Synthesis of dihydrobenzofurans via palladium-catalyzed annulation of 1,3-dienes by o -iodoaryl acetates

Article abstract of DOI:10.1021/jo100495t

The palladium-catalyzed annulation of 1,3-dienes by o-iodoaryl acetates provides an efficient approach to biologically interesting dihydrobenzofurans. The annulation is believed to proceed via (1) oxidative addition of the aryl iodide to Pd(0), (2) syn-ad

Full text of DOI:10.1021/jo100495t

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Synthesis of Dihydrobenzofurans via Palladium-Catalyzed Annulation of
1,3-Dienes by o-Iodoaryl Acetates
Roman V. Rozhkov and Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, Iowa 50011
larock@iastate.edu
Received March 16, 2010
The palladium-catalyzed annulation of 1,3-dienes byo-iodoaryl acetates provides anefficient approach
to biologically interesting dihydrobenzofurans. The annulation is believed to proceed via (1) oxidative
addition of the aryl iodide to Pd(0), (2) syn-addition of the resulting arylpalladium complex to the 1,3-
diene, (3) intramolecular coordination of the phenolic oxygen to the Pd center, (4) hydrolysis of the
acetyl group, and (5) reductive elimination of Pd(0), which regenerates the catalyst. This reaction is
quite general, regioselective, and stereoselective, and a wide variety of terminal, cyclic, and internal 1,3-
dienes, as well as electron-rich and electron-deficient o-iodoaryl acetates, can be utilized.
The dihydrobenzofuran unit is very common in natural
products and biologically significant synthetic compounds.1
Previously developed methodology for the synthesis of dihydro-
benzofurans has utilized the [3þ2] cycloaddition of phenols
to alkenes,2 the intramolecular acid-catalyzed cyclization of
allylic phenols3 and quinines,4 and the electrophilic cycliza-
tion of 2-(2-hydroxyethyl)phenyl diazonium salts,5 as well as
radical6 and transition metal-catalyzed7 cyclizations. Unfor-
tunately, these methods are not very general and, in most
cases, do not tolerate sensitive functional groups.
heterocyclic systems.8 Palladium-catalyzed annulations dev-
eloped in our laboratories9 have provided a versatile route
for the construction of complex cyclic systems, using 1,3-
dienes and o-iodoanilines 1,10 2-iodo-2-alkenoic acids 2,11
and o-iodophenols 3,12 which allow an elegant approach to
the heterocycles 4-6, respectively (eqs 1-3).
Heteroannulation reactions involving π-allylpallad-
ium intermediates are of great utility for the synthesis of
(1) (a) Dean, F. M. The Total Synthesis of Natural Products; ApSimon, J.,
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Chem. Soc. 2001, 123, 12202. (e) Pelly, S. C.; Govender, S.; Fernandes, M. A.;
Schmalz, H.-G.; de Koning, C. B. J. Org. Chem. 2007, 72, 2857.
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DOI: 10.1021/jo100495t
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Published on Web 05/19/2010
J. Org. Chem. 2010, 75, 4131–4134 4131
2010 American Chemical Society

Rozhkov and Larock
JOCArticle
iodide 7, led to only a trace amount of the desired annulation
product 9 and virtually all starting materials were recovered.
This is most likely due to the slower oxidative addition of
carbon-chlorine and carbon-bromine bonds to the Pd(0)
complex generated in situ.
The use of o-iodophenyl acetate and trans,trans-2,4-hex-
adiene gives exclusively the trans-dihydrobenzofuran 10 in
75% yield (Table 1, entry 3). The stereospecificity of this
annulation is presumably due to coordination of the pheno-
lic oxygen to the palladium center in the π-allylpalladium
intermediate (see the later mechanistic discussion).
Unfortunately, the latter annulation appears limited
to relatively unhindered 1,3-dienes and electron-deficient
o-iodophenols and only one example of this process utilizing
an electron-rich arene has been previously reported.12 Thus,
the reaction of 3 and 1,3-cyclohexadiene only affords a 44%
yield of the corresponding dihydrobenzofuran 6. Annula-
tions with electron-rich 2-iodo-4-methoxyphenol afforded
mainly dehalogenated products and only negligible amounts
of the desired dihydrobenzofurans.13 Our recent success in
the synthesis of dihydrofurocoumarins14 and dihydrofuro-
flavonoids15 by the palladium-catalyzed annulation of 1,3-
dienes using o-iodoacetoxycoumarins and o-iodoacetoxyfla-
vonoids respectively prompted further exploration of the
utility of this methodology for the synthesis of dihydroben-
zofurans. The major objective of this project was the devel-
opment of a general annulation methodology, which could
be successfully applied not only to a certain specific class of
substrates, such as coumarins and flavonoids, but might uti-
lize a broad range of o-iodoaryl acetates. We now wish to
report such success.
Next, a wide variety of electron-rich and electron-defi-
cient aryl iodides were studied. Annulation with termi-
nal, internal, and cyclic dienes and the electron-deficient
substrate 11 gave the desired annulation products 12-15
in excellent yields (Table 1, entries 4-7). We have also
compared our optimized acetate reaction conditions here
with those for aryl iodide 11 and the procedure used in our
earlier research employing o-iodophenols (Table 1, entry
4).12 Annulation of 2,3-dimethyl-1,3-butadiene by methyl
4-hydroxy-3-iodobenzoate under our recently developed
and previously reported reaction conditions afforded 70%
and 52% yields of the desired product 12, respectively.
Although the difference in yields is less dramatic compared
to that of the electron-rich substrate 7 (Table 1, entry 2),
our “optimal” reaction conditions have provided a quan-
titative yield of the annulation product 12. The annulations
of 2,3-dimethyl-1,3-butadiene by the electron-deficient
substrates 16 and 18 have also given the desired dihydro-
benzofrans 17 and 19 in 88% and 98% yields, respectively
(Table 1, entries 8 and 9). Although the acetate of the nitro-
substituted aryl halide 20 could not be prepared due to its
high propensity to hydrolyze, the annulation of 2,3-di-
methyl-1,3-butadiene by the corresponding phenol gave
the desired dihydrobenzofuran 21 in 72% yield (Table 1,
entry 10). Thus, one can employ the phenol itself and get
good yields of the corresponding dihydrobenzofuran if
there is a strong electron-withdrawing group present on
the phenol ring.
Since electron-rich aryl iodides failed to undergo annula-
tion in our previous studies,12,13 we examined the effective-
ness of our new methodology on substrates 22, 25, 27, and 29.
The annulation of 2,3-dimethyl-1,3-butadiene by aryl iodide
22 gave the desired annulation product 23 in 58% yield
(Table 1, entry 11). Surprisingly, employing 1-phenyl-1,3-
butadiene led to formation of the Heck product 24 in a 64%
yield (Table 1, entry 12). When using aryl iodide 22, the 1,3-
dienes 1,3-cyclohexadiene and trans,trans-2,4-hexadiene
gave inseparable, complex mixtures of what appeared to be
Heck-type products. This could be due to slower hydrolysis
of the acetyl group in the case of electron-rich phenols,
leading to β-hydride elimination of the π-allylpalladium
intermediate instead of cyclization.
We have studied the scope and limitations of the palladium-
catalyzed annulation of 1,3-dienes by various o-iodoaryl
acetates (eq 4) under our previous reaction conditions and
our newly developed reaction conditions (Table 1).14,15
The annulation of 1,3-cyclohexadiene by aryl iodide
7 gave the desired annulation product 8 in a 72% yield under
our newly developed reaction conditions (entry 1, see foot-
note a of Table 1 for the new procedure), compared to the
44% yield achieved previously.12 The use of 2,3-dimethyl-
1,3-butadiene gave an even higher 92% yield of dihydroben-
zofuran 9 (Table 1, entry 2). The same annulation carried out
with o-iodophenol, instead of o-iodophenyl acetate, gave
lower 48% yield. The yield of dihydrobenzofuran 9 obtained
with our previously reported reaction conditions for o-iodo-
phenol12 was only 18% and the dehalogenated phenol was
isolated in 70% yield as a major side product. These results
clearly demonstrate the superiority of our new “optimal”
acetate reaction conditions over our previously reported
procedure.
At this point, we examined the necessity of employing an
acetyl group and compared our optimal acetate reaction con-
ditions to our previously reported results using o-iodophe-
nol.12 Employing a methyl, benzyl, pivaloyl, or benzoyl
group on the phenolic oxygen of o-iodophenol in the reaction
with 2,3-dimethyl-1,3-butadiene did not lead to any signifi-
cant amount of dihydrobenzofuran 9, presumably due to a
slower rate of hydrolysis compared to the acetyl group. The
use of o-chloro- and o-bromophenyl acetates, instead of aryl
The increased steric hindrance in substrate 25 seems to
have little effect on the yield of dihydrobenzofuran 26
(Table 1, entry 13). Remarkably, the remote acetyl group
in the bis-acylated 4-iodoresorcinol 27 was not cleaved
during the course of the reaction with 2,3-dimethyl-1,3-
butadiene, giving annulated product 28 in a 40% yield
(Table 1, entry 14). The annulation of the sterically hindered
naphthalene 29 gave the desired product 30 in a 48% yield
(Table 1, entry 15).
(10) Larock, R. C.; Guo, L. Synlett 1995, 465.
(11) Gagnier, S. V.; Larock, R. C. J. Org. Chem. 2000, 65, 1525.
~
(12) Larock, R. C.; Berrios-Pena, N.; Narayanan, K. J. Org. Chem. 1990,
55, 3447.
~
(13) Berrios-Pena, N.; Larock, R. C. Unpublished results.
(14) (a) Rozhkov, R. V.; Larock, R. C. Org. Lett. 2003, 5, 797.
(b) Rozhkov, R. V.; Larock, R. C. J. Org. Chem. 2003, 68, 6314.
(15) (a) Rozhkov, R. V.; Larock, R. C. Tetrahedron Lett. 2004, 45, 911.
(b) Rozhkov, R. V.; Larock, R. C. Adv. Synth. Catal. 2005, 346, 1854.
4132 J. Org. Chem. Vol. 75, No. 12, 2010

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TABLE 1. Synthesis of Dihydrobenzofurans by Palladium-Catalyzed Annulation (eq 4)a
aThe o-iodoaryl acetate (0.25 mmol), Pd(dba)2 (5 mol %, 0.0125 mmol), dppe (5 mol %, 0.0125 mmol), Ag2CO3 (0.5 mmol), 1,3-diene (1.0 mmol), and
5 mL of a 4:1 1,4-dioxane/water mixture were stirred at 100 °C for 24 h. bSci-Finder compound database. cAll yields are isolated and based on a single run.
dThe o-iodophenol was used as the starting material. eThe o-iodophenol (0.25 mmol), Pd(OAc)2 (5 mol %, 0.0125 mmol), diene (1.75 mmol), Na2CO3
(0.5 mmol), LiCl (0.5 mmol), and DMF (5 mL) were heated at 100 °C for 72 h.
J. Org. Chem. Vol. 75, No. 12, 2010 4133

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SCHEME 1
the final product 37 with simultaneous regeneration of the
palladium catalyst 31.
Conclusions
In summary, we have developed an efficient palladium-
catalyzed annulation of 1,3-dienes by o-iodophenyl acetates,
which affords good yields of dihydrobenzofurans. The pro-
cess is quite general and regio- and stereoselective, and a wide
range of electron-deficient and electron-rich o-iodoaryl acet-
ates, as well as cyclic, terminal, and internal 1,3-dienes, can
be utilized. The presence of the acetyl group greatly improves
the yields in this process, particularly with aryl iodides
containing electron-donating substituents. However, highly
electron-rich o-iodoaryl acetates do tend to give somewhat
lower yields than electron-deficient aryl iodides and, in the
case of internal or aryl-substituted 1,3-dienes, Heck-type
products are sometimes observed.
Experimental Section
A possible mechanism for this annulation process is shown
in Scheme 1. Initial oxidative addition of the iodoarene 7 to
palladium(0) intermediate 31 generated in situ forms aryl-
palladium intermediate 32.16 Abstraction of the iodide by
Ag2CO3 leads to a cationic intermediate 33,17 presumably
stabilized by coordination to the neighboring acetyl group.
The higher reactivity of these cationic arylpalladium com-
plexes toward alkenes, compared to the neutral arylpalla-
dium complexes, is presumably responsible for the excellent
yields in our annulations.16b Complex 33 adds to the 1,3-
diene in a syn-fashion to give initially a σ-allylpalladium
complex and then π-allylpalladium intermediate 34.12 Co-
ordination of the acetoxy oxygen to the palladium atom,
leading to the formation of intermediate 35, restricts rotation
of the C-C bonds in the allyl moiety, and is presumably
responsible for the high stereoselectivity observed when
trans,trans-2,4-hexadiene is utilized (Table 1, entries 3 and
6). Since no hydrolysis of the acetate group in the starting
material 7 or the acetoxy group in the product 28 has been
observed under our reaction conditions, the deacylation of
intermediate 35 is presumably accelerated by coordination of
the acylated oxygen atom to the cationic palladium center.
The high correlation between the acidity (pKa) of the phe-
nolic precursors of our o-iodoaryl acetates and the annula-
tion yields further supports this deacylation step (Table 1).
Finally, complex 36 undergoes reductive elimination to give
General Procedure for the Synthesis of Dihydrobenzofu-
rans. The o-iodoaryl acetate (0.25 mmol), Pd(dba)2 (5 mol %,
0.0125 mmol), dppe (5 mol %, 0.0125 mmol), Ag2CO3 (0.5 mmol),
and 1,4-dioxane (4 mL) were stirred in a capped vial for 5 min,
and then water (1 mL) and the 1,3-diene (1.0 mmol) were
added. The resulting reaction mixture was stirred at 100 °C for
24 h, cooled to room temperature, and filtered, then the filtrate
was concentrated to give a yellow residue. The resulting
residue was purified by column chromatography with silica
gel as a solid phase and 4:1 hexanes/ethyl acetate as the eluent
to afford after solvent removal the final product. The follow-
ing new compound was prepared with this procedure.
Methyl 2-methyl-2-(1-methylethenyl)-2,3-dihydrobenzofuran-
5-carboxylate (12): obtained in a 100% yield as a colorless oil;
1H NMR (CDCl3) δ 1.55 (s, 3H), 1.80 (dd, J=1.2, 0.8 Hz, 3H),
3.02 (d, J=16.0 Hz, 1H), 3.24 (d, J=16.0 Hz, 1H), 3.85 (s, 3H),
4.84 (q, J = 1.2 Hz, 1H), 5.06 (q, J = 0.8 Hz, 1H), 6.78 (d, J =
8.4 Hz, 1H), 7.82 (d, J=0.8 Hz, 1H), 7.86 (dd, J=8.4, 0.8 Hz,
1H); 13C NMR (CDCl3) δ 18.9, 26.3, 40.9, 52.1, 91.8, 109.4,
110.6, 122.6, 127.1, 127.2, 131.4, 147.3, 163.2, 167.3; IR (neat)
1714, 1612 -1; m/z 232.1102 (calcd for C14H16O3, 232.1099).
The product characterization data for all other dihydroben-
zofurans prepared appear in the Supporting Information.
Acknowledgment. We gratefully acknowledge the donors
of the Petroleum Research Fund, administered by the Amer-
ican Chemical Society, for partial support of this research
and Johnson Matthey, Inc. and Kawaken Fine Chemicals
Co., Ltd. for donations of palladium acetate.
(16) (a) Heck, R. F. Org. React. 1982, 27, 345. (b) Amatore, C.; Jutand, A.
Acc. Chem. Res. 2000, 33, 314.
(17) (a) Karabelas, K.; Westerlund, C.; Hallberg, A. J. Org. Chem. 1985,
50, 3896. (b) Grigg, R.; Loganathan, V.; Santhakumar, V.; Sridrahan, V.;
Teasdale, A. Tetrahedron Lett. 1991, 32, 687.
Supporting Information Available: General experimental
procedures and spectral data for the compounds listed in Table 1.
This material is available free of charge via the Internet at http://
pubs.acs.org.
4134 J. Org. Chem. Vol. 75, No. 12, 2010