Solution-phase parallel synthesis of S-DABO analogues

Article abstract of DOI:10.1016/j.tetlet.2005.10.142

A simple and straightforward methodology for the parallel, solution-phase synthesis of a new series of S-DABO derivatives 1 and 2, bearing aromatic substituents at the C2 and C6 positions, has been developed. Starting from potassium ethyl malonates 3, thi

Full text of DOI:10.1016/j.tetlet.2005.10.142

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 65–67
Solution-phase parallel synthesis of S-DABO analogues
Andrea Togninelli, Caterina Carmi, Elena Petricci, Claudia Mugnaini, Silvio Massa,
Federico Corelli and Maurizio Botta*
`
Dipartimento Farmaco Chimico Tecnologico, Universita degli Studi di Siena, Via Aldo Moro, 53100 Siena, Italy
Received 23 September 2005; revised 25 October 2005; accepted 26 October 2005
Available online 16 November 2005
Abstract—A simple and straightforward methodology for the parallel, solution-phase synthesis of a new series of S-DABO deriv-
atives 1 and 2, bearing aromatic substituents at the C2 and C6 positions, has been developed. Starting from potassium ethyl malo-
nates 3, thiouracil intermediates 5 were prepared through parallel synthesis and isolated as pure products by simple extraction with
ethyl acetate. Selective S-benzylation of 5 was achieved in few minutes under microwave irradiation to give the title compounds 1,
which were oxidized in parallel to the corresponding sulfones 2. Some of the new compounds 1 showed potent inhibitory activity
against HIV-1 RT.
Ó 2005 Elsevier Ltd. All rights reserved.
Non-nucleoside reverse transcriptase inhibitors (NNR-
TIs) include more than 30 structurally different classes
of molecules showing high specificity for HIV-1.1
Among them, nevirapine and efavirenz (Fig. 1) are
potent inhibitors of HIV-1 RT used in combination
therapy with other drugs for the treatment of AIDS.
Dihydro-alkoxy-benzyl-oxopyrimidines (DABOs) (Fig.
1), which were firstly disclosed in 19922 and further
developed during the following years into S-DABOs
and related analogues,3 are an interesting class of
NNRTIs active at nanomolar concentration.
Based on previous findings,4 and with the aim of
investigating the influence of the arylalkyl moiety on
anti-HIV activity, we selected S-DABO derivatives of
general structure 1 and 2 as new potential NNRTIs.
O
H3C
HN
Classical methodologies for the synthesis of DABO
derivatives usually require long reaction times and
lengthy purification procedures.3b,c,f Accordingly,
during the course of our studies on the synthesis of
anti-HIV-1 agents with a pyrimidinone structure, we
became interested in developing efficient synthetic
methodologies for the preparation of small libraries of
the target compounds to be submitted to biological
evaluation.5
F3C
Cl
O
N
N
N
N
O
H
nevirapine (NVP)
efavirenz (EVZ)
O
O
R
R
HN
R'
HN
X
N
Solution-phase parallel synthesis (SPPS) and micro-
wave-assisted organic synthesis have emerged as power-
ful and complementary tools for the fast generation of
structurally diverse compounds.6 Therefore, as an exten-
sion of our ongoing investigations on the use of the
aforementioned techniques in organic synthesis,7 we
decided to combine the advantages of SPPS and micro-
wave irradiation to synthesize a small library of com-
pounds 1 and 2. The title compounds were synthesized
according to Scheme 1.
R'
R''
X
N
DABOs
X = O
1 X = S
2 X = SO2
S
-DABOs X = S
Figure 1.
*
Corresponding author. Tel.: +39 0577234306; fax: +39 577234333;
e-mail: botta@unisi.it
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.142

66
A. Togninelli et al. / Tetrahedron Letters 47 (2006) 65–67
Table 1. Chemical and physical data for the new compounds 1 and 2
O
O
O
O
i.
Compound
R
R0
R00
Mpa
(°C)
Yield
(%)
EtO
OK
EtO
R'
R
R
1a
1b
1c
1d
1e
1f
H
2,6-diCl
H
H
230–231 70
236–237 50
3(a,b)
4(a-d)
ii.
CH3 2,6-diCl
CH3 2,6-diCl 4-OCH3
CH3 2,6-diCl 4-F
CH3 2,6-diF
CH3 2,6-diF
CH3 4-F
CH3 2,6-diCl 4-OCH3
CH3 2,6-diF
CH3 4-F
219
67
205–206 50
3,5-diOCH3 228–230 60
4-NO2
4-NO2
248–250 57
246 56
241–244 50
253–255 62
251–252 58
1g
2a
2b
2c
O
O
R
R
4-NO2
4-NO2
HN
S
HN
iii.
N
S
N
H
a All the compounds were recrystallized from CH3CN.
R''
Finally, sulfides 1c,f, and g (0.2 mmol) were oxidized to
the corresponding sulfones 2(a–c) in a parallel way with
m-chloroperbenzoic acid (0.6 mmol).12,13 All sulfides 1
and sulfones 2 were obtained in more than 95% purity
after recrystallization, as shown by HPLC–MS analysis
(Table 1).
R'
R'
1(a-g)
5(a-d)
iv.
O
N
R
HN
The S-alkylation reactions performed using microwave
irradiation were compared in separate experiments with
the corresponding reactions carried out by conventional
heating. While similar results were obtained in terms of
yield, the MW-assisted procedure afforded the target
compounds in a far faster way. The combination of this
advantage with the easiness of execution of the parallel
synthesis opens up the route to a combinatorial
approach for the preparation of larger libraries of
compounds 1 and 2. In fact, the number of sulfides 1
can be increased using a larger number of malonates 3
(functionalization at position 5), phenylacetyl imidazol-
ides (functionalization at position 6) and benzyl halides
(functionalization at position 2) in order to amplify the
chemical diversity within the libraries.
S
O
O
R''
R'
2(a-c)
Scheme 1. Reagents and conditions: (i) MgCl2, Et3N, substituted
phenylacetic acid, N,N0-carbonyldiimidazole, CH3CN, rt, overnight,
360 rpm; (ii) thiourea, EtONa, EtOH, reflux, 16 h, 360 rpm; (iii)
substituted benzyl halides, K2CO3, dry DMF, MW, 130 °C, 5 min; (iv)
MCPBA, dry CH2Cl2, rt, 16 h, 360 rpm.
Potassium ethyl malonates 3(a,b)8 (5.04 mmol) were
partitioned in four separate reaction vessels and reacted
with substituted phenylacetyl imidazolides (2.67 mmol)
In conclusion, a simple and efficient procedure for the
synthesis of a small family of 6-arylmethyl-2-(arylmethyl-
thio)-5-methylpyrimidin-4(3H)-ones 1 and 6-arylmethyl-
2-(arylmethylsulfonyl)-5-methylpyrimidin-4(3H)-ones 2
has been developed. These new S-DABO analogues were
obtained in an easy, rapid, and profitable way using solu-
tion-phase parallel synthesis and MW-assisted organic
synthesis. The products obtained in each step did not
require any further purification before undergoing the
subsequent transformation. The whole methodology
shows combinatorial potential to the synthesis of larger
libraries of compounds which is ongoing in our laborato-
ries. Finally, it is interesting to note that some of the
reported compounds showed high inhibitory activity
against wild type enzyme without showing cytotoxicity
(e.g., 1c: IC50/wt = 0.0038 lM; CC50 = 32 lM and 2a:
IC50/wt = 0.006 lM; CC50 = 2.8 lM), thus favorably
comparing with inhibitors belonging to the same struc-
tural class already reported in the literature.3b,c
in a Buchi SyncoreÒ synthesizer9 in the presence of
¨
MgCl2 (6 mmol) and Et3N (7.67 mmol) in CH3CN,
according to the Clay et al.Õs procedure.10 Ketoesters
4(a–d) were obtained as pure products after a simple
extraction with ethyl acetate.
Compounds 4(a–d) (2.27 mmol) were then condensed in
parallel with thiourea (3.18 mmol) in the presence of
EtONa (4.55 mmol) in boiling ethanol, to give thio-
uracils 5(a–d) in excellent yield and good purity after
neutralization with acetic acid followed by extractions
in parallel with ethyl acetate. The spectroscopic
and analytical data of 5(a–d) are in agreement with
those reported in the literature.3f
In order to accelerate the reaction and improve the yield,
compounds 5(a–d) were selectively S-benzylated under
microwave irradiation. Thus, 5(a–d) (0.3 mmol) were
irradiated either in a closed or open vessel at 130 °C
for 5 min in the presence of the appropriate substituted
benzyl halide (0.3 mmol) and K2CO3 (0.3 mmol) in
DMF.11 Compounds 1 (Table 1) were obtained in good
yield and purity in only 5 min instead of 16 h as required
when conventional heating was used.
Acknowledgements
Support from the European TRIoH Consortium
(LSHB-2003-503480) is gratefully acknowledged. M.B.

A. Togninelli et al. / Tetrahedron Letters 47 (2006) 65–67
67
A.; Sbardella, G.; Artico, M.; Ragno, R.; Massa, S.;
Novellino, E.; Greco, G.; Lavecchia, A.; Musiu, C.; La
Colla, M.; Murgioni, C.; La Colla, P.; Loddo, R. J. Med.
Chem. 2001, 44, 2544–2554; (g) Nizi, E.; Botta, M.;
Corelli, F.; Manetti, F.; Messina, F.; Maga, G. Tetra-
hedron Lett. 1998, 39, 3307–3310.
thanks the Merck Research Laboratories for the 2004
Academic Development Program (ADP) Chemistry
Award. We thank Dr. Giovanni Maga (Istituto di Gene-
´
tica Molecolare CNR, Pavia, Italy) and Professor Jose
´
`
Este (Retrovirology Lab Research Fundacio irisCaixa,
Badalona, Spain) for biological evaluation of the newly
synthesized compounds.
4. Parlato, M. C.; Mugnaini, C.; Renzulli, M. L.; Corelli, F.;
Botta, M. Arkivoc 2004, V, 349–363.
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J. Comb. Chem. 2005, 7, 117–122; (b) Petricci, E.; Radi,
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