Optimized Liebeskind-Srogl coupling reaction between dihydropyrimidines and tributyltin compounds

Article abstract of DOI:10.1016/j.tetlet.2012.03.067

We developed an optimized Liebeskind-Srogl reaction in order to synthesize potentially biologically active 2-aryl-1,4-dihydropyrimidines. The pallado-catalyzed cross-coupling reaction between dihydropyrimidines and tributyltin derivatives appears particul

Full text of DOI:10.1016/j.tetlet.2012.03.067

Tetrahedron Letters 53 (2012) 2694–2698
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Tetrahedron Letters
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Optimized Liebeskind–Srogl coupling reaction between dihydropyrimidines
and tributyltin compounds
Qi Sun a,b, Franck Suzenet b, , Gérald Guillaumet b
⇑
a School of Pharmaceutical Sciences, Peking University, 38, Xueyuan Road, Haidian District, Beijing 100191, People’s Republic of China
b Institut of Organic and Analytical Chemistry, University of Orléans, UMR-CNRS 7311, rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France
a r t i c l e i n f o
a b s t r a c t
Article history:
We developed an optimized Liebeskind–Srogl reaction in order to synthesize potentially biologically
active 2-aryl-1,4-dihydropyrimidines. The pallado-catalyzed cross-coupling reaction between dihydro-
pyrimidines and tributyltin derivatives appears particularly efficient (67–95% yields) when using
CuBrÁMe2S as the copper cofactor.
Received 18 January 2012
Revised 14 March 2012
Accepted 20 March 2012
Available online 24 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Liebeskind–Srogl reaction
2-Aryl-1,4-dihydropyrimidines
Dihydropyrimidinthiones
Tributyltin derivatives
Dihydropyrimidines (1), which were first produced by the Ital-
ian chemist Biginelli in 1893,1 have a broad range of biological
activities, such as anti-viral, anti-tumor, anti-bacterial, and anti-
inflammatory activities.2 In addition, they are also regarded as cal-
methods, there are only a few methods reported in the literature
for further modifying this heterocyclic system.10
Recently, the 2-aryl-1,4-dihydropyrimidine heterocyclic scaf-
fold was reported to display a range of interesting pharmacological
properties. Compounds Bay 41-4109 (5, Fig. 1) and Bay 39-5493 (6,
Fig. 1) showed highly potent anti-hepatitis B replication activity
in vitro and in vivo.11 Another compound (7, Fig. 1), the Rho-asso-
ciated kinase isoform 1 (ROCK1) inhibitor, was reported as a poten-
tial therapeutic agent for cardiovascular diseases.12 Synthetic
routes to these 2-aryl-1,4-dihydropyrimidines are linear synthesis
(and do not allow aryl diversity at the end of the synthesis) with
low global yields (about 30%).12
cium channel blockers,3 -adrenergic antagonists,4 mitotic kinesin
a
Eg5 motor protein inhibitors,5 as well as potent HIV gp-120-CD4
inhibitors.6
During the past decade, the construction of dihydropyrimidine
cores (1) by condensation of various aldehydes (2), 1,3-dicarbonyl
compounds (3), and urea or thiourea (4) became one of the most
efficient examples of multicomponent reactions (Scheme 1). Vari-
ous Lewis acids were developed to catalyze this Biginelli condensa-
tion reaction under solvent-free7 or microwave conditions8 in good
to excellent yields. Asymmetric syntheses of the chiral dihydropy-
rimidine ring at position 4 were also performed by Zhu and Gong
with high ee values.9 In contrast to these fruitful synthetic
In 2004, an unprecedented pallado-catalyzed cross-coupling
reaction between dihydropyrimidine-2-thiones and boronic acids
in the presence of CuTC (Scheme 2) under microwave irradiation
was reported by Kappe.13 This work was an important
R1
4
O
X
O
O
3
5
6
R2
H3C
NH
Lewis acid
R1 CHO
+
+
H2N
NH2
H3C
R2
2
N
X
X= O, S
1
H
2
3
4
1
Scheme 1. Three components Biginelli condensation.
⇑
Corresponding author. Tel.: +33 2 38 49 45 80; fax: +33 2 38 41 72 81.
E-mail address: franck.suzenet@univ-orleans.fr (F. Suzenet).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.067

Q. Sun et al. / Tetrahedron Letters 53 (2012) 2694–2698
2695
F
breakthrough for the Liebeskind–Srogl cross-coupling reaction14
allowing the direct use of C@S function as electrophile. Dihydropy-
rimidine-2-thione derivatives provided 2-aryl-1,4-dihydropyrimi-
dines in 14–82% yields. Despite this success, the low yields
reported for a few aryl and heteroaryl boronic acids remained a
challenge for this reaction.
Since 2004, we have been engaged in the synthesis of dihydro-
pyrimidines using anhydrous ZnCl2 under solvent-free condi-
tions.15 Different substituted Biginelli products were provided by
this simple method. We also reported the efficient copper bromide
mediated pallado-catalyzed cross-coupling reaction of various het-
eroaromatic thioether derivatives with organostannanes.16 This
particular copper cofactor proved to be the successful strategy with
Cl
H
N
O
Cl
R
F
O
F
N
MeO
Me
N
N
H
N
N
H
F
Me
N
H
F
N
N
5, Bay 41-4109
6, Bay 39-5493
(R =
(R =
)
F
7
S
)
N
Figure 1. Examples of biologically active 2-aryl-1,4-dihydropyrimidines 5, 6, and 7.
R1
O
R1
O
Pd(PPh3)4, CuTC
THF, MW, 100oC
R2O
Me
NH
R2O
Me
N
ArB(OH)2
+
N
H
S
N
H
Ar
R1= phenyl
R2= Me, Et
Ar= phenyl, 4-ClC6H4, 3-MeC6H4,
2,6-(F2)C6H3, 2-thienyl
6 examples
(14-82%)
Scheme 2. Liebeskind–Srogl cross-coupling reaction between dihydropyrimidines and boronic acids.
Table 1
Coupling reaction between dihydropyrimidines and tributyltins
O
R1
O
R1
Pd(PPh3)4 5% mol
CuBr.Me2S (2.2equiv)
R2
Me
NH
R2
Me
N
R3SnBu3
+
THF, reflux 24h
R3
N
H
S
N
H
1a-g
10a-g
9a-m
Entry
Dihydro-pyrimidines 1a
Stannanes R3SnBu3
Products 9
Yield (%)b
O
Ph
O
EtO
N
10a
1
88
EtO
Me
NH
Me
O
N
H
Ph
9a
S1a
N
H
Ph
EtO
N
NO2
10b
2
3
4
1a
1a
1a
92
83
NO2
Me
O
N
H
9b
OMe
Ph
EtO
N
10c
Me
N
H
OMe9c
O
Ph
N
EtO
Me
N
10d
78
N
H
N
9d
(continued on next page)

2696
Q. Sun et al. / Tetrahedron Letters 53 (2012) 2694–2698
Table 1 (continued)
Entry
Dihydro-pyrimidines 1a
Stannanes R3SnBu3
Products 9
Yield (%)b
O
Ph
10e
S
EtO
N
N
5
6
1a
95
Me
O
N
H
S
9e
9f
Ph
10f
O
EtO
Me
1a
88
89
N
H
O
Cl
Cl
O
O
7
10a
MeO
Me
N
MeO
Me
NH
N
H
Ph9g
Ph9h
Ph9i
S 1b
N
H
NO2
NO2
O
O
8
10a
84
MeO
N
MeO
NH
Me
N
H
S1c
Me
N
H
OMe
OMe
O
O
9
10a
67
MeO
N
MeO
Me
NH
Me
N
H
S1d
N
H
F
F
O
Cl
O
Cl
10
10a
71
MeO
N
MeO
Me
NH
Me
N
H
Ph9j
S 1e
N
H
F
O
Cl
11
1e
10e
92
MeO
N
Me
N
H
S
9k
9l
Br
Br
O
O
12
10e
91
O
Me
N
MeO
Me
NH
N
N
H
S
H
1f
S

Q. Sun et al. / Tetrahedron Letters 53 (2012) 2694–2698
2697
Table 1 (continued)
Entry
Dihydro-pyrimidines 1a
Stannanes R3SnBu3
Products 9
Yield (%)b
10g
O
O
13
—
O
N
O
NH
Me
N
Me
N
H
H
S1g
9m
a
Refer to the Supplementary data.
Isolated yield by column chromatography.
b
Br
O
O
N
Br
Me
N
H
R
S
R
O
9l
O
O
NH
O
N
Me
N
H
S
1f
Me
N
H
S
O
11a
11b
: R=phenyl 86%
: R=2-thienyl 97%
O
NH
Me
N
S
H
12a
: R=phenyl
12b: R=2-thienyl
Br
O
O
O
10a
O
NH
NH
a
Me
N
O
84%
Me
N
H
14
O
H
13
Scheme 3. Selectivity of Liebeskind–Srogl reaction and Stille coupling reaction. Conditions and Reagents: (a) PdCl2(PPh3)2, PhMe, 100 °C, 48 h.
some specific substrates such as protecting-group-free 2-thiouracil
derivatives.17 Fortified by these experiments, we attempted to im-
prove cross-coupling reactions between dihydropyrimidinethiones
and organostannanes.
scope of this palladium-catalyzed cross-coupling reaction between
dihydropyrimidines and tributyltin derivatives.
Using the previously reported experimental conditions,17 we
explored the possibility to extend this cross-coupling reaction to
various organostannanes. The results are depicted in Table 1 (en-
tries 2–6). Dihydropyrimidine (1a) was reacted with electron-poor
(10b) or electron-rich aryltributylstannanes (10c) to provide the
corresponding products 9b and 9c in good yields (entries 2 and
3). While some heteroarylstannanes were reported to cross-couple
in low yields with CuTC,13 interestingly, with CuBrÁMe2S, the de-
sired products 9d (78%), 9e (95%), and 9f (88%), were isolated in
good to excellent yields (entries 4, 5, and 6).
The first experiment was performed between dihydropyrimi-
dine (1a) and phenyltributyltin (10a) using CuBrÁMe2S in refluxing
THF in the presence of a catalytic amount of Pd(PPh3)4. To our de-
light, product 9a (entry 1, Table 1) was isolated after column chro-
matography in 88% yield. MS analysis and 1H/13C NMR spectral
data in CDCl3 for compound 9a were in accordance with the results
reported in Kappe.13 All the protons and carbons for compounds 9
were observed and carefully assigned in DMSO-d6 by adding one
drop of trifluoroacetic acid18 or by using their HCl salts to fix the
isomer (see S8). In the absence of Pd(PPh3)4 or CuBrÁMe2S product
9a was not detected. These results encouraged us to explore the
Extension of this optimized Liebeskind–Srogl reaction to other
dihydropyrimidines (1b–f) was also investigated and results are
reported in Table 1 (entries 7–12). Various aryl groups on the

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Q. Sun et al. / Tetrahedron Letters 53 (2012) 2694–2698
695, 1999.; (c) Nagarathnam, D.; Miao, S. W.; Lagu, B.; Chiu, G.; Fang, J.; Dhar, T.
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dihydropyrimidine core were well tolerated in these coupling reac-
tion conditions and excellent yields of cross-coupled products
were obtained with 2-(tributylstannyl)thiophene as well as tribu-
tylstannylbenzene. Unfortunately, no desired product 9m was iso-
lated for the reaction of dihydropyrimidine 1g and vinyl tributyltin
10g.
By-products resulting from the Stille cross-coupling reaction
between bromoaryl–dihydropyrimidines 1f and organostannanes
were not observed and only the Liebeskind–Srogl adduct 9l was
isolated in good yield in accordance with the results of functional-
ized pyridinone reported by Liebeskind.19 To better understand
this selectivity between the Liebeskind–Srogl reaction and the
Stille cross-coupling reaction, compound 9l was then successfully
converted into 11a (yield: 86%) and 11b (yield: 97%) by cross-cou-
pling with 10a and 10e in the presence of PdCl2(PPh3)2 in toluene.
To our surprise, starting with the Stille cross-coupling reaction did
not afford the expected cross-coupled product. As the presence of
the thiocarbonyl function in 1f was probably a contributing factor,
we ran a test experiment with compound 1315 (the oxygenated
analog of 1f). The cross-coupled product 14 was isolated in an
excellent yield showing that the present selectivity between the
two cross-coupling reactions comes from the absence of reactivity
of the thio derivatives under Stille conditions (Scheme 3).
In summary, we have developed an optimized Liebeskind–Srogl
cross-coupling reaction to synthesize potentially biologically ac-
tive 2-aryl-1,4-dihydropyrimidines in good to excellent yields with
various heteroarylstannanes.
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Acknowledgments
12. Sehon, C. A.; Wang, G. Z.; Viet, A. Q.; Goodman, K. B.; Dowdell, S. E.; Elkins, P. A.;
Semus, S. F.; Evans, C.; Jolivette, L. J.; Kirkpatrick, R. B.; Dul, E.; Khandekar, S. S.;
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We thank the Foundation of French–China Science and its
Application (FFCSA) and the China Scholars Council (CSC) for finan-
cial support.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.03.
067.
15. Sun, Q.; Wang, Y. Q.; Ge, Z. M.; Cheng, T. M.; Li, R. T. Synthesis 2004, 1047–1051.
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Keromnes, A.; Lebret, B.; Guillaumet, G. Synthesis 2004, 2893–2899.
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18. There were two isomers (2:1), 1,4-dihydropyrimidine and 3,4-
dihydropyrimidine. We therefore added one drop of TFA in DMSO or used
their HCl salt to fix one isomer to obtain satisfactory, NMR spectra (see
Supplementary data).
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