Traceless synthesis of quinazoline-2,4-diones by curtius rearrangement reaction using poly(ethylene glycol) as soluble polymeric support

Article abstract of DOI:10.1002/jhet.5570440628

(Chemical Equation Presented) We have developed an efficient method to synthesize various quinazoline-2,4-diones using polyethylene glycol) as soluble polymeric support. The procedure of this reaction included: formation of acyl azide, efficient Curtius rearrangement, nucleophlic addition with amines to produce ureas, cyclization and concurrent cleavage of the resulted six-membered heterocycle from PEG-support in excellent yields. This method is mild and manipulation is easy.

Full text of DOI:10.1002/jhet.5570440628

Nov-Dec 2007
Traceless Synthesis of Quinazoline-2,4-diones By Curtius
Rearrangement Reaction using Poly(ethylene glycol) as Soluble
Polymeric Support
1421
Yanling Huang, Cuifen Lu, Zuxing Chen and Guichun Yang*
Ministry-of-Education Key Laboratory for the Synthesis and Application of Organic Functional Molecules,
Hubei University
Faculty of Chemistry and Chemical Engineering, Hubei University, Wuhan, Hubei, 430062, P. R. China
*
Corresponding author. E-mail: yangguichun@hubu.edu.cn
Received January 28, 2007
O
O
O
H
N
NCO
O
OH
RNH
2
OH
O
O
O
N
R
O
O
O
We have developed an efficient method to synthesize various quinazoline-2,4-diones using poly-
ethylene glycol) as soluble polymeric support. The procedure of this reaction included: formation of acyl
(
azide, efficient Curtius rearrangement, nucleophlic addition with amines to produce ureas, cyclization and
concurrent cleavage of the resulted six-membered heterocycle from PEG-support in excellent yields. This
method is mild and manipulation is easy.
J. Heterocyclic Chem., 44, 1421 (2007).
INTRODUCTION
Scheme 1
Quinazoline-2,4-dione derivatives have attracted
interest of pharmaceutical researchers and synthetic
chemists because of their versatile pharmacological activ-
ities [1], which involve sedative and antihypotensive
activites, as well as anticonvulsant activity against electro-
shock [2]. Moreover they show useful antiinflammatory
property and cause vasodilatation in animals [3]. Because
of its important application in medicine, various methods
have been developed to synthesize quinazoline-2, 4-diones
O
O
O
OH
O
3
Et N
OH
O
r. t.
O
1
O
2
ClCO Et
N3
O
Et
3
N,THF
o
NaN , H O
3
2
Toluene
o
o
-
10 C
-10 C
80 C
O
[
4], including solid phase organic synthesis [5].
2
In recent years, synthesis of small organic molecules on
NH
NH
O
R
soluble polymeric supports has become a significant field
in combinatorial chemistry [6]. It combines the advan-
tages of conventional solution chemistry (high reactivity,
lack of diffusion phenomena and easy analysis) and solid
phase organic synthesis (use of excessive reagents, easy
isolation and purification of products) [7]. Up to date, the
synthesis of quinazoline-2,4-diones on soluble polymeric
support has not been reported. Based on our experiences
in the combinatorial synthesis of heterocyclic compounds
on soluble polymeric support [8], we reported herein the
novel synthetic approach of quinazoline-2,4-diones using
PEG as soluble polymeric support by Curtius rearrange-
ment reaction, which is shown in Scheme 1
NCO
RNH
2
O
O
r. t.
O
O
3
4
H
O
N
K
CO
2
3
N
o
CH CN, 60 C
3
R
O
5
shown in Scheme 1, PEG reacted with phthalic anhydride
using triethylamine as base in dry CH Cl at r.t. to
2
2
quantitatively give PEG-bound phthalate ester 1. In this
step, PEG act both as soluble polymeric support and
protective group for carboxylic acid group. The reaction
proceeded to completion as monitored by the disappear-
RESULTS AND DISCUSSION
Considering the balance between loading capacity
and solubility profile of the resulting polymer-bound
derivatives, we chose PEG (MW 3400) as soluble poly-
meric support in synthesis of quinazoline-2,4-diones. As
-1
ance of the hydroxy at 3465 cm and appearance of the
-1
carboxylic acid and PEG-bound ester at 1680 cm and

1
1
422
Y. Huang, C. Lu, Z. Chen and G. Yang
Vol 44
-1
726 cm in IR spectrum. Compound 1 was treated with
spectrometer in CDCl
3
using TMS as internal standard. Mass
spectra were recorded on Finnigan LCQ DUO MS system.
Element analysis were determined by a VarioEL ꢀ(Germany)
analyzer.
Preparation of PEG-bound phthalate ester (1). Phthalic
anhydride (1.74 g, 11.76 mmol) and triethylamine(1.64 mL,
ethyl chloroformate in anhydrous THF in the presence of
triethylamine at -10 °C, and then a solution of sodium
azide in water, was added dropwise. After another 3 h at -
1
0 °C, the system gave PEG-bound acyl azide 2 with the
-1
absorption at 2137 cm for acyl azide. The reaction
proceeded efficiently, for PEG itself was a very good
phase transfer catalyst and avoiding using other PTC [9].
Compound 2 was readily converted to PEG-bound isocya-
nate 3 in toluene at 80 °C by Curtius rearrangement
1
1.76 mmol) was added to a solution of PEG (10.0 g) in dry
CH Cl (30 mL). The mixture was stirred overnight at rt. After
evaporation of the solvent at reduced pressure, the residue
was precipitated with cold Et O (400 mL). The precipitate
was then collected on a sintered glass funnel and thoroughly
washed with cold Et
give 1 (10.40 g, 99%). IR (NaCl): CO 1726(s) cm . H NMR:
ꢀ
1
2
2
2
-1
O (3ꢀ50 mL) and dried under vacuum to
2
reaction. The appearance of absorption at 2255 cm was
clear evidence for the formation of isocyanate. Compound
-
1
1
3.4-3.7 (m, 4n-O(CH CH ) O-); 7.71-8.23(m, 4H, H ),
2 2 n ph
1.0(s, 1H, COOH)
Preparation of PEG-bound acyl azide (2). To a solution of
3
was partioned into several segments and reacted with a
series of primary amines at r.t. in parallel to give 4. A
very efficient cleavage from PEG-bound urea 4 using
K CO in acetonitrile provided the corresponding crude
1 (10.40 g) in dry THF (50 mL) at -10 °C was added dropwise
triethylamine(1.64 mL, 11.76 mmol) over 30 min, then ethyl
chloroformate (1.16 mL, 11.76 mmol) over 30 min, the mixture
was stirred at -10 °C for 1 h. Then a solution of sodium azide
2
3
product 5, which was purified by recrystallization from
ethyl ether or column chromatography.
(0.77 g, 11.76 mmol) in water (28 mL) was added dropwise,
In order to obtain a wide diversity of quinazoline-2,4-
diones, a variety of primary amines were employed.
Aliphatic amines gave good results (in high purity and
good yields), while aromatic amines and highly-blocked
amines such as t-butyl amine and cyclohexylamine failed
to produce the desired product.
It is worthy of noting that the reaction was easily carried
out using PEG as soluble polymeric support, protective
group and phase transfer catalyst in mild conditions with
excellent yields. The polymer-supported products of each
step can be easily isolated and purified by simple
precipitating, which can remove the unreacted materials
continued stirring at -10 °C for 3 h. After evaporating THF, the
aqueous phase was extracted with CH Cl (3ꢀ30 mL), the
2
2
combined organic layer was washed with brine and dried over
anhydrous MgSO filtered, concentrated and precipitated with
4
,
cold Et O (400 mL). The precipitate was collected by filtration,
2
washed with cold Et O (3ꢀ50 mL) and dried under vacuum to
2
give 2 (9.6 g, 92.3%). IR (NaCl): CO 1726(s), CON 2137(s)
3
-
1
1
cm . H NMR:ꢀ 3.41-3.72 (m, 4nH, -O(CH CH ) O-), 7.51-
2
2 n
8
.13(m, 4H, H ).
ph
Preparation of PEG-bound isocyanate (3). The PEG-bound
acyl azide 2 (9.6 g) was stirred in toluene (40 mL) at 80 °C for 4
h, after evaporation of toluene to give the clean isocyanate 3 (9.4
g, 93.8%) without purification for further reaction. IR (NaCl):
-
1
CO 1726 (s), NCO 2255 (m) cm .
and by-products by washing with cold Et O, avoiding
2
General procedure preparation of PEG-bound urea (4).
The mixture of 3 (4.0 g) and aliphatic amines (2.5 mmol) was
stirred in dry CH Cl (30 mL) at r.t. for 7 h. After evaporation of
tedious work-up procedures in contrast to conventional
solution reaction [11,12]. The purity of intermediate
products was easily detected by TLC analysis to observe
whether the lower molecular reagent disappeared or not.
And the configuration of PEG-bound product was readily
2
2
the solvent at reduced pressure, the residue was precipitated with
cold Et O (250 mL), filtered, washed with cold Et O (3ꢀ50 mL)
2
2
and dried under vacuum to give 4.
1
analyzed by H NMR and IR without detaching material
Preparation of quinazoline-2, 4-dione (5). The appropriate
urea derivatives 4 were dissolved in acetonitrile (30 mL), then
K CO was added and the mixture was stirred at 60 °C for 6 h.
from the polymeric support in each step of the sequences
in contrast to insoluble polymers [5].
In conclusion, we have successfully developed an
elegant and efficient approach to synthesis of quinazoline-
2
3
After removing acetonitrile, the residue was redissolved in a
small amount of CH Cl , the detached PEG was precipitated by
2
2
adding cold Et O and removed by filtering. Then, the combined
2
2
,4-diones using PEG as soluble polymeric support, and
filtrate was evaporated to give crude product, which was
purified by recrystallization from ethyl ether or column chroma-
tography on silica gel (EtOAc-n-hexane, 1:4) to give desired
pure product 5.
meanwhile PEG act as monoprotection group and phase
transfer catalyst. This method was simple, the reaction
conditions were mild and the yields were excellent.
3
-Benzylquinazoline-2,4(1H,3H)-dione (5a). This compound
was obtained as a white solid in 92% yield by recrystallization
from ethyl ether. mp 226-226.4 °C (mp 227, lit. [10]). IR:
EXPERIMENTAL
-
1
1
CONH 1658(s), CO 1709(s), NH 3186(m) cm ; H NMR: ꢀ
5.29(s, 2H, NCH Ar), 7.07(d, J=7.8Hz, 1H, Hph), 7.23-7.32(m,
4H, H ), 7.53-7.63(m, 3H, H ), 8.15(d, J=8.4Hz, 1H, H ),
All organic solvents and base were dried by standard methods.
PEG and PEG-bound compounds were melted at 80 °C in
vacuum for 30 min before use to remove traces of moisture.
Melting points were measured on a WRS-1A digital melting
point apparatus. IR spectra were recorded on an IR-spectrum
2
ph
ph
ph
1
3
10.26(s, 1H, NH); C NMR: ꢀ NCH 44.4, 114.8, 115.2, 123.7,
2
127.9, 128.7(2C), 128.7 (2C), 129.1, 135.4, 137.0, 138.7,
+
152.3(CO), 162.6(CO); MS: m/e 253 [M +H]. Anal. Calcd. For
1
13
one (PE) spectrometer. H NMR (600 MHz) and C NMR (150
MHz) spectra were recorded on a Varian Unity INOVA 600
C H N O : C, 71.42; H, 4.79; N, 11.10. .Found: C, 71.36; H,
1
5
12
2
2
4.82; N, 11.15;

Nov-Dec 2007
Traceless Synthesis of Quinazoline-2,4-diones By Curtius Rearrangement Reaction
1423
3
-(2-Phenylethyl)quinazoline-2,4(1H,3H)-dione (5b). This
NMR: ꢀ CH 14.1, CH 20.6, CH 29.9, NCH 42.7, 118.7, 119.3,
3 2 2 2
compound was obtained as a white solid in 90% yield by
recrystallization from ethyl ether. mp 172-173 °C (mp 173-175,
lit.[11] ). IR: CONH 1649(s), CO 1712(s), NH 3190(m) cm ; H
124.9, 129.9, 134.3, 138.9, (CO) 151.1, (CO)163.0; MS: m/e
+
219 [M +H]. Anal. Calcd. For C H N O : C, 66.04; H, 6.47;
1
2
14
2
2
-1 1
N, 12.84. Found: C, 66.00; H, 6.42; N, 12.87.
NMR: ꢀ 2.87-3.04 (m, 2H, CH Ar), 4.32 (t, J=7.8Hz, 2H,
3-sec-Butylquinazoline-2,4(1H,3H)-dione (5h). This compound
was obtained as a white solid in 86% yield. mp 133.1-134.2 °C
(mp: 131-132, lit.[12] ). IR: CONH 1660(s), CO 1712(m), NH
2
NCH ), 7.12(d, J=8.4Hz, 1H, H ), 7.21-7.27 (m, 3H, H ), 7.31-
2
ph
ph
7
.65(m, 4H, H ), 8.15(d, J=8.4Hz, 1H, H ), 10.24 (s, 1H, NH);
ph ph
1
3
-1
1
C NMR: ꢀ CH 34.5, NCH 42.8, 115.1, 115.5, 119.7, 123.9,
3197(m) cm ; H NMR: ꢀ 0.92( t, J=7.8Hz, 3H, CH ), 1.56(d,
2
2
3
1
1
:
27.0, 128.8 (2C), 129.0(2C), 129.4, 135.5, 139.0, 152.4(CO),
J=7.2Hz, 3H, CH ), 1.90-2.24(m, 2H, CH ), 5.11(d, J=6.6Hz,
1H, NCH), 7.10(d, J=8.4Hz, 1H, H ), 7.21-7.26(m, 1H, H ),
ph ph
3
2
+
62.7(CO); MS: m/e 267 [M +H]. Anal. Calcd. For C H N O
1
6
14
2
2
C, 72.16; H, 5.30; N, 10.52. Found: C, 72.18; H, 5.33; N,
0.60.
7.59-7.62(m,1H, H ), 8.12(d, J=7.8Hz, 1H, H ), 10.55(s, 1H,
ph ph
1
3
1
NH); C NMR : ꢀ CH 11.4, CH 17.8, CH 26.3, NCH 51.6,
3 3 2
3
-(1-Phenyl ethyl) quinazoline-2,4(1H,3H)-dione(5c). This
114.7, 114.8, 123.2, 128.4, 134.8, 138.8, 152.7(CO), 162.9(CO);
+
compound was obtained as a white solid in 88% yield. mp 288-
MS: m/e 219 [M +H]. Anal. Calcd. For C H N O : C, 66.04;
1
2
14
2
2
2
1
89 °C (mp 289-292, lit. [11] ). IR: CONH 1652 (s), CO
714(s), NH 3194(m) cm ; H NMR: ꢀ 1.96(d, J=7.2Hz, 3H,
H, 6.47; N, 12.84; Found: C, 66.01 ; H, 6.44; N, 12.86.
-Propylquinazoline-2,4(1H,3H)-dione (5i). This compound
-1
1
3
CH ), 5.29(m, 1H, NCHCH ), 6.86(d, J=7.8Hz, 1H, H ), 7.20-
3
3
ph
was obtained as a white solid in 84% yield. mp 186.3-186.8 °C
(mp: 186-187, lit.[10]). IR: CONH 1638(s), CO 1722(s), NH
3197(m)cm ; H NMR: ꢀ 1.10 (t, J=7.2Hz, 3H, CH ), 1.65-
3
7
.35 (m, 4H, H ), 7.48-7.59(m, 3H, H ), 8.11 (d, J=7.8Hz, 1H,
ph ph
1
3
-1
1
H ), 10.02(s, 1H, NH); C NMR: ꢀ CH 18.5, NCH 49.8, 114.9,
ph
3
1
1
15.1, 120.4, 123.6, 127.8, 128.145(2C), 129.0 (2C), 135.6,
39.4, 141.25, 152.9(CO), 162.7(CO); MS: m/e 267 [M +H].
1
.77(m, 2H, CH ), 4.06 (t, J=7.2Hz, 2H, NCH ), 7.12(d,
2 2
+
J=7.8Hz, 1H, H ), 7.23-7.27(m, 1H, H ), 7.61-7.73(m, 1H,
ph
ph
1
3
Anal. Calcd. For C H N O : C, 72.16; H, 5.30; N, 10.52;
1
6
14
2
2
H ), 8.14(d, J=7.8Hz, 1H, H ), 10.01 (s, 1H, NH); C NMR :ꢀ
ph ph
Found: C, 72.13; H, 5.26; N, 10.58.
-(2-Furylmethyl) quinazoline-2,4(1H,3H)-dione (5d). This
compound was obtained as a white solid in 87% yield. mp
13.4-114.2 °C. IR: CONH 1716(s), CO 1772(s), NH 3504(m)
CH 10.3, CH 22.1, NCH 46.4, 114.3, 115.2, 123.3, 126.7,
3
2
2
+
3
1
34.8, 138.1, 148.5(CO), 160.5(CO); MS: m/e 205 [M +H].
Anal. Calcd. For C H N O : C, 64.69; H, 5.92; N, 13.72;
1
1
12
2
2
1
Found: C, 64.71; H, 5.95; N, 13.77.
-
1
1
cm ; H NMR: ꢀ 4.86(s, 2H, NCH ), 6.29~6.31(t, J=3.0Hz, 1H,
2
3-Methylquinazoline-2,4(1H,3H)-dione(5j). This compound
was obtained as a white solid in 78% yield. mp 242-243.4 °C
(mp 241, lit.[10] ). IR: CONH 1640(s), CO 1723(s), NH 3199
CHC), 6.34(d, J=3.0Hz, 1H, CHCHO), 7.33(d, J=1.2Hz, 1H,
OCH), 7.71-7.73(m, 2H, H ), 7.85-7.87(m, 2H, H ), 10.02 (s,
ph
ph
13
1
1
H, NH); C NMR: ꢀ NCH 34.2, 108.7, 110.4, 121.7, 123.4,
-1 1
2
(m) cm ; H NMR: ꢀ 3.19(d, J=6.0Hz, 3H, NCH ), 7.71-7.72(m,
3
24.5, 127.7, 132.0, 134.1, 142.4, 149.2, 152.5(CO), 167.6(CO);
13
2
H, H ), 7.83-7.86 (m, 2H, H ), 10.21 (s, 1H, NH); C NMR: ꢀ
ph ph
+
MS: m/e 243 [M +H]. Anal. Calcd. For C H N O : C, 64.46;
1
3
10
2
2
CH 29.6, 114.2, 121.7, 123.0, 128.5, 134.9, 138.3, 151.4(CO),
3
H, 4.16; N, 11.56. Found: C, 64.38; H, 4.20; N, 11.58.
-Heptyl quinazoline-2,4(1H,3H)-dione(5e). This compound
was obtained as a white solid in 90% yield. mp 136.2-136.8 °C.
+
1
61. (CO)2; MS: m/e 177 [M +H]. Anal. Calcd. For C H N O :
9 8 2 2
3
C, 61.36; H, 4.58; N, 15.90. Found: C, 61.33; H, 4.60 ; N, 15.92.
Acknowledgement. This work is supported by the National
Natural Sciences Fundation of China (No: 20372019).
-
1 1
IR: CONH 1638(s), CO 1726(m), NH 3196(m) cm ; H NMR: ꢀ
.88(t, J=7.2Hz, 3H, CH ), 1.21-1.41 (m, 10H, (CH ) ), 4.07 (t,
0
3
2 5
J=7.8Hz, 2H, NCH ), 7.09 (d, J=7.2Hz, 1H, H ), 7.23-7.27(m,
2
ph
1
9
H, H ), 7.60-7.63 (m, 1H, H ), 8.14(d, J=7.8Hz, 1H, H ),
REFERENCES
ph
ph
ph
1
3
.52 (s, 1H, NH); C NMR: ꢀ CH 14.1, CH 22.8, CH 26.5,
3
2
2
CH 27.3, CH 30.8, CH 32.1, NCH 42.9, 114.3, 114.7, 123.3,
2
2
2
2
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27.9, 133.9, 138.8, 151.4(CO), 162.3(CO); MS: m/e 261
+
[M +H]. Anal. Calcd. For C H N O : C, 69.20; H, 7.74; N,
15 20 2 2
1
0.76. Found: C, 69.17; H, 7.79; N, 10.81.
-Hexyl quinazoline-2,4(1H,3H)-dione(5f). This compound
was obtained as a white solid in 90% yield. mp 149.9-150.5 °C.
[
[
3] Haver, H. J. And Vidrio, H. J. J. Med. Chem. 1979, 22, 1548.
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IR: CONH 1638(s), CO 1726(s), NH 3196 (m)cm ; H NMR: ꢀ
.89(t, J=7.8Hz, 3H, CH ), 1.32-1.42(m, 8H, (CH ) ), 4.07(t,
0
3
2 4
J=7.8Hz, 2H, NCH ), 7.05 (d, J=7.2Hz, 1H, H ), 7.22-7.26(m,
2
ph
1
H, H ), 7.59-7.61(m, 1H, H ), 8.14(d, J=7.8Hz, 1H, H ), 9.19
ph ph ph
13
(s, 1H, NH); C NMR: ꢀ CH 14.0, CH 22.5, CH 26.6, CH
3 2 2 2
2
1
7.8, CH 31.5, NCH 41.1, 114.6, 114.7, 123.3, 128.5, 134.9,
2 2
38.3, 151.4(CO), 162.3 (CO); MS: m/e 247 [M +H]. Anal.
+
Calcd. For C H N O : C, 68.27; H, 7.37; N, 11.37. Found: C,
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14
18
2
2
6
8.28; H, 7.35; N, 11.43.
-Butyl quinazoline-2, 4(1H,3H)-dione(5g). This compound
was obtained as a white solid in 88% yield. mp 153-155.2 °C
3
(
3
mp: 156, lit.[10] ). IR: CONH 1637(s), CO 1725(s), NH
196(m)cm ; H NMR: ꢀ 0.87(t, J=7.8Hz, 3H, CH ), 1.12~1.18
3
-1
1
(
m, 2H, CH ), 1.53-1.60(m, 2H, CH ), 3.41(t, J=7.2 Hz 2H,
2
2
NCH ), 7.10(d, J=7.8Hz, 1H, H ), 7.22-7.28 (m, 1H, H ), 7.47-
2
ph
ph
1
3
7
.76(m, 1H, H ), 7.99(m, 1H, H ), 10.28(s, 1H, NH);
C
ph
ph

1
424
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Vol 44
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