Synlett, Table of Contents Synlett 2020; 31(12): 1185-1190DOI: 10.1055/s-0040-1707523 letter © Georg Thieme Verlag Stuttgart · New York Ortho-Directed Palladium-Catalyzed Direct C–H Functionalization of 3-Picolinyl- and 3-(2-Cyanoethyl)pyrimidin-4(3H)-ones with Aryl Halides Authors Sandra Collado Ruiz Mickaël Muselli Steven Frippiat Thierno Mamoudou Diallo Anissa Mohamed-Cherif Vincent Levacher Christine Baudequin∗ Laurent Bischoff∗ Christophe Hoarau∗ Recommend Article Abstract Buy Article(opens in new window) All articles of this category(opens in new window) Abstract The ortho-directed palladium-catalyzed direct C–H arylation of 3-picolinylpyrimidin-4-one was achieved by using various aryl halides. The method was extended to C–H arylation of pyrimidin-4-ones containing a methoxy group and an aryl group at the C5 site. The 2-cyanoethyl substituent was also evaluated as an ortho-directing group. The method gives access to novel N-substituted 2-aryl or 2,5-diaryl pyrimidin-4-ones. A standard three-step deprotection sequence for the picolinyl group was also studied. Key words Key wordspalladium catalysis - arylation - C–H functionalization - Suzuki coupling - pyrimidinones Full Text References References and Notes For reviews on Pd-catalyzed direct C(sp2)–H arylation of heterocycles (C–H/C–X couplings), see: 1a Verbitskiy EV, Rusinov GL, Chupakhin ON, Charushin VN. Synthesis 2018; 50: 193 1b Murakami K, Yamada S, Kaneda T, Itami K. Chem. Rev. 2017; 117: 9302 1c Abdoli M, Mirjafary Z, Saeidian H, Kakanejadifard A. RSC Adv. 2015; 5: 44371 1d Liang Y, Wnuk SF. Molecules 2015; 20: 4874 1e Rossi R, Bellina F, Lessi M, Manzini C. Adv. Synth. Catal. 2014; 356: 17 1f Yamaguchi J, Yamaguchi AD, Itami K. Angew. Chem. Int. Ed. 2012; 51: 8960 1g Zhao D, You J, Hu C. Chem. Eur. J. 2011; 17: 5466 1h Ackermann L, Vicente R, Kapdi AR. Angew. Chem. Int. Ed. 2009; 48: 9792 1i Bellina F, Rossi R. Tetrahedron 2009; 65: 10269 1j Alberico D, Scott ME, Lautens M. Chem. Rev. 2007; 107: 174 1k Satoh T, Miura M. Chem. Lett. 2007; 36: 200 1l Campeau L.-C, Fagnou K. Chem. Soc. Rev. 2007; 36: 1058 1m Seregin IV, Gevorgyan V. Chem. Soc. Rev. 2007; 36: 1173 For selected reviews on quinazolinone activities, see: 2a Gatadi S, Lakshmi TV, Nanduri S. Eur. J. Med. Chem. 2019; 170: 157 2b Khan I, Zaib S, Batool S, Abbas N, Ashraf Z, Iqbal J, Saeed A. Bioorg. Med. Chem. 2016; 24: 2361 2c Michael JP. Nat. Prod. Rep. 2004; 21: 650 For selected articles on pyrimidinone activities, see: 2d Sharma R, Gawande DY, Mohan C, Goel RK. Med. Chem. Res. 2016; 25: 1420 2e Sagong HY, Bauman JD, Patel D, Das K, Arnold E, LaVoie EJ. J. Med. Chem. 2014; 57: 8086 2f Bellomo A, Celebi-Olcum N, Bu X, Rivera N, Ruck RT, Welch CJ, Houk KN, Dreher SD. Angew. Chem. Int. Ed. 2012; 51: 6912 2g Summa V, Petrocchi A, Matassa VG, Taliani M, Laufer R, De Francesco R, Altamura S, Pace P. J. Med. Chem. 2004; 47: 5336 For selected patents on imidazolone activities, see: 2h Chen Y, O’Connor SJ, Guan D, Newcom J, Chen J, Yi L, Zhang H, Hunyadi LM, Natero R. WO 2004058727, 2004 2i Murugesan N, Tellew JE, Macor JE, Gu Z. WO 200001389, 2000 2j Murugesan N, Tellew JE, Macor JE, Gu Z. US 20020143024, 2002 For selected reviews on quinazolinone syntheses, see: 3a Rohokale RS, Kshirsagar UA. Synthesis 2016; 48: 1253 3b Maiden TM. M, Harrity JP. A. Org. Biomol. Chem. 2016; 14: 8014 3c Kshirsagar UA. Org. Biomol. Chem. 2015; 13: 9336 3d He L, Li H, Chen J, Wu X.-F. RSC Adv. 2014; 4: 12065 3e Connolly DJ, Cusack D, O’Sullivan TP, Guiry PJ. Tetrahedron 2005; 61: 10153 For selected articles on pyrimidinone syntheses, see: 3f Ramanjulu JM, DeMartino MP, Lan Y, Marquis R. Org. Lett. 2010; 12: 2270 3g Jeong JU, Chen X, Rahman A, Yamashita D, Luengo JI. Org. Lett. 2004; 6: 1013 3h Jezewski A, Jurczak J, Lidert Z, Tice CM. J. Heterocycl. Chem. 2001; 38: 645 3i Takahashi T, Hirokami S, Nagata M. J. Chem. Soc., Perkin Trans. 1 1998; 2653 3j Salimbeni A, Canevotti R, Paleari F, Poma D, Caliari S, Fici F, Cirillo R, Renzetti A, Subissi A, Belvisi L, Bravi G, Scolastico C, Giachetti A. J. Med. Chem. 1995; 38: 4806 3k Pinner A. Chem. Ber. 1889; 22: 1612 For selected articles on imidazolone syntheses, see: 3l Wu L, Burgess K. J. Am. Chem. Soc. 2008; 130: 4089 3m Baranov MS, Solntsev KM, Lukyanov KA, Yampolsky IV. Chem. Commun. 2013; 49: 5778 3n Baldridge A, Samanta SR, Jayaraj N, Ramamurthy V, Tolbert LM. J. Am. Chem. Soc. 2011; 133: 712 For reviews on the Liebeskind–Srogl cross-coupling reaction, see: 4a Cheng H.-G, Chen H, Liu Y, Zhou Q. Asian J. Org. Chem. 2018; 7: 490 4b Prokopcová H, Kappe CO. Angew. Chem. Int. Ed. 2009; 48: 2276 For the Liebeskind–Srogl cross-coupling reaction at a carbon atom of the quinazolinone, pyrimidinone or imidazolone nucleus, see: 5a Kriščiūnienė V, Matulevičiūtė G, Paliulis O, Rollin P, Šačkus A. Heterocycles 2016; 93: 150 5b Gosling S, Rollin P, Tatibouët A. Synthesis 2011; 3649 5c Sun Q, Suzenet F, Guillaumet G. J. Org. Chem. 2010; 75: 3473 5d Prokopcová H, Pisani L, Kappe CO. Synlett 2007; 43 5e Kusturin C, Liebeskind LS, Rahman H, Sample K, Schweitzer B, Srogl J, Neumann WL. Org. Lett. 2003; 5: 4349 5f Oumouch S, Bourotte M, Schmitt M, Bourguignon J.-J. Synthesis 2005; 25 6a Harayama T, Morikami Y, Shigeta Y, Abe H, Takeuchi Y. Synlett 2003; 847 6b Harayama T, Hori A, Serban G, Morikami Y, Matsumoto T, Abe H, Takeuchi Y. Tetrahedron 2004; 60: 10645 7 Muselli M, Baudequin C, Hoarau C, Bischoff L. Chem. Commun. 2015; 51: 745 8 Muselli M, Baudequin C, Perrio C, Hoarau C, Bischoff L. Chem. Eur. J. 2016; 22: 5520 9 Laclef S, Harari M, Godeau J, Schmitz-Afonso I, Bischoff L, Hoarau C, Levacher V, Fruit C, Besson T. Org. Lett. 2015; 17: 1700 10 For a selected article on the use of picolinyl group and picolinamide derivatives as ortho-directing groups, see: Pradhan S, De PB, Punniyamurthy T. J. Org. Chem. 2017; 82: 4883 11 For a recent review, see: Ping Y, Wang L, Ding Q, Peng Y. Adv. Synth. Catal. 2017; 359: 3274 12 Arumugam J, Brown HA, Jacobs HK, Gopalan AS. Synthesis 2011; 57 13 Sakamoto T, Kondo Y, Watanabe R, Yamanaka H. Chem. Pharm. Bull. 1986; 34: 2719 14 5-Methoxypyrimidin-3(4H)-one was synthesized according to the reported procedure, see: Myllymäki MJ, Käsnänen H, Kataja AO, Lahtela-Kakkonen M, Saario SM, Poso A, Koskinen AM. P. Eur. J. Med. Chem. 2009; 44: 4179 15 Boekelheide V, Linn WJ. J. Am. Chem. Soc. 1954; 76: 1286 For the deprotection of the pyridinyl group by Boekelheide rearrangement, see: 16a Mizuno Y, Endo T, Miyaoka T, Ikeda K. J. Org. Chem. 1974; 39: 1250 16b Endo T, Ikeda K, Kawamura Y, Mizuno Y. J. Chem. Soc., Chem. Commun. 1973; 673 17 Andreotti D, Miserazzi E, Nalin A, Pozzan A, Profeta R, Spada S. Tetrahedron Lett. 2010; 51: 6526 For selected articles on N-ethylcyano deprotection, see: 18a Tolstyakov VV. Chem. Heterocycl. Compd. 2017; 53: 719 18b Tanino T, Yamaguchi M, Matsuda A, Ichikawa S. Eur. J. Org. Chem. 2014; 1836 18c Touti F, Avenier F, Lefebvre Q, Maurin P, Hasserodt J. Eur. J. Org. Chem. 2010; 1928 18d Liao Y, Robinson BH. Tetrahedron Lett. 2004; 45: 1473 18e Duncia JV, Pierce ME, Santella JB. III. J. Org. Chem. 1991; 56: 2395 19 Huang J, Chan J, Chen Y, Borths CJ, Baucom KD, Larsen RD, Faul MM. J. Am. Chem. Soc. 2010; 132: 3674 20 Gorelsky SI. Organometallics 2012; 31: 794 21 Macdonald J, Oldfield V, Bavetsias V, Blagg J. Org. Biomol. Chem. 2013; 11: 2335 22 Bellina F, Cauteruccio S, Mannina L, Rossi R, Viel S. Eur. J. Org. Chem. 2006; 693 23a Lesieur M, Lazreg F, Cazin CS. J. Chem. Commun. 2014; 50: 8927 23b Storr TE, Baumann CG, Thatcher RJ, De Ornellas S, Whitwood AC, Fairlamb IJ. S. J. Org. Chem. 2009; 74: 5810 23c Storr TE, Firth AG, Wilson K, Darley K, Baumann CG, Fairlamb IJ. S. Tetrahedron 2008; 64: 6125 24 4-[6-Oxo-1-(pyridin-2-ylmethyl)-1,6-dihydropyrimidin-2-yl]benzonitrile (1bA); Typical Procedure An oven-dried screw-cap tube (10 mL) containing a magnetic stirrer bar was charged with N-picolinylpyrimidin-4(3H)-one (0.5 mmol), Pd(OAc)2 (10 mol%), PPh3 (20 mol%), CuI (2 equiv), and CsF (1.2 equiv). A solution of 4-iodobenzonitrile (2 equiv) in DMF (1.5 mL) was added and tube was purged with N2 and the tube was sealed. The mixture was stirred at 150 °C for 18 h then diluted with CH2Cl2 and filtered through a pad of cotton wool. The solution was then washed with 5% aq ammonia (2 × 25 mL) and brine (2 × 25 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, PE–EtOAc) to give a brown solid; yield: 144 mg (74%); mp 98–100 °C (CH2Cl2–pentane). IR (ATR): 3070, 2922, 2852, 2236, 1674, 1497, 1179, 838, 757, 555 cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.50 (ddd, J = 4.8, 1.6, 0.9 Hz, 1 H, Hpyr), 8.01 (d, J = 6.6 Hz, 1 H, C6–H), 7.72–7.62 (m, 5 H, Harom, Hpyr), 7.22–7.19 (m, 2 H, Hpyr), 6.53 (d, J = 6.6 Hz, 1 H, C5-H), 5.16 (s, 2 H, N–CH2). 13C NMR (75 MHz, CDCl3): δ = 161.2 (Cq), 159.8 (Cq), 154.2 (Cq), 152.1 (CH), 149.2 (CH), 138.6 (Cq), 136.5 (CH), 132.0 (2 × CHarom), 128.8 (2 × CHD), 122.4 (CH), 121.8 (CH), 117.7 (Cq), 114.5 (CH), 113.7 (Cq), 50.3 (N–CH2). HRMS (ESI-TOF): m/z [M + H]+ calcd for C17H13N4O: 289.1089; found: 289.1093. Supplementary Material Supplementary Material Supporting Information (PDF) (opens in new window)
