Highly enantioselective phenylacetylene addition to aldehydes catalyzed by a chiral N,O-ferrocene ligand

Article abstract of DOI:10.1016/j.tetasy.2003.12.002

Ferrocenyl oxazoline alcohols are found to be effective in catalyzing the addition reaction of an alkynylzinc reagent to aromatic and aliphatic aldehydes with up to 93% ee of the thus produced chiral propargyl alcohols.

Full text of DOI:10.1016/j.tetasy.2003.12.002

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 219–222
Highly enantioselective phenylacetylene addition to aldehydes
catalyzed by a chiral N,O-ferrocene ligand
Ming Li, Xia-Zhen Zhu, Ke Yuan, Bo-Xun Cao and Xue-Long Hou*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
Received 12 September 2003; revised 5 November 2003; accepted 7 November 2003
Abstract—Ferrocenyl oxazoline alcohols are found to be effective in catalyzing the addition reaction of an alkynylzinc reagent to
aromatic and aliphatic aldehydes with up to 93% ee of the thus produced chiral propargyl alcohols.
ꢀ 2003 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussions
Chiral propargylic alcohols are useful building blocks
for the enantioselective synthesis of complex molecules.1
In recent years, significant progress has been made in the
catalytic enantioselective addition reaction of acetylenes
to aldehydes.2 Many chiral ligands, such as N-methyl-
ephedrine,3 BINOL and its derivatives,4 and other
amino alcohol compounds,5 have successfully been used
in this reaction. Usually, a titanium complex or
Zn(OTf)2 was required in these catalytic systems. Some
procedures have also been developed by Chan and
co-workers6 and Pu and Xu7 independently, using
different ligands to catalyze the addition of phenylacet-
ylene to aromatic aldehydes in the absence of other
metal reagent except dialkylzinc. Recently, we have
reported the synthesis of chiral 1,10-N,O-ferrocenyl
ligands 1 and their application in the addition of
diethylzinc reagents to aldehydes, with up to 90.9% ee of
the corresponding alcohols being observed.8 Further
studies have shown that these ligands are also effective in
the reaction of phenylacetylene with aldehydes in the
presence of diethylzinc. Both aromatic and aliphatic
aldehydes are suitable substrates. Herein, we report our
results for the enantioselective addition of alkynylzinc to
aldehydes without the use of a titanium complex.
Chiral 1,10-N,O-ferrocenyl ligands 1 and 2 were syn-
thesized by known procedures (Scheme 1).8;9a To show
the effect of the hydroxymethyl substituent of the fer-
rocene ligand 1 in the reaction, ligands 3 and 4 with
dimethylhydroxymethyl and hydroxymethyl as substit-
uents were also synthesized using the same procedures as
illustrated in Scheme 2.
All of these ligands were tested in the addition reaction
of phenylacetylene with benzaldehyde using 10 mol % of
ligands and 220 mol % of diethylzinc (Eq. 1). The results
showed that the framework and the substituent on the
oxazoline ring of the ligands had a great impact on the
outcome of the reaction (Table 1). When the substituent
on the oxazoline ring was tert-butyl, 1,10-ferrocenyl
oxazoline alcohol 1b showed higher stereoselectivity
than 1,2-ferrocene 29 (entries 1 and 2). The results
showed that the hindrance of the hydroxymethyl moiety
on the other Cp ring affected the reactionÕs outcome
greatly. With dimethylhydroxymethyl and hydroxy-
methyl groups as substituents, a dramatic drop in
enantioselectivity of the reaction was observed, even
O
O
R2
R1
(S)-1a R1=i-Pr, R2=H
(S)-1b R1=t-Bu, R2=H
(S)-1c R1=Bn, R2=H
(R)-1d R1=H, R2=Ph
But
N
N
Ph
Fe
Ph
Fe
OH
OH
Ph
Ph
Keywords: Ferrocene ligand; Alkynylation; Aldehyde; Organozinc
reagent; Asymmetric addition.
2
* Corresponding author. Tel.: +86-2164163300x3502; fax: +86-21641-
67519; e-mail: xlhou@mail.sioc.ac.cn
Scheme 1.
0957-4166/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.12.002

220
M. Li et al. / Tetrahedron: Asymmetry 15 (2004) 219–222
selectivity and yield, other 1,10-ferrocene ligands as well
O
O
1. n-BuLi/THF, -78 ºC
as the effects of solvent and temperature on the reaction
were examined. Among the ligands and solvents tested,
ligand 1d, with Ph as the substituent on the oxazoline
ring in CH2Cl2, gave the best result (Table 1, entry 8 vs
entries 2–7). The temperature effect was also significant,
with a lower enantioselectivity being given at either
lower or higher than 0 ꢁC. However, the yield was higher
if the reaction proceeded at higher temperatures (entries
11 and 12).
Ph
Ph
Ph
N
N
Fe
Me
Fe
2. Me2CO
OH
Me
Br
3
O
O
1. n-BuLi/THF, -78 ºC
Ph
N
N
Fe
2. DMF
3. NaBH4, THF-MeOH
Fe
OH
Br
OH
H
4
H
ð1Þ
1. Et2Zn
2. PhCHO, ligand
Ph
Ph
Ph
Scheme 2.
Under the optimized condition, other aldehydes were
tested with the results shown in Table 2. It can be seen
that not only aromatic but also aliphatic aldehydes are
suitable substrates. In all cases, ligand 1d proved to be
when 20 mol % of the ligand was used (entries 9 and 10).
In pursuit of a good catalytic system with high enantio-
Table 1. The effect of reaction conditions on the enantioselectivity of the alkynylation of benzaldehydea
Entry
Ligand
Solvent
Yield (%)b
Ee (%)c
Configurationd
1
(S,Rp)-2
(S)-1b
(S)-1a
(S)-1c
(R)-1d
(R)-1d
(R)-1d
(R)-1d
(S)-3
Toluene
Toluene
Toluene
Toluene
Toluene
THF
74
82
78
87
84
68
88
90
93
95
85
99
23
63
70
60
85
90
86
87
32
40
63
49
(+)-(R)
(+)-(R)
(+)-(R)
(+)-(R)
())-(S)
())-(S)
())-(S)
())-(S)
(+)-(R)
(+)-(R)
())-(S)
())-(S)
2
3
4
5
6
7
Hexane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
8
9e
10e
11f
12g
(S)-4
(R)-1d
(R)-1d
a All reactions were carried out at 0 ꢁC with the ratio of ligand/phenylacetylene/Et2Zn/benzaldehyde ¼ 0.1:2.4:2.2:1.
b Isolated yield based on aldehyde.
c Determined by HPLC.
d Configurations were assigned by comparison with the sign of the specific rotation of known compounds.
e 20 mol % of ligand was used.
f The reaction was carried out at )20 ꢁC.
g The reaction was carried out at rt.
Table 2. Enantioselective alkynylation of aldehydes with ligand 1da
Entry
Aldehyde
Yield (%)b
Ee (%)c
Configurationd
1
p-BrC6H4CHO
o-ClC6H4CHO
o-ClC6H4CHO
m-O2NC6H4CHO
p-MeOC6H4CHO
1-Naphthaldehyde
1-Naphthaldehyde
a-Furan-CHO
c-C6H11CHO
86
72
82
87
82
84
86
85
74
72
88
88
88
82
86
67
89
82
90
88
93
82
81
65
83
75
54
59
())
())
())
())
())
())
())
())
())-(R)
())
())
())
())
())
2
3e
4
5
6
7e
8e
9e
10e
11e
12e
13
14e
PhCH2CHO
Me2CHCHO
Me3CCHO
PhCH@CHCHO
MeCH@CHCHO
a Run in 2 mL of CH2Cl2 at 0 ꢁC with ratio of ligand 1d/phenylacetylene/Et2Zn/aldehyde ¼ 0.1:2.4:2.2:1.
b Isolated yield based on aldehyde.
c Determined by HPLC.
d Configurations were assigned by comparison with the sign of specific rotation of known compounds.
e 20 mol % ligand was used.

M. Li et al. / Tetrahedron: Asymmetry 15 (2004) 219–222
221
effective and the propargylic alcohols were produced
with good chemical yields and enantioselectivity. Usu-
ally good enantioselectivity was provided for most of the
aromatic aldehydes when 10 mol % of the ligand was
used while a significant increase of ee value was
observed when 20 mol % of the ligand was used (Table 2,
see entry 2 vs entry 3 and entry 6 vs entry 7). When
20 mol % of the ligand was used as a catalyst, aliphatic
aldehydes reacted with the alkynylzinc reagent
smoothly, with good enantioselectivity (entries 9–
12) and 93% ee being obtained in the alkynylation of
1-naphthaldehyde, catalyzed by 20 mol % of 1d (entry 7).
ether (20 mL · 3) The organic layer was washed with
brine (20 mL · 2) and dried over Na2SO4. After removal
of the solvent under reduced pressure, the residue was
purified by column chromatography (silica gel, ethyl
acetate/petroleum 1:5) to afford 3 (177 mg, 57%). Mp,
20
D
66–68 ꢁC; ½aꢁ ¼ )117 (c 0.62, CHCl3); 1H NMR: d 1.46
(s, 3H), 1.53 (s, 3H), 4.12–4.22 (m, 4H), 4.27–4.29 (m,
1H), 4.42–4.45 (m, 2H), 4.72 (dd, J ¼ 8:7, 9.9 Hz, 1H),
4.81–4.83 (m, 1H), 4.92–4.93 (m, 2H), 5.26 (dd, J ¼ 8:4,
9.9 Hz, 1H), 7.26–7.38 (m, 5H); 13C NMR: d 167.3,
142.0, 128.6, 127.5, 126.6, 101.7, 74.6, 70.6, 70.5, 69.9,
69.8, 69.2, 68.9, 68.7, 68.6, 67.5, 67.0, 31.4, 31.1; MS:
m=z 389 (Mþ, 1), 390 (71), 388 (6), 372 (100), 283 (20),
193 (99), 163 (34); IR (KBr): 3369, 2970, 2926, 1643,
1605, 1480, 1378, 1120, 1026, 491 cmꢀ1; Anal. Calcd for
C22H23FeNO2: C, 67.88; H, 5.96; N, 3.60. Found: C,
67.63; H, 5.93; N, 3.36.
3. Conclusion
In conclusion, we have demonstrated that 1,10-ferrocene
oxazoline alcohol 1d is an effective catalyst for the
reaction of phenylacetylene with various aromatic and
aliphatic aldehydes under mild conditions. Good ees
and yields of products were obtained and the use of
other kinds of metal species is not required in the
reaction.
4.3. 1-[(S)-4-Phenyl-2,5-oxazolinyl]-10-(a-hydroxy-
methyl)-ferrocene 4
A solution of 1-[(S)-4-Phenyl-2,5-oxazolinyl]-10-bromo-
ferrocene10 (328 mg, 0.8 mmol) in THF (10 mL) was
cooled to )78 ꢁC and treated with n-butyllithium (1.6 M
in hexane, 0.5 mL, 0.8 mmol). The reaction mixture was
stirred for an additional 30 min after which DMF
(285 mg, 3.9 mmol) was added and the resulting mixture
stirred at 0 ꢁC for 20 min. H2O (10 mL) was added to the
reaction solution and the mixture then extracted with
ethyl ether (20 mL · 3). The organic layer was washed
with brine (20 mL · 2) and dried over Na2SO4. After
removal of the solvent under reduced pressure, the res-
idue was purified by column chromatography (silica gel,
ethyl acetate/petroleum 1:2) to afford formyl ferrocene.
The formyl ferrocene was dissolved in THF (6 mL) and
added to a solution of NaBH4 (66 mg, 1.7 mmol) in THF
(4 mL) and MeOH (2 mL). The reaction mixture was
stirred at rt for 5 h. Water (10 mL) was then added and
the resulting mixture extracted with ethyl ether
(20 mL · 3). The organic layer was washed with brine
(20 mL · 2) and dried over Na2SO4. After removal of the
solvent under reduced pressure, the residue was purified
by column chromatography (silica gel, ethyl acetate/
petroleum 1:3) to afford 4 (191 mg, 66%). Mp, 127–
4. Experimental
4.1. General
All reactions were performed under a dry argon atmo-
sphere. Toluene, hexane, and THF were freshly distilled
from sodium. Dichloromethane was freshly distilled
from calcium hydride. Reagents were used as received
without further purification, except for the aldehydes,
which were redistilled before use. Ligands 1a–d were
synthesized according to the literature.8 Ligand 2 was
synthesized according to the literature.9a Melting points
are uncorrected. NMR spectra were recorded on a
Varian AMX-300 spectrometer in CDCl3 at room tem-
perature. Chemical shifts are given in parts per million
downfield from tetramethylsilane. Optical rotations
were measured on a Perkin–Elmer 341MC polarimeter
with a thermally jacketed 10 cm cell at 20 ꢁC (concen-
tration c given as g/100 mL). IR spectra were recorded in
KBr and measured in cmꢀ1, using a Shimadzu IR-440
infrared spectrophotometer. Mass spectra were taken
using HP 5989A mass spectrometers. Elemental analyses
were performed on a Foss-Heraeus Vario EL instru-
ment. Enantiomeric excesses were determined by chiral
HPLC on a Chiralcel OD column.
20
1
128 ꢁC; ½aꢁ ¼ )160 (c 0.32, CHCl3); H NMR: d 3.45
D
(br, 1H), 4.19–4.27 (m, 4H), 4.30–4.31 (m, 1H), 4.35–
4.36 (m, 2H), 4.40–4.44 (m, 2H), 4.73–4.79 (m, 2H),
4.87–4.89 (m, 1H), 5.28 (dd, J ¼ 8:2, 9.9 Hz, 1H), 7.26–
7.40 (m, 5H); 13C NMR: d 168.1, 141.9, 128.7, 127.6,
126.7, 91.1, 74.7, 70.9, 70.7, 69.7, 69.6, 69.4, 69.1, 68.9,
68.6, 68.2, 60.0; MS: m=z 361 (Mþ, 4), 362 (100), 346 (5),
193 (91), 180 (25), 163 (43); IR (KBr): 3204, 2908, 1638,
1484, 1381, 1237, 1010, 493 cmꢀ1; Anal. Calcd for
C20H19FeNO2: C, 66.50; H, 5.30; N, 3.88. Found: C,
66.50; H, 5.15; N, 3.64.
4.2. 1-[(S)-4-Phenyl-2,5-oxazolinyl]-10-(a-dimethyl-
hydroxymethyl)-ferrocene 3
A solution of 1-[(S)-4-Phenyl-2,5-oxazolinyl]-10-bromo-
ferrocene10 (328 mg, 0.8 mmol) in THF (10 mL) was
cooled to )78 ꢁC and treated with n-butyllithium (1.6 M
in hexane, 0.5 mL, 0.8 mmol). The reaction mixture was
stirred for an additional 30 min, acetone (70 mg,
1.2 mmol) then added and the resulting mixture stirred
at 0 ꢁC for 20 min. Water (10 mL) was added to the
reaction solution and the mixture extracted with ethyl
4.4. General procedure for the catalytic asymmetric
addition of alkynylzinc to aldehydes
To a solution of phenylacetylene (123 mg, 1.2 mmol) in
CH2Cl2 (2 mL) was added Et2Zn (1.1 M in hexane,

222
M. Li et al. / Tetrahedron: Asymmetry 15 (2004) 219–222
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1.1 mL, 1.2 mmol) at room temperature. The resulting
mixture was stirred for 2 h after which ferrocene 1d
(26 mg, 0.05 mmol) was added and the reaction mixture
stirred for an additional 30 min. The reaction system
was cooled to 0 ꢁC at which point the aldehyde
(0.5 mmol) was added under an argon atmosphere. After
complete consumption of the substrate (monitored by
TLC), the reaction was quenched with saturated aque-
ous NH4Cl. The mixture was then extracted with diethyl
ether (10 mL · 3). The organic layer was washed with
brine (10 mL · 2), dried over Na2SO4, and evaporated
under reduced pressure to give an oily residue. Purifi-
cation of the residue by column chromatography gave
the corresponding optically active alcohol. The enan-
tiomeric excess was determined by HPLC analysis using
a Chiralcel column. The configuration was assigned by
comparison with the sign of the specific rotation of the
known compounds.
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Acknowledgements
This research was financially supported by the National
Natural Science Foundation of China, the Major Basic
Research
Development
Program
(Grant
No.
G2000077506), the National Outstanding Youth Fund,
the Chinese Academy of Sciences and the Shanghai
Committee of Science and Technology. We also thank
Prof. Li-Xin Dai for discussions.
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