Ionic liquid promoted one-pot synthesis of furo[2,3-d]pyrimidine-2,4(1H,3H) -diones

Article abstract of DOI:10.1007/s00706-006-0558-1

The three-component condensation of aldehyde, N,N′-dimethylbarbituric acid and alkyl or aryl isocyanide afforded the corresponding furo[2,3-d]pyrimidine-2,4(1H,3H)-diones in 1-butyl-3-methylimidazolium bromide as an ionic liquid in high yields at room tem

Full text of DOI:10.1007/s00706-006-0558-1

Monatshefte f€ur Chemie 138, 43–46 (2007)
DOI 10.1007/s00706-006-0558-1
Printed in The Netherlands
Short Communication
Ionic Liquid Promoted One-Pot Synthesis
of Furo[2,3-d]pyrimidine-2,4(1H,3H)-diones
ꢀ
Ahmad Shaabani , Ebrahim Soleimani, and Maria Darvishi
Department of Chemistry, Shahid Beheshti University, Tehran, Iran
Received July 8, 2006; accepted (revised) July 26, 2006
Published online December 8, 2006 # Springer-Verlag 2006
Summary. The three-component condensation of aldehyde, N,N0-dimethylbarbituric acid and alkyl or
aryl isocyanide afforded the corresponding furo[2,3-d]pyrimidine-2,4(1H,3H)-diones in 1-butyl-3-
methylimidazolium bromide as an ionic liquid in high yields at room temperature within several
minutes.
Keywords. Multicomponent reaction; Isocyanide; Ionic liquid; Furo[2,3-d]pyrimidine; [bmim]Br.
Introduction
It is well known that pyrimidine systems as purine analogues exhibit a wide range
of biological activities [1–4]. Among them, the furo[2,3-d]pyrimidine derivatives
act as sedatives, antihistamines, diuretics, muscle relaxants, and antiulcer agents.
The synthesis of furopyrimidines and 2-aminofuran derivatives has received
little attention, and only few procedures have been reported in literature [5–6].
During recent years, ionic liquids have attracted interest as environmentally benign
reagents due to their favorable properties and a variety of catalytic reactions have
been successful using ionic liquids [7]. The solvophobic properties of ionic liquids
are able to generate an internal pressure and promote the association of the reac-
tants in a solvent cavity during the activation process and accelerate a reaction. This
property of ionic liquids is very efficient for multicomponent reactions (MCRs) in
which the entropy of reaction is decreased in the transition state.
In continuation of our studies on the development of new routes for the synthesis
of organic compounds using ionic liquids [8] and our interest in isocyanide-based
MCRs [9], we developed the synthesis of furo[2,3-d]pyrimidine-2,4(1H,3H)-diones
via the three-component condensation of N,N0-dimethylbarbituric acid (1), aldehyde
ꢀ
Corresponding author. E-mail: a-shaabani@cc.sbu.ac.ir

44
A. Shaabani et al.
Scheme 1
2, and an alkyl or aryl isocyanide 3 in 1-butyl-3-methylimidazolium bromide
([bmim]Br) as the solvent and promotor at room temperature (Scheme 1).
Results and Discussion
As indicated in Table 1, the reaction of aldehydes with 1 and alkyl or aryl isocya-
nides afforded furo[2,3-d]pyrimidine-2,4(1H,3H)-diones in [bmim]Br as a promo-
ter in high yield within several minutes.
To explore the scope and limitations of this reaction, we studied the reactions of
1 and alkyl or aryl isocyanides with benzaldehydes bearing either electron-releas-
ing or electron-withdrawing substituents. We found that the presence of electron-
withdrawing functional groups is necessary for the formation of the desired product.
On the contrary, with aromatic aldehydes carrying electron-releasing groups (such
as 4-CH3, or 4-OCH3) products were obtained in poor yields.
To illustrate the need for [bmim]Br, the reaction of p-nitrobenzaldehyde, 1, and
cyclohexyl isocyanide was studied in the absence of [bmim]Br. The yield of pro-
duct was only 60% at room temperature after 24 h. Thus, obviously [bmim]Br is an
important component of the reaction.
One of the advantages of ionic liquids is their ability to function as a recyclable
reaction medium. We were able to separate [bmim]Br from the reaction medium
easily by washing with water and evaporating the solvent under vacuum, and reuse
the ionic liquid for subsequent reactions.
In conclusion, we describe ionic liquids (ILs) as novel and recyclable solvents
for the synthesis of highly functionalized 2-aminofuran derivatives via three com-
ponent condensation of 1, aldehyde, and alkyl or aryl isocyanide. This new pro-
Table 1. Synthesis of furo[2,3-d]pyrimidine-2,4(1H,3H)-diones in [bmim]Br
Entry
R1
R2
Product
Time=min
Yield=%
1
2
3
4
5
6
7
8
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
3-O2NC6H4
3-O2NC6H4
3-O2NC6H4
2-O2NC6H4
C6H5
Cyclohexyl
tert-Butyl
4a
4b
4c
4d
4e
4f
10
10
15
15
15
15
20
20
90
85
86
75
78
81
40
55
2,6-(Me)2C6H3
Cyclohexyl
tert-Butyl
2,6-(Me)2C6H3
Cyclohexyl
Cyclohexyl
4g
4h

Ionic Liquid Promoted One-Pot Synthesis
45
cedure offers several significant advantages, such as operational simplicity, mild
reaction conditions, enhanced rates, improved yields, ease of isolation of products,
recyclability, and the ecofriendly nature of the solvent, which makes it to an useful
and attractive strategy for the synthesis of 2-aminofuran derivatives.
Experimental
Melting points were measured on an Electrothermal 9200 apparatus. IR spectra were recorded on a
FT-IR 102MB BOMEM apparatus. Mass spectra were recorded on a FINNIGAN-MAT 8430 mass
spectrometer operating at an ionization potential of 70eV. 1H and 13C NMR spectra were recorded on a
BRUKER DRX-300 AVANCE spectrometer at 300.13 and 75.47MHz. 1H and 13C NMR spectra were
obtained on solutions in CDCl3 and DMSO-d6 using TMS as internal standard. N,N0-Dimethylbarbituric
acid, aldehydes, and isocyanides were purchased from Fluka and Merck and were used without
purification.
General Procedure
To a solution of 0.15 g 1 (1mmol), 1 mol aldehyde, and 1 mmol alkyl or aryl cyclohexyl isocyanide
were added 0.3 g [bmim]Br. The resulting mixture was stirred for 10min at room temperature. After
completion of the reaction, as indicated by TLC, the reaction mixture was washed with H2O
(2ꢁ10cm3) and the solid residue was recrystallized from CH2Cl2=n-hexane (2=1) to give the products.
All the products (except 4d, 4e, 4f, and 4g) are known compounds, which were characterized by IR
1
and H NMR spectral data and their mps compared with literature data reports [9b, 9f].
6-(Cyclohexylamino)-1,3-dimethyl-5-(3-nitrophenyl)furo[2,3-d]pyrimidine-2,4(1H,3H)-dione
(4d, C20H22N4O5)
Red crystals (0.30 g, 75%); mp 160–162ꢂC. IR (KBr): ꢀꢀ¼ 3280 (NH), 2930, 2856, 1705, 1660, 1528,
1341 cmꢃ1; MS: m=z (%) ¼ 398 (Mþ, 25), 316 (45), 299 (50), 288 (49), 258 (45), 242 (35), 187 (90),
141 (40), 67 (53), 55 (80), 41 (100); 1H NMR (CDCl3): ꢁ ¼ 1.23–1.95 (m, 5CH2–cyclohexyl), 3.19 (m,
CH–N–cyclohexyl), 3.40 (s, NCH3), 3.50 (s, NH), 3.58 (s, NCH3), 7.57–8.55 (m, H–Ar) ppm; 13C NMR
(CDCl3): ꢁ ¼ 24.65, 25.44 (C–cyclohexyl), 28.33, 29.48 (2NCH3), 33.89 (C–cyclohexyl), 55.54 (CH–
N–cyclohexyl), 95.43, 103.71, 121.52, 123.66, 128.99, 132.40, 135.58, 148.07, 149.29, 150.21,
151.08, 158.13 ppm.
6-(tert-Butylamino)-1,3-dimethyl-5-(3-nitrophenyl)furo[2,3-d]pyrimidine-2,4(1H,3H)-dione
(4e, C18H20N4O5)
Orange crystals (0.29 g, 78%); mp 195–197ꢂC. IR (KBr): ꢀꢀ¼ 3281 (NH), 2974, 1703, 1663, 1475,
1359 cmꢃ1; MS: m=z (%) ¼ 372 (Mþ, 20), 316 (90), 299 (60), 288 (30), 259 (55), 242 (50), 187 (95),
1
141 (100), 57 (95), 41 (95); H NMR (CDCl3): ꢁ ¼ 1.20 (s, C(CH3)3), 3.29 (s, NH), 3.41, 3.59 (2s,
2NCH3), 7.56–8.65 (m, H–Ar) ppm; 13C NMR (CDCl3): ꢁ ¼ 28.36, 29.48 (2NCH3), 30.23 (C(CH3)3),
54.77 (C(CH3)3), 95.02, 110.74, 122.00, 124.22, 128.89, 132.35, 136.04, 147.96, 148.37, 150.37, 151.95,
158.17 ppm.
6-(2,6-Dimethylphenylamino)-1,3-dimethyl-5-(3-nitrophenyl)furo[2,3-d]pyrimidine-
2,4(1H,3H)-dione (4f, C22H20N4O5)
Yellow crystals (0.34 g, 81%); mp 214–216ꢂC (dec). IR (KBr): ꢀꢀ¼ 32.84 (NH), 2916, 1702, 1660,
1497, 1343 cmꢃ1; MS: m=z (%) ¼ 420 (Mþ, 100), 403 (63), 348 (15), 288 (30), 272 (15), 242 (15),
1
1387 (30), 77 (20), 53 (10); H NMR (DMSO-d6): ꢁ ¼ 2.03 (s, 2CH3), 3.21, 3.33 (2s, 2NCH3), 6.72
(s, NH), 6.80–8.15 (m, H–Ar) ppm; 13C NMR (DMSO-d6): ꢁ ¼ 18.68 (2CH3) 28.42, 29.80 (2NCH3),
94.70, 101.72, 121.27, 123.61, 123.88, 128.97, 130.96, 132.06, 135.90, 137.81, 146.48, 147.23, 150.16,
151.50, 158.08 ppm.

46
A. Shaabani et al.: Ionic Liquid Promoted One-Pot Synthesis
6-(Cyclohexylamino)-1,3-dimethyl-5-(2-nitrophenyl)furo[2,3-d]pyrimidine-2,4(1H,3H)-dione
(4g, C20H22N4O5)
Yellow crystals (0.16 g, 40%); mp 193–194ꢂC (dec). IR (KBr): ꢀꢀ¼ 3390(NH), 2932, 2853, 1727,
1648, 1540, 1361 cmꢃ1; MS: m=z (%) ¼ 398 (Mþ, 5), 374 (7), 348 (10), 272 (100), 258 (35), 187 (30),
159 (95), 130 ( 95), 56 (20); 1H NMR (CDCl3): ꢁ ¼ 1.31–2.05 (m, 5CH2–cyclohexyl), 3.40 (s,
2NCH3), 3.82 (m, CH–N–cyclohexyl), 6.65 (s, NH), 7.38–9.32 (m, H–Ar) ppm; 13C NMR (CDCl3):
ꢁ ¼ 24.50, 25.31 (C-cyclohexyl), 28.28 (2NCH3), 32.77 (C–cyclohexyl), 49.86 (CH–N–cyclohexyl),
93.63, 112.19, 118.46, 125.05, 130.54, 137.26, 144.76, 149.05, 151.52, 172.26 ppm.
Acknowledgements
We gratefully acknowledge the financial support from the Research Council of Shahid Beheshti
University.
References
[1] Melik-Ogandzhanyan RG, Khachatryan VE, Gapoyan AS (1985) Russ Chem Rev 54: 262
[2] Figueroa-Villar JD, Carneiro CL, Cruz ER (1992) Heterocycles 34: 891
[3] Campaigne E, Ellis RL, Bradford M, Ho J (1996) J Med Chem 12: 339
[4] Blume F, Arndt F, Ress R (1988) Ger Patent 3712782
[5] a) Figueroa-Villar JD, Carneiro CL, Cruz ER (1992) Heterocycles 34: 891; b) Kobayashi K,
Tanaka H, Tanaka K, Yoneda K, Morikawa O, Konishi H (2000) Synth Commun 30: 4277;
c) Vilsmaier E, Baumheier R, Lemmert M (1990) Synthesis 995; d) Kawahara N, Nakajima T,
Itoh T, Ogura H (1984) Heterocycles 22: 2217; e) Qian CY, Nishino H, Kurosawa K, Korp JD
(1993) J Org Chem 58: 4448
[6] a) Nair V, Vinod AU, Abhilash N, Menon RS, Santhi V, Varma RL, Viji S, Mathewa S, Srinivasb R
(2003) Tetrahedron 59: 10279; b) Yadav JS, Subba Reddy BV, Shubashree S, Sadashiv K, Naidu JJ
(2004) Synthesis 2376
[7] a) Holbrey JD, Seddon KR (1999) Clean Product Processes 1: 223; b) Earle MJ, Seddon KR
(2000) Pure Appl Chem 72: 1391; c) Welton T (1999) Chem Rev 99: 2071; d) Wasserschied P,
Kiem M (2000) Angew Chem Int Ed 39: 3772; e) Sheldon R (2001) Chem Commun 2399;
f) Olivier-Bourbigou H, Magna L (2002) J Mol Catal A 182: 419; g) Wilks JS (2004) J Mol Catal A
214: 11; (h) Jain N, Kumar A, Chauhan S, Chauhan SMS (2005) Tetrahedron 61: 1015
[8] a) Shaabani A, Rahmati A, Naderi S (2005) Bioorg Med Chem Lett 15: 5553; b) Shaabani A,
Samadi S, Badri Z, Rahmati A (2005) Catal Lett 104: 39; c) Shaabani A, Rahmati A (2005) Catal
Lett 100: 177; d) Shaabani A, Rahmati A, Aghaaliakbari B (2006) Synth Commun 36: 65;
e) Shaabani A, Soleimani E, Maleki A (2006) Tetrahedron Lett 47: 3031
€
[9] a) Shaabani A, Soleimani E, Khavasi HR, Hoffmann RD, Rodewald UC, Poattgen R (2006)
Tetrahedron Lett 47: 5493; b) Shaabani A, Teimouri MB, Bijanzadeh HR (2002) Tetrahedron Lett
43: 9151; c) Shaabani A, Yavari I, Teimouri MB, Bazgir A, Bijanzadeh HR (2001) Tetrahedron 57:
1375; d) Shaabani A, Teimouri MB, Bazgir A, Bijanzadeh HR (2003) Mol Div 6: 199; e) Shaabani
A, Teimouri MB, Bijanzadeh HR (2004) Monatsh Chem 135: 441; f) Shaabani A, Teimouri MB,
Samadi S, Soleimani K (2005) Synth Commun 35: 535