Efficient and Green Preparation of 2-Amino-4H-chromenes by a Room-Temperature, Na2CO3-Catalyzed, Three-Component Reaction of Malononitrile, Benzaldehydes, and Phloroglucinol or Resorcinol in Aqueous Medium

Article abstract of DOI:10.1080/00397911.2015.1031249

The preparation of substituted 2-amino-4H-chromenes by a Na₂CO₃catalyzed reaction of malononitrile, benzaldehydes, and phloroglucinol or resorcinol in aqueous medium and at room temperature is reported. The merits of this procedure i

Full text of DOI:10.1080/00397911.2015.1031249

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Efficient and Green Preparation of 2-Amino-4H-
chromenes by a Room Temperature, Na2CO3-
Catalysed, Three-Component Reaction of Malononitrile,
Benzaldehydes, and Phloroglucinol or Resorcinol in
Aqueous Medium
Ishmael B Masesanea & Shetonde O. Mihigob
a Department of Chemistry, University of Botswana, Private Bag, Gaborone, Botswana
b Department of chemistry, University of Kinshasa, Kinshasa XI, DR, Congo
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Accepted author version posted online: 01 Apr 2015.
To cite this article: Ishmael B Masesane & Shetonde O. Mihigo (2015): Efficient and Green Preparation of 2-Amino-4H-
chromenes by a Room Temperature, Na2CO3-Catalysed, Three-Component Reaction of Malononitrile, Benzaldehydes,
and Phloroglucinol or Resorcinol in Aqueous Medium, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2015.1031249
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Efficient and green preparation of 2-amino-4H-chromenes by a room temperature,
Na2CO3-catalysed, three-component reaction of malononitrile, benzaldehydes, and
phloroglucinol or resorcinol in aqueous medium
Ishmael B Masesane1, Shetonde O. Mihigo2
1Department of Chemistry, University of Botswana, Private Bag, Gaborone, Botswana,
2Department of chemistry, University of Kinshasa, Kinshasa XI, DR, Congo
Abstract
The preparation of substituted 2-amino-4H-chromenes by a Na2CO3-catalysed reaction of
malononitrile, benzaldehydes and phloroglucinol or resorcinol in aqueous medium and at
room temperature is reported. The merits of this procedure include limited use of organic
solvents, easy workup technique and high purity of products. The 2-amino-4H-chromenes
were prepared in yields of 54-96%.
KEYWORDS: 2-amino-4H-chromenes, green reaction, phloroglucinol, resorcinol,
malononitrile
INTRODUCTION
Multicomponent coupling reactions (MCRs) in aqueous medium and at room temperature
are of great interest to synthetic chemists because they provide access to a large number
of organic molecules through a high atom economy and environmentally benign route.[1-9]
1

It is important to also note that the replacement of hazardous solvents with relatively
benign solvents is an important aspect of green chemistry. Water is the most
environmental benign, nonflammable and naturally available solvent and therefore the
obvious choice. Water also offers the benefit of cheaper and simple workup and
purification that can be carried out by phase separation techniques. Organic reactions in
aqueous media are therefore an attractive area in green chemistry.
As part of our broad interest in green chemistry[10] and the synthesis of organic
compounds with the chromene moiety,[11-13] we report the synthesis of 2-
aminochromenes by a Na2CO3-catalysed reaction of benzaldehydes, malononitrile and
phloroglucinol or resorcinol in aqueous media at room temperature. The synthesis of
substituted 2-amino-4H-chromenes is of currently interest mainly due to their activity
against human inflammatory diseases and cancer.[9, 14-18]
RESULTS AND DISCUSSION
In our model reaction, an equimolar mixture of benzaldehyde 1, malonitrile 2 and
phloroglucinol 3 was dissolved in MeOH (1 ml). To this solution was then added an
aqueous solution of Na2CO3 (19 ml, 30 mol%) and the suspension was stirred at room
temperature for 10 h to give 2-amino-4H-chromene 4 in 65% scheme 1. It is important to
note that Na2CO3 is produced in large quantities in Sua town, Botswana and has
extensive domestic use therefore relatively safe.
2

The mechanism of the reaction involves a Knoevenagel reaction of benzaldehyde 1 and
malononitrile 2 to give 5. Subsequent Michael addition of 3 to intermediate 5 gives 6.
Cyclisation of intermediate 6 proceed to give imine 7 followed by imine-enamine
tautomerism to afford the desired product 4 scheme 1.[3, 5,19,20]
To determine the optimal amount of Na2CO3, the model reaction was carried out using
various amounts. Thus, when the reaction was carried out with less than 30 ml% of
Na2CO3, a complex mixture was obtained. In the absence of the catalyst, only the starting
materials were detected by TLC. Increasing the Na2CO3 amount beyond the 30 mol%
threshold had no significant effect on the product yield. It was therefore concluded that
the optimum amount of the catalyst was 30 mol%. The pure product was recovered by
simple allowing the reaction mixture to stand at room temperature for about 30 minutes,
filtering off the resulting solid and washing it with ice cold methanol.
With the optimal amount of catalyst for the reaction in hand, various substituted
benzaldehydes were used in the three-component procedure and were found to be well
tolerated. Thus, 4-methoxybenzaldehyde 8 and 4-hydroxybenzaldehyde 9 reacted with
malononitrile 2 and phloroglucinol 3 to give 2-amino-4H-chromenes 17 and 18
respectively in yields above 75%. In addition, disubstituted aldehydes 10 and 11 reacted
with malononitrile 2 and phloroglucinol 3 under the described reaction conditions to give
the corresponding 2-amino-4H-chromenes 19 and 20 in 72 and 70% yields respectively.
Methyl substituted aldehydes 12, 13 and 14 also participated in the three-component
reaction to afford 2-amino-4H-chromenes 21, 22 and 23 in yields of 79% and better,
3

scheme 2. The results discussed thus far involved the use of benzaldehydes with electron-
donating substituents. To further test the broadness of the tolerance of this three-
component reaction, benzaldehydes 15 and 16 with electron-withdrawing nitro and
chloro groups respectively were subjected to the three-component reaction conditions to
afford the corresponding 2-amino-4H-chromenes 24 and 25 in high yields, scheme 2.
The scope and generality of the present method were further expanded to resorcinol 26
instead of phloroglucinol 3. It is instructive to note that there is literature precedent of the
reaction of resorcinol with malononotrile and benzylaldehydes in the presence of access
K2CO3 and under microwave irradiation.[21] In the context of our procedure, It was
established that resorcinol 26 participated in the MCR with malononitrile 2 and
benzaldehyde 1 to give 2-amino-4H-chromene 27 in 72% yield. Substituted
Benzaldehydes 8, 9, 11, 12, 13, 14, 15 and 16 also participated in the three component
reaction to give the corresponding chromenes in 54-89% yields, scheme 3. It is
worthwhile to mention that benzaldehydes with both electron-donating and electron-
withdrawing groups reacted smoothly with malononitrile 2 and resorcinol 26 to give the
corresponding products in moderate to excellent yields. While the relatively low yield for
31 can be attributed to steric hindrance in the Knoevenagel reaction due to the nearness
of the methyl group to the carbonyl group, it is not obvious to what the lower yield of 28
should be attributed, so no rational is offered in this paper.
EXPERIMENTAL
4

Laboratory grade chemicals and solvents were procured from Sigma-Aldrich and used
without any further purification. Reactions were monitored by TLC using Merck’s TLC
Silica gel 60 F254 aluminium sheets. Melting point measurements were determined on a
Stuart melting point apparatus and are uncorrected. Infrared spectra were recorded neat
on a Perkins Elmer FT-IR spectrophotometer 1000. High resolution mass spectra were
recorded on a GCT Premier mass spectrometer (Waters) with an ionization energy of 70
eV. NMR spectra were recorded on a Bruker Avance DPX 300 MHz NMR spectrometer
with TMS as an internal standard.
TYPICAL PROCEDURE FOR THE SYNTHESIS OF 2-AMINO-3-CYANO-5,7-
DIHYDROXY-4-PHENYL-4H-CHROMENE (4)
A mixture of benzaldehyde (0.30 g, 2.8 mmol), malononitrile (0.19 g, 2.8 mmol) and
phloroglucinol (0.36 g, 2.8 mmol) was dissolved in methanol (1.0 cm3) in a round bottom
flask. A solution of Na2CO3 (0.09 g, 0.8 mmol) in water (19.0 cm3) was then added to the
round bottom flask and the resulting suspension was stirred at room temperature for 10
hours. The solid formed was filtered off, washed with water followed by cold methanol
and dried in an oven at 100 oC to give 2-amino-3-cyano-5,7-dihydroxy-4-phenyl-4H-
chromene as a white powder in 65% yield. mp 162-164 oC; IR (neat) ν: 3331,3203, 2188,
1654, 1618, 1468 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 4.48 (1H, s, H-4), 5.98 (1H, d,
J = 1.5 Hz, H-6), 6.06 (1H, d, J = 1.5 Hz, H-8), 6.78 (2H, s, 2OH), 7.20 (5H, m, ArH),
9.57 (2H, br, NH2); 13C NMR (75 MHz, DMSO-d6) δ 36.8 (C-4), 58.0 (C-3), 94.2 (C-8),
99.3 (C-6), 102.8 (C-4a), 121.3 (CN), 126.6 (C-4’), 127.5 (C-2’ and 6’), 128.6 (C-3’ and
5

5’), 146.8 (C-1’), 150.9 (C-8a), 155.8 (C-7), 157.9 (C-5), 160.9 (C-2); HRMS-EI (m/z)
calcd for C16H12N2O3: 280.2848; found, 280.2853.
The following 2-amino-4H-chromenes that were prepared are known compounds and
were characterized on the basis of data that matched literature data: 27, 28,[7,22,23] 29,[22]
33,[7,22] 34, and 35,[22,22]
.
CONCLUSION
In conclusion we have described an efficient green synthesis of 2-amino-4H-chromenes
by the three-component Na2CO3-catalysed reaction of benzaldehydes, malononitrile and
phloroglucinol or resorcinol at room temperature. The most striking features of this route
to 2-amino-4H-chromenes are use of water as a solvent, reliance on use of relatively safe
Na2CO3 as a catalyst and the easy workup method.
ACKNOWLEDGEMENTS
The authors thank the Royal Society of Chemistry for financial support and SOM thanks
the Organization of the Prohibition of Chemical Weapons (OPCW) for an internship
support. The authors also thank Mr S. M. Marape for NMR experiments and Mr D.
Mosimanethebe and Dr K. Sichilingo for mass spectrometry experiments.
SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher’s website.
6

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Scheme 1: The model three-component reaction
9

Scheme 2: MCRs of substituted benzaldehydes, malononitrile and phloroglucinol
10

Scheme 3: MCRs of substituted benzaldehydes, malononitrile and resorcinol
11