Mancuso et al.
JOCArticle
reactions are very clean and efficient, and tolerate a wide
variety of functional groups. Furthermore, the iodine-
containing products can be further diversified by using a
number of subsequent palladium-catalyzed processes.
Herein we report a simple and efficient method for the
synthesis of 1H-isochromene and/or (Z)-1-(1-iodoalkyli-
dene)-1,3-dihydroisobenzofuran derivatives, based on the
iodocyclization of readily available 2-(1-alkynyl)benzylic
alcohols (eq 1). Isochromenes and 1,3-dihydroisobenzofurans
are important heterocyclic compounds, and there are several
examples of naturally occurring and biologically active
compounds containing these ring systems.27,28
Over the years, several groups have reported a variety of
synthetic approaches to isochromene and dihydroisobenzo-
furan derivatives by the heterocyclization of acyclic precur-
sors.29 In particular, we30 and the Barluenga group31 have
independently reported the formation of 4-iodo-1H-isochro-
menes by the iodocyclization of 2-(1-alkynyl)benzaldehydes
in the presence of suitable nucleophiles (eq 2).
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We have also previously disclosed the Pd(II)-catalyzed
cycloisomerization of 2-(1-alkynyl)benzylic alcohols to 1H-
isochromenes and/or (Z)-1-alkylidene-1,3-dihydroisobenzo-
furans, depending on the nature of the substrate and the
reaction conditions (eq 3).29k
´
€
N. A. M.; Baumeister, U.; Hartung, H.; Kluge, R.; Strohl, D.; Fanghanel,
€
E. Eur. J. Org. Chem. 2003, 47.
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The new methodology reported in this work is comple-
mentary to those previously reported procedures, and allows
for the direct synthesis of 3-iodo-1H-isochromenes, (Z)-1-(1-
iodoalkylidene)-1,3-dihydroisobenzofurans, and iodopyrano-
pyridines by the iodocyclization of variously substituted
2-(1-alkynyl)benzylic alcohols or 2-(1-alkynyl)-3-(hydroxy-
methyl)pyridines under mild conditions (see eq 1).
Results and Discussion
2-(2-Phenylethynyl)benzyl alcohol (1a, Y=CH, R1=R2=
R3 = H, R4 = Ph) was chosen as a model substrate for
determining the optimum conditions for the iodocyclization
reaction, using I2 or ICl as the iodine source and MeCN,
CH2Cl2, or EtOH as the solvent, in the presence of an inorganic
(NaHCO3, K2CO3, KHCO3, NaH) or organic (morpholine)
base. The results obtained are shown in Table 1.32
As can be seen from Table 1, the isochromene derivative 2a
derived from a 6-endo-dig cyclization was consistently obta-
ined in higher yield than the dihydroisobenzofuran deriva-
tive 3a derived from a 5-exo-dig cyclization. The optimal
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(b) Yue, D.; Della Ca, N.; Larock, R. C. J. Org. Chem. 2006, 71, 3381.
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(31) (a) Barluenga, J.; Vazquez-Villa, H.; Ballesteros, A.; Gonzalez, J. M.
J. Am. Chem. Soc. 2003, 125, 9028. (b) Barluenga, J.; Vazquez-Villa, H.;
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Merino, I.; Ballesteros, A.; Gonzalez, J. M. Chem.;Eur. J. 2006, 12, 5790.
(32) The reaction did not occur in the absence of base, as shown by blank
experiments.
898 J. Org. Chem. Vol. 75, No. 3, 2010