, d, J = 9.1 Hz, aromatic proton) 8.70 (1H, s,
+
+
+
NH); ms: m/z 271(1.5) [M+1] , 270(5) [M] , 254(2) [M-NH ] ,
2
+
+
226(1.07) [M-CONH ] , 185(2.96) [M-C H NO] , 184(8.45)
2
4 7
-1
1
+
+
2980 (CH), 2255 (CN) cm ; H nmr (deuteriochloroform): δ
[M-C H NO] , 183(6.31) [M-C H NO] , 170(43)
4 8 4 9

Mar-Apr 2002
Azocino[4,3-b]indole Core Structure for the Synthesis of Strychnos Alkaloids
317
+
+
(1.82 mmoles) of 11 were dissolved in 15 ml of dichloro methane
and cooled to 0°. The reaction mixture was treated with 0.23 g (2
mmoles) of trifluoro acetic acid and stirred for 12 hours at room
temperature. After 12 hours the reaction mixture was poured into
water and extracted with dichloromethane. The organic layer was
dried with anhydrous magnesium sulfate and the solvent was
evaporated. The crude product was chromatographed with silica
gel and ethyl acetate. The solvent was removed under reduced
pressure and the product was recrystallized from methanol to
afford 0.35 g (36%) of 12, mp: 197-198°; rf: 0.30 (ethyl acetate);
ir (potassium bromide): ν 3350 (NH), 2980 (CH), 1670 (C=O),
[M-C H NO ] , 169(71) [M-C H NO ] , 168(100) [M-
4
6
2
4
7
2
+
+
+
C H NO ] , 167(73) [M-C H NO ] , 131(20) [M-C H NO ] ,
4
8
2
4
9
2
7
9
2
+
+
130(45) [M-C H NO ] , 129(50) [M-C H NO ] , 128(45)
7
10
2
7
11
2
+
+
[M-C H NO ] , 118(47) [M-C H NO ] , 117(47) [M-
7
12
2
8
10
2
+
+
C H NO ] , 93(23) [M-C
H
NO ] , 92(14) [M-
8
11
H
2
10 11
2
+
+
C
NO ] , 91(62) [M-C
H
NO ] , 77(55) [M-
10 12
2
10 13
2
+
C H N O ] .
10 13
2 2
Anal. Calcd. for C H N O : C, 71.11; H, 6.67; N, 10.37.
Found: C, 71.04; H, 6.60; N, 10.41.
16 18
2 2
2-(1,2,3,4-Tetrahydrocarbazol-4-oxo-9-benzenesulfonyl-2-yl)-
butanamide (10).
-1 1
1325 and 1175 (S=O) cm ; H nmr (deuteriochloroform): δ 0.90
A solution of 1.25 g (4.63 mmoles) of 9 in 50 ml of
dichloromethane was cooled to 0°. After that 5 ml of 50% sodium
hydroxide, 100 mg of tetrabuthylammonium hydrogen sulfate
and 0.83 g (4.70 mmoles) of benzene sulfonyl chloride was
added, and the mixture stirred for 1 hour at room temperature,
washed with 50 ml of 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. The sol-
vent was removed and then the product was recrystallized from
ether to afford 1.6 g (84%) of 10, mp: 278-281°; rf: 0.49 (ethyl
acetate); ir (potassium bromide): ν 3400 (NH), 2980 (CH), 1695
(3H, m, J = 7.2 Hz, CH ), 1.25-1.50 (3H, m, CH and CH ), 1.75-
3
2
2.00 (2H, m, CH ), 2.45-2.65 (2H, m, CH ), 2.75 (1H, m, CH),
2
2
3.10 (1H, m, CH), 4.80 (1H, bs, NH), 6.85 (1H, d, J = 9.1 Hz, aro-
matic proton), 7.10 (2H, m, aromatic protons), 7.20-7.70 (4H, m,
aromatic protons), 7.85-7.95 (2H, m, aromatic protons); ms: m/z
+
+
+
395(1.5) [M+1] , 394(4.5) [M] , 254(12) [M-C H SO ] ,
6
4
2
+
+
253(12) [M-C H SO ] , 238(9) [M-C H NSO ] , 237(14) [M-
6
5
2
6
6
2
+
+
C H NSO ] , 168(40) [M-C
H
NSO ] , 167(36) [M-
N O] , 77(100) [M-
6
7
2
10 12
3
+
+
C
H
NSO ] , 141(42) [M-C
H
10 13
3
16 17
2
+
C H N SO ] .
16 17
2
3
Anal. Calcd. for C H N SO : C, 67.00; H, 5.58; N, 7.11.
22 22
2
3
Found: C, 66.92; H, 5.54; N, 7.18.
-1
1
(C=O), 1665 (C=O), 1350 and 1170 (S=O) cm ; H nmr
(deuteriochloroform): δ 1.05 (3H, m, J = 7.3 Hz, CH ), 1.72-1.82
3
REFERENCES AND NOTES
(2H, m, CH ), 1.86-1.90 (2H, m, CH ), 2.15-2.25 (2H, m, CH ),
2
2
2
2.85-2.95 (1H, m, CH), 3.40-3.50 (1H, m, CH), 5.40 (2H, bs,
[1] M. Amat, M. D. Coll, J. Bosch, E. Espinosa and E. Molins,
Tetrahedron , 8, 935 (1997).
NH ), 7.10 (1H, d, J = 8.9 Hz, aromatic proton), 7.15-7.40 (4H,
2
m, aromatic protons), 7.45 (1H, d, J = 8.9 Hz, aromatic proton),
7.55 (1H, d, J = 9.0 Hz, aromatic proton), 7.80-7.90 (2H, m, aro-
[2] M. Amat, A. Linares, M. L. Salas, M. Alveres and J.
Bosch, J. Chem. Soc. Chem. Commun., 420 (1988).
[3] M. Amat, M Alvares, J. Bonjoch, N. Casamitjana, J.
Gracia, R. Lavilla, X. Garcias and J. Bosch , Tetrahedron Letters, 31,
3453 (1990).
+
+
matic protons); ms: m/z 411(3) [M+1] , 410(9) [M] , 409(25)
+
+
+
[M-H] , 325(10) [M-C H NO] , 324(7) [M-C H NO] , 269(17)
4
7
4 8
+
+
[M-C H SO ] , 141(86) [M-C
H N O ] , 77(100) ) [M-
6
5
2
16 17 2 2
+
C H N SO ] .
16 17
2
4
[4] S. Patir, P. Rosenmund and P. H. Götz, Heterocycles, 43,
15 (1996).
Anal. Calcd. for C H N SO : C, 64.39; H, 5.36; N, 6.83.
22 22
2
4
Found: C, 64.45; H, 5.40; N, 6.75.
[5] S. Patir, Liebigs Ann., 1561 (1995).
[6] P. Magnus, N. L. Sear, C. S. Kim and N. Vicker, J. Org.
Chem., 57, 70 (1992).
[7] Y. Ergün, N. Bayraktar, S. Patir and G. Okay, J.
Heterocyclic Chem., 37, 11 (2000).
[8] B. Robinson, Chem. Rev., 63, 373 (1963).
[9] H. Fritz, M. S. Jamarani, J. W. Bats and H. J. Teuber,
Liebigs Ann. Chem., 705 (1993).
[10] C. R. Hauser and D. S. Hoffenberg, J. Org. Chem., 20,
1448 (1955).
4-Ethyl-2, 3, 4, 5, 6, 7-hexahydro-1,5-methano-3-oxo-7-(ben-
zene sulfonyl)-2H azocino[4,3-b]indole (12).
A solution of 1 g (2.4 mmoles) of 10 in 10 ml of methanol-
tetrahydrofurane (1:1) was cooled to 0° and treated with 18 mg
(4.8 mmoles) of sodium borohydride and the mixture stirred for 2
hours at room temperature. The reaction mixture was diluted
water and extracted with chloroform. The organic layer was dried
with anhydrous magnesium sulfate. The solvent was evaporated
to yielded 0.87 g of an oily crude product 11. After that, 0.75 g
[11] Noller, Org. Syntheses, Coll. Vol. II, 586 (1943).