Enantioselective alkynylation of carbonyl compounds with trimethoxysilylalkynes catalyzed by lithium binaphtholate

Article abstract of DOI:10.1016/j.tet.2010.07.080

Enantioselective alkynylation of aldehydes and ketones was accomplished using trimethoxysilylalkynes as alkynylating reagents and lithium 3,3′-diphenylbinaphtholate as a catalyst. Optically active propargylic alcohols were obtained in good to high chemica

Full text of DOI:10.1016/j.tet.2010.07.080

Tetrahedron 66 (2010) 7726e7731
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioselective alkynylation of carbonyl compounds with trimethoxysilylalkynes
catalyzed by lithium binaphtholate
*
Tomohiro Ueda, Kana Tanaka, Tomonori Ichibakase, Yuya Orito, Makoto Nakajima
Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 May 2010
Received in revised form 28 July 2010
Accepted 29 July 2010
Available online 6 August 2010
Enantioselective alkynylation of aldehydes and ketones was accomplished using trimethoxysilylalkynes
as alkynylating reagents and lithium 3,30-diphenylbinaphtholate as a catalyst. Optically active propargylic
alcohols were obtained in good to high chemical yields and enantioselectivities. Alkynylation of
acetylpyridines afforded biologically active pyridyl propargylic alcohols in good enantioselectivities.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Enantioselective catalysis
Alkynylation
Trimethoxysilylalkyne
Lithium binaphtholate
1. Introduction
the details of the enantioselective alkynylation of aldehydes and
ketones using trimethoxysilylalkynes in the presence of lithium
Optically active propargylic alcohols are important precursors
for the synthesis of a wide range of biologically active com-
pounds.1 Secondary alcohols are generally prepared by the enan-
tioselective reduction of ketones. However, secondary propargylic
alcohols are not prepared in this way because some alkynyl
ketones are prone to decomposition or isomerization even under
mild conditions. Moreover, tertiary propargylic alcohols cannot, in
principle, be prepared by the reduction. Therefore, the enantio-
selective alkynylation of carbonyl compounds is an alternative
approach to the preparation of chiral propargylic alcohols.2 The
first enantioselective catalytic approach was reported by Soai, who
used alkynylzinc as an alkynylating agent and an amino alcohol as
a catalyst.3 Since then, several cases of the enantioselective alky-
nylation of carbonyl compounds have been reported using various
catalysts.4e7
Recently another access to the propargylic alcohols was repor-
ted by Scheidt, who found that alkoxides activated trialkox-
ysilylalkynes to react with ketones as well as aldehydes.8,9 In their
report, they postulate the formation of hypervalent silicate10 from
trialkoxysilylalkyne and alkoxide. We previously reported that
lithium binaphtholate activated trimethoxysilyl enol ethers to form
hypervalent silicate, which reacted with an aldehyde to afford an
aldol adduct in high chemical and optical yields.11 Here, we disclose
binaphtholates as catalyst.12
2. Results and discussion
2.1. Alkynylation of aldehydes
We first investigated the alkynylation of benzaldehyde (1a) with
trimethoxy(phenylethynyl)silane (2a)13 in THF using lithium
binaphtholate14 prepared from binaphthol (4a) and BuLi as the
catalyst. The reaction proceeded smoothly to afforded the prop-
argylic alcohol in high yield, but the enantioselectivity was quite
low (Table 1, entry 1).15 Screening of the binaphthol derivatives
revealed that introduction of substituents at 3,30-position of
binaphthol increased the enantioselectivity. Among various 3,30-
substituted binaphthols tested, we found that the diphenyl
derivative (4h) gave the most promising selectivity (entry 8).
With the appropriate catalyst precursor in hand, we in-
vestigated alkynylation of benzaldehyde (1a) with various trime-
thoxysilylalkynes. A wide variety of trimethoxysilylalkynes reacted
with benzaldehyde to afford the adduct in high yields, however, the
reactivity and enantioselectivity depended on the substituent on
the opposite side of alkyne (Table 2). Cyclohexenyl (entry 3), ben-
zyloxymethyl (entry 4), and silyloxymethyl (entry 5) derivatives
gave lower selectivities, and the n-butyl derivative (entry 2) reacted
quite slowly with low selectivity.
Because the best result was obtained using the phenyl derivative
2a, we investigated the phenylethynylation of various aldehydes
* Corresponding author. Tel.: þ81 96 371 4680; fax: þ81 96 362 7692; e-mail
address: nakajima@gpo.kumamoto-u.ac.jp (M. Nakajima).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.07.080

T. Ueda et al. / Tetrahedron 66 (2010) 7726e7731
7727
Table 1
Table 3
Screening of binaphthol derivative in the phenylethynylation of benzaldehyde with
trimethoxy(phenyethynyl)silane
Phenylethynylation of various aldehydes with trimethoxy(phenyethynyl)silanea
Ph
X
OLi
OLi
OLi
OLi
Ph
H OH
R2
3
4h
O
(MeO)3Si
+
X
H OH
Ph
3aa
O
4
(MeO)3Si
+
(10 mol %)
R2
H
(10 mol %)
Ph
Ph
H
THF, 0 °C, 1 h
Ph
1
2a
Ph
THF, 0 °C, 2 h
Ph
ee, %b
1a
2a
Entry
R2 in aldehyde
Product
Yield, %a
ee, %b,c
Entry
X in binaphthol
Yield, %a
1
2
3
4
5
6
7
8
9
Ph (1a)
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
98
95
98
86
86
86
79
81
84
58
53
49
41
60
65
42
31
45
1
2
3
4
5
6
7
8
9
H (4a)
Cl (4b)
Br (4c)
I (4d)
COOMe (4e)
Me (4f)
SiMe3 (4g)
Ph (4h)
97
92
97
90
97
98
98
98
98
18
54
52
52
6
50
41
58
34
1-Naphthyl (1b)
2-Naphthyl (1c)
4-CF3C6H4 (1d)
4-MeOC6H4 (1e)
4-Me2NC6H4 (1f)
PhCH]CH (1g)
PhCH2CH2 (1h)
Cyclohexyl (1i)
3,5-Me2C6H3 (4i)
a
Silylalkyne 1.5 equiv, catalyst 10 mol %, 0 ꢀC, 1 h. See Experimental.
Isolated yield.
Determined by HPLC. The absolute configurations were determined by com-
a
b
c
Isolated yield.
Determined by HPLC.
b
parison of the sign of optical rotation of the product, see Experimental.
Table 2
First, we examined the phenylethynylation of acetophenone
under the conditions we used for the alkynylation of aldehydes. The
adduct was obtained in a high enantioselectivity but the chemical
yield was moderate (Table 4, entry 1, 59% yield, 76% ee). Again,
optimization of the reaction conditions and a search for chiral
catalysts did not identify any catalysts that were better than 3,30-
diphenylbinaphthol. Reaction at 0 ꢀC gave a better selectivity but
a lower yield (entry 5). We then tested slow addition of the ketone
to the mixture of catalyst and alkyne over 3 h to prevent self-aldol
reaction of acetophenone and found that the chemical yield was
significantly increased (entry 6). Increasing the number of equiva-
lents of alkyne gave a better chemical yield with no reduction of
enantioselectivity (entry 7).
Alkynylation of benzaldehyde with various trimethoxysilylalkynes
Ph
OLi
OLi
Ph
H OH
4h
O
(MeO)3Si
+
(10 mol %)
Ph
R1
Ph
H
R1
THF, 0 °C,1h
1a
2
3
Entry
R1 in silylalkyne
Product
Yield, %a
ee, %b
1
Ph (2a)
n-Bu (2b)
Cyclohexen-1-yl (2c)
BnOCH2 (2d)
(i-Pr)3SiOCH2 (2e)
3aa
3ab
3ac
3ad
3ae
98
85
89
90
94
58
21
46
38
41
2c
3
The results obtained from the reaction of 1.5 equiv trimethoxy
(phenylethynyl)silane 2a are summarized in Table 5. Similar
enantioselectivities and chemical yields were obtained using
4
5
a
Isolated yield.
Determined by HPLC.
18 h.
b
c
Table 4
Screening of the conditions of the phenylethynylation of acetophenone
X
with this derivative (Table 3). Naphthaldehydes 1b and 1c gave
results similar to those of benzaldehyde (entries 2 and 3). Electron-
deficient groups, such as trifluoromethyl, on benzene ring de-
creased the selectivity (entry 4), whereas electron-donating
groups, such as methoxy or dimethylamino, tend to increase the
OLi
OLi
X
Me OH
4
selectivity (entries
5 and 6). In particular, dimethylamino-
O
(MeO)3Si
+
(10 mol %)
benzaldehyde 1f gave the best enantioselectivity, 65%. The alky-
nylation proceeded smoothly with non-aromatic aldehydes, such as
cinnamaldeyde 1g, hydrocinnamaldehyde 1h, or cyclo-
hexylcarboxaldehyde 1i, however, the observed selectivities were
rather low (entries 7e9).
Ph
Ph
Me
Ph
THF, rt, 1 h
Ph
ee, %b
5a
2a
6aa
Entry
X in BINOL
Yield, %a
1
2
3
4
Ph (4h)
H (4a)
59
24
36
37
51
64
81
76
10
22
29
82
82
82
2.2. Alkynylation of ketones
Cl (4b)
Me (4f)
Ph (4h)
Ph (4h)
Ph (4h)
5c
6c,d
Chiral tertiary alcohols represent important structural motifs in
organic syntheses.16 The enantioselective alkynylations of alde-
hydes have been widely investigated, however, few successful re-
ports of the alkynylation of ketones exist due to their low
reactivities.17,18 As the reactivity of trialkoxysilylalkynes are suffi-
ciently high to react with ketones,8 we next started to investigate
the alkynylation of ketones.
7 c,d,e
a
Isolated yield.
Determined by HPLC.
0 ꢀC.
b
c
d
e
Slow addition of ketone over 3 h and an additional 1 h.
alkyne, 3 equiv.

7728
T. Ueda et al. / Tetrahedron 66 (2010) 7726e7731
Table 5
Ph
Phenylethynylation of various ketones with trimethoxy(phenyethynyl)silanea
Ph
OLi
OLi
OLi
OLi
Ph
Me OH
Py
4h
O
(MeO)3Si
+
Me
(10 mol %)
R1
2a or 2d
Py
R3 OH
R2
6
Ph
4h
R1
O
(MeO)3Si
+
THF, 0 °C,4 h
R1 = Ph
3-Pyridyl (10aa): 71% yield, 75% ee
4-Pyridyl (10ba): 80% yield, 75% ee
9a or 9b
10
(10 mol %)
R2 R3
Ph
THF, 0 °C, 4 h
5
2a
Ph
Entry
R2, R3 in ketone
Product
Yield, %b
ee, %c
R1 = CH2OCH2Ph
3-Pyridyl (10ad): 52% yield, 66% ee
4-Pyridyl (10bd): 59% yield, 60% ee
1
2
3
4
5
6
7
8
Ph, Me (5a)
6aa
6ba
6ca
6da
6ea
6fa
6ga
6ha
6ia
64
60
57
61
71
67
63
77
65
92
74
64
82
76
81
81
72
79
75
61
8
2-naphthyl, Me (5b)
4-MeC6H4, Me (5c)
4-MeOC6H4, Me (5d)
4-NO2C6H4, Me (5e)
4-FC6H4, Me (5f)
4-CF3C6H4, Me (5g)
Ph, Et (5h)
Scheme 2. Alkynylation of acetylpyridines.
3. Conclusion
9
Ph, i-Pr (5i)
We demonstrated the first example of enantioselective alkyny-
lation of carbonyl compounds using trialkoxysilylalkyne catalyzed
by chiral lithium binaphtholate. The reactivity was sufficiently high
that it could be applied to the catalytic alkynylation of ketones.
Although the enantioselectivities were modest, these results
demonstrate the synthetic utility of trimethoxysilylalkynes for the
synthesis of optically active propargylic alcohols as building blocks
for biologically active compounds.
10
11
12
PhCH2CH2, Me (5j)
Cyclohexyl, Me (5k)
tert-Bu, Me (5l)
6ja
6ka
6la
41
52
43
a
Silylalkyne 1.5 equiv, catalyst 10 mol %, 0 ꢀC, 4 h. See Experimental.
Isolated yield.
Determined by HPLC.
b
c
2-naphthaldehyde and 40-substituted acetophenones (entries 1e7).
Propiophenone 5h gave a decreased selectivity (entry 8), and iso-
butyrophenone 5i gave an almost racemic product (entry 9), which
suggests the bulkiness of the aliphatic group has inferior effect on
selectivity. Aliphatic ketones gave better chemical yields than
acetophenone, but with lower selectivities (entries 10e12).
Because the magnitude of the optical rotation of 6aa is small,
some confusion exists in the literatures regarding the relationship
between the sign of optical rotation and the molecule’s absolute
configuration.19 To determine the absolute configuration of 6aa, we
first attempted the direct ozonolysis of propargylic alcohol to the
corresponding acid, but only acetophenone was obtained. We next
investigated ozonolysis after the reduction of the alkyne to the
alkene. The obtained 6aa was reduced using Red-AlÒ to olefin
7aa20, which was then transformed into methyl ester 8aa21 via
ozonolysis (Scheme 1). The absolute configuration of the obtained
ester was unambiguously determined to be S by the sign of optical
rotation, which suggested that the original propargylic alcohol 6aa
had an S-configuration.
4. Experimental
4.1. General
Optical rotations were obtained using a JASCO DIP-370 digital
polarimeter. Infrared spectra were recorded using a JASCO FT/IR-
5300. 1H NMR and 13C NMR spectra were recorded using JEOL JNM-
ECX-400 (1H, 400 MHz; 13C, 100 MHz) spectrometer. Chemical shift
values are expressed in parts per million relative to internal tetra-
methylsilane. Coupling constants (J) are reported in hertz (Hz). Ab-
breviations are as follows: s, singlet; d, doublet; t, triplet; q, quartet;
m, multiplet; br, broad. Mass spectra were obtained by electron
impact with an ionization voltage of 70 eV using JEOL JMS-DX303
and JMS-BU20. HPLC was performed on JASCO PU-1580 with JASCO
UV-1575 (
l
¼254 nm), and chiral separations were performed using
Daicel chiralpak or chiralcel columns (
4
0.46ꢁ25 cm). Trimethoxy
(phenylethynyl)silane (2a) was prepared by the literature method.13
Binaphthol derivatives were prepared by the literature methods.24
1) O3, CH2Cl2
Red-Al®
Me OH
Ph
6aa
Me OH
Ph
7aa
Me OH
Ph COOMe
8aa
2) Ph3P
4.2. Preparation of trimethoxysilylalkynes
Ph
Et2O-PhMe
Ph
3) Br2, MeOH
4.2.1. 1-Hexynyltrimethoxysilane (2b). Hexyne (5.4 g, 66 mmol)
was added to the solution of ethylmagnesium bromide (prepared
from bromoethane 60 mmol and Mg 60 mmol) in ether (60 mL)
and the mixture was refluxed for 2 h. After adding ether (100 mL)
and Si(OMe)4 (10 mL, 66 mmol) at 0 ꢀC, the mixture was refluxed
for another 2 h. After evaporation of the ether, the residue was
extracted with ether and the resulting precipitate was filtered off.
The filtrate was evaporated and distilled in vacuo to give 2b as
a colorless oil (7.9 g, 65%).
Scheme 1. Determination of the absolute configuration of 6aa.
Pyridyl propargylic alcohols are important building blocks for the
synthesis of biologically active compounds,22 however, the successful
enantioselectivealkynylationofacetylpyridinehasnotbeenreported,
because nitrogen atom in pyridine ring deactivates the chiral Lewis
acid catalyst. Using a basic catalyst, our protocol may be applied to the
alkynylation of basic substrate, such as acetylpyridines. We next in-
vestigated the addition of phenylethyne 2a or benzyloxypropyne 2d
to 3-acetyl and 4-acetylpyridines (9a and 9b). As expected, the re-
action proceeded smoothly, and the corresponding alcohols 10 were
obtained in good chemical and optical yields (Scheme 2). These re-
sults constitute the highest chemical yield and enantioselectivity
reported to date for the alkynylation of acetylpyridines.23
Bp 81e83 ꢀC/5 mmHg. 1H NMR (CDCl3):
CH3), 1.44e1.58 (m, 4H, CH2CH2), 2.28 (t, 2H, J¼7.1 Hz, C^CCH2),
3.59 (s, 9H, OCH3). 13C NMR (CDCl3):
13.5, 19.2, 21.8, 30.2, 51.2,
d
0.92 (t, 3H, J¼7.3 Hz,
d
74.3, 108.4. IR (neat): n
(cmꢂ1) 2960, 2943, 2843, 2185, 1458, 1194,
1190. LR-EIMS: 187 (Mþꢂ15(CH3)), 171 (Mþꢂ31(OCH3)), 121 (bp).
HR-EIMS: calcd for C8H15O3Si 187.0791, found 187.0795.

T. Ueda et al. / Tetrahedron 66 (2010) 7726e7731
7729
4.2.2. 1-Cyclohexenylethynyltrimethoxysilane (2c). Bp 109e113 ꢀC/
IPA¼19/1, 1.0 mL/min): tR(min) 12.4 (minor), 14.3 (major). 1H NMR
3 mmHg.1HNMR(CDCl3):
d
1.61e1.62(m, 4H), 2.11e2.16(m, 4H, CH2),
(CDCl3):
d
1.02e1.17 (m, 21H, CHCH3), 2.16 (d, 1H, J¼5.8 Hz, OH),
3.60 (s, 9H, OCH3), 6.32 (t, 1H, J¼2.6 Hz, C]CH). 13C NMR (CDCl3):
5.51 (d, 1H, J¼5.8 Hz, PhCH), 7.32e7.39 (m, 3H, Ph), 7.53e7.55 (m,
2H, Ph). 13C NMR (CDCl3):
12.0, 17.9, 52.0, 64.6, 84.2, 85.5, 126.6,
128.3, 128.5, 140.5. IR (neat):
(cmꢂ1) 3367, 3088, 3064, 3032,
d
21.2, 22.0, 25.7, 28.6, 50.8, 80.1,107.4,119.8,138.8. IR (neat):
n
(cmꢂ1
)
d
2941, 2843, 2156,1458,1437,1194,1171, 1089. LR-EIMS: 226 (Mþ, bp),
211, 195, 121. HR-EIMS: calcd for C11H8O3Si 226.1025, found 226.1015.
n
2943, 2891, 2866, 2725, 2715, 1603, 1495, 1468, 1464, 1369, 1327,
1261, 1192, 1130, 1090, 1068, 1014. LR-FABMS: (NBAþNaI) 341 (Mþ).
HR-FABMS: (NBAþNaI) calcd for C19H30O2Si 341.1913, found
341.1926.
4.2.3. (3-Benzyloxy-1-propynyl)trimethoxysilane(2d). Bp 149e151 ꢀC/
4 mmHg. 1H NMR (CDCl3):
d
3.62. (s, 9H, OCH3), 4.23 (s, 2H, C^CCH2),
4.63 (s, 2H, PhCH2), 7.26e7.37 (m, 5H, Ph). 13C NMR (CDCl3):
50.9,
57.2, 71.3, 81.5, 101.7, 128.0, 128.1, 128.5, 137.1. IR (neat):
(cmꢂ1) 3032,
d
25
n
4.3.6. (R)-1-(1-Naphthyl)-3-phenyl-2-propyn-1-ol
(3ba)4d. [
a]
D
25
2945, 2845, 2185, 1495, 1456, 1437, 1387, 1354, 1259, 1193, 1087, 1089.
LR-EIMS: 265 (Mþꢂ1), 251, 121 (bp). HR-EIMS: calcd for C13H17O4Si
265.0893, found 265.0896.
þ16.8 (c 1.0, CHCl3), 53% ee. [lit.4d: [
a
]
þ29.1 (c 0.52 CHCl3), 94%
D
ee, R]. HPLC (Daicel chiralcel OD-H, hexane/IPA¼6/1, 1.0 mL/min):
tR(min) 11.1 (minor), 19.5 (major). 1H NMR (CDCl3):
d 2.38 (d, 1H,
J¼6.0 Hz, OH), 6.37 (d, 1H, J¼6.0 Hz, OCH), 7.32e7.33(m, 3H, AreH),
7.47e7.62 (m, 5H, AreH), 7.86e7.95 (m, 3H, AreH), 8.39 (d, 1H,
J¼8.2 Hz, AreH).
4.2.4. (3-Triisopropylsilyoxy-1-propynyl)-trimethoxysilane (2e). Bp
125e126 ꢀC/2 mmHg.1H NMR (CDCl3):
d
1.06e1.63 (m, 21H, CHCH3),
3.59 (s, 9H OCH3), 4.43 (s, 2H,). 13C NMR (CDCl3):
d
11.9, 17.8, 50.8,
22
52.2, 79.1, 104.7. IR (neat):
n
(cmꢂ1) 3312, 2945, 2892, 2868, 2189,
4.3.7. (S)-1-(2-Naphthyl)-3-phenyl-2-propyn-1-ol
(3ca)4c. [
a]
D
2123, 1463, 1384, 1369, 1263, 1194, 1101. LR-EIMS: 289 (MþꢂC3H7),
þ5.9 (c 1.0, CHCl3), 49% ee. [lit.4c: [
a
]
D
25 þ8.8 (c 0.69 CHCl3), 92% ee,
259 (bp). HR-EIMS: calcd for C12H25O4Si2 289.1310, found 289.1301.
S]. HPLC (Daicel chiralcel OD-H, hexane/IPA¼6/1, 1.0 mL/min):
tR(min) 10.9 (minor), 27.8 (major). 1H NMR (CDCl3):
d 2.36 (d, 1H,
4.3. Enantioselective alkynylation of aldehydes
J¼6.4 Hz, OH), 5.87 (d, 1H, J¼6.4 Hz, ArCH), 7.30e7.35(m, 3H,
AreH), 7.49e7.52 (m, 4H, AreH), 7.72e7.75 (m, 1H, AreH),
7.85e7.91 (m, 3H, AreH), 8.06 (s, 1H, AreH).
4.3.1. (S)-1,3-Diphenyl-2-propyn-1-ol (3aa)4c. A solution of n-BuLi
(0.094 mmol) in hexane (0.2 M, 0.48 mL) was added to the solution
of 3,30-diphenylbinaphthol (21 mg, 0.047 mmol) in THF (3 mL) at
0 ꢀC. Benzaldehyde (50 mg, 0.49 mmol) and alkyne (0.16 mL,
0.72 mmol) were successively added to the mixture, and the solu-
tion was stirred for 1 h at the same temperature. The reaction was
quenched with KF/KH2PO4 solution (15% KF, 10% KH2PO4, 2 mL),
and the mixture was extracted with EtOAc. The organic layer was
washed with brine, dried, and evaporated. Silica gel chromatogra-
phy afforded the alcohol 3aa as an oil (100 mg, 98%).
4.3.8. (S)-3-Phenyl-1-(4-trifluoromethylphenyl)-2-propyn-1-ol
22
27
(3da)4c. [
a
]
D
ꢂ3.0 (c 1.2, CHCl3), 41% ee. [lit.4c: [
a]
ꢂ6.9 (c 1.4,
D
CHCl3), 87% ee, S] HPLC (Daicel chiralcel OD-H, hexane/IPA¼6/1,
1.0 mL/min): tR(min) 5.7 (minor), 23.0 (major). 1H NMR (CDCl3):
d
2.38 (d, 1H, J¼6.0 Hz, OH), 5.76 (d, 1H, J¼6.0 Hz, ArCH), 7.32e7.35
(m, 3H, AreH), 7.46e7.48 (m, 2H, AreH), 7.66e7.70 (m, 2H, AreH),
7.74e7.76 (m, 2H, AreH).
[
a
]
22 ꢂ1.3 (c 0.9, CHCl3), 58% ee. [lit.4c: [
a
]
27 ꢂ2.4 (c 1.2, CHCl3),
4.3.9. (S)-1-(4-Methoxyphenyl)-3-phenyl-2-propyn-1-ol
D
D
22
27
86% ee, S]. HPLC (Daicel chiralcel OD-H, hexane/IPA¼9/1, 1.0 mL/
(3ea)4c. [
a
]
ꢂ4.2 (c 1.1, CHCl3), 60% ee. [lit.4c: [
a
]
ꢂ4.2 (c 1.7,
D
D
min): tR(min) 12.9 (minor), 21.1 (major). 1H NMR (CDCl3):
d
2.26 (d,
CHCl3), 80% ee, S]. HPLC (Daicel chiralcel OD-H, hexane/IPA¼6/1,
1H, J¼6.2 Hz, OH), 5.70 (d, 1H, J¼6.2 Hz, PhCH), 7.30e7.50 (m, 8H,
1.0 mL/min): tR(min) 11.0 (minor), 18.4 (major). 1H NMR (CDCl3):
Ph), 7.63 (d, 2H, J¼6.8 Hz, Ph).
d
2.21 (d, 1H, J¼6.2 Hz, OH), 3.83 (s, 3H, CH3) 5.65 (d, 1H, J¼6.2 Hz,
ArCH), 6.92e6.94 (m, 2H, AreH), 7.32e7.33 (m, 3H, AreH),
7.46e7.48 (m, 2H, AreH), 7.54e7.56 (m, 2H, AreH).
4.3.2. (S)-1-Phenyl-2-heptyn-1-ol (3ab)4c. [
a]
22 ꢂ3.9 (c 1.4, CHCl3),
D
25
21% ee. [lit.4c: [
a
]
ꢂ18.1 (c 1.3, CHCl3), 75% ee, S]. HPLC (Daicel
D
22
chiralcel OD-H, hexane/IPA¼19/1, 1.0 mL/min): tR(min) 8.2 (major),
4.3.10. 1-(4-Dimethylamino)-3-phenyl-2-propyn-1-ol (3fa)9a. [
a]
D
12.5 (minor).1H NMR (CDCl3):
d
0.92 (t, 3H, J¼7.1 Hz, CH3),1.40e1.57
ꢂ7.5 (c 1.2, CHCl3). HPLC (Daicel chiralcel OD-H, hexane/IPA¼6/1,
1.0 mL/min): tR (min) 10.0 (minor), 18.8 (major). 1H NMR (CDCl3):
(m, 4H, CH2), 2.06 (d,1H, J¼6.0 Hz, OH), 2.27e2.30 (m, 2H, CH2), 5.46
(d,1H, J¼6.0 Hz, PhCH), 7.28e7.40 (m, 3H, Ph), 7.54e7.56 (m, 2H, Ph).
d
2.15 (br,1H, OH), 3.00 (s, 6H, CH3) 5.61 (s,1H, ArCH), 6.73e6.76 (m,
2H, AreH), 7.31e7.32 (m, 3H, AreH), 7.47e7.50 (m, 4H, AreH).
22
4.3.3. (S)-3-Cyclohex-1-enyl-1-phenyl-2-propyn-1-ol (3ac) 7d. [
a]
D
22
ꢂ4.0 (c 1.2, CHCl3), 46% ee. [lit.7d. [
a
]
15 þ6.7 (c 0.4, CHCl3), 89% ee, R].
4.3.11. (S)-1,5-Diphenyl-1-penten-4-yn-3-ol (3ga)4c. [
a]
ꢂ1.6 (c
D
D
HPLC (Daicel chiralcel OD-H, hexane/IPA¼19/1, 1.0 mL/min):
1.1, CHCl3), 42% ee. [lit.4c: [
a]
27 ꢂ7.3 (c 0.5, CHCl3), 61% ee, S]. HPLC
D
tR(min) 10.7 (major), 14.7 (minor). 1H NMR (CDCl3):
d
1.55e1.67 (m,
(Daicel chiralcel OD-H, hexane/IPA¼9/1, 1.0 mL/min): tR (min) 12.6
4H, CH2), 2.09e2.15 (m, 5H, CH2, and OH), 5.58 (d, 1H, J¼6.4 Hz, C]
(minor), 32.6 (major). 1H NMR (CDCl3):
d
2.07 (d, 1H, J¼6.2 Hz, OH),
CH), 6.17 (s, 1H, OCH), 7.31e7.40 (m, 3H, Ph), 7.54e7.57 (m, 2H, Ph).
5.29 (dd, 1H, J¼6.2, 9.0 Hz, OCH), 6.39 (dd, 1H, J¼9.0, 16 Hz, C]CH),
6.85 (d, 1H, J¼16 Hz, PhCH), 7.27e7.49 (m 10H, AreH).
22
4.3.4. 4-Benzyloxy-1-phenyl-2-butyn-1-ol (3ad). [
a
]
ꢂ4.2 (c 1.1,
D
4.3.12. (S)-1,5-Diphenyl-1-pentyn-3-ol (3ha)4c. [
a
]
þ18.3 (c 1.4,
22
CHCl3), 38% ee. HPLC (Daicel chiralpak AD-H, hexane/IPA¼9/1,
D
27
1.0 mL/min): tR(min) 15.2 (major), 17.5 (minor). 1H NMR (CDCl3):
CHCl3), 31% ee. [lit.4c
[a
]
þ28.4 (c 1.1, CHCl3), 49% ee, S]. HPLC
D
d
2.15 (d,1H, J¼6.0 Hz, OH), 4.28 (s, 2H, C^CCH2), 4.61 (s, 2H, PhCH2),
5.54 (d, 1H, J¼6.0 Hz, C^CCH), 7.28e7.41 (m, 8H, Ph), 7.54e7.56 (m,
2H, Ph). 13C NMR (CDCl3):
57.2, 64.1, 71.4, 82.1, 86.5, 126.4, 127.7,
(Daicel chiralcel OD-H, hexane/IPA¼9/1, 1.0 mL/min): tR (min) 14.8
(minor), 26.2 (major). 1H NMR (CDCl3):
d
1.89 (d, 1H, J¼5.5 Hz, OH),
d
2.11e2.15 (m, 2H, CH2), 2.83e2.93 (2H, m, CH2), 4.55e4.65 (1H, m,
OCH), 7.20e7.36 (m, 8H, AreH), 7.43e7.46 (m, 2H, AreH).
128.0, 128.1, 128.3, 128.4, 137.0, 140.4. IR (neat): 3388, 3062, 3030,
2854, 1603, 1495, 1452, 1354, 1259, 1192, 1119, 1066 cmꢂ1. LR-EIMS:
251 (Mþꢂ1). HR-EIMS: calcd for C17H15O2 251.1072, found 251.1067.
20
4.3.13. (S)-1-Cyclohexyl-3-phenyl-2-propyn-1-ol (3ia)6c. [
a
]
D
þ4.1
(c 1.2, CHCl3), 45% ee. [lit.6c
[a
]
26 ꢂ9.2 (c 1.0, CHCl3), 96% ee, R]. HPLC
D
22
4.3.5. 1-Phenyl-4-triisopropylsilanyloxy-2-butyn-1-ol
ꢂ5.3 (c 1.1, CHCl3), 41% ee. HPLC (Daicel chiralcel OD-H, hexane/
(3ae). [
a
]
(Daicel chiralcel OD-H, hexane/IPA¼9/1, 1.0 mL/min): tR (min) 5.8
D
(minor), 11.6 (major). 1H NMR (CDCl3):
d 1.06e1.31 (m, 5H, CH2),

7730
T. Ueda et al. / Tetrahedron 66 (2010) 7726e7731
1.65e1.95 (m, 7H, OH and C6H11), 4.38 (t, 1H, J¼6.0 Hz, OCH),
7.30e7.32 (m, 3H, AreH), 7.43e7.45 (m, 2H, AreH).
7.32e7.36 (m, 3H, AreH), 7.47e7.49 (m, 2H, AreH), 7.65 (d, 2H,
J¼8.2 Hz), 7.84 (d, 2H, J¼8.2 Hz).
23
4.4. Enantioselective alkynylation of ketones
4.4.8. 1,3-Diphenyl-pent-1-yn-3-ol (6ha)17k. [
a]
ꢂ6.7 (c 1.0,
D
CHCl3), 61% ee. HPLC (Daicel chiralcel OD-H, hexane/IPA¼29/1,
4.4.1. (S)-2,4-Diphenyl-but-3-yn-2-ol (6aa)17k. n-BuLi (0.16 M in
hexane, 0.58 mL, 0.094 mmol) was added to a solution of (R)-3,30-
diphenylbinaphthol (21 mg, 0.047 mmol) in THF (3 mL) at 0 ꢀC
under an Ar atmosphere. Trimethoxy(phenylethynyl)silane
(156 mg, 0.71 mmol) was added to the mixture in one portion, and
then a solution of acetophenone (56 mg, 0.47 mmol) in THF
(0.5 mL) was added over 3 h at the same temperature. After stirring
for another 1 h, the reaction was quenched with tetrabutylammo-
nium fluoride (1.0 M in THF, 4 mL). The mixture was stirred for 0.5 h
and extracted with EtOAc. The organic layer was washed with
water and brine successively. Drying over sodium sulfate, and
concentration under reduced pressure and separation by silica gel
column chromatography afforded the alcohol (85 mg, 81%) as
a colorless oil. Enantiomeric excess was determined by chiral HPLC.
See the next section for the determination of the absolute
1.0 mL/min): tR (min) 9.4 (minor), 11.0 (major). 1H NMR (CDCl3):
d
1.03 (t, 3H, J¼7.3 Hz, eCH2CH3), 1.95e2.11 (m, 2H, eCH2CH3), 2.45
(s, 1H, OH), 7.30e7.40 (m, 6H AreH), 7.48e7.51 (m, 2H, AreH),
7.68e7.77 (m, 2H, AreH).
20
4.4.9. 4-Methyl-1,3-diphenyl-pent-1-yn-3-ol (6ia)25. [
a]
ꢂ1.0
D
(c 0.81, CHCl3), 8% ee. HPLC (Daicel chiralcel AD-H, hexane/IPA¼19/
1, 1.0 mL/min): tR (min) 10.5 (major), 15.9 (minor). 1H NMR (CDCl3):
d
0.89 (d, 3H, J¼6.8 Hz), 1.14(d, 3H, J¼6.8 Hz), 2.14e2.23 (m, 1H),
2.41 (s, 1H, OH), 7.28e7.39 (m, 6H, AreH), 7.49e7.51 (m, 2H, AreH),
7.67e7.69 (m, 2H, AreH).
16
4.4.10. 3-Methyl-1,5-diphenyl-pent-1-yn-3-ol (6ja)17d. [
a
]
þ6.0
D
(c 1.0, CHCl3), 41% ee. HPLC (Daicel chiralcel OD-H, hexane/IPA¼19/1,
1.0 mL/min): tR (min) 11.4 (minor), 16.2 (major). 1H NMR (CDCl3):
configuration.
d 1.63 (s, 3H, CH3), 2.01e2.10 (m, 2H), 2.91e2.95 (m, 2H), 7.18e7.22
(m, 8H, AreH), 7.43e7.46 (m, 2H, AreH).
16
[
a
]
ꢂ6.6 (c 1.0, CHCl3), 82% ee. HPLC (Daicel chiralcel OD-H,
D
hexane/IPA¼19/1, 1.0 mL/min): tR (min) 8.6 (minor), 10.5 (major).
17
1H NMR (CDCl3):
d
1.87 (s, 3H, CH3), 2.46 (s, 1H, OH), 7.30e7.50 (m,
4.4.11. 2-Cyclohexyl-4-phenyl-but-3-yn-2-ol (6ka)17g. [
a
]
D
þ2.7 (c
8H, AreH), 7.73e7.75 (m, 2H, AreH).
1.0, CHCl3), 52% ee. HPLC (Daicel chiralcel OD-H, hexane/IPA¼19/1,
1.0 mL/min): tR (min) 5.7 (minor), 7.9 (major). 1H NMR (CDCl3):
20
4.4.2. 2-(2-Naphthyl)-4-phenyl-but-3-yn-2-ol (6ba)17l. [
a]
þ17.4
d 1.14e1.30 (m, 5H), 1.51e1.52 (m, 1H), 1.54 (s, 3H, CH3), 1.68e1.71
(m, 1H), 1.82e1.84 (m, 2H), 1.91e1.95 (m, 1H), 2.02e2.05 (m, 1H),
7.30e7.31 (m, 3H, AreH), 7.41e7.44 (m, 2H, AreH).
D
(c 0.44, CHCl3), 76% ee. HPLC (Daicel chiralcel OD-H, hexane/IPA¼9/
1, 1.0 mL/min): tR (min) 8.6 (minor), 11.4 (major). 1H NMR (CDCl3):
d
1.95 (s, 3H, CH3), 2.59 (s, 1H, OH), 7.34e7.35 (m, 3H, AreH),
21
7.48e7.52 (m, 4H, AreH), 7.80e7.88 (m, 4H, AreH), 8.19 (s, 1H,
AreH).
4.4.12. 3,4,4-Trimethyl-1-phenyl-pent-1-yn-3-ol (6la)17d. [
a
]
D
þ2.2
(c 2.2, CHCl3), 43% ee. HPLC (Daicel chiralcel OD-H, hexane/IPA¼19/
1, 1.0 mL/min): tR (min) 5.5 (minor), 8.2 (major). 1H NMR (CDCl3):
18
4.4.3. 2-(4-Methylphenyl)-4-phenyl-but-3-yn-2-ol
(6ca)17l. [
a
]
d 1.12 (s, 9H, CCH3), 1.54 (s, 3H, CH3), 1.94 (s, 1H, OH), 7.29e7.31 (m,
D
ꢂ5.4 (c 0.56, CHCl3), 81% ee. HPLC (Daicel chiralcel OD-H, hexane/
3H, AreH), 7.41e7.43 (m, 2H, AreH).
IPA¼19/1, 1.0 mL/min): tR (min) (minor), 11.6 (major). 1H NMR
(CDCl3):
d
1.86 (s, 3H, CH3), 2.37 (s, 3H, AreCH3), 2.41 (s, 1H, OH),
4.5. Determination of the absolute configuration of chiral
7.19 (d, 2H, J¼8.2 Hz), 7.32e7.33 (m, 3H, AreH), 7.47e7.49 (m, 2H,
propargylic alcohol 6
AreH), 7.62 (d, 2H, J¼8.2 Hz).
4.5.1. (S)-2-Hydroxy-2-phenylpropanoic acid methyl ester (8aa)21. A
4.4.4. (S)-2-(4-Methoxyphenyl)-4-phenyl-but-3-yn-2-ol
solution of Red-AlÒ in toluene (65%, 0.54 mL) was added to a solu-
16
(6da)17l. [
a
]
19 ꢂ8.0 (c 0.44, CHCl3), 81% ee. [lit.17l
[a
]
25 þ10.2 (c 0.4,
tion of alcohol 6aa ([
a
]
ꢂ6.6 (c 1.0, CHCl3), 82% ee, 116 mg) in
D
D
D
CHCl3), 68% ee, R]. HPLC (Daicel chiralcel OD-H, hexane/IPA¼19/1,
ether (20 mL) at 0 ꢀC and the mixture was stirred at room tem-
perature for 4 h. The reaction was quenched by dropwise addition
of MeOH (5 mL) at 0 ꢀC. The mixture was dilute with EtOAc and
washed with a saturated solution of Rochelle’s salt. The organic
layer was dried over MgSO4, filtered, and concentrated under re-
duced pressure to yield a yellow oil, which was purified by column
chromatography (eluent: Hex/EtOAc¼8/1) to afford alkene 7aa
(105 mg, 90% yield) as a colorless oil.
1.0 mL/min): tR (min) 12.7 (minor), 21.3 (major). 1H NMR (CDCl3):
d
1.86 (s, 3H, CH3), 2.42 (s,1H, OH), 3.82 (s, 3H, OCH3), 6.90e6.93 (m,
2H), 7.32e7.35 (m, 3H, AreH), 7.47e7.49 (m, 2H, AreH), 7.64e7.67
(m, 2H, AreH).
17
4.4.5. 2-(4-Nitrophenyl)-4-phenyl-but-3-yn-2-ol
(6ea)17d. [
a]
D
ꢂ1.9 (c 1.0, CHCl3), 72% ee. HPLC (Daicel chiralcel OD-H, hexane/
22
20
IPA¼19/1, 1.0 mL/min): tR (min) 21.1 (minor), 26.3 (major). 1H NMR
Compound 7aa: [
a
]
ꢂ12.7 (c 2.5, CHCl3), 81% ee. [lit.20: [
a]
D
D
(CDCl3):
d
1.88 (s, 3H, CH3), 2.57 (s, 1H, OH), 7.34e7.36 (m, 3H,
þ12.8 (c 0.63, CHCl3), 91% ee, S]. HPLC (Daicel chiralcel OD-H,
AreH), 7.46e7.49 (m, 2H, AreH), 7.90 (d, J¼9.2 Hz, 2H, AreH), 8.25
hexane/IPA¼9/1, 1.0 mL/min): tR (min) 9.1 (major), 12.0 (minor). 1H
(m, 2H, AreH).
NMR (CDCl3):
d
1.80 (s, 3H, CH3), 6.50 (d, 1H, J¼16.0 Hz, CH]CH),
6.64 (d,1H, J¼16.0 Hz, CH]CH), 7.22e7.39 (m, 8H, AreH), 7.51e7.53
4.4.6. (S)-2-(4-Fluorophenyl)-4-phenyl-but-3-yn-2-ol (6fa)17l. [
a]
D
(m, 2H, AreH).
22
ꢂ8.5 (c 0.53, CHCl3), 79% ee. [lit.17l
[
a
]
D
25 þ5.0 (c 0.4, CHCl3), 54% ee,
Ozone was bubbled into a solution of the alkene 7aa
R]. HPLC (Daicel chiralcel OD-H, hexane/IPA¼19/1, 1.0 mL/min): tR
(105.3 mg, 0.47 mmol) in dichloromethane (20 mL) at ꢂ78 ꢀC
until a blue color persisted. Oxygen was then passed through the
solution and triphenylphosphine (123 mg, 0.47 mmol) was added
to the mixture at the same temperature. The resulting mixture
was stirred for 1 h at room temperature and concentrated under
reduced pressure to yield a colorless oil, which was purified by
silica gel column chromatography (eluent: Hex/EtOAc¼6/1) to
afford the corresponding aldehyde (53.8 mg, 76% yield) as a col-
orless oil.
(min) 8.2 (minor), 10.2 (major). 1H NMR (CDCl3):
d 1.86 (s, 3H, CH3),
2.46 (s, 1H, OH), 7.04e7.08 (m, 2H, AreH), 7.31e7.35 (m, 3H, AreH),
7.47e7.49 (m, 2H, AreH), 7.68e7.71 (m, 2H, AreH).
4.4.7. 2-(4-Trifluoromethylphenyl)-4-phenyl-but-3-yn-2-ol
24
(6ga)17k. [
a
]
ꢂ6.1 (c 1.6, CHCl3), 75% ee. HPLC (Daicel chiralcel
D
OD-H, hexane/IPA¼19/1, 1.0 mL/min): tR (min) 8.3 (minor), 10.1
(major). 1H NMR (CDCl3):
d
1.87 (s, 3H, CH3), 2.53 (s, 1H, OH),

T. Ueda et al. / Tetrahedron 66 (2010) 7726e7731
7731
2. Stoichiometric enantioselective alkynylation: Mukaiyama, T.; Suzuki, K.; Soai,
K.; Sato, T. Chem. Lett. 1979, 447e448.
Sodium bicarbonate (1.0 g, 12 mmol) was added to a solution of
the above aldehyde in MeOH/water (9:1, 1.4 mL). To the mixture
was added bromine (0.14 mL, 2.7 mmol) over 30 min with vigorous
stirring at room temperature. After stirring for 2 h, excess bromine
was decomposed using solid Na2S2O3. The mixture was filtered, and
the filtrate was extracted with EtOAc. The organic layer was washed
with brine, dried over Na2SO4, filtered, and concentrated in vacuo.
The obtained crude product was purified by column chromatog-
raphy (eluent: Hex/CH2Cl2¼3:2, 1:1, 1:3) to give the ester 8aa
(41.3 mg, 54% yield, 81% ee) as a colorless oil.
3. Niwa, S.; Soai, K. J. Chem. Soc., Perkin Trans. 1 1990, 937e943.
4. Amino alcohol catalysts with alkynylzinc: (a) Trost, B. M.; Weiss, A. H.; von
Wangelin, A. J. J. Am. Chem. Soc. 2006, 128, 8e9; (b) Dahmen, S. Org. Lett. 2004,
6, 2113e2116; (c) Wu, P.-Y.; Wu, H.-L.; Shen, Y.-Y.; Uang, B.-J. Tetrahedron:
Asymmetry 2009, 20, 1837e1841; (d) Zhong, J.-C.; Hou, S.-C.; Bian, Q.-H.; Yin,
M.-M.; Na, R.-S.; Zheng, B.; Li, Z.-Y.; Liu, S.-Z.; Wang, M. Chem.dEur. J. 2009, 15,
3069e3071.
5. Ti catalysts with alkynylzinc: (a) Gao, G.; Moore, D.; Xie, R.-G.; Pu, L. Org. Lett.
2002, 4, 4143e4146; (b) Li, X.-S.; Lu, G.; Kwok, W. H.; Chan, A. S. C. J. Am. Chem.
Soc. 2002, 124, 12636e12637; (c) Koyuncu, H.; Dogan, Ö Org. Lett. 2007, 9,
3477e3479.
[
a]
21 þ51 (c 1.3, CHCl3), 81% ee. [lit.21
[
a
]
D
24 þ55 (c 1.3, CHCl3), 81%
6. Metal triflate catalysts: (a) Yamaguchi, M.; Hayashi, A.; Minami, T. J. Org. Chem.
D
€
1991, 56, 4091e4092; (b) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem.
ee, S]. HPLC (Daicel chiralcel OD-H, hexane/IPA¼49/1, 0.5 mL/min):
Soc. 1999, 121, 11245e11246; (c) Frantz, D. E.; Fӓssler, R.; Carreira, E. M. J. Am.
Chem. Soc. 2000, 122, 1806e1807; (d) Anand, N. K.; Carreira, E. M. J. Am. Chem.
Soc. 2001, 123, 9687e9688; (e) Yamashita, M.; Yamada, K.; Tomioka, K. Adv.
Synth. Catal. 2005, 347, 1649e1652.
7. Other catalyses: (a) Corey, E. J.; Cimprich, K. A. J. Am. Chem. Soc. 1994, 116,
3151e3152; (b) Ooi, T.; Miura, T.; Ohmatsu, K.; Saito, A.; Maruoka, K. Org. Bio-
mol. Chem. 2004, 2, 3312e3319; (c) Takita, R.; Fukuta, Y.; Tsuji, R.; Ohshima, T.;
Shibasaki, M. Org. Lett. 2005, 7, 1363e1366; (d) Takita, R.; Yakura, K.; Ohshima,
T.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 13760e13761.
tR (min) 20.6 (major), 22.6 (minor). 1H NMR (CDCl3):
d 1.78 (s, 3H,
CH3), 3.75 (s, 1H, OH), 3.78 (s, 3H, OCH3), 7.28e7.38 (m, 3H, AreH),
7.54e7.55 (m, 3H, AreH).
4.6. Enantioselective alkynylation of acetylpyridines
4.6.1. 4-Phenyl-2-(pyridin-3-yl)-but-3-yn-2-ol (10aa)17k. [
a
]
24 ꢂ0.9
D
8. Lettan, R. B.; Scheidt, K. A. Org. Lett. 2005, 7, 3227e3230.
9. Base-catalyzed alkynylation with trimethylsilylacetylene: (a) Nakamura, E.;
Kuwajima, I. Angew. Chem., Int. Ed. Engl. 1976, 15, 498e499; (b) Yoshizawa, K.;
Shioiri, T. Tetrahedron Lett. 2005, 46, 7059e7063; (c) Kitazawa, T.; Minowa, T.;
Mukaiyama, T. Chem. Lett. 2006, 1002e1003.
(c 1.0, CHCl3), 75% ee. HPLC (Daicel chiralcel OD-H, hexane/IPA¼9/1,
1.0 mL/min): tR (min) 9.5 (minor), 12.2 (major). 1H NMR (CDCl3):
d
1.89 (s, 3H, CH3), 7.27e7.35 (m, 4H), 7.46e7.51 (m, 2H, AreH),
10. Orito, Y.; Nakajima, M. Synthesis 2006, 1391e1401.
8.01e8.03 (m, 1H, AreH), 8.54e8.56 (m, 1H, AreH), 8.99 (s, 1H,
AreH).
11. (a) Nakajima, M.; Orito, Y.; Ishizuka, T.; Hashimoto, S. Org. Lett. 2004, 6,
3763e3765; (b) Orito, Y.; Hashimoto, S.; Ishizuka, T.; Nakajima, M. Tetrahedron
2006, 62, 390e400; (c) Ichibakase, T.; Orito, Y.; Nakajima, M. Tetrahedron Lett.
2008, 49, 4427e4429.
4.6.2. 4-Phenyl-2-(pyridin-4-yl)-but-3-yn-2-ol (10ba)22b. [
a
]
23 þ1.6
D
12.
A
part of these results were reported as
a preliminary communication:
(c 1.0, CHCl3), 75% ee. HPLC (Daicel chiralcel OD-H, hexane/IPA¼4/1,
Tetrahedron Lett. 2010, 51, 2168e2169.
1.0 mL/min): tR (min) 7.3 (minor), 11.1 (major). 1H NMR (CDCl3):
13. (a) Chmielecka, J.; Chojnowski, J.; Eaborn, C.; Stanczyk, W. A. J. Chem. Soc., Perkin
Trans. 2 1985, 1779e1783; (b) Jun, C.-H.; Crabtree, R. H. J. Organomet. Chem.
1993, 447, 177e187.
14. Recent examples of using lithium binaphtholate as a catalyst: (a) Schiffers, R.;
Kagan, H. B. Synlett 1997, 1175e1178; (b) Holmes, I. P.; Kagan, H. B. Tetrahedron
Lett. 2000, 41, 7453e7456; (c) Hatano, M.; Ikeno, T.; Miyamoto, T.; Ishihara, K. J.
Am. Chem. Soc. 2005, 127, 10776e10777; (d) Hatano, M.; Ikeno, T.; Matsumura,
T.; Torii, S.; Ishihara, K. Adv. Synth. Catal. 2008, 350, 1776e1780; (e) Hatano, M.;
Horibe, T.; Ishihara, K. J. Am. Chem. Soc. 2010, 132, 56e57.
15. Dioxane or dimethoxymethane gave less satisfactory selectivities. Ether or
toluene gave no alkynylated adduct. Na or K salt of binaphthol gave racemic
products.
16. (a) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2004, 4095e4105;
(b) Ramón, D. J.; Yus, M. Angew. Chem., Int. Ed. 2004, 43, 284e287; (c) Riant, O.;
Hannedouche, J. Org. Biomol. Chem. 2007, 5, 873e888; (d) Hatano, M.; Ishihara,
K. Synthesis 2008, 1647e1675.
17. (a) Thompson, A. S.; Corley, E. G.; Huntington, M. F.; Grabowski, E. J. J. Tetra-
hedron Lett. 1995, 36, 8937e8940; (b) Tan, L.; Chen, C.-y.; Tillyer, R. D.;
Grabowski, E. J. J.; Reider, P. J. Angew. Chem., Int. Ed. 1999, 38, 711e713; (c) Jiang,
B.; Chen, Z.; Tang, X. Org. Lett. 2002, 4, 3451e3453; (d) Cozzi, P. G. Angew. Chem.,
Int. Ed. 2003, 42, 2895e2898; (e) Lu, G.; Li, X.; Jia, X.; Chan, W. L.; Chan, A. S. C.
Angew. Chem., Int. Ed. 2003, 42, 5057e5058; (f) Saito, B.; Katsuki, T. Synlett 2004,
1557e1560; (g) Cozzi, P. G.; Alesi, S. Chem. Commun. 2004, 2448e2449; (h)
Zhou, Y.; Wang, R.; Xu, Z.; Yan, W.; Liu, L.; Kang, Y.; Han, Z. Org. Lett. 2004, 6,
4147e4149; (i) Liu, L.; Wang, R.; Kang, Y.-F.; Chen, C.; Xu, X.-Q.; Zhou, Y.-C.; Ni,
M.; Cai, H.-Q.; Gong, M.-Z. J. Org. Chem. 2005, 70, 1084e1086; (j) Forrat, V. J.;
Prieto, O.; Ramón, D. J.; Yus, M. Chem.dEur. J. 2006, 12, 4431e4445; (k) Lu, G.;
Li, X.; Li, Y.-M.; Kwong, F. Y.; Chan, A. S. C. Adv. Synth. Catal. 2006, 348,
1926e1933; (l) Pathak, K.; Bhatt, A. P.; Abdi, S. H. R.; Kureshy, R. I.; Khan, N.-U.
H.; Ahmad, I.; Jasra, R. V. Chirality 2007, 19, 82e88.
d
1.84 (s, 3H, CH3), 7.33e7.35 (m, 3H, AreH), 7.45e7.47 (m, 2H,
AreH), 7.62 (d, 2H, J¼6.0 Hz), 8.59 (s, 2H, AreH).
20
4.6.3. 5-Benzyloxy-2-(pyridin-3-yl)-pent-3-yn-2-ol
(10ad). [a]
D
þ0.9 (c 1.1, CHCl3), 66% ee. HPLC (Daicel chiralcel OD-H, hexane/
IPA¼9/1, 1.0 mL/min): tR (min) 29.8 (minor), 37.2 (major). 1H NMR
(CDCl3):
d 1.85 (s, 3H, CH3), 4.27 (s, 2H), 4.59 (s, 2H), 7.26e7.34 (m,
6H, AreH), 7.93e7.95 (m, 1H, AreH), 8.50e8.54 (m, 1H, AreH), 8.90
(s, 1H, AreH). 13C NMR (CDCl3):
d
33.3, 57.3, 68.2, 71.8, 81.4, 89.0,
123.1, 128.0, 128.1, 128.5, 132.9, 137.2, 141.1, 146.8, 148.7. IR (neat):
n
(cmꢂ1) 3139, 2854, 1658, 1477, 1351, 1174, 1091, 1025, 740, 698. LR-
FABMS 268: ((MþH)þ, bp), 149, 91, 55. HR-FABMS: calcd for
C17H18NO2 ((MþH)þ) 268.1338, found 268.1337.
20
4.6.4. 5-Benzyloxy-2-(pyridin-4-yl)-pent-3-yn-2-ol
(10bd). [a]
D
þ1.8 (c 1.0, CHCl3), 60% ee. HPLC (Daicel chiralpak AD-H, hexane/
IPA¼9/1, 1.0 mL/min): tR (min) 9.2 (major), 10.8 (minor). 1H NMR
(CDCl3):
d 1.74 (s, 3H, CH3), 4.24 (s, 2H), 4.57 (s, 2H), 7.27e7.35 (m,
5H, AreH), 7.52 (d, 2H, J¼6.0 Hz), 8.48 (d, 2H, J¼6.0 Hz). 13C NMR
(CDCl3):
d 33.0, 57.3, 68.5, 71.8, 81.0, 89.0, 120.1, 127.9, 128.0, 128.4,
137.1, 149.2, 155.1. IR (neat): n
(cmꢂ1) 3087, 2854, 1600, 1457, 1390,
1180, 1074, 825, 740, 698. LR-FABMS: 268 ((MþH)þ, bp), 149, 81, 57.
HR-FABMS: calcd for C17H18NO2 ((MþH)þ) 268.1338, found
268.1337.
18. (a) Motoki, R.; Kanai, M.; Shibasaki, M. Org. Lett. 2007, 9, 2997e3000; (b)
Dhondi, P. K.; Carberry, P.; Choi, L. B.; Chisholm, J. D. J. Org. Chem. 2007, 72,
9590e9596.
25
22
19.
[
a
]
þ5.1 (c 0.35, CHCl3) for (R)-6aa in lit.17l; [
a
]
ꢂ4.0 (c 1.85, CHCl3) for (R)-
D
D
Supplementary data
6aa in lit.17j
.
20. Optical rotation of 7aa is known, however, the value is still small: Garcia, C.;
Walsh, P. J. Org. Lett. 2003, 5, 3641e3644.
21. Wu, H.-L.; Wu, P.-Y.; Shen, Y.-Y.; Uang, B.-J. J. Org. Chem. 2008, 73, 6445e6447.
22. (a) Arnoldi, A.; Betto, E.; Farina, G.; Formigoni, A.; Galli, R.; Griffini, A. Pestic. Sci.
1982, 13, 670e678; (b) Cussac, M.; Boucherle, A.; Pierre, J.-L.; Hache, J. Eur. J.
Med. Chem. 1974, 9, 651e657.
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.07.080.
References and notes
23. The only reported example for the phenylalkynylation of acetylpyridine shows
an unsatisfactory result (28% yield, 28% ee), see lit.17k. 10aa has antifungal
1. (a) Pu, L. Tetrahedron 2003, 59, 9873e9886; (b) Cozzi, P. G.; Hilgraf, R.;
Zimmermann, N. Eur. J. Org. Chem. 2004, 4095e4105; (c) Lu, G.; Li, Y.-M.; Li, X.-S.;
Chan, A. S. C. Coord. Chem. Rev. 2005, 249,1736e1744; (d) Trost, B. M.; Weiss, A. H.
Adv. Synth. Catal. 2009, 351, 963e983.
activity, see lit.22a
.
24. Wu, T. R.; Shen, L.; Chong, J. M. Org. Lett. 2004, 6, 2701e2704.
25. Miyamoto, H.; Yasaka, S.; Tanaka, K. Bull. Chem. Soc. Jpn. 2001, 74, 185e186.