Intramolecular Heck reaction of 2- and 3-iodoindole derivatives for the synthesis of β- and γ-carbolinones

Article abstract of DOI:10.1016/S0040-4020(02)00688-9

A new synthesis of β- and γ-carbolinone derivatives was achieved by an intramolecular Heck cyclisation from the corresponding 3-iodo-1H-indole-2-carboxylic acid allyl-amides 8 and 2-iodo-1H-indole-3-carboxylic acid allyl-amides 9.

Full text of DOI:10.1016/S0040-4020(02)00688-9

Tetrahedron 58 (2002) 6673–6678
Intramolecular Heck reaction of 2- and 3-iodoindole derivatives
for the synthesis of b- and g-carbolinones
b
a
a
Egle M. Beccalli,a Gianluigi Broggini, Alessandro Marchesini and Elisabetta Rossi
,
*
a
`
Istituto di Chimica Organica, Facolta di Farmacia, Universita degli Studi di Milano, via Venezian 21, 20133 Milano, Italy
Dipartimento di Scienze Chimiche, Fisiche e Matematiche dell’ Universita dell’ Insubria, via Lucini 3, 22100 Como, Italy
`
b
`
Received 23 April 2002; revised 22 May 2002; accepted 20 June 2002
Abstract—A new synthesis of b- and g-carbolinone derivatives was achieved by an intramolecular Heck cyclisation from the corresponding
3-iodo-1H-indole-2-carboxylic acid allyl-amides 8 and 2-iodo-1H-indole-3-carboxylic acid allyl-amides 9. q 2002 Elsevier Science Ltd. All
rights reserved.
As a part of our ongoing interest in developing new
synthetic strategies for the construction of carbolines,1 we
focused our attention on the intramolecular Heck reaction of
2-iodo-1H-indole-3-carboxylic acid allyl-amide and 3-iodo-
1H-indole-2-carboxylic acid allyl-amide derivatives to
obtain b- and g-carbolinone derivatives. The Heck reaction,
a palladium catalysed coupling reaction of an aryl or a vinyl
halide with an alkene, is a highly efficient and mild
procedure for C–C bond formation as well as for the
synthesis of heterocyclic compounds.2 The synthetic
strategy was thus to introduce a suitable allyl group on
the nitrogen atom of the indole carboxamide and hence
achieve palladium-catalysed ring closure to form b- and
g-carbolinones.
inhibitors containing the b-carbolinone ring system have
also been reported.9
The isomeric 2,5-dihydro-pyrido[4,3-b ]indol-1-ones
(g-carbolinones) are less widespread. The g-carbolinone
ring system is present in indolonaphtyridone III, which acts
as a conformationally restricted 5-HT3 receptor antagonist10
and in the potential antitumoral scaffold indolo[3,2-
c ]quinoline IV.11 Many of these compounds have been
patented and described as cannabinoid receptor modulators
for treating respiratory and non-respiratory diseases.12
In this paper we describe the synthesis of b- and
g-carbolinones, respectively, starting from 3-iodo-1-
methoxymethyl-1H-indole-2-carboxylic acid 3 and 2-iodo-
1-methoxymethyl-1H-indole-3-carboxylic acid 7, prepared
following Schemes 1 and 2. The 3-iodo-1H-indole-2-
carboxylic acid ethyl ester 113 was protected at the indolic
nitrogen and the obtained 3-iodo-1-methoxymethyl-1H-
The synthesis of b-3 and g-carbolinones4 has indeed
attracted some interest in the recent years and the
development of new synthetic methods is an interesting
research area.
The 1,2-dihydro-pyrido[3,4-b ]indol-1-one (b-carbolinone)
nucleus occurs in some natural alkaloids. For example,
bauerine C I, has been isolated from the terrestrial blue–
green alga Dichothrix baueriana GO-25-2.5 Sponges of the
genus Fascaplysinopsis are a rich source of alkaloids with
promising biological activities.6,7 One of these metabolites,
isolated from F. reticulata, is secofascaplysin II, the first
naturally occurring b-carbolinone7 (Fig. 1). b-Carbolinones
are also of interest in medicine and in recent years many of
these derivatives have been patented8 and described as
useful central nervous system depressant and antitumor
agents. A novel series of human leukocyte elastase (HLE)
Keywords: Heck reaction; Pd catalyst; intramolecular cyclization; indoles;
carbolines.
*
Corresponding author. Tel.: þ39-270-601774; fax: þ39-270-638473;
e-mail: egle.beccalli@unimi.it
Figure 1.
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00688-9

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E. M. Beccalli et al. / Tetrahedron 58 (2002) 6673–6678
Scheme 1.
obtained from 5 via nitrogen protection; subsequent alkaline
hydrolysis of 6 gave the acid 7 (Scheme 2).
From the acids 3 and 7, the corresponding allylamides 8a–d
and 9a–d were prepared via intermediate unisolated acyl
chlorides, and reaction with the suitable allylamines
1
(Schemes 3 and 4). The H and 13C NMR spectral data of
the tertiary amides 8b–d and 9b–d evidentiated the
presence of a mixture of rotamers in solution at room
temperature. As reported by literature data17 the rotameric
mixture is sensitive to the substitution pattern of the amide.
In fact for the secondary amide 8a and 9a the NMR data
exhibited a single set of resonance. Dreiding models
suggested that a bulky substituent in both C-2 and C-3
positions of the indole nucleus, significantly inhibits
rotation about the C-2 carbon–carboxamide bond. Further
evidence for the existence of rotamers was secured from a
variable temperature NMR spectra in DMSO-d6. Increasing
the temperature in intervals of approximately 208C resulted
in the coalescence of the signals until the spectra at 1008C
showed a first-order pattern for each group.
Scheme 2.
indole-2-carboxylic acid ethyl ester 2 hydrolysed to the
corresponding acid 3 (Scheme 1). The 2-iodo-1-benzene-
sulfonyl-1H-indole-3-carboxylic acid methyl ester 4 was
obtained in better yield than described14 (85 vs. 45% yield)
via lithiation with LDA of 1-benzenesulfonyl-1H-indole-3-
carboxylic acid methyl ester15 followed by electrophylic
substitution with iodine (see Section 1). Desulfonylation to
give compound 5 was achieved with tetrabutylammonium
fluoride (TBAF) in tetrahydrofuran.16 Compound 6 was
The cyclization reaction to give compounds 10a–d was
performed with a catalyst system containing 10 mol% of
palladium(II)acetate, 1.0 equiv. of tetrabutylammonium
Scheme 3.
Scheme 4.

E. M. Beccalli et al. / Tetrahedron 58 (2002) 6673–6678
6675
chloride (TBAC) and 2.5 equiv. of sodium hydrogen
carbonate in dimethylacetamide at 908C for the reported
time (Scheme 3). In the case of compounds 9b–d, better
results were obtained using 10 mol% of palladium(II)-
acetate, 20 mol% of triphenylphosphine, 3.0 equiv. of
potassium acetate in acetonitrile at reflux for the reported
time. In these conditions, besides the g-carbolinones
11b–d, the isomeric g-carbolinones with exocyclic double
bond, 12b–d were also obtained (Scheme 4). These
compounds isomerise in solution in a short time to more
stable isomers 11b–d. Only in the case of compound 9a
different conditions were necessary to obtain the cyclised
product: Pd(OAc)2 5 mol%, Ph3P 15 mol%, tetrapropyl-
ammonium bromide (TPAB) 1.0 equiv., AcOK 4.0 equiv. in
DMF at 808C for 1.5 h.
HCl and extracted with CH2Cl2 (2£20 ml). The organic
layer was dried (Na2SO4), filtered and evaporated and the
residue crystallized to give 1.20 g of 3, yield 91%, mp 160–
1628C (white crystals from hexane–Et2O). IR: 2930br,
1
1689, 1596 cm21; H NMR: 3.32 (3H, s), 4.50 (1H, br s,
D2O exch.), 6.02 (2H, s), 7.32 (1H, dt, J¼1.1, 8.1 Hz), 7.49
(1H, dt, J¼1.1, 8.1 Hz), 7.57 (1H, d, J¼8.1 Hz), 7.66 (1H, d,
J¼8.1 Hz); 13C NMR: 56.3 (CH3), 75.8 (CH2), 111.4, 122.6,
124.6, 127.6 (CHAr), 73.4, 127.4, 130.9, 139.7, 165.6 (C).
Anal. calcd for C11H10INO3: C, 39.90; H, 3.04; N, 4.23.
Found: C, 39.78; H, 3.00; N, 4.30.
1.1.3. 2-Iodo-1-sulfonyl-1H-indole-3-carboxylic acid
methyl ester 4.13 1-Sulfonyl-1H-indole-3-carboxylic acid
methyl ester (1.26 g, 4 mmol) was dissolved in anhydrous
THF (15 ml) and under N2, at 2708C LDA 2 M (2.5 ml,
5 mmol) was added. When the temperature was raised to
2508C, I2 (1.27 g, 5 mmol) in anhydrous THF (5 ml) was
added. The mixture was then allowed to warm to room
temperature, the solvent evaporated and the residue diluted
with brine and extracted with Et2O (2£20 ml). The organic
layer was washed with a solution of Na2S2O4 (1 g), dried
(Na2SO4) and evaporated to dryness. The residue was
purified by silica gel column chromatography, eluent
hexane–Et2O 2:1, to give compound 4, 1.55 g, 88% yield,
mp 1428C (white crystals from Et2O–hexane). IR: 1680,
1496 cm21; 1H NMR: 3.98 (3H, s), 7.35 (2H, m), 7.41–7.66
(3H, m), 7.95 (2H, m), 8.07 (1H, m), 8.43 (1H, m). Anal.
calcd for C16H12INO4S: C, 43.55; H, 2.74; N, 3.17. Found:
C, 43.71; H, 2.68; N, 3.09.
These results demonstrate once again the usefulness of the
intramolecular Heck reaction and establish an efficient
approach for the synthesis of b- and g-carbolinones.
1. Experimental
1.1. General
Melting points were determined on a Buchi 510 or an
Electrothermal 9100 apparatus and are uncorrected. IR
spectra were recorded on a Jasco IR Report 100 spectro-
photometer, in nujol mull for solids and as a liquid film for
1
oils. H NMR and 13C NMR spectra were recorded on a
Varian Gemini 200, Bruker AC 200 and Bruker Avance 300
spectrometer in CDCl3 solution unless otherwise stated.
Column chromatography was performed on Merck
Kieselgel 60, 0.063–0.2 mm. Evaporation was carried out
under vacuum in a rotary evaporator.
1.1.4. 2-Iodo-1H-indole-3-carboxylic acid methyl ester 5.
Compound 4 (442 mg, 1 mmol) was dissolved in anhydrous
THF (20 ml) and 1 M solution of tetrabutylammonium
fluoride (1 ml, 1 mmol) in THF was added. The mixture was
heated to reflux for 1.5 h then the solvent was evaporated
and the residue diluted with H2O (20 ml) and extracted with
CH2Cl2 (2£20 ml). The organic layer was dried (Na2SO4),
filtered and evaporated and the residue purified by silica gel
column chromatography, eluent CH2Cl2, to give compound
5, 297 mg, yield 99%, mp 1618C (white needles from
1.1.1. 3-Iodo-1-methoxymethyl-1H-indole-2-carboxylic
acid ethyl ester 2. 3-Iodo-1H-indole-2-carboxylic acid
ethyl ester 1 (1.58 g, 5 mmol) was dissolved in anhydrous
THF (20 ml) and NaH (300 mg, 7.5 mmol) was added
portionwise under N2 at 08C. After 15 min chloromethyl-
methylether (HAZARD: carcinogen) (0.76 ml, 10 mmol)
was added. The reaction was run for 1.5 h at 35–408C, the
solvent was then evaporated and the residue diluted with
1 M HCl, extracted with CH2Cl2 (2£20 ml) and dried over
Na2SO4. The organic layer was evaporated and the residue
purified by silica gel column chromatography, eluent
hexane–Et2O 4:1, to give 1.55 g of 2, 87% yield, mp 42–
448C (cream crystals from CH2Cl2–hexane). IR: 1685br,
1590 cm21; 1H NMR: 1.52 (3H, t, J¼7.3 Hz), 3.28 (3H, s),
4.50 (2H, q, J¼7.3 Hz), 5.96 (2H, s), 7.29 (1H, dt, J¼1.5,
8.1 Hz), 7.44 (1H, dt, J¼1.1, 8.4 Hz), 7.53 (1H, d,
J¼8.4 Hz), 7.61 (1H, d, J¼8.1 Hz); 13C NMR: 14.2, 56.2
(CH3), 62.8, 75.4 (CH2), 111.2, 121.9, 124.1, 127.3 (CHAr),
73.5, 127.5, 130.2, 138.9, 166.2 (C). Anal. calcd for
C13H14INO3: C, 43.47; H, 3.93; N, 3.90. Found: C, 43.64;
H, 3.89; N, 3.88.
1
CH2Cl2–hexane). IR: 3250, 1667, 1460 cm21; H NMR:
4.00 (3H, s), 7.20 (2H, m), 7.38 (1H, m), 8.16 (1H, m), 8.98
(1H, br s, D2O exch.); 13C NMR: 50.6 (CH3), 110.8, 122.2,
122.8, 123.6 (CHAr), 94.2, 113.8, 127.5, 138.2, 164.5 (C).
Anal. calcd for C10H8INO2: C, 39.89; H, 2.68; N, 4.65.
Found: C, 40.12; H, 2.80; N, 4.58.
1.1.5. 2-Iodo-1-methoxymethyl-1H-indole-3-carboxylic
acid methyl ester 6. To a solution of compound 5 (1.2 g,
4 mmol) in anhyd. THF (15 ml), 60% NaH (320 mg,
8 mmol) was added portionwise under nitrogen. After
15 min at room temperature, chloromethylmethylether
(1 ml, 12 mmol) was added. The reaction was stirred at
35–408C for 1 h, then the solvent was evaporated and the
residue diluted with 1 M HCl and extracted with CH2Cl2
(2£20 ml). The organic layer was dried (Na2SO4), filtered
and evaporated and the residue crystallized to give 1.31 g of
6, 95% yield, mp 81–828C (white crystals from CH2Cl2–
hexane). IR: 1699, 1461 cm21; 1H NMR: 3.36 (3H, s), 4.01
(3H, s), 5.70 (2H, s), 7.30 (2H, m), 7.56 (1H, m), 8.18 (1H,
m); 13C NMR: 51.3, 56.3 (CH3), 78.0 (CH2), 110.6, 121.8,
122.6, 123.6 (CHAr), 93.8, 113.3, 127.7, 138.8, 164.8 (C).
1.1.2. 3-Iodo-1-methoxymethyl-1H-indole-2-carboxylic
acid 3. Compound 2 (1.44 g, 4 mmol) was dissolved in
CH3OH (30 ml) and KOH (1.12 g, 20 mmol) in H2O (5 ml)
was added. The mixture was heated to reflux for 30 min,
then the solvent evaporated and the residue diluted with 1 M

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E. M. Beccalli et al. / Tetrahedron 58 (2002) 6673–6678
Anal. calcd for C12H12INO3: C, 41.76; H, 3.50; N, 4.06.
Found: C, 41.89; H, 3.41; N, 3.98.
90%, colourless oil; IR: 1630, 1530 cm21; 1H NMR (DMSO
at 1008C): 3.24 (3H, s); 3.97–4.28 (4H, br s), 5.21 (4H, br s),
5.47 (2H, s), 5.86 (2H, br s), 7.26 (1H, dt, J¼1.0, 8.0 Hz),
7.37 (2H, m), 7.63 (1H, d, J¼8.2 Hz); 13C NMR (DMSO at
1008C): 56.7 (CH3), 51.8 (2CH2), 76.2 (CH2), 119.1
(2CH2v), 112.0, 121.9, 122.5, 125.0 (CHAr), 133.8
(2CHv), 60.6, 130.2, 136.6, 137.6, 163.6 (C). Anal. calcd
for C17H19IN2O2: C, 49.77; H, 4.67; N, 6.83. Found: C,
49.99; H, 4.72; N, 6.79.
1.1.6. 2-Iodo-1-methoxymethyl-1H-indole-3-carboxylic
acid 7. To a solution of compound 6 (1.38 g, 4 mmol) in
CH3OH (30 ml) a solution of KOH (0.896 g, 16 mmol) in
H2O (5 ml) was added and the mixture was heated to reflux
for 1.5 h. The solvent was then evaporated and the residue
diluted with 1 M HCl and extracted with CH2Cl2 (2£20 ml).
The organic layer was dried (Na2SO4), filtered and
evaporated and the residue purified by silica gel column
chromatography, eluent CH2Cl2–Et2O 2:1, to give com-
pound 7, 920 mg, 70% yield, mp 1858C (white crystals from
CH2Cl2–hexane). IR: 3250br, 1655, 1495 cm21; 1H NMR:
3.39 (3H, s), 5.74 (2H, s), 7.30 (2H, m), 7.59 (1H, dd, J¼2.6,
6.2 Hz), 8.29 (1H, dd, J¼2.6, 6.2 Hz); 13C NMR: 56.7
(CH3), 78.5 (CH2), 110.9, 122.4, 123.2, 124.1 (CHAr), 95.5,
115.5,128.5,139.2, 169.5(C). Anal. calcdforC11H10INO3:C,
39.90; H, 3.04; N, 4.23. Found: C, 39.81; H, 2.99; N, 4.28.
1.2.4. 3-Iodo-1H-indole-2-carboxylic acid allyl-phenyl-
amide 8d. N-Allylaniline, eluent CH2Cl2–Et2O 20:1,
422 mg, yield 95%, pale yellow oil; IR: 1635, 1580 cm21
;
1H NMR (DMSO at 1008C): 3.29 (3H, s), 4.53 (2H, d,
J¼5.8 Hz), 5.17 (1H, dd, J¼1.5, 10.2 Hz), 5.25 (1H, dd,
J¼1.5, 17.2 Hz), 5.60 (2H, br s), 5.95 (1H, ddt, J¼5.8, 10.2,
17.2 Hz), 7.13–7.37 (8H, m), 7.57 (1H, d, J¼8.1 Hz); 13C
NMR (DMSO): 55.8 (CH3), 51.8, 74.6 (CH2), 117.7
(CH2v), 110.8, 121.0, 121.3, 124.2, 126.8, 128.2, 128.4
(CHAr), 126.6 (2CHAr), 132.7 (CHv), 62.1, 128.8, 135.7,
136.5, 140.9, 161.9 (C). Anal. calcd for C20H19IN2O2:
C, 53.83; H, 4.29; N, 6.28. Found: C, 53.90; H, 4.33; N,
6.19.
1.2. Synthesis of 3-iodo-1-methoxymethyl-1H-indole-2-
carboxamides 8a–d and 2-iodo-1-methoxymethyl-1H-
indole-3-carboxamides 9a–d: general procedure
To a mixture of compound 3 or 7 (1 mmol), CH2Cl2 (20 ml)
and DMF (0.05 ml), and oxalyl chloride (0.3 ml, 3 mmol)
were added. The reaction was run for 1 h at room
temperature and for 1 h at reflux. The solvent was
evaporated to dryness in vacuo, the residue taken up with
CH2Cl2 (20 ml) and the suitable allylamine (3 mmol) was
added at 08C. After 1 h at room temperature, the mixture
was washed with 1 M HCl. The organic layer was dried
(Na2SO4), filtered and evaporated and the residue purified
by silica gel column chromatography (eluent see below).
1.2.5. 2-Iodo-1H-indole-3-carboxylic acid allyl-amide 9a.
Allylamine, eluent CH2Cl2–Et2O 1:1, 333 mg, yield 90%,
mp 1228C (white plates from CH2Cl2–hexane); IR: 3275,
1
1620, 1530 cm21; H NMR: 3.35 (3H, s), 4.20 (2H, dd,
J¼5.5, 5.9 Hz), 5.24 (1H, dd, J¼1.5, 10.2 Hz), 5.36 (1H, dd,
J¼1.5, 17.2 Hz), 5.65 (2H, s), 6.03 (1H, ddt, J¼10.2, 17.2,
5.5 Hz), 6.22 (1H, br s, D2O exch.), 7.24 (2H, m), 7.54 (1H,
m), 7.96 (1H, m); 13C NMR: 55.5 (CH3), 51.6, 76.7 (CH2),
115.1 (CH2v), 110.6, 119.2, 120.9, 122.6 (CHAr), 135.4
(CHv), 90.2, 121.5, 126.7, 137.9, 163.7 (C). Anal. calcd for
C14H15IN2O2: C, 45.42; H, 4.08; N, 7.57. Found: C, 45.20;
H, 4.20; N, 7.69.
1.2.1. 3-Iodo-1H-indole-2-carboxylic acid allyl-amide 8a.
Allylamine, eluent CH2Cl2–Et2O 20:1, 339 mg, yield 92%,
mp 1208C (white crystals from CH2Cl2–hexane); IR: 3278,
1.2.6. 2-Iodo-1H-indole-3-carboxylic acid allyl-methyl-
amide 9b. N-Methylallylamine, purified by crystallization,
380 mg, quantitative yield, mp 89–908C (white crystals
1
1638, 1556 cm21; H NMR: 3.33 (3H, s), 4.19 (2H, dddd,
J¼1.5, 1.8, 5.5, 5.9 Hz), 5.28 (1H, ddd, J¼1.1, 1.5,
10.2 Hz), 5.41 (1H, ddd, J¼1.1, 1.8, 17.2 Hz), 5.84 (2H,
s), 6.02 (1H, ddt, J¼10.2, 17.2, 5.5 Hz), 6.70 (1H, br s, exch.
D2O), 7.29 (1H, dt, J¼1.5, 7.0 Hz), 7.41 (1H, dt, J¼1.5,
7.0 Hz), 7.53 (2H, m); 13C NMR: 56.3 (CH3), 42.4, 75.4
(CH2), 117.2 (CH2v), 111.0, 122.2, 123.1, 125.8 (CHAr),
133.5 (CHv), 63.3, 130.0, 133.6, 138.1, 161.6 (C). Anal.
calcd for C14H15IN2O2: C, 45.42; H, 4.08; N, 7.57. Found:
C, 45.99; H, 4.14; N, 7.35.
1
from Et2O); IR: 1617, 1530 cm21; H NMR (DMSO at
808C): 2.93 (3H, s), 3.27 (3H, s), 4.02 (2H, br s), 5.20 (2H,
dd, J¼9.6, 16.0 Hz), 5.57 (2H, s), 5.82 (1H, m), 7.13 (1H, dt,
J¼1.0, 7.8 Hz), 7.21 (1H, dt, J¼1.1, 8.2 Hz), 7.38 (1H, d,
J¼7.8 Hz), 7.64 (1H, d, J¼8.2 Hz); 13C NMR (DMSO at
808C): 34.9, 56.4 (CH3), 51.4, 77.8 (CH2), 118.0 (CH2v),
111.6, 119.2, 121.9, 123.6 (CHAr), 134.4 (CHv), 88.0,
121.1, 127.7, 138.6, 166.7 (C). Anal. calcd for
C15H17IN2O2: C, 46.89; H, 4.46; N, 7.29. Found: C,
46.70; H, 4.40; N, 7.35.
1.2.2. 3-Iodo-1H-indole-2-carboxylic acid allyl-methyl-
amide 8b. N-Methylallylamine, eluent hexane–Et2O 1:1,
340 mg, yield 88%, mp 116–1188C (cream crystals from
1.2.7. 2-Iodo-1H-indole-3-carboxylic acid diallyl-amide
9c. Diallylamine, eluent CH2Cl2–Et2O 6:1, 405 mg,
1
CH2Cl2–hexane); IR: 1632, 1531 cm21; H NMR (DMSO
1
at 1008C): 2.97 (3H, s), 3.25 (3H, s), 4.01 (2H, br s), 5.23–
5.36 (2H,m), 5.48 (2H, s), 5.90 (1H, m), 7.25–7.41 (3H, m),
7.62 (1H, d, J¼8.1 Hz); 13C NMR (DMSO at 808C): 35.6,
55.7 (CH3), 53.1, 74.7 (CH2), 117.3 (CH2v), 110.9, 120.9,
121.5, 124.0 (CHAr), 132.2 (CHv), 60.3, 129.0, 135.5,
136.6, 162.3 (C). Anal. calcd for C15H17IN2O2: C, 46.89; H,
4.46; N, 7.29. Found: C, 47.95; H, 4.53; N, 7.19.
quantitative yield, colourless oil; IR: 1630. 1520 cm21; H
NMR (DMSO at 808C): 3.26 (3H, s), 3.99 (4H, br s), 5.17
(4H, dd, J¼9.4, 13.4 Hz), 5.57 (2H, s), 5.82 (2H, m), 7.13
(1H, dt, J¼1.0, 7.9 Hz), 7.21 (1H, dt, J¼1.0, 8.1 Hz), 7.38
(1H, d, J¼7.9 Hz), 7.64 (1H, d, J¼8.1 Hz); 13C NMR
(DMSO at 808C): 56.4 (CH3), 49.2 (2CH2), 77.8 (CH2),
118.2 (2CH2v), 111.7, 119.0, 121.9, 123.6 (CHAr), 134.6
(2CHv), 88.1, 120.9, 127.7, 138.6, 166.8 (C). Anal. calcd
for C17H19IN2O2: C, 49.77; H, 4.67; N, 6.83. Found: C,
49.62; H, 4.56; N, 6.90.
1.2.3. 3-Iodo-1H-indole-2-carboxylic acid diallyl-amide
8c. Diallylamine, eluent hexane–Et2O 2:1, 370 mg, yield

E. M. Beccalli et al. / Tetrahedron 58 (2002) 6673–6678
6677
1.2.8. 2-Iodo-1H-indole-3-carboxylic acid allyl-phenyl-
amide 9d. N-Allylaniline, eluent CH2Cl2–Et2O 10:1,
357 mg, yield 80%, mp 74–758C (white crystals from
1.3.4. 2,9-Dihydro-9-methoxymethyl-4-methyl-2-phenyl-
1H-pirido[3,4-b ]indol-1-one 10d. Heated for 1.5 h, eluent
CH2Cl2–Et2O 20:1, 258 mg, yield 81%, mp 132–1348C
(cream crystals from hexane–Et2O); IR: 1656, 1605,
1
hexane–Et2O); IR: 1620, 1580 cm21; H NMR: 3.07 (3H,
s), 4.62 (2H, d, J¼5.9 Hz), 5.22 (1H, dd, J¼1.1, 10.0 Hz),
5.30 (1H, dd, J¼1.5, 17.2 Hz), 5.46 (2H, s), 6.10 (1H, m),
7.01–7.18 (7H, m), 7.36 (1H, dd, J¼1.8, 7.0 Hz), 7.52 (1H,
dd, J¼1.8, 6.6 Hz); 13C NMR: 56.0 (CH3), 53.2, 77.6 (CH2),
118.2 (CH2v), 110.4, 119.7, 121.6, 123.4, 126.8 (CHAr),
127.3, 128.7 (2CHAr), 133.8 (CHv), 86.5, 121.7, 127.8,
138.1, 143.0, 166.6 (C). Anal. calcd for C20H19IN2O2: C,
53.83; H, 4.29; N, 6.28. Found: C, 53.95; H, 4.35; N, 6.24.
1567 cm21 1H NMR: 2.65 (3H, s), 3.39 (3H, s), 6.43
;
(2H, s), 7.01 (1H, s), 7.35 (1H, m), 7.42–7.58 (6H, m), 7.74
(1H, d, J¼8.4 Hz), 8.17 (1H, d, J¼8.1 Hz); 13C NMR: 17.3,
56.2 (CH3), 75.1 (CH2), 112.0, 121.6, 123.2, 127.3, 127.5,
127.6, 127.7, 128.5, 129.6, 129.8 (CHAr), 112.5, 123.3,
126.6, 126.9, 141.3, 141.6, 155.8 (C). Anal. calcd for
C20H18N2O2: C, 75.45; H, 5.70; N, 8.80. Found: C, 75.33;
H, 5.82; N, 8.68.
1.3. Synthesis of b-carbolinones 10a–d: general
procedure
1.3.5. Synthesis of 2,5-dihydro-5-methoxymethyl-4-
methyl-1H-pirido[4,3-b]indol-1-one 11a and 2,3,4,5-tet-
rahydro-5-methoxymethyl-4-methylene-1H-pirido[4,3-
b ]indol-1-one 12a. To a solution of indole 9a (185 mg,
0.5 mmol) in DMF (5 ml) was added Pd(OAc)2 (6 mg,
5 mol%), triphenylphosphine (19 mg, 15 mol%), potassium
acetate (196 mg, 2 mmol) and tetrapropylammonium
bromide (TPAB) (133 mg, 0.5 mmol). The mixture was
stirred at 808C for 1.5 h, then after cooling washed with
brine and extracted with Et2O (2£20 ml). The organic layer
was dried (Na2SO4), filtered and evaporated and the residue
chromatographed by silica gel eluent CH2Cl2–CH3OH 50:1
to afford 11a, 32 mg, 26%, mp 216–2188C (white crystals
To a solution of indole 8a–d (1 mmol) in DMA (3 ml) was
added NaHCO3 (210 mg, 2.5 mmol), Pd(OAc)2 (22 mg,
10 mol%), TBAC (276 mg, 1 mmol) and the mixture was
heated at 908C with stirring for the reported time. After
completion of the reaction (tlc), the mixture was washed
with brine and extracted with Et2O (2£20 ml). The organic
layer was dried (Na2SO4), filtered and evaporated and the
residue chromatographed by silica gel (eluent see below).
1.3.1. 2,9-Dihydro-9-methoxymethyl-4-methyl-1H-
pirido[3,4-b] indol-1-one 10a. Heated for 6 h, eluent
hexane–Et2O 2:1, 186 mg, yield 77%, mp 195–1968C
(cream crystals from CH2Cl2–hexane); IR: 3270, 1652,
1535 cm21; 1H NMR: 2.68 (3H, s), 3.38 (3H, s), 6.31 (2H,
s), 7.06 (1H, s), 7.37 (1H, dt, J¼1.1, 8.1 Hz), 7.60 (1H, dt,
J¼1.1, 8.4 Hz), 7.74 (1H, d, J¼8.4 Hz), 8.19 (1H, d,
J¼8.1 Hz), 11.40 (1H, br s, exch. D2O); 13C NMR: 17.3,
56.1 (CH3), 75.1 (CH2), 111.7, 121.4, 123.1, 123.6, 127.5
(CHAr), 113.4, 126.7, 127.9, 141.1, 157.3 (C). Anal. calcd
for C14H14N2O2: C, 69.41; H, 5.82; N, 11.56. Found: C,
69.20; H, 5.91; N, 11.32.
from CH2Cl2–hexane); IR: 3380, 1643, 1543, 1462 cm21
;
1H NMR: 2.58 (3H, s), 3.34 (3H, s), 5.79 (2H, s), 7.18 (1H,
s), 7.35–7.59 (3H, m), 8.53 (1H, d, J¼7.2 Hz), 11.47 (1H,
br s, exch. D2O); 13C NMR: 16.8, 56.9 (CH3), 75.0 (CH2),
111.2, 122.9 125.5, 125.7, 135.2 (CHAr), 104.8, 109.5,
122.7, 140.4, 144.6, 160.5 (C). Anal. calcd for C14H14N2O2:
C, 69.41; H, 5.82; N, 11.56. Found: C, 69.58; H, 5.90; N,
11.40 and 12a, 70 mg, 56%, pale yellow oil; IR: 3290, 1639,
1465 cm21; 1H NMR: 3.46 (3H, s), 4.29 (2H, d, J¼1.8 Hz),
5.50 (1H, d, J¼1.8 Hz), 5.59 (2H, s), 5.77 (1H, br s, exch.
D2O), 5.90 (1H, d, J¼1.8 Hz), 7.35 (1H, dt, J¼1.5, 7.3 Hz),
7.41–7.71 (2H, m), 8.33 (1H, dd, J¼1.8, 7.0 Hz). Anal.
calcd for C14H14N2O2: C, 69.41; H, 5.82; N, 11.56. Found:
C, 69.50; H, 5.89; N, 11.49.
1.3.2. 2,9-Dihydro-9-methoxymethyl-2,4-dimethyl-1H-
pirido[3,4-b]indol-1-one 10b. Heated for 3 h, eluent
hexane–Et2O 1:1, 180 mg, yield 70%, mp 122–1258C
(pale yellow powder from Et2O); IR: 1642, 1587,
1.4. Synthesis of g-carbolinones 11b–d and 12b–d:
general procedure
1
1520 cm21; H NMR: 2.61 (3H, d, J¼1.1 Hz), 3.37 (3H,
s), 3.70 (3H, s), 6.33 (2H, s), 6.91 (1H, d, J¼1.1 Hz), 7.31
(1H, m), 7.44–7.70 (2H, m), 8.12 (1H, dd, J¼0.7, 8.1 Hz);
13C NMR: 16.9, 36.7, 55.8 (CH3), 74.7 (CH2), 111.5, 121.1,
122.8, 126.8, 127.8 (CHAr), 112.1, 123.0, 126.1, 126.9,
140.8, 155.8 (C). Anal. calcd for C15H16N2O2: C, 70.29; H,
6.29; N, 10.93. Found: C, 70.08; H, 6.19; N, 10.75.
To a solution of indole 9a–d (1 mmol) in dry acetonitrile
(15 ml), Pd(OAc)2 (22 mg, 10 mol%), triphenylphosphine
(52 mg, 20 mol%), TBAC (276 mg, 1 mmol), and
anhydrous potassium carbonate (414 mg, 3 mmol) were
added. The mixture was heated to reflux for the reported
time, the inorganic salts were filtered off and the solvent
removed in vacuo. The residue was diluted with water
(20 ml) and extracted with CH2Cl2 (2£20 ml). The organic
layer was dried, filtered and evaporated and the residue
chromatographed on silica gel (eluent see later) affording
compounds 11 and 12.18
1.3.3. 2-Allyl-2,9-dihydro-9-methoxymethyl-4-methyl-
1H-pirido[3,4-b]indol-1-one 10c. Heated for 1.5 h, eluent
hexane–Et2O 2:1, 214 mg, yield 76%, mp 113–1158C
(cream crystals from hexane–Et2O); IR: 1650, 1589,
1568 cm21 1H NMR: 2.62 (3H, s), 3.73 (3H, s), 4.75
;
(2H, d, J¼5.5 Hz), 5.25 (2H, m), 6.05 (1H, m), 6.35 (2H, s),
6.88 (1H, s), 7.32 (1H, t, J¼8.1 Hz), 7.55 (1H, t, J¼8.1 Hz),
7.71 (1H, d, J¼8.1 Hz), 8.14 (1H, d, J¼8.1 Hz); 13C NMR:
17.4, 56.1 (CH3), 50.9, 75.2 (CH2), 118.1 (CH2v), 121.4,
123.2, 111.8, 126.5, 127.2 (CHAr), 133.7 (CHv), 112.7,
118.4, 126.3, 126.9, 141.1, 155.5 (C). Anal. calcd for
C17H18N2O2: C, 72.32; H, 6.43; N, 9.92. Found: C, 72.51;
H, 6.31; N, 9.75.
1.4.1. 2,5-Dihydro-5-methoxymethyl-2,4-dimethyl-1H-
pirido[4,3-b]indol-1-one 11b and 2,3,4,5-tetrahydro-5-
methoxymethyl-2-methyl-4-methylene-1H-pirido[4,3-
b ]indol-1-one 12b. Reflux for 12 h, eluent from hexane–
Et2O 1:1 to Et2O to give: 9b (unreacted material), 107 mg,
28%, 11b 99 mg, yield 39%, mp 119–1218C (cream crystals
1
from Et2O); IR: 1654, 1591 cm21; H NMR: 2.55 (3H, s),

6678
E. M. Beccalli et al. / Tetrahedron 58 (2002) 6673–6678
Synthesis 2001, 2477–2483. (b) Beccalli, E. M.; Clerici, F.;
Marchesini, A. Tetrahedron 2001, 57, 4787–4792.
2. (a) Heck, R. F. Org. React. 1982, 27, 345–390. (b) Tsuji, J.
Palladium Reagents and Catalysts; Wiley: New York, 1995;
pp 125–168.
3.31 (3H, s), 3.71 (3H, s), 5.75 (2H, s), 7.08 (1H, s), 7.41
(2H, m), 7.54 (1H, d, J¼7.3 Hz), 8.53 (1H, dd, J¼1.5,
6.2 Hz); 13C NMR: 16.4, 36.5, 56.5 (CH3), 74.6 (CH2),
109.9, 122.4, 122.5, 124.9, 135.0 (CHAr), 104.6, 109.2,
124.8, 140.0, 144.5, 160.1 (C). Anal. calcd for C15H16N2O2:
C, 70.29; H, 6.29; N, 10.93. Found: C, 70.42; H, 6.36; N,
10.76 and 12b 66 mg, yield 26%, colourless oil; IR:
3. (a) Tahri, A.; De Borggraeve, W.; Buysens, K. J.; Van
Meervelt, L.; Compernolle, F.; Hoornaert, G. J. Tetrahedron
1999, 55, 14675–14684. (b) Tahari, A.; Buysens, K. J.; Van
der Eycken, E. V.; Vanderberge, D. M.; Hoornaert, G. J.
Tetrahedron 1998, 54, 13211–13226. (c) Fu¨rstner, A.; Ernst,
A.; Krause, H.; Ptock, A. Tetrahedron 1996, 52, 7329–7344.
(d) Dupas, G.; Duflos, J.; Queguigner, G. J. Heterocycl. Chem.
1983, 20, 967–970. (e) Mashelkar, U. C.; Usgaonkar, R. N.
Ind. J. Chem. Sect. B 1979, 17B(4), 407–408. (f) Mashelkar,
U. C.; Usgaonkar, R. N. Ind. J. Chem. Sect. B 1978, 16B(9),
782–785.
1615 cm21 1H NMR: 3.14 (3H, s), 3.43 (3H, s), 4.27
;
(2H, d, J¼1.8 Hz), 5.45 (1H, d, J¼1.8 Hz), 5.57 (2H, s),
5.86 (1H, d, J¼1.8 Hz), 7.32–7.57 (3H, m), 8.36 (1H, dd,
J¼1.8, 8.4 Hz). Anal. calcd for C15H16N2O2: C, 70.29; H,
6.29; N, 10.93. Found: C, 70.39; H, 6.33; N, 10.78.
1.4.2. 2-Allyl-2,5-dihydro-5-methoxymethyl-4-methyl-
1H-pirido[4,3-b]indol-1-one 11c and 2-allyl-2,3,4,5-tet-
rahydro-5-methoxymethyl-4-methylene-1H-pirido[4,3-
b ]indol-1-one 12c. Reflux for 3 h, eluent hexane–Et2O 1:1
to give: 9c (unreacted material), 98 mg, 24%, 11c 98 mg,
yield 35%, pale yellow oil; IR: 1659, 1592 cm21; 1H NMR:
2.56 (3H, s), 3.31 (3H, s), 4.74 (2H, d, J¼5.5 Hz), 5.20 (1H,
dd, J¼1.5, 16.9 Hz), 5.27 (1H, dd, J¼1.5, 10.2 Hz), 5.75
(2H, s), 6.03 (1H, m), 7.05 (1H, s), 7.40 (2H, m), 7.54 (1H,
d, J¼7.0 Hz), 8.53 (1H, d, J¼7.0 Hz); 13C NMR: 16.5, 56.5
(CH3), 50.1, 74.7 (CH2), 118.2 (CH2v), 109.1, 122.4,
122.6, 125.0, 133.8 (CHAr), 133.9 (CHv), 105.0, 109.8,
120.1, 140.0, 144.4, 159.4 (C). Anal. calcd for C17H18N2O2:
C, 72.32; H, 6.43; N, 9.92. Found: 72.43; H, 6.55; N, 9.78
and 12c, 107 mg, yield 38%, pale yellow oil; IR:
4. (a) Engler, T. A.; Wanner, J. J. Org. Chem. 2000, 65,
2444–2457. (b) Harada, K.; Someya, H.; Zen, S. Heterocycles
1994, 38, 1867–1880.
5. Larsen, L. K.; Moore, R. E.; Patterson, G. M. L. J. Nat. Prod.
1994, 57, 419–421.
6. Roll, D. M.; Ireland, C. M.; Lu, H. S. M.; Clardy, J. J. Org.
Chem. 1988, 53, 3276–3278.
7. Jimenez, C.; Quinoa, E.; Adamczereski, M.; Hunter, L. M.;
Crews, P. J. Org. Chem. 1991, 56, 3403–3410.
8. (a) Menta, E.; Pescalli, N.; Spinelli, S. (Novuspharma S.p.A.,
Italy). Patent No. WO 2001009129, 2001; Chem. Abstr., 134,
162922. (b) Ritzeler, O.; Castro, A.; Grenier, L.; Soucy, F.
(Aventis Pharma Deutschland G.m.b.H., Germany). Patent
No. 1134221, 2001; Chem. Abstr., 135, 242149. (c) Evanno,
Y.; Sevrin, M.; Maloizel, C.; Legalloudec, O.; George, P.
(Synthelabo S.A. Patent No. WO 9815552, 1998; Chem.
Abstr., 128, 282832.
1
1620 cm21; H NMR: 3.44 (3H, s), 4.22 (4H, m), 5.20–
5.33 (2H, m), 5.46 (1H, d, J¼1.8 Hz), 5.58 (2H, s), 5.86
(1H, d, J¼1.8 Hz), 6.0 (1H, m), 7.30–7.42 (2H, m); 7.49
(1H, dd, J¼1.5, 8.4 Hz), 8.38 (1H, dd, J¼1.5, 8.4 Hz). Anal.
calcd for C17H18N2O2: C, 72.32; H, 6.43; N, 9.92. Found: C,
72.40; H, 6.51; N, 9.85.
9. Vale, C. A.; Damewood, Jr. J. R.; Steelman, G. B.; Bryant, C.;
Gomes, B.; Williams, J. J. Med. Chem. 1995, 38, 86–97.
10. Clark, R. D.; Miller, A. B.; Berger, J.; Repke, D. B.;
Weinhardt, K. K.; Kowalczyk, B. A.; Eglen, R. M.; Bonhaus,
D. W.; Lee, C.-H.; Michel, A. D.; Smith, W. L.; Wong, E. H.
F. J. Med. Chem. 1993, 36, 2645–2657.
1.4.3. 2,5-Dihydro-5-methoxymethyl-4-methyl-2-phenyl-
1H-pirido[4,3-b]indol-1-one 11d and 2,3,4,5-tetrahydro-
5-methoxymethyl-4-methylene-2-phenyl-1H-pirido[4,3-
b]indol-1-one 12d. Reflux for 2 h, eluent CH2Cl2–Et2O
20:1. 11d 136 mg, yield 43%, mp 148–1508C (white
11. Mouaddib, A.; Joseph, B.; Hasnaoui, A.; Merour, J-Y.
Synthesis 2000, 549–556.
crystals from hexane–Et2O); IR: 1654, 1590 cm21 1H
;
NMR: 2.59 (3H, s), 3.35 (3H, s), 5.79 (2H, s), 7.19 (1H, s),
7.34–7.59 (8H, m), 8.51 (1H, d, J¼8.4 Hz); 13C NMR: 16.2,
56.3, 74.5, 108.9 (CHAr), 122.4 (2CHAr), 124.7 (CHAr),
127.3 (2CHAr), 128.1, 129.2 (2CHAr), 134.4 (CHv),
104.7, 109.6, 124.9, 139.8, 141.0, 144.2, 159.2 (C). Anal.
calcd for C20H18N2O2: C, 75.45; H, 5.70; N, 8.80. Found: C,
75.29; H, 5.86; N, 8.70 and 12d, 174 mg, yield 55%, mp
160–1628C (crystals from Et2O); IR: 1613, 1460 cm21; 1H
NMR: 3.47 (3H, s), 4.70 (2H, s), 5.53 (1H, d, J¼1.8 Hz),
5.63 (2H, s), 5.94 (1H, d, J¼1.8 Hz), 7.32–7.45 (7H, m),
7.54 (1H, d, J¼7.7 Hz), 8.37 (1H, d, J¼8.4 Hz). Anal. calcd
for C20H18N2O2: C, 75.45; H, 5.70; N, 8.80. Found: C,
75.26; H, 5.85; N, 8.72.
12. Leftheris, K.; Zhao, R.; Chen, B.-C.; Kiener, P.; Wu, H.;
Pandit, C. R.; Wrobleski, S.; Chen, P.; Hynes, J.; Longphre,
M.; Norris, D. J.; Spergel, S.; Tokarski, J. (Bristol-Myers
Squibb Company, USA). Patent No. 2001058869, 2001;
Chem. Abstr., 135, 166827C.
13. Sakamoto, T.; Nagano, T.; Kondo, Y.; Yamanaka, H. Chem.
Pharm. Bull. 1988, 36, 2248–2252.
14. Kondo, Y.; Yoshida, A.; Sakamoto, T. J. Chem. Soc., Perkin
Trans. 1 1996, 2331–2332.
15. Wenkert, E.; Moeller, P.; Piettre, S. J. Am. Chem. Soc. 1988,
110, 7188–7194.
16. Yasuhara, A.; Sakamoto, T. Tetrahedron Lett. 1998, 39,
595–596.
17. Lipshutz, B. H.; McCarthy, K. E.; Hungate, R. W. J. Org.
Chem. 1984, 49, 1218–1221.
References
18. It was not possible to record the 13C NMR spectra of
compounds 12 because of their isomerization, in solution, to
more stable compounds 11.
1. (a) Abbiati, G.; Beccalli, E. M.; Marchesini, A.; Rossi, E.