Synthesis and characterization of new 2-amino-4-(3,4-dihydro-7-methoxy-2,2- dimethyl-2H-benzopyran-6-yl)-6-(substituted phenyl)pyrimidines and their bioevaluation

Article abstract of DOI:10.2298/JSC110923008M

A series of eight novel 2-amino-4-(3,4-dihydro-7-methoxy-2,2-dimethyl-2H- benzopyran-6-yl)-6-(substituted phenyl)pyrimidines were designed and synthesized by utilizing benzene-1,3-diol as the starting material. The structures of the isolated products (6a-h) were established through ¹H-NMR, ¹³C-NMR, and FT-IR spectroscopic techniques and elemental analysis. The antimicrobial properties of the synthesized compounds were screened against gram positive (Bacillus pumilus, Bacillus subtilis and Streptococcus faecalis), gram negative bacteria (Enterococcus faecalis, Escherchia coli and Proteus vulgaris) and fungi (Pencillium expansum, Aspergillus niger and Candida albicans) using ampicillin and ketoconazole as reference compounds. Most of the compounds showed moderate to high antibacterial and antifungal activities against the studied strains, with inhibition zones between 8 and 30 mm.

Full text of DOI:10.2298/JSC110923008M

J. Serb. Chem. Soc. 77 (7) 859–866 (2012)
JSCS–4314
UDC 547.814+547.853+66.095.3:
615.281.004.12
Original scientific paper
Synthesis and characterization of new 2-amino-4-(3,4-dihydro-
-7-methoxy-2,2-dimethyl-2H-benzopyran-6-yl)-6-(substituted
phenyl)pyrimidines and their bioevaluation
1
1
*
YELLAJYOSULA LAKSHMI NARASIMHA MURTHY , KILARU PADMA SUHASINI
and ANJALI JHA2
1Department of Organic Chemistry, Andhra University, Visakhapatnam, India
and 2Department of Chemistry, Gitam Institute of Science,
GITAM University, Visakhapatnam, India
(Received 23 September 2011, revised 22 January 2012)
Abstract: A series of eight novel 2-amino-4-(3,4-dihydro-7-methoxy-2,2-dime-
thyl-2H-benzopyran-6-yl)-6-(substituted phenyl)pyrimidines were designed
and synthesized by utilizing benzene-1,3-diol as the starting material. The
1
structures of the isolated products (6a–h) were established through H-NMR,
13C-NMR, and FT-IR spectroscopic techniques and elemental analysis. The
antimicrobial properties of the synthesized compounds were screened against
gram positive (Bacillus pumilus, Bacillus subtilis and Streptococcus faecalis),
gram negative bacteria (Enterococcus faecalis, Escherchia coli and Proteus
vulgaris) and fungi (Pencillium expansum, Aspergillus niger and Candida al-
bicans) using ampicillin and ketoconazole as reference compounds. Most of the
compounds showed moderate to high antibacterial and antifungal activities
against the studied strains, with inhibition zones between 8 and 30 mm.
Keywords: benzopyran; chalcones; Claisen–Schmidt condensation; 2-amino
pyrimidine derivatives; antimicrobial activity.
INTRODUCTION
th
Antibiotics revolutionized medical care in the 20 century. However, the
emergence of super bugs, i.e., bacteria that resist the effects of the most powerful
1
antibiotics, are posing a great challenge to the field of medicine. In this sense,
nitrogen-containing heterocycles are an important class of compounds in
2
medicinal chemistry. As pyrimidines seem to possess a wide spectrum of bio-
3
logical activity, there has been considerable interest in the development of pre-
parative methods for the production of pyrimidines.
*Corresponding author. E-mail: murthyyln@gmail.com
doi: 10.2298/JSC110923008M
859
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MURTHY, SUHASINI and ANJALI
On the other hand, pyrimidines, being an integral part of DNA and RNA,
exhibit diverse pharmacological properties as effective bactericide, fungicide,
4
5
6
7
viricide, insecticide and meticide, antitubercular, antineoplastic, antitumor,
8
9
10
11
anti-inflammatory, diuretic, antimalarial, cardiovascular, calcium channel
blockers and many other classes of chemotherapeutic agents.
12
13
The benzopyran ring occurs frequently in natural products. However 3,4-di-
hydro-2H-benzopyrans occur rarely in nature but are useful degradation products
14
of a large number of natural products. They have been reported to show marked
15
pharmacological activities. The biological activity of many of the naturally oc-
curring compounds which incorporate a benzopyran ring has resulted in several
16
applications of various levels of saturation and oxidation in synthesis. Due to
the various biological functions associated with this skeleton, it has been fre-
17
quently employed as a key scaffold in drug research.
18
In view of these observations and in continuation of our work on biologi-
cally active heterocycles and their increasing importance in pharmaceutical and
biological fields, it was considered of interest to synthesize some new chemical
entities incorporating two active pharmacophores in a single molecular frame-
work and to evaluate their biological activities. In this respect, eight novel 2-ami-
no-4-(3,4-dihydro-7-methoxy-2,2-dimethyl-2H-benzopyran-6-yl)-6-(substituted
phenyl)pyrimidines (6a–h) were synthesized via benzopyranylchalcones and the
antimicrobial activities of the compact structures were screened.
EXPERIMENTAL
Materials, methods and instruments
All the chemicals and solvents used in this work were of analytical reagent grade (an-
hydrous) and purchased from Sigma–Aldrich. Melting points were determined using an elec-
1
tro-thermal apparatus in an open capillary tube and are uncorrected. The H-NMR and 13C-
-NMR spectra were recorded on a JEOL JNM Ex-90 instrument, at 90 and 22.5 MHz, res-
pectively, using TMS as an internal reference in CDCl3. The IR spectra were recorded in KBr
discs on a Thermo Nicolet 6700 FTIR spectrophotometer. The HPLC was performed using a
Shimadzu LC 6A instrument fitted with a Shimpack silica gel column using acetonitrile as the
solvent. The mass spectra were obtained on a Varian Atlas CH-7 mass spectrometer. Ele-
mental analyses were performed using an Elementar Vario EL elemental analyzer. Satis-
factory C, H, N analyses were obtained for all the compounds.
The steps involved in the synthesis of the new series of 2-amino-4-benzopyran-6-yl pyri-
midines from benzene-1,3-diol are depicted in Scheme 1.
Synthesis of 3,4-dihydro-7-hydroxy-2,2-dimethyl-2H-benzopyran (2)
To a solution of benzene-1,3-diol 1 (10 mmol) in dichloromethane (20 mL) was added
polyphosphoric acid (0.1 eq.) followed by 2-methyl-3-buten-2-ol (5 mmol) and the mixture
was stirred for 1 h at room temperature. The reaction mixture was heated at reflux for 4 h.
After cooling, the mixture was neutralized with saturated NaHCO3 and extracted with
dichloromethane. The solvent was removed and the residue recrystallized from n-hexane to
give a white crystalline solid in 68 % yield, which was characterized by its spectral data.19
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BIOEVALUATION OF NEW PYRIMIDINE DERIVATIVES
861
R: a) H, b) 4-CH3, c) 4-OCH3, d) 2,5-OCH3, e) N(Me)2, f) 4-Cl, g) 4-NO2, h) 4-CN
Scheme 1. The synthetic pathway to the new 2-amino benzopyrano pyrimidines 6a–h.
Synthesis of 6-acetyl-3,4-dihydro-7-hydroxy-2,2-dimethyl-2H-benzopyran (3)
3,4-Dihydro-7-hydroxy-2,2-dimethyl-2H-benzopyran (2) (8 mmol) was acetylated using
acetic acid (8 mmol) in the presence of freshly fused ZnCl2 (8 mmol) at 140–150 °C under
stirring for 15 min. After cooling to room temperature, HCl was added to the reaction mixture
to break the zinc chloride complex and in 5 min precipitation commenced. The precipitate was
washed with very dilute HCl to afford colorless needles in 54 % yield. The product was
characterized by its spectral data.19
Synthesis of 6-acetyl-3,4-dihydro-7-methoxy-2,2-dimethyl-2H-benzopyran (4)
To a solution of 6-acetyl-3,4-dihydro-7-hydroxy-2,2-dimethyl-2H-benzopyran 3 (8 mmol)
in acetone (20 mL), anhydrous K2CO3 (16 mmol) and dimethyl sulfate (8 mmol) were added
and the mixture was stirred at room temperature for 2 h. The reaction mixture was poured into
water, extracted with diethyl ether and dried over anhydrous Na2SO4. The residue was
chromatographed using n-hexane and ethyl acetate (9:1) to give the compound as a colorless
oil.
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MURTHY, SUHASINI and ANJALI
General method for the synthesis of 5a–h
To a stirred solution of 6-acetyl-3,4-dihydro-7-methoxy-2,2-dimethyl-2H-benzopyran 4
(6 mmol) and a substituted benzaldehyde (6 mmol) was added gradually BF3·Et2O (3 mmol)
at room temperature in dioxane. The solution was stirred for 2–3 h at room temperature. The
reaction was monitored by TLC. After completion of the reaction, the reaction mixture was
cooled to room temperature and diluted with moist diethyl ether (50 mL), washed with water
to discharge the color and the BF3·Et2O complex. The extracted ethereal solution was dried
over anhydrous Na2SO4, concentrated and recrystallized from dry ethanol to afford the
appropriate pure chalcone.
General procedure for the synthesis of 6a–h
6-(Substituted cinnamoyl)-3,4-dihydro-7-methoxy-2,2-dimethyl-2H-benzopyran (5 mmol)
and guanidine hydrochloride (5 mmol) were refluxed in presence of freshly prepared sodium
methoxide (5 mmol) in methanol for 4–5 h. The solvent was evaporated and the residue was
neutralized with 20 % HCl whereby a yellow solid separated out, which was filtered and crys-
tallized from ethanol to give yellow crystals.
Antimicrobial activity
The in vitro antimicrobial activity determination was performed by the well-diffusion
method20 using 100 µg ml-1. All the synthesized compounds (6a–h) were screened for anti-
bacterial activity against 3 gram positive bacteria Bacillus pumilus, Bacillus subtilis and
Streptococcus faecalis, 3 gram negative bacteria Enterococcus faecalis, Escherichia coli and
Proteus vulgaris and 3 fungi Pencillium expansum, Aspergillus niger and Candida albicans
using ampicillin and ketoconazole as standards in DMSO. DMSO showed no inhibition zone.
Nutrient agar (NA) and potato dextrose agar (PDA) were used as the basal medium for test
bacteria and fungi, respectively. Inhibition was recorded in millimeters by measuring the dia-
meter of the inhibition zone at the end of 24 h for bacteria and 48 h for fungi with a Hi
antibiotic zone scale at (35±2) °C. Each experiment was repeated twice and the average of the
two determinations was recorded. The results are summarized in Tables I and II.
RESULTS AND DISCUSSIONS
The characterization data of all the synthesized compounds are given in the
supplementary material to this paper.
Spectroscopy
21
According to the literature, condensation of benzene-1,3-diol 1 with 2-me-
thylbut-3-en-2-ol in presence of citric acid and phosphoric acid yielded 3,4-
dihydro-7-hydroxy-2,2-dimethyl-2H-benzopyran in 55 and 43 % yield, respecti-
vely. In the present attempts to modify the reaction conditions, polyphosphoric
acid was found to be a better condensing agent with 2-methyl-3-buten-2-ol lead-
ing to the cyclic benzopyran 2 in very good yield.
The preparation of 2-hydroxychalcones from 2-hydroxyacetophenones and
benzaldehydes generally presents some difficulties because they always partially
22
cyclize to flavanones during their synthesis, resulting in low yields. Hence
compound 3 was methylated to 4 using dimethyl sulfate to avoid byproducts and
1
to obtain only chalcones in good yields. The sharp singlet at δ 3.71 in the H-
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BIOEVALUATION OF NEW PYRIMIDINE DERIVATIVES
863
13
-NMR, the peak at δ 53.6 in the C-NMR and the disappearance of the band at
–1
3433 cm (OH) in the IR spectra confirmed the methoxy group of compound 4.
The synthesis of the title compounds was achieved via chalcone formation, which
was generated in situ by the Claisen–Schmidt condensation of 4 with different
aromatic aldehydes in presence of BF ·Et O within 2–3 h, without any side reac-
3
2
23
tions. Generally, in aqueous KOH- or NaOH-assisted synthesis of chalcones,
the reaction times were much longer (1–2 days), with a high probability of side
reactions, such as via the Cannizzaro reaction or aldol condensation. By using
BF ·Et O, the side reactions were reduced and chalcones were obtained exclu-
3
2
1
sively, in good yields. The H-NMR spectra of compounds 5a–h show doublets
of –CO–CH=CH–Ar and –CO–CH=CH–Ar at about δ 6.7 and 7.8 ppm, respec-
tively, and the signals around δ 120 and 140 ppm in the C-NMR spectra
confirmed the presence of the chalcone moiety.
13
Finally, the target compounds were obtained by cyclization of 5a–h in the
presence of sodium methoxide in methanol with guanidine hydrochloride to give
the products in good to excellent yields. The target compounds on purification
and crystallization formed bright yellow crystalline solids of 99 % purity by
HPLC. The synthesized 2-amino-4-benzopyran-6-ylpyrimidines (6a–h) exhibited
–1
characteristic primary amine bands at 3400–3100 cm and did not show any
–1
absorption band in the region of 1700–1600 cm , which indicates the absence of
–1
>C=O groups. The stretching peak of >C=N– appeared at 1600–1510 cm and
–1
the absorption band at 855–800 cm was characteristic of aromatic C–H bending
1
vibrations. The H-NMR spectrum showed the C -H proton as a singlet around δ
5
7.20–7.41 ppm and a broad signal around at δ 5.0 ppm due to the amino protons,
which disappeared on D O exchange and the aromatic protons appeared between
2
24
δ 7.2–7.9 ppm as a multiplet in all synthesized compounds as expected. In the
C-NMR spectra of the pyrimidines, the C carbon was the most deshielded car-
13
2
bon, appearing at δ 160 ppm, the C /C -carbons resonated at δ 157 ppm as ex-
4
6
25
pected. The C carbon resonated at δ 122 ppm nearer to the aromatic carbon
5
shifts.
Antimicrobial screening
In the assay of the antimicrobial activity, all eight newly synthesized title
compounds showed significant activity against E. coli with inhibition zones of 16
to 32 mm. Based on the inhibition zones shown by these compounds against all
nd
th
the tested bacterial strains, compound 6d with methoxy groups at 2 and 5
positions was found to be most effective against E. coli and B. subtilis, with acti-
vities nearly equal to those of the standard antibiotic ampicillin. This was explained
26
as being due to the dimethoxy molecule being lipophilic and good electron
mobility in the aromatic ring may enhance the activity. It was demonstrated that
increasing the number of methoxy groups on the phenyl ring or introducing an
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electronic donating substituent on the phenyl ring resulted in increased anti-
bacterial activity.
TABLE I. Inhibition zone (mean diameter of inhibition in mm) as a criterion of the antibac-
terial activities of the newly synthesized compounds
Gram-positive bacteria
B. pumilus B. subtilis S. faecalis
Gram-negative bacteria
Compound
E. faecalis
E. coli
P. vulgaris
6a
6b
6c
6d
6e
6f
6g
6h
11
12
20
27
15
8
11
10
25
14
15
23
29
18
14
19
11
28
12
16
21
23
16
–
15
13
24
13
14
18
20
17
14
16
–
16
18
27
32
21
24
22
19
31
9
11
14
22
16
12
11
10
20
Ampicillin
22
TABLE II. Inhibition zone (mean diameter of inhibition in mm) as a criterion of the antifungal
activities of the newly synthesized compounds
Fungi
A. niger
Compound
P. expansom
C. albicans
6a
6b
6c
6d
6e
6f
6g
6h
8
–
13
16
15
16
15
24
22
17
23
11
11
10
–
16
18
21
15
19
11
17
15
21
24
18
22
Ketoconazole
From the screening results, it was observed that the presence of nitro and
chloro groups at the phenyl ring in compounds 6f and 6g increased the antifungal
activity against A. niger and their activity was equipotent to those of the standard
ketoconazole. The other compounds, 6a–e and 6h, exhibited lower activities
compared with those of the standard ketoconazole.
CONCLUSIONS
In conclusion, eight novel 2-amino-4-benzopyran-6-yl pyrimidines (6a–h)
were synthesized from benzene-1,3-diol and were subjected to in vitro anti-
microbial activity screening against various pathogenic bacteria and fungi. The
screening results indicated that all the compounds exhibited moderate activity
against bacteria and fungi, except the 6d, 6f and 6g compounds. These diffe-
rences in activity depended on the substitution of different reactive groups on the
pyrimidine moiety. Further studies to explore the structure–activity relationship
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BIOEVALUATION OF NEW PYRIMIDINE DERIVATIVES
865
by structural modifications of the final investigated compounds to improve their
biological activity are in progress.
SUPPLEMENTARY MATERIAL
Analytical and spectral data of the synthesized compounds are available electronically
from http://www.shd.org.rs/JSCS/, or from the corresponding author on request.
И З В О Д
СИНТЕЗА И КАРАКТЕРИЗАЦИЈА НОВИХ 2-АМИНО-4-(3,4-ДИХИДРО-2,2-ДИМЕТИЛ-7-
МЕТОКСИ-2Н-БЕНЗОПИРАН-6-ИЛ)-6-(СУПСТИТУИСАНИ ФЕНИЛ)ПИРИМИДИНА И
ИСПИТИВАЊЕ ЊИХОВЕ БИОЛОШКЕ АКТИВНОСТИ
YELLAJYOSULA LAKSHMI NARASIMHA MURTHY1, KILARU PADMA SUHASINI1 и ANJALI JHA2
1Department of Organic Chemistry, Andhra University, Visakhapatnam, India и 2Department of Chemistry,
Gitam Institute of Science, GITAM University, Visakhapatnam, India
Синтетисана је нова серија од осам деривата 2-амино-4-(3,4-дихидро-2,2-диметил-7-ме-
токси-2Н-бензопиран-6-ил)-6(супституисани фенил)пиримидина, употребом бензен 1,3-ди-
ола као полазног једињења. Структура изолованих производа (6a–h) утврђена је спектро-
скопским техникама 1H-NMR, 13C-NMR и FT-IR и елементалном анализом. Испитана је
биолошка активност синтетисаних једињења према грам-позитивним (Bacillus pumilus, Bacil-
lus subtilis и Streptococcus faecalis) и грам-негативним (Enterococcus faecalis, Escherichia coli
и Proteus vulgaris) бактеријама и гљивама (Pencillium expansum, Aspergillus niger и Candida
albicans). Већина деривата показује умерену до високу антибактеријску и фунгицидну актив-
ност, са зонама инхибиције између 8 и 30 mm.
(Примљено 23. септембра 2011, ревидирано 22. јануара 2012)
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2012 Copyright (CC) SCS

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