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Electronic Supplementary Information (ESI)
Water opens the door to organolithium and Grignard reagents: exploring and comparing the reactivity of highly polar organometallic compounds in unconventional reaction media towards the synthesis of tetrahydrofurans
Luciana Cicco, Stefania Sblendorio, Rosmara Mansueto, Filippo M. Perna, Antonio Salomone, Saverio Florio, and Vito Capriati*
Dipartimento di Farmacia-Scienze del Farmaco, Università di Bari “Aldo Moro”, Consorzio C.I.N.M.P.I.S., Via E. Orabona 4, I-70125, Bari, Italy.
acid−L-alanine (9:1 mol/mol)] and the low melting mixture of D-fructose−urea (3:2 weight/weight)
were prepared by heating under stirring up to 90 °C for 10–30 min the corresponding individual
components until a clear solution was obtained. For 1H and 13C NMR spectra (1H NMR 400, 500 or
600 MHz; 13C NMR 100, 125 or 150 MHz), CDCl3 was used as the solvent. GC-‐MS spectrometry
analyses were performed on a gas chromatograph (dimethylsilicon capillary column, 30 m, 0.25
mm i.d.) equipped with a mass selective detector operating at 70 eV (EI). Elemental analyses were
performed by using a Carlo Erba CHNS-‐O EA1108-‐Elemental Analyzer. Analytical thin layer
chromatography (TLC) was carried out on precoated 0.25 mm thick plates of Kieselgel 60 F254;
visualization was accomplished by UV light (254 nm) or by spraying with a solution of 5 % (w/v)
ammonium molybdate and 0.2 % (w/v) cerium(III) sulfate in 100 ml 17.6 % (w/v) aq. sulfuric acid
and heating to 473 K for some time until blue spots appear. Some reactions involving air-‐sensitive
reagents were performed under argon in oven-‐dried glassware using syringe-‐septum cap technique.
The following solutions of Grignard reagents and organolithium reagents were commercially
available and were used with the following concentration: MeMgCl 3.0 M in THF, EtMgCl 2.0 M
in THF, i-PrMgCl 2.0 M in THF, allylMgCl 2.0 M in THF, 4-MeOC6H4MgBr 0.5 M in THF, 4-
ClC6H4MgBr 1.0 M in 2-MeTHF, 4-FC6H4MgBr 2.0 M in Et2O, MeLi 1.6 M in Et2O, EtLi 0.5 M in
benzene/cyclohexane, i-PrLi 0.7 M in pentane, n-BuLi 2.5 M in hexanes, PhLi 1.8 M in dibutyl
ether. Spectroscopic data of compounds 3a,1 3b,2 3c,3 3d,e,4 3f,5 3g,3 3j,6 3k,7 3l,4 3n8 and 4a9 are in
agreement with the literature. γ−Chloroketones 1a–d and cyclopropyl phenyl ketone 4a are
commercially available. Fully characterization data, including elemental analysis and copies of 1H
and 13C NMR spectra, have been reported for the new compounds 2a, 3h, 3i and 3m. 1 E. D. Butova, A. V. Barabash, A. A. Petrova, C. M. Kleiner, P. R. Schreiner and A. A. Fokin, J. Org. Chem. 2010, 75, 6229. 2 G. A. Moniz and J. L. Wood, J. Am. Chem. Soc., 2001, 123, 5095. 3 R. Mansueto, V. Mallardo, F. M. Perna, A. Salomone and V. Capriati, Chem. Commun. 2013, 49, 10160. 4 V. Mallardo, R. Rizzi, F. C. Sassone, R. Mansueto, F. M. Perna, A. Salomone and V. Capriati, Chem. Commun. 2014, 50, 8655. 5 Y. Maeda, T. Nishimura and S. Uemura, Chem. Lett. 2005, 34, 790. 6 C. Zhu and J. R. Falck, Angew. Chem. Int. Ed. 2011, 50, 6626. 7 P. P. Singh, S. Gudup, H. Aruri, U. Singh, S. Ambala, M. Yadav, S. D. Sawant and R. A. Vishwakarma, Org. Biomol. Chem., 2012, 10, 1587. 8 A. K. Diba, J. Begouin and M. Niggemann, Tetrahedron Lett., 2012, 53, 6629. 9 C. Clarke, S. Foussat, D. J. Fox, D. S. Pedersen and S. Warren, Org. Biomol. Chem., 2009, 7, 1323.
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2. Experimental Procedures
2.1 Preparation of 5-chloro-2-phenylpentan-2-ol (2a) and 2-methyl-2-phenyltetrahydrofuran
(3a) in THF. Typical Procedure.
To an anhydrous THF solution (1 mL) of the ketone 1a (0.5 mmol), 0.94 mL of the commercially
available MeLi (1.5 mmol in 1.6 M Et2O solution) were added dropwise, under argon, at −40 °C.
After 12 h stirring at RT, the reaction mixture was treated with 10% aq. NaOH for 3 h (or quenched
with H2O to isolate chlorohydrin 2a), and then extracted with Et2O (3 × 20 mL). The combined
organic phases were dried over Na2SO4 and the solvent was concentrated in vacuo. The crude
product was purified by flash-chromatography (silica gel, hexane/Et2O 80:20, Et3N 2%), to give 3a
in 70% yield. Spectroscopic data are in accord with the literature.1 The chlorohydrin 2a could be
purified by flash-chromatography on silica gel with hexane/AcOEt 80:20 as the eluent in 38% yield
(see Table 1 of the main text).
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2.2 Preparation of 2-ethyl-2-phenyltetrahydrofuran (3c) in deep eutectic solvents. Typical
procedure.
To a mixture of the ketone 1a (0.5 mmol) in 1 g of ChCl−Gly (1:2), 0.75 mL of the commercially
available EtMgCl (1.5 mmol in 2.0 M THF solution), handled under argon using conventional
Schlenk techniques, were quickly spread out at RT, under air, and vigorous stirring. After 10 min,
10 mL of 10% aq. NaOH were added and the mixture was stirred for additional 3 h, and then
extracted with Et2O (3 × 10 mL). The combined organic phases were dried over anhydrous Na2SO4
and the solvent was concentrated in vacuo. The crude product was purified by flash-
chromatography to give 3c in 75% yield.
PhCl
O1) EtMgCl, ChCl–Gly (1:2)
under air, RT, 10 min OEt
2) 10% aq. NaOH, 3 h1a 3c
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2.3 Preparation of 2-methyl-2-phenyltetrahydrofuran (3a) in water. Typical procedure.
To a suspension of the ketone 1a (0.5 mmol) in 1 mL of water, 0.94 mL of the commercially
available MeLi (1.5 mmol in 1.6 M Et2O solution), handled under argon using conventional
Schlenk techniques, were quickly spread out at RT, under air, and vigorous stirring. After 10 min,
10 mL of 10% aq. NaOH were added and the mixture was stirred for additional 3 h, and then
extracted with Et2O (3 × 10 mL). The combined organic phases were dried over anhydrous Na2SO4
and the solvent was concentrated in vacuo. The crude product was purified by flash-