Base-mediated decomposition of amide-substituted furfuryl tosylhydrazones: Synthesis and cytotoxic activities of enynyl-ketoamides

Article abstract of DOI:10.1021/jo502328j

Base-mediated decomposition of amide-substituted furfuryl tosylhydrazones afforded practical access to novel multifunctionalized enynyl-ketoamides. In addition, furfuryl tosylhydrazones with stable furan rings underwent an interesting tosyl-group migratio

Full text of DOI:10.1021/jo502328j

Article
pubs.acs.org/joc
Base-Mediated Decomposition of Amide-Substituted Furfuryl
Tosylhydrazones: Synthesis and Cytotoxic Activities of Enynyl-
Ketoamides
Fanghua Ji,† Hui Peng,† Xiaoting Zhang,† Wenhua Lu,‡ Shubin Liu,§ Huanfeng Jiang,† Bo Liu,*,#
and Biaolin Yin*,†
†School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510006, P.R. China
‡State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China
§Research Computing Center, University of North Carolina, Chapel Hill, North Carolina 27599-3420, United States
#Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou 510006, P.R. China
S
* Supporting Information
ABSTRACT: Base-mediated decomposition of amide-substituted furfuryl
tosylhydrazones afforded practical access to novel multifunctionalized
enynyl-ketoamides. In addition, furfuryl tosylhydrazones with stable furan
rings underwent an interesting tosyl-group migration to form sulfones, which
have potential synthetic applications. Some of the obtained enynyl-ketoamides
demonstrated good cytotoxicities against human tumor cell lines.
from a variety of readily available furfuryl carbenes is highly
desirable.9
INTRODUCTION
■
In recent years, furans have increasingly attracted the attention
of researchers in various areas of chemistry for two reasons.
First, furan derivatives such as furfural are some of the most
readily available and important synthetic platforms derived
from a biomass.1,2 Second, furans are particularly attractive
four-carbon starting materials for chemical transformations
because they not only demonstrate typical arene reactivity3 but
can also serve as the equivalent of alkenes, 1,3-dienes, alkynes,
1,4-diketones, and enol ethers owing to the low aromaticity of
the furan ring.4 To date, several methods that allow
dearomatization of the furan ring have been developed and
have been extensively used in the synthesis of numerous
bioactive molecules.5
Photolysis and pyrolysis of furfuryl diazomethanes have been
reported to produce enynones, presumably via furfuryl
carbenes.6 However, only a few simple furfuryl diazomethanes
have been used as substrates. Their exact yields have not been
reported, and the scope of the reactions has not been
thoroughly investigated. Moreover, the protocols for enynone
production require tedious manipulations and exceedingly
harsh conditions, resulting in partial decomposition of the
formed enynones and side reactions such as C−H insertion of
the furfuryl carbene intermediates. Given that enynones are
potent antitumor and antifungal agents,7 as well as valuable
synthons that bear double bonds, triple bonds, and carbonyl
functionalities (including Michael acceptors),8 the development
of a practical method to access structurally diverse enynones
Tosylhydrazones, prepared by the reaction of an aldehyde or
a ketone with tosylhydrazine, are extensively used in organic
syntheses to generate carbenes by treatment with a base, such
as sodium tert-butoxide or K2CO3, at a relatively low
temperature (∼100 °C).10 Theoretically, base-mediated
decomposition of suitable furfuryl tosylhydrazones can produce
furfuryl carbenes. Efficient in situ transformation of furfuryl
carbenes into enynones probably depends primarily on the
nature of the substituents on the furan ring, which governs the
stability of both the carbene and the formed enynones. We
hypothesized that introduction of suitable electron-withdrawing
substituents on the furan ring of furfuryl tosylhydrazones would
stabilize the furfuryl carbenes formed by treatment with a
suitable base. Whether such carbenes would also be trans-
formed into their corresponding enynones, some of which
would have both synthetic and medicinal importance, has never
been reported. Moreover, the influence of the substituents on a
furan ring on the decomposition reaction of furfuryl carbenes
has also not previously been disclosed.
Received: October 12, 2014
© XXXX American Chemical Society
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Article
RESULTS AND DISCUSSION
The pathway from furfuryl tosylhydrazones to enynones is
shown in Table 1, along with calculated total free energy
Scheme 1. Transformation of Furfuryl Carbenes into
Enynones
■
Table 1. Pathway from Furfuryl Tosylhydrazones to
Enynones with Calculated Total Free Energy Changes
(ΔG°) and Activation Barriers (ΔG⧧) of the Ring-Opening
a
Steps for Selected Carbenes
Table 2. Synthesis of Precursor 1
a
Energies were calculated at the M062X/6-311+G(d) level of theory
and are in kcal/mol.
changes (ΔG°) and activation barriers of the ring-opening step
(ΔG⧧) for selected carbenes. The ΔG⧧ values were small (5.0−
12.3 kcal/mol), and among the carbenes considered, B-1
showed the highest ΔG° and the lowest ΔG⧧ (5.0 kcal/mol).
On the basis of this information, we chose a series of furfuryl
tosylhydrazones (1) with moderately electron-withdrawing
amide groups at the α position and studied their base-mediated
decomposition to form enynyl-ketoamides, a structural element
of many natural products, pharmaceuticals, and synthetic
reagents.11 In addition, enynyl-ketoamides can be expected to
serve as useful six-carbon synthons owing to their multiple
functionalities (Scheme 1).12
Furfuryl tosylhydrazones 1 were conveniently prepared from
keto esters 313 by means of four successive steps (Table 2):
hydrolysis, acetyl chlorination, amidation, and condensation
with TsNHNH2. We used N,N-dimethyl-5-(phenyl(2-tosyl-
hydrazone)methyl)furan-2-carboxamide (1a) as the substrate
to optimize the reaction conditions for the base-catalyzed
decomposition reaction (Table 3). With K2CO3 as the base and
toluene as the solvent, the samples were reacted at 90 °C for 1
a
Isolated yields.
B
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a b
,
Table 3. Optimization of Conditions for Base-Mediated
Decomposition of 1a
Table 4. Synthesis of Enynyl-Ketoamides 2
a
b
entry
base
solvent
T (°C)
yield (%)
1
K2CO3
Cs2CO3
NaH
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
MeCN
DCE
90
90
90
90
90
90
90
90
90
90
90
90
80
100
90
49
2
trace
trace
15
3
4
NaOMe
KOtBu
NaOH
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
5
32
6
16
7
80
8
55
9
40
10
11
12
13
14
15
Dioxane
THF
30
58
c
DMF
ND
PhMe
PhMe
PhMe
7
50
71
d
LiOtBu
a
b
Reactions were performed on a 0.3 mmol scale. Yields were
1
determined by H NMR spectroscopy with mesitylene as the internal
standard. ND, not detected. Two equiv was used.
c
d
a
Reaction conditions unless stated otherwise: 1 (0.3 mmol), LiOtBu
h to afford desired product 2a in 49% yield along with some
unidentified byproducts (entry 1). To improve the yield of 2a,
we tested various parameters, including the solvent, reaction
temperature, and type and amount of base. Among the bases
tested, LiOtBu gave the highest yield (80%, entries 2−7). Other
solvents (MeCN, DCE, 1,4-dioxane, THF, and DMF) were
also tested with toluene proving to be the best of them (entries
8−12). Lowering the reaction temperature to 80 °C or raising it
to 100 °C decreased the yield (entries 13 and 14) as did
increasing the amount of LiOtBu to 2 equiv (entry 15).
b
c
(1.1 equiv), toluene (5 mL), 1 h, 90 °C. Isolated yields. Reaction
temperature, 120 °C.
substrate, 2p-1 (57%) and 2p-2 (20%) were obtained as major
and minor products, respectively. This outcome indicates that
the substitution pattern on the furan ring strongly affected the
regioselectivity of the ring opening reaction.
To further investigate how the substitution pattern on the
furan ring affected the ring-opening reaction, we subjected
several bicyclic amide-substituted furfuryl tosylhydrazones 5 (2-
aroyl-furo[2,3-c]quinolin-4-one-yl tosylhydrazones) to the
optimized reaction conditions (Table 5). Remarkably, none
With the reaction conditions optimized, we used a series of
furfuryl tosylhydrazones with various R, R1, and R2 groups to
investigate the substrate scope of the reaction (Table 4). With
the exception of 2f (X = 4-CF3), enynyl-ketoamides 2 were
obtained in moderate to good yields from 1 when both R1 and
R2 were methyl groups and R was a phenyl group, either
unsubstituted or with an electron-donating or -withdrawing
substituent (2a−2g). The low yield of 2f may have been due to
sensitivity of the CF3 group to the strong base (LiOtBu). When
R was a 2-naphthyl group, the expected product 2h was
obtained in good yield. However, when R was a 2-thienyl
group, the formation of 2i was not observed at 90 °C;
increasing the reaction temperature to 120 °C did result in the
formation of 2i but in a low yield (38%). The low yield was
likely due to the fact that the resonance stabilization energy of
the thiophene ring is lower than that of the phenyl ring. The
effects of various R1 and R2 groups were investigated next.
Good to excellent yields of enynyl-ketoamides were produced
when both R1 and R2 were alkyl groups (2a, 2j, and 2k) and
when one was an aryl group and the other was an alkyl group
(2l and 2m). When R1 was H, the expected reaction did not
occur as no 2n was detected. The failure to obtain 2n was
probably due to a side reaction involving insertion of the
carbene into the N−H bond. Novel Weinreb amide-substituted
enynone 2o was obtained in 55% yield. Interestingly, when 1p
(R = 2-furfyl), which has two furan rings, was used as the
a
Table 5. Synthesis of Tosyl-Group Migration Products 6
a
Reaction conditions: 5 (0.3 mmol), LiOtBu (1.1 equiv), toluene (5
mL), 1 h, 90 °C. Isolated Yield.
C
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of the expected furan ring-opening products were observed, and
instead sulfones 6 resulting from tosyl group migration were
obtained in good yields without opening of the furan ring. This
unexpected transformation provides a useful route to furyl
sulfones from 2-furyl tosylhydrazones,14 and we used this
protocol to synthesize a small library of furyl sulfones (6a−6e)
in good yields.
conditions (1.1 equiv LiOtBu, toluene, 1 h, 90 °C) (Scheme 4).
All three furfuryl tosylhydrazones were transformed into their
Scheme 4. Base-Mediated Decomposition of 1q−1s under
Optimized Conditions
To determine whether the migration of the sulfonyl group
occurred by means of an intramolecular or intermolecular
process, we performed a crossover experiment (Scheme 2).
Scheme 2. Crossover Experiment to Probe the Tosyl-Group
Migration Pathway
corresponding enynones but in low yields, probably owing to
instability of the products under the basic reaction conditions.
We investigated the cytotoxic activities of enynyl-ketoamides
2a, 2e, 2f, 2h, 2i, and 2o and enynyl-ketoester 2q on three
human cancer cell lines: HCT116, A549, and CAPAN2 (Table
6). At a concentration of 30 μmol/L, all of the tested enynyl-
ketoamides displayed fairly good cytotoxicities against all three
cancer cell lines (>97% inhibition). At 10 μmol/L, the enynyl-
ketoamides still demonstrated good cytotoxicities against
HCT116 (>93% inhibition), but only 2f and 2i retained their
potencies (99% and 93%, respectively) at the lower
concentration against A549 cells. Against CAPAN2 cells, the
cytotoxicities of all of the compounds at 10 μmol/L were
slightly lower than those at 30 μmol/L. At 5 μmol/L, the
cytotoxicities of most of the compounds decreased remarkably
with the exception of 2f, which showed 82% inhibition against
CAPAN2. The IC50 value of 2f against CAPAN2 cells was
determined to be 1.47 μM, which suggests that 2f might serve
as a lead for the development of novel, potent anticancer
agents.
Reaction of a 1:1 mixture of 5a and PhSO2Na under standard
reaction conditions gave sulfones 6a and 6f in a 4.5:1 ratio as
indicated by electrospray-ionization mass spectrometry. This
result suggests that the migration of the sulfonyl group
proceeded by an intermolecular process.
On the basis of the experimental outcomes described above,
we propose that sulfones 6 form by the mechanism outlined in
Scheme 3. The hydrazone salt (7) formed by deprotonation of
Scheme 3. Possible Mechanism for the Formation of 6
CONCLUSION
■
In summary, we investigated base-mediated decomposition
reactions of furfural tosylhydrazones with various substituents
on the furan ring and found that the outcome of the reactions
depended on the substitution pattern and the electronic nature
of the substituents. The reaction protocol was used to
synthesize novel enynyl-ketoamides in high yields from readily
available furans. In addition, we found that bicyclic 2-aroyl-
furo[2,3-c]quinolin-4-one-yl tosylhydrazones 5 did not provide
the corresponding enynyl-ketoamides but instead were trans-
formed into sulfones without opening of the furan ring via an
interesting tosyl-group migration. Some of the enynyl-
ketoamides demonstrated good cytotoxicity against human
tumor cell lines.
5 decomposes to diazo compound 8,15 which is then
transformed into carbene 9. Ring opening of 9 forms enynyl-
ketoamide 10, and Michael addition of sulfinate to 10 gives 11,
which is converted to 6 via protonation and subsequent
aromatization.
We next investigated the base-mediated decomposition of
furfuryl tosylhydrazones 1q−1s, which are the precursors of
carbenes B-2−B-4 (Table 1), respectively, under the optimized
EXPERIMENTAL SECTION
■
All reactions were performed under a nitrogen atmosphere. Unless
specified otherwise, all reagents and starting materials were purchased
from commercial suppliers and used as received. Solvents were purified
by means of standard literature procedures. FT-IR spectra were
recorded with thin film samples or KBr pellets, and peaks are
1
expressed in cm−1. H (400 MHz) and 13C (100 MHz) NMR spectra
were recorded using CDCl3 as a solvent, and product ratios were
D
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Table 6. Cytotoxic Activities of Selected Enynyl-Ketoamides and an Enynyl-Ketoester against HCT116, A549, and Capan2 Cells
1
determined from the H NMR spectra. Chemical shifts are expressed
in ppm downfield relative to tetramethylsilane. Coupling constants are
reported in Hz.The following abbreviations are used for splitting
patterns: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet),
and dd (double doublet). Analytical thin-layer chromatography was
performed on silica gels with a mixture of petroleum ether and ethyl
acetate as the eluent. High-resolution mass spectra were obtained with
an LCMS-IT-TOF mass spectrometer.
pressure, and then aqueous HCl (1.5 N, 25 mL) was added slowly to
acidify the aqueous solution to pH 2. The resulting solid was filtered,
washed with H2O, dried, and subjected to the next step without further
purification.
The solid was placed in a round-bottomed 50 mL flask equipped
with a condenser and a drying tube; SOCl2 (20 mL) was then added,
and the mixture was heated at reflux for 3 h. Excess SOCl2 was
removed under reduced pressure, and dry DCM (18 mL) was added
to the residue. To the resulting clear solution was added triethylamine
(5 mL), and then an amine (HNR1R2) was added in portions. After
the solution was stirred for 30 min, H2O (30 mL) was added. The
resulting mixture was extracted with ethyl acetate (10 mL × 3). The
combined organic layers were washed with saturated brine, dried over
General Procedure for the Preparation of 4. Aqueous NaOH
(1.5 N, 12 mL) was slowly added to a solution of 3 (12 mmol) and
THF (30 mL). The reaction mixture was stirred at room temperature
until the starting material disappeared, as indicated by thin-layer
chromatography. The organic solvent was removed under reduced
E
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sodium sulfate, and filtered, and the filtrate was concentrated under
reduced pressure to afford 4.
N,N-Dimethyl-5-(thiophene-2-carbonyl)furan-2-carboxamide
(4i). Light brown solid (1.5 g, 65%); mp 122−123 °C; IR (KBr): 2927,
1
1684, 1399, 1166, 750, 543 cm−1; H NMR (400 MHz, CDCl3): δ
5-Benzoyl-N,N-dimethylfuran-2-carboxamide (4a). White solid
(1.6 g, 90%); mp 77−78 °C; IR (KBr): 2987, 1743, 1455, 1374, 1243,
1048, 931, 848, 611 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.99−7.96
(m, 2H), 7.65−7.58 (m, 1H), 7.55−7.48 (m, 2H), 7.26 (t, J = 3.6 Hz,
1H), 7.15 (t, J = 3.6 Hz, 1H), 3.35 (s, 3H), 3.13 (s, 3H); 13C NMR
(101 MHz, CDCl3): δ 182.5, 159.47, 152.0, 151.4, 136.8, 133.0, 129.3,
128.6, 120.5, 117.2, 38.3, 36.6; Ion-trap HRMS (ESI): [M + H]+ calcd
for C14H14NO3, 244.0974; found, 244.0957.
8.27−8.13 (m, 1H), 7.75 (d, J = 4.8 Hz, 1H), 7.41 (d, J = 3.6 Hz, 1H),
7.22 (t, J = 4.4 Hz, 1H), 7.11 (d, J = 3.6 Hz, 1H), 3.36 (s, 3H), 3.15 (s,
3H); 13C NMR (101 MHz, CDCl3): δ 173.4, 159.6, 152.1, 150.5,
141.6, 134.6, 134.2, 128.5, 118.9, 117.0, 38.5, 36.5; Ion-trap HRMS
(ESI): [M + H]+ calcd for C12H12NO3S, 250.0538; found, 250.0521.
N-Allyl-5-benzoyl-N-methylfuran-2-carboxamide (4j). Light
brown oil (1.7 g, 73%); IR (film): 2917, 1726, 1456, 1347, 1168,
1
756, 551 cm−1; H NMR (400 MHz, CDCl3): δ 7.98 (d, J = 7.6 Hz,
N,N-Dimethyl-5-(4-methylbenzoyl)furan-2-carboxamide (4b).
Light yellow solid (2.0 g, 92%); mp 141−142 °C; IR (KBr): 2976,
2H), 7.61 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.27 (d, J = 3.6
Hz, 1H), 7.18−7.16 (m, 1H), 5.87 (s, 1H), 5.27 (d, J = 3.6 Hz, 1H),
5.24 (s, 1H), 4.22−4.15 (m, 2H), 3.29 (s, 1.5H), 3.08 (s, 1.5H); 13C
NMR (101 MHz, CDCl3): δ 182.4, 159.6, 159.1, 152.1, 150.9, 136.6,
133.0, 132.0, 129.3, 128.5, 120.3, 118.2, 117.8, 117.5, 117.0, 53.1, 51.2,
35.8, 34.3; Ion-trap HRMS (ESI): [M + H]+ calcd for C16H16NO3,
270.1130; found, 270.1112.
1
1702, 1511, 1260, 1165, 749 cm−1; H NMR (400 MHz, CDCl3): δ
7.90 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 7.6 Hz, 2H), 7.24 (d, J = 3.6 Hz,
1H), 7.14 (d, J = 3.6 Hz, 1H), 3.34 (s, 3H), 3.12 (s, 3H), 2.44 (s, 3H);
13C NMR (101 MHz, CDCl3): δ 182.1, 159.5, 152.2, 151.1, 143.9,
134.1, 129.5, 129.2, 120.0, 117.1, 38.3, 36.6, 21.7; Ion-trap HRMS
(ESI): [M + H]+ calcd for C15H16NO3, 258.1130; found, 258.1114.
5-(4-Methoxybenzoyl)-N,N-dimethylfuran-2-carboxamide (4c).
Light yellow solid (2.4 g, 85%); mp 125−126 °C; IR (KBr): 2984,
1690, 1516, 1269, 1165, 753, 549 cm−1; 1H NMR (400 MHz, CDCl3):
δ 8.03 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 3.6 Hz, 1H), 7.12 (d, J = 3.6
Hz, 1H), 6.98 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H), 3.33 (s, 3H), 3.09 (s,
3H); 13C NMR (101 MHz, CDCl3): δ 180.9, 163.6, 159.6, 152.4,
150.8, 131.8, 129.3, 119.5, 117.0, 113.9, 55.5, 38.3, 36.5; Ion-trap
HRMS (ESI): [M + H]+ calcd for C15H16NO4, 274.1079; found,
274.1063.
5-(3,5-Dimethylbenzoyl)-N,N-dimethylfuran-2-carboxamide (4d).
Light brown solid (2.4 g, 88%); mp 69−71 °C; IR (KBr): 2987, 1704,
1532, 1274, 1166, 766 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.49 (s,
2H), 7.18 (s, 1H), 7.15 (d, J = 3.6 Hz, 1H), 7.10 (d, J = 3.6 Hz, 1H),
3.29 (s, 3H), 3.06 (s, 3H), 2.32 (s, 6H); 13C NMR (101 MHz,
CDCl3): δ 183.0, 159.5, 152.1, 151.3, 138.2, 136.9, 134.7, 127.0, 120.4,
117.4, 38.3, 36.7, 21.3; Ion-trap HRMS (ESI): [M + H]+ calcd for
C16H18NO3, 272.1287; found, 272.1269.
(5-Benzoylfuran-2-yl)(morpholino)methanone (4k). Light brown
solid (1.4 g, 57%); mp 79−80 °C; IR (KBr): 2928, 1635, 1439, 1166,
1
749, 549 cm−1; H NMR (400 MHz, CDCl3): δ 7.97−7.90 (m, 2H),
7.51−7.47 (m, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.26−7.21 (m, 1H),
7.16−7.15 (m, 1H), 3.87−3.75 (m, 8H); 13C NMR (101 MHz,
CDCl3): δ 182.4, 158.1, 151.9, 150.7, 136.6, 133.1, 129.2, 128.6, 120.5,
117.8, 66.9, 47.2; Ion-trap HRMS (ESI): [M + H]+ calcd for
C16H16NO4, 286.1079; found, 286.1057.
5-Benzoyl-N-methyl-N-(3,4,5-trimethoxyphenyl)furan-2-carboxa-
mide (4l). White solid (1.9 g, 95%); mp 77−79 °C; IR (KBr): 2928,
1712, 1344, 1166, 1129, 750, 549 cm−1; 1H NMR (400 MHz, CDCl3):
δ 7.81 (d, J = 7.6 Hz, 2H), 7.57 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 7.6 Hz,
2H), 7.19 (d, J = 3.6 Hz, 1H), 6.52 (br, 1H), 6.44 (s, 2H), 3.80 (s,
3H), 3.78 (s, 6H), 3.47 (s, 3H); 13C NMR (101 MHz, CDCl3): δ
181.8, 158.9, 153.8, 152.7, 150.0, 139.1, 137.8, 136.1, 133.0, 129.5,
128.4, 119.7, 117.2, 104.3, 61.0, 56.3, 38.7; Ion-trap HRMS (ESI): [M
+ Na]+ calcd for C22H21NNaO6, 418.1267; found, 418.1261.
5-Benzoyl-N-(2-bromophenyl)-N-ethylfuran-2-carboxamide
(4m). White solid (1.8 g, 84%); mp 91−93 °C; IR (KBr): 2932, 1741,
1457, 1274, 754 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.83 (d, J = 7.6
Hz, 2H), 7.73−7.51 (m, 2H), 7.50−7.41 (m, 2H), 7.38−7.28 (m, 1H),
7.24−7.07 (m, 3H), 6.39 (br, 1H), 4.27−3.56 (m, 2H), 1.24 (t, J = 6.0
Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 182.1, 158.2, 152.7, 150.1,
140.5, 136.3, 133.9, 132.8, 130.7, 129.8, 129.5, 128.5, 127.8, 123.7,
119.5, 117.1, 44.8, 12.4; Ion-trap HRMS (ESI): [M + H]+ calcd for
C20H17BrNO3 [M + H]+ 398.0392; found, 398.0368.
N,N-Dimethyl-5-(4-nitrobenzoyl)furan-2-carboxamide (4e). Light
yellow solid (1.5 g, 70%); mp 164−166 °C; IR (KBr): 2976, 1706,
1
1512, 1269, 1165, 743, 551 cm−1; H NMR (400 MHz, CDCl3): δ
8.39−8.34 (m, 2H), 8.17−8.13 (m, 2H), 7.33 (d, J = 3.6 Hz, 1H), 7.15
(d, J = 3.6 Hz, 1H), 3.31 (s, 3H), 3.13 (s, 3H); 13C NMR (101 MHz,
CDCl3): δ 180.4, 159.2, 152.0, 151.4, 150.2, 141.6, 130.3, 123.8, 121.3,
117.2, 38.3, 36.6; Ion-trap HRMS (ESI): [M + H]+ calcd for
C14H13N2O5, 289.0824; found, 289.0805.
N,N-Dimethyl-5-(4-(trifluoromethyl)benzoyl)furan-2-carboxa-
mide (4f). White solid (1.7 g, 80%); mp 127−129 °C; IR (KBr): 2923,
1690, 1621, 1331, 1166, 750, 549 cm−1; 1H NMR (400 MHz, CDCl3):
δ 8.07 (d, J = 8.0 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 3.6
Hz, 1H), 7.14 (d, J = 3.6 Hz, 1H), 3.31 (s, 3H), 3.12 (s, 3H); 13C
NMR (101 MHz, CDCl3): δ 181.22, 159.29, 151.76, 151.54, 139.63,
134.28 (d, J = 32 Hz), 129.60, 126.2 (d, J = 250 Hz), 125.64−125.53
(q, J = 3.6 Hz, J = 7.3 Hz), 120.98, 117.17, 38.29, 36.54; Ion-trap
HRMS (ESI): [M + H]+ calcd for C15H13F3NO3, 312.0848; found,
312.0828.
5-Benzoyl-N-benzylfuran-2-carboxamide (4n). White solid (1.8 g,
93%); mp 145−146 °C; IR (KBr): 3066, 1655, 1165, 1019, 767, 551
1
cm−1; H NMR (400 MHz, CDCl3): δ 7.87 (d, J = 7.4 Hz, 2H), 7.59
(t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.38−7.28 (m, 5H), 7.28−
7.25 (m, 1H), 7.24 (d, J = 3.6 Hz, 1H), 7.16 (d, J = 3.6 Hz, 1H), 4.60
(d, J = 6.0 Hz, 2H); 13C NMR (101 MHz, CDCl3): δ 182.7, 157.6,
151.5, 150.8, 137.6, 136.8, 133.1, 129.2, 128.8, 128.7, 128.0, 127.7,
121.8, 115.4, 43.4; Ion-trap HRMS (ESI): [M + H]+ calcd for
C19H16NO3, 306.1130; found, 306.1109.
5-(2-Chlorobenzoyl)-N,N-dimethylfuran-2-carboxamide (4g).
N-Methoxy-N-methyl-5-(4-methylbenzoyl)furan-2-carboxamide
(4o). Light brown solid (1.9 g, 86%); mp 97−98 °C; IR (KBr): 2933,
1643, 1419, 1166, 817, 657, 549 cm−1; 1H NMR (400 MHz, CDCl3):
δ 8.02 (d, J = 8.0 Hz, 2H), 7.35−7.29 (m, 3H), 7.25 (d, J = 3.6 Hz,
1H), 3.81 (s, 3H), 3.39 (s, 3H), 2.44 (s, 3H); 13C NMR (101 MHz,
CDCl3): δ 181.9, 158.5, 153.3, 148.3, 144.1, 133.8, 129.9, 129.3, 119.6,
118.2, 61.9, 33.4, 21.7; Ion-trap HRMS (ESI): [M + H]+ calcd for
C15H16NO4, 274.1079; found, 274.1067.
5-(Furan-2-carbonyl)-N,N-dimethylfuran-2-carboxamide (4p).
Light brown oil (1.7 g, 72%); IR (film): 2934, 1620, 1337, 1165,
749, 550 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.72 (s, 1H), 7.60 (d,
J = 3.2 Hz, 1H), 7.55 (d, J = 4.0 Hz, 1H), 7.13 (d, J = 3.6 Hz, 1H),
6.64−6.63 (m, 1H), 3.37 (s, 3H), 3.14 (s, 3H); 13C NMR (101 MHz,
CDCl3): δ 168.4, 159.5, 151.2, 151.0, 150.8, 147.2, 120.2, 119.6, 117.0,
112.6, 38.3, 36.5; Ion-trap HRMS (ESI): [M + H]+ calcd for
C12H12NO4, 234.0766; found, 234.0754.
Light brown oil (1.8 g, 71%); IR (KBr): 2923, 1785, 1620, 1166,
1
750, 550 cm−1; H NMR (400 MHz, CDCl3): δ 7.48−7.46 (m, 2H),
7.40−7.37 (m, 1H), 7.33−7.29 (m, 1H), 7.15 (d, J = 3.6 Hz, 1H), 7.11
(d, J = 3.6 Hz, 1H), 3.28 (s, 3H), 3.10 (s, 3H); 13C NMR (101 MHz,
CDCl3): δ 182.2, 159.2, 152.1, 151.6, 137.1, 131.9, 130.3, 129.2, 127.8,
126.7, 121.0, 117.6, 38.1, 34.7; Ion-trap HRMS (ESI): [M + H]+ calcd
for C14H13ClNO3, 278.0584; found, 278.0566.
5-(2-Naphthoyl)-N,N-dimethylfuran-2-carboxamide (4h). Light
yellow solid (1.7 g, 72%); mp 117−119 °C; IR (KBr): 2933, 1692,
1619, 1345, 1166, 756 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.53 (s,
1H), 8.02−7.86 (m, 4H), 7.63−7.53 (m, 2H), 7.30 (d, J = 3.6 Hz,
1H), 7.17 (d, J = 3.6 Hz, 1H), 3.34 (s, 3H), 3.11 (s, 3H); 13C NMR
(101 MHz, CDCl3): δ 182.3, 159.5, 152.2, 151.4, 135.5, 134.0, 132.4,
131.1, 129.5, 128.6, 128.5, 127.9, 127.0, 125.0, 120.4, 117.3, 38.3, 36.6;
Ion-trap HRMS (ESI): [M + H]+ calcd for C18H16NO3, 294.1130;
found, 294.1111.
F
DOI: 10.1021/jo502328j
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Methyl 5-benzoylfuran-2-carboxylate (4q). White solid (1.5 g,
80%); mp 78.9−80.0 °C; IR (KBr): 2916, 1735, 1515, 1273, 1142,
3.08 (s, 3H), 2.42 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 159.2,
149.3, 148.6, 146.1, 144.8, 141.7, 138.7, 135.2, 129.9, 129.5, 128.3,
123.7, 117.0, 116.7, 38.5, 36.7, 21.7; Ion-trap HRMS (ESI): [M + H]+
calcd for C21H21N4O6S, 457.1182; found, 457.1179.
1
755, 418 cm−1; H NMR (400 MHz, CDCl3): δ 8.05 (d, J = 7.6 Hz,
2H), 7.61 (t, J = 7.2 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 7.27 (s, 2H),
3.94 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 182.2, 158.6, 153.9,
146.8, 136.2, 133.3, 129.7, 128.7, 120.0, 118.6, 52.5; Ion-trap HRMS
(ESI): [M + H]+ calcd for C13H11O4, 231.0657; found, 231.0656.
Phenyl(4-(p-tolyl)furan-2-yl)methanone (4r). Brown oil (450 mg,
N,N-Dimethyl-5-((2-tosylhydrazono)(4-(trifluoromethyl)phenyl)-
methyl)furan-2-carboxamide (1f). Yellow solid (1.1 g, 64%); mp
1
200−202 °C; IR (KBr): 3739, 3123, 1624, 1324, 1167, 750 cm−1; H
NMR (400 MHz, CDCl3): δ 9.71 (s, 1H), 7.89 (d, J = 8.0 Hz, 2H),
7.60 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.0 Hz,
2H), 7.05 (d, J = 3.6 Hz, 1H), 6.65 (d, J = 3.6 Hz, 1H), 3.26 (s, 3H),
3.03 (s, 3H), 2.41 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 158.6,
148.9, 146.0, 144.1, 139.3, 138.7, 134.8, 131.4, 129.3, 128.5, 127.8,
124.9, 124.9, 116.6, 116.4, 37.9, 36.1, 21.2; Ion-trap HRMS (ESI): [M
+ H]+ calcd for C22H21F3N3O4S, 480.1182; found, 480.1182.
1
67%); IR (film): 2918, 1742, 1647, 1284, 751, 571 cm−1; H NMR
(400 MHz, CDCl3): δ 8.05−7.98 (m, 2H), 7.94 (s, 1H), 7.61−7.58
(m, 1H), 7.54−7.48 (m, 3H), 7.41 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0
Hz, 2H), 2.37 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 182.6, 152.9,
142.5, 137.8, 137.3, 132.7, 129.7, 129.4, 128.9, 128.5, 127.9, 125.9,
118.9, 21.2; Ion-trap HRMS (ESI): [M + H]+ calcd for C18H15O2,
263.1072; found, 263.1061.
General Procedure for the Preparation of Hydrazones 1 and
5. A solution of pure TsNHNH2 (2.23 g, 12 mmol) in dry methanol
(20 mL) was stirred and heated to 60 °C until the TsNHNH2 was
completely dissolved. Then, carbonyl compounds (10 mmol) were
dropped into the mixture slowly. After ∼7−12 h, the crude products
were obtained as precipitates. The precipitates were washed by
petroleum ether then dried in vacuo to afford the pure products. The
reaction provides the N-tosylhydrazone derivatives in ∼60−90%
yields.
5-((2-Chlorophenyl)(2-tosylhydrazono)methyl)-N,N-dimethylfur-
an-2-carboxamide (1g). Yellow solid (1.2 g, 67%); mp 179−182 °C;
1
IR (KBr): 3739, 2929, 1622, 1166, 750 cm−1; H NMR (400 MHz,
CDCl3): δ 7.81 (d, J = 8.0 Hz, 2H), 7.68 (s, 1H), 7.49−7.41 (m, 2H),
7.41−7.34 (m, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 7.3 Hz, 1H),
7.00 (d, J = 3.6 Hz, 1H), 6.34 (d, J = 3.6 Hz, 1H), 3.21 (s, 3H), 3.04
(s, 3H), 2.41 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 159.5, 150.6,
149.6, 144.7, 142.1, 135.2, 132.7, 132.2, 130.6, 130.3, 129.6, 128.5,
128.1, 118.1, 113.3, 38.1, 36.8, 21.7; Ion-trap HRMS (ESI): [M + H]+
calcd for C21H21ClN3O4S, 446.0919; found, 446.0919.
N,N-Dimethyl-5-(naphthalen-2-yl(2-tosylhydrazono)methyl)-
furan-2-carboxamide (1h). White solid (1.3 g, 78%); mp 176−178
°C; IR (KBr): 3704, 2929, 1620, 1340, 1166, 750 cm−1; 1H NMR (400
MHz, DMSO): δ 11.17 (s, 1H), 7.95−7.92 (m, 5H), 7.83 (s, 1H),
7.54−7.47 (m, 5H), 7.25 (d, J = 3.6 Hz, 1H), 7.05 (d, J = 3.6 Hz, 1H),
3.21 (s, 3H), 2.99 (s, 3H), 2.42 (s, 3H); 13C NMR (101 MHz,
DMSO): δ 158.8, 148.5, 145.1, 143.8, 143.2, 135.5, 133.4, 133.0, 132.3,
129.5, 128.5, 128.2, 128.1, 127.9, 127.6, 127.3, 126.7, 124.7, 117.2,
116.8, 37.9, 36.0, 21.1; Ion-trap HRMS (ESI): [M + H]+ calcd for
C25H24N3O4S, 462.1468; found, 462.1467.
N,N-Dimethyl-5-(phenyl(2-tosylhydrazono)methyl)furan-2-car-
boxamide (1a). White solid (1.3 g, 80%); mp 203−204 °C; IR (KBr):
1
3354, 3007, 1620, 1268, 1166, 754, 552 cm−1; H NMR (400 MHz,
CDCl3): δ 7.83 (d, J = 9.2 Hz, 2H), 7.57−7.46 (m, 3H), 7.29 (d, J =
9.2 Hz, 2H), 7.24−7.20 (m, 2H), 7.02 (d, J = 3.6 Hz, 1H), 6.34 (d, J =
3.6 Hz, 1H), 3.28 (s, 3H), 3.08 (s, 3H), 2.43 (s, 3H); 13C NMR (101
MHz, CDCl3): δ 159.3, 151.2, 149.3, 144.6, 144.2, 135.0, 130.6, 129.5,
129.4, 128.8, 128.1, 127.8, 117.8, 113.9, 37.9, 36.4, 21.5; Ion-trap
HRMS (ESI): [M + H]+ calcd for C21H22N3O4S, 412.1313; found,
412.1313.
N,N-Dimethyl-5-(p-tolyl(2-tosylhydrazono)methyl)furan-2-car-
boxamide (1b). White solid (1.5 g, 76%); mp 164.5−166 °C; IR
(KBr): 3665, 2925, 1618, 1261, 1165, 751 cm−1; 1H NMR (400 MHz,
CDCl3): δ 7.82 (d, J = 8.2 Hz, 2H), 7.32−7.30 (m, 4H), 7.11 (d, J =
8.2 Hz, 2H), 7.02 (d, J = 3.6 Hz, 1H), 6.34 (d, J = 3.6 Hz, 1H), 3.30 (s,
3H), 3.09 (s, 3H), 2.42 (s, 3H), 2.41 (s, 3H); 13C NMR (101 MHz,
CDCl3): δ 159.6, 151.6, 149.4, 144.9, 144.3, 141.1, 135.3, 130.4, 129.6,
128.2, 128.0, 125.9, 117.9, 114.0, 38.1, 36.3, 21.6, 21.4; Ion-trap
HRMS (ESI): [M + H]+ calcd for C22H24N3O4S, 426.1467; found,
426.1467.
N,N-Dimethyl-5-(thiophen-2-yl(2-tosylhydrazono)methyl)furan-
2-carboxamide (1i). Yellow solid (600 mg, 40%); mp 166−168 °C;
1
IR (KBr): 3739, 3166, 2334, 1398, 1166, 749 cm−1; H NMR (400
MHz, DMSO): δ 11.04 (s, 1H), 7.80 (t, J = 8.0 Hz, 2H), 7.63 (d, J =
4.8 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 4.8 Hz, 1H), 7.20
(d, J = 4.0 Hz, 1H), 7.13 (d, J = 4.0 Hz, 1H), 7.08−7.03 (m, 1H), 3.21
(s, 3H), 3.01 (s, 3H), 2.39 (s, 3H); 13C NMR (101 MHz, DMSO): δ
158.7, 148.3, 144.0, 143.7, 139.5, 138.3, 135.3, 129.4, 129.2, 129.2,
127.8, 116.7, 116.6, 37.9, 36.0, 21.0; Ion-trap HRMS (ESI): [M + H]+
calcd for C19H20N3O4S2, 418.0874; found, 418.0874.
5-((4-Methoxyphenyl)(2-tosylhydrazono)methyl)-N,N-dimethyl-
4-Methyl-N′-((5-(morpholine-4-carbonyl)furan-2-yl)(phenyl)-
methylene)benzenesulfonohydrazide (1j). White solid (870 mg,
56%); mp 95−97 °C; IR (KBr): 3700, 2923, 1621, 1432, 1166, 748,
furan-2-carboxamide (1c). White solid (2 g, 82%); mp 188−190 °C;
1
IR (KBr): 3667, 2922, 1610, 1254, 1166, 1108, 752 cm−1; H NMR
1
549 cm−1; H NMR (400 MHz, CDCl3): δ 7.88 (d, J = 8.4 Hz, 1H),
(400 MHz, DMSO): δ 10.92 (s, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.46 (d,
J = 8.0 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 3.6 Hz, 1H),
6.99−6.95 (m, 2H), 6.95 (s, 1H), 3.78 (s, 3H), 3.22 (s, 3H), 3.00 (s,
3H), 2.41 (s, 3H); 13C NMR (101 MHz, DMSO): δ 161.9, 160.0,
149.4, 146.5, 144.8, 144.5, 136.8, 130.6, 129.2, 129.0, 118.1, 117.7,
115.0, 56.5, 39.2, 37.1, 22.2; Ion-trap HRMS (ESI): [M + H]+ calcd
for C22H24N3O5S, 442.1418; found, 442.1417.
7.80 (J = 8.4 Hz, 1H), 7.57−7.42 (m, 2H), 7.43−7.29 (m, 4H), 7.24−
7.20 (m, 1H), 7.04 (dd, J = 8.9, 3.6 Hz, 1H), 6.51 (dd, J = 8.9, 3.6 Hz,
1H), 3.74−3.72 (m, 8H), 2.42 (d, J = 6.2 Hz, 3H); 13C NMR (101
MHz, CDCl3 ): δ151.6, 151.4, 149.1, 144.8, 144.3, 135.2, 133.3, 132.4,
130.7, 129.6, 129.1, 128.3, 128.0, 118.1, 117.7, 114.0, 50.6, 34.3, 21.6;
Ion-trap HRMS (ESI): [M + H]+ calcd for C23H24N3O5S, 454.1414;
found, 454.1414.
N-Allyl-N-methyl-5-(phenyl(2-tosylhydrazono)methyl)furan-2-
carboxamide (1k). White solid (780 mg, 47%); mp 93−96 °C; IR
(KBr): 3694, 2917, 1723, 1445, 1344, 1168, 754 cm−1; 1H NMR (400
MHz, CDCl3): δ 7.82 (d, J = 8.0 Hz, 2H), 7.49 (dd, J = 9.1, 5.8 Hz,
3H), 7.29 (d, J = 8.0 Hz, 2H), 7.22−7.20 (m, 2H), 7.09−6.98 (m,
1H), 6.35 (d, J = 3.6 Hz, 1H), 5.82−5.80 (m, 1H), 5.22−5.20 (m,
2H), 4.14 (br, 1H), 3.44 (s, 2H), 3.22 (s, 1.5 H), 3.01 (s, 1.5 H), 2.43
(s, 3H); 13C NMR (101 MHz, CDCl3): δ 151.6, 149.1, 144.8, 144.3,
135.2, 133.3, 130.7, 129.6, 129.1, 128.3, 128.0, 118.1, 117.7, 114.1,
53.2, 35.7, 21.6; Ion-trap HRMS (ESI): [M + H]+ calcd for
C23H24N3O4S, 438.1465; found, 438.1465.
5-((3,5-Dimethylphenyl)(2-tosylhydrazono)methyl)-N,N-dime-
thylfuran-2-carboxamide (1d). White solid (2 g, 83%); mp 196−198
1
°C; IR (KBr): 3731, 2924, 2362, 1624, 1325, 1166, 748 cm−1; H
NMR (400 MHz, CDCl3): δ 9.59 (s, 1H), 7.90 (d, J = 8.0 Hz, 2H),
7.29 (t, J = 8.0 Hz, 2H), 7.05 (d, J = 3.6 Hz, 1H), 7.01 (d, J = 5.4 Hz,
3H), 6.61 (d, J = 3.6 Hz, 1H), 3.27 (s, 3H), 3.05 (s, 3H), 2.41 (s, 3H),
2.28 (s, 6H); 13C NMR (101 MHz, CDCl3): δ 158.9, 148.5, 147.0,
143.7, 141.2, 137.4, 135.2, 135.0, 131.1, 129.1, 127.8, 126.1, 116.6,
116.5, 38.0, 36.2, 21.2, 20.8; Ion-trap HRMS (ESI): [M + H]+ calcd
for C23H26N3O4S, 440.1623; found, 440.1623.
N,N-Dimethyl-5-((4-nitrophenyl)(2-tosylhydrazono)methyl)-
furan-2-carboxamide (1e). Yellow solid (900 mg, 60%); mp 170−
172 °C; IR (KBr): 3675, 2923, 1512, 1345, 1269, 1189, 743, 551 cm−1;
1H NMR (400 MHz, CDCl3): δ 9.78 (s, 1H), 8.20 (d, J = 8.5 Hz, 2H),
N-Methyl-5-(p-tolyl(2-tosylhydrazono)methyl)-N-(3,4,5-
trimethoxyphenyl)furan-2-carboxamide (1l). Yellow solid (1.5 g,
80%); mp 172−174 °C; IR (KBr): 3702, 2937, 1680, 1340, 1166,
1126, 752 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 8.0 Hz,
7.88 (d, J = 7.9 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 7.9 Hz,
2H), 7.05 (d, J = 3.3 Hz, 1H), 6.68 (d, J = 3.3 Hz, 1H), 3.27 (s, 3H),
G
DOI: 10.1021/jo502328j
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2H), 7.51−7.40 (m, 3H), 7.31 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 5.6 Hz,
2H), 6.35 (d, J = 3.6 Hz, 1H), 6.28 (s, 2H), 6.16 (br, 1H), 3.82 (s,
3H), 3.71 (s, 6H), 3.34 (s, 3H), 2.40 (s, 3H); 13C NMR (101 MHz,
CDCl3): δ 159.0, 153.4, 151.6, 147.8, 144.7, 144.2, 139.3, 137.2, 135.0,
130.4, 129.6, 129.4, 128.4, 127.9, 127.8, 117.5, 112.6, 104.0, 60.8, 56.0,
38.5, 21.5; Ion-trap HRMS (ESI): [M + H]+ calcd for C29H30N3O7S,
564.1799; found, 564.1798.
(KBr): 3730, 3300, 3059, 1665, 1614, 1343, 1166, 752 cm−1; 1H NMR
(400 MHz, CDCl3): δ 9.52 (s, 1H), 7.89 (t, J = 8.8 Hz, 2H), 7.64 (d, J
= 1.1 Hz, 1H), 7.49−7.45 (m, 2H), 7.34−7.38 (m, 5H), 6.59 (d, J =
3.5 Hz, 1H), 6.54 (dd, J = 3.4, 1.7 Hz, 1H), 2.41 (s, 3H); 13C NMR
(101 MHz, CDCl3): δ 147.4, 144.4, 144.1, 141.5, 136.1, 135.6, 129.7,
129.6, 128.8, 128.2, 128.1, 116.7, 111.6, 21.6; Ion-trap HRMS (ESI):
[M + Na]+ calcd for C18H16N2NaO3S, 363.0774; found, 363.0781.
N′-((5-Ethyl-4-oxo-4,5-dihydrofuro[2,3-c]quinolin-2-yl)(phenyl)-
methylene)-4-methylbenzenesulfonohydrazide (5a). White solid
(100 mg, 30%); mp 166−167 °C; IR (KBr): 3739, 2926, 1656,
N-(2-Bromophenyl)-N-ethyl-5-(phenyl(2-tosylhydrazono)-
methyl)furan-2-carboxamide (1m). Yellow solid (1.4 g, 79%); mp
193−196 °C; IR (KBr): 3730, 3285, 2980, 1642, 1309, 1166, 754, 547
1
1166, 754, 547 cm−1; H NMR (400 MHz, CDCl3): δ 8.03 (s, 1H),
1
cm−1; H NMR (400 MHz, CDCl3): δ 9.29 (s, 1H), 7.89 (d, J = 8.0
7.91 (d, J = 8.0 Hz, 2H), 7.77 (d, J = 7.6 Hz, 1H), 7.55−7.52 (m, 4H),
7.44 (d, J = 8.8 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.32−7.21 (m, 3H),
7.05 (s, 1H), 4.49−4.35 (m, 2H), 2.42 (s, 3H), 1.35 (t, J = 7.2 Hz,
3H); 13C NMR (101 MHz, CDCl3): δ 155.9, 153.3, 144.9, 144.9,
143.1, 137.3, 135.6, 131.3, 130.5, 130.3, 130.2, 129.5, 129.0, 128.8,
128.4, 125.2, 122.8, 116.7, 115.6, 107.0, 37.7, 22.0, 13.4; Ion-trap
HRMS (ESI): [M + H]+ calcd for C27H24N3O4S, 486.1465; found,
486.1465.
Hz, 2H), 7.80−7.45 (m, 1H), 7.42−7.27 (m, 9H), 7.20 (t, J = 7.0 Hz,
1H), 6.35 (d, J = 3.2 Hz, 1H), 5.99 (d, J = 3.2 Hz, 1H), 4.42−3.49 (m,
2H), 2.41 (s, 3H), 1.23 (t, J = 14.0, 6.8 Hz, 3H); 13C NMR (101 MHz,
CDCl3): δ 148.0, 146.7, 143.7, 140.2, 140.0, 135.1, 133.6, 130.3, 129.7,
129.6, 129.3, 129.2, 128.6, 128.1, 128.0, 127.8, 127.7, 123.4, 116.1,
115.8, 44.4, 21.2, 12.1; Ion-trap HRMS (ESI): [M + H]+ calcd for
C27H25BrN3O4S, 566.0725; found, 566.0725.
N-Benzyl-5-(phenyl(2-tosylhydrazono)methyl)furan-2-carboxa-
mide (1n). White solid (1.2 g, 66%); mp 151−153 °C; IR (KBr):
N′-((5-Ethyl-4-oxo-4,5-dihydrofuro[2,3-c]quinolin-2-yl)(p-tolyl)-
methylene)-4-methylbenzenesulfonohydrazide (5b). White solid
(121 mg, 27%); mp 192−194 °C; IR (KBr): 3678, 2925, 1661,
1
3730, 3061, 1657, 1165, 1021, 767, 551 cm−1; H NMR (400 MHz,
CDCl3): δ 7.85 (br, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.55−7.47 (m, 3H),
7.29−7.40 (m, 4H), 7.30 (d, J = 6.4 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H),
7.15 (dd, J = 7.2, 1.8 Hz, 2H), 7.05 (d, J = 3.6 Hz, 1H), 6.19 (d, J = 3.6
Hz, 1H), 4.62 (d, J = 6.0 Hz, 2H), 3.41 (s, 1H), 2.39 (s, 3H); 13C
NMR (101 MHz, CDCl3): δ 158.1, 151.1, 149.2, 145.1, 144.6, 138.3,
135.3, 131.1, 130.0, 129.9, 128.9, 128.8, 128.3, 128.1, 127.9, 127.6,
116.2, 115.5, 43.3, 21.7; Ion-trap HRMS (ESI): [M + H]+ calcd for
C26H24N3O4S, 474.1465; found, 474.1465.
1
1342, 1166, 749, 549 cm−1; H NMR (400 MHz, CDCl3): δ 9.77 (s,
1H), 7.92 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 8.0 Hz, 1H), 7.62−7.53 (m,
1H), 7.47−7.40 (m, 3H), 7.35−7.31 (m, 1H), 7.30 (d, J = 8.0 Hz,
2H), 7.14−7.18 (m, 3H), 4.42−4.39 (m, 2H), 2.42 (d, J = 6.0 Hz,
6H), 1.37 (t, J = 6.2 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 152.6,
150.4, 143.9, 142.3, 140.6, 140.1, 136.8, 135.3, 132.6, 129.4, 129.3,
129.0, 128.2, 128.0, 127.9, 124.7, 122.6, 115.7, 115.2, 110.0, 37.3, 21.4,
21.2, 12.8; Ion-trap HRMS (ESI): [M + H]+ calcd for C28H26N3O4S,
500.1622; found, 500.1622.
N′-((5-Ethyl-8-methyl-4-oxo-4,5-dihydrofuro[2,3-c]quinolin-2-
yl)(p-tolyl)methylene)-4-methylbenzenesulfonohydrazide (5c).
White solid (70 mg, 25%); mp 176.5−179 °C; IR (KBr): 3730,
3056, 1634, 1160, 1166, 769, 549 cm−1; 1H NMR (400 MHz, CDCl3):
δ 7.99 (br, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.55 (s, 1H), 7.36−7.33 (m,
6H), 7.16 (d, J = 7.6 Hz, 2H), 7.06−6.98 (m, 1H), 4.41 (d, J = 6.8 Hz,
2H), 2.42 (s, 9H), 1.34 (t, J = 6.8 Hz, 3H); 13C NMR (101 MHz,
CDCl3): δ 155.7, 153.0, 144.9, 144.5, 142.9, 141.4, 135.4, 134.9, 132.2,
130.6, 130.4, 130.0, 129.9, 128.4, 128.2, 125.7, 124.8, 116.3, 115.2,
106.8, 37.4, 21.7, 21.6, 20.8, 13.1; Ion-trap HRMS (ESI): [M + H]+
calcd for C29H28N3O4S, 514.1777; found, 514.1770.
N-Methoxy-N-methyl-5-(p-tolyl(2-tosylhydrazono)methyl)furan-
2-carboxamide (1o). Yellow solid (1.3 g, 70%); mp 179−182 °C; IR
1
(KBr): 3645, 2930, 1640, 1409, 1166, 817, 664, 549 cm−1; H NMR
(400 MHz, CDCl3): δ 9.73 (s, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.38 (d, J
= 8.0 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 3.6 Hz, 1H), 7.16
(d, J = 8.0 Hz, 2H), 6.63 (d, J = 3.6 Hz, 1H), 3.84 (s, 3H), 3.37 (s,
3H), 2.40 (s, 3H), 2.36 (s, 3H); 13C NMR (101 MHz, CDCl3): δ
157.5, 148.2, 146.8, 143.9, 139.9, 135.4, 132.6, 130.2, 129.4, 128.9,
128.3, 127.9, 118.4, 116.6, 61.9, 33.0, 21.4, 21.2; Ion-trap HRMS
(ESI): [M + H]+ calcd for C22H24N3O5S, 442.1416; found, 442.1415.
5-(Furan-2-yl(2-tosylhydrazono)methyl)-N,N-dimethylfuran-2-
carboxamide (1p). White solid (800 mg, 47%); mp 170−172 °C; IR
(KBr): 3672, 2926, 1624, 1344, 1166, 749 cm−1; 1H NMR (400 MHz,
CDCl3): δ 9.65 (s, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 0.8 Hz,
1H), 7.28 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 3.6 Hz, 1H), 6.97 (t, J = 3.6
Hz, 1H), 6.74 (d, J = 3.6 Hz, 1H), 6.61−6.52 (m, 1H), 3.28 (s, 3H),
3.08 (s, 3H), 2.39 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 159.7,
150.3, 148.4, 145.2, 144.5, 144.4, 135.2, 131.4, 129.6, 128.0, 117.7,
116.2, 112.6, 112.0, 38.3, 36.2, 21.6; Ion-trap HRMS (ESI): [M + H]+
calcd for C19H20N3O5S, 402.1104; found, 402.1104.
N′-((5-Ethyl-8-methyl-4-oxo-4,5-dihydrofuro[2,3-c]quinolin-2-yl)-
(phenyl)methylene)-4-methylbenzenesulfonohydrazide (5d). White
solid (67 mg, 33%); mp 160−163 °C; IR (KBr): 3730, 2983, 1650,
1
1268, 1164, 753, 548 cm−1; H NMR (400 MHz, CDCl3): δ 7.95 (s,
1H), 7.91 (d, J = 8.0 Hz, 2H), 7.57−7.54 (m, 4H), 7.37−7.39 (m,
6H), 7.05 (s, 1H), 4.42 (d, J = 7.4 Hz, 2H), 2.43 (d, J = 2.8 Hz, 6H),
1.35 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 155.5, 153.0,
144.6, 144.6, 142.9, 135.3, 134.9, 132.2, 131.0, 130.4, 130.0, 129.9,
128.7, 128.5, 128.4, 128.2, 124.8, 116.3, 115.2, 106.8, 37.4, 21.8, 20.8,
13.1; Ion-trap HRMS (ESI): [M + H]+ calcd for C28H26N3O4S,
500.1622; found, 500.1622.
Methyl 5-(Phenyl(2-tosylhydrazono)methyl)furan-2-carboxylate
(1q). White solid (1.2 g, 76%); mp 186.8−187.8 °C; IR (KBr):
3665, 2928, 1628, 1261, 1160, 754 cm−1; 1H NMR (400 MHz,
CDCl3): δ 7.89 (d, J = 8.2 Hz, 2H), 7.55−7.48 (m, 3H), 7.35 (d, J =
8.0 Hz, 2H), 7.27−7.20 (m, 2H), 7.13 (d, J = 3.6 Hz, 1H), 6.47 (d, J =
3.6 Hz, 1H), 3.88 (s, 3H), 2.44 (s, 3H); 13C NMR (101 MHz,
CDCl3): δ 158.8, 153.7, 145.3, 144.5, 144.4, 135.3, 130.8, 129.8, 129.7,
128.7, 128.5, 128.7, 119.2, 113.7, 52.0, 21.6; Ion-trap HRMS (ESI):
[M + H]+ calcd for C20H18N2O5S, 399.1009; found, 399.1006.
(E)-4-Methyl-N′-(phenyl(4-(p-tolyl)furan-2-yl)methylene)-
benzenesulfonohydrazide (1r). White solid (670 mg, 65%); mp
150.7−153.4 °C; IR (KBr): 3744, 3167, 1684, 1399, 1166, 754, 518
N′-((5-Ethyl-8-methoxy-4-oxo-4,5-dihydrofuro[2,3-c]quinolin-2-
yl)(phenyl)methylene)-4-methylbenzenesulfonohydrazide (5e).
White solid (70 mg, 44%); mp 234−237 °C; IR (KBr): 3743, 2921,
1
1660, 1288, 1166, 754, 549 cm−1; H NMR (400 MHz, DMSO): δ
11.37 (s, 1H), 8.19 (d, J = 8.6 Hz, 1H), 7.89−7.61 (m, 3H), 7.55−7.46
(m, 5H), 7.42 (d, J = 7.2 Hz, 2H), 7.19 (s, 1H), 7.11 (d, J = 8.6 Hz,
1H), 4.48 (d, J = 6.8 Hz, 2H), 3.97 (s, 3H), 2.47 (s, 3H), 1.32 (m,
3H); 13C NMR (101 MHz, DMSO): δ 160.4, 152.4, 148.5, 143.8,
140.4, 137.9, 135.3, 130.2, 129.9, 129.6, 129.0, 128.9, 128.6, 127.7,
127.6, 126.6, 111.0, 110.2, 109.3, 100.2, 55.6, 36.7, 21.1, 12.7; Ion-trap
HRMS (ESI): [M + H]+ calcd for C28H26N3O5S, 516.1572; found,
516.1572.
General Procedure for the Preparation of 2 and 6. The
mixture of furfural tosylhydrazone (0.3 mmol), toluene (5 mL),
LiOtBu (26.4 mg, 0.33 mmol) was stirred at 90 °C. After the
disappearance of 1 according to the TLC, the mixture was cooled to
room temperature, and the solid was filtered off. Removal of the
1
cm−1; H NMR (400 MHz, CDCl3): δ 9.54 (s, 1H), 7.92 (d, J = 8.0
Hz, 2H), 7.86 (s, 1H), 7.52−7.50 (m, 2H), 7.43−7.30 (m, 7H), 7.19
(d, J = 8.0 Hz, 2H), 6.84 (d, J = 0.6 Hz, 1H), 2.42 (s, 3H), 2.36 (s,
3H); 13C NMR (101 MHz, CDCl3): δ 148.1, 144.1, 141.3, 139.6,
137.9, 136.1, 135.6, 129.7, 129.6, 128.8, 128.3, 128.2, 128.1, 127.6,
126.0, 115.4, 21.6, 21.2; Ion-trap HRMS (ESI): [M + Na]+ calcd for
C25H22N2NaO3S, 453.1243; found, 453.1244.
N′-Furan-2-yl(phenyl)methylene)-4-methylbenzenesulfonohy-
drazide (1s). Brown solid (700 mg, 65%); mp 138.0−139.7 °C; IR
H
DOI: 10.1021/jo502328j
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
organic solvent provided the crude product, which then was purified
by column chromatography using petroleum ether and ethyl acetate as
the eluent to give 2 or 6.
(E)-N,N-Dimethyl-2-oxo-6-(thiophen-2-yl)hex-3-en-5-ynamide
(2i). Yellow oil (27 mg, 38%); IR (film): 2920, 1640, 1387, 1097, 671
cm−1; 1H NMR (400 MHz, CDCl3): δ 7.42 (dd, J = 5.2, 1.0 Hz, 1H),
7.3 (d, J = 3.6 Hz, 1H), 7.04 (dd, J = 5.2, 3.6 Hz, 1H), 6.98 (d, J = 16.0
Hz, 1H), 6.75 (d, J = 16.0 Hz, 1H), 3.02 (d, J = 6.4 Hz, 6H); 13C
NMR (101 MHz, CDCl3): δ 189.3, 166.1, 134.4, 133.4, 130.2, 128.0,
127.6, 121.8, 96.5, 91.4, 37.2, 34.6; Ion-trap HRMS (ESI): [M + Na]+
calcd for C12H11NNaO2S, 256.0403; found, 256.0400.
(E)-1-Morpholino-6-phenylhex-3-en-5-yne-1,2-dione (2j). Yellow
solid (55 mg, 68%); mp 88−90 °C; IR (KBr): 2924, 1643, 752, 673
cm−1; 1H NMR (400 MHz, CDCl3): δ 7.52−7.47 (m, 2H), 7.42−7.33
(m, 3H), 7.01 (d, J = 16.0 Hz, 1H), 6.80 (d, J = 16.0 Hz, 1H), 3.78−
3.73 (m, 2H), 3.72−3.68 (m, 4H), 3.52−3.47 (m, 2H); 13C NMR
(101 MHz, CDCl3): δ 188.9, 164.6, 134.2, 132.3, 130.0, 129.1, 128.7,
121.9, 103.6, 87.0, 67.0, 66.7, 46.4, 42.1; Ion-trap HRMS (ESI): [M +
Na]+ calcd for C16H15NNaO3, 292.0944; found, 292.0941.
(E)-N-Allyl-N-methyl-2-oxo-6-phenylhex-3-en-5-ynamide (2k).
Yellow oil (63 mg, 83%); IR (film): 2926, 1643, 1584, 1072, 754,
685 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.51−7.48 (m, 2H), 7.40−
7.33 (m, 3H), 6.99 (dd, J = 16.0, 1.4 Hz, 1H), 6.77 (d, J = 16.0, 1H),
5.96−5.54 (m, 1H), 5.29−5.20 (m, 2H), 4.07 (d, J = 6.0 Hz, 1H), 3.89
(d, J = 6.0 Hz, 1H), 3.01 (s, 1.5H), 2.98 (s, 1.5H); 13C NMR (101
MHz, CDCl3): δ 188.8, 164.5, 134.1, 132.2, 129.9, 128.9, 128.6, 121.8,
103.6, 86.9, 66.9, 66.6, 46.3, 42.0; Ion-trap HRMS (ESI): [M + Na]+
calcd for C16H15NNaO2, 276.0995; found, 276.0996.
(E)-N,N-Dimethyl-2-oxo-6-phenylhex-3-en-5-ynamide (2a). Yel-
low oil (54 mg, 80%); IR (film): 2950, 1647, 754 cm−1; 1H NMR (400
MHz, CDCl3): δ 7.51−7.46 (d, J = 7.2 Hz, 2H), 7.40−7.32 (m, 3H),
6.97 (d, J = 16.0 Hz, 1H), 6.76 (d, J = 16.0 Hz, 1H), 3.02 (d, J = 7.6
Hz, 6H); 13C NMR (101 MHz, CDCl3): δ 189.6, 166.2, 134.3, 132.2,
129.9, 128.6, 122.0, 103.1, 87.0, 37.3, 34.6; Ion-trap HRMS (ESI): [M
+ Na]+ calcd for C14H13NNaO2, 250.0844; found, 250.0844.
(E)-N,N-Dimethyl-2-oxo-6-(p-tolyl)hex-3-en-5-ynamide (2b). Yel-
low solid (71 mg, 98%); mp 50−52 °C; IR (KBr): 2923, 1646, 1582,
1103, 1062, 463 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.38 (d, J = 8.0
Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 16.0 Hz, 1H), 6.75 (d, J
= 16.0 Hz, 1H), 3.02 (d, J = 8.0 Hz, 6H), 2.37 (s, 3H); 13C NMR (101
MHz, CDCl3): δ 189.5, 166.0, 140.2, 133.6, 131.9, 129.2, 128.7, 118.6,
103.5, 86.4, 37.0, 34.3, 21.4; Ion-trap HRMS (ESI): [M + Na]+ calcd
for C15H15NNaO2, 264.0995; found, 264.0995.
(E)-6-(4-Methoxyphenyl)-N,N-dimethyl-2-oxohex-3-en-5-yna-
mide (2c). Yellow solid (66 mg, 86%); mp 64−65 °C; IR (KBr): 2927,
1
1643, 1584, 1248, 1029, 670 cm−1; H NMR (400 MHz, CDCl3): δ
7.43 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 16.0 Hz, 1H), 6.87 (d, J = 8.4 Hz,
2H), 6.72 (d, J = 16.0 Hz, 1H), 3.82 (s, 3H), 3.02 (d, J = 8.0 Hz, 6H);
13C NMR (101 MHz, CDCl3): δ 189.8, 166.3, 161.0, 134.0, 133.4,
129.11, 114.4, 114.0, 104.1, 86.5, 55.4, 37.2, 34.6; Ion-trap HRMS
(ESI): [M + Na]+ calcd for C15H15NNaO3, 280.0944; found,
280.0941.
(E)-N-Methyl-2-oxo-6-(p-tolyl)-N-(3,4,5-trimethoxyphenyl)hex-3-
en-5-ynamide (2l). Yellow solid (105 mg, 89%); mp 95−96 °C; IR
1
(KBr): 2950, 1648, 1047, 753, 671, 465 cm−1; H NMR (400 MHz,
(E)-6-(3,5-Dimethylphenyl)-N,N-dimethyl-2-oxohex-3-en-5-yna-
CDCl3): δ 7.50−7.48 (m, 2H), 7.41−7.33 (m, 3H), 6.91 (d, J = 16.0
Hz, 1H), 6.61 (d, J = 16.0 Hz, 1H), 6.38 (s, 2H), 3.82 (d, J = 6.0 Hz,
9H), 3.38 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 189.2, 166.6,
153.8, 137.9, 137.0, 134.3, 132.2, 130.0, 128.7, 127.9, 121.9, 104.3,
103.0, 86.8, 61.0, 56.4, 36.6; Ion-trap HRMS (ESI): [M + Na]+ calcd
for C22H21NNaO5, 402.1312; found, 402.1308.
(E)-N-(2-Bromophenyl)-N-ethyl-2-oxo-6-phenylhex-3-en-5-yna-
mide (2m). Yellow oil (100 mg, 88%); IR (film): 2885, 1649, 1388,
1266, 1100, 754, 674 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.62 (d, J
= 8.0 Hz, 1H), 7.55−7.44 (m, 2H), 7.36 (m, 4H), 7.29 (dd, J = 8.0, 1.4
Hz, 1H), 7.25−7.18 (m, 1H), 6.95 (d, J = 16.0 Hz, 1H), 6.79 (d, J =
16.0 Hz, 1H), 4.17 (m, 1H), 3.52 (m, 1H), 1.20 (t, J = 7.2 Hz, 3H);
13C NMR (101 MHz, CDCl3): δ 187.0, 165.1, 138.7, 133.5, 133.3,
mide (2d). Yellow oil (41 mg, 54%); IR (film): 2885, 1643, 1386,
1
1266, 1047, 754, 671 cm−1; H NMR (400 MHz, CDCl3): δ 7.12 (s,
2H), 7.03 (s, 1H), 6.97 (d, J = 16.0 Hz, 1H), 6.75 (d, J = 16.0 Hz, 1H),
3.03 (d, J = 8.4 Hz, 6H), 2.30 (s, 6H); 13C NMR (101 MHz, CDCl3):
δ 189.5, 166.0, 138.0, 133.8, 131.7, 129.7, 128.7, 121.3, 103.7, 86.2,
37.0, 34.4, 20.8; Ion-trap HRMS (ESI): [M + Na]+ calcd for
C16H17NNaO2, 278.1151; found, 278.1155.
(E)-N,N-Dimethyl-6-(4-nitrophenyl)-2-oxohex-3-en-5-ynamide
(2e). Yellow solid (64 mg, 78%); mp 131−132.5 °C; IR (KBr): 2929,
1641, 1104, 750, 671 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.22 (d, J
= 8.6 Hz, 2H), 7.63 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 16.0 Hz, 1H), 6.89
(d, J = 16.0 Hz, 1H), 3.04 (s, 6H); 13C NMR (101 MHz, CDCl3): δ
188.6, 165.7, 148.0, 135.9, 132.9, 128.6, 126.8, 123.8, 99.1, 90.9, 37.3,
34.8; Ion-trap HRMS (ESI): [M + Na]+ calcd for C14H12N2NaO4,
295.0689; found, 295.0681.
132.0, 131.3, 129.8, 129.5, 128.3, 128.1, 127.5, 123.1, 121.8, 102.1,
87.0, 43.4, 12.2; Ion-trap HRMS (ESI): [M + Na]+ calcd for
C20H16BrNNaO2, 404.0257; found, 404.0249.
(E)-N,N-Dimethyl-2-oxo-6-(4-(trifluoromethyl)phenyl)hex-3-en-5-
(E)-N-Methoxy-N-methyl-2-oxo-6-(p-tolyl)hex-3-en-5-ynamide
ynamide (2f). Yellow solid (20 mg, 23%); mp 70−71 °C; IR (KBr):
(2o). Yellow solid (42 mg, 55%); mp 49−50 °C; IR (KBr): 2940,
1
3442, 1644, 1390, 1321, 1115, 1085, 751, 671 cm−1; H NMR (400
1
1660, 1582, 1077, 755, 671 cm−1; H NMR (400 MHz, CDCl3): δ
MHz, CDCl3): δ 7.65−7.59 (m, 4H), 6.98 (d, J = 16.0 Hz, 1H), 6.85
(d, J = 16.0 Hz, 1H), 3.04 (d, J = 4.4 Hz, 6H); 13C NMR (101 MHz,
CDCl3): δ 188.7, 165.6, 135.0, 132.1, 127.2, 125.4, 125.3, 125.3, 100.1,
88.4, 37.0, 34.5; Ion-trap HRMS (ESI): [M + Na]+ calcd for
C15H12F3NNaO2, 318.0712; found, 318.0711.
7.44 (d, J = 8.0 Hz, 0.8H), 7.38 (d, J = 8.0 Hz, 1.2H), 7.18−7.14 (m,
2H), 6.90 (d, J = 16.0 Hz, 0.6H), 6.67 (d, J = 11.6 Hz, 0.4H), 6.61 (d, J
= 16.0 Hz, 0.6H), 6.37 (d, J = 11.6 Hz, 0.4H), 3.69 (s, 1.8H), 3.67 (s,
1.2H), 3.27 (s, 1.8H), 3.15 (s, 1.2H), 2.37 (s, 3H); 13C NMR (101
MHz, CDCl3): δ 189.7, 166.7, 140.4, 133.5, 132.1, 129.4, 125.4, 118.8,
103.8, 86.4, 62.3, 31.6, 21.7; Ion-trap HRMS (ESI): [M + Na]+ calcd
for C15H15NNaO3, 280.0944; found, 280.0942.
(E)-N,N-Dimethyl-5-(5-oxopent-3-en-1-yn-1-yl)furan-2-carboxa-
mide (2p-1). Brown solid (37 mg, 57%); mp 128−130 °C; IR (KBr):
2883, 1601, 1386, 1110, 755, 670 cm−1; 1H NMR (400 MHz, CDCl3):
δ 10.18 (d, J = 8.0 Hz, 0.3H), 9.62 (d, J = 8.0 Hz, 0.7H), 7.05 (d, J =
3.6 Hz, 1H), 6.88−6.79 (m, 2H), 6.57 (dd, J = 12.0, 7.8 Hz, 0.7H),
6.36 (dd, J = 11.2, 8.4 Hz, 0.3H) 3.31 (s, 3H), 3.11 (s, 3H); 13C NMR
(101 MHz, CDCl3): δ 192.5, 191.4, 159.3, 150.2, 139.4, 137.9, 136.6,
136.5, 130.2, 126.8, 119.4, 119.2, 117.5, 117.5, 92.7, 91.5, 90.3, 89.6,
38.4, 36.7; Ion-trap HRMS (ESI): [M + Na]+ calcd for C12H11NNaO3,
240.0631; found, 240.0628.
(E)-6-(2-Chlorophenyl)-N,N-dimethyl-2-oxohex-3-en-5-ynamide
(2g). Yellow oil (62 mg, 79%); IR (film): 2885, 1643, 1386, 1055, 754,
1
670 cm−1; H NMR (400 MHz, CDCl3): δ 7.53 (dd, J = 7.8, 1.4 Hz,
1H), 7.45 (d, J = 8.0 Hz, 1H), 7.35 (dd, J = 7.8, 1.6 Hz, 1H), 7.29 (s,
1H), 7.04 (d, J = 16.2 Hz, 1H), 6.87 (d, J = 16.2 Hz, 1H), 3.06 (d, J =
6.4 Hz, 6H); 13C NMR (101 MHz, CDCl3): δ 189.4, 166.0, 136.7,
135.0, 133.9, 130.9, 129.6, 128.0, 126.8, 122.0, 99.0, 91.5, 37.3, 34.7;
Ion-trap HRMS (ESI): [M + Na]+ calcd for C14H12ClNNaO2,
284.0449; found, 284.0444.
(E)-N,N-Dimethyl-6-(naphthalen-2-yl)-2-oxohex-3-en-5-ynamide
(2h). Yellow oil (103 mg, 81%); IR (film): 2912, 1644, 1060, 751, 473
1
cm−1; H NMR (400 MHz, CDCl3): δ 8.03 (s, 1H), 7.85−7.78 (m,
3H), 7.54−7.48 (m, 3H), 7.03 (d, J = 16.0 Hz, 1H), 6.83 (d, J = 16.0
Hz, 1H), 3.03 (d, J = 7.5 Hz, 6H); 13C NMR (101 MHz, CDCl3): δ
189.6, 166.1, 134.2, 133.5, 132.9, 132.8, 128.7, 128.4, 128.1, 128.1,
127.9, 127.6, 126.9, 119.1, 103.6, 87.3, 37.2, 34.6; Ion-trap HRMS
(ESI): [M + Na]+ calcd for C18H15NNaO2, 300.0995; found,
300.0990.
(E)-6-(Furan-2-yl)-N,N-dimethyl-2-oxohex-3-en-5-ynamide (2p-
2). Brown solid (13 mg, 20%); mp 55−57 °C; IR (KBr): 2948,
1
1624, 1390, 1110, 753, 671 cm−1; H NMR (400 MHz, CDCl3): δ
7.49 (d, J = 1.2 Hz, 1H), 6.98 (d, J = 16.4 Hz, 1H), 6.81−6.22 (m,
2H), 6.47 (m, 1H), 3.03 (d, J = 5.6 Hz, 6H); 13C NMR (101 MHz,
CDCl3): δ 189.0, 165.9, 145.6, 136.1, 133.5, 127.1, 118.9, 111.8, 92.5,
I
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Article
92.1, 37.2, 34.7; Ion-trap HRMS (ESI): [M + Na]+ calcd for
C12H11NNaO3, 240.0631; found, 240.0627.
(d, J = 9.0 Hz, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 7.2 Hz, 2H),
7.35−7.26 (m, 3H), 7.14 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 9.0 Hz, 2H),
4.73 (s, 2H), 4.39 (q, J = 7.0 Hz, 2H), 3.89 (s, 3H), 2.32 (s, 3H), 1.36
(t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 165.8, 160.3,
152.4, 144.2, 140.3, 138.7, 138.5, 135.5, 129.6, 129.1, 128.6, 127.0,
126.3, 125.8, 118.9, 108.9, 108.7, 100.2, 58.3, 55.3, 37.4, 33.7, 18.2,
12.4; Ion-trap HRMS (ESI): [M + H]+ calcd for C28H26NO5S,
488.1519; found, 488.1516.
(E)-Methyl 2-Oxo-6-phenylhex-3-en-5-ynoate (2q). Yellow oil (49
mg, 41%); IR (film): 3781, 2954, 1733, 1584, 1078, 755, 678 cm−1; 1H
NMR (400 MHz, CDCl3): δ 7.60 (m, 2H), 7.41−7.35 (m, 3H), 7.12
(d, J = 11.2 Hz, 1H), 6.62 (d, J = 11.2 Hz, 1H), 3.89 (s, 3H); 13C
NMR (101 MHz, CDCl3): δ 180.7, 162.3, 132.7, 130.0, 129.5, 128.5,
126.4, 122.1, 104.7, 88.0, 53.1; Ion-trap HRMS (ESI): [M + H]+ calcd
for C13H11O3, 215.0703; found, 215.0700.
(E)-5-Phenyl-2-(p-tolyl)pent-2-en-4-ynal (2r). Yellow oil (29 mg,
ASSOCIATED CONTENT
■
1
40%); IR (film): 2956, 2885, 1721, 1041, 851, 750, 536 cm−1; H
S
* Supporting Information
NMR (400 MHz, CDCl3): δ 10.62 (s, 1H), 7.55−7.52 (m, 2H), 7.41−
7.36 (m, 5H), 7.22 (d, J = 8.0 Hz, 2H), 7.06 (s, 1H), 2.38 (s, 3H); 13C
NMR (101 MHz, CDCl3): δ 191.3, 147.3, 139.2, 131.9, 131.2, 129.6,
129.2, 128.6, 128.0, 126.2, 122.1, 102.3, 84.9, 21.3; Ion-trap HRMS
(ESI): [M + H]+ calcd for C18H14NaO, 269.0937; found, 269.0935.
(E)-5-Phenylpent-2-en-4-ynal (2s). Yellow oil (19 mg, 40%); IR
(film): 2918, 1716, 1053, 755, 670 cm−1; 1H NMR (400 MHz,
CDCl3): δ 9.62 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 6.4 Hz, 2H), 7.43−
7.35 (m, 3H), 6.82 (d, J = 16.0 Hz, 1H), 6.65−6.42 (m, 1H); 13C
NMR (101 MHz, CDCl3): δ 193.0, 139.2, 132.5, 132.1, 129.9, 128.6,
121.8, 104.2, 86.0; Ion-trap HRMS (ESI): [M + H]+ calcd for C11H9O,
157.0653; found 157.0650.
The bioassay method, copies of H NMR and 13C NMR
1
spectra of all of the new compounds, computational details, and
coordinates of the structures. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: doctliu@263.net.
*E-mail: blyin@scut.edu.cn.
Notes
2-Benzyl-5-ethyl-1-tosylfuro[2,3-c]quinolin-4(5H)-one (6a). White
solid (100 mg, 73%); mp 208−210 °C; IR (KBr): 2990, 1764, 1378,
1243, 1055, 754, 673 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.79 (d, J
= 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 1H), 7.44
(m, 3H), 7.36−7.27 (m, 3H), 7.24 (s, 1H), 7.14 (d, J = 8.0 Hz, 2H),
4.76 (s, 2H), 4.44 (q, J = 7.0 Hz, 2H), 2.31 (s, 3H), 1.36 (t, J = 7.2 Hz,
3H); 13C NMR (101 MHz, CDCl3): δ 166.2, 152.5, 144.6, 141.9,
138.9, 137.1, 135.8, 129.9, 129.5, 129.4, 128.9, 127.6, 127.3, 126.7,
125.9, 122.7, 119.6, 115.4, 115.1, 37.6, 34.0, 21.6, 12.9; Ion-trap
HRMS (ESI): [M + Na]+ calcd for C27H23NNaO4S, 480.1245; found,
480.1240.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21272078, 81202398, and 21336002),
Fundamental Research Funds for the Central Universities
(2014ZG0027), Natural Science Foundation of Guangdong
Province, China (10351064101000000), and Program for New
Century Excellent Talents in Universities (NCET-12-0189).
5-Ethyl-2-(4-methylbenzyl)-1-tosylfuro[2,3-c]quinolin-4(5H)-one
(6b). White solid (107 mg, 76%); mp 208−209 °C; IR (KBr): 2953,
1722, 1059, 962, 757, 593 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.79
(dd, J = 8.4, 0.8 Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.52 (m, 1H),
7.45−7.38 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.26−7.24 (m,
1H), 7.13 (m, 4H), 4.71 (s, 2H), 4.44 (q, J = 7.6 Hz, 2H), 2.32 (s,
6H), 1.36 (t, J = 7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 166.7,
152.7, 144.7, 142.1, 139.2, 137.3, 137.1, 132.9, 130.1, 129.8, 129.7,
129.5, 127.8, 126.9, 126.1, 122.9, 119.6, 115.6, 115.3, 37.8, 33.8, 21.8,
21.3, 13.1; Ion-trap HRMS (ESI): [M + H]+ calcd for C28H26NO4S,
472.1572; found, 472.1577.
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1
(KBr): 2954, 2885, 1722, 1048, 756, 594 cm−1; H NMR (400 MHz,
CDCl3): δ 8.49 (s, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.0 Hz,
2H), 7.29 (s, 2H), 7.16 (d J = 8.0 Hz, 2H), 7.12 (d J = 8.0 Hz, 2H),
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129.3, 129.0, 127.2, 126.5, 125.4, 118.9, 114.9, 114.7, 37.2, 33.3, 21.3,
20.9, 20.5, 12.7; Ion-trap HRMS (ESI): [M + Na]+ calcd for
C29H28NO4S, 486.1752; found, 486.1734.
́
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(6d). White solid (113 mg, 80%); mp 209−210 °C; IR (KBr): 2955,
1720, 1055, 957, 750, 597 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.50
(s, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 7.6 Hz, 2H), 7.37−7.30
(m, 4H), 7.28 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 8.0 Hz, 2H), 4.78 (s,
2H), 4.43 (q, J = 6.8 Hz, 2H), 2.41 (s, 3H), 2.33 (s, 3H), 1.35 (t, J =
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(6e). White solid (131 mg, 90%); mp 232−234 °C; IR (KBr): 2948,
1719, 1056, 960, 770, 599 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.71
J
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K
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