Synthesis of 5-acyl-3,4-dihydropyrimidine-2-thiones via solvent-free, solution-phase and solid-phase Biginelli procedures

Article abstract of DOI:10.1055/s-0029-1217373

Compounds belonging to the 5-acyl-3,4-dihydropyrimidine-2-thione family were obtained using a solvent-free Biginelli condensation with or without the use of a catalyst. An unprecedented solid-phase procedure involving a polymer-supported aldehyde allowed

Full text of DOI:10.1055/s-0029-1217373

LETTER
1737
Synthesis of 5-Acyl-3,4-dihydropyrimidine-2-thiones via Solvent-Free,
Solution-Phase and Solid-Phase Biginelli Procedures
S
ynthesisof 5-Acy
o
l-3,4-dihydr
r
opyrimid
a
ine-2-thion
c
es io Comas,a David-Alexandre Buisson,a Romain Najman,a Frank Kozielski,b,1 Bernard Rousseau,a
Roman Lopez*a,2
a
CEA, LifeScience Division, iBiTec-S, Service de Chimie Bioorganique et de Marquage, Bat. 547, 91191 Gif sur Yvette, France
Laboratoire des Moteurs Moleculaires, Institut de Biologie Structurale (CEA-CNRS-UJF), 41 Rue Jules Horowitz, 38027,
b
Grenoble Cedex 01, France
Fax +33(1)58103848; E-mail: roman.lopez@ymail.com
Received 20 January 2009
OH
OH
Abstract: Compounds belonging to the 5-acyl-3,4-dihydropyrimi-
dine-2-thione family were obtained using a solvent-free Biginelli
condensation with or without the use of a catalyst. An unprecedent-
ed solid-phase procedure involving a polymer-supported aldehyde
allowed the preparation of a series of 5-aroyl derivatives starting
with crude diketones obtained from their corresponding aryl esters.
O
O
NH
EtO
NH
R
Me
N
S
N
S
R
H
H
Key words: multicomponent reaction, heterocycles, solid-phase
synthesis, b-diketones, monastrol
IC50 = 2.0 µM
IC50 = 0.2 µM
1 monastrol
3a R = H: enastron
3b R = Me: dimethylenastron
IC50 = 14 µM
R2
The 3,4-dihydropyrimidine-2-one core is a well known
pharmacophore found in many biologically active com-
pounds including natural products.3 The discovery in
1999 of 4-(3-hydroxyphenyl)-3,4-dihydropyrimidine-
2(1H)-thione, best known as monastrol (1; Figure 1),
which arrests cells in mitosis, reinforced the interest in
this class of compounds. Monastrol is a weak inhibitor of
the mitotic kinesin Eg5 (kinesin-5 family), responsible for
the formation of the bipolar spindle.4 Monastrol inhibits
the ATPase activity of Eg5 by binding to its motor
domain.5 Due to their specific functions during the cell
cycle, these proteins represent attractive, novel targets for
the development of new anti-cancer agents.6 We were
therefore interested in the synthesis of further analogues
of monastrol as potential Eg5 inhibitors.7
OH
R3
O
O
R1
NH
NH
Me
N
Me
S
N
R4
S
Me
IC50 = 0.15 µM
2
4
Figure 1 Biologically important dihydropyrimidine-2-thiones as
inhibitors of human kinesin Eg5
use of ionic liquids,8j–l novel catalysts8m–r and solvent-free
protocols,8s–v have recently been reported to be successful.
In contrast, the synthesis of 3,4-dihydropyrimidin-2(1H)-
thiones by the Biginelli reaction, i.e. replacing urea by
thiourea, has rarely been exemplified in those studies and
there have been only a few reports describing exclusively
their synthesis.9 Furthermore, we observed that 5-acyl de-
rivatives were usually ignored10 and the N-1 substituted
derivatives were frequently neglected.
O
Ar
O
O
EtO
NH
ArCHO
H2N
NH2
+
EtO
Me
O
N
H
O
Scheme 1 The original Biginelli multicomponent reaction8a
During our studies on 3,4-dihydropyrimidine-2-thiones as
Eg5 inhibitors, we noticed that the presence of an acyl
group at the 5-position improved the potency of the ana-
logues, as did the addition of an aryl moiety at the 4-posi-
tion. This observation allowed us to identify compounds
up to 100-fold more potent than racemic monastrol,7,11
such as compound 2 (Figure 1). This outcome was in
agreement with observations made by Surrey and Giannis
using enastron 3a and dimethylenastron 3b (Figure 1).12
In addition, we noticed that the alkyl moiety at N-1 in
compound 2 showed an interesting role that deserved to
be explored (Figure 1). Based on our SAR studies, we de-
cided to focus on the synthesis of 5-acyl-3,4-dihydropyri-
midine-2-thiones 4 with an aryl moiety on position 4
(Figure 1).
The synthesis of 3,4-dihydropyrimidin-2(1H)-ones by the
Biginelli reaction8a has been particularly successful start-
ing from an aromatic aldehyde, urea and ethyl acetoace-
tate in acidic ethanol (Scheme 1). Several groups have
developed improved protocols to overcome the prolonged
reaction time and low yields of this reaction whilst still al-
lowing the synthesis of more complex target molecules.8
Modern methodologies like microwave irradiation,8h,i the
SYNLETT 2009, No. 11, pp 1737–1740
x
x
.x
x
.2
0
0
9
Advanced online publication: 12.06.2009
DOI: 10.1055/s-0029-1217373; Art ID: D02609ST
© Georg Thieme Verlag Stuttgart · New York

1738
H. Comas et al.
LETTER
We report herein a convenient methodology for the syn- Looking for a convenient method to perform parallel syn-
thesis of 5-acyl-3,4-dihydropyrimidine-2-thiones using thesis without special equipment, the reactions were car-
either a one-pot, solvent-free protocol or an unprecedent- ried out in simple screw-capped vials placed in a metal
ed solvent-free, solid-phase approach. Both methods are rack, which ensured a uniform heat-transfer. The alde-
suitable for parallel modes.
hyde, diketone and thiourea (1:1:1.5) mixtures were heat-
ed for three hours without stirring (Scheme 2) and the
desired products were obtained in high purities based on
LC/MS analysis (Table 1).
Table 1 One-Pot, Solvent-Free Condensation of Thioureas, b-Dike-
tones and Aromatic Aldehydes Leading to Dihydropyrimidine
Thionesa
Entry R1
R2
R3
R4
Cat.b Yield
(%)c
R2
R3
R3
1
2
Me
2-OH
2-OMe
2-Cl
3-NO2
5-Br
5-Cl
5-OMe
5-OMe
H
H
–
–
–
–
–
+
–
+
–
+
–
–
+
–
–
–
–
–
–
+
+
+
+
–
+
–
+
93
O
O
O
CHO
R2
neat, 120 °C, 3 h
H
R1
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
H
81
NH
N
NH2
+ R4
R1
S
3
H
62
N
R4
S
4
2-OMe
3-OMe
3-OH
3-OH
3-OH
4-OH
4-OH
4-NMe2
H
H
92
Scheme 2 Biginelli condensation leading to the 5-acyl-3,4-dihydro-
pyrimidine-2-thione scaffold
5
H
59
6
Allyl
H
27d
67d
33d
73
The lowest yields were obtained in the case of mono-sub-
stituted benzaldehydes bearing an electron-donating
group (OH, OMe, NMe2) and/or when substituted thio-
ureas were used. The use of ytterbium triflate (0.05 equiv)
as catalyst slightly improved some reactions, affording
compounds in moderate yields.
7
H
8
H
Me
H
9
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
23
24
25
26
H
Me
H
39d
21d
78
This procedure allowed the isolation of the unsubstituted
N-derivatives (R4 = H) in excellent purity (>99% by
HPLC) through a very simple work-up carried out in par-
allel mode. The work-up consisted of crushing the result-
ing solid in the presence of diethyl ether, followed by
filtration and washings with hot water to remove the ex-
cess of thiourea. The yields ranged between 21 and 93%,
with the poorest corresponding to the 5-aroyl derivatives
(e.g. entries 1 vs 14 and 2 vs 15).
H
H
H
H
H
Me
H
45d
66
2-OH
2-OMe
2-Cl
3-NO2
5-Br
5-Cl
5-Cl
5-OMe
5-OMe
H
Ph
H
50
Ph
H
31
In agreement with previous reports, the combination of N-
substituted thioureas and b-diketones proved to be chal-
lenging. The formation of side-products did not allow the
isolation of the product by precipitation as described
above, and reverse-phase chromatography was necessary
to reach the high standards of purity (>99%) required for
the biological assays.
The preliminary SAR analysis on Eg57 prompted us to fo-
cus on the synthesis of aroyl analogs (R1 = aryl) bearing a
3-hydroxyl group as R3. With this purpose in mind, we
envisaged a ‘catch and release’ strategy on solid-phase
taking advantage of the OH function (Scheme 3). To
achieve this, 3-hydroxybenzaldehyde was therefore at-
tached to carboxylic acid resin 5 using a standard DCC/
DMAP esterification protocol, leading to resin 6.
Ph
2-Cl
Me
H
34
Ph
2-OMe
3-OMe
3-OH
3-OH
3-OH
3-OAc
4-OH
4-OH
H
65d
34
Ph
H
Ph
Allyl
H
25d
37d
35d
43
Ph
H
Ph
H
Me
Me
H
Ph
H
Ph
H
54
Ph
H
Me
H
28d
63
Ph
H
31d
Non-commercially available b-diketones were prepared
by treatment of the corresponding arylesters with acetone
in the presence of sodium hydride.13 Unfortunately, the
Biginelli condensation on resin 6 under classical
conditions14 failed to give the desired products 9. Howev-
er, compounds 9a–d could be obtained via the solvent-
free condensation between the supported aldehyde 6, thio-
Ph
H
H
Me
a All experiments were performed on 1 mmol scale.
b Yb(OTf)3 (0.05 equiv) was used as catalyst.
c Isolated yield after direct precipitation.
d Purification by preparative HPLC-MS (>99% purity).
Synlett 2009, No. 11, 1737–1740 © Thieme Stuttgart · New York

LETTER
Synthesis of 5-Acyl-3,4-dihydropyrimidine-2-thiones
1739
washed first with Et2O (2 × 1 mL), then hot water (2 × 1 mL) and
dried under vacuum over P2O5. When Et2O was added and the prod-
uct did not precipitate, the crude product was dissolved in DMSO
and purified by HPLC-MS affording pure compounds.
a
O
O
O
CHO
CO2H
loading
1 mmol/g
1-[4-(4-Hydroxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro-
pyrimidin-5-yl]ethanone (entry 9)
5
6
O
O
1H NMR (DMSO-d6): d = 10.19 (s, 1 H), 9.65 (s, 1 H), 9.43 (s, 1 H,
Ar-OH), 7.02 (d, J = 7.8 Hz, 2 H), 6.71 (d, J = 7.8 Hz, 2 H), 5.17 (d,
J = 3.7 Hz, 1 H), 2.32 (s, 3 H), 2.09 (s, 3 H). MS (ES+): m/z = 263.3
(M + H)+.
OEt
b
aryl esters
7a–d
crude
8a–d
X
X
OH
[4-(2,6-Dichlorophenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro-
pyrimidin-5-yl]phenylmethanone (entry 16)
1H NMR (DMSO-d6): d = 10.24 (s, 1 H), 9.42 (s, 1 H), 7.60–7.20
(m, 8 H), 6.39 (s, 1 H), 1.57 (s, 3 H). MS (ES+): m/z = 378.3 (M +
H)+.
X
O
c, d
9a
OMe
F
Cl
Br
8a–d
resin +
6
9b
9c
9d
10–15%
3 steps
NH
crude
Me
N
S
[4-(2,6-Dichlorophenyl)-1,6-dimethyl-2-thioxo-1,2,3,4-tetrahy-
dropyrimidin-5-yl]phenylmethanone (entry 17)
1H NMR (DMSO-d6): d = 9.43 (d, J = 2.5 Hz, 1 H), 7.80–7.20 (m,
8 H), 6.33 (s, 1 H), 3.63 (s, 3 H), 1.83 (s, 3 H). MS (ES+): m/z =
392.3 (M + H)+.
H
X
9a–d
Scheme 3 Solid-phase, solvent-free protocol using the supported
aldehyde. Reagents and conditions: (a) DCC, DMAP, 3-OH-benz-
aldehyde, CH2Cl2, r.t., 48 h; (b) NaH, acetone, Et2O, 3–5 d; (c) thiou-
rea, Yb(OTf)3 (0.05 equiv), 110 °C, 4 h; (d) K2CO3, MeOH, r.t. then
HPLC/MS purification.
Acknowledgment
We thank the ‘Conseil Regional Ile de France’ and l’Association
pour la Recherche sur le Cancer (ARC, contract number 5197) for
financial support.
urea and a large excess of diketone 8a–d in the presence
of catalytic amounts of Yb(OTf)3 at 110 °C. After remov-
al of all excess reagents by simple washings, cleavage was
performed using K2CO3/MeOH to afford pure compounds
after HPLC-MS purification. Although the overall yields
(10–15% for 3 steps) were low, this non-optimized, solid-
phase protocol allowed the preparation of compounds 9a–
d (X = OMe, Cl, Br, I) in excellent purities. Since very
few b-diketones are commercially available, this protocol
paves the way for major diversification on the aroyl part
of those adducts.
References and Notes
(1) Present address: The Beatson Institute for Cancer Research,
Garscube Estate, Switchback Road, Bearsden, Glasgow G61
1BD, UK
(2) Present address: Hybrigenics, 3-5 Impasse Reille, 75014
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In conclusion, we have synthesized a series of 5-acyl-3,4-
dihydropyrimidine-2-thiones using a solvent-free, solu-
tion-phase procedure even in the least favorable cases:
b-diketones and substituted thioureas. In the case of 3-
hydroxyl-substituted benzaldehyde, we showed that the
attachment of this aldehyde to a resin enabled the prepa-
ration of the Biginelli adduct starting directly from the
aryl ester precursors of the corresponding b-diketones.
Due to the ready availability of such esters compared to
the b-diketones, this methodology opens the way to the
facile synthesis of analogues with increased diversity at
the aroyl position, which are difficult to achieve via stan-
dard procedures. Details of the biological evaluation of
this promising series will be reported in due course.
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Solvent-Free Biginelli Condensations (Table 1); Typical Proce-
dure
In a screw-capped vial, a mixture of the aldehyde (1 mmol, 1 equiv),
the b-diketone (1 mmol, 1 equiv) and thiourea or N-alkylthiourea
(1.5 mmol, 1.5 equiv) was heated at 110 °C without stirring for 3 h.
In some cases (see Table 1), Yb(OTf)3 (0.05 equiv) was used as cat-
alyst. The reaction mixture was allowed to cool to room temperature
and was washed with Et2O (4 mL). The resulting solid was filtered,
Synlett 2009, No. 11, 1737–1740 © Thieme Stuttgart · New York

1740
H. Comas et al.
LETTER
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Synlett 2009, No. 11, 1737–1740 © Thieme Stuttgart · New York