A single-step synthesis of symmetrical 1,3-diarylisobenzofurans

Article abstract of DOI:10.1055/s-2006-948179

A convenient single-step synthesis of various symmetrically substituted 1,3-diarylisobenzofurans from readily available 3-methoxy-3H-isobenzofuran-1-one (1a) and two equivalents of aryl Grignard reagents is described. The title compounds are obtained in medium to high isolated yields. Crude isobenzofuran has also been trapped by maleimide, furnishing pure Diels-Alder adduct almost quantitatively. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-948179

LETTER
2035
A Single-Step Synthesis of Symmetrical 1,3-Diarylisobenzofurans
Synthesis of
1a
r
benzofu
a
r
ans h Benderradji, Malek Nechab, Cathy Einhorn, Jacques Einhorn*
Laboratoire d’Etudes Dynamiques et Structurales de la Sélectivité/UMR 5616, Université Joseph Fourier, BP 53, 38041 Grenoble
Cedex 9, France
Fax +33(4)76514836; E-mail: Jacques.Einhorn@ujf-grenoble.fr
Received 31 March 2006
Although 2a has been obtained in a satisfactory 60% over-
all yield, a more convenient one-step synthesis was
desirable for its routine preparation. In the literature, 1,3-
diphenylisobenzofuran has been obtained in one-step
Abstract: A convenient single-step synthesis of various symmetri-
cally substituted 1,3-diarylisobenzofurans from readily available 3-
methoxy-3H-isobenzofuran-1-one (1a) and two equivalents of aryl
Grignard reagents is described. The title compounds are obtained in
medium to high isolated yields. Crude isobenzofuran has also been processes7 from phenylmagnesium halide and benzo-
cyclobutadienequinone,7a monothiophthalic anhydride7b
trapped by maleimide, furnishing pure Diels–Alder adduct almost
or 2-cyanobenzaldehyde.7c None of these reactions is well
quantitatively.
Key words: Grignard reactions, Diels–Alder reactions, fused-ring
systems, heterocycles, nucleophilic addition
suited for larger-scale preparative purposes. A one-step
synthesis of 1,3-diphenylisobenzofuran from phenyl
Grignard reagent and readily available 3-chlorophthalide
has also been reported.7d Similarly, the synthesis of 4,7-
Benzo[c]furans or isobenzofurans have found interesting dimethoxy-1,3-diphenylisobenzofuran has been reported
applications in various fields of organic chemistry.1 Espe- starting from 3-bromo-4,7-dimethoxyphthalide.7e In both
cially, they are highly reactive dienes giving Diels–Alder cases, however, the yields of isobenzofurans were not
adducts with a large variety of dienophiles in high yields. very high (48 and 39%, respectively). In our hands too,
Diels–Alder adducts are valuable synthetic intermediates this approach gave a rather poor yield (20–30%) of
and their use for the synthesis of natural products and of isobenzofuran 2a, starting from 3-chlorophthalide and
polycyclic aromatic hydrocarbons is well documented.2 Grignard reagent 3a.
Particularly, aromatization of Diels–Alder adducts fur-
nishes naphthalenic compounds with substitution patterns
that are not easily available otherwise. We have previous-
ly reported this type of approach for the synthesis of
Herein, we report a straightforward and efficient one-step
synthesis of isobenzofuran 2a and of a series of symmet-
rically substituted 1,3-diarylisobenzofurans, by reaction
of 3-methoxyphthalide (1a) with two equivalents of aryl-
magnesium halide, followed by acidic work-up. Phthalide
1a is obtained very simply and quantitatively by refluxing
2-carboxybenzaldehyde (1b) overnight in methanol, with-
atropisomeric naphthalenic analogues of N-hydroxy-
phthalimide (NHPI), with the aim of developing new
enantioselective oxidation catalysts.3 More promising C2-
symmetric compounds with two stereogenic axes are
out any catalyst (Figure 1).8
easily available starting from symmetrical diarylisoben-
zofuran 2a.4 In our first synthesis4a isobenzofuran 2a has
O
MgBr
been prepared following a classical two-steps procedure:
first, reaction of commercially available 2-carboxybenz-
OMe
O
OMe
aldehyde (1b) with two equivalents of 2-methoxyphenyl-
magnesium bromide (3a) gave phthalide 4a.5 In a second
O
OR
step, reaction of phthalide 4a with the same Grignard
1a R = Me
1b R = H
3a
OMe
reagent 3a gave isobenzofuran 2a, after acidic work-up.6
Its reaction with maleimide gave Diels–Alder adduct 5a
(Scheme 1), which was next transformed into the targeted
C2-symmetric compounds.4
2a
O
O
OMe
O
OMe
O
1) 2 equiv 3a
1) 1 equiv 3a
maleimide
H
1b
4a
2a
5a
2) HCl
2) HCl
OMe
OMe
OMe
60%
96%
NH
O
overall
4a
H
Scheme 1 Synthesis of isobenzofuran 2a by a classical two-step
procedure followed by Diels–Alder reaction with maleimide
O
OMe
6a
5a
Figure 1
SYNLETT 2006, No. 13, pp 2035–2038
1
7
.0
8
.2
0
0
6
Advanced online publication: 09.08.2006
DOI: 10.1055/s-2006-948179; Art ID: D09706ST
© Georg Thieme Verlag Stuttgart · New York

2036
F. Benderradji et al.
LETTER
Addition of two equivalents of Grignard reagent 3a, at some extent. We have performed Diels–Alder reaction of
0 °C to a THF solution of 3-methoxyphthalide (1a), fol- crude 2a, obtained after acidic work-up but without chro-
lowed by acidic work-up, furnished isobenzofuran 2a in matographic purification, with maleimide. Gratifyingly, a
90% isolated yield after column chromatography. At 96% yield of pure Diels–Alder adduct 5a crystallized
0 °C, the order of addition is crucial: when 1a was added directly out of the reaction medium.
to Grignard reagent 3a, 2a was obtained in only 35–40%
Table 1 One-Step Synthesis of 1,3-Diarylisobenzofurans 2 from 1a
and Two Equivalents of Aryl Grignard Reagents 3
yield, along with about 35% of compound 6a, 5–10% of
phthalide 4a and small quantities of starting 1a. A high
yield (85%) of 2a could nevertheless be recovered if
addition of 1a to Grignard reagent 3a was performed at
–78 °C.
Entry
ArMgBr Methoda Yield of 2 (%)b Mp (°C)c
1
2
3
3a
3b
3c
A (B)
A
90 (85)
95
–
This method was found to be fairly general for the synthe-
sis of various symmetrical 1,3-diarylisobenzofurans, by
reaction of 1a with two equivalents of aryl Grignard
reagents (Scheme 2).
76–80
A
99
124–125
(lit.9 127–129)
4
5
6
7
3d
3e
3f
A
A
A
A
78
65
83
73
161–164
O
Ar
127 (128–130)d
93–94
1) 2 equiv ArMgBr (3)
2) HCl
O
O
OMe
Ar
3g
124–126
1a
3a
2
(lit.10 125)
Ar = 2-MeOPh
3i
3j
Ar = 4-PhPh
8
9
3h
3i
B
B
43
73
159–166
Ar = 1-Naphthyl
Ar = 1-Pyrenyl
3b Ar = 3-MeOPh
3k
3c Ar = 4-MeOPh
247.5–248.5
(lit.11 247–249)
3d Ar = 3,4,5-trisMeOPh
Ar = 2-Pyridinyl
Ar = PerfluoroPh
Ar = 4-CF3Ph
3l
3e
3f
Ar = Ph
3m
3n
3o
10
3j
A
77
165–167
Ar = 2-MePh
Ar = 4-MePh
Ar = 2-PhPh
(lit12 166)
3g
Ar = 2-Thienyl
3h
11
12
13
14
15
3k
3l
A
A
A
A
A
69
–
215–216
Scheme 2 Synthesis of various 1,3-diarylisobenzofurans from 1a
and 2 equiv Grignard reagent 3
3m
3n
3o
–
Our results are summarized in Table 1. Each of the three
bis(methoxyphenyl)isobenzofuran regioisomers 2a–c
have been obtained in excellent yields (entries 1–3). A
polymethoxylated isobenzofuran 2d has also been pre-
pared in good yield (entry 4). The parent, commercially
available, 1,3-diphenylisobenzofuran (2e) has been ob-
tained in a satisfactory 65% yield without optimization
(entry 5). Both 2- and 4-tolylmagnesium bromide 3f and
3g gave equally good yields of the corresponding 2f and
2g (entries 6 and 7). In the case of their biphenyl ana-
logues 3h and 3i, the ortho derivative gave a lower yield
(43% of 2h) than the para regioisomer (73% of 2i), prob-
ably for steric reasons (entries 8 and 9). Polycyclic Grig-
nard reagents 3j and 3k reacted well (entries 10 and 11).
In contrast, Grignard reagents with lower nucleophilicity
failed to react (3l and 3m) with 1a (entries 12 and 13) or
gave only medium yields, as for 3n (entry 14). At last, an
electron-rich heterocyclic Grignard reagent, such as 2-
thienylmagnesium bromide 3o, gave a high yield (85%) of
the corresponding valuable isobenzofuran 2o (entry 15).13
Isobenzofurans 2d,e,i–k crystallized directly from the
reaction medium after acidic hydrolysis and have been
obtained in high purity by simple filtration.
47
85
122–124
110–112
(lit13 113–113.5)
a Method A: addition of Grignard reagent at 0 °C to a THF solution of
1a. Method B: addition of a THF solution of 1a to the Grignard
reagent at –78 °C.
b Isolated yield.
c All new compounds have been identified by 1H NMR and 13C NMR
spectroscopy, and elemental analysis or HRMS.
d Commercially available.
We have attempted to generalize the present synthesis to
the preparation of unsymmetrical 1,3-diarylisobenzo-
furans, by one-pot sequential addition of two different
Grignard reagents to 1a, but without success. In fact,
when only one equivalent of Grignard reagent 3a was
added to 1a, 48% of isobenzofuran 2a, 19% of phthalide
4a along with 33% of unreacted starting material 1a were
obtained. According to this, a stepwise reaction of one,
two or three equivalents of 3a with the nucleophilic sites
of 1a is likely, as depicted in Scheme 3. Nucleophilic dis-
placement of the OMe group of 1a first generates 4a, with
reaction rate constant k1.14 Nucleophilic addition to the
lactone carbonyl group then generates intermediate 7a,
with rate k2. Finally, reaction of a third equivalent of 3a
1,3-Diarylisobenzofurans are stable, yet highly sensitive
to oxidation compounds. Air oxidation during work-up
and purification may lower the yield of isolated product to
Synlett 2006, No. 13, 2035–2038 © Thieme Stuttgart · New York

LETTER
Synthesis of 1,3-Diarylisobenzofurans
2037
OMe
OMe
–O
O
1 equiv 3a
k1
1 equiv 3a
O–
O–
OMe
OMe
O
1 equiv 3a
OMe
OMe
O
1a
O
O–
k2
k3
OMe
OMe
4a
7a
7a'
8a
HCl
HCl
2a
6a
Scheme 3
Trapping of Crude 2a as Diels–Alder Adduct 5a
with 7a (or its tautomeric form 7a¢) generates 8a, with rate
k3. Reaction rate constants have to be in the order k2 > k1
>> k3: even if Grignard reaction is performed with only
one equivalent of 3a, phthalide 4a does not accumulate in
the reaction medium but is prone to react with a second
molecule of 3a to give 7a. In contrast, 7a accumulates in
the reaction medium up to the total consumption of two
equivalents of 3a, and gives 2a after acidic hydrolysis.15
Intermediate 8a (generating 6a by acidic work-up) is not
formed, unless 1a is exposed to a large excess of 3a, as
was the case when 1a was added to 3a at 0 °C.
The remaining part of crude isobenzofuran 2a obtained as above,
corresponding to a 54.2 mmol calculated amount of pure 2a, was
dissolved in toluene (210 mL). Solid maleimide (5.56 g, 54.2 mmol)
was added at once under stirring at r.t. The yellow color of the reac-
tion medium faded rapidly and a voluminous precipitate formed.
After 6 h the solid was filtered, washed with toluene (70 mL) and
dried under vacuum, yielding pure Diels–Alder adduct 5a (22.36 g,
96%).4a
Representative Synthesis of Isobenzofurans by Method B:
Synthesis and Selected Data of 2i
Grignard reagent 3i was prepared from 4-bromobiphenyl (17.48 g,
75 mmol) and Mg (1.83 g, 1 equiv) in anhyd THF (75 mL). The
semi-crystalline Grignard reagent was cooled to –78 °C and a THF
(25 mL) solution of 1a (5.5 g, 33.5 mmol) was added dropwise un-
der argon. The temperature was raised progressively and the reac-
tion was stirred overnight at r.t. Acidic hydrolysis was performed by
adding dropwise a solution of concd HCl (10 mL) and H2O (20 mL),
at 0 °C and under argon. An orange precipitate formed rapidly. Af-
ter stirring for 1 h, the reaction mixture was filtered. The precipitate
was washed with H2O (100 mL) and EtOH (20 mL). Drying under
vacuum gave 2i (10.3 g, 73%), as an orange powder. An analytically
pure sample has been obtained after recrystallization from toluene,
mp 247.5–248.5 °C (Lit.11 247–249 °C). 1H NMR (300 MHz,
CDCl3): d = 7.06–7.09 (m, 2 H), 7.36–7.40 (m, 2 H), 7.46–7.51 (m,
4 H), 7.66–7.79 (m, 8 H), 7.88–7.92 (m, 2 H), 8.03–8.07 (m, 4 H)
ppm. 13C NMR (75 MHz, CDCl3): d = 120.5, 122.6, 125.3, 125.5,
127.0, 127.6, 127.7, 129.0, 130.7, 139.6, 140.7, 143.9 ppm. MS
(DCI, NH3): m/z (%) = 423 (100), 332 (5).
In conclusion, this procedure offers a new and straightfor-
ward one-step access to a large variety of symmetrical
1,3-diarylisobenzofurans 2, from readily available 3-
methoxyphthalide (1a) and aryl Grignard reagents. In
some cases isobenzofurans have been obtained in near
quantitative yields. Crude isobenzofuran 2a has also been
trapped very efficiently as its Diels–Alder adducts with
maleimide. This procedure may avoid purification of very
air-sensitive compounds.
Representative Synthesis of Isobenzofurans by Method A:
Synthesis and Selected Data of 2a
To a solution of 1a (11 g, 67 mmol) in anhyd THF (50 mL), was
added dropwise a THF solution of Grignard reagent 3a (164 mL,
0.86 M, 2.1 equiv), at 0 °C under argon. The reaction mixture was
stirred overnight at r.t. The beige suspension was hydrolyzed by
adding dropwise a solution of concd HCl (20 mL) and H2O (40 mL)
at 0 °C. The reaction mixture turned to bright orange with green flu-
orescence. Stirring was maintained under argon for 1 h. Then, Et2O
(50 mL) was added and the organic phase separated. The aqueous
phase was extracted with Et2O (3 × 50 mL). The combined organic
phases were washed with brine (2 × 50 mL) and sat. NaHCO3 (50
mL). The organic phase was dried over Na2SO4 and concentrated
under reduced pressure, giving crude 2a (23.86 g) as a viscous or-
ange oil. A sample (2.43 g) of this crude product was purified by
column chromatography on silica gel, with 95:5 hexane–EtOAc as
the eluent. The combined chromatographic fractions were concen-
trated and placed for several hours at 90 °C under high vacuum to
remove all remaining solvent. Pure 2a (2.03 g, 90%) was obtained
as a bright-yellow glassy solid (Table 1, entry 1).4a 1H NMR (300
MHz, CDCl3): d = 3.91 (s, 6 H), 6.87–6.93 (m, 2 H), 7.01–7.10 (m,
4 H), 7.29–7.34 (m, 2 H), 7.61–7.66 (m, 2 H), 7.72–7.76 (m, 2 H)
ppm. 13C NMR (75 MHz, CDCl3): d = 55.7, 111.7, 121.1, 121.4,
121.5, 123.3, 123.7, 128.8, 129.8, 142.6, 156.0 ppm. MS (DCI,
NH3): m/z (%) = 331 (100), 223 (15).
Acknowledgment
Financial support from both CNRS and Université Joseph Fourier –
Grenoble I is gratefully acknowledged.
References and Notes
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Synlett 2006, No. 13, 2035–2038 © Thieme Stuttgart · New York

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F. Benderradji et al.
LETTER
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Synlett 2006, No. 13, 2035–2038 © Thieme Stuttgart · New York