A convenient regioselective synthesis of 2,4-diarylfurans

Article abstract of DOI:10.1055/s-1999-3668

A facile three step process, under mild conditions, for the synthesis of 2,4-diarylfurans with the same or different substituents on the two aryl rings, starting from benzaldehydes and acetophenones, employing Haller-Bauer type cleavage of 2-aroyl-3,5-diarylfurans is described.

Full text of DOI:10.1055/s-1999-3668

SHORT PAPER
61
A Convenient Regioselective Synthesis of 2,4-Diarylfurans
Iris Francesconi, Alpa Patel, David W. Boykin*
Department of Chemistry, Georgia State University, Atlanta, Georgia 30303, USA
Fax: 4046511542; E-mail: chedwb@panther.gsu.edu
Received 4 May 1998; revised 27 July 1998
Abstract: A facile three step process, under mild conditions, for the
synthesis of 2,4-diarylfurans with the same or different substituents
on the two aryl rings, starting from benzaldehydes and acetophe-
nones, employing HallerÐBauer type cleavage of 2-aroyl-3,5-di-
arylfurans is described.
Key words: 2,4-diarylfurans, 2-aroyl-3,5-diarylfurans, non-enol-
izable ketone cleavage
Synthetic routes to 2,4-diarylfurans are limited.1,2 Conve-
nient procedures for preparing 2,4-diarylfurans with the
same or different substitutents on the two aryl rings are
even more rare. One method which seems to be general
for preparation of both types of substituted 2,4-diaryl-
furans involves the condensation of acetophenones with
1-amino-4,6-diphenyl-2-pyridone and subsequent metal-
lation of the ketimines with butyllithium at Ð78¡C fol-
lowed by reaction with phenacyl bromides.3 The addition
of dimethylsulfonium methylide to â-alkoxy-α,â-unsatur-
ated ketones is also a useful approach for synthesis of 2,4-
diarylfurans.4 For most substituents, both of these meth-
ods require synthesis of starting materials and the former
Scheme
one requires low temperature operations. For the latter ap-
proach synthesis of the required â-alkoxy-α,â-unsaturat-
number of 2,4,6-triarylpyryllium salts 3.11 Pederson re-
ported the conversion of the 2,4,6-triphenylpyryllium salt
3a into 2-benzoyl-3,5-diphenylfuran (4a) by the action of
base in the presence of iodine.12 The reaction is thought to
involve iodination of the anion of the pseudo base fol-
lowed by intramolecular displacement of iodide ion. The
scope of this reaction was not explored. We have found
the reaction to be general for a variety of substitutents on
the aryl rings and to proceed to give reasonable yields
(51Ð70%) of 2-aroyl-3,5-diarylfurans 4aÐ4i. In order to
obtain the desired 2,4-diarylfurans 5 from the 2-aroyl-3,5-
diarylfurans 4 we employed a HallerÐBauer type ap-
proach for cleavage of the non-enolizable ketone.13,14 Po-
tassium tert-butoxide in DMSO as the solvent at room
temperature produced dearoylation in satisfactory yields,
however, removal of DMSO and isolation of the 2,4-dia-
rylfuran was often cumbersome. A brief study of the ef-
fect of solvent on the dearoylation reaction demonstrated
that there is no significant dependence on solvent polarity
and that several solvents could be successfully used. For
example, cleavage of 4a in DMSO, DMF, N-methylpyrro-
lidin-2-one, dioxane, or benzene gave isolated yields of
72, 95, 85, 80, or 94%, respectively. We have found that
on the use of dioxane as solvent often the 2,4-diarylfurans
ed ketones is a multistep process which sometimes
involves the use of diazomethane.4,5 Synthesis of 2,4-di-
arylfurans directly from phenacyl bromides by electro-
chemical methods6, by reaction with nickel carbonyl in
8
7
DMF , by reaction with cuprous chloride , and by reaction
with sodium telluride9 have been reported. These methods
suffer from two or more of the following disadvantages:
only furans with the same substitutents on the two aryl rings
may be made, many of the phenacyl bromides are not com-
mercially available, only modest yields are obtained, key
reagents are toxic, and specialized equipment is required.
As part of a program focused on the development of anti-
infective agents we needed a convenient method for prepa-
ration of relatively large quantities of 2,4-diarylfurans.10
This report describes a simple three step synthetic method
starting from benzaldehydes and acetophenones which can
be used for preparation of 2,4-diarylfurans with the same or
different substitutents on the two aryl rings. The approach
employed is presented in the Scheme below.
The reaction of one equivalent of substituted benzalde-
hydes 1 with two equivalents of substituted aceto-
phenones 2 mediated by boron trifluoride etherate in
benzene has been reported for the synthesis of a large
Synthesis 1999, No. 1, 61Ð63 ISSN 0039-7881 © Thieme Stuttgart · New York

62
I. Francesconi et al.
SHORT PAPER
13C NMR (CDCl3): d = 182.1, 163.1, 160.7, 160.0, 155.9, 145.8,
137.3, 132.3, 131.4, 130.8, 126.7, 125.1, 122.7, 114.7, 113.9, 113.6,
108.4, 55.6, 55.5.
precipitate directly from the reaction mixture as analyti-
cally pure solids. Consequently, dioxane is our solvent of
choice for the dearoylation reaction.
2,4,6-Tris(4-nitrophenyl)- and 2,4,6-tris(4-cyanophenyl)-
pyryllium tetrafluoroborate were unstable, in our hands,
and could not be used in this process. We note that 2,4,6-
tris(4-N,N-dimethylaminophenyl)pyryllium tetrafluoro-
borate is reported to form only in very low yields.11 Thus,
the presence of either very strong electron donors or elec-
tron withdrawers represents apparent limitations of this
method.
3,5-Bis(4-bromophenyl)-2-(4-bromobenzoyl)furan (4c)
Mp 186Ð188¡C.
IR (KBr): ν = 1637 cmÐ1.
1H NMR (CDCl3): d = 7.84 (d, 2 H, J = 8.4 Hz), 7.63 (d, 6 H, J =
9.2 Hz), 7.55 (d, 2 H, J = 9.2 Hz), 7.52 (d, 2 H, J = 9.2 Hz), 6.97 (s,
1 H).
13C NMR (CDCl3): d = 182.1, 155.4, 146.1, 137.0, 136.8, 132.6, 131.8,
131.7, 131.4, 131.0, 130.9, 128.1, 127.8, 126.6, 124.0, 123.3, 110.2.
In summary, a convenient three step process, starting from
benzaldehydes and acetophenones, for preparation of 2,4-
3,5-Bis(3-bromophenyl)-2-(3-bromobenzoyl)furan (4d)
Mp 161Ð163¡C.
diarylfurans with the same or different substitutents on the IR (KBr): ν = 1646 cmÐ1.
1H NMR (CDCl3): d = 8.06 (s, 1 H), 7.91 (s, 1 H), 7.83 (d, 1 H, J =
8.0 Hz), 7.70 (s, 1 H), 7.69 (d, 1 H, J = 8.4 Hz), 7.66 (d, 1 H, J =
8.0 Hz), 7.53Ð7.47 (m, 3 H), 7.33 (m, 1 H), 7.32 (m, 1 H), 7.24 (m,
1 H), 6.97 (s, 1 H).
13C NMR (CDCl3): d = 181.7, 155.1, 146.2, 139.6, 136.7, 135.5,
133.9, 132.9, 132.7, 132.3, 131.9, 131.0, 130.8, 130.0, 130.0, 128.3,
128.2, 128.1, 123.8, 123.5, 122.6, 122.5, 110.7.
two aryl rings has been described. This method provides a
convenient complement to the recently reported two step
process, starting from benzaldehydes, for the synthesis of
2,5-diarylfurans.15
Melting points were determined in open capillary tubes using a
Thomas Hoover (Uni-Melt) or with a Mel-temp 3.0 capillary melting
point apparatus and are uncorrected. 1H and 13C NMR spectra were
recorded employing a Varian Unity+300 or a Varian VRX 400 spec-
trometer and chemical shifts(d) are in ppm relative to TMS unless
otherwise noted. IR spectra were recorded using a Perkin Elmer 2000
FT-IR instrument. Elemental analyses were obtained from Atlantic
Microlab Inc. (Norcross, GA). All chemicals and solvents were pur-
chased from Aldrich Chemical Co. or Fisher Scientific. All new com-
pounds gave satisfactory elemental analyses: C ± 0.39, H ± 0.33.
2-(4-Bromobenzoyl)-3-(3-bromophenyl)-5-(4-bromophenyl)-
furan (4e)
Mp 203Ð204¡C.
IR (KBr): ν = 1637 cmÐ1.
1H NMR (CDCl3): d = 7.80 (d, 2 H, J = 8.0 Hz), 7.73 (s, 1 H), 7.64Ð
7.58 (m, 6 H), 7.55 (d, 1 H, J = 7.6 Hz), 7.50 (d, 1 H, J = 8.0 Hz),
7.25 (d, 1 H, J = 8.0 Hz), 6.97 (s, 1 H).
13C NMR (CDCl3): d = 182.2, 155.5, 146.1, 136.6, 133.9, 132.6,
132.2, 131.8, 131.7, 131.4, 130.0, 128.1, 128.0, 127.8, 126.6, 124.0,
122.5, 110.3.
2-Aroyl-3,5-diarylfurans 4; General Procedure
Under nitrogen atmosphere, BF3 OEt2 (60 mmol) was added to a
¥
mixture of benzaldehyde (25 mmol) and acetophenone (50 mmol)
in anhydrous benzene (3 mL). The clear solution was heated to re-
flux for 2 h. After cooling to r.t. acetone (5 mL) was added and the
dark red solution was poured into Et2O (250 mL). The yellow pre-
cipitate was filtered, washed with Et2O and dried (CaSO4) under
vacuum. The dried 2,4,6-triarylpyryllium salt (10 mmol) was sus-
pended in acetone (50 mL). A solution of Na2CO3 (16 mmol) in H2O
(6.4 mL) was added and the mixture was stirred for 2 h at r.t. I2
(16 mmol) was added and stirring was continued for 16 h. The dark
mixture was poured into a solution of Na2S2O3 (160 mmol) in H2O
(250 mL) and the aqueous phase was extracted with CHCl3. The or-
ganic phase was washed with H2O, dried (Na2SO4) and the volume
was reduced under vacuum. The crude product was purified by col-
umn chromatography on silica gel (hexane/CHCl3); yield: 51Ð70%
(based upon the triarylpyryllium salt)
2-(3-Bromobenzoyl)-5-(3-bromophenyl)-3-(4-bromophenyl)-
furan (4f)
Mp 155Ð156¡C.
IR (KBr): ν = 1642 cmÐ1.
1H NMR (CDCl3): d = 8.11 (s, 1 H), 7.92 (s, 1 H), 7.87 (d, 1 H, J =
7.6 Hz), 7.70 (d, 2 H, J = 8.0 Hz), 7.54Ð7.48 (m, 5 H), 7.35 (t, 2 H),
6.98 (s, 1 H).
13C NMR (CDCl3): d = 181.6, 155.0, 146.1, 139.7, 137.1, 135.5,
133.0, 132.7, 131.7, 131.1, 131.0, 130.9, 130.8, 130.0, 128.3, 128.2,
123.7, 123.5, 123.3, 122.6, 110.7.
2-(4-Fluorobenzoyl)-3,5-bis(4-fluorophenyl)furan (4g)
Mp 159Ð160¡C.
IR (KBr): ν = 1642 cmÐ1.
2-Benzoyl-3,5-diphenylfuran (4a)
Mp 116Ð118¡C (Lit.12 mp 117Ð118¡C).
IR (KBr): ν = 1642 cmÐ1.
1H NMR (CDCl3): d = 8.01Ð7.96 (m, 2 H), 7.77Ð7.72 (m, 2 H),
7.63Ð7.58 (m, 2 H), 7.18Ð7.04 (m, 6 H), 6.89 (s, 1 H).
13C NMR (CDCl3): d = 181.9, 165.5 (JC,F = 253.8 Hz), 163.6 (JC,F
250.4 Hz), 163.1 (JC,F = 248.6 Hz), 155.4, 146.0, 137.1, 134.4 (JC,F
=
1NMR (CDCl3): d = 7.95 (d, 2 H, J = 6.8 Hz), 7.78 (d, 2 H, J =
7.2 Hz), 7.61 (d, 2 H, J = 7.2 Hz), 7.55Ð7.32 (m, 9 H), 6.98 (s, 1 H).
= 2.9 Hz), 132.4 (JC,F = 9.2 Hz), 131.3 (JC,F = 8.7 Hz), 128.2 (JC,F
2.9 Hz), 127.2 (JC,F = 8.7 Hz), 125.7 (JC,F = 3.5 Hz), 116.5 (JC,F
22.5 Hz), 115.6 (JC,F = 21.9 Hz), 115.5 (JC,F = 21.3 Hz), 109.7.
=
=
13C NMR (CDCl3): d = 183.6, 156.2, 146.3, 138.4, 137.8, 132.5,
132.4, 130.0, 129.6, 129.5, 129.4, 129.2, 128.6, 128.4, 128.3, 125.2,
110.0.
2-(4-Bromobenzoyl)-5-(4-bromophenyl)-3-(4-methoxy-
phenyl)furan (4h)
2-(4-Methoxybenzoyl)-3,5-bis(4-methoxyphenyl)furan (4b)
Mp 127¡C.
Mp 151Ð153¡C.
IR (KBr) ν = 1634 cmÐ1.
IR (KBr): ν = 1629 cmÐ1.
1H NMR (CDCl3) d = 8.00 (d, 2 H, J = 8.8 Hz), 7.71 (d, 2 H, J = 8.8
Hz), 7.61 (d, 2 H, J = 8.8 Hz), 6.96 (d, 2 H, J = 8.8 Hz), 6.92 (m, 4
H), 6.82 (s, 1 H), 3.88 (s, 3 H), 3.85 (s, 3 H), 3.83 (s, 3 H).
1H NMR (CDCl3): δ = 7.81(d, 2H, J = 8.4 Hz), 7.64Ð7.58 (m, 8 H),
6.97 (s, 1 H), 6.93 ( d, 2 H, J = 8.8 Hz), 3.85 (s, 3 H) .
Synthesis 1999, No. 1, 61Ð63 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
A Convenient Regioselective Synthesis of 2,4-Diarylfurans
63
13C NMR (CDCl3): δ = 182.3, 160.4, 155.2, 145.8, 138.2, 137.2,
132.5, 131.6, 131.4, 130.8, 128.4, 127.3, 126.6, 124.2, 123.8, 114.0,
110.4, 55.6
2-(3-Bromophenyl)-4-(4-bromophenyl)furan (5f)
Mp 112Ð113¡C.
1H NMR (CDCl3): δ = 7.84 (s, 1 H), 7.73 (s, 1 H), 7.61 (d, 1 H, J =
8.0 Hz), 7.51 (d, 2 H, J = 8.0 Hz), 7.40 (d, 1 H, J = 8.0 Hz), 7.37 (d,
2 H, J = 8.4 Hz), 7.26 (m, 1 H), 6.92 (s, 1 H).
3-(4-Bromophenyl)-2-(4-methoxybenzoyl)-5-(4-methoxy-
phenyl)furan (4i)
13C NMR (CDCl3): δ = 153.8, 138.7, 132.6, 132.2, 131.3, 130.8,
130.5, 127.8, 127.6, 127.1, 123.2, 122.6, 121.3, 105.0.
Mp 150Ð151¡C.
IR (KBr): ν = 1634 cmÐ1.
1H NMR (CDCl3): δ = 8.02 (d, 2 H, J = 8.8 Hz), 7.72 (d, 2 H, J =
8.8 Hz), 7.52 (d, 2 H, J = 9.2 Hz), 7.50 (d, 2 H, J = 9.2 Hz), 6.98 (d,
2 H, J = 8.8 Hz), 6.95 (d, 2 H, J = 8.8 Hz), 6.80 (s, 1 H), 3.90 (s, 3
H), 3.88 (s, 3 H).
2,4-Bis(4-fluorophenyl)furan (5g)
Mp 121Ð122¡C.
1H NMR (CDCl3): δ = 7.67 (m, 3 H), 7.49Ð7.44 (m, 2 H), 7.12Ð7.05
(m, 4 H), 6.82 (s, 1 H).
13C NMR (CDCl3): δ = 182.0, 163.3, 160.8, 156.2, 146.1, 136.3,
132.3, 131.8, 131.5, 131.1, 130.9, 126.8, 122.7, 122.4, 114.8, 113.7,
108.2, 55.7, 55.6.
13C NMR (CDCl3): δ = 162.6 (JC,F = 247.5), 162.3 (JC,F = 246.3 Hz),
154.4, 137.8, 128.7 (JC,F = 3.5 Hz), 127.8, 127.6 (JC,F = 7.5 Hz),
127.2 (JC,F = 2.9 Hz), 125.9 (JC,F = 8.1 Hz), 116.0 (JC,F = 21.9 Hz),
103.9.
2,4-Diarylfurans 5; Genereal Procedure
2-(4-Bromophenyl)-4-(4-methoxyphenyl)furan (5h)
Mp 172Ð174¡C.
H2O (15 mmol) was added to a suspension of KOBu-t (50 mmol) in
dioxane (25 mL). 2-Aroyl-3,5-diarylfuran (5 mmol) was added and
the stirring was continued for 30 min. The mixture was slowly
poured into ice water (250 mL) and stirred for 15 min. The off-white
precipitate was filtered, washed with H2O and dried (CaSO4) under
vacuum. In a few cases very fine precipitate formed; for these cases
the aqueous phase was extracted with CHCl3. The organic phase
was washed with H2O dried (Na2SO4) and reduced under vacuum.
The product was purified by column chromatography on silica gel
(hexane/CHCl3); yield: 57Ð91%.
1H NMR (CDCl3): δ = 7.66 (s, 1 H), 7.56 (d, 2 H, J = 8.8 Hz), 7.51
(d, 2 H, J = 8.8 Hz), 7.44 (d, 2 H, J = 8.8 Hz), 6.93 (d, 2 H, J =
8.8 Hz), 6.90 (s, 1 H), 3.85 (s, 3H).
13C NMR (CDCl3): δ = 159.3, 153.9, 137.7, 132.1, 129.9, 128.5,
127.2, 125.6, 125.0, 121.5, 114.6, 104.9, 55.6.
4-(4-Bromophenyl)-2-(4-methoxyphenyl)furan (5i)
Mp 170Ð172¡C.
1H NMR (CDCl3): δ = 7.71 (s, 1 H), 7.64 (d, 2 H, J = 8.8 Hz), 7.52
(d, 2 H, J = 8.4 Hz), 7.40 (d, 2 H, J = 8.4 Hz), 6.96 (d, 2 H, J =
8.8 Hz), 6.78 (s, 1 H), 3.86 (s, 3 H).
2,4-Diphenylfuran (5a)
Mp 109¡C (Lit.6 mp 109Ð110¡C).
1H NMR (CDCl3): δ = 7.73 (s, 1 H), 7.71 (d, 2 H, J = 7.2 Hz), 7.52
(d, 2 H, J = 7.2 Hz), 7.41Ð7.36 (m, 4 H), 7.27 (m, 2 H), 6.94 (s, 1 H).
13C NMR (CDCl3): δ = 159.7, 155.5, 137.6, 132.1, 131.8, 127.6,
125.6, 123.8, 120.9, 114.5, 102.4, 55.6.
13C NMR (CDCl3): δ = 154.9, 137.9, 132.4, 130.7, 128.8, 128.7,
128.4, 127.6, 127.1, 125.8, 123.9, 104.0.
Acknowledgement
2,4-Bis(4-methoxyphenyl)furan (5b)
This work was supported by NIH Grant NIAID AI 33363 (DWB), the
Fullbright Commission (IF), and the Georgia Research Alliance
(DWB).
Mp 188Ð190¡C (Lit.6 mp 191Ð192¡C).
1H NMR (CDCl3): δ = 7.63 (d, 2 H, J = 8.4 Hz), 7.62 (s, 1 H), 7.44
(d, 2 H, J = 8.4 Hz), 6.94 (d, 2 H, J = 8.8 Hz), 6.92 (d, 2 H, J =
8.8 Hz), 6.76 (s, 1 H), 3.84 (s, 3 H), 3.83 (s, 3 H).
13C NMR (CDCl3): δ = 159.5, 159.1, 155.0, 136.7, 128.2, 127.2,
125.6, 125.5, 124.2, 114.5, 114.4, 102.8, 55.6.
References
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Tong, S. Y.; Wong, H. N. C. Tetrahedron 1998, 54, 1955.
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39, 72.
2,4-Bis(4-bromophenyl)furan (5c)
Mp 154Ð156¡C (Lit.6 mp 159Ð160¡C).
1H NMR (CDCl3): δ = 7.72 (s, 1 H), 7.55 (d, 2 H, J = 8.8 Hz), 7.51
(d, 2 H, J = 8.8 Hz), 7.50 (d, 2 H, J = 8.4 Hz), 7.36 (d, 2 H, J = 8.4
Hz), 6.89 (s, 1 H).
13C NMR (CDCl3): δ = 154.1, 138.3, 132.0, 131.9, 131.1, 129.4,
127.6, 127.4, 125.4, 121.6, 121.0, 104.3.
(5) Weygand, C.; Bauer, E.; Henning, H. Ber. Dtsch. Chem. Ges.
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Jpn. 1989, 62, 2114.
(10) cf. Boykin, D.W.; Kumar, A.; Xiao, G.; Wilson, W.D.; Ben-
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(15) Bajic, M.; Kumar, A.; Boykin, D.W. Heterocyclic Commun.
1996, 2, 135.
2,4-Bis(3-bromophenyl)furan (5d)
Mp 81Ð83¡C.
1H NMR (DMSO-d6): δ = 8.38 (s, 1 H), 7.94 (s, 1 H), 7.91 (s, 1 H),
7.75 (d, 1 H, J = 7.6 Hz), 7.69 (d, 1 H, J = 7.4 Hz), 7.68 (s, 1 H), 7.51
(d, 1 H, J = 8.4 Hz), 7.48 (d, 1 H, J = 8.0 Hz), 7.44Ð7.36 (m 2 H).
13C NMR (DMSO-d6): δ = 152.3, 140.4, 133.9, 132.0, 130.8, 130.6,
130.1, 129.6, 127.8, 126.4, 125.8, 124.2, 122.1, 105.7.
2-(4-Bromophenyl)-4-(3-bromophenyl)furan (5e)
Mp 115Ð117¡C.
1H NMR (CDCl3): δ = 7.74 (s, 1 H), 7.65 (s, 1 H), 7.56 (d, 2 H, J =
8.8 Hz), 7.52 (d, 2 H, J = 8.8 Hz), 7.42 (m, 2 H), 7.24 (d, 1 H, J =
8.0 Hz), 6.91 (s, 1 H ).
13C NMR (CDCl3): δ = 154.4, 138.8, 134.5, 132.2, 130.6, 130.4,
129.6, 129.1, 127.6, 125.7, 124.6, 123.2, 121.9, 104.5.
Synthesis 1999, No. 1, 61Ð63 ISSN 0039-7881 © Thieme Stuttgart · New York