D-Fructose-derived β-amino alcohol catalyzed direct asymmetric aldol reaction in the presence of p-nitrophenol

Article abstract of DOI:10.1039/c3ra42029a

d-Fructose derived β-amino alcohols 2 and 3 were used as organocatalysts for direct asymmetric aldol reaction of various aromatic aldehydes with three kinds of cyclic ketones in the presence of different additives as a co-catalyst. The results showed that

Full text of DOI:10.1039/c3ra42029a

RSC Advances
View Article Online
View Journal | View Issue
PAPER
D-Fructose-derived b-amino alcohol catalyzed direct
asymmetric aldol reaction in the presence of p-
nitrophenol†
Cite this: RSC Adv., 2013, 3, 21084
a
a
ab
b
a
Longxia Li, Zhijie Fang,* Jie Fang, Jianguang Zhou and Yanfei Xiang
D-Fructose derived b-amino alcohols 2 and 3 were used as organocatalysts for direct asymmetric aldol
reaction of various aromatic aldehydes with three kinds of cyclic ketones in the presence of different
additives as a co-catalyst. The results showed that the combinations of b-amino alcohol 2 and p-
nitrophenol built up a novel catalytic system. Loading of 20 mol% 2 and 15 mol% p-nitrophenol gave
excellent yields (up to 98% with respect to aldehyde) of aldol reaction products with good
Received 24th April 2013
Accepted 12th August 2013
1
enantioselectivity (up to 87% ee). Accordingly, a mechanism for the reaction was proposed by H NMR
DOI: 10.1039/c3ra42029a
spectrum in this paper. Furthermore, the catalysts can be reused and have the significant catalyst
recovery (77–84%).
www.rsc.org/advances

exibility than glucosamine, D-fructose was selected as the
Introduction
chiral pool in our studies, with the aim of widening its use in
Carbohydrate-based derivatives as chiral catalysts in direct asymmetric transformations. We herein report D-fructose-
asymmetric aldol reactions have been exploited in recent derived organocatalysts 2 and 3 and their applications in direct
1–9
years. Most of these catalysts, with attached other chiral asymmetric aldol reactions. Based on a structural difference on
1
2,4–8
3
moieties such as acyl groups, proline,
or aminoacyl groups,
the carbohydrate moiety and less steric hindrance of the amino
have been used as organocatalysts in the direct asymmetric alcohol section than in 1, D-fructose derivatives 2 and 3 were
9
aldol process. Peddinti and co-workers rst reported the
glucosamine-based primary amine used independently as
bifunctional organocatalyst in asymmetric synthesis. They
proposed as promising catalysts in the reaction. To the best of
our knowledge, there are no reports about amino alcohols
derived from D-fructose used as chiral catalysts for the direct
proposed that glucosamine-derived organocatalyst 1 (Fig. 1) asymmetric aldol reaction.
bearing a free hydroxyl group vicinal to primary amine func-
Our group has taken a long-term goal of developing novel
tionality provided the best results in direct asymmetric aldol chiral building blocks for asymmetric synthesis of drugs and
reaction through hydrogen bonding between the proton on the their intermediates or natural products with carbohydrates as
hydroxyl moiety and the carbonyl group of the aldehyde. More starting materials, such as the synthesis of natural product D-
10
17
recently, Shen reviewed asymmetric reactions using D-glucos-
amine derivatives as catalyst, highlighting the importance of D-
glucosamine derivatives for applications in asymmetric aldol
reactions.
mannoheptulose, the stereocontrolled formation of protected
18
aminodeoxyalditols, and synthesis of topiramate and its
derivate from D-fructose. In this context, we synthesized two
kinds of D-fructose derived b-amino alcohols 2 and 3 (Fig. 1)
19
D-Fructose, readily available and highly functionalized with according to our previous reports20,21 to study their catalytic
several stereogenic centers, has been explored for numerous properties analogous to the reaction catalyzed by 1. Starting
asymmetric transformations like asymmetric addition of with commercially available D-fructose, two types of di-O-iso-
11
12
diethylzinc to aldehydes, 1,4-addition reactions, hydrogena- propylidene-b-D-fructopyranoses can be conveniently prepared
1
3
14
15
tions, oxygen transfer reactions, Diels–Alder reactions and
on a large scale in good yield with dry acetone using different
ratios of H SO as the catalyst. The nal products 2 and 3 were
16
epoxidation reactions. As it is cheaper and has more structural
2
4
received by esterication, hydrolysis, cyclic sulfation, azide
substitution and reduction reactions. The aldol reaction was
a
School of Chemical Engineering, Nanjing University of Science & Technology, Nanjing,

rst tested in the presence of 2 and 3; then, different additives
were employed to select the most efficient cocatalyst system;
nally, the optimized cocatalyst system was used to test the
2
10094, China. E-mail: zjfang@njust.edu.cn; Fax: +86-025-84316903; Tel: +86-025-
4316903
8

b
Chemical and Analytical Development, Suzhou Novartis Pharma Technology
Company Limited, Changshu, 215537, China
aldol reactions between different aromatic aldehydes and three
kinds of cyclic ketones, which give excellent yields (up to 98%
with respect to aldehyde) and good enantioselectivity (up to
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/c3ra42029a
1
2
1084 | RSC Adv., 2013, 3, 21084–21091
This journal is ª The Royal Society of Chemistry 2013

View Article Online
Paper
RSC Advances
Fig. 1 The structure of b-amino alcohols 1–3.
1
23–27
8
7% ee). A mechanism for the reaction was also proposed by H proline.
These additives could promote aldol reactions
NMR in this paper.
through hydrogen bonding or bind from the carboxyl group to
metals. Thus, we assumed that these additives could be also
applied to the direct asymmetric aldol reaction catalyzed by D-
fructose-derived b-amino alcohol. A series of additives was rst
Results and discussion
Since the success of L-proline as a chiral catalyst in the direct screened for efficiency in the aldol reaction between cyclohex-
asymmetric aldol reaction, chiral amines have demonstrated anone and 3-nitrobenzaldehyde in the presence of b-amino
their signicance in asymmetric C–C or heteroatom–C bond alcohols 2 or 3 (Table 1). As several reports suggested that chiral
22
formation. There have been a great deal of successful attempts reagents like 1-(2-hydroxynaphthalen-1-yl)naphthalen-2-ol
0 0
a,a,a ,a -tetraaryl-1,3-dioxolan-4,5-dimethanol
to ameliorate the efficiency of the aldol process, the most (BINOL)
or
remarkable improvement was attained by employing different (TADDOL) could improve the enantioselection through
24,28
additives, such as Lewis acids, 2,4-dinitrophenol, (R)- or (S)- hydrogen bonding,
(S)-BINOL was rst employed as an
binol, D-camphorsulfonic acid, or thiourea in combination with additive. Inconspicuous improvement of the enantioselectivity
a
Table 1 The effect of additives on yield and ee for the aldol reaction between 3-nitrobenzaldehyde and cyclohexanone catalyzed by D-fructose derivatives 2 or 3
f
ee (%)
b
c
Entry
Catalyst
Additive (mol%)
Solvent
Time (h)
Yield (%)
dr syn : anti
syn
anti
1
2
3
4
5
6
7
8
9
2
3
2
2
3
2
2
2
3
2
2
2
2
2
2
2
2
2
2
No
No
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
48
48
47
24
47
46
23
22
22
75
23
46
94
94
70
24
24
24
24
38
60
40
19
67
92
94
66
73
20
71
91
1 : 2.70
1 : 0.59
1 : 3.80
1 : 1.71
1 : 0.55
1 : 2.79
1 : 2.80
1 : 4.10
1 : 0.80e
1 : 4.30
1 : 0.78
1 : 0.76
1 : 3.19e
1 : 1.44
1 : 0.68
1 : 1.73e
1 : 1.79e
1 : 0.88e
1 : 2.13
2
24
31
32
15
45
59
58
4
47
33
26
73
72
31
34
19
45
43
73
50
73
68
46
82
83
84
31
80
48
36
54
75
74
3
(S)-BINOL (5)
(S)-BINOL (20)
(S)-BINOL (5)
p-Nitrophenol (10)
p-Nitrophenol (15)
p-Nitrophenol (20)
p-Nitrophenol (20)
10
11
12
13
14
15
16
17
18
19
F
3
CCOOH (20)
CH COOH (20)
PhCOOH (20)
Cl CCOOH (20)
3
3
8
TsOH (20)
Citric acid (20)
ZnCl
ZnCl
FeSO
Trace
80
31
Trace
Trace
Trace
2
(20)
(20)
(20)
d
d
d
2
DMSO : H
DMSO : H
DMSO : H
2
2
2
O ¼ 4 : 1
O ¼ 4 : 1
O ¼ 4 : 1
46
37
66
4
2
Pb(OAc) (20)
a
b
Reactions were performed with 3-nitrobenzaldehyde (0.2 mM) and cyclohexanone (0.3 mL) in the presence of catalyst (0.04 mM) and additive.
Isolated yields. Determined by H NMR (400 MHz) of the crude sample. 4a : 5a : catalyst ¼ 5 : 1 : 0.2. Determined by chiral HPLC analysis
c
1
d
e
f
(Chiralcel AD-3). Determined by chiral HPLC analysis.
This journal is ª The Royal Society of Chemistry 2013
RSC Adv., 2013, 3, 21084–21091 | 21085

View Article Online
RSC Advances
Paper
with slightly inferior yield was observed compared with the mol% and the reaction showed the dr increased from 1 : 2.8 to
reactions based on activation by only 2 or 3 (Table 1, entries 1– 1 : 4 (Table 1, entries 6–8) with lower yield. Finally, we found
5). Hence, other additives were tested in our research. Further that higher enantioselectivity and near-quantitative yield were
investigation found that strong acids like CF COOH, obtained by loading of 20 mol% 2 and 15 mol% p-nitrophenol
3
CCl
3
COOH, TsOH could improve the syn or anti products with into the reaction.
To explore the versatility of this catalytic system, further
lower yields, probably due to the protonation of amine under
acidic condition that lowered its nucleophilicity and therefore investigation between three types of cyclic ketones and several
reduced yields of the reactions (Table 1, entries 10, 13 and 14). aromatic aldehydes were screened to broaden the scope of
On the other hand, lower yields and enantioselectivity were substrates in the presence of 20 mol% 2 and 15 mol% p-nitro-
ꢁ
ꢁ
observed by using weak acidic additives (Table 1, entries 11, 12 phenol at ꢀ20 C or ꢀ40 C (Table 2). The reaction worked with
and 15). Several Lewis acids were also tested in our studies. aromatic aldehydes bearing both electron-donating and elec-
Lower yields and low-to-moderate enantioselectivities were tron-withdrawing groups to afford aldol adducts 6a–n. As can be
observed in both neat and DMSO–H
2
O conditions (entries 16– seen from the results summarized in Table 2, we found that the
19). Interestingly, however, p-nitrophenol proved to be the best yields of the reactions were dependent not only on the elec-
additive both in terms of yield and enantioselectivity when 2 tronic nature of the substituents on the aromatic aldehyde, but
was employed as cocatalyst in the reaction (Table 1, entries 1 also on their positions. For example, the aldol reaction between
and 6–8). Increasing the amount of p-nitrophenol from 10 mol cyclohexanone and 3-nitrobezaldehyde afforded aldol product
%
to 15 mol% gave higher yield and enantioselectivity for both 6a in a combined yield of 94% with 59% and 83% enantiose-
ꢁ
syn and anti products with less improvement for the dr (ratio of lectivity for syn and anti products in 23 h at ꢀ20 C (Table 2,
25
syn to anti products). In Da et al.'s report, they explored DNP entry 1). The 2-nitrobenzaldehyde as substrate gave rise to
2,4-dinitrophenol) as co-catalyst for asymmetric aldol reactions aldol product 6b in 23 h with near-quantitative yield and
(
by employing 20 mol% DNP with 20 mol% amino alcohol moderate enantioselectivities (Table 2, entry 3). The halo-
catalysts and received excellent results. Based on their results, substituted benzaldehydes provided the corresponding prod-
we increased the amount of p-nitrophenol from 15 mol% to 20 ucts with lower yields and enantioselectivity compared with
a
Table 2 Direct aldol reactions between various cyclic ketones and aromatic aldehydes catalyzed by 2/p-nitrophenol
d
ee (%)
ꢁ
b
c
Entry
R
n
Temp ( C)
Product
Time (h)
Yield (%)
dr syn : anti
syn
anti
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
3-NO
3-NO
2-NO
2-NO
4-NO
4-NO
2-NO
3-NO
4-NO
3-NO
3-Cl
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
1
1
1
3
2
2
2
2
2
2
2
ꢀ20
ꢀ40
ꢀ20
ꢀ40
ꢀ20
ꢀ40
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
6a
6a
6b
6b
6c
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
23
69
23
69
23
96
67
72
72
67
68
90
75
68
64
75
72
94
67
96
41
98
71
21
35
48
37
69
68
72
81
57
72
56
1 : 2.80
1 : 0.89
1 : 2.29
1 : 6.22
1 : 2.66
1 : 3.07
1 : 1.12
1 : 3.10
1 : 4.52
1 : 0.92
1 : 1.83
1 : 0.61
1 : 1.24
1 : 2.10
1 : 0.60
1 : 1.65
1 : 1.64
59
67
45
6
83
73
75
57
80
87
84
66
68
16
68
25
63
72
42
49
21
46
60
48
39
35
19
14
37
29
45
41
35
74
0
1
2
3
4
5
6
7
4-Cl
3-Br
4-Br
4-F
3-NO
2
-4-Cl
6m
6n
3-OMe
a
c
b
Reactions were performed with aldehyde (0.2 mM) and cyclic ketones (0.3 mL) in the presence of catalyst (0.04 mM) and additive. Isolated yields.
1
d
Determined by H NMR (400 MHz) of the crude sample. Determined by chiral HPLC analysis.
2
1086 | RSC Adv., 2013, 3, 21084–21091
This journal is ª The Royal Society of Chemistry 2013

View Article Online
Paper
RSC Advances
Table 3 Recovery and reuse of 2 between 3-nitrobenzaldehyde and cyclohexanone
d
ee (%)
a
a
b
Cycle
Recovery of 2 (%)
Time (h)
Yield (%)
dr syn : anti
syn
anti
c
1
2
3
4
5
84
81
80
77
79
24
24
24
24
24
93
88
90
91
89
1 : 2.39
48
46
48
48
45
81
78
80
79
80
1 : 2.68
1 : 2.41
1 : 2.77
1 : 2.62
a
b
c
d
Isolated yields. Determined by HPLC analysis. Determined by column chromatography. Determined by chiral HPLC analysis (Chiralcel AD-3).
nitrobenzaldehydes (Table 2, entries 1, 3, 5 and 11–15); an reaction. As a result, cyclohexanone showed the best activity
electron-donating group like methoxy can improve the enan- with shorter reaction time, higher yield and enantioselectivity
tioselectivity of the syn product compared with other tested as compared to cycloheptanone and cyclopentanone, possibly
groups (Table 2, entries 1, 3, 5 and 11–17). Reaction temperature due to the stability of the six-membered ring which can reduce
is another important impact factor. In our studies, reactions the energy of the transition state to reach the asymmetric
using three types of nitrobenzaldehyde were implemented at procedure (Table 2, entries 1, 8 and 10).
ꢁ
ꢁ
ꢀ
20 C and ꢀ40 C, respectively. The results showed that higher
We explored the recovery of 2 for model reactions, and found
ꢁ
enantioselectivity and dr were observed at ꢀ40 C with lower ee and dr slightly decreased. It is noteworthy that the catalyst
yield and longer reaction time when nitrobenzaldehydes were can be reused, and has the signicant catalyst recovery (77–
tested as substrate (Table 2, entries 2, 4 and 6), the results at 84%) (Table 3).
ꢁ
ꢀ
20 C were encouraging with higher yield, shorter reaction
As shown in Fig. 2, by comparing the ratios of proton inte-
time and higher enantioselectivity for most entries (Table 2, gration between benzaldehyde and the product at 10.15 ppm
entries 1, 3 and 5). Furthermore, the ring strain of cyclic ketones and 7.52 ppm, respectively, we found the proportion of (a) is
was also closely related to the yield and enantioselectivity of the much smaller than (b), and it revealed that the reaction
1
Fig. 2
H NMR spectra for different reaction systems and p-nitrophenol. (a) The reaction mixture of 3-nitrobenzaldehye, cyclohexanone and organocatalyst 2 with p-
1
nitrophenol as cocatalyst; (b) the same reaction conditions as (a) without p-nitrophenol; (c) H NMR spectrum of p-nitrophenol.
This journal is ª The Royal Society of Chemistry 2013
RSC Adv., 2013, 3, 21084–21091 | 21087

View Article Online
RSC Advances
Paper
The scope of application of this D-fructose catalyst for other
related transformations could be explored in the near future.
Experimental
General information
Reagents were purchased at the highest commercial quality and
used without further purication. Yields refer to chromato-
graphically homogeneous materials, unless otherwise stated.
Thin-layer chromatography (TLC) was carried out on silica gel
Fig. 3 Proposed transition state for the reaction.
60 F254 (EMD Chemicals Inc.) and detection was performed by
UV absorption (254 nm) where applicable, and by spraying with
ꢁ
5
0% sulfuric acid in ethanol followed by charring at ꢂ150 C, or
proceeded swily and completely when p-nitrophenol was
introduced to the reaction (Table 1, entries 1 and 7). Synchro-
nously, the hydroxyl proton of p-nitrophenol at 5.91 ppm dis-
appeared (Fig. 2a and c) and might be wrapped in low eld,
which meant that the proton of p-nitrophenol had probably
formed a hydrogen bond in the reaction process; on the other
hand, Abraham and Mobli reported that the proton of CHO
shied upeld when there was an intramolecular hydrogen
bond in the system. In our experiment, the proton of the alde-
hyde at 10.15 ppm became a double peak and shied upeld
by spraying with a solution of alkaline potassium permanganate
ꢁ
followed by charring at ꢂ100 C.
Silica gel (particle size 200–300 mesh) was used for column
chromatography. NMR spectra were recorded on a Bruker-400
400/100 MHz) spectrometer equipped with Sun workstations.
Multiplicities are quoted as singlet (s), doublet (d), doublet of
doublets (dd), triplet (t), or multiplet (m). All NMR signals were
assigned on the basis of H NMR, C NMR experiments. All
chemical shis are quoted on the d scale in parts per million
ppm). Enantiomer ratios were determined by HPLC. HPLC was
performed on an Aglient 1200 series system equipped with an
autosampler, fraction-collector, UV detector, and Daicel-Chir-
alpak AD-3 column and Chiralpak IA-3 column (3 mm, 4.6 ꢃ 250
mm). Optical rotations were measured on a Shengguang WZZ-
(
29
1
13
(
(Fig. 2a and b), which fully conrmed that the p-nitrophenol
activated carbonyl group of benzaldehyde through hydrogen
bond. Based on the evidence discussed above and the early
proposed mechanism for the amino alcohol catalyzed asym-
30–32
metric aldol reaction without additives,
the probable tran-
2B automatic polarimeter.
sition state for our catalyst system is suggested and shown in
Fig. 3. It is presumed that the reaction rst proceeded through
the dehydration of the carbinolamine intermediate, followed by
General procedure for direct asymmetric aldol reaction
the nucleophilic attack of the amine to the carbonyl groups of To a solution of 0.03 mmol p-nitrophenol and 0.3 mL of ketone
cyclic ketones. The C–C bond formation and hydrolysis of (cyclohexanone, cyclopentanone or cycloheptanone) were
the amine–aldol then proceeded. The carbonyl group of the introduced 0.2 mmol of aldehyde and 0.04 mmol of catalyst (2
aromatic aldehyde could be activated by hydrogen bonding or 3). The mixture was stirred under the designed temperature
with p-nitrophenol and hydroxyl group at the C-4 position of until the completion of the reaction (monitored by TLC). The
fructose derivatives. p-Nitrophenol matched with amino alcohol reaction mixture was directly puried by silica gel chromatog-
through hydrogen bonding for higher catalytic efficiency, and raphy to afford the corresponding product.
this cocatalyst system is analogous to the reaction catalyzed
33
by double hydrogen bonding, which not only activated the
carbonyl group of the aldehyde, but also stabilized the transi-
tion state.
General procedure for recycle experiment of 2
To a solution of 0.15 mmol p-nitrophenol and 1.5 mL of cyclo-
hexanone were introduced 1.0 mmol of 3-nitrobenzaldehyde
and 0.2 mmol of catalyst 2. The mixture was stirred under ꢀ20
Conclusions
ꢁ
C for 24 h. The reaction mixture was directly puried by silica
gel chromatography to afford the corresponding product and 2.
In summary, we have demonstrated the use of amino alcohol 2
as a catalyst with p-nitrophenol as co-catalyst for the direct
asymmetric aldol reaction between different cyclic ketones
and a variety of aldehydes. Yields and enantioselectivities are
moderate to good. Important features of this reaction are the
2
was desiccated to dryness and reused for the next recycle, the
recycle experiments were performed 5 times.
2-[Hydroxy(3-nitrophenyl)methyl]cyclohexanone (6a)
following: (1) b-Amino alcohol 2 as catalyst can be synthesized 2-[Hydroxy(3-nitrophenyl)methyl]cyclohexanone (6a): syn dia-
1
3
from natural D-fructose by simple and high yield reactions. (2) p- stereomer, H NMR (400 MHz, CDCl ) d (ppm) 1.54–2.17 (m,
Nitrophenol as co-catalyst is inexpensive, and readily commer- 6H), 2.35–2.53 (m, 2H), 2.61–2.2.70 (m, 1H), 3.2 (d, J ¼ 4 Hz, 1H),
cial available. (3) The reactions do not require strict conditions 5.49 (s, 1H), 7.52 (t, J ¼ 8 Hz, 1H), 7.65 (d, J ¼ 8 Hz, 1H), 8.12 (d, J
1
3
and can be conducted neat. (4) The catalyst can be reused and ¼ 8 Hz, 1H), 8.19 (s, 1H); C NMR (100 MHz, CDCl ) d (ppm)
3
has signicant catalyst recovery. (5) This is the rst example of a 24.7, 25.9, 27.9, 42.6, 56.7, 69.9, 120.9, 122.1, 129.2, 131.9, 143.7,
nonmetallic small-molecule catalyst, which is derived from D- 148.3, 214.3; anti diastereomer, [a]
2
3
D
+ 23.4 (c 1, CDCl
3
; 87% ee)
1
fructose for direct intermolecular asymmetric aldol reaction. (6)
H NMR (400 MHz, CDCl ) d (ppm) 1.47–2.09 (m, 6H), 2.25–2.36
3
2
1088 | RSC Adv., 2013, 3, 21084–21091
This journal is ª The Royal Society of Chemistry 2013

View Article Online
Paper
RSC Advances
(
m, 1H), 2.38–2.61 (m, 2H), 4.05 (d, J ¼ 4 Hz, 1H), 4.84–4.81 (dd, 55.0, 56.1, 70.1, 74.3, 120.5, 121.6, 122.2, 123.0, 129.3, 129.5,
J ¼ 4 Hz, 1H), 7.46 (t, J ¼ 8 Hz, 1H), 7.60 (d, J ¼ 8 Hz, 1H), 8.10 (d, 131.7, 132.7, 143.6, 145.2, 148.3, 220.0, 222.5.
1
3
J ¼ 8 Hz, 1H), 8.15 (s, 1H); C NMR (100 MHz, CDCl ) d (ppm)
3
2
1
4.7, 27.6, 30.7, 42.7, 57.1, 74.1, 122.0, 122.9, 129.3, 133.2, 143.2,
48.3, 214.9.
2
-[Hydroxy(4-nitrophenyl)methyl]cyclopentanone (6f) (mix,
syn/anti ¼ 1 : 0.15)
-[Hydroxy(4-nitrophenyl)methyl]cyclopentanone (6f) (mix, syn/
2
1
2
-[Hydroxy(2-nitrophenyl)methyl]cyclohexanone (6b)
anti ¼ 1 : 0.15): anti diastereomer, H NMR (400 MHz, CDCl ) d
3
(ppm) 1.63–1.83 (m, 2H), 1.88–2.09 (m, 2H), 2.09–2.34 (m, 1H),
2
-[Hydroxy(2-nitrophenyl)methyl]cyclohexanone (6b): syn dia-
1
2.34–2.55 (m, 2H), 4.78 (s, 0.13H), 4.85 (d, J ¼ 8 Hz, 0.15H), 7.54
stereomer, H NMR (400 MHz, CDCl
3
) d (ppm) 1.48–1.88 (m,
(
0
d, J ¼ 8 Hz, 2H), 8.22 (d, J ¼ 8 Hz, 2H); syn diastereomer, 2.79 (s,
5
3
1
H), 2.07–2.14 (m, 1H), 2.38–2.48 (m, 2H), 2.85–2.90 (m, 1H),
1
3
3
.75H), 5.43 (s, 0.87H); C NMR (100 MHz, CDCl ) d (ppm) 20.3,
.29 (br, 1H), 5.97 (s, 1H), 7.43 (t, J ¼ 8 Hz, 1H), 7.65 (t, J ¼ 8 Hz,
1
3
22.3, 26.8, 38.6, 39.0, 55.1, 56.1, 70.4, 74.4, 123.6, 123.7, 126.4,
27.4, 147.1, 148.6, 150.4, 219.8, 222.3.
H), 7.84 (d, J ¼ 8 Hz, 1H), 8.0 (d, J ¼ 8 Hz, 1H); C NMR (100
1
MHz, CDCl ) d (ppm) 24.8, 28.0, 42.5, 54.8, 66.6, 124.7, 127.9,
1
3
1
29.6, 133.2, 137.0, 147.1, 214.1; anti diastereomer, H NMR
(400 MHz, CDCl
3
) d (ppm) 1.59–2.49 (m, 8H), 2.68–2.81 (m, 1H), 2-[Hydroxy(3-nitrophenyl)methyl]cycloheptanone (6g)
4
¼
.2 (brs, 1H), 5.45 (d, J ¼ 8 Hz, 1H), 7.43 (t, J ¼ 8 Hz, 1H), 7.64 (t, J
2
-[Hydroxy(3-nitrophenyl)methyl]cycloheptanone (6g): syn dia-
1
3
8.4 Hz, 1H), 7.77 (d, J ¼ 8 Hz, 1H), 7.85 (d, J ¼ 8 Hz, 1H);
) d (ppm) 25.0, 27.8, 31.1, 42.8, 57.3, 69.8,
24.1, 128.4, 129.0, 133.1, 136.6, 148.7, 215.0.
C
1
stereomer, H NMR (400 MHz, CDCl
2
2
3
) d (ppm) 1.24–1.32 (m,
H), 1.41–1.54 (m, 1H), 1.59–1.74 (m, 2H), 1.77–1.95 (m, 3H),
.42–2.55 (m, 1H), 2.58–2.69 (m, 1H), 2.83–2.92 (m, 1H), 3.27
NMR (100 MHz, CDCl
3
1
(
8
(
br, 1H), 5.30 (s, 1H), 7.53 (t, J ¼ 8 Hz, 1H), 7.70 (d, J ¼ 8 Hz, 1H),
1
3
.12 (d, J ¼ 8 Hz, 1H), 8.22 (s, 1H); C NMR (100 MHz, CDCl
3
) d
2-[Hydroxy(4-nitrophenyl)methyl]cyclohexanone (6c)
ppm) 23.5, 23.9, 28.9. 29.1, 43.9, 57.1, 72.2, 121.0, 122.2, 129.2,
2
-[Hydroxy(4-nitrophenyl)methyl]cyclohexanone (6c): syn dia-
1
1
32.1, 144.3, 148.3, 217.6; anti diastereomer, H NMR (400 MHz,
CDCl ) d (ppm) 1.27–1.39 (m, 2H), 1.47–1.57 (m, 1H), 1.59–1.75
m, 2H), 1.76–1.82 (m, 2H), 2.18–2.59 (m, 2H), 2.80–3.01 (m,
1
stereomer, H NMR (400 MHz, CDCl ) d (ppm) 1.57–1.77 (m,
3
3
4
2
8
H), 1.81–1.90 (m, 1H), 2.08–2.16 (m, 1H), 2.34–2.45 (m, 1H),
(
.59–2.67 (m, 1H), 3.18 (d, J ¼ 4 Hz, 1H), 5.49 (s, 1H), 7.49 (d, J ¼
1
8
H), 3.63 (brs, 1H), 4.85 (d, J ¼ 8 Hz, 1H), 7.63 (d, J ¼ 8 Hz, 1H),
1
3
Hz, 2H), 8.21 (d, J ¼ 8 Hz, 2H); C NMR (100 MHz, CDCl
3
) d
13
.08 (d, J ¼ 8 Hz, 1H), 8.16 (t, 1H); C NMR (100 MHz, CDCl ) d
3
(ppm) 24.8, 25.9, 27.9, 42.6, 56.8, 70.1, 123.5, 126.6, 147.0, 149.0,
(ppm) 23.5, 28.2, 28.6, 44.1, 57.9, 74.7, 121.9, 122.8, 129.4, 133.1,
1
3
214.1; anti diastereomer, H NMR (400 MHz, CDCl ) d (ppm)
1
44.1, 148.3, 217.0.
1.52–1.74 (m, 4H), 1.79–1.87 (m, 1H), 2.07–2.17 (m, 1H), 2.31–
2
.42 (m, 1H), 2.54–2.64 (m, 1H), 4.08 (d, J ¼ 4 Hz, 1H), 4.90 (dd, J
1
3
2-[Hydroxy(3-chlorophenyl)methyl]cyclohexanone (6h)
¼
8 Hz, 1H), 7.51 (d, J ¼ 8 Hz, 2H), 8.21 (d, J ¼ 8 Hz, 2H);
C
NMR (100 MHz, CDCl ) d (ppm) 24.7, 27.6, 30.7, 42.7, 57.2, 74.0, 2-[Hydroxy(3-chlorophenyl)methyl]cyclohexanone (6h): syn dia-
3
1
1
23.6, 127.9, 147.6, 148.33, 214.8.
stereomer, H NMR (400 MHz, CDCl ) d (ppm) 1.48–1.75 (m,
3
5
2
H), 1.81–1.90 (m, 1H), 2.04–2.14 (m, 1H), 2.30–2.50 (m, 1H),
.52–2.62 (m, 1H), 3.09 (d, J ¼ 4 Hz, 1H), 5.36 (s, 1H), 7.13–7.35
2-[Hydroxy(2-nitrophenyl)methyl]cyclopentanone (6d) (mix,
1
3
3
(m, 4H); C NMR (100 MHz, CDCl ) d (ppm) 24.8, 25.9, 27.9,
syn/anti ¼ 1 : 0.36)
-[Hydroxy(2-nitrophenyl)methyl]cyclopentanone (6d) (mix, syn/
4
2.6, 57.0, 70.1, 123.8, 126.0, 127.1, 129.4, 134.2, 143.6, 214.5;
2
1
anti diastereomer, H NMR (400 MHz, CDCl
3
) d (ppm) 1.23–1.73
1
anti ¼ 1 : 0.36): anti diastereomer, H NMR (400 MHz, CDCl
3
) d
(m, 5H), 1.74–1.85 (m, 1H), 2.05–2.15 (m, 1H), 2.30–2.40 (m,
(
ppm) 1.68–1.74 (m, 2H), 1.94–2.15 (m, 4H), 2.36–2.50 (m, 1H),
1H), 2.44–2.52 (m, 1H), 2.53–2.62 (m, 1H), 3.99 (s, 1H), 4.68 (d, J
2
.65 (m, 1H), 5.85 (d, J ¼ 4 Hz, 1H), 7.37 (t, J ¼ 8 Hz, 1H), 7.69
13
¼
8 Hz, 1H), 7.14–7.30 (m, 4H); C NMR (100 MHz, CDCl ) d
3
(
m, 1H), 7.83 (d, J ¼ 8 Hz, 1H), 7.93 (d, J ¼ 8 Hz, 1H); syn dia-
(
ppm) 24.7, 27.7, 30.8, 42.7, 57.3, 74.3, 125.3, 127.1, 128.0, 129.6,
13
stereomer, 4.41 (brs, 0.36H), 5.37 (d, J ¼ 8 Hz, 0.36H); C NMR
100 MHz, CDCl ) d (ppm) 20.2, 20.5, 23.0, 26.6, 38.6, 54.8, 55.5,
6.7, 69.1, 124.0, 124.6, 128.1, 128.6, 129.0, 133.2, 133.4, 136.3,
134.3, 143.1, 215.2.
(
6
1
3
2-[Hydroxy(4-chlorophenyl)methyl]cyclohexanone (6i) (mix,
38.5, 147.0, 148.5, 218.8, 222.1.
syn/anti ¼ 1 : 1.27)
-[Hydroxy(4-chlorophenyl)methyl]cyclohexanone (6i) (mix, syn/
2
2
-[Hydroxy(3-nitrophenyl)methyl]cyclopentanone (6e) (mix,
1
anti ¼ 1 : 1.27): anti diastereomer, H NMR (400 MHz, CDCl
ppm) 1.46–1.62 (m, 2H), 1.62–1.74 (m, 2H), 1.75–1.89 (m, 1H),
-[Hydroxy(3-nitrophenyl)methyl]cyclopentanone (6e) (mix, syn/ 2.03–2.14 (m, 1H), 2.30–2.42 (m, 1H), 2.51–2.61 (m, 1H), 4.0 (d, J
3
) d
syn/anti ¼ 1 : 0.52)
2
(
1
anti ¼ 1 : 0.52): anti diastereomer, H NMR (400 MHz, CDCl ) d ¼ 4 Hz, 0.54H), 4.77 (dd, J ¼ 4 Hz, 0.56H), 7.23–7.33 (m, 4H); syn
3
1
3
(
2
ppm) 1.55–1.75 (m, 2H), 1.85–2.00 (m, 2H), 2.02–2.15 (m, 1H), diastereomer, 3.08 (d, J ¼ 4 Hz, 0.4H), 5.35 (s, 0.44H); C NMR
.23–2.47 (m, 1H), 4.77 (d, J ¼ 8 Hz, 0.41H), 7.52 (m, 2H), 8.02 (100 MHz, CDCl ) d (ppm) 24.7, 24.8, 25.9, 27.7, 27.9, 30.7, 42.6,
3
1
3
(m, 2H); anti diastereomer, 3.23 (s, 0.72H), 5.34 (s, 0.78H);
C
57.0, 57.3, 70.1, 74.1, 127.2, 128.3, 128.5, 132.7, 133.5, 139.5,
NMR (100 MHz, CDCl
3
) d (ppm) 20.3, 22.3, 26.8, 29.6, 38.6, 39.0, 139.9, 214.6, 215.3.
This journal is ª The Royal Society of Chemistry 2013
RSC Adv., 2013, 3, 21084–21091 | 21089

View Article Online
RSC Advances
Paper
2
-[Hydroxy(3-bromophenyl)methyl]cyclohexanone (6j)
3.01 (s, 1H), 3.81 (s, 3H), 5.37 (s, 1H), 6.83 (m, 3H), 7.25 (m, 1H);
1
3
C NMR (100 MHz, CDCl ) d (ppm) 24.9, 26.0, 27.9, 42.7, 55.2,
3
2-[Hydroxy(3-bromophenyl)methyl]cyclohexanone (6j): syn dia-
1
57.2, 70.1, 111.5, 112.4, 118.0, 129.2, 143.2, 159.6, 214.8; anti
stereomer, H NMR (400 MHz, CDCl
3
) d (ppm) 1.51–1.75 (m,
1
diastereomer, H NMR (400 MHz, CDCl ) d (ppm) 1.49–1.72 (m,
3
4
2
2
H), 1.80–1.90 (m, 1H), 2.04–2.14 (m, 1H), 2.32–2.49 (m, 1H),
4H), 1.74–1.84 (m, 1H), 2.03–2.13 (m, 1H), 2.31–2.40 (m, 1H),
.52–2.64 (m, 1H), 3.10 (d, J ¼ 4 Hz, 1H), 5.35 (s, 1H), 7.21 (m,
1
3
2.44–2.51 (m, 1H), 2.55–2.65 (m, 1H), 3.81 (s, 3H), 3.93 (s, 3H),
3
H), 7.37 (m, 1H), 7.48 (s, 1H); C NMR (100 MHz, CDCl ) d
1
3
4
.76 (d, J ¼ 8 Hz, 1H), 6.86 (m, 3H), 7.26 (m, 1H); C NMR (100
MHz, CDCl ) d (ppm) 24.7, 27.8, 30.9, 42.7, 55.2, 57.4, 74.7,
12.4, 113.4, 119.5, 129.3, 142.5, 159.7, 215.5.
(ppm) 24.8, 25.9, 27.9, 42.6, 57.0, 70.0, 122.5, 124.4, 129.0, 129.8,
1
3
130.1, 143.9, 214.5; anti diastereomer, H NMR (400 MHz,
1
CDCl ) d (ppm) 1.24–1.36 (m, 1H), 1.52–1.74 (m, 3H), 1.76–1.84
3
(m, 1H), 2.01–2.13 (m, 1H), 2.29–2.40 (m, 1H), 2.42–2.51 (m,
1
H), 2.52–2.62 (m, 1H), 4.02 (s, 1H), 4.74 (d, J ¼ 8 Hz, 1H), 7.22
Acknowledgements
1
3
(m, 2H), 7.42 (m, 1H), 7.49 (m, 1H); C NMR (100 MHz, CDCl
3
)
d (ppm) 24.8, 27.7, 30.8, 42.7, 57.3, 74.2, 122.6, 125.8, 129.9, We thank Jiangsu provincial science and technology project for
1
30.0, 143.3, 215.2.
nancial support (grant: BZ2010070) and technology supple-
ment by Suzhou Novartis Pharma Technology Company
Limited.
2-[Hydroxy(4-bromophenyl)methyl]cyclohexanone (6k) (mix,
syn/anti ¼ 1.26 : 1)
-[Hydroxy(4-bromophenyl)methyl]cyclohexanone (6k) (mix,
2
1
References
syn/anti ¼ 1.26 : 1): anti diastereomer, H NMR (400 MHz,
CDCl ) d (ppm) 1.47–1.73 (m, 4H), 1.75–1.88 (m, 1H), 2.04–1.13
m, 1H), 2.30–2.41 (m, 1H), 2.42–2.50 (m, 1H), 2.51–2.90 (m,
3
1
2
3
4
5
6
N. Dwivedi, S. S. Bisht and R. P. Tripathi, Carbohydr. Res.,
006, 341, 2737.
J. Pandey, N. Dwivedi, N. Singh, A. K. Srivastava, A. Tamarkar
and R. P. Tripathi, Bioorg. Med. Chem. Lett., 2007, 17, 1321.
A. Tsutsui, H. Takeda, M. Kimura, T. Fujimoto and
T. Machinami, Tetrahedron Lett., 2007, 48, 5213.
(
2
1
H), 3.99 (s, 0.41H), 4.75 (dd, J ¼ 8 Hz, 0.42H), 7.19 (m, 2H), 7.46
13
(m, 2H); syn diastereomer, 3.08 (s, 0.53H), 5.33 (s, 0.56H);
C
3
NMR (100 MHz, CDCl ) d (ppm) 24.7, 24.8, 25.9, 27.7, 27.9, 30.7,
4
1
2.6, 57.0, 57.3, 70.1, 74.2, 120.8, 121.7, 127.5, 128.7, 131.2,
31.5, 140.0, 140.5, 214.6, 215.3.
J. Agarwal and R. K. Peddinti, Tetrahedron: Asymmetry, 2010,
21, 1906.
2-[Hydroxy(4-ourophenyl)methyl]cyclohexanone (6l) (mix,
S. Pedatella, M. De Nisco, D. Mastroianni, D. Naviglio,
A. Nucci and R. Caputo, Adv. Synth. Catal., 2010, 353, 1443.
M. De Nisco, S. Pedatella, S. Bekta xs , A. Nucci and R. Caputo,
Carbohydr. Res., 2012, 356, 273.
syn/anti ¼ 1.41 : 1)
-[Hydroxy(4-ourophenyl)methyl]cyclohexanone (6l) (mix, syn/
2
1
anti ¼ 1.41 : 1): anti diastereomer, H NMR (400 MHz, CDCl
3
) d
7
8
J. Agarwal and R. K. Peddinti, Eur. J. Org. Chem., 2012, 6390.
N. Singh, J. Pandey and R. P. Tripathi, Catal. Commun., 2008,
(ppm) 1.52–1.89 (m, 5H), 2.04–2.14 (m, 1H), 2.29–2.49 (m, 2H),
2
0
4
2
1
2
.52–2.62 (m, 1H), 4.0 (d, J ¼ 4 Hz, 0.42H), 4.77 (d, J ¼ 8 Hz,
9
, 743.
.41H), 7.02 (m, 2H), 7.29 (m, 2H); syn diastereomer, 3.06 (d, J ¼
1
3
9
J. Agarwal and R. K. Peddinti, J. Org. Chem., 2011, 76, 3502.
Hz, 0.53H), 5.36 (s, 0.59H); C NMR (100 MHz, CDCl ) d (ppm)
3
1
1
0 C. Shen and P. F. Zhang, Curr. Org. Chem., 2013, 17, 1507.
1 H. Huang, H. Chen, X. Hu, C. Bai and Z. Zheng, Tetrahedron:
Asymmetry, 2003, 14, 297.
4.7, 24.8, 26.0, 27.7, 28.0, 30.8, 42.7, 57.2, 57.5, 70.2, 74.1,
15.1, 115.3, 127.4, 128.6, 136.7, 137.1, 160.7, 163.1, 214.8,
15.1.
1
1
1
2 Y. Mata, M. Di ´e guez, O. P `a mies and S. J. Woodward, J.
Organomet. Chem., 2007, 692, 4315.
3 H. Hang, Z. Zheng, H. Luo, C. Bai, X. Hu and H. Chen, Org.
Lett., 2003, 5, 4137.
4 W. Adam, C. R. Saha-M ¨o ller and C. G. Zhao, J. Org. Chem.,
2-[Hydroxy(4-chloro-3-nitrophenyl)methyl]cyclohexanone
(
6m) (mix, syn/anti ¼ 1.1 : 1)
-[Hydroxy(4-chloro-3-nitrophenyl)methyl]cyclohexanone (6m)
2
1
(
mix, syn/anti ¼ 1.1 : 1): anti diastereomer, H NMR (400 MHz,
CDCl ) d (ppm) 1.48–1.78 (m, 4H), 1.81–1.92 (m, 1H), 2.07–2.17
m, 1H), 2.31–2.44 (m, 1H), 2.44–2.52 (m, 1H), 2.53–2.66 (m,
1999, 64, 7492.
3
1
1
5 E. J. Enholm and S. Jiang, J. Org. Chem., 2000, 65, 4756.
6 B. Wang, X. Y. Wu, O. A. Wong, N. Brian, M. X. Zhao,
D. J. Chen and Y. Shi, J. Org. Chem., 2009, 74, 3986.
7 J. Cheng, Z. J. Fang, S. Li, B. H. Zheng and Y. H. Jiang,
Carbohydr. Res., 2009, 344, 2093.
(
1
H), 4.10 (d, J ¼ 4 Hz, 0.45H), 4.85 (dd, J ¼ 4 Hz, 0.46H); syn
13
diastereomer, 3.23 (s, 0.48H), 5.41 (s, 0.51H); C NMR (100
1
1
1
MHz, CDCl ) d (ppm) 24.6, 24.7, 25.9, 27.5, 27.8, 30.6, 40.5, 40.6,
3
5
1
6.5, 57.0, 69.4, 73.4, 123.0, 124.0, 125.3, 126.1, 130.5, 131.5,
31.6, 131.7, 141.8, 142.4, 147.8, 213.9, 214.6.
8 Y. H. Jiang, Z. J. Fang, Q. G. Zheng, H. L. Jia, J. Cheng and
B. H. Zheng, Synthesis, 2009, 2756.
9 D. D. Hu, Z. J. Fang, B. H. Zheng and L. X. Li, Chin. J. Pharm.,
2-[Hydroxy(3-methoxyphenyl)methyl]cyclohexanone (6n)
2011, 42, 645.
2
-[Hydroxy(3-methoxyphenyl)methyl]cyclohexanone (6n): syn 20 L. X. Li and Z. J. Fang, Chem. Res. Appl., 2012, 24, 146.
1
diastereomer, H NMR (400 MHz, CDCl
3
) d (ppm) 1.61–1.92 (m, 21 Z. J. Fang, L. X. Li and Y. H. Jiang, CN Pat., 102180915 A,
4H), 2.00–2.19 (m, 1H), 2.28–2.51 (m, 1H), 2.53–2.71 (m, 1H), 2011.
2
1090 | RSC Adv., 2013, 3, 21084–21091
This journal is ª The Royal Society of Chemistry 2013

View Article Online
Paper
RSC Advances
2
2
2
2
2
2
2 B. List, R. A. Lerener and C. F. Barbas III, J. Am. Chem. Soc., 28 P. Buston, Nature, 2003, 424, 145.
2
000, 122, 2395.
3 Y. S. Wu, Y. Chen, D. S. Deng and J. W. Cai, Synlett, 2005,
627.
4 Y. Zhou and Z. X. Shan, Tetrahedron: Asymmetry, 2006, 17,
671.
29 R. J. Abraham and M. Mobli, Magn. Reson. Chem., 2003, 41,
26.
30 G. F. Zhou, J. H. Fan and C. F. Barbas III, Tetrahedron Lett.,
2004, 45, 5681.
31 A. V. Malkov, M. A. Kabeshov, M. Bella, O. Kysilka,
D. A. Malyshev, K. pluhackova and P. Kocovsky, Org. Lett.,
2007, 9, 5473.
1
1
5 C. S. Da, L. P. Che, Q. P. Guo, F. C. Wu, X. Ma and Y. N. Jia, J.
Org. Chem., 2009, 74, 2541.
6 O. Reis, S. Eymur, B. Reis and A. S. Demir, Chem. Commun., 32 A. Pinaka, G. C. Vougioukalakis, D. Dimotikali,
2
009, 1088.
7 M. Penhoat, D. Barbry and C. Rolando, Tetrahedron Lett.,
011, 52, 159.
E. Yannakopoulou, B. Chankvetadze and K. Papadopoulos,
Chirality, 2013, 25, 119.
33 P. M. Pihko, Angew. Chem., Int. Ed., 2004, 43, 2062.
2
This journal is ª The Royal Society of Chemistry 2013
RSC Adv., 2013, 3, 21084–21091 | 21091