Synthesis of new β-carboline derivatives via 1,7-electrocyclisation of azomethine ylides

Article abstract of DOI:10.1055/s-2006-926400

A new route to the benzo[5,6]azepino[2,1-a]-β-carboline and indazolo[3,2-a]-β-carboline ring systems has been developed via the 1,7-dipolar electrocyclisation reactions of azomethine ylides derived from easily available β-carboline derivatives. Georg Thie

Full text of DOI:10.1055/s-2006-926400

PAPER
1273
Synthesis of New b-Carboline Derivatives via 1,7-Electrocyclisation of
Azomethine Ylides
N
a
ew
b
-Carboline Deri
i
k
via 1, 7-Ele
c
l
ó
A
z
s
omethine
Y
lide
s
Nyerges,*a Andrea Virányi,b Judit Tóth,b Gábor Blaskó,c László Tőkeb
Fax +36(1)4633648; E-mail: mnyerges@mail.bme.hu
Department of Organic Chemical Technology, Budapest University of Technology and Economics, P.O.B. 91, 1521 Budapest, Hungary
EGIS Pharmaceuticals Ltd., P.O.B. 100, 1475 Budapest, Hungary
b
c
Received 16 September 2005; revised 27 October 2005
reochemistry of pentacycles 7a–c was deduced by nOe
studies.
Abstract: A new route to the benzo[5,6]azepino[2,1-a]-b-carboline
and indazolo[3,2-a]-b-carboline ring systems has been developed
via the 1,7-dipolar electrocyclisation reactions of azomethine ylides
derived from easily available b-carboline derivatives.
We next chose to form the azomethine ylides 11a,b from
2-allyl-1-(2-nitrophenyl)-4,9-dihydro-3H-b-carbolinium
Key words: electrocyclic reactions, heterocycles, tandem reac- bromides 10a,b by dehydrohalogenation with triethy-
tions, ylides
lamine (Scheme 2). The synthesis of the starting materials
was carried out in a similar way as described for 4a–c.
Starting from tryptamine 1 and after the acylation with 2-
nitrobenzoyl chlorides, the obtained amides 8a,b were cy-
clised by the action of phosphoryl chloride. The reaction
of aryl-b-carbolines 9a,b with 11 resulted in the formation
of quaternary salts 10a,b. The reaction of 10a,b with tri-
ethylamine at room temperature in ethanol provided the
expected 3,13-dihydro-7H-indazolo[3,2-a]-b-carboline-
5-N-oxides 13a,b as orange precipitates.
Indazole-N-oxides 13a,b, according to our earlier results,4
probably arise from the fragmentation of the unstable
benz-1,2,6-oxadiazepine intermediates 12a,b, formed by
a 1,7-electrocyclisation of azomethine ylides 11a,b onto
the pendant nitro group. The seven-membered ring of 12
subsequently undergoes a ring contraction, resulting in the
elimination of acrolein and the production of indazol-N-
oxides 13a,b in good yields.
The 1,7-electrocyclisation of a variety 1,3-dipoles consti-
tutes a general route to seven-membered heterocycles.1
The investigation of such reactions of azomethine ylides
resulted in the development of a new approach to azepine
derivatives.2 Recently we published the first examples of
the 1,7-electrocyclisation of ester-stabilised a,b:g,d-un-
saturated azomethine ylides generated by the deprotona-
tion of isoquinolinium salts3 and the first 1,7-
electrocyclisation of an azomethine ylide onto a nitro
group.4
As a continuation of these studies our aim is to show the
generality of these methods as useful tools for the anella-
tion of benzazepine and indazole rings to different hetero-
cycles in a single step. In this paper we describe the
synthesis of some new b-carboline derivatives.
In conclusion, we have developed an efficient synthesis
from simple starting materials to the rarely described and
First we have attempted the preparation of benzo[5,6]aze-
pino[2,1-a]-b-carbolines with the simple adaptation of
our procedure used for the synthesis of benzo[5,6]azepi-
no[2,1-a]isoquinolines.3 The synthesis of precursors was
carried out according to the Bischler–Napieralski
procedure5 by cyclisation of amide 2 (prepared from
tryptamine 1) in the presence of POCl3, that resulted in the
formation of 3,4-dihydro-b-carboline 3. Subsequent reac-
tion with different bromoalkyl derivatives gave the qua-
ternary salts 4a–c (Scheme 1).
difficultly
accessible
benzo[5,6]azepino[2,1-a]-b-
carboline7 and indazolo[3,2-a]-b-carboline8 ring systems.
Column chromatography was performed using Merck Kieselgel 60
(70–230 mesh) TLC on aluminium sheets coated with Kieselgel 60
F254. Plates were stained with anisaldehyde solution (100 mL glacial
acetic acid, 2 mL concd H2SO4 and 1 mL anisaldehyde) and heated
to ca. 150 °C. IR spectra were measured on a Bruker VECTOR 22
FT-IR instrument. NMR spectra were recorded on a Bruker Avance
DRX-500 spectrometer. Chemical shifts are given relative to TMS.
All solvents were purified according to standard procedures.
Azomethine ylides 5 were generated by deprotonation
from salts 4a–c at room temperature in ethanol.6 Interme-
diates 5 undergo a 1,7-electrocyclisation reaction to form
azepine 6 and finally afford products 7a–c by a 1,5-hydro-
gen shift (Scheme 1). These compounds were isolated in
acceptable yields after column chromatography. The ste-
N-[2-(1H-3-Indolyl)ethyl]-3,3-diphenylacrylamide (2)
Tryptamine (1.60 g, 10 mmol) was dissolved in CH2Cl2 (40 mL)
and Et3N (0.71 mL, 1.01 g, 10 mmol) was added. This mixture was
cooled to 0 °C and freshly prepared 2-phenylcinnamoyl chloride
(10 mmol, from 2.24 g of 2-phenylcinnamic acid) dissolved in
CH2Cl2 (40 mL) was added dropwise. The reaction mixture was
stirred at r.t. for 16 h. The organic layer was washed with H2O
(2 × 30 mL) and brine (30 mL), dried (MgSO4) and evaporated in
vacuo to yield the product as a white powder.
SYNTHESIS 2006, No. 8, pp 1273–1278
x
x
.
x
x
.2
0
0
6
Advanced online publication: 27.03.2006
DOI: 10.1055/s-2006-926400; Art ID: P14705SS
© Georg Thieme Verlag Stuttgart · New York

1274
M. Nyerges et al.
PAPER
POCl3
Ph2C=CHCOCl
Et3N
NH
N
NH2
NH
NH
Ph
Ph
O
NH
Ph
2
1
3
Ph
RCH2Br
Et3N
Br
R
N
N
R
NH
NH
Ph
Ph
Ph
4a R = MeOOC-
4b R = Ph-
5
4c R = CH2=CH-
R
N
R
H
NH
N
NH
H
Ph
Ph
7a MeCOO-
7b Ph-
6
7c CH2=CH-
Scheme 1
NH
Br
N
CH2=CHCH2Br
NO2
POCl3
X
N
NH
NH
NH
O
NO2
O2N
X
X
8a X = H
8b X = Cl
9a X = H
9b X = Cl
10a X = H
10b X = Cl
N
N
O
N
Et3N
N
NH
NH
NH
– CH2=CHCHO
O
NO2
N
O
X
X
X
13a X = H
13b X = Cl
11a X = H
11b X = Cl
12a X = H
12b X = Cl
Scheme 2
Synthesis 2006, No. 8, 1273–1278 © Thieme Stuttgart · New York

PAPER
New b-Carboline Derivatives via 1,7-Electrocyclisation of Azomethine Ylides
1275
Yield: 3.00 g (82%); mp 166–168 °C.
(2 × CH), 127.1 (q), 126.1 (CH), 123.5 (q), 121.0 (CH), 114.2 (CH),
114.0 (q), 55.8 (CH3), 53.1 (CH2), 52.3 (CH2), 20.0 (CH2).
IR (KBr): 3281, 3053, 2961, 2847, 1631, 1574, 1538, 1461, 1442,
1360, 1224, 1209 cm–1.
Anal. Calcd for C28H25BrN2O2 (500.11): C, 67.19; H, 5.04; N, 5.60.
Found: C, 67.20; H, 5.05; N, 5.55.
1H NMR (500 MHz, CDCl3): d = 8.44 (s, 1 H, Ind-NH), 7.45 (d,
J = 7.9 Hz, 1 H, Ind-4¢H), 7.30 (d, J = 8.1 Hz, 1 H, Ar-H), 7.28–7.15
(m, 11 H, Ar-H), 7.06 (t, J = 7.4 Hz, 1 H, Ind-6¢H), 6.67 (d, J = 1.6
Hz, 1 H, Ind-2¢H), 5.39 (t, J = 5.6 Hz, 1 H, NHCO-), 3.45 (dt,
J = 5.6, 6.8 Hz, 2 H, CH2NH), 2.67 (t, J = 6.8 Hz, 2 H, CH2).
13C NMR (125 MHz, CDCl3): d = 166.8 (q), 149.5 (q), 141.7 (q),
138.3 (q), 136.2 (q), 129.2 (2 × CH), 128.4 (2 × CH), 128.3 (CH),
128.2 (2 × CH), 127.9 (2 × CH), 127.1 (q), 122.2 (CH), 121.9 (CH),
119.1 (CH), 118.7 (CH), 112.2 (q), 111.0 (CH), 39.3 (CH2), 24.7
(CH2).
2-Benzyl-1-(2,2-diphenylvinyl)-4,9-dihydro-3H-b-carbolin-2-
ium Bromide (4b)
The 1-(2,2-diphenylvinyl)-4,9-dihydro-3H-b-carboline (0.87 g, 2.5
mmol) was dissolved in anhyd CHCl3 (15 mL) and benzyl bromide
(0.36 mL, 0.50 g, 3 mmol) was added. The resulting solution was
heated for 48 h at reflux under an argon atmosphere. The solvent
was removed in vacuo and the residue was triturated with anhyd
Et2O. The yellow precipitate was filtered off, washed with Et2O (10
mL) and dried in vacuo to give a yellow powder.
Anal. Calcd for C25H22N2O (366.17): C, 81.93; H, 6.06; N, 7.65.
Found: C, 82.00; H, 6.15; N, 7.62.
Yield: 1.27 g (98%); mp 244 °C.
IR (KBr): 3056, 2956, 1620, 1597, 1571, 1534, 1435, 1337, 1298,
1261, 1233, 1183, 1149, 1077 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.57 (m, 3 H, Ar-H), 7.36 (m, 7 H,
Ar-H), 7.20 (m, 5 H, Ar-H), 7.11 (m, 5 H, Ar-H), 5.07 (br s, 2 H,
PhCH2), 3.89 (br s, 2 H, H-3), 3.10 (t, 2 H, J = 7.9 Hz, H-4).
13C NMR (125 MHz, CDCl3): d = 162.3 (q), 159.6 (q), 142.5 (q),
139.3 (q), 137.5 (q), 132.4 (q), 130.2 (CH), 129.7 (2 × CH), 129.6
(2 × CH), 129.5 (q), 129.4 (2 × CH), 129.1 (CH), 128.9 (CH), 128.3
(2 × CH), 128.2 (2 × CH), 128.1 (2 × CH), 126.6 (q), 124.1 (CH),
123.5 (q), 121.6 (CH), 120.8 (CH), 114.8 (CH), 114.3 (CH), 58.4
(CH2), 50.6 (CH2), 20.1 (CH2).
1-(2,2-Diphenylvinyl)-4,9-dihydro-3H-b-carboline (3)
Amide 2 (2.9 g, 7.9 mmol) was dissolved in anhyd toluene (30 mL)
and a solution of POCl3 (2 mL, 3.14 g, 20.5 mmol) in anhyd toluene
(10 mL) was added dropwise to the well-stirred mixture with exter-
nal ice-water cooling. The reaction mixture was stirred at reflux for
3 h followed by cooling to r.t. The solvent was decanted and the
semi-solid residue was stirred for 2 h with an excess of 10% aq
NaOH solution. The aqueos phase was washed with EtOAc (3 × 20
mL) and the combined organic extracts were washed with brine (25
mL), dried (MgSO4) and evaporated in vacuo to yield the product as
an orange solid.
Anal. Calcd for C32H27BrN2 (519.48): C, 74.11; H, 5.25; N, 5.41.
Found: C, 74.29; H, 5.35; N, 5.55.
Yield: 2.12 g (77%); mp 105–108 °C.
IR (KBr): 3127, 3056, 2928, 2875, 2832, 1620, 1604, 1580, 1542,
1495, 1443, 1370, 1320, 1304, 1280, 1206, 1155, 1076, 1032, 1018,
1005 cm–1.
2-Allyl-1-(2,2-diphenylvinyl)-4,9-dihydro-3H-b-carbolin-2-ium
Bromide (4c)
The 1-(2,2-diphenylvinyl)-4,9-dihydro-3H-b-carboline (0.87 g, 2.5
mmol) was dissolved in allyl bromide (8 mL). The resulting solu-
tion was heated for 24 h at reflux under an argon atmosphere. The
excess allyl bromide was removed in vacuo and the residue was trit-
urated with anhyd Et2O. The yellow precipitate was filtered off,
washed with Et2O (10 mL) and dried in vacuo to give a yellow pow-
der.
1H NMR (500 MHz, CDCl3): d = 8.45 (s, 1 H, Ind-NH), 7.49 (d,
J = 7.8 Hz, 1 H, Ind-4¢H), 7.27–7.14 (m, 10 H, Ar-H), 7.06–7.01 (m,
3 H, Ar-H), 6.65 (s, 1 H, vinyl-H), 3.77 (t, J = 8.1 Hz, 2 H, H-4),
2.71 (t, J = 8.1 Hz, 2 H, H-3).
13C NMR (125 MHz, CDCl3): d = 158.3 (q), 148.6 (q), 142.2 (q),
139.6 (q), 136.6 (q), 130.2 (2 × CH), 128.7 (5 × CH), 128.5
(3 × CH), 128.3 (q), 125.8 (CH), 125.2 (q), 124.5 (CH), 120.2 (CH),
120.0 (CH), 117.2 (q), 111.8 (CH), 48.9 (CH2), 19.3 (CH2).
Yield: 1.03 g (88%); mp 210–211 °C.
IR (KBr): 3055, 3028, 2922, 1619, 1600, 1572, 1493, 1445, 1323,
1262, 1202, 1157, 1115, 1075, 1029 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.60 (m, 3 H, Ar-H), 7.43–7.29
(m, 6 H, Ar-H), 7.17 (m, 3 H, Ar-H), 7.08 (m, 3 H, Ar-H), 5.59 (m,
1 H, allyl-H), 5.40 (m, 2 H, allyl-H), 4.50 (br s, 2 H, allyl-H), 3.91
(br s, 2 H, H-3), 3.12 (t, 2 H, J = 7.5 Hz, H-4).
13C NMR (125 MHz, CDCl3): d = 162.2 (q), 158.9 (q), 142.3 (q),
139.3 (q), 137.5 (q), 130.1 (CH), 130.0 (q), 129.7 (2 × CH), 129.6
(2 × CH), 129.5 (CH), 128.8 (2 × CH), 128.2 (2 × CH), 128.1 (q),
126.6 (q), 123.9 (CH), 123.5 (CH), 122.1 (CH), 121.5 (CH2), 120.9
(CH), 144.5 (CH), 114.2 (CH), 57.4 (CH2), 50.2 (CH2), 20.0 (CH2).
Anal. Calcd for C25H20N2 (348.16): C, 86.17; H, 5.79; N, 8.04.
Found: C, 86.20; H, 5.85; N, 7.99.
1-(2,2-Diphenylvinyl)-2-(methoxy-2-oxoethyl)-4,9-dihydro-3H-
b-carbolin-2-ium Bromide (4a)
The 1-(2,2-diphenylvinyl)-4,9-dihydro-3H-b-carboline (0.87 g, 2.5
mmol) was dissolved in anhyd CH2Cl2 (15 mL) and methyl bro-
moacetate (0.28 mL, 0.46 g, 3.0 mmol) was added. The resulted so-
lution was heated for 48 h at reflux under an argon atmosphere. The
solvent was removed in vacuo and the residue was triturated with
anhyd Et2O. The yellow precipitate was filtered off, washed with
Et2O (10 mL) and dried in vacuo to give a yellow powder.
Anal. Calcd for C28H25BrN2 (469.42): C, 71.78; H, 5.38; N, 5.98.
Found: C, 71.71; H, 5.35; N, 6.05.
Yield: 1.20 g (96%); mp 250–252 °C.
IR (KBr): 3056, 1747, 1653, 1620, 1597, 1572, 1534, 1437, 1338,
1305, 1216, 1181, 1151 cm–1.
1,7-Electrocyclisations; General Procedure
The corresponding 1-(2,2-diphenylvinyl)-4,9-dihydro-3H-b-carbo-
lin-2-ium bromide (0.75 mmol) was dissolved in anhyd MeOH (10
mL) and Et3N (0.11 mL, 1.5 mmol) was added. The reaction mix-
ture was stirred for 24 h at room temperature under an argon atmo-
sphere. The solvent was removed in vacuo, the residue was
dissolved in CH2Cl2 (15 mL) and washed with H2O (2 × 10 mL) and
brine (10 mL). The organic layer was dried (MgSO4) and evaporat-
ed in vacuo. The residue was further purified by column chromato-
graphy on silica gel (hexane–acetone, 3:1) to give products 7a–c.
1H NMR (500 MHz, CDCl3): d = 11.71 (s, 1 H, Ind-NH), 7.53 7.42
(m, 3 H, Ar), 7.36–7.15 (m, 8 H, Ar), 7.10–6.98 (m, 3 H, Ar), 6.88
(s, 1 H, vinyl-H), 4.97 s, (2 H, CH2CO2Me), 4.02 (br s, 2 H, H-3),
3.75 (s, 3 H, OMe), 3.12 (br s, 2 H, H-4).
13C NMR (125 MHz, CDCl3): d = 166.7 (q), 163.2 (q), 160.6 (q),
142.5 (q), 139.4 (q), 137.2 (q), 130.2 (CH), 129.9 (4 × CH), 129.5
(CH), 129.2 (CH), 128.9 (CH), 128.2 (2 × CH), 128.0 (CH), 127.9
Synthesis 2006, No. 8, 1273–1278 © Thieme Stuttgart · New York

1276
M. Nyerges et al.
PAPER
Methyl 15-Phenyl-7,8,13,13b-tetrahydro-5H-benzo[5,6]azepi-
no[2,1-a]-b-carboline-5-carboxylate (7a)
Brown oil, yield: 0.18 g (57%).
benzoyl chloride (10 mmol), dissolved in Et2O (40 mL), was added
dropwise. The reaction mixture was stirred at r.t. for 16 h. The or-
ganic layer was separated and washed with H2O (2 × 30 mL) and
brine (30 mL), dried (MgSO4) and evaporated in vacuo to yield
products 8a–c.
IR (KBr): 3331, 3051, 2950, 2918, 2829, 1735, 1655, 1490, 1449,
1326, 1266, 1203, 1177 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.99 (s, 1 H, H-13), 7.58 (d, 2 H,
J = 7.8 Hz, Ph-2¢ and 6¢H), 7.50 (d, J = 8.0 Hz, 1 H, H-4), 7.37 (t,
J = 7.4 Hz, 1 H, H-10), 7.28 (d, J = 8.0 Hz, 1 H, H-1), 7.25 (t,
J = 7.4 Hz, 1 H, H-11), 7.19–7.07 (m, 8 H), 5.28 (s, 1 H, H-5), 4.74
(s, 1 H, H-13b), 3.33 (m, 1 H, H-7), 3.31 (s, 3 H, MeO), 3.14 (m, 1
H, H-7), 2.89 (ddd, J = 2.7, 4.3, 16.0 Hz, 1 H, H-8), 2.76 (dt, J = 4.5,
16.0 Hz, 1 H, H-8).
13C NMR (125 MHz, CDCl3): d = 170.9 (q), 146.2 (q), 143.6 (q),
139.3 (q), 137.2 (q), 128.6 (3 × CH), 128.3 (3 × CH), 127.9
(3 × CH), 127.7 (3 × CH), 126.7 (CH), 126.6 (q), 126.3 (CH), 126.2
(q), 123.2 (CH), 119.7 (CH), 119.1 (CH), 113.0 (q), 111.1 (CH),
102.1 (CH), 76.5 (CH3), 62.9 (CH), 51.6 (CH), 48.0 (CH2), 21.5
(CH2).
3-[2-(2-Nitrophenylcarboxamido)ethyl]-1H-indole (8a)
White powder, yield: 2.93 g (95%); mp 189–190 °C.
IR (KBr): 3258, 1631, 1616, 1527, 1346, 1263, 1161, 1146 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 10.84 (s, 1 H, Ind-NH), 8.81
(t, J = 5.8 Hz, 1 H, CONH), 8.01 (dd, J = 1.0, 8.1 Hz, 1 H, Ar-6¢H),
7.75 (dt, J = 1.0, 8.1 Hz, 1 H, Ar-5¢H), 7.67 (dt, J = 1.0, 8.1 Hz, 1
H, Ar-4¢H), 7.58 (d, J = 7.1 Hz, 1 H, Ind-4¢H), 7.56 (d, J = 7.1 Hz,
1 H, Ind-7¢H), 7.36 (dd, J = 1.0, 8.1 Hz, 1 H, Ar-3¢H), 7.22 (d,
J = 2.0 Hz, 1 H, Ind-2¢H), 7.08 (t, J = 7.1 Hz, 1 H, Ind-5¢H), 7.00 (t,
J = 7.1 Hz, 1 H, Ind-6¢H), 3.52 (dt, J = 5.8, 7.4 Hz, 2 H, CH2NH),
3.37 (t, J = 7.4 Hz, 2 H, CH2).
13C NMR (125 MHz, DMSO-d6): d = 165.5 (q), 147.3 (q), 136.5
(q), 133.6 (CH), 132.9 (q), 130.8 (q), 129.2 (CH), 127.4 (q), 124.2
(CH), 123.0 (CH), 121.1 (CH), 118.5 (CH), 118.4 (CH), 111.8
(CH), 111.6 (CH), 40.3 (CH2), 25.0 (CH2).
HRMS (EI): m/z calcd for C28H24N2O2 (M+): 420.1837; found:
420.1838.
5,15-Diphenyl-7,8,13,13b-tetrahydro-5H-benzo[5,6]azepi-
no[2,1-a]-b-carboline (7b)
Brown oil, yield: 0.22 g (66%).
Anal. Calcd for C17H15N3O3 (309.11): C, 66.00; H, 4.89; N, 13.59.
Found: C, 65.95; H, 5.00; N, 13.60.
3-[2-(5-Chloro-2-nitrophenylcarboxamido)ethyl]-1H-indole
(8b)
White powder, yield: 3.06 g (89%); mp 195 °C.
IR (KBr): 3355, 3053, 2997, 2942, 2922, 2831, 1651, 1491, 1449,
1329, 1309, 1265, 1191, 1167, 1011 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.24 (br s, 1 H, NH), 7.52 (d,
J = 7.8 Hz, 2 H, Ph-2¢ and 6¢H), 7.33 (m, 3 H, Ar-H), 7.24 (m, 3 H,
Ar-H), 7.10–6.97 (m, 9 H, Ar-H and H-14), 6.87 (m, 2 H, Ar-H),
5.35 (br s, 1 H, H-5), 5.14 (br s, 1 H, H-13b), 3.01 (m, 2 H, H-7),
2.62 (m, 2 H, H-8).
13C NMR (125 MHz, CDCl3): d = 147.0 (q), 143.4 (q), 140.4 (q),
138.4 (q), 129.9 (2 × CH), 129.3 (2 × CH), 128.6 (CH), 128.5 (q),
128.3 (2 × CH), 128.1 (CH), 128.0 (2 × CH), 127.6 (CH), 127.3 (q),
127.1 (2 × CH), 126.8 (q), 126.0 (CH), 123.2 (q), 119.9 (CH), 119.1
(CH), 111.2 (CH), 110.1 (q), 103.8 (CH), 69.6 (CH), 53.8 (CH),
47.1 (CH2), 21.8 (CH2).
IR (KBr): 3410, 3294, 3112, 2915, 1640, 1567, 1521, 1457, 1438,
1388, 1349, 1311, 1251, 1229, 1195, 1106, 1088, 1076, 1051 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.00 (s, 1 H, Ind-NH), 7.98 (dd,
J = 1.1, 8.7 Hz, 1 H, Ar-6¢H), 7.63 (d, J = 7.8 Hz, 1 H, Ind-4¢H),
7.48 (ddd, J = 8.7, 2.2, 1.1 Hz, 1 H, Ar-5¢H), 7.37 (d, J = 7.8 Hz, 1
H, Ind-7¢H), 7.34 (d, J = 2.2 Hz, 1 H, Ar-3¢H), 7.21 (t, J = 7.8 Hz, 1
H, Ind-5¢H), 7.15 (s, 1 H, Ind-2¢H), 7.13 (t, J = 7.8 Hz, 1 H, Ind-
6¢H), 5.80 (s, 1 H, CONH), 3.83 (dd, J = 6.6, 6.2 Hz, 2 H, CH2NH),
3.14 (t, J = 6.6 Hz, 2 H, CH2).
13C NMR (125 MHz, CDCl3): d = 164.9 (q), 140.3 (q), 136.4 (q),
134.6 (q), 132.3 (q), 130.3 (CH), 128.9, 127.2 (q), 126.0 (CH),
122.5 (CH), 122.3 (CH), 119.6 (CH), 118.6 (CH), 112.4 (q), 111.3
(CH), 40.2 (CH2), 24.9 (CH2).
HRMS (EI): m/z calcd for C32H26N2 (M+): 438.2095; found:
438.2095.
15-Phenyl-5-vinyl-7,8,13,13b-tetrahydro-5H-benzo[5,6]azepi-
no[2,1-a]-b-carboline (7c)
Brown oil, yield: 0.15 g (51%).
Anal. Calcd for C17H14ClN3O3 (343.07): C, 59.46; H, 4.11; N,
12.25. Found: C, 59.51; H, 4.00; N, 12.19.
1-(2-Nitrophenyl)-4,9-dihydro-3H-b-carbolines (9)
IR (KBr): 3406, 3054, 2923, 2849, 1640, 1598, 1547, 1492, 1444,
1324, 1301, 1263, 1187, 1152, 1098, 1031 cm–1.
The corresponding amides (8 mmol) were dissolved in anhyd tolu-
ene (25 mL) and a solution of POCl3 (2 mL, 3.14 g, 20.5 mmol) in
anhyd toluene (10 mL) was added dropwise to the well-stirred mix-
ture with external ice-water cooling. The reaction mixture was
stirred at reflux for 1 h followed by cooling to r.t. The solvent was
decanted and the semi-solid residue was stirred overnight with an
excess of 10% aq NaOH solution. The aqueous phase was washed
with EtOAc (3 × 20 mL) and the combined organic extracts were
washed with brine (25 mL), dried (MgSO4) and evaporated in vacuo
to yield products 9a–c.
1H NMR (300 MHz, CDCl3): d = 8.15 (br s, 1 H, NH), 7.53 (d,
J = 7.8 Hz, 2 H, Ph-2¢ and 6¢H), 7.44–7.32 (m, 4 H, Ar-H), 7.27–
7.08 (m, 8 H, Ar-H), 5.54 (m, 2 H, vinyl-H), 5.48 (d, J = 2 Hz, 1 H,
H-5), 5.26 (s, 1 H, H-13b), 5.25 (d, J = 8 Hz, 1 H, vinyl-H), 3.34 (m,
1 H, H-7), 3.01 (m, 3 H, H-7 and H-8).
13C NMR (125 MHz, CDCl3): d = 147.0 (q), 144.5 (q), 140.7 (q),
136.6 (q), 129.9 (CH), 129.0 (2 × CH), 128.4 (2 × CH), 128.3 (q),
128.1 (CH), 128.0 (q), 127.8 (2 × CH), 127.5 (2 × CH), 126.3 (CH),
123.2 (CH), 120.1 (CH2), 119.9 (CH), 119.1 (CH), 117.5 (q), 111.1
(CH), 103.9 (q), 76.4 (CH), 53.5 (CH), 46.5 (CH2), 21.7 (CH2).
1-(2-Nitrophenyl)-4,9-dihydro-3H-b-carboline (9a)
Yellow powder, yield: 1.65 g (71%); mp 133–134 °C.
HRMS (EI): m/z calcd for C28H24N2 (M+): 388.1939; found:
388.1940.
IR (KBr): 3397, 3025, 2984, 2874, 1621, 1525, 1445, 1345, 1319,
1291, 1172, 1082 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 11.08 (s, 1 H, Ind-NH), 8.16
(d, J = 7.9 Hz, 1 H, Ar-6¢H), 7.85 (t, J = 7.9 Hz, 1 H, Ar-4¢H), 7.76
(t, J = 7.9 Hz, 1 H, Ar-5¢H), 7.63 (d, J = 8.2 Hz, 1 H, H-5 or H-8),
7.61 (d, J = 8.2 Hz, 1 H, H-5 or H-8), 7.34 (d, J = 7.9 Hz, 1 H, Ar-
3-[2-(2-Nitrophenylcarboxamido)ethyl]-1H-indoles (8);
General Procedure
Tryptamine (1.60 g, 10 mmol) was dissolved in Et2O (40 mL) and
an aq solution of NaOH (0.40 g in 10 mL) was added. The mixture
was cooled to 0 °C and the corresponding freshly prepared 2-nitro-
Synthesis 2006, No. 8, 1273–1278 © Thieme Stuttgart · New York

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New b-Carboline Derivatives via 1,7-Electrocyclisation of Azomethine Ylides
1277
3¢H), 7.20 (d, J = 8.2 Hz, 1 H, H-6 or H-7), 7.08 (d, J = 8.2 Hz, 1 H,
H-6 or H-7), 3.88 (t, J = 8.2 Hz, 2 H, 2 × H-4), 2.91 (t, J = 8.2 Hz,
2 H, 2 × H-3).
13C NMR (125 MHz, DMSO-d6): d = 157.3 (q), 148.6 (q), 137.2
(q), 133.9 (CH), 133.1 (q), 130.9 (CH), 130.4 (CH), 128.0 (q), 125.0
(q), 124.7 (CH), 124.1 (CH), 119.9 (CH), 119.8 (CH), 115.8 (q),
112.7 (CH), 48.9 (CH2), 18.9 (CH2).
J = 2.0, 9.0 Hz, 1 H, Ar-4¢H), 7.85 (d, J = 8.3 Hz, 1 H, H-5), 7.46 (t,
J = 8.3 Hz, 1 H, H-7), 7.41 (d, J = 8.3 Hz, 1 H, H-8), 7.23 (t, J = 8.3
Hz, 1 H, H-6), 5.91 (m, 1 H, CH=), 5.41 (d, J = 17.2 Hz, 1 H,
CH2=), 5.37 (d, J = 10.4 Hz, 1 H, CH2=), 4.42 (d, J = 5.1 Hz, 1 H,
NCH2), 4.40 (m, 2 H, 2 × H-3), 3.55 (m, 1 H, H-4), 3.47 (m, 1 H, H-
4).
13C NMR (125 MHz, CDCl3): d = 161.6 (q), 144.6 (q), 142.2 (q),
141.0 (q), 133.8 (CH), 130.2 (CH), 130.1 (CH), 129.5 (CH), 128.5
(CH), 126.8 (q), 125.5 (q), 125.1 (q), 124.0 (q), 122.4 (CH), 122.0
(CH), 121.4 (CH2), 113.6 (CH), 58.4 (CH2), 51.3 (CH2), 19.4 (CH2).
Anal. Calcd for C17H13N3O2 (291.10): C, 70.08; H, 4.50; N, 14.43.
Found: C, 69.91; H, 4.62; N, 14.44.
1-(5-Chloro-2-nitrophenyl)-4,9-dihydro-3H-b-carboline (9b)
Yellow powder, yield: 2.21 g (85%); mp 138–139 °C.
Anal. Calcd for C20H17BrClN3O2 (446.73): C, 53.93; H, 3.85; N,
9.44. Found: C, 54.00; H, 3.88; N, 9.39.
IR (KBr): 3067, 2942, 2837, 1593, 1528, 1341, 1320, 1307, 1279,
1174, 1155, 1080, 1042 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.32 (s, 1 H, Ind-NH), 7.97 (d,
J = 9.0 Hz, 1 H, Ar-6¢H), 7.61 (d, J = 7.9 Hz, 1 H, H-5), 7.47 (m, 2
H, Ar-H), 7.24–7.13 (m, 3 H, H-6, H-7 and H-8), 3.97 (t, J = 8.7 Hz,
2 H, 2 × H-4), 2.98 (t, J = 8.7 Hz, 2 H, 2 × H-3).
1,7-Electrocyclisations; General Procedure
The 2-allyl-b-carbolinium bromide (2 mmol) was dissolved in
EtOH (20 mL) and Et3N (0.42 mL, 0.30 g, 3.0 mmol) was added.
The reaction mixture was stirred for 24 h at r.t. The precipitated
products were filtered off, washed with EtOH and dried on air to
yield 13a,b.
13C NMR (125 MHz, CDCl3): d = 156.5 (q), 146.4 (q), 140.1 (q),
137.1 (q), 134.6 (CH), 130.6 (CH), 130.0 (CH), 127.4 (CH), 126.1
(CH), 125.4 (CH), 125.1 (CH), 120.6 (q), 118.1 (q), 112.1 (CH),
49.1 (CH2), 19.1 (CH2).
3,13-Dihydro-7H-indazolo[3,2-a]-b-carboline-5N-oxide (13a)
Orange powder, yield: 0.43 g (78%); mp >300 °C.
IR (KBr): 3419, 3157, 3061, 2927, 1624, 1504, 1437, 1371, 1347,
1297, 1235, 1178, 1144, 1116, 1091, 1007 cm–1.
Anal. Calcd for C17H12ClN3O2 (325.06): C, 62.76; H, 3.72; N,
12.92. Found: C, 62.67; H, 3.61; N, 12.71.
1H NMR (500 MHz, DMSO-d6): d = 11.77 (s, 1 H, H-13), 8.28 (d,
J = 8.5 Hz, 1 H, H-1), 7.57 (d, J = 8.5 Hz, 1 H, H-4), 7.56 (d, J = 7.7
Hz, 1 H, H-9), 7.47 (d, J = 7.7 Hz, 1 H, H-12), 7.30 (d, J = 8.5 Hz,
1 H, H-3), 7.22 (d, J = 8.5 Hz, 1 H, H-2), 7.17 (t, J = 7.7 Hz, 1 H,
H-10), 7.08 (t, J = 7.7 Hz, 1 H, H-11), 4.60 (t, J = 7.6 Hz, 2 H,
2 × H-7), 3.32 (t, J = 7.6 Hz, 2 H, 2 × H-8).
13C NMR (125 MHz, DMSO-d6): d = 137.9 (q), 128.5 (q), 126.5
(CH), 125.9 (q), 124.7 (CH), 123.9 (q), 122.5 (CH), 120.9 (CH),
120.0 (CH), 118.5 (CH), 113.6 (CH), 112.7 (q), 111.9 (CH), 110.8
(q), 107.1 (q), 41.3 (CH2), 19.3 (CH2).
Quaternary Salts; General Procedure
The 3,4-dihydro-b-carboline (5 mmol) was dissolved in allyl bro-
mide (10 mL). The resulting solution was heated for 24 h at reflux
under an argon atmosphere. The excess allyl bromide was removed
in vacuo and the residue was triturated with anhyd Et2O. The yellow
precipitate was filtered off, washed with Et2O and dried in vacuo to
yield products 10a–c.
2-Allyl-1-(2-nitrophenyl)-4,9-dihydro-3H-b-carbolinium
Bromide (10a)
Yellow powder, yield: 2.04 g (97%); mp 217 °C.
Anal. Calcd for C17H13N3O (275.11): C, 74.15; H, 4.76; N, 15.27.
Found: C, 74.00; H, 4.89; N, 15.30.
IR (KBr): 3406, 3017, 2877, 1643, 1617, 1599, 1526, 1437, 1341,
1304, 1271, 1228, 1196, 1148, 1100 cm–1.
2-Chloro-3,13-dihydro-7H-indazolo[3,2-a]-b-carboline-5N-ox-
ide (13b)
Orange powder, yield: 0.50 g (81%); mp >300 °C.
1H NMR (500 MHz, CDCl3): d = 11.89 (s, 1 H, Ind-NH), 8.37 (d,
J = 8.5 Hz, 1 H, Ar-6¢H), 8.33 (d, J = 7.5 Hz, 1 H, H-5), 7.74 (d,
J = 8.5 Hz, 1 H, Ar-3¢H), 7.69 (t, J = 8.5 Hz, 1 H, Ar-4¢H), 7.50 (d,
J = 7.5 Hz, 1 H, H-8), 7.41 (t, J = 8.5 Hz, 1 H, Ar-5¢H), 7.39 (t,
J = 7.5 Hz, 1 H, H-6), 7.17 (t, J = 7.5 Hz, 1 H, H-7), 5.80 (m, 1 H,
allyl), 5.38 (m, 2 H, allyl), 4.68 (m, 1 H, allyl), 4.38 (dd, J = 7.0,
15.5 Hz, 1 H, H-4), 4.26 (dd, J = 5.0, 15.5 Hz, 1 H, H-4), 4.11 (m,
1 H, allyl), 3.28 (m, 2 H, 2 × H-3).
13C NMR (125 MHz, DMSO-d6): d = 163.4 (q), 145.8 (q), 142.1
(q), 136.1 (q), 134.0 (CH), 130.1 (CH), 130.0 (CH), 129.3 (CH),
126.9 (q), 126.5 (CH), 125.1 (CH), 124.0 (q), 123.5 (q), 122.3 (CH),
121.9 (CH), 121.3 (CH2), 113.5 (CH), 58.2 (CH2), 51.3 (CH2), 19.4
(CH2).
IR (KBr): 3186, 3105, 2905, 1646, 1478, 1444, 1366, 1336, 1316,
1233, 1169, 1148, 1115, 1092, 1058 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 11.81 (s, 1 H, H-13), 8.46 (s,
1 H, H-1), 7.60 (dd, J = 9.3, 1.8 Hz, 1 H, H-9), 7.55 (d, J = 7.8 Hz,
1 H, H-4), 7.45 (d, J = 7.8 Hz, 1 H, H-3), 7.24 (dd, J = 9.3, 1.8 Hz,
1 H, H-12), 7.16 (dt, J = 9.3, 1.8 Hz, 1 H, H-10), 7.05 (dt, J = 9.3,
1.8 Hz, 1 H, H-11), 4.58 (t, J = 7.7 Hz, 2 H, 2 × H-7), 3.44 (t, J = 7.7
Hz, 2 H, 2 × H-8).
13C NMR (125 MHz, DMSO-d6): d = 137.7 (q), 128.1 (q), 126.9
(CH), 126.7 (q), 125.5 (q), 124.0 (q), 122.5 (CH), 119.8 (CH), 119.5
(CH), 118.4 (CH), 114.7 (CH), 113.2 (q), 111.7 (CH), 110.4 (q),
107.2 (q), 41.4 (CH2), 19.0 (CH2).
Anal. Calcd for C20H18BrN3O2 (412.29): C, 58.39; H, 4.41; N,
10.22. Found: C, 58.43; H, 4.44; N, 10.31.
Anal. Calcd for C17H12ClN3O (309.07): C, 66.01; H, 3.91; N, 13.59.
Found: C, 66.03; H, 3.89; N, 13.66.
2-Allyl-1-(5-chloro-2-nitrophenyl)-4,9-dihydro-3H-b-carbolin-
ium Bromide (10b)
Yellow powder, yield: 2.10 g (91%); mp 232–233 °C.
Acknowledgment
IR (KBr): 2979, 2925, 1619, 1595, 1566, 1536, 1434, 1340, 1297,
1267, 1234, 1121 cm–1.
1H NMR (500 MHz, CDCl3): d = 11.95 (br s, 1 H, NH), 8.62 (d,
J = 9.0 Hz, 1 H, Ar-5¢H), 8.37 (d, J = 2.0 Hz, 1 H, Ar-2¢H), 8.19 (dd,
This work was financially supported by the National Fund for Sci-
ence and Research, Hungary (OTKA Project No. T 046196). N.M.
thanks the Hungarian Academy of Sciences for a Bolyai J. fel-
lowship.
Synthesis 2006, No. 8, 1273–1278 © Thieme Stuttgart · New York

1278
M. Nyerges et al.
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Synthesis 2006, No. 8, 1273–1278 © Thieme Stuttgart · New York