Zahira Tber

Nicolas G Biteau

Luigi Agrofoglio

Julien Cros

Stéphane Goffinont

Bertrand Castaing

Cyril Nicolas

Vincent Roy

Microwave-Assisted Suzuki-Miyaura and Sonogashira Coupling of 4-Chloro-2-(trifluoromethyl)pyrido[1,2-e]purine Derivatives

Keywords: Nitrogen heterocycles, Fused-ring systems, Crosscoupling, C-C coupling, Base excision repair

The convenient preparation of three imidazo[1,2a]pyridine-2-carboxamide intermediates is reported through known Strecker-Ugi type multicomponent reactions, Tschitschibabin type condensations and further synthetic sequences. The derivatives were then efficiently converted to novel 4-chloro-2-(trifluoromethyl)pyrido[1,2-e]purines by way of their original reactions with 2,2,2-trifluoroacetamide, followed by subsequent dehydroxychlorination reactions. These compounds were crosscoupled under microwave irradiation through Suzuki-Miyaura and Sonogashira palladium(0) catalysis to various aromatic and alkynyl reagents, thus providing the related C-4 substituted pyrido[1,2e]purines of biological interest in good yields.

Introduction

Purines are essential ubiquitous heterocyclic aromatic compounds that consist of a pyrimidine molecule fused to an imidazole ring. They are the most abundant nitrogen-containing heterocycles in nature, [1] and accordingly exhibit crucial roles. They display wide range of biological activities in various cellular processes involving DNA and RNA, ATP, GTP, cyclic AMP, NADH, and coenzyme A. [1][2] Since the early 1900's, [3] the purine class of compounds have therefore spurred curiosity from the medicinal and organic synthetic chemistry community in generating analogs of variously substituted (heterocyclic) purines of biological interest. [START_REF]For recent reviews on synthetic methods for the preparation of purines and analogs as privileged scaffolds in medicinal chemistry see: a) M. Legraverend[END_REF] Noteworthy, for some specific pharmacological activities, purine derivatives have been found to be less potent, while their surrogates with an additional fused ring motif have been shown to possess better pharmacokinetic profiles, enhanced pharmacological activities and significant physicochemical properties. [5] The fused and extended imidazopyridines and their related compounds may indeed serve as valuable tools in chemical biology, as many polycyclic nucleosides are fluorescent. [START_REF] Bag | Fluorescent Analogues of Biomolecular Building Blocks: Design and Applications[END_REF] Moreover, important activities have been emphasized, such as antihypertension, [7] anti-inflammatory, [5a] human A3 adenosine receptor antagonism, [5b-e,8] and inhibition of PDE1/5 and tyrosine kinase EphB4. [9,5f] Pyrido [1,2-e]purines of type 1 have hence recently gained attention in this direction. The new chemical entities have been shown to behave as powerful PDE5 inhibitors, [9b-d] of which some had a better selectivity over PDE6 and PDE1 than sildenafil, [9b] anticancer agents able to induce apoptosis of certain cancer cell lines or intercalating drugs to fit between base pairs of oligodeoxynucleotides. [5g,10] Figure 1. Synthetic routes to pyrido [1,2-e]purines.

As illustrated in Fig. 1, the classical methods for the preparation of pyrido [1,2-e]purines commonly involve the formation of a suitably functionalized imidazo [1,2-a]pyridine system 2 (R 2 = NO, NO2, NH2; R 3 = C≡N, CO2R, CONH2), [START_REF] Pericherla | developments in the synthesis of imidazo[1,2a]pyridines see[END_REF] followed by construction of the C2-C3 annulated pyrimidine ring (path a). [5g,9b,10b,12] Various chemical approaches have been used in this respect, to give 2 in moderate to good yields, from substituted 2-aminopyridines and Tschitschibabin condensations, [9b,13] or Strecker-Ugi type cascade reactions. [5g,12a] Ehrlich-Sachs type cyclizations of 2nitrosopyridines were also used, albeit with much lower efficiencies. [10b,12b,14] The imidazo [1,2-a]pyridine derivatives 2 could then be reacted with guanidine, formamide, acetamidine [a] Zahira Tber, Nicolas G. Biteau, Dr. Cyril Nicolas, Dr. Vincent Roy, Prof. Dr. Luigi Agrofoglio, Institut de Chimie Organique et Analytique, UMR CNRS 7311, Université d'Orléans, Rue de Chartres -BP 6759, 45067 Orléans cedex 2, France. vincent.roy@univ-orleans.fr and luigi.agrofoglio@univ-orleans.fr http://www.icoa.fr/fr/agrofoglio [b] Julien Cros, Stéphane Goffinont, Dr. Bertrand Castaing, Centre de Biophysique Moléculaire, UPR CNRS 4301, Rue Charles Sadron, 45072 Orléans, France.

Supporting information for this article is given via a link at the end of the document.

acetate, triethyl orthoformate, ammonium formate, or acyl chloride reagents to give, after few other reactions, the expected pyrido [1,2-e]purines of type 1.

As miscellaneous, compounds 1 may also be readily available through few synthetic sequences and (i) ring-closing metathesis of 8,9-diallyl-6-chloro-purine 3 (path b), [10g] (ii) silver-catalyzed intramolecular hydroamination of terminal alkynes of type 4 (path c), [15] (iii) double C-H arylations of 9-phenylpurines 5, or (iv) consecutive Suzuki-Miyaura and direct C-H arylation of 9-(2bromophenyl)purines 6 (path b). [16] Intramolecular cyclization reactions of 1,3-bis(4-methoxybenzyl)-5-(pyridin-2ylamino)pyrimidine-2,4(1H,3H)-diones 7 could be performed otherwise (path d). [17] Worth noting, oxidatively damaged DNA, which result from the attack of sugar and base moieties by reactive oxygen species (ROS) are formed as byproducts of normal cell metabolism and during exposure to endogenous or exogenous chemical or physical agents. Guanine, having the lowest redox potential, is the DNA base the most susceptible to oxidation, yielding mutagenic 8-oxo-7,8-dihydroguanine (8-oxoG). In eukaryotic cells, 8-oxoG is primarily repaired by the base excision repair pathway (BER) initiated by the DNA N-glycosylase hOGG1. [18] Human molecular and epidemiological studies have shown that hOGG1 can affect significantly cancer proliferation and other diseases development, such as Neurodegenerative diseases (NDD). [19,20] hOGG1 is therefore considered as a pertinent pharmalogical target. [20,21] Along our ongoing research program directed at generating small molecule modulators of hOGG1, we were interested in the synthesis of pyrido [1,2-e]purine scaffolds that would feature a CF3 substituent at C-2 and an aromatic functional group at C-4 that would possibly be connected via a rigid carbon-carbon (Csp 2 -Csp) bond. Surprisingly, there is no example of such derivatives in the literature so far.

Herein, we thus report our studies concerning the straightforward and efficient preparation of such compounds (i.e., A). As depicted here above (Fig. 2), our retrosynthetic planning for the making of compounds A follows path a (e.g., Fig. 1). It requires novel 4-chloro-2-(trifluoromethyl)pyrido [1,2-e]purines B that would be derivatized through Pd-catalyzed cross-coupling chemistry. The synthesis of B would in turn, be achieved through dehydroxychlorination of hitherto unknown 2-(trifluoromethyl)pyrido [1,2-e]purin-4-ol derivatives C, obtained from the original reactions of imidazo [1,2-a]pyridine-2carboxamides D and 2,2,2-trifluoroacetamide (CF3(CO)NH2).

Results and Discussion

Synthesis

Carboxamides D would be readily prepared, using known reaction sequences from commercial heterocyclic 2-amidines E. Scheme 1. Synthesis of 4-chloro-2-(trifluoromethyl)pyrido [1,2-e]purine derivatives 17a-17c.

A set of aminoimidazo [1,2-a]pyridine-2-carboxamides 8a-8c (R 1 = H (a), 4-Me (b), 5-Me (c)) were thus generated as model substrates (Scheme 1). Following a desilylative Strecker-Ugi type multicomponent reaction, the 2-aminopyridine 9a was reacted with ethylglyoxalate 10 in the presence of TMSCN and 1,4diazabicyclo[2.2.2]octane (DABCO) under microwave irradiation (120 °C) to give 11a in moderate yield (60%). [5g,12a] 8a was afforded by subsequent reaction with aqueous ammonia at 70 °C for 48 h (81%). Compounds 8b and 8c were prepared otherwise according to a Tschitschibabin type condensation protocol. [9b] Aminopyridines 9b and 9c were therefore converted into imidazo [1,2-a]pyridine-2-carboxylates 12b (50%) and 12c (60%) respectively, by refluxing in EtOH (route a) or MeOH (route b) with ethyl bromopyruvate 13. The regioselective nitrations (e.g., H2SO4/HNO3) of 12b-c were then performed at 0 °C to provide the mono-nitro products 14b-c in good yields (81 vs. 70%). Next, the nitroesters 14b-c were stirred in a mixture of aqueous ammonia and THF at room temperature, to provide nitroamides 15b-c in excellent yields (90 and 91%). Reductions of 15b-c to the corresponding aminoamides 8b-c were achieved by catalytic hydrogenation (10% Pd-C, rt, route c), or treatment with Tin(II) chloride in EtOH at 100 °C under μW irradiation (route d). [9b] From the pyridine-carboxamide intermediates 8a-8c, annulation and chlorination reactions were then carried out by heating at 160 °C with CF3(CO)NH2 used as solvent (24 h) and treatment with an excess of SOCl2 under reflux (1.5 h). The 2-(trifluoromethyl)pyrido [1,2-e]purin-4-ol derivatives 16a-16c (58-73%) and 4-chloro-2-(trifluoromethyl)pyrido [1,2-e]purines 17a-17c were obtained in moderate to good yields (i.e., 60-77%).

Compounds 17a-17c in hands we decided to investigate further post-modification of the pyrimidine substitution pattern. Easy post-decoration of 4-chloro-pyrido [1,2-e]purines through nucleophilic substitutions with (aryl)-amines, alcohols and thiol reagents has already been described; [5g,12a] but to the best of our knowledge, there is no mention of their transition-metal catalyzed cross-coupling reactions with C-Nu.

The Suzuki-Miyaura reaction is a cornerstone of modern organic synthesis. Unlike many cross-coupling strategies, it is a routine, versatile and benign reaction that is cost-effective, scalable and maybe amenable to green chemistry principles and industrial standards. [22] It was successfully applied to many different coupling partners, including nitrogen-containing heterocycles using catalytic amount of palladium(II) acetate (0.1 eq.), Xantphos (0.2 eq.) as ligand and potassium carbonate (2 equiv.) as base in toluene at elevated temperature. In addition, conventional thermal heating could be replaced by microwave irradiation in a sealed reactor with major improvement in terms of yields and reaction times. [23] These conditions were thus tested with p-tolylboronic acid and chloropurine 17a as model substrate to give 18a in good yield (85%) after 50 min of reaction at 100 °C (Table 1, entry 1). Triphenyl phosphine, and BINAP, [24] together with Xantphos, [25] have become the most often used ligands for palladium-catalyzed carbon-carbon and the more challenging carbon-nitrogen bond-forming reactions. [START_REF] Beller | Applied Homogeneous Catalysis with Organometallic Compounds[END_REF]27] Thus, subsequent cross-coupling reactions were next conducted with PPh3 and BINAP, but a disappointing yield decrease was noticed (entries 2-3).

Of note, in situ generation of tetrakis(triphenylphosphine)palladium(0) through insertion of Pd(OAc)2 and PPh3 (entry 2) vs. direct addition of Pd(PPh3)4 (entry 4) did not produce any variation of the reaction yield (ca. 80%). When the influence of the solvent was assessed (H2O, H2O/DME, 1,4-dioxane), slight to dramatic decrease of the catalytic efficiency was noted (entries 5-7). It was also the case when Cs2CO3 was replaced by K2CO3 as base (entry 8). Finally, reaction temperature was increased to 120 °C to give a satisfactory 84% yield after a period of reaction of 30 min (entry 9). Interestingly, there was no cross-coupling reaction without a catalyst (entry 10), which excludes an addition/elimination pathway.

Table 1. Optimization of the conditions for the Suzuki-Miyaura coupling reaction of p-tolylboronic acid and compound 17a. [a] Entry [b] 9 Pd(OAc)2 Xantphos toluene 84 [c] 10 Pd(OAc)2 toluene traces [a] Typical reaction conditions: Ar atmosphere, compound 17a (1 eq.), ptolylboronic acid (1.5 eq.), K2CO3 (2 eq.) as base, catalyst (0.1 eq.), additional ligand (0.2 eq.), heating at 100 °C under microwave irradiation for 50 min in a sealed reactor. [b] Cs2CO3 (2 eq.) instead of K2CO3 (2 eq.) were added. [c] Heating was performed at 120 °C for 30 min.

The scope of the reaction was then explored using various organoboronic acids under the optimized aforementioned conditions (entry 9). As depicted in Scheme 2, yields obtained were good for most products (e.g., 65-85%). It is worth noting that a better reactivity was observed for boronic acids substituted with a methyl or an electron-withdrawing group. The outcomes were also indicative of the influence of the substituent position on the reactivity of the boronic acid. Comparing the same moiety, the psubstituted phenylboronic acid showed better reactivity than the respective m-and o-substituted phenylboronic acids. Furthermore, substitution by a methyl group at the C-7 or C-8 position of compounds 17 did not change significantly the yield of the catalysis.

Scheme 2. Scope of the Suzuki-Miyaura Reaction.

Having successfully established the efficacy of the Suzuki-Miyaura in constructing trifluoro purines with aromatic substituents at C-4 with a Csp 2 -Csp 2 bond, we next turned our attention to a palladium-catalyzed process allowing construction of Csp 2 -Csp bonds. The Sonogashira reaction has found extensive use in this respect, in natural products synthesis and for the making of complex molecules. [28] Various solvents, palladium species, copper(I) salts and bases were tested. Remarkably, few examples have been reported on halogeno [1,2-a]pyridines, [29] due to their possible antiviral, anticancer, antiulcer, antifungal and antibacterial properties. The substituted [1,2-a]pyridine compounds may also find applications as calcium channel blockers, benzodiazepine receptor agonists, herbicides, GABAA receptor modulators, and cyclin-dependent kinase (CDK) inhibitors, etc.,. [30] In some instances, PdCl2(PPh3)2 (0.05 eq.), Pd(OAc)2 (0.05 eq.) and PPh3 (0.1 eq.) or Pd(PPh3)4 (0.05 eq.) as catalysts were used with CuI (0.2 eq.) as co-catalyst in a mixture of DMF/Et3N (1:1, v/v) at 50 °C. [29,31] These conditions were thus employed with 17a and ethynylbenzene to give moderate to good yields (45-70%, Table 2, entries 1-3) of purine 27a after 60 min of reaction. Total conversion was observed with 1.2 eq. of the alkynyl reagent and 1 eq. of 17a, as monitored by TLC analysis of the crude reaction mixtures. The amount of the copper(I) iodide salt proved to be crucial, as it was not amenable to a lower loading without loss of the catalysis efficiency (55% vs. 70%, entries 3-4). Heating under microwave irradiation was also studied in order to improve the yields and to decrease reaction times. [23a-b] Notable, a 65% yield was obtained over 5 min of reaction at 90 °C (entry 5), whereas a satisfactory 75% of product 27a was afforded after 15 min at 70 °C (entry 5). The deprotonation of the acetylene may be an important step at the beginning of the cross-coupling reaction. However, the use of other bases (Cs2CO3, HN-i-Pr2, KOt-Bu, etc;,) was not explored. At that stage, we thought the conditions were acceptable to be evaluated with compounds 17ac and a range of variously substituted alkynyl (aromatic) reagents. Gratifyingly, yields of the coupled derivatives 27-34 were quite good for most products, as shown in Scheme 3. As expected, the stereoelectronic properties of the acetylenes were correlated with the performance in alkynylation reactions. As a rule, the arylacetylene with the most 4-R electron-donating ability produces the best chemical yield (OMe > H > Me > F, see compounds 28a-30a, 34a). Interestingly, it is the opposite of Plenio investigations on electronic effects for Tolanes synthesis. [32] Table 2. Optimization of the conditions for the Sonogashira coupling reaction of ethynylbenzene and compound 17a. [a] Entry Catalyst Ligand Time (min) Yield (%) of 27a [a] 1 Pd(OAc)2 PPh3 60 45 [b] 2 Pd(PPh3)4 -60 62

3 Pd(PPh3)2Cl2 -60 70 4 Pd(PPh3)2Cl2 -60 55 [c] 5 Pd(PPh3)2Cl2 -5 65 [d] 6 Pd(PPh3)2Cl2 -15 75 [e] [a] Typical reaction conditions: Ar atmosphere, compound 17a (1 eq.), ethynylbenzene (1.2 eq.), catalyst (0.05 eq.), copper(I) iodide (0.2 eq.), heating at 50 °C. [b] Pd(OAc)2 (0.05 eq.) as catalyst and PPh3 (0.1 eq.) as ligand were used. [c] CuI (0.1 eq.) was used as co-catalyst instead of CuI (0.2 eq.). [d] Heating was performed at 90 °C under W irradiation. [e] Heating was performed at 70 °C under W irradiation.

Comparing the same moiety, the p-substituted phenylalkynes showed enhanced product formation as regard to the oderivatives. The m-substituted ones behave in the medium range with slightly similar overall yield than the p-substituted compounds (74% vs. 80% for 30a (o-MeOPh) and 32a (p-MeOPh)). Noteworthy, substitution by a methyl group at the C-7 position of compounds 17 did not affect significantly the yield of the crosscoupled products (see 28b and 32b) while substitution at C-8 (i.e., 17c) gave no conversion. The starting materials were fully recovered when reactions were attempted with 3-ethynylanisole and 4-ethynyltoluene (e.g., 28c and 32c).

Scheme 3. Scope of the Sonogashira Reaction.

Conclusions

In conclusion, we have reported an efficient and easy way to provide novel pyrido [1,2-e] c) could be tolerated albeit it was not the case for the alkynylation reactions of compound 17c and 3-ethynylanisole or 4ethynyltoluene. Complementary studies to synthesize these important molecules are ongoing and biological evaluations on the 8-oxoguanine-DNA N-glycosylase hOGG1 isoform will be reported in due course.

Experimental Section

General Remarks. Unless otherwise stated, all solvents and commercially available reagents were used as purchased. N,N-Dimethylformamide anhydrous, 99.8% was purchased from Sigma-Aldrich. Thionyl chloride (SOCl2) was distilled prior to use. Reactions were monitored by thin-layer chromatography (TLC) using Merck Silica Gel 60 F254 pre-coated plates. Visualization of the developed chromatogram was performed under ultraviolet light (254 nm) and on staining by immersion in aqueous, acidic ceric ammonium molybdate (CAM; 470 mL H2O, 28 mL H2SO4, 24 g ammonium molybdate, 0.5 g cerium ammonium nitrate) followed by heating on a hot plate. Normal phase flash chromatography was performed in air on Silica Gel 60 (230-400 mesh). Organic solutions were concentrated under reduced pressure with a Buchi rotary evaporator.

Microwave activations were performed in sealed vessels using a Biotage Initiator system. The following settings were used: Normal absorption level, Fixed Hold Time: on. The internal temperature was measured by an IR- General Procedure for the Synthesis of Compounds 16a-c From Carboxamide Derivatives 8a-c (GP.1). A single-necked round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 2,2,2-trifluoroacetamide (10 equiv.) under argon atmosphere. The white solid was then heated at 110 °C until it melted and compound 8a-c (1 equiv.) was added. The reaction mixture was heated at 160 °C for 24 h. Afterwards, the mixture was allowed to reach room temperature (20 °C) and the crude residue was purified through silica gel column chromatography (SiO2, CH2Cl2 : MeOH 95:5) to afford the desired product 16a-c in moderate to good yield.

General Procedure for the Dehydroxychlorination of Pyrido[1,2e]purin-4-ol Derivatives 16a-c (GP.2).

A single-necked round-bottomed flask equipped with a reflux condenser under argon atmosphere was charged with compound 16a-c (1 equiv.) and CHCl3 (3 mL) and the mixture was stirred under refluxed for 10 minutes (flask A). In parallel, a single-necked round-bottomed flask under argon atmosphere was charged with SOCl2 (5 equiv.) and anhydrous DMF (280 μL) at 0 °C (icewater bath) and the mixture was stirred at the same temperature for 10 minutes (solution B). Solution B was then added to flask A, dropwise (syringe addition) and the reaction mixture was refluxed for 1.5 h under argon atmosphere. The reaction was poured into ice and water, the aqueous and organic layers were separated, and the organic phase was washed with water. The aqueous phase was then adjusted to pH 7 (sat. aq. NaHCO3) and extracted with Et2O. Afterwards, combined organic layers were dried (MgSO4), filtered through a cotton plug and evaporated under reduced pressure. The crude residue was purified by silica gel column chromatography (SiO2, CH2Cl2) to provide the desired product in moderate to good yield.

General Procedure for the Suzuki-Miyaura Cross-Coupling Reactions of Compounds 17a-c (GP.3). A 2-5 mL microwave vial under argon atmosphere was charged with a given boronic acid (1,5 equiv.), compound 17a-c (1 equiv.), K2CO3 (2 equiv.) and anhydrous toluene (2 mL). The mixture was deoxygenated by passing a stream of argon through a syringe and Pd(OAc)2 (0.1 equiv.) and Xantphos (0.2 equiv.) were added. The tube was closed with the cap and the reaction mixture was stirred at 120 °C under microwave irradiation for 30 minutes. H2O (20 mL) was then added and the organic phase was extracted thrice with AcOEt (3 × 5 mL). Next, combined organic layers were dried (MgSO4), filtered through a cotton plug and concentrated under vacuum. The crude product was purified by column chromatography over silica gel.

General Procedure for the Sonogashira Cross-coupling Reactions of Compounds 17a-c (GP.4). A 2-5 mL microwave vial under argon atmosphere was charged with a given alkynyl derivative (1.2 equiv.), compound 17a-c (1 equiv.), and 3 mL of Et3N-anhydrous DMF (1:1, v/v).

The mixture was deoxygenated by passing a stream of argon through a syringe and Pd(PPh3)2Cl2 (0.05 equiv.) and CuI (0.2 equiv.) were added.

The tube was closed with the cap and the reaction mixture was stirred at 70 °C under microwave irradiation for 15 minutes. H2O (20 mL) was then added and the organic phase was extracted thrice with AcOEt (3 × 5 mL).

Next, combined organic layers were dried (MgSO4), filtered through a cotton plug and concentrated under vacuum. The crude product was purified by column chromatography over silica gel.

Ethyl 3-aminoimidazo[1,2-a]pyridine-2-carboxylate (11a).

A 20-mL microwave vial under argon atmosphere was charged with 2aminopyridine (200 mg, 2.12 mmol) and ethyl glyoxalate solution (50% in toluene) (420L, 2.12 mmol). The mixture was stirred for 2 min at rt (20 °C) and 1,4-Diazabicyclo[2.2.2]octane (DABCO, 238 mg, 2.12 mmol) and THF (4 mL) were added. The solution was then cooled to 0-5 °C (ice-water bath) and TMSCN (265 L, 2.12 mmol) was added dropwise. The vial was capped and the reaction mixture was subsequently heated under microwave irradiation for 15 min at 120 °C. Next, sat. aq. K2CO3 was added and the organic solvents were evaporated under reduced pressure (rotary evaporation). The aqueous phase was extracted thrice with AcOEt, combined organic phases dried over Na2SO4, filtered through a cotton plug and evaporated in vacuo. The crude titled compound was purified by column chromatography (SiO2, CH2Cl2:MeOH 95:5) to afford 11a as a yellow precipitate (261 mg, 60%

7-Methyl-3-nitroimidazo[1,2-a]pyridine-2-carboxamide (15b).

A singlenecked round-bottomed flask equipped with a reflux condenser under argon atmosphere, was charged with 2-Amino-4-methylpyridine (2. 16 g, 20 mmol) and EtOH absolute (50 mL) and the mixture was heated at 70 °C until complete dissolution. Ethyl bromopyruvate (2.76 mL, 22 mmol) was then added dropwise and the reaction mixture was refluxed for 5 h. After solvent removal (rotary evaporation), the crude material was purified through silica gel chromatography (SiO2, CH2Cl2:MeOH, 99:1) to afford ethyl 7-methylimidazo [1,2-a] A round-bottomed flask under argon atmosphere was charged with compound 12b (3.5 g, 16.8 mmol) and the flask was cooled to 0-5 °C (icewater bath). Concentrated sulphuric acid (H2SO4 > 95%, 17 mL) was then added, followed by nitric acid (HNO3 65%, 2 mL) dropwise and the reaction mixture was stirred for 3 h at 0 °C. The mixture was carefully poured onto ice (250 g) and the yellow solid was filtered, rinsed with H2O (50 mL) and dried in vacuo. The crude residue was purified by column chromatography Thereafter, the product (3.3 g, 13.2 mmol) was inserted in a microwave vial under air atmosphere and a 28-30% aq. NH4OH solution (20 ml) and THF (1 ml) were added. The vial was capped and the mixture was subsequently stirred at room temperature for 20 h. The solvents were evaporated under vacuum and Methanol (50 mL) was added.

6-Methyl-3-nitroimidazo[1,2-a]pyridine-2-carboxamide (15c).

A singlenecked round-bottomed flask under argon atmosphere was charged with 2-amino-5-methylpyridine (5 g, 46 mmol) and 1,2-dimethoxyethane (DME, 50 mL). Ethyl bromopyruvate (5.77 mL, 46 mmol) was then added, dropwise and the reaction mixture was stirred for 45 minutes at room temperature. The precipitate was filtered, washed with Et2O and dried in vacuo to give a yellow solid. The solid was suspended in MeOH (50 mL) and the suspension was heated at 90 °C until complete dissolution (1.5 h).

The solution was concentrated and neutralized to pH 7. The mixture was extracted thrice with CH2Cl2, combined organic phases were dried (Na2SO4), filtered over a cotton plug and concentrated under vacuum. The residue was purified through silica gel chromatography (SiO2, CH2Cl2 : MeOH 95:5) to provide ethyl 6-methylimidazo [1,2-a]pyridine-2-carboxylate 12c as a yellow light solid (5.63 g, 60%).

Next, a round-bottomed flask under argon atmosphere was charged with compound 12c (4.0 g, 19.6 mmol) and the flask was cooled to 0-5 °C (icewater bath). Concentrated sulphuric acid (H2SO4 > 95%, 20 mL) was added, followed by nitric acid (HNO3 65%, 2.4 mL) dropwise and the reaction mixture was stirred for 3 h at 0 °C. The mixture was carefully poured onto ice (250 g) and the yellow solid was filtered, rinsed with H2O (50 mL) and dried in vacuo. The crude residue was purified by column chromatography (SiO2, CH2Cl2) to give ethyl 6-methyl-3-nitroimidazo [1,2a]pyridine-2-carboxylate 14c as a yellow solid (3.4 g, 70%). 1 H NMR (400 MHz, CDCl3): δH = 9.17 (br s, 1 H, HAr), 7.78 (d, J = 9.1 Hz, 1 H, HAr), 7.53 (dd, J = 9.2, 1.7 Hz, 1 H, HAr), 4.55 (q, J = 7.2 Hz, 2 H, OCH2CH3), 2.52 (s, 3 H, CH3), 1.45 (t, J = 7.1 Hz, 3 H, OCH2CH3) ppm. 13 Thereafter, the product (990 mg, 3.97 mmol) was inserted in a microwave vial under air atmosphere and 28-30% aq. NH4OH solution (4 ml) and THF (0.2 ml) were added. The vial was capped and the mixture was stirred at room temperature for 20 h. The solvents were evaporated under vacuum and methanol (10 mL) was added. The precipitate was filtered and washed further with a mixture of methanol and pentane (8:2) to afford compound 15c as a yellow solid (800 mg, 91%). m.p.: 300 °C (from MeOH); IR (neat) (νmax/cm -1 ): 3369, 3146, 1664, 1640, 1384, 1218, 1191, 834, 799,

Aminoimidazo[1,2-a]pyridine-2-carboxamide (8a).

A microwave vial under air atmosphere was charged with imidazo [1,2-a]pyridine 11a (550 mg, 2.44 mmol), 28-30% aq. NH4OH solution (10 ml) and THF (0.5 ml).

The vial was sealed and the mixture was stirred at 70 °C for 48 h (normal heating with an oil bath). The solvents were evaporated under vacuum and the residue was purified through neutral alumina column (Al2O3, CH2Cl2 : MeOH 9:1) to furnish compound 8a as a yellow solid (342 mg, 81%). m.

3-Amino-7-methylimidazo[1,2-a]pyridine-2-carboxamide (8b).

A single-necked round-bottomed flask under air atmosphere was charged with carboxamide 15b (500 mg, 2.27 mmol), 10% Pd/C and EtOH (≥95%). The suspension was degassed under vacuum and the flask was filled with H2 (H2-filled balloon) five times. The reaction mixture was stirred at 20 °C under hydrogen atmosphere (balloon of H2) for 14 h. Next, the mixture was filtered through celite and the filter residue was rinsed with MeOH. The solvents were evaporated (rotary evaporation) and the residue was purified by column chromatography (SiO2, CH2Cl2 : MeOH 95:5) to provide the titled compound as an off white precipitate (302 mg, 70%). m.p. > 260 °C; IR (neat): ṽ = 3674, 3390, 3270, 3106, 1656, 1614, 1456, 1409, 1245, 1066, 775, 521 cm -1 ; 1 H NMR (400 MHz, DMSO-d6): δH = 8.04 (d, J = 7.1 Hz, 1 H, HAr), 7.27 (br s, 1 H, NH), 7.11 (s, 1 H, HAr), 7.04 (br s, 1 H, NH), 6.67 (d, J = 7.1 Hz, 1 H, HAr), 6.06 (s, 2 H, NH2), 2.31 (s, 3 H, CH3) ppm; 13

3-Amino-6-methylimidazo[1,2-a]pyridine-2-carboxamide (8c).

A microwave vial under argon atmosphere was charged with carboxamide 15c (700 mg, 3.18 mmol), Tin (II) chloride dihydrate (3.56 g, 15.8 mmol) and EtOH (≥95%; 15 mL). The vial was sealed and the reaction mixture was heated under microwave irradiation at 100 °C for 10 min. After solvents removal (rotary evaporation) the crude residue was then diluted with EtOAc (50 mL) and the organic phase was washed successively with NaHCO3 (20 mL) and brine (30 mL). Next, the organic layer was dried (MgSO4), filtered through a cotton plug and evaporated under reduced pressure. The crude product was purifed by column chromatography over silica gel (CH2Cl2 : MeOH 95:5) to give 8c as a beige solid (452 mg, 75%). m.p.: 250-252 °C; IR (neat): ṽ = 3674, 3390, 3270, 3106, 2987, 1656, 1614, 1409, 1305, 1245, 1066, 1014, 775, 706, 603 cm -1 ; 1 H NMR (250 MHz, DMSO-d6): δH = 7.93 (s, 1 H, 7.26 (d, 2 H, J = 9.3 Hz, HAr + NH), 7.05 (br s, 1 H, NH), 6.92 (dd, J = 9.4, 1.5 Hz, 1 H, HAr), 6.04 (s, 2 H, NH2), 2.23 (s, 3 H, CH3) ppm. 13 C NMR (63 MHz, DMSO-d6) δC = 167.0 (C, CO), 135.9 (C, CAr), 135.0 (C, CAr), 126.3 (C, CHAr), 120.3 (C, CAr), 120.0 (CH, CHAr), 116.9 (CH, CHAr), 116.4 (CH, CHAr), 17.8 (CH3) ppm.

2-(Trifluoromethyl)pyrido[1,2-e]purin-4-ol (16a).

According to GP1, the reaction was performed with carboxamide 8a (200 mg, 1.13 mmol) and CF3(CO)NH2 (1.28 g, 11.35 mmol) to furnish compound 17a as a white solid (201 mg, 70%). m.p.: 310-312 °C; IR (neat): ṽ = 3231, 2987, 2900, 1641, 1599, 1478, 1349, 1259, 1127, 755, 514 cm -1 ; 1 H NMR (400 MHz, Methanol-d4): δH = 8.63 (d, J = 6.8 Hz, 1 H, HAr) ,7.62 (d, J = 9.3 Hz, 1 H, HAr), 7.51 (dd, J = 6.8, 9.3 Hz, 1 H, HAr), 7.02 (t, J = 6.8 Hz, 1 H, HAr) ppm; -2-(trifluoromethyl)pyrido[1,2-e]purin-4-ol (16b). According to GP1, the reaction was performed with carboxamide 8b (300 mg, 1.58 mmol) and CF3(CO)NH2 (1.78 g, 15.8 mmol) to furnish compound 16b as a white solid (310 mg, 73%). m.p.: 253-255 °C; IR (neat): ṽ = 3674, 2987, 1693, 1477, 1358, 1286, 1202, 1132, 997, 784 cm -1 According to GP1, the reaction was performed with carboxamide 8c (150 mg, 0.79 mmol) and CF3(CO)NH2 (1.78 g, 7.9 mmol) to give compound 16c as a white solid (122 mg, 58%). m.p.: 250-252 °C; IR (neat): ṽ = 3674, 2987, 1651, 1601, 1478, 1384, 1262, 1131, 995, 806 cm -1 ; 1 H NMR (400 MHz, Methanol-d4): δH = 8.44 (s, 1 H, HAr), 7.52 (d, J = 9.4 Hz, 1 H, HAr), 7.39 (d, J = 9.4 Hz, 1 H, HAr), 2.39 (s, 3 H, CH3)

7-Methyl

4-Chloro-2-(trifluoromethyl)pyrido[1,2-e]purine (17a).

According to GP2, the reaction was accomplished with purine 16a (150 mg, 0.59 mmol) and SOCl2 (214 μL, 2.95 mmol) to give compound 17a as a white solid (124 mg, 77%). m.p.: 210-211°C; IR (neat): ṽ = 3113, 3035, 1646, 1397, 1300, 1125, 911, 758 cm -1 ; 1 H NMR (250 MHz, CDCl3): δH = 8.86 (dd, J = 6.8, 1.0 Hz, 1 H, HAr), 7.88 (d, J = 6.8 Hz, 1 H, HAr), 7.76 (td, J = 6.8, 1.0 Hz, 1 H, HAr), 7.18 (td, J = 6.8, 1.0 Hz, 1 H, HAr) ppm; 13

4-Chloro-7-methyl-2-(trifluoromethyl)pyrido[1,2-e]purine (17b).

According to GP2, the reaction was accomplished with purine 16b (220 mg, 0.82 mmol) and SOCl2 (298 μL, 4.10 mmol) to give compound 17b as a beige solid (141 mg, 60%). m.p.: 220-222 °C; IR (neat): ṽ = 3051, 2928, 1650, 1555, 1497, 1356, 1435, 1374, 1257, 1199, 1130, 943, 890, 703 cm - 1 ; 1 H NMR (400 MHz, CDCl3): δH = 8.71 (d, J = 7.1 Hz, 1 H, HAr), 7.60 (d, J = 1.8 Hz, 1 H, HAr), 7.00 (dd, J = 7.1, 1.8 Hz, 1 H, HAr), 2.58 (s, 3 H, CH3) ppm; 13

4-Chloro-8-methyl-2-(trifluoromethyl)pyrido[1,2-e]purine

17c. According to GP2, the reaction was accomplished with purine 16c (140 mg, 0.52 mmol) and SOCl2 (190 μL, 2.6 mmol) to give compound 17c as a beige solid (97 mg, 65%). m.p.: 196-198 °C;IR (neat): ṽ = 3052, 2929IR (neat): ṽ = 3052, , 1651IR (neat): ṽ = 3052, , 1556IR (neat): ṽ = 3052, , 1498IR (neat): ṽ = 3052, , 1357IR (neat): ṽ = 3052, , 1436IR (neat): ṽ = 3052, , 1375IR (neat): ṽ = 3052, , 1256IR (neat): ṽ = 3052, , 1198IR (neat): ṽ = 3052, , 1129IR (neat): ṽ = 3052, , 1063, 943, 890, 794, 702 cm -1 ;, 943, 890, 794, 702 cm -1 ;1 H NMR (250 MHz, CDCl3): δH = 8.70-8.60 (m, 1 H, HAr), 7.79 (dd, J = 9.5, 1.2 Hz, 1 H, HAr), 7.62 (dd, J = 9.5, 1.8 Hz, 1 H, HAr), 2.50 (d, J = 1.2 Hz, 3 H, CH3) ppm; 13 C NMR (63 MHz, CDCl3): δC = 151.4 (C, CAr), 150.2 (C, CAr), 146.5 (q, J = 38.5 Hz, C-CF3), 145.8 (C, CAr), 138.1 (CH, CHAr), 134.0 (C, CAr), 124. 1 (C, CAr), 122.8 (CH, CHAr), 119.7 (q, J = 276.8 Hz, CF3), 118.6 (CH, CHAr), 18.3 (CH3) ppm; 19 F NMR (376 MHz,chromatography (SiO2,petroleum ether : EtOAc 7:3) to give compound 19a as a yellow solid (42 mg, 74%). m.p.: 191-192 °C; IR (neat): ṽ = 2987, 1639, 1570, 1398, 1346, 1247, 11156, 1050, 908, 755, 717 cm -1 ; 1 H NMR (400 MHz, CDCl3): δH = 9.04 (d, J = 7.8 Hz, 2 H, HAr), 8.86 (d, J = 6.8 Hz, 1 H, HAr), 7.84 (d, J = 9.3 Hz, 1 H, HAr), 7.68 (dd, J = 9.3, 6.8 Hz,1 H, HAr), 7.61 (q, J = 9.5, 8.1 Hz, 3 H, HAr), 7.07 (t, J = 6.8 Hz, 1 H, HAr) ppm; 13

4-(Naphthalen-1-yl)-2-(trifluoromethyl)pyrido[1,2-e]purine (26a).

According to GP3, the reaction was accomplished with compound 17a (50 mg, 183 μmol) and naphthalenyl-1-boronic acid. The crude product was purified by column chromatography (SiO2, petroleum ether : EtOAc 7:3) to give compound 26a as a yellow solid (45 mg, 70%). m.p.: 216-218 °C; IR (neat): ṽ = 3106, 2209, 1637, 1574, 1287, 1120, 1128, 954, 755, 686

7-Methyl-4-(p-tolyl)-2-(trifluoromethyl)pyrido[1,2-e]purine (18b).

According to GP3, the reaction was carried out with compound 17b (52 mg, 183 μmol) and p-tolylboronic acid. The crude product was purified by column chromatography (SiO2, petroleum ether : EtOAc 8:2) to give compound 18b as a yellow solid (50 mg, 80%). m.p.: 237-239 °C; IR (neat): ṽ = 2923, 1647, 1568, 1513, 1298, 1204, 1047, 897, 788

8-Methyl-4-(p-tolyl)-2-(trifluoromethyl)pyrido[1,2-e]purine (18c).

According to GP3, the reaction was accomplished with compound 17c (20 mg, 70 μmol) and p-tolylboronic acid. The crude product was purified by column chromatography (SiO2, petroleum ether : EtOAc 8:2) to give compound 18c as a yellow solid (19 mg, 78%). m.p.: 234-236 °C; IR (neat): ṽ = 2920, 1640, 1570, 1516, 1299, 1200, 1048, 890, 784 cm -1 ṽ = 2918, 2649, 1652, 1577, 1422, 1197, 1046, 937, 852, 708 cm -1 ; 1 H NMR (400 MHz, CDCl3): δH = 9. 13-9.08 (m, 2 H, HAr), 8.68-8.65 (m, 1 H, HAr), 7.75 (d, J = 9.4 Hz, 1 H, HAr), 7.56 (dd, J = 9.4, 1.8 Hz, 1 H, HAr), 7.44 (bd, J = 8.2, Hz, 2 H, HAr), 2.48 (bs, 3 H, CH3) ppm; 13

4-(Phenyl)ethynyl)-2-(trifluoromethyl)pyrido[1,2-e]purine (27a).

According to GP4, the reaction was accomplished with compound 17a (52 mg, 183 μmol) and phenylacetylene. The crude product was purified by column chromatography (SiO2, petroleum ether : CH2Cl2 4:6) to give compound 27a as a yellow solid (65 mg, 75%). m.p.: 216-218 °C; IR (neat): ṽ = 3106, 2209, 1637, 1574, 1287, 1120, 1128, 954, 755, 686, 598 cm -1 ; 1 H NMR (400 MHz, CDCl3): δH = 8.87(d, J = 6.9 Hz, 1 H, HAr), 7.89 (d, J = 9.4 Hz, 1 H, HAr), 7.81 (d, J = 7.2 Hz, 2 H, HAr), 7.73 (t, J = 7.9 Hz, 1 H, HAr), 7.55-7.35 (m, 3 H, HAr), 7.14 (t, J = 6.7 Hz, 1 H, HAr) ppm; 13

4-((4-Methylphenyl)ethynyl)-2-(trifluoromethyl)pyrido[1,2-e]purine (28a).

According to GP4, the reaction was accomplished with compound 17a (52 mg, 183 μmol) and 4-ethynyltoluene. The crude product was purified by column chromatography (SiO2, petroleum ether : EtOAc 5:5) to give compound 28a as a yellow solid (45 mg, 70%). m.p.: 236-237 °C; IR (neat): ṽ = 3455, 3015, 2946, 2205, 1739, 1367, 1407, 1216, 1149, 1128, 1087, 952, 817, 766 cm -1 ; 1 H NMR (400 MHz, CDCl3/TMS): δH = 8.85 (br d, J = 6.9 Hz, 1 H, HAr), 7.87 (d, J = 9.4 Hz, 1 H, HAr), 7.80-7.60 (m, 3 H,

Figure 2 .

 2 Figure 2. Retrosynthetic planning.

  sensor. NMR spectra were recorded at 298 K with a Bruker Avance III HD nanobay 400 MHz spectrometer equipped with a PABBO BBO probe, a Bruker Avance II and a Bruker DPX 250 MHz spectrometer. The nucleisignal assignments were done with the aid of 1 D [ 1 H NMR,13 C NMR, Distortionless Enhancement by Polarization Transfer (DEPT)] and 2 D Correlation Spectroscopy [( 1 H-1 H COSY and 1 H-13 C Heteronuclear Single Quantum Coherence (HSQC)] experiments. When appropriate or in case of ambiguous proton and carbon, assignments were established using19 F NMR and Heteronuclear Multiple-bond Correlation (HMBC).13 C and19 F spectra were acquired on a broad band decoupled mode.1 H NMR (400 or 250 MHz) chemical shift values are listed in parts per million (ppm) downfield from TMS as the internal standard or relative to the corresponding non-deuterated solvent. Data are reported as follows: chemical shift (ppm on the δ scale), multiplicity (s = singlet, d = doublet, dd = doublet of doublet, ddd = doublet of doublet of doublet, dt = doublet of triplet, t = triplet, q = quartet and m = multiplet), coupling constant J (Hz), and integration.13 C NMR (101 or 63 MHz) chemical shifts are given in ppm relative to the corresponding non-deuterated solvent or TMS as the internal standard.19 F NMR (376 MHz) chemical shifts are given in ppm. High-resolution mass spectra were recorded with a MaXis ESI qTOF ultrahigh-resolution mass spectrometer (FR2708, Orléans). Melting points (m.p., °C) were determined using a Fisher Scientific Fisherbrand 9300 apparatus in open capillaries and are uncorrected. Infrared spectra were recorded neat with a Thermo Scientific Nicolet IS10 FTIR spectrometer using diamond ATR golden gate sampling and are reported in wave numbers (cm -1 ).

(

  SiO2, CH2Cl2) to give ethyl 7-methyl-3-nitroimidazo[1,2-a]pyridine-2carboxylate 14b as a yellow solid(3.4 g, 81%). m.p.: 145 °C; 1 H NMR (400 MHz, CDCl3/TMS): δH = 9.23 (d, J = 7.2 Hz, 1 H, HAr), 7.60 (br s, 1 H, HAr), 7.17 (dd, J = 7.2, 1.7 Hz, 1 H, HAr), 4.54 (q, J = 7.2 Hz, 2 H, OCH2CH3), 2.56 (s, 3 H, CH3), 1.45 (t, J = 7.1 Hz, 3 H, OCH2CH3).13 C NMR (101 MHz, CDCl3): δC = 162.1 (C, CO), 145.4 (C, CAr), 143.3 (C, CAr), 143.3 (C, CAr), 140.8 (C, CAr), 126.6 (CH, CHAr), 120.3 (CH, CHAr), 118.0 (CH, CHAr), 63.0 (CH2, OCH2CH3), 21.8 (CH3), 14.1 (CH3, OCH2CH3) ppm.

  C NMR (101 MHz, CDCl3): δC = 162.1 (C, CO), 143.8 (C, CAr), 140.3 (C, CAr), 134.0 (C, CHAr), 128.5 (C, CAr), 125.3 (C, CHAr), 118.6 (C, CHAr), 100.1 (C, CAr), 63.0 (CH2, OCH2CH3) 18.9 (CH3), 14.1 (CH3, OCH2CH3) ppm.

(s, 1 H

 1 , HAr), 7.88 (s, 1 H, NH), 7.72 (d, J = 9.0 Hz, 1 H, HAr), 2.47 (s, 3 H, CH3) ppm; 13 C NMR (101 MHz, DMSO-d6): δC = 163.6 (C, CO), 144.7 (C, CAr), 143.4 (C, CAr), 134.5 (C, CHAr), 127.8 (C, CAr), 125.4 (C, CHAr), 117.5 (C, CHAr), 17.9 (CH3) ppm.

  p.: 233-236 °C; IR (neat): ṽ = 3381,3309, 3108, 1660, 1600, 1498, 1323, 1246, 698, 617, 510 cm -1 ; 1 H NMR (400 MHz, DMSO-d6): δH = 8.13 (d, J = 7.0 Hz, 1 H, HAr), 7.40 (br s, 1 H, NH), 7.34 (d, J = 9.3 Hz, 1 H, HAr), 7.14 (br s, 1 H, NH), 7.06 (dd, J = 12.3, 1.2 Hz, 1 H, HAr), 6.80 (t, J = 6.7 Hz, 1 H, HAr), 6.14 (s, 2 H, HAr) ppm; 13 C NMR (101 MHz, DMSO-d6): δC = 167.1 (C, CO), 136.7 (C, CAr), 135.4 (C, CAr), 123.1 (C, CHAr), 123.0 (C, CHAr), 117.5 (C, CHAr), 116.2 (C, CAr), 111.3 (C, CHAr) ppm.

  C NMR (101 MHz, DMSO-d6): δC = 167.1 (C, CO), 137.0 (C, CAr), 135.1 (C, CAr), 133.4 (C, CAr), 122.2 (CH, CHAr), 115.8 (C, CAr), 115.3 (CH, CHAr), 113.9 (CH, CHAr), 20.9 (CH3) ppm.

  13 C NMR (101 MHz, Methanol-d4): δC = 169.0 (C, CO), 150.3 (q = 34.6 Hz, C-CF3), 147.0 (C, CAr), 144.3 (C, CAr), 131.8 (CH, CHAr), 127.5 (C, CAr), 125.9 (CH, CHAr), 124.2 (q, J = 274.3 Hz, CF3), 118.8 (CH, CHAr), 113.9 (CH, CHAr) ppm; 19 F NMR (376 MHz, Methanol-d4): δF = -70.7 ppm; HRMS (ESI): m/z calcd. for C10H6F3N4O [M + H] + 255.0488; found 255.0488.

  ; 1 H NMR (250 MHz, Methanol-d4): δH = 8.52 (d, J = 7.1 Hz, 1 H, HAr), 7.37 (s, 1 H, HAr), 6.91 (dd, J = 7.1, 1.5 Hz, 1 H, HAr), 2.43 (s, 3 H, CH3) ppm; 19 F NMR (376 MHz, Methanol-d4): δF = -70.5 ppm; HRMS (ESI): m/z calcd. for C11H8F3N4O [M + H] + 269.0645; found 269.0647.

  C NMR (63 MHz, CDCl3): δC = 151.7 (C, CAr), 150.9 (C, CAr), 146.8 (q, J = 38.1 Hz, C-CF3), 146.0 (C, CAr), 134.6 (CH, CHAr), 134.0 (C, CAr), 125.7 (CH, CHAr), 119.7 (q, J = 274.1 Hz, CF3), 119.4 (CH, CHAr), 113.8 (CH, CHAr) ppm; 19 F NMR (376 MHz, CDCl3): δF = -68.0 ppm; HRMS (ESI): m/z calcd. for C10H5ClF3N4 [M + H] + 273.0149; found 273.014.

  C NMR (101 MHz, CDCl3) δC = 151.4 (C, CAr), 150.8 (C, CAr), 147.1 (C, CAr), 146.4 (q, J = 36.6 Hz, C-CF3), 146.3 (C, CAr), 134.3 (C, CAr), 124.6 (CH, CHAr), 119.7 (q, J = 274.1 Hz, CF3), 117.2(CH, CHAr), 116.8 (CH, CHAr), 22.6 (CH3) ppm; 19 F NMR (376 MHz, CDCl3): δF = -68.0 ppm; HRMS (ESI): m/z calcd. for C11H7ClF3N4 287.0306; found 287.0303.

  C NMR (101 MHz, CDCl3): δC = 155.6 (C, CAr), 150.4 (C, CAr), 147.4 (C, CAr), 147.4 (q, J = 37.1 Hz, C-CF3), 135.3 (C, CAr), 133.7 (CH, CHAr), 133.2 (C, CAr), 131.9 (CH, CHAr), 130.5 (2 × CH, CHAr), 129.0 (2 × CH, CHAr), 125.4 (CH, CHAr), 120.5 (q, J = 274.7 Hz, CF3), 119.2 (CH, CHAr), 112.8 (CH, CHAr) ppm; 19 F NMR (376 MHz, CDCl3): δF = -68.2 ppm; HRMS (ESI): m/z calcd. for C16H10F3N4 [M+H] + 315,0852; found 315.0855.

  cm -1 ; 1 H NMR (400 MHz, CDCl3): δH = 8.91 (d, J = 8.0 Hz, 2 H, HAr tol), 8.65 (d, J = 7.0 Hz, 1 H, HAr), 7.51 (s, 1 H, HAr), 7.40 (d, J = 8.0 Hz, 2 H, HAr tol), 6.83 (dd, J = 7.0, 1.6 Hz, 1 H, HAr), 2.51 (s, 3 H, CH3), 2.48 (s, 3 H, CH3) ppm; 13 C NMR (101 MHz, CDCl3): δC = 154.8 (C, CAr), 150.6 (C, CAr), 147.3 (C, CAr),146.8 (q, J = 36.9 Hz, C-CF3), 145.5 (C, CAr), 142.3 (C, CAr), 133.1 (C, CAr), 132.7 (C, CAr), 130.3 (2 × CH, CHAr tol), 129.7 (2 × CH, CHAr tol), 124.2 (CH, CHAr), 120.6 (q, J = 274.5 Hz, CF3), 116.9 (CH, CHAr), 115.6 (CH, CHAr), 22.4 (CH3), 21.9 (CH3) ppm; 19 F NMR (376 MHz, CDCl3): δF = -68.1 ppm; HRMS (ESI): m/z calcd. for C18H14F3N4 [M+H] + 343.1165; found 343.1165.

  ;1 H NMR (400 MHz, CDCl3): δH = 8.93(d, J = 8.2 Hz, 2 H, HAr tol), 8.62 (s, 1 H, HAr), 7.73(d, J = 9.5 Hz, 1 H, HAr), 7.50 (dd, J = 9.5, 1.8 Hz, 1 H, HAr), 7.41(d, J = 8.2 Hz, 2 H, tol), 2.48 (s, 3 H, CH3), 2.45 (d, J = 1.4 Hz, 3 H, CH3) ppm;13 C NMR (101 MHz, CDCl3): δC = 155.4 (C, CAr), 149.4 (C, 146.9 (C, CAr), 146.5 (q, J = 37.2 Hz, C-CF3), 142.4 (C, CAr), 136.9 (CH, CHAr), 133.0 (C, CAr), 132.7 (C, CAr), 130.4 (2 × CH, CHAr tol), 129.7 (2 × CH, CHAr tol), 122.8 (C, CAr), 122.5 (CH, CHAr), 120.6 (q, J = 274.7 Hz, CF3), 118.3 (CH, CHAr), 21.9 (CH3), 18.2 (CH3) ppm; 19 F NMR (376 MHz, CDCl3): δF = -68.2 ppm; HRMS (ESI): m/z calcd. for C18H14F3N4 [M+H] + 343.1165; found 343.1165. e]purine (22b). According to GP3, the reaction was accomplished with compound 17b (52 mg, 183 μmol) and 4-(trifluoromethoxy)phenylboronic acid. The crude product was purified by column chromatography (SiO2, petroleum ether : EtOAc 7:3) to give compound 22b as a yellow solid (52 mg, 70%). m.p.: 149-150 °C; IR (neat): ṽ = 2917, 1651, 1402, 1252, 1140, 1049, 1018, 673, 629, 509 cm -1 ; 1 H NMR (400 MHz, CDCl3): δH = 9.06 (d, J = 8.9 Hz, 2 H, HAr), 8.66 (d, J = 7.1 Hz, 1 H, HAr), 7.50 (s, 1 H, HAr), 7.42 (br d, J = 8.9 Hz, 2 H, HAr), 6.87 (br d, J = 7.1 Hz, 1 H, HAr), 2.52 (s, 3 H, CH3) ppm; 13 C NMR (101 MHz, CDCl3): δC = 152.9 (C, CAr), 151.7 (q, J = 1.8 Hz, C-OCF3), 151.0 (C, CAr), 147.6 (C, CAr), 146.7 (q, J = 37.2 Hz, C-CF3), 146.2 (C, CAr), 133.8 (C, CAr), 133.3 (C, CAr), 132.1 (2 × CH, CHAr), 124.5 (CH, CHAr), 120.8 (CH, CHAr), 120.6 (q, J = 258.2 Hz, OCF3), 120.4 (q, J = 274.5 Hz, CF3), 116.9 (CH, CHAr), 115.9 (CH, CHAr), 22.5 (CH3) ppm; 19 F NMR (376 MHz, CDCl3): δF = -57.5, -68.2 ppm; HRMS (ESI): m/z calcd. for C18H11F6N4O [M+H] + 413.0832; found 413.0829. 8-Methyl-4-(4-(trifluoromethoxy)phenyl)-2-(trifluoromethyl)pyrido[1,2-e]purine (22c). According to GP3, the reaction was carried out with compound 17c (20 mg, 69 μmol) and 4-(trifluoromethoxy)phenylboronic acid. The crude product was purified by column chromatography (SiO2, petroleum ether : EtOAc 8:2) to give compound 22c as a yellow solid (20 mg, 70%). m.p.: 139-140 °C; IR (neat):

  C NMR (101 MHz, CDCl3): δC = 153.7 (C, CAr), 151.8 (q, J = 2.1 Hz, C-OCF3), 149.9 (C, CAr), 147.3 (C, CAr), 137.5 (CH, CHAr), 133.8 (C, CAr), 133.2 (C, CAr), 132.2 (2 × CH, CHAr), 123.2 (C, CAr), 122.7 (CH, CHAr), 120.9 (2 × CH, CHAr), 122.5 (q, J = 138.1 Hz, OCF3), 119.7 (q, J = 146.5 Hz, CF3), 118.4 (CH, CHAr), 18.3 (CH3) ppm; 19 F NMR (376 MHz, CDCl3): δF = -57.5, -68.2 ppm; HRMS (ESI): m/z calcd. for C18H11F6N4O [M+H] + 413.0832; found 413.0829.

  C NMR (101 MHz, CDCl3): δC = 151.0 (C, CAr), 147.6 (q, J = 37.4 Hz, C-CF3), 146.6 (C, CAr), 142.4 (C, CAr), 136.3 (C, CAr), 134.5 (CH, CHAr), 133.0 (2 × CH, CHAr) , 130.4 (CH, CHAr), 128.6 (2 × CH, CHAr), 125.6 (CH, CHAr), 121.3 (C, CAr), 120.1 (q, J = 274.6 Hz, CF3), 119.3 (CH, CHAr), 113.3 (CH, CHAr), 101.3 (C, ≡C), 84.5 (C, C≡) ppm; 19 F NMR (376 MHz, CDCl3): δF = -68.0 ppm; HRMS (ESI): m/z calcd. for C18H9F3N4 [M+H] + 339.0852; found 339.0849.

  ppm;19 F NMR (376 MHz, Methanol-d4): δF = -70.6 ppm; HRMS (ESI): m/z calcd. for C11H8F3N4O [M + H] + 269.0645; found 269.0648.

  , 598 cm -1 ; 1 H NMR (400 MHz, CDCl3): δH = 8.92(d, J = 6.9 Hz, 1 H, HAr), 8.48- 8.40 (m, 1 H, HAr), 8.33 (dd, J = 7.2, 1.3 Hz, 1 H, HAr), 8.06 (d, J = 8.2 Hz, 1 H, HAr), 7.99-7.90 (m, 1 H, HAr), 7.80 (d, J = 9.4 Hz, 1H, HAr), 7.74-7.63 (m, 2 H, HAr), 7.61-7.48 (m, 2 H, HAr), 7.10 (t, J = 6.7 Hz, 1 H, HAr) ppm;13 C NMR (101 MHz, CDCl3) δC = 159.0 (C, CAr), 150.6 (C, CAr), 147.2 (q, J = 37.1 Hz, C-CF3), 147.0 (C, CAr), 134.7 (C, CAr), 134.4 (C, CAr), 133.8 (CH, CHAr), 131.7 (C, CAr), 131.7 (CH, CHAr), 131.2 (C, CAr), 131.2 (CH, CHAr), 128.7 (CH, CHAr), 127.3 (CH, CHAr), 126.4 (CH, CHAr), 125.7 (CH, CHAr), 125.5 (CH, CHAr), 125.3 (CH, CHAr), 120,5 (q, J = 274.7 Hz, CF3), 119.3 (CH, CHAr), 113.0 (CH, CHAr) ppm; 19 F NMR (376 MHz, CDCl3): δF = -67.9 ppm; HRMS (ESI): m/z calcd. for C20H11F3N4 [M+H] + 365,0952; found 355.0955.

Acknowledgments

The authors are grateful for financial suport from Centre National de la Recherche Scientifique (CNRS), Labex SynOrg (ANR-11-

CDCl3): δF = -68.0; HRMS (ESI): m/z calcd. for C11H7ClF3N4 287.0306; found 287.0306.

4-(p-Tolyl)-2-(trifluoromethyl)pyrido[1,2-e]purine (18a).

According to GP3, the reaction was performed with compound 17a (50 mg, 183 μmol) and p-tolylboronic acid. The crude product was purified by column chromatography (SiO2, petroleum ether : EtOAc 7:3) to give compound 18 as a yellow solid (51 mg, 85%). m.p. : 195-197 °C; IR (neat): ṽ = 2918, 2854, 1637, 1574, 1396, 1264, 1178, 1127, 1049, 890, 764, 717, 510 cm - 1 ; 1 H NMR (400 MHz, CDCl3): δH = 8.96 (d, J = 8.1 Hz, 2 H, HAr tol), 8.86 (d, J = 6.8 Hz, 1 H, HAr), 7.85 (d, J = 9.3 Hz, 1 H, HAr), 7.67 (ddd, J = 9.3, 6.8, 1.3 Hz, 1 H, HAr), 7.42 (d, J = 8.1 Hz, 2 H, HAr tol), 7.06 (t, J = 6.8 Hz, 1 H, HAr), 2.48 (s, 3 H, CH3) ppm; 13

4-(4-Methoxyphenyl)-2-(trifluoromethyl)pyrido[1,2-e]purine (21a).

According to GP3, the reaction was performed with compound 17a (50 mg, 183 μmol) and 4-methoxyphenylboronic acid. The crude product was purified by column chromatography (SiO2, petroleum ether : EtOAc 7:3) to give compound 21a as a yellow solid (43 mg, 69%). m.p.: 216-217 °C; IR (neat): ṽ = 2969, 1640, 1568, 1514, 1403, 1306, 1174, 1050, 715, 601 cm - 1 ; 1 H NMR (400 MHz, CDCl3): δH = 9.08 (d, J = 8.6 Hz, 2 H, HAr tol), 8.84 (d, J = 6.8 Hz, 1 H, HAr), 7.82 (d, J = 9.3 Hz, 1 H, HAr), 7.66 (t, J = 6.8 Hz, 1 H, HAr), 7.13 (d, J = 8.6 Hz, 2 H, HAr tol), 7.06 (t, J = 6.8 Hz, 1 H, HAr), 3.93 (s, 3 H, OCH3); 13

4-(4-Trifluoromethoxyphenyl)-2-(trifluoromethyl)pyrido[1,2-e]purine (22a).

According to GP3, the reaction was accomplished with compound 17a (50 mg, 183 μmol) and 4-(trifluoromethoxy)phenylboronic acid. The crude product was purified by column chromatography (SiO2, CH2Cl2 : petroleum ether 5:5) to give the titled compound as a yellow solid (53 mg, 73%). m.p.: °C; IR (neat): ṽ = 2918, 1641, 1582, 1510, 1386, 1343, 1248, 1050, 1019, 759, 717, 503, 643 cm -1 ; 1 H NMR (400 MHz, CDCl3): δH = 9. 10 (d, J = 8.7 Hz, 2 H, HAr), 8.84 (d, J = 6.8 Hz, 1 H, HAr), 7.80 (d, J = 9.3 Hz, 1 H, HAr), 7.69 (t, J = 6.8 Hz, 1 H, HAr), 7.43 (d, J = 8.4 Hz, 2 H, HAr), 7.09 (t, J = 6.8 Hz, 1 H, HAr) ppm; 13 C NMR (101 MHz, CDCl3): δC = 153.7 (C, CAr), 151.9 (q, J = 1.8 Hz, C-OCF3), 150.5 (C, CAr), 147.5 (C, CAr), 147.3 (q, J = 37.2 Hz, C-CF3), 133.9 (CH, CHAr), 133.7 (C, CAr), 133.0 (C, CAr), 132.2 (2 × CH, CHAr), 125.4 (CH, CHAr), 120.9 (CH, CHAr), 120.6 (q, J = 258.2 Hz, OCF3), 120.4 (q, J = 274.6 Hz, C, CF3), 119.1 (CH, CHAr), 113.0 (CH, CHAr) ppm; 19 F NMR (376 MHz, CDCl3) δF = -57.5, -68.2 ppm; HRMS (ESI): m/z calcd. for C17H9F6N4O [M+H] + 399.0675; found 399.0673.

4-(4-Trifluoromethylphenyl)-2-(trifluoromethyl)pyrido[1,2-e]purine (23a).

According to GP3, the reaction was accomplished with compound 17a (50 mg, 183 μmol) and 4-(trifluoromethyl)phenylboronic acid. The crude product was purified by column chromatography (SiO2, CH2Cl2 : petroleum ether 6:4) to give compound 23a as a yellow solid (56 mg, 80%). m.p.: 164-165 °C; IR (neat): ṽ = 2920, 1638, 1558, 1486, 1420, 1268, 1304, 1214, 1196, 1068, 1047, 891, 807, 719, 653 cm -1 ; 1 H NMR (400 MHz, CDCl3): δH = 9.15 (d, J = 8.1 Hz, 2 H, HAr), 8.86 (d, J = 6.8 Hz, 1 H, HAr), 7.84 (t, J = 8.1 Hz, 2 H, HAr), 7.72 (dd, J = 9.4, 6.6 Hz, 1 H, HAr), 7.11 (t, J = 6.8 Hz, 1 H, HAr) ppm; 13 C NMR (101 MHz, CDCl3): δC = 153.4 (C, CAr), 150.8 (C, CAr), 147.8 (C, CAr), 147.2 (q, J = 37.2 Hz, C-CF3), 138.4 (q, J = 1.6 Hz, C, CAr), 134.2 (CH, CHAr), 133.4 (C, CAr), 133.1 (q, J = 32.6 Hz, C-CF3), 130.6 (2 × CH, CHAr), 125.8 (q, J = 3.74 Hz, 2 × CH, CHAr), 125.5 (CH, CHAr), 124.1 (q, J = 272.5 Hz, CF3), 120.4 (q, J = 274.6 Hz, CF3), 119.2 (CH, CHAr), 113.1 (CH, CHAr) ppm; 19 4-(3-(Trifluoromethylphenyl)-2-(trifluoromethyl)pyrido[1,2-e]purine (25a). According to GP3, the reaction was carried out with compound 17a (50 mg, 183 μmol) and 3-(trifluoromethyl)phenylboronic acid. The crude product was purified by column chromatography (SiO2, petroleum ether : EtOAc 5:5) to give compound 25a as a yellow solid (54mg, 78%). m.p.: 143-144 °C; IR (neat): ṽ = 2921, 1642, 1581, 1498, 1260, 1094, 1075, 904, 759 cm -1 ; 1 H NMR (400 MHz, CDCl3): δH = 9.34 (s, 1 H, HAr), 9.29 (d, J = 7.9 Hz, 1 H, HAr), 8.86 (dd, J = 6.8, 1.2 Hz, 1 H, HAr), 7.90-7.78 (m, 2 H, HAr), 7.78-7.65 (m, 2 H, HAr), 7.11 (t, J = 6.8 Hz, 1 H, HAr) ppm; 13 C NMR (101 MHz, CDCl3): δC = 154.0 (C, CAr), 150.7 (C, CAr), 147.7 (C, CAr), 147.2 (q, J = 37.3 Hz, C-CF3), 136.0 (C, CAr), 134.1 (CH, CHAr), 133.6 (CH, CHAr), 133.2 (C, CAr), 131.4 (q, J = 32.5 Hz, C-CF3), 129.5 (CH, CHAr), 128.2 (q, J = 3.6 Hz, CH, CHAr), 127.1 (q, J = 4.0 Hz, CH, CHAr), 125.5 (CH, CHAr), 124.3 (q, J = 272.4 Hz, CF3), 120.9 (q, J = 258.4 Hz, CF3), 119.2 (CH, CHAr), 113.1 (CH, CHAr) ppm; 19 F NMR (376 MHz,CDCl3): δF = -62.6, -68.1 ppm; HRMS (ESI): m/z calcd. for C17H9F6N4 [M+H] + 383.0726; found 383.0726.

4-(3-Methylphenyl)-2-(trifluoromethyl)pyrido[1,2-e]purine (20a).

According to GP3, the reaction was achieved with compound 17a (40 mg, 147 μmol) and 3-methoxyphenylboronic acid. The crude product was purified by column chromatography (SiO2, petroleum ether : EtOAc 7:3) to give compound 20a as a yellow solid (39 mg, 65%). m.p.: 192-193 °C; IR (neat): ṽ = 2923, 1639, 1573, 1392, 1273, 1221, 1179, 1142, 1054, 924, 793, 754, 649, 624 cm -1 ; 1 H NMR (250 MHz, CDCl3): δH = 8.94-8.72 (m, 3 H, HAr), 7.83 (d, J = 9.4 Hz, 1 H, HAr), 7.66 (ddd, J = 9. 4, 6.8, 1.4 Hz, 1 H, HAr), 7.51 (t, J = 7.6 Hz, 1 H, HAr), 7.39 (d, J = 7.6 Hz, 1 H, HAr), 7.06 (td, J = 6.8, 1.1 Hz, 1 H, HAr), 2.54 (s, 3 H, CH3) ppm; 13

2-(Trifluoromethyl)-4-(2-(trifluoromethyl)phenyl)pyrido[1,2-e]purine (24a).

According to GP3, the reaction was performed with compound 17a (50 mg, 183 μmol) and 2-(trifluoromethyl)phenylboronic acid. The crude product was purified by column chromatography (SiO2, CH2Cl2) to give compound 24a as a yellow solid (52.5 mg, 75%). m.p.: 115-116 °C; IR (neat): ṽ = 2919, 2850, 1640, 1588, 1506, 1400, 1346, 1302,1126, 1067, 908, 759, 657, 525 cm -1 ; 1 H NMR (250 MHz, CDCl3): δH = 8.92 (d, J = 6.9, 1.3 Hz, 1 H, HAr), 7.92 (br d, J = 6.9 Hz, 2 H, HAr), 7.80-7.60 (m, 4 H, HAr), 7.13 (t, J = 6.7, 1.2 Hz, 1 H, HAr) ppm; 13 C NMR (63 MHz, CDCl3): δC = 157.4 (C, CAr), 151.0 (C, CAr), 146.9 (q, J = 37.4 Hz, C-CF3), 146.9 (C, CAr), 134.2 (CH, CHAr), 133.7-133.5 (m, C, CAr), 132.2 (CH, CHAr), 131.8 (CH, CHAr), 130.3 (CH, CHAr), 129.7 (q, J = 31.8 Hz, C-CF3), 127.7 (q, J = 5.0 Hz, CH, CHAr), 125.6 (CH, CHAr), 123.9 (q, J = 274.0 Hz, CF3), 120.3 (q, J = 272.5 Hz, CF3), 119.3 (CH, CHAr), 113.1 (C, CHAr) ppm; 19

4-Phenyl-2-(trifluoromethyl)pyrido[1,2-e]purine (19a).

According to GP3, the reaction was performed with compound 17a (50 mg, 183 μmol) and phenylboronic acid. The crude product was purified by column HAr), 7.23 (br d, J = 7.7 Hz, 2 H, HAr), 7.12 (br t, J = 6.0 Hz, 1 H, HAr), 2.41 (s, 3 H, CH3) ppm; 13

4-((4-Methoxyphenyl)ethynyl)-2-(trifluoromethyl) pyrido[1,2-e]purine (30a).

According to GP4, the reaction was performed with compound 17a (46.6 mg, 171 μmol) and 4-ethynylanisole. The crude product was purified by column chromatography (SiO2, petroleum ether : EtOAc 5:5) to give compound 30a as a yellow solid (54 mg, 86%). m.p.: 208-210 °C; IR (neat): ṽ = 3456, 3015, 2945, 2195, 1738, 1572, 1365, 1251, 1295, 1365, 1216, 1125, 1086, 954, 829, 763 cm -1 ; 1 H NMR (400 MHz, CDCl3): δH = 8.85 (br d, J = 6.5 Hz, 1 H, HAr), 7.87 (d, J = 9.2 Hz, 1 H, HAr), 7.76 (d, J = 8.3 Hz, 2 H, HAr anis), 7.72 (t, J = 6.5 Hz, 1 H, HAr), 7.12 (br t, J = 6.5 Hz, 1 H, HAr), 6.94 (d, J = 8.3 Hz, 2 H, HAr anis), 3.87 (s, 3 H, OCH3) ppm; 13

4-[2-(3-Methoxyphenyl)ethynyl]-2-(trifluoromethyl)pyrido[1,2e]purine (32a).

According to GP4, the reaction was achieved with compound 17a (52 mg, 183 μmol) and 3-ethynylanisole. The crude product was purified by column chromatography (SiO2, petroleum ether : EtOAc 5:5) to give compound 32a as a yellow solid (49.5 mg, 73%). m.p. : 194-195°C; IR (neat): ṽ = 3456, 3015, 2969, 2220, 1739, 1640, 1365, 1269, 1216, 1135, 1034, 907, 852 cm -1 ; 1 H NMR (400 MHz, CDCl3): δH = 8.87 (d, J = 6.9 Hz, 1 H, HAr), 7.89 (d, J = 9.3 Hz, 1 H, HAr), 7.78-7.69 (m, 1 H, HAr), 7.41 (d, J = 7.5 Hz, 1 H, HAr), 7.34 (t, J = 6.7 Hz, 2 H, HAr), 7.14 (t, J = 6.7 Hz, 1 H, HAr), 7.03 (d, J = 8.0 Hz, 1 H, HAr), 3.86 (s, 3 H, OCH3)

4-((2-Methoxyphenyl)ethynyl)-2-(trifluoromethyl)pyrido[1,2-e]purine (31a).

According to GP4, the reaction was carried out with compound 17a (52 mg, 183 μmol) and 2-ethynylanisole. The crude product was purified by column chromatography (SiO2, petroleum ether : EtOAc 5:5) to give compound 31a as a yellow solid (35 mg, 52%). m.p.: 204-205 °C; IR (neat): ṽ = 3455, 3015, 2922, 2200, 1738, 1637, 1409, 1216, 905, 503 cm -1 ; 1 H NMR (250 MHz, CDCl3): δH = 8.84 (d, J = 6.9 Hz, 1 H, HAr), 7.86 (d, J = 9.3 Hz, 1 H, HAr), 7.76-7.67 (m, 2 H, HAr), 7.51-7.36 (m, 1 H, HAr), 7.11 (t, J = 6.7 Hz, 1 H, HAr), 7.04-6.90 (m, 2 H, HAr), 4.00 (s, 3 H, OCH3) ppm; 13

4-((4-Fluoro-3-methylphenyl)ethynyl)-2-(trifluoromethyl) pyrido[1,2e]purine (34a).

According to GP4, the reaction was performed with compound 17a (52 mg, 183 μmol) and 4-ethynyl-1-fluoro-2methylbenzene. The crude product was purified by column chromatography (SiO2, petroleum ether : EtOAc 5:5) to give compound 34a as a yellow solid (41 mg, 60%). m.p.: 192-193 °C; IR (neat): ṽ = 3120, 2920, 2849, 2210, 1968, 1510, 1222, 1142, 800, 803 cm -1 ; 1 H NMR (250 MHz, CDCl3): δH = 8.86 (dt, J = 6.9, 1.2 Hz, 1 H, HAr), 7.89 (dt, J = 9. 4, 1.2 Hz, 1 H, HAr), 7.78-7.57 (m, 3 H, HAr), 7.13 (td, J = 6.9, 1.2 Hz, 1 H, HAr), 7.06 (t, J = 9.4 Hz, 1 H, HAr), 2.32 (d, J = 2.0 Hz, 3 H CH3) ppm; 13 According to GP4, the reaction was performed with compound 17a (52 mg, 183 μmol) and tert-butylacetylene. The crude product was purified by column chromatography (SiO2, petroleum ether : EtOAc 6:4) to give compound 33a as a yellow solid (38 mg, 65%). m.p.: 228-229 °C; IR (neat): ṽ = 3458, 2925, 2852, 2220, 1738, 1640, 1488, 1365, 1270, 1153, 900, 762, 762, 743 cm -1 ; 1 H NMR (400 MHz, CDCl3): δH = 8.83 (d, J = 6.8 Hz, 1 H, HAr), 7.86 (d, J = 9.4 Hz, 1 H, HAr), 7.78-7.64 (m, 1 H, HAr), 7.10 (t, J = 6.8 Hz, 1 H, HAr), 1.49 (s, 9 H) ppm; 13

7-Methyl-4-(p-tolylethynyl)-2-(trifluoromethyl)pyrido[1,2-e]purine (28b).

According to GP4, the reaction was performed with compound 17b (52 mg, 183 μmol) and 4-ethynyltoluene. The crude product was purified by column chromatography (SiO2, petroleum ether : EtOAc 7:3) to give compound 28b as a yellow solid (40 mg, 60%). m.p. : 198-200 °C; IR (neat): ṽ = 3455, 3015, 2946, 2205, 1739, 1367, 1407, 1216, 1149, 1128, 1087, 952, 817, 766 cm -1 ; 1 H NMR (400 MHz, CDCl3): δH = 8.69 (d, J = 7.0 Hz, 1 H, HAr), 7.68 (d, J = 8.0 Hz, 2 H, HAr), 7.57 (s, 1 H, HAr), 7.21 (d, J = 7.9 Hz, 2 H, HAr), 6.93 (d, J = 7.9 Hz, 1 H, HAr), 2.55 (s, 3 H, CH3), 2.40 (s, 3 H, CH3) ppm; 13 : 193-194 °C; IR (neat): ṽ = 3455, 3015, 2945, 2202, 1739, 1650, 1571, 1365, 1249, 1216, 1161, 1092,


Paolo Celli
email: pcelli@caltech.edu

Connor Mcmahan

Brian Ramirez

Anton Bauhofer

Christina Naify

Douglas Hofmann

Basile Audoly

Chiara Daraio
email: daraio@caltech.edu

Shape-morphing architected sheets with non-periodic cut patterns

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Imparting elastic sheets with a mesoscale architecture by folding [1,2], perforating [3][4][5], or patterning them [6][7][8],

enables the creation of materials with unusual characteristics, such as extreme extensibility [9], deployability [10,11] and auxeticity [12]. These properties can be leveraged to design sheets that morph into complex three-dimensional objects. For example, origami sheets can be turned into nearly-arbitrary shapes [13,14], but are typically challenging to fold [START_REF] Demaine | 33rd Int. Symp. on Comput. Geom. (SoCG[END_REF] or actuate [START_REF] Hawkes | [END_REF][17][18]. Patterned elastomeric sheets [6,19], bilayers [20] and sheets with smart hinges [21][22][23] can morph into three-dimensional surfaces via non-mechanical stimuli, but their fabrication is complex. Ribbon-and membrane-like flat mesostructures, made of elastic or brittle materials, can buckle out of plane and produce threedimensional geometries when subject to mechanical actuation in compression [24,25] or tension [26,[START_REF] Guo | npj Flexible Electron[END_REF]. However, compressive actuation requires pre-stretched substrates and non-trivial assembly processes, and the geometries obtained via tensile loads are limited to thin, arch-like features.

In contrast to shape-morphing origami or bilayer films, sheets with architected cut patterns can be easily fabricated via subtractive technologies. Their out-of-plane deformation can be triggered by manual forming [START_REF] Konaković | [END_REF]29], via the actuation of smart hinges [30], or by applying compressive boundary loads [25,31,32]. Recently, it has been demonstrated that sheets with periodic perforations can also buckle locally in tension [START_REF] Guo | npj Flexible Electron[END_REF][33][34][35][36], producing crease patterns that can be used for soft robotic locomotion [37] or as coatings for sunlight control [36]. However, since these buckling modes take place at the scale of the unit cells, the size of the transverse features they can produce cannot significantly exceed the typical length of the cuts. Non-periodic cut patterns have been seldom explored in this context: non-periodicity is known to lead to geometric frustration [38,39], i.e., the desired deformation mode is impeded by the geometric incompatibility between neighboring cells. In the few cases where non-periodic cut patterns have been explored, frustration has been avoided [40][START_REF] Ion | UIST '16[END_REF][START_REF] Mirzaali | [END_REF]. In particular, the effect of geometric frustration on the out-of-plane deformations of thin architected sheets has been ignored so far.

In this work, we study the tensile response of elastic sheets featuring non-periodic cut patterns, and intentionally leverage geometric frustration to induce controllable, global shape changes via buckling. In most of our designs, we use point-like boundary loads that induce large deformations in selected sub-domains of the sheets.

The inhomogeneous distribution of strains results into global buckling modes that make the sheets bend out of plane: we use this principle to obtain both dome-like surfaces, and patterns of wrinkles confined to pre-determined regions of the sheets. We show that the buckling pattern can be changed by applying the load at different points.

We also extend the method to initially cylindrical-rather than planar-sheets and to cut patterns arranged into non-rectangular grids, and we demonstrate the formation of persistent three-dimensional surfaces by using sheets made of elastic-plastic materials [35].

We start by analyzing a simple cut pattern featuring a large-amplitude, planar mode of deformation. A 108by-108 mm, 1.55 mm-thick natural rubber sheet is laser-cut [43] following a pattern of (i ) diamond-shaped cut-outs and (ii ) straight cut lines ending close to the diamonds' vertices. These two types of cuts are visible in black in the insets of Figure 1. The result is an array of 18×18 rhomboid tiles, visible in grey in the pictures, connected by thin hinges. The experimental traction curves (Figure 1) for unaxial tension reveal a strongly anisotropic and non-linear behavior (see the Experimental Section and SI Section S1 for details). When the tension is applied in the in-plane direction referred to as the x-direction (horizontal direction in the figure, black lines) the response is initially compliant up to a stretch value λ ∼ 1.3, and then becomes much stiffer. When the tension is applied in the perpendicular y-direction (vertical direction in the figure, gray lines), the response is stiff and approximately linear for the range of stretch investigated; no initial compliant regime is observed. We simulated the mechanical response of the architected sheet numerically as well, by meshing a rectangular domain with periodic cut-outs, and by using a finite-element (FE) model for a neo-Hookean material in plane strain (the plane strain assumption is Figure 1: Uniaxial tension test of a periodic sheet whose undeformed geometry is shown in (a). The plot in the background shows the loading curve when the applied tension is either along the horizontal direction (black lines) or along the vertical direction (grey lines), both from experiments (solid lines) and from finite element simulations (dashed lines). The vertical dash-dot line shows the maximum stretch predicted by the kinematic analysis, where a geometric-to-elastic transition takes place. Insets (a-d) show snapshots of a 4×4-tile portion of the sheet at different levels of deformation (scale bar is 6 mm). The red and blue overlaid lines are obtained by joining the diagonals in a particular row and column of tiles, respectively, and are used to predict the maximum stretch by a kinematic analysis.

applicable as the in-plane width of the hinges is smaller than their out-of-plane thickness, see SI Section S2). The traction curves predicted by simulation are in good agreement with the experiments (Figure 1).

The salient features of the loading curves can be explained by a kinematic analysis, in which the sheet is modeled as an array of rigid tiles connected by pin joints. Such networks can feature modes of deformation known as mechanisms [44], which are mapped to low-energy configurations of the elastic sheet involving bending and shear [5] at the joints only. A mechanism relies on the coordinated rotation of the tiles in response to applied tension (Figure 1, SI Section S3 and [45,46]). In particular, the maximum stretch attainable via a mechanism can be derived by a geometric argument, considering the broken lines connecting the diagonals of the tiles in a given row or column, see red and blue lines overlaid in Figure 1(a). As the length of these lines is preserved by mechanisms, the maximum stretch in the x or y direction is attained when the corresponding line is fully stretched out. For the cut design used in Figure 1, this maximum stretch is calculated by a geometric argument as λ x = 1.33 in the x-direction, as indicated by the dash-dotted line in the figure; this is indeed where the compliant-to-stiff transition is observed in the experimental and numerical traction curves. For this particular cut design, the line of diagonals in the y-direction is already straight in the initial configuration, see the blue line in Figure 1(a), meaning that no mechanism can be activated when the tension is applied in the y-direction; this is consistent with the absence of an initial compliant regime in the grey curves in Figure 1.

Next, we introduce a family of periodic cut patterns parameterized by design variables. Our generic pattern, sketched in Figure 2(a), is obtained by cutting out diamonds with alternating directions, centered at the nodes of a grid of N x × N y rectangles, each with dimensions l x × l y . The two families of diamonds are assigned different widths, w x and w y , so that the previous design comprising line-cuts can be recovered as the special case w y = 0.

The length of the diamonds is such that a gap (hinge) of width δ is present between adjacent diamonds. Three examples of periodic geometries cut out in natural rubber sheets are shown in Figure 2(b-d), for N x = N y = 18, l x = l y = 6 mm, and out-of-plane thickness t = 1.55 mm; note that the shape of the tiles, shown in light grey, can now vary from rhomboid to square. Experimental traction curves for three particular cutting patterns are plotted in the plane of stretches (λ x , λ y ) in Figure 2(e), and compared with the predictions of the kinematic analysis (see SI Section S3 for a detailed derivation),

λ y (λ x ) = d v l y sin γ + arccos λ x l x d h , (1)
where

d h = l 2 x + [l y -2w y -δ] 2 and d v = l 2 y + [l x -2w x -δ] 2
are the lengths of the diagonals of a tile, and γ is the angle between these diagonals. The design variables have a strong influence on tension tests. The cut pattern in Figure 2(b) gives rise to an auxetic mechanism [12] having a negative Poisson's ratio ν = -1; this is reflected by the positive slope of the black curve in Figure 2(d). By contrast, the mechanism associated with the cut pattern in Having analyzed a family of periodic cut patterns parameterized by the design variables w x and w y , we now investigate non-uniform designs, obtained by specifying arbitrary values of w x and w y in every cell of a rectangular grid; the cell size l x × l y is uniform throughout the sheet. Upon deformation, we expect that every unit cell of these non-periodic sheets will try to follow the mechanism corresponding to the local values of w x and w y , as described by Equation ( 1). However, mechanisms corresponding to neighboring cells are not geometrically compatible in general (see SI Section S3). Thus, we investigate how this incompatibility is resolved at the global level by buckling. As a first example, we consider a cut geometry where w x is constant while w y varies sinusoidally in the y-direction, see Figure 3(a1), using a 1.55 mm-thick natural rubber sheet with N x = 36, N y = 18, l x = 6 mm, l y = 2 l x . This x (y): this shows that the sheet is highly stretchable in the center, but inextensible along its upper and lower edges. (a2) A dome shape obtained when the sheet is pulled from two boundary points. (b1) Undeformed configuration of a specimen featuring two soft and auxetic regions in its interior, which give rise to two localized bumps upon pulling at the four corners (b2). (c1-c3) Undeformed and deformed configurations of another specimen, highlighting the influence of the boundary loading on the pattern of wrinkles. The right-halves of (b2), (c2) and (c3) are the stress maps of σ zz = ν(σ xx + σ yy ) (under the plane strain assumption); negative values of the average in-plane stress (σ xx + σ yy ) are taken as an indicator for buckling. (d1-d2) Shaping wrinkles: a C-shaped soft and auxetic region is embedded in a sheet by a suitable choice of the maps of w x and w y in the reference configuration (d1). The wrinkles localize upon the application of boundary loads (d2). The orange arrows indicate the boundary loads. Scale bar: 12 mm. choice of maps for w x and w y ensures that the top and bottom parts of the sheet are virtually undeformable, see the inset in Fig. 3(a1), while the center is highly stretchable. When the sheet is stretched by point-like forces, as in Figure 3(a2), the strong geometric incompatibility between the center and the edges produces a global buckling mode spanning the central region. Note that this buckling instability takes place in tension, unlike in the classical Euler buckling. For a given cut pattern, the dependence of the buckled configuration on the sheet's thickness t is similar to what can be expected from the classical theory of plates without cut-outs, see Section S6 for details.

As t increases, the onset of buckling occurs at larger critical stretches, consistent with the fact that the effective bending modulus is larger. An increased thickness also yields larger deflections and makes the buckling pattern spread further away from the the line of application of the force.

More complex buckling patterns can be obtained by letting both w x and w y vary along the sheet, either smoothly or abruptly. As an example, we study a sheet comprising two stretchable and auxetic islands surrounded by unstretchable and non-auxetic regions, see Figure 3(b1). This geometry induces strong geometric incompatibilities: when the sheet is stretched, the auxetic islands tend to swell in the transverse direction. This swelling is prevented by the surrounding stiff regions, and compressive in-plane stress appears, as confirmed by the FE simulations in Figure 3(b2). Ultimately, this leads to a buckling pattern made up of two domes localized on the auxetic islands, see Figure 3(b2). As another example, we study the response of a sheet with a more complex cut pattern obtained by varying both w x and w y sinusoidally along both the horizontal and vertical directions. The experimental results in (c2) and (c3), corresponding to actuation at the structures' corners or boundary mid-points, respectively, show markedly different wrinkle patterns, thereby highlighting the role of the applied force in selecting the pattern. Finally, in Figure 3(d1-d2), we show the response of a sheet featuring a C-shaped auxetic region separated from the rest of the sheet, which is unstretchable, by a sharp boundary. In this case, pulling the specimen as indicated by the orange arrows leads to wrinkles localized along the C-like domain. The wavelength of the wrinkles is comparable to the width of the C-shaped domain. These examples show that the buckling patterns can be tailored by engineering the sheet's local properties through the maps of w x and w y , and by choosing the points of application of the load.

Our approach can be extended to solids of revolution. For example, we pattern a sheet by varying w x and w y in vertical stripes, alternating regions of auxetic and not-auxetic behavior. We then roll the sheet, forming a tube, and pull on its ends. The applied tractions force the tube to expand at prescribed, auxetic sections and to contract at others [47], see Figure 4(a). Stretching the tube further produces a non-axisymmetric buckling bifurcation, with an azimuthal wavelength roughly comparable to the stripes' width. Cut patterns can also be attached to non-Cartesian grids, as illustrated in the example in Figure 4(b), where the petal-like sheet closes up into a pea pod shape when pulled at its ends.

The design strategy is not limited to elastic materials such as rubber. Permanent three-dimensional shapes can be obtained by using an elastic-plastic material [35]. This requires modifying the hinge design to avoid breakage: the new design, shown in the insets in Figure 4(c), was inspired by [48] and is discussed in SI Section S7. The deformation of two sheets featuring the same initial cut pattern, one made of natural rubber and one made of stiff PETG are compared in Figure S12. While they feature a similar buckling pattern, the second sheet deforms irreversibly, leaving a permanent pattern after load removal. We leverage the elastic-plastic behavior to sculpt axisymmetric shapes out of a planar PETG sheet, see Figure 4(c-d). As earlier with the tube, the cut patterns are graded along the axis, which allows us to select the radial expansion (hence the target radius) as a function of the axial coordinate. To obtain an even larger stretchability contrast, we use non-regular rectangular grids, i.e., we set l y (y) to take on larger values in the regions of large stretch. The irreversible deformations are obtained by stretching the sheet locally by hand, and a similar effect could be achieved using localized smart-material actuators or pressurized membranes. These structures are reminiscent of gridshells [49] and are easier to fabricate, especially at small scales.

In this work, we have demonstrated that geometric incompatibility can be leveraged to create three-dimensional objects from sheets with non-periodic cut-outs. By choosing the properties of the cuts locally, one can prescribe a map of maximum stretch, which is resolved when the sheet bends out of plane in response to boundary loads or local stretching. While the shapes we have obtained are relatively simple, these design principles could be extended to different families of mechanisms, and could be coupled to optimization and inverse-design strategies to obtain more complex shapes. Due to the flexibility of the fabrication process, which involves cutting mono-layer sheets, this approach could be used to produce three-dimensional structures at vastly different scales.

Experimental Section

Specimen fabrication. A Universal ILS9 120W laser cutter is used to create perforations. We mainly use 1.55 mmthick natural rubber sheets (McMaster-Carr, item no. 8633K71), but some 3.1 mm-and 0.75 mm-thick ones were also used (Grainger, items no. 1XWE5 and 8611K18). For the 1.55 mm-thick specimens, the machine is set to cut at 35% power and 5% speed, with an air assist flow rate of 100% to avoid burning the specimens. For the 3.1 mm-thick specimens, 45% power and 2.3% speed are selected. For the 0.75 mm-thick specimens, 30% power and 5% speed are selected. Since the laser beam has a finite cutting diameter, the hinges are not characterized by sharp corners but are de-facto beams having a finite length. The tube specimens are closed using double-sided tape glued to some tiles. PETG sheets (0.5 mm-thick) were perforated with the same laser cutter, with 3.0% power and 2.2% speed, and were also closed into surfaces of revolution using double-sided tape.

Material testing. Uniaxial tensile tests are conducted using an Instron ElectroPuls (Model E3000) system equipped with a 250 N load cell at a constant deformation rate of 2 mm s -1 . The specimens are stretched by pulling on some of the hinges using a customized fixture which allows for lateral expansion or contraction of the sheets being pulled (see SI Section S1). The tensile forces and displacements are measured with 1 mN and 5 µm accuracy, respectively, at an acquisition rate of 1 kHz. The force-displacement data obtained from the Instron WaveMatrix software is converted to stress-stretch data using the original sample dimensions. The data obtained is then subsampled to remove some of the noise (one every 10 measurements is kept). Finally, the stretch is adjusted to account for the self-weight elongation experienced by some specimens featuring a pronounced mechanism-like behavior along the direction parallel to the load.

Figure 2 :

 2 Figure 2: (a) Sketch of a generic periodic architecture parameterized by design variables. (b-d) Digital images of details of three periodic undeformed specimens, corresponding to different values of (w x , w y ) listed in Section S4 in the SI; scale bar is 6 mm. (e) Transverse stretch λ y as a function of the axial stretch λ x for simple traction along the x-direction, and for the same set of specimens: experiments (open symbols) versus preditions of the kinematic model (solid curves).

Figure 1

 1 Figure 1 and 2(c) has a positive Poisson's ratio. For both these cut patterns, the kinematic model in Equation (1)provides an accurate prediction of the transverse stretch λ y (λ x ) up to around λ x ∼ 1.3, where the joints start to stretch, see Figure2(e). Finally, the cut pattern in Figure2(d) is stiff when loaded in tension since the maximum stretch λ x = 1 predicted by the kinematic analysis is attained in the undeformed configuration (the diagonals of adjacent tiles are aligned). The effect of the design parameters δ and t on the in-plane response is investigated in the SI, Section S5.

Figure 3 :

 3 Figure 3: Out-of-plane morphing of sheets with non-periodic cut patterns. (a1) Cut pattern with gradient in the y direction. The inset to the right of the undeformed configuration highlights the tile diagonals (in red), that are inextensible by the local kinematic analysis, as well as a plot of the corresponding maximum stretch λ Mx (y): this shows that the sheet is highly stretchable in the center, but inextensible along its upper and lower edges. (a2) A dome shape obtained when the sheet is pulled from two boundary points. (b1) Undeformed configuration of a specimen featuring two soft and auxetic regions in its interior, which give rise to two localized bumps upon pulling at the four corners (b2). (c1-c3) Undeformed and deformed configurations of another specimen, highlighting the influence of the boundary loading on the pattern of wrinkles. The right-halves of (b2), (c2) and (c3) are the stress maps of σ zz = ν(σ xx + σ yy ) (under the plane strain assumption); negative values of the average in-plane stress (σ xx + σ yy ) are taken as an indicator for buckling. (d1-d2) Shaping wrinkles: a C-shaped soft and auxetic region is embedded in a sheet by a suitable choice of the maps of w x and w y in the reference configuration (d1). The wrinkles localize upon the application of boundary loads (d2). The orange arrows indicate the boundary loads. Scale bar: 12 mm.

Figure 4 :

 4 Figure 4: (a) An architected tube can expand or contract radially based on an initial stripe pattern. Beyond a critical tensile load, an azimuthal buckling pattern appears in the expanded regions. (b) Petal-shaped specimen generated from a non-rectangular grid. This sheet morphs into a pea pod-shaped object when pulled from its ends. (c-d) Sculpting axisymmetric shapes from a sheet made of an elastic-plastic material; the shapes are obtained by using graded cut patterns and by stretching out the sheets locally by hand. Scale bars: 12 mm.

Acknowledgements

This research was carried out at the California Institute of Technology and the Jet Propulsion Laboratory under a contract with the National Aeronautics and Space Administration, and funded through the President's and Director's Fund Program. This work is partially supported through the Foster and Coco Stanback Space Innovation Fund. P.C. wishes to thank D. Pasini of McGill University for useful suggestions, A. Constantinescu of École Polytechnique, and members of C.D.'s research group at Caltech for their input and suggestions. We also thank B.

Supporting Information

Supporting Information is available in tail of this manuscript.