Enantioselective addition of diethylzinc to aldehydes catalyzed by β-amino alcohols derived from (1R,2S)-norephedrine

Article abstract of DOI:10.1002/aoc.1583

β-Amino alcohols derived from (1R,2S)-norephedrine were synthesized and used as ligands in the catalytic enantioselective diethylzinc addition to benzaldehydes. N-alkylated (1R,2S)-norephedrine-based derivative 3a gave the highest enantioselectivity. The effects of different parameters on the enantioselectivity of the product were investigated. Copyright

Full text of DOI:10.1002/aoc.1583

Full Paper
Received: 22 June 2009
Revised: 8 October 2009
Accepted: 8 October 2009
Published online in Wiley Interscience: 26 November 2009
(www.interscience.com) DOI 10.1002/aoc.1583
Enantioselective addition of diethylzinc
to aldehydes catalyzed by β-amino alcohols
derived from (1R,2S)-norephedrine
Dilek Isik Tasgin and Canan Unaleroglu∗
β-Amino alcohols derived from (1R,2S)-norephedrine were synthesized and used as ligands in the catalytic enantioselective
diethylzinc addition to benzaldehydes. N-alkylated (1R,2S)-norephedrine-based derivative 3a gave the highest enantioselec-
c
tivity. The effects of different parameters on the enantioselectivity of the product were investigated. Copyright ꢀ 2009 John
Wiley & Sons, Ltd.
Keywords: asymmetric addition; norephedrine; chiral ligands; diethylzinc addition; β-amino alcohol
Introduction
substituent on norephedrine on the catalytic enantioselective
addition of diethylzinc to aldehyde. In this respect, we herein
describe the synthesis of norephedrine-based amino alcohol
ligands bearing pyrrole ring. These ligands were employed in
the asymmetric addition of diethylzinc to aromatic aldehydes to
test their catalytic efficiencies.
Enantioselective addition of diorganozinc reagents to aldehydes
is an important and fundamental synthetic method for the
formation of optically active secondary alcohols.[1] Therefore, a
remarkable number of chiral ligands such as diols,[2] diamines,[3]
aminothiols[4] and aminodisulfides[5] have been developed for
this reaction. Among them, amino alcohols[6] have been widely
used in the enantioselective 1,2-addition reactions. In recent
years, Ephedra-derived amino alcohols have been synthesized and
applied in diethylzinc addition reactions. The catalytic asymmetric
addition of diethylzinc to an aldehyde using the enantiomerically
pure norephedrine-based amino alcohols was first reported by
Soai et al.[7] The synthesized N,N-dialkylnorephedrines catalyzed
the diethylzinc addition with high enantioselectivities. Pyridine,
camphor and phenylfluorenyl-substituted norephedrine- and
pseudonorephedrine-derived amino alcohol-type compounds
have been introduced as new examples of mono N-alkykated
Ephedra-derived ligands (Fig. 1).[8] Substituents on the nitrogen
atom of Ephedra-derived compounds directly influence their
catalytic ability. In this context, Hitchcock et al. published a
detailed work searching for the substituent effect of mono-N-
alkylated norephedrine and pseudonorephedrine derivatives on
theasymmetricinduction.[8b] Anotherstudyevaluating theimpact
of substituents of β-aminoalcohol framework for a variety of
N-fluorenylphenyl was described by Sardina et al.[8c] Only two
examples of N-alkykated Ephedra derivatives were researched
in this study. The outcome of this work indicated that the
nature and stereochemistry of the substituents in N-alkykated
Ephedra derivatives remarkably influence their catalytic activity
and enantioselectivity.
Results and Discussion
Synthesis of Norephedrine-based Chiral Ligands
The norephedrine-based chiral amino alcohol ligands (1R,2S)-
3a[10] and novel (1R,2S)-3b, (1R,2S)-3c, (1R,2S)-4b and (1R,2S)-4c
were prepared as shown in Scheme 1. Pyrrole, N-methylpyrrole
and N-phenylpyrrole were formylated using the Vilsmeier–Haack
method. Condensations of pyrrole-2-carbaldehyde, N-methyl-
pyrrole-2-carbaldehyde and N-phenylpyrrole-2-carbaldehyde
with norephedrine in dry benzene under a Dean–Stark trap af-
forded the corresponding imines. These imines were reduced by
NaBH4 in methanol to their amino alcohols (1R,2S)-3a, (1R,2S)-3b
and (1R,2S)-3c in 70%, 60% and 70% yields, respectively. To ex-
amine the effect of a second alkyl group on norephedrine, amino
alcohols (1R,2S)-3b and (1R,2S)-3c were subjected to alkylation by
treatment with iodobutane in acetonitrile to obtain (1R,2S)-4b,c.
Asymmetric Addition of Diethylzinc to Aldehydes
The synthesized ligands have been employed as chiral ligands
in the asymmetric 1,2-addition of diethylzinc to benzaldehyde.
To determine the best reaction conditions, the activities of
the ligands (1R,2S)-3a and (1R,2S)-3b were tested in different
solvents and at different temperatures. The optimum quantities
of the ligands were found by changing their percentage in
We have recently reported the synthesis of chiral pyrrole
substituted norephedrine-based ligands and their application in
the enantioselective addition of diethylzinc to aldehydes.[9] We
foundthattheabsoluteconfigurationofnorephedrinedetermined
the stereochemistry of the products while the structural motif of
the substituent on norephedrine affected the efficiency of catalyst.
The results indicated that pyrrole framework on the ligands has an
impact on the asymmetric induction. Based on this observation,
we became interested in examining the effect of the pyrrole
∗
Correspondence to: Canan Unaleroglu, Hacettepe University, Chemistry
Department, Beytepe Campus, Ankara 06800, Turkey.
E-mail: canan@hacettepe.edu.tr
Hacettepe University, Department of Chemistry, 06800 Ankara, Turkey
c
Appl. Organometal. Chem. 2010, 24, 33–37
Copyright ꢀ 2009 John Wiley & Sons, Ltd.

D. I. Tasgin and C. Unaleroglu
R2
OH
R1
H3C
Ph
H
H
OH
NH
N
H
N
N
H
CH3
Ph
R1
CH3
[8a] (Wu et al.)
OH
R2
R1=Ph, R2=H [8b] (Hitchcock et al.)
R1=H, R2=Ph [8b]
R1=Ph, R2=H [8c] (Sardina et al.)
R1=H, R2=Ph [8c]
Figure 1. N-alkykated ephedra-derived ligands.
H
CH3
CH3
i
iv
ii, iii
O
N
N
*
*
*
*
N
R
N
R
N
R
N
H
R
HO
HO
1a=R: H
1b=R: CH3
1c=R: C6H5
2a-c
(1R,2S)-4b,c
(1R,2S)-3a-c
Scheme 1. Reagents and conditions: (i) DMF, POCl3, 0 ◦C to reflux; (ii) norephedrine, benzene, reflux; (iii) NaBH4, methanol, reflux; (iv) butyl iodide, K2CO3,
CH3CN, reflux.
toluene–hexane mixtures. The results are reported in Table 1.
Solvent optimization studies (Table 1, entries 1–4 and 8–11)
revealed that toluene–hexane mixture (1 : 1) at 0 ◦C to room
temperature provided ideal conditions (Table 1, entries 3 and
10). The ligands gave higher yields but lower enantioselectivities
in hexane (Table 1, entries 2, 9). Very low yields and lower
enantioselectivities were obtained in dichloromethane (Table 1,
entries 4 and 11). The effect of the catalyst amounts on
enantioselectivity was studied at 0 ◦C to room temperature
(Table 1, entries 3, 5, 6, 10, 12 and 13). The best results for
(1R,2S)-3a (78% ee) and (1R,2S)-3b (64% ee) were obtained with
5 mol% of catalyst (Table 1, entries 3 and 10). Performing the
reactions at 0 ◦C in toluene–hexane mixture with (1R,2S)-3a and
(1R,2S)-3b mainly affected the product yields (Table 1, entries 7
and 14). These results indicated that at 0 ◦C to room temperature,
5 mol% of catalyst in toluene–hexane (1 : 1) mixture are the best
conditions to obtain the highest enantioselectivity and these
conditions have been chosen for further studies. The ligand
(1R,2S)-3a bearing only unsubstituted pyrrole ring catalyzed the
reaction with higher enantiomeric excess (78%) than (1R,2S)-3b
(64% ee), which bears N-methyl substituted pyrrole. In order
to study the effect of steric hindrance, we have synthesized
(1R,2S)-3c bearing N-phenyl substituted pyrrole and tested its
catalytic efficiency. This ligand afforded the secondary alcohol
with 61% enantiomeric excess in 96% yield (Table 1, entry 16). The
highest enantiomeric excess (78%) was obtained with (1R,2S)-3a.
(1R,2S)-3b and (1R,2S)-3c gave the secondary alcohol with lower
enantiomeric excess (64 and 61%, respectively). In our previous
work,[9] we obtained a similar result with (1R,2S,R)-5a, which has
a similar skeleton to the ligands in this study. This is explicable
on the basis of the steric hindrance differences between the
structures of (1R,2S)-3a and (1R,2S)-3b,c ligands. It seems that
(1R,2S)-3a forms a well-organized organometallic complex which
gives rise to a good asymmetric induction in this catalytic system.
(1R,2S)-3a,(1R,2S)-3band(1R,2S)-3cafforded1-phenyl-1-propanol
with (R)-configuration. These observations are in agreement
with our previous results,[9] and also with the observation of
Hitchcock et al.[8b] and Sardina et al.[8c] In order to improve the
effect of a second substituent on (1R,2S)-3b and (1R,2S)-3c, we
further synthesized N-(1H-pyrrol-2-yl)methyl, N-butyl substituted
norephedrine derivative (1R,2S)-4b and (1R,2S)-4c. Efficiency of
these ligands was tested under the optimized conditions (Table 1,
entries 15 and 16). These catalytic systems afforded the products
with the lowest enantioselectivities (Table 1, entries 15 and 16). It
appears that the more sterically crowded structure of (1R,2S)-4b
and (1R,2S)-4c leads to a decrease in the enantioselectivity of the
reaction.
When these results are compared with those of the previously
published mono N-substituted (1R,2S)-norephedrine derivatives,
the catalytic efficiency of pyrrole substituted (1R,2S)-3a was found
superior to that of pyridine-substituted (1R,2S)-norephedrine
(3.3% ee)[8a] and much higher than that for N-fluorenylphenyl
substituted (1R,2S)-norephedrine (29% ee).[8c] On the other hand,
the easily obtained ligand, (1R,2S)-3a, affords 1-phenyl-1-propanol
with a comparable enantioselectivity to camphor[8b] and chiral
pyrrole-substituted norephedrine ligands.[9]
The enantioselective addition of diethylzinc to aldehydes
catalyzed by (1R,2S)-3a and (1R,2S)-3b were also tested in the
presence of additives. The additives caused adverse effects on the
yield and enantioselectivity of the reaction. A slight improvement
was observed in the yield of the reaction only with the ligand
(1R,2S)-3a in the presence of LiCl (Table 2).
The catalytic efficiency of the ligands (1R,2S)-3a and (1R,2S)-3b
was also tested in the addition of diethyzinc to substituted ben-
zaldehydes. The results shown in Table 3 demonstrated that the
substituentsofthephenylgrouphavenoticeableelectroniceffects
on the yields and enantioselectivities. Electron donating methoxy
group drastically lowered the yield and enantioselectivity (Table 3,
entries 2 and 7) and a slight decrease in the enantioselectivity of
product was observed with p-chloro substituted benzaldehyde
(Table 3, entries 3 and 8). Strongly electron withdrawing group
bearing p-nitrobenzaldehyde gave a disappointingly low enan-
tiomeric excess with both of the ligands (1R,2S)-3a and (1R,2S)-3b
(Table 3, entries 5 and 10). Similar results were reported for chiral
bis(amino alcohol)oxalamide ligand (5% ee) by Pedro et al.,[13]
and for 2-amino-substituted 1-sulfinylferrocenes chiral ligand
(26–28% ee) by Carretero et al.[14] The best enantioselectivity
c
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Copyright ꢀ 2009 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2010, 24, 33–37

Enantioselective addition of diethylzinc to aldehydes
Table 1. Asymmetric addition of diethylzinc to benzaldehydea
OH
O
H
Et2Zn
ligand
Entry
Ligand
Solvent
Toluene
Ligand (%)
Yieldb (%)
Eec (%)
Configurationd
1
(1R,2S)-3a
(1R,2S)-3a
(1R,2S)-3a
(1R,2S)-3a
(1R,2S)-3a
(1R,2S)-3a
(1R,2S)-3a
(1R,2S)-3b
(1R,2S)-3b
(1R,2S)-3b
(1R,2S)-3b
(1R,2S)-3b
(1R,2S)-3b
(1R,2S)-3b
(1R,2S)-3c
(1R,2S)-4b
(1R,2S)-4c
5
5
35
77
70
17
86
89
10e
55
75
73
35
70
72
16e
96
27
45
74
64
78
27
66
72
60
41
54
64
53
45
60
64
61
20
30
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
2
Hexane
3
Toluene + hexane
DCM
5
4
5
5
Toluene + hexane
Toluene + hexane
Toluene + hexane
Toluene
2.5
10
5
6
7
8
5
9
Hexane
5
10
11
12
13
14
16
15
16
Toluene + hexane
DCM
5
5
Toluene + hexane
Toluene + hexane
Toluene + hexane
Toluene + hexane
Toluene + hexane
Toluene + hexane
2.5
10
5
5
5
5
a Unless otherwise noted reaction was performed at 0 ◦C to room temperature.
b Yield refers to pure product after column chromatography.
c The ee values were determined by HPLC with a Chiralcel OD column; 3% 2-propanol in hexane, flow rate 0.7 ml min−1, UV detection (254 nm), tR
12.3 min for (R), 13.2 min for (S).
d The configuration of the main enantiomer was assigned according to the literature.[11]
e Reaction was performed at 0 ◦C.
Table 2. The addition of diethylzinc to benzaldehyde in the presence of additives in toluene–hexane mixture (1 : 1)
Entry
Ligand
Additive
LiCl (0.5 mmol)
Yielda (%)
eeb (%)
Configurationc
1
(1R,2S)-3a
(1R,2S)-3a
(1R,2S)-3a
(1R,2S)-3a
(1R,2S)-3a
(1R,2S)-3b
(1R,2S)-3b
(1R,2S)-3b
(1R,2S)-3b
(1R,2S)-3b
86
56
49
54
77
70
26
39
35
61
75
25
15
35
32
53
60
19
49
57
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
2
CuCl (0.5 mmol)
3
CuBr (0.5 mmol)
4
BuLi (0.1 mmol)
5
BuLi+LiCl (0.1 mmol + 0.5 mmol)
LiCl (0.5 mmol)
6
7
CuCl (0.5 mmol)
8
CuBr (0.5 mmol)
9
BuLi (0.1 mmol)
10
BuLi+LiCl (0.1 mmol + 0.5 mmol)
a Yield refers to pure product after column chromatography.
b The ee values were determined by HPLC with a Chiralcel OD column; 3% 2-propanol in hexane, flow rate 0.7 ml min−1, UV detection (254 nm), tR
12.3 min for (R), 13.2 min for (S).
c The configuration of the main enantiomer was assigned according to the literature.[11]
(84% ee) was achieved with p-bromo substituted benzaldehyde
using (1R,2S)-3a as ligand. (Table 3, entry 4).
the mono N-alkylated norephedrine based ligands, the easily
obtained (1R,2S)-3a afforded the product with the highest enan-
tioselectivity. Our studies have shown that the structure of the
substituent on the nitrogen atom of norephedrine has a signifi-
cant effect on catalytic activity. When the nitrogen substituents
were large in size as N-substituted pyrrole ligands, enantioselectiv-
ity was diminished. Finally, we have demonstrated that the easily
obtained pyrrole substituted norephedrine ligand is capable of
alkylating the aldehydes with high enantioselectivity (ee up to
Conclusions
In summary, we have prepared N- and N,N-substituted
norephedrine based ligands and successfully applied them in the
enantioselective 1,2-addition of diethylzinc to aldehydes. Among
c
Appl. Organometal. Chem. 2010, 24, 33–37
Copyright ꢀ 2009 John Wiley & Sons, Ltd.
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D. I. Tasgin and C. Unaleroglu
monitored by TLC. Then the mixture was cooled and the solvent
was evaporated. Crude products were washed with benzene.
Synthesized imines (1.22 mmol) were dissolved in 10 ml methanol
and added to a suspension of NaBH4 (0.051 g, 1.35 mmol) in 2 ml
methanol. The mixture was refluxed for 8 h and monitored by
TLC. When the reaction was completed, the mixture was cooled to
room temperature and quenched with 15 ml water. The mixture
was extracted with ether (3 × 10 ml) and dried over MgSO4.
The mixture was filtered and the solvent was evaporated. Crude
products (1R,2S)-3a, (1R,2S)-3b and (1R,2S)-3c were purified by
flash column chromatography (ethyl acetate–hexane 1 : 1).
(1R,2S)-2-[(1H-Pyrrol-2-yl)methylamino]-1-phenylpropan-1-ol
Table 3. The addition of diethylzinc to substituted benzaldehydes in
toluene–hexane mixture (1 : 1)
Yielda ee
Entry Ligand
Aldehyde
(%) (%) Configurationf
1
(1R,2S)-3a Benzaldehyde
70
78
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
2
(1R,2S)-3a p-MeO-benzaldehyde 10 20b
3
(1R,2S)-3a p-Cl-benzaldehyde
(1R,2S)-3a p-Br-benzaldehyde
(1R,2S)-3a p-Nitrobenzaldehyde
(1R,2S)-3b Benzaldehyde
50 75c
52 84d
4
5
55
73
4e
64
33
59
65
9
6
7
(1R,2S)-3b p-MeO-benzaldehyde 27
30
[(1R,2S)-3a]: yield 0.20 g, 70%. Viscous oil. [α]D = +13.3 (c 11.3,
8
(1R,2S)-3b p-Cl-benzaldehyde
(1R,2S)-3b p-Br-benzaldehyde
(1R,2S)-3b p-Nitrobenzaldehyde
52
60
39
CHCl3). Rf = 0.13 (ethyl acetate–hexane 2 : 1). 1H NMR (400 MHz,
CDCl3) δ: 9.01 (s, 1H, NH), 7.37–7.26 (m, 5H, Ar–H), 6.63–6.62
(m, 1H, pyrrole–H), 6.11–6.09 (m, 1H, pyrrole–H), 6.03 (br s, 1H,
pyrrole–H), 4.77 (d, 1H, J = 3.6 Hz, CHOH), 3.91 (d, 1H, J = 13.2 Hz,
NHCH2), 3.83 (d, 1H, J = 13.2 Hz, NHCH2), 2.99–2.93 (m, 1H,
CHCH3), 0.93 (d, 3H, J = 6.4 Hz, CH3). 13C NMR (100 MHz, CDCl3) δ:
141.6 (Ar–C), 129.6 (pyrrole–C), 128.2, 127.2, 126.1 (Ar–C), 117.7,
108.1, 106.9 (pyrrole–C), 74.1(CH–OH), 58.0(CH–CH3), 44.3(CH2),
14.1(CH3). IR (KBr) υ (cm−1) 3389, 2978, 2932, 2872, 2062, 1638,
1450, 1379, 1104, 1026. Anal. calcd for C14H18N2O: C, 73.01; H,
7.88; N, 12.16. Found: C, 72.94; H, 7.50; N, 11.89.
9
10
a Yield refers to pure product after column chromatography.
b The ee values were determined by HPLC with a Chiralcel OD
column; 3% 2-propanol in hexane, flow rate 0.7 ml min−1, UV detection
(254 nm), tR 19.8 min for (R), 22.5 min for (S).
c The ee values were determined by HPLC with a Chiralcel OD
column; 3% 2-propanol in hexane, flow rate 0.7 ml min−1, UV detection
(254 nm), tR 14.9 min for (S), 15.8 min for (R).
d The ee values were determined by HPLC with a Chiralcel OD
column; 3% 2-propanol in hexane, flow rate 0.7 ml min−1, UV detection
(254 nm), tR 15.4 min for (S), 16.2 min for (R).
e The ee values of their benzoate derivative were determined by HPLC
with a Chiralpak AD column; 10% 2-propanol in hexane, flow rate
0.5 ml min−1, UV detection (254 nm), tR 15.5 min for (R), 28.8 min for
(S).
(1R,2S)-2-[(1-methyl-1H-pyrrol-2-yl)methylamino]-1-phenyl-
propan-1-ol [(1R,2S)-3b]: yield 0.18 g, 60%. Viscous oil.
30
[α]D = −21.3 (c 28.8, CHCl3). Rf = 0.19 (ethyl acetate–hexane
1 : 1). 1H NMR (400 MHz, CDCl3) δ: 7.37–7.25 (m, 5H, Ar–H),
6.61–6.59 (m, 1H, pyrrole–H), 6.06–6.04 (m, 2H, pyrrole–H), 4.75
(d, 1H, J = 3.9 Hz, CHOH), 3.88 (d, 1H, J = 13.4 Hz, NHCH2), 3.83
(d, 1H, J = 13.4 Hz, NHCH2), 3.68 (s, 3H, CH3), 3.06–3.00 (m, 1H,
CHCH3), 2.41 (br s, 1H, CHOH), 0.91 (d, 3H, J = 6.5 Hz, CH3). 13C
NMR (100 MHz, CDCl3) δ: 141.4 (Ar–C), 129.8 (pyrrole–C), 128.1,
127.1, 126.1 (Ar–C), 122.6, 108.6, 106.9 (pyrrole–C), 73.1 (CH–OH),
58.1 (CH–CH3), 43.0 (CH2 NH), 33.7(N–CH3), 14.3(CH3). IR (KBr)
υ (cm−1) 3443, 2976, 2931, 2871, 1642, 1494, 1452, 1379, 1301,
1128, 704. Anal. calcd for C15H20N2O: C, 73.74; H, 8.25; N, 11.47.
Found: C, 73.35; H, 7.89; N, 11.29.
f The configuration of the main enantiomer was assigned according to
the literature.[11,12]
84%), and can be regarded as a good candidate for asymmet-
ric induction in view of the availability of both enantiomers of
norephedrine.
Experimental
General Methods
(1R,2S)-1-phenyl-2-[(1-phenyl-1H-pyrrol-2-yl)methylamino]
propan-1-ol [(1R,2S)-3c]: yield 0.26 g, 70%. Viscous oil.
All chemicals were purchased from Aldrich, and Sigma. Solvents
weredriedbeforeuseaccordingtostandardprocedures.Reactions
were monitored by thin-layer chromatography using precoated
silica plates (Kieselgel 60, F254, E. Merck), visualized with UV-
light. Flash column chromatography was employed using silica
gel (0.05–0.63 mm, 230–400 mesh ASTM, E. Merck). 1H NMR and
13C NMR spectra were performed on Brucker DPX-400, ultra shield,
400 MHz high performance digital FT-NMR spectrometer using
CDCl3 as solvent and tetramethylsilane (TMS) as internal standard.
Infrared spectra were recorded on a system 2000 Perkin-Elmer
spectrophotometer. All melting points were measured in sealed
tubes using an electrothermal digital melting point apparatus
(Gallenkamp). Enantiomeric excesses were determined by HPLC,
Thermo Finnigan equipped with an appropriate chiral phase
column (Chiralcell OD). Elemental analyses were done by using a
LECO CHNS-932 device.
30
[α]D = −68.9 (c 4.6, CHCl3). Rf = 0.23 (ethyl acetate–hexane
1 : 1). 1H NMR (400 MHz, CDCl3) δ: 7.45–7.35 (m, 5H, Ar–H),
7.27–7.12 (m, 5H, Ar–H), 6.77 (br s, 1H, pyrrole–H), 6.18 (br s, 2H,
pyrrole–H), 4.53 (d, 1H, J = 3.2 Hz, CHOH), 3.83 (s, 2H, NHCH2),
2.80–2.76 (m, 1H, CHCH3), 0.66 (d, 3H, J = 6.8 Hz, CH3). 13C
NMR (100 MHz, CDCl3) δ: 141.2, 140.3 (Ar–C), 131.2 (pyrrole–C),
129.3, 128.0, 127.5, 126.9, 126.1, 125.8 (Ar–C), 122.8, 109.8, 108.3
(pyrrole–C), 72.7 (CHOH), 57.6 (CHCH3), 43.0 (CH2 NH), 14.4 (CH3).
IR (KBr) υ (cm−1) 3357, 3064, 2969, 2927, 2855, 1597, 1499, 1451,
1324, 1195, 695. Anal. calcd for C20H22N2O: C, 78.40; H, 7.24; N,
9.14. Found: C, 78.00; H, 7.49; N, 9.12.
General Procedure for the Synthesis of N-butyl Substituted
Amino Alcohols
To a solution of (1R,2S)-3b or (1R,2S)-3c (3.48 mmol) in 5 ml
acetonitrile was added K2CO3 (0.96 g, 6.97 mmol) and butyl iodide
(0.79 ml, 6.97 mmol). The suspension was refluxed for 6 h and
the reaction was monitored by TLC. The mixture was cooled to
room temperature and quenched with 15 ml water. The mixture
was extracted with ether (3 × 10 ml) and dried over MgSO4
and concentrated under reduced pressure. Crude products was
General Procedure for the Synthesis of Amino Alcohols
Pyrrole-2-carbaldehydes (5.26 mmol) were dissolved in 10 ml
of benzene. To this solution was added (1R,2S)-norephedrine
(0.873 g, 5.78 mmol) under nitrogen atmosphere. The mixture
was refluxed under a Dean–Stark trap for 8 h. Reaction was
c
www.interscience.wiley.com/journal/aoc
Copyright ꢀ 2009 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2010, 24, 33–37

Enantioselective addition of diethylzinc to aldehydes
purified by flash column chromatography [ethyl acetate–hexane
1 : 6 (for 4b), ethyl acetate–hexane 1 : 1 (for 4c)].
J = 7.6 Hz, CH3). 13C NMR (100 MHz, CDCl3) δ: 144.7, 128.4, 127.4,
125.9 (Ar–C), 76.0 (CHOH), 31.9 (CH2CH3), 10.2 (CH2CH3).
(1R,2S)-2-{butyl[(1-methyl-1H-pyrrol-2-yl)methyl]amino}-1-
phenylpropan-1-ol (1R,2S) (4b): yield 0.31 g, 30%. Viscous oil.
Acknowledgments
30
[α]D = +41.1 (c 5.9, CHCl3). Rf = 0.34 (ethyl acetate–hexane
1 : 3). 1H NMR (400 MHz, CDCl3) δ: 7.32–7.16 (m, 5H, Ar–H),
6.51–6.50 (m, 1H, pyrrole–H), 6.06–6.00 (m, 2H, pyrrole–H), 4.59
(d, 1H, J = 6.4 Hz, CHOH), 3.65 (d, 1H, J = 13.6 Hz, NHCH2),
3.48 (d, 1H, J = 13.6 Hz, NHCH2), 3.27 (s, 3H, CH3), 3.17–3.10
(m, 1H, CHCH3), 2.57–2.50 (m, 1H, CH2 CH2N), 2.40–2.33 (m,
1H, CH2CH2N), 1.42–1.34 (m, 2H, CH2CH2CH3), 1.29–1.24 (m,
2H, CH2CH2CH3), 1.09 (d, 3H, J = 6.8 Hz, CHCH3), 0.94 (t, 3H,
J = 7.2 Hz, CH2CH3). 13C NMR (100 MHz, CDCl3) δ: 143.3 (Ar–C),
129.2 (pyrrole–C), 127.7, 126.5, 125.9 (Ar–C), 122.1, 109.4, 106.0
(pyrrole–C), 75.0 (CHOH), 58.7 (CHCH3), 49.6 (CH2N), 47.1 (CH2N),
33.2 (NCH3), 29.5 (CH2CH2), 20.3 (CH3CH2), 13.8 (CH3CH2), 8.7
(CH3CH). IR (KBr) υ (cm−1) 3425, 3022, 2954, 2927, 2866, 2798,
1706, 1661, 1497, 1452, 1300, 1011, 703. Anal. calcd for C19H28N2O:
C, 75.96; H, 9.39; N, 9.32. Found: C, 75.59; H, 9.17; N, 9.57.
The authors thank Hacettepe University for financial support (BAP
project 01G014).
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(1R,2S)-2-{butyl[(1-phenyl-1H-pyrrol-2-yl)methyl]amino}-1-
phenylpropan-1-ol (1R,2S)-4c: yield 0.44 g, 35%. Viscous oil.
30
[α]D = +23.2 (c 7.7, CHCl3). Rf = 0.84 (ethyl acetate–hexane
1 : 1). 1H NMR (400 MHz, CDCl3) δ: 7.39–7.10 (m, 10H, Ar–H),
6.74 (br s, 1H, pyrrole–H), 6.18 (br s, 2H, pyrrole–H), 4.51 (d, 1H,
J = 4.0 Hz, CHOH), 3.66 (d, 1H, J = 16.0 Hz, NCH2), 3.46 (d, 1H,
J = 16.0 Hz, NCH2), 3.07–3.01 (m, 1H, CHCH3), 2.60 (br s, 1H,
OH), 2.32–2.26 (m, 1H, CH2CH2N), 2.22–2.15 (m, 1H, CH2CH2N),
1.11–1.03 (m, 4H, CH2CH2CH3), 0.82 (d, 3H, J = 8.0 Hz, CHCH3),
0.78 (t, 3H, J = 8.0 Hz, CH2CH3). 13C NMR (100 MHz, CDCl3) δ:
142.6, 140.3 (Ar–C), 130.3 (pyrrole–C), 129.0, 127.8, 127.2, 126.8,
126.2, 126.1 (Ar–C), 122.9, 110.9, 107.9 (pyrrole–C), 73.9 (CHOH),
59.2 (CHCH3), 50.1 (CH2CH2N), 47.1 (CH2N), 29.6 (CH2CH2N), 20.4
(CH2CH3), 14.0 (CH3CH2), 9.3 (CH3CH). IR (KBr) υ (cm−1) 3437,
3026, 2954, 2923, 2809, 1592, 1497, 1178, 695. Anal. calcd for
C24H30N2O: C, 79.52; H, 8.34; N, 7.73. Found: C, 79.29; H, 8.70; N,
7.48.
General Procedure for the Enantioselective Diethylzinc Addi-
tion to Aldehydes
To a solution of chiral ligand [3a, 3b,3c,4b or 4c] (0.05 mmol)
in dry toluene–hexane mixture (5 ml) at 0 ◦C under the argon
atmosphere was added a solution of diethylzinc (2.2 mmol, 1.0 M
in hexane) via a syringe over a period of 5 min. After stirring for
5 h at the same temperature the aldehyde (0.1 ml, 1 mmol) was
added at 0 ◦C. The reaction mixture was stirred for 16 h at room
temperature and monitored by TLC. The reaction was quenched
with 5 ml of 1 M HCl solution. The organic layer was separated
and aqueous layer was extracted with ether (3 × 15 ml). The
combined organic layers were washed with 10 ml of brine, dried
over anhydrous MgSO4 and the solvent was evaporated under
reduced pressure. The crude product was purified by flash column
chromatography (EtOAc–hexane, 1 : 6).
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c
Appl. Organometal. Chem. 2010, 24, 33–37
Copyright ꢀ 2009 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/aoc