One-pot synthesis of 2-amino-4-aryl-3-carbalkoxy-7,7-dimethyl-5,6,7,8- tetrahydrobenzo[b]pyran derivatives catalyzed by KF/basic Al2O 3 under ultrasound irradiation

Article abstract of DOI:10.1081/SCC-200043233

Synthesis of 2-amino-4-aryl-3-carbalkoxy-7,7-dimethyl-5-oxo-5,6,7,8- tertrahydrobenzo[b]pyran derivatives was carried out in 81-98% yields by one-pot condensation of aromatic aldehydes with cyanoacetic esters and 5,5-dimethyl-1,3-cyclohexanedione catalyze

Full text of DOI:10.1081/SCC-200043233

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One‐Pot Synthesis of
2‐Amino‐4‐aryl‐3‐carbalkoxy‐7,7‐d
Derivatives Catalyzed by KF/
Basic Al2O3 Under Ultrasound
Irradiation
Ji‐Tai Li a , Wen‐Zhi Xu a , Li‐Chao Yang a
Tong‐Shuang Li a
&
a College of Chemistry and Environmental Science,
Hebei University, Key Laboratory of Analytical
Science and Technology of Hebei Province, Hezno
Road No. 88, Baoding, 071002, P. R. China
Version of record first published: 12 Jan 2011.
To cite this article: Ji‐Tai Li, Wen‐Zhi Xu, Li‐Chao
Yang & Tong‐Shuang Li (2004): One‐Pot Synthesis of
2‐Amino‐4‐aryl‐3‐carbalkoxy‐7,7‐dimethyl‐5,6,7,8‐tetrahydrobenzo[b]pyran
Derivatives Catalyzed by KF/Basic Al2O3 Under Ultrasound Irradiation, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 34:24, 4565-4571
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 24, pp. 4565–4571, 2004
One-Pot Synthesis of 2-Amino-4-aryl-
3-carbalkoxy-7,7-dimethyl-5,6,7,8-
tetrahydrobenzo[b]pyran Derivatives
Catalyzed by KF/Basic Al2O3 Under
Ultrasound Irradiation
*
Ji-Tai Li, Wen-Zhi Xu, Li-Chao Yang,
and Tong-Shuang Li
College of Chemistry and Environmental Science, Hebei University,
Key Laboratory of Analytical Science and Technology of Hebei
Province, Baoding, P. R. China
ABSTRACT
Synthesis of 2-amino-4-aryl-3-carbalkoxy-7,7-dimethyl-5-oxo-5,6,7,8-
tertrahydrobenzo[b]pyran derivatives was carried out in 81–98% yields
by one-pot condensation of aromatic aldehydes with cyanoacetic esters
*
Correspondence: Ji-Tai Li, College of Chemistry and Environmental Science,
Hebei University, Key Laboratory of Analytical Science and Technology of Hebei
Province, Hezno Road No. 88, Baoding 071002, P. R. China; Fax: þ86-312-
5079628; E-mail: orgsyn@mail.hbu.edu.cn.
4565
DOI: 10.1081/SCC-200043233
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Li et al.
and 5,5-dimethyl-1,3-cyclohexanedione catalyzed by KF/basic Al2O3 at
room temperature under ultrasound irradiation.
Key
Supported catalyst; Ultrasound; One-pot synthesis.
Words: Benzopyrans;
5,5-Dimethyl-1,3-cyclohexanedione;
Recently, 4H-benzo[b]pyran derivatives have attracted strong interest due
to their useful biological and pharmacological activities, and anticoagulant,
spasmolytic, diuretic, anticancer, and antianaphylactin[1] properties. Some
of them can be employed as photoactive materials[2] and utilized as potential
biodegradable agrochemicals.[3] In addition, polysubstitued 4H-pyrans consti-
tute a structural unit of a series of natural products,[4] and because of the
inherent reactivity of the built-in pyran rings, they are versatile synthetic
intermediates.[5] So the synthesis of this heterocyclic nucleus is of much
current importance. Elnagdi, Aal, and Yassin have performed the reaction
of arylmethylidenemalononitriles with 5,5-dimethyl-1,3-cyclohexanedione
catalyzed by piperidine in acetic acid solution to prepare 2-amino-4-aryl-3-
cyano-7,7-dimethyl-5-oxo-5,6,7,8-tertrahydro-4H-benzo[b]pyrans.[6] Recently,
Hassanien et al. have synthesized 5,6,7,8-tetrahydrobenzo[b]pyrans deriva-
tives through one-pot condensation of aromatic aldehydes, malononitrile,
and 5,5-dimethyl-1,3-cyclohexanedione catalyzed by ammonium acetate.[7]
Furthermore, Wang et al. have prepared 5-oxo-5,6,7,8-4H-benzo[b]pyran
derivatives catalyzed by KF-Al2O3 in DMF.[8] In addition, microwave
irradiation was also used to promote the condensation of 5,5-dimethyl-1,3-
cyclohexanedione and b-amino-b-carbethoxy styrene.[9] However, in spite
of their potential utility, some of the reported methods suffer drawbacks
such as longer reaction time, higher temperatures, and lower yields.
Ultrasound has increasingly been used in organic synthesis in the last
three decades. Compared with traditional methods, the procedure is more
convenient and easily controlled. A large number of organic reactions can
be carried out in higher yield, shorter reaction time, or milder conditions
under ultrasonic irradiation.[10,11]
In recent years, catalysts and reagents supported on inorganic substrates
have received increasing attentionbecause of their high level of chemoselectivity
and environmental compatibility as well as simplicity of operation and their
ready availability at low cost. In particular, KF/basic Al2O3 is known to be a
useful solid supported catalyst for various base-catalyzed organic reactions.[12]
In this paper, we wish to report an efficient and mild procedure for the
synthesis of 4H-benzo[b]pyran derivatives via one-pot condensation of
aromatic aldehydes with cyanoacetic esters and 5,5-dimethyl-1,3-cyclohexa-
nedione catalyzed by KF/basic Al2O3 under ultrasound irradiation (Sch. 1).

One-Pot Synthesis Under Ultrasound Irradiation
4567
Scheme 1.
EXPERIMENTAL
The KF/basic Al2O3 was prepared by the procedure reported in the
literature.[13] Melting points were uncorrected. IR spectra were recorded on
1
Bruker VECTOR 22. H NMR spectra were measured on Bruker ANAVCE
400 (400 MHz) spectrometer using TMS as internal standard and CDCl3 as
solvent. Sonication was performed on a Shanghai Branson-CQX ultrasonic
cleaner (with a frequency of 25 kHz and a nominal power of 250 W) and
SK 250 LH ultrasonic cleaner (with a frequency of 59 kHz and a nominal
power of 250 W; Shanghai Kudos Ultrasonic Instrument Co., Ltd.). The reac-
tion flask was located in the maximum energy area in the cleaner and addition
or removal of water was used to control the temperature of the water bath.
General Procedure
Aromatic aldehydes (1, 1 mmol), cyanoacetate (2, 1.1 mmol), 5,5-dimethyl-
1,3-cyclohexanedione (3, 1.1 mmol), KF/basic Al2O3 (145 mg), and anhy-
drous alcohol were added in a Pyrex flask (50 mL). The mixture was irradiated
in the water bath of an ultrasonic cleaner at 27–348C for the period as indi-
cated in Table 1. (Sonication was continued until the intermediate was disap-
peared as indicated by TLC.) The mixture was dissolved in acetone. The
catalyst was removed by filtration and washed with acetone. The solvent
was evaporated under reduced pressure to give a solid. The crude product
was purified by column chromatography on silica gel (200–300 mesh), and
eluted with petroleum ether or a mixture of petroleum ether and diethyl
ether. The authenticity was established by comparing their melting points
1
with these of the literature and the spectra data of IR, H NMR.
1
4g: H NMR (400 MHz, CDCl3): d ¼ 0.99 (s, 3H, CH3), 1.13 (s, 3H,
CH3), 2.18 (d, 1H, J ¼ 16.4 Hz, 8-H), 2.27 (d, 1H, J ¼ 16.4 Hz, 8-H), 2.49
(s, 2H, 6-H), 3.61 (s, 3H, OCH3), 4.82 (s, H, 4-H), 6.29 (br. s, 2H, NH2),

4568
Li et al.
Table 1. Condensation of 4-chlorobenzaldehyde, ethyl cyanoacetate and 5,5-
dimethyl-1,3-cyclohexanedione under different conditions.
Entry
Catalyst
Frequency, kHz
Solvent
T, min
Yield, %
1
2
3
4
5
6
K2CO3
KOH
25
25
EtOH
EtOH
EtOH
CH3OH
EtOH
EtOH
65
110
30
70
88
98
88
93
78
KF/Al2O3
KF/Al2O3
KF/Al2O3
KF/Al2O3
25
25
40
40
59
stirring
390
7.38–8.09 (m, 4H, Ar-H) ppm; nmax (KBr):3431, 3313, 3074, 2966, 1695,
1658, 1617, 1531, 1469, 1439, 1352, 799, 689 cm21
.
1
4k: H NMR (400 MHz, CDCl3): d ¼ 1.02 (s, 3H, CH3), 1.12 (s, 3H,
CH3), 1.16 (t, 3H, J ¼ 7.2 Hz, CH2CH3), 2.16 (d, 1H, J ¼ 16.4 Hz, 8-H),
2.24 (d, 1H, J ¼ 16.4 Hz, 8-H), 2.43 (s, 2H, 6-H), 4.05 (q, 1H, J ¼ 7.2 Hz,
OCH2CH3), 4.06 (q, 1H, J ¼ 7.2 Hz, OCH2CH3), 4.98 (s, H, 4-H), 6.26
(br. s, 2H, NH2), 7.12–7.28 (m, 3H, Ar-H) ppm; nmax (KBr):3428, 3310,
3057, 2963, 2927, 1694, 1655, 1613, 1559, 1516, 1467, 846 cm21
.
4l: 1H NMR (400 MHz, CDCl3): d ¼ 0.98 (s, 3H, CH3), 1.13 (s, 3H, CH3),
1.15 (t, 3H, J ¼ 7.2 Hz, CH2CH3), 2.17 (d, 1H, J ¼ 16.4 Hz, 8-H), 2.27 (d, 1H,
J ¼ 16.4 Hz, 8-H), 2.47 (s, 2H, 6-H), 4.04 (q, 1H, J ¼ 7.2 Hz, OCH2CH3),
4.05 (q, 1H, J ¼ 7.2 Hz, OCH2CH3), 4.81 (s, H, 4-H), 6.29 (br. s, 2H, NH2),
7.46 (d, 2H, J ¼ 4.8 Hz, Ar-H), 8.01 (d, 2H, J ¼ 4.8 Hz, Ar-H) ppm; nmax
(KBr): 3474, 3337, 2964, 2900, 1690, 1658, 1622, 1515, 1344, 829 cm21
.
The results are summarized in Tables 1 and 2. It can easily be seen that
one-pot condensation of aromatic aldehydes with methyl cyanoacetate or
ethyl cyanoacetate and 5,5-dimethyl-1,3-cyclohexanedione gives good
yields under ultrasound.
In order to improve the yield, we did the experiment with different catalysts
such as potassium hydroxide, potassium carbonate, and KF/basic Al2O3. We
found out that KF/basic Al2O3 improves the reaction more effectively. In the
present procedure, the KF/basic Al2O3 also could be recycled after simply
heating at 1208C for 4 h and the activity of the catalyst did not decrease
evidently. Further, we observed the effect of different frequencies of ultrasound
irradiation on this reaction. When the frequency was 25kHz, the reaction
required 30min and resulted the desired the product in 98% yield, while under
59kHz irradiation, the condensation reaction was completed in 40min with
93% yield. We also studied the effect of different solvents on the reaction, and
ethanol gave satisfactory results. Therefore, one-pot condensation was carried
out in ethanol catalyzed by KF/basic Al2O3 under 25kHz ultrasound irradiation.

One-Pot Synthesis Under Ultrasound Irradiation
4569

4570
Li et al.
As shown in Table 2, the condensation of aromatic aldehydes 1 with
methyl cyanoacetate (or ethyl cyanoacetate) 2 and 5,5-dimethyl-1,3-
cyclohexanedione 3 affords products 4 in good yields. The dramatic improve-
ment observed is with regard to reaction yields. For example, in the reaction of
2-cyano-3-aryl-1-acrylate and 3 catalyzed by KF/Al2O3 using stirring in
DMF,[8] 4c and 4e were obtained in 70% and 63% yields for 1–3 h, respect-
ively. However, the present one-pot procedure results 4c in 97% yield within
40 min and 4d in 96% yield within 30 min, respectively. When we carried out
the reaction in the absence of ultrasound, 4f was obtained in 78% yield for
390 min, while under ultrasound irradiation 4f resulted in 98% yield within
30 min. It is apparent that the condensation can be finished in shorter reaction
time to give good yields under ultrasound. Meanwhile, aromatic aldehydes
carrying either electron-donating or electron-withdrawing substituents all
reacted very well.
In conclusion, we have described a rapid and convenient procedure for
the synthesis of 2-amino-4-aryl-3-carbalkoxy-7,7-dimethyl-5-oxo-5,6,7,8-
tetrahydrobenzo[b]pyran derivatives catalyzed by KF/basic Al2O3 under
ultrasound irradiation.
ACKNOWLEDGMENTS
The project was supported by Educational Ministry of China and Natural
Science Foundation of Hebei Province (203107), P. R. China.
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Received in Japan 1 July 2004