Rapid One-pot Aspartic Acid-promoted Synthesis of Tetrahydrobenzo[b]pyrans in Water

Full text of DOI:10.1080/00304948.2016.1194127

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
ISSN: 0030-4948 (Print) 1945-5453 (Online) Journal homepage: http://www.tandfonline.com/loi/uopp20
Rapid One-pot Aspartic Acid-promoted Synthesis
of Tetrahydrobenzo[b]pyrans in Water
Shohreh Ameli, Abolghasem Davoodnia & Mehdi Pordel
To cite this article: Shohreh Ameli, Abolghasem Davoodnia & Mehdi Pordel (2016)
Rapid One-pot Aspartic Acid-promoted Synthesis of Tetrahydrobenzo[b]pyrans
in Water, Organic Preparations and Procedures International, 48:4, 328-336, DOI:
10.1080/00304948.2016.1194127
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Date: 21 July 2016, At: 07:26

Organic Preparations and Procedures International, 48:328–336, 2016
Copyright Ó Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2016.1194127
Rapid One-pot Aspartic Acid-promoted Synthesis of
Tetrahydrobenzo[b]pyrans in Water
Shohreh Ameli, Abolghasem Davoodnia, and Mehdi Pordel
Department of Chemistry, Mashhad Branch, Islamic Azad University, Mashhad,
Iran
One-pot multi-component reactions (MCRs) have proven to be superior to conventional
linear type processes that usually suffer from complex isolation procedures, produce sig-
nificant amounts of waste materials, and low yields of the products.1–3 These MCRs may
be useful for drug design, discovery and synthesis of natural products because of their
simplicity, efficiency, and high selectivity.4,5 They consist of two or more steps which
are carried out without isolation of any intermediate. They also provide a rapid and effi-
cient approach to organic transformations including the preparation of polyfunctional-
ized heterocycles.6–8 Still, great efforts are being made to develop new MCRs and
improve known ones such as the synthesis of polyfunctionalized 4H-pyrans, especially
tetrahydrobenzo[b]pyrans.
Pyrans are a large group of heterocycles with diverse and interesting biological activ-
ities. These compounds are reported to possess anti-bacterial, anti-cancer, spasmolytic,
anti-coagulant, anti-anaphylactin, diuretic and anti-anaphylactic activities.9–14 A number
of them have also been employed as photo-active materials15 and constitute the structural
unit of a series of natural products.16 In addition, they can be utilized as cognitive
enhancers for the treatment of neuro-degenerative disease, including Alzheimer, AIDS,
Huntington, Parkinson, and Down’s syndrome diseases.17 The most straightforward pro-
cedure for the synthesis of tetrahydrobenzo[b]pyrans is the one-pot three-component
cyclocondensation of dimedone with an aromatic aldehyde and malononitrile in the pres-
ence of Lewis and Brønsted acid catalysts such as rare-earth perfluorooctanoate [RE
(PFO)3],18 I2,19 nano-ZnO,20 tetra(n-butyl)ammonium bromide (TBAB),21 piperazine
22
under solvent-free ball-milling conditions,
PhB(OH)2,23 KF/Al2O3 under ultrasound
irradiation,24 nanomixed metal oxides,25 ionic liquid [bmim][BF4],26 NaBr under micro-
wave irradiation,27 hexadecyltrimethyl ammonium bromide (HTMAB),28 1,4-diazabicy-
clo[2.2.2]octane (DABCO),29 basic ionic liquid,30 carbon-based solid acid (CBSA),31
2,2,2-trifluoroethanol (TFE),32 and Na2SeO4.33 While each of these methods has its own
advantage, many suffer from limitations such as prolonged reaction times, the use of rela-
tively expensive catalysts, required utilization of organic solvents, un-satisfactory yields,
and tedious isolation procedures. Thus the discovery of a new and efficient catalyst with
high catalytic activity, short reaction times, recyclability, and simple reaction work-up
for the preparation of tetrahydrobenzo[b]pyrans is of great interest.
Received October 19, 2015; in final form February 3, 2016.
Address correspondence to Abolghasem Davoodnia, Department of Chemistry, Mashhad Branch,
Islamic Azad University, Mashhad, Iran. E-mail: adavoodnia@mshdiau.ac.ir or adavoodnia@yahoo.com
328

Synthesis of Tetrahydrobenzo[b]pyrans in Water
329
The low cost, availability, the absence of inflammability, of explosive, mutagenic,
and carcinogenic properties are some of the economic and environmental benefits
associated with water as solvent in a number of reactions.34,35 Furthermore, the net-
work of hydrogen bonds, the large surface tension, the high cohesive energy, specific
heat capacity, and polarity are some of the valuable properties of water that can dra-
matically influence the course of reactions performed in this medium.36–38 Our inter-
est in heterocycles,39–44 and in the development of environmentally friendly methods
for the synthesis of organic compounds led us to study the employment of re-usable
catalysts.45–54 We now report our results for an efficient synthesis of tetrahydrobenzo
[b]pyrans 4 in racemic form via a one-pot, three-component reaction of dimedone (1),
aromatic aldehydes (2), and malononitrile (3) using racemic aspartic acid
((§)-aspartic acid) as a novel organocatalyst (Scheme 1).
To determine suitable conditions for this transformation, we examined the reac-
tion of dimedone (1 mmol), 4-chlorobenzaldehyde (1 mmol), and malononitrile
Scheme 1
(1 mmol) as test reaction for the synthesis of compound 4b in the absence and pres-
ence of (§)-aspartic acid as catalyst. The conditions were optimized in terms of vari-
ous parameters such as the amount of catalyst, the effect of solvent and the influence
of temperature. The results are summarized in Table 1. None or only trace amounts of
the product 4b was formed in the absence of the catalyst in refluxing H2O or EtOH
and also under solvent-free conditions at high temperature (Entries 1–3) indicating
that the catalyst is necessary for the reaction. Table 1 indicates that under solvent-free
conditions and from among the solvents tested such as H2O, EtOH, MeOH, CHCl3,
MeCN and using varying amounts of the catalyst, the reaction proceeded more easily
and gave the highest yield, using 10 mol% of (§)-aspartic acid in H2O at reflux tem-
perature (Entry 8). No significant improvement in yields or reaction times was
observed using a higher amount of the catalyst (Entry 9). All subsequent reactions
were carried out in these optimized conditions.
To explore the generality of this method, we extended it to a range of aromatic alde-
hydes under the optimized reaction conditions. As illustrated in Table 2, in all cases the
expected products were obtained in high yields and short reaction times. Melting points,
TLC and the 1H NMR spectroscopic data were used to establish that only one product is
formed in all cases with no undesirable side-products being present after purification. Fac-
ile separation of the products from the catalyst makes this method useful for the synthesis
of tetrahydrobenzo[b]pyrans. Under the same conditions however, no reaction occurred
when aliphatic aldehydes were used. The products 4 were obtained in racemic form and
the structures were deduced from their spectral data and concordance of their mps with
those reported (Table 2).

330
Davoodnia et al.
Table 1
Optimization of Reaction Conditions for the Synthesis of Compound 4b Catalyzed by
(§)-Aspartic Acid*
Entry
Catalyst (mol%)
Solvent
T/ꢀC
Time/min
Yield (%)
1
None
None
None
1
H2O
EtOH
Reflux
Reflux
120
90
90
100
80
65
50
30
10
15
20
35
110
35
20
35
25
50
30
30
25
25
15
Trace
Trace
None
31
2
3
Solvent-free
H2O
H2O
4
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
80
5
3
46
64
6
5
H2O
H2O
7
7
78
96
8
10
12
10
10
10
7
H2O
H2O
9
97
77
10
11
12
13
14
15
16
17
18
19
20
21
22
H2O
H2O
60
r.t.
63
54
H2O
EtOH
EtOH
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
120
68
80
10
7
MeOH
MeOH
CHCl3
CHCl3
MeCN
MeCN
solvent-free
solvent-free
53
67
10
7
31
37
10
7
49
54
10
7
46
50
10
120
*Reaction conditions: dimedone 1 (1 mmol), 4-chlorobenzaldehyde 2b (1 mmol), and malono-
nitrile (1 mmol).
The applicability and efficiency of our catalyst was compared with some of the
reported methods for the synthesis of tetrahydrobenzo[b]pyrans as shown in Table 3. Our
very simple procedure gave higher yields in shorter times.
Since the stability and recyclability of catalysts are important factors in these meth-
ods, the recovery and catalytic activity of recycled (§)-aspartic acid was explored. After
completion of the reaction, the product was collected, and washed with cold water. Evap-
oration of the combined filtrates to dryness under reduced pressure gave the solid catalyst
which was dried at 60ꢀC under vacuum for 1 h, and could be re-used for the same experi-
ment without loss of activity over at least five catalytic cycles (93–96% yield of 4b). The
structure of (§)-aspartic acid catalyst is retained during those five cycles.
In conclusion, we have successfully developed a highly efficient and green method
for the synthesis of tetrahydrobenzo[b]pyrans in racemic form by one-pot three-compo-
nent cyclocondensation of dimedone, aromatic aldehydes, and malononitrile using inex-
pensive and readily available (§)-aspartic acid as catalyst. The reaction occur in water
and furnishes the expected products in high yields. Short reaction times, simple isolation
of the products, and usage of eco-friendly nontoxic catalyst and solvent are other features
of this procedure. In addition the catalyst was easily recovered and used in multiple cata-
lytic cycles.

Synthesis of Tetrahydrobenzo[b]pyrans in Water
331
Table 2
Synthesis of Tetrahydrobenzo[b]pyrans 4 using (§)-Aspartic Acid as Catalyst
Entry
1
Ar
Product
Time (min) Yield (%) mp (ꢀC) lit. mp (ꢀ C)
C6H5
15 94
230–232 227–22918
2
4-ClC6H4
10
96
212–213 213–21522
3
4-BrC6H4
10
98
210–211
21533
4
3-BrC6H4
13
95
231–233 230–23231
5
4-FC6H4
5
89
188–189 189–19122
(Continued on next page)

332
Davoodnia et al.
Table 2
Synthesis of Tetrahydrobenzo[b]pyrans 4 using (§)-Aspartic Acid as Catalyst
(Continued)
Entry
6
Ar
Product
Time (min) Yield (%) mp (ꢀC) lit. mp (ꢀ C)
4-HOC6H4
10
88
209–211 210–21231
7
3-O2NC6H4
7
88
214–215 210–21223
8
4-O2NC6H4
7
90
180–182 180–18129
9
4-MeOC6H4
15
95
201–202 200–20229
10
2-Thienyl
15
89
225–227 224–22626
Reaction conditions: dimedone 1 (1 mmol), an aromatic aldehyde 2 (1 mmol), malononitrile 3
(1 mmol), (§)-aspartic acid (10 mol% based on dimedone), H2O (5 ml), reflux.

Synthesis of Tetrahydrobenzo[b]pyrans in Water
333
Table 3
Comparison of the Efficiency of Various Catalysts for the Synthesis of Tetrahydrobenzo
[b]pyrans
Conditions
Catalyst
Solvent
T (ꢀC)
Other
Time (min) Yield (%)
Lit.
[RE(PFO)3]
I2
EtOH
DMSO
EtOH/H2O
EtOH
60
120
—
—
—
—
240–480
180–240
180–240
20–140
80–90
80–92
79–91
87–95
88–96
18
19
20
21
22
Nano ZnO
TBAB
Piperazine
r.t.
reflux
—
r.t. Ball-milling at 20–120
20–25 Hz
PhB(OH)2
KF/Al2O3
EtOH/H2O reflux
EtOH
—
27–34 Ultrasound
irradiation
30
20–240
61–88
81–98
23
24
Nano mixed
metal oxides
[bmim][BF4]
NaBr
EtOH
reflux
—
35–45
90–94
25
[bmim][BF4] 80
—
—
70–85 Microwave
irradiation
30–120
10–15
85–95
80–95
26
27
HTMAB
DABCO
H2O
H2O
80–95
reflux
—
—
—
—
—
—
—
180
120
59–95
75–97
50–94
85–98
80–95
80–98
28
29
30
31
32
33
Basic ionic liquid EtOH/H2O reflux
EtOH
TFE
5–240
10–20
300
CBSA
TFE
reflux
reflux
Na2SeO4
(§)-Aspartic acid
EtOH/H2O reflux
H2O reflux
40–210
5–15
88–98 This work
Experimental Section
All reagents and chemicals were available commercially from Aldrich and Merck, and
used without purification. Melting points were determined using a Stuart SMP3 melting
point apparatus. The IR spectra were recorded as KBr pellets on a Tensor 27 Bruker
spectrophotometer. The 1H NMR (300 & 400 MHz) spectra were determined using
Bruker 300 & 400 spectrometers in DMSO-d6 as the solvent with TMS as the internal
reference.
General Procedure for the Synthesis of Tetrahydrobenzo[b]pyrans (4)
A mixture of dimedone (1, 0.14 g, 1 mmol), the aromatic aldehyde 2 (1 mmol), malono-
nitrile (3, 0.07 g, 1 mmol), and (§)-aspartic acid (0.01 g, 0.1 mmol, 10 mol% based on
dimedone) in water (5 ml) was heated under reflux for 5–15 min. During the procedure,
the reaction was monitored by TLC on silica gel (n-hexane-ethyl acetate, 3:1). Upon com-
pletion of the reaction, the mixture was cooled to room temperature. The precipitated
solid was collected, washed with cold water (10 ml £ 3) and recrystallized from 96% eth-
anol (5 ml) to give products 4 in racemic form in high yields.

334
Davoodnia et al.
Larger Scale Preparation of 4b
A mixture of dimedone (1, 2.8 g, 20 mmol), the aromatic aldehyde 2 (20 mmol), malono-
nitrile (3, 1.4 g, 20 mmol), and (§)-aspartic acid (0.2 g, 2 mmol, 10 mol% based on
dimedone) in water (100 ml) was heated under reflux for 5–15 min. The progress of the
reaction was monitored by TLC (n-hexane-ethyl acetate, 3:1). Upon completion, the reac-
tion mixture was cooled to room temperature. The precipitated solid was collected,
washed with cold water (200 ml £ 3) and recrystallized from 96% ethanol (100 ml) to
give pure 4b in racemic form (95% yield).
Acknowledgements
The authors express their gratitude to the Islamic Azad University, Mashhad Branch for
financial support.
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