A domino microwave-assisted protocol for the synthesis of 2,6-disubstituted pyrimidinones

Article abstract of DOI:10.1055/s-0030-1261174

A practical microwave-assisted protocol for the synthesis of 2,6-disubstituted pyrimidinones has been developed. This approach is based on a domino Michael addition-cyclocondensation reaction between substituted thioureas/guanidines and acetylenecarboxyla

Full text of DOI:10.1055/s-0030-1261174

LETTER
1997
A Domino Microwave-Assisted Protocol for the Synthesis of 2,6-Disubstituted
Pyrimidinones
D
omino Microwave-A
a
ssisted Syn
r
thesis of
c
2, 6-Disubs
o
tituted Pyrimidinon
R
es adi,a,1 Gianni Casaluce,a,1 Maurizio Botta*a,b
a
Dipartimento Farmaco Chimico Tecnologico, University of Siena, Via Alcide de Gasperi 2, 53100 Siena, Italy
b
Sbarro Institute for Cancer Research and Molecular Medicine, Temple University,
BioLife Science Building, Suite 333, 1900 N 12th Street, Philadelphia, PA 19122, USA
Fax +39(0577)234333; E-mail: botta.maurizio@gmail.com
Received 10 June 2011
However, while the S-DABO family has been highly in-
vestigated, poor attention has been paid to N-DABO
counterpart. The classical approaches for the synthesis of
N-DABOs encompass the direct Pinner pyrimidine
Abstract: A practical microwave-assisted protocol for the synthe-
sis of 2,6-disubstituted pyrimidinones has been developed. This ap-
proach is based on a domino Michael addition–cyclocondensation
reaction between substituted thioureas/guanidines and acetylene-
carboxylates. The application of such protocol for the synthesis of synthesis9 or the C2 nucleophilic substitution on
DABOs10 or S-DABOs11 using the opportune amines.
not easily accessible N-DABO derivatives as potential antiviral
agents is also reported.
However, these approaches require long reaction times,
Key words: microwave, pyrimidinones, acetylenecarboxylates,
S-DABO, N-DABO
high temperatures and the use of nucleophiles in strong
excess that limits their applicability with not-easily acces-
sible amines. Accordingly, we became interested in the
development of a practical synthetic strategy for the prep-
The pyrimidine core is considered a very interesting ‘priv- aration of pyrimidin-4(3H)-one derivatives to be used for
ileged scaffold’ whose regioselective functionalization the synthesis of novel N-DABOs as potential anti-HIV
can lead to biologically active compounds directed agents. As part of our efforts in the development of new
against several different targets.2 Substituted pyrimidin- microwave-assisted procedures for the synthesis of het-
4(3H)-ones have in fact been widely explored in the erocycles with potential biological application,12 herein
search for novel anti-HIV agents: 1-[(2-hydroxyethyl)- we describe a simple and rapid microwave-assisted dom-
methyl]-6-(phenylthio)thymine (HEPT),3 1-(ethoxymeth- ino Michael addition–cyclocondensation protocol for the
yl)-6-(phenylmethyl)-5-propan-2-ylpyrimidine-2,4-dione
(EMV)4 and 3,4-dihydro-2-alkoxy 6-benzyl-4-oxopyrim-
idines (DABOs),5 showed a potent activity against reverse
transcriptase (RT) of human immunodeficiency virus
type-1 (HIV-1). Since their discovery in 1992, DABO an-
alogues have been the object of great interest and, over the
years, many derivatives (S-DABO6,7 and N-DABO8) char-
acterized by an high activity profile against both HIV-1
RT wild type (wt) and drug-resistant mutants have been
developed (Figure 1).
synthesis of 2,6-disubstituted pyrimidinones.
In 2003, Karpov and Müller reported the employment of
alkynones (synthetic equivalents to b-keto aldehydes) as
interesting building blocks for the synthesis of 2,4,6-
trisubstituted pyrimidines after heating for several hours
in the presence of a base.13,14 In 1981 Gupta et al. reported
the use of N-aryl acetamidines for the synthesis of 2,3,6-
trisubstituted pyrimidones which however were obtained
after heating for one or more days.15 We decided to im-
prove and expand such approaches using acetylenecar-
boxylates as b-keto ester synthetic equivalents and to
apply microwave irradiation to speed-up the synthesis of
2,6-disubstituted pyrimidin-4(3H)-ones upon reaction
with substituted thioureas/guanidines. The reaction is
based on a microwave-assisted Michael addition of the bi-
dentate nucleophiles on a polarized triple bond with the
formation of the intermediate I followed by intramolecu-
lar displacement of the alkoxy group of the ester to obtain
the desired pyrimidin-4(3H)-one ring (Table 1).
O
O
O
R3
HN
O
HN
O
HN
R4
R2
O
N
S
O
N
X
N
R1
OH
DABOs (X = O)
S-DABOs (X = S)
N-DABOs (X = N)
emivirine (EMV)
HEPT
The reaction conditions were optimized on the model re-
action reported in Table 1: the readily available ethyl 4-
(tetrahydro-2H-pyran-2-yloxy)but-2-ynoate (2; synthe-
sized using a reported procedure)16 was reacted with S-
methylisothiourea sulfate under microwave irradiation
changing reaction time, solvent and base while the tem-
perature was kept at the optimal value of 120 °C as estab-
lished in preliminary experiments17 (Table 1). We began
our investigation using the same conditions reported by
Figure 1 Substituted pyrimidin-4(3H)-ones active against HIV-1
SYNLETT 2011, No. 14, pp 1997–2000
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x
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x
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Advanced online publication: 10.08.2011
DOI: 10.1055/s-0030-1261174; Art ID: B10711ST
© Georg Thieme Verlag Stuttgart · New York

1998
M. Radi et al.
LETTER
Müller, using Na2CO3 as base and MeCN as solvent. Un- of the intermediate with general structure I confirmed the
fortunately no product was isolated but only the starting proposed mechanism and showed that Michael addition of
material was recovered (Table 1, entry 1). Considering the S-methylisothiourea on the polarized triple bond of 2 is
low solubility of 1 in this medium, we decided to explore the first step of the reaction. According to the optimized
other solvents. When the same reaction was performed in protocol, ethyl 4-(tetrahydro-2H-pyran-2-yloxy)but-2-
DMF, compound 3 was obtained in reasonable yields after ynoate (2; 1 equiv) and S-methylisothiourea sulfate (1.2
only 10 minutes. Increasing the reaction time had a posi- equiv) were dissolved in DMF or t-BuOH in presence of
tive effect on the yield of 3 and the best results were ob- Na2CO3 (2.4 equiv) and the resulting mixture was heated
tained by irradiation of the mixture for 20 minutes at 120 °C under microwave irradiation for 20 minutes.18
(Table 1, entries 2–4). The use of an organic base such as
triethylamine gave no results and the starting materials
were recovered unchanged (Table 1, entry 5). Protic sol-
The above optimized protocol was then applied to the syn-
thesis of new N-DABOs analogues (11 and 12) whose
synthesis following the above mentioned classical proce-
vents gave results comparable to those obtained with
dures proved, in our hands, to be unsuccessful. We started
DMF (Table 1, entries 6 and 7), while no reaction was ob-
therefore with the synthesis of the alkynone 9 as key inter-
mediate for the Michael addition–cyclocondensation pro-
served in solvent-free conditions (Table 1, entry 8). The
key role played by microwave irradiation in the outcome
tocol. Wittig olefination of commercially available 1-
of this domino Michael addition–cyclocondensation pro-
(2,6-difluorophenyl)ethanone (4) with (methoxymeth-
yl)triphenylphosphonium chloride and n-butyllithium at
–78 °C in THF gave the corresponding enol ether 5 which,
tocol was proved by the poor yields of 3 after 12 hours un-
der conventional heating (Table 1, entry 9) in conditions
similar to those previously used by Gupta et al.15 Isolation
Table 1 Optimization of the Microwave-Assisted Tandem Michael Addition–Cyclocondensation Protocol
+
NH2
2–
O
O
O
SO4
NH2
MeS
2
NH
OEt
OEt
HN
1
THPO
OTHP
µW
µW
MeS
N
MeS
N
2
H
3
OTHP
II
Entry Solvent
Base
Temp (°C) Time (min) Yield (%) Entry Solvent
Base
Temp (°C) Time (min) Yield (%)
1
2
3
4
5
MeCN
DMF
DMF
DMF
DMF
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Et3N
120a
120a
120a
120a
120a
20
10
20
30
20
–
6
7
8
9
EtOH
Na2CO3
Na2CO3
120a
120a
120a
120b
20
50
52
–
44
54
50
–
t-BuOH
20
solvent-free Et3N
20 + 20
DMF
Na2CO3
720
38
a Microwave irradiation.
b Conventional heating.
Br
Br
H
F
iii
iv
F
O
70%
OMe
F
O
O
OMe
H
F
i
ii
F
F
7
F
F
75%
F
F
97%
vi
6
5
4
9
v
F
F
34%
8
Scheme 1 Reagents and conditions: (i) (Methoxymethyl)triphenylphosphonium chloride, n-BuLi, THF, –78 °C to r.t.; (ii) BBr3, CH2Cl2, –78
°C, 2 h; (iii) CBr4, Ph3P, CH2Cl2, 0 °C, 10 min; (iv) n-BuLi, ClCOOMe, THF, –100 °C to r.t, 2 h; (v) dimethyl 1-diazo-2-oxopropylphosphonate,
K2CO3, MeOH, r.t., 12 h; (vi) PdCl2, CuCl2, CO, NaOAc, MeOH, r.t., 2 h.
Synlett 2011, No. 14, 1997–2000 © Thieme Stuttgart · New York

LETTER
Domino Microwave-Assisted Synthesis of 2,6-Disubstituted Pyrimidinones
1999
after cleavage with BBr3 followed by hydrolysis, gave the
O
aldehyde 6 in good yields.
HN
R2
Our original idea was to obtain the key intermediate 9 us-
ing a modified Corey–Fuchs protocol19 starting from the
aldehyde 6. Unfortunately, while the 1,1-dibromo-1-
alkene 7 was obtained in good yields, the conversion of 7
into the corresponding terminal acetylene followed by re-
action with methyl chloroformate did not afford the de-
sired product 9 but only a complex mixture of by-products
was obtained (Scheme 1). An alternative approach for the
synthesis of 9 was based on the condensation of aldehyde
6 with the Ohira–Bestmann reagent20,21 under mild reac-
tion conditions followed by carbonylation of the interme-
diate 8 under atmospheric pressure of CO.22 In our first
attempt, isolation of the terminal alkyne 8 and subsequent
carbonylation gave the desired compound 9 in a low 6%
yield, probably due to the high volatility of the isolated
alkyne 8.23
NH
i
N
N
F
R2
N
R1
NH2⋅HCl
Me
F
11a (41%)
11c (30%)
10a–d
i
O
O
R2
N
HN
+
R2
H2N
N
F
N
H
N
F
F
F
12b (23%)
12d (28%)
13b (23%)
13d (15%)
To overcome this drawback, we developed a one-pot,
two-step sequence, in which the alkyne 8 was formed ‘in
situ’ and directly submitted to the carbonylation reaction
thus obtaining the key intermediate 9 in 34% yield from
aldehyde 6. The reaction conditions in the carbonylation
step need to be carefully controlled and high dilutions are
needed in order to avoid conjugated diyne formation re-
sulting from the oxidative dimerization of terminal
alkynes under the influence of CuCl2.22 The substituted
guanidines 10a–d required for synthesis of the desired N-
DABO derivatives 11a,c and 12b,d (Scheme 2), were
synthesized in a few steps and high yields starting from
commercially available compounds (see Supporting In-
formation for details).
a: R1 = Me;
R2
=
=
MeO
b: R1 = H;
c: R1 = Me;
d: R1 = H;
R2
MeO
Scheme 2 Reagents and conditions: (i) Na2CO3, 9, t-BuOH, 120 °C,
mW, 20 min (for R2 = 4-methoxybenzyl) or 40 min (for R2 = 4-me-
thoxyphenylcyclopropyl).
in described represents an alternative and useful tool for
the synthesis of functionalized pyrimidinones with poten-
tial biological applications. The exploitation of such pro-
tocol for the synthesis of novel S-DABOs/N-DABOs as
HIV reverse transcriptase inhibitors is currently ongoing
and will be reported in due course.
Finally, compounds 10a–d and 9 were reacted under the
optimized Michael addition–cyclization conditions to ob-
tain the desired N-DABO derivatives 11a,c and 12b,d:
while compounds 11a,c were obtained as single products
in good yields, the lower yields of compounds 12b,d were
due to the contemporary formation of the regioisomers
13b,d. A similar behavior has been also reported in the lit-
erature for the condensation of b-keto esters with meth-
ylguanidine which gave a mixture of C2-methylamino
and N3-methyl derivatives.24 It was interesting to note
that the ratio of the two couples of regioisomers 12/13 was
influenced by the nature of the R2 group: while the less
hindered 4-methoxybenzyl group gave the products 12b/
13b in a 1:1 ratio, the more hindered 4-(methoxyphenyl-
cyclopropyl)methyl group afforded the corresponding
products 12d/13d in a 2:1 ratio, in favor of the desired N-
DABO derivative.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
This work was supported by the European Union: ‘CHAARM’,
Collaborative Project, (grant number HEALTHF3-2009-242135)
and ‘THINC’, Collaborative Project (grant number HEALTH-
2007-2.3.2-1). Financial support was also provided by the Italian
Ministero dell’Istruzione, dell’Università e della Ricerca, Prin 2008
research project (grant number 2008CE75SA_004).
References and Notes
In summary, a fast and practical protocol for the micro-
wave-assisted synthesis of 2,6-disubstituted pyrimidino-
nes has been developed. This approach is based on a
domino Michael addition–cyclocondensation reaction
which, under microwave irradiation, allowed to obtain in
a short time the desired 2,6-disubstituted pyrimidinone
derivatives starting from the opportune acetylenecarboxy-
lates and substituted thioureas/guanidines. The work here-
(1) These authors contributed equally to this work.
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Synlett 2011, No. 14, 1997–2000 © Thieme Stuttgart · New York

2000
M. Radi et al.
LETTER
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(18) Typical Experimental Procedure: In a microwave sealed
tube, S-methylisothiourea sulfate (1; 79 mg, 0.283 mmol),
ethyl 4-(tetrahydro-2H-pyran-2-yloxy)but-2-ynoate (2; 50
mg, 0.236 mmol) and Na2CO3 (60 mg, 0.566 mmol) in DMF
or t-BuOH (3 mL) were irradiated for 20 min in a self-
tunable CEM microwave synthesizer at 120 °C and finally
allowed to cool to r.t. When DMF was used as solvent, H2O
was added and the aqueous layer was extracted with EtOAc
(2 ×). The organic layers were collected, washed with brine,
dried over Na2SO4 and concentrate under reduced pressure.
When t-BuOH was used as solvent, the reaction mixture was
directly evaporated to dryness to give a solid crude material.
The residue was purified by flash chromatography
(petroleum ether–EtOAc) to obtain 2-(methylthio)-6-
[(tetrahydro-2H-pyran-2-yloxy)methyl]pyrimidin-4(3H)-
one (3; 52–54%) as a white solid. 1H NMR (400 MHz,
CDCl3): d = 12.68 (br s, 1 H), 6.34 (s, 1 H), 4.68 (s, 1 H),
4.52 (d, J = 16.0 Hz, 1 H), 4.32 (d, J = 16.0 Hz, 1 H), 3.77
(m, 1 H), 3.47 (m, 1 H), 2.48 (s, 3 H), 1.40–1.90 (m, 8 H).
13C NMR (100 MHz, CDCl3): d = 166.33, 165.29, 161.36,
105.81, 98.12, 67.81, 61.91, 30.33, 25.36, 18.93, 13.19. MS
(ESI): m/z = 257.3 [M + H]+.
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