Tetrahedron 60 (2004) 6593–6596

Synthesis of pyrimidine-containing 3-aminobutenolides

Ugo Chiacchio,a Daniela Iannazzo,b,* Anna Piperno,b Venerando Pistarà,a Antonio Rescifina,a
Giovanni Romeob and Roberto Romeob,*
a
Dipartimento di Scienze Chimiche, Università di Catania, Viale Andrea Doria 6, 95125 Catania, Italy
b
Dipartimento Farmaco-Chimico, Università di Messina, Viale SS. Annunziata, 98168 Messina, Italy
Received 20 April 2004; revised 13 May 2004; accepted 27 May 2004

Available online 19 June 2004

Abstract—An efficient synthesis of pyrimidine-containing butenolides is reported, starting from C-alkoxycarbonyl isoxazolidines. Two
competitive reaction routes are operating: the pathway leading to homo-N,O-nucleosides, based on the reduction of an ester group at C3, and
the reaction channel leading to butenolides promoted by the removal of the hydrogen atom at C3. The two reaction pathways can be easily
controlled according to the adopted experimental conditions
q 2004 Elsevier Ltd. All rights reserved.

1. Introduction

Recently, there has been a great deal of interest in the

synthesis of 2-(5H)furanones;1 this ring system constitutes
the central skeleton of a series of natural compounds such as
fimbrolides,2 dihydroxerulin,3 and protoanemonin.4 The
biological importance of these unsaturated lactones is well-
known: butenolides have been used to prepare peptide
analogues or HIV-1 protease inhibitors;5 protoanemonin, its
analogues and its derivatives possess antiviral, antibiotic
and anticancer activity,6 as well as 4-(1-alkynyl)-substituted
2-(5H)-furanones.7 On the basis of these considerations,
unsaturated analogues of nucleosides appear a focus of
much attention as potential antiviral and antitumor agents.8

We have recently reported a versatile entry to functionalized

2-(5H)furanones through a new rearrangement pattern of the
isoxazolidine nucleus, easily accessible by 1,3-dipolar
cycloaddition of nitrones with suitable alkenes.9 The
reaction consists of a basic treatment of isoxazolidines,
Figure 1.
suitably activated at position 3 of the nucleus with NaH at
room temperature.
and extendable to the preparation of all purine and
pyrimidine derivatives (Fig. 1).
The same reaction sequence has been exploited as a
synthetic route towards a new series of modified nucleo-
sides, potential candidates of a new class of antiviral agents.
Herein, we report the synthesis of pyrimidine derivatives of
2. Results and discussion
unsaturated lactones 1: the synthetic route appears versatile
The cycloaddition reaction between N-methyl-C-ethoxycar-
bonyl nitrone 210 (E/Z ratio 4:1) and allyl nucleobases 3
proceeded smoothly in anhydrous toluene at 80 8C for 14 h
Keywords: 1,3-Dipolar cycloaddition; Butenolides; Homo-nucleoside
analogues. to give isoxazolidines 4 and 5 in ca. 2:1 ratio and 93– 96%
* Corresponding authors. Tel.: þ39-90-356230; fax: þ39-90-6766562; yields.11 As reported,11 the successive reduction of the
e-mail address: rromeo@pharma.unime.it estereal group by treatment with LiAlH4 afforded the

0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.081
6594 U. Chiacchio et al. / Tetrahedron 60 (2004) 6593–6596

expected homo-N,O-nucleosides 6 and 7 in moderate yields

(Scheme 1).

However, the presence of the ethoxycarbonyl group at

position 3 in isoxazolidines 4 and 5 increases the acidity
of the hydrogen atom at the same position, thus suggesting
the possibility of an alternative reaction course following
the treatment of isoxazolidines 4 and 5 with basic reagents.
Thus, its deprotonation by NaH leads to the formation of
enolate 8 which evolves, via ring-opening, towards the
anion 9; the subsequent intramolecular nucleophilic acyl
substitution affords lactones 1a– c, in high yields (76 – 81%)
(Scheme 2).

Structural assignments have been performed on the basis of

spectroscopic data. The molecular formula of furanones
follows from an exact mass determination; the IR absorp-
tions of the carbonyl group at 1720 cm21 are in accord with
the g-lactones.

The 1H NMR spectra of compounds 1a show the H40 protons

as doublets at d 5.61, while H50 protons resonate as ddd at
5.17. Moreover, the methylene substituents at C50 give rise
two dd centered at d 3.67 and 4.07 and the N-methyl groups
resonate as doublets (J¼4.8 Hz) at d 2.49.

Scheme 1. (a) Toluene, sealed tube, 80 8C, 1 h; (b) LiAlH4, THF, 0 8C, 1 h.
With reference to the previously reported synthesis of
homo-N,O-nucleosides,11 the results obtained can be
rationalized by assuming that, starting from isoxazolidines
4 and 5, two different competing reaction routes are
operating. The use of a nucleophilic reagent such as
LiAlH4 induces a nucleophilic attack of the hydride ion to
the estereal functionality, so promoting the reduction
process towards the already reported homo-nucleosides 6
and 7.

Alternatively, the driving force for the transformation of 4

and 5 into 1 is represented by the low critical energy
required to induce an ionic center at position 30 of
isoxazolidines 4 and 5, which promotes the ring opening
of the heterocyclic system and the subsequent intra-
molecular lactonization. With NaH, the acid – base process
is the only one operating, with the exclusive formation of
Scheme 2. (a) NaH, THF, rt, 4 h. lactone 1.

Table 1. Reactions of isoxazolidines 4 and 5 with different reagents

Entry Compounds Conditionsa Product yields (%)b

1 4a/5a NaH, THF, 4 h 1a (81)

2 4b/5b NaH, THF, 4 h 1b (76)
3 4c/5c NaH, THF, 4 h d.p.c
4 4a/5a EtONa, THF, 4 h 1a (80)
5 4b/5b EtONa, THF, 4 h 1b (70)
6 4c/5c EtONa, THF, 4 h 1c (74)
7 4a/5a MeOH, NaBH4, 1 h, 0 8C 1a (40)
8 4b/5b MeOH, NaBH4, 1 h, 0 8C 1b (37)
9 4c/5c MeOH, NaBH4, 1 h,0 8C 1c (30)
10 4a/5a TBAF, THF, 1 h 1a (99)
11 4b/5b TBAF, THF, 1 h 1b (98)
12 4c/5c TBAF, THF, 1 h 1c (95)
13 4a –c MeOH/H2O 95/5 or dioxane/H2O 1/1, NaBH4, 1 h 6a–c (99)
14 5a –c MeOH/H2O 95/5 or dioxane/H2O 1/1, NaBH4, 1 h 7a–c (99)
a
Reaction performed at room temperature.
b
Isolated yield.
c
Decomposition products.
 U. Chiacchio et al. / Tetrahedron 60 (2004) 6593–6596
As a confirmation, also the use of different bases, with a
decreasing basicity, such as sodium ethoxide and TBAF, pro-
motes the same reaction path, leading to the formation of
lactones in better yields and with an easier work-up (Table 1).
Noteworthy, when isoxazolidines 4 and 5 have been reacted
with NaBH4, the formation of both homo-nucleosides or
lactones has been observed, according to the experimental
conditions adopted. With anhydrous MeOH, the exclusive
formation of lactones has been detected (40% yield)
together with decomposition products; while with MeOH/
water (95:5) or dioxane/water (1:1) as a solvent, the homo-
nucleosides were obtained in a nearly quantitative yield.
The results obtained can be rationalized on the basis of the
following considerations. With respect to LiAlH4, sodium
borohydride is less nucleophilic;12 thus, in MeOH anhy-
drous as solvent, the reaction route is driven by the basic
attack of NaBH4 at H30 , which leads to lactone 1. However,
when water is present in the reaction medium, the formation
of the enolate ion 8 is suppressed and thus the route towards
lactone 1 is blocked. The equilibrium turns back to the original
isoxazolidines and, then, through the attack of hydride ion
on the ester group, to the corresponding homo-nucleoside.
In conclusion, an efficient synthesis of pyrimidine contain-
ing butenolides is reported. Starting from isoxazolidines,
obtained by 1,3-dipolar cycloaddition of C-alkoxycarbonyl
nitrones with allyl nucleobases, two competitive reaction
routes are operating: the pathway leading to homo-N,O-
nucleosides, based on the reduction of ester group at C30 , and
the reaction channel leading to butenolides promoted by the
removal of the hydrogen atom at C30 . The two reaction
pathways can be easily controlled according to the adopted
experimental conditions.
Biological evaluation as potential antiviral agents of the
new series of pyrimidine butenolides is in progress.
3. Experimental
3.1. General
All melting points are uncorrected. Elemental analyses were
done on a C. Erba 1106 elemental analyzer. IR spectra were
recorded on a Perkin – Elmer Paragon 500 FT-IR Spectro-
meter using potassium bromide discs. 1H- and 13C NMR
spectra were recorded on a Varian Unity Inova 300 in
deuterated DMSO. Chemical shifts are expressed in ppm
from DMSO (2.50 ppm for 1H and 29.5 ppm for 13C). Thin-
layer chromatographic separations were performed on
Merck silica gel 60-F254 precoated aluminium plates.
Preparative separations were made by flash column
chromatography using Merck silica gel (0.035 – 0.070 mm)
eluant CHCl3/MeOH 95:5.
Compounds 4 and 5 have been previously reported.11
3.2. General procedure for the preparation of
pyrimidine butenolides 1a – c
Method A. (Entry 1– 3). To a solution of isoxazolidines
6595
4a – c/5a –c (2 mmol) in dry THF (20 mL) was added NaH
(48.0 mg, 2 mmol), and the mixture was stirred for 4 h at
room temperature, until the TLC showed the disappearance
of the starting material. The reaction mixture was then
quenched with water (0.5 mL) and evaporated under
reduced pressure. The residue was then purified by column
flash chromatography.
Method B. (Entry 4– 6). To a solution of isoxazolidines
4a – c/5a –c (2 mmol) in dry THF (10 mL) was added a
solution of sodium ethoxide (0.73 mL, 21 wt% solution in
denaturated ethyl alcohol, 2 mmol), the mixture was stirred
for 4 h at room temperature, until the TLC showed the
disappearance of the starting material. The reaction mixture
was then quenched with water (0.5 mL) and evaporated
under reduced pressure. The residue was then purified by
flash column chromatography.
Method C. (Entry 7– 9). NaBH4 (20.0 mg, 5 mmol) was
added at 0 8C to a stirred solution of isoxazolidines 4a –c/
5a – c (1 mmol) in dry MeOH (30 mL), and the mixture was
stirred for 1 h at the same temperature. The reaction mixture
was evaporated under reduced pressure. The residue was
then purified by flash column chromatography.
Method D. (Entry 10 – 12). To a solution of isoxazolidines
4a – c/5a –c (1 mmol) in dry THF (20 mL), TBAF (1.05 mL,
1.1 mmol, 1 M solution in THF) was added, and the mixture
was stirred at room temperature for 1 h. At the end of this
time, the solvent was removed and the residue was subjected
to silica gel flash column chromatography.
3.2.1. 5-Methyl-1-{[4-(methylamino)-5-oxo-2,5-dihydro-
furan-2-yl]methyl}pyrimidine-2,4(1H,3H)-dione (1a).
Yield 99%; white solid: mp 180 – 184 8C. IR (KBr) n
3270, 2850, 1752, 1710, 1660, 1618, 1559, 1450, 1370,
1320, 1260, 1165, 1150, 983, 775 cm21. 1H NMR
(DMSOd6, 300 MHz): d 1.72 (d, 3H, J¼0.8 Hz), 2.49 (d,
3H, N –CH3, J¼4.8 Hz), 3.67 (dd, 1H, H500 a, J¼6.9,
14.2 Hz,), 4.07 (dd, 1H, H500 b, J¼3.0, 14.2 Hz,), 5.17 (ddd,
1H, H50 , J¼2.0, 3.0, 6.9 Hz), 5.61 (d, 1H, H40 , J¼2.0 Hz),
5.67 (d, 1H, N – H, J¼4.8 Hz), 7.41 (q, 1H, H6, J¼0.8 Hz),
11.31 (bs, 1H, NH). 13C NMR (DMSOd6, 75 MHz): d
11.9, 30.7, 50.1, 78.6, 105.4, 108.1, 137.1, 141.7, 150.9,
164.2, 179.5. Anal. Calcd for C11H13N3O4: C, 52.59; H,
5.22; N, 16.73%. Found: C, 52.79; H, 5.20; N, 16.76%.
Exact mass calculated for C11H13N3O4: 251.0906. Found:
251.0907.
3.2.2. N-(5-Methyl-1-{[4-(methylamino)-5-oxo-2,5-di-
hydrofuran-2-yl]methyl}-2-oxo-1,2-dihydropyrimidin-
4-yl)acetamide 1b. Yield 98%; white solid: mp 153–
155 8C. IR (KBr) n 3300, 2928, 1762, 1714, 1666, 1628,
1567, 1500, 1374, 1313, 1259, 1232, 1170, 1141, 1037,
785 cm21. 1H NMR (DMSOd6, 300 MHz): d 2.08 (s, 3H),
2.56 (d, 3H, N –CH3, J¼4.9 Hz), 3.84 (dd, 1H, H500 a, J¼7.1,
14.0 Hz), 4.22 (dd, 1H, H500 b, J¼3.0, 14.0 Hz), 5.24 (ddd,
1H, H50 , J¼0.5, 3.0, 7.1 Hz), 5.64 (d, 1H, H40 , J¼0.5 Hz),
5.67 (d, 1H, NH, J¼4.9 Hz), 7.12 (d, 1H, J¼7.2 Hz), 7.96
(d, 1H, J¼7.2 Hz), 10.08 (bs, 1H, NH). 13C NMR (DMSOd6,
75 MHz): d 24.2, 30.6, 52.3, 78.0, 94.9, 105.4, 137.1, 149.6,
150.7, 162.6, 169.0, 170.9. Anal. Calcd for C12H14N4O4: C,
51.80; H, 5.07; N, 20.13%. Found: C, 51.55; H, 4.95; N,
6596 U. Chiacchio et al. / Tetrahedron 60 (2004) 6593–6596
19.95%. Exact mass calculated for C12H14N4O4: 278.1015.
Found: 278.1010.
3.2.3. 5-Fluoro-1-{[4-(methylamino)-5-oxo-2,5-dihydro-
furan-2-yl]methyl}pyrimidine-2,4(1H,3H)-dione 1c. Yield
95%; white solid: mp 175 –178 8C. IR (KBr) n 3285, 2890,
1770, 1698, 1675, 1630, 1570, 1490, 1382, 1318, 1265,
1220, 1165, 1100, 1027, 795 cm21. 1H NMR (DMSOd6,
300 MHz): d 2.50 (d, 3H, N –CH3, J¼4.7 Hz), 3.60 (dd, 1H,
H500 a, J¼6.9, 14.3 Hz), 3.99 (dd, 1H, H500 b, J¼3.3, 14.3 Hz),
5.11 (ddd, 1H, H50 , J¼0.6, 3.3, 6.9 Hz), 5.55 (d, 1H, H40 ,
J¼0.6 Hz), 5.62 (d, 1H, NH, J¼4.7 Hz), 7.92 (d, 1H, H6,
J¼6.7 Hz), 11.78 (bs, 1H, NH). 13C NMR (DMSOd6,
75 MHz): d 30.7, 50.5, 78.3, 105.3, 130.5, 137.2, 141.5,
149.6, 158.2, 169.1. Anal. Calcd for C10H10FN3O4: C,
47.06; H, 3.95; N, 16.47%. Found: C, 46.88; H, 3.94; N,
16.50%. Exact mass calculated for C10H10FN3O4:
255.0655. Found: 255.0653.
3.3. General procedure for the preparation of homo-
N,O-nucleosides 6 and 7 (entry 13 and 14)
Sodium borohydride (40.0 mg, 10 mmol) was added to a
solution of isoxazolidines 4a– c or 5a – c (1 mmol) in a 1:1
dioxane/water mixture (15 mL) or 95:5 methanol/water
mixture (15 mL), and the reaction was vigorously stirred
for 1 h, at 0 8C. After this period, the solvent was removed
and the residue was then purified by flash column
chromatography.
Acknowledgements
This work was supported by M.I.U.R. (project P.R.I.N. 2002
and F.I.R.B.).
References and notes
1. (a) Takayama, H.; Ichikawa, T.; Kuwajima, T.; Kitajima, M.;
Seki, H.; Aimi, N.; Nonato, M. G. J. Am. Chem. Soc. 2000,
122, 8635– 8639. (b) Langer, P.; Schneider, T.; Stall, M.
Chem. Eur. J. 2000, 6, 3204 –3214. (c) Langer, P.; Stall, M.
Angew. Chem., Int. Ed. Engl. 1999, 38, 1803 – 1805.
(d) Chiacchio, U.; Piperno, A.; Romeo, G.; Uccella, N.
Tetrahedron 1998, 54, 5695– 5708. (e) Cardellach, J.; Estopa,
C.; Font, J.; Moreno-Mañas, M.; Ortuño, R. M.; Sanchez-
Ferrando, F.; Valle, S.; Vilamayo, L. Tetrahedron 1982, 38,
2377 –2394.
2. (a) de March, P.; Font, J.; Gracia, A.; Quingying, Z. J. Org.
Chem. 1995, 60, 1814– 1822. (b) Kazlauskas, R.; Murphy,
P. T.; Quinn, R. J.; Wells, R. J. Tetrahedron Lett. 1997, 18,
37 – 40.
3. Rossi, R.; Bellina, F.; Catanese, A.; Mannina, L.; Valesin, D.
Tetrahedron 2000, 56, 479– 487.
4. Roussel, C.; Fihi, R.; Ciamala, K.; Audebert, P.; Vebrel, J.
New J. Chem. 2000, 24, 471–476.
5. (a) Ghosh, N.; McKee, S. P.; Thompson, W. J.; Darke, P. L.;
Zugory, J. C. J. Org. Chem. 1993, 58, 1025 – 1029.
(b) Hanessian, S.; Park, H.; Yang, R. Y. Synlett 1997,
351– 352. (c) Hanessian, S.; Park, H.; Yang, R. Y. Synlett
1997, 353– 354.
6. (a) Alonso, D.; Font, J.; Ortuno, R. M.; d’Angelo, J.; Guingant,
A.; Bois, C. Tetrahedron 1991, 47, 5895– 5900. (b) Raic-
Malic, S.; Hergold-Brundic, A.; Nagl, A.; Grdisa, M.; Pavelic,
K.; Declercq, E.; Mintas, M. J. Med. Chem. 1999, 42,
2673 –2678. (c) Raic-Malic, S.; Svedruzic, D.; Gazivoda, T.;
Marunovic, A.; Hergold-Brundic, A.; Nagl, A.; Balzarini, J.;
De Clercq, E.; Mintas, M. J. Med. Chem. 2000, 43,
4806 –4811. (d) Kupchan, S. M.; Eakin, M. A.; Thomason,
A. M. J. Med. Chem. 1971, 14, 1147– 1152.
7. Bellina, F.; Falchi, E.; Rossi, R. Tetrahedron 2003, 59,
9091 –9100.
8. Hakimelahi, G. H.; Mei, N.-W.; Moosavi-Movahedi, A. A.;
Davari, H.; Hakimelahi, S.; King, K-Y.; Hwu, J. R.; Wen,
Y.-S. J. Med. Chem. 2001, 44, 1749– 1757.
9. Chiacchio, U.; Corsaro, A.; Iannazzo, D.; Piperno, A.;
Procopio, A.; Rescifina, A.; Romeo, G.; Romeo, R. J. Org.
Chem. 2002, 67, 4380– 4383.
10. (a) Chiacchio, U.; Rescifina, A.; Iannazzo, D.; Romeo, G.
J. Org. Chem. 1999, 64, 28 – 36. (b) Merino, P.; Revuelta, J.;
Tejero, T.; Chiacchio, U.; Rescifina, A.; Romeo, G.
Tetrahedron 2003, 59, 3581– 3592. (c) Romeo, G.; Iannazzo,
D.; Piperno, A.; Romeo, R.; Corsaro, A.; Rescifina, A.;
Chiacchio, U. Mini-Rev. Org. Chem. 2004, 2, in press.
11. Chiacchio, U.; Genovese, F.; Iannazzo, D.; Librando, V.;
Merino, P.; Romeo, R.; Procopio, A.; Romeo, G. Tetrahedron
2004, 60, 441– 448.
12. Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry,
Part B: Reactions and Synthesis; 4th ed. Kluwer/Plenum: New
York, 2001; p. 262.