Sc(OTf)3-Catalyzed Diastereoselective Formal [3+2] Cycloaddition Reactions of Alkynylcyclopropane Ketones with Electron-Rich Aromatic Aldehydes to Yield 2,5-trans-Tetrahydrofurans

Article abstract of DOI:10.1002/ejoc.201600233

In contast to the general [4+2] cycloaddition reactions of alkynylcyclopropane ketones reported in the literature, we report herein a Sc(OTf)₃-catalyzed formal intermolecular [3+2] cycloaddition reaction of alkynylcyclopropane ketones with elec

Full text of DOI:10.1002/ejoc.201600233

DOI: 10.1002/ejoc.201600233
Full Paper
Cyclopropane Cycloaddition
Sc(OTf)3-Catalyzed Diastereoselective Formal [3+2]
Cycloaddition Reactions of Alkynylcyclopropane Ketones with
Electron-Rich Aromatic Aldehydes To Yield 2,5-trans-
Tetrahydrofurans
Chi Zhang,[a] Muyun Xu,[a] Jun Ren,[a] and Zhongwen Wang*[a,b]
Abstract: In contast to the general [4+2] cycloaddition reac- a 2,5-trans configuration. This is also quite different to the 2,5-
tions of alkynylcyclopropane ketones reported in the literature,
we report herein a Sc(OTf)3-catalyzed formal intermolecular
[3+2] cycloaddition reaction of alkynylcyclopropane ketones
with electron-rich aromatic aldehydes. 2,3,3,5-Tetrasubstituted
tetrahydrofurans were obtained by this method, and the tetra-
hydrofuran skeleton was diastereoselectively constructed with
cis configuration usually obtained from typical [3+2] cycloaddi-
tion reactions of most donor–acceptor cyclopropanes. Addition-
ally, the cycloadducts were subjected to a domino carbo-
palladation/C–H activation/C–C bond-formation process for the
highly efficient construction of polycyclic skeletons.
Introduction
ivity is quite different to that observed for the reactions of cy-
clo-
Various types of cycloaddition reactions of donor–acceptor cy-
clopropanes have been developed for the construction of struc-
turally diverse cyclic skeletons and they have been widely ap-
plied in organic synthesis.[1] Since being introduced by Zhang
and Schmalz,[2j] the alkynylcyclopropane (ACP) ketone has re-
cently proved to be a versatile building block in organic synthe-
sis.[2] As a novel type of donor–acceptor cyclopropane, the ACP
ketone has also attracted attention in recent years for its novel
cycloaddition reactions.[2k–2q] Zhang et al. reported a novel
IPrAuNTf2-cataylzed intermolecular [4+2] cycloaddition of the
ACP ketone with carbonyls to afford furan-fused dihydropyrans
in which the ACP ketone served as a 1,4-dipole (Scheme 1,
A).[2q] In our recent research on the intramolecular cross-
cycloaddition reactions of ACP ketones with carbonyls,[2k] we
found that under catalysis by Sc(OTf)3 an intermolecular [3+2]
cycloaddition took place in which the ACP ketone acted as a
1,3-dipole (Scheme 1, B). Additionally, examples of ACP ketones
as C3 synthons are quite limited. Besides our intramolecular
[3+2] example,[2k] the only other report refers to the [3+3]
cycloaddition with nitrones reported by Zhang et al.[2n] It was
also noted that this cycloaddition stereoselectively afforded the
2,5-trans-tetrahydrofuran skeleton.[3] This 2,5-trans stereoselect-
propane 1,1-diesters with aldehydes reported by Johnson and
co-workers.[4] Few 2,5-trans-tetrahydrofurans from the reactions
of donor–acceptor cyclopropanes with aldehydes have been
described.[5] Therefore we have explored this reaction and we
report herein our recent results on the intermolecular [3+2]
cycloaddition reactions of ACP ketones.
Scheme 1. Two different types of cycloaddition reactions of ACP ketones with
aldehydes.
Results and Discussion
[a] State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry,
Nankai University,
Tianjin 300071, P. R. China
[b] Collaborative Innovation Center of Chemical Science and Engineering,
(Tianjin),
The reaction of ACP ketone 1a and 3,4-dimethoxybenzaldehyde
(2a) was initially performed and the results are summarized in
Table 1. Several solvents were screened and when the reaction
was conducted in 1,2-dichloroethane (DCE) at 40 °C under catal-
ysis by Sc(OTf)3 (0.2 equiv.) a mixture of three diastereoisomers,
3aa, 4aa, and 5aa, was obtained in a ratio of 0.68:0.12:1
(Table 1, entry 1). The 2,5-cis isomers (4aa and 5aa) were the
major species, similarly to the case of cyclopropane 1,1-dies-
94 Weijin Road, Tianjin 300071, P. R. China
E-mail: wzwrj@nankai.edu.cn
www.nankai.edu.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600233.
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ters.[4] The structures of 3aa and 4aa were unambiguously con-
firmed by NMR, HRMS, and X-ray crystal analysis.[6] To our sur-
prise, when the solvent was switched to toluene, the diastereo-
selectivity of the three isomers changed to 1:0.17:0.17, with 3aa
as the major isomer (Table 1, entry 3). We found that the reac-
tion also proceeded smoothly at 0 °C with a better diastereose-
lectivity, with only a trace of 5aa observed (Table 1, entry 8).[7]
This condition was selected as optimal for further research. At
a lower temperature (–20 °C), the reaction gave a mixture of
3aa and 4aa (1:1.23), the latter being the major isomer (Table 1,
entry 9). These results (Table 1, entries 3, 8, and 9) suggest that
4aa is a kinetic product and 3aa and 5aa are thermodynamic
products.
Table 2. Scope of aldehydes in the Sc(OTf)3-catalyzed [3+2] cycloaddition of
1a.[a]
Entry
2 (equiv.)
Ar
Yield [%][b]
dr[c] (3/4)
1
2
3
4
5
6
7
8
2a (5.0)
2b (5.0)
2c (5.0)
2d (10.0)
2e (5.0)
2f (10.0)
2g (10.0)
2h (5.0)
3,4-(OMe)2Ph
3,4-OCH2OPh
4-BnOPh
82
79
90
95
93
5.5:1
7.2:1
5.9:1
5.9:1
5.0:1
3.3:1
5.0:1
–
4-MeOPh[d,e]
4-EtOPh[d]
Table 1. Optimization of reaction conditions.[a]
2-MeOPh[d]
2-thienyl[d,f]
4-Me2NPh
75
88
n.r.[g]
[a] Reagents and conditions: 1a (0.3 mmol), 2, molecular sieves (4 Å, 100 mg),
toluene (10 mL), stirring overnight, 0 °C. [b] Isolated combined yield. [c] Ratio
determined by 1H NMR analysis of the reaction mixture. [d] 0.3 equiv. of
Sc(OTf)3 was used. [e] 10 equiv. of 2 was used. [f] Reaction was carried out
at ambient temperature (20–25 °C). [g] n.r.: no reaction, a yellow precipitate
appeared instead.
Such a ring-opening rearrangement has often been observed
in cyclopropane ketones.[8] When R1 was the weak carbocation-
stabilizing group n-propyl (substrate 1e), the reaction was very
sluggish and gave a complex mixture of products when the
temperature was increased (Table 3, entry 5). The electronic
nature of substituent R2 on the alkyne moiety seemed to have
less influence on the reactivity (Table 3, entries 6–10). There
was no distinct difference between two substrates with an elec-
tron-poor (1f) or electron-rich (1g) phenyl group (Table 3, en-
tries 6 and 7). Trimethylsilyl-substituted (1h) and unsubstituted
(1i) substrates also worked well under catalysis by Sc(OTf)3
(Table 3, entries 8 and 9). Substrate 1j also reacted smoothly,
the terminal cyclopropane ring having no influence on the reac-
tion (Table 3, entry 10). Substituent R3 had a significant influ-
ence on the diastereoselectivity. Substrates with an electron-
poor (1k) or electron-rich (1l) phenyl group or a thienyl group
(1m) behaved normally (Table 3, entries 11–13). However, when
R3 was an alkyl group, both the reactivity and stereoselectivity
were quite different from those observed with the aromatic
substituents. When R3 was nBu (1n), the diastereoselectivity de-
creased significantly (Table 3, entry 14), and when R3 was the
bulky tBu group (1o), the reaction gave a complex mixture at
reflux instead of the desired products (Table 3, entry 15). These
results imply that both the electronic and steric properties of
R3 have a significant influence on the reactivity and stereo-
selectivity of the reaction.
Entry
Solvent
T [°C]
3aa[b]
4aa[b]
5aa[b]
1
2
3
4
5
6
7
8
9
DCE
DCM
toluene
THF[c]
CH3CN[c]
40
40
40
40
40
40
40
0
0.68
0.93
1
–
–
–
1
1
1
0.12
0.14
0.17
–
–
–
0.15
0.17
1.23
1
1
0.17
–
–
–
0.71
trace
0
[c]
CH3NO2
benzene
toluene[d]
toluene[e]
–20
[a] Reagents and conditions: 1a (0.06 mmol), 2a (1.5 equiv.), Sc(OTf)3
(0.2 equiv.), solvent (2 mL), 4 Å molecular sieves, 2 h. [b] Ratio was deter-
mined by 1H NMR analysis of the reaction mixture. [c] No reaction. [d]
5.0 equiv. of 2a was added and the reaction mixture was stirred for 4 h. [e]
0.4 equiv. of Sc(OTf)3 and 10.0 equiv. of 2a were added and the reaction
mixture was stirred overnight; about 60 % of 1a was consumed.
The scope of the aldehydes was explored next and the re-
sults are summarized in Table 2. Several alkoxybenzaldehydes
reacted smoothly and gave good-to-excellent yields and dia-
stereoselectivities (Table 2, entries 1–6). The reaction of thio-
phene-2-carbaldehyde (2g) also worked well at room tempera-
ture (Table 2, entry 7). However, the reaction of 4-(dimethyl-
amino)benzaldehyde (2h) failed and gave a yellow precipitate
instead of the desired product (Table 2, entry 8). We also tried
several other types of aldehydes/ketones. Unfortunately, benz-
aldehyde, electron-deficient aromatic aldehydes, and aliphatic
aldehydes/ketones were not suitable for this reaction.
We then screened the scope of ACP ketones 1 (Table 3).
When the donor group R1 on the cyclopropane ring was phenyl,
electron-deficient 4-ClPh, or weakly electron-rich 4-tBuPh, the
reactions proceeded smoothly (Table 3, entries 1–3). However,
when R1 was the strongly electron-rich 4-MeOPh, a rearrange-
ment cyclization occurred to give dihydrofuran product 7 in-
stead of the cycloaddition product (Table 3, entry 4). This might
To further understand the reaction mechanism, we separated
3aa, 4ca, and 5aa and treated them with Sc(OTf)3 independ-
ently (Scheme 2). We found that the reactions of 3aa and 5aa
at 40 °C gave similar results; the three diastereoisomers 3aa,
4aa, and 5aa were obtained and in a similar ratio. The reaction
of 4ca at 0 °C gave a mixture of 3ca and 4ca, with 3ca the
major isomer.
We suggest the plausible mechanism shown in Scheme 3.
be due to the activated C–C bond in the cyclopropane ring. The 2,5-cis isomer 4 was obtained in the first stage, which is
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Table 3. Scope of ACP ketones in the Sc(OTf)3-catalyzed [3+2] cycloaddition of 2a.[a]
Entry
1
R1
R2
R3
Yield [%][b]
dr[c] (3/4)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Ph
Ph
Ph
82
92
85
5.5:1
5.3:1
4.9:1
–
4-ClPh[d]
4-tBuPh
4-MeOPh
nPr
[e]
–
Ph
4-ClPh
3,4-(MeO)2Ph
Me3Si
n.r.[f]
83
–
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4.9:1
5.3:1
4.3:1
3.8:1
5.7:1
4.9:1
5.3:1
6.2:1
1.7:1
–
90
88
90
75
83
82
95
9
H
Ph
Ph
10
11
12
13
14
15
cyclopropyl
Ph
Ph
Ph
Ph
Ph
4-ClPh
4-MeOPh
2-thienyl
nBu[g]
tBu
Ph
Ph
90
n.r.[f]
[a] Reagents and conditions: 1a (0.3 mmol), 2 (5.0 equiv.), 4 Å molecular sieves (100 mg), toluene (8 mL), stirring for 4 h, 0 °C. [b] Isolated combined yield. [c]
Ratio determined by 1H NMR analysis of the reaction mixture. [d] 10.0 equiv. of 2a was used. [e] Compound 7 was obtained instead in 92 % yield. [f] n.r.: no
reaction; the reaction gave a complex mixture of products when heated at reflux. [g] Reaction was carried out at 40 °C.
Scheme 2.
similar to that reported by Johnson and co-workers for the at C3 and the phenyl group at C5 show a cis relationship. In the
[3+2] cycloaddition of cyclopropane 1,1-diesters.[4] The relative second stage, the C2–C3 or O-C2 bond in isomer 4 are cleaved
stereochemistry at C3 was not affected and the carbonyl group under the reaction conditions (thermal and Lewis acid) to give
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Scheme 3. Plausible mechanism for the intermolecular [3+2] cycloaddition of ACP ketones.
zwitterionic intermediate C or D. This is attributed to the push– O-C2 bond occurs to give isomer 3, 4, or 5. Replacing the
pull principle of the strong donor Ar group at C2 and the two phenyl R3 group by an alkyl group (1n) causes reduced dia-
acceptors (alkoxy and carbonyl). Reconnection of the C2–C3 or stereoselectivity as a result of the lower steric hindrance. The
Scheme 4. Domino intermolecular carbopalladation/C–H activation/C–C bond-forming reactions of cycloadducts 3.
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failure of 1o to react may be attributed to the bulky tBu group,
which makes the formation of the C2–C3 bond in the first [3+2]
stage more difficult. The weaker electron-donating propyl
group (R1) prevented the reaction of 1e. This proposed mecha-
nism is somewhat in accordance with those reported for cyclo-
propane 1,1-diesters in the literature.[4a,5c,9]
The cycloadducts obtained in this work, with the adjacent 3-
alkynyl and 2-phenyl groups in cis positions, provide a good
opportunity for the efficient construction of polycyclic skele-
tons. Zhu and co-workers have developed a domino intermo-
lecular carbopalladation/C–H activation/C–C bond-forming
process to construct oxindoles.[10] We successfully applied a
similar strategy to the cycloadducts 3. Thus, under catalysis by
Pd(OAc)2, 3ja and iodobenzene were heated at 140 °C in DMF
to afford the desired product 6ja in 60 % yield (Scheme 4).
Under similar conditions, 6la and 6ac were also obtained from
3la and 3ac, respectively. The structure of 6ja was unambigu-
ously confirmed by X-ray crystal analysis.[6]
Conclusions
Typical Procedure for Synthesis of ACP Ketone 1g (Route A):
Bromine (5.11 g, 31.9 mmol, 1.2 equiv.) was added dropwise to a
solution of chalcone 7 (5.50 g, 26.6 mmol, 1.0 equiv.) in DCM
(40 mL) at 0 °C. The mixture was stirred for 30 min at the same
temperature before quenching by the addition of a saturated
Na2S2O3 solution (50 mL). The aqueous phase was separated and
extracted with DCM (50 mL × 3). The organic phases were com-
bined and washed with brine. After drying with MgSO4, the solvent
was removed under vacuum. The residue was dissolved in EtOH
(40 mL), then NaOAc (3.28 g, 31.9 mmol, 1.2 equiv.) was added, and
the mixture was heated at reflux for 4 h. After cooling to room
temperature, the solvent was removed under vacuum and water
(100 mL) was added. The aqueous phase was extracted with DCM
(50 mL × 3). The organic phases were combined and washed with
brine. After drying with MgSO4, the solvent was removed under
vacuum, and the crude product was purified by flash chromatogra-
phy (PE/EA, 100:1) to give 8 (8.48 g, 90 %) as a mixture of Z/E iso-
mers. The data for 8 were the same as reported in the literature.
We have developed a strategy for the Sc(OTf)3-catalyzed [3+2]
cycloaddition of alkynylcyclopropane ketones with electron-rich
aromatic aldehydes. 2,5-trans-Configurated tetrahydrofurans
containing a quaternary carbon center were smoothly synthe-
sized in high-to-excellent yields with good diastereoselectivi-
ties. The cycloadducts were subjected to a domino carbo-
palladation/C–H activation/C–C bond-formation process for a
highly efficient construction of polycyclic skeletons.
Experimental Section
General: Unless otherwise noted, all commercial materials were
used without purification. Flash column chromatography was per-
formed on silica gel (200–300 mesh) by using petroleum/ethyl acet-
ate as eluting solvents. TLC was performed on silica gel GF254
plates and visualized by UV light (254 nm) or KMnO4. NMR (400 MHz
1
for H and 101 MHz for 13C) spectra were recorded in CDCl3 unless
[Pd(Ph3P)4] (162.9 mg, 0.141 mmol, 0.05 equiv.) and CuI (53.7 mg,
0.282 mmol, 0.1 equiv.) were added to a solution of 8 (810 mg,
2.82 mmol, 1.0 equiv.) in THF (4.0 mL) and Et3N (4.0 mL) under Ar.
The reaction mixture was flushed with Ar (3 ×) and 4-ethynyl-1,2-
dimethoxybenzene (549 mg, 3.38 mmol, 1.2 equiv.) was added by
syringe. The mixture was stirred for 4 h until TLC indicated comple-
tion of the reaction. The mixture was diluted with EtOAc (50 mL),
otherwise indicated at ambient temperature. The chemical shifts (δ)
are given in ppm and were measured with solvents as references
(for CDCl3, 1H: δ = 7.26 ppm; 13C NMR, δ = 77.1 ppm). IR spectra
were recorded as a film on KBr. Melting points were obtained with
an apparatus. High-resolution mass spectra were recorded with a
MALDI-TOF resource.
washed with 1
N HCl and brine, and dried with MgSO4. After remov-
ACP ketones 1a,[2o] 1b,[2l] 1f,[2l] 1j,[2o] 1k.[2l] and 1n[2p] were pre-
pared according to the literature and their data are the same as
reported. ACP ketones 1c, 1d, 1g, 1h, 1i, 1l, and 1m were synthe-
sized following the general route A,[2p] 1e was synthesized follow-
ing route B,[2k] and 1o was synthesized following route C11,2p (see
below).
ing the solvent under vacuum, the crude product was purified by
flash chromatography (PE/EA, 10:1) to give (E)-2-benzylidene-4-(3,4-
dimethoxyphenyl)-1-phenylbut-3-yn-1-one (9; 697.8 mg, 67 %) as a
1
yellow oil. H NMR (400 MHz, CDCl3): δ = 8.12 (d, J = 6.7 Hz, 2 H),
8.00 (d, J = 7.5 Hz, 2 H), 7.61–7.54 (m, 2 H), 7.50–7.44 (m, 5 H), 7.03
(d, J = 8.2 Hz, 1 H), 6.88–6.79 (m, 2 H), 3.89 (s, 3 H), 3.85 (s, 3 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 193.8, 150.2, 148.9, 144.5, 137.5,
135.1, 132.6, 130.6, 130.5, 129.0, 128.7, 128.2, 125.0, 121.3, 115.2,
114.1, 111.2, 101.3, 86.2, 56.1, 56.1 ppm.
Diastereoisomeric ratios were determined by 1H NMR analysis of the
crude products. NMR spectroscopic data for the major and minor
diastereoisomers have been reported in most cases. In some cases
the two diastereomers were inseparable, in these circumstances the
NMR spectroscopic data for the mixture of two diastereoisomers or
only the major diastereoisomer have been reported.
NaH (60 % in mineral oil, 79.6 mg, 1.99 mmol, 1.05 equiv.) was
added to a solution of trimethylsulfoxonium iodide (437.9 mg,
1.99 mmol, 1.05 equiv.) in DMSO (7 mL). The mixture was stirred for
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30 min until the solution turned clear, then 9 (697.8 mg, 1.89 mmol,
CDCl3): δ = 8.18 (d, J = 8.6 Hz, 2 H), 7.45–7.34 (m, 5 H), 7.22–7.18
1.00 equiv.) was added, and the mixture was stirred at room tem- (m, 3 H), 7.07–7.05 (m, 2 H), 6.94 (d, J = 8.6 Hz, 2 H), 3.86 (s, 3 H),
perature until TLC indicated completion of the reaction. Water
(30 mL) and EtOAc (30 mL) were added and the aqueous phase
was separated and extracted with EtOAc (30 mL × 2). The organic
phases were combined and washed with brine. After drying with
MgSO4, the solvent was removed under vacuum, and the crude
product was purified by flash chromatography (PE/EA, 20:1) to give
{1-[(3,4-dimethoxyphenyl)ethynyl]-2-
2.99 (t, J = 8.4 Hz, 1 H), 2.52 (dd, J = 8.9, 4.7 Hz, 1 H), 1.94 (dd, J =
7.5, 4.9 Hz, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 194.5, 163.2,
136.0, 131.8, 131.2, 129.3, 128.7, 128.1, 127.8, 127.3, 123.1, 113.3,
88.6, 84.6, 55.4, 37.1, 31.7, 22.8 ppm. IR (KBr): ν = 2839, 1667, 1600,
˜
1256, 1174, 1030, 846, 756 cm–1. HRMS (ESI): calcd. for C25H21O2 [M
+ H]+ 353.1536; found 353.1538.
[2-Phenyl-1-(phenylethynyl)cyclopropyl](thiophen-2-yl)-
methanone (1m): Yield 70 %; light-yellow oil. 1H NMR (400 MHz,
CDCl3): δ = 8.34 (dd, J = 3.9, 1.1 Hz, 1 H), 7.57 (dd, J = 5.0, 1.1 Hz,
1 H), 7.32–7.22 (m, 5 H), 7.18–7.11 (m, 3 H), 7.05–7.00 (m, 3 H), 3.08
(t, J = 8.5 Hz, 1 H), 2.42 (dd, J = 9.1, 4.5 Hz, 1 H), 1.89 (dd, J = 8.0,
4.5 Hz, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 187.9, 142.9, 135.9,
134.6, 134.2, 131.4, 129.0, 128.3, 128.2, 128.1, 128.0, 127.4, 123.0,
phenylcyclopropyl}(phenyl)methanone (1g; 556.6 mg, 77 %) as a
1
yellow oil. H NMR (400 MHz, CDCl3): δ = 8.10–8.08 (m, 2 H), 7.55–
7.52 (m, 1 H), 7.46–7.33 (m, 7 H), 6.67–6.60 (m, 2 H), 6.42 (s, 1 H),
3.82 (s, 3 H), 3.75 (s, 3 H), 3.03 (t, J = 8.3 Hz, 1 H), 2.51 (dd, J = 8.7,
4.5 Hz, 1 H), 1.96 (dd, J = 7.9, 4.5 Hz, 1 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 197.0, 149.1, 148.3, 132.6, 129.3, 128.9, 128.1, 128.0,
127.3, 124.3, 115.3, 114.0, 110.7, 86.6, 84.8, 55.9, 55.8, 38.0, 32.1,
88.4, 85.1, 39.3, 31.8, 25.6 ppm. IR (KBr): ν = 3060, 2924, 1639, 1492,
˜
23.6 ppm. IR (KBr): ν = 2930, 1674, 1513, 1256, 1136, 1025 cm–1
.
1411, 1354, 1263, 777, 755, 724 cm–1. HRMS (ESI): calcd. for
˜
HRMS (ESI): calcd. for C26H23O3 [M + H]+ 383.1642; found 383.1640.
C
22H16OS [M + Na]+ 351.0814; found 351.0818.
Compounds 1c, 1d, 1h, 1i, 1l, and 1m were also prepared according
to route A.
Synthesis of ACP Ketone 1e (Route B): nBuLi (1.6
M in hexane,
12.0 mL, 1.2 equiv.) was added dropwise to a solution of ethyl 4-
phenylbut-3-ynoate (10; 3.00 g, 15.94 mmol, 1.0 equiv.) in dry THF
(40 mL) at –78 °C. The mixture was stirred at the same temperature
for 0.5 h before butyraldehyde (1.38 g, 19.13 mmol, 1.2 equiv.) in
dry THF (10 mL) was added dropwise. The mixture was stirred at
–78 °C and the reaction was monitored by TLC. Upon completion,
the reaction was quenched with saturated NH4Cl solution and the
aqueous phase was separated and extracted with EtOAc
(30 mL × 2). The organic phases were combined and washed with
brine. After drying with MgSO4, the solvent was removed under
vacuum, and the crude product was purified by flash chromatogra-
phy (PE/EA, 40:1–20:1) to give 11 (1.50 g, 36 %) as a yellow oil.
{2-[4-(tert-Butyl)phenyl]-1-(phenylethynyl)cyclopropyl}(phenyl)-
1
methanone (1c): Yield 83 %; yellow oil. H NMR (400 MHz, CDCl3):
δ = 7.94–7.89 (m, 2 H), 7.36–7.32 (m, 1 H), 7.27–7.22 (m, 4 H), 7.15–
7.13 (m, 2 H), 7.01–6.92 (m, 3 H), 6.77–6.73 (m, 2 H), 2.87 (t, J =
8.4 Hz, 1 H), 2.34 (dd, J = 9.0, 4.6 Hz, 1 H), 1.78 (dd, J = 7.8, 4.6 Hz,
1 H), 1.19 (s, 9 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 197.0, 150.3,
137.0, 133.0, 132.6, 131.2, 129.3, 128.5, 128.0, 128.0, 127.8, 125.1,
123.2, 88.7, 84.7, 38.3, 34.6, 32.1, 31.5, 23.8 ppm. IR (KBr): ν = 2963,
˜
2868, 1674, 1597, 1490, 1446, 1366, 1265, 996, 838, 756, 692 cm–1
.
HRMS (ESI): calcd. for C28H27O [M + H]+ 379. 2056; found 379.2063.
[2-(4-Methoxyphenyl)-1-(phenylethynyl)cyclopropyl](phenyl)-
MsCl (0.79 g, 6.92 mmol, 1.2 equiv.) in DCM (10 mL) was added
dropwise to a solution of 11 (1.50 g, 5.76 mmol, 1.0 equiv.) and
Et3N (1.75 g, 17.28 mmol, 3.0 equiv.) in DCM (35 mL) at –10 °C, the
mixture was stirred at the same temperature and the reaction was
monitored by TLC. Upon completion, the reaction was quenched
with water and the aqueous phase was separated and extracted
with DCM (20 mL × 2). The organic phases were combined and
washed with brine. After drying with MgSO4, the solvent was re-
moved under vacuum, and the crude product was purified by flash
chromatography (PE/EA, 20:1) to give 12 (663.6 mg, 48 %) as a light-
1
methanone (1d): Yield 75 %; yellow oil. H NMR (400 MHz, CDCl3):
δ = 8.10–8.04 (m, 2 H), 7.57–7.51 (m, 1 H), 7.45–7.42 (m, 2 H), 7.32–
7.30 (m, 2 H), 7.21–7.14 (m, 3 H), 7.04–7.03 (m, 2 H), 6.95–6.93 (m,
2 H), 3.84 (s, 3 H), 2.97 (t, J = 8.5 Hz, 1 H), 2.53 (dd, J = 9.1, 4.7 Hz,
1 H), 1.90 (dd, J = 7.9, 4.7 Hz, 1 H) ppm. 13C NMR (101 MHz, CDCl3):
δ = 197.0, 159.0, 136.9, 132.6, 131.2, 129.8, 129.3, 128.1, 128.0, 127.9,
123.2, 114.0, 113.6, 88.5, 84.9, 55.4, 38.2, 32.2, 23.8 ppm. IR (KBr):
ν = 3060, 3004, 1671, 1610, 1516, 1446, 1251, 1178, 1035, 1005,
˜
833, 756, 692 cm–1. HRMS (ESI): calcd. for C25H20O2 [M + Na]+
375.1356; found 375.1360.
1
yellow oil. H NMR (400 MHz, CDCl3): δ = 7.53–7.47 (m, 2 H), 7.37–
Phenyl{2-phenyl-1-[(trimethylsilyl)ethynyl]cyclopropyl}-
methanone (1h): Yield 92 %; colorless solid, m.p. 65–67 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.05 (d, J = 7.7 Hz, 2 H), 7.55–7.51 (m, 1 H),
7.36 (dq, J = 25.8, 7.6 Hz, 6 H), 2.91 (t, J = 8.4 Hz, 1 H), 2.44 (dd, J =
9.0, 4.6 Hz, 1 H), 1.86 (dd, J = 7.8, 4.6 Hz, 1 H), –0.09 (s, 9 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 196.7, 136.7, 135.7, 132.6, 129.5,
128.8, 128.0, 127.8, 127.3, 104.5, 90.2, 38.5, 32.4, 23.6, –0.5 ppm. IR
7.30 (m, 3 H), 7.28–7.24 (m, 1 H), 4.28 (dd, J = 14.2, 7.1 Hz, 2 H),
2.50 (dd, J = 14.9, 7.5 Hz, 2 H), 1.62–1.51 (m, 2 H), 1.35 (t, J = 7.1 Hz,
3 H), 1.03–0.96 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3):
δ = 164.9, 153.2, 131.7, 128.5, 128.4, 123.2, 117.5, 95.9, 83.2, 61.4,
33.0, 21.6, 14.3, 14.0 ppm.
NaH (60 % in mineral oil, 131.6 mg, 3.29 mmol, 1.2 equiv.) was
added to a solution of trimethylsulfoxonium iodide (723.6 mg,
3.29 mmol, 1.2 equiv.) in DMSO (20 mL), the mixture was stirred for
30 min until the solution turned clear, then 12 (663.6 mg,
2.74 mmol, 1.0 equiv.) was added, and the mixture was stirred at
room temperature until TLC indicated completion of the reaction.
Water (30 mL) and EtOAc (30 mL) were added and the aqueous
phase was separated and extracted with EtOAc (30 mL × 2). The
organic phases were combined and washed with brine. After drying
with MgSO4, the solvent was removed under vacuum, and the
crude product was purified by flash chromatography (PE/EA, 40:1)
to give ethyl 1-(phenylethynyl)-2-propylcyclopropanecarboxylate
(13; 671.8 mg, 96 %) as a pale-yellow oil.
(KBr): ν = 2958, 2163, 1669, 1597, 1268, 1249, 1031, 865, 843 cm–1
.
˜
HRMS (ESI): calcd. for C21H23OSi [M + H]+ 319.1513; found 319.1514.
(1-Ethynyl-2-phenylcyclopropyl)(phenyl)methanone (1i): Yield
1
82 %; light-yellow oil. H NMR (400 MHz, CDCl3): δ = 8.04–7.99 (m,
2 H), 7.57–7.53 (m, 1 H), 7.46–7.37 (m, 4 H), 7.36–7.33 (m, 3 H), 2.89
(t, J = 8.5 Hz, 1 H), 2.44 (dd, J = 9.1, 4.8 Hz, 1 H), 2.05 (s, 1 H), 1.87
(dd, J = 7.9, 4.8 Hz, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 196.4,
136.4, 135.4, 132.8, 129.3, 128.7, 128.2, 128.1, 127.5, 82.1, 73.5, 37.2,
31.2, 22.5 ppm. IR (KBr): ν = 3705, 3289, 1675, 1449, 1264, 1173,
˜
694 cm–1. HRMS (ESI): calcd. for C18H15O [M + H]+ 247.1117; found
247.1119.
(4-Methoxyphenyl)[2-phenyl-1-(phenylethynyl)cyclopropyl]- Isopropylmagnesium chloride (1.0
M in THF, 7.9 mL, 3.0 equiv.) was
methanone (1l): Yield 86 %; light-yellow oil. 1H NMR (400 MHz,
added dropwise to a solution of ethyl 1-(phenylethynyl)-2-propylcy-
Eur. J. Org. Chem. 2016, 2467–2478
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
clopropanecarboxylate (13; 671.8 mg, 2.62 mmol, 1.0 equiv.) and General Procedure for the [3+2] Cycloaddition Reactions of ACP
N,O-dimethylhydroxylamine hydrochloride (383.3 mg, 3.93 mmol,
1.5 equiv.) in dry THF (16 mL) at –20 °C. The reaction mixture was
Ketones with Aldehydes: Sc(OTf)3 (0.06 mmol, 0.2 equiv.) was
added to a solution of ACP ketone 1 (0.3 mmol, 1 equiv.) and alde-
stirred at the same temperature for a further 15 min, then water hyde 2 (1.5 mmol, 5 equiv.) in toluene (8 mL) at 0 °C. The reaction
(20 mL) was added to quench the reaction. The aqueous phase
was separated and extracted with EtOAc (20 mL × 3), the combined
organic layers were washed with water and brine, and dried with
MgSO4. The solvent was removed under vacuum and the residue
was then added to a flask filled with dry THF (20 mL) under Ar.
mixture was stirred at 0 °C and monitored by TLC. Upon completion,
the reaction mixture was passed through a small plug of silica, elut-
ing with Et2O (20 mL), and the solvent was removed under vacuum.
The crude mixture was purified by flash chromatography to give
the pure products. For the cases in which the products were insepa-
rable from excess aldehyde, the excess aldehyde was oxidized by
Methylmagnesium bromide (3
M in diethyl ether, 1.3 mL, 1.5 equiv.)
was added dropwise at 0 °C. The mixture was stirred for an addi- using Montanari's modified Pinnick oxidation.[12] The resulting mix-
tional 2 h and water (20 mL) was added to quench the reaction. ture was dissolved in CH3CN (4 mL) and H2O (6 mL) and then
The aqueous phase was separated and extracted with EtOAc
(20 mL × 3), and the combined organic layers were washed with
water and brine, and dried with MgSO4. After removing the solvent
NaH2PO4 (100 mg) and 30 % H2O2 (0.15 mL, 1.32 mmol, 4.4 equiv.)
were added. Following the addition of NaClO2 (1.8 mmol,
6.0 equiv.), the reaction mixture was stirred overnight. Upon com-
under vacuum, the crude product was purified by flash chromatog- pletion, the reaction mixture was diluted with CH2Cl2 (20 mL) and
raphy (PE/EA, 80:1) to give 1-[1-(phenylethynyl)-2-propylcyclo- washed with a saturated NaHCO3 solution and brine. After drying
1
propyl]ethanone (1e; 350.0 mg, 59 %) as a light-yellow oil. H NMR
(400 MHz, CDCl3): δ = 7.45–7.43 (m, 2 H), 7.33–7.31 (m, 3 H), 2.55
(s, 3 H), 1.84 (dd, J = 8.7, 3.2 Hz, 1 H), 1.78–1.74 (m, 1 H), 1.67–1.44
(m, 4 H), 1.11 (dd, J = 7.3, 3.2 Hz, 1 H), 0.98 (t, J = 7.2 Hz, 3 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 205.9, 131.6, 128.3, 128.0, 123.4,
with MgSO4, the solvent was removed under vacuum, and the
crude products were purified by flash chromatography to give the
pure products. In some cases, the two diastereoisomers were sepa-
rated by preparative TLC.
[2-(3,4-Dimethoxyphenyl)-5-phenyl-3-(phenylethynyl)tetra-
hydrofuran-3-yl](phenyl)methanone (3aa): Yellow oil; yield (with
4aa): 117.5 mg (82 %). 1H NMR (400 MHz, CDCl3): δ = 8.07 (d, J =
7.9 Hz, 2 H), 7.50–7.48 (m, 2 H), 7.41–7.34 (m, 4 H), 7.32–7.20 (m, 8
H), 7.18–7.13 (m, 1 H), 6.84 (d, J = 8.3 Hz, 1 H), 5.94 (s, 1 H), 5.76
(dd, J = 10.0, 5.9 Hz, 1 H), 3.89 (s, 3 H), 3.77 (s, 3 H), 3.19 (dd, J =
12.4, 5.9 Hz, 1 H), 2.83 (dd, J = 12.4, 10.0 Hz, 1 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 195.9, 148.8, 148.2, 142.1, 135.7, 133.1, 131.3,
130.9, 129.8, 128.6, 128.5, 128.4, 128.0, 127.8, 125.7, 122.6, 120.3,
110.8, 110.2, 91.1, 87.9, 86.5, 80.2, 60.3, 55.9, 55.7, 49.6 ppm. IR (KBr):
88.3, 82.8, 34.8, 32.4, 29.9, 29.5, 29.0, 22.1, 13.9 ppm. IR (KBr): ν =
˜
2959, 2930, 1700, 1491, 1356, 755, 690 cm–1. HRMS (ESI): calcd. for
C16H19O [M + H]+ 227.1430; found 227.1433.
Synthesis of ACP Ketone 1o (Route C): [Pd(Ph3P)4] (123.6 mg,
0.107 mmol, 0.05 equiv.) and CuI (40.8 mg, 0.214 mmol, 0.1 equiv.)
were added to a solution of (Z)-2-bromo-4,4-dimethyl-1-phenyl-
pent-1-en-3-one (14, synthesized according to ref.[11]; 571.9 mg,
2.14 mmol, 1.0 equiv.) in THF (4.0 mL) and Et3N (4.0 mL) under Ar.
The reaction mixture was flushed with Ar (3 ×) and phenylacetylene
(262.3 mg, 2.57 mmol, 1.2 equiv.) was added by syringe. The mixture
was stirred at room temperature until TLC indicated completion of
the reaction. The mixture was diluted with EtOAc (50 mL), washed
ν = 2972, 1678, 1596, 1516, 1491, 1266, 1236, 1028, 757, 693 cm–1
.
˜
HRMS (ESI): calcd. for C33H29O4 [M + H]+ 489.2060; found 489.2052.
[2-(3,4-Dimethoxyphenyl)-5-phenyl-3-(phenylethynyl)tetra-
hydrofuran-3-yl](phenyl)methanone (4aa): Yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 7.92–7.90 (m, 2 H), 7.55–7.51 (m, 2 H), 7.37–
with 1
N HCl and brine, and dried with MgSO4. After removing
the solvent under vacuum, the crude product was purified by flash
chromatography (PE/EA, 100:1) to give (E)-4-benzylidene-2,2-di- 7.31 (m, 5 H), 7.30–7.17 (m, 7 H), 6.71 (dd, J = 8.3, 1.8 Hz, 1 H), 6.57
methyl-6-phenylhex-5-yn-3-one (15; 429 mg. 70 %) as a pale-yellow
(d, J = 1.8 Hz, 1 H), 6.51 (d, J = 8.3 Hz, 1 H), 5.61 (s, 1 H), 5.46 (dd,
J = 11.0, 5.2 Hz, 1 H), 3.67 (s, 3 H), 3.50 (s, 3 H), 3.17 (dd, J = 12.6,
1
oil. H NMR (400 MHz, CDCl3): δ = 7.90 (d, J = 7.1 Hz, 2 H), 7.51 (s,
1 H), 7.39–7.09 (m, 8 H), 1.33 (s, 9 H) ppm. 13C NMR (101 MHz, 11.0 Hz, 1 H), 2.68 (dd, J = 12.6, 5.2 Hz, 1 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 204.2, 144.7, 135.1, 131.1, 130.4, 130.2, 128.9, 128.7,
CDCl3): δ = 194.7, 148.9, 148.3, 140.6, 136.1, 132.6, 131.5, 130.4,
128.5, 123.0, 120.0, 100.2, 87.4, 44.7, 27.2 ppm.
130.0, 128.6, 128.6, 128.5, 127.9, 127.6, 126.4, 122.8, 120.6, 111.3,
110.6, 91.8, 90.7, 87.6, 80.2, 59.1, 55.8, 55.6, 45.8 ppm. IR (KBr): ν =
˜
2929, 1681, 1597, 1517, 1413, 1264, 1239, 1161, 1028, 758, 694 cm–1
.
NaH (60 % in mineral oil, 59.5 mg, 1.49 mmol, 1.0 equiv.) was added
to a solution of trimethylsulfoxonium iodide (327.4 mg, 1.49 mmol,
1.0 equiv.) in DMSO (6 mL). The mixture was stirred for 30 min until
the solution turned clear, then 15 (429.0 mg, 1.49 mmol, 1.0 equiv.)
was added, and the mixture was stirred at room temperature until
TLC indicated completion of the reaction. Water (15 mL) and EtOAc
(10 mL) were added and the aqueous phase was separated and
extracted with EtOAc (10 mL × 2), The organic phases were com-
bined and washed with brine. After drying with MgSO4, the solvent
was removed under vacuum, and the crude product was purified
by flash chromatography (PE/EA, 100:1) to give 2,2-dimethyl-1-[2-
phenyl-1-(phenylethynyl)cyclopropyl]propan-1-one (1o; 384.4 mg,
HRMS (ESI): calcd. for C33H29O4 [M + H]+ 489.2060; found 489.2056.
[2-(3,4-Dimethoxyphenyl)-5-phenyl-3-(phenylethynyl)tetra-
hydrofuran-3-yl](phenyl)methanone (5aa): Yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 8.01–7.96 (m, 2 H), 7.45–7.40 (m, 2 H), 7.38–
7.33 (m, 1 H), 7.28–7.21 (m, 4 H), 7.10–7.00 (m, 6 H), 6.90–6.84 (m,
2 H), 6.70 (d, J = 8.3 Hz, 1 H), 5.50 (s, 1 H), 4.96 (t, J = 7.9 Hz, 1 H),
3.72 (s, 3 H), 3.61 (s, 3 H), 3.18 (dd, J = 12.8, 7.4 Hz, 1 H), 2.63 (dd,
J = 12.8, 8.4 Hz, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 196.5,
148.9, 148.3, 141.2, 135.0, 133.3, 131.2, 130.2, 128.6, 128.3, 128.3,
128.1, 127.9, 126.4, 120.8, 111.4, 110.4, 100.0, 90.5, 90.0, 89.7, 86.4,
79.6, 58.8, 56.0, 55.8, 49.1 ppm. IR (KBr): ν = 2950, 1678, 1597, 1516,
1
˜
85 %) as a light-yellow oil. H NMR (400 MHz, CDCl3): δ = 7.26–7.20
1447, 1263, 1236, 1029, 757, 693 cm–1. HRMS (ESI): calcd. for
C33H29O4 [M + H]+ 489.2060; found 489.2057.
(m, 2 H), 7.19–7.16 (m, 3 H), 7.11–7.04 (m, 3 H), 6.97–6.92 (m, 2 H),
2.78 (t, J = 8.4 Hz, 1 H), 2.16 (dd, J = 8.9, 4.2 Hz, 1 H), 1.67 (dd, J =
7.8, 4.2 Hz, 1 H), 1.33 (s, 9 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
[2-(Benzo[d][1,3]dioxol-5-yl)-5-phenyl-3-(phenylethynyl)tetra-
209.5, 136.1, 131.1, 129.1, 128.2, 128.0, 127.9, 127.2, 123.3, 89.0, 84.4, hydrofuran-3-yl](phenyl)methanone (3ab): Yellow oil; yield (with
1
45.4, 39.6, 30.5, 26.7, 25.7 ppm. IR (KBr): ν = 3412, 2969, 1684, 1598,
4ab): 80.5 mg (79 %). H NMR (400 MHz, CDCl3): δ = 8.09–8.02 (m,
˜
1184, 1103, 1063, 754, 692 cm–1. HRMS (ESI): calcd. for C22H23O [M 2 H), 7.45–7.41 (m, 1 H), 7.39–7.24 (ddd, J = 23.0, 15.5, 7.5 Hz, 6 H),
+ H]+ 303.1743; found 303.1746.
7.23–7.14 (m, 7 H), 7.03 (dd, J = 8.1, 1.2 Hz, 1 H), 6.70 (d, J = 8.1 Hz,
2473 © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2016, 2467–2478
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Full Paper
1 H), 5.89 (s, 1 H), 5.85 (s, 2 H), 5.63 (dd, J = 10.0, 5.8 Hz, 1 H), 3.11
120.2, 109.4, 90.2, 89.1, 83.6, 80.8, 60.3, 54.2, 50.6 ppm. IR (KBr): ν =
˜
(dd, J = 12.3, 5.8 Hz, 1 H), 2.64 (dd, J = 12.3, 10.0 Hz, 1 H) ppm. 13C 3060, 1678, 1598, 1491, 1461, 1246, 1050, 1028, 756, 694 cm–1
.
NMR (101 MHz, CDCl3): δ = 195.7, 147.3, 147.1, 141.9, 135.6, 133.2,
132.6, 131.3, 129.8, 128.6, 128.5, 128.3, 128.1, 127.8, 125.7, 122.7,
121.3, 108.5, 107.5, 100.9, 91.3, 87.7, 86.1, 80.3, 60.2, 49.6 ppm. IR
HRMS (ESI): calcd. for C32H27O3 [M + H]+ 459.1955; found 459.1947.
Phenyl[5-phenyl-3-(phenylethynyl)-2-(thiophen-2-yl)tetra-
hydrofuran-3-yl]methanone (3ag): Yellow oil; yield (with 4ag):
(KBr): ν = 3414, 1721, 1490, 1445, 1239, 1039, 934, 757, 694 cm–1
.
˜
1
110.3 mg (88 %). H NMR (400 MHz, CDCl3): δ = 8.19–8.14 (m, 2 H),
HRMS (ESI): calcd. for C32H25O4 [M + H]+ 473.1747; found 473.1738.
7.51–7.45 (m, 1 H), 7.40–7.17 (m, 13 H), 6.94 (dd, J = 3.9, 0.4 Hz, 1
H), 6.74 (d, J = 3.9 Hz, 1 H), 6.07 (s, 1 H), 5.62 (dd, J = 10.0, 6.0 Hz,
1 H), 3.16 (dd, J = 12.5, 6.0 Hz, 1 H), 2.55 (dd, J = 12.5, 10.0 Hz, 1
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 194.8, 141.4, 140.7, 135.1,
133.5, 131.5, 129.9, 129.5, 128.7, 128.7, 128.6, 128.4, 128.3, 128.0,
[2-(Benzo[d][1,3]dioxol-5-yl)-5-phenyl-3-(phenylethynyl)tetra-
hydrofuran-3-yl](phenyl)methanone (4ab): Yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 7.84 (d, J = 7.7 Hz, 2 H), 7.53–7.47 (m, 2 H),
7.41–7.11 (m, 11 H), 6.65–6.60 (m, 2 H), 6.43–6.38 (m, 1 H), 5.71 (s,
2 H), 5.50 (s, 1 H), 5.36 (dd, J = 10.6, 5.3 Hz, 1 H), 3.13 (dd, J = 12.7,
10.6 Hz, 1 H), 2.65 (dd, J = 12.7, 5.3 Hz, 1 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 195.1, 147.6, 147.4, 140.3, 136.1, 132.5, 131.6, 131.5,
129.9, 128.6, 128.6, 128.5, 128.0, 127.6, 126.5, 122.7, 122.1, 108.4,
125.7, 125.4, 125.2, 91.2, 86.7, 83.1, 59.7, 48.8 ppm. IR (KBr): ν =
˜
3032, 1678, 1597, 1400, 1182, 757, 695 cm–1. HRMS (ESI): calcd. for
C29H23O2S [M + H]+ 435.1413; found 435.1405.
Phenyl[5-phenyl-3-(phenylethynyl)-2-(thiophen-2-yl)tetra-
hydrofuran-3-yl]methanone (4ag): Yellow oil. 1H NMR (400 MHz,
CDCl3): δ = 8.09 (d, J = 7.5 Hz, 2 H), 7.62–7.58 (m, 2 H), 7.51–7.47
(m, 1 H), 7.44–7.30 (m, 10 H), 7.12–7.08 (m, 1 H), 6.67–6.62 (m, 2 H),
6.11 (s, 1 H), 5.58 (dd, J = 11.3, 4.5 Hz, 1 H), 3.21 (dd, J = 12.8,
11.3 Hz, 1 H), 2.75 (dd, J = 12.8, 4.6 Hz, 1 H) ppm. 13C NMR (101 MHz,
107.7, 101.0, 91.9, 91.0, 87.5, 80.3, 59.0, 46.6 ppm. IR (KBr): ν = 2895,
˜
1680, 1489, 1446, 1248, 1039, 757, 693 cm–1. HRMS (ESI): calcd. for
C32H24O4 [M + Na]+ 495.1567; found 495.1569.
{2-[4-(Benzyloxy)phenyl]-5-phenyl-3-(phenylethynyl)tetra-
hydrofuran-3-yl}(phenyl)methanone (3ac): Yellow oil; yield (with
4ac): 142.4 mg (90 %). 1H NMR (400 MHz, CDCl3): δ = 7.98 (d, J = CDCl3): δ = 193.5, 141.7, 140.1, 135.7, 132.9, 131.6, 129.9, 128.8,
7.8 Hz, 2 H), 7.50 (d, J = 8.6 Hz, 2 H), 7.37–7.06 (m, 18 H), 6.85 (d,
J = 8.6 Hz, 2 H), 5.86 (s, 1 H), 5.61 (dd, J = 10.1, 5.9 Hz, 1 H), 4.93 (s,
2 H), 3.07 (dd, J = 12.2, 5.9 Hz, 1 H), 2.65 (dd, J = 12.2, 10.1 Hz, 1
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 195.7, 158.6, 142.2, 137.1,
135.6, 133.1, 131.3, 131.0, 129.8, 129.1, 128.6, 128.4, 128.3, 128.0,
127.9, 127.7, 127.4, 125.7, 122.7, 114.0, 91.1, 87.8, 86.2, 80.1, 69.9,
128.5, 128.5, 128.0, 127.9, 127.2, 126.5, 126.1, 122.5, 90.8, 88.0, 85.6,
80.6, 59.3, 44.9 ppm. IR (KBr): ν = 3415, 1681, 1639, 1619, 1240, 756,
˜
693 cm–1. HRMS (ESI): calcd. for C29H23O2S [M + H]+ 435.1413; found
435.1405.
[5-(4-Chlorophenyl)-2-(3,4-dimethoxyphenyl)-3-(phenyleth-
ynyl)tetrahydrofuran-3-yl](phenyl)methanone (3ba): Yellow oil;
yield (with 4ba): 104.4 mg (92 %). 1H NMR (400 MHz, CDCl3): δ =
7.95 (d, J = 7.7 Hz, 2 H), 7.39 (t, J = 7.3 Hz, 1 H), 7.22–7.31 (m, 6 H),
7.20–7.10 (m, 6 H), 7.04 (d, J = 8.2 Hz, 1 H), 6.73 (d, J = 8.2 Hz, 1 H),
5.79 (s, 1 H), 5.63 (dd, J = 9.6, 6.0 Hz, 1 H), 3.77 (s, 3 H), 3.66 (s, 3
H), 3.07 (dd, J = 12.4, 6.0 Hz, 1 H), 2.68 (dd, J = 12.4, 9.6 Hz, 1
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 195.7, 148.9, 148.3, 140.6,
60.1, 49.5 ppm. IR (KBr): ν = 3062, 1679, 1611, 1511, 1450, 1239,
˜
1173, 757, 695 cm–1. HRMS (ESI): calcd. for C38H31O3 [M + H]+
535.2268; found 535.2262.
[2-(4-Methoxyphenyl)-5-phenyl-3-(phenylethynyl)tetrahydro-
furan-3-yl](phenyl)methanone (3ad): Yellow oil; yield (with 4ad):
1
72.2 mg (95 %). H NMR (400 MHz, CDCl3): δ = 8.05–7.95 (m, 2 H),
7.53–7.47 (m, 2 H), 7.36–7.30 (m, 3 H), 7.26–7.17 (m, 4 H), 7.17–7.08 135.6, 133.3, 133.1, 131.2, 130.6, 129.7, 128.7, 128.6, 128.3, 127.9,
(m, 6 H), 6.81–6.74 (m, 2 H), 5.86 (s, 1 H), 5.61 (dd, J = 9.2, 6.2 Hz, 1 127.0, 122.5, 120.3, 110.8, 110.3, 91.2, 87.7, 86.6, 79.4, 60.2, 55.9,
H), 3.64 (s, 3 H), 3.07 (dd, J = 12.3, 5.8 Hz, 1 H), 2.66 (dd, J = 12.3,
55.7, 49.3 ppm. IR (KBr): ν = 2998, 1679, 1596, 1515, 1491, 1265,
˜
9.2 Hz, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 195.8, 159.5, 142.2,
1236, 1028, 757, 691 cm–1. HRMS (ESI): calcd. for C33H27ClO4 [M +
135.7, 133.1, 131.3, 130.8, 129.8, 129.1, 128.6, 128.5, 128.3, 128.0, Na]+ 545.1490; found 545.1493.
127.7, 125.8, 122.7, 113.1, 91.1, 87.9, 86.3, 80.2, 60.2, 55.3, 49.6 ppm.
[5-(4-Chlorophenyl)-2-(3,4-dimethoxyphenyl)-3-(phenyleth-
ynyl)tetrahydrofuran-3-yl](phenyl)methanone (4ba): Yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.91–7.85 (m, 2 H), 7.48–7.46 (m, 2
H), 7.36–7.30 (m, 5 H), 7.30–7.19 (m, 6 H), 6.70 (dd, J = 8.3, 1.9 Hz,
1 H), 6.54–6.52 (m, 2 H), 5.59 (s, 1 H), 5.42 (dd, J = 10.8, 5.4 Hz, 1
H), 3.68 (s, 3 H), 3.50 (s, 3 H), 3.10 (dd, J = 12.6, 10.8 Hz, 1 H), 2.68
(dd, J = 12.6, 5.4 Hz, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
IR (KBr): ν = 2927, 1679, 1611, 1513, 1446, 1248, 1173, 757, 694 cm–1
.
˜
HRMS (ESI): calcd. for C32H27O3 [M + H]+ 459.1955; found 459.1954.
[2-(4-Ethoxyphenyl)-5-phenyl-3-(phenylethynyl)tetrahydro-
furan-3-yl](phenyl)methanone (3ae): Yellow oil; yield (with 4ae):
1
136.2 mg (93 %). H NMR (400 MHz, CDCl3): δ = 8.10–8.04 (m, 2 H),
7.57 (d, J = 8.7 Hz, 2 H), 7.52–7.44 (m, 3 H), 7.39–7.32 (m, 4 H), 7.29–
7.20 (m, 6 H), 6.87 (d, J = 8.7 Hz, 2 H), 5.94 (s, 1 H), 5.72 (dd, J = 194.7, 148.9, 148.2, 139.2, 136.0, 133.6, 132.6, 131.5, 130.1, 129.9,
10.0, 5.9 Hz, 1 H), 4.02 (q, J = 7.0 Hz, 2 H), 3.17 (dd, J = 12.4, 5.9 Hz,
1 H), 2.79 (dd, J = 12.4, 10.0 Hz, 1 H), 1.40 (t, J = 7.0 Hz, 3 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 195.9, 158.9, 142.2, 135.8, 133.1,
128.7, 128.5, 127.7, 127.6, 122.6, 120.5, 111.2, 110.6, 91.5, 90.8, 87.7,
79.4, 59.0, 55.8, 55.6, 45.9 ppm. IR (KBr): ν = 2999, 1680, 1597, 1517,
˜
1492, 1264, 1239, 1161, 1028, 757, 692 cm–1. HRMS (ESI): calcd. for
131.4, 130.5, 129.8, 129.1, 128.6, 128.5, 128.3, 128.0, 127.7, 125.8, C33H27ClO4 [M + Na]+ 545.1490; found 545.1495.
122.8, 113.7, 91.1, 87.9, 86.4, 80.2, 63.5, 60.2, 49.6, 14.9 ppm. IR (KBr):
{5-[4-(tert-Butyl)phenyl]-2-(3,4-dimethoxyphenyl)-3-(phenyl-
ethynyl)tetrahydrofuran-3-yl}(phenyl)methanone (3ca): Yellow
oil; yield (with 4ca): 111.4 mg (85 %). 1H NMR (400 MHz, CDCl3): δ =
7.97 (d, J = 8.0 Hz, 2 H), 7.38 (t, J = 7.4 Hz, 1 H), 7.33–7.29 (m, 4 H),
7.28–7.24 (m, 2 H), 7.20–7.09 (m, 6 H), 7.07–7.02 (m, 1 H), 6.72 (d,
J = 8.3 Hz, 1 H), 5.84 (s, 1 H), 5.63 (dd, J = 10.0, 5.9 Hz, 1 H), 3.77 (s,
3 H), 3.66 (s, 3 H), 3.07 (dd, J = 12.4, 5.9 Hz, 1 H), 2.74 (dd, J = 12.4,
10.0 Hz, 1 H), 1.22 (s, 9 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
196.0, 150.7, 148.7, 148.2, 138.9, 135.7, 133.0, 131.3, 131.1, 129.7,
128.5, 128.3, 127.9, 125.5, 125.5, 122.6, 120.2, 110.7, 110.1, 90.9, 88.0,
ν = 3416, 1679, 1613, 1512, 1396, 1243, 1173, 1047, 757, 694 cm–1
.
˜
HRMS (ESI): calcd. for C33H29O3 [M + H]+ 473.2111; found 473.2107.
[2-(2-Methoxyphenyl)-5-phenyl-3-(phenylethynyl)tetrahydro-
furan-3-yl](phenyl)methanone (3af): Yellow oil; yield (with 4af):
1
106.8 mg (75 %). H NMR (400 MHz, CDCl3): δ = 7.82–7.76 (m, 3 H),
7.46–7.42 (m, 2 H), 7.36–7.12 (m, 11 H), 7.05–6.97 (m, 3 H), 6.60 (d,
J = 8.1 Hz, 1 H), 6.00 (s, 1 H), 5.56 (dd, J = 10.3, 5.1 Hz, 1 H), 3.15 (s,
3 H), 3.07 (t, J = 11.4 Hz, 1 H), 2.83 (dd, J = 12.0, 5.1 Hz, 1 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 196.1, 156.4, 141.8, 136.7, 132.3,
131.3, 129.5, 128.9, 128.6, 128.2, 127.8, 127.6, 127.5, 126.1, 123.0, 86.3, 80.0, 60.3, 55.9, 55.7, 49.4, 34.5, 31.4 ppm. IR (KBr): ν = 2961,
˜
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Full Paper
1679, 1596, 1515, 1492, 1463, 1267, 1236, 1028, 758, 692 cm–1
.
110.9, 110.2, 91.1, 86.2, 80.1, 60.2, 55.8, 55.7, 55.7, 49.3 ppm. IR (KBr):
HRMS (ESI): calcd. for C37H36O4 [M + Na]+ 567.2506; found 567.2499. ν = 2934, 1681, 1515, 1268, 1241, 1138, 1026 cm–1. HRMS (ESI):
˜
calcd. for C35H33O6 [M + H]+ 549.2272; found 549.2266.
{5-[4-(tert-Butyl)phenyl]-2-(3,4-dimethoxyphenyl)-3-(phenyl-
ethynyl)tetrahydrofuran-3-yl}(phenyl)methanone (4ca): Yellow
{2-(3,4-Dimethoxyphenyl)-5-phenyl-3-[(trimethylsilyl)ethyn-
yl]tetrahydrofuran-3-yl}(phenyl)methanone (3ha): Yellow oil;
oil. 1H NMR (400 MHz, CDCl3): δ = 7.96 (d, J = 7.7 Hz, 2 H), 7.56–
7.51 (m, 2 H), 7.46–7.36 (m, 5 H), 7.34–7.24 (m, 5 H), 6.77 (dd, J = yield (with 4ha): 126.2 mg (88 %). 1H NMR (400 MHz, CDCl3): δ =
8.3, 1.6 Hz, 1 H), 6.63 (d, J = 1.6 Hz, 1 H), 6.56 (d, J = 8.3 Hz, 1 H),
5.65 (s, 1 H), 5.49 (dd, J = 10.9, 5.2 Hz, 1 H), 3.72 (s, 3 H), 3.56 (s, 3
H), 3.26 (dd, J = 12.7, 10.9 Hz, 1 H), 2.71 (dd, J = 12.7, 5.2 Hz, 1 H),
1.33 (s, 9 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 194.8, 150.9, 148.8,
8.00 (d, J = 7.5 Hz, 2 H), 7.47–7.40 (m, 3 H), 7.34–7.28 (m, 4 H), 7.27–
7.21 (m, 1 H), 7.11–7.09 (m, 2 H), 6.79 (d, J = 8.0 Hz, 1 H), 5.79 (s, 1
H), 5.62 (dd, J = 10.0, 5.8 Hz, 1 H), 3.84 (s, 3 H), 3.83 (s, 3 H), 3.03
(dd, J = 12.3, 5.9 Hz, 1 H), 2.68 (dd, J = 12.3, 10.2 Hz, 1 H), 0.00 (s,
148.2, 137.4, 136.2, 132.5, 131.5, 130.5, 130.0, 128.6, 128.5, 127.6, 9 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 195.9, 148.7, 148.1, 142.0,
126.3, 125.5, 122.8, 120.6, 111.3, 110.5, 92.0, 90.7, 87.5, 80.1, 59.1,
135.6, 133.0, 131.0, 130.0, 128.6, 127.8, 127.7, 125.7, 120.1, 110.9,
110.3, 104.1, 96.5, 86.3, 80.1, 60.7, 56.0, 55.8, 49.6, 0.4 ppm. IR (KBr):
55.8, 55.6, 45.6, 34.7, 31.5 ppm. IR (KBr): ν = 2960, 1681, 1597, 1517,
˜
1491, 1265, 1240, 1161, 1028, 757, 693 cm–1. HRMS (ESI): calcd. for ν = 2958, 2166, 1679, 1596, 1516, 1450, 1260, 1237, 1029, 846 cm–1
.
˜
C
37H36O4 [M + Na]+ 567.2506; found 567.2512.
HRMS (ESI): calcd. for C30H33O4Si [M + H]+ 485.2143; found
485.2152.
2-(4-Methoxyphenyl)-5-phenyl-4-(phenylethynyl)-2,3-dihydro-
furan (7): Yellow oil; yield 98.3 mg (92 %). 1H NMR (400 MHz,
{2-(3,4-Dimethoxyphenyl)-5-phenyl-3-[(trimethylsilyl)ethyn-
CDCl3): δ = 8.10–8.04 (m, 2 H), 7.46–7.09 (m, 9 H), 6.82 (d, J = 8.8 Hz, yl]tetrahydrofuran-3-yl}(phenyl)methanone (4ha): Colorless
1
2 H), 5.58 (dd, J = 10.4, 8.8 Hz, 1 H), 3.71 (s, 3 H), 3.38 (dd, J = 15.1,
10.4 Hz, 1 H), 2.99 (dd, J = 15.1, 8.8 Hz, 1 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 159.5, 157.8, 134.1, 131.1, 130.4, 129.3, 128.4, 128.2,
127.8, 127.3, 126.6, 124.1, 114.1, 95.2, 91.5, 85.9, 81.9, 55.4,
solid, m.p.124–126 °C. H NMR (400 MHz, CDCl3): δ = 7.76–7.72 (m,
2 H), 7.42–7.40 (m, 2 H), 7.25–7.20 (m, 2 H), 7.17–7.13 (m, 1 H), 7.09–
7.05 (m, 3 H), 6.57 (dd, J = 8.3, 1.8 Hz, 1 H), 6.42–6.38 (m, 2 H), 5.39
(s, 1 H), 5.27 (dd, J = 10.8, 5.3 Hz, 1 H), 3.56 (s, 3 H), 3.39 (s, 3 H),
2.95 (dd, J = 12.6, 11.0 Hz, 1 H), 2.48 (dd, J = 12.6, 5.3 Hz, 1 H), 0.00
(s, 9 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 194.6, 148.8, 148.1,
140.5, 136.1, 132.4, 130.4, 130.1, 128.5, 127.8, 127.4, 126.4, 120.4,
111.1, 110.5, 108.4, 92.6, 90.7, 80.1, 59.4, 55.8, 55.5, 45.7, –0.2 ppm.
43.2 ppm. IR (KBr): ν = 2932, 2198, 1598, 1514, 1248, 1029, 757,
˜
692 cm–1. HRMS (ESI): calcd. for C25H20O2 [M + Na]+ 375.1356; found
375.1358.
{3-[(4-Chlorophenyl)ethynyl]-2-(3,4-dimethoxyphen-
yl)-5-phenyltetrahydrofuran-3-yl}(phenyl)methanone (3fa): Yel-
low oil; yield (with 4fa) 151.9 mg (83 %). 1H NMR (400 MHz, CDCl3):
δ = 7.95 (d, J = 7.5 Hz, 2 H), 7.45–7.35 (m, 3 H), 7.30–7.26 (m, 4 H),
IR (KBr): ν = 2923, 1675, 1455, 1243, 1139, 1047, 1024, 841 cm–1
.
˜
HRMS (ESI): calcd. for C30H32O4Si [M + Na]+ 507.1962; found
507.1961.
7.23–7.11 (m, 4 H), 7.06–7.02 (m, 3 H), 6.74 (d, J = 8.3 Hz, 1 H), 5.85 [2-(3,4-Dimethoxyphenyl)-3-ethynyl-5-phenyltetrahydrofuran-
(s, 1 H), 5.64 (dd, J = 10.2, 5.9 Hz, 1 H), 3.79 (s, 3 H), 3.69 (s, 3 H),
3.09 (dd, J = 12.4, 6.0 Hz, 1 H), 2.72 (dd, J = 12.4, 10.2 Hz, 1 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 195.7, 148.8, 148.3, 142.0, 135.7,
3-yl](phenyl)methanone (3ia): Yellow oil; yield (with 4ia):
137.5 mg (90 %). H NMR (400 MHz, CDCl3): δ = 7.93–7.87 (m, 2 H),
7.40–7.37 (m, 1 H), 7.35–7.33 (m, 2 H), 7.28–7.21 (m, 4 H), 7.20–7.11
1
134.6, 133.2, 132.5, 130.9, 129.7, 128.7, 128.6, 128.0, 127.8, 125.7, (m, 2 H), 7.02 (dd, J = 8.3, 1.7 Hz, 1 H), 6.71 (d, J = 8.3 Hz, 1 H), 5.74
121.1, 120.2, 110.8, 110.2, 90.0, 89.0, 86.5, 80.2, 60.3, 56.0, 55.8,
(s, 1 H), 5.59 (dd, J = 10.0, 5.9 Hz, 1 H), 3.77 (s, 3 H), 3.76 (s, 3 H),
3.02 (dd, J = 12.4, 6.0 Hz, 1 H), 2.66 (dd, J = 12.4, 10.1 Hz, 1 H), 2.48
49.5 ppm. IR (KBr): ν = 2935, 1680, 1595, 1515, 1490, 1266, 1236,
˜
1160, 1139, 1090, 1028 cm–1. HRMS (ESI): calcd. for C33H28ClO4 [M (s, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 195.5, 148.7, 148.1,
+ H]+ 523.1671; found 523.1665.
141.9, 135.4, 133.1, 130.4, 129.8, 128.5, 127.9, 127.7, 125.6, 120.1,
110.9, 110.1, 86.1, 82.3, 79.8, 79.5, 59.6, 55.8, 55.8, 49.4 ppm. IR (KBr):
{3-[(4-Chlorophenyl)ethynyl]-2-(3,4-dimethoxyphenyl)-5-phen-
ν = 3238, 2954, 1674, 1516, 1270, 1235, 1160, 1025, 750, 688 cm–1
.
˜
1
yltetrahydrofuran-3-yl}(phenyl)methanone (4fa): Yellow oil. H
HRMS (ESI): calcd. for C27H24O4 [M + Na]+ 435.1567; found 435.1570.
NMR (400 MHz, CDCl3): δ = 7.90–7.86 (m, 2 H), 7.55–7.51 (m, 2 H),
7.37–7.33 (m, 3 H), 7.30–7.19 (m, 7 H), 6.70 (dd, J = 8.3, 1.8 Hz, 1 H),
6.56 (d, J = 1.8 Hz, 1 H), 6.51 (d, J = 8.3 Hz, 1 H), 5.60 (s, 1 H), 5.44
(dd, J = 11.0, 5.2 Hz, 1 H), 3.67 (s, 3 H), 3.49 (s, 3 H), 3.17 (dd, J =
12.7, 11.0 Hz, 1 H), 2.67 (dd, J = 12.7, 5.2 Hz, 1 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 194.4, 148.9, 148.2, 140.4, 136.0, 134.7, 132.7,
[2-(3,4-Dimethoxyphenyl)-3-ethynyl-5-phenyltetrahydrofuran-
3-yl](phenyl)methanone (4ia): Yellow oil. 1H NMR (400 MHz,
CDCl3): δ = 7.85 (d, J = 7.9 Hz, 2 H), 7.51–7.49 (m, 2 H), 7.35–7.31
(m, 3 H), 7.29–7.15 (m, 3 H), 6.68–6.66 (m, 1 H), 6.55–6.45 (m, 2 H),
5.54 (s, 1 H), 5.39 (dd, J = 10.9, 5.1 Hz, 1 H), 3.64 (s, 3 H), 3.49 (s, 3
132.7, 130.3, 129.9, 128.8, 128.6, 127.9, 127.6, 126.3, 121.2, 120.6, H), 3.11 (dd, J = 12.7, 10.9 Hz, 1 H), 2.66 (s, 1 H), 2.60 (dd, J = 12.7,
111.2, 110.5, 92.8, 90.6, 86.5, 80.1, 59.0, 55.8, 55.6, 45.6 ppm. IR (KBr): 5.1 Hz, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 194.0, 148.9, 148.2,
ν = 3000, 2956, 1681, 1596, 1517, 1490, 1265, 1240, 1161, 1028,
140.3, 135.7, 132.6, 130.2, 130.0, 128.5, 127.9, 127.6, 126.3, 120.6,
˜
701 cm–1. HRMS (ESI): calcd. for C33H28ClO4 [M + H]+ 523.1671; 111.2, 110.5, 90.5, 86.6, 80.0, 76.0, 58.3, 55.8, 55.5, 45.7 ppm. IR (KBr):
found 523.1668.
ν = 3284, 1681, 1517, 1463, 1262, 1240, 1141, 1027, 732 cm–1. HRMS
˜
(ESI): calcd. for C27H24O4 [M + Na]+ 435.1567; found 435.1568.
{2-(3,4-Dimethoxyphenyl)-3-[(3,4-dimethoxyphenyl)ethynyl]-5-
phenyltetrahydrofuran-3-yl}(phenyl)methanone (3ga): Yellow
oil, inseparable from the minor isomer 4ga; yield (with 4ga):
[3-(Cyclopropylethynyl)-2-(3,4-dimethoxyphenyl)-5-phenyl-
tetrahydrofuran-3-yl](phenyl)methanone (3ja): Colorless solid;
yield (with 4ja): 117.4 mg (75 %); m.p. 122–124 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.93–7.86 (m, 2 H), 7.40–7.30 (m, 3 H), 7.27–
7.20 (m, 4 H), 7.17–7.11 (m, 1 H), 7.11–7.10 (m, 1 H), 6.98 (dd, J =
1
96.7 mg (90 %). H NMR (400 MHz, CDCl3): δ = 8.13 (d, J = 8.2 Hz,
2 H), 7.54–7.46 (m, 3 H), 7.45–7.25 (m, 7 H), 7.20 (d, J = 8.4 Hz, 1 H),
6.90–6.83 (m, 2 H), 6.63 (t, J = 3.7 Hz, 1 H), 6.01 (s, 1 H), 5.79 (dd,
J = 9.9, 5.8 Hz, 1 H), 3.87–3.80 (m, 12 H), 3.22 (dd, J = 12.3, 5.8 Hz, 8.2, 1.2 Hz, 1 H), 6.71 (d, J = 8.3 Hz, 1 H), 5.72 (s, 1 H), 5.54 (dd, J =
1 H), 2.82–2.77 (m, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 195.8,
10.0, 5.8 Hz, 1 H), 3.80 (s, 3 H), 3.77 (s, 3 H), 2.91 (dd, J = 12.2, 5.8 Hz,
149.6, 148.6, 148.5, 148.2, 142.0, 135.7, 132.9, 131.3, 129.7, 128.5, 1 H), 2.55 (dd, J = 12.2, 10.0 Hz, 1 H), 1.07–1.03 (m, 1 H), 0.60–0.50
128.4, 127.8, 127.6, 126.2, 125.6, 124.3, 120.1, 114.7, 113.9, 110.9, (m, 2 H), 0.38–0.25 (m, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
Eur. J. Org. Chem. 2016, 2467–2478
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196.3, 148.5, 148.0, 142.1, 135.7, 132.8, 131.3, 129.7, 128.4, 127.7, 6.67 (d, J = 8.3 Hz, 1 H), 5.69 (s, 1 H), 5.61 (dd, J = 10.1, 5.9 Hz, 1
127.6, 125.6, 120.1, 110.9, 110.1, 94.6, 86.1, 79.9, 73.4, 59.6, 55.8,
H), 3.71 (s, 3 H), 3.59 (s, 3 H), 2.97 (dd, J = 12.4, 5.9 Hz, 1 H), 2.78
55.7, 49.6, 7.9, 7.8, –0.3 ppm. IR (KBr): ν = 2907, 2238, 1677, 1596,
(dd, J = 12.4, 10.1 Hz, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
˜
1515, 1450, 1265, 1236, 1160, 1140, 1029, 699 cm–1. HRMS (ESI): 187.7, 148.7, 148.0, 141.9, 141.8, 134.9, 134.7, 131.2, 130.5, 128.5,
calcd. for C30H28O4 [M + Na]+ 475.1880; found 475.1886.
128.4, 128.3, 127.7, 127.6, 125.6, 122.3, 120.1, 110.6, 110.0, 90.7, 87.9,
86.3, 80.0, 60.3, 55.7, 55.5, 49.2 ppm. IR (KBr): ν = 3001, 1655, 1515,
˜
[3-(Cyclopropylethynyl)-2-(3,4-dimethoxyphenyl)-5-phenyl-
tetrahydrofuran-3-yl](phenyl)methanone (4ja): Yellow oil. 1H
NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 7.6 Hz, 2 H), 7.51–7.48 (m,
2 H), 7.35–7.29 (m, 3 H), 7.28–7.16 (m, 3 H), 6.62 (dd, J = 8.2, 1.6 Hz,
1 H), 6.50–6.45 (m, 2 H), 5.45 (s, 1 H), 5.37 (dd, J = 11.0, 5.1 Hz, 1
H), 3.65 (s, 3 H), 3.47 (s, 3 H), 3.02 (dd, J = 12.6, 11.0 Hz, 1 H), 2.51
(dd, J = 12.6, 5.1 Hz, 1 H), 1.27–1.21 (m, 1 H), 0.75–0.66 (m, 2 H),
0.62–0.53 (m, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 195.0, 148.7,
1411, 1265, 1161, 1140, 1028, 912, 758, 731, 697 cm–1. HRMS (ESI):
calcd. for C31H26O4S [M + Na]+ 517.1444; found 517.1446.
[2-(3,4-Dimethoxyphenyl)-5-phenyl-3-(phenylethynyl)tetra-
hydrofuran-3-yl](thiophen-2-yl)methanone (4ma): Yellow oil. 1H
NMR (400 MHz, CDCl3): δ = 7.96 (dd, J = 3.9, 0.9 Hz, 1 H), 7.64 (d,
J = 7.3 Hz, 2 H), 7.53–7.48 (m, 2 H), 7.47–7.33 (m, 7 H), 6.91 (dd, J =
4.8, 4.1 Hz, 1 H), 6.84 (dd, J = 8.3, 1.8 Hz, 1 H), 6.69 (d, J = 1.8 Hz, 1
148.2, 140.8, 136.2, 132.3, 130.8, 130.0, 128.5, 127.7, 127.4, 126.3, H), 6.62 (d, J = 8.3 Hz, 1 H), 5.55 (s, 1 H), 5.45 (dd, J = 10.4, 5.9 Hz,
120.5, 111.3, 110.5, 91.1, 90.7, 80.0, 77.9, 58.6, 55.8, 55.5, 45.7, 8.2,
1 H), 3.76 (s, 3 H), 3.65 (s, 3 H), 3.30 (dd, J = 12.7, 10.5 Hz, 1 H), 2.73
8.1, –0.1 ppm. IR (KBr): ν = 2975, 2243, 1680, 1516, 1261, 1110, 1025, (dd, J = 12.8, 5.9 Hz, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
˜
800, 734 cm–1. HRMS (ESI): calcd. for C30H29O4 [M + H]+ 453.2060; 187.6, 148.9, 148.3, 143.1, 140.4, 134.5, 133.9, 131.6, 129.7, 128.8,
found 453.2064.
128.6, 128.0, 127.4, 126.6, 122.7, 120.3, 110.8, 110.5, 91.7, 91.6, 87.3,
80.5, 59.1, 55.9, 55.7, 45.5 ppm. IR (KBr): ν = 2928, 1655, 1597, 1516,
˜
(4-Chlorophenyl)[2-(3,4-dimethoxyphenyl)-5-phenyl-3-(phenyl-
1411, 1262, 1240, 1139, 1027, 780, 757, 730 cm–1. HRMS (ESI): calcd.
for C31H26O4S [M + Na]+ 517.1444; found 517.1448.
ethynyl)tetrahydrofuran-3-yl]methanone (3ka): Yellow oil; yield
1
(with 4ka): 91.2 mg (83 %). H NMR (400 MHz, CDCl3): δ = 7.94 (d,
J = 8.5 Hz, 2 H), 7.45–7.43 (m, 2 H), 7.39–7.17 (m, 11 H), 7.06 (d, J =
8.1 Hz, 1 H), 6.79 (d, J = 8.3 Hz, 1 H), 5.82 (s, 1 H), 5.71 (dd, J = 9.8,
5.9 Hz, 1 H), 3.85 (s, 3 H), 3.73 (s, 3 H), 3.10 (dd, J = 12.3, 5.9 Hz, 1
H), 2.83 (dd, J = 12.3, 9.8 Hz, 1 H) ppm. 13C NMR (101 MHz, CDCl3):
δ = 194.8, 149.0, 148.4, 142.0, 139.6, 134.1, 131.3, 130.7, 128.7, 128.7,
128.5, 128.3, 127.8, 125.7, 122.4, 120.4, 110.9, 110.3, 91.4, 87.7, 86.7,
1-[2-(3,4-Dimethoxyphenyl)-5-phenyl-3-(phenylethynyl)tetra-
hydrofuran-3-yl]pentan-1-one (3na): Yellow oil, inseparable from
the minor isomer 4na, 3na/4na = 1:0.4; yield (with 4na): 169.5 mg
(90 %). 1H NMR (400 MHz, CDCl3): δ = 7.57 (d, J = 7.8 Hz, 0.4 H),
7.45–7.39 (m, 1 H), 7.38–7.13 (m, 12.6 H), 7.06 (s, 1 H), 6.98–6.96 (m,
0.4 H), 6.91–6.81 (m, 1.4 H), 6.77–6.72 (m, 1.4 H), 5.53 (dd, J = 10.2,
6.0 Hz, 1 H), 5.48 (s, 1 H), 5.14 (s, 0.4 H), 5.09 (t, J = 8.2 Hz, 0.4 H),
3.79–3.77 (m, 5.4 H), 3.68 (s, 3 H), 2.94 (dd, J = 12.6, 9.7 Hz, 0.4 H),
2.78–2.70 (m, 1 H), 2.69–2.61 (m, 1.4 H), 2.58–2.42 (m, 2 H), 1.49–
1.41 (m, 2 H), 1.25–1.12 (m, 2.8 H), 0.94–0.88 (m, 0.8 H), 0.77 (t, J =
7.2 Hz, 3 H), 0.61 (t, J = 7.2 Hz, 1.2 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 207.2, 207.1, 149.2, 148.8, 148.7, 148.4, 142.2, 140.4,
131.5, 131.5, 130.5, 128.6, 128.5, 128.5, 128.5, 128.4, 128.0, 127.7,
126.9, 125.7, 122.8, 122.6, 119.4, 119.3, 110.7, 110.2, 110.0, 109.9,
90.9, 90.5, 89.4, 87.4, 87.2, 85.8, 80.7, 80.4, 62.5, 59.7, 55.9, 55.8, 55.7,
48.6, 45.5, 41.5, 41.3, 25.7, 25.6, 22.2, 21.9, 13.9, 13.8 ppm. IR (KBr):
80.2, 60.4, 56.0, 55.8, 49.4 ppm. IR (KBr): ν = 2932, 1680, 1588, 1515,
˜
1264, 1236, 1092, 1028, 804, 757, 696 cm–1. HRMS (ESI): calcd. for
C33H27ClO4 [M + H]+ 523.1671; found 523.1662.
[2-(3,4-Dimethoxyphenyl)-5-phenyl-3-(phenylethynyl)tetra-
hydrofuran-3-yl](4-methoxyphenyl)methanone (3la): Colorless
oil; yield (with 4la): 136.1 mg (82 %). 1H NMR (400 MHz, CDCl3): δ =
8.00 (d, J = 8.7 Hz, 2 H), 7.37–7.35 (m, 2 H), 7.25 (t, J = 7.5 Hz, 2 H),
7.18–7.10 (m, 7 H), 7.05 (d, J = 8.3 Hz, 1 H), 6.74–6.65 (m, 3 H), 5.81
(s, 1 H), 5.64 (dd, J = 10.0, 5.9 Hz, 1 H), 3.76 (s, 3 H), 3.69 (s, 3 H),
3.65 (s, 3 H), 3.05 (dd, J = 12.4, 5.9 Hz, 1 H), 2.72 (dd, J = 12.4,
10.0 Hz, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 193.7, 163.4,
148.7, 148.2, 142.1, 132.4, 131.2, 131.0, 128.5, 128.4, 128.3, 127.6,
125.7, 122.7, 120.4, 113.1, 110.9, 110.1, 90.8, 88.3, 86.3, 80.1, 59.9,
ν = 2957, 1713, 1595, 1516, 1267, 1236, 1162, 1140, 1060, 1029,
˜
758, 697 cm–1. HRMS (ESI): calcd. for C31H33O4 [M + H]+ 469.2373;
found 469.2373.
55.9, 55.7, 55.4, 49.5 ppm. IR (KBr): ν = 2934, 1670, 1598, 1513, 1258,
{4-[Cyclopropyl(phenyl)methylene]-6,7-dimethoxy-2-phenyl-
3,3a,4,8b-tetrahydro-2H-indeno[1,2-b]furan-3a-yl}(phenyl)-
methanone (6ja): Methanone 3ja (76.1 mg, 0.17 mmol) and iodo-
benzene (52.0 mg, 0.25 mmol) were added to DMF (2.0 mL), the
reaction flask was flushed with Ar (3 ×), and then Pd(OAc)2 (1.9 mg,
0.0085 mmol) and NaOAc (27.9 mg, 0.34 mmol) were added under
Ar. The mixture was heated at 140 °C for 7 h until TLC showed the
total consumption of 3ja. After cooling to room temperature, water
was added and the mixture was extracted with Et2O (3 ×). The com-
bined organic layers were washed with brine, dried with MgSO4,
and concentrated under reduced pressure. The residue was purified
by flash chromatography (petroleum ether/EtOAc, 10:1) to give 6ja
(53.9 mg, 60 %) as a colorless solid, m.p. 211–212 °C, 1H NMR
(400 MHz, CDCl3): δ = 7.63 (d, J = 7.7 Hz, 2 H), 7.37–7.22 (m, 5 H),
7.21–7.04 (m, 8 H), 7.00–6.95 (m, 1 H), 6.79 (s, 1 H), 6.34 (s, 1 H),
5.68 (s, 1 H), 5.19 (s, 1 H), 4.51 (dd, J = 10.8, 5.2 Hz, 1 H), 3.67 (s, 3
H), 3.49 (t, J = 11.8 Hz, 1 H), 3.11 (s, 3 H), 2.34 (dd, J = 12.4, 5.3 Hz,
˜
1172, 1028, 757, 696, 615 cm–1. HRMS (ESI): calcd. for C34H30O5 [M
+ Na]+ 541.1985; found 541.1986.
[2-(3,4-Dimethoxyphenyl)-5-phenyl-3-(phenylethynyl)tetra-
hydrofuran-3-yl](4-methoxyphenyl)methanone (4la): Yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.96 (d, J = 8.8 Hz, 2 H), 7.52 (d, J =
7.5 Hz, 2 H), 7.35–7.32 (m, 4 H), 7.28–7.22 (m, 3 H), 6.73–6.66 (m, 3
H), 6.57 (s, 1 H), 6.51 (d, J = 8.3 Hz, 1 H), 5.61 (s, 1 H), 5.47 (dd, J =
11.0, 5.0 Hz, 1 H), 3.74 (s, 3 H), 3.66 (s, 3 H), 3.51 (s, 3 H), 3.18 (dd,
J = 12.7, 11.0 Hz, 1 H), 2.64 (dd, J = 12.7, 5.1 Hz, 1 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 192.6, 163.1, 148.8, 148.2, 140.7, 132.5, 131.5,
130.7, 128.8, 128.5, 128.5, 127.8, 126.3, 122.8, 120.6, 112.8, 111.3,
110.5, 92.2, 90.7, 87.3, 80.1, 58.8, 55.8, 55.6, 55.5, 45.5 ppm. IR (KBr):
ν = 2932, 1674, 1599, 1515, 1264, 1236, 1092, 1028, 804, 757, 696,
˜
615 cm–1. HRMS (ESI): calcd. for C34H30O5 [M + Na]+ 541.1985; found
541.1980.
[2-(3,4-Dimethoxyphenyl)-5-phenyl-3-(phenylethynyl)tetra- 1 H), 1.37 (m, 1 H), 0.31 (m, 1 H), 0.11 (m, 1 H), 0.01 (m, 1 H), –0.55
hydrofuran-3-yl](thiophen-2-yl)methanone (3ma): Yellow oil;
(m, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 200.8, 149.6, 141.4,
yield (with 4ma): 169.1 mg (95 %). 1H NMR (400 MHz, CDCl3): δ = 140.4, 137.5, 136.3, 135.9, 134.5, 134.3, 132.7, 130.1, 129.3, 129.0,
7.84 (d, J = 3.6 Hz, 1 H), 7.42 (d, J = 4.8 Hz, 1 H), 7.36–7.30 (m, 2 H),
128.8, 128.7, 128.5, 128.0, 127.4, 126.8, 107.6, 106.1, 89.0, 79.3, 69.4,
7.25–7.05 (m, 9 H), 6.98 (d, J = 8.0 Hz, 1 H), 6.84 (t, J = 4.4 Hz, 1 H),
55.9, 55.0, 45.5, 15.1, 4.8, 4.3 ppm. IR (KBr): ν = 1677, 1500, 1444,
˜
Eur. J. Org. Chem. 2016, 2467–2478
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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1280, 1227, 695 cm–1. HRMS (ESI): calcd. for C36H32O4 [M + Na]+
551.2193; found 551.2196.
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[4-(Diphenylmethylene)-6,7-dimethoxy-2-phenyl-3,3a,4,8b-
tetrahydro-2H-indeno[1,2-b]furan-3a-yl](4-methoxyphen-
yl)methanone (6la): Methanone 3la (106 mg, 0.2 mmol) and iodo-
benzene (61.2 mg, 0.3 mmol) were added to DMF (2.5 mL), the
reaction flask was flushed with Ar (3 ×), and then Pd(OAc)2 (2.2 mg,
0.01 mmol) and NaOAc (32.8 mg, 0.4 mmol) were added under Ar.
The mixture was heated at 140 °C for 7 h until TLC showed total
consumption of 3la. After cooling to room temperature, water was
added and the mixture was extracted with Et2O (3 ×). The com-
bined organic layers were washed with brine, dried with MgSO4,
and concentrated under reduced pressure. The residue was purified
by flash chromatography (petroleum ether/EtOAc, 5:1) to give 6ja
1
(77.2 mg, 65 %) as a pale-yellow oil. H NMR (400 MHz, CDCl3): δ =
[2]
7.50 (d, J = 7.6 Hz, 2 H), 7.38–7.34 (m, 2 H), 7.32–7.14 (m, 8 H), 7.09–
7.01 (m, 2 H), 6.95–6.90 (m, 3 H), 6.73 (d, J = 7.6 Hz, 2 H), 6.59 (d,
J = 7.6 Hz, 2 H), 5.92 (s, 1 H), 5.90 (s, 1 H), 4.53 (t, J = 8.2 Hz, 1 H),
3.83 (s, 3 H), 3.78 (s, 3 H), 3.56 (dd, J = 12.8, 9.2 Hz, 1 H), 3.32 (s, 3
H), 2.50 (dd, J = 12.8, 7.2 Hz, 1 H) ppm. 13C NMR (101 MHz, CDCl3):
δ = 195.3, 162.9, 150.6, 149.5, 144.2, 142.8, 141.5, 140.9, 135.6, 134.6,
133.2, 131.0, 129.8, 129.4, 129.4, 128.7, 128.6, 128.5, 128.0, 127.6,
127.4, 127.2, 112.9, 107.6, 106.9, 90.3, 80.0, 70.3, 56.1, 55.5, 55.2,
47.0 ppm. IR (KBr): ν = 1678, 1598, 1228, 697 cm–1. HRMS (ESI):
˜
calcd. for C40H34O5 [M + Na]+ 617.2298; found 617.2300.
[6-(Benzyloxy)-4-(diphenylmethylene)-2-phenyl-3,3a,4,8b-
tetrahydro-2H-indeno[1,2-b]furan-3a-yl](phenyl)methanone
(6ac): Methanone 3ac (80.1 mg, 0.15 mmol) and iodobenzene
(61.2 mg, 0.3 mmol) were added to DMF (2.0 mL), the reaction flask
was flushed with Ar (3 ×), and then Pd(OAc)2 (3.4 mg, 0.015 mmol)
and NaOAc (24.6 mg, 0.3 mmol) were added under Ar. The mixture
was heated at 140 °C for 20 h. After cooling to room temperature,
water was added and the mixture was extracted with Et2O (3 ×).
The combined organic layers were washed with brine, dried with
MgSO4, and concentrated under reduced pressure. The residue was
purified by flash chromatography (petroleum ether/EtOAc, 20:1) to
give unreacted 3ac (43.0 mg) and 6ac (22.8 mg, 54 % brsm) as a
colorless solid, m.p. 191–192 °C. 1H NMR (400 MHz, CDCl3): δ =
7.51–7.46 (m, 2 H), 7.43–7.14 (m, 18 H), 7.05–6.98 (m, 2 H), 6.94–
6.88 (m, 3 H), 6.53 (s, 1 H), 6.51 (s, 1 H), 6.03 (s, 1 H), 5.98 (s, 1 H),
4.57–4.47 (m, 3 H), 3.56 (dd, J = 12.6, 9.7 Hz, 1 H), 2.53 (dd, J = 12.6,
7.5 Hz, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 196.6, 159.3, 143.9,
142.5, 142.1, 141.4, 141.0, 137.2, 136.8, 135.3, 132.5, 129.7, 129.5,
129.4, 128.8, 128.7, 128.6, 128.5, 128.2, 128.1, 128.0, 127.7, 127.6,
127.5, 127.2, 126.8, 118.7, 109.6, 89.9, 80.0, 70.9, 69.5, 47.2 ppm. IR
[3]
[4]
[5]
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For Lewis-acid-promoted [3+2] cycloadditions of donor–acceptor cyclo-
propanes to aldehydes to yield trans-2,5-disubstituted tetrahydrofurans,
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(KBr): ν = 1678, 1597, 1257, 1228, 733, 697 cm–1. HRMS (ESI): calcd.
˜
for C44H34O3 [M + Na]+ 633.2400; found 633.2402.
Acknowledgments
The authors thank the National Natural Science Foundation of
China (NSFC) (grant numbers 21372126 and 21421062) for fi-
nancial support.
[6]
CCDC 1037685 (for 3ja), 1037686 (for 4ha), and 1443305 (for 6ja) contain
the supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic Data
Centre.
[7]
[8]
Several other Lewis acids, for example, SnCl4 and BF3·Et2O, did not effect-
ively catalyze this reaction in toluene. AlCl3 did catalyze the reaction
smoothly, but the result was similar to that in 1,2-dichloroethane.
a) W. Yang, L. Xu, Z. Chen, L. Zhang, M. Miao, H. Ren, Org. Lett. 2013, 15,
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2007, 46, 1726; Angew. Chem. 2007, 119, 1756; f) V. K. Yadav, R. Balamur-
Keywords: Domino reactions · Cycloaddition · C–H
activation · Oxygen heterocycles · Small-ring systems ·
Diastereoselectivity
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Eur. J. Org. Chem. 2016, 2467–2478
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
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Received: March 1, 2016
Published Online: April 24, 2016
Eur. J. Org. Chem. 2016, 2467–2478
www.eurjoc.org
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim