Aromatization of 1,6,7,7a-tetrahydro-2H-indol-2-ones by a novel process. Preparation of key-intermediate methyl 1-benzyl-5-methoxy-1H-indole-3-acetate and the syntheses of serotonin, melatonin, and bufotenin

Article abstract of DOI:10.1021/jo0110597

Imine 7 of 1,4-cyclohexanedione mono-ethylene ketal 6 was reacted with maleic anhydride, affording the cyclized adduct 8. Methyl esterification of 8, accompanied by transacetalization, led to the dihydrooxindole derivative 10. Aromatization of 10 was then accomplished with POCl₃, leading directly to the key-intermediate title compound 11 in 74% yield from ketone 6. Serotonin, melatonin, and bufotenin were then obtained by standard reactions.

Full text of DOI:10.1021/jo0110597

2252
J . Org. Chem. 2002, 67, 2252-2256
Ar om a tiza tion of 1,6,7,7a -Tetr a h yd r o-2H-in d ol-2-on es by a Novel
P r ocess. P r ep a r a tion of Key-In ter m ed ia te Meth yl
1-Ben zyl-5-m eth oxy-1H-in d ole-3-a ceta te a n d th e Syn th eses of
Ser oton in , Mela ton in , a n d Bu foten in
Gilbert Revial,† Ivan J abin,‡ Sethy Lim,† and Michel Pfau*,†
Laboratoire de Chimie Organique, CNRS (ESA 7084), ESPCI, 10 rue Vauquelin,
75231 Paris Cedex 05, France, and URCOM, Universite´ du Havre, Faculte´ des Sciences
et Techniques, 25 rue Philippe Lebon BP 540, 76058 Le Havre Cedex, France
michel.pfau@espci.fr
Received November 6, 2001
Imine 7 of 1,4-cyclohexanedione mono-ethylene ketal 6 was reacted with maleic anhydride, affording
the cyclized adduct 8. Methyl esterification of 8, accompanied by transacetalization, led to the
dihydrooxindole derivative 10. Aromatization of 10 was then accomplished with POCl3, leading
directly to the key-intermediate title compound 11 in 74% yield from ketone 6. Serotonin, melatonin,
and bufotenin were then obtained by standard reactions.
In tr od u ction
The Michael addition of imines reacting via their
secondary enamines tautomers has been well studied,
and many synthetic applications have been described.7
The reaction has been also extended to enantioselective
additions.8
Serotonin 1, melatonin 2, and bufotenin 3 are very
potent biologically active compounds and several syn-
theses have been reported:
One of the first reported reactions concerned the
addition of the N-cyclohexyl imine of cyclohexanone (4)
with maleic anhydride leading to compound 5 having the
indole-3-acetic acid skeleton9 (Scheme 1).
Compounds of type 5 appear to be good candidates for
the syntheses of tryptamine derivatives. Thus, our syn-
theses would start with an imine of 1,4-cyclohexanedione
mono-ethyleneketal, the reaction of which with maleic
anhydride could lead to a compound of type 5 from which
the needed functionality in the 5-position could be
obtained. Aromatization would then lead to a common
The 5-alkoxytryptamine derivatives are principally
synthesized by the Fischer method (e.g., melatonin1) or
the related J app-Klingeman/Abramovitch-Shapiro re-
actions, as well as by the Bischler synthesis. In these
methods, the six-carbon atoms ring of the targets is
already aromatic in the corresponding starting materials.
Alternatively, the syntheses start from a fully aromatic
skeleton, either from 5-alkoxyindoles with introduction
of the lateral chain (e.g., serotonin,2,3a melatonin,3b and
bufotenin2a) or from tryptamine derivatives with intro-
duction of the 5-alkoxy group (e.g., serotonin,4,5 melato-
nin,4,6 and bufotenin4).
(4) Somei, M.; Yamada, F.; Morikawa, H. Heterocycles 1997, 46, 91-
94.
(5) Saito, K.; Kikugawa, Y. J . Heterocycl. Chem. 1979, 16, 1325-
1328.
(6) Somei, M.; Fukui, Y.; Hasegawa, M.; Oshikiri, N.; Hayashi, T.
Heterocycles 2000, 53, 1725-1736.
(7) Pfau, M.; Ribie`re, C. J . Chem. Soc., Chem. Commun. 1970, 66-
67. Pfau, M.; Ribie`re, C. Bull. Soc. Chim. Fr. 1971, 2584-2590.
Ninomiya, I.; Naito, T.; Higuchi, S.; Mori, T. J . Chem. Soc., Chem.
Commun. 1971, 457-458. Pfau, M. (CNRS-ANVAR), 1974, CH 605
518; 1976, CH 611 589; 1976, F 7 622 823; 1977, CH 612 660; 1978,
F 2 359 807. Quick, J . Tetrahedron Lett. 1977, 327-330. Pfau, M.;
Ughetto-Monfrin, J . Tetrahedron 1979, 35, 1899-1904. Pfau, M.;
Ughetto-Monfrin, J .; J oulain, D. Bull. Soc. Chim. Fr. 1979, 627-632.
Kametani, T.; Surgenor, S. A.; Fukumoto, K. Heterocycles 1980, 14,
303-310. Hickmott, P. W. Tetrahedron 1982, 38, 3363-3446 (see p
3410). Miyajima, J .; Ito, K. Bull. Chem. Soc. J pn. 1985, 58, 2659-
2663. Hickmott, P. W.; Rae, B. Tetrahedron Lett. 1985, 26, 2577-2580.
Smith, A. B., III; Leenay, T. L. Tetrahedron Lett. 1988, 29, 2787-2790.
Dickman, D. A.; Heathcock, C. H. J . Am. Chem. Soc. 1989, 111, 1528-
1530. Smith, A. B., III; Leenay, T. L. J . Am. Chem. Soc. 1989, 111,
5761-5768. Hickmott, P. W.; J utle, K. K. J . Chem. Soc., Perkin Trans.
1 1990, 2399-2402. Heathcock, C. H.; Norman, M. H.; Dickman, D.
A. J . Org. Chem. 1990, 55, 798-811. Paulvannan, K.; Stille, J . R. J .
Org. Chem. 1992, 57, 5319-5328. Pfau, M.; Chiriacescu, M.; Revial,
G. Tetrahedron Lett. 1993, 34, 327-330. Pfau, M.; Felk, A.; Revial, G.
Tetrahedron Lett. 1994, 35, 1549-1552. Yamazaki, T.; Hiraoka, S.;
Kitazume, T. J . Org. Chem. 1994, 59, 5100-5103. Bonjoch, J .; Sole´,
D.; Garcia-Rubio, S.; Bosch, J . J . Am. Chem. Soc. 1997, 119, 7230-
7240. Gomaa, M. A. M.; Dopp, D. J . Heterocycl. Chem. 1998, 35, 339-
341. Lim, S.; J abin, I.; Revial, G. Tetrahedron Lett. 1999, 40, 4177-
4180.
We report here a new approach for the synthesis of
5-alkoxytryptamine derivatives which involve the syn-
thesis of the corresponding bicyclic skeleton, followed by
aromatization.
† Laboratoire de Chimie Organique, CNRS (ESA 7084).
‡ URCOM, Universite´ du Havre.
(1) Marais, W.; Holzapfel, C. W. Synth. Commun. 1998, 28, 3681-
3691. Hwang, K.-J .; Lee, T.-S. Synth. Commun. 1999, 29, 2099-2104.
Verspui, G.; Elbertse, G.; Sheldon, F. A.; Hacking, M. A. P. J .; Sheldon,
R. A. J . Chem. Soc., Chem. Commun. 2000, 1363-1364.
(2) (a) Speeter, M. E.; Anthony, W. C. J . Am. Chem. Soc. 1954, 76,
6208-6210. (b) Noland, W. E.; Hovden, R. A. J . Org. Chem. 1959, 24,
894-895.
(3) (a) Ek, A.; Witkop, B. J . Am. Chem. Soc. 1954, 76, 5579-5588.
(b) Szmuszkovicz, J .; Anthony, W. C.; Heinzelman, R. V. J . Org. Chem.
1960, 25, 857-859.
10.1021/jo0110597 CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/07/2002

Aromatization of 1,6,7,7a-Tetrahydro-2H-indol-2-ones
J . Org. Chem., Vol. 67, No. 7, 2002 2253
Sch em e 1
Sch em e 3
an oxindole, such a process can occur with compound 1012
since a CH2CH2 moiety is present in the six-atom ring,
thus avoiding a hydrogenolysis step.
Sch em e 2
Further standard reactions from indole 11 led to
serotonin 1 and melatonin 2, as well as to bufotenin 3
(Scheme 5).
Con clu sion
We have thus shown that key-intermediate 11, suited
for the preparation of 5-alkoxytryptamine derivatives,
can be readily synthesized through a novel aromatization
process, in good yield from commercially available ketone
6.
intermediate suitable to synthesize either serotonin and
melatonin or bufotenin.
Resu lts a n d Discu ssion
Exp er im en ta l Section
The benzyl imine (7) of commercial monoprotected 1,4-
cyclohexanedione 6 was reacted with maleic anhydride
to afford the crystalline adduct 8 in 96% yield from 6
(Scheme 2).
Ester 9 was readily obtained from acid 8 (90% yield),
and it was observed that if the esterification time was
extended from 0.5 to 4 h, a transacetalization followed,
leading directly to the desired compound 10 in 91% yield
from ketone 6 (Scheme 3).
Gen er a l. TLC was performed with glass plates (0.25 mm)
precoated with silica gel, and flash chromatography (FC) was
carried out with silica gel (200-450 mesh), using EtOAc/
hexanes as eluents (proportions given) unless otherwise stated.
GC-MS was performed with a HP 5890 GC apparatus (equipped
with a 12 m × 0.20 mm dimethylpolysiloxane capillary column)
linked to a HP 5971 EIMS. 1H and 13C NMR spectra of CDCl3
solutions were respectively recorded at 300 and 75.5 MHz.
Anhydrous solvents were freshly distilled under argon, CH2-
Cl2 over CaCl2, ether and THF over Na/benzophenone. All
reactions were performed under a nitrogen atmosphere. Unless
otherwise indicated, after extractions, organic phases were
washed with water and brine, dried over MgSO4, filtered, and
evaporated under reduced pressure.
N-(1,4-Dioxa sp ir o[4.5]d ecyl-7-id en e)ben zyla m in e (7).
A solution of 3.90 g (25.0 mmol) of commercial 1,4-cyclohex-
anedione mono-ethylene ketal 6 and 3.00 mL (27.5 mmol) of
benzylamine in 25 mL of toluene was heated under reflux in
a Dean-Stark apparatus for 6 h. The solvent was removed
under reduced pressure affording the crude imine 7 which was
directly used for the next step. An analytical sample was
obtained by molecular distillation: EIMS m/z (rel int) 245 (M+,
18), 173 (6), 159 (17), 158 (14), 154 (11), 126 (9), 101 (52), 91
The next step was the aromatization of compound 10.10
The reaction of POCl3 is known to transform oxindoles
into 2-chloroindoles which in turn can lead to indoles by
hydrogenolysis.11 Thus, ester 10 was reacted with POCl3
and, to our delight, indole 11 was directly obtained in
77% yield. Key-intermediate 11 was also obtained in 74%
yield from ketone 6 without purification of the intermedi-
ates.
The mechanism proposed for this novel type of aroma-
tization is shown in Scheme 4. Indeed, while HCl
elimination is not possible in the case reported above with
(8) Pfau, M.; Revial, G.; Guingant, A.; D’Angelo, J . J . Am. Chem.
Soc. 1985, 107, 273-274. Pfau, M.; Revial, G. (KIREX) PCT WO 85
04873, 1985. Mech a n ism s: Sevin, A.; Tortajada, J .; Pfau, M. J . Org.
Chem. 1986, 51, 1, 2671-2675. Sevin, A.; Masure, D.; Giessner-Prettre,
C.; Pfau, M. Helv. Chim. Acta 1990, 73, 552-573. Pfau, M.; Tomas,
A.; Lim, S.; Revial, G. J . Org. Chem. 1995, 60, 0, 1143-1147. J abin,
I.; Revial, G.; Tomas, A.; Lemoine, P.; Pfau, M. Tetrahedron: Asym-
metry 1995, 6, 1795-1812. Lucero, M. J .; Houk, K. N. J . Am. Chem.
Soc. 1997, 119, 9, 826-827. Review s: Revial, G.; Pfau, M. Org. Synth.
1991, 70, 35-46. Oare, D. A.; Heathcock, C. H. Top. Stereochem. 1991,
20, 87-170 (see p 114). D′Angelo, J .; Desmae¨le, D.; Dumas, F.;
Guingant, A. Tetrahedron: Asymmetry 1992, 3, 459-505. D′Angelo,
J .; Cave´, C.; Desmae¨le, D.; Dumas, F. Trends Org. Chem. 1993, 4, 555-
616. Guingant, A. Advances in Asymmetric Synthesis; J AI Press Inc.:
Greenwich, CT, 1997; vol. 2, 159-170. Recen t d evelop m en ts a n d
a p p lica tion s: Revial, G.; J abin, I.; Redolfi, M.; Pfau, M. Tetrahe-
dron: Asymmetry 2001, 12, 1683-1688 and ref 1 included.
(9) Pfau, M.; Ribie`re, C. Bull. Soc. Chim. Fr. 1976, 776-780.
(10) To this end, a preliminary attempt was tried with a first step
involving O-alkylation of compound 10 with Me2SO4 but aromatization
of the six-atom ring was observed instead, giving oxindole 10a , the
amidation of which with Me2NH afforded 10b.
(11) Kubo, A.; Nakai, T. Synthesis 1980, 365-366.

2254 J . Org. Chem., Vol. 67, No. 7, 2002
Revial et al.
Sch em e 4
cm-1; 1H NMR δ 1.18-1.34 (m, 1H), 1.67 (td, J ) 13.6, 3.7 Hz,
1H), 1.74-1.83 (m, 1H), 2.12-2.22 (m, 1H), 2.45 (d, J ) 14.3
Hz, 1H), 2.85 (dd, J ) 14.3, 2.7 Hz, 1H), 3.31 (d, J ) 16.3 Hz,
1H), 3.43 (d, J ) 16.3 Hz, 1H), 3.62-3.72 (m, 4H), 3.85-4.02
(m, 4H), 4.26 (d, J ) 15.1 Hz, 1H), 4.96 (d, J ) 15.1 Hz, 1H),
7.15-7.35 (m, 5H); 13C NMR δ 27.8, 28.7, 32.0, 36.3, 44.1, 51.9,
59.4, 64.4, 64.6, 109.5, 124.3, 127.3, 127.8 (2C), 128.5 (2C),
137.5, 153.2, 170.61, 170.64.
Sch em e 5
Meth yl 1-Ben zyl-5-m eth oxy-2-oxo-2,6,7,7a -tetr a h yd r o-
1H-in d ole-3-a ceta te (10). Crude imine 7 was obtained as
above, using in this instance 10.1 g (65.0 mmol) of 6 and 8.00
mL (73.3 mmol) of benzylamine. Its reaction performed as
above with maleic anhydride (7.32 g, 74.7 mmol) in 20 mL of
THF led to crude acid 8 which was dissolved in a mixture of
200 mL of MeOH, 20 mL of 2,2-dimethoxypropane, and 3.00 g
of PTSA. The solution was heated at reflux temperature for 4
h and evaporated. The residue was diluted with EtOAc and
washed with a saturated solution of NaHCO3. A FC (80:20)
afforded 80 mg of oxindole 10a (vide infra) and 19.3 g (91%
yield from ketone 6) of viscous ester 10: HRMS (EI) calcd for
C
19H21NO4 m/z 327.1471, found m/z 327.1468; EIMS m/z (rel
int) 327 (M+, 51), 312 (5), 296 (5), 268 (21), 267 (29), 252 (13),
195 (11), 194 (14), 176 (20), 91 (base), 77 (7); IR (film) 1735,
1660, 1600 cm-1; 1H NMR δ 1.33-1.50 (m, 1H), 2.11-2.21 (m,
1H), 2.32 (dd, J ) 8.5, 3.3 Hz, 2H), 3.33 (d, J ) 16.3 Hz, 1H),
3.43 (d, J ) 16.3 Hz, 1H), 3.65 (s, 3H), 3.70 (s, 3H), 3.78 (dd,
J ) 13.0, 4.6 Hz, 1H), 4.39 (d, J ) 15.4 Hz, 1H), 4.85 (d, J )
15.4 Hz, 1H), 5.56 (s, 1H), 7.19-7.38 (m, 5H); 13C NMR δ 27.4,
27.7, 28.8, 44.5, 51.9, 55.2, 58.3, 90.7, 116.2, 127.2, 127.7 (2C),
128.4 (2C), 137.9, 152.4, 164.2, 171.1, 172.2.
(base); 1H NMR (C6D6) δ 1.68-1.76 (m, 2H), 1.83-1.90 (m, 2H),
2.32 (dd, J ) 7.0, 6.6 Hz, 2H), 2.71 (dd, J ) 7.0, 6.6 Hz, 2H),
3.52-3.57 (m, 4H), 4.46 (s, 2H), 7.00-7.47 (m, 5H); 13C NMR
(C6D6) δ 25.8, 35.2, 35.9, 37.1, 55.1, 64.9 (2C), 108.8, 127-129
(5C), 142.0, 170.7.
1′-Ben zyl-2′-oxo-1′,2′,4′,6′,7′,7a ′-h exa h yd r osp ir o[1,3-d i-
oxola n e-2,5′-[5H]in d ole]-3′-a cetic Acid (8). A solution of
3.00 g (30.0 mmol, 1.2 equiv) of maleic anhydride in 12 mL of
THF was added dropwise to a solution of the crude imine 7
above, in 10 mL of THF at 0 °C. After stirring for 1 h, the
crystalline adduct 8 was filtered. Evaporation of the solvent
gave a residue which was purified by FC (80:20, then 100:0)
affording additional adduct 8, for a total of 8.25 g (96% yield
from 6). An analytical sample was obtained by recrystalliza-
tion: mp 199-201 °C (EtOAc/MeOH); calcd for C19H21NO5, C
66.46, H 6.16, N 4.08; found C 66.4, H 6.2, N 4.0; EIMS m/z
(rel int) 299 (M+ - 44, 10), 297 (25), 210 (13), 99 (38), 91 (base),
Meth yl 1-Ben zyl-5-m eth oxy-1H-in d ole-3-a ceta te (11).
To a solution of 6.50 g (19.9 mmol) of ester 10 in 22 mL of
acetonitrile and 5.3 mL (65.7 mmol, 3 equiv) of pyridine was
added dropwise 4.10 mL (44.0 mmol, 2 equiv) of POCl3, and
the mixture was stirred at 60 °C for 1 h. After cooling, water
was added, and the mixture was extracted with ether. The
organic layer was washed with a saturated solution of NaH-
CO3, followed by the usual workup. A FC (20:80) afforded 5.03
g of oily indole 11 in 82% yield (75% from ketone 6): HRMS
(CI, NH3) calcd for C19H19NO3 m/z 309.1365, found m/z
309.1360; EIMS m/z (rel int) 309 (M,+ 63), 250 (base), 159 (19),
144 (20), 91 (99); IR (film) 2940, 1740 cm-1; 1H NMR δ 3.68 (s,
3H), 3.73 (d, J ) 0.7 Hz, 2H), 3.84 (s, 3H), 5.19 (s, 2H), 6.82
(dd, J ) 8.8, 2.2 Hz, 1H), 7.04-7.30 (m, 8H); 13C NMR δ 31.2,
50.2, 51.9, 55.8, 100.9, 106.9, 110.6, 112.2, 126.8 (2C), 127.6,
127.7, 128.3, 128.7 (2C), 131.8, 137.5, 154.1, 172.4.
1-Ben zyl-5-m eth oxy-1H-in d ole-3-a ceta m id e (12). A so-
lution of 6.70 g (21.7 mmol) of indole 11 in 100 mL of MeOH
saturated with NH3 was stirred at room temperature for 8
days, leading to crystalline amide 8. The suspension was
flushed with nitrogen to remove NH3 and filtered. After
washing with MeOH, the crystals were dried over P2O5,
affording 5.29 g of pure 12 (83% yield13): mp 157 °C (MeOH)
[lit.14 156-157 °C (EtOH)]; calcd for C18H18N2O2, C 73.45, H
6.16, N 9.52; found C 73.3, H 6.1, N 9.5; EIMS m/z (rel int)
294 (M,+ 42), 276 (20), 250 (93), 91 (base); IR (CDCl3) 3380,
1
65 (14); IR (Nujol) 1715, 1645 cm-1; H NMR δ 1.29 (qd, J )
12, 4 Hz, 1H), 1.69 (dt, J ) 14, 3.7 Hz, 1H), 1.81 (qd, J ) 12,
3 Hz, 1H), 2.18-2.27 (m, 1H), 2.43 (d, J ) 14 Hz, 1H), 2.88
(dd, J ) 14, 2.6 Hz, 1H), 3.40 (d, J ) 15.5 Hz, 1H), 3.47 (d, J
) 15.5 Hz, 1H), 3.73 (dd, J ) 11.5, 5.8 Hz, 1H), 3.84-4.04 (m,
4H), 4.29 (d, J ) 15.1 Hz, 1H), 4.99 (d, J ) 15.1 Hz, 1H), 7.30-
7.37 (m, 5H), carboxylic H not observed; 13C NMR δ 27.7, 31.9,
32.0, 36.2, 44.5, 60.6, 64.6, 64.9, 109.5, 123.3, 127.9, 128.0 (2C),
128.9 (2C), 136.6, 154.6, 170.7, 172.6.
Meth yl 1′-Ben zyl-2′-oxo-1′,2′,4′,6′,7′,7a ′-h exa h yd r osp ir o-
[1,3-d ioxola n e-2,5′-[5H]in d ole]-3′-a ceta te (9). A mixture of
1.00 g (2.90 mmol) of acid 8, 3 mL of methanol, 1 mL (3 equiv)
of 2,2-dimethoxypropane, and a catalytic amount of PTSA was
heated at reflux temperature for 30 min. After evaporation of
the solvent and FC (40:60, then 100:0), 0.97 g (90% yield) of
oily ester 9 was obtained: HRMS (EI) calcd for C20H23NO5 m/z
357.1576, found m/z 357.1579; EIMS m/z (rel int) 357 (M+, 7),
326 (2), 312 (1), 297 (1), 99 (base), 91 (34); IR (film) 1736, 1670

Aromatization of 1,6,7,7a-Tetrahydro-2H-indol-2-ones
J . Org. Chem., Vol. 67, No. 7, 2002 2255
3140, 1690 cm-1; 1H NMR δ 3.70 (s, 2H), 3.83 (s, 3H), 5.26 (s,
2H), 5.52 (br s, 1H), 5.69 (br s, 1H), 6.86 (dd, J ) 8.8, 2.6 Hz,
1H), 7.00 (d, J ) 2.6 Hz, 1H), 7.05 (s, 1H), 7.07-7.14 (m, 2H),
7.18 (d, J ) 8.8 Hz, 1H), 7.22-7.35 (m, 3H); 13C NMR δ 33.0,
50.3, 55.9, 100.3, 107.9, 110.9, 112.9, 126.8 (2C), 127.8, 127.9,
128.0, 128.8 (2C), 132.0, 137.2, 154.5, 174.2.
of Et3N and 0.44 mL (4.7 mmol) of Ac2O. The mixture was
stirred at room temperature for 15 min and then extracted
with CH2Cl2. A FC (80:20, then 100:0) afforded 0.600 g (83%
yield) of crystalline melatonin. An analytical sample was
obtained through recrystallization: mp 117 °C (toluene/EtOAc)
[lit.3 116-118 °C (benzene)]; EIMS m/z (rel int) 232 (M,+ 29),
189 (1), 173 (base), 160 (95), 145 (17); IR (CDCl3) 3280, 2920
cm-1; 1H NMR δ 1.90 (s, 3H), 2.91 (t, J ) 6.8 Hz, 2H), 3.53 (t,
J ) 6.8 Hz, 1H), 3.57 (t, J ) 6.8 Hz, 1H), 3.83 (s, 3H), 5.85 (br
s, 1H), 6.84 (dd, J ) 8.8, 2.6 Hz, 1H), 6.95 (d, J ) 2.2 Hz, 1H),
7.02 (d, J ) 2.6 Hz, 1H), 7.23 (d, J ) 8.8 Hz, 1H), 8.59 (br s,
1H); 13C NMR δ 23.3, 25.3, 39.8, 55.9, 100.5, 112.1, 112.3,
112.4, 122.9, 127.7, 131.6, 154.0, 170.3 (1H and 13C NMR
spectra identical to those obtained with a commercial authentic
sample).
1-Ben zyl-5-m eth oxy-N,N-d im eth yl-1H-in d ole-3-a ceta -
m id e (15). In a closed vial, a solution of 2.40 g (7.80 mmol) of
ester 11 and 19 mg of NaCN in 30 mL of a Me2NH (10 M)
solution in methanol was heated at 50 °C for 4 days. After
evaporation of the amine excess and the solvent under reduced
pressure, addition of ether brought about the crystallization
of amide 15 which was filtered, washed with water and ether,
and dried over P2O5 (2.50 g, 90% yield). The same reaction
carried out with 8.86 g (29.0 mmol) of ester 11 in 76 mL of
the Me2NH solution, at room temperature for 6 days, afforded
9.40 g (91% yield) of amide 15. An analytical sample was
obtained by recrystallization: mp 128 °C (EtOAc); calcd for
2-(1-Ben zyl-5-m eth oxy-1H-in d ol-3-yl)eth yla m in e (13).
To a suspension of 1.20 g (31.6 mmol) of LiAlH4 in 245 mL of
ether was added 2.36 g (8.03 mmol) of amide 12, and the
mixture was heated at reflux temperature for 48 h. After
cooling, 5 mL of a 20% solution of potassium sodium tartrate
was added dropwise. The aluminum complexes were filtered
on Celite and after evaporation of the filtrate, a FC (MeOH/
CH2Cl2 10:90, then 20:80) afforded 1.36 g (60.5% yield) of oily
amine 13. An analytical sample was obtained by molecular
distillation (150 °C/0.02 Torr): calcd for C18H20N2O, C 77.11,
H 7.19, N 9.99; found C 77.2, H 7.1, N 9.9; EIMS m/z (rel int)
280 (M,+ 22), 251 (40), 250 (98), 91 (base); IR (film) 3360, 2930
cm-1; 1H NMR δ 1.61 (br s, 2H), 2.88 (t, J ) 6.6 Hz, 2H), 3.02
(t, J ) 6.6 Hz, 2H), 3.86 (s, 3H), 5.23 (s, 2H), 6.83 (dd, J ) 8.8,
2.2 Hz, 1H), 6.94 (s, 1H), 7.03-7.15 (m, 4H), 7.20-7.32 (m,
3H); 13C NMR (D2O) of hydrochloride δ 25.3, 42.3, 52.0, 58.6,
103.8, 111.4, 113.7, 114.1, 129.4 (2C), 130.0, 130.5, 130.9, 131.2
(2C), 134.4, 140.5, 155.8.
2-(5-Meth oxy-1H-in dol-3-yl)eth ylam in e (5-m eth oxytr ypt-
a m in e) (14). In 13 mL of THF was condensed at -78 °C ca.
40 mL NH3, followed by the addition of 0.640 g (28 mmol) of
Na (blue color). A solution of 1.30 g (4.60 mmol) of indole 13
in 1 mL of THF was added dropwise, and the mixture was
further stirred at -33 °C for 1 h 30. Isoprene was next added
dropwise at -50 °C until total discoloration of the mixture
occurred, followed by the addition of 1.00 g of NH4Cl. After
NH3 and solvent evaporation, water was added, and the
mixture was extracted with ether (K2CO3 drying). A FC
(MeOH/EtOAc 50:50 + 5% NH4OH) afforded 0.580 g (66%
yield) of crystalline 14: mp 122 °C (EtOAc) [lit.5 118-120 °C
(EtOH), lit.15 121.5-122.5 °C (benzene)]; calcd for C11H14N2O,
C 69.45, H 7.42, N 14.72; found C 69.5, H 7.4, N 14.8; EIMS
m/z (rel int) 190 (M,+ 32), 161 (75), 160 (base), 145 (22), 117
(10); IR (CDCl3) 3330, 3280, 2920 cm-1; 1H NMR δ 1.41 (br s,
2H), 2.88 (t, J ) 6.6 Hz, 2H), 3.02 (t, J ) 6.6 Hz, 2H), 3.85 (s,
3H), 6.85 (dd, J ) 8.8, 2.2 Hz, 1H), 6.97 (d, J ) 1.5 Hz, 1H),
7.04 (d, J ) 2.6 Hz, 1H), 7.21 (d, J ) 8.8 Hz, 1H), 8.46 (br s,
1H) [lit.5 spectrum in agreement with the data reported]; 13C
NMR δ 29.4, 42.2, 55.9, 100.7, 111.9, 112.1, 113.2, 123.0, 127.9,
131.7, 153.9.
C
20H22N2O2, C 74.51, H 6.88, N 8.69; found C 74.5, H 6.7, N
8.6; EIMS m/z (rel int) 322 (M,+ 20), 251 (16), 250 (82), 91
(base); IR (KBr) 3053, 1645 cm-1; 1H NMR δ 2.96 (s, 3H), 3.01
(s, 3H), 3.78 (s, 2H), 3.85 (s, 3H), 5.22 (s, 2H), 6.85 (dd, J )
9.0, 2.2 Hz, 1H), 7.03 (s, 1H), 7.05-7.15 (m, 4H), 7.20-7.31
(m, 3H); 13C NMR δ 31.3, 35.5, 37.7, 50.0, 55.8, 100.8, 107.8,
110.4, 112.1, 126.6 (2C), 127.2, 127.4, 128.2, 128.6 (2C), 131.7,
137.5, 153.9, 171.4.
2-(1-Ben zyl-5-m et h oxy-1H -in d ol-3-yl)-N,N-d im et h yl-
eth yla m in e (16). The same procedure above for obtaining
amine 13 was used with 1.41 g (37.2 mmol) of LiAlH4, 300
mL of ether, and 4.00 g (12.4 mmol) of amide 15. A FC (EtOH/
EtOAc 50:50 + 5% NH4OH) afforded 3.40 g (90% yield) of oily
amine 16. An analytical sample was obtained by molecular
distillation: calcd for C20H24N2O, C 77.89, H 7.84, N 9.08;
found C 77.9, H 7.8, N 9.1; EIMS m/z (rel int) 308 (M,+ 18),
251 (5), 250 (24), 159 (7), 144 (4), 91 (43), 58 (base); IR (film)
1
1620 cm-1; H NMR δ 2.34 (s, 6H), 2.60-2.69 (m, 2H), 2.87-
2.96 (m, 2H), 3.85 (s, 3H), 5.20 (s, 2H), 6.81 (dd, J ) 8.8, 2.2
Hz, 1H), 6.91 (s, 1H), 7.05-7.12 (m, 4H), 7.22-7.28 (m, 3H);
13C NMR δ 23.5, 45.5 (2C), 49.9, 55.8, 60.1, 100.9, 110.4, 111.7,
112.8, 126.3, 126.6 (2C), 127.4, 128.4, 128.6 (2C), 131.9, 137.7,
153.7.
3-(2-Am in oeth yl)-1H-in d ol-5-ol (ser oton in ) (1). At -78
°C, 2 mL of a BBr3 (1 M, 2 mmol) solution in CH2Cl2 was added
dropwise to a solution of 0.100 g (0.630 mmol) of indole 14 in
2 mL of CH2Cl2. The mixture was stirred at room temperature
overnight and then diluted with water and neutralized with
2.5 M NaOH. The aqueous phase was evaporated and the
amorphous solid residue dried over P2O5. A FC (MeOH/EtOAc
50:50 + 5% NH4OH) afforded 0.070 g (65% yield) of seroto-
nin: EIMS m/z (rel int) 176 (M,+ 22), 147 (50), 146 (base), 117
2-(5-Me t h oxy-1H -in d ol-3-yl)-N ,N -d im e t h yle t h yla m -
in e (17). The same procedure above for obtaining amine 14
was used with 15 mL of THF, ca. 100 mL of NH3, 1.57 g (68.4
mmol, 6 equiv) of Na, 3.51 g (11.4 mmol) of indole 16 in 15
mL of THF, 2.35 mL of isoprene, and 2 g of NH4Cl. A FC
(MeOH/EtOAc 50/50 + 5% NH4OH) afforded 2.00 g (80% yield)
of crystalline 17. An analytical sample was obtained by
recrystallization: mp 68 °C (cyclohexane); EIMS m/z (rel int)
218 (M,+ 18), 202 (2) 174 (2), 160 (9), 145 (5), 130 (3), 117 (5),
1
(7); IR (Nujol) 3480 cm-1; H NMR (DMSO-d6) δ 2.80 (t, J )
6.8 Hz, 2H), 2.92 (t, J ) 6.8 Hz, 2H), 5.45 (br s, 3H), 6.65 (dd,
J ) 8.8, 2.2 Hz, 1H), 6.87 (d, J ) 2.2 Hz, 1H), 7.08 (br s, 1H),
7.17 (d, J ) 8.8 Hz, 1H) 10.70 (br s, 1H) [lit.16 spectrum in
agreement with the data reported]; 13C NMR (DMSO-d6) δ
27.1, 41.2, 102.2, 110.4, 111.4, 111.7, 123.3, 127.8, 130.8, 150.3.
N-[2-(5-Meth oxy-1H-in d ol-3-yl)eth yl]a ceta m id e (m ela -
ton in ) (2). To a solution of 0.590 g (3.10 mmol) of indole 14
in 16 mL of CH2Cl2 were added dropwise 1.08 mL (7.8 mmol)
1
58 (base); IR (KBr) 1621, 1578 cm-1; H NMR δ 2.35 (s, 6H),
2.60-2.68 (m, 2H), 2.88-2.95 (m, 2H), 3.83 (s, 3H), 6.82 (dd,
J ) 8.8, 2.6 Hz, 1H), 6.91 (d, J ) 2.6 Hz, 1H), 7.03 (d, J ) 2.6
Hz, 1H), 7.16 (d, J ) 8.8 Hz, 1H), 8.55 (br s, 1H); 13C NMR δ
23.7, 45.4 (2C), 55.9, 60.2, 100.7, 111.9 (2C), 113.7, 122.5, 127.8,
131.6, 153.8.
P icr a te of com p ou n d 17: mp 177 °C (MeOH); calcd for
(12) To our knowledge, 1,6,7,7a-tetrahydro-2H-indol-2-ones of type
10 are not reported in the literature. The generality of the reaction is
presently tested in our laboratory with substituted R,â-ethylenic-γ-
lactams.
(13) A similar reaction carried out in the presence of 0.1 equiv of
NaCN for 24 h at 50 °C gave a comparable yield.
(14) J ulia, M.; Igolen, J .; Igolen, H. Bull. Soc. Chim. Fr. 1962, 1060-
1068.
C
13H18N2O + C6H3N3O7, C 51.01, H 4.73, N 15.66; found C
51.1, H 4.7, N 15.7; 1H NMR (DMSO-d6) δ 2.96 (s, 6H), 3.10-
3.17 (m, 2H), 3.39-3.48 (m, 2H), 3.88 (s, 3H), 6.85 (dd, J )
8.8, 2.6 Hz, 1H), 7.17 (d, J ) 2.6 Hz, 1H), 7.30 (d, J ) 2.6 Hz,
1H), 7.36 (d, J ) 8.8 Hz, 1H), 8.52 (s, 2H), 9.30 (br s, 1H),
10.91 (s, 1H).
3-[2-(Dim eth yla m in o)eth yl]-1H-in d ol-5-ol (bu foten in )
(3). The same procedure above for obtaining serotonin 3 was
used with 15 mL of 1 M BBr3 in CH2Cl2 and 1.67 g (7.65 mmol)
(15) Ghosal, S.; Mukherjee, B. J . Org. Chem. 1966, 31, 2284-2288.
(16) The Aldrich Library of NMR Spectra, 2nd ed.; Pouchert, C. J .,
Ed.; Aldrich Chemical Co., Inc.: St. Louis, 1983.

2256 J . Org. Chem., Vol. 67, No. 7, 2002
Revial et al.
of indole 17 in 9 mL of CH2Cl2. A FC (MeOH/EtOAc 25:75)
afforded 0.300 g (23% yield) of amorphous bufotenin: EIMS
m/z (rel int) 204 (M,+ 10), 160 (3), 159 (2), 146 (7), 117 (2), 58
1-Ben zyl-5-m eth oxy-N,N-d im eth yl-2-oxo-2,3-d ih yd r o-
1H-in d ole-3-a ceta m id e (10b). The same procedure above for
obtaining amide 15 was used with 0.910 g (2.80 mmol) of ester
10a and 15 mg of NaCN in 8 mL of the Me2NH solution with
heating for 48 h. The evaporation residue was extracted with
EtOAc and a FC (80:20) afforded 0.626 g (66% yield) of
crystalline amide 10b: mp 139 °C (EtOAc/hexane); calcd for
(base); IR (Nujol) 3620 cm-1 1H NMR (D2O) δ 2.76 (s, 6H),
;
2.95 (t, J ) 7.5 Hz, 2H), 3.18 (t, J ) 7.5 Hz, 2H), 6.86 (dd, J
) 8.8, 2.6 Hz, 1H), 7.02 (d, J ) 2.6 Hz, 1H), 7.15 (s, 1H), 7.38
(d, J ) 8.8 Hz, 1H); 13C NMR (D2O) δ 22.9, 45.5 (2C), 60.2,
105.2, 110.4, 114.6, 115.6, 127.8, 129.7, 134.2, 151.5.
C
20H22N2O3, C 70.99, H 6.55, N 8.28; found C 70.9, H 6.6, N
Dip icr a te of com p ou n d 3: mp 178 °C (MeOH) [lit.15 177-
178 °C (MeOH)]; calcd for C12H16N2O + 2 C6H3N3O7, C 43.51,
H 3.35, N 16.91; found C 43.8, H 3.3, N 17.4.
8.3; EIMS m/z (rel int) 338 (M,+ 24), 266 (53), 265 (base), 188
(12), 91 (22); IR (Nujol) 1700, 1640 cm-1; 1H NMR δ 2.62 (dd,
J ) 16.6, 9.6 Hz, 1H), 2.90 (s, 3H), 2.92 (s, 3H), 3.08 (dd, J )
16.6, 2.9 Hz, 1H), 3.64 (s, 3H), 3.94 (dd, J ) 9.6, 2.9 Hz, 1H),
4.76 (d, J ) 15.4 Hz, 1H), 4.86 (d, J ) 15.4 Hz, 1H), 6.49 (d,
J ) 8.5 Hz, 1H), 6.57 (dd, J ) 8.5, 2.6 Hz, 1H), 6.92-6.94 (m,
1H), 7.15-7.24 (m, 5H); 13C NMR δ 34.8, 35.6, 37.0, 42.5, 43.8,
55.6, 109.0, 112.0 (2C), 127.1 (2C), 127.4, 128.6 (2C), 130.7,
135.9, 136.7, 155.7, 169.7, 177.4.
Meth yl 1-Ben zyl-5-m eth oxy-2-oxo-2,3-d ih yd r o-1H-in -
d ole-3-a ceta te (10a ). A mixture of 1.50 g (4.70 mmol) of ester
10 and 0.8 mL of Me2SO4 in 3 mL of toluene was heated at 90
°C for 45 h. After cooling, neutralization was carried out in
an ice bath with dropwise addition of Et3N. Evaporation of
the solvent under reduced pressure was followed by a FC (50:
50) affording 0.765 g (50% yield) of viscous oxindole 10a : EIMS
m/z (rel int) 325 (M+, 31), 266 (20), 265 (72), 192 (10), 188 (7),
1
132 (7), 91 (base); IR (film) 1730, 1690 cm-1; H NMR δ 2.78
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of compounds 1, 2, 3, 7, 8, 9, 10, 10a , 10b, 11, 12, 13,
(dd, J ) 16.9, 4.4 Hz, 1H), 3.04 (dd, J ) 16.9, 8.1 Hz, 1H),
3.57 (s, 3H), 3.64 (s, 3H), 3.77 (dd, J ) 8.1, 4.4 Hz, 1H), 4.80
(d, J ) 15.5 Hz, 1H), 4.82 (d, J ) 15.5 Hz, 1H), 6.51 (d, J )
8.4 Hz, 1H), 6.59 (dd, J ) 8.4, 2.5 Hz, 1H), 6.79 (dd, J ) 2.5,
1.1 Hz, 1H), 7.10-7.25 (m, 5H); 13C NMR δ 34.8, 42.1, 43.9,
51.9, 55.6, 109.3, 111.5, 112.2, 127.2 (2C), 127.4, 128.6 (2C),
129.3, 135.8, 136.8, 155.8, 171.2, 176.2.
1
14, 15, 16, 17; H spectra of the dipicrate of 3, picrate of 17.
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