2-Amidinylindole-3-carbaldehydes: Versatile synthons for the preparation of α-carboline derivatives

Article abstract of DOI:10.1016/S0040-4020(00)00950-9

The 2-amidinylindole-3-carbaldehydes 1 are the key starting materials for the preparation of three classes of carbolines 2, 6 and 7 in which the pyridine ring is characterised by a different substitution patterns. The carbolines 2 which are functionalized with an amino group in position 2, were obtained directly by heating 1 in presence of SiO₂. The condensation of amidines 1 with arylmethylketones afforded unsaturated ketones 5 which on heating were transformed into 2,9-dialkyl-3-aroyl-9H-pyrido[2,3-b]indoles 7. Instead, prolonged reaction of amidines 1 with arylmethylketones in t-BuOH/t-BuOK gave 2-aryl-9H-pyrido[2,3-b]indoles 6. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00950-9

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 9991±9997
2-Amidinylindole-3-carbaldehydes: Versatile Synthons for the
Preparation of a-Carboline Derivatives
*
Emanuela Erba, M. Luisa Gelmi and Donato Pocar
Á
Istituto di Chimica Organica, Facolta di Farmacia e Centro Interuniversitario di Ricerca sulle Reazioni Pericicliche e Sintesi di Sistemi
Á
Etero-e Carbociclici, Universita degli Studi di Milano, Via Venezian, 21, I-20133 Milan, Italy.
Received 6 July 2000; revised 19 September 2000; accepted 5 October 2000
AbstractÐThe 2-amidinylindole-3-carbaldehydes 1 are the key starting materials for the preparation of three classes of carbolines 2, 6 and 7
in which the pyridine ring is characterised by a different substitution patterns. The carbolines 2 which are functionalized with an amino group
in position 2, were obtained directly by heating 1 in presence of SiO2. The condensation of amidines 1 with arylmethylketones afforded
unsaturated ketones 5 which on heating were transformed into 2,9-dialkyl-3-aroyl-9H-pyrido[2,3-b]indoles 7. Instead, prolonged reaction of
amidines 1 with arylmethylketones in t-BuOH/t-BuOK gave 2-aryl-9H-pyrido[2,3-b]indoles 6. q 2000 Elsevier Science Ltd. All rights
reserved.
Introduction
The biological importance of a-carboline is well known.
This ring is found in several alkaloids 2 and in carcinogenic
metabolites.3 Moreover, some synthetic pyrido[2,3-b]indole
derivatives are anxiolytic or neuroprotectant agents.4
Previous research work from this laboratory involved an
investigation into
a new synthesis of heterocyclic
compounds starting from 5-amino-v-triazolines and their
transformation products.1 New synthetic routes to substi-
tuted quinazolines and related heterocycles were discovered
and key intermediates for their synthesis were found in
special substituted amidines of general structure 1 for
which practical preparation procedures were set up.1 We
now report on new synthetic pathways to prepare several
substituted a-carbolines in which the above amidine
derivatives 1 were successfully used.
The formation of the a-carboline ring system has already
been described in the literature and different routes are
known which rely on the formation of the middle ring
through intramolecular cyclization of an N-containing
ortho-substituent in a 3-phenylpyridine substrate or on the
use of reactions affording the linkage of the ortho,ortho
positions in N-(2-pyridyl)anilines.5 The ready availability
of amidines 1 suggested that it would be possible to develop
Scheme 1.
Keywords: 5-amino-v-triazolines; amidines; a-carboline; pyrido[2,3-b]indole.
* Corresponding author. Tel.:139-0270601774; fax: 139-0270638473; e-mail: emanuela.erba@unimi.it
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00950-9

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E. Erba et al. / Tetrahedron 56 (2000) 9991±9997
Scheme 2.
new synthetic strategies involving the construction of the
pyridine ring on the pre-formed indole moiety.
absence of solvent. Probably the ring-closure reaction
occurs through the isomerization of the amidine into its
diaminoalkylidene tautomer followed by intramolecular
condensation of the a carbon with the aldehyde group and
water elimination (Scheme 2). Products 2 represent a new
class of substituted a-carboline derivatives and are charac-
Results and Discussion
1
terised in the H NMR spectrum by a typical singlet at dH
8.0±8.1 associated with H-4.
Taking into account the structural features of compounds 1
two schemes were ®rstly planned for the preparation of the
carboline ring i.e. (i) the intramolecular condensation of the
a-carbon of the amidine group with the formyl group (path
a, Scheme 1) and (ii) the synthesis of intermediates con-
taining a 2-azatriene system encompassing the 2,3-bond of
the indole moiety followed by an electrocyclization reaction
(path b, Scheme 1).
The desired products 2 were always obtained in mixture
with by-products which were identi®ed as 2-amino-3-
indolecarboxamides 3a,b on the basis of analytical and
spectroscopic evidences. The origin of these compounds
was explained by assuming the formation of a cyclic
ammonium intermediate (A) which produces an imine (B)
by ring-opening. On hydrolysis, B gives the ®nal compound
3 (Scheme 2). The structure of the indole derivatives 3a was
con®rmed by the independent synthesis of 3a from a-(2-
nitrophenyl)cyanoacetyl-morpholide (see Experimental).
According to path a, the known amidines 1a,b1 and the
newly prepared 1c, were transformed, both under basic
and acid catalysis, into the 3,9-dialkyl-2-morpholino-a-
carbolines 2a±c by an intramolecular condensation reac-
tion. The best results were obtained by heating a mixture
of compounds 1a±c with silica gel at 180±2008C in the
The synthetic procedure indicated as path b in Scheme 1,

E. Erba et al. / Tetrahedron 56 (2000) 9991±9997
9993
Scheme 3.
was achieved by reaction of compounds 1a±c with aryl-
methylketones 4a±d in the presence of sodium ethoxide
in ethanol affording the expected unsaturated ketones
5a±f in satisfactory yield (Scheme 3). Besides the main
products 5 an increasingly higher amount of 2-aryl-9-
alkyl-a-carbolines 6a±e was produced, when longer
reaction times (35±40 h) were used for the condensation
reaction. Compounds 6 were demonstrated to derive from
5. By prolonged heating of 5a in presence of sodium
ethoxide, 6a was formed. Better conditions for the for-
mation of 6a±e were the heating of 5a±f in presence of
potassium t-butoxide for 10 h. An explanation of this result
is contained in Scheme 3.
Heating of 5a±f in the presence of silica gel and in the
absence of solvent at 1808C for about 10 h afforded the
2,9-dialkyl-3-aroyl-a-carbolines 7a±f as the main products
(about 50% yield) accompanied by a minor amount of
compounds 2a±c (about 10% yield). The expected forma-
tion of products 7 occurred though an electrocyclization
process which was made irreversible by morpholine elimi-
nation and the consequent aromatization the ring (Scheme
4). Products 2 were produced by the process depicted in
Scheme 4, according to which an intermediate C was
produced by a cyclocondensation reaction. Final products
2 are formed by arylmethylketone elimination according to
a retro-Michael mechanism.

9994
E. Erba et al. / Tetrahedron 56 (2000) 9991±9997
Scheme 4.
In conclusion, readily available starting compounds have
been successfully used to develop new synthetic pathways
directed toward a-carbolines.
cyclohexene (1.75 g, 8.14 mmol) was added and the reac-
tion mixture was kept at room temperature for 5 h. The
crude reaction mixture was evaporated at reduced pressure,
taken up with water and extracted with CH2Cl2. The residue
was puri®ed by chromatography [ethyl acetate±cyclo-
hexane (1:9)] giving 2-bromo-1-(4-isopropenyl-cyclohex-
1-enylmethyl)-1H-indole-3-carbaldehyde. Yield 2.88 g,
Experimental
1
90%. Pale yellow oil, IR 1660 (CO); H NMR 1.32 (7H,
Mps were determined by a BuÈchi 510 (capillary) apparatus.
IR spectra were measured with a JASCO IR Report 100
instrument (Nujol; cm21). NMR spectra were obtained
with Bruker AC 200, Bruker Advance 300 and Varian
Gemini 200 instruments. J values are given in Hz for
solutions in CDCl3. 1-Benzyl-2-azido-1H-indole-3-carb-
aldehyde and 1-alkyl-9-benzyl-2-[1-(morpholin-4-yl)propyl-
ideneamino]-1H-indole-3-carbaldehydes 1a,b are known
compounds.1
m, 3CH21CH), 1.70 (3H, s, CH3), 4.63±4.82 (4H, m,
CH2N1CH2vC), 5.42±5.54 (1H, m, CHvC), 7.25±7.40
(3H, m, ArH), 8.28±8.39 (1H, m, H-4), 10.05 (1H, s,
CHO). Calcd for C19H20BrNO (358.29) C 63.69, H 5.63,
N 3.91 found: C 63.42, H 5.93, N, 3.70. 2-Bromo-1-(4-iso-
propenyl-cyclohex-1-enylmethyl)-1H-indole-3-carbaldehyde
(2.23 g, 6.33 mmol) was dissolved in 40 mL of DMSO at
room temperature and NaN3 (0.52 g, 8 mmol) was added.
After 48 h the reaction mixture was poured into 100 mL of
cold water and extracted with ethyl ether. The organic layer,
was dried with Na2SO4 and evaporated at reduced pressure
affording 2-azido-1-(4-isopropenyl-cyclohex-1-enylmethyl)-
1H-indole-3-carbaldehyde. Yield 2.21 g, 88% of product in
suf®ciently pure form for direct use; IR 2120 (N3), 1660
(CHO); 1H NMR 1.40±2.20 (7H, m, 3CH21CH), 1.70
2-(1-Morpholin-4-yl-propylidenamino)-1-(4-isopropenyl-
cyclohex-1-enylmethyl)-1H-indole-3-carbaldehyde 1c.
2-Bromo-1H-indole-3-carbaldheyde1 (2 g, 8.93 mmol) was
suspended in 10 mL of anhydrous THF in N2 atmosphere.
NaH (60% in oil) (0.71 g, 17.8 mmol) was added at room
temperature. After 30 min. 1-bromomethyl-4-isopropenyl-

E. Erba et al. / Tetrahedron 56 (2000) 9991±9997
9995
(3H, s, CH3), 4.55±4.77 (4H, m, CH2vC and CH2N), 5.45±
5.52 (1H, m, CHvC), 7.22±7.37 (3H, m, ArH), 8.01±8.12
(1H, m, H-4), 10.32 (1H, s, CHO).
Et2O). IR 3250±3350 (NH2), 1625 (CvO); 1H NMR 3.45±
3.92 (8H, m, morpholine), 5.19 (2H, s, CH2Ph), 5.35 (2H,
bs, NH2), 6.98±7.52 (9H, m, ArH). Calcd for C20H21N3O2
(335.40) C 71.62 H 6.31 N 12.53 found C 71.43 H 6.65 N
12.24.
2-Azido-1-(4-isopropenyl-cyclohex-1-enylmethyl)-1H-indole-
3-carbaldehyde (1.7 g, 5.6 mmol) was dissolved in CH2Cl2
(20 ml) and propionaldehyde (0.40 g, 7 mmol) and morpho-
line (0.61 ml, 7 mmol) was added. The reaction mixture was
stirred at room temperature for 12 h and the solution was
dried with Na2SO4 and evaporated. The residue was puri®ed
by chromatography [ethyl acetate±cyclohexane (2:3)]. The
main fraction was evaporated yielding 3.0 g of a yellow oil.
[2-Amino-1-(4-isopropenyl-cyclohex-1-enylmethyl)-1H-
indole-3-yl]morpholin-4-yl-methanone 3b. Yield 43%.
Mp 1648C (yellow crystals from Pri2O). IR 3250±3350
1
(NH2), 1630 (CvO); H NMR 1.60±2.16 (7H, m, 3CH2
and CH), 1.74 (3H, s, CH3Cv), 3.63±3.82 (8H, m, morpho-
line), 4.49 (2H, s, CH2N), 4.71±4.74 (2H, m, CH2vC), 5.43
(2H, bs, NH2), 5.58±5.61 (1H, m, CHvC), 7.05±7.33 (4H,
m, ArH). Calcd for C23H29N3O2 (379.50) C 72.79 H 7.70 N
11.01 found: C 72.52 H 7.84 N 10.92.
1
Yield 3.0 g, 70%. IR 1620 (CHO), H NMR 1.04 (3H, t,
Jˆ7.2 Hz, CH3), 1.32±2.18 (7H, m, 3CH21CH), 1.70 (3H,
s, CH3), 2.35±2.70 (2H, m, CH2), 3.60±3.91 (8H, m,
morpholine), 4.43 (2H, s, CH2N), 4.65±4.77 (2H, m,
CH2vC), 5.44±5.54 (1H, m, CHvC), 7.08±7.29 (3H, m,
ArH), 8.05±8.19 (1H, m, H-4), 9.64 (1H, s, CHO). Calcd for
C26H33N3O2 (403.57) C 77.38, N 8.24, N 10.41 found: C
77.10, H 8.46, N 10.05.
Synthesis of 3-[1-alkyl-2-(1-morpholin-4-yl-alkyliden-
amino)-1H-indol-3-yl]-1-phenyl-propenones 5a±f.
General procedure
Compounds 1a±c (1 mmol) and Na (2 mmol) were
dissolved in anhydrous ethanol (2 mL). 2-Aryl-methanone
4a±d (1 mmol) was added and the mixture was re¯uxed for
20 h. After solvent evaporation the crude reaction mixture
was taken up with water and extracted with CH2Cl2
(3£10 mL). The combined extracts were dried with
Na2SO4 and evaporated at reduced pressure. The crude resi-
due was chromatographed with ethyl acetate±cyclohexane
(1:4). The main fraction was crystallised whit the solvent
indicated affording pure 5a±f.
Synthesis of 3,9-dialkyl-2-morpholin-4-yl-9H-pyrido-
[2,3-b]indoles 2a±c and (2-amino-1-alkyl-1H-indol-3-yl)-
morpholin-4-yl-methanones 3a,b. General procedure
Compounds 1a±c (1 mmol) were mixed with silica gel
(80 mg) and heated at 1808C for 90 min until disappearance
of the starting material by TLC [ethyl acetate±cyclohexane
(1:1)]. The crude reaction mixture was puri®ed by chroma-
tography [pentane±ethyl acetate (1:0 to 1:1)] and two main
fractions were isolated containing 2a±c (®rst fraction) and
3a,b (second fraction) respectively.
3-[1-Benzyl-2-(1-morpholin-4-yl-propylidenamino)-1H-
indol-3-yl]-1-phenyl-propenone 5a. Yield 55%. Mp 120±
1218C (white crystals from EtOH). IR 1660 (CvO); H
1
9-Benzyl-3-methyl-2-morpholin-4-yl-9H-pyrido[2,3-b]-
indole 2a. Yield 37%. Mp 1308C (white crystals from
EtOH). H NMR 2.45 (3H, s, CH3), 3.27±3.31, 3.89±3.94
NMR 0.81 (3H, t, Jˆ7.2 Hz, CH3), 2.16±2.19 (2H, m,
CH2), 3.63±3.76 (8H, m, morpholine), 5.15 (2H, s,
CH2Ph), 7.00±8.06 (16H, m, 14 ArH1CHvCH). Calcd
for C31H31N3O2 (477.61) C 77.96 H 6.54 N 8.80 found: C
77.82 H 6.92 N 8.49.
1
(4H14H, 2m, morpholine), 5.62 (2H, s, CH2Ph), 7.18±7.34
(8H, m, ArH), 7.95 (1H, d, Jˆ7.7 Hz, H-5), 8.08 (1H, s, H-
5). Calcd for C23H23N3O (357.43) C 77.29 H 6.49 N 11.76
found: C 77.00 H 6.97 N 11.51.
3-[1-Benzyl-2-(1-morpholin-4-yl-propylidenamino)-1H-
indol-3-yl]-1-(4-methoxyphenyl)-propenone 5b. Yield
64%. Mp 958C (white crystals from EtOH). IR 1660
9-Benzyl-3-ethyl-2-morpholin-4-yl-9H-pyrido[2,3-b]-
indole 2b. Yield 36%. Mp 1138C (white crystals from
1
1
EtOH). H NMR 1.38 (3H, t, Jˆ7.2 Hz, CH3), 2.80 (2H,
(CvO), H NMR 0.82 (3H, t, Jˆ7.2 Hz, CH3), 2.13±2.23
q, Jˆ7.2 Hz, CH2), 3.23±3.27, 3.88±3.93 (4H14H, 2m,
morpholine), 5.62 (2H, s, CH2Ph), 7.17±7.40 (8H, m,
ArH), 7.98 (1H, d, Jˆ7.7 Hz, H-5), 8.15 (1H, s, H-4).
Calcd for C24H25N3O (371.46) C 77.60 H 6.78 N 11.31
found: C 77.42 H 6.92 N 11.35.
(2H, m, CH2), 3.64±3.78 (8H, m, morpholine), 3.89 (3H, s,
OCH3), 5.18 (2H, s, CH2Ph), 6.98 and 8,06 (212H, 2d,
Jˆ8.8 Hz, C6H4OCH3), 7.12±7.26 (8H, m, ArH), 7.40
(1H, d, J 15.2 Hz, CHvCHCO), 7.87 (1H, d, Jˆ15.2 Hz,
CHvCHCO), 7.92 (1H, d, Jˆ7.3 Hz, H-4). Calcd for
C32H33N3O3 (507.63) C 75.71 H 6.55 N 8.28 found: C
75.41 H 6.92 N 8.01.
9-(4-Isopropenyl-cyclohex-1-enylmethyl)-2-methyl-3-
morpholin-4-yl-9H-pyrido[2,3-b]indole 2c. Yield 42%.
1
Mp 1168C (white crystals from EtOH). H NMR 1.22±
3-[1-Benzyl-2-(1-morpholin-4-yl-propylidenamino)-1H-
indol-3-yl]-1-(4-bromophenyl)-propenone 5c. Yield 85%.
Mp 1768C (white crystals from EtOH). IR 1660 (CvO), 1H
NMR 0.81 (3H, t, Jˆ7.2 Hz, CH3), 2.09±2.26 (2H, m, CH2),
3.53±3.85 (8H, m, morpholine), 5.15 (2H, s, CH2Ph), 7.15±
7.96 (15H, m, 13 ArH1CHvCH). Calcd for C31H30BrN3O2
(556.50) C 66.91 H 5.43 N 7.55 found: C 66.64 H 5.61 N
7.36.
2.21 (7H, m, 3CH2 and CH), 1.68 (3H, s, CH3Cv), 2.43
(3H, s, CH3), 3.22±3.34, 3.86±3.99 (4H14H, 2m, morpho-
line), 4.63±4.71 (2H, m, CH2±N), 4.91±5.00 (2H, m,
CH2vC), 5.68±5.77 (1H, m, CHvC), 7.14±7.44 (3H, m,
ArH), 7.93 (1H, d, Jˆ7.4 Hz, H-5), 8.04 (1H. s, H-4). Calcd
for C26H31N3O (401.56) C 77.77 H 7.78 N 10.46 found: C
77.41 H 8.02 N 10.30.
(2-Amino-1-benzyl-1H-indole-3-yl)-morpholin-4-yl-metha-
none 3a. Yield 51%. Mp 1978C (yellow earth crystal from
3-[1-Benzyl-2(1-morpholin-4-yl-butylideneamino)-1H-
indol-3-yl]-1(4-methoxyphenyl)-propenone 5d. Yield

9996
E. Erba et al. / Tetrahedron 56 (2000) 9991±9997
1
72%. Mp 1568C (white crystal from EtOH). H NMR 5.73
70%. Mp 97 (white crystals from EtOH). IR 1660
(CvO),1H NMR 0.67 (3H, t, Jˆ7.2 Hz, CH3), 1.21±1.28
(2H, m, CH2), 2.10±2.29 (2H, m, CH2), 3.64±3.79 (8H, m,
morpholine), 3.89 (3H, s, OCH3), 5.15 (2H, s, CH2Ph), 7.11
and 8,06(212H, 2d, Jˆ8.7 Hz, C6H4OCH3), 7.14±7.28 (8H,
m, ArH), 7.41 (1H, d, Jˆ15.2 Hz, CHvCHCO), 7.86 (1H,
d, Jˆ15.2 Hz, CHvCHCO), 7.92 (1H, d, Jˆ8.0 Hz, H-4).
Calcd for C33H35N3O3 (521.67) C 75.98 H 6.76 N 8.05
found: C 75.72 H 6.95 N 7.89
(2H, s, CH2Ph), 7.10±7.74 (11H, m, ArH), 7.61 (1H, d,
Jˆ8.0 Hz, H-3), 8.04 (1H, d, Jˆ7.6 Hz, H-5), 8.31 (1H, d,
Jˆ8.0 Hz, H-4). Calcd for C22H16N2S (340.45) C 77.62 H
4.74 N 8.23 found: C 77.58 H 5.02 N 8.10.
9-(4-Isopropenyl-cyclohex-1-enylmethyl)-2-(4-methoxy-
phenyl)-9H-pyrido[2,3-b]indole 6e. Yield 59%. Mp 1498C
(white crystal from EtOH). 1H NMR 1.23 (7H, m,
3CH21CH), 1.71 (3H, s, CH3), 3.91 (3H, s, OCH3), 3.62±
3.74 (2H, m, CH2N), 5.10±5.14 (2H, m, CH2vC), 5.70±
5.74 (1H, m, CHvC), 7.07 and 8.18 (212H, 2d, Jˆ8.8 Hz,
C6H4OMe), 7.20±7.49 (3H, m, ArH), 7.62 (1H, d, Jˆ
8.0 Hz, H-3), 8.08 (1H, d, Jˆ7.6 Hz, H-5), 8.34 (1H, d,
Jˆ8.0 Hz, H-4). Calcd for C28H28N2O (408.54) C 82.32 H
6.91 N 6.86 found: C 82.41 H 7.06 N 8.48.
3-[1-Benzyl-2-(morpholin-4-yl-butylidenamino)-1H-indol-
3-yl]-1-thien-2-yl-propenone 5e. Yield 52%. Yellow oil.
1
IR 1600 (CvO), H NMR 0.68 (3H, t, Jˆ7.2 Hz, CH3),
1.60±1.63 (2H, m, CH2), 2.11±2.26 (2H, m, CH2), 3.65±
3.78 (8H, m, morpholine), 5.15 (2H, s, CH2Ph), 7.10±7.94
(14H, m, ArH). Calcd for C30H31N3O2S (497.60) C 72.41
H 6.28 N 8.44 found: C 72.01 H 6.54 N 8.09.
General procedure for the preparation of [2,9-dialkyl-
9H-pyrido[2,3-b]indol-3-yl]aryl-methanones 7a±f
3-[1(4-Isopropenyl-cyclohex-1-enylmethyl)-2-(1-morpho-
lin-4-yl-propylidenamino)-1H-indol-3-yl]-1(4-methoxy-
phenyl)-propenone 5f. Yield 61%.Yellow oil. IR 1605
1
Compounds 5a±f (1 mmol) were mixed with silica gel
(100 mg) and heated at 180±2008C for 10 h until disappear-
ance of the starting material [TLC, ethyl acetate±cyclo-
hexane (3:2)] yielding 7. The crude reaction product was
puri®ed by column chromatography [pentane±ethyl acetate
(1:0 to 19:1)].
(CvO), H NMR 0.78±2.52 (10H, m, 3CH21CH1CH3),
3.58±3.95 (8H, m, morpholine), 3.89 (3H. s, OCH3), 4.45
(2H, s, CH2N), 4.63±4.78 (2H, m, CH2vC), 5.48±5.59 (1H,
m, CHvC), 6.99±8.06 (10H, m, ArH). Calcd for
C35H41N3O3 (551.73) C 76.19 H 7.49 N 7.62 found: C
75.97 H 7.58 N 7.43.
General procedure for the preparation of 9-alkyl-2-aryl-
9H-pyrido[2,3-b]indoles 6a±e
(9-Benzyl-2-ethyl-9H-pyrido[2,3-b]indol-3-yl)phenyl-
methanone 7a. Yield 51%. Mp 1038C (white crystals from
1
EtOH). IR 1665 (CvO), H NMR 1.38 (3H, t, Jˆ7.2 Hz,
Compounds 5a±f (1 mmol) and t-BuOK (3 mmol) were
dissolved in t-BuOH (6 ml) and re¯uxed for 12 h. The
mixture was cooled and the precipitate was ®ltered. The
crude product was dissolved in CH2Cl2 and washed with
water. The organic layer was dried with Na2SO4 ad evapo-
rated. After crystallisation of the residue the pure product 7
was obtained.
CH3), 3.8 (2H, q, Jˆ7.2 Hz, CH2), 5.76 (2H, s, CH2Ph),
7.15±7.88 (13H, m, ArH), 7.97 (1H, d, Jˆ7.7 Hz, H-5),
8.30 (1H, s, H-4). Calcd for C27H22N2O (390.48) C 83.05
H 5.68 N 7.17 found: C 82.87 H 5.92 N 7.95.
(9-Benzyl-2-ethyl-9H-pyrido[2,3-b]indol-3-yl)-(4-meth-
oxyphenyl)-methanone 7b. Yield 70%. Mp 798C (white
crystals from EtOH). IR 1665 (CvO), H NMR 1.36 (3H,
1
9-Benzyl-2-phenyl-9H-pyrido[2,3-b]indole 6a. Yield
79%. Mp 1318C (white crystals from EtOH). H NMR
t, Jˆ7.2 Hz, CH3), 3.03 (2H, q, Jˆ7.2 Hz, CH2), 3.90 (3H, s,
OCH3), 5.75 (2H, s, CH2Ph), 6.98 and 7.87 (212H, 2d,
Jˆ8.5 Hz, C6H4OMe), 7.26±7.48 (8H, m, ArH), 7.98 (1H,
d, Jˆ7.7 Hz, H-5), 8.27 (1H, s, H-4). Calcd for C28H24N2O2
(420.51) C 79.98 H 5.75 N 6.67 found: C 79.74 H 5.96 N
6.38.
1
5.80 (2H, s, CH2Ph), 7.23±7.57 (11H, m, ArH), 7.72 (1H,
d, Jˆ8.2 Hz, H-3), 8.12 (1H, d, Jˆ7.8 Hz, H-5), 8.23 (2H, d,
Jˆ8.8 Hz, ArH), 8.40 (1H, d, Jˆ8.2 Hz, H-4). Calcd for
C24H18N2 (334.42) C 86.20 H 5.42 N 8.38 found: C 86.05
H 5.51 N 8.14.
(9-Benzyl-2-ethyl-9H-pyrido[2,3-b]indol-3-yl)-(4-bromo-
phenyl)-methanone 7c. Yield 45%. Mp 908C (pale yellow
crystals from EtOH). IR 1650 (CvO), 1H NMR 0.38 (3H, t,
Jˆ7.5 Hz, CH3), 3.07 (2H, q, Jˆ7.5 Hz, CH2), 5.75 (2H, s,
CH2Ph), 7.26±7.80 (12H, m, ArH), 7.98 (1H, d, Jˆ7.7 Hz,
H-5), 8.27 (1H, s, H-4). Calcd for C27H21BrN2O C 69.09 H
4.51 N 5.97 found: C 68.82 H 4.77 N 5.63.
9-Benzyl-2-(4-methoxyphenyl)-9H-pyrido[2,3-b]indole
6b. Yield 68%. Mp 1878C (white crystal from EtOH). H
1
NMR 3.89 (3H, s, OCH3), 5.78 (2H, s, CH2Ph), 7.02 and
8.17 (212H, 2d, Jˆ8.9 Hz, C6H4OCH3), 7.10±7.48 (8H, m,
ArH), 7.64 (1H, d, Jˆ8.2 Hz, H-3), 8.06 (1H, d, Jˆ8.4 Hz,
H-5), 8.35 (1H, d, Jˆ8.2 Hz, H-4). Calcd for C25H20N2O
(364.45) C 82.39 H 5.53 N 7.69 found: C 82.15 H 5.76 N
7.38.
(9-Benzyl-2-propyl-9H-pyrido[2,3-b]indol-3-yl)-(4-meth-
oxyphenyl)-methanone 7d. Yield 55%. Mp 1058C (white
crystals from EtOH). IR 1660 (CvO), 1H NMR 0.90±0.97
(3H, t, Jˆ7.2 Hz, CH3), 1.80±1.91(2H, m, CH2), 2.96±3.04
(2H, m, CH2), 3.91 (3H, s, OCH3), 5.74 (2H, s, CH2Ph),
6.95±7.88 (12H, m, ArH), 7.98 (1H, d, Jˆ7.2 Hz, H-5),
8.26 (1H, s, H-4). Calcd for C29H26N2O2 (434.54) C 80.16
H 6.03 N 6.45 found: C 79.97 H 6.35 N 6.23.
9-Benzyl-2-(4-bromophenyl)-9H-pyrido[2,3-b]indole 6c.
Yield 65%. Mp 1378C (white crystals from EtOH). H
NMR 5.80 (2H, s, CH2Ph), 7.28±8.13 (14H, s, ArH), 8.40
(1H, d, Jˆ8.1 Hz, H-4). Calcd for C24H17BrN2 (413.32) C
69.74 H 4.14 N 6.78 found C 69.45 H 4.25 N 6.64.
1
9-Benzyl-2-thien-2-yl-9H-pyrido-[2,3-b]indole 6d. Yield

E. Erba et al. / Tetrahedron 56 (2000) 9991±9997
9997
(9-Benzyl-2-propyl-9H-pyrido[2,3-b]indol-3yl)-thieno-2-
yl-methanone 7e. Yield 46%. Mp 998C (white crystals from
was dissolved in ethyl acetate, washed with aqueous
NaHCO3. The organic layer was dried and evaporated.
The residue was crystallised with ethyl acetate to afford
(2-amino-1H-indol-3-yl)-morpholin-4-yl-methanone (2.0 g,
75%), mp 2098C. 1H NMR 3.15±3.93 (8H, m, morpholine),
6.46 (2H, bs, NH2), 6.66±7.38 (4H, m, ArH), 10.59 (1H, bs,
NH). Calcd for C13H15N3O2 (245.28) C 63.66 H 6.16 N
17.13 found C 63.46 H 6.39 N 17.02.
1
EtOH).IR 1650 (CvO). H NMR 0.96 (3H, t, Jˆ7.2 Hz,
CH3), 1.88 (2H, q, Jˆ7.2 Hz, CH2), 3.07 (2H, t, Jˆ
7.2 Hz, CH2), 5.74 (2H, s, CH2Ph), 7.09±7.80 (11H, m,
ArH), 8.01 (1H, d, Jˆ7.7 Hz, H-5), 8.44 (1H, s, H-4).
Calcd for C26H22N2OS (410.47) C 76.08 H 5.32 N 6.82
found: C 75.86 H 5.46 N 6.56.
[2-Ethyl-9-(4-isopropenyl-cyclohex-1-enylmethyl)-9H-
pyrido[2,3-b]indol-3-yl]-(4-methoxyphenyl)-methanone
7f. Yield 31%. Mp 1158C (white crystals from Et2O). IR
(2-Amino-1H-indol-3-yl)-morpholin-4-yl-methanone was
alkylated with benzyl chloride according to a literature
method7 and afforded 3a (Mp 1978C, yield 17%).
1
1660, H NMR 0.80±2.37 (10H, 3CH21CH1CH3), 1.69
(3H, s, CH3), 3.02 (2H, q, Jˆ7.2 Hz, CH2), 3.94 (3H, s,
OCH3), 4.62±4.71 (2H, m, CH2N), 5.02±5.21 (2H, m,
CH2vC), 5.61±5.79 (1H, m, CHvC), 7.13±7.85 (7H, m,
ArH), 7.97 (1H, d, Jˆ8.4 Hz, H-5), 8.24 (1H, s, H-4). Calcd
for C31H32N2O2 (464.61) C 80.14 H 6.94 N 6.03 found: C
79.87 H 7.13 N 5.75.
References
1. Part 41. Erba, E.; Pocar, D.; Valle M. J. Chem. Soc., Perkin
Trans. 1 1999, 421±425 and references therein.
2. Molina, P.; Fresneda, P. M.; Sanz, M. A.; Foces-Foces, C.;
de Arellano, M. C. R. Tetrahedron 1998, 54, 9623±9638.
3. (a) Bhatti I. A.; Busby R. E.; Binmohamed M.; Parrick J. and
Shaw C. J. G. J. Chem. Soc., Perkin Trans 1 1997, 3581±3585.
(b) Kazerani S.; Novak S. J. Org. Chem. 1998, 63, 895±897.
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P. K.; Ila H.; Junjappa H. Tetrahedron Lett. 1999, 40, 3797±3800.
5. Greenhill, J. W. In Comprehensive Heterocyclic Chemistry,
Katritzky, A. R., Rees, C. W. Eds.; Pergamon: Oxford, 1984; 4,
pp 521±529.
Independent synthesis of (2-amino-1-benzyl-1H-indol-3-
yl)-morpholin-4-yl-methanone 3a
A solution of 3-(morpholin-4-yl)-2-(2-nitrophenyl)-3-oxo-
propionitrile (2.9 g, 10.8 mmol), obtained according to the
literature method6 (mp 1438C), in a mixture of acetic acid
(5 mL) and toluene (15 mL) was heated until an internal
temperature of 808C was reached. External heating was
removed and zinc powder (6.6 g, 101 mmol) was slowly
added portionwise to the vigorously stirred mixture main-
taining the internal temperature within the range of 80±
858C. After the addition of zinc was complete, the reaction
mixture was cooled, ®ltered and evaporated. The residue
6. Germain, C.; Bourdais, J. J. Heterocycl. Chem. 1976, 13, 1209±
1218.
7. Forbes, T.; Johnson, C. N.; Thompson, M. J. Chem. Soc., Perkin
Trans. 1 1992, 275±281.