Enantioselective alkynylation of aldehydes with chiral β-imino α-perfluoroalkylpropanol derivatives

Article abstract of DOI:10.1016/j.tetasy.2009.02.047

Chiral β-imino α-perfluoroalkylpropanol derivatives 1 were prepared by condensation of (2S,3S)-2-amino-3-perfluorooctyl-1-phenylpropan-3-ol 2 and aldehydes. Among them, (2S,3S)-1d prepared from 2 and salicylaldehyde catalyzed the asymmetric alkynylation o

Full text of DOI:10.1016/j.tetasy.2009.02.047

Tetrahedron: Asymmetry 20 (2009) 602–604
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective alkynylation of aldehydes with chiral b-imino
a-perfluoroalkylpropanol derivatives
*
Masaaki Omote, Yusuke Eto, Atsushi Tarui, Kazuyuki Sato, Akira Ando
Faculty of Pharmaceutical Sciences, Setsunan University, 45-1, Nagaotoge-cho, Hirakata 573-0101, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral b-imino
a-perfluoroalkylpropanol derivatives 1 were prepared by condensation of (2S,3S)-2-
Received 18 January 2009
Accepted 10 February 2009
Available online 3 April 2009
amino-3-perfluorooctyl-1-phenylpropan-3-ol 2 and aldehydes. Among them, (2S,3S)-1d prepared from
2 and salicylaldehyde catalyzed the asymmetric alkynylation of aldehydes using alkynylzincs to afford
the product in up to 81% ee.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The enantioselective alkynylation of an aldehyde has pro-
gressed significantly in the last decade. In 2000, a breakthrough
was caused by the first report on the alkynylation using an alkynyl-
zinc and N-methylephedrine.1 The paper clarified the high catalytic
performance of N-methylephedrine in that the amino alcohol par-
ticipates in the chelation to zinc allowing both the activation of the
alkynylzinc and the high stereocontrol of the reaction. Today,
many researchers are addressing this study, and many chiral ami-
no alcohols are elaborated as ligands.2–4 On the other hand, we
We have already synthesized (2S,3S)-1a (R = 1-naphthyl) of
which the
-perfluoroalkylated alcohol was a characteristic.6 The
high catalytic performance of (2S,3S)-1a was observed in the enan-
tioselective ethylation of benzaldehyde using diethylzinc to give
93% ee of the product quantitatively. Remarkably, the reaction time
was shortened compared to the related reactions reported before.
a
This is indicative of strong chelation of the
a-perfluoroalkylated
alcohol of 1 to zinc, affording a sterically hindered environment
around the zinc, which is enough to accelerate the ethyl transfer.
On the basis of this observation, we intended to apply 1 to the alk-
ynylation of aldehydes using an alkynylzinc which is less reactive
than diethylzinc. We initiated the study from conversion of 1 to
several derivatives to search a suitable ligand for the alkynylation.
The derivatives were prepared by condensation of 2 with alde-
hydes in the presence of MgSO4. The suspended material was fil-
tered off and the solvent was removed in vacuo to give 1a–h. 1H
NMR analysis and low resolution MS spectra indicated the forma-
tion of 1, and the peaks that originated from the formation of the
oxazolidine derivative were not observed. The purities of crude
1a–h were immediately confirmed by GC to be more than 95%,
however, they were hydrolyzed gradually during operations owing
to their instability toward moisture. These freshly prepared com-
pounds 1a–h were employed directly in the reaction. The results
on the alkynylation are summarized in Table 1. As shown in entry
1, ligand 1a was an effective chiral ligand in the ethylation giving
43% ee of the product in the alkynylation. Other ligands 1b and c
which were prepared from 2-naphthylaldehyde and benzaldehyde
also gave low ee’s of the products. In the case of 1d (entry 4), the ee
of the product was increased to 67%. The improved result for 1d
may be concerned with the phenolic alcohol capable of chelating
to zinc. Other ligands, 1e–h, were not suitable for this alkynylation.
This study clarified that a phenolic alcohol could increase the
originated chiral ligands containing b-imino
alcohols (2S,3S)-1.5 Their high asymmetric inductions were already
confirmed in the ethylation of aldehydes using diethylzinc. The
a-perfluoroalkylated
a
-
perfluoroalkylated alcohol of 1 seemed to chelate to the diethylzinc
strongly. Thereby, the sterically hindered environment around the
zinc could accelerate ethyl transfer. The successful result prompts
us to apply 1 to the enantioselective alkynylation of aldehydes
using alkynylzinc. This paper describes the preliminary results on
the alkynylation catalyzed by (2S,3S)-1 (see Fig. 1).
R
N
C8F17
OH
(2S,3S)-1
Figure 1. Structure of b-amino a-perfluoroalkylalcohol derivative.
* Corresponding author. Tel.: +81 72 866 3140; fax: +81 72 850 7020.
E-mail address: aando@pharm.setsunan.ac.jp (A. Ando).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.02.047

M. Omote et al. / Tetrahedron: Asymmetry 20 (2009) 602–604
603
Table 1
To investigate the effect of the Rf group on the asymmetric induc-
tion in the alkynylation, (2S,3S)-5d containing perfluorobutyl group
was subjected to the reaction under the same condition as entry 7 in
Table 2. The reaction was completedwithin 7 h to give the product in
94% yield. The chemical yield was almost similar as the case of 1d,
however, the ee of the product was dropped to 74%. The result dem-
onstrated that the Rf group played an important role to acquire the
high catalytic performance of the ligand. The same tendency was ob-
served in our previous result on the asymmetric ethyl addition to
aldehyde using diethylzinc.5 Next, we investigated the scope and
limitation of the alkynylation of 1d with different types of aldehyde.
The results are summarized in Table 3. Several aromatic or aliphatic
aldehydes were chosen for the study.
Catalytic performance of several
benzaldehyde with phenylacetylene in toluene
a-imino alcohols (2S,3S)-1 on the reaction of
NH2
MgSO4
MeOH
C8F17
Bn
1a-h
(2S,3S)-
+
RCHO
OH
OH
Ph
(2S,3S)-1 (10 mol%)
PhCHO + Ph
H
Et2Zn ( 2.0 equiv.)
( 2.0 equiv.)
Ph
3a
4a
Entry
R
Ligand
Yield (%)
eea,b (%)
1
2
3
4
5
6
7
8
1-Naphthyl
2-Naphthyl
Phenyl
2-Hydroxyphenyl
2-Pyridyl
1a
1b
1c
1d
1e
1f
97
99
96
99
98
92
96
99
43
23
45
67
Racemic
44
Racemic
30
Table 3
Result of the alkynylation with different aldehydes using 10 mol % of (2S,3S)-1d in
hexane
Entry
R of 3
Product
Yield (%)
eea (%)
2-Hydroxy-1-naphthyl
1-Hydroxy-2-naphthyl
61b
68
73
57
55
4
1g
1h
1
2
3
4
5
6
7
2-Cl–C6H4–
4-CF3–C6H4–
4-CH3–C6H4–
3-CH3–C6H4–
1-Naphthyl
4b
4c
4d
4e
4f
72
41
40
81
69
74
79
3,5-Di-tert-butyl-2-hydroxyphenyl
a
Determined by chiral HPLC analysis.
All configurations were (R), and determined by comparing the sign of specific
b
rotation with the reported ones.7
n-C7H15
–
4g
4h
Cyclohexyl
3
a
Determined by chiral HPLC analysis.
All configurations were R, and determined by comparing the sign of rotation
asymmetric induction of 1 but the steric environment around the
phenolic alcohol was severe for the asymmetric induction.
b
with the reported ones.
Next, we searched for better reaction conditions based on a sol-
vent and selection of different temperatures. The results are sum-
marized in Table 2. The result indicated that the reaction was
affected considerably by the solvent polarity. Use of non-polar sol-
vent improved the asymmetric induction of 1d (entries 1–4). The
ee of the product was increased to 79% by the conditions in which
the solvent was hexane and the reaction temperature was 0 °C at
the beginning and then gradually warmed to rt (entry 5). Keeping
the temperature at À10 °C caused a decrease of the ee to 56% due
to elongation of the reaction (entry 6). The best result was marked
when the reaction was conducted in hexane at a temperature of
À10 °C to rt to give 81% ee of the product (entry 7) (see Scheme 1).
As shown in entries 1–5, these aromatic aldehydes gave moder-
ate ee’s of the products regardless of the electron-withdrawing or -
donating substituent. However, significant differences in the reac-
tivity were observed on the para-substituted aldehydes (entries 2
and 3). In those aldehydes, ee’s of the product were almost similar
as other aromatic aldehydes, but their chemical yields dropped to
around 40%. Entries 6 and 7 indicated inefficiency of this alkynyla-
tion on aliphatic aldehydes. The difference in the reactivity will be
a useful hint for discussing the transition state.
3. Conclusions
In conclusion, we prepared imino alcohols, (2S,3S)-1a–h, and
evaluated their catalytic asymmetric induction in the alkynylation
of aldehyde using alkynylzinc. Among these, 1d prepared from 2
and salicylaldehyde catalyzed the alkynylation of benzaldehyde to
give the product in 81% ee quantitatively. Notably, the reaction was
completed within 7 h. The shortened reaction time accounts for
strongly activated alkynylzinc chelated by 1d. The mechanistic study
involving transition state of the zinc complex is now in progress.
Table 2
Result of the alkynylation under different conditions using 10 mol % of (2S,3S)-1d
Entry
Temperature (°C)
Solvent
Yield (%)
eea,b (%)
1
2
3
4
5
6
7
rt
rt
rt
rt
Toluene
Hexane
CH2Cl2
THF
Hexane
Hexane
Hexane
99
92
99
85
99
60
93
65
74
52
28
79
56
81
0 to rt
À10
4. Experimental
4.1. General
À10 to rt
a
Determined by chiral HPLC analysis.
All configurations were (R), and determined by comparing the sign of specific
b
rotation with the reported ones.7
All reactions were conducted under an argon atmosphere unless
noted otherwise. Chemicals were treated as follows: THF, ether,
and toluene were distilled from Na/benzophenone; other chemi-
cals were used as received. 1H and 13C NMR spectra were recorded
on GSX-400 (400 MHz, JEOL) or ECA-600 (600 MHz, JEOL) spec-
trometers and 19F NMR spectra were recorded on FT-NMR R-
1500 (60 MHz, Hitachi) or ECP-600 (600 MHz, JEOL) spectrometers
at ambient probe temperature and referenced as follows: 1H and
13C, TMS; 19F, BTF. IR spectra were measured on a Hitachi 270-30
IR spectrophotometer. Mass spectra were recorded on JMS-DX-
300 or JMS-700 T (JEOL) spectrometer. Ee was determined by
OH
N
OH
Bn
C4F9
(2S,3S)-5d
(10 mol%)
3a
+
4a 94% yield
Ph
H
TM
GLC with GAMMA DEX 225 Capillary Column (30 m  0.25 mm Â
Et2Zn
74% ee
0.25
l
m) or by HPLC with Chiralcel OD-H (0.46/ Â 25 cm, Daicel).
Scheme 1. Effect of the Rf group on the alkynylation.
Optical rotations were measured by DIP-140 (JASCO).

604
M. Omote et al. / Tetrahedron: Asymmetry 20 (2009) 602–604
4.1.1. General procedure for the alkynylation
4.1.6. (R)-3-Phenyl-1-p-tolylprop-2-yn-1-ol (4d)
To a suspension of MgSO4 (100 mg) in methanol (1.0 mL) were
added 2 (0.05 mmol) and salicylaldehyde (0.05 mmol) under an
atmosphere of Ar. After stirring for 30 min at room temperature,
the solid was filtered off and the filtrate was evaporated. The crude
1d was subjected directly to the next reaction. All amounts of
diethylzinc, phenylacetylene, aldehyde, and solvent were adjusted
based on that of 1d obtained. To the solution of 1d (0.05 mmol) in
hexane (4.0 mL) were added diethylzinc (1.0 mmol, 1.0 M in hex-
ane solution) and phenylacetylene (1.0 mmol) at room tempera-
ture. After stirring for 30 min at the same temperature, the
mixture was cooled to À10 °C and the solution of benzaldehyde
(0.5 mmol) in hexane (0.1 mL) was added slowly over an hour.
After the addition, the cooling apparatus was removed and the
mixture was stirred for 6 h at room temperature. The reaction
was quenched by addition of 10% of aqueous HCl and the organic
layer was collected. The aqueous layer was extracted with ether
and the combined organic layers were dried (MgSO4). After filtra-
tion of the solid, the solvent was removed in vacuo and the crude
product was purified by silica gel column chromatography
(ether:hexane = 1:9) to give 4a.
Seventy-three percentage of ee was determined by HPLC analy-
sis (10% IPA in hexanes, flow rate = 0.5 mL/min, 254 nm). Retention
time: tmajor = 20.0 min and tminor = 34.8 min.
4.1.7. (R)-3-Phenyl-1-m-tolylprop-2-yn-1-ol (4e)
Fifty-seven percentage of ee was determined by HPLC analysis
(10% IPA in hexanes, flow rate = 0.5 mL/min, 254 nm). Retention
time: tmajor = 22.5 min and tminor = 43.2 min.
4.1.8. (R)-1-(Naphthalen-1-yl)-3-phenylprop-2-yn-1-ol (4f)
Fifty-five percentage of ee was determined by HPLC analysis
(10% IPA in hexanes, flow rate = 0.5 mL/min, 254 nm). Retention
time: tmajor = 30.8 min and tminor = 61.4 min.
4.1.9. (R)-1-Phenyldec-1-yn-3-ol (4g)
Four percentage of ee was determined by HPLC analysis (10%
IPA in hexanes, flow rate = 0.5 mL/min, 254 nm). Retention time:
tmajor = 10.2 min and tminor = 22.2 min.
4.1.10. (R)-1-Cyclohexyl-3-phenylprop-2-yn-1-ol (4h)
Three percentage of ee was determined by HPLC analysis (10%
IPA in hexanes, flow rate = 0.5 mL/min, 254 nm). Retention time:
tmajor = 11.8 min and tminor = 21.0 min.
4.1.2. 2-(((2S,3S)-4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-Heptadeca-
fluoro-3-hydroxy-1-phenylundecan-2-yl-imino)methyl)phenol
(2S,2S)-1d
Yellow solid; mp 110.2–111.9 °C; 1H NMR (CDCl3) d: 12.3 (1H,
3
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