Improving methodology for the preparation of uracil derivatives from Fischer carbene complexes. Microwave activation

Article abstract of DOI:10.1016/S0022-328X(03)00756-3

The effect of the microwave irradiation on the reaction of alkynyl alkoxy carbene complexes with ureas is studied. The results show that the use of microwave activation could represent an alternative to the reaction in conventional conditions for the meta

Full text of DOI:10.1016/S0022-328X(03)00756-3

Journal of Organometallic Chemistry 684 (2003) 266ꢂ268
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Improving methodology for the preparation of uracil derivatives from
Fischer carbene complexes. Microwave activation
Aldo Spinella a,*, Tonino Caruso a, Umberto Pastore a, Susagna Ricart b,*
a Dipartimento di Chimica, Universita di Salerno, Via S. Allende, Baronissi, 84081 Salerno, Italy
b Departament de Materials Moleculars, Institut de Ciencia de Materials de Barcelona (CSIC), Campus de la UAB, E-08193 Bellaterra, Spain
Received 24 April 2003; received in revised form 18 July 2003; accepted 18 July 2003
Abstract
The effect of the microwave irradiation on the reaction of alkynyl alkoxy carbene complexes with ureas is studied. The results
show that the use of microwave activation could represent an alternative to the reaction in conventional conditions for the metal
carbene complex chemistry. In particular, is noteworthy that the use of large amounts of solvents could be drastically reduced or
even avoided and, in any case, reaction times were dramatically shortened.
# 2003 Elsevier B.V. All rights reserved.
Keywords: Carbene complexes; Microwave irradiation; Ureas; Cycloaddition
1. Introduction
compounds are formed while a single compound is
expected when RꢀR?.
/
The preparation of uracils with N1 and/or N3-alkyl
substituent has been of considerable interest to synthetic
chemists for their biological activities [1] and because
they are basic building blocks for the preparation of
oligonucleotides, polymeric analogues of nucleic acids
and non-nucleoside reverse transcriptase inhibitors [2].
These heterocycles can be assembled using appropri-
ate procedures proposed to this purpose, e.g. the
Biginelli reaction [3], among them, a new approach
has been developed for their preparation [4]. This
methodology relies on the reaction of alkynyl alkoxy
Fischer carbene complexes with substituted ureas. The
uracil compound was then obtained by oxidation of the
metal pentacarbonyl cycloadduct (Scheme 1).
In the present communication we have extended this
study to different mono and disubstituted ureas with the
aim to use them as a starting compounds for the
synthesis of uracil derivatives of biological interest.
2. Results and discussion
The results obtained are shown in the Table 1. The
yields in the expected products 3 for disubstituted ureas
(entries 1 and 3) were good albeit the long reaction time
required. However, when we tried to shortened the
reaction times by heating (THF or dioxane reflux) yields
dropped down considerably (60% in the better case).
Finally, some monosubstituted ureas were found as
useful starting material for the preparation of uracils
(entries 2, 4 and 6, Table 1) but once again long reaction
times were required and any improvement were ob-
tained by heating at reflux temperature.
A mechanism suggested for this conversion involves a
nucleophilic attack followed by a cyclisation reaction
(scheme 2). Of course, if the alkyl groups linked to
nitrogen atoms of ureas are different, two isomeric
We can conclude from this experiments, that,
although this methodology has its own synthetic value,
some limitations mainly due to the long reaction times
often required could represent a significant drawback
for preparative purposes.
* Corresponding authors. Tel.: ꢁ
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39-089-965-373; fax: ꢁ39-089-
/
965-296.
E-mail addresses: spinella@unisa.it (A. Spinella), ricart@icmab.es
(S. Ricart).
0022-328X/03/$ - see front matter # 2003 Elsevier B.V. All rights reserved.
doi:10.1016/S0022-328X(03)00756-3

A. Spinella et al. / Journal of Organometallic Chemistry 684 (2003) 266ꢂ
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268
267
Scheme 1.
dramatically decrease reaction time. In fact, we expected
that the use of carbene 1 and substituted ureas under
microwave irradiation should be effective for the rapid
preparation of uracils.
Table 1
Conventional reaction of ureas and carbene (1) at room temperature
Entry Ureas (2)
Time (h)
Product yield a (%)
R
R?
We decided to start considering microwave processes
without solvents and, during our investigation, several
experiments were performed under solvent-free condi-
tions using various irradiation powers for different
times. The best result (92% yield) was obtained just
irradiating a mixture of carbene 1 and dimethylurea for
only 5 min at 300 W of irradiation power. In a similar
way, we studied also the reaction of diethyl urea with
carbene 1. Under solvent free conditions 84% yield of
the expected product 3c was obtained in only 10 min
(Table 2).
1
2
3
4
5
6
CH3
CH3
CH3
H
48
48
3a 90
3b 71 (1:1.3) b
3c 94
CH2CH3
CH2CH3
allyl
CH2CH3
H
144
144
120
192
3d 69 (1:1.5) b
3e 58
allyl
H
allyl
3f 70 (1:3.2) b
a
Reaction conditions: 0.04 mmol of the carbene complex in dry
THF (1 ml), two equivalents of the corresponding urea, room
temperature.
b
Ratio of uracils with N1 or N3-alkyl substituent.
Reactions with monosubstituted ureas proved to be
very difficult in solvent free conditions under microwave
irradiation. In fact, unsatisfactory transformations were
obtained in these conditions (entries 2 and 5, Table 2).
However, when a small quantity of solvent (THF) was
added it was possible to obtain the expected products in
very short times and excellent yields (entries 3 and 6,
Table 2).
The case of diallylurea deserves a special comment.
Diallylurea reacted very slowly in fact, and compound
3e [11] was obtained in 58% yield after 5 days in
conventional conditions. When we tried to apply
microwave irradiation to this reaction in solvent free
conditions an unexpected result was obtained. The
derivative 3e was obtained together with another
compound 4 which after chromatographic separation
showed to be the main product of the reaction.
We decided then to investigate the application of
microwave irradiation to this process.
Microwave heating is one of the most promising non
conventional methodology nowadays used in organic
synthesis [5,6]. One of the first applications of micro-
wave to induce organic chemical reaction dates back
1969 when Vanderhoff described a successful emulsion
polimerization of butylacrylate, acrylic acid and
methacrylic acid under microwave irradiation [7]. How-
ever, only after the pioneering works of Geyde et al. [8]
and Giguere et al. [9] in 1986 really started the wide
application of this technology to organic synthesis and
microwave heating (MWH) has been successfully ap-
plied in recent years to a large number of chemical
reactions [10]. Use of microwave generally allows to
conduct organic reactions in a easy way and also

268
A. Spinella et al. / Journal of Organometallic Chemistry 684 (2003) 266ꢂ268
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Table 2
Reaction of ureas and carbene (1) under microwave irradiation
Entry
R
R?
Solvent
Microwave power a (W)
Irradiation time (min)
Yield b (%)
1
2
3
4
5
6
7
CH3
CH3
CH3
H
ꢂ
ꢂ/
/
300
300
400
250
300
400
350
5
5
3a 92
3b 20 (1:1.5)
3b 69 (1:1.5)
3c 84
CH3
H
THF
5
CH2CH3
CH2CH3
CH2CH3
Allyl
CH2CH3
ꢂ/
ꢂ/
THF
THF
10
10
5
H
H
H
3d 38 (1:1.5)
3d 63 (1:1.5)
3f 54 (1:3)
5
a
The microwave powers and the irradiation times selected are those which allow a full conversion. (stated by the disappearance of the starting
carbene complex).
b
Reaction conditions: all the reactions were conducted in a sealed pressure tube using a domestic microwave oven (0.04 mmol carbene complex,
0.08 mmol urea; THF 50 L, when indicated).
In order to understand the nature of this compound
several NMR experiments were performed and a careful
examination of the obtained data allowed to suggest for
this new compound a tetracarbonylic structure. The new
compound was clearly formed by 3e and, we found that
it is possible to obtain 4 [12] exposing 3e to microwave
or conventional heating.
We assumed that, in the microwave conditions, one of
the carbonyls was lost and replaced by the coordinated
double bond. As expected from this assumption longer
reaction times enhanced the yield on product 4.
References
[1] (a) M. Williams, M. Jarvis, Biochem. Pharmacol. 59 (2000)
1173;
(b) F. Czernecki, S. Ezzituoni, J. Org. Chem. 57 (1992) 7325.
[2] (a) See for example: H.-L. Gi, Y. Xiang, R.F. Schinazi, K. Zhao,
J. Org. Chem. 62 (1997) 88;
(b) E. Yashima, T. Tajima, N. Miyauchi, Biopolymers 32 (1992)
811.
[3] O. Kappe, Acc. Chem. Res. 33 (2000) 879.
[4] R. Polo, J.M. Moreto´, U. Schick, S. Ricart, Organometallics 17
(1998) 2135.
[5] D.M.P. Mingos, D.R. Baghurst, Chem. Soc. Rev. 20 (1991)
1ꢂ47.
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[6] R.A. Abramovitch, Org. Prep. and Proc. Int. 23 (1991) 685.
[7] J.W. Vanderhoff, US patent 3 432413, 1969.
[8] R. Gedye, F. Smith, K. Westaway, H. Ali, L. Baldisera, L.
Laberge, J. Rousell, Tetrahedron Lett. 27 (1986) 279.
[9] R.J. Giguere, T.L. Bray, S.M. Duncan, G. Majetich, Tetrahedron
Lett. 27 (1986) 4945.
3. Conclusions
In conclusion, we shown here that the use of a
microwave irradiation could represent an alternative to
the reaction in conventional conditions for the metal
carbene complexes chemistry. In particular, is note-
worthy that the use of large amounts of solvents could
be drastically reduced or even avoided and, in any case,
reaction times were dramatically shortened.
[10] S. Caddick, Tetrahedron 51 (1995) 10403.
1
[11] Compound 3e: H-NMR d (CDCl3): 7.52 (3H, m), 7.40 (3H, m),
6.02 (1H, m), 5.81 (1H, m), 5.36ꢂ
/
5.23 (5H, m), 5.00 (1H, d, Jꢀ
/
17.2 Hz), 4.37 (2H, bd, Jꢀ
/
5.3 Hz).13C NMR d (CDCl3): 50.2 (t),
62.4 (t), 118.2 (t), 119.1 (t), 127.3 (d), 128.0 (d), 129.0 ( 2C, d),
130.6 (2C, d), 131.0 (d), 131.5 (s), 131.6 (s), 146.7 (s), 147.0 (s),
198.2 (4C, s), 203.3 (s), 239.3 (s).
[12] Compound 4: 1H-NMR d (CDCl3): 7.55 (1H, m), 7.51 (2H, m),
7.38 (2H, d, Jꢀ
Jꢀ14.4, 4.8 Hz), 5.23 (1H, d, Jꢀ
Hz), 4.64 (1H, m), 4.33 (2H, d, Jꢀ
3.46 ( 1H, d, Jꢀ11.5 Hz), 3.44 (1H, d, Jꢀ
(CDCl3): 49.8 (t), 58.5 (t), 59.9 (t), 70.7 (d), 119.0 (t), 123.1 (d),
127.9 (2C, d), 128.8 (2C, d), 130.7 (d), 130.9 (d), 131.9 (s),
147.8 (s), 148.3 (s), 202.4 (s), 202.7 (s), 209.5 (s), 212.1 (s), 240.6
(s).
/
7.3 Hz), 7.08(1H, s), 5.80 (1H, m), 5.26 (1H, dd,
10.3 Hz), 4.98 (1H, d, Jꢀ17.8
6.3 Hz), 4.32 (1H, m),
16.2 Hz). 13C-NMR d
Acknowledgements
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The authors acknowledge the financial supports from
DGICYT (PPQ 2001-1545) and Join Action between
Spain (HI2001-0210) and Italy (IT657-2002). We thank
Mr. Massimiliano Bocchini for the help given during the
experimental work.
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