Microwave promoted improved regioselective synthesis of 1H,3H,6H[2]benzopyrano[4,3-d]pyrimidine-2,4-diones by radical cyclisation

Article abstract of DOI:10.1007/s13738-012-0171-7

In this work, two new effective methodologies have been adopted for the preparation of 5-(2′-bromobenzyloxy)pyrimidine-2,4-diones 6(a-k). In the first methodology, 5-hydroxy uracils 4(a-f) were alkylated with 2-bromobenzyl bromide 5a or 2-bromo-5-methoxy benzyl bromide 5b under phase transfer catalysis condition using lithium hydroxide/tetrabutyl ammonium bromide in N,N-dimethylformamide at 45 C, and in the second method, the microwave irradiation (MWI) protocol has been exploited by mixing 5-hydroxy uracils 4(a-f) with 30 % excess of 2-bromobenzyl bromide 5a or 2-bromo-5-methoxy benzyl bromide 5b. A catalytic amount of TBAB and potassium carbonate was added and irradiated in an open Erlenmeyer flask in a microwave oven for 3-12 min. The tributyltin hydride-mediated radical cyclisation of 6(a-k) was carried out under MWI to generate 1H,3H,6H[2]benzopyrano[4,3-d]pyrimidine-2,4-diones 7(a-k) in 80-89 % yield, and the reaction time was shortened compared to the previously reported conventional radical cyclisation method.

Full text of DOI:10.1007/s13738-012-0171-7

J IRAN CHEM SOC (2013) 10:55–62
DOI 10.1007/s13738-012-0171-7
ORIGINAL PAPER
Microwave promoted improved regioselective synthesis
of 1H,3H,6H[2]benzopyrano[4,3-d]pyrimidine-2,4-diones
by radical cyclisation
•
Pradipta Kumar Basu Amrita Ghosh
Received: 22 July 2011 / Accepted: 10 June 2012 / Published online: 9 October 2012
Ó Iranian Chemical Society 2012
Abstract In this work, two new effective methodologies
have been adopted for the preparation of 5-(20-bromoben-
zyloxy)pyrimidine-2,4-diones 6(a–k). In the first method-
ology, 5-hydroxy uracils 4(a–f) were alkylated with
2-bromobenzyl bromide 5a or 2-bromo-5-methoxy benzyl
bromide 5b under phase transfer catalysis condition using
lithium hydroxide/tetrabutyl ammonium bromide in N,N-
dimethylformamide at 45 °C, and in the second method,
the microwave irradiation (MWI) protocol has been
exploited by mixing 5-hydroxy uracils 4(a–f) with 30 %
excess of 2-bromobenzyl bromide 5a or 2-bromo-5-meth-
oxy benzyl bromide 5b. A catalytic amount of TBAB and
potassium carbonate was added and irradiated in an open
Erlenmeyer flask in a microwave oven for 3–12 min. The
tributyltin hydride-mediated radical cyclisation of 6(a–k)
was carried out under MWI to generate 1H,3H,6H[2]ben-
zopyrano[4,3-d]pyrimidine-2,4-diones 7(a–k) in 80–89 %
yield, and the reaction time was shortened compared to the
previously reported conventional radical cyclisation
method.
The construction of five- and six-membered rings, either in
separate or multi-step processes, has dominated many of
these developments. Application of radical reactions for the
synthesis of small molecules has become popular in the
past decade, largely in the context of carbon-centred radi-
cals [1–6]. Heteroatom-centred radicals are less common in
synthesis, because of the tedious preparations and insta-
bilities of the heteroatom radical precursors. Nitrogen-
containing compounds are part of the basis of life and are
one of the main classes of pharmacologically active agents.
The main goals of synthetic organic chemists are to find
many new and advanced methods for their preparations.
Radical reactions are of vital importance in biology and
medicine.
Aryl radical cyclisation has been at the forefront for
constructing carbon–carbon bonds in organic synthesis
[7–15]. Previously, Majumdar et al. [16] synthesised
2H-benzopyrano[3,2-c]quinolin-7(8H)-ones by a Bu3SnH-
mediated radical cyclisation of 4-(20-bromobenzyl-
oxy)quinolin-2(1H)-one derivatives. The synthesis of
various spiroheterocycles has also been reported [17] by
the tri-n-butyltin hydride-induced radical cyclisation of
5-(o-bromoaryloxymethylene)-6,7,8-trihydropyrido[2,3-d]
pyrimidine-2,4-(1H,3H)-diones. The synthesis of spiro-
[chroman-3,30(20H)-benzofurans] has also been explored
[18] from a number of 3-(2-bromophenoxymethyl)couma-
rins under similar reaction conditions. But all these meth-
ods involve the radical cyclisation procedure under
conventional thermal heating technique for a long period of
time and long reaction time period makes this process
environmentally hazardous. Thus, alternatively a simple,
general and improved methodology for the synthesis of
various important heterocyclic systems is required.
Keywords Microwave assisted ꢀ Radical cyclisation ꢀ
2-Bromobenzyl bromide ꢀ Azobisisobutyronitrile ꢀ
Tri-n-butyltin hydride
Introduction
The chemistry of free radical occupies a prominent position
in the synthetic organic chemistry for the last few years.
P. K. Basu (&) ꢀ A. Ghosh
Department of Chemistry, Hooghly Mohsin College,
P.O. Chinsurah, Dist. Hooghly, West Bengal 712101, India
e-mail: pkbasu74@gmail.com
Recently, microwave enhancement of organic reactions
has attracted the chemists [19] as this technique is
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J IRAN CHEM SOC (2013) 10:55–62
extremely useful in organic synthesis and the reactions can
be performed with high reaction rates, low by-products,
high yields and ease of experimental manipulations [20,
21]. It is now well established that microwave heating
technique is extremely a powerful tool to promote a variety
of chemical reactions [22–25] and the beauty of such
microwave-assisted reaction lies in its dramatically
reducing reaction time or sintering time [26], increasing the
overall yield and selectivity of the reaction, accelerating
the rate of the reaction of various thermally conducted
reactions and the simple and easy work-up procedure. It is
obvious that microwave-promoted organic synthesis is an
efficient and environment friendly synthetic route in
modern synthetic organic chemistry as well as in green
chemistry, and in particular, microwave irradiation (MWI)
technique under solvent-free conditions is extremely useful
in offering reduced pollution compared to the traditional
organic synthesis involving heating by conventional
methods [22–30], and in the solvent-free reactions, the
absorption of MWI is restricted to the reacting species only
[31]. In the conventional heating technique, reactants are
slowly activated by a conventional external heat source,
and the heat penetrates first through the walls of the vessel
for reaching the solvent and reactants and therefore is a
slow and inefficient method for transferring energy into the
reacting system. But, microwaves can create direct cou-
pling with the molecules of the entire reaction mixture and
the result is a rapid rise in temperature. There are many
organic transformations proceeding through radical chem-
istry and chemists wonder, if MWI can assist radical for-
mation, microwave-promoted free-radical chemistry is
increasingly being explored [32–41].
compared to our previously described conventional method
[65].
Here in addition to the previously established [65] six
cases of 5-(20-bromobenzyloxy)pyrimidine-2,4-diones
6(a–f), we have synthesised five new compounds 6(g–k)
and also their radical cyclised products 7(g–k). That means,
we have reported 11 such final compounds 7(a–k) using
MWI technique. For this, we have synthesised 1,3-dialkyl-
uracils 2(d–f) by the corresponding alkylation of uracil
followed by its bromination to give 5-bromo-1,3-dialkyl-
uracils 3(d–f) and subsequently to the corresponding
5-hydroxy-1,3-dialkyl-uracils 4(d–f). Compounds 4(d–f)
were transformed to compounds 6(g–k) by treating with
2-bromobenzyl bromide 5a or 2-bromo-5-methoxy benzyl
bromide 5b and the microwave-assisted tributyltin hydride-
mediated radical cyclisation of 6(g–k) afforded 7(g–k) by
the same procedure as adopted for the series of other
compounds.
Experimental
All the reagents were obtained from commercial sources
and used as received. Except methanol (which was HPLC-
grade), the remaining solvents were dried and distilled
before use. Elemental analyses and Mass spectra (ESI?)
were performed at the Indian Institute of Chemical Biol-
ogy, Kolkata. UV absorption spectra were recorded in
EtOH on a Shimadzu UV-2401 PC spectrophotometer
(kmax in nm) and IR spectra on KBr discs on a Perkin Elmer
L 120-000A apparatus (mmax in cm-1). Routine 1H and
13C{1H} NMR spectra were recorded with a Bruker DPX-
300 MHz instrument and Varian VRX-500 MHz instru-
ments at 298 K. The chemical shifts (d) are given in ppm
and the coupling constants (J) in Hz. In all cases, the sol-
vent for the NMR experiments was CDCl3 (99.9 %) and
It is well known that MWI enhanced the reaction rates
of Pd-catalysed C–C coupling such as the Stille, Suzuki,
Heck and Sonogashira reactions [42–56]. With these facts
in our mind, we also thought that MWI might promote
Bu3SnH-annulated radical cyclisation reactions, since
metal reagents and catalysts are good candidates to absorb
microwaves [57, 58].
1
the references were SiMe4 [for H and 13C {1H} NMR
experiments]. Silica gel [(60–120, 230–400 mesh), SRL,
India] was used for chromatographic separation. Silica gel
G [E-Marck (India)] and Silica gel 60F 254 [E-Marck
(Germany)] were used for TLC. Petroleum ether refers to
the fraction boiling between 60 and 80 °C. Reaction mix-
ture was irradiated in the CEM Discover microwave syn-
thesis system (Scheme 1).
In spite of increasing interest of MWI technique, the use
of this methodology in free-radical-based organic synthesis
is less common [59–63]. As a part of our recent research
activity, we became interested in building the 6-membered
fused pyran ring annulated pyrimidines by radical cycli-
sation exploiting MWI. It is well known that pyrimidine
derivatives are highly potentially biological active and they
have enormous medicinal applicability, and 5-substituted
uracils and their nucleosides are of immense biological
significance including their use in the chemotherapy of
cancer [64] and this fact motivated us to undertake the
synthesis of 1H,3H,6H[2]benzopyrano[4,3-d]pyrimidine-
2,4-diones 7(a–k) by aryl radical cyclisation. In this paper,
we highlight the microwave-assisted one pot facile method
Typical procedure for synthesis of 1,3-dialkyl-uracils
2(d–f)
Uracil (1.0 mmol) was dissolved in 5 ml DMF in a sealed
tube, and solid NaOH (1.25 mmol) and tetrabutylammonium
bromide (TBAB) (0.15 mmol) were added and the mixture
was cooled at 0–5 °C. Now, n-propyl bromide (2.50 mmol)
(for 2d) or n-butyl bromide (2.50 mmol) (for 2e) or
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J IRAN CHEM SOC (2013) 10:55–62
57
O
N
O
O
O
R2
R2
OH
R2
Br
H
N
N
N
(iii)
(ii)
(i)
N
d) R1 = R2 = C3H7
e) R1 = R2 = C4H9
f) R1 = R2 = C3H7O
N
O
O
N
O
N
O
1
R1
R1
R
H
1
2(d-f)
3(d-f)
4(d-f)
Scheme 1 (i) C3H7Br or C4H9Br or ClCH2CH2OMe (2.5 mmol), NaOH (1.25 mmol), TBAB (0.15 mmol), DMF, 60 °C, 2 h; (ii) MeOH, Br2,
reflux, 2 h; (iii) NaHCO3 (0.75 mmol), H2O, reflux, 4 h
68.9, 70.1, 100.7, 143.7, 151.4, 162.4; MS (EI): m/z = 228;
analysis: C10H16N2O4, calcd.: C, 52.62; H, 7.07; N,
12.27 %; found: C, 52.51; H, 7.19; N, 12.39 %.
2-chloroethyl methyl ether (2.50 mmol) (for 2f) was added
in three portions and the mixture was continuously stirred for
15 min at 0–5 °C, then for an additional period of 30 min at
room temperature and afterwards heated at 60 °C for 2 h. On
completion of the reaction as detected by TLC, the reaction
mixture was cooled to room temperature and it was diluted
with EtOAc (25 ml), washed with sat. aqueous NH4Cl
(10 ml), and extracted with EtOAc (3 9 20 ml). The com-
bined organic layers were dried (Na2SO4), filtered, and
concentrated by rotavapour. The crude mixture was purified
by SiO2 column chromatography using petroleum ether:-
EtOAc = 1:1 as eluant to give 2(d–f).
Typical procedure for synthesis
of 5-bromo-1,3-dialkyl-uracils 3(d–f)
1,3-Di-n-propyl-uracil 2d (1.0 mmol) or 1,3-di-n-butyl-
uracil 2e (1.0 mmol) or 1,3-bis-(2-methoxyethyl)uracil 2f
(1.0 mmol) was dissolved in 10 ml of methanol and bro-
mine was added drop wise at room temperature so long it
reacted with the corresponding 1,3-dialkyl-uracil; the
resulting solution was continuously stirred and then few
drops of excess bromine was also added. After the addition
was completed, the reaction mixture was refluxed for 2 h.
Next, it was allowed to cool at room temperature; methanol
was evaporated in rotavapour and the resulting gummy
mass was extracted with EtOAc (3 9 20 ml), washed with
NaHSO3 solution (5 ml) and dried over Na2SO4, filtered,
and concentrated by rotavapour. The crude mixture was
purified by SiO2 column chromatography using petroleum
ether:EtOAc = 1:1 as eluant to give 3d or 3e or 3f.
1,3-Di-n-propyl uracil (2d, C10 H16N O2) Yield: 85 %;
2
m.p.: colourless oil; IR (neat) t‹ = 2,966, 2,878, 1,705,
1
1,699, 1,661, 1,456 cm-1; H NMR (400 MHz, CDCl3)
d = 0.96 (t, 3H, J = 7.2 Hz, C–CH3), 0.98 (t, 3H,
J = 7.2 Hz, C–CH3), 1.78 (tq, J = 7.2, 7.6 Hz, 4H,
CH2CH2CH3), 3.72 (t, 2H, J = 7.6 Hz, –N–CH2), 3.92 (t,
2H, J = 7.6 Hz, –N–CH2), 5.70 (d, 1H, J = 8.0 Hz,
COCH=), 7.12 (d, 1H, J = 8.0 Hz, N–CH=); MS (EI):
m/z = 196; analysis: C10H16N2O2, calcd.: C, 61.2; H, 8.22;
N, 14.27 %; found: C, 61.29; H, 8.34; N, 14.16 %.
5-Bromo-1,3-di-n-propyl-uracil (3d, C10H15BrN2O2). Yield:
1,3-Di-n-butyl uracil (2e, C12H20N2O2) Yield: 80 %;
88 %; m.p.: 74–75 °C; IR (neat) t
‹ = 2,965, 2,875, 1,703,
1,647, 1,451 cm-1; 1H NMR (400 MHz, CDCl3) d = 0.95
(t, 3H, J = 7.2 Hz, C–CH3), 0.98 (t, 3H, J = 7.2 Hz, C–
CH3), 1.77 (tq, J = 7.2, 7.6 Hz, 4H, CH2CH2CH3), 3.75
(t, 2H, J = 7.6 Hz, –N–CH2), 3.97 (t, 2H, J = 7.6 Hz, –N–
CH2), 7.50 (s, 1H, N–CH=); MS (EI): m/z = 274; analysis:
C10H15BrN2O2, calcd.: C, 43.65; H, 5.50; N, 10.18 %;
found: C, 43.52; H, 5.40; N, 10.29 %.
m.p.: colourless oil; IR (neat) t‹ = 2,959, 2,874, 1,702,
1
1,681, 1,667, 1,458 cm-1; H NMR (500 MHz, CDCl3)
d = 0.90 (t, 6H, J = 7.5 Hz, C–CH3), 1.32 (q, 4H,
J = 7.5 Hz, CH2CH2CH3), 1.62 (t, 4H, J = 7.5 Hz,
–NCH2CH2CH2), 3.67 (t, 4H, J = 7.5 Hz, –N–CH2), 5.62
(d, 1H, J = 7.5 Hz, COCH=), 7.09 (d, 1H, J = 7.5 Hz,
N–CH=); MS (EI): m/z = 224; analysis: C12H20N2O2,
calcd.: C, 64.26; H, 8.99; N, 12.49 %; found: C, 64.12; H,
8.74; N, 12.61 %.
5-Bromo-1,3-di-n-butyl-uracil (3e, C12H19BrN2O2). Yield:
84 %; m.p.: 98–99 °C; IR (neat) t
‹ = 2,958, 2,871, 1,702,
1,640 cm-1; 1H NMR (500 MHz, CDCl3) d = 0.72 (t, 6H,
J = 7.5 Hz, C–CH3), 1.11 (sextet, 4H, J = 7.5 Hz, –N
CH2CH2CH2CH3), 1.43 (quintet, 4H, J = 7.5 Hz, –NCH2
CH2CH2CH3), 3.51 (t, 4H, J = 7.5 Hz, –N–CH2–), 9.28 (s,
1H, N–CH=); MS (EI): m/z = 302; analysis: C12H19Br
N2O2, calcd.: C, 47.54; H, 6.32; N, 9.24 %; found: C,
47.68; H, 6.50; N, 9.14 %.
1,3-Bis-(2-methoxyethyl)uracil (2f, C10H16N2O4) Yield:
78 %; m.p.: colourless oil; IR (neat) t‹ = 2,927, 1,707,
1
1,659, 1,455, 1,117 cm-1; H NMR (400 MHz, CDCl3)
d = 3.17 (s, 6H, OCH3), 3.45 (t, 4H, J = 6.4 Hz, –CH2–),
4.01 (t, 4H, J = 6.4 Hz, –N–CH2–), 5.51 (d, 1H,
J = 7.8 Hz, COCH=), 7.12 (d, 1H, J = 7.8 Hz, N–CH=);
13C NMR (100 MHz, CDCl3) d = 39.8, 49.2, 58.4, 58.8,
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J IRAN CHEM SOC (2013) 10:55–62
5-Bromo-1,3-bis-(2-methoxyethyl)-uracil (3f, C10H15Br
N2O4).
m/z = 244; analysis: C10H16N2O5, calcd.: C, 49.17; H,
6.60; N, 11.47 %; found: C, 49.28; H, 6.42; N, 11.59 %.
Yield: 80 %; m.p.: 127–128 °C; IR (neat)
t‹
= 2,941, 2,882, 1,708, 1,658 cm-1; 1H NMR (400 MHz,
CDCl3) d = 3.16 (s, 6H, OCH3), 3.45 (t, 4H, J = 7.6 Hz,
–CH2–), 3.76 (t, 2H, J = 6.4 Hz, –N–CH2–), 4.01 (t, 2H,
J = 7.6 Hz, –N–CH2–), 7.82 (s, 1H, N–CH=); MS (EI):
m/z = 306; analysis: C10H15BrN2O4, calcd.: C, 39.10; H,
4.92; N, 9.12 %; found: C, 39.22; H, 4.79; N, 9.25 %.
Typical procedure for synthesis
of 5-(20-bromobenzyloxy)pyrimidine-2,4-diones 6(a–k)
Method A
LiOH (1.60 mmol) was added in three portions over
20 min to a solution of 4 (1.0 mmol), TBAB (0.15 mmol),
and 2-bromobenzyl bromide 5a or 2-bromo-5-methoxy
benzyl bromide 5b (1.0 mmol) in DMF (10 ml) at 45 °C.
The mixture was stirred at this temperature for a further
2 h, after which the reaction mixture was diluted with
EtOAc (10 ml), washed with saturated aqueous NH4Cl
(25 ml), and extracted with EtOAc (3 9 20 ml). The
combined organic layers were dried (Na2SO4), filtered, and
concentrated by rotavapour. The crude mixture was puri-
fied by SiO2 column chromatography using petroleum
ether:EtOAc = 1:1 as eluant to give 6.
Typical procedure for synthesis
of 5-hydroxy-1,3-dialkyl-uracils 4(d–f)
5-Bromo-1,3-di-n-propyl-uracil 3d (1.0 mmol) or 5-bromo-
1,3-di-n-butyl-uracil 3e (1.0 mmol) or 5-bromo-1,3-di-(2-
methoxyethyl)uracil 3f (1.0 mmol) was dissolved in 10 ml
of water under refluxing condition, and sodium bicarbonate
(0.75 mmol) was added and refluxing was continued for 4 h
(completion of reaction was monitored by TLC). The
reaction mixture was cooled, acidified with 6(N) HCl,
extracted with CH2Cl2 (3 9 25 ml), washed with water
(5 ml) and dried over Na2SO4, filtered, and concentrated by
rotavapour. The crude mixture was purified by SiO2 column
chromatography using petroleum ether:EtOAc = 1:1 as
eluant to give 4d or 4e or 4f.
Method B
5-Hydroxy uracils 4 (1.0 mmol) was mixed with 30 %
excess of 2-bromobenzyl bromide 5a or 2-bromo-5-meth-
oxy benzyl bromide 5b (1.30 mmol), and a catalytic
amount of TBAB (0.15 mmol). The mixtures were adsor-
bed on potassium carbonate (0.6 mmol) and irradiated in
an open Erlenmeyer flask in a microwave oven for 3–8 min
(optimized time). The residual mass was cooled at room
temperature and was extracted with CH2Cl2 (2 9 50 ml),
washed with water and then with brine and dried (Na2SO4).
After removal of dichloromethane solvent, the crude
reaction mixture was purified by flash chromatography.
Elution of the column with an appropriate mixture of ethyl
acetate and petroleum ether gave the required products 6 in
excellent yield.
5-Hydroxy-1,3-di-n-propyl-uracil (4d, C10H16N2O3). Yield:
88 %; m.p.: 50–52 °C; IR (neat) t‹ = 3,331, 2,970, 1,695,
1,620, 1,456 cm-1; 1H NMR (400 MHz, CDCl3) d = 0.95
(t, 3H, J = 7.2 Hz, C–CH3), 0.97 (t, 3H, J = 7.2 Hz,
C–CH3), 1.74 (tq, J = 7.2, 7.6 Hz, 4H, CH2CH2CH3), 3.71
(t, 2H, J = 7.6 Hz, –N–CH2), 3.97 (t, 2H, J = 7.6 Hz,
–N–CH2), 6.15 (s, 1H, OH), 6.88 (s, 1H, N–CH=); 13C NMR
(100 MHz, CDCl3) d = 10.9, 11.2, 20.8, 22.1, 43.6, 51.2,
121.0, 131.6, 149.4, 161.1; MS (EI): m/z = 212; analysis:
C10H16N2O3, calcd.: C, 56.59; H, 7.60; N, 13.20 %; found:
C, 56.72; H, 7.70; N, 13.32 %.
5-Hydroxy-1,3-di-n-butyl-uracil (4e, C12H20N2O3). Yield:
81 %; m.p.: 85–86 °C; IR (neat) t
‹ = 3,320, 2,985, 1,676,
1,608, 1,442 cm-1; 1H NMR (400 MHz, CDCl3) d = 0.84
(t, 6H, J = 7.5 Hz, C–CH3), 1.18 (sextet, 4H, J = 7.5 Hz,
–N CH2CH2CH2CH3), 1.68 (quintet, 4H, J = 7.5 Hz,
–NCH2 CH2CH2CH3), 3.54 (t, 4H, J = 7.5 Hz, –N–CH2–),
8.48 (s, 1H, N–CH=), 6.85 (s, 1H, OH); MS (EI): m/z = 240;
analysis: C12H20N2O3, calcd.: C, 59.98; H, 8.39; N, 11.66 %;
found: C, 59.88; H, 8.26; N, 11.75 %.
1,3-Di-n-propyl-5-(20-bromobenzyloxy)pyrimidine-2,4-dione
(6g, C17H21BrN2O3). Yield: 92 %; m.p.: 71–72 °C; IR
(neat) t‹
= 2,936, 2,877, 1,704, 1,699, 1,456 cm-1; 1H NMR
(400 MHz, CDCl3) d = 0.88 (t, 3H, J = 7.2 Hz, C–CH3),
0.97 (t, 3H, J = 7.2 Hz, C–CH3), 1.61–1.70 (m, 4H,
CH2CH2CH3), 3.64 (t, 2H, J = 7.6 Hz, –N–CH2), 3.96
(t, 2H, J = 7.6 Hz, –N–CH2), 5.11 (s, 2H, O–CH2), 6.79 (s,
1H, =CH), 7.18–7.22 (m, 1H, ArH), 7.27–7.35 (m, 1H, ArH),
7.52–7.58 (m, 2H, ArH); 13C NMR (100 MHz, CDCl3)
d = 10.9, 11.4, 20.9, 22.2, 43.4, 51.2, 72.9, 123.4, 127.8,
129.1, 129.9, 130.5, 132.8, 133.4, 135.7, 150.3, 160.1; MS
(EI): m/z = 380; analysis: C17H21BrN2O3, calcd.: C, 53.55;
H, 5.55; N, 7.35 %; found: C, 53.68; H, 5.39; N, 7.49 %.
5-Hydroxy-1,3-bis-(2-methoxyethyl)-uracil (4f, C10H16N2
O5).
Yield: 79 %; m.p.: 137–138 °C; IR (neat) t
‹ =
3,328, 2,965, 1,684, 1,622, 1,457 cm-1
;
1H NMR
(400 MHz, CDCl3) d = 3.24 (s, 6H, OCH3), 3.47 (t, 4H,
J = 6.2 Hz, –CH2–), 4.18 (t, 4H, J = 6.2 Hz, –N–CH2–),
6.42 (s, 1H, OH), 6.92 (s, 1H, N–CH=); MS (EI):
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J IRAN CHEM SOC (2013) 10:55–62
59
1,3-Di-n-propyl-5-(20-bromobenzyloxy-50-methoxy)-pyrimi-
dine-2,4-dione (6h, C18H23BrN2O4). Yield: 86 %; m.p.:
Typical procedure for synthesis of 1H,3H,6H[2]
benzopyrano[4,3-d]pyrimidine-2,4-diones 7(a–k)
62–64 °C; IR (neat) t
‹ = 2,937, 2,877, 1,704, 1,661,
1,456 cm-1; 1H NMR (400 MHz, CDCl3) d = 0.90 (t, 3H,
J = 7.2 Hz, C–CH3), 0.97 (t, 3H, J = 7.2 Hz, C–CH3),
1.62–1.70 (m, 4H, CH2CH2CH3), 3.65 (t, 2H, J = 7.6 Hz,
–N–CH2), 3.79 (s, 3H, O–CH3), 3.96 (t, 2H, J = 7.6 Hz,
–N–CH2), 5.07 (s, 2H, O–CH2), 6.74–6.76 (d, 1H,
J = 8.8 Hz, ArH), 6.81 (s, 1H, =CH), 7.10 (s, 1H, ArH),
7.42–7.45 (d, 1H, J = 8.8 Hz, ArH); 13C NMR (100 MHz,
CDCl3) d = 10.9, 11.4, 20.9, 22.2, 43.4, 51.3, 55.7, 72.9,
113.4, 115.5, 116.0, 129.0, 133.3, 133.4, 133.6, 150.2, 159.3,
160.1; MS (EI): m/z = 410; analysis: C18H23BrN2O4,
calcd.: C, 52.56; H, 5.64; N, 6.81 %; found: C, 52.42; H,
5.72; N, 6.94 %.
A mixture of n-Bu3SnH (0.75 mmol, 1.5 equiv) and AIBN
(22 mg, 0.13 mmol, 0.25 equiv) in toluene (10 ml) was
added via a syringe pump over 1 h to a MWI at
100–110 °C under open-vessel conditions in the solution of
6 (0.5 mmol, 1.0 equiv) and AIBN (22 mg, 0.13 mmol,
0.25 equiv) in toluene (10 ml). The reaction was monitored
by TLC, and after completion of the reaction, solvent was
evaporated by rotavapour and it was extracted with CH2Cl2
(2 9 20 ml), washed with 1 % aqueous NH4OH (2 9
10 ml) and brine. Evaporation of the solvent furnished the
residual mass which was then magnetically stirred with
saturated solution of potassium fluoride. It was again
extracted with CH2Cl2 (3 9 10 ml) and was washed sev-
eral times with water and dried (Na2SO4). The residual
mass after removal of the solvent (CH2Cl2) was subjected
to flash column chromatography using petroleum ether:-
ethyl acetate (1:2) as eluant to give cyclised products 7.
Cyclised products 7(a–f) are known and were easily
identified by comparison of their spectroscopic data and
m.p.’s with those reported [65]. New products 7(g–k) were
characterised by elemental analyses, mass spectrometry,
1,3-Di-n-butyl-5-(20-bromobenzyloxy)pyrimidine-2,4-dione
(6i, C19H25BrN2O3). 1Yield: 84 %; m.p.: 87–88 °C;
1
IR (neat) t
‹
= 2,922, 2,861, 1,712, 1,690, 1,442 cm-1; H
NMR (400 MHz, CDCl3) d = 0.88 (t, 6H, J = 7.5 Hz, C–
CH3), 1.28 (sextet, 4H, J = 7.5 Hz, –NCH2CH2CH2CH3),
1.76 (quintet, 4H, J = 7.5 Hz, –NCH2CH2CH2CH3), 3.66
(t, 4H, J = 7.5 Hz, –N–CH2–), 5.18 (s, 2H, O–CH2), 6.88
(s, 1H, =CH), 7.31–7.39 (m, 1H, ArH), 7.41–7.55 (m, 2H,
ArH), 7.61–7.89 (m, 1H, ArH); MS (EI): m/z = 410;
analysis: C19H25BrN2O3, calcd.: C, 55.75; H, 6.16; N,
6.84 %; found: C, 55.61; H, 6.06; N, 6.99 %.
1
infrared and mono H, 13C{1H}-NMR spectroscopy.
1,3-Di-n-propyl-6H-[2]benzopyrano[4,3-d]pyrimidine-2,4-
dione (7g, C17H20N2O3). Yield: 88 %; white solid; m.p.:
1,3-Di-n-butyl-5-(20-bromobenzyloxy-50-methoxy)-pyrimi-
dine-2,4-dione (6j, C20H27BrN2O4). Yield: 87 %; m.p.:
101–102 °C; IR (neat) t
‹ = 2,940, 1,715, 1,649, 1,492
cm-1 1H NMR (400 MHz, CDCl3) d = 0.97 (t, 3H,
;
90–92 °C; IR (neat) t
‹ = 2,917, 2,861, 1,709, 1,650,
J = 7.2 Hz, C–CH3), 0.98 (t, 3H, J = 7.2 Hz, C–CH3),
1.64–1.82 (m, 4H, CH2CH2CH3), 3.85 (t, 2H, J = 7.6 Hz,
–N–CH2), 3.97 (t, 2H, J = 7.6 Hz, –N–CH2), 4.46 (s, 2H,
O–CH2), 7.25–7.38 (m, 1H, ArH), 7.42–7.66 (m, 2H, ArH),
7.68–7.88 (m, 1H, ArH); 13C NMR (100 MHz, CDCl3)
d = 11.0, 11.6, 19.3, 21.2, 48.7, 51.0, 65.4, 115.6, 117.9,
123.7, 126.5, 127.8, 129.2, 134.4, 137.7, 152.8, 164.6; MS
(EI): m/z = 300; analysis: C17H20N2O3, calcd.: C, 67.98;
H, 6.71; N, 9.33 %; found: C, 67.82; H, 6.88; N, 9.24 %.
1,440 cm-1; 1H NMR (400 MHz, CDCl3) d = 0.88 (t, 6H,
J = 7.5 Hz, C–CH3), 1.32 (sextet, 4H, J = 7.5 Hz,
–NCH2CH2CH2CH3), 1.71 (quintet, 4H, J = 7.5 Hz,
–NCH2CH2CH2CH3), 3.52 (t, 4H, J = 7.5 Hz, –N–CH2–),
3.88 (s, 3H, O–CH3), 5.15 (s, 2H, O–CH2), 6.92–6.99 (d, 1H,
J = 8.0 Hz, ArH), 6.98 (s, 1H, =CH), 7.11–7.21 (m, 1H,
ArH), 7.31–7.59 (d, 1H, J = 8.0 Hz, ArH); MS (EI):
m/z = 438; analysis: C20H27BrN2O4, calcd.: C, 54.68; H,
6.19; N, 6.38 %; found: C, 54.54; H, 6.36; N, 6.44 %.
1,3-Di-n-propyl-6H-[2]benzopyrano[4,3-d]8-methoxy pyr-
Yield: 82 %;
1,3-Bis-(2-methoxyethyl)-5-(20-bromobenzyloxy) pyrimi-
imidine-2,4-dione (7h, C18H22N2O4).
white solid; m.p.: 97–98 °C; IR (neat) t
‹
= 2,928, 1,710,
dine-2,4-dione (6k, C17H21BrN2O5). Yield: 78 %; m.p.:
1,651, 1,498 cm-1; 1H NMR (400 MHz, CDCl3) d = 0.94
(t, 3H, J = 7.2 Hz, C–CH3), 0.99 (t, 3H, J = 7.2 Hz, C–
CH3), 1.64–1.81 (m, 4H, CH2CH2CH3), 3.76 (t, 2H,
J = 7.6 Hz, –N–CH2), 3.89 (s, 3H, O–CH3), 3.98 (t, 2H,
J = 7.6 Hz, –N–CH2), 4.41 (s, 2H, O–CH2), 7.12–7.29 (m,
1H, ArH), 7.34–7.49 (m, 1H, ArH), 7.58 (s, 1H, ArH); MS
(EI): m/z = 330; analysis: C18H22N2O4, calcd.: C, 65.44;
H, 6.71; N, 8.48 %; found: C, 65.51; H, 6.58; N, 8.62 %.
98–99 °C; IR (neat) t
‹ = 2,908, 2,865, 1,722, 1,699,
1,468 cm-1; 1H NMR (400 MHz, CDCl3) d = 3.27 (s, 6H,
OCH3), 3.69 (t, 4H, J = 6.8 Hz, –CH2–), 4.14 (t, 4H,
J = 6.8 Hz, –N–CH2–), 5.23 (s, 2H, O–CH2), 6.97 (s, 1H,
=CH), 7.19–7.48 (m, 1H, ArH), 7.51–7.65 (m, 1H, ArH),
7.68–7.99 (m, 2H, ArH); MS (EI): m/z = 412; analysis:
C17H21BrN2O5, calcd.: C, 49.41; H, 5.12; N, 6.78 %;
found: C, 49.52; H, 5.30; N, 6.89 %.
123

60
J IRAN CHEM SOC (2013) 10:55–62
1,3-Di-n-butyl-6H-[2]benzopyrano[4,3-d]pyrimidine-2,4-dione
(7i, C19H24N2O3).
4(a–c) with either 2-bromobenzyl bromide 5a or 2-bromo-5-
methoxy benzyl bromide 5b in dry acetone in the presence of
anhydrous potassium carbonate. Herein, we have established
two new more effective methodologies for the preparation of
5-(20-bromobenzyloxy)pyrimidine-2,4-diones 6(a–k). In the
first methodology, 1,3-dialkyl-5-hydroxy uracils 4(a–f) can
be successfully alkylated with 2-bromobenzyl bromide 5a or
2-bromo-5-methoxy benzyl bromide 5b under phase transfer
catalysis condition using lithium hydroxide/tetrabutyl
ammonium bromide in N,N-dimethylformamide at 45 °C
with a shorter reaction time than the conventional acetone–
potassium carbonate method (Scheme 2; Table 1). This new
protocol involving reagents (LiOH, TBAB, DMF) are
apparently little expensive than the previous one; but con-
sidering the shorter reaction time and higher yield, this new
technique is considered to be more effective and energy
saving too.
Yield: 85 %; white solid; m.p.:
= 2,960, 1,705, 1,647, 1,480 cm-1
121–122 °C; IR (neat) t
‹
;
1H NMR (400 MHz, CDCl3) d = 0.99 (t, 6H, J = 7.5 Hz,
C–CH3), 1.29 (sextet, 4H, J = 7.5 Hz, –NCH2CH2
CH2CH3), 1.86 (quintet, 4H, J = 7.5 Hz, –NCH2CH2CH2
CH3), 3.69 (t, 4H, J = 7.5 Hz, –N–CH2–), 4.49 (s, 2H, O–
CH2), 7.03–7.28 (m, 1H, ArH), 7.32–7.69 (m, 2H, ArH),
7.71–7.97 (m, 1H, ArH); MS (EI): m/z = 328; analysis:
C19H24N2O3, calcd.: C, 69.49; H, 7.37; N, 8.53 %; found: C,
69.29; H, 7.39; N, 8.68 %.
1,3-Di-n-butyl-6H-[2]benzopyrano[4,3-d]8-methoxy pyrimi-
dine-2,4-dione(7j,C20H26N2O4). Yield: 72 %; white solid;
m.p.: 141–142 °C; IR (neat) t‹ = 2,911, 1,719, 1,678,
1,478 cm-1; 1H NMR (400 MHz, CDCl3) d = 0.89 (t, 6H,
J = 7.5 Hz, C–CH3), 1.39 (sextet, 4H, J = 7.5 Hz, –NCH2
CH2CH2CH3), 1.77 (quintet, 4H, J = 7.5 Hz, –NCH2
CH2CH2CH3), 3.59 (t, 4H, J = 7.5 Hz, –N–CH2–), 3.97
(s, 3H, O–CH3), 4.42 (s, 2H, O–CH2), 6.98–7.20 (m, 1H,
ArH), 7.37–7.59 (m, 1H, ArH), 7.98 (s, 1H, ArH); MS (EI):
m/z = 358; analysis: C20H26N2O4, calcd.: C, 67.02; H, 7.31;
N, 7.82 %; found: C, 67.12; H, 7.22; N, 7.67 %.
In addition, we have also exploited the MWI protocol in
synthesising the radical precursor 6(a–k) under solvent-
free condition. The syntheses were carried out by mixing of
1,3-dialkyl-5-hydroxy uracils 4(a–f) with 30 % excess of
2-bromobenzyl bromide 5a or 2-bromo-5-methoxy benzyl
bromide 5b, and a catalytic amount of TBAB (Scheme 2;
Table 1).
1,3-Bis-(2-methoxyethyl)-6H-[2]benzopyrano[4,3-d] pyr-
imidine-2,4-dione (7k, C18H22N2O6). Yield: 83 %; white
The mixtures were adsorbed on potassium carbonate and
irradiated in an open Erlenmeyer flask in a microwave oven
for 3–8 min (optimized time). The crude reaction mixture
after usual work-up was purified by column chromatogra-
phy. Elution of the column with an appropriate mixture of
ethyl acetate and petroleum ether gave the required prod-
ucts 6.
solid; m.p.: 118–119 °C; IR (neat) t
‹ = 2,935, 1,712, 1,629,
1,478 cm-1; 1H NMR (400 MHz, CDCl3) d = 3.27 (s, 6H,
OCH3), 3.69 (t, 4H, J = 6.8 Hz, –CH2–), 4.14 (t, 4H,
J = 6.8 Hz, –N–CH2–), 4.39 (s, 2H, O–CH2), 6.87–7.11
(m, 1H, ArH), 7.49–7.76 (m, 1H, ArH), 7.68–7.92 (m, 2H,
ArH); MS (EI): m/z = 362; analysis: C18H22N2O6, calcd.:
C, 59.66; H, 6.12; N, 7.73 %; found: C, 59.81; H, 6.02; N,
7.87 %.
We found that the above alkylation reaction using MWI
has advantages over conventional conditions [66] in sev-
eral aspects including shorter reaction times, cleaner
products, and simpler work-up procedures.
Results and discussion
Previously we reported [65] the radical cyclisation
mediated by tributyltin chloride and sodium cyanoboro-
hydride, which was carried out initially under refluxing
benzene conditions, in the reaction mixture maintained by
Previously we prepared [65] 5-(20-bromobenzyloxy)pyrim-
idine-2,4-diones 6(a–f) by refluxing 5-hydroxy uracils
Scheme 2 Method A: LiOH,
Br
TBAB, DMF, 45 °C; method B:
MWI (3–12 min), TBAB,
K2CO3
O
O
R2
R2
OH
O
Br
Method A
N
N
or
+
Br
N
Method B
O
N
R1
3
O
R
R1
3
R
3
5.
1
2
a) R = H
b) R3 = OCH3
4.
a) R = R = CH3
b) R1 = R2 = C2H5
6 (a-k)
c) R1 = C2H5, R2 = CH3
d) R1 = R2 = C3H7
e) R1 = R2 = C4H9
f) R1 = R2 = C3H7O
123

J IRAN CHEM SOC (2013) 10:55–62
61
Table 1 Preparation of radical precursors 6(a–k)
Entry
Product (6)
R1
R2
R3
MWI time
(A) (min)
% yield (A)
% yield (B)
m.p., °C
(lit [38] m.p., °C)
1
6a
6b
6c
6d
6e
6f
CH3
CH3
H
5
3
84
82
88
93
91
85
83
79
74
81
76
86
88
90
95
94
88
92
86
84
87
78
123–124 (124)
92–93 (92)
80–81 (82)
71–72 (70)
77–78 (78)
64–65 (64)
71–72 (–)
2
CH3
CH3
OCH3
H
3
C2H5
C2H5
C2H5
C2H5
C3H7
C3H7
C4H9
C4H9
C3H7O
C2H5
C2H5
CH3
8
4
OCH3
H
7
5
6
6
CH3
OCH3
H
6
7
6 g
6 h
6i
C3H7
C3H7
C4H9
C4H9
C3H7O
7
8
OCH3
H
8
62–64 (–)
9
9
87–88 (–)
10
11
6j
OCH3
H
12
8
90–92 (–)
6k
98–99 (–)
Product 7 (yield) mpoC (lit. [38] mpoC)
Scheme 3 Bu3SnH, AIBN,
PhMe, MWI (2.45 GHz, 1 h)
in open vessel
O
O
R2
N
O
R2
(84%)
7b (80%)
7c (88%)
7d (82%)
7e (86%)
7f (89%)
(88%)
(82%)
(85%)
141-142oC (142oC)
105-106oC (105oC)
94-95oC (95oC)
102-103oC (102oC)
97-98oC (98oC)
92-93oC (92oC)
101-102oC (--)
97-98oC (--)
O
7a
N
Br
N
R1
O
N
R1
O
3
3
R
R
7 (a-k)
7g
7h
7i
6(a-k)
121-122oC (--)
141-142oC (--)
118-119oC (--)
7 j (72%)
7k (83%)
(New Delhi), Government of India [F. PSW-013/11-12 (ERO)]. PKB
dedicates this paper in the commemoration of his beloved late father,
Sri Bharati Bhusan Basu. AG is grateful to DST (New Delhi) for
providing research fellowship (JRF). PKB is thankful to his depart-
mental colleagues Sri Latibuddin Thander and Mrs. Bhaswati Bhat-
tacharyya for their continuous help.
the addition of this reagent via a syringe pump. The reac-
tion furnished 1H,3H,6H[2]benzopyrano[4,3-d]pyrimidine-
2,4-diones (75–85 %). Performing the cyclisation under
microwave heating in an open vessel resulted in shortening
of the reaction time (1 h instead of 4 h for complete con-
sumption of starting material, as detected by TLC), but the
important factor is that yields were significantly improved
to 72–89 % (Scheme 3).
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