β-Hydroxyamide derivatives of salicylic acid as organocatalysts for enantioselective reductions of prochiral ketones

Article abstract of DOI:10.1016/j.tetasy.2013.05.016

In order to find the most effective catalyst for the enantioselective reduction of a prochiral ketone, a series of novel β-hydroxyamide derivatives of salicylic acid and chiral amino alcohols were synthesized. Different substituted prochiral ketones have been reduced in high yield (up to 99%) and the corresponding secondary alcohols are formed with good enantiomeric excess (up to 86%). The mechanism of this type of catalyst can be explained by considering the reaction mechanism for the CBS catalyst.

Full text of DOI:10.1016/j.tetasy.2013.05.016

Tetrahedron: Asymmetry xxx (2013) xxx–xxx
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
b-Hydroxyamide derivatives of salicylic acid as organocatalysts
for enantioselective reductions of prochiral ketones
⇑
Yılmaz Turgut , Murat Azizoglu, Aslı Erdogan, Nevin Arslan, Halil Hosgoren
Chemistry Department, Science Faculty, Dicle University, 21280 Diyarbakir, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
In order to find the most effective catalyst for the enantioselective reduction of a prochiral ketone, a series
of novel b-hydroxyamide derivatives of salicylic acid and chiral amino alcohols were synthesized. Differ-
ent substituted prochiral ketones have been reduced in high yield (up to 99%) and the corresponding sec-
ondary alcohols are formed with good enantiomeric excess (up to 86%). The mechanism of this type of
catalyst can be explained by considering the reaction mechanism for the CBS catalyst.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 24 April 2013
Accepted 24 May 2013
Available online xxxx
1. Introduction
the enantiotopic faces of the carbonyl compound and the affinity
of the ketone binding to boron due to the increased Lewis acidity
The synthesis of optically active compounds has become an
important area of research for pharmaceutical industries and
academic research institutions, as it is frequently observed that
individual enantiomers of a chiral drug molecule display contrast-
ing biological activities.1 This has forced organic chemists to
develop efficient and highly selective catalysts for the synthesis
of single enantiomers through asymmetric reactions. Among the
variety of asymmetric reactions leading to enantiomerically
pure alcohols, the enantioselective reduction of prochiral ketones
with borane in the presence of a chiral ligand has received
considerable attention.2 The reduction of ketones to enantiomeri-
cally enriched alcohols is a fundamental transformation in
synthetic organic chemistry.3 After Itsuno et al’s. pioneering work
in this field in the early 1980s,4 many asymmetric catalyst
systems have been investigated. Among them, the CBS
(Corey–Bakshi–Shibata) catalyst system developed by Corey
et al.5 attracts most attention from the scientific community for
its excellent enantioselectivity.
of the coordinated boron atom.13
There is a continuing interest in the development of new triden-
tate chiral ligands to be tested in the enantioselective borane
reduction of prochiral ketones. In order to obtain tridentate chiral
ligands, we synthesized b-hydroxyamide ligands 1–7 from salicylic
acid and commercially available amino alcohols and tested their
catalytic activity for the enantioselective borane reduction of pro-
chiral ketones.
2. Results and discussion
Hydroxy amides are anti-convulsants14
thrombin inhibitors,15 and RAR- -specific retinoid agonists16
hydroxy amides). They are also intermediates for the synthesis of
oxazolidinediones,17 oxindoles18 -hydroxy amides), b-lactams19
(a-hydroxyamides),
c
(a-
(a
(b-hydroxy amides), and antidepressant drugs, for example, (R)-
fluoxetine (b-hydroxy amides), and building blocks for the synthe-
sis of various natural products.20
Considering the potential coordination and H-bond donation
ability of b-hydroxyamides, some of them have been applied to
asymmetric catalysis as ligands or catalysts.21 With this analogy
in mind, chiral b-hydroxyamide ligands 1–7 were prepared from
salicylic acid and commercially available amino alcohols in two
steps (Scheme 1). First, salicylic acid was chlorinated with thionyl
chloride22 and then reacted, without purification, with chiral ami-
no alcohols in the presence of triethylamine to give b-hydroxya-
mide ligands 1–7 in moderate to good yields (40–72%)
(Scheme 1). The structures of all novel compounds were confirmed
by spectroscopic and elemental analyses.
In addition to a CBS system, other catalysts such as hydroxyl-
amides,6 sulfonamides,7 and phosphinamides,8and prolinol-
squaramides9 have also been developed as efficient catalysts for
the asymmetric reduction of ketones. As important intermediates
in the preparation of chiral oxazoline ligands,10 thiazoline li-
gands,11 and imidazoline ligands,12 many chiral b-hydroxyamides
have been synthesized from carboxylic acids and amino alcohols.
Considering the potential coordination and H-bond donation abil-
ity of b-hydroxyamides,6b some of them have been applied to
asymmetric catalysis as ligands or catalysts. In principle, bicyclic
oxazaborolidines obtained from tridentate ligands containing one
nitrogen and one oxygen atom can increase the differentiation of
Many catalysts have been developed for the borane asymmetric
reduction of ketones.21,23–27 With the desired ligands in hand, we
tested their catalytic activity in the asymmetric borane reduction
of a prochiral ketone.
⇑
Corresponding author. Tel.: +90 (412) 2488550; fax: +90 (412) 2488300.
E-mail address: yturgut@dicle.edu.tr (Y. Turgut).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.05.016
Please cite this article in press as: Turgut, Y.; et al. Tetrahedron: Asymmetry (2013), http://dx.doi.org/10.1016/j.tetasy.2013.05.016

2
Y. Turgut et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
O
N
H
OH
OH
3
ii
O
O
R1
O
R2
R3
R4
OH
Cl
i
N
ii
H
OH
OH
OH
OH
ii
1: R1 = Ph, R2 = R3 = R4 = H
1
2
3
4
2:
R = Bn, R = R = R = H
4: R1 = (CH3)2CH-, R2 = H, R3 = R4 = Ph
O
1
2
3
R = H, R = R = R4 = Ph
5:
6: R1 = H, R2 = Bn, R3 = R4 = Ph
N
H
HO
OH
7
Scheme 1. b-Hydroxyamides. Reagents and conditions: (i) SOCl2, reflux, 8 h; (ii) Et3N, amino alcohol, DCM, 0 °C, 0.5 h, then 25 °C, 24 h.
Generally, there are four key steps for the asymmetric borane
binds to the ketone substrate, for example, acetophenone, at the
more sterically accessible electron lone pair ( in the case of aceto-
reduction (Scheme 2):5,23d,28,31 The mechanistic model explains;
(i) the absolute stereochemistry of the reduction; (ii) the excellent
enantioselectivity obtained for the reduction; (iii) the excellent
rate enhancement of the reduction; and (iv) the turnover of the
catalyst. The initial step in the pathway is the rapid (and probably
reversible) coordination of BH3 to the Lewis basic nitrogen atom on
a
phenone) and cis to the vicinal BH3 group 3. This binding manner
minimizes the unfavorable steric interactions between the oxaz-
aborolidine and the ketone, and aligns the electronically deficient
carbonyl carbon atom and the coordinated BH3 for the stereoelec-
tronically favorable, face-selective hydride transfer via a six-mem-
bered transition state to form the reduction product 4. Thus, the
rate enhancement for the oxazaborolidine-catalyzed reduction is
due to the activation of the stoichiometric reducing agent BH3 by
coordination with the Lewis basic nitrogen atom of 1 with simulta-
neous intensification of the Lewis acidity of the boron atom in the
the
a face of oxazaborolidine 1 to form the cis-fused oxazaboroli-
dine.BH3 complex 2. The coordination of the electrophilic BH3 to
the nitrogen atom of 1 serves to activate BH3 as a hydride donor
and also to strongly increase the Lewis acidity of the endocyclic
boron atom. The strongly Lewis acidic complex 2 then readily
Ph
Ph
H
N
Ph
Ph
H
BH3·THF
i
O
O
B
2
N
B
1
R
H3B
R
H2BO
H
Ph
Ph
H
N
CH3
O
O
+
_
5
CH3
B
R
H2B
ii
O
CH3
iv
H
HCl, MeOH
B
H
Ph
H
H
6
BH3
Ph
Ph
R
O
_
B
R
O
HO
H
CH3
O
B
N
CH3
N
+
Ph
CH3
O
H2B
Ph
iii
H
H2B
H
4
3
Scheme 2. General accepted mechanism for the oxazaborolidine-catalyzed enantioselective reduction of ketones.
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Y. Turgut et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
3
Table 2
heterocycle for coordination to the ketone. This leads to subse-
quent enthalpically and entropically favorable face selective intra-
molecular hydride transfer.29 Dissociation of the reduction product
4 to regenerate the oxazaborolidine catalyst may occur by two dif-
ferent pathways: (1) reaction of the alkoxide ligand attached to the
endocyclic boron atom with the adjacent boron atom of 4 to regen-
erate 1 and form the borinate 5 by cycloelimination;30,31 or (2) by
the addition of BH3 to 4 to form a six-membered BH3-bridged spe-
cies 6, which decomposes to produce the catalyst-BH3 complex 2
and borinate 5.32 The facile disproportionation of 5 to afford dial-
koxyborane (RO)2BH and BH3 allows the efficient use of the three
hydrogen atoms of the stoichiometric reductant.33
Effect of the length of the catalyst generating period on the enantioselective reduction
of acetophenone with BH3ꢀS(Me)2 using b-hydroxyamide 7
Entry Catalyst generating period
(min)
Solvent Temp
Yield
(%)
ee
(%)
(°C)
1
2
3
4
5
20
30
40
50
60
THF
THF
THF
THF
THF
65
65
65
65
65
78 75
83 77
85 80
86 85
87 86
The structure of oxazaborolidine and the proposed mechanism
of prochiral ketone reduction are shown in Figure 1.
Initially, b-hydroxyamide 7 was selected as the catalyst and the
reduction of acetophenone was used as a model substrate in the
screening. The results are depicted in Table 1.
H
R1
O
O
RL
RS
OH
Table 1
B
N
B
H
OH
Effect of the catalyst amount, solvent, and temperature on the enantioselective
reduction of acetophenone with BH3ꢀS(Me)2 using b-hydroxyamide 7
O
or
R2
Entry
Cat. amount (%)
Solvent
Temp (°C)
Yielda (%)
eeb (%)
O
1
2
3
4
5
6
7
8
9
5
10
20
10
10
10
10
10
10
10
10
THF
THF
THF
Toluene
Toluene
Toluene
Toluene
THF
65
65
65
25
50
65
110
0
99
99
99
97
98
98
98
99
99
99
99
70
85
78
35
56
54
56
15
53
82
85
Figure 1. Proposed mechanism for the prochiral ketone reduction.
With the optimized conditions in hand, we tested b-hydroxya-
mides 1–7 in the asymmetric borane reduction of different substi-
tuted aromatic prochiral ketones, and the results are listed in
Table 3.
Table 3 clearly indicates that among the p-substituted aromatic
ketones, the highest and the lowest enantioselectivity were ob-
tained for 40-fluoroacetophenone and 40-nitroacetophenone with
53% and 25% ee, respectively. On the other hand, enantioselectivity
THF
THF
THF
25
50
65
10
11
a
Isolated yields of alcohols after purification by column chromatography.
Ee determined by HPLC analysis using the Chiralcel OD-H Column.
b
of
a-tetralone, which has a cyclic structure, decreased to 22% ee;
the enantioselectivity of isopropyl phenyl ketone decreased to
10% ee, while the lowest enantioselectivity was found to be 7%
ee for 2,2,2-trifluoroacetophenone.
It is known that the enantiomeric excess is sensitive to the sol-
vent and reaction temperature.
Two widely used solvents were selected in order to investigate
the effect of solvent; THF, and toluene. The results indicate that the
conversion rates of acetophenone to the corresponding alcohol in
THF increased more obviously than those in toluene under cata-
lytic conditions at the same temperatures. When the reaction of
acetophenone with chiral catalyst 7 was carried out under similar
experimental conditions, the corresponding alcohol was obtained
in 85% ee (99% yield) and 56% ee (98% yield) in THF and toluene
solution at reflux, respectively (Table 1, entries 2 and 7). This result
was further confirmed by the other experiments at reflux since
they also maintained good enantioselectivities and these condi-
tions were then applied to the reduction of other prochiral ketones.
In order to investigate the effect of the temperature, the reduc-
tion of acetophenone was carried out at various temperatures
ranging from 0 to 65 °C. At 0 °C, the ee was found to be 15%. When
the temperature was increased to 25 °C, the ee increased to 53%.
The temperature was then further increased to the refluxing tem-
perature of THF (65 °C). At this temperature, the enantioselectivity
was increased up to 85% as expected, with 99% yield of the second-
ary alcohol using 10 mol % of the catalyst 7 (Table 1, entries 8–11).
Another factor that can affect the enantioselectivity is the back-
ground reduction,6e which is related to the amount of the catalyst
loading in the reaction, as well as the reaction temperature and sol-
vent. As depicted in Table 1, when the catalyst loading was reduced
from 20 to 10 mol % or 5 mol %, the enantioselectivity was found to
be 78%, 85%, or 70%, respectively.
In the asymmetric reduction studies for catalyst 1, which con-
tains a primary alcohol moiety, one stereogenic center, and a phe-
nyl moiety in the stereogenic center, the reduction yield is very
high (from 89% to 99%), although the enantioselectivity is moder-
ate. The absolute configurations of the products were found to be
(R), while those of the alcohols formed by the reduction of isopro-
pyl phenyl ketone and 2-bromoacetophenone had an (S)-configu-
ration. Thus, they were determined to be (R) in most cases
through comparison of the specific rotation values with the litera-
ture data.21,34,35
Generally, electron deficient ketones give better results than
electron-rich ones.21 In the asymmetric reduction studies with cat-
alyst 2, the best enantioselectivity was found for the (S)-alcohol of
2-bromoacetophenone (53% ee) (Table 3, catalyst 3).
As can be seen in Table 3, when catalysts 1 and 2 are compared
in enantioselectivity and yield, it can be seen that catalyst 2 is a
better catalyst. This may be due to fact that the phenyl group is
slightly further from the stereocenter during the formation of
oxazaborolidine between catalyst 2 and boron. In Table 3, it can
seen that catalyst 3, which contains a secondary alcohol moiety
and two stereogenic centers, is a good reduction catalyst both in
terms of enantioselectivity and yield. By considering Table 3, one
can see that the highest enantiomeric excess was obtained at
86% ee from 40-bromoacetophenone, whereas the lowest enanti-
oselectivities were obtained as 20% and 3% ee from isopropyl phe-
nyl ketone and 2,2,2-trifluoroacetophenone, respectively (Table 3,
catalyst 3, entries 9 and 12). Catalyst 4 contains an isopropyl moi-
ety and a tertiary alcohol carbon in the stereocenter and has two
phenyl groups. In the reduction of catalyst 4, the enantioselectivity
was obtained in 90% yield and 15% ee for isopropyl phenyl ketone,
We also tested the effect of the catalyst generation period. As
shown in Table 2, when the reaction period was prolonged to
1 h, the enantioselectivity was increased, while extending the per-
iod of time to 1.5 h, has no effect on the enantioselectivity.
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Table 3
Enantioselective ketone reduction using BH3ꢀS(CH3)2 as reduction agents with b-hydroxyamides 1–7 as the catalyst
Entry Ketones
Catalyst 1
Catalyst 2
Catalyst 3
Catalyst 4
Catalyst 5
Catalyst 6
Catalyst 7
Yield
(%)a
ee
Config.c Yield
(%)a
ee
Config.c Yield
(%)a
ee
Config.c Yield
(%)a
ee
Config.c Yield
(%)a
ee
Config.c Yield
(%)a
ee
Config.c Yield
(%)a
ee
Config.c
(%)b
(%)b
(%)b
(%)b
(%)b
(%)b
(%)b
1
2
Acetophenone
40-
99 33d
98 29d
(R)
(R)
99 44
98 32
(R)
(R)
99 70
98 76
(S)
(S)
99 55
98 46
(R)
(R)
99 59
98 56
(R)
(R)
99 43
98 43
(R)
(R)
99 86
98 74
(S)
(S)
Methylacetophenone
40-
3
89 28d
(R)
89 16
(R)
89 62
(S)
89 35
(R)
89 40
(R)
85 20
(R)
85 70
(S)
Methoxyacetophenone
40-nitroacetophenone
40-Fluoroacetophenone
40-Chloroacetophenone
40-Bromoacetophenone
4
5
6
7
8
9
95 25e
99 53f
99 48f
99 27f
99 22g
90 10g
(R)
(R)
(R)
(R)
(R)
(S)
95 50
99 36
99 48
99 58
99 29
90 30
(R)
(R)
(R)
(R)
(R)
(R)
95 84
99 64
99 84
99 86
99 57
90 20
(S)
(S)
(S)
(S)
(S)
(R)
95 55
99 59
99 55
99 63
99 27
90 15
(R)
(R)
(R)
(R)
(R)
(S)
95 71
99 85
99 72
99 70
99 61
90 10
(R)
(R)
(R)
(R)
(R)
(R)
98 66
98 72
98 78
99 76
99 23
90 10
(R)
(R)
(R)
(R)
(R)
(R)
98 70
98 72
98 70
99 81
99 73
90 20
(S)
(S)
(S)
(S)
(S)
(R)
a-Tetralone
Isopropyl phenyl
ketone
2-Bromoacetophenone
Ethyl phenyl ketone
2,2,2-
10
11
12
99 33g
95 32g
93 07g
(S)
(R)
(R)
99 53
95 34
94 07
(S)
(R)
(R)
99 77
95 62
95 03
(R)
(S)
(S)
99 54
95 28
95 16
(S)
(R)
(S)
99 82
95 46
96 03
(S)
(R)
(R)
99 52
95 19
94 06
(S)
(R)
(S)
99 84
95 51
96 03
(R)
(S)
(S)
Trifluoroacetophenone
1. 1-Phenylethanol: dEluent: n-hexane-2-propanol: 95/5 v/v; flow rate, 1 mL/min. 254 nm; tR: 19.08 and 20.05 min.
2. 1-(4-methylphenyl)ethanol: dEluent: n-hexane-2-propanol: 95/5 v/v; flow rate, 1 mL/min. 254 nm; tR: 9.02 and 9.77 min.
3. 1-(4-methoxyphenyl)ethanol: dEluent: n-hexane-2-propanol: 95/5 v/v; flow rate, 1 mL/min. 254 nm; tR: 24.24 and 31.96 min.
4. 1-(4-nitrophenyl)ethanol: eEluent: n-hexane-2-propanol: 95/5 v/v; flow rate, 1 mL/min. 254 nm; tR: 45.70 and 56.55 min.
5. 1-(4-fluorophenyl)ethano: fEluent: n-hexane-2-propanol: 98/2 v/v; flow rate, 0.7 mL/min. 254 nm; tR: 8.88 and 9.74 min.
6. 1-(4-chlorophenyl)ethanol: fEluent: n-hexane-2-propanol: 98/2 v/v; flow rate, 0.7 mL/min. 254 nm; tR: 9.21 and 9.99 min.
7. 1-(4-bromolphenyl)ethanol: fEluent: n-hexane-2-propanol: 98/2 v/v; flow rate, 0.7 mL/min. 254 nm; tR: 9.87 and 10.82 min.
8. 1,2,3,4-Tetrahydro-1-naphthol: gEluent: n-hexane-2-propanol: 98/2 v/v; flow rate, 1 mL/min. 254 nm; tR: 19.11 and 20.81 min.
9. 2-Methyl-1-phenylpropanol: gEluent: n-hexane-2-propanol: 98/2 v/v; flow rate, 1 mL/min. 254 nm; tR: 12.69 and 15.23 min.
10. 2-Bromophenylethanol: gEluent: n-hexane-2-propanol: 98/2, v/v; flow rate, 1 mL/min. 254 nm; tR: 22.35 and 27.52 min.
11. 1-Phenyl-1-propanol: gEluent: n-hexane-2-propanol: 98/2, v/v; flow rate, 1 mL/min. 254 nm; tR: 16.55 and 19.55 min.
12. 2,2,2-trifluoro-1-phenylethanol: gEluent: n-hexane-2-propanol: 98/2, v/v; flow rate, 1 mL/min. 254 nm; tR: 38.67 and 46.54 min.
a
Yield determined after chromatographic purification.
Ee determined by HPLC (Daicel Chiralcel OD-H Column, for 4-methylacetophenone and 4-nitroacetophenone Daicel Chiralcel AS-3 Column).
Determined by comparison of the sign of the specific rotation with the literature value.
b
c

Y. Turgut et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
5
and in 95% yield and 16% ee for 2,2,2-trifluoroacetophenone (Ta-
ble 3, catalyst 3, entries 9 and 12). As can be seen in Table 3 for
the enantioselective reduction studies with catalyst 4, p-substi-
tuted prochiral ketones with electron-withdrawing groups gener-
ally exhibit better enantioselectivity than those having electron
donating ones (Table 3, catalyst 4). The ees of the corresponding
products decreased when increasing the size of the alkyl group. A
decrease in the enantioselectivity was found in the case of cyclic
The ee value determination was carried out using chiral HPLC
on a DaicelÒ Chiralcel OD-H and Chiralcel AS-3 column on BIORAD
model 2800 pump and BIORAD UV-detector. The absolute configu-
ration of the major enantiomer was assigned according to the sign
of the specific rotation.
4.2. Synthesis of b-hydroxyamides 1–7
a
-tetralone ketone (27% ee), which probably results from its rigid
4.2.1. 2-Hydroxy-N-[(1S)-2-hydroxy-1-phenylethyl]benzamide 1
To a 50 mL round-bottomed Schlenk flask were added salicylic
acid (2.0 g, 14.5 mmol) in dry chloroform (10 mL), thionyl chloride
(21 mL, 290 mmol), and dry DMF (catalytic amount). After being
refluxed for 8 h, the excess thionyl chloride and chloroform were
removed under vacuum. The yellow reaction mixture (acid chlo-
ride) was washed with dichloromethane (DCM) (3 ꢁ 25 mL) and
conformation. When catalyst 4 is considered generally, one cannot
say that it provides very high enantioselectivity, due to the steric
effects of the isopropyl groups on the alcoholic carbon. Further-
more, the low ee may sometimes result from the difficulty or slow-
ness of hydride transfer to the catalytic center due to the steric
repulsion between the phenyl groups in the ligand and the aryl
moieties of the aryl ketones.
concentrated in vacuo. IR (neat):
m
1780 cmꢂ1 (COCl) (lit.39
In previous studies, it has been reported that the structural
properties of the electronic arrangement of the catalyst can change
the stereoselectivity in the catalytic asymmetric reduction.36 When
catalyst 7, which has two stereogenic centers and contains an ind-
anol group, was used, the highest enantioselectivity (86% ee) and
yield (99%) were obtained for acetophenone, whereas the lowest
enantioselectivity was found for 2,2,2-trifluoroacetophenone (3%
ee) and isopropyl phenyl ketone (20% ee) as in the case of previous
catalysts. Except for 40-bromoacetophenone, the prochiral ketones
with p-substituted electron withdrawing groups displayed lower
enantioselectivity than 40-methylacetophenone (Table 3, catalyst
7). Another important method for finding efficient catalysts is to
arrange the electronic impacts of the catalyst.37 This is very impor-
tant for asymmetric conversions in which the stereoselectivity de-
pends only on non-covalent interactions. From the results obtained
for the enantioselective reduction catalyzed by a series of chiral b-
hydroxyamides 1–7,38 it was found that chiral b-hydroxyamides 3,
5, and 7 gave the best enantioselectivity, and the results are shown
Table 3.
1783 cmꢂ1). The acid chloride was dissolved in dry DCM (25 mL)
in an oven-dried Schlenk tube and the resulting solution was
cooled to 0 °C in an ice/water bath. To this was added dropwise a
solution of the (2S)-2-amino-2-phenylethanol (2.0 g, 15 mmol)
and dry Et3N (4.5 mL), in dry DCM (15 mL) over a period of 0.5 h
under an argon atmosphere. After the addition, the temperature
was allowed to reach 25 °C and the mixture was stirred at this tem-
perature for a further 24 h for the full conversion of material (mon-
itored by TLC). The reaction was quenched by water (2 ꢁ 10 mL).
The mixture was washed with saturated NaHCO3 (2 ꢁ 15 mL) and
water (2 ꢁ 15 mL), dried over Na2SO4, and concentrated under vac-
uum. The product was purified by column chromatography on sil-
ica gel using n-hexane/EtOAt 4:1 (v/v) as the eluent, (TLC Rf = 0.58).
The pure b-hydroxyamide 1 was obtained as yellow viscous oil
(1.5 g, 40% yield). ½a D20
ꢃ
¼ þ33:0 (c 1.12, CHCl3), IR (KBr, cmꢂ1):
3203, 3064, 2960, 1771, 1641, 1497, 1367, 700. 1H NMR (DMSO-
d6): d (ppm) quartet of AB spin system dA: 4.26 (t, 1H, J = 8.0 Hz,
CHH) and dB: 4.89 (dd, 1H, J = 8.0 Hz and 1.2 Hz CHH), 5.55 (dd,
1H, J1 = 8.0 Hz and J2 = 2.0 Hz, CH), 6.95–7.04 (m, 2H, Ar-H), 7.30–
7.50 (m, 6H, Ar-H), 7.71–7.73 (m, 1H, Ar-H), 12.19 (s, 1H, Ar-OH).
13C NMR (DMSO-d6): d (ppm) 68.29 (CH), 74.37 (CH2), 110.45
(Ar-C), 116.99 (Ar-C), 119.49 (Ar-C), 127.02 (Ar-C), 128.18 (Ar-C),
128.52 (Ar-C), 129.21 (Ar-C), 134.40 (Ar-C), 142.06 (Ar-C), 159.79
(Ar-C), 165.99 (C@O). Anal. Calcd for C15H15NO3 (257 g/mol): C,
70.04; H, 5.84; N, 5.45. Found: C, 70.20; H, 6.01; N, 5.47.
All other chiral b-hydroxyamides 2–7 were synthesized using a
similar procedure.
3. Conclusion
In conclusion, we have synthesized chiral b-hydroxyamide li-
gands 1–7 from salicylic acid and commercially available amino
alcohols in two steps, for enantioselective ketone reduction with
borane dimethyl sulfide as a reducing agent. Different prochiral ke-
tones were reduced with up to 86% ee and with good yield.
4.2.2. 2-Hydroxy-N-[(2S)-1-hydroxy-3-phenylpropan-2-yl]ben-
zamide 2
4. Experimental
4.1. General
Salicylic acid (1.0 g, 7.25 mmol), thionyl chloride (5.25 mL,
72.5 mmol), dry DMF (catalytic amount), and (2S)-2-amino-3-phe-
nyl-1-propanol (1.1 g, 7.28 mmol) were used. The product was
purified by column chromatography on silica gel using n-hexane/
EtOAt 5:1 (v/v) as the eluent, (TLC Rf = 0.38). The pure b-hydroxya-
mide 2 was obtained as a yellow viscous liquid (1.0 g, 51%).
All glassware was oven-dried for several hours at 120 °C,
assembled while hot and cooled in a stream of dry nitrogen gas.
All chemicals were reagent grade unless otherwise specified. Sol-
vents were dried according to established procedures by distilla-
tion under an argon atmosphere from the appropriate drying
agent. Silica gel 60 (Merck, 0.040–0.063 mm) and silica gel/TLC-
cards (F254) were used for flash column chromatography and
TLC. Melting points were determined with a Gallenkamp Model
apparatus with open capillaries. Infrared spectra were recorded
on a Mattson 1000 FTIR model spectrometer. Elemental analyses
were performed with a Carlo-Erba 1108 model apparatus. Optical
rotations were taken on a Perkin–Elmer 341 model polarimeter.
1H (400 MHz) and 13C (100 MHz) NMR spectra were recorded on
a Bruker AV400 high performance digital FT-NMR spectrometer.
Chemical shifts (d) and coupling constants (J) are expressed in
parts per million and Hertz, respectively.
½
a 2D0
ꢃ
¼ ꢂ19:0 (c 1.7, CHCl3), IR (KBr, cmꢂ1): 3431, 3027, 2962,
1774, 1643,1492, 1367, 799. 1H NMR (DMSO-d6): d (ppm) 2.88–
2.98 (m, 2H, –CH2-Ar), quartet of AB spin system dA: 4.19 (t, 1H,
J = 8.0 Hz, CHH), dB: 4.51 (t, 1H, J = 8.0 Hz CHH), 4.65 (t, 1H,
J = 8.0 Hz, –CH), 6.92 (t, 1H, J = 7.6 Hz Ar-H), 6.98 (d, 1H,
J = 8.4 Hz, Ar-H), 7.21–7.25 (m, 1H, Ar-H), 7.28–7.33 (m, 4H, Ar-
H), 7.42–7.45 (m, 1H, Ar-H), 7.59 (d, 1H, J = 7.6 Hz, Ar-H), 12.25
(s, 1H, Ar-OH). 13C NMR (DMSO-d6): d (ppm) 41.33 (Ar-CH2),
66.45 (HO-C), 71.59 (C-NH), 110.56 (Ar-C), 116.90 (Ar-C), 119.31
(Ar-C), 126.82 (Ar-C), 128.21 (Ar-C), 128.77 (Ar-C), 129.70 (Ar-C),
134.12 (Ar-C), 138.33 (Ar-C), 159.71 (Ar-C), 165.11 (C@O). Anal.
Calcd for C16H17NO3 (271 g/mol): C, 70.84; H, 6.27; N, 5.17. Found:
C, 70.88; H, 6.30; N, 5.20.
Please cite this article in press as: Turgut, Y.; et al. Tetrahedron: Asymmetry (2013), http://dx.doi.org/10.1016/j.tetasy.2013.05.016

6
Y. Turgut et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
4.2.3. 2-Hydroxy-N-[(1S,2R)-2-hydroxy-1,2-diphenylethyl]ben-
zamide 3
4.2.6. 2-Hydroxy-N-[(2S)-1-hydroxy-1,3-diphenylpropan-2-yl]-
benzamide 6
Salicylic acid (1.0 g, 7.25 mmol), thionyl chloride (5.0 mL,
72.5 mmol), dry DMF (catalytic amount), and (1S,2R)-(+)-2-ami-
no-1,2-diphenylethanol (1.5 g, 7.26 mmol) were used. The product
was purified by column chromatography on silica gel using tolu-
ene/MeOH 30:1 (v/v) as the eluent, (TLC Rf = 0.23). The pure b-
hydroxyamide 3 was obtained as a yellow solid (1.0 g, 42%). Mp
Salicylic acid (0.9 g, 6.52 mmol), thionyl chloride (4.69 mL,
64.5 mmol), dry DMF (catalytic amount) and (S)-(ꢂ)-2-amino-
1,1,3-triphenyl-1-propanol (2.0 g, 6.52 mmol) were used. The
product was purified by column chromatography on silica gel
using toluene/MeOH/Et3N 100:6:5 (v/v/v) as eluent, (TLC
Rf = 0.40). Pure b-hydroxyamide 6 was obtained as a solid (1.3 g,
178–179 °C, ½a 2D0
ꢃ
¼ þ40:0 (c 1, CH3CN). IR (KBr, cmꢂ1): 3419,
47%). Mp 153.3–156 °C, ½a D20
ꢃ
¼ ꢂ95:0 (c 1, CHCl3). IR (KBr, cmꢂ1):
3328, 3214, 3065, 3031, 2969, 1623, 1584, 1451, 1353,702. 1H
NMR (CDCl3): d (ppm) 5.01 (dd, 1H, J1 = 1.6 and J2 = 4.8 Hz, CH-
OH), 5.22 (dd, 1H, J1 = 1.6 and J2 = 6.8 Hz, CH-NH), 5.65 (d, 1H,
J = 4.8 Hz, CH-OH), 6.87–6.89 (m, 2H, Ar-H), 7.18–7.37 (m, 11H,
Ar-H), 7.81–7.83 (m, 1H Ar-H), 9.10 (d, 1H, J = 8.4 Hz, NH), 11.76
(br s, 1H, Ar-OH). 13C NMR (CDCl3): d (ppm) 59.25 (CH-OH),
74.83 (CH-NH), 116.93 (Ar-C), 117.55 (Ar-C), 119.22 (Ar-C),
127.17 (Ar-C), 127.27 (Ar-C), 127.54 (Ar-C), 128.04 (Ar-C), 128.09
(Ar-C), 128.68 (Ar-C), 129.22 (Ar-C), 133.82 (Ar-C), 140.65 (Ar-C),
143.21 (Ar-C), 159.10 (Ar-C), 166.88 (C@O). Anal. Calcd for
3406, 3059, 3025, 2958, 1633, 1594, 1489, 1448, 1358, 1146,
755. 1H NMR (DMSO-d6): d (ppm) quartet of AB spin system dA:
2.71 (dd, 1H, J1 = 2.0 Hz, J2 = 12.0 Hz, CHH), dB: 2.84 (dd, 1H,
J1 = 10.8 Hz, J2 = 2.8 Hz, CHH), 5.45–5.50 (m, 1H, CH-NH), 6.22 (s,
1H, OH), 6.77–6.80 (m, 2H, Ar-H), 7.06–7.41(m, 12H, Ar-H), 7.59–
7.70 (m, 5H, Ar-H), 8.40 (d, 1H, J = 9.6 Hz, NH), 11.70 (br s, 1H,
Ar-OH). 13C NMR (CDCl3): d (ppm) 36.64 (CH2), 57.32 (CH-NH),
80.64 (C-OH), 116.46 (Ar-C), 117.43 (Ar-C), 118.93 (Ar-C), 125.93
(Ar-C), 126.13 (Ar-C), 126.33 (Ar-C), 126.76 (Ar-C), 126.95 (Ar-C),
128.03 (Ar-C), 128.36 (Ar-C), 128.68 (Ar-C), 128.75 (Ar-C), 129.52
(Ar-C), 133.64 (Ar-C), 139.54 (Ar-C), 146.45 (Ar-C), 146.84 (Ar-C),
C21H19NO3 (333 g/mol): C, 75.65; H, 5.70; N, 4.20. Found: C,
75.66; H, 5.71; N, 4.20.
159.27 (Ar-ipsoC), 167.86 (C@O). Anal. Calcd for C28H25NO3
(423 g/mol): C, 79.43; H, 5.91; N, 3.31. Found: C, 79.50; H, 6.03;
N, 3.42.
4.2.4. 2-Hydroxy-N-[(2S)-1-hydroxy-3-methyl-1,1-diphenylbut-
an-2-yl]benzamide 4
Salicylic acid (1.1 g, 7.85 mmol), thionyl chloride (5.7 mL,
78.5 mmol), dry DMF (catalytic amount) and (2S)-(ꢂ)-2-amino-
3-methyl-1,1-diphenyl-1-butanol (2.0 g, 7.85 mmol) were used.
The product was purified by column chromatography on silica
gel using n-hexane/EtOAc 3:1 (v/v) as the eluent, (TLC
Rf = 0.34). Pure b-hydroxyamide 4 was obtained as a white solid
4.2.7. 2-Hydroxy-N-[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-
1-yl]benzamide 7
Salicylic acid (1.0 g, 7.25 mmol), thionyl chloride (5.25 mL,
72.28 mmol), dry DMF (catalytic amount), and (1R,2S)-(+)-cis-1-
amino-2-indanol (1.1 g, 7.90 mmol) were used. The product was
purified by column chromatography on silica gel using toluene/
EtOAc 30:10 (v/v) as the eluent, (TLC Rf = 0.50). Pure b-hydroxya-
mide 7 was obtained as a solid (1.4 g, 72%). Mp 135–137 °C,
(1.5 g, 51%). Mp 199.4–202 °C, ½a D20
¼ ꢂ107:0 (c 1, CHCl3). IR
ꢃ
(KBr, cmꢂ1): 3445, 3409, 3058, 3030, 2959, 1646, 1591, 1493,
1447, 1363, 1272, 707. 1H NMR (DMSO-d6): d (ppm) 0.78 (d,
3H, J = 6.8 Hz, CH(CH3)2), 0.96 (d, 3H, J = 6.8 Hz CH(CH3)2), 1.81–
1.85 (m, 1H CH(CH3)2), 5.18 (dd, 1H, J1 = 2.1 Hz, J2 = 10.0 Hz
CH-NH), 6.00 (s, 1H, OH), 6.84–6.90 (m, 3H, Ar-H), 7.06–7.70
(m, 11H, Ar-H), 8.26 (d, 1H, J = 10 Hz, NH), 11.77 (s, 1H, Ar-
OH). 13C NMR (CDCl3): d (ppm) 18.62 (CH3), 23.53 (CH3), 29.17
(CH(CH3)2), 58.37 (CH-OH), 81.36 (CH-NH), 117.46 (Ar-C),
117.50 (Ar-C), 119.21 (Ar-C), 125.71 (Ar-C), 126.04 (Ar-C),
126.66 (Ar-C), 126.77 (Ar-C), 128.21 (Ar-C), 128.55 (Ar-C),
129.11 (Ar-C), 133.64 (Ar-C), 146.75 (Ar-C), 147.85 (Ar-C),
½
a 2D0
ꢃ
¼ ꢂ5:6 (c 1.08, CHCl3). IR (KBr, cmꢂ1): 3312, 3070, 3040,
2925, 1630, 1592, 1457, 1305, 1172, 754. 1H NMR (DMSO-d6): d
(ppm) quartet of AB spin system dA: 3.00 (d, 1H, J = 16.0 Hz,
CHH), dB: 3.16 (dd, 1H, J1 = 5.2 Hz, J2 = 16.0 Hz, CHH), 4.56 (t, 1H,
J = 4.8 Hz, CHOH), 5.32 (br s, 1H, OH), 5.49 (dd, 1H; J1 = 5.2 Hz,
J2 = 8.0 Hz, CH-NH), 6.92–6.98 (m, 2H, Ar-H), 7.20–7.29 (m, 4H
Ar-H), 7.40 (t, 1H Ar-H), 8.08 (d, 1H, J = 8.0 Hz Ar-H), 8.99 (d, 1H,
J = 8 Hz, NH) 11.85 (s, 1H, Ar-OH). 13C NMR (CDCl3): d (ppm)
40.15 (from DEPT-135 spectra, CH2), 57.65 (C-NH, from HETCOR
spectra), 72.43 (C-OH, DEPT-135 spectra), 117.43 (Ar-C), 117.78
(Ar-C), 119.44 (Ar-C), 124.79 (Ar-C), 125.36 (Ar-C), 126.85 (Ar-C),
127.86 (Ar-C), 130.27 (Ar-C), 133.65 (Ar-C), 141.29 (Ar-C), 142.62
(Ar-C), 158.57 (Ar-ipsoC), 161.46 (C@O). Anal. Calcd for
158.82 (Ar-ipsoC), 168.11 (C@O). Anal. Calcd for
C24H25NO3
(375 g/mol): C, 76.80; H, 6.67; N, 3.73. Found: C, 76.81; H,
6.60; N, 3.72.
C16H15NO3 (269 g/mol): C, 71.36; H, 5.58; N, 5.20. Found: C,
4.2.5. 2-Hydroxy-N-[(1S)-2-hydroxy-1,2,2-triphenylethyl]benz-
amide 5
71.81; H, 6.00; N, 5.23.
Salicylic acid (0.48 g, 3.46 mmol), thionyl chloride (2.5 mL,
34.6 mmol), dry DMF (catalytic amount), and (S)-(ꢂ)-2-amino-
1,1,2-triphenylethanol (1.0 g, 3.46 mmol) were used. The product
was purified by column chromatography on silica gel using tolu-
ene/MeOH/Et3N 100:6:5 (v/v/v) as the eluent, (TLC Rf = 0.34). Pure
b-hydroxyamide 5 was obtained as a white solid (0.8 g, 57%). Mp
4.3. General procedure for the enantioselective reduction of
ketones with borane-dimethyl sulfide in the presence of b-
hydroxyamides 1–7
A 25 mL two-necked flask was charged with b-hydroxyamide
1–7 (0.05 mmol, 10%) in dry and fresh THF (3 mL), equipped with
a magnetic stirrer and a connection to the combined nitrogen/vac-
uum line and closed with a septum. The air in the flask was re-
placed by nitrogen. b-hydroxyamides 1–7 were dissolved in THF
(3 mL) with stirring and a solution of BH3ꢀSMe2 (0.5 mmol, 10 M)
complex was added at 0 °C by a syringe. After the mixture was stir-
red for 1 h at 65 °C, the freshly distilled ketone (0.5 mmol) in
freshly dried THF (2 mL) was added over a period of 1.5 h by a syr-
inge at the same temperature. The reaction mixture was kept stir-
ring at the 65 °C until the ketone was completely consumed. After
stirring for a further 30 min at rt, the reaction mixture was
quenched by the addition of MeOH (2 mL) and extracted with
CH2Cl2 three times. The combined organic extracts were washed
197–200 °C, ½a 2D0
ꢃ
¼ ꢂ296:0 (c 1, CHCl3). IR (KBr, cmꢂ1): 3449,
3059, 3029, 2955, 1632, 1521, 1492,1447, 1361, 1159, 750. 1H
NMR (DMSO-d6): d (ppm) 6.11 (d, 1H, J = 8.8 Hz, CH-NH), 6.34 (s,
1H, OH), 6.84–6.89 (m, 2H, Ar-H), 7.05–7.36 (m, 14H Ar-H), 7.61
(d, 2H; J = 7.6 Hz Ar-H), 7.41–7.76 (m, 1H Ar-H), 9.21 (d, 1H,
J = 7.2 Hz, NH) 11.68 (br s, 1H, Ar-OH). 13C NMR (CDCl3): d (ppm)
59.59 (CH-NH), 80.40 (C-OH), 117.46 (Ar-C), 117.58 (Ar-C),
119.24 (Ar-C), 126.58 (Ar-C), 126.68, 126.74, 126.94, 127.17,
127.36, 127.83, 128.40, 129.42, 129.71, 133.77, 139.91, 145.57
(Ar-C), 146.82 (Ar-C), 158.77 (Ar-ipsoC), 166.74. Anal. Calcd for
C27H23NO3 (409 g/mol): C, 79.22; H, 5.62; N, 3.42. Found: C,
79.30; H, 6.01; N, 3.42.
Please cite this article in press as: Turgut, Y.; et al. Tetrahedron: Asymmetry (2013), http://dx.doi.org/10.1016/j.tetasy.2013.05.016

Y. Turgut et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
7
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Acknowledgments
We would like to thank The Scientific and Technological Re-
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Please cite this article in press as: Turgut, Y.; et al. Tetrahedron: Asymmetry (2013), http://dx.doi.org/10.1016/j.tetasy.2013.05.016