One-pot Synthesis of 2-Amino-2-chromene and 2-Amino-3-cyano-4H-pyran Derivatives Promoted by Potassium Fluoride

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One-pot Synthesis of 2-Amino-2-
chromene and 2-Amino-3-cyano-4H-
pyran Derivatives Promoted by
Potassium Fluoride
Behrooz Malekia & Safoora Sheikha
a Department of Chemistry, Hakim Sabzevari University, Sabzevar,
96179-76487, Iran
Published online: 17 Aug 2015.
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To cite this article: Behrooz Maleki & Safoora Sheikh (2015) One-pot Synthesis of 2-Amino-2-
chromene and 2-Amino-3-cyano-4H-pyran Derivatives Promoted by Potassium Fluoride, Organic
Preparations and Procedures International: The New Journal for Organic Synthesis, 47:5, 368-378,
DOI: 10.1080/00304948.2015.1066647
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Organic Preparations and Procedures International, 47:368–378, 2015
Copyright Ó Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2015.1066647
One-pot Synthesis of 2-Amino-2-chromene and
2-Amino-3-cyano-4H-pyran Derivatives Promoted
by Potassium Fluoride
Behrooz Maleki and Safoora Sheikh
Department of Chemistry, Hakim Sabzevari University, Sabzevar, 96179-76487,
Iran
Pyrans and chromenes are important classes of heterocycles because their core fragments
are incorporated in a large variety of natural products and biologically active compounds.
They are of considerable interest as they display a broad range of pharmaceutical proper-
ties such as anti-tumor,1 anti-cancer,2 anti-microbial,3 anti-fungal,4 and anti-HIV charac-
ter.5 They are widely used as pigments,6 in cosmetics and as potential biodegradable
agrochemicals.7 Because of the wide range of pharmacological activities and industrial
applications, several methods for their preparation have been reported in the literature. 2-
Amino-2-chromene and 2-amino-3-cyano-4H-pyrane are generally prepared by the con-
densation of malononitrile, aldehydes and ethyl acetoacetate (or phenols) in the presence
of catalysts such as basic ionic liquid [1-(n-butyl)-3-methylimidazolium hydroxide
([bmim]OH)],8 p-dimethylaminopyridine (DMAP),9 Triton B,10 K2CO3,11 triethylbenzyl-
ammonium chloride (TEBACl),12 cetyltrimethylammonium chloride (CTACl),13
cetyltrimethylammonium bromide (CTABr),14 Na2CO3,15 NH4OAc,16 tetramethylguani-
dine,17 Mg/La mixed oxide,18 H14[Na P5W30O110],19 CuSO4.5H2O,20 methanesulfonic
acid,21 KF-Al2O3,22,23 NH3,24 NH4OH,25 and potassium phthalimide-N-oxyl.26 However,
these methods suffer from some draw-backs such as prolonged reactions times, utilization
of hazardous organic solvents, tedious work-ups and the use of large amounts of catalyst.
Potassium fluoride (KF) is an inexpensive, commercially available, and water-solu-
ble salt that has been utilized in various organic syntheses.27–29 Organic reactions per-
formed under solvent-free conditions have attracted much attention, particularly from the
viewpoint of green chemistry. Green chemistry approaches are most important due to the
reduction in the generation of by-products and of waste products.30–34 As a continuation
of our work on the development of methods using efficient and environmentally benign
reagents and catalysts,35–42 we now report that potassium fluoride is an excellent reagent
for the synthesis of 2-amino-2-chromene and 2-amino-2-cyano-4H-pyran derivatives
(Scheme 1).
Initially, the reaction of 1-naphthol (1 mmol), benzaldehyde (1 mmol), and malono-
nitrile (1.2 mmol) and potassium fluoride (0.2 mmol) was carried out under solvent-free
conditions at 110ꢀC (Table 1, Entry 1). The corresponding product 7a was obtained
Received March 8, 2015; in final form March 19, 2015.
Address correspondence to Behrooz Maleki, Department of Chemistry, Hakim Sabzevari
University, Sabzevar, 96179-76487, Iran. E-mail: malekibehrooz@gmail.com
368

One-pot Synthesis of 2-Amino-2-chromene and 2-Amino-3-cyano-4H-pyran 369
Scheme 1
rapidly in excellent yield. Encouraged by this result, we then employed this reaction as a
template to optimize the reaction conditions. The results were summarized in (Table 1,
Entries 2–6). To evaluate the effect of potassium fluoride, the reaction was examined in
the absence KF under solvent-free condition at 110ꢀC; no product was formed after
60 min at 110ꢀC (Entry 7).
The scope and generality of the present method were then further established by the
reaction of various aromatic aldehydes with malononitrile and phenol derivatives under
solvent-free condition at 110ꢀC. In all of the cases, the corresponding 2-amino-2-chro-
mene derivatives (7a–d, 8e–g, 9h–j) were obtained in good yields (Table 2).
To illustrate the applicability of our method, the preparation of 2-amino-3-cyano-4H-
pyran derivatives (10k–q) was also investigated. First, the reaction of benzaldehyde
(1 mmol), malononitrile (1.2 mmol) with ethyl acetoacetate (1 mmol) in the presence of
potassium fluoride under different conditions was chosen as model reaction. The best
yield was obtained with 0.2 mmol of KF at 110ꢀC under solvent-free conditions. Under
these parameters, various aromatic aldehydes were successfully condensed with malono-
nitrile and ethyl acetoacetate in the presence of KF (Table 2).
A possible mecanism for these reactions may involve initial abstraction of an
a-hydrogen of malononotrile by fluoride ion to give the anion of malononitrile and simul-
taneous activation of the carbonyl group of the aldehyde by coordination by potassium
ion. This would then be followed by nucleophilic attack by malononitrile ion on the

370
Maleki and Sheikh
Table 1
Optimization Process
Entry
Amount of KF (mmol)
Temperature (ꢀC)
Time (min)
Yield (%)
1
2
3
4
5
6
7
0.2
0.2
0.2
0.2
0.1
0.3
–
110
100
120
90
5
10
3
95
85
88
75
58
90
15
10
4
110
110
110
a
60
–
aNo reaction.
aldehyde, followed by loss of water to produce the arylidenemalononitriles. In the final
step, addition of the phenolates or acetoacetate ions (generated by attack of fluoride ion)
on the arylidenemalononitrile followed by cyclization would lead to the observed
products.
In order to illustrate the efficiency of our procedure, results for the preparation of
2-amino-2-chromenes and 2-amino-3-cyano-4H-pyrans previously reported are compared
with our data (Table 3). The present method using KF as reagent offers several advan-
tages such as excellent yields, a simple procedure, short reaction times, and facile work-
up.
In conclusion, we have developed a simple and green protocol for the synthesis of
2-amino-2-chromene and 2-amino-3-cyano-4H-pyran derivatives via a one-pot three-
component condensation reaction in the presence of KF. The new method is inexpensive,
eco-friendly and convenient.
Experimental Section
All reagents were obtained from commercial sources and were used without purification.
IR spectra were recorded as KBr pellets on a Shimadzu 435-U-04 spectrophotometer. 1H
and 13C NMR spectra were determined on a Bruker DRX-300 Avance spectrometer in
DMSO-d6 or CDCl3, and shifts are given in d downfield from tetramethylsilane (TMS) as
an internal standard. Melting points were determined using an Electrothermal 9200 appa-
ratus and are uncorrected. CAUTION: Although potassium fluoride is relatively less

One-pot Synthesis of 2-Amino-2-chromene and 2-Amino-3-cyano-4H-pyran 371
Table 2
One-Pot synthesis of 2-Amino-2-chromene and 2-Amino-3-cyano-4H-pyran Derivatives
mp (ꢀC)
Found
Lit.
Products
Time(min)
5
Yield (%)
95
211–209
210–21114
4
90
232
231–23214
5
89
238–240
236–23714
5
91
213–214
212–21414
(Continued on next page)

372
Maleki and Sheikh
Table 2
One-Pot synthesis of 2-Amino-2-chromene and 2-Amino-3-cyano-4H-pyran Derivatives
(Continued)
mp (ꢀC)
Found
Lit.
Lit.
Products
Products
Time(min)
Time(min)
Yield (%)
Yield (%)
mp (ꢀC)
Found
13
89
119–120
116–11714
10
90
186
185–18614
7
93
283–284
280–28214
35
76
96–97
94–9514
(Continued on next page)

One-pot Synthesis of 2-Amino-2-chromene and 2-Amino-3-cyano-4H-pyran 373
Table 2
One-Pot synthesis of 2-Amino-2-chromene and 2-Amino-3-cyano-4H-pyran Derivatives
(Continued)
mp (ꢀC)
Found
Lit.
Products
Time(min)
30
Yield (%)
82
162–163
161–16214
30
80
111–112
112–11414
10
90
194–195
190–19224
5
95
187–188
187–18824
(Continued on next page)

374
Maleki and Sheikh
Table 2
One-Pot synthesis of 2-Amino-2-chromene and 2-Amino-3-cyano-4H-pyran Derivatives
(Continued)
mp (ꢀC)
Found
Lit.
Products
Time(min)
7
Yield (%)
91
177–178
177–17824
10
10
15
89
83
75
190–191
182–183
197–198
191–19224
183–18424
196–19724
(Continued on next page)

One-pot Synthesis of 2-Amino-2-chromene and 2-Amino-3-cyano-4H-pyran 375
Table 2
One-Pot synthesis of 2-Amino-2-chromene and 2-Amino-3-cyano-4H-pyran Derivatives
(Continued)
mp (ꢀC)
Found
Lit.
Products
Time(min)
10
Yield (%)
84
179–180
180–18124
hazardous than many reagents, it is corrosive and toxic and care should be exercized in
its use.
General Procedure for the Synthesis of 2-Amino-2-chromenes
A mixture of the aldehyde (1 mmol), malononitrile (0.08 g, 1.2 mmol) and a- or b-naph-
thol (0.14 g, 1 mmol) or 1,3-dihydroxybenzene (0.11 g, 1 mmol), was stirred at room
temperature for two minutes, then 0.012 g (0.2 mmol) of KF was added and the mixture
was heated on an oil bath at 110ꢀC with stirring for the time show in Table 2. Upon com-
pletion of the reaction as indicated by TLC (hexane:ethyl acetate, 8:2), hot EtOH (96%,
1 ml) was added to the mixture which was stirred for 2 min. Then the reaction mixture
was poured onto crushed ice and the precipitated solid was collected, recrystallized from
ethanol (96%, 3 ml) to afford the pure 2-amino-2-chromene derivatives (7a–d, 8e–g,
9h–j).
General Procedure for the Synthesis 2-Amino-3-cyano-4H-pyrans
A mixture of the aldehyde (1 mmol), malononitrile (0.08 g, 1.2 mmol), and ethyl acetoa-
cetate (0.13 ml, 1 mmol) was stirred at room temperature for two minutes, then KF
(0.012 g, 0.2 mmol) was added and the mixture was heated in an oil bath at 110ꢀC with
stirring for the time shown in Table 2. Upon completion of the reaction as indicated by
TLC (hexane:ethyl acetate, 8:2), hot EtOH (96%, 1 ml) was added and the mixture stirred
for 2 min. Then the resulting crude reaction mixture was poured onto crushed ice and the
precipitated solid was collected and recrystallized from ethanol (96%, 3 ml) to afford the
pure 2-amino-3-cyano-4H-pyran derivatives (10k–q).

376
Maleki and Sheikh
Table 3
Comparison of Methods for the Synthesis of 2-Amino-2-chromene and 2-Amino-3-
cyano-4H-pyran Derivatives
Entry
Conditions
Time (min)
Yield (%)
7a
Present work
CTABr/H2O/ultrasonic/rt14
Triton B/Ethanol/rt10
5
95
92
87
95
90
89
73
86
80
90
85
90
98
150
85
CuSO4.5H2O/water/reflux20
methanesulfonic acid/CH3CN/reflux21
Present work
60
180
5
7c
KF-Al2O3/EtOH/reflux22
CTABr/H2O/ultrasonic/rt14
CuSO4.5H2O/water/reflux20
Present work
KF-Al2O3/EtOH/reflux23
NH3/ethanol/rt24
NH4OH/IR/Reflux25
300
360
150
10
10k
180
4
10
Acknowledgements
The author thanks the Research Council of Hakim Sabzevari University for partial sup-
port of this work.
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