Enantioselective alkynylation of aromatic aldehydes catalyzed by new chiral amino alcohol-based ligands

Article abstract of DOI:10.1016/S0957-4166(01)00384-6

A series of binaphthyl-derived amino alcohols were synthesized and used as catalytic ligands in the asymmetric alkynylation of aromatic aldehydes in the presence of a dialkylzinc reagent. The alkynylation of a variety of aromatic aldehydes gave the corres

Full text of DOI:10.1016/S0957-4166(01)00384-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2147–2152
Enantioselective alkynylation of aromatic aldehydes catalyzed by
new chiral amino alcohol-based ligands
Gui Lu, Xingshu Li, Zhongyuan Zhou, Wing Lai Chan* and Albert S. C. Chan*
Open Laboratory of Chirotechnology and Department of Applied Biology and Chemical Technology,
The Hong Kong Polytechnic University, Hong Kong
Received 19 July 2001; accepted 28 August 2001
Abstract—A series of binaphthyl-derived amino alcohols were synthesized and used as catalytic ligands in the asymmetric
alkynylation of aromatic aldehydes in the presence of a dialkylzinc reagent. The alkynylation of a variety of aromatic aldehydes
gave the corresponding chiral propargylic alcohols in 61–93% e.e. © 2001 Published by Elsevier Science Ltd.
1. Introduction
metric reduction of a,b-ynones via asymmetric
5 6
hydroboration or catalytic transfer hydrogenation.
Numerous binaphthyl-derived ligands have been
employed as chiral auxiliaries in catalytic reactions. The
easy preparation of binaphtho-azepines from readily
available 2,2%-bis(bromomethyl)-1,1%-binaphthyl precur-
sors and their successful applications in asymmetric
transformations revealed an excellent opportunity for
the study of the asymmetric catalytic properties of
binaphtho-azepino alcohol ligands in the alkynylation
reactions of aromatic aldehydes. In order to study the
relationship between ligand structure and the enantiose-
lectivity and catalytic activity, we prepared ligands 1–4
by reacting the appropriate chiral amino alcohols with
However, good yields and enantioselectivities have been
achieved only in the case of acetylenic alkyl ketones.
The asymmetric addition of alkynes to aromatic alde-
hydes have also been reported, but the systems with
good enantioselectivity required the use of large quanti-
1
,2
7,8
ties of chiral auxiliary. Other problems included the
formation of considerable amounts of side products
and only moderate enantioselectivity for the desired
9
10
products. Recently, Li et al. reported the use of
amino alcohols 5 and 6 and their derivatives to catalyze
the reaction of terminal alkynes with aromatic alde-
hydes to afford alkynols with e.e. of up to 85%.
(
R)- and (S)-bis(bromomethyl) binaphthyl and investi-
gated the catalytic alkynylation of aromatic aldehydes
utilizing these ligands.
OH
Ph
N
OH
Ph
N
Ph
Ph
(
1R,2S)-5
(1S,2R)-6
Chiral propargylic alcohols are useful building blocks
for enantioselective syntheses. Direct approaches to
the synthesis of these compounds involve the asym-
3
,4
Herein, we report the application of a binaphthyl
amino alcohol system in this interesting reaction. The
bulky chiral binaphthyl group is expected to affect the
catalytic center and thus may provide higher enantio-
selectivity in this reaction.
*
0
Corresponding authors. Tel.: +852 2766 5607; fax: +852 2364 9932;
e-mail: bcachan@polyu.edu.hk
957-4166/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0957-4166(01)00384-6

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G. Lu et al. / Tetrahedron: Asymmetry 12 (2001) 2147–2152
2
. Results and discussion
The catalytic properties of ligands 1–4 in asymmetric
alkynylation were explored in the reaction of 2-
chlorobenzaldehyde with phenylacetylene at 0°C in the
presence of dimethylzinc. Ligand 1 was very effective
and provided promising results (Table 1). The configu-
ration of the product was influenced mainly by the
chirality of the amino alcohol moiety of the ligand.
Amino alcohol ligands containing phenyl substituents
on the 1,2-positions were found to be more effective
than those containing methyl substituents.
Commercially available (R)- or (S)-binaphthol were
used in the synthesis of ligands 1–4 according to the
common method established in the synthesis of
1
1
azepine, as depicted in Scheme 1.
The structure of (1R,2S,3R)-1 was determined by sin-
gle-crystal X-ray diffraction analysis (Fig. 1).
OH
OH
a
OTf
OTf
CH3
CH3
b
99%
99%
c
d
CH2Br
CH2Br
(1S,2S,3R)-3
69%
65%
Scheme 1. (a) Tf O, Py, CH Cl ; (b) MeMgBr or MeMgI, NiCl (dppp), Et O; (c) NBS, benzoyl peroxide, CCl ; (d) (1R,2S)-(+)-2-
2
2
2
2
2
4
amino-1,2-diphenylethanol, acetonitrile.
Figure 1. X-Ray structure of (1R,2S,3R)-1.
Table 1. Alkynylation of 2-chlorobenzaldehyde with phenylacetylene in the presence of ligands 1–4
Ligand
(1R,2S,3R)-1
(1R,2R,3S)-2
(1S,2S,3R)-3
(1R,2R,3S)-4
Conv. (%)
e.e. (%)
\95
85 (+)
\95
35 (−)
\95
26 (+)
\95
24 (−)

G. Lu et al. / Tetrahedron: Asymmetry 12 (2001) 2147–2152
2149
While the mechanism of the reaction is still not clear
and we do not pretend to have a definite answer, it may
be helpful to explain the influence of the binaphthyl
moiety by speculating possible transition states of the
alkynyl transfer step. As shown in Fig. 2, for
3, the relevant naphthyl ring tilts up and the steric
effect of this moiety is not as significant as that in
(R)-binaphthyl. Consequently, in addition to the possi-
ble stereo-arrangement of the chlorobenzaldehyde as in
the case of (1R,2S,3R)-1, another possible arrangement
with the aryl ring of the aldehyde in a position near the
binaphthyl group occurs. This lowers the e.e. of the
product to 26%. It must be emphasized that this specu-
lation is only for the explanation of the results and a
much more in-depth study is needed to elucidate the
actual mechanism of the reaction.
(
(
1R,2S,3R)-1, the large steric hindrance of the chiral
R)-binaphthyl moiety (with the relevant naphthyl ring
tilting down) forces the aryl ring of the coordinated
chlorobenzaldehyde to take a position away from the
binaphthyl group, consequently the alkynyl transfer
1
2,13
provides (S)-product in high e.e.
As for (1S,2S,3R)-
C
O
C-Ph
Ar
(S)
H
H
Ar
R
N
R
O
Zn
Zn
Zn
O
N
O
R'
Ph
Ph
Ph
Ph
(1R,2S,3R)-1
C
C-Ph
Ar
H
R)
Ar
H
(
R
O
R
N
O
Zn
Zn
Zn
N
O
O
R'
Ph
Ph
Ph
Ph
(1S,2S,3R)-3
Figure 2. The possible transition state of the alkynylation.
Table 2. Effects of temperature and catalyst concentration on the alkynylation of aldehydes in the presence of (1R,2S,3R)-1
aThe absolute configuration is based on measurement of the optical rotation and comparison with the literature values.10

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G. Lu et al. / Tetrahedron: Asymmetry 12 (2001) 2147–2152
The effects of reaction temperature and the ratio of
optimum conditions derived from the above study, and
the results are summarized in Table 3.
(
1R,2S,3R)-1 to aldehyde were studied and the results
are summarized in Table 2.
All of the substituted benzaldehydes studied gave better
enantioselectivity as compared to benzaldehyde. The
results from entries 3 and 4 demonstrated that this
catalyst is applicable to both aromatic and aliphatic
acetylenes in the alkynylation of aromatic aldehydes.
In most cases complete conversions and good enan-
tioselectivities were obtained. Under the optimized con-
ditions, the methyl addition was essentially suppressed
and no other by-product was observed. The use of 0.2
equiv. of (1R,2S,3R)-1 increased the enantioselectivity
from 85 to 88% (entry 5 versus entry 6). When less than
The reactions of terminal alkynes with aliphatic alde-
hydes were found to give low enantioselectivities (36%
e.e. for the alkynylation of cyclohexanecarbox-
aldehyde).
0.1 equiv. of (1R,2S,3R)-1 was used, both the conver-
sion and enantioselectivity decreased (entries 3 and 4).
Higher enantioselectivity was obtained at ca. −20°C;
however, at this temperature the rate of reaction was
substantially slower than that at 0°C. At −30°C, the
reaction became very slow.
3. Conclusion
An array of aromatic aldehydes were employed for the
enantioselectivity study using (1R,2S,3R)-1 under the
A series of new binaphthyl amino alcohol ligands were
synthesized, and one of these ligands, (1R,2S,3R)-1,
a
Table 3. Asymmetric alkynylation of aromatic aldehydes

G. Lu et al. / Tetrahedron: Asymmetry 12 (2001) 2147–2152
2151
was found to be highly effective in the asymmetric
alkynylation of aldehydes. In the presence of 10 mol%
J=13 Hz, 2H, CH ), 3.64 (d, J=3.5 Hz, 1H, CH-N),
2
4.03 (d, J=12.5 Hz, 2H, CH ), 5.83 (d, J=3.5 Hz, 1H,
2
(
1R,2S,3R)-1, a variety of aromatic aldehydes were
CH-O), 7.00–7.16 (m, 10H, ArH), 7.26–7.31 (m, 2H,
ArH), 7.49–7.54 (m, 4H, ArH), 7.63–7.65 (m, 2H,
ArH), 7.99–8.04 (m, 4H, ArH).
converted to the corresponding chiral propargylic alco-
hols with good enantioselectivities and high conver-
sions. The results compared favorably with other
known amino alcohol ligands in similar reactions. The
design of other new binaphthyl amino alcohol ligands
and their applications in catalytic asymmetric alkynyla-
tion are in progress.
4.2.2. (S)-N-[(1S,2R)-1,2-Diphenyl-2-hydroxyethyl]-3,5-
dihydro-4H-dinaphtho[2,1-c:1%,2%-e]-azepine, (1S,2S,3R)-
1
3. Yield: 68%; H NMR (500 MHz, CDCl ) l: 3.20 (d,
3
J=12.5 Hz, 2H, CH ), 3.63 (d, J=3.5 Hz, 1H, CH-N),
2
4
.03 (d, J=12.5 Hz, 2H, CH ), 5.83 (d, J=3.5 Hz, 1H,
2
CH-O), 6.99–7.14 (m, 10H, ArH), 7.26–7.30 (m, 2H,
ArH), 7.48–7.52 (m, 4H, ArH), 7.62–7.64 (m, 2H,
ArH), 7.98–8.03 (m, 4H, ArH).
4
. Experimental
4
.1. General methods
4
.2.3.
(R)-N-[(1R,2S)-1-Methyl-2-phenyl-2-hydroxy-
All reactions were performed using oven-dried glass-
ware under an atmosphere of dry nitrogen. All solvents
were distilled and dried before use. Reagents were
purchased from either Acros or Aldrich chemical com-
panies and were used without further purification,
except for the aldehydes which were redistilled before
use.
ethyl]-3,5-dihydro-4H-dinaphtho[2,1-c:1%,2%-e]-azepine,
1
(1R,2R,3S)-4. Yield: 64%; H NMR (500 MHz, CDCl )
l: 0.82 (d, J=7 Hz, 3H, CH ), 3.11 (m, 1H, CH-N),
3
3
3.36 (d, J=12 Hz, 2H, CH ), 3.91 (d, J=12 Hz, 2H,
2
CH ), 5.22 (d, J=3.5 Hz, 1H, CH-O), 7.26–7.31 (m,
2
3H, ArH), 7.39–7.53 (m, 8H, ArH), 7.60–7.62 (m, 2H,
ArH), 7.97–8.01 (m, 4H, ArH).
Optical rotations were measured with a Perkin–Elmer
Model 341 polarimeter at 20°C. NMR spectra were
recorded on a Varian-500 spectrometer. Mass spectra
were obtained on a Finnigan Model Mat 95 ST mass
spectrometer. HPLC analyses (Chiralcel OD or OD-H
column from Daicel, IPA-hexane as eluent) were per-
formed using a Hewlett–Packard model HP 1050 LC
interfaced to an HP 1050 Series computer workstation.
4.3. General procedure for the nucleophilic addition of
10
alkynes to aldehydes
To a solution of phenylacetylene (52.7 mL, 0.48 mmol)
in toluene (1 mL), was added a solution of dimethylzinc
(2 M, 0.22 mL, 0.44 mmol) in toluene. The mixture was
stirred at 0°C for 30 min. A solution of (1R,2S,3R)-1
(9.82 mg, 0.02 mmol) in toluene (1 mL) was added.
After stirring the mixture for 30 min, the aldehyde (0.2
mmol) was added in one portion with a syringe. The
mixture was stirred at 0°C for 6–24 h, and the reaction
was then quenched with an aqueous HCl solution (5%,
2 mL). The mixture was extracted with diethyl ether
(3×2 mL). The organic layer was separated and concen-
trated at reduced pressure, and was purified using flash
chromatography and afforded the chiral alcohol. The
e.e. (%) value of the product was determined by HPLC
analysis.
4
.2. A general procedure for the syntheses of amino
alcohol ligands
11
A solution of (R)-2,2%-dibromomethyl-1,1%-binaphthyl
(
0.11 g, 0.25 mmol), containing Et N (0.07 mL, 0.5
3
mmol) in toluene (2 mL) was treated by dropwise
addition of a solution of (1R,2S)-(+)-2-amino-1,2-
diphenylethanol (0.053 g, 0.25 mmol) in CH CN (15
3
mL). The mixture was stirred under reflux for 24 h and
the solvent was removed. The residue obtained was
dissolved in CH Cl (4 mL) and the undissolved solid
2
2
was removed by filtration. The filtrate was evaporated
and the crude product obtained was purified via
column chromatography (silica gel, hexane:ethyl ace-
tate=4:1) to afford a white solid of (1R,2S,3R)-1,
Acknowledgements
We thank The Hong Kong Polytechnic University ASD
and the Hong Kong Research Grants Council (project
cERB03) for financial support of this study. G.L. also
wants to thank Dr. Ming Yan and Mr. Puierh Tong for
various assistance.
(
R)-N-[(1S,2R)-1,2-diphenyl-2-hydroxyethyl]-3,5-dihy-
dro-4H-dinaphtho[2,1-c:1%,2%-e]-azepine (0.80 g, 65%).
1
H NMR (500 MHz, CDCl ) l: 3.31 (d, J=12 Hz, 2H,
3
CH ), 3.47 (d, J=3 Hz, 1H, CH-N), 4.07 (d, J=12.5
2
Hz, 2H, CH ), 5.30 (d, J=3.5 Hz, 1H, CH-O), 6.78–
2
6
.80 (m, 2H, ArH), 7.05–7.07 (m, 4H, ArH), 7.17–7.31
m, 8H, ArH), 7.39–7.41 (m, 2H, ArH), 7.48–7.53 (m,
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