Reaction of diaryl-1,2-diones with homophthalic anhydride: Efficient formation of isobenzofuranone derivatives

Article abstract of DOI:10.1055/s-0030-1258216

The reactions of homophthalic anhydride with benzils afford isobenzofuranone derivatives.

Full text of DOI:10.1055/s-0030-1258216

PAPER
3741
Reaction of Diaryl-1,2-diones with Homophthalic Anhydride: Efficient
Formation of Isobenzofuranone Derivatives
R
eaction of Diaryl
i
-
1,2-dio
j
nes
w
i
a
th Homoph
y
thalic
A
nhydride Nair,*a Rony Rajan Paul,a Eringathodi Sureshb
a
Organic Chemistry Section, National Institute for Interdisciplinary Science and Technology (CSIR), Trivandrum 695019, India
Fax +91(471)2491712; E-mail: vijaynair_2001@yahoo.com
b
Analytical Science Discipline, Central Salt and Marine Research Institute, Bhavnagar 364002, India
Received 10 June 2010; revised 16 June 2010
(Scheme 1). The major isomer was separated by recrystal-
lisation from dichloromethane and was found to be (S)-3-
[(R)-2-oxo-1,2-diphenylethyl]isobenzofuran-1(3H)-one
(3a). The structure elucidation of 3a was aided by the usu-
Abstract: The reactions of homophthalic anhydride with benzils
afford isobenzofuranone derivatives.
Key words: homophthalic anhydride, benzil, heterocycles, ring
contraction, esterification
1
al spectroscopic methods. In the H NMR spectrum, the
methine protons were found at d = 4.71 and 6.25 ppm, and
the aromatic protons appeared between d = 7.89 and 7.25
ppm. The carbonyl peaks in the 13C NMR spectrum ap-
peared at d = 197.1 and 169.6 ppm. In the IR spectrum the
carbonyl groups exhibited absorption peaks at 1716 and
1707 cm–1. All other signals were also in good agreement
with the proposed structure. The final confirmation was
obtained by single-crystal X-ray analysis (Figure 1). The
Ever since the synthesis of benzil and its transformation
into benzilic acid by von Liebig1 (Liebig benzilic acid re-
arrangement) at the dawn of organic chemistry, diaryl-
1,2-diones have attracted much attention from organic
chemists.2 Inter alia, diaryl-1,2-diones, generically called
benzils, have found application in the synthesis of quinox-
alines.3 In the context of our work on the chemistry of 1,2-
diones, acyclic4 and cyclic,5 it was of interest to examine
the possibility of engaging diaryl-1,2-diones as dieno-
philes. In particular, we were curious about a possible re-
action of the diones with homophthalic anhydride, the
latter being predisposed to participate as dienes in Diels–
Alder cycloadditions.6 Parenthetically it may be men-
tioned that homophthalic anhydrides have found exten-
sive use in the construction of anthraquinones7 and other
complex carbocycles.8 It is also noteworthy that carbonyl
compounds such as aldehydes mainly undergo Perkin-
type condensation and not [4+2] cycloadditions with ho-
mophthalic anhydride.9
The present work commenced with the reaction of ho-
mophthalic anhydride (1) and benzil (2a) under neat con-
ditions at 145 °C (6 h) (Scheme 1). Workup of the
reaction mixture followed by chromatography afforded 3-
(2-oxo-1,2-diphenylethyl)isobenzofuran-1(3H)-one (3) in
85% yield as a diastereomeric mixture in the ratio 2:1
Figure 1 ORTEP plot of 3a
O
O
145 °C, 6 h
85% (2:1)
+
+
O
O
O
O
O
O
O
1
2a
O
O
3a
3b
Scheme 1 Reaction of homophthalic anhydride with benzil
SYNTHESIS 2010, No. 21, pp 3741–3744
x
x.
x
x
.
2
0
1
0
Advanced online publication: 18.08.2010
DOI: 10.1055/s-0030-1258216; Art ID: Z14710SS
© Georg Thieme Verlag Stuttgart · New York

3742
V. Nair et al.
PAPER
zoic acid (10) in 87% yield (Scheme 3). The structure of
the product was established by using usual spectroscopic
methods. In the 1H NMR spectrum a singlet appeared at d
= 2.11 ppm, corresponding to the methyl protons. The ar-
omatic protons appeared from d = 8.19 to 7.27 ppm. The
three carbonyl peaks were shown at d = 167.5, 166.2, and
164.0 ppm in the 13C NMR spectrum. The strong absorp-
tion bands at 1847, 1780, and 1689 cm–1 supported the
proposed structure. The structure was unambiguously es-
tablished by single-crystal X-ray analysis (Figure 2).
Table 1 Reactions of Homophthalic Anhydride with Various Ben-
zils
R
R
O
O
O
145 °C, 6 h
O
R
+
O
R
O
O
O
1
2
3–8
Entry
R
Product
Yield (%)a
85 (2:1)
1
2
3
4
5
6
Ph
3
4
5
6
7
8
O
O
O
4-ClC6H4
4-BrC6H4
4-FC6H4
73 (2.7:1)
58 (1.7:1)
80 (3.5:1)
60 (1.8:1)
56 (1.5:1)
O
145 °C, 6 h
87%
O
+
O
O
OH
O
O
O
1
9
10
3-O2NC6H4
4-MeOC6H4
Scheme 3 Reaction of homophthalic anhydride with ethyl pyruvate
a The isomeric ratios of the products are given in parentheses.
reaction was found to be general with various benzils 2
(Table 1).
On the basis of these results, we propose a plausible
mechanism for the formation of isobenzofuranone deriva-
tives (Scheme 2).
O
O
O
••
••
OH
+
O
O
O
2
1
O
O
O
O
Figure 2 ORTEP plot of 10
O
O
OEt
– CO2
O
O
••
O
O
OH
••
••
+
OEt
OH
••
– H2O
O
O
O
O
O
O
O
1
9
O
H2O
O
O
O
O
OH
O
O
O
O
OH
O
O
O
3
10
Scheme 2 Proposed mechanism for the reaction with benzils
Scheme 4 Mechanistic postulate for the formation of 10
In view of the success of the reaction of homophthalic an-
hydride (1) with benzils 2, it was extended to ethyl pyru-
vate (9) under the same reaction conditions. The reaction
yielded 2-(4-methyl-2,5-dioxo-2,5-dihydrofuran-3-yl)ben-
Mechanistically, the reaction may be viewed as occurring
via de-esterification of the initial condensation product
Synthesis 2010, No. 21, 3741–3744 © Thieme Stuttgart · New York

PAPER
Reaction of Diaryl-1,2-diones with Homophthalic Anhydride
3743
3-[1,2-Bis(4-fluorophenyl)-2-oxoethyl]isobenzofuran-1(3H)-
one (6)
Mp 218–220 °C.
followed by ring closure to afford the maleic anhydride
(Scheme 4).
In conclusion, a direct and efficient method for the synthe-
sis of isobenzofuranone derivatives was described. It can
be adapted to the synthesis of substituted maleic anhy-
dride.10
IR (neat): 2956, 1767, 1683, 1597, 1507 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.95–7.81 (m, 6.23 H), 7.59–6.89
(m, 10.24 H), 6.30–6.28 (d, J = 7.5 Hz, 1 H), 6.21–6.18 (d, J = 8.7
Hz, 0.28 H), 4.79–4.76 (d, J = 7.5 Hz, 1 H), 4.65–4.63 (d, J = 8.7
Hz, 0.28 H).
13C NMR (125 MHz, CDCl3): d = 194.8, 194.7, 168.5, 168.4, 147.3,
147.0, 133.3, 131.6, 129.4, 125.7, 123.9, 116.4, 116.0, 115.9, 80.8,
80.7, 57.2, 57.0.
MS–FAB: m/z [M + 1]+ calcd for C22H14F2O3: 365.09; found:
365.66.
Melting points were recorded on a Büchi melting point apparatus
and are uncorrected. 1H NMR spectra were recorded at 300 MHz on
a Bruker Avance DPX-300 MHz NMR spectrometer; 13C NMR
were recorded at 125 MHz. Chemical shifts are reported relative to
TMS (1H) and CDCl3 (13C) as the internal standards. EI-HRMS
(5000 resolution) and FAB+-HRMS were carried out on a JEOL
JMS 600H mass spectrometer. IR spectra were recorded on a
Nicolet Impact 400D FT-IR spectrophotometer. Commercial grade
solvents were distilled prior to use.
3-[1,2-Bis(3-nitrophenyl)-2-oxoethyl]isobenzofuran-1(3H)-one
(7)
Mp 244–246 °C.
IR (neat): 2956, 1765, 1699, 1527, 1474 cm–1.
Isobenzofuran-1(3H)-ones 3–8; General Procedure
Homophthalic anhydride (1; 1 equiv) and the appropriate benzil 2
(1.5 equiv) were placed in a pear-shaped crucible. The reaction mix-
ture was heated at 145 °C for 6 h. The residue was purified by col-
umn chromatography [silica gel (60–120 mesh), EtOAc–hexane,
15:85]; this afforded the corresponding product. Recrystallisation
(CH2Cl2) yielded the products as white crystalline solids.
1H NMR (300 MHz, CDCl3): d = 8.46–8.13 (m, 6.24 H), 7.86–7.34
(m, 11.84 H), 6.35–6.28 (m, 1.56 H), 5.06- 5.04 (d, J = 7.8 Hz, 1 H),
4.88–4.85 (d, J = 8.7 Hz, 0.56 H).
13C NMR (125 MHz, CDCl3): d = 192.0, 191.4, 166.4, 166.3, 146.3,
145.1, 143.8, 134.0.
MS–FAB: m/z [M + 1]+ calcd for C22H14N2O7: 419.08; found:
419.39.
(S)-3-[(R)-2-Oxo-1,2-diphenylethyl]isobenzofuran-1(3H)-one
(3a)
Mp 147–149 °C.
IR (neat): 3037, 2926, 1716, 1708, 1458, 1265, 1184 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.81–7.89 (m, 4 H), 7.26–7.58 (m,
10 H), 6.26 (d, J = 9 Hz, 1 H), 4.72 (d, J = 9 Hz, 1 H).
3-[1,2-Bis(4-methoxyphenyl)-2-oxoethyl]isobenzofuran-1(3H)-
one (8)
Mp 208–210 °C.
IR (neat): 2858, 1769, 1681, 1573, 1175 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.69–7.65 (m, 6 H), 7.59–7.15 (m,
12 H), 6.39–6.27 (m, J = 8.9 Hz, 1 H), 6.20–6.18 (d, J = 7.8 Hz,
0.50 H), 4.69 (d, J = 7.8 Hz, 1 H), 4.63–4.60 (d, J = 8.9 Hz, 0.50 H),
3.83 (s, 6 H).
13C NMR (125 MHz, CDCl3): d = 197.4, 196.2, 169.5, 167.5, 145.3,
145.1, 133.4, 131.3, 131.6, 131.3, 130.8, 129.8, 128.7, 128.5, 127.9,
127.7, 125.2, 124.3, 122.1, 121.5, 82.4, 78.7, 55.8, 55.2.
13C NMR (125 MHz, CDCl3): d = 197.1, 169.6, 148.6, 135.8, 134.5,
133.2, 129.5, 129.2, 128.8, 128.7, 128.2, 126.8, 126.5, 125.8, 123.9,
123.5, 81.9, 59.1, 58.2.
MS–FAB: m/z [M + 1]+ calcd for C22H16O3: 329.11; found: 329.03.
3-[1,2-Bis(4-chlorophenyl)-2-oxoethyl]isobenzofuran-1(3H)-
one (4)
Mp 217–219 °C.
IR (neat): 2926, 1766, 1681, 1591, 1490 cm–1.
MS–FAB: m/z [M + 1]+ calcd for C24H20O5: 389.41; found: 389.53.
2-(4-Methyl-2,5-dioxo-2,5-dihydrofuran-3-yl)benzoic Acid (10)
Homophthalic anhydride (1; 50 mg, 0.31 mmol, 1 equiv) and ethyl
pyruvate (9; 54 mg, 0.47 mmol, 1.5 equiv) were placed in a pear-
shaped crucible. The reaction mixture was heated at 145 °C for 6 h.
Trituration of the reaction mixture with CH2Cl2 afforded the prod-
uct as a white crystalline solid.
1H NMR (300 MHz, CDCl3): d = 7.85–7.83 (m, 5.5 H), 7.82–7.14
(m, 11 H), 6.67 (d, J = 9 Hz, 0.97 H), 6.27 (d, J = 6 Hz, 0.38 H),
4.75 (d, J = 6 Hz, 1 H), 4.62 (d, J = 9 Hz, 0.38 H).
13C NMR (125 MHz, CDCl3): d = 194.6, 193.8, 168.2, 147.1, 146,
139.5, 139.3, 133.9, 133.6, 129.2, 128.6, 128.5, 128.1, 125.7, 124.9,
124.7, 122.3, 80.2, 79.5, 57.4, 29.8, 29.6.
Yield: 62 mg (87%); mp 196–198 °C.
IR (neat): 2659, 1847, 1780, 1689, 1595, 1571, 1473, 1278 cm–1.
1H NMR (300 MHz, CDCl3–DMSO): d = 8.19 (d, J = 7.5 Hz, 1 H),
7.56–7.67 (m, 2 H), 7.27 (d, J = 7.5 Hz, 1 H), 2.11 (s, 3 H).
13C NMR (125 MHz, CDCl3–DMSO): d = 167.5, 166.2, 164.0,
144.5, 137.8, 132.1, 131.4, 130.3, 129.6, 128.6.
MS–FAB: m/z [M + 1]+ calcd for C12H8O5: 233.04; found: 233.15
MS–FAB: m/z [M + 1]+ calcd for C22H14Cl2O3: 397.03; found:
397.26.
3-[1,2-Bis(4-bromophenyl)-2-oxoethyl]isobenzofuran-1(3H)-
one (5)
Mp 211–214 °C.
IR (neat): 2854, 1771, 1684, 1587, 1178 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.77–7.71 (m, 6.32 H), 7.56–7.11
(m, 12.64 H), 6.28 (d, J = 8.9 Hz, 1 H), 6.18 (d, J = 7.8 Hz, 0.58 H),
4.74 (d, J = 7.8 Hz, 1 H), 4.61 (d, J = 8.9 Hz, 0.58 H).
Acknowledgment
13C NMR (125 MHz, CDCl3): d = 193.4, 193.2, 167.6, 167.5, 145.3,
145.1, 132.4, 132.3, 131.6, 131.3, 129.8, 129.2, 128.7, 128.5, 127.9,
127.7, 124.9, 124.2, 124, 122.1, 121.5, 79.4, 78.7, 55.9, 55.7.
MS–FAB: m/z [M + 1]+ calcd for C22H14Br2O3: 484.93; found:
484.94.
V.N. acknowledges the Department of Science and Technology
(DST), New Delhi for the Raja Ramanna Fellowship. The authors
also thank the Council of Scientific and Industrial Research for fi-
nancial assistance. Thanks are due to Mr. B. Adarsh, Ms Athira. N.
Raj, and Ms S. Viji for spectral data.
Synthesis 2010, No. 21, 3741–3744 © Thieme Stuttgart · New York

3744
V. Nair et al.
PAPER
Tetrahedron Lett. 1996, 37, 5623. (f) Nair, V.;
Radhakrishnan, K. V.; Sheela, K. C.; Rath, N. P.
Tetrahedron 1999, 55, 14199.
References
(1) von Liebig, J. Ann. Chem. 1838, 25, 1.
(2) For a review on benzilic acid rearrangement, see: Gill, G. B.
Comprehensive Organic Synthesis, Vol. 3; Trost, B. M.;
Fleming, I., Eds.; Pergamon: Oxford, 1991, 821.
(3) (a) Cheeseman, G. W. H.; Werstiuk, E. S. G. Adv.
Heterocycl. Chem. 1978, 22, 367. (b) Sakata, G.; Makino,
K.; Kurasama, Y. Heterocycles 1988, 27, 2481. (c) Porter,
A. E. A. Comprehensive Heterocyclic Chemistry, Part 2B,
Vol. 3; Katrizky, A. R.; Rees, C. W., Eds.; Pergamon:
Oxford, 1984, 157. (d) Brown, D. J. Quinoxalines:
Supplement II, In The Chemistry of Heterocyclic
Compounds; Taylor, E. C.; Wipf, P., Eds.; John Wiley &
Sons: New Jersey, 2004.
(6) (a) Yu, N.; Poulain, R.; Tartar, A.; Gesquiere, J.-C.
Tetrahedron 1999, 55, 13735. (b) Tamura, Y.; Wada, A.;
Sasho, M.; Kita, Y. Tetrahedron Lett. 1981, 22, 4283.
(c) Ramesh, N. G.; Iio, K.; Okajima, A.; Akai, S.; Kita, Y.
Chem. Commun. 1998, 2741. (d) Cushman, M.; Gentry, J.;
Dekow, F. W. J. Org. Chem. 1977, 42, 1111. (e) Cushman,
M.; Choong, T. C.; Valko, J. T.; Koleck, M. P. J. Org. Chem.
1980, 45, 5067. (f) Kita, Y.; Okunaka, R.; Honda, T.;
Shindo, M.; Taniguchi, M.; Kondo, M.; Sasho, M. J. Org.
Chem. 1991, 56, 119.
(7) Tamura, Y.; Sasho, M.; Akai, S.; Wada, A.; Kita, Y.
Tetrahedron 1984, 40, 4539.
(4) (a) Nair, V.; Pillai, A. N.; Menon, R. S.; Suresh, E. Org. Lett.
2005, 7, 1189. (b) Pillai, A. N.; Suresh, C. H.; Nair, V.
Chem. Eur. J. 2008, 14, 5851. (c) Nair, V.; Vellalath, S.;
Poonoth, M.; Suresh, E.; Viji, S. Synthesis 2007, 3195.
(d) Nair, V.; Mathew, S. C.; Biju, A. T.; Suresh, E. Synthesis
2008, 1078.
(5) (a) Nair, V.; Kumar, S. Synlett 1996, 1143. (b) Nair, V.;
Sheela, K. C.; Radhakrishnan, K. V.; Rajesh, C.; Treesa, P.
M. J. Heterocycl. Chem. 2000, 37, 659. (c) Thomas, A.;
Anilkumar, G.; Nair, V. Tetrahedron 1996, 52, 2481.
(d) Nair, V.; Sethumadhavan, D.; Nair, S. M.; Rath, N. P.;
Eigendorf, G. K. J. Org. Chem. 2002, 67, 7533. (e) Nair,
V.; Radhakrishnan, K. V.; Nair, A. G.; Bhadbhade, M. M.
(8) (a) Takahashi, M.; Shinoda, T.; Osada, H.; Nakajima, T.
Bull. Chem. Soc. Jpn 1975, 48, 2915. (b) Wakchaure, P. B.;
Easwar, S.; Argade, N. P. Synthesis 2009, 1667.
(c) Stanoeva, E.; Haimova, M.; Ognyanov, V. Liebigs Ann.
Chem. 1984, 389.
(9) (a) Nozawa, K.; Yamada, M.; Tsuda, Y.; Kawai, K.;
Nakajima, S. Chem. Pharm. Bull. 1981, 29, 3486. (b) Vara,
V.; Bello, T.; Albada, E.; Arrieta, A.; Pizzaro, J. L.;
Arriortua, M. I.; Lopez, X.; Cossio, F. P. Org. Lett. 2008, 10,
4759.
(10) For the synthesis and applications of substituted maleic
anhydride, see: (a) Kar, A.; Argade, N. P. Tetrahedron 2003,
59, 2991. (b) Mhaske, S. B.; Argade, N. P. J. Org. Chem.
2001, 66, 9038. (c) Adlington, R. M.; Baldwin, J. E.; Cox,
R. J.; Pritchard, G. J. Synlett 2002, 820.
Synthesis 2010, No. 21, 3741–3744 © Thieme Stuttgart · New York