Ugi reaction with isocyanoindoles

Article abstract of DOI:10.1023/B:RUJO.0000044548.07660.3c

Ugi reaction with 5-isocyanoindoles afforded a number of amino acids, β-lactams, and tetrazoles. The described approach can be applied to combinatorial synthesis of biologically active compounds of the indole series.

Full text of DOI:10.1023/B:RUJO.0000044548.07660.3c

Russian Journal of Organic Chemistry, Vol. 40, No. 6, 2004, pp. 847–853. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 6, 2004,
pp. 886–891.
Original Russian Text Copyright © 2004 by Mironov, Tokareva, Ivantsova, Mokrushin.
Dedicated to Full Member of the Russian Academy of Sciences
O.N. Chupakhin on his 70th Anniversary
Ugi Reaction with Isocyanoindoles
M. A. Mironov, M. I. Tokareva, M. N. Ivantsova, and V. S. Mokrushin
Ural State Technical University, ul. Mira 19, Yekaterinburg, 620002 Russia
e-mail: mir@htf.ustu.ru
Received January 12, 2004
Abstract—Ugi reaction with 5-isocyanoindoles afforded a number of amino acids, β-lactams, and tetrazoles.
The described approach can be applied to combinatorial synthesis of biologically active compounds of the
indole series.
The indole fragment constitutes a part of various
naturally occurring compounds, a number of which
exhibit pronounced biological activity. Therefore,
development of synthetic routes to indole-containing
structures attracts persistent interest of researchers.
Indoles having an isocyano group are produced by
some bacteria of the Pseudomonas family [1].
Examples are antibiotic B 371 and its derivatives
which possess a high antibacterial and fungicidal
activity [2]. It was shown that the presence of an iso-
cyano group is a necessary condition endowing such
compounds with the above sort of biological activity
[3]. In addition, the ability of isocyanides to participate
in various multicomponent reactions opens wide
prospects in the application of isocyanoindoles as base
structures for combinatorial libraries. For example,
indoles having a side-chain isocyano group were
recently used to search for new antibiotics by highly
efficient semiautomatic procedures [4].
having only a few definite substituents in positions 2
and 3 of the indole ring. On the other hand, the
classical procedure described in [7] turned out to be
unsuitable for the preparation of isocyanoindoles
having no substituents in positions 2 and 3 from the
corresponding formamides I. Therefore, we developed
a novel method which allowed us to obtain 5-isocyano-
1H-indole (IIa) and 1-methyl-1H-indole (IIb) with ac-
count taken of their instability (Scheme 1). To prevent
polymerization of compounds II, the reaction time
was shortened, and all operations were performed at
reduced temperature with strict control of pH. Initial
formamides I were synthesized from dihydroindole
following the known procedure [8]. Isocyanides II are
fairly unstable compounds which readily undergo
polymerization in solution, while crystalline samples
can be stored for several days at –18°C. Unfortunately,
compounds IIa and IIb cannot be subjected to bio-
logical testing; however, they can be used as starting
materials for the synthesis of various derivatives.
Studies in the field of biological and chemical
properties of isocyanoindoles are limited due to the
lack of convenient methods for their preparation since
classical procedures are often inapplicable to the syn-
thesis of heterocyclic isocyanides [5]. We previously
reported on the first synthesis of 5-isocyanoindoles by
reaction of 1,4-diisocyanobenzene with tertiary amines
[6]. The goal of the present study was to elucidate the
possibility of involving 5-isocyanoindoles in the Ugi
reaction with a view to obtain a wide series of their
derivatives as potential biologically active compounds.
The structure of compounds II was confirmed by
1
the IR and H NMR spectra. Both IIa and IIb showed
Scheme 1.
NHCHO
NC
POCl3, Et3N
N
R
N
R
Ia, Ib
IIa, IIb
The procedure proposed by us previously makes
it possible to synthesize 5-isocyanoindole derivatives
R = H (a), Me (b).
1070-4280/04/4006-0847 © 2004 MAIK “Nauka/Interperiodica”

MIRONOV et al.
848
Scheme 2.
O
R3
O
R4
N
H
NC
N
R5
MeOH
R2NH2
R3COR4
R5CH2COOH
+
+
+
R2
N
N
R1
R1
IIa, IIb
IIIa–IIId
IVa, IVb
Va, Vb
VIa–VIf
IIa, VIa, VIb, R1 = H; IIb, VIc–VIf, R1 = Me; IIIa, VIa, VIb, R2 = 1-benzylpiperidin-4-yl; IIIb, VIc, R2 = benzyl; IIIc, VId,
R2 = cyclopropyl; IIId, VIe, VIf, R2 = 2-(1H-indol-3-yl)ethyl; IVa, VIa, VIc, VIe, VIf, R3 = R4 = Me; IVb, VIb, VId, R3R4 =
(CH2)5; Va, VIa, VIb, VIe, VIf, R5 = Ph; Vb, VIc, VId, R5 = phthalimido.
in the IR spectra an absorption band at 2120 cm–1,
the desired products by reaction with formaldehyde,
1
which belongs to the isocyano group. The H NMR
presumably as a result of concurrent Mannich con-
densation at the 3-position of the initial isocyanide.
Thus the optimal set of initial reactants should include
such compounds which selectively react with the
isocyano group, the indole fragment remaining intact
(aliphatic ketones, strongly basic amines, and car-
boxylic, as well as some mineral, acids). Benzylpiper-
idine, cyclopropylamine, benzylamine, and tryptamine
(IIId) were used as amine component. By reactions
with compound IIId we succeeded in introducing one
more indole fragment into the products (VIe and VIf).
spectra of II contained a set of signals typical of
5-substituted indoles. In the H NMR spectrum of IIb
1
we observed signals from the aromatic protons as two
doublets at δ 7.63 ppm (4J = 1.5 Hz) and 7.43 ppm
(3J = 8.9 Hz) and a doublet of doublets at δ 7.18 ppm
(3J = 8.9, J = 1.5 Hz) (4-H, 7-H, and 6-H, respec-
4
tively). Also, signals from protons in the pyrrole
fragment were present as two doublets at δ 7.35 and
6.45 ppm (3J = 3.4 Hz). Protons in the N-methyl group
of IIb appeared as a singlet at δ 3.83 ppm.
It should be noted that the use of isocyanides as
a base structure for combinatorial libraries implies
application of the whole diversity of the Ugi reaction
[9]. However, the real choice is limited by the ability
of initial isocyanides to undergo polymerization: The
Ugi reaction should be faster than undesirable poly-
merization process. Taking into account published data
[10], we selected appropriate reagents, namely strongly
basic primary amines, aliphatic ketones, formaldehyde,
phthalylglycine, and phenylacetic acid. By reactions of
amines IIIa–IIId, ketones IVa and IVb, acids Va and
Vb, and isocyanides IIa and IIb in methanol we
obtained amino acid derivatives VIa–VIf (Scheme 2)
in good yields (70–75%). However, we failed to isolate
The structure of compounds VI was proved with
account taken of published data [11, 12]. The 1H NMR
spectra of compounds VIa–VIf contained signals from
the indole fragment (see above). In the aromatic
region, signals from the second indole fragment,
phthalimide moiety, and other aromatic groups were
also present. The NH proton gave a signal at δ 8.61–
8.87 ppm. Compounds VIa, VIc, VIe, and VIf showed
1
in the H NMR spectra a singlet from the methyl
protons at δ 1.40–1.62 ppm, and in the spectra of VIb
and VId we observed signals from the cyclohexane
fragment as a two-proton multiplet at δ 2.30–2.65 ppm
and eight-proton multiplet at δ 1.25–2.00 ppm. The
spectra of VIe and VIf also contained signals from the
Scheme 3.
N
N
N
NC
N
MeOH
R1NHR2
R3COR4
HN3
+
+
+
R1
R3
R4
N
N
N
R2
Me
Me
IIb
IIId, IIIe
IVa, IVb
VIIa–VIId
IIIe, VIIa, VIIb, R1R2 = (C2H4)2O; IIId, VIIc, VIId, R1 = H, R2 = 2-(1H-indol-3-yl)ethyl; IVa, VIIa, VIIc, R3 = R4 = Me; IVb,
VIIb, VIId, R3R4 = (CH2)5.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 6 2004

UGI REACTION WITH ISOCYANOINDOLES
849
Scheme 4.
R2
O
R3
N
R4
H
R4
NC
N
MeOH
R2COR3
COOH
+
+
H2N
N
N
O
R1
R1
IIa, IIb
IVb–IVe
VIIIa, VIIIb
IXa–IXf
IIa, IXa–IXc, R1 = H; IIb, IXd–IXf, R1 = Me; IVb, IXc, IXd, IXf, R2R3 = (CH2)5; IVc, IXa, R2R3 = (CH2)4; IVd, IXe, R2R3 =
(C2H4)2S; IVe, IXb, R2 = H, R3 = i-Pr; VIIIa, IXa, IXb, IXd, IXe, R4 = H; VIIIb, IXc, IXf, R4 = 3,4-(OCH2O)C6H3.
tryptamine fragment. All compounds VIa–VIf showed
in the mass spectra the molecular ion peaks whose
m/z values were consistent with the calculated mole-
cular weights. The mass spectra also contained peaks
from the fragment ion [M – 18]+ which is typical of
decomposition of the linear Ugi reaction products
under electron impact [11]. Compounds VIe and VIf
containing a tryptamine moiety gave rise to the
fragment ion with m/z 143, which corresponds to
3-vinylindole.
All compounds IXa–IXf showed the molecular ion
peak in the mass spectra. The main fragmentation
pattern includes dissociation of the C–C bond between
the ketone and isocyanide moieties, so that the mass
spectra contained the fragment ion corresponding to
1
oxoazetidine + ketone. In the H NMR spectra of
lactams IXa, IXb, IXd, and IXe, signals from protons
of the oxoazetidine ring appeared as two triplets in
the δ region 2.86–3.27 ppm with a coupling constant
of 4.0–4.3 Hz.
Thus, our results showd that 5-isocyanoindoles can
be used as starting material for synthesis of a large
number of derivatives, such as amino acids, β-lactams,
and tetrazoles, via Ugi reaction. Possible versions of
the Ugi reaction were examined, and limitations con-
cerning the initial reactants were determined. A wide
variety of structures available from isocyanoindoles by
the Ugi reaction demonstrates excellent prospects for
combinatorial synthesis. We plan to further extend the
developed approach to search for new indole-con-
taining biologically akcive compounds with the aid of
new highly productive methods.
Some inorganic acids, e.g., thiocyanic, hydro-
chloric, and hydrazoic, can successfully be involved in
the Ugi reaction [9]. In paticular, the reactions with
hydrazoic acid afforded tetrazolyl-substituted indoles
VIIa–VIId in high yield (Scheme 3). The mass spectra
of VIIa–VIId contained the molecular ion peaks and
fragment ion peaks from the amine–ketone moiety and
indole ring (m/z 130). Tryptamine derivatives VIIc and
VIId are characterized by the fragment ion peak with
m/z 143, and the ion peak with m/z 86 in the mass
spectra of VIIa and VIIb arises from the morpholine
1
moiety. In the H NMR spectra of VIIa–VIId we
observed signals from protons of the indole and methyl
and methylene groups. Protons of the morpholine ring
in VIIa and VIIb gave rise to two triplets (3J = 4.3 Hz)
at δ 3.40–3.56 and 2.33–2.44 ppm, and the spectra of
VIIc and VIId contained signals from the tryptamine
fragment.
EXPERIMENTAL
The progress of reactions and the purity of products
were monitored by thin-layer chromatography on
Silufol-254 and Sorbfil-254 plates using the following
solvent systems: chloroform; chloroform–ethanol, 9:1,
15:1, 20:1; chloroform–hexane, 1:1, 1:2, 2:1. The IR
spectra were recorded in KBr on a UR-20 spectrom-
It is known that the use in the Ugi reaction of
difunctional reagents, such as amino acids, opens wide
synthetic prospects; specifically, nonaromatic hetero-
cyclic structures can be obtained in this way [9]. By
reaction of isocyanides IIa and IIb, ketones IVb–IVd,
and amino acids VIIIa and VIIIb in methanol we
obtained β-lactams IXa and IXc–IXf (Scheme 4). In
the reaction with isobutyraldehyde (IVe) we isolated
compound IXb, but the yield was lower than in the
reactions with aliphatic ketones.
1
eter. The H NMR spectra were obtained on a Bruker
WM-250 instrument at 250 MHz using DMSO-d6 or
DMSO-d6–CCl4 as solvent and tetramethylsilane as
internal reference. The mass spectra (electron impact,
70 eV) were run on a Varian MAT 311A instrument
(accelerating voltage 3 kV) with direct sample
admission into the ion source. The melting points were
not corrected.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 6 2004

MIRONOV et al.
850
spectrum (DMSO-d6–CCl4), δ, ppm: 10.76 s (1H, NH),
5-Isocyanoindoles IIa and IIb (general proce-
8.59 s (1H, NH), 7.56 d (1H, 4-H, indole, 4J = 1.5 Hz),
dure). N-(1H-Indol-5-yl)formamide Ia or Ib, 7 mmol,
was added to a mixture of 20 ml of dry methylene
chloride, 3.36 ml of triethylamine, and 0.84 ml of
phosphoryl chloride. The mixture was stirred for
30 min at 5°C and was washed with 15 ml of a 10%
solution of KOH on cooling. The organic layer was
separated, and the solvent was quickly (within 5–
10 min) distilled off at a temperature not exceeding
30°C. The residue was carefully recrystallized from
hexane.
7.16–7.30 m (12H, 2Ph, 2-H, 7-H, indole), 7.00 d.d
3
4
(1H, 6-H, J = 8.6, J = 1.5 Hz), 6.29 br.s (1H, 3-H,
indole), 3.78 s (2H, CH2), 3.45–3.56 m (1H, CH),
3.44 s (2H, CH2), 2.88 br.t (2H, CH2N), 2.26 br.t (2H,
CH2N), 2.25–1.30 m (14H, 7CH2). Mass spectrum, m/z
(Irel, %): 548 [M]+ (4), 530 (8), 426 (24), 346 (37), 192
(29), 145 (38), 122 (26), 91 (100). Found, %: C 76.44;
H 7.26; N 10.14. C35H40N4O2. Calculated , %: C 76.61;
H 7.29; N 10.21.
5-Isocyanoindole (IIa). Yield 0.81 g (82%),
N-(1-Methyl-1H-indol-5-yl)-2-[benzyl(2-phthal-
1
mp 92–93°C. IR spectrum, cm–1: 2117 (NC). H NMR
imidoacetyl)amino]-2-methylpropionamide (VIc).
1
spectrum (DMSO-d6–CCl4), δ, ppm: 10.81 br.s (1H,
Yield 0.07 g (69%), mp 301–302°C. H NMR spec-
4
NH), 7.67 d (1H, 4-H, J = 1.5 Hz), 7.27 d (1H, 7-H,
trum (DMSO-d6–CCl4), δ, ppm: 8.85 s (1H, NH),
3
J = 8.5 Hz), 7.19 t (1H, 2-H, J = 2.7 Hz), 7.10 d.d
7.79–7.88 m (4H, Harom, phthalimide), 7.58 d (1H, 4-H,
3
4
4
3
(1H, 6-H, J = 8.5, J = 1.5 Hz), 6.33 t (1H, 3-H,
3J = 2.7 Hz).
indole, J = 1.8 Hz), 7.52 d (1H, 7-H, indole, J =
8.2 Hz), 7.12–7.46 m (7H, Ph, 2-H, 6-H, indole),
3
6.31 d (1H, 3-H, indole, J = 2.5 Hz), 4.88 s (2H,
5-Isocyano-1-methylindole (IIb). Yield 0.85 g
(78%), mp 70–71°C. IR spectrum, cm–1: 2115 (NC).
1H NMR spectrum (DMSO-d6–CCl4), δ, ppm: 7.63 d
CH2), 4.63 s (2H, CH2), 3.78 s (3H, NCH3), 1.40 s
(6H, 2CH3). Mass spectrum, m/z (Irel,%): 508 [M]+
(2), 490 (5), 363 (31), 160 (28), 148 (33), 146 (31),
91 (100). Found, %: C 71.00; H 5.68; N 11.18.
C30H28N4O4. Calculated, %: C 70.85; H 5.55; N 11.02.
4
3
(1H, 4-H, J = 1.5 Hz), 7.43 d (1H, 7-H, J = 8.9 Hz),
3
3
7.35 d (1H, 2-H, J = 3.4 Hz), 7.18 d.d (1H, 6-H, J =
8.9, 4J = 1.5 Hz), 6.45 d (1H, 3-H, 3J = 3.4 Hz), 3.83 s
(3H, NCH3).
N-(1-Methyl-1H-indol-5-yl)-1-[cyclopropyl-
(2-phthalimidoacetyl)amino]cyclohexanecarbox-
amide (VId). Yield 0.074 g (74%), mp 174–175°C.
1H NMR spectrum (DMSO-d6–CCl4), δ, ppm: 8.85 s
(1H, NH), 7.81–7.90 m (4H, Harom, phthalimide),
7.56 d (1H, 4-H, indole, 4J = 1.8 Hz), 7.22 d (1H, 7-H,
General procedure for the synthesis of com-
pounds VI. Amine IIIa–IIId, 0.2 mmol, ketone IVa or
IVb, 0.2 mmol, and acid Va or Vb, 0.2 mmol, were
added to a solution of 0.2 mmol of 5-isocyanoindole
in 0.2 ml of methanol, and the mixture was kept for
2–3 h. The precipitate was filtered off and recrys-
tallized from ethanol.
3
3
indole, J = 8.6 Hz), 7.13 d (1H, 2-H, indole, J =
3
4
2.4 Hz), 7.04 d.d (1H, 6-H, indole, J = 8.6, J =
1.8 Hz), 6.29 d (1H, 3-H, indole, J = 2.4 Hz), 4.74 s
3
N-(1H-Indol-5-yl)-2-[1-benzylpiperidin-4-yl-
(2H, CH2), 3.77 s (3H, NCH3), 2.85–3.00 m [1H,
CH(CH2)2], 2.30–2.47 m [2H, C(CH2)5], 1.90–2.10 m
[2H, C(CH2)5], 1.30–1.80 m [6H, C(CH2)5], 0.95–
1.18 m [4H, CH(CH2)2]. Mass spectrum, m/z (Irel, %):
499 [M + 1]+ (2), 498 [M]+ (8), 480 (2), 353 (72), 325
(49), 255 (12), 173 (4), 160 (86), 146 (70), 138 (100).
Found, %: N 11.23. C29H30N4O4. Calculated, %: N 11.24.
(phenylacetyl)amino]-2-methylpropionamide (VIa).
Yield 0.077 g (76%), mp 256–257°C. H NMR spec-
1
trum (DMSO-d6–CCl4), δ, ppm: 10.74 s (1H, NH),
8.20 s (1H, NH), 7.58 d (1H, 4-H, indole, 4J = 1.6 Hz),
7.15–7.32 m (12H, 2Ph, 2-H, 7-H, indole), 7.01 d.d
3
4
(1H, 6-H, J = 8.5, J = 1.6 Hz), 6.29 br.s (1H, 3-H,
indole), 3.78 s (2H, CH2), 3.55–3.61 m (1H, CH),
3.44 s (2H, CH2), 2.87 br.t (2H, CH2N), 2.25 br.t (2H,
CH2N), 1.76–1.91 m (4H, 2CH2), 1.54 s (6H, 2CH3).
Mass spectrum, m/z (Irel, %): 508 [M]+ (5), 490 (6), 372
(31), 246 (42), 166 (32), 132 (25), 91 (100). Found, %:
C 75.35; H 7.00; N 11.13. C32H36N4O2. Calculated, %:
C 75.56; H 7.08; N 11.01.
N-(1-Methyl-1H-indol-5-yl)-2-methyl-2-
{(2-phthalimidoacetyl)[2-(1H-indol-3-yl)ethyl]-
amino}propionamide (VIe). Yield 0.084 g (75%),
1
mp 253–254°C. H NMR spectrum (DMSO-d6–CCl4),
δ, ppm: 10.85 s (1H, NH, indole), 8.82 s (1H, NH),
7.81–7.90 m (4H, Harom, phthalimide), 7.59 s (1H, 4-H,
3
N-(1H-Indol-5-yl)-2-[1-benzylpiperidin-4-yl-
indole), 7.56 d (1H, 4-H, tryptamine, J = 8.9 Hz),
3
(phenylacetyl)amino]cyclohexanecarboxamide
7.36 d (1H, 7-H, tryptamine, J = 7.9 Hz), 7.25 s (1H,
1
(VIb). Yield 0.081 g (74%), mp 263–264°C. H NMR
2-H, tryptamine), 7.22 d (1H, 7-H, indole, 3J = 8.9 Hz),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 6 2004

UGI REACTION WITH ISOCYANOINDOLES
851
3
4
7.13 d (1H, 2-H, indole, J = 2.8 Hz), 6.99–7.09 m
CCl4), δ, ppm: 7.77 d (1H, 4-H, indole, J = 1.8 Hz),
(3H, 6-H, indole, 5-H, 6-H, tryptamine), 6.30 d (1H,
3-H, indole, J = 2.8 Hz), 4.60 s (2H, CH2), 3.60–
7.55 d (1H, 7-H, indole, 3J = 8.6 Hz), 7.42 d (1H, 2-H,
3
3
3
indole, J = 3.1 Hz), 7.31 d.d (1H, 6-H, indole, J =
8.6, 4J = 1.8 Hz), 6.53 d (1H, 3-H, indole, 3J = 3.1 Hz),
3.95 m (2H, CH2), 3.77 s (3H, NCH3), 3.10–3.30 m
(2H, CH2), 1.60 s (6H, 2CH3). Mass spectrum, m/z (Irel,
%): 562 [M + 1]+ (6), 561 [M]+ (14), 542 (52), 401
(100), 212 (24), 160 (27), 143 (79), 130 (15). Found,
%: C 70.51; H 5.53; N 12.34. C33H31N5O4. Calculated,
%: C 70.57; H 5.56; N 12.47.
3
3.91 s (3H, NCH3), 3.56 t [4H, O(CH2)2, J = 4.3 Hz],
3
2.44 t [4H, N(CH2)2, J = 4.3 Hz], 1.90–2.00 m [2H,
C(CH2)5], 1.15–1.78 m [8H, C(CH2)5]. Mass spectrum,
m/z (Irel, %): 367 [M + 1]+ (4), 366 [M]+ (16), 281
(100), 168 (70), 156 (43), 86 (8). Found, %: N 23.10.
C20H26N6O. Calculated, %: N 22.93.
N-(1-Methyl-1H-indol-5-yl)-2-methyl-2-{[2-(1H-
5-{1-[2-(1H-Indol-3-yl)ethylamino]-1-methyl-
ethyl}-1-(1-methyl-1H-indol-5-yl)tetrazole (VIIc).
Yield 0.069 g (87%), mp 207–208°C. H NMR spec-
indol-3-yl)ethyl]phenylacetylamino}propionamide
(VIf). Yield 0.075 g (76%), mp 217–218°C. H NMR
1
1
spectrum (DMSO-d6–CCl4), δ, ppm: 10.79 s (1H, NH,
indole), 8.61 s (1H, NH), 7.63 d (1H, 4-H, indole, 4J =
trum (DMSO-d6–CCl4), δ, ppm: 10.71 s (1H, NH,
3
indole), 7.32–7.41 m (4H, 4-H, indole, 2-H, 4-H, 7-H,
1.8 Hz), 7.51 d (1H, 4-H, tryptamine, J = 7.6 Hz),
3
3
tryptamine), 7.24 d (1H, 7-H, indole, J = 8.6 Hz),
7.34 d (1H, 7-H, tryptamine, J = 8.2 Hz), 6.98–
3
3
7.04 d.d (1H, 5-H, tryptamine, J = 8.6, J = 7.9 Hz),
7.25 m (11H, 3-H, 6-H, 7-H, indole, 2-H, 5-H, 6-H,
tryptamine, Ph), 6.30 d (1H, 3-H, indole, 3J = 2.8 Hz),
3.78 s (3H, NCH3), 3.70–3.95 m (2H, CH2), 3.64 s
(2H, CH2), 2.90–3.10 m (2H, CH2), 1.62 s (6H, 2CH3).
Mass spectrum, m/z (Irel, %): 493 [M + 1]+ (1), 492
[M]+ (2), 474 (3), 332 (100), 143 (79), 130 (11),
91 (16). Found, %: N 11.58. C31H32N4O2. Calculated,
%: N 11.37.
3
6.99 d (1H, 2-H, indole, J = 2.8 Hz), 6.92 d.d (1H,
3
3
6-H, tryptamine, J = 7.9, J = 7.9 Hz), 6.78 d.d (1H,
3
4
6-H, indole, J = 8.6, J = 1.8 Hz), 6.43 d (1H, 3-H,
3
indole, J = 2.8 Hz), 3.13 s (3H, NCH3), 2.64–2.68 m
[4H, (CH2)2NH], 1.25–1.53 m [1H, (CH2)2NH], 1.36 s
(6H, 2CH3). Mass spectrum, m/z (Irel, %): 399 [M]+ (2),
269 (10), 200 (20), 184 (24), 171 (31), 143 (40), 130
(90), 70 (100). Found, %: C 69.23; H 6.39; N 24.64.
C23H25N7. Calculated, %: C 69.15; H 6.31; N 24.54.
General procedure for the synthesis of tetra-
zolyl-substituted indoles VII. Amine IIId or IIIe,
0.2 mmol, ketone IVa or IVb, 0.2 mmol, and a 1 mM
solution of hydrazoic acid in 0.2 ml of benzene, were
added to a solution of 0.2 mmol of 5-isocyanoindole
IIb in 0.2 ml of methanol, and the mixture was kept
for 2–3 h. The precipitate was filtered off and recrys-
tallized from ethanol.
5-{1-[2-(1H-Indol-3-yl)ethylamino]-1-methyl-
cyclohexyl}-1-(1-methyl-1H-indol-5-yl)tetrazole
1
(VIId). Yield 0.06 g (69%), mp 195–196°C. H NMR
spectrum (DMSO-d6–CCl4), δ, ppm: 10.75 s (1H, NH,
indole), 7.34–7.39 m (3H, 4-H, indole, 4-H, 7-H,
tryptamine), 7.25 d (1H, 2-H, tryptamine, 3J = 1.8 Hz),
3
7.18 d (1H, 7-H, indole, J = 8.6 Hz), 7.04 d.d (1H,
3
3
1-(1-Methyl-1H-indol-5-yl)-5-(1-methyl-1-mor-
pholinoethyl)tetrazole (VIIa). Yield 0.047 g (72%),
5-H, tryptamine, J = 8.6, J = 7.9 Hz), 6.98 d (1H,
3
2-H, indole, J = 3.1 Hz), 6.93 d.d (1H, 6-H, trypta-
1
mine, 3J = 7.9, 3J = 7.9 Hz), 6.62 d.d (1H, 6-H, indole,
mp 196–197°C. H NMR spectrum (DMSO-d6–CCl4),
4
4
3
3J = 8.6, J = 1.8 Hz), 6.39 d (1H, 3-H, indole, J =
δ, ppm: 7.73 d (1H, 4-H, indole, J = 1.8 Hz), 7.54 d
(1H, 7-H, indole, 3J = 8.6 Hz), 7.41 d (1H, 2-H, indole,
3.1 Hz), 3.86 s (3H, NCH3), 2.75 t [2H, (CH2)2NH,
3
4
3J = 3.1 Hz), 7.27 d.d (1H, 6-H, indole, J = 8.6, J =
3
3J = 6.1], 2.59 t [2H, (CH2)2NH, J = 6.1 Hz], 1.85–
3
1.8 Hz), 6.52 d (1H, 3-H, indole, J = 3.1 Hz), 3.91 s
(3H, NCH3), 3.40 t [4H, O(CH2)2, J = 4.3 Hz], 2.33 t
1.94 m [2H, C(CH2)5], 1.26–1.60 m [9H, C(CH2)5,
(CH2)2NH]. Mass spectrum, m/z (Irel, %): 439 [M]+ (1),
240 (12), 184 (12), 171 (26), 143 (25), 130 (34), 110
(100). Found, %: N 22.23. C26H29N7. Calculated, %:
N 22.31.
3
3
[4H, N(CH2)2, J = 4.3 Hz], 1.36 s (6H, 2CH3). Mass
spectrum, m/z (Irel, %): 327 [M + 1]+ (4), 326 [M]+
(21), 241 (100), 198 (9), 156 (46), 128 (86), 86 (11).
Found, %: C 62.63; H 6.81; N 25.80. C17H22N6O. Cal-
culated, %: C 62.56; H 6.79; N 25.75.
General procedure for the synthesis of β-lactams
(IX). Ketone or aldehyde IVb–IVe, 0.2 mmol, and
β-amino acid VIIIa or VIIIb, 0.2 mmol, were added to
a solution of 0.2 mmol of 5-isocyanoindole IIa or IIb
in 0.2 ml of methanol, and the mixture was kept for
1-(1-Methyl-1H-indol-5-yl)-5-(1-methyl-1-mor-
pholinocyclohexyl)tetrazole (VIIb). Yield 0.058 g
1
(80%), mp 242–243°C. H NMR spectrum (DMSO-d6–
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 6 2004

MIRONOV et al.
852
2–3 h. The precipitate was filtered off and recrys-
tallized from ethanol.
CCl4), δ, ppm: 9.13 s (1H, NH), 7.73 s (1H, 4-H, in-
dole), 7.17–7.29 m (2H, 6-H, 7-H, indole), 7.15 d (1H,
2-H, indole, 3J = 2.8 Hz), 6.31 d (1H, 3-H, indole, 3J =
2.8 Hz), 3.79 s (3H, NCH3), 3.26 t [2H, CO(CH2)2N,
N-(1H-Indol-5-yl)-1-(2-oxoazetidin-1-yl)cyclo-
pentanecarboxamide (IXa). Yield 0.038 g (64%),
3
3J = 4.3 Hz], 2.86 t [2H, CO(CH2)2N, J = 4.3 Hz],
1
mp 223–224°C. H NMR spectrum (DMSO-d6–CCl4),
2.11–2.23 m [2H, C(CH2)5], 1.91–2.00 m [2H,
C(CH2)5], 1.15–1.78 m [6H, C(CH2)5]. Mass spectrum,
m/z (Irel, %): 326 [M + 1]+ (6), 325 [M]+ (28), 172 (3),
152 (100), 110 (51). Found, %: C 70.15; H 7.13;
N 12.97. C19H23N3O2.Calculated, %: C 70.13; H 7.12;
N 12.91.
δ, ppm: 10.80 br.s (1H, NH), 9.21 s (1H, NH), 7.70 d
4
3
(1H, 4-H, J = 1.5 Hz), 7.25 d (1H, 7-H, J = 8.5 Hz),
3
7.18 t (1H, 2-H, J = 2.4 Hz), 7.14 d.d (1H, 6-H,
4
3
3J = 8.5, J = 1.5 Hz), 6.32 t (1H, 3-H, J = 2.4 Hz),
3
3.27 t [2H, CO(CH2)2N, J = 4.2 Hz], 2.83 t [2H,
CO(CH2)2N, J = 4.2 Hz], 2.12–2.38 m (4H, 2CH2),
3
1.85–2.00 m (4H, 2CH2). Mass spectrum, m/z (Irel, %):
297 [M]+ (36), 186 (12), 138 (100), 110 (43). Found,
%: C 68.75; H 6.32; N 14.09. C17H19N3O2. Calculated,
%: C 68.68; H 6.39; N 14.13.
N-(1-Methyl-1H-indol-5-yl)-4-(2-oxoazetidin-1-
yl)tetrahydrothiopyran-4-carboxamide (IXe). Yield
0.053 g (78%), mp 193–194°C. H NMR spectrum
1
(DMSO-d6–CCl4), δ, ppm: 9.34 s (1H, NH), 7.75 s
(1H, 4-H, indole), 7.26 s (2H, 6-H, 7-H, indole), 7.18 d
N-(1H-Indol-5-yl)-3-methyl-2-(2-oxoazetidin-1-
yl)butyramide (IXb). Yield 0.023 g (41%), mp 154–
3
(1H, 2-H, indole, J = 2.8 Hz), 6.31 d (1H, 3-H,
3
1
indole, J = 2.8 Hz), 3.79 s (3H, NCH3), 3.27 t [2H,
155°C. H NMR spectrum (DMSO-d6–CCl4), δ, ppm:
CO(CH2)2N, 3J = 4.0 Hz], 2.89 t [2H, CO(CH2)2N, 3J =
4.0 Hz], 2.68–2.83 m (2H, S(CH2)4), 2.10–2.65 m [6H,
S(CH2)4]. Mass spectrum, m/z (Irel, %): 344 [M + 1]+
(11), 343 [M]+ (51), 170 (100), 146 (33), 128 (45).
Found, %: N 12.18. C18H21N3O2S. Calculated, %:
N 12.23.
10.78 br.s (1H, NH), 9.84 s (1H, NH), 7.84 d (1H, 4-H,
3
4J = 1.6 Hz), 7.27 d (1H, 7-H, J = 8.6 Hz), 7.18 t
3
3
(1H, 2-H, J = 2.5 Hz), 7.13 d.d (1H, 6-H, J = 8.6,
4J = 1.6 Hz), 6.31 t (1H, 3-H, J = 2.5 Hz), 4.06 d
(1H, J = 9.8 Hz, CH), 3.42 t [2H, J = 4.2 Hz,
3
3
3
3
CO(CH2)2N], 2.86 t [2H, J = 4.2 Hz, CO(CH2)2N],
2.10–2.17 m (1H, CH), 0.95 d (6H, 3J = 3.9 Hz, 2CH3).
Mass spectrum, m/z (Irel, %): 285 [M]+ (36), 158 (17),
126 (100), 97 (38). Found, %: C 67.18; H 6.60;
N 14.65. C16H19N3O2. Calculated, %: C 67.28; H 6.66;
N 14.73.
N-(1-Methyl-1H-indol-5-yl)-1-[4-(3,4-methylene-
dioxyphenyl)-2-oxoazetidin-1-yl]cyclohexanecar-
boxamide (IXf). Yield 0.052 g (59%), mp 176–177°C.
1H NMR spectrum (DMSO-d6–CCl4), δ, ppm: 9.14 s
(1H, NH), 7.66 d (1H, 4-H, indole, 4J = 1.8 Hz), 7.27 d
(2H, 7-H, indole, 3J = 8.6 Hz), 7.18 d (1H, 2-H, indole,
N-(1H-Indol-5-yl)-1-[4-(3,4-methylenedioxy-
phenyl)-2-oxoazetidin-1-yl]cyclohexanecarbox-
amide (IXc). Yield 0.062 g (72%), mp 167–168°C.
1H NMR spectrum (DMSO-d6–CCl4), δ, ppm: 10.81 br.s
3
4
3J = 2.8 Hz), 7.15 d.d (1H, 6-H, indole, J = 8.6, J =
4
1.8 Hz), 6.98 d (1H, 2-H, C6H3, J = 1.7 Hz), 6.87 d.d
(1H, 6-H, C6H3, J = 7.9, J = 1.7 Hz), 6.72 d (1H,
3
4
3
3
4
5-H, J = 7.9 Hz), 6.32 d (1H, 3-H, indole, J =
2.8 Hz), 5.94 br.s (2H, CH2O2), 4.69–4.71 m (1H, CH),
3.80 s (3H, NCH3), 3.27–3.35 m (1H, CH2CO), 2.66–
2.73 m (1H, CH2CO), 1.80–2.10 m [2H, C(CH2)5],
1.20–1.75 m [8H, C(CH2)5]. Mass spectrum, m/z
(Irel, %): 446 [M + 1]+ (5), 445 [M]+ (17), 272 (10), 172
(7), 150 (13), 124 (100), 81 (38). Found, %: N 9.38.
C26H27N3O4. Calculated, %: N 9.43.
(1H, NH), 9.04 s (1H, NH), 7.64 d (1H, 4-H, J =
1.3 Hz), 7.27 d (1H, 7-H, 3J = 8.5 Hz), 7.19 t (1H, 2-H,
3J = 2.4 Hz), 7.08 d.d (1H, 6-H, 3J = 8.5, 4J = 1.3 Hz),
6.96 d (1H, 2-H, C6H3, 4J = 1.2 Hz), 6.82 d.d (1H, 6-H,
3
4
C6H3, J = 7.9, J = 1.2 Hz), 6.71 d (1H, 5-H, C6H3,
3
3J = 7.9 Hz), 6.32 t (1H, 3-H, J = 2.4 Hz), 5.91 br.s
(2H, CH2O2), 4.69–4.71 m (1H, CH), 3.31 d.d (1H,
CH2CO, J = 5.4 Hz), 2.68 d.d (1H, CH2CO, J =
2.2 Hz), 1.80–2.10 m [2H, C(CH2)5], 1.20–1.75 m [8H,
C(CH2)5]. Mass spectrum, m/z (Irel, %): 431 [M]+ (22),
272 (63), 172 (7), 150 (13), 124 (100), 81 (38). Found,
%: C 69.68; H 5.72; N 9.69. C25H25N3O4. Calculated,
%: C 69.64; H 5.80; N 9.74.
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