Synlett, Table of Contents Synlett 2022; 33(08): 759-766DOI: 10.1055/s-0037-1610794 letter Synthesis of Cyclopropyl Pinacol Boronic Esters from Dibromocyclopropanes Zeina Neouchy ∗ a Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281 – S4, 9000 Ghent, Belgium , Jan Hullaert a Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281 – S4, 9000 Ghent, Belgium , Jonas Verhoeven b Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium , Lieven Meerpoel b Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium , Jan-Willem Thuring b Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium , Guido Verniest b Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium , Johan Winne a Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281 – S4, 9000 Ghent, Belgium› Author AffiliationsRecommend Article Abstract Buy Article All articles of this category Abstract The synthesis of cyclopropyl pinacol boronic esters from dibromocyclopropanes via Matteson–Pasto rearrangement is reported. The method is readily scalable and shows limited levels of stereoinduction, with a selectivity that is in part complementary to that observed in existing stereoselective borylcyclopropanation strategies. The method can be used to rapidly access borylcyclopropanes as interesting building blocks for diversely functionalized cyclopropanes. Key words Key wordsolefins - dibromocyclopropanes - borylcyclopropanes - pinacolborane - Matteson–Pasto rearrangement Full Text References References and Notes Selection of recent publications: 1a He J, Jiang H, Takise R, Zhu R.-Y, Chen G, Dai H.-X, Dhar TG. M, Shi J, Zhang H, Cheng PT. W, Yu J.-Q. Angew. Chem. Int. Ed. 2016; 55: 785 1b Ohtsuka K, Inagi S, Fuchigami T. ChemElectroChem 2017; 4: 183 1c Sandford C, Aggarwal VK. Chem. Commun. 2017; 53: 5481 1d Armstrong RJ, Niwetmarin W, Aggarwal VK. Org. Lett. 2017; 19: 2762 1e Gerleve C, Kischkewitz M, Studer A. Angew. Chem. Int. Ed. 2018; 57: 2441 1f Kischkewitz M, Gerleve C, Studer A. Org. Lett. 2018; 20: 3666 1g Clausen F, Kischkewitz M, Bergander K, Studer A. Chem. Sci. 2019; 10: 6210 1h André-Joyaux E, Kuzovlev A, Tappin ND. C. Angew. Chem. Int. Ed. 2020; 59: 13859 2a DeFrancesco H, Dudley J, Coca A. In Boron Reagents in Synthesis. Vol. 1236; Coca A.; ACS Symposium Series. New Haven, CT: 2016: 1-25 2b Song S, Gao P, Sun L, Kang D, Kongsted J, Poongavanam V, Zhan P, Liu X. Acta Pharm. Sin. B 2021; 1: 3035 3a Fujioka J, Amii H. Org. Lett. 2008; 10: 769 3b Lin H, Pei W, Wang H, Houk KN, Krauss IJ. J. Am. Chem. Soc. 2013; 135: 82 3c Miyamura S, Araki M, Suzuki T, Yamaguchi J, Itami K. Angew. Chem. Int. Ed. 2015; 54: 846 3d Spencer JA, Jamieson C, Talbot EP. A. Org. Lett. 2017; 19: 3891 3e Cai F, Li X. CN 108948057A 2018 3f Chen H, Daniels B, Hamilton G, Patel S, Stivala C, Zhao G. WO 2019072942 A1 2019 3g Wang D, Mück-Lichtenfeld C, Studer A. J. Am. Chem. Soc. 2019; 141: 14126 3h Medina JM, Kang T, Erbay TG, Shao H, Gallego GM, Yang S, Tran-Dubé M, Richardson PF, Derosa J, Helsel RT, Patman RL, Wang F, Ashcroft CP, Braganza JF, McAlpine I, Liu P, Engle KM. ACS Catal. 2019; 9: 11130 3i Aparece MD, Hu W, Morken JP. ACS Catal. 2019; 9: 11381 3j Merchant RR, Lopez JA. Org. Lett. 2020; 22: 2271 3k Wu F.-P, Luo X, Radius U, Marder TB, Wu X.-F. J. Am. Chem. Soc. 2020; 142: 14074 4 Neouchy Z, Verhoeven J, Kong H, Zhao Y, Wang W, Brambilla M, Van Hecke K, Meerpoel L, Thuring JW, Verniest G, Winne J. J. Org. Chem. 2021; 86: 17344 5a Danheiser RL, Savoca AC. J. Org. Chem. 1985; 50: 2401 5b Rubina M, Rubin M, Gevorgyan V. J. Am. Chem. Soc. 2003; 125: 7198 5c de Meijere A, Khlebnikov AF, Sünnemann HW, Frank D, Rauch K, Yufit DS. Eur. J. Org. Chem. 2010; 3295 5d Oosting P, Thomas E, Pamuk R, Folleas B, Brayer J.-L, De Carne CarnavaletB, Meyer C, Cossy J. WO 2014091167 A2 2014 5e Murakami R, Tsunoda K, Iwai T, Sawamura M. Chem. Eur. J. 2014; 20: 13127 5f Tian B, Liu Q, Tong X, Tian P, Lin G.-Q. Org. Chem. Front. 2014; 1: 1116 5g Parra A, Amenós L, Guisán-Ceinos M, López A, García RuanoJ. L, Tortosa M. J. Am. Chem. Soc. 2014; 136: 15833 5h Fawcett A, Pradeilles J, Wang Y, Mutsuga T, Myers EL, Aggarwal VK. Science 2017; 357: 283 5i Wang J, Shang M, Lundberg H, Feu KS, Hecker SJ, Qin T, Blackmond DG, Baran PS. ACS Catal. 2018; 8: 9537 5j Edwards A, Rubina M, Rubin M. Chem. Eur. J. 2018; 24: 1394 5k Shi Y, Gao Q, Xu S. J. Am. Chem. Soc. 2019; 141: 10599 5l Prasad HariD, Abell JC, Fasano V, Aggarwal VK. J. Am. Chem. Soc. 2020; 142: 5515 5m An L, Tong F.-F, Zhang S, Zhang X. J. Am. Chem. Soc. 2020; 142: 11884 5n Jiao Z.-F, Tian Y.-M, Guo X.-N, Radius U, Braunschweig H, Marder TB. J. Catal. 2021; 395: 258 5o Mykura RC, Songara P, Luc E, Rogers J, Stammers E, Aggarwal VK. Angew. Chem. Int. Ed. 2021; 60: 11436 5p Prasad HariD, Madhavachary R, Fasano V, Haire J, Aggarwal VK. J. Am. Chem. Soc. 2021; 143: 7462 6a Takai K, Toshikawa S, Inoue A, Kokumai R, Hirano M. J. Organomet. Chem. 2007; 692: 520 6b Ito H, Kosaka Y, Nonoyama K, Sasaki Y, Sawamura M. Angew. Chem. Int. Ed. 2008; 47: 7424 6c Zhong C, Kunii S, Kosaka Y, Sawamura M, Ito H. J. Am. Chem. Soc. 2010; 132: 11440 6d Benoit G, Charette AB. J. Am. Chem. Soc. 2017; 139: 1364 6e Murai M, Mizuta C, Taniguchi R, Takai K. Org. Lett. 2017; 19: 6104 6f Sayes M, Benoit G, Charette AB. Angew. Chem. Int. Ed. 2018; 57: 13514 6g Liu Y, Zhou Y, Li D, Chen H, Zhao J, Qu J. Org. Chem. Front. 2019; 6: 983 7a Fontani P, Carboni B, Vaultier M, Carrié R. Tetrahedron Lett. 1989; 30: 4815 7b Markó IE, Kumamoto T, Giard T. Adv. Synth. Catal. 2002; 344: 1063 7c Hussain MH, Li H, Hussain N, Ureña M, Caroll PJ, Walsh PJ. J. Am. Chem. Soc. 2009; 131: 6516 7d Phelan JP, Lang SB, Compton JS, Kelly CB, Dykstra R, Gutierrez O, Molander GA. J. Am. Chem. Soc. 2018; 140: 8037 7e Carreras J, Caballero A, Pérez PJ. Angew. Chem. Int. Ed. 2018; 57: 2334 8a Verhoeven J, De Vleeschouwer F, Kong H, Van Hecke K, Pande V, Sun W, Vos A, Wu T, Meerpoel L, Thuring J.-W, Verniest G. Chem. Eur. J. 2019; 25: 15419 8b Verhoeven J, Brambilla M, Chinta N, Hullaert JJ. A, Jouffroy LM, Meerpoel L, Neouchy Z, Thuring JW. J. F, Verniest GA. F, Winne JM. WO 2020249663 2020 8c Verhoeven J, Kong H, Zhao Y, Wang W, Pande V, Brambilla M, Van Hecke K, Meerpoel L, Thuring J.-W, Verniest G. Synlett 2021; 32: 892 8d Jouffroy L, Verhoeven J, Brambilla M, Verniest G, Kong H, Zhao Y, Wang W, Meerpoel L, Thuring JW, Winne J. Org. Lett. 2021; 23: 8828 9 Mąkosza M. Surv. Prog. Chem. 1980; 9: 1 10 General Dibromocyclopropanation ProcedureSubstrate 1 (1 equiv) and benzyltriethylammonium chloride (0.1 equiv) were dissolved in a mixture of bromoform (7 equiv) and dichloromethane (c1 = 0.75 M) and a solution of sodium hydroxide (25 M in H2O, 37 equiv) was added dropwise at room temperature and under argon atmosphere. The mixture was stirred at room temperature for 3–4 h. The product was extracted with Et2O (3×) while discarding the polymeric tar. The combined organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude was purified over silica gel column chromatography to afford the desired dibromocyclopropane. All dibromocyclopropanes were stored under argon in the freezer.(3a′S,6′R,6a′R)-2,2-Dibromo-6′-methoxy-2′,2′-dimethyldihydro-6′H-spiro{cyclopropane-1,4′-furo[3,4-d][1,3]dioxole} (2)Compound 2a (13.65 g, 38.13 mmol, 71%, orange oil) and compound 2b (1.10 g, 3.07 mmol, 6%, dark orange oil) were synthesized from methyl 2′,3′-isopropylidene-4′-methylidene-d-erythro furanoside (1a, 10 g, 53.70 mmol, 1 equiv) according to the general procedure (3 h stirring at room temperature). The analysis of the 1H NMR spectrum of the crude mixture indicates a ratio 2a/2b = 93:7. The crude was purified over silica gel column chromatography (elution with petroleum ether (PE) 100% then PE/EtOAc = 95:5 and 90:10) to afford the major isomer 2a followed by the fraction containing the minor isomer 2b. Compound 2a: IR (neat): ν max = 2988, 2935, 1372, 1200, 1104, 1083, 975, 867, 703, 666 cm–1. 1H NMR (400 MHz, CDCl3): δ = 5.13 (s, 1 H), 5.05 (d, J = 5.7 Hz, 1 H), 4.71 (d, J = 5.7 Hz, 1 H), 3.56 (s, 3 H), 2.00 (d, J = 9.5 Hz, 1 H), 1.96 (d, J = 9.5 Hz, 1 H), 1.46 (s, 3 H), 1.37 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 113.4, 108.9, 85.5, 82.0, 73.6, 57.2, 33.4, 29.6, 26.7, 26.1 ppm. GC–MS, LC–MS, and HRMS were not conclusive probably due to poor or no ionization.Compound 2b: 1H NMR (400 MHz, CDCl3): δ = 5.08 (s, 1 H), 4.73 (d, J = 5.7 Hz, 1 H), 4.65 (d, J = 5.7 Hz, 1 H), 3.33 (s, 3 H), 1.98 (d, J = 8.7 Hz, 1 H), 1.83 (d, J = 8.7 Hz, 1 H), 1.58 (s, 3 H), 1.38 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 113.7, 109.0, 85.9, 84.9, 71.1, 55.4, 35.7, 26.6, 26.0, 22.9 ppm. GC–MS: [M]+• = 355, 19.85 min. HRMS was not conclusive probably due to poor or no ionization.(±)-{[(2,2-Dibromo-1-methylcyclopropyl)methoxy]methyl}benzene (5)Compound 5 (288.5 mg, 0.86 mmol, 78%, orange oil) was synthesized from allyl ether 1b (178.5 mg, 1.10 mmol, 1 equiv) according to the general procedure (3 h stirring at room temperature). The crude was purified over silica gel column chromatography (elution with pentane/EtOAc = 99:1). IR (neat): ν max = 2859, 1453, 1361, 1088, 1074, 1028, 966, 850, 735, 694 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.39–7.27 (m, 5 H), 4.61–4.54 (m, 2 H), 3.63 (d, J = 10.1 Hz, 1 H), 3.59 (d, J = 10.1 Hz, 1 H), 1.57 (d, J = 7.6 Hz, 1 H), 1.49 (s, 3 H), 1.46 (d, J = 7.5 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 138.2, 128.5 (2 C), 127.9 (3 C), 76.1, 73.1, 36.0, 32.9, 29.7, 21.3 ppm. LC–MS: [M + NH4]+• = 352, 7.42 min. HRMS was not conclusive probably due to poor or no ionization.(±)-{(1R,3R)-3-[(Benzyloxy)methyl]-2,2-dibromocyclopropyl}benzene (6)Compound 6 (321 mg, 0.81 mmol, 74%, orange oil) was synthesized from allyl ether 1c (247 mg, 1.10 mmol, 1 equiv) according to the general procedure (4 h stirring at room temperature). The crude was purified over silica gel column chromatography (elution with pentane/EtOAc = 99:1). IR (neat): ν max = 3029, 2858, 1496, 1452, 1360, 1085, 1028, 812, 732, 693 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.42–7.25 (m, 10 H), 4.67 (d, J = 12.0 Hz, 1 H), 4.63 (d, J = 12.0 Hz, 1 H), 3.82–3.80 (m, 2 H), 2.66 (d, J = 8.4 Hz, 1 H), 2.27 (ddd, J = 8.4, 7.0, 6.0 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 138.0, 135.7, 128.9 (2 C), 128.6 (2 C), 128.5 (2 C), 128.0 (3 C), 127.9, 73.2, 71.5, 39.7, 34.8, 34.7 ppm. LC–MS: [M + NH4]+• = 414, 7.60 min. HRMS was not conclusive probably due to poor or no ionization.(±)-(2-{(1S,3R)-3-[(Benzyloxy)methyl]-2,2-dibromocyclopropyl}ethyl)benzene (7)Compound 7 (133 mg, 0.31 mmol, 28%, yellow oil) was synthesized from allyl ether 1d (277.6 mg, 1.10 mmol, 1 equiv) according to the general procedure (3.5 h stirring at room temperature). The crude was purified over silica gel column chromatography (elution with pentane/EtOAc = 99:1). IR (neat): ν max = 3027, 2921, 2854, 1495, 1453, 1270, 1086, 1027, 734, 695 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.36–7.20 (m, 10 H), 4.58 (d, J = 11.9 Hz, 1 H), 4.53 (d, J = 12.0 Hz, 1 H), 3.53 (d, J = 6.6 Hz, 2 H), 2.91–2.72 (m, 2 H), 1.96–1.80 (m, 2 H), 1.54–1.49 (m, 1 H), 1.30–1.23 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 141.0, 138.0, 128.6 (2 C), 128.5 (2 C), 128.4 (2 C), 127.8 (2 C), 127.7, 126.1, 72.9, 71.5, 35.9, 32.3, 34.33, 34.31, 34.2 ppm. LC–MS: [M + NH4]+• = 442, 7.77 min. HRMS was not conclusive probably due to poor or no ionization.(±)-(R)-{[(2,2-Dibromo-3,3-dimethylcyclopropyl)methoxy]methyl}benzene (8)Compound 8 (307 mg, 0.88 mmol, 80%, yellow oil) was synthesized from allyl ether 1e (194 mg, 1.10 mmol, 1 equiv) according to the general procedure (3 h stirring at room temperature). The crude was purified over silica gel column chromatography (elution with pentane/EtOAc = 99:1). The reaction was also performed on 1 g scale of 1e (5.68 mmol) to afford the desired product 8 (1.32 g, 3.79 mmol, 67%, yellow oil) and on 3 g scale of 1e (17 mmol) to afford the desired product 8 (4.26 g, 12.23 mmol, 72%, yellow oil). IR (neat): ν max = 2864, 1453, 1374, 1204, 1093, 1074, 994, 815, 734, 696 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.37–7.28 (m, 5 H), 4.60 (d, J = 11.9 Hz, 1 H), 4.53 (d, J = 11.9 Hz, 1 H), 3.67 (dd, J = 10.8, 6.7 Hz, 1 H), 3.51 (dd, J = 10.8, 6.8 Hz, 1 H), 1.62 (t, J = 6.7 Hz, 1 H), 1.42 (s, 3 H), 1.23 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 138.2, 128.6 (2 C), 127.9 (3 C), 73.1, 68.9, 44.8, 38.6, 28.6, 27.3, 19.7 ppm. LC–MS: [M + NH4]+• = 366, 7.37 min. HRMS was not conclusive probably due to poor or no ionization.(±)-({[(1R,3R)-2,2-Dibromo-3-propylcyclopropyl]methoxy}methyl)benzene (9)Compound 9 (320 mg, 0.79 mmol, 90% purity, 72%, orange oil) was synthesized from allyl ether 1f (209.3 mg, 1.10 mmol, 1 equiv) according to the general procedure (3 h stirring at room temperature). The crude was purified over silica gel column chromatography (elution with pentane/EtOAc = 99:1). IR (neat): n max = 2958, 2929, 2856, 1454, 1365, 1092, 1074, 1028, 734, 690 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.37–7.29 (m, 5 H), 4.59 (d, J = 11.8 Hz, 1 H), 4.53 (d, J = 11.9 Hz, 1 H), 3.60 (dd, J = 10.6, 7.0 Hz, 1 H), 3.48 (dd, J = 10.6, 6.7 Hz, 1 H), 1.97 (dt, J = 11.2, 6.9 Hz, 1 H), 1.69 (dt, J = 11.2, 7.0 Hz, 1 H), 1.55–1.36 (m, 4 H), 0.97 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 138.1, 128.6 (2 C), 127.9 (3 C), 73.2, 68.1, 34.6, 33.8, 32.6, 29.3, 21.8, 14.0 ppm. LC–MS: [M + NH4]+• = 380, 7.64 min. (±)-7,7-Dibromo-2-oxabicyclo[4.1.0]heptane (10)Compound 10 (194 mg, 0.76 mmol, 69%, orange oil) was synthesized from 3,4-dihydro-2H-pyran (1g, 0.1 mL, 1.10 mmol, 1 equiv) according to the general procedure (3 h stirring at room temperature). The crude was purified over silica gel column chromatography (elution with hexane/EtOAc = 95:5). IR (neat): ν max = 2928, 2859, 1446, 1234, 1150, 1060, 1018, 850, 754, 668 cm–1. 1H NMR (400 MHz, CDCl3): δ = 3.89 (d, J = 8.1 Hz, 1 H), 3.78 (dt, J = 10.9, 3.7 Hz, 1 H), 3.35 (ddd, J = 11.8, 11.0, 2.4 Hz, 1 H), 2.09–1.98 (m, 1 H), 1.94–1.72 (m, 3 H), 1.38 (dddd, J = 13.7, 8.0, 5.4, 2.6 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 64.6, 59.9, 35.9, 27.6, 20.6, 17.4 ppm. LC–MS: [M]+• = 256, 1.21 min. HRMS was not conclusive probably due to poor or no ionization.(±)-7,7-Dibromobicyclo[4.1.0]heptane (11)In a 250 mL three-neck round-bottomed flask, bromoform (0.22 mL, 12.5 mmol, 1.25 equiv) was added dropwise to stirred solution of cyclohexene 1h (1.01 mL, 10 mmol, 1 equiv), benzyltriethylammonium chloride (68.3 mg, 0.30 mmol, 0.03 equiv), and a 50% aqueous solution of sodium hydroxide (0.79 mL, 15 mmol, 1.5 equiv) in dichloromethane (10 mL) at room temperature. The mixture was stirred at 40 °C for 20 h. The reaction mixture was then treated with water (20 mL), and the product was extracted with Et2O (3 × 20 mL). The combined organic phase was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude was purified over silica gel column chromatography (elution with hexane/EtOAc = 95:5) to afford the desired product 11 (401.5 mg, 1.58 mmol, 16%) as a yellowish oil. Data are in accordance with the literature.12 1H NMR (400 MHz, CDCl3): δ = 2.05–1.95 (m, 2 H), 1.86–1.81 (m, 2 H), 1.60–1.55 (m, 2 H), 1.39–1.33 (m, 2 H), 1.25–1.14 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 45.0, 27.2 (2 C), 20.8 (2 C), 20.3 (2 C) ppm 11 General Procedure AIn an oven dried two-neck round-bottomed flask under argon atmosphere, dibromocyclopropane (1 equiv) was dissolved in anhydrous THF (c = 0.1 M). The solution was cooled to –100 °C (ethanol/liquid nitrogen bath), a solution of BuLi (2.5 M in hexane, 1.2 equiv) was added dropwise, and the reaction was stirred for 45 min. Then, a solution of pinacolborane (1 M in THF, 2 equiv) was added dropwise, and the resulting mixture was warmed to room temperature. Then, the reaction mixture was stirred for 18 h at 50 °C. The reaction was quenched by adding a saturated aqueous solution of NaHCO3. The product was extracted with EtOAc (3×). The combined organic phases were washed with water and brine. The combined organic phase was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude was purified over silica gel column chromatography to afford the desired cyclopropyl pinacol boronic ester.General Procedure BIn an oven-dried two-neck round-bottomed flask under argon atmosphere, dibromocyclopropane (1 equiv) was dissolved in anhydrous THF (c = 0.1 M). The solution was cooled to –100 °C (ethanol/liquid nitrogen bath), and a solution of BuLi (2.5 M in hexane, 1.2 equiv) was slowly added over 30 min using a syringe pump followed by a slow addition of a solution of pinacolborane (1 M in THF, 2 equiv) over 30 min using a syringe pump. The resulting mixture was stirred for 45 min at –100 °C then warmed to room temperature. Then, the reaction mixture was stirred for 18 h at 50 °C. The reaction was quenched by adding a saturated aqueous solution of NaHCO3. The product was extracted with EtOAc (3×). The combined organic phases were washed with water and brine. The combined organic phase was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude was purified over silica gel column chromatography to afford the desired cyclopropyl pinacol boronic ester. 2-((1R,3a′S,6′R,6a′R)-6′-Methoxy-2′,2′-dimethyldihydro-6′H-spiro{cyclopropane-1,4′-furo[3,4-d][1,3]dioxol}-2-yl)--4,4,5, 5-tetramethyl-1,3,2-dioxaborolane (3)Compound 3 (153.7 mg, 0.47 mmol, 52%, colorless oil, 3a/3b = 63:37) was synthesized from dibromocyclopropane 2a (322 mg, 0.90 mmol, 1 equiv) according to the general procedure A. The analysis of the 1H NMR spectrum of the crude mixture indicates a ratio 3a/3b = 66:34. The crude was purified over silica gel column chromatography (elution with PE/EtOAc = 95:5 to 90:10). The reaction was also performed on larger scale of 2a (1 g, 2.79 mmol) to afford 3 (659.8 mg, 2.02 mmol, 72%, 3a/3b = 66:34). For characterization purposes, both isomers were partially separated from each other over silica gel column chromatography (elution with PE/EtOAc = 95:5 to 90:10) to afford isomer 3b as a pure fraction (colorless oil) followed by a mixture of both isomers and then isomer 3a as a mixture containing 25% of minor isomer 3b (colorless oil). Compound 3a: IR (neat): ν max = 2980, 2930, 1456, 1411, 1370, 1324, 1244, 1210, 1144, 1102, 1041, 1010, 960, 865 cm–1. 1H NMR (400 MHz, CDCl3): δ = 4.97 (s, 1 H), 4.65 (d, J = 5.9 Hz, 1 H), 4.45 (d, J = 5.9 Hz, 1 H), 3.40 (s, 3 H), 1.49 (s, 3 H), 1.33 (s, 3 H), 1.25 (s, 6 H), 1.24 (s, 6 H), 1.22–1.21 (m, 1 H), 1.17 (dd, J = 11.1, 5.5 Hz, 1 H), 0.31 (dd, J = 11.1, 8.5 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 112.7, 109.4, 85.7, 85.4, 83.4 (2 C), 73.1, 56.1, 29.8, 26.7, 26.3, 25.5 (2 C), 24.5 (2 C), 10.8 ppm. GC–MS: [M]+• = 326, 15.24 min.Compound 3b: IR (neat): ν max = 2978, 2924, 1454, 1408, 1370, 1319, 1245, 1211, 1143, 1104, 1043, 1005, 962, 859 cm–1. 1H NMR (400 MHz, CDCl3): δ = 4.91 (s, 1 H), 4.79 (d, J = 5.9 Hz, 1 H), 4.61 (d, J = 5.9 Hz, 1 H), 3.28 (s, 3 H), 1.51 (s, 3 H), 1.35 (s, 3 H), 1.28 (d, J = 11.3, 5.6 Hz, 1 H), 1.22 (s, 12 H), 1.04 (dd, J = 8.7, 5.6 Hz, 1 H), 0.35 (dd, J = 11.3, 8.7 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 112.3, 108.2, 85.7, 83.4 (2 C), 82.0, 72.1, 55.0, 29.8, 26.6, 25.7, 25.0 (2 C), 24.7 (2 C), 10.1 ppm. GC–MS: [M]+• = 326, 14.39 min. HRMS was not recorded to confirm structural identity, but NMR and GC–MS data are fully in line with the proposed structure.2-((1S,3a′S,6′R,6a′R)-6′-Methoxy-2′,2′-dimethyldihydro-6′H-spiro{cyclopropane-1,4′-furo[3,4-d][1,3]dioxol}-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4)Compound 4 (66 mg, 0.20 mmol, 22% calculated, yellowish oil) was synthesized from dibromocyclopropane 2b (321 mg, 0.90 mmol, 1 equiv) according to the general procedure A. The analysis of the 1H NMR spectrum of the crude mixture indicates the presence of a single isomer of the product and several byproducts. The crude was purified over silica gel column chromatography (elution with PE/EtOAc = 98:2, 95:5, and then 90:10) to afford a fraction of a byproduct, then a fraction containing product 4 contaminated with traces of inseparable impurities, followed by a ca. 1:1 mixture of the product 4 and another byproduct, and finally a fraction containing product 4 contaminated with traces of inseparable impurities. 1H NMR (400 MHz, CDCl3): δ = 4.88 (s, 1 H), 4.60 (d, J = 5.9 Hz, 1 H), 4.52 (d, J = 5.9 Hz, 1 H), 3.28 (s, 3 H), 1.46 (s, 3 H), 1.27 (s, 3 H), 1.23 (s, 6 H), 1.21 (s, 6 H), 1.02–0.95 (m, 2 H), 0.54 (dd, J = 10.9, 8.2 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 112.0, 108.1, 85.5, 83.5 (2 C), 83.1, 72.2, 54.8, 26.6, 25.8, 24.92 (2 C), 24.86 (2 C), 17.9 (2 C) ppm. GC–MS: [M]+• = 326, 14.61 min. HRMS was not recorded to confirm structural identity, but NMR and GC–MS data are fully in line with the proposed structure.(±)-2-{(1R,2S)-2-[(Benzyloxy)methyl]-2-methylcyclopropyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12)Compound 12 (49.4 mg, 0.16 mmol, 54% combined yield) was synthesized from dibromocyclopropane 5 (100 mg, 0.30 mmol, 1 equiv) according to the general procedure A. The analysis of the 1H NMR spectrum of the crude mixture indicates a ratio 12a/12b = 55:45. The crude was purified over silica gel column chromatography (elution with pentane/EtOAc = 99:1 to 95:5) to afford isomer 12a (colorless oil), then a mixture of 12a/12b and finally isomer 12b (colorless oil). The individual isomers are described from pure analytical fractions. The NMR data of both isomers are in accordance with the literature.6dCompound 12a: 1H NMR (400 MHz, CDCl3): δ = 7.37–7.31 (m, 4 H), 7.28–7.24 (m, 1 H), 4.55 (d, J = 12.1 Hz, 1 H), 4.47 (d, J = 12.1 Hz, 1 H), 3.49 (d, J = 9.6 Hz, 1 H), 3.42 (d, J = 9.6 Hz, 1 H), 1.23 (s, 3 H), 1.20 (s, 6 H), 1.18 (s, 6 H), 0.72 (dd, J = 6.9, 3.6 Hz, 1 H), 0.68 (dd, J = 9.1, 3.5 Hz, 1 H), –0.12 (dd, J = 9.1, 7.0 Hz, 1 H) ppm. 13C NMR (175 MHz, CDCl3): δ = 139.1, 128.4 (2 C), 127.6 (2 C), 127.4, 83.1 (2 C), 75.6, 72.7, 25.1 (2 C), 24.7 (2 C), 23.7, 23.4, 18.0, 6.7 ppm. LC–MS: [M + NH4]+• = 320, 7.65 min.Compound 12b: 1H NMR (400 MHz, CDCl3): δ = 7.37–7.24 (m, 5 H), 4.54 (d, J = 12.1 Hz, 1 H), 4.50 (d, J = 12.1 Hz, 1 H), 3.42 (dd, J = 9.9, 0.9 Hz, 1 H), 3.14 (d, J = 9.9 Hz, 1 H), 1.25 (s, 3 H), 1.24 (s, 6 H), 1.22 (s, 6 H), 0.73 (dd, J = 9.6, 3.6 Hz, 1 H), 0.66 (dd, J = 6.5, 3.2 Hz, 1 H), –0.11 (dd, J = 9.6, 6.8 Hz, 1 H) ppm. 13C NMR (175 MHz, CDCl3): δ = 138.9, 128.4 (2 C), 127.7 (2 C), 127.5, 83.2 (2 C), 79.4, 72.6, 25.3 (2 C), 24.7 (2 C), 22.5, 18.0, 17.2, 4.8 ppm. LC–MS: [M + NH4]+• = 320, 7.63 min.(±)-{(1R,3R)-3-[(Benzyloxy)methyl]-2,2-dibromocyclopropyl}benzene (13)Compound 13 (73 mg, 0.20 mmol, 67% combined yield) was synthesized from dibromocyclopropane 6 (118.8 mg, 0.30 mmol, 1 equiv) according to the general procedure A. The analysis of the 1H NMR spectrum of the crude mixture indicates a ratio 13a/13b = 58:42. The crude was purified over silica gel column chromatography (elution with pentane/EtOAc = 98:2 to 90:10) to afford isomer 13b (colorless oil), then a mixture of 13a/13b and finally isomer 13a (yellowish oil). The individual isomers are described from pure analytical fractions. The NMR data of the minor isomer 13b are in accordance with the literature.6d The stereochemistry of the major isomer 13a was concluded from the stereochemistry of the minor isomer 13b.Compound 13a: IR (neat): ν max = 2972, 2926, 2861, 1446, 1386, 1324, 1214, 1143, 1062, 1020, 851, 735, 696 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.36–7.10 (m, 10 H), 4.61 (d, J = 12.1 Hz, 1 H), 4.57 (d, J = 12.1 Hz, 1 H), 3.65 (dd, J = 10.5, 5.8 Hz, 1 H), 3.43 (dd, J = 10.5, 6.9 Hz, 1 H), 2.25 (dd, J = 10.5, 5.4 Hz, 1 H), 2.07–2.01 (m, 1 H), 1.02 (s, 6 H), 0.89 (s, 6 H), 0.41 (dd, J = 10.5, 6.6 Hz, 1 H) ppm. 13C NMR (175 MHz, CDCl3): δ = 140.0, 138.8, 128.9 (2 C), 128.5 (2 C), 127.9 (2 C), 127.7 (2 C), 127.6, 126.0, 83.2 (2 C), 74.1, 72.4, 27.9, 24.9 (2 C), 24.5 (2 C), 22.2, 9.2 ppm. LC–MS: [M + NH4]+• = 382, 7.77 min. HRMS (ESI-TOF): m/z [M + NH4]+ calcd for C23H33BNO3: 382.2548; found: 382.2555.Compound 13b: 1H NMR (300 MHz, CDCl3): δ = 7.37–7.07 (m, 10 H), 4.57 (d, J = 11.9 Hz, 1 H), 4.52 (d, J = 11.9 Hz, 1 H), 3.79 (dd, J = 10.2, 6.5 Hz, 1 H), 3.59 (dd, J = 10.2, 8.0 Hz, 1 H), 2.12 (dd, J = 6.0, 5.3 Hz, 1 H), 1.78 (dddd, J = 9.8, 7.9, 6.6, 5.0 Hz, 1 H), 1.24 (s, 6 H), 1.22 (s, 6 H), 0.58 (dd, J = 9.8, 6.4 Hz, 1 H) ppm. 13C NMR (175 MHz, CDCl3): δ = 142.6, 138.8, 128.4 (4 C), 127.8 (2 C), 127.6, 125.9 (2 C), 125.8, 83.4 (2 C), 72.6, 71.1, 28.8, 27.8, 25.1 (2 C), 24.8 (2 C), 10.5 ppm. LC–MS: [M + NH4]+• = 382, 7.78 min.(±)-2-{(2R,3R)-2-[(Benzyloxy)methyl]-3-phenethylcyclopropyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (14)Compound 14 (46.7 mg, 0.12 mmol, 41%, colorless oil, 14a/14b = 55:45) was synthesized from dibromocyclopropane 7 (123 mg, 0.29 mmol, 1 equiv) according to the general procedure A. The analysis of the 1H NMR spectrum of the crude mixture indicates a ratio 14a/14b = 57:43. The crude was purified over silica gel column chromatography (elution with pentane/EtOAc = 98:2 to 95:5). The stereochemistry of isomers 14a and 14b could not be determined. Both isomers were described from the mixture, and some NMR signals could be attributed to the corresponding isomer. 1H NMR (400 MHz, CDCl3): δ = 7.35–7.14 (m, 20 H), 4.53–4.50 (m, 3 H), 4.47 (d, J = 11.9 Hz, 1 H 14a ), 3.59 (dd, J = 10.1, 6.7 Hz, 1 H 14a ), 3.47–3.39 (m, 2 H), 3.22 (dd, J = 10.5, 7.1 Hz, 1 H 14b ), 2.75–2.63 (m, 4 H), 1.90–1.81 (m, 1 H 14b ), 1.78–1.69 (m, 1 H 14b ), 1.63 (d, J = 7.4 Hz, 1 H 14a ), 1.59 (d, J = 7.5 Hz, 1 H 14a ), 1.24–1.20 (m, 26 H), 1.01–0.84 (m, 2 H), 0.08–0.14 (m, 1 H 14a + 1 H 14b ) ppm. 13C NMR (175 MHz, CDCl3): δ = 142.6, 142.4, 139.0, 138.9, 128.7 (2 C), 128.6 (2 C), 128.5 (2 C), 128.40 (2 C), 128.36 (2 C), 128.3 (2 C), 127.8 (2 C), 127.7 (2 C), 127.6, 127.5, 125.8, 125.7, 83.2 (2 C 14b ), 83.1 (2 C 14a ), 74.7 (C 14b ), 72.5 (C 14a ), 72.3 (C 14b ), 71.5 (C 14a ), 36.8 (C 14a ), 36.3(C 14b ), 36.0(C 14a ), 31.9 (C 14b ), 29.8, 25.5, 25.2 (2 C 14b ), 25.0 (2 C 14a ), 24.84 (2 C 14b ), 24.78 (2 C 14a ), 24.6, 24.3, 23.9 ppm. The boron-bound carbons were not detected due to quadrupolar relaxation. LC–MS: [M 14a + NH4]+• = 410, 8.06 min. LC–MS: [M 14b + NH4]+• = 410, 8.12 min.(±)-2-{(3R)-3-[(Benzyloxy)methyl]-2,2-dimethylcyclopropyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (15)Compound 15 (70 mg, 0.22 mmol, 73% combined, 15a/15b = 70:30) was synthesized from dibromocyclopropane 8 (104.4 mg, 0.30 mmol, 1 equiv) according to the general procedure B. The analysis of the 1H NMR spectrum of the crude mixture indicates a ratio 15a/15b = 68:32. The crude was purified over silica gel column chromatography (elution with pentane/EtOAc = 98:2 to 95:5) to afford isomer 15b (colorless oil), then a mixture of 15a/15b and finally isomer 15a (colorless oil). The individual isomers are described from pure analytical fractions. Compound 15a: IR (neat): ν max = 2925, 2854, 1453, 1370, 1316, 1274, 1214, 1144, 1073, 1028, 959, 852, 734, 696 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.34–7.26 (m, 5 H), 4.53 (d, J = 12.1 Hz, 1 H), 4.50 (d, J = 12.1 Hz, 1 H), 3.66 (dd, J = 10.6, 5.5 Hz, 1 H), 3.29 (dd, J = 10.6, 8.8 Hz, 1 H), 1.31–1.29 (m, 1 H), 1.24 (s, 6 H), 1.21 (s, 6 H), 1.18 (s, 3 H), 1.14 (s, 3 H), –0.38 (d, J = 6.6 Hz, 1 H) ppm. 13C NMR (175 MHz, CDCl3): δ = 139.0, 128.4 (2 C), 127.8 (2 C), 127.6, 83.1 (2 C), 72.4, 71.4, 29.9, 25.3 (2 C), 24.6 (2 C), 24.3, 23.5, 22.2, 13.5 ppm. LCMS: [M + NH4]+• = 334, 7.46 min. HRMS (ESI-TOF): m/z [M + NH4]+ calcd for C19H33BNO3: 334.2548; found: 334.2547.Compound 15b: IR (neat): ν max = 2922, 2855, 1433, 1389, 1377, 1315, 1238, 1138, 1098, 1073, 976, 861, 734, 697 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.37–7.27 (m, 5 H), 4.56 (d, J = 11.9 Hz, 1 H), 4.49 (d, J = 11.9 Hz, 1 H), 3.66 (d, J = 7.5 Hz, 2 H), 1.23 (d, J = 7.4 Hz, 1 H), 1.20 (s, 6 H), 1.19 (s, 6 H), 1.16 (s, 3 H), 1.15 (s, 3 H), –0.04 (d, J = 9.6 Hz, 1 H) ppm. 13C NMR (175 MHz, CDCl3): δ = 139.1, 128.4 (2 C), 127.9 (2 C), 127.5, 82.9 (2 C), 72.7, 68.9, 30.5, 29.9, 25.1 (2 C), 24.8 (2 C), 22.9, 17.5, 12.2 ppm. LC–MS: [M + NH4]+• = 334, 7.47 min. HRMS was not conclusive probably due to poor or no ionization.(±)-2-{(1S,2R,3S)-2-[(Benzyloxy)methyl]-3-propylcyclopropyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (16)Compound 16 (47.5 mg, 0.145 mmol, 48% combined yield) was synthesized from dibromocyclopropane 9 (119.5 mg, 0.30 mmol, 1 equiv) according to the general procedure A. The analysis of the 1H NMR spectrum of the crude mixture indicates a ratio 16a/16b = 62:38. The crude was purified over silica gel column chromatography (elution with pentane/EtOAc = 99:1 to 95:5) to afford isomer 16a (yellowish oil), then a mixture of 16a/16b and finally isomer 16b (colorless oil). The individual isomers are described from pure analytical fractions. The NMR data of the minor isomer 16b are in accordance with the literature.6d The stereochemistry of the major isomer 16a was concluded from the stereochemistry of the minor isomer 16b.Compound 16a: IR (neat): ν max = 2956, 2922, 2856, 1401, 1378, 1316, 1214, 1144, 1094, 1073, 854, 733, 695 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.38–7.27 (m, 5 H), 4.57 (d, J = 11.8 Hz, 1 H), 4.48 (d, J = 11.8 Hz, 1 H), 3.70 (dd, J = 10.1, 7.7 Hz, 1 H), 3.64 (dd, J = 10.1, 7.2 Hz, 1 H), 1.52–1.32 (m, 6 H), 1.21 (s, 6 H), 1.20 (s, 6 H), 0.91 (t, J = 7.2 Hz, 3 H), 0.15 (t, J = 9.4 Hz, 1 H) ppm. 13C NMR (175 MHz, CDCl3): δ = 139.1, 128.4 (2 C), 127.9 (2 C), 127.5, 82.9 (2 C), 72.9, 68.3, 27.9, 25.1 (2 C), 24.9 (2 C), 23.6, 22.7, 21.9, 14.2 ppm. The boron-bound carbon was not detected due to quadrupolar relaxation. LC–MS: [M + NH4]+• = 348, 7.97 min. HRMS (ESI-TOF): m/z [M + NH4]+ calcd for C20H35BNO3: 348.2704; found: 348.2700.Compound 16b: 1H NMR (400 MHz, CDCl3): δ = 7.35–7.27 (m, 5 H), 4.55 (d, J = 12.0 Hz, 1 H), 4.49 (d, J = 12.0 Hz, 1 H), 3.59 (dd, J = 10.4, 5.9 Hz, 1 H), 3.37 (dd, J = 10.4, 8.3 Hz, 1 H), 1.48–1.36 (m, 6 H), 1.21 (s, 12 H), 0.90 (t, J = 7.2 Hz, 3 H), –0.50 (t, J = 6.0 Hz, 1 H) ppm. 13C NMR (175 MHz, CDCl3): δ = 138.9, 128.5 (2 C), 127.8 (2 C), 127.6, 83.0 (2 C), 72.6, 70.5, 31.2, 24.8 (4 C), 23.2, 22.8, 22.0, 14.1 ppm. The boron-bound carbon was not detected due to quadrupolar relaxation. LC–MS: [M + NH4]+• = 348, 7.96 min.(±)-2-{(1R,6S,7S)-2-Oxabicyclo[4.1.0]heptan-7-yl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (17)Compound 17 (34.4 mg, 0.153 mmol, 38%, colorless oil, 17a/17b = 93:7) was synthesized from dibromocyclopropane 10 (102.4 mg, 0.40 mmol, 1 equiv) according to the general procedure A. The analysis of the 1H NMR spectrum of the crude mixture indicates a ratio 17a/17b = 91:9. The crude was purified over silica gel column chromatography (elution with hexane/EtOAc = 95:5 to 90:10). Only the major isomer 17a from the mixture was described. The NMR data of the major isomer 17a are in accordance with the literature.6e The stereochemistry of the minor isomer 17b was concluded from the stereochemistry of the major isomer 17a. 1H NMR (400 MHz, CDCl3): δ = 3.65 (dd, J = 3.0, 6.7 Hz, 1 H), 3.58–3.54 (m, 1 H), 3.34 (td, J = 10.7, 2.8 Hz, 1 H), 1.97–1.93 (m, 2 H), 1.53–1.39 (m, 2 H), 1.25–1.22 (m, 1 H), 1.19 (m, 12 H), 0.07 (dd, J = 7.6, 3.0 Hz, 1 H) ppm. 13C NMR (175 MHz, CDCl3): δ = 83.1 (2 C), 64.7, 57.2, 24.9 (2 C), 24.8 (2 C), 21.9, 20.5, 17.2, 8.3 ppm. LC–MS: [M + H]+• = 225, 6.34 min.(±)-2-{Bicyclo[4.1.0]heptan-7-yl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (18)Compound 18 (54 mg, 0.24 mmol, 40%, colorless oil, 18a/18b = 93:7) was synthesized from dibromocyclopropane 11 (152.4 mg, 0.60 mmol, 1 equiv) according to the general procedure B. The analysis of the 1H NMR spectrum of the crude mixture indicates a ratio 18a/18b = 93:7. The crude was purified over silica gel column chromatography (elution with pentane/EtOAc = 98:2). Only the major isomer 18a from the mixture was described. The NMR data of the major isomer 18a are in accordance with the literature.6e The stereochemistry of the minor isomer 18b was concluded from the stereochemistry of the major isomer 18a. 1H NMR (400 MHz, CDCl3): δ = 1.90–1.85 (m, 2 H), 1.68–1.62 (m, 2 H), 1.28–1.25 (m, 2 H), 1.21 (s, 12 H), 1.19–1.16 (m, 2 H), 1.14–1.11 (m, 2 H), –0.38 (t, J = 5.8 Hz, 1 H) ppm. 13C NMR (175 MHz, CDCl3): δ = 82.8 (2 C), 24.9 (4 C), 24.2 (2 C), 21.2 (2 C), 17.3 (2 C), 6.4 ppm 12 Grupe S, Von Wangelin AJ. ChemCatChem 2013; 5: 706 Supplementary Material Supplementary Material Supporting Information
