Ortho-Directed Palladium-Catalyzed Direct C–H Functionalization of 3-Picolinyl- and 3-(2-Cyanoethyl)pyrimidin-4(3H)-ones with Aryl Halides

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

palladium catalysis - arylation - C–H functionalization - Suzuki coupling - pyrimidinones

• 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, H_pyr), 8.01 (d, J = 6.6 Hz, 1 H, C6–H), 7.72–7.62 (m, 5 H, H_arom, H_pyr), 7.22–7.19 (m, 2 H, H_pyr), 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 (C_q), 159.8 (C_q), 154.2 (C_q), 152.1 (CH), 149.2 (CH), 138.6 (C_q), 136.5 (CH), 132.0 (2 × CH_arom), 128.8 (2 × CHD), 122.4 (CH), 121.8 (CH), 117.7 (Cq), 114.5 (CH), 113.7 (C_q), 50.3 (N–CH₂). HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₇H₁₃N₄O: 289.1089; found: 289.1093.