Lewis base-catalyzed electrophilic lactonization of selenyl bromide resin and facile solid-phase synthesis of furan-2(5H)-one derivatives

Article abstract of DOI:10.1002/aoc.3157

A facile solid-phase synthesis approach was developed for the rapid synthesis of multi-substituted furan-2(5H)-one derivatives libraries. The synthetic strategy included the selenyl bromide resin-induced electrophilic lactonization catalyzed by Lewis base, lithiation, nucleophilic substitution and oxidation-elimination of the selenium resins. The advantages of the new method are good yields, high purity, straightforward operations and high diversity of the products, lack of odor, and good stability of the selenium resins. Copyright

Full text of DOI:10.1002/aoc.3157

Full Paper
Received: 10 March 2014
Revised: 6 April 2014
Accepted: 6 April 2014
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI 10.1002/aoc.3157
Lewis base-catalyzed electrophilic lactonization
of selenyl bromide resin and facile solid-phase
synthesis of furan-2(5H)-one derivatives
Rong Jun Hea, Bing Chun Zhua,b and Yu Guang Wanga*
A facile solid-phase synthesis approach was developed for the rapid synthesis of multi-substituted furan-2(5H)-one derivatives
libraries. The synthetic strategy included the selenyl bromide resin-induced electrophilic lactonization catalyzed by Lewis
base, lithiation, nucleophilic substitution and oxidation–elimination of the selenium resins. The advantages of the new
method are good yields, high purity, straightforward operations and high diversity of the products, lack of odor, and good
stability of the selenium resins. Copyright © 2014 John Wiley & Sons, Ltd.
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
Keywords: electrophilic lactonization; Lewis base; selenium resins; solid-phase synthesis; furan-2(5H)-one derivatives library
diversity of products, easy work-up procedure and suitability
for building parallel libraries.
With the accelerated development of the drug discovery process,
Introduction
methodology development and rapid synthesis of natural prod-
Results and Discussion
uct-like compounds with privileged scaffolds have attracted
much attention.[1]
Initial studies focused on the electrophilic lactonization of poly-
Furan-2(5H)-one derivatives are an important structural unit
because they often occur in natural products and exhibit a
styrene-supported selenyl bromide 1[8] (dark-red resin; Br 1.02
mmol gꢀ1, which is called for selenyl bromide resin) and
broad range of biological activities.[2] Compounds containing
substituted but-3-enoic acid 2 in the presence of triethylamine
furan-2(5H)-one are considered potential anti-inflammatories,
antibiotics, antitumoral and antiviral agents, allergy, cyclooxy-
genase, seed germination and phospholipase A2 inhibitors,
plant growth regulators, insecticides, etc. (Fig. 1). Furthermore,
(TEA) at room temperature. The dark-red resin 1 was converted
to yellow resin 3 smoothly. The progress of the reaction was
monitored by the (FT-IR spectrum, which showed a strong peak
of carbonyl absorptions at 1770–1778 cmꢀ1. The desired product
relatively simple furan-2(5H)-one derivatives are also useful as
butenolides 4 could be then obtained from 3 through oxidation–
elimination with H2O2 (Table 1).
synthetic intermediates in the preparation of bioactive
compounds.[3]
The results clearly show that the yields of furan-2(5H)-ones
Combinatorial chemistry has become an extremely powerful
technique for the rapid synthesis of small, drug-like organic
libraries for the purpose of medicinal chemistry programs
(Table 1, 4c–4d) were 61–65% when the R1 group were alkyls.
In contrast, the yields of furan-2(5H)-ones (Table 1, 4a, 4b)
were very low when the R1 group were aryls. To optimize
within the pharmaceutical industry.[4] Solid-phase organic
the reaction conditions for aryl substituted but-3-enoic acid
synthesis (SPOS) is one of the core technologies used for
synthesis of the molecule libraries.[5] Our previous work has
2, we tested the reactions of 1 with 2a with reduced TEA
loadings under different temperatures in CH2Cl2. However,
established various heterocyclic compound libraries from
organoselenium resins.[6] As the continuation of our ongoing
both yield and purity of 4a were unsatisfactory (Table 2, En-
tries 1 and 2). However, we analyzed the effect of R1 and R2
efforts to generate pharmaceutically interesting heterocyclic
groups on double bonds of substituted but-3-enoic acid 2
compounds with SPOS, herein we describe an efficient
strategy for the preparation of substituted furan-2(5H)-one
from a selenopolystyrene resin, which included the selenyl
*
Correspondence to: Yu Guang Wang, College of Biological and Environmental
Engineering, Zhejiang University of Technology, Hangzhou, Zhejiang 310014,
People’s Republic of China. E-mail: yuguangw@zjut.edu.cn
bromide resin-induced electrophilic lactonization catalyzed
by Lewis base, lithiation, nucleophilic substitution (or addi-
tion) reaction and oxidation–elimination of the selenium
resins. Compared with known methodologies,[7] it has many
advantages, such as the stable and odorless solid-phase
selenium reagents compared with small molecular selenium
reagents used in the literature,7a good yield, high purity and
a College of Biological and Environmental Engineering, Zhejiang University of
Technology, Hangzhou, Zhejiang, 310014, People’s Republic of China
b Zhejiang Research Institute of Chemical Industry, Hangzhou, Zhejiang, 310023,
People’s Republic of China
Appl. Organometal. Chem. (2014)
Copyright © 2014 John Wiley & Sons, Ltd.

R. Jun He et al.
Hence it is clear that HMPA(Se) could effec-
tively activate the electrophilic ability of
selenyl bromide resin 1, in combination with
AgOTf; the activation effect is better and it
afforded a better product purity, which might
provide much benefit in further applications in
medicine synthesis. A plausible mechanism for
the above phenomena is depicted in Scheme 1.
The reaction of selenyl bromide resin 1 with
AgOTf afforded selenyl triflate resin 1′, which
was more activated due to the better leaving
group OTfꢀ. Selenophosphoramide 5 could
reinforce the electrophilicity at the selenium
atom of resin 1′ through a net polarization of
the electron density of the resultant Lewis
acid–base adduct.
Figure 1. Some biologically active compounds bearing the furan-2(5H)-one moiety.
With the optimized conditions in hand (Ta-
ble 2, entry 11), the resins 3 were prepared by electrophilic
lactonization of the resin 1 and substituted but-3-enoic acid
2. Oxidation–elimination of resins 3 was then carried out,
and furan-2(5H)-one derivatives 4 were synthesized in high
yields and good purities (Scheme 2). The results are described
in Table 3, which show that this methodology has very wide
application scopes.
Table 1. Solid-phase synthesis of furan-2(5H)-one derivatives 4 cata-
lyzed by TEA
Table 2. Solid-phase conditions optimization of electrophilic
lactonization of resin 1 with 2a
Products 4
R1
Phenyl
R2 R3 Yield (%)a Purities (%)b
4a
4b
4c
4d
4e
H
H
H
H
H
H
H
35
33
65
61
62
<70
<70
92
4-Methylphenyl
―(CH2)5―
Benzyl
H
H
90
Methyl
91
aYield of the crude product based on the loading of the resin 1
(Br, 1.02 mmol gꢀ1).
bDetermined by HPLC (λ = 254 nm).
Entry
Lewis base
Catalyst
Solvent,
temp. (°C )
Yield of Purity
4a (%)a (%)b
1
TEAc
—
—
—
—
—
—
—
—
—
—
CH2Cl2, r.t.
35
35
36
36
35
20
36
36
56
86
91
<70
<70
<70
<70
<70
—
and found, unlike alkyl, that aryl probably weakened the
electron density of the double bond, thus weakening the
electrophilic binding ability of selenium and double bond.
S. E. Denmark had reported that Lewis base could effectively
activate the electrophilic ability of selenium reagents[9]; there-
fore, we surveyed the catalytic effect of several Lewis bases
on the electrophilic lactonization of resin 1 with 2a. Our ef-
forts on the screenings of solvents and Lewis bases such as
pyridine, DBU, TEA, Ph3P and Ph3P¼O still did not help to
improve the reaction much at the beginning (Table 2,
entries 3–8). Fortunately, we found that the addition of
hexamethylphosphoramide (HMPA) enhanced the yield and
purity of product 4a much (entry 9). Further tests demon-
strated that the addition of selenophosphoramide 5 (HPMA
(Se)) much improved the reaction and both yield and
purity of product 4a increased obviously (entry 10) in THF.
Furthermore, we have noticed that HMPA(Se) in combination
with AgOTf enhanced the yield, and especially enhanced the
purity of product 4a (entry 11) in the mixed solvent THF
and DMF (5:1).
2
TEAc
CHCl3, r.t. ꢀ 60
THF, r.t. ꢀ 60
DMF, r.t. ꢀ 60
THF, r.t. ꢀ 60
THF, r.t. ꢀ 60
THF, r.t. ꢀ 60
THF, r.t. ꢀ 60
THF, r.t. ꢀ 60
THF, r.t. ꢀ 60
3
TEAc
TEAc
4
5
Pyridinec
DBUc
TEA,d Ph3Pe
TEA,d Ph3P Oe
TEA,d HMPAe
TEA,d HMPA(Se)e
6
7
<70
<70
82
8
9
10
11
90
TEA,d HMPA(Se)e AgOTfd THF:DMF
97
(5:1), r.t. ꢀ 60
aYield of crude product based on loading of resin 1 (Br, 1.02 mmol gꢀ1).
bDetermined by HPLC (λ = 254 nm, acetonitrile/H2O = 80/20 (v/v),
1.0 ml minꢀ1).
c3.0 equiv. (based on loading of resin 1).
d1.0 equiv. (based on loading of resin 1).
e0.1 equiv. (based on loading of resin 1).
r.t., room temperature.
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Copyright © 2014 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. (2014)

Solid-phase synthesis of furan-2(5H)-one derivatives
In order to obtain a variety of furan-2(5H)-one
derivative libraries, the 3-site of resin 3 was
derivatized by lithiation and nucleophilic substitu-
tion. Resin 3 was soaked in anhydrous THF for 6 h,
then reacted with LDA (lithium diisopropylamide)
at ꢀ70°C under nitrogen atmosphere to form
lithium resins, which reacted with halogenated
compounds to yield the resin 6. Resin 6 was then
treated with H2O2 to give the product 7(a–r) in
good yield and purity (Scheme 3). Results summa-
rized in Table 4 show that a variety of different
substitutions could be smoothly introduced at
the 3-site, further expanding the application scope
of this methodology.
Similarly, aldehyde or ketone could also be
smoothly reacted with the lithiation intermedi-
ate of resin 3 to form resin 8, which was
treated with H2O2 to give the products 9(a–o)
with hydroxyl groups in good yield and purity
(Scheme 4). The results are shown in Table 5.
Scheme 1. Selenophosphoramide 5 activation of selenium electrophile of resin 1.
Scheme 3. Solid-phase synthesis of furan-2(5H)-one derivatives 7. Re-
agents and conditions: (a) (1) LDA (1.2 equiv.), THF, ꢀ70°C; (2) R4X (X = I,
Br or Cl, 1.2 equiv.), THF ꢀ70°C for 45 min, then ꢀ30°C for 30 min; (b)
H2O2 (10.0 equiv.), THF, 0–25°C.
Scheme 2. Solid-phase synthesis of furan-2(5H)-one derivatives 4. Re-
agents and conditions: (a) AgOTf (1.0 equiv.), HMPA(Se) (0.1 equiv.), Et3
N (1.0 equiv.), THF, 0–60°C, 6–8 h; (b) H2O2 (10.0 equiv.), THF, 0–25°C.
Table 4. Solid-phase synthesis of furan-2(5H)-one derivatives 7
Table 3. Solid-phase synthesis of furan-2(5H)-one derivatives 4 cata-
lyzed by HMPA(Se) and AgOTf
7
R1
R2
R3
R4
Yield Purity
(%)a (%)b
Products 4
R1
R2
R3
Yield
(%)a
Purity
(%)b
7a
7b
7c
7d
7e
7f
Methyl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Methyl Methyl
Methyl Allyl
83
78
93
89
92
93
93
92
93
92
87
90
90
90
90
90
90
94
Methyl
4a
4b
4c
4d
4e
4f
Phenyl
H
H
H
H
H
H
H
H
H
H
H
H
H
91
90
97
91
91
91
90
90
89
90
88
94
90
84
90
90
97
96
Methyl
Methyl CH2COOMe 81
4-Methylphenyl
―(CH2)5―
Benzyl
Ethyl
H
H
H
CH2COOEt
Benzyl
81
83
92
n-Propyl
n-Butyl
H
H
H
H
H
H
H
97
97
97
96
96
95
97
96
CH2COOMe 81
83
CH2COOMe 82
Methyl
7g
7h
7i
n-Butyl
Methyl Methyl
n-Propyl
n-Octyl
n-Octyl
H
4g
4h
4i
Methyl
n-Butyl n-Hexyl
72
76
76
76
75
76
75
84
95
95
i-Propyl
7j
Phenyl
H
H
H
H
H
H
n-Propyl
Benzyl
Methyl
Methyl
Methyl
Methyl
t-Butyl
7k
7l
Phenyl
4j
4-Bromophenyl
Methyl
Phenyl
4k
4l
Methyl
85
7m
7n
7o
7p
7q
7r
4-Bromophenyl
4-Methylphenyl
―(CH2)5―
Methyl
Phenyl
Phenyl
Methyl
Methyl
Ethyl
4m
4n
4o
4p
H
96
93
96
96
4-Methoxylphenyl H
Methyl
Phenyl
Methyl
Methyl
Methyl
Methyl Methyl Methyl
Methyl
―(CH2)5―
―(CH2)5―
H
H
Methyl
85
85
Methyl
i-Propyl
aYield of crude product based on loading of resin 1 (Br, 1.02
mmol gꢀ1).
aYield of crude product based on loading of resin 1 (Br, 1.02 mmol gꢀ1).
bDetermined by HPLC (λ = 254 nm, acetonitrile/H2O = 80/20 (v/v),
1.0 ml minꢀ1).
bDetermined by HPLC (λ = 254 nm, acetonitrile/H2O = 80/20 (v/v),
1.0 ml minꢀ1).
Appl. Organometal. Chem. (2014)
Copyright © 2014 John Wiley & Sons, Ltd.
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R. Jun He et al.
divinylbenzene) for the preparation of selenenyl bromide resin
(1.02 mmol Br gꢀ1) according to the procedure described by
Nicolaou and co-workers[8] was purchased from commercial
sources. 1H 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. GC mas spec-
tra (IE) were recorded on an Agilent 6890N/5975 C gas chromato-
graph–tandem mass spectrometer; column: Agilent 19091S-433;
325°C; 30 m × 256 μm × 0.25 μm. Infrared spectra were recorded
on a Bruker Tensor 27 spectrometer. HPLC was performed on a
Waters e2695 high-performance liquid chromatograph (column,
SunFireTM C18 5 μm, 4.6 × 250 mm; mobile phase, acetonitrile/
H2O (80/20, v/v); flow rate 1.0 ml minꢀ1; Waters 2996 photodiode
array detector). High-resolution mass spectrometry (HRMS; EI)
was performed on an Agilent GCT Premier GC-MS instrument.
The samples were further purified by TLC for 13C NMR and
microanalyses.
Scheme 4. Solid-phase synthesis of furan-2(5H)-one derivatives 9. Re-
agents and conditions: (a) (1) LDA (1.2 equiv.), THF, ꢀ70°C; (2) R5R6CO
(1.2 equiv.), THF ꢀ70°C for 45 min, then ꢀ30°C for 30 min; (b) H2O2
(10.0 equiv.), THF, 0–25°C.
Table 5. Solid-phase synthesis of furan-2(5H)-one derivatives 9
9
R1
R2
R3
R5
R6 Yield Purity
(%)a
(%)b
9a Methyl
9b Methyl
9c Methyl
9d Methyl
9e Methyl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Phenyl
H
H
80
78
80
79
77
79
79
78
78
77
77
74
67
82
64
92
90
92
91
90
91
91
90
90
90
89
86
82
Typical Procedure for the Preparation of
Polystyrene-Supported 4-Selenyldihydrofuran-2(3H)-one
(Resin 3)
4-Bromophenyl
4-Methoxylphenyl
Benzyl
H
H
Methyl Phenyl
H
Under a positive pressure of nitrogen, silver triflate (0.154 g,
0.6mmol) was added to a suspension of the swollen selenyl bro-
mide resin 1 (0.59 g, 1.02 mmol Br gꢀ1) in 20 ml THF at 0°C, and
stirred for 15 min; 0.145g (0.06 mmol) HMPA(Se) and 4ml DMF
were then added, and the mixture was warmed to 25°C. 1.8 mmol
But-3-enoic acid derivative 2 in 12 ml THF/DMF (5:1) was added
dropwise to the reaction system. When dripping was completed,
0.6 mmol triethylamine was added; the mixture was heated to
50–60°C and stirred for 6.0–8.0 h.
The resin was collected on a filter and washed successively
with DMF (10 ml × 2), EtOAc (10 ml × 2), H2O (20 ml × 2), THF
(10 ml × 2), THF/ H2O (1:1; 10 ml × 2), THF (10 ml × 2), CH2Cl2
(10 ml × 2), and then dried under vacuum at 45°C overnight to
afford resin 3.
9f
Methyl
H
H
H
H
H
H
H
H
H
H
Cyclohexyl
H
9g Methyl
9h Methyl
Cyclopentyl
Ethyl
H
H
9i
9j
Methyl
Methyl
n-Propyl
n-Pentyl
n-Hexyl
n-Heptyl
CH3
H
H
9k Methyl
9l Methyl
9m Methyl
H
H
CH3
66
CH3
9n ―(CH2)5―
9o Methyl
―(CH2)5―
CH3
H
81
aYield of crude product based on loading of resin 1 (Br, 1.02 mmol gꢀ1).
bDetermined by HPLC (λ = 254 nm, acetonitrile/H2O = 80/20 (v/v),
1.0 ml minꢀ1).
Typical Procedure for the Preparation of Furan-2(5H)-one
Derivatives 4 (Products 4a–p)
Conclusion
The resin 3 was suspended in THF (20 ml), 30% H2O2 (6.0mmol)
was added at 0°C, and the mixture was stirred for 0.5 h, then
warmed to 25°C and stirred for 1–2 h. The mixture was filtered
and the resin was washed with THF (10 ml × 2), CH2Cl2 (15 ml × 3).
The filtrate was washed with saturated sodium chloride solution
(35 ml × 2), dried with anhydrous magnesium sulfate, and
evaporated to dryness under vacuum to obtain the crude prod-
ucts 4a–p. Further purification was via flash chromatography
with petroleum ether–EtOAc (6:1–4:1, v/v) as the eluent for mi-
We have developed an efficient and practical solid-phase parallel
synthetic route for a furan-2(5H)-one derivative library using poly-
mer-supported selenium resin. The synthetic strategy includes
selenopolystyrene resin-induced electrophilic lactonization
catalyzed by Lewis base, lithiation, nucleophilic substitution and
oxidation–elimination of the selenium resins. The advantages of
this method include straightforward operation and synthetic se-
quence, lack of odor, good stability of the supported selenium
species resin, good purity and high yield of the product. In addi-
tion, the easy workup procedure makes the method suitable for
building parallel libraries.
1
croanalysis. H NMR data of 4a–f, 4h, 4i, 4k, 4m, 4o and 4p are
provided online as supporting information, and were consistent
with data reported in the corresponding literature.
5-Octylfuran-2(5H)-one 4g
Colorless oil; 1H NMR (CDCl3) δ 7.43 (dd, J = 5.6, 1.6 Hz, 1H,
4-CH¼), 6.16 (dd, J = 5.6, 2.0 Hz, 1H, 3-CH¼), 5.12 (m, 1H, CH),
1.84–1.61 (m, 2H, CH2), 1.49–1.26 (m, 12H, 6 × CH2), 0.89 (t,
J = 6.4Hz, 3H, CH3); 13C NMR (CDCl3) δ 172.95 (C¼O), 154.30(4-
CH¼), 123.02(3-CH¼), 81.81(CH), 33.30, 31.81, 29.32, 29.25,
29.10, 24.86, 22.60 (7 × CH2), 14.08 (CH3). GC-MS (EI): m/z 196
(M+). HRMS (EI): m/z calcd for C12H20O2 [M]+: 196.1463; found:
196.1474.
Experimental
General Methods
Melting points were determined on an OptiMelt instrument and
were uncorrected. Starting materials were obtained from
commercial suppliers and used without further purification. THF
was distilled from sodium/benzophenone immediately prior to
use. Polystyrene (H 1000, 100–200 mesh, crosslinked with 1%
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Copyright © 2014 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. (2014)

Solid-phase synthesis of furan-2(5H)-one derivatives
5-(4-Bromophenyl)furan-2(5H)-one 4j
1747, 1663, 1370, 1047. HRMS (EI): m/z calcd for C9H12O4 [M]+:
184.0736; found: 184.0725.
1
Pale-yellow oil; H NMR (CDCl3) δ 7.56 (d, J = 8.0, 2H, Ar–H), 7.51
(d, J = 5.6, 1.8 Hz, 1H, 4-CH¼), 7.17 (d, J = 8.0, 2H, Ar–H), 6.25
(d, J = 5.6, 2.0 Hz, 1H, 3-CH¼), 5.97 (m, 1H, CH); 13C NMR (CDCl3)
δ 172.61(C¼O), 155.24, 133.32, 132.22, 128.15, 123.50, 121.26,
84.01. GC-MS (EI): m/z 238 (M+), 240 (M + 2)+. HRMS (EI): m/z calcd
for C10H7BrO2 [M]+: 237.9629; found: 237.9640.
Ethyl 2-(5-ethyl-2-oxo-2,5-dihydrofuran-3-yl)acetate 7d
1
Pale-yellow oil; H NMR (CDCl3) δ 7.39 (q, J = 2.0 Hz, 1H, 4-CH¼),
5.02–4.9 (qq, J = 6.0Hz, 2.0Hz, 1H, CH), 4.18 (q, J = 7.8Hz, 2H,
OCH2CH3), 3.34 (t, J = 2.0Hz, 2H, CH2COOCH3), 1.94–1.56 (m, 2H,
CHCH2CH3), 1.26 (t, J = 7.8Hz, 3H, O CH2CH3), 0.99 (t, J = 8.0 Hz, 3H,
CH3); 13C NMR (CDCl3) δ 173.09 (C¼O), 169.48 (COOEt), 151.30
(¼CH), 127.06 (C), 82.67 (CH), 61.28 (OCH2CH3), 30.47 (CH2COOEt),
26.40 (CH2), 14.08 (CH3), 8.91 (CH2CH3). GC-MS (EI): m/z 198 (M+).
IRνmax (cmꢀ1): 2960, 2871, 1756, 1748, 1666, 1369, 1048. HRMS
(EI): m/z calcd for C9H12O4 [M]+: 198.0892; found: 198.0901.
4-Phenyl-1-oxaspiro[4.5]dec-3-en-2-one 4l
White solid; m.p. 77–79°C; 1H NMR (CDCl3) δ 7.54–7.50 (m, 2H,
Ph–H), 7.49–7.44 (m, 3H, Ph–H), 6.16 (s, 1H, 3-CH¼), 2.01–1.94
(m, 2H, CH2), 1.88–1.72 (m, 8H, 4 × CH2); 13C NMR (CDCl3) δ
172.81 (C¼O), 171.79 (C¼), 131.14 (Ph–C), 130.33 (Ph–C), 128.98
(Ph–C), 127.63 (¼CH), 115.79 (Ph–C), 89.45(C), 34.53, 24.63,
22.24 (5 × CH2). GC-MS (EI): m/z 228 (M+). IRνmax (cmꢀ1): 3062,
2932, 1750, 1608, 1571, 1446, 1275. HRMS (EI): m/z calcd for
C15H16O2 [M]+: 228.1150; found: 228.1158.
3-Methyl-5-phenylfuran-2(5H)-one 7l
Colorless oil; 1H NMR (CDCl3) δ 7.44–7.32 (m, 3H, Ar–H), 7.29–7.22 (m,
2H, Ar–H), 7.13–7.10 (m, 1H, 4-CH¼), 5.88–5.83 (m, 1H, Ar–CH), 2.00
(s, 3H, CH3); 13C NMR (CDCl3) δ 174.27(C¼O), 148.36 (–CH¼), 135.12
(Ph–C), 129.47 (Ph–C), 129.04 (Ph–C), 128.91 (–C¼), 126.31 (Ar–C),
82.08 (Ph–CH), 10.55 (CH3). GC-MS (EI): m/z 147 (M+). IRνmax (cmꢀ1):
3031, 2960, 1749, 1468, 1342, 755, 697; GC-MS (EI): m/z 147 (M+).
HRMS (EI): m/z calcd for C11H10O2 [M]+: 174.0681; found: 174.0672.
5,5-Dimethyl-4-phenylfuran-2(5H)-one 4n
White solid; m.p. 89–91°C. 1H NMR (CDCl3) δ 7.56–7.53 (m, 2H,
Ph–H), 7.49–7.45 (m, 3H, Ph–H), 6.24 (s, 1H, 3-CH¼), 1.73 (s, 6H,
2 × CH3); 13C NMR (CDCl3) δ 172.09 (C¼O), 171.48 (C¼), 130.90
(Ph–C), 130.23 (Ph–C), 129.08 (Ph–C), 127.59 (¼CH), 114.78
(Ph–C), 87.38(CH), 26.29 (2 × CH3). GC-MS (EI): m/z 188 (M+). IRνmax
(cmꢀ1): 3062, 2924, 1766, 1740, 1611, 1445, 1371, 1116, 981.
HRMS (EI): m/z calcd for C12H12O2 [M]+: 188.0837; found:
188.0826.
3-Isopropyl-1-oxaspiro[4.5]dec-3-en-2-one 7r
1
White solid; m.p. 95–97°C; H NMR (CDCl3) δ 6.95 (s, 1H, 4-CH¼),
2.67–2.60 (m, 1H, CH), 1.76–1.24 (m, 10H, 5 × CH2), 1.15 (d,
J = 6.8Hz, 6H, 2 × CH3), 1.88–1.24 (m, 10H, 5 × CH2); 13C NMR
(CDCl3) δ 172.74 (C¼O), 150.52 (–CH¼), 139.11 (C¼), 85.76
(O–C), 35.01 (CH), 25.32 (CH2), 24.72 (CH2), 22.54 (CH2), 21.02
(CH3). GC-MS (EI): m/z 194 (M+). IRνmax (cmꢀ1): 3009, 2961, 2931,
2850, 1747, 1452, 1382, 1368. HRMS (EI): m/z calcd for C12H18O2
[M]+: 194.1307; found: 194.1298.
Typical Procedure for the Preparation of furan-2(5H)-one
Derivatives 7 (Products 7a–r)
Under a positive pressure of nitrogen, to a suspension of the
swollen prepared resin 3 (0.6 mmol) in THF (20 ml) was added
LDA (0.36 ml, 2 mmol mlꢀ1) at ꢀ70°C, stirred for 0.5 h. To this so-
lution was added 0.72 mmol alkyl halides (R4X) in THF via a sy-
ringe; the mixture was stirred for 45 min, warmed to ꢀ30°C and
stirred for a further 15 min. The reaction was quenched with 5
ml water. The mixture was filtered to obtain resin 6, which was
washed with H2O (30 ml × 2), THF (10 ml × 2), H2O (30 ml × 1),
THF (10 ml × 2), THF/H2O (1:1) (20 ml × 2), THF (10 ml × 1),
THF/H2O (1:1) (20 mL × 2) and THF (10 ml × 2).
Typical Procedure for the Preparation of Furan-2(5H)-one
Derivatives 9 (Products 9a–o)
Under a positive pressure of nitrogen, to a suspension of the
swollen prepared resin 3 (0.6 mmol) in THF (20 ml) was added
LDA (0.36 ml, 2 mmol mlꢀ1) at ꢀ70°C, stirred for 0.5 h. To this so-
lution was added 0.72 mmol aldehyde or ketone in THF via a sy-
ringe; the mixture was stirred for 45 min, warmed to ꢀ30°C and
stirred for a further 15 min. The reaction was quenched with 5
ml water. The mixture was filtered to obtain resin 8, which was
washed with H2O (30 ml × 2 ), THF (10 ml × 2), H2O (30 ml × 1),
THF (10 ml × 2), DMF (10 ml × 2), THF/H2O (1:1) (20 ml × 2), THF
(10 ml × 1), THF/H2O (1:1) (20 ml × 2) and THF (10 ml × 2).
The resin 8 was suspended in THF (20 ml), 30% H2O2 (6.0mmol)
was added at 0°C, and the mixture was stirred for 0.5 h, then
warmed to 25°C and stirred for 2 h. The mixture was filtered,
and the resin was washed with THF (10 ml × 2), CH2Cl2 (15 ml × 3).
The filtrate was washed with saturated sodium chloride solution
(35 ml × 2), dried with anhydrous magnesium sulfate, and evapo-
rated to dryness under vacuum to obtain the crude products
9a–n. Further purification was via flash chromatography with
petroleum ether–EtOAc (1:1, v/v) as the eluent for microanalysis.
1H NMR data of 9a, 9b, 9f, 9h–9l and 9n are given in the
supporting information, and were consistent with data reported
in the corresponding literature.
The resin 7 was suspended in THF (20 ml), 30% H2O2 (6.0mmol)
was added at 0 °C, and the mixture was stirred for 0.5 h, then
warm to 25 °C and stirred for 2h. The mixture was filtered, and
the resin was washed with THF (10 ml × 2), CH2Cl2 (15 ml × 3).
The filtrate was washed with saturated sodium chloride solution
(35 ml × 2), dried with anhydrous magnesium sulfate, and evapo-
rated to dryness under vacuum to obtain the crude products 7a–
r. Further purification was via flash chromatography with
petroleum ether–EtOAc (6:1–3:1, v/v) as the eluent for microanal-
1
yses. H NMR data of 7a, 7b, 7e–k and 7m–q are given in the
supporting information, and were consistent with data reported
in the corresponding literature.
Methyl 2-(4,5-dimethyl-2-oxo-2,5-dihydrofuran-3-yl)acetate 7c
1
Pale-yellow oil; H NMR (CDCl3) δ 5.11 (qq, J = 6.0 Hz, 2.0 Hz, 1H,
CH), 3.73 (s, 3H, OCH3), 3.35 (t, J = 2.0 Hz, 2H, CH2COOCH3), 1.84
(s, 3H, CH3), 1.42 (s, J = 6.0 Hz, 3H, CH3); 13C NMR (CDCl3) δ
172.95 (C¼O), 169.82 (COOCH3), 152.66 (¼CH), 126.53 (C), 78.04
(CH), 52.23 (COOCH3), 30.15 (CH2COOCH3), 16.68 (CH3), 14.74
(CH3). GC-MS (EI): m/z 184 (M+). IRνmax (cmꢀ1): 2960, 2871, 1758,
3-(Hydroxy(4-methoxyphenyl)methyl)-5-methylfuran-2(5H)-one 9c
Pale-yellow oil; 1H NMR (400 MHz): δ 7.33 (d, J = 9.0 Hz, 2H, Ar–H),
7.01 (d, J = 1.5 Hz, 1H, 4-CH¼), 6.91 (d, J = 9.0 Hz, 2H, Ar–H), 5.56
Appl. Organometal. Chem. (2014)
Copyright © 2014 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

R. Jun He et al.
(m, 1H, CH), 5.11 (m, 1H, CH), 3.81 (s, 3H, OCH3), 3.01 (s, 1H, OH),
1.45 (d, J = 6.9 Hz, 3H, CH3); 13C NMR (100 MHz): δ 172.47 (C¼O),
161.50 (Ar–C–OCH3), 151.02 (–CH¼), 138.23(¼CCO), 128.36
(Ar–C), 115.93 (Ar–C), 114.04 (Ar–C), 78.33 (CHCH3), 68.76 (CH–
OH), 55.01 (O–CH3), 18.91 (CH3). MS (EI) m/z 234 (M)+; IRνmax
(cmꢀ1): 3426, 3029, 2961, 2871, 1742, 1600, 956, 815; HRMS (EI):
m/z calcd for C13H14O4 [M]+: 234.0892; found: 234.0901.
(CH–CH3). GC-MS (EI) m/z 218 (M)+; IRνmax (cmꢀ1): 3410, 3028,
2962, 2928, 1748, 1320, 1249, 1110, 695, 753; HRMS (EI): m/z calcd
for C13H14O3 [M]+: 218.0943; found: 218.0952.
Acknowledgments
We are grateful for the financial support of the Natural Science
Foundation of China (Project No. 21202151) and the Science
and Technology Department of Zhejiang Province Foundation
of China (Project No. 2010C32022).
3-(1-Hydroxy-2-phenylethyl)-5-methylfuran-2(5H)-one 9d
Pale-yellow oil; 1H NMR(400 MHz): δ 7.36–7.29 (m, 5H, Ar–H), 7.15
(d, J = 1.6 Hz, 1H, 4-CH¼), 5.15–5.13 (m, 1H, CH), 5.04–5.02 (m, 1H,
CH), 3.08 (s, 1H, OH), 2.73–2.60 (m, 2H, CH2), 1.46 (d, J = 6.9 Hz, 3H,
CH3); 13C NMR (100 MHz): δ 172.61 (C¼O), 150.03 (–CH¼), 138.23
(C¼), 136.92 (Ar–C), 128.31 (Ar–C), 127.94 (Ar–C), 126.60 (Ar–C),
78.16 (CHCH3), 69.21 (CH–OH), 41.55 (CH2), 18.85 (CH3). GC-MS
(EI) m/z 218 (M)+; IRνmax (cmꢀ1): 3448, 3029, 1745, 1501, 1112,
753; 695. HRMS (EI): m/z calcd for C13H14O3 [M]+: 218.0943; found:
218.0952.
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3-(Hydroxy(phenyl)methyl)-4,5-dimethylfuran-2(5H)-one 9e
Pale-yellow oil; 1H NMR (400 MHz): δ 7.54–7.46 (m, 2H, Ph–H),
7.29–7.18 (m, 3H, Ph–H), 5.58 (t, J = 1.6Hz, 1H, CH–OH), 5.02 (q,
J = 6.0, 1H, CH), 3.44 (s, 1H, OH), 1.90 (s, 3H), 1.39 (d, J = 6.0Hz,
3H); 13C NMR(100 MHz): δ 173.02 (CO), 166.5, (¼CCH3), 137.89
(¼CCO), 136.56 (Ph–C), 129.01 (Ph–C), 128.64 (Ph–C), 126.03
(Ph–C), 78.57 (CHCH3), 69.31 (CH–OH), 20.085 (¼C–CH3), 17.45
(CH–CH3). GC-MS (EI) m/z 218 (M)+; IRνmax (cmꢀ1): 3408, 3023,
1749, 1248, 1110, 895, 753, 696. HRMS (EI): m/z calcd for
C13H14O3 [M]+: 218.0943; found: 218.0950.
3-(Cyclopentyl(hydroxy)methyl)-5-methylfuran-2(5H)-one 9g
Pale-yellow oil; 1H-NMR (400 MHz): δ 7.20 (d, J = 1.4Hz, 1H, 4-
CH¼), 5.10–5.04 (m, 1H, CH), 4.32 (m, 1H, CH), 3.02 (s, 1H, OH),
2.05–1.51 (m, 5H), 1.45 (d, J = 6.8Hz, 3H, CH3), 1.16–0.90 (m, 4H);
13C NMR (100 MHz): δ 172.70(C¼O), 150.48(–CH¼), 134.80(C¼),
78.01 (CHCH3), 71.85 (CH–OH), 42.55 (CH), 30.21 (CH2), 28.86
(CH2), 26.45 (CH2), 26.02 (CH2), 19.11 (CH3). GC-MS (EI) m/z 196
(M)+; IRνmax (cmꢀ1): 3438, 2978, 2930, 1743, 1321, 1113; HRMS
(EI): m/z calcd for C11H16O3 [M]+: 196.1099; found: 196.1105.
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3-(2-Hydroxypropan-2-yl)-5-methylfuran-2(5H)-one 9m
Colorless oil; 1H NMR (400 MHz): δ 7.19 (d, J = 1.4 Hz, 1H, 4-CH¼),
5.08–5.04 (m, 1H, 5-CH), 3.35 (s, 1H, OH), 1.63 (s, 6H, 2 × CH3), 1.45
(d, J = 6.9 Hz, 3H, CH3); 13C NMR(100 MHz): δ 172.24(C¼O), 150.12
(–CH¼), 137.26(C¼), 78.73 (CHCH3), 68.78 (CH¼OH), 26.51
(2 × CH3), 19.12 (CH3). GC-MS (EI) m/z 156 (M)+; IRνmax (cmꢀ1):
3438, 2931, 2856, 1747, 1457, 1321, 1200, 1114, 952; HRMS (EI):
m/z calcd for C8H12O3 [M]+: 156.0786; found: 156.0777.
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3-(1-Hydroxy-1-phenylethyl)-5-methylfuran-2(5H)-one 9o
Pale-yellow oil; 1H NMR (400 MHz): δ 7.59–7.54 (m, 2H, Ph–H),
7.24–7.16 (m, 3H, Ph–H), 7.10 (d, J = 1.6 Hz, 1H, 4-CH¼), 5.44 (dt,
J = 6.8, 1.6Hz, 1H, 5-CH), 3.41 (s, 1H, OH), 1.76 (s, 3H, CH3), 1.43 Supporting Information
(d, J = 6.9Hz, 3H, CH3); 13C NMR (100 MHz): δ 172.45 (C¼O),
151.03 (–CH¼), 141.35 (¼CCO), 136.28, 128.80, 128.37, 126.51
(6 × Ph–C), 78.27 (CHCH3), 71.22 (C–OH), 28.95 (C–CH3), 19.00
Additional supporting information may be found in the online
version of this article at the publisher’s web-site.
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Appl. Organometal. Chem. (2014)