3-Aminoquinazolinones as chiral ligands in catalytic enantioselective diethylzinc and phenylacetylene addition to aldehydes

Article abstract of DOI:10.1016/j.tetasy.2014.04.019

A series of readily known enantiomerically pure 3-aminoquinazolinones 1a-d were synthesised from easily accessible chiral pool α-hydroxy acids and α-amino acids in only four steps without any requirement of chromatography. These quinazolinones were examined as chiral ligands for catalytic enantioselective diethylzinc and phenylacetylene additions to aldehydes. For enantioselective alkylations, the effects of temperature, solvent, diethylzinc and ligand criteria were analysed, and the desired chiral alcohols were obtained in up to 86% ee. 3-Aminoquinazolinones 1a-d were also shown to be very useful ligands in enantioselective alkynylations of aldehydes. Based upon the optimised conditions, the corresponding propargylic alcohols were obtained in up to 94% ee.

Full text of DOI:10.1016/j.tetasy.2014.04.019

Tetrahedron: Asymmetry 25 (2014) 851–855
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Tetrahedron: Asymmetry
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3-Aminoquinazolinones as chiral ligands in catalytic enantioselective
diethylzinc and phenylacetylene addition to aldehydes
b
b
Semistan Karabuga a, , Idris Karakaya , Sabri Ulukanli
⇑
a Department of Chemistry, Faculty of Science and Letters, Kahramanmaras Sutcu Imam University, 46000 Kahramanmaras, Turkey
b Department of Chemistry, Faculty of Science and Letters, Osmaniye Korkut Ata University, 80000 Osmaniye, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of readily known enantiomerically pure 3-aminoquinazolinones 1a–d were synthesised from
Received 3 April 2014
Accepted 29 April 2014
Available online 2 June 2014
easily accessible chiral pool a-hydroxy acids and a-amino acids in only four steps without any require-
ment of chromatography. These quinazolinones were examined as chiral ligands for catalytic enantiose-
lective diethylzinc and phenylacetylene additions to aldehydes. For enantioselective alkylations, the
effects of temperature, solvent, diethylzinc and ligand criteria were analysed, and the desired chiral alco-
hols were obtained in up to 86% ee. 3-Aminoquinazolinones 1a–d were also shown to be very useful
ligands in enantioselective alkynylations of aldehydes. Based upon the optimised conditions, the corre-
sponding propargylic alcohols were obtained in up to 94% ee.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
3-aminoquinazolinones 1 not as aziridinating agents but also as
chiral ligands in the enantioselective phenylacetylene and diethyl-
Catalytic asymmetric synthesis has become one of the most
attractive areas of research and gives enantioenriched or enantio-
pure compounds in large quantities by using a small amount of
catalyst.1 Among the asymmetric reactions, organozinc additions
to aldehydes have attracted considerable attention to meet the
demands of organic synthons both in academia and in industry.2
In chiral ligand families, the nitrogen containing ones such as amino
alcohols,3–7 arylimines,8,9 pyridyl alcohols,10,11 oxazolines,12,13
quinolins,14–16 quinazolines and quinazolinones17,18 and their
derivatives19–23 have been widely used in this manner in recent
years.
zinc additions to aldehydes (Fig. 1).
N
N
R
R
N
N
O
O
N
O
OH
S
OH
NH2
Ph
Ph
1
2
i
t
1a;
1b;
1c;
1d;
R = Ph
R = Me,
R = Pr,
R = Bu,
In our previous work, chiral sulfoximine derivatives 2a–d from
3-aminoquinazolinones 1a–d were synthesised while the catalytic
activities of sulfoximines have been tested in enantioselective
alkylations of aldehydes.24 The related alcohols were obtained with
up to 92% ee. The lead tetraacetate oxidations of 3-aminoquinazoli-
nones 1a–d are also well known as aziridinating agents for alkenes
with different electron demands, for example, styrene and methyl
acrylate.25–27 High reagent and substrate-controlled diastereose-
lective aziridination is possible where a stereogenic centre is pres-
ent.28 3-Aminoquinazolinones 1a–d with a stereogenic centre at its
2-position has an environment similar to 1,3-aminoalcohols.
Therefore, we herein anticipated the possibility of using the known
Figure 1.
2. Results and discussions
3-Aminoquinazolinones 1a–d were readily prepared in four
steps using known procedures29–32 starting from enantiomerically
pure L-lactic acid 3a, L-valine 3b, L-t-leucine 3c and L-mandelic acid
3d (Scheme 1).24 Herein we tested these chiral molecules 1a–d as
ligands in catalytic asymmetric diethylzinc and phenylacetylene
additions to aldehydes.
At first, we examined Et2Zn (3 equiv, 1 M in hexane) addition to
benzaldehyde for the catalytic process using 10 mol % 3-aminoqui-
nazolinones 1a–d at 0 °C and toluene as the solvent. Since
3-aminoquinazolinone 1c had a better differentiated group on
⇑
Corresponding author. Tel.: +90 3442801456.
E-mail address: semistan@ksu.edu.tr (S. Karabuga).
http://dx.doi.org/10.1016/j.tetasy.2014.04.019
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

852
S. Karabuga et al. / Tetrahedron: Asymmetry 25 (2014) 851–855
O
O
O
N
R
c
b
a
R
R
HN
R
OH
OH
N
O
OAc
X
OAc
O
O
OH
1a-d
NH2
3
5a-d
4a-d
3a; R = Me, X= OH
3b; R = iPr, X= NH2
t
3c;
R = Bu, X= NH2
3d; R = Ph, X= OH
Scheme 1. Synthesis of the quinazolinone alcohols 1a–d. Reagents and conditions: (a) for 3a and 3d: AcCl (4.0 equiv), RT; for 3b and 3c: NaNO2 (4.0 equiv), AcOH, RT; (b)
SOCl2 (3.0 equiv), DMF (cat.), RT; (c) methyl 2-aminobenzoate (2.2 equiv), Et2O, RT; (d) hydrazine (5.0 equiv), EtOH, 150 °C.
the stereogenic centre among the quinazolinones, it afforded a
favourable enrichment of the products both in terms of enantio-
meric excess and yield (Table 1, entry 4). While 3-aminoquinazoli-
nones 1a and 1b yielded 1-phenyl-1-propanol in moderate
selectivity (Table 1, entries 1 and 2), 3-aminoquinazolinone 1d
did not allow the formation of any product ee (Table 1, entry 3).
We then continued to optimise the reaction conditions for solvent,
temperature, Et2Zn equivalent and amount of ligand. In order to
choose an appropriate solvent for the reaction condition, a series
of solvents commonly used in alkylation reactions such as toluene,
hexane, Et2O, THF, CH2Cl2 and TBME were screened. It was
observed that the solvent influenced the enantioselectivity and
product formation significantly. Among the solvents used in the
reaction, toluene remained the best in terms of product enantiose-
lectivity (71% ee). The ee and yield were obtained with very low
values when the reaction was conducted in the presence of hexane
(7% ee, 43% yield), THF (11% ee, 15% yield) or CH2Cl2 (32% ee, 54%
yield). On the other hand, when Et2O or TBME was used as the sol-
vent, the enantioselectivity of the products was moderate with 55%
ee and 60% ee. A decrease in temperature from 0 to À20 °C (Table 1,
entry 6) led to an increase in enantioselectivity from 71% ee to 83%
ee. However, lowering the reaction temperature to À40 °C, lowered
the product both in terms of enantioselectivity and yield (Table 1,
entry 7). Additionally, the amount of Et2Zn from 3 to 2 equiv
(Table 1, entry 9) led to a slight increase in enantioselectivity
(85% ee). The amount of ligand was reduced sequentially from
10% to 5% and then 2%, leading to a decrease in enantiomeric
excess (Table 1, entries 10 and 11). Eventually, the best results
(85% ee and 95% yield) were found when using 2 equiv of Et2Zn,
at À20 °C and 10 mol % ligand.
The optimised conditions (2 equiv Et2Zn, at À20 °C and
10 mol % ligand) were then applied to a variety of aryl substituted
aldehydes. As can be seen in Table 2, the chiral secondary alcohols
6a–h were achieved with good to excellent isolated yields (80–
99%) except for pyridine-2-carboxaldehyde (58%). Benzaldehyde,
p-tolualdehyde and m-methoxybenzaldehyde were converted into
their respective chiral alcohols with good enantioselectivities
(Table 2, entries 1, 4 and 5). Moderate product ees were obtained
from o-methoxybenzaldehyde and cinnamaldehyde (Table 2,
entries 3 and 7); we were unable to determine any reason as to
why o-chlorobenzaldehyde gave the lowest product ee of 3%. How-
ever, it was unsurprising that the pyridine-2-carboxaldehyde
derived alcohol gave poor enantioselectivity (19% ee), which was
probably due to zinc complexing through the pyridine nitrogen
and the hydroxyl oxygen formed during reaction and self-
catalysed.
Table 1
3-Aminoquinazolinones 1a–d catalysed diethylzinc addition to benzaldehyde
Entry
Ligand (%)
Temp. (°C)
eea (%)
Yieldb (%)
1
2
3
4
5
6
7
9
10
11
1a (10)
1b (10)
1d (10)
1c (10)
1c (10)
1c (10)
1c (10)
1c (10)c
1c (5)
0
0
0
0
RT
À20
À40
À20
À20
À20
50
43
0
71
49
83
72
85
79
60
85
78
67
96
98
93
65
95
95
63
1c (2)
a
b
c
Determined by chiral GC analysis (b-Dex column).
Isolated yields.
2 equiv Et2Zn used.
Table 2
Results of the enantioselective addition of Et2Zn to aldehydes promoted by 1c
OH
∗
O
1c
2 equiv. Et2Zn, 10% mol
tolune, -20 oC, 24 h
R
R
H
6a-h
Entry
Aldehyde
Product
eea (%)
Yieldc (%)
Configurationd
1
2
3
4
5
6
7
8
Benzaldehyde
6a
6b
6c
6d
6e
6f
85
3
95
93
80
99
84
85
99
58
(S)
(S)
(S)
(S)
(S)
(S)
—
o-Chlorobenzaldehyde
o-Methoxybenzaldehyde
m-Methoxybenzaldehyde
p-Tolualdehyde
1-Naphthylaldehyde
Cinnamaldehyde
71
80
86
34
67b
19
6g
6h
Pyridine-2-carboxaldehyde
—
a
b
c
Determined by chiral GC analysis (b-Dex column).
Determined by chiral HPLC (Chiralcel OD-H).
Isolated yields.
d
The absolute configurations of the products were assigned according to the literature.24

S. Karabuga et al. / Tetrahedron: Asymmetry 25 (2014) 851–855
853
slightly increased (Table 3, entry 3). There was an insignificant
decrease in the ee when using a ligand loading of 5% or 20%,
although the yield of product decreased to 65% when 5% ligand
was used (Table 3, entries 4 and 5). Further examination was car-
ried out to obtain a better enantioselectivity for the optimisation of
the reaction conditions such as solvent and temperature. The sol-
vents of TBME and toluene gave moderate enantiomeric excesses
just under 70%; acetonitrile, 1,4-dioxane, diethyl ether and hexane
gave between 80% ee and 89% ee. We carried on using THF, since it
was a solvent that showed high efficiency in terms of yield and
enantioselectivity. To further enhance the enantioselectivity, the
reaction was carried out at 25 °C and the enantiomeric excess
obtained was almost the same as 0 °C. The reaction temperature
was also reduced from 0 to À20 °C, and gave an ee value of 94%
(Table 3, entry 6). However, decreasing the temperature to
À30 °C did not lead to any increase in either in the product ee or
yield.
Table 3
3-Aminoquinazolinones 1a–d catalysed phenylacetylene addition to benzaldehyde
Entry
Ligand (%)
ee* (%)
Yield** (%)
1
2
3
4
5
6
7
8
9
1a (10)a
1a (10)b
1a (10)c
1a (20)c
1a (5)c
nd
77
90
89
89
94
21
30
11
75
75
87
84
65
87
79
20
40
1a (10)d
1b (10)b
1c (10)b
1d (10)b
*
Determined by chiral HPLC (Chiralcel OD-H).
Isolated yields.
**
a
Without Ti(OiPr)4.
b
With 25% Ti(OiPr)4.
c
With 40% Ti(OiPr)4.
d
In THF at À20 °C.
Catalytic asymmetric addition of phenyl acetylene to a series of
aldehydes was achieved under the optimised reaction conditions
(THF as a solvent, 10% 1a, 40% Ti(OiPr)4 at À20 °C for 24 h) (Table 3,
entry 6) and the results are summarised in Table 4. All of the alde-
hydes were converted into the corresponding propargylic alcohols
from reasonable to high yields. The results showed that the best
enantioselectivity (94% ee) was obtained for the benzaldehyde
derived secondary alcohol (entry 1). Additionally, strong electron
donating o-, m- and p-methoxy substituted benzaldehydes gave
almost as good as benzaldehyde derived propargylic alcohols with
88% ee, 92% ee and to 92% ee being obtained respectively (entries
5–7). Although, m- and p-substituted chlorobenzaldehydes
resulted in good asymmetric induction (entries 3 and 4), a dra-
matic decrease was observed in selectivity with the o-substituted
chlorobenzaldehyde (entry 2). o-Chlorobenzaldehyde also pro-
vided the lowest ee as in Et2Zn addition (Table 2, entry 2). In par-
In order to determine the catalytic effect of 3-aminoquinazoli-
nones 1a–d, we examined the enantioselective alkynylation of
aldehydes. The reaction was performed by using phenylacetylene,
Et2Zn and 10% 1a at 0 °C. Although a moderate yield was obtained,
we did not obtain any enantioselectivity in the absence of Ti(OiPr)4
as in alkylation (Table 3, entry 1). However, when the Ti(OiPr)4 was
present as a co catalyst, the resulting enantioselectivity of propar-
gylic alcohol 7a increased up to 77% ee instantaneously (Table 3,
entry 2). The other 3-aminoquinazolinones were also tested, but
1a remained the best of choice. While a more bulkier group in
the stereogenic center of ligand 1c provided the best selectivity
in Et2Zn addition, the best enantioselectivity in phenylacetylene
addition was observed with the less bulkier group containing
ligand 1a (Table 3, entry 2). When the amount of Ti(OiPr)4 was
increased from 25% to 40%, both the enantioselectivity and yield
Table 4
Results of the enantioselective addition of phenylacetylene to different aldehydes promoted by 1a
1a
10 mol%
OH
∗
O
40 mol% Ti(OiPr)4
Ph
+
R
2 equiv. Et2Zn
R
H
THF, -20 oC, 24h
Ph
2.0 equiv.
7a-j
Entry
Aldehyde
Product
eea (%)
Yieldb (%)
Configurationc
1
2
3
4
5
6
7
8
9
Benzaldehyde
7a
7b
7c
7d
7e
7f
7g
7h
7i
94
30
84
83
88
92
92
71
73
39
87
93
82
70
66
75
67
64
78
84
(R)33
(À)
o-Chlorobenzaldehyde
m-Chlorobenzaldehyde
p-Chlorobenzaldehyde
o-Methoxybenzaldehyde
m-Methoxybenzaldehyde
p-Methoxybenzaldehyde
m-Tolualdehyde
(R)33
(R)33
(R)34
(R)35
(R)33
(R)33
(R)33
—
p-Tolualdehyde
Cyclohexanecarbaldhyde
10
7j
a
b
c
Determined by chiral HPLC (Chiralcel OD-H).
Isolated yields.
The absolute configurations of the products were assigned according to the literatures.
O
OiPr
O
N
H
N
H
OiPr
OiPr
H
N
H
N
Zn
O
Ti
O
O
Me
(S)
N
O
N
Zn
(S)
Ti
iPrO
H
Ph
R
OiPr
R
B
A
Figure 2. Proposed mechanism and transition state geometries for the alkylation and alkynylation of aldehydes.

854
S. Karabuga et al. / Tetrahedron: Asymmetry 25 (2014) 851–855
ticular, m- and p-substituted tolualdehydes displayed moderate
enantioselectivities of 71% ee and 73% ee (entries 8 and 9), but
the addition to aliphatic cyclohexanecarbaldehyde afforded a low
product ee of 39% (entry 10).
In Figure 2, we have proposed a mechanism and transition state
geometries for the alkylation and alkynylation of aldehydes
(Fig. 2). In transition state A, the 3-aminoquinazolinone zinc com-
plex delivers the ethyl group to the si-face of the aldehydes giving
the (S)-1-aryl-1-propanol. In transition state B, the Ti-3-aminoqui-
nazolinone complex transfers the phenylacetylene group to the re-
face of the aldehydes resulting in an (R)-configuration for the prop-
argylic alcohols.
Mp: 118–120 °C; 1H NMR (CDCl3) d 1.60 (3H, d, J = 6.4 Hz, CH3-
CHOH), 4.36 (1H, d, J = 7.3 Hz, CH3CHOH), 4.85 (2H, s, QNH2),
5.21 (1H, m, CH3CHOH), 7.46 (1H, ddd, J = 8.1, 7.1 and 1.1 Hz, 6-H
(Q)), 7.64 (1H, ddd, J = 8.3, 1.1 and 0.4 Hz, 8-H (Q)), 7.73 (1H,
ddd, J = 8.3, 7.1 and 1.5 Hz, 7-H (Q)) and 8.20 (1H, ddd, J = 8.1, 1.5
and 0.4 Hz, 5-H (Q)); 13C NMR (CDCl3) d 22.5, 65.8, 120.3, 126.8,
127.1, 127.3, 134.7, 146.3, 159.7 and 162.2; IR (KBr, cmÀ1) 3429,
3316, 3203, 2982, 1670, 1600, 1475, 1270, 1251, 1190, 1131,
1038, 977, 903, 772 and 696.
4.3. (S)-3-Amino-2-(1-hydroxy-2-methylpropyl)quinazolin-4(3H)-
one 1b29
3. Conclusion
General procedure 1 was followed to obtain (S)-3-amino-2-(1-
hydroxy-2-methylpropyl)quinazolin-4(3H)-one 1b as a colourless
In conclusion, readily and easily prepared 3-aminoquinazoli-
nones 1a–d were examined in the catalytic asymmetric addition
of Et2Zn and phenylacetylene to a variety of aldehydes. We have
shown that 3-aminoquinazolinones 1a–d were not just good
reagents for the aziridination of alkenes, but were also efficient
catalysts in enantioselective alkylations and alkynylations. While
alkylation product ees obtained ranged from poor to high (3–
85%), the desired propargylic alcohols derived from aldehydes gave
up to 94% ee.
solid in a
yield of 90%. Mp: 138–140 °C; 1H NMR (CDCl3,
400 MHz) 0.82 (3H, d, J = 6.6 Hz, CHCH3CH3), 1.17 (3H, d,
J = 6.6 Hz, CHCH3CH3), 2.31 (1H, d sept., J = 6.84 and 3.50 Hz,
CHCH3CH3), 4.09 (1H, dd, J = 8.20 and 3.43 Hz, CHCHOH), 4.76
(2H, b, QNH2), 5.00 (1H, dd, J = 8.2 and 3.43 Hz, CHCHOH), 7.49
(1H, d, J = 8.0 Hz, 6-H (Q)), 7.69 (1H, d, J = 8.2 Hz, 8-H (Q)), 7.77
(1H, t, J = 8.2 Hz, 7-H (Q)) and 8.25 (1H, ddd, J = 8.0, 1.5 and
0.6 Hz, 5-H (Q)); 13C NMR (CDCl3, 100 MHz) d 15.4, 20.3, 32.5,
73.3, 120.3, 126.8, 127.1, 127.4, 134.7, 146.1, 158.5 and 162.3.
4. Experimental
4.1. General
4.4. (S)-3-Amino-2-(1-hydroxy-2,2-dimethylpropyl)quinazolin-
4(3H)-one 1c30
General procedure 1 was followed to obtain (S)-3-amino-2-(1-
hydroxy-2,2-dimethylpropyl)quinazolin-4(3H)-one 1c as a colour-
less solid in a yield of 87%. Mp: 134–136 °C; 1H NMR (CDCl3,
400 MHz) d 1.06 (9H, s, CH(CH3)3), 3.81 (1H, d, J = 9.9 Hz, CHOH),
4.72 (2H, s, QNH2), 5.20 (1H, d, J = 9.9 Hz, CH(CH3)3), (7.50 (1H,
ddd, J = 8.1, 7.1 and 1.2 Hz, 6-H (Q)), 7.70 (1H, ddd, J = 8.3, 1.2
and 0.5 Hz, 8-H (Q)), 7.78 (1H, ddd, J = 8.3, 7.1 and 1.5 Hz, 7-H
(Q)) and 8.20 (1H, ddd, J = 8.1, 1.5 and 0.5 Hz, 5-H (Q)); 13C NMR
(CDCl3, 100 MHz) d 26.2, 37.9, 74.8, 120.3, 126.8, 127.1, 127.5,
134.7, 146.2, 158.7 and 162.3.
All reactions were performed under an argon atmosphere using
Schlenk techniques. The solvents were dried and distilled prior to
use by the literature methods. Melting points were obtained in
an Electrothermal 9100 apparatus and are uncorrected. 1H and
13C NMR spectra were performed on a Varian spectrometer at
400 and 100 MHz in CDCl3 with tetramethylsilane as an internal
standard and signals were evaluated using Mestre Computer soft-
ware. The enantiomeric purity of the ligands and enantiomeric
excesses of alcohols were determined by using Perkin–Elmer Series
200, VWR Hitachi and Agilent HPLC 1100 Series System using Chi-
ralcel OD-H and Agilent 6850 GC system using chiral capillary b-
Dex column.
4.5. (S)-3-Amino-2-(hydroxy(phenyl)methyl)quinazolin-4(3H)-
one 1d32
4.2. General procedure 1 for the preparation of (S)-3-amino-2-
(1-hydroxyethyl)quinazolin-4(3H)-one 1a31
General procedure 1 was followed to obtain (S)-3-amino-2-
(hydroxy(phenyl)methyl)quinazolin-4(3H)-one 1d as a colourless
solid in a yield of 80%. Mp: 134–136 °C; [a]
20 = +4.1 (c 1.22,
D
At first, SOCl2 (272.9 mmol) was added dropwise to (S)-2-acet-
oxypropanoic acid 4a (68.23 mmol) at 0 °C. After the addition, the
reaction mixture was stirred for an additional 4 h at room temper-
ature. Excess SOCl2 was removed in vacuo after which acyl chloride
CHCl3); 1H NMR (CDCl3, 400 MHz) d 4.53 (2H, s, QNH2), 5.26 (1H,
d, J = 6.2 Hz, CHOH), 6.07 (1H, d, J = 6.2 Hz, CHOH), 7.27–7.36 (3H,
m, Ar-H), 7.42–7.44 (2H, m, Ar-H), 7.52 (1H, m, Ar-H), 7.80–7.82
(2H, m, Ar-H) and 8.25 (1H, d, J = 7.8 Hz, 5-H (Q)); 13C NMR (CDCl3,
100 MHz) d 71.6, 120.5, 127.0, 127.3, 127.5, 127.8, 128.7, 129.0,
134.9, 140.3, 146.0, 157.3 and 161.9.
was added to
a
suspension of methyl 2-aminobenzoate
(150 mmol) in diethyl ether (150 mL). After the addition was com-
plete, the mixture was stirred at room temperature overnight. The
reaction mixture was washed with 2 M HCl (2 Â 100 mL) and brine
(100 mL), the organic layer was dried over Na2SO4, and the solvent
was removed under reduced pressure. Crystallisation of the crude
mixture gave the corresponding amide (S)-methyl 2-(2-acetoxy-
propanamido)benzoate 5a in 85% yield and was used in the next
step without further purification. To a solution of amide 5a
(15.4 g, 58.0 mmol) in ethanol (20 mL) was added hydrazine
monohydrate (290 mmol) in a Schlenk flask. The mixture was stir-
red for 4 h at 150 °C. After concentration under reduced pressure,
water (50 mL) was added and the mixture was extracted with
diethyl ether (3 Â 50 mL). The organic layers were dried over Na2-
SO4 and the solvent was removed under vacuum. The residue was
crystallised from ethanol and gave (S)-3-amino-2-(1-hydroxy-
ethyl)quinazolin-4(3H)-one 1a as a colourless solid in 86% yield.
4.6. General procedure for the catalytic asymmetric addition of
Et2Zn to aldehydes
Ligand 1c (0.188 mmol) was dissolved in toluene (2 mL) and
Et2Zn (2 M in toluene, 2.26 mmol) was added in one portion after
which the reaction was stirred for 45 min. at ambient temperature.
The mixture was then cooled to À20 °C and the aldehyde
(1.88 mmol) was added as dissolved in toluene (2 mL) into the
reaction. The resulting mixture was stirred for 24 h at À20 °C.
The reaction was quenched with saturated ammonium chloride
(10 mL) and extracted with ethyl acetate (3 Â 10 mL). The com-
bined organic extracts were dried over Na2SO4 and concentrated.
Purification of the crude product was carried out by micro distilla-
tion under reduced pressure. The product was subjected to HPLC

S. Karabuga et al. / Tetrahedron: Asymmetry 25 (2014) 851–855
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4.7. General procedure for the catalytic asymmetric addition of
phenylacetylene to aldehydes
To a solution of phenylacetylene (200 mg, 1.96 mmol) in dry
THF (1 mL) under an argon atmosphere at room temperature was
added a solution of Et2Zn in hexane (1.9 mL, 1 M). After 3 h, a solu-
tion of ligand 1a (20 mg, 0.095 mmol) in 1 mL of dry THF was
added and stirred for 1 h. The stirred mixture was cooled to
À20 °C, followed by the addition of a solution of an aldehyde
(0.94 mmol) in 1 mL of dry THF. After the addition, the mixture
was stirred for 24 h at the same temperature. The reaction was
quenched by the addition of saturated ammonium chloride
(10 mL) and the mixture was extracted with ethyl acetate
(2 Â 10 mL). The combined organic layer was washed with brine,
dried over Na2SO4 and concentrated under vacuum. The crude
was purified by flash column chromatography (silica gel, 10:1 hex-
ane/EtOAc) to give the product. The enantiomeric excess was
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