Synthesis and characterization of novel 7-hydroxycoumarin derivatives

Article abstract of DOI:10.1007/s10600-013-0628-7

The synthesis of several coumarin Mannich bases is described. The reaction of natural 7-hydroxycoumarin with primary amines and two equivalents of formaldehyde in the presence of a base catalyst was studied. Several novel N-substituted angular 9,10-dihydro-2H,8H-chromeno[8,7-e][1,3]oxazin-2-ones were synthesized. Different aliphatic and aromatic amines have been used in the reaction, and the corresponding products were obtained with moderate to relatively good yields.

Full text of DOI:10.1007/s10600-013-0628-7

Chemistry of Natural Compounds, Vol. 49, No. 3, July, 2013 [Russian original No. 3, May–June, 2013]
SYNTHESIS AND CHARACTERIZATION OF NOVEL
7-HYDROXYCOUMARIN DERIVATIVES
1
2*
1,2
H. Mostafavi, R. Najjar, and E. Maskani
UDC 547.972
The synthesis of several coumarin Mannich bases is described. The reaction of natural 7-hydroxycoumarin
with primary amines and two equivalents of formaldehyde in the presence of a base catalyst was studied.
Several novel N-substituted angular 9,10-dihydro-2H,8H-chromeno[8,7-e][1,3]oxazin-2-ones were
synthesized. Different aliphatic and aromatic amines have been used in the reaction, and the corresponding
products were obtained with moderate to relatively good yields.
Keywords: 7-hydroxycoumarin, amines, oxazine, aminomethylation, Mannich reaction.
Coumarins are a very large group of 1,2-benzopyrone derivative that are widely distributed in a variety of natural
plant sources. Coumarins and their derivatives have attracted considerable attention due to their wide range of biological
activities such as antibacterial, antifungal, antiviral, antitubercular, antimalarial, anticoagulant, anti-inflammatory, anticancer,
antioxidant, and so on. Much effort, including the separation and purification of naturally occurring coumarins from a variety
of plants, as well as artificial synthesis of coumarin compounds with novel structures and properties, has been focused on the
research and development of coumarins as potential drugs. So far, some coumarins, for example, warfarin, acenocoumarol,
armillarisin A, hymecromone, and carbochromene have been approved for therapeutic purpose in clinic. More importantly, an
increasing number of coumarin compounds have displayed great potency in the treatment of various types of diseases [1–5].
Hence, the preparation of novel coumarin derivatives or modification of the natural 7-hydroxycoumarin seems an
interesting issue from both the chemical and biological points of view. The interest of investigators in the chemistry of Mannich
bases is constantly increasing, and this is due to not only their valuable pharmacological characteristics but also to the possibility
of formation of water-soluble salts suitable for studying of their biological activity. The aim of our work was to develop
procedures for synthesizing new aminomethyl derivatives of 7-hydroxycoumarin.
Mannich reaction conditions with appropriate ratio of substrate, amine, and formaldehyde in the presence of a base
[KOH, N,N-dimethylaminopyridine (DMAP)] is known to produce 3,4-dihydro-1,3-benzoxazine derivatives through
electrophilic substitution of [6–10].
R
N
10
HO
O
O
1
O
7
O
O
R
N
OH
HO
3
RNH
2CH O
2
+
2
r.t.
DMAP, reflux
5
1 - 10
1a - 10a
1b - 10b
R = 4-CH O-C H - (1a,b); 4-CH -C H - (2a,b); 4-Cl-C H - (3a,b); 4-O N-C H - (4a,b)
3
6
4
3
6
4
6
4
2
6 4
C H - (5a,b); C H -CH - (6a,b); n-C H - (7a,b); n-C H - (8a,b); s-C H - (9a,b)
6
5
6
5
2
3
7
4
9
4 9
n-C H - (10a,b)
6
13
Scheme 1
1) Laboratory for Synthesis of Natural and Pharmaceutical Compounds, Faculty of Chemistry, University of Tabriz,
5166616471, Tabriz, Iran; 2) Polymer Research Laboratory, Faculty of Chemistry, University of Tabriz, 5166616471, Tabriz,
Iran, fax: 0098 411 3340191, e-mail: najjar@tabrizu.ac.ir. Published in Khimiya Prirodnykh Soedinenii, No. 3, May–June,
2013, pp. 362–364. Original article submitted February 29, 2012.
0009-3130/13/4903-0423 02013 Springer Science+Business Media New York
423

TABLE 1. Melting Points and Yields of Compounds 1b–10b
Compound
Yield, %
Compound
Yield, %
Mp, ꢀC
Mp, ꢀC
146–147
131–132
159–160
173–174
156–157
78
75
83
40
88
122–123
67–68
61–63
58–59
88–89
93
44
52
47
48
1b
2b
3b
4b
5b
6b
7b
8b
9b
10b
1
TABLE 2. H NMR Spectra of 1b–10b (9,10-Dihydro-2H,8H-chromeno[8,7-e][1,3]oxazin-2-ones) (CDCl , ꢁ, ppm, J/Hz)
3
Compound
H-3*
H-4*
H-5*
H-6*
H-8
H-10
N(9) Substituent
6.23
6.23
6.25
6.29
6.23
6.22
6.23
6.20
6.24
7.60
7.60
7.61
7.64
7.63
7.63
7.62
7.62
7.63
7.24
7.23
7.25
7.30
7.23
7.27
7.24
7.24
7.23
6.76
6.75
7.76
6.82
6.75
6.79
6.73
6.73
6.72
5.37
5.41
5.39
5.49
5.43
4.93
4.94
4.93
4.74
4.79
4.78
4.93
4.82
4.18
4.17
4.17
4.20
3.74 (3H, s); 6.81 (2H, d); 7.10 (2H, d)
2.26 (3H, s); 7.06 (2H, d); 7.08 (2H, d)
7.07 (2H, d); 7.22 (2H, d)
1b
2b
3b
4b
5b
6b
7b
8b
9b
7.15 (2H, d); 8.19 (2H, d)
6.96 (2H, t); 7.14 (2H, d); 7.27 (1H, t)
3.90 (2H, s); 7.31 (2H, t); 7.32 (2H, t); 7.35 (1H, d)
0.93 (3H, t); 1.60 (2H, sex); 2.69 (2H, t)
0.93 (3H, t); 1.36 (2H, sex); 1.58 (2H, quin); 2.72 (2H, t)
0.90 (3H, t); 1.09 (3H, d); 1.42 (1H, m); 1.63 (1H, m);
2.88 (1H, sex)
5.86 (d)
4.99 (d)
4.94
6.24
7.62
7.24
2
6.73
4.17
0.89 (3H, t); 1.25–1.30 (8H, m); 1.56 (2H, m); 2.71 (2H, t)
10b
______
2
2
2
*H-3 (1H, d, J = 9.5); H-4 (1H, d, J = 9.5); H-5 (1H, d, J = 8.6); H-6 (1H, d, J = 8.6).
It is well known that several products may be formed during the Mannich reaction, depending on the substrate
structures and equivalents of formaldehyde [6]. The pyranodihydrobenzoxazines have been prepared by reaction of equimolar
amounts of primary amine and 7-hydroxycoumarin and two equivalents of formaldehyde or paraformaldehyde in the presence
of catalytic amounts of KOH [7–12]. This condensation was also carried out in acetic acid [13].
Pyranodihydrobenzoxazines are also formed by the action of formalin on Mannich base prepared from primary
amines [7]. Obviously, the synthesis of pyranodihydrobenzoxazines is a two-step process. 7-Hydroxycoumarin was added to
the N,N-di(hydroxymethyl)amine formed in situ by the reaction of formaldehyde (as formalin) with an adequate primary
amine (Scheme 1). A simultaneously occurring base-catalyzed C-and O-alkylation between the N,N-di(hydroxymethyl)amine
and 7-hydroxycoumarin then resulted in the formation of the final cyclic product [14–16].
Therefore, we annellated a 1,3-oxazine ring to the coumarin system via the reaction of 7-hydroxycoumarin and the
already formed N,N-di(hydroxymethyl)amine in the presence of DMAP, and the 1,3-oxazine ring was added exclusively to the
7,8-positions of the coumarin system.
Substituted anilines [4-methoxyaniline (1), 4-methylaniline (2), 4-chloroaniline (3), 4-nitroaniline (4), aniline (5)],
benzylamine (6), and aliphatic amines [n-propylamine (7), n-butylamine (8), sec-butylamine (9), and n-hexylamine (10)]
were used as the amine in this condensation.
If aniline were used as the amine, the experimental result showed that addition of the 1,3-dihydroxazine ring to the
coumarin system depended strongly on the structures of the starting anilines. The 9,10-dihydro-2H,8H-chromeno-
[8,7-e][1,3]oxazin-2-ones were not formed if anilines containing strong electron withdrawing or bulky substituents in the
ortho-position to the amine were used. The presence of strong electron withdrawing groups in positions meta or para to the
amine had little effect on the reaction. Pyranodihydrobenzoxazines were formed in satisfactory yields [14, 15].
As expected, the reaction of benzylamines and aniline with 7-hydroxycoumarin resulted in the formation of the corresponding
products with a satisfactory yield. The 1,3-dihydroxazine ring was smoothly annellated to 7-hydroxycoumarin using aliphatic
amines regardless of the structure or the presence of substituents. The reaction of 7-hydroxycoumarin with 4-nitroaniline did
not give the desired product, which can be attributed to the reduced nucleophilicity of the amine group in that compound. Also,
we could not synthesize pyranodihydrobenzoxazines using 2-aminopyrimidine as the amine.
424

1
The structure of the synthesized derivatives 1b–10b was confirmed by NMR spectroscopy. Thus, in the H NMR
spectra of 1b–10b, the signal for the H-8 proton of the coumarin ring disappears, and two 2H singlets appear for methylenes
that were characteristic of an annellated 1,3-dihydroxazine ring. For N-aryl derivatives 1b–5b and benzylamine 6b, the 10-CH
2
1
and 8-CH methylenes resonated at 4.18–4.93 and 4.93–5.49 ppm, respectively. However, the H NMR spectra of N-alkylamine
2
derivatives 7b–10b showed singlet peaks for 10-CH and 8-CH at 4.17–4.20 and 4.93–5.86 ppm, respectively.
2
2
EXPERIMENTAL
The course of reactions and purity of the products were monitored by TLC on Merck 60 F plates with elution by
254
CHCl –CH OH (9:1 or 19:1). Melting points were determined by an Electrothermal 9100 melting point equipment. NMR
3
3
spectra were recorded on a Bruker Avance 400 (400 MHz) spectrometer in CDCl using tetramethylsilane as an internal
3
standard.
General procedure for the preparation of the 9,10-dihydro-2H,8H-chromeno[8,7-e][1,3]oxazin-2-ones 1b–10b. A
solution of the appropriate primary amine (4.4 mmol) in dioxane (10 mL) was treated with formalin solution (35%, 0.9 mL,
10 mmol). The resulting mixture was held at room temperature and stirred vigorously for the required times: 3–5 h for substituted
anilines and benzylamines and 2 h for aliphatic amines. Then, hydroxycoumarin (0.85 g, 4 mmol) and a catalytic amount of
DMAP (20 mg) were added, and the reaction mixture was heated to 100ꢀC. The reaction was continued for 10–15 h in the case
of substituted anilines and benzylamines and 7 h for aliphatic amines. The course of all the reactions was monitored by TLC.
After completion of the reaction, the solvent was removed in a rotary evaporator. The oily residue was recrystallized from
2-propanol. Final purification of the products was carried out by preparative thin-layer chromatography (PTLC) using laboratory-
prepared plates with a thickness of 1 mm and CHCl –CH OH as eluent. The melting points and yields of the synthesized
3
3
products are given in Table 1. The spectral data of the products are summarized in Table 2.
ACKNOWLEDGMENT
The financial support from the Postgraduate Office of the University of Tabriz is gratefully acknowledged.
REFERENCES
1.
2.
3.
F. Borges, F. Roleira, N. Milhazes, L. Santana, and E. Uriarte, Curr. Med. Chem., 12, 887 (2005).
L. Wu, X. Wang, W. Xu, F. Farzaneh, and R. Xu, Curr. Med. Chem., 16, 4236 (2009).
M. E. Riveiro, N. D. Kimpe, A. Moglioni, R. Vazquez, F. Monczor, C. Shayo, and C. Davio, Curr. Med. Chem., 17,
1325 (2010).
4.
5.
6.
7.
8.
9.
M. V. Kulkarni, G. M. Kulkarni, C. H. Lin, and C. M. Sun, Curr. Med. Chem., 13, 2795 (2006).
M. Curini, G. Cravotto, F. Epifano, and G. Giannone, Curr. Med. Chem., 13, 199 (2006).
M. Tramontini, Synthesis, 12, 703 (1973).
R. B. Desai, J. Org. Chem., 26, 5251 (1961).
M. G. Patel and S. Sethna, J. Indian Chem. Soc., 39, 595 (1962).
D. R. Shridhar, C. V. R. Sastry, B. Lal, G. S. Raddi, K. K. Bhopale, R. S. Khokar, and K. Tripathi, Indian J. Chem.,
19B, 1065 (1980).
10.
11.
12.
13.
14.
15.
16.
J. N. Gadre and P. S. Raote, Indian J. Chem., 32B, 1285 (1993).
M. E. Kuehne, CIBA Corp., U. S. Pat. No. 3, 142, 676; Chem. Abstr., 61, 47921 (1964).
P. Eswaraiah, M. Nagesam, and M. S. Raju, Chim. Acta Turc., 19, 239 (1991).
N. Mohanty, K. K. Patnaik, and M. K. Rout, J. Indian Chem. Soc., 45, 969 (1968).
I. V. Nagorichna, M. M. Garazd, Ya. L. Garazd, and V. P. Khilya, Chem. Nat. Compd., 43, 15 (2007).
S. P. Bondarenko, M. S. Frasinyuk, and V. P. Khilya, Chem. Nat. Compd., 45, 492 (2009).
S. P. Bondarenko, M. S. Frasinyuk, and V. P. Khilya, Chem. Heterocycl. Compd., 46, 529 (2010).
425