Enantioselective Alkyne Addition to Aliphatic, Aromatic, and Vinyl Aldehydes Using Zn, iPrI, H8BINOL, and Ti(OiPr)4

Article abstract of DOI:10.1021/acs.joc.5b02185

A new catalytic system based on the readily available Zn, ⁱPrI, H₈BINOL, and Ti(OⁱPr)₄ has been developed which avoids the use of pyrophoric ZnEt₂. It can effectively catalyze the reaction of various terminal alkynes with aromatic, aliphatic, and vinyl aldehydes to generate chiral propargylic alcohols at room temperature with up to 98% yield and 98% enantiomeric excess. This new system signifciantly expands the substrate scope of the previously reported system using Zn, EtI, BINOL, and Ti(OⁱPr)₄.

Full text of DOI:10.1021/acs.joc.5b02185

Article
pubs.acs.org/joc
Enantioselective Alkyne Addition to Aliphatic, Aromatic, and Vinyl
i
Aldehydes Using Zn, PrI, H8BINOL, and Ti(OiPr)4
Wen-Cai Huang,†,‡ Winnie Liu,‡ Xue-Dan Wu,‡ Jun Ying,‡ and Lin Pu*,‡
†Department of Pharmaceutical and Bioengineering, School of Chemical Engineering, Sichuan University, Chengdu, China 610065
‡Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904-4319, United States
S
* Supporting Information
ABSTRACT: A new catalytic system based on the readily available Zn,
iPrI, H8BINOL, and Ti(OiPr)4 has been developed which avoids the use
of pyrophoric ZnEt2. It can effectively catalyze the reaction of various
terminal alkynes with aromatic, aliphatic, and vinyl aldehydes to
generate chiral propargylic alcohols at room temperature with up to
98% yield and 98% enantiomeric excess. This new system signifciantly
expands the substrate scope of the previously reported system using Zn,
EtI, BINOL, and Ti(OiPr)4.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
To explore the conditions for the alkyne addition to aliphatic
aldehydes, we studied the reaction of phenylacetylene with
cyclohexanecarboxaldehyde (Scheme 1). The reaction was
Over the past two decades, great progress has been made in the
catalytic asymmetric alkyne addition to aldehydes to generate
chiral propargylic alcohols, and a number of highly
enantioselective catalysts have been developed.1,2 Among
these is the catalyst system of 1,1′-bi-2-naphthol (BINOL) in
combination with ZnEt2, Ti(OiPr)4, and dicyclohexylamine
developed in our laboratory which has exhibited high
enantioselectivity and broad substrate scope.3 Although this
catalyst system is useful in the organic laboratory, because
ZnEt2 is spontaneously combustible upon exposure to air, its
use presents important safety issues in transportation, storage,
and operation when applied in large-scale industrial production.
Recently, we discovered that using the easily manageable and
inexpensive zinc powder in combination with EtI can replace
ZnEt2 in the presence of BINOL and Ti(OiPr)4 to carry out the
enantioselective alkyne addition to aromatic aldehydes with
90−96% enantiomeric excess (ee).4 However, when this
BINOL-based catalyst system is applied to the alkyne addition
to aliphatic aldehydes, the enantioselectivity is much lower (vide
infra). It would be highly desirable if this catalytic process could
be applied to the reaction of other substrates such as aliphatic
and vinyl aldehydes. Herein, we report our discovery that when
Scheme 1. Asymmetric Reaction of Phenylacetylene with
Cyclohexanecarboxaldehyde
conducted at room temperature in two steps by first mixing Zn,
an alkyl halide, a chiral ligand, and Ti(OiPr)4 in THF and then
adding an aldehyde and diethyl ether. We first tested the use of
BINOL, Ti(OiPr)4, and Zn in the presence of various alkyl
halides, and the results are summarized in Table 1. As shown in
entry 1, in the presence of Zn and EtI, the propargylic alcohol
product was obtained in high yield (92%) but with only 69% ee.
i
When a variety of other alkyl halides, including MeI, PrI,
benzyl bromide, allyl bromide, and 2-methylallyl bromide, were
used, the enantioselectivities were found to be in the range of
49−77% ee (Table 1, entries 2−11). In entries 9−11, CuI was
added to promote the reaction of the terminal alkynes.
Although there was some improvement in enantioselectivity,
it still did not meet the expectation.
i
octahydroBINOL (H8BINOL) and PrI are used in combina-
tion with Zn and Ti(OiPr)4, it can promote the reaction of
various alkynes with aliphatic, aromatic, and vinyl aldehydes
under very mild conditions with excellent enantioselectivity.
H8BINOL is a readily accessible chiral compound which has
found applications in many asymmetric processes.5 It can be
easily prepared from the partial hydrogenation of BINOL and is
also commercially available. To improve the enantioselectivity
for the asymmetric alkyne addition to the aliphatic aldehyde, we
Received: September 16, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b02185
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a
Table 1. Conditions for the Reaction of Phenylacetylene with Cyclohexanecarboxaldehyde in the Presence of (S)-BINOL
b
entry
chiral ligand
Zn (equiv)
RX (equiv)
EtI, 12
alkyne (equiv)
isolated yield (%)
ee (%)
1
2
3
4
5
6
7
8
(S)-BINOL
(S)-BINOL
(S)-BINOL
(S)-BINOL
(S)-BINOL
(S)-BINOL
(S)-BINOL
(S)-BINOL
(S)-BINOL
(S)-BINOL
(S)-BINOL
6
6
4
4
4
4
4
4
9
2
4
4
92
79
81
73
90
93
86
81
95
83
69
77
71
71
51
77
48
49
77
74
49
MeI, 12
iPrI, 12
6
6
BnBr, 6
6
2-Me-allyl-Br, 6
allyl-Br, 6
allyl-Br, 10
allyl-Br, 3
EtI, 12
6
10
3
c
9
6
c
10
6
BnBr, 6
c
11
6
allyl-Br, 6
4
95
a
b
c
THF (1 mL) was used in the first step, and diethyl ether (10 mL) was used in the second step. 0.4 equiv of ligand was used. 0.1 equiv of CuI was
used as additive.
tested the use of (S)-H8BINOL in place of (S)-BINOL for the
reaction of phenylacetylene with cyclohexanecarboxaldehyde.
The results are summarized in Table 2. As shown in entry 1, in
Table 2. Conditions for the Reaction of Phenylacetylene
with Cyclohexanecarboxaldehyde in the Presence of (S)-
a
H8BINOL
Zn
alkyne
isolated
ee
b
entry
chiral ligand
(equiv) RX (equiv) (equiv) yield (%) (%)
1
2
3
4
5
6
7
(S)-H8BINOL
(S)-H8BINOL
(S)-H8BINOL
(S)-H8BINOL
(S)-H8BINOL
(S)-H8BINOL
(S)-H8BINOL
(S)-H8BINOL
(S)-H8BINOL
6
6
6
6
6
6
4
6
6
EtI, 12
BnBr, 6
allyl-Br, 6
CH3I, 12
iPrI, 12
iPrI, 8
iPrI, 6
iPrI, 8
iPrI, 8
4
4
4
4
4
4
3
4
4
93
92
93
54
86
98
86
98
95
84
74
64
63
92
92
88
90
89
c
8
d
9
a
Figure 1. Products for the reaction of phenylacetylene with a variety of
THF (1 mL) was used in the first step, and diethyl ether (10 mL)
i
aldehydes in the presence of Zn, PrI, (S)-H8BINOL, and Ti(OiPr)4.
b
c
was used in the second step. 0.4 equiv of ligand was used. Reaction
time was 16 h + 8 h. Reaction time was 8 h + 16 h.
d
(91−92% ee) and high yields (89−98%) at room temperature.
We also studied the reaction of phenylacetylene with various
aromatic and vinyl aldehydes under the same conditions. As the
results listed in Figure 1 show, excellent enantioselectivity and
high yield are generally observed for a broad range of
aldehydes.
the presence of (S)-H8BINOL, Zn, EtI, and Ti(OiPr)4, the
reaction of phenylacetylene with cyclohexanecarboxaldehyde
gave high yield (93%) and significantly improved enantiose-
lectivity (84% ee). Encouraged by this result, we explored the
use of other alkyl halides for this reaction. Although alkyl
halides such as MeI, benzyl bromide, and allyl bromide were
found to give lower enantioselectivity than EtI (entries 2−4),
We have further extended the application of the Zn-iPrI-
H8BINOL-Ti(OiPr)4 catalyst system to the reaction of various
alkynes with various aldehydes, and the results are summarized
in Table 3. For the reactions of 1-hexyne and 4-phenylbutyne,
the first step was conducted at 45 °C and the second step at
room temperature. Under these conditions, the vinyl and alkyl
alkynes reacted with a variety of aldehydes to give good yields
and high enantioselectivities.
i
we were delighted to find that when PrI was used in place of
EtI, up to 92% ee was achieved for the reaction (entry 5).
When the amount of iPrI was reduced from 12 equiv to 8 equiv,
the yield was increased to 98% while the high enantioselectivity
was maintained (entry 6). Further decreasing the amount of the
reagents led to reduced yield and enantioselectivity (entry 7).
Shortening the reaction time gave slightly lower enantiose-
lectivity (entries 8 and 9). Thus, we have identified the
conditions in entry 6 as the optimized conditions.
We have applied the conditions in entry 6 of Table 2 to the
asymmetric reaction of phenylacetylene with other aliphatic
aldehydes. The results of these reactions and the structures of
the products are shown in Figure 1. These results demonstrate
that the addition of the alkyne to both secondary and primary
alkyl aldehydes in the presence of the new H8BINOL-Zn-iPrI-
Ti(OiPr)4 catalyst system gave excellent enantioselectivities
CONCLUSIONS
■
We have discovered that the substrate scope of a previously
reported catalytic asymmetric alkyne addition to aldehydes
processes can be greatly expanded by using H8BINOL and iPrI
in place of BINOL and EtI. We have demonstrated that this
new catalyst system can carry out the alkyne addition to
aliphatic aldehydes with high enantioselectivity at room
temperature. In addition, the new catalyst system can also
promote the enantioselective reaction of a variety of alkynes
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(R)-4-Methyl-1-phenylpent-1-yn-3-ol (2). Colorless oil, 85 mg,
98% yield; 91% ee determined by HPLC analysis (OD column, 10%
IPA in hexane, 1 mL/min, 254 nm). Retention time: tmajor = 7.1 min
and tminor = 13.5 min. 1H NMR (600 MHz, CDCl3): δ 7.37−7.36 (m,
2H), 7.24−7.19 (m, 3H), 4.33 (t, J = 6.0 Hz, 1H), 1.93−1.88 (m, 1H),
1.77 (d, J = 6.0 Hz, 2H), 1.00 (dd, J = 6.0, 6.6 Hz, 6H). These data are
consistent with those reported in ref 6.
Table 3. Addition of Alkynes to Aldehydes in the Presence of
a
i
Zn, PrI, (S)-H8BINOL, and Ti(OiPr)4
(R)-1-Phenylundec-1-yn-3-ol (3). Colorless oil, 109 mg, 89% yield;
91% ee determined by HPLC analysis (OD column, 10% IPA in
hexane, 1 mL/min, 254 nm). Retention time: tmajor = 7.2 min and tminor
1
= 19.8 min. H NMR (600 MHz, CDCl3): δ 7.36−7.35 (m, 2H),
7.24−7.19 (m, 3H), 4.52 (q, J = 6.6 Hz, 1H), 1.78−1.68 (m, 3H),
1.45−1.41 (m, 2H), 1.24−1.19 (m, 10H), 0.81 (t, J = 6.6 Hz, 3H).
These data are consistent with those reported in ref 6.
(R)-1-Phenylhept-1-yn-3-ol (4). Colorless oil, 85 mg, 90% yield;
91% ee determined by HPLC analysis (OD column, 10% IPA in
hexane, 1 mL/min, 254 nm). Retention time: tmajor = 6.7 min and tminor
1
= 18.7 min. H NMR (600 MHz, CDCl3): δ 7.37−7.36 (m, 2H),
7.24−7.19 (m, 3H), 4.52 (q, J = 6.0 Hz, 1H), 1.80−1.69 (m, 3H),
1.50−1.30 (m, 4H), 0.87 (t, J = 7.2 Hz, 3H). These data are consistent
with those reported in ref 7.
(R)-1,3-Diphenylprop-2-yn-1-ol (5). Colorless oil, 102 mg, 98%
yield; 96% ee determined by HPLC analysis (OD column, 10% IPA in
hexane, 1 mL/min, 254 nm). Retention time: tmajor = 15.1 min and
tminor = 30.7 min. 1H NMR (600 MHz, CDCl3): δ 7.54 (d, J = 7.8 Hz,
2H), 7.33−7.17 (m, 8H), 5.62 (d, J = 6.0 Hz, 1H), 2.18 (d, J = 6.0 Hz,
1H). These data are consistent with those reported in ref 4.
(R)-3-Phenyl-1-(p-tolyl)prop-2-yn-1-ol (6). White solid, 102 mg,
92% yield; 96% ee determined by HPLC analysis (OD column, 10%
IPA in hexane, 1 mL/min, 254 nm). Retention time: tmajor = 11.1 min
and tminor = 25.3 min. 1H NMR (600 MHz, CDCl3): δ 7.43−7.38 (m,
4H), 7.24−7.13 (m, 5H), 5.57 (s, 1H), 2.29 (s, 3H), 2.16 (s, 1H).
These data are consistent with those reported in ref 4.
(S)-3-Phenyl-1-(o-tolyl)prop-2-yn-1-ol (7). Colorless oil, 84 mg,
76% yield; 95% ee determined by HPLC analysis (OD column, 10%
IPA in hexane, 1 mL/min, 254 nm). Retention time: tmajor = 12.0 min
and tminor = 29.5 min. 1H NMR (600 MHz, CDCl3): δ 7.72−7.71 (m,
1H), 7.45−7.44 (m, 2H), 7.31−7.20 (m, 6H), 5.83 (s, 1H), 2.49 (s,
3H), 2.17 (s, 1H). These data are consistent with those reported in ref
4.
a
First step: Zn (3 mmol, 6 equiv), (S)-H8BINOL (0.2 mmol, 0.4
i
equiv), PrI (4 mmol, 8 equiv), an alkyne (2 mmol, 4 equiv), THF (1
mL), Ti(OiPr)4 (1 equiv), and 24 h at room temperature for 1-
ethynylcyclohexene and 45 °C for 1-hexyne or 4-phenylbutyne.
Second step: Et2O (10 mL), an aldehyde (0.5 mmol), and 16 h at
room temperature.
(R)-1-(3-Methoxyphenyl)-3-phenylprop-2-yn-1-ol (8). Colorless
oil, 110 mg, 92% yield; 95% ee determined by HPLC analysis (OD
column, 10% IPA in hexane, 1 mL/min, 254 nm). Retention time:
tmajor = 22.0 min and tminor = 38.3 min. 1H NMR (600 MHz, CDCl3): δ
7.42−7.38 (m, 2H), 7.24−7.22 (m, 4H), 7.12−7.10 (m, 2H), 6.82−
6.80 (m, 1H), 5.59 (d, J = 6.0 Hz, 1H), 3.76 (s, 3H), 2.21 (d, J = 6.6
Hz, 1H). These data are consistent with those reported in ref 8.
(R)-3-Phenyl-1-(4-(trifluoromethyl)phenyl)prop-2-yn-1-ol (9).
Colorless oil, 130 mg, 94% yield; 98% ee determined by HPLC
analysis (OD column, 10% IPA in hexane, 1 mL/min, 254 nm).
Retention time: tmajor = 10.2 min and tminor = 15.5 min. 1H NMR (600
MHz, CDCl3): δ 7.65−7.56 (m, 4H), 7.37−7.16 (m, 5H), 5.65 (d, J =
6.0 Hz, 1H), 2.27 (d, J = 6.0 Hz, 1H). These data are consistent with
those reported in ref 4.
(S)-1-(Naphthalen-1-yl)-3-phenylprop-2-yn-1-ol (10). Colorless
oil, 110 mg, 85% yield; 97% ee determined by HPLC analysis (OD
column, 10% IPA in hexane, 1 mL/min, 254 nm). Retention time:
tmajor = 18.8 min and tminor = 46.1 min. 1H NMR (600 MHz, CDCl3): δ
8.37 (d, J = 8.4 Hz, 1H), 7.93−7.85 (m, 3H), 7.59−7.46 (m, 5H),
7.33−7.29 (m, 3H), 6.35 (d, J = 6.0 Hz, 1H), 2.38 (d, J = 6.0 Hz, 1H).
These data are consistent with those reported in ref 4.
(R,E)-1,5-Diphenylpent-1-en-4-yn-3-ol (11). White solid, 100 mg,
85% yield; 92% ee determined by HPLC analysis (OD column, 20%
IPA in hexane, 1 mL/min, 254 nm). Retention time: tmajor = 11.3 min
and tminor = 34.2 min. 1H NMR (600 MHz, CDCl3): δ 7.39−7.14 (m,
10H), 6.77−6.73 (m, 1H), 6.33−6.27 (m, 1H), 5.19 (s, 1H), 2.00 (s,
1H). These data are consistent with those reported in ref 6.
(R,E)-1-Phenylhex-4-en-1-yn-3-ol (12). White solid, 71 mg, 83%
yield; 93% ee determined by HPLC analysis (OD column, 10% IPA in
hexane, 1 mL/min, 254 nm). Retention time: tmajor = 8.3 min and tminor
with a broad range of aldehydes. This process avoids the use of
the pyrophoric ZnEt2 and is useful in practice for the synthesis
of structurally diverse chiral propargylic alcohols.
EXPERIMENTAL SECTION
■
Typical Experimental Procedure for the Use of the H8BINOL-
Zn-iPrI-Ti(OiPr)4 Catalyst System in the Asymmetric Alkyne
Addition to Aldehydes. To a flame-dried 25 mL flask was added Zn
powder (3 mmol, 6 equiv) and (S)-H8BINOL (0.2 mmol, 0.4 equiv).
Then an alkyne (2 mmol, 4 equiv), THF (1 mL, dry), iPrI (4 mmol, 8
equiv), and Ti(OiPr)4 (1 equiv) were added via syringe under
nitrogen. After the mixture was stirred at room temperature for 24 h,
diethyl ether (10 mL, dry) was added followed by an aldehyde (0.5
mmol) and the stirring was continued for 16 h. Saturated ammonia
chloride solution (5 mL) was then added to quench the reaction. After
extraction with methylene chloride (2 × 10 mL) and concentration
under vacuum, the residue was purified by column chromatography on
silica gel with hexane and 5−10% ethyl acetate as the eluent to afford
the pure product. The ee value was determined by HPLC equipped
with a chiral column.
Characterizations of the Chiral Propargylic Alcohols in
Figure 1. (R)-1-Cyclohexyl-3-phenylprop-2-yn-1-ol (1). Colorless oil,
105 mg, 98% yield; 92% ee determined by HPLC analysis (OD
column, 10% IPA in hexane, 1 mL/min, 254 nm). Retention time:
tmajor = 7.5 min and tminor = 17.4 min. 1H NMR (600 MHz, CDCl3): δ
7.38−7.37 (m, 2H), 7.25−7.19 (m, 3H), 4.32 (t, J = 6.0 Hz, 1H),
1.88−1.05 (m, 12H). These data are consistent with those reported in
ref 6.
C
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1
= 30.0 min. H NMR (600 MHz, CDCl3): δ 7.38−7.37 (m, 2H),
1.97 (dd, J = 6.0, 1.2 Hz, 1H), 1.43−1.36 (m, 2H), 1.30−1.25 (m,
2H), 0.77 (td, J = 7.2, 1.2 Hz, 3H). These data are consistent with
those reported in ref 3c.
7.24−7.18 (m, 3H), 5.93−5.88 (m, 1H), 5.66−5.63 (m, 1H), 4.98 (s,
1H), 1.85 (s, 1H), 1.69 (d, J = 6.6 Hz, 1H). These data are consistent
with those reported in ref 6.
(R)-1-(p-Tolyl)hept-2-yn-1-ol (Entry 9). Colorless oil, 85 mg, 84%
yield; 91% ee determined by HPLC analysis (AD-H column, 10% IPA
in hexane, 1 mL/min, 220 nm). Retention time: tmajor = 8.5 min and
Characterizations of the Chiral Propargylic Alcohols in
Table 3. (R)-3-(Cyclohex-1-en-1-yl)-1-phenylprop-2-yn-1-ol (Entry
1). Colorless oil, 96 mg, 90% yield; 96% ee determined by HPLC
analysis (OD-H column, 10% IPA in hexane, 1 mL/min, 254 nm).
Retention time: tmajor = 17.2 min and tminor = 11.8 min. 1H NMR (600
MHz, CDCl3): δ 7.54 (d, J = 7.8 Hz, 2H), δ 7.36−7.24 (m, 3H),
6.15−6.14 (m, 1H), 5.55 (s, 1H), 2.14−2.08 (m, 4H), 1.63−1.55 (m,
4H). These data are consistent with those reported in ref 9.
(R)-3-Cyclohexenyl-1-p-tolylprop-2-yn-1-ol (Entry 2). Colorless
oil, 88 mg, 78% yield; 95% ee determined by HPLC analysis (OD-
H column, 10% IPA in hexane, 1 mL/min, 254 nm). Retention time:
tmajor = 17.1 min and tminor = 10.8 min. 1H NMR (600 MHz, CDCl3): δ
7.42 (d, J = 6.6 Hz, 2H), 7.17 (d, J = 6.0 Hz, 2H), 6.14 (s, 1H), 5.52
(s, 1H), 2.34 (s, 3H), 2.08−2.07 (m, 4H), 1.63−1.54 (m, 4H). These
data are consistent with those reported in ref 9.
1
tminor = 7.1 min. H NMR (600 MHz, CDCl3): δ 7.42−7.40 (m, 2H),
7.24−7.16 (m, 2H), 5.40 (d, J = 6.0 Hz, 1H), 2.34 (s, 3H), 2.27−2.24
(m, 2H), 2.03−2.02 (m, 1H), 1.55−1.49 (m, 2H), 1.44−1.38 (m, 2H),
0.90 (td, J = 7.2, 1.2 Hz, 3H). These data are consistent with those
reported in ref 3c.
(R)-1-(4-Chlorophenyl)hept-2-yn-1-ol (Entry 10). Colorless oil, 73
mg, 66% yield; 91% ee determined by HPLC analysis (AD-H column,
10% IPA in hexane, 1 mL/min, 220 nm). Retention time: tmajor = 8.2
1
min and tminor = 6.9 min. H NMR (600 MHz, CDCl3): δ 7.47−7.44
(m, 2H), 7.34−7.25 (m, 2H), 5.41 (s, 1H), 2.28−2.23 (m, 2H), 2.11−
2.08 (m, 1H), 1.54−1.40 (m, 4H), 0.93−0.88 (m, 3H). These data are
consistent with those reported in ref 3c.
(S)-1-(Naphthalen-1-yl)hept-2-yn-1-ol (Entry 11). Colorless oil, 81
mg, 68% yield; 92% ee determined by HPLC analysis (AD-H column,
10% IPA in hexane, 1 mL/min, 254 nm). Retention time: tmajor = 13.7
min and tminor = 8.8 min. 1H NMR (600 MHz, CDCl3): δ 8.30 (d, J =
8.4 Hz, 1H), 7.87−7.81 (m, 3H), 7.55−7.44 (m, 3H), 6.11 (d, J = 6.0
Hz, 1H), 2.28 (dt, J = 7.2, 1.8 Hz, 2H), 2.21 (d, J = 6.0 Hz, 1H), 1.55−
1.50 (m, 2H), 1.44−1.38 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H). These data
are consistent with those reported in ref 3c.
(R)-1-(4-Chlorophenyl)-3-(cyclohex-1-en-1-yl)prop-2-yn-1-ol
(Entry 3). White solid, 117 mg, 95% yield; 89% ee determined by
HPLC analysis (AD-H column, 4% IPA in hexane, 1 mL/min, 220
nm). Retention time: tmajor = 23.8 min and tminor = 21.7 min. [α]22
=
D
1
10.1 (c = 1.15, CHCl3). H NMR (600 MHz, CDCl3): δ 7.39 (d, J =
7.2 Hz, 2H), 7.25 (d, J = 7.2 Hz, 2H), 6.07 (s, 1H), 5.45 (s, 1H),
2.13−2.00 (m, 4H), 1.55−1.49 (m, 4H). 13C NMR (150 MHz,
CDCl3): δ 139.7, 136.3, 134.2, 128.9, 128.3, 120.1, 89.1, 85.8, 64.6,
29.2, 25.8, 22.4, 21.6. HRMS (M+) for C15H15OCl. Calcd: 246.0811.
Found: 246.0812.
(R)-1-(3-Methoxyphenyl)-5-phenylpent-2-yn-1-ol (Entry 12). Col-
orless oil, 103 mg, 77% yield; 96% ee determined by HPLC analysis
(AD-H column, 10% IPA in hexane, 1 mL/min, 220 nm). Retention
time: tmajor = 14.3 min and tminor = 12.8 min. [α]22 = 17.5 (c = 0.99,
(S)-3-(Cyclohex-1-en-1-yl)-1-(o-tolyl)prop-2-yn-1-ol (Entry 4).
Colorless oil, 100 mg, 88% yield; 91% ee determined by HPLC
analysis (AD-H column, 5% IPA in hexane, 1 mL/min, 254 nm).
Retention time: tmajor = 14.5 min and tminor = 11.8 min. [α]22D = −5.0
D
1
CHCl3). H NMR (600 MHz, CDCl3): δ 7.28−7.24 (m, 3H), 7.20−
7.19 (m, 3H), 7.05−7.03 (m, 2H), 6.84 (d, J = 7.8 Hz, 1H), 5.39 (d, J
= 5.4 Hz, 1H), 3.79 (s, 3H), 2.84 (t, J = 7.8 Hz, 2H), 2.56 (t, J = 7.8
Hz, 2H), 2.04 (d, J = 6.0 Hz, 1H). 13C NMR (150 MHz, CDCl3): δ
159.9, 142.8, 140.7, 129.8, 128.7, 128.6, 126.5, 119.1, 114.1, 112.2,
86.9, 80.9, 64.9, 55.5, 35.1, 21.2. HRMS (M+) for C18H18O2. Calcd:
266.1307. Found: 266.1310.
1
(c = 1.02, CHCl3). H NMR (600 MHz, CDCl3): δ 7.67 (s, 1H),
7.27−7.19 (m, 3H), 6.16 (s, 1H), 5.73 (s, 1H), 2.47 (s, 3H), 2.16−
2.10 (m, 4H), 1.65−1.59 (m, 4H). 13C NMR (150 MHz, CDCl3): δ
138.9, 136.2, 135.8, 130.9, 128.5, 126.7, 126.4, 120.3, 88.6, 86.0, 63.1,
29.3, 25.8, 22.4, 21.7, 19.2. HRMS (M+) for C16H18O. Calcd:
226.1358. Found: 226.1362.
(R)-1-Cyclohexyl-5-phenylpent-2-yn-1-ol (Entry 13). Colorless oil,
99 mg, 82% yield; 86% ee determined by HPLC analysis (OD column,
10% IPA in hexane, 1 mL/min, 220 nm). Retention time: tmajor = 8.9
min and tminor = 24.1 min. 1H NMR (600 MHz, CDCl3): δ 7.33−7.23
(m, 5H), 4.15−4.12 (m, 1H), 2.86 (t, J = 7.8 Hz, 2H), 2.55 (td, J = 7.8,
1.8 Hz, 2H), 1.83−1.76 (m, 4H), 1.70−1.66 (m, 2H), 1.53−1.46 (m,
1H), 0.99−1.29 (m, 5H). These data are consistent with those
reported in ref 2a.
(S)-3-(Cyclohex-1-en-1-yl)-1-(naphthalen-1-yl)prop-2-yn-1-ol
(Entry 5). Colorless oil, 113 mg, 86% yield; 95% ee determined by
HPLC analysis (OB-H column, 10% IPA in hexane, 1 mL/min, 220
nm). Retention time: tmajor = 22.0 min and tminor = 12.0 min. [α]22
=
D
−10.3 (c = 1.10, CHCl3). 1H NMR (600 MHz, CDCl3): δ 8.31 (d, J =
8.4 Hz, 1H), 7.85−7.81 (m, 3H), 7.56−7.45 (m, 3H), 6.22 (s, 1H),
6.16 (s, 1H), 2.31−2.30 (m, 1H), 2.15−2.08 (m, 4H), 1.62−1.56 (m,
4H). 13C NMR (150 MHz, CDCl3): δ 136.2, 136.0, 134.2, 130.8,
129.5, 128.9, 126.5, 126.0, 125.4, 124.8, 124.3, 120.3, 89.5, 86.0, 63.6,
29.3, 25.8, 22.4, 21.7. HRMS (M+) for C19H18O. Calcd: 262.1358.
Found: 262.1360.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02185.
(R)-3-(Cyclohex-1-en-1-yl)-1-cyclohexylprop-2-yn-1-ol (Entry 6).
Colorless oil, 96 mg, 88% yield; 85% ee determined by HPLC analysis
(OD-H column, 1.5% IPA in hexane, 1 mL/min, 220 nm). Retention
NMR spectra and HPLC plots of the propargylic alcohol
products (PDF)
time: tmajor = 50.1 min and tminor = 82.7 min. [α]22 = −6.6 (c = 1.00,
D
CHCl3). 1H NMR (600 MHz, CDCl3): δ 6.08 (s, 1H), 4.24−4.23 (m,
1H), 2.10−2.06 (m, 4H), 1.85−1.50 (m, 10H), 1.27−1.01 (m, 5H).
13C NMR (150 MHz, CDCl3): δ 135.2, 120.4, 87.7, 86.7, 67.9, 44.6,
29.5, 28.8, 28.4, 26.6, 26.2, 26.1, 25.8, 22.5, 21.7. HRMS (M+) for
C15H22O. Calcd: 218.1671. Found: 218.1672.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: lp6n@virginia.edu
(R)-1-(Cyclohex-1-en-1-yl)hept-1-yn-3-ol (Entry 7). Colorless oil,
82 mg, 85% yield; 88% ee determined by HPLC analysis (OB-H
column, 1% IPA in hexane, 1 mL/min, 220 nm). Retention time: tmajor
= 34.6 min and tminor = 26.1 min. 1H NMR (600 MHz, CDCl3): δ 6.07
(s, 1H), 4.45 (s, 1H), 2.07−1.18 (m, 15H), 0.89 (t, J = 7.2 Hz, 3H).
These data are consistent with those reported in ref 10.
(R)-1-Phenylhept-2-yn-1-ol (Entry 8). Colorless oil, 78 mg, 83%
yield; 90% ee determined by HPLC analysis (AD-H column, 10% IPA
in hexane, 1 mL/min, 220 nm). Retention time: tmajor = 7.8 min and
tminor = 6.9 min. 1H NMR (600 MHz, CDCl3): δ 7.40−7.39 (m, 2H),
7.24−7.11 (m, 3H), 5.30 (d, J = 4.8 Hz,1H), 2.13 (t, J = 7.2 Hz, 2H),
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Partial support of this work from the donors of the Petroleum
Research Fund administered by the American Chemical Society
is gratefully acknowledged. W.-C.H. gratefully acknowledges a
fellowship from China Scholarship Council (CSC) and Sichuan
University.
D
DOI: 10.1021/acs.joc.5b02185
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
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DOI: 10.1021/acs.joc.5b02185
J. Org. Chem. XXXX, XXX, XXX−XXX