Aqueous Iodine(III)-mediated stereoselective oxidative cyclization for the synthesis of functionalized fused dihydrofuran derivatives

Article abstract of DOI:10.1021/jo902553k

("Figure Presented") An efficient aqueous oxidative cyclization mediated by the combination of iodosobenzene with tetra-(n-butyl)ammonium iodide provides a new convenient and useful route to functionalized fused dihydrofuran derivatives in moderate to excellent yields with high diastereoselectivities.

Full text of DOI:10.1021/jo902553k

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activities have stimulated considerable synthetic efforts.3
Aqueous Iodine(III)-Mediated Stereoselective
Oxidative Cyclization for the Synthesis of
Functionalized Fused Dihydrofuran Derivatives
The radical cyclic addition of cyclic 1,3-dicarbonyl com-
pounds to appropriate olefins provides a versatile method
for the synthesis of fused dihydrofuran derivatives.4 When
electron-poor alkenes were employed as the substrates, the
radical reaction pathway resulted in the regioselective gen-
eration of product 1 with the carbon of 1,3-dicarbonyl
compounds added at the R-position of electron-poor alkenes
(path a, eq 1). Wang and co-workers reported a Mn(OAc)3-
mediated reversed regioselective radical cyclic addition (path
b, eq 1).5 However, according to the plausible reaction
pathway, only 1-(pyridin-2-yl)enones were suitable sub-
strates.
Yang Ye,† Linfei Wang,† and Renhua Fan*,†,‡
†Department of Chemistry, Fudan University, 220 Handan
Road, Shanghai 200433, China, and ‡Shanghai Key
Laboratory of Molecular Catalysts and Innovative Materials,
Department of Chemistry, Fudan University, 220 Handan
Road, Shanghai 200433, China
rhfan@fudan.edu.cn
Received December 3, 2009
Soaring environmental awareness demands “green”
chemical procedures. Hence, the development of efficient
and selective chemical reactions in water with the environ-
mentally friendly reagents via a simple procedure is desir-
able.6 Oxidative cyclization is one of the most important
methods for the synthesis of cyclic compounds. It can
directly convert the C-H bonds into the desired C-C or
C-X bonds to construct the expected cyclic compounds
An efficient aqueous oxidative cyclization mediated by
the combination of iodosobenzene with tetra-(n-butyl)-
ammonium iodide provides a new convenient and useful
route to functionalized fused dihydrofuran derivatives in
moderate to excellent yields with high diastereoselecti-
vities.
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1760 J. Org. Chem. 2010, 75, 1760–1763
Published on Web 02/08/2010
DOI: 10.1021/jo902553k
r
2010 American Chemical Society

Ye et al.
JOCNote
SCHEME 1
TABLE 1. Evaluation of Reaction Conditionsa
entry
reagents (equiv) and conditions
2a (%)b
1
2
3
4
5
6
7
8
9
PhI(OAc)2 (2), KOH (2), MeOH, 2 h
0
PhI(OAc)2 (2), Bu4NBr (1), t-BuOK (2), CH3CN, 12 h
PhI(OAc)2 (2), Bu4NI (1), t-BuOK (2), CH3CN, 12 h
PhI(OAc)2 (2), Bu4NI (1), CH3CN, 12 h
PhI(OAc)2 (2), Bu4NI (1), KOH (2), H2O, 24 h
PhIO (2), Bu4NI (1), H2O, 24 h
PhIO (2), Bu4NI (1), H2O, 45 °C, 24 h
PhIO (2), Bu4NI (1), H2O, 15 °C, 36 h
PhIO (2), KI (1), H2O, 24 h
0
15
0
11
65
18
43
0
without extra chemical transformations.7 On the other hand,
as oxidants, hypervalent iodine compounds have similar or
better oxidative properties than Tl(III), Hg(II), and Pb(IV)
derivatives, but without the toxic and concomitant environ-
mental problems of these heavy metal analogues. Due to
their benign environmental character, ready availability, and
versatility, hypervalent iodine compounds have been used
extensively in organic synthesis.8 In our previous papers,9 we
reported the formation of functionalized cyclopropanes9d
and oxetanes9f from the iodine(III)-mediated oxidative cycli-
zations of Michael adducts of 1,3-dicarbonyl compounds
with electron-poor alkenes (nitroolefins and chalcones)
(Scheme 1). Here we demonstrate an efficient stereoselective
construction of functionalized fused dihydrofurans via the
aqueous oxidative cyclizations mediated by the combination
of iodosobenzene with tetra-(n-butyl)ammonium iodide.
To verify our hypothesis, a set of experiments were carried
out to evaluate and optimize the most efficient conditions
using Michael adduct 3a, which was prepared from the
MgO-catalyzed addition of cyclohexane-1,3-dione to chal-
cone in 82% yield,10 as the model substrate (Table 1). With
the treatment of substrate 3a with the combinations of
PhI(OAc)2/Bu4NBr/t-BuOK9b or PhI(OAc)2/KOH in MeO-
H,7a which were effectual combinations in various oxidative
cyclizations, reactions did not afford any fused dihydro-
furan, and the decomposition of substrate was observed
(Table 1, entries 1 and 2). Interestingly, with Bu4NI instead
of Bu4NBr, the desired product 2a was obtained in 15% yield
while the decomposition products were isolated (69% cyclo-
hexane-1,3-dione, 74% chalcone) as the major byproducts
(Table 1, entry 3). The control experiment without base did
10 PhIO (2), KI (1), p-C12H25-C6H4SO3Na (1), H2O, 24 h
11 PhIO (1.5), Bu4NI (1.5), H2O, 16 h
0
85
aReaction conditions: substrate 3a (0.2 mmol), solvent (1 mL) at
30 °C, unless noted. bIsolated yield.
not yield product 2a (Table 1, entry 4). In the further
investigation, we discovered that the reaction could be
carried out in an open-air system with water as the solvent,
albeit in a lower yield (Table 1, entry 5). It is well-known that
the treatment of PhI(OAc)2 with aqueous KOH will lead to
the generation of PhIO. To inhibit the deleterious decom-
position of substrate arising from the basic conditions, PhIO
was utilized to replace the combination of PhI(OAc)2 and
KOH, and the yield of 2a was dramatically improved to 65%
(Table 1, entry 6). A higher temperature (45 °C) resulted in a
complicated reaction, while a lower temperature (15 °C)
slowed the reaction and gave rise to a lower yield of 2a
(Table 1, entries 7 and 8). Although the reaction was carried
out in water, no oxidative cyclization was observed with the
use of KI even in the presence of a surfactant (Table 1, entries
9 and 10). The best ratio of substrate, PhIO, and Bu4NI for
the reaction was 1:1.5:1.5, with which the yield of 2a in-
creased to 85% (Table 1, entry 11). No corresponding
cyclopropane or oxetane was isolated from the reactions.
The scope of this reaction was then investigated under
optimized conditions, and the results are summarized in
Table 2. The Michael adducts of chalcone with 5,5-dimethyl-
cyclohexane-1,3-dione (dimedone), 6-methyl-3H-pyran-
2,4-dione, chroman-2,4-dione (4-hydroxycoumarin), and
6-fluorochroman-2,4-dione (4-hydroxy-6-fluorocoumarin)
were effective substrates, and their reactions gave rise to
the corresponding fused dihydrofurans in good to excellent
yields (up to 90% yield). Products 2d, 2e, and 2f have similar
core structures with naturally occurring coumestans. When
the derivative of 2H-indene-1,3-dione 3g was employed as
the substrate, only the decomposition of substrate was
observed. Additionally, the aqueous oxidative cyclization
was found to tolerate a range of groups with different electro-
nic demands on the aromatic rings. For the substrates deri-
ved from different chalcones with an electron-donating or
an electron-withdrawing substitution, reactions proceeded
smoothly and afforded the corresponding products 2h-2p in
yields ranging from 56 to 85%. When the aryl group at
R2 was replaced by an alkyl group (substrates 3q and 3r), no
oxidative cyclization occurred under the same conditions.
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TABLE 2. Aqueous Oxidative Cyclizationa,b
FIGURE 1. X-ray diffraction structure of 2o.
SCHEME 2. Hypothesized Reaction Pathway
isobutyraldehyde, and cinnamaldehyde. All fused dihydro-
furans were formed with a high diastereoselectivity (trans/cis
> 95:5), and their structures were determined based on their
1H NMR (the observed coupling constants between two
methine protons were 4.6-5.2 Hz),5,11 13C NMR, HRMS,
and FT-IR spectra. The structure and the trans stereochemis-
try were further confirmed by the single-crystal diffraction
analysis of product 2o (Figure 1).
Reactions afforded PhI as the byproduct. Moreover,
during the reaction, we observed the generation of iodine,
which indicated that the oxidative cyclization might be
mediated by I2 or Iþ. However, when the combination of
PhIO/Bu4NI was replaced by those of PhIO/I2, I2/Bu4-
NOAc, NIS/Bu4NOAc, and ICl/Bu4NOAc, no dihydrofur-
an was formed. Additionally, no oxidative cyclization
occurred with Bu4NCl or Bu4NBr instead of Bu4NI. A
hypothesized reaction pathway for the PhIO/Bu4NI-media-
ted construction of fused dihydrofurans is shown in
Scheme 2. A higher reactive iodine(III) species 4, which is
generated from the depolymerization of the polymeric iodo-
sobenzene12 by Bu4NI,13 reacts with the enolate of Michael
aReaction conditions: substrate 3 (0.2 mmol), PhIO (0.3 mmol),
Bu4NI (0.3 mmol), H2O (1 mL) at 30 °C for 16 h. bIsolated yield.
(12) (a) Moriarty, R. M.; Rani, N.; Condeiu, C.; Duncan, M. P.; Prakash,
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from the enones, which were derived from acetaldehyde,
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€
1762 J. Org. Chem. Vol. 75, No. 5, 2010

Ye et al.
JOCNote
adduct 3 via a ligand exchange reaction8f,14 with the aid of
the resultant Bu4NOH to give rise to an intermediate 5.
Intermediate 5 is ready to undergo an intramolecular reduc-
tive elimination to afford fused dihydrofuran 2.15
In summary, we have developed an efficient method for
the construction of functionalized fused dihydrofurans via
an aqueous PhIO/Bu4NI-mediated stereoselective oxidative
cyclization of Michael adducts of cyclic 1,3-dicarbonyl com-
pounds with chalcones. The potential of this reaction system
can be evaluated by its simple procedure, mild conditions,
and adaptability to a wide variety of substrates. The further
development of the asymmetric reactions is ongoing and will
be reported in due course.
with saturated Na2S2O3 (25 mL) and extracted by ethyl acetate
(25 mL ꢀ 3). The organic layer was dried over Na2SO4 and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (15% ethyl acetate in hexanes)
to provide 2-benzoyl-3-phenyl-2,3,6,7-tetrahydrobenzofuran-
4(5H)-one 2a in 85% yield as colorless oil: 1H NMR (400
MHz, CDCl3) δ 7.80-7.83 (m, 2 H), 7.61 (t, J = 7.3 Hz, 1 H),
7.45 (t, J = 7.3 Hz, 2 H), 7.35 (t, J = 7.3 Hz, 2 H), 7.22-7.30 (m,
3 H), 5.87 (d, J = 4.6 Hz, 1 H), 4.41 (d, J = 4.6 Hz, 1 H), 2.72 (t,
J = 6.6 Hz, 2 H), 2.33 (t, J = 6.4 Hz, 2 H), 2.10-2.16 (m, 2 H);
13C NMR (100 MHz, CDCl3) δ 194.4, 193.0, 177.4, 141.2, 134.3,
133.3, 129.1, 129.0, 128.9, 127.7, 127.4, 116.6, 91.7, 49.0, 36.9,
24.0, 21.8; IR (KBr) 2949, 1696, 1639, 1597, 1393, 1226 cm-1
;
HRMS m/z calcd for C21H19O3 ([M þ H]þ) 319.1329, found
319.1327.
Experimental Section
Acknowledgment. Financial support from National
Natural Science Foundation of China (20702006) and
Shanghai Key Laboratory of Molecular Catalysts and Inno-
vative Materials, Department of Chemistry, Fudan Univer-
sity (2009KF02), is gratefully acknowledged.
Representative experimental procedure: The mixture of
Michael adduct 3a (64 mg, 0.2 mmol) and PhIO (66 mg,
0.3 mmol) in H2O (1 mL) was treated with Bu4NI (111 mg,
0.3 mmol). The reaction was allowed to stir at 30 °C for 16 h.
Upon completion by TLC, the reaction mixture was quenched
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Supporting Information Available: Experimental proce-
dures, characterization data, copies of 1H NMR and 13C
NMR of new compounds, and crystallographic data of com-
pound 2o (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 5, 2010 1763