Äîêóìåíò âçÿò èç êýøà ïîèñêîâîé ìàøèíû. Àäðåñ îðèãèíàëüíîãî äîêóìåíòà : http://www.chem.msu.ru/eng/misc/babaev/papers/119e.pdf Äàòà èçìåíåíèÿ: Thu Jan 20 20:18:36 2011 Äàòà èíäåêñèðîâàíèÿ: Sat Feb 12 03:14:37 2011 Êîäèðîâêà:

J. Comb. Chem. 2006, 8, 659-663

659

Articles
Efficient Pd(0)-Mediated Microwave-Assisted Arylation of 2-Substituted Imidazo[1,2-a]pyrimidines
D. S. Ermolat'ev,, V. N. Gimenez, E. V. Babaev, and E. Van der Eycken*, ´
Laboratory for Organic and MicrowaVe-Assisted Chemistry (LOMAC), Department of Chemistry, UniVersity of LeuVen, Celestijnenlaan 200F, B-3001 LeuVen, Belgium, and Chemistry Department, Moscow State UniVersity, Moscow 119992, Russia ReceiVed March 23, 2006 A short and practical synthesis of 2,3-substituted imidazo[1,2-a]pyrimidines, based on microwave-assisted Heck-type arylation of 2-substituted imidazo[1,2-a]pyrimidines, was developed. A 45-membered library of 2,3-substituted imidazo[1,2-a]pyrimidines was obtained with good yields and purities using this optimized protocol. Introduction Many 2,3-substituted imidazo[1,2-a]pyrimidines 5 (Scheme 1) are found to be biologically active.1 For example, 2,3diaryl imidazo[1,2-a]pyrimidines possess inhibitory activity against cyclooxigenase-2 (COX-2) with high selectivity in relation to COX-1.2,3 Therefore, they could be useful for the treatment of inflammation and diseases mediated by COX-2 with a reduced ulcerogenic potential. Moreover, these compounds have been shown recently to express anti-cancer activity.4 In addition, several 2-carboxamidoimidazo[1,2-a]pyrimidines 5 (R1 ) Ar, R2 ) CONH2) display analgesic, antipyretic, and anti-inflammatory activity5 and might serve as potent glutamate antagonists for the treatment of cancer.6 Differently substituted 2-carboxamidoimidazo[1,2-a]pyrimidines 5 were also reported to inhibit glycogen phosphorylase, making them useful in prophylactic and therapeutic treatment of diabetes, hyperglycemia, hypertension, and arteriosclerosis and as cardioprotectants.7 Within the framework of developing libraries of the aforementioned bioactive compounds, we are currently investigating the synthesis of various 2,3-substituted imidazo[1,2-a]pyrimidines, bearing a phenyl, carboxamide, or carboxylate function at the 2-position and an aromatic substituent at the 3-position of scaffold 5. To our knowledge, there is no general methodology described in the literature for the synthesis of such compounds. The main approach (Scheme 1, pathway A) starts from a suitable 1,2-diaryl-2-bromoethanone (2) which is reacted with 2-aminopyrimidine (1).4 Unfortunately, variation of the substituents R1 and R2 is restricted because of the limited availability of the starting 1,2-diaryl-2-bromoketones (2) and the low overall yields.3
* To whom correspondence should be addressed. Phone: +32 16327406. Fax: +32 16327990. E-mail: erik.vandereycken@chem.kuleuven.be. University of Leuven. Moscow State University.

Scheme 1

Only 3-monosubstituted compounds 6 are accessible via an alternative approach (Scheme 1, pathway C) involving bromination of the 3-position7 of the unsubstituted imidazo[1,2-a]pyrimidine (4), followed by Suzuki coupling with a suitable arylboronic acid.8 Although this sequence was successful, an additional step for the activation of the 3-position is required. It was recently reported that the 2-unsubstituted imidazo[1,2-a]pyrimidine scaffold 4 could be selectively arylated at the 3-position via a Heck-type reaction, which applies arylbromides in the presence of base and a catalytic amount of palladium (Scheme 1, pathway D).9 This method provided an efficient synthesis of monosubstituted 3-arylimidazo[1,2-a]pyrimidines 6, using commercially available aryl and heteroaryl bromides. However, our attempts to arylate the corresponding 2-substituted analogues, following the same Heck-type procedure, failed. To find proper arylation conditions, we started to investigate this reaction in more detail. Here, we report a hitherto unprecedented protocol for the arylation of the 3-position of 2-substituted imidazo[1,2-a]pyrimidines 7 using microwave irradiation (Scheme 1, pathway B).

10.1021/cc060031b CCC: $33.50 © 2006 American Chemical Society Published on Web 07/14/2006


660 Journal of Combinatorial Chemistry, 2006, Vol. 8, No. 5

Ermolat'ev et al.

Scheme 2

a

Scheme 3

a

Reaction conditions: (i) bromobenzene (1.35 equiv), Pd catalyst (8 mol %)/ligand (16 mol %), Cs2CO3 (1.1 equiv), 1,4-dioxane, and heating or MW-irradiation.

a

a Reaction conditions: (i) RBr (1.35 equiv), Pd(AcO) (8 mol %), PPh 2 3 (16 mol %), Cs2CO3 (1.1 equiv), 1,4-dioxane, MW 150 W, 20-60 min, 145 °C.

Table 1. Optimization of the Conditions for the Arylation of 7a with Bromobenzenea
entry 1 2 3 4 5 6 7 8 9 10
a

Table 2. Arylation of 2-Phenylimidazo[1,2-a]pyrimidine (7a) with Various Aryl Bromidesa
entry 1 2 3 4 5 6 7 8 9 10 11 product 5{1} 5{2} 5{3} 5{4} 5{5} 5{6} 5{7} 5{8} 5{9} 5{10} 5{11} R phenyl 4-fluorophenyl 4-chlorophenyl 4-trifluoromethylphenyl 2-fluorophenyl 3,5-difluorophenyl 4-methoxyphenyl 4-methanesulfonylphenyl isoquinol-4-yl pyridin-2-yl 4-tert-butylphenyl time (min) 30 20 35 25 60 50 60 25 60 50 55 yield (%) 96 95 82 84 86 65 54 80 67 55 46

conditions

catalyst/ligand Pd(OAc)2/Ph3P Pd(OAc)2/Ph3P Pd(OAc)2/Ph3P Pd(PPh3)2Cl2/Ph3P Pd(PPh3)4 Pd(OAc)2/Ph3P Pd(OAc)2/Ph3P Pd(OAc)2/Ph3P Pd(PPh3)2Cl2/Ph3P Pd(PPh3)4

temp (°C) 100 120 145 145 145 100 120 145 145 145

time (h) 72 72 72 72 72 4 1 0.5 0.5 0.5

yield (%) 24 42 56 4 15 32 70 96 0 20

MWb

All reactions were performed on a 0.5 mmol scale in 6 mL of 1,4-dioxane with 1.35 equiv of bromobenzene, 1.35 equiv of Cs2CO3, 8 mol % of the catalyst, and 16 mol % PPh3 (if necessary). b All the MW experiments were performed at 150 W maximum power.

a All reactions were performed on a 0.5 mmol scale in 6 mL of 1,4-dioxane with 1.35 equiv of aryl bromide, 1.35 equiv of Cs2CO3, 8 mol % Pd(OAc)2, and 16 mol % PPh3; all experiments were performed at 150 W maximum power and a ceiling temperature of 145 °C.

Results and Discussion We started to reinvestigate the arylation of 2-phenylimidazo[1,2-a]pyrimidine (7a) with bromobenzene by exploiting the previously described procedure9 for 2-unsubstituted imidazo[1,2-a]pyrimidines (Scheme 2). However, with the literature conditions, even after 3 days of conventional heating at 100 °C in 1,4-dioxane and application of Pd(AcO)2/PPh3 as the catalyst system and cesium carbonate as the base, a yield of only 24% was obtained for the desired arylated product 5{1} (Table 1, entry 1). The best conditions were found when the temperature was increased to 145 °C, which resulted in a moderate yield of 56% (Table 1, entry 3). Increasing the temperature of the reaction up to 180 °C led to a number of unidentified side products and to decomposition of the catalyst in a few hours. Switching the catalyst system to Pd(PPh3)2Cl2/PPh3 (Table 1, entry 4) or Pd(PPh3)4 (Table 1, entry 5) seemed to be deleterious for the reaction. As we have previously demonstrated the beneficial effects of the application of microwave irradiation for transition metal-catalyzed reactions,10,11 we decided to investigate the use of this technique for this arylation procedure. The reaction of 2-phenylimidazo[1,2-a]pyrimidine (7a) was tested under microwave irradiation at 100 °C in 1,4dioxane with Pd(OAc)2/PPh3 as the catalyst system and cesium carbonate as the base. However, after 4 h, the desired product 5{1} was obtained in only a 32% yield (Table 1, entry 6). When the ceiling temperature was increased to 120 °C, the reaction time could be shortened to 1 h and a good yield of 70% was obtained (Table 1, entry 7). A further increase of the temperature to 145 °C produced the product

in an excellent 96% yield, and the irradiation time could be shortened to a mere 30 min (Table 1, entry 8). In all cases, a slight excess of bromobenzene (1.35 equiv) was used to drive the arylation to completion. The use of more than 1.5 equiv of bromobenzene resulted in the formation of a significant amount of unidentified side products. To determine the scope and limitations of our microwaveassisted protocol, we investigated the arylation procedure with several aryl bromides (Scheme 3, Table 2). In agreement with the arylation mechanism proposed by Larsen et al.,9 we noticed that in almost all cases the more-reactive electronpoor aryl bromides resulted in high yields (80-96%) (Table 2, entries 1-5 and 8). The less-reactive aryl bromides such as 4-tert-butyl- (Table 2, entry 11) and 4-methoxyphenyl bromide (Table 2, entry 7) resulted in lower yields. The procedure could also be applied successfully for hetaryl bromides (Table 2, entries 9 and 10), although lower yields were obtained. Unexpectedly, 3,5-difluorobromobenzene was quite unreactive despite the two electron-withdrawing groups (Table 2, entry 6). An increase of the temperature to 160 °C during microwave irradiation did not improve the yield and resulted in decomposition. To further evaluate the applicability of our microwaveenhanced arylation procedure, we investigated different combinations of 2-arylimidazo[1,2-a]pyrimidines 7b-f, which were prepared according to standard procedures,12 with various arylbromides (Scheme 4, Table 3). To circumvent the problem of the poor solubility of several of the 2-arylimidazo[1,2-a]pyrimidines in 1,4-dioxane, the temperature was increased irradiation to 160 °C. The changeof 1,4-dioxane for DMF resulted in the formation of large amounts of


Pd(0)-Mediated Microwave-Assisted Arylation

Journal of Combinatorial Chemistry, 2006, Vol. 8, No. 5 661

Scheme 4

a

Scheme 5

a

a Reaction conditions: (i) aryl bromide (1.35 equiv), Pd(AcO) (8 mol 2 %), PPh3 (16 mol %), Cs2CO3 (1.1 equiv), 1,4-dioxane, MW 150 W, 2060 min, 160 °C.

Table 3. Arylation of 2-Arylimidazo[1,2-a]pyrimidines 7b-f
entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 product 5{12} 5{13} 5{14} 5{15} 5{16} 5{17} 5{18} 5{19} 5{20} 5{21} 5{22} 5{23} 5{24} 5{25} 5{26} 5{27} 5{28} 5{29} 5{30} 5{31} 5{32} 5{33} 5{34} 5{35} R1 4-Me 4-Me 4-Me 4-Me 4-Me 4-Me 4-MeO 4-MeO 4-MeO 4-MeO 4-MeO 4-MeO 4-F 4-F 4-F 4-F 4-F 4-F 4-Cl 4-Cl 4-Cl 4-Cl 4- MeSO2 4- MeSO2 R
2

a

time (min) 20 30 30 20 60 60 30 40 30 30 60 30 20 20 20 20 40 40 20 40 40 50 30 40

yield (%) 76 44 70 71 79 48 65 79 70 74 55 77 90 89 94 69 35 58 86 56 72 65 84 67

a Reaction conditions: (i) (1) acetone, reflux, 45 min, (2) NaHCO (4 3 equiv), EtOH/H2O (3:2), 65 °C, 1 h; (ii) aryl bromide (1.35 equiv), Pd(AcO)2 (8 mol %), PPh3 (16 mol %), Cs2CO3 (1.1 equiv), 1,4-dioxane, MW 150 W, 25-40 min, 145 °C.

H 4-F 4-MeSO2 4-CF3 Cl 4-MeO H 4-F 4-Cl 4-CF3 2-F 4-MeSO2 H 4-F 4-Cl 4-CF3 4-COMe 2-F H 4-F 4-CF3 4- MeSO2 4-F biphenyl-4-yl

Table 4. Arylation of Imidazo[1,2-a]pyrimidine-2-carboxylic Acid Derivatives 7 g-ia
entry 1 2 3 4 5 6 7 8 9 10
a

product 5{36} 5{37} 5{38} 5{39} 5{40} 5{41} 5{42} 5{43} 5{44} 5{45}

XR

1

R

2

time (min) 30 45 25 25 30 45 60 20 20 30

yield (%) 64 47 80 67 86 67 54 92 86 55

OEt OEt NHPh NHPh NHPh NHPh NHPh NHBn NHBn NHBn

4-CF3 H H 4-F 4-Cl 4-CF3 3,5-diF H 4-CF3 4-MeSO

2

All reactions were performed on a 0.5 mmol scale in 6 mL of 1,4-dioxane with 1.35 equiv of aryl bromide, 1.35 equiv of Cs2CO3, 8 mol % Pd(OAc)2, and 16 mol % PPh3; all experiments were performed at 150 W maximum power and a ceiling temperature of 145 °C.

a All reactions were performed on a 0.5 mmol scale in 6 mL of 1,4-dioxane with 1.35 equiv of aryl bromide, 1.35 equiv of Cs2CO3, 8 mol % Pd(OAc)2, and 16 mol % PPh3; all experiments were performed at 150 W maximum power and a ceiling temperature of 160 °C.

resinous material. Consistently, most activated aryl bromides bearing electron-withdrawing groups, gave good to excellent yields (Table 3, entries 3-5, 8-10, 12, 14-16, 21, and 23). Aryl bromides bearing electron-donating groups gave lower yields (Table 3, entry 6). The lower yields for 3-(2-fluoro)imidazo[1,2-R]pyrimidines 5{22} and 5{29} could probably be attributed to steric hindrance (Table 3, entries 11 and 18). Although 2-(4-methylsulfonylphenyl)imidazo[1,2-a]pyrimidine (7f) is hardly soluble in 1,4-dioxane, moderate to good yields were obtained at the elevated temperature of 160 °C (Table 3, entries 23 and 24). Finally, we turned our attention to the arylation of imidazo[1,2-a]pyrimidines bearing an ethyl carboxylate or carboxamide function at the 2-position (Scheme 5, Table 4).13 The starting imidazo[1,2-a]pyrimidines14,15 7g-i were prepared from commercially available ethyl 3-bromopyruvate 3a and 3-bromopyruvamides16,17 3b and c.

The reaction of ethyl imidazo[1,2-a]pyrimidine-2-carboxylate (7g) resulted in a considerable amount of decomposition products (Table 4, entries 1 and 2). The coupling of 1-bromo4-(methylsulfonyl)benzene with 7i unexpectedly resulted in the formation a lot of homo-coupled products, together with the desired compound (Table 4, entry 10). 1-Bromo-3,5difluorobenzene appeared to be quite unreactive and required 1 h of microwave irradiation to give the arylated product 5{42} in a 54% yield (Table 4, entry 7). In all other cases, the desired compounds were formed in good yields. In conclusion, we have developed a short and efficient microwave-enhanced protocol for the Pd(0)-mediated arylation of 2-substituted imidazo[1,2-a]pyrimidines at their 3-position. The general applicability of this procedure was proven by the synthesis of a small combinatorial library of various 2,3-substituted imidazo[1,2-a]pyrimidines. Moreover, we have demonstrated that this procedure could be applied for the synthesis of difficult to obtain imidazo[1,2-a]pyrimidines with 2-carboxamide or 2-carboxylate functions. Experimental Section General Methods. Melting points were determined using a Reichert-Jung Thermovar apparatus or an Electrothermal 9200 digital melting point apparatus and are uncorrected. 1 H NMR spectra were recorded on a Bruker Avance 300


662 Journal of Combinatorial Chemistry, 2006, Vol. 8, No. 5

Ermolat'ev et al.

instrument using CDCl3 as the solvent unless otherwise stated. The 1H and 13C chemical shifts are reported in parts per million relative to tetramethylsilane using the residual solvent signal as an internal reference. Mass spectra were recorded by using a Kratos MS50TC and a Kratos Mach III system. The ion source temperature was 150-250 °C, as required. High-resolution electrospray ionization mass spectra were performed with a resolution of 10 000. The lowresolution spectra were obtained with a HP5989A MS instrument. For thin-layer chromatography, analytical TLC plates (Alugram SIL G/UV254) and 70-230 mesh silica gel (E. M. Merck) were used. Microwave Irradiation Experiments. A monomode CEM-Discover microwave reactor (CEM Corporation, P.O. Box 200, Matthews, NC 28106) was used in the standard configuration as delivered, including proprietary software. All experiments were carried out in sealed microwaveprocess vials (10 mL) at the maximum power and temperature, as indicated in the tables. After completion of the reaction, the vial was cooled to 50 °C via air-jet cooling before it was opened. General Procedure for the Arylation of 2-Substituted Imidazo[1,2-a]pyrimidines. Imidazo[1,2-a]pyrimidine (0.5 mmol), cesium carbonate (180 mg, 0.55 mmol, 1.1 equiv), palladium acetate (9 mg, 8 mol %), and triphenylphosphine (21 mg, 16 mol %) were placed in a 10 mL MW vial . Then 1,4-dioxane (6 mL) and arylbromide (0.68 mmol, 1.35 equiv) were added. The mixture was degassed by the bubbling of argon gas through it for 5 min. The vial was sealed and exposed to microwave irradiation at 150 W maximum power and a ceiling temperature as indicated. The reaction mixture was diluted with 200 mL of dichloromethane and washed with water (3 â 300 mL), and then the organic phase was dried over anhydrous Na2SO4. The solvent was evaporated in vacuo, and the crude mixture was purified by column chromatography on silica gel using ethyl acetate-methanol (9:1) as the eluent. 2,3-Diphenylimidazo[1,2-a]pyrimidine 5{1}. Yield: 138 mg (96%). mp: 147-149 °C. 1H NMR (CDCl3): 8.55 (m, 1H), 8.23 (m, 1H), 7.78 (m, 2H), 7.53 (m, 5H), 7.28 (m, 3H), 6.82 (m, 1H). 13C NMR (CDCl3): 150.2, 148.3, 144.2, 133.9, 131.1, 130.9 (â2), 130.2 (â2), 129.8, 129.2, 128.7 (â4), 128.4, 119.8, 109.0. HR-MS (EI): C18H13N3 calcd 271.1109, found 271.1100. 3-(4-Fluorophenyl)-2-phenylimidazo[1,2-a]pyrimidine 5{2}. Yield: 145 mg (95%). mp: 174-176 °C. 1H NMR (CDCl3): 8.58 (m, 1H), 8.19 (m, 1H), 7.73 (m, 2H), 7.45 (m, 3H), 7.29 (m, 4H), 6.83 (m, 1H). 13C NMR (CDCl3): 165.2, 150.3, 148.3, 144.3, 133.9, 132.5, 130.9, 129.7 (â2), 128.8 (â2), 128.7 (â2), 128.6 (â2), 117.6, 109.2, 109.0. HR-MS (EI): C18H12FN3 calcd 289.1015, found 289.1007. 3-(4-Chlorophenyl)-2-phenylimidazo[1,2- a ]pyrimidine 5{3}. Yield: 132 mg (82%). mp: 178-180 °C. 1H NMR (CDCl3): 8.57 (m, 1H), 8.22 (m, 1H), 7.75 (m, 2H), 7.53 (d, 2H, J ) 7.3 Hz), 7.40 (d, 2H, J ) 7.3 Hz), 7.30 (m, 3H), 6.83 (m, 1H). 13C NMR (CDCl3): 150.4, 148.4, 144.5, 135.8, 132.5 (â2), 132.4, 132.3 (â2), 130.9 (â2), 130.5 (â2), 130.2, 128.6, 127.7, 118.5, 109.2. HR-MS (EI): C18H12N3Cl calcd 305.0720, found 305.0711.

3-[4-(Trifluoromethyl)phenyl]-2-phenylimidazo[1,2-a]pyrimidine 5{4}. Yield: 142 mg (84%). mp: 164-167 °C. 1 H NMR (CDCl3): 8.57 (m, 1H), 8.28 (m, 1H), 7.80 (d, 2H, J ) 7.8 Hz), 7.67 (m, 2H), 7.60 (d, 2H, J ) 7.7 Hz), 7.30 (m, 3H), 6.85 (m, 1H). 13C NMR (CDCl3): 150.7, 148.6, 145.1, 133.4, 131.8 (â2), 131.3, 130.9, 130.9 (â2), 128.9, 128.8(â4), 128.7, 127.1, 118.2, 109.4. HR-MS (EI): C19H12N3F3 calcd 339.0983, found 339.0980. 3-(2-Fluorophenyl)-2-phenylimidazo[1,2-a]pyrimidine 5{5}. Yield: 121 mg (84%). mp: 177-179 °C. 1H NMR (CDCl3): 8.60 (s, 1H), 8.08 (m, 1H), 7.77 (m, 2H), 7.58 (m, 1H), 7.36 (m, 6H), 6.87 (m, 1H). 13C NMR (CDCl3): 162.3, 150.8, 148.3, 145.6, 144.9, 133.5, 132.8, 131.1, 128.5, 128.2 (â2), 128.5 (â2), 128.2, 117.4, 114.1, 109.9, 105.2. HR-MS (EI): C18H12N3F calcd 289.1015, found 289.1014. 3-(3,5-Difluorophenyl)-2-phenylimidazo[1,2-a]pyrimidine 5{6}. Yield: 47 mg (65%). mp: 183-186 °C. 1H NMR (CDCl3): 8.64 (m, 2H), 7.65 (m, 2H), 7.35 (m, 6H), 7.07 (m, 1H). 13C NMR (CDCl3): 165.6, 162.5, 150.7, 148.5, 125.3, 144.9, 133.2, 132.3, 128.9, 128.9 (â2), 128.8 (â2), 117.2, 109.7, 105.7. HR-MS (EI): C18H11F2N3 calcd 307.0921, found 307.0910. 3-(4-Methoxyphenyl)-2-phenylimidazo[1,2-a]pyrimidine 5{7}. Yield: 81 mg (54%). mp: 181-183 °C. 1H NMR (CDCl3): 8.53 (m, 1H), 8.19 (m, 1H), 7.75 (m, 2H), 7.54 (d, 2H, J ) 7.3 Hz), 7.33 (m, 3H), 7.06 (d, 2H, J ) 7.3 Hz), 6.79 (m, 3H), 3.91 (s, 3H). 13C NMR (CDCl3): 160.4, 148.6, 143.5, 132.4, 132.0, 130.9, 128.9 (â2), 128.7 (â2), 127.7 (â2), 127.3 (â2), 126.1, 119.7, 114.6, 108.5, 55.9. HR-MS (EI): C19H15N3O calcd 301.1215, found 301.1211. 3-(4-Methanesulfonylphenyl)-2-phenylimidazo[1,2-a]pyrimidine 5{8}. Yield: 140 mg (80%). mp: 204-206 °C. 1 H NMR (CDCl3): 8.64 (s, 1H), 8.35 (d, 1H, J ) 6.4 Hz), 8.12 (d, 2H, J ) 8.2 Hz), 7.70 (m, 3H), 7.35 (m, 2H), 6.90 (m, 1H), 3.21 (s, 3H). 13C NMR (CDCl3): 151.0, 148.7, 145.4, 141.1, 134.9, 133.2, 131.6 (â2), 131.1, 129.0 (â4), 128.9, 117.8, 109.7, 44.7. HR-MS (EI): C19H15N3O2S calcd 349.0885, found 349.0879. 4-(2-Phenylimidazo[1,2-a]pyrimidin-3-yl)-isoquinoline 5{9}. Yield: 108 mg (67%). mp: 202-205 °C. 1H NMR (CDCl3): 9.47 (s, 1H), 8.66 (br, 1H), 8.19 (d, 1H, J ) 8.0 Hz), 7.82 (d, 1H, J ) 8.1 Hz), 7.70 (m, 3H), 7.42 (d, 1H, J ) 7.8 Hz), 7.23 (m, 3H), 6.79 (m, 1H). 13C NMR (CDCl3): 154.93, 150.74, 149.08, 146.48, 146.39, 133.16, 133.41, 132.47, 131.48, 129.13 (â2), 129.10 (â2), 128.84 (â2), 128.76 (â2), 128.27, 124.23, 114.32, 109.28. HR-MS (EI): C21H14N4 calcd 322.1218, found 322.1218. 2-Phenyl-3-(pyridin-2-yl)imidazo[1,2-a]pyrimidine 5{10}. Yield: 75 mg (55%). mp: 156-158 °C. 1H NMR (CDCl3): 8.50 (m, 2H), 8.42 (m, 1H), 8.02 (d, 2H, J ) 7.3 Hz), 7.82 (m, 1H), 7.44 (m, 5H), 6.84 (m, 1H). 13C NMR (CDCl3): 151.2, 150.2, 149.8, 147.4, 133.7, 133.5, 132.5, 132.4, 129.7 (â2), 129.1, 128.9, 128.8 (â2), 109.1, 106.8. HR-MS (EI): C17H12N4 calcd 272.1062, found 272.1057. 3-(4-tert-Butylphenyl)-2-phenylimidazo[1,2-a]pyrimidine 5{11}. Yield: 80 mg (49%). mp: 156-158 °C. 1H NMR (CDCl3): 8.63 (s, 1H), 8.25 (m, 1H), 7.77 (m, 2H), 7.55 (d, 2H, J ) 7.2 Hz), 7.36 (d, 2H, J ) 7.2 Hz), 7.32 (m, 3H), 6.78 (m, 1H), 1.40 (s, 9H). 13C NMR (CDCl3): 153.6,


Pd(0)-Mediated Microwave-Assisted Arylation

Journal of Combinatorial Chemistry, 2006, Vol. 8, No. 5 663 (5) Abignente, E.; Arena, F.; De Caprariis, P.; Montagnaro, G.; Rossi, F.; Lampa, E.; Giordano, L.; Vacca, C.; Marmo, E. Farmaco 1980, 35, 654-673. (6) Ikonomidou, H. Eur. Patent EP 1002535 A1, 2000. (7) Bradley, S. E.; Krulle, T. M.; Murray, P. J.; Rowley, R. J.; Sambrook Smith, C. P.; Thomas, G. H. Int. Patent WO 2004/ 104001 A2, December 2, 2004. (8) Enguehard, C.; Renou, J.-L.; Collot, V.; Hervet, M.; Raults, S.; Gueiffier, A. J. Org. Chem. 2000, 65, 6572-6575. (9) Wenjie, L.; Dorian, P. N.; Jensen, M. S.; Hoerner, R. S.; Javadi, G. J.; Cai, D.; Larsen, R. D. Org. Lett. 2003, 5, 4835-4837. (10) Kaval, N.; Bisztray, K.; Dehaen, W.; Kappe, C. O.; Van der Eycken, E. Mol. DiVersity 2003, 7, 125-133. (11) Kaval, N.; Van der Eycken, J.; Caroen, J.; Kappe, O.; Dehaen, W.; Strohmeier, G. A.; Van der Eycken, E. J. Comb. Chem. 2003, 5, 560-568. (12) Rival, Y.; Grassy, G.; Taudou, A.; Ecalle, R. Eur. J. Med. Chem. 1991, 26 (1), 13-18. (13) Abignente, E.; Sacchi, A.; Laneri, S.; Rossi, F.; D'Amico, M.; Berrino, L.; Calderaro, V.; Parrillo, C. Eur. J. Med. Chem. 1994, 29, 279-286. (14) Liebeschuets, J. W. Int. Patent WO 00/76970 A2, December 21, 2000. (15) Wang, G.-Z.; Mallat, T.; Baiker, A. Tetrahedron: Asymmetry 1997, 8 (13), 2133-2140. (16) Kluger, R.; Chow, J. F.; Croke, J. J. J. Am. Chem. Soc. 1984, 106 (14), 4017-4020. (17) Tully, W. R.; Gardner, C. R.; Gillespie, R. J.; Westwood, R. J. Med. Chem. 1991, 34, 2060-2067.
CC060031B

149.8, 147.4, 139.1, 133.1, 130.2, 129.3 (â2), 127.7 (â2), 127.1 (â2), 125.6 (â2), 109.3, 107.8, 32.7, 30.3 (â3). HRMS (EI): C22H21N3 calcd 327.1735, found 327.1732. Acknowledgment. E.V. thanks the F.W.O. (Fund for Scientific Research, Flanders, Belgium) and the Research Fund of the University of Leuven for financial support to the laboratory. D.E. is grateful to the University of Leuven for a scholarship and E.B. thanks RFBR for support (Grant 05-03-39022GFEN). We also wish to thank Prof. Dr. Wim Dehaen for his kind logistic support at the start of this project. Supporting Information Available. Experimental procedures and spectroscopic data for compounds 5{12-35}, 7g-i, and 5{36-45}. This material is available free of charge via the Internet at http://pubs.acs.org. References and Notes
(1) Casagrande, C.; Invernizzi, A.; Ferrari G. Farmaco 1968, 23, 1141-1145. (2) Farrerons, G. C.; Miguel Bono, I. J.; Fernandez A. M.; Monserat, V. C.; Lagunas, A. C.; Gimenez, G. F.; Fernandez, G. A. Int. Patent WO 00/08024 A1, February 17, 2000. (3) For the pyrimidine-based COX-2 inhibitors, see: (a) Almansa, A. F.; Cavalcanti, F. L.; Gomez, L. A.; Miralles, A.; Merlos, M.; Garcia-Rafanell, J.; Forn, J. J. Med. Chem. 2001, 44, 350-361. (b). Naylor, A.; Payne, J. J.; Pegg, N. A. Int. Patent WO 2002/096885 A1, May 12, 2002. (c). Weingarten, G.; Bravi, G. Int. Patent WO 2004018452 A1, April 3, 2004. (4) Catena, R. J. L.; Farrerons, G. L.; Fernandez, S. A.; Serra, C. C.; Balsa, L. D.; Lagunas, A. C.; Salcedo, R. C.; Fernandez, G. A. Int. Patent WO 2005/014598 A1, July 29, 2004.