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
Istituto di Chimica Organica, FacoltaÁ di Farmacia e Centro Interuniversitario di Ricerca sulle Reazioni Pericicliche e Sintesi di Sistemi
Etero-e Carbociclici, UniversitaÁ 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
Previous research work from this laboratory involved an metabolites.3 Moreover, some synthetic pyrido[2,3-b]indole
investigation into a new synthesis of heterocyclic derivatives are anxiolytic or neuroprotectant agents.4
compounds starting from 5-amino-v-triazolines and their
transformation products.1 New synthetic routes to substi- The formation of the a-carboline ring system has already
tuted quinazolines and related heterocycles were discovered been described in the literature and different routes are
and key intermediates for their synthesis were found in known which rely on the formation of the middle ring
special substituted amidines of general structure 1 for through intramolecular cyclization of an N-containing
which practical preparation procedures were set up.1 We ortho-substituent in a 3-phenylpyridine substrate or on the
now report on new synthetic pathways to prepare several use of reactions affording the linkage of the ortho,ortho
substituted a-carbolines in which the above amidine positions in N-(2-pyridyl)anilines.5 The ready availability
derivatives 1 were successfully used. 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: [email protected]

0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S 0040-402 0(00)00950-9
9992 E. Erba et al. / Tetrahedron 56 (2000) 9991±9997

Scheme 2.

new synthetic strategies involving the construction of the absence of solvent. Probably the ring-closure reaction
pyridine ring on the pre-formed indole moiety. occurs through the isomerization of the amidine into its
diaminoalkylidene tautomer followed by intramolecular
condensation of the a carbon with the aldehyde group and
Results and Discussion water elimination (Scheme 2). Products 2 represent a new
class of substituted a-carboline derivatives and are charac-
Taking into account the structural features of compounds 1 terised in the 1H NMR spectrum by a typical singlet at d H
two schemes were ®rstly planned for the preparation of the 8.0±8.1 associated with H-4.
carboline ring i.e. (i) the intramolecular condensation of the
a-carbon of the amidine group with the formyl group (path The desired products 2 were always obtained in mixture
a, Scheme 1) and (ii) the synthesis of intermediates con- with by-products which were identi®ed as 2-amino-3-
taining a 2-azatriene system encompassing the 2,3-bond of indolecarboxamides 3a,b on the basis of analytical and
the indole moiety followed by an electrocyclization reaction spectroscopic evidences. The origin of these compounds
(path b, Scheme 1). was explained by assuming the formation of a cyclic
ammonium intermediate (A) which produces an imine (B)
According to path a, the known amidines 1a,b1 and the by ring-opening. On hydrolysis, B gives the ®nal compound
newly prepared 1c, were transformed, both under basic 3 (Scheme 2). The structure of the indole derivatives 3a was
and acid catalysis, into the 3,9-dialkyl-2-morpholino-a- con®rmed by the independent synthesis of 3a from a-(2-
carbolines 2a±c by an intramolecular condensation reac- nitrophenyl)cyanoacetyl-morpholide (see Experimental).
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- Heating of 5a±f in the presence of silica gel and in the
methylketones 4a±d in the presence of sodium ethoxide absence of solvent at 1808C for about 10 h afforded the
in ethanol affording the expected unsaturated ketones 2,9-dialkyl-3-aroyl-a-carbolines 7a±f as the main products
5a±f in satisfactory yield (Scheme 3). Besides the main (about 50% yield) accompanied by a minor amount of
products 5 an increasingly higher amount of 2-aryl-9- compounds 2a±c (about 10% yield). The expected forma-
alkyl-a-carbolines 6a±e was produced, when longer tion of products 7 occurred though an electrocyclization
reaction times (35±40 h) were used for the condensation process which was made irreversible by morpholine elimi-
reaction. Compounds 6 were demonstrated to derive from nation and the consequent aromatization the ring (Scheme
5. By prolonged heating of 5a in presence of sodium 4). Products 2 were produced by the process depicted in
ethoxide, 6a was formed. Better conditions for the for- Scheme 4, according to which an intermediate C was
mation of 6a±e were the heating of 5a±f in presence of produced by a cyclocondensation reaction. Final products
potassium t-butoxide for 10 h. An explanation of this result 2 are formed by arylmethylketone elimination according to
is contained in Scheme 3. a retro-Michael mechanism.
9994 E. Erba et al. / Tetrahedron 56 (2000) 9991±9997

Scheme 4.

In conclusion, readily available starting compounds have cyclohexene (1.75 g, 8.14 mmol) was added and the reac-
been successfully used to develop new synthetic pathways tion mixture was kept at room temperature for 5 h. The
directed toward a-carbolines. 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-
Experimental hexane (1:9)] giving 2-bromo-1-(4-isopropenyl-cyclohex-
1-enylmethyl)-1H-indole-3-carbaldehyde. Yield 2.88 g,
Mps were determined by a BuÈchi 510 (capillary) apparatus. 90%. Pale yellow oil, IR 1660 (CO); 1H NMR 1.32 (7H,
IR spectra were measured with a JASCO IR Report 100 m, 3CH21CH), 1.70 (3H, s, CH3), 4.63±4.82 (4H, m,
instrument (Nujol; cm21). NMR spectra were obtained CH2N1CH2vC), 5.42±5.54 (1H, m, CHvC), 7.25±7.40
with Bruker AC 200, Bruker Advance 300 and Varian (3H, m, ArH), 8.28±8.39 (1H, m, H-4), 10.05 (1H, s,
Gemini 200 instruments. J values are given in Hz for CHO). Calcd for C19H20BrNO (358.29) C 63.69, H 5.63,
solutions in CDCl3. 1-Benzyl-2-azido-1H-indole-3-carb- N 3.91 found: C 63.42, H 5.93, N, 3.70. 2-Bromo-1-(4-iso-
aldehyde and 1-alkyl-9-benzyl-2-[1-(morpholin-4-yl)propyl- propenyl-cyclohex-1-enylmethyl)-1H-indole-3-carbaldehyde
ideneamino]-1H-indole-3-carbaldehydes 1a,b are known (2.23 g, 6.33 mmol) was dissolved in 40 mL of DMSO at
compounds.1 room temperature and NaN3 (0.52 g, 8 mmol) was added.
After 48 h the reaction mixture was poured into 100 mL of
2-(1-Morpholin-4-yl-propylidenamino)-1-(4-isopropenyl- cold water and extracted with ethyl ether. The organic layer,
cyclohex-1-enylmethyl)-1H-indole-3-carbaldehyde 1c. was dried with Na2SO4 and evaporated at reduced pressure
2-Bromo-1H-indole-3-carbaldheyde1 (2 g, 8.93 mmol) was affording 2-azido-1-(4-isopropenyl-cyclohex-1-enylmethyl)-
suspended in 10 mL of anhydrous THF in N2 atmosphere. 1H-indole-3-carbaldehyde. Yield 2.21 g, 88% of product in
NaH (60% in oil) (0.71 g, 17.8 mmol) was added at room suf®ciently pure form for direct use; IR 2120 (N3), 1660
temperature. After 30 min. 1-bromomethyl-4-isopropenyl- (CHO); 1H NMR 1.40±2.20 (7H, m, 3CH21CH), 1.70
 E. Erba et al. / Tetrahedron 56 (2000) 9991±9997 9995

(3H, s, CH3), 4.55±4.77 (4H, m, CH2vC and CH2N), 5.45± Et2O). IR 3250±3350 (NH2), 1625 (CvO); 1H NMR 3.45±
5.52 (1H, m, CHvC), 7.22±7.37 (3H, m, ArH), 8.01±8.12 3.92 (8H, m, morpholine), 5.19 (2H, s, CH2Ph), 5.35 (2H,
(1H, m, H-4), 10.32 (1H, s, CHO). 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
2-Azido-1-(4-isopropenyl-cyclohex-1-enylmethyl)-1H-indole- 12.24.
3-carbaldehyde (1.7 g, 5.6 mmol) was dissolved in CH2Cl2
(20 ml) and propionaldehyde (0.40 g, 7 mmol) and morpho- [2-Amino-1-(4-isopropenyl-cyclohex-1-enylmethyl)-1H-
line (0.61 ml, 7 mmol) was added. The reaction mixture was indole-3-yl]morpholin-4-yl-methanone 3b. Yield 43%.
stirred at room temperature for 12 h and the solution was Mp 1648C (yellow crystals from Pri2O). IR 3250±3350
dried with Na2SO4 and evaporated. The residue was puri®ed (NH2), 1630 (CvO); 1H NMR 1.60±2.16 (7H, m, 3CH2
by chromatography [ethyl acetate±cyclohexane (2:3)]. The and CH), 1.74 (3H, s, CH3Cv), 3.63±3.82 (8H, m, morpho-
main fraction was evaporated yielding 3.0 g of a yellow oil. line), 4.49 (2H, s, CH2N), 4.71±4.74 (2H, m, CH2vC), 5.43
Yield 3.0 g, 70%. IR 1620 (CHO), 1H NMR 1.04 (3H, t, (2H, bs, NH2), 5.58±5.61 (1H, m, CHvC), 7.05±7.33 (4H,
Jˆ7.2 Hz, CH3), 1.32±2.18 (7H, m, 3CH21CH), 1.70 (3H, m, ArH). Calcd for C23H29N3O2 (379.50) C 72.79 H 7.70 N
s, CH3), 2.35±2.70 (2H, m, CH2), 3.60±3.91 (8H, m, 11.01 found: C 72.52 H 7.84 N 10.92.
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, Synthesis of 3-[1-alkyl-2-(1-morpholin-4-yl-alkyliden-
ArH), 8.05±8.19 (1H, m, H-4), 9.64 (1H, s, CHO). Calcd for amino)-1H-indol-3-yl]-1-phenyl-propenones 5a±f.
C26H33N3O2 (403.57) C 77.38, N 8.24, N 10.41 found: C General procedure
77.10, H 8.46, N 10.05.
Compounds 1a±c (1 mmol) and Na (2 mmol) were
Synthesis of 3,9-dialkyl-2-morpholin-4-yl-9H-pyrido- dissolved in anhydrous ethanol (2 mL). 2-Aryl-methanone
[2,3-b]indoles 2a±c and (2-amino-1-alkyl-1H-indol-3-yl)- 4a±d (1 mmol) was added and the mixture was re¯uxed for
morpholin-4-yl-methanones 3a,b. General procedure 20 h. After solvent evaporation the crude reaction mixture
was taken up with water and extracted with CH2Cl2
Compounds 1a±c (1 mmol) were mixed with silica gel (3£10 mL). The combined extracts were dried with
(80 mg) and heated at 1808C for 90 min until disappearance Na2SO4 and evaporated at reduced pressure. The crude resi-
of the starting material by TLC [ethyl acetate±cyclohexane due was chromatographed with ethyl acetate±cyclohexane
(1:1)]. The crude reaction mixture was puri®ed by chroma- (1:4). The main fraction was crystallised whit the solvent
tography [pentane±ethyl acetate (1:0 to 1:1)] and two main indicated affording pure 5a±f.
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±
9-Benzyl-3-methyl-2-morpholin-4-yl-9H-pyrido[2,3-b]- 1218C (white crystals from EtOH). IR 1660 (CvO); 1H
indole 2a. Yield 37%. Mp 1308C (white crystals from NMR 0.81 (3H, t, Jˆ7.2 Hz, CH3), 2.16±2.19 (2H, m,
EtOH). 1H NMR 2.45 (3H, s, CH3), 3.27±3.31, 3.89±3.94 CH2), 3.63±3.76 (8H, m, morpholine), 5.15 (2H, s,
(4H14H, 2m, morpholine), 5.62 (2H, s, CH2Ph), 7.18±7.34 CH2Ph), 7.00±8.06 (16H, m, 14 ArH1CHvCH). Calcd
(8H, m, ArH), 7.95 (1H, d, Jˆ7.7 Hz, H-5), 8.08 (1H, s, H- for C31H31N3O2 (477.61) C 77.96 H 6.54 N 8.80 found: C
5). Calcd for C23H23N3O (357.43) C 77.29 H 6.49 N 11.76 77.82 H 6.92 N 8.49.
found: C 77.00 H 6.97 N 11.51.
3-[1-Benzyl-2-(1-morpholin-4-yl-propylidenamino)-1H-
9-Benzyl-3-ethyl-2-morpholin-4-yl-9H-pyrido[2,3-b]- indol-3-yl]-1-(4-methoxyphenyl)-propenone 5b. Yield
indole 2b. Yield 36%. Mp 1138C (white crystals from 64%. Mp 958C (white crystals from EtOH). IR 1660
EtOH). 1H NMR 1.38 (3H, t, Jˆ7.2 Hz, CH3), 2.80 (2H, (CvO), 1H 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, (2H, m, CH2), 3.64±3.78 (8H, m, morpholine), 3.89 (3H, s,
morpholine), 5.62 (2H, s, CH2Ph), 7.17±7.40 (8H, m, OCH3), 5.18 (2H, s, CH2Ph), 6.98 and 8,06 (212H, 2d,
ArH), 7.98 (1H, d, Jˆ7.7 Hz, H-5), 8.15 (1H, s, H-4). Jˆ8.8 Hz, C6H4OCH3), 7.12±7.26 (8H, m, ArH), 7.40
Calcd for C24H25N3O (371.46) C 77.60 H 6.78 N 11.31 (1H, d, J 15.2 Hz, CHvCHCO), 7.87 (1H, d, Jˆ15.2 Hz,
found: C 77.42 H 6.92 N 11.35. 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
9-(4-Isopropenyl-cyclohex-1-enylmethyl)-2-methyl-3- 75.41 H 6.92 N 8.01.
morpholin-4-yl-9H-pyrido[2,3-b]indole 2c. Yield 42%.
Mp 1168C (white crystals from EtOH). 1H NMR 1.22± 3-[1-Benzyl-2-(1-morpholin-4-yl-propylidenamino)-1H-
2.21 (7H, m, 3CH2 and CH), 1.68 (3H, s, CH3Cv), 2.43 indol-3-yl]-1-(4-bromophenyl)-propenone 5c. Yield 85%.
(3H, s, CH3), 3.22±3.34, 3.86±3.99 (4H14H, 2m, morpho- Mp 1768C (white crystals from EtOH). IR 1660 (CvO), 1H
line), 4.63±4.71 (2H, m, CH2 ±N), 4.91±5.00 (2H, m, NMR 0.81 (3H, t, Jˆ7.2 Hz, CH3), 2.09±2.26 (2H, m, CH2),
CH2vC), 5.68±5.77 (1H, m, CHvC), 7.14±7.44 (3H, m, 3.53±3.85 (8H, m, morpholine), 5.15 (2H, s, CH2Ph), 7.15±
ArH), 7.93 (1H, d, Jˆ7.4 Hz, H-5), 8.04 (1H. s, H-4). Calcd 7.96 (15H, m, 13 ArH1CHvCH). Calcd for C31H30BrN3O2
for C26H31N3O (401.56) C 77.77 H 7.78 N 10.46 found: C (556.50) C 66.91 H 5.43 N 7.55 found: C 66.64 H 5.61 N
77.41 H 8.02 N 10.30. 7.36.

(2-Amino-1-benzyl-1H-indole-3-yl)-morpholin-4-yl-metha- 3-[1-Benzyl-2(1-morpholin-4-yl-butylideneamino)-1H-
none 3a. Yield 51%. Mp 1978C (yellow earth crystal from indol-3-yl]-1(4-methoxyphenyl)-propenone 5d. Yield
9996 E. Erba et al. / Tetrahedron 56 (2000) 9991±9997

70%. Mp 97 (white crystals from EtOH). IR 1660 72%. Mp 1568C (white crystal from EtOH). 1H NMR 5.73
(CvO),1H NMR 0.67 (3H, t, Jˆ7.2 Hz, CH3), 1.21±1.28 (2H, s, CH2Ph), 7.10±7.74 (11H, m, ArH), 7.61 (1H, d,
(2H, m, CH2), 2.10±2.29 (2H, m, CH2), 3.64±3.79 (8H, m, Jˆ8.0 Hz, H-3), 8.04 (1H, d, Jˆ7.6 Hz, H-5), 8.31 (1H, d,
morpholine), 3.89 (3H, s, OCH3), 5.15 (2H, s, CH2Ph), 7.11 Jˆ8.0 Hz, H-4). Calcd for C22H16N2S (340.45) C 77.62 H
and 8,06(212H, 2d, Jˆ8.7 Hz, C6H4OCH3), 7.14±7.28 (8H, 4.74 N 8.23 found: C 77.58 H 5.02 N 8.10.
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). 9-(4-Isopropenyl-cyclohex-1-enylmethyl)-2-(4-methoxy-
Calcd for C33H35N3O3 (521.67) C 75.98 H 6.76 N 8.05 phenyl)-9H-pyrido[2,3-b]indole 6e. Yield 59%. Mp 1498C
found: C 75.72 H 6.95 N 7.89 (white crystal from EtOH). 1H NMR 1.23 (7H, m,
3CH21CH), 1.71 (3H, s, CH3), 3.91 (3H, s, OCH3), 3.62±
3-[1-Benzyl-2-(morpholin-4-yl-butylidenamino)-1H-indol- 3.74 (2H, m, CH2N), 5.10±5.14 (2H, m, CH2vC), 5.70±
3-yl]-1-thien-2-yl-propenone 5e. Yield 52%. Yellow oil. 5.74 (1H, m, CHvC), 7.07 and 8.18 (212H, 2d, Jˆ8.8 Hz,
IR 1600 (CvO), 1H NMR 0.68 (3H, t, Jˆ7.2 Hz, CH3), C6H4OMe), 7.20±7.49 (3H, m, ArH), 7.62 (1H, d, Jˆ
1.60±1.63 (2H, m, CH2), 2.11±2.26 (2H, m, CH2), 3.65± 8.0 Hz, H-3), 8.08 (1H, d, Jˆ7.6 Hz, H-5), 8.34 (1H, d,
3.78 (8H, m, morpholine), 5.15 (2H, s, CH2Ph), 7.10±7.94 Jˆ8.0 Hz, H-4). Calcd for C28H28N2O (408.54) C 82.32 H
(14H, m, ArH). Calcd for C30H31N3O2S (497.60) C 72.41 6.91 N 6.86 found: C 82.41 H 7.06 N 8.48.
H 6.28 N 8.44 found: C 72.01 H 6.54 N 8.09.

3-[1(4-Isopropenyl-cyclohex-1-enylmethyl)-2-(1-morpho- General procedure for the preparation of [2,9-dialkyl-

lin-4-yl-propylidenamino)-1H-indol-3-yl]-1(4-methoxy- 9H-pyrido[2,3-b]indol-3-yl]aryl-methanones 7a±f
phenyl)-propenone 5f. Yield 61%.Yellow oil. IR 1605
(CvO), 1H NMR 0.78±2.52 (10H, m, 3CH21CH1CH3), Compounds 5a±f (1 mmol) were mixed with silica gel
3.58±3.95 (8H, m, morpholine), 3.89 (3H. s, OCH3), 4.45 (100 mg) and heated at 180±2008C for 10 h until disappear-
(2H, s, CH2N), 4.63±4.78 (2H, m, CH2vC), 5.48±5.59 (1H, ance of the starting material [TLC, ethyl acetate±cyclo-
m, CHvC), 6.99±8.06 (10H, m, ArH). Calcd for hexane (3:2)] yielding 7. The crude reaction product was
C35H41N3O3 (551.73) C 76.19 H 7.49 N 7.62 found: C puri®ed by column chromatography [pentane±ethyl acetate
75.97 H 7.58 N 7.43. (1:0 to 19:1)].

General procedure for the preparation of 9-alkyl-2-aryl- (9-Benzyl-2-ethyl-9H-pyrido[2,3-b]indol-3-yl)phenyl-

9H-pyrido[2,3-b]indoles 6a±e methanone 7a. Yield 51%. Mp 1038C (white crystals from
EtOH). IR 1665 (CvO), 1H NMR 1.38 (3H, t, Jˆ7.2 Hz,
Compounds 5a±f (1 mmol) and t-BuOK (3 mmol) were CH3), 3.8 (2H, q, Jˆ7.2 Hz, CH2), 5.76 (2H, s, CH2Ph),
dissolved in t-BuOH (6 ml) and re¯uxed for 12 h. The 7.15±7.88 (13H, m, ArH), 7.97 (1H, d, Jˆ7.7 Hz, H-5),
mixture was cooled and the precipitate was ®ltered. The 8.30 (1H, s, H-4). Calcd for C27H22N2O (390.48) C 83.05
crude product was dissolved in CH2Cl2 and washed with H 5.68 N 7.17 found: C 82.87 H 5.92 N 7.95.
water. The organic layer was dried with Na2SO4 ad evapo-
rated. After crystallisation of the residue the pure product 7
(9-Benzyl-2-ethyl-9H-pyrido[2,3-b]indol-3-yl)-(4-meth-
was obtained. oxyphenyl)-methanone 7b. Yield 70%. Mp 798C (white
crystals from EtOH). IR 1665 (CvO), 1H NMR 1.36 (3H,
9-Benzyl-2-phenyl-9H-pyrido[2,3-b]indole 6a. Yield
t, Jˆ7.2 Hz, CH3), 3.03 (2H, q, Jˆ7.2 Hz, CH2), 3.90 (3H, s,
79%. Mp 1318C (white crystals from EtOH). 1H NMR
OCH3), 5.75 (2H, s, CH2Ph), 6.98 and 7.87 (212H, 2d,
5.80 (2H, s, CH2Ph), 7.23±7.57 (11H, m, ArH), 7.72 (1H,
Jˆ8.5 Hz, C6H4OMe), 7.26±7.48 (8H, m, ArH), 7.98 (1H,
d, Jˆ8.2 Hz, H-3), 8.12 (1H, d, Jˆ7.8 Hz, H-5), 8.23 (2H, d,
d, Jˆ7.7 Hz, H-5), 8.27 (1H, s, H-4). Calcd for C28H24N2O2
Jˆ8.8 Hz, ArH), 8.40 (1H, d, Jˆ8.2 Hz, H-4). Calcd for
(420.51) C 79.98 H 5.75 N 6.67 found: C 79.74 H 5.96 N
C24H18N2 (334.42) C 86.20 H 5.42 N 8.38 found: C 86.05
6.38.
H 5.51 N 8.14.

9-Benzyl-2-(4-methoxyphenyl)-9H-pyrido[2,3-b]indole (9-Benzyl-2-ethyl-9H-pyrido[2,3-b]indol-3-yl)-(4-bromo-
6b. Yield 68%. Mp 1878C (white crystal from EtOH). 1H phenyl)-methanone 7c. Yield 45%. Mp 908C (pale yellow
NMR 3.89 (3H, s, OCH3), 5.78 (2H, s, CH2Ph), 7.02 and crystals from EtOH). IR 1650 (CvO), 1H NMR 0.38 (3H, t,
8.17 (212H, 2d, Jˆ8.9 Hz, C6H4OCH3), 7.10±7.48 (8H, m, Jˆ7.5 Hz, CH3), 3.07 (2H, q, Jˆ7.5 Hz, CH2), 5.75 (2H, s,
ArH), 7.64 (1H, d, Jˆ8.2 Hz, H-3), 8.06 (1H, d, Jˆ8.4 Hz, CH2Ph), 7.26±7.80 (12H, m, ArH), 7.98 (1H, d, Jˆ7.7 Hz,
H-5), 8.35 (1H, d, Jˆ8.2 Hz, H-4). Calcd for C25H20N2O H-5), 8.27 (1H, s, H-4). Calcd for C27H21BrN2O C 69.09 H
(364.45) C 82.39 H 5.53 N 7.69 found: C 82.15 H 5.76 N 4.51 N 5.97 found: C 68.82 H 4.77 N 5.63.
7.38.
(9-Benzyl-2-propyl-9H-pyrido[2,3-b]indol-3-yl)-(4-meth-
9-Benzyl-2-(4-bromophenyl)-9H-pyrido[2,3-b]indole 6c. oxyphenyl)-methanone 7d. Yield 55%. Mp 1058C (white
Yield 65%. Mp 1378C (white crystals from EtOH). 1H crystals from EtOH). IR 1660 (CvO), 1H NMR 0.90±0.97
NMR 5.80 (2H, s, CH2Ph), 7.28±8.13 (14H, s, ArH), 8.40 (3H, t, Jˆ7.2 Hz, CH3), 1.80±1.91(2H, m, CH2), 2.96±3.04
(1H, d, Jˆ8.1 Hz, H-4). Calcd for C24H17BrN2 (413.32) C (2H, m, CH2), 3.91 (3H, s, OCH3), 5.74 (2H, s, CH2Ph),
69.74 H 4.14 N 6.78 found C 69.45 H 4.25 N 6.64. 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
9-Benzyl-2-thien-2-yl-9H-pyrido-[2,3-b]indole 6d. Yield H 6.03 N 6.45 found: C 79.97 H 6.35 N 6.23.
 E. Erba et al. / Tetrahedron 56 (2000) 9991±9997 9997

(9-Benzyl-2-propyl-9H-pyrido[2,3-b]indol-3yl)-thieno-2- was dissolved in ethyl acetate, washed with aqueous

yl-methanone 7e. Yield 46%. Mp 998C (white crystals from NaHCO3. The organic layer was dried and evaporated.
EtOH).IR 1650 (CvO). 1H NMR 0.96 (3H, t, Jˆ7.2 Hz, The residue was crystallised with ethyl acetate to afford
CH3), 1.88 (2H, q, Jˆ7.2 Hz, CH2), 3.07 (2H, t, Jˆ (2-amino-1H-indol-3-yl)-morpholin-4-yl-methanone (2.0 g,
7.2 Hz, CH2), 5.74 (2H, s, CH2Ph), 7.09±7.80 (11H, m, 75%), mp 2098C. 1H NMR 3.15±3.93 (8H, m, morpholine),
ArH), 8.01 (1H, d, Jˆ7.7 Hz, H-5), 8.44 (1H, s, H-4). 6.46 (2H, bs, NH2), 6.66±7.38 (4H, m, ArH), 10.59 (1H, bs,
Calcd for C26H22N2OS (410.47) C 76.08 H 5.32 N 6.82 NH). Calcd for C13H15N3O2 (245.28) C 63.66 H 6.16 N
found: C 75.86 H 5.46 N 6.56. 17.13 found C 63.46 H 6.39 N 17.02.

[2-Ethyl-9-(4-isopropenyl-cyclohex-1-enylmethyl)-9H- (2-Amino-1H-indol-3-yl)-morpholin-4-yl-methanone was

pyrido[2,3-b]indol-3-yl]-(4-methoxyphenyl)-methanone alkylated with benzyl chloride according to a literature
7f. Yield 31%. Mp 1158C (white crystals from Et2O). IR method7 and afforded 3a (Mp 1978C, yield 17%).
1660, 1H 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, References
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 1. Part 41. Erba, E.; Pocar, D.; Valle M. J. Chem. Soc., Perkin
79.87 H 7.13 N 5.75. Trans. 1 1999, 421±425 and references therein.
2. Molina, P.; Fresneda, P. M.; Sanz, M. A.; Foces-Foces, C.;
Independent synthesis of (2-amino-1-benzyl-1H-indol-3- de Arellano, M. C. R. Tetrahedron 1998, 54, 9623±9638.
yl)-morpholin-4-yl-methanone 3a 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.
A solution of 3-(morpholin-4-yl)-2-(2-nitrophenyl)-3-oxo- (b) Kazerani S.; Novak S. J. Org. Chem. 1998, 63, 895±897.
propionitrile (2.9 g, 10.8 mmol), obtained according to the 4. (a) Stolc S. Life Sci. 1999, 65, 1943±1950. (b) Barun O.; Patra
literature method6 (mp 1438C), in a mixture of acetic acid P. K.; Ila H.; Junjappa H. Tetrahedron Lett. 1999, 40, 3797±3800.
(5 mL) and toluene (15 mL) was heated until an internal 5. Greenhill, J. W. In Comprehensive Heterocyclic Chemistry,
temperature of 808C was reached. External heating was Katritzky, A. R., Rees, C. W. Eds.; Pergamon: Oxford, 1984; 4,
removed and zinc powder (6.6 g, 101 mmol) was slowly pp 521±529.
added portionwise to the vigorously stirred mixture main- 6. Germain, C.; Bourdais, J. J. Heterocycl. Chem. 1976, 13, 1209±
taining the internal temperature within the range of 80± 1218.
858C. After the addition of zinc was complete, the reaction 7. Forbes, T.; Johnson, C. N.; Thompson, M. J. Chem. Soc., Perkin
mixture was cooled, ®ltered and evaporated. The residue Trans. 1 1992, 275±281.