Solid-phase organic synthesis of 5-iodomethyl-dihydrofuran-2-ones with recyclable polymer-supported selenium bromide

Article abstract of DOI:10.1080/00397911.2010.524064

Reaction of polystyrene-supported selenium bromide with γ,δ-unsaturated acids and subsequent cleavage from the polymer by treatment with methyl iodide efficiently afforded 5-iodomethyl-dihydrofuran-2- ones in excellent yields. The polymeric reagent can be regenerated and reused as an environmentally friendly reagent. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.524064

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Solid-Phase Organic Synthesis of 5-
Iodomethyl-dihydrofuran-2-ones with
Recyclable Polymer-Supported Selenium
Bromide
Chao-Li Wang a , Shou-Ri Sheng a , Xin Cheng a & Ming-Zhong Cai a
a College of Chemistry and Chemical Engineering , Jiangxi Normal
University , Nanchang , China
Accepted author version posted online: 18 Jul 2011.Published
online: 06 Oct 2011.
To cite this article: Chao-Li Wang , Shou-Ri Sheng , Xin Cheng & Ming-Zhong Cai (2012) Solid-Phase
Organic Synthesis of 5-Iodomethyl-dihydrofuran-2-ones with Recyclable Polymer-Supported Selenium
Bromide, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 42:3, 320-327, DOI: 10.1080/00397911.2010.524064
To link to this article: http://dx.doi.org/10.1080/00397911.2010.524064
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Synthetic Communications1, 42: 320–327, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.524064
SOLID-PHASE ORGANIC SYNTHESIS OF
5-IODOMETHYL-DIHYDROFURAN-2-ONES
WITH RECYCLABLE POLYMER-SUPPORTED
SELENIUM BROMIDE
Chao-Li Wang, Shou-Ri Sheng, Xin Cheng, and
Ming-Zhong Cai
College of Chemistry and Chemical Engineering, Jiangxi Normal University,
Nanchang, China
GRAPHICAL ABSTRACT
Abstract Reaction of polystyrene-supported selenium bromide with c,d-unsaturated acids
and subsequent cleavage from the polymer by treatment with methyl iodide efficiently
afforded 5-iodomethyl-dihydrofuran-2-ones in excellent yields. The polymeric reagent can
be regenerated and reused as an environmentally friendly reagent.
Keywords 5-Iodomethyl-dihydrofuran-2-one; polystyrene-supported selenium bromide;
recyclable; selenium-mediated intramolecular cyclization; solid-phase organic synthesis
INTRODUCTION
Over the past few years, combinatorial chemistry has emerged as a powerful
tool in organic synthesis. As a result, the development of new methodology and the
adaptation of already existing methods to make them amenable to parallel synthesis
have become very active research topics.[1] Solid-phase organic synthesis (SPOS)
using insoluble solid supports such as polystyrene resins shows a number of advan-
tages as compared to solution chemistry. The most salient one is the possibility of
applying excesses of reagents and removing them without involving time-consuming
separation techniques.[2] Compounds bearing the substituted c-butyrolactone
moiety are widespread in nature and have received much interest because of their
physiological properties.[3] Moreover, functionalized c-butyrolactones have impor-
tant biological properties and are also known as starting material for the preparation
Received April 15, 2010.
Address correspondence to Shou-Ri Sheng, College of Chemistry and Chemical Engineering,
Jiangxi Normal University (Yaohu Campus), Nanchang, 330022, China. E-mail: shengsr@jxnu.edu.cn
320

SPOS OF 5-IODOMETHYL-DIHYDROFURAN-2-ONES
321
of pharmacologically active compounds.[4] So, many methods have been developed
for the synthesis of c-butyrolactone ring systems.[5] Among these methods, seleno-
promoted cyclization reactions of olefinic carboxylic acids are useful methods for
the construction of functionalized c-butyrolactones.[5a–5c,6] However, organosele-
nium reagents always have a foul smell and are quite toxic, which is often problematic
in organic synthesis. Since the first organoselenium resin[7] used in SPOS with a
combined advantage of decrease volatility and simplification of product workup
was reported in 1976, several research groups[8] have developed selenium-based
approaches for SPOS. Recently, our research group has been interested in the appli-
cation of organic selenium resins for the synthesis of some functional heterocyclic
compounds such as 5-iodoisoxazolines,[9] 2-iodomethyl-2,3-dihydrobenzofurans,[10]
and vinyl-substituted 1,3,4-oxadiazoles.[11] As part of an ongoing research program
focused on the use of polymeric organoselenium reagents in SPOS, we here describe
a simple and efficient synthetic approach to 5-iodomethyl-dihydrofuran-2-ones
(Scheme 1). To our knowledge, there has no report concerning the preparation of
5-iodomethyl-dihydrofuran-2-ones using this technology.
As previous reported,[8a] polymer-supported selenium bromide resin (1) was
conveniently prepared from commercial polystyrene by lithiation followed by
treatment with dimethyl diselenide to give methyl selenide resin via oxidation with
bromine to give reagent (1) as a dark red polymer.
Obviously, polymer-supported selenolactonization would be the key step for the
success of this protocol. Interestingly, simply stirring the resin 1 in tetrohydrofuran
(THF) at room temperature with 3.0 equiv of the c,d-unsaturated acids (2) resulted
in a rapid decolorization of the resin. After stirring for 2 h, the ring-closure reaction
on the solid phase was completed, which was determined by the elemental analysis of
5-selenomethyl-dihydrofuran-2-ones (3) (Br was undetectable). Additionally, the
reaction was also monitored by Fourier transform–infrared (FT-IR) of resin (3),
showing a single strong peak around 1770 cmꢀ1, which indicated that the lactoniza-
tion was complete. Furthermore, increasing the amount of c,d-unsaturated acid to
4 or 5 equiv, replacing THF with other solvents such as CH2Cl2 and CH3CN, or
prolonging the reaction time had little affect on the cyclization.
Finally, following our published method[9,10] for traceless cleavage of selenium
resin, the target compound 5-iodomethyl-dihydrofuran-2-one (4) was obtained in
excellent isolated yields (90–96%) by treatment of resin (3) with CH3I-NaI in
dimethylformamide (DMF) at 70 ꢁC for 20 h. The generality and efficiency of the
reaction were established by studying various substrates (Table 1).
As seen from Table 1, the only 5-exo-trig ring-closing reaction induced by
selenium bromide resin was preferred because the other possible regioisomer from
Scheme 1. Solid-phase synthetic route to 5-iodomethyl-dihydrofuran-2-ones.

322
C.-L. WANG ET AL.
Table 1. Preparation of 5-iodomethyl-dihydrofuran-2-ones (4a–4h)
Entry
R1
R2
R3
Product
Yield (%)a
1
2
H
H
H
4a
4ab
4ac
4b
4c
96
94
H
H
H
3
H
H
H
92
94 (dr 6:1)
95 (dr 6:1)
93 (dr 5:1)
90
4
H
H
Me
Et
5
H
H
6
H
H
C6H5CH2
4d
4e
7
H
Me
C6H5
H
Me
C6H5
H
8
H
4f
90
94
9
10
Me
C6H5
4g
4h
H
H
92
aOverall yields based on polymer-supported selenium bromide 1 (1.18 mmol Br=g).
bWith the third regenerated resin 1.
cWith the fourth regenerated resin 1.
Scheme 2. Conversion of methyl selenide resin (5) to 1.
a 6-endo-trig closure was not observed. For the a-substituted acids (2b, 2c, and 2d), a
mixture of two diastereoisomers was obtained, and NMR studies showed that syn
lactones were the major isomers (Table 1, entries 4–6). For a,a-disubstituted
substrates (2e and 2f), the cycliation also proceeded well, although with a little bit
lower yields of target compounds (4e and 4f) (Table 1, entries 7 and 8).
In addition, it should be noted that the polystyrene-supported selenium bromide
(1) is easily regenerated form the recovered methyl selenide resin (5) (Scheme 2)
and can be reused for the conversion of c,d-unsaturated acids to 5-iodomethyl-
dihydrofuran-2-ones (4). For example, after the fourth regeneration and use, the yield
of 5-iodomethyl-dihydrofuran-2-one (4a) (Table 1, entry 3) was almost same as when
freshly prepared selenium bromide resin was used.
In summary, we have developed an efficient protocol for the traceless solid-
phase synthesis of 5-iodomethyl-dihydrofuran-2-ones with excellent yields and easy
workup procedure, employing a selenium-based traceless linker strategy. Moreover,
the polymeric reagent can be recycled without further transformation and reused as
an environmentally benign reagent.
EXPERIMENTAL
1
Melting points were uncorrected. H NMR (400-MHz) and 13C NMR (100-
MHz) spectra were recorded on a Bruker Avance (400-MHz) spectrometer, using
CDCl3 as the solvent and TMS as internal standard. FT-IR spectra were taken on
a Perkin-Elmer SP One FT-IR spectrophotometer. Microanalyses were performed
with a Carlo Erba 1106 elemental analyzer. Polystyrene for the preparation of

SPOS OF 5-IODOMETHYL-DIHYDROFURAN-2-ONES
323
polystyrene-supported selenium bromide according to the procedure described by
Nicolaou[8a] was purchased from Aldrich (100–200 mesh, cross-linked with 1%
divinylbenzene). 4-Pentenoic acid (2a) is commercially available, and the other c,d-
unsaturated acids such as 2-methylpent-4-enoic acid (2b),[12] 2-ethylpent-4-enoic acid
(2c),[13] 2-allyl-3-bezenepropanoic acid (2d),[14] 2,2-dimethylpent-4-enoic acid (2e),[15]
2,2-diphenylpent-4-enoic acid (2f),[16] 4-methyl-4-pentenoic acid (2g),[17] and
4-phenyl-4-pentenoic acid (2h)[18] were prepared according to the reported method.[16]
DMF was distilled from calcium hydride, and THF was distilled from sodium benzo-
phenone immediately prior to use. Other reagents were obtained from commercial
suppliers and used without further purification.
Preparation of 5-Iodomethyl-dihydrofuran-2-ones:
General Procedure
Under a positive pressure of nitrogen, c,d-unsaturated acid 2 (3 mmol) was
added to polystyrene-supported selenium bromide 1 (1.0 g, 1.18 mmol Br=g) swollen
in THF (15 mL) for 30 min. The suspension was stirred at room temperature for 2 h.
The mixture was filtered, and the resin was washed with THF (10 mL ꢂ 3) and
CH2Cl2 (10 mL ꢂ 3) and dried under vacuum to afford dry 5-selenomethyl-
dihydrofuran-2-one resin 3. NaI (1.5 g) and CH3I (1.5 mL) were added to a suspen-
sion of the swollen resin 3 (1.0 g) in dry DMF (15 mL) under nitrogen. The suspension
was stirred at 75 ꢁC for 20 h. The mixture was filtered, and the residual resin 5 was
washed with CH2Cl2 (10 mL ꢂ 3). The filtrate was washed with saturated Na2S2O3
and H2O, extracted with ethyl acetate (10 mL ꢂ 3), dried over anhydrous Na2SO4,
and evaporated to furnish crude products 4a–4h with 93–98% purity as determined
by high-performance liquid chromatography (HPLC), which were further purified
by column chromatography (EtOAc=hexane, 20=1–12=1, v=v) over silica gel to
provide pure 5-iodomethyl-dihydrofuran-2-ones (4a–4h) for their 1H NMR,
13C NMR, and elemental analyses.
Selected Data
5-Iodomethyl-dihydrofuran-2-one (4a). Colorless oil (lit.[19] oil); 1H NMR:
d ¼ 4.60–4.55 (m, 1 H), 3.46–3.41 (m, 1 H), 3.34–3.30 (m, 1 H), 2.68–2.47 (m, 3 H),
2.05–1.94 (m, 1 H); 13C NMR: d ¼ 176.1, 78.5, 28.8, 28.0, 7.3; IR (neat):
n ¼ 1775 cmꢀ1. Anal. calcd. for C5H7IO2: C, 26.57; H, 3.12. Found: C, 26.38; H, 3.32.
3-Methyl-5-iodomethyl-dihydrofuran-2-one
(trans/cis ¼ 1:6)
(4b).
Colorless oil (lit.[20] oil); IR (neat): n ¼ 1770 cmꢀ1. Anal. calcd. for C6H9IO2: C,
30.02; H, 3.78. Found: C, 29.78; H, 3.93. Cis-3-methyl-5-iodomethyl-dihydrofuran-
1
2-one (major): H NMR: d ¼ 4.39–4.36 (m, 1 H), 3.41 (dd, J ¼ 5.7, 10.1 Hz, 1 H),
3.28–3.24 (m, 1 H), 2.78–2.68 (m, 2 H), 1.58 (q, J ¼ 10.7 Hz, 1 H), 1.31 (d, J ¼ 6.3 Hz,
3 H); 13C NMR: d ¼ 178.4, 76.4, 37.6, 36.1, 15.1, 6.8. Trans-3-methyl-5-iodomethyl-
1
dihydrofuran-2-one (minor): H NMR: d ¼ 4.61–4.57 (m, 1 H), 3.37 (dd, J ¼ 10.6,
4.4 Hz, 1 H), 3.27–3.25 (m, 1 H), 2.84–2.80 (m, 1 H), 2.34–2.30 (m, 1 H),
2.14–2.09 (m, 1 H), 1.30 (d, J ¼ 6.5 Hz, 3 H); 13C NMR: d ¼ 179.0, 76.6, 35.3,
34.2, 16.0, 7.0.

324
C.-L. WANG ET AL.
3-Ethyl-5-iodomethyl-dihydrofuran-2-one (trans/cis ¼ 1:6) (4c). Colorless
oil (lit.[5g] oil); IR (neat): n ¼ 1776 cmꢀ1. Anal. calcd. for C7H11IO2: C, 30.09; H, 4.36.
1
Found: C, 29.80; H, 4.57. Cis-3-ethyl-5-iodomethyl-dihydrofuran-2-one (major): H
NMR: d ¼ 4.43–4.35 (m, 1 H), 3.45 (dd, J ¼ 4.6, 10.1 Hz, 1 H), 3.27–3.25 (m, 1 H),
2.70–2.61 (m, 2 H), 1.95–1.63 (m, 2 H), 1.60–1.53 (m, 1 H), 1.01 (t, J ¼ 7.7 Hz, 3
H); 13C NMR: d ¼ 178.4, 76.6, 40.6, 33.2, 24.3, 11.6, 7.5. Trans-3-ethyl-5-
1
iodomethyl-dihydrofuran-2-one (minor): H NMR: d ¼ 4.60–4.55 (m, 1 H), 3.40–
3.35 (m, 1 H), 3.25 (d, J ¼ 7.4 Hz, 1 H), 2.72–2.60 (m, 1 H), 2.24–2.15 (m, 2 H),
1.61–1.50 (m, 2 H), 1.02 (t, J ¼ 7.7 Hz, 3 H); 13C NMR: d ¼ 177.9, 76.5, 42.6, 35.1,
23.4, 11.5, 6.8.
3-Benzyl-5-iodomethyl-dihydrofuran-2-one (trans/cis ¼ 1:5) (4d). Color-
less oil (lit.[20] oil); IR (neat): n ¼ 1778 cmꢀ1. Anal. calcd. for C12H13IO2: C, 45.59; H,
4.15. Found: C, 45.38; H, 4.38; Cis-3-benzyl-5-iodomethyl-dihydrofuran-2-one
1
(major): H NMR: d ¼ 7.35–7.24 (m, 5 H), 4.43–4.37 (m, 1 H), 3.37 (dd, J ¼ 10.6,
4.5 Hz, 1 H), 3.30 (dd, J ¼ 14.5, 4.5 Hz, 1 H), 3.21 (dd, J ¼ 10.6, 7.5 Hz, 1 H),
3.06–3.00 (m, 1 H), 2.84 (dd, J ¼ 14.5, 9.4 Hz, 1 H), 2.55–2.50 (m, 1 H), 1.72–1.65
(m, 1 H); 13C NMR: d ¼ 177.3, 138.1, 128.9, 128.8, 127.0, 76.7, 43.0, 36.2, 34.8,
1
6.6. Trans-3-benzyl-5-iodomethyl-dihydrofuran-2-one (minor): H NMR: d ¼ 7.36–
7.20 (m, 5 H), 4.37–4.31 (m, 1 H), 3.24–3.14 (m, 2 H), 3.11–3.02 (m, 1 H), 2.84
(dd, J ¼ 13.5, 8.7 Hz, 1 H), 2.25–2.04 (m, 2 H), 1.73–1.67 (m, 1 H); 13C NMR:
d ¼ 177.7, 137.8, 129.0, 128.8, 127.1, 76.8, 41.4, 36.7, 32.5, 7.2.
3,3-Dimethyl-5-iodomethyl-dihydrofuran-2-one (4e). White solid, mp
54–55 ꢁC (lit.[5g] 53.7–55.0 ꢁC); 1H NMR: d ¼ 4.45–4.40 (m, 1 H), 3.39 (dd,
J ¼ 10.5, 4.8 Hz, 1 H), 3.25 (dd, J ¼ 10.5, 7.3 Hz, 1 H), 2.34 (dd, J ¼ 12.8, 6.4 Hz,
1 H), 1.90 (dd, J ¼ 12.8, 9.5 Hz, 1 H), 1.30 (s, 3 H), 1.27 (s, 3 H); 13C NMR:
d ¼ 180.7, 75.0, 43.9, 41.0, 24.7, 7.2; IR (neat): n ¼ 1777 cmꢀ1. Anal. calcd. for
C7H11IO2: C, 33.09; H, 4.36. Found: C, 32.94; H, 4.52.
3,3-Diphenyl-5-iodomethyl-dihydrofuran-2-one (4f). White solid; mp
1
115–116 ꢁC (lit.[21] 116–117 ꢁC); H NMR (400 MHz, CDCl3): d ¼ 7.35–7.28 (m, 10
H), 4.44–4.34 (m, 1 H), 3.45–4.41 (m, 1 H), 3.32–3.29 (m, 1 H), 3.25–3.18 (m, 1 H),
2.70–2.63 (m, 1 H); 13C NMR: d ¼ 176.5, 141.6, 139.4, 129.2, 128.6, 128.1, 127.8,
127.5, 127.2, 75.5, 58.8, 44.1, 5.9; IR (neat): n ¼ 1765 cmꢀ1. Anal. calcd. for
C17H15IO2: C, 53.99; H, 4.00. Found: C, 53.78; H, 4.24.
5-Iodomethyl-5-methyl-dihydrofuran-2-one (4g). White solid; mp 45–46 ꢁC
(lit.[22] 44–45 ꢁC); 1H NMR: d ¼ 3.43 (d, J ¼ 10.5 Hz, 1 H), 3.36 (d, J ¼ 10.5 Hz, 1 H),
2.68–2.66 (m, 2 H), 2.35–2.32 (m, 1 H), 2.16–2.14 (m, 1 H), 1.63 (s, 3 H); 13C NMR:
d ¼ 175.5, 83.6, 32.7, 29.2, 25.8, 14.0; IR (neat): n ¼ 1768 cmꢀ1. Anal. calcd. for
C6H9IO2: C, 30.02; H, 3.78. Found: C, 29.80; H, 3.95.
5-Iodomethyl-5-phenyl-dihydrofuran-2-one (4h). White solid; mp 75–
1
76 ꢁC (lit.[22] 73–74 ꢁC); H NMR (400 MHz, CDCl3): d ¼ 7.40–7.36 (m, 5 H), 3.65
(s, 2 H), 2.84–2.45 (m, 4 H); 13C NMR (75 MHz, CDCl3): d ¼ 175.3, 140.5, 128.9,
128.5, 124.7, 85.9, 33.8, 29.1, 16.2; IR (neat): n ¼ 1779 cmꢀ1. Anal. calcd. for
C11H11IO2: C, 43.73; H, 3.67. Found: C, 43.50; H, 3.45.

SPOS OF 5-IODOMETHYL-DIHYDROFURAN-2-ONES
325
ACKNOWLEDGMENTS
We gratefully acknowledge financial support from the National Natural
Science Foundation of China (No. 21062007), Natural Science Foundation of
Jiangxi Province (No. 2008GZH0029), and the Research Program of Jiangxi
Province Department of Education (No. GJJ10385).
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