Visible-Light Induced Direct Synthesis of Polysubstituted Furans from Cyclopropyl Ketones

Article abstract of DOI:10.1021/acs.joc.6b00436

In this article, a photoredox protocol for the synthesis of furans via oxidative coupling of olefin generated in situ from cyclopropyl ketones with ketonic oxygen atom is presented. Moreover, bromination of furans in the presence of overstoichiometric oxidant has been achieved with high regioselectivity.

Full text of DOI:10.1021/acs.joc.6b00436

Article
pubs.acs.org/joc
Visible-Light Induced Direct Synthesis of Polysubstituted Furans
from Cyclopropyl Ketones
Liyan Feng, Hang Yan, Chao Yang, Dafa Chen, and Wujiong Xia*
State Key Lab of Urban Water Resource and Environment, Shenzhen Graduate School, Harbin Institute of Technology,
Harbin 150080 China
S
* Supporting Information
ABSTRACT: In this article, a photoredox protocol for the synthesis of furans via oxidative coupling of olefin generated in situ
from cyclopropyl ketones with ketonic oxygen atom is presented. Moreover, bromination of furans in the presence of over-
stoichiometric oxidant has been achieved with high regioselectivity.
one-pot procedure that consists of the ring opening of aryl
cyclopropyl ketones under nonacidic conditions and subsequent
direct unimolecular oxidative coupling of the ketonic oxygen
atom with Csp −H to deliver polysubstituted furans by visible-
light photocatalysis (Scheme 1d).
INTRODUCTION
■
As one of the most important heterocycles, furan derivatives have
exhibited versatile applications in organic synthesis as synthetic
intermediates1 and in the chemical industry to afford commercial
products such as pharmaceuticals, pesticides, and functional
polymers.2 Therefore, efficient synthesis of furans, especially in
atom-economical pathways, has attracted considerable attention
from the realm of organic synthesis.3 In this regard, transition
metal-catalyzed approaches for the assembly of furans meet the
criteria well with particular attraction in recent several decades.4
For instance, a seminal report and subsequent studies on
cycloisomerization of allenyl ketones by Marshall lit the way
to furan synthesis (Scheme 1, a),5 followed by Hashmi6 and
Gevorgyan7 for elaboration. Utimoto8 and Sheng9 groups
extended the substrate to propargyl ketones (Scheme 1b), and
Zhang10 has developed a series of two-component tandem
reactions with high diastereo- and enantioselectivity. Despite the
above advances, new methods for direct and regioselective
2
RESULTS AND DISCUSSION
■
Our initial investigation was focused on the strategy for trans-
formation of a strained cyclic benzophenone to an unsaturated
ketone that was essential for the sequential oxidative coupling
reaction. First, 1a was selected as the model substrate for initial
studies. We then introduced carbon tetrabromide as a oxidative
quencher that could simultaneously afford bromide ions as an
extremely weak base, which was well documented in previous
literature.14 Thus, 1a was submitted to the typical reaction con-
ditions of CBr4 (1.0 equiv) and Ru(bpy)3Cl2·6H2O (5.0 mol %)
in CH3CN under irradiation with a 5 W blue LED. Unexpectedly,
a product of 2,5-diphenylfuran 4a was isolated in 37% yield
after reaction for 12 h (Table 1, entry 1). The conversion of
compound 1a to 4a provides direct access to polysubstituted
furans, which stimulated us to explore it in detail.
2
coupling of carbonyl oxygen atom with Csp −H bonds should
be potentially of value in constructing furan rings. But a survey of
the literature showed that only one report from the Dixneuf
group documented the copper catalyzed oxidative coupling to
symmetric 2,5-diarylfurans from related unsaturated ketones
(Scheme 1c).11 More recently, a dual catalyst system suitable
for efficient construction of C−X bonds by direct addition of
heteroatom nucleophiles to alkenes has been established by
Nicewicz via a single electron transfer (SET)12 initiated by visible
light irradiation with photosensitizers, which has been well
documented as the most effective strategy to activate neutral
substrates for bond formation or mesolytic cleavage.13 Inspired
by the pioneering achievement, we are interested in exploiting
the photocatalytic protocols for styrene C−H functionalization
and discovering new reaction patterns in the oxidative C−O
bond formation. In this paper, we present a very intriguing
The optimization of the reaction conditions was thus con-
ducted by examination of other oxidative quenchers, such as
Na2S2O8, but this was ineffective for the reaction unless LiBr
was added as an external bromide ion source (Table 1, entries
6 and 8). In addition, the screening of conditions revealed
that polar solvents, such as CH3CN and CH3NO2, were more
effective possibly owing to their ability to stabilize the distonic
radical cations (see SI, Table S2),15 and Ru(dtbbpy)3(PF6)2
Special Issue: Photocatalysis
Received: February 27, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b00436
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Scheme 1. Stepwise Approach to Furans
complex was optimal for this visible-light system (Table 1,
entries 7−12).
It was particularly noteworthy that the spirocyclopropane
was also tolerated with the reaction conditions to contrib-
ute a novel dihydronaphthofuran 4t, but it partly underwent
further oxidative dehydrogenation to form 4t′ in a nearly 1:1
ratio. Attempts had been made here to get a single product by
examining the amount of CBr4 and rigorous degassing, but these
failed.
Moreover, decreasing the concentration of the reagent and
halving the stoichiometry of CBr4 but increasing the amount
of LiBr obviously increased the yield of 4a to 74% (Table 1,
entries 13−15). The catalyst loading could be decreased to
1 mol % without loss of effectiveness when a longer time was
employed (Table 1, entry 16). Control experiments documented
that either light or a photocatalyst was essential for the reaction
(Table 1, entries 2 and 3). The oxygen seemed to be friendly for
the dehydrogenation, while a tiny amount of water was just
opposite (Table 1, entries 4 and 5).
Interestingly, a stoichiometric amount of CBr4 presented a
novel bromination pathway of 2,5-unsymmetrically substituted
furans with high regioselectivity (see SI, Table S5). Analogous to
Fukuzumi’s and Nicewicz’s studies on selective arene C−H
bromination and amination via organic photocatalyst,16 this
electrophilic addition of Br− was attributed to the orientation of
the methoxyl group. Since direct bromination at a certain carbon
atom remained a considerable synthetic challenge,17 we herein
disclosed our efforts to develop a radical oxidative sequence to
the desired 3-bromofurans. As shown in Table 3, dibromofuran
5c and the monobromination products 5a, 5f, 5g, 5h, 5j, and 5l
were successfully prepared in moderate yields under the standard
reaction conditions except for the increased amount of CBr4
to twice the standard amount. Among these, the progress to
afford 5j did not work out so well even though more oxidant and
photocatalyst were employed with a prolonged exposure time to
6 days, yet a higher yield could be achieved by direct irradiation of
4j in a shorter time. The phenyl ring with an ortho-methoxyl
group was not ideal for the reaction due to the electronic effect
and steric hindrance; for example, 5n was separated in 53% yield
with trace amount of dibromofuran.
With the optimal conditions in hand, we then investigated the
scope of the reaction, and the results are listed in Table 2. As can
be seen, electron-donating 2- or 4-substituents of the phenyl ring
A were the inevitable choice for the oxidative quenching cycle of
the photocatalyst, and various 2,5-diphenylfurans were obtained
in moderate to good yields, except for 4v, which will be discussed
later. Electron-donating or -withdrawing substituents including
halogen and nitro groups on the other phenyl ring were well
tolerated with the reaction conditions. Additionally, the elec-
tronic effects of the substituents had a significant influence on
reaction time; electron-donating substituents could increase the
electron density, which was beneficial to nucleophilicity of the
ketonic oxygen atom, and vice versa. For example, the conversion of
4b and 4c could be completed in several hours whereas 4i with CF3
took a much longer time. On the other hand, different substituents
on the furans resulted in different solubility in acetonitrile, which
affected the yield due to the sensitivity of furans to light and acidic
environments. For instance, 4c was obtained in good isolated yield
since the product was precipitated after reaction.
As depicted in the preceding, the coupling reaction to date was
limited to aromatic ketones and failed for aliphatic ketones
(Table 2, 4v). To address this drawback, we next devised a
B
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Table 1. Selected Optimization of Reaction Conditions
a
b
entry
catalyst (mol %)
solvent (M)
oxidant (equiv)
additive (equiv)
H2O (1.0)
T (h)
yield (%)
1
3a (5)
3a (5)
--
CH3CN (0.1)
CH3CN (0.1)
CH3CN (0.1)
CH3CN (0.1)
CH3CN (0.1)
CH3CN (0.1)
CH3CN (0.1)
CH3CN (0.1)
CH3CN (0.1)
CH3CN (0.1)
CH3CN (0.1)
CH3CN (0.1)
CH3CN (0.1)
CH3CN (0.1)
CH3CN (0.05)
CH3CN (0.05)
CH3CN (0.05)
2a (1.0)
2a (1.0)
2a (1.0)
2a (1.0)
2a (1.0)
2b (1.0)
2a (1.0)
2b (1.0)
2a (1.0)
2a 1.0)
12
24
24
12
12
48
12
12
12
12
12
12
12
12
12
24
72
37
0
c
2
3
4
0
3a (5)
3a (5)
3a (5)
3a (5)
3a (5)
3b (5)
3c (5)
3d (5)
3e (5)
3c (5)
3c (5)
3c (5)
3c (1)
3c (1)
16
23
0
d
5
6
7
LiBr (1.0)
LiBr (1.0)
LiBr (1.0)
LiBr (1.0)
LiBr (1.0)
LiBr (1.0)
LiBr (0.5)
LiBr (0.5)
LiBr (1.0)
LiBr (1.0)
50
42
32
65
40
42
35
41
74
72
0
8
9
10
11
12
13
14
15
16
17
2a (1.0)
2a (1.0)
2a (1.0)
2a (0.5)
2a (0.5)
2a (0.5)
2a (0.5)
lutidine
a
b
c
d
Reaction conducted under irradiation of a blue LED strip open to air unless otherwise noted. Isolated yields. Without light. Air-free with N2.
strategy by which the nucleophilicity of alkyl ketone oxygen
could be mitigated tactfully by attaching an electron-withdrawing
group, such as carbethoxy, to anethene to increase the elec-
trophilicity of the radical cations. However, no reaction was
observed when the prepared substrate 6a (R2 = H, Table 4) was
subjected to the standard conditions. After optimization of the
reaction by increasing the amount of CBr4 (see SI, Table S6), the
desired product 7a was obtained in very high yield (94%).
Similarly, other products 7b−7h were also prepared in excellent
yield (Table 4). Notably, the reaction conditions were suitable
for synthesis of the alkyl substituted furans such as 7i and 7k in
acceptable yields. The product 7j containing a hindered group,
tert-butyl, was also obtained in 95% yield.
such as pallescensin A, a kind of furanosesquiterpene sharing an
annulated furan core in common with 7k.18
The mechanism of this transformation was complex and hard
to understand. Fortunately, intermediate B was isolated from the
reaction, which would be useful for the mechanism discussion.
But the oxidative ring-opening of 1a to afford B was not found in
the literature. To give mechanistic insight into the process, a
deuterium substrate, 1a-d2, was treated with Na2S2O8, LiBr, and
cat. Ru(bpy)3Cl2·6H2O under blue LED irradiation. The low
deuterium ratio of B-d2 indicated that the process involved both
β- hydride elimination and intermolecular hydrogen atom
transfer (HAT) steps (eq 1). When another substrate, 1w, was
treated under the standard reaction conditions, compound C was
separated in 38% yield, which suggested the formed radical inter-
mediate without stabilization from a carbonyl group preferred to
donate an electron to afford a conjugated alkene (eq 2) or to
Moreover, this strategy also demonstrated the potential value
in the construction of medicinal agents with anticancer activity
against breast cancer cell lines and natural product derivatives,
C
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a
Table 2. Scope of the 2,5-Diarylfurans Synthesis
a
Unless otherwise noted, all reactions were carried out with 1 (50 mg), CBr4 (0.5 equiv), LiBr (1.0 equiv), and 3c (1 mol %) in CH3CN (4 mL) at
room temperature under 5 W blue LED. Yields indicated are isolated yields.
decompose to other products. Moreover, the isolation of B was
always accompanied by the generation of final product 4a, which
would release HBr to the reaction system. And we proved that
the accumulated HBr little by little could facilitate the ring-
opening process (Table 5).
The possible mechanism is shown in Scheme 2. Initially, in
pathway A, photoexcited state *Ru(dtbbpy)32+ was quenched by
CBr4 to form a Ru(dtbbpy)33+ (E
= 1.10 V vs SCE)19 inter-
III/II
1/2
mediate, which oxidized anisole 1a-d2 to radical cation 8, a
species capable of undergoing mesolytic cleavage to afford the
distonic radical cation 9. Previous work in our laboratory demon-
strated that these distonic radical cations preferred to eliminate
a proton in the presence of 0.3 equiv of CBr4.20 The resulting
2+
free radical 10 was then reduced by excited *Ru(dtbbpy)3 to
give 11, which was acidized to afford B-d2; the high state
3+
Ru(dtbbpy)3 was utilized for the next cycle. Thus, a catalytic
amount of CBr4 was enough for this process. In pathway B, 1a
was transformed to B directly catalyzed by the released HBr in
the next step. Here the possible intermediate benzylic cation 12
was also not trapped by Br−.
Next, the mechanism of the transform from B to 4a was
verified by a control experiment. Compound B would not
D
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a,b
Table 3. Scope of 3-Bromofuran Synthesis
a
Unless otherwise noted, all reactions were carried out with 1 (50 mg), CBr4 (2.0 equiv), LiBr (1.0 equiv), and 3c (1 mol %) in CH3CN (4 mL) at
b
c
room temperature under 5 W blue LED. Yields indicated are iolated yield. The amount of CBr4 was increased to 3.0 equiv. to obtain the expected
product.
a,b
Table 4. Scope of the Furan-3-carboxylate Ethyl Ester Synthesis
a
Unless otherwise noted, all reactions were carried out with 6 (100 mg), CBr4 (2.0 equiv), LiBr (1.0 equiv), and 3c (1 mol %) in CH3CN (8 mL) at
b
c
room temperature under 5 W blue LED. Yields indicated are isolated yield. With cocatalyst 20 mol % TsOH.
transfer to 4a in acidic conditions under LED irradiation unless
oxidative quencher and photocatalyst were added (eqs 3 and 4),
which indicated that the aromatic cyclodehydration was an
oxidative process. When compound B was subjected to the
standard conditions, 4a was isolated in lower yield, and no
generation of 5a was observed (eq 5). These results suggested
that all of the 0.5 equiv of CBr4 was consumed in this oxidative
annulation step.
A plausible reaction pathway for the synthesis of furans is
illustrated in Scheme 3. The oxidation of the anethene moiety of
E
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a
Table 5. Screening of Acids for the Ring Opening
b
entry
acid (50% mol)
time (min)
yield (%)
1
2
3
HBr (concn)
HCl (concn)
TsOH·H2O
1
1
1
60
trace
20
a
b
Acid was added to the solution of 1a (1 mmol) in CH3CN (2 mL) with stirring. Isolated yield.
mild conditions. The bromofurans could also be achieved with
high regioselectivity by employment of an excess amount of
CBr4. We believe that this general SET coupling method will find
potential application in natural product and biologically active
compound synthesis.
EXPERIMENTAL SECTION
■
General Information. Unless otherwise stated, all reactions were
carried out in air and using distilled solvent, without any precautions to
exclude air and moisture unless otherwise noted. All reagents were
purchased from commercial suppliers and used without further puri-
fication. Melting points were uncorrected. Reactions were monitored by
thin-layer chromatography (TLC) carried out on commercial silica gel
plates (GF254) using UV light as a visualizing agent. Flash chro-
matography was performed on silica gel 60 (200−300 mesh). 1H, 13C,
and 19F NMR spectra were recorded in CDCl3 on 400 or 600 MHz
instrument. Chemical shifts for 1H NMR spectra were reported in δ ppm
referenced to an internal tetramethylsilane (TMS) standard. Chemical
shifts for 13C NMR spectra were reported in parts per million relative to
the center line signal of the CDCl3 triplet at 77.0 ppm. Abbreviations for
signal couplings are s, singlet; d, doublet; t, triplet; m, multiplet.
Coupling constants (J) are reported in hertz and refer to apparent peak
multiplications. High resolution mass spectra (HRMS) were obtained
on an iFunnel Q-TOF (ESI) mass spectrometer. GC-MS analysis was
performed on a spectrometer with an EI source.
General Procedure for the Synthesis of 1a−1t.22 Taking sub-
strate 1a as an example, to a mixture of 4.8 mmol of trimethylox-
osulfonium iodide and 1 equiv of NaH (60% mineral oil dispersion) in a
two-neck round-bottom flask under N2 atmosphere, 3 mL of anhydrous
THF was added to remove the mineral oil. Anhydrous DMSO (20 mL)
was introduced dropwise via syringe, which resulted in vigorous
evolution of hydrogen. After being stirred for nearly 30 min, the mixture
was clear and no gas bubbled off; 10 mL of a DMSO solution of
4.8 mmol of chalcone was added at 0 °C in an ice bath. The mixture was
warmed to room temperature with vigorous stirring for another 20 min
and then quenched with 20 mL of sat. aq NH4Cl, followed by 20 mL of
ethyl acetate. The mixture was transferred to a 250 mL separatory
funnel, and the organic phase was separated. The aqueous layer was
extracted with 3 × 20 mL of ethyl acetate. All organic portions were
combined and washed with 3 × 100 mL of brine to remove DMSO,
dried over magnesium sulfate, and filtered, and the solvent was removed
under vacuum to give a pale yellow oil, which was further purified by
flash chromatography (hexane/ethyl acetate = 15:1) to obtain 1a as a
colorless oil.
3+
B by Ru(dtbbpy)3 resulted in the formation of the radical
cation 13. Nucleophilic addition of ketone oxygen to benzyl
carbocation followed by deprotonation gave a radical 15, which
would be oxidated by O2 to afford the end furan adduct 4a and
released a new oxidative quencher at the same time according to
Huo’s report.21
In the presence of an excess amount of CBr4, 4-methoxylphenyl
could be oxidized by Ru(dtbbpy)33+ to afford the radical cation 16,
which would undergo charge delocalization to the furan ring.
The more stable dihydrofuran radical cation 17 enabled selective
addition of Br− to a certain carbon atom. Analogously, the
brominated furan radical 18 was apt to lose an electron to
afford 19, which released a proton to form the 3-bromofuran 5a
(Scheme 4).
(2-(4-Methoxyphenyl)cyclopropyl)(phenyl)methanone (1a). 1H NMR
(400 MHz, CDCl3): δ = 8.00−7.98 (m, 2H), 7.57−7.53 (m, 1H), 7.47−
7.44 (m, 2H), 7.11 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 3.79
(s, 3H), 2.83 (ddd, J = 8.0, 5.2, 4.1 Hz, 1H), 2.66 (ddd, J = 9.1,
6.7, 4.0 Hz, 1H), 1.89 (ddd, J = 9.1, 5.2, 4.1 Hz, 1H), 1.51 (ddd, J =
8.0, 6.7, 4.1 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ = 198.6, 158.4,
137.79, 132.8, 132.4, 128.5, 128.1, 127.4, 114.0, 55.3, 29.6, 29.2, 18.9.
HRMS m/z: calcd for C17H16O2 [M + H]+ 253.1224, found 253.1222.
CONCLUSION
■
In summary, we have developed a novel protocol for synthesis of
substituted furans from easily accessible cyclopropyl ketones via
oxidative C−C bond cleavage and C−O bond formation under
1
(2-(4-Methoxyphenyl)cyclopropyl)(p-tolyl)methanone (1b). H NMR
(400 MHz, CDCl3): δ = 7.89 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.2 Hz, 2H),
F
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Scheme 2. Mechanism for Ring Opening
Scheme 3. Mechanism for Oxidative Annulation
7.11 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 3.80 (s, 3H), 2.80
(ddd, J = 8.1, 5.2, 4.1 Hz, 1H), 2.64 (ddd, J = 9.1, 6.6, 4.0 Hz, 1H), 2.41
(s, 3H), 1.87 (ddd, J = 9.2, 5.2, 4.1 Hz, 1H), 1.48 (ddd, J = 8.0, 6.7, 4.1
Hz, 1H). 13C NMR (150 MHz, CDCl3): δ = 198.2, 158.3, 143.6, 135.2,
132.6, 129.2, 128.2, 127.4, 113.9, 55.3, 29.4, 29.0, 21.6, 18.8. HRMS
m/z: calcd for C18H18O2 [M + H]+ 267.1380, found 267.1388.
(4-Methoxyphenyl)(2-(4-methoxyphenyl)cyclopropyl)methanone
7.11 (d, J = 8.6 Hz, 2H), 6.94 (d, J = 8.9 Hz, 2H), 6.85 (d, J = 8.6 Hz,
2H), 3.87 (s, 3H), 3.80 (s, 3H), 2.78 (ddd, J = 8.3, 5.0, 4.3 Hz, 1H) 2.63
(ddd, J = 9.3, 6.6, 4.0 Hz, 1H), 1.86 (ddd, J = 9.1, 5.1, 4.2 Hz, 1H), 1.47
(ddd, J = 8.0, 6.6, 4.1 Hz, 1H). 13C NMR (150 MHz, CDCl3): δ = 197.1,
163.4, 158.3, 132.7, 130.8, 130.3, 127.4, 113.9, 113.7, 55.5, 55.3, 29.1,
28.8, 18.6. HRMS m/z: calcd for C18H18O3 [M + H]+ 283.1329, found
283.1329.
1
(1c). H NMR (400 MHz, CDCl3): δ = 7.98 (d, J = 8.9 Hz, 2H),
G
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Scheme 4. Mechanism for Regioselective Bromination of Furan
2-(4-Methoxyphenyl)cyclopropyl(4-tert butylpheny)lmethanone
(1d). 1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 8.4 Hz, 2H), 7.47
(d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H),
3.79 (s, 3H), 2.82 (ddd, J = 8.4, 5.1, 4.3 Hz, 1H), 2.63 (ddd, J = 8.6,
6.7, 4.2 Hz, 1H), 1.88 (ddd, J = 9.1, 5.0, 4.3 Hz, 1H), 1.48 (ddd,
J = 7.8, 6.8, 4.2 Hz, 1H), 1.33 (s, 9H). 13C NMR (100 MHz, CDCl3):
δ = 198.1, 158.4, 156.5, 135.2, 132.6, 128.0, 127.4, 125.4, 114.0, 55.3,
35.0, 31.1, 29.4, 29.0, 18.6. HRMS m/z: calcd for C21H24O2 [M + H]+
309.1850, found 309.1847.
(2-(4-Methoxyphenyl)cyclopropyl)(naphthalen-1-yl)methanone
(1e). 1H NMR (400 MHz, CDCl3): δ = 8.49 (d, J = 9.1 Hz, 1H), 7.96 (d,
J = 8.2 Hz, 1H), 7.94−7.80 (m, 2H), 7.53 (dtd, J = 14.1, 6.9, 1.5 Hz, 2H),
7.49 (t, J = 8.2 Hz, 1H), 7.13 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H),
3.79 (s, 3H), 2.78 (dddd, J = 12.0, 8.1, 5.9, 4.0 Hz, 2H), 2.03 (ddd, J =
9.2, 5.3, 4.1 Hz, 1H), 1.57 (ddd, J = 9.4, 8.1, 4.1 Hz, 1H). 13C NMR
(100 MHz, CDCl3): δ = 202.4, 158.4, 137.4, 133.8, 132.2, 132.1, 129.9,
128.4, 127.5, 127.4, 127.3, 126.3, 125.7, 124.5, 114.0, 55.3, 33.4, 30.3,
19.6. HRMS m/z: calcd for C21H18O2 [M + H]+ 303.1380, found
303.1377.
(4-Fluorophenyl)(2-(4-methoxyphenyl)cyclopropyl)methanone
(1f). 1H NMR (400 MHz, CDCl3): δ = 8.01 (dd, J = 8.8, 5.4 Hz, 2H),
7.12 (t, J = 8.8 Hz, 2H), 7.10 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H),
3.80 (s, 3H), 2.76 (ddd, J = 8.1, 5.0, 4.2 Hz, 1H), 2.65 (ddd, J = 9.2,
6.7, 4.0 Hz, 1H), 1.89 (ddd, J = 9.2, 5.1, 4.3 Hz, 1H), 1.52 (ddd, J =
7.8, 6.8, 4.2 Hz, 1H), 1.52 (ddd, J = 7.8, 6.8, 4.2 Hz, 1H). 13C NMR
(150 MHz, CDCl3): δ = 197.0, 165.6 (d, J = 254.3 Hz), 158.4, 134.1
(d, J = 2.9 Hz), 132.3, 130.6 (d, J = 9.2 Hz), 127.3, 115.6 (d, J = 21.8 Hz),
114.0, 55.3, 29.7, 29.1, 18.9. HRMS m/z: calcd for C17H15FO2 [M + H]+
271.1129, found 271.1132.
7.60 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz,
2H), 3.80 (s, 3H), 2.75 (ddd, J = 8.1, 5.1, 4.2 Hz, 1H), 2.66 (ddd, J = 9.4,
6.7, 4.0 Hz, 1H), 1.89 (ddd, J = 9.2, 5.1, 4.3 Hz, 1H), 1.53 (ddd, J = 7.9,
6.8, 4.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 197.5, 158.5, 136.5,
132.2, 131.8, 129.6, 128.0, 127.4, 114.1, 55.3, 29.9, 29.2, 19.1. HRMS
m/z: calcd for C17H15BrO2 [M + H]+ 331.0329, found 331.0334.
4-(Trifluoromethyl)phenyl)-2-(4-methyloxyphenyl)-
cycloprylmethanone (1i). 1H NMR (400 MHz, CDCl3): δ = 8.07 (d, J =
8.2 Hz, 2H), 7.72 (d, J = 8.2 Hz, 2H), 7.11 (d, J = 8.7 Hz, 2H), 6.86
(d, J = 8.7 Hz, 2H), 3.80 (s, 3H), 2.80 (ddd, J = 8.1, 5.1, 4.1 Hz, 1H), 2.80
(ddd, J = 8.1, 5.1, 4.1 Hz, 1H), 2.70 (ddd, J = 9.3, 6.8, 4.0 Hz, 1H), 1.94
(ddd, J = 9.2, 4.9, 4.4 Hz, 1H), 1.58 (ddd, J = 7.8, 6.9, 4.2 Hz, 1H).
13C NMR (100 MHz, CDCl3): δ = 197.7, 158.6, 140.5 (d, J = 1.0 Hz),
134.1 (q, J = 32.7 Hz), 131.9, 128.4, 127.4, 125.6 (q, J = 3.7 Hz), 123.6
(q, J = 272.6 Hz), 114.1, 55.3, 30.4, 29.6, 19.3. HRMS m/z: calcd for
C18H15F3O2 [M + H]+ 321.1097, found 321.1091.
[2-(4-Methoxyphenyl)cyclopropyl](4-nitrylphenyl)methanone
(1j). 1H NMR (400 MHz, CDCl3): δ = 8.30 (d, J = 8.9 Hz, 2H), 8.12
(d, J = 8.9 Hz, 2H), 7.11 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H),
3.81 (s, 3H), 2.80 (ddd, J = 8.0, 5.1, 4.0 Hz, 1H), 2.73 (ddd, J = 9.2,
6.9, 3.9 Hz, 1H), 1.97 (ddd, J = 9.3, 5.1, 4.4 Hz, 1H), 1.63 (ddd, J =
7.8, 6.9, 4.2 Hz, 1H). 13C NMR (150 MHz, CDCl3): δ = 197.2, 158.7,
150.1, 142.3, 131.6, 129.0, 127.3, 123.8, 114.1, 55.3, 30.9, 30.1, 19.7.
GC-MS (EI)m/z: 297, 147, 132, 115, 104, 91, 76.
2-(4-Methoxyphenyl)cyclopropyl(3-methoxy-phenyl)methanone
(1k). 1H NMR (400 MHz, CDCl3): δ = 7.58 (d, J = 7.7 Hz, 1H), 7.36
(t, J = 7.9 Hz, 1H), 7.10 (t, J = 7.9 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 6.85
(d, J = 8.7 Hz, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 2.80 (ddd, J = 8.1, 5.1,
4.2 Hz, 1H), 2.66 (ddd, J = 9.2, 6.7, 4.0 Hz, 1H), 1.88 (ddd, J = 9.1,
5.1, 4.2 Hz, 1H), 1.51 (ddd, J = 7.9, 6.7, 4.1 Hz, 1H). 13C NMR
(150 MHz, CDCl3): δ = 198.5, 159.8, 158.4, 139.1, 132.4, 129.5, 127.4,
120.8, 119.3, 114.0, 112.3, 55.4, 55.3, 29.8, 29.308, 19.0. HRMS m/z:
calcd for C18H18O3 [M + H]+ 283.1329, found 283.1322.
(3-Chlorophenyl)-2-(4-methoxyphenyl)cyclopropylmethanone
(1l). 1H NMR (400 MHz, CDCl3): δ = 7.50 (dd, J = 7.5, 1.5 Hz, 1H),
7.38 (td, J = 7.2, 1.6 Hz, 1H), 7.38 (dd, J = 7.5, 1.5 Hz, 1H), 7.31
(td, J = 7.2, 1.6 Hz, 1H), 7.09 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz,
2H), 3.78 (s, 3H), 2.75 (ddd, J = 9.1, 6.9, 4.0 Hz, 1H), 2.67 (ddd, J = 8.1,
5.1, 4.1 Hz, 1H), 1.93 (ddd, J = 9.2, 5.1, 4.3 Hz, 1H) 1.55 (ddd, J = 7.8,
(4-Chlorophenyl)-2-(4-methoxyphenyl)cyclopropylmethanone
(1g). 1H NMR (400 MHz, CDCl3): δ = 7.91 (d, J = 8.6 Hz, 2H), 7.41
(d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H),
3.79 (s, 3H), 2.75 (ddd, J = 8.1, 5.1, 4.2 Hz, 1H), 2.65 (ddd, J = 8.9,
6.7, 4.0 Hz, 1H), 1.89 (ddd, J = 9.2, 5.0, 4.3 Hz, 1H), 1.52 (ddd, J =
7.9, 6.8, 4.2 Hz, 1H). 13C NMR (150 MHz, CDCl3): δ = 197.3, 158.4,
139.2, 136.0, 132.1, 129.4, 128.8, 127.3, 114.0, 55.3, 29.9, 29.2, 19.0.
HRMS m/z: calcd for C17H15ClO2 [M + H]+ 287.0834, found 287.0833.
(4-Bromophenyl)-2-(4-methoxyphenyl)cyclopropylmethanone
1
(1h). H NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 8.6 Hz, 2H),
H
DOI: 10.1021/acs.joc.6b00436
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The Journal of Organic Chemistry
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7.0, 4.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 201.5, 158.4, 139.9,
132.0, 131.7, 131.3, 130.4, 129.2, 127.34 126.9, 113.9, 55.3, 33.6, 31.1,
20.2. HRMS m/z: calcd for C17H15ClO2 [M + H]+ 287.0834, found
287.0836.
128.27, 128.23, 113.77, 113.54, 55.22, 32.53, 31.09, 18.24, 16.68. HRMS
m/z: calcd for C18H18O2 [M + H]+ 267.1385, found 267.1389.
2-(4-Methoxyphenyl)-3′,4′-dihydro-1′H-spiro(cyclopropane-1,2′-
naphthalen)-1′-one (1t). 1H NMR (400 MHz, CDCl3): δ = 8.03 (d, J =
7.2 Hz, 1H), 7.43 (td, J = 7.2, 1.2 Hz, 1H), 7.31 (t, J = 7.2 Hz, 1H), 7.17
(d, J = 7.2 Hz, 1H), 7.15 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H),
3.79 (s, 3H), 2.95 (dd, J = 8.5, 7.7 Hz, 1H), 2.78−2.65 (m, 2H), 1.89
(ddd, J = 13.8, 8.8, 4.6 Hz, 2H), 1.64 (ddd, J = 13.8, 6.4, 4.9 Hz, 1H), 1.31
(dd, J = 7.1, 4.2 Hz, 1H). 13C NMR (150 MHz, CDCl3): δ = 198.2,
158.4, 143.9, 133.0, 132.7, 130.1, 128.8, 128.4, 126.9, 126.5, 113.5, 55.1,
34.1, 34.0, 27.8, 26.4, 20.4. HRMS m/z: calcd for C19H18O2 [M + H]+
279.1385, found 279.1385.
General Procedure for the Synthesis of 1u. A mixture of
anethene (3.4 g, 23 mmol) and Rh2(OAc)4 (35.5 mg, 0.08 mmol) was
dispersed in dried DCM under N2 atmosphere, a solution of diazo-
acetate (2.7 mL, 23 mmol) was introduced via a pressure-compensated
dropping funnel over a period of 12 h, and then the reaction stood for
another 12 h. The mixture was then concentrated, and the residue was
directly purified by flash chromatography (petroleum ether/ethyl
acetate = 15:1) to afford the cyclopropane derivative as colorless oil in
65% yield.
To the mixed solution in MeOH (20 mL) and THF (10 mL) of the
cyclopropane derivative (3.5 g, 15 mmol) was added 10 mL of NaOH
(aqueous 3 M solution), and the mixture was refluxed for 3 h. The
mixture was then concentrated under vacuum to remove MeOH and
THF. The residue then acidified to pH 3 (with aqueous 1 M HCl
solution), extracted with ethyl acetate (3 × 20 mL), and washed with
brine. The combined organic layers were dried with MgSO4, filtered, and
concentrated in vacuum to give the crude carboxylic acid. The acid was
purified by flash chromatography (petroleum ether/EtOAc = 5:1) to
obtain cyclopropyl acid as white solid in 90% yield.
To the solution of cyclopropyl acid (2.8 g, 12.1 mmol) and cat. DMF
in DCM was introduced oxalyl chloride (1.85 g, 14.5 mmol) via syringe
slowly with vigorous stirring over 10 min at room temperature. The
resulting mixture was stirred for another 1 h, and then the solution and
excess oxalyl chloride was removed under vacuum to afford a yellow
residue, which was dissolved in another 30 mL of DCM, followed
by addition of N,O-dimethylhydroxylamine hydrochloride (1.77 g,
18.2 mmol) and pyridyl (3.8 g, 48 mmol). The reaction was quenched
with aqueous 1 M HCl solution to pH 7, extracted with ethyl acetate,
washed with brine, dried with MgSO4, filtered, and concentrated to give
the crude Weinreb formamide, which was purified by flash chro-
matography (petroleum ether/EtOAc = 5:1) to afford colorless oil in
85% yield.
2-(2-Methoxyphenyl)cyclopropylphenylmethanone (1m). 1H NMR
(400 MHz, CDCl3): δ = 8.04−7.99 (m, 2H), 7.54 (t, J = 7.6 Hz, 1H),
7.45 (t, J = 7.6 Hz, 2H), 7.22 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H),
6.92 (t, J = 7.6 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H), 3.77 (s, 3H), 2.86
(ddd, J = 8.8, 7.0, 4.2 Hz, 1H), 2.80 (ddd, J = 7.9, 5.1, 4.3 Hz, 1H), 1.89
(ddd, J = 9.0, 5.2, 4.0 Hz, 1H), 1.55 (ddd, J = 7.9, 7.0, 3.9 Hz, 1H).
13C NMR (100 MHz, CDCl3): δ = 199.3, 158.5, 138.1, 132.6, 128.7,
128.4, 128.1, 127.7, 126.2, 120.4, 110.3, 55.3, 27.8, 25.5, 17.3. HRMS
m/z: calcd for C17H16O2 [M + H]+ 253.1224, found 253.1222.
(2-Methoxyphenyl)cyclopropyl(4-methoxyphenyl)methanone
(1n). 1H NMR (400 MHz, CDCl3): δ = 8.01 (d, J = 8.9 Hz, 2H), 7.22
(t, J = 7.8 Hz, 1H), 7.05 (d, J = 7.8 Hz, 1H), 6.93 (d, J = 8.9 Hz, 2H),
6.92 (t, J = 7.8 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 3.87 (s, 3H), 3.77
(s, 3H), 2.83 (ddd, J = 8.8, 7.0, 4.3 Hz, 1H), 2.76 (ddd, J = 7.9, 5.2,
4.3 Hz, 1H), 1.86 (ddd, J = 9.0, 5.1, 4.0 Hz, 1H), 1.50 (ddd, J = 7.7, 7.0,
3.9 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 197.6, 163.2, 158.5,
131.1, 130.4, 129.0, 127.6, 126.2, 120.4, 113.6, 110.3, 55.4, 55.3,
27.4, 24.9, 17.1. HRMS m/z: calcd for C18H18O3 [M + H]+ 283.1329,
found 283.1334.
(4-Fluorophenyl)-2-(2-methoxyphenyl)cyclopropylmethanone
(1o). 1H NMR (400 MHz, CDCl3): δ = 8.04 (dd, J = 8.8, 5.5 Hz, 2H),
7.23 (t, J = 7.6 Hz, 1H), 7.12 (t, J = 8.8 Hz, 2H), 7.05 (d, J = 7.6 Hz, 1H),
6.92 (t, J = 7.6 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 3.77 (s, 3H), 2.83 (ddd,
J = 8.7, 7.2, 4.2 Hz, 1H), 2.74 (ddd, J = 7.9, 5.0, 4.2 Hz, 1H), 1.89
(ddd, J = 9.1, 5.1, 4.1 Hz, 1H), 1.56 (ddd, J = 7.7, 7.0, 4.0 Hz, 1H).
13C NMR (100 MHz, CDCl3): δ = 197.7, 165.6 (d, J = 253.9 Hz), 158.5,
134.4 (d, J = 3.0 Hz), 130.7 (d, J = 9.2 Hz), 128.6, 127.8, 126.3, 120.4,
115.5 (d, J = 21.8 Hz), 110.3, 55.3, 27.7, 25.6, 17.2. HRMS m/z: calcd for
C17H15FO2 [M + H]+ 271.1134, found 271.1139.
4-(Trifluoromethyl)phenyl-2-(2-methyloxyphenyl)-
1
cycloprylmethanone (1p). H NMR (400 MHz, CDCl3): δ = 8.10
(d, J = 8.2 Hz, 2H), 7.72 (d, J = 8.2 Hz, 2H), 7.25 (t, J = 7.6 Hz, 1H), 7.06
(d, J = 7.6 Hz, 1H), 6.93 (t, J = 7.6 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 3.78
(s, 3H), 2.86 (ddd, J = 8.7, 7.2, 4.2 Hz, 1H), 2.75 (ddd, J = 7.8, 5.0,
4.4 Hz, 1H), 1.94 (ddd, J = 9.1, 5.1, 4.1 Hz, 1H), 1.62 (ddd, J = 7.6, 7.2,
4.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 198.5, 158.5, 140.8
(d, J = 1.0 Hz), 133.9 (q, J = 32.6 Hz), 128.4, 128.3, 128.0, 126.4, 125.5
(q, J = 3.7 Hz), 123.7 (q, J = 272.6 Hz) 120.4, 110.3, 55.3, 28.2, 26.5,
17.4. HRMS m/z: calcd for C18H15F3O2 [M + H]+ 321.1097, found
321.1103.
(4-Fluorophenyl)[2-(2,5-dimethoxyphenyl)cyclopropyl]-
methanone (1q). 1H NMR (400 MHz, CDCl3): δ = 8.03 (dd, J = 8.8,
5.5 Hz, 2H), 7.12 (t, J = 8.6 Hz, 2H), 6.79 (d, J = 8.8 Hz, 1H), 6.74 (dd,
J = 8.8, 2.9 Hz, 1H), 6.61 (d, J = 2.9 Hz, 1H), 3.78 (s, 3H), 3.73 (s, 3H),
2.83 (ddd, J = 8.9, 7.0, 4.2 Hz, 1H), 2.75 (ddd, J = 8.0, 5.1, 4.4 Hz, 1H),
1.89 (ddd, J = 9.1, 5.1, 4.1 Hz, 1H), 1.53 (ddd, J = 7.6, 7.1, 4.0 Hz, 1H).
13C NMR (100 MHz, CDCl3): δ = 197.5, 165.6 (d, J = 254.0 Hz), 153.6,
152.7, 134.4 (d, J = 2.9 Hz), 130.7 (d, J = 9.2 Hz), 130.0, 115.5 (d, J =
21.8 Hz), 113.1, 111.4, 111.3, 56.0, 55.7, 27.9, 25.5, 17.4. HRMS m/z:
calcd for C18H17FO3 [M + H]+ 301.1240, found 301.1249.
[4-(Trifluoromethyl)phenyl)]-2-[(2,5-dimethyloxyphenyl)-
cyclopryl]methanone (1r). 1H NMR (400 MHz, CDCl3): δ = 8.10 (d,
J = 8.1 Hz, 2H), 7.72 (d, J = 8.1 Hz, 2H), 6.80 (d, J = 8.8 Hz, 1H), 6.75
(dd, J = 8.8, 2.6 Hz, 1H), 6.63 (s, 1H), 3.78 (s, 3H), 3.73 (s, 3H), 2.86
(ddd, J = 7.6, 6.2, 3.5 Hz, 1H), 2.77 (ddd, J = 12.0, 5.9, 3.4 Hz, 1H), 1.93
(ddd, J = 9.1, 5.4, 1.4 Hz, 1H), 1.60 (ddd, J = 7.7, 5.0, 1.7 Hz, 1H).
13C NMR (100 MHz, CDCl3): δ = 198.3, 153.6, 152.7, 140.7 (d, J =
0.8 Hz), 134.0 (q, J = 32.6 Hz), 129.6, 128.4, 125.5 (q, J = 4.0 Hz), 123.7
(q, J = 272.5 Hz), 113.3, 111.5, 111.3, 55.9, 55.7, 28.4, 26.3, 17.6. HRMS
m/z: calcd for C19H17F3O3 [M + H]+ 351.1208, found 351.1208.
(2-(4-Methoxyphenyl)-1-methylcyclopropyl)(phenyl)methanone
(1s). 1H NMR (400 MHz, chloroform-d) δ 7.82−7.70 (m, 2H), 7.53−
7.47 (m, 1H), 7.48−7.40 (m, 2H), 7.24−7.15 (m, 2H), 6.96−6.88
(m, 2H), 3.82 (s, 3H), 2.62 (dd, J = 9.2, 6.9 Hz, 1H), 1.98 (dd, J = 9.2,
4.8 Hz, 1H), 1.20 (dd, J = 6.9, 4.8 Hz, 1H), 1.15 (s, 3H). 13C NMR
(150 MHz, CDCl3) δ 203.82, 158.41, 137.48, 131.64, 129.89, 128.68,
Phenylmagnesium bromide (1.0 M in THF, 6.0 mmol) was added
via syringe dropwise to the solution of the Weinreb formamide (1.0 g,
4.0 mmol) in THF under N2 atmosphere at room temperature, and the
reaction was stirred for an additional 4 h, quenched with sat. aq NH4Cl,
and extracted with ethyl acetate. The combined organic layers were
washed with sat. aq. NH4Cl and brine, dried (MgSO4), and concentrated
to give crude product that was subjected to chromatography on a short
silica column (petroleum ether/EtOAc = 15:1) to obtain 1u in 95%
yield.
(2-(4-Methoxyphenyl)-3-methylcyclopropyl)(phenyl)methanone
(1u). 1H NMR (600 MHz, CDCl3): δ = 8.07−7.98 (m, 2H), 7.60−7.54
(m, 1H), 7.51−7.42 (m, 2H), 7.15−7.07 (m, 2H), 6.88−6.80 (m, 2H),
3.79 (s, 3H), 2.92 (dd, J = 9.2, 5.0 Hz, 1H), 2.78 (dd, J = 6.7, 5.0 Hz, 1H),
2.00 (dp, J = 9.2, 6.3 Hz, 1H), 1.28 (d, J = 6.2 Hz, 3H). 13C NMR
(150 MHz, CDCl3): δ = 197.56, 158.14, 138.77, 132.91, 132.62, 128.48,
128.00, 127.38, 113.88, 77.21, 77.00, 76.79, 55.31, 34.49, 32.44, 28.61,
11.63. HRMS m/z: calcd for C18H18O2 [M + H]+ 267.1385, found
267.1391.
General Procedure for the Synthesis of 1w. Cyclopropyl alcohol
was prepared according to literature. To a solution of cyclopropyl
alcohol in DCM was added PCC (1.5 equiv) at room temperature under
N2. After complete conversion in about 1.5 h, Celite was added followed
by petroleum ether, and then the mixture was filtered and concentrated
in vacuo. The residue was purified on short silica column to afford
the target compound. To a solution of the aldehyde in dry THF was
added PhMgBr solution (1.0 M in THF, 1.3 equiv) dropwise at 0 °C.
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After stirring at room temperature for 5 h, the reaction then quenched
with sat. aq. NH4Cl and extracted with EtOAc. The organic layer was
washed with brine, dried over MgSO4, and concentrated in vacuo. The
residue was purified by column chromatography to give the desired
benzyl alcohol, which could be oxidated smoothly to 1w by PCC
yielding a white solid.
34.85, 31.41, 29.18, 14.03. HRMS m/z: calcd for C20H19FO4 [M + H]+
343.1340, found 343.1345.
Ethyl-2-(4-chlorobenzoyl)-3-(4-methoxyphenyl)cyclopropane-1-
carboxylate (6f). 1H NMR (600 MHz, CDCl3): δ = 7.96 (d, J = 8.5 Hz,
2H), 7.44 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 8.6 Hz, 2H), 6.87 (d, J =
8.6 Hz, 2H), 4.09 (q, J = 7.1 Hz, 2H), 3.80 (s, 3H), 3.30 (t, J = 6.2 Hz,
1H), 2.97 (dd, J = 9.4, 6.4 Hz, 1H), 2.58 (dd, J = 9.4, 6.0 Hz, 1H), 1.15
(t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3): δ = 192.63, 169.13,
158.78, 139.65, 135.23, 129.71, 129.69, 128.90, 127.65, 114.11, 61.09,
55.29, 34.81, 31.47, 29.22, 14.02. HRMS m/z: calcd for C20H19ClO4
[M + H]+ 359.1045, found 359.1042.
Ethyl-2-(4-methoxyphenyl)-3-(4-(trifluoromethyl)benzoyl)-
cyclopropane-1-carboxylate (6g). 1H NMR (600 MHz, CDCl3):
δ = 8.12 (d, J = 8.1 Hz, 2H), 7.74 (d, J = 8.2 Hz, 2H), 7.19−7.13 (m, 2H),
6.92−6.86 (m, 2H), 4.09 (q, J = 7.1 Hz, 2H), 3.81 (s, 3H), 3.33 (t, J =
6.2 Hz, 1H), 3.00 (dd, J = 9.4, 6.4 Hz, 1H), 2.63 (dd, J = 9.4, 6.0 Hz, 1H),
1.15 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3): δ = 193.05,
169.07, 158.88, 139.57, 134.50 (q, J = 32.6 Hz), 129.52, 128.63, 127.69,
125.73 (q, J = 3.5 Hz), 123.58 (q, J = 272.8 Hz), 114.18, 61.22,
55.33, 34.95, 31.66, 29.46, 14.03. HRMS m/z: calcd for C21H19F3O4
[M + H]+ 393.1308, found 393.1306.
Ethyl-2-(3-chlorobenzoyl)-3-(4-methoxyphenyl)cyclopropane-1-
carboxylate (6h). 1H NMR (400 MHz, CDCl3): δ = 7.63−7.56
(m, 1H), 7.43−7.36 (m, 2H), 7.32 (ddd, J = 7.6, 5.7, 2.9 Hz, 1H), 7.14−
7.08 (m, 2H), 6.88−6.82 (m, 2H), 4.18 (qd, J = 7.1, 4.2 Hz, 2H), 3.78
(s, 3H), 3.36 (t, J = 6.4 Hz, 1H), 3.04 (dd, J = 9.4, 6.1 Hz, 1H), 2.61 (dd,
J = 9.4, 6.5 Hz, 1H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz,
CDCl3): δ = 196.71, 168.72, 158.67, 138.74, 132.08, 131.52, 130.39,
129.92, 129.86, 129.67, 127.57, 127.49, 126.85, 113.97, 61.11, 55.21,
37.88, 33.64, 31.27, 14.10. HRMS m/z: calcd for C20H19ClO4 [M + H]+
359.1045, found 359.1050.
Ethyl-2-acetyl-3-(4-methoxyphenyl)cyclopropane-1-carboxylate
(6i). 1H NMR (400 MHz, CDCl3): δ = 7.09−7.03 (m, 2H), 6.87−6.81
(m, 2H), 4.17 (q, J = 7.2 Hz, 2H), 3.79 (s, 3H), 3.14 (t, J = 6.2 Hz, 1H),
2.48 (dd, J = 9.5, 6.3 Hz, 1H), 2.39 (dd, J = 9.5, 6.3 Hz, 1H), 2.32
(s, 3H), 1.27 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3):
δ = 202.78, 169.09, 158.68, 129.88, 129.81, 127.66, 127.51, 114.01,
61.14, 55.28, 37.66, 31.83, 30.82, 29.69, 14.11. HRMS m/z: calcd for
C15H18O4 [M + H]+ 263.1283, found 263.1279.
(E)-Ethyl-2-(4-methoxyphenyl)-3-pivaloylcyclopropane-1-carbox-
ylate (6j). 1H NMR (600 MHz, CDCl3): δ = 7.13−7.04 (m, 2H), 6.91−
6.81 (m, 2H), 4.23−4.11 (m, 2H), 3.79 (s, 3H), 3.13 (t, J = 6.2 Hz, 1H),
2.65 (dd, J = 9.4, 6.0 Hz, 1H), 2.43 (dd, J = 9.4, 6.5 Hz, 1H), 1.26 (t, J =
7.1 Hz, 3H), 1.20 (s, 9H). 13C NMR (150 MHz, CDCl3): δ = 209.26,
168.94, 158.62, 130.19, 127.63, 114.01, 60.99, 55.28, 44.27, 33.01, 32.16,
30.91, 29.51, 26.23, 14.16. HRMS m/z: calcd for C18H24O4 [M + H]+
305.1747, found 305.1755.
(Z)-Ethyl-2-(4-methoxyphenyl)-3-pivaloylcyclopropane-1-carbox-
ylate (6j′). 1H NMR (400 MHz, CDCl3): δ = 7.16 (d, J = 8.2 Hz, 2H),
6.82 (d, J = 8.2 Hz, 2H), 3.97 (q, J = 7.1 Hz, 2H), 3.78 (s, 3H), 3.27 (t, J =
5.5 Hz, 1H), 2.91 (dd, J = 9.8, 6.2 Hz, 1H), 2.56 (dd, J = 9.9, 4.7 Hz, 1H),
1.28 (s, 9H), 1.08 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3):
δ = 211.93, 168.91, 158.69, 129.86, 126.77, 113.62, 60.78, 55.22, 44.39,
34.21, 31.64, 28.62, 26.08, 14.11. HRMS m/z: calcd for C18H24O4
[M + H]+ 305.1747, found 305.1755.
Ethyl-2-(4-methoxyphenyl)-4-oxospiro[2.5]octane-1-carboxylate
(6k). 1H NMR (600 MHz, CDCl3): δ = 7.04 (d, J = 8.4 Hz, 2H), 6.78 (d,
J = 8.3 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H), 3.76 (s, 3H), 3.31 (d, J = 6.8 Hz,
1H), 2.91 (d, J = 6.8 Hz, 1H), 2.30 (dd, J = 14.8, 1.9 Hz, 1H), 2.23
(dd, J = 7.8, 2.8 Hz, 1H), 2.03 (ddd, J = 15.3, 7.4, 3.4 Hz, 2H), 1.90−1.81
(m, 2H), 1.78−1.68 (m, 1H), 1.65 (td, J = 14.2, 5.8 Hz, 1H), 1.29
(t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3): δ = 205.91, 169.81,
158.50, 129.78, 126.75, 113.63, 60.87, 55.15, 43.73, 41.53, 33.94, 32.35,
31.65, 26.21, 23.80, 14.12. HRMS m/z: calcd for C18H22O4 [M + H]+
303.1591, found 303.1598.
General Procedure for the Synthesis of 2,5-Diarylfurans
4a−4v. The mixture of ((2-aryl)cyclopropyl)(aryl)methanone
(1, 50 mg), 2 (0.5 equiv), LiBr (1.0 equiv), and photocatalyst 3
(1 mol %) in 4 mL of dry CH3CN was stirred under irradiation with a
100 cm blue LED round strip at room temperature. Upon completion of
the reaction (monitored via TLC), it was quenched by saturated
2-(2-(4-Methoxyphenyl)cyclopropyl)-1-phenylethan-1-one (1w).
1H NMR (400 MHz, chloroform-d) δ 8.03−7.92 (m, 2H), 7.61−7.53
(m, 1H), 7.47 (dd, J = 8.3, 6.9 Hz, 2H), 7.09−7.00 (m, 2H), 6.85−6.77
(m, 2H), 3.77 (s, 3H), 3.14 (dd, J = 16.5, 6.5 Hz, 1H), 2.98 (dd, J = 16.5,
7.0 Hz, 1H), 1.76 (dt, J = 9.3, 5.0 Hz, 1H), 1.48−1.38 (m, 1H), 0.99
(dt, J = 8.5, 5.2 Hz, 1H), 0.84 (dt, J = 8.7, 5.3 Hz, 1H). 13C NMR
(150 MHz, CDCl3) δ 199.43, 157.69, 136.82, 134.65, 133.05, 128.62,
128.14, 127.26, 113.73, 55.30, 43.41, 22.31, 17.79, 14.93. HRMS m/z:
calcd for C18H19O2 [M + H]+ 267.1385, found 267.1371.
General Procedure for the Synthesis of 6a−6k.23 Taking
substrate 6a as an example, a solution of chalcone (2.0 g, 8.4 mmol) and
ethyl (dimethylsulfuranylidene)acetate (1.87 g, 13 mmol) in DCM was
held overnight at 50 °C. The mixture was concentrated and eluted
through a silica gel (petroleum ether/EtOAc = 5:1) to give a mixture of
diastereoisomers, separated by flash chromatography (petroleum ether/
EtOAc = 20:1 to 5:1), and recrystallized from ethyl acetate/hexanes to
give the desired cyclopropane derivative.
Ethyl-2-benzoyl-3-(4-methoxyphenyl)cyclopropane-1-carboxy-
late (6a). 1H NMR (600 MHz, CDCl3): δ = 8.02 (d, J = 7.3 Hz, 2H),
7.56 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.18−7.13 (m, 2H),
6.90−6.84 (m, 2H), 4.08 (q, J = 7.1 Hz, 2H), 3.80 (s, 3H), 3.32
(t, J = 6.2 Hz, 1H), 3.03 (dd, J = 9.5, 6.4 Hz, 1H), 2.58 (dd, J = 9.5,
6.0 Hz, 1H), 1.14 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3):
δ = 193.81, 169.24, 158.71, 136.90, 133.20, 129.97, 128.55, 128.30,
127.67, 114.07, 60.99, 55.27, 34.94, 31.48, 29.18, 13.99. HRMS m/z:
calcd for C20H20O4 [M + H]+ 325.1434, found 325.1435.
Ethyl-2-(4-methoxyphenyl)-3-(4-methylbenzoyl)cyclopropane-1-
carboxylate (6b). 1H NMR (600 MHz, CDCl3): δ = 7.92 (d, J = 8.1 Hz,
2H), 7.25 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.6 Hz, 2H), 6.87 (d, J =
8.6 Hz, 2H), 4.08 (q, J = 7.1 Hz, 2H), 3.79 (s, 3H), 3.30 (t, J = 6.2 Hz,
1H), 3.01 (dd, J = 9.5, 6.5 Hz, 1H), 2.56 (dd, J = 9.5, 6.0 Hz, 1H), 2.40
(s, 3H), 1.14 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3):
δ = 193.39, 169.34, 158.69, 144.04, 134.48, 130.13, 129.38, 129.25,
128.56, 128.45, 127.69, 114.07, 60.97, 55.30, 34.95, 31.41, 29.11, 21.66,
14.02. HRMS m/z: calcd for C21H22O4 [M + H]+ 339.1591, found
339.1595.
Ethyl-2-(4-methoxybenzoyl)-3-(4-methoxyphenyl)cyclopropane-
1
1-carboxylate (6c). H NMR (600 MHz, CDCl3): δ = 8.03−7.98
(m, 2H), 7.17−7.13 (m, 2H), 6.95−6.90 (m, 2H), 6.88−6.84 (m, 2H),
4.08 (q, J = 7.1 Hz, 2H), 3.85 (d, J = 1.5 Hz, 3H), 3.79 (d, J = 1.5 Hz,
3H), 3.29 (t, J = 6.2 Hz, 1H), 2.99 (dd, J = 9.5, 6.5 Hz, 1H), 2.54
(dd, J = 9.5, 5.9 Hz, 1H), 1.14 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz,
CDCl3): δ = 192.21, 169.41, 163.57, 158.67, 130.63, 130.19, 130.05,
127.68, 114.06, 113.72, 60.96, 55.45, 55.30, 34.88, 31.27, 29.02, 14.04.
HRMS m/z: calcd for C21H22O5 [M + H]+ 355.1540, found 355.1541.
Ethyl-2-(1-naphthoyl)-3-(4-methoxyphenyl)cyclopropane-1-car-
boxylate (6d). 1H NMR (600 MHz, CDCl3): δ = 8.71 (d, J = 8.6 Hz,
1H), 8.05 (dd, J = 7.2, 1.0 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.87 (d, J =
8.1 Hz, 1H), 7.59 (ddd, J = 8.5, 6.9, 1.3 Hz, 1H), 7.53 (ddd, J = 8.0, 6.9,
1.1 Hz, 1H), 7.50 (dd, J = 8.0, 7.4 Hz, 1H), 7.18−7.14 (m, 2H), 6.89−
6.86 (m, 2H), 4.18−4.11 (m, 2H), 3.80 (s, 3H), 3.44 (t, J = 6.2 Hz, 1H),
3.10 (dd, J = 9.5, 6.2 Hz, 1H), 2.66 (dd, J = 9.5, 6.3 Hz, 1H), 1.19 (t, J =
7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3): δ = 197.45, 169.06, 158.75,
135.54, 133.86, 133.04, 130.23, 129.97, 128.63, 128.33, 128.01, 127.64,
126.48, 125.92, 124.34, 114.12, 61.18, 55.33, 37.75, 32.95, 30.38, 14.12.
HRMS m/z: calcd for C24H22O4 [M + H]+ 375.1591 found 375.1599
Ethyl-2-(4-fluorobenzoyl)-3-(4-methoxyphenyl)cyclopropane-1-
1
carboxylate (6e). H NMR (600 MHz, CDCl3): δ = 8.09−8.03 (m,
2H), 7.19−7.10 (m, 4H), 6.92−6.85 (m, 2H), 4.09 (q, J = 7.1 Hz, 2H),
3.80 (s, 3H), 3.31 (t, J = 6.2 Hz, 1H), 2.98 (dd, J = 9.4, 6.4 Hz, 1H), 2.58
(dd, J = 9.5, 6.0 Hz, 1H), 1.15 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz,
CDCl3): δ = 192.23, 169.20, 166.63, 164.94, 158.77, 133.37, 133.35,
130.98, 130.92, 129.80, 127.66, 115.79, 115.64, 114.12, 61.08, 55.30,
J
DOI: 10.1021/acs.joc.6b00436
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Na2CO3 (5 mL) and then extracted with EtOAc (3 × 5 mL). The
combined organic layers were washed with brine (2 × 5 mL), dried over
MgSO4, and concentrated. The residue was purified by flash column
chromatography (petroleum ether/ethyl acetate = 50:1) to afford the
title compound 4.
1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 8.2 Hz, 2H), 7.70−7.65
(m, 2H), 7.62 (d, J = 8.3 Hz, 2H), 6.98−6.91 (m, 2H), 6.81 (d, J =
3.5 Hz, 1H), 6.61 (d, J = 3.5 Hz, 1H), 3.84 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ = 159.45, 154.58, 151.12, 133.97, 133.96, 129.03, 128.71,
128.38, 128.28, 128.06, 125.74, 125.70, 125.67, 125.63, 125.58, 125.42,
123.42, 123.40, 122.88, 120.18, 114.26, 109.26, 105.86, 55.33. GC-MS
(EI) m/z: 318, 303, 275, 178, 159, 145, 102, 75.
2-(4-Methoxyphenyl)-5-phenylfuran (4a).24 Yield 36 mg, 72%
1
(12 h) as white solid, mp = 115.2−116.1 °C. H NMR (400 MHz,
CDCl3): δ = 7.72 (d, J = 7.9 Hz, 2H), 7.70−7.65 (m, 2H), 7.39 (t, J =
7.7 Hz, 2H), 7.27−7.22 (m, 1H), 6.96−6.91 (m, 2H), 6.71 (d, J = 3.4 Hz,
1H), 6.59 (d, J = 3.4 Hz, 1H), 3.83 (s, 3H). 13C NMR (100 MHz,
CDCl3):δ = 159.08, 153.44, 152.67, 130.90, 128.65, 127.06, 125.17,
123.89, 123.53, 114.17, 107.17, 105.63, 55.31. GC-MS (EI) m/z: 250,
235, 207, 178, 125, 77.
2-(4-Methoxyphenyl)-5-(4-nitrophenyl)furan (4j). Yield 38 mg,
77% (16 h) as orange solid, mp = 168.0−170.0 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.25 (d, J = 8.8 Hz, 2H), 7.82 (d, J = 8.8 Hz, 2H), 7.70
(d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 3.5 Hz, 1H),
6.67 (d, J = 3.5 Hz, 1H), 3.87 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ = 159.8, 155.8, 150.3, 146.0, 136.4, 125.7, 124.4, 123.4, 123.0, 114.3,
111.5, 106.4, 55.4. GC-MS (EI) m/z: 295, 280, 265, 249, 234, 206,
178, 76.
5-(4-Methoxyphenyl)-2-(4-tolyl)furan (4b).25 Yield 34 mg, 68%
1
(5 h) as white solid, mp = 150.3−152.1 °C. H NMR (400 MHz,
CDCl3): δ = 7.68−7.64 (m, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.19 (d, J =
8.0 Hz, 2H), 6.96−6.90 (m, 2H), 6.64 (d, J = 3.4 Hz, 1H), 6.58
(d, J = 3.4 Hz, 1H), 3.83 (s, 3H), 2.36 (s, 3H). 13C NMR (150 MHz,
CDCl3): δ = 158.93, 153.01, 152.90, 136.90, 129.33, 128.21, 125.07,
123.97, 123.50, 114.12, 106.42, 105.56, 55.30, 21.27. GC-MS (EI) m/z:
264, 249, 221, 178, 132, 91.
2-(3-Methoxyphenyl)-5-(4-methoxyphenyl)furan (4k). Yield 41 mg,
83% (20 h) as white solid, mp = 123.8−124.8 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.69−7.64 (m, 2H), 7.34−7.29 (m, 2H), 7.28−7.26
(m, 1H), 6.96−6.91 (m, 2H), 6.80 (dt, J = 6.2, 2.6 Hz, 1H), 6.70
(d, J = 3.4 Hz, 1H), 6.59 (d, J = 3.4 Hz, 1H), 3.86 (s, 3H), 3.83 (s, 3H).
13C NMR (100 MHz, CDCl3): δ = 159.9, 159.1, 153.5, 152.5, 132.2,
129.7, 125.2, 123.8, 116.2, 114.2, 112.6, 109.1, 107.5, 105.6, 55.3, 55.3.
GC-MS (EI) m/z: 280, 265, 237, 222, 194, 165, 135, 77. Anal. Calcd for
C18H16O3: C, 77.12; H, 5.75. Found: C, 76.95; H, 5.91.
2,5-Bis(4-methoxyphenyl)furan (4c).25 Yield 43 mg, 87% (21 h)
1
as white solid, mp = 197.0−198.0.°C. H NMR (400 MHz, CDCl3):
δ = 7.68−7.63 (m, 4H), 6.96−6.91 (m, 4H), 6.57 (s, 2H), 3.84 (s, 6H).
13C NMR (150 MHz, CDCl3): δ = 158.86, 152.75, 124.98, 124.03,
114.12, 105.56, 55.31. GC-MS (EI) m/z: 280, 265, 250, 222, 194,
165, 140.
2-(3-Chlorophenyl)-5-(4-methoxyphenyl)furan (4l). Yield 41 mg,
1
82% (20 h) as white solid, mp = 86.0−86.6 °C. H NMR (400 MHz,
CDCl3): δ = 7.96 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.43
(d, J = 8.0 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.20 (d, J = 3.5 Hz, 1H), 7.17
(t, J = 7.6 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.65 (d, J = 3.5 Hz, 1H), 3.84
(s, 3H). 13C NMR (100 MHz, CDCl3): δ = 159.3, 153.5, 148.9, 130.8,
129.8, 129.2, 127.6, 127.5, 126.8, 125.4, 123.6, 114.2, 113.2, 105.7, 55.3.
GC-MS (EI) m/z: 286, 284(1:3), 271, 269(1:3), 243, 241, 243, 205,
178. Anal. Calcd for C17H13ClO2: C, 71.71; H, 4.60. Found: C, 71.57;
H, 4.83.
2-(4-tert-Butyl phenyl)-5-(4-methoxyphenyl)furan (4d). Yield
1
37 mg, 73% (10 h) as white solid, mp = 129.7−130.6 °C. H NMR
(400 MHz, CDCl3): δ = 7.69−7.64 (m, 4H), 7.44−7.40 (m, 2H), 6.96−
6.92 (m, 2H), 6.66 (d, J = 3.4 Hz, 1H), 6.58 (d, J = 3.4 Hz, 1H), 3.84
(s, 3H), 1.34 (s, 9H). 13C NMR (150 MHz, CDCl3): δ = 158.9, 153.1,
152.9, 150.2, 128.2, 125.6, 125.1, 124.0, 123.4, 114.1, 106.6, 105.6, 55.3,
34.6, 31.3. GC-MS (EI) m/z: 306, 291, 276, 261, 250, 235, 145, 131, 77.
Anal. Calcd for C21H22O2: C, 82.32; H, 7.24. Found: C, 82.15; H, 7.43.
2-(4-Methoxyphenyl)-5-naphylfuran (4e). Yield 35 mg, 70% (7 h)
as pale yellow solid, mp = 92.3−92.7 °C. 1H NMR (400 MHz, CDCl3):
δ = 8.52 (d, J = 8.1 Hz, 1H), 7.91−7.87 (m, 1H), 7.82 (t, J = 7.8 Hz, 2H),
7.74−7.69 (m, 2H), 7.58−7.50 (m, 3H), 6.98−6.94 (m, 2H), 6.80 (d, J =
3.4 Hz, 1H), 6.71 (d, J = 3.4 Hz, 1H), 3.85 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ = 159.1, 153.9, 152.3, 134.0, 128.6, 128.5, 128.3, 126.5, 125.9,
125.8, 125.6, 125.4, 125.2, 123.9, 114.2, 111.4, 105.4, 55.3. GC-MS (EI)
m/z: 300, 285, 257, 288, 202, 150, 127, 77. Anal. Calcd for C21H16O2: C,
83.98; H, 5.37. Found: C, 83.85; H, 5.64.
2-(2-Methoxyphenyl)-5-phenylfuran (4m). Yield 37 mg, 74% (24 h)
1
as white solid, mp = 84.5−86.4 °C. H NMR (400 MHz, CDCl3):
δ = 7.99 (dd, J = 7.7, 1.4 Hz, 1H), 7.76 (d, J = 7.5 Hz, 2H), 7.40 (t, J =
8.0 Hz, 2H), 7.28−7.22 (m, 2H), 7.06 (t, J = 8.0 Hz, 1H), 7.03 (d, J =
3.4 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 6.76 (d, J = 3.4 Hz, 1H), 3.96
(s, 3H). 13C NMR (100 MHz, CDCl3): δ = 155.5, 152.3, 149.8, 130.9,
128.7, 128.0, 127.2, 125.8, 123.7, 120.8, 119.8, 112.2, 111.0, 107.4, 55.4.
GC-MS (EI) m/z: 250, 207, 178, 145, 125, 115, 105, 77. Anal. Calcd for
C17H14O2: C, 81.58; H, 5.64. Found: C, 81.49; H, 5.85.
2-(2-Methoxyphenyl)-5-(4-methoxyphenyl)furan (4n). Yield 37 mg,
75% (24 h) as white solid, mp = 107.5−108.9 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.96 (dd, J = 7.7, 1.6 Hz, 1H), 7.69 (d, J = 8.9 Hz, 2H),
7.26−7.20 (m, 1H), 7.04 (td, J = 7.7, 0.9 Hz, 1H), 7.00 (d, J = 3.4 Hz,
1H), 6.95 (t, J = 8.8 Hz, 3H), 6.62 (d, J = 3.4 Hz, 1H), 3.95 (s, 3H), 3.84
(s, 3H). 13C NMR (100 MHz, CDCl3): δ = 159.0, 155.3, 152.4, 149.1,
127.7, 125.6, 125.2, 124.1, 120.7, 119.9, 114.1, 112.2, 110.9, 105.8, 55.3,
55.3. GC-MS (EI) m/z: 280, 265, 237, 222, 194, 135, 77. Anal. Calcd for
C18H16O3: C, 77.12; H, 5.75. Found: C, 77.02; H, 5.81.
2-(4-Fluorophenyl)-5-(4-methoxyphenyl)furan (4f).25 Yield 38 mg,
77% (20 h) as white solid, mp = 133.3−134.5 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.71−7.64 (m, 4H), 7.12−7.05 (m, 2H), 6.96−6.92
(m, 2H), 6.64 (d, J = 3.4 Hz, 1H), 6.58 (d, J = 3.4 Hz, 1H), 3.85 (s, 3H).
13C NMR (150 MHz, CDCl3): δ = 162.78, 161.14, 159.08, 153.44,
151.81, 127.28, 127.26, 125.25, 125.20, 125.14, 123.75, 115.76, 115.61,
114.17, 106.81, 105.62, 55.35, 55.31. GC-MS (EI) m/z: 268, 225, 196,
145, 133, 123, 95, 75.
2-(4-Chlorophenyl)-5-(4-methoxyphenyl)furan (4g).25 Yield
2-(4-Fluorophenyl)-5-(2-methoxyphenyl)furan (4o). Yield 34 mg,
1
1
69% (24 h) as white solid, mp = 94.9−96.5 °C. H NMR (400 MHz,
42 mg, 84% (30 h) as white solid, mp = 171.5−172.0 °C. H NMR
CDCl3): δ = 7.95 (d, J = 7.7 Hz, 1H), 7.71 (dd, J = 8.8, 5.4 Hz, 2H),
7.28−7.22 (m, 1H), 7.10 (d, J = 8.7 Hz, 2H), 7.07−7.03 (m, 1H), 7.01
(d, J = 3.4 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 6.68 (d, J = 3.4 Hz, 1H),
3.95 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 162.0 (d, J = 246.9 Hz),
155.5, 151.4, 149.8, 128.0, 127.3 (d, J = 3.3 Hz), 125.7, 125.5 (d, J =
8.0 Hz), 120.8, 119.7, 115.71 (d, J = 21.9 Hz), 112.2, 111.0, 107.01
(d, J = 1.3 Hz), 55.4. 19F NMR (376 MHz, CDCl3) δ −114.46. GC-MS
(EI) m/z: 268, 225, 196, 145, 133, 95, 75. Anal. Calcd for C17H13FO2: C,
76.11; H, 4.88. Found: C, 75.73; H, 5.09.
2-(4-Trifluoromethylphenyl)-5-(2-methoxyphenyl)furan (4p).
Yield 35 mg, 70% (24 h) as white solid, mp = 96.7−98.3 °C.
1H NMR (400 MHz, CDCl3): δ = 7.97 (dd, J = 7.8, 1.6 Hz, 1H), 7.82 (d,
J = 8.1 Hz, 2H), 7.63 (d, J = 8.3 Hz, 2H), 7.30−7.25 (m, 1H), 7.09−7.04
(m, 2H), 6.98 (d, J = 8.3 Hz, 1H), 6.86 (d, J = 3.5 Hz, 1H), 3.96 (s, 3H).
13C NMR (100 MHz, CDCl3): δ = 155.7, 150.9, 150.7, 134., 128.6 (q, J =
32.4 Hz), 128.5, 126.0, 125.7 (q, J = 3.9 Hz), 124.2 (q, J = 271.7 Hz).
(400 MHz, CDCl3): δ = 7.68−7.62 (m, 4H), 7.38−7.33 (m, 2H), 6.96−
6.92 (m, 2H), 6.69 (d, J = 3.5 Hz, 1H), 6.59 (d, J = 3.5 Hz, 1H), 3.85
(s, 3H). 13C NMR (150 MHz, CDCl3): δ = 159.18, 153.75, 151.56,
132.59, 129.36, 128.86, 125.22, 124.69, 123.62, 114.18, 107.66, 105.71,
55.33. GC-MS (EI) m/z: 286, 284(1:3), 271, 269(1:3), 241, 178, 142,
111, 102, 75.
2-(4-Bromophenyl)-5-(4-methoxyphenyl)furan (4h).26 Yield
1
40.5 mg, 81% (30 h) as white solid, mp = 193.0−194.0 °C. H NMR
(400 MHz, CDCl3): δ = 7.69−7.64 (m, 2H), 7.61−7.56 (m, 2H),
7.54−7.47 (m, 2H), 6.98−6.92 (m, 2H), 6.72 (d, J = 3.5 Hz, 1H), 6.60
(d, J = 3.5 Hz, 1H), 3.85 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ = 159.3, 153.9, 151.6, 131.8, 129.8, 125.3, 125.0, 123.6, 120.7, 114.2,
107.8, 105.7, 55.3. GC-MS (EI) m/z: 330, 328(1:1), 315, 313(1:1), 205,
178, 165, 76.
2-(4-Trifluoromethylphenyl)-5-(4-methoxyphenyl)furan (4i).27
Yield 38 mg, 75% (20 h) as white solid, mp = 163.4−164.2 °C.
K
DOI: 10.1021/acs.joc.6b00436
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
123.6, 120.8, 119.4, 112.4, 111.1, 109.4, 55.4. 19F NMR (376 MHz,
CDCl3) δ −62.35. GC-MS (EI) m/z: 318, 299, 275, 178, 159, 145, 115,
77. Anal. Calcd for C18H13F3O2: C, 67.92; H, 4.12. Found: C, 67.79;
H, 4.45.
3-Bromo-2-(4-methoxyphenyl)-5-phenylfuran (5a). Yield 35 mg,
54% (52 h) as white solid, mp = 74.5−76.0 °C. H NMR (600 MHz,
1
CDCl3): δ = 8.01−7.95 (m, 2H), 7.68 (d, J = 7.7 Hz, 2H), 7.40 (t, J =
7.7 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H), 7.00−6.95 (m, 2H), 6.75
(s, 1H), 3.85 (s, 3H). 13C NMR (150 MHz, CDCl3): δ = 159.33, 151.98,
148.22, 129.78, 128.76, 127.86, 127.00, 123.67, 122.60, 113.94, 111.12,
96.35, 77.21, 77.00, 76.79, 55.31. GC-MS (EI) m/z: 330, 328(1:1), 315,
313(1:1), 287, 285(1:1), 221, 178, 165, 105, 77.
2-(4-Fluorophenyl)-5-(2,5-dimethoxyphenyl)furan (4q). Yield 36 mg,
73% (20 h) as white solid, mp = 102.9−104.2 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.72−7.66 (m, 2H), 7.50 (d, J = 3.0 Hz, 1H), 7.07 (t, J =
8.7 Hz, 2H), 7.03 (d, J = 3.5 Hz, 1H), 6.87 (d, J = 8.9 Hz, 1H), 6.77
(dd, J = 8.9, 3.1 Hz, 1H), 6.66 (d, J = 3.5 Hz, 1H), 3.88 (s, 3H), 3.84
(s, 3H). 13C NMR (100 MHz, CDCl3): δ = 162.1 (d, J = 246.9 Hz),
153.7, 151.5, 150.0, 149.5, 127.2 (d, J = 3.3 Hz), 125.5 (d, J = 8.0 Hz),
120.3, 115.73 (d, J = 21.9 Hz), 112.7, 112.6, 112.1, 111.4, 107.8
(d, J = 1.3 Hz), 55.8, 55.8. 19F NMR (376 MHz, CDCl3) δ −114.36.
GC-MS (EI) m/z: 298, 283, 255, 240, 212, 186, 149, 123, 75. Anal.
Calcd for C18H15FO3: C, 72.47; H, 5.07. Found: C, 72.33; H, 5.24.
2-(4-Trifluoromethylphenyl)-5-(2,5-dimethoxyphenyl)furan (4r).
Yield 35 mg, 70% (24 h) as white solid, mp = 107.0−107.9 °C.
1H NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 8.1 Hz, 2H), 7.64 (d, J =
8.1 Hz, 2H), 7.52 (d, J = 3.0 Hz, 1H), 7.08 (d, J = 3.6 Hz, 1H), 6.91
(d, J = 8.9 Hz, 1H), 6.87 (d, J = 3.6 Hz, 1H), 6.82 (dd, J = 8.9, 3.0 Hz,
1H), 3.92 (s, 3H), 3.87 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ = 153.7, 150.8, 150.7, 150.2, 133.9 (d, J = 1.3 Hz), 128.7 (q, J =
32.5 Hz), 125.7 (q, J = 3.8 Hz), 124.2 (q, J = 271.8 Hz), 123.7, 120.1,
113.2, 112.7, 112.26, 111.7, 109.5, 55.9, 55.9. 19F NMR (376 MHz,
CDCl3) δ −62.40. GC-MS (EI) m/z: 348, 333, 305, 290, 262, 174, 145.
Anal. Calcd for C19H15F3O3: C, 65.52; H, 4.34. Found: C, 65.38; H, 4.47.
5-(4-Methoxyphenyl)-3-methyl-2-phenylfuran (4s).28 Yield 26 mg,
3,4-Dibromo-2,5-bis(4-methoxyphenyl)furan (5c).30 Yield 49 mg,
63% (50 h) as white solid, mp = 139.6−140.5 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.00−7.91 (m, 4H), 7.02−6.95 (m, 4H), 3.86 (s, 6H).
13C NMR (150 MHz, CDCl3): δ = 159.7, 147.7, 127.1, 122.1, 114.0,
100.7, 55.4. GC-MS (EI) m/z: 440, 438, 437(1:2:1), 425, 423,
421(1:2:1), 331, 329(1:1), 235, 219, 135, 77.
3-Bromo-5-(4-fluorophenyl)-2-(4-methoxyphenyl)furan (5f). Yield
31 mg, 47% (85 h) as white solid, mp = 80.5−82.3 °C. 1H NMR (400
MHz, CDCl3): δ = 7.94 (d, J = 8.4 Hz, 2H), 7.67−7.59 (m, 2H), 7.09
(t, J = 8.4 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 6.67 (s, 1H), 3.85 (s, 3H).
13C NMR (150 MHz, CDCl3): δ = 162.4 (d, J = 248.1 Hz), 159.4, 151.1,
148.2, 126.2 (d, J = 3.2 Hz), 126.1, 125.5 (d, J = 8.1 Hz), 122.5, 115.9
(d, J = 22.0 Hz), 114.0, 110.8, 96.3, 55.3. 19F NMR (376 MHz, CDCl3)
δ −114.56. GC-MS (EI) m/z: 348, 346(1:1), 333, 331(1:1), 305,
303(1:1), 346, 339, 223, 176, 123, 95, 75. Anal. Calcd for C17H12BrFO2:
C, 58.81; H, 3.48. Found: C, 58.60; H, 3.60.
3-Bromo-5-(4-chlorophenyl)-2-(4-methoxyphenyl)furan (5g).
Yield 35 mg, 55% (72 h) as white solid, mp = 95.1−96.0 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.95 (d, J = 8.9 Hz, 2H), 7.59 (d, J = 8.5 Hz,
2H), 7.36 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 8.9 Hz, 2H), 6.73 (s, 1H), 3.86
(s, 3H). 13C NMR (150 MHz, CDCl3): δ = 159.5, 150.9, 148.6, 133.5,
129.0, 128.3, 127.1, 124.9, 122.4, 114.0, 111.6, 96.4, 55.3. GC-MS (EI)
m/z: 366, 364, 362(1:3:2), 351, 349, 347(1:3:2), 323, 321, 319(1:3:2),
255, 182, 139, 111, 75. Anal. Calcd for C17H12BrClO2: C, 56.15; H, 3.33.
Found: C, 56.03; H, 3.57.
3-Bromo-5-(4-bromophenyl)-2-(4-methoxyphenyl)furan (5h).
Yield 38 mg, 62% (82 h) as white solid, mp = 96.4−97.5 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.95 (d, J = 8.9 Hz, 2H), 7.53 (s, 4H), 6.98
(d, J = 8.9 Hz, 2H), 6.76 (s, 1H), 3.86 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ = 159.5, 151.0, 148.7, 132.0, 128.7, 127.1, 125.1, 122.4, 121.7,
114.0, 111.7, 96.4, 76.7, 55.3. GC-MS (EI) m/z: 410, 408, 406(1:2:1),
395, 393, 391(1:2:1), 301, 299(1:1), 205, 176, 155. Anal. Calcd for
C17H12Br2O2: C, 50.03; H, 2.96. Found: C, 49.86; H, 3.23.
1
52% (25 h) as white solid. H NMR (400 MHz, CDCl3): δ = 7.69
(d, J = 7.5 Hz, 2H), 7.64 (d, J = 8.2 Hz, 2H), 7.42 (t, J = 7.5 Hz, 2H), 7.26
(d, J = 7.0 Hz, 2H), 6.93 (d, J = 8.2 Hz, 2H), 6.48 (s, 1H), 3.84 (s, 3H),
2.32 (s, 3H). 13C NMR (150 MHz, CDCl3): δ = 158.94, 151.73, 147.46,
131.86, 128.51, 126.39, 125.09, 125.02, 123.86, 118.60, 114.11, 109.28,
55.32, 12.15. GC-MS(EI) m/z: 264, 249, 221, 178,, 132, 105, 77.
2-(4-Methoxyphenyl)-4,5-dihydronaphtho[1,2-b]furan (4t). Yield
1
18 mg, 36% (28 h) as white solid, mp = 103.5−105.0 °C. H NMR
(400 MHz, CDCl3): δ = 7.66 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 7.6 Hz,
1H), 7.23 (d, J = 7.5 Hz, 1H), 7.18 (d, J = 7.4 Hz, 1H), 7.10 (t, J = 7.4 Hz,
1H), 6.93 (d, J = 8.4 Hz, 2H), 6.49 (s, 1H), 3.84 (s, 3H), 2.98 (t, J =
7.8 Hz, 2H), 2.76 (t, J = 7.9 Hz, 2H). 13C NMR (150 MHz, CDCl3):
δ = 158.9, 153.3, 149.0, 134.5, 128.1, 127.9, 126.7, 126.0, 125.1, 124.1,
121.5, 118.9, 114.2, 105.0, 55.3, 29.0, 21.1. GC-MS (EI) m/z: 276, 261,
247, 231, 215, 202, 138, 115, 101, 89, 77. Anal. Calcd for C19H16O2: C,
82.58; H, 5.84. Found: C, 82.49; H, 5.93.
3-Bromo-2-(4-methoxyphenyl)-5-(4-(trifluoromethyl)phenyl)-
furan (5i). Yield 28 mg, 44% (60 h) as white solid, mp = 74.5−75.9 °C.
1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 8.5 Hz, 2H), 7.70
2-(4-Methoxyphenyl)naphtho[1,2-b]furan (4t′).29 Yield 18 mg,
1
36% (28 h) as white solid, mp = 111−112 °C. H NMR (400 MHz,
(d, J = 8.1 Hz, 2H), 7.61 (d, J = 8.2 Hz, 2H), 6.96 (d, J = 8.5 Hz, 2H),
6.80 (s, 1H), 3.84 (s, 3H). 13C NMR (150 MHz, CDCl3): δ = 159.68,
150.36, 149.31, 132.84, 129.34 (q, J = 32.5 Hz), 127.18, 125.80
(q, J = 3.8 Hz), 124.10 (q, J = 271.8 Hz), 123.60, 122.18, 114.04, 113.06,
96.53, 55.33. 19F NMR (376 MHz, CDCl3) δ −62.57. GC-MS (EI) m/z:
398, 396(1:1), 383, 381(1:1), 355, 353(1:1), 289, 173, 145. Anal. Calcd
for C18H12BrF3O2: C, 54.43; H, 3.05. Found: C, 54.27; H, 3.36.
3-Bromo-2-(4-methoxyphenyl)-5-(4-nitrophenyl)furan (5j). Yield
CDCl3): δ = 8.38 (d, J = 7.6 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.88
(d, J = 8.0 Hz, 2H), 7.64 (s, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.47 (t, J =
7.6 Hz, 1H), 7.02 (s, 1H), 7.01 (d, J = 8.0 Hz, 2H), 3.88 (s, 3H).
13C NMR (150 MHz, CDCl3): δ = 159.7, 155.5, 149.9, 131.2, 128.4,
126.3, 126.2, 125.0, 124.8, 123.7, 123.5, 121.3, 119.9, 119.5, 114.3, 100.9,
55.4. GC-MS (EI) m/z: 274, 259, 231, 202, 137, 101, 88, 75.
2-(4-Methoxyphenyl)-3-methyl-5-phenylfuran (4u).28 Yield 32 mg,
1
64% (20 h) as white solid, mp = 94.5−95.1. H NMR (600 MHz,
1
34 mg, 53% (6 d) as orange solid, mp = 160−162 °C. H NMR
CDCl3): δ = 7.72−7.67 (m, 2H), 7.66−7.61 (m, 2H), 7.40−7.34
(m, 2H), 7.25−7.21 (m, 1H), 7.00−6.95 (m, 2H), 6.59 (s, 1H), 3.85
(s, 3H), 2.28 (s, 3H). 13C NMR (150 MHz, CDCl3): δ = 158.44, 151.03,
148.27, 130.87, 128.61, 126.92, 126.67, 124.71, 123.47, 116.97, 114.01,
110.64, 55.30, 11.96. HRMS m/z: calcd for C18H16O2 [M]+ 264.1150,
found 264.1137.
(400 MHz, CDCl3): δ = 8.26 (d, J = 8.2 Hz, 2H), 7.99 (d, J = 8.1 Hz,
2H), 7.79 (d, J = 8.2 Hz, 2H), 7.00 (d, J = 8.1 Hz, 2H), 6.98 (s, 1H), 3.88
(s, 3H). 13C NMR (150 MHz, CDCl3): δ = 159.97, 150.48, 149.55,
146.58, 135.27, 127.39, 124.45, 123.74, 121.80, 114.95, 114.11, 96.92,
77.21, 77.00, 76.79, 55.38. GC-MS (EI) m/z: 375, 373(1:1), 360,
358(1:1), 345, 343(1:1), 329, 327(1:1), 314, 312(1:1), 205, 176. Anal.
Calcd for C17H12BrNO4: C, 54.57; H, 3.23; N, 3.74. Found: C, 54.32; H,
3.48; N, 3.70.
General Procedure for the Synthesis of 3-Bromo-2,5-diary-
lfurans. The mixture of ((2-aryl)cyclopropyl)(aryl)methanone (1, 50 mg),
2 (2.5 equiv unless otherwise stated), LiBr (1.0 equiv), and photo-
catalyst 3 (1.0 mol % unless otherwise stated) in 4 mL of dry CH3CN
was stirred and irradiated by a 100 cm blue LED round strip at room
temperature. Upon completion of the reaction (monitored by TLC), it
was quenched by saturated Na2CO3 (5 mL) and extracted with EtOAc
(3 × 5 mL). The combined organic layers were washed with brine
(2 × 5 mL), dried over MgSO4, and concentrated. The residue was
purified by flash column chromatography (petroleum ether/ethyl
acetate = 50:1) to afford the title products 5.
3-Bromo-5-(3-chlorophenyl)-2-(4-methoxyphenyl)furan (5l). Yield
1
40 mg, 63% (77 h) as white solid, mp = 103.0−103.9 °C. H NMR
(400 MHz, CDCl3): δ = 7.97 (d, J = 8.6 Hz, 2H), 7.89 (d, J = 7.9 Hz,
1H), 7.44 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.24 (s, 1H), 7.21
(t, J = 7.7 Hz, 1H), 6.98 (d, J = 8.6 Hz, 2H), 3.85 (s, 3H). 13C NMR
(150 MHz, CDCl3): δ = 159.5, 148.3, 148.2, 130.8, 130.1, 128.4, 128.2,
127.5, 127.2, 126.9, 122.3, 116.9, 114.0, 96.2, 55.3. GC-MS (EI) m/z:
366, 364, 362(1:3:2), 351, 349, 347(1:3:2), 323, 321, 319(1:3:2), 255,
L
DOI: 10.1021/acs.joc.6b00436
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The Journal of Organic Chemistry
Article
176, 139. Anal. Calcd for C17H12BrClO2: C, 56.15; H, 3.33. Found: C,
56.04; H, 3.57.
14.30. 19F NMR (376 MHz, CDCl3) δ −62.55. HRMS m/z: calcd for
C20H17FO4 [M + H]+ 341.1189, found 341.1195.
Ethyl 5-(4-Chlorophenyl)-2-(4-methoxyphenyl)furan-3-carboxy-
late (7f). Yield 93 mg, 93% (58 h) as white solid, mp = 119.1−
119.7 °C. 1H NMR (400 MHz, CDCl3): δ = 8.04 (d, J = 8.4 Hz, 2H),
7.64 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.05 (s, 1H),
6.98 (d, J = 8.4 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H), 3.87 (s, 3H), 1.37
(t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3): δ = 163.51, 160.54,
157.05, 150.55, 133.52, 129.97, 128.99, 128.37, 125.05, 122.22, 114.55,
113.57, 108.26, 60.58, 55.35, 14.30. HRMS m/z: calcd for C20H17ClO4
[M + H]+ 357.0894, found 357.0899.
Ethyl 2-(4-Methoxyphenyl)-5-(4-(trifluoromethyl)phenyl)furan-3-
carboxylate (7g). Yield 80 mg, 80% (60 h) as white solid, mp = 88.9−
89.6 °C. 1H NMR (400 MHz, CDCl3): δ = 8.09 (d, J = 8.8, 2H), 7.83
(d, J = 8.1 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 7.21 (s, 1H), 7.07−6.96
(m, 2H), 4.36 (q, J = 6.9 Hz, 2H), 3.90 (s, 3H), 1.40 (t, J = 7.0 Hz, 3H).
13C NMR (150 MHz, CDCl3): δ = 163.35, 160.71, 157.69, 150.02,
133.00, 130.07, 129.43 (q, J = 32.6 Hz), 125.83 (q, J = 4.0 Hz), 124.08
(q, J = 271.9 Hz), 123.81, 122.02, 114.68, 113.61, 109.84, 60.66, 55.35,
14.29. 19F NMR (376 MHz, CDCl3) δ −113.29. HRMS m/z: calcd for
C21H17F3O4 [M + H]+ 391.1157, found391.1159.
Ethyl 5-(3-Chlorophenyl)-2-(4-methoxyphenyl)furan-3-carboxy-
late (7h). Yield 95 mg, 95% (52 h) as white solid, mp = 100.2−100.6 °C.
1H NMR (400 MHz, CDCl3): δ = 8.07 (d, J = 8.0 Hz, 2H), 7.90
(d, J = 8.0 Hz, 1H), 7.51 (s, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.34 (t, J =
7.5 Hz, 1H), 7.24 (d, J = 8.6 Hz, 1H), 6.99 (d, J = 8.0 Hz, 2H), 4.34
(q, J = 7.1 Hz, 2H), 3.87 (s, 3H), 1.37 (t, J = 7.0 Hz, 3H). 13C NMR
(150 MHz, CDCl3): δ = 163.61, 160.56, 156.81, 147.93, 130.80, 130.31,
130.07, 128.48, 128.28, 127.77, 126.90, 122.18, 114.44, 113.59, 113.57,
60.56, 55.34, 14.33. HRMS m/z: calcd for C20H17ClO4 [M + H]+
357.0894, found 357.0897.
General Procedure for the Synthesis of 7i and 7k. The mixture
of ethyl-2-benzoyl-3-(4-methoxyphenyl)cyclopropane-1-carboxylate
(6, 100 mg), 2 (1.0 equiv), LiBr (1.0 equiv), and photocatalyst 3
(1.0 mol %) in 8 mL of dry CH3CN was stirred and irradiated by
a 100 cm blue LED round strip at room temperature. Upon completion
of the reaction (monitored by TLC), it was quenched with saturated
Na2CO3 (5 mL) and extracted with EtOAc (3 × 5 mL). The combined
organic layers were washed with brine (2 × 5 mL), dried over MgSO4,
filtered, and concentrated. The residue was directly purified by flash
column chromatography (petroleum ether/ethyl acetate = 20:1) to
afford the title products 7i and 7k.
3-Bromo-5-(2-methoxyphenyl)-2-(4-methoxyphenyl)furan (5n). Yield
1
34 mg, 53% (53 h) as white solid, mp = 105.4−107.2 °C. H NMR
(400 MHz, CDCl3): δ = 7.98 (d, J = 8.6 Hz, 2H), 7.90 (d, J = 7.7 Hz,
1H), 7.25 (d, J = 6.8 Hz, 1H), 7.05 (s, 1H), 7.03 (d, J = 7.5 Hz, 1H),
6.96 (t, J = 7.3 Hz, 3H), 3.95 (s, 3H), 3.85 (s, 3H). 13C NMR
(150 MHz, CDCl3): δ = 159.2, 155.5, 148.3, 147.1, 128.5, 127.0, 125.6,
122.8, 120.7, 118.8, 116.0, 113.9, 110.9, 96.5, 55.4, 55.3. GC-MS (EI)
m/z: 360, 358(1:1), 345, 343(1:1), 317, 315(1:1), 302, 300(1:1), 274,
275(1:1), 135, 77. Anal. Calcd for C18H15BrO3: C, 60.19; H, 4.21.
Found: C, 60.05; H, 4.38.
General Procedure for the Synthesis of 7a−7h. The mixture
of ethyl-2-benzoyl-3-(4-methoxyphenyl)cyclopropane-1-carboxylate
(6, 100 mg), 2 (2.0−2.5 equiv), LiBr (1.0 equiv), and photocatalyst 3
(1.0 mol %) in 8 mL of dry CH3CN was stirred and irradiated by a
100 cm blue LED round strip at room temperature. Upon completion of
the reaction (monitored by TLC), it was quenched by saturated
Na2CO3 (5 mL) and extracted with EtOAc (3 × 5 mL). The combined
organic layers were washed with brine (2 × 5 mL), dried over MgSO4,
filtered, and concentrated. The residue was purified by flash column
chromatography (petroleum ether/ethyl acetate = 20:1) to afford the
title products 7a−7h.
Ethyl 2-(4-Methoxyphenyl)-5-phenylfuran-3-carboxylate (7a).
Yield 95 mg, 96% (34 h) as white solid, mp = 95.5−96.0 °C. 1H NMR
(600 MHz, CDCl3): δ = 8.12−8.04 (m, 2H), 7.72 (d, J = 7.4 Hz, 2H),
7.41 (t, J = 7.7 Hz, 2H), 7.30 (t, J = 7.4 Hz, 1H), 7.06 (s, 1H), 7.02−6.96
(m, 2H), 4.33 (q, J = 7.1 Hz, 2H), 3.87 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H).
13C NMR (150 MHz, CDCl3): δ = 163.67, 160.42, 156.78, 151.62,
129.93, 129.87, 128.74, 127.83, 123.83, 122.44, 114.46, 113.52, 107.77,
60.49, 55.31, 14.30. HRMS m/z: calcd for C20H18O4 [M + H]+
323.1283, found 323.1285.
Ethyl 2-(4-Methoxyphenyl)-5-(p-tolyl)furan-3-carboxylate (7b).
Yield 81 mg, 81% (29 h) as white solid, mp = 84.3−84.5 °C. 1H NMR
(400 MHz, chloroform-d): δ = 8.06 (d, J = 8.1 Hz, 2H), 7.62 (d, J =
7.8 Hz, 2H), 7.22 (d, J = 7.7 Hz, 2H), 7.03−6.92 (m, 3H), 4.32 (q, J =
7.0 Hz, 2H), 3.87 (s, 3H), 2.38 (s, 3H), 1.37 (t, J = 6.9 Hz, 3H).
13C NMR (150 MHz, CDCl3): δ = 163.79, 160.37, 156.48, 151.92,
137.83, 129.92, 129.46, 127.21, 123.85, 122.58, 114.43, 113.54, 107.04,
60.48, 55.35, 21.34, 14.33. HRMS m/z: calcd for C21H20O4 [M + H]+
337.1440, found 337.1437.
Ethyl 2-(4-Methoxyphenyl)-5-methylfuran-3-carboxylate (7i).31
Yield 63 mg, 63% (20 h) as colorless oil. 1H NMR (600 MHz,
CDCl3): δ = 7.99−7.91 (m, 2H), 6.98−6.91 (m, 2H), 6.40 (d, J = 1.1 Hz,
1H), 4.27 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 2.33 (d, J = 0.9 Hz, 3H), 1.32
(t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3): δ = 163.90, 160.05,
156.21, 150.33, 129.64, 122.76, 113.38, 113.18, 108.50, 60.20, 55.27,
14.27, 13.30. HRMS m/z: calcd for C15H16O4 [M + H]+ 261.1127,
found 261.1119.
Ethyl 2,5-Bis(4-methoxyphenyl)furan-3-carboxylate (7c). Yield
1
89 mg, 89% (20 h) as white solid, mp = 64.0−65.0 °C. H NMR
(600 MHz, CDCl3): δ = 8.07−8.02 (m, 2H), 7.68−7.63 (m, 2H), 7.00−
6.97 (m, 2H), 6.96−6.93 (m, 2H), 6.93 (s, 1H), 4.32 (q, J = 7.1 Hz, 2H),
3.87 (s, 3H), 3.85 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz,
CDCl3): δ = 163.81, 160.29, 159.41, 156.21, 151.77, 129.85, 125.36,
122.90, 122.60, 114.41, 114.21, 113.51, 106.13, 60.46, 55.35, 55.34,
14.32. HRMS m/z: calcd for C21H20O5 [M + H]+ 353.1389, found
353.1397.
Ethyl 2-(4-Methoxyphenyl)-4,5,6,7-tetrahydrobenzofuran-3-car-
1
Ethyl 2-(4-Methoxyphenyl)-5-(naphthalen-1-yl)furan-3-carboxy-
late (7d). Yield 91 mg, 91% (37 h) as white solid, mp = 81.8−82.8 °C.
1H NMR (600 MHz, CDCl3): δ = 8.45 (d, J = 8.5 Hz, 1H), 8.14−8.07
boxylate (7k). Yield 65 mg, 65% (20 h) as colorless oil. H NMR
(600 MHz, CDCl3): δ = 7.81 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz,
2H), 4.26 (q, J = 7.0 Hz, 2H), 3.84 (s, 3H), 2.64 (dt, J = 21.5, 5.9 Hz,
4H), 1.85 (p, J = 5.7 Hz, 2H), 1.76 (p, J = 6.8, 6.2 Hz, 2H), 1.31 (t, J =
7.0 Hz, 3H). 13C NMR (150 MHz, CDCl3): δ = 164.69, 159.91, 156.05,
150.19, 129.81, 123.25, 118.88, 113.31, 112.34, 59.99, 55.28, 23.05,
22.93, 22.68, 22.63, 14.24. HRMS m/z: calcd for C18H20O4 [M + H]+
301.1440, found 301.1446.
General Procedure for the Synthesis of 7j. The mixture of ethyl-
2-benzoyl-3-(4-methoxyphenyl)cyclopropane-1-carboxylate (6, 100 mg),
2 (1.0 equiv), LiBr (1.0 equiv), p-TSA·H2O (20 mol %), and photo-
catalyst 3 (1.0 mol %) in 8 mL of dry CH3CN was stirred and irradiated
by a 100 cm blue LED round strip at room temperature. Upon
completion of the reaction (monitored by TLC), it was quenched
by saturated Na2CO3 (5 mL) and extracted with EtOAc (3 × 5 mL).
The combined organic layers were washed with brine (2 × 5 mL),
dried over MgSO4, filtered, and concentrated. The residue was directly
purified by flash column chromatography (petroleum ether/ethyl
acetate =20:1) to afford the title product 7j.
(m, 2H), 7.91 (d, J = 7.9 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.81 (d, J =
7.1 Hz, 1H), 7.58 (ddd, J = 8.5, 6.7, 1.5 Hz, 1H), 7.56−7.51 (m, 2H),
7.15 (s, 1H), 7.03−6.98 (m, 2H), 4.36 (q, J = 7.1 Hz, 2H), 3.87
(s, 3H), 1.39 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3):
δ = 163.76, 160.43, 157.20, 151.15, 133.88, 130.15, 130.09, 129.96,
129.01, 128.61, 127.44, 126.85, 126.81, 126.38, 126.28, 126.03, 125.24,
125.17, 122.42, 114.22, 113.73, 113.55, 112.01, 60.53, 55.29, 14.33.
HRMS m/z: calcd for C24H20O4 [M + H]+ 373.1440, found 373.1436.
Ethyl 5-(4-Fluorophenyl)-2-(4-methoxyphenyl)furan-3-carboxy-
late (7e). Yield 99 mg, 99% (45 h) as white solid, mp = 122.4−122.8 °C.
1H NMR (400 MHz, CDCl3): δ = 8.11−8.00 (m, 2H), 7.69 (ddd, J = 8.3,
5.3, 2.2 Hz, 2H), 7.10 (td, J = 8.8, 2.3 Hz, 2H), 7.04−6.94 (m, 2H), 4.32
(q, J = 7.1 Hz, 2H), 3.87 (s, 3H), 1.37 (t, J = 7.0 Hz, 3H). 13C NMR
(150 MHz, CDCl3): δ = 163.59, δ 162.44 (d, J = 248.0 Hz), 160.46,
156.80, 150.79, 129.92, 126.30 (d, J = 3.2 Hz), 125.71 (d, J = 8.1 Hz),
122.32, 115.90 (d, J = 22.0 Hz), 114.48, 113.55, 107.44, 60.54, 55.34,
M
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Article
Ethyl 5-(tert-Butyl)-2-(4-methoxyphenyl)furan-3-carboxylate (7j).
Yield 95 mg, 95% (30 h) as colorless oil. 1H NMR (400 MHz, CDCl3):
δ = 8.03−7.89 (m, 2H), 6.99−6.89 (m, 2H), 6.38 (s, 1H), 4.28 (q, J =
7.2 Hz, 2H), 3.84 (s, 3H), 1.33 (m, 12H). 13C NMR (150 MHz,
CDCl3): δ = 164.10, 162.31, 160.11, 155.89, 129.71, 122.99, 113.44,
112.78, 105.04, 60.26, 55.32, 32.58, 28.89, 14.37. HRMS m/z: calcd for
C18H22O4 [M + H]+ 303.1591, found 303.1615.
Mechanistic Studies. General Procedure for the Synthesis of
Deuterium Compound 1a-d2. ((Z)-2-(4-Methoxyphenyl)cyclopropyl-
3,3-d2)(phenyl)methanone, 1a-d2. 1H NMR (400 MHz, CDCl3)
δ 8.05−7.98 (m, 2H), 7.61−7.55 (m, 1H), 7.53−7.46 (m, 2H), 7.17−
7.10 (m, 2H), 6.91−6.84 (m, 2H), 3.83 (s, 3H), 2.84 (d, J = 4.0 Hz, 1H),
2.68 (d, J = 4.0 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 198.61, 158.35,
137.71, 132.79, 132.35, 128.48, 128.02, 127.33, 113.92, 55.26, 29.52,
29.04, 18.25 (q, J = 26.0, 25.4 Hz). HRMS m/z: calcd for C17H14D2O2
[M + H]+ 255.1354, found 255.1321.
((E)-2-(4-Methoxyphenyl)cyclopropyl-3,3-d2)(phenyl)methanone,
1a-d2. 1H NMR (400 MHz, CDCl3) δ 8.01−7.87 (m, 2H), 7.57−7.50
(m, 1H), 7.48−7.40 (m, 2H), 7.22−7.09 (m, 2H), 6.84−6.70 (m, 2H),
3.74 (s, 3H), 3.08 (d, J = 9.2 Hz, 1H), 2.87 (d, J = 9.2 Hz, 1H). 13C NMR
(150 MHz, CDCl3) δ 196.32, 158.23, 138.70, 132.48, 130.10, 128.51,
128.42, 128.00, 127.87, 113.37, 55.10, 28.95, 26.91, 26.83, 11.46−10.84
(m).
(No. 2015DX01), the Fundamental Research Funds for the
Central Universities (Grant No. HIT.BRETIV.201310), and
HLJNSF (No. B201406).
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The mixture of 1a or 1a-d2 (50 mg), Na2S2O8 (1.0 equiv), LiBr
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(E)-4-(4-Methoxyphenyl)-1-phenylbut-3-en-1-one.32 Yield 26 mg,
1
52% as a white solid. H NMR (400 MHz, CDCl3): δ = 8.00 (d, J =
7.6 Hz, 2H), 7.57 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.31
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b00436.
■
S
Optimization studies and characterization data of starting
materials and products (PDF)
Crystallographic data for compound 5a (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: xiawj@hit.edu.cn.
Notes
■
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
We are grateful for the financial support from China NSFC
(Nos. 21272047, 21372055, and 21472030), SKLUWRE
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