Novel chromeno [2,3-b]-pyrimidine derivatives as potential anti-microbial agents

Article abstract of DOI:10.1016/j.ejmech.2010.02.040

An efficient, microwave irradiated synthesis of novel chromeno[2,3-b]-pyrimidine derivatives was carried out. 2-Amino-3,4-dihydro-2H-chromene-3-carbonitrile was converted into imine using N,N-Dimethylacetaldehyde dimethylacetal to give the core intermediate, which was used for the preparation of chromenopyrimidine library, using acetic acid and different amine in microwave irradiation for 5?min. Structures of newly synthesized compounds were confirmed by spectral studies. Compound 6g was characterized by single crystal X-ray analysis. All the compounds were also screened for their anti-microbial activity. Few of the compounds are found to be potential antimicrobials.

Full text of DOI:10.1016/j.ejmech.2010.02.040

European Journal of Medicinal Chemistry 45 (2010) 2695e2699
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Novel chromeno [2,3-b]-pyrimidine derivatives as potential
anti-microbial agents
,
c
b
U. Sankappa Rai a, Arun M. Isloor b , Prakash shetty , A.M. Vijesh ,
*
Nithin Prabhu d, Shrikrishna Isloor d, M. Thiageeswaran d, Hoong-Kun Fun e
a Chemistry Department, Manipal Institute of Technology, Manipal, India
b Department of Chemistry, Organic Chemistry Division, National Institute of Technology Karnataka, Surathkal 575 025, India
c Department of Printing, Manipal Institute of Technology, Manipal, India
d Department of Microbiology, Veterinary College, KVAFSU, Hebbal, Bangalore 560 02, India
e X-ray Crystallography Unit, School of Physics, Universiti Sains Malaysia, 11800 USM, Penang, Malaysia
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, microwave irradiated synthesis of novel chromeno[2,3-b]-pyrimidine derivatives was carried
out. 2-Amino-3,4-dihydro-2H-chromene-3-carbonitrile was converted into imine using N,N-Dimethyla-
cetaldehyde dimethylacetal to give the core intermediate, which was used for the preparation of chro-
menopyrimidine library, using acetic acid and different amine in microwave irradiation for 5 min.
Structures of newly synthesized compounds were confirmed by spectral studies. Compound 6g was
characterized by single crystal X-ray analysis. All the compounds were also screened for their anti-
microbial activity. Few of the compounds are found to be potential antimicrobials.
Received 18 January 2010
Received in revised form
15 February 2010
Accepted 16 February 2010
Available online 20 February 2010
Keywords:
Ó 2010 Elsevier Masson SAS. All rights reserved.
Chromeno[2,3-b] pyrimidine
Chromene-3-carbonitrile
Antimicrobial study
1. Introduction
continuing efforts in designing novel heterocyclic molecules of bio-
logical importance [16,17].
Condensed heterocyclic systems are of considerable interest not
only because of their potential biological activity, but also because
of their versatility as synthones in organic transformations [1e3]. A
series of 1,6-naphthyrimidines have demonstrated antihuman
cytomegalovirus (HCMV) activity [4,5]. Pyrimidine and its deriva-
tives have been studied for over a century due to a variety of
chemical and biological significance [6].
Similarly, chromene derivatives are an important class of
compounds, widely present in plants, including edible vegetables
and fruits [7]. Numerous bioactive natural products have been
identified, and the presence of the chromene-based structure has
been associated with the capacity to prevent disease [8]. Synthetic
analogues have been developed over the years, some of them dis-
playing remarkable effects as pharmaceuticals [9], including anti-
fungal [10], anti-microbial [11], molluscidial [12], anticoagulant,
spasmolytic, diuretic, anticancer and antianaphylactic characteristics
[13]. Moreover, nitrogen-containing heterocycles [14,15] are also of
broad pharmaceutical interest and significance, which justifies our
2. Chemistry
2-Imino-2H-chromene-3-carbonitrile 3 was prepared using sali-
cylaldehyde and malononitrile in the presence of triethylamine [18].
2-Imino-2H-chromene-3-carbonitrile was reduced using sodium
borohydride in methanol to yield 2-amino-3,4-dihydro-2H-chro-
mene-3-carbonitrile 4. Further this amine was converted into imine
using N,N-Dimethylacetaldehyde dimethyl acetal to yield core
intermediate 5, which was used for the preparation of chromeno-
pyrimidine library, using acetic acid and different amine in micro-
wave irradiation (Fig. 1).
3. Antimicrobial studies
All the newly synthesized compounds were screened for their
antibacterial activity. For this, Staphylococcus aureus, Bacillus subtilis,
Escherichia coli and Pseudomonas aeruginosa microorganisms were
employed. Antimicrobial study was assessed by Minimum Inhibitory
Concentration (MIC) by serial dilution method [19]. Several colonies
of S. aureus, B. subtilis, E. coli and P. aeruginosa were picked off a fresh
isolation plate and inoculated in corresponding tubes containing
* Corresponding author. Tel.: þ91 824 2474000x3206; fax: þ91 824 2474033.
E-mail address: isloor@yahoo.com (A.M. Isloor).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.02.040

2696
U. Sankappa Rai et al. / European Journal of Medicinal Chemistry 45 (2010) 2695e2699
CHO
CN
NH
CN
NH
CN
CN
Ethanol/Triethylamine
NaBH4/Methanol
+
OH
O
O
2
1
2
3
4
R
HN
CN
N
DMF acetal
R-NH , AcOH
2
N
Reflux, 2 hr.
O
N
Microwave, 5 min
O
6
N
5
Fig. 1. Scheme for synthesis of Chromeno pyrimidines.
5 mL of trypticase soya broth. The broth was incubated for 6 h at
37 ꢀC until there was visible growth. Mc Farland No.5 standard was
prepared by adding 0.05 mL of 1% w/v BaCl2$2H2O in Phosphate
Buffered saline (PBS) to 9.95 mL of 1% v/v H2SO4 in PBS. The growth
of all the four cultures was adjusted to Mc Farland No.5 turbidity
standard using sterile PBS. This gives a 108 cfu/mL suspension. The
working inoculums of aforementioned four different microorgan-
isms containing 105 cfu/mL suspension was prepared by diluting the
108 cfu/mL suspension, 103 times in trypticase soya broth.
3 led to iminocoumarin derivative 3 in good yield [20]. The structure
of the iminocoumarin and coumarin derivatives were determined by
IR, 1H NMR, 13C NMR, mass spectra and elemental analysis. A singlet
peak at 8.83 ppm in 1H NMR indicates imine-NH and peak at 2231
(CN) in IR confirms the structure. Subsequent reduction of 3 using
sodiumborohydride in methanol medium resulted 2-amino-3,4-
dihydro-2H-chromene-3-carbonitrile 4.
N0-(3-cyano-3,4-dihydro-2H-chromen-2-yl)-N,N-dimethylimi-
doformamide 5 was prepared by refluxing 4 in N,N-Dimethlactal-
dehyde dimethylacetal for 1 h. Compound 5 is core intermediate for
the synthesis of chromeno[2,3-b]-pyrimidine library. Microwave
irradiation of intermediate 5 with different amines in acetic acid
gave chromeno[2,3-b]-pyrimidine derivatives 6(aek) within 5 min.
All compounds are characterized after purification by column
chromatography. A single crystal has been developed for compound
6g and its X-Ray structural analysis was carried out [21]. Spectral
data of all the compounds and C, H, N analyses are given in the
experimental part.
3.1. Preparation of anti-microbial suspension (50
mg/mL)
Dissolved 0.5 mg of each compound in 10 mL of trypticase soya
broth to get 50
mg/mL. This suspension was filter sterilized in
syringe filters.
3.2. Preparation of dilutions
In all, for each of the 11 anti-microbial compounds and standard
anti-microbial i.e. Ceftriaxone, 24 tubes of 5 mL capacity were
arranged in 4 rows with each row containing 6 tubes. Then 1.9 mL of
trypticase soya broth was added in the first tube in each row and 1 mL
5. Conclusions
A series of novel chromeno[2,3-b]-pyrimidine derivatives were
synthesized by microwave irradiation in reasonably good yields.
in the remaining tubes. Now, 100
ml of filtered anti-microbial
suspension was added to the first tube in each row and after mix-
ing the content, 1 mL was serially transferred from these tubes to the
second tube in each of the rows. The contents in the second tube of
each of the rows were mixed and transferred to the third tube in each
of the rows. This serial dilutionwas repeated till the sixth tube in each
of the rows. This provided anti-microbial concentrations of 50, 25,
Table 1
Antibacterial activity data in MIC (
m
g/mL).
Compound
No.
S. aureus
B.subtilis
E.coli
P.aeruginosa
6a
6b
6c
6d
6e
6f
Growth in all Growth in all Growth in all Growth in all
concentrations concentrations concentrations concentrations
Growth in all Growth in all Growth in all Growth in all
concentrations concentrations concentrations concentrations
Growth in all Growth in all Growth in all Growth in all
concentrations concentrations concentrations concentrations
1.6125
1.6125
1.6125
1.6125
1.6125
12.5, 6.25, 3.125, 1.6125 mg/mL in the first to sixth tube respectively in
each row. Finally,1 mL of 105 cfu/mL of S. aureus, B. subtilis, E. coli and
P. aerogenosa suspension were added to the first, second, third and
fourth rows of tubes respectively. Along with the test samples and
Ceftriaxone (standard), the inoculums control (without anti-
microbial compound) and broth control (without anti-microbial
compound and inoculum) were maintained. All the test sample and
control tubes were then incubated for 16 h at 37 ꢀC.
1.6125
1.6125
1.6125
1.6125
1.6125
3.125
25.00
50.00
Growth in all
concentrations
Growth in all
concentrations
Growth in all
concentrations
3.3. Interpretation
6g
6h
6i
Growth in all Growth in all
concentrations concentrations
Growth in all Growth in all
concentrations concentrations
After incubation, the tubes showing no visible growth was
considered to be representing the MIC. The details of results are
furnished in Table 1. Inoculums control showed visible growth,
where as the broth control showed no growth (Fig. 1).
Growth in all Growth in all 50.00
concentrations concentrations
50.00
6j
50.00
Growth in all Growth in all Growth in all
concentrations concentrations concentrations
6k
Growth in all Growth in all Growth in all 25.00
concentrations concentrations concentrations
4. Results and discussion
Ceftriaxone
(Standard)
Inoculum
control
Broth
control
3.125
1.6125
1.6125
1.6125
Iminocoumarin (2-imino-2H-chromene-3-carbonitrile)
3 was
prepared using Knoevenagel condensation procedure, in oneepot
reaction from 2-hydroxybenzaldehyde 1 and malononitrile 2 in the
presence of triethylamine. The spontaneous cyclization between the
ortho hydroxy group and the side-chain cyano group of intermediate
Growth in all Growth in all Growth in all Growth in all
concentrations concentrations concentrations concentrations
No growth
No growth
No growth
No growth

U. Sankappa Rai et al. / European Journal of Medicinal Chemistry 45 (2010) 2695e2699
2697
They were characterized by 1H NMR, 13C NMR, mass spectrometry,
IR studies and elemental analyses. Compound 6g was analyzed for
its molecular structure by single crystal X-ray crystallography. All
the newly synthesized compounds were screened for antibacterial
activity by MIC method. Among the screened samples 6a, 6b and 6c
have not showed any antibacterial property against all bacterial
strains. However compounds 6d, 6e, 6f, 6g and 6h have showed
(50 mL) was heated to reflux for 1 h. Reaction mixture was
concentrated and the residue was triturated with Diethyl ether to
get compound 5 as yellow solid (11 g, 84%). IR (cmꢁ1) 3406 (NH),
3003 (CH), 1699 (C]N),1280 (CeO). 1H NMR (300 MHz, DMSO-d6):
d
(ppm): 2.5 (m, 2H, CH2), 3.5 (m, 1H, CH), 4.8 (m, 1H, CH), 7.18e7.21
(1H, m, AreH); 7.24e7.29 (1H, m, AreH); 7.55e7.61 (2H, m, AreH),
8.4 (s, 1H, CH). MS: m/z ¼ 230 (Mþ). Anal. calcd. for C13H15N3O: C,
6812; H, 6.55; N, 18.34; Found: C, 68.08; H, 6.53; N, 18.31%.
excellent antibacterial activity at 1.6125
against S. aureus bacteria as compared to the standard drug Cef-
triaxone which is active at3.125 g/mL concentration. Similarly
compounds 6d, 6e, 6f, 6g and 6h have showed same activity as that
of the standard which is active at 1.6125 g/mL against B. subtilis.
mg/mL concentration
m
6.4. General procedure for synthesis of 5H-chromeno [2,3-d]
pyrimidin-4-amine derivatives 6(aek)
m
However none of the compounds were active against bacterial
strains E. coli and P. aeruginosa. Compounds 6d, 6e, 6f, 6g and 6h
have benzylpiperdine, benzyl, 4-chlorobenzyl, 1-naphthyl and 2,5-
dimethylphenyl substituents respectively, which is accounted for
their significant antibacterial activity.
A
slurry of N-(3-cyano-3,4-dihydro-2H-chromen-2-yl)-N,N-
dimethylformamide 5 (4.3 mmol), corresponding amine (4.3 mmol)
in acetic acid (2 mL) was irradiated in microwave for 5 min. Resulting
dark residue was poured to water, filtered the solid separated,
recrystallised from ethanol to get pure compound.
6. Experimental
6.4.1. 5H-chromeno [2,3-d]pyrimidin-4-amine (6a)
Yield 68%, M.p.190e193 ꢀC, IR (cmꢁ1) 3360 (NH), 3041 (CH),
Melting points were determined by open capillary method and
were uncorrected. The IR spectra (In KBr pellets) were recorded on
a Shimadzu FT-IR 157 spectrophotometer. 1H NMR and 13C NMR,
spectra were recorded on a PerkineElmer EM 300 MHz spec-
trometer using TMS as internal standard. The mass spectra were
recorded on a JEOL JMS-D 300 spectrometer operating at 70 eV.
Purity of the compounds was checked by TLC silica coated plates
obtained from Merck.
1606 (C]N), 1254 (CeO).1H NMR (300 MHz, CDCl3)
d (ppm):
3.94 (s, 2H, CH2), 6.6 (bs, 2H, NH2), 7.1e7.33 (m, 4H, AreH), 8.3
(s, 1H, AreH). 13C NMR : 161.3, 160.30, 155.6, 129.4, 1 28.27,
123.3, 122.1, 117.2, 99.1, 23.4. MS: m/z ¼ 200.2 (Mþ). Anal. calcd.
for C11H9N3O: C, 66.32; H, 4.55; N, 21.09. Found: C, 66.43; H,
6.48; N, 21.06%.
6.4.2. Preparation of N-(2,4-dichlorophenyl)-5H-chromeno[2,3-d]
pyrimidin-4-amine (6b)
6.1. Preparation of 2-imino-2H-chromene-3-carbonitrile (3)
Yield 73%, M.p.145e147 ꢀC, IR (cmꢁ1) 3406 (NH), 3053 (CH),
1642 (C]N), 1258 (CeO). 1H NMR (300 MHz, CDCl3)
d (ppm): 4.01
To a stirred solution of salicylaldehyde (10 g, 0.08 mol) and
malononitrile (5.41 g, 0.081 mol) in ethanol (150 mL) was added
triethylamine (1 mL, 0.0081 mol). The resulting mixture was
refluxed for 30 min and then allowed to cool at room temperature.
The formed precipitate was isolated by filtration and washed with
ethanol to get pure product as yellow solid and was recrystallised
from ethanol (12 g, 84%). M.p.140e141 ꢀC. IR (cmꢁ1) 3293 (NH), 2231
(s, 2H, CH2), 7.01e7.40 (m, 7H, AreH), 8.44 (s, 1H, AreH), 10.4
(bs,1H, NH). 13C NMR : 162.6, 159.9, 157.6, 155.9, 155.2, 149.9, 129.8,
129.3, 128.7, 128.2, 126.2, 124.5, 119.2, 116.7, 116.3, 94.5, 22.25. MS:
m/z ¼ 345.0 (Mþ). Anal. calcd. for C17H11Cl2N3O: C, 59.32; H, 3.22; N,
12.21%. Found: C, 59.26; H, 3.18; N, 12.18%.
6.4.3. Preparation of N-[2-methyl-4-(trifluoromethyl)phenyl]-5H-
chromeno[2,3-d]pyrimidin-4-amine (6c)
(CN), 1653 (CH),1256 (CeO). 1H NMR (300 MHz, DMSO-d6):
d (ppm):
7.18e7.21 (1H, m, AreH); 7.24e7.29 (1H, m, AreH); 7.55e7.61 (2H, m,
AreH); 8.37 (1H, d, J ¼ 0.9 Hz, 4H); 8.83 (1H, s NH). MS: m/z ¼ 171
(Mþ). Anal. calcd. for C10H6N2O: C, 70.58; H, 3.55; N, 16.46. Found: C,
70.31; H, 3.60; N, 16.37%.
Yield 70%, M.p.156e157 ꢀC, IR (cmꢁ1) 3386 (NH), 3062 (CH),1613
(C]N), 1251 (CeO). 1H NMR (300 MHz, CDCl3)
d (ppm): 2.3 (s, 3H,
CH3) 3.98 (s, 2H, CH2), 7.01e7.40 (m, 5H, AreH), 8.3 (s,1H, AreH), 7.6
(d, 1H, AreH, J ¼ 12), 7.64 (d, 1H, AreH, J ¼ 4), 8.42 (s, 1H, AreH),
10.1(bs, 1H, NH). 13C NMR: 162.34, 159.3, 157.4, 152.2, 144.8, 132.8,
129.4, 128.9, 126.8, 125.1, 123.2, 122.7, 121.5117.0, 96.6, 22.5, 20.7.
MS: m/z ¼ 358.2 (Mþ). Anal. calcd. for C19H14F3N3O: C, 63.86; H,
3.92; N, 11.76. Found: C, 63.73; H, 3.96; N, 11.69%.
6.2. Preparation of 2-amino-3,4-dihydro-2H-chromene-3-
carbonitrile (4)
To a mixture of 2-imino-2H-chromene-3-carbonitrile 3(12 g,
0.069 mol) in methanol (150 mL) was added sodium borohydride
(0.83 g, 0.034 mol) at 0 ꢀC. Reaction mixture was stirred for 20 min,
TLC analysis confirms the completion of reaction. Reaction mixture
was poured to water, precipitated solid was filtered, washed with
water and dried to get pure product (10 g, 83%). M.p. 150e152 ꢀC, IR
(cmꢁ1); 3406 (NH), 3003 (CH), 1699 (C]N), 1284 (CeO). 1H NMR
6.4.4. Preparation of N-(1-benzylpiperidin-4-yl)-5H-chromeno
[2,3-d]pyrimidine-4-amine (6d)
Yield 65%, M.p.248e250 ꢀC, IR (cmꢁ1) 3456 (NH), 3058 (CH),1603
(C]N), 126(CeO). 1H NMR (300 MHz, CDCl3)
d (ppm): 2.12 (m, 4H,
2CH2), 2.71 (bs, 2H, CH2), 3.12 (m, 2H, CH2), 3.7 (bs, 2H, CH2), 3.8 (m,
1H, CH), 4.1 (s, 2H, CH2), 4.3 (bs, 1H, NH), 7.01e7.25 (m, 2H, AreH),
7.32e7.45 (m, 7H, AreH), 8.2 (s, 1H, AreH). MS: m/z ¼ 373.2 (Mþ).
Anal. calcd. for C23H24N4O: C, 74.19; H, 6.45; N,15.04. Found: C, 74.17;
H, 6.39; N, 14.98%.
(300 MHz, DMSO-d6) d (ppm): 2.5 (m, 2H, CH2), 2.6 (bs, 1H, NH), 3.5
(m, 1H, CH), 4.8 (m, 1H, CH), 7.18e7.21 (m, 1H, AreH), 7.24e7.29
(m, 1H, AreH), 7.55e7.61 (m, 2H, AreH). MS: m/z ¼ 175 (Mþ). Anal.
calcd. for C10H10N2O: C, 68.97; H, 5.75; N, 16.09; Found: C, 68.95; H,
5.88; N, 16.08%.
6.4.5. Preparation of N-benzyl-5H-chromeno [2,3-d]pyrimidin-4-
amine (6e)
6.3. Preparation of N0-(3-cyano-3,4-dihydro-2H-chromen-2-yl)-N,
N-dimethylimido formamide (5)
Yield 75%, M.p.185e187 ꢀC, IR (cmꢁ1) 3486 (NH), 3054 (CH),
1603 (C]N), 1264 (CeO). 1H NMR (300 MHz, CDCl3)
d (ppm): 3.8 (s,
2H, CH2), 4.5 (s, 2H, CH2), 7.01e7.25 (m, 2H, AreH), 7.32e7.45 (m,
7H, AreH), 8.3 (s, 1H, AreH). 13C NMR : 161.2159.9, 156.0, 150.2,
139.9, 129.4, 128.3, 128.0, 127.6, 126.1, 123.3, 121.0.117.1, 95.6, 44.1,
A solution of 2-amino-3,4-dihydro-2H-chromene-3-carbonitrile
4 (10 g, 0.057 mol) in N,N-Dimethylformamide dimethylactal

2698
U. Sankappa Rai et al. / European Journal of Medicinal Chemistry 45 (2010) 2695e2699
Fig. 2. Molecular structure of 6g.
24.2. MS: m/z ¼ 290 (Mþ). Anal. calcd. for C18H15N3O: C, 74.72; H,
6.4.9. Preparation of N-tricyclo[5.2.1.03,8]dec-1-yl-5H-chromeno
[2,3-d]pyrimidin-4-amine (6i)
5.19; N, 14.52. Found: C, 74.67; H, 5.23; N, 14.54%.
Yield 61 %, M.p.167e169 ꢀC, IR (cmꢁ1) 3426 (NH), 3043 (CH),
6.4.6. Preparation of 4-(4-chlorobenzyl)-5H-chromeno [2,3-d]
pyrimidine (6f)
1608 (C]N), 1279 (CeO). 1H NMR (300 MHz, CDCl3)
d (ppm): 1e1.2
(m, 4H, 2CH2), 1.3e1.5 (m, 6H, CH2), 1.6e1.8 (m, 3H, CH), 2.2e2.4
(m, 2H, CH2), 3.8 (s, 3H, CH3), 7.1 (m, 1H, AreH), 7.3 (m, 1H, AreH),
7.4 (m, 2H, AreH), 8.5 (s, 1H, AreH). 13C NMR: 161.1, 159.6, 155.7,
150.2, 129.4, 128.0, 123.3, 121.5, 117.1, 95.6, 64.1, 40.7, 39.6, 37.7, 35.1,
Yield 71%, M.p.137e139 ꢀC, IR (cmꢁ1) 3896 (NH), 3048 (CH),
1606 (C]N), 1276 (CeO). 1H NMR (300 MHz, CDCl3)
d (ppm): 3.9
(s, 2H, CH2), 7.01e7.1 (m, 2H, AreH), 7.32e7.45 (m, 7H, AreH), 8.45
(s, 1H,AreH). 13C NMR: 161.5, 158.8, 155.5, 150.6, 140.1, 133.2, 129.9,
129.4, 129.0, 128.4, 123.4, 120.9, 117.2, 116.1, 25.3. MS: m/z ¼ 310
(Mþ). Anal. calcd. for C17H12ClN3O: C, 65.92; H, 3.90; N, 13.57.
Found: C, 65.86; H, 3.83; N, 13.48%.
Table 2
Crystal data and structure refinement of compound 6g.
Crystal data
C21H15N3O
6.4.7. Preparation of N-1-naphthyl-5H-chromeno [2,3-d]pyrimidin-
4-amine (6g)
Dx ¼ 1.349 Mg mꢁ3
Melting point ¼ 513e515 K
Mo Ka radiation
Mr ¼ 325.36
Yield 71%, M.p.240e242 ꢀC, IR (cmꢁ1) 345 6(NH), 3058 (CH),
Orthorhombic, Pbca
1603 (C]N), 1273 (CeO). 1H NMR (300 MHz, CDCl3)
d(ppm): 3.85
l
¼ 0.71073 Å
-Hall symbol: -P 2ac 2ab
Cell parameters from 4673
(s, 2H, CH2), 7.01e7.1 (m, 2H, AreH), 7.32e7.45 (m, 7H, AreH),
7.80e8.01 (m, 3H, AreH), 8.4 (s, 1H, AreH). 13C NMR: 161.9, 156.3,
150.2, 135.7, 134.4, 130.5, 129.8, 128.7, 128.6, 128.4, 127.2, 126.6,
126.3, 125.3, 124.7, 124.1, 122.7, 119.9,117.1, 94.1, 22.8. MS: m/z ¼ 326
(Mþ). Anal. calcd. for C21H15N3O: C, 77.54; H, 4.62; N, 12.91. Found:
C, 77.61; H, 4.65; N, 13.02%.
reflections
a ¼ 13.2762 (3) Å
b ¼ 8.8700 (2) Å
c ¼ 27.1997 (5) Å
V ¼ 3203.03 (12) Å3
Z ¼ 8
q
¼ 1.5e30.0ꢀ
m
¼ 0.09 mmꢁ1
T ¼ 100 K
Plate, colourless
0.57 ꢂ 0.38 ꢂ 0.03 mm
F000 ¼ 1360
Data collection
Bruker SMART APEXII CCD area-detector
Diffractometer
6.4.8. Preparation of N-(2,5-dimethylphenyl)-5H-chromeno[2,3-d]
pyrimidin-4-amine (6h)
4673 independent reflections
Yield 68%, M.p.198e200 ꢀC, IR (cmꢁ1) 3436 (NH), 3051 (CH),
Radiation source:
3649 reflections with I > 2
s(I)
1600 (C]N), 1274 (CeO). 1H NMR (300 MHz, CDCl3)
d(ppm): 2.3
fine-focus sealed tube
Monochromator: graphite
Detector resolution: 8.33 pixels mmꢁ1
T ¼ 100 K
Rint ¼ 0.042
(s, 3H, CH3), 2.4 (s, 3H, CH3), 3.95 (s, 2H, CH2), 6.72 (d, 2H,
AreH), 7.2e7.35 (m, 4H, AreH), 7.30e7.45 (m, 3H, AreH), 8.35
(s, 1H, AreH). 13C NMR: 161.4, 161.1, 150.7, 150.1, 136.8, 136.5,
132.4, 131.0, 130.5, 130.1, 128.8, 128.6, 125.2, 119.8, 117.0, 99.0,
q
q
max ¼ 30.0ꢀ
min ¼ 1.5ꢀ
u
scans
h ¼ ꢁ18 / 18
Absorption correction: multi-scan
(SADABS; Bruker, 2005)
k ¼ ꢁ12 / 12
l ¼ ꢁ37 / 38
22.5, 20.7, 17.15. MS: m/z
C19H17N3O: C, 75.23; H, 5.61; N, 13.85. Found: C, 75.31; H, 5.55;
N, 13.78%.
¼
304 (Mþ). Anal. calcd. for
Tmin ¼ 0.901, Tmax ¼ 0.997
27 104 measured reflections

U. Sankappa Rai et al. / European Journal of Medicinal Chemistry 45 (2010) 2695e2699
2699
30.9, 24.7, 14.7. MS: m/z ¼ 334.3 (Mþ). Anal. calcd. for C21H23N3O: C,
References
75.68; H, 6.91; N, 12.60. Found: C, 75.61; H, 6.85; N, 12.58%.
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6.4.10. Preparation of N-(3-fluoro-4-methylphenyl)-5H-chromeno
[2,3-d]pyrimidin-4-amine (6j)
Yield 69%, M.p.171e172 ꢀC, IR (cmꢁ1) 3456 (NH), 3081 (CH), 1620
(C]N), 1284 (CeO). 1H NMR (300 MHz, CDCl3)
d (ppm): 2.3 (s, 3H,
CH3), 4.05(s, 2H, CH2), 7.0e7.2(m, 2H, AreH), 7.2e7.35 (m, 4H, AreH),
7.5 (m,1H, AreH), 8.3 (s,1H, AreH).13C NMR: 162.2,161.3,158.1,156.4,
151.1, 140.5, 131.3, 129.4, 128.9, 123.2, 122.2, 118, 117.2, 105.6, 97.1,
26.6,15.1. MS: m/z ¼ 308.1 (Mþ). Anal. calcd. for C18H14FN3O: C, 70.35;
H, 4.59; N, 13.67. Found: C, 70.41; H, 4.65; N, 13.64%.
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istry 67 (21) (2006) 2398e2402.
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3784e3787.
6.4.11. Preparation of N-(5-methyl-1,3-thiazol-2-yl)-5H-chromeno
[2,3-d]pyrimidin-4-amine (6k)
Yield 64%, M.p.238e240 ꢀC, IR (cmꢁ1) 3449 (NH), 3043 (CH),1607
(C]N), 1254 (CeO). 1H NMR (300 MHz, CDCl3)
d (ppm): 2.2 (s, 3H,
CH3), 4.2 (s, 2H, CH2), 7.0e7.4 (m, 3H, AreH), 7.35 (m, 2H, AreH), 7.8
(s, 1H, thiazole-H), 8.45 (s, 1H, AreH). 13C NMR: 161.3, 157.8, 157.3,
156.3, 151.1, 133.9, 129.3128.3, 124.4, 122.0.117.3, 110.6, 98.9, 20. MS:
m/z ¼ 297.1 (Mþ). Anal. calcd. for C15H12N4OS: C, 60.81; H, 4.05; N,
18.91. Found: C, 60.71; H, 4.02; N, 18.87% (Fig. 2 and Table 2).
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Acknowledgements
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7012e7021.
AMI is thankful to Prof. Sandeep Sancheti, Director, National
Institute of Technology-Karnataka, India for providing research
facilities and encouragement and also thankful to Board for
Research in Nuclear Sciences, Department of Atomic Energy,
Government of India for ‘Young Scientist’ award.
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(2009) 523e524.