Synthesis of Analogues of Indole Alkaloids from Sea Sponges – Aplysinopsins by the Reaction of Amines with (4Z)-4-[(1H-indol-3-yl)-methylene]-1,3-oxazol-5(4H)-ones

Article abstract of DOI:10.1002/jhet.2382

A new two-step approach toward the synthesis of aplysinopsin analogues 5-(1-R-1H-indol-3-ylmethylene)-2-aryl-3,5-dihydroimidazol-4-ones consisting in obtaining and reaction of 4-(1-R-1H-indol-3-ylmethilene)-2-Ar-4H-oxazol-5-ones with amines was developed. The configuration of starting compounds and final products was determined by¹³С and¹H-nmr spectroscopy.

Full text of DOI:10.1002/jhet.2382

Month 2015
Synthesis of Analogues of Indole Alkaloids from Sea Sponges –
Aplysinopsins by the Reaction of Amines with (4Z)-4-[(1H-indol-3-yl)-
methylene]-1,3-oxazol-5(4H)-ones
Konstantin F. Suzdalev* and Maria N. Babakova
Chemical Department of Southern Federal University, Zorge Street 7, 344090 Rostov-on-Don, Russia
*
E-mail: konsuz@gmail.com
Received October 4, 2014
DOI 10.1002/jhet.2382
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
A new two-step approach toward the synthesis of aplysinopsin analogues 5-(1-R-1H-indol-3-
ylmethylene)-2-aryl-3,5-dihydroimidazol-4-ones consisting in obtaining and reaction of 4-(1-R-1H-indol-3-
ylmethilene)-2-Ar-4H-oxazol-5-ones with amines was developed. The configuration of starting compounds
1
3
1
and final products was determined by С and H-nmr spectroscopy.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
Reaction of acylglycines with aldehydes is well studied
6] and often leads to mixtures of isomeric oxazolones
7]. Their ratio and interconversion were earlier reviewed
8] and still stay the object of study [9]. As to analogous
reactions of indole-3-carbaldehydes, formed oxazolones
in early works were characterized as individual substances,
without specifying their stereochemical configuration
[
[
[
Marine organisms produce thousands of organic com-
pounds, many of which have an exceptionally high biolog-
ical activity [1]. Alkaloids 1, containing fragments of
indole and imidazole, are called aplysinopsins and kept in
sea sponges Astroides calicularis [2] and Samenospongia
aureus [3] (Fig. 1).
It was found that the compounds 1 have antimalarial and
antituberculosis activity [4]. However, the problem of cre-
ating medicines based on them is their low contents in the
feedstock and the low prevalence of sea sponges in the
ocean. In addition, intensive use of marine resources can
harm the environment. Solution of the problem is the syn-
thesis of natural substances 1 and their analogues.
Known methods of synthesis of aplysinopsins consist reac-
tion of indol-3-carbaldehydes with appropriate imidazolones
by fusion [2,5] or boiling in acetic acid in the presence of so-
dium acetate [3].
[
10a–c]. In particular, it concerns to the reaction of
-methylindole-3-carbaldehyde 2a with hippuric acid
10c]. However, data about stereochemistry and isomeriza-
1
[
tion of a similar natural oxazolone bearing indole moiety
were described in paper [10d].
Unlike papers [10a–c], we have found that the reactions
of indole-3-carbaldehydes 2a,b with aroylglycines result in
formation of mixtures of steric isomers with large predom-
inance of one of these (Table 1).
The minor component may be removed by double
recrystallization. Determination of configuration of iso-
mers and interconversion between them was investigated
We have developed an alternative method for the synthesis
of aplysinopsin analogues 7 by heating oxazolones 3a–e with
primary amines in ethylene glycol or dimethylformamide.
1
by the example of compounds 3a and 4a. In the H-nmr
spectrum of the oxazolone mixture obtained from
aldehyde 2a and hippuric acid, some signals are doubled,
indicating the presence of two steric forms. Thus, the
olefinic proton signals of isomers 3a and 4a are at 8.48
and 9.13 ppm. Determination of product configurations
RESULTS AND DISCUSSION
Starting oxazolones 3a–e were prepared by Erlenmeyer–
Plöchl reaction of indole-3-carbaldehydes 2a,b with
aroylglycines in acetic anhydride (Scheme 1).
1
13
was carried out by analyzing the H and C-nmr spectra
of this mixture, in which the component having the
©
2015 HeteroCorporation

K. F. Suzdalev and M. N. Babakova
Vol 000
data are consistent with ours, too: the olefinic proton
signal of a Z-product is in a higher field region of the
1
H-nmr spectrum as compared with an E-isomer.
Thus, determination of product configuration may be
1
carried out by means of H-nmr spectra. Based on this,
we determined percentage composition of isomer mixtures,
obtained by the reaction of indolecarbaldehydes with
aroylglycines (Table 1).
Figure 1. Natural aplysinopsins.
We investigated the interconversion of isomers 3a and
4a. Pure red Z-isomer 3a may be obtained by double re-
crystallization from toluene of the product, precipitated
from the reaction mixture. We tried to turn Z-isomer 3a
in E-isomer 4a by heating in polyphosphoric acid; but in
contrast to the described method [13], we did not observe
a total conversion of one substance to another. A mixture
of isomeric oxazolones with a prevalence of E-structure 4a
was obtained. Pure yellow E-isomer 4a was isolated by re-
crystallization of this mixture from chlorobenzene.
The sterically hindered yellow E-isomer 4a is partly
converted into the red Z-product 3a by heating in toluene
in the presence of trifluoroacetic acid. The reaction obvi-
ously passes through the protonated form 5a in which the
rotation around the single C–C bond is possible
(Scheme 1).
proton signal at 8.48 ppm predominates. In the low field
13
region of C-nmr spectrum recorded without suppres-
sion of carbon–proton coupling, doublets at 167.61 ppm
and 160.84 ppm belong to the carbon atoms of carbonyl
groups of Z- and E-isomers. Doublet multiplicity of each
C-signal corresponds to its splitting through three bonds
1
13
on the corresponding olefinic proton. The H,
C
3
heteronuclear coupling constant J value of the minor
CH
isomer (160.84 ppm) is 11.12Hz that unequivocally
proves its E-structure 4a. For another, the predominant
isomer (167.61 ppm), this constant is 4.50 Hz, which cor-
responds to the Z-configuration 3a. The values of these
constants are typical for such compounds; it is known
3
that a J
of E-isomer is always larger than that of
CH
the Z-isomer [11].
In accordance with the intensities of carbon signals in the
For the synthesis of aplysinopsin analogues, we used the
known reaction of oxazolones with amines [14]. Purified
1
3
С-nmr spectrum of a mixture of the isomers 3a and 4a, the
1
Z-structure 3a is predominant. The signal in the H-nmr
spectrum at 8.48 ppm is more intense than 9.13ppm; thus,
it belongs to the Z-isomer 3a. Earlier, analogous assign-
ments were made on the basis of HMBC, HSQC, and
Table 1
The ratio of oxazolone isomers 3, 4.
1
1
H, H-COSY NMR experiments of natural indole alkaloid
The ratio of isomers, %
almazolone. This alkaloid represent a mixture of E- and
Z-isomers similar to structures 3 and 4 (R = H and Ar =2-
phenylethyl). Curiously, the chemical shifts for similar
protons practically coincide with ours – 8.45 (for Z-) and
3
–5
R
Ar
Z (3)
E (4)
а
b
c
d
e
Me
Et
Me
Me
Et
Ph
Ph
87.0
80.5
88.0
97.6
100.0
13.0
19.5
12.0
2.4
9
.12 (for E-isomer) in the same solvent – CDCl [10d].
C
C
6
H
H
4
Me-4
3
6
4
OMe-4
The determination of oxazolone configurations was also
carried out using nuclear Overhauser effect [12]. These
Furan-2-yl
0.0
Scheme 1. Synthesis of isomeric starting oxazolones and interconversion between them.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Synthesis of Analogues of Alkaloids from Sea Sponges by the Reaction of Amines
with (4Z)-4-[(1H-indol-3-yl)-methylene]-1,3-oxazol-5(4H)-ones
Table 2
The ratio of imidazolone isomers 7, 8.
Ratio of isomers, %
1
7
,8
R
Ar
Ph
R
Z (7)
E (8)
a
Me
95.0
5.0
b
c
Me
Me
Ph
100.0
95.0
0.0
5.0
6 4
C H OMe-4
d
e
Me
Et
C
6
H
4
Me-4
100.0
100.0
0.0
0.0
Ph
f
Et
Fyran-2-yl
100.0
0.0
Scheme 2. Recyclization of oxazolones into imidazolones.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

K. F. Suzdalev and M. N. Babakova
Vol 000
Z-isomers of oxazolones 3a–e undergo recyclization of
CONCLUSION
ANRORC type with the formation of imidazolone deriva-
tives 7 and 8 under action of amines by refluxing in
dimethylformamide or ethylene glycol. In case of reacting
the starting compounds 3a,c with tryptamine, a mixture
of isomers 7a,c and 8a,c with a large predominance of
Z-structure 7 is formed. All other reactions lead to the
preparation of individual Z-isomers of 7b,d–f (Table 2).
The presence of small amounts of the isomeric products
In summary, we have developed an efficient approach
toward the synthesis of analogues of sea sponge indole
alkaloids from readily available 4-[(1H-indol-3-yl)-meth-
ylene]-1,3-oxazol-5(4H)-ones. The products may include
various pharmacophore groups that are important for cre-
ating combinatorial libraries of aplysinopsin analogues
with a view to their biological testing.
8
may be explained by Michael addition of amine to the
double bond of compound 6 and rotation around C–C bond
in the intermediate 9. The elimination of the amine from
compound 10, followed by cyclization of the intermediate
EXPERIMENTAL
IR spectra were taken on Varian 3100 FT-IR, Excalibur Series
instrument by means of Attenuated Total Reflectance method. H
and C-nmr spectra were recorded on Varian Unity 300 spec-
trometer (300 MHz). In the description of the nmr spectra of iso-
mer mixtures, the chemical shifts are listed separately for each
component.
1
1
1 leads to the E-isomer 8 (Scheme 2).
13
Carrying out of the reaction in mild conditions (the re-
flux in acetonitrile) allows obtaining the intermediate
amides 6a–e. Cyclization products derived from these
amides are formed mainly in a Z-configuration, contrasted
1
-Methyl-1H-indole-3-carbaldehyde (2a) [16]. 1H-indole-
3-carbaldehyde (29 g, 0.2 mol) was dissolved in dimethylsulfoxide
1
to natural alkaloids having E-structure [4]. In the H-nmr
spectra of imidazolones obtained from oxazolones 3a,c
and tryptamine, the olefinic proton signals are duplicated
and located in the fields of 8.40 and 9.40ppm. The ratio
of isomers 7 and 8 is 95:5%, with a predominance of
products having olefinic proton signals at 8.40ppm. Deter-
(50 mL) with gentle warming, and 50% NaOH (13 g NaOH,
0
2
.325 mol in 13 mL H O) was added in one portion. Then,
dimethylsulfate (29 mL, 0.3 mol) was added in 30 min. During
this addition, the reaction temperature was maintained lower
3
5
0°С. After that, the mixture was kept at rt for 1 h, heated to
0°С, and poured out into a water (60 mL). Precipitated
13
mining configuration was based on the nmr spectrum
C
light-brown residue was filtered (30.1 g, 95%), mp 66–68°С (lit.
mp – 68–70°С [17]).
of substance 7b; in its spectrum, recorded without suppres-
sion of carbon–proton coupling, carbon signal of C¼O
group is observed as a multiplet of four lines at
1-Ethyl-1H-indol-3-carboxaldehyde (2b).
carbaldehyde (29 g, 0.2 mol) was treated with diethylsulfate
33 ml, 0.25 mol) in the same manner as the preparation of 2a in
the presence of 50% NaOH (10 g NaOH, 0.25 mol in 10 mL
O) in dimethylsulfoxide (50 mL). A light pink residue was
1H-Indole-3-
(
1
70.71 ppm (superposition of two triplets). This indicates
a carbon signal splitting on the olefinic hydrogen and two
H
2
methylene protons of the substituent R . The value of the
1
obtained (35 g, 96%), mp 103–105°С; ir: (С¼С) 1600, (С¼O)
3
ꢀ
1 1
heteronuclear J constant between olefinic proton and
CH
1653 cm ; H-nmr (deuteriochloroform) δ 1.52 (t, 3H, СH );
3
the carbon atom of the C¼O group is 4.11Hz, correspond-
4.23 (q, 2H, СH ); 7.20–7.42 (m, 3H, H-5,6,7); 7.72 (s, 1H,
H-2); 8.23–8.34 (m, 1H, H-4); 9.97 (s, 1H, CHO). Anal. Calcd
for C11H11NO: C, 76.28; H, 6.40; N, 8.09. Found: C, 76.50; H,
6.30; N, 8.16.
2
ing to Z-configuration, which is typical of such compounds
[
11]. The E-isomer of natural aplysinopsin 1 (R =R =H,
1
3
R = R =CH , X =NCH CH ) have this constant J of
9
2
3
3
2
3
CH
1
(4Z,E)-4-[(1-Methyl-1H-indol-3-yl)methylene)]-2-phenyl-
.5Hz [4]. In a H-nmr spectrum of compound 7b, the ole-
1
,3–oxazol-5(4H)-one (the mixture of 3a and 4a).
The
finic proton signal is at 8.45 ppm. Accordingly, spectra of
mixtures of compounds 7a, 8a, and 7c, 8c show the
predominance of Z-structures 7a and 7c while signals of
olefinic protons of main isomers are in the region of 8.42
and 8.40ppm.
mixture of hippuric acid (8.95 g, 0.05 mol) and 1-methyl-1H-
indole-3-carbaldehyde (2a) (8 g, 0.05 mol) was heated in
acetic anhydride (20 mL) on a water bath for 5 h. Residue was
filtered, washed by acetic anhydride, and recrystallized from
toluene to give red crystals of the mixture of 3a and 4a in a
ratio of 87:13 (7.32 g, 48%), mp 178–180°С; ir: (С¼С)1653,
Earlier the configuration of aplysinopsins was deter-
mined by nuclear Overhauser effect [15] and is consistent
with our results: Olefinic proton signal of Z-product is in
a higher field as compared with the E-isomer. So, as well
as in the case of oxazolones 3a–e, the determination of a
ꢀ1
1
(
3
С¼O) 1780, 1760 cm ; H-nmr (deuteriochloroform) δ 3a:
.95 (s, 3H, СH ); 7.30–8.20 (m, 10H, HAr.); 8.40 (s, 1H,
3
С-nmr (deuteriochloroform)
suppression of spin–spin interaction of carbon atoms with
1
3
СH¼).
δ
3a (without
3
3
protons): 159.90 (t, JCH = 5.11 Hz, C-Ph); 167.61 (d, JCH
1
1
= 4.50 Hz, С¼O); H-nmr (deuteriochloroform) δ 4a: 8.08
configuration can also be made on the basis of H-nmr
1
3
(
m, H ); 9.13 (s, 1H, H ); С-nmr (deuteriochloroform) δ
Ar Ar
spectrum data: The signal of olefinic proton of Z-isomer
is always in a higher field than the signal of E-isomer.
It should be noted that in the above-mentioned papers
4
a (without suppression of carbon–proton coupling): 152.54
3
3
(
t, JCH = 4.80 Hz, С-Ph); 160.84 (d, JCH = 11.12 Hz, СO).
Anal. Calcd for C19 : C, 75.48; H, 4.67; N, 9.27.
14 2 2
H N O
[
14], concerning to conversion of oxazolones into
Found: C, 75.51; H, 4.60; N, 9.35.
imidazolones, the stereochemistry of the products was
not determined.
(4Z)-4-[(1-Methyl-1H-indol-3-yl)methylene)]-2-phenyl-1,3-
oxazol-5(4H)-one (3a). One gram of the mixture of 3a and 4a
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Synthesis of Analogues of Alkaloids from Sea Sponges by the Reaction of Amines
with (4Z)-4-[(1H-indol-3-yl)-methylene]-1,3-oxazol-5(4H)-ones
obtained in previous experiment was twice recrystallized from
(deuteriochloroform) δ 1.58 (t, 3H, CH СH ); 4.31 (q, 2H,
3 2
13
toluene to give 0.49 g of a pure Z-product. mp 182–183°С; С-
nmr (deuteriochloroform) δ (with suppression of carbonꢀproton
coupling): 33.76, 110.12, 111.37, 119.27, 122.08, 123.41,
CH СH ); 6.63 (dd, 1H, H ); 7.21–7.95 (m, 7H, H ); 8.33 (s,
3 2 fur Ar
1H, СH¼). Anal. Calcd for C18
9.15. Found: C, 70.66; H, 4.54; N, 9.28.
N-[1-[2-(1H-Indol-3-yl)ethylcarbamoyl]-2-(1-methyl-1H-
indol-3-yl)-vinyl]-benzamide (6a). The mixture of (4Z)-4-
H
14
N
2
O
3
: C, 70.58; H, 4.61; N,
1
1
25.20, 126.30, 127.68 (2C), 127.71, 127.90, 128.82 (2C),
32.31, 136.89, 137.20, 160.17 (С-Ph), 167.93 (С¼O). Anal.
Calcd for C H N O : C, 75.48; H, 4.67; N, 9.27. Found: C,
[(1-methyl-1H-indol-3-yl)methylene)]-2-phenyl-1,3-oxazol-5
(4H)-one (3a) (0.91 g, 0.003 mol) and tryptamine (0.48 g,
0.003 mol) was refluxed in acetonitrile (7 mL) for 1 h until the
color of starting oxazolone disappears. After cooling colorless
crystals of 6a were filtered (1.18 g, 85%), mp 134–136°С; ir:
19 14 2 2
7
5.39; H, 4.74; N, 9.19.
4E)-4-[(1-Methyl-1H-indol-3-yl)methylene)]-2-phenyl-1,3-
oxazol-5(4H)-one (4a). To (4Z)-4-[(1-methyl-1H-indol-3-yl)
methylene)]-2-phenyl-1,3-oxazol-5(4H)-one (3a) (0.91 g,
.003 mol) was added poliphosphoric acid (13 g), and the
(
ꢀ
1
1
0
(С¼С) 1600, (С¼O) 1633, 1687; (NH) 3367 cm
; H-nmr
mixture was heated for 1.5 h at 80–90°С. To the cooled oily
mixture, water (150–200 ml) was added and a yellow residue
precipitated. It was dried and recrystallized from chlorobenzene
to give 4a (0.4 g, 44%) as yellow needles, mp 243–244°С; ir:
(deuteriodimethylsulfoxide) δ: 3.92 (t, 2H, NHСH СH ); 3.45
2
2
(t, 2H, NHСH СH ); 3.65 (s, 3H, СH ); 6.90–8.15 (m, 16H,
2
2
3
Ar
H ); 8.15 (s, 1H, СH¼); 9.90 (s, 1H, NH); 10.65 (s, 1H, NH).
29 26 4 2
Anal. Calcd for C H N O : C, 75.30; H, 5.67; N, 12.11.
ꢀ
1 1
(
(
H
7
С–СAr.) 1580, 1599, (С¼С) 1625, (С¼O) 1740 cm ; H-nmr
deuteriochloroform) δ 3.92 (s, 3H, СH ); 7.26–8.07 (m, 10H,
Ar.); 9.11 (s, 1H, СH¼). Anal. Calcd for C19 : C,
5.48; H, 4.67; N, 9.27. Found: C, 75.40; H, 4.55; N, 9.38.
4Z,E)-4-[(1-Ethyl-1H-indol-3-yl)methylene)]-2-phenyl-1,3-
oxazol-5(4H)-one (the mixture of 3b and 4b). The compound
b (17.3 g, 0.1 mol) was heated for 6.5 h with hippuric acid
17.9 g, 0.1 mol) in the same manner as the obtaining of 3a, 4a.
Found: C, 75.40; H, 4.65; N, 12.38.
3
N-[2-(1-Methyl-1H-indol-3-yl)-1-(3-morpholne-4-yl-propyl-
carbamoyl)-vinyl]-benzamide (6b). In the same way as 6a,b
was prepared from oxazolone 3a (0.91 g, 0.003 mol) and 3-(N-
morpholine)propylamine (0.7 mL, 0.0048 mol) to give colorless
powder (1.09 g, 81%); mp 141–142°С; ir: (С¼O) 1646, 1630,
14 2 2
H N O
(
ꢀ
1
1
2
(
(NH) 3293 cm
СH ); 2.40 (m, 6H, 3NСH
O(СH ); 3.72 (s, 3H, СH
(deuteriochloroform) δ 6b (with suppression of carbon–proton
coupling): 25.03 (NimCH CH CH morph); 32.84 (N–CH ); 39.05
N CH CH CH Nmorph), 53.52 (2C, NCH2morph); 57.08
; H-nmr (deuteriochloroform) δ 1.65 (t, 2H,
); 3.40 (m, 2H, NHСH
3
); 7.10–8.00 (m, 13H, HAr). С-nmr
); 3.61 (m, 4H,
2
13
2
2
Precipitated residue was recrystallized from toluene to give the
2
)
2
mixture of 3b, 4b (14.5 g, 44.5%). mp 145–147°С; ir: (С¼С)
ꢀ
1 1
1
647, 1781, (С¼O) 1760 cm ; H-nmr (deuteriochloroform) δ
2
2
2
N
3
(
3
b: 1.56 (t, 3H, СH
3
); 4.30 (q, 2H, СH
Ar); 8.50 (s, 1H, СH). 4b: 1.52 (s, 1H, СH
Ar); 9.20 (s, 1H, СH¼). Anal. Calcd for C20
2
); 7.20–8.10 (m, 10H,
); 7.81–7.89 (m,
: C,
im
2
2
2
(N
imCH
2
CH
2
CH
2
N
morph), 66.84 (2C, OСH2morph); 108.75, 109.35,
H
H
7
3
1
1
1
18.43, 120.12, 120.65, 122.24, 124.95, 127.69(2C), 127.81(2C),
16 2 2
H N O
28.41, 129.98, 131.70, 133.25, 136.12 (СAr); 166.23 (C¼O);
5.48; H, 4.67; N, 9.27. Found: C, 75.70; H, 4.23; N, 9.40.
30 4 3
67.03 (C¼O). Anal. Calcd for C26H N O : C, 69.93; H, 6.77;
(
4Z,E)-4-[(1-Methyl-1H-indol-3-yl)methylene)]-2-(4-methyl-
N, 12.55. Found: C, 69.75; H, 6.64; N, 12.34.
N-[1-[2-(1H-Indol-3-yl)ethylcarbamoyl]-2-(1-methyl-1H-
indol-3-yl)-vinyl]-4-methoxybenzamide (6с). In the same
phenyl)-1,3-oxazol-5(4H)-one (the mixture of 3с and 4с). The
compound 2a (7.95 g, 0.05 mol) was heated for 3 h with [(4-
methylbenzoyl)amino]acetic acid (7.75 g, 0.05 mol) in the same
way as the preparation of 3a, 4a. Residue was recrystallized
from toluene to give the mixture of 3c, 4c (6.80 g, 43%) mp
way as 6a,c was prepared from oxazolone 3d (0.66 g, 0.002 mol)
and tryptamine (0.32 g, 0.002 mol) to give colorless powder
(
3
0.85 g, 86%). mp 146°С; ir: (С¼С) 1604, (С¼O) 1640, (NH)
ꢀ
1 1
1
(
86°С; ir: (С¼С)1600, 1633, (С¼O) 1740, 1767 cm ; H-nmr
deuteriochloroform) δ 3с: 2.46 (s, 3H, CH ); 3.95 (s, 3H,
); 7.27–8.10 (m, 9H, HAr); 8.48 (s, 1H, СH¼). 4с: 1.43 (s,
); 3.94 (s, 3H, NСH ); 7.86 (m, HAr); 9.12 (s, 1H,
СH¼). Anal. Calcd for C H N O : C, 75.48; H, 4.67; N, 9.27.
ꢀ1
1
337 cm ; H-nmr (deuteriodimethylsulfoxide) δ 3.92 (t, 2H,
3
NHСH СH ); 3.47 (q, 2H, NHСH СH ); 3.75 (s, 3H, OСH );
2
2
2
2
3
NСH
3
3
.88 (s, 3H, NСH ); 6.90–8.10 (m, 16H, H ); 9.49 (s, 1H, NH);
3
Ar
3
H, CH
3
3
1
0.60 (s, 1H, NH). Anal. Calcd for C30
H
28
N
4
O
3
: C, 73.15; H,
2
0
16
2
2
5.73; N, 11.37. Found: C, 73.08; H, 5.65; N, 11.43.
N-[1-[2-(1H-Indol-3-yl)ethylcarbamoyl]-2-(1-methyl-1H-
indol-3-yl)-vinyl]-4-methylbenzamide (6d). In the same
Found: C, 75.58; H, 4.80; N, 9.44.
4Z,E)-4-[(1-Methyl-1H-indol-3-yl)methylene)]-2-(4-methoxy-
(
phenyl)-1,3-oxazol-5(4H)-one (the mixture of 3d and 4d). The
compound 2a (7.95 g, 0.05 mol) was heated for 3 h with [(4-
methoxylbenzoyl)amino]acetic acid (10.45 g, 0.05 mol) in the
same way as the obtaining of 3a, 4a. Residue was recrystallized
from toluene to give the mixture of 3d, 4d (6.48 g, 39%), mp
way as 6a,d was prepared from oxazolone 3с (0.996 g, 0.003 mol)
and tryptamine (0.48 g, 0.003 mol) to give colorless powder
(1.27 g, 89%). mp 208°С; ir: (С¼С) 1606, (С¼O) 1633, (NH)
ꢀ
1
1
3340 cm
; H-nmr (deuteriodimethylsulfoxide) δ 2.42 (s, 3H,
СH ); 2.92 (t, 2H, NHСH СH ); 3.48 (q, 2H, NHСH СH ); 3.77
3
2
2
2
2
ꢀ
1 1
212°С; ir: (С¼С) 1603, 1640, (С¼O) 1760, 1780 cm ; H-nmr
(s, 3H, NСH ); 6.89–8.05 (m, 16H, H ); 9.50 (s, 1H, NH); 10.60
3 Ar
(
deuteriochloroform) δ 3d: 3.88 (s, 3H, OСH ); 3.92 (s, 3H,
(s, 1H, NH). Anal. Calcd for C H N O : C, 75.61; H, 5.92; N,
30 28 4 2
3
NCH
СH¼). 4d: 3.95 (s, 3H, OСH
Ar); 9.08 (s, 1H, СH¼). Anal. Calcd for C20
5.48%; H, 4.67; N, 9.27. Found: C, 75.32; H, 4.75; N, 9.46.
4Z)-4-[(1-Ethyl-1H-indol-3-yl)methylene)]-2-(2-furyl)-1,3-
oxazol-5(4H)-one (3e). The mixture of compound 2b (8.65 g,
,05 mol) and [(2-furoyl)amino]acetic acid (8.45 g, 0.05 mol)
3
); 7.00 (d, 2H, HAr); 7.25–8.12 (m, 10H, HAr); 8.45 (s, 1H,
); 3.98 (s, 3H, NCH ); 8.20 (m,
: C,
11.76. Found: C, 75.55; H, 5.80; N, 11.81.
N-{2-(1-Ethyl-1H-indol-3-yl)-1-[2-(5-fluoro-1H-indol-3-
yl)-ethylcarbamoyl]-vinyl}-benzamide (6e).
way as 6a,e was prepared from oxazolone 3b (0.316 g,
0.001 mol) and 5-fluorotryptamine (0.178 g, 0.001 mol) to
give colorless powder (0.242 g, 49%), mp 223–225°С; ir:
3
3
H
7
16 2 3
H N O
In the same
(
ꢀ
1
1
0
(С¼С)1613, (С¼O) 1640, 1667 (NH) 3300 cm
; H-nmr
was heated for 4 h in the same way as 3a, 4a. The residue was
(deuteriodimethylsulfoxide) δ 1.34 (t, 3H, СH СH N); 2.89
3
2
recrystallized from benzene, to give red crystals (1.45 g, 10%).
(t, 2H, NHСH СH ); 3.46 (q, 2H, NHСH СH ); 4.12 (q, 2H,
2 2 2 2
mp 190°С ir: (С¼С) 1593, 1660, (С¼O) 1751 cmꢀ
1 1
;
H-nmr
СH СH N); 6.75–8.15 (m, 17H, HAr); 9.62 (s, 1H, NH);
3
2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

K. F. Suzdalev and M. N. Babakova
Vol 000
1
5
0.72 (s, 1H, NH). Anal. Calcd for C30H27F N O : C, 72.86; H,
3-[3-(1H-Indol-3-yl)-propyl]-5-(1-methyl-1H-indol-3-ylmethylene)-
2-p-tolyl-5Z-3,5-dihydro-4H-imidazolo-4-on (7d). In the same
way as (7a, 8a) (Method B), 7d was obtained from (4Z)-4-[(1-
methyl-1H-indol-3-yl)methylene)]-2-(4-methylphenyl)-1,3-oxazol-
5(4H)-one (3с) (0.332g, 0.001 mol) and tryptamine (0.160g,
0.001 mol) by refluxing in ethyleneglycole for 30min to give
orange crystals (0.21 g, 46%), mp 240°С; ir: (С¼С) 1627,
4
2
.50; N, 11.33. Found: C, 72.65; H, 5.40; N, 11.40.
-[2-(1H-Indol-3-yl)-ethyl]-5-(1-methyl-1H-indol-3-ylmethylene)-
-phenyl-5Z,E-3,5-dyhidro-4H-imidazol-4-on (7a, 8a). (Method
A) Oxazolone 3a (0.6 g, 0.002 mol) and tryptamine (0.32 g,
.002 mol) was refluxed in dimethylformamide (3 mL) for 10 h.
3
2
0
The mixture was diluted with propan-2-ol, and then crystallization
was caused by friction. The crude residue was dissolved in
dimethylformamide (3 mL) and diluted by butan-1-ol (12 mL) for
purifying. The yellow powder of 7a, 8a was filtered (0.45 g, 51%),
mp 305–306°С. (Method B). Oxazolone 3a (0.3 g, 0.001 mol) and
tryptamine (0.16 g, 0.001 mol) was refluxed in ethylene glycol
ꢀ
1
1
(С¼O) 1687, (NH) 3333cm
thylsulfoxide) δ 2.42 (s, 3H, СH
s, 3H, NСH ); 3.95 (q, 2H, NСH CH ); 6.83–8.10 (m, 14H,
;
H-nmr (deuteriodime-
3
); 2.92 (t, 2H, NCH СH2.); 3.92
2
(
3
2
2
HAr.); 8.41 (s, 1H, СH¼); 10.62 (s, 1H, NH). Anal. Calcd for
O: С, 78.58; H, 5.72; N, 12.22. Found: С, 78.41; H,
.65; N, 12.31.
-(1-Ethyl-1H-indole-3-ylmethylene)-3-[3-(5-fluoro-1H-
indol-3-yl)-propyl]-2-phenyl-5Z-3,5-dihidro-4H-imidazol-
-on (7e). In the same way as (7a, 8a) (Method B), 7e was
30 26 4
С H N
5
(3 mL) for 30 min. The residue was filtered (0.122 g, 26%) and
5
washed by acetonitrile, mp 304–306°С; ir: (С¼С) 1640, (С¼O)
ꢀ
1 1
1
2
667, (NH) 3253 cm ; H-nmr (deuteriodimethylsulfoxide) δ 7a:
.92 (t, 2H, NCH СH ); 3.95 (s, 3H, СH3); 4.00 (t, 2H,
4
2
2.
obtained from oxazolone 3b (0.31 g, 0.001 mol) and 5-
fluorotryptamine (0.178 g, 0.001 mol) to give orange crystals
NСH CH ); 6.80–8.09 (m, 15H, H ); 8.42 (s, 1H, СH¼); 10.65
2
2
Ar.
(
s, 1H, NH). 8a: 7.90 (m, HAr); 9.43 (s, 1H, СH¼). Anal. Calcd
for С29 O: C, 78.36; H, 5.44; N, 12.60. Found: С, 78.40; H,
.48; N, 12.46.
-(1-Methyl-1H-indol-3-ylmethylene)-3-(3-morpholine-
-ylpropyl)-2-phenyl-5Z-3,5-dihydro-4H-imidazol-4-one (7b).
(
(
(
0.212 g, 45%), mp 243°С; ir: (С¼С) 1627, (С¼O) 1687,
24 4
H N
ꢀ1 1
NH) 3336 cm ; H-nmr (deuteriodimethylsulfoxide) δ 2.50
t, 3H, СH СH ); 2.85 (t, 2H, NCH СH ); 3.95 (t, 2H,
5
3
2
2
2.
5
NСH CH ); 4.32 (q, 2H, СH СH ); 6.68–8.15 (m, 14H,
2
2
3
2
4
H
Ar.); 8.43 (s, 1H, СH¼); 10.72 (s, 1H, NH). Anal. Calcd
for С30 OF: С, 75.61; H, 5.29; N, 11.76. Found: С,
5.69; H, 5.19; N, 11.85.
-(1-Ethyl-1H-indol-3-ylmethylene)-3-[3-(5-fluoro-1H-idol-
-yl)-propyl]-2-furan-3-yl-5Z-3,5-dihydro-4H-imidazol-4-one
The mixture of oxazolone 3a (0.6 g, 0.002 mol) and 3-
morpholinopropylamine (0.36 mL, 0.0024 mol) was refluxed in
dimethylformamide (3 mL) for 4.3 h. The mixture was cooled,
diluted with water, and extracted by chloroform (3 × 10 mL).
Eluate was washed twice with water, dried by sodium sulfate, and
the solvent was evaporated in vacuo up to the volume 10 mL. This
solution was subjected to aluminum oxide chromatography (eluent
25 4
H N
7
5
3
(
7f). In the same way as (7a, 8a) (Method B), 7f was obtained
from oxazolone 3e (0.31 g, 0.001 mol) and 5-fluorotryptamine
(
2
(
0.178 g, 0.001 mol) to give orange crystals (0.150 g, 32%), mp
–
chloroform column d=2cm, l=20cm). The first yellow fraction
,
ꢀ
1 1
44°С; ir: (С¼С) 1620, (С¼O) 1687, (NH) 3327 cm ; H-nmr
(R
f
= 0.59) was collected, and the solvent was evaporated. Propan-
deuteriodimethylsulfoxide) δ 1.55 (t, 3H, СH CH ); 2.93 (t,
3 2
2-ol (5 mL) was added to the residue. Precipitated product was
2
СH
H, NCH
СH
); 6.68–8.15 (m, 12H, HAr); 8.50 (s, 1H, СH¼); 10.78
(s, 1H, NH). Anal. Calcd for С H N O F: С, 72.09; H, 4.97;
2 2 2
СH2.); 4.08 (t, 2H, NСH CH ); 4.32 (q, 2H,
filtered off and washed with petroleum ether. Recrystallization
from propan-2-ol gave orange crystals (0.29 g, 34%), mp 82°С; ir:
3
2
ꢀ
1
1
28 23 4 2
(
С¼С, С–С ) 1593, 1620, (С¼O) 1680, 1700 cm
;
H-nmr
N); 2.20–2.40
); 3.90 (m, 5H,
); 7.10–8.00 (m, 10H, HAr.); 8.45 (s, 1H, СH¼).
С-nmr (deuteriochloroform) δ 7b (with suppression of carbon–
proton coupling): 25.65 (N CH CH CH Nmorph); 33.34 (N–CH3);
Ar.
N, 12.01. Found: С, 72.12; H, 4.90; N, 12.22.
(
deuteriochloroform) δ 1.75 (m, 2H, NСH
m, 6H, СH N(СH ); 3.60 (m, 4H, O(СH
NСH , NСH СH
2 2 2
СH СH
(
2
2
)
2
2 2
)
3
2
2
1
3
Acknowledgments. Research was carried out according the state
task of the Ministry of Education and Science of the Russian
Federation № 4.129.2014/K.
im
2
2
2
39.86 (NimCH
2 2 2
CH CH Nmorph), 53.43 (2C, NCH2morph); 55.67
(N
imCH CH CH N
2
2
2
morph), 66.79 (2C, OСH2morph); 109.76, 111.29,
1
1
1
19.17, 121.46, 122.04, 122.87, 128.23, 128.31(2C), 128.65(2C),
30.45, 130.56, 134.55, 136.16, 137.03 (С ); 158.50 (С -Ph);
Ar
im
13
70.73 (C¼O). С-nmr (deuteriochloroform) δ 7b (without
= 4.11,
: С, 72.87; H, 6.59;
REFERENCES AND NOTES
suppression of carbon–proton coupling): 170.71 dt, J
=3,18 (С¼O). Anal. Calcd for С26
N, 13.07. Found: С, 72.80; H, 6.70; N, 13.21.
-[3-(1H-Indol-3-yl)-propyl]-2-(4-methoxyphenyl)-5-(1-methyl-
H-indol-3-ylmethylene)-5Z,E-3,5-dihydro-4H-imidazol-4-
1
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1
1
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(
(
3
С¼С) 1607, 1633, (С¼O) 1687, (NH) 3327 cm
;
H-nmr
СH2.);
[
deuteriodimethylsulfoxide) δ 7с: 2.95 (t, 2H, NCH
2
.85 (s, 3H, NСH3); 3.92 (s, 3H, OСH ); 4.00 (q, 2H,
3
NСH
1
2
CH
2
); 6.83–8.09 (m, 14H, HAr.); 8.40 (s, 1H, СH¼);
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30 26 4 2
H, 5.47; N, 11.72.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet