A One-pot preparation of 1,3-diarylisobenzofuran

Article abstract of DOI:10.1246/cl.130398

A simple, practical, and efficient method for one-pot synthesis of symmetric and unsymmetrical 1,3-diarylisobenzofurans has been developed by sequential reactions of methyl 2-formylbenzoate with two identical or different aryl metal species.

Full text of DOI:10.1246/cl.130398

doi:10.1246/cl.130398
Published on the web June 7, 2013
1013
A One-pot Preparation of 1,3-Diarylisobenzofuran
Toshiyuki Hamura*1,2 and Ryosuke Nakayama1
1Department of Chemistry, School of Science and Technology, Kwansei Gakuin University,
2-1 Gakuen, Sanda, Hyogo 669-1337
2Japan Science and Technology Agency, ACT-C, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012
(Received April 25, 2013; CL-130398; E-mail: thamura@kwansei.ac.jp)
O
A simple, practical, and efficient method for one-pot
O
O
[Ar1]–
synthesis of symmetric and unsymmetrical 1,3-diarylisobenzo-
furans has been developed by sequential reactions of methyl
2-formylbenzoate with two identical or different aryl metal
species.
OMe
O
OMe
O–
O
step 2
step 1
Ar1
Ar1
H
I
III
II
Ar2
O
Ar2
O–
O
[Ar2]–
step 3
H+
step 4
Isobenzofuran is 10³ electron system with a quinoid
structure, which makes them a useful intermediate for natural
and unnatural product syntheses.1,2 Among various possibilities,
[4 + 2] cycloaddition with dienophiles is a reliable method for
the rapid construction of polycyclic structure.3
Ar1
Ar1
IV
V
Scheme 1.
We report herein an efficient access to functionalized
1,3-diarylisobenzofurans4 via sequential nucleophilic addition
to 2-formylbenzoate (Scheme 1). The first nucleophilic addition
of aryl anion to formylbenzoate I is a key step for selective
generation of adduct II (step 1), which, in turn, undergoes an
intramolecular transesterification to give phthalide III (step 2).
Second nucleophile addition to III (step 3) and subsequent acid
treatment efficiently gives symmetric and unsymmetrical diaryl-
isobenzofuran V (step 4).
Scheme 2 shows the model study for the first nucleophilic
addition to 2-formylbenzoate. Upon treatment of methyl
2-formylbenzoate (1a) with 1.1 equiv of PhMgBr (¹40 ¼
0 °C), the nucleophile selectively attacked the formyl group in
1a. Subsequent transesterification of the resulting adduct A gave
3-phenylphthalide (2a) in 86% yield.5 Importantly, the choice of
aryl metal species is crucial. Use of PhLi gave 2a only in 12%
yield, accompanied by a sizable amount of complex mixture of
products.
The next step is a second nucleophilic addition to phenyl-
phthalide 2a. Upon treatment of 2a with PhMgBr (¹40 ¼ 0 °C),
nucleophilic addition occurred cleanly and subsequent acid
treatment gave 1,3-diphenylisobenzofuran (3a) in 94% yield
(Scheme 3).6,7 Having a good results in hand, we then attempted
to perform all the steps in one pot,8-10 starting from the selective
nucleophilic addition to formylbenzoate (Scheme 3). When 1a
was treated with PhMgBr (1.1 equiv), and the TLC assay
confirmed the lactone formation, the second nucleophile
(1.2 equiv) was added to the reaction mixture, and subsequent
acid treatment (CF3CO2H, r.t.) gave isobenzofuran 3a in 85%
yield. Further experiments revealed that addition of 2.3 equiv of
PhMgBr at one time gave similar result (3a: 85%).
This one-pot reaction was applicable for various aryl
Grignard reagents (Table 1). Typical experimental procedure is
represented by double nucleophilic addition with (4-methoxy-
phenyl)magnesium bromide (Entry 1): To a solution of 2-
formylbenzoate 1a in THF was slowly added (4-methoxyphen-
yl)magnesium bromide (2.2 equiv in THF) at ¹40 °C. After
warming to 0 °C, CF3CO2H (5.2 equiv) was added to the
O
CO2Me
CO2Me
CHO
PhMgBr (1.1 equiv)
–40 0 °C
86%
cf. PhLi: 12%
O
OMgBr
Ph
Ph
1a
A
2a
Scheme 2.
1) PhMgBr
O
Ph
O
CO2Me
CHO
–40
0 °C
PhMgBr
–40 0 °C
O
2) CF3CO2H
Ph
Ph
1a
2a
3a
Scheme 3.
reaction mixture. Extractive workup followed by purification
by silica gel column chromatography gave diarylisobenzofuran
3b in 77% yield (Entry 1).11,12 Similarly, treatment of 1a with
(2-methoxyphenyl)magnesium bromide gave isomeric isoben-
zofuran 3c in 77% yield (Entry 2). Aryl Grignard reagent having
the electron-deficient fluoro group at the para-position is also
applicable for the reaction, affording diarylisobenzofuran 3d
(Entry 3). Moreover, dithienyl groups were cleanly introduced,
affording 84% yield of 1,3-dithienylisobenzofuran (3e), which is
attractive as a building block for oligomeric and ³-conjugated
molecules (Entry 4).13 Reaction of electron-donating substrate
1b with two kinds of aryl Grignard reagents also gave the
corresponding diarylisobenzofuran 3f and 3g in good yields,
respectively (Entries 5 and 6).
Moreover, two different benzene rings could be introduced
in one-pot by using two different aryl metal species (Table 2).
When phthalide 2a, selectively obtained by treatment of 1a
with PhMgBr (1.1 equiv in THF, ¹40 ¼ 0 °C), was treated with
(4-fluorophenyl)magnesium bromide (1.3 equiv in THF, ¹40 ¼
0 °C), unsymmetrical diarylisobenzofuran 4a was obtained in
75% yield after acidic workup (Entry 1). In a similar manner, the
successive nucleophilic addition with phenylmagnesium bro-
Chem. Lett. 2013, 42, 1013-1015
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1014
Table 1. One-pot preparation of symmetric 1,3-diarylisoben-
zofuran
Table 2. One-pot preparation of unymmetrical 1,3-diaryliso-
benzofuran
Ar2Li or
Ar2MgBr
Ar
Ar2
CO2Me
CF3CO2H
0 °C r.t.
Ar1MgBr
–40
ArMgBr
CO2Me
CF3CO2H
0 °C r.t.
O
O
–40
0 °C
CHO
0 °C –40
0 °C
CHO
1
3
Ar
Ar1
1a
4
Entry Formylbenzoate
Ar
Product Yield/%
Entry
Ar1
Ar2
Product
Yield/%
75
CO2Me
1a
3b
3c
3d
3e
3f
77
77
82
84
72
70
OMe
1a
4a
F
CHO
1a
2a
3a
4a
2a
4b
4c
4d
4e
68
67
65
47
51
MeO
MeO
3a
F
F
OMe
CN
S
4b
5b,c
6b
MeO
MeO
CO2Me
CHO
5a
6a
N
1b
S
O
3g
OMe
4f
a2.2-2.4 equiv of ArMgBr.
b
aAr2MgBr was used as a second nucleophile. Ar2Li was used
c
as a second nucleophile. Second nucleophile was added at
¹78 °C.
mide and (2-methoxyphenyl)magnesium bromide gave isoben-
zofuran 4b in 68% yield (Entry 2). The dual reactions in the
combination with electron-donating and/or electron-deficient
nucleophiles gave the corresponding products 4c-4e, respec-
tively (Entries 3-5). In these cases, however, the reaction of 2a
with (4-cyanophenyl)magnesium bromide and 2-pyridylmagne-
sium bromide gave poor results, only giving the complex
mixture of products. Reinvestigation of the reaction conditions
revealed that the use of the corresponding aryllithium cleanly
gave the desired products 4d and 4e, respectively (Entries 4 and
5).14 The successive processes also proved to be applicable
to the combination of (2-thienyl)magnesium bromide and
2-furyllithium, giving 4f, which could serve as a synthetic
intermediate for further elaboration to polyaromatic systems
(Entry 6).13
Br
CO2Me
CHO
MeO
F
MgBr
F
MgBr
0 °C
5
–40
–40
0 °C
–40
MgBr
MeO
–40
MgBr
0 °C
0 °C
CF3CO2H
CF3CO2H
OMe
F
Br
Br
O
O
For exploring further scope of the one-pot process, we
addressed the applicability for the divergent syntheses of
isomeric isobenzofuran from
a single starting material
(61%)
6
(60%)
(Scheme 4). Thus, the treatment of methyl 5-bromo-2-formyl-
benzoate (5)15 with (4-fluorophenyl)magnesium bromide fol-
lowed by (4-methoxyphenyl)magnesium bromide gave 6 in 61%
yield. The isomeric product 7 was accessible from the same
benzoate 5 in good yield by treating two nucleophiles at
opposite turn.
7
F
OMe
Scheme 4.
connected by aromatic rings, was accessible in one-pot under the
suitable conditions. Indeed, bis(isobenzofuran) 8, connected by
4,4¤-biphenyl, was obtained from 2-formylbenzoate 1a in good
yield by nucleophilic addition of Grignard reagent B to 1a,
The last but not the least point to note is that structurally
attractive bis(isobenzofurans), where two furan moieties are
Chem. Lett. 2013, 42, 1013-1015
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1015
R
145. j) Y.-M. Man, T. C. W. Mak, H. N. C. Wong, J. Org.
Chem. 1990, 55, 3214. k) D. Jiang, J. W. Herndon, Org. Lett.
2000, 2, 1267. l) S.-H. Chan, C.-Y. Yick, H. N. C. Wong,
Tetrahedron 2002, 58, 9413. m) J. E. Rainbolt, G. P. Miller,
J. Org. Chem. 2007, 72, 3020.
O
OC2Me
CHO
4
5
6
Recently, efficent synthetic method of functionalized 1,3-
diarylisobenzofurans was developed, see: J. Jacq, C.
Einhorn, J. Einhorn, Org. Lett. 2008, 10, 3757. See also
ref 2e.
For related two-steps preparation of 3-arylphthalide by
reaction of 2-carboxybenzaldehyde with two equivalents of
arylmagnesium halides, see: P. Canonne, J. Plamondon, M.
Akssira, Tetrahedron 1988, 44, 2903.
Conversion of 3-arylphthalide to isobenzofuran via nucleo-
philic addition of arylmagnesium halide was developed. For
selected examples, see: a) M. S. Newman, J. Org. Chem.
1961, 26, 2630. b) M. P. Cava, J. P. Van Meter, J. Am. Chem.
Soc. 1962, 84, 2008. c) M. P. Cava, J. P. Van Meter, J. Org.
Chem. 1969, 34, 538.
As for the dehydration of the lactol, generated by nucleo-
philic addition of aryl Grignard reagent to phthalide 2a,
CF3CO2H was most effective in comparison with the other
acids.
A convenient single-step synthesis of symmetrical 1,3-
diarylisobenzofuran was developed. However, unsymmetri-
cal derivatives could not be prepared by this method, see:
F. Benderradji, M. Nechab, C. Einhorn, J. Einhorn, Synlett
2006, 2035.
For one-step synthesis of diphenylisobenzofuran, see: a)
M. P. Cava, D. R. Napier, R. J. Pohl, J. Am. Chem. Soc.
1963, 85, 2076. b) R. H. Schlessinger, I. S. Ponticello,
J. Chem. Soc. D 1969, 1013b. c) L. Lepage, Y. Lepage,
Synthesis 1983, 1018.
Li
Li
1)
2) CF3CO2H, 0
R = C6H13
, 0 °C
1a
B
25 °C
R
MgBr
O
8 (45%)
R
Scheme 5.
transesterification, bis-addition of 4,4¤-dilithiobiphenyl to the
intermediate of the phthalide (structure not shown), and
dehydration under acidic conditions (Scheme 5).16
In summary, we developed a simple, practical, and efficient
method for one-pot synthesis of symmetric and unsymmetrical
1,3-diarylisobenzofurans by sequential reactions of methyl 2-
formylbenzoate with two identical or different aryl metal
species. Further studies are currently in progress.
7
8
This work was supported by Grant-in-Aid for Scientific
Research on Innovative Areas: “Organic Synthesis Based on
Reaction Integration” from MEXT, Japan. We also thank
Individual Special Research A from Kwansei Gakuin Univer-
sity. This work was partly supported by ACT-C, JST.
9
References and Notes
10 The successive process is classified as time integration,
where a sequence of reactions is conducted in one-pot by
adding components at intervals. For integration of reactions,
see: S. Suga, D. Yamada, J.-i. Yoshida, Chem. Lett. 2010, 39,
404.
1
a) A. O. Patil, A. J. Heeger, F. Wudl, Chem. Rev. 1988, 88,
183. b) J. Roncali, Chem. Rev. 1997, 97, 173. c) W.
Friedrichsen, Adv. Heterocycl. Chem. 1980, 26, 135. d) W.
Friedrichsen, Adv. Heterocycl. Chem. 1999, 73, 1.
2
For selective examples of the syntheses of isobenzofuran,
see: a) G. Wittig, L. Pohmer, Chem. Ber. 1956, 89, 1334. b)
M. P. Cava, M. J. Mitchell, A. A. Deana, J. Org. Chem.
1960, 25, 1481. c) R. N. Warrener, J. Am. Chem. Soc. 1971,
93, 2346. d) J. T. Sharp, C. E. D. Skinner, Tetrahedron Lett.
1986, 27, 869. e) Y. Kuninobu, Y. Nishina, C. Nakagawa, K.
Takai, J. Am. Chem. Soc. 2006, 128, 12376. f) Y. Nishina, T.
Kida, T. Ureshino, Org. Lett. 2011, 13, 3960.
a) G. Wittig, A. Krebs, Chem. Ber. 1961, 94, 3260. b) T.
Sasaki, K. Kanematsu, K. Hayakawa, M. Sugiura, J. Am.
Chem. Soc. 1975, 97, 355. c) W. C. Christopfel, L. L. Miller,
J. Org. Chem. 1986, 51, 4169. d) P. Binger, P. Wedemann,
R. Goddard, U. H. Brinker, J. Org. Chem. 1996, 61, 6462. e)
R. Rodrigo, Tetrahedron 1988, 44, 2093. f) T. Ernet, A. H.
Maulitz, E.-U. Würthwein, G. Haufe, J. Chem. Soc., Perkin
Trans. 1 2001, 1929. g) K. Mikami, H. Ohmura, Org. Lett.
2002, 4, 3355. h) Y. Luo, J. W. Herndon, Organometallics
2005, 24, 3099. i) H. N. C. Wong, Acc. Chem. Res. 1989, 22,
11 All new compounds were fully characterized by spectro-
scopic means. For details, see Supporting Information.
12 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
13 a) H. Zhang, A. Wakamiya, S. Yamaguchi, Org. Lett. 2008,
10, 3591. b) S. T. Meek, E. E. Nesterov, T. M. Swager, Org.
Lett. 2008, 10, 2991. c) J. A. Clement, P. Gunasekaran, A. K.
Mohanakrishnan, Tetrahedron 2009, 65, 4113.
14 Aryllithiums were generated by bromine-lithium exchange
of the corresponding arylbromides with t-BuLi at ¹78 °C.
15 For preparation of 5, see: R. Mirabdolbaghi, T. Dudding,
Org. Lett. 2012, 14, 3748.
16 For related two-steps synthesis of bis(isobenzofuran) deriv-
atives, see: a) S. A. Klassen, R. Boehme, S. D. Derrick, K.
Moock, A. E. Baker, D. E. Fogg, R. T. Boeré, P. W. Dibble,
Can. J. Chem. 2009, 87, 738. b) S. Leong-Neumann, S. D.
Derrick, P. W. Dibble, Tetrahedron Lett. 1995, 36, 4181.
3
Chem. Lett. 2013, 42, 1013-1015
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/