Novel synthesis of 3-substituted 2,3-dihydrobenzofurans via ortho -quinone methide intermediates generated in situ

Article abstract of DOI:10.1021/ol500290e

A new method is presented for the regioselective one-pot synthesis of 3-substituted 2,3-dihydrobenzofurans from 2-bromo-1-{2-[(triisopropylsilyl)oxy] phenyl}ethyl nitrate by fluoride-induced desilylation leading to o-quinone methide generation, Michael addition of different C, N, O, and S nucleophiles, and intramolecular 5-exo-tet elimination of a bromide anion. The method has potential synthetic applications in drug discovery.

Full text of DOI:10.1021/ol500290e

Letter
pubs.acs.org/OrgLett
Novel Synthesis of 3‑Substituted 2,3-Dihydrobenzofurans via ortho-
Quinone Methide Intermediates Generated in Situ
Abdul kadar Shaikh and George Varvounis*
Section of Organic Chemistry and Biochemistry, Department of Chemistry, University of Ioannina, 451 10 Ioannina, Greece
S
* Supporting Information
ABSTRACT: A new method is presented for the regioselective
one-pot synthesis of 3-substituted 2,3-dihydrobenzofurans from 2-
bromo-1-{2-[(triisopropylsilyl)oxy]phenyl}ethyl nitrate by fluo-
ride-induced desilylation leading to o-quinone methide generation,
Michael addition of different C, N, O, and S nucleophiles, and
intramolecular 5-exo-tet elimination of a bromide anion. The
method has potential synthetic applications in drug discovery.
thiophenol electrophilically, to afford 3-(phenylthiomethyl)-
mong the 2,3-dihydrobenzofurans that are substituted
Aonly at position 3, the most important biologically active 2,3-dihydrobenzofuran. In the absence of thiophenol, H-atom
abstraction gives 3-methyl-2,3-dihydrobenzofuran.3k
Less common methods of synthesizing 3-substituted 2,3-
representative is the prostaglandin (PG) D2 receptor
antagonist1 (Figure 1), while the 2,3-dihydrobenzofuran
dihydrobenzofurans are intramolecular enantioselective ring
opening of 2-oxetan-3-ylphenol catalyzed by (salen)Co(III)
complexes,4a intramolecular alkene carboacylation of [2-(allyl-
oxy)phenyl](quinolin-8-yl)methanones initiated by quinoline-
directed rhodium-catalyzed C−C σ-bond activation with
{RhCl(C2H4)2}2 or Rh(OTf)(COD)2,4b nickel-promoted
Favorskii-type rearrangement of 3-bromo-2,3-dihydro-4H-chro-
men-4-ones with NiCl2,4c intramolecular Heck−Matsuda
reaction of 2-(allyloxy)benzenediazonium tetrafluoroborates
with Pd(OAc)2 as the catalyst in an atmosphere of CO,4d 5-
exo-trig intramolecular carbolithiation of 1-[(3,3-dimethoxy-
prop-2-en-1-yl)oxy]-2-iodobenzene with n-BuLi and TMEDA
and elimination of the methoxide ion,4e asymmetric hydro-
genation of 3-methylbenzofuran at 10 bar of hydrogen in the
presence of the [Ru(cyclooctadiene)(2-methylallyl)2] catalyst,4f
and intramolecular copper-promoted Sandmeyer trifluoro-
methylation of 2-(allyloxy)anilines in the presence of i-
AmONO and 5-(trifluoromethyl)dibenzo[b,d]thiophenium
tetrafluoroborate (Umemoto’s reagent).4g
Although the synthesis of 3-substituted 2,3-dihydro-
benzofurans via o-quinone methide (o-QM) intermediates is
unknown, the parent compound and 2-substituted and 2,3-
disubstituted derivatives have been synthesized by this method.
Melumad and Breuer5a reported that the reaction of o-QM,
generated in situ from o-hydroxybenzyltrimethylammonium
iodide by the action of CH3S(O)CH2Na in DMSO, with
dimethyl sulfoxonium methylide, afforded the parent 2,3-
dihydrobenzofuran. A similar approach was recently reported
by Zhou and co-workers.5b Cesium carbonate was used to
induce elimination of a toluene-para-sulfinate anion from 2-
{(aryl)[(4-methylphenyl)sulfonyl]methyl}phenols to form o-
skeleton appears as a core element in numerous natural and
synthetic pharmacologically interesting compounds.1,2
Figure 1. N-Benzoyl-2-methylindole-3-acetic acid derivative. An
example of a biologically active 3-substituted 2,3-dihydrobenzofuran.
3-Substituted 2,3-dihydrobenzofurans have been synthesized
by a variety of methods such as intramolecular aryl radical and
Ullman-type cyclization, transition metal-catalyzed intramolec-
ular C−O coupling reactions, Heck-type reactions, hydro-
alkoxylation and carbenoid-saturated C−H bond insertion
reactions, the Parham cyclization process, intramolecular
Michael-type addition, intramolecular O-to-alkene 5-exo-trig
addition and O-to-oxirane addition, the use of benzyne
intermediates, Mitsunobu type cyclodehydration reactions,
cycloaddition reactions, and the application of biomimetic
chemistry, as described in the review article by Bertolini and
Pineschi.2b Since then, intramolecular aryl radical cyclization
has been, by far, the most commonly employed method for the
synthesis of a wide range of 3-substituted 2,3-dihydrobenzo-
furans.3 A recent example to illustrate this process is the
photoinduced radical reduction of 1-(allyloxy)-2-iodobenzene
initiated by CuI and NaOt-Bu to form the corresponding aryl
radical that undergoes 5-exo-trig radical cyclization to give the
primary radical of 3-methyl-2,3-dihydrobenzofuran which traps
Received: January 27, 2014
Published: February 26, 2014
© 2014 American Chemical Society
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Letter
QMs which are trapped by the sulfur ylides derived, for
example, from (2-ethoxy-2-oxoethyl)(dimethyl)sulfonium bro-
mide and a base. The resulting phenoxides undergo a trans-
elimination−cyclization process, to yield 2,3-disubstituted 2,3-
dihydrobenzofurans with >20:1 trans/cis selectivity. Osyanin
and co-workers5c used DBU to transform (2-hydroxyphenyl)-
N,N,N-trimethylmethanaminium iodides into o-QMs which
react with pyridinium acylmethylides to afford phenoxides that
cyclize by elimination of pyridine, to give 2-substituted 2,3-
dihydrobenzofurans.
Scheme 2. Plausible Mechanism for the Synthesis of 3-
Substituted 2,3-Dihydrobenzofurans
Recently we have reported6a a new method for o-QM
generation, via fluoride-induced desilylation of 2-(tert-butyl-
dimethylsilyloxy)benzyl nitrate and elimination of a nitrate
anion. The o-QM was trapped in situ by different C, N, O, and
S nucleophiles leading to 2-(substituted methyl)phenols. In
view of our continuing interest in substituted 2,3-dihydro-
benzofurans as pharmacologically active substances and due to
the lack of a versatile and efficient method of introducing
variable substitution at position 3 of these compounds, we now
present an application of our novel method for generating an o-
QM and trapping with a range of nucleophiles, by using nitrate
ester 6 as a precursor and incorporating into the one-pot
reaction an intramolecular 5-exo-tet elimination process, to
afford 3-substituted 2,3-dihydrobenzofurans. The starting
material used to synthesize nitrate ester 6 is commercially
available 2-hydroxyacetophenone 1 (Scheme 1). In the first
addition of TBAF at the same temperature. In the case of
MeOH or 2-PrOH these solvents were added instead of THF
to react also as nucleophiles. The reaction is postulated to
proceed by attack of a fluoride anion onto the silyl ether,
breakage of the Si−O bond, and elimination of a nitrate anion
to generate the corresponding o-QM in situ. The latter is then
trapped by different C, N, O, and S nucleophiles to generate
Michael addition phenoxide ion intermediates that undergo
intramolecular 5-exo-tet elimination of a bromide anion, to
afford 3-substituted 2,3-dihydrobenzofurans 7a−k. The type of
nucleophiles used, the products, and the yields obtained are
shown in Table 1.
In an effort to reduce by one the number of synthetic steps
from 2-hydroxyacetophenone 1 to the 3-substituted 2,3-
dihydrobenzofurans 7a−k, we thought of reacting dihalo
compound 5 with TBAF in THF at −78 °C so that fluoride
Si−O bond cleavage would bring on conjugate elimination of a
chloride anion (Cl instead of ONO2 in the mechanism of the
Scheme 1. Synthesis of 2-Bromo-1-{2‑[(triisopropylsilyl)-
oxy]phenyl}ethyl Nitrate 6 from 2-Hydroxyacetophenone 1
Table 1. Synthesized 3-Substituted 2,3-Dihydrobenzofurans
step of this synthesis, the hydroxy group of 1 is protected using
triisopropylsilyl chloride (TIPSCl), DMAP, and (i-Pr)2NH in
dichloromethane, to yield silyl ether 2 in 94% yield.
Bromination of 2 was achieved by triturating 2 with N-
bromosuccinimide and a catalytic amount of p-toluenesulfonic
acid (PTSA), as reported by Stavber and co-workers,6b to give
α-bromoacetophenone 3 in 65% yield. The carbonyl group of 3
was then selectively reduced by NaBH4 in THF to afford
alcohol 4 in 73% yield. In the next step, the hydroxy group of 4
was converted to a chloro atom by heating in SOCl2 and the
dihalo derivative 5 was isolated in 84% yield. Room
temperature reaction of dihalo compound 5 with 2 equiv of
AgNO3 in acetonitrile, as reported by Lehmann and co-
workers6c for the preparation of benzyl nitrates from benzyl
bromides, afforded regioselectively nitrate ester 6 in 96% yield.
In order to determine the applicability of the aforementioned
method of synthesizing regioselectively 3-substituted 2,3-
dihydrobenzofurans, nitrate ester 6 (Scheme 2) was dissolved
in dry THF under a nitrogen atmosphere, the temperature was
lowered to −78 °C, and then the appropriate nucleophile (RH)
was slowly added, over 1 min, followed by the dropwise
a
b
Isolated yields. Instead of using THF as a solvent, methanol or 2-
c
propanol were used. Sodium hydride was used to generate the anions.
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Scheme 2) and o-QM generation which, in the presence of
pyrrolidine, would undergo Michael addition followed by
intramolecular 5-exo-tet elimination of the bromide anion, to
afford 7a. To our surprise, this reaction instead of giving solely
7a, a second product, 1-(5-chloro-2,3-dihydro-1-benzofuran-3-
yl)pyrrolidine 8, was also isolated (Scheme 3). In the first
phenoxide anion intermediate undergoes conjugate elimination
of a nitrate anion.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures for all reactions and characterization
data for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Scheme 3. Synthesis of 1-(2,3-Dihydrobenzofuran-3-yl)-
pyrrolidine 7a and Its 5-Chloro Derivative 8 from [2-(2-
Bromo-1-chloroethyl)phenoxy](triisopropyl)silane 5
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: gvarvoun@cc.uoi.gr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the State Scholarship Foundation (I.K.Y.) of Greece
(for a studentship to A. K. S., Grant No. 1210) for support. We
appreciate the use of NMR and mass spectrometry facilities
funded by the Network of Research Supporting Laboratories of
the University of Ioannina and thank Dr. K. Tsiafoulis, and Dr.
V. Kontogianni, Dr. S. Papas, and Dr. A. Karkabounas, of the
University of Ioannina, for 2D NMR spectra and mass spectra,
respectively. We thank Dr. A. J. A. Cobb of the University of
Reading for the HRMS spectrum of compound 4.
experiment at −78 °C, 7a and 8 were isolated by SiO2 column
chromatography in 5% and 2% yield, respectively. When the
reaction was repeated at 0 °C followed by stirring at rt for 40
min, 7a and 8 were isolated by column chromatography in 10%
and 5% yield, respectively. At present we are not in a position
to suggest a plausible ionic or radical mechanism for the
formation of 8. Repeating this reaction and using instead of
THF and pyrrolidine either MeOH or 2-PrOH, to act as both
solvents and nucleophiles at 0 °C, afforded compounds 7d and
7e in only 12% and 8% yields, respectively (Scheme 4). No
chlorination products were detected in these two reactions.
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