A facile, one-pot, green synthesis of polysubstituted 4H-pyrans via piperidine-catalyzed three-component condensation in aqueous medium

Article abstract of DOI:10.1002/jhet.528

An efficient, one-pot method was described for the synthesis of various polysubstituted 4H-pyrans via piperidine catalyzed three-component condensation in aqueous medium. The reaction could be promoted effectively by adding sodium dodecyl sulfate to aqueo

Full text of DOI:10.1002/jhet.528

1
24
A Facile, One-Pot, Green Synthesis of Polysubstituted 4H-Pyrans
via Piperidine-Catalyzed Three-Component Condensation in
Aqueous Medium
Vol 48
Guo-Ping Lu and Chun Cai*
School of Chemical Engineering, Nanjing University of Science and Technology,
Nanjing 210094, China
*
E-mail: c.cai@mail.njust.edu.cn
Received January 27, 2010
DOI 10.1002/jhet.528
Published online 9 September 2010 in Wiley Online Library (wileyonlinelibrary.com).
An efficient, one-pot method was described for the synthesis of various polysubstituted 4H-pyrans via
piperidine catalyzed three-component condensation in aqueous medium. The reaction could be promoted
effectively by adding sodium dodecyl sulfate to aqueous medium.
J. Heterocyclic Chem., 48, 124 (2011)
INTRODUCTION
To replace organic solvent with nontoxic and cheap
water, many efforts have been made to synthesize poly-
substituted 4H-pyrans [17–22]; however, most of proce-
dures have merits, including long reaction time, harsh
conditions, tedious work-up procedures, cost of catalysts,
and so on. In an attempt to design a facile, pronounced
protocol to synthesize polysubstituted 4H-pyrans in water,
we have found piperidine to be an effective catalyst for
the synthesis of these compounds in aqueous medium via
a one-pot, three-component reaction (Scheme 1).
The chemical industry is one of the major contributors
to environment pollution, owing to the use of hazardous
chemicals and, in particular, large amounts of flammable,
volatile, and toxic organic solvents. Therefore, green
chemistry that emphasizes on the development of envi-
ronmentally benign chemical processes and technologies
has attracted much attention in recent years [1,2]. On one
hand, designing organic reactions in aqueous medium is
one of the most attractive areas in green chemistry [3–6].
Water as an abundant and environmentally benign solvent
offers several benefits including simple work-up proce-
dure, unique reactivity and selectivity, and so on.
RESULTS AND DISCUSSION
On the other hand, the multicomponent reaction has
become popular in the synthesis of heterocyclic compo-
nents due to its simple experimentations and atom econ-
omy [7,8]. Polysubstituted 4H-pyrans as an important
class of heterocyclic components present in many natu-
ral or synthetic compounds with important biological or
pharmacological activities such as antibacterial [9], anti-
cancer [10], and antiallergic [11]. Many methods such
as ionic liquid [12], solid base [13], Lewis acid [14,15],
and electrochemistry [16] have been used to synthesize
polysubstituted 4H-pyrans, but a lot of methods use vol-
atile and toxic organic solvents, which are the major
pollution source in chemical industry.
Initially, the reaction of benzaldehyde, malononitrile,
and ethylacetoacetate was selected as a model reaction to
optimize the reaction conditions (Table 1). When the reac-
tion was carried out in water with different catalysts
(Table 1, entries 1–5), it was found that piperidine was
more effective than other catalysts and a moderate yield
of 77% could be obtained after 1 h (Table 1, entry 5).
With the aim of improving the unsatisfactory reaction
yields, surfactants were added to the reaction. Remark-
ably, when sodium dodecyl sulfate (SDS) was subjected
to form a ensure adequate mixing by stirring for 5 min,
and then piperidine was added, a good yield of 85% was
obtained after 10 min (Table 1, entry 7), indicating that
V
C
2010 HeteroCorporation

January 2011
A Facile, One-Pot, Green Synthesis of Polysubstituted 4H-Pyrans via Piperidine-
Catalyzed Three-Component Condensation in Aqueous Medium
125
Scheme 1. The synthesis of polysubstituted 4H-pyrans catalyzed by piperidine in aqueous medium.
SDS could promote the reaction in water due to lower
mass transfer resistance and enlargement of the interfacial
area [23–25]. By changing the amount of piperidine from
possibility for large-scale operation, we also scaled up the
reaction to 40 mmol and the reaction proceeded well with
82% yield of the desired product (Table 1, entry 10).
With the optimized conditions in hand, various substi-
tuted benzaldehydes were used to explore the generality
and scope of this protocol (Table 2, entries 1–5). For
benzaldehydes with electron-withdrawing groups, the
1
0 to 5 mol %, the reaction yield was decreased to 72%
and only trace product was obtained in the absence of pi-
peridine (Table 1, entries 7–9), so 10 mol % of piperidine
was selected as catalyst in further studies. To show the
Table 1
Optimization of the reaction conditions.
a
b
Entry
Time
Catalyst (10 mol %)
Additive (0.1 g)
Yield (%)
1
2
3
4
5
6
7
8
5 h
5 h
5 h
5 h
1 h
1 h
KF/Al
MgO
L-proline
/KI/K CO
Piperidine
Piperidine
Piperidine
–
2
O
3
–
–
–
Trace
40
Trace
Trace
77
I
2
2
3
–
–
TX10
SDS
SDS
SDS
SDS
58
85
Trace
72
82
10 min
12 h
10 min
10 min
c
9
Piperidine
Piperidine
d
10
a
b
c
d
ꢀ
Reaction condition: benzaldehyde (2 mmol), malononitrile (2 mmol), ethylacetoacetate (2 mmol), catalyst (0.2 mmol), H
Isolated yield of product.
2
O (3 mL), 100 C.
5
The reaction was performed with 40 mmol benzaldehyde, 40 mmol malononitrile, 40 mmol ethylacetoacetate, 4 mmol piperidine, 2 g SDS,
mol % of piperidine was used.
ꢀ
6
0 mL H
2
O, 100 C.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1
26
G.-P. Lu and C. Cai
Vol 48
Table 2
a
Synthesis of various 2-amino-4H-pyrans and tetrahydro-4H-chromenes in aqueous medium.
ꢀ
1
b
ꢀ
Mp ( C)/(lit)
Entry
Time (min)
Temperature ( C)
Diketone
R
Product
Yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
10
10
10
10
60
5
100
100
100
100
100
80
80
80
80
80
2
2
2
2
2
3
3
3
3
3
3
3
H
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
7f
85
87
74
72
42
90
91
87
84
74
66
90
192–194 (195–196) [9]
180–182 (180–183) [9]
172–174 (172–174) [9]
172–174
4-O
2
N
4-Cl
4-Br
4-MeO
H
4-Cl
4-MeO
140–142 (142–144) [9]
228–230 (229–231) [22]
208–210 (208–210) [22]
198–200 (199–201) [22]
176–178 (177–178) [22]
212–214 (214–215) [22]
218–220 (220–222) [22]
216–218 (217–218) [22]
5
5
5
4-O
4-OH
4-(CH
2-Cl
2
N
0
1
2
5
5
80
80
3 2
) N
5
7g
a
2
Reaction condition: 1 (2 mmol), 5 (2 mmol), 2 or 3 (2 mmol), piperidine (0.2 mmol), SDS (0.1 g), H O (3 mL).
Isolated yield of product.
b
reactions were processed smoothly, but for benzalde-
Both 2-naphthol and 1-naphthol could react with various
benzaldehydes and give the desired products. Generally,
a prolonged reaction time was needed when benzalde-
hydes with electron-donating groups were used (Table
3, entries 3 and 8).
hydes containing electron-donating groups such as meth-
oxyl group, only a moderate yield of 42% could be
gained even after longer reaction time (Table 2, entry
5
), because the electron-donating group decreases the
activity of intermediate (arylidenemalononitrile), which
does not favor the following reaction to form the corre-
sponding 4H-pyran.
In an effort to expand the scope of the method, the
synthesis of diverse 2-amino-5-oxo-5,6,7,8-tetrahydro-
The scope of the protocol was also expanded to the
synthesis of various tetrahydrobenzo[a]xanthene-11-ones
successfully (Table 4). A test reaction using 2-naphthol,
compound 3, benzaldehyde in the presence of piperi-
ꢀ
dine/SDS in aqueous medium at 100 C was performed.
4
H-chromenes was undertaken (Table 2, entries 6–12).
To our delight, an excellent yield of 91% could be
obtained by simply prolonging the reaction time to 2 h
(Table 4, entry 1). The further investigations proved that
the reaction was not affected obviously by the character-
istic of the substituent group on benzaldehyde, when 2-
naphthol was used. However, 1-naphthol failed to give
the desired product even after 24 h (Table 4, entry 8).
In conclusion, we have developed a facile, green, and
effective method for the synthesis of polysubstituted
4H-pyrans catalyzed by piperidine in aqueous medium.
The procedure could be applied easily for large-scale
operation, owing to its simple operation, clear reaction
Because 3 is a more reactive methylene component
compared with ethylacetoacetate, various benzaldehydes
with electron-withdrawing or electron-donating groups
were used and reacted well to give the corresponding
4
H-pyrans in good yields after 5 min at lower tempera-
ture (Table 2, entries 6–11). The ortho-substituted benz-
aldehyde could also provide a satisfactory yield (Table
2
, entry 12).
The remarkable results obtained with the protocol
promoted us to use naphthols instead of ethylacetoace-
tate to synthesize polysubstituted 4H-pyrans (Table 3).
Table 3
Synthesis of various 2-amino-2-chromenes in aqueous medium.
a
1
b
ꢀ
Entry
Time (min)
Naphthol
R
Product
Yield (%)
Mp ( C)/(lit)
1
2
3
4
5
6
7
8
5
5
4a
4a
4a
4b
4b
4b
4b
4b
H
4-Cl
4-MeO
H
8a
8b
8c
8d
8e
8f
87
89
74
92
83
89
90
64
>270
206–208 (206–208) [19]
188–190 (190–191) [19]
204–206 (206–207) [19]
238–240 (239–241) [19]
230–232 (231–233) [19]
180–182 (182–183) [19]
202–204 (203–205) [19]
30
5
5
5
2
4-O N
4-Cl
4-MeO
5
30
8g
8h
3 2
4-(CH ) N
a
ꢀ
Reaction condition: 1 (2 mmol), 5 (2 mmol), 4a or 4b (2 mmol), piperidine (0.2 mmol), SDS (0.1 g), H
Isolated yield of product.
2
O (3 mL), 100 C.
b
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2011
A Facile, One-Pot, Green Synthesis of Polysubstituted 4H-Pyrans via Piperidine-
Catalyzed Three-Component Condensation in Aqueous Medium
127
Table 4
a
Synthesis of various tetrahydrobenzo[a]xanthene-11-ones in aqueous medium.
1
b
ꢀ
Mp ( C)/(lit)
Entry
Time (h)
R
Product
Yield (%)
1
2
3
4
5
6
7
2
1.5
1.5
3
H
4-Cl
9a
9b
9c
9d
9e
9f
91
92
85
89
77
88
90
150–152 (151–153) [26]
178–180 (180–182) [26]
176–178 (178–180) [26]
202–204 (204–205) [26]
200–202
4-O
2
N
4-MeO
2
3 2
4-(CH ) N
6
1.5
24
4-OH
2-Cl
H
222–224 (223–225) [26]
178–180 (179–180) [26]
–
9g
–
c
d
8
NR
a
ꢀ
2
Reaction condition: 1 (2 mmol), 3 (2 mmol), 4a (2 mmol), piperidine (0.2 mmol), SDS (0.1 g), H O (3 mL), 100 C.
Isolated yield of product.
1-Naphthol instead of 2-naphthol was used.
No reaction.
b
c
d
þ
profile, short reaction time, and high yields. In addition,
the reaction system could be successfully applied to a
variety of substrates to synthesize a wide variety of
polysubstituted 4H-pyrans in good to excellent yields.
(ES ) m/z 285 (M þ H). Anal. Calcd. for C16
H
16
N
2
O
3
: C,
7.59; N, 9.85; H, 5.67. Found: C, 67.49; N, 9.89; H, 5.87.
Compound 7a, 2-amino-7,7-dimethyl-5-oxo-4-phenyl-
6
5
6
2
,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (Table 2, entry
). Recrystallized from EtOH. Light yellow solid; m.p. 228–
ꢀ
1
6
30 C; 99% pure by LC-MS; H-NMR (300 MHz, DMSO-d ):
d ¼ 0.98 (s, 3H, ACH ), 1.06 (s, 3H, ACH ), 2.12 (d, 1H,
EXPERIMENTAL
3
3
J ¼ 16.1 Hz, ACH(H)A), 2.28 (d, 1H, J ¼ 16.1 Hz, ACH(H)
A), 2.52 (m, 2H, A(CH )A), 4.19 (s, ACH(C)A), 7.05 (s,
ANH ), 7.15–7.23 (m, 3H, aromatic), 7.29–7.34 (m, 2H, aro-
matic); C-NMR (75 MHz, DMSO-d
All reagents were obtained from commercial suppliers and
used without further purification. All melting points are deter-
mined uncorrected. Mass spectra were taken on a Agilent Liquid
chromatography-mass spectrometry (LC-MS) 1100 series instru-
ment in the electrospray ionization [positive electrospray ioniza-
2
2
13
6
): d ¼ 26.96, 28.54,
31.92, 35.74, 39.86, 50.15, 58.53, 112.93, 119.83, 126.69,
127.29, 127.30, 128.45, 128.45, 144.88, 158.65, 162.60,
1
13
þ
tion (ESI)] mode. H- and C-NMR spectra were recorded at
00 and 75 MHz, respectively, in DMSO-d , and chemical shifts
195.73; MS (ES ) m/z 295 (M þ H). Anal. Calcd. for
3
6
18 18 2 2
C H N O : C, 73.45; N, 9.52; H, 6.16. Found: C, 73.67; N,
were reported in ppm from internal trimethylsilyl (TMS) (d). All
products were identified by comparing of their spectral data and
m.p. with those reported in the literature. Elemental analyses
were performed on a Yanagimoto MT3CHN recorder.
9.55; H, 6.01.
Compound 8f, 2-amino-4-(4-chlorophenyl)-4H-benzo[h]-
chromene-3-carbonitrile (Table 3, entry 6). Recrystallized
ꢀ
from EtOH. White solid; m.p. 230–232 C; 99% pure by LC-
1
MS; H-NMR (300 MHz, DMSO-d
General procedure for the synthesis of polysubstituted
aqueous
6
): d ¼ 4.98 (s, 1H,
4
H-pyrans
catalyzed
by
piperidine
in
ACH(C)A), 7.12 (d, 1H, J ¼ 8.5 Hz, aromatic), 7.25 (s, 2H,
medium. Benzaldehyde (2 mmol), malononitrile (2 mmol), eth-
ylacetacetate (2 mmol), SDS (0.1 g), and distilled water (3 mL)
were added to a 25-mL round-bottom flask. The mixture was
ANH ), 7.30 (d, 2H, J ¼ 8.4 Hz, aromatic), 7.41 (d, 2H, J ¼
2
8.4 Hz, aromatic); 7.58–7.70 (m, 3H, aromatic), 7.92 (d, 1H, J
13
¼ 7.9 Hz, aromatic), 8.26 (d, 1H, J ¼ 8.1 Hz, aromatic); C-
ꢀ
stirred for 5 min at 100 C, followed by adding piperidine (0.4
NMR (75 MHz, DMSO-d
120.86, 122.90, 124.14, 126.19, 126.85, 126.99, 127.82,
128.82, 128.83, 129.70, 129.71, 131.70, 132.91, 142.9, 144.78,
6
): d ¼ 40.37, 56.09, 117.54, 120.46,
mmol) and stirring under reflux for 10 min. After completion,
the reaction mixture was cooled to room temperature. The pre-
cipitated solid was collected by filtration, washed by water,
dried, and recrystallized from ethanol to afford the pure product
in 85% isolated yield. The reactions for other substrates to syn-
thesize corresponding polysubstituted 4H-pyrans were performed
in the similar procedures. Sometimes, the products were recrys-
2
tallized from EtOH/H O (1:1 v/v) instead of ethanol.
Selected spectroscopic data for some of compounds.
Compound 6a, ethyl 6-amino-5-cyano-2-methyl-4-phenyl-
þ
160.32; MS (ES ) m/z 333 (M þ H). Anal. Calcd. for
20 2
C H13ClN O: C, 72.18; N, 8.42; H, 3.94. Found: C, 72.27; N,
8.23; H, 3.84.
Compound 9e, 12-(4-dimethylaminophenyl)-9,9-dimethyl-
8,9,10,12-tetrahydrobenzo[a]xanthen-11-one (Table 4, entry
5). Recrystallized from EtOH/H O (1/1, v/v). White solid;
2
ꢀ
1
m.p. 200–202 C; 98% pure by LC-MS; H-NMR (300 MHz,
DMSO-d ): d ¼ 0.94 (s, 3H, ACH ), 1.09 (s, 3H, ACH ),
6
3
3
4H-pyran-3-carboxylate (Table 2, entry 1). Recrystallized
from EtOH. White solid; m.p. 192–194 C; 98% pure by LC-
2.14 (d, 1H, J ¼ 16.3 Hz, ACH(H)A), 2.35 (d, 1H, J ¼ 16.2
ꢀ
Hz, ACH(H)A), 2.60 (m, 2H, ACH A), 2.78 (s, 6H,
2
1
MS; H-NMR (300 MHz, DMSO-d
ACH ), 2.33 (s, 3H, ACH ), 3.98–4.00 (m, 2H, ACH
.31 (s, 1H, ACH(C) A), 6.95 (s, 2H, ANH ), 7.16–7.33 (m,
6
): d ¼ 1.02–1.07 (m, 3H,
AN(CH
3
)
2
), 5.46 (s, 1H, ACH(C)A), 6.54 (d, 2H, J ¼ 8.5 Hz,
3
3
2
A),
aromatic), 7.09 (d, 2H, J ¼ 8.5 Hz, aromatic), 7.41–7.54 (m,
3H, aromatic), 7.88–7.93 (m, 2H, aromatic), 8.06 (d, 1H, J ¼
4
5
1
1
2
13
þ
H, aromatic); C-NMR (75 MHz, DMSO-d ): d ¼ 14.08,
8.3 Hz, aromatic); MS (ES ) m/z 398 (M þ H). Anal. Calcd.
6
8.49, 39.15, 57.53, 60.53, 107.58, 120.10, 127.20, 127.56,
27.57, 128.81, 128.82, 145.25, 156.97, 158.78, 165.81; MS
2
for C27H27NO : C, 81.58; N, 3.52; H, 6.85. Found: C, 81.47;
N, 3.43; H, 6.82.
Journal of Heterocyclic Chemistry
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G.-P. Lu and C. Cai
Vol 48
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet