Microwave-assisted reactions: three component process for the synthesis of 2-amino-2-chromenes under microwave heating

Article abstract of DOI:10.1002/jhet.13

A simple and efficient three component process for the synthesis of 2-amino-2-chromenes utilizing the reaction of aryl aldehydes 1a-1h with active methylenes 2a, b and 1-naphthol 3 in refluxing ethanol/piperidine under microwave-heating is described.

Full text of DOI:10.1002/jhet.13

March 2009
Microwave-Assisted Reactions: Three Component Process for the
Synthesis of 2-Amino-2-chromenes Under Microwave Heating
149
Ramadan A. Mekheimer and Kamal U. Sadek*
Department of Chemistry, Faculty of Science, El-Minia University, El-Minia 61519, Egypt
*E-mail: kusadek@yahoo.com
Received August 29, 2007
DOI 10.1002/jhet.13
Published online 18 February 2009 in Wiley InterScience (www.interscience.wiley.com).
A simple and efficient three component process for the synthesis of 2-amino-2-chromenes utilizing
the reaction of aryl aldehydes 1a–1h with active methylenes 2a,b and 1-naphthol 3 in refluxing ethanol/
piperidine under microwave-heating is described.
J. Heterocyclic Chem., 46, 149 (2009).
INTRODUCTION
Microwave-assisted reactions have received great inter-
est because of their simplicity in operation, enhanced
reaction rates, products with high purity, and better
yields compared to those conducted by conventional
heating [12–14]. Also, a three-component one step reac-
tion is of great interest for cost savings due to raw mate-
rials consumption, energy use, and time. We do believe
that combining microwave heating technique with a
three-component one step reaction will be beneficial and
interesting. In continuation to our interest for the synthe-
sis of azoles, azines, and fused rings [15–17], we report
herein the synthesis of 2-amino-2-chromenes via three-
component synthesis by using microwave technique.
Substituted 2-amino-2-chromenes have received con-
siderable attention due to their importance as pigments,
cosmetics, potential agrochemicals, and being the main
constituents of many natural products [1–5]. Accord-
ingly, their synthesis has received much attention from
organic chemists. These compounds are generally pre-
pared by multicomponent condensation of aromatic
aldehyde 1, active methylene derivatives 2 and activated
phenol or naphthol 3 in the presence of piperidine using
acetonitrile or ethanol as a solvent under conventional
heating for periods ranging from 2–3 h in moderate
yields [6–9]. Also, relatively benign reagents such as
cetyltrimethylammonium chloride (CTACl) and basic
alumina in water have been used [10]. Thus, substituted
2-amino-2-chromenes 4 will be produced in moderate to
good yields by heating a mixture of 1, 2, and 3 in water
in the presence of a catalytic amount of CTACl for 6 h
under reflux. It is obvious that, most of these require
prolonged reaction time, reagents in stoichiometric
amounts and provide moderate yields of the product.
Recently [11], a three component condensation in
MeOH in the presence of nanosized magnesium oxide
as a catalyst at room temperature has been reported.
Although, this process is efficient and convenient, the
usage of MeOH as a solvent for the reaction and work-
up is not recommended due to the toxicity.
RESULTS AND DISCUSSION
The synthesis of 2-amino-2-chromenes under conven-
tional heating technique requires prolonged reaction
time and affords moderate yields of products. Conduct-
ing a three-component synthesis of these target mole-
cules under microwave irradiation and, to the best of
our knowledge, has never been published before. Thus,
when a mixture of benzaldehyde 1a, malononitrile 2a
and a-naphthol 3 in 10 mL of ethanol and in the pres-
ence of piperidine as a catalyst was refluxed in a micro-
wave labstation for 5 min at 80ꢀC, the corresponding 2-
amino-2-chromene derivative 4a was obtained in almost
quantitative yield (Scheme 1). The structure of the
formed product was established by spectral and analyti-
cal data and also by comparison with authentic sample
synthesized by reaction of benzylidene malononitrile 5
with a-naphthol under conventional heating [18]. Thus,
In recent years, there has been extensive effort to
adapt green technologies in synthetic organic chemistry,
so as to minimize waste production, material and energy
consumption, and the use of hazardous compounds.
C
V
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R. A. Mekheimer and K. U. Sadek
Vol 46
Scheme 1
IR spectrum for compound 4a revealed both amino and
cyano groups at mmax 3400 and 2200 cmꢁ1, respectively.
1H NMR spectrum of this product revealed signals that
are in accord with the proposed structure. It reveals sig-
nals at d ¼ 4.77 (s, 1H, 4H-pyran); 6.8 (br, s, 2H, NH2),
6.93 (d, J ¼ 8 Hz, 1H, H-5), 7.08–7.23 (m, 5H, ArAH);
7.33–7.43 (m, 3H, ArAH), 7.52 (d, J ¼ 8 Hz, 1H, H-7),
8.10 (d, J ¼ 8 Hz, 1H, H-10). 13C NMR revealed sig-
nals at d ¼ 40.92, 61.06, 108.50, 116.6, 120.80, 123.20,
124.80, 125.90, 126.80, 126.92, 127.80, 129.10, 129.50,
133.22, 133.40, 142.90, 143.30, 158.60. To examine the
aromatic aldehyde substrate effect on the rate and over-
all yield, various aldehydes 1b–1d were used under the
aforementioned reaction conditions. From the results, we
can see that all reactions proceeded smoothly to afford
the corresponding 2-amino-2-chromene derivatives 4b–
4d in high yield. Slightly diminished yields were
observed when the substituent is an electron withdraw-
ing group.
the reaction products were established based on analyti-
cal and spectral data (cf. Experimental part for details).
Cyanothioacetamide (2b) was also examined as an
active methylene compound and the corresponding 2-
amino-2-chromen 4h was obtained.
In conclusion, in green chemistry it is generally rec-
ognized that the best reaction requires no solvent. In our
procedure we used a little amount of ethanol compared
to the quantities of starting materials. Refluxing under
microwave technique in the presence of this little
amount of solvent perform a homogenous heating,
which prevents charring of neat samples and offers a
simple and high yield process for the synthesis of 2-
amino-2-chromene derivatives.
EXPERIMENTAL
All melting points were determined on a Gallenkamp melt-
ing point apparatus and are uncorrected. The reactions were
conducted in milestone START-Labstation for microwave
enhanced chemistry provided with a sensor for adjusting the
temperature and a refluxing condenser. IR spectra (KBr) were
measured with a Schimadzu Model 470 spectrophotometer.
To examine the scope of such techniques, heteroaryl
and aliphatic aldehydes 1e–1h were also used and the
corresponding 2-amino-2-chromene derivatives 4e–4h
were obtained in high yields. The structure assigned for
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2009
Microwave-Assisted Reactions: Three Component Process for the Synthesis of
2-Amino-2-chromenes Under Microwave Heating
151
1H NMR (300 MHz) and 13C NMR (100 MHz) spectra were
measured on a Varian spectrometer using DMSO-d6 as solvent
and TMS as internal Standard, chemical shifts are expressed as
d ppm. Analytical data were determined on the Microanalytical
Data Unit at Cairo University. Compounds 4g,4h were found
identical with authentic samples [18].
General procedure for the synthesis of 2-amino-2-chro-
menes (4a–4g). A solution of the appropriate aldehyde 1, a-
naphthol (2) and active methylene 3 (0.01 mol) in ethanol (10
mL), and catalytic amount of piperidine (2 drops) was heated
under reflux in a milestone labstation at 80ꢀC for a period of
5–8 min. Upon standing at room temperature a solid product
was formed which was collected by filtration to afford com-
pounds 4a–4g. An additional amount of products were
obtained via evaporation of the solvent under reduced
pressure.
1H, H-5 or H-6), 7.22 (s, 2H, NH2); 7.33 (dd, J ¼ 8 Hz and
4.5 Hz, pyridine H-5); 7.50–7.70 (m, 4H, H-6 or H-5, H-7, H-
8, and pyridine H-6), 7.89 (d, J ¼ 8 Hz, 1H, H-7 or H-10);
8.24 (d, J ¼ 8 Hz,1H, H-7 or H-10), 8.46 (d, J ¼ 4.5 Hz, 1H,
pyridine H-4), 8.55 (s, 1H, pyridine H-2).
2-Amino-3-cyano-4-(4-pyridyl)-4H-benzo[h]chromene (4f).
Compound 4f (93%) was obtained as yellow crystals (ethanol).
M.P. 200–202ꢀC. Anal. Calcd. for C19H13N3O (299.33): C,
76.24; H, 4.38; N, 14.04. Found: C, 76.13; H, 4.34; N, 14.24.
1
IR (KBr): 3354 (NH2); 2220 (CN) cmꢁ1. H NMR (300 MHz,
DMSO-d6): d ¼ 4.97 (s, 1H, 4H-pyran), 7.14 (d, J ¼ 8 Hz,
1H, H-5 or H-6), 7.27 (m, 4H, pyridine H-3, pyridine H-5 and
NH2), 7.56–7.73 (m, 2H, H-8 or H-9), 7.66 (d, J ¼ 8 Hz, 1H,
H-6 or H-5), 7.80 (d, J ¼ 8 Hz, 1H, H-7 or H-10), 8.22 (d,
J ¼ 8 Hz, 1H, H-7, or H-10), 8.52 (d, 2H, J ¼ 5 Hz, pyridine
H-2 and H-6).
2-Amino-3-cyano-4-phenyl-4H-benzo[h]chromene (4a).
Compound 4a (93%) was obtained as colorless crystals (etha-
nol). M.P. 179–180ꢀC. Anal. Calcd. for C20H14N2O (298.35):
C, 80.52; H, 4.73; N, 9.40. Found: C, 80.40; H, 4.63; N, 9.50.
Acknowledgment. K. U. Sadek is grateful to the AvH Founda-
tion for donation of milestone microwave labstation, which is of
great help in finishing this work.
1
IR (KBr): 3420 (NH2); 2200 (CN) cmꢁ1. H NMR (300 MHz,
DMSO-d6): d ¼ 4.77 (s, 1H, 4H-pyran); 6.8 (br, s, 2H, NH2),
6.93 (d, J ¼ 8 Hz, 1H, H-5), 7.08–7.23 (m, 5H, ArAH); 7.33–
7.43 (m, 3H, ArAH), 7.52 (d, J ¼ 8 Hz, 1H, H-7), 8.10 (d,
J ¼ 8 Hz, 1H, H-10).
REFERENCES AND NOTES
[1] Ellis, G. P. In Chromenes, Chromanes and Chromones;
Weissberger, A.; Taylor, E. C., Eds.; John Wiley: New York, 1977;
Chapter 2, p 13.
2-Amino-3-cyano-4-(4-methoxyphenyl)-4H-benzo[h]chro-
mene (4b). Compound 4b (94%) was obtained as yellow crys-
tals (ethanol). M.P. 188–189ꢀC. Anal. Calcd. for C21H16N2O2
(328.36): C, 76.80; H, 4.91; N, 8.53. Found: C, 76.70; H,
[2] Hafez, E. A.; Elnagdi, M. H.; Elagamy, A. A.; El-Taweel,
F. A. M. Hetercycles 1987, 26, 903.
[3] Sofan, M. A.; El-Taweel, F. A. M.; Elnagdi, M. H. Liebigs
Ann Chem 1989, 935.
4.80; N, 8.33. IR (KBr): 3430 (NH2); 2200 (CN) cmꢁ1 1H
.
NMR (300 MHz, DMSO-d6): d ¼ 3.90 (s, 3H, OCH3), 4.54 (s,
1H, 4H-pyran), 6.82 (br, s, 2H, NH2), 7.0 (d, J ¼ 8 Hz, 1H,
H-5), 7.10–7.22 (m, 4H, ArAH), 7.39–7.40 (m, 3H, ArAH),
7.53 (d, J ¼ 8 Hz, 1H, H-7), 8.12 (d, J ¼ 8 Hz, 1H, H-10).
2-Amino-3-cyano-4-(4-chlorophenyl)-4H-benzo[h]chro-
mene (4c). Compound 4c (94%) was obtained as yellow crys-
tals (ethanol). M.P. 232–234ꢀC. Anal. Calcd. for C20H13ClN2O
(332.78): C, 72.18; H, 3.94; Cl, 10.65; N, 8.42. Found: C,
72.10; H, 3.70; Cl, 10.50; N, 8.20. IR (KBr): 3450 (NH2);
[4] Abdel Galil, F. M.; Riad, B. Y.; Sherif, S. M.; Elnagdi, M.
H. Chem Lett 1982, 11, 1123.
[5] Varma, R. S.; Dahyiya, R.
8038.
J Org Chem 1998, 63,
[6] Abdel-Latif, F. F. Indian J Chem 1990, 29B, 664.
[7] Elagamy, A. G. A.; El-Taweel, F. M. A. Indian J Chem
1990, 29B, 885.
[8] Elagamy, A. G. A.; El-Taweel, F. M. A.; Khodeir, M. N.
M.; Elnagdi, M. H. Bull Chem Soc Jpn 1993, 66, 464.
[9] Bioxham, J.; Dell, C. P.; Smith, C. W. Heterocycles 1994,
38, 399.
2200 (CN) cmꢁ1
.
1H NMR (300 MHz, DMSO-d6): d ¼ 4.55
(s, 1H, 4H-pyran), 6.70 (br, s, 2H, NH2), 7.1 (d, J ¼ 8 Hz,
1H, H-5), 7.21–7.33 (m, 4H, ArAH), 7.40–7.45 (m, 3H,
ArAH), 7.56 (d, J ¼ 8 Hz, 1H, H-7), 8.15 (d, J ¼ 8 Hz, 1H,
H-10).
[10] Ballini, R.; Bosica, G.; Conforti, M. L.; Maggi, R.;
Mazzacani, A.; Righi, P.; Sartori, G. Tetrahedron 2001, 57,
1395.
[11] Dalip, K.; Reddy, V. B.; Mishra, B. G.; Rana, R. K.; Nada-
gouda, M. N.; Varma, R. S. Tetrahedron 2007, 63, 3093.
[12] Richard, D.; Carpenter, K. S. L.; Mark, J. K. J Org Chem
2007, 72, 284.
2-Amino-3-cyano-4-(4-nitrophenyl)-4H-benzo[h]chromene
(4d). Compound 4d (85%) was obtained as yellow crystals
(ethanol). M.P. 240–241ꢀC. Anal. Calcd. for C20H13N3O3
(343.34): C, 69.96; H, 3.82; N, 12.24. Found: C, 69.80; H,
[13] Caddick, S. Tetrahedron 1995, 51, 10403.
[14] Majetich, G.; Wheless, K. In Microwave-Enhanced Chemis-
try; Kinsington, H. M.; Haswell, S. J., Eds.; American Chemical Soci-
ety: Washington, DC, 1997; p 455.
3.92; N, 12.13. IR (KBr): 3440 (NH2), 2220 (CN) cmꢁ1 1H
.
NMR (300 MHz, DMSO-d6): d ¼ 4.58 (s, 1H, 4H-pyran),
6.79 (br, s, 2H, NH2), 7.18 (d, J ¼ 8 Hz, 1H, H-5), 7.25–7.41
(m, 4H, ArAH), 7.46–7. 51 (m, 3H, ArAH), 7.61 (d, J ¼ 8
Hz, 1H, H-7), 8.21 (d, J ¼ 8 Hz, 1H, H-10).
[15] Mekheimer, R. A.; Abdelhameed, A. M.; Sadek, K. U.
Arkivoc 2007, 13, 269.
2-Amino-3-cyano-4-(3-pyridyl)-4H-benzo[h]chromene (4e).
Compound 4e (95%) was obtained as yellow crystals (ethanol).
M.P. 240–241ꢀC. Anal. Calcd. for C19H13N3O (299.33): C,
76.24; H, 4.38; N, 14.04. Found: C, 76.10; H, 4.50; N, 14.00.
[16] Barsy, M. A.; Abdel Latif, F. M.; Aref, A. M.; Sadek, K.
U. Green Chem 2002, 4, 196.
[17] Mekheimer, R. A.; Abdel Naby, H. A.; Abdelhameed, A.
M.; Sadek, K. U. Heterocycl Commun 2000, 6, 301.
[18] Elnagdi, M. H.; Elghndour, A. H. H.; Ibrahim, M. K. A.;
Abdel Hafiz, I. S. Z. Naturforsch 1992, 47B, 572.
1
IR (KBr): 4310 (NH2); 2220 (CN) cmꢁ1. H NMR (300 MHz,
DMSO-d6): d ¼ 4.90 (s, 1H, 4H-pyran); 7.11 (d, J ¼ 8 Hz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet