The synthesis of unusual isocoumarin derivatives: the chemistry of homophthalic acid

Article abstract of DOI:10.1016/j.tetlet.2007.01.098

Homophthalic acid was reacted with thionyl chloride/DMF and ethyl chloroformate/NEt₃ in the presence and absence of NaN₃. In all cases completely different isocoumarin derivatives were obtained. These unusual isocoumarin derivatives were characterized and their mechanism of formation is discussed.

Full text of DOI:10.1016/j.tetlet.2007.01.098

Tetrahedron Letters 48 (2007) 2151–2154
The synthesis of unusual isocoumarin derivatives:
the chemistry of homophthalic acid
a,b
Sevil Ozcan, Ertan Sßahinc, and Metin Balcia,
*
¨
aDepartment of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
bDepartment of Chemistry, Abant Izzet Baysal University, 14280 Bolu, Turkey
cDepartment of Chemistry, Atatu¨rk University, 25240 Erzurum, Turkey
Received 25 December 2006; revised 10 January 2007; accepted 18 January 2007
Available online 24 January 2007
Abstract—Homophthalic acid was reacted with thionyl chloride/DMF and ethyl chloroformate/NEt3 in the presence and absence of
NaN3. In all cases completely different isocoumarin derivatives were obtained. These unusual isocoumarin derivatives were charac-
terized and their mechanism of formation is discussed.
Ó 2007 Elsevier Ltd. All rights reserved.
Isocoumarins 1 represents an important class of natu-
rally occurring lactones that display a wide range of bio-
logical activities1 such as protease inhibitory properties,2
antifungal,3 cytotoxic,4 antimicrobial,5 antiallergic and
antimicrobial6 and antimalarial7 effects. These properties
of isocoumarin derivatives and the increasing number of
new isocoumarins in Nature have stimulated continued
interest in their synthesis. Recently, several methods
have been reported for the synthesis of isocoumarins
such as palladium catalyzed reactions, electrophilic aro-
matic substitution, cyclization of 2-allyl- and alkenyl-
benzoic acid, etc.8,2 The six-membered heterocyclic
ring skeleton of isocoumarins can be readily obtained
from aromatic keto acids 2 as well as from phthalic acid
3.2 Nakajima et al.9 and others10 reported the synthesis
of 3-substituted coumarins by condensation of a range
of acid chlorides with homophthalic acid at 200 °C.
Our investigation began with an attempted synthesis of
the diazide derived from homophthalic acid (3). N,N-
Dimethylchlorosulfite methaniminium chloride, formed
from thionyl chloride and dimethylformamide, has been
shown as an efficient reagent for the synthesis of acyl
azides from carboxylic acids.11 Thus in our study, homo-
phthalic acid 3 was reacted with thionyl chloride, DMF
and sodium azide in the presence of tetrabutylammo-
nium bromide as catalyst using CH2Cl2 as the solvent.
Unfortunately, the desired diazide derived from homo-
phthalic acid was not detected. Only, 6H-dibenzo-
[c,h]chromen-6-one12 (4) was formed in 41% yield, which
was characterized by comparison of its spectral data
with those published in the literature (Scheme 1).
A tentative mechanism for the formation of 4 is outlined
in Scheme 2. This reaction presumably occurs by the ini-
tial attack of acid chloride 5, formed under the reaction
conditions, at the methylene group of homophthalic
acid to form condensation product 6 (Scheme 2). Inter-
mediate 6 undergoes decarboxylation and cyclization to
produce isocoumarin derivative 7. Further cyclization of
O
O
COOH
COOH
R
O
COOH
13
7 and reduction of the carbonyl group in 8 with NaN3
1
2
3
O
Keywords: Homophthalic acid; Isocoumarin; Dibenzocromenone;
Sodium azide; Acyl azide.
COOH
O
1. SOCl2, DMF
*
Corresponding author. Tel.: +90 312 2105140; fax: +90 312
2101280; e-mail: mbalci@metu.edu.tr
COOH 2. NaN3, Bu4NBr
Pyridine, CH2Cl2,
reflux, 41%
4
To whom correspondence concerning the X-ray analysis should be
addressed. Tel.: +90 442 2314380; fax: +90 442 2360948; e-mail:
ertan@atauni.edu.tr
3
Scheme 1.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.098

¨
S. Ozcan et al. / Tetrahedron Letters 48 (2007) 2151–2154
2152
O
O
O
Cl
OH
-CO2
-H2O
O
O
O
COOH
COOH
5
OH
COOH
HOOC
O
7
6
3
HOOC
O
O
O
O
O
NaN3
-H2O
HO
O
8
4
9
Scheme 2.
followed by H2O elimination results in the formation of
4. This method represents an easy synthesis of dibenzo-
chromen-6-one derivatives in a single step.
urated with hydrogen chloride. As an alternative meth-
od for the formation of acyl azides, homophthalic acid
3 was treated with ethyl chloroformate in the presence
of triethylamine followed by the addition of a solution
of NaN3 in water. A careful examination of the reaction
mixture revealed the formation of four compounds
12–15 (isolated yields: 26.5%, 9.6%, 7.1%, 10.8%, respec-
tively) (Scheme 4). Compound 12 precipitated from the
reaction media. The other isomers were separated on a
silica gel column eluting with dichloromethane.
Since the azide anion was not incorporated into 4, the
same reaction was run in the absence of NaN3. Instead
of the formation of dibenzochromen-6-one 4, amino-
methylene compound 10 was formed as the sole prod-
uct in 69% yield (Scheme 3). Intermediate 10 was
identified by comparison of the spectral data with those
reported in the literature, obtained under Vilsmeier
conditions.14
COSY, HMQC and HMBC experiments allowed the
assignment of structures 12–15. For the formation of
13 we suggest a similar mechanism to that depicted in
Scheme 2. The intermediate 8 formed can undergo tau-
Intermediate 10 was further converted to isocoumarin
derivative 11 in 76% yield by reaction with methanol sat-
O
O
HCl
COOH
1. SOCl2, DMF
MeOH
O
O
O
N
reflux
COOH
2. Bu4NBr, pyridine
CH2Cl2, reflux
69%
O
3
H3CO
CH3
10
11
CH3
Scheme 3.
O
O
COOH
COOH
O
Cl-COOEt
O
O
+
NEt3, THF, rt
NaN3, H2O
O
Cl
3
O
O
12 (26.5%)
13 (9.6%)
O
OEt
O
H
N
O
O
O
O
+
O
O
14 (7.1%)
15 (10.8%)
EtO
O
Scheme 4.

¨
S. Ozcan et al. / Tetrahedron Letters 48 (2007) 2151–2154
2153
by trapping with ethyl chloroformate results in the
formation of compound 15.
O
O
O
O
MeI, K2CO3
O
CH3CN, 60 oC
1 h, 70%
O
The chlorine-containing compound 12 was treated with
CH3I in the presence of K2CO3 in acetonitrile leading to
the isocoumarin derivative 16 as a single compound in
70% yield (Scheme 5). Again, COSY, HMQC and
HMBC experiments confirmed the structure. HMBC
indicated the presence of a strong correlation between
the carbonyl group of the ketone and the double bond
proton and the ortho-aromatic proton. Finally, an
X-ray diffraction analysis of 16 was undertaken. The
results of this study confirmed, unambiguously the pro-
posed structure (Fig. 1). The compound crystallize in the
O
Cl
COOCH3
O
12
Scheme 5.
16
ꢀ
triclinic space group P1 (No. 2) with Z = 2; the iso-
chromene moiety is planar. The C(1)–C(6) disubstituted
benzene ring is twisted at a dihedral angle of 84.10(5)°
with respect to the isochromene ring system.
Next, homophthalic acid 3 was reacted with ethyl chloro-
formate and triethylamine in the absence of NaN3.
Surprisingly, none of the products obtained in Scheme
4 were formed. Instead, isocoumarin derivative 1715
was formed, in 43% yield, as the major product along
with anhydride 18 in 26% yield (Scheme 6). The struc-
ture of 17 was deduced from NMR spectral data.
Figure 1. ORTEP drawing of 16 at the 50% probability level.
In conclusion, the attempted synthesis of a diazide de-
rived from homophthalic acid failed, however, unusual
coumarin derivatives formed instead. The products iso-
lated were different depending on whether the reaction
was carried out in the prÀesence or absence of NaN3,
despite the fact that the N3 anion was not incorporated
into the molecule. NaN3 plays an important role in
determining the mode of these reactions; this role is
currently under investigation.
tomerization to form the corresponding enol, from
which it can easily be trapped with ethyl chloroformate
in the presence of a base. An HMBC experiment on 12
confirmed its structure, in particular, from correlation of
the carbon atom bearing the chlorine atom with the
double bond proton located on the isocoumarin ring
and the a-proton of the other benzene ring. Further-
more, the presence of 18 carbon resonances and other
spectral data supported the formation of an anhydride
structure. We assume that compound 14 is a secondary
product formed from 12 under the reaction conditions.
The ring opening of 12 followed by decarboxylation
and substitution of the chlorine atom by a carboxylate
anion would form lactone 14. A HMBC experiment
on 14 revealed a strong correlation (3JCH) between the
carbon atom (CH) of the lactone ring with the double
bond proton as well as with the a-proton of the second
benzene ring. Furthermore, the chemical shifts of the all
carbon atoms and other spectral data were in agreement
with the proposed structure. For the formation of 15 the
following mechanism is suggested. The initially formed
acyl chloride can react with azide to give the acyl azide
which can then rearrange to the corresponding isocya-
nate followed by trapping of the isocyanate functional-
ity with the acid –OH group under the reaction
conditions. Enolization of the carbonyl group followed
Crystallographic data (excluding structure factors) for
the structures in this Letter have been deposited with
the Cambridge Crystallographic Data Centre as supple-
mentary publication numbers CCDC 626642. Copies of
the data can be obtained, free of charge, on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[fax: +44(0) 1223 336033 or e-mail: deposit@ ccdc.cam.
ac.uk].
Acknowledgements
The authors are indebted to TUBITAK (The Scientific
and Technological Research Council of Turkey) and
TUBA (The Turkish Academy of Sciences). E.Sß. thanks
Ataturk University for the use of the X-ray diffracto-
¨
O
O
COOH
Cl-COOEt
O
O
+
COOH
NEt3, THF
OCOOEt
O
3
17 (43%)
18 (26%)
Scheme 6.

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S. Ozcan et al. / Tetrahedron Letters 48 (2007) 2151–2154
2154
7. Chinworrungsee, M.; Kittakoop, P.; Isaka, M.; Chan-
phen, R.; Tanticharoen, M.; Thebtaranonth, Y. J. Chem.
Soc., Perkin Trans. 1 2002, 2473.
meter purchased under Grant No. 2003/219 of the Uni-
versity Research Fund.
8. (a) Woon, E. C. Y.; Dhami, A.; Mahon, M. F.; Threadgill,
M. D. Tetrahedron 2006, 62, 4829; (b) Subramanian, V.;
Batchu, V. R.; Barange, D.; Pal, M. J. Org. Chem. 2005,
70, 4778; (c) Roy, H.; Sarkar, M. Synth. Commun. 2005,
35, 2177; (d) Cherry, K.; Parrain, J. L.; Thibonnet, J.;
Duchene, A.; Abarbri, M. J. Org. Chem. 2005, 70, 6669;
Suzuki, T.; Yamada, T.; Watanabe, K.; Katoh, T. Bioorg.
Med. Chem. Lett. 2005, 15, 2583; (e) Opatz, T.; Ferenc, D.
Eur. J. Org. Chem. 2005, 817; (f) Martinez, A.; Fernandez,
M.; Estevez, J. C.; Estevez, R. J.; Castedo, L. Tetrahedron
2005, 61, 485; (g) Yao, T.; Larock, R. C. J. Org. Chem.
2003, 68, 5936; (h) Liao, H.-Y.; Cheng, C. H. J. Org.
Chem. 1995, 60, 3711.
9. Kaji, H.; Yamada, M.; Kawai, K.; Nakajima, S. Org.
Prep. Proced. Int. 1986, 18, 253.
10. (a) Hussain, M.; Rama, N. H.; Hameed, S.; Malik, A.;
Khan, K. M. Nat. Prod. Res. 2005, 19, 41; (b) Zamani,
K.; Faghihi, K.; Ebrahimi, S. Turk. J. Chem. 2005, 29,
171.
Supplementary data
Spectral data on all compounds including the NMR
spectra are provided. Supplementary data associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2007.01.098.
References and notes
1. (a) Napolitane, E. Org. Prep. Proced. Int. 1997, 29, 631;
(b) Murray, R. D. H.; Mendez, J.; Brown, S. A. The
Natural Coumarins: Occurrence, Chemistry, and Biochem-
istry; J. Wiley: New York, 1982; (c) Barry, R. P. Chem.
Rev. 1964, 64, 229.
2. (a) Bihel, F.; Quelever, G.; Lelouard, H.; Petit, A.; da
Costa, C. A.; Pourquie, O.; Checler, F.; Thellend, A.;
Pierre, P.; Kraus, J.-L. Bioorg. Med. Chem. 2003, 11, 3141;
(b) Kang, S. Y.; Lee, K. Y.; Sung, S. H.; Park, M. J.; Kim,
Y. C. J. Nat. Prod. 2001, 64, 683; (c) Thrash, T. P.;
Welton, T. D.; Behar, V. Tetrahedron Lett. 2000, 41, 29.
3. Nozawa, K.; Yamada, M.; Tsuda, Y.; Kawai, K.; Naka-
jima, S. Chem. Pharm. Bull. 1981, 29, 2491.
4. Whyte, A. C.; Gloer, J. B.; Scott, J. A.; Mallock, D. J.
Nat. Prod. 1996, 59, 765.
5. Hussain, M. T.; Rama, N. H.; Malik, A. Indian J. Chem.,
Sect. B 2001, 40, 372.
6. (a) Matsuda, H.; Shimoda, H.; Yoshikawa, M. Bioorg.
Med. Chem. Lett. 1999, 7, 1445; (b) Yoshikawa, M.;
Harada, E.; Naitoh, Y.; Inoue, K.; Matsuda, H.; Shi-
moda, H.; Yamahara, J.; Murakami, N. Chem. Pharm.
Bull. 1994, 42, 2225.
11. Arrieta, A.; Aizpurua, J. M.; Palomo, C. Tetrahedron Lett.
1984, 25, 3365.
12. (a) Rayabarapu, D. K.; Shukla, P.; Cheng, C.-H. Org.
Lett. 2003, 5, 4903; (b) Harayama, T.; Yasuda, H.
Heterocycles 1997, 46, 61; (c) Balanikas, G.; Hussain,
N.; Amin, S.; Hecht, S. S. J. Org. Chem. 1988, 53,
1007.
13. Recently, we discovered that NaN3 can reduce the
carbonyl groups in quinones to the corresponding hydro-
xyl groups in high yield. See: Algi, F.; Balci, M. Synth.
Commun. 2006, 36, 2293.
14. (a) Belgaonkar, V. H.; Usgaonkar, R. N. Tetrahedron
Lett. 1975, 3849; (b) Deady, L. W.; Rodemann, T.
Heterocycl. Chem. 2001, 38, 1185.
15. Schnekenburger, J. Arch. Pharm. 1965, 298, 405.