University of Groningen Exploring asymmetric catalytic transformations Guduguntla, Sureshbabu

Exploring asymmetric catalytic transformations Guduguntla, Sureshbabu

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Enantioselective Synthesis of Di- and Tri- Arylated

All-Carbon Quaternary Stereocenters via Copper

Catalyzed Allylic Arylations with Organolithium

Compounds

The highly enantioselective copper(I)/N-heterocyclic carbene (NHC) catalyzed synthesis of di- and tri-arylated all-carbon quaternary stereocenters via asymmetric allylic arylation (AAAr) with aryl organolithium compounds is demonstrated. The use of readily available or easily accessible aryl organolithium reagents in combination with trisubstituted allyl bromides, in the presence of a copper/NHC catalyst, affords important di- and tri-arylated all-carbon quaternary stereocenters in good yields and enantioselectivities. This method tolerates a wide range of alkyl and substituted aryl groups in the starting allyl bromides, including less common biaryl moieties, which, in combination with diverse organolithium reagents, delivers a broad scope of products in an operationally straightforward and efficient manner.

This chapter is adapted from the original paper:

Guduguntla, S.; Gualtierotti, J. -B.; Goh, S. S.; Feringa, B. L. ACS Catal. 2016, 6, 6591.

4.1 Introduction

Catalytic methodologies to form congested all-carbon quaternary stereogenic centers are among the most challenging transformations in organic synthesis.1 Despite major progress in recent years,2 new and effective procedures to achieve this transformation are particularly warranted. This holds especially for sterically highly demanding di- and triaryl-substituted quaternary stereocenters, which are important structural units in bioactive compounds such as haplophytine3a and diazonamide A.3b In particular, triaryl methane structures4 serve as fluorescent molecules which have applications in cell imaging,5 selective sensors for metal ions,6 anticancer agents,7 and potassium ion channel blockers.8 Among the protocols reported recently, asymmetric allylic substitution (AAS) reactions have drawn major attention for the construction of these quaternary stereocenters due to the versatility and flexibility of the method.9 Pioneered by Bäckvall and van Koten in 1995,10 the AAS with organometallic reagents, catalyzed by copper11 or other transition metals,12 has proven to be incredibly effective in its capacity to deliver SN2′-products with tertiary carbon stereocenters in high yields and enantioselectivities. Via these methods, several useful synthons can be prepared which have been applied in the total synthesis of many natural products or biologically active compounds.13 However, despite the existence of well-established methods for the construction of tertiary carbon stereocenters, there are remarkably few methods based on AAS for the construction of all-carbon quaternary stereocenters. To the best of our knowledge, only a limited number of reports exist on the use of alkyl organometallic reagents as nucleophiles in allylic substitution forming quaternary stereocenters; these include the use of dialkyl zinc,14 boron,15 aluminum16 and Grignard reagents.17 Furthermore, methods using aryl organometallic reagents to prepare all-carbon quaternary stereocenters are scarce despite the fact that chiral diarylmethanes are highly relevant for the synthesis of natural products and pharmaceuticals.3,18 Importantly, Hoveyda and co-workers succeeded using diaryl zinc19 and aryl aluminum reagents,20 derived from the

corresponding organolithium reagents, whereas Hayashi and co-workers18d,21 achieved this transformation using aryl boronic esters, and Sawamura and co-workers22 very recently applied azoles as nucleophiles (Figure 1a).

Figure 1: Formation of all-carbon quaternary stereocenters with AAAr

In recent years, our group has reported a number of alternative AAS reactions combining highly reactive alkyl organolithium reagents as nucleophiles with allyl bromides or allyl ethers as electrophiles in the presence of a Cu(I)L catalytic system (L = Taniaphos or phosphoramidite) to achieve the formation of tertiary carbon stereocenters with excellent regio- and enantioselectivites.13j,23 We extended this protocol, again with alkyl organolithium reagents, to synthesize quaternary all-carbon stereocenters with good to high regio- and enantioselectivites.24 Early this year, we reported that the stereoselective formation of tertiary stereocenters via AAS could also be achieved with usually less-reactive aryl organolithium reagents in high regio- and very high enantioselectivities by switching to a Cu(I)-NHC catalytic system.18e Aryl lithium reagents have the important advantage, compared to many other organometallic species, of being either commercially available or very easy to prepare, even more so than their alkyl counterparts. They can be readily accessed in various ways such as metal−halogen exchange, direct metalation or ortho-metalation.25

the advantage of their ready availability, these lithium reagents often serve as precursors for other commonly used organometallic reagents.

Here, we report the first regio- and enantioselective Cu(I)-catalyzed asymmetric allylic arylation (Cu-AAAr) of trisubstituted allyl bromides using aryl organolithium compounds as nucleophiles to yield di- and tri-arylated quaternary all-carbon stereocenters with high regio- and very high enantioselectivities (SN2Ꞌ : SN2 up to 93:7, up to >99:1 er).

4.2 Results and discussion

We started our investigation of this transformation with trisubstituted allyl bromide 1a as model electrophile and commercially available PhLi as nucleophile in the presence of a catalytic amount of CuBr•SMe2 and chiral imidazolium salts (Table 1).18e When a solution of PhLi diluted in

n-hexane was added over 2h to an in situ-generated Cu(I)-NHC complex

(L1 or L2, 5 mol %) and allyl bromide in dry CH2Cl2 at –80 °C, we observed the chemoselective formation of desired SN2′-product 2a as a roughly equimolar mixture with the corresponding regioisomeric SN 2-product 3a. While imidazolium salts L1 and L2 had proven to be most suitable in the Cu-AAAr reaction to synthesize tertiary carbon stereocenters with aryl organolithium reagents,18e these chiral ligands did not lead to satisfactory results for quaternary centers as both branched and linear products were observed (entries 1 and 2, Table 1). We therefore pursued our investigation by screening for a more suitable carbene ligand. Salts L3 and L4 bearing o-tolyl or o-anisole groups on the two carbene nitrogens gave high regioselectivity (94:6 and 85:15) but almost no enantioselectivity (entries 3 and 4). Imidazolium salts bearing even bulkier substituents such as 2,4,6-Me3C6H2 (L5) or 2-i-PrC6H4 (L6) led to even higher regioselectivites (98:2 and 87:13), but only slightly better enantioselectivities (up to 67:33 er, entries 5 and 6). Similarly bulky substituent 2-MeNaphthyl L7 also gave high regio- and poor enantioselectivity (entry 7). In order to improve the enantioselectivity, we turned our attention to bifunctional ligands such as L8. However, this led to a drop in regioselectivity, which was attributed to the addition of PhLi

to the sulfonate group (entry 8). Moving from saturated imidazolium salts to unsaturated salts such as L9 and L10 led to a significant improvement in enantioselectivity (up to 75:25 er) while retaining good regioselectivity (up to 87:13, entries 9 and 10). Building on this promising regio- and enantioselectivity, we continued to screen different unsaturated chiral imidazolium salts. Disappointingly, increasing sterics like in bulky ligand precursors L11 and L12 resulted in very poor regio- and enantioselectivities (entries 11 and 12) while noncyclic carbene precursor L13 or C2-symmetric chiral bisoxazoline L14 led to reversals in branched to linear selectivity (entries 13 and 14). It was decided to switch carbene backbones altogether and test the activity of triazolium salts. While L15 again did not lead to satisfying results (entry 15), we were pleased to find that triazolium salt L16 gave 2a in 62% isolated yield with not only improved regioselectivity (75:25) but also excellent enantioselectivity of 97:3 er (entry 16). In order to simplify the protocol, we tested the in principle equivalent preformed copper complex CuClL16 in the reaction which gave identical results to the in situ-formed catalyst (entry 17).

entry ligand [Cu] 2a:3ab 2a, erc 1 L1 CuBr•SMe2 40:60 50:50 2 L2 CuBr•SMe2 60:40 50:50 3 L3 CuBr•SMe2 94:6 58:42 4 L4 CuBr•SMe2 85:15 54:46 5 L5 CuBr•SMe2 98:2 62:38 6 L6 CuBr•SMe2 87:13 67:33 7 L7 CuBr•SMe2 96:4 55:45 8 L8 CuBr•SMe2 44:56 n.d. 9 L9 CuBr•SMe2 87:13 75:25 10 L10 CuBr•SMe2 80:20 72:28 11 L11 CuBr•SMe2 44:56 55:45 12 L12 CuBr•SMe2 37:63 n.d. 13 L13 CuBr•SMe2 28:72 n.d. 14 L14 CuBr•SMe2 10:90 n.d. 15 L15 CuBr•SMe2 15:85 n.d. 16 L16 CuBr•SMe2 75:25 (62%)d 97:3 17 CuClL16 72:28 (61%)d 97:3

a) Conditions: Allyl bromide (0.2 mmol) in CH2Cl2 (2 mL). PhLi (0.3 mmol, 1.8 M

solution in n-dibutyl ether diluted with n-hexane to a final concentration of 0.3 M) was added over 2 h. All reactions gave full conversion. b) 2a/3a ratios and conversions determined by GC–MS and 1H-NMR analysis. c) Determined by chiral HPLC after conversion to the corresponding primary alcohol using a hydroboration–oxidation procedure (See experimental section). d) Isolated yield of 2a.

Having optimized conditions in hand, we investigated the substrate scope of the reaction of allyl bromides 1 with PhLi using chiral N-heterocyclic carbene complex CuClL16 as catalyst. First, the substitution at the aryl R1 position was varied while maintaining the alkyl R2 moiety as a methyl substituent in combination with PhLi as a nucleophile (Table 2). Substrates 1b, 1c and 1d, bearing a bromide at the ortho, meta or para positions of the aromatic ring, respectively, gave the desired products 2b, 2c and 2d (Table 2) with excellent enantioselectivites (97:3 to >99:1 er) and, with a few exceptions, moderate to good regioselectivities (70:30 to 92:8). The catalytic conversion also displayed high chemoselectivity, with no competing side reactions such as substitution or lithium-halogen

97

exchange observed. Notably, exceptionally high regio- and enantioselectivity was obtained when using ortho-bromo substituted 1b (99.5:0.5 er); this may be due to further halogen bonding interaction with the catalyst. In contrast, substrate 1e bearing an o-methoxy substituent led to product 2e with high enantioselectivity but with decreased regioselectivity. Substrates having either a p-methyl substituent (1f) or an extended conjugated system (1g) also gave the corresponding products 2f and 2g with good regio- and high enantioselectivity. Moving from cinnamyl type substrates to non cinnamyl allyl bromide 1h led to 2h (Table 2) with good regio- but moderate enantioselectivity.

Table 2. Substrate Scopea,b

a) Conditions: Allyl bromide 1 (0.2 mmol) in CH2Cl2 (2 mL). PhLi (0.3 mmol, 1.8 M

solution in dibutyl ether diluted with hexane to a final concentration of 0.4 M) was added over 2 h. All reactions gave full conversion. 2/3 ratios and conversions determined by GC–MS and 1H-NMR spectroscopy. Er determined by chiral HPLC after conversion to the corresponding primary alcohol using a hydroboration–oxidation procedure (see experimental section). b) Isolated yield of SN2' product. c) The absolute

configuration of 2a was assigned by comparing the sign of the optical rotation with the literature value (ref. 21).

We examined the substituent effect of the group R on the γ-position of the allyl bromide 1 using p-MeC6H4Li as a nucleophile on four different

substrates (Table 3). Substrates 1i and1j bearing methyl and ethyl substituents at the γ-position led to the desired products 2i and 2j (Table 3) with almost similar results in terms of regio- and enantioselectivity to model substrate 1a. Substrate 1k bearing a more sterically demanding i-propyl substituent at the γ-position gave the product 2k with similar regioselectivity to 2i and 2j but with moderate enantioselectivity (68:32 er). Having a phenyl substituent at the γ-position of the substrate (1l) allowed us to synthesize a rare chiral triaryl methane product 2l with three different aromatic groups and a synthetically flexible vinyl group in 34% isolated yield with good enantioselectivity (Table 3). Chiral all-carbon quaternary triarylmethane moieties are highly valuable, but as far as we know, very few methods exist for their synthesis.4

Table 3. Effect of γ-Substituenta,b

a) Conditions: Allyl bromide (0.2 mmol) in CH2Cl2 (2 mL). p-MeC6H4Li (0.4 mmol)

was diluted with n-hexane to a final concentration of 0.4 M and was added over 2 h. 2a/3a ratios and conversions determined by GC–MS and 1H-NMR analysis. Er determined by chiral HPLC after conversion to the corresponding primary alcohol using a hydroboration–oxidation procedure (see experimental section). b) Isolated yield of SN2' product. c) 10 mol % of CuClL16 was used.

Finally, we studied the scope of the reaction in terms of the aryl lithium partner under our standard conditions. These were readily prepared by adapting previously reported procedures18e and were tested on substrate 1b (Table 4). Fully deuterated PhLi gave the desired product 2m with

high regio- (93:7) and excellent enantioselectivity (>99:1 er). Adding diverse alkyl substituents at the para position of the aryl lithium did not affect the outcome of the reaction and gave products 2n and 2o with very high regio- and enantioselectivities. Electron rich p-methoxy substituted aryl lithium gave product 2p without any decrease in enantioselectivity but with slightly lower regioselectivity.

Table 4. Scope of Aryl lithium Compoundsa,b

a) Conditions: Allyl bromide (0.2 mmol) in CH2Cl2 (2 mL). Ar′Li (0.4 mmol) was

diluted with n-hexane to a final concentration of 0.4 M and was added over 2 h. All reactions gave full conversion. 2/3ratios and conversions determined by GC–MS and

1

H NMR analysis. Er determined by chiral HPLC after conversion to the corresponding primary alcohol using a hydroboration–oxidation procedure (see experimental section). b) Isolated yield of SN2' product. c) 10 mol % of CuClL16 was used and p-OMeC6H4Li

was diluted in toluene.

4.3 Conclusions

In summary, a highly enantioselective synthesis of quaternary all- carbon stereocenters via Cu-catalyzed direct allylic arylation using organolithium compounds is reported. A Cu(I)-NHC catalytic system proved to be essential for this transformation and allowed the preparation of a wide range of di- and tri-arylated vinyl methane compounds with good to excellent enantioselectivites. This transformation is also highly atom economical as LiBr is the only stoichiometric waste during this transformation.

4.4 Experimental section

4.4.1 General procedures

All reactions were carried out under nitrogen atmosphere in oven-dried glassware using standard Schlenk techniques. All allylic substitution reactions were performed in an ethanol bath cooled to –80 °C using a cryostat. Dichloromethane, diethyl ether, tetrahydrofuran and toluene were dried via a solvent purification system (MBRAUN SPS systems, MB-SPS-800). n-Hexane was dried and distilled over sodium. All copper-salts (CuBr•SMe2, CuCl), (1S,2S)-1,2-diphenylethane-1,2-diamine, (1R,2R)-1,2-diphenylethane-1,2-(1S,2S)-1,2-diphenylethane-1,2-diamine, L9, L10, L12, L13, L14, L15, L16, [Cu(IMes)Cl], Pd(OAc)2, (±)-BINAP, mesityl bromide, NaOt-Bu, anhydrous acetonitrile, PhLi (1.8 M in n-Bu2O), o-tolylmagnesium bromide (2.0 M in Et2O), n-BuLi (1.6 M in n-hexane), BH3•THF (1.0 M in THF), triethyl phosphonoacetate, DIBAL-H (1.2 M in toluene), solvents, starting compounds and PBr3 were purchased from commercial sources, and used without further purification. Ligands L1 and L2,26 L3,27 L4,28 L5,29 L6,27 L8,30 L7,31 and L1132 were prepared by following the indicated procedures described in the literature.

Racemic products were synthesized by reaction of the allyl bromides with the corresponding organolithium reagent at –80 °C in dichloromethane in the presence of [Cu(IMes)Cl] (5 mol %).

Flash column chromatography (FCC): Merck silica gel type 9385 230-400 mesh; TLC: Merck silica gel 60, 0.25 mm. Compounds were visualized by UV, phosphomolybdic acid and 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, Palo Alto, CA). Mass spectra were recorded on an AEI-MS-902 mass spectrometer (EI+) or a LTQ Orbitrap XL (ESI+). Carbon, hydrogen and nitrogen (CHN) elemental analyses were carried out on an EuroEA3000 element analyser. 1H- and 13C-NMR were recorded on a Varian AMX400 (400 and 100.59 MHz, respectively) or a

Varian VXR300 (300 and 75 MHz, respectively) using CDCl3 as solvent. Chemical shift values are reported in ppm with the solvent resonance as the internal standard (CHCl3:  7.26 for 1H,  77.0 for 13C). Data are reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz), and integration. Optical rotations were measured on a Schmidt +

Haensch polarimeter (Polartronic MH8) with a 10 cm cell (c given in

g/100 mL). Enantiomeric ratios were determined by HPLC analysis using a Shimadzu LC-10ADVP HPLC equipped with a Shimadzu SPD-M10AVP diode array detector.

Note: For compounds which could not be ionized on HRMS (ESI or APCI), GC–MS data (including fragmentation pattern) is reported instead.

4.4.2 GC–MS conditions are as follows

For compounds: 2b, 4b, 2c, 4c, 4d, 2h, 2j, 4j, 2k, 4k, 2l, 2m, 4m, 4n, 2o, 4o

Column Oven Temperature : 50.0 °C Injection Temperature : 250.0 °C

Oven Temperature Program:

Rate (°C/min) Temperature (°C) Hold time (min)

- 50.0 0.0

For compound: 4p

Column Oven Temperature : 150.0 °C Injection Temperature : 300.0 °C

Oven Temperature Program:

Rate (°C/min) Temperature (°C) Hold time (min)

- 150.0 0.0

10 300.0 40.0

4.4.3 General procedure for the synthesis of (E)-allyl bromides

The corresponding (E)-allyl bromides were synthesized via a three step procedure consisting of a Horner–Wadsworth–Emmons reaction, DIBAL-H reduction and PBr3 mediated bromination.

Procedure (A): General procedure for the Horner–Wadsworth– Emmons reaction.

To a stirred suspension of NaH (60% in mineral oil, 600 mg, 15.0 mmol, 1.5 equiv) in dry THF (30 mL, 0.5 M) at 0 °C was added triethyl phosphonoacetate (3.38 mL, 17.0 mmol, 1.7 equiv) dropwise over 15 min, subsequently allowed to warm to rt and stirred for a further 1 h. The corresponding ketone (10.0 mmol, 1.0 equiv) was dissolved in dry THF (10 mL, 1 M) and added dropwise to the reaction mixture. After stirring for 24 h at rt, the solution was cooled to 0 °C, quenched with saturated aq. NH4Cl (20 mL) solution, and the layers were separated. The aqueous layer was extracted with Et2O (3x20 mL) and the combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in

vacuo to give the crude product as an E:Z mixture. The crude product

was purified by flash column chromatography (FCC) on silica gel with (pentane/Et2O) mixtures to give the desired (E)-allyl ester as colourless oil. Physical data of all compounds matched reported literature data.8

Procedure (B): General procedure for the DIBAL-H reduction. To a stirred solution of the corresponding (E)-allyl ester (10.0 mmol, 1.0 equiv) in dry THF (20 mL, 0.5 M) at 0 °C was added DIBAL-H (1.2 M solution in toluene, 25.0 mL, 30.0 mmol, 3.0 equiv) dropwise. After the addition was completed, the solution was warmed to rt slowly and stirred overnight. Upon complete consumption of the starting material (as indicated by TLC), the reaction mixture was cooled to 0 °C and quenched sequentially with water (1.2 mL), 15% aq. NaOH (1.2 mL) and water (3.0 mL). After stirring at rt for 30 min, 5 to 10 g of anhydrous MgSO4 was added and the suspension stirred for another 30 min. The suspension was passed through a pad of celite and evaporation of the solvent led to the corresponding (E)-allyl alcohol as a colourless oil which was used in next step without further purification.8a

Procedure (C): General procedure for the bromination reaction with PBr3.

To a stirred solution of the corresponding (E)-allyl alcohol (10.0 mmol, 1.0 equiv) in anhydrous Et2O (20 mL, 0.5 M) at –15 °C was added neat PBr3 (0.48 mL, 5.0 mmol, 0.5 equiv) dropwise. After stirring for 30 min at this temperature, the reaction mixture was quenched with water and warmed to rt. After stirring for 10 min at rt, the reaction mixture was diluted with 20 mL of Et2O and the layers were separated. The organic layer was washed with saturated aq. NaHCO3 (10 mL) and saturated aq. NaCl (10 mL) solution, then dried over anhydrous MgSO4, filtered and concentrated in vacuo to give the corresponding (E)-allyl bromide in nearly quantitative yield. Physical data of compounds 1a, 1b, 1e and 1f match reported literature data.24a

(E)-1-Bromo-3-(4-bromobut-2-en-2-yl)benzene (1c): Obtained as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.53 (t, J = 1.8 Hz, 1H), 7.40 (dt, J = 8.0, 1.4 Hz, 1H), 7.31 (dt, J = 7.9, 1.4 Hz, 1H), 7.19 (t, J =

7.8 Hz, 1H), 6.07 (tq, J = 8.5, 1.4 Hz, 1H), 4.16 (d, J = 8.5 Hz, 2H), 2.10 (d, J = 1.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 144.3, 139.9, 130.7, 129.8, 129.0, 124.5, 123.9, 122.5, 28.7, 15.6.; HRMS (APCI+, m/z): calculated for C10H9 [M–HBr2]+: 129.0698, found: 129.0697.

(E)-1-Bromo-4-(4-bromobut-2-en-2-yl)benzene (1d): Obtained as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 8.4, 1.4 Hz, 2H), 7.26 (dd, J = 8.4, 1.3 Hz, 2H), 6.08 (tt, J = 8.5, 1.4 Hz, 1H), 4.17 (d,

J = 8.5 Hz, 2H), 2.12 (d, J = 1.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 141.0, 140.3, 131.4, 127.5, 123.4, 121.8, 28.9, 15.5; HRMS (APCI+,

m/z): calculated for C10H9 [M–HBr2]+: 129.0698, found: 129.0697.

(E)-2-(4-Bromobut-2-en-2-yl)naphthalene (1g): Obtained as a pale yellow oil, which upon time became pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.95 – 7.78 (m, 4H), 7.58 (dd, J = 8.6, 1.9 Hz, 1H), 7.54 – 7.43 (m, 2H), 6.26 (tq, J = 8.5, 1.4 Hz, 1H), 4.27 (d, J = 8.5 Hz, 2H), 2.27 (d, J = 1.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 141.3, 139.3, 133.3, 132.9, 128.2, 127.9, 127.5, 126.3, 126.1, 124.9, 124.0, 123.3, 29.5, 15.7; HRMS (APCI+, m/z): calculated for C14H13 [M–Br]+: 181.1011, found: 181.1009; Anal. Calcd for C14H13Br: C, 64.39; H, 5.02. Found: C, 64.72; H, 5.17.

(E)-(4-Bromo-2-methylbut-2-enyl)benzene (1h): Obtained as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.31 (dd, J = 8.0, 6.5 Hz, 2H), 7.27 – 7.20 (m, 1H), 7.18 (d, J = 7.4 Hz, 2H), 5.64 (tq, J = 8.4, 1.4 Hz, 1H), 4.05 (d, J = 8.4 Hz, 2H), 3.37 (s, 2H), 1.69 (d, J = 1.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 142.5, 138.9, 128.9, 128.4, 126.3, 122.4, 45.9, 29.2, 15.8; HRMS (APCI+, m/z): calculated for C11H13 [M–Br]+: 145.1011, found: 145.1011.

(E)-(4-Bromobut-2-en-2-yl)benzene (1i): Obtained as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.45 – 7.39 (m, 2H), 7.39 – 7.32 (m, 2H), 7.32 – 7.29 (m, 1H), 6.11 (tq, J = 8.6, 1.4 Hz, 1H), 4.21 (d, J = 8.5 Hz, 2H), 2.16 (d, J = 1.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 142.2, 141.5, 128.3, 127.8, 125.9, 122.8, 29.5, 15.6; HRMS (APCI+, m/z): calculated for C10H11 [M–Br]+: 131.0855, found: 131.0853.

(E)-(1-Bromopent-2-en-3-yl)benzene (1j): Obtained as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.45 – 7.28 (m, 5H), 5.97 (t, J = 8.6 Hz, 1H), 4.21 (dd, J = 8.7, 1.2 Hz, 2H), 2.63 (qd, J = 7.6, 1.3 Hz, 2H), 1.06 (td, J = 7.6, 1.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 147.9, 141.2, 128.4, 127.7, 126.5, 122.6, 29.0, 22.8, 13.4; HRMS (APCI+, m/z): calculated for C11H13 [M–Br]+: 145.1011, found: 145.1010.

(E)-(1-Bromo-4-methylpent-2-en-3-yl)benzene (1k): Obtained (E:Z = 90:10) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.34 – 7.27 (m, 3H), 7.17 (dt, J = 7.5, 1.3 Hz, 2H), 5.62 (t, J = 8.6 Hz, 1H), 4.18 (d, J = 8.6 Hz, 2H), 3.14 (hept, J = 7.0 Hz, 1H), 1.10 (d, J = 7.0 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 152.9, 141.5, 128.2, 127.7, 126.9, 123.9, 29.2, 28.0, 21.6.

(E)-1-Bromo-4-(3-bromo-1-phenylprop-1-enyl)benzene (1l): Obtained as a pale yellow viscous oil, which was upon time became a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.56 (dd, J = 8.3, 1.3 Hz, 2H), 7.30 (dq, J = 4.0, 2.9, 2.2 Hz, 3H), 7.25 – 7.19 (m, 2H), 7.16 (dd, J = 8.2, 1.3 Hz, 2H), 6.35 (td, J = 8.6, 1.2 Hz, 1H), 4.02 (dd, J = 8.6, 1.1 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 145.1, 140.6, 137.0, 131.7, 131.2, 128.3,

128.3, 127.7, 124.2, 122.1, 30.6; HRMS (APCI+, m/z): calculated for C15H11 [M–HBr2]+: 191.0855, found: 191.0854; Anal. Calcd for C15H12Br2: C, 51.17; H, 3.44. Found: C, 51.12; H, 3.56.

4.4.4 Procedure for the synthesis of (+)-CuClL16:

To an oven-dried Schlenk tube equipped with a septum and stirring bar was added L6 (100.0 mg, 0.21 mmol, 1.0 equiv), CuCl (25.0 mg, 0.25 mmol, 1.2 equiv) and NaOt-Bu (24.0 mg, 0.25 mmol, 1.2 equiv). The tube was evacuated and filled with nitrogen thrice. Dry CH2Cl2 (10 mL, 0.02 M) was added and the resulting solution was stirred under nitrogen at rt overnight. After complete consumption of the starting material (as indicated by TLC), celite was added to the reaction mixture and the volatiles evaporated. The residue was purified by FCC (CH2Cl2/MeOH, 1:0 to 98:2) to give the desired product as a pale greenish foamy solid. [α]D20 = +49.5 (c = 0.7 in CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.23 – 7.16 (m, 3H), 7.16 – 7.07 (m, 3H), 7.00 – 6.95 (m, 2H), 6.91 (d, J = 18.0 Hz, 2H), 6.81 – 6.73 (m, 2H), 5.29 – 5.19 (m, 3H), 4.97 (d, J = 15.6 Hz, 1H), 2.28 (s, 3H), 2.20 (s, 3H), 2.01 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 143.6, 141.8, 139.2, 138.7, 136.9, 134.2, 131.7, 130.8, 130.7, 130.6, 130.5, 130.4, 128.6, 82.7, 66.1, 61.4, 23.8, 20.6, 20.3; HRMS (ESI+, m/z): calculated for C26H26N3O [M–CuCl]+: 396.2070, found: 396.2062; Anal. Calcd for C26H26ClCuN3O: C, 63.02; H, 5.29. Found: C, 63.23; H, 5.19.

4.4.5 General procedure for the copper-catalyzed asymmetric allylic arylation with organolithium reagents

To a flame-dried Schlenk tube equipped with septum and stirring bar was added catalyst CuClL16 (5.0 mg, 0.01 mmol, 5 mol %). If the corresponding allyl bromide (0.2 mmol) was solid, it was added to the Schlenk tube simultaneously; the tube was then evacuated and filled with N2 thrice and dry CH2Cl2 (2 mL, 0.1 M) was added. If the corresponding allyl bromide was liquid, the Schlenk tube containing the catalyst was evacuated and filled with N2 thrice, before a solution of the liquid allyl bromide (0.2 mmol) in dry CH2Cl2 (2 mL, 0.1 M) was added. The reaction mixture was then cooled to –80 °C. In a separate Schlenk tube under N2, the corresponding aryllithium (1.5 equiv to 2.0 equiv) was diluted with dry n-hexane (except p-OMeC6H4Li, which was diluted with dry toluene) to a combined volume of 1 mL with a final concentration of 0.3 M to 0.4 M. This solution was added dropwise to the reaction mixture over 2 h via syringe pump. The flow of inert gas was turned off during the addition to prevent the organolithium drops from drying on the tip of the needle. Once the addition was complete, the mixture was stirred for another 30 min at –80 °C. The reaction mixture was quenched with a saturated aq. NH4Cl solution (2 mL), warmed to rt, diluted with diethyl ether (5 mL) and the layers were separated. The aqueous layer was extracted with Et2O (3 x 5 mL) and the combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was purified as described in each entry. Er values were determined by chiral HPLC analysis on the corresponding terminal alcohol obtained from a hydroboration-oxidation reaction.

108

4.4.6 General procedure for the hydroboration-oxidation of the corresponding alkenes 18d

BH3•THF (1.0 M solution in THF, 4.0 mL, 0.4 mmol, 2.0 equiv) was added to a solution of the corresponding mixture of alkenes (0.2 mmol, 1.0 equiv) in dry THF (2.0 mL, 0.1 M ) at 0 °C. The mixture was stirred for 10 min at 0 °C and a further 1 h at rt. The reaction mixture was cooled to 0 °C and quenched with 15% aq. NaOH (2.0 mL). 30% aq. H2O2 (2.0 mL) was added successively and the resulting mixture was stirred for 1 h at rt. The reaction mixture was diluted with saturated aq. NaCl (2.0 mL) and the layers were separated. The aqueous layer was extracted with Et2O (3 x 5 mL) and the combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified as described in each entry to afford the corresponding terminal alcohol.

4.4.7 Characterization and analysis of the molecules

(+)-(R)-1-Chloro-4-(2-phenylbut-3-en-2-yl)benzene (2a): Purified by FCC (flash column chromatography) (SiO2, pentane) to afford a mixture of SN2′:SN2 (91:9) product 2a (30 mg, yield = 61%) as a colourless oil.34 97:3 er (determined on 4a), [α]D20 = +9.0 (c = 1 in CHCl3); [lit.21 (S)-enantiomer (94.5:5.5 er): [α]D30 = –12.1 (c = 1.01 in CHCl3)]. 1H + 13C data of the compound matches with those reported in the literature.21

(–)-(R)-3-(4-Chlorophenyl)-3-phenylbutan-1-ol (4a): Purified by FCC (SiO2, 20% EtOAc/pentane) to afford 4a (30 mg, yield = 58%) as a colorless oil. 97:3 er, Chiralcel AD column, n-heptane/i-PrOH 95:5, 40 °C, 225 nm, retention times (min): 12.03 (minor) and 16.07 (major). [α]D20 = –1.2 (c = 1 in CHCl3); [lit.21 (S)-enantiomer (94.5:5.5 er): [α]D30 = +2.9 (c = 0.84 in CHCl3)]. 1H + 13C data of the compound matches with those reported in the literature.21

(–)-(R)-1-Bromo-2-(2-phenylbut-3-en-2-yl)benzene (2b): Purified by FCC (SiO2, pentane) to afford a mixture of SN2′:SN2 (92:8) product 2b (46 mg, yield = 80%) as a colorless oil. 99.5:0.5 er (determined on 4b), [α]D20 = –20.9 (c = 1 in CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.65 (dd, J = 7.9, 1.7 Hz, 1H), 7.57 (dd, J = 7.8, 1.4 Hz, 1H), 7.37 (td, J = 7.6, 1.4 Hz, 1H), 7.34 – 7.27 (m, 2H), 7.27 – 7.20 (m, 1H), 7.20 – 7.10 (m, 3H), 6.71 (dd, J = 17.4, 10.7 Hz, 1H), 5.24 (dd, J = 10.6, 0.9 Hz, 1H), 5.04 (dd, J = 17.4, 0.9 Hz, 1H), 1.92 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 147.3, 145.9, 144.9, 135.6, 129.6, 128.2, 128.1, 127.1, 126.9, 125.7, 124.2, 113.3, 51.4, 26.5; GC–MS (EI+) m/z (% relative intensity, ion): 13.9 min, 288 (30, M), 286 (20, M), 273 (15, M–CH3), 271 (15, M–CH3), 207 (95, M–Br), 192 (100, M–Br–CH3).

(+)-(R)-3-(2-Bromophenyl)-3-phenylbutan-1-ol (4b): Purified by FCC (SiO2, 20% EtOAc/pentane) to afford 4b (30 mg, yield = 58%) as a colourless oil. 99.5:0.5 er, Chiralcel OZ-H column, n-heptane/i-PrOH 98:2, 40 °C, 205 nm, retention times (min): 61.17 (minor) and 57.58 (major). [α]D20 = +15.7 (c = 1 in CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.61 (dd, J = 8.0, 1.6 Hz, 1H), 7.52 (dd, J = 7.9, 1.4 Hz, 1H), 7.40 – 7.32 (m, 1H), 7.31 – 7.23 (m, 2H), 7.22 – 7.15 (m, 1H), 7.12 (td, J = 8.1, 7.6, 1.5 Hz, 3H), 3.49 (m, 1H), 3.40 (td, J = 10.2, 9.6, 5.7 Hz, 1H), 2.99 (ddd,

110

J = 13.1, 9.0, 5.8 Hz, 1H), 2.35 (ddd, J = 13.1, 8.8, 5.8 Hz, 1H), 1.75 (s,

3H).; 13C NMR (100 MHz, CDCl3) δ 148.8, 145.4, 135.6, 129.1, 128.2, 128.1, 127.1, 126.4, 125.6, 124.2, 60.2, 46.7, 41.5, 29.4; GC–MS (EI+)

m/z (% relative intensity, ion): 16.5 min, 306 (10, M), 304 (10, M), 261

(85, M–C2H5O), 259 (90, M–C2H5O), 180 (100, M–Br–C2H5O), 165 (80, M–Br–C2H5O–CH3).

(+)-(R)-1-Bromo-3-(2-phenylbut-3-en-2-yl)benzene (2c): Purified by FCC (SiO2, pentane) to afford SN2′ product 2c (25 mg, yield = 44%) as a colourless oil.34 97:3 er (determined on 4c), [α]D20 = +1.1 (c = 1 in CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 1.8 Hz, 1H), 7.32 (dt, J = 7.3, 1.7 Hz, 1H), 7.30 – 7.20 (m, 2H), 7.22 – 7.13 (m, 3H), 7.10 (ddd, J = 11.8, 7.7, 1.5 Hz, 2H), 6.32 (ddd, J = 17.4, 10.6, 1.4 Hz, 1H), 5.19 (d, J = 10.5 Hz, 1H), 4.90 (d, J = 17.3 Hz, 1H), 1.75 (d, J = 1.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 150.6, 147.2, 145.7, 130.8, 129.5, 129.1, 128.1, 127.7, 126.7, 126.2, 122.3, 113.6, 50.1, 27.0; GC–MS (EI+) m/z (% relative intensity, ion): 14.2 min, 288 (10, M), 286 (10, M), 273 (10, M–CH3), 271 (9, M–CH3), 207 (100, M–Br), 192 (90, M–Br–CH3).

(–)-(R)-3-(3-Bromophenyl)-3-phenylbutan-1-ol (4c): Purified by TLC (SiO2, 10% 1,4-dioxane/n-hexane) to afford 4c (16 mg, yield = 52%) as a colourless oil. 97:3 er, Chiralcel OZ-H column, n-heptane/i-PrOH 98:2, 40 °C, 205 nm, retention times (min): 46.32 (minor) and 53.49 (major). [α]D20 = –1.0 (c = 0.5 in CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 1.7 Hz, 1H), 7.35 – 7.27 (m, 3H), 7.24 – 7.15 (m, 3H), 7.15 – 7.07 (m, 2H), 3.51 (t, J = 7.4 Hz, 2H), 2.42 (td, J = 7.1, 5.1 Hz, 2H), 1.66 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 154.5, 150.9, 132.8, 132.3, 131.7, 131.0, 129.7, 128.8, 128.6, 125.1, 62.6, 47.8, 46.6, 30.7; GC–MS (EI+) m/z (% relative intensity, ion): 16.840 min, 306 (9, M), 304 (10, M), 261 (100,

M–C2H5O), 259 (95, M–C2H5O), 180 (45, M–Br–C2H5O), 165 (40, M– Br–C2H5O–CH3).

(+)-(R)-1-Bromo-4-(2-phenylbut-3-en-2-yl)benzene (2d): Purified by FCC (SiO2, pentane) to afford SN2′ product 2d (35 mg, yield = 60%) as a colorless oil.34 97:3 er (determined on 4d), [α]D20 = +8.4 (c = 1 in CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.44 – 7.38 (m, 2H), 7.34 – 7.27 (m, 2H), 7.27 – 7.18 (m, 3H), 7.14 – 7.06 (m, 2H), 6.37 (dd, J = 17.3, 10.6 Hz, 1H), 5.22 (dd, J = 10.6, 1.0 Hz, 1H), 4.93 (dd, J = 17.3, 1.0 Hz, 1H), 1.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 147.5, 147.2, 145.9, 131.1, 129.7, 128.1, 127.7, 126.2, 120.0, 113.5, 49.9, 27.1; HRMS (APCI+, m/z): calculated for C16H15 [M–Br]+: 207.1168, found: 207.1167.

(–)-(R)-3-(4-Bromophenyl)-3-phenylbutan-1-ol (4d): Purified by FCC (SiO2, 20% EtOAc/pentane) to afford 4d (24 mg, yield = 56%) as a colourless oil. 97:3 er, Chiralcel OZ-H column, n-heptane/i-PrOH 98:2, 40 °C, 205 nm, retention times (min): 50.74 (minor) and 53.08 (major). [α]D20 = –1.7 (c = 1 in CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.39 (dd, J = 8.5, 1.5 Hz, 2H), 7.33 – 7.24 (m, 2H), 7.23 – 7.15 (m, 3H), 7.07 (dd, J = 8.6, 1.5 Hz, 2H), 3.50 (t, J = 7.4 Hz, 2H), 2.52 – 2.29 (m, 2H), 1.65 (d,

J = 1.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 148.4, 131.2, 129.0, 128.3, 127.0, 126.1, 119.8, 60.0, 44.9, 43.9, 28.0; GC–MS (EI+) m/z (% relative intensity, ion): 17.2 min, 306 (9, M), 304 (10, M), 261 (98, M– C2H5O), 259 (100, M–C2H5O), 180 (35, M–Br–C2H5O), 165 (38, M–Br– C2H5O–CH3); Anal. Calcd for C16H17BrO: C, 62.96; H, 5.61. Found: C, 63.03; H, 5.79.

(+)-(R)-1-Methoxy-2-(2-phenylbut-3-en-2-yl)benzene (2e): Purified by FCC (SiO2, 5-10% toluene/pentane) to afford SN2′ product 2e (16 mg,

yield = 34%) as a pale yellowish oil. 96:4 er (determined on 4e), [α]D20 = +8.3 (c = 1 in CHCl3); [lit.21 (S)-enantiomer (87.5:12.5 er): [α]D20 = –12.5 (c = 1.37 in CHCl3)]. 1H + 13C data of the compound matches with those reported in the literature.21

(+)-(R)-3-(2-Methoxyphenyl)-3-phenylbutan-1-ol (4e): Purified by TLC (SiO2, 2% EtOAc/CH2Cl2) to afford 4e (12 mg, yield = 50%) as a colorless oil. 96:4 er, Chiralcel AS-H column, n-heptane/i-PrOH 99:1, 40 °C, 215 nm, retention times (min): 35.61 (minor) and 28.12 (major). [α]D20 = +8.2 (c = 0.6 in CHCl3); [lit.21 (S)-enantiomer (87.5:12.5 er): [α]D25 = –22.2 (c = 0.96 in CHCl3)]. 1H + 13C data of the compound matches with those reported in the literature.21

(+)-(R)-1-Methyl-4-(2-phenylbut-3-en-2-yl)benzene (2f): Purified by FCC (SiO2, pentane) to afford a mixture of SN2′:SN2 (93:7) product 2f (27 mg, yield = 60%) as a colourless oil. 98:2 er (determined on 4f), [α]D20 = +4.9 (c = 1 in CHCl3); [lit.21 (S)-enantiomer (93.5:6.5 er): [α]D25 = –5.5 (c = 1.06 in CHCl3)]. 1H + 13C data of the compound matches with those reported in the literature.21

(–)-(R)-3-Phenyl-3-p-tolylbutan-1-ol (4f): Purified by FCC (SiO2, 15% EtOAc/pentane) to afford 4f (20 mg, yield = 60%) as a colorless oil. 98:2 er, Chiralcel OZ-H column, n-heptane/i-PrOH 97:3, 40 °C, 210 nm, retention times (min): 29.46 (minor) and 32.49 (major). [α]D20 = –1.1 (c = 1 in CHCl3); [lit.21 (S)-enantiomer (93.5:6.5 er): [α]D25 = +0.8 (c = 1.06 in CHCl3)]. 1H + 13C data of the compound matches with those reported in the literature.21

113

(–)-(R)-2-(2-Phenylbut-3-en-2-yl)naphthalene (2g): Purified by FCC (SiO2, pentane) to afford SN2′ product 2g (30 mg, yield = 58%) as a colourless oil. 97:3 er (determined on 4g), [α]D20 = –1.0 (c = 1 in CHCl3); [lit.21 (S)-enantiomer (95.5:4.5 er): [α]D30 = +5.1 (c = 1.06 in CHCl3)]. 1H + 13C data of the compound matches with those reported in the literature.21

(+)-(R)-3-(Naphthalen-2-yl)-3-phenylbutan-1-ol (4g): Purified by FCC (SiO2, 20% EtOAc/pentane) to afford 4g (23 mg, yield = 60%) as a colorless oil. 97:3 er, Chiralcel OJ-H column, n-heptane/i-PrOH 95:5, 40 °C, 225 nm, retention times (min): 46.39 (minor) and 56.31 (major). [α]D20 = +3.1 (c = 1 in CHCl3); [lit.21 (S)-enantiomer (95.5:4.5 er): [α]D30 = –1.7 (c = 0.90 in CHCl3)]. 1H + 13C data of the compound matches with those reported in the literature.21

(+)-(R)-(2-Methylbut-3-ene-1,2-diyl)dibenzene (2h): Purified by FCC (SiO2, pentane) to afford a mixture of SN2′:SN2 (85:15) product 2h (35 mg, yield = 78%) as a colorless oil.34 70:30 er (determined on 4h), [α]D20 = +19.6 (c = 1 in CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 4.2 Hz, 4H), 7.28 – 7.19 (m, 2H), 7.16 (dd, J = 4.9, 1.8 Hz, 2H), 6.91 – 6.81 (m, 2H), 6.19 (dd, J = 17.5, 10.8 Hz, 1H), 5.15 (dd, J = 10.8, 1.2 Hz, 1H), 5.06 (dd, J = 17.5, 1.2 Hz, 1H), 3.12 (d, J = 13.0 Hz, 1H), 3.05 (d, J = 13.0 Hz, 1H), 1.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 146.7, 146.6, 138.2, 130.7, 128.0, 127.4, 127.1, 126.0, 125.9, 112.2, 47.8, 45.2, 24.2; GC–MS (EI+) m/z (% relative intensity, ion): 12.3 min, 222 (10, M), 131 (100, M–C7H7), 115 (40, M–C8H10), 103 (10, M–C9H12).

(+)-(R)-3-Methyl-3,4-diphenylbutan-1-ol (4h): Purified by FCC (SiO2, 15% EtOAc/ pentane) to afford 4h (24 mg, yield = 76%) as a colourless oil. 70:30 er, Chiralcel OJ-H column, n-heptane/i-PrOH 99:1, 40 °C, 210

114

nm, retention times (min): 60.89 (minor) and 65.04 (major). [α]D20 = +21.6 (c = 1 in CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.28 (qd, J = 8.4, 3.9 Hz, 5H), 7.20 (td, J = 6.7, 1.9 Hz, 1H), 7.13 (dd, J = 5.0, 1.9 Hz, 2H), 6.78 (dd, J = 6.6, 2.9 Hz, 2H), 3.56 (td, J = 9.9, 5.8 Hz, 1H), 3.43 (td, J = 9.8, 5.6 Hz, 1H), 2.96 (d, J = 13.1 Hz, 1H), 2.83 (d, J = 13.1 Hz, 1H), 2.27 (ddd, J = 13.5, 9.3, 5.6 Hz, 1H), 1.87 (ddd, J = 13.5, 9.3, 5.8 Hz, 1H), 1.29 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 146.3, 137.9, 130.6, 128.2, 127.5, 126.6, 126.0, 125.9, 59.8, 51.2, 44.5, 40.9, 23.5; HRMS (ESI–, m/z): calculated for C17H19O [M–H]–: 239.1430, found: 239.1438.

(–)-(S)-1-Methyl-4-(2-phenylbut-3-en-2-yl)benzene (2i): Purified by FCC (SiO2, pentane) to afford a mixture of SN2′:SN2 (92:8) product 2i (30 mg, yield = 67%) as a colorless oil.35 98:2 er (determined on 4i), [α]D20 = –5.5 (c = 1 in CHCl3); [lit.21 (93.5:6.5 er): [α]D25 = –5.5 (c = 1.06 in CHCl3)]. 1H + 13C data of the compound matches with those reported in the literature.21

(+)-(S)-3-Phenyl-3-p-tolylbutan-1-ol (4i): Purified by FCC (SiO2, 15% EtOAc/pentane) to afford 4i (23 mg, yield = 68%) as a colorless oil. 98:2 er, Chiralcel OZ-H column, n-heptane/i-PrOH 95:5, 40 °C, 205 nm, retention times (min): 20.15 (minor) and 18.63 (major). [α]D20 = +0.6 (c = 1 in CHCl3); [lit.21 (93.5:6.5 er): [α]D25 = +0.8 (c = 1.06 in CHCl3)]. 1H + 13

C data of the compound matches with those reported in the literature.21

(–)-(S)-1-Methyl-4-(3-phenylpent-1-en-3-yl)benzene (2j): Purified by FCC (SiO2, pentane) to afford SN2′ product 2j (30 mg, yield = 63%) as a colorless oil.35 95:5 er (determined on 4j), [α]D20 = –5.5 (c = 1 in CHCl3);

1 H NMR (400 MHz, CDCl3) δ 7.34 – 7.24 (m, 2H), 7.24 – 7.17 (m, 3H), 7.14 – 7.06 (m, 4H), 6.46 (dd, J = 17.5, 10.7 Hz, 1H), 5.21 (dd, J = 10.7, 1.3 Hz, 1H), 4.81 (dd, J = 17.5, 1.3 Hz, 1H), 2.35 (s, 3H), 2.32 (q, J = 7.3 Hz, 2H), 0.80 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 146.9, 144.7, 143.8, 135.3, 128.7, 128.6, 128.5, 127.8, 125.8, 114.0, 53.7, 31.3, 21.0, 9.4; GC–MS (EI+) m/z (% relative intensity, ion): 13.3 min, 236 (25, M), 207 (100, M–C2H5), 192 (30, M–C3H8), 178 (20, M–C4H10).

(–)-(S)-3-Phenyl-3-p-tolylpentan-1-ol (4j): Purified by FCC (SiO2, 15% EtOAc/pentane) to afford 4j (26 mg, yield = 75%) as a colourless oil. 95:5 er, Chiralcel AS-H column, n-heptane/i-PrOH 99:1, 40 °C, 225 nm, retention times (min): 23.89 (minor) and 25.53 (major). [α]D20 = –0.92 (c = 1 in CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.23 (dd, J = 9.5, 5.8 Hz, 2H), 7.20 – 7.10 (m, 3H), 7.04 (brs, 4H), 3.40 (t, J = 7.4 Hz, 2H), 2.36 (t,

J = 7.4 Hz, 2H), 2.28 (s, 3H), 2.10 (q, J = 7.3 Hz, 2H), 0.64 (t, J = 7.3

Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 148.2, 145.1, 135.2, 128.6, 127.9, 127.7, 127.6, 125.7, 59.8, 48.1, 39.6, 30.6, 20.9, 8.5; GC–MS (EI+) m/z (% relative intensity, ion): 15.9 min, 254 (10, M), 225 (100, M–C2H5), 210 (10, M–C3H8), 209 (60, M–C2H5O).

(–)-(S)-1-Methyl-4-(4-methyl-3-phenylpent-1-en-3-yl)benzene (2k): Purified by FCC (SiO2, pentane) to afford a mixture of SN2′:SN2 (89:11) product 2k (27.0 mg, yield = 54%) as a colorless oil.35 68:32 er (determined on 4k), [α]D20 = –2.6 (c = 1 in CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.32 – 7.23 (m, 5H), 7.21 – 7.13 (m, 2H), 7.09 (d, J = 8.1 Hz, 2H), 6.41 (dd, J = 17.6, 11.0 Hz, 1H), 5.29 (dd, J = 11.0, 1.2 Hz, 1H), 4.89 (dd, J = 17.6, 1.2 Hz, 1H), 2.95 (hept, J = 6.7 Hz, 1H), 2.34 (d, J = 8.5 Hz, 3H), 0.89 (d, J = 6.6 Hz, 3H), 0.89 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 145.7, 142.9, 142.5, 135.0, 129.3, 129.2, 128.3, 127.5, 125.5, 115.5, 57.7, 32.0, 21.0, 19.2, 19.1; GC–MS (EI+) m/z (%

relative intensity, ion): 14.0 min, 250 (5, M), 207 (100, M–C3H7), 192 (20, M–C4H10), 178 (10, M–C5H12).

(+)-(R)-4-Methyl-3-phenyl-3-p-tolylpentan-1-ol (4k): Purified by TLC (SiO2, 15% 1,4-dioxane/n-hexane) to afford 4k (26 mg, yield = 75%) as a colourless oil. 68:32 er, Chiralcel OZ-H column, n-heptane/i-PrOH 95:5 40 °C, 205 nm, retention times (min): 23.57 (minor) and 17.65 (major). [α]D20 = +1.1 (c = 0.5 in CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.35 – 7.17 (m, 5H), 7.10 (s, 4H), 3.36 (t, J = 7.4 Hz, 2H), 2.65 (hept, J = 6.7 Hz, 1H), 2.37 (t, J = 7.4 Hz, 2H), 2.34 (s, 3H), 0.79 (d, J = 6.6 Hz, 3H), 0.79 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 144.5, 141.2, 135.4, 129.6, 129.5, 128.0, 127.3, 125.9, 59.9, 53.0, 42.6, 31.9, 20.9, 18.5, 18.4; GC–MS (EI+) m/z (% relative intensity, ion): 16.6 min, 268 (5, M), 225 (100, M–C3H7), 195 (25, M–C4H10O), 181 (40, M–C5H12O).

(–)-(S)-1-Bromo-4-(1-phenyl-1-p-tolylallyl)benzene (2l): Purified by FCC (SiO2, pentane) to afford SN2′ product 2l (25.0 mg, yield = 34%) as a colorless oil.35 82:18 er (determined on 4l), [α]D20 = –0.8 (c = 1 in CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 8.7 Hz, 2H), 7.35 – 7.20 (m, 3H), 7.15 – 7.05 (m, 4H), 7.02 – 6.95 (m, 4H), 6.82 (dd, J = 17.2, 10.7 Hz, 1H), 5.42 (dd, J = 10.7, 0.9 Hz, 1H), 4.87 (dd, J = 17.2, 0.9 Hz, 1H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 145.3, 145.0, 144.4, 142.1, 136.1, 132.1, 130.7, 130.1, 129.9, 128.5, 127.8, 126.4, 120.4, 116.6, 60.8, 20.9; HRMS (APCI+, m/z): calculated for C22H19 [M– Br]+: 283.1481, found: 283.1481.

117

(–)-(S)-3-(4-Bromophenyl)-3-phenyl-3-p-tolylpropan-1-ol (4l): Purified by TLC (SiO2, 10% 1,4-dioxane/n-hexane) to afford 4l (20 mg, yield = 73%) as a colourless oil. 82:18 er, Chiralcel OZ-H column, n-heptane/i-PrOH 95:5, 40 °C, 205 nm, retention times (min): 22.18 (minor) and 19.82 (major). [α]D20 = –0.9 (c = 1 in CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.37 (t, J = 8.6 Hz, 2H), 7.31 – 7.20 (m, 3H), 7.20 – 7.11 (m, 4H), 7.11 – 7.02 (m, 4H), 3.44 (t, J = 7.4 Hz, 2H), 2.85 (t, J = 7.4 Hz, 2H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 146.5, 146.4, 143.3, 135.9, 131.1, 130.6, 128.9, 128.8, 128.7, 128.1, 126.2, 120.0, 60.5, 54.5, 42.7, 20.9; GC–MS (EI+) m/z (% relative intensity, ion): 22.0 min, 337 (97, M–C2H5O), 335 (100, M–C2H5O), 256 (15, M–C2H5OBr), 241 (20, M–C3H8OBr), 179 (20, M–C8H10OBr).

(–)-(R)-1-Bromo-2-(2-pentadeuterophenylbut-3-en-2-yl)benzene (2m): Purified by FCC (SiO2, pentane) to afford a mixture of SN2′:SN2 (93:7) product 2m (55.0 mg, yield = 94%) as a colorless oil. >99:1 er (determined on 4m), [α]D20 = –20.1 (c = 1 in CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.64 (dd, J = 7.9, 1.7 Hz, 1H), 7.57 (dd, J = 7.8, 1.4 Hz, 1H), 7.36 (td, J = 7.6, 1.4 Hz, 1H), 7.14 (td, J = 7.6, 1.7 Hz, 1H), 6.71 (dd, J = 17.3, 10.6 Hz, 1H), 5.23 (dd, J = 10.6, 0.9 Hz, 1H), 5.03 (dd, J = 17.4, 0.9 Hz, 1H), 1.92 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 148.6, 147.7, 138.3, 132.3, 130.8, 129.8, 126.8, 115.9, 54.0, 29.1; GC–MS (EI+) m/z (% relative intensity, ion): 13.9 min, 293, (27, M) 291 (30, M), 278 (18, M–CH3), 276 (20, M–CH3), 212 (60, M–Br), 197 (100, M– CH3Br).

118

(+)-(R)-3-(2-Bromophenyl)-3-pentadeuterophenylbutan-1-ol (4m): Purified by FCC (SiO2, 15% EtOAc/pentane) to afford 4m (44.0 mg, yield = 75%) as a colourless oil. >99:1 er, Chiralcel OZ-H column, n-heptane/i-PrOH 98:2, 40 °C, 220 nm, retention times (min): 58.28 (major). [α]D20 = +5.2 (c = 1 in CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.58 (dd, J = 7.9, 1.7 Hz, 1H), 7.48 (dd, J = 7.9, 1.4 Hz, 1H), 7.32 (td, J = 7.6, 1.5 Hz, 1H), 7.08 (td, J = 7.6, 1.6 Hz, 1H), 3.45 (ddd, J = 10.7, 9.0, 5.8 Hz, 1H), 3.36 (ddd, J = 10.6, 8.7, 5.8 Hz, 1H), 2.95 (ddd, J = 13.0, 9.0, 5.8 Hz, 1H), 2.31 (ddd, J = 13.1, 8.8, 5.8 Hz, 1H), 1.72 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 145.4, 135.6, 129.1, 128.2, 127.1, 124.2, 60.2, 46.7, 41.6, 29.4; GC–MS (EI+) m/z (% relative intensity, ion): 16.5 min, 311 (8, M), 309 (10, M), 266 (100, M–C2H5O), 264 (100, M– C2H5O), 185 (97, M–C2H5OBr), 170 (58, M–C3H8OBr); Anal. Calcd for C16H12D5BrO: C, 61.94; H, 5.53. Found: C, 61.98; H, 5.82.

(–)-(R)-1-Bromo-2-(2-p-tolylbut-3-en-2-yl)benzene (2n): Purified by FCC (SiO2, pentane) to afford a mixture of SN2′:SN2 (94:6) product 2n (56.0 mg, yield = 93%) as a colorless oil.35 99.5:0.5 er (determined on 4n), [α]D20 = –27.3 (c = 1 in CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.61 (dd, J = 8.0, 1.7 Hz, 1H), 7.54 (dq, J = 7.9, 1.3 Hz, 1H), 7.38 – 7.29 (m, 1H), 7.16 – 7.06 (m, 3H), 7.02 (dd, J = 8.3, 1.9 Hz, 2H), 6.67 (ddd, J = 17.3, 10.6, 1.8 Hz, 1H), 5.27 – 5.12 (m, 1H), 5.00 (dd, J = 17.4, 1.4 Hz, 1H), 2.34 (s, 3H), 1.88 (d, J = 1.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 146.0, 145.1, 144.3, 135.5, 135.1, 129.6, 128.9, 128.0, 127.1, 126.7,

124.1, 113.0, 51.0, 26.4, 21.0; HRMS (APCI+, m/z): calculated for C17H17 [M–Br]+: 221.1324, found: 221.1314.

119

(+)-(R)-3-(2-Bromophenyl)-3-p-tolylbutan-1-ol (4n): Purified by TLC (SiO2, 8% 1,4-dioxane/n-hexane) to afford 4n (40.0 mg, yield = 70%) as a colourless oil. 99.5:0.5 er, Chiralcel AS-H column, n-heptane/i-PrOH 99:1, 40 °C, 220 nm, retention times (min): 26.30 (minor) and 29.30 (major). [α]D20 = +10.8 (c = 0.8 in CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.56 (dt, J = 8.0, 1.4 Hz, 1H), 7.48 (dt, J = 7.9, 1.4 Hz, 1H), 7.32 (td, J = 7.6, 1.4 Hz, 1H), 7.12 – 7.00 (m, 3H), 6.95 (dd, J = 8.2, 1.3 Hz, 2H), 3.45 (dddd, J = 10.5, 9.0, 5.8, 1.2 Hz, 1H), 3.35 (dddd, J = 10.5, 8.8, 5.8, 1.2 Hz, 1H), 2.94 (ddd, J = 14.2, 8.9, 5.9 Hz, 1H), 2.36 – 2.20 (m, 1H), 2.28 (s, 3H), 1.70 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 145.8, 145.5, 135.6, 135.0, 129.0, 128.9, 128.0, 127.0, 126.2, 124.2, 60.2, 46.3, 41.6, 29.4, 20.9; GC–MS (EI+) m/z (% relative intensity, ion): 17.3 min, 320 (25, M), 318 (30, M), 275 (80, M–C2H5O), 273 (100, M–C2H5O), 194 (60, M–C2H5OBr), 179 (65, M–C3H8OBr).

(–)-(R)-1-Bromo-2-(2-(4-t-butylphenyl)but-3-en-2-yl)benzene (2o): Purified by FCC (SiO2, 1% CHCl3/n-hexane) to afford a mixture of SN2′:SN2 (94:6) product 2o (64.0 mg, yield = 93%) as a colorless oil.36 99:1 er (determined on 4o), [α]D20 = –24.1 (c = 1 in CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.61 (dd, J = 7.9, 1.6 Hz, 1H), 7.55 (dt, J = 7.9, 2.2 Hz, 1H), 7.39 – 7.24 (m, 3H), 7.11 (td, J = 7.6, 1.6 Hz, 1H), 7.06 (d, J = 8.3 Hz, 2H), 6.68 (dd, J = 17.4, 10.6 Hz, 1H), 5.32 – 5.12 (m, 1H), 5.01 (d, J = 17.3 Hz, 1H), 1.90 (s, 3H), 1.33 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 151.1, 148.8, 147.9, 146.7, 138.2, 132.3, 130.6, 129.7, 129.1, 127.7, 126.9, 115.6, 53.6, 37.0, 34.1, 29.1; GC–MS (EI+) m/z (% relative intensity, ion): 16.7 min, 344 (9, M), 342 (10, M), 329 (23, M–CH3), 327 (25, M–CH3), 287 (40, M–C4H9), 285 (37, M–C4H9), 263 (20, M–Br).

(+)-(R)-3-(2-Bromophenyl)-3-(4-(t-butyl)phenyl)butan-1-ol (4o): Purified by TLC (SiO2, 10% 1,4-dioxane/n-hexane) to afford 4o (33.0 mg, yield = 50%) as a colourless oil. 99:1 er, Chiralcel OZ-H column, n-heptane/i-PrOH 98:2, 40 °C, 220 nm, retention times (min): 30.18 (minor) and 34.68 (major). [α]D20 = +4.3 (c = 0.4 in CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.59 (dd, J = 8.0, 1.7 Hz, 1H), 7.50 (dd, J = 7.8, 1.4 Hz, 1H), 7.35 (ddd, J = 8.0, 7.3, 1.4 Hz, 1H), 7.25 (d, J = 8.1 Hz, 2H), 7.10 (td, J = 7.6, 1.6 Hz, 1H), 7.05 – 6.95 (m, 2H), 3.50 (ddd, J = 10.7, 8.9, 5.8 Hz, 1H), 3.40 (ddd, J = 10.7, 8.7, 5.8 Hz, 1H), 2.98 (ddd, J = 13.1, 8.9, 5.8 Hz, 1H), 2.34 (ddd, J = 13.0, 8.7, 5.9 Hz, 1H), 1.74 (s, 3H), 1.29 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 148.4, 145.6, 145.6, 135.6, 129.1, 128.0, 127.0, 125.9, 125.0, 124.3, 60.3, 46.3, 41.7, 34.3, 31.4, 29.7; GC–MS (EI+) m/z (% relative intensity, ion): 19.0 min, 362 (25, M), 360 (30, M), 317 (98, M–C2H5O), 315 (100, M–C2H5O), 236 (16, M–C2H5OBr), 179 (70, M–C6H14OBr).

()-(R)-1-Bromo-2-(2-(4-methoxyphenyl)but-3-en-2-yl)benzene (2p): Purified by FCC (SiO2, 25% CHCl3/n-hexane) to afford a mixture of SN2′:SN2 (85:15) product 2p (57.0 mg, yield = 90%) as a colorless oil. 99:1 er (determined on 4p), [α]D20 = –27.5 (c = 1 in CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J = 7.9, 1.6 Hz, 1H), 7.54 (dd, J = 7.9, 1.3 Hz, 1H), 7.33 (td, J = 7.6, 1.4 Hz, 1H), 7.11 (td, J = 7.6, 1.6 Hz, 1H), 7.07 – 7.00 (m, 2H), 6.85 – 6.77 (m, 2H), 6.64 (dd, J = 17.4, 10.6 Hz, 1H), 5.18 (dd, J = 10.6, 1.0 Hz, 1H), 4.98 (dd, J = 17.4, 1.0 Hz, 1H), 3.80 (s, 3H), 1.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.2, 148.8, 148.0, 142.0, 138.3, 132.3, 130.7, 130.6, 129.7, 126.8, 116.2, 115.6, 57.8, 53.4, 29.1; HRMS (APCI+, m/z): calculated for C17H17O [M–Br]+: 237.1273, found: 237.1265.

(+)-(R)-3-(2-Bromophenyl)-3-(4-methoxyphenyl)butan-1-ol (4p): Purified by TLC (SiO2, 2% EtOAc/CH2Cl2) to afford 4p (32.0 mg, yield = 60%) as a colourless oil. 99:1 er, Chiralcel AS-H column, n-heptane/i-PrOH 97:3, 40 °C, 225 nm, retention times (min): 34.81 (minor) and 36.02 (major). [α]D20 = +5.8 (c = 0.5 in CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.52 (dd, J = 8.0, 1.6 Hz, 1H), 7.44 (dd, J = 7.8, 1.3 Hz, 1H), 7.27 (td, J = 7.7, 1.4 Hz, 1H), 7.03 (td, J = 7.6, 1.6 Hz, 1H), 6.98 – 6.87 (m, 2H), 6.81 – 6.63 (m, 2H), 3.71 (s, 3H), 3.42 (ddd, J = 10.6, 8.9, 5.8 Hz, 1H), 3.33 (ddd, J = 10.6, 8.6, 5.8 Hz, 1H), 2.88 (ddd, J = 14.1, 8.9, 5.8 Hz, 1H), 2.25 (ddd, J = 13.1, 8.7, 5.9 Hz, 1H), 1.66 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.0, 148.2, 143.5, 138.3, 131.6, 130.6, 130.0, 129.7, 126.8, 116.1, 62.9, 57.7, 48.7, 44.5, 31.9; GC–MS (EI+) m/z (% relative intensity, ion): 8.8 min, 336 (28, M), 334 (30, M), 291 (100, M– C2H5O), 289 (95, M–C2H5O), 210 (30, M–C2H5OBr), 179 (13, M– C3H8OBr).

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34) The product was obtained with an extra 5% (8 mg) of biphenyl, which is present in commercial PhLi and can be easily separated after conversion of the olefin into the corresponding alcohol.

35) The product was obtained with an extra 10% (6 mg) of 1-bromo-4-methylbenzene, which is present in aryllithium solution and can be easily separated after conversion of the olefin into the corresponding alcohol.

36) The product was obtained with an extra 6% (8 mg) of 1-bromo-4-tert-butylbenzene, which is present in aryllithium solution and can be easily separated after conversion of the olefin into the corresponding alcohol.