Preparation of pyrimidin-2-one derivatives via base-mediated decomposition of uracil-analogues Fischer carbene complex

Article abstract of DOI:10.1016/j.jorganchem.2013.09.015

A practical and efficient synthesis of pyrimidin-2-one derivatives from Fischer carbene complex uracil-analogues through base-mediated elimination reactions is described. The scope of the protocol has been explored with the preparation of a variety of pyrimidin-2-one derivatives by base mediated demetallation of N-1 and N-3 substituted uracil Fischer carbenes.

Full text of DOI:10.1016/j.jorganchem.2013.09.015

Journal of Organometallic Chemistry 749 (2014) 47e50
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Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Preparation of pyrimidin-2-one derivatives via base-mediated
decomposition of uracil-analogues Fischer carbene complex
Carmen Bocchino a, Antonella Carabellese a, Tonino Caruso a, Giorgio Della Sala a,
,
Susagna Ricart b, Aldo Spinella a
*
a Dipartimento di Chimica e Biologia, Università di Salerno, Via Giovanni Paolo II, 132 Fisciano, 84084 Salerno, Italy
b Departament de Materials Moleculars, Institut de Ciencia de Materials de Barcelona, CSIC, Campus de la UAB, E-08193 Bellaterra, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical and efficient synthesis of pyrimidin-2-one derivatives from Fischer carbene complex uracil-
analogues through base-mediated elimination reactions is described. The scope of the protocol has been
explored with the preparation of a variety of pyrimidin-2-one derivatives by base mediated deme-
tallation of N-1 and N-3 substituted uracil Fischer carbenes.
Received 12 August 2013
Received in revised form
7 September 2013
Accepted 12 September 2013
Ó 2013 Elsevier B.V. All rights reserved.
Keywords:
Fischer carbene
Pyrimidin-2-one derivatives
Triethylamine
Demetallation
1. Introduction
elimination of Fischer tungsten carbene uracil complexes for the
preparation of pyrimidine-2-one compounds.
Pyrimidin-2-one substructure is a part of many compounds
showing several biological activities ranging from pharmaceutical
to agricultural fields and their preparation has attracted an
increasing research interest [1,2].
In this communication we describe the preparation of pyr-
imidin-2-one derivatives 4,5 from Fischer carbene complex uracil-
analogues 2,3 through base-mediated elimination reactions.
Fischer carbenes have been widely used in organic synthesis [3e
5] and in the course of our studies on the reactivity of alkynyl
alkoxy carbene metal complexes, we have prepared several Fischer
carbene complex uracil-analogues 2,3 starting from carbene com-
plex 1 and substituted ureas [6,7] (Scheme 1).
These uracil-analogues can be considered as an useful inter-
mediate for the preparation of some heterocyclic derivatives. In
fact, uracil derivatives were easily obtained by oxidation of Fischer
tungstenecarbene uracil complexes [8]. During this latter study we
observed that a pyrimidine-2-one (4a) was obtained during the
oxidation of 2a with trimethylamine oxide. We considered the basic
condition as an explanation for the formation of elimination
product (Scheme 2).
2. Results
We started our study considering the effect of different bases on
Fischer tungstenecarbene 2a for the preparation of 1-methyl-4-
phenylpyrimidin-2(1H)-one (4a). Several reactions were conduct-
ed using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine and
triethylamine (TEA) as base. The results are reported in Table 1. DBU
gave quite good results using dichloroethane (DCE) as solvent while
reaction conducted in toluene resulted less effective (entries 1,2).
Pyridine gave unsatisfactory results while TEA showed best results
when used in molar ratio with DCE as solvent (entry 4). In order to
optimize the process a catalytic rather than a molar amount of base
was used. However, decreasing the amount of base also yield de-
creases (entry 5). Finally, the reaction was conducted without the
base in order to evaluate the heating effect. Under this condition
compound 4a was obtained in 33% yield (entry 6).
Furthermore, a base mediated elimination of tungsten oxa-
carbene was described for the preparation of pyranose glycals [9].
These results stimulated our investigation on base mediated
With this optimized conditions in our hands, we considered the
demetallation of uracil Fischer carbene 3a. As expected, taking into
account the steric hindrance brought about by the presence of the
pentacarbonyl moiety, this reaction proved to be more difficult
* Corresponding author. Tel.: þ39 089969585; fax: þ39 089969603.
E-mail address: spinella@unisa.it (A. Spinella).
0022-328X/$ e see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jorganchem.2013.09.015

48
C. Bocchino et al. / Journal of Organometallic Chemistry 749 (2014) 47e50
W(CO)5
R1
R1
O
N
N
base
R
N
H
O
R
N
OCH2CH3
R
2
4
(CO)5W
substituted ureas
W(CO)5
H
1
N
N
base
R
N
O
R
N
O
R1
R1
5
3
Scheme 1.
giving a mixture containing the desired product together with
secondary products. Improvements were obtained using large
excess of base. In fact, an excellent yield (91%) was achieved only
using 10 eq. of TEA (Table 2).
Finally, we studied the scope of this reaction using different
substrates (Table 3). Generally, good results were achieved and only
for N-allyl substituted complexes 2c and 3c the reaction was slow.
In particular 2c required 10 days in order to give a good yield.
Probably this result was due to the initial formation of compound 6
[7] which then is transformed into 4c.
Table 1
Optimization of base-mediated decomposition of Fischer tungstenecarbene 2a.
W(CO)5
Me
Me
O
N
N
base
Ph
N
O
Ph
N
80°C, 24h
H
2a
4a
Entry
Base (eq. mol.)
Solvent
4a (%)
1
2
3
4
5
6
DBU (1.0)
DBU (1.0)
Pyr (1.0)
NEt3 (1.0)
NEt3 (0.3)
e
DCE
Toluene
DCE
DCE
DCE
79
63
34
96
35
33
(OC)4W
N
Ph
N
H
O
DCE
6
Table 2
3. Conclusions
Effect of the base on Fischer tungstenecarbene 3a.
W(CO)5
H
In summary, we have developed a practical and efficient
methodology for the preparation of a variety of pyrimidin-2-ones
derivatives by base mediated demetallation of N-1 and N-3
substituted uracil Fischer carbenes.
N
N
base
Ph
N
O
Ph
N
O
80°C, 24h
Me
3a
Me
5a
4. Experimental
4.1. General methods
Entry
Base (eq. mol.)
Solvent
Yield 5a (%)
1
2
3
4
NEt3 (1.0)
NEt3 (2.0)
NEt3 (10)
NEt3 (20)
DCE
DCE
DCE
DCE
78
84
91
All reactions were carried out using freshly distilled and dried
solvents. Starting materials and reagents purchased from com-
mercial suppliers were generally used without purification.
Uracil carbenes 2 and 3 were prepared according to literature
100
H
W(CO) 5
Me
W(CO) 5
Me
W(CO) 5
reductive
elimination
Me
Me
BH+
N
N
N
N
B
Ph
N
4a
O
Ph
N
H
O
Ph
N
O
Ph
N
O
2a
Scheme 2.

C. Bocchino et al. / Journal of Organometallic Chemistry 749 (2014) 47e50
49
Table 3
Study of scope of reaction. Preparation of pyrimidine-2-one derivatives 4bed and 5b,c.a
Entry
Substrate
Pyrimidin-2(1H)-one
NEt3 (eq. mol.)
Reaction time (d)
Isolated yield (%)
W(CO)5
N
N
1
1
0.5
95
Ph
Ph
N
N
O
O
Ph
Ph
Ph
Ph
N
H
O
4b
2b
W(CO)5
N
N
2
1
10
87
N
H
O
4c
2c
W(CO)5
CH2Ph
CH2Ph
O
N
N
3
1
1
80
Ph
Ph
N
N
N
H
O
4d
2d
W(CO)5
NH
N
N
O
O
4
10
1
97
N
O
5b
3b
W(CO)5
NH
Ph
N
5
10
5
98
Ph
N
O
5c
3c
a
All reactions conducted in DCE at 80 ꢁC.
methods [7]. Reaction temperatures were measured externally;
reactions were monitored by TLC on Merck silica gel plates
(0.25 mm) and visualized by UV light. Flash chromatography was
performed on Merck silica gel (60, particle size: 0.040e
0.063 mm). Yields refer to chromatographically and spectro-
scopic (1H and 13C NMR) pure materials. NMR spectra were
recorded on a DRX 400 (400 MHz) spectrometer at room tem-
perature. CDCl3 was used as a solvent and residual chloroform
4.2.1. Compound 4a
1H NMR (400 MHz, CDCl3)
d
¼ 8.05 (d, 2H, J ¼ 7.2 Hz), 7.53 (d,1H,
J ¼ 6.8 Hz), 7.46 (m, 3H overlapped), 6.76 (d, 1H, J ¼ 6.8 Hz), 3.56 (s,
3H). 13C NMR (100.6 MHz, CDCl3)
d
¼ 171.5, 157.0, 148.2, 135.8, 131.9,
128.6, 127.7, 101.0, 38.8; IR (CHCl3): 1710, 1646, 1388 cmꢀ1; EI-MS
(70 eV) 185, 157, 115.
4.2.2. Compound 4b
(1H
d
¼ 7.26; 13C,
d
¼ 77.0) was used as an internal standard.
1H NMR (400 MHz, CDCl3)
d
¼ 8.07 (d, 2H, J ¼ 10.4 Hz), 7.68 (d,
Infrared spectra were obtained at a resolution of 2.0 cmꢀ1 with a
Vector 22 Bruker spectrometer. ESIMS was performed using a
Quattro micro API mass spectrometer (Micromass, Manchester,
UK) equipped with an electrospray ion source.
1H, J ¼ 10.8 Hz), 7.46 (m, 3H overlapped), 6.77 (d, 1H, J ¼ 10.8 Hz),
3.92 (t, 2H, J ¼ 11.5 Hz),1.78 (dt, 2H, J ¼ 15.0 Hz, J ¼ 7.5 Hz),1.37, 0.94
(t, 3H, J ¼ 7.2 Hz). 13C NMR (100.6 MHz, CDCl3)
¼ 171.1,156.3,147.6,
d
135.7, 131.8, 128.6, 127.7, 100.9, 51.5, 30.1, 19.7, 13.5; IR (CHCl3):
2960, 1659, 1616, 1523, 765 cmꢀ1; EI-MS (70 eV) 229 (Mþ þ H), 228.
4.2. General experimental representative procedure
4.2.3. Compound 4c
A solution of metallocarbene (0.4 mmol) and base in dry solvent
(8 mL), was stirred, in a round bottomed flask equipped with a
condenser, at the temperature of 80 ꢁC until metallocarbene was
completely consumed. Then the solvent was evaporated in vacuo.
The crude mixture was purified by flash chromatography (elution
with CHCl3 and then with CHCl3/CH3OH mixtures 4:1).
1H NMR (400 MHz, CDCl3)
d
¼ 8.04 (d, 2H, J ¼ 6.8 Hz), 7.69 (d,1H,
J ¼ 6.9 Hz), 7.49 (m, 3H overlapped), 6.80 (d, 1H, J ¼ 6.9 Hz), 5.99 (m,
1H), 5.31 (m, 2H), 4.56 (m, 3H). 13C NMR (100.6 MHz, CDCl3)
d
¼ 171.4, 156.2, 147.1, 135.6, 132.1, 131.4, 128.7, 127.9, 119.4, 101.1,
52.5; IR (CHCl3): 1647, 1614, 1493, 1363, 765 cmꢀ1; EI-MS (70 eV)
213 (Mþ þ H), 199, 164, 153.

50
C. Bocchino et al. / Journal of Organometallic Chemistry 749 (2014) 47e50
4.2.4. Compound 4d
(d, 1H, J ¼ 10.0 Hz), 4.92 (d, 1H, J ¼ 17.5 Hz), 4.50 (d, 2H, J ¼ 5.0 Hz),
1H NMR (400 MHz, CDCl3)
d
¼ 8.08 (d, 2H, J ¼ 7.6 Hz), 7.64 (d,1H,
13C NMR (100.6 MHz, CDCl3)
127.7, 118.4, 106.0, 50.1, 47.7.
d
¼ 163.3, 131.4, 130.7, 128.8, 128.7,
J ¼ 6.9 Hz), 7.46 (m, 3H overlapped), 7.36 (m, 5H overlapped), 6.75
(d, 1H, J ¼ 7.2 Hz), 5.14 (s, 2H). 13C NMR (100.6 MHz, CDCl3)
d
¼ 171.6, 156.9, 147.1, 136.0, 135.3, 132.3, 129.4, 129.0, 128.9, 128.8,
128.2, 101.6, 53.6; IR (CHCl3): 1645, 1613, 1492, 1362, 763 cmꢀ1; EI-
Acknowledgements
MS (70 eV) 285 (Mþ þ Na), 263 (Mþ þ H), 158, 109.
Financial support from Università di Salerno is gratefully
acknowledged. The authors thank Mr. Mirko Novella for the help
given in the experimental work.
4.2.5. Compound 5a
1H NMR (400 MHz, CDCl3)
d
¼ 8.55 (d, 2H, J ¼ 4.3 Hz), 7.53 (m,
3H overlapped), 7.37 (m, 3H), 6.23 (d, 1H, J ¼ 4.3 Hz), 3.44 (s, 3H).
13C NMR (100.6 MHz, CDCl3)
¼ 164.3, 160.7, 157.5, 133.0, 130.6,
129.1, 127.7, 105.5, 35.7; IR (CHCl3): 1671, 1658, 1358 cmꢀ1
d
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4.2.6. Compound 5b
1H NMR (400 MHz, CDCl3)
d
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4.2.7. Compound 5c
1H NMR (400 MHz, CDCl3)
d
¼ 8.60 (d,1H, J ¼ 5.0 Hz), 7.51 (m, 3H
overlapped), 7.37 (m, 2H), 6.25 (d, 1H, J ¼ 5.0 Hz), 5.90 (m, 1H), 5.18
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