Synthesis of novel norephedrine-based chiral ligands with multiple stereogenic centers and their application in enantioselective addition of diethylzinc to aldehyde and chalcone

Article abstract of DOI:10.1016/j.tetasy.2006.02.005

Novel norephedrine-based chiral ligands with multiple stereogenic centers were conveniently prepared from norephedrine and N-substituted pyrrole. These novel chiral ligands were used to catalyze the enantioselective addition of diethylzinc to aldehydes and to chalcone in high yields and with good to high enantioselectivities. The absolute configuration of products was found to be affected by the stereogenic centers on the norephedrine part of the novel chiral ligands.

Full text of DOI:10.1016/j.tetasy.2006.02.005

Tetrahedron: Asymmetry 17 (2006) 742–749
Synthesis of novel norephedrine-based chiral ligands with multiple
stereogenic centers and their application in enantioselective
addition of diethylzinc to aldehyde and chalcone
Canan Unaleroglu,a,* A. Ebru Aydina and Ayhan S. Demirb,*
aDepartment of Chemistry, Hacettepe University, Beytepe Campus, 06532 Ankara, Turkey
bDepartment of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
Received 21 November 2005; accepted 6 February 2006
Available online 15 March 2006
Abstract—Novel norephedrine-based chiral ligands with multiple stereogenic centers were conveniently prepared from norephedrine
and N-substituted pyrrole. These novel chiral ligands were used to catalyze the enantioselective addition of diethylzinc to aldehydes
and to chalcone in high yields and with good to high enantioselectivities. The absolute configuration of products was found to be
affected by the stereogenic centers on the norephedrine part of the novel chiral ligands.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
ture.8 As reported in previous studies, the substituent
on the nitrogen atom of norephedrine plays an impor-
tant role in the enantioselectivity of the addition.1a,2,7d
Catalytic asymmetric C–C bond formation is an impor-
tant field of synthetic chemistry. Considerable attention
has been devoted to the development of new chiral
ligands to be used in asymmetric catalysis over the past
decade.1 The success of catalytic asymmetric synthesis is
critically dependent on the structural features of chiral
ligands as well as their availability. Among the whole
variety of chiral ligands used in asymmetric synthesis,
b-amino alcohol-based ligands have been extremely
promising compounds.2 Most of the amino alcohols
used in asymmetric reactions as chiral ligands are amino
acid derivatives,3 ephedrine derivatives,4 borneol deriva-
tives,5 and pyrrolidine derivatives.6 They have become
the most-often used ligands because of their easy avail-
ability, simple preparation, and efficient asymmetric
induction.
Herein, we report the effect of the presence of an N-
substituted chiral pyrrole as a substituent on norephe-
drine, during enantioselective addition reactions. We
designed novel chiral ligands conveniently and efficiently
from norephedrine and N-substituted pyrrole carbalde-
hyde. We tested the efficiency of these novel ligands in
asymmetric induction with diethylzinc addition reaction
to benzaldeydes and to chalcone.
2. Results and discussion
2.1. Synthesis of chiral ligands
Optically active N-substituted pyrroles (S)-1 and (R)-1
were prepared from both enantiomers of the commer-
cially available amine and 5-chloropent-3-ene-2-one as
described previously.9 The formylation of (S)-1 and
(R)-1 using DMF and POCl3 was performed in pen-
tane/diethyl ether. We obtained C-3 [(S)-2 in 70% yield,
(R)-2 in 68% yield] and C-2 [(S)-3 in 24% yield, (R)-3 in
21% yield] formulated products under conditions (i)
(pyrrole/DMF/POCl3, 1:1:1 at 0 ꢁC to rt) as shown in
Scheme 1. Under a different Vilsmeier–Haack reaction
conditions (ii) where the molar ratios of pyrrole,
N-Alkylated derivatives of norephedrine have been
reported by Soai et al.7 to catalyze diethylzinc addition
to aliphatic and aromatic aldehydes with high asymmet-
ric induction. To the author’s knowledge, little work on
asymmetric diethylzinc addition to enones with nore-
phedrine derivatives has been published in the litera-
*
Corresponding authors. Tel.: +90 312 297 7962; fax: +90 312 299
2163 (C.U.); tel.: +90 312 210 3242 (A.S.D.); e-mail addresses:
canan@hacettepe.edu.tr; asdemir@metu.edu.tr
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.02.005

C. Unaleroglu et al. / Tetrahedron: Asymmetry 17 (2006) 742–749
743
N
i
ii
O
*
Ph
H
(S)-1
(R)-1
O
(S)-2
(R)-2
)-3
)-3
(S
(R
+
+
N
N
*
H
* Ph
Ph
iii
iii
(S)-3
(R)-3
(S)-2
(R)-2
H
N
HN
*
HO
Ph
*
*
N
*
Ph
N
HO
* Ph
* Ph
)-5a
)-5a
)-5b
(1S,2R,S
(1S,2R,S)-4a
(1R,2S,R)-4a
(1S,2R,R)-4b
(1R,2S,S)-4b
(1R,2S,R
(1S,2R,R
(1R,2S,S)
-5b
Scheme 1. Reagents and conditions: (i) DMF, POCl3, 0 ꢁC to rt (pyrrole/DMF/POCl3, 1:1:1); (ii) DMF, POCl3, 0 ꢁC (pyrrole/DMF/POCl3,
1:10:10); (iii) norephedrine, benzene, reflux and then LiAlH4, ether, reflux.
Table 1. The effect of stereogenic centers of chiral ligands 4a,b and
5a,b on the absolute configuration of 1-phenylpropan-1-ol in diethyl-
zinc addition to benzaldehydea
DMF, and POCl3 were 1:10:10 at 0 ꢁC, C-2 [(S)-3, (R)-3]
and C-3 [(S)-2, (R)-2] formulated products were formed
in 52%, 53%, 43%, and 40% yield, respectively. The
Entry
Ligand
eeb (%)
Absolute configuration
of product
products were characterized using one- and two-dimen-
sional NMR techniques. Reductive amination of alde-
hydes with norephedrine furnished chiral ligands 4a
and b and 5a and b by using LiAlH4 without isolating
the corresponding imines. All possible stereoisomers
(1S,2R,S)-4a (69%), (1R,2S,R)-4a (71%), (1S,2R,R)-4b
(73%), (1R,2S,S)-4b (70%), (1S,2R,S)-5a (72%),
(1R,2S,R)-5a (70%), (1S,2R,R)-5b (68%), (1R,2S,S)-5b
(73%) are isolated after purification of the crude prod-
ucts by column chromatography.
1
2
3
4
5
6
7
8
(1S,2R,S)-4a
(1R,2S,R)-4a
(1S,2R,R)-4b
(1R,2S,S)-4b
(1S,2R,S)-5a
(1R,2S,R)-5a
(1S,2R,R)-5b
(1R,2S,S)-5b
75
69
51
46
68
57
51
43
S
R
S
R
S
R
S
R
a 5 mol % ligand in toluene at 0 ꢁC to rt.
b The ee values were determined by HPLC with a Chiralcel-OD col-
umn; 2% 2-propanol in hexane, flow rate: 1 mL/min, UV detection
(254 nm) tR: 17 min for (R), 19 min for (S).
2.2. Enantioselective diethylzinc addition to aldehydes
The addition of diethylzinc to benzaldehyde was investi-
gated first in order to examine the catalytic behavior of
ligands 4a and b and 5a and b (Scheme 2). The reactions
were screened in toluene at 0 ꢁC to rt in the presence of
4a and b and 5a and b at different molar ratios (2.5–
20%). The best results were obtained by using
(1S,2R,S)-4a (75% ee, 70% yield) and (1S,2R,S)-5a
(68% ee, 65% yield) as catalysts in a 5 mol % ratio.
Ligand (1S,2R,S)-4a was used to investigate the effect of
temperature on the diethylzinc addition to benzalde-
hyde. As shown in Table 2, similar enantioselectivities
were obtained at 0 ꢁC to rt and at 0 ꢁC. When the reac-
tion was carried out at ꢀ20 ꢁC, the ee of the product
decreased to 10%. No product formation was observed
at ꢀ78 ꢁC. We also carried out the reaction in different
solvents and solvent mixtures (Table 2, entries 5–8).
Comparable enantiomeric excesses of the products were
noted in CH2Cl2 and toluene/hexane. The highest ee
(75%) was obtained by using toluene as the solvent
(Table 2, entry 1).
O
OH
5 mol% Catalyst
H
*
+
Et2Zn
o
Toluene, 0 C-rt
Scheme 2.
Table 1 shows the absolute configurations of 1-phenyl-
propan-1-ol obtained by using the ligands 4a and b
and 5a and b. These results indicate that the stereochem-
istry of norephedrine plays a crucial role with regards to
the absolute configuration of the product.
The reactions were performed in different solvents and
solvent mixtures for the ligand (1S,2R,S)-5a at 0 ꢁC to
rt (Table 2, entries 9–13). In this case, the highest enan-
tiomeric excess (68%) was obtained in toluene (Table 2,
entry 9).

744
C. Unaleroglu et al. / Tetrahedron: Asymmetry 17 (2006) 742–749
Table 2. Diethylzinc addition to benzaldehyde with (1S,2R,S)-4a and (1S,2R,S)-5a
Entry
Ligand
Solvent
Temp (ꢁC)
Time (h)
Yield (%)a
eeb (%)
Conf.
1
2
3
4
5
6
7
8
(1S,2R,S)-4a
(1S,2R,S)-4a
(1S,2R,S)-4a
(1S,2R,S)-4a
(1S,2R,S)-4a
(1S,2R,S)-4a
(1S,2R,S)-4a
(1S,2R,S)-4a
(1S,2R,S)-5a
(1S,2R,S)-5a
(1S,2R,S)-5a
(1S,2R,S)-5a
(1S,2R,S)-5a
Toluene
Toluene
Toluene
Toluene
0 to rt
0
16
16
16
16
16
24
20
24
16
16
16
16
16
70
68
77
—
71
41
82
5
65
62
57
72
5
75
74
10
—
72
69
72
31
68
58
62
62
4
S
S
S
—
S
S
S
S
S
S
S
S
S
ꢀ20
ꢀ78
CH2Cl2
0 to rt
0 to rt
0 to rt
0 to rt
0 to rt
0 to rt
0 to rt
0 to rt
0 to rt
Tolene/CH2Cl2 (5:1)
Toluene/hexane (5:1)
Toluene/THF (5:1)
Toluene
9
10
11
12
13
CH2Cl2
Tolene/CH2Cl2 (5:1)
Toluene/hexane (5:1)
Toluene/THF (5:1)
a Isolated yield.
b The ee values were determined by HPLC with a Chiralcel-OD column; 2% 2-propanol in hexane, flow rate: 1 mL/min, UV detection (254 nm) tR:
17 min for (R), 19 min for (S).
Table 3. Effects of Ti(O-i-Pr)4/ligand system and various additives on the enantioselective addition of diethylzinc to benzaldehyde
Entry
Liganda
Ti(O-i-Pr)4/ligand
Additive
Yield (%)b
ee (%)
Conf.
1
2
3
4
5
6
7
8
(1S,2R,S)-4a
(1S,2R,S)-4a
(1S,2R,S)-4a
(1S,2R,S)-4a
(1S,2R,S)-4a
(1S,2R,S)-4a
(1S,2R,S)-5a
(1S,2R,S)-5a
(1S,2R,S)-5a
(1S,2R,S)-5a
(1S,2R,S)-5a
(1S,2R,S)-5a
5
15
100
—
—
—
5
15
100
—
—
—
—
—
—
74
75
78
65
98
96
70
73
76
40
92
82
62
56
48
70
64
60
58
52
43
61
57
51
S
S
S
S
S
S
S
S
S
S
S
S
LiCl (0.92 mmol)
BuLi (0.196 mmol)
[LiCl (0.92 mmol) + BuLi (0.196 mmol)]
—
—
—
LiCl (0.92 mmol)
BuLi (0.196 mmol)
[LiCl (0.92 mmol) + BuLi (0.196 mmol)]
9
10
11
12
a 5 mol % ligand.
b Isolated yield.
It has been reported that the chiral catalyst in the pres-
ence of Ti(O-i-Pr)4 has an enhancement effect on the
enantioselectivity.10 We decided to test the diethylzinc
addition reaction with ligands (1S,2R,S)-4a and
(1S,2R,S)-5a in the presence of Ti(O-i-Pr)4.
75% ee by using (1S,2R,S)-4a and in 65% yield with
68% ee by using (1S,2R,S)-5a.
The addition reaction of diethylzinc to benzaldehyde
was carried out with various additives (LiCl, BuLi,
LiCl/BuLi). As summarized in Table 3, no increase in
the ee values were observed. Only BuLi appeared to
have an increasing effect on the chemical yield.
The asymmetric addition of diethylzinc with 5 mol %
ligand (1S,2R,S)-4a in toluene at 0 ꢁC to rt was per-
formed applying the Ti(O-i-Pr)4/ligand (entries 1–3 in
Table 3). The reaction with a molar ratio of Ti(O-i-
Pr)4/(1S,2R,S)-4a (5:1) gave (S)-1-phenylpropanol in
74% yield with 62% ee (entry 1) and (S)-1-phenylpro-
pan-1-ol was formed in 75% yield with 56% ee when
the Ti(O-i-Pr)4/(1S,2R,S)-4a ratio was 15 (entry 2).
The addition reaction with Ti(O-i-Pr)4/(1S,2R,S)-4a
(100:1) gave (S)-1-phenylpropanol in 78% yield with
48% ee. Increasing the Ti(O-i-Pr)4/ligand ratios lowered
the enantioselectivity from 62% to 48% for these reac-
tion conditions. The same ratios as given above for
Ti(O-i-Pr)4/ligand were used in the asymmetric addition
of diethylzinc to benzaldehyde with (1S,2R,S)-5a as
ligand. The increasing Ti(O-i-Pr)4/ligand ratios decreased
the enantioselectivity from 58% ee to 52% ee and 43% ee
(Table 3, entries 7–9). When the diethylzinc addition
reaction was achieved in the absence of Ti(O-i-Pr)4,
(S)-1-phenylpropan-1-ol was formed in 70% yield with
We continued to test the catalytic efficiency of ligand
(1S,2R,S)-4a and (1S,2R,S)-5a on various aldehydes,
as shown in Table 4. The diethylzinc additions to p-
methoxybenzaldehyde gave the lowest yield and enan-
tiomeric excesses. The best ee value (88%) was obtained
with p-trifluoromethylbenzaldehyde. Accordingly, the
electron withdrawing group enhanced the enantioselec-
tivity while electron donating groups such as methoxy
lowered enantioselectivity.
2.3. The enantioselective addition of diethylzinc to
chalcone
The enantioselective conjugate addition reaction of
organozinc reagents to enones by using chiral catalysts
is a particular focus of interest and has been applied in
numerous total syntheses. However, whereas most of

C. Unaleroglu et al. / Tetrahedron: Asymmetry 17 (2006) 742–749
745
Table 4. The diethylzinc addition to various benzaldehyde with chiral ligand (1S,2R,S)-4a and (1S,2R,S)-5a in toluene
Entry
Ligand
Aldehyde
Time (h)
Yield (%)a
ee (%)b
Conf.
1
2
3
4
5
6
7
8
9
10
(1S,2R,S)-4a
(1S,2R,S)-4a
(1S,2R,S)-4a
(1S,2R,S)-4a
(1S,2R,S)-4a
(1S,2R,S)-5a
(1S,2R,S)-5a
(1S,2R,S)-5a
(1S,2R,S)-5a
(1S,2R,S)-5a
Benzaldehyde
16
20
8
16
16
16
16
16
16
16
70
30
67
98
72
65
32
74
76
75
75
S
p-Methoxybenzaldehyde
o-Methoxybenzaldehyde
p-Chlorobenzaldehyde
p-Trifluoromethylbenzaldehyde
Benzaldehyde
p-Methoxybenzaldehyde
o-Methoxybenzaldehyde
p-Chlorobenzaldehyde
p-Trifluoromethylbenzaldehyde
30c
48d
72e
83f
68
S
S
S
R11
S
26
50
48
88
S
S
S
R11
a Isolated yield.
b The ee values were determined by HPLC with a Chiralcel-OD column.
c 3% 2-propanol in hexane, flow rate: 1 mL/min, UV detection (254 nm) tR: 35 min for (R), 39 min for (S).
d 2% 2-propanol in hexane, flow rate: 1 mL/min, UV detection (254 nm) tR: 28 min for (S), 39 min for (R).
e 3% 2-propanol in hexane, flow rate: 0.5 mL/min, UV detection (254 nm) tR: 23 min for (R), 25 min for (S).
f 5% 2-propanol in hexane, flow rate: 0.8 mL/min, UV detection (254 nm) tR: 9.11 min for (R), 10.92 min for (S).
O
O
20 mol% Catalyst
Ni(acac)2
*
+
Et2Zn
Scheme 3.
the catalysts provide excellent enantioselectivities in the
reactions of cyclic enones, the reactions of acyclic enones
result in relatively low enantioselectivity, with only
some ligands providing very high enantioselectivity.12
Soai et al.1b,8b used the catalyst formed from N,N-di-
butylnorephedrine and Ni(acac)2 in the addition of the
diethylzinc to chalcone with a 1:1.2:2.0 molar ratio of
Ni:ligand:substrate leading to the product with 45% ee
and with 1:1.2:17 (Ni:L:S) molar ratio leading the prod-
uct with 20% ee.
The best selectivity was obtained with (1S,2R,R)-4b
(53% ee and 70% yield). The asymmetric induction of
ligand (1S,2R,R)-4b formed the product with compa-
rible ees (53%) at 1:20:100 (Ni:L:S) molar ratio under
the same reaction conditions.
Table 5 demonstrates the effect of the stereogenic centers
of the ligands 4a and b and 5a and b on the absolute
configuration of 1,3-diphenylpentan-1-one. It appears
that the stereogenic centers on the norephedrine plays
a crucial role with regards to the absolute configuration
of 1,3-diphenylpentan-1-one.
We examined the enantioselective conjugate addition of
diethylzinc to chalcone as a model system with 20 mol %
of the chiral ligands 4a and b and 1 mol % of Ni(acac)2
in acetonitrile at ꢀ30 ꢁC (Scheme 3). The catalyst was
prepared by treatment of 1 mol % of Ni(acac)2 and
20 mol % of ligand in 3 mL of acetonitrile at reflux.
Ligand (1S,2R,R)-4b was used to examine the effect of
the temperature and solvent on the addition reaction.
The reaction was carried out at different temperatures
in acetonitrile and in different solvents at ꢀ30 ꢁC, as
shown in Table 6. The highest ee (53%) was obtained
in acetonitrile at ꢀ30 ꢁC. Reducing the temperature
from ꢀ30 to ꢀ45 ꢁC did not obviously affect the
enantioselectivity.
Ligands (1S,2R,S)-4a, (1R,2S,R)-4a, and (1R,2S,S)-4b
gave 32–42% ee and 80–93% chemical yields (Table 5).
Table 5. Enantioselective conjugate addition of diethylzinc to chalcone
using Ni(acac)2–ligands 4a,b and 5a,b as catalystsa
We performed a series of reactions to find out the effects
of the Ni:L ratios on the diethylzinc addition to chal-
cone at ꢀ30 ꢁC and in CH3CN. We examined the ratio
of Ni:L (Table 7). The enantiomeric excess of the reac-
tion depends on the Ni:L ratio and the highest ee
(53%) was obtained by using Ni:L ratios in the range
of 1:20 and 1:30. Under these reaction conditions, the
best yield (70%) and ee (53%) was obtained by using
chalcone:L in a 10:2 ratio.
Entry
Ligand
Yieldb (%)
eec (%)
Conf.
1
2
3
4
5
6
(1S,2R,S)-4a
(1R,2S,R)-4a
(1R,2S,S)-4b
(1S,2R,R)-4b
(1R,2S,R)-5a
(1R,2S,S)-5b
80
93
80
70
72
81
32
36
42
53
48
28
R
S
S
R
S
S
a All reactions were carried out with 20 mol % ligand and 1 mol %
Ni(acac)2 in acetonitrile at ꢀ30 ꢁC for 6 h.
b Isolated yield.
We tested the catalytic effect of ligands 5a and b using
the optimized reaction conditions, which were found
by using ligands 4a and b, for the 1,4-addition reaction
to chalcone. Ligand (1R,2S,S)-5b provided the addition
c The ee values were determined by HPLC with a Chiralcel-OD col-
umn. 0.5% 2-propanol in hexane, flow rate: 1 mL/min, UV detector
(254 nm) tR: 14.11 min for (S), 15.35 min for (R).

746
C. Unaleroglu et al. / Tetrahedron: Asymmetry 17 (2006) 742–749
Table 6. The effect of the solvent and temperature on the diethylzinc addition to chalcone with ligand (1S,2R,R)-4b
Entry
Solvent
Temp (ꢁC)
Time (h)
Yielda (%)
ee (%)
Conf.
1
2
3
4
5
6
7
8
9
CH3CN
CH3CN
CH3CN
CH2Cl2
ꢀ30
ꢀ45
0
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ30
6
6
6
6
6
6
6
6
6
70
76
70
6
70
74
82
86
83
53
52
11
2
17
14
6
R
R
R
R
R
R
R
R
R
Toluene
Toluene/THF (10:1)
n-Hexane/THF (10:1)
CH3CN/THF (10:1)
DMF
27
19
a Isolated yield.
purchased from Aldrich. Enantiomeric excesses were
determined by HPLC analysis using a Thermo Finnigan
Surveyor equipped with an appropriate chiral phase
column.
Table 7. The effect of the Ni:L molar ratio in the presence of 20 mol %
(1S,2R,R)-4b on the diethylzinc addition to chalcone
Entry
Ni:L
Yielda (%)
ee (%)
Conf.
1
2
3
1:1
1:20
1:30
64
70
60
26
53
53
R
R
R
4.2. Formylation of 2-substituted pyrroles
a Isolated yield.
Conditions i: 2-Substituted pyrrole (S)-1 (0.213 g,
1 mmol) and dimethylformamide (0.074 g, 1 mmol) were
dissolved in 5 mL of pentane/ether (5:3). This solution
was cooled to 0 ꢁC and POCl3 (0.230 g, 1.5 mmol) added
with stirring over 1.5 h. Stirring was continued over-
night at rt and the iminium salt precipitated as a red
oil and the upper layer was decanted. Then 4 M NaOH
(15 mL) was added to the red oil with stirring and cool-
ing of the solution. After 1 h, the aqueous mixture was
extracted with chloroform (2 · 10 mL). The combined
organic layers were dried over MgSO4 and concentrated.
The crude product was purified by flash column chro-
matography (EtOAc/hexane, 1:3).
product, (S)-1,3-diphenylpentane-1-one in 81% yield
with 28% ee (Table 5, entries 5 and 6). By using
(1R,2S,R)-5a, (S)-1,3-diphenylpentane-1-one was obtain-
ed with 48% ee and 72% yield.
3. Conclusion
In summary, we have synthesized novel chiral ligands
with multiple stereogenic center from norephedrine
and N-substituted pyrrole. Moderate enantioselectivities
were obtained with (1S,2R,S)-4a and (1S,2R,S)-4a in the
addition of diethylzinc to aldehydes and with (1S,2R,R)-
4b and (1S,2R,R)-4b in the addition of diethylzinc to
chalcone. In both reactions, the absolute configuration
of the products are mainly controlled by the stereogenic
centers of norephedrine on chiral ligands 4a and b and
5a and b.
Conditions ii: 2-Substituted pyrrole (S)-1 (0.213 g,
1 mmol) and dimethylformamide (0.740 g, 10 mmol)
were dissolved in a 5 mL of pentane/ether (5:3). This
solution was cooled to 0 ꢁC and POCl3 (1.530 g,
10 mmol) added with stirring over 1.5 h. Stirring was
continued overnight at 0 ꢁC and the iminium salt precip-
itated as a red oil and the upper layer was decanted.
Then 4 M NaOH (15 mL) was added to the red oil with
stirring and cooling of the solution. After 1 h, the aque-
ous mixture was extracted with chloroform (2 · 10 mL).
The combined organic layers were dried over MgSO4
and concentrated. The crude product was purified by
flash column chromatography (EtOAc/hexane, 1:3).
4. Experimental
4.1. General
All solvents were dried before use according to standard
procedures. Melting points were obtained using an elec-
trothermal digital melting point apparatus (Gallenk-
4.2.1.
2-Methyl-1-((1S)-1-phenylethyl)-1H-pyrrole-3-
1
amp). H and 13C NMR spectra were measured with a
carbaldehyde, (S)-2. Light yellow solid (0.149 g, 70%),
Bruker 400 MHz NMR spectrometer using CDCl3 as
solvent at room temperature. Chemical shifts (parts
per million) were reported relative to Me4Si. Coupling
constant were expressed as J values in Hertz unit. Opti-
cal rotations were measured with a Autopol IV polari-
meter. Infrared spectra were recorded on Mattson 1000
FTIR spectrometer. All reactions were carried out under
an Ar atmosphere and monitored by thin-layer chroma-
tography (TLC) on Merck silica gel plates (60 F-254)
using UV light or phosphomolybdic acid in methanol.
E. Merck silica gel (60, particle size 0.040–0.063 mm)
was used for flash chromatography. Diethylzinc was
mp = 107–108 ꢁC. Rf = 0.71 (EtOAc/hexane, 1:3).
25
½aꢁD ¼ ꢀ21:9 (c 0.8, CHCl3). IR (KBr): 3144, 2981,
2840, 1653, 1499, 1145, 1228, 1141 cmꢀ1 1H NMR
;
(CDCl3) d (ppm): 1.78 (d, 3H, J = 7.1, CHCH3), 2.35
(s, 3H, CH3), 5.33 (q, 1H, J = 7.0, CHCH3), 6.57 (d,
1H, J = 3.2, CH-4), 6.65 (d, 1H, J = 3.2, CH-5), 6.93
(d, 2H, J = 7.4, ArH), 6.90–7.30 (m, 3H, ArH), 9.78
(s, 1H, CHO). 13C NMR (CDCl3) d (ppm): 10.4, 22.1,
54.9, 109.1, 118.5, 122.9, 125.6, 127.7, 128.9, 136.8,
141.8, 185.2 (CO). Anal. Calcd for C14H15NO: C,
78.84; H, 7.09; N, 6.57. Found: C, 78.55; H, 7.31; N,
6.30.

C. Unaleroglu et al. / Tetrahedron: Asymmetry 17 (2006) 742–749
747
4.2.2.
2-Methyl-1-((1R)-1-phenylethyl)-1H-pyrrole-3-
by flash column chromatography (EtOAc/MeOH/
hexane, 1:1:6).
carbaldehyde, (R)-2. Light yellow solid (0.145 g,
68%), mp = 107–108 ꢁC. Rf = 0.71 (EtOAc/hexane,
25
1:3). ½aꢁD ¼ þ21:1 (c 0.8, CHCl3). IR (KBr): 3144,
4.3.1. (1S,2R)-2-((2-Methyl-1-((1S)-1-phenylethyl)-1H-
pyrrol-3-yl)methylamino)-1-phenylpropan-1-ol (1S,2R,S)-
2981, 2840, 1653, 1499, 1145, 1228, 1141, 1029 cmꢀ1
.
1H NMR (CDCl3) d (ppm): 1.76 (d, 3H, J = 7.1,
CHCH3), 2.34 (s, 3H, CH3), 5.27 (q, 1H, J = 7.0,
CHCH3), 6.51 (d, 1H, J = 3.2, CH-4), 6.67 (d, 1H,
J = 3.2, CH-5), 6.86 (d, 2H, J = 7.4, ArH), 6.94–7.43
(m, 3H, ArH), 9.76 (s, 1H, CHO). 13C NMR (CDCl3)
d (ppm): 12.2, 18.1, 54.8, 108.6, 118.6, 122.8, 125.3,
127.6, 128.7, 137.1, 141.9, 184.8 (C@O). Anal. Calcd
for C14H15NO: C, 78.84; H, 7.09; N, 6.57. Found: C,
78.60; H, 7.24; N, 6.45
4a. White solid (2.82 g, 69%), mp = 99.5–100.5 ꢁC.
25
Rf = 0.24 (EtOAc/MeOH/hexane, 1:1:6). ½aꢁD ¼ þ3:7
(c 11, CHCl3). IR (KBr): 3093, 3054, 2977, 2900, 1488,
1
1450, 1141, 1326, 1121, 1133 cmꢀ1. H NMR (CDCl3)
d (ppm): 0.81 (d, 3H, J = 6.8, CHCH3), 1.84 (d, 3H,
J = 7.2, NCHCH3), 2.08 (s, 3H, CH3), 3.00–3.06 (m,
1H, NHCHCH3), 3.73 (d, 1H, J = 12.8, NHCH2), 3.76
(d, 1H, J = 12.8, NHCH2), 4.79 (d, 1H, J = 3.6,
CHOH), 5.28 (q, 1H, J = 7.2, NCHCH3), 6.13 (d, 1H,
J = 3.2, CH), 6.77 (d, 1H, J = 3.2, CH), 6.97 (d, 2H,
J = 7.2, ArH), 7.13–7.31 (m, 8H, ArH). 13C NMR
(CDCl3) d (ppm): 10.4, 15.7, 22.8, 43.4, 55.5, 58.3,
72.6, 108.2, 116.9, 118.7, 125.1, 125.8, 125.9, 126.7,
127.1, 128.4, 129.0, 141.7, 144.0. Anal. Calcd for
C23H15N2O: C, 79.27; H, 8.10; N, 8.04. Found: C,
79.17; H, 7.99; N, 8.04.
4.2.3.
5-Methyl-1-((1S)-1-phenylethyl)-1H-pyrrole-2-
carbaldehyde, (S)-3. Brown oil (0.111 g, 52%).
25
Rf = 0.87 (EtOAc/hexane, 1:3). ½aꢁ ¼ ꢀ118:9 (c 11,
CHCl3). IR (KBr): 3026, 2973, 2807D, 2774, 1658, 1481,
1447, 1284, 1185, 1029 cmꢀ1 1H NMR (CDCl3) d
.
(ppm): 2.05 (d, 3H, J = 7.1, CHCH3), 2.12 (s, 3H,
CH3), 6.15 (d, 1H, J = 3.8, CH-4), 7.02 (d, 1H,
J = 3.9, CH-3), 7.13 (q, 1H, J = 7.0, CHCH3), 7.26 (d,
2H, J = 7.9, ArH) 7.36–7.47 (m, 3H, ArH), 9.60 (s,
1H, CHO). 13C NMR (CDCl3) d (ppm): 14.2, 18.5,
53.2, 111.6, 125.7, 126.1, 126.9, 128.1, 128.4, 132.2,
140.8, 141.2, 178.3 (C@O). Anal. Calcd for C14H15NO:
C, 78.84; H, 7.09; N, 6.57. Found: C, 78.72; H, 6.86;
N, 6.67.
4.3.2. (1R,2S)-2-((2-Methyl-1-((1R)-1-phenylethyl)-1H-
pyrrol-3-yl)methylamino)-1-phenylpropan-1-ol (1R,2S,R)-
4a. White solid (2.90 g, 71%), mp = 101–102 ꢁC.
25
Rf = 0.24 (EtOAc/MeOH/hexane, 1:1:6). ½aꢁD ¼ ꢀ3:2
(c 13, CHCl3). IR (KBr): 3060, 3027, 2977, 2900, 2830,
1486, 1444, 1411, 1322, 1241, 1132 cmꢀ1 1H NMR
.
(CDCl3) d (ppm): 0.81 (d, 3H, J = 6.5, CHCH3), 1.84
(d, 3H, J = 7.1, NCHCH3), 2.09 (s, 3H, CH3), 2.98–
3.04 (m, 1H, NHCHCH3), 3.72 (d, 1H, J = 12.9,
NHCH2), 3.77 (d, 1H, J = 12.9, NHCH2), 4.88 (d, 1H,
J = 4.0, CHOH), 5.28 (q, 1H, J = 7.2, NCHCH3), 6.14
(d, 1H, J = 2.8, CH), 6.78 (d, 1H, J = 2.8, CH), 6.96
(d, 2H, J = 7.2, ArH), 7.23–7.32 (m, 8H, ArH). 13C
NMR (CDCl3) d (ppm): 10.3, 14.7, 22.9, 43.6, 55.5,
58.1, 72.6, 107.9, 115.5, 118.9, 125.9, 127.1, 127.5,
128.3, 128.5, 129.1, 129.6, 141.9, 144.1.
4.2.4.
5-Methyl-1-((1R)-1-phenylethyl)-1H-pyrrole-2-
carbaldehyde, (R)-3. Brown oil (0.113 g, 53%).
25
Rf = 0.87 (EtOAc/hexane, 1:3). ½aꢁD ¼ þ119:7 (c 11,
CHCl3). IR (KBr): 3026, 2973, 2807, 2774, 1658, 1481,
1447, 1284, 1185, 1029 cmꢀ1 1H NMR (CDCl3) d
.
(ppm): 1.99 (d, 3H, J = 7.1, CHCH3), 2.06 (s, 3H,
CH3), 6.09 (d, 1H, J = 3.9, CH-4), 6.96 (d, 1H,
J = 3.9, CH-3), 7.15 (q, 1H, J = 6.8, CHCH3), 7.19 (d,
2H, J = 7.8, ArH), 7.26–7.57 (m, 3H, ArH), 9.54 (s,
1H, CHO). 13C NMR (CDCl3) d (ppm): 14.2, 18.5,
53.2, 111.6, 125.7, 126.1, 126.9, 128.4, 132.1, 140.8,
141.1, 178.2(C@O).
4.3.3. (1S,2R)-2-((2-Methyl-1-((1R)-1-phenylethyl)-1H-
pyrrol-3-yl)methylamino)-1-phenylpropan-1-ol (1S,2R,R)-
4b. Brown oil (2.98 g, 73%), Rf = 0.24 (EtOAc/
25
MeOH/hexane, 1:1:6). ½aꢁD ¼ þ5:6 (c 7.3, CHCl3); IR
(KBr): 3060, 2975, 2928, 1489, 1446, 1320, 1216 cmꢀ1
.
4.3. General procedure for the synthesis of pyrrole-based
derivatives of norephedrine
1H NMR (CDCl3) d (ppm): (400 MHz, CDCl3); 0.79
(d, 3H, J = 6.4, CHCH3), 1.96 (d, 3H, J = 7.2,
NHCHCH3), 1.98 (s, 3H, CH3), 2.95–3.01 (m, 1H,
NHCHCH3), 3.78 (d, 2H, J = 13.6, NHCH2), 3.85 (d,
1H, J = 13.6, NHCH2), 4.73 (d, 1H, J = 3.6, CHOH),
5.29 (q, 1H, J = 7.2, NCHCH3), 5.82 (d, 1H, J = 3.3,
CH), 6.00 (d, 1H, J = 3.4, CH), 7.07 (d, 2H, J = 7.2,
ArH), 7.22–7.34 (m, 8H, ArH). 13C NMR (CDCl3) d
(ppm): 10.3, 14.9, 22.8, 43.7, 55.5, 58.2, 72.9, 107.9,
116.6, 118.2, 125.9, 126.7, 126.7, 127.8, 128.8, 129.1,
129.9, 141.9, 144.1. Anal. Calcd for C23H15N2O: C,
79.27; H, 8.10; N, 8.04. Found: C, 79.10.; H, 8.05; N,
8.01.
Formylated pyrrole (2.5 g, 11.74 mmol) was dissolved in
10 mL dry benzene. To this solution was added norephe-
drine ( 1.76 g, 11.74 mmol) in 10 mL of dry benzene un-
der argon. The mixture was refluxed under a Dean Stark
trapp apparatus for 3 days, and the imine was then con-
centrated to dryness without purification. Imine (4.28 g,
12.36 mmol) in dry ether (10 mL) was added to the sus-
pension of LAH (0.54 g, 13.60 mmol) in dry ether
(50 mL). After the addition was completed, the mixture
was heated under argon for 10 h. The reaction was
quenched by sequential addition of water (15 mL),
15% NaOH (10 mL), and water (10 mL). The mixture
was filtered off and the white precipitate refluxed three
times with dry ether. The mixture was filtered off, the
organic layers combined, and dried over MgSO4. After
evaporation of solvent, the crude product was purified
4.3.4. (1R,2S)-2-((2-Methyl-1-((1S)-1-phenylethyl)-1H-
pyrrol-3-yl)methylamino)-1-phenylpropan-1-ol (1R,2S,S)-
4b. Brown oil (2.86 g, 70%). Rf = 0.24 (EtOAc/
25
MeOH/hexane, 1:1:6). ½aꢁD ¼ ꢀ4:5 (c 9.2, CHCl3), IR
(KBr): 3060, 3027, 2977, 2900–2830, 1492, 1450, 1323,

748
C. Unaleroglu et al. / Tetrahedron: Asymmetry 17 (2006) 742–749
1219 cmꢀ1
.
1H NMR (CDCl3) d (ppm): 0.83 (d, 3H,
4.3.8. (1R,2S)-2-((5-Methyl-1-((1S)-1-phenylethyl)-1H-
pyrrol-2-yl)methylamino)-1-phenylpropan-1-ol (1R,2S,S)-
J = 6.5, CHCH3), 1.84 (d, 3H, J = 7.1, NCHCH3),
2.08 (s, 3H, CH3), 2.99–3.05 (m, 1H, NHCHCH3),
3.71 (d, 2H, J = 12.9, NHCH2), 3.76 (d, 1H, J = 12.9,
NHCH2), 4.81 (d, 1H, J = 3.7, CHOH), 5.28 (q, 1H,
J = 7.2, NCHCH3), 6.15 (d, 1H, J = 2.9, CH), 6.78
(d, 1H, J = 2.9, CH), 6.97 (d, 2H J = 7.2, ArH), 7.23–
7.32 (m, 8H, ArH). 13C NMR (CDCl3) d (ppm): 10.4,
15.7, 22.8, 43.4, 55.5, 58.3, 72.6, 108.2, 116.9, 118.3
125.9, 126.0, 126.4, 127.1, 127.5, 128.3, 129.1, 141.8,
144.0.
5b. Brown oil (2.98 g, 73%). Rf = 0.32 (EtOAc/hexane,
27
1:1). ½aꢁD ¼ ꢀ22:5 (c 14, CHCl3), IR (KBr): 3428, 3087,
2974, 2930–2868, 1495, 1449, 1406, 1333, 1291,
1110 cmꢀ1 1H NMR (CDCl3) d (ppm): 0.80 (d, 3H,
.
J = 6.5, CHCH3), 1.96 (d, 3H, J = 7.2, NCHCH3),
2.03 (s, 3H, CH3), 2.93–2.99 (m, 1H, CHCH3), 3.74 (d,
1H, J = 13.6, NHCH2), 3.81 (d, 1H, J = 13.6, NHCH2),
4.70 (d, 1H, J = 3.7, CHOH), 5.69 (q, 1H, J = 7.2,
NCHCH3), 5.82 (d, 1H, J = 3.2, CH), 5.99 (d, 1H,
J = 3.7, CH), 7.08 (d, 2H, J = 7.4, ArH), 7.21–7.37 (m,
8H, ArH). 13C NMR (CDCl3) d (ppm): 14.2, 14.6,
19.8, 44.1, 52.6, 57.8, 73.1, 107.2, 107.7, 125.9, 126.1,
126.9, 127.0, 128.0, 128.6, 129.4, 130.1, 141.1, 142.5.
4.3.5. (1S,2R)-2-((5-Methyl-1-((1S)-1-phenylethyl)-1H-
pyrrol-2-yl)methylamino)-1-phenylpropan-1-ol (1S,2R,S)-
5a. Brown oil (2.94 g, 72%). Rf = 0.32 (EtOAc/hexane,
27
1:1). ½aꢁD ¼ þ28:2 (c 11, CHCl3). IR (KBr): 3059, 3054,
2973, 2927, 1493, 1449, 1407, 1291, 1108 cmꢀ1
.
1H
4.4. General procedure for the addition of diethylzinc to
aldehyde
NMR (CDCl3) d (ppm): 0.79 (d, 3H, J = 6.5, CHCH3),
1.95 (d, 3H, J = 7.2, NHCHCH3), 2.05 (s, 3H, CH3),
2.93–2.98 (m, 1H, NHCHCH3), 3.75 (d, 1H, J = 13.6,
NHCH2), 3.82 (d, 1H, J = 13.6, NHCH2), 4.71 (d, 1H,
J = 3.5, CHOH), 5.73 (q, 1H, J = 7.1, NCHCH3), 5.83
(d, 1H, J = 3.1, CH), 5.98 (d, 1H, J = 3.2, CH), 7.11
(d, 2H, J = 7.1, ArH), 7.19–7.38 (m, 8H, ArH). 13C
NMR (CDCl3) d (ppm): 14.2, 14.6, 19.8, 44.1, 52.6,
57.9, 73.1, 107.2, 107.7, 125.9, 126.1, 126.9, 127.0,
127.9, 128.6, 129.4, 130.3, 141.1, 142.5. Anal. Calcd
for C23H15N2O: C, 79.27; H, 8.10; N, 8.04. Found: C,
79.01; H, 7.82; N, 8.09.
To a solution of chiral ligands (1S,2R,S)-4a (0.0174 g,
0.05 mmol) in dry toluene (5 mL) at 0 ꢁC under an argon
atmosphere was added a solution of diethylzinc (2 mL,
1.0 M in hexane) via a syringe. After stirring for 6 h at
0 ꢁC, the aldehyde (0.1 mL, 1.00 mmol) was added into
the mixture. The reaction mixture was stirred at room
temperature and the reaction monitored by TLC. The
reaction was quenched by the addition of 10 mL of
1 M HCl solution. The layers were separated and aque-
ous layer was extracted with dichloromethane
(3 · 20 mL). The combined organic layers were washed
with brine, dried over MgSO4, and the solvent evapo-
rated under reduced pressure. The crude product was
purified by flash column chromatography (silica gel, elu-
ent: EtOAc/hexane, 1:6). (S)-1-Phenylpropan-1-ol was
isolated as a colorless oil in 70% yield with 75% ee.
The ee values were determined by HPLC with a Chiral-
cel-OD column; 2% 2-propanol in hexane, flow rate:
1 mL/min, UV detection (254 nm) tR: 17 min for (R),
19 min for (S). 1H NMR (CDCl3) d (ppm): 0.94 (t,
3H, J = 7.6, CH2CH3), 1.71–1.86 (m, 2H, CH2CH3),
2.12 (s, 1H, OH), 4.58 (t, 1H, J = 6.8, CH), 7.24–7.36
(m, 5H, ArH).
4.3.6. (1R,2S)-2-((5-Methyl-1-((1R)-1-phenylethyl)-1H-
pyrrol-2-yl)methylamino)-1-phenylpropan-1-ol (1R,2S,R)-
5a. Brown oil (2.86 g, 70%). Rf = 0.31 (EtOAc/hexane,
27
1:1). ½aꢁD ¼ ꢀ31:0 (c 10, CHCl3). IR (KBr): 3425, 3060,
2974, 2930–2868, 1495, 1449, 1407, 1291, 1112 cmꢀ1. 1H
NMR (CDCl3) d (ppm): 0.80 (d, 3H, J = 6.5, CHCH3),
1.96 (d, 3H, J = 7.2, NCHCH3), 2.03 (s, 3H, CH3),
2.96–3.00 (m, 1H, NHCHCH3), 3.78 (d, 1H, J = 13.6,
NHCH2), 3.84 (d, 1H, J = 13.6, NHCH2), 4.71 (d, 1H,
J = 3.7, CHOH), 5.69 (q, 1H, J = 7.2, NCHCH3), 5.82
(d, 1H, J = 3.3, CH), 5.99 (d, 1H, J = 3.3, CH), 7.08
(d, 2H, J = 7.4, ArH), 7.19–7.37 (m, 8H, ArH). 13C
NMR (CDCl3): d ppm 14.2, 14.4, 19.6, 44.0, 52.7,
57.8, 73.0, 107.3, 107.8, 125.9, 126.0, 126.9, 126.9,
128.0, 128.6, 129.5, 130.2, 141.2, 142.4.
4.5. General procedure for the addition of diethylzinc to
aldehyde in the presence of Ti(O-i-Pr)4
4.3.7. (1S,2R)-2-((5-Methyl-1-((1R)-1-phenylethyl)-1H-
pyrrol-2-yl)methylamino)-1-phenylpropan-1-ol (1S,2R,R)-
Chiral ligand (0.0174 g, 0.05 mmol) and Ti(O-i-Pr)4
(0.071 g, 0.25 mmol) were mixed in dry toluene at room
temperature. After 1 h, diethylzinc (2 mL, 1.0 M solution
in hexane) was added at 0 ꢁC. The mixture was stirred for
1 h and then benzaldehyde (0.1 mL, 1 mmol) was added
at 0 ꢁC. The mixture was stirred at room temperature for
16 h. The reaction was quenched with saturated ammo-
nium chloride solution, extracted with dichloromethane
(2 · 25 mL), and dried over MgSO4. The purification
of crude product was accomplished by flash column
chromatography (Silica gel, eluent: EtOAc/hexane, 1:6).
5b. Brown oil (2.78 g, 68%). Rf = 0.32 (EtOAc/hexane,
27
1:1). ½aꢁD ¼ þ20:6 (c 15.7, CHCl3). IR (KBr): 3425,
3027, 2976, 2930–2864, 1497, 1451, 1405, 1291,
1112 cmꢀ1 1H NMR (CDCl3) d (ppm): 0.82 (d, 3H,
.
J = 6.5, CHCH3), 1.97 (d, 3H, J = 7.2, NCHCH3),
2.09 (s, 3H, CH3), 2.95–3.01 (m, 1H, NHCHCH3),
3.78 (d, 1H, J = 13.6, NHCH2), 3.85 (d, 1H, J = 13.6,
NHCH2), 4.71 (d, 1H, J = 3.7, CHOH), 5.71 (q, 1H,
J = 7.1, NCHCH3), 5.86 (d, 1H, J = 2.5, CH), 6.00 (d,
1H, J = 3.3, CH), 7.10 (d, 2H, J = 7.6, Ph) 7.19–7.38
(m, 8H, Ph). 13C NMR (CDCl3) d (ppm): 14.2, 14.4,
19.6, 44.0, 52.7, 57.8, 73.0, 107.3, 107.8, 125.9, 126.0,
126.9, 127.0, 128.0, 128.6, 129.4, 130.3, 141.3, 142.5.
Anal. Calcd for C23H15N2O: C, 79.27; H, 8.10; N,
8.04. Found: C, 79.05; H, 7.94; N, 8.13.
4.6. General procedure for the addition of diethylzinc to
chalcone
A solution of Ni(acac)2 (0.026 g, 0.01 mmol) and chiral
ligand (1S,2R,R)-4b (0.069 g, 0.2 mmol) in acetonitrile

C. Unaleroglu et al. / Tetrahedron: Asymmetry 17 (2006) 742–749
749
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was stirred and refluxed for 1 h under an argon atmo-
sphere. The solution was cooled to room temperature
and chalcone (0.208 g, 1 mmol) was added. The mixture
was cooled to ꢀ30 ꢁC and a solution of diethylzinc
(1.5 mL, 1 M solution in hexane) was added. The color
changed from bright green to a dark brown red. Stirring
was continued at ꢀ30 ꢁC for 6 h. The mixture was
quenched with 1 M HCl (10 mL) and extracted with
dichloromethane (3 · 20 mL). The combined organic
layers were washed with brine and dried over MgSO4.
After evaporation of the solvent, crude product was
purified by flash column chromatography (silica gel, elu-
ent: EtOAc/hexane, 1:20). (R)-1,3-Diphenylpentane-1-
one was isolated as light yellow solid in 70% yield with
53% ee. The ee values were determined by HPLC with
a Chiralcel-OD column. 0.5% 2-propanol in hexane,
flow rate: 1 mL/min, UV detector (254 nm) tR:
1
14.11 min for (S), 15.35 min for (R). H NMR (CDCl3)
d (ppm): 0.85 (t, 3H, J = 7.4, CH2CH3), 1.67–1.71 (m,
1H, CH2CH3), 1.80–1.83 (m, 1H, CH2CH3), 3.22–3.30
(m, 3H, CHCH2), 7.18–7.29 (m, 5H, ArH), 7.43–7.45
(m, 2H, ArH), 7.52–7.55 (m, 1H, ArH), 7.90–7.92 (m,
2H, ArH).
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Acknowledgments
This work was financially granted by Hacettepe Univer-
sity (project no. 01G014). A.S.D. thanks for the support
from the Turkish Academy of Sciences (TUBA) and the
¨
Middle East Technical University.
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