Synthesis of vinca alkaloids and related compounds 95. Attempted build-up of the aspidospermidine skeleton by [4+2] cycloaddition. Some unexpected reactions, and formation of a new ring system

Article abstract of DOI:10.3987/com-00-9146

The reaction of the 2-vinylindole derivative (10) with methyl 4-formylbutanoate (11a) gave a pyrido[1,2-a]indole (13), instead of the expected seco-aspidospermidine (12). Similarly, this cycloaddition reaction failed with the vinyl-enamide (19), the produ

Full text of DOI:10.3987/com-00-9146

HETEROCYCLES, VOL. 55, NO. 5, 2001, PP. 873 – 880, Received, 19th December, 2000
SYNTHESIS OF VINCA ALKALOIDS AND RELATED COMPOUNDS 95.1
ATTEMPTED BUILD-UP OF THE ASPIDOSPERMIDINE SKELETON BY
[4+2] CYCLOADDITION. SOME UNEXPECTED REACTIONS, AND
FORMATION OF A NEW RING SYSTEM
István Vágóa,b, György Kalausa *, István Greinerb, Mária Kajtár-Peredyc, János
Brlikb, Lajos Szabóa and Csaba Szántaya,c *
a. Department for Organic Chemistry, Technical University of Budapest, Gellért
tér 4, H-1521 Budapest, Hungary
b. Chemical Works of Gedeon Richter Ltd, Gyömr_i út 19-21, H-1103 Budapest,
Hungary
c. Institute of Chemistry, Chemical Research Centre, Hungarian Academy of
Sciences, Pusztaszeri út 59-67, H-1525, Budapest, Hungary
Abstract – The reaction of the 2-vinylindole derivative (10) with methyl 4-
formylbutanoate (11a) gave a pyrido[1,2-a]indole (13), instead of the expected
seco-aspidospermidine (12). Similarly, this cycloaddition reaction failed with the
vinyl-enamide (19), the products were two 5H-pyrido[1',2':1,8]azocino[5,4-b]-
indole derivatives, (20 and 21).
Using our formerly developed synthetic strategy based on [4+2] cycloaddition reactions,2 we achieved the
synthesis of (±)-19-ethoxycarbonyl-19-demethylvincadifformine (1).3 This alkaloid-like molecule,
containing the anilinoacrylate structural unit, had already been converted in several steps by Brennan and
Saxton4 into a natural product, (±)-12-demethoxy-N(1)-acetylcylindrocarine (2), belonging to the
aspidospermine group. Consequently, our synthesis constituted the formal synthesis of this compound.
Since the above conversion gave the target molecule only in a moderate yield, we wanted to find a
pathway involving the [4+2] cycloaddition reaction, successfully used in the build-up of vincadifformine-
tabersonine type of molecules.5 Our aim was the preparation of deethylaspidospermidine (3a), and then of
aspidospermidine (3b).
N
N
N
H
H
H
COOC2H5
COOC2H5
R
N
H
N
N
H
H
H
O
COOCH3
3 a R=H
b R=C2H5
1
2
NH3+Cl-
NH
R1
a
N
COOC2H5
N
H
R2
H
4
R1
R2
Reagents and conditions:
5
6
7
8
9
CPh3
CPh3
CPh3
CPh3
H
COOC2H5
CH2OH
CHO
CH=CH2
CH=CH2
CH=CH2
(a) Ph3CCl, TEA, CHCl3, rt
(b) LiAlH4, THF, 0 °C
(c) MnO2, CHCl3, rt
(d) CH3P+Ph3Br-, C4H9Li, THF, rt
(e) AcOH, H2O, 70 °C
(f) PhCHO, MeOH, 0 °C and
NaBH4, MeOH, 0 °C
b
c
d
e
f
10 Bn
Scheme 1

Starting from 2-ethoxycarbonyltryptamine hydrochloride (4),6 its Nb-trityl derivative (5) was prepared in
basic medium. 5 was reduced with metal hydride to the alcohol (6), which was oxidized with
manganese(V) oxide to furnish the aldehyde (7). The latter compound, was transformed into the vinyl
derivative (8) by the help of the ylid derived from triphenylmethylphosphonium bromide. On removal of
the protecting group, compound (9) was made to react with benzaldehyde, and the resulting Schiff base,
without isolation, was converted into the secondary amine (10) (Scheme 1).
First, the reaction of 10 with methyl 4-formylbutanoate (11a)7 was tried in the hope of achieving the
desired cycloaddition to 12, by interaction of the diene structural part of 10 – consisting the indole ring
and the vinyl group – and the enamine derived from the secondary amine and the aldehyde. It was found,
however, that instead of [4+2] cycloaddition the product (13) was formed. Very likely the first step was
the addition of 11a to the vinyl group of 10, followed by enolization of the formyl group. Subsequent
dehydration involving the indole-NH group resulted in 13 (Scheme 2).
CHO
11 a R=H
b R=CH5
2
R
COOCH3
Bn
COOCH3
12
Bn
N
COOCH3
and / or
N
H
H
N
N
H
toluene
10 + 11a
∆
NHBn
N
13
COOCH3
Scheme 2
If the reacting aldehyde had only one hydrogene atom in α-position (11b),8 the reaction gave no definite
product. The next notion was to utilise our former experience,9 i.e. to try to form an enamide unit in the
molecule that would readily react with the diene under suitable reaction conditins to furnish the desired
[4+2] cycloaddition product.
O
N
toluene, xylene or decalin
benzene
(TsOH)
9 + 11b
∆
N
H
∆
O
14
O
N
N
H
H
and / or
N
H
N
15
Scheme 3

The interaction of 9 and 11b was effected at the boiling point of benzene to give the expected compound
(14), which, however, did not yield the cycloaddition product (15) even on refluxing in toluene, xylene or
decalin, either in the presence or absence of p-toluenesulfonic acid. The starting materials was recovered
unchanged (Scheme 3).
In view of the above results, we attributed the failure of the cycloaddition reaction to the presence of the
mobile hydrogene atom of the indole ring. Therefore it was substituted by a methyl group, and the
reactions described above were carried out with these compounds (Scheme 4).
NH
R
8
N
CH3
Reagents and conditions:
16 R=CPh3
b
c
(a) NaH, DMF, CH3I, 0 °C
(b) AcOH, H2O, 70 °C
(c) PhCHO, MeOH, 0 °C and
NaBH4, MeOH, 0 °C
17 R=H
18 R=Bn
Scheme 4
The boiling of 18 in toluene, xylene or decalin, with or without p-toluenesulfonic acid, neither with 11a
nor with 11b resulted in a definite product, the starting materials suffered decomposition.
When the primary amine (17) was made to react with 11b in benzene, a well-defined product was
obtained. This enamide (19) was refluxed in toluene in the presence of p-toluenesulfonic acid. This
reaction gave two isomeric tetracyclic compounds, representing a new heterocyclic ring system (20) and
(21). The formation of the isomers occurs by addition of the vinyl side chain to the enamide structural
part (Scheme 5).
O
N
benzene
xylene / ∆
TsOH
17 + 11b
∆
N
CH3
19
O
O
N
N
H
+
N
N
H
CH3
CH3
20
21
Scheme 5
In conclusion it can be stated that non-activated 2-vinylindole derivatives, in contrast with our earlier
experience,2 do not react as dienes under the given conditions in the reactions described above; they
undergo addition reactions of different types instead.

ACKNOWLEDGEMENT
The authors are grateful to the National Scientific Research Foundation (OTKA T/12-31920) for financial
support of this work.
EXPERIMENTAL
Melting points are uncorrected and were obtained using Hotstage microscope Betius apparatus. IR spectra
1
13
were obtained using a Specord JR-75 Spectrophotometer. H and C NMR spectras were recorded on a
Varian VXL-400 Spectrometer. Chemical shifts (in ppm) are relative to internal standard
1
tetramethylsilane. Mutual H-1H couplings are given only once, at their first occurrences. MS spectra
were recorded using a VG-TRIO-2 quadrupol Mass Spectrometer. Column chromatography was
accomplished using Merck Kieselgel 60 Mesh. Preparative thin layer chromatography was performed
with Silica gel plates F254 (Merck).
3-[2-(Tritylamino)ethyl]-1H-indole-2-carboxylic acid ethyl ester (5)
To a solution of 17 g (0.061 mol) of tritylchloride in 150 mL of dry chloroform 10.0 g (0.037 mol) of 2-
(ethoxycarbonyl)tryptamine hydrocloride was added in one portion. To the resulted suspension 15 mL of
triethylamine (0.108 mol) in 30 mL of dry chloroform was added over a period of 1 h. During the
addition, the suspension was slowly dissolved. After the addition was complete, the reaction mixture was
stirred for 3 h. The solution was extracted with water, dried with magnesium sulfate, concentrated in
vacuum. The resulted oil was dissolved in 100 mL of ether. Hydrogen chloride in ether was added to the
solution until the pH became acidic. The precipitated salt was filtered, washed with diethyl ether. The
hydrochloride salt was suspended in chloroform (200 mL), treated with 2M sodium hydroxide solution
and water subsequently. The organic phase was dried with magnesium sufhate, and evaporated in vacuum.
The resulted oil was crystallised with methanol as a white powder, 14.7 g (84 %), mp 142-144 ºC; IR
(KBr): 3340 (indole-NH), 1680 cm-1 (CO). MS m/z (%): 474 (2/30), 397 (14/30), 258 (32/30), 243
(100.0), 165 (25.0), 86 (49.0). 1H NMR δΗ (CDCl3): 1.34 + 4.35 (3H+5H, t+q, Jvic=7.0 Hz; COOEt), 1.77
(1H, br s; NH), 2.51 (2H, br t, J=6.8 Hz; CH2NH), 3.33 (2H, t, J=6.8 Hz; C3-CH2), 7.05-7.65 (19H, m;
3xPh+C4-H+C5-H+C6-H+C7-H), 8.78 (1H, br s; indole-NH). 13C NMR δC (CDCl3):
14.46(COOCH2CH3), 25.82 (C3-CH2), 44.31(CH2NH), 60.71 (COOCH2CH3), 70.87 (NH-CPh3), 111.67
(C7), 120.1 (C4), 121.04 (C5), 122.63 (C3), 123.77 (C3a), 125.59 (C6), 126.12 (3xC4’), 127.68
(3xC2’+3xC6’), 128.39 (C2), 128.59 (3xC3’, 3xC5’), 135.82 (C7a), 146.20 (3xC1’), 162.43 (COOEt).
Anal. Calcd for C32H30N2O2: C, 80.98; H, 6.37; N, 5.90. Found: C, 80.90; H, 6.37; N, 6.05.
{3-[2-(Tritylamino)ethyl]-1H-indol-2-yl}methanol (6)
0.91 g (24 mmol) of LiAlH4 was suspended in 50 mL of dry THF under argon. The suspension was
cooled under 5 ºC with an ice bath, than 4.75 g (10 mmol) of 5 in 50 mL of THF solution was added
droppwise. After the addition, the reaction mixture was allowed to warm to rt, and was stirred for 1 h.
Cooled to 0 ºC, the excess of the LiAlH4 was destroyed with slow addition of 5 mL of 2M sodium
hydroxide solution to the reaction mixture. The inorganic salts were separated with filtration, and the
filtrate was concentrated in vacuum. The precipitated product was treated with methanol and filtered to
yield 3.0 g (69 %) as a white crystal, mp 199-200 ºC; IR (KBr): 3270 (indole-NH) cm-1; MS m/z (%): 258
(18.0), 243 (100.0), 189 (29.0), 165 (54.0), 142 (20.0), 115 (13.0) ); 1H NMR δΗ (CDCl3+DMSO-d6):
2.42 (2H, t, J=6.9 Hz; CH2NH), 2.62 (2H, br s; OH+NH), 2.93 (2H, t, J=6.9 Hz; C3-CH2), 4.76 (2H, s;
C2-CH2), 6.97 (1H, ddd, J0=7.8 + 7.0, Jm=1.0 Hz; C5-H), 7.06-7.20 (10H, m, 6-H+3xC4’-H+3xC3’-
H+3xC5’-H), 7.28-7.40 (8H, m; 3xC2’-H+3xC6’-H+C4-H+C7-H), 9.44 (1H, br s; indole-NH); 13C NMR
δC (CDCl3+DMSO-d6): 2.10 (C3-CH2), 44.24 (CH2NH), 55.90 (C2-CH2), 70.86 (NH-CPh3), 109.44 (C3),
110.79 (C7), 118.59+118.62 (C4+C5), 121.27 (C6), 126.03 (3xC4’), 127.56 (3xC2’), 128.18 (C3a),
128.51 (3xC3’+3xC5’), 135.54+135.62 (C2+C7a), 146.01 (3xC1’). Anal. Calcd for C30H28N2O2: C,
83.30; H, 6.52; N, 6.48. Found: C, 83.32; H, 6.54; N, 6.49.
3-[2-(Tritylamino)ethyl]-1H-indole-2-carbaldehyde (7)
To a magnetically stirred solution of 6.0 g (0.014 mol) of 6 in 200 mL of chloroform, manganese dioxide
(15 g, 0.17 mol) was added. The suspension was stirred for 2.5 h, flittered. The filtrate was concentrated
in vacuum to yield a yellow oil, which was crystallised from methanol to give 5.4 g (90 %) of 7, mp 187-
189 ºC; IR (KBr): 3310 (indole-NH), 1650 cm-1 (CHO); MS m/z (%): 243 (100.0), 165 (60.0), 130 (8.0),
115 (8.0), 77 (8.0). 1H NMR δΗ (CDCl3): 1.65 (1H, br s; NH), 2.55 (2H, t J=6.9 Hz; CH2NH), 3.26 (2H, t,

J=6.9 Hz; C3-CH2), 7.05-7.4 (18H, m; 3xPh+C4-H+C5-H+C6-H), 7.61 (1H, m; C7-H), 8.96 (1H, br s;
indole-NH), 10.04 (CHO). 13C NMR δC (CDCl3): 25.12 (C3-CH2), 44.84 (CH2NH), 71.01 (NH-CPh3),
112.26 (C7), 120.57 (C4), 121.68 (C5), 126.30 (3xC4’), 126.97 (C3), 127.54 (C6), 127.73 (C3a), 127.83
(3xC2’+3xC6’), 128.50 (3xC3’+3xC5’), 132.77 (C7a), 137.42 (C2), 145.93 (3xC1’), 180.72 (CHO). ).
Anal. Calcd for C30H26N2O2: C, 83.69; H, 6.09; N, 6.51. Found: C, 83.51; H, 6.09; N, 6.4.
Trityl-[2-(2-vinyl-1H-indol-3-yl)ethyl]amine (8)
To a stirred solution of 1.9 g (1.16 mmol) of methyltriphenylphosphonium bromide in 20 mL of dry THF,
1.9 mL (4.75 mmol) of 2.5 M n-butyllithium was added under argon. After stirring the yellow solution for
30 min, the solution of 0.5 g (1.16 mmol) of 7 in 20 mL of dry THF was added, and the reaction mixture
was stirred for 1 h. The THF was removed in vacuum, the residue was dissolved in dichloromethane,
washed with water, dried with magnesium sulfate, concentrated in vacuum, to give a yellow residue,
which was crystallised from methanol to yield 4.4 g (88 %) as a yellow powder, mp 182-184 ºC
decomp.; IR (KBr): 420 (indole-NH), 3060, 2930, 2870, 1640 cm-1 (vinyl CH=CH2); MS m/z (%): 24
(100.0), 194 (10.0), 185 (29.0), 165 (63.0), 156 (56.0), 129 (15.0), 115 (5.0), 91 (8.0), 77 (10.0); HRMS
Calcd for MH+: 429.23306 found 429.233167. 1H NMR δΗ (CDCl3): 1.66 (1H, br s; NH), 2.45 (2H, t,
J=7.0 Hz; CH2NH), 2.98 (2H, t, J=7.0 Hz; C3-CH2), 5.25+5.43 (2x1H, 2xdd, Jgem=0.8, Jcis=11.2 and
Jtrans=17.5 Hz, respectively; CH=CH2), 6.90 (1H, dd, J=11.2 and 17.5 Hz; CH=CH2), 6.98-7.44 (19H, m,
3xPh+C4-H+C5-H+C6-H, C7-H), 7.99 (1H, br s; indole-NH). ). 13C NMR δC (CDCl3): 25.27 (C3-CH2),
44.10 (CH2NH), 70.96 (NH-CPh3), 110.46 (C7), 110.87 (CH=CH2), 114.13 (C3), 119.37+119.48
(C4+C5), 123.05 (C6), 125.91 (CH=CH2), 126.12 (3xC4’), 127.70 (3xC2’+3xC6’), 128.65
(3xC3’+3xC5’), 128.94 (C3a), 132.96 (C7a), 136.20 (C2), 146.24 (3xC1’).
[2-(2-Vinyl-1H-indol-3-yl)ethyl]amine (9)
0.85 g (2 mmol) of 8 was dissolved in the mixture of 20 mL of acetic acid and 0.5 mL of water. The
solution was heated under argon at 60 ºC for 1 h, and then allowed to cool to rt. The resulted dark solution
was diluted with 200 mL of water, the triphenylmethanol was removed by extraction with ether. The pH
of the watery phase was adjusted to a value of 8 with sodium carbonate solution, extracted with
dichloromethane, the extract was dried with magnesium sulfate, evaporated to dryness in vacuum. The
resulted brown oil, 0.24 g (64 %) was known to be unstable,10 therefore the product was immediately
submitted to the next step without further purification.
Benzyl-[2-(2-vinyl-1H-indol-3-yl)ethyl]amine (10)
0.3 g (1.6 mmol) of 9, 0.187 g (1.75 mmol) of benzaldehyde and 3 g of molcular sieve (3A) were allowed
to stand overnight in 10 mL of methanol at 5 ºC. The molecular sieve was filtered off, the filtrate was
cooled to 0 ºC and 0.15 g (4.0 mmol) of NaBH4 was added. After stirring the reaction mixture for 1 h,
acidified with 1 N HCl to pH 1, diluted with water, extracted the excess of benzyl alcohol with diethyl
ether. The pH of the watery phase was adjusted to 8 with 25% sodium carbonate solution, extracted with
dichloromethane. The extract was dried with magnesium sulfate, and concentrated in vacuum. The
purification of the crude product with column chromatography on silica gel, using 10 % methanol in
dichloromethane as the eluent gave 0.24 g (54 %) 10 as an unstable yellow oil. IR (neat): 3030, 3070 cm-1
(vinyl CH=CH2); MS m/z (%): 276 (0.15), 261 (9.0), 157 (21.0), 120 (20.0), 91 (100.0), 77 (31.0); HRMS
Calcd for M+: 276.162648 found 276.162530. 1H NMR δΗ (CDCl3): 1.60 (1H, br s; NH), 2.95+3.02
(2x2H, 2xt; J=70 Hz; C3-CH2CH2NH), 3.80 (2H, s; NCH2Ph), 5.22+5.44 (2x1H, 2xdd, Jgem=0.8, Jcis=11.2
and Jtrans=17.5 Hz, respectively; CH=CH2), 6.87 (1H, dd, J=11.2 and 17.5 Hz; CH=CH2), 7.00-7.60 (9H,
m; Ph+C4-H+C-5H+C6-H+C7-H), 8.14 (1H, br s; indole-NH). 13C NMR δC (CDCl3): 24.68 (C3-CH2),
49.92 (CH2NH), 53.82 (NCH2Ph), 110.62 (C7), 111.22 (CH=CH2), 113.83 (C3), 119.17+119.57 (C4+C5),
123.11 (C6), 125.59 (CH=CH2), 126.83 (C4’), 127.99 (C3’+C5’), 128.35 (C2’C6’), 128.81 (C3a), 132.88
(C7a), 136.29 (C2), 140.29 (C1’).
3-[10-(2-Benzylaminoethyl)-8,9-dihydropyrido[1,2-a]indol-7-yl]propionic acid methyl ester (13)
0.1 g (0.36 mmol) of 10 and 0.05 g (0.38 mmol) of methyl 4-formylbutanoate (11a) were heated at reflux
for 4 h. The solution was concentrated in vacuum, and the crude product was purified by column
chromatography on silica gel, using 50 % acetone in hexane as the eluent, gave 67 mg (48 %) yellowish
oil. IR (neat): 1720 cm-1 (CO). ). MS m/z (%): 388 (2.0), 315 (5.0), 268 (78.0), 194 (35.0), 180 (26.0),
120 (22.0), 91 (100.0). HRMS Calcd for M+: 388.21508 found 388.21412. 1H NMR δΗ (CDCl3): 2.28 (2H,
td, J=7.2 and 1.2 Hz; C8-H2), 2.52 (4H, s; C7-CH2CH2), 2.9-3.0 (6H, m; C9-H2+C10-CH2CH2N), 3.68
(3H, s; OCH3), 3.83 (2H, s; N-CH2Ph), 6.90 (br t, J=1.2 Hz; C6-H), 7.06 (1H, ddd, J1,2=7.2, J2,3=6.7 and

J2,4=1.3 Hz; C2-H), 7.15 (1H, ddd, J3,4=7.1 and J1,3=1.2 Hz; C3-H), 7.29 (1H, ddd, J1,4=0.8 Hz; C4-H),
7.20-7.30 (5H, m; Ph), 7.49 (1H, ddd; C1-H). NOE: 6.90 (C6-H) -> 7.29 (C4-H), 2.52 (C7-CH2); 2.52
(C7-(CH2CH2) -> 6.90 (C6-H), 2.28 (C8-H2), 3.68 (OCH3); 7.49 (C1-H) -> 7.06 (C2-H), 2.95 (C10-CH2).
13C NMR δC (CDCl3): 20.33 (C9), 24.17 (C10-CH2), 24.64 (C8), 29.95 (C7-CH2), 32.90 (CH2COOCH3),
49.08 (CH2NH), 51.70 (OCH3), 53.47 (NHCH2Ph), 108.00 (C4), 108.50 (C10), 118.38 (C1), 119.25 (C7),
119.80 (C2), 121.43 (C3), 127.23 (C4’), 128.27 (C3’+C5’), 128.37 (C10a), 128.48 (C2’+C6’), 131.28
(C9a), 133.66 (C4a), 139.0 (C1’), 173.35 (COOCH3).
3-[(3’-Ethyl-4’, 5’-dihydro-1H-pyridine-6’-on-1’-yl)ethyl]-2-vinylindole (14)
0.2 g (1 mmol) of 9 and 0.19 g (1.1 mmol) of ethyl 4-formylhexanoate (11b) were heated at refluxed in
50 mL of benzene for 2.5 h. After the reaction mixture was cooled to rt, the solvent was removed in
vacuum. Purification of the residue by chromatography on a silica gel column, using 50 % acetone in
hexane as eluent, gave 0.2 g of (63 %) 14 as a yellow gum. IR (neat): 3305 (indole-NH), 2920,2965,2870
(vinyl CH=CH2), 1650 cm-1 (CO). MS m/z (%): 294 (12.0), 169 (100.0), 156 (57.0), 138 (14.0), 129
(20.0), 110 (19.0), 39 (30.0). 1H NMR δΗ (CDCl3): 0.84 (3H, t; J=7.5 Hz; C3’-CH2CH3), 1.87 (2H, qtd,
J=7.5, 1.0, 1.4 Hz; C3’-CH2CH3), 2.12 (2H, ttd, J=8.0, 1.0 and 1.2 Hz; C4’-H2), 2.45 (2H, t, J=8.0 Hz;
C5’-H2), 3.06 (2H, t, J=7.0 Hz; C3-CH2), 3.65 (2H, t, J=7.0 Hz; CH2N), 5.24+5.48 (2x1H, 2xd, Jcis=11.2
and Jtrans=17.5 Hz, respectively; CH=CH2), 5.40 (1H, tt, J=1.4 and 1.2 Hz; C2’-H), 6.83 (1H, dd, J=11.2
and 17.5 Hz; CH=CH2), 7.08 (1H, ddd, Jo=7.8 and 7.0, Jm=1.0 Hz; C5-H), 7.17 (1H, ddd, Jo=8.1 and 7.0,
Jm=1.3 Hz; C6-H), 7.28 (1H, ddd, Jo=8.1, Jm=1.0, Jp=0.9 Hz; C7-H), 7.59 (1H, ddd, Jo=7.8, Jm=1.3, Jp=0.9
Hz; C4-H), 8.22 (1H, br s; indole-NH). 13C NMR δC (CDCl3): 12.30 (C3’-CH2CH3), 23.04 (C3-CH2),
24.10 (C4’), 26.61 (C3’-CH2CH3), 31.33 (C5’), 47.51 (CH2N), 110.63 (C7), 111.34 (CH=CH2), 112.76
(C3), 118.90+119.62 (C5+C4), 120.81 (C3’), 123.10 (C6), 124.08 (C2’), 125.47 (CH=CH2), 128.75 (C3a),
133.17 (C7a), 136.29 (C2), 168.84 (NCO).
[2-(1-Methyl-2-vinyl-1H-indol-3-yl)ethyl]tritylamine (16)
25 mg (0.6 mmol) of 60 % NaH was suspended in 5 mL of dry DMF, then 0.21 g (0.5 mmol) of 8 was
added in a solution of 2 mL DMF. After stirring the dark green solution for 15 min, 0.14 g (1 mmol) of
methyliodide was added. The mixture was stirred for an other 30 min. The solvent and the excess of
methyliodide was removed in vacuum, the residue was dissolved in dichloromethane, washed with water,
dried over magnesium sulfate and evaporated to yield a yellow oil, which was crystallised from acetone-
methanol as a yellow powder, 0.137 g (89 %), mp 135-136 ºC decomp. IR (KBr): 3060, 3010, 2920, 1610
cm-1 (vinyl CH=CH2). MS m/z (%):243 (100.0), 199 (27.0), 170 (79.0), 165 (56.0), 154 (12.0), 128 (8.0),
115 (8.0), 91 (6.0), 77 (5.0). 1H NMR δΗ (CDCl3): 1.7 (1H, br s; NH), 2.47 (2H, t, J=7.1 Hz; CH2NH),
3.03 (2H, t, J=7.1 Hz; C3-CH2), 3.69 (3H, s; NCH3), 5.46+5.55 (2x1H, 2xdd, Jgem=1.5, Jcis=11.7 and
Jtrans=17.7 Hz, respectively; CH=CH2), 6.76 (1H, dd, J=17.7 and 11.7; CH=CH2), 7.00-7.50 (19H, m;
3xPh+C4-H+C5-H+C6-H+C7-H). 13C NMR δC (CDCl3): 26.06 (C3-CH2), 30.75 (NCH3), 44.41
(CH2NH), 71.04 (NHCPh3), 108.93 (C7), 112.21 (C3), 117.98 (CH=CH2), 119.06+119.22 (C4+C5),
122.08 (C6), 126.13 (CH=CH2+3xC4’), 127.70 (3xC2’+3xC6’), 127.92 (C3a), 128.69 (3xC3’+3xC5’),
134.96 (C7a), 137.44 (C2), 146.25 (3xC1’). Anal. Calcd for C32H30N2: C, 86.84; H, 6.83; N, 6.33. Found:
C, 86.76; H, 6.84; N, 6.21.
2-(1-Methyl-2-vinyl-1H-indol-3-yl)ethylamine (17)
To prepare 17, the same procedure was used, as in the case of 9, starting from 0.88 g (2 mmol) of 16. The
resulted crude product, 0.29 g (72 %) was unstable, and used for the next step without further purification.
Benzyl-[2-(1-methyl-2-vinyl-1H-indol-3-yl)ethyl]amine (18)
For the preparation of 18, the same procedure was used, as in the case of 10, starting from 0.13 g (0.65
mmol) of 17. Chromatographic purification of the crude product gave 0.11 g (58 %) of 17 as an unstable
yellow oil. IR (neat): 1610 cm-1 (vinyl CH=CH2). MS m/z (%): 290 (4.0), 275 (5.0), 171 (80.0), 158
(20.0), 120 (26.0), 91 (100.0); HRMS Calcd for M+: 290.1783 found 290.1779. 1H NMR δΗ (CDCl3):
1.85 (1H, br s; NH), 2.95+3.08 (2x2H, 2xt, J=7.2 Hz; C3-CH2CH2NH), 3.72 (3H, s; NCH3), 3.81 (2H, s;
NHCH2Ph), 5.49+5.61 (2x1H, 2xdd, Jgem=1.5, Jcis=11.7 and Jtrans=17.8 Hz, respectively; CH=CH2), 6.79
(1H, dd, J=17.8 and 11.7; CH=CH2), 7.05-7.60 (9H, m; Ph+C4-H+C5-H+C6-H+C7-H). 13C NMR δC
(CDCl3): 25.41 (C3-CH2), 30.76 (NCH3), 49.95 (CH2NH), 53.83 (NHCH2Ph), 109.10 (C7), 112.02 (C3),
118.21 (CH=CH2), 119.02+119.2 (C4+C5), 122.19 (C6), 126.02 (CH=CH2), 126.85 (C4’), 127.78 (C3a),
128.05 (C3’+C6’), 134.92 (C7a), 137.50 (C2), 140.14 (C1’).

5-Ethyl-1-[2-(1-methyl-2-vinyl-1H-indol-3-yl)ethyl]-3,4-dihydro-1H-pyridin-2-one (19)
The same method was used to prepare 19, as for 14, starting from 0.2 g (1 mmol) of 17. The
chromatographic purification of the crude product yield 0.22 g (71 %) of 19 as a light gum. IR (neat):
2960, 2910, 2880 (vinyl CH=CH2) 1660 (CO) cm-1. MS m/z (%): 308 (34.0), 183 (80.0), 170 (100.0), 154
(16.0), 128 (19.0), 115 (12.0), 40 (42.0); HRMS Calcd for MH+: 309.19669 found 309.19584. 1H NMR
δΗ (CDCl3): 0.90 (3H, t, J=7.3 Hz; C3’-CH2CH3), 1.93 (2H, qtd, J=7.3, 1.0 and 1.4 Hz; C3’-CH2CH3),
2.15 (2H, ttd, J=8.0, 1.0 and 1.2 Hz; C4’-H2), 2.46 (2H, t, J=8.0 Hz; C5-H2), 3.11 (2H, t, J=7.4 Hz; C3-
CH2), 3.66 (2H, t, J=7.4 Hz; CH2N), 3.74 (3H, s; NCH3), 5.53+5.69 (2x1H, 2xdd, Jgem=1.3, Jcis=11.8 and
Jtrans=17.8 Hz, respectively; CH=CH2), 5.54 (1H, tt, J=1.4 and 1.2 Hz; C2’-H), 6.79 (1H, dd, J=17.8 and
11.8 Hz; CH=CH2), 7.10 (1H, ddd, Jo=7.8 and 7.0, Jm=1.2 Hz; C5-H), 7.21 (1H, ddd, Jo=8.2 and 7.0,
Jm=1.2 Hz; C6-H), 7.26 (1H, ddd, Jo=8.2, Jm=1.2, Jp=0.8 Hz; C7-H), 7.63 (1H, ddd, Jo=7.8, Jm=1.2, Jp=0.8
Hz; C4-H). 13C NMR δC (CDCl3): 12.29 (C3’-CH2CH3), 23.88 (C3-CH2), 24.14 (C4’), 26.66 (C3’-
CH2CH3), 30.75 (NCH3), 31.82 (C5’), 47.25 (CH2N), 109.08 (C7), 110.98 (C3), 118.11 (CH=CH2),
118.80+119.32 (C4+C5), 120.88 (C3’), 122.24 (C6), 123.93 (C2’), 125.82 (CH=CH2), 127.79 (C3a),
134.96 (C7a), 137.49 (C2), 168.77 (NCO).
(±)-(7aR,8R)-8-Ethyl-5-methyl-7a,8,9,10,13,14-hexahydro-5H-pyrido[1',2':1,8]azocino[5,4-b]indol-11-
one (20) and (±)(7aR,8S)-8-ethyl-5-methyl-7a,8,9,10,13,14-hexahydro-5H-pyrido[1',2':1,8]azocino[5,4-
b]indol-11-one (21)
0.2 g (3.2 mmol) of 19 and 20 mg of p-toluolsulfonic acid monohydride was dissolved in 20 mL of
toluene. The mixture was heated at reflux for 3 h. The solvent was removed in vacuum, and the residue
was purified by preparative TLC (eluent: 10% methanol in dichloromethane), which yielded 51 mg
(25 %) of 20 as a yellow gum. IR (neat): 3020 (vinyl CH=CH2) 1630 (CO) cm-1. MS m/z (%): 308
(100.0), 293 (32.0), 279 (45.0), 251 (10.0), 194 (27.0), 182 (64.0), 167 (46.0), 54 (21.0), 39 (22.0);
HRMS Calcd for M+: 308.18886 found 308.18873. 1H NMR δΗ (CDCl3): 0.88 (3H, t, J=7.5 Hz; C8-
CH2CH3), 1.22+1.45 (2x1H, 2xdqd, Jgem=13.7, Jvic=7.5+8.5 and 7.5+4.8 Hz, respectively; C8-CH2CH3),
1.48 (1H, dddd, Jgem=13.5, J9β,10α=9.0, J9β,10β=6.2, J8α,9β=8.3 Hz; C9-Hβ), 1.64 1H, ddddd, J7aβ,8α=6.2,
J8α,9α=4.2 Hz; C8-Hα), 2.04 (1H, dddd, J9α,10α=6.6, J9α,10β=5.3 Hz; C9-Hα), 2.35+2.46 (2x1H, 2xddd,
Jgem=17.5 Hz; C10-H2), 3.00-3.15 (2H, m; C14-H2), 3.65 (3H, s; NCH3), 4.00+4.11 (2x1H, 2xddd,
Jgem=13.8, J13,14=5.8+3.2 and 8.7+3.6 Hz, respectively; C13-H2), 4.05 (1H, ddd, J7,7aβ=8.0, J6,7aβ=1.2 Hz;
C7a-Hβ), 5.72 (1H, dd, J6,7=11.0 Hz; C7-H), 6.71 (1H, dd, J=11.0 Hz; C6-H), 7.11 (1H, ddd, J1,2=7.8,
J2,3=6.4, J2,4=1.7 Hz; C2-H), 7.23 (1H, ddd, J3,4=8.2, J1,3=1.3 Hz; C3-H), 7.26 (1H, ddd, J1,4=0.7 Hz; C4-
H), 7.52 (1H, ddd, J=0.7 Hz; C1-H). NOE: 1.64 (C8-Hα) -> 5.72 (C7-H), 4.05 (7a-Hβ), 0.87+1.45+1.22
(C8-Et), 2.35 (C10-Hα), 2.04 (C9-Hα); 5.72 (C7-H) -> 6.71 (C6-H), 1.64 (C8-Hα), 2.04 (C9-Hα), 4.05
(C7a-Hβ); 6.71 (C6-H) -> 5.72 (C7-H), 3.65 (NCH3). 13C NMR δC (CDCl3): 11.46 (C8-CH2CH3), 23.06
(C9), 25.37 (C8-CH2CH3), 25.40 (C14), 29.86 (NCH3), 30.61 (C10), 40.20 (C13), 40.89 (C8), 59.33
(C7a), 108.90 (C4), 112.96 (C14a), 118.60 (C1), 119.26 (C2), 122.48 (C3), 122.63 (C6), 127.48 (C14b),
131.95 (C5a), 132.77 (C7), 137.23 (C4a), 170.05 (C11) and 18 mg (9 %) of 21 as a yellow gum. IR
(neat): 3020 (vinyl CH=CH2) 1630 (CO) cm-1. MS m/z (%): 308 (100.0), 293 (36.0), 279 (55.0), 251
(18.0), 194 (30.0), 182 (48.0), 167 (38.0), 54 (27.0), 39 (30.0); HRMS Calcd for M+: 308.1888 found
308.1888. 1H NMR δΗ (CDCl3): 0.77 (3H, t, J=7.3 Hz; C8-CH2CH3), 1.20-1.40 (2H, m; C8-CH2CH3),
1.70-1.95 (3H, m; C8-Hβ+C9-H2), 2.40-2.60 (2H, m; C10-H2), 2.68+3.26 (2x1H, 2xddd, Jgem=16.0,
J13,14=8.8+1.7 and 8.5+1.5 Hz, respectively; C14-H2), 3.09+4.56 (2x1H, 2xddd, Jgem=13.5 Hz; C13-H2),
3.67 (3H, s; NCH3), 3.95 (1H, dddd, J7,7aβ=8.6, J7aβ,8β=3.8, J6,7aβ=1.0, Jb=1.0 Hz; C7a-Hβ), 5.96 (1H, dd,
J6,7=11.0 Hz; C7-H), 6.72 (1H, dd J=11.0 Hz; C6-H), 7.13 (1H, ddd, J1,2=7.9, J2,3=6.6, J2,4=1.4 Hz; C2-H),
7.25 (1H, ddd, J3,4=8.2, J1,3=1.2 Hz; C3-H), 7.28 (1H, ddd, J1,4=0.7 Hz; C4-H), 7.57 (1H, ddd, J=0.4 Hz;
C1-H). NOE: 3.95 (C7a-Hβ)-> 1.80 (C8-Hβ), 3.09 (C13-Hβ), 0.77+1.28 (C8-Et), 3.26 (C14-Hβ), 5.96 (C7-
H); 5.96 (C7-H) -> 6.72 (C6-H), 1.28 (C8-CH2CH3), 3.95 (C7a-Hβ); 3.67 (NCH3) -> 6.72 (C6-H), 7.28
(C4-H). 13C NMR δC (CDCl3): 11.45 (C8-CH2-CH3), 22.73 (C9), 24.79 (C14), 25.21 (C8-CH2CH3),
30.06 (NCH3), 30.77 (C10), 38.98 (C8), 41.88 (C13), 56.83 (C7a), 108.97 (C4), 113.66 (C14a), 118.58
(C1), 119.30 (C2), 122.38 (C3), 122.58 (C6), 127.42 (C14b), 128.90 (C7), 133.37 (C5a), 137.27 (C4a),
169.77 (C11).
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