Synthesis of pyran annulated heterocyclic scaffolds: A highly convenient protocol using dimethylamine

Article abstract of DOI:10.1007/s11164-014-1873-5

A facile and rapid three-component synthesis of pharmaceutically diverse pyran annulated heterocycles has been developed via a one-pot condensation of aromatic aldehydes, malononitrile, and different enolizable C-H-activated acidic compounds in the presen

Full text of DOI:10.1007/s11164-014-1873-5

Res Chem Intermed
DOI 10.1007/s11164-014-1873-5
Synthesis of pyran annulated heterocyclic scaffolds:
a highly convenient protocol using dimethylamine
Rathinam Ramesh Appaswami Lalitha
•
Received: 26 September 2014 / Accepted: 13 November 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract A facile and rapid three-component synthesis of pharmaceutically
diverse pyran annulated heterocycles has been developed via a one-pot condensa-
tion of aromatic aldehydes, malononitrile, and different enolizable C–H-activated
acidic compounds in the presence of dimethylamine as a newer and effective org-
ano-catalyst in ethanol under mild reaction conditions. Selectivity of various pyran
derivatives depends on the structure of enolates. The present protocol has synthetic
advantages of excellent yields in much shorter reaction times with no
chromatography.
Keywords Three-component reaction ꢀ Pyran annulated heterocycles ꢀ Click
synthesis ꢀ Dimethylamine
Introduction
The development of newer synthetic methodologies for the construction of
heterocyclic scaffolds is a fast-developing area in the field of drug-delivery
research. Dihydropyran derivatives are ‘privileged’ structural motifs, which
constitute the significant core of several natural products [1]. They exhibit potential
activities against TNF-mediated diseases such as, Alzheimer’s disease, amyotrophic
lateral sclerosis, Parkinson and Huntington diseases [2, 3]. In addition, 2-amino-4H-
pyrans bearing nitrile functionality show greater applications in the treatment of
psoriatic arthritis, rheumatoid arthritis, and cancer therapy [4–7] and are also useful
intermediates for the synthesis of diverse organic molecules such as, pyridones,
lactones, imidoesters, and aminopyrimidines [8, 9]. It is valuable to reveal that a
R. Ramesh ꢀ A. Lalitha (&)
Department of Chemistry, Periyar University, Periyar Palkalai Nagar, Salem 636 011, Tamil Nadu,
India
e-mail: lalitha2531@yahoo.co.in
123

R. Ramesh, A. Lalitha
number of drug molecules containing 4H-pyran moiety are used in the treatment of
several disorders, such as asthma, ischemia, hypertension, and urinary incontinence
[
10–14]. Very interestingly, 4H-pyrans can be converted into pyridine analogues,
which are related to the calcium antagonists of the dihydropyridines [15, 16]. Due to
the wide applications of the pyran nucleus, a number of synthetic methods have
been reported with catalysts like, DMAP [17], K PO [18], CaCl [19], piperazine
3
4
2
[
20], NH –SiO [21], SBSSA [22], lactose [23], etc., many of them suffered from
2 2
any one of the demerits such as, prolonged reaction times, expensive catalysts, low
yields, and harsh reaction conditions. Hence, still there is a need for the
development of alternate high-yielding newer methodologies using very inexpen-
sive catalysts under mild reaction conditions. In this paper, we report for the first
time the dimethylamine catalyzed one-pot, click synthesis of pyran annulated
heterocyclic compounds in excellent yields.
Experimental
Reagents and equipment
All of the reagents and solvents were purchased from commercial sources and were
freshly used after being purified by standard techniques. Reactions were monitored
by TLC using silica gel pre-coated plates with ethyl acetate/hexanes as the mobile
phase. Melting points were measured using an Electrothermal apparatus and are
1
uncorrected. H NMR spectra were recorded on a Bruker DRX-300 spectrometer at
3
TMS (0 ppm) as an internal standard. C NMR spectra were recorded at 75 MHz
00 MHz and were referenced to the solvent (DMSO-d at 2.51 ppm) relative to
6
1
3
and were referenced to the solvent (DMSO-d at 39.49 ppm). Infrared spectra were
6
recorded on a Bruker FT-IR27 spectrometer using KBr pellets.
General procedure for the synthesis of pyran annulated heterocycles
To a stirred mixture of aromatic aldehyde (2.0 mmol) and malononitrile (2.0 mmol)
in ethanol (10 ml), a catalytic amount of DMA (5 mol%) was added at room
Table 1 Optimization of suitable solvent for the synthesis of 4b
a
Entry
Solvent
CH OH
Time (min)
Yield (%)
1
2
3
4
5
6
3
12
4
89
98
81
83
86
74
EtOH
i-PrOH
30
45
17
45
2
H O
EtOH:H
2
O(1:1)
CH CN
3
Reaction conditions: 4-chlorobenzaldehyde, malononitrile, dimedone (2 mmol each) and DMA (5 mol%)
in ethanol (10 ml) at room temperature
a
Isolated yield of 4b
1
23

Synthesis of pyran annulated heterocyclic scaffolds
temperature. To the precipitated solid materials, ethanolic solution of dimedone or
ethyl acetoacetate or barbituric acid (2.0 mmol) was added and from the resulting
solution, the products get precipitated within the time mentioned in Tables 1, 2, 3,
and 4. For 4H-benzo[h]chromenes, 1-naphthol (2.0 mmol) was added to the
arylidenemalononitrile and stirred at 70 °C until the solid appeared. The products
were filtered, air-dried, and recrystallized from ethanol.
Spectral data
0
2
3
-Amino-4-(4-fluorophenyl)-7,7 -dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-
-carbonitrile (4c)
-
1
Colorless crystals; mp 186–188 °C; IR (KBr) (mmax, cm ) 3,371, 3,318 (NH2),
1
2
,208 (CN), 1,687 (C=O), 1,248 (C–O–C); H NMR (300 MHz, DMSO-d ) d
6
(
(
ppm): 0.94 (s, 3H, CH ), 1.03 (s, 3H, CH ), 2.13 (d, 2H, CH , J = 16.2 Hz), 2.28
3 3 2
d, 2H, CH , J = 16.2 Hz), 4.21 (s, 1H, CH) 7.02 (s, 2H, NH ), 7.13 (d, 2H, ArH,
2
2
1
3
J = 8.7 Hz), 7.18 (d, 2H, ArH, J = 8.7 Hz); C NMR (75 MHz, DMSO-d ) d
6
(
ppm): 26.80, 28.28, 31.74, 34.89, 49.94, 58.14, 112.59, 114.84, 119.58, 128.95,
40.86, 158.47, 159.27, 162.47, 195.68.
1
0
2-Amino-7,7 -dimethyl-4-(3-nitrophenyl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-
carbonitrile (4i)
-
1
Colorless crystals; mp 214–216 °C; IR (KBr) (mmax, cm ) 3,382, 3,319 (NH2),
1
2
,198 (CN), 1,689 (C=O), 1,246 (C–O–C); H NMR (300 MHz, DMSO-d ) d
6
0
Table 2 Synthesis of 2-amino-7,7 -dimethyl-5-oxo-tetrahydro-4H-chromene-3-carbonitriles
a
Product 4(a–k)
b
Entry
R
Time (min)
Yield (%)
M.p. (°C)
Found
Reported (Refs.)
1
2
3
4
5
6
7
8
9
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
6
4
95
98
97
97
93
96
94
92
96
95
95
228–230
212–214
186–188
180–182
200–202
218–220
196–198
232–234
214–216
210–212
228–230
232–233 [20]
213–215 [20]
189–191 [20]
183–185 [20]
203–204 [20]
219–220 [20]
201–202 [20]
238–240 [24]
214–216 [20]
214–215 [20]
232–233 [20]
4-Cl
4-F
5
4-NO
4-OH
4-Br
2
5
9
6
4-OMe
3-OH
7
10
6
3-NO
2
1
1
a
0
2-Cl
4j
7
1
2-NO
2
4k
6
0
Synthesis of 2-amino-7,7 -dimethyl-5-oxo-tetrahydro-4H-chromene-3-carbonitrile derivatives. Reac-
tion conditions: aldehyde (2.0 mmol), malononitrile (2.0 mmol), DMA (5 mol%), and dimedone
2.0 mmol) at RT
(
b
Isolated yield
123

R. Ramesh, A. Lalitha
Table 3 Synthesis of 6-amino-5-cyano-4H-pyran-3-carboxylates
a
Product 6(a–k)
b
Entry
R
Time (min)
Yield (%)
M.p. (°C)
Found
Reported (Refs.)
1
2
3
4
5
6
7
8
9
H
6a
6b
6c
6d
6e
6f
8
6
93
96
94
96
92
95
92
90
95
95
94
188–190
174–176
172–174
170–172
192–194
176–178
138–140
158–160
178–180
190–192
178–180
191–192 [20]
174–175 [20]
170–172 [20]
174–176 [20]
196 [25]
4-Cl
4-F
7
4-NO
4-OH
4-Br
2
7
10
8
176–178 [20]
136–137 [20]
162–164 [26]
183–185 [20]
191–193 [20]
180–181 [20]
4-OMe
3-OH
6g
6h
6i
9
11
8
3-NO
2-Cl
2
1
1
a
0
6j
9
1
2-NO
2
6k
8
Synthesis of 6-amino-5-cyano-4H-pyran-3-carboxylates. Reaction conditions: aldehyde (2.0 mmol),
malononitrile (2.0 mmol), DMA (5 mol %), and ethyl acetoacetate (2.0 mmol) at RT
b
Isolated yield
Table 4 Synthesis of 7-amino-2,4-dioxo-tetrahydro-1H-pyrano[2,3-d]pyrimidine-6-carbonitrile derivatives
a
Product 8(a–k)
b
Entry
R
Time (min)
Yield (%)
M.p. (°C)
Found
Reported (Refs.)
1
2
3
4
5
6
7
8
9
H
8a
8b
8c
8d
8e
8f
20
15
16
15
25
16
25
25
15
18
18
90
93
92
93
88
92
89
87
92
91
91
220–222
238–240
218–220
236–238
[300
222–224 [27]
4-Cl
4-F
242–243 [27]
–
4-NO
4-OH
4-Br
2
237–238 [27]
[300 [27]
208–210
252–254
202–204
248–250
204–206
216–218
–
–
–
–
–
–
4-OMe
3-OH
8g
8h
8i
3-NO
2-Cl
2
1
1
a
0
1
8j
2-NO
2
8k
Synthesis of 7-amino-2,4-dioxo-tetrahydro-1H-pyrano[2,3-d]pyrimidine-6-carbonitriles. Reaction conditions:
aldehyde (2.0 mmol), malononitrile (2.0 mmol), DMA (5 mol %), and barbituric acid (2.0 mmol) at RT
b
Isolated yield
(
ppm): 0.96 (s, 3H, CH ), 1.05 (s, 3H, CH ), 2.15 (d, 2H, CH , J = 16.2 Hz), 2.30
3 3 2
(
J = 5.7 Hz), 7.99 (s, 1H, ArH), 8.09 (t, 1H, ArH, J = 6.3 Hz); C NMR (75 MHz,
d, 2H, CH , J = 15.9 Hz), 4.43 (s, 1H, CH) 7.18 (s, 2H, NH ), 7.67 (d, 2H, ArH,
1
2
2
3
DMSO-d ) d (ppm): 26.71, 28.29, 31.79, 35.41, 49.85, 57.22, 111.77, 119.31,
6
1
21.64, 121.74, 129.98, 134.15, 146.97, 147.76, 158.62, 163.13, 195.72.
1
23

Synthesis of pyran annulated heterocyclic scaffolds
Ethyl-6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylate (6a)
-
1
Light yellowish white crystals; mp 188–190 °C; IR (KBr) (mmax, cm ) 3,404, 3,329
1
(
NH ), 2,190 (CN), 1,694 (C=O), 1,260 (C–O–C); H NMR (300 MHz, DMSO-d )
2 6
d (ppm): 1.02 (t, 3H, CH , J = 7.2 Hz), 2.31 (s, 3H, CH ), 3.95 (q, 2H, CH ,
3
3
2
J = 3.6 Hz), 4.29 (s, 1H, CH), 6.90 (s, 2H, NH ), 7.15 (d, 2H, ArH, J = 7.8 Hz),
7
2
1
.21 (t, 1H, ArH J = 7.5 Hz), 7.31 (t, 2H, ArH, J = 7.5 Hz); C NMR (75 MHz,
3
DMSO-d ) d (ppm): 13.68, 18.09, 38.93, 57.23, 60.11, 107.22, 119.68, 126.77,
6
1
27.15, 128.40, 144.85, 156.55, 158.44, 165.41.
Ethyl-6-amino-5-cyano-2-methyl-4-(3-nitrophenyl)-4H-pyran-3-carboxylate (6i)
-
1
Colorless crystals; mp 178–180 °C; IR (KBr) (mmax, cm ) 3,396, 3,325 (NH2),
1
2
,197 (CN), 1,688 (C=O), 1,252 (C–O–C); H NMR (300 MHz, DMSO-d ) d
6
(
J = 6.6 Hz), 4.53 (s, 1H, CH), 7.10 (s, 2H, NH ), 7.64 (d, 2H, ArH, J = 7.5 Hz),
ppm): 1.02 (t, 3H, CH , J = 7.2 Hz), 2.35 (s, 3H, CH ), 3.97 (q, 2H, CH ,
3 3 2
2
1
3
7
.99 (s, 1H, ArH), 8.12 (t, 1H, ArH, J = 3.6 Hz); C NMR (75 MHz, DMSO-d ): d
6
(
ppm) 13.61, 18.27, 38.91, 56.31, 60.30, 106.22, 119.33, 121.70, 121.95, 130.16,
34.17, 147.32, 147.75, 157.78, 158.62, 165.06.
1
7-Amino-5-(4-chlorophenyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrano[2,3-d]
pyrimidine-6-carbonitrile (8b)
-
1
White solid; mp 238–240 °C; IR (KBr) (m , cm ) 3,388, 3,327 (NH ), 3,170 (N–H),
max
2
1
,195 (CN), 1,715 (C=O), 1,487 (C–N), 1,247 (C–O–C); H NMR (300 MHz, DMSO-d )
2
6
d (ppm): 4.24 (s, 1H, CH), 7.17 (s, 2H, NH ), 7.23 (d, 2H, ArH, J = 5.8 Hz), 7.34 (d, 2H,
2
13
ArH, J = 5.8 Hz), 11.12 (s, 1H, NH), 11.96 (s, 1H, NH); C NMR (75 MHz, DMSO-d )
6
d (ppm): 35.50, 58.67, 88.44, 119.49, 128.64, 129.69, 131.71, 149.47, 149.91, 152.74,
158.04, 162.95.
7-Amino-5-(4-nitrophenyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrano[2,3-d]
pyrimidine-6-carbonitrile (8d)
-
1
White solid; mp 236–238 °C; IR (KBr) (m , cm ) 3,380, 3,322 (NH ), 3,181 (N–H),
max
2
1
,197 (CN), 1,698 (C=O), 1,483 (C–N), 1,245 (C–O–C); H NMR (300 MHz, DMSO-d )
2
6
d (ppm): 4.41 (s, 1H, CH), 7.19 (s, 2H, NH ), 7.57 (d, 2H, ArH, J = 8.7 Hz), 8.12 (d, 2H,
2
13
ArH, J = 8.7 Hz), 11.13 (s, 1H, NH), 12.16 (s, 1H, NH); C NMR (75 MHz, DMSO-d )
d (ppm): 35.54, 58.12, 87.39, 119.08, 124.92, 130.36, 146.62, 149.71, 151.73, 152.76,
6
157.37, 162.58.
2
-Amino-4-(4-chlorophenyl)-4H-benzo[h]chromene-3-carbonitrile (10b)
-
1
White solid; mp 230–232 °C; IR (KBr) (mmax, cm ) 3,394, 3,337 (NH ), 2,206
2
1
(
CN), 1,667 (C=O), 1,283 (C–O–C); H NMR (300 MHz, DMSO-d ) d (ppm): 4.84
6
(
ArH), 7.48 (d, 2H, ArH, J = 9.0 Hz), 7.77 (d, 2H, ArH, J = 9.0 Hz), 8.27 (d, 1H,
s, 1H, CH), 6.42 (s, 2H, NH ), 7.06 (d, 1H, ArH, J = 9.0 Hz), 7.24–7.28 (m, 4H,
2
123

R. Ramesh, A. Lalitha
1
3
ArH, J = 6.0 Hz); C NMR (75 MHz, DMSO-d ) d (ppm): 39.12, 55.73, 119.80,
6
1
20.22, 122.14, 122.36, 123.62, 125.53, 125.87, 126.55, 127.63, 128.21, 129.84,
32.73, 133.90, 142.36, 146.98, 160.42.
1
2
-Amino-4-(4-nitrophenyl)-4H-benzo[h]chromene-3-carbonitrile (10d)
-
1
White solid; mp 186–188 °C; IR (KBr) (mmax, cm ) 3,387, 3,329 (NH ), 2,196
2
1
(
CN), 1,663 (C=O), 1,278 (C–O–C); H NMR (300 MHz, DMSO-d ) d (ppm): 4.79
6
(
ArH), 7.49 (d, 2H, ArH, J = 9.0 Hz), 7.68 (d, 2H, ArH, J = 9.0 Hz), 8.24 (d, 1H,
s, 1H, CH), 6.47 (s, 2H, NH ), 6.92 (d, 1H, ArH, J = 9.0 Hz), 7.31–7.36 (m, 4H,
2
1
3
ArH, J = 6.0 Hz); C NMR (75 MHz, DMSO-d ) d (ppm): 38.92, 55.32, 118.98,
6
1
21.02, 122.21, 122.42, 123.57, 125.48, 125.13, 125.94, 127.42, 128.54, 130.68,
32.03, 134.12, 142.53, 147.62, 161.28.
1
Results and discussion
To optimize reaction conditions, the experiment was initially carried out with
4-chlorobenzaldehyde (3b) and malononitrile (2) in ethanol containing two drops of
dimethylamine as an organo-base catalyst. The resulting solution has been stirred at
room temperature where the 2-benzylidenemalononitrile was formed as a solid within
0
2 min, to which an ethanolic solution of 5,5 -dimethylcyclohexane-1,3-dione or
dimedone (1) was added, resulting in a clear solution. The product, 2-amino-4-(4-
0
chlorophenyl)-7,7 -dimethyl-5-oxo-tetrahydro-4H-chromene-3-carbonitrile (4b) pre-
cipitated within 2 min with high purity, but in the absence of DMA, the reaction was
sluggish with low conversions.
In order to fix a suitable reaction medium and amount of catalyst, the model reaction
was performed with different solvents such as, methanol, ethanol, 2-propanol,
acetonitrile, and water, and it was observed that ethanol would be the best medium
yielding 98 % of 4b with 5 mol% of the catalyst. Further increase in the quantity of
catalyst did not show any significant change on the yield and reaction time. With these
optimized reaction conditions, various aromatic aldehydes (3a–k) were utilized to
synthesize a series of 2-amino-tetrahydro-4H-chromenes (Scheme 1).
From the results shown in Table 2, it is evident that almost all the studied
aldehydes bearing both electron-withdrawing and electron-donating substituents
provided a very good yield of the corresponding tetrahydro-4H-chromenes. The
formation of the cyclized tetrahydro-4H-chromene derivatives was confirmed by the
1
H NMR spectrum in which the two singlets at 0.94 and 1.03 ppm indicate the two
Scheme 1 Synthesis of
2-amino-tetrahydro-4H-
chromene-3-carbonitrile
derivatives
1
23

Synthesis of pyran annulated heterocyclic scaffolds
methyl groups of the dimedone moiety, another singlet at d 4.21 ppm corresponds to
the (–CH–) methine proton and the peak at d 7.02 ppm as singlet represents the
-
-
1
1
existence of an amino group. The IR spectrum shows a strong peak at 2,208 cm
that specifies the nitrile functionality and peaks at 3,371 and 3,318 cm
representing the presence of free NH group.
2
In continuation of this multicomponent reaction, we have also tried to examine
the catalytic efficiency of DMA with other C–H-activated acidic compounds such as
ethyl acetoacetate (5) and barbituric acid (7) under the above optimized reaction
conditions, where also good yields of the corresponding pyran derivatives (6a–k)
and (8a–k) have been observed and the results are summarized in Tables 3 and 4
(
Scheme 2 and 3).
In the case of 1-naphthol (9), the reaction proceeded smoothly at higher
temperature and the best results (10a–k) were achieved while refluxing the reaction
mixture at 70 °C (Table 5; Scheme 4). From the results obtained in all the cases, it
is clear to state that the reaction proceeded in a rapid manner and provided excellent
yields with higher purity. All the synthesized pyran annulated heterocycles were
1
13
characterized by IR, H NMR, C NMR, and their melting points compared with
literature.
A plausible mechanism for the three-component synthesis of pyran annulated
heterocycles using DMA in ethanol has been proposed in Scheme 5. Initially,
aromatic aldehyde was made to react with malononitrile in the presence of catalyst
to provide the Knoevenagel product, i.e., arylidenemalononitrile (I). Then, ethanolic
solution of diketone was added to the reaction mixture, leading to the Michael
addition with the arylidenemalononitrile followed by cyclization where the reaction
occurs very rapidly, and within a few minutes resulting in the formation of highly
pure target molecule (III).
Scheme 2 Synthesis of
6-amino-5-cyano-4H-pyran-3-
carboxylate derivatives
Scheme 3 Synthesis of
7-amino-2,4-dioxo-tetrahydro-
1H-pyrano[2,3-d]pyrimidine-6-
carbonitriles
123

R. Ramesh, A. Lalitha
Table 5 Synthesis of 2-amino-4H-benzo[h]chromene-3-carbonitriles
a
Product 10(a–k)
b
Entry
R
Time (min)
Yield (%)
M.p. (°C)
Found
Reported (Refs.)
1
2
3
4
5
6
7
8
9
H
10a
10b
10c
10d
10e
10f
10g
10h
10i
6
4
5
4
8
5
8
8
5
6
6
92
96
95
95
89
96
90
90
94
92
93
210–212
230–232
228–230
186–188
240–242
242–244
174–176
224–226
202–204
236–238
206–208
215–217 [28]
230–232 [29]
236–237 [30]
188–189 [31]
246–248 [30]
239–241 [30]
176–179 [29]
250–253 [28]
208–211 [29]
250–251 [32]
209–210 [33]
4-Cl
4-F
4-NO
4-OH
4-Br
2
4-OMe
3-OH
3-NO
2
1
1
a
0
2-Cl
10j
1
2-NO
2
10k
Synthesis of 2-amino-4H-benzo[h]chromene-3-carbonitriles. Reaction conditions: aldehyde
2.0 mmol), malononitrile (2.0 mmol), DMA (5 mol%), and 1-naphthol (2.0 mmol) at 70 °C
(
b
Isolated yield
Scheme 4 Synthesis of
2-amino-4H-benzo[h]chromene-
3-carbonitrile derivatives
Scheme 5 A plausible mechanism for the formation of pyran annulated heterocycles
Conclusions
In summary, we have finely developed a rapid and newer protocol for the synthesis
of tetrahydro-4H-chromene, 4H-pyran, 1H-pyrano[2,3-d]pyrimidine, and 4H-
benzo[h]chromene derivatives under mild reaction conditions via a one-pot,
three-component reaction using 5 mol% of dimethylamine as an effective organo-
catalyst. The present method offers notable advantages, such as, high atom-
economy, easy isolation of products, and operational simplicity, which makes the
methodology an important technique for the synthesis of valuable O-heterocycles.
1
23

Synthesis of pyran annulated heterocyclic scaffolds
Further applications of densely functionalized pyran derivatives of this protocol are
under progress in our laboratory.
Acknowledgments R. R. gratefully acknowledges the financial support from DST-Inspire Fellowship
(No: DST/INSPIRE Fellowship/2012/690), New Delhi, India.
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