An Efficient and Convenient Approach to the Synthesis of Benzopyrans by a Three-Component Coupling of One-Pot Reaction

Article abstract of DOI:10.1055/s-2003-42030

A general and practical chemistry route to the synthesis of polyfunctionlized benzopyrans using tetrabutylammonium bromide (TBABr) as the catalyst (10 mol%) is described. This method provides several advantages such as neutral conditions, high yields and simple work-up procedure. In addition, water was chosen as a green solvent.

Full text of DOI:10.1055/s-2003-42030

LETTER
2001
An Efficient and Convenient Approach to the Synthesis of Benzopyrans by a
Three-Component Coupling of One-Pot Reaction
S
ynthesis of Be
o
nzopyrans by
n
a
T
hree-Co
g
mponent
C
o
-
upling Shou Jin,* Jin-Chong Xiao, Su-Juan Wang, Tong-Shuang Li, Xin-Ru Song
Department of Chemistry, College of Chemistry and Environmental Science, Hebei University, Baoding 071002, P. R. China.
Fax +86(312)5016914; E-mail: orgsyn@mail.hbu.edu.cn
Received 25 July 2003
tivated phenol using base or amide as catalysts.10 Each of
Abstract: A general and practical chemistry route to the synthesis
the above methods has its own merit, while some of these
methods are plagued by the limitation of poor yields, dif-
ficult work-up and effluent pollution. Consequently, there
of polyfunctionlized benzopyrans using tetrabutylammonium
bromide (TBABr) as the catalyst (10 mol%) is described. This
method provides several advantages such as neutral conditions,
high yields and simple work-up procedure. In addition, water was is scope for further renovation toward mild conditions, in-
chosen as a green solvent.
creased of variation of the substituents in the components
and better yields.
Key words: benzopyrans, tetrabutylammonium bromide, synthesis
As a good phase transfer catalyst, tetrabutylammonium
bromide has been used in a number of organic reactions.
However, the use of TBABr as a catalyst in the synthesis
of these polyfunctionalized benzopyrans has not been re-
ported. In this manuscript, we wish to report a general and
highly efficient route for the synthesis of benzopyrans us-
ing an inexpensive and commercially available TBABr as
catalyst. This is an one-pot combination using water as a
green solvent that not only preserves the simplicity but
also consistently gives the corresponding products in
good to excellent yields (Scheme 1).
At the beginning of the new century, with the increasing
environmental concerns and the regulatory constrains
faced in the chemical and pharmaceutical industries, de-
velopment of environmentally benign organic reactions
has become a crucial and demanding research area in
modern organic chemical research.1 Recently Wender
defined the ‘ideal synthesis’ as one in which the target
components is produced in one step, in quantitative yield
from readily available and inexpensive starting materials
in resource-effective and environmentally acceptable
process.2 The one-pot multicomponent condensations
represent a possible instrument to perform a near ideal
synthesis because they possess one of the aforementioned
qualities, namely the possibilities of building-up complex
molecules with maximum simplicity and brevity.3
In recent years, polyfunctionalized benzopyrans and their
derivatives have attracted strong interest due to their
useful biological and pharmacological properties, such as
anticoagulant, spasmolytic, diuretic, antianaphylactin, an-
ticancer.4 In addition, they also constitute a structural unit
of a series of natural products5 and because of the inherent
reactivity of the inbuilt pyran ring are versatile synthesis.6
Furthermore, these compounds can be employed as cos-
metics, pigments7 and utilized as potential biodegradable
agrochemicals.8 Thus, synthesis of the heterocyclic nucle-
us is of much current importance. The art of performing
efficient chemical transformation coupling three or more
components in a single operation by a catalytic process
avoiding stoichiometric toxic reagents, large amounts of
solvents and expensive purification techniques represents
a fundamental target of the modern organic synthesis.9
Several conventional synthesis of these polyfunctional-
ized benzopyrans involves three-component, one-pot
condensation of malononitrile with an aldehyde and an ac-
Scheme 1
In a typical general experimental procedure, a solution of
malononitrile, an aromatic aldehyde and an activated phe-
nol in water was heated under reflux water in the presence
of a catalytic amount of TBABr (10 mol%) for a certain
period of time required to complete the reaction, resulting
in the formation of benzopyrans, the reaction mixture was
extracted with ether or ethyl acetate. After drying over an-
hydrous sodium sulfate, the solid product was purified by
recrystallization from ethanol.
To study the generality of this process, several examples
illustrating this method for the synthesis those polyfunc-
tionalized benzopyrans were studied. The results are sum-
marized in Table 1. The effect of electron and the nature
of substituents on the aromatic ring did not show strongly
obvious effects in terms of yields under this reaction con-
ditions. The three-component cyclocondensation reaction
proceeded smoothly under refluxing water to give the cor-
responding products 4 in high yields. Benzoaldehyde and
other aromatic aldehydes containing electron-withdraw-
ing groups (such as nitro groups, halides) or electron-
donating groups (such as hydroxy group, alkoxyl group,
SYNLETT 2003, No. 13, pp 2001–2004
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Advanced online publication: 08.10.2003
DOI: 10.1055/s-2003-42030; Art ID: U15103ST.pdf
© Georg Thieme Verlag Stuttgart · New York

2002
T.-S. Jin et al.
LETTER
Table 1 Tetrabutylammonium Bromide-Catalyzed Synthesis of Benzopyrans
Entry
R1
Phenol
Product
Yieldsa,b (%) Mp (°C)
Found
Reported10
232
1
2
C6H5 1a
1-Naphthol
1-Naphthol
1-Naphthol
1-Naphthol
1-Naphthol
1-Naphthol
1-Naphthol
1-Naphthol
1-Naphthol
1-Naphthol
1-Naphthol
2-Naphthol
2-Naphthol
2-Naphthol
2-Naphthol
2-Naphthol
4a
4b
4c
4d
4e
4f
89
95
93
87
88
85
84
88
92
91
89
79
75
77
82
75
206–207
231–232
216–218
236–237
213–215
239–241
214–216
242–244
249–251
182–183
203–205
206–208
259–261
185–186
250–252
190–191
4-ClC6H4 1b
3
3-ClC6H4 1c
4
2-ClC6H4 1d
5
2,4-Cl2C6H3 1e
4-NO2C6H4 1f
3-NO2C6H4 1g
3,4-OCH2OC6H3 1h
4-OHC6H4 1i
4-CH3OC6H4 1j
4-Me2NC6H4 1k
4-ClC6H4 1l
6
7
4g
4h
4i
214.5–216
8
9
252
182
10
11
12
13
14
15
16
4j
4k
4l
208
2-ClC6H4 1m
4-NO2C6H4 1n
3,4-OCH2OC6H3 1o
4-CH3OC6H4 1p
4m
4n
4o
4p
261–263
192
a Isolated yields.
b Reaction conditions.11
dimethylamino group) were employed and reacted well to aromatic aldehyde. The reaction could be carried out in
give the corresponding benzopyrans in good to excellent the absence of TBABr at different time intervals (3 h, 6 h,
yields.
12 h) when the same reaction mixture (1b, malononitrile
and 1-naphthol) was subjected to heating in refluxing
water. The yields of these runs were 19%, 37%, 42%, re-
spectively. Under the identical condition, the rate of the
reaction was affected by the presence of TBABr and the
yields were 72% and 95% after different time intervals
(3 h, 6 h). Thus, 10 mol% TBABr was chosen as a quan-
titative catalyst for these reactions. In addition, it must be
pointed out that all of these reactions were carried out in
water and those products were characterized by 1H NMR,
IR and elemental analyses.
The reaction of 1-naphthol or 2-naphthol with an aromatic
aldehyde and malononitrile gave different experimental
results. For instance, 4-chlorobenzoaldehyde reacted with
malononitrile and 1-naphthol or 2-naphthol under the re-
fluxing water and gave yields of 2-amino-2-chromenes 4b
(95%) and 4l (79%), respectively. When 4-nitrobenzalde-
hyde was treated with malononitrile and 1-naphthol or 2-
naphthol under the same conditions, the isolated yields of
corresponding compounds were 4f (85%) and 4n (77%).
We conclude that 1-naphthol exhibits higher reactivity
than 2-naphthol does.
We propose the possible following mechanism to account
for the reaction.10 An aromatic aldehyde 1 was firstly con-
densed with malononitrile 2 to afford a-cyanocinnamoni-
trile derivative 5. The step (1 + 2→5) can be regarded as
a fast knoevenagel addition. With a model reaction, the
knoevenagel reaction of malononitrile and aromatic alde-
hydes can be carried out in water without any catalyst.
Thus we think that the second step requires the presence
of TBABr probably. The phenol ortho C-alkylation by re-
action with the electrophilic C=C double bond giving the
intermediate 6. Then the intermediate 6 was cyclized by
the nucleophilic attack of OH group on the cyano (CN)
moiety and gave the intermediate 7. Finally the expected
The catalyst plays a crucial role in the success of the reac-
tion in terms of the rate and the yields. For example,
4-chlorobenzoaldehyde reacted with malononitrile and 1-
naphthol in the presence of 1 mol% TBABr to give the
product 4b in quantitative yield (67%) at refluxing water
after six hours of reaction time. Increasing of the catalyst
to 5 mol% and 10 mol% results in accelerating the reac-
tion yields to 85% and 95% respectively. Use of just 10
mol% TBABr in refluxing water is sufficient to push the
reaction forward. Higher amounts of the catalyst did not
improve the results to a greater extent. The yields are, in
general, very high regardless of the structural variations in
Synlett 2003, No. 13, 2001–2004 © Thieme Stuttgart · New York

LETTER
Synthesis of Benzopyrans by a Three-Component Coupling
2003
Scheme 2
products 4 were afforded by addition and elimination of
water (7→8→4) (Scheme 2). In this process, TBABr as
an emulsifying agent makes the mixture more even, which
contributes to promote these reactions.
(7) Ellis, G. P. The Chemistry of Heterocyclic Compounds, In
Chromenes, Chromanes and Chromeones; Weissberger, A.;
Taylor, E. C., Eds.; Wiley: New York, 1977, 13.
(8) (a) Hafez, E. A. A.; Elnagdi, M. H.; Elagamey, A. G. A.;
El-Taweel, F. M. A. A. Heterocycles 1987, 26, 903.
(b) Abdel Galil, F. M.; Riad, B. Y.; Sherif, S. M.; Elnagdi,
M. H. Chem. Lett. 1982, 1123.
(9) Mizuno, N.; Misono, M. Chem. Rev. 1998, 98, 199.
(10) (a) Abdel-Larif, F. F. Indian J. Chem, Sect. B 1990, 29, 664.
(b) Elagamey, A. G. A.; El-Taweel, F. M. A. A. Indian J.
Chem., Sect. B 1990, 29, 885. (c) Kuthan, J.; Sebek, P.;
Bohm, S. Advances in Heterocyclic Chemistry; Katritzky, A.
R., Ed.; Academic Press, Inc.: New York, 1995.
In conclusion, we have described a general and highly ef-
ficient procedure for the preparation of polyfunctional-
ized benzopyrans by TBABr-catalyzed, three component
condensation under the refluxing water. In addition, it is
possible to apply the tenets of green chemistry to the gen-
eration of biologically interesting products using aqueous
media approaches, which are less expensive and less toxic
than those with organic solvents. Moreover, the procedure
offers several advantages including high yields, opera-
tional simplicity, cleaner reactions, minimal environmen-
tal impact which makes it a useful and attractive process
for the synthesis of these compounds.
(d) Bioxham, J.; Dell, C. P.; Smith, C. W. Heterocycles
1994, 38, 399. (e) Elagamey, A. G. A.; Sawllim, S. Z.;
El-Taweel, F. M. A.; Elnagdi, M. H. Collect. Czech. Chem.
Commun. 1988, 53, 1534.
(11) General Procedure for the Preparation of Benzopyrans:
A mixture of an aromatic aldehyde (1 mmol), malononitrile
(1 mmol), phenol (1 mmol) and TBABr (10 mol%) in H2O
(20 mL) was stirred at refluxing for 6 h. The progress of the
reaction was monitored by thin layer chromatograph. After
completion of the reactions, the mixture was cooled to r.t.
and extracted by Et2O and EtOAc. The organic phase was
collected and dried over anhyd Na2SO4. Then evaporate the
solvent under reduced pressure and get the crude products.
The crude products were purified by recrystallization by
EtOH. Data of some compounds are shown below:
Compound 4a, 2-Amino-3-cyano-4-(phenyl)-4H-benzo-
Acknowledgment
This project was supported by the National Natural Science Found-
ation of China (29872011 and 29572039), Educational Ministry
of China, Educational Department of Hebei Province (990104),
Science and Technology Commission of Hebei Province.
References
chromene. Mp 210–211 °C (from EtOH): IR (KBr): nmax
=
(1) Anastas, P.; Williamson, T. Green Chemistry, Frontiers in
Benign Chemical Synthesis and Procedures; Oxford Science
Publications: Oxford, 1998.
(2) Wender, P. A.; Handy, S. L.; Wright, D. L. Chem. Ind.
(London) 1997, 765.
3454, 3318, 3020, 2932, 2205, 1656, 1600, 1572, 1450,
1372, 1267, 1100, 1022, 811, 744 cm–1. 1H NMR: d = 4.90
(s, 1 H, H-4), 7.10 (s 2 H, NH2), 7.07–7.12 (m, 6 H, H-5, H-
2¢, H-3¢, H-4¢, H-5¢, H-6¢), 7.56–7.66 (m, 3 H, H-6, H-8, H-
9), 7.94 (d, 1 H, J = 8.4 Hz, H-7 or H-10), 8.23 (d, 1 H,
J = 8.4 Hz, H-10 or H-7). Anal. Calcd for C20H14N2O: C,
80.54; H, 4.70; N, 9.39. Found: C, 80.40; H, 4.75; N, 9.37.
Compound 4c, 2-Amino-3-cyano-4-(3-chlorophenyl)-4H-
benzo-chromene. Mp 216–218 °C (from EtOH). IR (KBr):
(3) Hudlicky, T. Chem. Rev. 1996, 96, 3.
(4) (a) Foye, W. O. Prinicipi di Chimica Farmaceutica Piccin;
Padova: Italy, 1991, 416. (b) Andreani, L. L.; Lapi, E. Boll.
Chim. Farm. 1960, 99, 583. (c) Chem. Abstr. 1982, 96,
135383e. (d) Bonsignore, L.; Loy, G.; Secci, D.; Calignano,
A. Eur. J. Med. Chem. 1993, 28, 517. (e) Chem. Abstr.
1986, 104, 224915f.
(5) (a) Hatakeyama, S.; Ochi, N.; Numata, H.; Takano, S. J.
Chem. Soc., Chem. Commun. 1988, 1202. (b) Cingolant, G.
M.; Pigini, M. J. Med. Chem. 1969, 12, 531.
(6) O’Callaghan, C. N.; Mc Murry, T. B. H. J. Chem. Res.,
Synop. 1995, 214.
n
max = 3455, 3340, 3023, 2930, 2210, 1645, 1600, 1580,
1470, 1378, 1266, 1030, 816, 750, 700 cm–1. 1H NMR: d =
4.98 (s, 1 H, H-4), 7.24 (s, 2 H, NH2), 7.12–7.38 (m, 4 H, H-
4¢, H-5¢, H-6¢, H-5), 7.23 (s, 1 H, H-2¢), 7.56–7.66 (m, 3 H,
H-6, H-8, H-9), 7.89 (d, 1 H, J = 8.4 Hz, H-7 or H-10), 8.26
(d, 1 H, J = 8.4 Hz, H-10 or H-7). Anal. Calcd for
C20H13ClN2O: C, 72.18; H, 3.91; N, 8.42. Found: C, 72.11;
H, 4.01; N, 8.40.
Synlett 2003, No. 13, 2001–2004 © Thieme Stuttgart · New York

2004
T.-S. Jin et al.
LETTER
+ H-5), 7.55–7.65 (m, 3 H, H-6, H-8, H-9), 7.88 (d, 1 H,
J = 8.4 Hz, H-7 or H-10), 8.22 (d, 1 H, J = 8.4 Hz, H-10 or
H-7). Anal. Calcd for C21H14N2O3: C, 73.68; H, 4.09; N,
8.19. Found: C, 73.70; H, 4.00; N, 8.25.
Compound 4k, 2-Amino-3-cyano-4-(4-dimethylamino-
phenyl)-4H-benzo-chromene. Mp 203–205 °C (from
EtOH). IR (KBr): nmax = 3465, 3340, 3090, 2955, 2863,
2806, 2193, 1662, 1605, 1570, 1522, 1400, 1380, 1342,
1262, 1190, 1100, 800, 750 cm–1. 1H NMR d = 2.84 [s, 6 H,
N(CH3)2], 4.75 (s, 1 H, H-4), 7.03–7.10 (m, 3 H, H-5 or
NH2), 6.65 (d, 2 H, J = 8.4 Hz, H-2¢, H-6¢ or H-3¢, H-5¢), 7.06
(d, 2 H, J = 8.4 Hz, H-3¢, H-5¢ or H-2¢, H-6¢), 7.53–7.64 (m,
3 H, H-6, H-8, H-9), 7.88 (d, 1 H, J = 8.4 Hz, H-7 or H-10),
8.24 (d, 1 H, J = 8.4 Hz, H-10 or H-7). Anal. Calcd for
C22H19N3O: C, 77.42; H, 5.57; N, 12.32. Found: C, 77.36; H,
5.60; N, 12.23.
Compound 4d, 2-Amino-3-cyano-4-(2-chlorophenyl)-
4H-benzo-chromene. Mp 236–237 °C (from EtOH). IR
(KBr): nmax = 3476, 3320, 2915, 2195, 1664, 1600, 1410,
1360, 1275, 1180, 1040, 805, 750 cm–1. 1H NMR: d = 5.41
(s, 1 H, CH), 7.20 (s, 2 H, NH2), 7.01 (d, 1 H, J = 8.4 Hz, H-
5), 7.25–7.31 (m, 3 H, H-4¢, H-5¢, H-6¢), 7.45 (d, 1 H, J = 8.4
Hz, H-3¢), 7.56–7.67 (m, 3 H, H-6, H-8, H-9), 7.89 (d, 1 H,
J = 8.4 Hz, H-7 or H-10), 8.24 (d, 1 H, J = 8.4 Hz, H-10 or
H-7). Anal. Calcd for C20H13ClN2O: C, 72.18; H, 3.91; N,
8.42. Found: C, 72.11; H, 4.00; N, 8.39.
Compound 4e, 2-Amino-3-cyano-4-(2,4-dichlorophenyl)-
4H-benzo-chromene. Mp 213–215 °C (from EzOH). IR
(KBr): nmax = 3454, 3336, 3030, 2186, 1667, 1600, 1572,
1466, 1378, 1200, 1050, 860, 811, 755 cm–1. 1H NMR d =
5.47 (s, 1 H, H-4), 7.30 (s, 2 H, NH2), 6.98 (d, 1 H, J = 8.4
Hz, H-6¢), 7.60 (s, 1 H, H-3¢), 7.39–7.59 (m, 2 H, H-5, H-5¢),
7.69–7.89 (m, 3 H, H-6, H-8, H-9), 8.03 (d, 1 H, J = 8.4 Hz,
H-7 or H-10), 8.25 (d, 1 H, J = 8.4 Hz, H-10 or H-7). Anal.
Calcd for C20H12Cl2N2O: C, 65.39; H, 3.27; N, 7.63. Found:
C, 65.23; H, 3.25; N, 7.60.
Compound 4n, 3-Amino-2-cyano-1-(4-nitrophenyl)-1H-
benzo-chromene. Mp 185–186 °C (from EtOH). IR (KBr):
nmax = 3430, 3325, 2190, 1650, 1610, 1582, 1540, 1502,
1340, 1244, 1200, 1070, 810 cm–1. 1H NMR d = 5.45 (s, 1 H,
H-4), 7.20 (s, 2 H, NH2), 7.36–7.52 (m, 3 H, H-6, H-7, H-9
or H-10), 7.69–8.03 (m, 2 H, H-5 and H-8), 7.98 (d, 1 H,
J = 9.2 Hz, H-10 or H-9), 7.44 (d, 2 H, H-2¢ and H-6¢), 8.15
(d, 2 H, H-3¢ and H-5¢). Anal. Calcd for C20H13N3O3: C,
69.97; H, 3.79; N, 12.24. Found: C, 70.10; H, 3.88; N, 12.08.
Compound 4o, 2-Amino-3-cyano-4-(dioxymethylene-
phenyl)-4H-benzo-chromene. Mp 250–252 °C (from
EtOH). IR (KBr): nmax = 3443, 3340, 3045, 2886, 2195,
1657, 1600, 1580, 1500, 1454, 1400, 1234, 1195, 1040, 811,
743 cm–1. 1H NMR d = 5.25 (s, 1 H, H-4), 5.91 (s, 2 H, -
OCH2O-), 6.95 (s, 2 H, NH2), 6.66–6.80 (m, 3 H, H-2¢, H-5¢,
H-6¢), 7.86–7.95 (m, 2 H, H-5 or H-8), 7.91 (d, 1 H, J = 8.0
Hz, H-9 or H-10), 7.20–7.49 (m, 3 H, H-6, H-7, H-10). Anal.
Calcd for C21H14N2O3: C, 73.68; H, 4.09; N, 8.19; Found: C,
73.72; H, 3.99; N, 8.06.
Compound 4f, 2-Amino-3-cyano-4-(4-nitrophenyl)-4H-
benzo-chromene. Mp 239–241 °C (from EtOH). IR (KBr):
max = 3460, 3335, 2196, 1665, 1600, 1575, 1536, 1500,
n
1346, 1270, 1195, 1100, 805, 770 cm–1. 1H NMR d = 5.12 (s,
1 H, H-4), 7.29 (s, 2 H, NH2), 7.05 (d, 1 H, J = 8.4 Hz, H-5),
7.51–7.72 (m, 3 H, H-6, H-8, H-9), 7.52 (d, 2 H, H-2¢, H-6¢),
7.90 (d, 1 H, J = 8.4 Hz, H-7 or H-10), 8.15 (d, 2 H, H-3¢, H-
5¢), 8.27 (d, 1 H, J = 8.4 Hz, H-10 or H-7). Anal. Calcd for
C20H13N3O3: C, 69.97; H, 3.79; N, 12.24. Found: C, 70.09;
H, 3.99; N, 12.12.
Compound 4h, 2-Amino-3-cyano-4-(3,4-dioxymethyl-
enephenyl)-4H-benzo-chromene. Mp 242–244 °C (from
EtOH). IR (KBr): nmax = 3434, 3320, 2905, 2196, 1670,
1605, 1575, 1490, 1405, 1380, 1225, 1190, 1040, 790, 770
cm–1. 1H NMR d = 4.88 (s, 1 H, H-4), 5.92 (s, 2 H, CH2),
6.74–6.85 (m, 3 H, H-2¢, H-5¢, H-6¢), 7.10–7.13 (m, 3 H, NH2
Synlett 2003, No. 13, 2001–2004 © Thieme Stuttgart · New York