Boryl Acrylaldehyde: An Elusive Member of the α-Boryl Aldehyde Class of Reagent

Abstract

We describe a synthetic route to boryl acrylaldehyde, an amphoteric molecule that features BMIDA and aldehyde functionalities attached to an sp²-carbon center. As the project unfolded, conventional protocols based on aldol condensation turned out to be unsuccessful. We eventually zeroed in on oxidative conditions that preserved the BMIDA group and delivered the desired aldehyde functionality. During our investigation, it became clear that boryl alcohol displays hemilabile N–B bonding, which differs dramatically from the previously described congeners with the sp³-carbon center connected to boron. We have attempted to understand the origins of this behavior using DFT calculations. Overall, boryl acrylaldehyde can be considered as an attractive entry point in synthetic methods. These studies are underway in our laboratory.

Key words

boron - boryl aldehydes - amphoteric molecules - hemilability - boryl - oximes - boryl hydrazones

• References and Notes

• 1a Matteson DS, Majumdar D. J. Am. Chem. Soc. 1980; 102: 7588
• 1b Matteson DS, Majumdar D. Organometallics 1983; 2: 1529
• 1c Tripathy PB, Matteson DS. Synthesis 1990; 200
• 1d Matteson DS. J. Org. Chem. 2013; 78: 10009
• 2a He Z, Yudin AK. J. Am. Chem. Soc. 2011; 133: 13770
• 2b Fernández NL. G, Medina RE, Vallejos MM. J. Org. Chem. 2022; 87: 4680
• 2c He Z, Zajdlik A, Yudin AK. Dalton Trans. 2014; 43: 11434
• 2d Lee CF, Diaz DB, Holownia A, Kaldas SJ, Liew SK, Garrett GE, Dudding T, Yudin AK. Nat. Chem. 2018; 10: 1062
• 2e Diaz DB, Scully CC, Liew SK, Adachi S, Trinchera P, St Denis JD, Yudin AK. Angew. Chem. Int. Ed. 2016; 55: 12659
• 3 Gonzalez JA, Ogba OM, Morehouse GF, Rosson N, Houk KN, Leach AG, Cheong PH. Y, Burke MD, Lloyd-Jones GC. Nat. Chem. 2016; 8: 1067
• 4 Mancilla T, Contreras R, Wrackmeyer B. J. Organomet. Chem. 1986; 307: 1
• 5 Kaldas SJ, Tien C.-H, Gomes GD. P, Meyer S, Sirvinskas M, Foy H, Dudding T, Yudin AK. Org. Lett. 2021; 23: 324
• 6a Holownia A, Tien C.-H, Diaz DB, Larson RT, Yudin AK. Angew. Chem. Int. Ed. 2019; 131: 15292
• 6b Tien C.-H, Trofimova A, Holownia A, Kwak BS, Larson RT, Yudin AK. Angew. Chem. Int. Ed. 2021; 60: 4342
• 7 Lipshutz BH, Bošković ŽV, Aue DH. Angew. Chem. Int. Ed. 2008; 47: 10183
• 8 Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Petersson GA, Nakatsuji H, Li X, Caricato M, Marenich AV, Bloino J, Janesko BG, Gomperts R, Mennucci B, Hratchian HP, Ortiz JV, Izmaylov AF, Sonnenberg JL, Williams-Young D, Ding F, Lipparini F, Egidi F, Goings J, Peng B, Petrone A, Henderson T, Ranasinghe D, Zakrzewski VG, Gao J, Rega N, Zheng G, Liang W, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Throssell K, Montgomery JA. Jr, Peralta JE, Ogliaro F, Bearpark MJ, Heyd JJ, Brothers EN, Kudin KN, Staroverov VN, Keith TA, Kobayashi R, Normand J, Raghavachari K, Rendell AP, Burant JC, Iyengar SS, Tomasi J, Cossi M, Millam JM, Klene M, Adamo C, Cammi R, Ochterski JW, Martin RL, Morokuma K, Farkas O, Foresman JB, Fox DJ. Gaussian 16, Revision C.01. Gaussian, Inc; Wallingford: 2016
• 9 Weigend F, Ahlrichs R. Phys. Chem. Chem. Phys. 2005; 7: 3297
• 10 Marenich AV, Cramer CJ, Truhlar DG. J. Phys. Chem. B 2009; 113: 6378
• 11 Boryl MIDA Alcohol 8MIDA (890 mg, 6.1 mmol, 3.0 equiv) and borylated pinacol ester 7b (400 mg, 2.0 mmol, 1.0 equiv) were placed in an oven-dried flask equipped with a stir bar. DMSO (0.5 M) was then added, and the resultant solution was stirred at 100 °C for 23 h. The reaction mixture was then cooled to room temperature and poured into H₂O. The mixture was diluted with EtOAc, and the layers were separated. The aqueous layer was extracted three times with EtOAc. The combined organic phases were washed with H₂O and brine, then dried over MgSO₄, filtered, and concentrated in vacuo. The crude product was washed with Et₂O three times to obtain the boryl MIDA alcohol 8 as a white solid (47% yield, 215 mg). The ¹H, ¹³C, and ¹¹B NMR spectra of 8 were taken in DMSO-d ₆ and in CD₃CN solvents. ¹H NMR (400 MHz, CD₃CN): δ = 6.03 (q, J = 6.8 Hz, 1 H), 4.20 (d, J = 3.8 Hz, 2 H), 3.89 (s, 4 H), 2.83 (t, J = 4.0 Hz, 1 H), 2.79 (s, 3 H), 1.71 (dd, J = 6.8, 0.8 Hz, 3 H) ppm. ¹³C NMR (126 MHz, CD₃CN): δ = 170.0, 135.3, 63.3, 59.7, 48.1, 14.2 ppm. ¹¹B NMR (128 MHz, CD₃CN): δ = 11.4 ppm. ¹H NMR (400 MHz, DMSO-d ₆): δ = 5.88 (q, J = 6.7 Hz, 1 H), 4.73 (s, 1 H), 4.16 (d, J = 16.9 Hz, 2 H), 4.06 (s, 2 H), 3.92 (d, J = 16.8 Hz, 2 H), 2.76 (s, 3 H), 1.66 (d, J = 6.7 Hz, 3 H) ppm. ¹³C NMR (126 MHz, DMSO-d ₆): δ = 169.5, 132.5, 62.1, 58.2, 47.2, 14.0 ppm. ¹¹B NMR (128 MHz, DMSO-d ₆): δ = 11.3 ppm. HRMS (DART-AccuTOF 4G) [M + NH₄ ⁺]: m/z calcd for C ₉ H ₁₈ BN ₂ O ₅ : 245.1303; found: 245.1309.
• 12 Boryl MIDA Aldehyde 3cTo an oven-dried round-bottom flask equipped with a magnetic stir bar was added MIDA boronate 8 (100 mg, 0.44 mmol, 1.0 equiv) dissolved in anhydrous MeCN (0.1 M). Dess–Martin periodinane (205 mg, 0.48 mmol, 1.1 equiv) was added, and the resulting mixture was stirred at room temperature for 1 h. Upon completion, as indicated by TLC analysis, the solvent was removed in vacuo to afford a pale-yellow residue. To the residue was added a 1:1 mixture of saturated aqueous NaHCO₃ and saturated aqueous Na₂S₂O₃ followed by the addition of EtOAc. The organic layer was separated. The aqueous layer was extracted once more with EtOAc. The combined organic layers were washed with water and saturated brine solution. The organic layer was then dried over Na₂SO₄ and concentrated in vacuo to yield the crude MIDA-boronate as a solid. The crude product was then purified by flash column chromatography with a short pad of silica gel (eluted with EtOAc) to afford 3c as a bench-stable solid (92% yield, 91 mg).¹H NMR (400 MHz, DMSO-d ₆): δ = 10.26 (d, J = 1.7 Hz, 1 H, E-isomer), 9.44 (d, J = 1.7 Hz, 3 H, Z-isomer), 7.33 (q, J = 7.2 Hz, 3 H, Z-isomer), 7.19 (q, J = 7.3 Hz, 1 H, E-isomer), 4.28 (dt, J = 17.0, 2.9 Hz, 8 H), 3.99 (dt, J = 16.9, 1.7 Hz, 8 H), 2.67 (d, J = 1.7 Hz, 9 H, Z-isomer), 2.65 (d, J = 1.6 Hz, 3 H, E-isomer), 2.19 (dd, J = 7.6, 1.7 Hz, 3 H, E-isomer), 2.15 (dd, J = 7.2, 1.7 Hz, 9 H, Z-isomer) ppm. ¹³C NMR (126 MHz, DMSO-d ₆): δ = 201.5, 197.0, 169.1, 169.1, 167.0, 157.1, 62.6, 62.6, 47.0, 46.9, 14.5, 14.1 ppm. ¹¹B NMR (128 MHz, DMSO-d ₆): δ = 10.2 ppm. HRMS (DART-AccuTOF 4G) [M + H⁺]: m/z calcd for C ₉ H ₁₃ BNO ₅ : 226.0881; found: 226.0887.
• 13 Hanwell MD, Curtis DE, Lonie DC, Vandermeersch T, Zurek E, Hutchison GR. J. Cheminf. 2012; 4: 17
• 14 Legault, C. Y. CYLview20 2020.
• 15 Boryl MIDA Oxime 9 To a round-bottom flask equipped with a magnetic stir bar was added boryl MIDA aldehyde 3c (23 mg, 0.1 mmol, 1.0 equiv). A solution of MeCN/H₂O (1:1) was added at room temperature under air. Hydroxylamine hydrochloride (0.11 mmol, 1.1 equiv) was added to the resulting solution under air. The reaction was stirred at room temperature for 8 h, after which brine was added, and the product was extracted into EtOAc, dried over sodium sulfate, concentrated, and purified by column chromatography (eluted with 100% EtOAc) to give 9 as a white solid (89% yield, 22 mg). ¹H NMR (500 MHz, CDCl₃): δ = 8.29 (s, 1 H), 6.67 (q, J = 7.2 Hz, 1 H), 4.03–3.87 (m, 4 H), 2.82 (s, 3 H), 1.91 (d, J = 7.1 Hz, 3 H) ppm. ¹¹B NMR (96 MHz, CD₃CN): δ = 11.2 ppm. HRMS (DART-AccuTOF 4G) [M + H⁺]: m/z calcd for C₉H₁₄BN₂O₅: 241.0996; found: 241.0999. The ¹³C NMR assignment was deduced from the HSQC and HMBC NMR spectra.
• 16 Boryl MIDA Phenylhydrazine 10To a round-bottom flask equipped with a magnetic stir bar was added boryl MIDA aldehyde 3c (23 mg, 0.1 mmol, 1.0 equiv), followed by MeCN (0.1 M). Phenylhydrazine (0.11 mmol, 1.1 equiv) was added to the resulting solution under air. The reaction was stirred at room temperature for 4 h, after which brine was added, and the product was extracted into EtOAc, dried over sodium sulfate, concentrated, and purified by column chromatography (eluted with 100% EtOAc) to give 10 as a white solid (65% yield, 21 mg). ¹H NMR (400 MHz, CDCl₃): δ = 7.95 (s, 1 H), 7.28–7.16 (m, 2 H), 6.94–6.77 (m, 3 H), 6.55 (q, J = 7.2 Hz, 1 H), 4.04 (d, J = 16.5 Hz, 2 H), 3.90 (d, J = 16.4 Hz, 2 H), 2.80 (s, 3 H), 1.91 (d, J = 7.2 Hz, 3 H) ppm. ¹³C NMR (126 MHz, CDCl₃): δ = 168.2, 144.5, 141.8, 140.9, 129.7, 120.4, 113.0, 63.9, 47.3, 14.6 ppm. ¹¹B NMR (128 MHz, CDCl₃): δ = 11.5 ppm. HRMS (DART-AccuTOF 4G) [M + H⁺]: m/z calcd for C₁₅H₁₉BN₃O₄: 316.1469; found: 316.1473.