Nickel-catalyzed asymmetric cross-couplings of racemic propargylic halides with arylzinc reagents

Article abstract of DOI:10.1021/ja805165y

A stereoconvergent method for the catalytic asymmetric Negishi cross-coupling of racemic secondary propargylic halides with arylzinc reagents has been developed. Neither family of compounds has previously been shown to be a suitable partner in such coupling processes. From a practical point of view, it is noteworthy that the catalyst components (NiCl₂·glyme and pybox ligand 1) are commercially available. Copyright

Full text of DOI:10.1021/ja805165y

Nickel-Catalyzed Asymmetric Cross-Couplings of Racemic Propargylic Halides
with Arylzinc Reagents
Sean W. Smith and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
SUPPORTING INFORMATION
Table of Contents
I. General
1
1
II. Preparation of Substrates
III. Asymmetric Negishi Cross-Coupling Reactions
IV. Determination of Absolute Stereochemistry
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I. General
All reactions were carried out in oven-dried glassware under an atmosphere of
argon. All chemicals, including NiCl2•glyme (Strem), ligand 1 (Aldrich; Strem), ZnEt2
(Strem), and glyme (Fluka), were purchased and used without further purification.
II. Preparation of Substrates
These procedures have not been optimized.
Synthesis of Propargylic Alcohols (representative procedure). A 100-mL flask was
charged with the alkyne (10.0 mmol), evacuated, and back-filled with argon. THF (50
mL) was added via syringe, and then the solution was cooled to –78 °C in a dry
ice/acetone bath. A solution of n-BuLi (1.6 M solution in hexanes; 6.6 mL, 10.5 mmol)
was added dropwise via syringe. After 20 min, the aldehyde (11.0 mmol) was added
via syringe. The solution was allowed to warm to room temperature, and then the
reaction was quenched with sat aq ammonium chloride (25 mL). The layers were
separated, and the aqueous layer was extracted with methylene chloride (2 x 50 mL).
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The combined organic layers were washed with brine (50 mL), dried over MgSO4,
filtered, and concentrated. The resulting oil was purified via flash chromatography
(hexanes/ethyl acetate or pentane/diethyl ether), which furnished the propargylic
alcohol as an oil.
Me2PhSi
OH
n-Bu
(±)-1-(Dimethyl(phenyl)silyl)hept-1-yn-3-ol. Prepared from
(dimethylphenylsilyl)acetylene and valeraldehyde via the representative procedure.
1H NMR (CDCl3, 300 MHz) δ 7.65-7.61 (m, 2H), 7.43-7.38 (m, 3H), 4.41 (t, J = 6.9 Hz,
1H), 1.78-1.64 (m, 2H), 1.49-1.32 (m, 4H), 0.93 (t, J = 6.9 Hz, 3H), 0.43 (s, 6H).
13C NMR (CDCl3, 75 MHz) δ 133.9, 130.3, 129.7, 128.2, 108.9, 87.5, 63.1, 45.3, 37.6,
27.6, 26.2, 22.6, 22.3, 14.3, 14.1.
IR (film) 3384, 2959, 2872, 2361, 2171, 1675, 1428 cm-1.
HRMS (ESI) calcd for C15H22OSi (M+Na+) 269.1332, found 269.1332.
Synthesis of Propargylic Bromides (representative procedure). A 500-mL flask
was charged with imidazole (1.3 g, 19.5 mmol), evacuated, and back-filled with argon.
Methylene chloride (100 mL) was added via syringe, and then the propargylic alcohol
(16.3 mmol). The solution was stirred for 15 min, and then
dibromotriphenylphosphorane (8.24 g, 19.5 mmol) was added. When the reaction was
complete according to TLC analysis, the reaction was quenched by the addition of silica
gel. The solvent was removed under reduced pressure, and then the plug of silica gel
was subjected to flash chromatography (hexanes/ethyl acetate or pentane/diethyl
ether), which furnished the propargylic bromide as an oil.
TMS
Br
Me
(±)-(3-Bromobut-1-ynyl)trimethylsilane [2004440-80-8]. A 500-mL flask was
charged with imidazole (5.8 g, 85 mmol), evacuated, and back-filled with argon.
Methylene chloride (350 mL) was added via syringe, followed by (±)-4-
(trimethylsilyl)but-3-yn-2-ol (11.8 mL, 70.4 mmol). This solution was allowed to stir for
15 min, and then it was cooled to 0 °C. Next, PPh3Br2 (36.0 g, 85.0 mmol) was added,
and then the reaction mixture was removed from the ice bath and allowed to stir at
room temperature for 4 h, at which time TLC showed that the reaction was complete.
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The solvent was removed under reduced pressure, and to the resulting solid was added
Et2O:hexanes (1:1; 300 mL). This mixture was allowed to stir for 30 min. Next, the solid
was removed by filtration, and the solution was concentrated to an oil. The product
was purified by distillation (40 °C, 3.5 torr), which afforded 13.1 g (92%) of a colorless
oil.
TMS
Br
n-Bu
(±)-(3-Bromohept-1-ynyl)trimethylsilane. Prepared from (±)-1-(trimethylsilyl)hept-
1-yn-3-ol via the representative procedure.
1H NMR (CDCl3, 300 MHz) δ 4.48 (t, J = 6.6 Hz, 1H), 1.98 (q, J = 6.6 Hz, 2H), 1.54-1.44
(m, 2H), 1.33 (sextet, J = 7.2 Hz, 2H), 0.92 (t, J = 7.2 Hz, 3H), 0.18-0.16 (m, 9H).
13C NMR (CDCl3, 75 MHz) δ 104.2, 92.0, 39.6, 37.6, 29.7, 22.1, 14.1, –0.02.
IR (film) 2959, 2863, 2361, 2338, 2174, 1457, 1250 cm-1.
HRMS (EI) calcd for C9H16BrSi (M–Me+) 231, found 231.
TMS
Br
O
OEt
3
(±)-Ethyl 6-bromo-8-(trimethylsilyl)oct-7-ynoate. Prepared from (±)-ethyl 6-
hydroxy-8-(trimethylsilyl)oct-7-ynoate via the representative procedure.
1H NMR (CDCl3, 300 MHz) δ 4.47 (t, J = 6.7 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 2.29 (t, J
= 7.1 Hz, 2H), 1.97 (q, J = 6.8 Hz, 2H), 1.63 (sextet, J = 7.1 Hz, 2H), 1.57-1.48 (m, 2H), 1.22
(t, J = 7.1 Hz, 3H), 0.14 (s, 9H).
13C NMR (CDCl3, 75 MHz) δ 173.5, 103.8, 92.2, 60.5, 39.4, 37.1, 34.3, 27.0, 24.2, 14.5, –
0.1.
IR (film) 2958, 2867, 2360, 2340, 2170, 1735, 1457, 1373, 1250, 1181 cm-1.
+
LRMS (EI) calcd for C12H20BrO2Si (M–CH3 ) 303, found 303.
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TMS
Br
4
Et
(±)-(Z)-(3-Bromododec-9-en-1-ynyl)trimethylsilane. Prepared from (±)-(Z)-1-
(trimethylsilyl)dodec-9-en-1-yn-3-ol via the representative procedure.
1H NMR (CDCl3, 300 MHz) δ 5.41-5.26 (m, 2H), 4.49 (t, J = 6.8 Hz, 1H), 2.08-1.94 (m,
6H), 1.57-1.47 (m, 2H), 1.40-1.30 (m, 4H), 0.95 (t, J = 7.5 Hz, 3H), 0.17 (s, 9H).
13C NMR (CDCl3, 75 MHz) δ 132.0, 129.1, 104.2, 92.0, 39.8, 37.6, 29.7, 28.4, 27.4, 27.1,
20.8, 14.6, –0.2.
IR (film) 3005, 2961, 2932, 2857, 2360, 2340, 2172, 1457, 1250 cm-1.
LRMS (EI) calcd for C15H27Si (M–Br+) 235, found 235.
TMS
Br
i-Bu
(±)-(3-Bromo-5-methylhex-1-ynyl)trimethylsilane. Prepared from (±)-5-methyl-1-
(trimethylsilyl)hex-1-yn-3-ol via the representative procedure.
1H NMR (CDCl3, 300 MHz) δ 4.50 (t, J = 7.3 Hz, 1H), 1.94-1.86 (m, 3H), 0.92 (dd, J =
6.5, 2.6 Hz, 6H), 0.16 (s, 9H).
13C NMR (CDCl3, 75 MHz) δ 104.3, 91.9, 48.7, 36.1, 27.0, 22.1, 22.0, 0.01.
IR (film) 2960, 2871, 2360, 2340, 2173, 1469, 1250, 1170 cm-1.
LRMS (EI) calcd for C10H19Si (M–Br+) 167, found 167.
Me2PhSi
Br
n-Bu
(±)-(3-Bromohept-1-ynyl)dimethyl(phenyl)silane. Prepared from (±)-1-
(dimethyl(phenyl)silyl)hept-1-yn-3-ol via the representative procedure.
1H NMR (CDCl3, 300 MHz) δ 7.70-7.60 (m, 2H), 7.45-7.38 (m, 3H), 4.57 (t, J = 6.9 Hz,
1H), 2.10-2.02 (m, 2H), 1.65-1.50 (m, 2H), 1.39 (sextet, J = 7.2 Hz, 2H), 0.96 (t, J = 9.6 Hz,
3H), 0.47-0.44 (m, 6H).
13C NMR (CDCl3, 75 MHz) δ 136.8, 133.4, 129.8, 128.2, 105.9, 90.1, 39.5, 37.4, 29.8,
22.1, 14.2, –0.7.
IR (film) 2959, 2862, 2361, 2339, 1428, 1250, 1116 cm-1.
+
LRMS (EI) calcd for C9H16BrSi (M–C6H5 ) 231, found 231.
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Br
Et
(±)-(3-Bromopent-1-ynyl)cyclohexane. Prepared from (±)-1-cyclohexylpent-1-yn-3-
ol via the representative procedure.
1H NMR (CDCl3, 300 MHz) δ 4.58-4.51 (m, 1H), 2.49-2.38 (m, 1H), 1.98 (quintet, J =
6.1 Hz, 2H), 1.82-1.62 (m, 4H), 1.50-1.24 (m, 6H), 1.06 (t, J = 7.2 Hz, 3H).
13C NMR (CDCl3, 75 MHz) δ 92.6, 79.4, 40.6, 33.8, 32.6, 29.3, 26.1, 24.9, 12.0.
IR (film) 2972, 2932, 2854, 2360, 2340, 2234, 1448, 1173 cm-1.
LRMS (EI) calcd for C11H17 (M–Br+) 149, found 149.
t-Bu
Br
Cl
3
(±)-5-Bromo-8-chloro-2,2-dimethyloct-3-yne. A 300-mL flask was charged with
pyridinium chlorochromate (5.2 g, 24 mmol), evacuated, and back-filled with argon.
CH2Cl2 (100 mL) and 4-chlorobutanol (2.0 mL, 20 mmol) were added, and then the
resulting dark-brown reaction mixture was stirred for 3 h at r.t. Next, Et2O (100 mL)
was added, leading to the precipitation of a brown solid. The mixture was allowed to
stand at r.t. for 2 h, and then it was filtered through a plug of silica gel (washed with
Et2O). The solvent was removed, and the resulting aldehyde was converted into the
propargylic bromide by the two representative procedures described above.
1H NMR (CDCl3, 300 MHz) δ 4.59 (t, J = 6.0 Hz, 1H), 3.58 (t, J = 6.7 Hz, 2H), 2.17-2.08
(m, 2H), 2.05-1.96 (m, 2H), 1.20 (s, 9H).
13C NMR (CDCl3, 75 MHz) δ 97.0, 77.6, 44.2, 37.6, 37.4, 30.9, 30.4, 27.8.
IR (film) 2969, 2867, 2360, 2340, 2236, 1475, 1456, 1363, 1264 cm-1.
LRMS (EI) calcd for C10H16BrCl (M–Br+) 171, found 171.
TMS
Cl
n-Bu
(±)-(3-Chlorohept-1-ynyl)trimethylsilane. Prepared from (±)-1-
(trimethylsilyl)hept-1-yn-3-ol via the representative procedure, substituting
dichlorotriphenylphosphorane for dibromotriphenylphosphorane.
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1H NMR (CDCl3, 300 MHz) δ 4.50 (t, J = 6.8 Hz, 1H), 1.92 (q, J = 7.4 Hz, 2H), 1.55-1.44
(m, 2H), 1.36 (sextet, J = 7.7 Hz, 2H), 0.92 (t, J = 7.2 Hz, 3H), 0.18-0.16 (m, 9H).
13C NMR (CDCl3, 75 MHz) δ 103.6, 91.1, 49.1, 39.0, 28.5, 22.1, 14.1, 0.0.
IR (film) 2960, 2934, 2874, 2864, 2361, 2339, 2179, 1465, 1457, 1251 cm-1.
LRMS (EI) calcd for C9H16ClSi (M–Me+) 187, found 187.
III. Asymmetric Negishi Cross-Coupling Reactions
Synthesis of Arylzinc Reagents (General Procedure). In a glovebox, Et2Zn (neat;
366 µL, 3.5 mmol) was added dropwise to a solution of the boronic acid (2.5 mmol) in
glyme (5.0 mL) in a 20-mL vial. The vial capped and heated at 60 °C for 12 h.
Asymmetric Cross-Coupling (General Procedure). In a glovebox, a 4-mL vial was
charged with NiCl2•glyme (3.3 mg, 0.015 mmol), (–)-1 (7.7 mg, 0.020 mmol), and glyme
(1.3 mL). The solution was stirred for 10 min, and then the arylzinc reagent was added
(0.50 M in glyme; 2.0 mL, 1.0 mmol). Next, the vial was capped with a septum and
removed from the glovebox. The reaction mixture was stirred for 10 min at room
temperature, placed in a –20 °C bath, and then stirred for 10 min. The propargylic
bromide (0.50 mmol) was added via syringe, and then the reaction mixture was stirred
for 14 h at –20 °C. Next, the excess arylzinc reagent was quenched with ethanol (0.3
mL), and the reaction mixture was passed through a short plug of silica (eluting with
1:1 hexanes:Et2O) in order to remove inorganic salts and most of the glyme. The filtrate
was concentrated, and the resulting oil was purified by flash chromatography.
Trimethyl(3-phenylhept-1-ynyl)silane (eq 2). In a glovebox, a 4-mL vial was
charged with NiCl2•glyme (8.2 mg, 0.038 mmol), (–)-1 (19.1 mg, 0.049 mmol), and glyme
(1.25 mL). The solution was stirred for 10 min, and then a solution of ZnPh2 (Strem,
99%; 153 mg, 0.70 mmol, 1.4 equiv; in 1.25 mL of glyme) was added. Next, the vial was
capped with a septum and removed from the glovebox. The reaction mixture was
stirred for 10 min at room temperature, placed in a –20 °C bath, and then stirred for 10
min. (±)-(3-Bromohept-1-ynyl)trimethylsilane (124 mg, 0.50 mmol) was added via
syringe, and then the reaction mixture was stirred for 1 h at –20 °C. Next, the excess
arylzinc reagent was quenched with ethanol (0.3 mL), and the reaction mixture was
passed through a short plug of silica (eluting with 1:1 hexanes:Et2O) in order to remove
inorganic salts and most of the glyme. The filtrate was concentrated, and the resulting
oil was purified by flash chromatography (0→5% Et2O in hexanes), which furnished the
title compound as a colorless oil (98.0 mg, 80% yield) with 91% ee (for characterization
data and information on the ee assay, see the description of eq 3).
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Trimethyl(3-phenylhept-1-ynyl)silane (eq 3). The compound was prepared
according to the General Procedure with (±)-(3-bromohept-1-ynyl)trimethylsilane (124
mg, 0.50 mmol). After purification by flash chromatography (0→5% Et2O in hexanes),
the title compound was isolated as a colorless oil (110 mg, 90% yield) with 92% ee.
[α]D22 = +12 (c = 1.0, CHCl3). Chiral GC analysis of the product: Chirasil Dex CB
column; method: 100 °C→130 °C @ 10 °C/min, hold 10 min, then →170 °C @ 9 °C/min,
hold 5 min; flow rate 1.0 mL/min; retention times: 15.5 min (major), 15.3 min (minor).
1H NMR (CDCl3, 500 MHz) δ 7.37-7.23 (m, 5H), 3.65 (t, J = 7.2 Hz, 1H), 1.77-1.72 (m,
2H), 1.48-1.29 (m, 4H), 0.91 (t, J = 7.1 Hz, 3H), 0.26 (s, 9H).
13C NMR (CDCl3, 125 MHz) δ 142.3, 128.6, 127.7, 126.8, 108.8, 87.2, 39.0, 38.7, 29.7,
22.6, 14.2, 0.4.
IR (film) 3086, 3063, 3029, 2958, 2934, 2873, 2860, 2361, 2339, 2172, 1494, 1453, 1249
cm-1.
LRMS (EI) calcd for C16H24Si (M+) 244, found 244.
(3-(Benzo[d][1,3]dioxol-5-yl)but-1-ynyl)trimethylsilane (Table 1, entry 1). The
compound was prepared according to the General Procedure with (±)-(3-bromobut-1-
ynyl)trimethylsilane (103 mg, 0.50 mmol). After purification by flash chromatography
(0→5% Et2O in hexanes), the title compound was isolated as a colorless oil (100 mg, 69%
yield) with 95% ee.
[α]D22 = +9.5 (c = 1.0, CHCl3). HPLC analysis of the product: Daicel CHIRALPAK OJ-
H column; solvent system: 100% hexanes; 1.0 mL/min; retention times: 6.5 min (major),
6.9 min (minor).
The second run was performed with (+)-1. The product was isolated as a colorless
oil (103 mg, 72% yield) with 91% ee.
1H NMR (CDCl3, 300 MHz) δ 6.89 (d, J = 1.7 Hz, 1H), 6.81 (dd, J = 8.0 Hz, 1.7 Hz,
1H), 6.75 (d, J = 8.0 Hz, 1H), 5.94 (s, 2H), 3.70 (q, J = 14.3 Hz, 1H), 1.43 (d, J = 7.1 Hz, 3H),
0.17 (s, 9H).
13C NMR (CDCl3, 75 MHz) δ 147.9, 146.4, 137.3, 120.1, 109.7, 108.4, 107.7, 101.1, 86.4,
32.8, 25.1, 0.4.
IR (film) 2961, 2930, 2897, 2777, 2361, 2339, 2169, 1505, 1487, 1438, 1297, 1249 cm-1.
LRMS (EI) calcd for C14H18O2Si (M+) 246, found 246.
Trimethyl(3-p-tolylhept-1-ynyl)silane (Table 1, entry 2). The compound was
prepared according to the General Procedure with (±)-(3-bromohept-1-
ynyl)trimethylsilane (124 mg, 0.50 mmol). After purification by flash chromatography
(0→5% Et2O in hexanes), the title compound was isolated as a colorless oil (121 mg, 94%
yield) with 94% ee.
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[α]D22 = +7.7 (c = 1.0, CHCl3). Chiral GC analysis of the product: Chirasil Dex CB
column; method: 100 °C→130 °C @ 10 °C/min, hold 10 min, then →170 °C @ 9 °C/min,
hold 5 min; flow rate 1.0 mL/min; retention times: 18.0 min (major), 17.9 min (minor).
The second run was performed with (+)-1. The product was isolated as a colorless
oil (116 mg, 90% yield) with 92% ee.
1H NMR (CDCl3, 300 MHz) δ 7.23 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 8.2 Hz, 2H), 3.59 (t, J
= 7.2 Hz, 1H), 2.33 (s, 3H), 1.74-1.66 (m, 2H), 1.44-1.25 (m, 4H), 0.88 (t, J = 7.0 Hz, 3H),
0.17 (s, 9H).
13C NMR (CDCl3, 75 MHz) δ 139.3, 136.3, 129.3, 127.6, 109.1, 86.9, 38.7, 38.6, 29.7,
22.6, 21.3, 14.2, 0.5.
IR (film) 2958, 2933, 2860, 2360, 2340, 1271, 1513, 1457, 1249 cm-1.
LRMS (EI) calcd for C17H26Si (M+) 258, found 258.
Trimethyl(3-(naphthalen-2-yl)hept-1-ynyl)silane (Table 1, entry 3). The compound
was prepared according to the General Procedure, except that 6.0% catalyst, 7.8% (–)-1,
and 3.0 equiv of the arylzinc reagent were used, with (±)-(3-bromohept-1-
ynyl)trimethylsilane (124 mg, 0.50 mmol). After purification by flash chromatography
(0→4% Et2O in hexanes), the title compound was isolated as a colorless oil (107 mg, 72%
yield) with 93% ee.
[α]D22 = +2.6 (c = 1.0, CHCl3). HPLC analysis of the product: Daicel CHIRALPAK
OD-H column; solvent system: 100% hexanes; 1.0 mL/min; retention times: 8.3 min
(major), 11.2 min (minor).
The second run was performed with (+)-1. The product was isolated as a colorless
oil (100 mg, 68% yield) with 92% ee.
1H NMR (CDCl3, 300 MHz) δ 7.83-7.78 (m, 4H), 7.50-7.43 (m, 3H), 3.79 (t, J = 7.1 Hz,
1H), 1.85-1.77 (m, 2H), 1.46-1.29 (m, 4H), 0.88 (t, J = 7.0 Hz, 3H), 0.21-0.20 (m, 9H).
13C NMR (CDCl3, 75 MHz) δ 139.7, 133.7, 132.6, 128.3, 128.0, 127.9, 126.3, 126.2, 126.1,
125.7, 108.8, 87.5, 39.1, 38.4, 29.7, 22.7, 14.3, 0.5.
IR (film) 3055, 2958, 2859, 2361, 2340, 2169, 1943, 1507, 1457, 1249 cm-1.
LRMS (EI) calcd for C20H26Si (M+) 294, found 294.
(3-(2-Methoxyphenyl)hept-1-ynyl)trimethylsilane (Table 1, entry 4). The
compound was prepared according to the General Procedure (except that the reaction
was run at room temperature for 6 h, and the arylzinc reagent was prepared in toluene),
with (±)-(3-bromohept-1-ynyl)trimethylsilane (124 mg, 0.50 mmol) and the arylzinc
reagent (~0.3 M in toluene; 3.3 mL, 1.0 mmol). After purification by flash
chromatography (0→5% Et2O in hexanes), the title compound was isolated as a
colorless oil (51.0 mg, 37% yield) with 91% ee.
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[α]D22 = +16 (c = 1.0, CHCl3). HPLC analysis of the product: Daicel CHIRALPAK OD
column; solvent system: 100% hexanes; 0.2 mL/min; retention times: 23.7 min (major),
24.8 min (minor).
The second run was performed with (+)-1. The product was isolated as a colorless
oil (56.0 mg, 41% yield) with 92% ee).
1H NMR (CDCl3, 300 MHz) δ 7.53 (dd, J = 7.5, 1.7 Hz, 1H), 7.21 (td, J = 8.1, 5.7 Hz,
1H), 6.98-6.95 (m, 1H), 6.85-6.83 (m, 1H), 4.12 (dd, J = 8.6, 5.2 Hz, 1H), 3.82 (s, 3H), 1.74-
1.67 (m, 1H), 1.63-1.55 (m, 1H), 1.47-1.26 (m, 4H), 0.89 (t, J = 7.2 Hz, 3H), 0.18 (s, 9H).
13C NMR (CDCl3, 75 MHz) δ 156.3, 130.7, 128.7, 127.8, 120.8, 110.5, 109.5, 86.3, 55.6,
36.7, 32.0, 29.7, 22.5, 14.2, 0.5.
IR (film) 2958, 2860, 2836, 2360, 2340, 2169, 1600, 1588, 1492, 1464, 1438, 1246 cm-1.
LRMS (EI) calcd for C17H26OSi (M+) 274, found 274.
Ethyl 6-(4-(tert-butoxymethyl)phenyl)-8-(trimethylsilyl)oct-7-ynoate (Table 1,
entry 5). The compound was prepared according to the General Procedure with (±)-
ethyl 6-bromo-8-(trimethylsilyl)oct-7-ynoate (153 mg, 0.50 mmol). After purification by
flash chromatography (0→12% Et2O in hexanes), the title compound was isolated as a
colorless oil (153 mg, 76% yield) with 94% ee.
[α]D22 = +7.0 (c = 1.0, CHCl3). HPLC analysis of the product: Daicel CHIRALPAK OD
column; solvent system: 0.2% i-PrOH in hexanes; 0.1 mL/min; retention times: 57.5 min
(major), 62.9 min (minor).
The second run was performed with (+)-1. The product was isolated as a colorless
oil (151 mg, 75% yield) with 94% ee.
1H NMR (CDCl3, 300 MHz) δ 7.28 (br s, 4H), 4.42 (s, 2H), 4.10 (q, J = 7.1 Hz, 2H), 3.61
(t, J = 7.3 Hz, 1H), 2.27 (t, J = 7.3 Hz, 2H), 1.75-1.57 (m, 4H), 1.50-1.32 (m, 2H), 1.29 (s,
9H), 1.24 (t, J = 7.1 Hz, 3H), 0.16 (s, 9H).
13C NMR (CDCl3, 75 MHz) δ 173.9, 140.8, 138.4, 127.9, 127.6, 108.6, 87.3, 73.6, 64.1,
60.4, 38.5, 38.3, 34.5, 27.9, 27.0, 24.9, 14.5, 0.4.
IR (film) 2973, 2864, 2360, 2340, 2171, 1734, 1388, 1363 cm-1.
LRMS (EI) calcd for C23H35O3Si (M–Me+) 387, found 387.
(Z)-(3-(3-Methoxyphenyl)dodec-9-en-1-ynyl)trimethylsilane (Table 1, entry 6).
The compound was prepared according to the General Procedure with (±)-(Z)-(3-
bromododec-9-en-1-ynyl)trimethylsilane (158 mg, 0.50 mmol). After purification by
flash chromatography (0→4% Et2O in hexanes), the title compound was isolated as a
colorless oil (135 mg, 79% yield) with 94% ee.
July 4, 2008
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[α]D22 = +16 (c = 1.0, CHCl3). HPLC analysis of the product: Daicel CHIRALPAK
OD-H column; solvent system: 100% hexanes; 1.0 mL/min; retention times: 11.4 min
(major), 8.7 min (minor).
The second run was performed with (+)-1. The product was isolated as a colorless
oil (133 mg, 78% yield) with 94% ee.
1H NMR (CDCl3, 300 MHz) δ 7.26-7.21 (m, 1H), 6.95-6.90 (m, 2H), 6.80-6.76 (m, 1H),
5.43-5.27 (m, 2H), 3.82 (s, 3H), 3.62 (t, J = 7.2 Hz, 1H), 2.08-1.96 (m, 4H), 1.78-1.68 (m,
2H), 1.48-1.25 (m, 6H), 0.96 (t, J = 7.4 Hz, 3H), 0.19 (s, 9H).
13C NMR (CDCl3, 75 MHz) δ 159.9, 143.9, 131.9, 129.6, 129.4, 120.1, 113.3, 112.2, 108.7,
87.4, 55.4, 39.0, 38.7, 29.8, 29.0, 27.3, 27.2, 20.7, 16.6, 0.4.
IR (film) 3003, 2933, 2856, 2360, 2340, 2171, 1601, 1586, 1488, 1456, 1436 cm-1.
LRMS (EI) calcd for C22H34OSi (M+) 342, found 342.
(3-(Benzo[d][1,3]dioxol-5-yl)-5-methylhex-1-ynyl)trimethylsilane (Table 1, entry
7). The compound was prepared according to the General Procedure with (±)-(3-
bromo-5-methylhex-1-ynyl)trimethylsilane (124 mg, 0.50 mmol). After purification by
flash chromatography (0→5% Et2O in hexanes), the title compound was isolated as a
colorless oil (100 mg, 69% yield) with 95% ee.
[α]D22 = +10 (c = 1.0, CHCl3). HPLC analysis of the product: Daicel CHIRALPAK OJ-
H column; solvent system: 100% hexanes; 1.0 mL/min; retention times: 5.0 min (major),
5.5 min (minor).
The second run was performed with (+)-1. The product was isolated as a colorless
oil (103 mg, 72% yield) with 91% ee.
1H NMR (CDCl3, 300 MHz) δ 6.86 (d, J = 1.6 Hz, 1H), 6.75 (d, J = 1.5 Hz, 1H), 6.74 (d,
J = 0.6 Hz, 1H), 5.94 (s, 2H), 3.59 (dd, J = 9.2, 6.6 Hz, 1H), 1.82-1.59 (m, 2H), 1.49-1.39 (m,
1H), 0.92 (d, J = 6.5 Hz, 6H), 0.16 (s, 9H).
13C NMR (CDCl3, 75 MHz) δ 147.9, 146.4, 136.5, 120.6, 108.9, 108.3, 108.1, 101.1, 87.0,
48.4, 36.8, 26.1, 23.1, 22.2, 0.4.
IR (film) 2957, 2870, 2776, 2361, 2339, 2168, 1504, 1487, 1249 cm-1.
LRMS (EI) calcd for C17H24O2Si (M+) 288, found 288.
(3-(4-Fluorophenyl)hept-1-ynyl)dimethyl(phenyl)silane (eq 4). The compound
was prepared according to the General Procedure with (±)-(3-bromohept-1-
ynyl)dimethyl(phenyl)silane (155 mg, 0.50 mmol). After purification by flash
chromatography (0→5% Et2O in hexanes), the title compound was isolated as a
colorless oil (140 mg, 86% yield) with 90% ee.
[α]D22 = –7.3 (c = 1.0, CHCl3). Chiral GC analysis of the desilylated product: Chirasil
Dex CB column; method: 100 °C→130 °C @ 10 °C/min, hold 10 min, then →170 °C @ 9
July 4, 2008
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°C/min, hold 5 min; flow rate 1.0 mL/min; retention times: 8.2 min (major), 8.4 min
(minor).
The second run was performed with (+)-1. The product was isolated as a colorless
oil (145 mg, 89% yield) with 85% ee.
1H NMR (CDCl3, 300 MHz) δ 7.67-7.63 (m, 2H), 7.40-7.29 (m, 5H), 7.00 (t, J = 8.8 Hz,
2H), 3.67 (t, J = 7.2 Hz, 1H), 1.78-1.68 (m, 2H), 1.45-1.26 (m, 4H), 0.89 (t, J = 7.1 Hz, 3H),
0.43-0.41 (m, 6H).
13C NMR (CDCl3, 75 MHz) δ 137.8, 133.9, 129.6, 129.2, 129.1, 128.1, 115.6, 115.3, 110.5,
85.5, 38.7, 38.4, 29.7, 22.6, 14.3, –0.3.
19F NMR (CDCl3, 282 MHz) δ –117.0.
IR (film) 3069, 2958, 2932, 2860, 2360, 2340, 2172, 1604, 1508, 1428, 1249 cm-1.
LRMS (EI) calcd for C21H25FSi (M+) 324, found 324.
(3-(4-tert-Butylphenyl)pent-1-ynyl)triisopropylsilane (eq 5). The compound was
prepared according to the General Procedure with (±)-(3-bromopent-1-
ynyl)triisopropylsilane (152 mg, 0.50 mmol). After purification by flash
chromatography (0→4% Et2O in hexanes), the title compound was isolated as a
colorless oil (136 mg, 77% yield) with 92% ee.
[α]D22 = +14 (c = 1.0, CHCl3). Chiral GC analysis of the desilylated product: Chirasil
Dex CB column; method: 100 °C→130 °C @ 10 °C/min, hold 10 min, then →170 °C @ 9
°C/min, hold 5 min; flow rate 1.0 mL/min; retention times: 15.2 min (major), 15.8 min
(minor).
The second run was performed with (+)-1. The product was isolated as a colorless
oil (150 mg, 84% yield) with 93% ee.
1H NMR (CDCl3, 300 MHz) δ 7.35-7.28 (m, 4H), 3.63 (dd, J = 8.4, 5.3 Hz, 1H), 1.88-
1.62 (m, 2H), 1.32 (s, 9H), 1.10-1.08 (m, 21H), 1.02 (t, J = 7.3 Hz, 3H).
13C NMR (CDCl3, 75 MHz) δ 149.4, 139.0, 127.4, 125.4, 110.2, 83.4, 40.1, 34.7, 32.4,
31.7, 19.0, 12.0, 11.6.
IR (film) 2961, 2865, 2361, 2340, 2169, 1507, 1463 cm-1.
LRMS (EI) calcd for C24H40Si (M+) 356, found 356.
6-(Hex-4-yn-3-yl)-2,3-dihydrobenzo[b][1,4]dioxine (Table 2, entry 1). The
compound was prepared according to the General Procedure with (±)-4-bromohex-2-
yne (80.5 mg, 0.50 mmol). After purification by flash chromatography (0→4% Et2O in
hexanes), the title compound was isolated as a colorless oil (87.0 mg, 81% yield) with
90% ee.
July 4, 2008
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[α]D22 = +4.8 (c = 1.0, CHCl3). Chiral GC analysis of the product: Chirasil Dex CB
column; method: 100 °C→190 °C @ 5 °C/min, hold 30 min; flow rate 1.0 mL/min;
retention times: 12.0 min (major), 11.9 min (minor).
The second run was performed with the (+)-1. The product was isolated as a
colorless oil (87.6 mg, 81% yield) with 86% ee.
1H NMR (CDCl3, 300 MHz) δ 6.90-6.86 (m, 1H), 6.79 (d, J = 1.2 Hz, 2H), 4.24 (s, 4H),
3.43-3.35 (m, 1H), 1.85 (d, J = 2.5 Hz, 3H), 1.73-1.63 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H).
13C NMR (CDCl3, 75 MHz) δ 143.4, 142.3, 136.4, 120.6, 117.2, 116.4, 81.1, 78.5, 64.6,
64.5, 38.9, 31.9, 12.0, 3.9.
IR (film) 2967, 2931, 2874, 2361, 2339, 1952, 1734, 1683, 1590, 1506 cm-1.
LRMS (EI) calcd for C14H16O2 (M+) 216, found 216.
5-(Hex-4-yn-3-yl)-1-methyl-1H-indole (Table 2, entry 2). The compound was
prepared according to the General Procedure, except that 6.0% catalyst, 7.8% (–)-1, and
3.0 equiv of the arylzinc reagent were used, with (±)-4-bromohex-2-yne (80.5 mg, 0.50
mmol). After purification by flash chromatography (0→25% CH Cl in hexanes), the
2
2
title compound was isolated as a colorless oil (84.0 mg, 80% yield) with 86% ee.
[α]D22 = +3.6 (c = 0.5, CHCl3). HPLC analysis of the product: Daicel CHIRALPAK
OD-H column; solvent system: 2.0% i-PrOH in hexanes; 1.0 mL/min; retention times:
7.9 min (major), 8.5 min (minor).
The second run was performed with (+)-1. The product was isolated as a colorless
oil (80.5 mg, 76% yield) with 82% ee.
1H NMR (CDCl3, 300 MHz) δ 7.66-7.65 (m, 1H), 7.33-7.25 (m, 2H), 7.07 (d, J = 3.0 Hz,
1H), 6.50 (dd, J = 3.1, 0.7 Hz, 1H), 3.79 (s, 3H), 3.70-3.63 (m, 1H), 1.94 (d, J = 2.4 Hz, 3H),
1.86 (quintet, J = 7.2 Hz, 2H), 1.05 (t, J = 7.3 Hz, 3H).
13C NMR (CDCl3, 75 MHz) δ 135.9, 133.9, 129.3, 128.7, 121.6, 119.6, 109.3, 101.0, 82.2,
78.1, 39.8, 33.1, 32.4, 12.3, 4.0.
IR (film) 2962, 2927, 2871, 2819, 2360, 2340, 1513, 1490 cm-1.
LRMS (EI) calcd for C15H17N (M+) 211, found 211.
1-(Hex-3-yn-2-yl)-4-methoxybenzene (Table 2, entry 3). The compound was
prepared according to the General Procedure with (±)-2-bromohex-3-yne (80.5 mg, 0.50
mmol). After purification by flash chromatography (0→4% Et2O in hexanes), the title
compound was isolated as a colorless oil (70.5 mg, 75% yield) with 93% ee.
[α]D22 = –2.7 (c = 0.50, CHCl3). Chiral GC analysis of the product: Chirasil Dex CB
column; method: 100 °C→130 °C @ 10 °C/min, hold 10 min, then →170 °C @ 9 °C/min,
hold 5 min; flow rate 1.0 mL/min; retention times: 15.8 min (major), 15.6 min (minor).
July 4, 2008
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The second run was performed with (+)-1. The product was isolated as a colorless
oil (72.6 mg, 77% yield) with 89% ee.
1H NMR (CDCl3, 300 MHz) δ 7.29 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 3.79 (s,
3H), 3.69 (qt, J = 7.1, 2.3 Hz, 1H), 2.22 (qd, J = 7.5, 2.2 Hz, 2H), 1.43 (d, J = 7.1 Hz, 3H),
1.15 (t, J = 7.5 Hz, 3H).
13C NMR (CDCl3, 75 MHz) δ 158.4, 136.5, 128.0, 114.0, 83.7, 82.7, 55.5, 31.2, 25.2, 14.6,
12.8.
IR (film) 2973, 2935, 2839, 2361, 2339, 2057, 1734, 1676, 1601, 1511 cm-1.
LRMS (EI) calcd for C13H16O (M+) 188, found 188.
1-(1-Cyclohexylpent-1-yn-3-yl)-4-methoxybenzene (Table 2, entry 4). The
compound was prepared according to the General Procedure with (±)-(3-bromopent-1-
ynyl)cyclohexane (115 mg, 0.50 mmol). After purification by flash chromatography
(0→5% Et2O in hexanes), the title compound was isolated as a colorless oil (81.9 mg,
64% yield) with 89% ee.
[α]D22 = +6.3 (c = 1.0, CHCl3). HPLC analysis of the product: Daicel CHIRALPAK OJ-
H column; solvent system: 100% hexanes; 1.0 mL/min; retention times: 8.8 min (major),
12.8 min (minor).
The second run was performed with (+)-1. The product was isolated as a colorless
oil (77.6 mg, 61% yield) with 89% ee.
1H NMR (CDCl3, 300 MHz) δ 7.27 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 3.79 (s,
3H), 3.51 (ddd, J = 13.8, 5.9, 2.0 Hz, 1H), 2.47-2.37 (m, 1H), 1.86-1.62 (m, 6H), 1.52-1.38
(m, 3H), 1.38-1.24 (m, 3H), 0.96 (t, J = 7.2 Hz, 3H).
13C NMR (CDCl3, 75 MHz) δ 158.3, 135.3, 128.6, 113.8, 87.7, 81.9, 55.4, 38.7, 33.3, 32.4,
29.4, 26.2, 25.1, 11.9.
IR (film) 2927, 2853, 2361, 2339, 1884, 1611, 1508, 1448 cm-1.
LRMS (EI) calcd for C18H24O (M+) 256, found 256.
1-(1-Chloro-7,7-dimethyloct-5-yn-4-yl)-4-methylbenzene (Table 2, entry 5). The
compound was prepared according to the General Procedure with (±)-5-bromo-8-
chloro-2,2-dimethyloct-3-yne (126 mg, 0.50 mmol). After purification by flash
chromatography (0→5% Et2O in hexanes), the title compound was isolated as a
colorless oil (109 mg, 83% yield) with 92% ee.
[α]D22 = –2.6 (c = 1.0, CHCl3). Chiral GC analysis of the product: Chirasil Dex CB
column; method: 100 °C→170 °C @ 10 °C/min, hold 20 min, then →190 °C @ 10
°C/min, hold 5 min; flow rate 1.0 mL/min; retention times: 14.0 min (major), 13.8 min
(minor).
July 4, 2008
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The second run was performed with (+)-1. The product was isolated as a colorless
oil (104 mg, 79% yield) with 91% ee.
1H NMR (CDCl3, 300 MHz) δ 7.25 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 7.8 Hz, 2H), 3.63-
3.55 (m, 2H), 3.54 (t, J = 6.3 Hz, 1H), 2.33 (s, 3H), 1.95-1.67 (m, 4H), 1.24 (s, 9H).
13C NMR (CDCl3, 75 MHz) δ 139.7, 136.3, 129.3, 127.4, 92.7, 79.6, 45.2, 36.8, 36.4, 31.6,
30.5, 27.7, 21.3.
IR (film) 2967, 2361, 2340, 1684, 1607, 1456 cm-1.
LRMS (EI) calcd for C17H23Cl (M+) 262, found 262.
Pent-1-yne-1,3-diyldibenzene (Table 2, entry 6). The compound was prepared
according to the General Procedure with (±)-(3-bromopent-1-ynyl)benzene (112 mg, 0.50
mmol). After purification by flash chromatography (0→4% Et2O in hexanes), the title
compound was isolated as a colorless oil (92.1 mg, 84% yield) with 89% ee.
[α]D22 = –4.5 (c = 1.6, CHCl3). HPLC analysis of the product: Daicel CHIRALPAK OJ-
H column; solvent system: 100% hexanes; 1.0 mL/min; retention times: 21.7 min
(major), 20.2 min (minor).
The second run was performed with (+)-1. The product was isolated as a colorless
oil (89.0 mg, 81% yield) with 88% ee.
1H NMR (CDCl3, 300 MHz) δ 7.47-7.25 (m, 10H), 3.79 (t, J = 7.5 Hz, 1H), 1.92-1.81 (m,
2H), 1.01 (t, J = 7.3 Hz, 3H).
13C NMR (CDCl3, 75 MHz) δ 142.2, 131.9, 128.7, 128.0, 127.8, 126.9, 124.1, 91.7, 83.6,
40.2, 32.0, 12.2.
IR (film) 2968, 2361, 2339, 2200, 1684, 1598, 1559, 1490 cm-1.
LRMS (EI) calcd for C17H16 (M+) 220, found 220.
Trimethyl(3-phenylhept-1-ynyl)silane (eq 6). The compound was prepared
according to the General Procedure with (±)-(3-chlorohept-1-ynyl)trimethylsilane (101
mg, 0.50 mmol) (Note: the reaction was run for 48 h). After purification by flash
chromatography (0→5% Et2O in hexanes), the title compound was isolated as a
colorless oil (76 mg, 62% yield) with 91% ee.
The second run was performed with (+)-1. The product was isolated as a colorless
oil (73 mg, 60% yield) with 91% ee. For characterization data, see the description of eq
3.
July 4, 2008
S–14

OMe
OMe
OMe
H
Me
5-(But-3-yn-2-yl)-1,2,3-trimethoxybenzene [931103-15-0] (Scheme 1). In a glovebox,
a 100-mL flask was charged with NiCl2•glyme (33 mg, 0.15 mmol), (–)-1 (77 mg, 0.20
mmol), and glyme (8.3 mL). The solution was stirred for 10 min, and then the arylzinc
reagent was added (0.50 M in glyme; 20.0 mL, 10.0 mmol). Next, the flask was capped
with a septum and removed from the glovebox. The reaction mixture was stirred for 10
min at room temperature, and then (±)-(3-bromobut-1-ynyl)trimethylsilane (1.03 g, 5.0
mmol) was added via syringe. The reaction mixture was stirred for 6 h at room
temperature, and then the excess arylzinc reagent was quenched with ethanol (2.0 mL).
The mixture was passed through a short plug of silica (eluting with 1:1 hexanes:Et2O) in
order to remove inorganic salts and most of the glyme. The filtrate was concentrated,
and to the resulting oil was added methanol (25 mL) and K2CO3 (2.0 g, 15 mmol). The
resulting heterogeneous mixture was stirred at room temperature for 1 h. The mixture
was then diluted with EtOAc (~25 mL) and washed with aq HCl (1 M). The aqueous
layer was extracted with EtOAc (2 x 75 mL), and then the combined organic layers were
washed with brine, dried over MgSO4, filtered, and concentrated. The resulting oil was
purified by flash chromatography (20% Et2O in hexanes; residual 1,2,3-
trimethoxybenzene (from quenching of the arylzinc reagent) was removed under
reduced pressure and gentle heating (200 mtorr, 50 °C)), which furnished the desired
product as a light-yellow oil (725 mg, 66%; 92% ee).
[α]D22 = +13 (c = 1.0, CHCl3). HPLC analysis of the product: Daicel CHIRALPAK OJ-
H column; solvent system: 1.0% i-PrOH in hexanes; 1.0 mL/min; retention times: 25.0
min (major), 21.2 min (minor).
1H NMR (CDCl3, 300 MHz) δ 6.61 (s, 2H), 3.87 (s, 6H), 3.83 (s, 3H), 3.71 (qd, J = 7.1,
2.5 Hz, 1H), 2.29 (d, J = 2.6 Hz, 1H), 1.51 (d, J = 7.2 Hz, 3H).
A second run was performed with (+)-1. The product was obtained as a light-yellow
oil (757 mg, 69%; 93% ee).
[α]D22 = –11 (c = 1.0, CHCl3).
July 4, 2008
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IV. Assignment of Absolute Configuration
H2
3.0% NiCl2•glyme
Et
3.9% (–)-1
Pd/C
n-Bu
Ph
Me
Br Ph ZnEt
2.0 equiv
glyme, –20 °C
Me
(S)-Hexan-2-ylbenzene [99439-78-8].
1H NMR (CDCl3, 500 MHz) δ 7.31-7.17 (m, 5H), 2.68 (sextet, J = 6.9 Hz, 1H), 1.64-1.50
(m, 2H), 1.33-1.11 (m, 7H), 0.86 (t, J = 7.0 Hz, 3H).
[α]D22 = +16 (c = 1.0, heptane). Literature data for (S) enantiomer: [α]D22 = +21 (c = 1.0,
heptane).1
1) LiAlH4
2) PCC
t-Bu
Me
3) CBr4, PPh3
4) n-BuLi; TMSCl
TMS
O
n-Bu
n-Bu
O
t-Bu
Ph
Ph
Trimethyl(3-phenylhept-1-ynyl)silane. The BHT ester2 was converted into the title
compound, and the stereochemistry of the cross-coupling product illustrated in eq 2, eq
3, and eq 6 was assigned by comparing elution orders on a Chirasil Dex CB GC column
(for assay information and for characterization data of the title compound, see the
experimental description for eq 3 in Section III).
July 4, 2008
S–16

References
(1) Pyne, S. G. J. Org. Chem. 1986, 51, 81–87.
(2) Dai, X.; Strotman, N. A.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 3302–3303.
July 4, 2008
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