Ultrasonics Sonochemistry 11 (2004) 393–397

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Ultrasound-assisted synthesis of 2-amino-2-chromenes with

cetyltrimethylammonium bromide in aqueous media
Tong-Shou Jin *, Jin-Chong Xiao, Su-Juan Wang, Tong-Shuang Li
Department of Chemistry, College of Chemistry and Environmental Science, Hebei University, Baoding 071002, PR China
Received 7 July 2003; accepted 6 October 2003
Available online 13 November 2003

Abstract

A general and practical synthetic route to 2-amino-2-chromenes in water in the presence of cetyltrimethylammonium bromide
(CTABr) as catalyst is described under ultrasound irradiation.

2003 Elsevier B.V. All rights reserved.

Keywords: Chromene; Ultrasound; CTABr; Green synthesis

1. Introduction Benzopyrans and their derivatives occupy an impor-

At the beginning of the new century, a shift in em-
phasis in chemistry is apparent with the desire to de-
velop environmentally benign routes to a myriad of
materials using non-toxic reagents, solvents and cata-
lysts [1]. Recently ‘‘ideal synthesis’’ was defined as one in
which the target compound is generated in one step, in
quantitative yield from readily available and inexpensive
starting materials in a resource-effective and environ-
mentally acceptable process [2]. One-pot multicompo-
nent condensations represent a possible instrument to
perform a near ideal synthesis because they possess one
of the aforementioned qualities, namely the possibility
of building-up complex molecules with maximum sim-
plicity and brevity [3]. Recently organic reactions in
water without use of harmful organic solvents have at-
tracted much attention, because water is a cheap, safe,
and environmentally benign solvent [4]. In the course of
our investigations to develop new synthetic methods in
water, we examined the synthesis of 2-amino-2-chro-
menes in water, as a green solvent, which represents
a remarkable benefit for its high polarity.
*
Corresponding author. Tel.: +86-312-5079361; fax: +86-312-
5016914.
E-mail address: orgsyn@mail.hbu.edu.cn (T.-S. Jin).
tant place in the realm of natural and synthetic organic
chemistry because of their biological and pharmaco-
logical properties such as antisterility and anticancer
agents [5]. In addition, polyfunctionalized benzopyrans
constitute a structural unit of a number of natural
products and because of the inherent reactivity of the
inbuilt pyran ring are versatile synthons [6]. Moreover,
they can also be employed as cosmetics and pigments [7]
and utilized as potential biodegradable agrochemicals
[8]. These findings stimulated our interest in the syn-
thesis of heterocyclic derivatives of these ring systems
for their great importance. Strategies for the synthesis of
these compounds have varied from one-pot to multistep
approaches which lack the simplicity [9]. The most
simple and straightforward procedure involves three-
component, one-pot condensation of malononitrile, an
aldehyde and a phenol in organic solvents (such as
ethanol) and in the presence of piperidine [10].
In last three decades, ultrasound has interestingly
been used in organic synthesis [11]. This method is more
convenient and easily controlled compared with the
traditional method. CTABr, as a phase transfer catalyst,
has been used for many organic reactions [12]. Thus, in
this manuscript we wish to describe an ultrasound-
accelerated synthesis of 2-amino-2-chromenes from an
aldehyde, malononitrile and naphthol catalyzed by us-
ing a catalytic amount of CTABr under ultrasonic waves
(Scheme 1).

1350-4177/$ - see front matter
2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.ultsonch.2003.10.002
394 T.-S. Jin et al. / Ultrasonics Sonochemistry 11 (2004) 393–397
Scheme 1.
2. Method
2.1. Apparatus and analysis
The melting points were determined on a XT4 melt-
ing point apparatus and were uncorrected. The products
were characterized by IR spectra, 1 HNMR spectra and
by comparison of their melting points with literature
values. IR spectra were recorded on a Perkin–Elmer 983
G spectrometer (KBr). 1 HNMR spectra were deter-
mined on Bruker 400 (400 MHz), using DMSO as sol-
vent and tetramethylsilane (TMS) as internal reference.
All chemicals used were obtained commercially. Soni-
cation was performed in a Shanghai Branson-CQX
ultrasonic cleaner with a frequency of 25 kHz and a
nominal power of 500 W.
2.2. General procedure
An equimolar (1 mmol) mixture of aldehyde 1, malo-
nonitrile 2, phenol 3 and CTABr (10 mol%) in water
(10 ml) was put into a conical reaction flask. The flask
was located at the maximum energy area in the cleaner
and addition or removal of water was used to control
the temperature of the water bath. After 2.5 h, the
mixture was extracted with diethyl ether or ethyl acetate.
The organic phase was separated and dried over anhy-
drous Na2 SO4 . The solvent was evaporated under re-
duced pressure and the resulting solid was purified by
recrystallization from hot methanol to afford the pure
products 4. Selected data of some compounds are shown
below:
Compound 4a:
IR (KBr) mmax : 3454, 3318, 3020, 2932, 2205, 1656,
1600, 1572, 1450, 1372, 1267, 1100, 1022, 811, 744 cm
1 ;
dH 4.90 (s, 1H, H-4), 7.10 (s 2H, NH2 ), 7.07–7.12 (m,
6H, H-5,20 ,30 ,40 ,50 ,60 ), 7.56–7.66 (m, 3H, H-6,8,9), 7.94
(d, 1H, J ¼ 8:4, H-7), 8.23 (d, 1H, J ¼ 8:4, H-10).
Compound 4c:
IR (KBr) mmax : 3455, 3340, 3023, 2930, 2210, 1645,
1600, 1580, 1470, 1378, 1266, 1030, 816, 750, 700 cm
1 ;
dH 4.98 (s, 1H, H-4), 7.24 (s, 2H, NH2 ), 7.13 (d, 1H,
J ¼ 8:4, H-5), 7.32–7.38 (m, 4H, H-40 ,50 ,60 ), 7.23 (s, 1H,
H-20 ), 7.56–7.66 (m, 3H, H-6,8,9), 7.89 (d, 1H, J ¼ 8:4,
H-7), 8.26 (d, 1H, J ¼ 8:4, H-10).
Compound 4d:
IR (KBr) mmax : 3475, 3320, 3021, 2920, 2195, 1660,
1595, 1400, 1360, 1278, 1185, 1100, 1040, 805, 750 cm
1 ;
dH 5.41 (s, 1H, CH), 7.20 (s, 2H, NH2 ), 7.01 (d, 1H,
J ¼ 8:4, H-5), 7.25–7.31 (m, 3H, H-40 ,50 ,60 ), 7.45 (d, 1H,
J ¼ 8:4, H-30 ), 7.56–7.67 (m, 3H, H-6,8,9), 7.89 (d,
1H, J ¼ 8:4, H-7), 8.24 (d, 1H, J ¼ 8:4, H-10).
Compound 4e:
IR (KBr) mmax : 3454, 3336, 3022, 2182, 1667, 1600,
1572, 1500, 1466, 1378, 1200, 1050, 860, 811, 755 cm
1 ;
dH 5.47 (s, 1H, H-4), 7.30 (s, 2H, NH2 ), 6.98 (d, 1H,
J ¼ 8:4, H-60 ), 7.59–7.61 (m, 2H, H-30 , 50 ), 7.39 (d, 1H,
H-5), 7.69–7.89 (m, 3H, H-6,8,9), 8.03 (d, 1H, J ¼ 8:4,
H-7), 8.25 (d, 1H, J ¼ 8:4, H-10).
Compound 4f:
IR (KBr) mmax : 3460, 3335, 2196, 1665, 1600, 1575,
1536, 1500, 1346, 1270, 1195, 1100, 805, 770 cm
1 ; dH
5.12 (s, 1H, H-4), 7.29 (s, 2H, NH2 ), 7.05 (d, 1H,
J ¼ 8:4, H-5), 7.5–7.7 (m, 3H, H-6,8,9), 7.52 (d, 2H, H-
20 ,60 ), 7.90 (d, 1H, J ¼ 8:4, H-7), 8.15 (d, 2H, H-30 ,50 ),
8.27 (d, 1H, J ¼ 8:4, H-10).
Compound 4i:
IR (KBr) mmax : 3430, 3325, 2190, 1650, 1610, 1582,
1540, 1502, 1340, 1244, 1200, 1070, 810 cm
1 ; dH 5.45 (s,
1H, H-4), 7.20 (s, 2H, NH2 ), 7.38 (d, 1H, J ¼ 8:4, H-9),
7.40–7.52 (m, 2H, H-6,7), 7.69–8.03 (m, 2H, H-5 and
H-8), 7.98 (d, 1H, J ¼ 9:2, H-10), 7.44 (d, 2H, H-20 and
H-60 ), 8.15 (d, 2H, H-30 and H-50 ).
3. Results and discussion
A series of substituted aromatic aldehydes 1 were
treated with malononitrile 2 and phenol 3 in the pres-
ence of CTABr under ultrasonic irradiation, the pro-
ducts were obtained in good to excellent yields. All of
the results are shown in Table 1.
We examined several experiments and found that the
effect of the catalyst and the mole ratio showed crucial
effect on these conversions. For example, benzaldehyde
1a reacted with malononitrile and 1-naphthol in the
presence of 1 mol% CTABr to give the expected com-
pound 4a in yield (70%) at 25–30 C under ultrasonic
irradiation after 2.5 h of reaction time. Increasing con-
centration of CTABr to 5 and 10 mol% results in raising
 T.-S. Jin et al. / Ultrasonics Sonochemistry 11 (2004) 393–397 395

Table 1
Synthesis of 2-amino2-chromene using CTABr as catalyst under ultrasound irradiation
Entry R1 Phenol Product Yielda (%) Mp (C) (Lit.)
1 C6 H5 1a 1-Naphthol 4a 92 210–211
2 4-ClC6 H4 1b 1-Naphthol 4b 95 231–232 (232) [10]
3 3-ClC6 H4 1c 1-Naphthol 4c 88 229–230
4 2-ClC6 H4 1d 1-Naphthol 4d 86 236–237
5 2,4-ClC6 H4 1e 1-Naphthol 4e 85 212–214
6 4-NO2 C6 H4 1f 1-Naphthol 4f 94 239–241
7 3-NO2 C6 H4 1g 1-Naphthol 4g 91 212–214 (214.5–216) [10]
8 C6 H5 1h 2-Naphthol 4h 78 280–282 (278–280) [10]
9 4-NO2 C6 H4 1i 2-Naphthol 4i 80 185–186
10 4-ClC6 H4 1j 2-Naphthol 4j 83 206–208 (208) [10]
11 2-ClC6 H4 1k 2-Naphthol 4k 72 259–261 (261–263) [10]
12 4-OHC6 H4 1l 1-Naphthol 5l 90 187–188 (188–189.5) [14]
13 4-CH3 OC6 H4 1m 1-Naphthol 5m 88 116–117 (114.5–115) [14]
14 3,4-OCH2 OC6 H3 1n 1–Naphthol 5n 83 200–201 (198–200) [14]
15 3-CH3 O-4-OHC6 H3 1o 1–Naphthol 5o 85 137–139 (136.5–139) [14]
16 4-Me2 NC6 H4 1p 1-Naphthol 5p 84 179–180 (180–181) [14]
17 3,4-OCH2 OC6 H3 1q 2–Naphthol 5q 78 201–202 (198–200) [14]
18 4-CH3 OC6 H4 1r 2-Naphthol 5r 82 116–117 (114.5–115) [14]
19 4-ClC6 H4 1s Resorcinol 5s 84 161–162 (162–163) [14]
20 2-ClC6 H4 1t Resorcinol 5t 90 94–95 (95–96) [14]
21 3,4-OCH2 OC6 H3 1u Resorcinol 5u 87 198–200 (198–200) [14]
22 4-CH3 OC6 H4 1v Resorcinol 5v 88 112–114 (114.5–115) [14]
a
Yields refers to the isolated products.

the reaction yield to 83% and 92%, respectively. Inter-
estingly, the efficient catalysis by CTABr was not ob-
served in the reactions carried out in organic solvents
such as ethanol and dichloromethane. The intermediates
(a-cyanocinnamonitrile derivative 5) were only ob-
tained. The solvent effect shows the unique property of
water to induce the hydrophobic interactions between
the substrates and the catalyst. It is worth noting that
almost no product can be obtained after 10 h in the
absence of the catalyst under ultrasonic irradiation.
Therefore, 10 mol% CTABr was chosen as a quantita-
tive catalyst for the reactions.
According to the results we have obtained in Table 1,
the scope and limitation of this method are investigated.
The effect of electron deficiency and the nature of the
substituents on the aromatic ring showed some effect
on this conversion. Benzaldehyde and other aromatic
aldehydes carrying electron-withdrawing substituents
(entries 1a–1k) reacted well under sonication with high
yields. Mention must be made here that para substituted
aromatic aldehydes gave higher yields of 2-amino-2-
chromenes than ortho and meta substituted aromatic
aldehydes did. However, aromatic aldehydes with elec-
tron-donating substituents (entries 1l–1r) do not give the
expected compounds but obtain the a-cyanocinnamo-
nitrile derivatives. We propose, as an explanation for the
result, that electron-donating substituents on the aro-
matic ring develop the electron density of C@C double
bond in the intermediate 5, which may be disadvanta-
geous to the reaction of the phenol ortho C-alkylation
with electrophilic C@C double bond. Therefore, the
present procedure is a selective preparation of 2-amino-
2-chromenes. Trials to introduce a pyran ring in resor-
cinol were unsuccessful. For example, when electron rich
aromatic aldehydes like anisaldehyde, piperonal and
electron deficient aldehydes such as o- and p-chloro-
benzaldehyde failed to provide the expected chromenes
but produced the a-cyanocinnamonitrile. Secondly, the
reaction of 1-naphthol or 2-naphthol with aromatic
aldehyde and malononitrile gave different results. For
instance, benzaldehyde reacted with malononitrile and
1-naphthol or 2-naphthol and gave yields of chromenes
4a (92%) and 4h (78%), respectively. When 4-nitro-
benzaldehyde was treated with malononitrile and
1-naphthol or 2-naphthol, the isolated yields of com-
pounds were 4f (94%) and 4i (80%), respectively. We
conclude 1-naphthol reveals higher reactivity than 2-
naphthol. In addition, the reaction rates and yields were
dramatically enhanced by ultrasound. The rate en-
hancement under ultrasound may be attributed to the
cavitation [13] and the activation of the catalyst and
substrates by sonic waves. It must be pointed out that all
of these reactions were carried out in water.
We propose the possible following mechanism to
account for the reaction [10]. The aldehyde 1 first con-
denses with malononitrile 2 to afford a-cyanocinnamo-
nitrile derivative 5. This step (1 + 2 fi 5) can be regarded
as a fast knoevenagel addition. With a model reaction,
the knoevenagel reaction of malononitrile and aromatic
aldehydes can be carried out in water without any cat-
alyst under ultrasonic irradiation. Thus we think
that the second step requires the presence of CTABr
396 T.-S. Jin et al. / Ultrasonics Sonochemistry 11 (2004) 393–397
Scheme 2.
probably. The phenol ortho C-alkylation by reaction
with the electrophilic C@C double bond giving the in-
termediate 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
products 4 were afforded by addition and elimination of
water (7 fi 8 fi 4) (Scheme 2). In this process, CTABr as
an emulsifying agent forms colloidal dispersion systems
with organic substrates and makes the mixture more
even, which contributes to promote these reactions.
O [4] (a) P.A. Grieco, Organic synthesis in water, Blackie, London,
CN H CN
1
+ 1
R H CN R CN
1 2 5 (c) B. Cornils, W.A. Herrmann, Aqueous––phase Organometallic
4. Conclusion
In summary, we have described a practical and effi-
cient procedure for the preparation of 2-amino-2-
chromenes through the three-component reaction of
aromatic aldehydes, malononitrile and phenols using a
catalytic amount of CTABr as catalyst under ultrasonic
irradiation. In addition, these reactions, which proceed
sluggishly in organic solvents, attest to the unique
property of water as a reaction medium. This procedure
offers several advantages including mild reaction con-
ditions, cleaner reaction, high yields of products as well
as a simple experimental and isolated procedure which
makes it a useful and attractive process for the synthesis
of these compounds. Mostly important, water has been
chosen as a green solvent for these reactions.
Acknowledgements
This project is supported by NSFC (29872011).
Educational Ministry of China, Educational Depart-
ment of Hebei Province (990104), Science and Tech-
nology Commission of Hebei Province.
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