A domino desulfitative coupling and decarboxylative coupling of 3,4-dihydropyrimidine-2-thiones with copper(I) carboxylates

Article abstract of DOI:10.1016/j.cclet.2016.12.034

A novel and general carbon-nitrogen and carbon-carbon cross-coupling reaction between 3,4-dihydropyrimidine-2-thiones and copper(I) carboxylates were performed in the presence of palladium acetate. The copper(I) carboxylates act not only as desulfurative

Full text of DOI:10.1016/j.cclet.2016.12.034

Accepted Manuscript
Title: A domino desulfitative coupling and decarboxylative
coupling of 3,4-dihydropyrimidine-2-thiones with copper(I)
carboxylates
Author: <ce:author id="aut0005"
author-id="S1001841717300189-
d891010f04cbf5dbc029becbf187493f"> Zhang
Zhang<ce:author id="aut0010"
author-id="S1001841717300189-
4e8e02c7d3c1719670120a53e56b694b"> Shi-Hong
Lu<ce:author id="aut0015" author-id="S1001841717300189-
805cc028826c7e8cccaf51875344c282"> Bin Xu<ce:author
id="aut0020" author-id="S1001841717300189-
ac244ccb28faa440fd29393618bc9026"> Xi-Cun
Wang
PII:
S1001-8417(17)30018-9
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.cclet.2016.12.034
CCLET 3945
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Chinese Chemical Letters
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10-11-2016
6-12-2016
12-12-2016
Please cite this article as: Zhang Zhang, Shi-Hong Lu, Bin Xu, Xi-Cun
Wang, A domino desulfitative coupling and decarboxylative coupling of 3,4-
dihydropyrimidine-2-thiones with copper(I) carboxylates, Chinese Chemical Letters
http://dx.doi.org/10.1016/j.cclet.2016.12.034
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Original article
A domino desulfitative coupling and decarboxylative coupling of 3,4-
dihydropyrimidine-2-thiones with copper(I) carboxylates
Zhang Zhang,a,b* Shi-Hong Lu,a,b Bin Xu,a,b Xi-Cun Wang a,b*
a Key Laboratory of Eco-Environment-Related Polymer Materials, Ministry of Education of China, Lanzhou 730070, China
b Gansu Key Laboratory of Polymer Materials, College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou 730070, China
 Corresponding authors.
E-mail addresses: zhangz@nwnu.edu.cn (Z. Zhang); wangxicun@nwnu.edu.cn (X.-C. Wang)

Graphical Abstract
A novel and general carbon-nitrogen and carbon-carbon cross-coupling reaction between dihydropyrimidinthiones and copper(I) carboxylates
protocol was performed in the presence of palladium acetate. The copper(I) carboxylates act not only as desulfurative reagents but also as
sources of carbon nucleophiles.
ARTICLE INFO
Article history:
Received 10 November 2016
Received in revised form 6 December 2016
Accepted 12 December 2016
Available online
ABSTRACT
A novel and general carbon-nitrogen and carbon-carbon cross-coupling reaction between 3,4-dihydropyrimidine-2-thiones and copper(I) carboxylates
were performed in the presence of palladium acetate. The copper(I) carboxylates act not only as desulfurative reagents but also as sources of carbon
nucleophiles. A wide array of highly substituted and functionalized pyrimidines scaffolds were synthesized in good yields.
Keywords: Dihydropyrimidinthiones, Desulfitative, Copper(I) carboxylates, Decarboxylative, Cross-coupling
1. Introduction
Transition metal-catalyzed carbon-carbon and carbon-heteroatom cross-coupling reactions belong to the most powerful and flexible
transformations known to organic chemists and have revolutionized the art and practice of synthesis in the last two decades [1]. The
mild reaction conditions, high functional group tolerance, and broad availability of starting materials make this method more attractive.
For example, Pd-catalyzed the formation of carbon-carbon and carbon-heteroatom bond have attracted remarkable attention [2-9].
In 2000, a novel and mechanistically unprecedented Pd-catalyzed C-C cross-coupling protocol for the synthesis of ketones from
thiol esters and boronic acids under neutral, anaerobic conditions was reported by Liebeskind and Srogl [10-12]. Then, a lot of methods
were developed for the C-C bond formation via the Pd and/or Cu, Ni-catalyzed the desulfurative cross-coupling reaction of thioethers
or thioesters with arylboronic acids [13-15]. A key feature of these desulfitative carbon-carbon couplings [16] is the requirement of
stoichiometric amounts of a Cu(I) carboxylate, such as Cu(I)-thiophene-2-carboxylate (CuTC) [17] or Cu(I)-3-methylsalicylate as a
metalcofactor. Because of the high thiophilicity of the Cu(I) salt, it often used as a desulfurization reagents.
Recently, we developed a domino desulfitative coupling and acylation process through the three-component reaction of 3,4-
dihydropyrimidine-2-thiones, alkynes with copper(I) Carboxylates using palladium acetate as catalyst (Scheme 1) [18]. Wherein,
copper(I) carboxylates act not only as desulfurative reagents but also as sources of nucleophilic carboxylates. In continuation of our
interest in the synthesis of highly substituted and functionalized pyrimidines, we expanded the application scope of copper(I)
carboxylates in the intermolecular desulfitative and decarboxylative coupling reaction of two molecules of 3,4-dihydropyrimidine-2-
thione with one copper(I) carboxylate (Scheme 1). Herein, copper(I) carboxylates act not only as desulfurative reagents but also as
sources of carbon nucleophiles. This novel transformation, involving desulfitative, aromatic and decarboxylative reactions in a one-pot
process was very efficient.
In the last decade, a rapidly growing number of decarboxylative reactions have been discovered. Their key advantage over

traditional cross-coupling reactions is that they draw on stable and readily available carboxylate salts as sources of carbon nucleophiles
rather than expensive and sensitive organometallic reagents [19, 20]. In this type of reaction, a copper(I) or silver(I) catalyst mediates
the extrusion of CO2 from the carboxylates while a palladium-complex catalyzes the coupling of the resulting carbon nucleophiles with
carbon electrophiles.
2. Results and discussion
Initially, the influence on the model reaction of various parameters such as catalysts, ligands, solvents was examined, and the results
are summarized in Table 1. To optimize the reaction conditions, the cross-coupling reaction between DHPM (1a) with copper(I)-
thiophene-2-carboxylate (CuTC) (2a) was tested as the model reaction. Clearly, Pd catalyst and ligand are essential for the entire
process (entries 1-3). Next, we tested the effect of different kinds of Pd catalyst. Obviously, Pd(acac)2 and Pd(PPh3)4 were not good for
the reaction to form the product 3a in a low yield (entries 4 and 5). When PdCl2, PdCl2(dppf) and Pd(PPh3)2Cl2 were used as the
catalyst, the yield of the product 3a was moderate (entries 6-8). Compared with the catalyst on the above, Pd(OAc)2 was the optimal
catalyst to deliver the target product 3a in 75 % yield (entry 9). Among the tested phosphine ligands such as DPE-Phos, PPh3, X-Phos,
PCy3 and dppp, DPE-Phos was the best one (entries 9-12). Finally, the effect of solvent was also investigated, and DMF was better
than xylene and toluene (entries 14 and 15). To sum up, the optimal conditions are as follows: Pd(OAc)2 as a catalyst, DPE-Phos as a
ligand, DMF as a solvent at 140 oC for 36 h, which afforded the desired product in the highest isolated yield.
With the optimized reaction conditions in hand, we used DHPMs and CuTC to test the reaction scope (Scheme 2). In general,
moderate to good yields were obtained under the standard reaction conditions (3a-3p). The reaction tolerated a variety of
dihydropyrimidine-2-thiones substituents and obtained a series of pyrimidine derivatives via C-N and C-C cross-coupling reaction. We
also found that the reactions of dihydropyrimidine-2-thione bearing electron-donating groups (Me and OMe) on the phenyl ring
provided higher yields than those containing electron-withdrawing groups (F, Br and Cl) on the phenyl ring. It is noteworthy that 4-(4-
bromophenyl) substituted pyrimidine-2-thioneonly gave single-substituted product (3l), and the structure of 3l was confirmed by X-ray
crystallographic analysis with CCDC No. 1475601 (Fig. 1). When electron-withdrawing group was a nitro group at the DHPM, the
reaction almost did not take place (3q). Meanwhile, the para-substituted DHPMs gave the target products in higher yields compared
with the meta or ortho-substituted DHPMs under the optimized reaction conditions (3b-3k).
To expand the scope of differentiated Cu(I) carboxylates in the coupling reaction, we explored the copper(I) furan-2-carboxylate
(CuFC) with DHPMs in the standard reaction conditions. The reaction also can proceeded smoothly and obtained the satisfactory
results (Scheme 3).
Next, on the basis of literatures in the last few years [21, 22], We explored a variety of copper(I) carboxylates. Including, either
electron-with drawing or electron copper(I) Benzoic-carboxylate series or copper(I) picolinate-2-carboxylate and copper(I) aliphatic
carboxylicacids, the reactions of Cu(I) carboxylates with DHPM (1a) did not take place. However, when the cross-coupling reaction of
copper(I) picolinate with DHPM (1a), a new product was detected and the new product was 7a, the structure of which was confirmed
1
by the H NMR, 13C NMR and MS. Next, in order to further explore experiments, we examined the possibility of the coupling of 7a
with copper(I)-thiophene-2-carboxylate (CuTC). To our delight, the desired product 3a was obtained in a satisfactory yield (Scheme 4).
Thus, we hypothesized that the 7a possible an intermediate in this reaction process. Unfortunately, the proposed mechanism of the
protocol not has a reliable explanation in the present and the follow-up work needs to further exploration in our laboratory.
3. Conclusion
In conclusion, we have developed a simple domino process between dihydropyrimidinthiones (DHPMs) and copper(I) carboxylates
(CuTC, CuFC) in the presence of palladium acetate to synthetize a series of highly substituted and functionalized pyrimidines. In this
reaction, we successfully achieved constructing the carbon-nitrogen bond and carbon-carbon bond in one pot. Besides, the copper(I)
carboxylate is not only as desulfurative reagents but also as a sources of carbon nucleophile.
4. Experimental
General procedure for the synthesis of (3a-3q): Under argon atmosphere, DHPMs 1 (0.2 mol, 55.2 mg), CuTC (3.0 equiv, 0.6
mol, 114 mg), Pd(OAc)2 (5 mol%, 0.01 mol, 2.2 mg), DPE-Phos (6 mol%, 0.012 mol, 7.0 mg) were added into a Schlenk tube dried by
Hot-gun. The tube was stopped and degassed with Nitrogen for three times. Then DMF (2 mL) were added by syringe. The mixture
was stirred under Nitrogen atmosphere at 140 °C for 36 h. Then the mixture was cooled down to room temperature with 4 mL saturated
solution of NH4Cl added to quench the reaction and extracted with ethyl acetate (3×10 mL). The organic layers were combined and
dried with anhydrous MgSO4 and extracted by acetic ether and evaporated in vacuum and further purified by column chromatography

on silica gel with ethyl acetate / Petroleum ether (1:10-1:3) to give the corresponding compounds (3a-3q). When CuTC (3.0 equiv., 0.6
mol, 114 mg) is replaced by CuFC (3.0 equiv., 0.6 mol, 104 mg) in the above conditions, products (5a-5e) can be obtained.
Compound 3a: Yellow solid (yield: 75 %), m.p. 145 – 146 ºC. 1H NMR (600 MHz, CDCl3): δ 7.54 (d, 2H, J = 7.2 Hz), 7.39 (t, 2H, J
= 6.4 Hz), 7.33 – 7.27 (m, 4H), 7.23 (t, 3H, J = 7.8 Hz), 7.06 (d, 1H, J = 2.8 Hz), 6.96 (s, 1H), 6.93, (t, 1H, J= 4.8 Hz), 4.25 – 4.12 (m,
4H), 2.56 (s, 3H), 2.54 (s, 3H), 1.25( t, 3H, J = 1.2 Hz), 1.06 (t, 3H, J = 1.2 Hz). 13C NMR (150 MHz, CDCl3): δ 168.10 , 167.01,
166.17, 164.17, 158.84, 153.97, 149.06, 140.76, 139.72, 137.40, 130.08, 129.58, 129.53, 128.36, 128.31, 128.25, 127.86, 127.50,
127.22, 119.96, 112.31, 61.67, 60.41, 54.81, 22.88, 21.26, 14.24, 13.63; HRMS: calcd. for C32H31N4O4S+ [M+H]+: 567.2066; found
567.2063.
Single crystal X-ray diffraction for 3l: Colorless crystal sample with the size of 0.34 mm × 0.33 mm × 0.27 mm of 3l was chosen
under a microscope. Then crystal data was collected on a Bruker SMART ApexII CCD diffractometer using graphite-monochromated
Mo Kα radiation (λ=0.71073 Å) at 300.79 K. The structure was solved using a direct method and refined by full-matrix least squares
on F2 using the SHELXTL crystallographic software package.
Acknowledgment
Financial support from the National Natural Science Foundation of China (Nos. 21362032 and 21362031), the NSF of Gansu
Province (No. 1208RJYA083).
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Fig. 1 X-raycrystal structureof compound 3l.

Scheme 1. A desulfurative coupling arylation process.

Scheme 2. Scope of the DHPMs with copper(I)-thiophene-2-carboxylate (CuTC).

Scheme 3. Scope of the DHPMs with copper(I) furan-2-carboxylate (CuFC).

Scheme 4. Synthesis of compound 3a.

Table 1
Optimization of the reaction of DHPM (1a) with CuTC (2a).a
Entry
1
2
3
4
5
6
7
8
Pd
/
Pd(OAc)2
/
Pd(acac)2
Pd(PPh3)4
PdCl2
PdCl2(dppf)
Pd(PPh3)2Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Ligand
/
/
DPE-Phos
DPE-Phos
DPE-Phos
DPE-Phos
/
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Xylene
Toluene
Yield (%)b
N.R
25
N.R
25
32
67
53
64
75
66
64
67
61
35
28
/
9
DPE-Phos
PPh3
X-Phos
PCy3
dppp
DPE-Phos
DPE-Phos
10
11
12
13
14
15
aReaction conditions: 1a (0.20 mol), 2a [copper(I)-thiophene-2-carboxylate (CuTC)] (3.0 equiv., 114 mg), catalyst (5 mol%, 0.01 mol), ligand (6 mol%,
0.12 mol), solvent (2 mL), 36 h, 140 oC, N2.
bIsolated yield by column chromatography.