Reaction of 3,4-dihydro-β-carbolines with 4-fluorophenyl-nitrile oxide

Article abstract of DOI:10.2174/157017810791514913

The reaction of 3,4-dihydro-β-carboline 5a with the nitrile oxide generated from 4-fluoro-Nhydroxybenzenecarboximidoyl chloride (6) gave novel adduct 7a that on standing at 26 °C in CDCl₃ was isomerized to species 8. As an extension, the reacti

Full text of DOI:10.2174/157017810791514913

Letters in Organic Chemistry, 2010, 7, 377-382
377
Reaction of 3,4-Dihydro-ꢀ-Carbolines with 4-Fluorophenyl-Nitrile Oxide
Mátyás Milena,b, Péter Ábrányi-Balogha, András Dancsób, Gyula Simigb and György Keglevich*,a
aDepartment of Organic Chemistry and Technology, Budapest University of Technology and Economics, H-1521
Budapest, Hungary
bEGIS Pharmaceuticals PLC., Division for Chemical Research, H-1475 Budapest, P.O.B. 100, Hungary
Received February 08, 2010: Revised April 22, 2010: Accepted April 26, 2010
Abstract: The reaction of 3,4-dihydro-ꢀ-carboline 5a with the nitrile oxide generated from 4-fluoro-N-
hydroxybenzenecarboximidoyl chloride (6) gave novel adduct 7a that on standing at 26 °C in CDCl3 was isomerized to
species 8. As an extension, the reaction of the dihydro-ꢀ-carbolines substituted on C(1) (5b-e) afforded the analogous
adducts (7b-e). In case of using two equivalents of reagent 6, the corresponding 1,2,4-triazole-2-oxide (10b-e) was also
formed beside the adduct (7b-e).
Keywords: Alkaloides, 3,4-dihydro-ꢀ-carboline, nitrile oxide, cycloaddition, oxadiazolo-pyrido-indole.
1. INTRODUCTION
2. RESULTS AND DISCUSSION
The tetrahydro-ꢀ-carboline ring system can be found in
numerous compounds having interesting biological
activities. An optically active form of the tetracyclic alkaloid
harmicine (1) was isolated from the leaf extracts of
Malaysian plant Kopsia griffithii [1]. Similar tetracyclic
compounds containing the ꢀ-carboline skeleton exhibit
various biological and pharmaceutical properties. Meyers
and his coworkers reported on ꢀ-carboline compounds (such
as 2) that were used as inhibitors of mitogen-activated
protein kinase [2].
The reaction of 3,4-dihydro-ꢀ-carbolines (5a-e) with a
suitable nitrile oxide seemed to be usable to establish the D
ring of the tetracycle. The nitrile oxides are often used in
cycloadditions to provide various heterocyclic compounds
[5,6]. The corresponding nitrile oxides can be generated in
situ from the precursors of type chloro-oxime [7] or nitro
compound [8].
The starting compounds were 3,4-dihydro-ꢀ-carbolines
(5a-e). In the first approach, the reaction was carried out
using 1 equivalent of nitrile oxide generated from 4-fluoro-
N-hydroxybenzene-carboximidoyl chloride (6) in the
presence of triethylamine in dichloromethane to give the
expected oxadiazolo-pyrido-indole derivatives (7a-e)
(Scheme 1) in excellent yields (Table 1). The structure of the
new compounds was confirmed by NMR, IR and mass
spectroscopy.
O
N
N
N
H
COOMe
N
MeOOC
H
H
It was found that on standing at 26 °C in an NMR tube,
7a was converted to isomer 8. In DMSO-d6, the extent of
isomerization was only several per cent after 4 days, but in
CDCl3 after the same period of time, the conversion to 8 was
95%, presumably due to the traces of DCl (Scheme 2). The
NMR spectrum was of diagnostic value, as the sharp singlet
of 7a at 6.80 ppm which was characteristic to the CH unit
decreased, while a new, relatively broad peak developed at
8.80 ppm. The latter one is due to the =NH group of the
isomerised product 8. The structure of compound 8 was
1
2
Analogues, used in therapy containing two heteroatoms
in D ring are also known [3,4].
N
N
N
H
N
H
N
O
R
3
1
4
identified by H and 13C NMR data. The assignment was
promoted by two-dimensional COSY, HSQC and HMQC
spectra.
R = 4-Cl-C6H4, t-Bu, Pr
It is noteworthy that the by-product (8) got decomposed
slowly in the mixture of acetonitrile–water used as the
solvent in the LC-MS analysis. From among the second
We tried to synthesize novel tetracycles containing two
or more heteroatoms in D ring.
generation
of
by-products,
tetrahydro-ꢀ-carbolinone
derivative 9 known from the literature [9] could be isolated,
the structure of which was identified by H NMR and mass
spectroscopy. Beside this, the presence of 4-fluorobenzamide
was also pointed out in the mixture by the LC-MS utilizing
1
*Address correspondence to this author at the Department of Organic
Chemistry and Technology, Budapest University of Technology and
Economics, H-1521 Budapest, Hungary; Tel: +36 1 4631111/5883; Fax:
+36 1 4633648; E-mail: keglevich@mail.bme.hu
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

378 Letters in Organic Chemistry, 2010, Vol. 7, No. 5
Milen et al.
Cl
N
26°C
OH
F
CH2Cl2, Et3N
+
N
N
N
N
N
R
H
O
H
R
F
6
5a-e
7a-e
R = H(a), Me(b), Et(c), i-Pr(d), Ph(e)
Scheme 1.
an authentic sample. Corsaro et al. observed the formal loss
of benzonitrile in the case of cycloadducts that were
analogous to compound 7a. The decomposition occurred in
several days in solutions at 26 °C in the presence of air [10].
views of 7b and 10b are shown in Figs. (1 and 2),
respectively. We note the folded conformation of 10b caused
by ꢀ-ꢀ interactions. The 1,2,4-triazole-2-oxide moiety is
already known [11], however, to the best of our knowledge,
no X-ray structure for it has been reported. Our data confirm
the fact that can be expected, according to which the moiety
is a typically aromatic one (Fig. 3).
Table 1. Yields
of
Product
Oxadiazolo-Pyrido-Indole
Derivatives
Entry
Yield (%)
It has been proven that triazole oxide 10b was formed
from cycloadduct 7b by the addition of a second unit of
nitrile oxide. Compound 7b was reacted with 2 equivalents
4-fluoro-N-hydroxybenzenecarboximidoyl chloride (6) in the
presence of triethylamine. In this case, the triazole oxide
(10b) was isolated in 26% yield. Modelling of the reaction
mechanism will be published elsewhere.
1
2
3
4
5
7a, 91
7b, 95
7c, 98
7d, 98
7e, 97
After this, the reaction was extended to the 1-ethyl-, 1-
isopropyl- and 1-phenyl-3,4-dihydro-ꢀ-carbolines (5c-e). In
all cases, it was found that a mixture of products 7c-e and
10c-e was formed (Scheme 3). Compounds 7c and 7d were
isolated in ca. 60% yield, while 10c and 10d were obtained
in ca. 9% yield (Table 2, entries 3 and 4). Compounds 7e
and 10e were prepared in 67 and 33% yields, respectively
(Table 2, entry 5). Products (7c-e and 10c-e) were
characterized by NMR and IR spectral data. Compound 7e
was found to crystallize with 0.5 equivalent of acetonitrile.
According to thermogravimetric measurement, half of the
solvent is lost prior to melting, between 98.6 and 129.8 °C.
The reaction of 1-methyl-3,4-dihydro-ꢀ-carboline (5b)
was also studied under the same conditions but using 2
equivalents of 4-fluoro-N-hydroxybenzenecarboximidoyl
chloride (6). The reaction of 5b with the corresponding
nitrile oxide (generated from 6) resulted in the formation of
two products, tetracycle 7b and 1,2,4-triazole-2-oxide 10b
(Scheme 3). The products 7b and 10b were obtained in 61
and 35% yield, respectively (Table 2, entry 2). The structure
of the products (7b and 10b) was proved by NMR
spectroscopy and single crystal X-ray analysis. Perspective
F
26°C
F
CDCl3
N
N
95%
N
N
H
N
NH
H
O
4 days
O
7a
8
+ H2O
- 4-FC6H4CONH2
NH
O
N
H
9
Scheme 2.

Reaction of 3,4-Dihydro-ꢀ-Carbolines
Letters in Organic Chemistry, 2010, Vol. 7, No. 5
379
F
N
N
H
N
R
O
7b-e
26°C
CH2Cl2, Et3N
+
6
N
6
F
+
N
H
R
O
5b-e
N
N
F
N
O
N
H
R
10b-e
R = Me(b), Et(c), i-Pr(d), Ph(e)
Scheme 3.
It was not possible to isolate the corresponding triazole
oxide from the reaction of 5a and the nitrile oxide obtained
from 6. However, according to LC-MS, the by-product under
discussion was present in the crude mixture in a quantity of
2% (Mr = 444.4).
3. EXPERIMENTAL
3.1. General
Melting points were determined on a Kofler-Boëtius
micro apparatus and were not corrected. 1H NMR (500
MHz) and 13C NMR (125 MHz) spectra were taken on a
Varian Unity Inova 500 MHz spectrometer. Chemical shifts
are downfield to tetramethylsilane. The couplings are given
in Hz.
Table 2. Yields as Indicators of the Product Composition in
the Reaction of 3,4-Dihydro-ꢀ-Carbolines with a
Nitrile Oxide
Entry
Yield (%)
The FT-IR spectra were recorded on a Bruker Vector 22
spectrometer, using KBr pellets of solids. Single crystal X-
ray measurements were carried on a Rigaku R-Axis Spider
instrument.
1
2
3
4
5
7a, 55
7b, 61
7c, 61
7d, 60
7e, 67
10b, 35
10c, 8
3,4-Dihydro-ꢀ-carbolines were obtained in a simple
procedure from N-acyl-tryptamine with phosphorus oxy-
chloride [12,13]. 4-Fluoro-N-hydroxybenzenecarboximidoyl
10d, 10
10c, 33
Fig. (1). Perspective view of 7b.

380 Letters in Organic Chemistry, 2010, Vol. 7, No. 5
Milen et al.
Fig. (2). Perspective view of 10b.
chloride was synthesized from 4-fluorobenzaldehyde
3.4. 3-(4-Fluorophenyl)-5,6,11,11b-tetrahydro[1,2,4]oxa-
according to the procedure by Christian Peifer et al. [14].
diazolo[4',5':1,2]pyrido[3,4-b]indole 7a
White crystals; mp 170–172 °C; (Found: C, 69.99; H,
4.51; N, 14.02. C18H14FN3O requires C, 70.35; H, 4.59; N,
13.67%); ꢂmax(KBr)/cm–1 1603, 1507, 1237, 1158, 839 and
744; ꢃH(CDCl3) 8.41 (bs, 1H), 7.60–7.57 (m, 2H), 7.47–7.45
(m, 1H), 7.37–7.35 (m, 1H), 7.23–7.20 (m, 1H), 7.18–7.14
(m, 2H), 7.12–7.09 (m, 1H), 6.80 (s, 1H), 3.76–3.71 (m, 1H),
3.51–3.49 (m, 1H) and 2.63–2.61 (m, 2H); ꢃC(CDCl3) 164.2
(d, J = 151.0) (CF=), 158.3 (C=), 137.0 (C=), 130.2 (d, J =
8.8) (CH=), 129.2 (C=), 126.2 (C=), 123.2 (CH=), 121.3 (d,
J = 3.4) (C=), 119.9 (CH=), 118.7 (CH=), 116.2 (d, J = 22.0)
(CH=), 111.7 (CH=), 111.5 (C=), 88.7 (CH), 42.6 (CH2) and
20.4 (CH2).
Fig. (3). Selected geometric parameters of the 1,2,4-triazole-2-
oxide moiety in 10b.
3.2. General Method for the Preparation of 7a-e
To a stirred solution of the appropriate 3,4-dihydro-ꢀ-
carboline derivatives (5a-e) (1 mmol) and triethylamine
(0.15 ml, 1 mmol) in dichloromethane (20 ml) was added 4-
fluoro-N-hydroxybenzenecarboximidoyl chloride (0.162 g, 1
mmol) in one portion. The solution was stirred at 26 °C until
the starting material disappeared (1–8 hours). The reaction
mixture was washed with 1% hydrogen chloride (10 ml) and
water (2 ꢁ 10 ml). The organic layer was dried (MgSO4),
concentrated in vacuo and recrystallised from acetonitrile.
3.5. 2-[(4-Fluorophenyl)(imino)methyl]-2,3,4,9-tetrahydro-
1H-ꢀ-carbolin-1-one 8
ꢃH (CDCl3) 9.91 (bs, 1H), 8.80 (b, 1H), 7.62–7.60 (m,
1H), 7.55 (b, 2H), 7.28–7.25 (m, 1H), 7.17–7.14 (m, 1H),
7.09 (~t, J = 8.5, 2H), 7.01–6.99 (m, 1H), 4.33 (m, 2H) and
3.22 (t, J = 6.5, 2H); ꢃC (CDCl3): 163.8 (d, J = 250.0) (CF=),
162.1 (CO), 138.3 (C=), 134.2 (C=), 128.4 (CH=), 126.3
(C=), 125.9 (CH=), 124.8 (C=), 122.0 (C=), 120.6 (CH=),
120.5 (CH=), 115.6 (d, J = 22.0) (CH=), 112.8 (CH=), 49.4
(CH2) and 21.3 (CH2); m/z 307.1132 (M+ C18H14FN3O
requires 307.1121).
3.3. General Method for the Preparation of 7a-e and
10b-e
To a stirred solution of the appropriate 3,4-dihydro-ꢀ-
carboline derivatives (5a-e) (5 mmol) and triethylamine (1.5
ml, 10 mmol) in dichloromethane (30–80 ml) was added 4-
fluoro-N-hydroxybenzenecarboximidoyl chloride (1.62 g, 10
mmol) in one portion. The solution was stirred at 26 °C for 1
day. The reaction mixture was washed with 5% hydrogen
chloride (15 ml) and water (2 ꢁ 20 ml). The organic layer
was dried (MgSO4) and concentrated to give the product(s).
Separation was performed by column chromatography (silica
gel, dichloromethane–methanol 99.5:0.5) to give 7a-e and
10b-e. Products were recrystallised from acetonitrile.
3.6. 3-(4-Fluorophenyl)-11b-1-methyl-5,6,11,11b tetrahydro
[1,2,4]oxadiazolo[4',5':1,2]pyrido[3,4-b]indole 7b
White crystals; mp 219–221 °C; (Found: C, 70.94; H,
5.04; N, 13.08. C19H16FN3O requires C, 71.01; H, 5.02; N,
13.08%);
ꢂ
max(KBr)/cm–1 3201, 1424, 842 and 741;
ꢃH(CDCl3) 8.32 (b, 1H), 7.55 (~dd, J1 = 5.3, J2 = 8.8, 2H),
7.44–7.42 (m, 1H), 7.39–7.37 (m, 1H), 7.23–7.20 (m, 1H),
7.15 (~t, J = 8.7, 2H), 7.12–7.09 (m, 1H), 3.83–3.78 (m, 1H),
3.46–3.40 (m, 1H), 2.57–2.55 (m, 2H) and 2.03 (s, 3H);
ꢃC(CDCl3) 164.0 (d, J = 251.0) (CF=), 158.4 (C=), 136.7

Reaction of 3,4-Dihydro-ꢀ-Carbolines
Letters in Organic Chemistry, 2010, Vol. 7, No. 5
381
3.10. 3-(4-Fluorophenyl)-11b-(1-methylethyl)-5,6,11,11b-
tetrahydro[1,2,4]oxadiazolo[4',5':1,2]pyrido[3,4-b]indole
7d
(C=), 132.6 (C=), 130.1 (d, J = 8.8) (CH=), 126.3 (C=),
123.0 (CH=), 121.9 (d, J = 3.4) (C=), 119.8 (CH=), 118.6
(CH=), 116.1 (d, J = 22.0) (CH=), 111.7 (CH=), 109.9 (C=),
95.9 (C), 42.2 (CH2), 25.0 (CH3) and 20.5 (CH2).
White crystals; mp 208–210 °C; (Found: C, 71.93; H,
5.87; N, 12.14. C21H20FN3O requires C, 72.19; H, 5.87; N,
12.14%); ꢀmax(KBr)/cm–1 3273, 1393, 1223 and 757;
ꢁH(CDCl3) 8.20 (bs, 1H), 7.59 (~dd, J1 = 5.3, J2 = 8.8, 2H),
7.46–7.45 (m, 1H), 7.38–7.37 (m, 1H), 7.22–7.19 (m, 1H),
7.16 (~t, J = 8.7, 2H), 7.12–7.09 (m, 1H), 3.83–3.79 (m, 1H),
3.51–3.45 (m, 1H), 2.64–2.63 (m, 1H), 2.62–2.60 (m, 1H),
2.54 (~hp, J = 6.8, 1H), 1.28 (d, J = 6.6, 3H) and 1.04 (d, J =
7.0, 3H); ꢁC(CDCl3) 164.1 (d, J = 251.0) (CF=), 158.0 (C=),
136.7 (C=), 131.4 (C=), 130.2 (d, J = 8.8) (CH=), 126.4
(C=), 123.0 (CH=), 122.0 (d, J = 3.4) (C=), 119.8 (CH=),
118.5 (CH=), 116.1 (d, J = 22.0) (CH=), 111.6 (CH=), 111.2
(CH=), 99.9 (C), 43.8 (CH2), 36.3 (CH), 20.5 (CH2), 17.5
(CH3) and 15.9 (CH3).
3.7. 1-(3-{2-[3,5-bis(4-Fluorophenyl)-2-oxido-1H-1,2,4-tri-
azol-1-yl]ethyl}-1H-indol-2-yl)ethanone 10b
White crystals; mp 219–221 °C; (Found: C, 68.02; H,
4.46; N, 12.28. C26H20F2N4O2 requires C, 68.12; H, 4.40; N,
12.22%); ꢀmax(KBr)/cm–1 3373, 1657, 1535, 1491 and 1221;
ꢁH(DMSO-d6) 11.43 (bs, 1H), 8.46 (~dd, J1 = 5.5, J2 = 9.0,
2H), 7.39 (~t, J = 8.9, 2H), 7.37–7.35 (m, 1H), 7.22–7.21 (m,
1H), 7.21–7.20 (m, 1H), 7.18–7.14 (m, 4H), 6.78–6.75 (m,
1H), 4.63 (t, J = 6.2, 2H), 3.45 (t, J = 6.3, 2H) and 2.31 (s,
3H); ꢁC(DMSO-d6) 190.7 (CO), 162.9 (d, J = 248.5) (CF=),
162.5 (d, J = 247.6) (CF=), 143.0 (C=), 136.0 (C=), 135.8
(C=), 131.9 (C=), 130.1 (CH=), 128.2 (CH=), 127.4 (C=),
125.5 (C=), 123.5 (d, J = 2.9) (CH=), 123.2 (d, J = 2.9)
(CH=), 119.9 (CH=), 119.5 (C=), 116.5 (C=), 115.8 (d, J =
22.0) (CH=), 115.5 (d, J = 22.0) (CH=), 112.7 (CH=), 44.2
(CH2), 27.9 (CH3) and 22.5 (CH2).
3.11. 1-(3-{2-[3,5-bis(4-Fluorophenyl)-2-oxido-1H-1,2,4-
triazol-1-yl]ethyl}-1H-indol-2-yl)-2-methylpropan-1-one
10d
White crystals; mp 188–191 °C; (Found: C, 68.95; H,
4.99; N, 11.48. C28H24F2N4O2 requires C, 69.13; H, 4.97; N,
11.52%); ꢀmax(KBr)/cm–1 3351, 1664, 1534, 1489, 1220, 840
and 747; ꢁH(CDCl3) 8.66 (bs, 1H), 8.55 (~dd, J1 = 5.5, J2 =
8.8, 2H), 7.44–7.42 (m, 1H), 7.30–7.29 (m, 1H), 7.29–7.28
(m, 1H), 7.22–7.18 (m, 2H), 7.17(~dd, J1 = 5.1, J2 = 8.8,
2H), 6.97–6.94 (m, 3H), 4.75 (t, J = 6.5, 2H), 3.65 (t, J = 6.5,
2H), 3.05 (hp, J = 6.8, 1H) and 1.11 (d, J = 6.8, 6H);
ꢁC(CDCl3) 196.7 (CO), 163.6 (d, J = 252.0) (CF=), 163.4 (d,
J = 250.5) (CF=), 143.5 (C=), 137.4 (C=), 135.6 (C=), 130.8
(C=), 129.9 (d, J = 8.8) (CH=), 128.6 (d, J = 8.3) (CH=),
128.1 (C=), 126.6 (CH=), 123.1 (d, J = 3.4) (C=), 123.0 (d, J
= 2.9) (C=), 121.0 (CH=), 120.3 (CH=), 117.8 (C=), 115.8
(d, J = 22.0) (CH=), 115.6 (d, J = 21.5) (CH=), 111.8 (CH=),
44.8 (CH2), 36.9 (CH), 23.6 (CH2) and 18.8 (2xCH3).
3.8. 11b-Ethyl-3-(4-fluorophenyl)-5,6,11,11b-tetrahydro
[1,2,4]oxadiazolo[4',5':1,2]pyrido[3,4-b]indole 7c
White crystals; mp 168–170 °C; (Found: C, 71.31; H,
5.52; N, 12.64. C20H28FN3O requires C, 71.63; H, 5.41; N,
12.53%); ꢀmax(KBr)/cm–1 3315, 1603, 1512, 1399, 1224 and
1157; ꢁH(CDCl3) 8.33 (bs, 1H), 7.57 (~dd, J1 = 5.3, J2 = 8.6,
2H), 7.44–7.42 (m, 1H), 7.37–7.36 (m, 1H), 7.21–7.19 (m,
1H), 7.16 (~t, J = 8.6, 2H), 7.11–7,08 (m, 1H), 3.82–3.78 (m,
1H), 3.44–3.38 (m, 1H), 2.63–2.58 (m, 1H), 2.57–2.54 (m,
1H), 2.39–2.32 (m, 1H), 2.23–2.14 (m, 1H) and 1.17 (t, J =
7.3, 3H); ꢁC(CDCl3) 164.0 (d, J = 251.0) (CF=), 158.2 (C=),
136.7 (C=), 132.4 (C=), 130.1 (d, J = 8.8) (CH=), 126.3
(C=), 122.9 (CH=), 122.0 (d, J = 3.4) (C=), 119.8 (CH=),
118.5 (CH=), 116.1 (d, J = 22.0) (CH=), 111.6 (CH=), 110.2
(C=), 98.0 (C), 42.3 (CH2), 30.4 (CH2), 20.5 (CH2) and 7.5
(CH3).
3.12. 3-(4-Fluorophenyl)-11b-phenyl-5,6,11,11b-tetrahy-
dro[1,2,4]oxadiazolo[4',5':1,2]pyrido[3,4-b]indole 7e
White crystals; mp 126–128 °C; (Found: C, 71.98; H,
4.87; N, 12.27. C24H18FN3O requires C, 74.33; H, 4.86; N,
12.13%); ꢀmax(KBr)/cm–1 3364, 1601, 1454, 1429 and 752;
ꢁH(CDCl3) 8.05 (bs, 1H), 7.61–7.59 (m, 2H), 7.55 (~dd, J1 =
5.4, J2 = 8.9, 2H), 7.51–7.49 (m, 1H), 7.42–7.39 (m, 3H),
7.37–7.35 (m, 1H), 7.26–7.24 (m, 1H), 7.16–7.12 (m, 3H),
3.75–3.71 (m, 1H), 3.42–3,36 (m, 1H), 2.69–2.66 (m, 2H);
ꢁC(CDCl3) 164.1 (d, J = 251.0) (CF=), 157.4 (C=), 139.9
(C=), 136.9 (C=), 130.5 (C=), 130.13 (d, J = 8.3) (CH=),
129.5 (CH=), 128.4 (CH=), 127.6 (CH=), 126.1 (C=), 123.2
(CH=), 121.6 (d, J = 2.9) (CH=), 119.9 (CH=), 118.7 (CH=),
116.1 (d, J = 22.0) (CH=), 112.3 (C=), 111.7 (CH=), 98.0
(C), 41.2 (CH2), 20.6 (CH2).
3.9. 1-(3-{2-[3,5-bis(4-Fluorophenyl)-2-oxido-1H-1,2,4-tri-
azol-1-yl]ethyl}-1H-indol-2-yl)-2-propan-1-one 10c
White crystals; mp 222–224 °C; (Found: C, 68.70; H,
4.72; N, 11.89. C27H22F2N4O2 requires C, 68.64; H, 4.69; N,
11.86%); ꢀmax(KBr)/cm–1 3276, 1653, 1491 and 846;
ꢁH(DMSO-d6) 11.41 (bs, 1H), 8.44 (~dd, J1 = 5.6, J2 = 8.9,
2H), 7.39 (~t, J = 8.9, 2H), 7.41–7.34 (m, 1H), 7.21–7.19 (m,
1H), 7.18–7.16 (m, 1H), 7.13–7.11 (m, 4H), 6.75–6.72 (m,
1H), 4.65 (t, J = 6.0, 2H), 3.45 (t, J = 6.1, 2H), 2.67 (q, J =
7.2, 2H) and 0.95 (t, J = 7.2, 3H); ꢁC(DMSO-d6) 193.6 (CO),
162.9 (d, J = 248.5) (CF=), 162.5 (d, J = 247.6) (CF=), 143.1
(C=), 135.9 (C=), 135.8 (C=), 131.5 (C=), 130.1 (d, J = 8.8)
(CH=), 128.2 (d, J = 8.8) (CH=), 127.4 (C=), 125.4 (CH=),
123.5 (d, J = 2.9) (C=), 123.2 (d, J = 3.4) (C=), 119.8 (CH=),
119.4 (CH=), 116.3 (C=), 115.8 (d, J = 22.0) (CH=), 115.47
(d, J = 22.0) (CH=), 112.6 (CH=), 44.1 (CH2), 32.4 (CH2),
22.5 (CH2) and 7.6 (CH3).
3.13. (3-{2-[3,5-bis(4-Fluorophenyl)-2-oxido-1H-1,2,4-tri-
azol-1-yl]ethyl}-1H-indol-2-yl)(phenyl)methanone 10e
White crystals; mp 210–211 °C; (Found: C, 71.39; H,
4.41; N, 10.79. C31H22F2N4O2 requires C, 71.53; H, 4.26; N,

382 Letters in Organic Chemistry, 2010, Vol. 7, No. 5
Milen et al.
10.76%); ꢀmax(KBr)/cm–1 3453, 3131, 1640, 1536 and 1491;
ꢁH(CDCl3) 8.54 (~dd, J1 = 5.5, J2 = 7.1, 2H), 8.44 (bs, 1H),
7.60–7.58 (m, 2H), 7.57–7.54 (m, 1H), 7.47–7.44 (m, 2H),
7.31 (m, 1H), 7.30 (m, 1H), 7.26–7.18 (m, 5H), 7.00–6.99
(m, 1H), 6.98–6.95 (m, 2H), 4.72 (t, J = 6.2, 2H) and 3.59 (t,
J = 6.2, 2H); ꢁC(CDCl3) 187.7 (CO), 163.6 (d, J = 251.5)
(CF=), 163.3 (d, J = 250.0) (CF=), 143.3 (C=), 138.3 (C=),
137.3 (C=), 135.9 (C=), 132.4 (CH=), 131.2 (C=), 129.9 (d,
J = 8.8) (CH=), 128.8 (C=), 128.7 (d, J = 8.3) (CH=), 128.5
(CH=), 128.0 (CH=), 126.8 (CH=), 123.1 (d, J = 2.9) (C=),
123.0 (d, J = 3.4) (C=), 121.3 (C=), 120.6 (CH=), 120.0
(CH=), 115.7 (d, J = 22.0) (CH=), 115.5 (d, J = 22.0) (CH=),
111.8 (CH=), 44.9 (CH2) and 23.5 (CH2).
[2]
Meyers, M.J.; Trujillo, J.I.; Vernier, W.F.; Anderson, D.R.; Reitz,
D.B.; Buchler, I.P.; Hegde, S.G.; Mahoney, M.W.; Wu, K.K.
Preparation of beta-carboline compounds and analogues thereof for
use as mitogen-activated protein kinase-activated protein kinase-2
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Fourtillan, J.-B.; Fourtillan, M. Preparation of 3H,11H-
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Padwa, A. in 1,3-Dipolar Cycloaddition, Wiley-Interscience: New
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[3]
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Grundmann, Ch. Synthesis of heterocyclic compounds with the aid
of nitrile oxides. Synthesis 1970, 7, 344-359.
Liu, K.-Ch.; Shelton B.R.; Howe, R.K. A particularly convenient
preparation of benzohydroximinoyl chlorides (nitrile oxide
precursors). J. Org. Chem. 1980, 45, 3916-3918.
[8]
[9]
Mukaiyama, T.; Hoshino, T. The reaction of primary nitro paraffins
with isocyanates. J. Am. Chem. Soc. 1960, 82, 5339-5342.
Bracher, F.; Hildebrand, D. ꢂ-Carboline alkaloids. I. Syntheses of
1-aryl- and 1-alkenyl-ꢂ-carbolines by palladium-catalyzed coupling
reactions. Liebigs Ann. Chem. 1992, 12, 1315-1319.
Corsaro, A.; Perrini, G.; Caramella, P.; Albini F.M.; Bandiera, T.
Selectivity in cycloadditions. XIV. Cycloadducts of benzonitrile
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Gilchrist, T.L.; Harris, C.J.; Hawkins, D.G.; Moody C.J.; Rees,
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CONCLUSION
In summary, novel fused tetracycles (7a-e) were prepared
by the reaction of 3,4-dihydro-ꢂ-carboline derivatives (5a-e)
with a nitrile oxide. A novel isomerization of 7a, and the
further degradation of the isomer (8) so formed was also
observed. Using two equivalents of the nitrile oxide in the
reaction of 1-substituted dihydrocarbolines (5b-e), the
corresponding 1,2,4-triazole-2-oxide (10b-e) was also
formed. Products 10b-e were formed from compounds 5b-e
in a second addition reaction.
[10]
[11]
[12]
[13]
DEDICATION
Hulinska, H.; Taufmann, P.; Frycova H.; Protiva, M. 1-Methyl-, 1-
phenyl, and 1-[2-(2-dimethylaminoethoxy)phenyl]-2,3,4,9-tetra-
hydro-1H-pyrido[3,4-b]indole and their 2-substituted derivatives.
Synthesis and pharmacological screening. Collect. Czech. Chem.
Commun. 1988, 53, 373-380.
Dedicated to Professor József Reiter on the occasion of
his 70th birthday.
[14]
Peifer, Ch.; Kinkel, K.; Abadleh, M.; Schollmeyer D.; Laufer, S.
From five- to six-membered rings: 3,4-diarylquinolinone as lead
for novel p38MAP kinase inhibitors. J. Med. Chem. 2007, 50,
1213-1221.
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