Subscribe to RSS
Please copy the URL and add it into your RSS Feed Reader.
https://www.thieme-connect.de/rss/thieme/en/10.1055-s-00000083.xml
Synlett 2019; 30(15): 1805-1809
DOI: 10.1055/s-0037-1611898
DOI: 10.1055/s-0037-1611898
letter
Deuterated Aryl Alkyl Ethers Synthesis via Nucleophilic Etherification of Aryl Alkyl Ethers and Thioethers with Deuterated Alcohols
We thank Hunan University for the funding support.Further Information
Publication History
Received: 12 June 2019
Accepted after revision: 09 July 2019
Publication Date:
15 August 2019 (online)
Abstract
A transition-metal-free etherification protocol that is capable of synthesizing deuterated ethers is described. A wide range of aryl alkyl ethers and thioethers were suitable for this transformation owing to the mild reaction conditions. Besides, a series of sterically bulky deuterated alcohols were successfully incorporated into cyano-substituted arenes. The results of mechanistic studies suggested this reaction might take place via nucleophilic aromatic substitution pathway.
Supporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0037-1611898.
- Supporting Information
-
References and Notes
- 1a Persidis A. Nat. Biotech. 1998; 16: 488
- 1b Lappin G, Temple S. Radiotracers in Drug Development . CRC Press; Boca Raton: 2006
- 1c Halford B. Chem. Eng. News 2016; 94: 32
- 1d Gant TG. J. Med. Chem. 2014; 57: 3595
- 1e Isin EM, Elmore CS, Nilsson GN, Thompson RA, Weidolf L. Chem. Res. Toxicol. 2012; 25: 532
- 1f Elmore CS. Annu. Rep. Med. Chem. 2009; 44: 515
- 1g Koniarczyk J, Hesk D, Overgard A, Davies IW, McNally A. J. Am. Chem. Soc. 2018; 140: 1990
- 1h Lockley WJ. S, McEwen A, Cooke R. J. Labelled Compd. Radiopharm. 2012; 55: 235
- 1i Mullard A. Nat. Rev. Drug Discovery 2016; 15: 219
- 1j Elmore CS, Bragg RA. Bioorg. Med. Chem. Lett. 2015; 25: 167
- 1k Harbeson SL, Tung RD. Med. Chem. News 2014; 8
- 1l Shao L, Hewitt MC. Drug News Perspect. 2010; 23: 398
- 2a Wiberg KB. Chem. Rev. 1955; 55: 713
- 2b Pocker Y, Exner JH. J. Am. Chem. Soc. 1968; 90: 6764
- 2c Caldwell RA. J. Org. Chem. 1970; 35: 1193
- 2d Bailey WF, Patricia JJ. J. Organomet. Chem. 1988; 35: 1
- 2e Simmons EM, Hartwig JF. Angew. Chem. Int. Ed. 2012; 51: 3066
- 2f Soulard V, Villa G, Vollmar DP, Renaud P. J. Am. Chem. Soc. 2018; 140: 155
- 2g Zhu Y, Zhou J, Jiao B. ACS Med. Chem. Lett. 2013; 4: 349
- 2h Zhang Y, Tortorella MD, Wang Y, Liu J, Tu Z, Liu X, Bai Y, Wen D, Lu X, Lu Y, Talley JJ. ACS Med. Chem. Lett. 2014; 5: 1162
- 2i Maltais F, Jung YC, Chen M, Tanoury J, Perni RB, Mani N, Laitinen L, Huang H, Liao S, Gao H, Tsao H, Block E, Ma C, Shawgo RS, Town C, Brummel CL, Howe D, Pazhanisamy S, Raybuck S, Namchuk M, Bennani YL. J. Med. Chem. 2009; 52: 7993
- 3a MacWood GE, Urey HC. J. Chem. Phys. 1936; 4: 402
- 3b Atzrodt J, Derdau V, Fey T, Zimmermann J. Angew. Chem. Int. Ed. 2007; 46: 7744
- 3c Alexakis E, Hickey MJ, Jones JR, Kingston LP, Lockley WJ. S, Mather AN, Traci S, Wilkinson DJ. Tetrahedron Lett. 2005; 46: 4291
- 3d Taglang C, Martínez-Prieto LM, del Rosal I, Maron L, Poteau R, Philippot K, Chaudret B, Perato S, Lone AS, Puente C, Dugave C, Rousseau B, Pieters G. Angew. Chem. Int. Ed. 2015; 54: 10474
- 3e Giagou T, Meyer MP. Chem. Eur. J. 2010; 16: 10616
- 3f Klinman JP. J. Phys. Org. Chem. 2010; 23: 606
- 3g Marcus DM, McLachlan KA, Wildman MA, Ehresmann JO, Kletnieks PW, Haw JF. Angew. Chem. 2006; 118: 3205
- 3h Cleland WW. Arch. Biochem. Biophys. 2005; 433: 2
- 3i Busenlehner LS, Armstrong RS. Arch. Biochem. Biophys. 2005; 433: 34
- 3j Bergner G, Albert CR, Schiller M, Bringmann G, Schirmeister T, Dietzek B, Niebling S, Schlücker S, Popp J. Analyst 2011; 136: 3686
- 4a Desmarets C, Kuhl S, Schneider R, Fort Y. Organometallics 2002; 21: 1554
- 4b Gómez-Gallego M, Sierra MA. Chem. Rev. 2011; 111: 4857
- 4c Alonso F, Beletskaya IP, Yus M. Chem. Rev. 2002; 102: 4009
- 4d Johansen SK, Sørensen L, Martiny L. J. Labelled Compd. Radiopharm. 2005; 48: 569
- 4e Janni M, Peruncheralathan S. Org. Biomol. Chem. 2016; 14: 3091
- 4f Kuriyama M, Hamaguchi N, Yano G, Tsukuda K, Sato K, Onomura O. J. Org. Chem. 2016; 81: 8934
- 4g Donald CS, Moss TA, Noonan GM, Roberts B, Durham CE. Tetrahedron Lett. 2014; 55: 3305
- 4h Atzrodt J, Derdau V, Kerr WJ, Reid M. Angew. Chem. Int. Ed. 2018; 57: 3022
- 5a Yu RP, Hesk D, Rivera N, Pelczer I, Chirik PJ. Nature 2016; 529: 195
- 5b C–H Bond Activation, Vol. 292. Yu J.-Q, Shi Z. Springer; Berlin: 2010
- 5c Mkhalid IA. I, Barnard JH, Marder TB, Murphy JM, Hartwig JF. Chem. Rev. 2010; 110: 890
- 5d Lyons TW, Sanford MS. Chem. Rev. 2010; 110: 1147
- 5e Colby DA, Bergman RG, Ellman JA. Chem. Rev. 2010; 110: 624
- 6 Loh Y, Nagao K, Hoover AJ, Hesk D, Rivera NR, Colletti SL, Davies IW, MacMillan DW. C. Science 2017; 358: 1182
- 7 Hale LV. A, Szymczak NK. J. Am. Chem. Soc. 2016; 138: 13489
- 8 Neubert L, Michalik D, Bahn S, Imm S, Neumann H, Atzrodt J, Derdau V, Holla W, Beller M. J. Am. Chem. Soc. 2012; 134: 12239
- 9a Wang X, Zhu M, Schuman DP, Zhong D, Wang W, Wu L, Liu W, Stoltz BM, Liu W. J. Am. Chem. Soc. 2018; 140: 10970
- 9b Juhl M, Kim MJ, Lee HY, Baik MH, Lee JW. Synlett 2019; 30: 997
- 10a Anders E, Markus F. Tetrahedron Lett. 1987; 28: 2675
- 10b Haase M, Goerls H, Anders E. Synthesis 1998; 195
- 10c Koniarczyk JL, Hesk D, Overgard A, Davies IW, McNally A. J. Am. Chem. Soc. 2018; 140: 1990
- 10d Hilton MC, Dolewski RD, McNally A. J. Am. Chem. Soc. 2016; 138: 13806
- 10e Shimada M, Sugimoto O, Sato A, Tanji K. Heterocycles 2011; 83: 837
- 10f Hilton MC, Dolewski RD, McNally A. J. Am. Chem. Soc. 2016; 138: 13806
- 10g Deng Z, Lin JH, Xiao JC. Nat. Commun. 2016; 7: 10337
- 11a U.S. Food & Drug Administration, New Drug Application (NDA): 208082; https://www.accessdata.fda.gov/scripts/cder/daf/ index.cfm?event=overview.process&varApplNo=208082.
- 11b Mullard A. Nat. Rev. Drug Discovery 2017; 16: 305
- 11c Schmidt C. Nat. Biotechnol. 2017; 35: 493
- 12a Williamson A. Philos. Mag. 1850; 37: 350
- 12b Williamson A. Justus Liebigs Ann. Chem. 1851; 77: 37
- 12c Williams A. Concerted Organic and Bio-Organic Mechanisms . CRC Press; Boca Raton: 1999
- 12d Hill M, Dronsfield A. Educ. Chem. 2002; 39: 47
- 12e Kopecky DJ, Rychnovsky SD. J. Org. Chem. 2000; 65: 191
- 12f Fuhrmann E, Talbiersky J. Org. Process Res. Dev. 2005; 9: 206
- 13a Wang X, Li C, Wang X, Wang Q, Dong X, Duan A, Zhao W. Org. Lett. 2018; 20: 4267
- 13b Wang X, Tang Y, Long C, Dong W, Li C, Xu X, Zhao W, Wang X. Org. Lett. 2018; 20: 4749
- 14a Jina H, Gaob Z, Zhoua S, Qian C. Synlett 2019; 30: 982
- 14b Barham JP, Dalton SE, Allison M, Nocera G, Young A, John MP, McGuire T, Campos S, Tuttle T, Murphy JA. J. Am. Chem. Soc. 2018; 140: 11510
- 14c Rotstein BH, Stephenson NA, Vasdev N, Liang SH. Nat. Commun. 2014; 109: 4365
- 14d Scales S, Johnson S, Hu Q, Do Q, Richardson P, Wang F, Braganza J, Ren S, Wan Y, Zheng B, Faizi D, McAlpine I. Org. Lett. 2013; 159: 2156
- 14e Uehata K, Kawakami T, Suzuki H. J. Chem. Soc., Perkin Trans. 2002; 1: 696
- 14f Politanskaya L, Malykhin E, Shteingarts V. Eur. J. Org. Chem. 2001; 405
- 14g Barham JP, Coulthard G, Kane RG, Delgado N, John MP, Murphy JA. Angew. Chem. Int. Ed. 2016; 55: 4492
- 14h Murphy JA, Khan TA, Zhou S.-Z, Thomson DW, Mahesh M. Angew. Chem. Int. Ed. 2005; 44: 1356
- 14i Murphy JA, Zhou S.-Z, Thomson DW, Schoenebeck F, Mahesh M, Park SR, Tuttle T, Berlouis LE. A. Angew. Chem. Int. Ed. 2007; 46: 5178
- 14j Murphy JA, Garnier J, Park SR, Schoenebeck F, Zhou S.-Z, Turner AT. Org. Lett. 2008; 10: 1227
- 14k Farwaha HS, Bucher G, Murphy JA. Org. Biomol. Chem. 2013; 11: 8073
- 15a Handel H, Pasquini MA, Pierre JL. Tetrahedron 1980; 36: 3205
- 15b Pauton M, Aubert C, Bluet G, Gruss-Leleu F, Roy S, Perrio C. Org. Process Res. Dev. 2019; 23: 900
- 15c Murphy J, Rohrbach S, Smith AJ, Pang JH, Poole DL, Tuttle T, Chiba S. Angew. Chem. Int. Ed. 2019; 58
- 15d Kwan EE, Zeng Y, Besser HA, Jacobsen EN. Nat. Chem. 2018; 10: 917
- 15e Terrier F. Modern Nucleophilic Aromatic Substitution . Wiley-VCH; Weinheim: 2013
- 15f Kaga A, Hayashi H, Hakamata H, Oi M, Uchiyama M, Takita R, Chiba S. Angew. Chem. Int. Ed. 2017; 56: 11807
- 15g Barham JP, Coulthard G, Emery K, Doni E, Cumine F, Nocera G, John MP, Berlouis LE. A, McGuire T, Tuttle T, Murphy JA. J. Am. Chem. Soc. 2016; 138: 7402
- 15h De S, Ghosh S, Bhunia S, Shiekh JA, Bisai A. Org. Lett. 2012; 14: 4466
- 15i Tanimoro K, Ueno M, Takeda K, Kirihata M, Tanimori S. J. Org. Chem. 2012; 77: 7844
- 15j Cuthbertson J, Gray VJ, Wilden JD. Chem. Commun. 2014; 50: 2575
- 16 Experimental Procedures General Procedure 1 An oven-dried vial (4 ml) equipped with a magnetic stir bar was charged with 2-(methoxy)benzonitrile (1a, 0.2 mmol, 26.6 mg). The vial was then moved into a N2-filled glovebox. KOt-Bu (0.4 mmol, 44.8 mg), 4-phenylcyclohexan-1-d-1-ol (2a, 0.4 mmol, 46.8 mg), and 1,4-dioxane (0.2 mL) were added to the vial. The vial was capped, and the resulting reaction mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was then allowed to cool to room temperature, diluted with Et2O (3 ml), and then filtered through a plug of silica gel, washing with THF. The crude mixture was concentrated in vacuo and purified by flash column chromatography on silica gel to provide the corresponding product 3a (43.1 mg, 78% yield) as a white solid (eluent: hexanes/EtOAc = 30:1); mp 138.6 ℃ . 1H NMR (400 MHz, CDCl3): δ = 7.60 (d, J = 7.7 Hz, 1 H), 7.55 (t, J = 8.0 Hz, 1 H), 7.36 (t, J = 7.4 Hz, 2 H), 7.27 (t, J = 8.1 Hz, 3 H), 7.07 (d, J = 8.5 Hz, 1 H), 7.02 (t, J = 7.6 Hz, 1 H), 2.66 (t, J = 11.8 Hz, 1 H), 2.33 (d, J = 12.1 Hz, 2 H), 2.08 (d, J = 12.1 Hz, 2 H), 1.78 (t, J = 13.0 Hz, 2 H), 1.67 (t, J = 12.9 Hz, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 159.98, 146.09, 134.19, 134.03, 128.55, 126.84, 126.35, 120.83, 116.80, 114.23, 103.35, 77.43 (t, J = 21.5 Hz), 43.33, 32.22, 32.03 ppm. HRMS (ESI): m/z calcd for C19H18DNONa [M + Na]: 301.1422; found: 301.1414. IR (neat): 3057, 2944, 2890, 2225, 1597, 1488, 1454, 1292, 746 cm–1. General Procedure 2 An oven-dried vial (4 ml) equipped with a magnetic stir bar was charged with 2′-methoxy-3-(methylthio)-(1,1′-biphenyl)-4-carbonitrile (4h, 0.2 mmol, 51 mg). The vial was then moved into a N2-filled glovebox. KOt-Bu (0.4 mmol, 44.8 mg), cyclooctan-1-d-1-ol (5h, 0.4 mmol, 51.4 mg), and 1,4-dioxane (0.2 mL) were added to the vial. The vial was capped, and the resulting reaction mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was then allowed to cool to room temperature, diluted with Et2O (3 mL), and then filtered through a plug of silica gel, washing with THF. The crude mixture was concentrated in vacuo and purified by flash column chromatography on silica gel to provide the corresponding product 6h (55.7 mg, 83% yield) as a rose-red solid (eluent: hexanes/Et2O = 10:1); mp 85.8 °C. 1H NMR (400 MHz, CDCl3): δ = 7.55 (d, J = 7.9 Hz, 1 H), 7.39 (t, J = 7.8 Hz, 1 H), 7.31 (d, J = 7.5 Hz, 1 H), 7.26 (s, 1 H), 7.10 (d, J = 10.6 Hz, 2 H), 7.02 (d, J = 8.3 Hz, 1 H), 3.84 (s, 3 H), 2.01–1.93 (m, 4 H), 1.89–1.78 (m, 2 H), 1.67 (dd, J = 13.2, 6.4 Hz, 1 H), 1.58 (dt, J = 12.8, 7.6 Hz, 6 H), 1.28 (d, J = 11.5 Hz, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 159.49, 156.42, 144.82, 133.33, 130.63, 129.93, 129.20, 121.75, 121.17, 117.16, 115.47, 111.56, 101.37, 79.18 (t, J = 21.6 Hz), 55.69, 31.47, 27.15, 25.72, 23.03 ppm. HRMS (ESI): m/z calcd for C22H24DNO2Na [M + Na]: 359.1840; found: 359.1838. IR (neat): 3025, 2925, 2853, 2223, 1605, 1556, 1465, 1405, 1244, 754 cm–1.