Tandem α-Arylation/Cyclization of 4-Haloacetoacetates with Arynes: A Metal-Free Approach toward 4-Aryl-3-(2 H)-furanones

Article abstract of DOI:10.1021/acs.joc.9b00488

An efficacious, metal-free strategy has been developed for the synthesis of 4-aryl-3-(2H)-furanones. The reaction proceeds via the nucleophilic addition of an active methylene compound to the aryne followed by ring closing of the adduct. The reaction proceeds under mild conditions, is applicable for gram-scale synthesis of 4-aryl-3-(2H)-furanones, and is general for a range of substituted arynes and haloacetates.

Full text of DOI:10.1021/acs.joc.9b00488

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Note
Tandem #-Arylation/Cyclization of 4-Haloacetoacetates with
Arynes: A Metal-Free Approach towards 4-Aryl-3-(2H)-Furanones
Jubi John, Vishnu K Omanakuttan, Aneeja T, Cherumuttathu H Suresh, Peter G. Jones, and Henning Hopf
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 04 Apr 2019
Downloaded from http://pubs.acs.org on April 4, 2019
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The Journal of Organic Chemistry
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Tandem -Arylation/Cyclization of 4-Haloacetoacetates with Arynes: A
Metal-Free Approach towards 4-Aryl-3-(2H)-Furanones
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Jubi John,*a,b Vishnu K. Omanakuttan,a,b Aneeja T.,a Cherumuttathu H. Suresh,a,b Peter G. Jones,c
Henning Hopf*d
aChemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (CSIR-
NIIST), Thiruvananthapuram-695019, India.
bAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India.
cInstitut für Anorganische und Analytische Chemie, Technische Universität Braunschweig, Hagenring 30, D-38106
Braunschweig, Germany.
dInstitut für Organische Chemie, Technische Universität Braunschweig, Hagenring 30, D-38106 Braunschweig, Germany.
Supporting Information Placeholder
O
O
O
TMS
OTf
F- source
X
R1
+
OR2
R1
O
R2O
ABSTRACT: An efficacious, metal-free strategy has been developed for the synthesis of 4-aryl-3-(2H)-furanones. The reaction
proceeds via the nucleophilic addition of an active methylene compound to the aryne followed by ring closing of the adduct. The
reaction proceeds under mild conditions, is applicable for gram scale synthesis of 4-aryl-3-(2H)-furanones and is general for a range
of substituted arynes and haloacetates.
The chemistry of arynes,1 and the associated primarily metal-
free methodologies2 have been in the limelight since the
introduction of their fluoride induced generation from ortho-
silyl aryltriflates.3 These highly reactive intermediates have
been skilfully utilized in a variety of cycloadditions,4
insertions,5 multicomponent reactions6 and also in the total
synthesis of natural products.7 The extreme reactivity of
arynes can be attributed to factors such as high electrophilicity
(associated with the low-lying LUMO) and the strained
carbon-carbon triple bond. These features have also triggered
research on the reactivity of neutral nucleophiles towards
arynes which has resulted in excellent methodologies for
arylation.1 In contrast, the addition of 1,3-diactivated
methylene species across the aryne carbon-carbon triple bond
have lead to the generation of 1,2-disubstituted arenes via an
insertion pathway.5 Tambar and Stoltz first reported the
insertion of -ketoesters into arynes which proceeded through
a formal [2+2] cycloaddition/fragmentation cascade via the
malonamides8a and β-ketoamides8b which participated in an -
arylation by exploiting the presence of a secondary amide NH
proton which transfers quickly to the intermediate aryl anion B
(Scheme 1b) thereby preventing the insertion of arynes with
1,3-dicarbonyls. Recently, Mohanan and co-workers reported
a decarbethoxylative arylation strategy employing arynes and
fluoromalonamates towards α-aryl-α-fluoroacetamides.9
Scheme 1. Reactions of 1,3-dicarbonyl compounds with
arynes: Insertion vs arylation
1a. Insertion5
O
O
R1
O
TMS
R1
F- source
EWG
+
R1
EWG
OTf
EWG
A
1b. -Arylation8
R1
O
R1
O
O
O
TMS
+
F- source
R1
NHR2
H
N
R2
O
B
(Scheme 1a).5b Later,
R2HN
O
OTf
benzocyclobutene intermediate
A
several groups reported the insertion of different 1,3-
1c. This work: Tandem -Arylation/Cyclization
diactivated
cyanomethyldiphenylphosphine
toleuenesulfonylacetonirile,5d -keto sulfones5e or -
ketophosphonates5f into arynes (Scheme 1a). C-Arylation of
1,3-dicarbonyl compounds with arynes was effected by the
groups of Mhaske and Rodriguez (Scheme 1b).8 They used
methylene
species
such
oxide,5c
as
p-
O
O
O
O
TMS
OTf
F- source
X
+
R1
OR2
R1
R2O
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The 3-(2H)-furanone moiety is found as a core structure
inmany natural products; e g. in bullatenone, jatrophone,
geiparvarin.10 Furthermore,
wide range of biological
regiospecificity was also observed in the reaction between 3-
chloro-1,2-benzyne and ethyl-4-chloroacetoacetate 2a wherein
the product 12 was isolated in 61% yield. Nevertheless, the
reactions of some other 4-substituted-1,2-benzynes with 4-
chloroacetoacetates afforded an inseparable mixture of
regioisomers. In the case of 4-methoxybenzyne the products
13 and 14 were obtained as a mixture of regioisomers in the
ratios 1:1.3 and 1:1.8 respectively. Whereas, the reactions of
2a and 2b with 4-methyl benzyne afforded the products 15 and
16 in good yields but as 1:1 regioisomeric mixtures. The
reactions of 4-chloro benzyne with 2a and 2b also afforded the
corresponding substituted furanones 17-18 as mixtures of
regioisomers and in slightly lower yields than the former.
1
2
3
4
5
6
7
8
a
properties such as antiulcer, antiallergic, anti-inflammatory
and antitumor activities have been reported for substituted 3-
(2H)-furanones which makes them interesting targets for
organic and medicinal chemists.11 The known synthetic routes
towards this heterocyclic motif include transformations of
substituted furans, cyclizations of α-hydroxy-1,3-diketones
and allenic hydroxy ketones, transition-metal and organo-
catalyzed protocols.10c, 12 Recently, we have also reported on
the synthesis of 4-substituted-3-(2H)-furanones by the Pd-
catalyzed reaction of 4-haloacetoacetates with activated
alkenes, imines and diazocompounds.13 Inspired by the reports
on the reactions of 1,3-diactivated methylene species and
arynes and reflecting our continued interest in the
development of synthetic protocols towards 4-substituted 3-
9
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12
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Table 1. Generality of 4-aryl-3-(2H)-furanone synthesis
with various arynes
R
(2H)-furanones, we speculated that
a reaction of 4-
O
OTf
O
KF/18C-6
CH3CN
0 oC-rt, 5 h
haloacetoacetate with an aryne would result in a new
methodology for accessing 4-aryl-3-(2H)-furanones via a
tandem -arylation/cyclization pathway (Scheme 1c).
R
+
Cl
CO2R
TMS
RO
O
2a
2b
, R = Et
, R = Me
1a-1i
3-18
We initiated the investigations with 2-(trimethylsilyl)phenyl
trifluoromethanesulfonate 1a and ethyl 4-chloroacetoacetate
2a as substrates. The first reaction of 1a with 2a was
perfomred in the presence of 5 equivalents of CsF (which is
the F- source for the generation of benzyne and also a base) in
CH3CN at room temperature. As expected, 4-phenyl-3-(2H)-
furanone 3 was isolated from the reaction in 27% yield after 4
h (Scheme 2).
O
O
O
O
RO
RO
3
X-ray of
5
6
, R = Et (67%)
, R = Me (68%)
3
4
, R = Et (70%)
a
, R = Me (73%)(69%)
F
F
MeO
MeO
O
O
O
O
O
O
Scheme 2. Synthesis of 4-aryl-3-(2H)-furanone from benzyne
and 4-chloroacetoacate
MeO
MeO
RO
RO
b
9
(48%)
10
11
, R = Et (71%)
, R = Me (73%)
7
8
, R = Et (64%)
, R = Me (67%)
O
OTf
O
MeO
CsF
CH3CN
rt, 4 h
O
O
O
+
Cl
CO2Et
O
MeO
TMS
EtO
O
Cl
O
RO
RO
1a
2a
3
(27%)
O
EtO
13
14
, R = Et (67%, 1:1.3)
, R = Me (70%, 1:1.8)
c
12
, R = Et (61%)
The optimization of the reaction conditions were continued
with 1a and 2a and was found to be a combination of 1.25
equivalents of benzyne precursor, 1.0 equivalent of 4-
haloacetoacetate, 5.0 equivalents of KF/18C-6 in CH3CN at 0
oC, and subsequent stirring at room temperature for 5 h.14
These optimized conditions for the tandem -
arylation/cyclization methodology were utilized for studying
the generality of differently substituted arynes (Table 1). Both
ethyl 2a and methyl acetoacetates 2b participated in the
cascade reaction with simple benzyne affording the
corresponding 4-phenyl-furanones 3 and 4 in 70% and 73%
yields respectively. The compound 4 was also made on the
gram scale and that too in good yields (69%). The reactions of
2a and 2b with 6-(trimethylsilyl)-2,3-dihydro-1H-inden-5-yl
triflate afforded the expected products 5 and 6 in good yields.
Disubstituted aryne precursors such as 4,5-dimethoxy-ortho-
silylphenyl triflate and 4,5-difluoro-ortho-silylphenyl triflate
also participated in the tandem reaction with 4-
haloacetoacetates furnishing the 4-arylated furanones 7-9 in
moderate to good yields. Importantly, the reaction of 4,5-
difluoro-ortho-silylphenyl triflate was found to be complete in
2 h at 0 oC. Interestingly, the fluoride-induced tandem reaction
of 3-methoxy-1,2-benzyne with 2a and 2b afforded furanones
10 and 11 as single regioisomers and in good yields. High
Cl
O
Me
O
O
O
O
O
Cl
Me
O
O
RO
RO
RO
RO
c
17
18
, R = Et (62%, 1:1.2)
15
16
, R = Et (71%, 1:1)
, R = Me (75%, 1:1)
c
, R = Me (66%, 1:1.4)
Reaction conditions: 1 (1.25 equiv.), 2 (1.0 equiv.), KF (5.0
a
equiv.), 18C-6 (5.0 equiv.), CH3CN (4.0 mL), 0 oC-rt, 5 h.
started with 1.0 gm of 2b, b 0 oC, 2 h. c 0 oC, 4 h.
We then turned our attention in bringing variations to the 4-
haloacetoacetate part and thereby chose ethyl 4-bromo-3-
oxopentanoate 2c with the idea of introducing a methyl group
at the second position of the 3(2H)-furanone moiety (Table 2).
The reaction was found to work well with simple benzyne
which afforded the 2-methyl-4-phenyl-3(2H)-furanone 19 in
69% yield. A 1.2:1 regioisomeric mixture of substituted
furanones 20 was obtained in good yield by the reaction of 2c
with 4-methyl benzyne. However, our attempt to introduce two
methyl groups at the second position of 3(2H)-furanone with
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ethyl 4-bromo-4-methyl-3-oxopentanoate 2d was unsuccessful
1
(intractable reaction mixture) even on heating.
2
3
+ Benzyne
+
Benzyne
4
5
6
7
10.0
TS1
1.8
0.0
8
9
-5.1
b
+ Benzyne
-10.0
-30.0
-50.0
-70.0
-90.0
-110.0
10
11
12
13
14
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-34.0
c
HF +
TS3
-71.6
TS2
-84.3
-84.7
f
-92.5
-88.3
d
e
+ HF
g
-102.0
+ HF
Reaction Coordinate
Figure 1. Energy profile for the mechanism of the formation of 4-aryl-3-(2H)-furanone.
Reaction conditions: 1 (1.25 equiv.), 2 (1.0 equiv.), KF (5.0
equiv.), 18C-6 (5.0 equiv.), CH3CN (4.0 mL), 0 oC-rt, 5 h. a 60 oC,
6 h.
Our next effort was to check the reactivity of 4-bromo-3-oxo-
N-phenylbutanamide 2e toward the present tandem reaction.
The reactions with unsubstituted benzyne (1a) and dimethoxy
benzyne (1c) afforded substituted furanones 22 & 23 in
To our dismay, the reaction of 1-
bromopentane-2,4-dione 2f failed to furnish the expected
product 24 under the optimized conditions.
A plausible mechanism for the formation of 4-aryl-3-(2H)-
furanone (Figure 1) is computed using M06L/SMD/6-
311G(d,p) level density functional theory (SI). The fluoride-
induced formation of enolate (a to b via TS1) is nearly barrier-
less and the subsequent formation of the anionic benzyne
adduct c is spontaneous and highly exothermic. Similarly, the
proton abstraction from HF by the aryl anion c has to take
place instantaneously due to the formation of the highly
exothermic product d, the arylated ester-flouride ion complex.
At this stage, F- anion abstracts the proton from the remaining
C-H bond to form the arylated enolate-HF complex (e). The
transition state TS2 for this reaction suggests the barrier height
4.0 kcal/mol. The enolate f undergoes an intramolecular
cyclisation through the formation of an SN2 type transition
state TS3 to yield the final product in association with the
leaving group Cl- (g). The activation barrier for the cyclisation
is 13.1 kcal/mol and the exothermic character of the overall
reaction is 102.0 kcal/mol.
moderate yields.
Table 2. Generality of 4-aryl-3-(2H)-furanone synthesis with
various 4-haloacetoacates
O
O
R
OTf
KF/18C-6
CH3CN
O
+
Br
R2
R1
R4
R2
R3
0 oC-rt, 5 h
R3
TMS
, R2 = Me, R3 = H,
R4 = OEt
EtO
2c
O
1
19-21
, R ,R3 = Me, R4 = OEt
2
2d
2e
2f
, R ,R3 = H, R4 = NHPh
2
, R ,R3 = H, R4 = Me
2
Me
O
O
O
O
Me
O
O
O
O
EtO
EtO
EtO
EtO
(63%, 1.2:1)
a
19
20
21
(69%)
(not isolated)
Finally, we tried to synthetically modify the 3(2H)-furanone
skeleton by introducing amine functions at the fifth position.
These heterocyclic analogs of prostaglandins15 were
synthesized by treating furanones with various amines in
MeOH at 40 oC for 4 hours. From all the reactions, the
corresponding azaprostaglandin analogues were isolated in
good to excellent yields (Scheme 3).
MeO
O
O
O
MeO
O
O
N
H
N
H
O
22
24
(52%)
(not isolated)
23
(48%)
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fluorescent indicator (POLYGRAM®SIL G/UV254). Gravity
Page 4 of 9
1
2
3
4
5
6
7
8
column chromatography was performed using silica gel, and
mixtures of hexanes/ethyl acetate were used for elution.
Melting points were measured with a Büchi 530 melting point
apparatus and are uncorrected. NMR spectra were recorded
with Bruker Avance-300 (300 MHz for 1H NMR, 75 MHz for
Scheme 3. Synthesis of heterocyclic analogs of prostaglandins
from 4-aryl-3-(2H)-furanone 4
1
13C{1H} NMR), Bruker DRX-400 (400.1 MHz for H NMR,
100.6 MHz for 13C{1H} NMR) and Bruker AMX-500 (500
MHz for 1H NMR, 125 MHz for 13C{1H} NMR)
spectrophotometer instruments. All spectra were measured at
300 K, unless otherwise specified. The chemical shifts  are
given in ppm and referenced to the external standard TMS or
O
9
O
MeOH
40 oC, 4 h
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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30
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60
+
R
NH2
R
N
H
O
1
MeO
internal solvent standard. H NMR coupling constants (J) are
O
4
25a 25c
26-28
-
reported in Hertz (Hz), and multiplicities are indicated as
follows s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet), dd (doublet of doublets). Mass spectra were with a
ThermoFinnigan MAT95XL, a ThermoFisher Scientific LTQ
Orbitrap Velos, and an Agilent 6890 gas chromatograph with
JMS-T100GC spectrometer or with a ESI/HRMS at 60,000
resolution using Thermo Scientific Exactive mass
spectrometer with orbitrap analyzer.
O
O
O
N
2
O
N
5
O
N
O
H
H
H
26
27
28
(77%)
(80%)
(75%)
Synthesis and characterization of 4-aryl-3(2H)-furanones
Reaction conditions: 4 (1.0 equiv.), 22 (1.05 equiv.), MeOH (2.0
mL), 40 oC, 4 h.
5-Ethoxy-4-phenylfuran-3(2H)-one (3). Following the
general experimental procedure, 2-(trimethylsilyl) phenyl
trifluoromethanesulfonate 1a (227 mg, 1.25 equiv.), ethyl-4-
chloroacetoacetate 2a (100 mg, 0.61 mmol), KF (177 mg, 5.0
equiv.), 18C-6 (806 mg, 5.0 equiv.) in CH3CN (4.0 mL) at 0
oC and subsequent stirring at room temperature for 5 h. The
crude product was purified over silica gel (100-200 mesh)
column chromatography (30% ethyl acetate in hexanes) to
afford the desired product 3 as a pale brown solid (87 mg,
In conclusion, we have developed a tandem process for the
synthesis of 4-aryl-3-(2H)-furanone from benzyne and 4-
haloacetoacetates. The reaction was found to be general
towards a variety of substituted arynes, and in some cases
regiospecificity was observed. The reaction proceeds via a
tandem -arylation-intramolecular cyclization pathway. We
have shown that additional substituents can be introduced to
the second or fifth position of the 3(2H)-furanone moiety by
using appropriately substituted 4-halo-1,3-diketo compounds.
Finally, different heterocyclic analogs of prostaglandins were
synthesized from 4-phenyl-3(2H)-furanone. We are currently
investigating the effect of substituents on the activated carbon
of 4-haloacetoacetates and the results will be reported in due
course.
o
1
70%). Analytical data of 3: Mp: 104-106 C. H NMR (300
MHz, CDCl3, TMS): δ 7.80-7.77 (m, 2H), 7.31-7.26 (m, 2H),
7.15-7.10 (m, 1H), 4.61 (s, 2H), 4.52 (q, 2H, J = 9.0 Hz), 1.45
(t, 3H, J = 9.0 Hz) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ
194.1, 180.6, 129.5, 128.2, 126.0, 125.9, 93.9, 74.6, 66.6, 14.8
ppm. HRMS (EI) m/z: (M)+ calcd for C12H12O3 204.0786;
Found: 204.0797.
5-Methoxy-4-phenylfuran-3(2H)-one (4). Following the
general experimental procedure, 2-(trimethylsilyl) phenyl
trifluoromethanesulfonate 1a (248 mg, 1.25 equiv.), methyl-4-
chloroacetoacetate 2b (100 mg, 0.66 mmol), KF (192 mg, 5.0
equiv.), 18C-6 (872 mg, 5.0 equiv.) in CH3CN (4.0 mL) at 0
oC and subsequent stirring at room temperature for 5 h. The
crude product was purified over silica gel (100-200 mesh)
column chromatography (30% ethyl acetate in hexanes) to
afford the desired product 4 as an off-white solid (92 mg,
73%). For the gram scale preparation of 4, yield was 69%
Experimental Section
General experimental methods: All chemicals were of the
best grade commercially available and were used without
further
purification.
Benzyne
triflate 1a,
1c,
1e,
precursors
2-
(trimethylsilyl)phenyl
(trimethylsilyl)phenyl
(trimethylsilyl)phenyl
4,5-dimethoxy-2-
3-methoxy-2-
4-methyl-2-
triflate
triflate
(trimethylsilyl)phenyl trifluoromethanesulfonate 1h and 4-
methoxy-2-(trimethylsilyl)phenyl triflate 1g were purchased
from TCI Chemicals. Benzyne precursor 2-chloro-6-
(trimethylsilyl)phenyl triflate 1f, ethyl 4-chloroacetoacetate
2a, methyl 4-chloroacetoacetate 2b, CsF, KF, 18-C-6 and
TBAF were purchased from Sigma Aldrich. Benzyne
precursors 6-(trimethylsilyl)indan-5-yl triflate 1b, 4,5-
difluoro-2-(trimethylsilyl)phenyl trifluoromethanesulfonate 1d
o
1
(1.29 g). Analytical data of 4. Mp: 59-61 C. H NMR (300
MHz, CDCl3, TMS): δ 7.78-7.75 (m, 2H), 7.31-7.26 (m, 2H),
7.15-7.10 (m, 1H), 4.62 (s, 2H), 4.12 (s, 3H) ppm. 13C{1H}
NMR (75 MHz, CDCl3): δ 194.1, 180.8, 129.2, 128.2, 126.1,
126.0, 94.1, 74.7, 56.7 ppm. HRMS (EI) m/z: (M)+ calcd for
C11H10O3 190.0624; Found: 190.0628.
and
4-chloro-2-(trimethylsilyl)phenyl
4-(2,3-Dihydro-1H-inden-5-yl)-5-ethoxyfuran-3(2H)-one
(5). Following the general experimental procedure, 6-
(trimethylsilyl)indan-5-yl triflate 1b (258 mg, 1.25 equiv.),
ethyl-4-chloroacetoacetate 2a (100 mg, 0.61 mmol), KF (177
mg, 5.0 equiv.), 18C-6 (806 mg, 5.0 equiv.) in CH3CN (4.0
mL) at 0 oC and subsequent stirring at room temperature for 5
h. The crude product was purified over silica gel (100-200
mesh) column chromatography (30% ethyl acetate in hexanes)
trifluoromethanesulfonate 1i were purchased from ABCR
chemicals. 4-bromoacetoacetates were prepared by following
reported procedures.16 All solvents were purified according to
standard procedures; dry solvents were obtained according to
the literature methods and stored over molecular sieves.
Analytical thin layer chromatography was performed on
polyester sheets pre-coated with silica gel containing
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to afford the desired product 5 as a pale yellow solid (99 mg,
mmol), KF (192 mg, 5.0 equiv.), 18C-6 (872 mg, 5.0 equiv.)
o
1
o
1
2
3
4
5
6
7
8
67%). Analytical data of 5. Mp: 70-72 C. H NMR (300
MHz, CDCl3, TMS): δ 7.63 (s, 1H), 7.51-7.47 (m, 1H), 7.16-
7.13 (d, 1H, J = 6.0 Hz), 4.59 (s, 2H), 4.49 (q, 2H, J = 6.0 Hz),
2.87-2.79 (m, 4H), 2.03-1.93 (m, 2H), 1.43 (t, 3H, J = 6.0 Hz)
ppm. 13C{1H} NMR (75 MHz, CDCl3): 194.3, 180.5, 144.1,
142.1, 127.0, 124.1, 124.1, 122.2, 94.4, 74.5, 66.5, 33.0, 32.7,
25.5, 14.9. ppm. HRMS (EI) m/z: (M)+ calcd for C15H16O3
244.1094; Found: 244.1086.
4-(2,3-Dihydro-1H-inden-5-yl)-5-methoxyfuran-3(2H)-one
(6). Following the general experimental procedure, 6-
(trimethylsilyl)indan-5-yl triflate 1b (279 mg, 1.25 equiv.),
methyl-4-chloroacetoacetate 2b (100 mg, 0.66 mmol), KF
(192 mg, 5.0 equiv.), 18C-6 (872 mg, 5.0 equiv.) in CH3CN
in CH3CN (4.0 mL) at 0 C for 2 h. The crude product was
purified over silica gel (100-200 mesh) column
chromatography (30% ethyl acetate in hexanes) to afford the
desired product 9 as a light yellow oil (72 mg, 48%).
Analytical data of 9. TLC (SiO2): Rf 0.26 (50% ethyl acetate in
1
hexane). H NMR (300 MHz, CDCl3, TMS): δ 7.72-7.65 (m,
1H), 7.60-7.55 (m, 1H), 7.09-7.00 (m, 1H), 4.63 (s, 2H), 4.15
(s, 3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 193.6, 180.6,
121.8, 121.8, 121.8, 121.7, 117.0, 116.7, 114.7, 114.5, 92.5,
74.8, 57.0 ppm. HRMS (EI) m/z: (M)+ calcd for C11H8F2O3
226.0436; Found: 226.0441.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5-Ethoxy-4-(3-methoxyphenyl)furan-3(2H)-one
(10).
Following the general experimental procedure, 3-methoxy-2-
(trimethylsilyl)phenyl triflate 1e (250 mg, 1.25 equiv.), ethyl-
4-chloroacetoacetate 2a (100 mg, 0.61 mmol), KF (177 mg,
5.0 equiv.), 18C-6 (806 mg, 5.0 equiv.) in CH3CN (4.0 mL) at
o
(4.0 mL) at 0 C and subsequent stirring at room temperature
for 5 h. The crude product was purified over silica gel (100-
200 mesh) column chromatography (30% ethyl acetate in
hexanes) to afford the desired product 6 as a pale yellow solid
o
0 C and subsequent stirring at room temperature for 5 h. The
o
1
(103 mg, 68%). Analytical data of 6. Mp: 123-125 C. H
NMR (300 MHz, CDCl3, TMS): δ 7.60 (s, 1H), 7.50-7.47 (m,
1H), 7.15-7.13 (d, 1H, J = 6.0 Hz), 4.61 (s, 2H), 4.10 (s, 3H),
2.87-2.79 (m, 4H), 2.03-1.94 (m, 2H) ppm. 13C{1H} NMR (75
MHz, CDCl3): δ 194.3, 180.7, 144.2, 142.2, 126.7, 124.2,
124.1, 122.3, 94.6, 74.6, 56.5, 33.0, 32.7, 25.5 ppm. HRMS
crude product was purified over silica gel (100-200 mesh)
column chromatography (30% ethyl acetate in hexanes) to
afford the desired product 10 as a pale yellow solid (101 mg,
o
1
71%). Analytical data of 10. Mp: 67-69 C. H NMR (300
MHz, CDCl3, TMS): δ 7.45-7.44 (m, 1H), 7.42-7.38 (m, 1H),
7.22-7.17 (m, 1H), 6.71-6.66 (m, 1H), 4.60 (s, 2H), 4.52 (q,
2H, J = 6.0 Hz), 3.75 (s, 3H), 1.45 (t, 3H, J = 6.0 Hz) ppm.
13C{1H} NMR (75 MHz, CDCl3): 194.1, 180.6, 159.4, 130.8,
129.1, 118.4, 111.8, 111.3, 93.7, 74.6, 66.7, 55.2, 14.8. ppm.
HRMS (EI) m/z: (M)+ calcd for C13H14O4 234.0892; Found:
234.0882.
(EI) m/z: (M)+ calcd for
230.0933.
C14H14O3 230.0937; Found:
4-(3,4-Dimethoxyphenyl)-5-ethoxyfuran-3(2H)-one
(7).
Following the general experimental procedure, 4,5-dimethoxy-
2-(trimethylsilyl)phenyl triflate 1c (273 mg, 1.25 equiv.),
ethyl-4-chloroacetoacetate 2a (100 mg, 0.61 mmol), KF (177
mg, 5.0 equiv.), 18C-6 (806 mg, 5.0 equiv.) in CH3CN (4.0
mL) at 0 oC and subsequent stirring at room temperature for 5
h. The crude product was purified over silica gel (100-200
mesh) column chromatography (30% ethyl acetate in hexanes)
to afford the desired product 7 as a pale brown solid (103 mg,
5-Methoxy-4-(3-methoxyphenyl)furan-3(2H)-one
(11).
Following the general experimental procedure, 3-methoxy-2-
(trimethylsilyl)phenyl triflate 1e (271 mg, 1.25 equiv.),
methyl-4-chloroacetoacetate 2b (100 mg, 0.66 mmol), KF
(192 mg, 5.0 equiv.), 18C-6 (872 mg, 5.0 equiv.) in CH3CN
o
(4.0 mL) at 0 C and subsequent stirring at room temperature
o
1
64%). Analytical data of 7. Mp: 136-138 C. H NMR (300
MHz, CDCl3, TMS): δ 7.51 (d, 1H, J = 1.8 Hz), 7.32 (dd, 1H,
J1 = 8.4 Hz, J2 = 2.1 Hz ), 6.80 (d, 1H, J = 8.4 Hz), 4.59 (s,
2H), 4.51 (q, 2H, J =7.2 Hz), 3.84 (s, 3H), 3.81 (s, 3H), 1.45
(t, 3H, J = 7.2 Hz) ppm. 13C{1H} NMR (75 MHz, CDCl3):
194.2, 180.2, 148.6, 147.1, 122.3, 118.4, 111.0, 109.5, 74.5,
66.5, 55.8, 55.7, 14.8 ppm. HRMS (EI) m/z: (M)+ calcd for
C14H16O5 264.0992; Found: 264.0984.
for 5 h. The crude product was purified over silica gel (100-
200 mesh) column chromatography (30% ethyl acetate in
hexanes) to afford the desired product 11 as a pale yellow
solid (106 mg, 73%). Analytical data of 11. Mp: 95-97 C. H
NMR (300 MHz, CDCl3, TMS): δ 7.42-7.41 (m, 1H), 7.39-
7.35 (m, 1H), 7.22-7.17 (m, 1H), 6.71-6.67 (m, 1H), 4.61 (s,
2H), 4.12 (s, 3H), 3.75 (s, 3H) ppm. 13C{1H} NMR (75 MHz,
CDCl3): δ 194.0, 180.8, 159.4, 130.6, 129.1, 118.5, 111.7,
111.5, 93.9, 74.7, 56.7, 55.2 ppm. HRMS (EI) m/z: (M)+ calcd
for C12H12O4 220.0730; Found: 220.0725.
o
1
4-(3,4-Dimethoxyphenyl)-5-methoxyfuran-3(2H)-one
(8).
Following the general experimental procedure, 4,5-dimethoxy-
2-(trimethylsilyl)phenyl triflate 1c (296 mg, 1.25 equiv.),
methyl-4-chloroacetoacetate 2b (100 mg, 0.66 mmol), KF
(192 mg, 5.0 equiv.), 18C-6 (872 mg, 5.0 equiv.) in CH3CN
4-(3-Chlorophenyl)-5-ethoxyfuran-3(2H)-one
(12).
Following the general experimental procedure, 2-chloro-6-
(trimethylsilyl)phenyl triflate 1f (253 mg, 1.25 equiv.), ethyl-
4-chloroacetoacetate 2a (100 mg, 0.61 mmol), KF (177 mg,
5.0 equiv.), 18C-6 (806 mg, 5.0 equiv.) in CH3CN (4.0 mL) at
o
(4.0 mL) at 0 C and subsequent stirring at room temperature
for 5 h. The crude product was purified over silica gel (100-
200 mesh) column chromatography (30% ethyl acetate in
hexanes) to afford the desired product 8 as a brown solid (110
o
0 C for 4 h. The crude product was purified over silica gel
(100-200 mesh) column chromatography (30% ethyl acetate in
hexanes) to afford the desired product 12 as a pale yellow
viscous liquid (89 mg, 61%). Analytical data of 12. TLC
o
1
mg, 67%). Analytical data of 8. Mp: 122-124 C. H NMR
(300 MHz, CDCl3, TMS): δ 7.47 (d, 1H, J = 2.1 Hz), 7.27 (dd,
1H, J1 = 8.4 Hz, J2 = 2.1 Hz ), 6.78 (d, 1H, J = 8.4 Hz), 4.61
(s, 2H), 4.12 (s, 3H), 3.84 (s, 3H), 3.81 (s, 3H) ppm. 13C{1H}
NMR (75 MHz, CDCl3): δ 194.2, 180.5, 148.6, 147.3, 122.1,
118.5, 111.1, 109.7, 74.6, 56.7, 55.9 ppm. HRMS (EI) m/z:
(M)+ calcd for C13H14O5 250.0836; Found: 250.0828.
1
(SiO2): Rf 0.37 (50% ethyl acetate in hexane). H NMR (500
MHz, CDCl3, TMS): δ 7.89 (t, 1H, J = 1.5 Hz), 7.81 (d, 1H, J
= 8Hz), 7.28 (d, 1H, J = 8 Hz,), 7.16 (dd, 1H, J1 = 7.5 Hz, J2 =
1.0 Hz) 4.69 (s, 2H) 4.62 (q, 2H, J = 6.0 Hz) 1.54 (t, 3H, J =
6.0 Hz) ppm. 13C{1H} NMR (125 MHz, CDCl3): 193.7, 180.6,
134.1, 129.4, 125.9, 125.6, 123.8, 74.7, 67.0, 14.9 ppm.
HRMS (ESI): calcd for C12H11ClNaO3, (M+Na)+: 261.0289,
Found: 261.0298.
4-(3,4-Difluorophenyl)-5-methoxyfuran-3(2H)-one
(9).
Following the general experimental procedure, 4,5-difluoro-2-
(trimethylsilyl)phenyl trifluoromethanesulfonate 1d (276 mg,
1.25 equiv.), methyl-4-chloroacetoacetate 2b (100 mg, 0.66
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 9
5-Ethoxy-4-(4-methoxyphenyl)furan-3(2H)-one & 5-ethoxy-
4-(3-methoxyphenyl)furan-3(2H)-one (13). Following the
general experimental procedure, 4-methoxy-2-
chloroacetoacetate 2b (100 mg, 0.66 mmol), KF (192 mg, 5.0
equiv.), 18C-6 (872 mg, 5.0 equiv.) in CH3CN (4.0 mL) at 0
oC and subsequent stirring at room temperature for 5 h. The
crude product was purified over silica gel (100-200 mesh)
column chromatography (30% ethyl acetate in hexanes) to
afford the desired product 16 as a pale brown solid and as
regioisomers in a ratio of 1:1 (101 mg, 75%). Analytical data
of 16. Mp: 57-59 C. H NMR (300 MHz, CDCl3, TMS): δ
7.66-7.62 (m, 2H), 7.59-7.58 (m, 1H), 7.54-7.51 (m, 1H),
7.20-7.14 (m, 1H), 7.11-7.08 (m, 2H), 6.96-6.93 (m, 1H), 4.61
(s, 2H), 4.60 (s, 2H), 4.10 (s, 3H), 4.10 (s, 3H), 2.29 (s, 3H),
2.26 (s, 3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): 194.2,
194.2, 180.8, 180.7, 137.7, 135.7, 129.0, 128.9, 128.1, 126.9,
126.7, 126.2, 125.9, 123.2, 94.2, 94.0, 74.7, 56.6, 56.6, 21.6,
21.2 ppm. HRMS (EI) m/z: (M)+ calcd for C12H12O3
204.0786; Found: 204.0796.
1
2
3
4
5
6
7
8
(trimethylsilyl)phenyl triflate 1g (250 mg, 1.25 equiv.), ethyl-
4-chloroacetoacetate 2a (100 mg, 0.61 mmol), KF (177 mg,
5.0 equiv.), 18C-6 (806 mg, 5.0 equiv.) in CH3CN (4.0 mL) at
o
0 C and subsequent stirring at room temperature for 5 h. The
o
1
crude product was purified over silica gel (100-200 mesh)
column chromatography (30% ethyl acetate in hexanes) to
afford the desired product 13 as a pale yellow solid and as
regioisomers in a ratio of 1.3:1 (96 mg, 67%). Analytical data
9
o
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
of 13. Mp: 132-134 C. H NMR (300 MHz, CDCl3, TMS): δ
7.74-7.69 (m, 2.6H), 7.45-7.44 (m, 1H), 7.41-7.38 (m, 1H),
7.22-7.17 (m, 1H), 6.86-6.81 (m, 2.6H), 6.70-6.66 (m, 1H),
4.59 (s, 2H), 4.58 (s, 2.6H), 4.55-4.46 (m, 4.6H), 3.75 (s, 3H),
3.73 (s, 3.9H) 1.47-1.41 (m, 7H) ppm. 13C{1H} NMR (75
MHz, CDCl3): 194.2, 194.0, 180.6, 180.2, 159.4, 157.7, 130.8,
129.1, 127.2, 121.9, 118.4, 113.7, 111.7, 111.3, 93.7, 93.6,
74.5, 74.5, 66.7, 66.5, 55.2, 55.1, 14.9, 14.8 ppm. HRMS (EI)
m/z: (M)+ calcd for C13H14O4 234.0892; Found: 234.0888.
4-(4-Chlorophenyl)-5-ethoxyfuran-3(2H)-one
chlorophenyl)-5-ethoxyfuran-3(2H)-one (17). Following the
general experimental procedure, 4-chloro-2-
&
4-(3-
(trimethylsilyl)phenyl trifluoromethanesulfonate 1i (254 mg,
1.25 equiv.), ethyl-4-chloroacetoacetate 2a (100 mg, 0.61
mmol), KF (177 mg, 5.0 equiv.), 18C-6 (806 mg, 5.0 equiv.)
5-Methoxy-4-(4-methoxyphenyl)furan-3(2H)-one
methoxy-4-(3-methoxyphenyl)furan-3(2H)-one (14). Following
the general experimental procedure, 4-methoxy-2-
&
5-
o
in CH3CN (4.0 mL) at 0 C for 4 h. The crude product was
(trimethylsilyl)phenyl triflate 1g (271 mg, 1.25 equiv.),
methyl-4-chloroacetoacetate 2b (100 mg, 0.66 mmol), KF
(192 mg, 5.0 equiv.), 18C-6 (872 mg, 5.0 equiv.) in CH3CN
purified over silica gel (100-200 mesh) column
chromatography (30% ethyl acetate in hexanes) to afford the
desired product 17 as a pale yellow oil and as regioisomers in
a ratio of 1:1.2 (90 mg, 62%). Analytical data of 17. TLC
o
(4.0 mL) at 0 C and subsequent stirring at room temperature
1
for 5 h. The crude product was purified over silica gel (100-
200 mesh) column chromatography (30% ethyl acetate in
hexanes) to afford the desired product 14 as a pale yellow and
as regioisomers in a ratio of 1.8:1 (102 mg, 70%). Analytical
data of 14. Mp: 86-88 oC. 1H NMR (300 MHz, CDCl3, TMS):
δ 7.71-7.66 (m, 3.7H), 7.42-7.41 (m, 1H), 7.39-7.35 (m, 1H),
7.22-7.17 (m, 1H), 6.86-6.81 (m, 3.8H), 6.71-6.67 (m, 1H),
4.61 (s, 2H), 4.60 (s, 3.6H), 4.12 (s, 3H), 4.10 (s, 5.7H), 3.75
(s, 3H), 3.73 (s, 5.6H). 13C{1H} NMR (75 MHz, CDCl3):
194.2, 180.5, 159.5, 157.8, 130.6, 129.1, 127.3, 121.7, 118.5,
113.7, 111.7, 111.5, 93.9, 74.7, 56.6, 55.2 ppm. HRMS (ESI)
m/z: (M+H)+ calcd for C12H13O4 221.0808; Found: 221.0808.
(SiO2): Rf 0.38 (50% ethyl acetate in hexane). H NMR (300
MHz, CDCl3, TMS): δ 7.82-7.81 (m, 1H), 7.79-7.72 (m,
3.6H), 7.26-7.19 (m, 3.4H), 7.10-7.06 (m, 1H), 4.61 (s, 2H),
4.61 (s, 2.4H), 4.58-4.40 (m, 4.4H), 1.49-1.43 (m, 6.6H) ppm.
13C{1H} NMR (75 MHz, CDCl3): 194.0, 193.8, 180.6, 180.5,
134.0, 131.3, 131.3, 129.4, 128.3, 128.0, 127.0, 125.9, 125.6,
123.7, 93.0, 92.8, 74.7, 67.1, 67.0, 14.8 ppm. HRMS (ESI)
m/z: (M)+ calcd for C12H12ClO3 239.0469; Found: 239.0469.
4-(4-Chlorophenyl)-5-methoxyfuran-3(2H)-one
chlorophenyl)-5-methoxyfuran-3(2H)-one (18). Following the
general experimental procedure, 4-chloro-2-
&
4-(3-
(trimethylsilyl)phenyl trifluoromethanesulfonate 1i (275 mg,
1.25 equiv.), methyl-4-chloroacetoacetate 2b (100 mg, 0.66
mmol), KF (192 mg, 5.0 equiv.), 18C-6 (872 mg, 5.0 equiv.)
5-Ethoxy-4-(p-tolyl)furan-3(2H)-one
tolyl)furan-3(2H)-one (15). Following
&
5-ethoxy-4-(m-
the general
o
experimental procedure, 4-methyl-2-(trimethylsilyl)phenyl
trifluoromethanesulfonate 1h (238 mg, 1.25 equiv.), ethyl-4-
chloroacetoacetate 2a (100 mg, 0.61 mmol), KF (177 mg, 5.0
equiv.), 18C-6 (806 mg, 5.0 equiv.) in CH3CN (4.0 mL) at 0
oC and subsequent stirring at room temperature for 5 h. The
crude product was purified over silica gel (100-200 mesh)
column chromatography (30% ethyl acetate in hexanes) to
afford the desired product 15 as a pale brown solid and as
regioisomers in a ratio of 1:1 (95 mg, 71%). Analytical data of
15. Mp: 75-77 oC. 1H NMR (300 MHz, CDCl3, TMS): δ 7.69-
7.64 (m, 2H), 7.63-7.62 (m, 1H), 7.55-7.52 (m, 1H), 7.20-7.15
(m, 1H), 7.11-7.07 (m, 2H), 6.96-6.93 (m, 1H), 4.59 (s, 2H),
4.59 (s, 2H), 4.54-4.46 (m, 4H), 2.29 (s, 3H), 2.26 (s, 3H)
1.46-1.41 (m, 6H) ppm. 13C{1H} NMR (75 MHz, CDCl3):
194.2, 194.2, 180.6, 180.5, 137.7, 135.5 129.2, 128.9, 128.1,
126.8, 126.7, 126.4, 125.9, 123.1, 94.0, 93.9, 74.5, 66.6, 66.5,
21.6, 21.2, 14.8 ppm. HRMS (EI) m/z: (M)+ calcd for
C13H14O3 218.0937; Found: 218.0926.
in CH3CN (4.0 mL) at 0 C for 4 h. The crude product was
purified over silica gel (100-200 mesh) column
chromatography (30% ethyl acetate in hexanes) to afford the
desired product 18 as a pale yellow oil and as regioisomers in
a ratio of 1:1.4 (101 mg, 66%). Analytical data of 18. TLC
1
(SiO2): Rf 0.32 (50% ethyl acetate in hexane). H NMR (300
MHz, CDCl3, TMS): δ 7.79-7.77 (m, 1H), 7.76-7.71 (m,
3.8H), 7.25-7.17 (m, 3.8H), 7.10-7.07 (m, 1H), 4.62 (s, 2H),
4.62 (s, 2.8H), 4.14 (s, 3H), 4.13 (s, 4.2H) ppm. 13C{1H} NMR
(75 MHz, CDCl3): 193.9, 193.7, 180.9, 180.8, 134.1, 131.4,
131.1, 129.4, 128.3, 127.8, 127.1, 126.0, 125.6, 123.8, 93.2,
93.0, 74.8, 56.9, 56.9 ppm. HRMS (EI) m/z: (M)+ calcd for
C11H9ClO3 224.0240; Found: 224.0252.
5-ethoxy-2-methyl-4-phenylfuran-3(2H)-one
(19).
Following the general experimental procedure, 2-
(trimethylsilyl) phenyl trifluoromethanesulfonate 1a (167 mg,
1.25 equiv.), ethyl 4-bromo-3-oxopentanoate 2c (100 mg, 0.45
mmol), KF (130 mg, 5.0 equiv.), 18C-6 (592 mg, 5.0 equiv.)
o
5-Methoxy-4-(p-tolyl)furan-3(2H)-one & 5-methoxy-4-(m-
in CH3CN (3.0 mL) at 0 C and subsequent stirring at room
tolyl)furan-3(2H)-one
(16).
Following
the
general
temperature for 5 h. The crude product was purified over silica
gel (100-200 mesh) column chromatography (30% ethyl
acetate in hexanes) to afford the desired product 19 as a pale
experimental procedure, 4-methyl-2-(trimethylsilyl)phenyl
trifluoromethanesulfonate 1h (258 mg, 1.25 equiv.), methyl-4-
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The Journal of Organic Chemistry
yellow solid (69 mg, 69%). Analytical data of 19. Mp: 77-79
111.9, 111.9, 96.0, 74.9, 56.0 ppm. HRMS (EI) m/z: calcd for
C18H17NO4, (M)+: 311.1158, Found: 311.1152.
1
oC. H NMR (500 MHz, CDCl3, TMS): δ 7.88 (d, 2H, J = 7.5
1
2
3
4
5
6
7
8
9
Hz), 7.35 (t, 2H, J = 7.5 Hz), 7.18 (t, 1H, J = 7.0 Hz), 4.74 (q,
1H, J = 7.0 Hz,), 4.58 (q, 2H, J = 7.0 Hz,), 1.57 (d, 3H, 7.0
Hz), 1.52 (t, 3H, J = 7.0 Hz,) ppm. 13C{1H} NMR (125 MHz,
CDCl3): δ 196.9, 179.2, 129.8, 128.2, 125.9, 125.8, 92.4, 82.8,
66.4, 16.7, 14.8 ppm. HRMS (ESI) m/z: calcd for C13H14NaO3,
(M+Na)+: 241.0835, Found: 241.0826.
5-(hexylamino)-4-phenylfuran-3(2H)-one (26). 5-methoxy-
4-phenylfuran-3(2H)-one 4 (100 mg, 1.0 equiv., 0.53 mmol)
and n-hexylamine 25a (1.1 equiv.) were weighed into a dry
Schlenk tube. Dry methanol (2.0 mL) was added and the
reaction mixture was stirred at 40 oC for 4 h. Upon completion
of the reaction, the solvent was removed and the residue was
subjected to column chromatography on neutral alumina using
hexanes/ethyl acetate mixture as eluent to afford the product
26 as a pale yellow viscous liquid (110 mg, 80%). Analytical
data of 26. TLC (SiO2): Rf 0.23 (50% ethyl acetate in hexane).
1H NMR (500 MHz, CDCl3, TMS): δ 7.42-7.38 (m, 4H), 7.22-
7.20 (m, 1H), 5.63 (brs, 1H), 4.62 (s, 2H), 3.41 (m, 2H), 1.67-
1.66 (m, 2H), 1.62-1.59 (m, 2H), 1.32-1.25 (m, 4H), 0.90 (t,
3H, J = 7.0 Hz) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ
191.1, 176.8, 130.7, 129.2, 127.4, 126.1, 93.7, 74.5, 41.6,
31.3, 30.1, 29.7, 26.3, 22.5, 13.9 ppm. HRMS (ESI) m/z:
(M+Na)+ calcd for C16H21NNaO2 282.1465; Found: 282.1455.
5-(benzylamino)-4-phenylfuran-3(2H)-one (27): 5-methoxy-
4-phenylfuran-3(2H)-one 4 (100 mg, 1.0 equiv., 0.53 mmol)
and benzylamine 25b (1.1 equiv.) were weighed into a dry
Schlenk tube. Dry methanol (2.0 mL) was added and the
reaction mixture was stirred at 40 oC for 4 h. Upon completion
of the reaction, the solvent was removed and the residue was
subjected to column chromatography on neutral alumina using
hexanes/ethyl acetate mixture as eluent to afford the product
27 as a pale yellow viscous liquid (105 mg, 75%). Analytical
data of 27. TLC (SiO2): Rf 0.19 (50% ethyl acetate in hexane).
1H NMR (500 MHz, CDCl3, TMS): δ 7.42- 7.29 (m, 9H),
7.21-7.19 (m, 1H), 5.9 (brs, 1H), 4.65 (s, 2H), 4.60 (d, 2H, J =
6.0 Hz,) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ 191.5,
176.5, 136.8, 130.4, 129.1, 129.1, 128.2, 127.5, 127.4, 126.3,
94.1, 74.6, 45.4 ppm. HRMS (ESI) m/z: (M+Na)+ calcd for
C17H15NNaO2 288.0995; Found: 288.0988.
5-Ethoxy-2-methyl-4-(p-tolyl)furan-3(2H)-one & 5-ethoxy-
2-methyl-4-(m-tolyl)furan-3(2H)-one (20). Following the
general
experimental
procedure,
4-methyl-2-
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(trimethylsilyl)phenyl trifluoromethanesulfonate 1h (176 mg,
1.25 equiv.), ethyl 4-bromo-3-oxopentanoate 2c (100 mg, 0.45
mmol), KF (130 mg, 5.0 equiv.), 18C-6 (592 mg, 5.0 equiv.)
o
in CH3CN (3.0 mL) at 0 C and subsequent stirring at room
temperature for 5 h. The crude product was purified over silica
gel (100-200 mesh) column chromatography (30% ethyl
acetate in hexanes) to afford the desired product 20 as a pale
yellow solid and as regioisomers in a ratio of 1.2:1 (66 mg,
o
1
63%). Analytical data of 20. Mp: 140-142 C. H NMR (500
MHz, CDCl3, TMS): δ 7.76-7.73 (m, 3.2H), 7.62 (d, 1.2H, J =
8.0 Hz) 7.24 (t, 1.2H, J = 8.0 Hz), 7.16 (d, 2H, J = 8.5 Hz),
7.00 (d, 1.2H, J = 7.5 Hz,) 4.75-4.70 (m, 2.2H), 4.60-4.55 (m,
4.4H), 2.36 (s, 3.6H), 2.33 (s, 3H), 1.57 (d, 3.6H, J = 1.5 Hz),
1.56 (d, 3H, J = 1.5 Hz), 1.53-1.49 (m, 6.6H) ppm. 13C{1H}
NMR (125 MHz, CDCl3): 197.0, 179.3, 179.1, 137.7, 135.4,
129.6, 128.9, 128.1, 126.8, 126.7, 126.7, 125.9, 123.1, 92.5,
92.4, 82.8, 66.4, 66.3, 21.6, 21.2, 16.7, 14.9. ppm. HRMS
(ESI) m/z: calcd for C14H16NaO3, (M+Na)+: 255.0992, Found:
255.0984.
4-phenyl-5-(phenylamino)furan-3(2H)-one (22). Following
the general experimental procedure, 2-(trimethylsilyl) phenyl
trifluoromethanesulfonate 1a (148 mg, 1.25 equiv.), 4-bromo-
3-oxo-N-phenylbutanamide 2e (100 mg, 0.39 mmol), KF (114
mg, 5.0 equiv.), 18C-6 (516 mg, 5.0 equiv.) in CH3CN (3.0
mL) at 0 oC and subsequent stirring at room temperature for 5
h. The crude product was purified over silica gel (100-200
mesh) column chromatography (40% ethyl acetate in hexanes)
to afford the desired product 22 as a pale brown solid (51 mg,
5-(phenethylamino)-4-phenylfuran-3(2H)-one
(28).
5-
methoxy-4-phenylfuran-3(2H)-one 4 (100 mg, 1.0 equiv., 0.53
mmol) and 2-phenylethylamine 25c (1.1 equiv.) were weighed
into a dry Schlenk tube. Dry methanol (2.0 mL) was added
o
1
o
52%). Analytical data of 22. Mp: 158-160 C. H NMR (300
MHz, CDCl3, TMS): δ 7.43-7.38 (m, 3H), 7.37-7.36 (m, 1H),
7.35-7.32 (m, 1H), 7.30-7.29 (m, 1H), 7.28-7.26 (m, 1H),
7.24-7.20 (m, 3H), 7.15-7.09 (m, 1H), 4.65 (s, 2H) ppm.
13C{1H} NMR (75 MHz, CDCl3): 192.2, 174.9, 136.2, 130.2,
129.8, 129.8, 128.3, 127.3, 125.8, 121.8, 96.4, 75.2 ppm.
HRMS (EI) m/z: calcd for C16H13NO2, (M)+: 251.0946, Found:
251.0941.
and the reaction mixture was stirred at 40 C for 4 h. Upon
completion of the reaction, the solvent was removed and the
residue was subjected to column chromatography on neutral
alumina using hexanes/ethyl acetate mixture as eluent to
afford the product 28 as a pale yellow viscous liquid (114 mg,
77%). Analytical data of 28. TLC (SiO2): Rf 0.18 (50% ethyl
acetate in hexane). 1H NMR (500 MHz, CDCl3, TMS): δ 7.36-
7.19 (m, 10H), 5.58 (brs, 1H), 4.62 (s, 2H), 3.68 (q, 2H, J =
6.3 Hz,), 2.92 (t, 2H, J = 6.6 Hz,) ppm. 13C{1H} NMR (125
MHz, CDCl3): δ 190.4, 176.7, 137.5, 132.2, 132.1, 132.0,
130.0, 129.1, 129.0, 128.8, 128.6, 128.5, 127.4, 127.2, 126.4,
94.5, 74.8, 42.8, 36.2 ppm. HRMS (ESI) m/z: (M+Na)+ calcd
for C18H17NNaO2 302.1152; Found: 302.1157.
4-(3,4-dimethoxyphenyl)-5-(phenylamino)furan-3(2H)-one
(23). Following the general experimental procedure, 4,5-
dimethoxy-2-(trimethylsilyl)phenyl triflate 1c (175 mg, 1.25
equiv.), 4-bromo-3-oxo-N-phenylbutanamide 2e (100 mg, 0.39
mmol), KF (114 mg, 5.0 equiv.), 18C-6 (516 mg, 5.0 equiv.)
o
in CH3CN (3.0 mL) at 0 C and subsequent stirring at room
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
temperature for 5 h. The crude product was purified over silica
gel (100-200 mesh) column chromatography (80% ethyl
acetate in hexanes) to afford the desired product 23 as an
amorphous solid (58 mg, 48%). Analytical data of 23. TLC
1
(SiO2): Rf 0.29 (80% ethyl acetate in hexane). H NMR (300
Optimisation studies, theoretical calculations and copies of
MHz, CDCl3, TMS): δ 7.33-7.28 (m, 3H), 7.24-7.21 (m, 2H),
7.15-7.09 (m, 1H), 6.99 (s, 1H), 6.86 (s, 2H), 4.69 (s, 2H),
3.82 (s, 6H) ppm. 13C{1H} NMR (75 MHz, CDCl3): 191.7.
174.5, 149.7, 148.1, 135.9, 129.4, 125.3, 122.2, 121.1, 119.9,
NMR
spectra
for
all
the
compounds.
X-ray crystallography data and CIF file for 3.
AUTHOR INFORMATION
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The Journal of Organic Chemistry
Page 8 of 9
Carbophosphinylation
of
Arynes
with
Corresponding Authors
Cyanomethyldiphenylphosphine Oxide. Chem. Lett. 2005, 34, 1538.
(d) Yoshida, H.; Watanabe, M.; Morishita, T.; Ohshita, J.; Kunai, A.
Insertion of Arynes into Carbon–Halogen σ-Bonds: Regioselective
1
2
Email: jubijohn@niist.res.in
Email: h.hopf@tu-bs.de
3
4
5
6
7
8
9
Acylation of
Aaromatic Rings. Chem. Commun. 2007, 1505. (e)
Huang, X.; Xue, J. A Novel Multicomponent Reaction of Arynes, β-
Keto Sulfones, and Michael-Type Acceptors:ꢀ A Direct Synthesis of
Polysubstituted Naphthols and Naphthalenes. J. Org. Chem. 2007, 72,
3965. (f) Liu, Y.-L.; Liang, Y.; Pi, S.-F.; Li, J.-H. Selective synthesis
of O-Acylbenzylphosphonates by Insertion Reactions of Arynes into
Beta-Ketophosphonates. J. Org. Chem. 2009, 74, 5691. (g) Liu, Z.;
Larock, R. C. Intermolecular C−N Addition of Amides and S−N
Addition of Sulfinamides to Arynes. J. Am. Chem. Soc. 2005, 127,
13112. (h) Yoshida, H.; Yoshida, R.; Takaki, K. Synchronous Ar-F
and Ar-Sn Bond Formation through Fluorostannylation of Arynes.
Angew. Chem., Int. Ed. 2013, 52, 8629. (i) Li, Y.; Chakrabarty, S.;
ORCID
Jubi John: 0000-0003-0483-2026
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
JJ thanks Alexander von Humboldt Foundation for an experienced
research grant. VKO thank UGC for research fellowship.
Mück-Lichtenfeld,
C.;
Studer,
A.
Ortho-Trialkylstannyl
Arylphosphanes by C-P and C-Sn Bond Formation in Arynes. Angew.
Chem., Int. Ed. 2016, 55, 802. (j) Ahire, M. M.; Khan, R.; Mhaske, S.
B. Synthesis of o-Methyl Trifluoromethyl Sulfide Substituted
Benzophenones via 1,2-Difunctionalization of Aryne by Insertion into
the C–C Bond. Org. Lett. 2017, 19, 2134.
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The Journal of Organic Chemistry
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