Efficient PPA-SiO2-catalyzed synthesis of β-enaminones under solvent-free conditions

Article abstract of DOI:10.3390/molecules181215182

An efficient method has been developed for the synthesis of β-enaminones under solvent-free reaction conditions using PPA-SiO2 as catalyst. The reaction yields were good to excellent (up to 90%). This methodology affords high selectivity and good tolerance of a variety of different functional groups present on both aromatic and aliphatic amines. In addition, the methodology is environmentally benign and cost-effective due to absence of solvent and easy work-up.

Full text of DOI:10.3390/molecules181215182

Molecules 2013, 18, 15182-15192; doi:10.3390/molecules181215182
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
Efficient PPA-SiO2-catalyzed Synthesis of β-enaminones Under
Solvent-Free Conditions
Muhammad Nisar 1,*, Ihsan Ali 1, Muhammad Raza Shah 2, Mughal Qayum 3,*,
Muhammad Zia-Ul-Haq 4, Umer Rashid 5,* and Md. Saiful Islam 6
1
Institute of Chemical Sciences, University of Peshawar, Peshawar-25120, Pakistan;
E-Mail: ihsanali7@yahoo.com
2
H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences,
University of Karachi, Karachi 75270, Pakistan; E-Mail: raza_shahm@yahoo.com
3
Department of Pharmacy, Kohat University of Science and Technology, Kohat-26000, Pakistan
4
The Patent Office, Karachi 74400, Pakistan; E-Mail: ahirzia@gmail.com
5
Institute of Advanced Technology, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
6
Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400 UPM Serdang,
Selangor, Malaysia; E-Mail: mdsaifulislam@upm.edu.my
* Authors to whom correspondence should be addressed; E-Mails: akhund54@gmail.com (M.N.);
dr.mughalqayum@kust.edu.pk or mu_afridii@yahoo.com (M.Q.); umer.rashid@yahoo.com (U.R.);
Tel.: +92-091-585-4660 (M.N.); Fax: +92-091-585-4660 (M.N.); Tel.: +92-300-565-4250 (M.Q.);
Fax: +92-922-554-556 (M.Q.); Tel.: +60-38-946-7393 (U.R.); Fax: +60-38-946-7004 (U.R.).
Received: 30 September 2013; in revised form: 14 November 2013 / Accepted: 14 November 2013 /
Published: 10 December 2013
Abstract: An efficient method has been developed for the synthesis of β-enaminones
under solvent-free reaction conditions using PPA-SiO2 as catalyst. The reaction yields were
good to excellent (up to 90%). This methodology affords high selectivity and good
tolerance of a variety of different functional groups present on both aromatic and aliphatic
amines. In addition, the methodology is environmentally benign and cost-effective due to
absence of solvent and easy work-up.
Keywords: solvent free; 5,5-dimethylcyclohexan-1,3-dione; PPA-SiO2; β-enaminones

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1. Introduction
Enaminones are chemical compounds including an amino group coupled through a C=C bridge
to a carbonyl group. They are versatile synthetic intermediates [1–3] that combine the ambident
electrophilicity of an enone with the ambident nucleophilicity of an enamine. They be easily
synthesized and purified because the carbonyl group conjugates with the enamine therefore, imparts an
additional stability to the enaminone motif [1].
Enaminones are important building blocks in organic synthesis which can be further transformed
into valuable bioactive nitrogen heterocylces [4–6], natural therapeutic agents and alkaloids [5,6].
They are also used as precursors for the synthesis of various types of compounds like N-substituted
carbazolones [7], peptides [8], quinolines [9,10], azocompounds [11,12], α,β-aminoacids [13,14] that
serve important roles in asymmetric catalysis via chelating agents [15]. Enaminones are known to
affect several physiological functions themselves or are precursors for such molecules, in particular as
anticonvulsant [16], anti-epileptic [17], anti-inflammatory [18] and antitumor agents [19–21].
Owing to the significant role of enaminones in organic synthesis considerable efforts have been made
for their synthesis. The most straightforward route is the direct condensation of the 1,3-dicarbonyl with
an amine under reflux with azeotropic removal of the water formed [22]. Some improved methods
subsequently reported for this transformation are SiO2/microwaves [23], NaAuClO4 [24], iodine [25],
HClO4·SiO2 [26], SiO2-sulphuric acid [27], SiO2-NaHSO4 [28], tris(hydrogensulfato) boron or
trichloroacetic acid [29], ionic liquids [30], and silica-supported Fe(HSO4)3 [31]. Other synthetic
approaches that lead towards β-enaminones are the reductive cleavage of isoxazoles [29], the use of
expensive catalysts like [BMIM]BF4, cyclization of amino acids [32], and copper-mediated aminolysis
of dithioacetals [33]. However, some of these methods suffer from certain drawbacks such as
formation of side products, low selectivity and use of toxic reagents and solvents.
Over the past few decades, solid-supported catalysts have been viewed as unique acid catalysts in
the sense that the effective surface area of the active phase can be increased many-fold, since the
activity and selectivity of the precursor center dispersed on the surface of support is improved.
Polyphosphoric acid (PPA) absorbed on silica gel is certainly one of the green catalysts that is easily
prepared and have been used for various organic transformations [34].
In continuation of our interest toward the development of new protocols [35], we report herein that
PPA-SiO2SiO2 can be used as a cheap and efficient catalyst for the synthesis of β-enaminones under
solvent free conditions by direct transformation of 1,3-dicarbonyls with various aromatic and aliphatic
amines. To the best of our knowledge the use of PPA-SiO2 as an efficient catalyst for the synthesis of
biologically and synthetically significant β-enaminones has not been previously reported.
2. Results and Discussion
The reaction conditions were optimized by taking the reaction between 1,2-diaminomethane-phenylene
and dimedone as model reaction. Initially, the model reaction was carried out without catalyst in
ethanol at reflux for 2 h and only 30% of the desired product was obtained. (Table 1, Entry 1). The
model reaction was carried out in protic solvents (like H2O, CH3OH and C2H5OH) and aprotic solvents
(like CH3CN, CHCl3 and tetrahydrofuran (THF)) using PPA-SiO2. Considering the yields, methanol

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and ethanol were found to be the best solvents (Table 1). However, when the reaction was carried out
under solvent free condition, both yield and reaction time were significantly improved at about 70 °C
as compared to the reaction carried out in solution (Table 1, Entry 8).
Table 1. Comparative study of the solvent versus solvent free reaction conditions
for enaminones.
H2N
O
H
N
NH2
PPA-SiO2 (Cat)
O
NH2
2a
Catalyst
O
3a
1a
Entry a
Solvent
Ethanol
Water
Temperature (°C) Time (min) Yield b (%)
1.
2.
3.
4.
5.
6.
7.
8.
−
Reflux
80
4h
90
30
Traces
70
PPA-SiO2
PPA-SiO2
PPA-SiO2
PPA-SiO2
PPA-SiO2
PPA-SiO2
Methanol
Ethanol
CH3CN
Chloroform
THF
Reflux
Reflux
Reflux
Reflux
Reflux
70
130
140
140
130
140
40
71
48
56
Traces
Solvent free PPA-SiO2
88
a Reaction conditions: see typical procedure; PPA-SiO2 110 mg/mmol; b Isolated yield.
2.1. Effect of Loading Catalyst
In order to optimize the amount of PPA-SiO2 used as catalyst, the model reaction was carried out
for the formation of desired product with varying amounts, i.e., 50, 80, 110, 130 and 150 mg. It was
observed that the rate of reaction and yield of the product increased with the increase of catalyst load.
The optimum amount of catalyst turned out to be 110 mg/mmol. Above 110 mg the catalyst showed no
significant effect on the yield of products (Table 2).
Table 2. Effect of PPA-SiO2 as catalyst, loading for the synthesis of β-enaminones (3a).
Entry a
Catalyst (mg)
Time (min)
Yield b (%)
1.
2.
3.
4.
5.
50
80
60
50
40
45
45
50
64
89
86
86
110
130
150
a Reaction conditions: see typical procedure; b Isolated yield.
2.2. Amines Substrate Scope
The substrates were evaluated for the effects of different substituents (both aromatic and aliphatic
amines) on the β-enaminone analogues. The formation of desired products was investigated as shown
in Scheme 1. It was observed that the reaction conditions tolerate many functional groups, including

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electron withdrawing (nitro), electron donating (methoxy) and halides functions on the aromatic
moiety as well as in aliphatic amines. The aromatic amines were found to be more reactive than aliphatic
amines (Table 3).
Scheme 1. Synthetic pathway for the preparation of β-enaminones.
Table 3. Synthesis of β-enaminones (3a–k) in the presence of PPA-SiO2 as catalyst.
Time
(min)
Yield b Observed
Lit.
Entry a
R
Product
(%)
mp (°C)
mp (°C)
1,2-Phenylene
1.
40
89
187–188
186 [30]
-dimethanamine
2.
3.
4.
5.
C6H5-
40
45
40
40
68
74
74
88
152–154
201–202
201–202
215–217
−
H
N
4-OCH3C6H5-
4-CH3C6H5-
4-BrC6H5-
199 [34]
199 [34]
219 [32]
3c
H3CO
O

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Table 3. Cont.
Time
(min)
Yield b Observed
Lit.
Entry a
R
Product
(%)
mp (°C)
mp (°C)
6.
4-NO2C6H5
50
60
67
194–195
191 [32]
(1S,2S)-(+)1-Amino-1-
phenyl-1,3-proanediol
7.
71
70
48
103–105
176–178
270–272
−
−
−
D-Threo-2-amino-1-
(4-nitrophenyl)-1,3-
propanediol
8.
60
4-(methyl)
cyclohexane
carboxylic acid
9.
140
2-(1-(methyl)
10.
145
30
50
90
155–158
181–183
−
−
cyclohexyl)acetic acid
Isonicotinic acid
Hydrazide
11.
a
Reaction conditions: all the reaction were carried under solvent free conditions by heating the reaction flask in an oil
bath at 70–80 °C, and withg 110 mg/mmol of PPA-SiO2 as catalyst. The reaction progress was monitored by TLC (ethyl
acetate: n-hexane 5:1); b Isolated yield.
After the successful completion of the synthesis of β-enaminone analogues we proceeded to study
the reaction of various amines both aliphatic and aromatic under solvent free conditions. The study
was extended to explore the reaction of isonicotinohydrazide. Variation in the product was observed
when isonicotinohydrazide was made to react with dimedone (Entry 11, Table 3), and N'-(3-(2-
isonicotinoylhydrazinyl)-5,5-dimethylcyclohex-2-enylidene)isonicotino-hydrazide (3k) was obtained in
90% yield within 30 min. The variation in product is due to the increased reactivity of this hydrazide.
2.3. Proposed Mechanism
The catalyst PPA-SiO2 activates the ketonic carbon for nucleophilic attack on the amino group. The
active species in PPA-SiO2‐catalyzed synthesis of β-enaminones are the amino-alcohol and imine
intermediates. Finally, the target product β-enaminone would be released on dehydration of the imine
intermediate. The proposed mechanism for the formation of β-enaminones is given in Scheme 2.

Molecules 2013, 18
Scheme 2. Proposed mechanism for the formation of β-enaminones.
15187
O
O
O
R
R
N
H2N R
O
R
N
N
H
H
O
H
H
HO
OH
PPA
PPA
PPA
PPA
-H2O
III
II
I
IV
SiO2
SiO2
SiO2
SiO2
PPA = polyphosphoric acid
3. Experimental
3.1. General
The commercially available solvents used were purified by using standard purification methods.
The other reagents and amines were purchased and used as received without further purification. The
chiral amines (1S,2S)-(+)-1-amino-1-phenyl-1,3-proanediol and D-threo-2-amino-1-(4-nitrophenyl)-
1,3-propanediol used were Sigma-Aldrich (St. Louis, MO, USA). These amines are single isomers
having fixed stereochemistry and therefore give single products without any ambiguity. The NMR
spectra of the products were recorded using a Bruker Avance spectrometer (Bruker, Karlsruhe,
1
13
Germany) operating at 300 or 400 MHz for the H-NMR spectra and 75 or 100 MHz for C-NMR
spectra. CDCl3 was used as an NMR solvent and TMS was taken as internal standard. The compounds
were also analyzed by mass spectra (EI-MS) spectroscopic analysis, performed on a Finnigan-MAT-311-A
apparatus (Finnigan MAT, Waltham, CA, USA) and the values were reported in m/z (rel. abund.%).
CHN analysis was carried out by using Carlo Erba Strumentasion-Mod-1106, Milan, Italy. Melting
points of the synthesized compounds were determined with Electrothermal melting point apparatus
(Essex, UK) and are uncorrected. IR spectroscopic analysis was performed on Shimadzu-IR-460
(Shimadzu Corporation, Kyoto, Japan) for neat samples. Isolated yields refer to the amount obtained
either by recrystalization from a suitable binary solvent system or column chromatography on silica
gel (200–300 mesh), using a mixture of ethyl acetate and n-hexane as eluent.
3.2. Preparation of PPA-SiO2 Catalyst
PPA-SiO2 was prepared by the reported method [23] with slight modifications. A round-bottom
flask already dried at 120 °C was charged with a magnetic bar, polyphosphoric acid (2.5 g) and CHCl3
(120 mL) and the mixture was stirred for 1 h at 50 °C. SiO2 (100–200 mesh, 5.1 g) was added and the
stirring was continued for another 1 h. The excess of chloroform was evaporated under vacuum using
rotary evaporator. The solids obtained were dried under vacuum oven for 4 h at 120 °C.

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3.3. Typical Procedure for PPA-SiO2 Catalyzed Synthesis of β-Enaminones
To a mixture of dicarbonyl compound (dimedone, 1 mmol, 140 mg) and 1,2-diaminomethane-
phenylene (1 mmol, 0.14 mL) PPA-SiO2 (110 mg/mmol) was added in in one lot and the resulting
yellow mixture was stirred at 70–80 °C for the specified time shown in the Table 3. After the
completion of reaction or sufficient amount of product formation (indicated by TLC) the reaction
mixture was cooled and the yellow product slurry was collected by filtration on dilution with ethyl
acetate or dichloromethane. The insoluble catalyst was separated by filtration and concentrated under
reduced pressure. The cured product obtained was purified in most cases by recrystallization in binary
solvent system using EtOH-H2O (2:1), while some of the product (in case of solid amines) was also
purified by using column chromatography. The structures and purity of all of the products were
confirmed by NMR (1H-NMR and 13C-NMR) EIMS, IR and CHN analysis. The data for new
representative examples are listed below:
1
3-(2-(Aminomethyl)benzylamino)-5,5-dimethylcyclohex-2-enone (3a). H-NMR (CDCl3, 300 MHz)
δ = 8.31 (s, 2H, NH2), 8.41 (brs, 1H, NH), 7.08–7.04 (m, 4H, Ar-H), 4.96 (s, 1H, CH), 4.14 (s, 2H,
13
CH2-NH2), 2.14 (s, 2H, CH2), 2.03 (s, 2H, CH2), 0.93 (s, 6H, 2CH3); C-NMR (CDCl3, 75 MHz)
δ = 197.8 (C=O), 165.1 (-NH-C=), 137.3, 128.0, 127.7, 127.3, 126.5 (aromatic carbons), 94.9 (C=CH),
48.9 (CH2), 46.5 (CH2), 44.1 (CH2), 42.7 (CH2), 32.6 (2CMe2), 27.9 (2CH3); IR (neat): ʋ 3,288, 1,650,
1,593, 1,537, 1,234, 790 cm−1; EIMS m/z (%): 258.15 [M++H], (8.51). Anal. Calcd. for C16H22N2O: C,
74.38; H, 8.58; N, 10.84. Found: C, 74.45; H, 8.50; N, 10.89.
3-((1R,2S)-1,3-Dihydroxy-1-phenylpropan-2-ylamino)-5,5-dimethylcyclohex-2-enone (3g). 1H-NMR
(400 MHz, CDCl3) δ = 7.37–7.19 (m, 5H, Ar-H), 6.34 (brs, 1H, NH), 5.80 (s, 1H, CH, C-2), 5.18 (s, 1H,
OH), 5.07 (s, 1H, OH), 4.13–3.81 (m, 4H, C-1'', C-2'', 3''), 2.47–2.21 (m, 4H, 2CH2, C-2,6), 0.94 (s, 3H,
CH3), 0.67 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ = 196.8 (C=O), 163.1 (NH-C=), 148.4, 147.1,
139.5, 138.5, 132.5, 130.0 (aromatic carbons), 102.2 (C=CH), 68.1 (CH-OH), 62.1 (CH-NH),
60.7 (CH2-OH), 49.7 (CH2), 42.3 (CH2), 33.6 (2CMe2), 27.3 (CH3), 26.5 (CH3); IR (neat): ʋ 3,608,
3,540, 3,214, 3,018, 2,924, 1,648, 1,559, 1,229, 739 cm−1; EIMS m/z (%): 290.0 [M++H], (74.9). Anal.
Calcd. for C16H22NO3: C, 69.54; H, 8.02; N, 5.07. Found: C, 69.60; H, 8.05; N, 5.10.
3-((1S,2R)-1,3-Dihydroxy-1-(4-nitrophenyl)propan-2-ylamino)-5,5-dimethylcyclohex-2-enone
(3h).
1H-NMR (400 MHz, CDCl3) δ = 8.11 (d, J = 8.8 Hz, 2H, Ar-H, C-2',6') 7.47 (d, J = 8.8 Hz, 2H, Ar-H,
C-3'-5'), 5.12 (s, 1H, CH, C-2), 3.06 (s, 2H, OH), 3.30 (t, J = 2.8 Hz, 2H, C-3'', 2'') 3.12 (s, 2H, C-1'')
2.15 (d, J = 16.0 Hz, C-6), 2.01 (d, J = 17.2 Hz, C-4), 0.92 (s, 3H, CH3), 0.77 (s, 3H, CH3); 13C-NMR
(100 MHz, CDCl3) δ = 197.1 (C=O), 165.6 (NH-C=), 149.4, 147.1, 126.5, 123.3 (aromatic carbons),
94.3 (C=CH), 69.15 (CH-OH), 60.1 (CH-NH), 59.5 (CH2-OH), 48.7 (CH2), 43.3 (CH2), 32.6 (2CMe2),
27.9 (2CH3), 27.5 (2CH3); IR (neat): ʋ 3,590, 3,540, 3,198, 3,010, 2,952, 1,644, 1,589, 1,249, 719 cm−1;
EIMS m/z (%) 335.1 [M++1], (20.8): Anal. Calcd. for C17H22N2O5: C, 61.07; H, 6.63; N, 8.38. Found:
C, 61.01; H, 6.59; N, 8.43.
4-((5,5-Dimethyl-3-oxocyclohex-1-enylamino)methyl)cyclohexanecarboxylic
acid
(3i).
1H-NMR
(400 MHz, CDCl3) δ = 6.93 (s, 1H, NH); 4.76 (s, 1H, CH), 2.82–2.78 (m, 4H, 2H, 2CH2), 2.16 (m, 2H,

Molecules 2013, 18
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CH2NH), 2.10 (m, 1H, CH, C-4'), 1.93 (m, 4H, 2CH2, C-3', C-5'), 1.77, 1.31 (m, 2H, CH2, C-6'), 1.47,
13
(m, 1H, C-1'), 1.27, 0.94 (m, 2H, CH2, C-2'), 0.91 (s, 3H, CH3), 0.87 (s, 3H, CH3); C-NMR (CDCl3,
100 MHz) δ = 193.6 (C=O), 176.7 (Carboxylic acid carbon), 162.9 (NH-C=), 93.6 (C=CH),
50.2 (CH2-C=O), 48.2 (CH2-NH), 42.5 (CH), 42.0 (CH2), 38.7 (CH), 35.5 (CHCOOH), 32.1 (2CMe2),
29.5 (CH2), 27.9 (CH3), 27.8. (CH3). IR (neat): ʋ 3,251, 2,937, 1,683, 1,516, 1,240, 1,149, 769 cm−1;
EIMS m/z (%): 279.1 [M++1], (53.5). Anal. Calcd. for C16H25NO3: C, 68.79; H, 9.02; N, 5.01. Found:
C, 68.75; H, 9.00; N, 5.10.
1
2-(1-((5,5-Dimethyl-3-oxocyclohex-1-enylamino)methyl)cyclohexyl)acetic acid (3j). H-NMR (400 MHz,
CDCl3) δ = 7.52 (brs, 1H, NH), 5.43 (s, 1H, CH), 3.19 (s, 2H, CH2NH), 2.45 (s, 2H, CH2), 2.31 (s, 2H,
13
CH2), 2.20 (s, 2H, CH2), 1.4–1.3 (m, 10H, 5CH2), 1.05 (s, 3H, CH3), 1.03 (s, 3H, CH3); C-NMR
(100 MHz, CDCl3) δ = 195.5 (C=O), 175.9 (COOH), 168.5 (NH-C=), 109.5 (C=CH), 51.6 CH2),
48.1 (CH2NH), 43.8 (CH2), 40.6 (C-3'') 32.7 (2CMe2), 28.3, 28.0 (2CH3), 25.4 (C-6', C-2') 22.6, 21.4,
(C-4', 5',3'). IR (KBr): ʋ 2,927, 2,848, 1,708, 1,643, 1,581, 1,373, 1,247, 1,143 cm−1; EIMS m/z (%):
293.30 [M++H] (13.7). Anal. Calcd. for C17H27NO3: C, 69.59; H, 9.28; N, 4.77. Found: C, 69.55; H,
9.20; N, 4.70.
(E)-N'-(3-(2-Isonicotinoylhydrazinyl)-5,5-dimethylcyclohex-2-enylidene)isonicotinohydrazide
(3k).
1H-NMR (400 MHz, CDCl3) δ = 10.84 (brs, 2H, NH), 8.52 (d, J = 5.6 Hz, 4H, Ar-H), 7.76 (d, J = 6 Hz,
13
4H, Ar-H), 5.81 (s, 1H, CH), 2.40 (s, 4H, 2CH2), 1.04 (s, 6H, 2CH3). C-NMR (100 MHz, CDCl3)
δ = 164.8 (2NH-C=O), 149.7 (NH-C=), 121.7, (aromatic carbons), 90.1 (C=CH), 48.9 (CH2),
40.3 (CH2), 32.2 (2CMe2), 27.4 (2CH3); IR (KBr) ʋ 2,938, 2,889, 1,674, 1,558, 1,481, 1,367, 1,261,
1,147, 698 cm−1; EIMS m/z (%): 378.1 [M++H), (100.0). Anal. Calcd. for C20H22N6O2: C, 63.48; H,
5.86; N, 22.21. Found: C, 63.40; H, 5.80; N, 22.18.
4. Conclusions
In conclusion, we have successfully developed an efficient strategy for the synthesis of novel
and known β-enaminone analogues by the treatment of various aromatic and aliphatic amines with
a 1,3-dicarbonyl compound (dimedone) in the presence of PPA-SiO2 under solvent free conditions.
This methodology showed a wide substrate scope for amines (both aliphatic and aromatic). The
advantages of this acceptable protocol are chemoselectivity, short reaction times, cleaner reaction
profiles, simplicity, low cost, high yield and finally accordance with the green chemistry protocols. It
is proposed that the methodology can be utilized for large-scale ecofriendly preparation of such a
synthetically important class of compounds. Further exploration of the biological applications of the
presented compounds is under investigation in our laboratory.
Acknowledgments
We gratefully acknowledge the Higher Education Commission of Pakistan for providing the
financial support under the Indigenous PhD programme.

Molecules 2013, 18
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Conflicts of Interest
The authors declare no conflict of interest.
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Sample Availability: Samples of the novel compounds are available from the authors.
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