Ultrasound irradiation promotes the synthesis of new 1,2,4-triazolo[1,5-a]pyrimidine

Ultrasonics Sonochemistry 21 (2014) 958–962

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Ultrasound irradiation promotes the synthesis of new 1,2,4-triazolo [1,5-a]pyrimidine Clarissa P. Frizzo, Elisandra Scapin, Mara R.B. Marzari, Taiana S. München, Nilo Zanatta, Helio G. Bonacorso, Lilian Buriol ⇑, Marcos A.P. Martins ⇑ Núcleo de Química de Heterociclos, Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil

a r t i c l e

i n f o

Article history: Received 15 June 2013 Received in revised form 28 November 2013 Accepted 11 December 2013 Available online 21 December 2013 Keywords: Ultrasound 1,2,4-Triazolo[1,5-a]pyrimidine Enaminones Trifluoromethyl enones

a b s t r a c t Ultrasonic irradiation was used in the synthesis of a series of novel 1,2,4-triazolo[1,5-a]pyrimidines. The products were synthetized from the cyclocondensation reaction of 1,1,1-trifluoro-4-metoxy-3-alken-2one [CF3C(O)CH@C(R)OMe, where R = Ph, 4-F-C6H4, 4-Br-C6H4, 4-I-C6H4, 4-CH3-C6H4, 4-CH3O-C6H4, Thien-2-yl, Biphen-4-yl] or b-enaminones [RC(O)CH@CHNMe2, where R = Ph, 4-F-C6H4, 4-Br-C6H4, 4-IC6H4, 4-CH3-C6H4, 4-CH3O-C6H4, 4-NO2-C6H4, Thien-2-yl, Biphen-4-yl, Naphth-2-yl, Pyrrol-2-yl, CCl3] with 5-amino-1,2,4-triazole in acetic acid at 99 °C with 5–17 min of ultrasound irradiation. This methodology has shown several advantages, such as shorter reaction times, mild conditions, high regioselectivity, and excellent yields, when compared with conventional thermal heating (oil bath). Ó 2013 Elsevier B.V. All rights reserved.

1. Introduction Triazolo [1,5-a]pyrimidine derivatives have attracted a lot of attention in the medical field due to their broad-spectrum biological activities as cardiovascular vasodilators [1] and human A2a adenosine and A3 receptor ligands [2]. Additionally, substituted triazolopyrimidine-2-sulfonamides, such as flumetsulam [3], florasulam [4], and metosulam [5], have shown excellent herbicidal and plant growth regulation [6]. Consequently, various derivatives of 1,2,4-triazolo[1,5-a]pyrimidine have found applications in pharmaceutics, agriculture, and other areas [7]. The synthesis of triazolopyridines from the heterocyclization of aminotriazole and 1,3-dieletrophiles such as enaminones, chalcones, dicarbonyl and substituted vinyl ketones is conventionally performed in the reflux of acetic acid, acetonitrile, ethanol, or pyridine/HCl; however, significant variations in yields and reaction times limit the choice of substrates that can be utilized. The synthesis of trifluoromethylated triazolo[1,5-a]pyrimidine from trifluoromethylated substrates is limited [8]. The incorporation of fluorine into a drug allows simultaneous modulation of electronic, lipophilic and steric parameters, all of which can critically influence both the pharmacodynamic and pharmacokinetic properties of drugs. The small size, very low polarizability, and the strong inductive effect are responsible for biophysical and chemical properties such as

⇑ Corresponding authors. Tel.: +55 5532208756. E-mail addresses: [email protected] (L. Buriol), [email protected] (M.A.P. Martins). 1350-4177/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ultsonch.2013.12.007

hydrophobicity, acidity/basicity, reactivity, as well as the conformation of compounds where fluorine atoms or the trifluoromethyl group is present [9]. Additionally, the development in the last few years of synthetic protocols employing ultrasound irradiation has led to an important change in organic reactions and has permitted the activation of poorly reactive substrates [10]. Notable features of the ultrasonic irradiation method include enhanced reaction rates, the formation of purer products at high yields, easier manipulation, and improved energy conservation, when compared with the conventional thermal heating method (oil bath) [11]. These characteristics for using ultrasound irradiation are demonstrated in the synthesis of various heterocycles described in the literature [12]. Our research group has published about the synthesis of azolopyrimidines, both under ultrasound irradiation and with the conventional method. The results showed that the use of ultrasound furnishes shorter reaction times than the microwave method and higher yields [13,14]. Over the past 20 years, our research group has been studying the synthesis of 4-alkoxy-1,1,1-trihalo-3-alken-2-ones and their effectiveness in heterocyclic preparations [15]. During this time we have supported the importance of these halogen-containing building blocks in heterocyclic synthesis and more recently we have been focusing our attention on minimizing waste generation, reducing reaction time, and improving yields, by using ionic liquid [16], solvent-free solutions [17], microwave [16d,e,18], and ultrasound irradiation [8a,13] to promote the reactions. Therefore, in the continuation of our work, and considering the importance of

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triazolo[1,5-a]pyrimidine and the restrictions to its synthesis, we will describe an efficient and mild approach to the synthesis of regiospecific 1,2,4-triazolo[1,5-a]pyrimidines under ultrasonic irradiation and compare the results with those from conventional thermal heating.

Table 2 Synthesis of compounds 3a-h.

O F3 C

R

2. Results and Discussion

Entry

a

Ph

F3 C

+

NH2

N N

1a

i

NH

Ph 4-F-C6H4 4-Br-C6H4 4-I-C6H4 4-CH3-C6H4 4-CH3O-C6H4 Thien-2-yl Biphen-4-yl

3a 3b 3c 3d 3e 3f 3g 3h

Time (min)

Temperature (°C)

Yielda (%)

1 2 3 4 5 6

CH3CN CH3CN EtOH AcOH AcOH AcOH

5 10 5 5 10 10

81 81 78 99 99 99

0 7 0 84 66 52

Oil Bath

Ultrasound

94 84 97 85 91 88 95 97

84 82 81 87 80 78 60 84

N

N Me + N Me

NH2

N

N N

i

NH

N

4a

5a

2

i: US

a

Entry

Solvent

Time (min)

Temperature (°C)

yield (%)a

1 2 3 4 5 6

AcOH AcOH AcOH AcOH EtOH EtOH

5 10 15 17 5 15

99 99 99 99 75 75

55 72 76 93 5 15

Yield of isolated product.

Table 4 Synthesis of compounds 5a-l.

O Me N Me

R

+

N

i or ii

NH

R

Product

Ph 4-F-C6H4 4-Br-C6H4 4-I-C6H4 4-CH3-C6H4 4-OCH3-C6H4 4-NO2-C6H4 Biphen-4-yl Naphth-2-yl Thien-2-yl Pirrol-2-yl CCl3

5a 5b 5c 5d 5e 5f 5g 5h 5i 5j 5k 5l

Yield of isolated product.

N

N N N

R

2

i: AcOH, reflux, 16 h.

a

NH2

N

4a-l

3a

Solvent

Yield (%)a

Product

CF3

Entry

Yield of isolated product.

ii: US, AcoH, 5-15 min, 99ºC

O

i: US

a

2

Table 3 Optimization reaction for compound 5a.

N N

2

N N

Yield of isolated product.

Ph

N

N

R

CF 3

R

1 2 3 4 5 6 7 8

i or ii

NH

N

i: AcOH, reflux, 6 h

Table 1 Optimization reactions for obtaining compound 3a.

OMe

N

+

N

N

NH 2

1a-h

We started our investigation by examining the cyclocondensation reaction of 1,1,1-trifluoro-4-methoxy-4-phenyl-3-alken-2one (1a) with aminotriazole (2), under ultrasound irradiation. The ultrasound amplitude was established based on the relation between temperature reached by theses solvents during 5 min of irradiation. Solvents such as AcOH, EtOH, and CH3CN reached the highest temperature when an amplitude of 20% was tested to optimize the reaction. According to Table 1, the reactions in AcOH lead to products that have higher yields than for other solvents. Thus, the best reaction condition for obtaining compound 3a was when AcOH was used as the solvent at 99 °C for 5 min. The optimization reaction was used as a model for the synthesis of novel 1,2,4-triazolo[1,5-a]pyrimidines 3b–h and the products were obtained at a yield of between 78% and 97%. The reactions were also performed using the conventional method (oil bath), based on the literature [14,19]. Thus, the mixture of 1,1,1-trifluoro-4-methoxy-3-alken-2-ones 1a–h with aminotriazole 2 in AcOH was refluxed for 6 h to obtain compounds 3a–h at yields of between 70% and 97%. The results are shown in the Table 2. These results prove the efficiency of ultrasonic irradiation for this reaction and the value of synthesizing 7-trifluoromethyltriazolo[1,5-a]pyrimidines. It is important to highlight that 1,2,4-triazolo[1,5-a]pyrimidines 3b–h are novel compounds – their synthesis and spectral properties are described here for the first time. Only compound 3a has been previously described using 2-ethoxyvinyl trifluoromethyl ketones and 2,2-diethoxyvinyl trifluoromethyl ketone with 3-amino-1,2,4-triazole and conventional thermal heating [8b]. Continuing with our work, we also evaluated the synthesis of 7-aryl-1,2,4-triazolo[1,5-a]pyrimidine from the cyclocondensation reaction of b-enaminone 4a with aminotriazole 2 under ultrasound irradiation. The solvents and conditions tested were the same as those tested in the reaction with 1,1,1-trifluoro-4-metoxy-3-alken-2-ones. According to Table 3, the best condition for total conversion of the reactants into 7-aryl-1,2,4-triazolo[1,5-a]pyrimidine 5a was by heating AcOH at 99 °C for 17 min, using 20% amplitude. Subsequently, we investigated the scope of this reaction by extending the synthesis to other 1,2,4-triazolo[1,5-a]pyrimidines,

O

OMe

5a-l ii: AcOH, 99ºC, 17 min. Yield (%)a Oil Bath

Ultrasound

94 89 89 85 91 90 82 89 96 90 85 83

93 76 83 90 96 96 82 91 94 76 74 79

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using the condition aforementioned. The 7-aryl-1,2,4-triazolo[1,5-a] pyrimidines 5b–l were obtained at yields of between 65% and 96% (Table 4). To prove the effect of the ultrasound irradiation for this reaction, they were also synthesized using the conventional method (oil bath) [14]. Thus, the mixture of b-enaminone (4a–l) and aminotriazole 2 in AcOH was stirred under reflux for 16 h to furnish the compounds 5a–l at yields of between 73% and 96% (Table 4). It is worth noting that compounds 5e, 5i and 5j are described here for the first time. Compounds 5a–d,f–h have previously been described using salt vinyloqous iminium salts [20], and compounds 5k,l have been described using N,N-dimethylformamide dimethyl acetal instead of enaminones [21]. The ultrasonic cavitation process provokes higher energy by formation, growth, and collapse of several million microscopic vapor bubbles (voids) in the liquid [22]. This cavitationally induced phenomenon is known to activate reactant molecules entering into cavity and consequently converts them into reactive intermediates. In the reactions studied in this paper, the effects of ultrasonic irradiation are probably physical. The higher temperature and the formation of the stable colloidal particles enable it to shorten the reaction time. The formation of chemical species that are able to accelerate the reaction is possible; however, the formation of intermediates was not monitored. Thus, it is not possible to affirm that chemical effects are occurring [22]. The structures of compounds 3a–h and 5b–l were determined using 1H and 13C NMR spectroscopy and mass spectrometry. The compounds exhibited chemical shifts of protons (1H NMR spectra) that are typical for these type of compounds. For example, we can cite compound 3c – the chemical shift of H6 was 8.65 ppm and for H2 it was 7.88 ppm. The same compound showed 13C NMR spectra with chemical shifts at the C5 and C2 of 160.7 and 157.4 ppm, respectively. Additionally, signals of the C6, C7, and CF3 groups appeared at 105.1, 135.9 and 118.7 ppm as a quartet with 3J4, 2J39 and 1J274 Hz, respectively, due to a 13CA19F scalar coupling. Another example analyzed was the compound 5a which presented chemical shifts at 7.25 ppm for the H6, a signal at 8.56 ppm for the H2, and a signal at 8.88 ppm for the H5. This information corresponds with the proposed structure that was confirmed by X-ray diffraction for compound 5a, as shown in Fig. 1. The crystal data and details about data collection and structural refinement are given in Table 5 [23].

Table 5 Crystal data and structure refinement of 7-Phenyl-1,2,4-triazolo[1,5-a]pyrimidine (5a). CCDC No.

941736

Formula Mr Temperature (K) Wavelength (Å) Crystal system, space group Unit cell parameters a (Å) b (Å) c (Å) a (°) b (°) c (°) V (Å3) Z Density (calculated) (mg/m3) Absorption coefficient (mm-1) F (000) Crystal size (mm) h Range for data collection (°) Limiting indices Reflections collected / unique Completeness to h = 30.08 (%) Absorption correction Max. and min. transmission Refinement method Data / restraints / parameters Goodness-of-fit on F2 Final R indices [I > 2d(I)] R indices (all data) Largest diff. peak and hole (e A-3)

C11H8N4 196.21 293(2) 0.71073 Orthorhombic, p212121 7.2004(4) 10.3021(6) 12.7074(7) 90 90 90 942.63(9) 4 1.383 0.089 408 0.35 x 0.21 x 0.19 2.55 to 27.92 -10 6 h 6 10, -15 6 k 6 15, -23 6 l 6 23 8529 / 2264 [R(int) = 0.0226] 98.8 Gaussian 0.9833 and 0.9695 Full-matrix least-square on F2 2264 / 0 / 136 1.031 R1 = 0.0401, wR2 = 0.0983 R1 = 0.0623, wR2 = 0.1124 0.106 and -0.161

3. Experimental 3.1. Materials The reagents and solvents used were obtained from commercial suppliers without further purification. The reactions in ultrasound were done with a tapered microtip probe (6 mm) connected to a Sonics Vibra-Cell™ (500 W) ultrasonic processor equipped with an integrated temperature control probe. The device operates at 20 kHz of frequency and the amplitude was set to 20% of the maximum power output. The equipment can operate at a maximum temperature of 99 °C. 1H and 13C NMR spectra were recorded on a Bruker DPX 400 (1H at 400.13 MHz and 13C at 100.62 MHz) and Bruker DPX-200 (1H at 200.13 MHz and 13C at 50.32 MHz) in CDCl3/TMS solutions at 298 K. Chemical shifts (d) are given in ppm. Mass spectra were registered in a HP 5973 MSD connected to a HP 6890 GC and interfaced by a Pentium PC. The GC was equipped with a split-splitless injector, cross-linked to a HP-5 capillary column (30 m, 0.32 mm i.d.), and helium was used as the carrier gas. The melting points were measured using a Microquímica MQAPF 301. 3.2. Synthesis of 1,1,1-trifluoro-4-methoxy-4-phenyl-3-alken-2-one 1,1,1-Trifluoro-4-methoxy-4-phenyl-3-alken-2-one 1a–h were obtained from the acylation reaction of enol ether or acetal with trifluoroacetic anhydride, in accordance with the methodology developed in our laboratory [15b,c]. 3.3. Synthesis of b-enaminones

Fig. 1. ORTEP of 7-Phenyl-1,2,4-triazolo[1,5-a]pyrimidine 5a.

b-Enaminones 4a–l were prepared from the reaction of N,Ndimethylformamide dimethylacetal with methyl ketones, in accordance with the methodology developed in our laboratory [15a].

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3.4. General procedure for the preparation of 1,2,4-triazolo[1,5-a] pyrimidines 3a–h and 5a–l under ultrasonic irradiation A mixture of the 3-amino-1,2,4-triazole 2 (1.0 mmol) and the precursor 1,3-dieletrophilic 1 or 4 (1.0 mmol) in AcOH (5 mL) was placed in a 10 mL vessel. The reaction mixtures were then sonicated by an ultrasonic probe of 6 mm and amplitude of 20%, at a programmed temperature of between 75 °C and 99 °C, for 5–17 min. After the reaction time, the solvent was removed under reduced pressure. Chloroform (10 mL) was added and the resulting mixture was washed with distilled water (3  10 mL), dried on sodium sulfate (Na2SO4), and the solvent was then removed under reduced pressure. The products 3a–h and 5a–l were recrystallized from hexane and obtained in their pure form. 3.5. General procedure for the preparation of 1,2,4-triazolo[1, 5-a]pyrimidines 3a–h and 5a–l using conventional thermal heating method (oil bath) A mixture of the 3-amino-1,2,4-triazole 2 (1.0 mmol) and the precursor 1,3-dieletrophilic 1 or 4 (1.0 mmol) in AcOH (5 mL) were placed in a round-bottomed flask and magnetically stirred for 16 h under reflux. After the reaction time, the solvent was removed in a rotary evaporator. Chloroform (10 mL) was added, and the resulting mixture was washed with distilled water (3  10 mL), dried on sodium sulfate (Na2SO4), and the solvent was then removed under reduced pressure. The products 3a–h and 5a–l were recrystallized from hexane and obtained in their pure form. 7-Trifluoromethyl-5-phenyl-1,2,4-triazolo[1,5-a]pyrimidine (3a): mp 144 °C–146 °C; 1H NMR (200 MHz, CDCl3): d = 7.60–7.59 (m, 3H, H-Ar), 7.92 (s, 1H, H2), 8.26–8.21 (m, 2H, H-Ar), 8.63 (s, 1H, H6). 13C NMR (100 MHz, CDCl3): d = 108.7 (q, 3J2, C6), 120.0 (q, 1J275, CF3), 127.5, 128.8, 132.3, 134.0 (C-Ar), 156.6 (q, 2J35, C7), 161.9 (C3a), 168.3 (C5). MS (EI, 70 eV): m/z % = 264 (M+, 100), 195 (8), 77 (10). 7-Trifluoromethyl-5-(4-fluorophenyl)-1,2,4-triazolo[1,5-a]pyrim idine (3b): mp 135 °C–139 °C; 1H NMR (200 MHz, CDCl3): d = 7.27 (dd, 2H, 3J8, 3J9, H-Ar), 7.87 (s, 1H, H2), 8.27 (dd, 2H, 3J8, 3J9, H-Ar), 8.63 (s, 1H, H6). 13C NMR (100 MHz, CDCl3): d = 105.2 (q, 3J4, C6), 116.5 (d, 2J22, C-Ar), 118.7 (q, 1J275, CF3), 130.2 (d, 3J9, C-Ar), 131.2 (d, 4J3, Ar), 135.7 (q, 2J39, C7), 156.1 (C3a), 157.3 (C2), 160.6 (C5), 165.4 (d, 1J255, Ar). MS (EI, 70 eV): m/z % = 282 (M+, 100), 263 (6), 213 (7), 133 (6). 5-(4-Bromophenyl)-7-trifluoromethyl-1,2,4-triazolo[1,5-a]pyrim idine (3c): mp 173 °C–175 °C; 1H NMR (200 MHz, CDCl3): d = 8.65 (s, 1H, H6), 8.13 (d, 2H, H-Ar), 7.88 (s, 1H, H2), 7.73 (d, 2H, HAr). 13C NMR (100 MHz, CDCl3): d = 105.1 (q, 3J4, C6), 118.7 (q, 1 J274, CF3), 127.5, 129.3, 132.6. 133.8 (C-Ar), 135.9 (q, 2J39, C7), 156.1 (C3a), 157.4 (C2), 160.7 (C5). MS (EI, 70 eV): m/z % = 344 (M+2, 98), 342 (M+, 100), 263 (14), 193 (3). 7-Trifluoromethyl-5-(4-iodophenyl)-1,2,4-triazolo[1,5-a]pyrimidine (3d): mp 178 °C–179 °C; 1H NMR (200 MHz, CDCl3): d = 7.86 (s, 1H, H2), 7.95 (m, 4H, H-Ar), 8.63 (s, 1H, H6). 13C NMR (100 MHz, CDCl3): d = 105.0 (q, 3J4, C6), 118.7 (q, 1J273, CF3), 128.7, 129.1, 134.3, 138.6 (C-Ar), 135.7 (q, 2J38, C7), 156.0 (C3a), 157.4 (C2), 160.8 (C5). MS (EI, 70 eV): m/z % = 389.9 (M+, 100), 263 (17). 7-Trifluoromethyl-5-(4-methylphenyl)-1,2,4-triazolo[1,5-a]pyrimidine (3e): mp 157 °C–158 °C; 1H NMR (200 MHz, CDCl3): d = 2.47 (s, 3H, CH3), 7.38 (d, 2H, H-Ar), 7.88 (s, 1H, H2), 8.15 (d, 2H, H-HAr), 8.61 (s, 1H, H6). 13C NMR (100 MHz, CDCl3): d = 21.4 (CH3), 105.2 (q, 3J4, C6), 118.9 (q, 1J275, CF3), 127.8, 130.0, 132.3, 143.3 (C-Ar), 135.5 (q, 2J38, C7), 156.2 (C3a), 157,1 (C2), 161.8 (C5). MS (EI, 70 eV): m/z % = 278 (M+, 100), 250 (14), 167 (15), 91 (13). 7-Trifluoromethyl-5-(4-metoxyphenyl)-1,2,4-triazolo[1, 5-a]pyrimidine (3f): mp 159 °C–161 °C; 1H NMR (200 MHz, CDCl3):

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d = 3.91 (s, 3H, OCH3), 7.07 (d, 2H, H-Ar), 7.83 (s, 1H, H2), 8.22 (d, 2H, H-Ar), 8.58 (s, 1H, H6). 13C NMR (100 MHz, CDCl3): d = 55.5 (OCH3), 105.0 (q, 3J4, C6), 114.7 (C3a), 118.7 (q, 1J275, CF3), 127.4, 129.7, 156.2, 156.9 (C-Ar), 135.5 (q, 2J39, C7), 161.3 (C2), 163.3 (C5). MS (EI, 70 eV): m/z % = 294 (M+, 100), 251 (14), 224 (5). 7-Trifluoromethyl-5-(thien-2-yl)-1,2,4-triazolo[1,5-a]pyrimidine (3g): mp 133 °C–135 °C; 1H NMR (200 MHz, CDCl3): d = 7.21 (t, 3J4, 1H, thien-2-yl), 7.25 (d, 3J5, 1H, thien-2-yl), 7.72 (s, 1H, H2), 7.92 (d, 3J3, 1H, thien-2-yl), 8.57 (s, 1H, H6). 13C NMR (100 MHz, CDCl3): d = 104.8 (q, 3J2, C6), 118.7 (q, 1J275, CF3), 128.9, 130.3, 134.2, 140.9 (C-thien-2-yl), 135.5 (q, 2J38, C7), 155.9 (C3a), 156.6 (C2), 157.1 (C5). MS (EI, 70 eV): m/z % = 270 (M+, 100), 167 (6), 91 (8). 5-(Biphen-4-yl)-7-trifluoromethyl-1,2,4-triazolo[1,5-a]pyrimidine (3h): mp: 185 °C–187 °C; 1H NMR (200 MHz, CDCl3): d = 7.52–7.41 (m, 3H, H-Ar), 7.68–7.65 (m, 2H, H-Ar), 7.79 (d, 2H, H-Ar), 7.93 (s, 1H, H2), 8.31 (d, 2H, H-Ar), 8.63 (s, 1H, H6). 13C NMR (100 MHz, CDCl3): d = 106.6 (q, 3J2, C6), 118.8 (q, 1J275, CF3), 126.6, 127, 128, 128.5, 128.7, 138.5, 143.3 (C-Ar), 133.9 (q, 2 J38, C7), 155.5 (C3a), 156.3 (C2), 160.7 (C5). MS (EI, 70 eV): m/z % = 340 (M+, 100), 263 (1), 69 (1). 7-Phenyl-1,2,4-triazolo[1,5-a]pyrimidine (5a): mp 128 °C– 132 °C; 1H NMR (200 MHz, CDCl3): d = 7.25 (d, 3J4, 1H, H5), 7.61– 7.64 (m, 3H, H-Ar), 8.08–8.13 (m, 2H, H-Ar), 8.56 (s, 1H, H2), 8.88 (d, 3J4, 1H, H5). 13C NMR (100 MHz, CDCl3): d = 109.0 (C6), 128.9, 129.2, 129.6, 131.9 (C-Ar), 148.3 (C7), 154.3 (C5), 155.8 (C3a), 156.3 (C2). MS (EI, 70 eV): m/z % = 196 (M+, 100), 77 (10), 140 (4), 168 (10). 7-(4-Fluorophenyl)-1,2,4-triazolo[1,5-a]pyrimidine (5b): mp 233 °C–236 °C; 1H NMR (200 MHz, CDCl3): d = 7.23 (d, 3J4, 1H, H6), 7.27–7.36 (m, 2H, H-Ar), 8.17 (dd, 3J9, 3J5, 2H, H-Ar), 8.57 (s, 1H, H2), 8.89 (d, 3J4, 1H, H5). 13C NMR (100 MHz, CDCl3): d = 108.8 (q, 3J3, C6), 116.3 (d, 2J22, C-Ar), 118.8 (q, 1J275, CF3), 130.2 (d, 3J9, C-Ar),131.2 (d, 3J3, C-Ar), 135.7 (q, 2J39, C7), 156.1 (C5), 157.3 (C3a), 160.6 (C2), 165.4 (d, 1J254, C-Ar). MS (EI, 70 eV): m/z % = 214 (M+, 100), 95 (5), 120 (4), 186 (5). 7-(4-Bromophenyl)-1,2,4-triazolo[1,5-a]pyrimidine (5c): mp 217 °C–220 °C; 1H NMR (200 MHz, CDCl3): d = 7.27 (d, 3J3, 1H, H6), 7.76 (d, 2H, H-Ar), 8.03 (d, 2H, H-Ar), 8.57 (s, 1H, H2), 8.89 (d, 3J4, 1H, H5). 13C NMR (100 MHz, CDCl3): d = 108.8 (C6), 126.8, 128.4, 130.7, 132.3 (C-Ar), 147.2 (C7), 154.3 (C5), 155.9 (C3a), 156.3 (C2). MS (EI, 70 eV): m/z % = 276 (M+2, 98), 274 (M+, 100), 195 (20). 7-(4-Iodophenyl)-1,2,4-triazolo[1,5-a]pyrimidine (5d): mp 210 °C–215 °C; 1H NMR (200 MHz, CDCl3): d = 7.23 (d, 3J4, 1H, H6), 7.86 (d, 3J8, 2H, H-Ar), 7.96 (d, 3J8, 2H, H-Ar), 8.55 (s, 1H, H2), 8.87 (d, 3J4, 1H, H5). 13C NMR (100 MHz, CDCl3): d = 99.1 (CAr), 108.7 (C6), 129.0, 130.6, 138.2 (C-Ar), 147.3 (C7), 154.3 (C5), 155.9 (C3a), 156.2(C2). MS (EI, 70 eV): m/z % = 322 (M+, 100), 195 (12), 113 (6). 7-(4-Methylphenyl)-1,2,4-triazolo[1,5-a]pyrimidine (5e): mp 183 °C–186 °C; 1H NMR (200 MHz, CDCl3): d = 2.49 (s, 1H, CH3), 7.23 (d, 3J4, 1H, H6), 7.42 (d, 3J8, 2H, Ar), 8.05 (d, J8, 2H, Ar), 8.58 (s, 1H, H2), 8.86 (d, 3J4, 1H, H5). 13C NMR (100 MHz, CDCl3): d = 21.4 (CH3), 108.5 (C6), 126.8, 129.2, 129.5, 142.6 (C-Ar), 148.4 (C7), 154.1 (C5), 155.7 (C3a), 156.3 (C2). MS (EI, 70 eV): m/z % = 210 (M+, 100), 186 (16), 115(14). 7-(4-Methoxyphenyl)-1,2,4-triazolo[1,5-a]pyrimidine (5f): mp 183 °C–186 °C; 1H NMR (200 MHz, CDCl3): d = 3.89 (s, 1H, CH3), 7.07 (d, 3J9, 2H, H-Ar), 7.9 (d, 3J4, 1H, H6), 8.13 (d, 3J9, 2H, H-Ar), 8.54 (s, 1H, H2), 8.81 (d, 3J4, 1H, H5). 13C NMR (100 MHz, CDCl3): d = 55.5 (CH3), 107.9 (C6), 114.3, 121.6, 131.1, 147.9 (C-Ar), 154.0 (C7), 155.5 (C5), 156.3 (C3a), 162.5 (C2). MS (EI, 70 eV): m/z % = 226 (M+, 100), 195 (6). 7-(4-Nitrophenyl)-1,2,4-triazolo[1,5-a]pyrimidine (5g): mp 241 °C–246 °C; 1H NMR (200 MHz, CDCl3): d = 7.70 (d, 3J4, 1H,

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H6), 8.44 (s, 4H, H-Ar), 8.72 (s, 1H, H2), 9.00 (d, 3J4, 1H, H5). 13C NMR (100 MHz, CDCl3): d = 110.4 (C6), 123.4, 130.6, 130.8, 135.3 (C-Ar), 144.9 (C7), 148.7 (C5), 155.0 (C3a), 155.4 (C2). MS (EI, 70 eV): m/z % = 241 (M+, 100), 195 (25), 113(26). 7-(Biphen-4-yl)-1,2,4-triazolo[1,5-a]pyrimidine (5h): mp 193 °C –195 °C; 1H NMR (200 MHz, CDCl3): d = 7.30 (d, 3J4, 1H, H6), 7.50 (m, 3H, H-Ar), 7.70 (d, 3J7, 2H, H-Ar), 7.85 (d, 3J8, 2H, H-Ar), 8.23 (d, 3J8, 2H, H-Ar), 8.60 (s, 1H, H2), 8.91(d, 3J4, 1H, H5). 13C NMR (100 MHz, CDCl3): d = 108.8 (C6), 127.1, 127.2, 128.1, 128.9, 129.7 (C-Ar), 139.5 (C7), 144.7, 147.9 (C-Ar), 154.3 (C2), 155.7 (C3a), 156.0 (C5). MS (EI, 70 eV): m/z % = 272 (M+, 100), 245 (7), 152 (7). 7-(Naphth-2-yl)-1,2,4-triazolo[1,5-a]pyrimidine (5i): mp 145 °C –148 °C; 1H NMR (200 MHz, CDCl3): d = 7.37 (d, 3J4, 1H, H6), 7.60– 7.69 (m, 2H, H-Ar), 7.92–8.10 (m, 4H, H-Ar), 8.61 (s, 1H, H2), 8.74 (s, 1H, H-Ar), 8.91 (d, 3J4, 1H, H5). 13C NMR (100 MHz, CDCl3): d = 109.0 (C6), 124.9, 126.7, 127.0, 127.6, 128.3, 128.5, 129.0, 130.5, 132.6, 134.5 (C-Ar), 148.0 (C7), 154.1 (C5), 155.7 (C3a), 156.3 (C2). MS (EI, 70 eV): m/z % = 246 (M+, 100), 127 (5). 7-(Thien-2-yl)-1,2,4-triazolo[1,5-a]pyrimidine (5j): mp 172 °C– 174 °C; 1H NMR (200 MHz, CDCl3): d = 7.33 (m, 1H, H-Ar), 7.47 (d, 3 J4, 1H, H6), 7.82 (d, 3J5, 1H, H-Ar), 8.46 (d, 3J3, 1H, H-Ar), 8.63 (s, 1H, H2), 8.81 (d, 3J4, 1H, H5). 13C NMR (100 MHz, CDCl3): d = 105.6 (C6), 128.4, 130.4 (C-Ar), 132.8 (C7), 133.5 (C-Ar), 141.7 (C5), 153.6 (C3a), 155.5 (C-Ar), 156 (C2). MS (EI, 70 eV): m/z % = 202 (M+, 100), 146 (7), 121 (6), 69 (4). 7-(Pyrrol-2-yl)-1,2,4-triazolo[1,5-a]pyrimidine (5k): mp 196 °C –199 °C; 1H NMR (200 MHz, CDCl3): d = 6.44 (d, 3J1, 1H, H-Ar), 7.35 (s, 1H, H2), 7.63 (d, 3J4, H6), 7.72 (d, 3J1, 1H, H-Ar), 8.68 (d, 3 J2,1H, H-Ar), 8.74 (d, 3J4,1H, H5), 12.10 (s, broad, 1H, N-H). 13C NMR (100 MHz, CDCl3): d = 103.0 (C6), 111.9, 114.9, 121.7, 124.9 (C-Ar), 139.0 (C7), 153.8 (C5), 155.2 (C3a), 156.2 (C2). MS (EI, 70 eV): m/z % = 185 (M+, 100), 158 (3), 144 (5), 104 (3). 7-Trichloromethyl-1,2,4-triazolo[1,5-a]pyrimidine (5l): mp 105 °C–107 °C; 1H NMR (200 MHz, CDCl3): d = 7.80 (d, 3J4, 1H, H6), 8.72 (s, 1H, H2), 9.04 (d, 3J4, 1H, H5). 13C NMR (100 MHz, CDCl3): d = 87.7 (CCl3), 106.8 (C6), 144.8 (C7), 154.4 (C5), 155.7 (C3a), 156.5 (C2).MS (EI, 70 eV): m/z % = 238(19), 236(20), 201 (M+, 100), 201 (M + 2, 67), 166 (10), 110 (9). 4. Conclusion We have developed a fast, new, practical and simple method for the preparation of 1,2,4-triazolo[1,5-a]pyrimidine. New trifluoromethylated 1,2,4-triazolo[1,5-a]pyrimidines were synthesized with high regioselectivity in short reaction times and at excellent yields. These compounds, especially those having the trifluoromethyl group in their structure, are excellent models for studies on the biological activities. Acknowledgments The authors are grateful for the financial support from the National Council for Scientific and Technological Development (CNPq – Universal Proc. No. 578426/2008-0; 471519/2009-0), the Rio Grande do Sul Research Support Foundation (FAPERGS/CNPq-PRONEX Edital No. 008/2009, Proc. No. 10/0037-8), and the Coordination for Improvement of Higher Education Personnel (CAPES/ PROEX). The fellowships from CNPq (M.A.P.M., T.S.M., M.R.B.M., N.Z., H.G.B.), and CAPES (L.B.) are also acknowledged.

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