Expedient preparation of 4,6-dihalo-3-arylisobenzofuran- 1(3H)-ones from 3,5-dihalo-n-ethylbenzamides

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Expedient Preparation of 4,6-Dihalo-3-
arylisobenzofuran-1(3H)-ones from 3,5-
Dihalo-N-ethylbenzamides
Lynn M. Bradley a , Carleton G. Collins a , Erica R. Tabakin a & David
A. Hunt a
a Department of Chemistry, The College of New Jersey, Ewing, New
Jersey, USA
Version of record first published: 07 Apr 2010.
To cite this article: Lynn M. Bradley, Carleton G. Collins, Erica R. Tabakin & David A. Hunt
(2010): Expedient Preparation of 4,6-Dihalo-3-arylisobenzofuran-1(3H)-ones from 3,5-Dihalo-N-
ethylbenzamides, Organic Preparations and Procedures International: The New Journal for Organic
Synthesis, 42:2, 187-190
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Organic Preparations and Procedures International, 42:187–190, 2010
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304941003727045
Expedient Preparation of
4,6-Dihalo-3-arylisobenzofuran-1(3H)-ones
from 3,5-Dihalo-N-ethylbenzamides
Lynn M. Bradley, Carleton G. Collins, Erica R. Tabakin,
and David A. Hunt
Department of Chemistry, The College of New Jersey, Ewing, New Jersey, USA
3,5-Dihalobenzoic acid derivatives have long been known as scaffolds for compounds ex-
hibiting a variety of biological activities. For example, compounds incorporating this moi-
ety exhibit phytotoxicity,1 selective inhibition of 11β-HSD1 for the treatment of metabolic
syndrome,2 MCH 1 receptor antagonism,3 and serve as intermediates in the preparation of
liquid crystals, fungicides, organo-tin antitumor compounds, insecticides, and quinolones
possessing antibiotic activity.4
While our previous studies have shown that 3,5-dichloro tertiary benzamides are meta-
lated para to the carboxamide group,5 we have found that use of secondary amides derived
from 3,5-dihalobenzoic acids (1, X = Cl, F) result in exclusive ortho-metalation. In light
of the paucity of methods available to prepare highly ring-functionalized derivatives of
3,5-dihalobenzoic acids, coupled with recent studies documenting the unique antitumor
properties of benzolactones,6 we now describe the application of the chelation-controlled
directed ortho-metalation reaction in this series as a useful method for the preparation of
4,6-dihalo-3-arylisobenzofuran-1(3H)-ones.
Metalation of 3,5-dihalo secondary benzamides (1) with sec-butyllithium resulted
in exclusive ortho-directed metalation. Use of an aromatic aldehyde as the electrophile
results in a lithioalkoxy intermediate (3) which undergoes nucleophilic attack upon the
adjacent amide carbonyl during work-up with a concomitant loss of ethylamine, resulting
in the formation of an aryl substituted dihalobenzofuranone (4, Table 1). This methodology
should be applicable to a wide variety of both aromatic and aliphatic aldehydes based on
reported reactions of aldehydes with aryllithium reagents generated by the directed ortho-
metalation strategy.7 Studies of these systems as well as the scope and limitations of this
process will be the focus of future investigations.
Submitted June 26, 2009.
Address correspondence to Lynn M. Bradley, Department of Chemistry, The College of New
Jersey, P. O. Box 7718, Ewing, NJ 08628-0718, USA. E-mail: bradley@tcnj.edu
187

188
Bradley et al.
H
C2H5
N
C2H5
Li
O
N
Li
O
O
O
N
C2H5
O-Li+
X
o
Li ArCHO
r.t.
1. -78 C
s-BuLi/TMEDA
H
O
o
2. H2O
Ar
THF/-78 C
H
X
X
X
X
X
X
Ar
X
1a: X= Cl
1b: X= F
2
4
3
Experimental Section
Tetrahydrofuran was purchased as anhydrous (Fluka) and was stored under nitrogen. sec-
Butyllithium (1.3 M in cyclohexane/hexane) was purchased from Acros Organics (the
1
actual concentration was determined by colorimetric titration8 prior to use). H NMR
(300 MHz) and 13C NMR (75 MHz) data were acquired in CDCl3 on a Varian Gemini
300 nuclear magnetic resonance spectrometer using tetramethylsilane (TMS) as internal
standard CDCl3 lock. IR data were determined from a Perkin-Elmer Model Spectrum
2000 FT-IR spectrometer. GC/MS data were obtained from an Agilent Technologies 6850
GC/5973 MSD. Microanalyses were carried out by Quantitative Technologies, Inc., White-
house, NJ. All melting points were determined on a Mel-Temp heating block apparatus and
are uncorrected.
General Procedure
The 3,5-dihalogenated secondary benzamide (1 mmol), anhydrous THF (5 mL), and
TMEDA (290 mg; 2.5 mmol) in anhydrous THF (5 mL) were charged to a 100 mL
three-neck oven-dried flask equipped with a stir bar, nitrogen inlet, and low tempera-
ture thermocouple. The mixture was cooled to −78◦C using a Dry Ice/acetone bath, and
sec-butyllithium (2.5 equivalents relative to the starting benzamide) was added while the
temperature was maintained below −70◦C. The reaction mixture was stirred for 30 min
at which point a solution of 1.5 equivalent of the aromatic aldehyde in anhydrous THF
(2 mL) was added, it was allowed to warm to room temperature overnight under nitrogen
Table 1
Preparation of 4,6-Dihalo-3-arylisobenzofuran-1(3H)-ones
Compound
X
Ar
Yield (%)
4a
4b
4c
4d
4e
4f
Cl
F
Cl
F
Cl
F
Cl
F
phenyl
phenyl
2-furyl
2-furyl
2-thienyl
2-thienyl
p-anisyl
p-anisyl
90
88
91
64
97
77
73
98
4g
4h

4,6-Dihalo-3-arylisobenzofuran-1(3H)-ones
189
and was quenched with water (100 mL). The mixture was then extracted with ethyl ac-
etate (3 × 40 mL), with occasional use of a saturated sodium chloride solution (35 mL)
to alleviate emulsion formation. The organic layer was washed with a solution of satu-
rated ammonium chloride (40 mL), dried (MgSO4), filtered, and concentrated in vacuo
to afford the crude product. Purification was achieved by chromatography on silica gel
(9:1 hexanes/MTBE), recrystallization, trituration (hexanes/MTBE), or a combination of
trituration/chromatography.
4,6-Dichloro-3-phenylisobenzofuran-1(3H)-one (4a) was isolated as a white solid
(chromatography), mp. 118–120◦C; IR: 1776 (lactone) cm−1; 1H NMR (CDCl3): δ 7.85 (d,
Jm-H = 1.7 Hz, 1, ArH), 7.60 (d, Jm-H = 1.7 Hz, 1, ArH), 7.40–7.16 (m, 5, ArH), 6.35 (s, 1,
CHO). 13C nmr (CDCl3): δ 168.1, 144.9, 137.1, 135.0, 133.8, 130.8, 130.1, 129.9, 129.2,
128.4, 124.4, 82.7. Mass Spec: m/z = 279 (M+).
Anal. Calcd for C14H8Cl2O2: C, 60.24; H, 2.89. Found: C, 60.46; H, 2.71.
4,6-Difluoro-3-phenylisobenzofuran-1(3H)-one (4b) was isolated as a pale yellow
solid (trituration), mp. 70–72◦C. IR: 1765 (lactone) cm−1; 1H NMR (CDCl3): δ 7.46 (dd,
JH,F = 6.6 Hz, Jm-H = 1.8 Hz, 1, ArH), 7.40–7.24 (m, 5, ArH), 7.08 (td, JH-F = 8.7 Hz,
Jm-H = 2.1 Hz, 1, ArH), 6.46 (s, 1, CHO). 13C nmr (CDCl3): δ 168.2, 164.1, 157.2, 134.7,
129.9, 129.2, 128.4, 127.2, 126.4, 110.4, 108.8, 80.7. Mass Spec: m/z = 246 (M+).
Anal. Calcd for C14H8F2O2: C, 68.29; H, 3.25. Found: C, 68.63; H, 3.56.
4,6-Dichloro-3-(2-furyl)isobenzofuran-1(3H)-one (4c) was isolated as an off-white
solid (chromatography), 9.mp. 115.5–117◦C; IR: 1778 (lactone) cm−1; 1H NMR (CDCl3):
δ 7.83(d, Jm-H = 1.5 Hz, 1, ArH), 7.63 (d, Jm-H = 1.5 Hz, 1, ArH), 7.38 (dd, JfuranH2,H3
=
2.0 Hz, JfuranH2,H4 = 0.8 Hz, 1, ArH) 6.50 (dd, JfuranH4,H3 = 3.3 Hz, JfuranH4,H2 = 0.6 Hz, 1,
ArH), 6.40 (s, 1, CHO), 6.39 (dd, JfuranH3,H4 = 3.6 Hz, JfuranH3,H2 = 1.8 Hz, 1, ArH). 13C
nmr (CDCl3): δ 167.5, 146.1, 144.5, 142.1, 137.4, 134.8, 130.8, 130.2, 124.5, 112.6, 111.1,
74.8. Mass Spec: m/z = 268 (M+).
Anal. Calcd for C12H6Cl2O3: C, 53.56; H, 2.25. Found: C, 53.27; H, 2.25.
4,6-Difluoro-3-(2-furyl)isobenzofuran-1(3H)-one (4d) was isolated as a pale yellow
1
oil (chromatography); IR: 3525 (hydrate); 1777 (lactone) cm−1; H nmr (CDCl3): δ 7.47
(dd, JH,F = 6.6 Hz, Jm-H = 1.8 Hz, 1, ArH), 7.41 (m, 1, furanH2), 7.13 (td, JH,F = 8.6 Hz,
Jm-H = 1.8 Hz, 1, ArH), 6.48 (s, 1, CHO), 6.46 (d, JfuranH4,H3 = 3.3 Hz, 1, ArH), 6.39 (dd,
JfuranH3,H4 = 3.3 Hz, JfuranH3,H2 = 1.8 Hz, 1, ArH). 13C nmr (CDCl3): δ 168.0, 164.5, 157.3,
146.1, 144.6, 129.0, 128.4, 111.5, 111.2, 110.1, 108.9, 73.3. Mass Spec: m/z = 236 (M+).
Anal. Calcd for C12H6F2O3·1/3H2O: C, 59.55; H, 2.76. Found: C, 59.77; H, 3.25.
4,6-Dichloro-3-(2-thienyl)isobenzofuran-1(3H)-one (4e) was isolated as an off-
white solid (trituration/chromatography), mp. 107.5–109.5◦C; IR: 1774 (lactone) cm−1
;
1H nmr (CDCl3): δ 7.84 (d, Jm-H = 1.8 Hz, 1, ArH), 7.64 (d, Jm-H = 1.5 Hz, 1, ArH), 7.38
(dd, JH2,H3 = 5.4 Hz, JH2,H4 = 0.9 Hz, 1, ArH), 7.14 (dd, JH4,H3 = 3.6 Hz, J = 1.2 Hz,
1, ArH), 7.01 (dd, JH3,H2 = 5.1 Hz, JH3,H4 = 3.6 Hz, 1, ArH), 6.63 (s, 1, CHO). 13C nmr
(CDCl3): δ 167.3, 144.1, 137.4, 136.4, 135.0, 130.9, 129.4, 128.2, 127.3, 127.1, 124.4,
77.2. Mass Spec: m/z = 284 (M+).
Anal. Calcd for C12H6Cl2O2S: C, 50.54; H, 2.12. Found: C, 50.83; H, 2.31.
4,6-Difluoro-3-(2-thienyl)isobenzofuran-1(3H)-one (4f) was isolated as a yellow oil
(chromatography); IR: 1774 (lactone) cm−1; 1H NMR (CDCl3): δ 7.46 (dd, JH,F = 6.6 Hz,
Jm-H = 2.1 Hz, 1, ArH), 7.37 (dd, JthiopheneH2,H = 5.1 Hz, JthiopheneH2,H4 = 1.2 Hz, 1, ArH),
2

190
Bradley et al.
7.16 (dd, JthiopheneH4,H3 = 3.0 Hz, JthiopheneH4,H2 = 1.2 Hz, 1, ArH), 7.13 (td, JH,F = 6.6 Hz,
Jm-H = 2.1 Hz, 1, ArH), 7.02 (dd, JthiopheneH3,H2 = 5.1 Hz, JthiopheneH3,H4 = 3.0 Hz, 1, ArH),
6.72 (s, 1, CHO). 13C nmr (CDCl3): δ 167.4, 164.4, 157.3, 151.0, 137.1, 130.4, 128.8,
127.9, 127.5, 110.5, 108.9, 75.8. Mass Spec: m/z = 252 (M+).
Anal. Calcd for C12H6F2O2S·1/3C6H14: C, 59.86; H, 3.80. Found: C, 59.91; H, 3.81.
4,6-Dichloro-3-(p-anisyl)isobenzofuran-1(3H)-one (4g) was isolated as a white
solid (trituration/chromatography), mp. 107.5–109◦C; IR: 1773 (lactone) cm−1; 1H NMR
(CDCl3): δ 7.84 (d, Jm-H = 1.5 Hz, 1, ArH), 7.59 (d, Jm-H = 1.8 Hz, 1, ArH), 7.10 (d, Ja,b
= 9.0 Hz, 2, ArH), 6.86 (d, Jb,a = 9.0 Hz, 2, ArH), 6.32 (s, 1, CHO), 3.79 (s, 3, OCH3).
13C nmr (CDCl3): δ 169.0, 160.8, 145.0, 136.9, 134.8, 130.7, 129.8, 129.7, 125.6, 124.2,
114.4, 82.4, 55.5. Mass Spec: m/z = 308 (M+).
Anal. Calcd for C15H10Cl2O3: C, 58.28; H, 3.26. Found: C, 58.30; H, 3.31.
4,6-Difluoro-3-(p-anisyl)isobenzofuran-1(3H)-one (4h) was isolated as a white solid
1
(chromatography), mp. 100–103◦C. IR: 1764 (lactone) cm−1; H NMR (CDCl3): δ 7.45
(dd, JH,F = 6.6 Hz, Jm-H = 2.1 Hz, 1, ArH), 7.16 (d, Ja,b = 9.0 Hz, 2, ArH), 7.07 (td, JH-F
=
8.6 Hz, Jm-H = 2.0 Hz, 1, ArH), 6.88 (d, Jb,a = 9.0 Hz, 2, ArH), 6.42 (s, 1, CHO), 3.79 (s, 3,
OCH3). 13C nmr (CDCl3): δ 168.3, 166.6, 160.9, 157.7, 131.5, 129.6, 128.8, 126.5, 114.6,
110.3, 108.7, 80.7, 55.6. Mass Spec: m/z = 276 (M+).
Anal. Calcd for C15H10F2O3: C, 65.22; H, 3.62. Found: C, 65.44; H, 3.59.
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