Rh(III)-Catalyzed Cascade Nucleophilic Addition/Annulation of 2-Diazo-1,3-diketones with 1,3-Dicarbonyl Compounds to Access 6,7-Dihydrobenzofuran-4(5 H)-ones

Article abstract of DOI:10.1021/acs.joc.1c00259

A Rh(III)-catalyzed cascade nucleophilic addition/intramolecular annulation of 2-diazo-1,3-diketones with 1,3-dicarbonyl compounds (e.g., 1,3-diketones and β-keto esters) is achieved to afford 6,7-dihydrobenzofuran-4(5H)-ones in up to 91% yields. Notably, a wide range of substrates and functional groups were well-tolerated under the optimized reaction conditions to give desired products in moderate to excellent yields with release of N2 and H2O as byproducts. Moreover, the method described is scalable and adaptable to late-stage functionalization.

Full text of DOI:10.1021/acs.joc.1c00259

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Article
Rh(III)-Catalyzed Cascade Nucleophilic Addition/Annulation of
2‑Diazo-1,3-diketones with 1,3-Dicarbonyl Compounds To Access
6,7-Dihydrobenzofuran-4(5H)‑ones
Yinsong Wu, Xinwei He,* Mengqing Xie, Ruxue Li, Yi Ning, Jiahui Duan, Enshen Zhang,
and Yongjia Shang*
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ABSTRACT: A Rh(III)-catalyzed cascade nucleophilic addition/intramolecular annulation of 2-diazo-1,3-diketones with 1,3-
dicarbonyl compounds (e.g., 1,3-diketones and β-keto esters) is achieved to afford 6,7-dihydrobenzofuran-4(5H)-ones in up to 91%
yields. Notably, a wide range of substrates and functional groups were well-tolerated under the optimized reaction conditions to give
desired products in moderate to excellent yields with release of N2 and H2O as byproducts. Moreover, the method described is
scalable and adaptable to late-stage functionalization.
catalyzed transformation of 1-(arylethynyl)-7-oxabicyclo-
[4.1.0]heptan-2-ones (Scheme 1b).9 Despite considerable
efforts toward their synthesis, there still is a strong demand
for more efficient synthetic approaches.
INTRODUCTION
■
Fused and substituted furan derivatives are important hetero-
cycles which widely exist in natural products, drugs, and other
bioactive molecules and exhibit extraordinary biological
activities.1 Among them, the 6,7-dihydrobenzofuran-4(5H)-
one skeleton and derivatives thereof not only are present in
natural products (Figure 1)2 but also play a role as an
Diazo compounds have been widely used as a powerful
substrate for the construction of natural and unnatural
compounds via transition-metal-catalyzed addition, insertion,
cyclization, C−H activation, rearrangement, and others.10,11
Recently, Bi and co-workers described a catalyst-dependent
chemoselective formal insertion of α-diazo esters into C−C or
C−H bonds of 1,3-dicarbonyl compounds leading to a 1,4-
dicarbonyl product containing an all-carbon α-quaternary
center and 2-alkylated 1,3-dicarbonyl products (Scheme
2a).12 On the other hand, Lee and co-workers developed a
novel and selective Ru-catalyzed cyclization of cyclic
diazodicarbonyls with β-ketoamides for the synthesis of
cyclohexanone-fused γ-butenolides via C−C coupling and
amide cleavage process by aniline extrusion (Scheme 2b).13
Figure 1. Selected examples of natural 6,7-dihydrobenzofuran-4(5H)-
one derivatives.
important intermediate in the preparation of a wide range of
synthetic compounds with diverse biological applications.3 To
date, considerable efforts have been devoted to construct 6,7-
dihydrobenzofuran-4(5H)-one derivatives.4 Recently, the
unique structures are typically constructed by the simple and
efficient domino and three-component reactions starting from
dimendone (Scheme 1a).5−8 In addition, Hashmi and co-
workers demonstrated that 6,7-dihydrobenzofuran-4(5H)-ones
and benzofurans can be formed from chemoselective gold(I)-
Received: February 2, 2021
Published: May 20, 2021
https://doi.org/10.1021/acs.joc.1c00259
© 2021 American Chemical Society
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Scheme 1. Previous Synthetic Strategies for 6,7-Dihydrobenzofuran-4(5H)-ones
Scheme 2. Transition-Metal-Catalyzed C−C Bond Formation of Diazo Compounds with 1,3-Dicarbonyl Compounds
We previously reported the Rh-catalyzed diazo compounds
with various substrates for the construction of heterocycles.14
As a result of our continued exploration in this area, we herein
report a novel and efficient Rh(III)-catalyzed cascade
nucleophilic addition/intramolecular annulation of 2-diazo-
1,3-diketones with 1,3-dicarbonyl compounds affording 6,7-
dihydrobenzofuran-4(5H)-ones in moderate to excellent yields
(Scheme 2c).
1, entries 3−6). Further investigation indicated that
[Cp*RhCl2]2 (1 mol %) together with AgSbF6 (20 mol %)
as a cocatalyst was the optimal catalyst system (Table 1, entries
7−16). The subsequent solvent screening revealed that DMF
(N,N-dimethyl formamide), MeCN, toluene, THF (tetrahy-
drofuran), and ethanol did not improve the yield of product 3a
(Table 1, entries 17−22). Finally, examining the effect of
temperature and reaction time ultimately provided the optimal
conditions listed in entry 2 in Table 1.
Having obtained the optimized conditions, we next explored
the substrate scope using various cyclic 2-diazo-1,3-diketones
and 1,3-diketones (Table 2). Benzoylacetones bearing an
electron-donating and electron-withdrawing substituent (e.g.,
Me, OMe, Cl, Br) smoothly reacted with diazo compound 1a
to give the corresponding products 3a−3e in 76−87% yields.
Chloro and bromo substituents at the para- and ortho-position
of benzene ring were well tolerated, which makes this
transformation particularly attractive in terms of increasing
the molecular complexity via transition-metal-catalyzed cou-
pling reactions. Aside from benzoylacetones, 1,3-diphenylpro-
RESULTS AND DISCUSSION
■
We began our investigation utilizing 2-diazo-5,5-dimethylcy-
clohexane-1,3-dione (1a) and 1-phenylbutane-1,3-dione (2a)
as the model substrates in the presence of Rh2(OAc)4 and
AgSbF6 as the catalyst system in 1,2-dichloroethane (DCE) at
80 °C for 5 h, and only a trace amount of product 3a was
monitored (Table 1, entry 1). To our delight, the desired
product 3a was isolated in 83% yield when [Cp*RhCl2]2 was
used as the catalyst (Table 1, entry 2). The transformation did
not take place by using other transition-metal catalysts (Table
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a
In order to investigate the efficiency and utility of this
method, an acyclic 2-diazo-1,3-diketone, such as 3-diazopen-
tane-2,4-dione (6), was also compatible with the reaction
conditions, delivering the corresponding products 7a and 7b in
87% and 79% yields, respectively (Scheme 2a). Furthermore, a
gram-scale reaction was carried out, giving the corresponding
product 3f with almost comparable yield (0.89 g, 86%). Then,
further synthetic transformations of the products were
performed to showcase the applicability of this methodology.
Derivatizations of compound 3f were performed by reacting
with hydrazine hydrate, generating a fused-tricyclic product
7,7-dimethyl-3,4-diphenyl-7,8-dihydro-6H-furo[4,3,2-de]-
cinnoline 8 in 67% yield (Scheme 3c). In addition, treating
compounds 3f, 3r, and 3v with sodium borohydride and
hydroxylamine hydrochloride successfully realized the for-
mation of the products 9, 10, and 11 in 65%, 85%, and 68%
yields, respectively (Scheme 3c). The structures of 9, 10, and
11 were confirmed by X-ray diffraction (see the Supporting
Information).
In order to have more insight toward the reaction
mechanism, we initially performed the H/D exchange
experiment in deuterium oxide under the standard conditions,
affording the deurerated product 2f-d1 in 71% yield (Scheme
4a). Spectroscopic data showed that one H atom on the
methylene group of 2f was exchanged with a deuterium atom
(>99%). Furthermore, we determined the kinetic isotope effect
(KIE) of this cascade reaction. A KIE value of 1.4 was
determined from two parallel independent kinetic reactions,
giving the corresponding product 3f in 51% and 36% yields,
respectively (Scheme 4b). On the basis of these results and
literature precedents,11,12 a plausible reaction mechanism was
proposed in Scheme 4c. The catalyst [Cp*RhCl2]2 initially
reacted with cocatalyst AgSbF6 to form the active catalyst
species [Cp*RhL2]2 (L = SbF6), followed by the formation of
metalcarbene species A with release of the N2 molecule.
Subsequent, the metalcarbene species A reacted with
intermediate B resulting from the enolization of 1,3-diketones
2 to form intermediate C through an intermolecular
nucleophilic addition. Then the protonolysis of the Rh−C
bond of intermediate C produced the intermediate D and
regenerated the active catalyst for a new catalytic cycle. Finally,
intermediate D was proposed to undergo enol−ketone
tauisomerization and intramolecular nucleophilic cyclization
followed by dehydration to eventually furnish the desired
products 3.
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
Rh2(OAc)4
[Cp*RhCl2]2
Rh(PPh3)Cl
Pd(OAc)2
additive
solvent
yield/%
1
2
3
4
5
6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
CsOAc
Ag2CO3
AgOTf
AgNTf2
AgBF4
Cs2CO3
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DMF
DCM
MeCN
toluene
THF
C2H5OH
DCE
DCE
DCE
DCE
trace
83
trace
nr
trace
nr
68
[Ru(p-cymene)Cl2]2
CuI
c
7
d
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
8
82
9
trace
trace
46
trace
32
trace
73
80
trace
trace
trace
trace
56
trace
74
75
10
11
12
13
14
e
15
f
16
17
18
19
20
21
22
g
23
h
24
25
i
61
82
j
26
a
Reaction conditions: 1a (1 mmol), 2a (1 mmol), catalyst (1 mol %),
and additive (20 mol %) in solvent (3 mL) at 80 °C for 5 h. Isolated
yields. The catalyst loading was 0.5 mol %. The catalyst loading was
2 mol %. The additive loading was 10 mol %. The additive loading
was 30%. 50 °C. 100 °C. For 3 h. For 6 h. nr = no reaction.
b
c
d
e
f
g
h
i
j
pane-1,3-dione (2f), and acetylacetone (2g) were also suitable
substrates, affording the corresponding products 3f and 3g in
91% and 67% yields, respectively. Subsequently, 2-diazocyclo-
hexane-1,3-dione bearing substituents such as hydrogen (1b),
monomethyl (1c), phenyl (1d), and 4-chlorophenyl (1f) were
detected, giving the corresponding products 3h−3j and 3t in
47−69% yields. In addition, a series of desired products 3k−3s
were obtained in satisfactory yields (41−75%) through the
cross reaction of different cyclic diazo compounds with 1,3-
diketones. Notably, the reaction also proceeded well by using
1-phenylpentane-1,3-dione and 4-methyl-1-phenylpentane-1,3-
dione as substrates, and the corresponding products 3u and 3v
were obtained in 86% and 89% yield, respectively.
Next, we tried to extend the scope of the reaction with
respect to the β-keto esters (Table 3). Various 4,5,6,7-
tetrahydrobenzofuran-3-carboxylates were obtained in moder-
ate to good yields with wide functional group compatibility:
aryl (bearing with halogen, nitro group), alkyl, and
trifluoromethyl groups were all tolerated. β-Keto esters bearing
a strong electron-withdrawing group had higher reactivity,
producing the corresponding products in higher yields (5c,
5h). Unfortunately, β-keto esters bearing either a cyclopropyl
(4f) or 2-furyl (4g) group failed to provide the corresponding
products 5i and 5j.
CONCLUSIONS
■
In summary, we have developed a mild and efficient strategy
for construction 6,7-dihydrobenzofuran-4(5H)-ones through
Rh(III)-catalyzed cascade C−H insertion/annulation of 2-
diazo-1,3-diketones with 1,3-dicarbonyl compounds and β-keto
esters. This intermolecular annulation procedure undergoes a
cascade nucleophilic addition and intramolecular nucleophilic
annulation process. Particularly noteworthy is that the
byproducts of N2 and H2O in the reaction make the process
environmentally benign. In addition, this operationally simple
method offers direct access to an important furan skeleton
starting from simple and readily available 1,3-dicarbonyl
compounds and may find applications in medicinal chemistry.
EXPERIMENTAL SECTION
General Information. Reactions were monitored by using thin-
layer chromatography (TLC) on commercial silica gel plates (GF
■
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a b
,
Table 2. Substrate Scope
a
Reaction conditions: cyclic 2-diazo-1,3-diketones 1 (1 mmol), 1,3-diketones 2 (1 mmol), [Cp*RhCl2]2 (1 mol %), and AgSbF6 (20 mol %) in
b
DCE (3 mL) at 80 °C for 5 h. Isolated yields.
a b
,
Table 3. Synthesis of 6,7-Dihydrobenzofuran-4(5H)-ones from Cyclic 2-Diazo-1,3-diketones with β-Keto Esters
a
Reaction conditions: cyclic 2-diazo-1,3-diketones 1 (1 mmol), β-keto esters 4 (1 mmol), [Cp*RhCl2]2 (1 mol %), and AgSbF6 (20 mol %) in
b
DCE (3 mL) at 80 °C for 5 h. Isolated yields.
254). Visualization of the developed plates was performed under UV
lights (GF 254 nm). Flash column chromatography was performed on
CDCl3 solution. Chemical shifts as internal standard were referenced
to CDCl3 (δ = 7.26 for H and δ = 77.16 for 13C{1H} NMR) as an
1
1
silica gel (200−300 mesh). H and 13C NMR spectra were recorded
internal standard. HRMS analysis with a quadrupole time-of-flight
mass spectrometer yielded ion mass/charge (m/z) ratios in atomic
mass units. IR spectra were measured as dry films (KBr), and the
peaks are reported in terms of wavenumber (cm−1). The melting
points were measured using an SGWX-4 melting point apparatus.
on a 300 and 400 MHz spectrometer. Chemical shifts were expressed
in parts per million (δ); the signals were reported as s (singlet), br s
(broad singlet), d (doublet), dd (doublet of doublet), t (triplet), q
(quartet), and m (multiplet); and coupling constants (J) were given
in Hz. 13C{1H} NMR spectra were recorded at 75 and 100 MHz in
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Scheme 3. Further Studies
AgSbF6 (20 mol %) in 1,2-dihaloethane (3 mL) was heated to 80 °C
in an oil bath for 5 h. After the reaction completed (as determined
using TLC), the reaction mixture was cooled to room temperature,
extracted with dichloromethane (3 × 10 mL), and washed with brine.
The organic layers were combined, dried over Na2SO4, filtered, and
then evaporated under vacuum. The residue was purified using flash
column chromatography with a silica gel (200−300 mesh), using
ethyl acetate and petroleum ether (1:6, v/v) as the elution solvent to
give desired product 3.
Scheme 4. Control Experiments and Proposed Mechanism
Gram-Scale Synthesis of Compound 3f. A mixture of 2-diazo-
5,5-dimethylcyclohexane-1,3-dione 1a (498 mg, 3 mmol), 1,3-
diphenylpropane-1,3-dione 2f (672 mg, 3 mmol), [Cp*RhCl2]2 (1
mol %), and AgSbF6 (20 mol %) in 1,2-dihaloethane (3 mL) was
heated to 80 °C in an oil bath for 5 h. After the reaction completed
(as determined using TLC), the reaction mixture was cooled to room
temperature, extracted with dichloromethane (3 × 20 mL), and
washed with brine. The organic layers were combined, dried over
Na2SO4, filtered, and then evaporated under vacuum. The residue was
purified using flash column chromatography with silica gel (200−300
mesh), using ethyl acetate and petroleum ether (1:6, v/v) as the
elution solvent to give desired product 3f in 86% yield (0.89 g).
3-Benzoyl-2,6,6-trimethyl-6,7-dihydrobenzofuran-4(5H)-one
(3a). The title compound was prepared from 2-diazo-5,5-
dimethylcyclohexane-1,3-dione and 1-phenylbutane-1,3-dione accord-
ing to the general procedures and purified by column chromatography
(petroleum ether/ethyl acetate 6:1, Rf = 0.5) to afford a white solid in
83% yield (234 mg); mp 152−154 °C; 1H NMR (300 MHz, CDCl3)
δ 7.80 (d, J = 8.1 Hz, 2H), 7.54 (t, J = 8.1 Hz, 1H) 7.54−7.40 (m,
2H), 2.77 (s, 2H), 2.35 (s, 3H), 2.32 (s, 2H), 1.15 (s, 6H); 13C{1H}
NMR (75 MHz, CDCl3) δ 192.0, 191.5, 164.5, 155.8, 138.4, 133.2,
129.4, 128.4, 119.7, 1118.3, 52.4, 37.4, 35.4, 28.7, 13.0; IR (KBr) ν
2957, 2356, 1673, 1656, 1594, 1581, 1447, 1426, 1380, 1323, 1302,
1227, 1056, 1009, 899, 716, 699 cm−1; HRMS (APCI-TOF) m/z: [M
+ H]+ calcd for C18H19O3 283.1329; found 283.1333.
General Procedure for the Synthesis of Dihydrobenzofur-
an-4(5H)-ones 3. A mixture of cyclic 2-diazo-1,3-diketones 1 (1
mmol), 1,3-diketones 2 (1 mmol), [Cp*RhCl2]2 (1 mol %), and
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2,6,6-Trimethyl-3-(4-methylbenzoyl)-6,7-dihydrobenzofuran-
4(5H)-one (3b). The title compound was prepared from 2-diazo-5,5-
dimethylcyclohexane-1,3-dione and 1-(p-tolyl)butane-1,3-dione ac-
cording to the general procedures and purified by column
chromatography (petroleum ether/ethyl acetate 6:1, Rf = 0.5) to
3-Acetyl-2,6,6-trimethyl-6,7-dihydrobenzofuran-4(5H)-one (3g).
The title compound was prepared from 2-diazo-5,5-dimethylcyclo-
hexane-1,3-dione and pentane-2,4-dione according to the general
procedures and purified by column chromatography (petroleum
ether/ethyl acetate 6:1, Rf = 0.5) to afford a yellow solid in 67% yield
1
1
afford a white solid in 76% yield (225 mg); mp 151−152 °C; H
(148 mg); mp 46−48 °C; H NMR (400 MHz, CDCl3) δ 2.72 (s,
2H), 2.64 (s, 3H), 2.41(s, 3H), 2.39(s, 2H), 1.14(s, 6H); 13C{1H}
NMR (100 MHz, CDCl3) δ 197.2, 193.3, 165.0, 158.4, 119.8, 118.1,
53.3, 37.6, 35.1, 32.1, 28.6, 13.8; IR (KBr) ν 2960, 2364, 1678, 1662,
1556, 1492, 1413, 1371, 1301, 1213, 1089, 835, 516 cm−1; HRMS
(APCI-TOF) m/z: [M + H]+ calcd for C13H17O3 221.1172; found
221.1168.
NMR (300 MHz, CDCl3) δ 7.70 (d, J = 8.7 Hz, 2H), 7.19 (d, J = 8.7
Hz, 2H), 2.76 (s, 2H), 2.39 (s, 3H), 2.33(s, 3H), 2.32 (s, 2H), 1.15
(s, 6H); 13C{1H} NMR (75 MHz, CDCl3) δ 192.3, 191.2, 164.5,
155.6, 144.1, 135.9, 129.7, 129.2, 119.8, 118.4, 52.5, 37.5, 35.5, 28.7,
22.0, 13.0; IR (KBr) ν 2961, 2369, 1673, 1645, 1596, 1577, 1509,
1426, 1320, 1227, 1169, 1148, 1023, 905, 844, 773 cm−1; HRMS
(APCI-TOF) m/z: [M + H]+ calcd for C19H21O3 297.1481; found
297.1482.
3-Benzoyl-2-methyl-6,7-dihydrobenzofuran-4(5H)-one (3h). The
title compound was prepared from 2-diazocyclohexane-1,3-dione and
1-phenylbutane-1,3-dione according to the general procedures and
purified by column chromatography (petroleum ether/ethyl acetate
6:1, Rf = 0.5) to afford a white solid in 60% yield (153 mg); mp 109−
110 °C; 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 3.0 Hz, 2H), 7.54
(t, J = 3.0 Hz, 1H), 7.42 (t, J = 3.0 Hz, 2H), 2.90 (t, J = 2.4 Hz, 2H),
2.44 (t, J = 2.4 Hz, 2H), 2.33 (s, 3H), 2.21−2.16 (m, 2H); 13C{1H}
NMR (100 MHz, CDCl3) δ 192.5, 191.6, 165.5, 155.2, 138.5, 133.3,
129.5, 128.5, 121.0, 118.5, 38.1, 23.5, 22.6, 12.9; IR (KBr) ν 2956,
2355, 1670, 1654, 1595, 1579, 1446, 1425, 1379, 1321, 1300, 1226,
1055, 1008, 898, 715, 698 cm−1; HRMS (APCI-TOF) m/z: [M +
H]+ calcd for C16H15O3 255.1016; found 255.1012.
3-Benzoyl-2,6-dimethyl-6,7-dihydrobenzofuran-4(5H)-one (3i).
The title compound was prepared from 2-diazo-5-methylcyclo-
hexane-1,3-dione and 1,3-diphenylpropane-1,3-dione according to
the general procedures and purified by column chromatography
(petroleum ether/ethyl acetate 6:1, Rf = 0.5) to afford a white solid in
65% yield (215 mg); mp 181−182 °C; 1H NMR (400 MHz, CDCl3)
δ 7.79 (dt, J1 = 1.0 Hz, J2 = 4.3 Hz, 2H), 7.53 (dd, J1 = 1.0 Hz, J2 = 4.5
Hz, 1H), 7.41 (t, J = 4.7 Hz, 2H), 2.97 (m, 1H), 2.54 (m, 1H), 2.46
(m, 2H), 2.32 (s, 3H), 2.19 (m, 1H), 1.16 (d, J = 4.0 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 192.1, 191.4, 165.1, 155.4,
3-(4-Methoxybenzoyl)-2,6,6-trimethyl-6,7-dihydrobenzofuran-
4(5H)-one (3c). The title compound was prepared from 2-diazo-5,5-
dimethylcyclohexane-1,3-dione and 1-(4-methoxyphenyl)butane-1,3-
dione according to the general procedures and purified by column
chromatography (petroleum ether/ethyl acetate 6:1, Rf = 0.5) to
1
afford a white solid in 78% yield (244 mg); mp 135−136 °C; H
NMR (300 MHz, CDCl3) δ 7.79 (d, J = 9.6 Hz, 2H), 6.87 (d, J = 9.6
Hz, 2H), 3.86 (s, 3H), 2.76 (s, 2H), 2.33 (s, 2H), 2.32(s, 3H), 1.16
(s, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ 192.0, 191.1, 164.5,
155.4, 144.0, 135.8, 129.6, 129.1, 119.8, 118.3, 52.4, 37.4, 35.4, 28.7,
21.9, 12.9; IR (KBr) ν 2960, 2368, 1672, 1643, 1595, 1575, 1508,
1425, 1319, 1225, 1168, 1147, 1020, 904, 842, 771 cm−1; HRMS
(APCI-TOF) m/z: [M + H]+ calcd for C19H21O4 313.1434; found
313.1437.
3-(4-Chlorobenzoyl)-2,6,6-trimethyl-6,7-dihydrobenzofuran-
4(5H)-one (3d). The title compound was prepared from 2-diazo-5,5-
dimethylcyclohexane-1,3-dione and 1-(4-chlorophenyl)butane-1,3-
dione according to the general procedures and purified by column
chromatography (petroleum ether/ethyl acetate 6:1, Rf = 0.5) to
afford a yellow solid in 87% yield (276 mg); mp 91−92 °C; 1H NMR
(400 MHz, CDCl3) δ 7.70 (d, J = 5.5 Hz, 2H), 7.34 (d, J = 5.5 Hz,
2H), 2.75 (s, 2H), 2.34 (s, 3H), 2.30 (s, 2H), 1.13 (s, 6H); 13C{1H}
NMR (100 MHz, CDCl3) δ 192.0, 190.1, 164.8, 156.2, 139.3, 136.8,
130.6, 126.6, 119.4, 117.8, 52.3, 37.3, 35.3, 28.5, 12.8; IR (KBr) ν
2960, 2362, 2339, 1674, 1654, 1583, 1419, 1317, 1220, 1147, 1087,
1045, 893, 837, 759 cm−1; HRMS (APCI-TOF) calcd for C18H18ClO3
[M + H]+ 317.0939; found 317.0940.
138.3, 133.2, 129.4, 128.3, 48.4, 31.4, 30.7, 21.1, 12.9; IR (KBr) ν
2960, 2360, 2338, 1676, 1657, 1586, 1421, 1319, 1223, 1151, 1090,
1044, 895, 841, 760 cm−1; HRMS (APCI-TOF) m/z: [M + H]+ calcd
for C17H17O3 269.1172; found 269.1170.
3-Benzoyl-2-methyl-6-phenyl-6,7-dihydrobenzofuran-4(5H)-one
(3j). The title compound was prepared from 2-diazo-5-phenylcyclo-
hexane-1,3-dione and 1-phenylbutane-1,3-dione according to the
general procedures and purified by column chromatography
(petroleum ether/ethyl acetate 6:1, Rf = 0.5) to afford a white solid
in 69% yield (227 mg); mp 121−123 °C; 1H NMR (500 MHz,
CDCl3) δ 7.83 (d, J = 3.0 Hz, 2H), 7.56 (t, J = 3.0 Hz 1H), 7.44 (t, J
= 3.2 Hz, 2H), 7.37 (t, J = 3.0 Hz, 2H), 7.30 (t, J = 2.0 Hz, 3H), 3.60
(m, 1H), 3.16 (m, 2H), 2.72 (m, 2H), 2.36 (s, 3H); 13C{1H} NMR
(125 MHz, CDCl3) δ 191.4, 164.9, 156.1, 142.6, 138.6, 133.5, 129.7,
129.3, 128.7, 127.7, 127.2, 121.1, 118.7, 45.5, 41.4, 31.5, 12.3; IR
(KBr) 2926, 2364, 1677, 1647, 1580, 1497, 1456, 1436, 1409, 1380,
1325,1306, 1237, 1209, 1045, 908, 765, 733, 694, 669 cm−1; HRMS
(APCI-TOF) m/z: [M + H]+ calcd for C22H19O3 331.1329; found
331.1323.
2-Methyl-3-(4-methylbenzoyl)-6,7-dihydrobenzofuran-4(5H)-
one (3k). The title compound was prepared from 2-diazocyclohexane-
1,3-dione and 1-(p-tolyl)butane-1,3-dione according to the general
procedures and purified by column chromatography (petroleum
ether/ethyl acetate 6:1, Rf = 0.5) to afford a white solid in 53% yield
(142 mg); mp 129−130 °C; 1H NMR (500 MHz, CDCl3) δ 7.71 (d,
J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 2.90 (t, J = 6.0 Hz, 2H),
2.44 (t, J = 6.0 Hz, 2H), 2.40 (s, 3H), 2.31 (s, 3H), 2.21−2.16 (m,
2H); 13C{1H} NMR (125 MHz, CDCl3) δ 192.7, 191.2, 165.5, 154.8,
144.1, 135.8, 129.7, 129.2, 121.0, 118.6, 38.1, 23.5, 22.6, 22.0, 12.9; IR
(KBr) ν 2956, 2355, 1670, 1654, 1595, 1579, 1446, 1425, 1379, 1321,
1300, 1226, 1055, 1008, 898, 715, 698 cm−1; HRMS (APCI-TOF)
m/z: [M + H]+ calcd for C17H17O3 2695.1172; found 269.1170.
2,6-Dimethyl-3-(4-methylbenzoyl)-6,7-dihydrobenzofuran-
4(5H)-one (3l). The title compound was prepared from 2-diazo-5-
methylcyclohexane-1,3-dione and 1-(p-tolyl)butane-1,3-dione accord-
3-(3-Bromobenzoyl)-2,6,6-trimethyl-6,7-dihydrobenzofuran-
4(5H)-one (3e). The title compound was prepared from 2-diazo-5,5-
dimethylcyclohexane-1,3-dione and 1-(2-bromophenyl)butane-1,3-
dione according to the general procedures and purified by column
chromatography (petroleum ether/ethyl acetate 6:1, Rf = 0.5) to
1
afford a white solid in 76% yield (275 mg); mp 121−122 °C; H
NMR (400 MHz, CDCl3) δ 7.89 (t, J = 1.3 Hz, 1H), 7.71−7.68 (m,
1H), 7.67−7.64 (m, 1H), 7.29 (t, J = 4.8 Hz, 1H), 2.78 (s, 2H), 2.37
(s, 3H), 2.32 (s, 2H), 1.16 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3) δ 192.0, 190.0, 164.8, 156.6, 140.4, 135.9, 132.3, 130.0, 127.9,
122.7, 119.6, 117.8, 52.4, 37.4, 35.5, 28.7, 13.1; IR (KBr) ν 2964,
2368, 2343, 1664, 1639, 1581, 1562, 1427, 1379, 1305, 1217, 1147,
1049, 927, 904, 750, 729 cm−1; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C18H18BrO3 361.0434; found 361.0433.
3-Benzoyl-6,6-dimethyl-2-phenyl-6,7-dihydrobenzofuran-4(5H)-
one (3f). The title compound was prepared from 2-diazo-5,5-
dimethylcyclohexane-1,3-dione and 1,3-diphenylpropane-1,3-dione
according to the general procedures and purified by column
chromatography (petroleum ether/ethyl acetate 6:1, Rf = 0.5) to
1
afford a white solid in 91% yield (313 mg); mp 181−182 °C; H
NMR (400 MHz, CDCl3) δ 7.88 (dd, J = 8.0, 1.2 Hz, 2H), 7.57−7.50
(m, 3H), 7.39 (t, J = 8.0 Hz, 2H), 7.31−7.25 (m, 3H), 2.87 (s, 2H),
2.34 (s, 2H), 1.18 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ
192.5, 192.1, 165.0, 152.2, 137.5, 133.8, 129.6, 129.1, 129.0, 128.9,
128.8, 126.1, 121.6, 117.5, 52.2, 37.6, 35.5, 28.8; IR (KBr) ν 2968,
2368, 2351, 1718, 1683, 1527, 1444, 1350, 1336, 1236, 1058, 1035,
734, 680 cm−1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C23H21O3 345.1485; found 345.1493.
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ing to the general procedures and purified by column chromatography
(petroleum ether/ethyl acetate 6:1, Rf = 0.5) to afford a yellow solid
in 68% yield (193 mg); mp 108−109 °C; 1H NMR (400 MHz,
CDCl3) δ 7.68 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 2.98−
2.91 (m, 1H), 2.58−2.50 (m, 1H), 2.47−2.40 (m, 2H), 2.37 (s, 3H),
2.29 (s, 3H), 2.22−2.13 (m, 1H), 1.15 (m, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 192.3, 191.1, 165.1, 155.0, 144.1, 135.8, 129.7, 129.2,
120.7, 118.5, 46.6, 31.6, 30.8, 21.9, 21.2, 12.9; IR (KBr) ν 2963, 2366,
1673, 1645, 1596, 1577, 1509, 1426, 1320, 1226, 1169, 1148, 1021,
905, 843, 772 cm−1; HRMS (APCI-TOF) m/z: [M + H]+ calcd for
C18H19O3 283.1329; found 283.1331.
3-(4-Methoxybenzoyl)-2-methyl-6,7-dihydrobenzofuran-4(5H)-
one (3m). The title compound was prepared from 2-diazocyclo-
hexane-1,3-dione and 1-(4-methoxyphenyl)butane-1,3-dione accord-
ing to the general procedures and purified by column chromatography
(petroleum ether/ethyl acetate 6:1, Rf = 0.5) to afford a white solid in
56% yield (158 mg); mp 129−130 °C; 1H NMR (400 MHz, CDCl3)
δ 7.70 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 2.87 (t, J = 6.0
Hz, 2H), 2.42 (t, J = 6.0 Hz, 2H), 2.37 (s, 3H), 2.29 (s, 3H), 2.19−
2.13 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 192.7, 191.2,
165.5, 154.8, 144.1, 135.8, 129.7, 129.2, 121.0, 118.6, 38.1, 23.5, 22.6,
22.0, 12.9; IR (KBr) ν 2956, 2355, 1670, 1654, 1595, 1579, 1446,
1425, 1379, 1321, 1300, 1226, 1055, 1008, 898, 715, 698. cm−1;
HRMS (APCI-TOF) m/z: [M + H]+ calcd for C17H17O4 285.1121;
found 285.1124.
3-(4-Methoxybenzoyl)-2,6-dimethyl-6,7-dihydrobenzofuran-
4(5H)-one (3n). The title compound was prepared from 2-diazo-5-
methylcyclohexane-1,3-dione and 1-(4-methoxyphenyl)butane-1,3-
dione according to the general procedures and purified by column
chromatography (petroleum ether/ethyl acetate 6:1, Rf = 0.5) to
afford a white solid in 65% yield (194 mg); mp 91−92 °C; 1H NMR
(400 MHz, CDCl3) δ 7.98−7.64 (m, 2H), 7.01−6.75 (m, 2H), 3.85
(s, 3H), 3.01−2.94 (m, 1H), 2.61−2.52 (m, 1H), 2.52−2.44 (m, 2H),
2.30 (s, 3H), 2.25−2.17 (m, 1H), 1.17 (d, J = 6.4 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 192.3, 189.9, 165.1, 163.7, 154.5, 131.9,
131.2, 120.6, 118.4, 113.7, 55.5, 46.5, 46.4, 31.5, 30.8, 21.1, 12.8;
ppm; IR (KBr) ν cm−1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C18H19O4 299.1278; found 299.1281.
3-(4-Chlorobenzoyl)-2-methyl-6,7-dihydrobenzofuran-4(5H)-
one (3o). The title compound was prepared from 2-diazocyclohexane-
1,3-dione and 1-(4-chlorophenyl)butane-1,3-dione according to the
general procedures and purified by column chromatography
(petroleum ether/ethyl acetate 6:1, Rf = 0.5) to afford a yellow
solid in 65% yield (188 mg); mp 113−115 °C; 1H NMR (500 MHz,
CDCl3) δ 7.74 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 2.90 (t, J
= 6.0 Hz, 2H), 2.44 (t, J = 6.0 Hz, 2H), 2.34 (s, 3H), 2.25−2.12 (m,
2H); 13C{1H} NMR (125 MHz, CDCl3) δ 192.6, 190.3, 165.7, 155.6,
139.6, 136.9, 130.8, 128.8, 120.9, 118.2, 38.1, 23.5, 22.6, 12.9, 12.8; IR
(KBr) ν 2961, 2363, 2340, 1676, 1653, 1586, 1420, 1319, 1221, 1148,
1086, 1046, 893, 837, 758 cm−1; HRMS (APCI-TOF) m/z: [M +
H]+ calcd for C16H14ClO3 289.0626; found 289.0630.
in 57% yield (180 mg); mp 101−102 °C; 1H NMR (400 MHz,
CDCl3) δ 7.94 (t, J = 1.7 Hz, 1H), 7.69 (m, 2H), 7.30 (dd, J = 12.7,
4.8 Hz, 1H), 2.93 (t, J = 6.3 Hz, 2H), 2.45 (t, 6.3 Hz, 2H), 2.36 (s,
3H), 2.21 (dd, J = 12.9, 6.5 Hz, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 192.5, 190.0, 186.7, 156.8, 140.1, 135.9, 132.1, 129.9, 127.9,
122.6, 120.6, 117.8, 37.9, 23.3, 22.4, 12.9; IR (KBr) ν 2965, 2369,
2345, 1665, 1641, 1583, 1564, 1429, 1381, 1307, 1219, 1149, 1051,
929, 905, 752, 731 cm−1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C16H14O3Br 333.0125; found 333.0121.
3-Benzoyl-2-phenyl-6,7-dihydrobenzofuran-4(5H)-one (3r). The
title compound was prepared from 2-diazocyclohexane-1,3-dione and
1,3-diphenylpropane-1,3-dione according to the general procedures
and purified by column chromatography (petroleum ether/ethyl
acetate 6:1, Rf = 0.5) to afford a white solid in 75% yield (237 mg);
mp 101−102 °C; 1H NMR (400 MHz, CDCl3) δ 7.92 (m, 2H), 7.55
(m, 3H), 7.41 (t, 5.0 Hz, 2H), 7.30 (m, 3H), 3.02 (t, J = 4.0 Hz, 2H),
2.48 (t, J = 3.0 Hz, 2H), 2.25 (m, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 207.3, 192.8, 192.7, 165.9, 151.5, 137.3, 133.8, 129.6, 129.0,
128.9, 128.7, 125.9, 122.6, 117.5, 37.8, 31.1, 23.6, 22.5; IR (KBr) ν
2922, 2360, 1675, 1649, 1579, 1495, 1450, 1434, 1407, 1378,
1320,1304, 1232, 1211, 1043, 906, 762, 731, 691, 668 cm−1; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C21H17O3 317.1172; found
317.1170.
3-Acetyl-2-methyl-6,7-dihydrobenzofuran-4(5H)-one (3s). The
title compound was prepared from 2-diazocyclohexane-1,3-dione
and pentane-2,4-dione according to the general procedures and
purified by column chromatography (petroleum ether/ethyl acetate
6:1, Rf = 0.5) to afford a yellow liquid in 41% yield (79 mg); 1H NMR
(300 MHz, CDCl3) δ 2.85 (t, J = 6.3 Hz, 2H), 2.64 (s, 3H), 2.53 (t, J
= 6.3 Hz, 2H), 2.45 (s, 3H), 2.20−2.12 (m, 2H); 13C{1H} NMR (125
MHz, CDCl3) δ 197.3, 193.7, 165.8, 157.7, 119.8, 119.2, 38.7, 32.1,
32.0, 23.5, 13.6; IR (KBr) ν 2372, 2339, 1381 cm−1; HRMS (APCI-
TOF) m/z: [M + H]+ calcd for C11H13O3 193.0859; found 193.0858.
3-Acetyl-6-(4-chlorophenyl)-2-methyl-6,7-dihydrobenzofuran-
4(5H)-one (3t). The title compound was prepared from 5-(4-
chlorophenyl)-2-diazocyclohexane-1,3-dione and pentane-2,4-dione
according to the general procedures and purified by column
chromatography (petroleum ether/ethyl acetate 6:1, Rf = 0.5) to
1
afford a white solid in 47% yield (142 mg); mp 148−150 °C; H
NMR (300 MHz, CDCl3) δ 7.32 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4
Hz, 2H), 3.58−3.46 (m, 1H), 3.19−2.96 (m, 2H), 2.83−2.78 (m,
2H), 2.67 (s, 3H), 2.48 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ
197.0, 191.8, 164.7, 158.8, 140.6, 133.3, 129.2, 128.2, 119.8, 119.1,
45.8, 40.2, 32.1, 31.2, 13.7; IR (KBr) ν 2960, 2364, 1678, 1662, 1556,
1492, 1413, 1371, 1301, 1213, 1089, 835, 516 cm−1; HRMS (APCI-
TOF) m/z: [M + H]+ calcd for C17H16ClO3 303.0782; found
303.0778.
3-Benzoyl-2-ethyl-6,6-dimethyl-6,7-dihydrobenzofuran-4(5H)-
one (3u). The title compound was prepared from 2-diazo-5,5-
dimethylcyclohexane-1,3-dione and 1-phenylpentane-1,3-dione ac-
cording to the general procedures and purified by column
chromatography (petroleum ether/ethyl acetate 6:1, Rf = 0.5) to
3-(4-Chlorobenzoyl)-2,6-dimethyl-6,7-dihydrobenzofuran-4(5H)-
one (3p). The title compound was prepared from 2-diazo-5-
methylcyclohexane-1,3-dione and 1-(4-chlorophenyl)butane-1,3-
dione according to the general procedures and purified by column
chromatography (petroleum ether/ethyl acetate 6:1, Rf = 0.5) to
1
afford a yellow liquid in 86% yield (254 mg); H NMR (400 MHz,
CDCl3) δ 7.79 (d, J = 4.4 Hz, 2H), 7.52 (t, J = 4.8 Hz, 1H), 7.40 (t, J
= 5.0 Hz, 2H), 2.77(s, 2H), 2.67 (q, J = 4.8 Hz, 2H), 2.30 s, 2H), 1.21
(t, J = 4.8 Hz, 3H), 1.14 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3)
δ 192.2, 191.9, 164.2, 162.7, 138.5, 133.2, 129.3, 128.4, 119.7, 116.2,
52.3, 37.5, 35.4, 28.7, 27.3, 21.3; IR (KBr) ν 2958, 2355, 1674, 1652,
1590, 1583, 1449, 1427, 1389, 1320, 1300, 1225, 1057, 1010, 900,
715, 702 cm−1; HRMS (APCI-TOF) m/z: [M + H]+ calcd for
C19H21O3 297.1485; found 297.1486.
1
afford a yellow solid in 69% yield (209 mg); mp 131−132 °C; H
NMR (400 MHz, CDCl3) δ 7.74−7.71 (m, 2H), 7.39−7.36 (m, 2H),
3.00−2.95 (m, 1H), 2.60−2.53 (m, 1H), 2.49−2.44 (m, 2H), 2.34 (s,
3H), 2.23−2.15 (m, 1H); 13C{1H}NMR (100 MHz, CDCl3) δ 192.4,
190.3, 165.4, 158.0, 139.5 136.7, 130.7, 128.7, 120.3, 117.9, 46.5, 31.4,
30.8, 21.1 12.9; IR (KBr) ν 2961, 2363, 2340, 1675, 1655, 1585,
1420, 1318, 1221, 1149, 1089, 1046, 894, 839, 761 cm−1; HRMS
(APCI-TOF) m/z: [M + H]+ calcd for C17H16ClO3 303.0782; found
303.0781.
3-Benzoyl-2-isopropyl-6,6-dimethyl-6,7-dihydrobenzofuran-
4(5H)-one (3v). The title compound was prepared from 2-diazo-5,5-
dimethylcyclohexane-1,3-dione and 4-methyl-1-phenylpentane-1,3-
dione according to the general procedures and purified by column
chromatography (petroleum ether/ethyl acetate 6:1, Rf = 0.5) to
3-(2-Bromobenzoyl)-2-methyl-6,7-dihydrobenzofuran-4(5H)-
one (3q). The title compound was prepared from 2-diazocyclohexane-
1,3-dione and 1-(2-bromophenyl)butane-1,3-dione according to the
general procedures and purified by column chromatography
(petroleum ether/ethyl acetate 6:1, Rf = 0.5) to afford a white solid
1
afford a white solid in 89% yield (275 mg); mp 118−119 °C; H
NMR (400 MHz, CDCl3) δ 7.80 (d, J = 4.4 Hz, 2H), 7.54 (t, J = 4.4
Hz, 1H), 7.41 (t, J = 5.0 Hz, 2H), 3.08 (m, 1H), 2.78 (s, 2H), 2.30 (s,
2H), 1.24 (d, J = 4.4 Hz, 6H), 1.16 (s, 6H); 13C{1H} NMR (100
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MHz, CDCl3) δ 192.0, 191.5, 154.5, 160.2, 138.4, 133.1, 129.3, 128.3,
119.6, 117.2, 52.3, 37.4, 35.3, 28.6, 20.6, 12.7; IR (KBr) ν 2957, 2350,
1672, 1654, 1585, 1589, 1450, 1431, 1391, 1322, 1298, 1227, 1059,
1013, 901, 715, 702 cm−1; HRMS (APC) m/z: [M + H]+ calcd for
311.1642; found 311.1648.
Hz), 119 (q, JC−F = 257 Hz), 118.9, 118.0, 62.5, 52.3, 37.2, 35.3, 28.5,
13.9; 19F NMR (377 MHz, CDCl3) δ −62.8; IR (KBr) ν 2365, 1673,
1597, 1584, 1561, 1498, 1461, 1410, 1354, 1317, 1237, 1206, 1177,
1119, 1077, 1015, 953, 900, 773, 761, 731, 710, 692, 671, 657, 616,
578, 544, 480 cm−1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C14H16F3O4 305.0995; found 305.0988.
Ethyl 6-Methyl-4-oxo-2-phenyl-4,5,6,7-tetrahydrobenzofuran-3-
carboxylate (5f). The title compound was prepared from 2-diazo-5-
methylcyclohexane-1,3-dione and ethyl 3-oxo-3-phenylpropanoate
according to the general procedures and purified by column
chromatography (petroleum ether/ethyl acetate 6:1, Rf = 0.5) to
afford a yellow solid in 56% yield (168 mg); mp 65−67 °C; 1H NMR
(400 MHz, CDCl3) δ 7.71 (d, J = 7.6 Hz, 2H), 7.43−7.37 (m, 3H),
4.40 (q, J = 7.2 Hz, 2H), 3.02 (dd, J = 4.4 Hz, 21.2 Hz, 1H), 2.64−
2.53 (m, 2H), 2.52−2.45 (m, 1H), 2.42−2.27 (m, 2H), 1.35 (t, J =
7.2 Hz, 3H), 1.20 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 191.9, 165.3, 164.3, 163.0, 129.1, 128.4, 126.4, 120.4, 111.3,
61.6, 46.3, 31.2, 30.4, 20.9, 13.8; IR (KBr) ν 2975, 2365, 2342, 1743,
1687, 1626, 1578, 1457, 1363, 1276, 1201, 1124, 1052, 1025, 860,
419 cm−1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H19O4
299.1278; found 299.1280.
2-(4-Chlorophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydrobenzo-
furan-3-carboxylate (5g). The title compound was prepared from 2-
diazo-5-methylcyclohexane-1,3-dione and ethyl 3-(4-chlorophenyl)-3-
oxopropanoate according to the general procedures and purified by
column chromatography (petroleum ether/ethyl acetate 6:1, Rf = 0.5)
to afford a yellow solid in 65% yield (217 mg); mp 116−118 °C; 1H
NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.6 Hz, 2H), 7.38 (d, J = 8.6
Hz, 2H), 4.40 (q, J = 7.2 Hz, 2H), 3.02 (dd, J = 4.4 Hz, 16.0 Hz, 1H),
2.64−2.57 (m, 2H), 2.51−2.48 (m, 1H), 2.35−2.27 (m, 1H), 1.36 (t,
J = 7.2 Hz, 3H), 1.20 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 192.1, 165.7, 164.4, 152.4, 135.4, 129.0, 128.0, 127.4, 120.8,
112.0, 62.0, 46.7, 31.5, 30.7, 21.2, 14.1; IR (KBr) ν 2980, 2364, 2346,
1746, 1691, 1622, 1579, 1458, 1364, 1275, 1219, 1126, 1052, 1026,
860, 743, 419 cm−1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C18H18ClO4 333.0888; found 333.0895.
Ethyl 6,6-Dimethyl-4-oxo-2-phenyl-4,5,6,7-tetrahydrobenzo-
furan-3-carboxylate (5a). The title compound was prepared from
2-diazo-5,5-dimethylcyclohexane-1,3-dione and ethyl 3-oxo-3-phenyl-
propanoate according to the general procedures and purified by
column chromatography (petroleum ether/ethyl acetate 6:1, Rf = 0.5)
1
to afford a yellow solid in 75% yield (234 mg); mp 58−59 °C; H
NMR (500 MHz, CDCl3) δ 7.73−7.71 (m, 2H), 7.6−7.49 (m, 3H),
4.40 (q, J = 3.0 Hz, 2H), 2.81 (s, 2H), 2.43 (s, 2H), 1.35 (t, J = 3.0
Hz, 3H), 1.18 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 192.0,
165.0, 164.5, 153.8, 129.4, 128.9, 128.7, 126.7, 119.9, 111.5, 61.8,
52.6, 37.4, 35.3, 28.7, 14.1; IR (KBr) ν 2964, 2362, 2339, 1726, 1680,
1560, 1492, 1438, 1365, 1325, 1222, 1195, 1028, 769, 684 cm−1;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H21O4 313.1434;
found 313.1438.
Ethyl 2-(4-Chlorophenyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-
benzofuran-3-carboxylate (5b). The title compound was prepared
from 2-diazo-5,5-dimethylcyclohexane-1,3-dione and ethyl 3-(4-
chlorophenyl)-3-oxopropanoate according to the general procedures
and purified by column chromatography (petroleum ether/ethyl
acetate 6:1, Rf = 0.5) to afford a yellow solid in 68% yield (236 mg);
mp 110−111 °C; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 4.4 Hz,
2H), 7.38 (d, J = 4.4 Hz, 2H), 4.37(q, J = 7.2 Hz, 2H), 2.80 (s, 2H),
2.43 (s, 2H), 1.35 (t, J = 4.4 Hz, 3H), 1.17(s, 6H); 13C{1H} NMR
(100 MHz, CDCl3) δ 191.9, 165.1, 164.3, 162.8, 135.4, 129.0, 128.0,
127.4, 120.0, 111.9, 61.9, 52.6, 50.3, 37.4, 35.3, 28.7, 14.1; IR (KBr) ν
2965, 2361, 2337, 1729, 1681, 1563, 1494, 1440, 1366, 1324, 1221,
1197, 1025, 771, 681 cm−1; HRMS (APCI-TOF) m/z: [M + H]+
calcd for C19H20ClO4 347.1045; found 347.1051.
Ethyl 6,6-Dimethyl-2-(3-nitrophenyl)-4-oxo-4,5,6,7-tetrahydro-
benzofuran-3-carboxylate (5c). The title compound was prepared
from 2-diazo-5,5-dimethylcyclohexane-1,3-dione and ethyl 3-(3-nitro-
phenyl)-3-oxopropanoate according to the general procedures and
purified by column chromatography (petroleum ether/ethyl acetate
6:1, Rf = 0.5) to afford a white solid in 88% yield (315 mg); mp 127−
Ethyl 6-Methyl-4-oxo-2-(trifluoromethyl)-4,5,6,7-tetrahydro-
benzofuran-3-carboxylate (5h). The title compound was prepared
from 2-diazo-5-methylcyclohexane-1,3-dione and ethyl 4,4,4-trifluoro-
3-oxobutanoate according to the general procedures and purified by
column chromatography (petroleum ether/ethyl acetate 6:1, Rf = 0.5)
1
129 °C; H NMR (300 MHz, CDCl3) δ 8.62 (t, J = 1.7 Hz, 1H), δ
8.22 (m, 1H), δ 8.11(m, 1H), δ 7.61 (t, J = 1.8 Hz, 1H), δ 4.44 (q, J =
6.0 Hz, 2H), 2.85 (s, 2H), 2.46 (s, 2H), 1.38 (t, J = 6.0 Hz 2H), 1.19
(s, 6H); 13C{1H} NMR (75 MHz, CDCl3) δ 207.3, 191.8, 165.8,
163.9, 151.1, 148.5, 132.3, 130.5, 129.9, 123.8, 121.6, 120.1, 113.5,
62.3, 52.6, 37.4, 35.4, 28.7, 14.1; IR (KBr) ν 2978, 2365, 2341, 1729,
1683, 1564, 1497, 1441, 1367, 1329, 1220, 1193, 1027, 770, 685
cm−1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H20O6
358.1285; found 358.1288.
1
to afford a white solid in 80% yield (232 mg); mp 67−69 °C; H
NMR (400 MHz, CDCl3) δ 4.41(q, J = 7.2 Hz, 2H), 3.03 (dd, J = 4.4
Hz, 16.0 Hz, 1H), 3.06−3.00 (m, 1H), 2.65−2.58 (m, 2H), 2.53−
2.46 (m, 1H), 2.33−2.27 (m, 1H), 1.36 (t, J = 7.2 Hz, 3H), 1.20 (d, J
= 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 191.4, 167.3,
161.0, 140.2 (d, JC−F = 43.2 Hz), 119.8, 119.7, 118.1 (d JC−F = 2.4
Hz), 117.1, 62.6, 46.4, 31.3, 30.5, 21.0, 14.0, 19F NMR (377 MHz,
CDCl3) δ −62.9 IR (KBr) ν 2361, 1669, 1595, 1580, 1559, 1496,
1449, 1405, 1350, 1317, 1237, 1206, 1177, 1119, 1077, 1015, 953,
900, 773, 761, 731, 710, 692, 673, 657, 616, 578, 544, 484 cm−1;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H14F3O4 291.0839;
found 291.0831.
Ethyl 2-Isopropyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydrobenzo-
furan-3-carboxylate (5d). The title compound was prepared from
2-diazo-5,5-dimethylcyclohexane-1,3-dione and ethyl 4-methyl-3-
oxopentanoate according to the general procedures and purified by
column chromatography (petroleum ether/ethyl acetate 6:1, Rf = 0.5)
1
1-(4-Benzoyl-2-methyl-5-phenylfuran-3-yl)ethan-1-one (7a).
The title compound was prepared from 3-diazopentane-2,4-dione
and 1,3-diphenylpropane-1,3-dione according to the general proce-
dures and purified by column chromatography (petroleum ether/
ethyl acetate 6:1, Rf = 0.5) to afford a yellow solid in 87% yield (266
to afford a yellow solid in 53% yield (148 mg); mp 47−49 °C; H
NMR (400 MHz, CDCl3) δ 4.34 (q, J = 7.2 Hz, 2H), 3.54 (m, 1H),
2.71 (s, 2H), 2.39 (s, 2H), 1.37 (t, J = 7.2 Hz, 3H), 1.26 (d, J = 6.8
Hz, 6H), 1.13 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 192.0,
166.2, 164.6, 163.4, 118.3, 109.8, 53.2, 37.5, 35.1, 28.7, 27.2, 21.0,
14.3; IR (KBr) ν 2961, 2360, 1679, 1663, 1557, 1494, 1415, 1375,
1398, 1210, 1089, 833, 517, 496 cm−1; HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C16H23O4 279.1591; found 279.1583.
1
mg); mp 152−154 °C; H NMR (400 MHz, CDCl3) δ 7.94 (d, J =
7.2 Hz, 2H), 7.57−7.52 (m, 3H), 7.42 (t, J = 7.6 Hz, 2H), 7.30−7.25
(m, 3H), 2.73 (s, 3H), 3.28 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 193.6, 192.8, 157.1, 149.5, 137.5, 133.8, 129.4, 128.9, 128.7,
128.7, 125.8, 125.1, 120.3, 30.0, 14.9; IR (KBr) ν 2968, 2366, 1719,
1672, 1559, 1542, 1508, 1490, 1325, 1220, 1050, 618, 419 cm−1;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H17O3 305.1172;
found 305.1167.
Ethyl 6,6-Dimethyl-4-oxo-2-(trifluoromethyl)-4,5,6,7-tetrahydro-
benzofuran-3-carboxylate (5e). The title compound was prepared
from 2-diazo-5,5-dimethylcyclohexane-1,3-dione and ethyl 4,4,4-
trifluoro-3-oxobutanoate according to the general procedures and
purified by column chromatography (petroleum ether/ethyl acetate
6:1, Rf = 0.5) to afford a yellow solid in 67% yield (205 mg); mp 45−
47 °C; 1H NMR (400 MHz, CDCl3) δ 4.40 (q, J = 7.2 Hz, 2H), 2.80
(s, 2H), 2.43 (s, 2H), 1.36 (t, J = 6.4 Hz, 3H), 1.16 (s, 6H); 13C{1H}
NMR (100 MHz, CDCl3) δ 191.2, 166.8, 160.9, 140.5 (q, JC−F = 43
1-(4-Benzoyl-2,5-dimethylfuran-3-yl)ethanone (7b). The title
compound was prepared from 3-diazopentane-2,4-dione and 1-
phenylbutane-1,3-dione according to the general procedures and
purified by column chromatography (petroleum ether/ethyl acetate
7377
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Article
6:1, Rf = 0.5) to afford a white solid in 79% yield (191 mg); mp 86−
(petroleum ether/ethyl acetate 3:1); mp 228−229 °C; 1H NMR (400
MHz, CDCl3) δ 7.93 (d, J = 7.2 Hz, 2H), 7.54−7.49 (m, 3H), 7.40 (t,
J = 8.0 Hz, 3H), 7.25−7.21 (m, 3H), 6.70 (s, 1H), 2.87 (t, J = 6.2 Hz,
2H), 2.70 (t, J = 6.2 Hz, 2H), 2.09−2.02 (m, 2H); 13C{1H} NMR
(100 MHz, CDCl3) δ 194.0, 156.0, 150.6, 150.0, 137.1, 133.3, 129.4,
128.5, 128.3, 125.3, 117.0, 116.6, 23.0, 21.7, 21.2; IR (KBr) ν 2950,
2365, 1660, 1638, 1596, 1561, 1489, 1445, 1410, 1341, 1230, 1192,
1071, 932, 901, 767, 751, 710, 690 cm−1; HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C21H18NO3 332.1281; found 332.1273.
1
87 °C; H NMR (400 MHz, CDCl3) δ 7.56 (dd, J = 4.2 Hz, 1.0 Hz,
2H), 7.42−7.36 (m, 3H), 2.63 (s, 3H), 2.45 (s, 3H), 2.41 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 200.0, 193.5, 156.2, 149.3,
129.2, 129.1, 128.9, 126.5, 124.3, 123.5, 31.9, 30.0, 14.8; IR (KBr) ν
2364, 2337, 1730, 1714, 1683, 1653, 1633, 1560, 1543, 1506, 1456,
1431, 1415, 1396, 1377, 1336, 1023, 669 cm−1; HRMS (ESI) m/z:
[M + H]+ calcd for C15H15O3 243.1016; found 243.1021.
General Procedure for the Synthesis of 7,7-Dimethyl-3,4-
diphenyl-7,8-dihydro-6H-furo[4,3,2-de]cinnoline 8. A mixture
of 3-benzoyl-6,6-dimethyl-2-phenyl-6,7-dihydrobenzofuran-4(5H)-
one 3f (344 mg, 1 mmol) and hydrazine hydrate (0.3 mL) in
acetonitrile (3 mL) was heated to 80 °C in an oil bath for 3 h. After
the reaction completed (as determined using TLC), the reaction
mixture was cooled to room temperature, and the solvent was
removed under reduced pressure. The residue was purified using flash
column chromatography with a silica gel (200−300 mesh), using
petroleum ether, ethyl acetate, and triethylamine (300:100:5, v/v) as
the elution solvent to give the desired product 8 in 67% yield.
7,7-Dimethyl-3,4-diphenyl-7,8-dihydro-6H-furo[4,3,2-de]-
cinnoline (8). Yellow solid (228 mg, 67%); Rf = 0.4 (petroleum ether/
ethyl acetate/triethylamine 300:100:5); mp 67−68 °C; 1H NMR
(400 MHz, CDCl3) δ 7.57 (dd, 2H, J = 4.3 Hz, J = 0.9 Hz), 7.42 (t, J
= 4.0 Hz, 1H), 7.31 (t, J = 5.0 Hz, 2H), 7.24 (q, J = 1.4 Hz, 1H), 7.18
(m, 4H), 3.00 (s, 2H), 2.93 (s, 2H), 1.24 (s, 6H); 13C{1H} NMR
(100 MHz, CDCl3) δ 157.0, 154.6, 154.2, 148.8, 136.9, 129.8, 129.7,
129.3, 128.6, 128.5, 128.4, 128.1, 116.7, 108.4, 41.7, 37.9, 36.7, 29.2;
IR (KBr) ν 3418, 2957, 2925, 2854, 2360,2341, 1732, 1652, 1634,
1558, 1541, 1506, 1489, 1445, 1385, 1728, 1160, 1122, 1067, 1021,
925, 766, 728, 692, 668, 659, 517 cm−1; HRMS (ESI) m/z: [M + H]+
calcd for C23H21N2O 341.1648; found 341.1641.
General Procedure for the Synthesis of 3-(Hydroxy-
(phenyl)methyl)-6,6-dimethyl-2-phenyl-6,7-dihydro-
benzofuran-4(5H)-one 9. A mixture of 3-benzoyl-6,6-dimethyl-2-
phenyl-6,7-dihydrobenzofuran-4(5H)-one 3f (344 mg, 1 mmol), and
sodium borohydride (76 mg, 2 mmol) in tetrahydrofuran (3 mL) was
stirred at room temperature under a nitrogen atmosphere for 30 min.
After the reaction completed (as determined using TLC), the reaction
mixture was concentrated under reduced pressure. The residue was
purified using flash column chromatography with a silica gel (200−
300 mesh), using petroleum ether and ethyl acetate (8:1, v/v) as the
elution solvent to give the desired product 9 in 65% yield.
(E)-(4-(Hydroxyimino)-2-isopropyl-6,6-dimethyl-4,5,6,7-
tetrahydrobenzofuran-3-yl)(phenyl)methanone (11). White solid
(110 mg, 68%); Rf = 0.4 (petroleum ether/ethyl acetate 3:1); mp
152−153 °C; H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 7.2 Hz,
2H), 7.52 (t, J = 7.2 Hz, 1H), 7.40 (t, J = 7.6 Hz, 2H), 7.15 (s, 1H),
2.94−2.87 (m, 1H), 2.59 (s, 2H), 2.49 (s, 2H), 1.18 (d, J = 6.8 Hz,
6H), 1.11 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 193.3, 160.7,
154.4, 150.2, 138.4, 133.1, 129.7, 128.3, 115.9, 114.1, 37.2, 35.9, 32.9,
28.9, 27.4, 21.4; IR (KBr) ν 2948, 2352, 1658, 1643, 1601, 1565,
1492, 1463, 1398, 1334, 1226, 1200, 1070, 945, 903, 765, 748, 706,
695 cm−1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H24NO3
326.1751; found 326.1754.
1
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00259.
Detailed copies of NMR spectra for all compounds; X-
ray structures of 3a, 9, 10, and 11 (PDF)
Accession Codes
CCDC 2015794, 2070138, and 2082018−2082019 contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
■
3-(Hydroxy(phenyl)methyl)-6,6-dimethyl-2-phenyl-6,7-dihydro-
Corresponding Authors
benzofuran-4(5H)-one (9). White solid (226 mg, 65%); Rf = 0.5
1
Xinwei He − Key Laboratory of Functional Molecular Solids,
Ministry of Education, Anhui Laboratory of Molecule-Based
Materials (State Key Laboratory Cultivation Base), College
of Chemistry and Materials Science, Anhui Normal
University, Wuhu 241000, P. R. China; orcid.org/0000-
0002-1974-2464; Email: xinweihe@mail.ahnu.edu.cn
Yongjia Shang − Key Laboratory of Functional Molecular
Solids, Ministry of Education, Anhui Laboratory of Molecule-
Based Materials (State Key Laboratory Cultivation Base),
College of Chemistry and Materials Science, Anhui Normal
University, Wuhu 241000, P. R. China; orcid.org/0000-
0001-9873-9150; Email: shyj@mail.ahnu.edu.cn
(petroleum ether/ethyl acetate 8:1); mp 53−55 °C; H NMR (400
MHz, CDCl3) δ 7.52 (d, J = 6.8 Hz, 2H), 7.44−7.38 (m, 5H), 7.34 (t,
J = 7.2 Hz, 2H), 7.29 (t, J = 3.6 Hz, 2H), 6.02 (d, J = 12.0 Hz, 1H),
5.93 (d, J = 12.0 Hz, 1H), 2.89 (s, 2H), 2.46 (q, J = 16.0 Hz, 2H),
1.21 (d, J = 3.2 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 196.4,
167.9, 150.2, 143.4, 129.7, 128.9, 128.7, 128.6, 127.5, 126.8, 126.4,
121.2, 120.6, 68.0, 51.9, 37.7,35.7, 29.0, 28.4; IR (KBr) ν 2982, 2359,
1714, 1675, 1583, 1563, 1494, 1438, 1405, 1367, 1325, 1289, 1224,
1185, 1089, 1063, 1037, 825, 773, 754, 689, 665, 597, 526 cm−1;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C23H23O3 347.1642;
found 347.1635.
General Procedure for the Synthesis of Compounds 10 and
11. A mixture of 3-benzoyl-2-phenyl-6,7-dihydrobenzofuran-4(5H)-
one 3r (316 mg, 1 mmol), or 3-benzoyl-2-isopropyl-6,6-dimethyl-6,7-
dihydrobenzofuran-4(5H)-one 3v (310 mg, 1 mmol), hydroxylamine
hydrochloride (209 mg, 1.5 mmol), and sodium bicarbonate (252 mg,
1.5 mmol) in ethanol (3 mL) was heated to 80 °C in an oil bath for 2
h. After the reaction completed (as determined using TLC), the
reaction mixture was cooled to room temperature, and the solvent was
removed under reduced pressure. The residue was purified using flash
column chromatography with silica gel (200−300 mesh), using
petroleum ether and ethyl acetate (3:1, v/v) as the elution solvent to
give the desired product 10 and 11 in 85% and 82% yield,
respectively.
Authors
Yinsong Wu − Key Laboratory of Functional Molecular Solids,
Ministry of Education, Anhui Laboratory of Molecule-Based
Materials (State Key Laboratory Cultivation Base), College
of Chemistry and Materials Science, Anhui Normal
University, Wuhu 241000, P. R. China
Mengqing Xie − Key Laboratory of Functional Molecular
Solids, Ministry of Education, Anhui Laboratory of Molecule-
Based Materials (State Key Laboratory Cultivation Base),
College of Chemistry and Materials Science, Anhui Normal
University, Wuhu 241000, P. R. China
(E)-3-((Hydroxyimino)(phenyl)methyl)-2-phenyl-6,7-dihydro-
benzofuran-4(5H)-one (10). White solid (282 mg, 85%); Rf = 0.4
7378
https://doi.org/10.1021/acs.joc.1c00259
J. Org. Chem. 2021, 86, 7370−7380

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
synthesis of angular furanocoumarins: Angelicin, oroselone &
oroselol. Tetrahedron 1995, 51, 3087−3094.
Ruxue Li − Key Laboratory of Functional Molecular Solids,
Ministry of Education, Anhui Laboratory of Molecule-Based
Materials (State Key Laboratory Cultivation Base), College
of Chemistry and Materials Science, Anhui Normal
University, Wuhu 241000, P. R. China
Yi Ning − Key Laboratory of Functional Molecular Solids,
Ministry of Education, Anhui Laboratory of Molecule-Based
Materials (State Key Laboratory Cultivation Base), College
of Chemistry and Materials Science, Anhui Normal
University, Wuhu 241000, P. R. China
Jiahui Duan − Key Laboratory of Functional Molecular Solids,
Ministry of Education, Anhui Laboratory of Molecule-Based
Materials (State Key Laboratory Cultivation Base), College
of Chemistry and Materials Science, Anhui Normal
University, Wuhu 241000, P. R. China
Enshen Zhang − Key Laboratory of Functional Molecular
Solids, Ministry of Education, Anhui Laboratory of Molecule-
Based Materials (State Key Laboratory Cultivation Base),
College of Chemistry and Materials Science, Anhui Normal
University, Wuhu 241000, P. R. China
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The work was partially supported by the National Natural
Science Foundation of China (No. 21772001), the Anhui
Provincial Natural Science Foundation (No. 1808085MB41),
and Cultivation Project for University Outstanding Talents of
Anhui Province (2019).
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