KOAc-promoted alkynylation of α-C-H bonds of ethers with alkynyl bromides under transition-metal-free conditions

Article abstract of DOI:10.1039/c4ob00002a

A novel KOAc-promoted α-position C-H activation and alkynylation of ethers with alkynyl bromides to 2-alkynyl ethers has been developed under transition-metal-free and simple reaction conditions. In addition, this methodology can also be extended to the vinylation of ethers with vinyl bromides in excellent regio- and stereo-selectivity. A wide range of direct C(sp)-C(sp³) and C(sp²)-C(sp³) bonds has been formed through this protocol, which offers a new and alternative route. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00002a

Organic &
Biomolecular Chemistry
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KOAc-promoted alkynylation of α-C–H bonds
of ethers with alkynyl bromides under
transition-metal-free conditions†
Cite this: Org. Biomol. Chem., 2014,
12, 2969
Jiajun Zhang,a Pinhua Li*a and Lei Wang*a,b
A novel KOAc-promoted α-position C–H activation and alkynylation of ethers with alkynyl bromides to
2-alkynyl ethers has been developed under transition-metal-free and simple reaction conditions. In
addition, this methodology can also be extended to the vinylation of ethers with vinyl bromides in excel-
lent regio- and stereo-selectivity. A wide range of direct C(sp)–C(sp3) and C(sp2)–C(sp3) bonds has been
formed through this protocol, which offers a new and alternative route.
Received 1st January 2014,
Accepted 5th March 2014
DOI: 10.1039/c4ob00002a
www.rsc.org/obc
KOtBu,2b,c,4b,k,r–v and NaOtBu2d in the presence of an effective
Introduction
ligand except one example.4k
The transition-metal catalyzed direct conversion of C–H bonds
Substituted tetrahydrofurans are not only valuable building
into C–C bonds has been one of the most attractive subjects in blocks in organic synthesis, but also are ubiquitous motifs
contemporary organic chemistry. In the past few decades, sig- present in biological, pharmaceutical and natural products.5
nificant efforts have been made on C–H activation and In general, they are usually accessible through the α-C(sp3)–H
functionalization, and various high efficiency and versatile pro- activation/functionalization of tetrahydrofuran (THF),6 such as
tocols have been explored.1 Despite remarkable advances Ni-catalyzed arylation of THF,7 Fe(II)-catalyzed CDC reaction of
achieved in this field, critical issues such as stoichiometric THF with malonates,8 Cu- and Ir-catalyzed carbenoid insertion
amounts of metal waste and the presence of metal impurities of ethyl diazoacetate into α-C–H of THF,9 Cr-promoted reaction
in the final product may restrict their practical applicability. of alcohols with THF to 2-tetrahydrofuranyl ethers,10 AIBN-
Hence, the green and economical platform for mediating mediated alkenylation of THF with vinyl triflones,11 TBHP-pro-
organic transformations is demanded. Recently, Itami, Kwong/ moted reaction of phenylacetylene with THF to allylic ether,12
Lei, Shi, and Shirakawa/Hayashi have reported the astonishing and BEt3- and Me2Zn-mediated addition of THF with alde-
results on the construction of C–C bonds from unactivated aro- hydes and aldimines under air, respectively.13 2-Alkynyl cyclic
matic rings by direct C–H activation without the aid of tran- ethers, potential structural motifs of bioactive molecules and
sition metals,2 and these breakthroughs might bring in a new materials, have been successfully prepared by region-specific
era of organic synthesis.3 From the viewpoint of green chem- α-position alkynylation of cyclic ethers.14–16 In 1988, Ley
istry, the organic reactions carried out under transition-metal- converted 2-benzenesulphonyl cyclic ethers to 2-alkynyl tetra-
free conditions, avoiding metal contamination in the final pro- hydrofuran by treatment with the corresponding organozinc
ducts, have been paid much attention in modern organic syn- agents (Scheme 1).14 In 1996, Fuchs developed a synthetic
thesis, especially in the pharmaceutical industry. In the past strategy to produce 2-alkynyl cyclic ethers through the alkyny-
two years, a variety of protocols for the direct C–H bond acti- lation of α-position C–H bonds in cyclic ethers with acetylenic
vation and functionalization in the absence of transition triflones under peroxide or AIBN or UV-irradiation.15 Most
metals have been established.4 The representative systems are recently, Anderson reported an efficient Pd-catalyzed synthesis
of 2-alkynyl oxacycles from their cyclic and acyclic
carbonates.16
aDepartment of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000,
Encouraged by the above transformations, and in continu-
P R China. E-mail: leiwang@chnu.edu.cn; Fax: +86-561-309-0518;
ation of our and others interest in transformation of C(sp3)–
Tel: +86-561-380-2069
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
H bonds into C(sp3)–C bonds,17 we conceived that alkynylation
of α-position C–H bonds of ethers with alkynyl bromides
without the assistance of a transition metal may be possible.
Herein, we wish to report an efficient reaction of alkynyl bro-
mides with cyclic ethers for direct C(sp)–C(sp3) bond for-
Chemistry, Chinese Academy of Sciences, Shanghai 200032, P R China
†Electronic supplementary information (ESI) available: Detailed procedures,
analytical data, and 1H, 13C NMR and HRMS spectra of all intermediates and
products or other electronic format. CCDC 955471. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c4ob00002a
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Table 1 Effect of a base and a catalyst on the reactiona
Entry
Base
Catalyst
Yieldb (%)
1
2
3
4
Na2CO3
Na2CO3
Na2CO3
Na2CO3
KOAc
—
59
Pd(OAc)2
CuI
AgBF4
—
NR
NR
NR
93
5
6
7
8
9
NaOAc
NaHCO3
(NH4)2CO3
K2CO3
KHCO3
Cs2CO3
K3PO4
NaF
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
74
52
47
43
42
32
21
18
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Scheme 1 Preparation of 2-alkynyl tetrahydrofurans.
KF
13
LiOtBu
NaOtBu
KOtBu
KOH
NR
NR
NR
NR
NR
NR
NR
NR
32
mation through KOAc-promoted α-position C–H activation and
alkynylation of ethers under transition-metal-free and simple
reaction conditions (Scheme 1). Moreover, this methodology
can also be extended to the vinylation of α-C–H bonds of
ethers with vinyl bromides with excellent regio- and stereo-
selectivity.
NaOH
Et3N
DBU
DABCO
—
—
—
a Reaction conditions: 1a (0.30 mmol), 2a (2.0 mL, excess, as well as
solvent), catalyst (5.0 mol%) if needed, base (0.60 mmol), at 150 °C for
12 h. b Isolated yield.
Results and discussion
In the initial investigation of the reaction of alkynyl bromides
to ethers, phenylethynyl bromide (1a) and tetrahydrofuran
(THF, 2a) were chosen as model substrates. When the model
reaction was carried out in the presence of Na2CO3 at 150 °C
in a sealed pressure tube for 12 h without an additional
solvent, a direct alkynylation product (3a) of THF via α-posi-
tion C–H bond activation was isolated in 59% yield (Table 1,
entry 1).
Encouraged by this positive result, further investigation on
the addition of a transition metal to the reaction was exam-
ined. Unfortunately, transition metals, such as Pd(OAc)2, CuI,
and AgBF4, completely shut down the reaction (Table 1, entries
2–4). To improve the desired product yield, detailed investi-
gation on the effect of a base on the reaction was examined. To
our delight, KOAc exhibited the highest reactivity to the reac-
tion among the tested bases, providing 93% yield of 3a
(Table 1, entry 5). Other bases, such as NaOAc, NaHCO3,
(NH4)2CO3, K2CO3, KHCO3, Cs2CO3, K3PO4, NaF, and KF, were
inferior and generated 3a in 13–74% yields (Table 1, entries
6–14). However, when the reaction was performed in the pres-
ence of LiOtBu, NaOtBu, KOtBu, KOH, NaOH, Et3N, DBU, or
DABCO as a base, no 3a was detected and starting materials
were unchanged and recovered (Table 1, entries 15–22).
However, only 32% yield of 3a was generated in the absence of
any base, catalyst and additive (Table 1, entry 23).
bipyridine (Bipy), 8-hydroxyquinoline (8-HQ), and 1,1′-bis-
(diphenylphosphino)ferrocene (Dppf) were added to the
KOtBu, NaOtBu or LiOtBu system which promoted the reaction,
but failed (Table S1, ESI,† entries 1–18).
With respect to the base loading, 2 equiv. of KOAc was
found to be optimal. When the model reaction was carried out
in the presence of KOAc, a significant reaction temperature
effect was observed. When the reaction was performed at less
than 100 °C, poor yields of 3a were obtained. The optimal
temperature was found to be 150 °C (Table 2, entries 1–7).
Table 2 Effect of temperature on the model reactiona
Entry
Temp. (°C)
Yieldb (%)
1
2
3
4
5
6
7
80
100
120
140
150
160
170
22
40
64
80
93
93
90
To further examine the effect of ligand for the improvement
of model reaction, L-proline, N,N,N′,N′-tetramethylethylenedi-
a Reaction conditions: 1a (0.30 mmol), 2a (2.0 mL, excess), KOAc
(0.60 mmol) at the temperature indicated in this table for 12 h.
amine (TMEDA), 1,10-phenanthroline (1,10-Phen) and 2,2′- b Isolated yield.
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Table 3 Effect of solvent on the model reactiona
Entry
Solvent/temp. (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
9
DMF/150
DMA/150
NMP/150
DMSO/150
CH3CN/100
HOAc/100
CH3CH2OH/100
CH3NO2/100
DCE/100
NR
7
NR
NR
5
NR
NR
NR
13
10
Toluene/150
Trace
a Reaction conditions: 1a (0.30 mmol), 2a (2.0 mL, excess), KOAc
(0.60 mmol), solvent (2.0 mL) at the temperature indicated in this
table for 12 h. b Isolated yield.
The final investigation revealed that an additional solvent,
such as DMF, DMA, NMP, DMSO, CH3CN, HOAc, CH3CH2OH,
CH3NO2, DCE (1,2-dichloroethane) or toluene has a great nega-
tive effect on the reaction (Table 3, entries 1–10). The opti-
mized reaction conditions for the model reaction were in the
presence of KOAc at 150 °C for 12 h.
Scheme 2 KOAc-promoted direct alkynylation of tetrahydrofuran
under transition-metal free conditions. Reaction conditions:
1
(0.30 mmol), 2a (2.0 mL, excess, as well as solvent), KOAc
a
With the optimized reaction conditions in our hand, a
variety of substituted phenylethynyl bromides were selected to
couple with tetrahydrofuran for the synthesis of 2-alkynyl-tetra-
hydrofurans (Scheme 2). Pleasingly, phenylethynyl bromides
with electron-donating groups, such as MeO, Me, n-Pr and
t-Bu, at the para-, meta-, or ortho-positions of phenyl rings
underwent the reaction smoothly with THF (2a), generating
the corresponding products 3b–g in good yields (75–86%).
Meanwhile, phenylethynyl bromides with electron-withdraw-
ing groups, such as CH3CO and F3C, also proceeded well with
THF to afford the desired products 3k and 3l in 74% and 76%
yields, respectively. Moreover, substrates with halogen substi-
tuents such as F, Cl, and Br could be well transformed into the
target products 3h–j in good yields. In addition, metal- and
ortho-substituents could also be well tolerated in this reaction
(3m and 3n).
(0.60 mmol), at 150 °C for 12 h; isolated product yields after
chromatography.
Considering the importance of direct functionalization of
different ethers, other simple ethers were also tested to couple
with phenylethynyl bromide derivatives under optimized con-
ditions (Scheme 3). 2-Methyl tetrahydrofuran was first tested
to couple with different phenylethynyl bromides. We were sur-
prised to find that reaction selectively occurred at the methyne
group, affording the corresponding products in good yields
and excellent regio-selectivity (3o–q). Tetrahydropyran and 1,4-
dioxane were also found to react smoothly with phenylethynyl
bromide or (4-tert-butylphenyl)ethynyl bromide to generate the
alkynylation products 3r–t in moderate yields. Moreover, when
benzene fused tetrahydrofurans, such as 2,3-dihydrobenzo-
furan and 1,3-dihydroisobenzofuran, were employed, the
anticipated products, 3u and 3v, were obtained in 55% and
46% yields, respectively. Notably, this methodology could also
Scheme 3 KOAc-promoted direct alkynylation of other simple ethers
under transition-metal free conditions. Reaction conditions:
1
(0.30 mmol), 2 (2.0 mL, excess, as well as solvent), KOAc (0.60 mmol), at
150 °C for 12 h; isolated product yields after chromatography.
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be extended to chain-like ethers. 1,2-Dimethoxyethane reacted
smoothly with 1a to afford the corresponding product 3w in
moderate yield, along with excellent regio-selectivity. In
addition, the substrate scope of alkyne bromide was extended
to aliphatic alkyne bromides, such as 1-(bromoethynyl)cyclo-
hexanol and 1-bromohept-1-yne, and satisfactory results were
achieved (Scheme 3, 3x and 3y).
Additionally, the regio-selectivity of direct alkynylation of
1,3-dioxolane with phenylethynyl bromide was investigated
under the present reaction conditions. The results showed that
82% total yield of 3x and 3x′ was isolated with a ratio of 65 : 17
(Scheme 4), which indicated that the stability of free radicals
plays an important role in this reaction.
Later on, the vinylation of α-C–H bonds of ethers with vinyl
bromides in the presence of KOAc was also examined, and the
results are shown in Scheme 4. When a mixture of cis- and
trans-(2-bromovinyl)benzene (1 : 5) reacted with tetrahydro-
furan and 2-methyltetrahydrofuran to generate the corres-
ponding products 5a and 5b in moderate yields respectively
with excellent regio- and stereo-selectivity. The prepared (Z)-2-
bromovinyl phenyl ethers,18a 4b and 4c, reacted with THF
under the optimized reaction conditions, providing the corres-
ponding exclusive (Z)-type products 5c and 5d (Scheme 5) in
moderate yields. It also provides an effective and alternative
Scheme 6 Proposed reaction mechanism.
route to vinyl cycloethers with excellent regio- and stereo-selec-
tivity.12,15b,19 Moreover, the representative structure of 5d was
confirmed by X-ray single crystal analysis.20
To investigate the reaction mechanism, the related experi-
ments were performed. When a radical scavenger, 2,2,6,6-tetra-
methylpiperidyl-1-oxyl (TEMPO, 1.5 equiv.), was added to the
standard reaction system, the reaction was completely shut
down, along with formation of a radical-trapping product,
detected by GC/MS (see the ESI† for details), suggesting that a
carbon-centered radical of THF is probably involved in this
reaction. In addition, when reaction was carried out under
strictly anhydrous and anaerobic conditions, no product was
detected and only starting materials were recovered, and the
added peroxide (such as H2O2) could improve the reaction sig-
nificantly. Based on the experimental results, a proposed
mechanism of KOAc-promoted direct C–H alkynylation of
simple ethers is depicted in Scheme 6. Firstly, a tetrahydro-
furan radical (I) was generated in the presence of small
amounts of peroxide in THF (2a). Subsequently, a radical
addition of the obtained (I) to phenylethynyl bromide (1a)
occurred smoothly to afford a bromovinyl radical (II), which
generated a bromine free radical and the final product (3a)
through a bromine radical elimination process. Finally, the
bromine radical abstracted a hydrogen radical from THF (2a)
to generate intermediate (I) with the aid of a suitable base
(KOAc).
Scheme 4 Regio-selectivity investigation of direct alkynylation of 1,3-
dioxolane with phenylethynyl bromide.
Conclusion
In conclusion, we have established a novel Csp–Csp3 bond for-
mation through KOAc-promoted direct C–H alkynylation of
simple ethers under transition-metal free and simple reaction
conditions.21 Different substituted phenylethynyl bromides
and common simple ethers could be cross-coupled smoothly
to afford the corresponding products in good to excellent
Scheme 5 Direct vinylation of α-C–H bonds of ethers with vinyl
bromides.
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yields. In addition, this methodology can also be extended to 89.11, 84.46, 68.60, 67.92, 33.42, 25.50. HRMS (EI) ([M]+) Calcd
the direct C–H vinylation of ethers with excellent regio- and For C12H12O: 172.0888, found: 172.0883.
stereo-selectivity. A wide range of direct Csp–Csp3 and Csp2–
Csp3 bonds could be constructed through this protocol,
offering a brand new and alternative route for the synthesis of
2-alkynyl- and 2-alkenyl ethers.22 Further detailed investigation
of the reaction mechanism and application of this kind of
strategy is underway in our laboratory.
2-((4-Methoxyphenyl)ethynyl)tetrahydrofuran (3b). Colorless
1
oil. H NMR (400 MHz, CDCl3) δ: 7.37 (d, J = 8.4 Hz, 2H), 6.83
(d, J = 8.8 Hz, 2H), 4.82–4.79 (m, 1H), 4.04–3.99 (m, 1H),
3.88–3.85 (m, 1H), 3.80 (s, 3H), 2.25–2.19 (m, 1H), 2.13–2.03
(m, 2H), 1.99–1.92 (m, 1H); 13C NMR (100 MHz, CDCl3) δ:
159.55, 133.16, 114.90, 113.82, 87.59, 84.37, 68.69, 67.88,
55.25, 33.45, 25.51. HRMS (EI) ([M]+) Calcd For C13H14O2:
202.0994, found: 202.0990.
Experimental section
All the bromoalkynes18b and bromo alkenes,18a such as (Z)-2-
bromovinyl phenyl ethers, 4b and 4c, as starting materials
were prepared according to the reported procedure in the lit-
erature.18a,b All the chemicals and solvents were purchased
from commercial suppliers and used without further purifi-
2-(p-Tolylethynyl)tetrahydrofuran (3c). Colorless oil. 1H
NMR (400 MHz, CDCl3) δ: 7.33 (d, J = 8.0 Hz, 2H), 7.11 (d, J =
7.6 Hz, 2H), 4.83–4.80 (m, 1H), 4.05–3.99 (m, 1H), 3.89–3.84
(m, 1H), 2.34 (s, 3H), 2.26–2.20 (m, 1H), 2.13–2.04 (m, 2H),
1.99–1.92 (m, 1H); 13C NMR (100 MHz, CDCl3) δ: 138.33,
131.61, 128.97, 119.71, 88.31, 84.59, 68.66, 67.91, 33.44, 25.51,
21.46. HRMS (ESI) ([M + H]+) Calcd For C13H15O: 187.1123,
found: 187.1123.
1
cation. All reactions were carried out under air. H NMR and
13C NMR spectra were measured on a Bruker Avance NMR
spectrometer (400 MHz or 100 MHz, respectively) in CDCl3 as
a solvent and recorded in ppm relative to the internal tetra-
methylsilane standard. 1H NMR data are reported as follows: δ,
chemical shift; coupling constants (J values are given in hertz,
Hz) and integration. Abbreviations to denote the multiplicity
of a particular signal were s (singlet), d (doublet), t (triplet),
q (quartet), m (multiplet), and br (broad singlet). High resolu-
tion mass spectroscopy data of the products were collected on
a Waters Micromass GCT instrument using EI (70 eV) or an
Agilent Technologies 6540 UHD Accurate-Mass Q-TOF LC/MS
using ESI.
2-((4-n-Propylphenyl)ethynyl)tetrahydrofuran (3d). Colorless
1
oil. H NMR (400 MHz, CDCl3) δ: 7.35 (d, J = 8.0 Hz, 2H), 7.11
(d, J = 8.0 Hz, 2H), 4.83–4.80 (m, 1H), 4.05–3.99 (m, 1H),
3.89–3.84 (m, 1H), 2.58 (t, J = 7.6 Hz, 2H), 2.26–2.19 (m, 1H),
2.12–2.06 (m, 2H), 1.99–1.92 (m, 1H), 1.67–1.60 (m, 2H), 0.94
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 143.08,
131.59, 128.36, 119.98, 88.35, 84.62, 68.66, 67.87, 37.90, 33.45,
25.48, 24.29, 13.71. HRMS (ESI) ([M + H]+) Calcd For C15H19O:
215.1436, found: 215.1441.
A typical procedure for KOAc-promoted alkynylation of α-C–H
bonds of ethers with alkynyl bromides
Under an air atmosphere, a 10 mL oven-dried sealable reaction
vessel equipped with a magnetic stir bar charged with phenyl-
ethynyl bromide (1a, 54.3 mg, 0.30 mmol), KOAc (59 mg,
0.60 mmol) and tetrahydrofuran (THF, 2a, 2.0 mL, excess, as
well as solvent) was added to the sealed vessel in one portion.
The rubber septum was then replaced by a Teflon-coated screw
cap, and the reaction vessel was placed in an oil bath at 150 °C
for 12 h. After the reaction was completed, it was cooled to
room temperature and diluted with ethyl acetate. The resulting
solution was directly filtered through a pad of silica gel using a
sintered glass funnel, and concentrated under reduced
pressure. The residue was purified by flash chromatography on
silica gel (eluant: petroleum ether–ethyl acetate = 10 : 1 to
25 : 1, v/v) to obtain the desired pure product, 2-(phenyl-
ethynyl)tetrahydrofuran (3a).
2-((4-(tert-Butyl)phenyl)ethynyl)tetrahydrofuran (3e). Color-
1
less oil. H NMR (400 MHz, CDCl3) δ: 7.38 (d, J = 8.4 Hz, 2H),
7.32 (d, J = 8.4 Hz, 2H), 4.83–4.80 (m, 1H), 4.05–4.00 (m, 1H),
3.89–3.84 (m, 1H), 2.26–2.19 (m, 1H), 2.13–2.04 (m, 2H),
1.99–1.92 (m, 1H), 1.31 (s, 9H); 13C NMR (100 MHz, CDCl3) δ:
151.44, 131.42, 125.20, 119.80, 88.36, 84.56, 68.67, 67.87,
34.72, 33.47, 31.17, 25.48. HRMS (ESI) ([M + H]+) calcd for
C16H21O: 229.1592, found: 229.1588.
2-(Phenylethynyl)tetrahydrofuran (3a).16 Colorless oil. 1H
2-(m-Tolylethynyl)tetrahydrofuran (3f). Colorless oil. 1H
NMR (400 MHz, CDCl3) δ: 7.45–7.43 (m, 2H), 7.30–7.29 (m, NMR (400 MHz, CDCl3) δ: 7.27–7.24 (m, 2H), 7.21–7.17 (m,
3H), 4.83–4.80 (m, 1H), 4.05–3.99 (m, 1H), 3.89–3.83 (m, 1H), 1H), 7.13–7.11 (m, 1H), 4.84–4.81 (m, 1H), 4.05–4.00 (m, 1H),
2.26–2.19 (m, 1H), 2.13–2.04 (m, 2H), 1.98–1.92 (m, 1H); 13C 3.90–3.84 (m, 1H), 2.32 (s, 3H), 2.26–2.20 (m, 1H), 2.14–2.04
NMR (100 MHz, CDCl3) δ: 131.70, 128.24, 128.21, 122.83, (m, 2H), 2.01–1.93 (m, 1H); 13C NMR (100 MHz, CDCl3) δ:
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137.86, 132.31, 129.12, 128.76, 128.10, 122.61, 88.71, 84.61, 197.25, 136.29, 131.80, 128.12, 127.70, 92.55, 83.68, 68.48,
68.62, 67.90, 33.44, 25.48, 21.18. HRMS (ESI) ([M + H]+) calcd 68.06, 33.30, 26.55, 25.51. HRMS (ESI) ([M + H]+) calcd for
for C13H15O: 187.1123, found: 187.1123.
C14H15O2: 215.1072, found: 215.1071.
2-((4-(Trifluoromethyl)phenyl)ethynyl)tetrahydrofuran (3l).
Colorless oil. H NMR (400 MHz, CDCl3) δ: 7.57–7.55 (m, 2H),
2-(o-Tolylethynyl)tetrahydrofuran (3g). Colorless oil. 1H
NMR (400 MHz, CDCl3) δ: 7.41 (d, J = 7.6 Hz, 1H), 7.22–7.18
(m, 2H), 7.15–7.11 (m, 1H), 4.89–4.86 (m, 1H), 4.06–4.01 (m,
1H), 3.92–3.86 (m, 1H), 2.43 (s, 3H), 2.28–2.22 (m, 1H),
2.16–2.07 (m, 2H), 2.02–1.93 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ: 140.21, 132.00, 129.34, 128.27, 125.45, 122.56, 93.07,
83.34, 68.72, 67.83, 33.59, 25.41, 20.65. HRMS (EI) ([M]+) calcd
For C13H14O: 186.1045, found: 186.1044.
1
7.54–7.52 (m, 2H), 4.84–4.81 (m, 1H), 4.05–3.99 (m, 1H),
3.90–3.85 (m, 1H), 2.29–2.22 (m, 1H), 2.14–2.05 (m, 2H),
2.01–1.95 (m, 1H); 13C NMR (100 MHz, CDCl3) δ: 131.92,
129.99 (q, JCF = 32.4 Hz), 126.64, 125.14 (q, JCF = 3.8 Hz),
123.88 (q, JCF = 270.4 Hz), 91.66, 83.12, 68.42, 68.07, 33.29,
25.50. HRMS (EI) ([M]+) calcd for C13H11F3O: 240.0762, found:
240.0763.
2-((4-Fluorophenyl)ethynyl)tetrahydrofuran (3h). Colorless
1
oil. H NMR (400 MHz, CDCl3) δ: 7.42–7.39 (m, 2H), 7.00–6.96
2-((3-Fluorophenyl)ethynyl)tetrahydrofuran (3m). Colorless
oil. H NMR (400 MHz, CDCl3) δ: 7.29–7.25 (m, 1H), 7.24–7.20
(m, 1H), 7.13 (d, J = 9.6 Hz, 1H), 7.04–7.00 (m, 1H), 4.83–4.80
(m, 1H), 4.04–3.99 (m, 1H), 3.90–3.85 (m, 1H), 2.27–2.21 (m,
1H), 2.14–2.06 (m, 2H), 2.00–1.94 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ: 162.28 (d, JCF = 244.8 Hz), 129.77 (d, JCF = 8.6 Hz),
1
(m, 2H), 4.80–4.77 (m, 1H), 4.03–3.97 (m, 1H), 3.88–3.82 (m,
1H), 2.25–2.18 (m, 1H), 2.10–2.05 (m, 2H), 1.98–1.91 (m, 1H);
13C NMR (100 MHz, CDCl3) δ: 162.46 (d, JCF = 247.8 Hz),
133.58 (d, JCF = 8.3 Hz), 118.90 (d, JCF = 3.5 Hz), 115.45 (d, JCF
21.9 Hz), 88.78, 83.39, 68.51, 67.93, 33.36, 25.49. HRMS (EI)
([M]+) calcd For C12H11FO: 190.0794, found: 190.0789.
=
127.58 (d, JCF = 3.1 Hz), 124.66 (d, JCF = 9.5 Hz), 118.50 (d, JCF
=
22.7 Hz), 115.60 (d, JCF = 21.0 Hz), 90.09, 83.23 (d, JCF = 3.4
Hz), 68.46, 68.01, 33.33, 25.49. HRMS (EI) ([M]+) calcd for
C12H11FO: 190.0794, found: 190.0793.
2-((4-Chlorophenyl)ethynyl)tetrahydrofuran (3i). Colorless
oil. H NMR (400 MHz, CDCl3) δ: 7.36 (d, J = 8.4 Hz, 2H), 7.27
1
(d, J = 8.4 Hz, 2H), 4.81–4.78 (m, 1H), 4.03–3.98 (m, 1H),
3.89–3.83 (m, 1H), 2.26–2.20 (m, 1H), 2.12–2.03 (m, 2H),
2.00–1.91 (m, 1H); 13C NMR (100 MHz, CDCl3) δ: 134.28,
132.93, 128.54, 121.32, 90.10, 83.35, 68.51, 67.99, 33.34, 25.50.
HRMS (EI) ([M]+) calcd For C12H11ClO: 206.0498, found:
206.0501.
2-((2-Fluorophenyl)ethynyl)tetrahydrofuran (3n). Colorless
oil. H NMR (400 MHz, CDCl3) δ: 7.45–7.41 (m, 1H), 7.31–7.26
1
(m, 1H), 7.10–7.03 (m, 2H), 4.87–4.84 (m, 1H), 4.05–4.00 (m,
1H), 3.90–3.85 (m, 1H), 2.28–2.22 (m, 1H), 2.16–2.08 (m, 2H),
2.00–1.94 (m, 1H); 13C NMR (100 MHz, CDCl3) δ: 162.77 (d, JCF
= 250.1 Hz), 133.62 (d, JCF = 1.3 Hz), 129.97 (d, JCF = 7.9 Hz),
123.81 (d, JCF = 3.7 Hz), 115.41 (d, JCF = 20.8 Hz), 111.38 (d, JCF
= 15.6 Hz), 94.41 (d, JCF = 3.4 Hz), 77.82 (d, JCF = 0.9 Hz), 68.58,
67.97, 33.36, 25.42. HRMS (EI) ([M]+) calcd for C12H11FO:
190.0794, found: 190.0798.
2-((4-Bromophenyl)ethynyl)tetrahydrofuran (3j). Colorless
1
oil. H NMR (400 MHz, CDCl3) δ: 7.43 (d, J = 8.4 Hz, 2H), 7.29
(d, J = 8.4 Hz, 2H), 4.81–4.78 (m, 1H), 4.04–3.98 (m, 1H),
3.89–3.84 (m, 1H), 2.27–2.20 (m, 1H), 2.13–2.05 (m, 2H),
2.00–1.93 (m, 1H); 13C NMR (100 MHz, CDCl3) δ: 133.15,
131.48, 122.49, 121.79, 90.30, 83.41, 68.52, 68.00, 33.32, 25.50.
HRMS (ESI) ([M + H]+) calcd For C12H12BrO: 251.0072, found:
251.0072.
2-Methyl-2-(phenylethynyl)tetrahydrofuran (3o). Colorless
1
oil. H NMR (400 MHz, CDCl3) δ: 7.44–7.42 (m, 2H), 7.30–7.29
(m, 3H), 4.06–3.95 (m, 2H), 2.34–2.28 (m, 1H), 2.20–2.12 (m,
1H), 2.03–1.98 (m, 1H), 1.90–1.83 (m, 1H), 1.65 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ: 131.68, 128.18, 128.07, 123.01,
92.36, 82.73, 76.40, 67.65, 40.18, 27.72, 25.72. HRMS (ESI)
([M + H]+) calcd for C13H15O: 187.1123, found: 187.1124.
2-((4-Acetyphenyl)ethynyl)tetrahydrofuran
(3k). Colorless
1
oil. H NMR (400 MHz, CDCl3) δ: 7.88 (d, J = 8.4 Hz, 2H), 7.49
(d, J = 8.0 Hz, 2H), 4.83–4.80 (m, 1H), 4.03–3.98 (m, 1H),
3.89–3.83 (m, 1H), 2.58 (s, 3H), 2.28–2.20 (m, 1H), 2.13–2.04
(m, 2H), 1.99–1.91 (m, 1H); 13C NMR (100 MHz, CDCl3) δ:
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2-Methyl-2-(p-tolylethynyl)tetrahydrofuran
(3p). Colorless 131.74, 129.04, 128.07, 127.79, 126.85, 124.63, 121.08, 109.99,
1
oil. H NMR (400 MHz, CDCl3) δ: 7.32 (d, J = 7.6 Hz, 2H), 7.10 91.35, 82.05, 76.22, 34.48, 26.47. HRMS (EI) ([M]+) calcd for
(d, J = 7.6 Hz, 2H), 4.06–3.94 (m, 2H), 2.34 (s, 3H), 2.31–2.27 C18H14O2: 262.0994, found: 262.0999.
(m, 1H), 2.22–2.11 (m, 1H), 2.05–1.95 (m, 1H), 1.90–1.83 (m,
1H), 1.64 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 137.99, 131.46,
128.82, 119.82, 91.48, 82.72, 76.32, 67.50, 40.08, 27.65, 25.61,
21.32. HRMS (EI) ([M]+) calcd for C14H16O: 200.1201, found:
200.1199.
1-(4-((1,3-Dihydroisobenzofuran-1-yl)ethynyl)phenyl)etha-
none (3v). Colorless oil. 1H NMR (400 MHz, CDCl3) δ: 7.89 (d,
J = 8.0 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 7.45–7.43 (m, 1H),
7.37–7.35 (m, 2H), 7.29–7.27 (m, 1H), 6.14 (s, 1H), 5.31–5.28
(m, 1H), 5.16–5.13 (m, 1H), 2.59 (s, 3H); 13C NMR (100 MHz,
2-((4-Chlorophenyl)ethynyl)-2-methyltetrahydrofuran (3q).
1
Colorless oil. H NMR (400 MHz, CDCl3) δ: 7.34 (d, J = 8.0 Hz,
2H), 7.26 (d, J = 8.0 Hz, 2H), 4.03–3.94 (m, 2H), 2.31–2.26 (m,
1H), 2.18–2.09 (m, 1H), 2.03–1.97 (m, 1H), 1.90–1.83 (m, 1H),
1.63 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 133.96, 132.80,
128.39, 121.39, 93.28, 81.51, 76.23, 67.61, 39.99, 27.56, 25.62.
HRMS (EI) ([M]+) calcd For C13H13ClO: 220.0655, found:
220.0654.
CDCl3) δ: 197.16, 138.74, 138.60, 136.39, 131.85, 128.24,
128.02, 127.78, 127.22, 121.75, 121.06, 90.39, 85.10, 73.69,
72.91, 26.48. HRMS (EI) ([M]+) calcd For C18H14O2: 262.0994,
found: 262.0993.
(3,4-Dimethoxybut-1-yn-1-yl)benzene (3w). Colorless oil. 1H
NMR (400 MHz, CDCl3) δ: 7.47–7.45 (m, 2H), 7.33–7.32 (m,
3H), 4.45–4.41 (m, 1H), 3.69–3.66 (m, 2H), 3.54 (s, 3H), 3.47 (s,
3H); 13C NMR (100 MHz, CDCl3) δ: 131.82, 128.56, 128.28,
122.34, 86.85, 84.86, 74.92, 71.07, 59.37, 56.89. HRMS (ESI)
([M + H]+) calcd for C12H15O2: 191.1072, found: 191.1075.
2-(Phenylethynyl)tetrahydro-2H-pyran (3r).16 Colorless oil.
1H NMR (400 MHz, CDCl3) δ: 7.48–7.46 (m, 2H), 7.32–7.27 (m,
3H), 4.53–4.51 (m, 1H), 4.09–4.04 (m, 1H), 3.63–3.57 (m, 1H),
1.95–1.87 (m, 2H), 1.84–1.77 (m, 1H), 1.65–1.57 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ: 131.76, 128.29, 128.22, 122.77,
88.15, 85.19, 67.46, 66.64, 32.20, 25.69, 21.84.
1
2-(Phenylethynyl)-1,4-dioxane (3s).15a Colorless oil. H NMR
(400 MHz, CDCl3) δ: 7.47–7.45 (m, 2H), 7.32–7.31 (m, 3H),
4.59–4.57 (m, 1H), 3.96–3.92 (m, 2H), 3.78–3.68 (m, 4H); 13C
NMR (100 MHz, CDCl3) δ: 131.87, 128.70, 128.27, 122.07,
86.56, 84.32, 70.41, 66.46, 66.40, 65.80.
1-((Tetrahydrofuran-2-yl)ethynyl)cyclohexanol (3x).22 Color-
less oil. 1H NMR (400 MHz, CDCl3) δ: 4.63–4.61 (m, 1H),
3.97–3.92 (m, 1H), 3.83–3.80 (m, 1H), 2.27 (br, s, 1H),
2.17–2.15 (m, 1H), 2.05–1.88 (m, 5H), 1.68–1.66 (m, 2H),
1.58–1.50 (m, 4H), 1.24–1.21 (m, 2H); 13C NMR (100 MHz,
CDCl3): δ: 88.04, 83.90, 68.42, 68.03, 67.64, 39.74, 33.32, 25.21,
25.04, 23.21.
2-((4-(tert-Butyl)phenyl)ethynyl)-1,4-dioxane (3t). Colorless
1
oil. H NMR (400 MHz, CDCl3) δ: 7.40 (d, J = 8.0 Hz, 2H), 7.33
(d, J = 8.4 Hz, 2H), 4.59–4.56 (m, 1H), 3.96–3.92 (m, 2H),
3.79–3.67 (m, 4H), 1.31 (s, 9H); 13C NMR (100 MHz, CDCl3) δ:
151.98, 131.60, 125.27, 119.01, 86.70, 83.59, 70.49, 66.55,
66.38, 65.84, 34.78, 31.13. HRMS (EI) ([M]+) calcd for
C16H20O2: 244.1463, found: 244.1468.
2-(Hept-1-yn-1-yl)tetrahydrofuran (3y).23 Colorless oil. 1H
NMR (400 MHz, CDCl3) δ: 4.57–4.55 (m, 1H), 3.98–3.93 (m,
1H), 3.82–3.76 (m, 1H), 2.21 (t, J = 7.0 Hz, 2H), 2.15–2.08 (m,
1H), 2.04–2.00 (m, 1H), 1.96–1.87 (m, 2H), 1.54–1.47 (m, 2H),
1.33–1.26 (m, 4H), 0.90 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ: 85.21, 79.74, 68.33, 67.56, 33.42, 30.94, 28.23, 25.31,
22.09, 18.63, 13.88.
1-(4-((2,3-Dihydrobenzofuran-2-yl)ethynyl)phenyl)ethanone
(3u). Colorless oil. 1H NMR (400 MHz, CDCl3) δ: 7.90 (d, J =
8.4 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 7.2 Hz, 1H),
7.23–7.19 (m, 1H), 6.98–6.95 (m, 1H), 6.87 (d, J = 8.0 Hz, 1H),
2-(Phenylethynyl)-1,3-dioxolane (3z).24 Colorless oil. 1H
4.87–4.83 (m, 1H), 4.65–4.61 (m, 1H), 4.56–4.52 (m, 1H), 2.60 NMR (400 MHz, CDCl3) δ: 7.48–7.46 (m, 2H), 7.36–7.32 (m,
(s, 3H); 13C NMR (100 MHz, CDCl3) δ: 197.16, 159.33, 136.15, 3H), 5.90 (s, 1H), 4.17–4.13 (m, 2H), 4.01–3.98 (m, 2H); 13C
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NMR (100 MHz, CDCl3) δ: 131.94, 128.99, 128.31, 121.60, 2.02–1.96 (m, 1H), 1.94–1.89 (m, 1H), 1.72–1.63 (m, 1H); 13C
93.45, 85.21, 84.45, 64.61.
NMR (100 MHz, CDCl3) δ: 160.49, 149.13, 134.03, 133.49,
128.87, 128.62, 125.43, 119.62, 118.70, 116.49, 105.27, 73.67,
67.94, 32.33, 26.03. HRMS (ESI) ([M
C19H18NO2: 292.1338, found: 292.1338.
+
H]+) calcd For
1
4-(Phenylethynyl)-1,3-dioxolane (3z′). Colorless oil. H NMR
(400 MHz, CDCl3) δ: 7.47–7.45 (m, 2H), 7.34–7.32 (m, 3H), 5.11
(s, 1H), 5.08 (s, 1H), 4.95 (t, J = 6.0 Hz, 1H), 4.21–4.18 (m, 1H),
3.95–3.92 (m, 1H); 13C NMR (100 MHz, CDCl3) δ: 131.81,
128.73, 128.29, 122.08, 95.20, 86.22, 85.65, 70.59, 65.81. HRMS
(EI) ([M]+) calcd for C11H10O2: 174.0681, found: 174.0677.
(E/Z)-(2-Bromovinyl)benzene (E-4a and Z-4a) [E/Z = 5/1]. 1H
NMR (400 MHz, CDCl3) δ: 7.45–7.39 (m, 1H), 7.37–7.34 (m,
5H), 7.15 (d, J = 14.0 Hz, 1H), 7.11 (d, J = 8.4 Hz, 0.2H), 6.81 (d,
J = 14.0 Hz, 1H), 6.48 (d, J = 8.4 Hz, 0.2H).
(E)-2-Styryl-tetrahydrofuran (E-5a).12 Colorless oil. 1H NMR
(400 MHz, CDCl3) δ: 7.41–7.39 (m, 2H), 7.33–7.30 (m, 2H),
7.27–7.22 (m, 1H), 6.61 (d, J = 16.0 Hz, 1H), 6.23 (dd, J = 16.0,
6.0 Hz, 1H), 4.52–4.47 (m, 1H), 4.02–3.97 (m, 1H), 3.89–3.83
(m, 1H), 2.18–2.10 (m, 1H), 2.03–1.94 (m, 2H), 1.77–1.71 (m,
1H); 13C NMR (100 MHz, CDCl3) δ: 136.76, 130.43, 130.32,
128.40, 127.39, 126.36, 79.56, 68.08, 32.30, 25.82.
(E/Z)-2-Styryltetrahydrofuran (E-5a and Z-5a) [E/Z
=
5/1].12 1H NMR (400 MHz, CDCl3) δ: 7.40–7.38 (m, 2H),
7.35–7.30 (m, 2.8H), 7.28–7.22 (m, 1.2H), 6.61 (d, J = 11.6 Hz,
0.2H), 6.60 (d, J = 15.6 Hz, 1H), 6.22 (dd, J = 16.0, 6.4 Hz, 1H),
5.72 (dd, J = 11.6, 8.8 Hz, 0.2H), 4.71–4.65 (m, 0.2H), 4.52–4.47
(m, 1H), 4.01–3.96 (m, 1.2H), 3.88–3.79 (m, 1.2H), 2.17–2.12
(m, 1.2H), 2.03–1.94 (m, 2.4H), 1.75–1.71 (m, 1.2H).
(E)-2-Methyl-2-styryl-tetrahydrofuran (E-5b). Colorless oil.
1H NMR (400 MHz, CDCl3) δ: 7.41–7.39 (m, 2H), 7.34–7.30 (m,
2H), 7.25–7.21 (m, 1H), 6.57 (d, J = 16.0 Hz, 1H), 6.26 (d, J =
16.0 Hz, 1H), 3.97–3.94 (m, 2H), 2.03–1.96 (m, 3H), 1.83–1.76
(m, 1H), 1.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 137.10,
135.43, 128.38, 127.08, 126.69, 126.27, 82.29, 67.54, 37.76,
26.68, 25.63. HRMS (EI) ([M]+) calcd For C13H16O: 188.1201,
found: 188.1202.
(E/Z)-2-Methyl-2-styryltetrahydrofuran (E-5b and Z-5b) [E/Z =
5/1]. 1H NMR (400 MHz, CDCl3) δ: 7.40–7.38 (m, 2.4H),
7.33–7.29 (m, 2.6H), 7.24–7.21 (m, 1H), 6.61 (d, J = 8.4 Hz,
0.2H), 6.56 (d, J = 16.0 Hz, 1H), 6.61 (d, J = 16.0 Hz, 1H), 6.20
(d, J = 7.2 Hz, 0.2H), 4.26–4.21 (m, 0.2H), 3.97–3.94 (m, 2H),
2.01–1.80 (m, 4.8H), 1.62 (s, 0.6H), 1.42 (s, 3H).
(Z)-4-((1-Phenyl-2-(tetrahydrofuran-2-yl)vinyl)oxy)benzonitrile
1
Acknowledgements
(5c). White solid. H NMR (400 MHz, CDCl3) δ: 7.52–7.50 (m,
2H), 7.30–7.27 (m, 3H), 7.25–7.21 (m, 2H), 6.99–6.93 (m, 3H),
5.92 (d, J = 8.0 Hz, 1H), 4.80–4.74 (m, 1H), 3.97–3.92 (m, 1H),
3.80–3.75 (m, 1H), 2.12–2.07 (m, 1H), 2.01–1.87 (m, 2H),
1.72–1.67 (m, 1H); 13C NMR (100 MHz, CDCl3) δ: 157.11,
149.90, 134.59, 129.41, 128.33, 125.71, 121.59, 118.83, 115.70,
74.04, 67.82, 32.33, 26.04. HRMS (ESI) ([M + H]+) calcd for
C18H19O2: 267.1385, found: 267.2382.
This work was financially supported by the National Science
Foundation of China (no. 21172092 and 21372095).
Notes and references
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F. Glorius, Aldrichimica Acta, 2012, 45, 31; (d) N. Kuhl,
M. N. Hopkinson, J. Wencel-Delord and F. Glorius, Angew.
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(Z)-4-((1-Phenyl-2-(tetrahydrofuran-2-yl)vinyl)oxy)benzonitrile
(5d). White solid. 1H NMR (400 MHz, CDCl3) δ: 7.54 (d, J =
8.0 Hz, 2H), 7.46–7.45 (m, 2H), 7.31–7.27 (m, 3H), 7.05 (d, J =
8.0 Hz, 2H), 5.98 (d, J = 8.0 Hz, 1H), 4.70–4.65 (m, 1H),
3.96–3.91 (m, 1H), 3.80–3.74 (m, 1H), 2.11–2.05 (m, 1H),
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Paper
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2978 | Org. Biomol. Chem., 2014, 12, 2969–2978
This journal is © The Royal Society of Chemistry 2014