Studies on Cu(I)-catalyzed synthesis of simple 3-substituted 1,2-allenes and optically active 2-substituted secondary 2,3-allenols

Article abstract of DOI:10.1016/j.tet.2009.02.061

The sequential treatment of terminal alkynes or propargylic alcohols with n-BuLi and MOMCl afforded the corresponding propargylic methyl ethers, which would react with primary alkyl Grignard reagents under the catalysis of CuBr to afford 3-substituted 1,2-allenes or 2-substituted secondary 2,3-allenols, respectively. The reaction may be applied to the synthesis of optically active 2-substituted secondary 2,3-allenols with up to >99% ee without any protection to the free hydroxyl group in the starting 4-hydroxy-2-alkynyl methyl ethers.

Full text of DOI:10.1016/j.tet.2009.02.061

Tetrahedron 65 (2009) 3695–3703
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Tetrahedron
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Studies on Cu(I)-catalyzed synthesis of simple 3-substituted 1,2-allenes
and optically active 2-substituted secondary 2,3-allenols
*
Jing Li, Chao Zhou, Chunling Fu, Shengming Ma
Laboratory of Molecular Recognition and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027, Zhejiang, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The sequential treatment of terminal alkynes or propargylic alcohols with n-BuLi and MOMCl afforded
the corresponding propargylic methyl ethers, which would react with primary alkyl Grignard reagents
under the catalysis of CuBr to afford 3-substituted 1,2-allenes or 2-substituted secondary 2,3-allenols,
respectively. The reaction may be applied to the synthesis of optically active 2-substituted secondary 2,3-
allenols with up to >99% ee without any protection to the free hydroxyl group in the starting 4-hydroxy-
2-alkynyl methyl ethers.
Received 22 December 2008
Received in revised form 21 February 2009
Accepted 24 February 2009
Available online 3 March 2009
Keywords:
Alcohols
Ó 2009 Elsevier Ltd. All rights reserved.
Allenes
Asymmetric synthesis
Copper
Grignard reaction
1. Introduction
and the kinetic resolution of racemic 2,3-allenols is restricted to the
substrates with one or two carbon units such as methyl, ethyl,
The synthesis of allenes is of current interest due to their high
and unique reactivities demonstrated in organic synthesis.1,2 Of
particular interest is the chemistry of 2,3-allenols,3 which have
been used for the synthesis of 2,5-dihydrofurans,4 epoxides,5 3-
halo-3-alkenals,6 etc. Thus, there is a need to develop a general,
convenient, and practical synthesis of optically active 2,3-allenols
with the chiral centers connected with the hydroxyl group. The
racemic form of this class of compounds is usually prepared by
ethenyl, or acetylenyl directly connected to the hydroxylated car-
bon atom.15 In this paper we wish to report a relatively general
synthesis of optically active 2,3-allenols from the easily available
propargylic alcohols (Scheme 1).
R2
OH
R1
OH
R1
R1
MeO
Scheme 1.
metal-mediated reaction of propargylic bromide with aldehydes7
HO
9
or ketones8 and the Crabbe reaction of propargylic alcohols. Fur-
´
thermore, optically active 2,3-allenols are usually prepared by the
enantioselective reduction of 1,2-allenyl ketones,10 the reaction of
optically active propargylic/allenic metallic reagents with alde-
2. Results and discussion
hydes,11 Crabbe reaction of optically active terminal propargylic
´
alcohols,12 chiral ligand-mediated reaction of propargylic/allenic
metallic reagents with aldehydes,13 the reduction of optically active
4-hydroxy-2-alkynyl methyl ether with LiAlH4,10 the diaster-
eoselective 1,2-addition of optically active 1,2-allenyl aldehydes or
ketones with Grignard reagents,14 and the kinetic resolution of
racemic 2,3-allenols.15 However, the synthesis of optically active
2,3-allenols is still not so easy since some of the reagents or catalyst
for these known methods are not easily available or expensive10–14
To examine this method, firstly, the reaction of methyl 3-phe-
nylpropargyl ether 1a with n-C4H9MgBr was studied with different
amounts of CuBr and the Grignard reagent.16 No product was
formed without catalyst (entry 1, Table 1). Further studies indicated
that 10 mol % of CuBr and 2 equiv of n-C4H9MgBr were enough to
ensure a good yield of 3-phenylhepta-1,2-diene 2a (Table 1).
Then we designed a one-pot procedure for the synthesis of
3-substituted 1,2-allenes
2 from simple terminal alkynes 3
(Table 2). n-BuLi was added dropwise to a solution of terminal al-
kynes 3 in Et2O at -40 ꢀC. After half an hour, MOMCl was added
dropwise at the same temperature, the resulting mixture was then
treated with 10–20 mol % CuBr at room temperature, which was
followed by dropwise addition of the Grignard reagent. In this way,
* Corresponding author. Fax: þ86 21 62237360.
E-mail address: masm@mail.sioc.ac.cn (S. Ma).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.061

3696
J. Li et al. / Tetrahedron 65 (2009) 3695–3703
Table 1
Table 3
CuBr-catalyzed reaction of 1a with n-C4H9MgBr
CuBr-catalyzed reaction of racemic 5a with n-C4H9MgBr
n-C4H9
CuBr
Et2O
Ph
Ph
CuBr
Et2O, rt
n-C4H9MgBr
in Et2O (1 M)
Ph
+
n-C4H9MgBr
+
Ph
OCH3
n-C4H9
H3CO
OH
HO
6a
1a
2a
5a
Entry
CuBr (mol %)
n-C4H9MgBr (equiv)
Yield (%)
Entry
n-C4H9MgBr
(equiv)
Catalyst
(mol %)
Temp
NMR yield
(ꢀC)
of 6aa (%)
1
2
3
4
5
6
7
0
1.5
5
10
20
10
10
2
2
2
2
2
1.5
1.2
0
60
72
81
82
77
48
1b
2
3
4
5
6
7
8
3
4
4
4
4
4
4
4
20
10
20
30
50
20
20
20
20
20
20
20
20
20
ꢁ20
ꢁ30
ꢁ30
ꢁ30
ꢁ30
rt
0
43
52
52
53
Complicated
Complicated
48
30
53
55 (53)
45
46
27 (26)
0
ꢁ20
ꢁ40
ꢁ30
ꢁ30
ꢁ30
ꢁ30
ꢁ30
9
4
10
11
12
13
14
4.5
4.67
4.83
5
Table 2
One-pot synthesis of 3-substituted 1,2-allenes 2 from terminal alkynes 3
R1
R2MgBr, CuBr
n-BuLi, Et2O
MOMCl
R1
4.67c
-40 °C, 0.5 h -40°C to rt, T1
rt, T2
R2
a
Yields were determined by 1H NMR analysis with 1,3,5-trimethylbenzene as the
2
3
internal standard. The isolated yield is given in the parentheses.
b
Entry
R1
R2
R2MgBr
(equiv)
CuBr
(equiv)
T1
(h)
T2
(h)
Isolated
yield (%)
THF was used as solvent.
A solution of n-C4H9MgCl (1.0 M) in Et2O was used.
c
1
2
3
4
Ph (3a)
n-C4H9 (3b)
Ph (3a)
n-C4H9
Ph
C2H5
Ph
2.0
2.0
2.0
2.0
0.2
0.1
0.2
0.1
1.5
0.5
2
1.5
15.5
1
86 (2a)
57a (2a)
75 (2b)
60a (2c)
ꢁ30 ꢀC, at which the reaction afforded the product 6a in 52% NMR
yield (entry 3, Table 3). When the reaction was conducted with 4.5
or 4.67 equiv of the Grignard reagent, the yield was slightly higher
(entries 10 and 11, Table 3). The best result was obtained when the
reaction was conducted by asymmetric synthesis at ꢁ30 ꢀC with
4.67 equiv of n-C4H9MgBr, affording the target product 6a in 55%
NMR yield (53% isolated yield) (entry 11, Table 3).
It should be noted that when a solution of n-C4H9MgCl
(1.0 M) in Et2O was used, the yield of racemic 6a was only 26%
(entry 14, Table 3). After careful analysis of the reaction mix-
ture, the byproducts are allylic alcohol 7a, which was formed
by the reaction of 6a with n-C4H9MgX,17 the hydrometallation–
elimination product 8a, and the direct reduction product 9a.
However, the reaction with n-C4H9MgBr gave a much better
selectivity (Scheme 3).
With the optimized reaction conditions in hand (entry 11, Table
3), the scope of the CuBr-catalyzed reaction of racemic 4-hydroxy-
4-aryl-2-butynyl methyl ethers 5 with R2MgBr was studied (Table
4). It can be concluded that 4-hydroxy-4-aryl-2-butynyl methyl
ethers 5 with different Grignard reagents can be used to prepare
differently substituted 2-alkyl-2,3-allenols 6 in moderate yields. It
should be noted that with the increased steric hindrance of R1, the
yield dropped probably due to the possible steric interaction be-
tween R1 and R2 (compare entry 3 with entry 4, Table 4). It should
be also noted that when R1 is methyl, its reaction with n-
C4H9MgBr is low yielding (entry 9, Table 4). The reaction of 5a
with 4 equiv of phenyl magnesium bromide afforded 1,2-
diphenyl-2,3-butadienol 6i in low yield (22%) with 39% of the
reactant being recovered (entry 10, Table 4); when the reaction
temperature was raised from ꢁ30 ꢀC to room temperature, both
1,2-diphenyl-2,3-butadienol 6i and 1,2,4-triphenyl-2-butenol 7i
were formed in 33% NMR yield in the crude reaction mixture
(entry 11, Table 4), which was formed by the carbometalation of
the resulting 2,3-allenols with PhMgBr;17 When 6 equiv of
Grignard reagent were used, 1,2,4-tripheny-2-butenol 7i was
formed in 48% isolated yield as the only product (entry 12, Table
4). In addition, when vinyl magnesium chloride or allyl magne-
sium chloride in THF solution was added, only trace amount of the
product was afforded.
n-C6H13 (3c)
0.5
15.5
a
Biphenyl was formed in about 5–6% yield.
3-substituted 1,2-allenes 2 were formed in moderate to good yields
from terminal alkynes in a one-pot manner.
Then, we proposed to synthesize optically active 2-substituted
secondary 2,3-allenols by following the same protocol. Firstly, we
tried to synthesize racemic 2-substituted secondary 2,3-allenols
from terminal propargylic alcohols via a one-pot procedure de-
scribed above, unfortunately, a complicated mixture was formed.
Then, we started to pursue the step-wise procedure.
By treating the racemic propargylic alcohols 4 with n-BuLi and
the subsequent reaction with MOMCl, the racemic 4-hydroxy-4-
aryl-2-butynyl methyl ethers 5 were prepared in moderate yields
(Scheme 2).
R
R
1) n-BuLi, -78 °C, THF
2) MOMCl, -78 °C to -20 °C
H3CO
OH
OH
4
5
5a R = Ph (60%)
5b R = p-CH3C6H4 (69%)
5c R = m,p-OCH2OC6H3 (60%)
5d R = p-CH3OC6H4 (68%)
Scheme 2.
Then racemic 4-hydroxy-4-phenyl-2-butynyl methyl ether 5a
was used as the model substrate to optimize the condition for its
reaction with n-C4H9MgBr. When racemic 5a was treated with
3 equiv of n-C4H9MgBr in THF under the catalysis of 20 mol % CuBr
at ꢁ20 ꢀC, no 2-butyl-1-phenyl-2,3-butadienol 6a was formed
(entry 1, Table 3). The reaction with 4 equiv of n-C4H9MgBr in Et2O
under the catalysis of 10 mol % CuBr at ꢁ30 ꢀC gave the product 6a
in moderate yield (43%) (entry 2, Table 3). The effect of the amounts
of CuBr on the yield of 6a is not obvious (compare entries 2–5, Table
3). Then we tried to optimize the reaction temperature (compare
entries 6–9, Table 3), the best reaction temperature was found to be
It is known that optically active terminal propargylic alcohols 4
can be easily prepared from racemic propargylic alcohols 4 through

J. Li et al. / Tetrahedron 65 (2009) 3695–3703
3697
n-C5H11
n-C4H9
n-C4H9
+
Ph
Ph
HO
7a
HO
Ph
n-C4H9MgX
20 mol% CuBr
Et2O, -30 °C, 10 h
+
6a
in Et2O (1 M)
H3CO
OH
H
Ph
5a
4.67 equiv
+
H3C
Ph
OH
HO
8a
9a
Isolated yieldsa
Recovery of
X
6a(%)
7a(%)
8a (%)
9a (%)
5aa(%)
Cl
Br
26 (27)
51 (53)
6 (9)
7 (9)
17 (21)
9 (12)
12 (17)
8 (11)
(6)
(4)
Scheme 3. aThe NMR yields are given in the parentheses with 1,3,5-trimethylbenzene as the internal standard.
Table 4
Table 6
CuBr-catalyzed reaction of racemic 4-hydroxy-4-aryl-2-butynyl methyl ethers 5
CuBr-catalyzed reaction of optically active 4-hydroxy-4-aryl-2-butynyl methyl
with Grignard reagents
ethers 5 with Grignard reagents
R2
R2
R1
R1
20 mol% CuBr
Et2O, -30 °C
R2MgBr
20 mol% CuBr
Et2O, -30°C
R2MgBr
in Et2O
+
R1
R1
+
H3CO
OH
in Et2O (1 M)
H3CO
OH
HO
6
HO
6
4.67 equiv
4.67 equiv
5
5
Entry R1
R2
ee of
5 (%)
6
Recovery of
Entry
R1
Ph (5a)
p-CH3C6H4 (5b)
m,p-OCH2OC6H3 (5c)
p-CH3OC6H4 (5d)
Ph (5a)
Ph (5a)
Ph (5a)
Ph (5a)
CH3 (5e)
R2
Yield of 6a (%)
Recovery of 5a (%)
5a (%)
Isolated yielda (%) ee (%)
1
2
3
4
5
6
7
8
n-C4H9
n-C4H9
n-C4H9
n-C4H9
C2H5
n-C3H7
n-C5H11
n-C6H13
51 (53) (6a)
50 (52) (6b)
33 (33) (6c)
45 (50) (6d)
35 (36) (6e)
43 (46) (6f)
48 (50) (6g)
44 (56) (6h)
(7)
(4)
(2)
(6)
(1)
(1)
(6)
(2)
(5)
(20)
(39)
(0)
(0)
1
2
3
Ph (R-5a)
Ph (S-5a)
p-CH3C6H4
(R-5b)
n-C4H9 98.2 50 (53) (R-6a)
n-C4H9 96.1 48 (52) (S-6a)
n-C4H9 99.2 47 (45) (R-6b)
99.5
99.2
97.5
(4)
(6)
(0)
4
5
6
7
8
p-CH3C6H4
(S-5b)
n-C4H9 98.6 45 (46) (S-6b)
98.9
98.5
96.9
95.3
95.8
(0)
(6)
(6)
(7)
(0)
m,p-OCH2OC6H3 n-C4H9 98.6 26 (30) (R-6c)
(R-5c)
m,p-OCH2OC6H3 n-C4H9 97.1 28 (33) (S-6c)
(S-5c)
p-CH3OC6H4
(R-5d)
b
9
n-C4H9
10
11c
12c
Ph (5a)
Ph (5a)
Ph (5a)
Phb
Phb
Phe
22 (25) (6i)
33 (33)d (6i)
f
n-C4H9 96.7 48 (51) (R-6d)
a
The NMR yields are given in the parentheses with 1,3,5-trimethylbenzene as the
p-CH3OC6H4
(S-5d)
n-C4H9 96.4 49 (56) (S-6d)
internal standard.
b
Grignard reagent (4 equiv) was used.
c
The reaction temperature was raised from ꢁ30 ꢀC to room temperature.
9
Ph (R-5e)
Ph (S-5e)
Ph (R-5f)
Ph (S-5f)
Ph (R-5g)
Ph (R-5h)
C2H5
C2H5
98.2 40 (38) (R-6e)
96.1 35 (40) (S-6e)
99.5
99.5
99.7
97.9
99.6
99.6
(8)
(5)
(7)
(5)
(11)
(10)
d
10
11
12
13
14
1,2,4-Triphenyl-2-butenol 7i was formed in 33% NMR yield in the crude reaction
n-C3H7 98.2 37 (41) (R-6f)
n-C3H7 96.1 39 (42) (S-6f)
n-C5H11 98.2 49 (57) (R-6g)
n-C6H13 98.2 51 (58) (R-6h)
mixture.
e
Grignard reagent (6 equiv) was used.
1,2,4-Triphenyl-2-butenol 7i was formed in 48% isolated yield.
f
a
The NMR yields are given in the parentheses with 1,3,5-trimethylbenzene as the
Table 5
internal standard.
Synthesis of optically active 4-hydroxy-4-aryl-2-butynyl methyl ethers 5
1) BuLi, -78 °C
2) MOMCl, -78 °C
R
OH
R
OH
Novozym 435-catalyzed kinetic resolution.18 By treating the opti-
cally active propargylic alcohols 4 with n-BuLi and the subsequent
reaction with MOMCl, the optically active 4-hydroxy-4-aryl-2-
H3CO
3) -78 °C to -20 °C
5
4
butynyl methyl ethers
(Table 5).
5 were prepared in moderate yields
Entry
R
Time (h) ee of 4 (%)
5
Isolated yield (%) ee (%)
The reaction of these optically active 4-hydroxy-4-aryl-2-
butynyl methyl ethers 5 with R2MgBr afforded the optically active
1
2
3
4
5
6
7
8
Ph (S-4a)
Ph (R-4a)
p-CH3C6H4 (S-4b)
p-CH3C6H4 (R-4b)
m,p-OCH2OC6H3 (S-4c) 22
m,p-OCH2OC6H3 (R-4c) 23
19
16
14
20
99.6
99.9
99.9
99.5
99.3
96.0
97.2
96.7
63 (R-5a)
66 (S-5a)
67 (R-5b)
61 (S-5b)
62 (R-5c)
57 (S-5c)
61 (R-5d)
61 (S-5d)
98.2
96.1
99.2
98.6
98.6
97.1
96.7
96.4
a-allenols 6 without obvious racemization (Table 6).
3. Conclusion
p-CH3OC6H4 (S-4d)
p-CH3OC6H4 (R-4d)
16
16
We have developed a one-pot procedure for the synthesis of 3-
substituted 1,2-allenes from terminal alkynes and a new route for

3698
J. Li et al. / Tetrahedron 65 (2009) 3695–3703
the synthesis of optically active 2-substituted secondary 2,3-alle-
nols from optically active 4-hydroxy-4-aryl-2-butynyl methyl
ethers. Due to the easy availability of the starting materials and the
synthetic potential of the products,3–6 this method may be useful in
organic synthesis. Further studies in this area are being pursued in
our laboratory.
6H), 0.92 (t, J¼6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 208.6, 136.5,
128.3, 126.5, 125.9, 105.0, 78.0, 31.7, 29.5, 29.1, 27.8, 22.7, 14.1; IR
(neat) n
(cmꢁ1) 2955, 2928, 2857, 1941, 1597, 1494, 1452, 1378, 1075;
MS (70 eV, EI) m/z (%): 200 (Mþ, 8.56), 130 (100).
4.2. Synthesis of racemic 4-hydroxy-4-aryl-2-alkynyl
methyl ethers
4. Experimental section
The (R)- and (S)-5a–5d have been fully characterized (see Sec-
tions 4.4.1–4.4.8), thus, only the 1H NMR spectra were recorded for
the racemic 5a–5d.
4.1. Synthesis of 3-substituted 1,2-allenes
4.1.1. 3-Phenyl-1,2-heptadiene (2a)
Typical procedure. To a solution of phenylacetylene 3a (1.020 g,
10.0 mmol) in anhydrous ether (20.0 mL) was added dropwise
4.2.1. 4-Hydroxy-4-phenyl-2-butynyl methyl ether (5a)
To a solution of 1-phenyl-2-propynol 4a (1.3310 g, 10.1 mmol) in
anhydrous Et2O (20 mL) was added dropwise n-BuLi (8.0 mL, 2.5 M
in hexanes, 20.0 mmol) at ꢁ78 ꢀC under nitrogen within 8 min.
After addition, the resulting solution was stirred at ꢁ78 ꢀC for 0.5 h,
which was followed by dropwise addition of MOMCl (0.68 mL,
d¼1.06 g/mL, 0.72 g, 9.0 mmol). The resulting mixture was warmed
up to ꢁ30 ꢀC naturally. After being stirred for 16 h as monitored by
TLC, the mixture was quenched with 1 N HCl (10 mL) and extracted
with ether (3ꢂ10 mL). The combined organic layer was washed
with saturated brine (20 mL) and dried over anhydrous sodium
sulfate. After evaporation, the residue was purified by flash chro-
matography on silica gel (eluent: petroleum ether/ethyl acetate¼5/
1) to afford 5a10 (0.9508 g, 60%): oil; 1H NMR (400 MHz, CDCl3)
a
solution of n-BuLi in hexanes (4.0 mL, 2.5 M in hexanes,
10.0 mmol) at ꢁ40 ꢀC under nitrogen within 10 min. After being
stirred for 0.5 h, MOMCl (0.810 g, 10.1 mmol) was added dropwise
at ꢁ40 ꢀC, which was followed by warming up to room temperature
naturally for about 1.5 h. Then CuBr (0.280 g, 1.95 mmol) and a so-
lution of n-C4H9MgBr in Et2O (20.0 mL, 1 M in Et2O, 20.0 mmol)
were added dropwise sequentially to the reaction mixture for 0.5 h
at room temperature. After being stirred for 1.5 h as monitored by
TLC, the reaction mixture was quenched with an aqueous solution
of saturated ammonium chloride (5 mL), extracted with ether
(3ꢂ20 mL), washed with saturated brine (20 mL), and dried over
anhydrous sodium sulfate. Evaporation and column chromatogra-
phy on silica gel (eluent: petroleum ether/ethyl acetate¼40/1)
afforded 2a19 (1.473 g, 86%): liquid; 7.46–7.40 (m, 2H), 7.37–7.30 (m,
2H), 7.24–7.17 (m, 1H), 5.08 (t, J¼3.3 Hz, 2H), 2.48–2.38 (m, 2H),
1.62–1.50 (m, 2H),1.50–1.36 (m, 2H), 0.95 (t, J¼7.4 Hz, 3H); 13C NMR
d
7.56–7.50 (m, 2H), 7.42–7.30 (m, 3H), 5.51 (s, 1H), 4.18 (d, J¼2.0 Hz,
2H), 3.39 (s, 3H), 2.54 (br s, 1H).
4.2.2. 4-Hydroxy-4-(40-methylphenyl)-2-butynyl methyl ether (5b)
Typical procedure. To a solution of 1-(40-methylphenyl)-2-pro-
pynol 4b (1.4652 g, 10.0 mmol) in anhydrous THF (30 mL) was
added dropwise n-BuLi (8.8 mL, 2.5 M in hexanes, 22.0 mmol) at
ꢁ78 ꢀC under nitrogen within 10 min. After addition, the resulting
solution was stirred at ꢁ78 ꢀC for 0.5 h, which was followed by
dropwise addition of MOMCl (1.14 mL, d¼1.06 g/mL, 1.21 g,
15.0 mmol). The resulting mixture was warmed up to ꢁ20 ꢀC nat-
urally. After being stirred for 12 h as monitored by TLC, the mixture
was quenched with an aqueous solution of saturated ammonium
chloride (5 mL) and extracted with ether (3ꢂ10 mL). The combined
organic layer was washed with saturated brine (10 mL) and dried
over anhydrous sodium sulfate. After evaporation, the residue was
purified by flash chromatography on silica gel (eluent: petroleum
ether/ethyl acetate¼5/1 to 3/1) to afford 5b (1.3118 g, 69%): oil; 1H
(75 MHz, CDCl3)
29.2, 22.5, 14.0; IR (neat)
d 208.6, 136.5, 128.3, 126.5, 125.9, 105.0, 78.0, 30.0,
n
(cmꢁ1) 2956, 2929, 2860, 1940, 1597,
1494, 1452, 1378, 1075; MS (70 eV, EI) m/z (%): 172 (Mþ, 8.76), 130
(100).
The following compounds were prepared similarly.
4.1.2. 3-Phenyl-1,2-heptadiene (2a)
The reaction of 1-hexyne 3b (0.823 g, 10.0 mmol), n-BuLi
(4.2 mL, 2.5 M in hexanes, 10.5 mmol), MOMCl (0.76 mL, d¼1.06 g/
mL, 0.806 g, 10.5 mmol), CuBr (0.144 g, 1.0 mmol), and PhMgBr
(20.0 mL, 1 M in Et2O, 20.0 mmol) in anhydrous ether (20.0 mL)
afforded 2a19 (0.978 g, 57%): liquid; 1H NMR (300 MHz, CDCl3)
d
7.48–7.43 (m, 2H), 7.39–7.32 (m, 2H), 7.26–7.19 (m, 1H), 5.10 (t,
J¼3.3 Hz, 2H), 2.50–2.41 (m, 2H), 1.64–1.53 (m, 2H), 1.53–1.39 (m,
2H), 0.98 (t, J¼7.4 Hz, 3H).
NMR (300 MHz, CDCl3)
d
7.43 (d, J¼7.9 Hz, 2H), 7.19 (d, J¼7.9 Hz,
2H), 5.48 (dt, J1¼6.0 Hz, J2¼1.5 Hz, 1H), 4.19 (d, J¼1.5 Hz, 2H), 3.40
4.1.3. 3-Phenyl-1,2-pentadiene (2b)
(s, 3H), 2.36 (s, 3H), 2.27 (br s, 1H).
The reaction of phenylacetylene 3a (1.024 g, 10.0 mmol), n-BuLi
(4 mL, 2.5 M in hexanes, 10.0 mmol), MOMCl (0.815 g, 10.1 mmol),
CuBr (0.280 g, 1.95 mmol), and C2H5MgBr (20.0 mL, 1 M in Et2O,
20.0 mmol) in anhydrous ether (20.0 mL) afforded 2b19 (1.086 g,
The following compounds were prepared according to this
procedure.
4.2.3. 4-Hydroxy-4-(30,40-methylenedioxyphenyl)-2-butynyl
methyl ether (5c)
75%): liquid; 1H NMR (300 MHz, CDCl3)
d 7.46–7.40 (m, 2H), 7.37–
7.30 (m, 2H), 7.25–7.18 (m, 1H), 5.12 (t, J¼3.6 Hz, 2H), 2.50–2.39 (m,
The reaction of 1-(30,40-methylenedioxyphenyl)-2-propynol 4c
(1.7588 g, 10.0 mmol), n-BuLi (8.8 mL, 2.5 M in hexanes,
22.0 mmol), and MOMCl (1.16 mL, d¼1.06 g/mL, 1.208 g, 15.0 mmol)
in anhydrous THF (30 mL) afforded 5c (1.3208 g, 60%): oil; 1H NMR
2H), 1.17 (t, J¼7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d
208.3, 136.5,
128.3, 126.5, 125.9, 106.7, 78.8, 22.3, 12.4; IR (neat)
n
(cmꢁ1) 2967,
2931, 2872, 1941, 1597, 1494, 1453, 1379, 1075, 1031; MS (70 eV, EI)
m/z (%): 144 (Mþ, 69.8), 129 (100).
(300 MHz, CDCl3)
d
7.04 (d, J¼1.8 Hz, 1H), 6.99 (ddd, J1¼7.9 Hz,
J2¼1.8 Hz, J3¼0.6 Hz, 1H), 6.78 (d, J¼7.9 Hz, 1H), 5.96 (s, 2H), 5.41
(dt, J1¼5.7 Hz, J2¼1.5 Hz,1H), 4.18 (d, J¼1.5 Hz, 2H), 3.39 (s, 3H), 2.46
(d, J¼5.7 Hz, 1H).
4.1.4. 3-Phenyl-1,2-nonadiene (2c)
The reaction of 1-octyne 3c (1.102 g, 10.0 mmol), n-BuLi (4.2 mL,
2.5 M in hexanes, 10.5 mmol), MOMCl (0.76 mL, d¼1.06 g/mL,
0.806 g, 10.5 mmol), CuBr (0.144 g, 1.0 mmol), and PhMgBr
(20.0 mL, 1 M in Et2O, 20.0 mmol) in anhydrous ether (20.0 mL)
afforded 2c19 (1.201 g, 60%): liquid; 1H NMR (300 MHz, CDCl3)
4.2.4. 4-Hydroxy-4-(40-methoxyphenyl)-2-butynyl methyl
ether (5d)
The reaction of 1-(40-methoxyphenyl)-2-propynol 4d (1.330 g,
8.2 mmol), n-BuLi (7.25 mL, 2.5 M in hexanes, 18.1 mmol), and
MOMCl (0.75 mL, d¼1.06 g/mL, 0.795 g, 9.9 mmol) in anhydrous THF
d
7.46–7.41 (m, 2H), 7.38–7.30 (m, 2H), 7.25–7.18 (m, 1H), 5.08 (t,
J¼3.2 Hz, 2H), 2.47–2.38 (m, 2H), 1.62–1.51 (m, 2H), 1.49–1.29 (m,

J. Li et al. / Tetrahedron 65 (2009) 3695–3703
3699
(30 mL) afforded 5d (1.1562 g, 68%): oil; 1H NMR (300 MHz, CDCl3)
(m, 2H), 1.44–1.17 (m, 4H), 0.84 (t, J¼7.2 Hz, 3H). According to
the 1H NMR analysis of the crude reaction mixture there was
2% of 5b remaining.
d
7.49–7.43 (m, 2H), 6.93–6.87 (m, 2H), 5.47 (d, J¼5.4 Hz, 1H), 4.19 (d,
J¼1.5 Hz, 2H), 3.81 (s, 3H), 3.40 (s, 3H), 2.24 (d, J¼5.4 Hz, 1H).
4.3. CuBr-catalyzed reaction of racemic 4-aryl-4-hydroxy-2-
butynyl methyl ethers 5a–5d with Grignard reagents
4.3.4. 2-Butyl-1-(30,40-methylenedioxyphenyl)-2,3-butadien-
1-ol (6c)
To a mixture of 4-hydroxy-4-(30,40-methylenedioxyphenyl)-2-
butynyl methyl ether 5c (65.7 mg, 0.30 mmol) and CuBr (8.7 mg,
0.06 mmol) in anhydrous Et2O (1.6 mL) was added dropwise a so-
lution of n-C4H9MgBr in Et2O (1.4 mL, 1 M in Et2O, 1.4 mmol) to
afford 6c6b (24.1 mg, 33%): liquid; 1H NMR (300 MHz, CDCl3)
The (R)- and (S)-6a–6i have been fully characterized (see Section
4.5), thus, only the 1H NMR spectra were recorded for the racemic
6a–6i.
4.3.1. Synthesis of 2-butyl-1-phenyl-2,3-butadien-1-ol (6a),
2-butyl-1-phenyl-2-octen-1-ol (7a), 1-phenyl-2,3-butadien-
1-ol (8a), and 1-phenyl-2-butyn-1-ol (9a)
d
6.88–6.85 (m, 1H), 6.83 (dd, J1¼7.8 Hz, J2¼1.5 Hz, 1H), 6.76 (d,
J¼7.8 Hz, 1H), 5.95 (s, 2H), 5.06–4.95 (m, 3H), 2.24 (d, J¼3.6 Hz, 1H),
1.89–1.69 (m, 2H), 1.44–1.20 (m, 4H), 0.85 (t, J¼7.2 Hz, 3H).
According to the 1H NMR analysis of the crude reaction mixture
there was 6% of 5c remaining.
Typical procedure. To a dried Schlenk tube were added CuBr
(8.9 mg. 0.06 mmol), anhydrous Et2O (1.6 mL), and 4-hydroxy-4-
phenyl-2-butynyl methyl ether 5a (52.6 mg, 0.30 mmol) at room
temperature. A solution of n-C4H9MgCl in Et2O (1.4 mL, 1 M in Et2O,
1.4 mmol) was then added dropwise to this resulting mixture at
ꢁ30 ꢀC under nitrogen. After the addition was over, the reaction
mixture was stirred for 10 h at ꢁ30 ꢀC as monitored by TLC,
quenched with saturated ammonium chloride solution (2 mL) at
ꢁ30 ꢀC, extracted with ether at room temperature (3ꢂ10 mL),
washed with saturated brine (10 mL), and dried over anhydrous
sodium sulfate. According to the 1H NMR analysis of the crude re-
action mixture there was 6% of 5a remaining. Evaporation and
column chromatography on silica gel (eluent: petroleum ether/
ethyl acetate¼20/1 to 10/1) afforded 6a20 (16.0 mg, 26%), 7a
(4.5 mg, 6%), 8a17 (7.5 mg, 17%), and 9a21 (5.1 mg, 12%).
4.3.5. 2-Butyl-1-(40-methoxyphenyl)-2,3-butadien-1-ol (6d)
To a mixture of 4-hydroxy-4-(40-methoxyphenyl)-2-butynyl
methyl ether 5d (61.3 mg, 0.30 mmol) and CuBr (8.6 mg,
0.06 mmol) in anhydrous Et2O (1.6 mL) was added dropwise
a
solution of n-C4H9MgBr in Et2O (1.4 mL, 1 M in Et2O,
1.4 mmol) to afford 6d6b (30.9 mg, 45%): liquid; 1H NMR
(300 MHz, CDCl3) 7.32–7.26 (m, 2H), 6.91–6.84 (m, 2H), 5.06–
d
4.95 (m, 3H), 3.81 (s, 3H), 2.21 (d, J¼3.9 Hz, 1H), 1.87–1.71 (m,
2H), 1.43–1.18 (m, 4H), 0.84 (t, J¼7.2 Hz, 3H). According to the
1H NMR analysis of the crude reaction mixture there was 1% of
5d remaining.
Compound 6a: liquid; 1H NMR (300 MHz, CDCl3)
d
7.40–7.26 (m,
4.3.6. 2-Ethyl-1-phenyl-2,3-butadien-1-ol (6e)
5H), 5.13–5.07 (m, 1H), 5.05–4.96 (m, 2H), 2.27 (d, J¼4.5 Hz, 1H),
To a mixture of 4-hydroxy-4-phenyl-2-butynyl methyl ether 5a
(53.5 mg, 0.30 mmol) and CuBr (8.6 mg, 0.06 mmol) in anhydrous
Et2O (1.6 mL) was added dropwise a solution of C2H5MgBr in Et2O
(1.4 mL, 1 M in Et2O, 1.4 mmol) to afford 6e13a (19.0 mg, 35%): liq-
1.88–1.73 (m, 2H), 1.43–1.19 (m, 4H), 0.84 (t, J¼7.1 Hz, 3H).
Compound 7a: liquid; 1H NMR (300 MHz, CDCl3)
d 7.40–7.24 (m,
5H), 5.61 (t, J¼7.2 Hz, 1H), 5.16 (d, J¼2.7 Hz, 1H), 2.10–1.92 (m, 3H),
1.89–1.76 (m, 2H), 1.44–1.10 (m, 10H), 0.90 (t, J¼6.8 Hz, 3H), 0.82 (t,
uid; 1H NMR (300 MHz, CDCl3)
d 7.41–7.27 (m, 5H), 5.14–5.09 (m,
J¼7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d
142.8, 141.2, 128.2, 127.3,
1H), 5.09–4.98 (m, 2H), 2.24 (d, J¼3.9 Hz, 1H), 1.90–1.75 (m, 2H),
0.97 (t, J¼7.4 Hz, 3H). According to the 1H NMR analysis of the crude
reaction mixture there was 1% of 5a remaining.
126.5, 78.2, 31.7, 31.6, 29.5, 27.6, 27.5, 23.0, 22.6,14.1,13.9; IR (neat)
n
(cmꢁ1) 3386, 2958, 2869, 1603, 1454, 1377, 1009; MS (70 eV, EI) m/z
(%): 260 (Mþ, 67.0), 189 (100); HRMS calcd for C18H28O (Mþ):
260.2140, found: 260.2137.
4.3.7. 1-Phenyl-2-propyl-2,3-butadien-1-ol (6f)
Compound 8a: liquid; 1H NMR (300 MHz, CDCl3)
d
7.44–7.26 (m,
To a mixture of 4-hydroxy-4-phenyl-2-butynyl methyl ether 5a
(51.8 mg, 0.29 mmol) and CuBr (8.6 mg, 0.06 mmol) in anhydrous
Et2O (1.6 mL) was added dropwise a solution of n-C3H7MgBr in Et2O
(1.4 mL, 1 M in Et2O, 1.4 mmol) to afford 6f22 (24.0 mg, 43%): liquid;
5H), 5.45 (q, J¼6.6 Hz, 1H), 5.32–5.25 (m, 1H), 5.00–4.88 (m, 2H),
2.16 (d, J¼3.9 Hz, 1H).
Compound 9a: liquid; 1H NMR (300 MHz, CDCl3)
d 7.57–7.51 (m,
2H), 7.42–7.29 (m, 3H), 5.47–5.40 (m,1H), 2.15 (d, J¼6.0 Hz,1H),1.91
1H NMR (300 MHz, CDCl3)
d 7.42–7.27 (m, 5H), 5.13–5.07 (m, 1H),
(d, J¼2.4 Hz, 3H).
5.06–4.95 (m, 2H), 2.27 (d, J¼4.5 Hz, 1H); 1.87–1.72 (m, 2H), 1.48–
1.34 (m, 2H), 0.86 (t, J¼7.2 Hz, 3H). According to the 1H NMR
analysis of the crude reaction mixture there was 6% of 5a
remaining.
4.3.2. Synthesis of 2-butyl-1-phenyl-2,3-butadien-1-ol (6a),
2-butyl-1-phenyl-2-octen-1-ol (7a), 1-phenyl-2,3-butadien-
1-ol (8a), and 1-phenyl-2-butyn-1-ol (9a)
To a mixture of 4-hydroxy-4-phenyl-2-butynyl methyl ether 5a
(52.9 mg, 0.30 mmol) and CuBr (8.7 mg, 0.06 mmol) in anhydrous
Et2O (1.6 mL) was added dropwise a solution of n-C4H9MgBr in Et2O
(1.4 mL, 1 M in Et2O, 1.4 mmol) to afford 6a20 (31.1 mg, 51%), 7a
(5.4 mg, 7%), 8a17 (4.0 mg, 9%), and 9a21 (3.7 mg, 8%). According to
the 1H NMR analysis of the crude reaction mixture there was 4% of
5a remaining.
4.3.8. 2-Pentyl-1-phenyl-2,3-butadien-1-ol (6g)
To a mixture of 4-hydroxy-4-phenyl-2-butynyl methyl ether 5a
(52.1 mg, 0.30 mmol) and CuBr (8.8 mg, 0.06 mmol) in anhydrous
Et2O (1.6 mL) was added dropwise a solution of n-C5H11MgBr in
Et2O (1.4 mL, 1 M in Et2O, 1.4 mmol) to afford 6g23 (30.8 mg, 48%):
liquid; 1H NMR (300 MHz, CDCl3)
d 7.40–7.27 (m, 5H), 5.13–5.06 (m,
1H), 5.06–4.95 (m, 2H), 2.24 (d, J¼4.2 Hz, 1H), 1.90–1.72 (m, 2H),
1.46–1.35 (m, 2H), 1.32–1.18 (m, 4H), 0.84 (t, J¼6.9 Hz, 3H).
According to the 1H NMR analysis of the crude reaction mixture
there was 2% of 5a remaining.
4.3.3. 2-Butyl-1-(40-methylphenyl)-2,3-butadien-1-ol (6b)
To a mixture of 4-hydroxy-4-(40-methylphenyl)-2-butynyl
methyl ether 5b (56.8 mg, 0.30 mmol) and CuBr (8.6 mg,
0.10 mmol) in anhydrous Et2O (1.6 mL) was added dropwise
4.3.9. 2-Hexyl-1-phenyl-2,3-butadien-1-ol (6h)
a
solution of n-C4H9MgBr in Et2O (1.4 mL, 1 M in Et2O,
1.4 mmol) to afford 6b6b (32.2 mg, 50%): liquid; 1H NMR
(300 MHz, CDCl3)
7.26 (d, J¼8.1 Hz, 2H), 7.15 (d, J¼7.8 Hz, 2H),
5.08–4.95 (m, 3H), 2.35 (s, 3H), 2.20 (d, J¼4.2 Hz, 1H), 1.87–1.73
To a mixture of 4-hydroxy-4-phenyl-2-butynyl methyl ether 5a
(53.1 mg, 0.30 mmol) and CuBr (8.7 mg, 0.06 mmol) in anhydrous
Et2O (1.6 mL) was added dropwise a solution of n-C6H13MgBr in
Et2O (1.4 mL, 1 M in Et2O, 1.4 mmol) to afford 6h24 (30.8 mg, 44%):
d

3700
J. Li et al. / Tetrahedron 65 (2009) 3695–3703
liquid; 1H NMR (300 MHz, CDCl3)
d
7.42–7.26 (m, 5H), 5.12–5.06 (m,
11.0 mmol), and MOMCl (0.58 mL, d¼1.06 g/mL, 0.615 g, 7.5 mmol)
in THF (25 mL) afforded S-(ꢁ)-5a10 (0.5778 g, 66%, 96.1% ee; HPLC
1H), 5.06–4.95 (m, 2H), 2.27 (d, J¼4.2 Hz, 1H); 1.90–1.72 (m, 2H),
1.46–1.33 (m, 2H), 1.33–1.16 (m, 6H), 0.86 (t, J¼6.6 Hz, 3H).
According to the 1H NMR analysis of the crude reaction mixture
there was 5% of 5a remaining.
condition: Chiralcel AD-H, n-hexane/i-PrOH¼90/10, 0.8 mL/min,
20
l¼230 nm, tR 11.7 (major),13.6 (minor); [
a]
ꢁ16.0 (c 0.70, CHCl3)):
D
oil; 1H NMR (300 MHz, CDCl3)
d 7.58–7.50 (m, 2H), 7.43–7.30 (m,
3H), 5.52 (d, J¼6.0 Hz, 1H), 4.19 (d, J¼1.5 Hz, 2H), 3.40 (s, 3H), 2.36
4.3.10. 1,2-Diphenyl-2,3-butadien-1-ol (6i)
To a mixture of 4-hydroxy-4-phenyl-2-butynyl methyl ether
5a (52.0 mg, 0.30 mmol) and CuBr (8.9 mg, 0.06 mmol) in an-
(br s, 1H). This compound has been prepared in the literature10 in
20
77% ee. However, according to our careful study, the [
a
]
value
D
20
reported ([
a]
ꢁ41.5 (c 0.28, CHCl3)) therein should be wrong.
D
hydrous Et2O (1.8 mL) was added dropwise
PhMgBr in Et2O (1.2 mL, 1 M in Et2O, 1.2 mmol) to afford 6i20
(14.1 mg, 22%): liquid; 1H NMR (300 MHz, CDCl3)
7.49–7.43
(m, 2H), 7.40–7.32 (m, 3H), 7.32–7.23 (m, 4H), 7.22–7.14 (m, 1H),
5.76–5.68 (m, 1H), 5.31 (dd, J1¼6.0 Hz, J2¼2.4 Hz, 1H), 5.25 (dd,
J1¼6.0 Hz, J2¼2.4 Hz, 1H), 2.32 (d, J¼5.7 Hz, 1H). According to
the 1H NMR analysis of the crude reaction mixture there was
39% of 5a remaining.
a solution of
4.4.3. (4R)-(þ)-4-Hydroxy-4-(40-methylphenyl)-2-butynyl methyl
ether (R-(þ)-5b)
d
The reaction of (1S)-(þ)-1-(40-methylphenyl)-2-propynol S-
(þ)-4b18 (0.4642 g, 99.9% ee, 3.2 mmol), n-BuLi (2.8 mL, 2.5 M in
hexanes, 7.0 mmol), and MOMCl (0.36 mL, d¼1.06 g/mL, 0.382 g,
4.8 mmol) in anhydrous THF (20 mL) afforded R-(D)-5b (0.4034 g,
67%, 99.2% ee; HPLC condition: Chiralcel AD-H, n-hexane/i-
PrOH¼90/10, 0.8 mL/min, ¼230 nm, tR 15.3 (major), 12.7 (minor);
l
20
4.3.11. 1,2,4-Triphenyl-2-butenol (7i)
[a
]
þ16.4 (c 0.80, CHCl3)): oil; 1H NMR (300 MHz, CDCl3)
d 7.43 (d,
D
To a mixture of 4-hydroxy-4-phenyl-2-butynyl methyl ether 5a
(51.8 mg, 0.29 mmol) and CuBr (8.8 mg, 0.06 mmol) in anhydrous
Et2O (1.2 mL) was added dropwise a solution of PhMgBr in Et2O
(1.8 mL, 1 M in Et2O, 1.8 mmol) to afford 7i (42.3 mg, 48%): liquid;
J¼8.1 Hz, 2H), 7.19 (d, J¼8.1 Hz, 2H), 5.49 (d, J¼6.3 Hz, 1H), 4.19 (d,
J¼1.5 Hz, 2H), 3.40 (s, 3H), 2.36 (s, 3H), 2.21 (d, J¼6.3 Hz, 1H); 13C
NMR (75 MHz, CDCl3)
59.7, 57.4, 21.0; IR (neat)
d 137.9, 137.6, 129.0, 126.4, 86.6, 81.6, 64.0,
n
(cmꢁ1) 3404, 2928, 2264, 1994, 1908,
1H NMR (300 MHz, CDCl3)
d
7.30–7.16 (m, 11H), 7.12 (d, J¼7.2 Hz,
1795, 1614, 1513, 1449, 1358, 1279, 1188, 1095, 1002; MS (70 eV, EI)
m/z (%): 190 (Mþ, 32.2), 115 (100); HRMS calcd for C12H14O2 (Mþ):
190.0994, found: 190.0993.
2H), 7.00–6.94 (m, 2H), 6.05 (t, J¼7.4 Hz, 1H), 5.44 (s, 1H), 3.27 (d,
J¼7.2 Hz, 2H), 2.15 (br s, 1H); 13C NMR (75 MHz, CDCl3)
d 143.9,
141.9, 140.7, 137.4, 129.4, 128.4, 128.3, 128.1, 128.0, 127.4, 127.1, 127.0,
126.6, 125.9, 78.4, 34.8; IR (neat)
n
(cmꢁ1) 3408, 1601, 1493, 1452,
4.4.4. (4S)-(ꢁ)-4-Hydroxy-4-(40-methylphenyl)-2-butynyl methyl
ether (S-(ꢁ)-5b)
1064, 1029, 1007; MS (70 eV, EI) m/z (%): 300 (Mþ, 5.16), 282
(MþꢁH2O, 47.8),194 (100); HRMS calcd for C22H20O (Mþ): 300.1514,
found: 300.1512.
The reaction of (1R)-(ꢁ)-1-(40-methylphenyl)-2-propynol R-
(ꢁ)-4b18 (0.9112 g, 99.5% ee, 6.2 mmol), n-BuLi (5.5 mL, 2.5 M in
hexanes, 13.7 mmol), and MOMCl (0.71 mL, d¼1.06 g/mL, 0.753 g,
9.4 mmol) in anhydrous THF (30 mL) afforded S-(ꢁ)-5b (0.7201 g,
61%, 98.6% ee; HPLC condition: Chiralcel AD-H, n-hexane/i-
4.4. Synthesis of optically active 4-hydroxy-4-aryl-2-alkynyl
methyl ethers (5a–5d)
PrOH¼90/10, 0.8 mL/min, ¼230 nm, tR 12.5 (major), 15.1 (minor);
l
20
4.4.1. (4R)-(þ)-4-Hydroxy-4-phenyl-2-butynyl methyl ether
(R-(þ)-5a)
[a
]
ꢁ14.1 (c 0.75, CHCl3)): oil; 1H NMR (300 MHz, CDCl3)
d 7.43 (d,
D
J¼8.1 Hz, 2H), 7.19 (d, J¼8.1 Hz, 2H), 5.49 (d, J¼6.0 Hz, 1H), 4.19 (d,
Typical procedure. To a solution of (1S)-(þ)-1-phenyl-2-propynol
S-(þ)-4a18 (1.3166 g, 99.6% ee, 10.0 mmol) in anhydrous THF
(50 mL) was added dropwise n-BuLi (8.8 mL, 2.5 M in hexanes,
22.0 mmol) at ꢁ78 ꢀC under nitrogen within 10 min. After addition,
the resulting solution was stirred at ꢁ78 ꢀC for 0.5 h, which was
followed by dropwise addition of MOMCl (1.14 mL, d¼1.06 g/mL,
1.21 g, 15.0 mmol). The resulting mixture was warmed up to ꢁ20 ꢀC
naturally. After being stirred for 19 h as monitored by TLC, the
mixture was quenched with an aqueous solution of saturated am-
monium chloride (10 mL) and extracted with ether (3ꢂ20 mL). The
combined organic layer was washed with saturated brine (20 mL)
and dried over anhydrous sodium sulfate. After evaporation, the
residue was purified by flash chromatography on silica gel (eluent:
petroleum ether/ethyl acetate¼5/1 to 3/1) to afford R-(þ)-5a
(1.1139 g, 63%, 98.2% ee; HPLC condition: Chiralcel AD-H, n-hexane/
J¼1.5 Hz, 2H), 3.40 (s, 3H), 2.36 (s, 3H), 2.21 (br s, 1H); 13C NMR
(75 MHz, CDCl3)
57.6, 21.1; IR (neat)
d 138.2, 137.5, 129.2, 126.5, 86.5, 82.0, 64.3, 59.9,
n
(cmꢁ1) 3403, 2928, 2270, 1994, 1909, 1798,
1613, 1512, 1450, 1358, 1188, 1095; MS (70 eV, EI) m/z (%): 190 (Mþ,
35.3), 115 (100). Elemental analysis calcd for C12H14O2 (%): C, 75.76;
H, 7.42. Found: C, 75.83; H, 7.47.
4.4.5. (4R)-(þ)-4-Hydroxy-4-(30,40-methylenedioxyphenyl)-2-
butynyl methyl ether (R-(þ)-5c)
The reaction of (1S)-(þ)-1-(30,40-methylenedioxyphenyl)-2-
propynol S-(þ)-4c18 (1.5592 g, 99.3% ee, 8.9 mmol), n-BuLi (7.8 mL,
2.5 M in hexanes, 19.5 mmol), and MOMCl (1.00 mL, d¼1.06 g/mL,
1.060 g, 13.2 mmol) in anhydrous THF (30 mL) afforded R-(þ)-5c
(1.2152 g, 62%, 98.6% ee; HPLC condition: Chiralcel AD-H, n-hexane/
i-PrOH¼90/10, 0.8 mL/min, ¼230 nm, tR 12.7 (major),11.3 (minor);
l
20
i-PrOH¼90/10, 0.8 mL/min,
l
¼230 nm, tR 13.8 (major), 12.0 (mi-
[a
]
þ30.5 (c 0.78, CHCl3)): oil; 1H NMR (300 MHz, CDCl3)
d 7.06–
D
20
nor); [a]
D
þ18.1 (c 1.34, CHCl3)): oil; 1H NMR (300 MHz, CDCl3)
7.03 (m, 1H), 7.00 (ddd, J1¼8.1 Hz, J2¼1.7 Hz, J3¼0.6 Hz, 1H), 6.79 (d,
J¼8.1 Hz,1H), 5.97 (s, 2H), 5.43 (dt, J1¼6.0 Hz, J2¼1.7 Hz,1H), 4.19 (d,
J¼1.8 Hz, 2H), 3.40 (s, 3H), 2.21 (d, J¼6.0 Hz, 1H); 13C NMR
d
7.58–7.50 (m, 2H), 7.43–7.30 (m, 3H), 5.52 (d, J¼6.0 Hz, 1H), 4.19
(d, J¼1.8 Hz, 2H), 3.40 (s, 3H), 2.32–2.24 (m, 1H); 13C NMR (75 MHz,
CDCl3)
(neat)
d
140.4, 128.3, 128.1, 126.4, 86.5, 81.8, 64.1, 59.7, 57.4; IR
(100 MHz, CDCl3)
d 147.5, 147.2, 134.5, 120.0, 107.8, 107.1, 100.9, 86.4,
n
(cmꢁ1) 3396, 2992, 2264,1960,1889,1812,1603,1494,1453,
81.5, 63.7, 59.6, 57.3; IR (neat) n
(cmꢁ1) 3396, 2896, 2270, 2216,
1376, 1358, 1279, 1189, 1095, 1003; MS (70 eV, EI) m/z (%): 176 (Mþ,
18.4), 115 (100); HRMS calcd for C11H12O2 (Mþ): 176.0837, found:
176.0833.
2029, 1854, 1610, 1488, 1444, 1359, 1248, 1188, 1094, 1039; MS
(70 eV, EI) m/z (%): 220 (Mþ, 100). Elemental analysis calcd for
C12H12O4 (%): C, 65.45; H, 5.49. Found: C, 65.42; H, 5.45.
4.4.2. (4S)-(ꢁ)-4-Hydroxy-4-phenyl-2-butynyl methyl ether
(S-(ꢁ)-5a)
4.4.6. (4S)-(ꢁ)-4-Hydroxy-4-(30,40-methylenedioxyphenyl)-2-
butynyl methyl ether (S-(ꢁ)-5c)
The reaction of (1R)-(ꢁ)-1-phenyl-2-propynol R-(ꢁ)-4a18
(0.6604 g, 99.9% ee, 5.0 mmol), n-BuLi (4.4 mL, 2.5 M in hexanes,
The reaction of (1R)-(ꢁ)-1-(30,40-methylenedioxyphenyl)-2-
propynol R-(ꢁ)-4c18 (1.5666 g, 96.0% ee, 8.9 mmol), n-BuLi (7.8 mL,

J. Li et al. / Tetrahedron 65 (2009) 3695–3703
3701
2.5 M in hexanes, 19.6 mmol), and MOMCl (1.00 mL, d¼1.06 g/mL,
1.060 g, 13.2 mmol) in anhydrous THF (30 mL) afforded S-(ꢁ)-5c
(1.1070 g, 57%, 97.1% ee; HPLC condition: Chiralcel AD-H, n-hexane/
1.00, CHCl3)): liquid; 1H NMR (300 MHz, CDCl3)
d
7.40–7.27 (m, 5H),
5.10 (br s, 1H), 5.06–4.95 (m, 2H), 2.27 (br s, 1H), 1.88–1.73 (m, 2H),
1.46–1.19 (m, 4H), 0.84 (t, J¼7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3)
i-PrOH¼90/10, 0.8 mL/min,
l
¼230 nm, tR 11.3 (major),12.6 (minor);
d 204.0, 142.1, 128.3, 127.7, 126.7, 108.2, 79.8, 74.1, 29.6, 27.6, 22.3,
20
[
a]
ꢁ31.2 (c 0.76, CHCl3)): oil; 1H NMR (300 MHz, CDCl3)
d
7.06–
13.9; IR (neat) n
(cmꢁ1) 3396, 2929, 1956, 1603, 1494, 1454, 1378,
D
7.03 (m, 1H), 7.00 (ddd, J1¼8.1 Hz, J2¼1.8 Hz, J3¼0.6 Hz, 1H), 6.79 (d,
J¼8.1 Hz,1H), 5.97 (s, 2H), 5.43 (dt, J1¼6.0 Hz, J2¼1.8 Hz,1H), 4.19 (d,
J¼1.5 Hz, 2H), 3.40 (s, 3H), 2.17 (d, J¼6.0 Hz, 1H); 13C NMR (75 MHz,
1190, 1086, 1020; MS (70 eV, EI) m/z (%): 202 (Mþ, 2.65), 107 (100).
According to the 1H NMR analysis of the crude reaction mixture
there was 4% of R-(þ)-5a remaining.
CDCl3)
59.8, 57.7; IR (neat)
d 147.8, 147.6, 134.5, 120.2, 108.1, 107.3, 101.2, 86.2, 82.2, 64.2,
n
(cmꢁ1) 3396, 2896, 2270, 2029, 1854, 1732,
4.5.2. (1S)-(þ)-2-Butyl-1-phenyl-2,3-butadien-1-ol (S-(þ)-6a)
To a solution of (4S)-(ꢁ)-4-hydroxy-4-phenyl-2-butynyl methyl
ether S-(ꢁ)-5a (52.3 mg, 96.1% ee, 0.30 mmol) and CuBr (8.8 mg,
0.06 mmol) in anhydrous Et2O (1.6 mL) was added dropwise a so-
lution of n-C4H9MgBr in Et2O (1.4 mL, 1 M in Et2O, 1.4 mmol) to
afford S-(þ)-6a20 (28.6 mg, 48%, 99.2% ee; HPLC condition: Chiralcel
1610, 1504, 1488, 1359, 1248, 1094, 1039; MS (70 eV, EI) m/z (%): 220
(Mþ, 100); HRMS calcd for C12H12O4 (Mþ): 220.0736, found:
220.0740.
4.4.7. (4R)-(þ)-4-Hydroxy-4-(40-methoxyphenyl)-2-butynyl
methyl ether (R-(þ)-5d)
OD-H, n-hexane/i-PrOH¼90/10, 0.8 mL/min,
l¼230 nm, tR 11.7
20
The reaction of (1S)-(þ)-1-(40-methoxyphenyl)-2-propynol S-
(þ)-4d18 (1.9950 g, 97.2% ee, 12.3 mmol), n-BuLi (10.8 mL, 2.5 M in
hexanes, 27.1 mmol), and MOMCl (1.40 mL, d¼1.06 g/mL, 1.484 g,
18.5 mmol) in anhydrous THF (30 mL) afforded R-(þ)-5d (1.5444 g,
61%, 96.7% ee; HPLC condition: Chiralcel AD-H, n-hexane/i-
(major), 12.2 (minor); [
(300 MHz, CDCl3)
a
]
D
þ141.4 (c 0.96, CHCl3)): liquid; 1H NMR
d
7.40–7.27 (m, 5H), 5.09 (s, 1H), 5.06–4.95 (m,
2H), 2.27 (d, J¼3.9 Hz,1H),1.88–1.73 (m, 2H),1.42–1.19 (m, 4H), 0.84
(t, J¼7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d
204.0, 142.1, 128.3,
(cmꢁ1
)
127.7, 126.7, 108.2, 79.8, 74.0, 29.6, 27.5, 22.3, 13.9; IR (neat)
n
PrOH¼90/10, 0.8 mL/min,
l
¼230 nm, tR 22.0 (major), 18.0 (minor);
3396, 2929, 1956, 1603, 1454, 1020; MS (70 eV, EI) m/z (%): 202 (Mþ,
3.19), 107 (100). According to the 1H NMR analysis of the crude
reaction mixture there was 6% of S-(ꢁ)-5a remaining.
20
[
a]
þ24.6 (c 1.06, CHCl3)): oil; 1H NMR (300 MHz, CDCl3)
d 7.49–
D
7.42 (m, 2H), 6.93–6.87 (m, 2H), 5.47 (dt, J1¼6.0 Hz, J2¼1.5 Hz, 1H),
4.19 (d, J¼1.5 Hz, 2H), 3.81 (s, 3H), 3.40 (s, 3H), 2.24 (d, J¼6.0 Hz,
1H); 13C NMR (100 MHz, CDCl3)
d
159.4, 132.8, 127.9, 113.8, 86.6,
4.5.3. (1R)-(ꢁ)-2-Butyl-1-(40-methylphenyl)-2,3-butadien-1-ol
(R-(ꢁ)-6b)
81.8, 63.8, 59.8, 57.4, 55.2; IR (neat) n
(cmꢁ1) 3412, 2935, 2276, 2014,
1893, 1611, 1587, 1512, 1359, 1249, 1176, 1093, 1033; MS (70 eV, EI)
m/z (%): 206 (Mþ, 74.7), 145 (100). Elemental analysis calcd for
C12H14O3 (%): C, 69.88; H, 6.84. Found: C, 69.82; H, 6.82.
To a solution of (4R)-(þ)-4-hydroxy-(40-methylphenyl)-2-butynyl
methyl ether R-(þ)-5b (57.2 mg, 99.2% ee, 0.30 mmol) and CuBr
(8.8 mg, 0.06 mmol) in anhydrous Et2O (1.6 mL) was added dropwise
a solution of n-C4H9MgBr in Et2O (1.4 mL, 1 M in Et2O, 1.4 mmol) to
afford R-(ꢁ)-6b (30.5 mg, 47%, 97.5% ee; HPLC condition: Chiralcel
4.4.8. (4S)-(ꢁ)-4-Hydroxy-4-(40-methoxyphenyl)-2-butynyl methyl
ether (S-(ꢁ)-5d)
OD-H, n-hexane/i-PrOH¼90/10, 0.8 mL/min,
l
¼230 nm, tR 6.3
20
The reaction of (1R)-(ꢁ)-1-(4-methoxyphenyl)-2-propynol R-
(ꢁ)-4d18 (1.1255 g, 96.7% ee, 7.0 mmol), n-BuLi (6.1 mL, 2.5 M in
hexanes, 15.3 mmol), and MOMCl (0.80 mL, d¼1.06 g/mL, 0.848 g,
10.4 mmol) in THF (30 mL) afforded S-(ꢁ)-5d (0.8744 g, 61%, 96.4%
(major), 5.9 (minor); [
a
]
ꢁ107.5 (c 0.83, CHCl3)): liquid; 1H NMR
D
(300 MHz, CDCl3)
d
7.26 (d, J¼7.8 Hz, 2H), 7.16 (d, J¼7.8 Hz, 2H), 5.07–
4.96 (m, 3H), 2.35 (s, 3H), 2.23 (d, J¼4.2 Hz, 1H), 1.87–1.72 (m, 2H),
1.42–1.19 (m, 4H), 0.85 (t, J¼7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3)
ee; HPLC condition: Chiralcel AD-H, n-hexane/i-PrOH¼90/10,
d 203.9,139.1,137.5,129.0,126.7,108.3, 79.8, 73.8, 29.6, 27.7, 22.3, 21.2,
20
0.8 mL/min,
l
¼230 nm, tR 18.0 (major), 21.9 (minor); [
a]
ꢁ19.5 (c
13.9; IR (neat) n
(cmꢁ1) 3406, 2928, 1955, 1614, 1513, 1030; MS (70 eV,
D
1.33, CHCl3)): oil; 1H NMR (300 MHz, CDCl3)
d
7.50–7.43 (m, 2H),
EI) m/z (%): 216 (Mþ, 0.58), 201 (MþꢁCH3, 8.16), 121 (100); HRMS
6.93–6.87 (m, 2H), 5.47 (d, J¼6.0 Hz, 1H), 4.19 (d, J¼1.5 Hz, 2H), 3.81
calcd for C15H20O (Mþ): 216.1514, found: 216.1515.
(s, 3H), 3.39 (s, 3H), 2.28 (d, J¼6.3 Hz,1H); 13C NMR (75 MHz, CDCl3)
d
n
159.5, 132.8, 127.9, 113.8, 86.5, 81.9, 63.9, 59.8, 57.6, 55.2; IR (neat)
(cmꢁ1) 3417, 2936, 2278, 2014, 1893, 1611, 1587, 1514, 1359, 1249,
4.5.4. (1S)-(þ)-2-Butyl-1-(40-methylphenyl)-2,3-butadien-1-ol
(S-(þ)-6b)
1174, 1094, 1032; MS (70 eV, EI) m/z (%): 206 (Mþ, 62.5), 145 (100);
To
a
solution of (4S)-(ꢁ)-4-hydroxy-(40-methylphenyl)-2-
HRMS calcd for C12H14O3 (Mþ): 206.0943, found: 206.0943.
butynyl methyl ether S-(ꢁ)-5b (57.3 mg, 98.6% ee, 0.30 mmol) and
CuBr (8.6 mg, 0.06 mmol) in Et2O (1.6 mL) was added dropwise
a solution of n-C4H9MgBr in Et2O (1.4 mL, 1 M in Et2O, 1.4 mmol) to
afford S-(þ)-6b (29.1 mg, 45%, 98.9% ee; HPLC condition: Chiralcel
4.5. CuBr-catalyzed reaction of optically active 4-aryl-4-
hydroxy-2-butynyl methyl ethers 5a–5d with Grignard
reagents
OD-H, n-hexane/i-PrOH¼90/10, 0.8 mL/min,
l
¼230 nm, tR 5.8
20
(major), 6.3 (minor); [
(300 MHz, CDCl3)
a]
þ106.2 (c 0.76, CHCl3)): liquid; 1H NMR
D
4.5.1. (1R)-(ꢁ)-2-Butyl-1-phenyl-2,3-butadien-1-ol (R-(ꢁ)-6a)
Typical procedure. To a dried Schlenk tube were added CuBr
(8.7 mg. 0.06 mmol), anhydrous Et2O (1.6 mL), and (4R)-(þ)-4-hy-
droxy-4-phenyl-2-butynyl methyl ether R-(þ)-5a (53.0 mg, 98.2%
ee, 0.30 mmol) at room temperature. A solution of n-C4H9MgBr in
Et2O (1.4 mL, 1 M in Et2O, 1.4 mmol) was then added dropwise to
this resulting mixture at ꢁ30 ꢀC under nitrogen. After the addition
was over, the reaction mixture was stirred for 10.5 h as monitored
by TLC, quenched with saturated ammonium chloride solution
(2 mL), extracted with ether (3ꢂ10 mL), washed with saturated
brine (10 mL), and dried over anhydrous sodium sulfate. Evapora-
tion and column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate¼20/1) afforded R-(ꢁ)-6a20 (30.2 mg, 50%, 99.5%
d
7.26 (d, J¼8.1 Hz, 2H), 7.15 (d, J¼8.1 Hz, 2H),
5.08–4.95 (m, 3H), 2.35 (s, 3H), 2.22 (d, J¼4.2 Hz, 1H), 1.87–1.72 (m,
2H), 1.42–1.19 (m, 4H), 0.84 (t, J¼7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 203.9, 139.1, 137.5, 129.0, 126.7, 108.3, 79.8, 73.8, 29.6, 27.7,
22.3, 21.2,13.9; IR (neat) n
(cmꢁ1) 3397, 2927,1955,1614,1513,1030;
MS (70 eV, EI) m/z (%): 216 (Mþ, 0.62), 201 (MþꢁCH3, 8.63), 121
(100); HRMS calcd for C15H20O (Mþ): 216.1514, found: 216.1512.
4.5.5. (1R)-(ꢁ)-2-Butyl-1-(30,40-methylenedioxyphenyl)-2,3-
butadien-1-ol (R-(ꢁ)-6c)
To a mixture of (4R)-(þ)-4-hydroxy-4-(30,40-methylenedioxy-
phenyl)-2-butynyl methyl ether R-(þ)-5c (68.0 mg, 98.6% ee,
0.31 mmol) and CuBr (8.5 mg, 0.06 mmol) in anhydrous Et2O
(1.6 mL) was added dropwise a solution of n-C4H9MgBr in Et2O
(1.4 mL, 1 M in Et2O, 1.4 mmol) to afford R-(ꢁ)-6c6b (19.7 mg, 26%,
ee; HPLC condition: Chiralcel OD-H, n-hexane/i-PrOH¼90/10,
20
0.8 mL/min,
l
¼230 nm, tR 12.5 (major), 11.7 (minor); [
a
]
ꢁ131.8 (c
D

3702
J. Li et al. / Tetrahedron 65 (2009) 3695–3703
98.5% ee; HPLC condition: Chiralcel OD-H, n-hexane/i-PrOH¼90/10,
0.06 mmol) in anhydrous Et2O (1.6 mL) was added dropwise a so-
lution of C2H5MgBr in Et2O (1.4 mL, 1 M in Et2O, 1.4 mmol) to afford
S-(þ)-6e (17.5 mg, 35%, 99.5% ee; HPLC condition: Chiralcel OD-H,
20
0.8 mL/min,
l¼230 nm, tR 9.8 (major), 7.9 (minor); [
a]
ꢁ97.6 (c
D
1.23, CHCl3)): liquid; 1H NMR (300 MHz, CDCl3)
d
6.86 (d, J¼1.5 Hz,
1H), 6.83 (dd, J1¼8.1 Hz, J2¼1.5 Hz,1H), 6.76 (d, J¼7.8 Hz,1H), 5.95 (s,
2H), 5.06–4.95 (m, 3H), 2.26–2.18 (m, 1H), 1.89–1.69 (m, 2H), 1.43–
1.19 (m, 4H), 0.84 (t, J¼7.2 Hz, 3H). According to the 1H NMR analysis
of the crude reaction mixture there was 6% of R-(þ)-5c remaining.
n-hexane/i-PrOH¼90/10, 0.8 mL/min, ¼230 nm, tR 7.2 (major), 7.8
l
20
(minor); [
CDCl3)
a
]
D
þ128.7 (c 0.35, CHCl3)): liquid; 1H NMR (300 MHz,
d
7.41–7.27 (m, 5H), 5.14–5.09 (m, 1H), 5.09–4.98 (m, 2H),
2.25 (d, J¼4.2 Hz, 1H), 1.90–1.76 (m, 2H), 0.97 (t, J¼7.5 Hz, 3H); 13C
NMR (100 MHz, CDCl3) d 203.9, 142.1, 128.2, 127.6, 126.6, 109.8, 80.0,
4.5.6. (1S)-(þ)-2-Butyl-1-(30,40-methylenedioxyphenyl)-2,3-
butadien-1-ol (S-(þ)-6c)
74.0, 20.8, 11.9; IR (neat) n
(cmꢁ1) 3384, 2966, 1957, 1603, 1454,
1018; MS (70 eV, EI) m/z (%): 174 (Mþ, 4.33), 173 (MþꢁH, 16.6), 107
(100). According to the 1H NMR analysis of the crude reaction
mixture there was 5% of S-(ꢁ)-5a remaining.
To a mixture of (4S)-(ꢁ)-4-hydroxy-4-(30,40-methylenedioxy-
phenyl)-2-butynyl methyl ether S-(ꢁ)-5c (64.5 mg, 97.1% ee,
0.29 mmol) and CuBr (8.6 mg, 0.06 mmol) in anhydrous Et2O (1.6 mL)
was added dropwise a solution of n-C4H9MgBr in Et2O (1.4 mL, 1 M in
Et2O, 1.4 mmol) to afford S-(þ)-6c6b (20.3 mg, 28%, 96.9% ee; HPLC
4.5.11. (1R)-(ꢁ)-1-Phenyl-2-propyl-2,3-butadien-1-ol (R-(ꢁ)-6f)
To a solution of (4R)-(þ)-4-hydroxy-4-phenyl-2-butynyl methyl
ether R-(þ)-5a (51.6 mg, 98.2% ee, 0.29 mmol) and CuBr (8.7 mg,
0.06 mmol) in anhydrous Et2O (1.6 mL) was added dropwise a solu-
tion of n-C3H7MgBr in Et2O (1.4 mL,1 M in Et2O,1.4 mmol) to afford R-
(ꢁ)-6f13a (20.2 mg, 37%, 99.7% ee; HPLC condition: Chiralcel OD-H, n-
condition: Chiralcel OD-H, n-hexane/i-PrOH¼90/10, 0.8 mL/min,
20
l
¼230 nm, tR 7.9 (major), 9.9 (minor); [
a
]
þ96.2 (c 1.11, CHCl3)):
D
liquid; 1H NMR (300 MHz, CDCl3)
d
6.86 (d, J¼1.5 Hz, 1H), 6.83 (dd,
J1¼7.8 Hz, J2¼1.5 Hz,1H), 6.76 (d, J¼7.8 Hz,1H), 5.95 (s, 2H), 5.06–4.95
(m, 3H), 2.24 (d, J¼3.9 Hz, 1H), 1.89–1.69 (m, 2H), 1.43–1.19 (m, 4H),
0.84 (t, J¼7.2 Hz, 3H). According to the 1H NMR analysis of the crude
reaction mixture there was 6% of S-(ꢁ)-5c remaining.
hexane/i-PrOH¼90/10, 0.8 mL/min, ¼230 nm, tR 7.4 (major), 6.8
l
20
20
(minor); [
a
]
ꢁ123.2 (c0.60, CHCl3) (lit.13a
[a]
ꢁ120 (c1.75, CHCl3))):
D
D
liquid; 1H NMR (300 MHz, CDCl3)
d 7.42–7.27 (m, 5H), 5.13–5.07 (m,
1H), 5.06–4.95 (m, 2H), 2.24 (d, J¼4.2 Hz,1H),1.87–1.72 (m, 2H),1.48–
4.5.7. (1R)-(ꢁ)-2-Butyl-1-(40-methoxyphenyl)-2,3-butadien-1-ol
(R-(ꢁ)-6d)
1.34 (m, 2H), 0.86 (t, J¼7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 204.0,
142.1, 128.3, 127.8, 126.7, 108.1, 79.8, 74.1, 30.0, 20.7, 13.8; IR (neat)
n
To
a
solution of (4R)-(þ)-4-hydroxy-(40-methoxyphenyl)-2-
(cmꢁ1) 3396, 2959, 1956, 1602, 1453, 1016; MS (70 eV, EI) m/z (%) 188
(Mþ, 4.28), 107 (100); HRMS calcd for C13H16O (Mþ): 188.1201, found:
188.1203. According to the 1H NMR analysis of the crude reaction
mixture there was 7% of R-(þ)-5a remaining.
butynyl methyl ether R-(þ)-5d (61.0 mg, 96.7% ee, 0.30 mmol) and
CuBr (8.8 mg, 0.06 mmol) in anhydrous Et2O (1.6 mL) was added
dropwise a solution of n-C4H9MgBr in Et2O (1.4 mL, 1 M in Et2O,
1.4 mmol) to afford R-(ꢁ)-6d6b (33.2 mg, 48%, 95.3% ee; HPLC condi-
tion: Chiralcel OD-H, n-hexane/i-PrOH¼90/10, 0.8 mL/min,
l
¼230 nm,
4.5.12. (1S)-(þ)-1-Phenyl-2-propyl-2,3-butadien-1-ol (S-(þ)-6f)
To a solution of (4S)-(ꢁ)-4-hydroxy-4-phenyl-2-butynyl methyl
ether S-(ꢁ)-5a (52.2 mg, 96.1% ee, 0.30 mmol) and CuBr (8.6 mg,
0.06 mmol) in anhydrous Et2O (1.6 mL) was added dropwise a so-
lution of n-C3H7MgBr in Et2O (1.4 mL, 1 M in Et2O, 1.4 mmol) to
afford S-(þ)-6f (21.9 mg, 39%, 97.9% ee; HPLC condition: Chiralcel
20
tR 8.6 (major), 7.4 (minor); [
a
]
ꢁ144.6 (c 0.57, CHCl3)): liquid; 1H NMR
D
(300 MHz, CDCl3) d 7.31–7.27 (m, 2H), 6.90–6.86 (m, 2H), 5.05–4.96 (m,
3H), 3.81 (s, 3H), 2.21 (d, J¼4.2 Hz,1H),1.87–1.71 (m, 2H),1.43–1.19 (m,
4H), 0.84 (t, J¼7.2 Hz, 3H). According to the 1H NMR analysis of the
crude reaction mixture there was 7% of R-(þ)-5d remaining.
OD-H, n-hexane/i-PrOH¼90/10, 0.8 mL/min,
l
¼230 nm, tR 6.9
20
4.5.8. (1S)-(þ)-2-Butyl-1-(40-methoxyphenyl)-2,3-butadien-1-ol
(S-(þ)-6d)
(major), 7.4 (minor); [
(300 MHz, CDCl3)
a]
þ122.2 (c 0.72, CHCl3)): liquid; 1H NMR
D
d
7.42–7.27 (m, 5H), 5.13–5.07 (m, 1H), 5.06–4.95
To
a
solution of (4S)-(ꢁ)-4-hydroxy-(40-methoxyphenyl)-2-
(m, 2H), 2.27 (d, J¼4.5 Hz, 1H), 1.88–1.70 (m, 2H), 1.48–1.34 (m, 2H),
0.87 (t, J¼7.2 Hz, 3H). According to the 1H NMR analysis of the crude
reaction mixture there was 5% of S-(ꢁ)-5a remaining.
butynyl methyl ether S-(ꢁ)-5d (62.0 mg, 96.4% ee, 0.30 mmol) and
CuBr (8.7 mg, 0.06 mmol) in anhydrous Et2O (1.6 mL) was added
dropwise a solution of n-C4H9MgBr in Et2O (1.4 mL, 1 M in Et2O,
1.4 mmol) to afford S-(þ)-6d6b (34.3 mg, 49%, 95.8% ee; HPLC
4.5.13. (1R)-(ꢁ)-2-Pentyl-1-phenyl-2,3-butadien-1-ol (R-(ꢁ)-6g)
To a solution of (4R)-(þ)-4-hydroxy-4-phenyl-2-butynyl methyl
ether R-(þ)-5a (53.2 mg, 98.2% ee, 0.30 mmol) and CuBr (8.6 mg,
0.06 mmol) in anhydrous Et2O (1.6 mL) was added dropwise a so-
lution of n-C5H11MgBr in Et2O (1.4 mL, 1 M in Et2O, 1.4 mmol) for
8 h to afford R-(ꢁ)-6g (31.8 mg, 49%, 99.6% ee; HPLC condition:
condition: Chiralcel OD-H, n-hexane/i-PrOH¼90/10, 0.8 mL/min,
20
l
¼230 nm, tR 7.5 (major), 8.6 (minor); [
a
]
þ138.3 (c 0.59, CHCl3)):
D
liquid; 1H NMR (300 MHz, CDCl3)
d 7.32–7.27 (m, 2H), 6.91–6.84 (m,
2H), 5.05–4.96 (m, 3H), 3.80 (s, 3H), 2.25 (d, J¼4.2 Hz, 1H), 1.87–1.71
(m, 2H), 1.43–1.31 (m, 2H), 1.31–1.19 (m, 2H), 0.84 (t, J¼7.2 Hz, 3H).
Chiralcel OD-H, n-hexane/i-PrOH¼90/10, 0.8 mL/min, ¼230 nm, tR
l
20
4.5.9. (1R)-(ꢁ)-2-Ethyl-1-phenyl-2,3-butadien-1-ol (R-(ꢁ)-6e)
To a solution of (4R)-(þ)-4-hydroxy-4-phenyl-2-butynyl methyl
ether R-(þ)-5a (53.2 mg, 98.2% ee, 0.30 mmol) and CuBr (8.8 mg,
0.06 mmol) in anhydrous Et2O (1.6 mL) was added dropwise a so-
lution of C2H5MgBr in Et2O (1.4 mL, 1 M in Et2O, 1.4 mmol) to afford
R-(ꢁ)-6e13a (20.8 mg, 40%, 99.5% ee; HPLC condition: Chiralcel OD-
6.8 (major), 6.2 (minor); [
NMR (300 MHz, CDCl3)
a]
ꢁ118.5 (c 1.05, CHCl3)): liquid; 1H
D
d
7.40–7.27 (m, 5H), 5.12–5.07 (m, 1H),
5.06–4.95 (m, 2H), 2.31 (d, J¼3.9 Hz, 1H), 1.92–1.71 (m, 2H), 1.47–
1.33 (m, 2H), 1.32–1.18 (m, 4H), 0.85 (t, J¼6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3)
d 204.0, 142.1, 128.3, 127.7, 126.7, 108.3, 79.8, 74.1,
31.4, 27.8, 27.1, 22.4, 14.0; IR (neat) n
(cmꢁ1) 3387, 2928, 1956, 1603,
H, n-hexane/i-PrOH¼90/10, 0.8 mL/min,
l
¼230 nm, tR 7.8 (major),
1453, 1018; MS (70 eV, EI) m/z (%) 216 (Mþ, 2.89), 201 (MþꢁCH3,
2.69), 107 (100); HRMS calcd for C15H20O (Mþ): 216.1514, found:
216.1512. According to the 1H NMR analysis of the crude reaction
mixture there was 11% of R-(þ)-5a remaining.
20
7.2 (minor);
[a]
D
ꢁ129.8 (c 0.54, CHCl3)): liquid; 1H NMR
(300 MHz, CDCl3)
d
7.41–7.27 (m, 5H), 5.14–5.09 (m, 1H), 5.09–4.98
(m, 2H), 2.26 (d, J¼3.3 Hz, 1H), 1.90–1.76 (m, 2H), 0.97 (t, J¼7.5 Hz,
3H). According to the 1H NMR analysis of the crude reaction mix-
ture there was 8% of R-(þ)-5a remaining.
4.5.14. (1R)-(ꢁ)-2-Hexyl-1-phenyl-2,3-butadien-1-ol (R-(ꢁ)-6h)
To a solution of (4R)-(þ)-4-hydroxy-4-phenyl-2-butynyl methyl
ether R-(þ)-5a (51.6 mg, 98.2% ee, 0.29 mmol) and CuBr (8.8 mg,
0.06 mmol) in anhydrous Et2O (1.6 mL) was added dropwise a so-
lution of n-C6H13MgBr in Et2O (1.4 mL, 1 M in Et2O, 1.4 mmol) to
4.5.10. (1S)-(þ)-2-Ethyl-1-phenyl-2,3-butadien-1-ol (S-(þ)-6e)
To a solution of (4S)-(ꢁ)-4-hydroxy-4-phenyl-2-butynyl methyl
ether S-(ꢁ)-5a (49.9 mg, 96.1% ee, 0.28 mmol) and CuBr (8.6 mg,

J. Li et al. / Tetrahedron 65 (2009) 3695–3703
3703
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Nedolya, N. A. Synthesis 2004, 735; (h) Tius, M. A. Acc. Chem. Res. 2003, 36, 284;
(i) Wei, L.-L.; Xiong, H.; Hsung, R. P. Acc. Chem. Res. 2003, 36, 773; (j) Lu, X.;
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afford R-(ꢁ)-6h (34.6 mg, 51%, 99.6% ee; HPLC condition: Chiralcel
OD-H, n-hexane/i-PrOH¼90/10, 0.8 mL/min,
l¼230 nm, tR 6.6
20
(major), 6.1 (minor); [
a
]
ꢁ114.8 (c 1.12, CHCl3)): liquid; 1H NMR
D
(300 MHz, CDCl3)
d
7.40–7.27 (m, 5H), 5.12–5.07 (m, 1H), 5.06–4.95
(m, 2H), 2.29 (br s, 1H), 1.87–1.72 (m, 2H), 1.44–1.33 (m, 2H), 1.33–
1.15 (m, 6H), 0.85 (t, J¼6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d
204.0, 142.1, 128.3, 127.7, 126.7, 108.3, 79.8, 74.1, 31.6, 28.9, 27.9,
27.4, 22.6, 14.0; IR (neat)
n
(cmꢁ1) 3390, 2927, 1956, 1603, 1454,
1021; MS (70 eV, EI) m/z (%) 230 (Mþ, 5.29), 107 (100); HRMS calcd
for C16H22O (Mþ): 230.1671, found: 230.1675. According to the 1H
NMR analysis of the crude reaction mixture there was 10% of R-
(þ)-5a remaining.
Acknowledgements
Financial support from the National Natural Science Foundation
of China (20732005) and the State Basic and Development Research
Program (2006CB806105) is greatly appreciated. S.M. is a Qiu Shi
Adjunct Professor at Zhejiang University. We thank Mr. Wangqing
Kong in this group for reproducing the results presented in entry 2
of Table 2 and entries 3 and 10 of Table 6.
9. Crabbe´, P.; Fillion, H.; Andre´, D.; Luche, J.-L. J. Chem. Soc., Chem. Commun.1979, 859.
10. Yu, C.-M.; Kim, C.; Kweon, J.-H. Chem. Commun. 2004, 2494.
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8, 4089.
Supplementary data
12. Ma, S.; Hou, H.; Zhao, S.; Wang, G. Synthesis 2002, 1643.
13. (a) Yu, C.-M.; Yoon, S.-K.; Baek, K.; Lee, J.-Y. Angew. Chem., Int. Ed. 1998, 37, 2392;
(b) Schultz-Fademrecht, C.; Wibbeling, B.; Fro¨hlich, R.; Hoppe, D. Org. Lett. 2001,
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G.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 496.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.02.061.
References and notes
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