A new approach to fused furan ring systems and benzofurans: Intramolecular cyclization reactions of unsaturated acyloxy sulfone derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.03.120

Unsaturated acyloxy sulfones 3 undergo intramolecular cyclization upon deprotonation with LHMDS in THF. Dehydration and double bond isomerization of the products upon exposure to acid, gave the fused ring furans, 4, in good yields. This strategy could be

Full text of DOI:10.1016/j.tetlet.2011.03.120

Tetrahedron Letters 52 (2011) 2935–2939
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A new approach to fused furan ring systems and benzofurans: intramolecular
cyclization reactions of unsaturated acyloxy sulfone derivatives
⇑
Yuan Liu, Hollie K. Jacobs, Aravamudan S. Gopalan
Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM 88003-8001, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Unsaturated acyloxy sulfones 3 undergo intramolecular cyclization upon deprotonation with LHMDS in
THF. Dehydration and double bond isomerization of the products upon exposure to acid, gave the fused
ring furans, 4, in good yields. This strategy could be readily adapted to prepare substituted benzofurans
12 from the cyclization reactions of acyloxy sulfones 11 prepared from phenols. Finally, this approach
could be successfully modified to access dihydropyrans and benzopyrans.
Received 7 March 2011
Revised 17 March 2011
Accepted 23 March 2011
Available online 1 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Intramolecular cyclization
Fused furan rings
Benzofurans
Annulation
Acyloxy sulfone
Methods for the synthesis of fused furan ring systems have been
of much interest over the years.1 The interest in this area has been
partly stimulated by the occurrence of a number of furanosesqui-
terpene natural products2 having interesting structural skeletons
such as pallescensin A, tubipofurane, and echinofuran. Attesting
to this interest is a recent total synthesis of pallascensin A, in
which the annulation of the furan ring to a functionalized decalone
was accomplished by reaction of dichlorocarbene with the enol
ether of the decalone followed by treatment of the dichlorocyclo-
propane intermediate with base.3 Another route that was recently
disclosed to fused furan ring systems used Au(III) to catalyze the
cycloisomerization of 2-alkynylcycloalk-2-enols.4
The benzofuran scaffold has been identified as a ‘privileged
structure’ in medicinal chemistry.5 Members of this class of com-
pounds have shown biological activities ranging from antifungal
and antimicrobial to antagonists for the H3 receptor and angioten-
sin II.6 Hence the syntheses of benzofurans have received much
greater attention and a number of different synthetic routes have
been reported to access this class of molecules.7 Recently, the syn-
thesis of 3-alkenylbenzofurans has been achieved using tandem
palladium catalyzed oxidative cyclization followed by Heck
coupling with unsaturated carbonyl substrates.8 Another approach
involves intramolecular Wittig cyclization on a phenolic ester fol-
lowed by elimination of triphenylphosphine oxide to give the ben-
zofuran.9 Recently, polycyclic fused benzofurans were prepared by
a TiCl4 mediated Baylis–Hillman reaction of aromatic cyclic 1,2-
diones with cycloalkenones followed by cyclization of the interme-
diates with methanesulfonic acid.10 An interesting solid phase syn-
thesis that involves the intramolecular alkylation of an aryloxy
sulfonyl carbanion on an epoxide to generate an intermediate that
loses formaldehyde and sulfinate to generate 3-arylbenzofuran
ring systems has been reported.11 Another approach to substituted
furans involves the deprotonation and subsequent reaction of a re-
sin bound
c-methoxy allyl sulfone with aldehydes, followed by
ring closure to the furan ring system accompanied by cleavage
from the solid support upon treatment with acid.12
Given the importance and interest in the synthesis of fused
furan ring systems, we thought that a general method to annulate
furan ring systems onto readily accessible cycloalkenones would
be a valuable method that would complement existing methodol-
ogies. The plan was to take advantage of some of our earlier work
on the intramolecular cyclization reactions of
c and d acyloxy sulf-
ones which was used to prepare a variety of chiral nonracemic
O
O
O
O
R'
R'
EWG
R
R
R
O
EWG
A
Fused-ring furans
O
R'
EWG
O
R'
X
X
EWG
Benzofurans
Scheme 1.
B
⇑
Corresponding author. Tel.: +1 575 646 2589; fax: +1 575 646 2649.
E-mail address: agopalan@nmsu.edu (A.S. Gopalan).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.120

2936
Y. Liu et al. / Tetrahedron Letters 52 (2011) 2935–2939
2 eq. HCHO (37% aq.)
2 eq. PhSO2Na
2 eq. AcOH, EtOH,
reflux, 3 d, 54%
We decided to demonstrate the viability of this annulation
O
O
method using commercially available 2-cyclohexenone as the
model starting material and a sulfone group as the EWG. The con-
version of cyclohexenone to ketosulfone 1 by a two-step procedure
that involves initial formation of a sulfide followed by its oxidation
to sulfone [(i) benzenethiol, HCHO, Et3N, EtOH, reflux, 5 d; (ii) ox-
one] has been reported.14,15 However, we found that the desired
ketosulfone 1 could be obtained directly in one step by treatment
of 2-cyclohexen-1-one with 2 equiv each of formaldehyde (37%
aqueous solution), sodium benzenesulfinate and acetic acid in eth-
anol at reflux for 3 days (Scheme 2). Acetic acid is a required re-
agent for the formation of the desired product. Subsequently, the
reduction of 1 using DIBALH in dichloromethane at 0 °C, gave the
unsaturated hydroxysulfone 2 in 82% yield after purification. A
variety of acyloxy sulfones, 3, were prepared in good yields by
treating 2 with 1.2 equiv of the desired acid chloride in CH2Cl2 in
the presence of triethylamine as base (Table 1). In some cases,
the yields of the desired esters were low when triethyl amine
was used as base. For those substrates, the yields were greatly im-
proved by using pyridine as base in dichloromethane in the pres-
ence of a catalytic amount (12 mol %) of polystyrene supported-
DMAP16 in place of triethylamine.17
SO2Ph
1
1.5 eq DIBALH,
CH2Cl2, 0°C,
5 h, 82%
O
1.2 eq. RCOCl, CH2Cl2,
5 eq. Et3N or
2.5 eq. pyridine,
OH
O
R
SO2Ph
SO2Ph cat. PS-DMAP
2
3
Scheme 2.
dihydrofurans/pyrans.13 Our proposed synthetic approach to fused
furan ring systems and benzofurans is shown in Scheme 1. In the
key step, we hypothesized that the intramolecular cyclization of
carbanions derived from substrates of the type A having a strong
electron withdrawing moiety, would proceed to give a lactol that
would dehydrate and isomerize to give the furan ring. We also
hypothesized that similar chemistry with type B substrates would
lead to a useful synthesis of benzofurans. In this publication, we re-
port that acyloxy sulfones of the type A and B, undergo efficient
intramolecular cyclization reactions and provide a new method
for the preparation of functionalized fused furan ring systems
and benzofurans.
With the unsaturated acyloxy sulfones 3 in hand, their intramo-
lecular cyclization reactions were examined. The sulfone 3a was
Table 1
Synthesis of fused ring furans 4 via intramolecular cyclization of acyloxy sulfones 3
O
1. 1.1 eq. LHMDS, THF, -78°C to rt
2. p-TsOH, benzene, rt
1.2 eq. RCOCl,
CH2Cl2, base
R
2
3
SO2Ph
4
Entry
1
Acyl sulfone 3
Yield (%)
62a
Fused furan 4
Yield (%)
66
O
O
O
SO2Ph
SO2Ph
4a
3a
O
O
Ph
O
Ph
2
3
4
5
72a
70c
75
71
89
0
SO2Ph
SO2Ph
4b
3b
O
42a
88b
O
O
OEt
O
OEt
O
SO2Ph
SO2Ph
4c
3c
O
49a
80b
O
O
Cl
Cl
O
O
SO2Ph
SO2Ph
4d
3d
O
67b
SO2Ph
SO2Ph
4e
3e
O
O
6
69a
SO2Ph
3f
a
b
c
5.0 equiv Et3N as base.
2.5 equiv pyridine as base and polymer supported-DMAP (0.12 equiv).
Dehydration/isomerization step was carried out at 50 °C for 10 h.

Y. Liu et al. / Tetrahedron Letters 52 (2011) 2935–2939
2937
O
HO
R
R
R
O
R
OH
O
R
O
O
O
i. LHMDS, THF
ii. sat'd NH4Cl
p-TsOH
SO2Ph
SO2Ph
SO2Ph
+
SO2Ph
SO2Ph
3
4
Scheme 3.
mixture with a catalytic amount of p-TsOH leads to the dehydra-
tion of the lactol and isomerization of double bond, to give the
more stable furan ring.
OH
O
O
1.1 eq. DIBALH
CH2Cl2, 0 oC,
5h, 91%
SO2Ph
SO2Ph
Ref. 20
This methodology can easily be adapted to annulate pyran rings
onto cycloalkenones. The sulfone 519 was prepared following a lit-
erature procedure that involves a Baylis–Hillman reaction with vi-
nyl sulfone.20 The ketosulfone 5 was reduced by treatment with
DIBALH to the unsaturated hydroxysulfone 6 (Scheme 4), which
was then converted to the butanoyl derivative 7. Treatment of
unsaturated sulfone 7, with LHMDS using standard conditions fol-
lowed by dehydration of the intermediate product gave the dihyd-
ropyran product 8 in 72% yield after chromatographic purification.
The presence of the isolated double bond in the cyclohexane ring of
8 is a useful handle for further synthetic manipulation in this class
of intermediates.
6
5
5.5 eq. butyryl chloride
4.5 eq. Et3N,
CH2Cl2, 0°C to rt, 50%
O
1. 1.1 eq. LHMDS,
THF, -78 to 0 oC
O
O
SO2Ph
2. p-TsOH,
benzene, rt, 72%
SO2Ph
8
7
Scheme 4.
Having successfully demonstrated the usefulness of our meth-
odology for the synthesis of fused furans, its adaptation to the
preparation of benzofurans was very appealing. The first goal
was to develop a convenient synthetic route to the phenol 10
which could be converted to the acyloxy sulfones required for this
study (Scheme 5). Commercially available 2-(chloromethyl)-phe-
nyl acetate was treated with sodium benzenesulfinate in DMF at
room temperature to give the corresponding sulfone 9 in 86% yield
after chromatographic purification. In order to obtain the other
acyl derivatives, the acetate 9, was hydrolyzed using a 1:1 mixture
of saturated sodium bicarbonate/methanol to give phenol 10. The
acyloxy sulfones 11, were prepared by treatment of phenol 10 with
the desired acid chloride in the presence of pyridine and catalytic
polystyrene-DMAP in dichloromethane (Table 2).
The intramolecular cyclization reaction of sulfone 9 was first
examined (Table 2). Treatment of 9 with 1.5 equiv of LHMDS in
THF at À78 °C resulted in cyclization to give a mixture of the cor-
responding lactol/ketophenol as the products. The crude product
was treated with catalytic p-TsOH in refluxing benzene for 12 h
to give benzofuran 12a in 96% yield after purification. In contrast
to the synthesis of fused ring furans 4, the dehydration did not pro-
ceed at room temperature and required harsher conditions. The re-
sults of the cyclization of substrates 11b–11d (Table 2) clearly
deprotonated with 1.1 equiv of LHMDS at À78 °C in THF. The reac-
tion mixture was initially maintained at this temperature for 6 h
and then subsequently at room temperature for 20 h. After work
up, the desired products of the intramolecular cyclization, a diaste-
reomeric mixture of lactols and the corresponding open-chain
hydroxyketones (as evidenced by 1H NMR and IR spectra), was iso-
lated. When the crude reaction product was treated with a cata-
lytic amount of p-TsOH in benzene for 16 h at room temperature,
dehydration followed by isomerization occurred to give bicyclic
furan 4a in 66% yield after chromatographic purification (Table
1).18 In the case of the benzoate 3b, the intramolecular cyclization
proceeded smoothly but it was necessary to heat the intermediate
lactol/hydroxyketone mixture at 50 °C for 10 h to effect furan for-
mation. The intramolecular cyclization was found to tolerate a
variety of functionalized acyl groups (3c–3e) and in all cases the
substituted fused furans were obtained in good yields. An excep-
tion was the sensitive acrylate derivative 3f which did not undergo
the desired cyclization under the standard conditions. Presumably,
the starting material polymerized under the reaction conditions.
The generation of fused ring furans 4 could be rationalized by
the pathway shown in Scheme 3. It is important to point out that
the protons
on the methylene adjacent to the carbonyl of the acyl moiety. For-
mation of the carbanion to the sulfone followed by its reaction
a to the sulfone are of comparable acidity to those
a
with the acyl group gives a mixture of lactol and hydroxyketone
products after work-up.13 Treatment of the lactol/hydroxyketone
OH
OH
PhSO2Na,
DMF, rt, 64%
O
SO2Ph
I
Ref. 21
O
O
1.2 eq. PhSO2Na,
DMF, rt, 86%
O
O
CH3
Cl
O
CH3
SO2Ph
14
13
1.5 eq. butyryl chloride
2.5 eq. pyridine,
cat. PS-DMAP,
CH2Cl2, 0°C to rt, 91%
O
9
sat'd NaHCO3/
MeOH (1:1),
rt, 84%
1. 1.2 eq. LHMDS
THF, -78oC to rt
O
O
R
OH
O
1.2 eq. RCOCl
2.5 eq. pyridine
PS-DMAP (cat)
CH2Cl2, 0°C to rt
SO2Ph
SO2Ph
SO2Ph
SO2Ph
2. p-TsOH, benzene
reflux, 24 h, 63%
16
11
10
15
Scheme 5.
Scheme 6.

2938
Y. Liu et al. / Tetrahedron Letters 52 (2011) 2935–2939
Table 2
Synthesis of substituted benzofurans 12
O
1. 1.5 eq LHMDS, THF, -78°C, 5 h
2. p-TsOH, benzene or toluene, reflux
1.2 eq. RCOCl, 2.5 eq. pyridine
PS-DMAP (cat), CH2Cl2, 0°C to rt
R
10
11
12 SO2Ph
Entry
1
Acyloxy sulfone
Yield (%)
Benzofuran 12
Yield (%)
96a
O
O
O
_
SO2Ph
SO2Ph
O
12a
9
O
O
OEt
O
OEt
O
2
3
4
73
87
77
68b
63c
84c
SO2Ph
SO2Ph
12b
11b
O
O
O
Cl
Cl
O
O
SO2Ph
SO2Ph
O
12c
11c
SO2Ph
SO2Ph
12d
11d
a
b
c
Benzene, reflux, 12 h.
Benzene, reflux, 48 h.
Toluene, reflux, 16 h.
demonstrate the broad application of this method to prepare
substituted benzofurans.
References and notes
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We also examined the extension of this methodology to the
synthesis of benzopyrans. Iodophenol 13 was prepared from 2,3-
dihydrobenzofuran by a known procedure (Scheme 6).21 The requi-
site sulfone 14 was prepared by reaction of iodide 13, with sodium
benzenesulfinate in DMF. Treatment of 14 with butyryl chloride
using conditions described earlier gave acyloxy sulfone 15 in 91%
yield. Sulfone 15 was treated with 1.2 equiv of LHMDS in THF to
give a mixture of products that upon dehydration with p-TsOH in
benzene at reflux gave the benzopyran 16 in 63% overall yield for
two steps.
The first goal of this project was to develop a new methodology
for the annulation of furans to cycloalkenones. The intramolecular
cyclization reactions of acyloxy sulfones 3 to give fused ring furans
4 clearly established the viability of the proposed route. Using
analogous chemistry, we were able to extend the application of
this strategy to make substituted benzofurans, a class of com-
pounds known for their biological activities. The extension of this
chemistry to prepare dihydropyrans and benzopyrans further en-
hances the value of this study. It is now important to expand the
scope of this furan annulation methodology to other cycloalkenon-
es. It is also of interest to study the cyclization chemistry of sub-
strates A and B (Scheme 1), which have electron withdrawing
groups other than the sulfonyl moiety. This will broaden the diver-
sity of products that one can obtain using this chemistry.
Acknowledgments
This research was partly supported by grants from the National
Institutes of Health under PHS Grant no. S06 GM08136 and
1SC3GM084809-01.

Y. Liu et al. / Tetrahedron Letters 52 (2011) 2935–2939
2939
12. Arvanitis, E. A.; Craig, D.; Timm, A. P. ARKIVOC 2002, 19–27.
13. Jacobs, H. K.; Gopalan, A. S. J. Org. Chem. 1994, 59, 2014.
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7768.
lactol/ketosulfone mixture was dissolved in benzene (5 mL) and a catalytic
amount of p-TsOH was added to the solution. The reaction was stirred at rt for
8 h. The reaction mixture was diluted with EtOAc (50 mL), washed with
NaHCO3 (3 Â 10 mL), dried (Na2SO4) and the solvent removed in vacuo. The
crude product was purified by radial chromatography (20% EtOAc in hexane) to
give 4a (0.113 g, 65.7%) as a white solid; mp 79–80 °C; IR (KBr) 2927, 2867,
16. PS-DMAP: 4% cross-linked poly(styrene-co-divinylbenzene) 1.5 mmol/g from
Biotage.
1559 cmÀ1
;
1H NMR (200 MHz, CDCl3) d 8.03À7.79 m, 2H), 7.67–7.40 (m, 3H),
17. All of the compounds prepared in this paper were characterized by IR, 1H and
13C NMR and elemental analysis.
2.99 (t, J = 7.3 Hz, 2H), 2.58–2.29 (m, 4H), 1.87–1.15 (m, 6H), 0.98 (t, J = 7.3 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 159.4, 150.4, 143.3, 133.0, 129.3, 127.0,
121.0, 115.9, 29.1, 23.0, 22.6, 22.5, 22.0, 21.2, 14.1; Anal. Calcd for C17H20SO3:
C, 67.08; H, 6.62. Found: C, 66.92; H, 6.86.
18. 3-Benzenesulfonyl-2-propyl-4,5,6,7-tetrahydrobenzofuran (4a).
A solution of
LHMDS (1 M in THF, 0.62 mL, 0.62 mmol) was added dropwise to a solution
of 3a (0.182 g, 0.57 mmol) in THF (10 mL) at À78 °C under N2 and the reaction
mixture was stirred at À78 °C for 6 h and then at rt for 20 h. The reaction was
quenched with saturated 10% acetic acid solution (5 mL) and the THF was
removed in vacuo. The residue was dissolved in EtOAc (50 mL), washed with
brine (10 mL), dried (Na2SO4) and the solvent removed in vacuo. The crude
19. Hwu, J. R.; Hakimelahi, G. H.; Chou, C. Tetrahedron Lett. 1992, 33, 6469–6472.
20. Wang, W.; Yu, M. Tetrahedron Lett. 2004, 45, 7141–7143.
21. Zewge, D.; King, A.; Weissman, S.; Tschaen, D. Tetrahedron Lett. 2004, 45, 3729–
3732.