Isosteviol-proline conjugates as highly efficient amphiphilic organocatalysts for asymmetric three-component Mannich reactions in the presence of water

Article abstract of DOI:10.1002/hlca.201100265

In this work, six isostevioli-amino acid conjugates were designed and synthesized through simple condensation on a large scale without protecting group (Scheme). These amphiphilic organocatalysts mediated asymmetric three-component Mannich reactions of cy

Full text of DOI:10.1002/hlca.201100265

Helvetica Chimica Acta – Vol. 95 (2012)
43
IsosteviolꢀProline Conjugates as Highly Efficient Amphiphilic
Organocatalysts for Asymmetric Three-Component Mannich Reactions in the
Presence of Water
by Ya-Jie Ana)b), Chuan-Chuan Wanga), Zi-Ping Liua), and Jing-Chao Tao*a)
a) Department of Chemistry, New Drug Research and Development Center, Zhengzhou University,
Zhengzhou 450052, P. R. China (fax: þ 8637167767200; e-mail: jctao@zzu.edu.cn)
b) Henan Commerce Science Institute Co., Ltd., Zhengzhou 450052, P. R. China
In this work, six isosteviolꢀamino acid conjugates were designed and synthesized through simple
condensation on a large scale without protecting group (Scheme). These amphiphilic organocatalysts
mediated asymmetric three-component Mannich reactions of cyclohexanone and anilines with aromatic
aldehydes in the presence of H2O. Meanwhile, the isosteviolꢀproline conjugate 3b has been established
as a highly efficient catalyst (Table 1), and afforded syn-Mannich products with excellent diastereose-
lectivities (syn/anti up to 98 :2) and enantioselectivities (up to > 99% ee; Table 3). The transition state of
the reaction in the presence of H2O is proposed (Fig. 2).
Introduction. – The asymmetric Mannich reaction is one of the most important CꢀC
bond forming reactions for the production of optically enriched b-amino carbonyl
motifs [1]. It has been considered as a crucial synthetic methodology in the synthesis of
pharmaceutically valuable compounds and natural products [2]. The first organo-
catalyst-mediated direct asymmetric Mannich reaction was reported by List [3],
followed by excellent contributions from several groups [4]. Then, the amino acid
derivatives have been utilized as efficient catalysts. However, most of these reactions
proceed in polar organic solvents [5].
Water is the most friendly medium, which avoids the problems of pollution that are
inherent with organic solvents [6]. There is an endeavor to develop highly
´
enantioselective Mannich reaction in the presence of H2O. Ibrahem and Cordova [7]
have reported that l-proline catalyzes the three-component Mannich reaction in
DMSO/H2O. Then, the application of amino acid derivatives in asymmetric Mannich
´
reactions in aqueous media was further extended by excellent work by Cordova and co-
workers [8], and Wang and co-workers [9]. Although these reactions proceeded in an
aqueous solution, the polar organic solvents were dominant. The first finding that the
direct asymmetric Mannich reaction is promoted by a primary amino acid derivative in
a purely aqueous system was reported by Lu and co-workers [10]. Then, the application
of l-serine and l-proline derivatives in H2O were reported by Teo et al. [11], and
Hayashi et al. [12], respectively; however, only moderate yields were obtained using
cyclohexanone as the ketone part.
Results and Discussion. – As mentioned above, the reports about direct asymmetric
Mannich reactions in a purely aqueous system is rather sparse. We have previously
ꢀ 2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 95 (2012)
disclosed direct aldol reactions [13] and a-aminoxylation reactions [14] in aqueous
media promoted by isosteviolꢀproline conjugates. In the work presented here, we
designed and synthesized the amphiphilic isosteviolꢀamino acid conjugates 1 – 3 by a
simple condensation without protecting group (Scheme), and evaluated their catalytic
properties in asymmetric three-component Mannich reactions in the presence of H2O.
Meanwhile, the amphiphilic proline derivatives 4 [15] and 5 [16] with long alkyl chains
were also tested under these reaction conditions, to compare them with the catalysts 1 –
3 (see Fig. 1).
Scheme. Preparation of Amphiphilic Catalysts 1 – 3
Fig. 1. Structures of the Catalysts
First, the catalytic effect of the amphiphilic catalysts 1 – 5 for the asymmetric three-
component Mannich reaction in the presence of H2O was investigated, by performing
the reaction of 4-nitrobenzaldehyde, aniline, and cyclohexanone as a model, and the
results are compiled in Table 1. All of the isosteviolꢀamino acid conjugates 1 – 3 afford

Helvetica Chimica Acta – Vol. 95 (2012)
Table 1. Catalyst Screeninga)b)
45
Entry
Catalyst
Yield [%]c)
syn/antid)
ee [%]d)e)
1
2
3
4
5
6
7
8
1a
2a
3a
1b
2b
3b
4
97
61
46
77
69
90
36
95
71 : 29
77: 23
81 : 19
84 : 16
83 : 17
91 : 9
74
81
88
84
82
98
48
2
57: 43
45 : 55
5
a) For the screened catalysts, see Fig. 1. b) Reaction conditions: cyclohexanone (6; 0.75 mmol, 3 equiv.),
aniline (7; 0.25 mmol, 1 equiv.), 4-nitrobenzaldehyde (8; 0.25 mmol, 1 equiv.), and catalyst (10 mol-%)
in H2O (0.1 ml) for 23 h. c) Yield of isolated product. d) Determined by HPLC analysis on a Chiralpak
AD-H column. e) Value for the syn-product.
higher activities than long-chain alkyl-substituted proline derivatives 4 and 5, and gave
the syn-configured products (Entries 1 – 6 vs. 8 and 9). The configurations of the
Mannich products were determined by their NMR data (1H-NMR coupling constants)
and their behavior on HPLC analysis in comparison with the literature [7 – 9]. These
observations hint at the different effect of aggregation of catalysts on the surface of
H2O molecules. By application of the isosteviolꢀamino acid conjugates, it turned out
that the l-proline derivatives 3a and 3b were more suitable for the asymmetric three-
component Mannich reaction in the presence of H2O, due to the rational matching of l-
proline and the chiral cavity of isosteviol. Catalyst 3b led to the highest yield and
stereoselectivities in the presence of H2O (Entry 6).
The optimum condition was investigated, therefore, with catalyst 3b. The results are
collected in Table 2. The reaction, when carried out in the absence of H2O, led to
significantly lower dr and ee values (Entry 1). Addition of different amounts of H2O to
the reaction mixture was beneficial for the diastereo- and enantioselectivities. The
optimum amount of H2O was determined as 22 equiv. (0.1 ml) relative to the substrate,
thereby affording the product with high yield and stereoselectivity (Entry 6). The
addition of excess amount of H2O (44 equiv. or 110 equiv.) to the mixture did not lead
to any significant improvement in the activity and stereoselectivity (Entries 7 and 8).
The yield and ee value decreased when brine was used as reaction medium (Entry 9).
Then, excellent stereoselectivity was achieved by using PBS (phosphate buffered
saline) solutions (pH, 7.7) as solvent; however, the yield was poor (Entry 12). The
diastereoselectivity decreased with a reduced amount of cyclohexanone (Entry 13).
Then, the optimized reaction conditions were applied to Mannich reactions with
various aromatic aldehydes and amines (Table 3). Among the reactions of cyclo-

46
Helvetica Chimica Acta – Vol. 95 (2012)
Table 2. Optimization of Reaction Conditionsa)
Entry
H2O
Yield [%]b)
syn/antic)
ee [%]c)d)
1
2
3
4
5
6
7
8
9e)
10f)
11g)
12h)
13g)
–
74
82
79
78
83
90
78
73
78
64
49
48
61
67: 33
91 : 9
91 : 9
85
95
96
96
96
98
96
97
96
95
98
98
96
1 equiv.
2 equiv.
5 equiv.
10 equiv.
0.1 ml
0.2 ml
0.5 ml
brine
PBS, 4.5
PBS, 7.7
PBS, 9.1
0.1 ml
89 : 11
90 : 10
91 : 9
88 : 12
88 : 12
90 : 10
89 : 11
94 : 6
91 : 9
87: 13
a) Reaction conditions: cyclohexanone (6; 0.75 mmol, 3 equiv.), aniline (7; 0.25 mmol, 1 equiv.), 4-
nitrobenzaldehyde (8; 0.25 mmol, 1 equiv.), and catalyst 3b (10 mol %) in aqueous solvent for 23 h.
b) Yield of isolated product. c) Determined by HPLC analysis on a Chiralpak AD-H column. d) Value for
f
g
the syn-product. e) 0.1 ml of sat. NaCl soln. ) 0.1 ml of phosphate buffered saline (PBS) soln. ) 2 Equiv.
of cyclohexanone were used.
hexanone, aniline, and substituted benzaldehydes, nitrobenzaldehydes gave the best
diastereoselectivities (up to >99 :1 dr) and enantioselectivities (up to 99% ee),
although the yield was unsatisfactory with 2-nitrobenzaldehyde (Entry 2). It was rather
strange that the 4-fluorobenzaldehyde gave the anti-configured product with poor
stereoselectivity (Entry 3). The optimized conditions were extended to a series of
aromatic amines with 4-nitrobenzaldehyde as acceptor (Entries 5 – 10). The electronic
effect of the substituent of aniline 7 was the important factor for the stereoselectivity.
The halogenated anilines afforded high yields and excellent stereoselectivities in a
short time (Entries 8 and 9). Meanwhile, good yield and high enantiostereoselectivity
were obtained with 3-methylaniline (Entry 10). However, the alkoxy-substituted
anilines, afforded poor stereoselectivities with this catalytic system (Entries 6 and 7).
The configurations of the Mannich products were determined by their NMR data
and their behavior on HPLC analysis in comparison with the literature [7 – 9].
Although the mechanism of the actual Mannich reaction has yet to be elucidated, the
stereochemical course catalyzed by the amphiphilic catalyst 3b with cyclohexanone as
the donor molecule can be explained by a plausible transition state as depicted in Fig. 2.
With the mediation of the amphiphilic catalyst via H-bond formation, the aqueous
media and the organic reactants generate a biphase system. In the H2O-surrounded

Helvetica Chimica Acta – Vol. 95 (2012)
47
Table 3. Direct Asymmetric Mannich Reactions of Cyclohexanonea)
Entry
R1
R2
Product
Time [h]
Yield [%]b)
syn/antic)
ee [%]c)d)
1
2
3
4
5
6
7
8
9
H
H
H
H
4-Me
4-MeO
4-EtO
4-Cl
3-Br
3-Me
4-NO2
2-NO2
4-F
9a
9b
9c
9d
9e
9f
9g
9h
9i
23
23
23
23
4
4
4
4
4
90
38
46
70
56
48
75
> 99
90
98
91 : 9
> 99 : 1
44 : 56
61 : 39
76 : 24
49 : 51
46 : 54
94 : 6
98
> 99
62
82
89
48
37
> 99
> 99
97
4-Br
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
95 : 5
90 : 10
10
9j
4
a) Reaction conditions: cyclohexanone (6; 0.75 mmol, 3 equiv.), aromatic amines 7 (0.25 mmol,
1 equiv.), aromatic aldehydes 8 (0.25 mmol, 1 equiv.), and catalyst 3b (10 mol-%) in H2O (0.1 ml).
b) Yield of isolated product. c) Determined by HPLC analysis on a Chiralpak AD-H column. d) Value for
the syn-product.
Fig. 2. Proposed transition state of the reaction
organic microphase, the substrates and the catalyst assemble in a special order, and the
transition state can be stabilized by H-bonding between the N-atom of the (Z)-
configured imine and the COO group of the proline moiety of the catalyst. In the
transition state, the Si-face of the in situ generated acceptor imine is selectively
attacked by the catalytically generated enamine. Thus, the asymmetric Mannich
reaction catalyzed by 3b affords syn-configured products.

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Helvetica Chimica Acta – Vol. 95 (2012)
Conclusions. – In summary, the organocatalyst-mediated asymmetric three-
component Mannich reaction in the presence of H2O has been described. Among
the synthesized isosteviolꢀamino acid conjugates, the proline-derived amphiphilic
catalyst 3b exhibited good activity and stereoselectivity for the reaction of cyclo-
hexanone, substituted anilines and aromatic aldehydes, and led to high enantioselec-
tivities of the syn-products with H2O as the reaction medium. Further investigations on
the application of the amphiphilic isosteviolꢀproline conjugates in different asym-
metrically catalyzed processes are in progress and will be reported in due course.
Experimental Part
General. All chemicals were used as received unless otherwise noted. Reagent-grade solvents were
distilled prior to use. Chromatography was performed on silica gel (SiO2; 200 – 300 mesh). Enantiomeric
excess (ee) was determined by HPLC at r.t. with a Labtech 2006 pump equipped with Labtech UV600
ultradetector and Chiralpak AD-H (4.6 mm ꢁ 250 mm). M.p.: XT5A apparatus; uncorrected. Optical
rotations: Perkin Elmer 341 polarimeter. IR Spectra: Thermo Nicolet IR200 unit. 1H- and 13C-NMR
spectra: Bruker DPX 400 NMR spectrometer with TMS as an internal reference. HR-MS: Waters
Micromass Q-Tof MicroTM instrument using the ESI technique.
General Procedure for Preparation of Chiral Catalysts 1a – 3a (GP1). Isosteviol (6.36 g, 20 mmol)
was dissolved in SOCl2 (20 ml), and the mixture was stirred at r.t. for 1 h. After evaporating the solvent
under vacuum, amino acid (20 mmol) and CF3COOH (20 ml) were added. The resulting soln. was stirred
at r.t. for 2 h. Under cooling with an ice/water bath, Et2O (40 ml) was added carefully to give a fine white
precipitate that was vacuum-filtered, washed with Et2O (5 ml ꢁ 2), and dried at r.t. for 2 h to give the
hydrochloride as a fine white powder. The white powder was dissolved in 40 ml of warm 95% EtOH, and
propylene oxide (10 ml) was then added. Stirring was discontinued, and the soln. was left for
crystallization at r.t. for 7 h. The crystalline product was vacuum-filtered and dried at r.t. in vacuo to give
product 1a – 3a.
(2S)-O-(ent-16-Oxobeyerane-19-carbonyl)serine (¼O-(16,18-Dioxobeyeran-18-yl)-l-serine; 1a) was
prepared according to the GP1 using l-serine. Yield 6.73 g (83%). White solid. M.p. 125 – 1268. [a]D20
¼
ꢀ50.6 (c ¼ 0.25, MeOH). IR: 3418, 2949, 2848, 1735, 1651, 1149, 1128. 1H-NMR (400 MHz, DMSO): 7.95
(br. s, 1 H); 2.89 (s, 1 H); 2.73 (s, 1 H); 2.01 (d, J ¼ 13.0, 1 H); 1.89 – 1.85 (m, 1 H); 1.78 – 1.73 (m, 2 H);
1.69 – 1.62 (m, 4 H); 1.53 – 1.50 (m, 1 H); 1.40 – 1.32 (m, 5 H); 1.23 – 1.11 (m, 4 H); 1.16 (s, 3 H); 1.02 – 0.87
(m, 3 H); 0.92 (s, 3 H); 0.73 (s, 3 H). 13C-NMR (100 MHz, DMSO): 221.3; 179.2; 162.9; 67.8; 56.6; 54.4;
53.9; 48.4; 48.3; 43.4; 41.2; 39.9; 38.2; 37.2; 36.3; 31.3; 29.3; 22.1; 20.4; 20.3; 19.2; 13.7. HR-ESI-MS:
428.2413 ([M þ Na]þ, C23H35NNaOþ5 ; calc. 428.2407).
(2S,3R)-O-(ent-16-Oxobeyerane-19-carbonyl)threonine (¼O-(16,18-Dioxobeyeran-18-yl)-l-threo-
nine; 2a) was prepared according to the GP1 using l-threonine. Yield 7.17 g (86%). White solid. M.p.
122 – 1238. [a]2D0 ¼ ꢀ50.3 (c ¼ 0.50, MeOH). IR: 3412, 2948, 2847, 1734, 1638, 1165, 1129. 1H-NMR
(400 MHz, DMSO): 5.19 (q, J ¼ 2.8, 1 H); 3.36 (br. s, 2 H); 3.33 (d, J ¼ 2.2, 1 H); 2.11 (d, J ¼ 12.7, 1 H);
1.83 – 1.75 (m, 2 H); 1.69 – 1.59 (m, 5 H); 1.51 – 1.33 (m, 6 H); 1.23 (d, J ¼ 6.4, 3 H); 1.16 – 1.05 (m, 4 H);
1.11 (s, 3 H); 0.95 – 0.81 (m, 2 H); 0.86 (s, 3 H); 0.61 (s, 3 H). 13C-NMR (100 MHz, DMSO): 221.7; 175.9;
168.8; 70.1; 57.8; 56.8; 54.3; 53.8; 48.5; 48.4; 44.0; 41.5; 39.7; 38.0; 37.8; 37.2; 29.0; 21.6; 20.5; 20.3; 19.3;
17.2; 13.8. HR-ESI-MS: 420.2750 ([M þ H]þ, C24H38NO5þ ; calc. 420.2745).
(2S,4R)-4-[(ent-16-Oxobeyerane-19-carbonyl)oxy]proline (¼(4R)-4-[(16,18-Dioxobeyeran-18-
yl)oxy]-l-proline; 3a) was prepared according to the GP1 using l-proline. Yield 7.42 g (86%). White
solid. M.p. 176 – 1788. [a]2D0 ¼ ꢀ56.7 (c ¼ 0.13, CHCl3). IR: 3601, 3448, 2955, 2849, 1733, 1654, 1149, 1130.
1H-NMR (400 MHz, CDCl3): 5.23 (s, 1 H); 4.13 (d, J ¼ 1.68, 1 H); 3.60 (s, 1 H); 3.38 (s, 1 H); 2.62 (d, J ¼
20, 1 H); 2.44 (s, 1 H); 2.29 (s, 1 H); 2.18 (d, J ¼ 12, 3 H); 1.88 – 1.78 (m, 2 H); 1.66 – 1.38 (m, 10 H); 1.18
(s, 3 H); 1.12 – 1.09 (m, 2 H); 0.95 (s, 3 H); 0.98 – 0.85 (m, 2 H); 0.69 (s, 3 H). 13C-NMR (100 MHz,
CDCl3): 222.5; 176.5; 173.1; 72.3; 59.7; 57.0; 54.5; 54.1; 49.8; 48.6; 48.4; 43.8; 41.4; 39.6; 39.4; 38.0; 37.5;
37.2; 35.4; 28.9; 21.5; 20.3; 19.8; 19.0; 13.8. HR-ESI-MS: 454.2569 ([M þ Na]þ, C25H37NNaO5þ ; calc.
454.2570).

Helvetica Chimica Acta – Vol. 95 (2012)
49
General Procedure for Preparation of Chiral Catalysts 1b – 3b (GP2). A soln. of compound 1a – 3a
(20 mmol) and NaBH4 (1.71 g; 30 mmol) in dry EtOH (100 ml) was stirred at 08 for 2 h. The mixture was
then concentrated under vacuum, and treated with CHCl3 and H2O. The org. layer was separated and
washed with sat. aq. NaCl soln. Then, the solvent was dried (anh. MgSO4) and evaporated under vacuum
to afford crude product. After recrystallization from MeOH, the catalyst 1b – 3b was obtained as a white
powder.
(2S)-O-(ent-16-Hydroxybeyerane-19-carbonyl)serine (¼O-[(16a)-16-Hydroxy-18-oxobeyeran-18-
yl]-l-serine; 1b) was prepared according to GP2 using l-serine. Yield 7.82 g (96%). White solid. M.p.
148 – 1498. [a]2D0 ¼ ꢀ43.3 (c ¼ 0.64 in MeOH). IR: 3404, 2938, 2845, 1716, 1637, 1455, 1231, 1175, 1147.
1H-NMR (400 MHz, DMSO): 4.36 – 4.34 (m, 1 H); 4.09 – 4.05 (m, 1 H); 3.66 – 3.64 (m, 1 H); 3.53 – 3.52
(m, 1 H); 2.13 (d, J ¼ 11.6, 1 H); 1.72 – 1.48 (m, 8 H); 1.43 – 1.39 (m, 2 H); 1.32 – 1.22 (m, 2 H); 1.19 – 1.16
(m, 1 H); 1.12 (s, 3 H); 1.09 – 0.91 (m, 6 H); 0.81 (s, 3 H); 0.65 (s, 3 H). 13C-NMR (100 MHz, DMSO):
176.9; 169.4; 78.8; 64.9; 57.1; 56.4; 56.0; 55.5; 53.7; 49.0; 43.7; 43.1; 42.1; 38.0; 37.7; 34.2; 29.0; 25.5; 21.6;
20.3; 19.2; 19.0; 13.6. HR-ESI-MS: 430.2569 ([M þ Na]þ, C23H37NNaO5þ ; calc. 430.2564).
(2S,3R)-O-(ent-16-Hydroxybeyerane-19-carbonyl)threonine (¼O-[(16a)-16-Hydroxy-18-oxobeyer-
an-18-yl]-l-threonine; 2b) was prepared according to GP2 using l-threonine. Yield 8.00 g (95%). White
solid. M.p. 145 – 1468. [a]2D0 ¼ ꢀ36.1 (c ¼ 0.7 in MeOH). IR: 3417, 2940, 2844, 1713, 1635, 1453, 1406, 1228,
1147, 1026. 1H-NMR (400 MHz, DMSO): 5.26 (q, J ¼ 3.4, 1 H); 3.73 – 3.69 (dd, J ¼ 4.0, 1 H); 3.40 – 3.38
(m, 1 H); 2.20 (d, J ¼ 12.6, 1 H); 1.96 (br. s, 1 H); 1.78 – 1.58 (m, 8 H); 1.50 – 1.44 (m, 2 H); 1.38 – 1.22 (m,
3 H); 1.31 (d, J ¼ 6.4, 3 H); 1.14 (s, 3 H); 1.11 – 0.96 (m, 5 H); 0.87 (s, 3 H); 0.93 – 0.83 (m, 1 H); 0.71 (s,
3 H). 13C-NMR (100 MHz, DMSO): 175.7; 170.9; 78.8; 69.5; 60.2; 57.8; 57.0; 55.9; 49.0; 43.9; 43.0; 42.1;
38.1; 37.6; 34.2; 29.2; 25.5; 21.5; 21.2; 20.3; 19.3; 17.1; 14.5; 14.1. HR-ESI-MS: 444.2726 ([M þ Na]þ,
C24H39NNaOþ5 ; calc. 444.2721).
(2S,4R)-4-[(ent-16-Hydroxybeyerane-19-carbonyl)oxy]proline (¼(4R)-4-{[(16a)-16-Hydroxy-18-
oxobeyeran-18-yl]oxy}-l-proline; 3b) was prepared according to GP2 method using l-proline. Yield
8.15 g (94%). White solid. M.p. 167 – 1708. [a]D20 ¼ ꢀ50.0 (c ¼ 0.12, MeOH). IR: 3422, 2926, 2847, 1719,
1
1596, 1438, 1384, 1176, 1150. H-NMR (400 MHz, CDCl3): 5.26 (s, 1 H); 4.20 (s, 1 H); 3.81 (d, J ¼ 5.6,
2 H); 3.30 (d, J ¼ 16.4, 1 H); 2.39 – 2.30 (m, 2 H); 2.14 (d, J ¼ 16.4, 1 H); 1.74 – 1.70 (m, 6 H); 1.53 – 1.38
(m, 5 H); 1.29 – 1.23 (m, 2 H); 1.17 (s, 3 H); 1.07 – 0.73 (m, 9 H); 0.89 (s, 3 H); 0.73 (s, 3 H). 13C-NMR
(100 MHz, CDCl3): 177.0; 80.1; 72.7; 60.6; 57.0; 55.7; 55.0; 50.2; 43.8; 42.5; 42.0; 41.9; 41.6; 40.3; 39.7; 38.1;
37.7; 35.0; 33.7; 28.9; 24.9; 21.7; 20.4; 18.8; 13.8. HR-ESI-MS: 456.2726 ([M þ Na]þ, C25H39NNaO5þ ; calc.
456.2726).
General Procedure for the Asymmetric Mannich Reactions of Cyclohexanone (Table 3). The mixture
of aldehyde (0.25 mmol, 1 equiv.), catalyst 3b (10 mmol-%), and aniline (0.25 mmol, 1 equiv.) in H2O
(0.1 ml) were stirred for 1 h at r.t. followed by addition of cyclohexanone (0.75 mmol, 3 equiv.). After
stirring for the corresponding reaction time at r.t., the resulting mixture was purified by TLC on SiO2
(petroleum ether (PE)/AcOEt) to provide the product.
2-[(4-Nitrophenyl)(phenylamino)methyl]cyclohexanone (9a). HPLC (for syn): Daicel Chiralpak
AD-H; hexane/i-PrOH 85 :15; flow rate, 1.0 ml/min, UV 254 nm; tR(major) 22.4, tR(minor) 16.0 min. IR:
3416, 3045, 2923, 2853, 1706, 1598, 1515, 1342, 1258. 1H-NMR (400 MHz, CDCl3; syn-isomer): 8.14 (dd,
J ¼ 1.7, 8.7, 2 H); 7.56 (d, J ¼ 8.7, 2 H); 7.18 (t, J ¼ 8.2, 2 H); 6.68 (t, J ¼ 7.3, 1 H); 6.49 (d, J ¼ 7.7, 2 H); 4.85
(d, J ¼ 4.4, 1 H); 4.71 (d, J ¼ 5.3, 1 H); 2.86 – 2.83 (m, 1 H); 2.43 – 2.32 (m, 2 H); 2.08 – 1.92 (m, 2 H);
1.65 – 1.60 (m, 4 H). 13C-NMR (100 MHz, CDCl3, syn-isomer): 210.6; 149.5; 147.0; 146.5; 129.2; 128.5;
123.6; 118.3; 113.9; 57.31; 56.1; 42.4; 29.0; 27.0; 24.9.
2-[(2-Nitrophenyl)(phenylamino)methyl]cyclohexanone (9b). HPLC (for syn): Daicel Chiralpak
OD-H; hexane/i-PrOH 85 :15, flow rate, 0.8 ml/min; UV 254 nm; tR(major) 30.0, tR(minor) 55.8 min. IR:
3378, 3056, 2934, 2857, 1698, 1586, 1515, 1353. 1H-NMR (400 MHz, CDCl3, syn-isomer): 7.96 (d, J ¼ 8.0,
1 H); 7.77 (d, J ¼ 7.8, 2 H), 7.53 (t, J ¼ 7.3, 1 H); 7.49 (t, J ¼ 8.0, 1 H); 7.10 (t, J ¼ 7.8, 2 H); 6.70 (t, J ¼ 7.3,
1 H); 6.57 (d, J ¼ 8.0, 2 H); 5.63 (d, J ¼ 4.3, 1 H); 5.47 (d, J ¼ 7.0, 1 H); 3.01 – 2.96 (m, 1 H); 2.48 – 2.31 (m,
2 H); 2.11 – 2.02 (m, 2 H); 1.72 – 1.57 (m, 4 H). 13C-NMR (100 MHz, CDCl3; syn-isomer): 210.2; 149.2;
146.6; 137.2; 133.1; 130.3; 129.2; 128.0; 125.1; 118.4; 114.0; 55.4; 52.2; 42.4; 29.7; 28.4; 27.3; 25.0.
2-[(4-Fluorophenyl)(phenylamino)methyl]cyclohexanone (9c). HPLC (for syn): Daicel Chiralpak
AD-H; hexane/i-PrOH 85 :15; flow rate, 1.0 ml/min; UV 254 nm; tR(major) 24.2, tR(minor) 15.6 min. IR:

50
Helvetica Chimica Acta – Vol. 95 (2012)
3399, 3051, 2937, 2862, 1705, 1602, 1505, 1316, 1221, 837, 750, 692. 1H-NMR (400 MHz, CDCl3; syn-
isomer): 7.47 (dd, J ¼ 7.3, 2 H); 7.10 – 7.08 (m, 2 H); 7.00 – 6.97 (m, 2 H); 6.77 (q, J ¼ 6.8, 1 H); 6.58 – 6.55
(m, 2 H); 4.80 (d, J ¼ 4.4, 1 H); 4.67 (d, J ¼ 6.6, 1 H); 2.81 – 2.76 (m, 1 H); 2.44 – 2.30 (m, 2 H); 1.94 – 1.62
(m, 6 H). 13C-NMR (100 MHz, CDCl3; syn-isomer): 212.5; 163.0; 160.6; 147.1; 137.5; 129.1; 117.6; 115.3;
113.6; 57.3; 56.7; 41.9; 31.3; 27.8; 23.8.
2-[(4-Bromophenyl)(phenylamino)methyl]cyclohexanone (9d). HPLC (for syn): Daicel Chiralpak
AD-H; hexane/i-PrOH 85 :15, flow rate, 1.0 ml/min; UV 254 nm; tR(major) 21.0; tR(minor) 15.6 min. IR:
3396, 3050, 2935, 2861, 1704, 1601, 1502, 1315, 1070, 1008, 825, 750, 692. 1H-NMR (400 MHz, CDCl3; syn-
isomer): 7.43 – 7.41 (m, 2 H); 7.29 – 7.25 (m, 2 H); 7.10 – 7.06 (m, 2 H); 6.69 – 6.63 (m, 1 H); 6.54 – 6.52 (m,
2 H); 4.76 (d, J ¼ 4.0, 1 H); 4.63 (d, J ¼ 6.3, 1 H); 2.79 – 2.75 (m, 1 H); 2.43 – 2.28 (m, 2 H); 1.99 – 1.89 (m,
2 H); 1.78 – 1.57 (m, 4 H). 13C-NMR (100 MHz, CDCl3, syn-isomer): 212.3; 147.1; 141.0; 131.5; 129.2;
129.1; 120.8; 117.7; 113.6; 57.2; 56.4; 42.0; 31.5; 27.9; 24.0.
2-{[(4-Methylphenyl)amino](4-nitrophenyl)methyl}cyclohexanone (9e). HPLC (for syn): Daicel
Chiralpak AD-H, hexane/i-PrOH 80 :20; flow rate, 0.8 ml/min; UV 254 nm, tR(major) 26.6; tR(minor)
24.9 min. IR: 3388, 3021, 235, 2861, 1706, 1616, 1517, 1448, 1344, 1127, 855, 810, 702. 1H-NMR (400 MHz,
CDCl3; syn-isomer): 8.14 (d, J ¼ 8.5, 2 H); 7.59 – 7.55 (m, 2 H); 6.89 (d, J ¼ 8.0, 2 H); 6.44 (d, J ¼ 8.4, 2 H);
4.86 (d, J ¼ 4.4, 1 H); 4.72 (d, J ¼ 7.6, 1 H); 2.88 – 2.82 (m, 1 H); 2.42 – 2.30 (m, 2 H); 2.17 (s, 3 H); 2.05 –
1.89 (m, 3 H); 1.74 – 1.70 (m, 2 H); 1.62 – 1.56 (m, 1 H). 13C-NMR (100 MHz, CDCl3; syn-isomer): 211.8;
150.1; 146.9; 130.7; 128.3; 127.2; 123.6; 113.6; 57.9; 57.0; 42.3; 31.9; 27.8; 24.4; 20.3.
2-{[(4-Methoxyphenyl)amino)(4-nitrophenyl)methyl}cyclohexanone (9f). HPLC (for syn): Daicel
Chiralpak AD-H; hexane/i-PrOH 80 :20; flow rate, 0.8 ml/min; UV 254 nm; tR(major) 35.7; tR(minor)
38.1 min. IR: 3394, 3027, 2935, 2861, 1705, 1600, 1513, 1463, 1344, 1245, 1036, 854, 822. 1H-NMR
(400 MHz, CDCl3; syn-isomer): 8.15 (d, J ¼ 8.6, 2 H); 7.58 – 7.54 (m, 2 H); 6.69 – 6.64 (m, 2 H); 6.46 (d,
J ¼ 8.8, 2 H); 4.80 (d, J ¼ 4.2, 1 H); 4.65 (d, J ¼ 5.6, 1 H); 3.68 (s, 3 H); 2.84 – 2.80 (m, 1 H); 2.42 – 2.30 (m,
2 H); 1.98 – 1.89 (m, 2 H); 1.78 – 1.62 (m, 4 H). 13C-NMR (100 MHz, CDCl3; syn-isomer): 211.8; 152.4;
150.0; 147.0; 140.7; 128.3; 123.6; 115.6; 114.8; 58.7; 57.0; 55.6; 43.4; 31.8; 27.7; 24.4.
2-{[(4-Ethoxyphenyl)amino](4-nitrophenyl)methyl}cyclohexanone (9g). HPLC: Daicel Chiralpak
AD-H; hexane/i-PrOH 80 :20; flow rate, 0.8 ml/min; UV 254 nm: tR(major) 30.1; tR(minor) 25.8 min. IR:
1
3395, 3067, 2934, 2865, 1706, 1597, 1512, 1478, 1344, 1235, 854, 820. H-NMR (400 MHz, CDCl3; syn-
isomer): 8.13 (d, J ¼ 8.6, 2 H); 7.57 – 7.53 (m, 2 H); 6.66 (d, J ¼ 8.8, 2 H); 6.44 (d, J ¼ 8.8, 2 H); 4.79 (d, J ¼
4.2, 1 H); 4.65 (d, J ¼ 5.6, 1 H); 3.88 (q, J ¼ 6.9, 2 H); 2.83 – 2.79 (m, 1 H); 2.44 – 2.29 (m, 2 H); 1.94 – 1.86
(m, 2 H); 1.76 – 1.58 (m, 4 H); 1.32 (t, J ¼ 6.9, 3 H). 13C-NMR (100 MHz, CDCl3; syn-isomer): 211.8;
151.8; 150.1; 147.0; 140.7; 128.4; 123.6; 115.6; 115.1; 63.9; 58.7; 57.0; 42.3; 31.8; 27.8; 24.4; 14.9.
2-{[(4-Chlorophenyl)amino](4-nitrophenyl)methyl}cyclohexanone (9h). HPLC (for syn): Daicel
Chiralpak AD-H; hexane/i-PrOH 80 :20; flow rate, 0.8 ml/min, UV 254 nm; tR(major) 29.9, tR(minor)
24.3 min. IR: 3428, 3024, 2943, 2858, 1702, 1600, 1512, 1346, 1108, 729, 708. 1H-NMR (400 MHz, CDCl3;
syn-isomer): 8.13 (d, J ¼ 8.4, 2 H); 7.55 – 7.51 (m, 2 H); 6.99 (d, J ¼ 8.7, 2 H); 6.41 (d, J ¼ 8.7, 2 H); 4.81 (d,
J ¼ 4.3, 1 H); 4.65 (d, J ¼ 5.3, 1 H); 2.85 – 2.83 (m, 1 H); 2.44 – 2.28 (m, 2 H); 1.91 – 1.58 (m, 6 H).
13C-NMR (100 MHz, CDCl3; syn-isomer): 211.9; 149.4; 147.0; 145.4; 129.0; 128.3; 123.7; 122.6; 114.6;
57.9; 56.9; 42.4; 32.1; 27.8; 24.5.
2-{[(3-Bromophenyl)amino](4-nitrophenyl)methyl}cyclohexanone (9i). HPLC (for syn): Daicel
Chiralpak AD-H; hexane/i-PrOH 80 :20; flow rate, 0.8 ml/min, UV 254 nm; tR(major) 26.8, tR(minor)
17.9 min. IR: 3397, 3070, 2937, 2861, 1705, 1677, 1594, 1518, 1479, 1344, 853, 763, 702. 1H-NMR (400 MHz,
CDCl3; syn-isomer): 8.08 (d, J ¼ 8.5, 2 H); 7.53 – 7.49 (m, 2 H); 6.87 – 6.83 (m, 1 H); 6.71 – 6.69 (m, 1 H);
6.63 – 6.62 (m, 1 H); 6.37 – 6.35 (m, 1 H); 4.82 (d, J ¼ 4.1, 1 H); 4.66 (d, J ¼ 5.1, 1 H); 2.85 – 2.80 (m, 1 H);
2.35 – 2.24 (m, 2 H); 1.86 – 1.83 (m, 2 H); 1.67 – 1.55 (m, 4 H). 13C-NMR (100 MHz, CDCl3; syn-isomer):
211.6; 149.2; 148.2; 147.0; 130.4; 128.5; 123.6; 120.8; 116.6; 112.3; 56.7; 42.3; 32.1; 28.8; 27.0; 24.8.
2-{[(3-Methylphenyl)amino](4-nitrophenyl)methyl}cyclohexanone (9j). HPLC (for syn): Daicel
Chiralpak AD-H, hexane/i-PrOH 80 :20; flow rate, 0.8 ml/min, UV 254 nm; tR(major) 23.7, tR(minor)
1
17.8 min. IR: 3380, 3038, 2921, 2855, 1706, 1604, 1518, 1489, 1344, 854, 772, 694. H-NMR (400 MHz,
CDCl3; syn-isomer): 8.14 (d, J ¼ 8.6, 2 H); 7.57 (t, J ¼ 8.4, 2 H); 6.96 (t, J ¼ 7.7, 1 H); 6.51 – 6.48 (m, 1 H);
6.36 (s, 1 H); 6.28 (d, J ¼ 7.9, 1 H); 4.87 (d, J ¼ 4.5, 1 H); 4.73 (d, J ¼ 5.2, 1 H); 2.88 – 2.84 (m, 1 H); 2.42 –

Helvetica Chimica Acta – Vol. 95 (2012)
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2.32 (m, 2 H); 2.19 (s, 3 H); 1.96 – 1.60 (m, 6 H). 13C-NMR (100 MHz, CDCl3; syn-isomer): 211.8; 150.1;
139.0; 128.6; 123.6; 119.0; 114.9; 114.4; 110.9; 110.4; 57.0; 56.3; 42.4; 32.0; 29.0; 27.8; 24.4.
The authors are grateful to the Natural Science Foundation of China (NSFC 20772113) for the
financial support.
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Received June 23, 2011