Deuterated Aryl Alkyl Ethers Synthesis via Nucleophilic Etherification of Aryl Alkyl Ethers and Thioethers with Deuterated Alcohols

Shuai Li; Xia Wang; Xin-Ge Yang; Gui-Quan Yu; Xue-Qiang Wang

doi:10.1055/s-0037-1611898

Synlett, Inhaltsverzeichnis

Synlett 2019; 30(15): 1805-1809
DOI: 10.1055/s-0037-1611898

letter

Deuterated Aryl Alkyl Ethers Synthesis via Nucleophilic Etherification of Aryl Alkyl Ethers and Thioethers with Deuterated Alcohols

Shuai Li

^aMolecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, Hunan University, Changsha, Hunan 410082, P. R. of China eMail: wangxq@hnu.edu.cn

,

Xia Wang

^aMolecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, Hunan University, Changsha, Hunan 410082, P. R. of China eMail: wangxq@hnu.edu.cn

,

Xin-Ge Yang∗

^bCollege of Chemistry and Chemical Engineering, Linyi University, Linyi, Shandong 276000, P. R. of China eMail: yxgyg@163.com

,

Gui-Quan Yu

^cLanling County Inspection and Testing Center, Linyi, Shandong 277700, P. R. of China

,

Xue-Qiang Wang ∗

^aMolecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, Hunan University, Changsha, Hunan 410082, P. R. of China eMail: wangxq@hnu.edu.cn

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Abstract

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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.

Key words

deuterium - ether - thioether - etherification - nucleophilic aromatic substitution

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Referenzen

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.

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