Stereoselective synthesis of 2,3-disubstituted dihydrobenzofuran using alkyne Prins type cyclization to vinylogous carbonates

Article abstract of DOI:10.1007/s12039-011-0162-8

An intramolecular, alkyne Prins type cyclization of vinylogous carbonates derived from o-alkynyl phenols is developed for the stereoselective construction of trans-2,3-disubstituted dihydrobenzofuran derivatives. Strong Lewis acids like TMSOTf catalyse th

Full text of DOI:10.1007/s12039-011-0162-8

c
J. Chem. Sci. Vol. 123, No. 6, November 2011, pp. 943–949. ꢀ Indian Academy of Sciences.
Stereoselective synthesis of 2,3-disubstituted dihydrobenzofuran using
alkyne Prins type cyclization to vinylogous carbonates
SANTOSH J GHARPURE∗ and V PRASATH
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, India
e-mail: sjgharpure@iitm.ac.in
Abstract. An intramolecular, alkyne Prins type cyclization of vinylogous carbonates derived from o-alkynyl
phenols is developed for the stereoselective construction of trans-2,3-disubstituted dihydrobenzofuran deriva-
tives. Strong Lewis acids like TMSOTf catalyse this reaction efficiently. The presence of mildly electron
donating groups on aryl rings increases the efficiency of the reaction.
Keywords. Vinylogous carbonates; Prins cyclization; Lewis acids; Sonogashira coupling.
1. Introduction
for developing highly diastereoselective strategies for
this important class of molecules. Over the years,
Prins cyclization has emerged as a useful method for
the synthesis of tetrahydropyrans (THPs) and tetrahy-
drofurans (THFs).16 Vinylogous carbonate, which has
proved to be excellent functional group for the synthe-
sis of cyclic ethers under radical17 and anionic con-
ditions,18 has also been found to be useful in the
Lewis/Bronsted acid mediated Prins cyclization lead-
ing to THP derivatives.19 Even though most of the
efforts on Prins cyclization used olefins; alkynes too
have been shown to participate efficiently in the synthe-
sis of THFs and THPs.20 In continuation of our inter-
est on using vinylogous carbonates in the synthesis
of cyclic ethers,21 particularly under non-radical con-
ditions,22 we describe here an efficient and a highly
diastereoselective synthesis of trans-2,3-disubstituted
dihydrobenzofuran employing alkyne Prins cyclization
to vinylogous carbonates.
2,3-Disubstituted dihydrobenzofuran moiety is ubiqui-
tous in nature and molecules possessing this skeleton
display remarkably diverse biological activity. Many
of these natural products are constituents of traditional
medicines and have been implicated with diverse bio-
logical activity such as antimicrobial,1 antioxidant,2
antimitotic,3 antiangiogenic,4 neuritogenic5 and even
HIV integrase inhibition activity.6 As a result, a varie-
ty of methods have been developed over the years
for the stereoselective synthesis of this motif.7 Acid
catalysed [3 + 2] cycloaddition of styrene derivatives
with quinones,8 cyclodehydration of hydroxyphe-
nols,9 anion or radical induced cyclization of sub-
stituted iodophenols,10 Rh(I) catalysed catalytic C–H
insertion,11 reactions of 2-hydroxyaryl-α,β-unsaturated
ketones with dimethylsulfonium carbonylmethylides,12
Pd-catalysed cyclizations13 and reduction of benzofu-
rans14 are some of the prominent methods used for
the synthesis of 2,3-disubstituted dihydrobenzofurans.
Chiral Rh(II)-catalysed intramolecular C–H insertion
reaction has also been reported for enantioselective syn-
thesis of this motif.15 Though majority of these methods
give access to cis isomer of 2,3-disubstituted dihy-
drobenzofuran, it is the trans isomer which is more
prevalent in many of the natural products. All these
methods have their advantages but many suffer from
moderate diastereoselectivity. Thus, there is still need
2. Results and discussion
Recently, Cho et al. reported TMSOTf mediated
synthesis of 5- and 6-exocyclic products, cis-2,3,5-
trisubstituted THFs, and cis-2,3,6-trisubstituted THPs
by Prins type reaction between terminally substituted
alkynyl alcohols and aldehydes.20 When this type of
reaction was attempted by them with 2-alkynylphenols
1 with aldehydes 2 in the presence of TMSOTf, it gene-
rated the chalcones 3, chroman-4-ones 4 and hydrated
products 5 depending on the substituent on the alkyne
in moderate yields (scheme 1).23 These products are
∗For correspondence
943

944
Santosh J Gharpure and V Prasath
Scheme 1. TMSOTf-Promoted addition of alkynes to aldehydes.
Scheme 2. Retrosynthesis for 2,3-disubstituted dihydrobenzofurans.
Scheme 3. Synthesis of the vinylogous carbonate 7a.
formed by the reaction of alkyne directly with the alde- Prins type cyclization. However, this oxonium ion gene-
hyde rather than by formation of oxonium ion from phe- ration by intermolecular reaction of a phenol and an
nol and aldehyde followed by subsequent cyclization.
aldehyde is non-trivial. To circumvent this problem, we
We envisioned that if the phenolic OH of 2- argued that the 2,3-disubstituted dihydrobenzofurans 6
alkynylphenol is engaged in the reaction for generating could be readily assembled by carrying out intramole-
oxonium ion in the presence of Lewis acid, the reaction cular alkyne Prins cyclization of the alkynyl vinylo-
could lead to 2,3-disubstituted dihydrobenzofuran via a gous carbonates 7 using an appropriate Lewis acid
Table 1. Optimization of the alkyne Prins cyclization for the synthesis of 2,3-
disubstituted dihydrobenzofurans.
S.No
Lewis acid
Equiv.
Time (h)
Yield (%)a
d.r.b
1
2
3
4
5
6
7
BF3·OEt2
TMSOTf
TMSOTf
TiCl4
FeCl3
CF3SO3H
CF3CO2H
1.1
1.1
1.8
1.1
1.1
1.1
1.1
24
6
5
15
24
15
24
74
79
65
30
0c
(≥19:1)
(≥19:1)
(≥19:1)
(≥19:1)
-
44
(≥19:1)
0c
-
b
1
c
aIsolated yield. Determined on crude reaction mixture by H NMR. Unreacted
starting material recovered

Stereoselective synthesis of 2,3-disubstituted dihydrobenzofuran using alkyne Prins type cyclization
945
Table 2. Synthesis of the iodo vinylogous carbonates 8.
Sr. No.
R1
R2
Product
Yield (%)a
1.
2.
3.
4.
5.
Me
t Bu
Cl
Ph
C4H4
H
H
H
H
C4H4
8b
8c
8d
8e
8f
89
87
90
64b
90
aIsolated yield. b24% of cis isomer of vinylogous carbonate was also obtained
(scheme 2). It was rationalized that the vinylogous are not good for effecting this alkyne Prins cycliza-
carbonate moiety derived from phenol will serve as tion and hence TMSOTf was chosen as the catalyst
a surrogate for oxonium ion. The alkynyl vinylogous of choice for further study. The structure of the dihy-
carbonates 7 in turn can be synthesized from the corres- drobenzofuran derivative 6a rests secured from its spec-
ponding iodides 8 by Sonogashira coupling reaction. tral data.1 The stereochemistry of dihydrobenzofuran 6a
The o-iodo vinylogous carbonates 8 can be obtained was ascertained as trans, based on coupling constants of
from substituted o-iodophenol derivatives 9.
H2 and H3 protons (J = 6.3 Hz) which was comparable
To test the hypothesis, synthesis of the alkyne 7a with that reported earlier for similar compounds. Fur-
was initiated. Thus, reaction of o-iodophenol (9a) with ther support was provided by the NOE studies in which
ethyl propiolate in the presence of N-methylmorpholine irradiation of H3 proton resulted in enhancement in
(NMM) gave the o-iodo vinylogous carbonate 8a in the CH2CO2Et intensity and vice versa (see supporting
good yield. The iodo vinylogous carbonate 8a was information).
then subjected to Pd catalysed Sonogashira coupling
reaction to furnish the enyne 7a in excellent yield for the synthesis of trans-2,3-disubstituted dihydroben-
(scheme 3). zofurans, synthesis of various vinylogous carbonates 8
To study the scope of this alkyne Prins cyclization
The feasibility of the envisaged intramolecular was undertaken. Various iodophenols 9 were subjected
alkyne Prins cyclization of enyne 7a was studied next to Michael addition with ethyl propiolate to give the
using various Lewis acids. Reaction of the enyne 7a corresponding o-iodo vinylogous carbonates 8 (table 2).
with BF3·OEt2 in CH2Cl2 at 0◦C gratifyingly gave the In general, the formation of iodo vinylogous carbon-
2,3-disubstituted dihydrobenzofuran 6a in good yield ates 8 was uneventful and in all the cases excellent
and excellent diastereoselectivity (table 1, entry 1). The yields were obtained. Only in the case of the iodophe-
reaction time was substantially reduced when TMSOTf nol 9e, the reaction led to formation of a mixture of
was used as the Lewis acid for effecting this transfor- cis and trans vinylogous carbonates 8e which could be
mation with slight increase in yield (table 1, entry 2). separated by column chromatography on silica gel.
Increasing the amount of TMSOTf did not show further
Table 3 describes the scope of this intramolecular
improvements in the reaction time or the yield (table 1, alkyne Prins cyclization to vinylogous carbonates. In all
entry 3). When TiCl4 was used to promote the reac- the cases, the requisite alkynyl vinylogous carbonates 7
tion, it resulted in the formation of dihydrobenozofu- were prepared by Sonogashira coupling of the iodide 8
ran 6a in only 30% yield; whereas FeCl3 was found with aryl acetylene 10 using Pd(OAc)2/PPh3/CuI as the
to be ineffective in this reaction (table 1, entries 4– catalyst. In general, the reaction proceeded smoothly
5). While a strong Bronsted acid like CF3SO3H gave furnishing the coupling products 7.
moderate yield albeit with good diastereoselectivity, the
milder trifluoroacetic acid failed to promote the alkyne
Prins cyclization (table 1, entries 6–7). Based on these
results it was clear that mild Lewis or Bronsted acids
1
All the compounds exhibited spectral data consistent with their structures,
see supporting information.

946
Santosh J Gharpure and V Prasath
Table 3. Scope of the alkyne Prins cyclization for the synthesis of 2,3-disubstituted dihydrobenzofurans.
S. No.
Iodide vinylogous carbonate (8)
Aryl acytelene (10)
Yield(%)a
Dihydrobenzofuran (6)b
Step I
Step II
1
2
3
8b
8c
8d
C6H5CCH
C6H5CCH
C6H5CCH
82
83
90
53
60
35
4
5
8e
8f
C6H5CCH
C6H5CCH
87
88
53
81
6
7
8
8a
8b
8c
p-MeC6H4CCH
p-MeC6H4CCH
p-MeC6H4CCH
92
86
91
69
64
62

Stereoselective synthesis of 2,3-disubstituted dihydrobenzofuran using alkyne Prins type cyclization
Table 3. (continued).
947
S. No.
Iodide vinylogous carbonate (8)
Aryl acytelene (10)
Yield(%)a
Step I Step II
Dihydrobenzofuran (6)b
9
8d
p-MeC6H4CCH
80
55
10
11
8e
8f
p-MeC6H4CCH
p-MeC6H4CCH
85
91
36
67
O
CO2Et
Me
O
6l
12
13
8a
8a
p-(MeO)C6H4CCH
p-(CN)6H4CCH
85
83
0c
0c
aIsolated yields. bd.r. was determined on crude reaction mixture by 1H NMR and found to be ≥19:1 in all cases.
cDecomposition during the reaction
The alkyne Prins cyclization was studied on these
Formation of the 2,3-disubstituted dihydrobenzofu-
alkynyl vinylogous carbonates 7. The reaction was ran can be explained with the help of the mechanism
found to work very well with mildly electron donat- as shown in figure 1. Initially, the carbonyl group of
ing alkyl substituents on any of the aryl rings (table 3, the vinylogous carbonate moiety complexes with the
entries 1–2 and 6–8). The presence of electron with- Lewis acid leading to the formation of the oxonium
drawing chlorine on one of the aryl ring led to the for- ion 10. This oxonium ion 10 is trapped by alkyne
mation of the product in moderate yield (table 3, entry in a Prins type reaction generating a vinyl cation 11.
4). Interestingly, when a methyl substituent was intro- The vinyl cation 11 gets trapped with water during
duced in the other aryl ring, the yield of the reaction the work-up generating enol 12 which on tautomeriza-
showed some improvement (table 3, entry 9). Phenyl tion generates the 2,3-disubstituted dihydrobenzofuran
substitution on the aryl ring in general resulted in the 6. Formation of trans isomer during tautomerization is
moderate efficiency (table 3, entries 4 and 10); whereas perhaps the outcome of the protonation event which
the naphthyl ring bearing substrates furnished the dihy- happens in such a way so as to minimize steric repul-
drobenzofurans 6f and 6l in excellent yields. Interest- sion between the substituents on C2 and C3 of the dihy-
ingly, the presence of relatively stronger electron releas- drobenzofuran moiety. It is pertinent to mention that
ing (OMe) or electron withdrawing group (CN) in one changing the solvent from CH2Cl2 to ether did not result
of the aryl ring led to extensive decomposition and no in formation of triflate derivative by trapping of vinyl
dihydrobenzofuran formation could be detected (table cation 11 with the triflate ion as observed by Cho and
3, entries 12–13).
co-workers.

948
Santosh J Gharpure and V Prasath
Figure 1. Mechanism of formation for trans-2,3-disusbstituted dihydrobenzofuran.
3. Conclusion
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We thank the Department of Science and Technology
(DST) and Council of Scientific and Industrial Research
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ate the NMR facility provided by the DST under the
IRPHA program to the Department of Chemistry, IIT
Madras. We are grateful to CSIR, New Delhi for the
award of a research fellowship to VP.

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