The use of K-10/ultrasound in the selective synthesis of unsymmetrical β-enamino ketones

Article abstract of DOI:10.1055/s-1998-2107

p-Phenyl substituted β-enamino ketones 2a-p and cyclic β-enamino ketones 4, 6a-f have been prepared by a selective method by dispersing 1,3- diketones and amines on montmorillonite K-10 under sonication.

Full text of DOI:10.1055/s-1998-2107

SYNTHESIS
July 1998
1019
The Use of K-10/Ultrasound in the Selective Synthesis of Unsymmetrical â-Enamino
Ketones
Claudete J. Valduga, Adriana Squizani, Hugo S. Braibante, Mara E.F.Braibante*
Departamento de Química, Universidade Federal de Santa Maria, Santa Maria, RS, 97105-900, Brazil
Fax +55(220)8031; E-mail: mara@quimica.ufsm.br
Received 24 January 1997; revised 15 December 1997
Abstract: p-Phenyl substituted β-enamino ketones 2a–p and
cyclic β-enamino ketones 4, 6a–f have been prepared by a selec-
tive method by dispersing 1,3-diketones and amines on montmo-
para group in the aromatic ring is used to evaluate its ef-
rillonite K-10 under sonication.
tives of 2-acylcycloalkanones, using the same methodolo-
gy,8 but with sonication. In this work, substitution of the
fect on the reactivity of the diketone carbonyl groups to-
wards condensation with amines using solid support.
Key words: β-enamino ketones, montmorillonite, ultrasound
The development of facile synthetic methods leading to β-
enamino compounds and their derivatives, without side
products, constitutes an active area of investigation in
synthetic organic chemistry. The enamino group is a use-
ful precursor for a variety of heterocyclic compounds1–4
and is common in compounds with pharmacological prop-
erties. Recently, the enamino ketone moiety has attracted
much interest because it is a possible intermediate for the
preparation of a part of the side chain of taxol.5 The syn-
thesis of heterocyclesusing N-immobilized enamino com-
pounds has been recently applied in combinatorial
chemistry.6 We have previously described the synthesis of
a series of β-enamino α,β-unsaturated ketones and esters
using alumina7 and montmorillonite (K-10).8 There is no
reported systematic method for preparing unsymmetrical
β-enamino ketones. The standard methods for the prepa-
ration of β-enamino ketones involve the direct condensa-
tion of amines and diketones using a stream of gaseous
amine, ammonium acetate and reflux in aromatic solvent
with azeotropic removal of the water1, 9 or the reaction of
lithiated Schiff’s base from imines with esters.10
The β-enamino ketones 2a–p were prepared by dispersing
p-substituted benzoylacetones 111 and ammonia or prima-
ry amines on montmorillonite K-10 under ultrasound. The
reaction conditions for these compounds are summarized
in Table 1. This method was successfully applied to cyclic
β-enamino ketones, thus the reaction of 2-acetylcyclopen-
tanones 3 and 2-acetylcyclohexanones 5 with amines af-
forded cyclic β-enamino ketones 4a–f and 6a–f in good
yields (Scheme 2), using the same method of solid support
K-10 under sonication (Table 2). The different regio-
chemistry observed starting from diketones with four or
five membered rings is due to the different reactivity of
carbonyl groups, according to the results reported previ-
ously.1
Although Ando12 observed that the use of ultrasound/alu-
mina changed the main reaction pathway in the substitu-
tion reaction, this was not seen in the reactions described
in our work. The same products were isolated with either
mechanical agitation or sonication. When only mechani-
cal agitation was used, low yields with lengthened reac-
tion times were observed and large amounts of starting
materials were recovered.
In continuation of our investigation exploring the use of
montmorillonite as solid support in the synthesis and reac-
tivity of these compounds, we now wish to report the se-
lective synthesis of unsymmetrical p-phenyl substituted
β-enamino ketones (Scheme 1) and β-enamino deriva-
These structures were unambiguously established based
on the 1H NMR spectra by NOESY experiment for 4b and
Scheme 1
Scheme 2

SYNTHESIS
Papers
Table 1. p-Phenyl Substituted β-Enamino Ketones 2aÐp Prepared
1020
Producta Yieldb mp (°C) or
Reaction 1H NMR (CDCl3/TMS)
13C NMR (CDCl3/TMS)
(%)
bp (°C)/Torr
Time (h) δ, J (Hz)
δ
2a
2b
67
141
10
2.00 (s, 3H), 10.06 (br, 2H), 5.99 (s, 1H), 21.27, 90.64, 126.02, 127.29, 129.69,
7.28–7.85 (m, 5Harom 139.68, 163.47, 187.52
)
85
95
90
6
2.00 (s, 3H), 2.63 (s, 3H), 10.10 (br, 2H), 5.60 21.17, 22.60, 127.05, 128.79, 137.50,
(s, 1H), 7.18 (d, 2Harom, J = 8.4), 7.77 (d, 140.99, 162.83, 189.14, 191.98.
2Harom, J = 8.4)
2c
127–128
5
1.95 (s, 3H), 3.78 (s, 3H), 10.08 (br, 2H), 5.64 22.55, 55.13, 91.57, 113.29, 128.82,
(s, 1H), 6.86 (d, 2Harom, J = 8.7), 7.83 (d, 132.89, 161.73, 188.34
2Harom, J = 8.7)
2d
2e
2f
78
87
86
175–176
75
10
2
2.08 (s, 3H), 5.65 (s, 1H), 10.26 (br, 2H), 7.97 21.30, 90.79, 122.35, 126.93, 145.20,
(d, 2Harom, J = 8.9), 8.21 (d, 2Harom, J = 8.9)
148.50, 165.36, 184.13
1.98 (s, 3H), 2.93 (d, 3H, J = 5.0), 4.96 (br, 19.8, 29.65, 92.05, 126.64, 128.12, 130.34,
1H), 5.67 (s, 1H), 7.34–7.90 (m, 5H) 140.51, 165.98, 187.64
96–97
2
1.96 (s, 3H), 2.30 (s, 3H), 2.91 (d, 3H, J = 19.02, 21.24, 29.46, 91.66, 126.53, 128.70,
5.3), 5.60 (s, 1H), 7.11 (d, 2H, J = 7.6), 7.70 137.71, 140.45, 165.44, 187.44
(d, 2H, J = 7.6), 11.20 (br, 1H)
2g
2h
2i
80
45
70
67
64
40
72
73
84–85
138
5
5
2.00 (s, 3H), 2.94 (d, 3H, J = 5.29), 3.79 (s, 18.84, 29.26, 55.00, 91.13, 113.10, 128.38,
3H), 5.62 (s, 1H), 6.87 (d, 2H, J = 8.9), 7.82 133.00, 161.33, 165.01, 186.60
(d, 2H, J = 8.9), 11.20 (br, 1H)
2.08 (s, 3H), 3.04 (d, 3H, J = 5.4), 5.65 (s, 18.96, 29.67, 92.32, 123.18, 127.50,
1H), 7.93 (d, 2H, J = 9.0), 8.20 (d, 2H, J = 145.92, 148.56, 167.28, 184.07
9.0), 10.26 (br, 1H)
120/2
155/2
105/2
110
6
1.25 (d, 6H, J = 6.3), 2.04 (s, 3H), 3.66 (m, 22.26, 23.15, 44.26, 91.10, 126.21, 127.47,
1H), 5.58 (s, 1H), 7.34–7.85 (m, 5H), 11.46 128.65, 140.00, 162.96, 186.54
(br, 1H)
2j
6
1.27 (d, 6H, J = 6.4), 2.05 (s, 3H), 2.34 (s, 18.90, 21.15, 23.62, 44.73, 91.39, 126.68,
3H), 3.67 (m, 1H), 4.26 (br, 1H), 5.58 (s, 1H), 128.62, 137.72, 140.31, 163.15, 187.11
7.16 (d, 2H, J = 8.0), 7.65 (d, 2H, J = 8.0)
2k
2l
5
1.25 (d, 6H, J = 6.4), 2.03 (s, 3H), 3.78 (m, 18.57, 23.34, 44.30, 54.71, 90.67, 112.87,
1H), 5.56 (s, 1H), 6.86 (d, 2H, J = 8.9), 7.83 128.10, 132.72, 161.07, 162.60, 186.05
(d, 2H, J = 8.9), 11.30 (br, 1H)
16
6
1.31 (d, 6H, J = 6.4), 2.13 (s, 3H), 3.85 (m, 18.75, 23.34, 45.02, 91.99, 123.06, 127.38,
1H), 5.59 (s, 1H), 7.94 (d, 2H, J = 9.1), 8.21 145.89, 148.41, 164.85, 183.62
(d, 2H, J = 9.1), 11.58 (br, 1H)
2m
2n
60
1.99 (s, 3H), 4.45 (d, 2H, J = 6.2), 5.71 (s, 19.17, 46.76, 92.38, 126.70, 127.30,
1H), 7.27–7.40 (m, 3Harom), 7.81–7.94 (m, 127.96, 128.68, 130.36, 137.59, 140.20,
2Harom), 11.73 (br, 1H)
164.68, 187.80
89
5
2.01 (s, 3H), 2.34 (s, 3H), 4.47 (d, 2H, J = 19.29, 21.27, 46.88, 92.33, 126.76, 126.88,
6.2), 5.71 (s, 1H), 6.91 (d, 2Harom, J = 8.2), 127.36, 137.77, 140.68, 164.41, 187.87
7.29 (s, 5Harom), 7.78 (d, 2Harom, J = 8.2),
11.69 (br, 1H)
2o
2p
70
95
92
24
20
2.00 (s, 3H), 3.77 (s, 3H), 4.46 (d, 2H, J = 19.19, 46.73, 55.04, 91.87, 113.21, 126.67,
6.4), 5.68 (s, 1H), 6.85 (d, 2Harom, J = 8.9), 128.56, 128.62, 132.82, 137.77, 161.53,
7.27 (s, 5Harom), 7.85 (d, 2Harom, J = 8.9), 164.40, 187.08
11.64 (br, 1H)
148
2.09 (s, 3H), 4.54 (d, 2H, J = 6.4), 5.71 (s, 19.29, 47.09, 92.89, 123.25, 126.79,
1H), 7.32 (s, 5Harom), 8.07 (d, 2Harom, J = 8.9), 127.66, 128.83, 136.99, 145.75, 148.72,
8.21 (d, 2Harom, J = 8.9), 11.90 (br, 1H)
166.29, 184.71
a All compounds gave satisfactory elemental analyses: C ± 0.21, H ± 0.10, N ± 0.06.
b Yield of pure isolated products.

SYNTHESIS
July 1998
1021
Table 2. Cyclic β-Enamino Ketones 4, 6 Prepared
Prod-
ucta
Yieldb (%)
mp (°C)
or bp (°C)/Torr
1H NMR (CDCl3/TMS),
δ, J (Hz)
13C NMR (CDCl3/TMS),
δ
4, 6
4
6
4
6
4
6
4
6
a
b
c
95
80
65
103
1.46–1.53 (m, 2H), 1.64 (m, 4H), 2.08 21.35, 22.76, 35.11,
1.98–2.37 (m, 2H), (s, 3H), 2.22 (t, 2H, 42.83, 101.92,
2.03 (s, 3H), 6.20 J = 7.60), 2.29 (t, 175.45, 208.76
2.63, 23.63, 25.43,
27.70, 30.69, 101.50,
158.22, 198.38
(br, 1H)
2H, J = 7.60), 5.43
(br, 1H),
75
78
73
70
87/3
98/3
1.78–2.11 (m, 2H), 1.67 (m, 4H), 2.01 15.30, 20.84, 27.50,
1.93 (s, 6H), 2.27 (t, (s, 3H), 2.08 (m, 29.80, 38.60,
2H, J = 7.6), 2.48 (t, 4H), 2.84 (d, 3H), 101.81, 159.28,
20.97, 22.17, 23.64
24.12, 24.20, 30.48,
106.33, 181.4, 198.02
2H, J = 7.2), 10.23 11.12 (br, 1H)
182.01
(br, 1H)
132/3
121
176/3
119
1.59–2.29 (m, 2H), 1.49 (m, 4H), 2.10 15.54, 20.00, 25.89,
1.87 (s. 3H), 2.31– (s, 3H), 2.31 (m, 38.72, 66.32,
2.61 (m, 4H), 4.39 4H), 4.39 (d, 2H, J = 102.66, 126.85,
21.17, 22.39, 25.59,
25.84, 27.00, 45.19,
100.13, 126.03,
126.50, 128.03,
138.03, 160.65, 195.41
(d, 2H, J = 6.7), 6.96),
7.21–7.41 (m, 5H), (m, 5H), 11.84 (br, 138.51, 158.26,
10.75 (br, 1H) 1H)
201.57
7.20–7.33 128.14, 128.38,
d
e
82
70
76
70
1.61–1.78 (m, 2H), 1.54–1.60 (m, 4H), 23.28, 24.73, 35.36,
2.31 (t, 2H, J = 2.19–2.33 (m, 4H), 100.00, 126.96,
7.01), 3.02 (t, 2H, J 7.31–7.35 (m, 5H), 127.69, 128.30,
21.66, 23.63, 27.11,
30.58, 100.93, 126.26,
127.67, 128.43,
= 7.01), 6.02 (br, 7.36 (br, 1H)
1H), 7.42–7.68 (m,
5H)
132.78, 175.27,
199.86
142.63, 161.64, 196.17
107
109
2.24–2.51 (m, 2H), 1.40–1.79 (m, 4H), 21.12, 24.91, 30.60,
2.52–2.74 (m, 4H), 2.24 (t, 2H, J = 36.40, 115.90,
3.35 (s, 3H), 7.28– 7.04), 2.41 (t, 2H, J 126.20, 127.70,
7.68 (m, 5H), 10.07 = 7.11), 2.94 (d, 3H, 128.40, 134.90,
21.65, 23.11, 26.15,
27.55, 28.66, 99.67,
126.18, 127.49,
127.87, 142.83,
(br, 1H)
J = 7.02), 7.29–7.40 152.60, 187.60
165.22, 193.13
(m, 5H), 11.97 (br,
1H)
f
87
65
96
128
1.73–1.98 (m, 2H), 1.48–1.65 (m, 4H), 22.46, 24.78, 35.95,
2.63 (t, 2H, J = 6.4), 2.27 (t, 2H, J = 48.40, 104.58,
2.83 (t, 2H, J = 6.4), 7.11), 2.44 (t, 2H, J 126.64, 126.89,
4.59 (d, 2H, J = = 7.05), 4.51 (d, 2H, 127.73, 128.13,
6.2), 7.20–7.97 (m, J = 7.03), 7.29–7.43 128.29, 128.35,
10H), 10.77 (br, (m, 10H), 9.61 (br, 131.08, 132.74,
21.94, 23.35, 26.57,
27.92, 46.29, 100.50,
126.58, 126.92,
127.33, 127.79,
128.35, 128.77,
138.09, 142.96,
164.26, 194.20
1H)
1H)
155.79, 200.00
a All compounds gave satisfactory elemental analyses: C ± 0.26, H ± 0.23, N ± 0.16.
b Yield of pure isolated products.
6b, by the interaction of the nitrogen bonded methyl (R1) 1,3-diketones and low yield of the corresponding enamino
with the methyl in the double bond (R) for 4b which, how- ketones.
ever, was not observed for 6b.
In conclusion, the supported reaction using K-10 and ul-
As shown in Tables 1 and 2, a variety of β-enamino ke- trasound provides a general procedure for a highly selec-
tones was obtained using this procedure and no byprod- tive method for the synthesis of unsymmetrical β-
ucts were observed. The use of K-10 as solid support has enamino ketones.
become very useful in synthetic organic chemistry be-
cause of its enhanced selectivity due to its lamellar swell-
ing structure and large surface area, the availability of
both Bronsted and Lewis surface acidic sites, milder reac-
tion conditions and ease of workup. The combined use of
Melting points were determined with a Microquímica APF-301 ap-
paratus and are uncorrected. 1H and 13C NMR spectra were recorded
on a Bruker AC-80 and Varian XL-200 spectrometer in CDCl3/
TMS. Elemental analyses were carried out on a Vario CHN-stan-
dard analyzer. Capillary GC analyses were performed on a Carlo
Erba , Mega Series 5400 chromatograph equipped with a split/split-
less injector and FID detector. An ultrasound bath (water), Thorn-
ton, 50–60 Hz, 110/220 volts, 1.0 amps was used, the water bath
montmorillonite and ultrasonic irradiation showed rate
enhancements, high yields and short reaction times. In the
absence of sonication the reaction was stirred at ambient
temperature for 24 hours resulting in a large amount of

SYNTHESIS
Papers
1022
remained at r.t. though ambient cooling (the temperature of the bath
never exceeded 35°C).
(1) Greenhill,J.V., Chem. Soc. Rev. 1977, 6, 277.
(2) Kashima,C., Heterocycles 1979, 12, 1343.
(3) Braibante, M. E. F.; Braibante, H.S.; Missio, L. J. Heterocycl.
Chem. 1996, 34, 1243.
â-Enamino Ketones 2a–p , 4a–f and 6a–f ; General Procedure:
Amines (2 mmol; for 2a, 4a and 6a 25 % aq NH4OH was used) were
added to the p-substituted benzoylacetones 1, 2-acetylcyclopen-
tanones 3 or 2-acetylcyclohexanone 5 (1 mmol) dispersed on mont-
morillonite K-10 (0.3 g; Fluka). The mixture was placed in an
ultrasound bath (the temperature of the bath never exceeded 35˚C) for
the time reported in Table 1 (for 4a–f, 6a–f, 20 h) . The products were
extracted by washing the montmorillonite with CH2Cl2 (4 × 10 mL),
dried (MgSO4), filtered and the solvent was removed in vacuum to
yield the crude products. Compounds 2a,b and g were purified by re-
crystallization from EtOH and 2m–p were recrystallized from diiso-
propyl ether. For 2h and 2l the purification was performed by flash
column chromatography on silica gel (Aldrich, 230–400 mesh) using
hexane/CH2Cl2 (8:1) as eluent. Solid compounds 4a,d–f and 6a,d–f
were purified by recrystallization from diisopropyl ether.
(4) Pedrosa, R.; Vicente, M. J. Heterocycl. Chem. 1987, 24, 709.
(5) Dondoni, A.; Perrone,D. Synthesis 1993 , 1162.
(6) Gordeev, M.; Patel,D.; Gordon, E. J.Org.Chem. 1996, 61, 924
(7) Braibante, M.E.F.; Braibante, H. S.; Salvatore, S. J. Química No-
va, 1990, 13, 67; Chem. Abstr. 1991, 114, 121 426.
(8) Braibante, M.E.F.; Braibante, H. S.; Missio, L.; Andricopulo, A.
Synthesis 1994, 898.
(9) Baraldi,P.G.; Simoni,D.; Manfredini,S. Synthesis 1983, 902.
(10) Bartoli, G.; Cimarelli, C.; Palmieri, G.; Bosco, M.; Dalpozzo, R.
Synthesis 1990, 895.
(11) p-Substituted benzoylacetones were prepared according to the
published procedure, J.Am.Chem.Soc. 1950, 72, 1352 and p- ni-
trobenzoylacetone was prepared by the reaction of p-nitro-
acetophenone, acetic anhydride and boron trifluoride,
J.Am.Chem.Soc.1946, 68, 2742.
(12) Ando, T. ; Sumi, S.; Kawate, T.; Ichihara, J.; Hanafusa, T.
J. Chem. Soc., Chem. Commun. 1984, 439.
We are grateful to the Fundação de Amparo à Pesquisa do Estado do
Rio Grande do Sul (FAPERGS) and the Deutsche Gesellschaft für
Technische Zusammenarbeit (GTZ) for financial support, and to fel-
lowships from Coordenação de Aperfeiçoamento de Pessoal de Nível
Superior (CAPES) (C.J.V and A.S.).