Cyclic carboxylic anhydrides as new reagents for formation of chromone ring

Article abstract of DOI:10.1002/jhet.1721

The propensity of cyclic carboxylic anhydrides to undergo ring-opening was exploited in a reaction with 2'-hydroxy-α-heteroarylacetophenones leading to the formation of chromones. New simple method was developed for the synthesis of 2-(ω-carboxyalkyl)-3-h

Full text of DOI:10.1002/jhet.1721

Month 2013
Cyclic Carboxylic Anhydrides as New Reagents for Formation of
Chromone Ring
a
b
c
c
*
Mykhaylo S. Frasinyuk, Svitlana P. Bondarenko, Nataliia V. Gorbulenko, Alexander V. Turov, and
Volodymyr P. Khilyac
aInstitute of Bioorganic and Petrochemistry of NAS of Ukraine, Murmanska st. 1, Kyiv, 02094, Ukraine
bNational University of Food Technologies, Volodymirska st. 68, Kyiv, 01601, Ukraine
cTaras Shevchenko Kyiv National University, Volodymirska st. 64, Kyiv, 01601, Ukraine
*
E-mail: mfras@i.kiev.ua
Received February 19, 2012
DOI 10.1002/jhet.1721
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
The propensity of cyclic carboxylic anhydrides to undergo ring-opening was exploited in a reaction with
2’-hydroxy-a-heteroarylacetophenones leading to the formation of chromones. New simple method was
developed for the synthesis of 2-(o-carboxyalkyl)-3-heteroarylchromones without protecting either the
phenolic or the carboxylic groups. Treatment with hydrazine led to the formation of 3(5)-(o-carboxyalkyl)-
5(3)-(2,4-dihydroxyphenyl)-4-heteroarylpyrazoles.
J. Hetercyclic Chem., 00, 00 (2013).
INTRODUCTION
chromones show high antihistamine activity, which is
atypical for flavonoids [10] (see Fig. 1). Additionally, the
introduction of an azaheterocycle into flavonoids increases
their conjugation with DNA through stacking interactions
and formation of hydrogen bonds. In this article, we report
the chemical modification of chromone skeletons necessary
to secure new heterocycles for biological evaluation.
The 4H-[1]-benzopyran-4-one (chromone) system is a
part of the heterocyclic skeleton of widely distributed natural
compounds. The best known are the flavones and isofla-
vones, which contain aryl substituents in position 2 or 3,
respectively [1]. Several minor groups of natural compounds
with chromone ring are represented by polyketides, chro-
mone alkaloids, and antibiotics [2], which also contain nitro-
gen atoms in their structures. Typically, these compounds
possess saturated (un)fused piperidine or pyrrolidine rings
at position 6 or 8 of chromone ring. Also, imidazole [3],
pyrrole [4], isoquinoline [5], and benzoxazole [6] moieties
are found in the molecules of chromone alkaloids. Moreover,
synthesis of mimics of these compounds is widely used for
making different modifications in the flavonoids. Various
nitrogen-containing flavonoid derivatives were synthesized
using alkaloid rohitukine as a starting model. Some of them
have shown potential activity against cyclin-dependent
kinases [7], including cyclin-dependent kinase inhibitor
Flavopiridol, which is under clinical development [8].
Replacement of carbon and/or oxygen atoms in natural
flavonoids with nitrogen atoms usually leads to the retention
of biological activity and sometimes the appearance of new
biological properties. Thus, 3-arylquinazolinones (1, X=Y=N)
as well as the initial genistein structure (1, X = O, Y = C)
possess estrogenic properties [9], and 3-(5-tetrazolyl)
RESULTS AND DISCUSSION
One of the important pathways for obtaining isoflavones and
3-hetarylchromones involves derivatives substituted in position
2 of the chromone ring. In most cases, this method includes
cyclization of 2’-hydroxy-2-(hetero)arylacetophenones with
formic, acetic, and oxalic acids derivatives. High molecular
weight carboxylic acid derivatives have limited applicability
in this method. Some synthetic procedures were reported
previously for the synthesis of isoflavones 2, carrying
carboxyalkyl attachment in position 2 of chromone ring. These
compounds were developed for immunoassay techniques for
the epidemiological screening of the isoflavonoid plant
phytoestrogens such as daidzein and genistein [11,12] and
were utilized as haptens for coupling with proteins in the
development and validation of immunological tests [13]. Thus,
2-(o-carboxyalkyl)isoflavones 2 were obtained in multistep
reactions of particularly О-methylated deoxybenzoins with
© 2013 HeteroCorporation

M. S. Frasinyuk, S. P. Bondarenko, N. V. Gorbulenko, A. V. Turov, and V. P. Khilya
Vol 000
as 2-cyanomethylbenzimidazole, its 1-methyl derivative, 2-
benzothiazoleacetonitrile, and 4-methylthiazoleacetonitrile [16].
The optimal conditions for obtaining acids 4–6 is to treat
the compounds 3a–g for extended period with large excess
of commercially available succinic or glutaric anhydride in
pyridine at room temperature. This method does not
require the protection of phenolic and carboxylic groups
or the activation of carboxylic group as their acid chlorides.
The reaction was quenched with water to afford the o-(3-
heteroaryl-7-hydroxy-4-oxochromen-2-yl)propionic acids
4a–g or the o-(3-heteroaryl-7-hydroxy-4-oxochromen-2-yl)
butyric acids 4c–g. The reaction was also effected using
diglycolic anhydride, leading to {(3-heteroaryl-7-hydroxy-
4-oxochromen-2-yl)methoxy}acetic acids 6d–g. The ac-
ylation of the 4-hydroxy group of ketones 3a–g and/or the
7-hydroxy group of chromone ring does not occur under
these conditions.
The presence of the carboxylic group and azaheterocyclic
moiety in compounds 4–6 discourages the acylation of the
phenol hydroxylic group during on treatment with acyl
chlorides in pyridine. To synthesize 7-O-acyl derivatives
4h, 5h, and 6h, we used 4-O-pivaloyl derivative of ketone
3h, which was obtained by acylation of 3d with an equivalent
quantity of pivaloyl chloride in pyridine. It was interesting
that the compound 3h in DMSO-d6 exists as one isomer in
contrast to compounds 3a–g, which exist as keto-enolic
tautomers. We studied the NOE spectra of compound 3h in
various solvents for confirm its structure. In CDCl3 solution,
we observed only 5–7% of ketone form. The observed NOE
established that the conformation of 3h is predominantly
enolic. Although the existence of the enaminoketone form
was not contradicted by NOE. When a mixture of DMSO-
d6 and С6D6 was used as solvent, NOE spectra confirmed
the enaminoketone form because of the presence of NH
interaction with neighboring H-4 proton of benzimidazole
ring (Fig. 2).
Figure 1. General structures of (aza)isoflavonoid estrogens.
ethoxycarbonyl alkyl carbonyl chlorides followed by the
intramolecular formation of chromone ring and subsequent
deprotection of phenolic and carboxylic groups [11]. A further
improvement of this method was the use of acetone as a
solvent for the one-pot exhaustive acylation and cyclization
of (un)protected deoxybenzoins into chromone ring with
subsequent deblocking of carboxylic group [12,13]. An alter-
native method for the 2-carboxymethyl isoflavones synthesis
was developed starting from 2-bromomethyl isoflavones [14].
In many cases, replacement of 3-aryl with 3-heteroaryl
substituent in isoflavones requires a different synthetic
approach for obtaining the target 3-heteroarylchromones. The
nature of heterocyclic substituent in position 3 of chromone
ring places some limitations on the use of standard methods
for the synthesis of isoflavones, whereas other procedures
are applicable only for synthesis of 3-heteroarylchromones.
Although ethyl oxalyl chloride reacts normally with 2,4-
dihydroxy-a-heteroarylacetophenones in pyridine [15], the
use of ethoxycarbonylalkylcarbonyl chlorides was not
previously reported. From this point of view, the develop-
ment of facile method for the synthesis of 2-carboxyalkyl-3-
heteroarylchromones is of current importance for biological
screening and is the subject of this report.
Science a-heteroaryl-2’,4’-dihydroxyacetophenones 3a–g
contain an activated methylene group, we hoped to develop a
one-step synthesis of 2-(o-сarboxyalkyl)-3-azaheteroaryl
isoflavones 4–6 using anhydrides of aliphatic a,o-dicarboxylic
acids.
The starting a-heteroaryl-2,4-dihydroxyacetophenone
derivatives 4a–g were obtained by Hoesh reaction of (un)
substituted resorcinol with 2-azaheteroaryl acetonitriles such
Isoflavone derivatives are useful intermediates for the
synthesis of various 2-hydroxyphenyl substituted pyrazoles
[15,17], pyrimidines [15,18,19], pyrazolo[1,5-a]pyrimidines
[20], and isoxazoles [15,21], which can be obtained by
Figure 2. Observed NOE interactions in tautomers (compound 3h) in CDCl3 solution (a) and in DMSO-d6/C6D6 mixture (b).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Cyclic Carboxylic Anhydrides as New Reagents for Formation of Chromone Ring
cleavage of chromone ring with binucleophiles. These
compounds are interesting targets because of their biological
activity. For example, 4-aryl and 4-heteroaryl derivatives of
pyrazole and isoxazole possess heat shock protein 90
(Hsp90) inhibitor activity [17].
CONCLUSION
In addition to well-known reagents for the formation chro-
mone ring (Vilsmeier–Haack reagent, acetic and trifluoroacetic
anhydrides, ethyl oxalyl chloride, etc.), we developed a
method that utilizes commercially available anhydrides of
aliphatic a,o-dicarboxylic acids. We demonstrated that
2-carboxyalkyl-3-hetaryl chromones were synthesized by this
procedure without any protection of phenolic and carboxylic
groups. In addition, the interaction of these compounds with
hydrazine leads to the formation of carboxyalkyl substituted
4-hetaryl-3(5)-(2,4-dihydroxyphenyl)pyrazoles.
We studied the reaction of acids 4–6 with hydrazine to
obtain pyrazole derivatives with a carboxyalkyl substituent.
Heating these compounds with hydrazine hydrate in ethanol
led to the formation of 3(5)-(o-сarboxyalkyl)-4-heteroaryl-5
(3)-(2,4-dihydroxyphenyl)pyrazoles 7a,c,d and 8c,d,h and 3(5)-
сarboxymethoxymethyl-4-heteroaryl-5(3)-(2,4-dihydroxyphe-
nyl)pyrazole derivatives 9g,h (Scheme 1). Structures were
1
confirmed by 13С and Н NMR spectroscopy. In contrast to
1Н NMR spectra of pyrazoles 7–9, assignment of 13C NMR
peaks was complicated by the presence of both tautomeric
forms, which leads to broadening of carbon atom peaks,
nearest to pyrazole nitrogen atoms. All assignments were
carried out using HMQC, HMBC, and NOESY methods.
EXPERIMENTAL
NMR spectra were recorded on a Varian VXR 300 (300 MHz)
or a Varian Mercury 400 (400 MHz) spectrometers (Varian Inc.,
Palo Alto, CA). TMS (1H, d = 0.00) was used as an internal stan-
dard, and chemical shifts are given in d (ppm) and J values in
Scheme 1. Reagents and conditions: (1) a,o-dicarboxylic acid anhydride (5–6 equiv), anhydrous pyridine, 25ꢀC, 72 h, then H2O; (2) pivaloyl choride
(1.2 equiv), pyridine, 25ꢀC, 24 h, then H2O, 0ꢀC, 5 h; (3) N2H4, ethanol, reflux, 4 h.
1
1
2
2
2
2
2
2
2
2
2
2
2
1
2
1
2
2
2
2
2
2
2
2
2
2
1
1
2
2
2
2
2
2
2
2
2
2
2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. S. Frasinyuk, S. P. Bondarenko, N. V. Gorbulenko, A. V. Turov, and V. P. Khilya
Vol 000
hertz. 13C NMR spectra were recorded on a Varian Mercury 400
(100 MHz) spectrometer using mixture 1:1 of DMSO-d6 and
CCl4 as solvent. Solvent DMSO-d6 (13C, d = 39.5) was used as
an internal reference. IR spectra were recorded on a Nicolet Nexus
470 ESP FT/IR spectrometer (Thermo Nicolet, Madison, WI).
Melting points were determined in open capillarity tubes with an
Buchi B-535 apparatus and uncorrected (Agilent Technologies,
Santa Clara, CA). Mass spectra were obtained with a Agillent
1100 using chemical ionization (Merck KGaA, Darmstadt,
Germany). TLC was conducted on Merck silica gel 60F254 plates
(Lachema, Brno, Czech Republic). All compounds were homoge-
nous on TLC. Pyridine was redistilled from CaH2.
28.7, 30.8, 101.2, 111.8, 114.7, 121.4, 124.6, 130.4, 145.9, 155.0,
161.1, 168.7, 172.9, 174.7; MS (CI) m/z (%): 379.1 (100, MH+).
Anal. Calcd for C21H18N2O5: C, 66.66; H, 4.80; N, 7.40. Found:
C, 66.45; H, 4.98; N, 7.13.
3-[7-Hydroxy-3-(1-methyl-1H-benzimidazol-2-yl)-4-oxo-4H-
chromen-2-yl]propanoic acid (4c).
This compound was
obtained as colorless solid (539 mg, 74% yield); mp 278–280ꢀC;
IR (KBr): 3067, 2929, 1643, 1639, 1457, 1394 cmÀ1; H NMR
1
(300 MHz): d 2.68 (t, 2H, J = 7.6 Hz, CH2COOH), 2.85 (t, 2H,
J = 7.6Hz, CH2-3), 3.63 (s, 3H, NCH3), 6.94 (d, 1H, J = 2.3 Hz,
H-8’), 6.98 (dd, 1H, J = 2.3, 8.8Hz, H-6’), 7.25 (1H, m, H-5’’),
7.31 (1H, m, H-6’’), 7.62 (1H, m, H-7’’), 7.68 (1H, m, H-4’’),
7.94 (d, 1H, J = 8.8 Hz, H-5’), 10.96 (s, 1H, OH-7’), 12.25 (s, 1H,
COOH); 13C NMR (100 MHz, CCl4 + DMSO-d6): 27.8, 30.3,
30.4, 102.1, 109.9, 113.2, 115.0, 115.3, 118.9, 121.4, 122.1,
126.8, 135.5, 142.2, 147.1, 157.2, 163.1, 168.5, 172.6, 173.9; MS
(CI) m/z (% ) = 365.1 (100, MH+). Anal. Calcd for C20H16N2O5:
C, 65.93; H, 4.43; N, 7.69. Found: C, 65.88; H, 4.27; N, 7.43.
3-[6-Ethyl-7-hydroxy-3-(1-methyl-1H-benzimidazol-2-yl)-4-oxo-
2-Ethyl-5-hydroxy-4-[2-(1-methyl-1,3-dihydro-2H-benzimidazol-
2-ylidene)acetyl]phenyl pivalate (3h). Pivaloyl chloride (2.71 mL,
22 mmol) was added dropwise to a stirred solution of 6.2 g (20 mmol)
compound 3d in 25 mL of dry pyridine at 0ꢀC and stirred at room
temperature for 24 h. The reaction mixture was poured into 500 mL
of cool water, and the formed precipitate was filtered off, washed
with cold water to give crude product, which was crystallized
from methanol to give compound 3h (5.9 g, 75%) as yellow-green
solid, mp 196–198ꢀC; IR (KBr): 2969, 1742, 1566, 1536, 1479,
4H-chromen-2-yl]propanoic acid (4d).
This compound was
obtained as colorless solid (377 mg, 48% yield); mp >300ꢀC; IR
(KBr): 3067, 2928, 1642, 1470 cmÀ1; 1H NMR (400 MHz): d 1.19
(t, 3H, J=7.6Hz, CH3CH2-6’), 2.63 (q, 2H, J=7.6Hz, CH2-6’),
2.67 (t, 2H, J=7.6Hz, CH2COOH), 2.85 (t, 2H, J=7.6Hz, CH2-3),
3.63 (s, 3H, NCH3), 6.95 (s, 1H, H-8’), 7.23 (1H, m, H-5’’), 7.30
(1H, m, H-6’’), 7.59 (1H, m, H-7’’), 7.66 (1H, m, H-4’’), 7.80
(s, 1H, H-5’), 11.03 (s, 1H, OH-7’), 12.56 (s, 1H, COOH); 13C
NMR (100 MHz, CCl4 +DMSO-d6): d 13.8, 22.4, 27.9, 30.3, 30.5,
101.6, 110.3, 113.3, 114.7, 119.0, 121.6, 122.3, 124.7, 130.6,
135.7, 142.5, 147.6, 155.6, 161.2, 168.6, 173.0, 174.2; MS (CI) m/z
(%): 393.1 (100, MH+). Anal. Calcd for C22H20N2O5: C, 67.34; H,
5.14; N, 7.14. Found: C, 67.56; H, 5.32; N, 7.38.
1
1118 cmÀ1; H NMR (300 MHz, CDCl3): d 1.19 (t, 3H, J=7.6Hz,
CH3CH2-2’), 1.38 (s, 9H, (CH3)3CCOO) 2.48 (q, 2H, J = 7.6 Hz,
CH3CH2-2’), 3.61 (s, 3H, NCH3), 5.69 (s, 1H, CHC = O) 6.56
(s, 1H, H-6’), 7.16–7.34 (m, 4H, benzimidazole ring), 7.47 (s, 1H,
H-3’), 12.79 (s, 1H, OH-5’), 14.20 (s, 1H, NH); 13C NMR
(100 MHz, CCl4 +DMSO-d6): d 15.0, 22.5, 26.7, 29.1, 38.6, 71.5,
108.6, 110.5, 111.8, 118.5, 122.1, 122.4, 124.5, 127.8, 130.3, 131.7,
151.3, 152.2, 160.9, 175.4, 182.9; MS (CI) m/z (%): 395.3 (100,
MH+). Anal. Calcd for C23H26N2O4: C, 70.03; H, 6.64; N, 7.10.
Found: C, 70.30; H, 6.42; N, 7.18.
General procedure for synthesis of chromones 4–6. Acid
anhydride (10 mmol for succinic or 12 mmol for glutaric and
diglycolic) was added to a stirred solution of substituted ketone
3a–h (2 mmol) in 10 mL of dry pyridine at room temperature.
After standing for 72 h at room temperature, the reaction
mixture was poured out into 100 mL of cool water, and the
formed precipitate was filtered off, washed with cold water, and
crystallized from methanol.
3-[6-Hexyl-7-hydroxy-3-(1-methyl-1H-benzimidazol-2-yl)-4-
oxo-4H-chromen-2-yl]propanoic acid (4e). This compound was
obtained as colorless solid (673 mg, 75% yield); mp 150–152ꢀC; IR
(KBr): 3060, 2928, 1737, 1631, 1583, 1470 cmÀ1 1H NMR
;
(400 MHz): d 0.86, 1.32, 1.58, 2.63, (4m, 3H, 6H, 2H, 4H, Hex-
6’ and CH2COOH), 2.85 (t, 2H, J = 7.6 Hz, CH2-3), 3.62 (s, 3H,
NCH3), 6.94 (s, 1H, H-8’), 7.21 (1H, m, H-5’’), 7.27 (1H, m, H-
6’’), 7.52 (1H, m, H-7’’), 7.63 (1H, m, H-4’’), 7.75 (s, 1H, H-5’),
10.94 (s, 1H, OH-7’), 12.03 (s, 1H, COOH); 13C NMR (100 MHz,
CCl4 +DMSO-d6): 13.9, 22.1, 27.8, 28.6, 29.0, 29.3, 30.2, 30.5,
31.2, 101.4, 109.8, 113.2, 114.6, 118.9, 121.2, 121.9, 125.4, 128.9,
135.6, 142.4, 147.3, 155.5, 161.1, 168.0, 172.6, 173.9; MS (CI) m/z
(%): 449.1 (100, MH+). Anal. Calcd for C26H28N2O5: C, 69.63; H,
6.29; N, 6.25. Found: C, 69.39; H, 6.18; N, 6.48.
3-[6-Ethyl-7-hydroxy-3-(4-methyl-1,3-thiazol-2-yl)-4-oxo-4H-
chromen-2-yl]propanoic acid (4f). This compound was obtained
as colorless solid (532 mg, 74% yield); mp 275–276ꢀC; IR (KBr):
3231, 2976, 1700, 1617, 1578, 1249 cmÀ1; 1H NMR (400 MHz): d
1.19 (t, 3H, J=7.6Hz, CH3CH2-6’), 2.43 (s, 3H, CH3-4’’), 2.63
(q, 2H, J =7.6Hz, CH2-6’), 2.76 (t, 2H, J=7.6Hz, CH2COOH),
3.56 (t, 2H, J = 7.6 Hz, CH2-3), 6.89 (s, 1H, H-8’), 7.34 (s, 1H,
H-5’’), 7.83 (s, 1H, H-5’), 11.00 (s, 1H, OH-7’), 12.31 (s, 1H,
COOH); 13C NMR (100 MHz, CCl4 + DMSO-d6): d 13.6, 16.9,
22.4, 29.2, 30.7, 101.0, 114.1, 114.2, 115.2, 124.6, 130.3,
150.0, 154.7, 157.0, 160.8, 167.2, 173.0, 173.4; MS (CI) m/z (%):
360.2 (100, MH+). Anal. Calcd for C18H17NO5S: C, 60.16; H,
4.77; N, 3.90; S, 8.92. Found: C, 60.16; H, 4.77; N, 3.90; S, 8.92.
3-[3-(1,3-Benzothiazol-2-yl)-7-hydroxy-4-oxo-6-propyl-4H-
3-[3-(1H-Benzimidazol-2-yl)-7-hydroxy-4-oxo-4H-chromen-2-
yl]propanoic acid (4a).
This compound was obtained as
colorless solid (336mg, 48% yield); mp 271–272ꢀC; IR (KBr):
3060, 2913, 1657, 1630, 1556, 1460 cmÀ1; H NMR (400MHz):
1
d 2.79 (t, 2H, J = 7.6 Hz, CH2COOH), 3.45 (t, 2H, J = 7.6 Hz,
CH2-3), 6.92 (d, 1H, J = 2.3 Hz, H-8’), 7.00 (dd, 1H, J = 2.3,
8.8 Hz, H-6’), 7.21 (m, 2H, H-5’’ and H-6’’), 7.64 (m, 2H, H-4’’
and H-7’’), 8.01(d, 1H, J = 8.8 Hz, H-5’), 11.02 (s, 1H, OH-7’),
12.63 (s, 2H, COOH and NH); 13C NMR (100MHz,
CCl4 + DMSO-d6): d 28.8, 30.8, 101.9, 112.0, 115.1, 115.4,
121.5, 126.9, 145.7, 156.7, 163.1, 169.1, 173.0, 174.7; MS (CI)
m/z (%): 351.2 (100, MH+). Anal. Calcd for C19H14N2O5: C,
65.14; H, 4.03; N, 8.00. Found: C, 65.24; H, 4.18; N, 8.22.
3-[3-(1H-Benzimidazol-2-yl)-6-ethyl-7-hydroxy-4-oxo-4H-
chromen-2-yl]propanoic acid (4b).
obtained as colorless solid (431 mg, 57% yield); mp 273–274ꢀC;
IR (KBr): 3556, 2963, 1644, 1626, 1560, 1418, 1305 cmÀ1 1H
This compound was
;
NMR (DMSO-d6, 400 MHz): d 1.18 (t, 3H, J=7.6Hz, CH3CH2-6’),
2.63 (q, 2H, J = 7.6 Hz, CH2-6’), 2.76 (t, 2H, J = 7.6 Hz,
CH2COOH), 3.45 (t, 2H, J = 7.6 Hz, CH2-3), 6.93 (s, 1H, H-8’),
7.22 (m, 2H, H-5’’ and H-6’’), 7.65 (m, 2H, H-4’’ and H-7’’),
7.85 (s, 1H, H-5’), 11.10 (s, 1H, OH-7’), 12.50 (s, 2H, COOH
and NH); 13C NMR (100 MHz, CCl4 + DMSO-d6): d 13.7, 22.5,
chromen-2-yl]propanoic acid (4g).
This compound was
obtained as colorless solid (540 mg, 66% yield); mp 227–229ꢀC;
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Cyclic Carboxylic Anhydrides as New Reagents for Formation of Chromone Ring
1
IR (KBr): 3118, 2960, 1698, 1614, 1574, 1374cmÀ1; H NMR
(300 MHz): d 0.92 (m, 3H, CH3CH2CH2-6’), 1.63 (m, 2H,
СH3CH2CH2-6’), 2.62 (m, 2H, СH3CH2CH2-6’), 2.82 (t, 2H,
J=7.6Hz, CH2COOH), 3.65 (t, 2H, J=7.6Hz, CH2-3), 6.94
(s, 1H, H-8’), 7.46 (1H, m, H-5’’), 7.53 (1H, m, H-6’’), 7.83 (s,
1H, H-5’), 8.01 (1H, m, H-7’’), 8.15 (1H, m, H-4’’), 11.13 (s, 1H,
OH-7’), 12.20 (s, 1H, COOH); 13C NMR (100 MHz,
CCl4 +DMSO-d6): d 13.7, 22.1, 29.6, 30.8, 31.4, 101.2, 114.1,
114.3, 121.0, 122.3, 124.4, 125.4, 125.6, 129.0, 135.2, 151.0,
154.8, 159.5, 161.4, 169.4, 173.1, 173.6; MS (CI) m/z (%): 410.1
(100, MH+). Anal. Calcd for C22H19NO5S: C, 64.53; H, 4.68; N,
3.42; S, 7.83. Found: C, 64.45; H, 4.39; N, 3.24; S, 7.66.
NCH3), 6.95 (s, 1H, H-8’), 7.24 (1H, m, H-5’’), 7.31 (1H, m,
H-6’’), 7.60 (1H, m, H-7’’), 7.67 (1H, m, H-4’’),7.76 (s, 1H,
H-5’), 10.95 (s, 1H, OH-7’), 12.06 (s, 1H, COOH); 13C NMR
(100 MHz, CCl4 + DMSO-d6): d 13.9, 22.0, 22.1, 28.6, 29.0,
29.3, 30.2, 31.2, 31.4, 32.5, 101.5, 109.8, 113.2, 114.6, 119.0,
121.2, 121.9, 125.3, 125.4, 128.9, 135.5, 142.4, 155.5, 161.1,
168.9, 173.3, 174.0; MS (CI) m/z (%): 463.3 (100, MH+). Anal.
Calcd for C27H30N2O5: C, 70.11; H, 6.54; N, 6.06. Found: C,
70.32; H, 6.48; N, 6.28.
4-[6-Ethyl-7-hydroxy-3-(4-methyl-1,3-thiazol-2-yl)-4-oxo-4H-
chromen-2-yl]butanoic acid (5f). This compound was obtained
as colorless solid (500 mg, 67% yield); mp 196–198ꢀC; IR (KBr):
3101, 2964, 1708, 1616, 1573, 1365 cmÀ1; 1H NMR (400 MHz): d
1.20 (t, 3H, J = 7.6 Hz, CH3CH2-6’), 2.02 (m, 2H, CH2-3), 2.37
(m, 2H, CH2COOH), 2.46 (s, 3H, CH3-4’’), 2.64 (q, 2H,
J = 7.6 Hz, CH2-6’), 3.34 (m, 2H, CH2-4), 6.91 (s, 1H, H-8’),
7.31 (s, 1H, H-5’’), 7.83 (s, 1H, H-5’), 10.95 (s, 1H, OH-7’),
12.05 (s, 1H, COOH); 13C NMR (100 MHz, CCl4 + DMSO-d6):
d 13.6, 16.9, 22.4, 22.5, 32.4, 33.1, 101.1, 114.2, 114.3, 115.2,
124.6, 130.2, 150.0, 154.8, 157.1, 160.9, 161.0, 168.4, 173.5;
MS (CI) m/z (%): 374.1 (100, MH+). Anal. Calcd for
C19H19NO5S: C, 61.11; H, 5.13; N, 3.75; S, 8.59. Found: C,
61.33; H, 5.35; N, 3.59; S, 8.86.
3-[7-[(2,2-Dimethylpropanoyl)oxy]-6-ethyl-3-(1-methyl-1H-
benzimidazol-2-yl)-4-oxo-4H-chromen-2-yl]propanoic
acid
(4h). This compound was obtained as colorless solid (639 mg,
67% yield); mp 225–226ꢀC; IR (KBr): 3471, 2973, 1747, 1653,
1472, 1109 cmÀ1; H NMR (300MHz): d 1.18 (t, 3H, J = 7.6 Hz,
1
CH3CH2-6’), 1.38 (s, 9H, (CH3)3CCOO-7’), 2.63 (q, 2H,
J = 7.6 Hz, CH2-6’), 2.70 (t, 2H, J = 7.6 Hz, CH2COOH), 2.89
(t, 2H, J=7.6Hz, CH2-3), 3.66 (s, 3H, NCH3), 7.27 (1H, m, H-5’’),
7.34 (1H, m, H-6’’), 7.62 (s, 1H, H-8’), 7.64 (1H, m, H-7’’), 7.70
(1H, m, H-4’’), 8.02 (s, 1H, H-5’), 12.35 (s, 1H, COOH); 13C NMR
(100 MHz, CCl4 +DMSO-d6): d 13.9, 22.4, 26.6, 27.9, 30.1, 30.2,
38.8, 109.8, 111.7, 113.8, 119.0, 120.3, 121.3, 122.1, 125.4, 134.2,
135.6, 142.4, 146.7, 153.1, 154.1, 169.5, 172.5, 174.1, 175.2; MS
(CI) m/z (%): 477.2 (100, MH+). Anal. Calcd for C27H28N2O6: C,
68.05; H, 5.92; N, 5.88. Found: C, 67.82; H, 6.17; N, 5.84.
4-[3-(1,3-Benzothiazol-2-yl)-7-hydroxy-4-oxo-6-propyl-4H-
chromen-2-yl]butanoic acid (5g). This compound was obtained
as colorless solid (381 mg, 45% yield); mp 242–244ꢀC; IR (KBr):
1
3421, 2961, 1704, 1614, 1571, 1373cmÀ1; H NMR (400MHz):
4-[7-Hydroxy-3-(1-methyl-1H-benzimidazol-2-yl)-4-oxo-4H-
chromen-2-yl]butanoic acid (5c). This compound was obtained
as colorless solid (446 mg, 59% yield); mp 240–241ꢀC; IR (KBr):
d 0.93 (m, 3H, CH3CH2CH2-6’), 1.61 (m, 2H, CH2CH2-6’), 2.08
(m, 2H, CH2-3), 2.36 (m, 2H, CH2COOH), 2.61 (m, 2H, CH2-6’),
3.40 (m, 2H, CH2-4), 7.00 (s, 1H, H-8’), 7.44 (1H, m, H-5’’),
7.51 (1H, m, H-6’’), 7.79 (s, 1H, H-5’), 8.05 (1H, m, H-7’’), 8.12
(1H, m, H-4’’), 10.96 (s, 1H, OH-7’), 12.02 (s, 1H, COOH); 13C
NMR (100MHz, CCl4 + DMSO-d6): d 13.8, 22.1, 23.2, 31.5,
33.0, 34.6, 101.3, 113.5, 114.1, 121.0, 122.4, 124.4, 125.3, 125.4,
129.2, 135.3, 151.1, 155.1, 159.7, 162.7, 170.6, 173.8, 175.1; MS
(CI) m/z (%): 424.1 (100, MH+). Anal. Calcd for C23H21NO5S: C,
65.23; H, 5.00; N, 3.31; S, 7.57. Found: C, 64.98; H, 5.26; N,
3.25; S, 7.68.
1
3436, 3025, 1714, 1635, 1625, 1391 cmÀ1; H NMR (300 MHz):
d 1.88 (m, 2H, CH2-3), 2.25 (m, 2H, CH2COOH), 2.63 (m, 2H,
CH2-4), 3.63 (s, 3H, NCH3), 6.94 (d, 1H, J = 2.3 Hz, H-8’), 6.97
(dd, 1H, J = 2.3, 8.8 Hz, H-6’), 7.23 (1H, m, H-5’’), 7.30 (1H, m,
H-6’’), 7.60 (1H, m, H-7’’), 7.67 (1H, m, H-4’’), 7.94 (d, 1H,
J = 8.8 Hz, H-5’), 10.91 (s, 1H, OH-7’), 12.00 (s, 1H, COOH);
13C NMR (100 MHz, CCl4 + DMSO-d6): d 22.0, 30.2, 31.4, 32.5,
102.1, 109.8, 113.3, 115.0, 115.2, 119.0, 121.3, 122.0, 126.8,
135.6, 142.4, 147.1, 157.3, 163.1, 169.3, 173.4, 174.1; MS (CI)
m/z (%): 379.2 (100, MH+). Anal. Calcd for C21H18N2O5: C,
66.66; H, 4.80; N, 7.40. Found: C, 66.43; H, 4.99; N, 7.26.
4-[7-[(2,2-Dimethylpropanoyl)oxy]-6-ethyl-3-(1-methyl-1H-
benzimidazol-2-yl)-4-oxo-4H-chromen-2-yl]butanoic acid (5h).
This compound was obtained as colorless solid (569 mg, 58%
yield); mp 207–208ꢀC; IR (KBr): 3443, 2972, 1759, 1652,
4-[6-Ethyl-7-hydroxy-3-(1-methyl-1H-benzimidazol-2-yl)-4-oxo-
4H-chromen-2-yl]butanoic acid (5d).
This compound was
1471, 1096 cmÀ1 1H NMR (300 MHz):
; d 1.18 (t, 3H,
obtained as colorless solid (585 mg, 72% yield); mp 257–259ꢀC;
J = 7.6 Hz, CH3CH2-6’), 1.38 (s, 9H, (CH3)3CCOO-7’), 1.91
(m, 2H, CH2-3), 2.27 (m, 2H, CH2COOH), 2.65 (m, 4H, CH2-4
and CH2-6’), 3.65 (s, 3H, NCH3), 7.25 (1H, m, H-5’’), 7.32
(1H, m, H-6’’), 7.62 (1H, m, H-7’’), 7.63 (1H, s, H-8’), 7.69
(1H, m, H-4’’), 8.02 (s, 1H, H-5’), 12.07 (s, 1H, COOH); 13C
NMR (100 MHz, CCl4 + DMSO-d6): d 13.9, 21.8, 22.4, 26.6,
30.2, 31.5, 32.5, 38.8, 109.8, 111.7, 113.8, 119.0, 120.3, 121.3,
122.0, 125.4, 134.1, 135.6, 142.5, 146.6, 153.1, 154.2, 170.2,
173.3, 174.2, 175.2; MS (CI) m/z (%): 491.1 (100, MH+). Anal.
Calcd for C28H30N2O6: C, 68.56; H, 6.16; N, 5.71. Found: C,
68.34; H, 6.28; N, 5.66.
IR (KBr): 3226, 2965, 1641, 1632, 1471, 1258cmÀ1; H NMR
1
(400MHz): d 1.23 (t, 3H, J = 7.6 Hz, CH3CH2-6’), 1.93 (m, 2H,
CH2-3), 2.23 (m, 2H, CH2COOH), 2.67 (m, 4H, CH2-4 and
CH2-6’), 3.66 (s, 3H, NCH3), 6.91 (s, 1H, H-8’), 7.25 (1H, m,
H-5’’), 7.28 (1H, m, H-6’’), 7.55 (1H, m, H-7’’), 7.65 (1H, m,
H-4’’), 7.76 (s, 1H, H-5’), 10.80 (s, 1H, OH-7’), 12.15 (s, 1H,
COOH); 13C NMR (100 MHz, CCl4 + DMSO-d6): d 13.6, 22.0,
22.4, 30.2, 31.4, 32.5, 101.4, 109.7, 113.2, 114.7, 118.9, 121.2,
121.9, 124.6, 130.2, 135.5, 142.4, 147.3, 155.6, 161.0, 168.9,
173.3, 174.0;. MS (CI) m/z (%): 407.1 (100, MH+). Anal. Calcd
for C23H22N2O5: C, 67.97; H, 5.46; N, 6.89. Found: C, 67.88;
H, 5.18; N, 7.10.
{[6-Ethyl-7-hydroxy-3-(1-methyl-1H-benzimidazol-2-yl)-4-oxo-
4H-chromen-2-yl]methoxy}acetic acid (6d). This compound was
obtained as colorless solid (466 mg, 57% yield); mp 272–273ꢀC; IR
4-[6-Hexyl-7-hydroxy-3-(1-methyl-1H-benzimidazol-2-yl)-4-
oxo-4H-chromen-2-yl]butanoic acid (5e). This compound was
obtained as colorless solid (583 mg, 63% yield); mp 125–127ꢀC;
(KBr): 3430, 2965, 1649, 1589, 1487, 1400 cmÀ1 1H NMR
;
(300 MHz): d 1.20 (t, 3H, J=7.6Hz, CH3CH2-6’), 2.66 (q, 2H,
J=7.6Hz, CH2-6’), 3.64 (s, 3H, NCH3), 4.11 (s 2H, CH2COOH),
4.51 (s 2H, CH2-2’), 7.00 (s, 1H, H-8’), 7.26 (1H, m, H-5’’), 7.32
(1H, m, H-6’’), 7.62 (1H, m, H-7’’), 7.68 (1H, m, H-4’’), 7.82
1
IR (KBr): 3061, 2928, 1713, 1627, 1586, 1470cmÀ1; H NMR
(300MHz): d 0.86, 1.29, 1.57, 1.86, 2.38, 2.63 (6 m, 3H, 6H, 2H,
2H, 2H, 4H, Hex-6’ and CH2CH2CH2COOH), 3.63 (s, 3H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. S. Frasinyuk, S. P. Bondarenko, N. V. Gorbulenko, A. V. Turov, and V. P. Khilya
Vol 000
(s, 1H, H-5’), 11.12 (s, 1H, OH-7’); 13C NMR (100 MHz,
CCl4 +DMSO-d6): d 13.7, 22.5, 30.3, 67.1, 67.4, 101.7, 110.0,
114.3, 114.9, 118.9, 121.5, 122.3, 124.7, 130.7, 135.7, 142.1,
146.4, 155.7, 161.5, 163.9, 170.7, 174.0; MS (CI) m/z (%): 409.2
(100, MH+). Anal. Calcd for C22H20N2O6: C, 64.70; H, 4.94; N,
6.86. Found: C, 64.56; H, 4.78; N, 7.11.
(m, 2H, H-4’’ and H-7’’), 9.51 (br. s, 1H, OH-4’), 12.00 (br. s, 3H,
COOH, NH and OH-2’); 13C NMR (100 MHz, CCl4 +DMSO-d6):
d 21.4, 32.4, 104.6, 104.7, 107.0, 109.4, 109.5, 121.5, 130.4, 138.2,
143.6, 147.0, 147.3, 156.9, 159.0, 173.8; MS (CI) m/z (%): 365.1
(100, MH+). Anal. Calcd for C19H16N4O4: C, 62.63; H, 4.43; N,
15.38. Found: C, 62.47; H, 4.56; N, 15.11.
3-[3-(2,4-Dihydroxyphenyl)-4-(1-methyl-1H-benzimidazol-2-yl)-
{[6-Ethyl-7-hydroxy-3-(4-methyl-1,3-thiazol-2-yl)-4-oxo-4H-
1H-pyrazol-5-yl]propanoic acid (7c).
obtained as colorless solid (295 mg, 78% yield); mp 284–285ꢀC;
IR (KBr): 3086, 2945, 1638, 1488, 1164 cmÀ1 1H NMR
This compound was
chromen-2-yl]methoxy}acetic acid (6f).
This compound was
obtained as colorless solid (383 mg, 51% yield); mp 182–184ꢀC;
IR (KBr): 3428, 3105, 2965, 1738, 1614, 1574, 1247 cmÀ1; H
1
;
(300 MHz): d 2.55 (t, 2H, J=7.6Hz, CH2COOH), 2.85 (t, 2H,
J=7.6Hz, CH2-3), 3.32 (s, 3H, NCH3), 6.09 (dd, 1H, J=2.4,
8.4 Hz, H-5’), 6.33 (d, 1H, J=2.4Hz, H-3’), 6.60 (d, 1H,
J=8.4Hz, H-6’), 7.23 (m, 2H, H-5’’ and H-7’’), 7.50 (m, 1H, H-7’’),
7.66 (m, 1H, H-4’’), 9.53 (br. s, 1H, OH-4’); 13C NMR (100 MHz,
CCl4 +DMSO-d6): d 20.7, 30.0, 32.5, 103.0, 104.9, 106.8, 108.1,
109.8, 118.7, 121.3, 121.7, 127.9, 135.4, 142.8, 145.1, 146.5, 148.2,
156.6, 158.6, 173.2; MS (CI) m/z (%): 379.2 (100, MH+). Anal. Calcd
for C20H18N4O4: C, 63.49; H, 4.80; N, 14.81. Found: C, 63.46; H,
NMR (300 MHz): d 1.21 (t, 3H, J = 7.6 Hz, CH3CH2-6’), 2.46
(s, 3H, CH3-4’’), 2.64 (q, 2H, J = 7.6Hz, CH2-6’), 4.24 (s 2H,
CH2COOH), 5.23 (s 2H, CH2-2’), 6.96 (s, 1H, H-8’), 7.34 (s, 1H,
H-5’’), 7.85 (s, 1H, H-5’), 10.95 (s, 1H, OH-7’), 12.02 (s, 1H,
COOH); 13C NMR (100MHz, CCl4 + DMSO-d6): d 13.6, 16.8,
22.4, 67.4, 68.1, 101.3, 114.4, 115.1, 115.9, 124.6, 130.6, 150.3,
154.8, 156.4, 161.2, 162.8, 171.0, 173.4; MS (CI) m/z (%): 376.1
(100, MH+). Anal. Calcd for C18H17NO6S: C, 57.59; H, 4.56; N,
3.73; S, 8.54. Found: C, 57.68; H, 4.36; N, 3.66; S, 8.56.
{[3-(1,3-Benzothiazol-2-yl)-7-hydroxy-4-oxo-6-propyl-4H-
4.56; N, 15.08.
3-[3-(5-Ethyl-2,4-dihydroxyphenyl)-4-(1-methyl-1H-benzimidazol-
chromen-2-yl]methoxy}acetic acid (6g).
This compound was
obtained as colorless solid (545 mg, 64% yield); mp 302–303ꢀC;
2-yl)-1H-pyrazol-5-yl]propanoic acid (7d). This compound was
obtained as colorless solid (236 mg, 58% yield); mp 166–168ꢀC; IR
IR (KBr): 3118, 2960, 1698, 1614, 1574, 1374cmÀ1; H NMR
1
(KBr): 3180, 2963, 1710, 1620, 1459, 1403 cmÀ1 1H NMR
;
(400MHz): d 0.91 (m, 3H, CH3CH2CH2-6’), 1.57 (m, 2H,
CH2CH2-6’), 2.57 (m, 2H, CH2-6’), 4.00 (s 2H, CH2COOH),
5.31 (s 2H, CH2-2’), 7.26 (s, 1H, H-8’), 7.45 (1H, m, H-5’’), 7.55
(1H, m, H-6’’), 7.77 (s, 1H, H-5’), 8.08 (1H, m, H-7’’), 8.16 (1H,
m, H-4’’), 11.08 (s, 1H, OH-7’), 12.08 (s, 1H, COOH); 13C NMR
(100MHz, CCl4 + DMSO-d6): d 13.7, 21.9, 31.3, 68.6, 69.6,
101.6, 114.0, 114.4, 121.2, 122.4, 124.6, 125.5, 125.6, 129.5,
135.4, 151.1, 155.1, 159.3, 162.2, 166.0, 173.7, 173.8; MS (CI)
m/z (%): 426.0 (100, MH+). Anal. Calcd for C22H19NO6S: C,
62.11; H, 4.50; N, 3.29; S, 7.54. Found: C, 62.28; H, 4.39; N,
3.18; S, 7.48.
(300 MHz): d 0.63 (t, 3H, J = 7.6, CH3CH2-5’), 2.14 (q, 2H,
J = 7.6, CH2-5’), 2.56 (t, 2H, J = 7.6 Hz, CH2COOH), 2.86 (t, 2H,
J = 7.6Hz, CH2-3), 3.31 (s, 3H, NCH3), 6.37 (s, 1H, H-3’), 6.40
(s, 1H, H-6’), 7.23 (m, 2H, H-5’’ and H-6’’), 7.50 (m, 1H, H-7’’),
7.66 (m, 1H, H-4’’), 9.42 (s, 1H, OH-4’); 13C NMR (100 MHz,
CCl4 + DMSO-d6): d 13.4, 20.7, 21,3, 30.0, 32.6, 102.6, 104.8,
107.5, 109.6, 118.6, 120.9, 121.3, 121.7, 126.9, 135.4, 142.6,
145.4, 146.3, 148.2, 154.2, 155.9, 173.2; MS (CI) m/z (%): 407.1
(100, MH+). Anal. Calcd for C22H22N4O4: C, 65.01; H, 5.46; N,
13.78. Found: C, 64.84; H, 5.56; N, 13.66.
4-[3-(2,4-Dihydroxyphenyl)-4-(1-methyl-1H-benzimidazol-2-yl)-
{[7-[(2,2-Dimethylpropanoyl)oxy]-6-ethyl-3-(1-methyl-1H-
benzimidazol-2-yl)-4-oxo-4H-chromen-2-yl]methoxy}acetic acid
(6h). This compound was obtained as colorless solid (768 mg,
78% yield); mp 237–238ꢀC; IR (KBr): 2973, 1758, 1647, 1620,
1H-pyrazol-5-yl]butanoic acid (8c). This compound was obtained
as colorless solid (247 mg, 63% yield); mp 267–268ꢀC; IR (KBr):
3379, 3116, 2945, 1618, 1412, 1242 cmÀ1; 1H NMR (300 MHz): d
1.76 (m, 2H, CH2-3), 2.18 (m, 2H, CH2COOH), 2.64 (m, 2H,
CH2-4), 3.34 (s, 3H, NCH3), 6.07 (dd, 1H, J=2.4, 8.4Hz, H-5’),
6.31 (d, 1H, J=2.4Hz, H-3’), 6.57 (d, 1H, J=8.4Hz, H-6’), 7.23
(m, 2H, H-5’’ and H-6’’), 7.50 (m, 1H, H-7’’), 7.66 (m, 1H, H-4’’),
9.53 (s, 1H, OH-4’); 13C NMR (100 MHz, CCl4 +DMSO-d6): d
23.7, 24.1, 30.1, 32.9, 103.0, 104.8, 106.9, 108.3, 109.9, 118.7,
121.4, 121.8, 127.7, 135.4, 142.7, 146.0, 146.7, 148.1, 156.7,
158.6, 173.8; MS (CI) m/z (%): 393.2 (100, MH+). Anal. Calcd for
C21H20N4O4: C, 64.28; H, 5.14; N, 14.28. Found: C, 64.42; H,
1
1474, 1104 cmÀ1; H NMR (300 MHz): d 1.19 (t, 3H, J=7.6Hz,
CH3CH2-6’), 1.38 (s, 9H, (CH3)3CCOO-7’), 2.66 (q, 2H,
J=7.6Hz, CH2-6’), 3.66 (s, 3H, NCH3), 4.14 (s 2H, CH2COOH),
4.55 (s 2H, CH2-2’), 7.27 (1H, m, H-5’’), 7.33 (1H, m, H-6’’),
7.63 (1H, m, H-7’’), 7.68 (1H, m, H-4’’), 7.69 (s, 1H, H-8’), 8.05
(s, 1H, H-5’); 13C NMR (100 MHz, CCl4 +DMSO-d6): d 13.9,
22.4, 26.7, 30.4, 38.8, 67.1, 67.3, 110.0, 112.1, 114.8, 119.1,
120.5, 121.4, 122.2, 125.4, 134.5, 135.7, 142.3, 145.8, 153.5,
154.3, 165.2, 170.7, 174.3, 175.2; MS (CI) m/z (%): 493.2 (100,
MH+). Anal. Calcd for C27H28N2O7: C, 65.84; H, 5.73; N, 5.69.
Found: C, 65.68; H, 5.92; N, 5.58.
5.00; N, 14.07.
4-[3-(5-Ethyl-2,4-dihydroxyphenyl)-4-(1-methyl-1H-benzimidazol-
2-yl)-1H-pyrazol-5-yl]butanoic acid (8d).
obtained as colorless solid (269 mg, 64% yield); mp 214–216ꢀC; IR
(KBr): 3218, 2963, 1616, 1473, 1407, 1238 cmÀ1 1H NMR
This compound was
General procedure for synthesis compounds 7–9.
The
hydrazine hydrate (8 mmol) was added to a stirred solution of
1 mmol chromone 4–6 in 10 mL of ethanol. The reaction
mixture was refluxed for 4 h, neutralized by acetic acid to pH 7
and diluted by water. The precipitate was filtered off, washed
with cold water, and crystallized from mixture ethanol–water.
3-[4-(1H-Benzimidazol-2-yl)-3-(2,4-dihydroxy–phenyl)-1H-
pyrazol-5-yl]propanoic acid (7a). This compound was obtained
as colorless solid (211 mg, 58% yield); mp 199–201ꢀC; IR (KBr):
;
(300 MHz): d 0.60 (t, 3H, J=7.6, CH3CH2-5’), 1.78 (m, 2H, CH2-3),
2.12 (q, 2H, J=7.6, CH2-5’), 2.18 (m, 2H, CH2COOH), 2.65 (m,
2H, CH2-4), 3.32 (s, 3H, NCH3), 6.36 (m, 1H, H-3’), 6.39 (s, 1H,
H-6’), 7.23 (m, 2H, H-5’’ and H-6’’), 7.49 (m, 1H, H-7’’), 7.65
(m, 1H, H-4’’), 9.35 (s, 1H, OH-4’); 13C NMR (100MHz,
CCl4 + DMSO-d6): d 13.4, 21.3, 23,8, 24.1, 30.0, 32.9, 102.6,
104.7, 107.6, 109.7, 118.7, 120.9, 121.4, 121.9, 126.6, 135.4,
142.6, 146.4, 146.5, 148.2, 154.3, 155.9, 173.8; MS (CI) m/z (%):
421.3 (100, MH+). Anal. Calcd for C23H24N4O4: C, 65.70; H,
5.75; N, 13.32. Found: C, 65.98; H, 5.56; N, 13.21.
1
3172, 3106, 1622, 1605, 1550, 1401 cmÀ1; H NMR (300 MHz):
2.63 (t, 2H, J=7.6Hz, CH2COOH), 3.04 (t, 2H, J=7.6Hz, CH2-3),
6.23 (dd, 1H, J= 2.4, 8.4 Hz, H-5’), 6.37 (d, 1H, J=2.4Hz, H-3’),
6.95 (d, 1H, J=8.4Hz, H-6’), 7.19 (m, 2H, H-5’’ and H-6’’), 7.54
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Cyclic Carboxylic Anhydrides as New Reagents for Formation of Chromone Ring
[7] (a) Murthi, K. K.; Dubay, M.; McClure, C.; Brizuela, L.;
Boisclair, M. D.; Worland, P. J.; Mansuri, M. M.; Pal, K. Bioorg Med
Chem Lett 2000, 10, 1037; (b) Kim, K. S.; Sack, J. S.; Tokarski, J. S.;
Qian, L.; Chao, S. T.; Leith, L.; Kelly, Y. F.; Misra, R. N.; Hunt, J. T.;
Kimball, S. D.; Humphreys, W. G.; Wautlet, B. S.; Mulheron, J. G.; Webster,
K. R. J Med Chem 2000, 43, 4126; (c) Kim, K. S. U.S. patent 5,849,733,
1998; (d) Sivakumar, M.; Mascarenhas, M.; Sarde, A.; Jadhav, P. K.; Shukla,
M.; Joshi, K.; Rathos, M. Patent WO2007/148158, 2007; (e) Schoepfer, J.;
Fretz, H.; Chaudhuri, B.; Muller, L.; Seeber, E.; Meijer, L.; Lozach, O.;
Vangrevelinghe, E.; Furet, P. J Med Chem 2002, 45, 1741.
[8] (a) Czech, J.; Hofmann, D.; Naik, R.; Sedlacek, H. H. Int J
Oncol 1995, 6, 31; (b) Sedlacek, H. H.; Hofmann, D.; Czech, J.; Kolar,
C.; Seeman, G.; Gussow, D.; Bosslet, K. Chimia 1991, 45, 311.
[9] Gungor, T.; Chen, Y.; Golla, R.; Ma, Z.; Corte, J. R.; Northrop,
J. P.; Bin, B.; Dickson, J. K.; Stouch, T.; Zhou, R.; Johnson, S. E.;
Seethala, R.; Feyen, J. H. M. J Med Chem 2006, 49, 2440.
[10] (a) Nohara, A.; Ishiguro, T.; Ukawa, K.; Kato, T.; Sawa, Y. JP
patent 78,018,573, 1978; Chem Abstr 1978, 89, 6328x; (b) Nohara, A.;
Ishiguro, T.; Ukawa, K.; Kato, T.; Sawa, Y. JP patent 78,018,574, 1978;
Chem Abstr 1978, 89, 24320t; (c) Nohara, A.; Ishiguro, T.; Ukawa, K.;
Kato, T.; Sawa, Y. JP patent 78,018,575, 1978; Chem Abstr 1978, 89,
43430v; (d) Nohara, A.; Ishiguro, T.; Ukawa, K.; Kato, T.; Sawa, Y. JP
patent 78,018,572, 1978; Chem Abstr 1978, 89, 43431w; (e) Kato, T.;
Nohara, A.; Kawarazaki, T.; Sawa, Y. JP patent 78,116,376, 1978; Chem
Abstr 1979, 90, 103963d.
[11] Pelter, A.; Ward, R. S.; Whalley, J. Synthesis 1998, 1973.
[12] Al-Maharik, N.; Mutikainen, I.; Wahala, K. Synthesis 2000, 411.
[13] Houerou, C.; Bennetau-Pelissero, C.; Lamothe, V.; Menn, F.;
Babin, P.; Bennetau, B. Tetrahedron 2000, 56, 295; (b) Shinkaruk, S.;
Lamothe, V.; Schmitter, J.-M.; Fructus, A.; Sauvant, P.; Vergne, S.;
Degueil, M.; Babin, P.; Bennetau, B.; Bennetau-Pelissero, C. J Agric
Food Chem 2008, 56, 6809.
[14] Al-Maharik, N. I.; Kaltia, S. A. A.; Mutikainen I.; Wahala K. J
Org Chem 2000, 65, 2305.
[15] Frasinyuk, M. S.; Khilya, V. P. Chem Heterocyc Compd 1999,
35, 3.
[16] (a) Khilya, V. P.; Grishko, L. G.; Sokolova, T. N. Chem
Heterocyc Compd 1975, 11, 1353; (b) Gorbulenko, N. V.; Frasinyuk,
M. S.; Khilya, V. P. Chem Heterocyc Compd 1994, 30, 405; (c) Gorbulenko,
N. V.; Turov, A. V.; Khilya, V. P. Chem Heterocyc Compd 1995, 31, 441;
(d) Frasinyuk, M. S.; Gorbulenko, N. V.; Khilya, V. P. Chem Heterocyc
Compd 1997, 33, 1078; (e) Frasinyuk, M. S.; Turov, A. V.; Khilya, V. P.
Chem Heterocyc Compd 1998, 34, 923.
[17] (a) Cheung, K.-M. J.; Matthews, T. P.; James, K.; Rowlands, M.
G.; Boxall, K. J.; Sharp, S. Y.; Maloney, A.; Roe, S. M.; Prodromou, C.;
Pearl, L. H.; Aherne, G. W.; McDonald, E.; Workman, P. Bioorg Med Chem
Lett 2005, 15, 3338; (b) Dymock, B. W.; Barril, X.; Brough, P. A.;
Cansfield, J. E.; Massey, A.; McDonald, E.; Hubbard, R. E.; Surgenor, A.;
Roughley, S. D.; Webb, P.; Workman, P.; Wright, L.; Drysdale, M. J. J
Med Chem 2005, 48, 4212; (c) Barril, X.; Beswick, M. C.; Collier, A.;
Drysdale, M. J.; Dymock, B. W.; Fink, A.; Grant, K.; Howes, R.; Jordan,
A. M.; Massey, A.; Surgenor, A.; Wayne, J.; Workmanb, P. , Wright, L.
Bioorg Med Chem Lett 2006, 16, 2543; (d) Brough, P. A.; Aherne, W.;
Barril, X.; Borgognoni, J.; Boxall, K.; Cansfield, J. E.; Cheung, K.-M. J.;
Collins, I.; Davies, N. G. M.; Drysdale, M. J.; Dymock, B.; Eccles, S. A.;
Finch, H.; Fink, A.; Hayes, A.; Howes, R.; Hubbard, R. E.; James, K.;
Jordan, A. M.; Lockie, A.; Martins, V.; Massey, A.; Matthews, T. P.;
McDonald, E.; Northfield, C. J.; Pearl, L. H.; Prodromou, C.; Ray, S.;
Raynaud, F. I.; Roughley, S. D.; Sharp, S. Y.; Surgenor, A.; Walmsley, D.
L.; Webb, P.; Wood, M.; Workman, P.; Wright, L. J Med Chem 2008, 51, 196.
[18] Frasinyuk, M. S.; Bondarenko, S. P.; Khilya, V. P. Chem Nat
Compd 2006, 42, 673.
4-[4-(1,3-Benzothiazol-2-yl)-3-(2,4-dihydroxy-5-propylphenyl)-
1H-pyrazol-5-yl]butanoic acid (8g).
This compound was
obtained as colorless solid (341mg, 78% yield); mp 182–184ꢀC;
IR (KBr): 3234, 2957, 1705, 1621, 1525, 1453 cmÀ1; H NMR
1
(300 MHz): d 0.84 (m, 3H, CH3CH2CH2-5’), 1.49 (m, 2H,
CH2CH2-5’), 1.95 (m, 2H, CH2-3), 2.34 (m, 2H, CH2-5’), 2.40
(m, 2H, CH2COOH), 3.05 (m, 2H, CH2-4), 6.47 (s, 1H, H-3’),
6.87 (s, 1H, H-6’), 7.29 (1H, m, H-5’’), 7.42 (1H, m, H-6’’), 7.88
(2H, m, H-7’’), 7.92 (1H, m, H-4’’), 9.31 (s, 1H, OH-4’), 9.45 (s,
1H, OH-2’), 12.45 (br. s, 2H, COOH and NH); 13C NMR
(100 MHz, CCl4 + DMSO-d6): d 13.8, 22.6, 23.6, 26.2, 31.0, 33.4,
102.7, 107.1, 111.6, 119.3, 120.9, 121.7, 123.7, 125.2, 131.9,
134.2, 143.7, 148.3, 152.7, 154.6, 157.0, 161.8, 174.1; MS (CI)
m/z (%): 438.2 (100, MH+). Anal. Calcd for C23H23N3O4S: C,
63.14; H, 5.30; N, 9.60; S, 7.33. Found: C, 63.37; H, 5.11; N,
9.46; S, 7.48.
{[3-(5-Ethyl-2,4-dihydroxyphenyl)-4-(4-methyl-1,3-thiazol-2-yl)-
1H-pyrazol-5-yl]methoxy}acetic acid (9f).
obtained as colorless solid (288 mg, 74% yield); mp 134–135ꢀC;
IR (KBr): 3205, 2963, 1714, 1619, 1522, 1418 cmÀ1 1H NMR
This compound was
;
(300 MHz): d 1.06 (t, 3H, J = 7.6, CH3CH2-5’), 2.33 (s, 3H,
CH3-4’’), 2.42 (q, 2H, J = 7.6, CH2-5’), 4.10 (s, 2H,
CH2COOH), 4.85 (s, 2H, CH2O), 6.45 (s, 1H, H-3’), 6.85 (s, 1H,
H-6’), 7.00 (s, 1H, H-5’’), 9.25 (s, 2H, OH-2’ and OH-4’); 13C
NMR (100 MHz, CCl4 + DMSO-d6): d 14.3, 16.7, 21.9, 64.4,
66.7, 103.1, 107.2, 112.4, 112.5, 121.0, 131.0, 141.9, 144.1,
150.7, 154.5, 156.8, 160.1, 171.3; MS (CI) m/z (%): 390.2 (100,
MH+). Anal. Calcd for C18H19N3O5S: C, 55.52; H, 4.92; N,
10.79; S, 8.23. Found: C, 55.28; H, 4.76; N, 10.95; S, 8.42.
{[4-(1,3-Benzothiazol-2-yl)-3-(2,4-dihydroxy-5-propylphenyl)-
1H-pyrazol-5-yl]methoxy}acetic acid (9g). This compound was
obtained as colorless solid (369 mg, 84% yield); mp 241–243ꢀC;
1
IR (KBr): 3229, 2958, 1731, 1623, 1530, 1351 cmÀ1; H NMR
(300 MHz): d 0.86 (m, 3H, CH3CH2CH2-5’), 1.51 (m, 2H,
CH2CH2-5’), 2.42 (m, 2H, CH2-5’), 4.19 (s, 2H, CH2COOH),
5.00 (s, 2H, CH2O), 6.50 (s, 1H, H-3’), 6.90 (s, 1H, H-6’), 7.30
(1H, m, H-5’’), 7.44 (1H, m, H-6’’), 7.90 (1H, m, H-7’’), 7.94
(1H, m, H-4’’), 9.35 (s, 1H, OH-4’), 9.47 (br. s, OH-2’); 13C
NMR (100 MHz, CCl4 + DMSO-d6): d 13.8 22.6, 31.0, 64.8,
66.8, 102.8, 106.3, 112.4, 119.5, 121.0, 121.7, 123.9, 125.3,
132.0, 134.1, 143.1, 145.3, 152.5, 154.6, 157.4, 161.3, 171.4;
MS (CI) m/z (%): 440.1 (100, MH+). Anal. Calcd for
C22H21N3O5S: C, 60.12; H, 4.82; N, 9.56; S, 7.30. Found: C,
60.33; H, 4.68; N, 9.54; S, 7.45.
REFERENCES AND NOTES
[1] Harborne, J. B.; Baxter, H.; Handbook of Natural Flavonoids;
Wiley: New York, 1999; Vol. 1,2, pp 1800.
[2] Buckingham, J.; Baggaley, K. H.; Roberts, A. D.; Szabo, L. F.;
Dictionary of Alkaloids, 2nd ed. with CD-ROM; CRC Press: Boca Raton,
2010; pp 1–2374.
[3] Kshetra, M.; Biswas, K. M.; Mallik, H. Phytochemistry 1986,
25, 1727.
[4] Kawai, Y.; Furihate, K.; Seto, H.; Otake, N. Tetrahedron Lett
1985, 26, 3273.
[19] Olugbade, T. A.; Usifoh, C. O.; Oluwadiya, J. O.. J Heterocyclic
Chem 1990, 27, 1727; (b) Zhang, C.-J., Han, W.-Y., Gao, M.-X., Xu, F.-F.;
Zhang, Z.-T. J Heterocyclic Chem 2011, 48, 1073.
[20] Zhang, Z.-T., Ma, Y.-Q., Liang, Y., Xue, D.; He, Q. J Heterocyclic
Chem 2011, 48, 279.
[21] Bondarenko, S. P.; Frasinyuk, M. S.; Khilya, V. P. Chem Nat
Compd 2007, 43, 402.
[5] Kobayashi, K.; Nishino, C.; Ohya, J.; Sato, S.; Mikawa, T.;
Shiobara Y.; Kodama, M. J Antibiot 1988, 41, 502.
[6] Moriyama, M.; Tahara, S.; Ingham, J. L., Mizutani J. Phyto-
chemistry 1993, 32, 1317.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet