A versatile and regiospecific synthesis of functionalized 1,3-diarylisobenzofurans

Article abstract of DOI:10.1021/ol801550a

(Chemical Equation Presented) A convenient, versatile, and regiospecific synthesis of functionalized 1,3-diarylisobenzofurans has been developed. It involves chemoselective addition of arylmagnesium reagents to the aldehyde function of o-aroylbenzaldehydes, themselves readily obtained by lead tetraacetate oxidation of N-aroylhydrazones of salicylaldehydes. Various functional groups, including nitro, iodo, or ester functionalities, have thus been positioned with complete regiospecificity on the 1,3-diphenylisobenzofuran backbone.

Full text of DOI:10.1021/ol801550a

ORGANIC
LETTERS
2008
Vol. 10, No. 17
3757-3760
A Versatile and Regiospecific Synthesis
of Functionalized
1,3-Diarylisobenzofurans
Je´roˆme Jacq, Cathy Einhorn, and Jacques Einhorn*
De´partement de Chimie Mole´culaire (SERCO), UMR-5250, ICMG FR-2607, UniVersite´
Joseph Fourier, 301 Rue de la Chimie, BP 53, 38041 Grenoble Cedex 9, France
jacques.einhorn@ujf-grenoble.fr
Received June 20, 2008
ABSTRACT
A convenient, versatile, and regiospecific synthesis of functionalized 1,3-diarylisobenzofurans has been developed. It involves chemoselective
addition of arylmagnesium reagents to the aldehyde function of o-aroylbenzaldehydes, themselves readily obtained by lead tetraacetate oxidation
of N-aroylhydrazones of salicylaldehydes. Various functional groups, including nitro, iodo, or ester functionalities, have thus been positioned
with complete regiospecificity on the 1,3-diphenylisobenzofuran backbone.
Benzo[c]furans or isobenzofurans constitute a valuable class
of heterocyclic compounds, possessing structural features and
reactivity profiles closely related to o-quinodimethanes.1
They are highly reactive dienes, and their Diels-Alder
reaction with dienophiles for the synthesis of natural and
non-natural products is well documented.2 During our
ongoing research on new analogues of N-hydroxyphthalimide
(NHPI),3 we have been searching for convenient access to
functionally diverse 1,3-diarylisobenzofurans. Whereas vari-
ous synthetic pathways to 1,3-diarylisobenzofurans are
known,1,4 none of them were totally satisfactory for our
purpose.
One of the most convenient and general syntheses of 1,3-
diarylisobenzofurans is the reaction of an arylmagnesium
reagent with 3-arylphthalides.5 Isobenzofurans are formed
via 1,4 water elimination from an intermediate lactol6 under
acidic conditions (Scheme 1, path A).
Among numerous methods, 3-arylphthalides can be pre-
pared by reacting two equivalents of an arylmagnesium
(4) For recent methods, see for example: (a) Kuninobu, Y.; Nishina,
Y.; Nakagawa, C.; Takai, K. J. Am. Chem. Soc. 2006, 128, 12376. (b)
(1) For reviews on isobenzofuran chemistry, see: (a) Friedrichsen, W.
AdV. Heterocycl. Chem. 1980, 26, 135. (b) Friedrichsen, W. AdV. Heterocycl.
Chem. 1999, 73, 1. (c) Steel, P. G. Sci. Synth. 2001, 10, 87.
Benderradji, F.; Nechab, M.; Einhorn, C.; Einhorn, J. Synlett 2006, 2035.
(5) (a) Guyot, A.; Catel, J. Bull. Soc. Chim. Fr. (3) 1906, 35, 1124. (b)
Newman, M. S. J. Org. Chem. 1961, 26, 2630. (c) Cava, M. P.; Van Meter,
J. P. J. Am. Chem. Soc. 1962, 84, 2008. (d) Cava, M. P.; Van Meter, J. P.
J. Org. Chem. 1969, 34, 538. (e) Dodge, J. A.; Bain, J. D.; Chamberlin,
A. R. J. Org. Chem. 1990, 55, 3214.
(2) (a) Rodrigo, R. Tetrahedron 1988, 44, 2093. (b) Peters, O.;
Friedrichsen, W. Trends Heterocycl. Chem. 1995, 4, 217.
(3) (a) Einhorn, C.; Einhorn, J.; Marcadal-Abbadi, C.; Pierre, J.-L. J.
Org. Chem. 1999, 64, 4542. (b) Nechab, M.; Einhorn, C.; Einhorn, J. Chem.
Commun. 2004, 1500. (c) Nechab, M.; Kumar, D. N.; Philouze, C.; Einhorn,
C.; Einhorn, J. Angew. Chem., Int. Ed. 2007, 46, 3080.
(6) (a) Baker, W.; Mc Omie, J. F. W.; Pope, G. A.; Preston, D. R.
J. Chem. Soc. 1961, 2965. (b) Courtot, P.; Sachs, D. H. Bull. Soc. Chim.
Fr. 1965, 2259.
10.1021/ol801550a CCC: $40.75
Published on Web 07/31/2008
2008 American Chemical Society

Scheme 1
.
Synthetic Strategies to 1,3-Diarylisobenzofurans
Scheme 2. Kotali’s Approaches to o-Acylbenzaldehydes
of the hydrazone formally replaces the phenolic hydroxyl
group, has been elucidated by Kotali and Katritzky.9d The
reaction has been extended to the synthesis of tris- and
reagent with an o-carboxybenzaldehyde.7 Thus, two different
aryl groups can be placed at the 1 and 3 positions of the
isobenzofuran core. While using this methodology, however,
we faced several of its limitations: functionalized 3-arylphtha-
lides are not commercially available and have to be prepared
via multisteps and nongeneral syntheses. The reactivity of
3-arylphthalides toward arylmagnesium reagents strongly
depends on the nucleophilicity of these. Thus, weakly
nucleophilic Grignard reagents such as pentafluorophenyl-
magnesium bromide or Knochel’s o-nitrophenylmagnesium
iodide8 did not react at all with 3-phenylphthalide. Finally,
the weak electrophilicity of the lactone function leads to
unselective reactions with Grignard reagents if the 3-phe-
nylphthalide backbone is substituted with other electrophilic
functions, such as nitro groups.
Table 1. Lead(IV) Acetate Oxidation of N-Aroylhydrazones of
Salicylaldehydes
Our reasoning was that a lactol should similarly be formed
by Grignard addition to the aldehyde function of an o-
aroylbenzaldehyde (Scheme 1, path B). This alternative
approach could possibly overcome some of the prior limita-
tions, as the electrophilic character of an aldehyde is much
more pronounced than that of a lactone. In this context,
however, the availability of o-aroylbenzaldehydes becomes
a deciding issue. In fact, o-ketobenzaldehydes remain a
seldom used class of compounds, and older methods for their
synthesis are rather tedious. Fortunately, Kotali discovered
a very interesting synthesis of o-diacylbenzenes, by lead
tetraacetate (LTA) oxidation of N-acylhydrazones of o-
hydroxyacylbenzenes.9 The mechanism of this original
carbon-carbon bond forming reaction, where the acyl group
(7) Canonne, P.; Plamondon, J.; Akssira, M. Tetrahedron 1988, 44, 2903.
(8) (a) Sapountzis, I.; Knochel, P. Angew. Chem., Int. Ed. 2002, 41,
1610. For reviews on functionalized organomagnesium reagents, see: (b)
Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn,
T.; Sapountsis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003, 42, 4302. (c)
Knochel, P. In Handbook of Functionalized Organometallics; Wiley-VCH:
New York, 2005. (d) Ila, H.; Baron, O.; Wagner, A. J.; Knochel, P. Chem.
Commun. 2006, 583.
(9) (a) Kotali, A.; Tsoungas, P. G. Tetrahedron Lett. 1987, 28, 4321.
(b) Kotali, A.; Glaveri, U.; Pavlidou, E.; Tsoungas, P. G. Synthesis 1990,
1172. (c) Katritzky, A. R.; Kotali, A. Tetrahedron Lett. 1990, 31, 6790. (d)
Katritzky, A. R.; Harris, P. A.; Kotali, A. J. J. Org. Chem. 1991, 56, 5049.
(e) Kotali, A. Tetrahedron Lett. 1994, 35, 6753. (f) Kotali, A.; Papapetrou,
M.; Dimos, V. Org. Prep. Proced. Int. 1998, 30, 159. (g) Kotali, A.;
Lafazanis, I. S.; Harris, P. A. Tetrahedron Lett. 2007, 48, 7181. For similar
reactions using phenyliodosodiacetate, see: (h) Moriarty, R. M.; Berglund,
B. A.; Rao, M. S. C. Synthesis 1992, 318. (i) Kotali, A.; Koulidis, A.; Wang,
H.-M.; Chen, L.-C. Org. Prep. Proced. Int. 1996, 28, 622. For reviews,
see:(j) Kotali, A. Cur. Org. Chem. 2002, 6, 965. (k) Kotali, A.; Harris,
P. A. Org. Prep. Proced. Int. 2003, 35, 583.
a Isolated yields.
3758
Org. Lett., Vol. 10, No. 17, 2008

Table 2. Synthesis of Functional 1,3-Diarylisobenzofurans
a Isolated yields; yields determined by 1H NMR of the crude reaction product are shown in parentheses. b Reaction performed by adding a THF solution
of 2a to a THF solution of 3b at -40 °C. c Reaction performed by adding a THF solution of 2a to a THF solution of 3d at -20 °C. d Reaction performed
at -78 °C.
tetraacylbenzenes,9b,e of o-acylbenzoic acid esters,9c,i and of
o-acylbenzaldehydes.9f Kotali prepared o-acylbenzaldehydes
by LTA oxidation of either N-formylhydrazones of o-
hydroxyacylbenzenes or N-acylhydrazones of salicylalde-
hydes (Scheme 2).
For our purpose, the second approach was by far more
convenient and versatile, as numerous functional N-aroyl-
hydrazides as well as functional salicylaldehydes are com-
mercially available. We chose this approach to synthesize a
series of functionally diverse o-aroylbenzaldehydes (Table
1). The synthesis of starting hydrazones 1a-1l was straight-
forward.10 LTA oxidation of N-acylhydrazones of salicyla-
ldehydes has so far been limited to a few cases of
unfunctionalized compounds such as 2a. We found that the
yield of 2a can be slightly improved by performing the LTA
oxidation of 1a at 0 °C instead of 25 °C (89% versus 77%
yield). The reaction could also be scaled up from 5 to 100
mmol (entry 1, Table 1).
The Kotali reaction appeared to have broad functional group
tolerance. Hydrazones, functionalized at the hydrazide aromatic
moiety by nitro or iodo groups at any of the para, meta, or
ortho positions (1b-1g), all furnished the corresponding o-
ketoaldehydes 2b-2g in good isolated yields (entries 2-7,
Table 1). The Kotali reaction was also compatible with bromo
(10) Nearly quantitative yields of hydrazones were obtained within
minutes by simple mixing of a salicylaldehyde with a stoichiometric amount
of N-aroylhydrazide, in acetic acid at room temperature. Alternatively, we
found that N-acylhydrazones of salicylaldehyde can also be prepared
conveniently in high yields by reacting 1 equiv of an acid chloride with
commercially available salicylaldehyde hydrazone in the presence of Hu¨nig’s
base.
Org. Lett., Vol. 10, No. 17, 2008
3759

or nitro groups on the salicylaldehyde moiety: thus 1h and 1i
gave the corresponding o-ketoaldehydes 2h and 2i in 70 and
82% yields (entries 8 and 9, Table 1). A supplementary free
phenol function was unfavorable, as 1j gave o-ketoaldehyde
2j in only 3% yield (entry 10, Table 1). Replacing the free
phenol by a methoxy group restored more usual behavior, 1k
giving 2k in 46% yield (entry 11, Table 1). Functional groups
could also be present at both aromatic moieties: LTA oxidation
of 1l gave 2l in 78% yield (entry 12, Table 1).
With a series of diversly functionalized o-ketoaldehydes
in hand, we next studied their reaction with aromatic
Grignard reagents (Table 2). In a first experiment, one
equivalent of phenylmagnesium bromide 3a was added to a
THF solution of 2a, at -78 °C. After acidic hydrolysis, 1,3-
diphenylisobenzofuran 4a was the unique reaction product,
as indicated by TLC and NMR analysis of the crude and
comparison with a commercial sample of 4a. This result
clearly indicates a chemoselective addition of Grignard
reagent 3a to the sole aldehyde function of 2a. Grignard
addition was still selective at 0 °C, as 4a was isolated in
88% yield from the corresponding experiment (entry 1, Table
2). We next examined the reaction of 2a with functionalized
Grignard reagents8 such as 3b, 3c, and 3d. Gratifyingly the
corresponding, previously unknown isobenzofurans 4b-4d
were all obtained in good yields (entries 2-4, Table 2).11
were thus readily prepared in good yields, reacting the
corresponding o-ketoaldehydes 2b-2g with Grignard reagent
3a (entries 5-10, Table 2). Functional groups are also
tolerated on the aldehyde-bearing aromatic ring. Thus,
bromo-, nitro-, and methoxyisobenzofurans 4j, 4k, and 4l
have been prepared from 2h, 2i, and 2k (entries 11-13,
Table 2). These results are worthy of note, as few 1,3-
diarylisobenzofurans functionalized at the central carbocycle
have been synthesized so far, using lengthy and nongeneral
syntheses.13 Finally, 1,3-diphenylisobenzofurans, simulta-
neously and regiospecifically functionalized at all three
carbocycles with various functional groups, can also be
prepared without difficulty. Thus, 4m has been obtained in
79% yield reacting o-ketoaldehyde 2k with Grignard reagent
3e (entry 14, Table 2).
In summary, we have developed convenient and general
access to functional 1,3-diarylisobenzofurans, involving
chemoselective addition of arylmagnesium reagents to o-
aroylbenzaldehydes, themselves readily obtained by LTA
oxidation of salicylaldehydes N-aroylhydrazones. This new
method is highly functional group tolerant. It is also totally
regiospecific, as the position of each functional group on
the 1,3-diphenylisobenzofuran backbone is directly related
to their original position on the N-aroylhydrazide-, salicy-
laldehyde-, or Grignard reagent aromatic rings.
Acknowledgment. The financial support from the CNRS,
Universite´ Joseph Fourier, and Cluster de Recherche Chimie
de la Re´gion Rhoˆne-Alpes are duly acknowledged.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Another interesting issue was the reaction of aromatic
Grignard reagents with functional o-ketoaldehydes. Syntheti-
cally valuable nitro-12 and iodoisobenzofurans 4b and 4e-4i
OL801550A
(11) Isobenzofurans have been obtained in good purities after standard
workup. Isolated yields have been determined after purification by column
chromatography. Yields have also been determined by 1H NMR of the crude,
as purification resulted, in some cases, in significant loss of product due to
air oxidation.
(12) A mixture of 4e and 4f has been obtained by direct nitration of 4a
in sulfuric acid. See: Amat-Gerri, F.; Lempe, E.; Lissi, E. A.; Rodriguez,
F. J.; Trull, F. R. J. Photochem. Photobiol. A 1996, 93, 49.
(13) See, for example: (a) Villessot, D.; Lepage, Y. Tetrahedron Lett.
1977, 17, 1495. (b) Lepage, L.; Lepage, Y. J. Heterocycl. Chem. 1978, 15,
793. (c) Schmitz, C.; Aubry, J. M.; Rigaudy, J. Tetrahedron 1982, 38, 1425.
(d) Lepage, L.; Lepage, Y. Synthesis 1983, 1018. (e) Christopfel, W. C.;
Miller, L. L. Tetrahedron 1987, 43, 3681. (f) Passerieux, D.; Casteignau,
M.; Lepage, L.; Lepage, Y. Bull. Soc. Chim. Fr. 1989, 441.
3760
Org. Lett., Vol. 10, No. 17, 2008