A metal-free tandem C-C/C-O bond formation approach to diversely functionalized tetrasubstituted furans

Article abstract of DOI:10.1021/jo4023342

A novel and efficient method for the synthesis of diversely functionalized furans is developed via DBU-mediated tandem Michael addition/5-exo-dig- cycloisomerization of enynes and keto-methylenes. This [3 + 2]-annulation is operationally simple under metal-free reaction conditions with 100% atom economy and broad substrate scope.

Full text of DOI:10.1021/jo4023342

Article
pubs.acs.org/joc
A Metal-Free Tandem C−C/C−O Bond Formation Approach to
Diversely Functionalized Tetrasubstituted Furans
Chada Raji Reddy* and Motatipally Damoder Reddy
Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, Andhra Pradesh, India
S
* Supporting Information
ABSTRACT: A novel and efficient method for the synthesis of diversely functionalized furans is developed via DBU-mediated
tandem Michael addition/5-exo-dig-cycloisomerization of enynes and keto-methylenes. This [3 + 2]-annulation is operationally
simple under metal-free reaction conditions with 100% atom economy and broad substrate scope.
1,4-dicarbonyl compound reactions (Paal−Knorr synthesis).6
INTRODUCTION
■
During the past decade, numerous alternative approaches have
The development of an atom-economical approach for the
efficient construction of diversely functionalized molecules
been developed, and predominantly these reactions are either
alkyne- or allene-assisted cyclizations.7−14 Among the alkyne-
from easily accessible starting materials is continuously a special
based strategies to polysubstituted furans, cyclizations of
enynones are particularly attractive (Scheme 1). For instance,
attention for synthetic organic chemists.1 Furan is one of the
extensively studied oxygenated heterocycles because of its
broad occurrence in many natural products,2 pharmaceuticals,3
Scheme 1. Furan Synthesis from Enynones
and functional materials.4 For example, two sesquiterpenoids (I
and II) isolated from the mycelia of edible mushroom Pleurotus
cornucopiae fermented on rice,2i the pukalide class of molecules
(III),2e and angelone (IV)2d are some of the representative
natural products possessing substituted furan skeleton (Figure
1). Several of the natural furans have shown exciting biological
activities, such as anticancer, antidiabetic, and antiallergic
activities, etc.2 In addition, substituted furans are also useful
building blocks in organic synthesis.5
Consequently, substantial consideration has been paid on the
advance of effective methods to synthesize these heterocyclic
compounds after the discovery of traditional condensation of
enynedione compounds were successfully utilized to prepare
trisubstituted furans (path A) through the intramolecular
cyclization.9 In 2004, Larock and co-workers demonstrated 2-
(1-alkynyl)-2-alkene-1-ones as suitable starting materials for
substituted furans via gold-catalyzed cyclization.10a,b Later,
these enynones were vastly explored for the synthesis of
diversely functionalized furans by several research groups in the
presence of various metal catalysts (path B).10c−n Notably,
Zhang and co-workers have vastly explored the efficacy of 2-(1-
Figure 1. Structures of representative natural products having furan
framework.
Received: October 18, 2013
© XXXX American Chemical Society
A
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alkynyl)-2-alkene-1-ones in the synthesis of diversely sub-
stituted furnans.10g−n In addition, 2-alken-4-yn-1-ones (mostly
in Z-form) were also used to synthesize substituted furans
(path C).11
While a majority of the above cyclizations required metal
catalyst to promote the carbon−oxygen bond formation, metal-
free reactions from these enynones are rather scarce.11e,f
Further, in all the above methods, the substitutions on the furan
ring originated from the enynone, which contribute 4-carbons
and oxygen through the intramolecular cyclization. Herein, we
report a metal-free intermolecular cyclization strategy for the
synthesis of tetrasubstituted furans from enynones (C2
synthon), which allows diverse substitutions on the furan ring
(path D).
screening of bases (Cs2CO3, DABCO, DMAP and DBU) for
the reaction of 1a with 2a revealed that DBU is the base of
choice in affording the 86% yield of 3aa (entries 3 to 6, Table
1). Additional optimization revealed that variation in the
amount of DBU employed or changing the solvent has little
influence on the outcome of the reaction (entries 7 to 13, Table
1). Thus, the optimized procedure for the tandem Michael
addition/5-exo-dig-cycloisomerization was chosen as follows:
the reaction was carried out in acetonitrile in presence of 1
equiv of DBU at refluxing conditions (entry 7, Table 1). It is
noteworthy to mention that the reaction at room temperature
provided the Michael addition product A,16 and when the
temperature raised to reflux, the desired furan was accom-
plished.
Following our current interest in alkyne-based strategies
toward heterocycles,15 we envisioned a new [3 + 2] annulation
comprising the Michael addition of keto-active methylene on to
2-alken-4-yn-1-one would provide the 1,4-ynone, which
subsequently undergo the 5-exo-dig-cycloisomerization for the
construction of tetrasubstituted furans. We also envisaged that
the process would occur in one pot and possesses more
potential in the synthesis of diversely functionalized furans, as
the substrates are accessible with a range of groups. To our
knowledge, the intermolecular version using enynones has not
been reported (path D), in which two different substrates can
combine in one step to form furan ring, potentially with higher
diversity.
After optimizing the reaction conditions, generality of the
present [3 + 2]-annulation reaction was investigated. Thus, a
series of substiuted 1,3-cyclohexanediones treated with
enynone 1a, as summarized in Scheme 2. Several 1,3-
Scheme 2. Scope of Cyclic 1,3-Diketones in Furan
a
Synthesis
RESULTS AND DISCUSSION
■
To test the hypothesis, we began the investigation by treatment
of enynone 1a with 5,5-dimethyl-1,3-cyclohexanedione (2a) in
presence of K2CO3 in dichloromethane, which provided the
expected furan 3aa in 40% yield (entry 1, Table 1). Despite low
conversion, this first result showed the feasibility of the
envisioned strategy. Encouraged by this result, we further
examined the same reaction under various conditions to
improve the product yield. The use of K2CO3 in acetonitrile
helped in improving the yield to 54% (entry 2, Table 1). The
Table 1. Preliminary Optimization Studies
a
Reaction conditions: 1a (1.0 mmol), cyclic 1,3-dione 2 (1.1 mmol),
DBU (1.0 mmol), CH3CN (9 mL), at 85 °C.
b
cyclohexanediones, having C5-alkyl (products 3ab and 3ad)
or C5-aryl substitution (products 3ae to 3ai), were smoothly
participated in the tandem reaction to provide the correspond-
ing furans in excellent yields (Scheme 2).
entry
base/equiv
solvent
time (h)
yield (%)
1
K2CO3/2
K2CO3/2
CS2CO3/2
DABCO/1
DMAP/1
DBU/2
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
toluene
dioxane
THF
30
24
24
24
24
14
15
20
30
30
14
14
26
40
54
41
59
34
86
98
91
86
81
94
90
79
2
3
Next, the developed tandem reaction was tested with other
keto-active methylenes, and the results are summarized in
Table 2. Acyclic 1,3-diketones such as pentane-2,4-dione (2j)
and 1,3-diphenylpropane-1,3-dione (2k) were also employed in
the reaction to afford furans 3aj and 3ak in 71% and 95% yields
(entries 1 and 2, Table 2), respectively. Further, β-keto esters
also turned out to be excellent substrates in the present method
to afford substituted furans 3al to 3an in good yields (entries
3−5, Table 2). Interestingly, 3-oxo-3-arylpropanenitriles 2o−2t
underwent [3 + 2]-annulation with 1a to give the
corresponding 2-aryl-3-cyano furans 3ao−3at in good yield
(entries 6−11, Table 2). Additionally β-keto Sulphone 2u was
also found to be compatible in the tandem reaction with 1a
affording 3au in 73% yield (entry 12, Table 2). It is worth
4
5
6
7
DBU/1
8
DBU/0.5
DBU/0.2
DBU/0.1
DBU/1
9
10
11
12
13
DBU/1
DBU/1
a
Reaction conditions: 1a (1.0 mmol), 5,5-dimethylcyclohexane-1,3-
dione 2a (1.1 mmol) in solvent (9 mL) at reflux temperature. Yields
b
of the isolated products after chromatography.
B
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b
Table 2. Reaction of 1a with Acyclic Keto-Active Methylenes
a
b
Isolated yields. Reaction conditions: Enynone 1a (1.0 mmol), keto-active methylene 2 (1.1 mmol), DBU (1.0 mmol), CH3CN (9 mL), 85 °C.
noting that only one example is known in the literature for the
synthesis of 3-cyano or 3-sulfonyl furans from alkynones.9c
Subsequently, the scope of the reaction was studied with
enynones possessing different substitutions on the alkyne
functionality under the optimized conditions (Table 3). A wide
range of 5-aryl-1-phenylpent-2-en-4-yn-1-ones, 1b−1h, com-
prising either an eletron-donating or electron-withdrawing
subtituted phenyl group on the alkyne, were found to be
suitable for the present [3 + 2]-annulation providing the
corresponding furans 3ba−3ha in excellent yields (entries 1−7,
Table 3). Other enynones with 1-naphthyl (1i) or 2-thiophenyl
(1j) substitution on the alkyne were also found to be excellent
substrates in yielding the furans 3ia and 3ja in 97 and 96%
yields, respectively (entries 8 and 9, Table 3). Gratifyingly,
enynones 1k and 1l with alkyl substitution on the alkyne
functionality also furnsihed the substitued furans 3ka and 3la
(entries 10 and 11, Table 3) in good yields.
After successfully optimizing the conditions for the synthesis
of substituted furans with various structurally diverse enynones
and 1,3-diketones, we turned our attention in the use of
substrates containing diverse electron-withdrawing groups in
conjugation to enyne (Scheme 3). Accordingly, reaction of 1m
possessing an unsaturated ketone with 2a was verified under
DBU/CH3CN conditions, and to our satisfaction, the
formation of furan 3ma (96%) was observed. Similarly, enynes
comprising an unsaturated esters (1n and 1o) or amide (1p)
were also found to be well-suited substrates for the tandem
reaction with 2a to afford the corresponding furans 3na−3pa,
respectively, in high yield. Interestingly, enynes containing
cyano (1q) or nitro (1r) substitution on the olefin also reacted
with the 1,3-diketone 2a to yield 3qa (84%) and 3ra (81%). To
the best of our knowledge, synthesis of substituted furans from
the enynes 1p−1r hitherto is not reported, and this study
comprises the first example of such study. Reaction of enyne
having conjugation to cyclic ketone (1s) with 2a proceeded
C
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b
Table 3. Scope of Substitution on Alkyne Terminus of
Enynone
Table 4. Synthesis of Bis-furan Moieties
b
entry
enyne (1)
time (h)
furan (3)
yield (%)
1
R4 = 4-Me-Ph, 1b
R4 = 4-MeO-Ph, 1c
R4 = 2,4-di-MeO-Ph, 1d
R4 = 3-CF3-Ph, 1e
R4 = 4-Cl-Ph, 1f
20
18
21
23
20
20
20
18
22
22
24
3ba
3ca
3da
3ea
3fa
95
97
90
95
96
96
86
97
96
90
74
2
3
4
5
6
R4 = 2-I-Ph, 1g
3ga
3ha
3ia
7
R4 = 4-NO2-Ph, 1h
R4 = 1-Napthyl, 1i
R4 = 2-Thiophenyl, 1j
R4 = PhCHCH, 1k
R4 = nC8H17, 1l
8
9
3ja
10
11
3ka
31a
a
Reaction conditions: Enynone 1 (1.0 mmol), 2a (1.1 mmol), DBU
b
(1.0 mmol), CH3CN (9 mL), 85 °C. Isolated yields.
Scheme 3. Reactions of Enynes Linked with Different
a
Electron-Withdrawing Groups
a
b
Isolated yields. Reaction conditions: Entnone (0.4 mmol), 2a (0.84
mmol), DBU (0.8 mmol), CH3CN (9 mL), 85 °C for 20 h.
Scheme 4. Proposed Mechanism for the C−C/C−O Bond
Formation
A possible mechanism is outlined in Scheme 4. We believe
that the Michael addition of active-methylene 2a to the
conjugated ketone 1a (C−C bond formation) in the presence
of base (DBU) offers the intermediate A, which exists as enol
form. Subsequently, intermediate A undergoes 5-exo-dig-
cyclization (C−O bond formation) to give B, followed by
isomerization of the double bond, leading to the formation of
furan 3aa. A substantial support for this mechanism was
evidence by the isolation and characterization of intermediate
A,16 which independently on treatement with DBU afforded
the furan 3aa. It is important to mention that the intermediate
A type precursors for the synthesis of furans have been made
earlier from propargylic alcohols through the nucleophilic
substitution reaction.17 However, the substrates were limited to
the propargylic alcohols flanked on one side by an aryl (phenyl)
group and on the other side with an acetylenic group.
Moreover, the use of acid catalyst (in majority cases metal
catalyst) is essential for nucleophilic substitution reaction
a
Reaction conditions: Enyne 1 (1.0 mmol), 2a (1.1 mmol) CH3CN (9
mL), at 85 °C. Yields are given for the isolated products after
chromatography.
well to give the furan 3sa in 94% yield. The above results clearly
demonstrate the additional diversity of the reaction in obtaining
the furans with various functionalities, which are handy for
further transformations.
Finally, versatality of the reaction was explored with
substrates having either two enynone frameworks tethered to
phenyl ring (4a and 4b) or two enyne units based on cyclic
ketone (4c and 4d). Thus, reaction of 4a−4d with 1,3-diketone
2a furnished the corresponding bis-furanyl derivatives 5a−5d in
good yields (entries 1 to 4, Table 4).
D
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263 (M + H)+; HRMS (ESI) m/z calcd for C18H15O2 (M + H)+
263.1066, found 263.1059.
between propargylic alcohol and a dicarbonyl compound or
enoxysilane. In contrast, the present method offers the
intermediate A from enynones through Michael addition
reaction, which expand the choice of substitutions on furan
ring, and the simple base is sufficient to promote the formation
of precursor A as well as cyclization to furan.
In summary, we have developed a novel DBU-promoted [3 +
2]-annulation reaction for the synthesis of substituted furans
involving of (E)-2-alken-4-yn-1-ones with keto-active methyl-
enes. The reaction was shown to proceed through a tandem
Michael addition/5-exo-dig-cycloisomerization. The present
protocol is efficient for varied substituted enynes as well as
several active methylenes including cyclic and acyclic 1,3-
diketones, β-keto esters, nitriles, and sulfone. Salient features of
this operationally simple protocol are metal-free reaction
conditions, 100% atom economy, and broad substrate scope
to obtain diversely functionalized furans. Importantly, several
functional groups such as keto, ester, amide, sulfone, nitro and
cyano groups could be installed on the furan ring, thus
providing opportunities for further elaboration of the products.
(E)-5-(3,5-Dimethoxyphenyl)-1-phenylpent-2-en-4-yn-1-one (1d).
1
1.37 g, 94% yield, yellow solid: mp 86−88 °C; H NMR (500 MHz,
CDCl3) δ 7.99 (dd, J = 7.2, 1.4 Hz, 2H), 7.58 (t, J = 7.3 Hz, 1H), 7.49
(t, J = 7.3 Hz, 2H), 7.41 (d, J = 8.5 Hz, 1H), 7.39 (d, J = 15.5 Hz, 1H),
7.19 (d, J = 15.5 Hz, 1H), 6.49 (dd, J = 8.4, 2.4 Hz, 1H), 6.45 (d, J =
2.4 Hz, 1H), 3.90 (s, 3H), 3.84 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 188.8, 162.2, 161.6, 137.3, 134.9, 132.9, 131.4, 128.5, 128.3, 105.1,
98.2, 97.0, 91.1, 55.7, 55.3; IR (KBr) νmax = 3052, 2957, 2836, 2184,
1654, 1580, 1464, 1334, 1209, 1161, 958, 826, 684 cm−1; MS (ESI) m/
z 293 (M + H)+; HRMS (ESI) m/z calcd for C19H17O3 (M + H)+
293.1172, found 293.1171.
(E)-1-Phenyl-5-(3-(trifluoromethyl)phenyl)pent-2-en-4-yn-1-one
1
(1e). 1.26 g, 84% yield, pale yellow crystals: mp 80−81 °C; H NMR
(500 MHz, CDCl3) δ 8.01 (dd, J = 8.2, 1.5 Hz, 2H), 7.79 (s, 1H), 7.69
(d, J = 7.8 Hz, 1H), 7.65−7.59 (m, 2H), 7.54−7.47 (m, 4H), 7.11 (d, J
= 15.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 188.1, 136.8, 134.8,
133.7, 133.1, 131.5, 128.9, 128.5, 128.3, 125.6, 125.6, 123.8, 123.0,
121.6, 96.7, 88.8; IR (KBr) νmax = 3060, 2926, 2197, 1660, 1591, 1441,
1344, 1298, 1118, 950, 805, 690 cm−1; MS (ESI) m/z 301 (M + H)+;
HRMS (ESI) m/z calcd for C18H12OF3 (M + H)+ 301.0834, found
301.0829.
(E)-5-(4-Chlorophenyl)-1-phenylpent-2-en-4-yn-1-one (1f). 1.25
g, 94% yield, pale yellow solid: mp 93−94 °C; H NMR (500 MHz,
1
EXPERIMENTAL SECTION
■
CDCl3) δ 8.00 (dd, J = 8.2, 1.4 Hz, 2H), 7.60 (t, J = 7.3 Hz, 1H), 7.50
(t, J = 7.5 Hz, 2H), 7.47−7.43 (m, 3H), 7.37−7.34 (m, 2H), 7.11 (d, J
= 15.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 188.6, 137.2, 135.6,
133.4, 133.3, 133.2, 128.9, 128.7, 128.6, 124.6, 120.8, 97.9, 88.7; IR
(KBr) νmax = 3060, 2919, 2195, 1652, 1574, 1483, 1332, 1256, 1005,
968, 826, 695 cm−1; MS (ESI) m/z 267 (M + H)+; HRMS (ESI) m/z
calcd for C17H12OCl (M + H)+ 267.0571, found 267.0562.
General Methods. Reactions were monitored by thin-layer
chromatography carried out on silica plates using UV-light and
anisaldehyde or potassium permanganate or β-naphthol for visual-
ization. Column chromatography was performed on silica gel (60−120
mesh) using n-hexane and ethyl acetate as eluent. Evaporation of
solvents was conducted under reduced pressure at temperatures less
1
than 45 °C. FTIR spectra were recorded on KBr thin film. H NMR
and 13C NMR spectra were recorded in CDCl3 solvent on a 300, 500,
and 600 MHz NMR spectrometer. Chemical shifts δ and coupling
constants J are given in ppm (parts per million) and Hz (hertz),
respectively. Chemical shifts are reported relative to residual solvent as
(E)-5-(2-Iodophenyl)-1-phenylpent-2-en-4-yn-1-one (1g). 1.57 g,
1
88% yield, pale yellow crystals: mp 70−71 °C; H NMR (500 MHz,
CDCl3) δ 8.00 (dd, J = 8.1, 1.5 Hz, 2H), 7.89 (dd, J = 8.1, 1.1 Hz, 1H),
7.61 (t, J = 7.4 Hz, 1H), 7.54−7.49 (m, 4H), 7.35 (td, J = 7.6, 1.1 Hz,
1H), 7.16 (d, J = 15.4 Hz, 1H), 7.07 (td, J = 7.8, 1.7 Hz, 1H); 13C
NMR (125 MHz, CDCl3) δ 188.7, 138.8, 137.0, 133.5, 133.2, 133.0,
130.4, 128.7, 128.6, 128.5, 127.9, 124.6, 101.2, 100.6, 90.9; IR (KBr)
νmax = 2925, 2192, 1656, 1591, 1568, 1438, 1330, 1248, 999, 753, 689
cm−1; MS (ESI) m/z 359 (M + H)+; HRMS (ESI) m/z calcd for
C17H12OI (M + H)+ 358.9927, found 358.9925.
an internal standard for H and 13C (CDCl3 δ 7.26 ppm for H and
77.0 ppm for 13C). Mass spectra were obtained on VG 70−70H or
LC/MSD trapSL spectrometer operating at 70 eV using direct inlet
system.
1
1
Substituted enynes 1a−1q have been prepared using the literature
procedure,18,11e,f compounds 1s, 4c, and 4d have been prepared using
the literature procedure,19 and known compounds data have been
compared with the reported data. Characterization data for new
compounds is given below.
General Procedure for the Preparation of Substituted
Enynes (1a−1q). To a solution of acetylenic aldehyde (5.0 mmol)
in 20 mL of THF was added corresponding Wittig ylide (5.5 mmol) at
0 °C. The reaction mixture was stirred at the room temperature for 12
h. After the completion of reaction, the mixture was concentrated in
vacuo. The residue was purified by column chromatography on silica
gel (EtOAc:hexanes) to afford the corresponding product.
(E)-1-Phenyl-5-(p-tolyl)pent-2-en-4-yn-1-one (1b). 1.13 g, 92%
yield, brown solid: mp 66−67 °C; 1H NMR (300 MHz, CDCl3) δ 8.00
(dd, J = 6.8, 1.5 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.54−7.39 (m, 5H),
7.18 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 15.8 Hz, 1H), 2.38 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 188.2, 139.5, 136.9, 132.8, 132.3, 131.7,
(E)-5-(4-Nitrophenyl)-1-phenylpent-2-en-4-yn-1-one (1h). 1.18 g,
1
85% yield, pale yellow solid: mp 130−132 °C; H NMR (500 MHz,
CDCl3) δ 8.24 (dd, J = 9.0, 1.8 Hz, 2H), 8.01 (d, J = 8.2 Hz, 2H), 7.67
(dd, J = 8.7, 1.5 Hz, 2H), 7.62 (t, J = 8.4 Hz, 1H), 7.55−7.50 (m, 3H),
7.12 (d, J = 15.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 188.2, 147.4,
136.7, 134.5, 133.4, 132.6, 131.8, 128.7, 128.4, 123.6, 123.4, 95.8, 91.9;
IR (KBr) νmax = 3068, 2924, 2195, 1649, 1515, 1444, 1336, 1251, 854,
692 cm−1; MS (ESI) m/z 279 (M + H)+; HRMS (ESI) m/z calcd for
C17H12O3N (M + H)+ 279.0889, found 279.0885.
(E)-5-(Naphthalen-1-yl)-1-phenylpent-2-en-4-yn-1-one (1i). 1.30
1
g, 92% yield, pale yellow solid: mp 85−86 °C; H NMR (300 MHz,
CDCl3) δ 8.35 (d, J = 8.3 Hz, 1H), 8.04 (dd, J = 6.8, 1.5 Hz, 2H), 7.89
(t, J = 6.8 Hz, 2H), 7.77 (d, J = 8.3 Hz, 1H), 7.66−7.48 (m, 7H), 7.25
(d, J = 15.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 188.5, 137.0,
133.0, 132.8, 131.3, 129.9, 128.6, 128.5, 128.4, 128.3, 127.0, 126.5,
125.7, 125.1, 124.8, 121.2, 119.7, 97.5, 92.5; IR (neat) νmax = 3055,
2919, 2185, 1657, 1592, 1447, 1270, 1008, 950, 768, 689 cm−1; MS
(ESI) m/z 283 (M + H)+; HRMS (ESI) m/z calcd for C21H15O (M +
H)+ 283.1117, found 283.1112.
129.0, 128.4, 128.3, 124.8, 118.9, 99.7, 87.3, 21.2; IR (KBr) νmax
=
3057, 2919, 2185, 1652, 1577, 1443, 1330, 1253, 995, 812, 689 cm−1;
MS (ESI) m/z 247 (M + H)+; HRMS (ESI) m/z calcd for C18H15O
(M + H)+ 247.1117, found 247.1115.
(E)-5-(4-Methoxyphenyl)-1-phenylpent-2-en-4-yn-1-one (1c).
1.16 g, 89% yield, yellow solid: mp 160−162 °C; H NMR (300
(E)-1-Phenyl-5-(thiophen-2-yl)pent-2-en-4-yn-1-one (1j). 1.13 g,
95% yield, brown solid: mp 77−78 °C; 1H NMR (500 MHz, CDCl3)
δ 8.00 (dd, J = 8.4, 1.4 Hz, 2H), 7.60 (t, J = 7.3 Hz, 1H), 7.50 (t, J =
7.5 Hz, 2H), 7.42 (d, J = 15.6 Hz, 1H), 7.40 (dd, J = 5.2, 1.2 Hz, 1H),
7.35 (dd, J = 3.7, 1.2 Hz, 1H), 7.14 (d, J = 15.6 Hz, 1H), 7.05 (dd, J =
5.2, 3.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 188.3, 136.9, 133.7,
132.1, 129.3, 128.9, 128.5, 128.3, 127.4, 124.3, 122.0, 96.7, 92.2; IR
(KBr) νmax = 3105, 2172, 1652, 1581, 1415, 1358, 1295, 1200, 1013,
1
MHz, CDCl3) δ 8.00 (dd, J = 6.8, 1.5 Hz, 2H), 7.60 (t, J = 7.5 Hz,
1H), 7.54−7.45 (m, 4H), 7.41 (d, J = 15.9 Hz, 1H), 7.14 (d, J = 15.9
Hz, 1H), 6.90 (d, J = 6.8 Hz, 2H), 3.85 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 188.5, 160.4, 137.1, 133.5, 132.8, 131.8, 128.4, 128.3, 125.3,
114.0, 100.0, 87.0, 72.4, 55.0; IR (KBr) νmax = 2957, 2933, 2866, 2188,
1649, 1576, 1463, 1333, 1254, 1018, 824, 689 cm−1; MS (ESI) m/z
E
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953, 703 cm−1; MS (ESI) m/z 239 (M + H)+; HRMS (ESI) m/z calcd
for C15H11OS (M + H)+ 239.0525, found 239.0519.
691 cm−1; MS (ESI) m/z 387 (M + H)+; HRMS (ESI) m/z calcd for
C28H19O2 (M + H)+ 387.1380, found 387.1378.
(2E,6E)-1,7-Diphenylhepta-2,6-dien-4-yn-1-one (1k). 1.02 g, 79%
yield, brown solid: mp 95−96 °C; 1H NMR (300 MHz, CDCl3) δ 7.98
(d, J = 7.5 Hz, 2H), 7.60 (t, J = 7.2 Hz, 1H), 7.50 (t, J = 7.3 Hz, 2H),
7.44 (d, J = 7.0 Hz, 2H), 7.41−7.39 (m, 4H), 7.14−7.07 (m, 2H), 6.38
(d, J = 16.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 188.5, 143.8,
137.0, 135.5, 132.9, 132.5, 129.2, 128.6, 128.5, 128.3, 126.5, 124.9,
107.2, 99.2, 90.3; IR (KBr) νmax = 3057, 2923, 2168, 1653, 1564, 1445,
1372, 1255, 995, 819, 695 cm−1; MS (ESI) m/z 259 (M + H)+; HRMS
(ESI) m/z calcd for C19H15O (M + H)+ 259.1117, found 259.1110.
(E)-1-Phenyltridec-2-en-4-yn-1-one (1l). 1.19 g, 89% yield, pale
yellow liquid: 1H NMR (500 MHz, CDCl3) δ 7.95 (dd, J = 8.5, 1.4 Hz,
2H), 7.57 (t, J = 7.3 Hz, 1H), 7.48 (t, J = 7.3 Hz, 2H), 7.27 (d, J = 15.6
Hz, 1H), 6.90 (dt, J = 15.6, 2.3 Hz, 1H), 2.42 (td, J = 7.2, 2.3 Hz, 2H),
1.61−1.55 (m, 2H), 1.45−1.38 (m, 2H), 1.34−1.25 (m, 8H), 0.89 (t, J
= 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 188.9, 137.2, 132.8,
132.4, 128.5, 128.3, 126.2, 102.0, 79.2, 31.7, 29.0, 28.9, 28.8, 28.3, 22.5,
19.8, 14.0; IR (neat) νmax = 2925, 2854, 2210, 1661, 1592, 1450, 1287,
1009, 959, 693 cm−1; MS (ESI) m/z 269 (M + H)+; HRMS (ESI) m/z
calcd for C19H25O (M + H)+ 269.1899, found 269.1897.
General Procedure for the Preparation of 4c and 4d. To a
solution of 3-phenylpropiolaldehyde (5.0 mmol) in 20 mL of
THF:H2O (8:2) was added cyclic ketone (cyclohexanone or
dihydro-2H-thiopyran-4(3H)-one), (2.5 mmol) and NaOH (3.0
mmol), stirred at 0 °C for 2 h. After the completion of reaction, the
mixture was diluted with H2O (20 mL) and extracted with EtOAc (10
mL × 2); organic layer was washed with H2O, brine, dried over
Na2SO4, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (EtOAc:hexanes) to afford the
corresponding product (4c, 4d).
(2E,6E)-2,6-Bis(3-phenylprop-2-yn-1-lidene)cyclohexanone (4c).
0.52 g, 65% yield, brown solid: mp 146−147 °C; 1H NMR (300
MHz, CDCl3) δ 7.55−7.46 (m, 4H), 7.41−7.31 (m, 6H), 6.98 (s, 2H),
2.93 (td, J = 7.5, 1.9 Hz, 4H), 1.93−1.81 (m, 2H); 13C NMR (75
MHz, CDCl3) δ 186.2, 145.3, 131.8, 129.1, 128.4, 122.6, 118.2, 103.8,
87.3, 28.9, 21.6; IR (KBr) νmax = 3054, 2937, 2871, 2189, 1658, 1597,
1577, 1440, 1308, 1173, 902, 756, 687 cm−1; MS (ESI) m/z 323 (M +
H)+; HRMS (ESI) m/z calcd for C24H19O (M + H)+ 323.1430, found
323.1424.
(E)-Benzyl 5-phenylpent-2-en-4-ynoate (1o). 1.21 g, 93% yield,
white solid: mp 65−66 °C; 1H NMR (500 MHz, CDCl3) δ 7.47 (dd, J
= 8.1, 1.5 Hz, 2H), 7.39−7.28 (m, 8H), 7.02 (d, J = 15.7 Hz, 1H), 6.35
(d, J = 15.7 Hz, 1H), 5.22 (s, 2H); 13C NMR (75 MHz, CDCl3) δ
165.5, 135.6, 131.8, 129.5, 129.2, 128.5, 128.3, 128.2, 128.1, 127.6,
125.5, 98.6, 86.2, 66.4; IR (KBr) νmax = 3064, 3033, 2954, 2198, 1715,
1617, 1311, 1252, 1164, 959, 754, 692 cm−1; MS (ESI) m/z 263 (M +
H)+; HRMS (ESI) m/z calcd for C18H15O2 (M + H)+ 263.1067,
found 263.1060.
(3Z,5Z)-3,5-Bis(3-phenylprop-2-yn-1-ylidene)dihydro-2H-thiopyr-
an-4(3H)-one (4d). 0.53 g, 62% yield, brown solid: mp 96−98 °C; 1H
NMR (300 MHz, CDCl3) δ 7.54−7.47 (m, 4H), 7.43−7.32 (m, 6H),
6.99 (s, 2H), 3.94 (s, 4H); 13C NMR (75 MHz, CDCl3) δ 184.7,
141.7, 131.9, 129.4, 128.4, 122.2, 118.1, 104.7, 86.4, 30.9; IR (KBr)
νmax = 3050, 2951, 2859, 2191, 1657, 1593, 1447, 1211, 1014, 950, 691
cm−1; MS (ESI) m/z 341 (M + H)+; HRMS (ESI) m/z calcd for
C23H17OS (M + H)+ 341.0994, found 341.0995.
3-Hydroxy-5,5-dimethyl-2-(5-oxo-1,5-diphenylpent-1-yn-3-
yl)cyclohex-2-enone (A). To a solution of 1 (1.0 mmol) in 9 mL of
acetonitrile was added ketomethylene 2 (1.1 mmol) and DBU (1.0
mmol) at room temperature and stirred for 3 h. After the completion
of reaction, the mixture was concentrated in vacuo. The residue was
purified by column chromatography on silica gel (EtOAc:hexanes) to
afford the title compound A in 96% yield (357 mg), as a brown solid:
1H NMR (500 MHz, CDCl3) δ 9.90 (br s, 1H), 8.00 (dd, J = 7.3, 1.2
Hz, 2H), 7.63−7.37 (m, 6H), 7.31−7.22 (m, 2H), 4.69 (t, J = 4.9 Hz,
1H), 3.66 (dd, J = 18.3, 5.0 Hz, 1H), 3.42 (dd, J = 18.5, 4.6 Hz, 1H),
2.40 (d, J = 6.9 Hz, 2H), 2.23 (s, 2H), 1.08 (s, 3H), 1.04 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 199.7, 196.9, 172.5, 135.9, 133.8, 131.7,
128.7, 128.3, 128.2, 128.1, 122.8, 112.4, 88.5, 83.5, 50.4, 43.5, 43.0,
31.3, 28.6, 27.8, 22.0; IR (KBr) νmax = 3409, 3034, 2957, 2854, 2191,
1711, 1653, 1580, 1401, 1265, 1107, 985, 760 cm−1; MS (ESI) m/z
395 (M + Na)+; HRMS (ESI) m/z calcd for C25H24O3Na (M + Na)+
395.1617, found 395.1614.
General Procedure for the Synthesis of Tetrasubstituted
Furans (3). To a solution of 1 (1.0 mmol) in 9 mL of acetonitrile was
added keto-active methylene 2 (1.1 mmol) and DBU (1.0 mmol) at
room temperature, and the mixture was then heated to 85 °C and
stirred for 8−30 h. After the completion of reaction, the mixture was
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (EtOAc:hexanes) to afford the
corresponding product.
Synthesis of (E)-2-(3-Phenylprop-2-yn-1-ylidene)-3,4-dihy-
dronaphthalen-1(2H)-one (1s). To a solution of 3-phenylpropio-
laldehyde (5.0 mmol) in 20 mL of THF:H2O (8:2) was added 3,4-
dihydronaphthalen-1(2H)-one (5.0 mmol) and NaOH (5.0 mmol),
stirred at 0 °C for 3 h. After the completion of reaction, the mixture
was diluted with H2O (20 mL) and extracted with EtOAc (10 mL ×
2); organic layer was washed with H2O, brine, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (EtOAc:hexanes) to afford the title
1
compound 1s (1.05 g, 81% yield) as a white solid: mp 75−77 °C; H
NMR (300 MHz, CDCl3) δ 8.12 (dd, J = 7.8, 1.1 Hz, 1H), 7.55−7.48
(m, 3H), 7.39−7.34 (m, 4H), 7.28 (d, J = 7.6 Hz, 1H), 7.02 (t, J = 1.7
Hz, 1H), 3.16 (td, J = 6.9, 1.5 Hz, 2H), 3.04 (d, J = 6.9 Hz, 2H); 13C
NMR (75 MHz, CDCl3) δ 185.8, 144.7, 143.8, 133.4, 132.9, 131.7,
129.0, 128.4, 128.3, 128.0, 127.0, 122.6, 116.6, 102.2, 86.9, 28.4, 28.2;
IR (KBr) νmax = 3050, 2952, 2185, 1657, 1590, 1447, 1270, 1008, 768,
689 cm−1; MS (ESI) m/z 259 (M + H)+; HRMS (ESI) m/z calcd for
C19H15O (M + H)+ 259.1117, found 259.1115.
General Procedure for the Preparation of Substituted Enyne
(4a, 4b). To a solution of diacetylenic aldehyde (3.0 mmol) in 20 mL
of THF was added corresponding Wittig ylide (6.6 mmol) at 0 °C.
The reaction mixture was stirred at the room temperature for 3 h.
After the completion of reaction, the mixture was concentrated in
vacuo. The residue was purified by column chromatography on silica
gel (EtOAc:hexanes) to afford the corresponding product (4a, 4b).
(2E,2′E)-5,5′-(1,2-Phenylene)bis(1-phenylpent-2-en-4-yn-1-one)
(4a). 0.60 g, 62% yield, brown solid: mp 218−219 °C; 1H NMR (300
MHz, CDCl3) δ 7.79 (dd, J = 8.7, 1.5 Hz, 1H), 7.67 (dd, J = 8.5, 1.3
Hz, 2H), 7.39−7.06 (m, 12H), 6.79 (s, 1H), 6.92 (d, J = 15.5 Hz, 1H),
6.87 (d, J = 15.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 188.6, 137.0,
134.5, 133.7, 132.4, 131.0, 129.2, 128.8, 128.5, 124.7, 97.2, 92.1; IR
(neat) νmax = 3057, 2921, 2851, 2189, 1656, 1588, 1446, 1255, 999,
951, 760, 689 cm−1; MS (ESI) m/z 387 (M + H)+; HRMS (ESI) m/z
calcd for C28H19O2 (M + H)+ 387.1380, found 387.1375.
2-Benzyl-6,6-dimethyl-3-(2-oxo-2-phenylethyl)-6,7-dihydroben-
zofuran-4(5H)-one (3aa). 364 mg, 98% yield, white solid: mp 118−
119 °C; 1H NMR (500 MHz, CDCl3) δ 8.02 (d, J = 7.7 Hz, 2H), 7.54
(dd, J = 7.7, 6.6 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H), 7.25 (dd, J = 7.7, 6.6
Hz, 2H), 7.20−7.16 (m, 3H), 4.28 (s, 2H), 3.94 (s, 2H), 2.70 (s, 2H),
2.32 (s, 2H), 1.15 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 196.6,
194.8, 165.1, 152.0, 137.2, 136.7, 132.9, 128.48, 128.46, 128.4, 128.3,
126.5, 119.1, 111.3, 52.2, 37.3, 35.1, 33.5, 32.1, 28.5; IR (KBr) νmax
=
3061, 2958, 2931, 1671, 1589, 1453, 1350, 1216, 1048, 771, 691 cm−1;
MS (ESI) m/z 373 (M + H)+; HRMS (ESI) m/z calcd for C25H25O3
(M + H)+ 373.1798, found 373.1797.
(2E,2′E)-5,5′-(1,3-Phenylene)bis(1-phenylpent-2-en-4-yn-1-one)
(4b). 0.68 g, 69% yield, brown solid: mp 188−189 °C; 1H NMR (300
MHz, CDCl3) δ 8.00 (dd, J = 8.5, 1.3 Hz, 4H), 7.70−7.35 (m, 12H),
7.12 (d, J = 15.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 188.7, 137.1,
135.3, 133.6, 133.3, 132.6, 128.7, 128.6, 128.5, 124.6, 122.9, 97.6, 88.5;
IR (neat) νmax = 2921, 2851, 2190, 1651, 1594, 1445, 1215, 1011, 958,
2-Benzyl-3-(2-oxo-2-phenylethyl)-6,7-dihydrobenzofuran-4(5H)-
one (3ab). 320 mg, 93% yield, white solid: mp 143−144 °C; 1H NMR
(300 MHz, CDCl3) δ 8.01 (d, J = 7.2 Hz, 2H), 7.53 (dd, J = 7.4, 7.2
Hz, 1H), 7.44 (t, J = 7.2 Hz, 2H), 7.25 (dd, J = 7.4, 7.2 Hz, 2H), 7.20−
7.13 (m, 3H), 4.27 (s, 2H), 3.92 (s, 2H), 2.82 (t, J = 6.2 Hz, 2H), 2.41
F
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1
(t, J = 6.2 Hz, 2H), 2.21−2.09 (m, 2H); 13C NMR (75 MHz, CDCl3)
δ 196.6, 195.2, 165.9, 151.7, 137.2, 136.8, 132.8, 128.4, 128.4, 128.3,
solid: mp 158−159 °C; H NMR (500 MHz, CDCl3) δ 8.04 (dd, J =
8.4, 1.4 Hz, 2H), 7.57 (t, J = 7.5 Hz, 1H), 7.47 (t, J = 7.9 Hz, 2H), 7.28
(d, J = 7.8 Hz, 2H), 7.25−7.17 (m, 3H), 6.78−6.68 (m, 3H), 5.95 (s,
2H), 4.33 (s, 2H), 3.95 (s, 2H), 3.51−3.42 (m, 1H), 3.06 (dd, J = 17.1,
5.0 Hz, 1H), 2.94 (dd, J = 17.1, 11.1 Hz, 1H), 2.72−2.57 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 196.6, 193.8, 165.1, 152.3, 147.8, 146.4,
137.1, 136.7, 136.5, 133.0, 128.6, 128.5, 128.4, 128.3, 126.6, 120.2,
119.7, 111.4, 108.4, 107.0, 101.0, 45.5, 41.0, 33.5, 32.1, 31.5; IR (KBr)
νmax = 2918, 2851, 1670, 1586, 1489, 1347, 1219, 1039, 772 cm−1; MS
(ESI) m/z 465 (M + H)+; HRMS (ESI) m/z calcd for C30H25O5 (M +
H)+ 465.1696, found 465.1690.
128.2, 126.5, 120.3, 111.4, 37.8, 33.4, 32.0, 23.3, 22.4; IR (KBr) νmax
=
3062, 3029, 2944, 1671, 1587, 1454, 1343, 1214, 1010, 889, 752 cm−1;
MS (ESI) m/z 345 (M + H)+; HRMS (ESI) m/z calcd for C23H21O3
(M + H)+ 345.1485, found 345.1483.
2-Benzyl-6-methyl-3-(2-oxo-2-phenylethyl)-6,7-dihydrobenzofur-
an-4(5H)-one (3ac). 347 mg, 97% yield, white solid: mp 138−139 °C;
1H NMR (500 MHz, CDCl3) δ 8.03 (d, J = 7.7 Hz, 2H), 7.55 (dd, J =
7.7, 6.6 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.27 (t, J = 7.7 Hz, 2H),
7.22−7.18 (m, 3H), 4.31 (s, 2H), 3.94 (s, 2H), 2.88 (dd, J = 4.4, 16.4
Hz, 1H), 2.52−2.38 (m, 3H), 2.21 (dd, J = 10.9, 15.4 Hz, 1H), 1.14 (d,
J = 5.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 196.6, 194.9, 165.7,
151.9, 137.2, 136.7, 132.9, 128.5, 128.4, 128.3, 128.2, 126.5, 119.9,
111.3, 46.3, 33.4, 32.0, 31.4, 30.6, 20.9; IR (KBr) νmax = 3029, 2908,
1671, 1588, 1452, 1344, 1215, 1042, 769 cm−1; MS (ESI) m/z 359 (M
+ H)+; HRMS (ESI) m/z calcd for C24H23O3 (M + H)+ 359.1641,
found 359.1638.
2-Benzyl-6-(furan-2-yl)-3-(2-oxo-2-phenylethyl)-6,7-dihydroben-
zofuran-4(5H)-one (3ai). 337 mg, 82% yield, white solid: mp 155−
157 °C; 1H NMR (500 MHz, CDCl3) δ 8.03 (dd, J = 8.5, 1.4 Hz, 2H),
7.56 (t, J = 7.5 Hz, 1H), 7.46 (t, J = 7.9 Hz, 2H), 7.34 (d, J = 1.7 Hz,
1H), 7.30−7.19 (m, 5H), 6.30 (dd, J = 3.5, 1.8 Hz, 1H), 6.06 (d, J =
3.5 Hz, 1H), 4.32 (d, J = 13.1 Hz, 2H), 3.94 (s, 2H), 3.67−3.59 (m,
1H), 3.20 (dd, J = 17.2, 5.2 Hz, 1H), 3.02 (dd, J = 17.2, 10.1 Hz, 1H),
2.76 (dd, J = 16.5, 4.3 Hz, 1H), 2.68 (dd, J = 16.6, 11.2 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 196.6, 193.2, 164.4, 155.6, 152.4, 141.6,
137.1, 136.7, 132.9, 128.7, 128.6, 128.5, 128.3, 126.6, 120.3, 111.4,
110.1, 104.8, 42.4, 34.4, 33.5, 32.1, 28.5; IR (KBr) νmax = 3025, 2917,
1679, 1589, 1454, 1337, 1211, 1045, 745 cm−1; MS (ESI) m/z 411 (M
+ H)+; HRMS (ESI) m/z calcd for C27H23O4 (M + H)+ 411.1590,
found 411.1587.
2-(4-Acetyl-2-benzyl-5-methylfuran-3-yl)-1-phenylethanone
(3aj). 235 mg, 71% yield, pale yellow oil: 1H NMR (300 MHz, CDCl3)
δ 7.98 (dd, J = 7.6, 1.7 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.49 (t, J =
7.6 Hz, 2H), 7.28−7.22 (m, 3H), 7.21−7.17 (m, 2H), 4.10 (s, 2H),
4.02 (s, 2H), 2.57 (s, 3H), 2.39 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 197.3, 194.8, 158.5, 151.3, 140.1, 137.9, 133.5, 129.7, 128.6, 128.5,
128.3, 126.8, 125.1, 115.9, 33.6, 32.7, 26.4, 21.5; IR (KBr) νmax = 2921,
1619, 1414, 1243, 780, 689 cm−1; MS (ESI) m/z 333 (M + H)+;
HRMS (ESI) m/z calcd for C22H21O3 (M + H)+ 333.1485, found
333.1482.
2-(4-Benzoyl-2-benzyl-5-phenylfuran-3-yl)-1-phenylethanone
(3ak). 433 mg, 95% yield, pale yellow oil: 1H NMR (300 MHz,
CDCl3) δ 8.03 (dd, J = 7.2, 1.3 Hz, 2H), 7.88 (dd, J = 7.2, 1.8 Hz, 2H),
7.75 (dd, J = 7.0, 1.5 Hz, 2H), 7.53−7.16 (m, 12H), 7.14−7.08 (m,
2H), 4.24 (s, 2H), 4.08 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 197.6,
196.4, 151.5, 137.7, 136.8, 136.6, 133.2, 133.0, 132.6, 131.6, 129.8,
129.7, 128.6, 128.5, 128.4, 128.2, 128.0, 127.9, 127.7, 127.5, 126.6,
115.9, 33.6, 32.5; IR (KBr) νmax = 2920, 2846, 1687, 1645, 1580, 1448,
1342, 1215, 898, 754, 692 cm−1; MS (ESI) m/z 479 (M + Na)+;
HRMS (ESI) m/z calcd for C32H25O3 (M + H)+ 457.1798, found
457.1794.
2-Benzyl-6-isopropyl-3-(2-oxo-2-phenylethyl)-6,7-dihydrobenzo-
furan-4(5H)-one (3ad). 351 mg, 91% yield, white solid: mp 88−89
1
°C; H NMR (500 MHz, CDCl3) δ 8.03 (dd, J = 8.2. 1.4 Hz, 2H),
7.56 (t, J = 7.3 Hz, 1H), 7.46 (t, J = 7.3 Hz, 2H), 7.30−7.25 (m, 2H),
7.22−7.18 (m, 3H), 4.31 (s, 2H), 3.93 (s, 2H), 2.85 (dd, J = 17.0, 4.7
Hz, 1H), 2.55 (dd, J = 17.0, 11.1 Hz, 1H), 2.47 (dd, J = 16.2, 3.8 Hz,
1H), 2.24 (dd, J = 16.2, 12.8 Hz, 1H), 2.14−2.05 (m, 1H), 1.71−1.62
(m, 1H), 0.95 (dd, J = 6.7, 2.6 Hz, 6H); 13C NMR (75 MHz, CDCl3)
δ 196.6, 195.2, 166.3, 152.0, 137.2, 136.8, 132.9, 129.2, 128.5, 128.4,
128.3, 126.5, 120.0, 111.2, 42.1, 41.9, 33.4, 32.1, 31.9, 26.9, 19.7, 19.4;
IR (KBr) νmax = 3028, 2960, 1692, 1672, 1593, 1451, 1343, 1213,
1049, 753 cm−1; MS (ESI) m/z 387 (M + H)+; HRMS (ESI) m/z
calcd for C26H27O3 (M + H)+ 387.1954, found 387.1949.
2-Benzyl-3-(2-oxo-2-phenylethyl)-6-phenyl-6,7-dihydrobenzofur-
an-4(5H)-one (3ae). 416 mg, 99% yield, white solid: mp 136−137 °C;
1H NMR (300 MHz, CDCl3) δ 8.05 (d, J = 7.5 Hz, 2H), 7.57 (dd, J =
7.5, 6.0 Hz, 1H), 7.47 (t, J = 7.5 Hz, 2H), 7.38−7.17 (m, 10H), 4.34
(s, 2H), 3.96 (s, 2H), 3.62−3.49 (m, 1H), 3.16−2.98 (m, 2H), 2.81−
2.60 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 196.6, 193.8, 165.2,
152.3, 142.5, 137.1, 136.7, 132.9, 128.8, 128.7, 128.5, 128.4, 128.3,
127.0, 126.6, 126.5, 120.2, 111.4, 45.1, 41.2, 33.5, 32.0, 31.1; IR (KBr)
νmax = 3028, 2908, 1670, 1588, 1452, 1345, 1218, 1047, 772 cm−1; MS
(ESI) m/z 421 (M + H)+; HRMS (ESI) m/z calcd for C29H25O3 (M +
H)+ 421.1798, found 421.1794.
2-Benzyl-6-(4-methoxyphenyl)-3-(2-oxo-2-phenylethyl)-6,7-dihy-
drobenzofuran-4(5H)-one (3af). 436 mg, 97% yield, white solid: mp
121−123 °C; 1H NMR (500 MHz, CDCl3) δ 8.04 (dd, J = 8.2, 1.4 Hz,
2H), 7.57 (t, J = 7.3 Hz, 1H), 7.47 (t, J = 7.9 Hz, 2H), 7.28 (d, J = 7.6
Hz, 2H), 7.23−7.19 (m, 3H), 7.17 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7
Hz, 2H), 4.34 (s, 2H), 3.95 (s, 2H), 3.80 (s, 3H), 3.54−3.46 (m, 1H),
3.07 (dd, J = 17.1, 5.0 Hz, 1H), 2.96 (dd, J = 17.2, 11.3 Hz, 1H), 2.73−
2.57 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 196.6, 194.0, 165.3,
158.4, 152.2, 137.1, 136.7, 134.6, 132.9, 128.5, 128.4, 128.4, 128.3,
127.6, 126.5, 120.2, 114.0, 111.4, 55.1, 45.4, 40.4, 33.5, 32.0, 31.4; IR
(KBr) νmax = 3028, 2922, 2850, 1671, 1585, 1454, 1343, 1251, 1040,
754 cm−1; MS (ESI) m/z 451 (M + H)+; HRMS (ESI) m/z calcd for
C30H27O4 (M + H)+ 451.1903, found 451.1895.
Ethyl 5-benzyl-2-methyl-4-(2-oxo-2-phenylethyl)furan-3-carbox-
ylate (3al). 242 mg, 67% yield, pale yellow oil: H NMR (300 MHz,
1
CDCl3) δ 8.02 (dd, J = 7.0, 1.5 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.48
(t, J = 7.7 Hz, 2H), 7.29−7.14 (m, 5H), 4.29 (s, 2H), 4.10 (q, J = 7.2
Hz, 2H), 3.99 (s, 2H), 2.35 (s, 3H), 1.01 (t, J = 7.2 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 196.3, 163.7, 150.3, 143.6, 142.4, 133.1,
129.0, 128.6, 128.3, 128.2, 126.6, 125.3, 115.0, 109.4, 60.1, 34.8, 32.1,
21.4, 13.9; IR (KBr) νmax = 2929, 1678, 1443, 1201, 759, 688 cm−1;
MS (ESI) m/z 363 (M + H)+; HRMS (ESI) m/z calcd for C23H23O4
(M + H)+ 363.1590, found 363.1596.
Ethyl 5-benzyl-4-(2-oxo-2-phenylethyl)-2-phenylfuran-3-carbox-
ylate (3am). 334 mg, 79% yield, pale yellow oil: 1H NMR (300 MHz,
CDCl3) δ 8.03 (dd, J = 7.9, 1.9 Hz, 2H), 7.88 (dd, J = 6.9, 1.9 Hz, 2H),
7.60−7.53 (m, 1H), 7.51−7.43 (m, 2H), 7.41−7.33 (m, 3H), 7.31−
7.18 (m, 5H), 4.32 (s, 2H), 4.08 (q, J = 7.2 Hz, 2H), 4.01 (s, 2H), 1.01
(t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 196.4, 164.0, 156.5,
151.2, 137.3, 136.8, 133.0, 131.5, 130.2, 128.9, 128.6, 128.5, 128.4,
128.0, 127.9, 127.7, 126.5, 115.5, 60.2, 34.6, 32.2, 13.8; IR (KBr) νmax
= 2921, 2851, 1693, 1489, 1212, 1096, 753, 690 cm−1; MS (ESI) m/z
447 (M + Na)+; HRMS (ESI) m/z calcd for C28H25O4 (M + H)+
425.1747, found 425.1736.
2-Benzyl-6-(4-(dimethylamino)phenyl)-3-(2-oxo-2-phenylethyl)-
6,7-dihydrobenzofuran-4(5H)-one (3ag). 458 mg, 99% yield, violet
1
color solid: mp 143−144 °C; H NMR (300 MHz, CDCl3) δ 8.05
(dd, J = 8.2, 1.5 Hz, 2H), 7.57 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 6.8 Hz,
2H), 7.32−7.19 (m, 5H), 7.13 (d, J = 8.3 Hz, 2H), 6.71 (d, J = 8.3 Hz,
2H), 4.33 (s, 2H), 3.95 (s, 2H), 3.52−3.39 (m, 1H), 3.07 (dd, J = 17.3,
5.3 Hz, 1H), 2.95 (dd, J = 16.6, 11.3 Hz, 1H), 2.93 (s, 6H), 2.76−2.57
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 196.7, 194.4, 165.7, 152.1,
149.6, 137.2, 136.7, 132.9, 130.4, 128.5, 128.4, 128.4, 128.3, 127.3,
126.5, 120.1, 112.6, 111.4, 45.6, 40.5, 40.4, 33.5, 32.1, 31.4; IR (KBr)
νmax = 3021, 2911, 2851, 1669, 1522, 1451, 1345, 1216, 1047, 772
cm−1; MS (ESI) m/z 464 (M + H)+; HRMS (ESI) m/z calcd for
C31H30O3N (M + H)+ 464.2220, found 464.2227.
Ethyl 5-benzyl-4-(2-oxo-2-phenylethyl)-[2,2′-bifuran]-3-carboxy-
1
late (3an). 314 mg, 76% yield, pale yellow oil: H NMR (300 MHz,
6-(Benzo[d][1,3]dioxol-4-yl)-2-benzyl-3-(2-oxo-2-phenylethyl)-
6,7-dihydrobenzofuran-4(5H)-one (3ah). 450 mg, 97% yield, white
CDCl3) δ 8.34 (d, J = 1.5 Hz, 1H), 8.02 (dd, J = 7.2, 1.5 Hz, 2H),
G
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7.62−7.54 (m, 1H), 7.52−7.44 (m, 2H), 7.41 (7, J = 1.7 Hz, 1H),
7.32−7.19 (m, 5H), 6.89 (d, J = 1.5 Hz, 1H), 4.30 (s, 2H), 4.10 (q, J =
7.2 Hz, 2H), 3.99 (s, 2H), 1.01 (t, J = 7.2 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 196.4, 163.8, 150.4, 148.2, 144.5, 143.6, 142.4, 137.4,
136.8, 133.1, 128.6, 128.5, 128.4, 128.1, 126.6, 116.7, 115.0, 109.5,
60.2, 34.9, 32.2, 14.0; IR (KBr) νmax = 2922, 2846, 1695, 1448, 1338,
1218, 1098, 772 cm−1; MS (ESI) m/z 437 (M + Na)+; HRMS (ESI)
m/z calcd for C26H23O5 (M + H)+ 415.1540, found 415.1536.
5-Benzyl-4-(2-oxo-2-phenylethyl)-2-phenylfuran-3-carbonitrile
128.7, 128.5, 128.2, 127.3, 124.5, 124.5, 116.3, 115.9, 114.6, 94.4, 33.5,
32.6; IR (KBr) νmax = 3029, 2922, 2853, 2226, 1680, 1598, 1501, 1336,
1233, 837, 752 cm−1; MS (ESI) m/z 396 (M + H)+; HRMS (ESI) m/z
calcd for C26H19O2NF (M + H)+ 396.1394, found 396.1389.
2-(2-Benzyl-5-phenyl-4-(phenylsulfonyl)furan-3-yl)-1-phenyle-
1
thanone (3au). 359 mg, 73% yield, pale blueish semisolid; H NMR
(500 MHz, CDCl3) δ 8.02 (d, J = 7.2 Hz, 2H), 7.70−7.45 (m, 8H),
7.44−7.31 (m, 5H), 7.30−7.15 (m, 5H), 4.44 (s, 2H), 3.97 (s, 2H);
13C NMR (125 MHz, CDCl3) δ 196.2, 155.8, 152.2, 145.0, 141.8,
136.6, 133.2, 132.8, 130.4, 129.8, 129.4, 128.7, 128.6, 128.4, 128.2,
1
(3ao). 335 mg, 89% yield, pale yellow solid: mp 112−123 °C; H
NMR (500 MHz, CDCl3) δ 7.98 (dd, J = 7.1, 1.5 Hz, 2H), 7.93 (dd, J
= 7.2, 1.8 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.51−7.37 (m, 6H), 7.29−
7.25 (m, 2H), 7.23−7.18 (m, 2H), 4.12 (s, 2H), 4.04 (s, 2H); 13C
NMR (125 MHz, CDCl3) δ 194.7, 158.1, 151.7, 136.2, 135.9, 133.5,
129.7, 128.9, 128.7, 128.6, 128.5, 128.2, 128.0, 126.8, 125.7, 116.0,
114.6, 94.6, 33.6, 32.7; IR (KBr) νmax = 3030, 2922, 2852, 2224, 1681,
1598, 1448, 1337, 1217, 994, 754, 690 cm−1; MS (ESI) m/z 378 (M +
H)+; HRMS (ESI) m/z calcd for C26H20O2N (M + H)+ 378.1488,
found 378.1493.
127.9, 126.9, 126.8, 123.8, 114.6, 114.8, 34.0, 32.4; IR (KBr) νmax
=
2928, 2823, 1669, 1614, 1503, 1421, 1304, 1259, 989, 773, 696 cm−1;
MS (ESI) m/z 493 (M + H)+; HRMS (ESI) m/z calcd for C31H25O4S
(M + H)+ 493.1468, found 493.1465.
6,6-Dimethyl-2-(4-methylbenzyl)-3-(2-oxo-2-phenylethyl)-6,7-di-
hydrobenzofuran-4(5H)-one (3ba). 366 mg, 95% yield, white solid:
mp 118−119 °C; 1H NMR (500 MHz, CDCl3) δ 8.00 (d, J = 7.9 Hz,
2H), 7.54 (dd, J = 7.9, 6.9 Hz, 1H), 7.44 (t, J = 7.9 Hz, 2H), 7.07 (s,
4H), 4.28 (s, 2H), 3.89 (s, 2H), 2.67 (s, 2H), 2.30 (s, 2H), 2.28 (s,
3H), 1.15 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 196.4, 194.6, 164.9,
152.1, 136.6, 135.9, 134.0, 132.7, 129.0, 128.4, 128.3, 128.2, 119.0,
111.0, 52.1, 37.2, 35.0, 33.4, 31.6, 28.4, 20.8; IR (KBr) νmax = 3061,
2958, 2931, 1671, 1589, 1453, 1350, 1216, 1048, 771, 691 cm−1; MS
(ESI) m/z 387 (M + H)+. HRMS (ESI) m/z calcd for C26H27O3 (M +
H)+ 387.1954, found 387.1949; C25H24O3Na (M + Na)+ 95.1617,
found 395.1614.
2-(4-Methoxybenzyl)-6,6-dimethyl-3-(2-oxo-2-phenylethyl)-6,7-
dihydrobenzofuran-4(5H)-one (3ca). 390 mg, 97% yield, white solid:
mp 110−111 °C; 1H NMR (300 MHz, CDCl3) δ 8.02 (d, J = 8.3 Hz,
2H), 7.58−7.52 (m, 1H), 7.48−7.42 (m, 2H), 7.11 (d, J = 9.0 Hz,
2H), 6.80 (d, J = 9.0 Hz, 2H), 4.29 (s, 2H), 3.87 (s, 2H), 3.75 (s, 3H),
2.68 (s, 2H), 2.31 (s, 2H), 1.11 (s, 6H); 13C NMR (75 MHz, CDCl3)
δ 196.6, 194.8, 165.0, 158.2, 152.4, 136.7, 132.8, 129.5, 129.2, 128.4,
128.3, 119.1, 113.9, 111.0, 55.1, 52.2, 37.3, 35.1, 33.5, 31.3, 28.5; IR
(neat) νmax = 3028, 2926, 2851, 1679, 1595, 1454, 1341, 1251, 1042,
758 cm−1; MS (ESI) m/z 403 (M + H)+. HRMS (ESI) m/z calcd for
C26H27O4 (M + H)+ 403.1903, found 403.1900.
5-Benzyl-4-(2-oxo-2-phenylethyl)-2-(p-tolyl)furan-3-carbonitrile
1
(3ap). 344 mg, 88% yield, pale yellow solid: mp 166−167 °C; H
NMR (300 MHz, CDCl3) δ 7.98 (dd, J = 7.2, 1.3 Hz, 2H), 7.82 (d, J =
8.3 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 7.31−
7.16 (m, 7H), 4.10 (s, 2H), 4.02 (s, 2H), 2.38 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 194.7, 158.5, 151.3, 140.0, 136.3, 136.0, 133.5, 129.5,
128.7, 128.6, 128.5, 128.2, 126.8, 125.4, 125.0, 115.8, 114.8, 93.8, 33.6,
32.6, 21.4; IR (KBr) νmax = 3030, 2922, 2854, 2224, 1687, 1598, 1581,
1450, 1336, 1217, 989, 771, 690 cm−1; MS (ESI) m/z 392 (M + H)+;
HRMS (ESI) m/z calcd for C27H22O2N (M + H)+ 392.1645, found
392.1644.
5-Benzyl-2-(4-methoxyphenyl)-4-(2-oxo-2-phenylethyl)furan-3-
carbonitrile (3aq). 370 mg, 91% yield, pale yellow solid: mp 134−135
1
°C; H NMR (300 MHz, CDCl3) δ 7.98 (dd, J = 7.0, 1.5 Hz, 2H),
7.87 (d, J = 8.8 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.7 Hz,
2H), 7.30−7.17 (m, 5H), 6.95 (d, J = 8.8 Hz, 2H), 4.10 (s, 2H), 4.01
(s, 2H), 3.85 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 194.8, 160.6,
158.4, 150.8, 136.4, 135.9, 133.5, 128.7, 128.6, 128.5, 128.2, 126.8,
126.7, 120.9, 115.6, 115.0, 114.2, 92.8, 55.3, 33.5, 32.5; IR (KBr) νmax
= 2922, 2840, 2222, 1691, 1607, 1503, 1451, 1304, 1257, 989, 772, 690
cm−1; MS (ESI) m/z 408 (M + H)+; HRMS (ESI) m/z calcd for
C27H22O3N (M + H)+ 408.1594, found 408.1586.
2-(3,5-Dimethoxybenzyl)-6,6-dimethyl-3-(2-oxo-2-phenylethyl)-
6,7-dihydrobenzofuran-4(5H)-one (3da). 388 mg, 90% yield, pale
1
yellow solid: mp 124−125 °C; H NMR (500 MHz, CDCl3) δ 8.01
(dd, J = 7.2, 1.4 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.45 (t, J = 7.5, Hz,
2H), 7.03 (d, J = 8.8 Hz, 1H), 6.40−6.38 (m, 2H), 4.31 (s, 2H), 3.83
(s, 2H), 3.76 (s, 3H), 3.70 (s, 3H), 2.68 (s, 2H), 2.29 (s, 2H), 1.11 (s,
6H); 13C NMR (125 MHz, CDCl3) δ 196.5, 194.7, 164.7, 157.8,
152.0, 136.9, 132.7, 130.2, 128.3, 128.1, 117.9, 110.7, 103.8, 98.3, 55.1,
52.2, 37.3, 35.1, 33.5, 28.5, 25.7; IR (KBr) νmax = 2957, 2930, 1671,
1612, 1589, 1454, 1352, 1210, 1042, 772, 691 cm−1; MS (ESI) m/z
433 (M + H)+; HRMS (ESI) m/z calcd for C27H29O5 (M + H)+
433.2009, found 433.1998.
6,6-Dimethyl-3-(2-oxo-2-phenylethyl)-2-(3-(trifluoromethyl)-
benzyl)-6,7-dihydrobenzofuran-4(5H)-one (3ea). 418 mg, 95% yield,
white solid: mp 88−89 °C; 1H NMR (300 MHz, CDCl3) δ 8.03 (dd, J
= 7.5, 1.5 Hz, 2H), 7.55 (t, J = 7.5 Hz, 1H), 7.48−7.41 (m, 4H), 7.40−
7.36 (m, 2H), 4.35 (s, 2H), 3.98 (s, 2H), 2.68 (s, 2H), 2.32 (s, 2H),
1.11 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 196.6, 194.8, 165.4,
151.1, 138.2, 136.6, 133.0, 131.9, 128.9, 128.5, 128.4, 125.3, 125.2,
123.5, 123.4, 119.0, 111.9, 52.3, 37.3, 35.2, 33.5, 31.9, 28.5; IR (KBr)
νmax = 3064, 2961, 2934, 1692, 1673, 1591, 1451, 1330, 1125, 757, 691
cm−1; MS (ESI) m/z 441 (M + H)+, 463 (M + Na)+; HRMS (ESI) m/
z calcd for C26H24F3O3 (M + H)+ 441.1672, found 441.1679.
2-(4-Chlorobenzyl)-6,6-dimethyl-3-(2-oxo-2-phenylethyl)-6,7-di-
hydrobenzofuran-4(5H)-one (3fa). 389 mg, 96% yield, white solid:
mp 132−133 °C; 1H NMR (300 MHz, CDCl3) δ 8.02 (dd, J = 7.2, 1.3
Hz, 2H), 7.55 (td, J = 7.2, 2.1 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.22
(d, J = 8.5, 2H), 7.12 (d, J = 8.5, 2H), 4.32 (s, 2H), 3.89 (s, 2H), 2.67
(s, 2H), 2.31 (s, 2H), 1.11 (s, 6H); 13C NMR (75 MHz, CDCl3) δ
196.6, 194.8, 165.2, 151.6, 136.7, 135.7, 133.0, 132.4, 129.9, 128.6,
128.5, 128.4, 119.1, 111.6, 52.3, 37.4, 35.2, 33.5, 31.5, 28.5; IR (KBr)
νmax = 3062, 2959, 2928, 1672, 1590, 1452, 1214, 1048, 754, 691 cm−1;
5-Benzyl-2-(3-chlorophenyl)-4-(2-oxo-2-phenylethyl)furan-3-car-
bonitrile (3ar). 353 mg, 86% yield, pale yellow solid: mp 149−151 °C;
1H NMR (500 MHz, CDCl3) δ 7.98 (dd, J = 7.2, 1.4 Hz, 2H), 7.88−
7.85 (m, 2H), 7.61 (t, J = 7.5 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.40−
7.35 (m, 2H), 7.28 (t, J = 7.6 Hz, 2H), 7.23−7.18 (m, 3H), 4.11 (s,
2H), 4.04 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 194.5, 156.3, 152.4,
135.9, 135.8, 135.0, 133.6, 130.2, 129.7, 129.2, 128.8, 128.7, 128.6,
128.5, 128.2, 126.9, 124.9, 123.1, 116.4, 114.2, 33.5, 32.7; IR (KBr)
νmax = 3030, 2922, 2852, 2226, 1691, 1597, 1450, 1335, 1216, 990,
769, 689 cm−1; MS (ESI) m/z 412 (M + H)+; HRMS (ESI) m/z calcd
for C26H19ClO2N (M + H)+ 412.1098, found 412.1095.
Methyl 4-(5-benzyl-3-cyano-4-(2-oxo-2-phenylethyl)furan-2-yl)-
benzoate (3as). 343 mg, 79% yield, pale yellow solid: mp 161−163
1
°C; H NMR (500 MHz, CDCl3) δ 8.10 (dd, J = 8.6, 1.8 Hz, 2H),
8.00 (dd, J = 8.6, 1.5 Hz, 2H), 7.98 (dd, J = 8.2, 1.4 Hz, 2H), 7.61 (t, J
= 7.3 Hz, 1H), 7.50 (t, J = 7.9 Hz, 2H), 7.28 (t, J = 6.9 Hz, 2H), 7.24−
7.19 (m, 3H), 4.12 (s, 2H), 4.05 (s, 2H), 3.94 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 194.4, 166.2, 156.5, 152.9, 135.9, 135.8, 133.6, 131.7,
130.6, 130.1, 128.8, 128.7, 128.5, 128.2, 126.9, 124.7, 116.7, 114.2,
96.5, 52.2, 33.5, 32.7; IR (KBr) νmax = 2952, 2923, 2225, 1722, 1684,
1607, 1433, 1281, 1107, 990, 754, 689 cm−1; MS (ESI) m/z 436 (M +
H)+; HRMS (ESI) m/z calcd for C28H22O4N (M + H)+ 436.1543,
found 436.1535.
5-Benzyl-2-(4-fluorophenyl)-4-(2-oxo-2-phenylethyl)furan-3-car-
bonitrile (3at). 288 mg, 72% yield, pale yellow solid: mp 117−119 °C;
1H NMR (300 MHz, CDCl3) δ 7.98 (dd, J = 7.4, 1.3 Hz, 2H), 7.92
(dd, J = 8.9, 5.3 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.7 Hz,
2H), 7.30−7.09 (m, 7H), 4.11 (s, 2H), 4.02 (s, 2H); 13C NMR (75
MHz, CDCl3) δ 194.6, 164.9, 161.6, 157.2, 151.7, 136.2, 135.9, 133.6,
H
dx.doi.org/10.1021/jo4023342 | J. Org. Chem. XXXX, XXX, XXX−XXX

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MS (ESI) m/z 407 (M + H)+, 429 (M + Na)+; HRMS (ESI) m/z
calcd for C25H24ClO3 (M + H)+ 407.1408, found 407.1415.
29.7, 29.5, 29.3, 29.2, 28.7, 28.1, 25.9, 22.6, 14.1; IR (KBr) νmax =
2924, 2854, 1730, 1668, 1457, 1398, 1248, 1081, 761, 696 cm−1; MS
(ESI) m/z 409 (M + H)+. HRMS (ESI) m/z calcd for C27H37O3 (M +
H)+ 409.2737, found 409.2729.
2-(2-Iodobenzyl)-6,6-dimethyl-3-(2-oxo-2-phenylethyl)-6,7-dihy-
drobenzofuran-4(5H)-one (3ga). 479 mg, 96% yield, white solid: mp
106−107 °C; 1H NMR (300 MHz, CDCl3) δ 8.01 (dd, J = 7.5, 1.5 Hz,
2H), 7.80 (d, J = 6.8 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.44 (t, J = 7.5
Hz, 2H), 7.23 (t, J = 8.3 Hz, 1H), 7.15 (dd, J = 7.5, 2.3 Hz, 1H), 6.89
(dd, J = 7.5, 1.5 Hz, 1H), 4.34 (s, 2H), 4.03 (s, 2H), 2.68 (s, 2H), 2.31
(s, 2H), 1.12 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 196.4, 194.6,
165.3, 150.6, 139.8, 139.4, 136.8, 132.8, 129.9, 128.5, 128.4, 128.3,
128.2, 119.2, 112.3, 100.2, 52.2, 37.6, 37.4, 35.1, 33.8, 28.6; IR (KBr)
νmax = 3059, 2958, 2928, 1694, 1672, 1587, 1453, 1351, 1214, 1048,
753, 690 cm−1; MS (ESI) m/z 499 (M + H)+, 521 (M + Na)+; HRMS
(ESI) m/z calcd for C25H24IO3 (M + H)+ 499.0765, found 499.0769.
6,6-Dimethyl-2-(4-nitrobenzyl)-3-(2-oxo-2-phenylethyl)-6,7-dihy-
drobenzofuran-4(5H)-one (3ha). 358 mg, 86% yield, pale yellow
2-Benzyl-6,6-dimethyl-3-(2-oxopropyl)-6,7-dihydrobenzofuran-
1
4(5H)-one (3ma). 279 mg, 96% yield, white solid: mp 96−97 °C; H
NMR (300 MHz, CDCl3) δ 7.32−7.17 (m, 5H), 3.88 (s, 2H), 3.69 (s,
2H), 2.66 (s, 2H), 2.30 (s, 2H), 2.20 (s, 3H), 1.11 (s, 6H); 13C NMR
(75 MHz, CDCl3) δ 205.5, 194.8, 165.3, 151.8, 137.2, 128.6, 128.4,
126.6, 124.3, 119.0, 52.2, 38.2, 37.3, 35.2, 32.0, 29.7, 28.6; IR (KBr)
νmax = 3057, 2903, 1722, 1671, 1532, 1457, 1214, 1021, 967, 751 cm−1;
MS (ESI) m/z 311 (M + H)+. HRMS (ESI) m/z calcd for
C20H22O3Na (M + Na)+ 333.1461, found 333.1460.
Ethyl 2-(2-benzyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydrobenzo-
furan-3-yl)acetate (3na). 295 mg, 87% yield, colorless liquid: 1H
NMR (300 MHz, CDCl3) δ 7.34−7.23 (m, 3H), 7.22−7.16 (m, 2H),
4.14 (q, J = 7.1 Hz, 2H), 3.92 (s, 2H), 3.64 (s, 2H), 2.66 (s, 2H), 2.31
(s, 2H), 1.25 (t, J = 7.1 Hz, 3H), 1.11 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 194.5, 170.8, 165.0, 151.5, 137.2, 128.5, 128.4, 126.6, 119.2,
1
solid: mp 152−153 °C; H NMR (600 MHz, CDCl3) δ 8.13 (d, J =
8.6 Hz, 2H), 8.03 (d, J = 7.5 Hz, 2H), 7.56 (t, J = 7.1 Hz, 1H), 7.48−
7.44 (m, 2H), 7.37 (d, J = 8.6 Hz, 2H), 4.36 (s, 2H), 4.03 (s, 2H), 2.68
(s, 2H), 2.33 (s, 2H), 1.12 (s, 6H); 13C NMR (75 MHz, CDCl3) δ
196.4, 194.7, 165.5, 150.3, 146.6, 144.8, 136.4, 133.0, 129.3, 128.4,
128.3, 123.6, 118.9, 112.2, 52.1, 37.2, 35.0, 33.3, 31.8, 28.4; IR (KBr)
νmax = 3066, 2959, 2929, 1672, 1593, 1452, 1346, 1048, 755, 690 cm−1;
MS (ESI) m/z 418 (M + H)+; HRMS (ESI) m/z calcd for C25H24NO5
(M + H)+ 418.1649, found 418.1645.
111.2, 60.7, 52.2, 37.3, 35.2, 31.9, 29.3, 28.5, 14.1; IR (KBr) νmax
=
2961, 2928, 1736, 1672, 1586, 1453, 1219, 1030, 772 cm−1; MS (ESI)
m/z 341 (M + H)+; 363 (M + Na); HRMS (ESI) m/z calcd for
C21H25O4 (M + H)+ 341.1747, found 341.1751.
Benzyl 2-(2-benzyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydrobenzo-
furan-3-yl)acetate (3oa). 369 mg, 92% yield, white solid: mp 67−
68 °C; 1H NMR (500 MHz, CDCl3) δ 7.38−7.29 (m, 5H), 7.28−7.24
(m, 2H), 7.23−7.19 (m, 1H), 7.18−7.11 (m, 2H), 5.12 (s, 2H), 3.90
(s, 2H), 3.70 (s, 2H), 2.65 (s, 2H), 2.31 (s, 2H), 1.10 (s, 6H); 13C
NMR (75 MHz, CDCl3) δ 194.5, 170.6, 165.0, 151.6, 137.1, 135.8,
129.6, 128.5, 128.3, 128.2, 128.0, 126.6, 119.2, 111.0, 66.6, 52.2, 37.2,
35.1, 31.9, 29.3, 28.5; IR (KBr) νmax = 3032, 2959, 2923, 1740, 1674,
1589, 1455, 1352, 1216, 1165, 1048, 771 cm−1; MS (ESI) m/z 403 (M
+ H)+; HRMS (ESI) m/z calcd for C26H27O4 (M + H)+ 403.1903,
found 403.1894.
6,6-Dimethyl-2-(naphthalen-1-ylmethyl)-3-(2-oxo-2-phenyleth-
yl)-6,7-dihydrobenzofuran-4(5H)-one (3ia). 409 mg, 97% yield, pale
yellow solid: mp 89−90 °C; 1H NMR (300 MHz, CDCl3) δ 8.01 (dd,
J = 9.8, 2.7 Hz, 1H), 7.95 (dd, J = 7.5, 1.5 Hz, 2H), 7.81 (dd, J = 7.5,
2.7 Hz, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.55−7.37 (m, 5H), 7.33 (t, J =
8.3 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 4.38 (s, 2H), 4.26 (s, 2H), 2.65
(s, 2H), 2.30 (s, 2H), 1.09 (s, 6H); 13C NMR (75 MHz, CDCl3) δ
196.5, 194.9, 165.1, 151.4, 136.7, 133.6, 132.9, 132.8, 131.7, 128.6,
128.4, 128.3, 127.4, 126.5, 126.1, 125.6, 125.4, 123.4, 119.3, 111.7,
52.3, 37.3, 35.2, 33.5, 29.7, 28.5; IR (KBr) νmax = 3057, 2958, 2927,
1671, 1591, 1451, 1351, 1216, 1049, 775, 690 cm−1; MS (ESI) m/z
423 (M + H)+, 445 (M + Na)+; HRMS (ESI) m/z calcd for C29H27O3
(M + H)+ 423.1955, found 423.1960.
2-(2-Benzyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-3-
yl)-N,N-diethylacetamide (3pa). 315 mg, 86% yield, colorless liquid:
1H NMR (500 MHz, CDCl3) δ 7.31−7.27 (m, 2H), 7.26−7.18 (m,
3H), 4.02 (s, 2H), 3.70 (s, 2H), 3.43 (q, J = 7.2 Hz, 2H), 3.37 (q, J =
7.0 Hz, 2H), 2.66 (s, 2H), 2.31 (s, 2H), 1.19 (t, J = 7.0 Hz, 3H), 1.12−
1.093 (m, 9H); 13C NMR (75 MHz, CDCl3) δ 195.1, 169.3, 165.0,
152.3, 137.7, 128.6, 128.5, 126.4, 119.0, 112.1, 52.5, 42.3, 40.6, 37.4,
35.2, 32.2, 28.6, 28.1, 14.2, 13.0; IR (KBr) νmax = 2961, 2928, 1736,
1622, 1586, 1451, 1270, 1190, 779 cm−1; MS (ESI) m/z 341 (M +
H)+; 368 (M + H); HRMS (ESI) m/z calcd for C23H30NO3 (M + H)+
368.2220, found 368.2222.
6,6-Dimethyl-3-(2-oxo-2-phenylethyl)-2-(thiophen-2-ylmethyl)-
6,7-dihydrobenzofuran-4(5H)-one (3ja). 362 mg, 96% yield, brown
1
solid: mp 114−115 °C; H NMR (300 MHz, CDCl3) δ 8.03 (dd, J =
7.5, 1.5 Hz, 2H), 7.54 (dd, J = 7.5, 2.3 Hz, 1H), 7.45 (t, J = 7.5 Hz,
2H), 7.13 (dd, J = 5.3, 1.5 Hz, 1H), 6.89 (dd, J = 5.3, 3.0 Hz, 1H), 6.83
(d, J = 4.5 Hz, 1H), 4.32 (s, 2H), 4.13 (s, 2H), 2.70 (s, 2H), 2.32 (s,
2H), 1.12 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 196.4, 194.8, 165.1,
152.2, 139.5, 136.7, 132.9, 128.4, 128.3, 126.8, 125.5, 124.2, 119.1,
111.3, 52.2, 37.3, 35.1, 33.4, 28.5, 26.5; IR (KBr) νmax = 3066, 2959,
2868, 1692, 1672, 1589, 1451, 1351, 1214, 1049, 755, 692 cm−1; MS
(ESI) m/z 379 (M + H)+, 401 (M + Na)+; HRMS (ESI) m/z calcd for
C23H23O3S (M + H)+ 379.1362, found 379.1358.
2-(2-Benzyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-3-
1
yl)acetonitrile (3qa). 246 mg, 84% yield, colorless liquid: H NMR
(300 MHz, CDCl3) δ 7.44−7.29 (m, 5H), 3.02 (t, J = 7.4 Hz, 2H),
2.77 (s, 2H), 2.66 (t, J = 7.4 Hz, 2H), 2.38 (s, 2H), 1.16 (s, 6H); 13C
NMR (75 MHz, CDCl3) δ 193.1, 165.6, 147.9, 130.5, 129.6, 128.0,
127.6, 121.3, 118.6, 118.4, 52.8, 37.5, 34.8, 28.5, 22.4, 16.3; IR (KBr)
νmax = 2959, 2868, 2248, 1678, 1592, 1449, 1218, 1047, 959, 769, 699
cm−1; MS (ESI) m/z 294 (M + H)+. HRMS (ESI) m/z calcd for
C19H20O2N (M + H)+ 294.1488, found 294.1484.
2-Benzyl-6,6-dimethyl-3-(nitromethyl)-6,7-dihydrobenzofuran-
4(5H)-one (3ra). 253 mg, 81% yield, pale yellow solid: mp 134−135
°C; 1H NMR (300 MHz, CDCl3) δ 7.41−7.15 (m, 5H), 5.46 (s, 2H),
4.01 (s, 2H), 2.71 (s, 2H), 2.35 (s, 2H), 1.13 (s, 6H); 13C NMR (75
MHz, CDCl3) δ 194.3, 165.5, 155.4, 130.9, 128.9, 128.6, 127.2, 118.6,
108.1, 68.0, 52.0, 37.1, 32.4, 29.7, 28.6; IR (KBr) νmax = 2958, 2842,
1671, 1562, 1525, 1443, 1229, 1047, 959, 768, 691 cm−1; MS (ESI) m/
z 314 (M + H)+. HRMS (ESI) m/z calcd for C18H20O4N (M + H)+
314.1386, found 314.1381.
2-Cinnamyl-6,6-dimethyl-3-(2-oxo-2-phenylethyl)-6,7-dihydro-
benzofuran-4(5H)-one (3ka). 358 mg, 90% yield, brown solid: mp
124−125 °C; 1H NMR (600 MHz, CDCl3) δ 7.97 (t, J = 8.3 Hz, 2H),
7.50−7.45 (m, 1H), 7.41−7.35 (m, 2H), 7.25−7.18 (m, 3H), 7.15−
7.11 (d, J = 8.0 Hz, 2H), 6.30 (ddd, J = 15.8, 8.3, 4.2 Hz, 1H), 6.14
(dd, J = 15.8, 1.5 Hz, 1H), 4.29 (d, J = 4.2 Hz, 2H), 3.43 (dd, J = 9.8,
2.6 Hz, 2H), 2.64 (s, 2H), 2.25 (s, 2H), 1.05 (s, 6H); 13C NMR (75
MHz, CDCl3) δ 196.7, 194.4, 165.3, 150.6, 139.6, 136.7, 132.9, 132.0,
129.5, 128.4, 128.3, 127.3, 126.1, 124.8, 116.8, 111.4, 52.3, 39.3, 37.4,
35.1, 33.5, 28.5; IR (KBr) νmax = 3061, 2960, 2930, 1671, 1597, 1455,
1352, 1214, 1049, 754, 693 cm−1; MS (ESI) m/z 399 (M + H)+, 421
(M + Na); HRMS (ESI) m/z calcd for C27H27O3 (M + H)+ 399.1955,
found 399.1964.
6,6-Dimethyl-2-nonyl-3-(2-oxo-2-phenylethyl)-6,7-dihydrobenzo-
2-Benzyl-6,6-dimethyl-3-(1-oxo-1,2,3,4-tetrahydronaphthalen-2-
1
furan-4(5H)-one (3la). 302 mg, 74% yield, pale yellow oil: H NMR
yl)-6,7-dihydrobenzofuran-4(5H)-one (3sa). 374 mg, 94% yield,
1
(300 MHz, CDCl3) δ 8.05 (dd, J = 7.4, 1.7 Hz, 2H), 7.59−7.41 (m,
3H), 4.28 (s, 2H), 2.70 (s, 2H), 2.52 (t, J = 7.5 Hz, 2H), 2.31 (s, 2H),
1.62−1.51 (m, 2H), 1.34−1.20 (m, 12H), 1.12 (s, 6H), 0.87 (t, J = 3.4
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 196.9, 195.0, 164.6, 154.5,
136.9, 132.9, 128.5, 128.4, 119.0, 109.8, 52.4, 37.5, 35.3, 33.7, 31.8,
white solid: mp 183−184 °C; H NMR (300 MHz, CDCl3) δ 8.10
(dd, J = 7.8, 1.2 Hz, 1H), 7.46 (td, J = 7.5, 1.4 Hz, 1H), 7.33−7.28 (m,
3H), 7.25−7.20 (m, 4H), 3.96 (s, 2H), 3.77 (d, J = 10.7 Hz, 1H), 3.07
(ddd, J = 12.5, 8.9, 4.3 Hz, 1H), 2.95 (dd, J = 5.6, 4.3 Hz, 1H), 2.71 (d,
J = 17.1 Hz, 1H), 2.66 (d, J = 17.3 Hz, 1H), 2.62 (dd, J = 17.3, 4.0 Hz,
I
dx.doi.org/10.1021/jo4023342 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1H), 2.32 (d, J = 16.2 Hz, 1H), 2.23 (d, J = 16.2 Hz, 1H), 2.06−1.99
(m, 1H), 1.13 (s, 3H), 1.09 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
196.2, 193.5, 165.4, 150.9, 143.4, 137.5, 132.9, 132.6, 128.5, 128.4,
128.3, 127.5, 126.5, 118.4, 117.2, 52.1, 45.2, 37.3, 34.9, 32.2, 30.0, 29.5,
28.7, 28.3; IR (KBr) νmax = 3027, 2957, 2934, 2866, 1669, 1449, 1229,
1041, 715 cm−1; MS (ESI) m/z 341 (M + H)+; 399 (M + H); HRMS
(ESI) m/z calcd for C27H27O3 (M + H)+ 399.1955, found 399.1953.
General Procedure for the Synthesis of Substituted Bis-
furans (5). To a solution of 4 (0.4 mmol) in 9 mL of acetonitrile was
added keto-active methylene 2a (0.84 mmol) and DBU (0.8 mmol) at
room temperature, and the mixture was then heated to 85 °C for 20 h.
After the completion of the reaction, the mixture was concentrated in
vacuo. The residue was purified by column chromatography on silica
gel (EtOAc:hexanes) to afford the corresponding bis-furan 5.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
M.D.R. thanks CSIR, New Delhi, for research fellowship.
C.R.R. thanks CSIR, New Delhi, for financial support as part of
XII-five year plan project under title ORIGIN (CSC-108).
REFERENCES
■
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2,2′-(1,2-Phenylenebis(methylene))bis(6,6-dimethyl-3-(2-oxo-2-
phenylethyl)-6,7-dihydrobenzofuran-4(5H)-one) (5a). 215 mg, 81%
1
yield, brown solid: mp 167−168 °C; H NMR (600 MHz, CDCl3) δ
7.94 (dd, J = 7.1, 1.5 Hz, 4H), 7.53 (t, J = 7.1 Hz, 2H), 7.42 (t, J = 7.9
Hz, 4H), 7.10−7.04 (m, 4H), 4.19 (s, 4H), 3.97 (s, 4H), 2.61 (s, 4H),
2.27 (s, 4H), 1.08 (s, 12H); 13C NMR (75 MHz, CDCl3) δ 196.5,
194.8, 165.1, 151.2, 136.8, 135.3, 132.9, 129.8, 128.4, 128.3, 127.2,
119.3, 111.8, 52.3, 37.3, 35.2, 33.5, 29.7, 28.6; IR (KBr) νmax = 2950,
2925, 2854, 1671, 1594, 1450, 1351, 1214, 1048, 753, 689 cm−1; MS
(ESI) m/z 667.2 (M + H)+; HRMS (ESI) m/z calcd for C44H43O6 (M
+ H)+ 667.3054, found 667.3050.
2,2′-(1,3-Phenylenebis(methylene))bis(6,6-dimethyl-3-(2-oxo-2-
phenylethyl)-6,7-dihydrobenzofuran-4(5H)-one) (5b). 237 mg, 89%
1
yield, brown solid: mp 201−203 °C; H NMR (600 MHz, CDCl3) δ
7.99 (dd, J = 7.5, 1.9 Hz, 4H), 7.52 (t, J = 7.1 Hz, 2H), 7.42 (t, J = 7.9
Hz, 4H), 7.7 (t, J = 7.5 Hz, 1H), 7.05−7.00 (m, 3H), 4.27 (s, 4H),
3.86 (s, 4H), 2.65 (s, 4H), 2.30 (s, 4H), 1.10 (s, 12H); 13C NMR (75
MHz, CDCl3) δ 196.7, 194.7, 165.2, 151.9, 137.6, 136.8, 132.9, 128.9,
128.8, 128.4, 128.3, 126.8, 119.2, 111.4, 52.3, 37.4, 35.2, 33.6, 32.0,
28.6; IR (KBr) νmax = 2958, 2924, 2854, 1690, 1670, 1589, 1452, 1351,
1214, 1048, 991, 754, 690 cm−1; MS (ESI) m/z 667.3 (M + H)+, 689.3
(M + Na)+; HRMS (ESI) m/z calcd for C44H43O6 (M + H)+
667.3054, found 667.3050.
3,3′-(2-Oxocyclohexane-1,3-diyl)bis(2-benzyl-6,6-dimethyl-6,7-
(5) For reviews on furans, see: (a) Wong, H. N. C.; Hou, X. L.;
Yeung, K. S.; Huang, H. In Modern Heterocyclic Chemistry; Ivarez-
Builla, J., Vaquero, J.-J., Barluenga, J., Eds.; Wiley-VCH: Weinheim,
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(d) Brown, R. C. D. Angew. Chem., Int. Ed. 2005, 44, 850.
dihydrobenzofuran-4(5H)-one) (5c). 224 mg, 93% yield, brown solid:
1
mp 106−107 °C; H NMR (300 MHz, CDCl3) δ 7.32−7.15 (m,
10H), 4.13−3.88 (m, 6H), 2.64 (s, 4H), 2.49−2.30 (m, 2H), 2.25 (s,
4H), 2.15−2.05 (m, 2H), 2.01−1.90 (m, 2H), 1.09 (s, 12H); 13C
NMR (75 MHz, CDCl3) δ 204.6, 194.6, 165.3, 151.2, 138.1, 128.7,
128.3, 126.2, 118.8, 116.2, 52.6, 47.0, 37.5, 35.2, 33.5, 32.5, 28.7, 28.5,
25.9; IR (KBr) νmax = 3021, 2959, 2914, 2867, 1669, 1465, 1342, 1222,
1064, 715, 698 cm−1; MS (ESI) m/z 603 (M + H)+; HRMS (ESI) m/z
calcd for C40H43O5 (M + H)+ 603.3105, found 603.3099.
(6) (a) Paal, C. Ber. Dtsch. Chem. Ges. 1884, 17, 2756. (b) Knorr, L.
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Milton, M. D.; Hidai, M.; Uemura, S. Angew. Chem., Int. Ed. 2003, 42,
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M. J. Am. Chem. Soc. 2008, 130, 13528. (c) Cao, H.; Jiang, H.; Yao, W.;
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3,3′-(4-Oxotetrahydro-2H-thiopyran-3,5-diyl)bis(2-benzyl-6,6-di-
methyl-6,7-dihydrobenzofuran-4(5H)-one) (5d). 228 mg, 92% yield,
1
brown solid: mp 86−87 °C; H NMR (500 MHz, CDCl3) δ 7.31−
7.18 (m, 10H), 3.96 (q, J = 12.7 Hz, 4H), 3.76 (t, J = 12.9 Hz, 2H),
2.80 (d, J = 12.9 Hz, 2H), 2.68−2.60 (m, 5H), 2.32−2.21 (m, 5H)
1.09 (s, 12H); 13C NMR (125 MHz, CDCl3) δ 202.0, 194.5, 165.4,
151.5, 137.7, 128.6, 128.4, 126.3, 118.5, 115.0, 52.3, 49.6, 37.4, 34.9,
34.5, 32.4, 28.6, 28.4; IR (KBr) νmax = 2957, 2925, 2854, 1716, 1666,
1587, 1450, 1351, 1214, 1048, 971, 763 cm−1; MS (ESI) m/z 621 (M
+ H)+, 643 (M + Na)+; HRMS (ESI) m/z calcd for C39H41O5S (M +
H)+ 621.2669, found 621.2672.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: rajireddy@iict.res.in.
J
dx.doi.org/10.1021/jo4023342 | J. Org. Chem. XXXX, XXX, XXX−XXX

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