Regio- and Enantioselective Copper-Catalyzed Allylic Alkylation of Ortho-Substituted Cinnamyl Bromides with Grignard Reagents

Article abstract of DOI:10.1021/acs.joc.5b00371

A highly efficient method for the copper-catalyzed asymmetric allylic alkylation of ortho-substituted cinnamyl bromides with Grignard reagents is reported. The use of a catalytic system comprising CuBr·SMe₂ and TaniaPhos as chiral ligands gives

Full text of DOI:10.1021/acs.joc.5b00371

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Article
Regio- and Enantioselective Copper-Catalyzed Allylic Alkylation
of Ortho-Substituted Cinnamyl Bromides with Grignard Reagents
Nathalie Carolien van der Molen, Theodora D Tiemersma-
Wegman, Martín Fañanás-Mastral, and Ben L. Feringa
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00371 • Publication Date (Web): 22 Apr 2015
Downloaded from http://pubs.acs.org on April 27, 2015
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Regio- and Enantioselective Copper-Catalyzed Allylic Alkylation of
Ortho-Substituted Cinnamyl Bromides with Grignard Reagents
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Nathalie C. van der Molen, Theodora D. TiemersmaꢀWegman, Martín Fañanásꢀ
Mastral*‡ and Ben L. Feringa*
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Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG
Groningen, The Netherlands.
‡Present address: Department of Organic Chemistry and Center for Research in
Biological Chemistry and Molecular Materials (CIQUS), University of Santiago de
Compostela, 15782 Santiago de Compostela, Spain
b.l.feringa@rug.nl, martin.fananas@usc.es
Abstract
A highly efficient method for the copperꢀcatalyzed asymmetric alylic alkylation of
orthoꢀsubstituted cinnamyl bromides with Grignard reagents is reported. The use of a
catalytic system comprising CuBr•SMe2 and TaniaPhos as chiral ligand gives rise to a
range of branched products with excellent regioꢀ and enantioselectivity.
Introduction
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Copperꢀcatalyzed asymmetric allylic alkylation (AAA) has become a powerful tool for
the the introduction of configurationally defined stereogenic carbon atoms.1 Since the
pioneering work of Bäckvall and van Koten,2 in which they described the use of an
arenethiolatoꢀcopper complex for the AAA of allyl esters with Grignard reagents,
several highly efficient methods based on phosphoramidite,3 diphosphine,4 phosphineꢀ
phosphite 5 and NHC ligands6 have been reported for the AAA of different allyl
substrates with these organometallic compounds. While these methodologies usually
afford the corresponding branched products with very high regioꢀ and
enantioselectivity, the use of important orthoꢀsubstituted cinnamyl substrates still
represents a challenge in this field, especially when the AAA is performed with
MeMgBr, as the regioꢀ and enantioselectivity reached decreases significantly (Scheme
1aꢀb).3b,5a
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Scheme 1. Copper-catalyzed AAA of ortho-substituted cinnamyl substrates with
MeMgBr
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a) Alexakis et al. (ref 3b)
Cl
OMe
OMe
CuTC 3 mol%
L1 3.3 mol%
R
X
+ MeMgBr
6
O
O
CH2Cl2, -78 oC
P N
X
7
8
9
X = H: SN2':SN2 89:11
96% ee
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X = OMe: SN2':SN2 84:16
66% ee
L1
b) Schmaltz et al. (ref 5a)
Cl
Ph
CuBr•SMe2 2.5 mol%
L2 3 mol%
R
Ph
Ph
O
O P
O
+ MeMgBr
TBME, -78 oC
X
O
O
X
Ph
PPh2
L2
Ph
X = H: SN2':SN2 98:2
99% ee
X = OMe: SN2':SN2 85:15
93% ee
c) This work
CuBr•SMe2 5 mol%
L3 6 mol%
R
X
PPh2
Ph2P
N
Br
+ MeMgBr
CH2Cl2, -78 oC
X
Fe
X = Br, Cl, CH3, OMe, OTBS
SN2':SN2 up to >99:1
up to 99% ee
L3
(R,R)-TaniaPhos
The resulting orthoꢀsubstituted chiral allyl compounds are of particular importance for
synthetic applications as they can be versatile precursors of carboꢀ and heterocycles
through various cyclization reactions.7 Therefore the development of an efficient and
highly selective catalytic method for the AAA of orthoꢀsubstituted substrates remains an
important goal.
The combination of CuBr•SMe2 with TaniaPhos L3 has emerged as an excellent
catalyst for the introduction of the methyl unit via copperꢀcatalysed AAA.4 However,
the use of this catalytic system has not been reported for the copperꢀcatalyzed AAA of
orthoꢀsubstituted cinammyl substrates. Herein, we present a highly regioꢀ and
enantioselective CuBr•SMe2/TaniaPhos catalyzed AAA of orthoꢀsubstituted cinammyl
bromides with MeMgBr (Scheme 1c). This transformation is also extended to the use of
other Grignard reagents.
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Results and discussion
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We started our investigation by carrying out the reaction between orthoꢀbromo
cinnamyl bromide 1a and MeMgBr in CH2Cl2 at ꢀ78 ºC (Table 1). When we performed
the reaction at this temperature using 1.5 equiv of MeMgBr, branched product 2a was
formed with very good regioselectivity but with incomplete conversion (entry 1). A
longer reaction time slightly improved the conversion but not sufficiently (entry 2).
Complete conversion could be achieved by the use of 3 equiv of MeMgBr at ꢀ78 ºC
which allowed to obtained 2a with near perfect SN2´:SN2 ratio and enantiomeric excess
(99% ee) (entry 4). A higher temperature (ꢀ70 ºC) also helped to reach full conversion
using only 1.5 equiv of MeMgBr, however product 2a was obtained with slightly lower
regioꢀ and enantioselectivity in this case (entry 3).
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Table 1. Optimization of the copper-catalyzed AAA of 1a.
Nº equiv
Entrya
Temp
(oC)
2a ee
(%)d
n.d.f
n.d.f
98
Conv (%)b,c
2a:3ad
MeMgBr
1.5
1
2e
3
ꢀ78
ꢀ78
ꢀ70
ꢀ78
80
94:6
>99:1
96:4
1.5
90
1.5
full (70)
full (71)
4
3.0
99:1
99
aReaction conditions: A solution of 1a (1.0 equiv, 0.25 mmol) in CH2Cl2 (1 mL) added
to a solution of catalyst and MeMgBr in CH2Cl2 (2 mL); reaction run over 16 h.
1
c
bDetermined by HꢀNMR analysis. Yield of isolated product shown in brackets.
dDetermined by GC analysis. eReaction stirred for 48 h. fn.d. = not determined.
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Once having established the optimized conditions for the copperꢀcatalyzed AAA of 1a,
we set out to investigate the compatibility of this method with substrates bearing
different orthoꢀsubstituents (Table 2). To our delight the CuBr•SMe2/TaniaPhos system
proved to be also very efficient for the enantioselective methylation of chloroꢀ, methylꢀ
and alkoxyꢀsubstituted substrates 1b-e leading in all cases to the formation of the
corresponding branched product 2b-e with excellent regioꢀ and enantioselectivity
(entries 2ꢀ5). Different alkyl Grignard reagents were also used in this transformation.
Similarly, the use of EtMgBr and n-HexMgBr in combination with bromoꢀ and
methoxyꢀsubstituted substrates 1a and 1d gave rise to the corresponding products 2 with
excellent selectivities (entries 6ꢀ12). We found that reactions involving EtMgBr proceed
with better selectivities when a solution of 1.1 equiv of this Grignard reagent (reverse
addition) is added to the mixture of catalyst and allyl bromide (entries 6ꢀ7 and 11ꢀ12).
Finally, a decrease in the regioselectivity of the reaction was observed when EtMgBr
was used for the AAA of methylꢀsubstituted substrate 1c, although product 2j was still
obtained with excellent enantioselectivity (entry 12).8 To illustrate the synthetic utility
of the current methodology we performed the synthesis of 2g on a larger scale (0.98
mmol) obtaining the title compound with similar yield and selectivity.
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Table 2. Scope of the reaction
Entrya
Yield (%)b
2:3c
2, ee(%)d
1, X
R
1
1a, Br
Me
71
99:1
2a, 99
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1b, Cl
1c, CH3
1d, OMe
1e, OTBS
1a, Br
Me
Me
Me
Me
Et
69
87
53 f
>99:1
98:2
2b, 98
2c, 98
2d, 96
2e, >99
2f, 99
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4
>99:1
97:3
5
77
6
7e
40
90:10
92:8
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1a, Br
Et
76
2f, 99
8
1a, Br
nꢀHex
Et
87 (76)g
46f
93:7 (91:9)g 2g, 98 (98)g
9
1d, OMe
1d, OMe
1c, CH3
1c, CH3
92:8
94:6
2h, 93
2i, 99
2j, 92
2j, 96
10
11
12e
nꢀHex
Et
45f
90
75:25
78:22
Et
88
aReaction conditions: see Table 1, entry 4. Yield of isolated product. Determined by
b
c
d
e
GC analysis. Determined by GC or HPLC analysis. 1.1 equiv of EtMgBr; reverse
f
g
addition. Lower yields are due to instability of substrate 1d. Reaction performed on a
0.98 mmol scale.
Conclusion
In summary, we have shown that CuBr•SMe2/TaniaPhos is an efficient catalyst for the
AAA of orthoꢀsubstituted cinnamyl substrates. The reaction with MeMgBr proceeds
with excellent regioꢀ and enantioselectivity independent of the nature of the ortho
substituent. Longer alkyl Grignard reagents are also tolerated by this catalytic system
and the corresponding branched products are also obtained with excellent chemoꢀ,
regioꢀ, and enantioselectivities.
Experimental section
General Procedures
Chromatography was performed on silica gel (230ꢀ400 mesh). Thin layer
chromatography was performed on silica plates. Compounds were visualized by UV
and cerium/molybdenum or potassium permanganate staining. Progress and conversion
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of the reaction were determined by GCꢀMS. Mass spectra were recorded on a mass
spectrometer using orbitrap analyzer. 1Hꢀ and 13CꢀNMR were recorded on 400 MHz and
100.59 MHz using CDCl3 as solvent. Chemical shift values are reported in ppm with the
9
1
13
solvent resonance as the internal standard (CHCl3: δ 7.26 for H, δ 77.0 for C). 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 polarimeter with a 10 cm cell (c given in g/100 mL).
Enantiomeric excess values were determined by chiral HPLC analysis using a diode
array detector.
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All reactions were carried out under a nitrogen atmosphere using oven dried glassware
and using standard Schlenk techniques. All reagents, CuBr•SMe2 and TaniaPhos (L3)
were purchased from commercial sources and used without further purification.
Dichloromethane was used from a solvent purification system. Allyl bromides 1 were
synthesized from the corresponding benzaldehydes following a threeꢀsteps Hornerꢀ
WadsworthꢀEmmons/DibalꢀH reduction/PBr3 bromination sequence according to
literature procedures.9
General procedure for the copper-catalyzed AAA of ortho-substituted cinammyl
bromides 1
A Schlenk tube equipped with septum and stirring bar was charged with CuBr•SMe2
(0.01 mmol, 2.05 mg, 5 mol%) and Rp,RꢀTaniaphos (L3) (0.012 mmol, 8.24 mg, 6
mol%). CH2Cl2 (2.0 mL) was added and the solution was stirred for 15 min at room
temperature. The mixture was cooled to ꢀ78 °C and the corresponding Grignard reagent
(solution in Et2O, 3 equiv) was added dropwise. The corresponding allyl bromide 1 (0.2
mmol) was dissolved in CH2Cl2 (0.8 mL) and added dropwise to the reaction mixture
over 1 h via a syringe pump. Once the addition was complete the resulting mixture was
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further stirred at ꢀ78 °C overnight. The reaction was quenched with MeOH (0.5 mL)
and the mixture allowed to reach room temperature. Aqueous NH4Cl solution (2 mL)
was added to the mixture and the organic phase was separated. The resulting aqueous
layer was extracted with Et2O (3 x 5 mL) and the combined organic layers were dried
over MgSO4. The solvent was removed under reduced pressure to yield a yellow oil,
which was purified by flash chromatography (pentane) to yield the corresponding
products 2.
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Note: Regioselectivity was measured by GC analysis carried out on a sample obtained
after aqueous extraction with Et2O, which has been passed through a short plug of silica
gel to remove transition metal residues.
(-)-(S)-1-Bromo-2-(but-3-en-2-yl)benzene (2a). Obtained as a 99:1 mixture of 2a and
1
3a as a colorless oil (71% yield, 2a 99% ee, [α]D20= ꢀ33.5 (c = 1.0 CHCl3). H NMR
(400 MHz, CDCl3) δ 7.55 (d, J = 7.9 Hz, 1H), 7.32ꢀ7.18 (m, 2H), 7.06 (td, J = 2.1, 8.3
Hz, 1H), 6.01 (ddd, J = 5.6, 10.8, 16.8 Hz, 1H), 5.17ꢀ5.05 (m, 2H), 3.99 (quin, J = 6.8
13
Hz, 1H), 1.34 (d, J = 7.0 Hz, 3H). C NMR (100 MHz, CDCl3) δ 144.4, 141.5, 132.9,
128.2, 127.6, 127.6, 124.4, 113.9, 41.1, 19.5. Enantiomeric excess determined by chiral
GC analysis, CPꢀChiralsilꢀDexꢀCB (25 m x 0.25 mm x 0.25 ꢁm), initial temp. 40 °C,
then 10 °C/min to 95°C (final temp) for 45 min, retention times (min): 32.7 (major) and
33.8 (minor); retention time 3a: 53.4 min. HRMS (APCI+, m/z): calcd. for C10H11 [M(ꢀ
HBr)+H] 131.0855, found 131.0853
(-)-(S)-1-Chloro-2-(but-3-en-2-yl)benzene (2b). Obtained as a colorless oil (69% yield,
1
98 % ee, [α]D20 = ꢀ33.8 (c = 0.7 CHCl3). H NMR(400 MHz, CDCl3) δ 7.36 (d, J = 7.9
Hz, 1H), 7.27ꢀ7.19 (m, 2H), 7.14 (td, J = 2.6, 7.9 Hz, 1H), 6.01 (ddd, J = 5.7, 10.8, 16.9
13
Hz, 1H), 5.16ꢀ5.05 (m, 2H), 4.01 (quin, J = 6.6 Hz, 1H), 1.35 (d, J = 7.0 Hz, 3H). C
NMR (100 MHz, CDCl3) δ 142.8, 141.5, 133.5, 129.5, 128.1, 127.3, 126.9, 113.9, 38.8,
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19.3. Enantiomeric excess determined by chiral GC analysis, CPꢀChiralsilꢀDexꢀCB (25
m x 0.25 mm x 0.25 ꢁꢁm), initial temp. 40 °C, then 10 °C/min to 95 °C (final temp) for
40 min, retention times (min): 20.9 (major) and 21.5 (minor). HRMS (APCI+, m/z):
calcd. for C10H11 [M(ꢀHCl)+H] 131.0855, found 131.0853.
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(-)-(S)-1-Methyl-2-(but-3-en-2-yl)benzene (2c). Obtained as a 98:2 mixture of 2c and
3c as a colorless oil (87% yield, 94% conversion, 2c 98% ee), [α]D20 = ꢀ5.8 (c = 1.0
1
CHCl3), (lit.10 (99% ee) [α]D20= ꢀ6.99 (c = 1.0 CHCl3)). H NMR(400 MHz, CDCl3) δ
7.24ꢀ7.06 (m, 4H), 6.00 (ddd, J = 6.2, 10.6, 16.9 Hz, 1H), 5.11ꢀ4.94 (m, 2H), 3.71 (quin,
13
J = 6.6 Hz, 1H), 2.36 (s, 3H), 1.36 (d, J = 7.0 Hz, 3H). C NMR (100 MHz, CDCl3) δ
143.4, 142.8, 135.5, 130.3, 126.2, 126.2, 125.9, 113.0, 38.6, 19.9, 19.4. Enantiomeric
excess determined by chiral GC analysis, CPꢀChiralsilꢀDexꢀCB (25 m x 0.25 mm x 0.25
ꢁm), initial temp. 40 °C, then 10 °C/min to 95 °C (final temp) for 40 min, retention
times (min): 14.8 (minor) and 15.0 (major); retention time 3c: 18.3 min. HRMS
(APCI+, m/z): calcd. for C11H15 [M+H] 147.1168, found 147.1166
(-)-(S)-1-Methoxy-2-(but-3-en-2-yl)benzene (2d). Obtained as a colorless oil (53%
yield, 96% ee, [α]D20 = ꢀ34.2 (c = 0.6, CHCl3), (lit.5a (93% ee, 85:15 SN2':SN2) [α]D20= ꢀ
1
1.9 (c = 0.6 CHCl3)). H NMR(400 MHz, CDCl3) δ 7.23ꢀ7.12 (m, 2H), 6.92 (t, J = 7.5
Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.06 (ddd, J = 6.2, 10.3, 16.5 Hz, 1H), 5.11ꢀ4.97 (m,
2H), 3.93 (quin, J = 6.6 Hz, 1H), 3.84 (s, 3H), 1.32 (d, J = 7.0 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ 156.7, 142.8, 134.0, 134.0, 127.4, 127.0, 125.6, 112.8, 110.5, 35.5,
19.4. Enantiomeric excess determined by chiral GC analysis, Beta DEX tm 225 (30 m x
0.25 mm x 0.25 ꢁm), initial temp. 40°C, then 10 °C/min to 95°C for 5 min, then 0.2
°C/min to 150 °C (final temp) for 20 min, retention times (min): 20.3 (minor) and 20.6
(major). HRMS (APCI+, m/z): calcd. for C11H15O [M+H] 163.1117, found 163.1116.
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(-)-(S)-1-(((tert-butyl)dimethylsilyl)oxy)-2-(but-3-en-2-yl)benzene (2e). Obtained as a
97:3 mixture of 2e and 2e as a colorless oil (77% yield, 5e >99% ee, [α]D = ꢀ26.6 (c =
2.5, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 7.6 Hz, 1H), 7.08 (t, J = 7.3 Hz,
1H), 6.93 (t, J = 7.3 Hz, 1H), 6.81 (d, J = 7.9 Hz, 1H), 6.06 (ddd, J = 5.5, 11.1, 16.4 Hz,
1H), 5.09ꢀ5.00 (m, 2H), 3.95 (quin, J = 6.4 Hz, 1H), 1.31 (d, J = 7.0 Hz, 3H), 1.04 (s,
9H), 0.26 (d, J = 4.1 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 152.7, 142.8, 136.0,
127.7, 126.7, 121.1, 118.4, 112.8, 35.2, 25.8, 19.5, 18.3, ꢀ4.1. Enantiomeric excess
determined by chiral HPLC analysis, Chiralcel ODꢀH column, nꢀheptane/iꢀPrOH 100:0,
40 °C, 210 nm, retention times (min): 8.5 (major) and 9.2 (minor). HRMS (ESI+, m/z):
calcd. for C16H27OSi [M+H] 263.1826, found 263.1816.
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(-)-(S)-1-Bromo-2-(pent-1-en-3-yl)benzene (2f). Obtained as a 92:8 mixture of 2f and
3f as a colorless oil (76% yield, 2f 99% ee, [α]D = ꢀ7.3 (c = 1.0, CHCl3). 1H NMR (400
MHz, CDCl3) δ 7.55 (dd, J = 1.0, 8.1 Hz, 1H), 7.26 (t, J = 3.5 Hz, 1H), 7.20 (dd, J =
1.4, 4.6 Hz, 1H), 7.05 (td, J = 1.8, 8.3 Hz, 1H), 5.91 (ddd, J = 7.2, 10.3, 17.1 Hz, 1H),
5.14ꢀ5.01 (m, 2H), 3.75 (q, J = 7.3 Hz, 1H), 1.82ꢀ1.68 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ 143.4, 140.5, 132.9, 128.4, 127.5, 127.5, 125.0, 115.0,
49.4, 27.9, 11.9. Enantiomeric excess determined by chiral GC analysis, CPꢀChiralsilꢀ
DexꢀCB (25 m x 0.25 mm x 0.25 ꢁm), initial temp. 40 °C, then 10 °C/min to 75°C, then
0.5 °C/min to 120 °C (final temp), retention times (min): 54.3 (major) and 54.8 (minor);
retention time 3f: 83.3 min. HRMS (APCI+, m/z): calcd. for C11H13 [M(ꢀHBr)+H]
145.1012, found 145.1011.
(-)-(S)-1-Bromo-2-(non-1-en-3-yl)benzene (2g). Obtained as a 93:7 mixture of 2g and
3g as a colorless oil (87% yield, 2g 98% ee, [α]D = ꢀ2.4 (c = 1.0, CHCl3). 1H NMR (400
MHz, CDCl3) δ 7.56 (d, J = 7.9 Hz, 1H), 7.32ꢀ7.20 (m, 2H), 7.05 (td, J = 1.8, 8.2 Hz,
1H), 5.93 (ddd, J = 7.3, 9.7, 16.5 Hz, 1H), 5.16ꢀ5.02 (m, 2H), 3.87 (q, J = 7.2 Hz, 1H),
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1.72 (q, J = 7.3 Hz, 2H), 1.43ꢀ1.20 (m, 8H), 0.97ꢀ0.81 (m, 3H). C NMR (100 MHz,
CDCl3) δ 143.6, 140.8, 132.9, 128.4, 127.5, 127.4, 124.9, 114.8, 47.7, 35.0, 31.8, 29.3,
27.3, 22.7, 14.1. Enantiomeric excess determined by chiral GC analysis, Chiraldex Gꢀ
TA (30 m x 0.25 mm x 0.25 ꢁm), initial temp. 40 °C, then 10 °C/min to 95 °C for 5
min, then 2 °C/min to 150 °C (final temp) for 20 min, retention times (min): 37.2
(minor) and 38.3 (major); retention time 3g: 38.6 min. HRMS (APCI+, m/z): calcd. for
C15H21 [M(ꢀHBr)+H] 201.1638, found 201.1634.
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(+)-(S)-1-Methoxy-2-(pent-1-en-3-yl)benzene (2h). Obtained as a 92:8 mixture of 2h
and 3h as a colorless oil (46% yield, 2h 93% ee, [α]D = +7.5 (c = 0.9, CHCl3). 1H NMR
(400 MHz, CDCl3) δ 7.23ꢀ7.10 (m, 2H), 6.93 (t, J = 7.3 Hz, 1H), 6.87 (d, J = 8.2 Hz,
1H), 5.99 (ddd, J = 7.6, 10.0, 17.2 Hz, 1H), 5.07ꢀ4.97 (m, 2H), 3.82 (s, 3H), 3.65 (q, J =
7.3 Hz, 1H), 1.81ꢀ1.63 (m, 2H), 0.88 (t, J = 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
157.1, 141.8, 132.9, 127.8, 126.9, 120.6, 113.9, 55.5, 43.9, 27.4, 12.2. Enantiomeric
excess determined by chiral GC analysis, CPꢀChiralsilꢀDexꢀCB (25 m x 0.25 x 0.25
ꢁm), initial temp. 40 °C, then 10 °C/min to 95 °C (final temp) for 40 min, retention
times (min): 21.9 (major) and 22.1 (minor); retention time 3h: 32.0 min. HRMS
(APCI+, m/z): calcd. for C12H17O [M+H] 177.1274, found 177.1272.
(+)-(S)-1-Methoxy-2-(non-1-en-3-yl)benzene (2i). Obtained as a 94:6 mixture of 2i
and 3i as a colorless oil (45% yield, 2i 99% ee, [α]D = +10.5 (c = 1.0, CHCl3). 1H NMR
(400 MHz, CDCl3) δ 7.22ꢀ7.10 (m, 2H), 6.95ꢀ6.89 (m, 1H), 6.86 (d, J = 7.9 Hz, 1H),
5.98 (ddd, J = 7.7, 10.3, 17.1 Hz, 1H), 5.05ꢀ4.94 (m, 2H), 3.82 (s, 3H), 3.73 (q, J = 7.4
Hz, 1H), 1.72ꢀ1.63 (m, 2H), 1.33ꢀ1.20 (m, 8H), 0.92ꢀ0.83 (m, 3H). 13C NMR (100
MHz, CDCl3) δ 157.0, 142.0, 133.1, 127.8, 126.8, 120.6, 113.6, 110.7, 55.5, 42.11,
34.6, 31.9, 31.8, 29.7, 29.3, 27.5, 22.7, 14.1. Enantiomeric excess determined by chiral
GC analysis, CPꢀChiralsilꢀDexꢀCB (25 m x 0.25 mm x 0.25 ꢁm), initial temp. 40 °C,
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then 10 °C/min to 95 °C for 5 min, then 2 °C/min to 150 °C (final temp) for 20 min,
retention times (min): 40.7 (minor) and 40.8 (major); retention time 3i: 68.1 min.
HRMS (ESI+, m/z): calcd. for C16H25O [M+H] 233.1900, found 233.1890.
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(+)-(S)-1-Methyl-2-(pent-1-en-3-yl)benzene (2j). Obtained as a 78:22 mixture of 2j
and 3j as a colorless oil (88% yield, 2j 96% ee, [α]D = +6.3 (c = 0.2, CHCl3), (lit.11
(83% ee) [α]D20 = +19.6 (c = 0.8 CHCl3)). 1H NMR (400 MHz, CDCl3) δ 7.21ꢀ7.05 (m,
4H), 5.88 (ddd, J = 7.7, 10.3, 17.3 Hz, 1H), 5.05ꢀ4.91 (m, 2H), 3.40 (q, J = 7.4 Hz, 1H),
2.33 (s, 3H), 1.85ꢀ1.66 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
142.4, 141.8, 135.9, 130.3, 126.7, 126.1, 125.4, 114.0, 46.7, 27.9, 19.6, 12.2.
Enantiomeric excess determined by chiral GC analysis, CPꢀChiralsilꢀDexꢀCB (25 m x
0.25 mm x 0.25 ꢁm), initial temp. 40 °C, then 10 °C/min to 75°C, then 0.5 °C/min to
120 °C (final temp), retention times (min): 31.1 (major) and 31.6 (minor); retention time
3j: 52.2 min. MS: m/z 160.1 (21.2, M+), 131.0 (100), 115.0 (29.4), 91.0 (24.3).
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Acknowledgments Financial support from The Netherlands Organization for Scientific
Research (NWOꢀCW), the National Research School of Catalysis (NRSCꢀC) and the
Ministry of Education, Culture and Science (Gravitation Program 024.001.035) is
gratefully acknowledged. We thank M. Smith (GC and HPLC) (University of
Groningen) for technical assistance.
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Supporting Information H, C spectra and GC and HPLC traces for compounds 2.
This material is available free of charge via the Internet at http://pubs.acs.org.
References
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1 For recent reviews, see: a) Harutyunyan, S.; den Hartog, T.; Geurts, K.; Minnaard, A. J.; Feringa, B. L.
Chem. Rev. 2008, 108, 2824ꢀ2852; b) Falciola, C. A.; Alexakis, A. Eur. J. Org. Chem. 2008, 3765ꢀ3780;
c) Alexakis, A.; Bäckvall, J. E.; Krause, N.; Pàmies, O.; Diéguez, M. Chem. Rev. 2008, 108, 2796ꢀ2823;
d) Langlois, J.ꢀB.; Alexakis, A. Top. Organomet. Chem. 2012, 38, 235ꢀ268; e) Baslé, O.; Denicourtꢀ
Nowicki, A.; Crévisy, C.; Mauduit, M. In Copper-Catalyzed Asymmetric Synthesis (Alexakis, A.; Krause,
N.; Woodward, S.; Eds.), WileyꢀVCH, Weinheim, 2014, Chapter 4.
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M.; FañanásꢀMastral, M.; Feringa, B. L. J. Am. Chem. Soc. 2012, 134, 4108ꢀ4111. h) Hornillos, V.;
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8 We have seen in this and previous work (see ref. 4) that MeMgBr in combination with CuBr
•SMe2 and
Taniaphos performs the AAA with excellent selectivity almost independently on the nature of the allyl
bromide. Longer alkyl Grignard reagents behave slightly different and selectivity values sometimes
depend on the nature of the substrate. Here the presence of a coordinating group in the ortho position
might stabilize the intermediate σꢀCu(III) complex and favor a high SN2':SN2 ratio while that stabilization
is not possible with a nonꢀcoordinating group such as Me thus leading to a decrease in regioselectivity. A
similar effect was previously observed in the copperꢀcatalyzed AAA with organolithium reagents:
FañanásꢀMastral, M.; Pérez, M.; Bos, P. H.; Rudolph, A.; Harutyunyan, S. R.; Feringa, B. L. Angew.
Chem. Int. Ed., 2012, 51, 1922ꢀ1925.
9 a) Srikrishna, A.; Satyanarayana, G.; Desai,, U. V. Synth Commun. 2007, 37, 965. b) Marshall, J. A.;
Trometer, J. D.; Cleary, D. G. Tetrahedron, 1989, 45, 391. c) Bussas, R.; Münsterer, H.; Kresze, G. J.
Org. Chem. 1983, 48, 2828. d) Lu, Z.; Shen, M.; Yoon, T. P. J. Am. Chem. Soc. 2011, 133, 1162.
10 Kiuchi, H.; Takahashi, D.; Funaki, K.; Sato, T.; Oi, S. Org. Lett., 2012, 14, 4502ꢀ4505.
11 Lee, Y.; Li, B.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 11625ꢀ11633.
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