Citrus juice: Green and natural catalyst for the solvent-free silica supported synthesis of β-enaminones using grindstone technique

Article abstract of DOI:10.2174/1386207321666180102115733

Aim and Objective: Citrus Juice as an efficient, cost-effective and green catalyst employed for one-pot synthesis of various β-substituted enaminones through the reaction of β-dicarbonyl compounds with different primary amines in a solvent-free conditions on silica gel as solid surface using grindstone technique in high yields and short reaction times. The presented procedure is operationally simple, practical and green. Material and Methods: The wide application of this procedure is demonstrated by the use of various substituted amines to react with β-dicarbonyl compounds. The method was successfully applied for primary amines (15 entries) and the related enaminones were well synthesized in good to excellent yields. Melting points were measured on an Electro thermal 9100 apparatus. 1HNMR and 13C NMR spectra were recorded on a FTNMR BRUKER DRX 500 Avence spectrometer. Chemical shifts were given in ppm from TMS as internal references and CDCl3 was used as the solvent as well. The IR spectra were recorded on a Perkin Elmer FT-IR GX instrument. The chemicals used in this work were purchased from Merck and Fluka chemical companies. Results: Grinding synthesis of citrus juice catalyzed enamination of 1,3-dicarbonyls (acetylacetone, methyl and ethyl-3-oxobutanoate) with various primary amines (aromatic and aliphatic) under solvent-free silica supported conditions was examined and studied (15 entries) and the obtained enaminones were well synthesized in good to excellent yields. Furthermore, the effect of various catalysts on the yield and reaction time for grinding synthesis of 3-phenylamino-but-2-enoic acid ethyl ester (1) by this method has evaluated as well. Conclusion: a novel, efficient and green protocol for the grinding synthesis of enaminones using citrus juice as natural catalyst has been presented. This methodology is user friendly, green and low cost procedure under mild reaction condition with faster reaction rates. The citrus juice is inexpensive and non-toxic which makes the process convenient, more economic and benign. Furthermore, applying grindstone technique in solvent-free conditions, use of silica gel as a solid and heterogeneous surface in reaction, high yields of products, cleaner reaction profiles, and availability of the reagents makes this method a better choice for synthetic chemists.

Full text of DOI:10.2174/1386207321666180102115733

19
Send Orders for Reprints to reprints@benthamscience.ae
Combinatorial Chemistry & High Throughput Screening, 2018, 21, 19-25
RESEARCH ARTICLE
ISSN: 1386-2073
eISSN: 1875-5402
Citrus Juice: Green and Natural Catalyst for the Solvent-free Silica
Impact
Factor:
0.952
Supported Synthesis of β-Enaminones using Grindstone Technique
BENTHAM
S
CIENCE
Omid Marvi* and Leila Zare Fekri
Department of Chemistry, Payam Noor University, P.O. Box 19395-3697, Tehran, Iran
Abstract: Aim and Objective: Citrus Juice as an efficient, cost-effective and green catalyst
employed for one-pot synthesis of various β-substituted enaminones through the reaction of β-
dicarbonyl compounds with different primary amines in a solvent-free conditions on silica gel as
solid surface using grindstone technique in high yields and short reaction times. The presented
procedure is operationally simple, practical and green.
Material and Methods: The wide application of this procedure is demonstrated by the use of various
substituted amines to react with β-dicarbonyl compounds. The method was successfully applied for
primary amines (15 entries) and the related enaminones were well synthesized in good to excellent
yields. Melting points were measured on an Electro thermal 9100 apparatus. 1HNMR and 13C NMR
spectra were recorded on a FTNMR BRUKER DRX 500 Avence spectrometer. Chemical shifts were
given in ppm from TMS as internal references and CDCl3 was used as the solvent as well. The IR
spectra were recorded on a Perkin Elmer FT-IR GX instrument. The chemicals used in this work
were purchased from Merck and Fluka chemical companies.
A R T I C L E H I S T O R Y
Received: November 17, 2016
Revised: May 2, 2017
Accepted: November 29, 2017
Results: Grinding synthesis of citrus juice catalyzed enamination of 1,3-dicarbonyls (acetylacetone,
methyl and ethyl- 3-oxobutanoate) with various primary amines ( aromatic and aliphatic) under
solvent-free silica supported conditions was examined and studied (15 entries) and the obtained
enaminones were well synthesized in good to excellent yields. Furthermore, the effect of various
catalysts on the yield and reaction time for grinding synthesis of 3-phenylamino- but- 2- enoic acid
ethyl ester (1) by this method has evaluated as well.
DOI:
10.2174/1386207321666180102115733
Conclusion: a novel, efficient and green protocol for the grinding synthesis of enaminones using
citrus juice as natural catalyst has been presented. This methodology is user friendly, green and low
cost procedure under mild reaction condition with faster reaction rates. The citrus juice is
inexpensive and non-toxic which makes the process convenient, more economic and benign.
Furthermore, applying grindstone technique in solvent-free conditions, use of silica gel as a solid and
heterogeneous surface in reaction, high yields of products, cleaner reaction profiles, and availability
of the reagents makes this method a better choice for synthetic chemists.
Keywords: Citrus juice, silica, β-enaminone, solvent-free, grinding, green catalyst.
coumarins and chromenes, as well as in the three-component
reaction for chromene synthesis has been reported [9b].
1. INTRODUCTION
The enaminones are a very important class of organic
compounds with stable structural motifs due to their
occurrence in versatile building blocks for the synthesis of
important heterocyclic compounds, nitrogen containing
compounds, natural products, pharmaceutical drugs with
antiepileptic, anticonvulsant and antitumor properties [1-3].
Furthermore, non-conventional methods such as microwave
and ultrasound are reported as well [10-12]. However, most
of these techniques involved harsh reaction conditions,
expensive and harmful reagents, organic solvents, use of
moisture sensitive metal triflates and tedious workup [4, 5a].
Therefore, the development of rapid and eco-friendly
approaches has crucial importance in the synthesis of these
compounds.
The synthesis of enaminones and enamino esters has
been reported through the condensation reactions of carbonyl
compounds with primary and secondary amines with various
acid catalysts like Yb(OTf)3 [4], Zn(O4Cl)2 [5, 6], InBr3 [7],
CoCl2 [8], LiHSO4·SiO2 [9a]. Recently, the hydrolysate of
bovine tendons for the multigram scale synthesis of
On the other hand, the application of catalysts prepared
from renewable sources like biodiesel has afforded
importance in organic synthesis. Biodiesel has become
beguiling nowadays for its environmental benefits and it
seems an opposite alternative fuels for future. It is made
from renewable biological sources such as vegetable oils and
animal fats. It is biodegradable and nontoxic and has low
emission profiles and environmentally beneficial as well
*Address correspondence to this author at the Department of Chemistry,
Payam Noor University, P.O. Box 19395-3697, Tehran, Iran;
E-mail: marviomid@yahoo.com
1875-5402/18 $58.00+.00
© 2018 Bentham Science Publishers

20 Combinatorial Chemistry & High Throughput Screening, 2018, Vol. 21, No. 1
Marvi and Fekri
[5b]. Also, it is widely acknowledged that there is a growing
need for more environmentally acceptable processes in the
chemical industry. This trend towards what has become
known as ‘Green Chemistry’ or ‘Sustainable Technology’
necessitates a paradigm shift from traditional concepts of
process efficiency, that focus largely on chemical yield, to
one that assigns economic value to eliminating waste at
source and avoiding the use of toxic and/or hazardous
substances [5c].
4.66 (s, 1H), 6.69-7.31 (m, 5H arom.), 11.41 (s, 1H, NH);
13C NMR (125 MHz, CDCl3): δ= 16.1 (CH2CH3), 19.8
(CH3), 59.1 (CH2), 92.8 (=CH), 122.6 (CH), 125.0 (CH),
127.2 (CH) , 135.7 (qC), 157.5 (N-C=), 185.6 (O=C).
3-Benzylamino- but- 2- enoic acid ethyl ester (2): Oil
(Oil) [19b], IR (neat, cm-1): 3286, 3077, 2963, 1661, 1612,
1517, 1221, 1179, 1148, 1075, 931, 751; 1H NMR (500
MHz, CDCl3): δ= 1.18 (t, J= 7.3 Hz, 3H), 1.91 (s, 3H), 4.18
(q, J= 7.3 Hz, 2H), 4.30 (d, J= 6.4 Hz, 2H), 4.52 (s, 1H),
7.07-7.32 (m, 5H arom.),11.18 (s, 1H, NH); 13C NMR (125
MHz, CDCl3): δ= 14.8 (CH2CH3), 18.1 (CH3), 45.9 (PhCH2),
57.1 (CH2), 82.0 (=CH), 127.2 (CH), 125.9 (CH), 128.5
(CH), 138.4 (qC), 161.1 (N-C=), 171.8 (O=C).
Due to acidic nature, citrus juice as a natural catalyst has
been found to be a suitable replacement for different
homogeneous acid catalysts that is well compatible with a
so-called green process as well [13].
3-(1-Phenylethanamino)-but- 2- enoic acid ethyl ester
(3): Oil (Oil) [19a], IR (neat, cm-1): 3229, 3014, 2991, 1680,
1619, 1539, 1225, 1181, 1163, 1058, 989, 742; 1H NMR
(500 MHz, CDCl3): δ= 1.23 (s, 3H), 1.36 (t, J= 7.3 Hz, 3H),
2.12 (d, J= 4.7 Hz, 3H), 4.05 (m, 1H), 4.22 (q, J= 7.3 Hz,
2H), 4.62 (s, 1H), 7.15-7.46 (m, 5H arom.), 11.10 (s, 1H,
NH); 13C NMR (125 MHz, CDCl3): δ= 14.1 (CH2CH3), 18.5
(CH3), 22.5 (CH3CH), 56.5 (CH2CH3), 61.1 (CHCH3), 82.3
(=CH), 116.1 (CH), 125.5 (CH), 128.4(CH), 129.0 (qC) ,
162.8 (N-C=), 171.1 (O=C).
2. MATERIALS AND METHODS
Melting points were measured on an Electro thermal
9100 apparatus. 1HNMR and 13C NMR spectra were
recorded on a FTNMR BRUKER DRX 500 Avence
spectrometer. Chemical shifts were given in ppm from TMS
as internal references and CDCl3 was used as the solvent as
well. The IR spectra were recorded on a Perkin Elmer FT-IR
GX instrument. The chemicals used in this work were
purchased from Merck and Fluka chemical companies.
3-Allylamino- but- 2- enoic acid ethyl ester (4): Oil (Oil)
[19c], IR (neat, cm-1): 3294, 3069, 2971, 1663, 1619, 1511,
1275, 1161, 1055, 958, 753; 1H NMR (500 MHz, CDCl3): δ=
1.21 (t, J= 7.3 Hz, 3H), 3.68 (s, 3H), 3.84-3.89 (m, 2H), 4.18
(q, J= 7.3 Hz, 2H), 4.89 (s, 1H), 5.15-5.29 (m, 2H), 5.83-
5.95 (m, 1H), 8.64 (s, 1H, NH); 13C NMR (125 MHz,
CDCl3): δ= 14.0 (CH2CH3), 24.7 (CH3), 49.4 (CH2C=), 61.8
(CH2CH3), 81.8 (=CH), 117.2 (=CH2), 135.6 (=CH-CH2),
161.1 (N-C=), 171.6 (O=C).
2.1. Nutritional Properties of Citrus Juice
Mineral content, moisture content and ash [14d,15],
vitamin A [16], vitamin C [17] and pH value [18] were
determined by the methods described in the relevant
references.
2.2. Preparation of Citrus Juice from the Fruits of Citrus
3-Methylamino- but- 2- enoic acid ethyl ester (5): Oil
(Oil) [19c], IR (neat, cm-1): 3286, 3044, 2981, 1648, 1612,
1531, 1275, 1151, 1141, 1096, 948, 799; 1H NMR (500
MHz, CDCl3): δ= 1.22 (t, J= 7.3 Hz, 3H), 1.93 (s, 3H), 2.85
(d, J= 7.4 Hz, 3H), 4.12 (q, J= 7.3 Hz, 2H), 4.59 (s, 1H),
11.85 (s, 1H, NH); 13C NMR (125 MHz, CDCl3): δ=14.0
(CH2CH3), 18.5 (CH3), 46.1 (NCH3), 57.5 (CH2CH3), 81.2
(=CH), 161.8 (N-C=), 172.0 (O=C).
The citrus juice prepared from fresh fruits was extracted
mechanically and centrifuged using Centrifuge (JENUS
TDL-4) and the clear portion of the juices was applied as a
catalyst in the reactions.
2.3. Typical Procedure
In a typical experiment (entry 11), 5 drops (0.25 mL)
citrus juice and 1 g silica gel (200- 400 mesh) was ground
together in a mortar using pestle for 2 min. To this mixture,
acetylacetone (3 mmol) and aniline (4 mmol) were then
added and grinding was continued at room temperature for
the time presented in Table 1 to complete the reaction
(monitored by TLC, n-hexane/ chloroform, 3/1). After
completing the reaction, the product was extracted with
CH2Cl2 (2×15 mL) and silica gel filtered off. The organic
layer after washing with water was dried over MgSO4,
filtered and the solvent was evaporated under vacuum to
afford the product 11. Solid products recrystallized from di-
isopropyl ether and oil products were purified column
chromatography using hexane and ethyl acetate (3:1) as an
eluent. All isolated products were characterized by melting
3-(Pyrimidin-2-ylamino)but- 2- enoic acid methyl ester
(6): m.p. 163-165°C (161-163°C) [19c], IR (KBr, cm-1):
3329, 3168, 2774, 2681, 1649, 1559, 1578, 1478, 1357,
1
1223, 803; H NMR (500 MHz, CDCl3): δ= 1.80 (s, 3H),
3.78 (s, 3H), 4.65 (s, 1H), 5.51(br. s, NH), 6.58-6.60 (2H
arom., t, J= 8.7 Hz ); 13C NMR (125 MHz, CDCl3): δ= 20.39
(CH3), 52.59 (OCH3), 84.2 (=CH), 111.4 (CH), 157.0 (CH),
158.2 (CH), 139.8 (qC), 185.1 (N-C=), 185.4 (O=C).
3-(2-Methyl-phenylamino)- but- 2- enoic acid methyl
ester (7): m.p. 27-30°C (26-27°C) [19c]; IR (KBr, cm-1):
3435, 2691, 1641, 1599, 1439, 1275, 1139, 875, 798; 1H
NMR (500 MHz, CDCl3): δ= 1.32 (s, 3H), 1.85 (s, 3H), 3.49
(s, 3H), 4.69 (s, 1H), 6.77-7.16 (m, 4H arom.), 10.49 (s, 1H,
NH); 13C NMR (125 MHz, CDCl3): δ= 14.9 (CH2CH3), 18.9
(CH3), 51.2 (PhCH3), 84.1 (=CH), 123.1 (CH), 126.1 (CH),
127.0 (CH), 131.1 (CH), 135.8 (qC), 136.2 (CH3-C arom.),
160.6 (N-C=), 170.2 (O=C).
1
points (solids), IR, HNMR and 13CNMR spectrometric data
and were compared with the literature [19].
3-Phenylamino- but- 2- enoic acid ethyl ester (1): Oil
(Oil) [19b], IR (neat, cm-1): 3435, 3016, 2951,1642, 1513,
1291, 1128, 1089, 979, 758; 1H NMR (500 MHz, CDCl3): δ=
1.21 (t, J= 7.3 Hz, 3H), 1.96 (s, 3H), 4.19 (q, J= 7.3 Hz, 2H),
3-(4-Bromo-phenylamino)- but- 2- enoic acid methyl
ester (8): m.p. 120-122°C (121-123°C) [19c]; IR (KBr, cm-

Citrus Juice: Green and Natural Catalyst for the Solvent-free Silica
Combinatorial Chemistry & High Throughput Screening, 2018, Vol. 21, No. 1 21
1): 3449, 3336, 3106, 1628, 1584, 1496, 1334, 1257, 1124,
4- Benzylamino-3-penten-2-one (15): Oil (Oil) [19a], IR
(neat,cm-1): 3281, 3046, 2980, 1643, 1608, 1535, 1256,
1141, 1125, 1068, 969, 790; 1H NMR (500 MHz, CDCl3): δ=
1.83 (s, 3H), 2.05 (s, 3H), 4.36 (d, 2H), 4.97 (s, 1H), 6.83-
7.25 (m, 5H, arom.), 11.17 (s, 1H, NH); 13C NMR (125
MHz, CDCl3): δ= 18.5 (CH3), 22.8 (COCH3), 57.7 (CH2),
80.6 (=CH), 123.7 (CH), 125.1 (CH), 127.5 (CH), 136.4
(qC), 162.2 (N-C=), 191.8 (O=C).
1
1063, 744; H NMR (500 MHz, CDCl3): δ= 1.99 (t, J= 7.2
Hz, 3H), 3.63 (s, 3H), 4.73 (s, 1H, CH), 6.96 (d, J= 8.7 Hz,
2H), 7.43 (d, J= 8.7 Hz, 2H), 10.34 (s, 1H, NH); 13C NMR
(125 MHz, CDCl3): δ= 19.7 (CH3), 51.5 (OCH3), 84.8
(=CH), 116.5 (C-Br), 133.4 (CH), 137.7 (CH), 137.7 (qC),
160.4 (N-C=), 170.7 (O=C).
4-(2,4-Dinitrophenylamino)-3-penten-2-one (9): m.p.
173-175°C (170-172°C) [19a]; IR (KBr, cm-1): 3183, 3012,
1
3. RESULTS AND DISCUSSIONS
2954, 1654, 1623, 1567, 1484, 1263, 1165, 1003, 830; H
NMR (500 MHz, CDCl3): δ= 2.07 (s, 3H, CH3), 2.40 (s, 3H,
CH3), 5.62 (s, 1H, vinyl), 8.28-9.04 (m, 3H arom.), 13.26 (s,
1H, NH); 13C NMR (125 MHz, CDCl3): δ= 23.9 (CH3), 29.2
(COCH3), 97.8 (=CH), 126.4 (CH), 126.9 (CH), 128.5 (CH),
130.9 (CH), 131.3 (CH), 147.6 (qC), 162.3 (N-C=), 197.2
(O=C).
In continuation of our efforts on this methodology, here
we report grinding synthesis of β-amino-α,β-unsaturated
esters and ketones applying citrus juice as an efficient acidic
catalyst on silica gel as support in a simplified, rapid way
and generally without the use of any solvent in excellent
yields [14a-c]. Proximate nutritional composition of citrus
juice has been evaluated and is shown in Table 1. The citrus
juice acts as the effective acid catalyst by activating the
carbonyl group of the β-dicarbonyl compound in this
reaction (Scheme 1).
4-Methylamino-3-penten-2-one (10): m.p. 35-38°C (31-
33°C) [19a]; IR (KBr, cm-1): 3264, 3088, 2980, 1655, 1635,
1566, 1281, 1155, 1067, 974, 789; 1H NMR (500 MHz,
CDCl3): δ= 1.92 (s, 3H), 1.97 (s, 3H), 2.85 (d, J= 5.6 Hz,
3H), 11.84 (s, 1H, NH); 13C NMR (125 MHz, CDCl3): δ=
18.8 (CH3), 28. (NCH3), 29.1 (OCCH3), 94.9 (=CH), 163.1
(N-C=), 192.4 (O=C).
The nutritional composition of applied citrus juices is
presented in Table 1. The moisture content of lime (90.8%)
is higher than that of other juices (88.3-90.2%). The orange
juice has higher ash, pH, phosphorus, potassium and vitamin
C contents, with values of 0.4%, 3.8, 17 mg/100 g, 200
mg/100 g and 50 mg/100 g respectively. However, in
applying lime juice with the lowest pH (2.3), the products
were obtained in the highest yields.
4-Phenylamino-3-penten-2-one (11): m.p. 46-48°C (49-
50°C) [19b]; IR (KBr, cm-1): 3437, 3371, 3009, 2996, 1651,
1
1529, 1350, 1321, 1168, 736; H NMR (500 MHz, CDCl3):
δ= 1.80 (s, 3H), 2.30 (s, 3H), 3.65 (s, 1H), 6.29-7.05 (m, 5H
arom.), 9.89 (s, 1H, NH); 13C NMR (125 MHz, CDCl3): δ=
19.1 (CH3), 28.9 (OCCH3), 96.4 (=CH), 124.1 (CH), 125.7
(CH), 128.3 (CH), 139.1 (qC), 159.3 (N-C=), 195.7 (O=C).
The juice of lime contains citric acid (5% - 8%) and
ascorbic acid (the main components of the juice) and acts as
the effective acid catalyst by activating the carbonyl group of
the dicarbonyl compound in this reaction. The juice is highly
soluble in water and thus acts as a homogeneous catalyst in
aqueous systems as well. However, dicarbonyl compounds
are less soluble in water only and thus using the pure citrus
juice also acts as a green solvent better than the water. Citric
acid (2-hydroxy-1,2,3-propanetricarboxylic acid) is a weak
tricarboxylic acid that is naturally concentrated in citrus
fruits. Among fruits, citric acid is most concentrated in
lemon and lime, comprising as much as 8% of the dry fruit
weight. Lime has a slightly higher acid content (on average)
than lemon do about 6% for lime, compared to 4.5% for
lemon. The composition of acids in the two also differs. The
acid in lemon juice is almost entirely citric acid, which also
makes up most of the acid in lime. However, lime includes
about 10% each of succinic acid and malic acid which has an
effect on their flavor [14d]. Here, we only emphasize minor
differences and advantages that are due to the use of various
citrus juices with different acidic identities (pH values). The
reaction is carried out in a solvent-free and open reaction
system, and the key step is the NH2 attack on the carbonyl
group in dicarbonyl compound. This increases with the
increase in acidic identity of citrus juice (lime, pH= 2.3) on
the surface of silica along increase in polarity of C=O.
4-(4-Nitro-phenylamino)-3-penten-2-one (12): m.p.
136-138°C (137-139°C) [19d]; IR (KBr, cm-1): 3489, 3369,
3005, 2995, 1666, 1615, 1350, 1280, 1193, 1114, 840, 786;
1H NMR (500 MHz, CDCl3): δ= 2.15 (s, 3H), 2.20 (s, 3H),
4.48 (s, 1H), 7.20 (d, 2H arom., J= 8.6 Hz), 8.20 (d, 2H
arom., J= 8.7 Hz), 12.78 (s, 1H, NH); 13C NMR (125 MHz,
CDCl3): δ= 20.5 (CH3), 29.6 (COCH3) , 101.2 (=CH), 120.3
(CH), 121.8 (CH), 125.1 (CH), 128.3 (CH), 143.5 (qC),
145.3 (O-C arom.), 157.0 (N-C=), 197.9 (O=C).
4-(3,4-Dimethyl-phenylamino)-3-penten-2-one
m.p. 97-99°C (95-9°C) [19d]; IR (KBr, cm-1): 3485, 3365,
3125, 2990, 1649, 1643, 1496, 1348, 1321, 1128, 856, 767;
1H NMR (500 MHz, CDCl3): δ= 1.69 (s, 3H), 2.05 (s, 3H),
2.37 (s, 3H), 2.39 (s, 3H), 3.49 (s, 1H), 6.40-7.53 (m, 3H
arom.), 9.85 (s, 1H, NH); 13C NMR (125 MHz, CDCl3): δ=
17.6 (PhCH3), 18.2 (PhCH3), 19.3 (CH3), 28.5 (COCH3),
98.7 (=CH), 123.5 (CH), 126.9 (CH), 128.1 (CH), 131.0
(CH3-C arom.), 131.8 (CH3-C arom.), 136.7 (qC), 158.8 (N-
C=), 197.5 (O=C).
(13):
4-(4-Chloro-phenylamino)-3-penten-2-one (14): m.p.
59-61°C (61-64) [19d]; IR (KBr, cm-1): 3479, 3386, 3201,
1
3011, 2994, 1620, 1495, 1288, 1182, 1089, 831; H NMR
(500 MHz, CDCl3): δ= 1.94 (s, 3H), 2.33 (s, 3H), 3.88 (s,
1H), 6.62 (d, 2H arom., J= 8.7), 7.12 (d, 2H arom., J= 8.8),
10.03 (s, 1H, NH); 13C NMR (125 MHz, CDCl3): δ= 18.5
(CH3), 23.8 (COCH3), 96.3 (=CH), 123.0 (CH), 124.1 (CH),
125.9 (CH), 135.1 (CH), 135.9 (C-Cl), 141.8 (qC), 158.3 (N-
C=), 196.6 (O=C).
Due to acidic nature, aqueous citrus juice as a natural and
green catalyst has been found to be a suitable replacement
for various homogeneous acid solutions. In this regard, we
examined various concentrations of HCl (pH= 1.5, 2, 2.5, 3,
3.5 and 4) on silica for the reaction entry 1 under the same
conditions and the yields obtained 95, 94, 94, 91, 90 and

22 Combinatorial Chemistry & High Throughput Screening, 2018, Vol. 21, No. 1
Marvi and Fekri
87% respectively. These values show that there is no notable
difference in use of similar acid solutions. In fact, the main
advantage of the desired method is applying an eco-friendly
and economic process for the synthesis of enaminones using
citrus juice as natural, clean and green catalyst instead of the
polluting and toxic materials such as common acid solutions.
Reaction times (grinding time) in all reactions have been
optimized to obtain the highest yields as well (Table 2).
products were obtained in excellent yields (entries 13).
However, in the presence of an electron withdrawing group,
such as NO2, moderate yield of the product was obtained
(entries 9, 12). Further when diverse aliphatic amines were
studied, high yields of products were obtained as well
(entries 2-5, 10 and 15).
In addition to the mild conditions of the method and its
high results, another notable case is the simplicity of product
isolation that offers a significant advantage. A comparison of
efficiency of this method with various catalysts employed for
the synthesis of 1 was carried out (Table 3). Slightly higher
isolated yield was found in this procedure compared to other
methods.
The scope of application of the presented method is
demonstrated by using the various substituted aromatic and
aliphatic amines to react with beta dicarbonyls. The aliphatic
amines (entries 2-5, 10, 15) also worked well to form the
products in high yields.
Also, as shown in Table 2, the yields obtained for lime
were higher whereas the reaction times were shorter than
those by other juices. These observations can be attributed to
the more acidic identity of the lime juice (pH= 2.3).
CONCLUSION
In summary, a novel, efficient and green protocol for the
grinding synthesis of enaminones using citrus juice as
natural catalyst has been presented. This methodology is user
friendly, green and low cost procedure under mild reaction
condition with faster reaction rates. The citrus juice is
inexpensive and non-toxic which makes the process
convenient, more economic and benign. Furthermore,
applying grindstone technique in solvent-free conditions, use
of silica gel as a solid and heterogeneous surface in reaction,
high yields of products, cleaner reaction profiles, and
availability of the reagents makes this method a better choice
for synthetic chemists.
As mentioned above, the wide application of this
procedure is demonstrated by the use of various substituted
amines to react with β-dicarbonyl compounds. The method
was successfully applied for primary amines (15 entries) and
the related enaminones were well synthesized in good to
excellent yields.
In order to generalize the above catalytic protocol,
enamination of 1,3-dicarbonyls with various amines was
studied as depicted in Table 2. When 1,3-dicarbonyl
compounds were reacted with an aryl amine with an electron
donating substituent such as CH3, the corresponding
Table 1. Proximate nutritional composition of citrus juice.
Citrus Juice
Lime
Lemon
Orange
Grapefruit
Moisture (g/100 g)
Ash (g/100 g)
90.8
0.3
2.3
14
90.59
0.2
2.6
2
88.3
0.4
3.8
11
17
1
90.2
0.2
3.4
9
pH
Calcium (mg/100 g)
Phosphorus (mg/100 g)
Sodium (mg/100 g)
Potassium (mg/100 g)
Vitamin A (IU)
13
6
15
2
0.8
124
200
46
0.9
162
440
38
117
50
200
3
Vitamin C (mg/100 g)
30
50
Scheme 1. Citrus juice catalyzed grinding synthesis of enaminones (1-15) under solvent-free conditions on silica.

Citrus Juice: Green and Natural Catalyst for the Solvent-free Silica
Combinatorial Chemistry & High Throughput Screening, 2018, Vol. 21, No. 1 23
Table 2. The yields and reaction times for citrus juice catalyzed solvent-free silica supported grinding synthesis of enaminones.
Reaction Time, min
Lemon /Lime
Orange /Grapefruit
Yield*, %
Lemon /Lime
Product
Amine
Dicarbonyl
Compound
Entry
Orange/Grapefruit
15/10
20/15
92/95
90/90
1
2
20/15
20/20
92/96
91/90
20/10
15/15
90/94
89/91
3
15/10
20/20
91/94
87/90
4
5
15/10
20/15
92/96
90/91
15/10
20/15
91/94
90/89
6
7
15/10
20/20
92/94
88/90
15/10
15/15
92/95
91/93
8
9
15/10
20/20
86/89
84/85
15/10
15/15
89/95
87/91
10
11
15/10
20/20
90/92
87/90
15/10
20/15
90/91
88/89
12
13
15/10
15/20
94/96
92/94
20/15
20/20
90/94
89/91
14
15
15/15
20/15
92/96
93/90
* Isolated Yields.

24 Combinatorial Chemistry & High Throughput Screening, 2018, Vol. 21, No. 1
Marvi and Fekri
Table 3. Effect of various catalysts on the synthesis of enaminone (1) by grinding method.a
Entry
Catalyst
SiO2
Catalyst loading
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
1g
5 drops/1g
1g
45
10
25
45
30
30
30
25
58
95
79
62
86
73
71
67
Lime/SiO2
Al2O3(acidic)
Al2O3(neutral)
Lime/Al2O3(neutral)
nano-Alumina
nano-Fe3O4
ZnCl2
1g
5 drops/1g
0.005g
0.005g
1g
a In all reactions, at first, β-dicarbonyl compound and solid catalyst were ground together in a mortar using pestle for 2 min and then amine was added to the mixture and grinding was
continued.
[4]
[5]
Epifano, F.; Genoveseb, S.; Curinib, M. Ytterbium triflate catalyzed
synthesis of β-enaminones. Tetrahedron Lett., 2007, 48, 2717-2720.
(a) Das, B.; Venkateswarlu, K.; Majhi, A.; Reddy, M. R.; Reddy, K.
N.; Rao, Y. K.; Ravikumar, K.; Sridhar, B. Highly efficient, mild
and chemo-and stereoselective synthesis of enaminones and
enamino esters using silica supported perchloric acid under solvent-
free conditions. J. Mol. Catal. A: Chem., 2006, 246, 276-281. (b)
Syakirah, N.; Sulaiman, T. and S. Overview of catalysts in biodiesel
production. ARPN J. Eng. & Appl. Sci., 2016, 11, 439-448. (c)
Arends, I.; Sheldon, R.; Hanefeld, U. Green Chemistry and
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
Catalysis. 2007 WILEY-VCH Verlag GmbH
& Co. KGaA,
Weinheim.
ACKNOWLEDGEMENTS
[6]
[7]
Giuseppe, B.; Marcella, B.; Manuela, L.; Enrico M.; Paolo, M.;
Letizia, S. Zn (ClO4) 2· 6H2O as a powerful catalyst for the
conversion of β-ketoesters into β-enamino esters. Synlett , 2004,
239-242.
The authors thank Roodsar Payam Noor University for
financial support.
Zhang, Z. -H.; Yin, L.; Wang, Y. -M. A General and efficient
method for the preparation of βꢀenamino ketones and esters
catalyzed by indium tribromide. Adv. Synth. Catal., 2006, 348, 184-
190.
SUPPLEMENTARY MATERIAL
Supplementary material is available on the publisher's
website along with the published article.
[8]
[9]
Zhang, Z. -H.; Hu, J. -Y. Cobalt (II) chloride-mediated synthesis of
beta-enamino compounds under solvent-free conditions. J. Braz.
Chem. Soc., 2006, 17, 1447-1451.
(a) Hasaninejad, A.; Zare, A.; Mohammadizadeh, M. R.; Shekouhy,
M. Silica-supported LiHSO4 as a highly efficient, heterogeneous and
reusable catalytic system for the solvent-free synthesis of β-
enaminones and β-enaminoesters. J. Iran. Chem.Soc., 2010, 7, 69-
76. (b) Sangsuwan, R.; Sangher, S.; Aree, T.; Mahidol, C.;
Ruchirawat, S.; Kittakoop, P. An organocatalyst from renewable
materials for the synthesis of coumarins and chromenes: three-
component reaction and multigram scale synthesis. RSC Adv., 2014,
4, 13708-13718.
REFERENCES
[1]
(a) Li, G.; Watson, K.; Buckheit, R.W.; Zhang Y. Total synthesis of
Anibamine, a novel natural product as a chemokine receptor CCR5
antagonist. Org. Lett., 2007, 9, 2043-2046; (b) White, J. D.; Lhle, D.
C. Tandem photocycloaddition retro-Mannich fragmentation of
enaminones. A route to spiropyrrolines and the tetracyclic core of
koumine. Org. Lett., 2006, 8, 1081-1084; (c) Abass, M.; Mostafa,
B. B. Synthesis and evaluation of molluscicidal and larvicidal
activities of some novel enaminones derived from 4-
hydroxyquinolinones: Part IX. Bioorg. Med. Chem., 2005, 13, 6133-
6144; (d) Eshghi, H.; Seyedi, S. M.; Safaei, E.; Vakili, M.;
Farhadipour, A.; Bayat-Mokhtari, M. Silica supported Fe(HSO4)3 as
an efficient, heterogeneous and recyclable catalyst for synthesis of
β-enaminones and β-enamino esters. J. Mol. Catal. A: Chem., 2012,
363, 430-436.
[10] Datta, B.; Pasha, M. A. Silica sulfuric acid–mediated synthesis of β-
enaminones and β-enaminoesters under microwave irradiation.
Phosphorus Sulfur Silicon Relat. Elem., 2011, 186, 171-177.
[11] Andrade, C. K. Z.; Barreto, A. D. F. S.; Silva, W. A. Microwave
assisted solvent-, support-and catalyst-free synthesis of enaminones.
ARKIVOC, 2008, 2008, 226-232.
[12] Martins, M. A. P.; Rossatto, M.; Prola, L. D. T.; Pizzuti, L.;
Moreira, D. N.; Campos, P. T.; Frizzo, C. P.; Zanatta, N.;
Bonacorso, H. G. Ultrasound promoted the synthesis of N-
propargylic β-enaminones. Ultrason. Sonochem., 2012, 19, 227-
231.
[13] Pal, R. New greener alternative for biocondensation of aldehydes
and indoles using lemon juice: Formation of bis-, tris-, and
tetraindoles. Int. J. Org. Chem., 2013, 3, 136-142.
[14] (a) Habibi, D.; Marvi, O. Microwaveꢀinduced solventꢀfree synthesis
of βꢀketo esters using montmorillonite KSF and K10 clays as
efficient and recyclable heterogeneous solid acids. Chinese J.
Chem., 2008, 26, 522-524; (b) Marvi, O.; Giahi, M. Montmorillonite
KSF clay as novel and recyclable heterogeneous catalyst for the
microwave mediated synthesis of indan-1, 3-diones. Bull. Korean
Chem. Soc., 2009, 30, 2918-2920; (c) Marvi, O.; Nikpasand, M.
[2]
[3]
Neto, B. A. D.; Lapis, A. A. M.; Bernd, A. B.; Russowsky, D.
Studies on the Eschenmoser coupling reaction and insights on its
mechanism. Application in the synthesis of Norallosedamine and
other alkaloids. Tetrahedron, 2009, 65, 2484-2496; (b) Epperson,
M. T.; Gin, D. Y. Enantiospecific Synthesis of the bridged
pyrrolizidine core of asparagamine A: Dipolar dycloadditions of
azomethine ylides derived from the sulfonylation of vinylogous
amides. Angew. Chem. Int. Ed., 2002, 41, 1778-1780.
(a) Eddington, N. D.; Cox, D. S.; Roberts, R. R.; Stables, J. P.;
Powell, C.B.; Scott, K.R. Enaminones-versatile therapeutic
pharmacophores. Further advances. Curr. Med. Chem., 2000, 7,
417-436; (b) Zhao, Y.; Zhao, J.; Zhou, Y.; Lei, Z.; Li, L.; Zhang, H.
Efficient synthesis of β-amino-α, β-unsaturated carbonyl
compounds. New J. Chem., 2005, 29, 769-772.

Citrus Juice: Green and Natural Catalyst for the Solvent-free Silica
Combinatorial Chemistry & High Throughput Screening, 2018, Vol. 21, No. 1 25
Solvent-free synthesis of phthalazine-2(1H)-carboxamide
orange juice as an experimental model. Int. J. Microbiol., 2005, 8,
49-53.
derivatives using K-10 clay under microwave irradiation. Lett. Org.
Chem., 2013, 10, 353-357. (d) Muller, M.; Irkens-Kiesecker, U.;
Rubinstein, B.; Taiz, L. On the mechanism of hyperacidification in
lemon, Comparison of the vacuolar H+-ATPase activities of fruits
and epicotyls. J. Biol. Chem. 1996, 271, 1916-1924.
[19] (a) Gao, Y.; Zhang, Q.; Xu, J. A Convenient and effective method
for synthesizing βꢀaminoꢀα, βꢀunsaturated esters and ketones. Synth.
Commun., 2004, 34, 909-916; (b) Braibante, M. E. F. Braibante, H.
S.; Missio, L.; Andricopulo, A. Synthesis and reactivity of β-amino
α, β-unsaturated ketones and esters using K-10 montmorillonite.
Synthesis, 1994, 1994, 898-900; (c) Zhang, Z. -H.; Ma, Z. -C.; Mo,
L. -P. Enamination of 1, 3-dicarbonyl compounds catalyzed by tin
tetrachloride. Indian J. Chem., B, 2007, 46, 535-539. (d) Gholap, A.
R.; Chakor, N. S.; Daniel, T.; Lahoti, R. J.; Srinivasan, K. V. A
remarkably rapid regioselective synthesis of β-enaminones using
silica chloride in a heterogeneous as well as an ionic liquid in a
homogeneous medium at room temperature. J. Mol. Catal. A: Chem.
2006, 245, 37-46.
[15] AOAC (2012) Official Methods of Analysis. Association of Official
Analytical Chemists, Washington DC, 2012.
[16] Kirk, R. S.; Sawyer, R. Pearson’s Composition and Analysis of
Food. 1987, 9th Ed, Church-Hill Livingstone, Edinburgh 1987.
[17] Barakat, M. Z.; Shahab, S. K.; Darwish, N.; Zahermy, E. I.
Determination of ascarbic acid from plants. Anal. Biochem., 1973,
53, 225-245.
[18] Ferrati, A. R.; Tavolaro, P.; Destro, M. T.; Landgraf, M.; Franco, B.
D. A comparison of ready-to-use systems for evaluating the
microbiological quality of acidic fruit juices using non-pasteurized