Solid-state synthesis of β-enamino ketones from solid 1,3-dicarbonyl compounds and ammonium salts or amines

Article abstract of DOI:10.1055/s-0028-1087914

A facile amination of solid 1,3-dicarbonyl compounds with ammonium salts or amines in solid state has been achieved by mechanochemical grinding in the presence of KHSO₄ and SiO₂. Most of the reactions proceed smoothly at room temperature under solid-state conditions and give their corresponding β-imino derivatives in high yields. The method has the advantage of simple manipulation and mild conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087914

818
LETTER
Solid-State Synthesis of b-Enamino Ketones from Solid 1,3-Dicarbonyl
Compounds and Ammonium Salts or Amines
Solid-State Sy
a
h
nthesis of
b
-
i
-
o Keton
L
es iang Xu,a Cheng-Ping Li,b Jing-Hua Li*a
College of Pharmacuetical Sciences, Zhejiang University of Technology, 310032 Hangzhou, P. R. of China
College of of Biology and Environmental Engineering, Zhejiang Shuren University, 310015 Hangzhou, P. R. of China
E-mail: lijh@zjut.edu.cn
b
Received 16 October 2008
pound it took a long reaction time to complete the reaction
using excess ammonia source, and in many cases the reac-
tions gave low yields.
Abstract: A facile amination of solid 1,3-dicarbonyl compounds
with ammonium salts or amines in solid state has been achieved by
mechanochemical grinding in the presence of KHSO4 and SiO2.
Most of the reactions proceed smoothly at room temperature under
solid-state conditions and give their corresponding b-imino deriva-
tives in high yields. The method has the advantage of simple manip-
ulation and mild conditions.
Moreover, in the case of some Lewis acid catalyzed reac-
tions, the failure of catalyst recycling renders these meth-
ods environmentally unsound. Although different
methods are available for the synthesis of b-enaminones,
development of convenient, high-yielding and ‘green’ ap-
proach is still highly desirable.
Key words: enamination, 1,3-dicarbonyl compounds, solid state,
mechanochemistry
Organic solid-state reactions are highly promising new
tools for solvent-free sustainable synthesis and produc-
tion.31 Costly workup is obsolete while few wastes are
formed and resources and energy saved. Currently, grow-
ing efforts of the scientific community of chemistry rely
upon the development of economical processes based on
the principles of green chemistry.24 Based on these, so our
research interest is to realize an environmentally benign
and efficiently synthetic methodology under solid-state
conditions. We herein report a mechanochemical protocol
for the condensation of solid 1,3-dicarbonyl compounds
with ammonium salts or solid amines using a catalytic
amount of KHSO4/SiO2 at solid phase and room tempera-
ture.
b-Enamino ketones have attracted considerable attention
over the past decades and found wide application in syn-
thetic chemistry and pharmaceutical chemistry.1–3 Some
drugs,4 such as anticonvulsant,5 anti-inflammatory
agents,6 and antitumor agents7 can be prepared from b-
enamino ketones. On the other hand, substituted b-enam-
ino ketones are useful intermediates for the synthesis of
heterocycles like pyridinones,3a quinolines,3b oxazoles,3c
pyrroles,3d isoxazole derivatives,3e tetrahydrobenzox-
azines,3f and polyazaheterocycles.3g
With growing interest in preparing biologically active
compounds, it is important to find facile, ‘green’ and prac-
tical methods for preparation of b-enamino ketones. The
most common route for the synthesis of b-enamino com-
pounds involves the direct condensation of 1,3-dicarbonyl
compounds with ammonium salts or amines in benzene or
toluene at reflux temperature with azeotropic removal of
water.8 The condensation of b-keto esters with excess am-
monium salts as the ammonia source in methanol9 or ace-
tic acid10 was also reported. To improve the yield and
speed up the reaction, some other catalysts or mediators
have been developed, such as HCl,11 H2SO4,12 PTSA,13
AcOH,14 HClO4,15 TMSOTf,16 montmorillonite K10,17,18
I2,11b BF3·OEt2,19 Al2O3,20 silica gel,21 Zn(ClO4)2·6H2O,22
CeCl3·7H2O,23 NaAuCl4,24 erbium(III) triflate25 and natu-
ral clays.26 Recently, this condensation reaction has also
been performed in water27,28 or in ionic liquid medium.29
Firstly, the efficiency of various solid-acid catalysts was
investigated in the model reaction conditions: benzoyl-
acetone (5 mmol), ammonium acetate (5 mmol), and cat-
alyst (10 mol%) in solid phase ground in a mortar at room
temperature, and the results are summarized in Table 1.
The results revealed that KHSO4/SiO2 (the weight ratio of
KHSO4 to SiO2 was 1:1) was superior (Table 1, entry 10)
with respect to the catalyst loadings, reaction times, and
product yields. Using the recycled KHSO4/SiO2 as the
catalyst, the catalytic efficiency shows almost no remark-
able change (Table 1, entry 14). Entry 1 shows the reac-
tion without addition of any catalyst, only 56% yield was
obtained after 150 minutes. p-Toluenesulfonic acid gave a
good result of the reaction, but it was laborious to separate
it from the reaction mixture (Table 1, entry 2). Although
the reaction also proceeded with SiO2 or KHSO4, respec-
tively, it took long reaction time and gave low yield
(Table 1, entries 8 and 9) compared to those obtained with
the combination of KHSO4/SiO2. Lower catalyst loading
can be used with a decline in reaction rate, and higher cat-
alyst loading shows not to boost the reaction (Table 1, en-
tries 11 and 12). If this reaction was carried out in a liquid
solution, the reaction rate and yield were lower (Table 1,
An improved procedure has been subsequently reported.
The reaction of amines with b-keto esters catalyzed by
InBr3 under solvent-free conditions was carried out suc-
cessfully.30 However, for a solid 1,3-dicarbonyl com-
SYNLETT 2009, No. 5, pp 0818–0822
x
x.
x
x.
2
0
0
9
Advanced online publication: 16.02.2009
DOI: 10.1055/s-0028-1087914; Art ID: W16308ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Solid-State Synthesis of β-Enamino Ketones
819
entries 7 and 13). So we chose to perform the KHSO4/ same conditions, reactions of some solid 1,3-dicarbonyl
SiO2-catalyzed reaction in solid state as the standard con- compounds (Table 2, entries 13 and 14) took longer time
ditions.
due to steric factors.
In order to extend the present method to synthesize differ-
ent kinds of b-enamino ketones, the condensation be-
tween solid 1,3-dicarbonyl compounds and solid
substituted anilines was explored, and the results are sum-
marized in Table 3.32 For most of the solid substituted
anilines tested, good yields were obtained when the reac-
tions were carried out at room temperature. The presence
of an electron-withdrawing group on the phenyl ring or
some deactivating group in 1,3-diketones slightly de-
creased the reactivity of the substrate which led to a need
for longer time to complete the reaction (Table 3, entries
8–11).
Table 1 Condensation of Benzoylacetone with Ammonium Acetate
in the Presence of Various Solid Acids under Various Reaction Con-
ditionsa
O
NH2
O
O
catalyst
r.t.
NH4OAc
+
Entry Catalyst
Time (min) Yield (%)b
1
2
neat
150
20
56
97
89
78
81
87
69
54
80
98
84
97
52
94
PTSA
Table 2 Solid-State Reactions of Solid 1,3-Dicarbonyl Compounds
with Different Ammonium Salts
3
phosphotungstic acid
phosphomolybdenum acid
cationic resin 732c
TiO2, H2SO4
HCld
60
4
80
O
O
KHSO4, SiO2
grinding, r.t.
O
NH2
R2
+
NH4 X
5
100
45
R1
R2
R1
2
6
1
Entry 1, R1 and R2
Ammonium Time
2
Yield
(%)a
7
150
150
90
salt
(min)
8
SiO2
1
2
3
4
5
6
7
8
9
1a, R1 = Ph, R2 = Me
NH4HCO3
15
2a 94
2a 98
2a 96
2a 91
2a 94
2a 98
2a 49
9
KHSO4
1a
1a
1a
1a
1a
1a
1a
(NH4)2CO3 10
e
10
11
12
13
14
KHSO4, SiO2
15
NH4OAc
NH4SCN
10
20
f
KHSO4, SiO2
80
g
KHSO4, SiO2
15
(NH4)2HPO4 25
HCOONH4 15
h
KHSO4, SiO2
150
25
i
KHSO4, SiO2
NH4Cl
(NH4)2SO4 120
120
a General reaction conditions: grinding reactants with catalyst togeth-
er at r.t.
2a
5
b Isolated products.
1b, R1 = 4-MeOC6H4,
NH4OAc
20
2b 98
C Cationic resin 732: polystyrene–sulfonic acid.
d Conditions: 5 mol% HCl at reflux temperature in benzene.
e Conditions: 10 mol% catalyst was used.
f Conditions: 5 mol% catalyst was used.
g Conditions: 30 mol% catalyst was used.
h Conditions: 5 mL of CH2Cl2 was added.
i The catalyst was reused.
R2 = Me
10
11
12
13
1c, R1 = 4-FC6H4, R2 = Me NH4OAc
15
2c 95
2d 98
2e 92
2f 94b
1d, R1 = Ph, R2 = COOEt (NH4)2HPO4 15
1e, 1,3-cyclohexanedione NH4OAc 30
1f, 5,5-dimethyl-1,3-cyclo- HCOONH4 35
hexanedione
To evaluate the scope and limitations of this solid-state
reaction, various solid 1,3-dicarbonyl compounds were
treated with a range of ammonium salts in the presence of
catalytic amount (10 mol%) of KHSO4/SiO2 by grinding
and the results are summarized in Table 2.32
14
15
1g, R1 = Ph, R2 = Ph
1h, R1 = 2-thienyl, R2 = Me NH4OAc
NH4OAc
70
20
2g 91b
2h 97
a Yields are given for isolated products.
b The reactions were performed at 50 °C.
First, benzoylacetone was treated with ammonium salts
such as NH4HCO3, (NH4)2CO3, NH4OAc, NH4SCN,
(NH4)2HPO4, HCOONH4, NH4Cl, (NH4)2SO4. It was
found that the ammonium salts of weak acids provided
high yields of products in short reaction times. Other solid
1,3-dicarbonyl compounds also gave satisfying results
(Table 2, entries 9–15). Compared to the corresponding
reaction with benzoylacetone (Table 2, entry 3) under the
In summary, this paper describes an efficient and practical
process for the synthesis of b-enamino ketones. The reac-
tion was carried out at room temperature in the solid state
without solvent. The most important advantages of this
Synlett 2009, No. 5, 818–822 © Thieme Stuttgart · New York

820
S.-L. Xu et al.
LETTER
Table 3 Condensation of 1,3-Dicarbonyl Compounds with Substitutional Anilines
R3
O
O
R3
KHSO4, SiO2
grinding, r.t.
O
HN
+
H2N
R1
R2
R1
R2
1
3
Entry
1
1
R3
Time (min)
Product 3
Yield (%)a
99
1a
1a
1a
1a
1b
1c
1d
1e
1f
4-MeO
4-Cl
10
15
30
12
15
18
15
45
35
50
120
45
3a
3b
3c
3d
3e
3f
2
98
3
4-O2N
4-Me
96
4
96
5
4-MeO
4-MeO
4-O2N
4-O2N
4-MeO
2,5-Cl2
4-Me
97
6
96
7
3g
3h
3i
98
8
93b
91b
90
9
10
11
12
1f
3j
1g
1h
3k
3l
90b
95
4-Cl
a Yields are given for isolated products.
b The reactions were performed at 50 °C.
(4) Eddington, N. D.; Cox, D. S.; Khurana, M.; Salama, N. N.;
Stables, J. P.; Harrison, S. J.; Negussie, A.; Taylor, R. S.;
Tran, U. Q.; Moore, J. A.; Barrow, J. C.; Scott, K. R. Eur. J.
Med. Chem. 2003, 49.
method are short reaction time, mild reaction conditions,
clean product, high yield, and minimal waste.
(5) Azzaro, M.; Geribaldi, S.; Videau, B. Synthesis 1981, 880.
(6) Dannhardt, G.; Bauer, A.; Nowe, U. J. Prakt. Chem. 1998,
340, 256.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(7) Boger, D. L.; Ishizaki, T.; Wysocki, J. R.; Munk, S. A.;
Kitos, P. A.; Suntornwat, O. J. Am. Chem. Soc. 1989, 111,
6461.
References and Notes
(1) (a) Tomioka, K.; Ando, K.; Takemasa, Y.; Koga, K. J. Am.
Chem. Soc. 1984, 106, 2718. (b) Georg, I. G.; Kant, J.
Tetrahedron Lett. 1988, 29, 403. (c) Lubell, W. D.;
Kitamura, M.; Noyori, R. Tetrahedron: Asymmetry 1991, 2,
543. (d) Bartoli, G.; Cimarelli, C.; Marcantoni, E.; Palmieri,
G.; Petrini, M. J. Org. Chem. 1994, 59, 5328.
(2) (a) Bartoli, G.; Bosco, M.; Cimarelli, C.; Dalpozzo, R.;
Guercio, G.; Palmieri, G. J. Chem. Soc., Perkin Trans. 1
1993, 2081. (b) Bartoli, G.; Bosco, M.; Cimarelli, C.;
Dalpozzo, R.; Palmieri, G. J. Chem. Soc., Perkin Trans. 1
1992, 2095. (c) Bartoli, G.; Bosco, M.; Cimarelli, C.;
Dalpozzo, R.; Munno, G. D.; Guercio, G.; Palmier, G.
J. Org. Chem. 1992, 57, 6020.
(3) (a) Alberola, A.; Calvo, L. A.; Ortega, A. G.; Ruiz, M. C. S.;
Yustos, P. J. Org. Chem. 1999, 64, 9493. (b) Chaaban, I.;
Greenhill, J. V.; Akhtar, P. J. Chem. Soc., Perkin Trans. 1
1979, 1593. (c) Augusti, R.; Kascheres, C. J. Org. Chem.
1993, 58, 7079. (d) Eberlin, M. N.; Kascheres, C. J. Org.
Chem. 1988, 53, 2084. (e) Al-Omran, F.; El-Khair, A. A.
J. Heterocycl. Chem. 2005, 45, 307. (f) Müller, A.; Maier,
A.; Neumann, R.; Maas, G. Eur. J. Org. Chem. 1998, 1177.
(g) Bejan, E.; Aït-Haddou, H.; Daran, J. C.; Balavoine,
G. G. A. Eur. J. Org. Chem. 1998, 2907.
(8) (a) Baraladi, P. G.; Simoni, D.; Manfredini, S. Synthesis
1983, 902. (b) Martin, D. F.; Janusonis, G. A.; Martin, B. B.
J. Am. Chem. Soc. 1961, 83, 73. (c) Ferraz, H. M. C.;
Oliceira, E. O.; Payret-Arrua, M. E.; Brandt, C. A. J. Org.
Chem. 1995, 60, 7357. (d) Kloek, J. A.; Leschinsky, K. L.
J. Org. Chem. 1978, 43, 1460. (e) Soloshonok, V. A.;
Kukhar, V. Tetrahedron 1996, 52, 6953. (f) Leflemme, N.;
Dallemange, P.; Rault, S. Synthesis 2002, 1740.
(9) (a) Zhu, G.; Chen, Z.; Zhang, X. J. Org. Chem. 1999, 64,
6907. (b) Garaldi, P. G.; Simoni, D.; Manfredini, S.
Synthesis 1983, 902. (c) Marchalin, S.; Kuthan, J. Collect.
Czech. Chem. Commun. 1983, 48, 3112. (d) Marchalin, S.;
Kuthan, J. Collect. Czech. Chem. Commun. 1984, 49, 1395.
(10) Rodríguez, H.; Reyes, O.; Suarez, M.; Garay, H. E.; Pérez,
R.; Cruz, L. J.; Verdecia, Y.; Martín, N.; Seoane, C.
Tetrahedron Lett. 2002, 43, 439.
(11) (a) Saeed, A. A. H. J. Chem. Eng. Data 1984, 29, 358.
(b) Hauser, C. R.; Reynolds, G. A. J. Am. Chem. Soc. 1948,
70, 2402. (c) Coffey, S.; Thomson, J. K.; Wilson, F. J.
J. Chem. Soc. 1936, 856.
(12) Martin, D. F.; Janusonis, G. A.; Martin, B. B. J. Am. Chem.
Soc. 1961, 83, 73.
Synlett 2009, No. 5, 818–822 © Thieme Stuttgart · New York

LETTER
Solid-State Synthesis of β-Enamino Ketones
821
(13) (a) Hickmot, P. W.; Sheppard, G. J. Chem. Soc., Perkin
Trans. 1 1972, 1038. (b) Bieräugel, H.; Akkerman, J. M.;
Lapierre Armande, J. C.; Pandit, U. K. Recl. Trav. Chim.
Pays-Bas 1976, 95, 266. (c) Gravel, D.; Labelle, M. Can. J.
Chem. 1985, 63, 1874. (d) Yapi, A. D.; Mustofa, M.;
Valentin, A.; Chavignon, O.; Teulade, J. C.; Mallie, M.;
Chapat, J.-P.; Blache, Y. Chem. Pharm. Bull. 2000, 48,
1886.
(14) (a) Naringrekar, V. H.; Stella, V. J. J. Pharm. Sci. 1990, 79,
138. (b) Brown, R. J.; Carver, F. W. S.; Hollingsworth, B. L.
J. Org. Chem. 1967, 32, 2624. (c) Brandt, C. A.; Da Silva,
A. C. M. P.; Pancote, C. G.; Brito, C. L.; Da Silveira, M. A.
B. Synthesis 2004, 1557.
3-Amino-1-(4-methoxyphenyl)but-2-en-1-one (2b)33b
Mp 106–108 °C. 1H NMR (500 MHz, CDCl3): d = 2.04 (s, 3
H), 3.85 (s, 3 H), 5.11 (br, 1 H,NH), 5.70 (s, 1 H), 6.89–6.92
(m, 2 H), 7.85–7.88 (m, 2 H), 10.13 (br, 1 H, NH). 13C NMR
(125 MHz, CDCl3): d = 22.95, 55.36, 91.88, 113.43, 129.03,
132.90, 161.89, 162.14, 188.65.
3-Amino-1-(4-fluorophenyl)but-2-en-1-one (2c)33b
Mp 106–108 °C. 1H NMR (500 MHz, CDCl3): d = 2.06 (s, 3
H), 5.21 (br, 1 H, NH), 5.67 (s, 1 H), 7.06–7.09 (m, 2 H),
7.87–7.90 (m, 2 H), 10.19 (br, 1 H, NH). 13C NMR (125
MHz, CDCl3) d = 22.95 91.99, 115.14 (d, J = 20 Hz), 129.39
(d, J = 9 Hz), 136.40, 136.42 163.30 (d, J = 56 Hz), 165.52,
188.08.
(15) Das, B.; Venkateswarlu, K.; Majhi, A.; Reddy, R. M.;
Reddy, N. K.; Rao, K. Y.; Ravikumar, K.; Sridhar, B. J. Mol.
Catal. A: Chem. 2006, 246, 276.
(16) Cartaya-Marin, C. P.; Henderson, D. G.; Soeder, R. W.
Synth. Commun. 1997, 27, 4275.
(17) (a) Rechsteimer, B.; Texier-Boullet, F.; Hamelin, J.
Tetrahedron Lett. 1993, 34, 5071. (b) Braibante, H. T. S.;
Braibante, M. E. F.; Rosso, G. B.; Oriques, D. A. J. Braz.
Chem. Soc. 2003, 14, 994.
Ethyl 2-Amino-4-oxo-4-phenylbut-2-enoate (2d)
Mp 49–51 °C; lit.33c 50–51 °C. 1H NMR (500 MHz, CDCl3):
d = 1.41 (t, 3 H, J = 7 Hz), 4.38 (q, 2 H, J = 7 Hz), 6.04 (br,
1 H, NH), 6.67 (s, 1 H), 7.46–7.54 (m, 3 H), 7.96–9.98 (m, 2
H), 9.49 (br, 1 H, NH). 13C NMR (125 MHz, CDCl3): d =
14.13, 62.70, 93.26, 127.45, 128.44, 131.29, 139.28, 147.49,
163.88, 191.80.
3-Aminocyclohex-2-enone (2e)
Mp 128–130 °C; lit.33d 133 °C. 1H NMR (500 MHz, CDCl3):
d = 1.97 (m, 2H), 2.29 (t, 2H, J = 6 Hz), 2.35 (t, 2H, J = 6
Hz), 4.67 (br, 2H, NH), 5.26 (s, 1H). 13C NMR (125 MHz,
D2O) d = 23.89, 30.60, 36.94, 99.56, 177.00, 203.01.
3-Amino-5,5-dimethylcyclohex-2-enone (2f)
(18) Valduga, C. J.; Squizani, A.; Braibante, H. S.; Braibante,
M. E. F. Synthesis 1998, 1019.
(19) Stefane, B.; Polanc, S. Synlett 2004, 698.
(20) Texier-Bouliet, F. Synthesis 1985, 679.
(21) Gao, Y.-H.; Zhang, Q.-H.; Xu, J.-X. Synth. Commun. 2004,
34, 909.
(22) Bartoli, G.; Bosco, M.; Locatelli, M.; Marcantoni, E.;
Melchiorre, P.; Sambri, L. Synlett 2004, 239.
(23) Khodaei, M. M.; Khosropour, A. R.; Kookhazadeh, M.
Synlett 2004, 1980.
Mp 164–166 °C; lit.33d 165–167 °C. 1H NMR (500 MHz,
CDCl3): d = 1.08 (s, 6 H), 2.16 (s, 2 H), 2.20 (s, 2 H), 4.71
(br, 2 H, NH), 5.25 (s, 1 H). 13C NMR (125 MHz, D2O) d =
28.35, 32.88, 42.65, 49.86, 99.27, 163.46, 197.31.
3-Amino-1,3-diphenylprop-2-en-1-one (2g)33e
Mp 78–79 °C. 1H NMR (500 MHz, CDCl3) d = 5.46 (br, 1
H, NH), 6.16 (s, 1 H), 7.42–7.53 (m, 6 H), 7.64–7.65 (m, 2
H), 7.94–7.96 (m, 2 H), 10.43 (br, 1 H, NH). 13C NMR (125
MHz, CDCl3) d = 91.93, 126.36, 127.24, 128.32, 129.06,
130.74, 131.06, 137.63, 140.36, 162.88, 190.26.
3-Amino-1-(thiophen-2-yl)but-2-en-1-one (2h)
Mp 168–170 °C; lit.33b 168–170 °C. 1H NMR (500 MHz,
CDCl3): d = 2.03 (s, 3 H), 5.31 (br, 1 H,NH), 5.60 (s, 1 H),
7.05–7.56 (m, 3 H), 9.91 (br, 1 H, NH). 13C NMR (125 MHz,
CDCl3): d = 22.73, 92.00, 127.73, 127.87, 130.21, 146.99,
162.82, 182.21.
(24) Arcadi, A.; Bianchi, G.; Di Giuseppe, S.; Marinelli, F. Green
Chem. 2003, 5, 64.
(25) Dalpozzo, R.; Nino, A. D.; Nardi, M.; Russo, B.; Procopio,
A. Synthesis 2006, 1127.
(26) Silva, F. C.; De Souza, M. C. B. V.; Ferreira, V. F.; Sabino,
S. J.; Antunes, O. A. C. Catal. Commun. 2004, 5, 151.
(27) Stefani, H. A.; Costa, I. M.; de O. Silva, D. Synthesis 2000,
1526.
(28) Khosropour, A. R.; Khodaei, M. M.; Kookhazadeh, M.
Tetrahedron Lett. 2004, 45, 1725.
(29) Khodaei, M. M.; Khosropour, A. R.; Kookhazadeh, M. Can.
J. Chem. 2005, 83, 209.
(30) Zhang, Z.-H.; Yin, L.; Wang, Y.-M. Adv. Synth. Catal. 2006,
348, 184.
(31) Kaupp, G.; Schmeyers, J.; Boy, J. Chemosphere 2001, 43,
55.
3-(4-Methoxyphenylamino)-1-phenylbut-2-en-1-one
(3a)33f
Mp 100–102 °C. 1H NMR (500 MHz, CDCl3): d = 2.07 (s, 3
H), 3.82 (s, 3 H), 5.86 (s, 1 H), 6.89–6.91 (m, 2 H), 7.10–7.12
(m, 2 H), 7.41–7.46 (m, 3 H), 7.90–7.92 (m, 2 H), 12.92 (br,
1 H, NH). 13C NMR (125 MHz, CDCl3): d = 20.27, 55.52,
93.59, 114.37, 126.64, 127.05, 128.28, 130.80, 131.46,
140.16, 157.89, 163.21, 188.47.
(32) General Procedure for the Preparation of b-Enamino
Ketones
A mixture of the solid 1,3-dicarbonyl compound (5 mmol),
amine (or ammonium, 5 mmol), and KHSO4/SiO2 (0.136 g,
weight ratio 1:1) was ground in a mortar at r.t. for the
appropriate time. After completion of the reaction as
indicated by TLC, the reaction mixture was extracted with
CH2Cl2 (2 × 10 mL). The combined organic layers were
dried over Na2SO4 and concentrated under reduced pressure
to give a product with high purity. The solid product could
be further purified by recrystallization in PE (Table 2,
entries 1–15) or in EtOH (Table 3, entries 1–12).
3-Amino-1-phenylbut-2-en-1-one (2a)
3-(4-Chlorophenylamino)-1-phenylbut-2-en-1-one (3b)
Mp 126–128 °C; lit.33g 128–129 °C. 1H NMR (500 MHz,
CDCl3): d = 2.12 (s, 3 H), 5.91 (s, 1 H), 7.09–7.15 (m, 2 H),
7.31–7.34 (m, 2 H), 7.41–7.48 (m, 3 H), 7.90–7.92 (m, 2 H),
13.07 (br, 1 H, NH). 13C NMR (125 MHz, CDCl3): d = 20.30,
94.63, 125.80, 127.01, 128.26, 129.23, 131.02, 131.15,
137.20, 139.71, 161.63, 188.88.
3-(4-Nitrophenylamino)-1-phenylbut-2-en-1-one (3c)33h
Mp 140–142 °C. 1H NMR (500 MHz, CDCl3): d = 2.33 (s,
3 H), 6.04 (s, 1 H), 7.25–7.28 (m, 2 H), 7.44–7.47 (m, 2 H),
7.50–7.52 (m, 1 H), 7.88–7.93 (m, 2 H), 8.21–8.25 (m, 2 H),
13.41 (br, 1 H, NH). 13C NMR (125 MHz, CDCl3): d = 21.18,
97.54, 122.26, 125.22, 127.30, 128.50, 131.73, 139.20,
144.13, 145.18, 159.16, 189.99.
Mp 138–140 °C; lit.33a 144–145 °C. 1H NMR (500 MHz,
CDCl3): d = 2.06 (s, 3 H), 5.21 (br, 1 H, NH), 5.74 (s, 1 H),
7.39–7.45 (m, 3 H), 7.87–7.89 (m, 2 H), 10.22 (br, 1 H, NH).
13C NMR (125 MHz, CDCl3): d = 22.92, 92.34, 127.10,
128.22, 130.83, 140.20, 162.91, 189.54.
1-Phenyl-3-(p-tolylamino)but-2-en-1-one (3d)33i
Mp 114–116 °C. 1H NMR (500 MHz, CDCl3): d = 2.10 (s,
Synlett 2009, No. 5, 818–822 © Thieme Stuttgart · New York

822
S.-L. Xu et al.
LETTER
3 H), 2.35 (s, 3 H), 5.87 (s, 1 H), 7.05–7.07 (m, 2 H), 7.15–
7.25 (m, 2 H), 7.40–7.46 (m, 3 H), 7.90–7.93 (m, 2 H), 13.03
(br, 1 H, NH). 13C NMR (125 MHz, CDCl3): d = 20.38,
20.97, 93.92, 124.85, 127.06, 128.27, 129.76, 130.82,
135.72, 136.02, 140.14, 162.60, 188.48.
CDCl3): d = 1.05 (s, 6 H), 2.15 (s, 2 H), 2.32 (s, 2 H), 3.78
(s, 3 H), 5.34 (s, 1 H), 6.82 (dd, 2 H, J = 2, 7 Hz), 7.04 (dd,
2 H, J = 2, 7 Hz), 7.28 (s, 1 H).13C NMR (125 MHz, CDCl3):
d = 28.27, 32.76, 43.02, 50.36, 55.46, 96.96, 114.37, 126.07,
131.14, 157.46, 162.87, 197.61.
1-(4-Methoxyphenyl)-3-(4-methoxyphenylamino)but-2-
3-(2,5-Dichlorophenylamino)-5,5-dimethylcyclohex-2-
enone (3j)
en-1-one (3e)33j
Mp 142–143 °C. 1H NMR (500 MHz, CDCl3): d = 2.05 (s, 3
H), 3.82 (s, 3 H), 3.86 (s, 3 H), 5.82 (s, 1 H), 6.88–6.94 (m,
4 H), 7.09–7.11 (m, 2 H), 7.89–7.91 (m, 2 H), 12.85 (br, 1
H, NH). 13C NMR (125 MHz, CDCl3): d = 20.26, 55.36,
55.49, 93.05, 113.47, 114.31, 126.57, 128.90, 131.67,
132.81, 157.74, 161.87, 162.41, 187.62.
Mp 182–184 °C. 1H NMR (500 MHz, CDCl3): d = 1.14 (s, 6
H), 2.26 (s, 2 H), 2.39 (s, 2 H), 5.61 (s, 1 H), 6.12 (br, 1 H),
7.07–7.42 (m, 3 H). 13C NMR (125 MHz, CDCl3): d = 28.28,
32.89, 43.74, 50.34, 100.78, 124.56, 125.27, 125.96, 130.79,
133.30, 136.28, 158.05, 198.18. IR (KBr) 3442, 3225, 2953,
2873, 1597, 1537, 1464, 1402, 1364, 1269, 1092, 1048, 925,
893, 827, 743, 519 cm–1. MS (EI): m/z (%) = 285 (42), 283
(50), 268 (20), 266 (20), 227 (36), 192 (100), 164 (28). Anal.
Calcd for C14H15Cl2NO: C, 59.17; H, 5.32; N, 4.93. Found:
C, 59.09; H, 5.28; N, 4.90.
1-(4-Fluorophenyl)-3-(4-methoxyphenylamino)but-2-en-
1-one (3f)
Mp 116–118 °C. 1H NMR (500 MHz, CDCl3): d = 2.06 (s, 3
H), 3.82 (s, 3 H), 5.80 (s, 1 H), 6.89–6.91 (m, 2 H), 7.07–7.11
(m, 4 H), 7.90–7.93 (m, 2 H), 12.87 (br, 1 H, NH). 13C NMR
(125 MHz, CDCl3): d = 20.25, 55.49, 93.15, 114.37, 115.16
(d, J = 21 Hz), 126.63, 129.24 (d, J = 9 Hz), 131.35, 136.36
(d, J = 4 Hz), 157.94, 163.38 (d, J = 22 Hz), 165.47, 186.94.
IR (KBr): 3440, 1599, 1543, 1515, 1496, 1462, 1436, 1328,
1251, 1198, 1105, 1031, 855, 779, 520 cm–1. MS (EI): m/z
(%) = 286 (18), 285 (100) [M+], 284 (70), 270 (18), 190 (11),
162 (36), 147 (22), 123 (71), 108 (9), 95 (27). Anal. Calcd
for C17H16FNO2: C, 71.56; H, 5.65; N, 4.91. Found: C,
71.51; H, 5.60; N, 4.87.
1,3-Diphenyl-3-(p-tolylamino)prop-2-en-1-one (3k)33m
Mp 120–122 °C. 1H NMR (500 MHz, CDCl3): d = 2.23 (s, 3
H), 6.05 (s, 1 H), 6.68–7.95 (m, 14 H), 12.90 (br, 1 H, NH).
13C NMR (125 MHz, CDCl3): d = 20.79, 96.57, 123.21,
127.22, 128.33, 128.38, 128.49, 129.31, 129.55, 131.17,
133.86, 135.94, 136.80, 139.98, 161.74, 189.43.
3-(4-Chlorophenylamino)-1-(thiophen-2-yl)but-2-en-1-
one (3l)
Mp 80–82 °C. 1H NMR (500 MHz, CDCl3): d = 2.11 (s, 3 H),
5.78 (s, 1 H), 7.06–7.61 (m, 7 H), 12.71 (br, 1 H, NH). 13
C
Ethyl 2-(4-Nitrophenylamino)-4-oxo-4-phenylbut-2-
enoate (3g)
NMR (125 MHz, CDCl3): d = 20.31, 94.51, 125.74, 127.89,
128.14, 129.34, 130.66, 131.21, 137.24, 146.56, 161.33,
181.88. IR (KBr): 3441, 3095, 1623, 1562, 1481, 1418,
1373, 1381, 1229, 1093, 1031, 824, 834, 766, 722, 502
cm–1. MS (EI): m/z (%) = 279 (25), 278 (39), 277 (67), 276
(84), 244 (87), 111 (100), 83 (8). Anal. Calcd for
Mp 98–99 °C. 1H NMR (500 MHz, CDCl3): d = 1.22 (t, 3 H,
J = 7 Hz), 4.28 (q, 2 H, J = 7 Hz), 6.67 (s, 1 H), 7.04–7.05
(m, 2 H), 7.47–7.51 (m, 2 H), 7.57–7.60 (m, 1 H), 7.97–7.99
(m, 2 H), 8.19–8.21 (m, 2 H), 11.95 (br, 1 H, NH). 13C NMR
(125 MHz, CDCl3): d = 13.83, 62.79, 101.02, 120.30,
125.09, 127.77, 128.76, 132.95, 138.10, 143.72, 145.72,
146.95, 163.64, 191.94. IR (KBr): 3441, 2981, 1373, 1619,
1585, 1510, 1337, 1281, 1226, 1163, 1108, 1051, 1016, 831,
853, 750, 591, 552, 493 cm–1. MS (EI): m/z (%) = 341 (5),
340 (33) [M+], 339 (31), 294 (14), 268 (18), 267 (84), 236
(26), 221 (15), 105 (100), 77 (42). Anal. Calcd for
C18H16N2O5: C, 63.52; H, 4.74; N, 8.23. Found: C, 63.50; H,
4.67; N, 8.14.
C14H12ClNOS: C, 60.54; H, 4.35; N, 5.04. Found: C, 60.50;
H, 4.31; N, 5.01.
(33) (a) Baraldi, P. G. Synthesis 1983, 902. (b) Singh, B.;
Lesher, G. Y. J. Heterocycl. Chem. 1990, 27, 2085.
(c) Baraldi, P. G. Tetrahedron 1987, 43, 235. (d) Wang,
G.-W. Green Chem. 2006, 8, 1080. (e) Sviridov, S. I.
Tetrahedron 2007, 63, 12195. (f) Simunek, P. Tetrahedron
2005, 61, 8130. (g) Boatman, S. J. Org. Chem. 1966, 31,
1785. (h) Tan, S. F.; Ang, K. P.; Jayachandran, H. J. Chem.
Soc., Perkin Trans. 2 1983, 1011. (i) Khodaei, M. M.;
Khosropour, A. R.; Kookhazadeh, M. Can. J. Chem. 2005,
83, 209. (j) Lyubchanskaya, V. M.; Mukhanova, T. I.;
Panisheva, E. K.; Alekseeva, L. M.; Granik, V. G. Khim.
Farm. Zh. 1995, 29, 40; Chem. Abstr. 1995, 124, 145843.
(k) Zhuo, J.-C. Magn. Reson. Chem. 1997, 355, 311.
(l) Vovk, M. B. Russ. J. Org. Chem. 2007, 43, 256.
(m) Bannikova, Y. N.; Khalturina, V. V.; Sedegova, E. A.;
Maslivets, A. N. Russ. J. Org. Chem. 2007, 43, 154.
3-(4-Nitrophenylamino)cyclohex-2-enone (3h)33k
Mp 176–178 °C.1H NMR (500 MHz, CDCl3): d = 2.07–2.11
(m, 2 H), 2.42 (t, 2 H, J = 7 Hz), 2.56 (t, 2 H, J = 6 Hz), 5.85
(s, 1 H), 6.83 (br, 1 H, NH), 7.26–7.29 (m, 2 H), 8.19–8.21
(m, 2 H). 13C NMR (125 MHz, CDCl3): d = 21.65, 29.82,
36.55, 103.13, 121.31, 125.32, 143.35, 144.94, 159.90,
198.94.
3-(4-Methoxyphenylamino)-5,5-dimethylcyclohex-2-
enone (3i)
Mp 186–188 °C; lit.33l 186–188 °C. 1H NMR (500 MHz,
Synlett 2009, No. 5, 818–822 © Thieme Stuttgart · New York