Novel efficient synthesis of 3,4-dihydro-6-substituted-3-phenylpyrimidin- 2(1H)-ones

Article abstract of DOI:10.1016/j.tetlet.2005.07.101

A new attractive and convenient strategy for the synthesis of 3,4-dihydro-6-substituted-3-phenylpyrimidin-2(1H)-ones is described. Photolysis (λ = 254 nm) of 4-allyl-tetrazolones in alcoholic solutions produces the corresponding pyrimidinones as the sole product in nearly quantitative yields, with simultaneous extrusion of molecular nitrogen. Work-up procedures consist in the simple evaporation of the solvent under reduced pressure, in mild conditions. Heats of reaction for the photocleavage process of 4-allyltetrazolones were calculated, indicating high stability of the resulting products.

Full text of DOI:10.1016/j.tetlet.2005.07.101

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6757–6760
Novel efficient synthesis of
3,4-dihydro-6-substituted-3-phenylpyrimidin-2(1H)-ones
a
b
a,
*
´
Luıs M. T. Frija, Igor V. Khmelinskii and M. Lurdes S. Cristiano
aCIQC, Departamento de Quı´mica e Bioquı´mica, F.C.T. Universidade do Algarve, Campus de Gambelas, 8005-039 Faro, Portugal
bCMQA, Departamento de Quı´mica e Bioquı´mica, F.C.T. Universidade do Algarve, Campus de Gambelas, 8005-039 Faro, Portugal
Received 17 June 2005; revised 18 July 2005; accepted 20 July 2005
Available online 11 August 2005
Abstract—A new attractive and convenient strategy for the synthesis of 3,4-dihydro-6-substituted-3-phenylpyrimidin-2(1H)-ones is
described. Photolysis (k = 254 nm) of 4-allyl-tetrazolones in alcoholic solutions produces the corresponding pyrimidinones as the
sole product in nearly quantitative yields, with simultaneous extrusion of molecular nitrogen. Work-up procedures consist in the
simple evaporation of the solvent under reduced pressure, in mild conditions. Heats of reaction for the photocleavage process of
4-allyltetrazolones were calculated, indicating high stability of the resulting products.
Ó 2005 Elsevier Ltd. All rights reserved.
3,4-Dihydro-pyrimidin-2(1H)-ones are compounds that
have drawn widespread attention, due to their medical
applications.1 For instance, dihydropyrimidinone deriv-
atives have been screened for antihypertension,2 anti-
bacterial,3 anti-inflammatory4 and anticarcinogenic5
activities or as selective a1a-andrenergic receptor antag-
onists.6 The described synthetic routes to these com-
pounds generally involve multi-step transformations
that are essentially based on the Biginelli condensation
methodology.7–9 The present paper reports a new syn-
thetic route to 3,4-dihydro-6-substituted-3-phenylpyrim-
idin-2(1H)-ones 5 from 5-allyloxy-1-aryltetrazoles 3 in
nearly quantitative yields. Interestingly, compounds 5
constitute a novel structural class of pyrimidinones, with
no published description or synthesis to the best of our
knowledge.
alcohols and also by the introduction of substituents on
the phenyl ring attached to the tetrazolyl system. Allyl
tetrazolyl ethers 3 can be used as intermediates for selec-
tive conversion of allylic alcohols into the corresponding
alkenes through transfer hydrogenolysis catalysed by
Pd/C.12 Also, when heated neat or in solution, these
ethers can be quantitatively converted to the corre-
sponding 4-allyltetrazolones 4 via a concerted Claisen-
type isomerisation, affording exclusively the [3,30]
isomers.11,13,14
It has been observed that photolysis of a range of
tetrazolyl derivatives, in solution or isolated in inert
cryogenic matrices, may proceed through several
photochemical processes, all of them involving cleavage
of the tetrazole ring.15–18 Several photoproducts are ob-
served, with their chemical nature and relative ratio
depending on their thermochemical stability and the
structure of the starting tetrazole. One of the reaction
channels for photodegradation is the initial photoclea-
vage of the formally single bonds N1–N2 and N3–N4,
with loss of N2. Sustained by this knowledge and by
our experience concerning the synthesis and reactivity
of 5-allyloxytetrazoles, we have formulated the possibil-
ity of formation of 3,4-dihydro-6-substituted-3-phenyl-
pyrimidin-2(1H)-ones 5 from 4-allyl-tetrazolones 4 by
photolysis, via molecular nitrogen extrusion followed
by ring closure.
In previous contributions, we have reported results of
our investigation on the structure and reactivity of 5-
allyloxytetrazoles 3 (Scheme 1). These compounds can
be obtained from allylic alcohols 2 through reaction
with commercially available 5-chloro-1-phenyltetrazole
1,10 in high yields (around 80%).11 A wide range of these
compounds can be synthesised, by using different allylic
Keywords: Tetrazoles; Tetrazolones; Allyl alcohols; Photolysis;
Pyrimidinones.
*
Optimised experimental conditions for the photochemi-
Corresponding author. Tel.: +351 289800100x7642; fax: +351
289819403; e-mail: mcristi@ualg.pt
cal conversion of 4-allyltetrazolones 4a–c19–21 (Scheme 1)
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.101

6758
L. M. T. Frija et al. / Tetrahedron Letters 46 (2005) 6757–6760
HO
Cl
N
O
NaH
+
THF
N
N
N
N
R
N
1
2
N
3
R
N
70-85 %
Heat
O
O
hν, 254 nm
(16w)
Alcoholic sol.
N
NH
a: R=H;
N
b: R=CH3;
c: R=Ph;
N
- N2
R
N
5
4
N
R
90 - 97 %
> 98 %
Scheme 1.
into 3,4-dihydro-6-substituted-3-phenylpyrimidin-2- (1H)-
ones 5a–c,22–24 are now presented and discussed. Solu-
tions of the 4-allyl-tetrazolones 4a–c were irradiated in
cyclohexane, carbon tetrachloride, acetonitrile, metha-
nol, ethanol, 1-propanol and 1-hexanol. Irradiations
(k = 254 nm, 16 W low-pressure Hg lamp) were con-
ducted using a merry-go-round and an immersion-well
photochemical reactor (Applied Photophysics), placed
at a distance of 5 cm from the lamp and immersed in
water (25 °C) for cooling. Gas evolution from the solu-
tion was observed, corresponding to the photoelimi-
nated molecular nitrogen.
The products are formed in nearly quantitative yields
and their isolation is carried out by simple evaporation
of the solvent under reduced pressure in mild conditions.
The isolated dihydropyrimidinones can be stored as
highly stable compounds. In our experiments, the
amounts of 4-allyltetrazolone used varied between 100
and 300 mg. However, we believe that this methodology
can easily be scaled up (>5 g). The introduction of sub-
stituents on the allylic part (e.g., phenyl in 4c) only
affects the time required for complete conversion
(around 5 h for 4c, as opposed to 3 h for compound
4a). Thus, we consider that the methodology can be
applied to a wider range of 4-allyl-1-substituted tetra-
zolones, allowing for the introduction of chemical
diversity.
Photolysis of 4-allyl-tetrazolones 4a–c in cyclohexane,
carbon tetrachloride and acetonitrile, leads to the
formation of 3,4-dihydro-6-substituted-3-phenylpyrimi-
din-2(1H)-ones 5a–c as sole primary photoproducts.
However, it was observed that in these solvents, the
photoproducts 5a–c are photochemically unstable,
undergoing a rapid decomposition to afford a mixture
of secondary photoproducts identified as aniline, phe-
nyl-, and allyl-isocyanates. Thus, it was never possible
to obtain the required pyrimidinones as sole products
when irradiations were performed in cyclohexane, car-
bon tetrachloride or acetonitrile.
A probable explanation for the photostability exhibited
by these compounds in alcoholic solutions, as opposed
to cyclohexane, acetonitrile and carbon tetrachloride,
is based on an efficient solvation through strong associ-
ation between pyrimidinones 5a–c and solvent mole-
cules. Considering that the alcohols used can form
relatively strong hydrogen bonds, we think that the sta-
bilisation can be attributed to these phenomena, since
pyrimidinones 5a–c bear several putative atoms capable
of forming hydrogen bonds with solvent molecules, as
depicted in structure 6. Product solvation would then
be very efficient, through stable ÔcagesÕ enclosing the
pyrimidinone molecules and preventing their photode-
composition. The influence of these cage effects is also
related to the kinetic energy of the primary photoprod-
ucts and to the viscosity of the solvent, affecting the pho-
tolysis quantum yields. In the alcoholic solutions, the
pyrimidinones have more difficulty in forming molecular
fragments upon excitation due to the Ôsolvent cageÕ, this
effect increasing with the increase in alcohol viscosity.
Also, the absorbed energy is more efficiently dissipated
though the solvated complex, preventing relaxation
through other pathways leading to photocleavage.
Photolysis of the same tetrazolones 4a–c in the protic
solvents methanol, ethanol, 1-propanol or 1-hexanol
also led to formation of 3,4-dihydro-6-substituted-3-
phenylpyrimidin-2(1H)-ones 5a–c as the sole primary
photoproducts. However, in these solvents, pyrimidin-
ones 5a–c remained photostable even after extended
periods of irradiation and no secondary photoproducts
were ever detected throughout the exposure. The only
by-product produced in these reactions is N2, which is
spontaneously eliminated from the reaction mixture.
To our knowledge, this method has not been described
previously and provides a valid access to a range of
3,4-dihydro-6-substituted-3-phenylpyrimidin-2(1H)-ones.

L. M. T. Frija et al. / Tetrahedron Letters 46 (2005) 6757–6760
6759
tetrazolone 4a was followed, until the stationary point
was obtained. The geometry at this point was optimised
by the eigenvector method and led to the transition
structure (TS1). Rotation of the allylic chain in TS1
and N2 exclusion leads to a biradicalar complex (BC1)
with the terminal carbon of the allylic chain (C1) very
R
O
H
H
N
R
O
H
O
N
R
R
H
O
O
H
6
˚
distant from N1 (4.72 A). Subsequent reaction coordi-
nate calculations considering that C1 approaches N1
provided a biradicalar complex (BC2) thermodynami-
cally more stable by 19.1 kcal/mol. The formation of
pyrimidinone 5a from BC2 ensues through 1,2-migra-
tion of hydrogen and formation of a new C1–N1 single
bond, in an exothermic process. Similarly, reaction
coordinates for the formation of compounds 5b–c were
obtained. Calculated heats of formation for tetrazolones
4b–c (79.6 and 111.9 kcal/mol) are also substantially
higher than those calculated for the corresponding
photoproducts 5b–c (ꢀ4.9 and 29.2 kcal/mol). Thus,
based on the results of these semi-empirical calculations,
we can conclude that the pyrimidinones 5 are thermody-
namically more stable than the corresponding starting
tetrazolones 4.
1
Analysis of H NMR spectra for compound 5b was ob-
tained in deuterated chloroform, acetonitrile and meth-
anol. In CDCl3 and CD3OD, all protons connected to
carbon atoms show a similar chemical shift. In CD3CN,
the resonances for the same protons are shifted down-
field by 0.25–0.35 ppm. The signal due to the resonance
of the proton connected to the nitrogen (N–H) appears
at 10.2 and 9.1 ppm in CDCl3 and CD3CN, respectively,
and is not observed in methanol.
In order to facilitate the mechanistic interpretation of
the photocleavage, semi-empirical molecular orbital cal-
culations were performed, using the PM-3 Hamil-
tonian25 provided in the MOPAC 97 program.26 The
proposed reaction pathways for the formation of 3,4-
dihydro-3-phenylpyrimidin-2(1H)-one 5a from 4a are
presented in Figure 1. Considering N2 elimination, the
increase in the N1–N2 and N3–N4 bond lengths in
In summary, we have successfully synthesised 3,4-di-
hydro-6-substituted-3-phenylpyrimidin-2(1H)-ones 5a–c
from 4-allyl-tetrazolones 4a–c through photolysis,
in excellent yields, providing an alternative synthetic
Figure 1. Energy profile for the formation of 3,4-dihydro-3-phenylpyrimidin-2(1H)-one 5a. MOPAC (PM-3) optimised structures.

6760
L. M. T. Frija et al. / Tetrahedron Letters 46 (2005) 6757–6760
´
18. Gomez-Zavaglia, A.; Reva, I. D.; Frija, L.; Cristiano, M.
methodology to this class of compounds. Further inves-
tigations are in progress.
L.; Fausto, R. J. Photochem. Photobiol. A: Chem.,
submitted for publication.
19. 1-Phenyl-4-(prop-2-enyl) tetrazol-5-one 4a from 1-phenyl-
5-(prop-2-enyloxy) tetrazole 3a (1.00 g; 4.90 mmol) heated
neat at 150 °C for 3 h. 1H NMR (CDCl3): d 4.65 (2H, d, J
5.7), 5.30–5.50 (2H, m), 5.90–6.10 (1H, m), 7.40–7.60 (3H,
m), 8.00 (2H, d, J 6.86); mmax.: 1729 (C@O), 1598, 1504,
1388 and 757 cmꢀ1; MS (EI), m/z 202 [M]+. Found: C,
59.8; H, 5.2; N, 28.1%. Calcd for C10H10N4O: C, 59.4; H,
5.0; N, 27.7%.
Acknowledgements
The authors are grateful to FCT, Portugal and FEDER
for financial support (POCTI/P/FCB/33580/00 and
SFRH/BD/17945/2004 (LMTF)).
20. 4-(1-Methylprop-2-enyl)-tetrazol-5-one 4b from 1-phenyl-
5-[(E)-but-2-enyloxy]tetrazole 3b, 150 °C, 2 h. 1H NMR
(CDCl3): d 1.65 (3H, d, J 5.7), 4.90–5.10 (1H, m), 5.22–5.4
(2H, m), 6.0–6.2 (1H, m), 7.30–7.55 (3H, m), 7.95 (2H, d, J
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Calcd for C11H12N4O: C, 61.1; H, 5.6; N, 25.9%.
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22. 3,4-Dihydro-3-phenylpyrimidin-2(1H)-one 5a from 4a
(0.10 g; 0.49 mmol) irradiated in methanol (50 mL), 3 h.
The solvent was evaporated under reduced pressure at
room temperature to give 5a, 92% isolated yield. 1H NMR
(CDCl3): d 4.65–4.68 (2H, d), 5.25–5.50 (1H, m), 7.12–7.2
(1H, m), 7.37–7.43 (2H, m), 7.50–7.57 (2H, t), 10.35 (1H,
s); mmax.: 3212 (NH), 3054, 1693 (C@O), 1590, 1566, 1496,
1368, 1230, 1059, 756 cmꢀ1; MS (EI), m/z 175 [M+H]+.
23. 3,4-Dihydro-6-methyl-3-phenylpyrimidin-2(1H)-one
5b
from 4b, in methanol, irradiated 3.5 h, 97% isolated yield.
1H NMR (CDCl3): d 1.58–1.62 (2H, s), 3.75–3.78 (2H, d),
5.22–5.30 (1H, m), 6.15–6.25 (1H, m), 7.05–7.17 (2H, m),
7.25–7.42 (2H, m), 10.20 (1H, s); mmax.: 3284 (NH), 3085,
1681 (C@O), 1598, 1548, 1484, 1446, 1378, 1230, 1068,
755 cmꢀ1; MS (EI), m/z 189 [M+H]+; Acc. Mass (CI):
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1
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6.45 (1H, m), 6.70–6.75 (1H, m), 6.85–7.05 (2H, m), 7.10–
7.35 (6H, m), 9.90 (1H, s); mmax.: 3220 (NH), 3066, 1701
(C@O), 1581, 1543, 1422, 1345, 1226, 1066, 756 cmꢀ1; MS
(EI), m/z 251 [M+H]+; Acc. mass (CI): found =
251.11809, calcd for C16H15N2O: 251.11844.
´
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