A Novel Approach to Substituted α-Carbamoyl Phosphonates: Useful Reagents for the Horner–Wadsworth–Emmons Olefination

Abstract

α-Carbamoyl phosphonates are useful reagents for the Horner–Wadsworth–Emmons olefination of aldehydes en route to medicinally relevant polysubstituted acrylamides. A new synthetic approach to these reagents has been developed. The methodology relies on the microwave-promoted Wolff rearrangement of α-acyl-α-diazophosphonates with trapping of the ketene intermediate in situ with various amines.

Key words

Michael acceptors - α-diazo-β-oxophosphonates - Wolff rearrangement - ketene trapping - Horner–Wadsworth–Emmons olefination - one-pot procedure

• References

• 1 Baell JB, Nissink JW. M. ACS Chem. Biol. 2018; 13: 36
• 2a Jackson PA, Widen JC, Harki DA, Brummond KM. J. Med. Chem. 2017; 60: 839
• 2b Bauer RA. Drug Discovery Today 2015; 20: 1061
• 3 Baell JB, Walters MA. Nature 2014; 513: 481
• 4 Deng X, Kong L, Zhao Y, He J, Peng L.-Y, Li Y, Zhao Q.-S. Nat. Prod. Bioprospect. 2012; 2: 210
• 5 Selvaraju K, Mofers A, Pellegrini P, Solomonsson J, Ahlner A, Morad V, Hillert E.-K, Espinosa B, Arner ES. J, Jensen L, Molamström J, Turkina MV, D’Arcy P, Walters MA, Sunnerhagen M, Linder S. Sci. Rep. 2019; 9841
• 6 Gan F.-F, Kaminska KK, Yang H, Liew C.-Y, Leow P.-C, So C.-L, Tu LN. L, Roy A, Yap C.-W, Kang T.-S, Chui W.-K, Chew E.-H. Antioxid. Redox Signaling 2013; 19: 1149
• 7a Jovanović M, Zhukovsky D, Podolski-Renić A, Domračeva I, Žalubovskis R, Senćanski M, Glišić S, Sharoyko V, Tennikova T, Dar’in D, Pešić M, Krasavin M. Eur. J. Med. Chem. 2019; 181: 111580
• 7b Jovanović M, Zhukovsky D, Podolski-Renić A, Žalubovskis R, Dar’in D, Sharoyko V, Tennikova T, Pešić M, Krasavin M. Eur. J. Med. Chem. 2020; 191: 112119
• 8 Kato MJ, Furlan M. Pure Appl. Chem. 2007; 79: 529
• 9 McGrath NA, Raines RT. Acc. Chem. Res. 2011; 44: 752
• 10a Albrecht A, Koszuk JF, Modranka J, Rozalski M, Krajewska U, Janecka A, Studzian K, Janecki T. Bioorg. Med. Chem. 2008; 16: 4872
• 10b Blaszczyk E, Krawczyk H, Janecki T. Synlett 2004; 2685
• 11 Kim S, Lim C, Lee S, Lee S, Cho H, Lee J.-Y, Shim DS, Park HD, Kim S. ACS Comb. Sci. 2013; 15: 208
• 12 Hernández-Fernández E, Fernández-Zertuche M, García-Barradas O, Muñoz-Muñiz O, Ordóñez M. Synlett 2006; 440
• 13 Dhameja M, Pandey J. Asian J. Org. Chem. 2018; 7: 1502
• 14 Safrygin A, Dar’in D, Kantin G, Krasavin M. Eur. J. Org. Chem. 2019; 4721
• 15a Dayoub W, Diab Y, Doutheau A. Tetrahedron Lett. 2001; 42: 8455
• 15b Kim S, Sutton SC, Guo C, LaCour TG, Fuchs PL. J. Am. Chem. Soc. 1999; 121: 2056
• 16a Chen YP, Chantegrel B, Deshayes C. Heterocycles 1995; 41: 175
• 16b Zhang W, Romo D. J. Org. Chem. 2007; 72: 8939
• 17a Patil BS, Vasanthakumar G.-R, Babu VV. S. Lett. Pept. Sci. 2002; 9: 232
• 17b Presset M, Coquerel Y, Rodrigez J. J. Org. Chem. 2009; 74: 415
• 17c Sudrik SG, Chavan SP, Chandrakumar KR. S, Pal S, Date SK, Chavan SP, Sonawe HR. J. Org. Chem. 2002; 67: 1574
• 18 Dar’in D, Kantin G, Krasavin M. Chem. Commun. 2019; 55: 5239
• 19 Synthesis of 2a–l; General Procedure: Diazo ketophosphonate 5 (1.2 mmol) and amine (1 mmol) were dissolved in anhydrous toluene (2 mL) and placed in a 5 mL microwave vial. The solution was then irradiated at 140 °C for 1 h. The resulting mixture was concentrated in vacuo and subjected to flash column chromatography on SiO₂ (n-hexane/acetone, gradient from 85:15 to 60:40) to afford phosphonamide 2.
• 20 Characterization data of selected compounds: Compound 2d: Yield: 168 mg (54%); light-brown solid; mp 39.0–40.3 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.27 (d, J = 8.2 Hz, 1 H), 7.24–7.15 (m, 2 H), 7.08–6.99 (m, 1 H), 4.63–4.52 (m, 1 H, NCH ₂CH₂), 4.25–4.12 (m, 4 H, OCH ₂CH₃), 4.11–4.00 (m, 1 H, NCH ₂CH₂), 3.37–3.14 (m, 3 H, NCH₂CH ₂, CH), 1.53 (dd, J = 18.1, 6.9 Hz, 3 H, CH₃), 1.36 (t, J = 6.2 Hz, 3 H, OCH₂CH ₃), 1.32 (t, J = 6.1 Hz, 3 H, OCH₂CH ₃). ¹³C NMR (101 MHz, CDCl₃): δ = 167.0 (d, J = 4.2 Hz), 142.9, 131.7, 127.4, 124.5, 123.9, 117.5, 63.1 (d, J = 6.6 Hz), 62.5 (d, J = 6.9 Hz), 48.6, 39.3 (d, J = 132.7 Hz), 27.9, 16.5 (d, J = 2.4 Hz), 16.4 (d, J = 2.5 Hz), 12.5 (d, J = 6.9 Hz). ³¹P NMR (162 MHz, CDCl₃): δ = 24.17. HRMS-ESI: m/z [M + Na] calcd for C₁₅H₂₂NNaO₄P: 312.1359; found: 312.1359. Compound 2g: Yield: 170 mg (48%); yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.53–7.45 (m, 2 H), 7.38–7.26 (m, 3 H), 4.48 (d, J = 22.8 Hz, 1 H, CH), 4.31–4.19 (m, 2 H, OCH ₂CH₃), 4.1–3.94 (m, 2 H, OCH ₂CH₃), 3.62–3.31 (m, 4 H, NCH₂), 1.81–1.42 (m, 7 H), 1.39–1.25 (m, 4 H, OCH₂CH ₃, NCH₂CH₂CH ₂), 1.20 (t, J = 7.1 Hz, 3 H, OCH₂CH ₃). ¹³C NMR (101 MHz, CDCl₃): δ = 167.11 (d, J = 3.1 Hz), 132.30 (d, J = 9.6 Hz), 129.46 (d, J = 6.0 Hz), 128.58 (d, J = 2.9 Hz), 127.64 (d, J = 3.5 Hz), 63.41 (d, J = 6.5 Hz), 62.51 (d, J = 7.2 Hz), 50.57 (d, J = 143.8 Hz), 48.68, 46.28, 28.92, 27.40, 26.82, 26.43, 16.41 (d, J = 6.1 Hz), 16.26 (d, J = 6.3 Hz). ³¹P NMR (162 MHz, CDCl₃): δ = 20.32. HRMS-ESI: m/z [M + Na] calcd for C₁₈H₂₈NNaO₄P: 376.1648; found: 376.1645. Compound 2i: Yield: 261 mg (66%); yellowish solid; mp 118.9–120.6 °C. ¹H NMR (400 MHz, CDCl₃): δ = 11.87 (s, 1 H, NH), 8.78 (dd, J = 8.4, 1.2 Hz, 1 H), 7.92 (dd, J = 8.0, 1.6 Hz, 1 H), 7.57 (ddd, J = 8.7, 7.2, 1.6 Hz, 1 H), 7.15 (ddd, J = 8.2, 7.3, 1.2 Hz, 1 H), 4.29–4.09 (m, 4 H, OCH ₂CH₃), 2.77 (dd, J = 20.5, 9.7 Hz, 1 H, CH), 2.69 (s, 3 H, CH₃), 2.29–2.17 (m, 2 H), 1.87–1.74 (m, 2 H), 1.74–1.61 (m, 2 H), 1.40–1.26 (m, 8 H), 1.26–1.13 (m, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 202.4, 167.7 (d, J = 4.1 Hz), 140.6, 135.1, 131.6, 122.6, 122.0, 120.9, 62.5 (d, J = 7.1 Hz), 62.3 (d, J = 6.6 Hz), 56.6 (d, J = 130.9 Hz), 37.6 (d, J = 3.8 Hz), 31.9 (d, J = 3.3 Hz), 31.8 (d, J = 7.9 Hz), 30.89, 28.5, 26.0, 25.9, 16.38, 16.33. ³¹P NMR (162 MHz, CDCl₃): δ = 23.22. HRMS-ESI: m/z [M + H] calcd for C₂₀H₃₀NNaO₅P: 396.1934; found: 396.1936. Compound 2j: Yield: 181 mg (58%); white solid; mp 97.4–99.1 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.81 (s, 1 H, NH), 7.60–7.54 (m, 2 H), 7.33–7.28 (m, 2 H), 7.13–7.06 (m, 1 H), 4.27–4.20 (m, 2 H, OCH ₂CH₃), 4.16 (m, 2 H, OCH ₂CH₃), 2.19 (dd, J = 21.6, 10.5 Hz, 1 H, CH), 1.44–1.25 (m, 7 H, OCH₂CH ₃, CH₂CHCH₂), 0.82–0.67 (m, 2 H, CH ₂CHCH₂), 0.55–0.40 (m, 2 H, CH₂CHCH ₂). ¹³C NMR (101 MHz, CDCl₃): δ = 165.9, 138.0, 128.9, 124.2, 119.8, 63.4 (d, J = 6.8 Hz), 62.8 (d, J = 7.0 Hz), 52.20 (d, J = 130.1 Hz), 16.51 (d, J = 5.8 Hz), 16.40 (d, J = 6.0 Hz), 9.4 (d, J = 4.6 Hz), 4.42, 4.27. ³¹P NMR (162 MHz, CDCl₃): δ = 25.01. HRMS-ESI: m/z [M + Na] calcd for C₁₅H₂₂NNaO₄P: 334.1179; found: 334.1181.
• 21 One-Pot Procedure for the Preparation of 1a from 5a: β-Ketophosphonate 5a (1.2 mmol) and aniline (1 mmol) were dissolved in toluene and placed in a 5 mL microwave vial. The solution was irradiated at 140 °C for 1 h. Upon cooling to r.t., NaH (1.5 mmol, 60% suspension in mineral oil) was added portionwise. After the evolution of hydrogen gas stopped, 4-chlorobenzaldehyde (1 mmol) was added. The reaction mixture was stirred at r.t. overnight and washed with ice-cold water (10 mL). The aqueous phase was back-extracted with Et₂O (2 × 10 mL) and the combined organics was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was subjected to flash column chromatography.
• 22 Peters J.-U, Capuano T, Weber S, Kritter S, Saegesser M. Tetrahedron Lett. 2008; 49: 4029
• 23 Zhao S, He Y.-H, Wu D, Guan Z. J. Fluorine Chem. 2010; 131: 597