Organocatalytic asymmetric aza-Michael addition of aniline to chalcones under solvent-free conditions

Article abstract of DOI:10.1016/j.tetasy.2008.09.006

The first enantioselective Michael addition of aniline to chalcones was promoted by cheap and commercially available chincona alkaloids under solvent-free conditions. Variously substituted chalcones were examined as substrates giving the conjugate adducts

Full text of DOI:10.1016/j.tetasy.2008.09.006

Tetrahedron: Asymmetry 19 (2008) 2149–2152
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Organocatalytic asymmetric aza-Michael addition of aniline to chalcones
under solvent-free conditions
a
a
b
a,
Arrigo Scettri a, , Antonio Massa , Laura Palombi , Rosaria Villano , Maria Rosaria Acocella
*
*
a Dipartimento di Chimica, Università di Salerno, Via Ponte Don Melillo 84084, Fisciano (Salerno), Italy
b Istituto di Chimica Biomolecolare-CNR trav. La Crucca 3, Reg. Baldinca, 07040 Li Punti (Sassari), Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 July 2008
Accepted 12 September 2008
Available online 9 October 2008
The first enantioselective Michael addition of aniline to chalcones was promoted by cheap and commer-
cially available chincona alkaloids under solvent-free conditions. Variously substituted chalcones were
examined as substrates giving the conjugate adducts in moderate to good enantioselectivity. The simple
experimental procedure had no work-up and short reaction times, which are the notable advantages.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Furthermore, all of these reactions are performed in organic sol-
vent and the necessity to use dilute conditions to improve the ee is
Over the past decade, the use of chiral organic molecules as cat-
alysts1 has represented an important area of research, and is recog-
nized as an efficient and reliable strategy for the asymmetric
synthesis of valuable chiral compounds.2 This type of catalysis
has several benefits when compared to the use of transition metal
complexes. The metal-free organic catalysts are usually more sta-
ble, commercially available, non-toxic, less expensive and allow
us to perform the reactions in mild conditions.
sometimes required.6a With all of these precedents in mind, we
decided to explore the ability of aniline to react as a nucleophile
with chalcones for the asymmetric aza-Michael reaction by hydro-
gen bond activation. Herein, we report the first enantioselective
organocatalytic solvent-free aza-Michael addition of aniline to
chalcones using cinchona alkaloids as catalysts.
2. Results and discussion
Due to the operational and economical advantages associated
with organocatalysis, many enantioselective organocatalytic reac-
tions for C–C bond formation have been developed, while only a
few examples have been reported for aza-Michael addition.3
The aza-Michael reaction, involving the conjugate addition of
Preliminarily, a control experiment performed on chalcone 1a
(Fig. 1), chosen as representative substrate, pointed out the very
poor contribution given by the background non-asymmetric reac-
tion: in fact, the corresponding adduct 3a was obtained in only
3% yield after 24 h (Fig. 2).
nitrogen nucleophiles to a,b-unsaturated carbonyl compounds, al-
lows us to generate a C–N bond, so that it constitutes an important
step in the synthesis of bioactive natural compounds.4 Most of the
aza-Michael organocatalytic reactions are amine catalyzed and
proceed via an enamine or iminium intermediate5 can avoid the
possible competition between the nucleophile and the catalyst that
can compromise the enantiomeric excess. Consequently, the
appropriate choice of the nucleophile represents a critical factor
for obtaining a good level of enantioselectivity.
A different approach involves the use of organic molecules driv-
ing the enantioselective addition of the nucleophile onto the
acceptor by hydrogen bonding, but it should be noted that only a
few examples have been reported.6 Particularly, poorly nucleo-
philic amine derivatives, such as hydrazones,6a benzylhydroxylam-
ines6c and indoles,6d have been used, while no examples of a direct
conjugate amination involving the use of an amine as a nucleophile
has been reported.
Ph
O
NH
O
cinchona
alkaloids
PhNH2
+
Ph
Ph
Ph
Ph
solvent free
1a
2
3a
Figure 1.
As shown in Table 1, activation of the carbonyl functionality by
hydrogen bonding was found to promote the formation of adduct
3a in rather high yields with all the organocatalysts tested
(0.1 equiv) (Fig. 2), used under solvent-free conditions. However,
only
cinchonine
enantioselectivity.
c
afforded
a
promising
level
of
Notably, less satisfactory results were obtained by carrying out
the reaction at ꢀ20 °C (entries 7 and 8) while a significant
improvement both in terms of efficiency and enantioselectivity
* Corresponding authors. Tel.: +39 0899 65374; fax: +39 0899 65296 (A.S.).
E-mail address: scettri@unisa.it (A. Scettri).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.09.006

2150
A. Scettri et al. / Tetrahedron: Asymmetry 19 (2008) 2149–2152
N
N
N
OH
OH
OH
H3CO
N
N
N
c
b
a
N
N
N
OH
OH
OH
H3CO
H3CO
H3CO
N
N
N
f
e
d
Figure 2.
Table 1
Ph
R
Asymmetric aza-Michael addition of aniline to 1a promoted by cinchona alkaloids
O
NH
O
cinchonine
Organocatalysta
Time (h)
Yield 3ab (%)
ee 3ac (%)
+
Entry
PhNH2
R
R'
R'
1
2
3
4
5
6
7
8
9
Cinchonidine a
Quinidine b
Cinchonine c
Quinine d
20
20
20
20
20
20
18
20
24
>99
>99
75
88
80
88
48
35
>99
ꢀ16
3
49
9
0
1
43
ꢀ8
58
1
2
3
Figure 3.
Hydroquinine e
Hydroquinidine f
Cinchonined
c
Table 2
Cinchonidined
a
Solvent-free aza-Michael addition of PhNH2 to chalcones catalyzed by 20 mol %
cinchonine
Cinchonine c
a
The reactions were performed using 0.25 mmol of chalcone, 0.5 mmol of aniline
in presence of 10 mol % catalyst without solvent at room temperature.
Entry
R
R0
t/T (h/rt)
Prod.
Yielda (%)
eeb (%)
b
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
24
48
24
24
24
24
24
48
24
24
24
3a
3b
3c
3d
3e
3f
3g
3h
3i
>99
44
76
50
68
81
72
45
50
>99
48
58
49
42
35
35
40
27
49
52
31
11c
The yields refer to the chromatographically pure compounds.
The enantiomeric excess was determined by HPLC analysis using CHIRALPAK
c
4-MeOC6H4
4-MeC6H4
2-Thienyl
2-Furyl
3-OMeC6H4
4-ClC6H4
Ph
AD-H column.
d
The reaction was performed at ꢀ20 °C.
4-MeOC6H4
4-MeC6H4
4-ClC6H4
Ph
Ph
Ph
was observed by increasing the organocatalyst c loading to
0.2 equiv (Table 1, entry 9). In fact, cinchonine c was the most
effective catalyst resulting in quantitative conversion and leading
to 58% of enantiomeric excess in reduced reaction times when
compared to the usual 2–5 days requested for other aza-Michael
organocatalyzed reactions.6a–c
10
11
3m
3n
4-NO2C6H4
a
The yields refer to chromatographically pure compounds.
b
The enantiomeric excess was determined by HPLC analysis using CHIRALPAK
AD-H column.
c
The reaction was performed using 10 mol % cinchonine at room temperature.
One of the problems in the organocatalytic aza-Michael reaction
is the possible competition between the nucleophile and the cata-
lyst; in fact the amine reagent could lead to the generation of an
achiral intermediate and therefore to the formation of a racemic
product. To verify this possibility, we decided to carry out the reac-
tion in the presence of a reduced amount of aniline (1.2 equiv)
which caused a decrease in yield and ee (88% yield; 49% ee). This
result further confirms that no formation of an iminum ion occurs,
due to the low nucleophilicity of aniline, as already observed in the
control experiment performed in the absence of organocatalyst.
The catalytic properties of cinchonine can be reasonably ex-
plained through the proposed transition state model of Jorgensen,
in which the hydroxyl group of catalyst establishes a hydrogen
bond with the carbonyl and the quinuclide group is linked to the
aniline.6a
The corresponding products were obtained in 24 h (except for
entries 2 and 8) at room temperature in good yield and with
enantioselectivities varying from 27% to 58%. As shown in Table
2, the presence of a substituent on the benzoyl ring resulted in a
slightly higher enantiomeric excess when compared to the effect
displayed on the other aromatic moiety (entries 8, 9, 10 vs entries
2, 3, 7).
Moreover, the introduction of electron-withdrawing substitu-
ent as a nitro group, led to a significant decrease in yield and
enantioselectivity (Table 2, entry 11).
3. Conclusion
Having found an optimal protocol for the reaction, we pro-
ceeded to examine the scope and limitation of the method using
variously substituted chalcones as substrates (Fig. 3).
In conclusion, we have developed the first example of a solvent-
free asymmetric aza-Michael addition of aniline to chalcones
catalyzed by a commercially available and inexpensive cinchona

A. Scettri et al. / Tetrahedron: Asymmetry 19 (2008) 2149–2152
2151
alkaloid. In all cases, the reactions can be performed without a sol-
4.2.2. 3-(3-Methoxyphenyl)-1-phenyl-3(phenylamino)propan-
1-one 3g
White solid m/z 332 [M+H+], 354 [M+Na+]; IR (KBr, neat) 3365,
1675, 1576, 1487 cmꢀ1; [
D = ꢀ12.5 (c 0.5, CHCl3) 40% ee; HPLC
vent, thanks to the very good solubility in aniline of the differently
substituted chalcones used. The simple experimental procedure,
the solvent-free conditions and, thus the absence of work-up, short
reaction times, good conversions and enantioselectivities are the
notable advantages of the protocol.
a]
analysis Chiralpak AD-H hexane/iPrOH 90:10 flow rate 0.6 ml tR
(major) = 31.95, tR (minor) = 36.87 min; 1H NMR (CDCl3,
400 MHz): d 7.92 (2H, d, J = 7.8 Hz); 7.57 (1H, t, J = 7.2 Hz); 7.45
(2H, t, J = 7.8 Hz); 7.25 (1H, t, J = 7.7 Hz); 7.12–7.01 (4H, m);
6.79–6.77 (1H, m); 6.67 (1H, t, J = 7.3 Hz); 6.58 (2H, d, J = 7.8 Hz);
4.98 (1H, dd, J = 8.3; 5.1 Hz); 4.55 (1H, br s); 3.77 (3H, s); 3.51
(1H, dd, J = 16.1; 5.1 Hz); 3.43 (1H, dd, J = 16.1; 8.3 Hz); 13C NMR
(CDCl3, 400 MHz): d 198.7; 160.5; 147.6; 145.4; 134.6; 133.4;
129.1; 128.1; 119.7; 118.22; 114.4; 133.3; 112.2; 55.7; 54.8;
46.8; Anal. Calcd for C22H21NO2: C, 79.73; H, 6.39; N, 4.23. Found:
C, 79.60; H, 6.50; N, 4.10.
4. Experimental
4.1. General
All chemicals were purchased from Sigma–Aldrich and were
used without any further purification. TLC was performed on Sil-
ica Gel 60 F254 0.25 mm on glass plates (Merck) and non-flash
chromatography was performed on silica gel (0.063–0.200 mm)
(Merck). All 1H NMR and 13C NMR spectra were recorded with a
DRX 400 MHz Bruker instrument, by using CDCl3 (d = 7.26 ppm
in 1H NMR spectra and d = 77.0 ppm in 13C NMR spectra) as sol-
vent (400.135 MHz for 1H and 100.03 MHz for 13C). Data for 1H
NMR are reported as follows: chemical shift (d in ppm, multiplic-
ity (s singlet, d doublet, t triplet, dd doublet of doublets, m mul-
tiplet) and coupling constant (J in hertz). Optical rotations were
measured on a JASCO DIP-1000 polarimeter operating at the so-
dium D line at room temperature. Concentration is given in g/
100 ml. IR spectra were recorded on a Bruker spectrometer. The
HPLC analyses were performed with Waters Associates equipment
(Waters 2487 Dual k absorbance Detector) using CHIRALPK AD-H
column with Hexane/Isopropyl alcohol mixtures and flow rate as
indicated. HPLC methods were calibrated with the corresponding
racemic mixtures.
4.2.3. 1-(4-Xhlorophenyl)-3-phenyl-3-(phenylamino)propan-1-
one 3m
Yellow solid m/z 336 [M+H+], 338 [M+Na+]; IR (KBr, neat) 3448,
1679, 1504, 1285; [
a
]D = ꢀ5.8 (c 0.55, CHCl3) 31% ee; HPLC analysis
Chiralpak AD-H hexane/iPrOH 80:20 flow rate 0.6 ml tR (ma-
jor) = 18.6, tR (minor) = 23.6 min; 1H NMR (CDCl3, 400 MHz): d
7.83 (2H, d, J = 8.5 Hz); 7.45–7.40 (4H, m) 7.33 (2H, t, J = 7.3 Hz);
7.27–7.23 (1H, m); 7.11 (2H, t, J = 8.2 Hz); 6.69 (1H, t, J = 8.2 Hz);
6.58 (2H, d, J = 8.2 Hz); 5.02 (1H, ft, J = 5.9 Hz); 4.54 (1H, br s);
3.47 (1H, dd, J = 16.1; 5.5 Hz); 3.41 (1H, dd, J = 16.1; 7.2 Hz); 13C
NMR (CDCl3, 400 MHz): d 197.6; 147.4; 145.9; 143.3; 140.4;
130.1; 129.7; 129.4; 127.9; 126.9; 121.9; 118.4; 114.3; 55.18;
46.7; Anal. Calcd for C21H18ClNO: C, 75.11; H, 5.40; N, 4.17; O,
4.76. Found: C, 75.05; H, 5.50; N, 4.12.
Mass spectrometry analysis was carried out using an electro-
spray spectrometer Waters 4 micro quadruple.
The elemental analyses were calculated with FLASH EA 1112
Thermo equipment.
The known compounds (Table 2, entries 1, 2, 4, 5, 7 and 11)
have been identified by comparison of spectral data with those re-
ported.7 The absolute configurations of the optically active com-
pounds 3g and 3n were determined on the basis of the measured
specific rotations compared with literature values.8 All the other
absolute configurations were assigned by analogy.
4.2.4. 1-(4-Methoxyphenyl)-3-phenyl-3-(phenylamino)propan-
1-one 3i
White solid m/z 332 [M+H+], 354 [M+Na+]; 370 [M+K+]; IR (KBr,
neat) 3430, 1680, 1547, 1261, 1171; [
a]D = ꢀ5.2 (c 0.5, CHCl3) 49%
ee; HPLC analysis Chiralpak AD-H hexane/iPrOH 90:10 flow rate
0.6 ml tR (major) = 43.9, tR (minor) = 51.5 min; 1H NMR (CDCl3,
400 MHz): d 7.89 (2H, d, J = 8.8 Hz); 7.44 (2H, d, J = 7.5 Hz); 7.32
(2H, t, J = 7.5 Hz); 7.24 (1H, t, J = 7.2 Hz); 7.08 (2H, d, J = 8.8 Hz);
6.65 (1H, t, J = 7.3 Hz); 6.55 (2H, d, J = 7.7 Hz); 4.97 (1H, dd,
J = 7.7; 5.0 Hz); 4.61 (1H, br s); 3.86 (3H, s); 6.45 (1H, dd,
J = 15.7; 5.0 Hz); 3.34 (1H, dd, J = 15.7; 7.7 Hz); 13C NMR (CDCl3,
400 MHz): d 197.2; 164.1; 147.5; 143.6; 131.1; 129.5; 129.2;
127.7; 126.8; 118.1; 114.3; 114.2; 55.9; 55.4; 46.4; Anal. Calcd
for C22H21NO2: C, 79.73; H, 6.39; N, 4.23. Found: C, 79.57; H,
6.45; N, 4.15.
4.2. Typical experimental procedure
To
a mixture of chalcone (0.25 mmol) and cinchonine
(0.05 mmol), 2 equiv (0.5 mmol) of aniline was added and the
resulting solution was stirred at room temperature for 24 h.
TLC indicated the completion of the reaction. The crude mix-
ture was directly purified by column chromatography (silica
gel, petroleum ether/ethyl acetate mixtures) to obtain pure
products.
4.2.5. 3-Phenyl-3-(phenylamino)-1-p-tolylpropan-1-one 3l
White solid m/z 316 [M+H+] 338 [M+Na+]; IR (KBr, neat) 3387,
1667, 1602, 1504; [
a]
D = ꢀ16.0 (c 0.5, CHCl3) 52% ee; HPLC analysis
Chiralpak AD-H hexane/iPrOH 98:2 flow rate 0.8 ml tR (ma-
jor) = 35.6, tR (minor) = 39.7 min; 1H NMR (CDCl3, 400 MHz): d
7.83 (2H, d, J = 8.2 Hz); 7.46 (2H, d, J = 7.2 Hz); 7.34 (2H, t,
J = 7.2 Hz); 7.26–7.24 (3H, m); 7.11 (2H, t, J = 7.4 Hz); 6.69 (1H, t;
J = 7.4 Hz); 6.57 (2H, d, J = 8.2 Hz); 5.01 (1H, dd, J = 7.6; 5.1 Hz);
4.60 (1H, br s); 3.50 (1H, dd, J = 16.0; 5.1 Hz); 3.39 (1H, dd,
J = 16.0; 7.6 Hz); 2.41 (3H, s); 13C NMR (CDCl3, 400 MHz): d
198.4, 147.5; 144.8; 143.6; 135.2; 129.8; 129.5; 129.3; 128.8;
127.7; 126.8; 118.2; 114.2; 55.3; 46.7; 22.1; Anal. Calcd for
C22H21NO: C, 83.78; H, 6.71; N,4.44. Found: C, 83.60; H, 6.60, N,
4.35.
4.2.1. 1-Phenyl-3-(phenylamino)-3-p-tolylpropan-1-one 3c
White solid m/z 316.5 [M+H+], 338 [M+Na+]; IR (KBr, neat) 3446,
1683, 1661, 1580; [a]D = +3.9 (c 0.5, CHCl3) 42% ee; HPLC analysis
Chiralpak AD-H hexane/iPrOH 98:2 flow rate 0.7 ml tR (ma-
jor) = 55.29, tR (minor 57.65 min; 1H NMR (CDCl3, 400 MHz): d
7.92 (2H, d, J = 7.4 Hz); 7.56 (1H, t, J = 7.4 Hz); 7.45 (2H, t,
J = 7.6 Hz); 7.3 (2H, d, J = 7.9 Hz); 7.15–708 (4H, m); 6.66 (1H, t,
J = 7.4 Hz); 6.57 (2H, d, J = 7.9 Hz); 4.99 (1H, ft, J = 7.1); 4.52 (1H,
br s), 3.52 (1H, dd, J = 16.1; 5.2 Hz); 3.41 (1H, dd; J = 16.1;
7.6 Hz); 2.32 (3H, s) 13C NMR (CDCl3, 400 MHz): d 198.3; 147.5;
140.4; 137.4; 133.8; 129.9; 129.5; 129.1; 128.6; 126.7; 117.1;
114.2; 54.9; 46.8; 21.5. Anal. Calcd for C22H21NO: C, 83.78; H,
6.71; N, 4.44. Found: C, 83.60; H, 4.32; N, 4.30.
Acknowledgment
We are grateful to MIUR for financial support.

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