Synthesis of Sulfonylated Lactones via Ag-Catalyzed Cascade Sulfonylation/Cyclization of 1,6-Enynes with Sodium Sulfinates

Article abstract of DOI:10.1021/acs.joc.6b02416

A novel strategy for the synthesis of sulfonylated lactones via Ag-catalyzed radical addition/cyclization reaction of 1,6-enynes and sodium sulfinates has been developed. The reaction presents high stereoselectivity under mild conditions with C4 prochiral center construction in one step. The ESR experiments and relevant mechanistic studies indicated that a radical pathway should be involved in this transformation.

Full text of DOI:10.1021/acs.joc.6b02416

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Note
Synthesis of Sulfonylated Lactones via Ag-Catalyzed Cascade
Sulfonylation/Cyclization of 1,6-Enynes with Sodium Sulfinates
Wanqing Wu, Songjian Yi, Yue Yu, Wei Huang, and Huanfeng Jiang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02416 • Publication Date (Web): 28 Dec 2016
Downloaded from http://pubs.acs.org on December 29, 2016
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Synthesis of Sulfonylated Lactones via AgꢀCatalyzed
Cascade Sulfonylation/Cyclization of 1,6ꢀEnynes with
Sodium Sulfinates
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Wanqing Wu,* Songjian Yi, Yue Yu, Wei Huang and Huanfeng Jiang*
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of
Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640,
China
Fax: (+86) 20ꢀ8711ꢀ2906; Eꢀmail: cewuwq@scut.edu.cn, jianghf@scut.edu.cn
Abstract: A novel strategy for the synthesis of sulfonylated lactones via Agꢀcatalyzed
radical addition/cyclization reaction of 1,6ꢀenynes and sodium sulfinates has been
developed. The reaction presents high stereoselectivity under mild conditions with C4
prochiral center construction in one step. The ESR experiments and relevant
mechanistic studies indicated that a radical pathway should be involved in this
transformation.
There has been a growing interest in the rational design of drugꢀframework molecules
through the introduction of different kinds of special functional groups.1 Owing to the
distinctive structure and electronic features, the sulfonyl group is one of the most
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important members of this family, which has been extensively exploited in medicinal
chemistry and agrochemical industry.2 In view of these applications, several elegant
methods for incorporating the sulfonyl group into organic molecules by transition
metalꢀcatalyzed3 as well as free radicalꢀmediated4 pathways have been established.
Nevertheless, the scope of sulfonyl substrates was usually limited and the reaction
conditions were relatively harsh. Therefore, the development of versatile and efficient
methods for constructing different useful skeletons bearing sulfonyl group is highly
desirable.
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In addition, αꢀmethyleneꢀγꢀbutyrolactones are ubiquitous subunits in a wide variety
of sequiterpenes, which are known to possess significant biological activities.5 The
exocyclic double bond is considered not only to be responsible for the interesting
biological properties of γꢀlactones, but also serve as a functional group for further
manipulations in organic synthesis.6 The development of methods facilitating the
synthesis of γꢀlactones has attracted attention from many research groups due to their
intriguing biological activities and their potential as synthetic intermediates7,8 For
example, Zhang’s group has reported the Rhꢀcatalyzed oxidative cyclization of the
enyne substrates to construct the γꢀlactone products.7d Recently, a Pdꢀcatalyzed
intermolecular carboesterification of alkenes with alkynes for the synthesis of
αꢀmethyleneꢀγꢀbutyrolactones has been developed by our group.9a However, most of
these methods required prefunctionalized precursors or noble transitionꢀmetals, which
generated the haloꢀsubstituted double bond products. Besides, to the best of our
knowledge, the introduction of sulfone groups into the unique lactone skeleton is still
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less explored. As part of our continuing program on γꢀlactone synthesis9 and
sulfonylation reactions,10 herein, we disclose a convenient and concise method for the
construction of diverse sulfonylated lactones by using sulfinate sodium as the key
starting materials and AgNO3 as catalyst in a oneꢀpot manner.11 This method provides
an efficient entry to the monoꢀsubstituted alkene lactone products with C4 prochiral
center, which should find the potential applications in natural product synthesis and
medicinal chemistry (Scheme 1).
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Scheme 1. Methods for Sulfonylated γꢀLactones
Initially, we chose 2ꢀmethylallyl 3ꢀphenylpropiolate (1a) and sodium
benzensulfinate (2a) as the model substrates for the condition optimization (Table 1).
As expected, when 1a was treated with 2a in the presence of 10 mol % of AgNO3 and
K2S2O8 as oxidant at 90 oC for 12 h, the desired sulfonylated lactone 3aa was detected
in 40% GC yield (Table 1, entry 1). And the molecular structure of 3aa was
unambiguously determined by Xꢀray crystallographic analysis (see the Supporting
Information for details).12 Subsequent survey on a series of representative oxidants
revealed that K2S2O8 gave the best result, however, TBHP, CuO, DDQ or PhI(OAc)2
was not suitable for this reaction (Table 1, entries 2ꢀ5). These results suggested that
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both Ag(0) and Ag(I) were efficient for this cyclization reaction, although the yields
were not enhanced obviously (Table 1, entries 6ꢀ8). According to the literature,13 we
supposed that the nitrates or diluted nitric acid might have an acceleration effect on
this reaction, and different nitrates as well as diluted nitric acid were screened for this
transformation. When 2.0 equivalents of Zn(NO3)2·6H2O was used as an additive, the
desired product 3aa was obtained in 58% yield (Table 1, entry 13). Pleasingly, when
0.25 mL HNO3 (0.4 M) was added into the reaction, the yield of 3aa was improved to
74% (Table 1, entry 15). Control experiments indicated that the product yield declined
obviously in the absence of Ag catalyst (Table 1, entry 16). Additionally, when
lowering the reaction temperature, the yield of 3aa declined dramatically. Thus, the
optimized reaction conditions were affirmed as follows: 10 mol % AgNO3 as the
catalyst, 2.0 equiv of K2S2O8 and HNO3 (0.4 M, 0.25 mL) as the additive in CH3CN
at 90 °C for 12 h.
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Table 1. Optimization of Reaction Conditionsa
Entry a
Catalyst
Oxidant
Additive
Yield (%)b
1
2
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
Ag2O
K2S2O8
TBHP
ꢀ
40
N.R.
N.D.
N.R.
N.R.
25
-
3
CuO
4
DDQ
-
5
PhI(OAc)2
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
ꢀ
6
ꢀ
7
AgCO3
Ag
ꢀ
34
8
ꢀ
22
9
AgNO3
AgNO3
Fe(NO3)3
Ca(NO3)2
trace
trace
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AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
-
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
Mg(NO3)2 6H2O
9
.
Cu(NO3)2 3H2O
14
58
34
74
23
.
Zn(NO3)2 6H2O
HNO3 (4.0 equiv)
HNO3 (1.0 equiv)
HNO3 (1.0 equiv)
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a Reaction conditions: All reactions were performed with 1a (0.1 mmol), 2a (2.0 equiv), catalyst (10 mol %),
o
additive (2.0 equiv), 1.0 mL solvent at 90 C for 12 h unless otherwise noted. N.R. = no reaction. N.D. = not
detected. b Determined by GCꢀMS.
With the optimized conditions in hand, the substrate scope of sodium sulfinates was
examined. As shown in Table 2, the reactions of sodium benzensulfinates bearing
both electronꢀdonating (e.g., Me, tꢀBu) and electronꢀwithdrawing groups (e.g., F, CF3)
at paraꢀposition on the aryl ring worked well under the optimal conditions and
afforded the corresponding γꢀlactones 3aaꢀ3ai in moderate yields. In most cases,
1
excellent Z/E ratios were obtained, which were determined by HꢀNMR analysis.
Metaꢀ and orthoꢀsubstituents on the phenyl ring were well tolerated under this
condition (3aj, 3ak). The transformation of disubstituted substrate also proceeded
well to give the desired product 3al. To our delight, the alkyl sodium sulfinates, such
as methyl, ethyl and cyclopropyl were compatible with this protocol and transferred to
the corresponding products 3amꢀ3ao in good to excellent yields. However, the
reactions of heterocyclic substituted sodium sulfinates failed to provide the desired
products under the current catalytic conditions (3ap and 3aq).
Table 2. The Reactions of 1a with Different Sodium Sulfinates 2a, b
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a Reaction conditions: 1a (0.5 mmol), 2 (1.0 mmol), AgNO3 (10 mol %), K2S2O8 (2 equiv) and HNO3 (0.4 M, 0.25
mL) in 2 mL CH3CN at 90 oC for 12 h unless otherwise noted. n.d. = not detected. b Determined by GCꢀMS. cThe
ratio of E/Z was determined by 1HꢀNMR analysis.
After successfully investigating the range of sodium sulfinates, we next evaluated
the scope of 1,6ꢀenynes. As depicted in Table 3, for the paraꢀposition of phenyl ring,
the reactions with electronꢀwithdrawing groups (e.g., F, CF3) provided similar yields
to those with electronꢀdonating groups (e.g., Me, Et). Interestingly, the reaction of
2ꢀmethylallyl 3ꢀ(4ꢀ(trifluoromethyl)phenyl) propiolate gave 3fa in 75% yield.
Moreover, the 1,6ꢀenynes with metaꢀsubstituent at ring position were found to be
suitable for this reaction and transfer to the corresponding products 3gaꢀ3ia in
moderate yields. It was worth noting that 2ꢀF substitution on the phenyl ring provided
the better yield (67%) than that with 2ꢀCl substitution. The dependence of the yield
upon substitution partners was likely relied on the corresponding steric hindrance.
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When R1 was alkyl substitution, the reaction proceeded smoothly to provide the target
products 3la and 3ma in 65% and 62% yields, respectively. In addition, the
heterocyclic group, such as thienyl, attached to the triple bond was also compatible
with the reaction conditions, affording the desired lactone product 3oa in moderate
yield. Substrate with germinal substituents could be converted to the corresponding
product 3na in 72% yield. When substituted allylic enyne substrate was applied to the
standard conditions, 72% yield of product 3pa was isolated, whereas no reaction
occurred in the case of unsubstituted olefin (R2 = H), indicating that the substituents
in the internal position of the alkene affected the yield dramatically.
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Table 3. The Reactions of Different 1,6ꢀEnynes 1 with 2aa, b
AgNO3 (10 mol %)
H
K2S2O8 (2.0 equiv)
HNO3 (1.0 equiv)
R1
R2
O
O
O
R1
+
Ph SO2Na
SO2Ph
CH3CN (2 mL)
90 oC, 12 h
O
R2
1
2a
3
R'
R'
H
H
R'
H
O
O
O
SO2Ph
SO2Ph
E/Zc
O
O
SO2Ph
E/Z
O
3ba,
R' = Me, 77%,
> 20:1
3ja,
R' = F, 67%,
3ga,
E/Z
= 5:1
R' = Me, 60%,
> 20:1
3ca, R' = Et, 74%, E/Z = 7:1
3da, R' = F, 70%, E/Z = 3:1
3ka, R' = Cl, trace
3ha, R' = Cl, 60%, E/Z = 3:1
3ia, R' = Br, 45%, E/Z = 1:1
H
3ea,
3fa,
E/Z
R' = Cl, 65%,
= 12:1
H
R' = CF3, 75%,
E/Z
= 9:1
O
O
SO2Ph
O
SO2Ph
O
Me
H
3la, 65%, E/Z > 20:1
3ma, 62%, E/Z > 20:1
Me
O
H
S
H
SO2Ph
O
O
O
3na, 72%, E/Z > 20:1
SO2Ph
SO2Ph
O
O
3pa, 72%, E/Z= 7:1
3oa,
E/Z
= 6:1
52%,
a Reaction conditions: 1a (0.5 mmol), 2 (1.0 mmol), AgNO3 (10 mol %), K2S2O8 (2 equiv) and HNO3 (0.4 M, 0.25
c
mL) in 2 mL CH3CN at 90 oC for 12 h unless otherwise was noted. b Determined by GCꢀMS. The ratio of E/Z was
determined by 1HꢀNMR analysis.
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Furthermore, the reaction is scalable and practical since a synthetically useful yield
(52%) of the sulfonylated lactone product was obtained when the reaction was
performed on 5 mmol scales (Scheme 2).
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Scheme 2. GramꢀScale of the Reaction
To gain more insight into the mechanism of this reaction, several control
experiments were performed (see the Supporting Information for details). First, when
the radical scavenger TEMPO (2 equiv) or BHT (2 equiv) was added under the
standard conditions, the yield of product 3aa declined obviously, indicating the
transformation should proceed via a freeꢀradical pathway. The electron spin resonance
(ESR) experiments were further conducted to support the sulfonyl radical
intermediate.14 An isotopic labeling study with D2O was then performed and the
kinetic isotope effect radio of 3am/3amꢀd was 0.42, which suggested that the source
of hydrogen might come from HNO3 or H2O. Moreover, the observation of pH
experiment was consistent with our assumption. The value increased from 0.40 to
0.61, suggesting that the diluted nitric acid could stimulate the last step of hydrolysis
and enhance the product yield. It should be noted that when using the complex
PhSO2Ag (A) as the catalyst, the reaction proceeded smoothly and afforded the
lactone product in 51% yield, which proved that A should be the key intermediate in
this process.
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Base on the above results and previous reports, a possible mechanism for this
transformation was proposed in Scheme 3. First, complex A is formed from sodium
sulfinate and AgNO3, which is supposed to be the key step in this transformation.
When A is generated, it may undergo the Path A involving a sliverꢀpromoted
generation of the sulfonyl radical B (Scheme 4, Path A), which subsequently adds to
1a to give the alkyl radical D. Another possibility for the formation of the alkyl
radical D is the addition of A to 1a and provides the silver(I) species C, followed by
the oxidation to form the alkyl radical D (Scheme 4, Path B). The resulting alkyl
radical D then undergoes an intramolecular radical addition and cyclization reaction
to afford the intermediate E. Finally, there may be a SET process to E from Ag(0) to
Ag(I) and then give a vinyl anion H, which was subsequently protonated by HNO3 or
H2O to give the desired product 3aa. The model reaction was also monitored by mass
spectrometry experiment (See the Supporting Information for details). It is worth
noting that the ESIꢀMS shows peaks at m/z 304.9914 and m/z 705.1578, which are
corresponding to [G+H]+ and [F+H]+, respectively. These signals suggested that the
sulfonyl radical was formed during the reaction, which strongly supporting our
hypothesis that a radical pathway should be involved in this chemical process.
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Scheme 3. Tentative Mechanism
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In conclusion, we have established a highly efficient protocol for the synthesis of
various
sulfonylated
lactones
via
Agꢀcatalyzed
radical
cascade
sulfonylation/cyclization of 1,6ꢀenynes with sodium sulfinates, which would be useful
in organic synthesis and medicinal chemistry. With the green sodium sulfinate and
AgNO3 catalyst, this reaction shows high efficiency and selectivity, as well as broad
substrate scope. The exocyclic monoꢀsubstituted double bond and C4 prochiral center
also make the present protocol very attractive, which will find its potential
applications in the synthesis of more complex and significant pharmaceuticals.15
Experimental Section
General Information. Melting points were measured with a melting point instrument
1
and were uncorrected. H and 13C NMR spectra were recorded using a 400/600 MHz
NMR spectrometer. The chemical shifts are referenced to signals at 7.26 and 77.0
ppm, respectively, and CDCl3 is solvent. IR spectra were recorded on an FTꢀIR
spectrometer using KBr discs. Melting points were taken on an electrothermal melting
point apparatus and without correction. GC–MS was obtained using electron
ionization. HRMS was obtained with a LCMSꢀITꢀTOF mass spectrometer. TLC was
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performed by using commercially prepared 100–400 mesh silica gel plates and
visualization was effected at 254 nm.
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General procedure for the preparation of 1,6ꢀenyne derivatives (1). To a mixture
of propiolic acid (10.0 equiv) and allyl alcohol (1.2 equiv) in CH2Cl2 (5 mL) was
added a solution of DMAP (10 mol %) and DCC (1.5 equiv) in CH2Cl2 (5 mL) at 0 °C.
The reaction mixture was stirred for 10 h at 25 °C and filtered through a short plug of
silica gel, which was rinsed with hexanes/EtOAc = 2/1. The filtrate was concentrated
in vacuum and the residue was purified by column chromatography on silica gel
(hexanes/EtOAc = 10/1) to give 1.
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General procedure for the preparation of sodium sulfinate derivatives (2). To a
mixture of sodium bicarbonate (2.0 equiv) and sodium sulfite (2.0 equiv) in H2O, was
added sulfonyl chloride (5 mmol) at room temperature. The reaction mixture was
o
stirred for 10 h at 80 C and then cooled down to room temperature. Excess H2SO4
was added to make the solution reach pH = 1 and extracted with ethyl acetate (3 × 20
mL). The combined organic layer was removed under vacuum and then about 10 mL
H2O was added to dissolve the solid. The solvent was basified with aqueous NaOH to
reach pH = 8 and was removed under vacuum to afford the sodium sulfinates 2.
General procedure for the preparation of sulfonylated γꢀlactones (3). To a dried
Schlenk tube was charged with 1,6ꢀenynes 1 (0. 5 mmol, 1.0 equiv), sodium sulfinates
2 (1.0 mmol, 2.0 equiv.), AgNO3 (0.05 mmol, 0.1 equiv.), K2S2O8 (1.0 mmol, 2.0
equiv.), HNO3 (0.4 M, 0.25 mL) and CH3CN (2 mL), which was equipped with a
o
magnetic stirring bar. The mixture was stirred for 12 h at 80 ~ 90 C. After the
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reaction was completed, saturated NaHCO3 solvent (2 mL) was added to stop the
reaction, and then ethyl acetate (3 × 5 mL) was added into the tube. The combined
organic layers were washed with brine to neutral, dried over MgSO4, and concentrated
in vacuum. Purification of the residue on a preparative TLC afforded the desired
products 3.
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(E)ꢀ3ꢀBenzylideneꢀ4ꢀmethylꢀ4ꢀ((phenylsulfonyl)methyl)dihydrofuranꢀ2(3H)ꢀone
(3aa): Yellow solid (131 mg, 77% yield), m.p. = 129.1 ꢀ 130.2 oC; 1H NMR (400 MHz,
CDCl3) δ ppm 7.75 (d, J = 7.8 Hz, 2H), 7.71 (s, 1H), 7.63 (t, J = 7.3 Hz, 1H), 7.52 (t,
J = 7.6 Hz, 2H), 7.41 ꢀ 7.36 (m, 3H), 7.31 ꢀ 7.28 (m, 2H), 4.72 (d, J = 9.6 Hz, 1H),
4.29 (d, J = 9.6 Hz, 1H), 3.54 (d, J = 14.5 Hz, 1H), 3.17 (d, J = 14.5 Hz, 1H), 1.67 (s,
3H); 13C NMR (101 MHz, CDCl3) δ ppm 170.6, 140.5, 139.7, 134.0, 133.2, 132.5,
129.5, 129.4, 129.1, 128.7, 127.4, 76.3, 60.8, 41.9, 24. 6; IR (KBr) νmax 3628, 3111,
2925, 1753, 1641, 1524, 1310, 1146 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd
for C19H18O4SNa 365.0818; Found 365.0823.
(E)ꢀ3ꢀBenzylideneꢀ4ꢀmethylꢀ4ꢀ(tosylmethyl)dihydrofuranꢀ2(3H)ꢀone
(3ab):
o
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Yellow solid (137 mg, 77% yield), m.p. = 134.2 ꢀ 135.6 C; H NMR (400 MHz,
CDCl3) δ ppm 7.70 (s, 1H), 7.62 (d, J = 7.7 Hz, 2H), 7.41 ꢀ 7.36 (m, 3H), 7.34 ꢀ 7.25
(m, 4H), 4.71 (d, J = 9.6 Hz, 1H), 4.28 (d, J = 9.6 Hz, 1H), 3.53 (d, J = 14.5 Hz, 1H),
3.15 (d, J = 14.5 Hz, 1H), 2.42 (s, 3H), 1.66 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
ppm 170.7, 145.1, 139.6, 137.6, 133.2, 132.5, 129.9, 129.5, 129.2, 128.7, 127.4, 76.3,
60.9, 41.9, 24.5, 21.6; IR (KBr) νmax 3685, 3114, 2982, 1753, 1639, 1526, 1309, 1143
cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C20H20O4SNa 379.0975; Found
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379.0973.
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3ꢀBenzylideneꢀ4ꢀ(((4ꢀethylphenyl)sulfonyl)methyl)ꢀ4ꢀmethyldihydrofuranꢀ2(3H)ꢀ
one (3ac): Yellow solid (136 mg, 74% yield), m.p. = 120.4 ꢀ 121.9 oC; E isomer + Z
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isomer H NMR (400 MHz, CDCl3) δ ppm 7.71 (s, 1H), 7.66 (d, J = 7.8 Hz, 2H),
7.42 ꢀ 7.36 (m, 3H), 7.34ꢀ 7.28 (m,4H), 4.73 (d, J = 9.6 Hz, 1H), 4.29 (d, J = 9.6 Hz,
1H), 3.55 (d, J = 14.5 Hz, 1H), 3.17 (d, J = 14.5 Hz, 1H), 2.72 (q, J = 7.4 Hz, 2H),
1.68 (s, 3H), 1.25 (t, J = 7.3 Hz, 3H); E isomer 13C NMR (101 MHz, CDCl3) δ ppm
170.6, 151.3, 139.7, 137.9, 133.3, 132.6, 129.6, 129.3, 129.0, 128.9, 128.8, 127.6,
76.4, 61.0, 42.0, 289, 24.5, 15.1; IR (KBr) νmax 3690, 3117, 2981, 2756, 1755, 1641,
1525, 1478, 1144 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C21H22O4SNa
393.1131; Found 393.1134.
(E)ꢀ3ꢀBenzylideneꢀ4ꢀ(((4ꢀisopropylphenyl)sulfonyl)methyl)ꢀ4ꢀmethyldihydrofura
o
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nꢀ2(3H)ꢀone (3ad): Yellow solid (147 mg, 77% yield), m.p. = 112.1 ꢀ 113.5 C; H
NMR (400 MHz, CDCl3) δ ppm 7.70 (s, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.42 ꢀ 7.36 (m,
3H), 7.36 (d, J = 8.1 Hz, 2H), 7.32 ꢀ 7.28 (m, 2H), 4.73 (d, J = 9.6 Hz, 1H), 4.28 (d, J
= 9.6 Hz, 1H), 3.54 (d, J = 14.5 Hz, 1H), 3.17 (d, J = 14.5 Hz, 1H), 2.97 (dt, J = 13.5,
6.8 Hz, 1H), 1.68 (s, 3H), 1.25 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ
ppm 170.7, 155.8, 139.6, 137.9, 133.2, 132.5, 129.5, 129.2, 128.7, 127.6, 127.5, 76.3,
60.9, 41.9, 34.2, 24.4, 23.5; IR (KBr) νmax 3692, 3117, 2978, 2753, 1756, 1640, 1525,
1478, 1311, 1145 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C22H24O4SNa
407.1288; Found 407.1286.
3ꢀBenzylideneꢀ4ꢀ(((4ꢀ(tertꢀbutyl)phenyl)sulfonyl)methyl)ꢀ4ꢀmethyldihydrofuranꢀ2
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(3H)ꢀone (3ae): Yellow solid (99 mg, 50% yield), m.p. = 123.5 ꢀ 124.1 C; E isomer
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+ Z isomer H NMR (400 MHz, CDCl3) δ ppm 7.68 ꢀ 7.65 (m, 2H), 7.63 (s, 1H),
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7.49ꢀ7.47 (m, 2H), 7.37 ꢀ 7.33 (m, 3H), 7.29 ꢀ 7.28 (m, 2H), 4.72 (d, J = 9.6 Hz, 1H),
4.23 (d, J = 9.6 Hz, 1H), 3.52 (d, J = 14.6 Hz, 1H), 3.20 (d, J = 14.6 Hz, 1H), 1.62 (s,
3H), 1.27 (s, 9H); E isomer 13C NMR (101 MHz, CDCl3) δ ppm 170.6, 157.9, 139.5,
137.3, 133.0, 132.3, 129.3, 129.1, 128.5, 127.1, 126.2, 76.1, 60.7, 41.6, 35.0, 30.7,
24.4; IR (KBr) νmax 3686, 3115, 2971, 2757, 1756, 1639, 1549, 1478, 1312, 1147 cmꢀ1;
HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C23H26O4SNa 421.1444; Found
421.1447.
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(E)ꢀ3ꢀBenzylideneꢀ4ꢀ(((4ꢀfluorophenyl)sulfonyl)methyl)ꢀ4ꢀmethyldihydrofuranꢀ2(
o
3H)ꢀone (3af): Yellow solid (133 mg; 74% yield), m.p. = 134.5 ꢀ 135.4 C; 1H NMR
(400 MHz, CDCl3) δ ppm 7.78 ꢀ 7.73 (m, 2H), 7.72 (s, 1H), 7.43 ꢀ 7.36 (m, 3H), 7.32
ꢀ 7.27 (m, 2H), 7.18 (t, J = 8.3 Hz, 2H), 4.73 (d, J = 9.6 Hz, 1H), 4.29 (d, J = 9.6 Hz,
1H), 3.50 (d, J = 14.5 Hz, 1H), 3.18 (d, J = 14.4 Hz, 1H), 1.68 (s, 3H); 13C NMR (101
MHz, CDCl3) δ ppm 170.6, 165.9 (d, J = 257.4 Hz), 139.8, 136.6 (d, J = 2.0 Hz),
133.3, 132.4, 130.4 (d, J = 9.7 Hz), 129.6, 129.2, 128.8, 116.8 (d, J = 22.7 Hz), 76.2,
61.1, 42.0, 24.8; 19F NMR (376 MHz, CDCl3) δ ppm ꢀ102.45 (s); IR (KBr) νmax 3692,
3114, 2984, 2766, 1754, 1639, 1525, 1480, 1320, 1144 cmꢀ1; HRMS (ESIꢀTOF) m/z:
[M + Na]+ Calcd for C19H17FO4SNa 383.0724; Found 383.0728.
(E)ꢀ3ꢀBenzylideneꢀ4ꢀ(((4ꢀchlorophenyl)sulfonyl)methyl)ꢀ4ꢀmethyldihydrofuranꢀ2
(3H)ꢀone (3ag): Yellow solid (139 mg, 74% yield), m.p. = 132.5 ꢀ 133.6 oC; 1H NMR
(400 MHz, CDCl3) δ ppm 7.72 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.3 Hz,
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2H), 7.42 ꢀ 7.38 (m, 3H), 7.32 ꢀ 7.28 (m, 2H), 4.73 (d, J = 9.6 Hz, 1H), 4.30 (d, J =
9.6 Hz, 1H), 3.51 (d, J = 14.5 Hz, 1H), 3.18 (d, J = 14.5 Hz, 1H), 1.69 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ ppm 173.9, 140.9, 140.0, 138.9, 133.2, 132.3, 129.7,
129.6, 129.2, 128.9, 128.8, 76.2, 60.9, 41.9, 24.8; IR (KBr) νmax 3691, 3110, 2983,
2766, 1755, 1634, 1526, 1478, 1321, 1145 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+
Calcd for C19H17ClO4SNa 399.0428; Found 399.0430.
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(E)ꢀ3ꢀBenzylideneꢀ4ꢀmethylꢀ4ꢀ(((4ꢀ(trifluoromethyl)phenyl)sulfonyl)methyl)dihy
drofuranꢀ2(3H)ꢀone (3ah): Yellow solid (96 mg, 47% yield), m.p.= 140.2 ꢀ 141.3 oC;
1H NMR (400 MHz, CDCl3) δ ppm 7.83 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H),
7.68 (s, 1H), 7.40 ꢀ 7.34 (m, 3H), 7.29 ꢀ 7.24 (s, 2H), 4.70 (d, J = 9.6 Hz, 1H), 4.27 (d,
J = 9.6 Hz, 1H), 3.49 (d, J = 14.4 Hz, 1H), 3.17 (d, J = 14.4 Hz, 1H), 1.66 (s, 3H); 13C
NMR (151 MHz, CDCl3) δ 170.4, 143.0, 140.0, 135.8 (q, J = 33.3 Hz), 133.2, 132.2,
129.7, 129.2, 128.8, 128.1, 126.6 (q, J = 3.5 Hz), 122.9 (q, J = 271.5 Hz), 76.2, 60.8,
41.9, 24.9; 19F NMR (376 MHz, CDCl3) δ ppm ꢀ63.40 (s); IR (KBr) νmax 3689, 3112,
2978, 2753, 1755, 1638, 1478, 1311, 1145 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+
Calcd for C20H17F3O4SNa 433.0692; Found 433.0695.
(E)ꢀ3ꢀBenzylideneꢀ4ꢀmethylꢀ4ꢀ(((4ꢀ(trifluoromethoxy)phenyl)sulfonyl)methyl)dih
1
ydrofuranꢀ2(3H)ꢀone (3ai): Yellow oil (140 mg, 66% yield); H NMR (400 MHz,
CDCl3) δ 7.79 (d, J = 8.8 Hz, 2H), 7.71 (s, 1H), 7.42 ꢀ 7.36 (m, 3H), 7.33 (s, 1H), 7.32
ꢀ 7.28 (m, 3H), 4.74 (d, J = 9.6 Hz, 1H), 4.28 (d, J = 9.6 Hz, 1H), 3.51 (d, J = 14.5 Hz,
1H), 3.23 (d, J = 14.5 Hz, 1H), 1.68 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 170. 6,
153.1, 139.9, 138.6, 133.2, 132.2, 131.0, 130.0, 129.8, 129.6, 129.2, 128.7, 121.1,
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76.2, 60.9, 41.9, 24.7; F NMR (376 MHz, CDCl3) δ ꢀ57.69 (s); IR (KBr) νmax 3690,
3111, 2983, 2767, 1755, 1640, 1525, 1256, 1150 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M +
Na]+ Calcd for C20H17F3O5SNa 449.0641; Found 449.0644.
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(E)ꢀ3ꢀBenzylideneꢀ4ꢀmethylꢀ4ꢀ((oꢀtolylsulfonyl)methyl)dihydrofuranꢀ2(3H)ꢀone
(3aj): Yellow oil (106 mg, 60% yield); 1H NMR (400 MHz, CDCl3) δ ppm 7.92 (d, J
= 7.9 Hz, 1H), 7.73 (s, 1H), 7.49 (t, J = 7.4 Hz, 1H), 7.41 ꢀ 7.39 (m, 3H), 7.38 ꢀ 7.29
(m, 3H), 7.27 (d, J = 3.5 Hz, 1H), 4.69 (d, J = 9.7 Hz, 1H), 4.38 (d, J = 9.7 Hz, 1H),
3.64 (d, J = 14.4 Hz, 1H), 3.07 (d, J = 14.4 Hz, 1H), 2.43 (s, 3H), 1.73 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ ppm 170.6, 139.6, 138.7, 137.5, 134.1, 133.4, 133.0,
132.8, 129.5, 129.3, 129.1, 128.8, 126.9, 76.8, 60.0, 42.1, 24.8, 20.1; IR (KBr) νmax
3694, 3111, 2982, 2768, 1756, 1663, 1526, 1478, 1310, 1245, 1142 cmꢀ1; HRMS
(ESIꢀTOF) m/z: [M + Na]+ Calcd for C20H20O4SNa 379.0975; Found 379.0978.
(E)ꢀ3ꢀBenzylideneꢀ4ꢀmethylꢀ4ꢀ((mꢀtolylsulfonyl)methyl)dihydrofuranꢀ2(3H)ꢀone
1
(3ak): Yellow oil (128 mg, 72% yield); H NMR (400 MHz, CDCl3) δ ppm 7.66 (s,
1H), 7.51 ꢀ 7.47 (m, 2H), 7.38 ꢀ 7.33 (m, 5H ), 7.26 ꢀ 7.24 (m, 2H), 4.68 (d, J = 9.6 Hz,
1H), 4.23 (d, J = 9.6 Hz, 1H), 3.48 (d, J = 14.5 Hz, 1H), 3.11 (d, J = 14.5 Hz, 1H),
2.35 (s, 3H), 1.62 (s, 3H); 13C NMR (101 MHz, CDCl3) δ ppm 170.7, 140.4 139.8,
139.7, 134.7, 133.3, 132.5, 129.5, 129.3, 129.2, 128.7, 127.6, 124.5, 76.3, 60.8, 41.9,
24.6, 21.2; IR (KBr) νmax 3691, 3112, 2984, 2769, 1753, 1635, 1525, 1478, 1308,
1241, 1140 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C20H20O4SNa
379.0975; Found 379.0976.
(E)ꢀ3ꢀBenzylideneꢀ4ꢀ(((2,5ꢀdimethylphenyl)sulfonyl)methyl)ꢀ4ꢀmethyldihydrofur
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anꢀ2(3H)ꢀone (3al): Yellow solid (100 mg, 54% yield), m.p. = 107.02 ꢀ 108.5 oC; 1H
NMR (400 MHz, CDCl3) δ 7.65 (s, 2H), 7.35 ꢀ 7.32 (m, 3H), 7.24 ꢀ 7.22 (m, 2H),
7.20 (s, 1H), 7.06 (d, J = 7.6 Hz, 1H), 4.62 (d, J = 9.5 Hz, 1H), 4.30 (d, J = 9.5 Hz,
1H), 3.55 (d, J = 14.4 Hz, 1H), 2.98 (d, J = 14.4 Hz, 1H), 2.30 (s, 3H), 2.28 (s, 3H),
1.66 (s, 3H); 13C NMR (101 MHz, CDCl3) δ ppm 170.6, 139.5, 138.3, 136.9, 134.7,
134.2, 133.4, 133.0, 132.7, 130.9, 129.5, 129.0, 128.8, 76.7, 59.8, 42.0, 24.8, 20.7,
19.5; IR (KBr) νmax 3694, 3112, 2983, 2758, 1754, 1637, 1527, 1481, 1307, 1248,
1139 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C21H22O4SNa 393.1131;
Found 393.1131.
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(E)ꢀ3ꢀBenzylideneꢀ4ꢀmethylꢀ4ꢀ((methylsulfonyl)methyl)dihydrofuranꢀ2(3H)ꢀone
o
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(3am): White solid (121 mg, 87% yield), m.p. = 120.4 ꢀ 121.5 C; H NMR (400
MHz, CDCl3) δ ppm 7.77 (s, 1H), 7.45 ꢀ 7.43 (m, 3H), 7.37 ꢀ 7.35 (m, 2H), 4.68 (d, J
= 9.6 Hz, 1H), 4.27 (d, J = 9.6 Hz, 1H), 3.43 (d, J = 14.2 Hz, 1H), 3.14 (d, J = 14.2
Hz, 1H), 2.82 (s, 3H), 1.71 (s, 3H); 13C NMR (101 MHz, CDCl3) δ ppm 170.6, 139.7,
133.3, 132.7, 129.6, 129.0, 128.8, 76.0, 59.2, 43.7, 41.6, 24.6; IR (KBr) νmax 3692,
3113, 2984, 2767, 1752, 1631, 1525, 1479, 1307, 1242, 1138 cmꢀ1; HRMS (ESIꢀTOF)
m/z: [M + Na]+ Calcd for C14H16O4SNa 303.0662; Found 303.0661.
(E)ꢀ3ꢀBenzylideneꢀ4ꢀ((ethylsulfonyl)methyl)ꢀ4ꢀmethyldihydrofuranꢀ2(3H)ꢀone
(3an): White solid (135 mg, 92% yield), m.p. = 114.8 ꢀ 115. 9 oC; 1H NMR (400 MHz,
CDCl3) δ ppm 7.75 (s, 1H), 7.43 ꢀ 7.41 (m, 3H), 7.35 ꢀ 7.34 (m, 2H), 4.64 (d, J = 9.6
Hz, 1H), 4.29 (d, J = 9.7 Hz, 1H), 3.33 (d, J = 14.1 Hz, 1H), 2.99 (d, J = 14.1 Hz, 1H),
2.85 (q, J = 7.4 Hz, 2H), 1.71 (s, 3H), 1.22 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz,
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CDCl3) δ ppm 170.6, 139.5, 133.7, 133.0, 129.5, 128.9, 128.8, 76.2, 56.1 50.1, 41.5,
24.8, 6.6; IR (KBr) νmax 3695, 3113, 2985, 2760, 1755, 1527, 1480, 1310, 1242, 1137
cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C15H18O4SNa 317.0818; Found
317.0820.
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(E)ꢀ3ꢀBenzylideneꢀ4ꢀ((cyclopropylsulfonyl)methyl)ꢀ4ꢀmethyldihydrofuranꢀ2(3H)ꢀ
one (3ao): Yellow solid (119 mg, 78% yield), m.p. = 109.2 ꢀ 110.3 oC; 1H NMR (400
MHz, CDCl3) δ ppm 7.77 (s, 1H), 7.43 ꢀ 7.42 (m, 3H ), 7.38 ꢀ 7.36 (m, 2H), 4.66 (d, J
= 9.6 Hz, 1H), 4.27 (d, J = 9.6 Hz, 1H), 3.45 (d, J = 14.2 Hz, 1H), 3.15 (d, J = 14.3
Hz, 1H), 1.72 (s, 3H), 1.24 ꢀ 1.23 (m, 1H), 1.12 ꢀ 1.11 (m, 2H), 0.97 ꢀ 0.95 (m, 2H);
13C NMR (101 MHz, CDCl3) δ ppm 170.7, 139.6 133.4, 132.9, 129.6, 129.1, 128.8,
76.3, 58.4, 41.5, 31.9, 24.7, 5.2, 5.1; IR (KBr) νmax 3694, 3112, 2983, 2766, 1754,
1639, 1526, 1478, 1321, 1246, 1136 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd
for C16H18O4SNa 329.0818; Found 329.0816.
(E)ꢀ4ꢀMethylꢀ3ꢀ(4ꢀmethylbenzylidene)ꢀ4ꢀ((phenylsulfonyl)methyl)dihydrofuranꢀ2
(3H)ꢀone (3ba): Yellow solid (137 mg, 77% yield), m.p. = 140.2 ꢀ 140.3 oC; 1H NMR
(400 MHz, CDCl3) δ 7.77 (d, J = 7.8 Hz, 2H), 7.65 (s, 1H), 7.63 (d, J = 7.5 Hz, 1H),
7.52 (t, J = 7.6 Hz, 2H), 7.24 ꢀ 7.16 (m, 4H), 4.72 (d, J = 9.6 Hz, 1H), 4.26 (d, J = 9.6
Hz, 1H), 3.63 (d, J = 14.6 Hz, 1H), 3.20 (d, J = 14.6 Hz, 1H), 2.38 (s, 3H), 1.69 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 170.9, 140.5, 140.1, 139.9, 134.0, 131.3, 130.2,
129.5, 129.4, 129.4, 127.4, 76.3, 60.7, 41.8, 24.2, 21.3; IR (KBr) νmax 3689, 3112,
2983, 2772, 1751, 1637, 1524, 1478, 1310, 1242, 1145 cmꢀ1; HRMS (ESIꢀTOF) m/z:
[M + Na]+ Calcd for C20H20O4SNa 379.0975; Found 379.0978.
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one (3ca): Yellow solid (137mg, 74% yield), m.p. = 131.7 ꢀ 132.8 C, E isomer + Z
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isomer H NMR (400 MHz, CDCl3) δ ppm 7.70 (d, J = 8.0 Hz, 2H), 7.60 (s, 1H),
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7.56 (t, J = 7.4 Hz, 1H), 7.46 (d, J = 7.4 Hz, 2H), 7.22 ꢀ 7.09 (m, 4H), 4.65 (d, J = 9.6
Hz, 1H), 4.21 (d, J = 9.6 Hz, 1H), 3.55 (d, J = 14.6 Hz, 1H), 3.12 (d, J = 14.6 Hz, 1H),
2.60 (dt, J = 15.2, 7.6 Hz, 2H), 1.64 (s, J = 8.0 Hz, 3H), 1.18 (t, J = 7.3 Hz, 3H); E
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isomer C NMR (101 MHz, CDCl3) δ ppm 170.9, 146.4, 140.5, 139.9, 133.9, 131.4,
130.4, 129.6, 129.4, 128.2, 127.4, 76.4, 60.6, 41.8, 28.7, 24.3, 15.2; IR(KBr) νmax
3691, 3112, 2980, 2769, 1752, 1636, 1525, 1478, 1311, 1144 cmꢀ1; HRMS (ESIꢀTOF)
m/z: [M + Na]+ Calcd for C21H22O4SNa 393.1131; Found 393.1133.
3ꢀ(4ꢀFluorobenzylidene)ꢀ4ꢀmethylꢀ4ꢀ((phenylsulfonyl)methyl)dihydrofuranꢀ2(3H
)ꢀone (3da): Yellow solid (75.6 mg, 70% yield), m.p. = 133.2 ꢀ 134.6 oC; E isomer +
Z isomer 1H NMR (400 MHz, CDCl3) δ 7.95 ꢀ 7.89 (m, 0.75H), 7.85 ꢀ 7.73 (m, 2H),
7.65 (t, J = 7.3 Hz, 1.6H), 7.55 (dd, J = 13.6, 6.2 Hz, 2H), 7.31 (dd, J = 7.9, 5.6 Hz,
1.4H), 7.12 ꢀ 7.10 (m, 2H), 6.76 (s, 0.25H), 4.74 (d, J = 9.6 Hz, 1H), 4.27 (d, J = 9.6
Hz, 1H), 3.50 (d, J = 14.5 Hz, 1H), 3.19 (d, J = 14.5 Hz, 1H), 3.56 ꢀ 3.13 (m, 2H),
1.69 (s, 3H); E isomer 13C NMR (101 MHz, CDCl3) δ 170.6, 163.2 (d, J = 251.7 Hz),
140.4, 138.5, 134.1, 133.4 (d, J = 8.7 Hz), 132.3, 131.4 (d, J = 8.4 Hz), 129.5, 127.4,
116.0 (d, J = 22.0 Hz), 76.3, 60.8, 41.8, 24.3; IR (KBr) νmax 3685, 3114, 2982, 1753,
1639, 1526, 1309, 1143 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C19H17FO4SNa 383.0724; Found 383.0726.
3ꢀ(4ꢀChlorobenzylidene)ꢀ4ꢀmethylꢀ4ꢀ((phenylsulfonyl)methyl)dihydrofuranꢀ2(3H
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)ꢀone (3ea): Yellow solid (122 mg, 65% yield), m.p. = 124.6 ꢀ 125.4 oC; E isomer 1H
NMR (400 MHz, CDCl3) δ 7.74 (d, J = 7.7 Hz, 2H), 7.63 (d, J = 7.5 Hz, 1H), 7.59 (s,
1H), 7.51 (t, J = 7.7 Hz, 1H), 7.34 (d, J = 8.3 Hz, 2H), 7.22 (d, J = 8.3 Hz, 2H), 4.73
(d, J = 9.6 Hz, 1H), 4.22 (d, J = 9.6 Hz, 1H), 3.44 (d, J = 24.1 Hz, 1H), 3.22 (d, J =
14.6 Hz, 1H), 1.60 (s, 3H); E isomer 13C NMR (101 MHz, CDCl3) δ 170.4, 140.2,
138.2, 135.5, 134.0, 132.8, 131.5, 130.4, 129.4, 128.9, 127.3, 76.0, 60.7, 41.7, 24.4;
IR (KBr) νmax 3692, 3100, 2983, 2770, 1752, 1637, 1523, 1485, 1308, 1245, 1148
cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C19H17ClO4SNa 399.0428; Found
399.0432.
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4ꢀMethylꢀ4ꢀ((phenylsulfonyl)methyl)ꢀ3ꢀ(4ꢀ(trifluoromethyl)benzylidene)dihydrof
uranꢀ2(3H)ꢀone (3fa): Yellow solid (153 mg, 75% yield), m.p. = 141.5 ꢀ 142.9 oC; E
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isomer + Z isomer H NMR (400 MHz, CDCl3) δ ppm 7.96 ꢀ 7.77 (m, 2H), 7.79 ꢀ
7.69 (m, 2H), 7.62 (t, J = 9.1 Hz, 3H), 7.56 ꢀ 7.48 (m, 3H), 7.40 (d, J = 8.0 Hz, 1H),
4.76 (d, J = 9.6 Hz, 1H), 4.23 (d, J = 9.6 Hz, 1H), 3.32 (d, J = 14.5 Hz, 1H), 3.20 (d, J
= 14.5 Hz, 1H), 1.57 (s, 3H); E isomer 13C NMR (101 MHz, CDCl3) δ ppm 170.1,
140.2, 137.7, 137.1, 134.4, 134.1, 130.0 (q, J = 224.0 Hz), 129. 5, 129.1, 127.5, 127.2,
125.5 (q, J = 3.5 Hz), 75.8, 61.1, 41.8, 24.9; E isomer 19F NMR (376 MHz, CDCl3) δ
ppm ꢀ62.86 (s); IR (KBr) νmax 3692, 3110, 2983, 2771, 1754, 1641, 1526, 1477, 1322,
1141 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C20H17F3O4SNa 433.0692;
Found 433.0695.
(E)ꢀ4ꢀMethylꢀ3ꢀ(3ꢀmethylbenzylidene)ꢀ4ꢀ((phenylsulfonyl)methyl)dihydrofuranꢀ2
(3H)ꢀone (3ga): Yellow solid (106 mg, 60% yield), m.p.= 137.7 ꢀ 138.8 oC; 1H NMR
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(400 MHz, CDCl3) δ ppm 7.76 (d, J = 7.6 Hz, 2H), 7.69 (s, 1H), 7.64 (t, J = 7.3 Hz,
1H), 7.53 (t, J = 7.5 Hz, 2H), 7.32 ꢀ 7.25 (m, 1H), 7.20 (d, J = 7.5 Hz, 1H), 7.11 (s,
2H), 4.71 (d, J = 9.6 Hz, 1H), 4.30 (d, J = 9.6 Hz, 1H), 3.60 (d, J = 14.5 Hz, 1H), 3.18
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(d, J = 14.5 Hz, 1H), 2.35 (s, 3H), 1.67 (s, 3H); C NMR (101 MHz, CDCl3) δ ppm
170.8, 140.7, 140.0, 138.6, 134.0, 133.2, 132.3, 130.4, 130.0, 129.5, 128.6, 127.4,
126.2, 76.4, 61.0, 41.9, 24.6, 21.4; IR (KBr) νmax 3690, 3110, 2982, 2770, 1754, 1641,
1525, 1478, 1311, 1146 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C20H20O4SNa 379.0975; Found 379.0974.
(E)ꢀ3ꢀ(3ꢀChlorobenzylidene)ꢀ4ꢀmethylꢀ4ꢀ((phenylsulfonyl)methyl)dihydrofuranꢀ2
(3H)ꢀone (3ha): Yellow oil (112 mg, 60% yield), E isomer + Z isomer 1H NMR (400
MHz, CDCl3) δ ppm 7.82 ꢀ 7.64 (m, 2H), 7.58 ꢀ 7.49 (m, 2H), 7.46 ꢀ 7.43 (m, 2H),
7.28 ꢀ 7.13 (m, 3H), 7.09 (d, J = 5.9 Hz, 0.75H), 6.69 (s, 0.25H), 4.47 ꢀ 4.67 (m, 1H),
4.19 ꢀ 4.08 (m, 1H), 3.41 ꢀ 3.11 (m, 2H), 1.58 (s, 1.25H), 1.48 (s, 1.75H). E isomer +
Z isomer 13C NMR (101 MHz, CDCl3) δ ppm 170.1, 167.5, 140.4, 140.2, 138.5,
137.8, 134.9, 134.5, 134.2, 134.0, 133.9, 133.6, 133.6, 132.5, 130.4, 129.9, 129.6,
129.5, 129.4, 129.3, 129.2, 128.8, 128.7, 127.4, 127.2, 126.8, 75.8, 74.3, 63.0, 60.9,
43.6, 41.6, 24.8, 24.6. IR (KBr) νmax 3689, 3107, 2981, 2772, 1755, 1641, 1562, 1477,
1309, 1145 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C19H17ClO4SNa
399.0428; Found 399.0432.
3ꢀ(3ꢀBromobenzylidene)ꢀ4ꢀmethylꢀ4ꢀ((phenylsulfonyl)methyl)dihydrofuranꢀ2(3H
)ꢀone (3ia): Yellow oil (94 mg, 45% yield); E isomer + Z isomer 1H NMR (400 MHz,
CDCl3) δ ppm 7.92 ꢀ 7.85 (m, 1.5H), 7.78 (d, J = 7.7 Hz, 1H), 7.66 (dd, J = 23.8, 8.6
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Hz, 2H), 7.53 (dd, J = 16.6, 8.5 Hz, 2.5H), 7.47 ꢀ 7.39 (m, 1H), 7.30 ꢀ 7.17 (m, 1.5H),
6.77 (s, .0.5H), 4.84 ꢀ 4.76 (m, 1H), 3.50 ꢀ 3.19 (m, 2H), 1.67 (s, 0.5H), 1.57 (s, 0.5H);
E isomer + Z isomer 13C NMR (101 MHz, CDCl3) δ ppm 170.0, 167.5, 140.4, 140.2,
138.4, 137.7, 135.2, 134.5, 134.0, 133.9, 133.7, 133.3, 132.6, 132.5, 132.2, 131.6,
130.1, 129.6, 129.4, 129.2, 127.5, 127.3, 127.2, 122.5, 121.8 75.8, 74.3, 63.1, 60.9,
43.7, 41.7, 24.8, 24.6; IR (KBr) νmax 3689, 3108, 2981, 2769, 1750, 1636, 1555, 1476,
1306, 1141 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C19H17BrO4SNa
442.9923; Found 442.9925.
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3ꢀ(2ꢀFluorobenzylidene)ꢀ4ꢀmethylꢀ4ꢀ((phenylsulfonyl)methyl)dihydrofuranꢀ2(3H
)ꢀone (3ja): Yellow oil (120mg, 67%yield); E isomer + Z isomer 1H NMR (400 MHz,
CDCl3) δ ppm 7.82 ꢀ 7.64 (m, 2H), 7.65 ꢀ 7.61 (m, 2H), 7.58 ꢀ 7.48 (m, 2H), 7.39 (dd,
J = 13.4, 7.1 Hz, 1H), 7.21 (dt, J = 25.7, 7.4 Hz, 2H), 7.09 (t, J = 8.9 Hz, 1H), 4.79 (d,
J = 9.5 Hz, 1H), 4.22 (d, J = 9.7 Hz, 1H), 3.43 (d, J = 15.8 Hz, 1H), 3.26 (d, J = 14.4
Hz, 1H), 1.53 (s, 3H); E isomer 13C NMR (101 MHz, CDCl3) δ ppm 169.9, 159.5 (d,
J = 247.6 Hz), 140.3, 135.0, 133.9, 132.2 (d, J = 2.9 Hz), 131.3 (d, J = 8.2 Hz), 129.9
(d, J = 2.2 Hz), 129.3, 127.2, 124.1 (d, J = 3.6 Hz), 121.0 (d, J = 15.0 Hz), 115.9 (d, J
= 21.5 Hz), 75.5, 60.5, 42.0, 23.5; Z isomer 13C NMR (101 MHz, CDCl3) δ ppm
167.4, 160.2 (d, J = 253.1 Hz), 140.4, 133.4, 131.7, 131.3, 131.6(d, J = 6.7 Hz), 129.4
(d, J =11.9 Hz), 127.5, 127.4, 123.4 (d, J = 3.6 Hz), 120.5 (d, J = 12.0 Hz), 114.9 (d, J
= 21.9 Hz), 74.3, 63.1, 43.5, 24.7; 19F NMR (376 MHz, CDCl3) δ ꢀ110.68, ꢀ113.48; IR
(KBr) νmax 3688, 3105, 2981, 2769, 1757, 1653, 1568, 1482, 1310, 1146 cmꢀ1; HRMS
(ESIꢀTOF) m/z: [M + Na]+ Calcd for C19H17FO4SNa 383.0724; Found 383.0728.
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(E)ꢀ3ꢀEthylideneꢀ4ꢀmethylꢀ4ꢀ((phenylsulfonyl)methyl)dihydrofuranꢀ2(3H)ꢀone
(3la): Yellow solid (91 mg, 65% yield), m.p. = 136.8 ꢀ 138.2 oC; 1H NMR (400 MHz,
CDCl3) δ ppm 7.89 (d, J = 7.4 Hz, 2H), 7.69 ꢀ 7.63 (m, 1H), 7.57 (t, J = 7.6 Hz, 2H),
6.20 (q, J = 7.3 Hz, 1H), 4.72 (d, J = 9.7 Hz, 1H), 4.13 (d, J = 9.8 Hz, 1H), 3.32 ꢀ 3.15
(m, 2H), 2.12 (d, J = 7.3 Hz, 3H), 1.56 (s, 3H); 13C NMR (101 MHz, CDCl3) δ ppm
168.9, 140.7, 139.8, 134.0, 132.6, 129.5, 127.6, 74.6, 63.5, 42.5, 24.7, 13.8; IR (KBr)
νmax 3692, 3111, 2982, 2769, 1753, 1662, 1528, 1479, 1310, 1147 cmꢀ1; HRMS
(ESIꢀTOF) m/z: [M + Na]+ Calcd for C14H16O4SNa 303.0662; Found 303.0660.
(E)ꢀ3ꢀHexylideneꢀ4ꢀmethylꢀ4ꢀ((phenylsulfonyl)methyl)dihydrofuranꢀ2(3H)ꢀone
(3ma): Yellow solid (104 mg, 62% yield), m.p. = 84.1 ꢀ 85.2 oC; 1H NMR (400 MHz,
CDCl3) δ 7.88 (d, J = 7.7 Hz, 2H), 7.67 ꢀ 7.61 (m, 1H), 7.58 ꢀ 7.54 (m, 2H), 6.09 (t, J
= 7.6 Hz, 1H), 4.70 (d, J = 9.7 Hz, 1H), 4.12 (d, J = 9.7 Hz, 1H), 3.34 ꢀ 3.14 (m, 2H),
2.78 ꢀ 2.47 (m, 2H), 1.55 (s, 3H), 1.42 ꢀ 1.32 (m, 2H), 1.26 ꢀ 1.25 (m, 2H), 0.84 (t, J =
6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ ppm 168.7, 145.2, 140.6, 134.0, 131.7,
129.5, 127.5, 74.5, 63.5, 42.3, 31.2, 28.5, 27.2, 24.8, 22.3, 13.8; IR (KBr) νmax 3682,
3110, 2971, 2761, 1751, 1662, 1527, 1477, 1307, 1141 cmꢀ1; HRMS (ESIꢀTOF) m/z:
[M + Na]+ Calcd for C18H24O4SNa 359.1288; Found 359.1289.
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anꢀ2(3H)ꢀone (3na): Yellow solid (120 mg, 72% yield), m.p. = 136.4 ꢀ 137.5 C; H
NMR (400 MHz, CDCl3) δ ppm 7.73 (s, 1H), 7.69 (d, J = 7.7 Hz, 2H), 7.63 (t, J = 7.4
Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.02 (s, 1H), 6.97 (s, 2H), 4.68 (d, J = 9.6 Hz, 1H),
4.25 (d, J = 9.6 Hz, 1H), 3.37 (d, J = 14.5 Hz, 1H), 3.14 (d, J = 14.5 Hz, 1H), 2.32 (s,
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3H), 2.18 (s, 3H), 1.50 (s, 3H); 13C NMR (101 MHz, CDCl3) δ ppm 170.4, 140.5,
139.4, 139.3, 136.5, 133.9, 132.8, 131.2, 129.7, 129.3, 127.9, 127.2, 126.2, 75.8, 61.1,
41.9, 24.9, 21.1, 19.9; IR (KBr) νmax 3687, 3111, 2983, 2771, 1755, 1658, 1527, 1479,
1311, 1147 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C21H22O4SNa 393.1131;
Found 393.1131.
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4ꢀMethylꢀ4ꢀ((phenylsulfonyl)methyl)ꢀ3ꢀ(thiophenꢀ3ꢀylmethylene)dihydrofuranꢀ2(
3H)ꢀone (3oa): Yellow oil (90 mg, 52% yield); E isomer + Z isomer 1H NMR (400
MHz, CDCl3) δ ppm 7.91 ꢀ 7.82 (m, 2H), 7.66 ꢀ 7.60 (m, 2H), 7.56 ꢀ 7.51 (m, 2H),
7.42 (s, 1H), 7.21 (d, J = 5.0 Hz, 1H), 4.78 (d, J = 9.7 Hz, 1H), 4.29 (d, J = 9.7 Hz,
1H), 3.75 (d, J = 14.6 Hz, 1H), 3.26 (d, J = 14.6 Hz, 1H), 1.81 (s, 2.25H), 1.69 (s,
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0.25H); E isomer C NMR (101 MHz, CDCl3) δ 171.0, 140.4, 134.1, 133.2, 130.2,
129.6, 129.5, 128.7, 127.6, 127.5, 127.3, 76.9, 60.2, 41.3, 23.3; Z isomer 13C NMR
(101 MHz, CDCl3) δ ppm 168.3, 140.6, 134.7, 134.1, 134.0, 132.8, 132.4, 130.6,
128.5, 127.6, 125.3, 74.5, 63.6, 43.9, 24.5; IR (KBr) νmax 3692, 3109, 2982, 2769,
1747, 1634, 1528, 1307, 1244, 1141 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd
for C17H16O4S2Na 371.0382; Found 371.0385.
3ꢀBenzylideneꢀ4ꢀethylꢀ4ꢀ((phenylsulfonyl)methyl)dihydrofuranꢀ2(3H)ꢀone (3pa):
Yellow oil (128 mg, 72% yield); E isomer + Z isomer 1H NMR (400 MHz, CDCl3) δ
ppm 7.83ꢀ 7.72 (m, 1H), 7.62 (d, J = 7.8 Hz, 2H), 7.52 (t, J = 7.2 Hz, 1H), 7.42 ꢀ 7.37
(m, 2H), 7.30 ꢀ 7.18 (m, 4H), 4.69 (d, J = 9.9 Hz, 1H), 4.29 (d, J = 10.0 Hz, 1H), 3.41
(d, J = 14.6 Hz, 1H), 3.19 (d, J = 14.5 Hz, 1H), 2.09 ꢀ 1.84 (m, 2H), 0.83 (t, J = 7.3
Hz, 3H); E isomer 13C NMR (101 MHz, CDCl3) δ ppm 171.0, 140.8, 140.4, 133.8,
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133.3, 130.8, 129.4, 129.3, 128.8, 128.6, 127.2, 73.8, 61.4, 45.5, 31.6, 8.3; Z isomer
13C NMR (101 MHz, CDCl3) δ ppm 167.9, 140.9, 140.5, 133.9, 133.3, 132.6, 129.9,
129.4, 129.1, 127.9, 127.5, 73.2, 62.2, 47.0, 30.8, 7.8; IR (KBr) νmax 3685, 3059, 2976,
2768, 1751, 1639, 1525, 1480, 1308, 1239, 1145 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M +
H]+ Calcd for C20H21O4S 357.1155; Found 357.1153.
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Acknowledgements
The authors thank the National Key Research and Development Program of China
(2016YFA0602900), the National Natural Science Foundation of China (21472051
and 21490572), Pearl River S&T Nova Program of Guangzhou (201610010160) for
financial support.
Supporting Information
1H and 13C NMR spectra for all compounds prepared. This material is available free
of charge via the Internet at http://pubs.acs.org.
Crystallographic data for 3aa (CIF)
Spectral data for all new compounds and crystal data for 3aa (PDF)
REFERENCES
(1) For selected articles on improvement of pharmaceutical molecules, see: (a) Gobbi,
S.; Zimmer, C.; Belluti, F.; Rampa, A.; Hartmann, R. W.; Recanatini, M.; Bisi, A.
J. Med. Chem. 2010, 53, 5347. (b) Kersten, K. M.; Matzger, A. J. Chem. Commun.
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 29
1
2
3
4
5
6
7
8
9
2016, 52, 5281. (c) Mehta, J. V.; Gajera, S. B.; Patel, M. N. Med. Chem. Commun.
2016, 7, 1367. (d) Plano, D.; Karelia, D. N.; Pandey, M. K.; Spallholz, J. E.; Amin,
S.; Sharma, A. K. J. Med. Chem. 2016, 59, 1946. (e) Tan, D.; Loots, L.; Friscic, T.
Chem. Commun. 2016, 52, 7760. (f) Xu, W.; Wang, X.ꢀB.; Wang, Z.ꢀM.; Wu, J.ꢀJ.;
Li, F.; Wang, J.; Kong, L.ꢀY. Med. Chem. Commun. 2016, 7, 990.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2) For selected articles on sulfones, see: (a) TfeltꢀHansen, P.; DeVries, P.; Saxena, P.
R. Drugs, 2000, 60, 1259. (b) Schnellhammer, P. F. Expert Opin. Pharmacother.
2002, 3, 1313. (c) Mitchell, G.; Bartlett, D. W.; Fraser, T. E. M.; Hawkes, T. R.;
Holt, D. C.; Townson, J. K. R.; Wichert, A. Pest Manage. Sci. 2001, 57, 120. (d)
Boger, P. J. Pestic. Sci. 2003, 28, 324. e) Emmett, E. J.; Hayter, B. R.; Willis, M.
C. Angew. Chem. Int. Ed. 2014, 53, 10204. (f) RichardsꢀTaylor, C. S.; Blakemore,
D. C.; Willis, M. C. Chem. Sci. 2014, 5, 222. (g) Bachi, M. D.; Korshin, E. E.;
Hoos, R.; Szpilman. A. M.; Ploypradith, P.; Xie, S.; Shapiro, T. A.; Posner, G. J.
Med. Chem. 2003, 46, 2516. (h) Mitchell, G.; Bartlett, D. W.; Fraser, T. E. M.;
Hawkes, T. R.; Holt, D. C.; Townson, J. K.; Wichert, R. A; Pest Manag. Sci. 2001,
57, 120.
(3) For selected examples for transition metalꢀcatalyzed reactions, see: (a) Chen, C.;
Su, J.; Tong, X. Chem. Eur. J. 2013, 19, 5014. (b) Ma, X.ꢀT.; Dai, R.ꢀH.; Zhang, J.;
Gu, Y.; Tian, S.ꢀK. Adv. Synth. Catal. 2014, 356, 2984. (c) Taniguchi, N. Eur. J.
Org, Chem. 2014, 5691. (d) Taniguchi, T.; Idota, A.; Ishibashi, H. Org. Biomol.
Chem. 2011, 9, 3151. (e) Zeng, X.; Lilie. L.; Nakamura, E. Org. Lett. 2012, 14,
954.
26
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Page 27 of 29
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(4) For selected examples for freeꢀradicalꢀmediated reactions, see: (a) Gao, Y.; Wu,
W.; Huang, Y. Huang, K.; Jiang, H. Org. Chem. Front. 2014, 1, 361. (b) Meyer, A.
U.; Jäger, S.; Hari, D. P.; König, B. Adv. Synth. Catal. 2015, 357, 2050. (c) Wei,
W.; Liu, C.; Yang, D.; Wen, J.; You, J.; Wang, H. Adv. Synth. Catal. 2015, 357,
987. (d) Xiao, F.; Chen, H.; Xie, H.; Chen, S.; Yang L.; Deng, G.ꢀJ. Org. Lett.
2014, 16, 50. (e) Zheng, L.; Zhou, Z.ꢀZ.; He, Y.ꢀT.; Li, L.ꢀH.; Ma, J.ꢀW.; Qiu, Y.ꢀF.;
Zhou, P.ꢀX.; Liu, X.ꢀY.; Xu, P.ꢀF.; Liang, Y.ꢀM. J. Org. Chem. 2016, 81, 66.
(5) For selected examples for αꢀmethyleneꢀγꢀbutyrolactone products, see: (a)
Hoffmann, H. M. R.; Rabe, J. Angew. Chem. Int. Ed. Engl. 1985, 24, 94. (b)
Kitson, R. R. A.; Millemaggi, A.; Taylor, R. J. K. Angew. Chem. Int. Ed. 2009, 48,
9426. c) Hu, J.ꢀF.; Patel, R.; Li, B.; Garo, E.; Hough, G. W.; Goering, M. G.; Yoo,
H.ꢀD.; O’NeilꢀJohnson, M.; Eldridge, G. R. J. Nat. Prod. 2007, 70, 604. (d)
Hwang, D.ꢀR.; Wu, Y.ꢀS.; Chang, C.ꢀW.; Lien, T.ꢀW.; Chen, W.ꢀC.; Tan, U.ꢀK.;
Hsu, J. T. A.; Hsieh, H.ꢀP. Bioorg. Med. Chem. 2006, 14, 83.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(6) (a) Lachia, M.; Wolf, H. C.; Mesmaeker, A. D. Bioorg. Med. Chem. Lett. 2014, 24,
2123. (b) Li, R.ꢀJ.; Zhu, R.ꢀX.; Y.ꢀY.; Zhou, J.ꢀC.; Zhang, J.ꢀZ.; Wang, S.; Ye, J.ꢀP.;
Wang, Y.ꢀH.; MorrisꢀNatschke, S. L.; Lee, K.ꢀH.; Lou, H.ꢀX. J. Nat. Prod. 2013,
76, 1700. (c) Ramachandran, P. V.; Pratihar, D.; Nair, H. N. G.; Waltersa, M.;
Smith, S.; YipꢀSchneider, M. T.; Wu, H.; Schmidt, C. M. Bioorg. Med. Chem. Lett.
2010, 20, 6620. (d) Xu, Y.ꢀJ.; Tang, C.ꢀP.; Tan, M.ꢀJ.; Ke, C.ꢀQ.; Wu, T.; Ye, Y.
Chemistry & Biodiversity, 2010, 7, 151. (e) Ramachandran, P. V.; Nicponski, D.
27
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The Journal of Organic Chemistry
Page 28 of 29
1
2
3
4
5
6
R.; Nair, H. N. G.; Helppi, M. A.; Gagare, P. D.; Schmidt, C. M.; YipꢀSchneider,
M. T. Bioorg. Med. Chem. Lett. 2013, 22, 6911.
7
8
9
(7) For selected examples for constructing the lactone skeletons, see: (a) Kitagaki, S.;
Shibata, D.; Mukai, C. Tetrahedron Lett. 2007, 48, 1735. (b) Raju, A. R.; Le, T.;
Taylor, C. D.; Howell, A. R. Org. Lett. 2007, 9, 1699. (c) Yin, G.; Liu, G. Angew.
Chem. Int. Ed. 2008, 47, 5442. (d) Tong, X.; Li, D.; Zhang, Z.; Zhang, X. J. Am.
Chem. Soc. 2004, 126, 7601. (e) Edward, M. G.; Kenworthy, M. N.; Kitson, R. R.
A.; Scott, M. S.; Taylor, R. J. K. Angew. Chem. Int. Ed. 2008, 47, 1935.
(8) (a) Jang, H.ꢀY.; Gong, H.; Zhang, J.; Brodbelt, J. S.; Krische, M. J. J. Am. Chem.
Soc. 2006, 127, 6174. (b) Ramachandran, P. V.; Graner, G.; Pratichar, D. Org. Lett.
2007, 9, 4753. (c) Cateni, F.; Zilic, J.; Zacchigna, M.; Bonivento, P.; Frausin, F.;
Scarcia, V.; Eur. J. Med. Chem. 2006, 41, 192. (d) Leclercq, C.; Marko, I. E.
Tetrahedron Lett. 2005, 46, 7229. (e) Hodgson, D. M.; Talbot, E. P. A.; Clark, P.
Org. Lett. 2011, 13, 2594. (f) Yan, Y.; En, D.; Zhuang, Z.; Guo, Y.; Liao, W.ꢀW.
Tetrahedron Lett. 2014, 55, 479.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(9) (a) Zhang, Z.; Wu, W.; Liao, J.; Li, J.; Jiang, H. Chem. Eur. J. 2015, 21, 6708. (b)
Zhang, Z.; Ouyang, L.; Wu, W.; Li, J.; Zhang, Z.; Jiang, H.; J. Org. Chem. 2014,
79, 10734. (c) Li, J.; Yang, W.; Yang, S.; Huang, L.; Wu, W.; Sun. Y.; Jiang, H.
Angew. Chem. Int. Ed. 2014, 53, 7219. (d) Huang, L.; Wang, Q.; Wu, W.; Jiang, H.
J. Org. Chem. 2014, 79, 7734.
(10)(a) Tang, X.；Huang, L.；Qi, C.；Wu, X.；Wu, W. Jiang, H. Chem. Commun. 2013,
49, 6102. (b) Xu, Y.; Tang, X.; Hu, W.; Wu W.; Jiang, H. Green Chem. 2014, 16,
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2
3
4
5
6
7
8
9
3720. (c) Li, X.; Xu, Y.; Wu, W.; Jiang, C.; Qi, C.; Jiang, H. Chem. Eur. J. 2014,
20, 7911. (d) Tang, X.; Huang, L.; Xu, Y.; Yang, J.; Wu, W.; Jiang, H. Angew.
Chem. Int. Ed. 2014, 53, 4205. (e) Xu, Y.; Zhao, J.; Tang, X.; Wu, W.; Jiang, H.
Adv. Synth. Catal. 2014, 356, 2029.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(11)For examples using the sodium sulfinates as the sulfonyl sources, see: (a) Chen,
C.; Waser, J. Org. Lett. 2015, 17, 736. (b) Emmett, E. J.; Hayter, B. R.; Willis, M.
C. Angew. Chem. Int. Ed. 2014, 53, 10204. (c) Xiao, F.; Chen, H.; Xie, H.; Chen,
S.; Yang, L.; Deng, G.ꢀJ. Org. Lett. 2014, 16, 50.
(12)CCDC 1483589 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(13)Li, Y.ꢀM.; Sun, M.; Wang, H.ꢀL.; Tian, Q.ꢀP.; Yang, S.ꢀD. Angew. Chem. Int. Ed.
2013, 52, 3972.
(14)Li, Z.; Zhang, Y.; Zhang, L.; Liu, Z.ꢀQ. Org. Lett. 2014, 16, 382.
(15)Wu. W.; Yi. S.; Jiang. H. Chin. Pat. Appl. 105481806, April 13, 2016.
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