Studies on the Cu(I)-catalyzed regioselective anti-carbometallation of secondary terminal propargylic alcohols

Article abstract of DOI:10.1021/jo0524021

A highly regioselective Cu(I)-catalyzed anti-carbometallation of secondary terminal propargylic alcohols with 1° alkyl or aryl Grignard reagents affording 2-substituted allylic alcohols was developed. By using this method, optically active allylic alcohols can be prepared from the optically active propargylic alcohols without obvious loss of the enantiopurity. The cyclic organometallic intermediate formed may undergo an iodination or a Pd(0)-catalyzed coupling reaction to afford stereo-defined allylic alcohols.

Full text of DOI:10.1021/jo0524021

Studies on the Cu(I)-Catalyzed Regioselective anti-Carbometallation
of Secondary Terminal Propargylic Alcohols
Zhan Lu† and Shengming Ma*,†,‡
Laboratory of Molecular Recognition and Synthesis, Department of Chemistry, Zhejiang UniVersity,
Hangzhou 310027, Zhejiang, People’s Republic of China, and State Key Laboratory of Organometallic
Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, People’s Republic of China
masm@mail.sioc.ac.cn
ReceiVed NoVember 21, 2005
A highly regioselective Cu(I)-catalyzed anti-carbometallation of secondary terminal propargylic alcohols
with 1° alkyl or aryl Grignard reagents affording 2-substituted allylic alcohols was developed. By using
this method, optically active allylic alcohols can be prepared from the optically active propargylic alcohols
without obvious loss of the enantiopurity. The cyclic organometallic intermediate formed may undergo
an iodination or a Pd(0)-catalyzed coupling reaction to afford stereo-defined allylic alcohols.
Introduction
reaction of secondary propargylic alcohols afforded a mixture
of two regioisomeric products, while the reaction of tertiary
propargylic alcohols afforded the linear products as the major.3c,d
In one of our ongoing projects, we need to prepare the highly
loaded secondary allylic alcohols. However, when we ran the
similar reaction of 3-butyn-2-ol with n-C5H11MgBr in ether
under the catalysis of 10 mol % CuI at -10 °C to room
temperature,3 a mixture of 3-methyleneoctan-2-ol (2a) and
3-nonen-2-ol (3a) in 32% yield and with a ratio of 19:81 was
formed upon hydrolysis. In this reaction, 3-nonen-2-ol (3a) was
the major product (entry 1, Table 1). Thus, detailed studies were
performed to optimize the regioselectivity for this Cu(I)-
catalyzed carbometallation of secondary propargylic alcohols,
with the aim to prepare 2a-type products with high selectivity.
In this paper, we wish to disclose these results.
As a result of the presence of the carbon-carbon triple bond
and the hydroxyl group, as well as the easy availability of
propargylic alcohols,1 their synthetic potentials have been
extensively demonstrated.2 Duboudin et al. reported that the Cu-
(I)-catalyzed carbomagnesiation of primary propargyl alcohol
with Grignard reagents in ether leads to the highly selective
formation of 2-substituted prop-2-enols via the hydroxyl-group
controlled anti-carbomagnesiation.3,4 It was also noted that the
* Corresponding author. Fax: (+86) 21-64167510.
† Zhejiang University.
‡ Chinese Academy of Sciences.
(1) For reviews on the synthesis of chiral propargylic alcohols, see: (a)
Frantz, D. E.; Fassler, R.; Tomooka, C. S.; Carreira, E. M. Acc. Chem.
Res. 2000, 33, 373. (b) He, Q.; Ma, S. Chin. J. Org. Chem. 2002, 22, 375.
(c) Pu, L. Tetrahedron 2003, 59, 9873.
(2) (a) Nakamura, M.; Liang, C.; Nakamura, E. Org. Lett. 2004, 6, 2015.
(b) Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2002, 124, 4178. (c)
Trost, B. M.; Oi, S. J. Am. Chem. Soc. 2001, 123, 1230. (d) Ma, S.; Wu,
B.; Zhao, S. Org. Lett. 2003, 5, 4429. (e) Trost, B. M.; Ball, Z. T.; Joge,
T. Angew. Chem., Int. Ed. 2003, 42, 3415. (f) Nishibayashi, Y.; Inada, Y.;
Yoshikawa, M.; Hidai, M.; Uemura, S. Angew. Chem., Int. Ed. 2003, 42,
1495. (g) Nishibayashi, Y.; Yoshikawa, M.; Inada, Y.; Milton, M. D.; Hidai,
M.; Uemura, S. Angew. Chem., Int. Ed. 2003, 42, 2681. (h) Nishibayashi,
Y.; Inada, Y.; Hidai, M.; Uemura, S. J. Am. Chem. Soc. 2003, 125, 6060.
(3) (a) Duboudin, J. G.; Jousseaume, B. Synth. Commun. 1979, 9, 53.
(b) Duboudin, J. G.; Jousseaume, B. J. Organomet. Chem. 1979, 168, 1.
For carbometallation of propargylic alcohols affording regioisomeric
mixtures, see: (c) Normant, J. F.; Alexakis, A.; Villieras, J. J. Organomet.
Chem. 1973, 57, C99. (d) Alexakis, A.; Normant, J. F.; Villieras, J. J. Mol.
Catal. 1975/76, 1, 43.
Results and Discussion
When a solution of n-C5H11MgBr in THF was used instead
of that in Et2O, the ratio of 2a/3a was reversed to 87:13, with
a combined yield of 42% (entry 2, Table 1). When THF was
applied throughout the whole reaction process, the reaction
afforded 2a and 3a in combined 43% yield with a ratio of 2a/
3a as high as 93:7 (entry 3, Table 1). Similar results were
(4) (a) Tessier, P. E.; Nguyen, N.; Clay, M. D.; Fallis, A. G. Org. Lett.
2005, 7, 767. (b) Tessier, P. E.; Penwell, A. J.; Souza, F. E. S.; Fallis, A.
G. Org. Lett. 2003, 5, 2989.
10.1021/jo0524021 CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/02/2006
J. Org. Chem. 2006, 71, 2655-2660
2655

Ma and Lu
TABLE 1. Optimization of Reaction Conditions for CuI-Catalyzed Addition of n-C5H11MgBr with 3-Butyn-2-ol
entry
solvent
Et2O
Et2O
THF
temp
catalyst (mol %)
time (h)
2a/3a
yield of 2a + 3ab (%)
1a
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
-10 °C∼rt
-10 °C∼rt
-10 °C∼rt
-10 °C∼rt
-10 °C∼rt
-10 °C∼rt
-78 °C∼rt
-78 °C∼rt
-78 °C∼rt
-78 °C∼rt
-78 °C∼rt
-78 °C∼rt
0 °C
10
10
10
10
10
10
10
10
10
20
50
100
50
50
50
50
50
17
5
5
5
5
5
5
5
5
5
5
5
5
10
5.5
12
7
19:81
87:13
93:7
88:12
92:8
92:8
93:7
93:7
93:7
91:9
93:7
87:13
89:11
86:14
91:9
91:9
91:9
32
42
43
42
52
44
44
19
46
63
75
70
76
73
67
66
57
1,4-dioxane
benzene
toluene
benzene
THF
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
-10 °C
-20 °C
-30 °C
-40 °C
a A solution of n-C5H11MgBr in Et2O was used. b Combined yield determined by 1H NMR spectra using 1,3,5-trimethylbenzene as the internal standard.
TABLE 2. Effect of Catalyst on the Addition of n-C5H11MgBr with 3-Butyn-2-ol
entry
CuX
time (h)
yield of 2a + 3aa (%)
2a:3a
1
2
3
4
5
CuI
5
17.5
17.5
7
46
43
47
29
32
93:7
95:5
94:6
91:9
91:9
CuCl
CuBr
CuCl2
CuBr2
7
1
a Combined yield determined by H NMR spectra using 1,3,5-trimethylbenzene as the internal standard.
observed when a solution of 3-butyn-2-ol in 1,4-dioxane,
benzene, or toluene was treated with a THF solution of n-C5H11-
MgBr at -10 °C to rt (entries 4-6, Table 1). When the reaction
was performed at -78 °C to rt, the yields were lower (entries
7 and 8, Table 1). When the amount of CuI was increased to
20 or 50%, the yields were higher, with a similar regioselectivity
(entries 9-11, Table 1). With 100 mol % of CuI, both the yield
and the ratio were poorer (compare entry 11 with entry 12, Table
1). With 50 mol % of CuI, the effect of temperature was also
studied (entries 14-17, Table 1). Thus, we concluded conditions
A (entry 11, Table 1) for Table 4 should be 10 mmol of alcohol
in 15 mL of toluene, 50 mol % CuI, 3.5 equiv of Grignard
reagents, and at a temperature of -78 °C to rt.
The effect of different Cu(I) or Cu(II) catalysts was also
studied (Table 2), implying that the results of the Cu(I)-catalyst
(entries 1-3, Table 2) are better than those with Cu(II)-catalysts
(entries 4 and 5, Table 2).
It should be noted that the 10 mol % CuCl-catalyzed reaction
afforded the products in slightly better regioselectivity than the
reaction catalyzed by CuI (compare entry 2 with entry 1, Table
2). Thus, the conditions for the CuCl-catalyzed reaction of 1a
with the THF solution of n-C5H11MgBr in toluene were also
optimized (Table 3). The best results were observed when the
reaction was conducted at -78 °C to rt (entry 3, Table 3).
With conditions A and B (conditions B for Table 4: 10 mmol
of alcohol in 15 mL of toluene, 10 mol % CuCl, 3.5 equiv of
Grignard reagents, and -78 °C to rt) in hand, the scope of the
Cu(I)-catalyzed carbometallation of a THF solution of R2MgBr
with different secondary propargylic alcohols in toluene was
studied with some typical results summarized in Table 4. From
the results in Table 4, the following points should be noted:
(1) The yields under conditions A are usually higher than
conditions B, while the regioselectivity for the reaction catalyzed
by CuCl is, in most cases, higher than that with CuI. (2) For
the substrates with R1 and R2 being alkyl, the regioselectivity
is R1-dependent: the regioselectivity for R1 being Me is much
higher than that with R1 being Et (1b), n-Pr (1c), or n-C5H11
(1d) (compare entries 1-10 with entries 13-22, Table 4). (3)
The results of R2 ) phenyl were very poor (entries 11 and 12,
Table 4). (4) The two products 2 and 3 can be easily separated
by chromatography on silica gel.
If iodination was applied instead of protonation, 4-iodo-3-
(n-pentyl)-3(Z)-buten-2-ol 4a can be isolated in 66% yield,
which may undergo Sonogashira coupling with terminal alkynes
2656 J. Org. Chem., Vol. 71, No. 7, 2006

Studies on Cu(I)-Catalyzed anti-Carbometallation
TABLE 3. Optimization of Reaction Conditions for CuCl-Catalyzed Addition of n-C5H11MgBr with 3-Butyn-2-ol
entry
temp
time (h)
2a:3a
yield of 2a + 3aa (%)
1
2
3
-10 °C∼rt
-30 °C∼rt
-78 °C∼rt
15
20.5
17.5
87:13
93:7
95:5
39
28
43
a Combined yield determined by H NMR spectra using 1,3,5-trimethylbenzene as the internal standard.
1
TABLE 4. CuX-Catalyzed Addition of Grignard Reagents with Terminal Propargylic Alcohols
entry
R1
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
Et
n-C3H7
n-C3H7
n-C5H11
n-C5H11
R2
conditionsa
time (h)
2:3b
yield of 2c (%)
yield of 3c (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
n-C5H11
n-C5H11
n-C6H13
n-C6H13
n-C7H15
n-C7H15
n-C8H17
n-C8H17
n-C4H9
n-C4H9
Ph
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
5
18
18
18
18
18
18
18
18
18
18
18
5
17
17
17
22
18
18
15
19
19
93:7 (2a:3a)
94:6 (2a:3a)
90:10 (2b:3b)
92:8 (2b:3b)
90:10 (2c:3c)
93:7 (2c:3c)
88:12 (2d:3d)
91:9 (2d:3d)
92:8 (2e:3e)
94:6 (2e:3e)
41:59 (2f:3f)
42:58 (2f:3f)
80:20 (2g:3g)
85:15 (2g:3g)
86:14 (2h:3h)
83:17 (2h:3h)
79:21 (2i:3i)
82:18 (2i:3i)c
77:23 (2j:3j)
86:14 (2j:3j)
83:17 (2k:3k)
88:12 (2k:3k)
70
43
62
39
77
45
73
29
65
37
20
18
58
17
61
18
75
18
50
24
59
19
5
3
7
4
8
4
10
3
4
1
30
24
13
2
8
4
21
4
14
3
12
3
Ph
n-C5H11
n-C5H11
n-C6H13
n-C6H13
n-C8H17
n-C8H17
n-C5H11
n-C5H11
n-C5H11
n-C5H11
a Conditions A: 10 mmol of alcohol, 3.5 equiv of Grignard reagents (1 M), 50 mol % CuI, 15 mL of toluene, and -78 °C∼rt. Conditions B: 10 mmol
of alcohol, 3.5 equiv of Grignard reagents, 10 mol % CuCl, 15 mL of toluene, and -78 °C∼rt. b Determined by NMR analysis. c Isolated yield.
and Kumada-type coupling with PhMgBr to afford the corre-
sponding coupling products 6a-c and 7a, respectively(Scheme
1).5 The coupling reaction with PhB(OH)2 or n-C4H9ZnBr gave
very poor yields of the protonation product 2a as the major
byproduct.
an obvious loss of the enantiopurity either by protonation or
by iodination in 63 or 59% isolated yields, respectively (Scheme
3). The absolute configurations of (R)-(+)-2a and (R)-(+)-4a
was tentatively assigned on the basis of the assumption that no
reaction occurred to the chiral center in (R)-1a.
The in-situ formed cyclic organometallic intermediate A may
also undergo a Pd-catalyzed Kumada-type coupling reaction
directly with PhI to afford 7a and 8a in 70% combined yield
with a ratio of 92:8 by NMR (Scheme 2).4,6 After chromato-
graphic separation, pure 7a was isolated easily in 62% yield.
With optically active (R)-3-butyn-2-ol ((R)-1a),7,8 optically
active allylic alcohols (R)-2a and (R)-4a can be prepared without
In conclusion, a highly regio- and stereoselective Cu(I)-
catalyzed carbometallation of secondary propargylic alcohols
with alkyl Grignard reagents affording 2-substituted allylic
alcohols was developed upon reacting with H+ or I+. The A-type
cyclic organometallic intermediate formed may undergo iodi-
nation or a Pd(0)-catalyzed coupling reaction to afford stereo-
defined allylic alcohols. The iodide formed by iodination may
(5) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467. (b) Kollhofer, A.; Pullmann, T.; Plenio, H. Angew. Chem., Int. Ed.
2003, 42, 1056. (c) Tykwinski, R. Angew. Chem., Int. Ed. 2003, 42, 1566.
(d) Gelman, D.; Buchwald, S. Angew. Chem., Int. Ed. 2003, 42, 5993. (e)
Sakai, N.; Annaka, K.; Konakahara, T. Org. Lett. 2004, 6, 1527. (f) Ma,
S.; Ren, H.; Wei, Q. J. Am. Chem. Soc. 2003, 125, 4817. (g) Shi, M.; Liu,
L.; Tang, J. J. Org. Chem. 2005, 70, 10420.
(6) (a) Duboudin, J. G.; Jousseaume, B.; Bonakdar, A. J. Organomet.
Chem. 1979, 168, 227. (b) Duboudin, J. G.; Jousseaume, B. J. Organomet.
Chem. 1979, 168, 233. (c) Negishi, E.; Zhang, Y.; Cederbaum, F. E.; Webb,
M. B. J. Org. Chem. 1986, 51, 4080. (d) Fallis, A. G.; Forgione, P.
Tetrahedron 2001, 57, 5899.
(7) Gallagher, W. P.; Maleczka, R. E. J. Org. Chem. 2003, 68, 6775.
(8) The sample used in this study was purchased from Acros Organics.
J. Org. Chem, Vol. 71, No. 7, 2006 2657

Ma and Lu
SCHEME 1
SCHEME 2
General Procedure I for the Synthesis of Propargylic Alco-
hols. Several drops of ethyl bromide were added to a mixture of
magnesium turnings (120 mmol) and I2 (a few crystals) in THF
under a nitrogen atmosphere. Upon the initiation of the Grignard
reaction, the remaining ethyl bromide (120 mmol) was added
dropwise, which was followed by stirring for 2 h at room
temperature. A stream of acetylene was bubbled at -20 °C (not
above 10 °C) for 45 min. Then an aldehyde (100 mmol) was added
at less than -30 °C, which was followed by a natural warming to
room temperature. After the complete conversion of the starting
material, as monitored by TLC, the reaction mixture was cooled to
0 °C, quenched with saturated NH4Cl, extracted with diethyl ether,
and dried over anhydrous Na2SO4. The evaporation of the solvent
and the distillation afforded the propargylic alcohols.
undergo a Sonogashira or Kumada-type coupling reaction.
Although the exact nature of the solvent effect is not clear, the
difference in regioselectivity may be explained by the easy
formation of the cyclic metalacyclic intermediate A in a medium
containing THF. Further studies in this area are being conducted
in our laboratory.
Experimental Section
Starting Materials. Racemic 3-butyn-2-ol (1a)9 and (R)-1a are
commercially available and used as is.
(9) Jacobs, T. L.; Petty, W. L.; Teach, E. G. J. Am. Chem. Soc. 1960,
82, 4094.
2658 J. Org. Chem., Vol. 71, No. 7, 2006

Studies on Cu(I)-Catalyzed anti-Carbometallation
SCHEME 3
Synthesis of 1-Pentyn-3-ol (1b).9 Yield ) 50% (62 °C/42
mmHg; lit. 52.4-52.6 °C/35 mmHg). Liquid; 1H NMR (400 MHz,
CDCl3) δ 4.33-4.17 (m, 1H), 2.44 (s, 1H), 2.34-2.20 (br s, 1H),
1.77-1.60 (m, 2H), 1.00 (t, J ) 7.4 Hz, 3H).
22.1, 14.0; MS (m/z) 142 (M+, 1.35), 71 (100); IR (neat, cm-1
)
3361, 2930, 2861, 1647, 1458.
3a:11 Liquid; 1H NMR (400 MHz, CDCl3) δ 5.61 (dt, J1 ) 15.5
Hz, J2 ) 7.0 Hz, 1H), 5.48 (dd, J1 ) 15.5 Hz, J2 ) 6.6 Hz, 1H),
4.28-4.18 (m, 1H), 1.99 (q, J ) 7.1 Hz, 2H), 1.70 (br s, 1H),
1.38-1.26 (m, 6H), 1.23 (d, J ) 6.4 Hz, 3H), 0.87 (t, J ) 6.6 Hz,
3H); 13C NMR (CDCl3, 100 MHz) δ 134.0, 131.1, 68.9, 32.0, 31.3,
28.8, 23.3, 22.5, 14.0; MS (m/z) 142 (M+, 1.65), 71 (100); IR (neat,
cm-1) 3354, 2927, 1670, 1458.
General Procedure II for the Cu(I)-Catalyzed Carbometa-
lation of Propargylic Alcohols and the Subsequent Protonation.
Conditions A: To a solution of propargylic alcohol (10.0 mmol)
in dry toluene (15 mL) under a nitrogen atmosphere was added
CuI (5.0 mmol, 50 mol %) at room temperature. The requisite
Grignard reagent (3.5 equiv, 1 M in THF, 35 mmol) was then added
dropwise to the reaction mixture at less than -70 °C, which was
followed by a natural warming to room temperature. After complete
conversion of the starting material, as monitored by TLC, the
reaction mixture was cooled to 0 °C, quenched with saturated NH4-
Cl, extracted with diethyl ether (3 × 30 mL), and dried over
anhydrous Na2SO4. After evaporation, the NMR ratio was deter-
mined by using 1,3,5-trimethylbenzene as the internal standard (140
µL, 1.0 mmol). Chromatography on silica gel (eluent: petroleum
ether/ethyl acetate ) 20/1∼40/1) of the crude product afforded the
desired product.
Conditions B: To a solution of propargylic alcohol (10.0 mmol)
in dry toluene (15 mL) under a nitrogen atmosphere was added
CuCl (1.0 mmol, 10 mol %) at room temperature. The requisite
Grignard reagent (3.5 equiv, 1 M in THF, 35 mmol) was then added
dropwise to the reaction mixture at less than -70 °C, which was
followed by a natural warming to room temperature. After complete
conversion of the starting material, as monitored by TLC, the
reaction mixture was cooled to 0 °C, quenched with saturated NH4-
Cl, extracted with diethyl ether (3 × 30 mL), and dried over
anhydrous Na2SO4. After evaporation, the NMR ratio was deter-
mined by using 1,3,5-trimethylbenzene as the internal standard (140
µL, 1.0 mmol). Chromatography on silica gel (eluent: petroleum
ether/ethyl acetate ) 20/1∼40/1) of the crude product afforded the
desired product.
Procedure for the Cu(I)-Catalyzed Carbometalation of Pro-
pargylic Alcohols and Iodination. Synthesis of (Z)-3-Iodometh-
yleneoctan-2-ol (4a). To a solution of 1a (1.4001 g, 20.0 mmol)
in dry toluene (30 mL) was added CuI (1.8977 g, 10.0 mmol, 50
mol %) at room temperature under a nitrogen atmosphere. A
solution of n-C5H11MgBr in THF (70 mL, 3.5 equiv, 1 M in THF)
was then added dropwise to the reaction mixture at less than -70
°C. After the addition, the mixture was warmed gradually to room
temperature and monitored by TLC. After complete conversion of
the starting material, the reaction was quenched subsequently with
the dropwise addition of a solution of I2 (18.0031 g, 3.5 equiv, 70
mmol) in THF (50 mL) at -40 °C. After being warmed to 0 °C
for 0.5 h, the reaction mixture was treated with a saturated aqueous
solution of Na2S2O3 at 0 °C. After extraction with diethyl ether (3
× 30 mL), drying over anhydrous Na2SO4, and evaporation, the
NMR yields were determined by NMR analysis using 1,3,5-
trimethylbenzene as the internal standard (140 µL, 1 mmol) (4a/
5a ) 92:8, combined yield of 4a and 5a: 76%). Chromatography
on silica gel (eluent: petroleum ether/ethyl acetate ) 20/1) afforded
4a (3.5792 g, 66%).
1
Liquid; H NMR (400 MHz, CDCl3) δ 5.89 (s, 1H), 4.78 (q, J
) 6.4 Hz, 1H), 2.30-2.15 (m, 2H), 1.86-1.74 (br s, 1H), 1.53-
1.42 (m, 2H), 1.37-1.29 (m, 4H), 1.27 (d, J ) 6.8 Hz, 3H), 0.89
(t, J ) 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 153.1, 74.0,
73.1, 31.9, 31.6, 28.2, 22.4, 20.7, 14.0; MS (m/z) 268 (M+, 5.14),
71 (100); IR (neat, cm-1) 3356, 2928, 2859, 1603, 1459. HRMS
calcd for C9H17OI: 268.0324. Found: 268.0348.
3-Methyleneoctan-2-ol (2a) and 3-(E)-Nonen-2-ol (3a). Condi-
tions A: The reaction of 1a (0.7016 g, 10.0 mmol), CuI (0.9489 g,
5.0 mmol, 50 mol %), and n-C5H11MgBr in THF (1 M, 35 mL, 35
mmol) afforded 2a (1.0012 g, 75%) and 3a (0.0681 g, 5%).
Conditions B: The reaction of 1a (0.7022 g, 10.0 mmol), CuCl
(0.0990 g, 1.0 mmol, 10 mol %), and n-C5H11MgBr in THF (1 M,
35 mL, 35 mmol) afforded 2a (0.6098 g, 43%) and 3a (0.0408 g,
3%).
Procedure for the Sonogashira Coupling Reaction of 4a with
Terminal Alkynes. (Z)-3-Pentyl-6-phenylhex-5-yn-3-en-2-ol (6a).
A mixture of Pd(PPh3)2Cl2 (0.0017 g, 1 mol %, 0.0025 mmol),
CuI (0.0007 g, 1.4 mol %, 0.0035 mmol), 4a (0.0679 g, 0.25 mmol),
phenylacetylene (0.0518 g, 0.50 mmol), and Et3N (1 mL) in DMSO
(1 mL) was heated at 40-45 °C over a period of 1 h under nitrogen.
After complete conversion of the starting materials, as monitored
by TLC, the reaction mixture was cooled to room temperature and
quenched with 3 mL of water. The organic layer was separated,
and the aqueous layer was extracted with diethyl ether (3 × 5 mL).
The combined organic layer was dried over Na2SO4. Evaporation
1
2a:10 Liquid; H NMR (400 MHz, CDCl3) δ 4.99 (s, 1H), 4.76
(s, 1H), 4.24-4.16 (m, 1H), 2.11-1.92 (m, 3H), 1.49-1.39 (m,
2H), 1.38-1.20 (m, 7H), 0.87 (t, J ) 6.6 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 153.5, 107.8, 70.8, 31.7, 31.6, 27.7, 22.5,
(10) Vykhrestyuk, N. I.; Bagatchenko, G. S.; Gordash, T.; Yu, T.;
Tikhonov, V. P.; Tkachenko, D. A.; Chernyshev, I. A. Zh. Prikl. Spektrosk.
1977, 26, 526.
(11) Fuller, J. C.; Stangeland, E. L.; Goralski, C. T.; Singaram, B.
Tetrahedron Lett. 1993, 34, 257.
J. Org. Chem, Vol. 71, No. 7, 2006 2659

Ma and Lu
and column chromatography on silica gel (eluent: petroleum ether/
ethyl acetate ) 30/1) afforded 6a (0.0557 g, 92%). Liquid; 1H NMR
(400 MHz, CDCl3) δ 7.47-7.40 (m, 2H), 7.37-7.30 (m, 3H), 5.55
(s, 1H), 5.10 (q, J ) 6.7 Hz, 1H), 2.30-2.15 (m, 2H), 2.15-2.10
(br s, 1H), 1.57-1.46 (m, 2H), 1.42-1.30 (m, 7H), 0.93 (t, J )
6.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 158.6, 131.2, 128.3,
128.0, 123.4, 104.1, 94.4, 86.0, 68.9, 31.7, 30.6, 28.0, 22.5, 21.5,
14.0; MS (m/z) 242 (M+, 79.57), 43 (100); IR (neat, cm-1) 3361,
2928, 2858, 2197, 1595, 1450. HRMS calcd for C17H22O: 242.1671.
Found: 242.1662.
Pd-Catalyzed Kumada-Type Coupling Reaction of the Or-
ganometallic Intermediate A with PhI. Synthesis of (Z)-3-
Benzylideneoctan-2-ol (7a). To a solution of 1a (0.3517 g, 5.0
mmol) in dry toluene (8 mL) was added CuI (0.4777 g, 2.5 mmol,
50 mol %) at room temperature under a nitrogen atmosphere. A
solution of n-C5H11MgBr in THF (18 mL, 3.5 equiv, 1 M in THF,
18 mmol) was then added dropwise to the reaction mixture at less
than -70 °C. Then the mixture was warmed gradually to room
temperature and monitored by TLC. After complete conversion of
the starting material, a solution of Pd(PPh3)4 (0.0584 g, 1 mol %,
0.05 mmol) and PhI (3.5911 g, 3.5 equiv, 18 mmol) in THF (5
mL) was added with a syringe to the reaction mixture. After the
addition, the reaction mixture was stirred under reflux for 1 h and
quenched with the saturated NH4Cl at 0 °C. After extraction with
diethyl ether (3 × 30 mL), drying over anhydrous Na2SO4, and
evaporation, the NMR yields were determined by NMR analysis
using 1,3,5-trimethylbenzene as the internal standard (140 µL, 1
mmol; 7a/8a ) 92:8, combined yield of 7a and 8a, 70%).
Chromatography on silica gel (eluent: petroleum ether/ethyl acetate
) 20/1) afforded 7a (0.6748 g, 62%).
(Z)-3-Pentyldec-3-en-5-yn-2-ol (6b). A mixture of Pd(PPh3)2-
Cl2 (0.0018 g, 1 mol %, 0.0025 mmol), CuI (0.0007 g, 1.4 mol %,
0.0035 mmol), 4a (0.0681 g, 0.25 mmol), 1-hexyne (0.0421 g, 0.50
mmol), and Et3N (1 mL) in DMSO (1 mL) was stirred over a period
of 18 h under nitrogen at room temperature. After complete
conversion of the starting materials, as monitored by TLC, the
reaction mixture was quenched with 3 mL of water. The organic
layer was separated, and the aqueous layer was extracted with
diethyl ether (3 × 5 mL). The combined organic layer was dried
over Na2SO4. Evaporation and column chromatography on silica
gel (eluent: petroleum ether/ethyl acetate ) 40/1) afforded 6b
Procedure for the Synthesis of (R)-(+)-2a. To a solution of
(R)-1a (0.0704 g, 1.0 mmol) in dry toluene (1.5 mL) under a
nitrogen atmosphere was added CuI (0.5 mmol, 50 mol %) at room
temperature. The requisite Grignard reagent (3.5 equiv, 1 M in THF,
3.5 mmol) was then added dropwise to the reaction mixture at less
than -70 °C, which was followed by a natural warming to room
temperature. After complete conversion of the starting material, as
monitored by TLC, the reaction mixture was cooled to 0 °C,
quenched with saturated NH4Cl, extracted with diethyl ether (3 ×
10 mL), and dried over anhydrous Na2SO4. The NMR ratio of 2a/
3a (93:7) was determined by using 1,3,5-trimethylbenzene as the
internal standard (35 µL, 0.25 mmol). Chromatography on silica
gel (eluent: petroleum ether/ethyl acetate ) 20/1) afforded (R)-
(+)-2a (0.0894 g, 63%, ee ) 98%, determined after its conversion
to the corresponding acetate); [R]20D ) +8.0 (c 1.17, CHCl3). The
data of compound (R)-(+)-2a are the same as that for racemic 2a.
Procedure for the Synthesis of (R)-(+)-4a. To a solution of
1a (0.0704 g, 1.0 mmol) in dry toluene (1.5 mL) was added CuI
(0.0950 g, 0.5 mmol, 50 mol %) at room temperature under a
nitrogen atmosphere. A solution of n-C5H11MgBr in THF (3.5 mL,
3.5 equiv, 1 M in THF) was then added dropwise to the reaction
mixture at less than -70 °C. Then the mixture was warmed
gradually to room temperature and monitored by TLC. After
complete conversion of the starting material, the reaction was
quenched subsequently with the dropwise addition of a solution of
I2 (0.8900 g, 3.5 equiv, 3.5 mmol) in THF (5 mL) at -40 °C, and
then the reaction mixture was warmed to 0 °C for 0.5 h and treated
with a saturated aqueous solution of Na2S2O3 at 0 °C. After
extraction with diethyl ether (3 × 30 mL), drying over anhydrous
Na2SO4, and evaporation, the NMR ratio of 4a/5a (94:6) was
determined by NMR analysis using 1,3,5-trimethylbenzene as the
internal standard (35 µL, 0.25 mmol). Chromatography on silica
gel (eluent: petroleum ether/ethyl acetate ) 20/1) afforded (R)-
(+)-4a (0.1597 g, 59%, ee ) 98%; HPLC conditions: Chiralcel
AS-H, hexane/i-PrOH ) 90/10, 0.8 mL/min, n ) 230 nm, tR 4.8
1
(0.0421 g, 75%). Liquid; H NMR (400 MHz, CDCl3) δ 5.28 (s,
1H), 4.88 (q, J ) 6.7 Hz, 1H), 2.33 (t, J ) 7.0 Hz, 2H), 2.18-2.02
(m, 3H), 1.55-1.37 (m, 6H), 1.37-1.23 (m, 7H), 0.94-0.83 (m,
6H); 13C NMR (CDCl3, 100 MHz) δ 156.7, 104.5, 95.7, 76.9, 68.9,
31.7, 30.90, 30.86, 28.1, 22.5, 22.0, 21.4, 19.2, 14.0, 13.6; MS (m/
z) 222 (M+, 34.29), 43 (100); IR (neat, cm-1) 3374, 2929, 2212,
1640, 1465. HRMS calcd for C15H26O: 222.1984. Found: 222.1969.
(Z)-2-Methyl-6-pentyloct-3-yn-5-en-2,7-diol (6c). A mixture of
Pd(PPh3)2Cl2 (0.0036 g, 2 mol %, 0.005 mmol), CuI (0.0013 g,
2.6 mol %, 0.0068 mmol), 4a (0.0654 g, 0.24 mmol), 2-methyl-
3-butyn-2-ol (0.0438 g, 0.50 mmol), and Et3N (1 mL) in DMSO
(1 mL) was stirred over a period of 2 h under nitrogen at room
temperature. After complete conversion of the starting materials,
as monitored by TLC, the reaction mixture was quenched with 3
mL of water. The organic layer was separated, and the aqueous
layer was extracted with diethyl ether (3 × 5 mL). The combined
organic layer was dried over Na2SO4. Evaporation and column
chromatography on silica gel (eluent: petroleum ether/ethyl acetate
) 3/1) afforded 6c (0.0515 g, 94%). Liquid; 1H NMR (400 MHz,
CDCl3) δ 5.29 (s, 1H), 4.89 (q, J ) 6.7 Hz, 1H), 2.38 (br s, 2H),
2.20-2.03 (m, 2H), 1.53 (s, 6H), 1.49-1.38 (m, 2H), 1.36-1.26
(m, 7H), 0.88 (t, J ) 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ
158.4, 103.6, 99.0, 78.6, 68.7, 65.6, 31.6, 31.40, 31.37, 27.9, 22.5,
21.3, 14.0; MS (m/z) 224 (M+, 0.13), 206 (M+ - H2O, 66.59), 43
(100); IR (neat, cm-1) 3346, 2929, 2860, 2216, 1624, 1456, 1362,
1244, 1166. HRMS calcd for C14H22O (M+ - H2O): 206.1671.
Found: 206.1664.
Procedure for the Kumada Coupling Reaction of 4a with
PhMgBr. Synthesis of (Z)-3-Benzylideneoctan-2-ol (7a). To a
solution of 4a (0.0641 g, 0.24 mmol) in dry THF (1 mL) under a
nitrogen atmosphere was added Pd(PPh3)4 (0.0140 g, 5 mol %,
0.012 mmol) at room temperature. A solution of PhMgBr in THF
(0.75 mL, 1 M, 0.75 mmol) was then added dropwise to the reaction
mixture at 0 °C, which was followed by a natural warming to room
temperature. After complete conversion of the starting materials,
as monitored by TLC, the reaction was quenched with a saturated
aqueous solution of NH4Cl at 0 °C. The organic layer was separated,
and the aqueous layer was extracted with diethyl ether (3 × 5 mL).
The combined organic layer was dried over Na2SO4. Evaporation
and column chromatography on silica gel (eluent: petroleum ether/
ethyl acetate ) 40/1) afforded 7a (0.0430 g, 82%). Liquid; 1H NMR
(400 MHz, CDCl3) δ 7.37-7.31 (m, 2H), 7.27-7.17 (m, 3H), 6.38
(s, 1H), 4.91 (q, J ) 6.5 Hz, 1H), 2.36-2.27 (m, 2H), 1.70-1.53
(m, 3H), 1.46-1.32 (m, 7H), 0.98-0.90 (m, 3H); 13C NMR (CDCl3,
100 MHz) δ 145.2, 137.5, 128.7, 128.1, 126.4, 125.9, 65.9, 32.0,
29.8, 29.1, 22.6, 21.6, 14.1; MS (m/z) 218 (M+, 2.86), 147 (100);
IR (neat, cm-1) 3356, 2928, 2859, 1599. HRMS calcd for
C15H22O: 218.1671. Found: 218.1664.
(minor), 5.1 (major)); [R]20 ) +10.4 (c 1.80, CHCl3). The data
D
of compound (R)-(+)-4a are the same as that for racemic 4a.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (No. 20420130645), and
Cheung Kong Scholar Program is greatly appreciated. S.M. is
jointly appointed by Zhejiang University and Shanghai Institute
of Organic Chemistry. This work was conducted at Zhejiang
University.
Supporting Information Available: Experimental details for
all the products not listed in the text and 1H and 13C NMR spectra
of all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO0524021
2660 J. Org. Chem., Vol. 71, No. 7, 2006