Reactivity of 3-formyl- and 3-cyanothiochromones toward some N- and C-nucleophiles. Novel synthesis of 3-substituted 2-aminothiochromones

Article abstract of DOI:10.1016/j.tet.2010.06.066

The reactions of 3-formylthiochromone with o-phenylenediamines, o-aminobenzenethiol, and indoles proceeded at the aldehyde group to give 3-(benzimidazol-2-yl)thiochromone, 3-(benzothiazol-2-yl)thiochromone, and 3-di(indol-3-yl)methylthiochromones, respect

Full text of DOI:10.1016/j.tet.2010.06.066

Tetrahedron 66 (2010) 7322e7328
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Reactivity of 3-formyl- and 3-cyanothiochromones toward some N- and
C-nucleophiles. Novel synthesis of 3-substituted 2-aminothiochromones
,
b
a
Vyacheslav Ya. Sosnovskikh a , Dmitri V. Sevenard , Vladimir S. Moshkin ,
*
Viktor O. Iaroshenko c, Peter Langer c
a Department of Chemistry, Ural State University, 620083 Ekaterinburg, Russian Federation
b Hansa Fine Chemicals GmbH, BITZ, Fahrenheitstrasse 1, 28359 Bremen, Germany
c
€
Institut für Chemie, Universitat Rostock, Albert-Einstein-Strasse 3a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The reactions of 3-formylthiochromone with o-phenylenediamines, o-aminobenzenethiol, and indoles
proceeded at the aldehyde group to give 3-(benzimidazol-2-yl)thiochromone, 3-(benzothiazol-2-yl)
thiochromone, and 3-di(indol-3-yl)methylthiochromones, respectively. 3-Formyl- and 3-cyanothio-
chromones react with primary aromatic amines and phenylhydrazine to give the corresponding anils and
phenylhydrazones of 3-formyl- and 2-amino-3-formylthiochromones. The reaction of 3-cyanochro-
mones with o-phenylenediamines gave 2-amino-3-[(2-aminophenyl)iminomethyl]-4H-chromen-4-ones.
Ó 2010 Published by Elsevier Ltd.
Received 19 April 2010
Received in revised form
7 June 2010
Accepted 28 June 2010
Available online 3 July 2010
Keywords:
3-Formyl- and 3-cyanothiochromones
Anils and phenylhydrazones of 3-formyl-
and 2-amino-3-formylthiochromones
3-(Benzimidazol-2-yl)- and
3-(benzothiazol-2-yl)thiochromones
3-Di(indol-3-yl)methylthiochromones
Nucleophilic addition
Regioselectivity
1. Introduction
capable of undergoing intramolecular heterocyclizations.4,5 Along
with this route, the initial attack can occurat the 3-RCOgroupas well
Derivatives of 4H-1-benzopyran-4-one, also known as 4H-chro-
men-4-ones or chromones, belong to an important class of natural
oxygen-containing heterocycles that are widely distributed among
many plants.1 Many natural and synthetic chromone derivatives
exhibit various types of biological activity2 and find use as valuable
synthetic intermediates in the preparation of pharmacologically
relevant products and new heterocyclic systems.3 In recent years, 3-
formyl- and 3-acylchromones have attracted considerable attention
as highly reactive compounds, which can serve as the starting ma-
terials in syntheses of a whole series of heterocycles with useful
properties due to three strong electrophilic centers (carbon atoms C-
2 and C-4 of the chromone system and the RCO group).4 These
(1,2-addition), which does not exclude the variant of recyclization
due to the internal nucleophilic substitution.5
While 3-formylchromones 1 have been extensively investigated
regarding their chemical properties,4 little attention has been paid
toward the reactivity of 3-formylthiochromones 2, probably owing to
the lack of general methods for the preparation of these compounds.
Only a handful of papers describing some reactions of 3-for-
mylthiochromone 2 with a number of N-nucleophiles6 and such
C-nucleophiles as indolinium or benzothiazolinium salts,7 the Wit-
tigeHorner reagent of diethyl a
-(benzylthio)benzylphosphonate,8 and
malonic acid (with 3-formylthioflavone)9 are present in the literature.
All these reactions proceed by nucleophilic 1,2-addition to give 3-
substituted thiochromones without opening of the thiopyrone ring.
The first synthesis of thiochromone 2 from 3-(hydroxymethylene)
thiochroman-4-one 3 and N-chlorosuccinimide was reported by
Chen and Reynolds in 1979.10 However, on repeating their procedure,
Giles and Marson11 were unable to obtain 2; instead, they found that
this reactionafforded thechlorinated ketones:3-chlorothiochroman-
4-one, 3-chlorothiochromone, and 2,3-dichlorothiochrome. The re-
action of thiochroman-4-one 4 with the VilsmeiereHaack reagent
compounds possess a highly polarized C2eC3
p-bond and their
reactions with dinucleophiles start predominantly from the attack
of the unsubstituted C-2 atom (1,4-addition) and are accompanied
by pyrone ring-opening to form the
b-dicarbonyl intermediate
* Corresponding author. Fax: þ7 343 261 59 78; e-mail address: vyacheslav.
sosnovskikh@usu.ru (V.Ya. Sosnovskikh).
0040-4020/$ e see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tet.2010.06.066

V.Ya. Sosnovskikh et al. / Tetrahedron 66 (2010) 7322e7328
7323
affords 4-chloro-2H-thiochromene-3-carbaldehyde 5, however, with
excessof reagentat100 ꢀC for 4days, thiochromone2 was obtained in
29% yield together with aldehyde 5 as a major product (40% yield).11
An alternative synthesis of 3-formylthiochromone 2 relies on the
Sarett oxidation of 3-(hydroxymethyl)thiochromone 6, which in turn
was obtained by hydrolysis of 3-(bromomethyl)thiochromone.9 Very
recently,12 we reported the preparation of 2 in good yield (67%) via
a chlorinationedehydrochlorination sequence by treating of 3-for-
myl-4H-thiochroman-4-one 3 with sulfuryl chloride (Fig. 1). This
simple and convenient method allowed us to investigate some
chemical properties of the thiochromone system in more detail.
2D 1He13C HSQC and HMBC experiments. Consequently, structure
7 should be revised to 8 (Scheme 1).
4'
5'
3a'
O
O
N
6'
N
5
8
4
4a
8a
3
7a' 7'
6
7
2'
X
2
S
7a-d
X
S
8a-d
X
[O]
+
a
b
X = NH ( ), NMe ( ),
c
d
NPh ( ), S (
)
O
-
O
O
NH2
XH
CHO
CHO
CHO
+
S
X
X
2
1 (X = O), 2 (X = S)
1', 2'
p-NH2C6H4OMe
X = O
H
O
S
O
O
S
OMe
O
S
O
N
N
OH
3
4
S
9
10
Scheme 1.
Cl
S
O
S
CHO
CH2OH
On the other hand, we found that reaction of 2 with o-amino-
phenol gave only the known imine 9.6 A similar reaction with p-
anisidine in ethanol also proceeded at the formyl group to afford
compound 10 in 77% yield without the formation of any side
products arising from Michael-type addition onto the C-2 atom of
the thiopyrone moiety. It should be noted that, in contrast to the
arylimines derived from 1,17 products 9 and 10 are rather stable
compounds, which do not react with amines, alcohols, and water
under usual reaction conditions.
5
6
Figure 1.
2. Results and discussion
Continuing our studies on the synthetic potential of
3-substituted chromones,13 we were interested in the reactivity of
3-formylthiochromone 2. As mentioned above, some reactions of 2
with N-nucleophiles, such as hydroxylamine, hydrazine, ethyl-
enediamine, and primary aromatic amines, have already been
studied before.6 Condensation of 2 with o-phenylenediamines and
o-aminobenzenethiol was reported to afford 1-benzothiopyrano
[2,3-b]-1,5-benzodiazepines 7aec and 1-benzothiopyrano[2,3-b]-
1,5-benzothiazepine 7d in low yields (13e33%). However, the
seven-membered ring formation was not firmly established and in
light of the known behavior 3-formylchromones 1 in reactions with
o-phenylenediamine, which afforded 3-(benzimidazol-2-yl)chro-
mones,14,15 it was anticipated that the cyclization stage would
proceed via a 1,2-addition process (five-membered ring formation,
compounds 8aed) rather than the alternative intramolecular 1,4-
nucleophilic addition (compounds 7aed). We therefore repeated
the reactions of thiochromone 2 with o-phenylenediamines and o-
aminobenzenethiol following the literature method (ethanol,
reflux). Close scrutiny of the 1H spectral data provided in Ref. 6
revealed that the seven-membered structure 7 was assigned erro-
neously; the structural assignment of the reaction products as the
benzimidazole 8a and benzthiazole 8d was made on the basis of 1H
and 13C NMR spectral analysis and comparison of the spectroscopic
data with the data reported for related systems.14,16 In particular,
Recently,18 we have reported that the reaction of 3-for-
mylchromones 1 with indoles could proceed either as double ad-
dition at the CHO group (1,2-addition) or as 1,4-addition at C-2 with
concomitant opening of the pyrone ring and subsequent intra-
molecular cyclization due to the phenolic hydroxy and aldehyde
groups. The analogous reaction of 3-formylthiochromone 2 with
indole and its methylated derivatives occurred exclusively via 1,2-
addition. As in the case of aromatic aldehydes,19 this reaction does
not stop after mono-addition but affords bis-adducts 11aec in var-
iable yields 22e73%. The 1H and 13C NMR spectra of 11aec in DMSO-
d6 are characterized by twice the number of the indole protons and
carbons suggesting their equivalence. Owing to a deshielding effect
of the carbonyloxygen, the H-5 proton in these compounds is shifted
downfield to 8.3e8.4 ppm; the signal at ca.
d 6.3 ppm is due to the
resonance of the CH proton. (Thiochromon-3-yl)bis(indol-3-yl)
methanes 11aec represent a new class of tris(heteroaryl)methanes,
in which two different heterocycles with remarkably important bi-
ological and pharmaceutical activities are linked at the same carbon
atom. The reaction of 2 with malononitrile (reflux, water) afforded
the expected dicyanomethylidene derivative 12 in 68% yield. It is
obvious from these results and from the literature data6e9 that the
reactions of 2 with primary amines, indoles, and methylene active
compounds proceed exclusively by nucleophilic 1,2-addition of the
nucleophile to the formyl group rather than conjugate addition and
thiopyrone ring-opening (Scheme 2).
the benzimidazole protons of 8a (
d
7.18e7.24 m, H-50, H-60;
7.62e7.72 m, H-40, H-70; 12.74 s, NH) compare well with those
(d
7.18e7.23 m, H-50, H-60;
After a detailed study of the chemical behavior of 2 with dif-
ferent mono- and dinucleophiles, we have found that this com-
pound is much less reactive than 3-formylchromone 1 and mainly
behaves as an aromatic aldehyde. All attempts to obtain five- and
of 3-(benzimidazol-2-yl)chromone
7.63e7.70 m, H-40, H-70; 12.64 s, NH) the structure of which was
confirmed by X-ray diffraction analysis.14 In addition, all the signals
in the 1H and 13C NMR spectra of 8a were assigned on the basis of

7324
V.Ya. Sosnovskikh et al. / Tetrahedron 66 (2010) 7322e7328
a carbonyl band at 1610e1630 cmꢁ1, that is, considerably lower
R1
N
than those of chromones (1650e1670 cmꢁ1).
R2
O
The reaction of 2 with hydroxylamine represents a simple and
convenient method for the preparation of the hitherto unexplored 3-
cyanothiochromone 15, which we decided to use in the reactions with
N-nucleophiles in order to determine whether the cyano group in 15
influence the SeC bond cleavage. It is well-knownthat introduction of
the electron-withdrawing CNgroup at the 3-positionof thechromone
system significantly changes the reactivity of the pyrone ring with
respect to nucleophiles, and provides broad synthetic potential for
3-cyanochromone.22 Among the diverse transformations of this
compound, one of the most important is its conversion, under basic
conditions, into 2-amino-3-formylchromone. The reaction includes
the nucleophilic 1,4-additionwith concomitantopening of the pyrone
ring and subsequent intramolecular cyclization at the cyano group.
Unfortunately, all our attempts to prepare 2-amino-3-for-
mylthiochromone from 15 underavarietyof conditions were fruitless.
Very recently,23 we have shownthat the initial Michael addition of
phenylhydrazine to 3-cyanochromone, depending on the reaction
conditions, leads to three different types of products, 5-amino-4-
R2
N
R1
2
N
R2
S
NCCH2CN
O
R1
11a-c
1 = R2 = H ( );
CN
CN
a
R
R1 = H, R2 = Me ( );
b
R1 = Me, R2 = H (c)
S
12
Scheme 2.
six-membered heterocycles from 2 and dinucleophiles, such as
hydroxylamine, hydrazines, and amidines under the same condi-
tions that had previously been used for the corresponding reactions
of 3-formylchromone 1,4,5,13 failed. In all cases, the reactions pro-
ceeded without cleavage of the thiopyrone ring and only 1,2-ad-
dition at the aldehyde group took place, leading to 3-substituted
thiochromones. Thus, we were unable to recyclise phenyl-
hydrazone 13, prepared from 2 and phenylhydrazine base (reflux,
benzene, 4 h), into the corresponding pyrazole 130 under a variety
of conditions. Also, it is known that the reactions of 2 with hydra-
zine and hydroxylamine result in the formation of azine 146
and 3-cyanothiochromone 159 as the sole products, whereas
3-formylchromone 1 easily reacts with these reagents affording
a number of rearranged products4,5,13 (Scheme 3).
salicyloyl-1-phenylpyrazole,
2-aminochromone-3-carbaldehyde
phenylhydrazone, and 1-phenylchromeno[4,3-c]pyrazol-4(1H)-one,
and the 1,2-addition at the CN group was not observed at all. As the
unsubstituted C-2 atom of 3-cyanochromones is more susceptible to
nucleophilic attack than the cyano group, we thought that this Mi-
chael-type addition could possibly be extended to the thiochromone
series. Indeed, we found thatthe reactionof 15 with phenylhydrazine,
carried out in refluxing benzene in the presence of a catalytic amount
of triethylamine, gave a new product in 67% yield. This compound
was characterized as the phenylhydrazone of 2-amino-3-for-
mylthiochromone 16, which represents a new derivative of the
2-aminothiochromone family. Previously, 3-substituted 2-amino-
thiochromones were obtained via a C-acylation reaction of active
methylene compounds with thiosalicylic acid derivatives followed by
an in situ cyclization reaction24 and from 2-methylthio-3-cyano-
thiochromones under the action of amines.25 In our case, a Michael
addition takes place leading to cleavage of the SeC bond (this is a rare
case of the SeC bond cleavage in the thiochromone series; other ex-
amples see Ref. 8,26). It is noteworthy that due to the chemical
equivalency of the 3-CHO group and C-2 (masked aldehydic group)
the formation of hydrazone 13 from 2 can be explained by both 1,2-
and 1,4-addition, whereas the structure of hydrazone 16 indicates
unambiguously the primary attack at C-2 (intermediate A) followed
by recyclizationwith the participation of the cyano group (Scheme 3).
In accordance with this, when 3-cyanothiochromone 15 was
treated with benzylamine and p-anisidine at reflux in toluene in the
presence of a catalytic amount of triethylamine for 1 and 12 h, re-
spectively, 2-amino-3-(benzyliminomethyl)- and 2-amino-3-(ani-
syliminomethyl)thiochromones 17 and 18 were formed as the sole
products. In the lightof this finding weenvisaged that the reaction of
15 with o-phenylenediaminewould produce the corresponding anil.
Indeed, we found that 15 smoothly reacted with 2 equiv of o-phe-
nylenediamine under the same conditions to produce the expected
2-amino-3-[(2-aminophenyl)iminomethyl]thiochromone 19 in 64%
yield (Scheme 4). This behavior of 3-cyanothiochromone 15 closely
resembles that already reported27 for 3-cyanochromone and clearly
indicates that the C-2 atom of 15 is susceptible to nucleophilic attack
and makes it an attractive building block for the synthesis of 2-
aminothiochromone derivatives. The latter have attracted consid-
erable interest because of their biological significance.24
O
S
SH
O
N
N
N
Ph
2
13'
14
N2H4
X
NH2NHPh
2
X
NH2OH
O
O
S
NHPh
NHPh
CN
N
S
15
13
NH2NHPh
SH
O
O
S
NHNHPh
N
CN
NH2
A
16
Scheme 3.
The observed striking differences in reactivity between 1 and 2
appears to be connected with the difficulty met by the nucleophile
in cleaving the thiopyrone SeC bond arising from the less elec-
tronegative character of the sulfur atom, which strongly reduces
the electrophilicity of the 2-position, and the greater aromaticity of
the thiochromone system as compared with chromones (structures
10 and 20, Fig. 1). In fact, there is some double-bond character to
Interestingly, when 17 was treated with benzylamine and
triethylamine in refluxing toluene for 12 h, 2,6,9-triazabicyclo
[3.3.1]nonane 20 incorporating an annelated thiochromone sys-
tem was isolated in 28% yield. To the best of our knowledge, the
only example of 2,6,9-triazabicyclo[3.3.1]nonanes with fused
heterocyclic ring system are derivatives, which were obtained by
20
ꢀ
ꢀ
S1eC2 (1.712 A) and C3eC4 (1.457 A) in 3-formylthiochromone 2,
indicating a significant contribution of the resonance form 20 in-
volving the delocalization of the lone pair on sulfur into the car-
bonyl (for thiophene S1eC2 (1.712 A)).21 This delocalization is also
ꢀ
reflected in the IR spectra of thiochromone derivatives, which have

V.Ya. Sosnovskikh et al. / Tetrahedron 66 (2010) 7322e7328
7325
which were converted into the known benzimidazoles 22a,b14,15c,32 at
reflux in acetic acid for 3 h (Scheme 5). A possible mechanism for the
transformation of 21 into 22, which includes several additioneelimi-
nation sequences, has been suggested by us in preceding communi-
cation.27 Compounds 21a and 22a were used for comparison of their
spectral data with those of derivatives 8a and 19.
O
S
NH
N
N
S
Bn
N
N
H
20
O
20'
PhMe
NH2
O
O
O
O
O
S
O
S
R
CN
R
NH2
CN
CH2Ph
N
PhCH2NH2
N
C6H6/Et3N
NH2
NH2
Hb
N
Ha
15
17
21a-c
AcOH
NH2
NH2
H2N
O
OMe
O
O
N
R
OMe
N
H
O
S
R = H (a), Me (b), Cl (c)
22a,b
N
N
Hb
Hb
NH2
Scheme 5.
S
N
N
Ha
Ha
19
18
3. Conclusion
Scheme 4.
In conclusion, we have shown that 3-formylthiochromone re-
acts with primary aromatic amines, phenylhydrazine, and indoles
at the aldehyde group to give the corresponding addition products
in good yields. At the same time, the reactions of 3-cyanothio-
chromone with primary amines and phenylhydrazine proceed as
1,4-nucleophilic addition with subsequent opening of the thiopyr-
one ring and cyclization with the participation of the cyano group
reaction of 5-amino-3,4-diphenylthieno[2,3-c]pyridazine-6-car-
baldehyde with aliphatic primary amines.28 The main interest of
€
these compounds lies in their structural similarity to Troger’s
bases 200, which provide relatively rigid chiral frameworks for the
construction of chelating and biomimetic systems.29 A suitable
mechanism for the formation of tetrahydro[1,5]diazocines has
been reported.28,30
into
imines
and
phenylhydrazone
of
2-amino-3-for-
mylthiochromone. Thus, a hitherto unknown reactivity pattern of
the thiochromone system was observed.
It can be concluded from these data that the electron-with-
drawing cyano group enhances the electrophilicity of the C-2 atom
of 15 and thus favors both 1,4-addition and cyclization of an open
intermediate to the final product. This is a novel approach to the
synthesis of 3-substituted 2-aminothiochromones, which has ad-
vantages with regard to ease of operation and the ready availability
of starting materials. However, in contrast to the results found in
the 3-cyanochromone series,13 the expected products were not
formed in the reaction of 15 with hydroxylamine. Presumably, the
amino group of hydroxylamine was not nucleophilic enough to add
to the C-2 position, which was rendered somewhat less electro-
philic by the adjacent lone pair on sulfur.
4. Experimental
4.1. General
1H (400 MHz) and 13C (100 MHz) NMR spectra were recorded on
a Bruker DRX-400 spectrometer in DMSO-d6 and CDCl3 with TMS as
an internal standard. IR spectra were recorded on a PerkineElmer
Spectrum BX-II instrument (KBr) and Bruker Alpha instrument
(ATR, ZnSe). Elemental analyses were performed at the Micro-
analysis Services of the Institute of Organic Synthesis, Ural Branch,
Russian Academy of Sciences. All solvents used were dried and
distilled per standard procedures. The starting 3-formyl-4H-thio-
The 1H NMR spectra of thiochromone derivatives 17e19 in
DMSO-d6 consisted of a characteristic singlet due to the CH]N
proton at
d
9.0e9.2 ppm and two singlets due to the resonances of
chroman-4-one
3
was prepared according to described
the non-equivalent NH2 protons at
d
9.1e9.3 (Ha) and
procedure.12
11.5e11.8 ppm (Hb). Addition of CD3CO2D resulted in the disap-
pearance of the two latter signals. It is reasonable to assume that
the non-equivalence of the NH2 protons is connected with an
intramolecular hydrogen bond involving Hb and the imine nitrogen
atom. This explains the formation of E-anils 17e19, exclusively. The
most interesting feature of the 1H NMR spectrum of the pseudo-
4.1.1. 4-Oxo-4H-thiochromene-3-carbaldehyde (2). Freshly distilled
SO2Cl2 (1.5 g, 11.4 mmol) was added carefully to a well stirred so-
lution of 3-formylthiochroman-4-one 3 (2.0 g, 10.4 mmol) in CHCl3
(100 mL). After stirring at rt for 20 h, the formed orange solution
was evaporated under reduced pressure. The resulting brown semi-
solid was purified by filtration through a pad of silica gel (10 cm, the
elution solventeCHCl3) to give a product as a yellow powder. Yield
1.3 g (67%), mp 157e158 ꢀC (lit.11b mp 162e163 ꢀC); 1H NMR
€
Troger’s base 20 is the anisochrony of the NeCH2 protons reflecting
its chiral nature (AB-system with 2JAB¼13.0 Hz at 3.64 ppm); the CH
protons appear as singlet at
d 5.35 ppm while the NH protons res-
onate at 9.5 ppm (slightly broad).
(200 MHz, CDCl3) d 7.60e7.75 (m, 3H, H-6, H-7, H-8), 8.63 (m,1H, H-
5), 8.79 (s, 1H, H-2), 10.40 (s, 1H, CHO).
Recently,27 we reported on the reaction of unsubstituted 3-cyano-
chromone with o-phenylenediamine at reflux in ethanol (benzene can
also be used) and on the basis of 1Hand13CNMRspectroscopyusing2D
HSQC, HMBC, and NOESY experiments found that in contrast to the
literature data,31,32 the product was 2-amino-3-[(2-aminophenyl)imi-
nomethyl]chromone 21a. Now we have extended this reaction to
6-substituted 3-cyanochromones and obtained compounds 21aec,
4.2. Compounds 8e10
4.2.1. 3-(1H-Benzimidazol-2-yl)-4H-thiochromen-4-one (8a).
This compound was prepared from thiochromone
2 and

7326
V.Ya. Sosnovskikh et al. / Tetrahedron 66 (2010) 7322e7328
o-phenylenediamine according to the procedure described pre-
viously.6a Yield 140 mg (34%), mp 246e248 ꢀC (lit.6a mp
1H, H-6, J¼8.2, 7.2,1.2 Hz), 7.72 (ddd, 1H, H-7, J¼8.2, 7.2, 1.4 Hz), 7.85
(d, 1H, H-8, J¼8.2 Hz), 7.95 (s, 1H, H-2), 8.42 (dd, 1H, H-5, J¼8.2,
1.4 Hz), 10.85 (d, 2H, 2NH, J¼1.8 Hz). Anal. Calcd for C26H18N2OS: C,
76.82; H, 4.46; N, 6.89. Found: C, 76.56; H, 4.52; N, 6.64.
247e248 ꢀC); 1H NMR (400 MHz, DMSO-d6)
d 7.18e7.24 (m, 2H, H-
50, H-60), 7.62e7.72 (m, 2H, H-40, H-70), 7.77 (ddd, 1H, H-6, J¼8.2, 7.2,
1.2 Hz), 7.86 (ddd, 1H, H-7, J¼8.2, 7.2, 1.5 Hz), 8.08 (dd, 1H, H-8,
J¼8.2, 1.0 Hz), 8.62 (dd, 1H, H-5, J¼8.2, 1.4 Hz), 9.71 (s, 1H, H-2),
4.3.2. 3-Di(2-methylindol-3-yl)methyl-4H-thiochromen-4-one
12.74 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6)
d
113.2 (C40/C70),
(11b). Yield 330 mg (73%), yellow powder, mp 310e312 ꢀC; IR (KBr)
118.7 (C70/C40), 122.3 (C50/C60), 122.7 (C60/C50), 123.8 (C3), 128.1
(C8), 128.7 (C5), 129.2 (C7), 132.2 (C4a), 132.7 (C6), 134.9 (C3a0),
137.0 (C8a), 142.8 (7a0), 143.6 (C2), 148.1 (C20), 177.6 (C4).
3404, 3258, 1603, 1586, 1539 cmꢁ1 1H NMR (400 MHz, DMSO-d6)
;
d
2.08 (s, 6H, 2 Me), 6.17 (s, 1H, CH), 6.71 (ddd, 2H, 2H-50, J¼7.8, 7.1,
0.9 Hz), 6.90 (ddd, 2H, 2H-60, J¼8.0, 7.1, 1.0 Hz), 6.98 (d, 2H, 2H-40,
J¼8.0 Hz), 7.22 (d, 2H, 2H-70, J¼8.0 Hz), 7.59 (ddd, 1H, H-6, J¼8.2,
7.2, 1.1 Hz), 7.71 (ddd, 1H, H-7, J¼8.3, 7.2, 1.4 Hz), 7.80 (s, 1H, H-2),
7.87 (d, 1H, H-8, J¼8.2 Hz), 8.32 (dd, 1H, H-5, J¼8.2, 1.4 Hz), 10.77 (s,
4.2.2. 3-(1,3-Benzothiazol-2-yl)-4H-thiochromen-4-one (8d). This
compound was prepared from thiochromone 2 and o-amino-
thiophenol according to the procedure described previously.6b
Yield 105 mg (28%), mp 183e185 ꢀC (lit.6b mp 187e188 ꢀC); 1H
2H, 2 NH); 13C NMR (100 MHz, DMSO-d6)
d 12.5, 35.3, 110.5, 111.0,
118.4, 118.7, 120.1, 127.6, 128.1, 128.7, 128.8, 131.4, 131.9, 132.9, 135.5,
136.1, 137.5, 138.6, 178.0. Anal. Calcd for C28H22N2OS: C, 77.39; H,
5.10; N, 6.45. Found: C, 77.10; H, 5.04; N, 6.31.
NMR (400 MHz, DMSO-d6)
d
7.47 (ddd, 1H, H-60, J¼8.0, 7.2, 1.1 Hz),
7.56 (ddd, 1H, H-50, J¼8.0, 7.2, 1.3 Hz), 7.78 (ddd, 1H, H-6, J¼8.1, 7.2,
1.2 Hz), 7.87 (ddd, 1H, H-7, J¼8.0, 7.2, 1.5 Hz), 8.06 (ddd, 1H, H-70,
J¼8.0, 1.1, 0.7 Hz), 8.10 (ddd, 1H, H-8, J¼8.0, 1.2, 0.5 Hz), 8.18 (ddd,
1H, H-40, J¼8.0, 1.3, 0.7 Hz), 8.61 (ddd, 1H, H-5, J¼8.1, 1.5, 0.5 Hz),
4.3.3. 3-Di(1-methylindol-3-yl)methyl-4H-thiochromen-4-one
(11c). Yield 200 mg (58%), pink powder, mp 284e286 ꢀC; IR (KBr)
9.89 (s, 1H, H-2); 1H NMR (400 MHz, CDCl3)
d
7.41 (ddd, 1H, H-60,
1613, 1588, 1547 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d 3.69 (s, 6H,
J¼8.0, 7.2, 1.0 Hz), 7.51 (ddd, 1H, H-50, J¼8.2, 7.2, 1.2 Hz), 7.64e7.75
(m, 3H, H-6, H-7, H-8), 8.00 (d, 1H, H-70, J¼8.0 Hz), 8.05 (d, 1H, H-40,
J¼8.2 Hz), 8.77 (dd, 1H, H-5, J¼7.5, 1.8 Hz), 9.56 (s, 1H, H-2); 13C
2 Me), 6.33 (s, 1H, CH), 6.87 (s, 2H, 2H-20), 6.95 (ddd, 2H, 2H-50,
J¼7.9, 7.1, 0.9 Hz), 7.13 (ddd, 2H, 2H-60, J¼8.1, 7.1, 1.0 Hz), 7.33 (d, 2H,
2H-40, J¼7.9 Hz), 7.39 (d, 2H, 2H-70, J¼8.2 Hz), 7.62 (ddd, 1H, H-6,
J¼8.2, 7.2, 1.2 Hz), 7.72 (ddd, 1H, H-7, J¼8.2, 7.2, 1.4 Hz), 7.86 (d, 1H,
H-8, J¼8.2 Hz), 7.94 (s, 1H, H-2), 8.41 (dd, 1H, H-5, J¼8.2, 1.4 Hz); 13C
NMR (100 MHz, DMSO-d6)
d
122.4 (C40/70), 122.7 (C70/40), 125.4
(C3), 126.4 (C50/60), 126.7 (C60/50), 128.0 (C8), 128.9 (C5), 129.3 (C7),
131.7 (C4a), 132.7 (C6), 136.4 (C7a0), 136.6 (C8a), 143.7 (C2), 151.6
(C3a0),160.7 (C20),176.7 (C4). Anal. Calcd for C16H9NOS2: C, 65.06; H,
3.07; N, 4.74. Found: C, 65.09; H, 2.99; N, 4.51.
NMR (100 MHz, DMSO-d6)
d 32.8, 33.7, 110.2, 116.0, 119.0, 119.4,
121.7, 127.2, 127.7, 128.1, 128.8, 128.9, 131.6, 131.9, 136.4, 137.6 (2C),
138.7, 177.8. Anal. Calcd for C28H22N2OS: C, 77.39; H, 5.10; N, 6.45.
Found: C, 77.24; H, 4.99; N, 6.34.
4.2.3. 3-[(2-Hydroxyphenyl)iminomethyl]-4H-thiochromen-4-one
(9). This compound was prepared from thiochromone 2 and o-
aminophenol according to the procedure described previously.6b
Yield 120 mg (91%), mp 193e194 ꢀC (lit.6b mp 190e191 ꢀC); 1H
4.3.4. 2-[(4-Oxo-4H-thiochromen-3-yl)methylene]malononitrile
(12). A mixture of 2 (200 mg, 1.05 mmol), malononitrile (70 mg,
1.06 mmol), and water (7 mL) was heated to reflux for 3 h. After
cooling, the resulting solid was filtered, dried, and recrystallized
from xylene. Yield 170 mg (68%), brown cubic crystals, mp
220e222 ꢀC; IR (KBr) 3019, 2226, 2172, 1623, 1585, 1559,
NMR (400 MHz, DMSO-d6)
d
6.85 (td, 1H, H-50, J¼7.5, 1.3 Hz), 6.91
(dd, 1H, H-30, J¼8.1, 1.3 Hz), 7.11 (ddd, 1H, H-40, J¼8.1, 7.2, 1.5 Hz),
7.22 (dd, 1H, H-60, J¼7.9, 1.5 Hz), 7.72 (ddd, 1H, H-6, J¼8.1, 7.2,
1.2 Hz), 7.82 (ddd, 1H, H-7, J¼8.2, 7.2, 1.5 Hz), 8.01 (dd, 1H, H-8,
J¼8.2, 1.0 Hz), 8.49 (dd, 1H, H-5, J¼8.1, 1.5 Hz), 8.99 (s, 1H, HC]N),
9.07 (s, 1H, OH), 9.53 (s, 1H, H-2).
1515 cmꢁ1 1H NMR (400 MHz, DMSO-d6)
; d 7.74 (t, 1H, H-6,
J¼7.6 Hz), 7.86 (t 1H, H-7, J¼7.6 Hz), 8.04 (d, 1H, H-8, J¼8.0 Hz), 8.42
(s, 1H, ]CH), 8.43 (d, 1H, H-5, J¼8.0 Hz), 9.36 (s, 1H, H-2). Anal.
Calcd for C13H6N2OS: C, 65.53; H, 2.54; N, 11.76. Found: C, 65.58; H,
2.30; N, 11.50.
4.2.4. 3-[(4-Methoxyphenyl)iminomethyl]-4H-thiochromen-4-one
(10). A mixture of 2 (200 mg, 1.05 mmol), p-anisidine (135 mg,
1.1 mmol), and ethanol (6 mL) was refluxed for 5 h. After cooling, the
resulting solid was filtered, washed with ethanol, and dried. Yield
240 mg (77%), orange powder, mp 152e153 ꢀC; IR (ATR, ZnSe) 1620,
4.4. Compounds 13, 15e19
4.4.1. 4-Oxo-4H-thiochromene-3-carbaldehyde N-phenylhydrazone
(13). A solution of 2 (150 mg, 0.79 mmol) and phenylhydrazine
(90 mg, 0.83 mmol) in benzene (4 mL) was heated to reflux for 4 h.
After cooling, the resulting solid was filtered, washed with benzene,
and dried. Yield 130 mg (57%), orange cubic crystals, mp
222e224 ꢀC; IR (KBr) 3244, 1603, 1587, 1573, 1554, 1526,
1605, 1589, 1567, 1529, 1498 cmꢁ1 1H NMR (400 MHz, DMSO-d6)
;
d
3.79 (s, 3H, MeO), 7.00 (d, 2H, Ar, J¼8.9 Hz), 7.29 (d, 2H, Ar, J¼8.9 Hz),
7.71 (ddd, 1H, H-6, J¼8.1, 7.2, 1.2 Hz), 7.81 (ddd, 1H, H-7, J¼8.2, 7.2,
1.5 Hz), 8.00 (dd, 1H, H-8, J¼8.2, 1.0 Hz), 8.48 (dd, 1H, H-5, J¼8.1,
1.5 Hz), 8.87 (s, 1H, HC]N), 9.22 (s, 1H, H-2). Anal. Calcd for
C17H13NO2S:C, 69.13;H, 4.44;N,4.74. Found:C, 69.02;H, 4.39; N,4.56.
1494 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d
6.77 (tt, 1H, H-40, J¼7.3,
1.1 Hz), 7.10 (dd, 2H, H-20, H-60, J¼8.5, 1.1 Hz), 7.23 (dd, 2H, H-30, H-
50, J¼8.5, 7.3 Hz), 7.66 (ddd, 1H, H-6, J¼8.1, 7.1, 1.2 Hz), 7.76 (ddd, 1H,
H-7, J¼8.2, 7.1, 1.5 Hz), 7.95 (dd, 1H, H-8, J¼8.2, 0.8 Hz), 8.24 (s, 1H,
HC]N), 8.45 (dd, 1H, H-5, J¼8.1, 1.5 Hz), 8.88 (s, 1H, H-2), 10.61 (s,
4.3. General procedure for the synthesis of 3-di(indol-3-yl)
methylthiochromones (11aec)
A mixture of 2 (200 mg, 1.05 mmol) and the corresponding in-
dole (3.2 mmol) was heated for 7e8 h at 90e95 ꢀC. The resulting
solid was recrystallized from xyleneebutanol to give compound 11.
1H, NH); 13C NMR (100 MHz, DMSO-d6)
d 112.6, 119.5, 128.0, 128.5,
128.6, 129.6, 129.7, 131.3, 131.6, 132.2, 133.4, 137.2, 145.5, 177.5. Anal.
Calcd for C16H12N2OS: C, 68.55; H, 4.31; N, 9.99. Found: C, 68.17; H,
4.00; N, 9.87.
4.3.1. 3-Di(indol-3-yl)methyl-4H-thiochromen-4-one
(11a). Yield
65 mg (22%), pale violet powder, mp 235e236 ꢀC; IR (ATR, ZnSe)
4.4.2. 4-Oxo-4H-thiochromene-3-carbonitrile (15). This compound
was prepared according to the procedure described earlier.9 Yield
570 mg (83%), orange crystals, mp 227e229 ꢀC (lit.9 mp
3407, 3388, 3293, 1599, 1576, 1539 cmꢁ1 1H NMR (400 MHz,
;
DMSO-d6)
d
6.35 (s, 1H, CH), 6.87 (d, 2H, 2H-20, J¼1.8 Hz), 6.90 (ddd,
2H, 2H-50, J¼7.9, 7.1, 0.9 Hz), 7.05 (ddd, 2H, 2H-60, J¼8.0, 7.1, 1.0 Hz),
229e230 ꢀC); 1H NMR (400 MHz, DMSO-d6)
d
7.75 (ddd, 1H, H-6,
7.32 (d, 2H, 2H-40, J¼8.0 Hz), 7.36 (d, 2H, 2H-70, J¼8.1 Hz), 7.61 (ddd,
J¼8.1, 7.2, 1.2 Hz), 7.87 (ddd, 1H, H-7, J¼8.2, 7.2, 1.5 Hz), 8.05 (ddd,

V.Ya. Sosnovskikh et al. / Tetrahedron 66 (2010) 7322e7328
7327
1H, H-8, J¼8.2, 1.2, 0.5 Hz), 8.40 (ddd, 1H, H-5, J¼8.1, 1.5, 0.5 Hz),
mp 242e243 ꢀC; IR (ATR, ZnSe) 3243, 3211, 1595, 1574, 1561,
1504 cmꢁ1 1H NMR (400 MHz, DMSO-d6)
3.64 (AB-system, 2H,
9.45 (s, 1H, H-2).
;
d
CH2, J¼13.0 Hz), 5.35 (s, 2H, 2 CH), 7.27e7.38 (m, 5H, Ph), 7.46
(ddd, 2H, 2H-6, J¼8.0, 7.3, 1.2 Hz), 7.56 (td, 2H, 2H-7, J¼7.5,
1.5 Hz), 7.63 (dd, 2H, 2H-8, J¼8.0, 1.0 Hz), 8.24 (dd, 2H, 2H-5,
J¼8.0, 1.5 Hz), 9.50 (br s, 2H, 2 NH); 13C NMR (100 MHz, DMSO-
4.4.3. 2-Amino-4-oxo-4H-thiochromene-3-carbaldehyde N-phenyl-
hydrazone (16). A mixture of 15 (200 mg, 1.07 mmol), phenyl-
hydrazine (140 mg, 1.28 mmol), and two drops of triethylamine in
toluene (5 mL) was heated to reflux for 5 h. After cooling, the
resulting solid was filtered, washed with toluene, and dried. Yield
210 mg (67%), gold plates, mp 250e252 ꢀC; IR (KBr) 3251, 1600,
d6)
d 53.1, 61.0, 106.2, 126.0, 126.8, 127.5, 128.4, 129.1, 129.4, 131.0,
132.2, 137.2, 153.4, 174.6. Anal. Calcd for C27H19N3O2S2: C, 67.34;
H, 3.98; N, 8.73. Found: C, 66.95; H, 3.63; N, 8.62.
1573, 1530, 1509, 1488 cmꢁ1 1H NMR (400 MHz, DMSO-d6)
; d 6.72
(t, 1H, H-40, J¼7.3 Hz), 6.87 (dd, 2H, H-20, H-60, J¼8.4, 1.0 Hz), 7.22
(dd, 2H, H-30, H-50, J¼7.4, 8.4 Hz), 7.49 (ddd, 1H, H-6, J¼8.2, 6.9,
1.5 Hz), 7.61 (td, 1H, H-7, J¼7.5, 1.5 Hz), 7.65 (dd, 1H, H-8, J¼8.0,
1.0 Hz), 8.30 (dd,1H, H-5, J¼8.0,1.5 Hz), 8.69 (s,1H, HC]N), 9.35 (br
4.5. General procedure for the synthesis of 2-amino-3-[(2-
aminophenyl)iminomethyl]-4H-chromen-4-ones (21aec)
s, 2H, NH2), 10.15 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6)
d
103.4,
A solution of the corresponding 3-cyanochromone (1.0 mmol),
o-phenylenediamine (1.0 mmol) and two drops of triethylamine in
benzene or ethanol (5 mL) was heated to reflux for 3e4 h. Then the
reaction mixture was cooled and the formed precipitate filtered,
washed with benzene, and dried.
111.8, 118.7, 126.2, 127.3, 128.5, 129.2, 129.7, 131.6, 131.8, 139.7, 145.6,
157.8, 176.8. Anal. Calcd for C16H13N3OS: C, 65.06; H, 4.44; N, 14.23.
Found: C, 65.05; H, 4.16; N, 14.15.
4.4.4. 2-Amino-3-[(benzyl)iminomethyl]-4H-thiochromen-4-one
(17). A mixture of 15 (150 mg, 0.8 mmol), benzylamine (85 mg,
0.8 mmol), and two drops of triethylamine in toluene (3 mL) was
heated to reflux for 1 h. After cooling, the resulting solid was filtered,
washed with toluene, then ether and dried. Yield 170 mg (73%), pale
yellow powder, mp 218e219 ꢀC; IR (KBr) 3236, 3210, 1615, 1590,
4.5.1. 2-Amino-3-[(2-aminophenyl)iminomethyl]-4H-chromen-4-
one (21a). Yield 230 mg (48%), yellow cubic crystals, mp
218e219 ꢀC (ethanol) (lit.32 mp 217 ꢀC); IR (KBr) 3330, 3180, 1664,
1601, 1559, 1521, 1498, 1462 cmꢁ1 1H NMR (400 MHz, DMSO-d6)
;
d
5.02 (s, 2H, NH2), 6.59 (ddd, 1H, H-50, J¼7.8, 7.3, 1.0 Hz), 6.73
1576, 1527, 1509 cmꢁ1
;
1H NMR (400 MHz, DMSO-d6)
d
4.73 (s, 2H,
(dd, 1H, H-30, J¼7.8, 0.8 Hz), 6.87 (dd, 1H, H-60, J¼7.8, 0.8 Hz), 6.93
(ddd, 1H, H-40, J¼7.8, 7.3, 1.0 Hz), 7.41e7.47 (m, 2H, H-6, H-8), 7.71
(ddd, 1H, H-7, J¼8.2, 7.4, 1.6 Hz), 8.06 (dd, 1H, H-5, J¼7.7, 1.6 Hz),
8.91 (s, 1H, HC]N), 9.30 (s, 1H, NH), 10.39 (s, 1H, NH). Anal. Calcd
for C16H13N3O2: C, 68.81; H, 4.69; N, 15.05. Found: C, 69.04; H,
4.67; N, 15.09.
CH2), 7.24e7.38 (m, 5H, Ph), 7.45e7.50 (m, 1H, H-6), 7.58e7.62 (m,
2H, H-7, H-8), 8.28 (d,1H, H-5, J¼7.7 Hz), 9.03 (s, 1H, HC]N), 9.08 (br
s, 1H, NH), 11.81 (br s, 1H, NH). Anal. Calcd for C17H14N2OS: C, 69.36;
H, 4.79; N, 9.52. Found: C, 68.94; H, 4.52; N, 9.22.
4.4.5. 2-Amino-3-[(4-methoxyphenyl)iminomethyl]-4H-thiochro-
men-4-one (18). A mixture of 15 (150 mg, 0.8 mmol), p-anisidine
(110 mg, 0.9 mmol), and two drops of triethylamine in toluene (4 mL)
was heated to reflux for 12 h. After cooling, the resulting solid was
filtered, washed with toluene, and recrystallized from butanol. Yield
70 mg (28%), pale yellow powder, mp 203e205 ꢀC; IR (KBr) 3178,
4.5.2. 2-Amino-3-[(2-aminophenyl)iminomethyl]-6-methyl-4H-
chromen-4-one (21b). Yield 180 mg (38%), yellow powder, mp
244e245 ꢀC (ethanol); IR (KBr) 3340, 1663, 1607, 1561, 1499,
1474 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d 2.41 (s, 3H, Me), 4.99 (s,
2H, NH2), 6.58 (td, 1H, H-50, J¼7.5, 1.4 Hz), 6.72 (dd, 1H, H-30, J¼7.9,
1.4 Hz), 6.86 (dd, 1H, H-60, J¼7.9, 1.4 Hz), 6.92 (td, 1H, H-40, J¼7.5,
1.4 Hz), 7.34 (d, 1H, H-8, J¼8.4 Hz), 7.51 (ddq, 1H, H-7, J¼8.4, 2.3,
0.6 Hz), 7.84 (dq, 1H, H-5, J¼2.3, 0.6 Hz), 8.90 (s, 1H, HC]N), 9.22
(br s, 1H, NH), 10.35 (br s, 1H, NH). Anal. Calcd for C17H15N3O2: C,
69.61; H, 5.15; N, 14.33. Found: C, 69.84; H, 5.06; N, 14.49.
3056, 1638, 1601, 1590, 1575, 1544, 1505 cmꢁ1 1H NMR (400 MHz,
;
DMSO-d6)
d
3.77 (s, 3H, MeO), 6.97 (d, 2H, H-30, H-50, J¼8.9 Hz), 7.22
(d, 2H, H-20, H-60, J¼8.9 Hz), 7.48e7.53 (m 1H, H-6), 7.61e7.66 (m, 2H,
H-7, H-8), 8.30(d,1H, H-5, J¼8.0 Hz), 9.15 (s,1H, HC]N), 9.30(br s,1H,
NH),11.73(brs,1H, NH).Anal. CalcdforC17H14N2O2S:C,65.79;H, 4.55;
N, 9.03. Found: C, 65.44; H, 4.24; N, 8.84.
4.5.3. 2-Amino-6-chloro-3-[(2-aminophenyl)iminomethyl]-4H-chro-
4.4.6. 2-Amino-3-[(2-aminophenyl)iminomethyl]-4H-thiochromen-
4-one (19). A mixture of 15 (200 mg, 1.07 mmol), o-phenylenedi-
amine (240 mg, 2.22 mmol), and two drops of triethylamine in
toluene (5 mL) was heated to reflux for 7 h. After cooling, the
resulting solid was filtered, washed with toluene, and dried. Yield
200 mg (64%), yellow powder, mp 208e210 ꢀC; IR (ATR, ZnSe) 3395,
men-4-one (21c). Yield 295 mg (64%), yellow powder, mp
248e250 ꢀC; IR (KBr) 3212, 1654, 1605, 1553, 1497, 1457 cmꢁ1 1H
;
NMR (400 MHz, DMSO-d6)
d
5.01 (s, 2H, NH2), 6.58 (td, 1H, H-50,
J¼7.5, 1.4 Hz), 6.72 (dd, 1H, H-30, J¼7.9, 1.4 Hz), 6.87 (dd, 1H, H-60,
J¼7.9, 1.4 Hz), 6.92 (td, 1H, H-40, J¼7.5, 1.4 Hz), 7.51 (d, 1H, H-8,
J¼8.8 Hz), 7.74 (dd, 1H, H-7, J¼8.8, 2.7 Hz), 7.96 (d, 1H, H-5,
J¼2.7 Hz), 8.88 (s, 1H, HC]N), 9.40 (br s, 1H, NH), 10.42 (br s, 1H,
NH). Anal. Calcd for C16H12ClN3O2: C, 61.25; H, 3.86; N, 13.39.
Found: C, 61.36; H, 3.76; N, 13.10.
1576, 1549, 1486 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d 4.99 (s, 2H,
NH2), 6.59 (td, 1H, H-40, J¼7.6, 1.3 Hz), 6.72 (dd, 1H, H-30, J¼7.9,
1.2 Hz), 6.88 (dd, 1H, H-60, J¼7.8, 1.2 Hz), 6.93 (td, 1H, H-50, J¼7.5,
1.3 Hz), 7.48e7.53 (m, 1H, H-6), 7.61e7.66 (m, 2H, H-7, H-8), 8.31 (d,
1H, H-5, J¼8.0 Hz), 9.10 (s, 1H, HC]N), 9.25 (br s, 1H, NH), 11.46 (br
s, 1H, NH); 13C NMR (100 MHz, DMSO-d6)
d
104.5, 115.2, 117.3, 118.5,
4.6. 3-(Benzimidazol-2-yl)chromones 22a,b
126.3,126.8,127.6,128.5,129.4,131.9,132.1,138.0,142.7,158.3,163.1,
177.9. Anal. Calcd for C16H13N3OS: C, 65.06; H, 4.44; N, 14.23; S,
11.06. Found: C, 65.11; H, 4.41; N, 14.21; S, 10.99.
4.6.1. 3-(1H-Benzimidazol-2-yl)-4H-chromen-4-one (22a). A solu-
tion of 21a (480 mg, 1.72 mmol), in acetic acid (10 mL) was heated
to reflux for 3 h. Then the reaction mixture was evaporated and
5 mL of water was added. After cooling, the resulting solid was
filtered, washed with diluted acetic acid, and dried. Yield 370 mg
(82%), yellow powder, mp 270e272 ꢀC (lit.32 mp 270 ꢀC, lit.15c mp
4.4.7. 16-Benzyl-6,7,14,15-tetrahydro-7,15-epiminobis(8H,16H-di-
thiochromeno)[2,3-b:2,3-f][1,5]diazocine-8,16-dione (20). A mixture
of 17 (150 mg, 0.51 mmol), benzylamine (55 mg, 0.51 mmol), and
two drops of triethylamine in toluene (3 mL) was heated to reflux
for 12 h. After cooling, the resulting solid was filtered, washed
with toluene, and dried. Yield 70 mg (28%), a colorless powder,
268 ꢀC); 1H NMR (400 MHz, DMSO-d6) 7.18e7.23 (m, 2H, H-50, H-
d
60), 7.63 (ddd, 1H, H-6, J¼8.0, 7.1, 1.0 Hz), 7.63e7.70 (m, 2H, H-40, H-
70), 7.82 (dd, 1H, H-8, J¼8.6, 0.8 Hz), 7.93 (ddd, 1H, H-7, J¼8.6, 7.1,

7328
V.Ya. Sosnovskikh et al. / Tetrahedron 66 (2010) 7322e7328
12. Sevenard, D. V.; Vorobyev, M.; Sosnovskikh, V. Y.; Wessel, H.; Kazakova, O.;
1.7 Hz), 8.28 (dd, 1H, H-5, J¼8.0, 1.7 Hz), 9.38 (s, 1H, H-2), 12.64 (s,
€
Vogel, V.; Shevchenko, N. E.; Nenajdenko, V. G.; Lork, E.; Roschenthaler, G.-V.
Tetrahedron 2009, 65, 7538e7552.
1H, NH).
13. Sosnovskikh, V. Y.; Moshkin, V. S.; Kodess, M. I. Tetrahedron Lett. 2008, 49,
6856e6859.
4.6.2. 3-(1H-Benzimidazol-2-yl)-6-methyl-4H-chromen-4-one
(22b). This compound was prepared from 21b according to the
procedure described for compound 22a. Yield 145 mg (43%), yellow
powder, mp 258e260 ꢀC (lit.15c mp 256 ꢀC); 1H NMR (400 MHz,
14. (a) Sigg, I.; Haas, G.; Winkler, T. Helv. Chim. Acta 1982, 65, 275e279; (b) Rihs, G.;
Sigg, I.; Haas, G.; Winkler, T. Helv. Chim. Acta 1985, 68, 1933e1935.
15. (a) Ghosh, C. K. Heterocycles 2004, 63, 2875e2898; (b) Fitton, A. O.; Houghton,
P. G.; Suschitzky, H. Synthesis 1979, 337e339; (c) Ghosh, C. K.; Khan, S. Synthesis
1980, 701e702.
16. Chandrashekhar, N.; Thomas, B.; Gayathri, V.; Ramanathan, K. V.; Nanje Gowda,
N. M. Magn. Reson. Chem. 2008, 46, 769e774.
17. Fitton, A. O.; Frost, J. R.; Houghton, P. G.; Suschitzky, H. J. Chem. Soc., Perkin Trans.
DMSO-d6)
d
2.50 (s, 3H, Me), 7.18e7.23 (m, 2H, H-50, H-60),
7.62e7.69 (m, 2H, H-40, H-70), 7.71 (d, 1H, H-8, J¼8.6 Hz), 7.74 (dd,
1H, H-7, J¼8.6, 2.0 Hz), 8.05 (dq, 1H, H-5, J¼2.0, 0.8 Hz), 9.35 (s, 1H,
H-2), 12.61 (s, 1H, NH).
1 1979, 1691e1694.
18. (a) Sosnovskikh, V. Y.; Irgashev, R. A. Tetrahedron Lett. 2007, 48, 7436e7439; (b)
Sosnovskikh, V. Y.; Irgashev, R. A.; Levchenko, A. A. Tetrahedron 2008, 64,
6607e6614.
Supplementary data
19. (a) Maiti, A. K.; Bhattacharyya, P. J. Chem. Res., Synop. 1997, 424e425; (b)
Zeng, X.-F.; Ji, S.-J.; Wang, S.-Y. Tetrahedron 2005, 61, 10235e10241; (c) Ko, S.;
Lin, C.; Tu, Z.; Wang, Y.-F.; Wang, C.-C.; Yao, C.-F. Tetrahedron Lett. 2006, 47,
487e492; (d) Xia, M.; Wang, S.; Yuan, W. Synth. Commun. 2004, 34,
3175e3182; (e) Lin, X.-F.; Cui, S.-L.; Wang, Y.-G. Synth. Commun. 2006, 36,
3153e3160; (f) Mo, L.-P.; Ma, Z.-C.; Zhang, Z.-H. Synth. Commun. 2005, 35,
1997e2004; (g) Chen, D.; Yu, L.; Wang, P. G. Tetrahedron Lett. 1996, 37,
4467e4470; (h) Chakrabarty, M.; Ghosh, N.; Basak, R.; Harigaya, Y. Tetra-
hedron Lett. 2002, 43, 4075e4078; (i) Ji, S.-J.; Wang, S.-Y.; Zhang, Y.; Loh, T.-P.
Tetrahedron 2004, 60, 2051e2055; (j) Wang, S.-Y.; Ji, S.-J. Tetrahedron 2006,
62, 1527e1535.
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.06.066.
References and notes
1. Ellis, G. P. Chromenes, Chromanones, and Chromones. The Chemistry of Hetero-
cyclic Compounds; Wiley: New York, NY, 1977; Vol. 31.
20. Adams, H.; Bailey, N. A.; Giles, P. R.; Marson, C. M. Acta Crystallogr. 1991, C47,
1332e1334.
21. Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.; Orpen, A. G.; Taylor, R.
J. Chem. Soc., Perkin Trans. 2 1987, S1eS19.
22. (a) Ghosh, C. K.; Karak, S. K. J. Heterocycl. Chem. 2005, 42, 1035e1042; (b) Ra-
shid, M. A.; Rasool, N.; Appel, B.; Adeel, M.; Karapetyan, V.; Mkrtchyan, S.;
Reinke, H.; Fischer, C.; Langer, P. Tetrahedron 2008, 64, 5416e5425.
23. Sosnovskikh, V. Y.; Moshkin, V. S.; Kodess, M. I. J. Heterocycl. Chem. 2010, 47,
629e633.
2. Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893e930.
3. (a) Langer, P. Synlett 2007, 1016e1025; (b) Nohara, A.; Kuriki, H.; Saijo, T.; Su-
gihara, H.; Kanno, M.; Sanno, Y. J. Med. Chem. 1977, 20, 141e145; (c) Nohara, A.;
Umetani, T.; Ukawa, K.; Sanno, Y. Chem. Pharm. Bull. 1974, 22, 2959e2965; (d)
Ukawa, K.; Ishiguro, T.; Wada, Y.; Nohara, A. Heterocycles 1986, 24, 1931e1941;
(e) Hsung, R. P. J. Org. Chem. 1997, 62, 7904e7905.
4. (a) Ghosh, C. K. J. Heterocycl. Chem. 1983, 20, 1437e1445; (b) Sabitha, G. Al-
drichimica Acta 1996, 29, 15e25; (c) Ghosh, C. K.; Patra, A. J. Heterocycl. Chem.
2008, 45, 1529e1547.
24. (a) Brown, R.E.; Lustgarten, D.M. U.S. Patent 4,013,771, 1977; (b) Kikionis, S.;
McKee, V.; Markopoulos, J.; Igglessi-Markopoulou, O. Tetrahedron 2008, 64,
5454e5458.
5. (a) Hsung, R. P.; Zificsak, C. A.; Wei, L.-L.; Zehnder, L. R.; Park, F.; Kim, M.; Tran,
T.-T. T. J. Org. Chem. 1999, 64, 8736e8740; (b) Sosnovskikh, V. Y.; Moshkin, V. S.;
Kodess, M. I. Tetrahedron 2008, 64, 7877e7889; (c) Sosnovskikh, V. Y.; Irgashev,
R. A.; Moshkin, V. S.; Kodess, M. I. Izv. Akad. Nauk, Ser. Khim. 2008, 2107e2115,
Russ. Chem. Bull., Int. Ed. 2008, 57, 2146e2115.
6. (a) Nakazumi, H.; Endo, T.; Nakaue, T.; Kitao, T. J. Heterocycl. Chem. 1985, 22,
89e92; (b) Nakazumi, H.; Torigoe, N.; Kuriyama, T.; Kitao, T. Chem. Express 1986,
1, 21e24.
25. (a) Rudorf, W.-D.; Augustin, M. J. Prakt. Chem. 1981, 323, 55e62; (b) Eiden, F.;
Schiinemann, J. Arch. Pharm. (Weinheim) 1985, 318, 1096e1100.
€
26. Usachev, B. I.; Sosnovskikh, V. Y.; Shafeev, M. A.; Roschenthaler, G.-V.
Phosphorus, Sulfur, and Silicon, 2005, 180, 1315e1319.
27. Sosnovskikh, V. Y.; Moshkin, V. S.; Kodess, M. I. Tetrahedron Lett. 2009, 50,
6515e6518.
28. Quintela, J. M.; Alvarez-Sarandés, R.; Peinador, C.; Maestro, M. J. Chem. Soc.,
Perkin Trans. 1 1998, 3557e3560.
7. (a) Nakazumi, H.; Maeda, K.; Yagi, S.; Kitao, T. J. Chem. Soc., Chem. Commun. 1992,
1188e1189; (b) Yagi, S.; Maeda, K.; Nakazumi, H. J. Mater. Chem. 1999, 9,
2991e2997.
29. (a) Cudero, J.; Pardo, C.; Ramos, M.; Gutierrez-Puebla, E.; Monge, A.; Elguero, J.
Tetrahedron 1997, 53, 2233e2240; (b) Cerrada, L.; Cudero, J.; Elguero, J.; Pardo,
C. J. Chem. Soc., Chem. Commun. 1993, 1713e1714.
8. Chen, C. H.; Kelts, L. W.; Luss, H. R.; Fox, J. L. J. Org. Chem. 1984, 49, 5143e5147.
9. Nakazumi, H.; Endo, T.; Sonoda, H.; Kitao, T. J. Heterocycl. Chem. 1985, 22,
821e824.
30. Molina, P.; Arques, A.; Tárraga, A.; Obón, M. R.; Foces-Foces, C.; Jagerovic, N.;
Elguero, J. Tetrahedron 1998, 54, 997e1004.
31. Ghosh, C. K.; Tewari, N. J. Org. Chem. 1980, 45, 1964e1968.
32. Risitano, F.; Grassi, G.; Foti, F. J. Heterocycl. Chem. 2001, 38, 1083e1086.
10. Chen, C. H.; Reynolds, G. A. J. Org. Chem. 1979, 44, 3144e3147.
11. (a) Giles, P. R.; Marson, C. M. Tetrahedron Lett. 1990, 31, 5227e5230; (b) Giles, P.
R.; Marson, C. M. Tetrahedron 1991, 47, 1303e1310; (c) Giles, P. R.; Marson, C. M.
Aust. J. Chem. 1992, 45, 439e443.