A novel and facile synthesis of 7,8-diacylcoumarins

Article abstract of DOI:10.1016/j.tetlet.2007.07.202

Oxidation of N-carbonylhydrazones of 7-hydroxy-8-acetylcoumarin with lead tetraacetate results in the synthesis of 7,8-diacylcoumarins in good yields. The reaction proceeds via the transformation of a hydroxy into an acyl group reported for the first time

Full text of DOI:10.1016/j.tetlet.2007.07.202

Tetrahedron Letters 48 (2007) 7181–7183
A novel and facile synthesis of 7,8-diacylcoumarins
Antigoni Kotali,a,* Ioannis S. Lafazanisa and Philip A. Harrisb
aLaboratory of Organic Chemistry, Department of Chemical Engineering, University of Thessaloniki, Thessaloniki 54124, Greece
bGlaxoSmithKline, 1250 South Collegeville Road, PO Box 5089, Collegeville, PA 19426-0989, USA
Received 25 May 2007; revised 27 July 2007; accepted 30 July 2007
Available online 2 August 2007
Abstract—Oxidation of N-carbonylhydrazones of 7-hydroxy-8-acetylcoumarin with lead tetraacetate results in the synthesis of 7,8-
diacylcoumarins in good yields. The reaction proceeds via the transformation of a hydroxy into an acyl group reported for the first
time in heterocyclic chemistry.
Ó 2007 Elsevier Ltd. All rights reserved.
It is well-known that coumarin is a biologically active
substance, with numerous metabolites, and is wide-
spread in Nature.1 Coumarin derivatives have been used
widely for the treatment of a variety of diseases such as
heart disease,2–4 lymphoedema and other high-protein
edemas.5 They have also found pharmaceutical applica-
tions in the treatment of patients with chronic venous
insufficiency,6 skin cancer,7 renal cell carcinoma,8 pros-
tate cancer9 as well as in the treatment of thermal inju-
ries.10 They may also be useful in preventing oxidative
stress and apoptosis in HIV infection.11
an earlier method found in our laboratory13–15 (Scheme
1). The method involves treatment of the N-acylhydra-
zone of an o-hydroxyaryl ketone with lead tetraacetate
(LTA) and results in the transformation of the hydroxy
into an acyl group.14
Thus, 7-hydroxycoumarin (1) was initially reacted with
acetic anhydride to give 7-acetoxycoumarin (2), which
on treatment with aluminium chloride afforded5 7-hy-
droxy-8-acetylcoumarin (3). N-Carbonylhydrazones (4)
of 7-hydroxy-8-acetylcoumarin were then prepared16
and subsequently oxidized with LTA.17 Compounds
(4) and (5) are new and they were identified by MS,
1H and 13C NMR spectra and elemental analyses
(Tables 1 and 2). Hydrazones 4a–d were formed as mix-
tures of two isomers in ca. 1:1 ratio as shown by their
Having in mind the biological activity of the coumarin
nucleus as well as the importance of the presence of acyl
substituents at ortho positions in aromatic systems12 we
designed a synthesis of 7,8-diacylcoumarins (5) applying
A
C
B
O
O
OCOMe
O
O
OH
O
O
OH
O
O
OH
COMe
Me
NNHCOR
4
1
2
3
D
A: Ac2O reflux/1.5 h/90%
B: AlCl3/125-170 oC/2 h/74%
C: RCONHNH2 /propan-1-ol/reflux/24 h/90-98%
D: Pb(OAc)4 /THF/r.t./2-24 h/65-90%
O
O
COR
COMe
5
Scheme 1. Synthesis of 7,8-diacylcoumarins 5.
Keywords: 7,8-Diacylcoumarins; Transformation; N-Acylhydrazones; Lead tetraacetate.
*
Corresponding author. Tel.: +30 2310 996253; fax: +30 2310 996253; e-mail: kotali@eng.auth.gr
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.202

7182
A. Kotali et al. / Tetrahedron Letters 48 (2007) 7181–7183
Table 1. Preparationa and MS data of compounds 4 and 5
Compound
R
Yield (%)
Mpb (°C)
Molecular formulac
13H12N2O4
C19H16N2O4
C18H14N2O5
C18H13N3O6
MS m/z (ES+)
4a
4b
4c
4d
4e
4f
Me
96
98
96
91
93
92
90
90
92
73
90
75
78
65
248–250
C
283 (M+23), 261 (M+1)
359 (M+23), 337 (M+1), 202
361 (M+23), 339 (M+1)
368 (M+1)
324 (M+1)
329 (M+1), 271, 202
313 (M+23), 291 (M+1), 245, 202
231 (M+1)
329 (M+23), 307 (M+1)
331 (M+23), 309 (M+1), 291, 215
360 (M+23), 338 (M+1)
294 (M+1)
p-MeC6H4
p-HOC6H4
o-NO2C6H4
p-Pyridyl
2-Thienyl
OEt
241.5–243.8
275.5–276.3
217.3–219.1
287–288
258.4–260.6
193.7
174–175.8
169.5–170.7
191.5–193.5
172.5–174.5
152.5–154.5
153.2–154.2
130.4–132.4
C
C
17H13N3O4
16H12N2O4S
4g
5a
5b
5c
5d
5e
5f
C14H14N2O5
C13H10O4
C19H14O4
C18H12O5
C18H11NO6
Me
p-MeC6H4
p-HOC6H4
o-NO2C6H4
4-Pyridyl
2-Thienyl
OEt
C
17H11NO4
C16H10O4S
C14H12O5
321 (M+23), 298 (M), 215
283 (M+23), 261 (M+1), 217, 215, 187
5g
a The molar ratio of hydrazone/LTA for the preparation of compounds 5 was 1:1.3 for 4a and 4b, 1:1.7 for 4c, 1:1.5 for 4d and 4g and 1:2 for 4e and
4f whereas the reaction time was 3 h for 4a, 2 h for 4b, 4c, 4d and 4f and 24 h for 4e and 4g.
b Melting points are uncorrected.
c Satisfactory microanalyses were obtained for all the compounds 4 and 5.
Table 2. 1H NMR and 13C NMR data of compounds 4 and 5
Compounda 1H NMRb d, J (Hz)
13C NMRb
d
4a
4b
4c
4d
4e
2.10 (s, 3H), 2.21 (s, 3H), 2.35 (s, 3H), 2.43 (s, 3H),
6.19–6.23 (m, 2H), 6.86–6.89 (m, 2H), 7.49–7.55 (m, 2H), 115.2, 129.0, 129.7, 143.4, 144.7, 145.0, 149.6, 152.6, 153.2, 158.7,
7.92–7.96 (m, 2H), 10.49 (s, 1H), 10.80 (s, 1H),
11.8 (br, 1H), 12.2 (br,1H)
18.0,18.3, 20.8, 21.3, 111.2, 111.3, 111.4, 111.5, 112.0, 113.0, 113.7,
159.8, 160.0, 160.2, 166.5, 172.7
2.30 (s, 3H), 2.34 (s, 3H), 2.42 (s, 3H), 2.54 (s, 3H),
6.27–6.31 (m, 2H), 6.96–6.99 (m, 2H), 7.22–7.24 (m, 2H), 113.8, 127.8, 128.1, 128,7, 128.9, 129.9, 130.0, 130.9, 141.5, 142.0,
7.36–7.65 (m, 6H), 7.89–7.91 (m, 2H), 8.00–8.03 (m, 2H), 144.7,144.9, 145.0, 148.0, 152.4, 153.5, 154.0, 157.4,159.8, 159.9,
19.0, 20.9, 21.8, 23.7, 109.4, 111.3, 111.4, 111.5 111.8, 111.9, 112.8,
10.05 (br, 1H), 11.22 (br, 2H), 12.55 (s, 1H)
160.1, 163.8, 165.0
2.21 (s, 3H), 2.46 (s, 3H), 6.20–6.23 (m, 2H), 6.71
(d, 1H, J = 8.3), 6.84–6.91 (m, 5H), 7.52–7.57 (m, 4H),
7.82 (d, 2H, J = 8.3), 7.93 (d, 2H, J = 9.5), 9.65 (s, 1H),
9.88 (s, 1H), 10.15 (s, 2H), 10.90 (s, 2H)
19.4, 24.3, 110.0, 111.9, 112.0, 112.2, 112.5, 113.5, 114.5, 115.5,
124.1, 124.2, 125.1, 130.6, 131.0, 131.1, 145.3, 145.6, 153.1, 154.0,
154.1, 158.0, 160.4, 160.5, 160.6, 160.7, 160.9, 161.0, 161.1, 161.2,
161.5, 165.0
2.19 (s, 3H), 2.32 (s, 3H), 6.13–6.23 (m, 2H), 6.74–6.92
(m, 2H), 7.31 (d, 1H, J = 8.4), 7.53–7.98 (m, 10H),
8.16 (d, 1H, J = 8.0), 10.56 (s, 1H), 11.42 (s, 1H),
11.49 (s, 1H), 11.91 (s, 1H)
19.0, 19.6, 111.9, 112.1, 113.1, 113.4, 114.2, 115.1, 124.2, 124.3,
124.9, 129.8, 130.0, 130.3, 130.6, 130.7, 130.8, 131.8, 132.8, 134.4,
134.7, 145.2, 145.4, 145.5, 146.7, 146.8, 147.3, 153.1, 153.7, 153.8,
156.4, 159.3, 160.4, 160.5, 163.5, 169.4
2.25 (s, 3H), 2.43 (s, 3H), 6.20–6.22 (m, 2H), 6.88–6.70
(m, 2H), 7.38–7.95 (m, 8H), 8.60–8.76 (m, 4H), 10.49
(s, 1H), 1.30 (br, 1H), 11.40 (br, 1H), 11.96 (s, 1H)
19.7, 24.4, 110.2, 112.0, 112.2, 112.5, 113.1, 113.6, 114.2, 114.3,
122.3, 122.6, 123.3, 130.7, 131.0, 141.2, 142.1, 145.4, 145.5, 150.5,
150.6, 150.7, 153.0, 153.8, 155.7, 158.7, 160.4, 160.7, 162.9, 163.6
4f
2.25 (s, 3H), 6.20 (d, 1H, J = 9.6), 6.86–7.12 (m, 2H),
7.51–7.99 (m, 4H), 10.10 (s, 1H), 11.06 (s, 1H)
24.0, 112.1, 112.2, 112.6, 113.5, 113.9, 127.3, 130.2, 131.0, 135.3,
145.4, 145.5, 153.0, 158.3, 160.6, 160.7
4g
1.25 (t, 3H, J = 7.0), 2.23 (s, 3H), 4.17 (q, 2H,
J = 7.0), 6.22 (d, 1H, J = 9.5), 6.88 (d, 1H, J = 8.5),
7.53 (d, 1H, J = 8.5), 7 (d, 1H, J = 9.5), 10.47 (br, 1H),
11.58 (br, 1H)
15.3, 19.0, 34.9, 107.1, 112.0, 113.9, 114.0, 130.0, 137.9, 145.5,
153.6, 154.8, 160.1, 160.6
5a
5b
2.44 (s, 3H), 2.59 (s, 3H), 6.61 (d, 1H, J = 9.6),
7.85 (d, 1H, J = 8.1), 7.93 (d, 1H, J = 8.1), 8
(d, 1H, J = 9.6)
28.2, 31.9, 119.4, 122.9, 126.2, 129.8, 130.8, 137.0, 149.7, 149.9,
159.3, 198.9, 201.0
2.39 (s, 3H), 2.61 (s, 3H), 6.67 (d, 1H, J = 9.6),
7.34 (dd, 2H, J = 7.8), 7.43 (d, 1H, J = 7.9), 7.62
(dd, 2H, J = 7.8), 7.94 (d, 1H, J = 7.9), 8.19
(d, 1H, J = 9.6)
21.2, 31.8, 117.9, 129.9, 124.5, 129.1, 129.3, 129.7, 130.0, 133.5,
140.3, 143.5, 144.3, 150.4, 158.6, 194.6, 199.7
5c
2.56 (s, 3H), 6.62 (d, 1H, J = 9.5), 6.85 (dd, 2H,
J = 8.6), 7.39 (d, 1H, J = 7.8), 7.59 (dd, 2H,
J = 8.6), 7.86 (d, 1H, J = 7.8), 8.13 (d, 1H,
J = 9.5), 10.57 (s, 1H)
32.6, 116.2, 118.4, 121.7, 125.1, 128.1, 130.0, 130.4, 133.2, 141.4,
144.2, 151.0, 159.3, 163.4, 193.9, 200.6

A. Kotali et al. / Tetrahedron Letters 48 (2007) 7181–7183
7183
Table 2 (continued)
Compounda
1H NMRb d, J (Hz)
13C NMRb
d
5d
5e
2.68 (s, 3H), 6.50 (d, 1H, J = 9.7), 7.10 (d, 1H,
J = 8.0), 7.46–7.50 (m, 2H), 7.78–7.83 (m, 3H),
8.20 (d, 1H, J = 8.0)
31.5, 119.9, 123.0, 124.9, 126.0, 128.6, 129.2, 129.3, 131.8, 132.2,
134.8, 135.6, 142.2, 146.8, 150.3, 158.7, 192.2, 200.5
2.71 (s, 3H), 6.52 (d, 1H, J = 9.5), 7.28 (d, 1H,
J = 9.5), 7.48 (dd, 2H, J = 5.4), 7.64 (d, 1H,
J = 7.8), 7.77 (d, 1H, J = 9.5), 8.74 (dd, 2H,
J = 5.4)
32.1, 118.9, 121.5, 122.3, 124.6, 130.0, 130.3, 140.9, 142.4, 142.9,
150.9, 151.7, 158.3, 194.6, 198.8
5f
2.74 (s, 3H), 6.51 (d, 1H, J = 9.7), 7.12 (d, 1H,
J = 8.7), 7.48–7.52 (m, 2H), 7.61 (d, 1H, J = 7.9),
7.73–7.78 (m, 2H)
32.4, 118.7, 121.1, 124.6, 126.4, 129.0, 131.0, 135.4, 135.6, 141.1,
142.5, 143.3, 151.1, 158.6, 187.0, 199.7
5g
1.39 (t, 3H, J = 7.2), 2.70 (s, 3H), 4.38 (q, 2H,
J = 7.2), 6.53 (d, 1H, J = 9.8), 7.54 (d, 1H,
J = 8.2), 7.73 (d, 1H, J = 9.8), 7.88 (d, 1H,
J = 8.2)
14.2, 32.2, 62.6, 119.3, 122.3, 125.9, 128.3, 130.3, 133.1, 142.6,
143.9, 159.0, 165.0, 200.7
a Data for compounds 4a–4e are for isomeric mixtures whereas for 4f and 4g are for a single isomer.
b 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were recorded in DMSO-d6.
4. Roma, G.; Braccio, M. D.; Carrieri, A.; Grossi, G.;
NMR spectra whereas, hydrazones 4f and 4g were
formed as single isomers. Both hydrazones (4) as well
as diacyl derivatives (5) show prominent peaks corre-
sponding to the ion [M+1] in their mass spectra (Table
1). The carbonyl carbons in 7,8-diacylcoumarins 5 ap-
peared at 200.7 to 187.0 ppm in the 13C NMR spectra
whereas, in hydrazones 4 the peaks appearing at 172.7
to 159.9 ppm were assigned to amide carbonyl (Table 2).
Leoncini, G.; Grazia Signorello, M.; Carotti, A. Bioorg.
Med. Chem. 2003, 11, 123–138.
5. Casley-Smith, J. R. Coumarins: Biology, Applications and
Mode of Actions; John Wiley: England, 1997, pp 143–184.
6. Vanscheidt, W.; Rabe, E.; Naser-Hijazi, B.; Ramelet, A.
A.; Partsch, H.; Diehm, C.; Schultz-Ehrenburg, U.;
Spengel, F.; Wirsching, M.; Gotz, V.; Schnitkern, J.;
Henneicke-von Zepelin, H. H. Vasa 2002, 31, 185–190.
7. Abramov, M. A.; Dehaen, W. Synthesis 2000, 1529–1531.
8. Mohler, J. L.; Williams, B. D.; Freeman, J. A.; Marshall,
M. E. Coumarins: Biology, Applications and Mode of
Actions; John Wiley: England, 1997, pp 241–255.
9. Ebbinghaus, S. W.; Mohler, J. L.; Marshall, M. E.
Coumarins: Biology, Applications and Mode of Actions;
John Wiley: England, 1997, pp 209–221.
10. Piller, N. B. Coumarins: Biology, Applications and Mode of
Actions; John Wiley: England, 1997, pp 185–208.
11. Greenspan, H. C. Immunol. Today 1994, 14, 209–213.
12. Kotali, A.; Harris, P. A. Org. Prep. Proced. Int. 2003,
583–605.
13. Kotali, A.; Tsoungas, P. G. Tetrahedron Lett. 1987, 28,
4321–4322.
14. Kotali, A. Curr. Org. Chem. 2002, 26, 965–985, and
references cited therein.
In conclusion, 7,8-diacylcoumarins have been prepared
in good yields by a facile method that involves transfor-
mation of a hydroxy into an acyl group (step D, Scheme
1). This transformation is reported for the first time in
heterocycles. This is considered to be significant with
our previous findings on the transformation of a pheno-
lic hydroxy into an acyl group in benzene derivatives.14
By analogy, it is not unreasonable to assume that the
presence of the hydroxy group in N-carbonylhydrazones
(4) is crucial to the mechanism of the reaction.15 The
experimental simplicity, generality and low cost of the
reagents add to the synthetic value of this method.
Furthermore, 7,8-diacylcoumarins could serve as inter-
mediates to various heterocycles with possible pharma-
ceutical properties.
15. Katritzky, A. R.; Harris, P. A.; Kotali, A. J. Org. Chem.
1991, 56, 5049–5051.
16. Preparation of 7-hydroxy-8-acetylcoumarin N-carbonylhyd-
razones (4). A mixture of 7-hydroxy-8-acetylcoumarin 3
(5 mmol) and the corresponding hydrazide, in the molar
ratio 1:1 were refluxed in propanol (20 ml), for 24 h. The
mixture was allowed to cool and the resulting precipitate
was filtered and subsequently dried to afford the pure
products 4 as white solids (Tables 1 and 2).
Acknowledgement
The authors thank the Royal Society of Chemistry for
financial support of this work.
17. Preparation of 7,8-diacylcoumarins 5. Lead tetracetate was
added to a stirred solution of hydrazone 4 (1 mmol) in
THF (20 ml), in an ice bath. The molar ratios of
hydrazone/LTA and the reaction times are presented in
Table 1. The mixture was then stirred at rt with the
exception of 4f, which was stirred in an ice bath. The oily
product obtained after filtration of lead diacetate and
condensation of the filtrate was subjected to column
chromatography (silica gel 70–230 mesh) eluting with a
mixture of petroleum ether/ethyl acetate 1:1 to afford pure
products 5 as white solids (Tables 1 and 2).
References and notes
1. O’Kennedy, R.; Thornes, R. D. Coumarins: Biology,
Applications and Mode of Actions; John Wiley: England,
1997, pp 333–336.
2. Ten Berg, J. M.; Kedler, J. C.; Plokker, T. H.; Van Hout,
B. A. Pharmacoeconomics 2002, 20, 847–853.
3. Becker, R. C. N. Engl. J. Med. 2002, 347, 969–974.