Intermolecular cyclocondensation reaction of 3,4-dihydropyrimidine-2-thione under the Mitsunobu reaction conditions

Article abstract of DOI:10.1016/j.cclet.2010.12.041

A self-intermolecular cyclocondensation reaction of 3,4-dihydropyrimidine- 2-thione (DHPM) to give a novel tricyclic structure containing DHPM core in the presence of diethyl azodicarboxylate (DEAD) and triphenylphosphine (TPP) at room temperature is repo

Full text of DOI:10.1016/j.cclet.2010.12.041

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 679–682
www.elsevier.com/locate/cclet
Intermolecular cyclocondensation reaction
of 3,4-dihydropyrimidine-2-thione under
the Mitsunobu reaction conditions
*
Yu Xia Da, Zhang Zhang, Zheng Jun Quan
Key Laboratory of Eco-Environment-Related Polymer Materials, Ministry of Education,
Gansu Key Laboratory of Polymer Materials, College of Chemistry and Chemical Engineering,
Northwest Normal University, Lanzhou 730070, China
Received 11 October 2010
Abstract
A self-intermolecular cyclocondensation reaction of 3,4-dihydropyrimidine-2-thione (DHPM) to give a novel tricyclic structure
containing DHPM core in the presence of diethyl azodicarboxylate (DEAD) and triphenylphosphine (TPP) at room temperature is
reported.
# 2010 Zheng Jun Quan. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Mitsunobu reaction; Cyclocondensation; 3,4-Dihydropyrimidine-2-thiones
In the past decades, 3,4-dihydropyrimidinones (Biginelli compounds or DHPMs) [1] and their derivatives have
attracted considerable interest [2] due to their heterocyclic scaffold and interesting pharmacological properties, such
as calcium channel modulation, anti-hypertension, a1a adrenergic agonist and mitotic kinesin inhibition, and hepatitis
B virus replication suppression. The N-substituted reaction of dihydropyrimidinones is one approach to
functionalizing the dihydropyrimidinone ring in order to achieve important bioactive properties [3]. For instance,
substitution at the third nitrogen is possible, and the products can be strongly rendering strong anti-inflammatory,
antihypertensive, analgesic, and anticancer activities [4].
In recent publications, we have disclosed some methods for the scaffold decoration of DHPMs [5]. In continuation
of our interest in the generation of diversely substituted and novel types of privileged scaffolds of the DHPM core, we
herein report the self-intermolecular cyclocondensation reaction of 3,4-dihydropyrimidine-2-thione under the
Mitsunobu reaction conditions.
During the courseof ourrecent attempts to synthesize theN1-propargylicDHPMs, we used 3,4-dihydropyrimidine-2-
thione (1a) and propargylic alcohol as starting material in tetrahydrofuran (THF) in the presence of diethyl
azodicarboxylate (DEAD) and triphenylphosphine (TPP) at room temperature for 24 h (Scheme 1). Incidentally, we did
not obtain the desired product N1- or N3-propargylic 3,4-dihydropyrimidine-2-thione. Instead, a new compound, as a
* Corresponding author.
E-mail address: quanzhengjun@hotmail.com (Z.J. Quan).
1001-8417/$ – see front matter # 2010 Zheng Jun Quan. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.12.041

[()TD$FIG]
680
Y.X. Da et al. / Chinese Chemical Letters 22 (2011) 679–682
Scheme 1. The reaction of DHPM 1a under Mitsunobu conditions.
single product, was isolated in 85% yield after 24 h. Extensive analysis of this compound was performed to elucidate the
structure. Tooursurprise, massspectrometryindicatedthatthisproductresultedfromtheeliminationofonesulphur atom
and four hydrogen atoms between two molecular of 3,4-dihydropyrimidine-2-thione. Elemental analysis confirmed this
finding. The 1H NMR was clean and exhibited five symmetrical signals, which devoted to CH3, CH3CH2O, CH3CH2O,
CH2O, and CH groups, respectively. These facts along with the 13C NMR spectrum led us to propose the tricyclic
structure 2a. This hypothesis was eventually confirmed by a single-crystal X-ray diffraction study (Scheme 1) which
demonstrated the tricyclic structure of compound 2a [6]. It should be emphasized that it is the first example of a self-
intermolecular cyclocondensation reaction between two 3,4-dihydropyrimidine-2-thione molecular.
Next, isopropanol was used to replace propargylic alcohol and compound 2a was also obtained in good yield.
Interestingly, 2a was also obtained in yield 84% in the absence of any alcohol under above described reaction
conditions [7]. Optimization studies demonstrated that utilizing anhydrous THF as solvent showed excellently high
performance than acetone, CH2Cl2, and MeCN. It is also demonstrated that clean completion of this reaction needed
24 h at r. t. in THF needing two equivalents of TPP and DEAD. We further carried out the self-intermolecular
cyclocondensation reaction of other substituted 3,4-dihydropyrimidine-2-thiones. Treatment of dihydropyrimidine-
thiones 1b–e with 2 equiv. of DEAD and TPP in THF for 24 h gave the corresponding coupling products 2b–e in good
yields (Scheme 2). However, o-position at the phenyl ring has apparent affect on the yields of products. For instance,
the chloro and methoxyl group at the o-position of phenyl ring could not be transformed into corresponding
cyclocondensation products, but a coupling product similar as compound 7 in Scheme 3 was detected by LC-Mass
experiments. Extension of this preliminary work is undergoing in our laboratory now.
[()TD$FIG]
R
R
R
O
O
O
DEAD, PPh
3
H C
3
N
S
+
N
OC H
2 5
C H O
NH
C H O
NH
2
5
2 5
THF, rt, 24 h
C H O
N
2
5
N
CH
H C
3
N
H
S
H C
3
N
H
S
3
O
1
1
2
R
2a: R = H, 84%: 2b: R= 4-CH3, 86%; 2c: R = 4-CH3O, 83%; 2d: R = 4-Cl, 82%; 2e: R = 4-NO2, 78%.
Scheme 2. The reactions of DHPMs under Mitsunobu conditions.

[()TD$FIG]
Y.X. Da et al. / Chinese Chemical Letters 22 (2011) 679–682
681
Ar
O
O
Ar
CO C H
2 5
2
H
S
CO C H
2
2
5
Ph P
3
N
OC H
2 5
C H O
N
HN
C H O C
N
Ph P
3
2 5
+
N
N
N
N
PPh
3
2
5
2
N
H
CH
H C
3
N
H
4
S
C H O C
3
C H O C
CO C H
2
5 2
5
2
5
2
2
2
5
1
3
O
Ar
O
Ar
CO C H
2 5
2
5
HN NH
C H O C
+
C H O
NH
C H O
N
2
5
2
5
2
5 2
PPh
3
H C
N
H
S
S
H C
N
H
S
3
3
6
Ar
O
Ar
O
H
N
H
N
H C
3
H C
S
3
N
OC H
2 5
N
OC H
2 5
DEAD
Oxidation reaction
C H O
N
2
5
C H O
N
2
2
5
- Ph P=S
3
S
N
H
CH
N
H
CH
3
3
O
Ar
4
PPh
O
Ar
3
6
7
Scheme 3. The plausible mechanism.
It has been reported that treatment of 2-thioxo-4-quinalinone with DEAD afforded [1,3,4]thiadiazolo[2,3- b:5,4-
b’]diquinazoline-12,15-dione as the main product [8]. However, the same material 2-thioxo-4-quinalinone was
transformed to [1,2,4]thiadiazolo[3,2-b:5,4-b0]diquinazoline-8,15-dione by an oxidative cyclocondensation in the
presence of P2O5, sulfuric acid or iodine [9]. Thus a possible pathway in the cyclocondensation process of 3,4-
dihydropyrimidin-thione is shown in Scheme 3. The first step is the irreversible formation of the Morrison–Brunn–
Huisgen (MBH) betaine 3 [10]. In step 2, this betaine 3 deprotonates the 3,4-dihydropyrimidin-thione 1 to form the
ionic species 4 and 5. 5 upon reacting with another 3,4-dihydropyrimidin-thione 1 forms the key phosphonium salt 6
and the hydrazine EtO2CNH-NHCO2Et. At this stage, 4 attacks 6 to lead to 7 as well as the triphenylphosphine sulfide
Ph3P(S). Formation of the product 2 is a completed by the oxidative cyclocondensation of 7 in the presence of DEAD
as an oxidizing agent.
In conclusion, we reported here an efficient cyclocondensation reaction between two 3,4-dihydropyrimidine-2-
thiones under the Mitsunobu reaction conditions. Yields are generally high, and the reaction occurs readily under very
mild conditions with excellent chemoselectivity. We think this reaction affording a novel tricyclic structure containing
DHPM core could be of great interest since to our knowledge there has no example of direct cyclocondensation
reaction between 3,4-dihydropyrimidine-2-thiones.
Acknowledgments
We are thankful for the financial support from the National Nature Science Foundation of China (No. 20902073),
the Natural Science Foundation of Gansu Province (No. 096RJZA116), and Scientific and Technological Innovation
Engineering program of Northwest Normal University (nwnu-kjcxgc-03-64).
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[7] Typical Experimental Procedure: To a solution of TPP (0.534 g, 2 mmol) in THF (5 mL) was added 3,4-dihydropyrimidine-2-thione 1
(1 mmol). To this clear solution was added DEAD (0.348 g, 2 mmol) over 5 min. The reaction was then stirred at room temperature for 24 h.
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.
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C
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