Direct Access to New Gem-Difluorinated Pyrido[1,2-a] Pyrimidine-2-one Systems

The pyrido[1,2-a]pyrimidine core is of great pharmaceutical importance due to its potent and significant biological activities as an anti-inflammatory,[1] antiallergic,[2] analgesic,[3] and anticancer agent (3-5 antifolate),[4] and its anti-aggressive activities.[5] In fact, there are two types of position isomers within the same family; pyrido[1,2-a]pyrimidin-2-ones and pyrido[1,2-a] pyrimidin-4-ones (Figure 1). They are associated in the synthesis of broad range of biologically active heterocycles such as antiulcerative agents,[6] tranquilizers and antipsychotic drugs (Pirenperone),[7] inhibitors of polyhydroxylase, or inhibitors of dihydrofolate reductase in humans (hDHFR)[8] (Figure 1). The first synthesis of pyrido[1,2-a]pyrimidin-2-ones was described in 1961 by Lappin et al. by cyclocondensation between various 2-aminopyridines and α,β-acetylenic esters such as methyl propiolate. However, the use of these conditions leads to the formation of two different compounds[9] (Scheme 1). While several synthetic routes have been developed to obtain these pyrido[1,2-a]pyrimidin-2-ones, few synthetic methodologies have been published in the literature for the regioselective synthesis of pyrido[1,2-a]pyrimidin-2-ones. The Harriman group investigated the reactivity of the fluorinated alkyne ethyl 4,4,4-trifluorobut-2-ynoate with the 2-aminopyridine that led to the formation of 4-(trifluoromethyl)-2H-pyrido[1,2-a]pyrimidin2-one as the sole product with an excellent yield[10] (Scheme 2).


Introduction
The pyrido [1,2-a]pyrimidine core is of great pharmaceutical importance due to its potent and significant biological activities as an anti-inflammatory, [1] antiallergic, [2] analgesic, [3] and anticancer agent (3-5 antifolate), [4] and its anti-aggressive activities. [5] In fact, there are two types of position isomers within the same family; pyrido[1,2-a]pyrimidin-2-ones and pyrido [1,2-a] pyrimidin-4-ones ( Figure 1). They are associated in the synthesis of broad range of biologically active heterocycles such as antiulcerative agents, [6] tranquilizers and antipsychotic drugs (Pirenperone), [7] inhibitors of polyhydroxylase, or inhibitors of dihydrofolate reductase in humans (hDHFR) [8] (Figure 1). The first synthesis of pyrido[1,2-a]pyrimidin-2-ones was described in 1961 by Lappin et al. by cyclocondensation between various 2-aminopyridines and α,β-acetylenic esters such as methyl propiolate. However, the use of these conditions leads to the formation of two different compounds [9] (Scheme 1). While several synthetic routes have been developed to obtain these pyrido [   In view of the importance of the 2H-pyrido[1,2-a]pyrimidin-2-one scaffold, our laboratory team studied the extension of this heterocyclic family. We discovered a new series of synthesized molecules exhibiting in vitro activity against the host cell invasion by E. tenella parasites. This investigation revealed a "chief" compound with a "pyrido[1,2-a]pyrimidin-2-one ", with an IC50 value of 15 μM. [11] Furthermore, it is well established that the incorporation of a fluorine atom into organic compounds can alter or modify their physiochemical properties and enhance their metabolic stability. The unique properties of fluorine have an exceptional impact on the electronic, lipophilic, and steric parameters, and acidity or basicity of organofluorinated molecules. [12] Much attention has been drawn in recent years to the difluoromethylene group (CF 2 ) due to its special physical and chemical properties. [13]

General Methods
Most reagents were obtained from commercial sources and used as received. Thin-Layer Chromatography (TLC) was performed on Merck 60F254 plates. Column Chromatography was carried out with Merck silica gel 60 (0.040-0.063 mm, 230-400 mesh). All 1 H NMR, 13 C NMR and 19 F NMR spectra were recorded on a 300 MHz Bruker Avance FT-NMR spectrometer (300 MHz, 75 or 282 MHz, respectively). All chemical shifts are given as δ value (ppm) with reference to tetramethylsilane (TMS) as an internal standard. The peak patterns are indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet. The coupling constants J are reported in Hertz (Hz). Electrospray ionization High-Resolution Mass Spectrometry Experiments (HRMS) were performed on a hybrid Tandem Quadrupole/Time-Of Flight (Q-TOF) instrument, equipped with a pneumatically assisted electrospray (Z-spray) ion source (Micromass, Manchester, U.K.) operated in positive mode.

Results and Discussion
Due to the valuable role of 2H-pyrido[1,2-a]pyrimidin-2-one derivatives as well as the important pharmacological role of the CF 2 moiety, we planed to look for an access to new gem-difluorinated-2H-pyrido[1,2-a]pyrimidin-2-one derivatives. Our investigation started by exploring the cycloaddition reaction between two different 2-aminopyridines and gem-difluorinated alkynes. The corresponding gem-difluorinated alkynes were prepared in the laboratory following a known synthetic strategy. [14] The cycloaddition reaction was done in ethanol at room temperature. Following the same mechanism as that described by Harriman's group. [10] The cycloaddition reactions between three different gem-difluorinated alkynes 1a-c and 2-aminopyridines 2a-b were successfully conducted, leading to the formation of pyrido[1,2-a] pyrimidin-2-ones 3a-f with good to excellent yields (70-93%) ( Table  1). Moreover, the reactions proceeded very cleanly, and the desired products were obtained as a solid in pure form after filtration. As product 3b bears a reactive carbon-bromide bond connected to the phenyl group, it seemed important to test the reactivity of this bond in order to achieve further transformations. Therefore, a palladium catalyzed Heck coupling reaction was carried out on pyrido[1,2-a] pyrimidin-2-one 3b with methyl acrylate.

*=Isolated yield
The best conditions for performing this coupling reaction were found to be a catalytic amount of palladium (II) acetate [Pd(OAc) 2 , 5 mol%], triphenyl phosphine [PPh 3 , 10 mol%] and triethylamine as base and heating in a sealed tube at 120°C. The reaction gave the desired product 4 (E/Z = 94/6) that was easily purified by recrystallization and was isolated with a 60% of overall yield. A typical Suzuki-Miyaura cross coupling reaction [15] was then tested on pyrido[1,2-a]pyrimidin-2-one 3b using a variety of phenyl boronic acids in order to achieve further transformation. The reactions were performed in a mixture of dioxane/water (3/1) with Palladium (II)bis(triphenylphosphine) dichloride [PdCl 2 (PPh 3 ) 2 ] (5 mol%) as catalyst and Potassium carbonate (K 2 CO 3 ) as base. The desired products 5a-e were isolated in a yield ranging between 70-94%. The results are summarized in Table 2. Despite of their ability to facilitate the oxidative addition step in Suzuki-Miyaura cross coupling reaction, the presence of EWG such as a CF 3 group (entry 5, Table 2) in phenyl boronic acids has the disadvantage to induce a partial protodeboronation in presence of aqueous base which globally decreases the yield of the cross-coupling reaction. [16][17][18]

Summary
In summary, we have provided a straightforward access to a new gem-difluorinated pyrido[1,2-a]pyrimidine-2-ones using a practical and genersal method. We first established a concise onepot strategy for the synthesis of gem-difluorinated pyrido[1,2-a] pyrimidin-2-ones by condensation of 2-aminopyridines with gemdifluorinated methyl propiolates. These compounds were then used as building blocks to synthesize a new 4-[(3-substitutedphenyl) difluoromethyl]-2H-pyrido[1,2-a]pyrimidin-2-ones via crosscoupling reactions. This valuable strategy is being applied to the production of a wide range of compounds that are currently under biological evaluation.