The legend of 4-aminocoumarin: Use of the Delepine reaction for synthesis of 4-iminocoumarin

Article abstract of DOI:10.1007/s11164-012-0694-7

Use of the Delepine reaction for synthesis of 4-aminocoumarin from 4-chlorocoumarin was not successful. The product was 4-iminocoumarin instead of 4-aminocoumarin. The 4-iminocoumarin was characterized by elemental analysis and spectral studies (FT-IR,

Full text of DOI:10.1007/s11164-012-0694-7

Res Chem Intermed (2013) 39:1385–1391
DOI 10.1007/s11164-012-0694-7
´
The legend of 4-aminocoumarin: use of the Delepine
reaction for synthesis of 4-iminocoumarin
•
Ahmed A. Al-Amiery Abdul Amir H. Kadhum
•
•
Y. K. Al-Majedy Hiba H. Ibraheem
•
•
•
Ali A. Al-Temimi Redah I. Al-Bayati
Abu Bakar Mohamad
Received: 11 June 2012 / Accepted: 18 June 2012 / Published online: 4 July 2012
Ó Springer Science+Business Media B.V. 2012
´
Abstract Use of the Delepine reaction for synthesis of 4-aminocoumarin from
4-chlorocoumarin was not successful. The product was 4-iminocoumarin instead of
4-aminocoumarin. The 4-iminocoumarin was characterized by elemental analysis
1
and spectral studies (FT-IR, H NMR, 13C NMR). Density functional theory cal-
culations for 4-iminocoumarin were performed using molecular structure with
optimized geometry. Molecular orbital calculations provided a detailed description
of the orbitals, including spatial characteristics, nodal patterns, and the contributions
of individual atoms.
´
Keywords 4-Aminocoumarin Á 4-Chlorocoumarin Á Delepine Á
4-Hydroxycoumarin Á 4-Iminocoumarin
Introduction
An overview of efforts directed toward the synthesis of new chemical compounds
and natural products with expected biological activity is of interest to researchers
nowadays because drug resistance has become a growing problem in the treatment
of infectious diseases caused by bacteria and fungi [1–6]. Coumarin and its
derivatives are among the most active classes of compounds with a wide range of
biological activity [7, 8], including anticoagulant, estrogenic, dermal photosensi-
tizing, antimicrobial, vasodilator, molluscicidal, antihelmintic, sedative and
A. A. Al-Amiery (&) Á A. A. H. Kadhum Á A. B. Mohamad
Department of Chemical and Processing Engineering, Faculty of Engineering and Built
Environment, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor, Malaysia
e-mail: dr.ahmed1975@gmail.com
A. A. Al-Amiery Á Y. K. Al-Majedy Á H. H. Ibraheem Á A. A. Al-Temimi Á R. I. Al-Bayati
Biotechnology Division, Applied Science Department, University of Technology,
Baghdad 10066, Iraq
123

1386
A. A. Al-Amiery et al.
hypnotic, analgesic, and hypothermic action [9–16]. In addition, coumarins have
been shown to inhibit N-methyl-N-nitrosourea, aflatoxin B1, and 7,12-dimethyl-
benz(a)anthracene-induced mammary carcinogenesis in rats [17, 18]. More recently,
coumarin derivatives had been evaluated for their ability to inhibit human
immunodeficiency virus [19, 20]. Only five papers have been published on the
synthesis of 4-aminocoumarin and in each of these the melting point of
4-aminocoumarin has been different [21–25]. In 2010 Stamboliyska et al. [26]
prepared 4-aminocoumarin by melting 4-hydroxycoumarin with ammonium acetate,
in accordance with the method reported by Manolov and Danchev [22]; again the
melting point was different. In this study we tried to synthesize 4-aminocoumarin
´
from 4-chlorocoumarin by use of the Delepine reaction, but the product was proved
by IR, NMR spectroscopy, and elemental analysis to be 4-iminocoumarin.
Results and discussion
The reaction sequence outlined in Scheme 1 was used for synthesis of 4-imino-
coumarin. We started from 4-hydroxycoumarin (1) which is commercially available
or, alternatively, readily accessible [26]. Addition of phosphorous oxychloride to
4-hydroxycoumarin yielded 4-chlorocoumarin which is easily converted to 4-imi-
´
nocoumarin via the Delepine reaction.
´
The Delepine reaction is the organic synthesis of primary amines by reaction of a
benzyl or alkyl halide with hexamethylenetetramine (HMTA) followed by acid
hydrolysis of the quaternary ammonium salt [27, 28]. The mechanism postulated for
synthesis of 4-iminocoumarin is depicted in Scheme 2.
In the IR spectrum of 4-iminocoumarin the lactone carbonyl stretching frequency
was observed at 1,718 cm-1, imino (C=N) stretching appeared at 1,646.1 cm-1, and
C–C aromatic was at 1,604.9 cm-1. The frequency of N–H stretching was
3,390 cm-1, that of aromatic C–H was at 3,077.8 cm-1, and that of aliphatic C–H at
2,927.2 cm-1. It is very clear from the IR spectrum that our product contains an
1
imino group, carbonyl, and aliphatic C–H, and no NH2 group. In the H NMR
spectrum of 4-iminocoumarin, a 2H singlet from the CH2 protons was observed at
3.85 ppm and a multiplet from the aromatic ring protons at 7.37–8.05 ppm. The
absence of peaks of C=C (doublet at 4.5 ppm and triplet at 5.5 ppm) for the lactone
ring is good evidence of the formation of an imine and not an amine. This 13C NMR
spectral analysis of iminocoumarin, combined with information from 1H NMR
spectroscopy, can be used as a guide for future synthetic work.
N
N
Scheme 1 Reaction for
synthesis of 4-iminocoumarin
O
O
O
O
N
N
POCl3
OH
O
Cl
O
O
O
NH2
NH
123

The legend of 4-aminocoumarin
1387
O
O
O
N
O
N
N
N
HCl/ H2O
N
N
Cl
Cl
N
N
O
O
O
O
NH2
NH
Scheme 2 Mechanism postulated for synthesis of 4-iminocoumarin
Computational studies
Atomic charges and stability
Theoretical studies of iminocoumarin revealed the atomic charges were affected by
the presence of the ring substituent. The optimized geometry is shown in Fig. 1, and
the atomic charges calculated for the compound are listed in Table 1. It is apparent
from Table 1 that the highest atomic charge is at O(3) (-0.5649); the next highest is
at N(12) (-0.3909). These results clearly indicate that these two atoms are the most
reactive sites in reactions and bonding with metals. The calculated bond and twist
angles and the 3D geometrical structure indicated the molecule is not planar.
Density functional theory (DFT)
DFT calculations were performed for iminocoumarin. The optimized molecular
structure of the most stable form is shown in Fig. 1. The calculated energies and
relative energies are listed in Table 2. Molecular orbital calculations provide a
detailed description of the orbitals, including spatial characteristics, nodal patterns,
and individual atom contributions. The contour plots of the frontier orbitals for the
ground state of 4-iminocoumarin are shown in Fig. 2, including the highest
occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital
(LUMO). It is interesting to see that these orbitals are substantially distributed over
the conjugation plane. It can be seen from Fig. 2 that the HOMO orbitals are located
on the substituent of the molecule whereas the LUMO orbitals resemble those of the
unsubstituted molecule; substitution thus has an effect on electron-donor activity but
only a small effect on electron-acceptor activity. The energy levels of the HOMO
and LUMO of 4-iminocoumarin are listed in Table 3. The energy gap between
HOMO and LUMO is approximately 8.1 eV. This low value for the HOMO–LUMO
energy gap explains the charge-transfer interaction which occurs within the
molecule. The dipole was also calculated and is given in Table 2.
123

1388
A. A. Al-Amiery et al.
Fig. 1 3D geometrical structure of 4-iminocoumarin
Table 1 Atomic charges of 4-iminocoumarin
Atom
Charge
Atom
Charge
Atom
Charge
0.27405
Atom
Charge
O(1)
C(2)
O(3)
C(4)
C(5)
-0.140303
0.632609
C(6)
C(7)
-0.0646747
-0.0238036
-0.0878448
-0.0175618
-0.110702
C(11)
N(12)
H(13)
H(14)
H(15)
H(16)
H(17)
H(18)
H(19)
0.0254396
0.0249266
0.0283406
0.110465
-0.390919
0.0383662
0.071976
-0.564933
-0.155057
0.325985
C(8)
C(9)
C(10)
0.0236411
Table 2 Total energy and
dipole moment (Debye) for
iminocoumarin
Total energy
Dipole moment
6.6713
12.7813 kcal/mol
Experimental
The chemicals used for the synthesis were supplied by Sigma–Aldrich. The purity of
the compounds was checked by thin layer chromatography on silica gel G plates
with benzene–ethyl acetate–methanol (40:30:30 v/v) and toluene–acetone (75:25
v/v) as mobile phases. The spots were located under UV light (254 and 365 nm). IR
spectra were obtained on a Thermo Scientific Nicolet 6700 FT-IR spectrometer
123

The legend of 4-aminocoumarin
1389
HOMO
LUMO
HOMO-1
LUMO+1
Fig. 2 HOMO and LUMO orbitals for 4-iminocoumarin
Table 3 HOMO and LUMO
orbital energies (eV)
HOMO
LUMO
-2.895
HOMO-1
-12.104
LUMO?1
-0.549
-11.070
(without use of KBr or CsI). 1H NMR spectra were obtained on a Jeol jnm-ECP400
FT-NMR system. Elemental microanalysis was performed with a model 5500-Carlo
Erba C.H.N elemental analyzer. A Gallenkamp M.F.B.600.010 F melting point
apparatus was used to measure the melting points of all the prepared compounds.
Synthesis of 4-chlorocoumarin
4-Hydroxycoumarin (3 g, 0.0185 mol) and 7 mL POCl3 were heated under reflux
for 2 h. After cooling the mixture was poured on to crushed ice with vigorous
stirring. The solid obtained was isolated by filtration and washed with cold water.
Yield (60 %) MP. 90 °C (lit. 89–91 °C) [29].
IR spectrum, m, cm-1: 3043 (C–H aromatic), 1700.1 (C=O), 1634.2 (C=C),
1609.1 (C=C aromatic), (C–O), 764(C–Cl).
123

1390
A. A. Al-Amiery et al.
1H NMR spectrum (400 MHz, CDCl3), d, ppm (J, Hz): 6.62 (1H, s, C=C–H
alkene); 7.88–7.30 (4H, m, C–H aromatic).
Elemental analysis Found, %: C 59.85; H 2.79. C9H5ClO2. Calculated, %: C
60.23; H 2.31.
´
Synthesis of 4-iminocoumarin (Delepine reaction)
A mixture of 4-chlorocoumarin (0.0298 mol) and HMTA (4.61 g, 0.0328 mol) in
chloroform (CHCl3) (50 mL) was stirred at room temperature for 24 h then
´
concentrated under vacuum to give the crude Delepine adduct. Ethanol (25 mL,
95 %) and 12 M hydrochloric acid (HCl) (7.5 mL) were added to this solid. After
stirring at room temperature for 6 h, the heterogeneous reaction mixture was cooled
in an ice bath and filtered to remove ammonium chloride (NH4CI). The filter cake
was washed with EtOH (200 mL, 95 %). The combined filtrate was extracted with
CH2Cl2 (2 9 200 mL) and concentrated to give the 4-iminocoumarin. UV–visible
spectroscopy in ethanol, 290 and 310 nm, melting point 255 °C; lit. for 4-amino-
coumarin; 226–228 °C [26], 161.5–162 °C [21], 199 °C [25], 232–234 °C [21],
241–243 °C [23].
IR spectrum, m, cm-1: 3390 (N–H), 3077.8 (C–H aromatic), 2927.2 (C–H
aliphatic), 1718 (C=O), 1646.1 (C=N), 1604.9 (C–C aromatic).
1H NMR spectrum (400 MHz, CDCl3), d, ppm (J, Hz): 3.85 (2H, s, J = 7.389,
CH2); 7.37–8.05 (4H, m, C–H aromatic).
13C NMR spectrum (125 MHz, CDCl3), d, ppm: 20 (C4); 103 (C5); 118 (C7); 124
(C8); 127 (C9); 152 (C6); 162 (C11); 164 (C2).
Elemental analysis Found, %: C 66.70; H 4.38; N 8.69. C9H7NO2. Calculated, %:
C 65.99; H 4.01; N 8.50.
Conclusions
In this study a new method was used for synthesis of 4-iminocoumarin. The product
was characterized by use of a variety of spectroscopic methods and elemental
analysis. A mechanism for synthesis of the target compound has been postulated.
Acknowledgments The authors gratefully acknowledge Universiti Kebangsaan Malaysia for support of
this project.
References
1. A.A. Al-Amiery, A.A. Mohammed, H. Ibrahim, World Acad. Sci. Eng. Technol. 57, 433 (2009)
2. A.A. Al-Amiery, Y. Al-Majedy, H. Abdulreazak, H. Abood, Bioinorg. Chem. Appl. 2011, 1–6 (2011)
3. A.A. Al-Amiery, Y. Al-Majedy, H. Ibrahim, A. Temimi, Org. Med. Chem. Lett. 2, 1–7 (2012)
4. A.A. Al-Amiery, A. Kadhum, A. Mohamad, Bioinorg. Chem. Appl. 2012, 1–5 (2012)
5. A.A. Al-Amiery, A.A. Mohammed, G.M. Alhyali, J. Appl. Sci. Res. 7(4), 470 (2011)
6. A.A. Al-Amiery, Res. Chem. Intermed. 38, 745–759 (2012)
7. A. El-Agrody, M. Abd El-Latif, N. El-Hady, A. Fakery, A. Bedair, Molecules 6, 519 (2001)
8. S. Kovalenko, I. Bylov, K. Sytnik, V. Chernykh, Y. Bilokin, Molecules 5, 1146 (2000)
123

The legend of 4-aminocoumarin
1391
9. S. Parmer, R. Kumar, J. Med. Chem. 11, 635 (1968)
10. Y.D. Reddy, V.V. Somayajulu, J. Indian Chem. Soc. 58, 599 (1981)
11. T.O. Soine, J. Pharm. Sci. 53, 231 (1964)
12. M.M. Dutta, B.N. Goswani, J.C.S. Kataky, J. Heterocycl. Chem. 23, 793 (1986)
13. A.A. Al-Amiery, A. Musa, A. Kadhum, A. Mohamad, Molecules 16, 6833 (2011)
14. A.A. Al-Amiery, A. Kadhum, A. Mohamad, Molecules 17, 5713 (2012)
15. A. Kadhum, A.A. Al-Amiery, A. Musa, A. Mohamad, Int. J. Mol. Sci. 12, 5747 (2011)
16. A. Kadhum, A. Mohamad, A.A. Al-Amiery, M. Takriff, Molecules 16, 6969 (2011)
17. A.A. Al-Amiery, R. Al-Bayati, K. Saour, M. Radi, Res. Chem. Intermed. 38, 559 (2012)
18. V. Kelly, E. Ellis, M. Manson, Cancer Res. 60, 957 (2000)
19. S. Kirkiacharian, D. Thuy, S. Sicsic, R. Bakhchinian, R. Kurkjian, T. Tonnaire, Farmaco 57, 703
(2002)
20. D. Suzuki, M. Yu, L. Xie, S. Morris, K. Lee, Med. Res. Rev. 23, 322 (2003)
21. V. Zagorevskii, N. Dudykina, Zh. Obsch. Khim. 32, 2384 (1962)
22. I. Manolov, N. Danchev, Eur. J. Med. Chem. Chim. Ther. 30, 531 (1995)
23. H. Uno, M. Kurokawa, H. Nishimura, Chem. Pharm. Bull. 24, 644 (1976)
24. I. Ivanov, S. Karagiosov, I. Manolov, Arch. Pharm. (Weinh.) 61, 324 (1991)
25. A.P. Chavan, J. Chem. Res. 3, 179 (2006)
26. B. Stamboliyska, V. Janevska, B. Shivachev, P. Nikolova, G. Stojkovic, B. Mikhova, E. Popovski,
Arkivoc X, 62 (2010)
´
27. M. Delepine, Bull. Soc. Chim. Fr. 13, S. 352–361 (1895)
28. R. Alexander, Name Reactions in Organic Chemistry, 2nd edn. (Academic Press, New York, 1961)
29. D.P. Spalding, H.S. Mosher, F.C. Whitmore, J. Am. Chem. Soc. 72, 5338 (1950)
123