One-pot cascade synthesis of 2,3-disubstituted 2,3-dihydrobenzofurans via ortho-quinone methide intermediates generated in situ

Article abstract of DOI:10.1039/c4ra15024d

A simple and efficient one-pot cascade reaction for the regioselective synthesis of trans or cis/trans 2,3-disubstituted 2,3-dihydrobenzofurans is reported. The method involves fluoride-induced desilylation, generation of o-quinone methide (o-QM) by chloride or nitrate anion elimination, Michael addition and intramolecular 5-exo-tet elimination of a bromide anion. Nitrate, acetoxy and chloride anions are compared as leaving groups in the formation of the in situ generated o-QM.

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One-pot cascade synthesis of 2,3-disubstituted 2,3-dihydrobenzofurans via ortho-
quinone methide intermediates generated in situ
Abdul kadar Shaikh and George Varvounis*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A simple and efficient one-pot cascade reaction for the
regioselective synthesis of trans or cis/trans 2,3-disubstituted
2,3-dihydrobenzofurans is reported. The method involves
fluoride-induced desilylation, generation of o-quinone
10 methide (o-QM) by chloride or nitrate anion elimination,
Michael addition and intramolecular 5-exo-tet elimination of
a bromide anion. Nitrate, acetoxy and chloride anions are
compared as leaving groups in the formation of the in situ
generated o-QM.
15 Introduction
2,3ꢀDisubstituted 2,3ꢀdihydrobenzofurans are found in an
increasing number of biologically active molecules and natural
products. For example, cis 2ꢀethoxyꢀ3ꢀhydroxyethyl derivative 1
and trans acetic acid 2ꢀarylꢀ3ꢀylmethyl ester derivative 2 were
20 isolated from Rhododendron mariae Hance species,1
aminophenethylethanol derivatives 3 have demonstrated antiꢀ
multi drug resistance (MDR) properties2 while (+)ꢀlithospermic
acid is a potent and nontoxic antiꢀHIV agent that inhibits HIVꢀ1
integrase.3
Fig.
1
Natural and biologically active 2,3ꢀdisubstituted 2,3ꢀ
50 dihydrobenzofurans.
have been used again to synthesise 2,3ꢀdihydrobenzofurans. This
time, (2ꢀhydroxybenzyl)trimethylammonium iodides were heated
to reflux in acetonitrile and in the presence of DBU to generate
the corresponding oꢀQMs in situ that reacted with pyridinium
55 acylmethylides to give 2ꢀsubstituted 2,3ꢀdihydrobenzofurans.15
A
25
The synthesis of 2,3ꢀdihydrobenzofurans has been reviewed
recently.4 The best developments in the past 10 years towards the
synthesis of 2,3ꢀdisubstituted 2,3ꢀdihydrobenzofurans were by
cyclodehydration of 2ꢀ(2ꢀhydroxyethyl)phenols,5 asymmetric
formal [4+1] cycloaddition of camphorꢀderived sulfonium salts
different concept involved the generation of oꢀQMs in situ from
2ꢀ(1ꢀtosylmethyl)phenols using caesium carbonate as base while
reaction with sulfur ylides led to the synthesis of transꢀ2,3ꢀ
disubstitutedꢀ2,3ꢀdihydrobenzofurans.16
Subsequently,
an
60 oxidative method for the generation of oꢀQMs was reported. 2ꢀ
Alkylsubstituted phenols were oxidised by silver oxide to
generate oꢀQMs in situ that were reacted with sulfur ylides to
afford 2,3ꢀdisubstituted 2,3ꢀdihydrobenzofurans in excellent
diastereoselectivity.17
In our previous work we have reported a new method for
generating oꢀQM in situ that involves fluorideꢀinduced
desilylation of 2ꢀ(tertꢀbutyldimethylsilyloxy)benzyl nitrate and
elimination of a nitrate anion. An important feature of this
method is the ease of elimination of the nitrate group which is the
70 key to rapid oꢀQM formation. Michael addition to the oꢀQM
formed in situ by different C, N, O, and S nucleophiles led to a
variety of 2ꢀ(substituted methyl)phenols.18a Subsequently, this
method was applied toward the regioselective synthesis of 3ꢀ
substituted 2,3ꢀdihydrobenzofurans. This was accomplished by
75 fluoride anion cleavage of the Si−O bond of 2ꢀbromoꢀ1ꢀ{2ꢀ
[(triisopropylsilyl)oxy]phenyl}ethyl nitrate followed by conjugate
elimination of nitrate anion from the resulting phenoxide anion
30 with aldimines,6 tandem Claisen rearrangement and
intramolecular hydroaryloxylation of allyl aryl ethers,7
intramolecular CH–insertion reactions,8 palladiumꢀcatalyzed
acyloxyarylation of benzofurans via dearomatization with
arylboronic and carboxylic acids,9 intramolecular azaꢀ
35 spiroannulation onto benzofurans using chiral rhodium
catalysis,10 intramolecular Michael additionꢀlactonization of [2ꢀ
(α,βꢀunsaturated carbonyl)phenoxy]acetic acids by organic and
organometallic catalysts,11 cerium ammonium nitrateꢀmediated
oxidative dimerization of pꢀalkenylphenols12 and through
40 reactions of 2ꢀhydroxyarylꢀα,βꢀunsaturated ketones with
dimethylsulfonium carbonylmethylides.13 The first report of a
2,3ꢀdihydrobenzofuran synthesis via an oꢀquinone methide (oꢀ
QM) intermediate was the C−H insertion reaction on the oꢀQM
derived from (2ꢀhydroxybenzyl)trimethylammonium iodide by
45 dimethyl sulfoxonium methylide in base, followed by
intramolecular substitution of trimethylamine, that gave the
parent compound.14 After fortyꢀfour years, oꢀQM intermediates
65
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intermediate to produce oꢀQM in situ. Michael addition of 40 dichloromethane afforded acetoxy derivative 8, in 97% yield.
different C, N, O and S nucleophiles to the transient oꢀQM
species gave a higher substituted phenoxide anion intermediate
which cyclised to the final product by intramolecular 5ꢀexo-tet
elimination of bromide anion.18b
This reaction was similar to that used for the acetylation of
mesitol.21 In order to verify the feasibility of transforming acetate
8 into dihydrobenzofuran 9 (Scheme 1), acetate 8 was treated
with pyrrolidine in THF at −78 °C followed by dropwise addition
5
In view of our continuing interest in 2,3ꢀdihydrobenzofurans as 45 of TBAF at −78 °C. The reaction did not afford
pharmacologically active substances and due to the lack of a
versatile and efficient method of introducing variable substitution
at position 3 of the 2ꢀsubstituted 2,3ꢀdihydrobenzofurans, we now
dihydrobenzofuran 9 but instead benzofuran 10 was isolated in
89% yield.
When the reaction of compound 8 was repeated with
pyrrolidine in THF but this time dropwise addition of TBAF at
10 present an application of our novel method for generating an oꢀ
QM and trapping with N, O, and S nucleophiles by using 8, 14 50 either 0 °C or at room temperature, compound 10 was obtained in
and 18 as precursors and incorporating into the oneꢀpot reaction
an intramolecular 5ꢀexoꢀtet elimination process, to afford 2,3ꢀ
disubstituted 2,3ꢀdihydrobenzofurans.
85% and 72% yield, respectively. Also, reaction of compound 8
with methyl thioglycolate in THF at −78 °C followed by
dropwise addition of TBAF gave compound 10 in 84% yield.
Furthermore, by using methanol both as nucleophile and solvent
55 the reaction at −78 °C with dropwise addition of TBAF afforded
compound 10 in 92% yield (Table 1). From the yields of
compound 10 obtained in these reactions, it is reasonable to
conclude that at −78 °C the oꢀQM intermediate 11 formed
(Scheme 2) is more stable than at higher temperatures. On the
60 other hand, the acetoxy anion has been proved to serve as a good
leaving group during the generation of oꢀQMs, as described from
precursors such as acetic acid 4ꢀacetoxyꢀ2ꢀhydroxyꢀ6ꢀ
methylbenzyl ester and acetic acid 5ꢀbenzylꢀ2ꢀ(tertꢀ
butyldimethylsilanyloxy)benzyl ester, during the synthesis of
65 natural product Alboatrin22 and bioactive Puupehedione,23
respectively. In these precursors, hydrogen bonding such as that
proposed between the carbonyl oxygen and the αꢀhydrogen atom
of the ester group of compound 8 (Scheme 2) and its role in
abstracting this proton, are not feasible.
15
Results and discussion
Herein, we report a simple synthesis of 2,3ꢀdisubstituted 2,3ꢀ
dihydrobenzofurans from commercially available starting
materials via the generation of an appropriate oꢀQM in situ. To
20 accomplish this goal we planned the synthesis of oꢀQM precursor
8 from 2ꢀhydroxybenzaldehyde 4. Compound 8 was designed so
that after fluorideꢀinduced cleavage of the TIPS protecting group,
elimination of acetoxy anion and oꢀQM generation, nucleophilic
addition of a nucleophile (RH) to the oꢀQM 11a (Path b, Scheme
25 2) would lead to phenoxide anion 12a that could cyclise by
bromo anion elimination to afford 2,3ꢀdisubstituted 2,3ꢀ
dihydrobenzofurans 13a. For the synthesis of compound 8
(Scheme 1), compound 4 was converted to the acrylate 5 by a
Wittig condensation19 that is, treating 4 with triphenyl phosphine
30 and ethyl bromoacetate in water. Acrylate 5 was obtained in 84%
yield. The hydroxy group of 5 was then protected by introducing
a triisopropylsilyl group using TIPSCl, DMAP, and (iꢀPr)2NH in
dichloromethane, to afford 6 in 90% yield. The latter was then
reacted with Nꢀbromosuccinimide20 and water to give
35 bromohydrin derivative 7, in 78% yield. Acetylation of alcohol 7
with acetic anhydride and a catalytic amount of DMAP in
70 Table 1 Synthesis of ethyl 1ꢀbenzofuranꢀ2ꢀcarboxylate 10 using a N, O
or S nucleophile.
Product
Yielda
Entry
1
RH
89% at ꢀ78 °C
85% at 0 °C
72% at rt
CO2Et
CO2Et
NH
O
O
10
10
10
SH
2
3
84% at ꢀ78 °C
92% at ꢀ78 °C
COOEt
COOEt
COOMe
TIPSCl, HN(i-Pr)2
DMAP, CH2Cl2
CHO
OH
BrCH2COOEt
PPh3, LiOH
LiCl, water
90%
OH
OTIPS
CH3OHb
CO2Et
reflux, 15 min
O
4
5
6
84%
THF-water
(1:1)
NBS
aIsolated yields. bInstead of using THF as a solvent, methanol was used.
78%
Br
CO2Et
Br
COOEt
The outcome of this reaction can be explained on the basis of
75 the proposed mechanism depicted in Scheme 2. The first step of
the reaction involves cleavage of the Si–O σꢀbond of compound 8
by fluoride ion followed by conjugation by a loneꢀpair of the
negatively charged oxygen atom into the aromatic ring and
elimination of acetic acid (Path a). The prerequisite for
80 elimination of acetic acid is a strong hydrogen bond between the
carbonyl oxygen of the acetoxy group and the acidic proton of the
tertiary carbon atom bonded to a bromine atom and an ester
group. The carbanion of the resulting intermediate 11 is stabilised
by the aforementioned electronꢀwithdrawing groups but more
85 stability is provided to the molecule when it aromatises by
conjugation to give intermediate phenoxide 12. The alkene πꢀ
pyrrolidine
TBAF,THF
-78 °C
Ac2O, DMAP
CH2Cl2, 97%
OAc
OH
CO2Et
O
89%
OTIPS
OTIPS
10
8
7
pyrrolidine
TBAF,THF
-78 °C
N
CO2Et
O
9
Scheme 1 Attempted synthesis of ethyl 3ꢀpyrrolidinꢀ1ꢀylꢀ2,3ꢀdihydroꢀ1ꢀ
benzofuranꢀ2ꢀcarboxylate 9.
2
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electrons of the styrene moiety of 12 are displaced by conjugation
yield.
into the aromatic benzene ring as the charged oxygen atom of the
molecule approaches the carbon atom bearing the bromine atom
In order to test the applicability of this reaction it was repeated
using methyl thioglycolate instead of pyrrolidine. The only
and ester group. The resulting intermediate carbanion 13 is 35 product isolated was the trans isomer of the dihydrobenzofuran
5
stabilized by conjugation but further stabilization is delivered by
the exoꢀtet elimination of bromine ion and the formation of the
fully aromatic benzofuran 10. A similar type of cyclisation has
been described by Mérour and coꢀworkers.24
16, obtained in 59% yield (Scheme 4). A third nucleophile,
methanol, was used also as solvent. By dissolving compound 14
in methanol lowering the temperature to −78 °C and then adding
TBAF dropwise at −78 °C, two products were obtained after
40 separation
by
column
chromatography,
the
trans
a
dihydrobenzofuran 17a and the cis dihydrobenzofuran 17b in
16% and 19% yield, respectively. The formation of the trans 17a
and cis 17b isomers in the case of methanol being used as
nucleophile in contrast to the formation of trans 9 and trans 16
45 isomers in the case of pyrrolidine and methyl thioglycolate being
used as nucleophiles, respectively, is probably due to the smaller
size of methanol relative to pyrrolidine and methyl thioglycolate,
allowing nucleophilic attack by methanol on both planes of the
methide βꢀcarbon atom of the planar oꢀQM intermediate.
OAc
O
O
. .
RH
Br
a
a
b
a
Path b
H
RH
H
H
CO2Et
CO2Et
CO2Et
Br
Br
TBAF
THF
-78 °C
O
O
O
Si(i-Pr)3
Si(i-Pr)3
..
F
Bu4N
11a
..
8
8
Path a
R
Br
CO2Et
Br
Br
..
CO2Et
CO2Et
O
O
O
12a
11
12
R
CO2Et
Br
CO2Et
CO2Et
O
O
O
13a
13
10
10 Scheme 2. Proposed mechanism for the synthesis of ethyl 1ꢀbenzofuranꢀ
2ꢀcarboxylate 10.
50
The failure of obtaining compound 9 from compound 8 led us
to change the acetoxy group on compound 8 to a chloro atom, as
on benzyl chloride derivative 14 (Scheme 3), in the hope that
15 after treating the latter with TBAF cleavage of the Si−O σꢀbond
would occur leading to chloride anion elimination and oꢀQM
generation. Compound 14, obtained in 90% yield by heating
benzyl alcohol derivative 7 in neat thionyl chloride at 65 oC, was
then treated with pyrrolidine in THF at −78 °C followed by
20 dropwise addition of TBAF at −78 °C, to afford trans
dihydrobenzofuran 9 in 54% yield. In this reaction (Scheme 3), it
is proposed that cleavage of the Si–O σꢀbond of compound 14 by
fluoride ion and conjugation of the oxygen atom loneꢀpair into
the aromatic ring with concomitant elimination of chloride anion,
25 generates oꢀQM 11a. The latter undergoes Michael addition by
pyrrolidine and the resulting phenoxide intermediate 15 cyclises
via an exo-tet elimination of a bromide anion to afford the trans
isomer of dihydrobenzofuran 9, as the only product and in 54%
Scheme 4 Synthesis of dihydrobenzofurans 16 and 17 from propanoate
14 using methyl thioglycolate and methanol as nucleophiles.
In order to compare the efficiency of the nitrate anion,
compared to the chloride anion, as leaving group during the
55 generation of the oꢀQM, the nitrate ester 18 was prepared from
the dihalo compound 14 using a method reported by Lehmann
and coꢀworkers.25 Compound 14 was stirred overnight with 2
equivalents of silver nitrate in acetonitrile to afford
regioselectively nitrate ester 18, in 96% yield. This reaction
60 occurred most probably via an SN1 mechanism involving
elimination of chloride anion and formation of a stabilized
benzylic carbocation prior to addition by the nitrate anion. The
14
AgNO3
MeCN
95%
CO2Me
Br
COOEt
ONO2
S
N
HSCH2CO2Me
pyrrolidine
COOEt
COOEt
TBAF, THF
-78 °C
TBAF,THF
-78 °C
O
O
OTIPS
76%
84%
16
18
9
TBAF
MeOH
-78 °C
OCH3
OCH3
COOEt
COOEt
+
O
O
17b 43%
17a 37%
Scheme 5 Synthesis of dihdrobenzofurans 9, 16 and 17 from ethyl 2ꢀ
65 bromoꢀ3ꢀ(nitrooxy)ꢀ3ꢀ{2ꢀ[(triisopropylsilyl)oxy]phenyl}propanoate
using pyrrolidine, methyl thioglycolate and methanol as nucleophiles.
18
30 Scheme 3 Synthesis of ethyl 3ꢀpyrrolidinꢀ1ꢀylꢀ2,3ꢀdihydrobenzofuranꢀ2ꢀ
carboxylate 9.
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nitrate ester 18 in THF at −78 °C in the presence of pyrrolidine or
methyl thioglycolate and the nitrate ester 18 in methanol at −78
°C were then subjected to dropwise addition of TBAF. These
reactions led to the isolation of the corresponding 2,3ꢀ
disubstituted 2,3ꢀdihydrobenzofurans 9, 16, 17a and 17b, in 76,
84, 37 and 43% yields, respectively (Scheme 5). The yields of
dihydrobenzofurans 9, 16, 17a and 17b using propanoate 18 as
starting material are much higher than the corresponding yields
using propanoate 14. This confirms the higher efficiency of the
3. (a) Y. L. Lin, C. N. Wang, Y. J. Shiao, T. Y. Liu and W. Y. Want, J.
5
60
Chin. Chem. Soc., 2003, 50, 1079; (b) I. S. AbdꢀElazem, H. S. Chen,
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65 6. Y. Cheng, X.ꢀQ. Hu, S. Gao, L.ꢀQ. Lu, J.ꢀR. Chen and W.ꢀJ. Xiao,
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Nambu and S. Hashimoto, Synlett, 2014, 25, 288.
10 nitrate anion, compared to the chloride anion, as leaving group
during the generation of the oꢀQMs in the aforementioned
reactions.
The novelty of this method resides in the cascade reaction that
involves Si−O and C−ONO2 (or less efficiently C−Cl) bond
15 cleavage leading to oꢀQM generation, followed by
C−N/C−O/C−S bond formation, C−Br bond cleavage and C−O
bond formation that leads to ring closure. The advantage of oneꢀ
pot cascade reactions over stepwise reactions is their economy in
solvents, reagents, adsorbents and energy.26
70 9. K. Hata, Z. He, C. G Daniliuc, K. Itami and A. Studer, Chem.
Commun., 2014, 50, 463.
10. T. Shibuta, S. Sato, M. Shibuya, N. Kanoh, T. Taniguchi, K. Monde
and Y. Iwabuchi, Heterocycles, 2014, 89, 631.
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75
and A. D. Smith, Chem. Eur. J., 2014, 20, 9762; (b) S. Jiang, B. Hu,
X. Yu and W. Deng, Chin. J. Chem., 2014, 32, 694.
12. P.ꢀY. Chen, Y.ꢀH Wu, M.ꢀH. Hsu, T.ꢀP. Wang and E.ꢀC. Wang,
Tetrahedron, 2013, 69, 653.
13. S. Malik, U. K. Nadir and P. S. Pandey, Tetrahedron, 2009, 65, 3918.
20 Conclusions
80 14. E. Breuer and D. Melumad, Tetrahedron Lett., 1969, 10, 1875.
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2013, 78, 5505.
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Chem. Commun., 2013, 49, 1660.
85 17. B. Wu, M.ꢀW. Chen, Z.ꢀS. Ye, C.ꢀB. Yu and Y.ꢀG. Zhou, Adv. Synth.
Catal., 2014, 356, 383.
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14, 584; (b) A. K. Shaikh and G. Varvounis, Org. Lett., 2014, 16,
1478.
In conclusion, we have presented a new oneꢀpot cascade
regioselective synthesis of trans or cis/trans 2,3ꢀdisubstituted 2,3ꢀ
dihydrobenzofurans from either ethyl 2ꢀbromoꢀ3ꢀchloroꢀ3ꢀ{2ꢀ
[(triꢀisopropylsilyl)oxy]phenyl}propanoate or ethyl 2ꢀbromoꢀ3ꢀ
25 (nitrooxy)ꢀ3ꢀ{2ꢀ[(triisopropylsilyl)oxy]phenyl}propanoate,
the
latter providing higher yields of products. The reaction takes
place by fluorideꢀinduced Si−O σꢀbond cleavage from nꢀ
tetrabutylammonium fluoride followed by chloride anion or
nitrate anion elimination to generate the corresponding oꢀQM
30 intermediate. Michael addition of a N, O or S nucleophile to the
oꢀQM gives a phenoxide anion intermediate which undergoes
intramolecular 5ꢀexoꢀtet elimination of a bromide anion to afford
the respective trans or cis/trans 2,3ꢀdisubstituted 2,3ꢀdihydroꢀ
benzofuran. Similar reactions using ethyl 3ꢀ(acetyloxy)ꢀ2ꢀbromoꢀ
90 19. J. Wu and C. Yue, Syn. Comm., 2006, 36, 2939.
20. S. Bar, Can. J. Chem., 2010, 88, 605.
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Helv. Chim. Acta, 2001, 84, 2198.
35 3ꢀ{2ꢀ[(triisopropylsilyl)oxy]phenyl}propanoate
as
starting
material gives only the fully aromatic parent benzofuran. The
methodology described will be useful in the synthesis of natural
products and pharmacologically active compounds.
100 25. C. Webler, A. Homann, U. Fricke, J. Lehmann, Eur. J. Med. Chem.
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Acknowledgements
40 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. A.
45 Karkabounas, of the University of Ioannina, for NMR and mass
spectra, respectively.
Notes and references
Section of Organic Chemistry and Biochemistry, Department of
Chemistry, University of Ioannina, 451 10 Ioannina, Greece;
50 E-mail: gvarvoun@cc.uoi.gr
† Electronic Supplementary Information (ESI) available:
1
[Experimental details, characterization data, H and 13C NMR
spectra for all new compounds]. See DOI: 10.1039/b000000x/
4
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A simple and efficient one-pot cascade reaction for the regioselective synthesis of trans or
cis/trans-2,3-disubstituted 2,3-dihydrobenzofurans, is described.
Nu
Nu
Br
CO2Et
CO2Et
Nu
O
O
Br
CO2Et
O
X
Br
CO2Et
O
Si(iPr)3
F