Catalytic asymmetric Michael addition with curcumin derivative

Article abstract of DOI:10.1039/c0ob00757a

Catalytic asymmetric Michael additions with curcumin derivatives were achieved by a new series of tertiary amine-thiourea organocatalysts to afford the Michael adducts in high yields and excellent enantioselectivities.

Full text of DOI:10.1039/c0ob00757a

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PAPER
Catalytic asymmetric Michael addition with curcumin derivative†
Wenjun Li, Wenbin Wu, Feng Yu, Huicai Huang, Xinmiao Liang and Jinxing Ye*
Received 21st September 2010, Accepted 5th January 2011
DOI: 10.1039/c0ob00757a
Catalytic asymmetric Michael additions with curcumin derivatives were achieved by a new series of
tertiary amine–thiourea organocatalysts to afford the Michael adducts in high yields and excellent
enantioselectivities.
Introduction
Curcumin, obtained from the spice turmeric, has been used as
a dietary spice and herbal medicine for centuries. Recently, the
development of curcumin derivatives has drawn much attention
because of their considerable biological activities including anti-
malarial, anti-angiogenesis and anti-oxidant activities.1 Besides,
curcumin also acts as a selective cyclooxygenase-1 (COX-1)
inhibitor, which plays an important role in inflammation and
carcinogenesis.2
As one of the most important Michael additions in organic
chemistry, the conjugate addition of nitroolefins has attracted
much attention, which could be attributed to the construction of
chiral building blocks.3–4 In recent years, various nucleophiles, such
as nitroalkanes,5 malonate esters,6 a,a-dicyanoolefins,7 aldehydes8
Fig. 1 Structure of tertiary amine–thiourea catalysts.
and ketones9 have been developed for the Michael additions
of nitroolefins. For asymmetric synthesis, organocatalysts have
exhibited high catalytic activities and will hold tremendous
potential in the future.10 It is worthwhile to note that massive
progress has been made in the development of tertiary amine–
thiourea organocatalysts, which are an efficient tool for promoting
the Michael addition of nitroolefins (Fig. 1, 1a–1d).11–14 Although
chemists have made great effort towards the Michael addition
of nitroolefins, the development of a new type of organocatalyst
and search for new nucleophiles remain a great challenge. To the
best of our knowledge, although enantioselective Michael addition
reactions of 1,3-diketones to nitroolefins have been developed,15
asymmetric enantioselective Michael addition reactions of curcumin
to nitroolefins have not been reported so far.16 Herein we pre-
sented the enantioselective organocatalytic Michael additions of
curcumin derivatives to nitroolefins with high yields and up to
97% ee value for the first time.
Results and discussion
We started our investigations using tertiary amine–thiourea
organocatalysts (1a–1d) to promote the reaction and the rep-
resentative results are summarized in Table 1. To our delight,
the reaction of nitroolefin 2a and curcumin derivative 3a in the
presence of 10 mol% of 1a–1d afforded the Michael adduct 4a
in good conversions (78–87%) with good enantioselectivities (80–
89%) after 5 h (entries 1–4). This outcome demonstrated that
the Michael addition of nitroolefin 2a and curcumin derivative 3a
could be efficiently catalyzed by the chiral tertiary amine–thiourea
organocatalysts.
Encouraged by the promising results obtained, we designed and
synthesized a new series of tertiary amine–thiourea organocat-
alysts, which consisted of 9-amino(9-deoxy)epiquinine and 1,2-
diphenylethene-diamine moieties (Fig. 1, 1e–1n). Then we ex-
plored these organocatalysts (1e–1n) for the Michael reaction.
Gratifyingly, up to 95% conversion with 95% ee was obtained in
the presence of 10 mol% of 1e, which bears two CF3 groups in the
sulfonamide NHSO2R2 (entry 5). We next examined the catalytic
activities of other organocatalysts (1f–1n), which had different
substituents on the sulfonamide NHSO2R2. Further investigations
revealed that the position and the number of CF3 groups in the
sulfonamide would influence the enantioselectivity. For example,
92% and 86% ee values were obtained in the presence of 1f
Engineering Research Centre of Pharmaceutical Process Chemistry, Min-
istry of Education, School of Pharmacy, East China University of
Science and Technology, 130 Meilong Road, Shanghai 200237, China.
E-mail: yejx@ecust.edu.cn
† Electronic supplementary information (ESI) available. CCDC reference
numbers 794851. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c0ob00757a
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Table 1 Catalyst screen for the Michael reaction between 2a and 3a
Table 2 Solvent and catalyst loading screens for the Michael reaction
between 2a and 3a
Entrya
Catalyst
Conv. (%)b
ee (%)c
Entrya
Solvent
Time/h
Conv. (%)b
ee (%)c
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
87
78
84
86
95
93
94
94
97
95
91
91
95
88
80
81
86
89
95
92
86
96
97
90
87
96
93
51
1
2
CH2Cl2
Toluene
CHCl3
CH2Cl2
CH2Cl2
5
5
5
12
12
97
94
93
97
92
97
84
81
96
92
3
4d
5e
a Reaction conditions: A mixture of 2a (0.05 mmol), 3a (0.075 mmol)
and catalyst 1i (10 mol%) in the solvent (0.3 mL) was stirred at
room temperature for the time given in the table. b The conversion was
determined by the crude 1H NMR. c Determined by HPLC. d Catalyst
(5 mol%). e Catalyst (2 mol%).
9
10
11
12
13
14
a Reaction conditions: A mixture of 2a (0.05 mmol), 3a (0.075 mmol) and
catalyst (10 mol%) in CH2Cl2 (0.3 mL) was stirred at room temperature for
5 h. b The conversion was determined by the crude 1H NMR. c Determined
by HPLC.
reduced to 2 mol%, 92% conversion and 92% ee were still achieved
after 12 h (entry 5). These encouraging outcomes indicated that
this type of organocatalyst (1e–1n) may have great potential in
catalyzing the Michael addition of nitroolefins efficiently.
With the optimized reaction conditions in hand, the scope of the
Michael reaction was investigated. As illustrated in Table 3, a wide
range of aryl nitroolefins, which bear electron-rich and electron-
deficient groups on the o-, m-, p-positions of benzene ring, reacted
with curcumin derivative (3a) smoothly with high yields (73–
96%) and excellent enantioselectivities (89–97%) (entries 1–13).
Noticeably, the methodology was also applicable to heterocyclic
nitroolefins. For example, up to 62% yield with 93% ee was
obtained when (2-nitrovinyl)furan was used (entry 14). Moreover,
alkyl nitroolefins also exhibited high reactivities. The Michael
addition of curcumin derivative to nitropent-1-ene gave 82% yield
with 92% ee (entry 15). While other alkyl nitroolefins, such as
3-methyl-1- nitrobut-1-ene, resulted in 72% yield with 84% ee
(entry16). To our delight, the Michael additions of other curcumin
derivatives (3b–3e) to nitroolefin also achieved good results (entries
17–20). High yields ranging from 72% to 82% with excellent
enantioselectivities (90–96%) were observed correspondingly.
In order to determine the absolute configuration of the Michael
addition adduct, enantiopure 4ea was fortunately obtained. The
absolute stereoconfiguration of 4ea was determined to be S by
X-ray crystal structural analysis (Fig. 2).17 A plausible transition
state was proposed to illustrate the stereochemical outcome of
the Michael addition (Fig. 3). The curcumin derivative and
nitroolefin were separately activated by the tertiary amine and
thiourea through hydrogen bonding. This may direct the attack
of the curcumin derivative toward one enantioface of the double
bond. The sulfonamide group simultaneously blocks the other
enantioface of the double bond through steric hindrance to give
the S adduct with an excellent ee value.
and 1g (entry 6–7). The reaction proceeded to 94% conversion
with 96% ee using 10 mol% of 1h, which bears two chlorine
groups on the aromatic ring (entry 8). It seemed that the strong
electron-withdrawing group in the sulfonamide would be helpful
to the enantioselective control. As we expected, the best results
(97% conversion, 97% ee) were obtained if a nitro group was
introduced to the aromatic ring (entry 9). However, when the
electron-withdrawing group in the sulfonamide was replaced with
an electron-donating one, the ee values decreased to 90% and
87% (entries 10–11) in the presence of 1j (R2 = CH3) and 1k
(R2 = 4-CH3C6H4). When bulkier groups in the sulfonamide were
introduced to the catalyst (1l, R2 = 2,4,6-Me3C6H2; 1m, R2 = 2,4,6-
i-Pr3C6H2), a slight decrease of conversion and enantioselectivity
was induced (entries 12–13), which could be attributed to the
steric block between the catalyst and the substrate. However,
if the (S,S)-1,2-diphenyl-ethenediamine was replaced with the
(R,R)-1,2-diphenyl-ethenediamine, 1n instead of catalyst 1e, the
enantioselectivity decreased to 51% with 88% of conversion, but
the configuration of the Michael adduct was not altered (entry
14). Therefore, it could be concluded that the (S,S)-1,2-diphenyl-
ethenediamine would match 9-amino(9-deoxy)epiquinine and the
configuration of the desired adduct was mainly determined by
9-amino(9-deoxy)epiquinine.
Having identified organocatalyst 1i as the best choice in the
catalyst family, the effect of solvent was consequently taken into
account. Noticeably, 3a was soluble in dichloromethane, partially
soluble in toluene, CHCl3 and insoluble in other solvents. As
shown in Table 2, the reaction in toluene and CHCl3 resulted in
lower enantioselectivities (entries 2–3). As we know, low catalyst
loading and fast reaction rate are vital goals in organocatalysis.
Therefore, we next promoted the reaction in the presence of a
lower catalyst loading. To our delight, good results could still
be obtained when a lower catalyst loading was employed. In the
presence of 5 mol% of 1i, up to 97% conversion and 96% ee were
obtained after 12 h (entry 4). Even when the catalyst loading was
Conclusions
In conclusion, catalytic asymmetric Michael additions with cur-
cumin derivatives were achieved by a new series of tertiary amine–
thiourea organocatalysts, which bear tertiary amine, thiourea
and sulfonamide. It is noteworthy that the Michael additions of
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Table 3 Enantioselective Michael reactions of nitroolefins 2 with curcumin derivatives 3 in the presence of 1i
Entrya
R1 (2)
R2 (3)
t/h
Yield (%, 4)b
ee (%)c
1
2
3
4
5
6
7
8
C6H5(2a)
C6H5(3a)
12
72
72
72
18
18
72
72
24
24
24
18
24
72
48
96
144
72
72
72
96(4aa)
86(4ba)
81(4ca)
74(4da)
81(4ea)
85(4fa)
76(4ga)
93(4ha)
82(4ia)
92(4ja)
73(4ka)
85(4la)
84(4ma)
62(4na)
82(4oa)
72(4pa)
78(4ab)
72(4ac)
73(4ad)
82(4ae)
96
97
93
90
90
95
92
90
89
96
95
91
90
93
92
84
90
92
96
92
2-ClC6H4(2b)
3-ClC6H4(2c)
4-ClC6H4(2d)
3-BrC6H4(2e)
2-FC6H4(2f)
3-FC6H4(2g)
4-FC6H4(2h)
4-MeOC6H4(2i)
2,3-(MeO)2C6H3(2j)
2,4-(MeO)2C6H3(2k)
4-MeC6H4(2l)
2-Naphthyl(2m)
2-Furanyl(2n)
n-Pr(2o)
C6H5(3a)
C6H5(3a)
C6H5(3a)
C6H5(3a)
C6H5(3a)
C6H5(3a)
C6H5(3a)
9
C6H5(3a)
10
11
12
13
14
15
16d,e
17
18d
19d
20
C6H5(3a)
C6H5(3a)
C6H5(3a)
C6H5(3a)
C6H5(3a)
C6H5(3a)
i-Pr (2p)
C6H5(3a)
C6H5(2a)
4-MeC6H4(3b)
4-ClC6H4(3c)
2-FC6H4(3d)
3-MeO-4-AcOC6H3(3e)
C6H5 (2a)
C6H5 (2a)
C6H5(2a)
a Reaction conditions: A mixture of 2 (0.15 mmol), 3 (0.225 mmol) and 1i (5 mol%) in CH2Cl2 (0.9 mL) was stirred at room temperature for the time given
in the table. b Isolated yield. c Determined by HPLC. d Catalyst (20 mol%). e The ratio of E/Z = 25 : 1.
curcumin derivatives to nitroolefins have not been reported yet.
This methodology could afford the required Michael adducts in
high yields and excellent enantioselectivities with only 5 mol%
catalyst loading. Besides, the Michael reaction has distinguished
tolerance for aryl, heteroaryl and alkyl nitroolefins. Further
research in this field are ongoing and the results will be presented
in the future.
Experimental
Fig. 2 X-Ray crystal structure of 4ea.
General methods
Proton nuclear magnetic resonance (1H NMR) spectra and carbon
nuclear magnetic resonance (13C NMR) spectra were recorded on a
Bruker AV-400 spectrometer (400 MHz and 100 MHz). Chemical
shifts for protons are reported in parts per million downfield
from tetramethylsilane and are referenced to residual protium in
the NMR solvent (CDCl3: d 7.26, (CD3)2CO: d 2.05). Chemical
shifts for carbon are reported in parts per million downfield from
tetramethylsilane and are referenced to the carbon resonances
of the solvent (CDCl3: d 77.16, (CD3)2CO: d 29.87). Data are
represented as follows: chemical shift, integration, multiplicity
(br = broad, s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet), coupling constants in Hertz (Hz). Mass spectra
(EI) were measured on a Waters Micromass GCT spectrometer.
Mass spectra (ESI) were measured on a Waters Micromass LCT
spectrometer. Optical rotations were measured on an Autopol III
automatic polarimeter. High performance liquid chromatography
(HPLC) was performed on an Agilent 1200 Series chromatography
Fig. 3 Proposed catalytic transition state.
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system using a Chiracel AS-H column (0.46 cm ¥ 25 cm) as noted.
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General procedure for the synthesis of organocatalysts
were purified by silica gel chromatography to yield the desired
addition products.
Reaction of (1S,2S)-1,2-diphenylethane-1,2-diamine with 4-
nitrobenzene-1-sulfonyl
chloride. 4-Nitrobenzene-1-sulfonyl
4-(2-Nitro-1-phenylethyl)-1,7-diphenylhepta-1,6-diene-3,5-dione
chloride (2.21 g, 10 mmol) in anhydrous THF (25 mL) was added
dropwise to a solution of (1S,2S)-1,2-diphenylethane-1,2-diamine
(2.12 g, 10 mmol), triethylamine (2.02 g, 20 mmol) and anhydrous
THF (20 mL) with ice-cooling. The reaction mixture was warmed
to room temperature and stirred for 12 h. TLC indicated the
reaction was completed. The residue was purified by silica gel
chromatography to afford◦the pure product as a white solid in
(4aa). The product was obtained in 96% yield, yellow solid.
◦
Mp = 138–140 C; [a]D22 -210.0 (c 0.99, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d (ppm) 7.75 (d, J = 16.0 Hz, 1H), 7.58–7.56
(m, 2H), 7.51–7.46 (m, 3H), 7.44–7.35 (m, 7H), 7.32–7.29 (m,
2H), 7.27–7.23 (m, 2H), 6.95 (d, J = 16.0 Hz, 1H), 6.73 (d, J =
16.0 Hz, 1H), 4.82–4.72 (m, 3H), 4.60–4.54 (m, 1H). 13C NMR
(100 MHz, CDCl3): d (ppm) 192.9, 191.8, 146.3, 145.4, 136.2,
133.8, 133.7, 131.5, 131.2, 129.1, 128.9, 128.7, 128.3, 128.1, 123.7,
123.1, 78.3, 67.5, 42.9. HRMS (EI): exact mass calculated for M+
(C27H23NO4) requires m/z 425.1627, found m/z 425.1637. The
enantiomeric excess was determined by HPLC. [AS-H column,
254 nm, Hexane : EtOH = 4 : 1, 0.8 mL min-1]: 12.1 min (major),
15.9 min (minor), ee = 96%.
1
94% yield. Mp = 135–136 C; [a]2D2 = 22.5 (c = 0.99, CHCl3); H
NMR (400 MHz, CDCl3): d (ppm) 7.98 (d, J = 8.8 Hz, 2H), 7.54
(d, J = 8.8 Hz, 2H), 7.22–7.17 (m, 10H), 4.50 (d, J = 4.4 Hz,
1H), 4.22 (d, J = 4.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): d
(ppm) 149.3, 146.0, 141.1, 138.9, 128.6, 127.8, 127.7, 126.7, 126.3,
123.7, 63.2, 60.1. HRMS (ESI): exact mass calculated for [M+H]+
(C20H19N3O4S) requires m/z 398.1175, found m/z 398.1177.
4-(1-(2-Chlorophenyl)-2-nitroethyl)-1,7-diphenylhepta-1,6-di-
ene-3,5-dione (4ba). The product was obtained in 86% yield,
Isothiocyanate formation. The product was prepared follow-
ing the literature procedure.12d To a solution of 9-amino(9-
deoxy)epihydroquinine (8.0 g, 24.7 mmol) and DCC (5.1g,
24.7 mmol) in dry THF (50 mL) at -10 ◦C was added CS2
(10.7 g, 148.5 mmol) in one portion. The reaction mixture was
warmed slowly to room temperature over a period of 3 h and then
stirred at room temperature overnight. The solvent was removed
under reduced pressure and the residue was purified by silica gel
chromatography to afford the pure product as a yellow solid in
80% yield.
1
yellow oil. [a]2D2 -155.4 (c 0.99, CH2Cl2); H NMR (400 MHz,
CDCl3): d (ppm) 7.73 (d, J = 16.0 Hz, 1H), 7.58–7.54 (m, 3H),
7.51–7.49 (m, 2H), 7.45–7.37 (m, 7H), 7.31–7.29 (m, 1H), 7.23–
7.17 (m, 2H), 6.90 (d, J = 16.0 Hz, 1H), 6.84 (d, J = 16.0 Hz,
1H), 5.11–5.93 (m, 3H), 4.87–4.83 (m, 1H). 13C NMR (100 MHz,
CDCl3): d (ppm) 192.9, 191.7, 146.2, 145.7, 134.0, 133.8, 133.7,
131.4, 131.2, 130.5, 129.4, 129.1, 129.0, 128.9, 128.8, 127.4, 124.4,
122.4, 76.5, 65.4, 53.4. HRMS (EI): exact mass calculated for M+
(C27H22NO4Cl) requires m/z 459.1237, found m/z 459.1252. The
enantiomeric excess was determined by HPLC. [AS-H column,
254 nm, Hexane : EtOH = 4 : 1, 0.8 mL min-1]: 12.4 min (major),
15.1 min (minor), ee = 97%.
Thiourea formation. To a solution of N-((1S,2S)-2-amino-
1,2-diphenylethyl)-4-nitrobenzenesulfonamide (1.07 g, 2.7 mmol)
in anhydrous THF (20 mL) was added 2-((S)-isothiocyanato(6-
4-(1-(3-Chlorophenyl)-2-nitroethyl)-1,7-diphenylhepta-1,6-di-
ene-3,5-dione (4ca). The p◦roduct was obtained in 81% yield,
yellow solid. Mp = 123–124 C; [a]2D2 -193.6 (c 0.50, CH2Cl2); 1H
NMR (400 MHz, CDCl3): d (ppm) 7.76 (d, J = 16.0 Hz, 1H), 7.59–
7.55 (m, 2H), 7.51–7.48 (m, 3H), 7.45–7.36 (m, 6H), 7.31–7.29 (m,
1H), 7.24–7.22 (m, 2H), 7.19–7.17 (m, 1H), 6.94 (d, J = 16.0 Hz,
1H), 6.74 (m, J = 16.0 Hz, 1H), 4.81–4.69 (m, 3H), 4.57–4.52 (m,
1H). 13C NMR (100 MHz, CDCl3): d (ppm) 192.6, 191.5, 146.6,
145.9, 138.5, 134.8, 133.7, 133.6, 131.6, 131.4, 130.3, 129.1,129.0,
128.9, 128.7, 128.6, 128.4, 126.5, 123.5, 123.1, 77.8, 67.0, 42.6.
HRMS (EI): exact mass calculated for M+ (C27H22NO4Cl) requires
m/z 459.1237, found m/z 459.1239. The enantiomeric excess was
determined by HPLC. [AS-H column, 254 nm, Hexane : EtOH =
4 : 1, 0.8 mL min-1]: 11.8 min (major), 16.8 min (minor), ee = 93%.
methoxyquinolin-4-yl)methyl)-8-vinyl-quinuclidine
(1.0
g,
2.7 mmol) at room temperature. The solution was stirred
overnight. TLC indicated completion of the reaction. The
reaction mixture was concentrated under vacuum. The residue
was purified by silica gel chromatography to afford the pure
product 1i as a yellow solid in 82% yield. Mp = 149–150 ◦C; [a]D22
1
-7.5 (c 1.0, CHCl3); H NMR (400 MHz, (CD3)2CO): d (ppm)
8.77–8.76 (m, 1H), 8.06–7.94 (m, 4H), 7.69–7.67 (m, 2H), 7.53 (br,
1H), 7.45–7.43 (m, 1H), 7.10–6.93 (m, 10H), 5.83–5.72 (m, 2H),
4.99–4.88 (m, 2H), 4.77–4.75 (m, 1H), 4.05 (s, 3H), 3.31–3.18 (m,
3H), 2.69 (br, 2H), 2.30 (br, 1H), 2.06–2.05 (m, 2H), 1.69–1.58 (m,
3H), 1.41–1.35 (m, 1H), 1.03–0.99 (m, 1H). 13C NMR (100 MHz,
(CD3)2CO): d (ppm) 205.1, 170.1, 157.9, 149.4, 147.7, 146.9,
144.8, 141.6, 138.3, 138.1, 131.6, 128.2, 128.0, 127.9, 127.8, 127.5,
127.2, 123.6, 121.7, 113.9, 102.9, 102.8, 63.4, 59.7, 55.5, 55.4,
41.1, 39.5, 27.6, 27.4, 25.7, 20.1, 13.7. HRMS (ESI): exact mass
calculated for [M+H]+ (C41H43N6O5S2) requires m/z 763.2736,
found m/z 763.2726.
4-(1-(4-Chlorophenyl)-2-nitroethyl)-1,7-diphenylhepta-1,6-di-
ene-3,5-dione (4da). The product was obtained in 74% yield,
◦
yellow solid. Mp = 149–150 C; [a]2D2 -179.6 (c 0.50, CH2Cl2);
1H NMR (400 MHz, CDCl3): d (ppm) 7.77 (d, J = 16.0 Hz, 1H),
7.59–7.57 (m, 2H), 7.54–7.48 (m, 3H), 7.45–7.37 (m, 7H), 7.31–
7.29 (m, 1H), 7.24–7.22 (m, 2H), 6.94 (d, J = 16.0 Hz, 1H), 6.73
(d, J = 16.0 Hz, 1H), 4.79–4.66 (m, 3H), 4.58–4.52 (m, 1H). 13C
NMR (100 MHz, CDCl3): d (ppm) 192.6, 191.5, 146.6, 145.9,
134.8, 134.2, 133.6, 131.6, 131.4, 129.5, 129.3, 129.1, 129.0, 128.9,
128.7, 123.5, 122.8, 78.1, 67.3, 42.4. HRMS (EI): exact mass
calculated for M+ (C27H22NO4Cl) requires m/z 459.1237, found
m/z 459.1250. The enantiomeric excess was determined by HPLC.
General procedure for asymmetric Michael addition
To a solution of trans-b-substituted nitroolefins 2 (0.15 mmol)
in dichloromethane (0.9 mL) were added curcumin derivates 3
(0.225 mmol) and catalyst 1i (0.0075 mmol). The reaction mixture
was stirred at room temperature for the time indicated in Table
3 and then the solvent was removed under vacuum. The residues
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[AS-H column, 254 nm, Hexane : EtOH = 4 : 1, 0.8 mL min-1]: 11.5
min (major), 15.3 min (minor), ee = 90%.
254 nm, Hexane : EtOH = 4 : 1, 0.8 mL min-1]: 11.4 min (major),
15.3 min (minor), ee = 90%.
4-(1-(3-Bromophenyl)-2-nitroethyl)-1,7-diphenylhepta-1,6-di-
ene-3,5-dione (4ea). The p◦roduct was obtained in 81% yield,
yellow solid. Mp = 117–118 C; [a]2D2 -187.2 (c 0.50, CH2Cl2); 1H
NMR (400 MHz, CDCl3): d (ppm) 7.76 (d, J = 16.0 Hz, 1H), 7.59–
7.55 (m, 2H), 7.51–7.47 (m, 4H), 7.45–7.36 (m, 7H), 7.23–7.15 (m,
2H), 6.94 (d, J = 16.0 Hz, 1H), 6.74 (d, J = 16.0 Hz, 1H), 4.81–
4.68 (m, 3H), 4.56–4.50 (m, 1H). 13C NMR (100 MHz, CDCl3): d
(ppm) 192.5, 191.5, 146.6, 145.9, 138.8, 133.7, 133.6, 131.6, 131.5,
131.4, 131.3, 130.5, 129.1, 129.0, 128.9, 128.8, 126.9, 123.5, 123.1,
123.0, 77.8, 67.0, 42.5. HRMS (EI): exact mass calculated for M+
(C27H22NO4Br) requires m/z 503.0732, found m/z 503.0737. The
enantiomeric excess was determined by HPLC. [AS-H column,
254 nm, Hexane : EtOH = 4 : 1, 0.8 mL min-1]: 12.4 min (major),
17.2 min (minor), ee = 90%.
4-(1-(4-Methoxyphenyl)-2-nitroethyl)-1,7-diphenylhepta-1,6-di-
ene-3,5-dione (4ia). The product was obtained in 82% yield,
◦
yellow solid. Mp = 126–127 C; [a]2D3 -179.6 (c 0.50, CH2Cl2);
1H NMR (400 MHz, CDCl3): d (ppm) 7.76 (d, J = 16.0 Hz, 1H),
7.59–7.57 (m, 2H), 7.51–7.47 (m, 3H), 7.47–7.36 (m, 6H), 7.21–
7.19 (m, 2H), 6.95 (d, J = 16.0 Hz, 1H), 6.82–6.80 (m, 2H), 6.74 (d,
J = 16.0 Hz, 1H), 4.77–4.67 (m, 3H), 4.55–4.49 (m, 1H), 3.73 (s,
3H). 13C NMR (100 MHz, CDCl3): d (ppm) 193.1, 192.0, 159.3,
146.2, 145.3, 133.8, 133.7, 131.4, 131.2, 129.3, 129.0, 128.9, 128.7,
127.9, 123.8, 123.0, 114.4, 78.5, 67.6, 55.1, 42.3. HRMS (EI): exact
mass calculated for M+ (C28H25NO5) requires m/z 455.1733, found
m/z 455.1740. The enantiomeric excess was determined by HPLC.
[AS-H column, 254 nm, Hexane : EtOH = 4 : 1, 0.8 mL min-1]: 15.4
min (major), 21.5 min (minor), ee = 89%.
4-(1-(2-Fluorophenyl)-2-nitroethyl)-1,7-diphenylhepta-1,6-diene-
3,5-dione (4fa). The◦product was obtained in 85% yield, yellow
solid. Mp = 136–137 C; [a]2D2 -184.8 (c 0.50, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d (ppm) 7.77 (d, J = 16.0 Hz, 1H), 7.58–
7.49 (m, 5H), 7.46–7.37 (m, 6H), 7.27–7.21 (m, 2H), 7.08–7.01 (m,
2H), 6.93 (d, J = 16.0 Hz, 1H), 6.79 (d, J = 16.0 Hz, 1H), 4.91–
4.76 (m, 4H). 13C NMR (100 MHz, CDCl3): d (ppm) 192.6, 191.7,
162.3, 159.8, 146.3, 145.7, 133.8, 133.7, 131.5, 131.3, 131.1, 131.0,
130.2, 130.1, 129.1, 129.0, 128.9, 128.7, 124.7, 123.8, 122.8, 116.2,
116.0, 76.7, 65.3, 38.6. HRMS (EI): exact mass calculated for M+
(C27H22NO4F) requires m/z 443.1533, found m/z 443.1538. The
enantiomeric excess was determined by HPLC. [AS-H column,
254 nm, Hexane : EtOH = 4 : 1, 0.8 mL min-1]: 13.7 min (major),
15.8 min (minor), ee = 95%.
4-(1-(2,3-Dimethoxyphenyl)-2-nitroethyl)-1,7-diphenyl-hepta-
1,6-diene-3,5-dione (4ja). The product was obtained in 92% yield,
1
yellow oil. [a]2D3 -179.2 (c 0.50, CH2Cl2); H NMR (400 MHz,
CDCl3): d (ppm) 7.67 (d, J = 16.0 Hz, 1H), 7.55–7.50 (m, 5H),
7.42–7.38 (m, 6H), 6.95–6.92 (m, 1H), 6.83–6.77 (m, 4H), 6.99–
6.93 (m, 2H), 4.85–4.75 (m, 2H), 4.02 (s, 3H), 3.80 (s, 3H). 13C
NMR (100 MHz, CDCl3): d (ppm) 193.6, 192.6, 152.7, 147.2,
145.6, 145.1, 134.0, 133.8, 131.2, 131.0, 129.4, 129.0, 128.9, 128.8,
128.7, 124.7, 124.0, 123.5, 121.2, 112.6, 76.8, 65.1, 60.8, 55.6, 38.6.
HRMS (EI): exact mass calculated for M+ (C29H27NO6) requires
m/z 485.1838, found m/z 485.1833. The enantiomeric excess was
determined by HPLC. [AS-H column, 254 nm, Hexane : EtOH =
4 : 1, 0.8 mL min-1]: 12.4 min (major), 17.1 min (minor), ee = 96%.
4-(1-(2,4-Dimethoxyphenyl)-2-nitroethyl)-1,7-diphenyl-hepta-
1,6-diene-3,5-dione (4ka). The product was obtained in 73%
yield, yellow oil. [a]D23 -96.8 (c 0.50, CH2Cl2); 1H NMR (400 MHz,
CDCl3): d (ppm) 7.74 (d, J = 16.0 Hz, 1H), 7.59–7.57 (m, 2H),
7.49–7.46 (m, 3H), 7.42–7.37 (m, 6H), 7.08 (m, J = 8.4 Hz, 1H),
6.93 (d, J = 16.0 Hz, 1H), 6.77 (d, J = 16.0 Hz, 1H), 6.40–
6.35 (m, 2H), 4.99–4.88 (m, 2H), 4.74–4.67 (m, 2H), 3.86 (s,
3H), 3.72 (s, 3H). 13C NMR (100 MHz, CDCl3): d (ppm) 193.5,
192.5, 160.8, 158.3, 145.6, 144.6, 134.1, 133.9, 131.5, 131.2, 131.0,
129.0, 128.9, 128.8, 128.6, 124.3, 123.2, 115.9, 104.6, 99.2, 76.9,
65.5, 55.5, 55.2, 39.4. HRMS (EI): exact mass calculated for M+
(C29H27NO6) requires m/z 485.1838, found m/z 485.1837. The
enantiomeric excess was determined by HPLC. [AS-H column,
254 nm, Hexane : EtOH = 4 : 1, 0.8 mL min-1]: 13.4 min (major),
17.5 min (minor), ee = 95%.
4-(1-(3-Fluorophenyl)-2-nitroethyl)-1,7-diphenylhepta-1,6-diene-
3,5-dione (4ga). The product was obtained in 76% yield, yellow
solid. Mp = 137–138 ◦C; [a]D22 -126.4 (c 0.99, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d (ppm) 7.77 (d, J = 16.0 Hz, 1H), 7.59–
7.48 (m, 5H), 7.45–7.36 (m, 6H), 7.27–7.24 (m, 1H), 7.09–7.01
(m, 2H), 6.96–6.92 (m, 2H), 6.75 (d, J = 16.0 Hz, 1H), 4.81–4.69
(m, 3H), 4.60–4.54 (m, 1H). 13C NMR (100 MHz, CDCl3): d
(ppm) 192.6, 191.5, 164.1, 161.6, 146.6, 145.8, 138.9, 133.6, 131.6,
131.4, 130.7, 130.6, 129.1, 129.0, 128.9, 128.7, 123.9, 123.5, 123.0,
115.5, 115.4, 115.3, 115.2, 77.9, 67.1, 42.6. HRMS (EI): exact mass
calculated for M+ (C27H22NO4F) requires m/z 443.1533, found
m/z 443.1535. The enantiomeric excess was determined by HPLC.
[AS-H column, 254 nm, Hexane : EtOH = 4 : 1, 0.8 mL min-1]: 11.7
min (major), 17.1 min (minor), ee = 92%.
4 - (1 - (4 - Fluorophenyl) - 2 - nitroethyl) - 1,7 - diphenylhepta - 1,6-
4-(2-Nitro-1-p-tolylethyl)-1,7-diphenylhepta-1,6-diene-3,5-dione
(4la). ◦The product was obtained in 85% yield, yellow solid. Mp =
diene-3,5-dione (4ha). The product was obtained in 93% yield,
◦
yellow solid. Mp = 92–93 C; [a]2D2 -209.6 (c 0.50, CH2Cl2);
94–95 C; [a]2D3 -202.8 (c 0.49, CH2Cl2); H NMR (400 MHz,
1
1H NMR (400 MHz, CDCl3): d (ppm) 7.77 (d, J = 16.0 Hz,
1H), 7.5–7.47 (m, 5H), 7.45–7.36 (m, 6H), 7.26–7.29 (m, 2H),
7.01–6.93 (m, 3H), 6.75 (d, J = 16.0 Hz, 1H), 4.81–4.69 (m,
3H), 4.60–4.54 (m, 1H). 13C NMR (100 MHz, CDCl3): d (ppm)
192.7, 191.7, 163.6, 161.1, 146.5, 145.7, 133.7, 132.1, 132.0, 131.5,
131.4, 129.9, 129.8, 129.1, 129.0, 128.9, 128.7, 123.6, 122.9, 116.1,
115.9, 78.3, 67.5, 42.3. HRMS (EI): exact mass calculated for M+
(C27H22NO4F) requires m/z 443.1533, found m/z 443.1534. The
enantiomeric excess was determined by HPLC. [AS-H column,
CDCl3): d (ppm) 7.75 (d, J = 16.0 Hz, 1H), 7.58–7.56 (m, 2H),
7.51–7.46 (m, 3H), 7.46–7.35 (m, 6H), 7.18–7.16 (m, 2H), 7.10–
7.08 (m, 2H), 6.95 (d, J = 16.0 Hz, 1H), 6.74 (d, J = 16.0 Hz,
1H), 4.79–4.69 (m, 3H), 4.56–4.50 (m, 1H), 2.26 (s, 3H). 13C
NMR (100 MHz, CDCl3): d (ppm) 193.1, 191.9, 146.2, 145.3,
138.0, 133.8, 133.7, 133.1, 131.4, 131.2, 129.7, 129.0, 128.9, 128.7,
128.0, 123.8, 123.1, 78.4, 67.5, 42.7, 21.0. HRMS (EI): exact mass
calculated for M+ (C28H25NO4) requires m/z 439.1784, found m/z
439.1789. The enantiomeric excess was determined by HPLC.
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[AS-H column, 254 nm, Hexane : EtOH = 4 : 1, 0.8 mL min-1]:
11.2 min (major), 15.1 min (minor), ee = 91%.
4-(2-Nitro-1-phenylethyl)-1,7-dip-tolylhepta-1,6-diene-3,5-
dione (4ab). The product was obtained in 78% yield, yellow
solid. Mp = 147–148 ◦C; [a]D23 -130.4 (c 0.99, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d (ppm) 7.72 (d, J = 16.0 Hz, 1H), 7.49–
7.45 (m, 3H), 7.38–7.36 (m, 2H), 7.29–7.28 (m, 4H), 7.22–7.16 (m,
5H), 6.90 (d, J = 16.0 Hz, 1H), 6.69 (d, J = 16.0 Hz, 1H), 4.80–
4.68 (m, 3H), 4.59–4.54 (m, 1H). 13C NMR (100 MHz, CDCl3):
d (ppm) 193.0, 191.9, 146.3, 145.4, 142.2, 141.9, 136.4, 131.1,
131.0, 129.8, 129.7, 128.9, 128.7, 128.2, 128.1 ,122.8, 122.2, 78.3,
67.4, 43.0, 21.6, 21.5. HRMS (EI): exact mass calculated for M+
(C29H27NO4) requires m/z 453.1940, found m/z 453.1945. The
enantiomeric excess was determined by HPLC. [AS-H column,
254 nm, Hexane : EtOH = 8 : 1, 0.8 mL min-1]: 13.5 min (major),
20.9 min (minor), ee = 90%.
4-(1-(Naphthalen-1-yl)-2-nitroethyl)-1,7-diphenylhepta-1,6-di-
ene-3,5-dione (4ma). The product was obtained in 84% yield,
◦
yellow solid. Mp = 129–130 C; [a]2D3 -166.8 (c 0.49, CH2Cl2);
1H NMR (400 MHz, CDCl3): d (ppm) 7.81–7.75 (m, 5H), 7.57–
7.55 (m, 2H), 7.47–7.32 (m, 12H), 6.97 (d, J = 16.0 Hz, 1H), 6.75
(d, J = 16.0 Hz, 1H), 4.86–4.82 (m, 3H), 4.76–4.70 (m, 1H). 13C
NMR (100 MHz, CDCl3): d (ppm) 192.6, 191.8, 149.6, 146.2,
145.5, 142.7, 133.8, 133.7, 131.4, 131.2, 129.1, 129.0, 128.8, 128.7,
124.1, 123.0, 110.7, 109.1, 75.9, 64.2, 36.9. HRMS (EI): exact mass
calculated for M+ (C31H25NO4) requires m/z 475.1784, found m/z
475.1786. The enantiomeric excess was determined by HPLC. [AS-
H column, 254 nm, Hexane : EtOH = 4 : 1, 0.8 mL min-1]: 13.6 min
(major), 18.9 min (minor), ee = 90%.
1,7-Bis(4-chlorophenyl)-4-(2-nitro-1-phenylethyl)hepta-1,6-di-
ene-3,5-dione (4ac). The product was obtained in 72% yield,
◦
4-(1-(Furan-2-yl)-2-nitroethyl)-1,7-diphenylhepta-1,6-diene-3,5-
dione (4na). The product was obtained in 62% yield, yellow
solid. Mp = 128–129 ◦C; [a]D23 -192.8 (c 0.48, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d (ppm) 7.72 (d, J = 16.0 Hz, 1H), 7.60–7.52
(m, 5H), 7.44–7.39 (m, 7H), 6.88 (d, J = 16.0 Hz, 1H), 6.77 (d, J =
16.0 Hz, 1H), 6.25–6.22 (m, 2H), 4.87–4.78 (m, 3H), 4.69–4.63 (m,
1H). 13C NMR (100 MHz, CDCl3): d (ppm) 192.6, 191.8, 149.6,
146.2, 145.6, 142.7, 133.8, 133.7, 131.4, 131.2, 129.1, 129.0, 128.8,
128.7, 124.1, 123.0, 110.7, 109.0, 75.9, 64.2, 36.9. HRMS (EI):
exact mass calculated for M+ (C25H21NO5) requires m/z 415.1420,
found m/z 415.1428. The enantiomeric excess was determined by
HPLC. [AS-H column, 254 nm, Hexane : EtOH = 8 : 1, 0.8 mL
min-1]: 24.7 min (major), 28.6 min (minor), ee = 93%.
yellow solid. Mp = 143–144 C; [a]2D3 -200.8 (c 0.49, CH2Cl2);
1H NMR (400 MHz, CDCl3): d (ppm) 7.69 (d, J = 16.0 Hz, 1H),
7.52–7.48 (m, 2H),7.43–7.34 (m, 10H), 7.30–7.28 (m, 2H), 6.90 (d,
J = 16.0 Hz, 1H), 6.68 (d, J = 16.0 Hz, 1H), 4.75–4.68 (m, 3H),
4.57–4.51 (m, 1H). 13C NMR (100 MHz, CDCl3): d (ppm) 192.7,
191.6, 144.8, 143.9, 137.6, 136.1, 132.2, 132.1, 130.0, 129.8, 129.4,
129.3, 129.1, 128.4, 128.1, 123.9, 123.2, 78.2, 67.7, 42.9. HRMS
(EI): exact mass calculated for M+ (C27H21NO4Cl2) requires m/z
493.0848, found m/z 493.0867. The enantiomeric excess was
determined by HPLC. [AS-H column, 254 nm, Hexane : EtOH =
4 : 1, 0.8 mL min-1]: 12.9 min (major), 24.1 min (minor), ee = 92%.
1,7-Bis(2-fluorophenyl)-4-(2-nitro-1-phenylethyl)hepta-1,6-di-
ene-3,5-dione (4ad). The product was obtained in 73% yield,
◦
4-(1-Nitropentan-2-yl)-1,7-diphenylhepta-1,6-diene-3,5-dione
yellow solid. Mp = 121–122 C; [a]2D3 -164.4 (c 0.49, CH2Cl2);
(4oa). ◦ The product was obtained in 82% yield, yellow solid. Mp =
1H NMR (400 MHz, CDCl3): d (ppm) 7.88 (d, J = 16.0 Hz, 1H),
7.62–7.56 (m, 2H), 7.47–7.35 (m, 4H), 7.29–7.27 (m, 2H), 7.23–
7.08 (m, 6H), 7.04 (d, J = 16.0 Hz, 1H), 6.82 (d, J = 16.0 Hz,
1H), 4.80–4.77 (m, 3H), 4.58–4.52 (m, 1H). 13C NMR (100 MHz,
CDCl3): d (ppm) 192.9, 191.9, 163.1, 163.0, 160.6, 160.4, 138.65;
138.62, 137.97; 137.95, 136.2, 132.93; 132.85, 132.67; 132.58,
129.6, 129.0, 128.3, 128.1, 126.12; 126.05, 125.64; 125.57, 124.65;
124.61, 124.56; 124.53, 122.0, 121.9, 116.47; 116.40, 116.25;
116.18, 78.1, 67.1, 43.0. HRMS (EI): exact mass calculated for M+
(C27H21NO4F2) requires m/z 461.1439, found m/z 461.1440. The
enantiomeric excess was determined by HPLC. [AS-H column,
254 nm, Hexane : EtOH = 4 : 1, 0.8 mL min-1]: 13.1 min (major),
15.9 min (minor), ee = 96%.
1
89–90 C; [a]2D3 -129.0 (c 0.99, CH2Cl2); H NMR (400 MHz,
CDCl3): d (ppm) 7.75–7.71 (m, 2H), 7.60–7.58 (m, 4H), 7.43–7.40
(m, 6H), 6.94–6.86 (m, 2H), 4.67–4.55 (m, 2H), 4.50 (d, J = 9.2 Hz,
1H), 3.18–3.12 (m, 1H), 1.52–1.33 (m, 4H), 0.92 (t, J = 7.2 Hz,
3H). 13C NMR (100 MHz, CDCl3): d (ppm) 193.8, 193.3, 145.7,
145.6, 133.9, 133.8, 131.3, 131.2, 129.1, 129.0, 128.8, 124.6, 123.4,
76.1, 65.6, 36.9, 31.5, 29.7, 19.7, 13.8. HRMS (EI): exact mass
calculated for M+ (C24H25NO4) requires m/z 391.1784, found m/z
391.1786. The enantiomeric excess was determined by HPLC. [AS-
H column, 254 nm, Hexane : EtOH = 30 : 1, 0.8 mL min-1]: 19.4
min (major), 21.1 min (minor), ee = 92%.
4-(3-Methyl-1-nitrobutan-2-yl)-1,7-diphenylhepta-1,6-diene-3,5-
dione (4pa). The product was obtained in 72% yield, yellow solid.
1,7-Bis(4-hydroxy-3-methoxyphenyl)-4-(2-nitro-1-phenylethyl)-
◦
Mp = 151–152 C; [a]D23 = + 5.3 (c = 0.99, CH2Cl2); H NMR
(400 MHz, CDCl3): d (ppm) 7.78 (d, J = 16.0 Hz, 1H), 7.56–7.54
(m, 2H), 7.42–7.27 (m, 10H), 6.82 (d, J = 16.0 Hz, 1H), 3.69–
3.63 (m, 1H), 3.50–3.42 (m, 1H), 3.30–3.28 (m, 1H), 2.91–2.84
(m, 1H), 1.20 (d, J = 6.8 Hz, 3H), 1.10 (d, J = 6.8 Hz, 3H). 13C
NMR (100 MHz, CDCl3): d (ppm) 193.1, 179.7, 142.2, 137.9,
135.0, 130.3, 129.1, 129.0, 128.2, 128.0, 127.2, 119.0, 106.5, 87.2,
45.5, 37.1, 34.7, 34.6, 29.7, 21.2, 19.8. HRMS (EI): exact mass
calculated for M+ (C24H25NO4) requires m/z 391.1784, found m/z
391.1786. The enantiomeric excess was determined by HPLC. [AS-
H column, 254 nm, Hexane : EtOH = 4 : 1, 0.8 mL min-1]: 8.4 min
(major), 9.8 min (minor), ee = 84%.
hepta-1,6-diene-3,5-dione (4ae). The product was obtained in
1
◦
82% yield, yellow solid. Mp = 85–86 C; [a]2D3 -207.2 (c 0.99,
1
CH2Cl2); H NMR (400 MHz, CDCl3): d (ppm) 7.69 (d, J =
16.0 Hz, 1H), 7.43 (d, J = 16.0 Hz, 1H), 7.30–7.24 (m, 4H), 7.18–
7.00 (m, 7H), 7.86 (d, J = 16.0 Hz, 1H), 6.64 (d, J = 16.0 Hz,
1H), 4.79–4.70 (m, 3H), 4.58–4.52 (m, 1H), 3.87 (s, 3H), 3.84 (s,
3H), 2.32 (s, 3H), 2.31 (s, 3H). 13C NMR (100 MHz, CDCl3): d
(ppm) 192.8, 191.7, 168.6, 168.5, 151.5, 151.4, 145.6, 144.7, 142.4,
142.2, 136.1, 132.7, 132.6, 129.1, 128.3, 128.1, 123.9, 123.5, 123.4,
122.2, 121.9, 111.9, 111.8, 78.2, 67.3, 55.9, 53.4, 42.9, 29.6, 20.6.
HRMS (EI): exact mass calculated for M+ (C33H31NO10) requires
m/z 601.1948, found m/z 601.1949. The enantiomeric excess was
2510 | Org. Biomol. Chem., 2011, 9, 2505–2511
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determined by HPLC. [AS-H column, 254 nm, Hexane : EtOH =
1 : 1, 0.5 mL min-1]: 15.7 min (major), 22.1 min (minor), ee = 92%.
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Acknowledgements
This work was supported by National Natural Science Foundation
of China (20902018), Shanghai Pujiang Program (08PJ1403300)
and Innovation Program of Shanghai Municipal Education Com-
mission (11ZZ56).
10 (a) B. List, J. Am. Chem. Soc., 2000, 122, 9336; (b) P. I. Dalko and L.
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11 For reviews on thiourea-based organocatalysts see: (a) P. R. Schreiner,
Chem. Soc. Rev., 2003, 32, 289; (b) P. M. Pihko, Angew. Chem., Int. Ed.,
2004, 43, 2062; (c) Y. Takemoto, Org. Biomol. Chem., 2005, 3, 4299;
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12 For the synthesis of bifunctional amine-thiourea organocatalysts (1a–
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17 The crystallographic data of 4ea for this paper has been deposited
in the Cambridge Structural Database, Cambridge Crystallographic
Data Centre, Cambridge CB2 1EZ, United Kingdom (CSD reference
no. 794851). See the ESI†.
8 For selected examples of organocatalyzed asymmetric Michael addi-
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