Synthesis of 6,7-diacylcoumarins via the transformation of a hydroxy into a carbonyl group

Article abstract of DOI:10.1080/00397910802250911

The synthesis of 6,7-diacylcoumarins is reported via the oxidation of 6-acetyl-7-hydroxycoumarin N-acylhydrazones with lead tetraacetate. The procedure involves transformation of hydroxy into an acyl group and formation of a new C-C bond. Copyright Taylor & Francis Group, LLC.

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Synthesis of 6,7-
Diacylcoumarins via the
Transformation of a Hydroxy
into a Carbonyl Group
Antigoni Kotali a , Ioannis S. Lafazanis a & Philip A.
Harris b
a Laboratory of Organic Chemistry, Department of
Chemical Engineering, University of Thessaloniki,
Thessaloniki, Greece
b GlaxoSmithKline, Collegeville, Pennsylvania, USA
Version of record first published: 20 Oct 2008.
To cite this article: Antigoni Kotali, Ioannis S. Lafazanis & Philip A. Harris (2008):
Synthesis of 6,7-Diacylcoumarins via the Transformation of a Hydroxy into a Carbonyl
Group, Synthetic Communications: An International Journal for Rapid Communication
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Synthetic Communications1, 38: 3996–4006, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802250911
Synthesis of 6,7-Diacylcoumarins via the
Transformation of a Hydroxy into a
Carbonyl Group
Antigoni Kotali,1 Ioannis S. Lafazanis,1 and Philip A. Harris2
1Laboratory of Organic Chemistry, Department of Chemical Engineering,
University of Thessaloniki, Thessaloniki, Greece
2GlaxoSmithKline, Collegeville, Pennsylvania, USA
Abstract: The synthesis of 6,7-diacylcoumarins is reported via the oxidation of
6-acetyl-7-hydroxycoumarin N-acylhydrazones with lead tetraacetate. The proce-
dure involves transformation of hydroxy into an acyl group and formation of a
new C–C bond.
Keywords: N-acylhydrazones, 6,7-diacyl-2H-chromen-2-ones, coumarins, lead
tetraacetate, oxidation, transformation
Linear 6,7-disubstituted coumarins, a class of fused-ring hetero-
cycles, also well known as chromen-2-ones, are widely found in the
nature and show interesting biological activity.[1] Generally, naturally
occurring coumarins are found in several plants, including grasses, orch-
ids, citrus fruits, and legumes, and are involved in the actions of plant
growth hormones and growth regulators, the control of respiration,
photosynthesis, and defense against infection.[2] In addition, these com-
pounds exhibit a variety of pharmacological properties. Among these
properties, their cytotoxic effects have been most extensively investi-
gated.[3] However, they also play an important role in medicine as
anti-HIV,[4] cytotoxic,[5] anticoagulant,[6] antibacterial,[7] oestrogenic,[8]
Received March 18, 2008.
Address correspondence to Antigoni Kotali, Laboratory of Organic
Chemistry, Department of Chemical Engineering, University of Thessaloniki,
Thessaloniki 54124, Greece. E-mail: kotali@eng.auth.gr
3996

Synthesis of 6,7-Diacylcoumarins
3997
anti-inflammatory,[9] antioxidant,[10] and fluorescent[11] agents. Further-
more, several coumarins bearing different groups on the aromatic ring
were synthesized and tested to find more active analogs. Psoralen and
esculetin are typical examples among the natural 6,7-substituted cou-
marin derivatives with cytotoxic activity.[3] In addition, the linear furano-
coumarins isopimpinellin and imperatorin are ingested regularly as part
of the humandiet as they are present in the rind and pulp oflimes, in
lemon and lime oils, and in celery, parsnip, and parsley; are analgesic;[12]
and have been found to alter enzyme activities and reduce DNA adduct
formation by polycyclic aromatic hydrocarbons in various tissues of
mice.[13,14] On the other hand, 6,7-dimethylcoumarin derivatives are typi-
cal examples among the interesting synthetic analogs with antiangiogenic
and simultaneous fluorescent activity, giving the ability for both imaging
and inhibition against angiogenesis at the same time.[15] Because the
pharmacological and biochemical properties and therapeutic applications
of coumarins depend[2] upon the pattern of substitution and alterations in
the structure of coumarins could change their cytotoxic properties, it is
not difficult to understand why the design and the synthesis of substituted
coumarin derivatives is of great importance to many researchers.
Recently, we synthesized[16] 7,8-diacylcoumarins in our laboratory,
and we would like further to synthesize linear 6,7-diacyl derivatives.
Depending on this knowledge, on our interest in coumarin deriva-
tives,[16] and on the applications of the reactions of o-hydroxy arylketone
N-acylhydrazones[17] with lead tetraacetate (LTA) in organic synthesis,
we studied the synthesis of 6,7-diacylcoumarins 4 according to Scheme 1.
The synthetic scheme proceeds via reaction of 6-acetyl-7-hydroxycou-
marin N-acylhydrazones 3 with LTA and involves transformation of a
hydroxy into a carbonyl group.
Scheme 1. Preparation of 6,7-diacylcoumarins 4.

3998
A. Kotali, I. S. Lafazanis, and P. A. Harris
Scheme 2. Preparation of 6- and 8-acetyl-7-hydroxycoumarin 1 and 6.
Starting coumarin 1 has been reported in the literature as obtained as
a mixture with the isomer 7-hydroxy-8-acetylcoumarin 6 under treatment
of 7-acetoxycoumarin 5 with aluminum chloride (Scheme 2).[18]
Recrystallization of this mixture results in the isolation of 7-hydroxy-
8-acetylcoumarin 6 in 74% yield as a solid, whereas the desired 6-acetyl
derivative 1 remains in the filtrate along with some quantity of 8-acetyl
isomer 6 and 7-hydroxycoumarin. Removal of the solvent and subjection
of the filtrate mixture to column chromatography afforded the desired
6-acetyl derivative 1 in only minor traces to 5% pure yield, whereas the
most quantity of the product is obtained as a mixture with the isomer
7-hydroxy-8-acetylcoumarin. Trying to optimize the yield for coumarin
1, we applied two subsequent purifications via column chromatography
as well as recrystallization from ethanol. In this way, 6-acetyl isomer 1
could be isolated in 14% yield. However, because the yield was still
low, we decided to run two series of experiments to synthesize 6,7-diacyl-
coumarins using as the starting carbonyl substrate: (i) pure 6-acetyl-7-
hydroxycoumarin (method A, Scheme 1) and (ii) the mixture of 6- and
8-acetyl-7-hydroxycoumarin as it was in the filtrate without any further
purifications (method B, Scheme 3).
In method A, a series of 6-acetyl-7-hydroxycoumarin N-carbonylhy-
drazones 3 were prepared in very good yields, 92 to 75% (Scheme 1).
Hydrazones 3 are new compounds, and they were identified by their
Scheme 3. Alternative preparation of 6,7-diacylcoumarins 4.

Synthesis of 6,7-Diacylcoumarins
3999
spectral data and by either exact mass measurement or elemental analy-
sis. Hydrazones 3 were subsequently oxidized with LTA to lead to the
formation of the desired products 4 in good yields, 60–73%. The reaction
conditions, the yields of formation of the new compounds 3 and 4, and
their melting points are presented in Table 1. The desired linear 6,7-
diacylcoumarins were isolated by column chromatography and identified
by their spectral data and by either exact mass measurement or elemental
analysis.
In method B, the mixture of 6- and 8-acetyl-7-hydroxycoumarin 1
and 6 was treated with the appropriate hydrazides 2 to produce mixtures
of the corresponding hydrazones 3 and 7, which subsequently afforded
mixtures of the corresponding 6,7- and 7,8-diacylcoumarins 4 and 8
under treatment with LTA. The desired linear pure 6,7-diacyl-coumarins
4 were isolated by column chromatography in 35–48% yield (Table 1) and
identified by comparison of their spectral data with those of the authentic
samples prepared by method A. Isomers 8 that were also formed during
the reactions are known compounds, and their synthesis was recently
reported.[16]
In addition, reaction of hydrazone 4e with phenyliodosodiacetate
(PID) led to the formation of 4e in yields comparable to the LTA yield
(Table 1). This is in accordance with our previous findings about the
transformation of the hydroxy into a carbonyl group.[17]
Concerning the mechanism of the transformation reactions, it is not
unreasonable to assume that it works analogously to the mechanism
that we proposed for the transformation of o-hydroxyacetophenone
N-benzoylhydrazone into 1-acetyl-2-benzoylbenzene.[19]
In conclusion, the transformation of a hydroxy into an acyl group
(1 ! 3 ! 4 in Scheme 1) was applied in coumarins, giving the ability
for the synthesis of linear ortho-diacylsubstituted derivatives. The pre-
sence of two acyl groups at neighboring positions is always desirable in
aromatic derivatives. However, there are no other general methods for
such derivatives.[20] The transformation has been proven to be the most
appropriate way to synthesize ortho-diacylsubstituted heterocycles. The
simplicity of the method, the low cost of the reagents, and the good yield
add to the synthetic value of the transformation. In addition, 6,7-diacyl-
coumarins 4 could also serve as very useful intermediates to various
heterocycles with possible pharmaceutical properties.
EXPERIMENTAL
All the solvents for the reactions and chromatography were purchased
from Merck, whereas all hydrazides 2 from Aldrich. Compound 5 was

4000

Synthesis of 6,7-Diacylcoumarins
4001
prepared according to the literature procedure.[18] Compound 1 was pre-
pared according to the literature procedure[18] with additional two col-
umns of chromatography and a recrystallization of the final obtained
fraction mixture of 1 þ 6 (Scheme 2). Thin-layer chromatography (TLC)
plates were Merck plastic plates with silica gel 60 F254 (70–230 mesh). Col-
umn chromatography was performed on silica gel 60 F254 (70–230 mesh).
The NMR spectra were recorded on a Bruker Avance 400 spectrometer
(1H MHz 400.15, 13C 100.62 MHz) in dimethyl sulfoxide (DMSO) using
the signal of the solvent as the internal standard (residual DMSO for
1H: d 2.50 ppm, 13C d 39.5 ppm). Either elemental analysis or exact mass
measurement have been provided for all the new compounds 3 and 4.
Typical Procedure for Formation of 6-Acetyl-7-hydroxycoumarin
N-Acylhydrazones 3
A mixture of 6-acetyl-7-hydroxycoumarin 1 (5 mmol) and the corre-
sponding hydrazide in molar ratio 1:1 were refluxed in propanol-1
(20 ml) for 24 h. The mixture was allowed to cool, and the precipitate
was filtered and subsequently dried to afford the pure products 3 as white
solids (Table 1).
Typical Procedure for Formation of 6,7-Diacylcoumarins 4 (Method A)
Lead tetracetate was added to a stirred solution of hydrazone 3 (1 mmol)
in tetrahydrofuran (THF) (20 ml), in an ice bath. The molar ratio of
hydrazone=lead tetraacetate (LTA) and the reaction times are presented
in Table 1. The mixture was then stirred at rt. The oily product obtained
after filtration of lead diacetate and condensation of the filtrate was sub-
jected to column chromatography (silica gel 70–230 mesh) and was eluted
with a mixture of petroleum ether=ethylacetate 1:1 to afford the pure pro-
ducts 4 as white solids (Table 1).
Typical Procedure for Formation of 6,7-Diacylcoumarins 4 (Method B)
A mixture of 6- and 8-acetyl-7-hydroxycoumarin 1 and 6 (5 mmol), pre-
pared according to the literature procedure,[18] was treated with the
appropriate hydrazide 2, in molar ratio 1:1, under reflux in propanol-1
(20 ml), for 24 h. The mixture was allowed to cool, and the precipitate
was filtered and subsequently dried to afford mixtures of hydrazones
3 and 7. These mixtures of hydrazones were further used without any
purification. Thus, lead tetracetate was added to a stirred solution of

4002
A. Kotali, I. S. Lafazanis, and P. A. Harris
the mixture of 3 and 7 (1 mmol) in THF (20 ml), in an ice bath. The molar
ratio of the mixture of hydrazones=LTA and the reaction time are pre-
sented in Table 1. The reaction mixture was then stirred at rt. The oily
product obtained after filtration of lead diacetate and condensation
of the filtrate was subjected to column chromatography (silica gel
70–230 mesh) and was eluted with a mixture of petroleum ether=
ethylacetate 1:1 to afford the pure products 4 as white solids (Table 1).
Oxidation of Hydrazone 3e with PID
Phenyliodosodiacetate (PID) was added to a stirred solution of hydrazone
3e (1 mmol) in dichloromethane (20 ml) in an ice bath. The molar ratio of
hydrazone=LTA and the reaction time are presented in Table 1. The mixture
was then stirred at rt. The oily product obtained after condensation of the
solvent was subjected to column chromatography (silica gel 70–230 mesh)
and was eluted with a mixture of petroleum ether=ethylacetate 1:1 to afford
the pure coumarin 4e as white solid (Table 1).
Data on Compound 3a
1H NMR (400MHz, DMSO-d6): d 2.51 (s, 3H), 6.27 (d, 1H, J ¼ 9.3 Hz),
6.85 (s, 1H), 7.55–7.63 (m, 3H), 7.93–8.05 (m, 4H), 11.45 (s, 1H), 14.27 (s,
1H); 13C NMR (100 MHz, DMSO-d6): d 14.2, 103.8, 111.1, 112.3, 117.2,
128.1 128.4, 129.3, 132.1, 132.7, 144.4, 155.7, 156.9, 160.0, 162.4, 164.5;
MS m=z (ESþ): 345 (Mþ23), 323 (Mþ1); CHN: C, 67.01%; H, 4.43%;
N, 8.70%. Calculated for C18H14N2O4: C, 67.07%; H, 4.38%; N, 8.69%.
Data on Compound 3b
1H NMR (400 MHz, DMSO-d6): d 2.40 (s, 3H), 6.27 (d, 1H, J ¼ 9.4 Hz),
6.86 (s, 1H), 6.96–7.02 (m, 2H), 7.41–7.45 (m, 1H), 7.93–7.98 (m, 2H),
8.03 (s, 1H), 11.40 (s, 1H), 11.69 (s, 1H), 12.18 (s, 1H); 13C NMR
(100 MHz, DMSO-d6): d too insoluble; HRMS (ESIþ) m=z: calcd. for
C18H14N2O5: 699.16976 (2MþNa); 361.07949 (MþNa); found:
699.16964 (2MþNa); 361.07891 (MþNa).
Data on Compound 3c
1H NMR (400 MHz, DMSO-d6): d 2.47 (s, 3H), 6.27 (d, 1H, J ¼ 9.4 Hz),
6.62 (s, 1H), 7.77–7.89 (m, 3H), 7.97 (d, 1H, J ¼ 9.7 Hz), 8.04 (s, 1H), 8.19

Synthesis of 6,7-Diacylcoumarins
4003
(d, 1H, J ¼ 8.0 Hz), 11.4 (s, 1H), 11.8 (s, 1H); 13C NMR (100 MHz,
DMSO-d6): d 14.2, 103.8, 111.2, 112.35, 117.1, 124.3, 129.5, 130.1,
130.5, 131.4, 134.2, 144.3, 146.6, 155.75, 156.3, 160.1, 162.2, 162.9;
HRMS (ESIþ) m=z calcd. for C18H13N3O6: 757.15009 (2MþNa),
390.06966 (MþNa); found: 757.15059 (2MþNa), 390.06929 (MþNa).
Data on Compound 3d
1H NMR (400 MHz, DMSO-d6): d 2.47 (s, 3H), 6.27 (d, 1H, J ¼ 9.5 Hz),
6.71 (d, 1H, J ¼ 3.1 Hz), 6.84 (s, 1H), 7.41 (d, 1H, J ¼ 3.3 Hz), 7.96–7.98
(m, 2H), 8.06 (s, 1H), 11.31 (s, 1H), 14.06 (s, 1H). Compound 3a was too
insoluble for 13C NMR; HRMS (ESI þ) m=z calcd. for C16H12N2O5:
647.13847 (2Mþ23), 335.06380 (MþNa);found: 647.13924 (2MþNa),
335.06370 (MþNa).
Data on Compound 3e
1H NMR (400 MHz, DMSO-d6): d 2.52 (s, 3H), 6.27 (d, 1H, J ¼ 9.5 Hz),
7.24 (s, 1H), 7.91–7.92 (m, 2H), 7.95–7.98 (m, 2H), 8.05 (s, 1H), 11.37 (s,
1H), 14.07 (s, 1H); 13C NMR (100 MHz, DMSO-d6): d 14.4, 103.7, 111.1,
112.3, 117.2, 128.1, 129.4, 130.5, 132.6, 136.6, 144.35, 155.7, 156.8, 158.9,
160.0, 162.3; HRMS (ESI þ) m=z calcd. for C16H12N2O4S: 679.09339
(2MþNa), 351.04155 (MþNa); found: 679.09440 (2MþNa), 351.04099
(MþNa).
Data on Compound 3f
Compound 3a was too insoluble for H1 and 13C NMR; HRMS (ESIþ)
m=z calcd. for C13H12N2O4: 543.14863 (2MþNa), 283.06893 (MþNa);
found: 543.14873 (2Mþ2Na), 283.06915 (MþNa).
Data on Compound 4a
1H NMR (400 MHz, DMSO-d6): d 2.53 (s, 3H), 6.64 (d, 1H, J ¼ 9.7 Hz),
7.43–7.61 (m, 6H), 8.17 (d, 1H, J ¼ 9.7 Hz), 8.55 (s, 1H); 13C NMR
(100 MHz, DMSO-d6): d 27.6, 116.6, 118.5, 119.8, 129.3, 129.4, 129.5,
130.2, 132.1, 133.0, 133.8, 137.0, 144.1, 144.2, 156.5, 159.9, 195.8,
197.4; HRMS (ESIþ) m=z calcd. for C18H12O4: 293.08058 (MþH);
found: 293.08084 (MþH).

4004
A. Kotali, I. S. Lafazanis, and P. A. Harris
Data on Compound 4b
1H NMR (400 MHz, DMSO-d6): d 2.55 (s, 3H), 6.64 (d, 1H, J ¼ 9.7 Hz),
6.80–6.81 (m, 1H), 6.96 (d, 1H, J ¼ 8.2 Hz), 7.15 (d, 1H, J ¼ 7.7 Hz),
7.44–7.49 (m, 2H), 8.16 (d, 1H, J ¼ 9.7 Hz), 8.54 (s, 1H), 11.32 (s, 1H);
13C NMR (100 MHz, DMSO-d6): d 27.6, 116.4, 118.2, 118.5, 119.8,
119.9, 121.2, 132.1, 132.4, 132.7, 136.7, 143.1, 144.1, 156.4, 159.9,
161.2, 197.4, 200.6; MS m=z (ESþ): 331 (Mþ23), 309 (Mþ1), 215;
CHN: C, 69.84%; H, 3.72%. Calculated for C18H12O5: C, 70.13%; H,
3.92%.
Data on Compound 4c
1H NMR (400 MHz, DMSO-d6): d 2.53 (s, 3H), 6.69 (d, 1H,
J ¼ 9.7 Hz), 7.45 (s, 1H), 7.56 (d, 1H, J ¼ 8.2 Hz), 7.78–7.85 (m, 2H),
7.11 (d, 1H, J ¼ 8.2 Hz), 8.16 (d, 1H, J ¼ 9.7 Hz), 8.27 (s, 1H); 13C
NMR (100 MHz, DMSO-d6): d 28.4, 117.7, 119.0, 121.0, 124.5, 129.6,
130.6, 131.2, 133.2, 133.4, 135.7, 138.7, 143.0, 147.6, 154.6, 159.2,
192.25, 199.5; HRMS (ESIþ) m=z calcd. for C18H11NO6: 697.10650
(2MþNa), 360.04786 (Mþ2Na); found: 697.10710 (2MþNa),
360.04790 (MþNa).
Data on Compound 4d
1H NMR (400 MHz, DMSO-d6): d 2.56 (s, 3H), 6.65–6.67 (m, 2H), 7.07
(d, 1H, J ¼ 3,5 Hz), 7.53 (s, 1H), 7.96 (m, 1H), 8.16 (d, 1H, J ¼ 9.7 Hz),
8.51 (s, 1H); 13C NMR (100 MHz, DMSO-d6): d 27.3, 113.1, 118.1,
119.4, 119.5, 122.0, 129.6, 131.0, 133.05, 141.8, 149.3, 151.6, 155.4,
159.25, 181.1, 197.3; HRMS (ESIþ) m=z calcd. for C16H10O5:
587.09487 (2Mþ23), 305.04204 (MþNa); found: 587.09477 (2MþNa),
305.04183 (MþNa).
Data on Compound 4e
1H NMR(400 MHz, DMSO-d6): d 2.53 (s, 3H), 6.64 (d, 1H, J ¼ 9.7 Hz),
7.43–7.57 (m, 2H), 7.59–7.61 (m, 2H), 8.17 (d, 1H, J ¼ 9.7 Hz), 8.55 (s,
1H); 13C NMR (100 MHz, DMSO-d6): d 27.6, 116.6, 118.5, 119.8,
129.3, 129.4, 132.1, 133.0, 133.85, 137.0, 144.1, 144.2, 156.5, 159.9,
195.8, 197.4; MS (ESIþ) m=z: 321 (MþNa), 215; CHN: C, 64.06%; H,
3.30%. Calculated for C16H10O4S: C, 64.42%; H, 3.38%.

Synthesis of 6,7-Diacylcoumarins
Data on Compound 4f
4005
1H NMR (400 MHz, DMSO-d6): d 2.43 (s, 3H), 2.52 (s, 3H), 6.60 (d, 1H,
J ¼ 9.5 Hz), 7.54 (s, 1H), 8.07 (d, 1H, J ¼ 9.5 Hz), 8.22 (s, 1H); 13C NMR
(100 MHz, DMSO-d6): d 28.6, 30.2, 116.0, 116.7, 120.2, 130.6, 133.8,
143.7, 144.4, 155.8, 159.9, 199.4, 202.0; MS (ESIþ) m=z: 253 (MþNa),
231 (MþH); CHN: C, 67.66%; H, 4.30%. Calculated. for C13H10O4: C,
67.82%; H, 4.38%.
ACKNOWLEDGMENT
The authors are grateful to the Royal Society of Chemistry for financial
support of this work.
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