Regioselective cyclodehydration of ortho-hydroxy acetyl aryloxyketones to benzofuran

Article abstract of DOI:10.1002/jhet.5570440434

(Chemical Equation Presented) ortho-Hydroxy acetyl benzofuran derivatives have been synthesized in a regioselective cyclodehydration of aryloxyketones obtained from β-resacetophenone and α-halo ketones.

Full text of DOI:10.1002/jhet.5570440434

Jul-Aug 2007
945
Regioselective Cyclodehydration of ortho-Hydroxy Acetyl
Aryloxyketones to Benzofuran
Jagdish M. Patel and Shubhangi S. Soman*
Department of Chemistry, Faculty of Science,
The Maharaja Sayajirao University of Baroda, Vadodara 390 002, India.
E-mail: shubhangiss@rediffmail.com, jakpatel21@yahoo.com
Received July 14, 2006
R'
R
R
R
OH
OH
OH
O
O
OH
O
R'COCH2X
O
KOH, Ethanol
OH
+
O
O
O
R'
O
R'
ortho-Hydroxy acetyl benzofuran derivatives have been synthesized in a regioselective cyclodehydration
of aryloxyketones obtained from ꢀ-resacetophenone and ꢁ-halo ketones.
J. Heterocyclic Chem., 44, 945 (2007).
N. Trivedi et al. did not report the formation of angular
isomer in their synthesis of 1-(3-hydroxy-6,7,8,9-tetra-
hydrodibenzofuran-2-yl)-ethanone (linear isomer) [3],
which now has been reported here.
In the present communication we report the regio-
selective cyclodehydration of aryloxyketones in an intra-
molecular Aldol type condensation to benzofuran
derivatives. The reaction sequence for different title
compounds is outlined in Scheme 1.
INTRODUCTION
o-Hydroxy acetophenone are versatile building blocks
serving a variety of applications such as pharmaceuticals,
fine chemicals and specialty polymers. They are impor-
tant starting materials in the synthesis of chalcones [1],
flavonoids [2], psoralens and angelicins [3], 4-hydroxy
coumarins [4], which are well known naturally occurring
compounds having diverse pharmacological properties
along with benzofurans [5]. Naturally occurring
Pongaglabol (8-hydroxy-5-phenyl-furo[2,3-h]benzo[b]-
pyran-7-one) have been synthesized from Phloroaceto-
phenone [6]. Some bioactive compounds have been
synthesized from Visnaginone (5-acetyl-6-hydroxy-4-
methoxybenzo[b]furan) [7]. Hydroxylated benzofurans
such as Euparin [8], Coumestrol [9], dehydrotremetone
[10] or Cicerfuran [11] plays important role in natural
defense mechanism of their plants. One pot synthesis of
similar homologues has also been studied [12].
Synthesis of benzofuran based on MacLeod's work is
well documented [13-16]. The synthetic pathway
followed by MacLeod et al. has been employed to prepare
the title compounds [17]; where the cyclodehydration of
aryloxyketone to benzofuran has been carried out in
alkaline medium instead of the generally used sulfuric
acid, polyphosphoric acid, phosphorus (III) oxychloride
and zinc chloride. The disadvantage with the acid catalyst
is the mixture of 2- and 3-substituted benzofuran in the
product by rearrangement [18]. Many instances of
rearrangement leading to 2-aryl benzofuran have been
observed depending on the condition (structure of ketone,
medium, temperature) [19].
RESULTS AND DISCUSSION
1-(2,4-Dihydroxyphenyl)-ethanone 1a [21], on conden-
sation with different ꢁ-halo ketones, e.g. ꢁ-bromo cyclo-
hexanone, phenacyl bromide and mono chloroacetone, in
presence of anhydrous potassium carbonate/dry acetone
gave 2-(4-acetyl-3-hydroxyphenoxy)-cyclohexanone 2a, 2-
(4-acetyl-3-hydroxyphenoxy)-1-phenyl-ethanone 3a and 1-
(4-acetyl-3-hydroxyphenoxy)-propan-2-one 4a respectively.
Further, 2-(4-acetyl-3-hydroxyphenoxy)-1-phenyl-ethanone
3a when subjected to cyclization in 0.1 N ethanolic
potassium hydroxide showed two products on tlc with very
little difference in rf values, which were then separated on
column chromatography with silica gel (60-120 mesh) and
petroleum ether 60-80 °C. The two products were
characterized as 1-(6-hydroxy-3-phenylbenzofuran-5-yl)-
ethanone 7a-linear isomer and 1-(4-hydroxy-3-
phenylbenzofuran-5-yl)-ethanone 8-angular isomer by nmr
1
spectra. The H nmr showed singlets at ꢂ 7.05 (1H, C7-H)
and ꢂ 8.13 (1H, C4-H) corresponding to the aromatic
protons for linear isomer 7a and doublets (ortho coupling) at
ꢂ 6.95-6.98 (1H, J = 8.8 Hz, C7-H) and ꢂ 7.58-7.61 (1H, J =
8.8 Hz, C6-H) again corresponding to the aromatic protons
for angular isomer 8. Further, 13C nmr values ꢂ 129.179 (C-
4) and ꢂ 161.214 (C-6) for linear isomer and ꢂ 129.306 (C-
6) and ꢂ 160.694 (C-4) for angular isomer corroborated the
cyclic structure. The mechanism as established by MacLeod
et al. is an intramolecular Aldol condensation in which the
Most of the study done hitherto has been on coumarin
nucleus which shows the formation of linear furo-
coumarin as the exclusive product with no emphasis on
the formation of angular furocoumarin except as reported
by A. Guiotto et al. using the said procedure [20]. Even K.

946
J. M. Patel and S. S. Soman
Scheme 1
Vol 44
O
Br
R
OH
OH
ClCH2COCH3
O
K2CO3, KI, acetone, reflux
K2CO3, acetone, reflux
1a,b
C6H5COCH2Br
K2CO3, acetone, reflux
R
R
R
O
O
OH
O
OH
O
O
OH
O
O
O
C6H5
O
CH3
2a,b
4a,b
3a,b
KOH, ethanol,
reflux
KOH, ethanol,
reflux
KOH, ethanol,
reflux
R
R
R
OH
OH
O
OH
O
O
O
O
O
CH3
C6H5
5 a,b
7 a,b
+
9 a,b
+
+
C6H5
CH3
O
OH
O
O
OH
OH
O
O
O
6
8
10
a: R=H
b: R=CH3
phenoxide ion formed promotes attack at the exocyclic
carbonyl function through the resonance stabilized
carbanion generated at the position para relative to the
phenoxide ion. The irreversibility of the process is
established by abstraction of the proton from the newly
formed ring junction. On acidification water is
spontaneously eliminated from the labile ꢀ-hydroxy
dihydrofuran ring system to give the unsaturated
benzofuran. Although the carbanion generated para to the
phenoxide ion is resonance stabilized, the formation of the
carbanion generated ortho to the phenoxide ion cannot be
ruled out as it is the basis for the formation of two isomers.
The low yield of angular isomer compared to the linear
isomer, which is approximately in the ratio of 1:3, is in
accordance with the theory postulated above. To confirm the
cyclization products and to get the higher yield of the linear
isomer, we started with 1-(2,4-dihydroxy-3-methylphenyl)-
ethanone 1b, which gave the expected results.
Similar observations were recorded for the cyclization of
2-(4-acetyl-3-hydroxyphenoxy)-cyclohexanone 2a and 1-
(4-acetyl-3-hydroxyphenoxy)-propan-2-one 4a. Potassium
carbonate and triethylamine in place of potassium
hydroxide failed to improve the overall yield of the
cyclization reaction. Cyclization, especially in case of
phenacyl bromide took more time comparatively, because
of the stabilization of exocyclic carbonyl function by the
phenyl ring. The structures of the compounds have been
established on the basis of their elemental analyses and
spectral (ir and nmr) data as shown in Table 1. The long
range coupling between C3 – CH3 and C2 – H in
1
compounds 9a, 9b and 10 have been confirmed by H –
COSY spectra.

Jul-Aug 2007
Regioselective Cyclodehydration of ortho-Hydroxy Acetyl Aryloxyketones to Benzofuran
947

948
J. M. Patel and S. S. Soman
Vol 44
EXPERIMENTAL
Melting points (uncorrected) were determined using
a
scientific capillary melting point apparatus. Purity of the
compounds was checked by tlc on Acme's silica gel G plates
using UV/Iodine vapour as visualizing agent and Acme's silica
gel (60-120 mesh) was used for column chromatographic
purification. Elemental analyses were carried out on Perkin-
Elmer C, H, N, S analyzer (Model-2400). Infrared spectra were
recorded on Perkin-Elmer FT-IR spectrometer (spectrum RX1)
using potassium bromide optics. Nmr spectra were recorded on
Brucker 300 MHz spectrophotometer except where mentioned.
Chemical shifts are relative to tetramethylsilane on ꢀ-scale with
deuteriochloroform as solvent. Coupling constants are given in
Hz and relative peak areas are in agreement with all
assignments.
General procedure for the preparation of 2a, 2b, 3a, 3b, 4a
and 4b. To a stirred solution of 1-(2,4-dihydroxyphenyl)-
ethanone 1a (5 g, 0.033 moles) and anhydrous potassium
carbonate (5.68 g, 0.041 moles) in (30 ml) dry acetone was
added drop wise a solution of phenacyl bromide (6.54 g, 0.033
moles) in (20 ml) dry acetone at reflux temperature. Reflux
was continued for 12 hours. The reaction mixture was
concentrated to dryness and then poured into ice water and the
solid collected by filtration. The crude product was purified by
column chromatography using petroleum ether (60-80°C):
ethyl acetate mixture and crystallized therein to give white
crystals (4.7 g, 52.9%) of 2-(4-acetyl-3-hydroxyphenoxy)-1-
phenyl-ethanone 3a.
Potassium iodide was added in catalytic amount in the
preparation of compounds 4a and 4b by the said procedure.
General procedure for the preparation of 5a, 5b, 6, 7a, 7b,
8, 9a, 9b and 10. 2-(4-Acetyl-3-hydroxyphenoxy)-1-phenyl-
ethanone 3a (1 g, 0.0037 moles) was dissolved in 0.1 N
ethanolic potassium hydroxide (100 ml) and refluxed for 30
hours. The excess ethanol was then removed by distillation in
vacuo and the reaction mixture was poured into ice-hydrochloric
acid and the solid collected by filtration. The crude product
showed two products on tlc developing with petroleum ether
(60-80°C) and visualizing in iodine. Both the products were
separated by column chromatography using petroleum ether (60-
80°C) as eluent. The first product (non polar) to come out of the
column was characterized as 1-(4-hydroxy-3-phenylbenzofuran-
5-yl)-ethanone 8-angular isomer and obtained as light greenish
yellow crystals (0.086 g, 9.21%).
The second product from the column was characterized as 1-(6-
hydroxy-3-phenylbenzofuran-5-yl)-ethanone 7a-linear isomer
and obtained as light greenish yellow crystals (0.22 g, 23.57%).
Cyclization for compounds 5a, 5b, 6, 9a, 9b and 10 took 18
hours for completion of reaction.
Acknowledgement The authors are thankful to the Department
of Chemistry, The Maharaja Sayajirao University of Baroda for
providing the necessary facilities. The authors are also thankful to
1
BIOARC-Alembic and Sun Pharma, Baroda for H nmr spectra.
One of the authors (JMP) is thankful to AICTE (National Doctoral
Fellowship) for providing financial assistance.
REFERENCES
[1] Dhar, D. N.; Lal, J. B. J. Org. Chem. 1958, 23, 1159.
[2] Matsumura, H.; Tsuchiya, T.; Takeda, T.; Imafuku, K. Bull.

Jul-Aug 2007
Regioselective Cyclodehydration of ortho-Hydroxy Acetyl Aryloxyketones to Benzofuran
949
Chem. Soc. Jpn. 1983, 56, 2037.
[3] Soman, S. S.; Trivedi, K. N. J. Indian Chem. Soc. 1990, 67,
997.
[13] Zhang, Bang-Le; Wang, Fang-Dao; Yue, Jian-Min Synlett
2006, 4, 567.
[14] Garazd, Ya. L.; Garazd, M. M.; Khilya, V. P. Chemistry of
Natural Compounds 2005, 41, 388.
[15] Cruz, Maria del Carmen; Tamariz, Joaquin Tetrahedron Lett.
2004, 45, 2377.
[16] Traven, Valery F.; Rozhkov, Roman V.; Tolmachev,
Alexander Yu.; Kuznezova, Natalja A.; Podhaluzina, Natalja Ya.;
Carberry, Edward A. Heterocyclic Communications, 1997, 3, 339.
[17] MacLeod, J. K.; Worth, B. R. Tetrahedron Lett. 1972, 237.
[18] Thomas, K. K.; Bokadia, M. M. J. Indian Chem. Soc. 1968,
45, 265.
[19a] Davies, W.; Middleton, S. Chem. Ind. (London) 1957, 1999;
[b] Davies, W; Middleton, S. J. Chem. Soc. 1959, 3544; [c] Kost, A. N.;
Budylin, V. A.; Sterligov, D. O.; Natreievna, E. D. Zh. Org. Khim 1970,
6, 150; Chem. Abstr. 1970, 73, 98705.
[4] Boyd, J.; Robertson, A. J. Chem. Soc. 1948, 174.
[5] Katritzky, A. R.; Boulton, A. J. Recent Advances in the
Chemistry of benzo [b]furan and its Derivatives. Part I: Occurrence
and synthesis: Advances in Heterocyclic Chemistry, Academic Press,
New York, 1975, Vol 18, pp 337-482.
[6] Alam, S.; Sarkar, Z.; Islam, A. J. Chem. Sci. 2004, 116, 29.
[7] Abdel Hafez, O. M.; Ahmed, Kh. M.; Haggag, E. E.
Molecules 2001, 6, 396.
[8] Kamthong, B.; Robertson, A. J. Chem. Soc. 1939, 925.
[9] Emerson, O. H.; Bickoff, E. M. J. Am. Chem. Soc. 1958, 80,
4381.
[10] DeGraw, J.; Bonner, W. A. J. Org. Chem. 1962, 27, 3917.
[11] Stevenson, P. C.; Veitch, N. C. Phytochemistry 1998, 48,
947.
[20] Rodighiero, P.; Palumdo, M.; Magno, S. M.; Manzini, P.;
Gia, O.; Piro, R.; Guiotto, A. J. Heterocycl. Chem. 1986, 23, 1405.
[21] Cooper, S. R. Org. Synth. 1941, 21, 103.
[12] Csekei, M.; Novak, Z.; Timari, G.; Kotschy, A. ARKIVOC
2004, vii, 285.