One-Pot Synthesis of 2-Cyano-1,4-diketones: Applications to Synthesis of Cyanosubstituted Furans, Pyrroles, and Dihydropyridazines

Article abstract of DOI:10.1021/acs.joc.6b01672

A convenient synthetic route for the construction of functionalized 2-cyano-1,4-diketones has been established from the nucleophilic substitution of 2-bromoacetophenones with NaCN via the in situ-generated β-ketonitriles. This method was further applied to the synthesis of cyanosubstituted furans, pyrroles, or dihydropyridazines, which were obtained in good to excellent yields using Bi(OTf)₃, NH₄OAc, or N₂H₄. The key structures were confirmed by X-ray single crystal diffraction analysis.

Full text of DOI:10.1021/acs.joc.6b01672

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Note
One-pot Synthesis of 2-Cyano-1,4-diketones: Applications to Synthesis
of Cyanosubstituted Furans, Pyrroles and Dihydropyridazines
Chieh-Kai Chan, Yi-Ling Chan, Yu-Lin Tsai, and Meng-Yang Chang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01672 • Publication Date (Web): 04 Aug 2016
Downloaded from http://pubs.acs.org on August 5, 2016
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One-pot Synthesis of 2-Cyano-1,4-diketones: Applications to
Synthesis of Cyanosubstituted Furans, Pyrroles and
Dihydropyridazines
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Chieh-Kai Chan, Yi-Ling Chan, Yu-Lin Tsai and Meng-Yang Chang*
*mychang@kmu.edu.tw
Department of Medicinal and Applied Chemistry, and General Research Centers of R&D office, Kaohsiung
Medical University, Kaohsiung 807, Taiwan
ABSTRACT
A convenient synthetic route for the construction of functionalized 2-cyano-1,4-diketones has
been established from the nucleophilic substitution of 2-bromoacetophenones with NaCN via the
in situ-generated β-ketonitriles. This method was further applied to the synthesis of
cyanosubstituted furans, pyrroles or dihydropyridazines, which were obtained in good to
excellent yields using Bi(OTf)3, NH4OAc or N2H4. The key structures were confirmed by X-Ray
single crystal diffraction analysis.
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1,4-Diketones are valuable synthetic building blocks for the preparation of heterocyclic
compounds such as furans, pyrroles, thiophenes, selenophenes and pyridazines.1 A variety of
synthetic routes have been developed for the construction of 1,4-diketones, including the one-
carbon expansion of 1,3-dicarbonyl compounds,2 oxidative coupling of enolates,3 acylation of
homoenolate synthons,4 photolytic dimerization of β-ketosulfones,5 nucleophilic substitution of
enolates with α-haloketones6 and other methods.7 Aseries of 2-cyano-1,4-diketones (1) are found
in numerous bioactive molecules and functionalized materials.8 Due to the versatile possible
transformations of the cyano group, the introduction of a cyano substitutent is of significant
interest.9 As shown in Scheme 1, a number of reported methods for the formation of 2-cyano-
1,4-diketones 1 have been studied, including the Mn(OAc)3-facilitated oxidation of β-ketonitriles
with styrene,10 Ba(OH)2-activated addition of 1,4-enediones with NaCN,11 NaNH2-promoted
benzoylative decyanation of O-aroylmandelonitriles with acrylonitrile,12 and additional
approaches.13 Accordingly, further synthetic application for 1 is a continuing need. Therefore,
Alexakis and coworkers developed a NHC-catalyzed domino annulation of 1 with ynals to afford
the vitamin B1 analogues.14
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With the known synthetic routes, the extra addition of the reagent was the common point,
including the reaction conditions of Mn(OAc)2/AcOH,10 Ba(OH)2/EtOH,11 NaNH2/DMF,12
13
Hunig’s base/MgCl2 or TMSCN/TBAF.14 Compared with the reports, our protocol for the
synthesis of 2-cyano-1,4-diketones performed a one-pot and convenient route via treatment of
substituted 2-bromoacetophenones 2 with NaCN in the co-solvent of dioxane and water. No extra
reagents are need to added.
Scheme 1. Synthesis of 2-cyano-1,4-diketones 1
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Recently, we utilized β-ketosulfone as the building block to prepare diversified
benzoannulated frameworks.15 Following that success, further synthetic applications of β-
ketonitriles 3 were attempted. We found that when the sulfonyl group was substituted with a
cyano group, the NaCN-mediated double reaction with two equiv of 2-bromoacetophenones 2
was observed in addition to the predicted mono-nucleophilic substitution. To the best of our
knowledge, 1 was isolated in combination with 3 using 1.5 equiv of NaCN in yields of 55% (for
1a) and 40% (for 3a), respectively. Therefore, we aimed to use sodium cyanide in the same
reaction condition to prepare a series of functionalized 2-cyano-1,4-diketones 1.
To examine the one-pot transformation from 2 to 1 and 3, 2-bromoacetophenone (2a, Ar =
Ph) was selected as the model substrate. As shown in Table 1, the nucleophilic substitution
reactions of 2a with the use of sodium cyanide (NaCN), potassium cyanide (KCN) and copper(I)
cyanide (CuCN) were tested. Initially, the reaction of 2a with 1.1 equiv of NaCN in the co-solvent
of dioxane and water for 3 h at room temperature gave 1a (25%) and 3a (60%) with recovered
2a in 13% yield (entry 1). When 1.5 equiv of NaCN was used, 1a was increased to the yield of
55% and 3a was decreased to 40% yield (entry 2). When the amount of NaCN was increased to
2.2 equiv, 1a was obtained in the yield of 80% with trace amounts of 3a (entry 3). A similar yield
of 1a was obtained in the reaction of 2a with 3.5 equiv of NaCN (entry 4). Furthermore, reactions
of 2a with 2.2 or 3.5 equiv of KCN were attempted; 1a was isolated in moderate yield (75%,
60%) with 3a (20%, 10%) in entries 5-6. Different amounts of CuCN were also tested with 2a,
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but only trace amounts of 3a were obtained with recovered starting material 2a (entries 7-9).
Solvents were also screened for their effect on the reaction. When the reaction was performed in
MeCN, THF, MeOH or DMF, 1a was isolated in a lower yield (58%, 62%, 60% and 65%) with
only a small amount of 3a (10%, 15%, 18% and 16%) and trace amount of recovered 2a at room
temperature (entries 10-13). Increasing the temperature to 100 oC gave the desired product 1a in
60% yield with 10% yield of 3a, but some unknown products were also isolated (entry 14).
Notably, 2a reacted with 2.2 equiv of NaCN effectively in a mixture of dioxane and water for 3
h at room temperature to give 1a in 80% yield.
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Table 1. Reaction conditions for the construction of 1aa
yield (%)b
entry cyanide (equiv) solvent (v/v)
T (oC)
1a 3a
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9
NaCN (1.1)
NaCN (1.5)
NaCN (2.2)
NaCN (3.5)
KCN (2.2)
KCN (3.5)
CuCN (1.5)
CuCN (2.2)
CuCN (3.5)
dioxane/H2O (9/1) 25
25 60c
dioxane/H2O (9/1) 25
dioxane/H2O (9/1) 25
dioxane/H2O (9/1) 25
dioxane/H2O (9/1) 25
dioxane/H2O (9/1) 25
dioxane/H2O (9/1) 25
dioxane/H2O (9/1) 25
dioxane/H2O (9/1) 25
MeCN/H2O (9/1) 25
55 40
d
80
75
─
─
d
75 20
60 10
d
─
─
─
17c
12c
10c
d
d
10 NaCN (2.2)
11 NaCN (2.2)
12 NaCN (2.2)
13 NaCN (2.2)
14 NaCN (2.2)
58 10c
62 15c
60 18c
65 16c
60 10e
THF/H2O (9/1)
25
MeOH/H2O (9/1) 25
DMF/H2O (9/1) 25
dioxane/H2O (9/1) 100
aConditions: 2a (2.0 mmol), co-solvent (10 mL), 3 h. bIsolated yield. c2a was recovered (entry 1, 13%; entry 7, 70%; entry
8, 63%; entry 9, 50%; entries 10-13, trace amounts). dNo observation. e10% of unknown products were isolated.
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Based on these results, a reaction mechanism was proposed and is shown in Scheme 2.
Initially, the SN2 reaction of 2 with NaCN took place to form nitrile 3. We believe the excess
equiv of NaCN also acts as a base to conduct deprotonation of 3 producing intermediate A and
NaBr, followed by the SN2 reaction of A with starting 2 to yield the desired product 1. With the
optimal reaction conditions in hand (Table 1, entry 3), we further investigated the substrate scope
and limitation of this reaction. Various 2-bromoacetophenones 2 were subjected to the reaction
under identical conditions, and the representative results and yields are shown in Table 2, entries
1-12. Substituted 2-bromoacetophenones 2 reacted readily with NaCN in dioxane and water at
room temperature to afford functionalized 2-cyano-1,4-diketones 1 in good to excellent yields.
The reaction demonstrated a wide tolerance toward a variety of substituted groups such as
electron-withdrawing groups 4-fluorophenyl (1b, 82%) and 4-trifluoromethylphenyl (1g, 83%)
and electron-donating groups, 4-methoxyphenyl (1c, 87%), 3-methoxyphenyl (1e, 85%), 3,4,5-
trimethoxyphenyl (1i, 86%), 3,4-methylenedioxyphenyl (1j, 85%), 4-methylphenyl (1d, 83%),
2-naphthyl (1f, 90%), and biphenyl (1h, 88%). The structure of 1f was also determined by single-
crystal X-ray crystallography.16 In this one-pot protocol, the preparation of pseudosymmetrical
1a-1j was effective with good yields. To our delight, we further explored the unsymmetrical 1
through the reaction of 2d (Ar = 4-MePh) and 2k (Ar = 2,4-(MeO)2Ph) under identical reaction
conditions to give 1k (55%). As expected, 2b and 2c reacted with NaCN to afford 1l and 1m
(62%) at an approximate ratio of 1:1 (Figure 1). The configuration of newly form C-C bond in
the 1k was assigned by NOE-cross correlations spectroscopic studies (Figure 2). According to
the results of Table 2 and entry 11, 1k was obtained in a sole isomer. We think that the reaction
selectivity of 2d (Ar = 4-MeC6H4) and 2k (Ar = 2,4-(MeO)2C6H3), NaCN was preferred to react
with 2d due to 2k with the 2-methoxy substituent performed a more steric hindrance.
Subsequently, in situ generated β-ketonitrile reacted with 2k to produce 1k. From the results, no
observation of two isomers has been detected. With the results of Table 2 and entry 12, 1l and
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1m were obtained in the inseparated mixture. We think that the reaction selectivity has not been
performed in the NaCN-mediated one-pot reaction due to no steric hindrance was formed
between 2b (Ar = 4-FC6H4) and 2c (Ar = 4-MeOC6H4). From the result, the mixture of 1l and
1m with a ratio of 1:1 was observed. Based on the formation of the sole 1k and the inseparated
mixture of 1l and 1m, we envision that 2-methoxy substituent on the aryl group with a steric
hindrance is an important factor to affect the formation of unsymmetrical 2-cyano-1,4-diketone.
Therefore, the reaction trend is attributed to the preparation of pseudosymmetrical 2-cyano-1,4-
diketone.
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Figure 1. Structures of 1l and 1m
Scheme 2. Possible mechanism
Table 2. Scope of Substituted 2-Bromoacetophenonesa,b
entry 2, Ar1, Ar2
1 (%)b
1a, 80
1b, 82
1c, 87
1d, 83
1e, 85
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2a, Ph, Ph
2b, 4-FC6H4, 4-FC6H4
2c, 4-MeOC6H4, 4-MeOC6H4
2d, 4-MeC6H4, 4-MeC6H4
2e, 3-MeOC6H4, 3-MeOC6H4
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2f, 2-naphthyl, 2-naphthyl
2g, 4-CF3C6H4, 4-CF3C6H4
2h, 4-PhC6H4, 4-PhC6H4
1f, 90
1g, 83
1h, 88
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2i, 3,4,5-(MeO)3C6H2, 3,4,5-(MeO)3C6H2 1i, 86
2j, 3,4-OCH2OC6H3, 3,4-OCH2OC6H3 1j, 85
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2d, 4-MeC6H4, 2k, 2,4-(MeO)2C6H3
2b, 4-FC6H4, 2c, 4-MeOC6H4
1k, 55
1l, 1m 62c
aConditions: 2 (2.0 mmol), NaCN (4.4 mmol), 3 h, rt. bIsolated yields. c1 : 1 of ratio.
Figure 2. NOE correlation of 1k
Due to the unique versatility of 1,4-diketone, we further explored the applications of 1 in
the construction of heterocyclic five-membered ring moieties.17 Within this structural family,
furans and pyrroles are particularly meaningful molecules and commonly synthesized in organic
chemistry.18 Cyanosubstituted furans and pyrroles are widely used in medical chemistry and have
been prepared by numerous research groups.19
Table 3. Synthesis of 3-Cyano five-member rings 4 and 5a,b
entry
1, Ar1, Ar2
4, 5 (%)c
4a, 88
4b, 86
4c, 90
4d, 89
4e, 88
4f, 92
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1a, Ph, Ph
1b, 4-FC6H4, 4-FC6H4
1c, 4-MeOC6H4, 4-MeOC6H4
1d, 4-MeC6H4, 4-MeC6H4
1e, 3-MeOC6H4, 3-MeOC6H4
1f, 2-naphthyl, 2-naphthyl
1g, 4-CF3C6H4, 4-CF3C6H4
4g, 65
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1h, 4-PhC6H4, 4-PhC6H4
4h, 87
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1i, 3,4,5-(MeO)3C6H2, 3,4,5-(MeO)3C6H2 4i, 89
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12d
13d
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18
1j, 3,4-OCH2OC6H3, 3,4-OCH2OC6H3
1k, 4-MeC6H4, 2,4-(MeO)2C6H3
1l, 4-MeOC6H4, 4-FC6H4
1m, 4-FC6H4, 4-MeOC6H4
1a, Ph, Ph
4j, 88
4k, 89
4l, 75
4m, 78
5a, 85
5b, 83
5c, 86
5d, 87
5e, 86
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1b, 4-FC6H4, 4-FC6H4
1c, 4-MeOC6H4, 4-MeOC6H4
1d, 4-MeC6H4, 4-MeC6H4
1e, 3-MeOC6H4, 3-MeOC6H4
b
aConditions: 1 (1.0 mmol), 2 h. For 4: Bi(OTf)3 (13 mg, 2.0 mol %), rt; for 5: NH4OAc (160 mg, 2.1 mmol), reflux.
cIsolated yield. dInseparated mixture (1l : 1m = 1 : 1).
Due to our previous work in the synthesis of substituted furans,15b we believed that Bi(OTf)3
was an effective reagent to form the furan motif and thus chose it as the Lewis acid to react with
1 to afford furan skeletons. The treatment of Bi(OTf)3 with 1 readily gave the desired furans 4 in
entries 1-11 in good to excellent yields (65-92%). Because of the inseparated mixture of 1l and
1m (Table 1, entries 12-13), the mixture reacted with Bi(OTf)3. Fortunately, in this step, 4l and
4m could be separated in 75% and 78% yields (entries 12-13), respectively. We also adopted our
experience with NH4OAc-mediated domino aminocyclization15a for the synthesis of 3-
cyanosubstitutedpyrroles from 1. Therefore, NH4OAc (1.5 mmol) was added to solution of 1a-e
in MeOH at reflux to give the desired pyrroles 5a-e (entries 14-18). All yields are shown in Table
3, and the NOE-cross correlations of 4l and 4m are depicted in Figure 3.
Figure 3. NOE correlation of 4l and 4m.
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In addition to five-membered furans and pyrroles, the application of this reaction to the six-
membered dihydropyridazine was our goal. Pyridazines are versatile in the synthesis of natural
products, which are useful synthetic intermediates,20 and are known to exhibit important
pharmacological activities.21 Among their derivatives, dihydropyridazines represent an important
intermediate for aromatized pyridazines. Recently, we published a protocol for the synthesis of
substituted pyridazines mediated by In(OTf)3.22 As shown in Table 4, compounds 1a-f were
subjected to this cyclocondensation with N2H4 7a in MeOH at reflux, and the corresponding
products 6a-f were obtained in high yields (entries 1-6). Encouraged by these results,
phenylhydrazine was also tested in this conversion. Fortunately, the reaction of 1 with
phenylhydrazine 7b easily gave triphenylpyridazine 6g in a yield of 90% (entry 7).
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Table 4. Synthetic route to 3-Cyano dihydropyridazines 6a,b
entry
1, Ar1, Ar2
7, R
6 (%)c
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5
6
7
1a, Ph, Ph
7a, H 6a, 95
7a, H 6b, 96
1b, 4-FC6H4, 4-FC6H4
1c, 4-MeOC6H4, 4-MeOC6H4 7a, H 6c, 94
1d, 4-MeC6H4, 4-MeC6H4 7a, H 6d, 95
1e, 3-MeOC6H4, 3-MeOC6H4 7a, H 6e, 93
1f, 2-naphthyl, 2-naphthyl
1a, Ph, Ph
7a, H 6f, 90
7b, Ph 6g, 90
aConditions: 1 (1.0 mmol), 0.5 h, rt. bFor 6a-6f: N2H4 7a (1.0 mL); for 6g: PhNHNH2 7b (1.0 mmol). cIsolated yields.
In summary, a convenient protocol for the synthesis of functionalized 2-cyano-1,4-diketones
in good yields was developed. Further investigation regarding synthetic applications of 2-cyano-
1,4-diketones including cyanosubstituted furans, pyrroles and dihydropyridazines, was
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conducted. The structure of some products were confirmed by X-ray crystallography.
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EXPERIMENT SECTION
General
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All other reagents and solvents were obtained from commercial sources and used without
further purification. Reactions were routinely carried out under an atmosphere of dry nitrogen
with magnetic stirring. Products in organic solvents were dried with anhydrous magnesium
sulfate before concentration in vacuo. Melting points were determined with a melting apparatus.
13
1H and C NMR spectra were recorded on a spectrometer operating at 400 and at 100 MHz,
respectively. Chemical shifts (δ) are reported in parts per million (ppm) and the coupling
constants (J) are given in Hertz. High resolution mass spectra (HRMS) were measured with a
mass spectrometer microTOF-Q by ESI using a hybrid ion-trap. X-ray crystal structures were
obtained with a diffractometer (CAD4, Kappa CCD). Infrared spectra were collected with neat
material (oil or solid) on a FT-IR spectrometer, and ATR correction was performed on the spectra
obtained.
General synthetic procedure for synthesis of 1a-1l is as follows
NaCN (sodium cyanide, 216 mg, 4.4 mmol) was added to a solution of substituted
-
bromoacetophenones 2 (2.0 mmol) in the co-solvent of 1,4-dioxane and water (10 mL, v/v = 9:1)
at rt. The reaction mixture was stirred at rt for 3 h, and the solvent was concentrated. The residue
was diluted with water (10 mL) and the mixture was extracted with EtOAc (3 x 20 mL). The
combined organic layers were washed with brine, dried, filtered and evaporated to afford crude
product. Purification on silica gel (hexanes/EtOAc = 10/1~4/1) afforded 1a-1m.
2-Benzoyl-4-oxo-4-phenylbutanenitrile (1a).14
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According to the general procedure, reaction was performed in the presence of NaCN (216 mg,
4.4 mmol) and 2a (398 mg, 2.0 mmol) in the co-solvent of 1,4-dioxane and water (10 mL, v/v =
9:1) at rt for 3 h. Purification on silica gel (hexanes/EtOAc = 5/1) afforded 1a (80%, 421 mg; for
Table 1 and entry 3). Colorless solid; mp = 64-65 oC (recrystallized from hexanes and EtOAc);
HRMS (ESI, M++Na) calcd for C17H13NO2Na 286.0844, found 286.0840; 1H NMR (400 MHz,
CDCl3): δ 8.09-8.06 (m, 2H), 7.97-7.95 (m, 2H), 7.64 (t, J = 7.6 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H),
7.51 (t, J = 7.6 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H), 5.05 (dd, J = 4.4, 8.8 Hz, 1H), 4.05 (dd, J = 8.8,
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18.4 Hz, 1H), 3.55 (dd, J = 4.4, 18.4 Hz, 1H); C NMR (100 MHz, CDCl3): δ 194.6, 188.9,
135.1, 134.5, 133.9, 133.8, 128.9 (2x), 128.8 (2x), 128.7 (2x), 128.0 (2x), 116.9, 37.4, 33.0; FT-
IR (cm-1): 2932, 2242, 1782, 1680, 1234, 740, 693. For 3a (60%, 174 mg; Table 1 and entry 1).23
Colorless solid; mp = 79-80 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na)
calcd for C9H7NONa 168.0425, found 168.0428; 1H NMR (400 MHz, CDCl3): δ 7.93-7.91 (m,
2H), 7.68-7.64 (m, 1H), 7.55-7.50 (m, 2H), 4.09 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 187.1,
134.7, 134.3, 129.1 (2x), 128.4 (2x), 113.7, 29.3; FT-IR (cm-1): 2922, 2263, 1696, 1597, 1217,
756, 688.
2-(4-Fluorobenzoyl)-4-(4-fluorophenyl)-4-oxobutanenitrile (1b).14
According to the general procedure, reaction was performed in the presence of NaCN (216 mg,
4.4 mmol) and 2b (434 mg, 2.0 mmol) in the co-solvent of 1,4-dioxane and water (10 mL, v/v =
9:1) at rt for 3 h. Purification on silica gel (hexanes/EtOAc = 5/1) afforded 1b (82%, 491 mg).
Colorless solid; mp = 68-69 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na)
calcd for C17H11F2NO2Na 322.0656, found 322.0652; 1H NMR (400 MHz, CDCl3): δ 8.14-8.11
(m, 2H), 8.03-8.00 (m, 2H), 7.24-7.15 (m, 4H), 4.99 (dd, J = 4.4, 9.2 Hz, 1H), 4.06 (dd, J = 9.2,
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18.0 Hz, 1H), 3.51 (dd, J = 4.4, 18.0 Hz, 1H); C NMR (100 MHz, CDCl3): δ 193.1, 187.3,
166.6 (d, J = 256.2 Hz), 166.3 (d, J = 255.5 Hz), 131.8 (d, J = 9.8 Hz, 2x), 131.7 (d, J = 3.0 Hz),
131.0 (d, J = 9.1 Hz, 2x), 130.4 (d, J = 2.3 Hz), 116.7, 116.4 (d, J = 22.0 Hz, 2x), 116.1 (d, J =
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22.0 Hz, 2x), 37.3, 33.0; FT-IR (cm-1): 2931, 2244, 1723, 1686, 1232, 832, 745.
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2-(4-Methoxybenzoyl)-4-(4-methoxyphenyl)-4-oxobutanenitrile (1c).
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According to the general procedure, reaction was performed in the presence of NaCN (216 mg,
4.4 mmol) and 2c (458 mg, 2.0 mmol) in the co-solvent of 1,4-dioxane and water (10 mL, v/v =
9:1) at rt for 3 h. Purification on silica gel (hexanes/EtOAc = 4/1) afforded 1c (87%, 563 mg).
Colorless solid; mp = 107-108 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na)
calcd for C19H17NO4Na 346.1055, found 346.1052; 1H NMR (400 MHz, CDCl3): δ 8.04 (d, J =
8.8 Hz, 2H), 7.93 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 4.99 (dd,
J = 4.8, 8.8 Hz, 1H), 3.98 (dd, J = 8.8, 18.0 Hz, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.46 (dd, J = 4.8,
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18.0 Hz, 1H); C NMR (100 MHz, CDCl3): δ 193.1, 187.3, 164.6, 164.0, 131.3 (2x), 130.8,
130.5 (2x), 128.3, 126.8, 117.4, 114.2 (2x), 113.9, 55.5, 55.4, 37.1, 32.7; FT-IR (cm-1): 2936,
2244, 1678, 1596, 1171, 843, 796.
2-(4-Methylbenzoyl)-4-oxo-4-(p-tolyl)butanenitrile (1d).
According to the general procedure, reaction was performed in the presence of NaCN (216 mg,
4.4 mmol) and 2d (426 mg, 2.0 mmol) in the co-solvent of 1,4-dioxane and water (10 mL, v/v =
9:1) at rt for 3 h. Purification on silica gel (hexanes/EtOAc = 6/1) afforded 1d (83%, 484 mg).
Colorless solid; mp = 141-142 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na)
calcd for C19H17NO2Na 314.1157, found 314.1153; 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J =
8.0 Hz, 2H), 7.89 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 5.03 (dd,
J = 4.4, 8.4 Hz, 1H), 4.06 (dd, J = 8.4, 17.6 Hz, 1H), 3.51 (dd, J = 4.4, 17.6 Hz, 1H), 2.45 (s, 3H),
2.43 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 194.3, 188.5, 145.9, 145.0, 132.9, 131.6, 129.8 (2x),
129.5 (2x), 129.1 (2x), 128.4 (2x), 117.2, 37.5, 33.0, 21.8, 21.7; FT-IR (cm-1): 2923, 2242, 1694,
1677, 1238, 820, 759.
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2-(3-Methoxybenzoyl)-4-(3-methoxyphenyl)-4-oxobutanenitrile (1e).
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According to the general procedure, reaction was performed in the presence of NaCN (216 mg,
4.4 mmol) and 2e (458 mg, 2.0 mmol) in the co-solvent of 1,4-dioxane and water (10 mL, v/v =
9:1) at rt for 3 h. Purification on silica gel (hexanes/EtOAc = 4/1) afforded 1e (85%, 550 mg).
colorless oil; HRMS (ESI, M++Na) calcd for C19H17NO4Na 346.1055, found 346.1048; 1H NMR
(400 MHz, CDCl3): δ 7.68 (d, J = 7.6 Hz, 1H), 7.57-7.54 (m, 2H), 7.47-7.37 (m, 3H), 7.19 (d, J
= 7.6 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 5.01 (dd, J = 4.4, 8.8 Hz, 1H), 4.04 (dd, J = 8.8, 18.0 Hz,
1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.54 (dd, J = 4.4, 18.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ
194.5, 188.8, 160.0, 159.9, 136.5, 135.2, 130.0, 129.8, 121.4, 121.2, 120.8, 120.5, 116.9, 113.0,
112.3, 55.43, 55.37, 37.7, 33.3; FT-IR (cm-1): 2940, 2246, 1723, 1685, 1262, 732, 684.
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2-(2-Naphthoyl)-4-(naphthalen-2-yl)-4-oxobutanenitrile (1f).
According to the general procedure, reaction was performed in the presence of NaCN (216 mg,
4.4 mmol) and 2f (498 mg, 2.0 mmol) in the co-solvent of 1,4-dioxane and water (10 mL, v/v =
9:1) at rt for 3 h. Purification on silica gel (hexanes/EtOAc = 6/1) afforded 1f (90%, 654 mg).
Colorless solid; mp = 145-146 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na)
calcd for C25H17NO2Na 386.1157, found 386.1154; 1H NMR (400 MHz, CDCl3): δ 8.69 (s, 1H),
8.56 (s, 1H), 8.11-7.88 (m, 8H), 7.69-7.57 (m, 4H), 5.28 (dd, J = 4.4, 8.8 Hz, 1H), 4.30 (dd, J =
8.8, 17.6 Hz, 1H), 3.75 (dd, J = 4.4, 17.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 194.6, 188.9,
136.2, 135.9 (2x), 132.6, 132.4, 132.3, 131.4, 130.4, 129.9, 129.7, 129.4, 129.1, 129.0, 128.8,
127.84, 127.83, 127.2, 127.1, 123.9, 123.5, 117.2, 37.8, 33.3; FT-IR (cm-1): 2926, 2245, 1678,
1626, 1189, 834, 753. Single-crystal X-ray diagram: crystal of 1f was grown by slow diffusion
of EtOAc into a solution of 1f in CH2Cl2 to yield colorless prisms. The compound crystallizes in
the triclinic crystal system, space group P -1, a = 7.9748(3) Å, b = 8.5090(4) Å, c = 13.9508(6)
Å, V = 889.17(7) Å3, Z = 2, dcalcd = 1.357 g/cm3, F(000) = 380, 2 range 1.51-26.55o, R indices
(all data) R1 = 0.0401, wR2 = 0.0959.
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4-Oxo-2-(4-(trifluoromethyl)benzoyl)-4-(4-(trifluoromethyl)phenyl)butanenitrile (1g).14
According to the general procedure, reaction was performed in the presence of NaCN (216 mg,
4.4 mmol) and 2g (534 mg, 2.0 mmol) in the co-solvent of 1,4-dioxane and water (10 mL, v/v =
9:1) at rt for 3 h. Purification on silica gel (hexanes/EtOAc = 5/1) afforded 1g (83%, 663 mg).
Colorless solid; mp = 96-97 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na)
calcd for C19H11F6NO2Na 422.0592, found 422.0585; 1H NMR (400 MHz, CDCl3): δ 8.21 (d, J
= 8.4 Hz, 2H), 8.10 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 8.4 Hz, 2H), 5.02
(dd, J = 4.0, 9.2 Hz, 1H), 4.15 (dd, J = 9.2, 18.0 Hz, 1H), 3.60 (dd, J = 4.0, 18.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3): δ 193.8, 188.1, 137.7, 136.6, 135.9 (q, J = 33.4 Hz), 135.5 (q, J = 32.6
Hz), 129.4 (2x), 128.6 (2x), 126.2 (q, J = 3.8 Hz, 2x), 126.1 (q, J = 3.0 Hz, 2x), 123.4 (q, J =
271.4 Hz), 123.2 (q, J = 270.6 Hz), 116.1, 37.7, 33.5; FT-IR (cm-1): 2926, 2255, 1718, 1687,
1323, 1131, 1067.
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2-([1,1'-Biphenyl]-4-carbonyl)-4-([1,1'-biphenyl]-4-yl)-4-oxobutanenitrile (1h).
According to the general procedure, reaction was performed in the presence of NaCN (216 mg,
4.4 mmol) and 2h (550 mg, 2.0 mmol) in the co-solvent of 1,4-dioxane and water (10 mL, v/v =
9:1) at rt for 3 h. Purification on silica gel (hexanes/EtOAc = 6/1) afforded 1h (88%, 731 mg).
Colorless solid; mp = 158-159 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na)
calcd for C29H21NO2Na 438.1470, found 438.1467; 1H NMR (400 MHz, CDCl3): δ 8.18 (d, J =
8.4 Hz, 2H), 8.08 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.67-
7.63 (m, 4H), 7.52-7.48 (m, 4H), 7.46-7.41 (m, 2H), 5.11 (dd, J = 4.4, 8.8 Hz, 1H), 4.16 (dd, J =
8.8, 18.0 Hz, 1H), 3.60 (dd, J = 4.4, 18.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 194.3, 188.4,
147.3, 146.7, 139.5, 139.3, 134.0, 132.6, 129.6 (2x), 129.01 (2x), 128.99 (2x), 128.8 (2x), 128.6,
128.4, 127.6 (2x), 127.4 (2x), 127.3 (2x), 127.2 (2x), 117.1, 37.6, 33.1; FT-IR (cm-1): 2910, 2348,
1713, 1682, 1266, 763, 680.
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4-Oxo-2-(3,4,5-trimethoxybenzoyl)-4-(3,4,5-trimethoxyphenyl)butanenitrile (1i).
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According to the general procedure, reaction was performed in the presence of NaCN (216 mg,
4.4 mmol) and 2i (578 mg, 2.0 mmol) in the co-solvent of 1,4-dioxane and water (10 mL, v/v =
9:1) at rt for 3 h. Purification on silica gel (hexanes/EtOAc = 4/1) afforded 1i (86%, 763 mg).
Colorless solid; mp = 155-156 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na)
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calcd for C23H25NO8Na 466.1478, found 466.1472; H NMR (400 MHz, CDCl3): δ 7.29 (br s,
2H), 7.19 (br s, 2H), 5.00 (dd, J = 4.4, 8.8 Hz, 1H), 4.01 (dd, J = 8.8, 18.0 Hz, 1H), 3.91 (s, 3H),
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3.89 (s, 6H), 3.88 (s, 3H), 3.86 (s, 6H), 3.49 (dd, J = 4.4, 18.0 Hz, 1H); C NMR (100 MHz,
CDCl3): δ 193.5, 187.7, 153.1 (2x), 153.0 (2x), 143.8, 143.2, 130.2, 128.8, 117.1, 106.4 (2x),
105.5 (2x), 60.84, 60.79, 56.2 (2x), 56.1 (2x), 37.4, 32.9; FT-IR (cm-1): 2938, 2311, 1671, 1585,
1417, 1337, 1127.
4-(Benzo[d][1,3]dioxol-5-yl)-2-(benzo[d][1,3]dioxole-5-carbonyl)-4-oxobutanenitrile (1j).
According to the general procedure, reaction was performed in the presence of NaCN (216 mg,
4.4 mmol) and 2j (486 mg, 2.0 mmol) in the co-solvent of 1,4-dioxane and water (10 mL, v/v =
9:1) at rt for 3 h. Purification on silica gel (hexanes/EtOAc = 4/1) afforded 1j (85%, 597 mg).
Colorless solid; mp = 131-132 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na)
calcd for C19H13NO6Na 374.0641, found 374.0636; 1H NMR (400 MHz, CDCl3): δ 7.72 (dd, J =
1.6, 8.4 Hz, 1H), 7.60 (dd, J = 1.6, 8.4 Hz, 1H), 7.48 (d, J = 1.6 Hz, 1H), 7.41 (d, J = 1.6 Hz, 1H),
6.90 (dd, J = 8.4, 18.8 Hz, 2H), 6.08 (s, 2H), 6.05 (s, 2H), 4.94 (dd, J = 4.4, 9.2 Hz, 1H), 3.98
(dd, J = 9.2, 17.6 Hz, 1H), 3.43 (dd, J = 4.4, 17.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 192.7,
186.9, 153.2, 152.5, 148.6, 148.3, 130.2, 128.7, 125.8, 124.8, 117.2, 108.5, 108.3, 108.1, 107.8,
102.2, 102.0, 37.4, 33.0; FT-IR (cm-1): 2924, 2311, 1720, 1678, 1444, 1254, 1036.
4-(2,4-Dimethoxyphenyl)-2-(4-methylbenzoyl)-4-oxobutanenitrile (1k).
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According to the general procedure, reaction was performed in the presence of NaCN (216 mg,
4.4 mmol), 2d (213 mg, 1.0 mmol) and 2k (259 mg, 1.0 mmol) in the co-solvent of 1,4-dioxane
and water (10 mL, v/v = 9:1) at rt for 3 h. Purification on silica gel (hexanes/EtOAc = 4/1)
afforded 1k (55%, 371 mg). Colorless solid; mp = 108-109 oC (recrystallized from hexanes and
EtOAc); HRMS (ESI, M++Na) calcd for C20H19NO4Na 360.1212, found 360.1204; 1H NMR (400
MHz, CDCl3): δ 7.97 (d, J = 8.4 Hz, 2H), 7.87 (d, J = 8.8 Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H), 6.53
(dd, J = 2.4, 8.8 Hz, 1H), 6.47 (d, J = 2.4 Hz, 1H), 5.03 (dd, J = 4.4, 8.8 Hz, 1H), 4.00 (dd, J =
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8.8, 18.8 Hz, 1H), 3.94 (s, 3H), 3.86 (s, 3H), 3.59 (dd, J = 4.4, 18.8 Hz, 1H), 2.44 (s, 3H); C
NMR (100 MHz, CDCl3): δ 193.4, 189.2, 165.4, 161.6, 145.5, 133.2 (2x), 131.9, 129.7 (2x),
129.1 (2x), 118.8, 117.7, 105.6, 98.2, 55.6, 42.7, 33.2, 21.8; FT-IR (cm-1): 2926, 2242, 1694,
1657, 1600, 1254, 1213.
2-(4-fluorobenzoyl)-4-(4-methoxyphenyl)-4-oxobutanenitrile (1l) and 4-(4-Fluorophenyl)-2-
(4-methoxybenzoyl)-4-oxobutanenitrile (1m).
According to the general procedure, reaction was performed in the presence of NaCN (216 mg,
4.4 mmol), 2b (217 mg, 1.0 mmol) and 2c (229 mg, 1.0 mmol) in co-solvent of 1,4-dioxane and
water (10 mL, v/v = 9:1) at rt for 3 h. Purification on silica gel (hexanes/EtOAc = 4/1) afforded
1l and 1m (in Table 2, for entry 12, 62%, 193 mg; for entry 13, 62%, 193 mg). Two inseparated
isomers, ratio = 1:1. Colorless solid; mp = 108-109 oC (recrystallized from hexanes and EtOAc);
HRMS (ESI, M++Na) calcd for C18H14FNO3Na 334.0855, found 334.0852; 1H NMR (400 MHz,
CDCl3): δ 8.14 (d, J = 8.8 Hz, 1H), 8.12 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.25-7.21
(m, 2H), 6.97 (d, J = 8.8 Hz, 2H), 5.00 (dd, J = 4.4, 9.2 Hz, 1H), 4.06 (dd, J = 9.2, 17.6 Hz, 1H),
3.89 (s, 3H), 3.51 (dd, J = 4.4, 18.0 Hz, 1H).
General synthetic procedure for synthesis of compounds 4a-4m is as follows
Bi(OTf)3 (13 mg, 0.02 mmol) was added to a solvent of 1 (1.0 mmol) in dry MeNO2 (5 mL)
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at rt. The reaction mixture was stirred at rt for 2 h, and the solvent was concentrated. The residue
was diluted with water (10 mL) and the mixture was extracted with EtOAc (3 x 20 mL). The
combined organic layers were washed with brine, dried, filtered and evaporated to afford crude
product. Purification on silica gel (hexanes/EtOAc = 10/1~5/1) afforded 4a-4m.
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2,5-Diphenylfuran-3-carbonitrile (4a).19i
According to the general procedure, reaction was performed in the presence of Bi(OTf)3 (13 mg,
0.02 mmol) and 1a (263 mg, 1.0 mmol) in dry MeNO2 (5 mL) at rt for 2 h. Purification on silica
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gel (hexanes/EtOAc = 6/1) afforded 4a (88%, 216 mg). Colorless solid; mp = 115-116 C
(recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for C17H11NONa 268.0738,
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found 268.0735; H NMR (400 MHz, CDCl3): δ 8.07 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.8 Hz,
2H), 7.54-7.36 (m, 6H), 6.87 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 158.7, 153.6, 130.1, 129.1
(2x), 129.0 (2x), 128.9, 128.7, 128.1, 125.3 (2x), 124.2 (2x), 114.9, 107.7, 93.4; FT-IR (cm-1):
2924, 2229, 1727, 1486, 1242, 762, 684.
2,5-Bis(4-fluorophenyl)furan-3-carbonitrile (4b).
According to the general procedure, reaction was performed in the presence of Bi(OTf)3 (13 mg,
0.02 mmol) and 1b (299 mg, 1.0 mmol) in dry MeNO2 (5 mL) at rt for 2 h. Purification on silica
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gel (hexanes/EtOAc = 6/1) afforded 4b (86%, 242 mg). Colorless solid; mp = 112-113 C
(recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for C17H9F2NONa
304.0550, found 304.0543; 1H NMR (400 MHz, CDCl3): δ 8.05-8.02 (m, 2H), 7.70-7.67 (m, 2H),
7.22-7.13 (m, 4H), 6.80 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 163.6 (d, J = 250.2 Hz), 163.0
(d, J = 248.7 Hz), 157.9, 152.8, 127.5 (d, J = 9.1 Hz, 2x), 126.1 (d, J = 8.3 Hz, 2x), 125.0 (d, J =
3.8 Hz), 124.3 (d, J = 3.0 Hz), 116.5 (d, J = 22.0 Hz, 2x), 116.2 (d, J = 22.0 Hz, 2x), 114.7, 107.3,
93.2; FT-IR (cm-1): 2920, 2229, 1599, 1496, 1234, 1160, 832.
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2,5-Bis(4-methoxyphenyl)furan-3-carbonitrile (4c).
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According to the general procedure, reaction was performed in the presence of Bi(OTf)3 (13 mg,
0.02 mmol) and 1c (323 mg, 1.0 mmol) in dry MeNO2 (5 mL) at rt for 2 h. Purification on silica
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(recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for C19H15NO3Na
328.0950, found 328.0943; 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J = 8.8 Hz, 2H), 7.64 (d, J =
8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.70 (s, 1H), 3.88 (s, 3H), 3.86
(s, 3H); 13C NMR (100 MHz, CDCl3): δ 160.9, 160.0, 158.6, 153.0, 127.0 (2x), 125.7 (2x), 121.9,
121.2, 114.5 (2x), 114.4 (2x), 114.3, 105.9, 91.6, 55.44, 55.40; FT-IR (cm-1): 2925, 2225, 1614,
1508, 1252, 1177, 833.
2,5-Di-p-tolylfuran-3-carbonitrile (4d).
According to the general procedure, reaction was performed in the presence of Bi(OTf)3 (13 mg,
0.02 mmol) and 1d (291 mg, 1.0 mmol) in dry MeNO2 (5 mL) at rt for 2 h. Purification on silica
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gel (hexanes/EtOAc = 5/1) afforded 4d (89%, 243 mg). Colorless solid; mp = 134-135 C
(recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for C19H15NONa 296.1051,
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found 296.1045; H NMR (400 MHz, CDCl3): δ 7.95 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.0 Hz,
2H), 7.30 (d, J = 7.6 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 6.79 (s, 1H), 2.42 (s, 3H), 2.39 (s, 3H);
13C NMR (100 MHz, CDCl3): δ 158.8, 153.5, 140.4, 138.9, 129.8 (2x), 129.6 (2x), 126.2, 125.5,
125.3 (2x), 124.1 (2x), 115.2, 106.9, 92.5, 21.5, 21.4; FT-IR (cm-1): 2921, 2227, 1508, 1496, 818,
716, 495.
2,5-Bis(3-methoxyphenyl)furan-3-carbonitrile (4e).
According to the general procedure, reaction was performed in the presence of Bi(OTf)3 (13 mg,
0.02 mmol) and 1e (323 mg, 1.0 mmol) in dry MeNO2 (5 mL) at rt for 2 h. Purification on silica
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(recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for C19H15NO3Na
328.0950, found 328.0943; 1H NMR (400 MHz, CDCl3): δ 7.65 (dq, J = 1.6, 8.0 Hz, 1H), 7.57
(dd, J = 1.6, 2.4 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.30 (dt, J = 1.6, 7.6
Hz, 1H), 7.24 (dd, J = 1.6, 2.4 Hz, 1H), 7.00 (ddd, J = 1.2, 2.8, 8.4 Hz, 1H), 6.92 (ddd, J = 1.2,
2.8, 8.4 Hz, 1H), 6.86 (s, 1H), 3.90 (s, 3H), 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 160.02,
160.00, 158.6, 153.5, 130.2, 130.1, 130.0, 129.2, 117.9, 116.8, 116.2, 114.8, 114.3, 110.4, 110.0,
108.0, 93.6, 55.43, 55.38; FT-IR (cm-1): 2939, 2228, 1597, 1491, 1229, 1041, 706.
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2,5-Di(naphthalen-2-yl)furan-3-carbonitrile (4f).
According to the general procedure, reaction was performed in the presence of Bi(OTf)3 (13 mg,
0.02 mmol) and 1f (363 mg, 1.0 mmol) in dry MeNO2 (5 mL) at rt for 2 h. Purification on silica
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gel (hexanes/EtOAc = 6/1) afforded 4f (92%, 318 mg). Colorless solid; mp = 178-179 C
(recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for C25H15NONa 368.1051,
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found 368.1048; H NMR (400 MHz, CDCl3): δ 8.58 (d, J = 1.2 Hz, 1H), 8.25 (d, J = 1.2 Hz,
1H), 8.19 (dd, J = 2.0, 8.8 Hz, 1H), 8.02-7.85 (m, 6H), 7.79 (dd, J = 2.0, 8.8 Hz, 1H), 7.59-7.51
(m, 4H), 7.01 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 158.9, 153.9, 133.8, 133.31, 133.29, 133.1,
129.0, 128.9, 128.8, 128.3, 127.89, 127.87, 127.5, 127.04, 126.96, 126.8, 125.0, 125.4, 125.3,
123.3, 122.2, 121.9, 115.1, 108.4, 93.8; FT-IR (cm-1): 2924, 2228, 1725, 1502, 858, 814, 472.
2,5-Bis(4-(trifluoromethyl)phenyl)furan-3-carbonitrile (4g).
According to the general procedure, reaction was performed in the presence of Bi(OTf)3 (13 mg,
0.02 mmol) and 1g (399 mg, 1.0 mmol) in dry MeNO2 (5 mL) at rt for 2 h. Purification on silica
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gel (hexanes/EtOAc = 6/1) afforded 4g (65%, 248 mg). Colorless solid; mp = 159-160 C
(recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for C19H9F6NONa
404.0486, found 404.0483; 1H NMR (400 MHz, CDCl3): δ 8.19 (d, J = 8.0 Hz, 2H), 7.85 (d, J =
8.0 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.05 (s, 1H); 13C NMR (100 MHz,
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CDCl3): δ 157.6, 153.1, 133.9, 133.4, 132.0 (q, J = 32.6 Hz), 131.3 (q, J = 27.2 Hz), 126.5 (q, J
= 234.2 Hz), 126.3 (q, J = 236.5 Hz), 126.2 (q, J = 3.8 Hz, 2x), 126.0 (q, J = 3.7 Hz, 2x), 125.7
(2x), 124.6 (2x), 113.9, 109.8, 95.6; FT-IR (cm-1): 2924, 2238, 1324, 1169, 1111, 1070, 841.
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2,5-Di([1,1'-biphenyl]-4-yl)furan-3-carbonitrile (4h).
According to the general procedure, reaction was performed in the presence of Bi(OTf)3 (13 mg,
0.02 mmol) and 1h (415 mg, 1.0 mmol) in dry MeNO2 (5 mL) at rt for 2 h. Purification on silica
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gel (hexanes/EtOAc = 6/1) afforded 4h (87%, 346 mg). Colorless solid; mp = 203-204 C
(recrystallized from hexanes and EtOAc); HRMS (ESI, M++H) calcd for C29H20NO 398.1545,
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found 398.1538; H NMR (400 MHz, CDCl3): δ 8.16 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 8.4 Hz,
2H), 7.76 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4
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Hz, 2H), 7.51-7.46 (m, 4H), 7.43-7.37 (m, 2H), 6.93 (s, 1H); C NMR (100 MHz, CDCl3): δ
158.6, 153.5, 142.8, 141.7, 140.1, 139.9, 129.0 (2x), 128.9 (2x), 128.0, 127.8, 127.71 (2x), 127.66
(2x), 127.6, 127.1 (2x), 127.0 (2x), 126.9, 125.8 (2x), 124.7 (2x), 115.0, 107.9, 93.5; FT-IR (cm-
1): 2923, 2229, 1484, 842, 768, 726, 694.
2,5-Bis(3,4,5-trimethoxyphenyl)furan-3-carbonitrile (4i).
According to the general procedure, reaction was performed in the presence of Bi(OTf)3 (13 mg,
0.02 mmol) and 1i (443 mg, 1.0 mmol) in dry MeNO2 (5 mL) at rt for 2 h. Purification on silica
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gel (hexanes/EtOAc = 6/1) afforded 4i (89%, 379 mg). Colorless solid; mp = 146-147 C
(recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for C23H23NO7Na
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448.1372, found 448.1366; H NMR (400 MHz, CDCl3): δ 7.27 (s, 2H), 6.90 (s, 2H), 6.79 (s,
1H), 3.96 (s, 6H), 3.94 (s, 6H), 3.92 (s, 3H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 158.8,
153.8, 153.7, 153.4, 140.0, 139.2, 124.3, 123.3, 115.1, 107.4, 102.9 (2x), 102.0 (2x), 93.1, 61.04,
61.02, 56.3 (6x); FT-IR (cm-1): 2939, 2225, 1591, 1501, 1247, 1127, 1003.
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2,5-Bis(benzo[d][1,3]dioxol-5-yl)furan-3-carbonitrile (4j).
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According to the general procedure, reaction was performed in the presence of Bi(OTf)3 (13 mg,
0.02 mmol) and 1j (351 mg, 1.0 mmol) in dry MeNO2 (5 mL) at rt for 2 h. Purification on silica
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(recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for C19H11NO5Na
356.0535, found 356.0530; 1H NMR (400 MHz, CDCl3): δ 7.60 (dd, J = 1.6, 8.0 Hz, 1H), 7.48
(d, J = 2.0 Hz, 1H), 7.21 (dd, J = 1.6, 8.0 Hz, 1H), 7.14 (d, J = 2.0 Hz, 1H), 6.92 (d, J = 8.4 Hz,
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1H), 6.87 (d, J = 8.4 Hz, 1H), 6.68 (s, 1H), 6.05 (s, 2H), 6.02 (s, 2H); C NMR (100 MHz,
CDCl3): δ 158.2, 152.9, 149.1, 148.3, 148.2, 124.0, 123.1, 122.3, 120.3, 118.5, 115.2, 108.9,
108.8, 106.4, 105.6, 104.7, 101.7, 101.5, 92.1; FT-IR (cm-1): 2923, 2224, 1733, 1487, 1288, 1232,
1037.
5-(2,4-dimethoxyphenyl)-2-(p-tolyl)furan-3-carbonitrile (4k).
According to the general procedure, reaction was performed in the presence of Bi(OTf)3 (13 mg,
0.02 mmol) and 1k (337 mg, 1.0 mmol) in dry MeNO2 (5 mL) at rt for 2 h. Purification on silica
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gel (hexanes/EtOAc = 5/1) afforded 4k (89%, 284 mg). Colorless solid; mp = 143-144 C
(recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for C20H17NO3Na
342.1106, found 342.1100; 1H NMR (400 MHz, CDCl3): δ 7.94 (d, J = 8.0 Hz, 2H), 7.81 (d, J =
8.8 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 6.99 (s, 1H), 6.60 (dd, J = 2.4, 8.8 Hz, 1H), 6.55 (d, J =
2.4 Hz, 1H), 3.95 (s, 3H), 3.86 (s, 3H), 2.42 (s, 3H);13C NMR (100 MHz, CDCl3): δ 161.0, 157.4,
157.2, 149.9, 140.0, 129.7 (2x), 126.9, 125.8, 125.2 (2x), 115.6, 111.4, 110.4, 105.1, 98.7, 92.6,
55.50, 55.48, 21.5; FT-IR (cm-1): 2924, 2228, 1725, 1606, 1459, 1213, 779.
5-(4-Fluorophenyl)-2-(4-methoxyphenyl)furan-3-carbonitrile (4l).
According to the general procedure, reaction was performed in the presence of Bi(OTf)3 (13 mg,
0.02 mmol) and 1l (311 mg, 1.0 mmol) in dry MeNO2 (5 mL) at rt for 2 h. Purification on silica
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(recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for C18H12FNO2Na
316.0750, found 316.0744; 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J = 9.2 Hz, 2H), 7.70-7.66
(m, 2H), 7.17-7.11 (m, 2H), 7.02 (d, J = 9.2 Hz, 2H), 6.77 (s, 1H), 3.88 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 162.6 (d, J = 250.4 Hz), 159.2, 152.0, 127.1 (2x), 126.0 (d, J = 8.4 Hz, 2x),
125.3 (d, J = 3.0 Hz), 120.9, 116.1 (d, J = 22.0 Hz, 2x), 115.2, 114.6 (2x), 107.20, 107.19, 91.7,
55.4; FT-IR (cm-1): 2924, 2225, 1614, 1510, 1497, 1259, 825.
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2-(4-Fluorophenyl)-5-(4-methoxyphenyl)furan-3-carbonitrile (4m).
According to the general procedure, reaction was performed in the presence of Bi(OTf)3 (13 mg,
0.02 mmol) and 1l (311 mg, 1.0 mmol) in dry MeNO2 (5 mL) at rt for 2 h. Purification on silica
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gel (hexanes/EtOAc = 5/1) afforded 4m (39%, 114 mg). Colorless solid; mp = 111-112 C
(recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for C18H12FNO2Na
316.0750, found 316.0746; 1H NMR (400 MHz, CDCl3): δ 8.05-8.02 (m, 2H), 7.64 (d, J = 8.8
Hz, 2H), 7.21-7.17 (m, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.72 (s, 1H), 3.86 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 163.4 (d, J = 250.1 Hz), 160.2, 153.9, 129.8 (d, J = 208.4 Hz), 127.3 (d, J = 8.4
Hz, 2x), 125.8 (2x), 124.6 (d, J = 3.8 Hz), 121.5, 116.3 (d, J = 22.8 Hz, 2x), 115.0, 114.5 (2x),
114.4, 106.0, 55.4; FT-IR (cm-1): 2924, 2228, 1615, 1506, 1473, 1251, 835.
General synthetic procedure for synthesis of compounds 5a-5e is as follows
NH4OAc (160 mg, 2.1 mmol) was added to a solvent of 1 (1.0 mmol) in MeOH (5 mL) at
rt. The reaction mixture was refluxed for 2 h. The reaction mixture was cooled to rt, concentrated
and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine,
dried, filtered and evaporated to afford crude product. Purification on silica gel (hexanes/EtOAc
= 8/1~3/1) afforded 5a-5e.
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According to the general procedure, reaction was performed in the presence of NH4OAc (160
mg, 2.1 mmol) and 1a (263 mg, 1.0 mmol) in MeOH (5 mL) at reflux for 2 h. Purification on
silica gel (hexanes/EtOAc = 4/1) afforded 5a (85%, 208 mg). Colorless solid; mp = 223-224 oC
(recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for C17H12N2Na 267.0898,
found 267.0892; 1H NMR (400 MHz, CDCl3): δ 11.51 (br s, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.38
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(d, J = 8.0 Hz, 2H), 7.16-7.02 (m, 5H), 6.96-6.92 (m, 1H), 6.42 (d, J = 2.8 Hz, 1H); C NMR
(100 MHz, CDCl3): δ 139.2, 133.2, 130.3, 129.4, 128.0 (2x), 127.9 (2x), 127.6, 126.5, 126.0 (2x),
124.2 (2x), 117.2, 109.1, 89.9; FT-IR (cm-1): 3424, 2256, 1649, 1026, 1000, 766, 632.
2,5-Bis(4-fluorophenyl)-1H-pyrrole-3-carbonitrile (5b).
According to the general procedure, reaction was performed in the presence of NH4OAc (160
mg, 2.1 mmol) and 1b (299 mg, 1.0 mmol) in MeOH (5 mL) at reflux for 2 h. Purification on
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silica gel (hexanes/EtOAc = 4/1) afforded 5b (83%, 233 mg). Colorless solid; mp = 83-84 C
(recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for C17H10F2N2Na
303.0710, found 303.0712; 1H NMR (400 MHz, CDCl3): δ 11.45 (br s, 1H), 7.71-7.66 (m, 2H),
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7.52-7.47 (m, 2H), 7.02-6.95 (m, 2H), 6.95-6.89 (m, 2H), 6.50 (d, J = 2.4 Hz, 1H); C NMR
(100 MHz, CDCl3): δ 162.1 (d, J = 247.2 Hz), 161.6 (d, J = 245.6 Hz), 138.7, 132.7, 128.2 (d, J
= 7.6 Hz, 2x), 127.1 (d, J = 3.0 Hz), 126.4 (d, J = 7.6 Hz, 2x), 126.1 (d, J = 3.1 Hz), 117.4, 115.4
(d, J = 21.9 Hz, 2x), 115.2 (d, J = 21.3 Hz, 2x), 109.3, 90.3; FT-IR (cm-1): 3422, 2218, 1505,
1221, 1025, 999, 774.
2,5-bis(4-methoxyphenyl)-1H-pyrrole-3-carbonitrile (5c).
According to the general procedure, reaction was performed in the presence of NH4OAc (160
mg, 2.1 mmol) and 1c (323 mg, 1.0 mmol) in MeOH (5 mL) at reflux for 2 h. Purification on
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silica gel (hexanes/EtOAc = 3/1) afforded 5c (86%, 262 mg). Colorless solid; mp = 97-98 C
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(recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for C19H16N2O2Na
327.1110, found 327.1108; 1H NMR (400 MHz, CDCl3+d6DMSO): δ 11.15 (br s, 1H), 7.65 (d, J
= 8.8 Hz, 2H), 7.45 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 6.78 (d, J = 8.8 Hz, 2H), 6.45
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(d, J = 2.8 Hz, 1H), 3.71 (s, 3H), 3.70 (s, 3H); C NMR (100 MHz, CDCl3): δ 159.2, 158.5,
139.4, 133.0, 127.6 (2x), 126.0 (2x), 123.9, 122.7, 118.1, 113.8 (2x), 113.8 (2x), 108.2, 89.3,
55.00, 54.96; FT-IR (cm-1): 3498, 2224, 1645, 1025, 1000, 828, 769.
2,5-Di-p-tolyl-1H-pyrrole-3-carbonitrile (5d).
According to the general procedure, reaction was performed in the presence of NH4OAc (160
mg, 2.1 mmol) and 1d (291 mg, 1.0 mmol) in MeOH (5 mL) at reflux for 2 h. Purification on
silica gel (hexanes/EtOAc = 4/1) afforded 5d (87%, 237 mg). Colorless solid; mp = 183-184 oC
(recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for C19H16N2Na 295.1211,
found 295.1204; 1H NMR (400 MHz, CDCl3): δ 8.84 (br s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.41
(d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 6.69 (d, J = 2.8 Hz, 1H),
2.40 (s, 3H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 139.4, 138.9, 137.7, 133.1, 129.9 (2x),
129.8 (2x), 127.9, 126.9, 125.6 (2x), 124.3 (2x), 117.6, 109.7, 91.1, 21.3, 21.2; FT-IR (cm-1):
3242, 2922, 2224, 1508, 1460, 820, 792.
2,5-Bis(3-methoxyphenyl)-1H-pyrrole-3-carbonitrile (5e).
According to the general procedure, reaction was performed in the presence of NH4OAc (160
mg, 2.1 mmol) and 1e (323 mg, 1.0 mmol) in MeOH (5 mL) at reflux for 2 h. Purification on
silica gel (hexanes/EtOAc = 3/1) afforded 5e (86%, 262 mg); Colorless solid; mp = 129-130 oC
(recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for C19H16N2O2Na
327.1110, found 327.1104; 1H NMR (400 MHz, CDCl3): δ 11.42 (br s, 1H), 7.37-7.31 (m, 2H),
7.24-7.16 (m, 4H), 6.78 (ddd, J = 0.8, 2.4, 8.0 Hz, 1H), 6.70 (ddd, J = 1.2, 3.6, 8.0 Hz, 1H), 6.62
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(d, J = 2.8 Hz, 1H), 3.75 (s, 3H), 3.74 (s, 3H); C NMR (100 MHz, CDCl3): δ 159.6, 159.5,
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139.5, 133.5, 131.0, 129.5, 129.5, 118.7, 117.7, 117.2, 113.9, 112.4, 111.6, 110.7, 110.4, 110.0,
90.6, 55.1, 55.0; FT-IR (cm-1): 3418, 2218, 1592, 1491, 1234, 1026, 784.
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General synthetic procedure for synthesis of compounds 6a-6f is as follows
N2H4 (80%, 1.0 mL) was added to a solvent of 1 (1.0 mmol) in 1,4-dioxane (5 mL) at rt.
The reaction mixture was stirred at rt for 3 h, and the solvent was concentrated. The residue was
diluted with water (10 mL) and the mixture was extracted with EtOAc (3 x 20 mL). The combined
organic layers were washed with brine, dried, filtered and evaporated to afford crude product.
Purification on silica gel (hexanes/EtOAc = 10/1~5/1) afforded 6a-6f.
3,6-Diphenyl-2,5-dihydropyridazine-4-carbonitrile (6a).20a
According to the general procedure, reaction was performed in the presence of N2H4 (80%, 1.0
mL) and 1a (263 mg, 1.0 mmol) in 1,4-dioxane (5 mL) at rt for 3 h. Purification on silica gel
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(hexanes/EtOAc = 5/1) afforded 6a (95%, 246 mg). Colorless solid; mp = 177-178 C
(recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for C17H13N3Na 282.1007,
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found 282.1003; H NMR (400 MHz, CDCl3): δ 7.87 (br s, 1H), 7.77-7.74 (m, 2H), 7.63-7.61
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(m, 2H), 7.53-7.47 (m, 3H), 7.46-7.42 (m, 3H), 3.54 (s, 2H); C NMR (100 MHz, CDCl3): δ
149.8, 142.2, 135.0, 131.5, 131.0, 130.0, 129.2 (2x), 128.6 (2x), 127.6 (2x), 125.9 (2x), 120.2,
71.8, 24.8; FT-IR (cm-1): 3302, 2195, 1627, 1472, 1339, 772, 693. Single-crystal X-ray diagram:
crystal of 6a was grown by slow diffusion of EtOAc into a solution of 6a in CH2Cl2 to yield
colorless prisms. The compound crystallizes in the monoclinic crystal system, space group P 21/c,
a = 26.157(2) Å, b = 7.4363(5) Å, c = 6.8127(5) Å, V = 1315.79(17) Å3, Z = 4, dcalcd = 1.309
g/cm3, F(000) = 544, 2 range 0.78-26.44o, R indices (all data) R1 = 0.0715, wR2 = 0.0457.
3,6-bis(4-fluorophenyl)-2,5-dihydropyridazine-4-carbonitrile (6b).
According to the general procedure, reaction was performed in the presence of N2H4 (80%, 1.0
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mL) and 1b (299 mg, 1.0 mmol) in 1,4-dioxane (5 mL) at rt for 3 h. Purification on silica gel
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(hexanes/EtOAc = 5/1) afforded 6b (96%, 283 mg). Colorless solid; mp = 204-205 C
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(recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for C17H11F2N3Na
318.0819, found 318.0815; 1H NMR (400 MHz, CDCl3): δ 10.34 (br s, 1H), 7.71 (d, J = 8.8 Hz,
1H), 7.69 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.11 (t, J = 8.8
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Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 3.42 (s, 2H); C NMR (100 MHz, CDCl3): δ 163.3 (d, J =
249.4 Hz), 162.9 (d, J = 247.8 Hz), 148.4 (2x), 139.3, 131.3 (d, J = 3.1 Hz), 130.0 (d, J = 8.3 Hz,
2x), 127.3 (d, J = 8.3 Hz, 2x), 120.3 (d, J = 3.1 Hz), 115.2 (d, J = 22.0 Hz, 2x), 114.8 (d, J = 21.3
Hz, 2x), 68.9, 24.0; FT-IR (cm-1): 3419, 2200, 1648, 1511, 1244, 1026, 999. Single-crystal X-ray
diagram: crystal of 6b was grown by slow diffusion of EtOAc into a solution of 6b in CH2Cl2 to
yield colorless prisms. The compound crystallizes in the monoclinic crystal system, space group
P 21/c, a = 27.100(4) Å, b = 7.4176(12) Å, c = 6.8847(11) Å, V = 1372.8(4) Å3, Z = 4, dcalcd
=
1.429 g/cm3, F(000) = 608, 2 range 0.76-26.47o, R indices (all data) R1 = 0.1825, wR2 = 0.4718.
3,6-Bis(4-methoxyphenyl)-2,5-dihydropyridazine-4-carbonitrile (6c).
According to the general procedure, reaction was performed in the presence of N2H4 (80%, 1.0
mL) and 1c (323 mg, 1.0 mmol) in 1,4-dioxane (5 mL) at rt for 3 h. Purification on silica gel
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(hexanes/EtOAc = 3/1) afforded 6c (94%, 300 mg). Colorless solid; mp = 143-144 C
(recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for C19H17N3O2Na
342.1219, found 342.1215; 1H NMR (400 MHz, CDCl3): δ 7.92 (br s, 1H), 7.67 (d, J = 9.2 Hz,
2H), 7.55 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 9.2 Hz, 2H), 3.85 (s, 3H),
3.84 (s, 3H), 3.48 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 161.6, 149.6, 142.0, 130.5, 129.1 (2x),
127.7, 127.4 (2x), 123.7, 120.8, 114.5 (2x), 113.9 (2x), 70.0, 55.4, 55.3, 24.8; FT-IR (cm-1): 3357,
2192, 1607, 1394, 1256, 1178, 835.
3,6-Di-p-tolyl-2,5-dihydropyridazine-4-carbonitrile (6d).
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According to the general procedure, reaction was performed in the presence of N2H4 (80%, 1.0
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(recrystallized from hexanes and EtOAc); HRMS (ESI, M++H) calcd for C19H18N3 288.1501,
found 288.1493; 1H NMR (400 MHz, CDCl3): δ 8.01 (br s, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.49
(d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 3.49 (s, 2H), 2.40 (s, 6H);
13C NMR (100 MHz, CDCl3): δ 149.8, 142.2, 141.3, 140.1, 132.2, 129.8 (2x), 129.2 (2x), 128.6,
127.4 (2x), 125.8 (2x), 120.6, 70.8, 24.8, 21.4, 21.3; FT-IR (cm-1): 3316, 2193, 1609, 1471, 1338,
1185, 819.
3,6-Bis(3-methoxyphenyl)-2,5-dihydropyridazine-4-carbonitrile (6e).
According to the general procedure, reaction was performed in the presence of N2H4 (80%, 1.0
mL) and 1e (323 mg, 1.0 mmol) in 1,4-dioxane (5 mL) at rt for 3 h. Purification on silica gel
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(hexanes/EtOAc = 3/1) afforded 6e (93%, 297 mg). Colorless solid; mp = 130-131 C
(recrystallized from hexanes and EtOAc); HRMS (ESI, M++H) calcd for C19H18N3O2 320.1399,
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found 320.1393; H NMR (400 MHz, CDCl3): δ 8.06 (br s, 1H), 7.39-7.25 (m, 4H), 7.17-7.11
(m, 2H), 7.02 (dd, J = 2.4, 8.4 Hz, 1H), 6.97 (dd, J = 2.4, 8.4 Hz, 1H), 3.83 (s, 6H), 3.50 (s, 2H);
13C NMR (100 MHz, CDCl3): δ 159.9, 159.7, 149.5, 141.9, 136.4, 132.6, 130.3, 129.5, 120.1,
119.7, 118.4, 116.9, 116.0, 112.9, 110.9, 71.7, 55.4, 55.3, 24.8; FT-IR (cm-1): 3329, 2195, 1580,
1491, 1337, 1234, 785.
3,6-Di(naphthalen-2-yl)-2,5-dihydropyridazine-4-carbonitrile (6f).
According to the general procedure, reaction was performed in the presence of N2H4 (80%, 1.0
mL) and 1f (363 mg, 1.0 mmol) in 1,4-dioxane (5 mL) at rt for 3 h. Purification on silica gel
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(hexanes/EtOAc = 3/1) afforded 6f (90%, 323 mg). Colorless solid; mp = 202-203 C
(recrystallized from hexanes and EtOAc); HRMS (ESI, M++H) calcd for C25H18N3 360.1501,
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found 360.1497; 1H NMR (400 MHz, CDCl3): δ 8.14 (s, 1H), 8.08 (d, J = 9.2 Hz, 2H), 8.04 (s,
1H), 7.97 (d, J = 8.4 Hz, 2H), 7.94-7.90 (m, 2H), 7.89-7.84 (m, 2H), 7.70 (dd, J = 2.0, 8.4 Hz,
1H), 7.59-7.52 (m, 4H), 3.72 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 149.6, 142.0, 134.3, 134.0,
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133.0, 132.9, 132.5, 129.3, 128.8, 128.6, 128.6, 128.3, 127.9, 127.8, 127.7, 127.15, 127.08, 126.6,
126.0, 124.2, 123.6, 122.9, 120.4, 72.5, 24.7; FT-IR (cm-1): 3300, 2193, 1623, 1472, 1400, 820,
731.
2,3,6-Triphenyl-2,5-dihydropyridazine-4-carbonitrile (6g).
Phenylhydrazine (227 mg, 2.1 mmol) was added to a solvent of 1a (263 mg, 1.0 mmol) in 1,4-
dioxane (5 mL) at rt. The reaction mixture was stirred at rt for 3 h, and the solvent was
concentrated. The residue was diluted with water (10 mL) and the mixture was extracted with
EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried, filtered and
evaporated to afford crude product. Purification on silica gel (hexanes/EtOAc = 10/1~5/1)
afforded 7 (90%, 302 mg). Colorless solid; mp = 120-121 oC (recrystallized from hexanes and
EtOAc); HRMS (ESI, M++Na) calcd for C23H17N3Na 358.1320, found 358.1317; 1H NMR (400
MHz, CDCl3): δ 7.93-7.90 (m, 2H), 7.50-7.46 (m, 3H), 7.33-7.27 (m, 5H), 7.23-7.15 (m, 4H),
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7.05-7.01 (m, 1H), 3.60 (s, 2H); C NMR (100 MHz, CDCl3): δ 150.5, 143.5, 143.0, 134.5,
131.7, 130.2, 129.8 (2x), 128.6 (2x), 128.39 (2x), 128.37 (2x), 126.5 (2x), 125.0 (2x), 123.4 (2x),
120.2, 77.0, 26.0; FT-IR (cm-1): 3061, 2195, 1593, 1493, 1337, 759, 695. Single-crystal X-ray
diagram: crystal of 7 was grown by slow diffusion of EtOAc into a solution of 7 in CH2Cl2 to
yield colorless prisms. The compound crystallizes in the triclinic crystal system, space group P -
1, a = 9.9929(2) Å, b = 13.6834(3) Å, c = 14.2187(4) Å, V = 1814.91(8) Å3, Z = 4, dcalcd = 1.227
g/cm3, F(000) = 704, 2 range 1.47-26.39o, R indices (all data) R1 = 0.0651, wR2 = 0.1484.
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Supporting Information
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Spectroscopic data for all compounds and X-ray analysis data of 1f, 6a, 6b and 6g. This
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information is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*Email: mychang@kmu.edu.tw
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors would like to thank the Ministry of Science and Technology of the Republic of China
for financial support (MOST 105-2113-M-037-001). This study is supported partially by
Kaohsiung Medical University “Aim for the Top Universities Grant, grant No. KMU-
TP104PR15”.
REFERENCES
(1) (a) In Comprehensive Heterocyclic Chemistry; Bird, C. W., Cheeseman, G. W. H., Eds.;
Pergamon Press: New York, 1984; Vol. 4. (b) Ferreira, V. F.; de Sousa, M. C. B. V.; Cunha,
A. C.; Pereira, L. O. R.; Ferreira, M. L. G. Org. Prep. Proced. Int. 2001, 33, 4155.
(2) (a) Lai, S.; Zercher, C. K.; Jasinski, J. P.; Reid, S. N.; Staples, R. J. Org. Lett. 2001, 3, 4169.
(b) Ronsheim, M. D.; Hilgenkamp, R. K.; Zercher, C. K. Org. Synth. 2004, Coll. Vol. 10, 526.
(c) Xue, S.; Liu, Y.-K.; Li, L.-Z.; Guo, Q.-X. J. Org. Chem. 2005, 70, 8245. (d) Xue, S.; Li,
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