Facile conversion of Biginelli 3,4-dihydropyrimidin-2(1H)-thiones to 2-(2-hydroxy-2-arylvinyl) dihydropyrimidines via Eschenmoser coupling

Article abstract of DOI:10.1016/j.tetlet.2009.02.027

A one-pot, two-step synthesis protocol for the conversion of Biginelli 3,4-dihydropyrimidin-2(1H)-thiones to 2-(2-hydroxy-2-arylvinyl) dihydropyrimidine (DHPM) derivatives via Eschenmoser sulfide contraction coupling is described. Solution phase as well a

Full text of DOI:10.1016/j.tetlet.2009.02.027

Tetrahedron Letters 50 (2009) 1838–1843
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Tetrahedron Letters
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Facile conversion of Biginelli 3,4-dihydropyrimidin-2(1H)-thiones to
2-(2-hydroxy-2-arylvinyl) dihydropyrimidines via Eschenmoser coupling
Sukhdeep Singh a, Andreas Schober a, Michael Gebinoga a, G. Alexander Groß b,
*
a MacroNanoÒ, Junior Research Group Microfluidics and Biosensors, Technische Universität Ilmenau, Institute for Micro and Nanotechnologies,
Gustav-Kirchhoff Str. 5, 98693 Ilmenau, Germany
b Department of Physical Chemistry and Microreaction Technology, Technische Universität Ilmenau, Institute for Micro and Nanotechnologies,
Gustav-Kirchhoff Str. 5, 98693 Ilmenau, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot, two-step synthesis protocol for the conversion of Biginelli 3,4-dihydropyrimidin-2(1H)-thi-
ones to 2-(2-hydroxy-2-arylvinyl) dihydropyrimidine (DHPM) derivatives via Eschenmoser sulfide con-
traction coupling is described. Solution phase as well as solid-supported protocol was carried out for
the decoration of the Biginelli DHMP scaffold at the C-2 position. The scope of the optimized protocol
is demonstrated for different DHMP precursors.
Received 18 January 2009
Revised 2 February 2009
Accepted 3 February 2009
Available online 8 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Eschenmoser
Sulfide contraction
Eschenmoser coupling
Polymer supported
Triphenylphosphine
DHPM
Biginelli
Privileged structure
Drug research
1. Introduction
tion inhibitors,5 mitotic kinesin inhibitors6 and
a1a-adrenergic
receptor antagonists.7 Several natural marine polycyclic guanidine
alkaloids such as crambine, batzelladine B (potent HIV gp-120CD4
inhibitors) and ptilomycalin alkaloids also consist DHPM-derived
structures in their skeleton, and the Biginelli route was chosen
for their total synthesis.8 It seems to be reasonable that DHPMs
are privileged structures for drug research.
The search for new valuable drug candidates demands on the
diversity, which can be created by combinatorial methods on a
particular template and on the accessibility of appropriate scaf-
folds. One such template class is the 3,4-dihydropyrimidin-
2(1H)ones/thione core 1, which represents a class of heterocyclic
molecules that have attracted a considerable interest to medicinal
chemists.1 The one-pot three-component Biginelli reaction2 has
been known for more than a century for the preparation of 3,4-
dihydropyrimidin-2(1H)-ones (DHPMs). In the past decades, the
scope of this cyclocondensation reaction was gradually extended
by variation of the three building blocks, which developed an ac-
cess to a large number of structurally diverse DHPMs.3 Various
diversification methods for Biginelli products can be found in the
literature.4
Due to the ongoing search for small molecular stem cell mod-
ulators, we looked for suitable scaffolds with known multiple
drug effects. Despite the fact that pyrimidine derivatives are
found in a wide range of biologically active molecules,9 there
are only some derivatization methodologies known for the Bigi-
nelli DHPMs 1 at the C-2 positions. Whereas alkylation and acyl-
ation protocols were found in the literature,10 and only a few
examples make use of a C-2 O/S substitution strategy (Fig. 1).
An appropriate synthetic method would be very useful to pre-
pare new chemical entities.
The nonplanar DHPM derivatives are attractive molecules for
drug research because of their known multifaceted pharmacologi-
cal profiles. Introduction of DHPMs resulted in the discovery of
new kind of calcium channel modulators,1 hepatitis B virus replica-
In 2004, Lengar and Kappe described a microwave-assisted
Pd(0)-catalyzed/Cu(I)-mediated carbon–carbon cross coupling of
3,4-dihydropyrimidine-2-thiones
1 with boronic acids which
yields 2-aryl-1,4-dihydropyrimidines 2.11 A similar kind of palla-
dium-catalyzed C–C Suzuki/Sonogashira coupling of 2-chloropyr-
imidine with boronic acids or alkynes for the synthesis of C-2
* Corresponding author.
E-mail address: alexander.gross@tu-ilmenau.de (G. Alexander Groß).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.027

S. Singh et al. / Tetrahedron Letters 50 (2009) 1838–1843
1839
O
R1
O
R1
N
R2O
N
R2O
N
R3
N
H
Ar
X=S
[ref. 11]
R3
R4
X=O
[ref. 12]
(R4 = Ar, Alkyne)
2
O
R1
3
R2O
NH
2
X=S
1
N
H
X=O
[ref. 13]
R3
X
O
R1
N
[ref. 14]
O
R1
N
R2O
N
1
R2O
N
R3
YR4
R3
YR4
(Y = S, O, N)
(Y = S, O, N)
4
5
Figure 1. Reported methods to derive Biginelli DHPMs 1 at C-2 position.
employing conventional peptide coupling agents.13 Matloobi and
Kappe have reported a microwave-assisted nucleophilic displace-
ment of C-2 sulfones of DHPM derivatives with a variety of nucle-
ophiles to furnish C-2 decorated pyrimidines 5.14 However, in the
latter two cases mostly hetero-S, N and O nucleophiles were used,
except of malononitrile which led to the formation of a C–C bond at
C-2 position.
O
S
R4
O
O
S
Br
R4
R4
R2
base
thiophile
7
R2
N
R1
R3
R2
N
R1
R3
N
R1
R3
Br
6
9
8
We envisaged the Eschenmoser sulfide contraction method to
receive a new C–C bond at the C-2 position of 1. In general,
classical Eschenmoser sulfide contraction conditions15 yield
vinylogous amides of type 9. The reaction sequences involve
the alkylation of secondary or tertiary thioamide moieties 6
Scheme 1. Eschenmoser coupling reaction (Sulfide contraction).
functionalized pyrimidines 3 was recently described by Srinivasan
and co-workers12 Kang et al. described a two-step procedure to
convert Biginelli DHPMs to the C-2 functionalized pyrimidines 4
with
a-bromoketones 7. The sulfur extraction from the received
intermediate 8 forms product 9 with a new carbon–carbon bond
(Scheme 1).
via
a tautomerization–activation-coupling (TAC) process by
Table 1
Screening of alkylation conditions for selective functionalization of C-2 sulfur
O
O
O
Br
EtO
N
base/solvent
a.t. / 30 min.
EtO
NH
+
Me
N
S
N
H
Me
S
H
O
7a
10a
1a
Entry
Base (1.5 equiv)
Solvent
Product
Isolated yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Et3N
Et3N
Et3N
Et3N
Et3N
DBU
DBU
DBU
DCM
DMF
Dioxane
THF
MeCN
DCM
DMF
Dioxane
THF
THF
DMF
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
88
78
69
82
64
87
74
60
76
67
81
92
45
71
DBU
Pyridine
Pyridine
K2CO3
K2CO3
K2CO3
Acetone
DCM
DMF

1840
S. Singh et al. / Tetrahedron Letters 50 (2009) 1838–1843
not increase the yield significantly. A chromatographic work-up
O
O
R1
O
R1
was necessary to isolate the desired product 11a from the phos-
phine sulfide. Additionally, the reaction was carried out with trioc-
tylphosphine. But in both cases, an excessive chromatographic
work-up was necessary to separate the desired product 11a from
the phosphine and phosphine sulfides. Hence, this one-pot method
using dissolved thiophilic phosphines suffers from poor purity and
hard work-up. To overcome this problem, we made use of poly-
mer-supported triphenylphosphine, which acts as thiophilic agent
Br
R4
R2O
R2O
NH
N
7
R4
R3
N
H
S
R3
N
H
10
S
O
1
O
R1
O
R1
as well as scavenger for unreacted
a-bromoketones 7. Therefore,
sulfide
contraction
R2O
N
OH
R4
commercially available polymer bound triphenylphosphine (poly-
styrene, 2% DVD, 3 mmol/g, Fluka) was used. Upon comparing
the products obtained with PPh3 (1.5 equiv) and trioctylphosphine
(1.5 equiv) with polymer bound PPh3 (1.5 equiv), it was found that
in the latter case the desired product 11a was obtained exclusively.
In order to study the role of base in sulfide contraction step, we did
an independent experiment in which a purified 10a was treated
with polymer bound PPh3 in acetone at 80 °C. It was found that in-
stead of sulfide contraction the deprotection of the C-2 sulfur took
place, and the starting DHPM 1a was observed.
R2O
NH
R4
R3
N
H
R3
N
H
S
O
11
intermediate
Scheme 2. Eschenmoser coupling route to C-2 functionalized 1,4-dihydropyrimi-
dines 11.
After optimizing the one-pot two-step reaction, we studied dif-
ferent C-4 substituted Biginelli substrates with phenacyl bromide
7a (Table 2). To further explore the scope of this one-pot reaction,
2. Experimental and results
we used a variety of
current conditions (Table 3). It was found that
a
-bromoketones 7a–j with DHPM 1a under
-bromoketones
We made use of this route for the formation of C-2 modified
DHPM derivatives of type 11. Initially, we optimized the alkylation
a
7a–j bearing different substituents on the phenyl ring underwent
of
5-ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-
the Eschenmoser coupling very well within 10 h.17
2(1H)-thione 1a with phenacyl bromide 7a under basic conditions.
Various base/solvent combinations were investigated (Table 1). It
was found that 1.5 equiv of K2CO3 in acetone furnished the desired
product 10a within 30 min in 92% yield at room temperature. The
use of other organic bases such as Et3N, DBU and pyridine led to
lower yields (Table 1). No side reaction products such as ester
cleavage or di-alkylation were detected in the LC–MS analysis.
Even, the generally possible thiazolopyrimidine formation was also
not detected at any stage of the reaction.16 But prolonged reaction
times or increased reaction temperatures led to lower yields of the
desired product 10a.
In each case, the corresponding C-2-substituted products were
obtained in a synthetically useful manner (Tables 2 and 3). All re-
ceived products were purified by a chromatographic work-up
(usual conditions: Silica 60, ethyl acetate/hexane 20:80). It was ob-
served that the 1H NMR spectra of all the products 11 (Table 2)
show a duplicate set of some signals (approximately 3:1 ratio)
due to different tautomers of 11 in solution. But all products shown
in Table 2 were well characterized by 1H NMR, 13C NMR, IR and
HRMS.
3. Summary
To develop a useful one-pot protocol, the selective alkylation of
the C-2 sulfur of 1 with
a-bromoketones 7 has to be followed by
In summary, thiono derivatives of DHPM derivatives 1 readily
undergo Eschenmoser sulfide contraction in a one-pot two-step
procedure and furnish dihydropyrimidines of type 11. The one-
pot procedure includes the selective alkylation of DHPMs 1 at
the subsequential elimination of the bridged sulfur by addition of
a thiophilic agent (Scheme 2). To furnish the desired C–C coupled
product 11a as depicted in Scheme 2, triphenylphosphine was
added as the thiophilic agent. It was found that 10a get slowly con-
verted into the desired product 11a if the reaction was heated to
80 °C. After 10 h, 78% overall yield of 11a was obtained. Further in-
crease in temperature, reaction time or quantity of phosphine did
C-2 position with
a-bromoketones 7 and the subsequent
elimination of the bridged sulfur assisted by solid-supported
triphenylphosphine.
Table 2
Eschenmoser coupling for different Biginelli substrates
1
1
O
R
O
R
i. K2CO3(1.5 eq.) / Acetone
ii. Phenacyl bromide (1.2 eq.)
25 °C / 30 min.
EtO
NH
EtO
N
OH
iii
PPh3
Me
N
H
S
N
H
Me
(1.5 eq.) 80 °C / 10 h
1a-d
11a, k-m
Entry
DHPM 1
R1
Product 11
Isolated yield (%)
1
2
3
4
1a
1b
1c
1d
Ph
11a
11k
11l
80
82
78
75
4-OMe–C6H4
2,4-(OMe)2–C6H3
3,4,5-(OMe)3–C6H2
11m

S. Singh et al. / Tetrahedron Letters 50 (2009) 1838–1843
1841
Table 3
Conversion of 3,4dihydropyrimidin-2(1H)-thione 1a to 2-(2-hydroxy-2-arylvinyl)dihydropyrimidines 11a–j
O
PPh3
(1.5 eq.)
80 oC / 10 h
O
O
i. K2CO3(1.5 eq.) / acetone
EtO
N
EtO
NH
N
OH
R4
EtO
ii. -bromoketone 7 (1.2 eq.)
R4
Me
N
H
S
a.t. / 30 min.
Me
N
H
S
Me
N
H
O
1a
10
11
Entry
a
-Bromoketone 7
Product 11
Isolated yield (%)
O
EtO
a
PhCOCH2Br
80
N
OH
Me
N
H
O
EtO
b
c
d
e
f
4-BrC6H4COCH2Br
4-PhC6H4COCH2Br
4-CNC6H4COCH2Br
3-NO2C6H4COCH2Br
3-BrC6H4COCH2Br
82
78
88
90
83
N
OH
Me
N
H
Br
O
EtO
N
OH
Me
N
H
O
EtO
N
OH
Me
N
H
CN
O
EtO
N
OH
NO2
Me
N
H
O
EtO
N
OH
Br
Me
N
H
(continued on next page)

1842
S. Singh et al. / Tetrahedron Letters 50 (2009) 1838–1843
Table 3 (continued)
Entry
a
-Bromoketone 7
Product 11
Isolated yield (%)
O
g
h
i
b-C10H7COCH2Br
77
EtO
N
OH
Me
N
H
O
4-ClC6H4COCH2Br
91
86
84
EtO
N
OH
Me
N
H
Cl
O
2,5-(OMe)2C6H3COCH2Br
EtO
N
OH
OMe
Me
N
H
MeO
O
j
4-OMeC6H3COCH2Br
EtO
Me
N
OH
N
H
OMe
D.; Singh, S. Tetrahedron. Lett. 2007, 48, 1349–1352; (e) Singh, K.; Singh, S.
Tetrahedron 2008, 64, 11718–11723.
Acknowledgments
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Kramer, T.; Niewoehner, U.; Pleiss, U.; Stoltefuss, J.; Graef, E.; Koletzki, D.;
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Schlemmer, K.-H.; Haebich, D.; Ruebsamen-Waigmann, H. Science 2003, 299,
893–896.
The authors thank Professor Dr. J.M. Köhler, (Dept. of Physical
Chemistry and Microreaction Technology, TU-Ilmenau) for his sup-
port and helpful discussion and Dr. M. Friedrich (Inst. for inorganic
chemistry and analytical chemistry, FSU-Jena) for his supporting
NMR measurements. Financial support from the Federal Ministry
of Education and Research, Germany and by the Thuringian Minis-
try of Culture (FKZ03ZIK062, FZK03ZIK465) is gratefully
acknowledged.
6. Mayer, T. U.; Kapoor, T. M.; Haggarty, S. J.; King, R. W.; Schreiber, S. L.;
Mitchison, T. J. Science 1999, 286, 971–974.
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Merck Whitehouse Station, 2001.
Supplementary data
Available experimental procedures and analytical characteriza-
tion data for compounds are provided. Characteristic data of se-
lected compounds 11 are presented. Supplementary data
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2009.02.027.
10. (a) Atwal, K. S.; Rovnyak, G. C.; O’Reilly, B. C.; Schwartz, J. J. Org. Chem. 1989, 54,
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26, 1189–1192.
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References and notes
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Singh. K.; Singh, S. Mini Rev. Med. Chem. 2009, 9, 95–106.
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3. Kappe, C. O. Tetrahedron 1993, 49, 6937–6963.
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17. General procedure: Conversion of 3,4-dihydropyrimidin-2(1H)-thione to 2-(2-
hydroxy-2-arylvinyl)-dihydropyrimidine. To
a
stirred solution of 5-
(1a)
ethoxycarbonyl-6-methyl-4-aryl-3,4-dihydro-pyrimidin-2(1H)-thione

S. Singh et al. / Tetrahedron Letters 50 (2009) 1838–1843
1843
(0.36 mmol, 1 equiv) in acetone (2 mL), subsequently K2CO3 (75 mg,
0.54 mmol, 1.5 equiv) and the -bromoketone 7 (0.43 mmol, 1.2 equiv) were
(TLC monitoring). For work-up, 1 mL EtOAc was added to the reaction mixture,
and the polymer was filtered. The filtrate was concentrated under reduced
pressure and subjected to a flash chromatography system (Intelli-Flash 310,
Varian; Silica 60) using 30% ethyl acetate in hexane to obtain pure samples of
11. The 1H NMR spectra of all products 11 show two sets of signals with
approximate 3:1 intensity. This is due to different conformations of the C2–C
bond as well as the possible tautomerism of the dihydropyrimidin core 11.
a
added at ambient temperature. After stirring for ca. 30 min at ambient
temperature (TLC monitoring, until all DHPM get consumed), polymer bound
triphenylphosphine (0.54 mmol) (polystyrene, 2% DVB, 3 mmol/g, Fluka
93093) was added in one portion, and the reaction temperature was shifted
to 80 °C. Stirring was continued for additional 10 h to complete the reaction