A facile and efficient synthesis of 2-amino-3-cyano-4H-chromenes and tetrahydrobenzo[b]pyrans using 2,2,2-trifluoroethanol as a metal-free and reusable medium

Article abstract of DOI:10.1016/j.jfluchem.2012.05.014

A highly efficient one-pot three-component regioselective synthesis of 2-amino-3-cyano-4H-chromene and tetrahydrobenzo[b]pyran derivatives has been developed by annulation of aldehydes, malononitrile, and resorcinol or dimedone under reflux conditions in

Full text of DOI:10.1016/j.jfluchem.2012.05.014

Journal of Fluorine Chemistry 141 (2012) 11–15
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
A facile and efficient synthesis of 2-amino-3-cyano-4H-chromenes and
tetrahydrobenzo[b]pyrans using 2,2,2-trifluoroethanol as a metal-free and
reusable medium
*
Samad Khaksar , Ahmad Rouhollahpour, Saeed Mohammadzadeh Talesh
Department of Chemistry, Ayatollah Amoli Branch, Islamic Azad University, Amol, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
A highly efficient one-pot three-component regioselective synthesis of 2-amino-3-cyano-4H-chromene
and tetrahydrobenzo[b]pyran derivatives has been developed by annulation of aldehydes, malononitrile,
and resorcinol or dimedone under reflux conditions in 2,2,2-trifluoroethanol without the use of a catalyst
or any other additive.
Received 18 January 2012
Received in revised form 13 May 2012
Accepted 14 May 2012
Available online 23 May 2012
ß 2012 Elsevier B.V. All rights reserved.
Keywords:
Fluorinated solvent
Malononitrile
Resorcinol
Metal-free
1. Introduction
derivatives, in recent years efforts have been made in developing
new methodologies for the synthesis of these compounds. A
Pyran annulated heterocyle derivatives represent an important
class of oxygen-containing heterocycles being the main compo-
nents of many natural occurring products, and are widely
employed as cosmetics, pigments [1], and potential biodegradable
agrochemicals [2] and exhibit a wide spectrum of biological
activities [3–12]. 4H-Pyran can also serve as useful building blocks
in the generation of a variety of natural products showing
molluscicidal, antibacterial, anticancer, antitubercular, antimicro-
bial, anti-coagulant, antiallergic, antibiotic, hypolipidemic, and
immunomodulating activities [13–20]. In addition, they can be
used as cognitive enhancers, for the treatment of neurodegenera-
tive disease, including Alzheimer’s disease, amyotrophic lateral
sclerosis, Huntington’s disease, Parkinson’s disease, AIDS associat-
ed dementia and Down’s syndrome as well as for the treatment of
schizophrenia and myoclonus [21]. Hence, an easy access to pyran
derivatives is highly desirable as they possess unique pharmaco-
logical properties. The most straightforward synthesis of this
heterocyclic system involves a three-component coupling of
aromatic aldehyde, malononitrile and activated phenol. Tradition-
ally, this reaction was catalyzed by a basic catalyst such as
piperidine [22]. In view of the great importance of pyran
variety of reagents, such as ionic liquids [23], hexadecyltrimethyl
ammonium bromide [24], Mg/La mixed metal oxides [25], Cu(II)
oxymetasilicate [26], cetyltrimethylammonium bromide [27],
organic bases [28,29], MgO [30], tetrabutylammonium fluoride
[31], silica nanoparticle [32] and DBU under microwave-irradia-
tion [33] have been employed to achieve the synthesis of these
molecules. Recently, the electrochemical synthesis of benzopyrans
has been reported via three component reaction in the presence of
NaBr as an electrolyte [34]. These methods, however, suffer from
drawbacks such as unsatisfactory yields, acidic or basic catalysts,
extended reaction times, elevated temperatures, tedious work-up,
anhydrous organic solvents and the use of stoichiometric and/or
relatively expensive reagents. Moreover, the main disadvantage of
almost all existing methods is that the catalysts are destroyed in
the work-up procedure and cannot be recovered or reused.
Therefore, the search continues for a better catalyst for the
synthesis of pyrans in terms of operational simplicity, reusability,
economic viability, and greater selectivity. The use of fluorinated
solvent, as chemical reaction media in place of conventional
volatile organic solvents, has grown dramatically in recent years
[35–50]. Fluorinated alcohols possess interesting physiochemical
properties, which include lower boiling points and higher melting
points than their non-fluorinated counterparts, high polarity,
strong hydrogen bond donation properties and the ability to
solvate water. Due to the current challenges for developing
environmentally benign synthetic processes and in continuation of
* Corresponding author. Fax: +98 121 2517071.
E-mail addresses: S.khaksar@iauamol.ac.ir, samadkhaksar@yahoo.com
(S. Khaksar).
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2012.05.014

12
S. Khaksar et al. / Journal of Fluorine Chemistry 141 (2012) 11–15
R
HO
OH
CN
3
HO
O
4a-n
NH2
O
CN
CN
TFE
R
O
O
+
O
H
R
Reflux, 5 h
CN
1
5
2
O
NH2
6a-n
Scheme 1. Synthesis of pyran annulated heterocycles.
our interest in the application of fluorinated solvents for various
organic transformations [51–56] we report a new, convenient,
mild and efficient procedure for the synthesis of pyran annulated
heterocyles, which are obtained through one-pot three-compo-
nent condensation reaction of aldehydes, malononitrile, and
resorcinol as well as condensation of aldehydes, malononitrile,
and cyclic 1,3-diketones under reflux conditions in 2,2,2-trifluor-
oethanol without the use of a catalyst or any other additives
(Scheme 1).
intra-molecular cyclization that may take place in the formation of
the final product. The probable mechanism is given in Scheme 2.
Although there is no solid evidence to support the catalytic
mechanism of TFE in the reaction, it is surely reasonable to
propose that the reactions carried out in fluorinated alcohols are
Table 1
Synthesis of 2- amino-4H-chromenes derivatives in TFE.
Entry
1
Aldehyde
Product
4 yield (%) Ref.
2. Results and discussion
4a
90 [33]
CHO
In an initial endeavor, the reaction was carried out by simply
mixing benzaldehyde, malononitrile and resorcinol (Table 1,
entry 1) in trifluoroethanol and refluxing the resulting mixture for
5 h. The corresponding substituted 2-amino-4H-chromene 4a
was obtained in high yield (90%). Encouraged by this success, we
extended this reaction to a range of aldehydes 1a–o under similar
conditions to furnish the respective substituted 2-amino-4H-
chromene 4a–o in good yields. The results are summarized in
Table 1.
As shown in Table 1, aromatic aldehydes carrying either
electron-donating or electron-withdrawing substituents reacted
efficiently giving excellent yields (Table 1, entries 2–12). It is
noteworthy to mention that the structural variation of the
aldehyde and substituents on the aromatic ring did not show
any obvious effect on this conversion, because the desired products
were obtained in high yields in relatively short reaction times. The
experimental procedure is very efficient, convenient, rapid and has
the ability to tolerate a variety of other functional groups, such as
methoxyl, amino, nitro, and halides under these reaction condi-
tions. Furthermore, acid sensitive aldehydes [57,58] worked well
without any decomposition or polymerization under these
reaction conditions (entries 10, 11 and 14). However aliphatic
aldehydes did not undergo condensation under this reaction
condition.
2
3
4
5
4b
4c
4d
4e
95 [33]
96 [33]
95 [33]
93 [33]
CHO
Cl
CHO
F
CHO
Br
O2N
CHO
6
4f
92 [33]
CHO
MeO2C
O2N
7
8
4g
4h
90 [33]
90 [33]
CHO
CHO
F
9
4i
4j
88 [33]
90 [34]
CHO
10
CHO
MeO
The present protocol was extended using dimedone and the
reaction of benzaldehyde, malononitrile, and dimedone was
carried out under similar reaction conditions. The desired product
6a was obtained in 90% yield. The reaction of other aromatic
aldehydes substituted with Cl, Br, F, Me, NO2, and MeO was also
performed with dimedone and malononitrile, the desired products
6b–k were isolated in good yields (Table 2, entries 2–11).
The reaction of trans-cinnamaldehyde with malononitrile and
dimedone was performed and the product 6l was obtained in good
yield (entry 12). Interestingly, aliphatic aldehydes were also
suitable for this transformation (Table 1, entries 13 and 14) giving
moderate yield. The result using HFIP at reflux condition was
similar to that in TFE.
11
12
4k
4l
90 [27]
85 [34]
O
O
CHO
CHO
N
13
14
15
4m
4n
4o
90 [34]
80 [34]
90 [34]
CHO
CHO
S
O
The mechanism of this reaction can be seen as sequential
reactions involving Knoevenagel reaction, Michael addition and an
N
CHO

S. Khaksar et al. / Journal of Fluorine Chemistry 141 (2012) 11–15
13
Table 2
Synthesis of tetrahydrobenzo[b]pyran derivatives in TFE.
O
CN
H
R
CN
TFE
+
+
H2O
N
Entry
1
Aldehyde
Product
4 yield (%) Ref.
R
H
Reflux
CN
B
CN
6a
90 [32]
CHO
CHO
C
A
CN
2
3
4
6b
6c
6d
95 [32]
85 [32]
90 [32]
R
Cl
OH
OH
CHO
Cl
TFE
C
+
D
E
CHO
O2N
O2N
R
5
6
6e
6f
92 [32]
90 [31]
CHO
CN
CHO
O
F
NH2
F
7
8
6g
6h
6i
90 [31]
80 [31]
85 [32]
80 [31]
CHO
Scheme 2. Plausible mechanism for the formation of pyran annulated heterocyclic
Br
compounds.
CHO
Br
When we carried out the reaction in TFE at room temperature, the
reaction proceeded very slowly to give very poor yields.
9
CHO
MeO
10
6j
3. Conclusions
Me
CHO
CHO
In summary, we have developed efficient synthesis 2-amino-
4H-chromene and tetrahydrobenzo[b]pyran derivatives via one-
pot condensation of aldehydes, malononitrile and resorcinol or
dimedone in TFE without using any catalyst or additives. In
contrast to the existing methods using potentially hazardous
catalysts/additives, this new method offers the following competi-
tive advantages: (i) avoiding the use of any base, metal or Lewis
acid catalyst (ii) short reaction time, (iii) ease of product isolation/
purification by non-aqueous work-up, (iv) high chemoselectivity,
(v) no side reaction, and (vi) low costs and simplicity in process and
handling. The recovered TFE can be reusable.
Me
Me
11
12
6k
6l
90 [31]
90 [31]
CHO
13
14
6m
6n
80 [32]
80 [32]
CHO
CHO
acid-catalyzed. The weak Brønsted acidity (pKa = 12.4 for TFE and
9.3 for HFIP) and strong ionizing power may be relevant to its
unique role in this transformation. The polarity effect and
hydrogen bond donor ability might not be important in this case.
Actually the hydrogen bond donating ability of these solvents
drops as temperature rises owing to the fact that hydrogen-bond
formation is exothermic [59,60]. Although fluorinated alcohols is
known to have a remarkable stabilizing effect for cationic species
due to its high polarizability and low nucleophilicity, the
synthesis of pyrans does not go through a discrete carbocation
intermediate. The polar transition state of the reaction could be
stabilized well by the high ionizing solvent TFE.
Interestingly, the reaction did not proceed to completion when
either ethanol or water alone was used as solvent, even at reflux
conditions. This method not only affords the products in excellent
yields but also avoids the problems associated with catalyst cost,
handling, safety, and pollution. One of the major advantages of this
protocol is the isolation and purification of the products, which
have been achieved by simple filtration and crystallization of the
crude products. After the reaction, TFE can be easily separated (by
distillation) and reused without decrease in its activity. For
example, the reaction of benzaldehyde, malononitrile and dime-
done afforded the corresponding tetrahydrobenzo[b]pyran deriv-
ative in 90%, 90%, 90%, 88% and 88% isolated yield over five cycles.
4. Experimental
4.1. General procedure for the preparation of 2-amino-3-cyano-4H-
chromenes
Aldehyde (1 mmol), resorcinol (1 mmol) and malononitrile
(1 mmol) were dissolved in TFE (2 mL) and was refluxed for the
stipulated time. The progress of the reaction is monitored by TLC.
After completion of the reaction, the corresponding solid product 4
was obtained through simple filtering, and recrystallized from
ethanol to yield the highly pure 2-amino-4H-chromene deriva-
tives. The physical data (mp, IR, NMR) of known compounds were
found to be identical with those reported in the literature
[27,33,34].
4.2. General procedure for the preparation of
tetrahydrobenzo[b]pyrans
Aldehyde (1 mmol), dimedone (1 mmol) and malononitrile
(1 mmol) were dissolved in TFE (2 mL) and was refluxed for 5 h.
After completion of the reaction as indicated by TLC, the products
were isolated by filtration (for solid products) or after selective
evaporation of the TFE (for liquid products) to yield the highly pure
tetrahydrobenzo[b]pyran derivatives. The physical data (mp, IR,

14
S. Khaksar et al. / Journal of Fluorine Chemistry 141 (2012) 11–15
NMR) of known compounds were found to be identical with those
reported in the literature [31,32].
6.39–6.49 (m, 3H), 6.89 (br s, 2H, NH2), 7.09–7.22 (m, 6H), 9.70 (br
s, 1H, OH). 13C NMR (100 MHz DMSO-d6):
= 40.2, 56.6, 102.6,
d
Spectroscopic data for selected examples are shown below:
2-Amino-3-cyano-7-hydroxy-4-phenyl-4H-chromene (4a).
Light yellow solid, mp: 231–233 8C. IR (KBr): 3428, 3217, 2190,
112.8, 113.9, 115.6, 115.8, 116.2, 116.5, 121.0, 129.6, 129.7, 130.3,
131.4, 131.5, 143.0, 149.2, 155.7, 157.6, 160.6.
2-Amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-
4H-chromene-3-carbonitrile (6a). White solid; mp: 234–235 8C;
1650, 1580 cmÀ1
.
1H NMR (400 MHz, DMSO-d6):
d
= 4.61 (s, 1H),
6.85 (br s, 2H, NH2), 6.40–7.31 (m, 8H), 9.68 (br s, 1H). 13C NMR
(100 MHz, DMSO-d6): = 42.3, 56.2, 102.1, 112.3, 113.7, 120.5,
1H NMR (400 MHz, DMSO-d6):
d = 0.96 (s, 3H), 1.05 (s, 3H), 2.11 (d,
d
J = 16.2 Hz, 1H), 2.25 (d, J = 16.2 Hz, 1H), 2.51 (s, 2H), 4.18 (s, 1H),
6.98 (s, 2H), 7.13–7.21 (m, 3H), 7.28 (t, J = 7.3 Hz, 2H); 13C NMR
126.6, 127.3, 128.5, 129.8, 146.3, 148.8, 157.1, 160.2.
2-Amino-3-cyano-7-hydroxy-4-(4-bromophenyl)-4H-chro-
mene (4d). Light yellow solid, mp: 224–226 8C. IR (KBr): 3471,
(100 MHz, DMSO-d6): d = 26.7, 28.4, 31.7, 35.5, 38.6, 49.9, 58.2,
112.7, 119.7, 126.5, 127.1, 128.3, 144.7, 158.4, 162.4, 195.6.
2-Amino-4-(4-chlorophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-
tetrahydro-4H-chromene-3-carbonitrile (6b). White solid; mp:
215–216 8C; 1H NMR (400 MHz, DMSO-d6):
d = 0.95 (s, 3H), 1.03 (s,
3337, 2194, 1641, 1578 cmÀ1 1H NMR (400 MHz, DMSO-d6):
.
d
= 4.64 (s, 1H), 6.90 (br s, 2H, NH2), 6.40–7.84 (m, 7H), 9.71 (br s,
1H, OH). 13C NMR (100 MHz, DMSO-d6):
d
= 41.2, 56.3, 102.6,
112.0, 113.7, 120.2, 121.4, 130.1, 130.3, 132.1, 147.2, 149.5, 157.8,
160.5.
3H), 2.10 (d, J = 16.2 Hz, 1H), 2.24 (d, J = 16.2 Hz, 1H), 2.50 (s, 2H),
4.20 (s, 1H), 7.17 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.05 (s,
2-Amino-3-cyano-7-hydroxy-4-(3-nitrophenyl)-4H-chro-
mene (4g). Yellow solid, mp: 169–170 8C. IR (KBr): 3440, 3345,
2H); 13C NMR (100 MHz, DMSO-d6):
d = 26.8, 28.3, 31.9, 35.1, 40.1,
49.9, 57.9, 112.3, 119.6, 128.3, 129.1, 132.1, 143.8, 158.5, 162.6,
195.8.
2-Amino-4-(2-chlorophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-
tetrahydro-4H-chromene-3-carbonitrile (6c). White solid; mp:
191–192 8C; 1H NMR (400 MHz, DMSO-d6):
d = 0.95 (s, 3H), 1.02 (s,
3H), 2.10 (d, J = 16.2 Hz, 1H), 2.25 (d, J = 16.2 Hz, 1H), 2.50 (s, 2H),
4.21 (s, 1H), 7.02 (s, 1H), 7.10 (t, J = 8.8 Hz, 2H), 7.14–7.22 (m, 2H);
13C NMR (100 MHz, DMSO-d6):
d = 27.3, 28.8, 32.2, 35.4, 50.4, 58.6,
113.1, 115.4, 115.5, 120.2, 129.4, 129.5, 141.4, 141.4, 159.1, 160.1,
162.5, 163.1, 196.1.
2192, 1650, 1585 cmÀ1. 1H NMR (400 MHz, DMSO-d6):
d
= 4.85 (s,
1H), 7.05 (br s, 2H, NH2), 6.45–8.10 (m, 7H), 9.78 (br s, 1H, OH). 13
NMR (100 MHz, DMSO-d6): = 42.1, 58.3, 102.4, 111.9 112.7,
C
d
120.2, 121.1, 123.7, 128.2, 129.6, 131.4, 133.4, 139.3, 148.7, 149.0,
157.5, 160.3.
2-Amino-3-cyano-7-hydroxy-4-(2-fluorophenyl)-4H-chro-
mene (4h). Yellow solid, mp: 200–202 8C. IR (KBr): 3424, 3333,
2190, 1651, 1587 cmÀ1. 1H NMR (400 MHz, DMSO-d6):
d
= 4.87 (s,
1H), 6.85 (br s, 2H, NH2), 6.38–7.25 (m, 7H), 9.69 (br s, 1H, OH). 13
C
NMR (100 MHz, DMSO-d6):
d
= 41.5, 54.5, 102.2, 112.4, 115.5 (d,
2-Amino-7,7-dimethyl-4-(4-nitrophenyl)-5-oxo-5,6,7,8-tet-
rahydro-4H-chromene-3-carbonitrile (6d). Yellow solid; mp:
151–152 8C; 1H NMR (400 MHz,DMSO-d6):
d = 0.95 (s, 3H), 1.04 (s,
2JC–F = 22.0 Hz), 115.8, 120.4, 124.7, 128.8 (d, 3JC–F = 8.4 Hz), 129.5,
1
129.8, 132.7, 149.1, 157.2, 160.6 (d, JC–F = 246.1 Hz).
2-Amino-3-cyano-7-hydroxy-4-(4-methylphenyl)-4H-chro-
3H), 2.12 (d, J = 15.6 Hz, 1H), 2.26 (d, J = 15.6 Hz, 1H), 2.50 (s, 2H),
4.37 (s, 1H), 7.17 (s, 2H), 7.44 (d, J = 8.2 Hz, 2H), 8.17 (d, J = 8.2 Hz,
mene (4i). Yellow solid, mp: 184–186 8C. IR (KBr): 3409, 3332,
2194, 1656, 1589 cmÀ1. 1H NMR (400 MHz, DMSO-d6):
d
= 2.24 (s,
3H), 4.56 (s, 1H), 6.81 (br s, 2H, NH2), 6.38–7.10 (m, 7H), 9.66 (br s,
1H, OH). 13C NMR (100 MHz, DMSO-d6):
= 20.5, 42.2, 56.4, 102.1,
2H); 13C NMR (100 MHz, DMSO-d6):
d = 26.9, 28.2, 34.8, 35.6, 49.9,
57.1, 112.1, 119.3, 123.6, 128.6, 146.3, 152.2, 158.7, 163.1, 195.8.
2-Amino-4-(4-methoxyphenyl)-7,7-dimethyl-5-oxo-5,6,7,8-
tetrahydro-4H-chromene-3-carbonitrile (6i). Yellow solid; mp:
200–202 8C; 1H NMR (400 MHz, DMSO-d6):
d = 0.95 (s, 3H), 1.04 (s,
d
112.3, 113.8, 120.6, 127.2, 129.5, 129.8, 135.6, 143.4, 148.7, 156.9,
160.1.
2-Amino-3-cyano-7-hydroxy-4-(4-methoxyphenyl)-4H-
chromene (4j). Yellow solid, mp: 110–112 8C. IR (KBr): 3424, 3333,
3H), 2.09 (d, J = 16.2 Hz, 1H), 2.24 (d, J = 16.2 Hz, 1H), 2.51 (s, 2H),
3.72 (s, 1H), 4.13 (s, 1H), 6.84 (d, J = 8.1 Hz, 2H), 6.94 (s, 2H), 7.06 (d,
2190, 1651, 1587 cmÀ1. 1H NMR (400 MHz, DMSO-d6):
d
= 3.51 (s,
3H), 4.53 (s, 1H), 6.84 (br s, 2H, NH2), 6.43–7.21 (m, 7H), 9.63 (br s,
1H, OH). 13C NMR (100 MHz, DMSO-d6):
= 41.3, 55.8, 56.0, 102.2,
J = 8.1 Hz, 2H); 13C NMR (100 MHz, DMSO-d6):
d = 26.8, 28.4, 31.7,
34.8, 50.1, 54.9, 58.5, 112.9, 113.6, 119.7, 128.2, 136.8, 158.1, 158.5,
162.1, 195.6.
d
112.3, 113.5, 120.6, 126.4, 129.7, 136.5, 142.0, 148.4, 152.7, 156.8,
160.4.
Acknowledgment
2-Amino-3-cyano-7-hydroxy-4-(4-dimethylaminophenyl)-
4H-chromene (4k). Yellow solid, mp: 193–195 8C. IR (KBr): 3415,
This research is supported by the Islamic Azad University,
Ayatollah Amoli Branch.
3330, 2190, 1654, 1585 cmÀ1 1H NMR (400 MHz, DMSO-d6):
.
d
= 2.84 (s, 6H), 4.46 (s, 1H), 6.77 (br s, 2H, NH2), 6.37–6.97 (m, 7H),
9.66 (br s, 1H, OH). 13C NMR (100 MHz, DMSO-d6):
d
= 41.2, 42.2,
References
56.8, 101.9, 112.1, 112.5, 114.4, 120.7, 127.8, 129.8, 134.1, 148.7,
149.2, 156.7, 159.9.
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2-Amino-3-cyano-7-hydroxy-4-(2-thienyl)-4H-chromene
(4 m). Yellow solid, mp: 204–205 8C. IR (KBr): 3422, 3332, 2193,
1653, 1568 cmÀ1
.
1H NMR (400 MHz, DMSO-d6):
d
= 4.97 (s, 1H),
6.91 (br s, 2H, NH2), 6.38–7.35 (m, 6H), 9.76 (br s, 1H, OH). 13C NMR
(100 MHz, DMSO-d6): = 41.4, 56.4, 102.2, 112.4, 113.4, 120.5,
d
124.0, 125.0, 126.7, 129.8, 148.5, 151.5, 157.4, 160.3.
2-Amino-3-cyano-7-hydroxy-4-(2-furyl)-4H-chromene (4n).
Yellow solid, mp: 189–191 8C. IR (KBr): 3420, 3331, 2193, 1651,
1589 cmÀ1. 1H NMR (400 MHz, DMSO-d6):
d
= 4.75 (s, 1H), 6.92 (br
s, 2H, NH2), 6.13–7.50 (m, 6H), 9.74 (br s, 1H, OH). 13C NMR
(100 MHz, DMSO-d6): = 39.4, 53.2, 102.3, 105.4, 110.2, 111.0,
d
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