thiones stabilized by trifluoromethyl-containing β-diketones

Journal Pre-proof Tetrahydropyrimidinones/thiones stabilized by trifluoromethyl-containing β-diketones Rasheed A. Adigun, Frederick P. Malan, Mohammed O. Balogun, Natasha October PII:

S0022-2860(19)31390-0

DOI:

https://doi.org/10.1016/j.molstruc.2019.127281

Reference:

MOLSTR 127281

To appear in:

Journal of Molecular Structure

Received Date: 9 August 2019 Revised Date:

18 October 2019

Accepted Date: 22 October 2019

Please cite this article as: R.A. Adigun, F.P. Malan, M.O. Balogun, N. October, Tetrahydropyrimidinones/ thiones stabilized by trifluoromethyl-containing β-diketones, Journal of Molecular Structure (2019), doi: https://doi.org/10.1016/j.molstruc.2019.127281. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.

Tetrahydropyrimidinones/thiones Diketones

Stabilized

by

Trifluoromethyl-Containing

β-

Rasheed A. Adiguna, Frederick P. Malana, Mohammed O. Balogunb, Natasha Octobera,* a

Department of Chemistry, University of Pretoria, Lynnwood Road, Hatfield, Pretoria, 0002, South Africa b Biopolymer Modification & Therapeutics Lab, Chemicals Cluster, Council for Scientific and Industrial Research, Meiring Naude Road, Brummeria, Pretoria 0001, South Africa *Corresponding author: Natasha October E-mail: [email protected], Tel: +27 124204905 Graphical Abstract

Highlights •

Sixteen new compounds from two different classes of pyrimidinones/thiones were prepared.

•

A chemoselective reaction pathway directed by the presence of either trifluoromethyl (CF3) or methyl (CH3) groups in the diketone precursor was observed.

•

The compounds were structurally confirmed using 1H, 13C, COSY, HSQC and HMBC NMR techniques, as well as SCXRD techniques (four examples).

•

The HMBC displayed rare and interesting one-bond correlations without interfering with the structural interpretation. 1

Abstract A library of new hydropyrimidinone/thione compounds was synthesized via the classical Biginelli reaction using hydrated cerium(III) chloride as the catalyst. The presence of a trifluoromethyl or methyl group in the diketone starting material has been established to selectively control the outcome of the Biginelli reaction where one of the two possible pyrimidinone/thione compounds is formed. The results showed that the electronic effects of substituents of the diketone directly affect the product formation. The synthesized compounds were fully characterized using 1H, 13C, and two dimensional NMR (2D NMR) spectroscopy, single crystal X-ray diffractometry, FT-IR, and ESI-HDMS techniques. We also report on the uncommon one-bond correlations which were observed in the HMBC spectra and the interesting long-range heteronuclear coupling of fluorine to hydrogen and carbon. Keywords:

tetrahydropyrimidinone;

Biginelli

reaction;

trifluoromethyl;

Claisen

condensation; heteronuclear coupling; hydrated cerium(III) chloride

1.

Introduction

Pyrimidinones as a class of N-heterocyclic compounds have been extensively researched [1– 3] primarily due to the various therapeutic and medicinal properties they exhibit [4–7] such as the inhibition of mitotic kinesin protein [8,9], anti-tuberculosis [10–12], treatment of benign prostate cancer [13,14], antibacterial [15,16] and antifungal [17–19] activities. In addition, they act as DNA synthesis inhibitors in Escherichia coli, cytidine deaminase enzyme inhibitors, as well as metaphase inhibitors [4,20]. Interestingly, a structural-activity relationship between pyrimidinones and the Hantzsch dihydropyridine (DHP), especially the Nifedipine calcium channel inhibitor [21,22] has been found. This relationship further enhanced the interest in the study of dihydropyrimidinones (DHPM). The classical Biginelli multicomponent reaction allows for the reliable synthesis of an extensive range of

2

pyrimidinones and pyrimidinthiones, employing the feasible and versatile derivatives of 1,3dicarbonyl compounds, urea or thiourea and aldehydes [20,23–26]. The efficiency of multicomponent reactions (MCRs) [27] and the molecular diversity that could be introduced via the three starting materials offer the opportunity to manipulate and alter the system to create a wide range of DHPM derivatives with different biological activities [21,28–31]. Both tetrahydropyrimidinones and DHPMs are well-known classes of organic compounds, but there are few reports on how the electronic effects of the β-diketone substituents direct the product formation during the Biginelli reaction. Ryabukhin et al. [32] established the reaction pathway dependence of Biginelli reaction on the inductive effect of the diketone substituents using CF3 and CH3 on the same diketone in the presence of substituted thiourea/urea. However, we could not find in the literature explicit reports on experiments to compare the electronic effects of the electron-withdrawing group CF3 and the electrondonating group CH3 using different diketone precursors under the same reaction conditions with unsubstituted thiourea/urea. Previous works on similar structures established the synthetic possibility of pyrimidinones using fluorinated or alkylated β-ketoesters individually under different conditions. For instance, Burgart et al. [33] established the possibility of synthesizing bicyclic heterocycles from fluorinated tetrahydropyrimidines, while Chupakhin and co-workers [34] demonstrated the synthesis of fluorinated tetrahydropyrimidinones from different fluorine-containing β-diketones. Liang-Ce et al. [35] synthesized thiophenecontaining tetrahydropyrimidinones using para-toluene sulfonic acid as the catalyst while Rong and co-workers [36] performed the Biginelli reaction to obtain spiro heterocycles from the reaction of isatins under a solvent-free condition. Sathicq et al. [37] and Palermo et al. [38] performed similar reactions using Preyssler heteropolyacids and Vanadium Keggin heteropolyacids respectively as the catalysts encapsulated in a silica framework.

3

Tetrahydropyrimidinones were obtained but with an aliphatic ester group at position 5 of the pyrimidinones. Apart from the classical Biginelli reaction for the synthesis of tetrahydropyrimidinones, other methods have been reported in the literature. For example, Inman et al. obtained tetrahydropyrimidinones from the cyclization reaction of heterocumulenes and 2vinylazetidines using palladium(II) acetate/triphenylphosphine as the catalyst [39] while Wan et al. performed the first four-component reaction of tetrahydropyrimidinthiones using enaminone and aromatic amine in addition to the usual aldehyde and thiourea [40]. Here, we report the synthesis of new sets of tetrahydropyrimidinones/thiones starting from different trifluoromethyl-containing dicarbonyl compounds, and structurally compare the resulting products to the alkylated DHPMs by means of both solid and solution characterization techniques.

2.

Results and Discussion

In the synthetic scheme towards a range of functionalized pyrimidinones/thiones, various 1,3diketones were employed as precursors. These 1,3-diketones (3a-d) were synthesized in high yields (>85%, for 3b-d) via Claisen condensation [41–43], with simple modifications (Scheme 1), using functionalized ketones (1a-c) and esters (2a-b). The substituents on the resulting 1,3-diketones were strategically selected in order to probe any electronic effect(s) that may be prominent during the synthesis of the corresponding pyrimidinones/thiones. All of the synthesized diketones were isolated as keto-enols and are in agreement with previous reports [44], which were established using 1H-NMR spectroscopy and single-crystal X-ray diffractometry (SCXRD).

4

Scheme 1: Synthesis of diketones 3a-3d. Reagents and conditions: (3a): (i) NaOEt, r.t., 25 mins; (ii) 0 °C, Et2O, r.t., 4 h, AcOH (3b-d): NaOMe, absolute EtOH, r.t., 3 h, HCl.

The 1H-NMR spectra of the diketones highlighted these electronic differences with the central unsaturated C(3)-proton signal of the diketone with electron-donating substituents (CH3) appearing higher upfield (δH 6.13 ppm), as compared to the diketones with electronwithdrawing substituents (para-halo arenes, CF3) appearing lower downfield (δH 6.53-6.58 ppm). The SCXRD structures of 3b (previously reported [44]) and 3d (Figure 1) were elucidated, which revealed the typical [45] keto-enol tautomerism containing the intramolecular hydrogen bond O2-H2···O1 (1.76 Å). Bond lengths were observed which averaged between typical C=C, C-C, C=O, and C-O bonds as can be expected in most conjugated systems of keto-enol compounds [45].

Figure 1: Molecular structure of the keto-enol compounds 3b and 3d, containing an intramolecular hydrogen bond (blue line). Ellipsoids are drawn at 50% probability level. 5

With the synthesis of the diketones, a range of sixteen new pyrimidinone/thione compounds was synthesized via the classical Biginelli reaction using hydrated cerium(III) chloride (CeCl3.7H2O) as a Lewis acid catalyst (Scheme 2, Scheme 5). Although hydrated cerium chloride (CeCl3.7H2O) has been previously used for the synthesis of DHPM using the multicomponent Biginelli reaction [46,47], we could not find in the chemical literature its use in the synthesis of tetrahydropyrimidinones/thiones containing CF3 moiety. Even though there are other faster methods for the synthesis of stable tetrahydropyrimidinones/thiones, like the use of microwaves under a “solventless” condition [48], this CeCl3-based method has an advantage as a batch synthesis method in terms of industrial scalability and adaptability to flow chemistry-type reactors. Microwave-assisted organic synthesis (MAOS) is majorly applicable to small scale synthesis and scalability is still a challenge [49] because of nonuniform heating and penetration depth problems [50].

Scheme 2: Synthesis of DHPM 6a-6d, Reagents and conditions: CeCl3.7H2O, absolute EtOH, 65 oC, 3 h.

6

The reaction of diketone 3a with aldehydes 4a/b and ureas 5a/b (Scheme 2) gave the expected DHPMs 6a-d in moderate to high yields (66-85%, after purification). The 1H-NMR and

13

C-NMR spectra confirmed the formation of the pyrimidinones/thiones 6a-d with

several diagnostic signals observed. For instance, the change in the 1H signal of the CH3 singlet from 2.19 ppm in 3a to 1.68-1.73 ppm in 6a-d indicating a more shielding effect when its carbonyl neighbour was lost in 6a-d. In addition, the upfield methine signal also results from the formation of a stereogenic centre at C4. All of these products 6a-6d have been isolated as mixtures of both enantiomers, as determined by SCXRD technique. In general, stable tetrahydropyrimidinones/thiones could be formed when a strong electronwithdrawing group such as CF3 is present in the 1,3-dicarbonyl precursor [33]. This is clear from the mechanism in Scheme 3 which has been adapted [51–53] to propose a mechanism for the CeCl3-catalyzed reaction. In the previously proposed mechanisms for the Biginelli reaction [51,52], the tetrahydro product IX was an intermediate in the reactions involving alkylated β-diketones. As it was observed, when the reaction involves CF3, the reaction is completed with the cyclization step after the proton-loss step from the nucleophilic attack of nitrogen lone pair of electrons on the carbonyl C6 (VIII), to form the stable tetrahydro product IX containing three stereogenic centres as shown in Scheme 3.

7

Scheme 3: A predicted mechanism for the formation of tetrahydropyrimidinones/thiones 7a-l [52,53].

However, in the case of alkylated β-diketones with CH3 for example, a tandem dehydration of the alcohol intermediate occurs to form the DHPM (6a-d) containing one stereogenic centre. The alcohol in X is protonated which makes it a good leaving group as water and therefore leads to the formation of the alkene product XII as shown in Scheme 4 [51,52]. It is therefore obvious that the presence of CF3 prevents the protonation of the alcohol to form the dehydrated products. This could be attributed to the electronic interaction between the OH and the highly electron-deficient carbon atom with three geminal fluorine atoms in CF3 which prevents the subsequent dehydration reaction as compared to the carbon atom in CH3. This has been found to occur in the reactions utilizing the diketones 3b-d. Variation of the para-

8

substituted aryl group on C(4) did not appear to influence the stereo- or enantioselectivity of the reaction.

Scheme 4: The dehydration step to form the DHPM products

Scheme 5: Synthesis of the tetrahydropyrimidinones/thiones. Reagents and conditions: CeCl3.7H2O, absolute EtOH, 65 oC, 3 h. The use of asymmetrical 1,3-dicarbonyl compounds in the Biginelli reaction could, theoretically, result in the formation of two possible structural isomers (Figure 2). In this case, the pyrimidine moiety may cyclize either at the α-C to the CF3 group or the α-C to the arene moiety, resulting in the formation of compounds of type A or B, respectively [33,34].

9

Figure 2: Products of possible isomers A and B. In agreement with the previous findings [33,34], based on the 1H-NMR and SCXRD data of compounds 6a-d and 7a-l, all of the synthesized pyrimidinones/thiones are of type A, with no form of type B that could be detected. Evident from the 1H-NMR spectra of 7a-l is that all of the pyrimidinone/thione products containing a C(6)-CF3 group stabilize the hydroxyl group against protonation for the dehydration step, unlike the products containing the CH3 group. The tetrahydro products gave rise to the two extra protons of OH and C(5)-H observed in the 1

H-NMR of 7a-l as compared to 6a-d with CH3 at position C(6). Contrary to the 1H-NMR

spectra of 6a-d, extra signals relating to the formation of two additional stereogenic centres (C(5) and C(6), three total) were seen by the observation of two additional signals: the first relating to the O-H moiety at either δH 7.16-7.37 ppm (pyrimidinones) or at δH 7.71-7.84 ppm (pyrimidinthiones), as well as a second signal relating to the C(5)-H moiety between δH 4.394.61 ppm. The 1H-NMR signal relating to the C(4)-H moiety of 7a-l shifted slightly upfield between δH 4.91-5.00 ppm as compared to δH 5.24-5.28 ppm of 6a-d, indicative of an increased shielding that C(4)-H experiences in compounds 7a-l. The increase in the chemical shift in 6a-d may be attributed to the reinforced magnetic anisotropy effect of the adjacent πelectrons of the allylic group at C-5 and C-6 and benzoyl group at C-5 which is in close proximity to C(4)-H. Even though 7a-l possess a CF3 group which is expected to exert a

10

strong inductive effect on adjacent protons, its far proximity to C(4)-H may render its influence less effective on this proton. Earlier reports on the splitting of both C6-CF3 and the CF3 carbon at position 6 in the

13

C-

NMR spectra into a quartet is well established [33,34]. This splitting was observed in compounds 3b-d as well as compounds 7a-l with similar coupling constants as reported in the literature. For instance, the C6-CF3 and CF3 signals in 13C appear at 81.9 ppm (2JCF =30.6 Hz) and 123.7 ppm (1JCF = 287.8 Hz) respectively in compound 7a. Furthermore, the presence of CF3 at position C(6) was established from the SCXRD structures of compounds 7c and 7g and from the

19

F-NMR of all the trifluorinated compounds at around δF -79 ppm. The

19

F-

NMR spectra of compounds 7e-h containing a para-fluoro functionality on the benzoyl group at C(5) exhibit an additional signal at around δF -105 ppm.

3.

SCXRD Structural Characterization

The X-ray structures of 6b and 6c confirmed their racemic nature by crystallising in the centrosymmetric space group P21/n. The (4R)-enantiomers of both 6b and 6c are shown in the perspective views of their molecular structures (Figure 3). In both structures, a distorted boat conformation of the heterocycle is seen with the plane through the four coplanar atoms forming a dihedral angle of -102.4(3)° (6b) and -101.01(16)° (6c) with the arene substituent of C(4), which adopts an axial orientation with respect to the mean plane of the heterocycle.

11

Figure 3: Molecular structures of compounds 6b (a) and 6c (b). Thermal ellipsoids are drawn at 50% level. For clarity, the co-crystallised EtOH molecule of 6b has been omitted.

The hydrogen atom of the chiral centre C(4) is situated on the opposite face relative to the substituted arene and aroyl groups. The mean plane of the pyrimidinone ring intersects the mean plane of the para-substituted arene on C(4) at 62.8(1)° (6b) and 62.8(1)° (6c) respectively, whereas the mean plane of the pyrimidinone intersects the mean plane of the 4'F arene on C(5) at 82.3(4)° (6b) and 79.6(5)° (6c) respectively. Apart from the obvious C2-X bond distance differences (X = S, 1.681(4) Å, 6b; X = O, 1.2344(19) Å, 6c), the only major difference in terms of molecular configuration is seen in the direction of distortion of the pyrimidinone heterocycle from the C4-C5-C6-C1 torsion angles (-177.8(3)° for 6b, 169.71(14)° for 6c). In both structures, intermolecular N-H···O and O-H···S hydrogen bonds form molecular dimers and also link these dimers to extend into a three-dimensional network. All other bond lengths and angles were observed to fall within the expected ranges [54].

Furthermore, the single crystal structures of 7c and 7g (Figure 4) unambiguously confirmed the predicted connectivity of the respective functional groups and is in agreement with the 12

previous findings [32,55–57]. All of the compounds 7a-l contain three chiral centres (C(4), C(5), C(6) atoms). The chiral configurations of both 7c and 7g have been assigned by means of SCXRD as (4R, 5R, 6S). However, since the single crystals of both 7c and 7g crystallized in the centrosymmetric monoclinic C2/c space group, both compounds crystallized as racemates, i.e. enantiomeric pairs of each compound were distinguished in the crystals. In fact, the asymmetric unit cell of 7c contained the pair of two isolated enantiomeric molecules. Unfortunately, no absolute configuration in any of the abovementioned crystal structures could be made because, in all of the above examples, the compounds crystallised in achiral, centrosymmetric (polar) space groups. An enantiomerically pure sample should crystallise in a non-centrosymmetric chiral space group and would usually have a Flack parameter of close to 0 (within standard uncertainty) for a particular conformation.

Figure 4: Molecular structures of compounds 7c (a) and 7g (b). Thermal ellipsoids are drawn at 50% level. An intramolecular hydrogen bond within 7g is shown as a blue line. For clarity, a molecule of co-crystallised CH2Cl2 within each of 7c and 7g has been omitted.

13

It does seem to be sterically unfavourable for the enantiomeric pure compound of the corresponding (4R, 5S, 6S)-diastereomers to exist because of the bulky nature of the substituted C(4)-arene and C(5)-aroyl moieties [33,58]. The structures of both 7c and 7g exhibit half-chair conformations with the heterocycle mean plane through the five coplanar atoms (C4-N3-C2-N1-C6) intersecting at 53.3(9)° (7c) and 49.9(5)° (7g) with the mean plane of the C4-C5-C6 inclined-section of the heterocycle, as well as forming a dihedral angle of 29.9(7)° (7c) and 25.0(4)° (7g) with C5. As can be expected [33], the benzoyl and aryl substituents of 7a-l all occupy equatorial positions within the heterocycle, which was confirmed by 1H-NMR with coupling constants (3JHH) of c.a. 11 Hz (C(4)-H, C(5)-H) [34,48], as well as crystallographically from their respective solid state structures. This is in agreement with the previously reported similar structures [32,55–57]. This is rationalized to be due to steric reasons where generally the group with higher conformational energy occupies the equatorial position which gives more stability in preference to the neighbouring group which occupies the axial position. By extension, the same argument is applicable to the preferential equatorial position of the CF3 group relative to the OH group (axial position) at C(6). Apart from the intramolecular O-H···O hydrogen bond present in 7g, several other sets of either two O-H···O or N-H···O hydrogen bonds form dimers with two pyrimidinone molecules, which extend to form a three-dimensional network by means of additional OH···O, N-H···O, or N-H···Cl hydrogen bonds. Additionally, the three-dimensional packing of pyrimidinones 6b, 6c, 7c, and 7g is illustrated in Figure 5. Within each structure, distinct intermolecular hydrogen bonds are observed, with the exception of 7g, which additionally exhibits O-H···O intramolecular hydrogen bonds to collectively extend in three dimensions to form a complex hydrogen-bonded network. The hydrogen-bonded network within each structure is unique in several ways: (i) Compound 6b

14

shows an

(12) network in a figure 8-type motif. This hydrogen-bonded ring consists of two

N-H···O and two O-H···S hydrogen bonds. Additionally, each sulphur atom acts as another hydrogen bond acceptor (C-H···S) from a third pyrimidinthione molecule. (ii) The hydrogen bond network of compound 6c differs from that of 6b in the sense that an

(8) network is

formed from two N-H···O bonds to form pairs of pyrimidinone dimers. In addition, the other N-H moiety of each pyrimidinone molecule forms an additional N-H···O hydrogen bond to other pyrimidinone molecules in an extended three-dimensional network. (iii) A similar network was observed with compound 7c by again observing an

(8) network consisting of

two N-H···O bonds. However, the carbonyl oxygen atom from each pyrimidinone molecule acts as a secondary intermolecular hydrogen bond acceptor from the alcohol moiety of another pyrimidinone molecule. (iv) By extension of the latter, compound 7g shows an interesting zig-zag hydrogen-bonded motif through alternating sets of

(8) networks.

However, in contrast to 7c, each carbonyl oxygen atom from each pyrimidinone molecule exhibits an intramolecular hydrogen bond involving the alcohol moiety of the same molecule, which then links to an adjacent pyrimidinone molecule through an

(4) network that

contains two bifurcate hydrogen bonds.

15

Figure 5: Packing diagrams of compounds 6b (a), 6c (b), 7c (c), and 7g (d), all viewed along the b-axis. Hydrogen bond interactions are indicated with the blue dotted lines.

4.

2D NMR Analysis of Compounds 6b and 7f

As mentioned above, the spectral data for the synthesized compounds were fully assigned using 1H,

13

C, COSY, HSQC and HMBC 2D NMR techniques. Compounds 6b and 7f

(Figure 6) were chosen as representative compounds. NMR data of previously reported similar structures were assigned based on 1D NMR techniques [33,34,59] and most did not explicitly assign all the five single protons in the tetrahydropyrimidinones/thiones. However, as for the use of 2D NMR techniques for similar structures, we could only find the work of Ryabukhin et al. [32], who utilized the Nuclear Overhauser Effect Spectroscopy (NOESY) 16

experiment to establish the relative configuration of the tetrahydropyrimidinones. We, therefore, opted for a structural comparison between the tetrahydropyrimidinthione 7f and DHPM 6b using different 1D and 2D NMR techniques. The 1H-NMR of compound 7f showed the presence of one 3H singlet at δH 3.62 ppm which was assigned to the methoxy at C21. Two 1H doublets were observed at δH 4.53 (3JHH = 11.5) and δH 4.92 ppm (3JHH = 11.5) with strong correlations in the COSY spectrum. Their coupling constant is indicative of the axial coupling [34] and this was corroborated by SCXRD. These were tentatively assigned as C5-H and C4-H, respectively. The peak at δH 4.53 ppm had a four-bond correlation with δH 7.74 ppm. The long-range coupling is possible because of the preferred half-chair conformation of the DHPM ring. Since the two singlets beyond δH 8 ppm could only be the amide NHs [60,61], therefore, the singlet at δH 7.74 ppm was assigned to the C6-OH while the correlating peaks at δH 4.53 and 4.92 ppm were assigned to the C5-H and C4-H respectively. In the aromatic region, there were strong correlations between the doublets at δH 6.73 and δH 7.32 ppm and between δH 7.19 and δH 7.86 ppm. The 13C peaks of the benzoyl group together with C6 and C7 were easily assigned based on their multiplicity and coupling constants, thanks to the heteronuclear coupling of carbon to the para-fluoro and CF3 group. As the coupling constant decreases with distance [60], the following peaks were assigned; C6 (δC 80.6, q, 2JCF = 31.1) [32,34], C11,13 (δC 115.8, d, 2JCF = 22.0), C7 (δC 123.0, q, 1JCF = 288.0) [32,34], C10,14 (δC 131.1, dd, 3JCF = 9.6), C9 (δC 134.1, 4JCF = 2.4), C12 (δC 165.1, d, 1JCF = 253.0). The HSQC spectra with one bond correlations were used for the following assignments as shown in Table 1. The

13

C peaks on the benzoyl group agreed with the initial assignments.

The remaining peaks of compound 7f were assigned based on the HMBC correlations as shown in Figure 6.

17

Table 1: Some 1H and 13C chemical shifts of compound 7f based on HSQC and HMBC No

1

C20

H

13

1

H

13

C

No

C

3.62

55.07

C15

128.85

C5

4.53

46.55

C18

159.11

C4

4.92

55.11

C2

176.82

C17,19

6.73

113.62

C8

193.69

C11,13

7.19

115.76

N3

8.99

C16,20

7.32

129.96

N1

9.00

C10,14

7.86

131.1

Figure 6: Some definitive HMBC correlations of compound 7f and 6b

The peaks of compound 6b were assigned as shown in Table 2 using the same procedure for compound 7f. Some definitive HMBC correlations for compound 6b are shown in Figure 6 above.

18

Table 2: 1H and 13C chemical shifts (in ppm) of compound 6b

1

No N1

13

H

C

10.31 (1H, d, J = 1.82 Hz) 174.4

C2 N3

9.62 (1H, dd, J = 3.5, 1.7 Hz)

C4

5.21 (1H, d, J = 3.4 Hz)

1

No

H

13

C

C10,14

7.58 (2H, dd, J = 8.6, 5.7 Hz

131.3 (d, J = 9.3 Hz )

C11,13

7.27 (2H, t, J = 8.8 Hz)

116.21 (d, J = 22.1 Hz)

C12

164.7 (d, J = 250.4 Hz)

55.4

C15

135.6

C5

110.7

C16,20

7.10 (2H, d, J = 8.7 Hz)

128.1

C6

141.7

C17,19

6.88 (2H, d, J = 8.7 Hz)

114.4

18.4

C18

C8

193.7

C21

C9

137.00 (d, J = 3.21 Hz)

1.73 (3H, s)

C7

159.2 3.70 (3H, s)

Interestingly, the HMBC spectra for compounds 6b and 7f displayed one-bond correlations (1JCH). In compound 7f, all the aromatic protons showed one-bond correlations while all the alkyl protons in compound 6b displayed one-bond correlations in addition to the aromatic protons. Furthermore, the 1JCH signals in 6b were all split at 90o by the alkyl protons. This 1

JCH correlation in HMBC is rarely observed and only occurs when its signals cannot be

suppressed in the HMBC experiment [62]. As expected, the 1H and

13

C peaks around the pyrimidinthione ring in 6b and 7f varied

depending on their relative position to the C5 and C6. Both the 1H peaks for N1 and N3 were more shielded in 7f than 6b and therefore appeared more upfield which suggests that the influence of the allylic group in 6b at C5 and C6 has a greater deshielding effect due to the magnetic anisotropy of the sp2-C, as alluded earlier. The

13

appeared slightly more downfield. In 6b, both the 1H and

C peak of the C=S at C2 in 7f

13

C peaks of C4 appeared more

19

downfield due to its simultaneous allylic and benzylic positions as compared to only the benzylic position in 7f. The 13C chemical shifts of C5 and C6 in 6b are far greater than 7f as expected because of the magnetic anisotropy of the sp2 C5 and C6 which is absent in sp3 carbons. 5.

Fluorescence Properties

To investigate the general fluorescence properties of the synthesized compounds, 6a, 6b and 7e, 7f were chosen as the representative compounds from the DHPM and tetrahydro products respectively (Figure 7). A molar concentration of 5x10-3 M of each compound was prepared in acetone and excited at a wavelength of 290 nm using a Horiba Fluoromax-4 spectrofluorometer equipped with a xenon lamp light source and a photomultiplier detector. DHPM compounds 6a and 6b with CH3 showed emission wavelengths at 434 and 433 nm respectively while the emission wavelengths of the tetrahydro products 7e and 7f with CF3 showed a hypsochromic shift at 414 and 420 nm respectively. In addition, the fluorescence intensities of the tetrahydro products 7e and 7f were far higher than that of the DHPMs 6a and 6b. Compounds 6a and 7e with the urea functionality showed higher intensities than their corresponding thiourea analogues 6b and 7f. These findings are in agreement with the earlier report of Vitório et al. that compounds with electron-withdrawing groups like CF3 show more fluorescence intensities than compounds with electron-donating groups like CH3 [63]. By implication, compounds with more electronegative oxygen would also show higher fluorescence intensities than their sulphur analogues.

20

Figure 7: Fluorescence spectra of 6a, 6b (a) and 7e, 7f (b) in acetone at an excitation wavelength of 290 nm

6.

Conclusions

Using the classical Biginelli reaction, sixteen new hydropyrimidinones/thiones were prepared. The dependence of the product type on the electronic nature of the substituent at the α-position to the carbonyl group of the diketone was established and the different products were structurally compared using SCXRD. The use of CeCl3 as the catalyst was established to give stable tetrahydropyrimidinones, in addition to its previous use for DHPM synthesis. However, its use did not influence the chemoselectivity of the reaction. The compounds were fully characterized using different two dimensional NMR techniques. The fluorobenzoyl group displayed interesting long-range coupling in the 1H and

13

C NMR together with the

uncommon one-bond correlations in the HMBC which did not interfere with the spectra interpretation. All the High Definition Mass Spectrometry (HDMS) data showed the expected masses for all the compounds with an additional proton in the positive mode except for

21

compound 7k which took up an extra sodium ion. The biological activities of the synthesized compounds are being investigated.

7.

Experimental

7.1

General

Gallenkamp melting point apparatus was used for the melting point determination in open capillary tubes and are uncorrected. 1H- and

13

C-NMR spectra were recorded on either a

Bruker Avance 400 (at 400.21 MHz for 1H and 100.64 MHz for 13C) or 300 (at 300.13 MHz for 1H and 75.48 MHz for 13C) spectrometers using CDCl3 or DMSO-d6 as solvents at room temperature. Chemical shifts were recorded as parts per million (ppm) using tetramethylsilane as an internal standard.

19

F-NMR was recorded on Bruker Avance 400 at

376.54 MHz using CFCl3 as an internal standard and recorded in ppm. 2D NMR experiments were recorded on Bruker Avance 400. Mass analyses were performed on Waters® Synapt G2 High Definition Mass Spectrometry (HDMS) system with flow injection analysis (FIA) using electrospray ionization (ESI) probe. The MS data were acquired and processed on MassLynx™ software (version 4.1). FT-IR measurements were made on a Bruker Alpha Platinum-ATR spectrometer as neat. All reagents and solvents were purchased from SigmaAldrich, South Africa and used without further purification.

7.2

X-ray crystallography

Single crystal diffraction of compounds 3b, 3d, 6b, 6c, 7c, and 7g was performed using Quazar multi-layer optics monochromated Mo Kα radiation (k = 0.71069 Å) on a Bruker D8 Venture Kappa geometry diffractometer with duo Iµs sources, a Photon 100 CMOS detector and APEX III control software [64]. All X-ray diffraction measurements were performed at 150(1) K. Data reduction was performed using SAINT+ [32] and the intensities were

22

corrected for absorption using SADABS [65]. All structures were solved by direct methods with SHELXS-97 [66] using the SHELXL-2014/7 [67] interface. All H atoms were placed in geometrically idealised positions and constrained to ride on their parent atoms. For data collection and refinement parameters, see Supplementary Information. The X-ray crystallographic coordinates for structures 3d, 6b, 6c, 7c, and 7g have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under CCDC deposition numbers 1920014-1920018. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

Synthesis of 1-(4'-fluorophenyl)butane-1,3-dione (3a): NaOEt (1.23 g, 18.13 mmol) was added to ethyl acetate (7.3 mL, 74.16 mmol) and the mixture was stirred at room temperature for 25 minutes. The resulting mixture was placed in an ice bath to which 4'-fluoroacetophenone (2.0 mL, 16.48 mmol) was slowly added and allowed to continue stirring. Et2O (5.0 mL) was added to the mixture after the formation of a precipitate, stirred for a while, and then allowed to stand for four hours at room temperature. The precipitate was filtered, washed with Et2O (3 x 10.0 mL) and dried. The solid obtained was dissolved in distilled water and acidified with glacial acetic acid (10.0 mL) to precipitate the product from solution. The precipitated product was filtered and dried to give the pure product. Orange solid; Yield: 37%; 1H NMR (400 MHz, CDCl3: δH 7.89 (dd, 3JHH = 8.9, 4JHF = 5.4 Hz, 2H, ArH), 7.12 (dd, 3

JHH = 9.0, 3JHF = 8.4 Hz, 2H, ArH), 6.13 (s, 1H, C=CH), 2.19 (s, 3H, CH3). 13C NMR (101

MHz, Chloroform-d): δC 192.9, 183.0, 165.3 (d, 1JCF = 253.5 Hz), 131.3 (d, 4JCF = 3.0 Hz), 129.5 (2C, d, 3JCF = 9.1 Hz), 115.8 (2C, d, 2JCF = 21.9 Hz), 96.4, 25.6.

General procedure for the synthesis of substituted diketones 3b-d (3d as example): 4'chloroacetophenone (0.50 mL, 3.86 mmol) was added to a solution of ethyl trifluoroacetate

23

(0.5 mL, 4.20 mmol) containing 5.4 M sodium methoxide (0.8 mL, 4.60 mmol) in ethanol (8.0 mL). The reaction mixture was stirred at room temperature for 3 hours, after which the mixture was diluted with cold water and 2 N HCl (5.0 mL). The resulting mixture was left to stand overnight to obtain a precipitate. The precipitate was filtered, washed with cold water and air dried to give the pure compound. 4,4,4-trifluoro-1-phenylbutane-1,3-dione (3b): White crystals; Yield: 97%; m.p. 37-39 oC (lit.: 38-40 oC). 1H NMR (400 MHz, CDCl3): δH 7.96 (m, 2H, ArH), 7.64 (m, 1H, ArH), 7.52 (dd, 3JHH = 8.5, 3JHH = 7.1 Hz, 2H, ArH), 6.58 (s, 1H, C=CH).

13

C NMR (101 MHz,

Chloroform-d) δC 186.2, 177.4 (q, 2JCF = 36.3 Hz), 134.1, 132.9, 129.0 (2C), 127.6 (2C), 117.2 (q, 1JCF = 283.4 Hz), 92.3 (q, 3JCF = 2.1 Hz). 1-(4'-fluorophenyl)-4,4,4-trifluorobutane-1,3-dione (3c): Colourless crystals; Yield: 95%; m.p. 40-42 oC (lit.: 42-43 oC). 1H NMR (400 MHz, CDCl3): δH 8.00 (m, 2H, ArH), 7.19 (m, 2H, ArH), 6.53 (s, 1H, C=CH). 13C NMR (101 MHz, Chloroform-d): δC 185.3, 176.7 (q, 2JCF = 36.4 Hz), 166.4 (d, 1JCF = 257.1 Hz), 130.3 (2C, d, 3JCF = 9.5 Hz), 129.3 (d, 4JCF = 3.2 Hz), 117.2 (q, 1JCF = 282.9 Hz), 116.4 (2C, d, 2JCF = 22.2 Hz), 92.2 (d, 3JCF = 2.1 Hz). 1-(4'-chlorophenyl)-4,4,4-trifluorobutane-1,3-dione (3d): Yellow solid; Yield: 86%; m.p. 6062 oC (lit.: 63-64 oC). 1H NMR (400 MHz, CDCl3): δH 7.91 (m, 2H, ArH), 7.50 (m, 2H, ArH), 6.54 (s, 1H, C=CH). 13C NMR (101 MHz, CDCl3): δC 184.9, 177.4 (q, 2JCF = 36.4 Hz), 140.6, 131.3, 129.4 (2C), 128.9 (2C), 117.1 (q, 1JCF = 283.2 Hz), 92.3 (q, 3JCF = 2.1 Hz).

General procedure for the synthesis of 6-methyl-3,4-dihydropyrimidinones/thiones (6a-d) (6c as

example):

1-(4'-fluorophenyl)butane-1,3-dione (3a,

50

mg,

0.278

mmol),

4'-

Chlorobenzaldehyde (39.1 mg, 0.278 mmol) and urea (50 mg, 0.833 mmol) were added to ethanol (1.0 mL), followed by the addition of CeCl3.7H2O (25 mol%). The reaction mixture was refluxed at 65 oC for 3 hours. The mixture was allowed to cool to room temperature and

24

poured into crushed ice, stirred for 10 minutes, filtered, washed with cold water and air dried. The solid obtained was recrystallized from hot ethanol to obtain the pure product. 4-(4'-methoxyphenyl)-5-(4'-fluorobenzoyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one

(6a):

Yellow solid; Yield: 84%; m.p. 215-217 oC. FT-IR: ν (cm-1) = 3333 (NH), 3065 (CH), 1688 (C=OPh), 1607 (C=O), 1507 (C=C). 1H NMR (400 MHz, DMSO-d6): δH 9.16 (d, 4JHH = 1.9 Hz, 1H, NH), 7.75 (dd, 3JHH = 3.3, 4JHH = 2.0 Hz, 1H, NH), 7.53 (dd, 3JHH = 8.7, 4JHF = 5.6 Hz, 2H, ArH), 7.26 (t, 3JHH,HF = 8.8 Hz, 2H, ArH), 7.12 (d, 3JHH = 8.7 Hz, 2H, ArH), 6.86 (d, 3

JHH = 8.7 Hz, 2H, ArH), 5.24 (d, 3JHH = 3.1 Hz, 1H, CH), 3.70 (s, 3H, OCH3), 1.68 (s, 3H,

CH3).

13

C NMR (101 MHz, DMSO-d6): δC 193.6, 164.4 (d, 1JCF = 249.5 Hz), 158.9, 152.6,

145.4, 137.8 (d, 4JCF = 2.9 Hz), 136.8, 131.1 (2C, d, 3JCF = 9.0 Hz), 127.9 (2C), 116.1 (2C, d, 2

JCF = 21.9 Hz), 114.2 (2C), 109.9, 55.5, 55.2, 19.0. ESI-HDMS (m/z) calculated for

C19H17FN2O3: 340.1223, found: 341.1284 (M+H)+. 4-(4'-methoxyphenyl)-5-(4'-fluorobenzoyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-thione (6b): Yellow solid; Yield: 85%; m.p. 205-207 oC. FT-IR: ν (cm-1) = 3280 (NH), 3168 (CH), 1572 (C=OPh), 1460 (C=C), 1188 (C=S). 1H NMR (400 MHz, DMSO-d6): δH 10.31 (d, 4JHH = 1.8 Hz, 1H, NH), 9.62 (dd, 3JHH = 3.5, 4JHH = 1.7 Hz, 1H, NH), 7.58 (dd, 3JHH = 8.6, 4JHF = 5.6 Hz, 2H, ArH), 7.27 (t, 3JHH,HF = 8.8 Hz, 2H, ArH), 7.10 (d, 3JHH = 8.7 Hz, 2H, ArH), 6.88 (d, 3

JHH = 8.7 Hz, 2H, ArH), 5.21 (d, 3JHH = 3.4 Hz, 1H, CH), 3.70 (s, 3H, OCH3), 1.73 (s, 3H,

CH3).

13

C NMR (101 MHz, DMSO-d6): δC 193.7, 174.4, 164.7 (d, 1JCF = 250.4 Hz), 159.2,

141.7, 137.0 (d, 4JCF = 3.2 Hz), 135.6, 131.3 (2C, d, 3JCF = 9.3 Hz), 128.1 (2C), 116.2 (2C, d, 2

JCF = 22.0 Hz), 114.4 (2C), 110.7, 55.5, 55.4, 18.4. ESI-HDMS (m/z) calculated for

C19H17FN2O2S: 356.0995, found: 357.1063 (M+H)+. 4-(4'-chlorophenyl)-5-(4'-fluorobenzoyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one

(6c):

Orange crystals; Yield: 66%; m.p. 235-237 oC. FT-IR: ν (cm-1) = 3324 (NH), 3073 (CH), 1699 (C=OPh), 1593 (C=O), 1496 (C=C). 1H NMR (400 MHz, DMSO-d6): δH 9.26 (d, 4JHH =

25

1.9 Hz, 1H, NH), 7.85 (dd, 3JHH = 3.4, 4JHH = 2.0 Hz, 1H, NH), 7.55 (m, 2H, ArH), 7.38 (m, 2H, ArH), 7.28 (m, 2H, ArH), 7.24 (m, 2H, ArH), 5.28 (d, 3JHH = 3.2 Hz, 1H, CH), 1.68 (s, 3H, CH3).

13

C NMR (101 MHz, DMSO-d6): δC 193.3, 164.4 (d, 1JCF = 249.6 Hz), 152.4,

146.4, 143.6, 137.9 (d, 4JCF = 3.0 Hz), 132.3, 131.1 (2C, d, 3JCF = 9.0 Hz), 128.9 (2C), 128.7 (2C), 116.1 (2C, d, 2JCF = 21.8 Hz), 109.3, 55.2, 19.2. ESI-HDMS (m/z) calculated for C18H14ClFN2O2: 344.0728, found: 345.0774 (M+H)+. 4-(4'-chlorophenyl)-5-(4'-fluorobenzoyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-thione

(6d):

Yellow solid; Yield: 67%; m.p. 227-228 oC. FT-IR: ν (cm-1) = 3296 (NH), 3080 (CH), 1570 (C=OPh), 1202 (C=S). 1H NMR (300 MHz, DMSO-d6, ppm) δH 10.41 (s, 1H, NH), 9.72 (s, 1H, NH), 7.60 (dd, 3JHH = 8.3, 4JHF = 5.7 Hz, 2H, ArH), 7.41 (d, 3JHH = 8.3 Hz, 2H, ArH), 7.28 (t, 3JHH,HF = 8.8 Hz, 2H, ArH), 7.22 (d, 3JHH = 8.4 Hz, 2H, ArH), 5.27 (s, 1H, CH), 1.72 (s, 3H, CH3).

13

C NMR (75 MHz, DMSO-d6): δC 193.5, 174.7, 164.7 (d, 1JCF = 250.5 Hz),

142.7, 142.3, 137.0 (d, 4JCF = 3.0 Hz), 132.8, 131.4 (2C, d, 3JCF = 9.2 Hz), 129.1 (2C), 128.8 (2C), 116.2 (2C, d, 2JCF = 21.8 Hz), 110.0, 55.2, 18.6. ESI-HDMS (m/z) calculated for C18H14ClFN2OS: 360.0499, found: 361.0588 (M+H)+. General procedure for the synthesis of trifluoro-tetrahydropyrimidinones/thiones (7a-l) (7i as example): 1-(4'-Chlorophenyl)-4,4,4-trifluorobutane-1,3-dione (150.0 mg, 0.60 mmol), 4'methoxybenzaldehyde (73.0 µL, 0.60 mmol) and urea (108.0 mg, 1.80 mmol) were added to ethanol (2.0 mL), followed by the addition of CeCl3.7H2O (25 mol%). The reaction mixture was refluxed at 65 oC for 3 hours. The mixture was allowed to cool to room temperature and poured into crushed ice, stirred for 10 minutes, filtered, washed with cold water and air dried. The solid obtained was recrystallized from hot ethanol to obtain the pure product. 5-benzoyl-4-hydroxy-6-(4'-methoxyphenyl)-4-(trifluoromethyl)tetrahydropyrimidin-2(1H)one (7a): White solid; Yield: 81%. m.p. 199-200 oC. FT-IR: ν (cm-1) = 3373 (NH), 3220 (OH), 3072 (CH), 1668 (C=OPh), 1505 (C=O), 1339 (C=C), 1168 (CF). 1H NMR (400 MHz,

26

DMSO-d6): δH 7.72 (m, 2H, ArH), 7.69 (d, 4JHH = 1.5 Hz, 1H, NH), 7.52 (m, 1H, ArH), 7.38 (m, 2H, ArH), 7.30 (m, 2H, ArH), 7.21 (s, 1H, OH), 7.16 (d, 4JHH = 1.7 Hz, 1H, NH), 6.73 (d, 3

JHH = 8.8 Hz, 2H, ArH), 4.93 (d, 3JHH = 11.2 Hz, 1H, CH), 4.39 (d, 3JHH = 11.2 Hz, 1H, CH),

3.61 (s, 3H, OCH3). 13C NMR (101 MHz, DMSO-d6): δC 196.3, 159.3, 154.3, 137.8, 133.7, 130.7, 130.0 (2C), 129.0 (2C), 128.2 (2C), 123.7 (q, 1JCF = 287.8 Hz), 113.9 (2C), 81.9 (q, 2

JCF = 30.7 Hz), 55.4, 54.4, 48.5. 19F NMR (377 MHz, DMSO): δF -79.84. ESI-HDMS (m/z)

calculated for C19H17F3N2O4: 394.1140, found: 395.1224 (M+H)+. 5-benzoyl-4-hydroxy-6-(4'-methoxyphenyl)-4-(trifluoromethyl)tetrahydropyrimidin-2(1H)thione (7b): White solid; Yield: 77%; m.p. 203-205 oC. FT-IR: ν (cm-1) = 3382 (NH), 3179 (OH), 2923 (CH), 1679 (C=OPh), 1509 (C=C), 1253 (C=S), 1182 (CF). 1H NMR (400 MHz, DMSO-d6): δH 9.01 (s, 1H, NH), 8.98 (s, 1H, NH), 7.75 (d, 3JHH = 7.4 Hz, 2H, ArH), 7.71 (s, 1H, OH), 7.51 (t, 3JHH = 7.4 Hz, 1H, ArH), 7.37 (t, 3JHH = 7.8 Hz, 2H, ArH), 7.32 (d, 3JHH = 8.7 Hz, 2H, ArH), 6.74 (d, 3JHH = 8.7 Hz, 2H, ArH), 4.94 (d, 3JHH = 11.5 Hz, 1H, CH), 4.53 (d, 3JHH = 11.5 Hz, 1H, CH), 3.62 (s, 3H, OCH3). 13C NMR (101 MHz, DMSO-d6): δC 195.4, 177.2, 159.4, 137.7, 133.8, 130.3 (2C), 129.3, 129.0 (2C), 128.3 (2C), 123.3 (q, 1JCF = 287.7 Hz), 114.0 (2C), 81.1 (q, 2JCF = 31.1 Hz), 55.5, 55.4, 46.9. 19F NMR (377 MHz, DMSO): δF 78.88. ESI-HDMS (m/z) calculated for C19H17F3N2O3S: 410.0912, found: 411.1029 (M+H)+. 5-benzoyl-4-hydroxy-6-(4'-chlorophenyl)-4-(trifluoromethyl)tetrahydropyrimidin-2(1H)-one (7c): White solid; Yield: 80%; m.p. 198-200 oC. FT-IR: ν (cm-1) = 3528 (NH), 3227 (OH), 3095 (CH), 1665 (C=OPh), 1490 (C=O), 1445 (C=C), 1173 (CF). 1H NMR (400 MHz, DMSO-d6): δH 7.79 (s, 1H, NH), 7.71 (m, 2H, ArH), 7.52 (m, 1H, ArH), 7.44 (d, 3JHH = 8.6 Hz, 2H, ArH), 7.37 (m, 2H, ArH), 7.31 (s, 1H, NH), 7.30 (s, 1H, OH), 7.24 (d, 3JHH = 8.5 Hz, 2H, ArH), 4.98 (d, 3JHH = 11.1 Hz, 1H, CH), 4.44 (d, 3JHH = 11.1 Hz, 1H, CH).

13

C NMR

(101 MHz, DMSO-d6): δC 196.0, 154.2, 137.9, 137.7, 133.9, 133.0, 130.8 (2C), 129.1 (2C), 128.6 (2C), 128.2 (2C), 123.6 (q, 1JCF = 287.7 Hz), 81.9 (q, 2JCF = 30.8 Hz), 54.5, 48.3. 19F

27

NMR (377 MHz, DMSO): δF -79.77. ESI-HDMS (m/z) calculated for C18H14ClF3N2O3: 398.0645, found: 399.0747 (M+H)+. 5-benzoyl-4-hydroxy-6-(4'-chlorophenyl)-4-(trifluoromethyl)tetrahydropyrimidin-2(1H)thione (7d): White solid; Yield: 83%; m.p. 215-216 oC. FT-IR: ν (cm-1) = 3373 (NH), 3177 (OH), 3049 (CH), 1679 (C=OPh), 1496 (C=C), 1195 (CF), 1083 (C=S). 1H NMR (400 MHz, DMSO-d6): δH 9.15 (s, 1H, NH), 9.10 (s, 1H, NH), 7.79 (s, 1H, OH), 7.77 (m, 2H, ArH), 7.53 (m, 1H, ArH), 7.45 (d, 3JHH = 8.5 Hz, 2H, ArH), 7.37 (m, 2H, ArH), 7.26 (d, 3JHH = 8.5 Hz, 2H, ArH), 5.00 (d, 3JHH = 11.5 Hz, 1H, CH), 4.58 (d, 3JHH = 11.5 Hz, 1H, CH).

13

C NMR

(101 MHz, DMSO-d6): δC 195.3, 177.3, 137.6, 136.5, 134.0, 133.3, 131.1 (2C), 129.1 (2C), 128.6 (2C), 128.3 (2C), 123.3 (q, 1JCF = 288.0 Hz), 80.9 (q, 1JCF = 31.2 Hz), 55.4, 46.7. 19F NMR (377 MHz, DMSO): δF -78.82. ESI-HDMS (m/z) calculated for C18H14ClF3N2O2S: 414.0417, found: 415.0452 (M+H)+. 5-(4'-fluorobenzoyl)-4-hydroxy-6-(4'-methoxyphenyl)-4 (trifluoromethyl)tetrahydropyrimidin2(1H)-one (7e): White solid; Yield: 76%; m.p. 185-186 oC. FT-IR: ν (cm-1) = 3444 (NH), 3203 (OH), 3072 (CH), 1661 (C=OPh), 1600 (C=O), 1507 (C=C), 1179 (CF). 1H NMR (400 MHz, DMSO-d6): δH 7.82 (m, 2H, ArH), 7.72 (d, 4JHH = 1.7 Hz, 1H, NH), 7.32 (m, 2H, ArH), 7.23 (s, 1H, OH), 7.20 (m, 2H, ArH), 7.16 (d, 4JHH = 1.9 Hz, 1H, NH), 6.73 (d, 3JHH = 8.8 Hz, 2H, ArH), 4.91 (d, 3JHH = 11.1 Hz, 1H, CH), 4.41 (d, 3JHH = 11.1 Hz, 1H, CH), 3.62 (s, 3H, OCH3). 13C NMR (101 MHz, DMSO-d6): δC 194.9, 165.4 (d, 1JCF = 252.8 Hz), 159.3, 154.3, 134.6 (d, 4JCF = 2.7 Hz), 131.3 (2C, d, 3JCF = 9.6 Hz), 130.6, 130.0 (2C), 123.7 (q, 1JCF = 287.5 Hz), 116.1 (2C, d, 2JCF = 21.9 Hz), 113.9 (2C), 81.7 (q, 2JCF = 30.8 Hz), 55.4, 54.4, 48.5.

19

F NMR (377 MHz, DMSO): δF -79.81, -105.62. ESI-HDMS (m/z) calculated for

C19H16F4N2O4: 412.1046, found: 413.1072 (M+H)+. 5-(4'-fluorobenzoyl)-4-hydroxy-6-(4'-methoxyphenyl)-4 (trifluoromethyl)tetrahydropyrimidin2(1H)-thione (7f): White solid; Yield: 62%; m.p. 182-183 oC. FT-IR: ν (cm-1) = 3396 (NH),

28

3171 (OH), 3075 (CH), 1679 (C=OPh), 1505 (C=C), 1248 (C=S), 1189 (CF). 1H NMR (400 MHz, DMSO-d6): δH 9.00 (s, 1H, NH), 8.99 (s, 1H, NH), 7.86 (dd, 3JHH = 8.9, 4JHF = 5.5 Hz, 2H, ArH), 7.74 (s, 1H, OH), 7.32 (d, 3JHH = 8.7 Hz, 2H, ArH), 7.19 (t, 3JHH,HF = 8.8 Hz, 2H, ArH), 6.73 (d, 3JHH = 8.7 Hz, 2H, ArH), 4.92 (d, 3JHH = 11.5 Hz, 1H, CH), 4.53 (d, 3JHH = 11.5 Hz, 1H, CH), 3.62 (s, 3H, OCH3).

13

C NMR (101 MHz, DMSO-d6): δC 194.0, 177.2,

165.5 (d, 1JCF = 253.0 Hz), 159.5, 134.4 (d, 4JCF = 2.4 Hz), 131.4 (2C, d, 3JCF = 9.5 Hz), 130.3 (2C), 129.2, 123.3 (q, 1JCF = 287.9 Hz), 116.1 (2C, d, 2JCF = 22.0 Hz), 114.0 (2C), 81.0 (q, 2

JCF = 31.1 Hz), 55.5, 55.4, 46.9.

19

F NMR (377 MHz, DMSO): δF -78.86, -105.42. ESI-

HDMS (m/z) calculated for C19H16F4N2O3S: 428.0818, found: 429.0908 (M+H)+. 5-(4'-fluorobenzoyl)-4-hydroxy-6-(4'-chlorophenyl)-4-(trifluoromethyl)tetrahydropyrimidin2(1H)-one (7g): White solid; Yield: 82%; m.p. 180-182 oC. FT-IR: ν (cm-1) = 3418 (NH), 3199 (OH), 3067 (CH), 1657 (C=OPh), 1597 (C=O), 1491 (C=C), 1192 (CF). 1H NMR (400 MHz, DMSO-d6): δH 7.84 (m, 2H, ArH), 7.80 (d, 4JHH = 1.7 Hz, 1H, NH), 7.44 (d, 3JHH = 8.5 Hz, 2H, ArH), 7.32 (s, 1H, OH), 7.30 (d, 4JHH = 1.7 Hz, 1H, NH), 7.24 (d, 3JHH = 8.6 Hz, 2H, ArH), 7.20 (t, 3JHH,HF = 8.8 Hz, 2H, ArH), 4.97 (d, 3JHH = 11.1 Hz, 1H, CH), 4.46 (d, 3JHH = 11.1 Hz, 1H, CH).

13

C NMR (101 MHz, DMSO-d6): δC 194.6, 165.5 (d, 1JCF = 253.1 Hz),

154.2, 137.8, 134.5 (d, 4JCF = 2.6 Hz), 133.0, 131.4 (2C, d, 3JCF = 9.4 Hz), 130.8 (2C), 128.6 (2C), 123.6 (q, 1JCF = 288.2 Hz), 116.2 (2C, d, 2JCF = 22.0 Hz), 81.9 (q, 2JCF = 30.7 Hz), 54.4, 48.3.

19

F NMR (377 MHz, DMSO): δF -79.73, -105.31. ESI-HDMS (m/z) calculated for

C18H13ClF4N2O3: 416.0551, found: 417.0590 (M+H)+. 5-(4'-fluorobenzoyl)-4-hydroxy-6-(4'-chlorophenyl)-4-(trifluoromethyl)tetrahydropyrimidin2(1H)-thione (7h): White solid; Yield: 79%; m.p. 191-192 oC. FT-IR: ν (cm-1) = 3394 (NH), 3175 (OH), 3075 (CH), 1681 (C=OPh), 1490 (C=C), 1245 (C=S), 1191 (CF). 1H NMR (400 MHz, DMSO-d6): δH 9.15 (s, 1H, NH), 9.12 (s, 1H, NH), 7.89 (dd, 3JHH = 8.9, 4JHF = 5.5 Hz, 2H, ArH), 7.80 (s, 1H, OH), 7.46 (d, 3JHH = 8.5 Hz, 2H, ArH), 7.26 (d, 3JHH = 8.6 Hz, 2H,

29

ArH), 7.20 (t, 3JHH,HF = 8.8 Hz, 2H, ArH), 4.99 (d, 3JHH = 11.5 Hz, 1H, CH), 4.61 (d, 3JHH = 11.5 Hz, 1H, CH). 13C NMR (101 MHz, DMSO-d6): δC 193.9, 177.3, 165.6 (d, 1JCF = 253.2 Hz), 136.5, 134.4 (d, 4JCF = 2.6 Hz), 133.3, 131.5 (2C, d, 3JCF = 9.5 Hz), 131.1 (2C), 128.6 (2C), 123.3 (q, 1JCF = 288.0 Hz), 116.2 (2C, d, 2JCF = 21.9 Hz), 80.9 (q, 2JCF = 31.3 Hz), 55.4, 46.7.

19

F NMR (377 MHz, DMSO): δF -78.75, -105.15. ESI-HDMS (m/z) calculated for

C18H13ClF4N2O2S: 432.0322, found: 433.0363 (M+H)+. 5-(4'-chlorobenzoyl)-4-hydroxy-6-(4'-methoxyphenyl)-4(trifluoromethyl)tetrahydropyrimidin-2(1H)-one (7i): White solid; Yield: 92%; m.p. 198-199 o

C. FT-IR: ν (cm-1) = 3438 (NH), 3205 (OH), 3066 (CH), 1656 (C=OPh), 1610 (C=O), 1492

(C=C), 1174 (CF). 1H NMR (400 MHz, DMSO-d6): δH 7.75 (s, 1H, NH), 7.73 (d, 3JHH = 8.73, 2H, ArH), 7.44 (d, 3JHH = 8.7 Hz, 2H, ArH), 7.31 (d, 3JHH = 8.8 Hz, 2H, ArH), 7.28 (s, 1H, NH), 7.16 (s, 1H, OH), 6.73 (d, 3JHH = 8.7 Hz, 2H, ArH), 4.91 (d, 3JHH = 11.1 Hz, 1H, CH), 4.39 (d, 3JHH = 11.4, 1H, CH), 3.62 (s, 3H, OCH3). 13C NMR (101 MHz, DMSO-d6): δC 195.1, 159.3, 154.3, 138.8, 136.4, 130.5, 130.2 (2C), 130.0 (2C), 129.2 (2C), 123.6 (q, 1JCF = 287.7 Hz), 114.0, 81.7 (q, 2JCF = 30.8 Hz), 55.4, 54.3, 48.6. 19F NMR (377 MHz, DMSO): δF -79.78. ESI-HDMS (m/z) calculated for C19H16ClF3N2O4: 428.0751, found: 429.0817 (M+H)+. 5-(4'-chlorobenzoyl)-4-hydroxy-6-(4'-methoxyphenyl)-4(trifluoromethyl)tetrahydropyrimidin-2(1H)-thione (7j): White solid; Yield: 89%; m.p. 198200 oC. FT-IR: ν (cm-1) = 3422 (NH), 3178 (OH), 3077 (CH), 1686 (C=OPh), 1492 (C=C), 1247 (C=S), 1177 (CF). 1H NMR (400 MHz, DMSO-d6): δH 9.02 (s, 1H, NH), 9.00 (s, 1H, NH), 7.80 (d, 3JHH = 8.5 Hz, 2H, ArH), 7.77 (s, 1H, OH), 7.44 (d, 3JHH = 8.5 Hz, 2H, ArH), 7.33 (d, 3JHH = 8.7 Hz, 2H, ArH), 6.74 (d, 3JHH = 8.8 Hz, 2H, ArH), 4.93 (d, 3JHH = 11.5 Hz, 1H, CH), 4.55 (d, 3JHH = 11.5 Hz, 1H, CH), 3.63 (s, 3H, OCH3).

13

C NMR (101 MHz,

DMSO-d6): δC 194.4, 177.1, 159.5, 138.9, 136.3, 130.3 (2C), 130.3 (2C), 129.2 (2C), 129.2,

30

123.3 (q, 1JCF = 288.0 Hz), 114.0 (2C), 80.9 (q, 2JCF = 31.3 Hz), 55.4, 55.4, 47.0.

19

F NMR

(377 MHz, DMSO): δF -78.80. ESI-HDMS (m/z) calculated for C19H16ClF3N2O3S: 444.0522, found: 445.0643 (M+H)+. 5-(4'-chlorobenzoyl)-4-hydroxy-6-(4'-chlorophenyl)-4-(trifluoromethyl)tetrahydropyrimidin2(1H)-one (7k): White solid; Yield: 96%; m.p. 200-202 oC. FT-IR: ν (cm-1) = 3420 (NH), 3200 (OH), 3069 (CH), 1657 (C=OPh), 1592 (C=O), 1487 (C=C), 1187 (CF). 1H NMR (400 MHz, DMSO-d6): δH 7.81 (d, 4JHH = 1.7 Hz, 1H, NH), 7.76 (d, 3JHH = 8.7 Hz, 2H, ArH), 7.45 (d, 3JHH = 8.7 Hz, 2H, ArH), 7.44 (d, 3JHH = 8.6 Hz, 2H, ArH), 7.37 (s, 1H, OH), 7.30 (d, 4JHH = 1.7 Hz, 1H, NH), 7.25 (d, 3JHH = 8.5 Hz, 2H, ArH), 4.97 (d, 3JHH = 11.0 Hz, 1H, CH), 4.45 (d, 3JHH = 11.2 Hz, 1H, CH). 13C NMR (101 MHz, DMSO-d6): δC 194.9, 154.2, 139.0, 137.7, 136.3, 133.1, 130.8 (2C), 130.2 (2C), 129.3 (2C), 128.6 (2C), 123.6 (q, 1JCF = 287.7 Hz), 81.8 (q, 2JCF = 30.8 Hz), 54.4, 48.5.

19

F NMR (377 MHz, DMSO): δF -79.72. ESI-HDMS (m/z)

calculated for C18H13Cl2F3N2O3: 432.0255, found: 455.0177 (M+Na)+. 5-(4'-chlorobenzoyl)-4-hydroxy-6-(4'-chlorophenyl)-4-(trifluoromethyl)tetrahydropyrimidin2(1H)-thione (7l): White solid; Yield: 91%; m.p. 204-205 oC. FT-IR: ν (cm-1) = 3339 (NH), 3172 (OH), 3078 (CH), 1686 (C=OPh), 1488 (C=C), 1191 (CF), 1084 (C=S). 1H NMR (400 MHz, DMSO-d6) δH 9.15 (s, 1H, NH), 9.14 (s, 1H, NH), 7.84 (s, 1H, OH), 7.82 (d, 3JHH = 8.7 Hz, 2H, ArH), 7.46 (d, 3JHH = 8.6 Hz, 2H, ArH), 7.45 (d, 3JHH = 8.7 Hz, 2H, ArH), 7.26 (d, 3

JHH = 8.5 Hz, 2H, ArH), 4.99 (d, 3JHH = 11.4 Hz, 1H, CH), 4.61 (d, 3JHH = 11.5 Hz, 1H,

ArH).

13

C NMR (101 MHz, DMSO-d6): δC 194.3, 177.3, 139.1, 136.4, 136.2, 133.3, 131.1

(2C), 130.3 (2C), 129.3 (2C), 128.6 (2C), 123.3 (q, 1JCF = 288.3 Hz), 80.9 (q, 2JCF = 31.4 Hz), 55.4, 46.8.

19

F NMR (377 MHz, DMSO): δF -78.71. ESI-HDMS (m/z) calculated for

C18H13Cl2F3N2O2S: 448.0027, found: 449.0084 (M+H)+.

31

Acknowledgement We are grateful to the National Research Foundation (South Africa) (Grant number: 105152) and the University of Pretoria, South Africa for their financial supports.

References [1]

S.S. Maurya, S.I. Khan, A. Bahuguna, D. Kumar, D.S. Rawat, Synthesis, antimalarial activity, heme binding and docking studies of N -substituted 4-aminoquinolinepyrimidine molecular hybrids, Eur. J. Med. Chem. 129 (2017) 175–185. doi:10.1016/j.ejmech.2017.02.024.

[2]

A. Mobinikhaledi, M. Zendehdel, M.H. Nasab, M.A.B. Fard, An efficient synthesis of some novel bicyclic thiazolopyrimidine derivatives, Heterocycl. Commun. 15 (2009) 451–458. doi:10.1515/HC.2009.15.6.451.

[3]

J.-P. Wan, Y. Lin, Y. Liu, Catalytic Asymmetric Biginelli Reaction for the Enantioselective Synthesis of 3,4- Dihydropyrimidinones (DHPMs), Curr. Org. Chem. 18 (2014) 687–699. doi:10.2174/138527281806140415235855.

[4]

S.K. Guchhait, G. Priyadarshani, Synthesis of 2-Arylpyridopyrimidinones, 6Aryluracils, and Tri- and Tetrasubstituted Conjugated Alkenes via Pd-Catalyzed Enolic C-O Bond Activation-Arylation, J. Org. Chem. 80 (2015) 6342–6349. doi:10.1021/acs.joc.5b00771.

[5]

P.Z. Zhang, J.A. Li, L. Zhang, A. Shoberu, J.P. Zou, W. Zhang, Metal-free radical C-H methylation of pyrimidinones and pyridinones with dicumyl peroxide, Green Chem. 19 (2017) 919–923. doi:10.1039/c6gc03355e.

[6]

K. Kaur, M. Jain, R.P. Reddy, R. Jain, Quinolines and structurally related heterocycles as antimalarials, Eur. J. Med. Chem. 45 (2010) 3245–3264. doi:10.1016/j.ejmech.2010.04.011.

[7]

D.H. Slee, Y. Chen, X. Zhang, M. Moorjani, M.C. Lanier, E. Lin, J.K. Rueter, J.P. Williams, S.M. Lechner, S. Markison, S. Malany, M. Santos, R.S. Gross, K. Jalali, Y. Sai, Z. Zuo, C. Yang, J.C. Castro-Palomino, M.I. Crespo, M. Prat, S. Gual, J.L. Díaz, J. Saunders, 2-Amino-N-pyrimidin-4-ylacetamides as A2A Receptor Antagonists: 1. Structure-Activity Relationships and Optimization of Heterocyclic Substituents, J. Med. Chem. 51 (2008) 1719–1729. doi:10.1021/jm701185v.

[8]

H.G.O. Alvim, T.B. Lima, A.L. De Oliveira, H.C.B. De Oliveira, F.M. Silva, F.C. Gozzo, R.Y. Souza, W.A. Da Silva, B.A.D. Neto, Facts, presumptions, and myths on the solvent-free and catalyst-free Biginelli reaction. What is catalysis for?, J. Org. Chem. 79 (2014) 3383–3397. doi:10.1021/jo5001498.

[9]

L.M. Ramos, A.Y. Ponce De Leon Y Tobio, M.R. Dos Santos, H.C.B. De Oliveira, A.F. Gomes, F.C. Gozzo, A.L. De Oliveira, B.A.D. Neto, Mechanistic Studies on Lewis Acid Catalyzed Biginelli Reactions in Ionic Liquids: Evidence for the Reactive Intermediates and the Role of the Reagents, J. Org. Chem. 77 (2012) 10184–10193. doi:10.1021/jo301806n. 32

[10] B. China Raju, R. Nageswara Rao, P. Suman, P. Yogeeswari, D. Sriram, T.B. Shaik, S.V. Kalivendi, Synthesis, structure-activity relationship of novel substituted 4Hchromen-1,2,3,4-tetrahydropyrimidine-5-carboxylates as potential anti-mycobacterial and anticancer agents, Bioorg. Med. Chem. Lett. 21 (2011) 2855–2859. doi:10.1016/j.bmcl.2011.03.079. [11] R.K. Yadlapalli, O.P. Chourasia, K. Vemuri, M. Sritharan, R.S. Perali, Synthesis and in vitro anticancer and antitubercular activity of diarylpyrazole ligated dihydropyrimidines possessing lipophilic carbamoyl group, Bioorg. Med. Chem. Lett. 22 (2012) 2708–2711. doi:10.1016/j.bmcl.2012.02.101. [12] A.R. Trivedi, V.R. Bhuva, B.H. Dholariya, D.K. Dodiya, V.B. Kataria, V.H. Shah, Novel dihydropyrimidines as a potential new class of antitubercular agents, Bioorg. Med. Chem. Lett. 20 (2010) 6100–6102. doi:10.1016/j.bmcl.2010.08.046. [13] D. Nagarathnam, S.W. Miao, B. Lagu, G. Chiu, J. Fang, T.G.M. Dhar, J. Zhang, S. Tyagarajan, M.R. Marzabadi, F. Zhang, W.C. Wong, W. Sun, D. Tian, J.M. Wetzel, C. Forray, R.S.L. Chang, T.P. Broten, R.W. Ransom, T.W. Schorn, T.B. Chen, S. O’Malley, P. Kling, K. Schneck, R. Bendesky, C.M. Harrell, K.P. Vyas, C. Gluchowski, Design and Synthesis of Novel α(1a) Adrenoceptor-Selective Antagonists. 1. Structure-Activity Relationship in Dihydropyrimidinones, J. Med. Chem. 42 (1999) 4764–4777. doi:10.1021/jm990200p. [14] T.G.M. Dhar, D. Nagarathnam, M.R. Marzabadi, B. Lagu, W.C. Wong, G. Chiu, S. Tyagarajan, S.W. Miao, F. Zhang, W. Sun, D. Tian, Q. Shen, J. Zhang, J.M. Wetzel, C. Forray, R.S.L. Chang, T.P. Broten, T.W. Schorn, T.B. Chen, S. O’Malley, R. Ransom, K. Schneck, R. Bendesky, C.M. Harrell, K.P. Vyas, K. Zhang, J. Gilbert, D.J. Pettibone, M.A. Patane, M.G. Bock, R.M. Freidinger, C. Gluchowski, Design and Synthesis of Novel α(1a) Adrenoceptor-Selective Antagonists. 2. Approaches to Eliminate Opioid Agonist Metabolites via Modification of Linker and 4Methoxycarbonyl-4-phenylpiperidine Moiety, J. Med. Chem. 42 (1999) 4778–4793. doi:10.1021/jm990201h. [15] A. Kamal, M. Shaheer Malik, S. Bajee, S. Azeeza, S. Faazil, S. Ramakrishna, V.G.M. Naidu, M.V.P.S. Vishnuwardhan, Synthesis and biological evaluation of conformationally flexible as well as restricted dimers of monastrol and related dihydropyrimidones, Eur. J. Med. Chem. 46 (2011) 3274–3281. doi:10.1016/j.ejmech.2011.04.048. [16] T.N. Akhaja, J.P. Raval, 1,3-dihydro-2H-indol-2-ones derivatives: Design, Synthesis, in vitro antibacterial, antifungal and antitubercular study, Eur. J. Med. Chem. 46 (2011) 5573–5579. doi:10.1016/j.ejmech.2011.09.023. [17] H.M. Aly, M.M. Kamal, Efficient one-pot preparation of novel fused chromeno[2,3d]pyrimidine and pyrano[2,3-d]pyrimidine derivatives, Eur. J. Med. Chem. 47 (2012) 18–23. doi:10.1016/j.ejmech.2011.09.040. [18] J. Lal, S.K. Gupta, D. Thavaselvam, D.D. Agarwal, Design, synthesis, synergistic antimicrobial activity and cytotoxicity of 4-aryl substituted 3,4-dihydropyrimidinones of curcumin, Bioorg. Med. Chem. Lett. 22 (2012) 2872–2876. doi:10.1016/j.bmcl.2012.02.056. [19] A.M. Maharramov, M.A. Ramazanov, G.A. Guliyeva, A.E. Huseynzada, U.A. Hasanova, N.G. Shikhaliyev, G.M. Eyvazova, S.F. Hajiyeva, I.G. Mamedov, M.M. 33

Aghayev, Synthesis, investigation of the new derivatives of dihydropyrimidines and determination of their biological activity, J. Mol. Struct. 1141 (2017) 39–43. doi:10.1016/j.molstruc.2017.03.084. [20] Y. Xie, J. Wang, N-Heterocyclic carbene-catalyzed annulation of ynals with amidines: access to 1,2,6-trisubstituted pyrimidin-4-ones, Chem. Commun. 54 (2018) 4597– 4600. doi:10.1039/c8cc02023j. [21] C.O. Kappe, Biologically active dihydropyrimidones of the Biginelli-type - a literature survey, Eur. J. Med. Chem. 35 (2000) 1043–1052. doi:10.1016/S0223-5234(00)011892. [22] N.D. Watermeyer, K. Chibale, M.R. Caira, Pharmacologically Relevant Bifunctional Compounds Containing Chloroquinoline and Dihydropyrimidone Moieties: Syntheses and Crystal Structures of a Target Molecule and Selected Intermediates, J. Chem. Crystallogr. 39 (2009) 753–760. doi:10.1007/s10870-009-9568-2. [23] M. Kamal Raj, H.S.P. Rao, S.G. Manjunatha, R. Sridharan, S. Nambiar, J. Keshwan, J. Rappai, S. Bhagat, B.S. Shwetha, D. Hegde, U. Santhosh, A mechanistic investigation of Biginelli reaction under base catalysis, Tetrahedron Lett. 52 (2011) 3605–3609. doi:10.1016/j.tetlet.2011.05.011. [24] I. Suzuki, Y. Iwata, K. Takeda, Biginelli reactions catalyzed by hydrazine type organocatalyst, Tetrahedron Lett. 49 (2008) 3238–3241. doi:10.1016/j.tetlet.2008.03.080. [25] I. Suzuki, Y. Suzumura, K. Takeda, Metal triflimide as a Lewis acid catalyst for Biginelli reactions in water, Tetrahedron Lett. 47 (2006) 7861–7864. doi:10.1016/j.tetlet.2006.09.019. [26] C. Oliver Kappe, 100 Years of the Biginelli Dihydropyrimidine Synthesis, Tetrahedron. 49 (1993) 6937–6963. doi:10.1016/S0040-4020(01)87971-0. [27] Z. Long, L. Mao, M. Liu, Q. Wan, Y. Wan, X. Zhang, Y. Wei, Marrying multicomponent reactions and aggregation-induced emission (AIE): New directions for fluorescent nanoprobes, Polym. Chem. 8 (2017) 5644–5654. doi:10.1039/c7py00979h. [28] Â. de Fátima, T.C. Braga, L. da S. Neto, B.S. Terra, B.G.F. Oliveira, D.L. da Silva, L. V. Modolo, A mini-review on Biginelli adducts with notable pharmacological properties, J. Adv. Res. 6 (2015) 363–373. doi:10.1016/j.jare.2014.10.006. [29] H. Nagarajaiah, A. Mukhopadhyay, J.N. Moorthy, Biginelli reaction: an overview, Tetrahedron Lett. 57 (2016) 5135–5149. doi:10.1016/j.tetlet.2016.09.047. [30] A.C. Boukis, B. Monney, M.A.R. Meier, Synthesis of structurally diverse 3,4dihydropyrimidin-2(1H)-ones via sequential Biginelli and Passerini reactions, Beilstein J. Org. Chem. 13 (2017) 54–62. doi:10.3762/bjoc.13.7. [31] M. Pasupathi, N. Santhi, M.P. Pachamuthu, G. Alamelu Mangai, C. Ragupathi, Aluminium and titanium modified mesoporous TUD-1: A bimetal acid catalyst for Biginelli reaction, J. Mol. Struct. 1160 (2018) 161–166. doi:10.1016/j.molstruc.2018.02.009. [32] S. V Ryabukhin, A.S. Plaskon, E.N. Ostapchuk, D.M. Volochnyuk, O. V Shishkin, A.A. Tolmachev, CF3-substituted 1,3-dicarbonyl compounds in the Biginelli reaction 34

promoted by chlorotrimethylsilane, J. Fluorine Chem. 129 (2008) 625–631. doi:10.1016/j.jfluchem.2008.05.004. [33] Y. V. Burgart, O.G. Kuzueva, M. V. Pryadeina, C.O. Kappe, V.I. Saloutin, Fluorocontaining 1,3-Dicarbonyl Compounds in the Synthesis of Pyrimidine Derivatives, Russ. J. Org. Chem. 37 (2001) 869–880. doi:10.1023/A:1012473901354. [34] V.I. Saloutin, Y. V. Burgart, O.G. Kuzueva, C.O. Kappe, O.N. Chupakhin, Biginelli condensations of fluorinated 3-oxo esters and 1,3-diketones [1], J. Fluorine Chem. 103 (2000) 17–23. doi:10.1016/S0022-1139(99)00216-X. [35] R. Liang-Ce, Y. Zha, S. Xia, L. Ji, J. Zhang, P. Cai, An Efficient and Facile Synthesis of 5-(Thiophene-2-carbonyl)-6- (trifluoromethyl)-tetrahydro-pyrimidin-2(1H)-one and 6-(Thiophen-2-yl)-4,5- dihydropyrimidin-2(1H)-one from Same Substrates Under Different Conditions, J. Heterocycl. Chem. 53 (2016) 56–63. doi:10.1002/jhet.2299. [36] H. Xu, L. Yan, Y. Qin, Z. Xu, Z. Ling, L. Rong, An Efficient and Facile Multicomponent Reaction for the Synthesis of 5’,6’-dihydro-6’-hydroxy-6’(trifluoromethyl)-1’H-spiro[indoline-3,4’-pyrimidine]-2,2’(3’H)-dione Derivatives under Solvent-Free Conditions, J. Heterocycl. Chem. 54 (2017) 2493–2500. doi:10.1002/jhet. [37] Á.G. Sathicq, D.M. Ruiz, T. Constantieux, J. Rodriguez, G.P. Romanelli, letter Preyssler Heteropoly Acids Encapsulated in a Silica Framework for an Efficient Preparation of Fluorinated Hexahydropyrimidine Derivatives under Solvent-Free Conditions, Synlett. 25 (2014) 881–883. doi:10.1055/s-0033-1340845. [38] V. Palermo, Á. Sathicq, T. Constantieux, J. Rodríguez, P. Vázquez, G. Romanelli, New Vanadium Keggin Heteropolyacids Encapsulated in a Silica Framework: Recyclable Catalysts for the Synthesis of Highly Substituted Hexahydropyrimidines Under Suitable Conditions, Catal. Letters. 145 (2015) 1022–1032. doi:10.1007/s10562-015-1498-3. [39] G.A. Inman, D.C.D. Butler, H. Alper, Mild Pd(OAc)2/PPh3 Catalyzed Cyclization Reactions of 2-Vinylazetidines with Heterocumulenes: An Atom-Economy Synthesis of Tetrahydropyrimidinone, Tetrahydropyrimidinimine, and Thiazinanimine Analogs, Synlett. 2001 (2001) 0914–0919. doi:10.1055/s-2001-14665. [40] J.P. Wan, C. Wang, Y. Pan, Novel four-component reaction towards diastereoselective synthesis of tetrahydropyrimidinthiones, Tetrahedron. 67 (2011) 922–926. doi:10.1016/j.tet.2010.12.011. [41] C. Liu, Z. Cui, X. Yan, Z. Qi, M. Ji, X. Li, Synthesis, fungicidal activity and mode of action of 4-phenyl-6-trifluoromethyl-2-aminopyrimidines against Botrytis cinerea, Molecules. 21 (2016) 828. doi:10.3390/molecules21070828. [42] A. Gómez-Valdemoro, R. Martínez-Máñez, F. Sancenón, F.C. García, J.M. García, Functional Aromatic Polyethers: Polymers with Tunable Chromogenic and Fluorogenic Properties, Macromolecules. 43 (2010) 7111–7121. doi:10.1021/ma101106a. [43] N.Y. Wang, W.Q. Zuo, Y. Xu, C. Gao, X.X. Zeng, L.D. Zhang, X.Y. You, C.T. Peng, Y. Shen, S.Y. Yang, Y.Q. Wei, L.T. Yu, Discovery and structure-activity relationships study of novel thieno[2,3-b]pyridine analogues as hepatitis C virus inhibitors, Bioorg. Med. Chem. Lett. 24 (2014) 1581–1588. doi:10.1016/j.bmcl.2014.01.075. 35

[44] P.A. Stabnikov, L.G. Bulusheva, N.I. Alferova, A.I. Smolentsev, I.A. Korol’kov, N. V. Pervukhina, I.A. Baidina, Crystal structures of 1,1,1-trifluoro-4-hydroxy-4-phenyl-but3-en-2-one, 2,2,6,6-tetramethyl-3-hydroxy-hept-3-en-5-one, 2,2,6,6-tetramethyl-3methylamino-hept-3-en-5-one and a study of the ability of these ligands to complex formation with metals, J. Struct. Chem. 53 (2012) 740–747. [45] J.C. Sloop, P.D. Boyle, A.W. Fountain, W.F. Pearman, J.A. Swann, Electron-Deficient Aryl β-Diketones: Synthesis and Novel Tautomeric Preferences, Eur. J. Org. Chem. 2011 (2011) 936–941. doi:10.1002/ejoc.201001451. [46] D.S. Bose, L. Fatima, H.B. Mereyala, Green chemistry approaches to the synthesis of 5-alkoxycarbonyl-4-aryl-3,4-dihydropyrimidin-2(1H)-ones by a three-component coupling of one-pot condensation reaction: Comparison of ethanol, water, and solventfree conditions, J. Org. Chem. 68 (2003) 587–590. doi:10.1021/jo0205199. [47] N. October, N.D. Watermeyer, V. Yardley, T.J. Egan, K. Ncokazi, K. Chibale, Reversed chloroquines based on the 3,4-dihydropyrimidin-2(1H)-one scaffold: Synthesis and evaluation for antimalarial, β-haematin inhibition, and cytotoxic activity, ChemMedChem. 3 (2008) 1649–1653. doi:10.1002/cmdc.200800172. [48] R.C. Khunt, J.D. Akbari, A.T. Manvar, S.D. Tala, M.F. Dhaduk, H.S. Joshi, A. Shah, Green chemistry approach to synthesis of some new trifluoromethyl containing tetrahydropyrimidines under solvent free conditions, ARKIVOC. xi (2008) 277–284. [49] C.O. Kappe, D. Dallinger, The impact of microwave synthesis on drug discovery, Nat. Rev. Drug Discov. 5 (2006) 51–63. doi:10.1038/nrd1926. [50] S. Horikoshi, N. Serpone, Microwave Flow Chemistry as a Methodology in Organic Syntheses, Enzymatic Reactions, and Nanoparticle Syntheses, Chem. Rec. 19 (2019) 118–139. doi:10.1002/tcr.201800062. [51] F.S. Falsone, C.O. Kappe, The Biginelli dihydropyrimidone synthesis using polyphosphate ester as a mild and efficient cyclocondensation/dehydration reagent, Arkivoc. 2001 (2001) 122–134. doi:10.3998/ark.5550190.0002.214. [52] J.J. Li, Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications, 5th ed., Springer Science and Business Media, 2014. [53] C.O. Kappe, A Reexamination of the Mechanism of the Biginelli Dihydropyrimidine Synthesis. Support for an N -Acyliminium Ion Intermediate, J. Org. Chem. 62 (1997) 7201–7204. [54] F.L. Yang, J. Zhang, C.S. Yao, 5-Benzoyl-4-hydr-oxy-6-(4-nitro-phen-yl)-4trifluoromethyl-3,4,5,6-tetrahydropyrimidin-2(1H)-one monohydrate, Acta Crystallogr. Sect. E Struct. Reports Online. E65 (2008) o87–o88. doi:10.1107/S160053680804124X. [55] H. Xu, L. Yan, Y. Qin, Z. Xu, Z. Ling, L. Rong, An Efficient and Facile Multicomponent Reaction for the Synthesis of 5′,6′-dihydro-6′-hydroxy-6′(trifluoromethyl)-1′H-spiro[indoline-3,4′-pyrimidine]-2,2′(3′H)-dione Derivatives under Solvent-Free Conditions, J. Heterocycl. Chem. 54 (2017) 2493–2500. doi:10.1002/jhet.2851. [56] S. V. Ryabukhin, A.S. Plaskon, S.S. Bondarenko, E.N. Ostapchuk, O.O. Grygorenko, O. V. Shishkin, A.A. Tolmachev, Acyl pyruvates as synthons in the Biginelli reaction, 36

Tetrahedron Lett. 51 (2010) 4229–4232. doi:10.1016/j.tetlet.2010.06.032. [57] Y. Ma, C. Qian, L. Wang, M. Yang, Lanthanide Triflate Catalyzed Biginelli Reaction. One-Pot Synthesis of Dihydropyrimidinones under Solvent-Free Conditions, J. Org. Chem. 65 (2000) 3864–3868. doi:10.1021/jo9919052. [58] V.A. Mamedov, L. V Mustakimova, A.T. Gubaidullin, S. V Vdovina, I.A. Litvinov, V. Reznik, Dichloroacetylaroylmethanes as Two-Carbon Synthons in the Biginelli Reaction, Chem. Heterocycl. Compd. 42 (2006) 1229–1232. [59] O.C. Agbaje, O.O. Fadeyi, S.A. Fadeyi, L.E. Myles, C.O. Okoro, Synthesis and in vitro cytotoxicity evaluation of some fluorinated hexahydropyrimidine derivatives, Bioorg. Med. Chem. Lett. 21 (2011) 989–992. doi:10.1016/j.bmcl.2010.12.022. [60] R.J. Anderson, D.J. Bendell, P.W. Groundwater, Organic Spectroscopic Analysis, Royal Society of Chemistry, 2007. doi:10.1039/9781847551566. [61] Donald L. Pavia, G.M. Lampman, G.S. Kriz, J.R. Vyvyan, Introduction to Spectroscopy, 5th ed., Cengage Learning, 2015. [62] J. Furrer, D. Thévenet, Suppressing one-bond correlations in HMBC spectra: improved performance for the BIRD-HMBC pulse sequence, Magn. Reson. Chem. 47 (2009) 239–248. doi:10.1002/mrc.2380. [63] F. Vitório, T.M. Pereira, R.N. Castro, G.P. Guedes, C.S. Graebin, A.E. Kümmerle, Synthesis and mechanism of novel fluorescent coumarin-dihydropyrimidinone dyads obtained by the Biginelli multicomponent reaction, New J. Chem. 39 (2015) 2323– 2332. doi:10.1039/c4nj02155j. [64] APEX3 (including SAINT and SADABS), Bruker AXS Inc., Madison, WI, (2016). [65] G.M. Sheldrick, Program for the refinement of crystal structures, SHELXL97. (1997). [66] G.M. Sheldrick, SHELXT - Integrated space-group and crystal-structure determination, Acta Crystallogr. Sect. A Found. Adv. A71 (2015) 3–8. doi:10.1107/S2053273314026370. [67] G.M. Sheldrick, Crystal structure refinement with SHELXL, Acta Crystallogr. Sect. C Struct. Chem. C71 (2015) 3–8.

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Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: