S1

Supplementary Information

for:

Catalyst-Controlled Reverse Selectivity in C-C Bond Formation:

NHC-Cu-Catalyzed α-Selective Allylic Alkylation with Organolithium Reagents

Stefano F. Pizzolato, Massimo Giannerini, Pieter H. Bos, Martín Fañanás-Mastral*

and Ben L. Feringa*

Stratingh Institute for Chemistry, University of Groningen,

Nijenborgh 4, 9747 AG, Groningen, The Netherlands.

martin.fananas@usc.es, b.l.feringa@rug.nl

Contents

General Methods S2

General Procedures for the Copper-Catalyzed Allylic Alkylation of S3

Allylic Halides with Organolithium Reagents

Optimization Study: Additional Data S5

Product Characterization S12

References S18

1H NMR and 13C NMR Spectra of New Compounds S19

Electronic Supplementary Material (ESI) for ChemComm.This journal is © The Royal Society of Chemistry 2015

S2

General Methods

Chromatography: Merck silica gel type 9385 230-400 mesh, TLC: Merck silica gel 60, 0.25 mm.

Components were visualized by UV light (254 nm) and/or phosphomolybdic acid or potassium

permanganate staining. Progress and conversion of the reaction were determined by GC-MS (GC,

HP6890: MS HP5973) with an HP1 or HP5 column (Agilent Technologies 19091s-433, Palo Alto,

CA). Mass spectra were recorded on an AEI-MS-902 mass spectrometer (EI) or a LTQ Orbitrap

XL (APCI; ESI). 1H NMR and 13C NMR were recorded on a Varian AMX400 (400 and 100.59

MHz, respectively) or a Varian VXR200 (200 and 50 MHz, respectively) using CDCl3 as solvent.

Chemical shift values are reported in ppm with the solvent resonance as the internal standard

(CHCl3: δ = 7.26 ppm for 1H, δ = 77.0 ppm for 13C). Data are reported as follows: chemical shift,

multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quint = quintuplet, sept = septet, br =

broad, m = multiplet), coupling constants (Hz) and integration (nH). All reactions were carried out

under a nitrogen atmosphere using oven dried glassware or using standard Schlenk techniques.

CH2Cl2 was dried and distilled over calcium hydride; toluene was dried and distilled over sodium; nhexane was dried over molecular sieves. Cinnamyl bromide (1a), cinnamyl chloride (1j), NatOBu,

KtOBu and all copper-salts (CuCl CuSCN, CuTC [Copper(I)-thiophene-2-carboxylate] and

CuBr.SMe2) were purchased from Sigma-Aldrich and used without further purification. Allyl

bromides 1b-k were prepared following literature procedures (1b1, 1c2, 1d1, 1e1, 1f3, 1g4, 1h5, 1i6,

1k3). Organolithium reagents were purchased from Sigma-Aldrich (MeLi (1.6 M in diethyl ether),

EtLi (0.5 M in benzene/cyclohexane 9:1), nHexLi (2.3 M in nhexane), secBuLi (1.4 M in

cyclohexane), PhLi (1.8 M in dibutyl ether)) or from Acros (nBuLi (1.6 M in nhexane), isoBuLi (1.6

M in nheptane)). Ligands L1-2-3-6-8 were purchased from Sigma-Aldrich. Ligands L4,7 L5,8 L77

and L99 were prepared as reported in the literature.

S3

General Procedures for the Copper-Catalyzed Allylic Alkylation of Allylic Halides with

Organolithium Reagents

General Procedure (A) for Cu-NHC catalyzed allylic alkylation of allylic halides with

organolithium reagents (preformation of the catalyst by addition of NaOtBu or KOtBu).

A flame-dried Schlenk tube equipped with septum and stirring bar under nitrogen atmosphere is

charged with copper salt (0.015 mmol, 5 mol%), NHC ligand salt (0.0165 mmol, 5.5 mol%) (the

copper and ligand salts used in each experiment are reported in the optimization and scope tables)

and solid base (NaOtBu or KOtBu as reported) (0.0165 mmol, 5.5 mol%). The tube is evacuated and

backfilled with nitrogen three times, then dry CH2Cl2 (1 mL) is added and the solution is stirred

under nitrogen at r.t. for 30 min. The solution is cooled down (at the reported temperature) and

stirred over 10 min. The allylic halide (0.3 mmol) is dissolved in dry CH2Cl2 (1 mL), injected in the

mixture under stirring and stirred over 10 min. In a separate flame-dried Schlenk tube, the

organolithium reagent (reported equivalents) is diluted to a combined volume of 1 mL with dry

hexane (dry toluene was employed in the case of MeLi due to gelation) under nitrogen and slowly

injected dropwise in the reaction mixture (over the reported time) using a syringe pump. The flow of

inert gas was turned off during the addition to prevent the drops of organolithium reagent from

drying on the tip of the needle. Once the addition is complete, the mixture is stirred for 2 h. The

reaction is quenched with NH4Cl sat. (2 mL), the mixture is warmed up to r.t., diluted with CH2Cl2

(5 mL) and the layers are separated. The aqueous layer is extracted with CH2Cl2 (3 x 5 mL) and the

combined organic layers are dried over Na2SO4, filtered and the solvent is evaporated in vacuo.

Purification is performed by column chromatography on silica gel using different mixtures of

pentane:Et2O as eluent. Note: Gas chromatography analysis is carried out to determine the

SN2:SN2’:homocoupling ratio on a sample obtained after work up, which has been passed through a

short plug of silica gel to remove transition metal residues.

General Procedure (B) for Cu-NHC catalyzed allylic alkylation of allylic halides with

organolithium reagents (preformation of the catalyst by addition of nBuLi).

A flame-dried Schlenk tube equipped with septum and stirring bar under nitrogen atmosphere is

charged with CuBr.SMe2 (0.015 mmol, 5 mol%) and NHC ligand salt (0.0165 mmol, 5.5 mol%) (the

ligand salt used in each experiment are reported in the optimization and scope tables). The tube is

evacuated and backfilled with nitrogen three times, then dry CH2Cl2 (1 mL) is added and the

solution is stirred under nitrogen at r.t. for 10 min. The solution is cooled down to -80 °C, then 2

drops of nBuLi (0.0165 mmol, 5.5 mol%, 1.6 M) are injected in the mixture and stirred over 15 min.

The addition of allylic halide and organolithium reagent, work up of the reaction and analysis are

performed as previously described in Procedure (A).

S4

General Procedure (C) for Cu-NHC catalyzed allylic alkylation of allylic halides with

organolithium reagents (without preformation of the catalyst).

A flame-dried Schlenk tube equipped with septum and stirring bar under nitrogen atmosphere is

charged with CuBr.SMe2 (0.015 mmol, 5 mol%) and NHC ligand salt (0.0165 mmol, 5.5 mol%) (the

ligand salt used in each experiment are reported in the optimization and scope tables). The tube is

evacuated and backfilled with nitrogen three times, then dry CH2Cl2 (1 mL) is added and the

solution is stirred under nitrogen at r.t. for 10 min. The solution is cooled down to -80 °C and stirred

over 10 min. The addition of allylic halide and organolithium reagent, work up of the reaction and

analysis are performed as previously described in Procedure (A).

S5

Optimization Study: Additional Data

A. Blank reactions in different solvents

Ph Br + nBuLiSolvent , T

Ph Ph+nBu

nBu

α−product γ−product

Ph+

Ph

1a

2a 3a Ph

Ph

homocoupling products

Allylic substitutionproducts

4

Table S1

Entrya Solvent Addition time Temperature Conversion (%)b 2a:3a:4 (%)b

1 CH2Cl2 3 h -80 °C 83 48:16:36

2 CH2Cl2 3 h r.t. full 47:19:34

3 CH2Cl2 direct r.t. full 48:21:31

4 toluene 3 h -80 °C 50 57:15:28

5 toluene 3 h 0 °C full 50:21:29

6 toluene 3 h r.t. full 49:25:26

7 toluene direct r.t. full 54:23:23

8 THF 3 h -80 °C full 21:5:74

9 MTBE 3 h -80 °C full 53:17:30

a Reaction conditions: 0.3 mmol of 1a in 2 mL of dry solvent. nBuLi (0.45 mmol, 1.6 M in hexane) diluted with dry hexane (final

conc. 0.45 M) added over 3h. Reaction mixture was further stirred for 2 h at -80 oC. b Determined by GC and 1H NMR.

Preliminary results obtained by addition of to a solution of cinnamyl bromide in CH2Cl2 at -80 °C

over 3 hours showed incomplete conversion, low selectivity and large amount of homocoupling

products (Table S1, entry 1). Performing the reaction at room temperature with long or short time of

addition of nBuLi afforded full conversion without any improvement in regioselectivity (entries 2-3).

The use of toluene afforded similar results in all the previous conditions (entries 4-7). The use of a

coordinating solvent as THF afforded full conversion unfortunately with large quantities of

homocoupling products (entry 8). The use of MTBE yielded result comparable to CH2Cl2 (entry 9).

S6

B. Catalyzed reactions in different solvents

Ph Br + nBuLi Ph Ph+nBu

nBu

α−product γ−product

Ph+

Ph

1a

2a 3a Ph

Ph

homocoupling products

Allylic substitutionproducts

4

CuBr.SMe2

5 mol%

solvent, -80 °C

L1 5.5 mol%

NaOtBu 5.5 mol%

Table S2

Entrya Solvent Copper Ligand Conversion (%)b 2a:3a:4 (%)b

1 CH2Cl2 full 95:5:-

2 CH2Cl2 full 73:17:10

3 CH2Cl2 80 49:18:33

4 CH2Cl2 83 48:16:36

5 toluene full 94:4:2

6 toluene 50 53:20:27

7 THF full 21:5:74

8 THF full 21:5:74

9 MTBE full 53:17:30

10 MTBE full 53:17:30

a Reaction conditions: General Procedure (A). 0.015 mmol of CuBr·SMe2, 0.0165 mmol of L1 and 0.0165 mmol of NaOtBu in 1 mL

of dry solvent cooled at -80 C̊. 0.3 mmol of 1a in 1 mL of dry solvent added to the cooled mixture. nBuLi (0.45 mmol, 1.6 M in

hexane) diluted with dry hexane (final conc. 0.45 M) added over 3h. Reaction mixture further stirred for 2 h at -80 oC. b Determined

by GC and 1H NMR.

When CuBr.SMe2 and IAd.HBF4 (L1) were used in CH2Cl2, good regioselectivity was observed as

well as full conversion and complete suppression of the side-reactions leading to homocoupling

products (Table S2, entry 1). When the ligand was removed, the selectivity of the reaction dropped,

yielding significant amount of branched and homocoupling products (entry 2). When only the

copper salt was removed (entry 3) the selectivity of the reaction was completely compromised,

affording results not significantly different from the blank reaction (entry 4). The use of toluene as

solvent led to comparable results obtained with CH2Cl2, affording good (entry 5) or bad selectivity

(entry 6) depending on the presence of the catalyst. When THF or MTBE were used, the catalytic

system resulted to be ineffective due to the high reactivity of the organolithium specie (entries 7-10).

S7

C. Screening of copper salts

Ph Br + nBuLi Ph Ph+nBu

nBu

α−product γ−product

Ph+

Ph

1a

2a 3a Ph

Ph

homocoupling products

Allylic substitutionproducts

4

CuX 5 mol%

CH2Cl2, -80 °C

L1 5.5 mol%

NaOtBu 5.5 mol%

Table S3

Entrya CuX Conversion (%)b 2a:3a:4 (%)b

1 CuBr.SMe2 full 95:5:-

2 CuTCc 55 83:9:8

3 CuCl 96 72:10:18

4 CuSCN full 92:8:-

a Reaction conditions: General Procedure (A). 0.015 mmol of copper salt (CuX), 0.0165 mmol of L1 and 0.0165 mmol of NaOtBu in 1

mL of dry CH2Cl2 cooled at -80 C̊. 0.3 mmol of 1a in 1 mL of dry CH2Cl2 added to the cooled mixture. nBuLi (0.45 mmol, 1.6 M in

hexane) diluted with dry hexane (final conc. 0.45 M) added over 3h. Reaction mixture further stirred for 2 h at -80 oC. b Determined

by GC and 1H NMR. c CuTC = (Copper(I)-thiophene-2-carboxylate)

The conditions which afforded the best result by employing CuBr.SMe2 (Table S3, entry 1) were

also applied to other commercially available copper precursors. The use of copper(I)-thiophene-2-

carboxylate (CuTC) caused a dramatic decrease in conversion (entry 2). The use of CuCl caused a

significant decrease in selectivity (entry 3). When CuSCN was used, only the regioselectivity was

affected by a slight decrease (entry 4).

S8

D. Effects of base

Ph Br + nBuLi Ph Ph+nBu

nBu

α−product γ−product

Ph+

Ph

1a

2a 3a Ph

Ph

homocoupling products

Allylic substitutionproducts

4

CuBr.SMe2

5 mol%

CH2Cl2, -80 °C

L1 5.5 mol%

Base 5.5 mol%

Table S4

Entry Base Conversion (%)a 2a:3a:4 (%)b

1b NaOtBu full 95:5:-

2b KOtBu full 95:5:-

3c nBuLi full 93:7:-

4d - full 95:5:-

a Determined by GC and 1H NMR. b Reaction conditions: General Procedure (A). 0.015 mmol of CuBr·SMe2, 0.0165 mmol of L1 and

0.0165 mmol of base (NaOtBu or KOtBu) in 1 mL of dry CH2Cl2 cooled at -80 C̊. 0.3 mmol of 1a in 1 mL of dry CH2Cl2 added to the

cooled mixture. nBuLi (0.45 mmol, 1.6 M in hexane) diluted with dry hexane (final conc. 0.45 M) added over 3h. Reaction mixture

further stirred for 2 h at -80 oC. c Reaction conditions: General Procedure (B). 0.015 mmol of CuBr·SMe2 and 0.0165 mmol of L1 in 1

mL of dry CH2Cl2 cooled at -80 C̊. nBuLi (0.0165 mmol, 1.6 M in hexane) injected in the mixture and stirred over 15 min. 0.3 mmol

of 1a in 1 mL of dry CH2Cl2 added to the cooled mixture. nBuLi (0.45 mmol, 1.6 M in hexane) diluted with dry hexane (final conc.

0.45 M) added over 3h. Reaction mixture stirred for 2 h at -80 oC. d Reaction conditions: General Procedure (C). 0.015 mmol of

CuBr·SMe2 and 0.0165 mmol of L1 in 1 mL of dry CH2Cl2 cooled at -80 C̊. 0.3 mmol of 1a in 1 mL of dry CH2Cl2 added to the

cooled mixture. nBuLi (0.45 mmol, 1.6 M in hexane) diluted with dry hexane (final conc. 0.45 M) and added via syringe pump over 3

h. Reaction mixture stirred for 2 h at -80 oC.

Different common bases, used to generate in situ the carbene specie starting from the corresponding

NHC ligand salt, were screened. NaOtBu and KOtBu, charged as solids in the reaction flask together

with CuBr.SMe2 and L1 (General Procedure A), gave comparable results in term of good conversion

and selectivity (Table S4, entries1-2). nBuLi (1.6 M in hexane) could also be used, by injection in the

reaction mixture prior the addition of the substrate (General Procedure B), with similar results

(entries 3). Eventually, the addition of an external base could be avoided (General Procedure C), by

harnessing the basicity of the organolithium compound and the slow addition. The formation of the

carbene occurs before any other chemical process, forming in situ the catalyst and affording the

product without any erosion of the selectivity (entry 4).

S9

E. Effects of temperature

Ph Br + nBuLi Ph Ph+nBu

nBu

α−product γ−product

Ph+

Ph

1a

2a 3a Ph

Ph

homocoupling products

Allylic substitutionproducts

4

CuBr.SMe2

5 mol%

L1 5.5 mol%

CH2Cl2, T

Table S5

Entrya Temperature (oC) Conversion (%)b 2a:3a:4 (%)b

1 -50 full 76:19:5

2 -74 full 88:10:2

3 -80 full 95:5:-

4 -82 full 94:5:1

a Reaction conditions: General Procedure (C). 0.015 mmol of CuBr·SMe2 and 0.0165 mmol of L1 in 1 mL of dry CH2Cl2. 0.3 mmol

of 1a in 1 mL of dry CH2Cl2 added to the cooled mixture (reported temperature). nBuLi (0.45 mmol, 1.6 M in hexane) diluted with

dry hexane (final conc. 0.45 M) and added via syringe pump over 3 h. Reaction mixture stirred for 2 h at -80 oC. b Determined by GC

and 1H NMR.

The test reaction was performed at different temperatures to highlight its effect on the selectivity.

When the reaction was performed at temperatures higher than -80 oC, the selectivity was

significantly affected (Table S5, entries 1-2). Performing the reaction of -80 oC afforded the best

results (entry 3). When the temperature was further decrease, no improvement was observed (entry

4).

S10

F. Effects of addition time

Ph Br + nBuLi Ph Ph+nBu

nBu

α−product γ−product

Ph+

Ph

1a

2a 3a Ph

Ph

homocoupling products

Allylic substitutionproducts

4

CuBr.SMe2

5 mol%

CH2Cl2, -80 °C

L1 5.5 mol%

Table S6

Entrya Addition time Conversion (%)b 2a:3a:4 (%)b

1 3 hr full 95:5:-

2 1 hr full 84:6:10

3 90 sec full 66:10:24

a Reaction conditions: General Procedure (C). 0.015 mmol of CuBr·SMe2 and 0.0165 mmol of L1 in 1 mL of dry CH2Cl2 cooled at -

80 C̊. 0.3 mmol of 1a in 1 mL of dry CH2Cl2 added to the cooled mixture. nBuLi (0.45 mmol, 1.6 M in hexane) diluted with dry

hexane (final conc. 0.45 M) added over reported time. Reaction mixture stirred for 2 h at -80 oC. b Determined by GC and 1H NMR.

The test reaction was performed with different time of addition of nBuLi to the reaction mixture to

investigate its effect on the selectivity. While a slow addition in 3 hours ensures good selectivity

(Table S6, entry 1), shortening to 1 hour mainly caused a significant production of homocoupling

products (entry 2). Worse results were obtained when fast addition in 90 seconds was performed

(entry 3), showing the slow addition to be a key parameter in order to guide the reaction through the

catalytic cycle.

G. Large scale test

The optimized condition were also applied to a 3.0 mmol scale (10 times larger than previously

described) with a reduced catalyst loading (2 mol%), while the concentration of the substrate and

organolithium were not modified (respectively 0.15 M in CH2Cl2 and 0.36 M in hexane). The

selectivity of the reaction was not affected by the larger scale and reduced catalyst content.

α:γ =

97:3 a

Ph Br nBuLi Ph nBu + Ph

nBuCuBr.SMe2

2 mol%

(12.33

mg)

CH2Cl2 (20

mL), -80

oC SN2-product SN2'-product3.0 mmol

(0.591

g)

1.2 eq., 3.6

mmol (2

.25 mL)

(1.6

M

in

hexane)

diluted to

10

mL with

hexane,

injected over 3

h

L2 2.2

mol%

(21.13 mg)

0.15 M

in

CH2Cl2

+

yield 86

%

(0

.449 g)

Reaction conditions: General Procedure (C). 0.06 mmol of CuBr·SMe2 and 0.066 mmol of L2 in 10 mL of dry CH2Cl2 cooled at -

80 C̊. 3.0 mmol of 1a dissolved in 10 mL of dry CH2Cl2 and added to the cooled mixture. nBuLi (3.6 mmol, 1.6 M in hexane) diluted

with dry hexane (final conc. 0.36 M) added over 3 h. Reaction mixture stirred for 2 h at -80 oC. a Determined by GC and 1H NMR.

S11

H. Preliminary studies on olefin geometry retention

In preliminary studies, a Z:E = 70:30 mixture of o-methoxycinnamyl bromide was converted into a

Z:E = 68:32 mixture of the corresponding alkylated linear product, with a regioselectivity of α:γ =

95:5, (yield not determined).

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

-50

0

50

100

150

200

250

300

350

400

450

500GMG112cr_cdcl3_Proton_20120521153323GMG112cr

5.19

2.19

2.39

1.00

2.24

4.10

4.11

4.15

4.15

4.16

4.17

4.17

4.21

4.21

5.94

5.98

5.99

6.02

6.03

6.04

6.08

6.36

6.40

6.44

6.47

6.47

6.51

6.67

6.73

1

2

3

4

5

6

O7

CH38

9

10

11

Br12

13

14

15

16

17

18

O19

CH320

21

22

23

Br24

starting bromide, Z:E = 70:30

Et2O1H 9

Et2O

1H 22

1H 22

2H 23

1H 11

Z-bromide E-bromide

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

-50

0

50

100

150

200

250

300

350

400

450

500

550

600

650

700

750

800

GMG114cr

0.32

2.20

0.17

1.02

2.00

0.52

0.44

4.98

4.98

4.98

4.99

5.00

5.00

5.03

5.07

5.70

5.72

5.73

5.74

5.75

5.77

5.94

5.96

5.97

5.99

6.00

6.01

6.18

6.20

6.21

6.22

6.22

6.24

6.26

6.49

6.49

6.50

6.52

6.52

6.53

6.68

6.68

6.69

6.72

6.73

1

2

3

4

5

6

O7

CH38

9

10

11

12

13

14

CH315

16

17

18

19

20

21

O22

CH323

24

25

26

27

28

29

CH330

31

32

33

34

35

36

O37

CH338

39

40

CH241

42

43

44

CH345

Z-linear

1H 9

E-linear

1H 25 1H10

branched

1H 40

1H 24

1H 41

product distribution:Z:E = 68:32

alpha:gamma = 95:5

starting from linear bromide:Z:E = 70:30

CH2Cl2

Reaction conditions: General Procedure (C). 0.015 mmol (5.0 mol%) of CuBr·SMe2 and 0.0165 mmol (5.0 mol%) of L2 in 1 mL of dry CH2Cl2 cooled at -80 C̊. 0.3 mmol of substrate dissolved in 1 mL of dry CH2Cl2 and added to the cooled mixture. nBuLi (0.36 mmol, 1.6 M in hexane) diluted with dry hexane (final conc. 0.36 M) added over 3 h. Reaction mixture stirred for 2 h at -80 oC. Ratios determined by GC and 1H NMR.

S12

Product Characterization

(E)-Hept-1-enylbenzene (2a)

Synthesized according to General Procedure C. Colorless oil obtained

as a 98:2 mixture of 2a and 3a after column chromatography (SiO2,

pentane), [78% yield] from 1a as starting material and nBuLi. A 94:6

mixture of 2a and 3a was obtained after column chromatography (SiO2, pentane), [85% yield] from

1j as starting material and nBuLi. The physical data were identical in all respects to those previously

reported.10 2a: 1H NMR (400 MHz, CDCl3, 25 °C) δ 7.36 (d, J = 7.7 Hz, 2H), 7.29 (t, J = 7.5 Hz,

2H), 7.20 (t, J = 7.1 Hz, 1H), 6.39 (d, J = 15.9 Hz, 1H), 6.24 (dt, J = 15.9, 7.1 Hz, 1H), 2.21 (q, J =

7.1 Hz, 2H), 1.54-1.44 (m, 2H), 1.40-1.31 (m, 4H), 0.89 (t, J = 5.7 Hz, 3H). 13C NMR (100.59 MHz,

CDCl3, 25 °C) δ 137.9, 131.2, 129.7, 128.4, 126.7, 125.9, 33.0, 31.4, 29.1, 22.6, 14.1. HRMS (ESI)

m/z [M+] calcd for C13H18: 174.1403; found: 174.0923.

(E)-Pent-1-enylbenzene (2b)

Synthesized according to General Procedure C from 1a as starting material

and EtLi. Colorless oil obtained as a 96:4 mixture of 2b and 3b after column

chromatography (SiO2, pentane), [60% yield]. The physical data were

identical in all respects to those previously reported.11 2b: 1H NMR (400 MHz, CDCl3, 25 °C) δ 7.35

(d, J = 7.9 Hz, 2H), 7.30 (t, J = 7.7 Hz, 2H), 7.19 (t, J = 6.7 Hz, 1H), 6.39 (d, J = 15.9 Hz, 1H),

6.28–6.18 (m, 1H), 2.20 (q, J = 7.1 Hz, 2H), 1.56–1.45 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H). 13C NMR

(100.59 MHz, CDCl3, 25 °C) δ 137.9, 131.0, 129.9, 128.4, 126.7, 125.9, 35.1, 22.5, 13.7. HRMS

(APCI) m/z [M+H]+ calcd for C11H15: 147.1168; found: 147.1155.

(E)-(5-Methyl)-hex-1-enylbenzene (2c)

Synthesized according to General Procedure C from 1a as starting material

and isoBuLi. Colorless oil obtained as a 97:3 mixture of 2c and 3c after

column chromatography (SiO2, pentane), [76% yield]. The physical data

were identical in all respects to those previously reported.11 2c: 1H NMR (400 MHz, CDCl3, 25 °C)

δ 7.35 (d, J = 7.3 Hz, 2H), 7.29 (t, J = 7.3 Hz, 2H), 7.19 (t, J = 7.1 Hz, 1H), 6.38 (d, J = 15.8 Hz,

1H), 6.22 (dt, J = 15.6, 6.8 Hz, 1H), 2.25 (dt, J = 7.8, 7.2 Hz, 2H), 1.62 (sept, J = 6.6 Hz, 1H), 1.36

S13

(q, J = 7.3 Hz, 2H), 0.93 (d, J = 6.6 Hz, 6H). 13C NMR (100.59 MHz, CDCl3, 25 °C) δ 138.0, 131.3,

129.5, 128.4, 126.7, 125.8, 38.5, 30.9, 27.5, 22.5. HRMS (ESI) m/z [M+] calcd for C13H18: 174.1403;

found: 174.0923.

(E)-Non-1-enylbenzene (2d)

Synthesized according to General Procedure C from 1a as starting

material and nHexLi. Colorless oil obtained as a 98:2 mixture of 2d

and 3d after column chromatography (SiO2, pentane), [70% yield].

The physical data were identical in all respects to those previously reported.12 2d: 1H NMR (400

MHz, CDCl3, 25 °C) δ 7.34 (d, J = 7.2 Hz, 2H), 7.29 (t, J = 7.3 Hz, 2H), 7.19 (t, J = 7.2 Hz, 1H),

6.38 (d, J = 15.8 Hz, 1H), 6.23 (dt, J = 15.8, 6.8 Hz, 1H), 2.21 (dt, J = 6.8, 1.1 Hz, 2H), 1.47 (quint,

J = 6.8 Hz, 2H), 1.40-1.20 (m, 8H), 0.89 (t, J = 6.9 Hz, 3H). 13C NMR (100.59 MHz, CDCl3, 25 °C)

δ 137.9, 131.2, 129.6, 128.4, 126.7, 125.9, 33.0, 31.8, 29.4, 29.2, 22.6, 14.1. HRMS (APCI) m/z

[M+H]+ calcd for C15H23: 203.1799; found: 203.1775.

(E)-But-1-enylbenzene (2e)

Synthesized according to General Procedure C from 1a as starting material and

MeLi. Colorless oil obtained as a 91:9 mixture of 2e and 3e, [full conversion,

yield not determined]. The product was not purified due to the high volatility

and Rf similar to toluene, used for diluting the MeLi. Analysis was performed by comparing the

physical data with precedent literature.13 2e: 1H NMR (400 MHz, CDCl3, 25 °C) δ 7.40-7.19 (m,

5H), 6.46 (d, J = 15.9 Hz, 1H), 6.33 (dt, J = 15.9, 6.0 Hz, 1H), 2.30 (dq, J = 7.3, 5.8 Hz, 2H), 1.17 (t,

J = 7.4 Hz, 3H). 13C NMR (100.59 MHz, CDCl3, 25 °C) δ 137.9, 132.6, 128.7, 128.4, 126.7, 125.8,

26.05, 13.6. LRMS (ESI) m/z (abundance%, ion label): 51(6), 63(4), 65(6), 77(7), 78(6), 89(4),

91(24), 102(4), 103(4), 104(4), 115(45), 116(12), 117(100), 118(11), 128(5), 131(11, M+-H),

132(44, M+), 210(5, M++H).

(E)-(2-Methyl)-hex-1-enylbenzene (2f)

Synthesized according to General Procedure C from 1a as starting material

and secBuLi. Colorless oil obtained as a 90:10 mixture of 2f and 3f after

S14

column chromatography (SiO2, pentane) [50% yield]. The physical data were identical in all respects

to those previously reported.14 2f: 1H NMR (400 MHz, CDCl3, 25 °C) δ 7.35 (d, J = 7.2 Hz, 2H),

7.29 (t, J = 7.6 Hz, 2H), 7.19 (t, J = 7.2 Hz, 1H), 6.38 (d, J = 15.8 Hz, 1H), 6.22 (dt, J = 15.8, 7.2

Hz, 1H), 2.22 (ddd, J = 13.8, 6.4, 1.1 Hz, 1H), 2.05 (ddd, J = 13.8, 7.4, 3.7 Hz, 1H), 1.57–1.47 (m,

1H), 1.46–1.36 (m, 1H), 1.27–1.14 (m, 1H), 0.92 (t, J = 6.7 Hz, 3H), 0.90 (t, J = 7.3 Hz, 3H). 13C

NMR (100.59 MHz, CDCl3, 25 °C) δ 138.3, 131.1, 130.20, 128.8, 127.1 126.3, 40.5, 35.3, 29.5,

19.5, 11.9. HRMS (APCI) m/z [M+H]+ calcd for C13H19: 175.1481, found: 175.0954.

(E)-4-(Hept-1-enyl)-1-chlorobenzene (2g)

Synthesized according to General Procedure C from 1b as starting

material and nBuLi. Colorless oil obtained as a 98:2 mixture of 2g

and 3g after column chromatography (SiO2, pentane), [86% yield].

The physical data were identical in all respects to those previously reported.15 2g: 1H NMR (400

MHz, CDCl3, 25 °C) δ 7.30–7.22 (m, 4H), 6.33 (d, J = 15.8 Hz, 1H), 6.20 (dt, J = 15.7, 6.7 Hz, 1H),

2.20 (dt, J = 7.8, 6.7 Hz, 2H), 1.47 (quint, J = 7.2 Hz, 2H), 1.40–1.28 (m, 4H), 0.91 (t, J = 6.9 Hz,

3H). 13C NMR (100.59 MHz, CDCl3, 25 °C) δ 136.4, 132.2, 132.0, 128.5, 128.5, 127.1, 33.0, 31.4,

29.0, 22.5, 14.0. HRMS (EI) m/z [M+] calcd for C13H17Cl: 208.1019, found: 208.1018.

(E)-4-(Hept-1-enyl)-1-bromobenzene (2h):

Synthesized according to General Procedure C from 1c as starting

material and nBuLi. Colorless oil obtained as a 98:2 mixture of 2h

and 3h after column chromatography (SiO2, pentane), [86% yield].

The physical data were identical in all respects to those previously reported.16 2h: 1H NMR (400

MHz, CDCl3, 25 °C) δ 7.40 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H), 6.31 (d, J = 15.9 Hz, 1H),

6.22 (dt, J = 15.9, 6.6 Hz, 1H), 2.19 (dt, J = 7.2, 6.7 Hz, 2H), 1.47 (quint, J = 7.3 Hz, 2H), 1.39–1.27

(m, 4H), 0.90 (t, J = 7.1 Hz, 3H). 13C NMR (100.59 MHz, CDCl3, 25 °C) δ 136.9, 132.1, 131.5,

128.5, 127.4, 120.3, 33.0, 31.4, 28.9, 22.5, 14.0. HRMS (APCI) m/z [M+H]+ calcd for C13H1881Br:

255.0571, found: 255.0933.

(E)-4-(Hept-1-enyl)-1-trifluoromethylbenzene (2i)

Cl

Br

S15

Synthesized according to General Procedure C from 1d as starting

material and nBuLi. Colorless oil obtained as a 98:2 mixture of 2i

and 3i after column chromatography (SiO2, pentane), [75% yield].

The physical data were identical in all respects to those previously reported.14 2i: 1H NMR (400

MHz, CDCl3, 25 °C) δ 7.54 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.2 Hz, 2H), 6.41 (d, J = 15.8 Hz, 1H),

6.34 (dt, J = 15.8, 6.1 Hz, 1H), 2.24 (dt, J = 7.1, 6.9 Hz, 2H), 1.49 (quint, J = 7.2 Hz, 2H), 1.40–1.29

(m, 4H), 0.91 (t, J = 6.9 Hz, 3H). 13C NMR (100.59 MHz, CDCl3, 25 °C) δ 141.4, 134.1, 128.5,

126.0, 125.6, 125.4, 123.0, 33.0, 31.4, 28.8, 22.5, 14.0. HRMS (APCI) m/z [M-CF3]+ calcd for

C13H17 [M-CF3]+: 173.1325, found: 173.1312.

(E)-Methyl-4-(hept-1-enyl)benzoate (2j)

Synthesized according to General Procedure C from 1e as starting

material and nBuLi. Colorless oil obtained as a 99:1 mixture of 2j

and 3j after column chromatography (SiO2, pentane:Et2O = 94:6),

[72% yield]. The physical data were identical in all respects to

those previously reported.17 2j: 1H NMR (400 MHz, CDCl3, 25 °C) δ 7.96 (dt, J = 8.4, 1.8 Hz, 2H),

7.38 (d, J = 8.4 Hz, 2H), 6.41 (d, J = 15.9 Hz, 1H), 6.35 (dt, J = 15.9, 6.10 Hz, 1H), 3.90 (s, 3H),

2.23 (dt, J = 7.2, 5.7 Hz, 2H), 1.48 (quint, J = 7.1 Hz, 2H), 1.39–1.28 (m, 4H), 0.91 (t, J = 6.9 Hz,

3H). 13C NMR (100.59 MHz, CDCl3, 25 °C) δ 167.0, 142.5, 134.2, 129.8, 129.0, 128.2, 125.7, 51.9,

33.1, 31.4, 28.8, 22.5, 14.0. HRMS (APCI) m/z [M+H]+ calcd for C15H21O2: 233.1536, found:

233.1476.

(E)-2-(Hept-1-enyl)-1-methoxybenzene (2k)

Synthesized according to General Procedure C from 1f as starting

material and nBuLi. Colorless oil obtained as a 96:4 mixture of 2k and

3k after column chromatography (SiO2, pentane:Et2O = 98:2), [83%

yield]. The physical data were identical in all respects to those previously reported.18 2k: 1H NMR

(400 MHz, CDCl3, 25 °C) δ 7.42 (dd, J = 7.6, 1.5 Hz, 1H), 7.18 (dt, J = 6.4, 1.6 Hz, 1H), 6.91 (t, J =

7.5 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 6.71 (d, J = 15.9 Hz, 1H), 6.22 (dt, J = 15.9, 6.9 Hz, 1H), 3.85

(s, 3H), 2.23 (dt, J = 7.0, 6.6 Hz, 2H), 1.48 (quint, J = 7.2 Hz, 2H), 1.39–1.29 (m, 4H), 0.91 (t, J =

6.9 Hz, 3H). 13C NMR (100.59 MHz, CDCl3, 25 °C) δ 156.2, 132.0, 127.7, 127.0, 126.3, 124.1,

120.6, 110.8, 55.4, 33.4, 31.5, 29.2, 22.6, 14.1. LRMS (ESI) m/z (abundance%, ion label): 51(3),

F3C

O

O

O

S16

77(6), 91(36), 103(5), 108(7), 115(19), 117(8), 119(17), 121(26), 131(16), 134(20), 147(100),

161(4), 204(40, M+).

(E)-(Oct-2-enyloxy)methylbenzene (2l)

Synthesized according to General Procedure C from 1g as starting

material and nBuLi. Colorless oil obtained as a 85:15 mixture of 2l

and 3l after column chromatography (SiO2, pentane:Et2O = 98:2),

[90% yield]. The spectra were compared with precedent literature.19 2l: 1H NMR (400 MHz, CDCl3,

25 °C) δ 7.38–7.32 (m, 4H), 7.31–7.26 (m, 1H), 5.78–5.66 (m, 1H), 5.66–5.55 (m, 1H), 4.51 (s, 2H),

3.98 (dt, J = 6.1, 0.8 Hz, 2H), 2.06 (dt, J = 7.1, 6.8 Hz, 2H), 1.45–1.20 (m, 6H), 0.90 (t, J = 6.6 Hz,

3H). 13C NMR (100.59 MHz, CDCl3, 25 °C) δ 135.1, 128.3, 127.8, 127.5, 127.4, 126.1, 71.8, 71.0,

32.3, 31.4, 28.7, 22.5, 14.0. HRMS (APCI) m/z [M+H]+ calcd for C15H23O: 219.1743, found:

219.1720.

(E)-Hept-1-enylbenzoate (2m)

Synthesized according to General Procedure C from 1h as starting

material and nBuLi. Colorless oil obtained as pure 2m from a 90:10

mixture of 2m and 3m after column chromatography (SiO2,

pentane:Et2O = 80:1), [72% yield]. The physical data were

identical in all respects to those previously reported.20 2m: 1H NMR (400 MHz, CDCl3, 25 °C) δ

8.09 (d, J = 8.2 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.31 (dt, J = 12.4, 1.4 Hz,

1H), 5.61 (dt, J = 12.4, 7.5 Hz, 1H), 2.07 (dq, J = 7.4, 6.3 Hz, 2H), 1.43 (quint, J = 7.1 Hz, 2H),

1.38–1.28 (m, 4H), 0.89 (t, J = 6.9 Hz, 3H). 13C NMR (100.59 MHz, CDCl3, 25 °C) δ 163.9, 135.5,

133.3, 129.8, 129.3, 128.4, 115.7, 31.2, 29.2, 27.3, 22.4, HRMS (APCI) m/z [M+H]+ calcd for

C15H21O2: 233.1536, found: 233.1515.

6-Pentadecene (2n)

Synthesized according to General Procedure C from 1i as

starting material and nBuLi. Colorless oil obtained as a 75:25

mixture of 2n and 3n after column chromatography (SiO2, pentane), [95% yield]. The physical data

O

O

O

S17

were identical in all respects to those previously reported.21 2n: 1H NMR (400 MHz, CDCl3, 25 °C)

δ 5.41–5.36 (m, 2H), 2.05–1.86 (m, 4H), 1.43–1.16 (m, 18H), 0.97–0.79 (m, 6H). 13C NMR (100.59

MHz, CDCl3, 25 °C) δ 130.7, 33.0, 32.9, 32.3, 31.8, 30.0, 29.9, 29.7, 29.7, 29.5, 23.1, 22.9, 14.5,

14.4. One 13C signal is missing or overlapping (C=C double bond). LRMS (ESI) m/z (abundance%,

ion label): 55(99), 69(100), 83(76), 97(66), 111(26), 125(8), 210(20, M+).

(Z)-Hept-1-enylbenzene (2o)

Synthesized according to General Procedure C from 1k (Z:E ratio = 94:6)

as starting material and nBuLi. Colorless oil obtained as a 94:6 mixture of

2o (Z:E ratio = 94:6) and 3o after column chromatography (SiO2, pentane),

[77% yield]. The physical data were identical in all respects to those previously reported.15 (Z)-2o: 1H NMR (400 MHz, CDCl3, 25 °C) δ 7.38-7.28 (m, 4H), 7.25-7.23 (m, 1H), 6.43 (d, J = 11.7 Hz,

1H), 5.69 (dt, J = 11.7, 7.3 Hz, 1H), 2.35 (qt, J = 7.3, 1.7 Hz, 2H), 1.48 (quint, J = 7.3 Hz, 2H), 1.39-

1.28 (m, 4H), 0.91 (t, J = 7.1 Hz, 3H). 13C NMR (100.59 MHz, CDCl3, 25 °C) δ 133.4, 128.8, 128.5,

128.2, 126.8, 126.5, 31.7, 29.8, 28.7, 22.6, 14.1. HRMS (APCI) m/z [M+H]+ calcd for C13H19:

175.1481, found: 175.1479.

(Z)-Non-1-enylbenzene (2p)

Synthesized according to General Procedure C from 1k (Z:E ratio =

86:14) as starting material and nHexLi. Colorless oil obtained as a

93:7 mixture of 2p (Z:E ratio = 86:14) and 3p after column

chromatography (SiO2, pentane), [63% yield]. The physical data were identical in all respects to

those previously reported.22 (Z)-2p: 1H NMR (400 MHz, CDCl3, 25 °C) δ 7.41–7.31 (m, 4H), 7.23

(t, J = 6.9 Hz, 1H), 6.45 (d, J = 11.6 Hz, 1H), 5.72 (dt, J = 11.7, 7.3 Hz, 1H), 2.38 (qd, J = 7.5, 1.7

Hz, 2H), 1.47 (quint, J = 7.3 Hz, 2H), 1.39-1.24 (m, 8H), 0.93 (dd, J = 8.2, 4.5 Hz, 3H). 13C NMR

(100.59 MHz, CDCl3, 25 °C) δ 138.2, 133.6, 129.1, 129.0, 128.4, 126.7, 32.2, 30.3, 29.7, 29.5, 29.0,

23.0, 14.4. HRMS (APCI) m/z [M+H]+ calcd for C15H22: 202.1722, found: 202.1733.

S18

References

(1) A. W. van Zijl, L. A. Arnold, A. J. Minnaard, and B. L. Feringa, Adv. Synth. Catal., 2004, 346,

413-420.

(2) M. L. Hammond, R. A. Zambias, M. A. Chang, N. P. Jensen, J. McDonald, K. Thompson, D. A.

Boulton, I. E. Kopka, K. M. Hand, E. E. Opas, T. Bach, P. Davies, D. E. Macintyre, R. J. Bonney

and J. L. Humes, J. Med. Chem., 1990, 33, 908-918.

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Cohen, Bioorg. Med. Chem. Lett., 2009, 19, 4863-4867.

(5) M. Lombardo, S. Morganti and C. J. Trombini, J. Org. Chem., 2003, 68, 997-1006.

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2563.

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S19

1H NMR and 13C NMR Spectra of New Compounds

mixture

2f 3f

2f : 3f = 90 : 10

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)

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S20

O O2l :

3l = 85 : 15

mixture

2l 3l

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)

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