S1

SUPPORTING INFORMATION

One-Pot Sustainable Synthesis of Tertiary Alcohols by Combining Ruthenium-

Catalyzed Isomerization of Allylic Alcohols and Chemoselective Addition of

Polar Organometallic Reagents in Deep Eutectic Solvents

Luciana Cicco,a María J. Rodríguez-Álvarez,b Filippo M. Perna,a Joaquín García-Alvarezb,* and Vito Capriatia,*

a 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.

b Laboratorio de Compuestos Organometálicos y Catálisis (Unidad Asociada al CSIC). Departamento de Química Orgánica e Inorgánica (IUQOEM), Centro de Innovación en Química Avanzada (ORFEO-CINQA), Facultad de Química, Universidad de Oviedo, E-33071, Oviedo, Spain

* Corresponding authors: garciajoaquin@uniovi.es; fax: (+34) 098 510 3446vito.capriati@uniba.it; fax: (+39) 080 544 2539

TABLE OF CONTENTS

1. General Procedures p. S2

2. Protocols p. S3

3. Spectroscopic data p. S4

4. 1H and 13C NMR spectra p. S6

5. References p. S15

Electronic Supplementary Material (ESI) for Green Chemistry.This journal is © The Royal Society of Chemistry 2017

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1. General Procedures

Allylic alcohols 1a,f were purchased from commercial sources. Allylic alcohols 1b–e were prepared

according to conventional procedures. Deep Eutectic Solvents [choline chloride (ChCl)−glycerol

(Gly) (1:2 mol/mol); ChCl−D-fructose (Fruc) (1:2 mol/mol); ChCl−ethylene glycol (EG) (1:2

mol/mol); D-fructose−urea (2:3 w/w); ChCl−urea (1:2 mol/mol); ChCl−D-sorbitol (Sorb) (1:1

mol/mol); ChCl−L-proline (Prol) (5:2 mol/mol); ChCl−H2O (1:2 mol/mol); ChCl−lactic acid (Lac)

(1:2 mol/mol); L-proline−glycerol (2:5 mol/mol); lactic acid−L-alanine (Alan) (9:1 mol/mol)] were

prepared by heating under stirring at 75 °C for 10–30 min the corresponding individual components

until a clear solution was obtained. All other reagents and solvents were of the highest quality

available. 1H-NMR spectra were obtained using a Bruker DPX-400 (1H, 400.13 MHz) spectrometer

for routine experiments, CDCl3 was used as the solvent. Gas chromatography (GC) analyses were

performer on a Hewlett Packard 6890 Series II chromatograph. 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). Infrared (IR) spectra were recorded on a

Diffuse Reflectance sampling cell. 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). Reactions involving air-sensitive reagents were performed under argon in oven-dried

glassware using syringe-septum cap technique. The following solutions of organomagnesium and

organolithium reagents were commercially available and were used with the following

concentration: n-Bu2Mg 1.0 M in heptane, EtMgBr 1.0 M in THF, MeLi 1.6 M in Et2O, n-BuLi 1.6

M in hexanes, PhLi 1.8 M in dibutyl ether, sec-BuLi 1.4 M in cyclohexanes. Spectroscopic data of

compounds 1b–e,[1] 2a,c[2a] 2b,d,[2b] 2e,[2c] 2f,[2d] 3a,[3a] and 3b,d[3b] are in agreement with those

reported in the literature.

S3

2. Protocols

Preparation of 3-phenyl-heptan-3-ol (3a) in Deep Eutectic Solvents. Typical procedure. Allylic

alcohol 1a (0.5 mmol) and 0.5 g of the eutectic mixture 1ChCl/2EG (previously degassed with Ar)

were introduced into a sealed tube under an Ar atmosphere. The acetate ruthenium(IV) complex

[Ru(3:3-C10H16)Cl(2-O,O-CH3CO2)] (5 mol%, 5b) was then added at rt under Ar. The reaction

mixture was stirred for 30 min at 50 °C. Once the isomerization was completed (GC analysis), 0.94

mL of the commercially available n-BuLi (1.5 mmol in 1.6 M hexanes solution), were quickly

spread out through the mixture at rt, under air and vigorous stirring. After 3 sec, 2 mL of sat. aq.

solution of Rochelle salt were added, and the mixture was extracted with 2-MeTHF (3 × 2 mL). The

combined organic phases were dried over anhydrous MgSO4, and the solvent was concentrated in

vacuo. The crude product was purified by flash chromatography to give 3a in 90% yield.

General procedure for the catalyst recycling. The recyclability of complex 5b was investigated

using the isomerization of -vinylbenzyl alcohol (1a) to propiophenone (2a) as a model reaction.

Thus, 0.5 g of the eutectic mixture 1ChCl/2Urea (previously degassed with Ar) and allylic alcohol

1a (0.5 mmol) were introduced into a sealed tube under an Ar atmosphere. The acetate

ruthenium(IV) complex [Ru(3:3-C10H16)Cl(2-O,O-CH3CO2)] (5 mol%, 5b) was then added at rt

under Ar. The reaction mixture was stirred for 30 min at 50 °C. Once the isomerization was

completed (GC analysis) the eutectic phase was extracted with 2-MeTHF (3 × 2 mL). Next, 0.5

mmol of -vinylbenzyl alcohol (1a) was again added to the eutectic mixture and the reaction was

stirred again under the same conditions for 90 min. This procedure was repeated up to three

consecutive times. The ruthenium leaching in the recycling studies was measured by inductively

coupled plasma-mass spectrometry (ICP-MS) analysis (1st cycle: 872 ± 10 μg of ruthenium leached;

2nd cycle: 197 ± 7 μg of ruthenium leached).

S4

3. Spectroscopic data

3-Phenyl-heptan-3-ol (3a): colorless oil, 1H NMR (400 MHz, CDCl3) δ 7.43–7.34 (m, 5 H), 7.28–7.22 (m, 1 H), 1.92–1.80 (m, 4 H), 1.31–1.27 (m, 4 H), 0.89–0.85 (t, J = 6.0 Hz, 3 H), 0.81–0.76 (t, J = 6.0 Hz, 3 H); 13C NMR (400 MHz, CDCl3) δ 7.8, 14.1, 23.2, 25.7, 35.5, 42.4, 77.1, 125.4, 126.3, 128.0, 146.2; GC-MS (70 eV) m/z (%) 175 (M+, 1), 163

(7),146 (5), 135 (100), 105 (12), 77 (11); FT-IR (film, cm-1): 3468, 3027, 2958, 2872, 1602, 1446, 1310, 760, 700.

1-Methyl-1'-phenylpropan-1-ol (3b): colorless oil, 1H NMR (400 MHz, CDCl3) δ 7.51–7.45 (m, 2 H), 7.39–7.34 (m, 2 H), 7.28–7.23 (m, 1 H), 1.91–1.82 (m, 2 H), 1.57 (s, 3 H), 0.85–0.80 (t, J = 7.2 Hz, 3 H); 13C NMR (400 MHz, CDCl3) δ 8.5, 29.7, 36.7, 77.3, 124.9, 126.5, 128.1, 147.7; GC-MS (70 eV) m/z (%) 135 (M+, 15), 121 (100), 91 (9), 77 (19), 57 (12); FT-IR (film, cm-1): 3400,

2969, 2929, 2359, 1676, 1493, 1446, 760, 600.

4-Methyl-3-phenyl-hexan-3-ol (3c): dr 1/1 (inseparable mixture of diastereomers), colorless oil, 1H NMR (400 MHz, CDCl3) δ 7.43–7.34 (m, 4 H), 7.28–7.25 (m, 1 H), 1.98–1.89 (m, 2 H), 1.79–1.72 (m, 2 H), 1.45–1.27 (m, 1 H), 1.01–0.94 (t, J = 9.0 Hz, 3 H), 0.88–0.70 (t, J = 9.0 Hz, 6 H); 13C NMR (400 MHz, CDCl3) δ 8.0, 12.7, 12.8, 13.7, 23.3, 24.1, 31.9, 32.2, 44.7,

44.9, 79.8, 79.9, 126.0, 126.1, 126.2, 127.8, 127.9, 145.2, 145.6; GC-MS (70 eV) m/z (%) 174 (M+, 1), 163 (7), 145 (5), 135 (100), 105 (12), 107 (3), 91 (8), 77 (11), 79 (4); FT-IR (film, cm-1): 3492, 2967, 2935, 2876, 1461, 1446, 1379, 953, 757, 702.

1,1-Diphenylpropan-1-ol (3d): colorless oil, 1H NMR (400 MHz, CDCl3) δ 7.51–7.48 (m, 4 H), 7.40–7.35 (m, 4 H), 7.31–7.26 (t, J = 7.2 Hz, 2 H), 2.42–2.35 (q, J = 7.2 Hz, 2 H), 0.98–0.93 (t, J = 7.2 Hz, 3 H); 13C NMR (150 MHz, CDCl3) δ 8.3, 34.5, 78.4, 126.1, 126.2, 128.1, 147.0; HRMS (FAB+) calcd for M-OH]+ 195.1174, found 195.1177; FT-IR (film, cm-1): 3556, 2950, 1420, [

1120, 760, 600.

3-(2-Methoxyphenyl)heptan-3-ol (3f): colorless oil, 1H NMR (400 MHz, CDCl3) δ 7.32–7.22 (m, 2 H), 7.00–6.91 (m, 2 H), 2.08–1.99 (m, 2 H), 1.98–1.75 (m, 2 H), 1.30–1.27 (m, 4 H), 0.90–0.85 (t, J = 6.0 Hz, 3 H) 0.84–0.79 (t, J = 6.0 Hz, 3 H); 13C NMR (400 MHz, CDCl3) δ 8.3, 14.1, 23.4, 26.2, 33.1, 39.7, 55.4, 77.3, 111.7, 120.6, 127.9, 130.1, 133.1, 157.2; GC-MS (70 eV) m/z (%) 206 (M+, 16), 193 (72), 165 (100), 147

(40), 121 (51), 91 (51), 77 (17), 57 (10); FT-IR (film, cm-1): 3498, 2958, 2932, 1673, 1598, 1486, 1464, 1237, 1028, 754.

OH

OH

OH

OH

OCH3

OH

S5

3-(p-Tolyl)heptan-3-ol (3g): colorless oil, 1H NMR (400 MHz, CDCl3) δ 7.30–7.28 (d, J = 9.0 Hz, 2 H), 7.19–7.16 (d, J = 9.0 Hz, 2 H), 2.37 (s, 3 H), 1.92–1.75 (m, 5 H), 1.30–1.26 (m, 3 H), 0.89–0.85 (t, J = 6.0 Hz, 3 H), 0.82–0.77 (t, J = 6.0 Hz, 3 H); 13C NMR (400 MHz,

CDCl3) δ 7.8, 14.0, 20.9, 23.1, 25.7, 35.3, 42.3, 77.0, 125.3, 128.7, 135.7, 143.1; GC-MS (70 eV) m/z (%) 206 (M+), 189 (14), 177 (46), 149 (71), 131 (14), 91 (21), 57 (100); FT-IR (film, cm-1): 3460, 2950, 2930, 2861, 1500, 1459, 1381, 1150, 959, 812.

3-(4-Bromophenyl)heptan-3-ol (3h), colorless oil, 1H NMR (400 MHz, CDCl3) δ 7.48–7.45 (d, J = 9.0 H z, 2 H), 7.28–7.26 (d, J = 9.0 Hz, 2H), 1.86–1.78 (m, 4 H), 1.29–1.23 (m, 4 H), 0.88–0.83 (m, 3 H), 0.79–0.74 (m, 3 H); 13C NMR (400 MHz, CDCl3) δ 8.1, 14.4, 23.4, 25.9; GC-MS (70 eV) m/z (%) 254 (M+, 16), 241 (6), 213 (7), 144 (8), 129 (9), 91

(18), 77 (4), 57 (100); FT-IR (film, cm-1): 3468, 2958, 2934, 2871, 1590, 1485, 1461, 1393, 1074, 1009, 824.

3-(Naphthalen-1-yl)heptan-3-ol (3i): colorless oil, 1H NMR (400 MHz, CDCl3) δ 8.63–8.61 (m, 3 H), 7.88–7.87 (m, 1 H), 7.77–7.75 (m, 1 H), 7.64–7.62 (m, 1 H), 7.48–7.45 (m, 1 H), 2.33–2.28 (m, 2 H), 2.17–2.09 (m, 2 H), 1.27 (m, 4 H), 0.81–0.77 (m, 6 H); 13C NMR (400 MHz, CDCl3) δ 8.6, 14.4, 23.5, 26.5, 34.6, 41.6, 79.3, 125.2, 125.4, 125.6, 126.6, 128.6, 129.7, 131.4, 135.2, 141.3; GC-MS (70 eV) m/z (%) 242 (M+), 213 (62),

185 (57), 167 (13), 141 (10), 127 (22), 85 (34), 57 (100); FT-IR (film, cm-1): 3468, 3027, 2958, 2872, 1602, 1446, 1310, 760, 700.

3-Methyl-octan-3-ol (3j): colorless oil, 1H NMR (400 MHz, CDCl3 ) δ 2.33–2.25 (m, 2 H), 1.51–1.29 (m, 4 H), 1.26–1.24 (m, 4 H), 1.01 (s, 3 H), 0.79–0.74 (m, 6 H); 13C NMR (400 MHz, CDCl3) δ 8.1, 13.7, 22.6, 23.6, 26.2, 32.4, 34.0, 41.2, 72.6; GC-MS (70 eV) m/z (%) 143 (M+, 1), 115 (32), 97 (12), 73 (100), 55 (49); FT-IR (film, cm-1): 3390, 2933, 2861, 1462,

1377, 1261, 1152, 1101, 1020, 934, 902, 805.

HO

OH

OH

H3C

OH

Br

S6

1H and 13C NMR spectra of 3-phenyl-heptan-3-ol (3a)

1H NMR 400MHz, CDCl3

13C NMR 400MHz, CDCl3

OH

OH

S7

1H and 13C NMR spectra of 1-methyl-1'-phenyl-propan-1-ol (3b)

1H NMR 400MHz, CDCl3

13C NMR 400MHz, CDCl3

OH

OH

S8

1H and 13C NMR spectra of 4-methyl-3-phenyl-hexan-3-ol (3c)

1H NMR 400MHz, CDCl3

13C NMR 400MHz, CDCl3

OH

OH

S9

1H spectra of 1,1-diphenyl-propan-1-ol (3d)

1H NMR 400MHz, CDCl3

13C NMR 400MHz, CDCl3

OH

OH

S10

1H and 13C spectrum of 3-(2-methoxyphenyl)heptan-3-ol (3f)

1H NMR 400MHz, CDCl3

13C NMR 400MHz, CDCl3

OCH3

OH

OCH3

OH

S11

1H and 13C NMR spectra of 3-(p-tolyl)heptan-3-ol (3g)

1H NMR 400MHz, CDCl3

13C NMR 400MHz, CDCl3

OH

H3C

OH

H3C

S12

1H and 13C NMR spectra of 3-(4-bromophenyl)heptan-3-ol (3h)

1H NMR 400MHz, CDCl3

13C NMR 400MHz, CDCl3

OH

Br

OH

Br

S13

1H and 13C NMR spectra of 3-(naphthalen-1-yl)heptan-3-ol (3i)

1H NMR 400MHz, CDCl3

13C NMR 400MHz, CDCl3

HO

HO

S14

1H spectrum of 3-methyl-octan-3-ol (3j)

1H NMR 400MHz, CDCl3

13C NMR 400MHz, CDCl3

OH

OH

S15

5. References

[1] M. Lafrance, M. Roggen, E. M. Carreira, Angew. Chem. 2012, 124, 3527–3530; Angew. Chem. Int. Ed. 2012, 51, 3470–3473.

[2] (a) B. Skillinghaug, C. Skoeld, J. Rydfjord, F. Svensson, M. Behrends, J. Saevmarker, P. J. R. Sjoeberg, M. Larhed, J. Org. Chem. 2014, 79, 12018–12032; (b) Y. Li, D. Xue, W. Lu, C. Wang, Z.-T. Liu, J. Xiao, Org. Lett. 2014, 16, 66–69; (c) A. Borah, L. Goswami, K. Neog, P. Gogoi, J. Org. Chem. 2015, 80, 4722–4728; (d) E. Erbing, A. Vázquez-Romero, A. Bermejo Gómez, A. E. Platero-Prats, F. Carson, X. Zou, P. Tolstoy, B. Martín-Matute, Chem. Eur. J. 2016, 22, 15659–15663.

[3] (a) G. Huelgas, L. K. LaRochelle, L. Rivas, Y. Luchinina, R. A. Toscano, P. J. Carroll, P. J. Walsh, C. Anaya de Parrodi, Tetrahedron, 2011, 67, 4467–4474; (b) Y.-X. Liao, C.-H. Xing, Q.-S. Hu, Org. Lett. 2012, 14, 1544–1547.