Uncatalyzed addition of indoles and N-methylpyrrole to 3-formylchromones: synthesis and some reactions of (chromon-3-yl)bis(indol-3-yl)methanes and E-2-hydroxy-3-(1-methylpyrrol-2-ylmethylene)chroman-4-ones

Article abstract of DOI:10.1016/j.tet.2008.05.032

(Chromon-3-yl)bis(indol-3-yl)methanes and E-2-hydroxy-3-(1-methylpyrrol-2-ylmethylene)chroman-4-ones have been obtained in good yields from 3-formylchromones on reaction with indoles and N-methylpyrrole under solvent-free conditions. Reactions of (chromon

Full text of DOI:10.1016/j.tet.2008.05.032

Tetrahedron 64 (2008) 6607–6614
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Uncatalyzed addition of indoles and N-methylpyrrole to 3-formylchromones:
synthesis and some reactions of (chromon-3-yl)bis(indol-3-yl)methanes
and E-2-hydroxy-3-(1-methylpyrrol-2-ylmethylene)chroman-4-ones
*
Vyacheslav Ya. Sosnovskikh , Roman A. Irgashev, Anna A. Levchenko
Department of Chemistry, Ural State University, 620083 Ekaterinburg, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
(Chromon-3-yl)bis(indol-3-yl)methanes and E-2-hydroxy-3-(1-methylpyrrol-2-ylmethylene)chroman-
4-ones have been obtained in good yields from 3-formylchromones on reaction with indoles and N-
methylpyrrole under solvent-free conditions. Reactions of (chromon-3-yl)bis(indol-3-yl)methanes with
guanidine carbonate and hydrazine hydrate proceed with the participation of the chromone ring system
and lead to the formation of the corresponding pyrimidines and pyrazoles bearing the bis(indol-3-yl)-
methyl moiety.
Received 6 March 2008
Received in revised form 21 April 2008
Accepted 8 May 2008
Available online 11 May 2008
Keywords:
3-Formylchromones
Azoles
Ó 2008 Elsevier Ltd. All rights reserved.
Conjugate addition
(Chromon-3-yl)bis(indol-3-yl)methanes
2-Hydroxy-3-(1-methylpyrrol-2-
ylmethylene)chroman-4-ones
Pyrimidines
Pyrazoles
1. Introduction
afford novel acetals, 3-(diarylmethylene)-2-methoxychroman-4-
ones 4. Oxidation of pyrazoles with benzhydryl moiety 5, derived
3-Formylchromones 1 are an important and well-studied class
of 3-substituted chromones, which can serve as the starting ma-
terials for the syntheses of a broad range of heterocyclic systems
due to the presence of three electrophilic centers in their molecules
(the C-2 and C-4 atoms of the chromone system and the carbonyl
carbon of 3-formyl group).1 The reactivity of 3-formylchromones 1
is of considerable current interest. Most pertinent to the present
research are the reactions involving the additions of C-mono-
nucleophiles to 1 (with the exception of active methylene com-
pounds). To the best of our knowledge, there are only two related
examples reported in the literature. Harnisch has investigated the
addition of tertiary aromatic amines to the formyl group of 3-for-
mylchromone 1 and obtained 3-benzhydrylchromones 2, which
were subsequently oxidized with Pb(OAc)4 in AcOH to the cationic
(chromon-3-yl)diarylmethine dyes 3.2 Very recently,3 there has
been a communication of the reaction of 1 with a range of tertiary
aromatic amines, anisole, and 1,3-dimethoxybenzene to give 3-
benzhydrylchromones 2, which by the oxidation with p-chloranil
from 2 and hydrazines, gave 4,4-diaryl-2,4-dihydrochromeno[4,3-
c]pyrazoles 6 (Fig. 1).3
However, published data on the reactions of 3-for-
mylchromones 1 with azoles, such as indoles and pyrroles, are
scarce. It is known that they react with pyrrole at the aldehyde
group to form meso-tetrakis(chromon-3-yl)porphyrins.4 At the
same time, indoles and pyrroles react readily with aldehydes and
ketones to form bis(indolyl)methane5 and dipyrromethane6 de-
rivatives, which are important bioactive metabolites of terrestrial
and marine origin.7 Chromones are more widely distributed in
nature, especially in the plant kingdom, and exhibit low toxicity
along with a wide spectrum of useful properties. They have been
shown to be tyrosine and protein kinase C inhibitors, as well as
antifungal, antiviral, antitubulin, and antihypertensive agents.
Chromone derivatives are also active at benzodiazepine receptors
and on lipoxygenases and cyclooxygenases.8 We envisaged that the
combination of a chromone system with indole or pyrrole rings
would allow the development of a new class of biologically active
molecules and useful synthetic building blocks in organic and
medicinal chemistry.
In this context, our attention was drawn to the fact that, al-
though 1,2-addition of nucleophilic indoles and pyrroles to
* Corresponding author. Fax: þ7 343 261 59 78.
E-mail address: vyacheslav.sosnovskikh@usu.ru (V.Ya. Sosnovskikh).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.032

6608
V.Ya. Sosnovskikh et al. / Tetrahedron 64 (2008) 6607–6614
R2
NR2
N
R3
O
R3
O
2
O
R1
CHO
O
O
N
AcO
NR2
R2
R1
CHO
R
O
N
O
1
R3
O
1a-e
R2
3
7a-j
O
Ar
Ar
O
Ar
Chromone R1
R2
H
R3 Product Yield (%)
Ar
1a
1a
1a
1b
1b
1b
1c
1c
1d
1e
H
H
H
H
7a
7b
7c
7d
7e
7f
54
65
37
68
78
51
79
61
55
58
O
O
OMe
Me
H
2
4
H
Me
H
Me
Me
Me
MeO
MeO
Cl
H
R
N
R
N
Me
H
H
N
N
OH
Me
H
Ar
Ar
H
7g
7h
7i
Ar
Ar
O
6
H
Me
H
5
H
NO2
H
H
7j
Figure 1.
Scheme 1.
carbonyl compounds and tertiary aromatic amines to 3-for-
mylchromones 1 has been well studied,2–6 the use of 1 as an ac-
ceptor in the reaction with azoles as nucleophiles has never been
reported. Based on the literature data,1 one could assume that the
and 3-formyl-6-nitrochromone 1e with indole under solvent-free
conditions gave polymeric products, which were insoluble in
standard solvents. However, the use of butanol as solvent in the
presence of catalytic HClO4 at w20 ꢀC made it possible to produce
bis-adduct 7i in 55% yield from 1d and indole. Under similar con-
ditions, the reaction of indole with 1e resulted in resinification of
the reaction mixture, and bis-adduct 7j was synthesized on heating
of the reactants in water at 85–90 ꢀC for 5 h as a mixture with E-2-
hydroxy-6-nitro-3-(indol-3-ylmethylene)chroman-4-one 8a in
variable amounts (for 1d these conditions were inappropriate, and
only a polymeric product was isolated instead of 7i). The solvent-
free reaction between 1e and N-methylindole afforded a mixture of
bis-adduct 7k and E-2-hydroxy-6-nitro-3-(1-methylindol-3-ylme-
thylene)chroman-4-one 8b in a ratio of 33:67. It is noteworthy that
the formation of 7 can be explained by both 1,2- and 1,4-addition
reactions, whereas structure 8 indicates unambiguous attack at C-2
followed by recyclization involving the phenolic OH and CHO group
(Fig. 2).
A similar reaction of 6,8-dibromo-3-formylchromone 1f with
indole proceeded exclusively via 1,4-addition followed by recycli-
zation to form a mixture of E-8c (91%) and Z-8c (9%) (Scheme 2). An
attempt to obtain the corresponding mono- or bis-adduct by
treatment of 2-amino-3-formylchromone11 with indole under sol-
vent-free conditions failed and only starting material was re-
covered. Reaction of 3-cyanochromone with indole in refluxing
pyridine gave a high melting solid (mp w315 ꢀC) in low yield,
which was insoluble in solvents such as DMSO, DMF, AcOH, and
acetone, which was not investigated in detail.
reactions of
p-electron-rich azoles and 3-formylchromones 1
would proceed either at the CHO group (1,2-addition) or at the C-2
atom (1,4-addition). The latter reaction is usually accompanied by
pyrone ring opening followed by recyclization due to the phenolic
hydroxyl and aldehyde groups. We have shown quite recently9 that
the reaction of 3-(polyfluoroacyl)chromones with indoles and N-
methylpyrrole proceeds solely through 1,4-addition, and after
recyclization involving the OH and RFCO groups, affords a mixture
of Z- and E-isomers of 3-(azolylmethylene)-2-hydroxy-2-(poly-
fluoroalkyl)chroman-4-ones substantially favoring the Z-isomer. At
the same time, (chromon-3-yl)bis(indol-3-yl)methanes and E-2-
hydroxy-3-(1-methylpyrrol-2-ylmethylene)chroman-4-ones have
been obtained in good yields from 3-formylchromones 1 on
reaction with indoles and N-methylpyrrole under solvent-free
conditions.10 Herein, we report full details of this study. In addition
to our preliminary communication,10 some novel (chromon-3-
yl)bis(indol-3-yl)methanes as well as pyrimidines and pyrazoles
bearing bis(indol-3-yl)methyl moiety have been prepared.
2. Results and discussion
We found that, unlike 3-(polyfluoroacyl)chromones,9 3-for-
mylchromones 1a–c react with excess indole, 1-methyl- or
2-methylindole (3 equiv) to give (chromon-3-yl)bis(indol-3-
yl)methanes 7a–h. The reaction occurs at 85–90 ꢀC in 5 h and re-
quires no solvent or catalyst. As in the case of aromatic aldehydes,
this reaction does not stop after mono-addition but affords bis-
adducts 7a–h in 37–79% yields (Scheme 1). The same compounds
were formed but in lower yields when 1 equiv of indole was used
(e.g., 7e was obtained in 52% yield). Since the 3-position of indole is
the preferred site for electrophilic reactions, substitution occurred
exclusively at this position, and N-substituted products were not
detected in the reaction mixture. Note that under classical condi-
tions (reflux in solvent in the presence of acid or base), 3-for-
mylchromones reacted with indoles to give complicated mixtures
of products.
In the case of chromones 1a–d, we suppose that indoles initially
attack the CHO group at the 3-position, as occurs in the case of
Me
N
O
O
O
O2N
O2N
N
R
O
OH
N
Me
E-8a (R = H),
E-8b (R = Me)
7k
The reaction turned out to be very sensitive to the nature of the
substituent at C-6 of 1. Reaction of 6-chloro-3-formylchromone 1d
Figure 2.

V.Ya. Sosnovskikh et al. / Tetrahedron 64 (2008) 6607–6614
6609
O
with remarkably important biological and pharmaceutical activi-
ties are linked at the same carbon atom. In addition, in view of the
easy functionalization of the chromone ring at the 2- and 4-posi-
tions by nucleophilic reagents, compounds 7 could serve as
promising building blocks for novel three-dimensional molecules
of structural and physicochemical interest. In connection with this,
it was of interest to evaluate the reactivity of compounds 7 toward
some electrophilic and nucleophilic reagents. We have found that
bis-adducts 7c and 7h react with an excess of sodium hydride and
MeI in refluxing THF to afford 3-[bis(1,2-dimethylindol-3-yl)me-
thyl]chromones 10a,b in high yields. Thus, methylation of 7c,h was
achieved without destruction of the chromone ring system
(Scheme 4).
Br
CHO
O
Br
1f
N
H
HN
O
O
Br
Br
+
NH
O
OH
O
OH
Br
Br
Z-8c
E-8c
Me
HN
N
Scheme 2.
Me
O
Me
O
aromatic aldehydes.5 A plausible pathway includes nucleophilic
1,2-addition of indoles to give compounds 9, which through highly
delocalized cation A afford bis-adducts 7. However, the presence of
electron-withdrawing substituents on the benzene ring of the
chromones favors the alternative nucleophilic 1,4-addition and
inhibits the formation of bis-adducts 7. This pathway includes the
Michael addition of indoles to the C-2 atom with concomitant
opening of the pyrone ring and subsequent intramolecular cycli-
zation of intermediate B at the CHO group to chromanone 8. We
also cannot exclude the formation of 7 from 8 through cation A. The
change in the reaction pathway in the case of 1e,f is probably due to
the fact that the attack on the C-2 atom is accompanied by the
cleavage of the C–O bond, and the strong electron-withdrawing
groups favor stabilization of the leaving phenolate anion, thus
facilitating the pyrone ring opening (Scheme 3).
R
R
MeI
NaH
N
H
N
Me
O
O
Me
Me
7c,h
10a, R = H, 83%
10b, R = MeO, 74%
Scheme 4.
It is known that reactions of chromones, and especially 2-
unsubstituted chromones, with amines proceed at the C-2 atom
with pyrone ring opening to
b
-aminovinylketones,13 however,
compound 7a did not react with benzylamine in DMF at 85 ꢀC for
5 h and only starting material was recovered. To demonstrate the
ability of bis-adducts 7 to undergo heterocyclization reactions,
compounds 7a,d were allowed to react with guanidine carbonate
and hydrazine hydrate. Our results showed that 7a,d smoothly
react with guanidine carbonate in refluxing DMF for 7 h to produce
the expected 2-amino-4-(2-hydroxyaryl)-5-[bis(indol-3-yl)me-
thyl]pyrimidines 11a,b in good yields (Scheme 5). In the NMR
The 1H NMR spectra of compounds 7a–j in DMSO-d6 are char-
acterized by the doubled number of the indole protons suggesting
their equivalence and two singlets or doublets with J¼0.6–1.0 Hz as
a result of allylic coupling due to the CH and H-2 protons at d 5.92–
spectra of these products in DMSO-d6, a singlet at
for the pyrimidine proton H-4 appeared in place of the disappear-
ance of a signal at 7.88–7.91 ppm assigned to a proton at 2-posi-
tion of chromones 7a,d. It was also observed that all protons of the
benzene ring shifted to higher field and, hence, opening of the
pyrone ring took place under the action of guanidine carbonate.
The amino group and the methine proton appeared as two singlets
d 8.03–8.05 ppm
6.06 and 7.66–8.01 ppm, respectively. The geometrical isomers 8c
were identified by comparison of the 1H NMR chemical shifts of the
olefinic and indole H-20 hydrogens in both isomers. The diagnostic
signal for the olefinic proton in the Z-isomer, which appeared at
7.75 ppm, was shifted downfield in the E-isomer (8.23 ppm) due to
the deshielding effect of the carbonyl group as indicated in the case
of the reaction of 3-(polyfluoroacyl)chromones with indoles.9 In
addition, another characteristic feature of the 1H NMR spectrum in
d
at
d 6.51–6.54 (2H) and 5.65–5.66 (1H) ppm; the signals at d 10.3
(1H) and 10.8 (2H) ppm are due to the resonances of OH and NH
protons, respectively.
The reactions of chromones 7a,d with an excess of hydrazine
hydrate in refluxing isopropanol for 8 h led to the formation of the
previously unknown pyrazoles 12a,b with bis(indol-3-yl)methyl
moiety in 80 and 52% yields, respectively (Scheme 5). Thus, the
DMSO-d6 was the appearance of two doublets at
d 9.20 and
7.95 ppm (JH,NHz3.0 Hz) for the indole H-20 proton of the Z- and E-
isomers, respectively. The assignment of the indole signals is based
on the literature data.12
(Chromon-3-yl)bis(indol-3-yl)methanes 7 represent a new class
of tris(heteroaryl)methanes, in which two different heterocycles
O
O
O
OH
O
O
N
N
CHO
CHO
R2
R2
1,4-AN
R1
R1
R1
1,2-AN
N
OH
R2
9
1
B
N
R2
-OH
R2
N
O
O
O
O
O
O
N
R2
R1
R1
R1
-H+
N
-OH
N
N
R2
OH
R2
R2
8
7
A
Scheme 3.

6610
V.Ya. Sosnovskikh et al. / Tetrahedron 64 (2008) 6607–6614
ready accessibility and high reactivity of 7 toward dinucleophiles
have made them useful substrates for constructing highly func-
tionalized biologically and medicinally important products.
substituents facilitate the initial nucleophilic addition at the C-2
atom and the electron-donating methyl group complicates this
process as it was observed in the case of indoles. Attempts to use
pyrrole in the reaction with chromones 1a,c,f failed to produce the
desired product under solvent-free conditions, affording only an
intractable brown gum even at room temperature. The formation of
compounds 13, in which the more nucleophilic C-2 atom of the
pyrrole ring is involved, follows the reaction pathway described in
Scheme 6.
NH2
O
O
Ind
Ind
OH
N
N
R
(NH2)2C=NH
Ind
Ind
R
7a,d
O
O
O
11a, R = H, 65%
11b, R = Me, 68%
R1
CHO
R1
N2H4
Me
N
+
N
Me
1,4-AN
O
OH
H
N
H
O
H
N
H
R2
R2
N
O
R
N
1a,d-f
1,2-AN
X
Ind
Ind
Ind
Ind
R
Me
N
O
Me
N
O
OH
12'
12''
R1
R1
12a, R = H, 80%
12b, R = Me, 52%
O
OH
O
Ind = indol-3-yl
R2
R2
14
E-13a-d
Scheme 5.
It is important that the 1H NMR spectra of 12a,b in a DMSO-d6
solution (the solubility of these compounds in CDCl3 is very small)
showed two sets of signals due to the possibility of annular pro-
totropy of the pyrazole ring. It is well known that annular tau-
tomerism in NH azoles is a very fast process in the NMR time
scale.14 However, in each of our cases, four signals exhibiting
broadening at higher frequency values were observed, indicating
that pyrazoles 12a,b exist in DMSO-d6 as a 7:3 mixture of tautomers
120 and 1200, respectively, due to the presence of intramolecular
hydrogen bonds in each tautomer (OH/N and NH/O). The
structural assignments were based on the signals due to the NH and
OH protons at ca. dNH¼11.0–11.2, dOH¼13.0 ppm (tautomer 120) and
dNH¼12.5, dOH¼9.7–9.9 ppm (tautomer 1200), which are very similar
to those of 4-arylmethyl-3(5)-(2-hydroxyphenyl)pyrazoles pre-
pared by treatment of 3-benzylchromones with hydrazine hydrate
in hot pyridine.15 Tautomers 120 are the more abundant (70%) since
their intramolecular O–H/N]C hydrogen bond is stronger than
the intramolecular N–H/O–C hydrogen bond in tautomers 1200. It
should be noted that the 1NMR spectra of 4-arylmethyl-3(5)-(2-
hydroxyphenyl)pyrazoles15 and 4-benzhydryl-3(5)-(2-hydrox-
Chromone R1
R2 Product Yield (%)
1a
1d
1e
1f
H
Cl
H
H
13a
13b
13c
13d
58
68
77
83
NO2
Br
H
Br
Scheme 6.
The choice between structures 13 and 14 was made in favor of
the former on the basis of spectroscopic data. The 1H NMR spectra
of compounds 13a–d in DMSO-d6 consisted of a characteristic
singlet due to the exo-methylene proton in the region of
7.83 ppm and two doublets due to the CH and OH protons at
6.54 and 7.79–8.22 ppm (J¼6.0–6.6 Hz), respectively. The main
features of the 13C NMR spectrum of product 13a were resonances
at 93.5 (C-2) and 179.6 ppm (C]O), and no signal was observed at
153–155 ppm, where the C-2 atom of chromones usually appears.
Comparison of these data with the 1H and 13C NMR spectra of
carbinols of type 14, which have recently been synthesized under
Baylis–Hillman conditions by the reaction of chromone or 6-
methylchromone with aromatic and heteroaromatic aldehydes,18
unambiguously proved the structures of 13.
d
7.72–
6.39–
d
yphenyl)pyrazoles3 in CDCl3 were well resolved with only the OH (
10.7–11.0 ppm) and NH ( 10.0–10.3 ppm) signals. Thus, in this
d
d
solvent the proton exchange is too fast and only average signals
were observed. Previously, 2-amino-4-(2-hydroxyaryl)-5-(di-
alkylaminomethyl)pyrimidines and 4-(dialkylaminomethyl)-3(5)-
(2-hydroxyphenyl)pyrazoles were obtained by the reaction of
3-(dialkylaminomethyl)chromones with guanidine carbonate in
the presence of EtONa and hydrazine hydrate, respectively.16
Next, taking into account the above results and that the pyrrole
ring is an important structural fragment of many natural and
biologically active substances,17 it was of interest to evaluate the
reactivity of 3-formylchromones 1 with N-methylpyrrole. We an-
ticipated that N-methylpyrrole might undergo similar bis-addition
to give the corresponding bis-adducts. However, significantly dif-
ferent reactivity was observed in this case. Unlike indoles, N-
methylpyrrole reacted with 1a,d–f under solvent-free conditions
exclusively via 1,4-addition followed by recyclization to form E-2-
hydroxy-3-(1-methylpyrrol-2-ylmethylene)chroman-4-ones 13a–d
in good yields. The reactions were complete within 45 min and no
bis-adducts of type 7 were observed even in the crude products. 3-
Formyl-6-methylchromone 1b did not react with N-methylpyrrole
under the same conditions. Obviously, the electron-withdrawing
We anticipated that chromanones 13, prepared from 3-for-
mylchromones 1 and N-methylpyrrole, under the action of dinu-
cleophiles, such as hydrazine and hydroxylamine, might undergo
nucleophilic addition reactions giving novel pyrazole and isoxazole
derivatives. However, the deformylation of 13 under mild reaction
conditions limited our attempts to synthesize these compounds. In
fact, treatment of 13b,c with hydrazine hydrate in refluxing ethanol
gave only pyrazolines 15a,b in 28 and 21% yield, respectively. Their
formation is readily explained by the deformylation of 13b,c into
the corresponding pyrrolylchalcones followed by heterocyclization
to 15a,b (Scheme 7). In the 1H NMR spectra of these compounds,
the three protons attached to the C-4 and C-5 carbon atoms of the
pyrazoline unit gave an ABX spin system (
d
¼ 3:24—3:60,
CH2
dCH¼5.00 ppm; JAB¼16.4–16.8, JAX¼10.7–10.9, JBX¼7.9–9.5 Hz).
Treatment of chromanone 13b with hydroxylamine hydrochlo-
ride (2 equiv) in refluxing ethanol in the presence of a catalytic
amount of HCl produced only a high melting solid (mp w300 ꢀC) in
low yield. Measurement of the 1H and 13C NMR spectra of this
compound was unsuccessful due to low solubility in solvents such
as DMSO, DMF, AcOH, and acetone.

V.Ya. Sosnovskikh et al. / Tetrahedron 64 (2008) 6607–6614
6611
H
N
H-7, 3J¼8.5, 7.2 Hz, 4J¼1.7 Hz), 7.92 (d, 1H, H-2, 4J¼0.6 Hz), 8.09 (dd,
1H, H-5, 3J¼8.0 Hz, 4J¼1.7 Hz). Anal. Calcd for C28H22N2O2: C, 80.36;
H, 5.30; N, 6.69. Found: C, 80.05; H, 5.24; N, 6.62.
H
Me
N
Me
N
O
O
R
N
R
N2H4
O
OH
4.2.3. 3-[Bis(2-methylindol-3-yl)methyl]chromone (7c)
Yield 37%, mp 310–312 ꢀC; IR (KBr) 3403, 3230, 1631, 1606, 1570,
13b,c
1492, 1465 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d 2.15 (s, 6H, 2Me),
15a, R = Cl, 28%
15b, R = NO2, 21%
5.95(brs,1H, CH), 6.74 (ddd, 2H, 2H-50, 3J¼8.0, 7.1 Hz,4J¼0.8 Hz), 6.92
4
(ddd, 2H, 2H-60, 3J¼8.0, 7.1 Hz, J¼0.9 Hz), 7.09 (d, 2H, 2H-70,
Scheme 7.
3J¼8.0 Hz), 7.24 (d, 2H, 2H-40, 3J¼8.0 Hz), 7.47 (ddd, 1H, H-6, 3J¼8.0,
7.2 Hz, 4J¼0.9 Hz), 7.61 (d, 1H, H-8, 3J¼8.4 Hz), 7.70 (d, 1H, H-2,
4J¼1.0 Hz), 7.78 (ddd,1H, H-7, 3J¼8.4, 7.2 Hz, 4J¼1.7 Hz), 8.05 (dd,1H,
H-5, 3J¼8.0 Hz, 4J¼1.7 Hz), 10.80 (s, 2H, 2NH). Anal. Calcd for
3. Conclusions
In conclusion, we have shown that the reaction of 3-for-
mylchromones with indoles is a simple and practical method for
the preparation of a new class of biologically interesting (chromon-
3-yl)bis(indol-3-yl)methanes. The reaction with N-methylpyrrole
proceeds via 1,4-addition followed by recyclization to E-2-hydroxy-
3-(1-methylpyrrol-2-ylmethylene)chroman-4-ones. The resulting
products are of considerable interest as reactive precursors for the
synthesis of other useful organic materials.
C28H22N2O2:C,80.36;H,5.30;N,6.69.Found:C, 79.98;H, 5.17;N,6.51.
4.2.4. 3-[Bis(indol-3-yl)methyl]-6-methylchromone (7d)
Yield 68%, mp 252–254 ꢀC; IR (KBr) 3350, 1631, 1607, 1572,
1483 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d 2.42 (s, 3H, Me), 6.04 (s,
1H, CH), 6.90 (ddd, 2H, 2H-50, 3J¼7.9, 7.1 Hz, 4J¼1.0 Hz), 6.96 (d, 2H,
2H-20, J¼1.8 Hz), 7.03–7.08 (m, 2H, 2H-60), 7.32–7.37 (m, 4H, 2H-40,
2H-70), 7.50 (d, 1H, H-8, 3J¼8.6 Hz), 7.60 (dd, 1H, H-7, 3J¼8.6,
4J¼2.2 Hz), 7.88 (s, 1H, H-2), 7.89 (br s, 1H, H-5), 10.85 (br d, 2H,
2NH, J¼1.8 Hz). Anal. Calcd for C27H20N2O2$0.5p-Me2C6H4: C, 81.38;
H, 5.51; N, 6.12. Found: C, 81.35; H, 5.55; N, 5.96.
4. Experimental
4.1. General
4.2.5. 3-[Bis(1-methylindol-3-yl)methyl]-6-methylchromone (7e)
1H (400 MHz) and 13C (100 MHz) NMR spectra were recorded on
a Bruker DRX-400 spectrometer in DMSO-d6 with TMS as the in-
ternal standard. IR spectra were recorded on a Perkin–Elmer
Spectrum BX-II instrument as KBr discs. Elemental analyses were
performed at the Microanalysis Services of the Institute of Organic
Synthesis, Ural Branch, Russian Academy of Sciences. Melting
points are uncorrected. All solvents used were dried and distilled
per standard procedures. The starting 3-formylchromones 1a–f
were prepared according to described procedure.19
Yield 78%, mp 262–263 ꢀC; IR (KBr) 1640, 1619, 1577, 1546, 1486,
1473 cmꢁ1 1H NMR (400 MHz, DMSO-d6)
; d 2.42 (s, 3H, Me), 3.69
(s, 6H, 2MeN), 6.04 (br s, 1H, CH), 6.95 (ddd, 2H, 2H-50, 3J¼7.8,
4
7.1 Hz, J¼0.9 Hz), 6.96 (s, 2H, 2H-20), 7.13 (ddd, 2H, 2H-60, 3J¼8.1,
4
7.1 Hz, J¼1.0 Hz), 7.36 (d, 2H, 2H-40, 3J¼7.8 Hz), 7.39 (d, 2H, 2H-70,
3J¼8.1 Hz), 7.50 (d, 1H, H-8, 3J¼8.6 Hz), 7.60 (dd, 1H, H-7, 3J¼8.6 Hz,
4J¼2.2 Hz), 7.88 (d, 1H, H-5, 4J¼2.2 Hz), 7.89 (d, 1H, H-2, 4J¼0.6 Hz).
Anal. Calcd for C29H24N2O2: C, 80.53; H, 5.59; N, 6.48. Found: C,
80.39; H, 5.71; N, 6.58.
4.2. General procedure for the synthesis of 3-[bis(indol-3-
yl)methyl]chromones (7a–h)
4.2.6. 3-[Bis(2-methylindol-3-yl)methyl]-6-methylchromone (7f)
Yield 51%, mp 263–264 ꢀC; IR (KBr) 3401, 3270, 1633, 1616, 1574,
1484 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d 2.13 (s, 6H, 2Me), 2.41
A solution of 3-formylchromone 1 (2.5 mmol) in an excess of
indole, 1-methyl- or 2-methylindole (7.5 mmol) was heated at 85–
90 ꢀC for 5 h. Completion of the reaction was determined by the
appearance of the solid reaction mixture. The precipitate, obtained
from the hot solution, was twice recrystallized from n-butanol/p-
xylene (4:1), washed with ethanol, and dried at 90 ꢀC for 1 day to
give compounds 7 as colorless crystals.
(s, 3H, Me), 5.92 (br s, 1H, CH), 6.73 (ddd, 2H, 2H-50, 3J¼8.0, 7.1 Hz,
4J¼0.8 Hz), 6.91 (ddd, 2H, 2H-60, 3J¼8.0, 7.1 Hz, 4J¼0.9 Hz), 7.07 (d,
2H, 2H-70, 3J¼8.0 Hz), 7.23 (d, 2H, 2H-40, 3J¼8.0 Hz), 7.52 (d, 1H, H-8,
3J¼8.6 Hz), 7.60 (dd, 1H, H-7, 3J¼8.6 Hz, 4J¼2.2 Hz), 7.66 (d, 1H, H-2,
4J¼1.0 Hz), 7.81 (d, 1H, H-5, 4J¼2.2 Hz), 10.78 (s, 2H, 2NH). Anal.
Calcd for C29H24N2O2: C, 80.53; H, 5.59; N, 6.48. Found: C, 80.15; H,
5.41; N, 6.43.
4.2.1. 3-[Bis(indol-3-yl)methyl]chromone (7a)
4.2.7. 3-[Bis(indol-3-yl)methyl]-6-methoxychromone (7g)
Yield 54%, mp 233–234 ꢀC; IR (KBr) 3389, 1633, 1614, 1572,
Yield 79%, mp 187–188 ꢀC; IR (KBr) 3426, 3326, 1628, 1617, 1606,
1465 cmꢁ1
;
1H NMR (400 MHz, DMSO-d6)
d
6.05 (d, 1H, CH,
1573, 1515, 1485 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d 3.85 (s, 3H,
4J¼0.8 Hz), 6.91 (ddd, 2H, 2H-50, 3J¼8.0, 7.1 Hz, 4J¼1.0 Hz), 6.98 (d,
2H, 2H-20, J¼1.8 Hz), 7.06 (ddd, 2H, 2H-60, 3J¼8.0, 7.1 Hz, 4J¼1.0 Hz),
7.36 (dd, 4H, 2H-40, 2H-70, 3J¼8.0 Hz, 4J¼1.0 Hz), 7.49 (ddd, 1H, H-6,
3J¼8.0, 7.2 Hz, 4J¼1.0 Hz), 7.60 (dd, 1H, H-8, 3J¼8.5 Hz, 4J¼1.0 Hz),
7.78 (ddd, 1H, H-7, 3J¼8.5, 7.2 Hz, 4J¼1.7 Hz), 7.91 (d, 1H, H-2,
4J¼0.8 Hz), 8.10 (dd, 1H, H-5, 3J¼8.0 Hz, 4J¼1.7 Hz), 10.86 (d, 2H,
2NH, J¼1.8 Hz). Anal. Calcd for C26H18N2O2: C, 79.98; H, 4.65; N, 7.17.
Found: C, 79.66; H, 4.47; N, 6.99.
MeO), 6.06 (d,1H, CH, J¼0.7 Hz), 6.90 (ddd, 2H, 2H-50, 3J¼7.9, 7.1 Hz,
4J¼0.8 Hz), 6.97 (d, 2H, 2H-20, J¼2.0 Hz), 7.03–7.08 (m, 2H, 2H-60),
7.33–7.37 (m, 4H, 2H-40, 2H-70), 7.38 (dd, 1H, H-7, 3J¼9.1 Hz,
4J¼3.1 Hz), 7.46 (d, 1H, H-5, 4J¼3.1 Hz), 7.56 (d, 1H, H-8, 3J¼9.1 Hz),
7.90 (s, 1H, H-2), 10.85 (d, 2H, 2NH, J¼2.0 Hz). Anal. Calcd for
C
27H20N2O3$0.5p-Me2C6H4: C, 78.63; H, 5.32; N, 5.92. Found: C,
78.62; H, 5.28; N, 5.71.
4.2.8. 3-[Bis(2-methylindol-3-yl)methyl]-6-methoxychromone (7h)
4.2.2. 3-[Bis(1-methylindol-3-yl)methyl]chromone (7b)
Yield 61%, mp 289–290 ꢀC; IR (KBr) 3388, 3290, 1628, 1612, 1576,
Yield 65%, mp 265–266 ꢀC; IR (KBr) 1631, 1608, 1572, 1465 cmꢁ1
;
1484 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d 2.13 (s, 6H, 2Me), 3.83 (s,
1H NMR (400 MHz, DMSO-d6)
d
3.70 (s, 6H, 2Me), 6.04 (d, 1H, CH,
3H, MeO), 5.93 (s, 1H, CH), 6.73 (t, 2H, 2H-50, 3J¼7.5 Hz), 6.91 (t, 2H,
4J¼0.6 Hz), 6.95 (ddd, 2H, 2H-50, 3J¼7.8, 7.0 Hz, 4J¼0.9 Hz), 6.98 (s,
2H, 2H-20), 7.13 (ddd, 2H, 2H-60, 3J¼8.2, 7.0 Hz, 4J¼1.0 Hz), 7.38 (t,
4H, 2H-40, 2H-70, 3J¼8.2 Hz), 7.49 (ddd, 1H, H-6, 3J¼8.0, 7.2 Hz,
4J¼1.0 Hz), 7.60 (dd, 1H, H-8, 3J¼8.5 Hz, 4J¼1.0 Hz), 7.79 (ddd, 1H,
2H-60, J¼7.5 Hz), 7.06 (d, 2H, 2H-70, J¼8.0 Hz), 7.23 (d, 2H, 2H-40,
3J¼8.0 Hz), 7.37–7.41 (m, 2H, H-7, H-5), 7.59 (d, 1H, H-8, 3J¼9.0 Hz),
7.68 (d, 1H, H-2, 4J¼0.9 Hz), 10.77 (s, 2H, 2NH). Anal. Calcd for
3
3
C
29H24N2O3:C, 77.66;H, 5.39;N, 6.25. Found:C, 77.27;H, 5.38;N, 6.17.

6612
V.Ya. Sosnovskikh et al. / Tetrahedron 64 (2008) 6607–6614
4.2.9. 3-[Bis(indol-3-yl)methyl]-6-chlorochromone (7i)
NMR (400 MHz, DMSO-d6) (E-8c, 91%)
d
6.66 (d, 1H, CH, J¼6.7 Hz),
Indole (760 mg, 6.50 mmol) and two drops of 50% HClO4 were
added to a hot solution of 6-chloro-3-formylchromone 1d (450 mg,
2.16 mmol) in n-butanol (5 mL). The resulting dark-red reaction
mixture was kept for 24 h at w20 ꢀC, then the precipitated crystals
were filtered, washed with ethanol, and recrystallized from n-bu-
tanol to give compound 7i as colorless crystals. Yield 500 mg (55ꢁ%1),
7.20–7.30 (m, 2H, H-50, H-60), 7.53 (d, 1H, H-70, 3J¼7.8 Hz), 7.88 (d,
3
1H, H-40, J¼7.6 Hz), 7.95 (d, 1H, H-20, J¼2.4 Hz), 7.95 (d, 1H, H-7,
4J¼2.4 Hz), 8.12 (d, 1H, H-5, 4J¼2.4 Hz), 8.20 (d, 1H, OH, J¼6.7 Hz),
8.23 (s, 1H, ]CH), 12.34 (s, 1H, NH); (Z-8c, 9%) d 6.52 (br s, 1H, CH),
7.75 (s, 1H, ]CH), 9.20 (d, 1H, H-20, J¼3.1 Hz), 10.89 (br s, 1H, OH),
12.11 (br s, 1H, NH). Anal. Calcd for C18H11Br2NO3: C, 48.14; H, 2.47;
N, 3.12. Found: C, 48.45; H, 2.48; N, 3.01.
mp 235–236 ꢀC; IR (KBr) 3407, 1638, 1605, 1568, 1467, 1455 cm
;
1H NMR (400 MHz, DMSO-d6)
d
6.03 (s, 1H, CH), 6.91 (t, 2H, 2H-50,
3J¼7.5 Hz), 6.99 (d, 2H, 2H-20, J¼2.0 Hz), 7.06 (t, 2H, 2H-60,
4.2.14. 3-[Bis(1,2-dimethylindol-3-yl)methyl]chromone (10a)
3J¼7.5 Hz), 7.35 (d, 2H, 2H-70, J¼8.0 Hz), 7.36 (d, 2H, 2H-40, 3J¼
Powdered sodium hydride (110 mg, 4.58 mmol) was added to
a solution of 7c (360 mg, 0.86 mmol) in THF (10 mL) and the mix-
ture was refluxed for 2 h. Then to a stirred suspension MeI (2.5 g,
17.7 mmol) was added in one portion, the resulting mixture was
heated at reflux for 1 h, and allowed to stand for 1 day at room
temperature. The inorganic salts were filtered off and washed with
THF (5 mL). Evaporation of the filtrate at heating gave a solid, which
was recrystallized from a n-BuOH/p-xylene mixture to give color-
less crystals. Yield 320 mg (83%), mp 209–210 ꢀC; IR (KBr) 1645,
3
8.0 Hz), 7.67 (d, 1H, H-8, 3J¼9.0 Hz), 7.82 (dd, 1H, H-7, 3J¼9.0 Hz,
4J¼2.6 Hz), 7.94 (s, 1H, H-2), 8.02 (d, 1H, H-5, 4J¼2.6 Hz), 10.87 (br d,
2H, 2NH, J¼2.0 Hz); 13C NMR (100 MHz, DMSO-d6)
d 29.1, 111.5,
115.5, 118.4, 118.7, 120.9, 121.0, 124.0, 124.2, 124.4, 126.3, 126.8,
129.7, 133.8, 136.7, 154.4, 155.1, 174.7. Anal. Calcd for C26H17ClN2O2:
C, 73.50; H, 4.03; N, 6.59. Found: C, 73.15; H, 3.72; N, 6.32.
4.2.10. 3-[Bis(indol-3-yl)methyl]-6-nitrochromone (7j)
A mixture of 3-formyl-6-nitrochromone 1e (350 mg, 1.60 mmol)
and indole (560 mg, 4.79 mmol) in water (5 mL) was heated at 85–
90 ꢀC for 5 h. The resultant product was filtered, washed with
water, dried, and recrystallized from n-butanol/toluene (1:1) to
give compound 7j as pale yellow crystals. Yield 400 mg (58%), mp
1614, 1608, 1572, 1558, 1463 cmꢁ1 1H NMR (400 MHz, DMSO-d6)
;
d
2.22 (s, 6H, 2Me), 3.64 (s, 6H, 2NMe), 5.97 (d, 1H, CH, J¼1.0 Hz),
6.76 (ddd, 2H, 2H-50, 3J¼7.9, 7.1 Hz, 4J¼0.9 Hz), 6.98 (ddd, 2H, 2H-60,
3J¼8.0, 7.1 Hz, 4J¼1.0 Hz), 7.12 (d, 2H, 2H-70, 3J¼8.0 Hz), 7.36 (d, 2H,
2H-40, 3J¼7.9 Hz), 7.47 (ddd, 1H, H-6, 3J¼8.0, 7.1 Hz, 4J¼1.0 Hz), 7.62
(d, 1H, H-8, 3J¼8.4 Hz), 7.70 (d, 1H, H-2, 4J¼1.0 Hz), 7.80 (ddd, 1H, H-
7, 3J¼8.4, 7.1 Hz, 4J¼1.7 Hz), 8.00 (dd, 1H, H-5, 3J¼8.0 Hz, 4J¼1.7 Hz);
204–205 ꢀC; 1H NMR (400 MHz, DMSO-d6)
d 6.04 (s, 1H, CH), 6.91
3
(t, 2H, 2H-50, J¼7.5 Hz), 7.02 (d, 2H, 2H-20, J¼1.8 Hz), 7.06 (t, 2H,
3
3
2H-60, J¼7.5 Hz), 7.37 (d, 2H, 2H-70, J¼8.0 Hz), 7.38 (d, 2H, 2H-40,
3J¼8.0 Hz), 7.86 (d, 1H, H-8, 3J¼9.2 Hz), 8.01 (s, 1H, H-2), 8.54 (dd,
1H, H-7, 3J¼9.2 Hz, 4J¼2.8 Hz), 8.79 (d, 1H, H-5, 4J¼2.8 Hz), 10.89 (br
d, 2H, 2NH, J¼1.8 Hz); according to the 1H NMR spectrum, com-
pound 7j contained 5% of 8a. Anal. Calcd for C26H17N3O4: C, 71.72;
H, 3.94; N, 9.65. Found: C, 71.42; H, 3.93; N, 9.28.
13C NMR (100 MHz, DMF-d7)
d 10.5, 29.6, 31.9, 109.6, 110.7, 119.0,
119.1, 120.5, 124.1, 125.9, 126.0, 127.5, 128.3, 129.4, 134.5, 134.8,
137.3, 155.3, 156.9, 176.7. Anal. Calcd for C30H26N2O2: C, 80.69; H,
5.87; N, 6.27. Found: C, 80.38; H, 5.72; N, 6.14.
4.2.15. 3-[Bis(1,2-dimethylindol-3-yl)methyl]-6-methoxy-
chromone (10b)
4.2.11. E-2-Hydroxy-6-nitro-3-(indol-3-ylmethylene)chroman-4-
one (8a)
This compound was prepared from 7h analogously to 10a. Yield
74%, mp 211–212 ꢀC; IR (KBr) 1641, 1615, 1584, 1559, 1482,
This compound was obtained analogously to 7j. Yield 10%, mp
1468 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d 2.22 (s, 6H, 2Me), 3.64
244–246 ꢀC; 1H NMR (400 MHz, DMSO-d6)
d
6.65 (br d, 1H, CH,
(s, 6H, 2NMe), 3.81 (s, 3H, MeO), 5.98 (d, 1H, CH, J¼1.0 Hz), 6.76
J¼6.2 Hz), 7.24 (td, 1H, H-50, 3J¼7.7 Hz, 4J¼1.0 Hz), 7.28 (td, 1H, H-60,
3J¼7.7 Hz, 4J¼1.0 Hz), 7.31 (d, 1H, H-8, 3J¼9.0 Hz), 7.54 (d, 1H, H-70,
3J¼7.7 Hz), 7.89 (d, 1H, H-40, 3J¼7.7 Hz), 7.96 (d, 1H, H-20, J¼2.8 Hz),
8.23 (br d, 1H, OH, J¼6.2 Hz), 8.28 (s, 1H, ]CH), 8.41 (dd, 1H, H-7,
3J¼9.0 Hz, 4J¼2.9 Hz), 8.65 (d, 1H, H-5, 4J¼2.9 Hz), 12.34 (br s, 1H,
NH); according to the 1H NMR spectrum, compound 8a contained
14% of 7j. Anal. Calcd for C18H12N2O5: C, 64.29; H, 3.60; N, 8.33.
Found: C, 64.32; H, 4.06; N, 8.05.
(ddd, 2H, 2H-50, 3J¼8.0, 7.1 Hz, J¼1.0 Hz), 6.98 (ddd, 2H, 2H-60,
4
3J¼8.0, 7.1 Hz, 4J¼1.0 Hz), 7.10 (d, 2H, 2H-70, 3J¼8.0 Hz), 7.36 (d, 2H,
2H-40, 3J¼8.0 Hz), 7.37 (d, 1H, H-5, 4J¼3.1 Hz), 7.39 (dd, 1H, H-7,
3J¼9.0 Hz, 4J¼3.1 Hz), 7.59 (d, 1H, H-8, 3J¼9.0 Hz), 7.68 (d, 1H, H-2,
4J¼1.0 Hz). Anal. Calcd for C31H28N2O3$H2O: C, 75.28; H, 6.11; N,
5.66. Found: C, 75.29; H, 6.20; N, 5.34.
4.2.16. 2-Amino-4-(2-hydroxyphenyl)-5-[bis(indol-3-
yl)methyl]pyrimidine (11a)
4.2.12. 3-[Bis(1-methylindol-3-yl)methyl]-6-nitrochromone (7k)
and E-2-hydroxy-6-nitro-3-(1-methylindol-3-ylmethylene)-
chroman-4-one (8b)
A mixture of 7a (250 mg, 0.64 mmol) and guanidine carbonate
(230 mg, 1.28 mmol) in DMF (5 mL) was refluxed for 7 h. After cool-
ing, water (40 mL) was added and the solid obtained was filtered,
washed with water, and purified by boiling in toluene and filtration.
Yield 200 mg (65%), mp 277–278 ꢀC; IR (KBr) 3436, 3398, 3317, 3135,
This mixture was obtained analogously to 7a–h. 1H NMR
(400 MHz, DMSO-d6) (7k, 33%)
d 3.70 (s, 6H, 2Me), 6.03 (d, 1H, CH,
4J¼0.7 Hz), 6.96 (ddd, 2H, 2H-50, 3J¼7.8, 7.0 Hz, 4J¼0.9 Hz), 7.02 (s,
2H, 2H-20), 7.14 (ddd, 2H, 2H-60, 3J¼8.1, 7.0 Hz, 4J¼1.0 Hz), 7.37–7.42
(m, 4H, 2H-40, 2H-70), 7.88 (d, 1H, H-8, 3J¼9.2 Hz), 8.04 (d, 1H, H-2,
4J¼0.7 Hz), 8.55 (dd, 1H, H-7, 3J¼9.2 Hz, 4J¼2.9 Hz), 8.78 (d, 1H, H-5,
1654, 1589, 1572, 1543, 1510, 1484, 1453 cmꢁ1 1H NMR (400 MHz,
;
DMSO-d6)
d 5.65 (s, 1H, CH), 6.51 (s, 2H, NH2), 6.61 (t, 1H, H-4,
3J¼7.5 Hz), 6.66 (br s, 2H, 2H-20), 6.81 (t, 2H, 2H-50, 3J¼7.5 Hz), 6.89 (d,
1H, H-6, 3J¼8.0 Hz), 6.95 (d, 1H, H-3, J¼8.0 Hz), 7.02 (t, 2H, 2H-60,
3
4J¼2.9 Hz); (8b, 67%)
d
3.95 (s, 3H, Me), 6.65 (d, 1H, CH, J¼7.0 Hz),
3J¼7.5 Hz), 7.13 (d, 2H, 2H-40, 3J¼8.0 Hz), 7.17 (t, 1H, H-5, 3J¼8.0 Hz),
7.32(d, 2H, 2H-70, 3J¼8.0 Hz),8.03(s,1H, H-6pyrim.),10.33(s,1H, OH),
7.26–7.37 (m, 2H, H-50, H-60), 7.32 (d, 1H, H-8, 3J¼9.1 Hz), 7.62 (d,
3
3
1H, H-70, J¼8.1 Hz), 7.91 (d, 1H, H-40, J¼7.7 Hz), 7.97 (s, 1H, H-20),
8.19 (d, 1H, OH, J¼7.0 Hz), 8.25 (s, 1H, ]CH), 8.41 (dd, 1H, H-7,
3J¼9.1 Hz, 4J¼2.9 Hz), 8.64 (d, 1H, H-5, 4J¼2.9 Hz).
10.78 (s, 2H, 2NH); 13C NMR (100 MHz, DMSO-d6)
d 33.3,111.4, 115.9,
117.4, 118.2, 118.3, 119.0, 120.8, 120.9, 123.8, 123.9, 124.5, 126.2, 129.8,
136.6, 154.9, 158.9, 161.4, 164.1. Anal. Calcd for C27H21N5O$0.5H2O: C,
73.62; H, 5.03; N, 15.90. Found: C, 73.41; H, 4.89; N, 15.81.
4.2.13. 6,8-Dibromo-2-hydroxy-3-(indol-3-ylmethylene)-
chroman-4-one (8c)
This compound was obtained analogously to 7a–h in 30% yield
as orange crystals, mp 255–256 ꢀC (n-butanol/toluene, 1:1); IR
(KBr) 3468, 3385, 1634, 1619, 1585, 1559, 1544, 1516, 1489 cmꢁ1; 1H
4.2.17. 2-Amino-4-(2-hydroxy-5-methylphenyl)-5-[bis(indol-3-
yl)methyl]pyrimidine (11b)
This compound was prepared from 7d analogously to 11a. Yield
68%, mp 261–262 ꢀC; IR (KBr) 3418, 3329, 3182, 1658, 1608, 1591,

V.Ya. Sosnovskikh et al. / Tetrahedron 64 (2008) 6607–6614
6613
1572, 1541, 1502, 1456 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d
1.83 (s,
179.6 (dtd, C-4, J¼6.2, 4.1, 1.7 Hz). Anal. Calcd for C15H13NO3: C,
3H,Me),5.66(s,1H,CH), 6.54(s, 2H,NH2), 6.65(d,1H,H-6, 4J¼2.0 Hz),
6.70 (d, 2H, 2H-20, J¼2.0 Hz), 6.83 (t, 2H, 2H-50, 3J¼7.5 Hz), 6.84 (d,1H,
H-3, 3J¼8.2 Hz), 6.98 (dd, 1H, H-4, 3J¼8.2 Hz, 4J¼2.0 Hz), 7.03 (t, 2H,
70.58; H, 5.13; N, 5.49. Found: C, 70.38; H, 5.14; N, 5.41.
4.3.2. E-6-Chloro-2-hydroxy-3-(1-methylpyrrol-2-
ylmethylene)chroman-4-one (13b)
3
3
2H-60, J¼7.5 Hz), 7.11 (d, 2H, 2H-40, J¼7.9 Hz), 7.33 (d, 2H, 2H-70,
3J¼8.1 Hz), 8.05 (s, 1H, H-6 pyrim.), 10.29 (s, 1H, OH), 10.81 (d, 2H,
2NH, J¼2.0 Hz). Anal. Calcd for C28H23N5O: C, 75.49; H, 5.20; N,15.72.
Found: C, 75.18; H, 5.02; N, 15.35.
Yield 68%, mp 193–194 ꢀC; IR (KBr) 3253, 1637, 1605, 1579, 1557,
1539, 1492 cmꢁ1 1H NMR (400 MHz, DMSO-d6)
; d 3.78 (s, 3H, Me),
6.31 (dd,1H, H-40, J¼3.5, 2.6 Hz), 6.41 (d,1H, H-2, J¼6.3 Hz), 6.78 (br d,
1H, H-50, J¼3.4 Hz), 7.11 (d, 1H, H-8, 3J¼8.8 Hz), 7.28 (br t, 1H, H-30,
J¼1.5 Hz), 7.62 (dd, 1H, H-7, 3J¼8.8 Hz, 4J¼2.7 Hz), 7.76 (s, 1H, ]CH),
7.79 (d, 1H, H-5, 4J¼2.7 Hz), 7.92 (d, 1H, OH, J¼6.3 Hz). Anal. Calcd for
4.2.18. 2-{4-[Bis(indol-3-yl)methyl]-1H-pyrazol-3-yl}phenol (12a)
A solution of 7a (350 mg, 0.90 mmol) and 60% hydrazine hy-
drate (300 mg, 3.59 mmol) in isopropanol (20 mL) was refluxed for
8 h. After partial evaporation of the solvent the product was iso-
lated by filtration, washed with isopropanol, and dried to give
a colorless powder. Yield 290 mg (80%), mp 260–261 ꢀC; IR (KBr)
3437, 3409, 3291, 1650, 1619, 1587, 1547, 1507, 1454 cmꢁ1; 1H NMR
C15H12ClNO3:C,62.19;H, 4.17;N,4.83. Found:C,62.13;H, 4.35;N,4.55.
4.3.3. E-2-Hydroxy-6-nitro-3-(1-methylpyrrol-2-
ylmethylene)chroman-4-one (13c)
Yield 77%, mp 229–230 ꢀC; IR (KBr) 3325, 1652, 1615, 1594, 1569,
(400 MHz, DMSO-d6) (120a, OH/N, 70%)
7.35 (m, 15H, arom.), 10.76 (br s, 2H, 2NH ind.), 11.21 (br s, 1H, NH),
13.00 (br s, 1H, OH); (1200a, NH/O, 30%)
5.73 (br s, 1H, CH), 6.60–
7.35 (m, 15H, arom.), 9.88 (br s, 1H, OH), 10.76 (br s, 2H, 2NH ind.),
12.52 (br s, 1H, NH); 13C NMR (100 MHz, DMSO-d6)
19.9, 30.2,
d
5.97 (br s, 1H, CH), 6.60–
1522, 1511, 1491 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d 3.80 (s, 3H,
Me), 6.34 (dd, 1H, H-40, J¼4.0, 2.5 Hz), 6.54 (d, 1H, H-2, J¼6.0 Hz),
6.82 (dd, 1H, H-50, J¼4.0, 1.0 Hz), 7.30 (d, 1H, H-8, 3J¼9.1 Hz), 7.33 (t,
1H, H-30, J¼1.7 Hz), 7.83 (s, 1H, ]CH), 8.22 (d, 1H, OH, J¼6.0 Hz),
8.40 (dd, 1H, H-7, 3J¼9.1 Hz, 4J¼2.9 Hz), 8.61 (d, 1H, H-5, 4J¼2.9 Hz).
Anal. Calcd for C15H12N2O5: C, 60.00; H, 4.03; N, 9.33. Found: C,
60.06; H, 3.95; N, 9.34.
d
d
111.5, 115.8, 117.7, 118.2, 118.8, 119.0, 120.8, 122.4, 123.2, 123.5, 126.3,
126.8, 128.6, 129.6, 136.6, 146.2, 153.3 (all signals are broadened).
Anal. Calcd for C26H20N4O: C, 77.21; H, 4.98; N, 13.85. Found: C,
76.98; H, 5.03; N, 13.69.
4.3.4. E-6,8-Dibromo-2-hydroxy-3-(1-methylpyrrol-2-
ylmethylene)chroman-4-one (13d)
4.2.19. 2-{4-[Bis(indol-3-yl)methyl]-1H-pyrazol-3-yl}-4-
methylphenol (12b)
Yield 83%, mp 205–206 ꢀC; IR (KBr) 3300, 1629, 1584, 1562, 1537,
1488 cmꢁ1 1H NMR (400 MHz, DMSO-d6)
; d 3.79 (s, 3H, Me), 6.33
This compound was prepared from 7d analogously to 12a. Yield
52%, mp 227–228 ꢀC; IR (KBr) 3405, 3370, 1639, 1617, 1592, 1552,
1500,1476,1455 cmꢁ1; 1H NMR (400 MHz, DMSO-d6) (120b, OH/N,
(dd,1H, H-40, J¼4.0, 2.5 Hz), 6.53 (d, 1H, H-2, J¼6.6 Hz), 6.81 (dd,1H,
H-50, J¼4.0, 1.0 Hz), 7.31 (t, 1H, H-30, J¼1.7 Hz), 7.78 (s, 1H, ]CH),
7.91 (d, 1H, H-7, 4J¼2.4 Hz), 8.12 (d, 1H, H-5, 4J¼2.4 Hz), 8.20 (d, 1H,
OH, J¼6.6 Hz). Anal. Calcd for C15H11Br2NO3: C, 43.62; H, 2.68; N,
3.39. Found: C, 43.71; H, 2.87; N, 3.25.
70%)
arom.),10.79 (br s, 2H, 2NH ind.),11.04 (br s,1H, NH),12.97 (br s,1H,
OH); (1200b, NH/O, 30%)
2.01 (br s, 3H, Me), 5.75 (br s, 1H, CH),
d 1.78 (br s, 3H, Me), 5.99 (br s, 1H, CH), 6.75–7.37 (m, 14H,
d
6.75–7.37 (m, 14H, arom.), 9.65 (br s, 1H, OH), 10.73 (br s, 2H, 2NH
ind.), 12.48 (br s, 1H, NH). Anal. Calcd for C27H22N4O: C, 77.49; H,
5.30; N, 13.39. Found: C, 77.41; H, 5.35; N, 13.56.
4.3.5. 4-Chloro-2-[5-(1-methylpyrrol-2-yl)-4,5-dihydropyrazol-3-
yl]phenol (15a)
A solutionof 13b (300 mg,1.04 mmol)and60%hydrazine hydrate
(160 mg, 3.11 mmol) in ethanol (5 mL) was refluxed for 2.5 h and the
solvent was evaporated to half of its initial volume. After cooling, the
precipitate formed was filtered, washed with aqueous ethanol, and
dried to give colorless needles. Yield 80 mg (28%), mp 128–129 ꢀC; IR
(KBr) 3292, 1614, 1593, 1564, 1488 cmꢁ1; 1H NMR (400 MHz, CDCl3)
4.3. General procedure for the synthesis of E-2-hydroxy-3-(1-
methylpyrrol-2-ylmethylene)chroman-4-ones (13a–d)
A solution of 3-formylchromone 1 (1.0 mmol) in an excess of
N-methylpyrrole (3.0 mmol) was heated at 85–90 ꢀC for 45 min.
Completion of the reaction was determined by the appearance of
the solid reaction mixture. The precipitate, obtained from the hot
solution, was cooled and treated with hexane (5 mL). The residue
was filtered, washed with hexane, recrystallized from n-butanol/
dioxane (3:1), and washed with ethanol to give compounds 13 as
yellow crystals.
d
3.24 (dd, 1H, CHH, J¼16.4, 7.9 Hz), 3.44 (dd, 1H, CHH, J¼16.4,
10.7 Hz), 3.67 (s, 3H, Me), 5.00 (dd,1H, CH, J¼10.7, 7.9 Hz), 6.05–6.08
(m, 2H, H-40, H-50), 6.63 (t, 1H, H-30, J¼2.2 Hz), 6.94 (d, 1H, H-6,
3J¼8.7 Hz), 7.15 (d, 1H, H-3, 4J¼2.6 Hz), 7.20 (dd, 1H, H-5, 3J¼8.7 Hz,
4J¼2.6 Hz),10.3–11.5 (br s, 2H, NH, OH). Anal. Calcd for C14H14ClN3O:
C, 60.98; H, 5.12; N, 15.24. Found: C, 60.63; H, 5.10; N, 15.16.
4.3.6. 2-[5-(1-Methylpyrrol-2-yl)-4,5-dihydropyrazol-3-yl]-4-
nitrophenol (15b)
4.3.1. E-2-Hydroxy-3-(1-methylpyrrol-2-ylmethylene)chroman-4-
one (13a)
This compound was prepared from 13c analogously to 15a. Yield
21%, mp 171–172 ꢀC; IR (KBr) 3288, 1630, 1593, 1565, 1525,
Yield 58%, mp 190–191 ꢀC; IR (KBr) 3376, 3277, 1645, 1608, 1585,
1557, 1485 cmꢁ1
;
1H NMR (400 MHz, DMSO-d6)
d
3.77 (s, 3H, Me),
1486 cmꢁ1 1H NMR (400 MHz, DMSO-d6)
; d 3.32 (dd, 1H, CHH,
6.29 (dd, 1H, H-40, J¼4.0, 2.5 Hz), 6.39 (d, 1H, H-2, J¼6.3 Hz), 6.75
J¼16.8, 9.5 Hz), 3.60 (dd, 1H, CHH, J¼16.8, 10.9 Hz), 3.62 (s, 3H, Me),
5.00 (ddd, 1H, CH, J¼10.9, 9.5, 2.6 Hz), 5.90 (dd, 1H, H-40, J¼3.5,
2.7 Hz), 6.01 (dd, 1H, H-50, J¼3.5, 1.7 Hz), 6.72 (t, 1H, H-30, J¼2.2 Hz),
7.12 (d, 1H, H-6, 3J¼9.0 Hz), 7.98 (d, 1H, NH, J¼2.6 Hz), 8.14 (dd, 1H,
(dd, 1H, H-50, J¼4.0, 1.2 Hz), 7.04 (d, 1H, H-8, 3J¼8.0 Hz), 7.12 (ddd,
1H, H-6, 3J¼7.8, 7.3 Hz, J¼0.9 Hz), 7.24 (t, 1H, H-30, J¼1.8 Hz), 7.58
4
(ddd, 1H, H-7, 3J¼8.0, 7.3 Hz, 4J¼1.7 Hz), 7.72 (s, 1H, ]CH), 7.79 (d,
1H, OH, J¼6.3 Hz), 7.86 (dd, 1H, H-5, 3J¼7.8 Hz, 4J¼1.7 Hz); 13C NMR
4
H-5, 3J¼9.0 Hz, 4J¼2.8 Hz), 8.23 (d, 1H, H-3, J¼2.8 Hz), 12.22 (br s,
(100 MHz, DMSO-d6)
d
34.0 (qd, Me, J¼139.7, 2.4 Hz), 93.5 (ddd, C-
1H, OH). Anal. Calcd for C14H14N4O3: C, 58.73; H, 4.93; N, 19.57.
Found: C, 58.40; H, 4.71; N, 19.60.
2, J¼169.7, 10.6, 3.4 Hz), 110.1 (ddd, C-40, J¼172.9, 7.8, 3.4 Hz), 116.8
(dm, C-30, J¼172.2 Hz),118.5 (dd, C-8, J¼162.8, 7.5 Hz),121.6 (ddd, C-
3, J¼7.8, 4.5, 1.3 Hz), 121.7 (dd, C-5, J¼163.3, 7.9 Hz), 125.9 (t, C-4a,
J¼4.9 Hz), 126.5 (d, ]CH, J¼153.7 Hz), 126.5 (ddd, C-6, J¼161.8, 8.4,
1.3 Hz), 127.1 (qd, C-20, J¼6.7, 1.8 Hz), 129.7 (dquintd, C-50, J¼186.4,
8.0, 3.6 Hz), 135.5 (ddd, C-7, J¼160.6, 9.2, 2.0 Hz), 157.2 (m, C-8a),
Acknowledgements
This work was financially supported by the RFBR (Grant 06-03-
32388) and CRDF (Grant BP2M05).

6614
V.Ya. Sosnovskikh et al. / Tetrahedron 64 (2008) 6607–6614
7. Chakrabarty, M.; Basak, R.; Harigaya, Y. Heterocycles 2001, 55, 2431–2447.
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