Formation of the same pyrimido[1,2-a]indoles from 1-(oxiran-2-ylmethyl)-1H- indole or [1,3]oxazolo[3,2-a]indole derivatives in its reactions with aromatic amines

Article abstract of DOI:10.1016/j.tet.2013.07.074

Reactions of two isomers - 2-chloro-1-(oxiran-2-ylmethyl)-1H-indole-3- carbaldehyde or 2-(chloromethyl)-2,3-dihydro[1,3]oxazolo[3,2-a]indole-9- carbaldehyde with aromatic amines lead to the same products in both cases - hydrochlorides of pyrimido[1,2-a]indole derivatives containing two fragments of an amine per one part of the indole nucleus. Its structure was confirmed by X-ray analysis of the crystals base, obtained by alkali treatment of the reaction product (when aryl is 4-MeOC₆H₄).

Full text of DOI:10.1016/j.tet.2013.07.074

Tetrahedron 69 (2013) 8785e8789
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Formation of the same pyrimido[1,2-a]indoles from 1-(oxiran-2-
ylmethyl)-1H-indole or [1,3]oxazolo[3,2-a]indole derivatives in its
reactions with aromatic amines
,
a
b
Konstantin F. Suzdaleva , Sophia V. Den’kina , Valerii V. Tkachev
*
a Chemical Department of Southern Federal University, Zorge Street 7, 344090 Rostov-on-Don, Russian Federation
b Institute of Problems of Chemical Physics, Russian Academy of Sciences, N.N. Semyonov Street 1, 142432 Czernogolovka, Moscow Region, Russian
Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 May 2013
Received in revised form 6 July 2013
Accepted 22 July 2013
Available online 31 July 2013
Reactions of two isomersd2-chloro-1-(oxiran-2-ylmethyl)-1H-indole-3-carbaldehyde or 2-(chlor-
omethyl)-2,3-dihydro[1,3]oxazolo[3,2-a]indole-9-carbaldehyde with aromatic amines lead to the same
products in both casesdhydrochlorides of pyrimido[1,2-a]indole derivatives containing two fragments of
an amine per one part of the indole nucleus. Its structure was confirmed by X-ray analysis of the crystals
base, obtained by alkali treatment of the reaction product (when aryl is 4-MeOC6H4).
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Indole
Oxiran
[1,3]Oxazolo[3,2-a]indole
Recyclization
Pyrimido[1,2-a]indoles
1. Introduction
aminoalcohols.2 On the other hand, there are a number examples
of chlorine substitution in 2-chloroindole-3-carbaldehydes.3 This
In a previous paper, we found that the direction of the reaction
of 2-chloroindole-3-carbaldehyde with epihalogenohydrines
depends on the type of the initial halogenohydrin. The use of epi-
bromohydrin leads to aldehyde 2, whereas the analogous reaction
with epichlorohydrin produces a derivative of tricyclic [1,3]oxazolo
[3,2-a]indole ring system 3 (Scheme 1)1
allows to suggest the pyrimidine cycle formation in reactions of
compound 2 with primary amines. As to the compound 3, we
earlier showed its reactions with secondary amines run as oxazole
ring-opening process with the formation of 2-aminoindoles, having
2-hydroxy-3-chloropropyl chain at the indole nitrogen.1 In the case
of primary amines such open chain products can undergo further
cyclization. Thus the compound 3 may a priori react with primary
amines to give either open chain products, either compounds
having five- or six-membered ring, condensed with the indole
moiety.
1
O
O
O
Br
NaOH
Cl
O
O
Cl
Cl
O
The aim of this work is to investigate recyclizations of poly
functional systems 2 and 3 under the action of primary aromatic
amines.
N
N
NaOH
N
O
H
2
1
3
Cl
Scheme 1. Interaction of compound 1 with epihalogenohydrines.
2. Results and discussion
In the present paper the reactions of both aldehydes 2 and 3
with amines are discussed. It is known that reactions of 1-(Oxiran-
2-ylmethyl)-1H-indole-3-carboxaldehyde (the analog of com-
pound 2 without a chlorine atom) with amines initially give 1,2-
We have surprisingly found that reactions of isomers 2 or 3 with
aromatic amines lead to the same products in both cases. Elemental
analysis, IR and NMR 1H data showed these products to be hydro-
chlorides, containing two fragments of an amine per one part of the
indole core. Treating these hydrochlorides with 40% aqueous NaOH
gave bases. But their structure seemed to be ambiguous. We sug-
gested two formulas 4 and 5 (or 40 and 50 for bases), which
* Corresponding author. Tel.: þ7 918 856 7100; fax: þ7 863 297 5151; e-mail
addresses: konsuz@gmail.com, consuz@mail.ru (K.F. Suzdalev).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.07.074

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K.F. Suzdalev et al. / Tetrahedron 69 (2013) 8785e8789
correspond to spectral data and two pathways to each of them from
compound 2 or 3 (Scheme 2). The structure 4 may be formed by the
usual oxirane ring opening through intermediates 6 and 7. The
same product 4 may be obtained from tricyclic aldehyde 3 by
chlorine substitution and further reaction of amine at the carbonyl
group of aldehyde 8. The alternative structure 5 may be produced
from oxirane 2 through the key intermediate 9, which may arise
both from the open-chain compound 6 and from the product of
chorine substitution 10. The appearance of structure 5 from com-
pound 3 is also possible because the formation of intermediates like
11 and 12 is a quite plausible route: our data concerning the re-
actions of compound 3 with secondary amines show the formation
of compounds of type 11.1
the rightdits atom C(34) lies in the plane of indole core (only
ꢀ
0.02 A output), and the atoms C(32) and C(33) leave0it in the op-
0
ꢀ
posite directions at 0.40 and ꢀ0.34 A [as well as C (32 ) and C (33 )
ꢀ
at ꢀ0.16 and 0.51 A]. The position of the oxygen atom O(32) for
both enantiomers is the same, and is fundamentally different from
the location of the atom O(2) of the left molecule. This can be seen
from Fig. 2, which demonstrates how the relative positions of
fragments of two molecules differ when they overlap in the plane
of indole core (the left structure is drawn by shaded, rightdby
dashed lines).
Note that the positions of the upper benzene rings differ slightly,
while the location of lower methoxyphenyl substituents differs
more significantly.
Scheme 2. Reactions of compounds 2 and 3 with aromatic amines.
In order to determine which structure (4 or 5) is formed, we
performed X-ray analysis of the crystals base, obtained by treating
the reaction product (R¼4-MeOC6H4) with 40% aqueous NaOH. It
was shown that the product structure corresponded to formula of 5
(Fig. 1). It should be noted that the mass spectra of all hydrochlo-
rides 5(aec) show peaks with a maximum molecular mass MþꢀHCl
and are identical to spectra of corresponding bases 50(aec). It in-
dicates a permanence of the organic skeleton during reactions with
alkali.
In conclusion, it must be said that the left and right molecules
shown in Fig. 1, drawn by the shaded lines represent two different
conformations of the same enantiomer. Thus, in the investigated
single crystal contains two enantiomers in three different
conformations.
In order to understand, which way of forming structure 5 is
preferred, we conducted the reaction of compound 2 with p-tolu-
idine with a limited time. In these conditions, we were able to
isolate and identify the product of the initial oxirane ring disclosure
6b. In its 1H NMR spectra we observed changes in the character of
signals of the aliphatic protons in comparison with initial com-
pound 2, as well as observing the CHO-group intact. From this we
can conclude that the product 5 is formed by the sequence
2/6/9/5. For the synthesis of 5 from the tricyclic compound 3
the sequence 3/11/12/5 is favorable.
The X-ray crystal structure of molecule 50c (Fig. 1) displays
several interesting features.
Compound 50c includes an asymmetric carbon atom in the 3
position. Both enantiomers are contained in a single crystal in
unequal proportions. The independent part of the unit cell con-
tains two molecules. The left one in Fig. 1 is the S-enantiomer. The
right structure is either an S- or R-enantiomer, which is distributed
statistically in the ratio of 0.69/0.31. It is noteworthy that the OH
group is common in both molecules (The less populated bonds
between atoms are drawn by unshaded lines). For convenience of
description, atomic numbers of the right molecule are increased at
the 30 with respect to the left one. Note that in the left molecule
indole atoms and N(5) are in the mean-square plane with a maxi-
The formation of some 1,2,3,4-tetrahydropyrimido[1,2-a]indole
derivatives has been earlier observed when 2-chloroindole-3-
carbaldehyde was alkylated with 3-chloro-N,N-diethyl- and 3-
chloro-N,N-dimethyl-propylamine in 17 and 29% yield, re-
spectively together with other products.4 Similar tricyclic-2-
aminoindoles were obtained by intramolecular 1,3-dipolar cyclo-
addition of 1-u
-azidoalkylindoles.5 An accidental obtaining of
a pyrimido[1,2-a]indole with aromatic pyrimidine ring from 1-
methoxy-6-nitroindole-3-carboxaldehyde has been described by
Japanese authors.6 Most similar to structure of 5 compounds having
ꢀ
mum deviation from it 0.02 A. The atoms C(2), C(4) and C(3) de-
ꢀ
viate from this plan in one side by 0.06, 0.19 and 0.83 A. A
fundamentally different pattern is observed for the molecule on

K.F. Suzdalev et al. / Tetrahedron 69 (2013) 8785e8789
8787
Fig. 1. Molecular structure of compound 50c (thermal ellipsoids are drawn at the 30% probability level).
pyrimido[1,2-a]indoles containing aminoalcohol fragment, de-
veloped in this paper, will be useful to search for biologically active
compounds.
3. Experimental section
3.1. General
All commercially available compounds were used without fur-
ther purification. The starting compounds 2 and 3 were obtained by
described protocols.1 IR spectra were taken on Varian 3100 FT-IR,
Excalibur Series instrument by means of Attenuated Total Re-
flectance (ATR) method. 1H and 13C NMR spectra were recorded on
Bruker DPX-250 instrument. Mass-spectra were obtained on Varian
MAT-44 spectrometer.
The X-ray datasets for 50c were collected on a Xcalibur (Agilent
Fig. 2. Superposition of left and right molecules from Fig. 1 (hydrogen atoms are
removed).
Technologies) diffractometer with CCD camera Eos (Mo Ka,
ꢀ
l
¼0.71073 A). The structure was solved by direct methods and
using Fourier techniques and was refined by the full-matrix least
squares against F2 with anisotropic thermal parameters for all non-
hydrogen atoms. The hydrogen atoms were positioned geo-
metrically and refined using the riding model. All calculations were
carried out with the use of the SHELXTL program package.12
the same heterocyclic ring skeleton without OH-group in position 3
were synthesized by the reaction of 1-acyl-2-phenylpyrazolidines
with Vilsmeier reagent.7
Unlike these studies, the synthesized compounds 5(aec),
50(aec), and 6b contain
a pharmacophore fragment, a 1,2-
aminoalcohol in a saturated pyrimidine ring. In recent years there
has been an increased interest of derivatives having a 3-amino-2-
hydroxypropyl group on indole nitrogen, which promotes water
solubility [our hydrochlorides 5(aec) are water soluble]. Thus,
aminoalcohols in 5-methoxyindole series have a cytotoxic effect,
which may be used in the treatment of cancer.8 It was found that
the aminoalcohols derived from indolocarbazole alkaloid ana-
logues display cytotoxicity against the cell lines representative of
solid tumors and leukemia.9 During study of a new class of non-
peptide inhibitors of HIV-1 protease, 1,2-aminoalcohols, contain-
ing fragments of anthranilic acid and indole were synthesized.10 We
have earlier shown that the 1,2-unsaturated ketones in indole se-
ries having an aminoalcohol moiety at the nitrogen atom exhibit
local anesthetic and antiarrhythmic activity, higher than that of
well-known, widely used drugsdnovocaine, lidocaine, and mar-
caine.11 This allows us to hope that the method of synthesis of
3.2. N-[(1E)-(3-Hydroxy-1-phenyl-1,2,3,4-tetrahydropyrimido
[1,2-a]indol-10-yl)methylene]benzenaminium chloride (5a)
3.2.1. Method A (from compound 2). To compound 2 (943 mg,
4 mmol) in propan-2-ol (5 mL) was added aniline (0.73 mL,
8 mmol). The reaction mixture was refluxed for 5 h. After cooling to
room temperature, the precipitate was filtered off, washed with
propan-2-ol, diethyl ether and dried to give the crude product
(820 mg, 50%) as yellow powder. To obtain spectroscopically pure
sample it was recrystallized from ethanol [Found: C, 71.59; H, 5.47;
Cl, 8.82; N, 10.44. C24H22ClN3O requires C, 71.37; H, 5.49; Cl, 8.78; N,
10.40%]; mp 226e228 ꢁC; nmax 3236, 1638, 1593, 1560, 1491 cmꢀ1
dH (250 MHz, DMSO-d6) 3.62e3.73 (1H, m, NCH2), 4.02e4.21 (3H,
m, NCH2, NindCH2), 4.49e4.59 (1H, m, CH), 5.96 (1H, d, J 2.3, OH),
6.74e7.78 (14H, m, HAr, CH]N), 8.19 (1H, d, J 7.2, HInd-9),
;

8788
K.F. Suzdalev et al. / Tetrahedron 69 (2013) 8785e8789
10.33e10.60 (1H, bp, NþH); dC (60 MHz, CF3COOD): 45.8, 56.5, 61.4,
97.9,109.7,117.4 (2C),117.6,119.9, 122.4, 125.4, 126.9 (2C),127.0 (2C),
130.0 (2C), 131.0, 132.6 (2C), 137.7, 138.3, 142.6, 145.3, 155.1; m/z 367
(20, MþꢀHCl), 77 (100%).
(1H, m, H-9), dC (60 MHz, CF3COOD): 45.9, 55.9, 56.2, 56.8, 61.6,
98.0, 109.8, 116.1 (2C), 117.9 (2C), 119.7 (2C), 120.1, 122.6, 125.42,
127.0, 129.0 (2C), 133.7, 135.9, 137.8, 145.9, 155.4, 157.5, 161.1; m/z
427 (94, MþꢀHCl), 123 (40), 108 (100), 77 (48%).
3.2.2. Method B (from compound 3). To compound 3 (943 mg,
4 mmol) in propan-2-ol (5 mL) was added aniline (0.73 mL,
8 mmol). The reaction mixture was refluxed and a product began to
precipitate through 45 min. The resulting mixture was additionally
refluxed for 1 h. After cooling the formed precipitate was filtered
off, washed with propan-2-ol, diethyl ether and dried to give the
crude product 5a (1.17 g, 73%) as yellow powder. For obtaining
spectroscopically pure substance it was recrystallized from ethanol.
Mp and IR data are the same as in method A.
3.4.2. Method B (from compound 3). To compound 3 (943 mg,
4 mmol) in propan-2-ol (5 mL) was added 4-methoxylaniline
(984 mg, 8 mmol). The reaction mixture was refluxed and a prod-
uct began to precipitate through 30 min. The resulting mixture was
additionally refluxed for 1 h. Formed precipitate was filtered off,
washed propan-2-ol, diethyl ether and dried to give the crude
product (1.57 g, 85%) as yellow powder. For obtaining spectro-
scopically pure substance it was recrystallized from ethanol. Mp
and IR data are the same as in method A.
3.3. N-{(1E)-[3-Hydroxy-1-(4-methylphenyl)-1,2,3,4-tetrahydro-
pyrimido[1,2-a]indol-10-yl]methylene}-4-methylbenzenamin-
ium chloride (5b)
3.5. 1-Phenyl-10-[(phenylimino)methyl]-1,2,3,4-tetrahydrop-
yrimido[1,2-a]indol-3-ol (50a)
To compound 5a (808 mg, 2 mmol) in mixture of water (20 mL)
and ethanol (5 mL) was added dropwise 40% aqueous solution of
sodium hydroxide (2 mL). The reaction mixture was stirred at room
temperature for 20 min. Precipitate was filtered off, washed with
water and dried to give the crude product (370 mg, 50%), which was
recrystallized from propan-2-ol to give the title compound (50a)
(260 mg, 35%) as pale yellow powder [Found: C, 78.76; H, 5.78; N,
11.49. C24H21N3O requires C, 78.45; H, 5.76; N, 11.44%]; mp
3.3.1. Method A (from compound 2). To compound 2 (943 mg,
4 mmol) in propan-2-ol (5 mL) was added 4-methylaniline
(856 mg, 8 mmol). The reaction mixture was refluxed for 3 h and
retained at room temperature overnight. The formed precipitate
was filtered off, washed with propan-2-ol, diethyl ether and dried
to give the crude product (820 mg, 48%) as yellow powder. For
obtaining spectroscopically pure substance it was recrystallized
from ethanol [Found: C, 71.91; H, 5.98; Cl, 8.16; N, 9.67. C26H26ClN3O
requires C, 72.29; H, 6.07; Cl, 8.21; N, 9.73%]; mp 256e258 ꢁC; nmax
165e168 ꢁC; nmax 3324, 1604, 1584, 1561, 1531, 1501, 1485 cmꢀ1
; dH
(250 MHz, CDCl3), 2.14e2.94 (1H, bp, OH), 3.75 (1H, dd, J 12.6, 4.1,
NCH2), 3.87 (1H, dd, J 12.6, 2.2, NCH2), 4.05e4.25 (2H, m, NindCH2),
4.45e4.54 (1H, m, CH), 6.58e7.30 (11H, m, HAr), 7.75 (1H, s, CH]N),
8.42e8.50 (1H, m, HInd-9); dC (60 MHz, CDCl3) 47.6, 56.3, 62.4, 97.1,
107.8, 121.2 (2C), 121.5, 121.8, 122.7, 124.2, 125.2 (2C), 126.3, 126.7,
129.2 (2C), 130.7 (2C), 134.8, 146.3, 148.1, 154.0, 154.5; m/z 367 (70,
Mþ), 77 (100%).
3223, 1638, 1593, 1567, 1492, 1466 cmꢀ1
; dH (250 MHz, DMSO-d6)
2.28 (3H, s, CH3), 2.43 (3H, s, CH3), 3.58e3.77 (1H, m, NCH2),
4.03e4.26 (3H, m, NCH2, NindCH2), 4.51e4.62 (1H, m, CH), 5.93 (1H,
d, J 2.84, OH), 6.68e7.62 (12H, m, HAr, CH]N), 8.21 (1H, d, J¼7.3,
Hind-9), 10.28e10.50 (1H, bp, NþH); dC (60 MHz, CF3COOD): 19.4,
19.9, 45.7, 56.4, 61.4, 97.4, 109.5, 117.3 (2C), 117.8, 119.8, 122.5, 125.2,
126.8 (2C), 130.5 (2C), 133.0 (2C), 135.9, 137.5, 138.0, 139.7, 142.5,
145.5, 155.0; m/z 395 (41, MþꢀHCl), 91 (100), 65 (51%).
3.6. 1-(4-Methylphenyl)-10-{(E)-[(4-methylphenyl)imino]
methyl}-1,2,3,4-tetrahydropyrimido[1,2-a]indol-3-ol (50b)
3.3.2. Method B (from compound 3). To compound 3 (943 mg,
4 mmol) in propan-2-ol (5 mL) was added 4-methylaniline
(856 mg, 8 mmol). The reaction mixture was refluxed and a prod-
uct began to precipitate through 20 min. The resulting mixture was
additionally refluxed for 1 h. Formed precipitate was filtered off,
washed with propan-2-ol, diethyl ether and dried to give the crude
product (1.22 g, 71%) as yellow powder. For obtaining spectro-
scopically pure substance it was recrystallized from ethanol. Mp
and IR data are the same as in method A.
To compound 5b (600 mg, 1.4 mmol) in mixture of water
(20 mL) and ethanol (5 mL) was added dropwise 40% aqueous so-
lution of sodium hydroxide (2 mL). The reaction mixture was stir-
red at room temperature for 20 min. Precipitate was filtered off,
washed with water and dried to give the crude product 50b (510 mg,
92%). It was recrystallized from propan-2-ol to give the title com-
pound (50b) (400 mg, 72%) as pale yellow powder [Found: C, 78.76;
H, 6.48; N, 10.49. C26H25N3O requires C, 78.96; H, 6.37; N, 10.62%];
mp 175e178 ꢁC; nmax 3497, 1612, 1569, 1539, 1508, 1475 cmꢀ1
; dH
3.4. N-{(1E)-[3-Hydroxy-1-(4-methoxyphenyl)-1,2,3,4-tetrahy-
dropyrimido[1,2-a]indol-10-yl]methylene}-4-methoxybenzen-
aminium chloride (5c)
(250 MHz, CDCl3): 2.26 (3H, s, CH3), 2.37 (3H, s, CH3), 3.72 (1H, dd, J
12.6, 4.1, NCH2), 3.87 (1H, dd, J 12.6, 2.2, NCH2), 4.05e4.25 (2H, m,
NindCH2), 4.45e4.54 (1H, m, CH), 6.58e7.30 (11H, m, HAr), 7.66 (1H,
s, CH]N), 8.42e8.50 (1H, m, Hind-9); dC (60 MHz, CDCl3) 21.3, 21.4,
47.5, 56.5, 62.5, 96.7, 107.5, 121.1 (2C), 121.3, 121.9, 122.5, 125.7 (2C),
126.9, 129.7 (2C), 131.3 (2C), 133.6, 134.7, 136.7, 145.4, 146.4, 151.8,
154.3; m/z 395 (80, Mþ), 91 (100), 65 (41%).
3.4.1. Method A (from compound 2). To compound 2 (943 mg,
4 mmol) in propan-2-ol (5 mL) was added 4-methoxylaniline
(984 mg, 8 mmol). The reaction was refluxed and a product be-
gan to precipitate through 2 h. The resulting mixture was addi-
tionally refluxed for 1 h. Formed precipitate was filtered off, washed
propan-2-ol, diethyl ether and dried to give the crude product
(870 mg, 47%) as yellow powder. For obtaining spectroscopically
pure substance it was recrystallized from ethanol [Found: C, 67.51;
H, 5.78; Cl, 7.44; N, 9.17. C26H26ClN3O3 requires C, 67.31; H, 5.65; Cl,
7.64; N, 9.06%]; mp 235e238 ꢁC; nmax 3216, 1629, 1594, 1566,
3.7. 1-(4-Methoxyphenyl)-10-{(E)-[(4-methoxyphenyl)imino]
methyl}-1,2,3,4-tetrahydropyrimido[1,2-a]indol-3-ol (50c)
To compound 5c (630 mg, 1.4 mmol) in mixture of water (20 mL)
and ethanol (5 mL) was added dropwise 40% aqueous solution of
sodium hydroxide (2 mL). The reaction mixture was stirred at room
temperature for 20 min. Precipitate was filtered off, washed with
water and dried to give the crude product 50c (460 mg, 77%). It was
recrystallized from propan-2-ol to give the title compound (50c)
(150 mg, 25%) as pale yellow powder [Found: C, 72.75; H, 5.87; N,
9.79. C26H25N3O3 requires C, 73.05; H, 5.89; N, 9.83%]; mp
1491 cmꢀ1
; dH (250 MHz, DMSO-d6): 3.53e3.63 (1H, m, NCH2), 3.69
(3H, s, OCH3), 3.80 (3H, s, OCH3), 3.82e3.90 (1H, m, NCH2),
3.96e4.23 (2H, m, NindCH2), 4.36e4.46 (1H, m, CH), 5.61 (1H, d, J
3.6, OH), 6.58 (2H, d, J 9.0, C6H4); 6.72 (2H, d, J 9.0, C6H4); 6.98e7.12
(4H, m, H-7, H-8, C6H4), 7.18e7.44 (3H, m, CH]N, C6H4), 8.22e8.33

K.F. Suzdalev et al. / Tetrahedron 69 (2013) 8785e8789
8789
200e202 ꢁC; nmax 3484, 3328, 1605, 1582, 1560, 1542, 1508, 1459,
1444 cmꢀ1
dH (250 MHz, CDCl3): 2.33e3.05 (1H, bp, OH), 3.67 (1H,
7.22e7.37 (2H, m, Hind-5 and Hind-6), 7.54e7.67 (1H, m, Hind-7),
8.04e8.17 (1H, m, Hind-4), 10.01 (1H, s, CH]O); dC (60 MHz, CDCl3)
20.8, 48.3, 51.4, 69.3, 110.5, 114.1 (2C), 118.5, 122.6, 123.5, 124.6,
128.3, 128.7, 130.3 (2C), 137.9, 140.6, 145.8, 185.2; m/z 342 (3, Mþ),
120 (100), 91 (26), 77 (15%).
;
dd J 12.1, 4.9 NCH2), 3.79 (3H, s, OCH3), 3.84 (3H, s, OCH3),
3.79e3.90 (1H, m, NCH2), 4.03e4.19 (2H, m, NindCH2), 4.43e4.55
(1H, m, CH), 6.67e7.35 (11H, m, HAr), 7.59 (1H, s, CH]N), 8.46e8.54
(1H, m, 9-H); dC (60 MHz, CDCl3): 47.5, 55.9, 56.1, 56.9, 62.4, 96.4,
107.5, 114.4 (2C), 116.1 (2C), 121.2, 121.8, 122.0 (2C), 122.5, 127.0,
127.8 (2C), 134.6, 140.5, 146.6, 147.6, 153.6, 156.9, 158.7; m/z 427 (90,
Mþ), 123 (34), 108 (100), 77 (37%).
References and notes
1. Suzdalev, K. F.; Den’kina, S. V.; Borodkin, G. S.; Tkachev, V. V.; Kiskin, M. A.;
Kletsky, M. E.; Burov, O. N. Tetrahedron 2011, 67, 8775e8779.
2. Suzdalev, K. F.; Den’kina, S. V.; Starikova, A. A.; Dvurechensky, V. V.; Kletsky, M.
E.; Burov, O. N. Mendeleev Commun. 2011, 21, 231e233.
3. For a review see: Den’kina, S. V.; Suzdalev, K. F. Chem. Heterocycl. Compd. 2013,
48, 1581e1613 Russian Original: Khim. Geterotsikl. Soedin. 2012, 48, 1696e1727.
4. (a) Coppola, G. M.; Hardtmann, G. E. J. Heterocycl. Chem. 1979, 16, 769e772; (b)
Andreani, A.; Greci, L.; Tosi, G.; Sgarabotto, P.; Ugozzoli, F. J. Heterocycl. Chem.
1988, 25, 29e32.
The crystallographic parameters for 50c at T¼200.01(10) K are as
follows: C26H25N3O3, fw¼427.49, monoclinic system, space group P
ꢀ
ꢀ
ꢀ
cmꢀ3
,
(1 21/n 1), a¼14.5789(3) A, b¼11.0663(3) A, C¼27.8596(6) A,
3
ꢀ
b¼97.148(2)ꢁ, V¼4459.80(19) A , Z¼8, Rcalcd¼1.273
g
m
¼0.84 cmꢀ1, 9196 measured reflections, 6782 reflections with
I>2.0
(I>2
s
(I), Rint¼0.0212, GooF.1.041, R1 (I>2 (I))¼0.0476, wR2
s
s
(I))¼0.100. CCDC 932060.
5. De la Mora, M. A.; Cuevas, E.; Muchowski, J. M.; Cruz-Almanza, R. Tetrahedron
Lett. 2001, 42, 5351e5353.
6. Yamada, K.; Yamada, F.; Shiraishi, T.; Tomioka, S.; Somei, M. Heterocycles 2009,
77, 971e982.
3.8. 2-Chloro-1-{2-hydroxy-3-[(4-methylphenyl)amino]pro-
pyl}-1H-indole-3-carbaldehyde (6b)
7. (a) Gorin, B. I.; Golubeva, G. A.; Sviridova, L. A.; Dovgilevich, A. V.; Bundel, Y. G.
Khim. Geterotsikl. Soedin. 1983, 19, 397e401; (b) Golubeva, G. A.; Sviridova, L. A.;
Makeeva, E. A.; Komarov, D. S.; Gorin, B. I. Chem. Heterocycl. Compd. 1995, 31,
330e336 Russian Original: Khim. Geterotsikl. Soedin. 1995, 31, 381e387.
8. Maya, A. B. S.; Peґrez-Melero, C.; Salvador, N.; Pelaez, R.; Caballero, E.; Medarde,
M. Bioorg. Med. Chem. 2005, 13, 2097e2107.
9. Caballero, E.; Adeva, M.; Calderon, S.; Sahagun, H.; Tome, F.; Medarde, M.; Fer-
nandez, J. L.; Lopez-Lazaro, M.; Ayuso, M. J. Bioorg. Med. Chem. 2003,11, 3413e3421.
10. Di Santo, R.; Costi, R.; Artico, M.; Massa, S.; Ragno, R.; Marshall, G. R.; La Colla, P.
Bioorg. Med. Chem. 2002, 10, 2511e2526.
11. (a) Suzdalev, K. F.; Den’kina, S. V.; Galenko-Yaroshevskii, P. A.; Varshalkina, I. A.;
Cherednik, I. L.; Sheikh-Zade, Yu. R.; Taran, O. A.; Takhchidi, Ch. P., Sakhnov, S.
N.; Dolskaya, O. A.; Lisitsyna, N. P.; Bguasheva, B. A.; Bogus, S. K. Russian Patent
2,408,592, 2011; Chem. Abstr. 2011, 154, 125248. (b) Suzdalev, K. F.; Babakova,
M. N. Russ. J. Org. Chem. 2005, 41, 233e237 Russian Original: Zh. Organ. Khim.
2005, 41, 243e246.
To compound 2 (471 mg, 2 mmol) in propan-2-ol (5 mL) was
added 4-methylaniline (428 mg, 4 mmol). The reaction mixture
was refluxed for 1.5 h and cooled. The product was precipitated
after rubbing with a glass rod against the wall of the flask. It was
filtered off, washed with propan-2-ol and recrystallized from
a mixture of benzene and light petroleum (1:1) to give the title
compound (6b) (240 mg, 35%) as pale yellow powder [Found: C,
66.84; H, 5.61; Cl, 10.38; N, 8.20. C19H19ClN2O2 requires C, 66.57; H,
5.59; Cl, 10.34; N, 8.17%]; mp 168e170 ꢁC; nmax
; dH (250 MHz,
DMSO-d6) 2.15 (3H, s, CH3), 3.04e3.27 (2H, m, NCH2), 3.98e4.15
(1H, m, CH), 4.23e4.54 (2H, m, NindCH2), 5.28 (1H, d J 5.4, OH), 5.45
(1H, t J 6.0, NH), 6.56 (2H, d, J 8.2, H4-tolyl), 6.91 (2H, d, J 8.2, H4-tolyl),
12. Sheldrick, G. M. SHELXTL v. 6.14, Structure Determination Software Suite; Bruker
AXS: Madison, Wisconsin, USA.