Synthesis of new peptidyl- and glycosylpyrimidine derivatives

Article abstract of DOI:10.3184/174751911X13083314900282

A new series of 2-N-(phthalyl- or tosylamino acid)pyrimidines have been synthesised from the coupling of pyrimidine derivatives with phthalyl- or tosylamino acids. Hydrazinolysis of 2-N-phthalyl derivatives afforded unprotected amino acid derivatives. New

Full text of DOI:10.3184/174751911X13083314900282

JOURNAL OF CHEMICAL RESEARCH 2011
RESEARCH PAPER 355
JUNE, 355–360
Synthesis of new peptidyl- and glycosylpyrimidine derivatives
Aly A. Aly* and Mohamed S. Behalo
Chemistry Department, Faculty of Science, Benha University, Benha, Egypt
A new series of 2-N-(phthalyl- or tosylamino acid)pyrimidines have been synthesised from the coupling of pyrimi-
dine derivatives with phthalyl- or tosylamino acids. Hydrazinolysis of 2-N-phthalyl derivatives afforded unprotected
amino acid derivatives. New derivatives of peptidylpyrimidines have been synthesised from the reaction of pyrimi-
dine derivatives with α-amino acids methyl ester hydrochloride viz different routes. Also, new glycosides have been
prepared from the reaction of pyrimidine derivatives with α-D-glucopyranosyl bromide. Most of the synthesised
compounds showed a significant antimicrobial activity.
Keywords: pyrimidines, α-amino acids, peptidylpyrimidines, glycosides, antimicrobial activity
Nitrogen-containing heterocyclic compounds have displayed
a broad spectrum of biological effects. Within the synthesis
of heterocyclic N-containing compounds, pyrimidine and its
derivatives attracted considerable attention as they are often
present in biologically active compounds and there are many
examples of biological activities found for small molecules
based on pyrimidine moiety.1–5 They are of great importance in
the fundamental metabolism for uracil, thiamine and cytosine,
which are three bases found in the nucleotide. Hence pyrimi-
dine bases play significant role in vital biochemical process for
humans and animals.6–10
α-Amino acids and their esters have been reported to be
biologically active as anticancer agents,11 pseudo analogues of
the naturally occurring antibiotic sparsomycin,12 chromogenic
substrates of proteolytic enzymes,13 rat kidney enzyme inhibi-
tors,14 and inhibitors of mammalian collagenase.15 Also, it is
used as intermediate in the synthesis of prodrugs for cancer
treatment,16 the antibiotic reutericyclin17 and cell adhesive
agents used for the synthesis of cyclic peptides.18 Glycosides
extensively exist in animals and plants and take on an impor-
tant biological function.19 Significant antibacterial and anti-
cancer activities of glycosides have attracted many workers to
attempt to improve the biological activity of these compounds
by the glycosylation in order to increase their solubility in
water and guidance quality.20–22 Guided by the above observa-
tions, and in continuation of our interest in the synthesis of
heterocycles of medical applications,23–25 we report here a
convenient synthesis of new pyrimidine derivatives conjugated
with flexible amino acids and glycosyl moiety as side chains
hoping that the produced compounds will have improved
biological potential.
DL-phenylalanyl)oxy- or mercaptopyrimidines (5a–f),
Scheme 1. On the other hand, the reaction of pyrimidine
derivative 2a and chloroacetic acid in methanolic sodium
methoxide solution gave [4-(3-nitrophenyl)-6-(phenoxathiin-
2-yl)pyrimidin-2-yloxy]acetic acid (6), Scheme 2.
Refluxing of compound 6 with thionyl chloride on a water
bath for 2h gave pyrimidinyloxyacetyl chloride 7a, which was
in situ treated with sodium azide28 to yield the corresponding
pyrimidinyloxyacetyl azide 7b. Recently, there has been a
growing interest in the synthesis of peptides for medicinal
applications.29–31 Promoted by this fact, we report here the
synthesis of new peptidylpyrimidine derivatives for increasing
the bioactivity of the synthesised compounds. Thus, the con-
densation of compound 6 with α-amino acids methyl ester
hydrochloride in presence of tetrahydrofuran containing DCC
afforded the corresponding pyrimidinylamino acid derivatives
8a–c, which can also be obtained viz two other routes:
(1) Condensation of pyrimidinyloxyacetyl chloride 7a
with the same α-amino acids methyl ester hydrochlo-
ride in dioxane containing triethylamine.
(2) Condensation of pyrimidinyloxyacetyl azide 7b with
the same α-amino acids methyl ester hydrochloride.32
Hydrazinolysis of methyl {2-[4-(3-nitrophenyl)-6-(phenox-
athiin-2-yl)pyrimidin-2-yloxy]acetylamino}acetate (8a) in
ethanol gave the corresponding acid hydrazide 9. The diazoti-
sation of 9 in acidic medium afforded the corresponding acid
azide 10, which coupled with the same α-amino acids methyl
ester hydrochloride to give the corresponding dipeptide deriva-
tives 11a–c. Finally, the reaction of pyrimidine derivatives
2a,b with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide
in ethanol containing potassium hydroxide afforded the corre-
sponding glycoside derivatives 12a,b (Scheme 2). The struc-
tures of the synthesised compounds were assigned on the basis
of elemental analysis and spectral data. (cf. experimental)
Results and discussion
The reaction of 3-(3-nitrophenyl)-1-(phenoxathiin-2-yl)-
propenone (1) with urea and/or thiourea in ethanolic sodium
ethoxide solution, afforded the key precursor pyrimidine deriv-
atives 2a,b. The structures of compounds 2a,b were estab-
lished on the basis of its elemental analysis and spectral data
(Scheme 1).
The coupling of compounds 2a and/or 2b with N-
phthalyamino acids and N-tosylamino acids viz glycine,
DL-alanine and DL-phenylalanine in the presence of N,N′-
dicyclohexylcarbodiimide (DCC) as the condensing agent26,27
in a one-step reaction at room temperature, yielded 2-N-
(phthalyl- glycyl, DL-alanyl or DL-phenylalanyl)pyrimidines
3a–f and 2-N-(tosyl-glycyl, DL-alanyl or DL-phenylalanyl)
pyrimidines 4a–f, respectively.
Antimicrobial activity
The antimicrobial activity of the synthesised compounds
was determined in vitro using the hole plate and filter paper
methods 33 against a variety of bacteria and fungi.
Comparative studies of our prepared compounds and stan-
dard drug were also carried out. The Gram+ve bacteria were
Bacillus subtilis, Rhodococcus equi; the Gram–ve bacteria
were Escherichia coli, Pseudomonas aeruginosa and the fungi
were Penicillium notatum and Aspergillus niger. Ampicillin
and Mycostatin were used as standard drugs for antibacterial
and antifungal activity respectively. The results are illustrated
in Table 1. The investigation of antibacterial and antifungal
screening data revealed that all tested compounds showed
moderate to good activity compared to standard drugs used.
Also, the presence of tosyl group in the amino acids moiety of
synthesised compounds enhanced their activities compared
Hydrazinolysis of N-phthalyl derivatives 3a–f with an
ethanolic solution of hydrazine hydrate furnished 4-(3-
nitrophenyl)-6-(phenoxathiin-2-yl)-2-(glycyl-, DL-alanyl- or
* Correspondent. E-mail: alymaboud@yahoo.com

356 JOURNAL OF CHEMICAL RESEARCH 2011
Scheme 1 (i) EtONa, reflux 8h; (ii) N-phthalylamino acids, DCC, THF; (iii) N-tosylamino acids; DCC, THF; (iv) N2H4.H2O, EtOH.
(20 mL)]. The reaction mixture was heated under reflux for 8 h,
then cooled, added to ice-cold water (50 mL) and acidified with HCl
(20 mL). The precipitate formed was filtered off and recrystallised to
give 2a and 2b; IR for 2a; ν = 3390–3200 (OH, NH), 1670 cm−1 (CO);
with phthalyl group. Furthermore, the removal of the phthalyl
group from compounds decreased the activities.
In conclusion, we have demonstrates the scope for the utility
of pyrimidine derivatives for construction of novel pyimidinyl-
amino acid derivatives, dipeptidylpyrimidines and glycoside
derivatives of valuable antimicrobial activity.
1
IR for 2b; ν = 2280 (SH), 1605 (CN), 1260 cm−1 (CS); H NMR
(DMSO-d6) for 2a: 7.12–8.20 (m, 12H, ArH), 8.50 (brs, 1H, NH,
exchangeable); 1H NMR (DMSO-d6) for 2b: 7.10–8.15 (m, 12H,
ArH), 8.52 (brs, 1H, NH, exchangeable).
Experimental
4-(3-Nitrophenyl)-6-(phenoxathiin-2-yl)-2-N-(phthalyl- or tosylg-
lycyl-, DL-alanyl or DL-phenylalanyl)oxy- or mercaptopyrimidines
(3,4)a–f: An N-phthayl- or N-tosylamino acids (4 mmol) viz (glycine,
DL-alanine and DL-phenylalanine) and pyrimidine derivatives 2a
and/or 2b (4 mmol) were dissolved in tetrahydrofuran (30 mL). The
reaction mixture was cooled to 0 °C, then N,N′-dicyclohexylcarbodi-
imide (1.03 g, 5 mmol) was added and the reaction mixture was stirred
for 24 h at 0 °C, and for another 24 h at room temperature. The pre-
cipitated dicyclohexylurea was filtered off and the filtrate was washed
with 1N HCl (10 mL), 5% NaHCO3 (10 mL), dried on anhydrous
sodium sulfate and left overnight. It was then filtered off, then the fil-
trate was evaporated in vacuo and the solid residue was recrystallised
from proper solvents to give (3,4)a–f. IR of 3a–f: ν = 2960–2850
(aliphatic CH), 1765–1740, 1720–1710 cm−1 (CO); IR of 4a–f:
Melting points are uncorrected. IR spectra in KBr were recorded on a
Perkin–Elmer 298 spectrophotometer.1H NMR spectra were obtained
on an Varian Gemini 200 MHz instrument using TMS as internal
reference with chemical shifts expressed as δ ppm. Mass spectra were
recorded on a Shimadzu GCMS-QP 1000 instrument (70 eV EI mode).
Microanalytical data was carried out in the Microanalytical Center,
Cairo university, Egypt. Analytical TLC was carried out using Merk
60 F254 aluminium sheets and visualised by UV light (254 nm).
4-(3-Nitrophenyl)-6-phenoxathiin-2-ylpyrimidin-2-ol(thiol) (2a,b):
To a mixture of 3-(3-nitrophenyl)-1-phenoxathiin-2-ylpropenone (1)
(3.75 g, 10 mmol), urea (0.6 g, 10 mmol) and/or thiourea (0.76 g,
10 mmol) in ethanol (40 mL) was added an ethanolic sodium ethoxide
solution [prepared from sodium (0.28 g) and absolute ethanol

JOURNAL OF CHEMICAL RESEARCH 2011 357
Scheme 2 i) ClCH2COOH, MeONa, reflux 3h; ii) SOCl2, reflux 2h; iii) NaN3, dry acetone, stirring 1h; iv) DCC, THF; v) dioxane, Et3N;
vi) EtOAc, Et3N; vii) N2H4.H2O, EtOH; viii) NaNO2 /AcOH; ix) EtOAc, Et3N; x) EtOH, KOH.
ν = 3230–3100 (NH), 1725–1710 (CO), 1360–1320, 1150–1125 cm−1
and the insoluble product was removed by filtration. The filtrate was
evaporated to dryness in vacuo to give the oily residue which was
added to acetone (10 mL), followed by addition (20 mL) of ether, and
the solution was kept at 0 °C for 8 h. The product formed was col-
lected by filtration, which upon recrystallisation from a proper solvent
gave 5a–f. IR: ν = 3390–3310 (NH2), 1725–1715 cm−1 (CO); 1H NMR
(CDCl3) for 5a: 4.50 (s, 2H, CH2), 5.95 (brs, 2H, NH2), 6.95–7.85 (m,
12H, ArH); 1H NMR (CDCl3) for 5b: 1.15 (d, 3H, CH3), 4.95 (q, 1H,
CH), 5.93 (brs, 2H, NH2), 6.95–7.92 (m, 12H, ArH).
1
(SO2). H NMR (DMSO-d6) for 3a: 4.15 (s, 2H, CH2), 6.95–7.90
1
(m, 16H, ArH); H NMR (DMSO-d6) for 3b: 1.4 (d, 3H, CH3), 4.55
(q, 1H, CH), 7.10–8.05 (m, 16H, ArH); 1H NMR (DMSO-d6) for 3e:
1.15 (d, 3H, CH3), 4.85 (q, 1H, CH), 7.12–8.10 (m, 16H, ArH);
1H NMR (DMSO-d6) for 4a: 2.25 (s, 3H, CH3), 4.20 (s, 2H, CH2),
7.11–8.20 (m, 16H, ArH), 8.40 (s, 1H, NH, exchangeable); 1H NMR
(CDCl3) for 4b: 1.10 (d, 3H, CH3), 2.20 (s, 3H, CH3), 5.2 (q, 1H, CH),
6.95–8.10 (m, 16H, ArH), 8.35 (s, 1H, NH, exchangeable); 1H NMR
(DMSO-d6) for 4f: 2.23 (s, 3H, CH3), 2.60 (d, 2H, CH2), 4.80 (t, 1H,
CH), 7.15–8.10 (m, 21H, ArH), 8.50 (s, 1H, NH, exchangeable).
4-(3-Nitrophenyl)-6-(phenoxathiin-2-yl)-2-(glycyl-, DL-alanyl) or
DL-phenylalanyl-oxy- or mercaptopyrimidines (5a–f): A mixture
of N-phthalyl derivatives 3a–f (10 mmol) and hydrazine hydrate
(0.7 mL) in ethanol (25 mL) was refluxed for 4 h. The solvent was
removed in vacuo and (10 mL) of 0.5N hydrochloric acid was added
to the dried residue, the suspension was kept in an ice-bath for 2 h,
[4-(3-Nitrophenyl)-6-(phenoxathiin-2-yl)pyrimidin-2-yloxy]acetic
acid (6): A mixture of 2a (3.32 g, 8 mmol), chloroacetic acid (0.76 g,
8 mmol) and sodium methoxide (0.35 g of sodium in 20 mL of metha-
nol) in methanol (30 mL) was heated under reflux for 3 h. After
the evaporation of solvent, the residue was dissolved in ice-cold water
and acidified with HCl (20 mL). The formed solid was filtered off
and recrystallised from ethanol to give 6. Yield, 2.7 g (71%); m.p.
1
234–236 °C; IR: ν = 3400–3200 (OH), 1695 cm−1 (CO); H NMR

358 JOURNAL OF CHEMICAL RESEARCH 2011
Table 1 Antimicrobial activity of some synthesised compounds
Compd. No
Gram +ve bacteria
Gram -ve bacteria
Fungi
Bacillus
subtilis
Rhodococcus
equi
Escherichia
coli
Pseudomonas
aeruginosa
Penicillium
notatum
Aspergillus
niger
A
MIC
A
MIC
A
MIC
A
MIC
A
MIC
A
MIC
3a
3c
3d
3f
4b
4c
4e
5a
5c
5f
20
22
20
21
24
25
24
18
20
18
23
125
250
250
500
125
125
250
500
250
250
125
21
24
18
19
23
22
24
19
21
16
21
125
500
250
125
250
500
125
250
250
125
250
14
20
17
18
22
23
20
18
17
16
23
125
250
125
250
500
250
125
250
125
500
125
13
22
12
18
21
22
21
20
16
16
20
125
250
250
125
250
125
250
500
125
250
250
18
19
17
18
20
22
21
17
15
16
18
250
125
500
250
125
250
125
500
250
125
125
17
18
16
17
19
20
21
15
15
15
19
250
125
250
250
125
500
125
250
125
250
125
8a
8b
11a
11c
12a
12b
Ampicillin
Mycostatin
20
22
21
20
19
25
--
125
125
500
125
125
125
--
22
20
19
17
21
24
--
125
125
500
250
250
125
--
22
21
20
16
22
26
--
250
500
250
125
250
250
--
19
20
19
18
21
25
--
125
500
250
125
125
125
--
18
17
20
22
21
--
250
500
250
125
500
--
18
17
20
20
19
--
500
125
125
250
250
--
23
125
25
125
A, Antimicrobial activity of tested compounds; MIC, Minimum inhibitory concentration; Numbers in the table represent the inhibi-
tion zone diameter (r mm) of either fungal growth or bacterial cell for each compound; r > 20 mm, high active; r > 12 mm, moder-
ately active; r > 6 mm, slightly active; -, no inhibition was observed.
Table 2 Physical data of compounds 2a,b and (3–5)a–f
Compd
Yield /%
M.p./o C
(Solvent)*
Mol. formula
(MW)
Analysis Calcd / (Found)
H
C
N
2a
2b
3a
3b
3c
3d
3e
3f
73
70
74
65
68
70
76
62
67
66
74
62
69
71
62
63
60
67
68
73
213–215 (EtOH)
193–195 (EtOH)
201–203 (BuOH)
225–227 (EtOH)
195–197 (EtOH)
236–238 (B)
C22H13N3O4S (415.42)
C22H13N3O3S2 (431.49)
C32H18N4O7S (602.57)
C33H20N4O7S (616.60)
C39H24N4O7S (692.70)
C32H18N4O6S2 (618.64)
C33H20N4O6S2 (632.67)
C39H24N4O6S2 (708.76)
C31H22N4O7S2 (626.66)
C32H24N4O7S2 (640.69)
C38H28N4O7S2 (716.78)
C31H22N4O6S3 (642.73)
C32H24N4O6S3 (656.75)
C38H28N4O6S3 (732.85)
C24H16N4O5S (472.47)
C25H18N4O5S (486.50)
C31H22N4O5S (562.60)
C24H16N4O4S2 (488.54)
C25H18N4O4S2 (502.57)
C31H22N4O4S2 (578.66)
63.61 (63.93)
61.24 (61.43)
63.78 (63.97)
64.28 (64.11)
67.62 (67.40)
62.13 (62.01)
62.65 (62.90)
66.09 (66.25)
59.42 (59.29)
59.99 (59.70)
63.67 (63.42)
57.93 (57.71)
58.52 (58.73)
62.28 (62.41
61.01) (61.23
61.72 (61.49)
66.18 (66.36)
59.00 (59.26)
59.75 (59.93)
64.34 (64.56)
3.15
3.41
3.04
3.29
3.01
3.25
3.27
3.10
3.49
3.23
2.93
2.71
3.19
3.32
3.41
3.65
3.54
3.31
3.78
3.52
3.94
3.62
3.45
3.21
3.68
3.91
3.85
3.98
3.41
3.65
3.73
3.45
3.94
4.11
3.30
3.52
3.61
3.93
3.83
3.98
10.12 (10.01)
9.74 (9.50)
9.30 (9.10)
9.09 (9.26)
8.09 (8.24)
9.06 (9.23)
8.86 (8.60)
7.90 (7.62)
8.94 (8.62)
8.74 (8.96)
7.82 (7.98)
8.72 (8.96)
8.53 (8.23)
7.65 (7.41)
11.86 (11.61)
11.52 (11.76)
9.96 (9.65)
11.47 (11.21)
11.15 (11.32)
9.68 (9.45)
241–243 (DMF)
250–252 (DMF)
210–212 (EtOH)
185–187 (MeOH)
197–199 (EtOH)
213–215 (B)
4a
4b
4c
4d
4e
4f
226–228 (BuOH)
236–238 (BuOH)
252–254 (DMF)
244–246 (BuOH)
207–209 (EtOH)
232–234 (B)
5a
5b
5c
5d
5e
5f
260–262 (DMF)
270–272 (DMF)
* EtOH, ethanol; BuOH, n-butanol; B, benzene; DMF, N,N’-dimethylformamide; MeOH, methanol.

JOURNAL OF CHEMICAL RESEARCH 2011 359
(CDCl3): δ = 4.3 (s, 2H, CH2), 7.10–8.15 (m, 12 H, ArH), 9.60 (s, 1H,
OH, exchangeable); Anal. Calcd for C24H15N3O6S (473.46): C, 60.88;
H, 3.19; N, 8.88. Found: C, 60.61; H, 3.02; N, 8.99%.
1HNMR (DMSO-d6): δ = 3.85 (s, 2H, CH2), 4.20 (s, 2H, OCH2), 5.85
(brs, 2H, NH2), 7.10–8.12 (m, 12H, ArH), 8.95, 9.10 (2s, 2H, 2NH,
exchangeable); Anal. Calcd for C26H20N6O6S (544.54): C, 57.35; H,
3.70; N, 15.43. Found: C, 57.49; H, 3.91; N, 15.21%.
[4-(3-Nitrophenyl)-6-(phenoxathiin-2-yl)pyrimidin-2-yloxy]acetyl
azide (7b): A saturated solution of sodium azide (0.33 g, 5 mmol) in
water (5 mL) was added dropwise to a stirred solution of pyrimidi-
nyloxyacetyl chloride 7a (3 mmol) [prepared from the refluxing of
pyrimidinyloxyacetic acid 6 (2 g) and thionyl chloride (8 mL) on a
water bath for 2 h, then cooled and added to petroleum ether 40/60
(40 mL). The solid formed was filtered off and dried to give 7a] at
0–5 °C, then the reaction mixture was stirred for further 1 h at room
temperature. The reaction mixture was added to crushed ice (50 g) and
the precipitated product was collected by filtration to give 7b which
used in situ.
Preparation of compounds (11a–c); general procedure
Compound 9 (2.7 g, 5 mmol) was dissolved in a mixture of [acetic
acid (8 mL), HCl (5 mL) and water (10 mL)], the solution was cooled
to 0 °C. To this cold solution was added a solution of sodium nitrite
(1 g) in water (5 mL) dropwise over 10 min. and the reaction was
allowed to proceed for another 15 min at 0 °C. The acid azide 10 was
precipitated as a syrup which taken up in cold ethyl acetate (40 mL),
then washed with cold 5% NaHCO3 (25 mL) and dried over anhy-
drous Na2SO4. The dried solution of azide 10 was added to α-amino
acids methyl ester hydrochloride (6 mmol) viz glycine, DL-alanine
and DL-phenylalanine in ethyl acetate (25 mL) containing triethyl-
amine (3 mL). The reaction mixture was stirred for 5 h at 5 °C and
then for another 10 h at room temperature, then washed with 1N HCl
(20 mL), 5% NaHCO3 (20 mL) and dried over anhydrous Na2SO4.
The dried solution was evaporated in vacuo and the residue was
recrystallised from n-butanol to give 11a–c.
Methyl (2-{2-[4-(3-nitrophenyl)-6-(phenoxathiin-2-yl)pyrimidin-2-
yloxy]acetylamino}acetylamino)acetate (11a): Yield, (67%); M.p.
212–214 °C; IR: ν = 3240–3190 (NH), 1725, 1680–1675 cm−1 (CO);
1H NMR (DMSO-d6): δ = 2.90 (s, 3H, CH3), 3.95, 4.10 (2s, 4H, 2CH2),
4.30 (s, 2H, OCH2), 7.13–8.10 (m, 12H, ArH), 8.80, 8.90 (2s, 2H,
2NH, exchangeable);Anal. Calcd for C29H23N5O8S (601.59): C, 57.90;
H, 3.85; N, 11.64. Found: C, 57.70; H, 3.63; N, 11.81%.
Methyl 2-(2-{2-[4-(3-nitrophenyl)-6-(phenoxathiin-2-yl)pyrimidin-
2-yloxy]acetylamino}acetylamino)propionate (11b): Yield, (60%);
M.p. 202–204 °C; IR: ν = 3250–3200 (NH), 1723, 1680–1670 cm−1
(CO); 1H NMR (DMSO-d6): δ = 1.95 (d, 3H, CH3), 2.95 (s, 3H, CH3),
3.90 (s, 2H, CH2), 4.25 (s, 2H, OCH2), 4.35 (q, 1H, CH), 7.12–8.15
(m, 12H, ArH), 8.75, 8.80 (2s, 2H, 2NH, exchangeable); Anal. Calcd
for C30H25N5O8S (615.61): C, 58.53; H, 4.09; N, 11.38. Found:
C, 58.72; H, 4.23; N, 11.19%.
Methyl 2-(2-{2-[4-(3-nitrophenyl)-6-(phenoxathiin-2-yl)pyrimidin-
2-yloxy]acetylamino}acetylamino)-3-phenylpropionate (11c): Yield,
(57%); M.p. 197–199 °C; IR: ν = 3245–3185 (NH), 1720, 1680–
1675 cm−1 (CO); Anal. Calcd for C36H29N5O8S (691.71): C, 62.51; H,
4.23; N, 10.12. Found: C, 62.38; H, 4.10; N, 10.26%.
Preparation of compounds (8a–c); general procedure
Method a: To a solution of α-amino acids methyl ester hydrochloride
viz glycine, DL-alanine and DL-phenylalanine (6 mmol) in tetrahy-
drofuran (40 mL) was added triethylamine (3 mL). The solution was
kept for 30 min at 0–5 °C and the precipitated triethylamine hydro-
chloride was filtered off. To the filtrate at 0 °C was added pyrimidi-
nyloxyacetic acid 6 (4 mmol) and N,N′-dicyclohexylcarbodiimide
(4 mmol). The reaction was allowed to proceed for 3 h at 0 °C with
stirring, for 3 h at 5 °C and for 24 h at room temperature. The precipi-
tated dicyclohexylurea was filtered off, the filtrate was evaporated to
dryness under reduced pressure and the residue was recrystallised
from tetrahydrofuran to give 8a–c. Yield for 8a (74%), 8b (72%),
8c (68%).
Method b: Pyrimidinyloxyacetyl chloride 7a (4 mmol) was dis-
solved in dioxane (40 mL) and added to a solution of the same α-
amino acids methyl ester hydrochloride (6 mmol) in dioxane (20 mL)
containing triethylamine (3 mL). The reaction mixture was stirred for
30 min at room temperature followed by refluxing for 3–4 h (TLC).
The reaction mixture was cooled, then the precipitated triethylamine
hydrochloride was filtered off and the filtrate was washed with 5%
NaHCO3 (20 mL), then dried over anhydrous Na2SO4. Evaporation of
the solvent under reduced pressure gave the solid product which
recrystallised to give 8a–c. Yield for 8a (69%), 8b (65%), 8c (61%).
Method c: To a solution of pyrimidinyloxyacetyl azide 7b (4 mmol)
in ethyl acetate was added the same α-amino acids methyl ester hydro-
chloride (6 mmol) and triethylamine (3 mL). The reaction mixture
was stirred for 5 h at 5 °C and for 10 h at room temperature, then
cooled, added to 1N HCl (25 mL), 5% NaHCO3 (25 mL) and dried
over anhydrous Na2SO4. The solution was evaporated under reduced
pressure and the residual material was recrystallised to give 8a–c.
Yield for 8a (63%), 8b (61%), 8c (65%).
Preparation of compounds (12a,b): A mixture of compounds (2a or
2b) (2 mmol) was dissolved in ethanol (20 mL) containing KOH
(2 mmol) and stirred at room temperature for 30 min. The tetra-O-
acetyl-α-D-glucopyranosyl bromide (2 mmol) was then added to the
reaction mixture which was stirred at rom temperature for 12 h. The
mixture was filtered, washed with water and recrystallised from proper
solvent to give the compounds 12a,b; IR for compounds 12a,b:
υ = 1705–1700 cm−1 (CO).
Methyl{2-[4-(3-nitrophenyl)-6-(phenoxathiin-2-yl)pyrimidin-2-yloxy]-
acetylamino}acetate (8a): M.p. 210–212 °C; IR: ν = 3340–3230
(NH), 1725, 1680 cm−1 (CO); 1H NMR (CDCl3): δ = 2.95 (s, 3H, CH3),
3.90 (s, 2H, CH2), 4.30 (s, 2H, OCH2), 7.16–8.10 (m, 12H, ArH), 8.95
(s, 1H, NH, exchangeable); Anal. Calcd for C27H20N4O7S (544.54):
C, 59.55; H, 3.70; N, 10.29. Found: C, 59.68; H, 3.86; N, 10.13%.
Methyl 2-{2-[4-(3-nitrophenyl)-6-(phenoxathiin-2-yl)pyrimidin-2-
yloxy]acetylamino}propionate (8b): M.p. 236–238 °C; IR: ν = 3350–
4-(3-Nitrophenyl)-6-(phenoxathiin-2-yl)-2-(tetra-O-acetyl-β-D-
glucopyranosyloxy)pyrimidine (12a): Yield, 56% (n-butanol); m.p.
1
122–124 °C; H NMR (CDCl3): δ = 1.90–2.10 (4s, 12H, 4 CH3CO),
3.30–4.10 (m, 5H, H-sugar), 4.30 (m, 2H, CH2), 6.98–8.10 (m, 12H,
ArH); Anal. Calcd for C36H31N3O13S (745.71): C, 57.98; H, 4.19;
N, 5.63. Found: C, 57.65; H, 4.25; N, 5.74%.
1
3220 (NH), 1720, 1675 cm−1 (CO); H NMR (CDCl3): δ = 1.60 (d,
4-(3-Nitrophenyl)-6-(phenoxathiin-2-yl)-2-(tetra-O-acetyl-β-D-glu-
copyranosylsulfanyl)pyrimidine (12b): Yield, 50% (ethanol); m.p.
3H, CH3), 2.90 (s, 3H, CH3), 4.20 (s, 2H, CH2), 4.80 (q, 1H, CH),
7.10–8.15 (m, 12H, ArH), 8.75 (s, 1H, NH, exchangeable); Anal.
Calcd for C28H22N4O7S (558.56): C, 60.21; H, 3.97; N, 10.03. Found:
C, 60.03; H, 3.62; N, 10.21%.
1
131–133 °C; H NMR (CDCl3): δ = 1.92–2.30 (4s, 12H, 4 CH3CO),
3.20–4.10 (m, 5H, H-sugar), 4.25 (m, 2H, CH2), 7.10–8.25 (m, 12H,
ArH); Anal. Calcd for C36H31N3O12S2 (761.78): C, 56.76; H, 4.10;
N, 5.52. Found: C, 56.51; H, 4.18; N, 5.41%.
Methyl 2-{2-[4-(3-nitrophenyl)-6-(phenoxathiin-2-yl)pyrimidin-2-
yloxy]acetylamino}-3-phenylpropionate (8c): M.p. 205–257 °C; IR:
1
ν = 3330–3190 (NH), 1722, 1670 cm-1 (CO); H NMR (DMSO-d6):
The author is grateful to the Botany Department, Benha
University, for biological screening.
δ = 2.90 (s, 3H, CH3), 4.10 (s, 2H, OCH2), 4.25 (d, 2H, CH2), 4.90
(t, 1H, CH), 7.10–8.15 (m, 17H, ArH), 8.98 (s, 1H, NH); Anal. Calcd
for C34H26N4O7S (634.66): C, 64.34; H, 4.13; N, 8.83. Found:
C, 64.46; H, 4.25; N, 8.62%.
N-Hydrazinocarbonylmethyl-2-[4-(3-nitrophenyl)-6-(phenoxathiin-
2-yl)pyrimidin-2-yloxy]acetamide (9): Compound 8a (2.7 g, 5 mmol)
was suspended in ethanol (25 mL) and refluxed, until a clear solution
was obtained. To this solution, hydrazine hydrate (0.3 mL, 6 mmol)
was added and the solution was kept at 0–5 °C for 24 h, the solvent
was removed in vacuo and to the dried residue was added (10 mL) of
0.5N hydrochloric acid and the solid which separated was recrystal-
lised from ethanol to give 9.Yield, 1.7 g (63%); M.p. 231–233 °C; IR:
ν = 3410–3200 (multiple bands, NH2 and NH), 1680–1675 cm−1 (CO);
Received 27 April2011; accepted 8 June 2011
Paper 1100677 doi: 10.3184/174751911X13083314900282
Published online: 11 July 2011
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