Synthesis of 2-arylamino-1-azaazulenes

Article abstract of DOI:10.3987/COM-16-S(S)48

A series of 2-arylamino-1-azaazulenes were synthesized by the Buchwald-Hartwig cross coupling reaction. The resulting compounds were characterized by¹H NMR,¹³C NMR, HRMS analyses, and elemental analysis. X-Ray crystallographic analysis revealed that 2-(1-naphthylamino)-1-azaazulene exists in dimeric form with two intermolecular N-H...N hydrogen bonds in its crystal structure.

Full text of DOI:10.3987/COM-16-S(S)48

624
HETEROCYCLES, Vol. 95, No. 1, 2017
HETEROCYCLES, Vol. 95, No. 1, 2017, pp. 624-635. © 2017 The Japan Institute of Heterocyclic Chemistry
Received, 29th August, 2016, Accepted, 17th October, 2016, Published online, 15th December, 2016
DOI: 10.3987/COM-16-S(S)48
SYNTHESIS OF 2-ARYLAMINO-1-AZAAZULENES
Satoru Tsukada,* Makoto Nakazawa, Yuya Okada, Keito Ohtsu, Noritaka
Abe, and Takahiro Gunji
Department of Pure and Applied Chemistry, Faculty of Science and Technology,
Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba 278-8510, Japan
E-mail: tsukada@rs.tus.ac.jp
Abstract – A series of 2-arylamino-1-azaazulenes were synthesized by the
Buchwald-Hartwig cross coupling reaction. The resulting compounds were
1
13
characterized by H NMR, C NMR, HRMS analyses, and elemental analysis.
X-Ray crystallographic analysis revealed that 2-(1-naphthylamino)-1-azaazulene
exists in dimeric form with two intermolecular N–H…N hydrogen bonds in its
crystal structure.
Nitrogen-containing heteroaromatic compounds are one of the most popular and important class of
organic compounds studied in different fields of modern day research. Azaazulenes are the structural
isomers of quinoline and the heteroatomic analogues of azulene. In particular, 1-azaazulenes exhibit
1
remarkable physical and chemical properties such as a large dipole moment (µ = 3.05 D), unique
2
-5
reactivity, and potential biological activities. In recent years, 2-amino-1-azaazulene derivatives have
6
,7
7,8
been studied as
-arylamino-1-azaazulenes are potentially bioactive and hence deserve more attention from the scientific
community. However, there are limited reports on the synthesis, and chemical and physical properties.
a
ligand for metal ions,
and as anticancer agents.
Especially,
2
6
,8-12
2
-Arylamino-1-azaazulenes were synthesized by only amination of 2-halo-1-azaazulenes.
The
arylation of 2-amino-1-azaazulenes have not been investigated. Here we report the synthesis of a novel
series of 2-arylamino-1-azaazulenes via Buchwald-Hartwig cross coupling, along with the study of their
UV-Vis absorption properties. The arylations of 2-amino-1-azaazulenes were not succeeded under the
same condition of amination of 2-haloazaazulenes. We found that 2-arylamino-1-azaazulenes were
successfully synthesized by Buchwald-Hartwig cross coupling using phosphine ligand such as Xantphos
and BINAP.
All 2-arylamino-1-azaazulenes were successfully synthesized by the Buchwald-Hartwig cross coupling
reaction of aryl halide and arylamine. 1a was synthesized by using a slightly modified version of the
Dedicated to Prof. Dr. Masakatsu Shibasaki on the occasion of his 70th birthday

HETEROCYCLES, Vol. 95, No. 1, 2017
625
6
,8
method in our previous work. The reaction of 2-bromo-1-azaazulene 2a and 2-aminoazulene 3 in the
1
3
presence of Pd (dba) , Xantphos (9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene), Cs CO , and
2
3
2
3
1
8-crown-6 (Scheme 1) gave 1a in 24% yield. In this reaction, 1-(1-azaazlulen-2-yl)-2-aminoazulene 4
was also obtained in 18% yield. Under a non-catalytic condition, both 1a and 4 could not be obtained.
This result indicated that 4 was generated as by-product of Pd catalyzed cross coupling reaction. However,
only 32% of product yield was obtained when the same reagent system was applied for the synthesis of
1
b. In an attempt to enhance the product yield, the palladium catalyst and phosphine ligand were changed
1
4
to Pd(dppf)Cl and BINAP (2,2’-bis(diphenylphosphino)-1,1’-binaphthyl). Under these reaction
2
conditions, 1b was obtained in 70% yield. 1c was also obtained in 30% yield by using the same catalyst
and ligand (Scheme 2). 2-Arylamino-1-azaazulenes 6, 8, 10, and 12 were synthesized under the
conditions similar to those used for 1a, in 26%, 13%, 28%, and 51% yields, respectively (Scheme 3–5).
1
b, 1c, and 8 could be also synthesized under a non-catalytic reaction in 9%, 3%, and 75% yields,
respectively. On the other hands, 6, 10, and 12 were not obtained by a non-catalytic reaction. Therefore,
the Buchwald-Hartwig cross coupling reaction of 2-aminoazaazulene was useful for synthesis of
1
2
2
-arylamino-1-azaazulenes. We note that 8 was already synthesized by another method.
Scheme 1
Scheme 2
Pd (dba) , Xantphos, Cs CO
2
3
2
3
NH
18-crown-6, THF
N
NH2
+
Br
N
reflux, 24 h
2d
5
6 : 26%
Scheme 3

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HETEROCYCLES, Vol. 95, No. 1, 2017
Pd (dba) , Xantphos, Cs CO
3
2
3
2
1
8-crown-6, 1,4-dioxane
NH
Cl
+
H N
N
2
N
reflux, 24 h
2e
7
8 : 13%
Scheme 4
Pd (dba) , Xantphos, Cs CO
3
R2
2
3
2
18-crown-6, 1,4-dioxane
R1
NH
Ar
10 : Ar = 1-naphthyl 28%
NH2
+
N
N
reflux, 24 h
2
d
1
2
9
1
: R = H, R = Br
12 : Ar = 2-naphthyl 51%
1
2
1 : R = Br, R = H
Scheme 5
Figure 1. (a) ORTEP drawings of 10 with thermal ellipsoids at the 50% probability level. (b) Packing
structure of 10. Hydrogen bonds are displayed as broken lines. Selected bond lengths (Å): C1–N1
1
.3629(13), C1–N2 1.3530(14), C2–N2 1.4179(13), N2–H1 0.915(14).
Table 1. Summary of crystal data of 10
Empirical formula
Formula weight
Crystal system
Space group
a / Å
C H N
2
270.32
Orthorhombic
Pbca
21.558(2)
10.2034(11)
19.017(2)
3793.9(7)
8
T / K
Dcalcd / g cm
103
1
9
14
-
3
1.293
0.077
1136
13851
2549
0.0340
0.0887
1.040
-
1
µ (Mo K
F (000)
Reflection collected
Independent reflections
R1 (I > 2σ(I))
α
) / mm
b / Å
c / Å
V / Å
3
wR2 (all data)
Goodness of fit on F
2
Z
The molecular structure of 10 was successfully determined by single-crystal X-ray diffraction analysis
Figure 1 and Table 1). To the best of our knowledge, this is the first report of the crystal structure of
-arylamino-1-azaazulenes. Single crystals of 10 were obtained by recrystallization from ethyl acetate at
(
2

HETEROCYCLES, Vol. 95, No. 1, 2017
627
room temperature. The azaazulene core and amino group including the hydrogen on the N atom are
highly planar. The dihedral angle between the plane of the azaazulene core and the naphthalene ring is
5
1.62°. The C1–N1 (1.3629(13) Å) and C1–N2 (1.3530(14) Å) bonds are slightly longer than the C2–N2
1
5
bond (1.4179(13) Å) and comparable to the aromatic C–N bond such as that in pyridine. The
aminoazaazulene unit forms two intermolecular N2–H…N1 hydrogen bonds (1.989 Å) between the two
1
6-18
monomers (Figure 1b). In other words, 10 exists as a dimer in crystal state. The CH…π interactions
between H on C8 of the azaazulene and naphthalene ring seems to be exist in a dimer form.
UV-Vis absorption spectra of 2-arylamino-1-azaazulenes and 2d are shown in Figure 2. In comparison to
d, all 2-arylamino-1-azaazulenes showed a large molar extinction coefficient ε and redshift. For example,
2
the longest absorption wavelength of 1a red-shifted by about 50 nm compared with that of 2d. This
indicates the delocalization of the π electrons on azaazulene and the amine through two tautomeric forms
6
1
a and 1a’ (Scheme 6). This type of tautomerism is known for bis(1-azaazulen-2-yl)amines. We
observed that red shift of absorption spectrum of 1a by addition of hydrochloric acid to methanol solution
of 1a. This result also indicated that the existence of the two tautomeric forms. The details of tautomerism
and pKa values are currently under investigation. The ε value for ethyl ester-substituted 1b at 440 nm,
which is the absorption maximum in the visible region, is about 1.5 times larger than that for 1a and 1c
(Figure 2a), and about 2 times larger than that for other 2-arylamino-1-azaazulenes (Figure 2b).
Figure 2. UV-Vis spectra of (a) 1a–1c and 2d and (b) 1a, 2d, 6, 8, 10, and 12 in THF
Scheme 6

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HETEROCYCLES, Vol. 95, No. 1, 2017
In summary, a series of 2-arylamino-1-azaazulenes were successfully synthesized in moderate to yields.
X-Ray crystallographic analysis of 10 reveals a highly planar structure that straddles the azaazulene core
and amino group including the hydrogen on the N atom. Moreover, the plane of the azaazulene core and
the naphthalene ring is twisted. As per the crystal structure, 10 forms a dimer with two intermolecular N–
H…N hydrogen bonds. The UV-Vis absorption spectra of the 2-arylamino-1-azaazulenes show a large ε
and redshift compared with the case of amino azulene 2d, in the visible region. Additionally, ε of the
ethyl ester-substituted 1b is larger than that for 1a, 1c, and other 2-arylamino-1-azaazulenes.
EXPERIMENTAL
Unless otherwise indicated, all reactions were carried out under argon atmosphere. All solvents were
distilled, dried over 3Å or 4Å molecular sieves, and degassed using nitrogen before use. Column
chromatography was performed using Wako gel C-200 (spherical, neutral). Aniline, Cs CO , 18-crown-6,
2
3
and BINAP were purchased from Wako Pure Chemical Industries. 1-Naphthylamine,
-bromonaphthalene, and Xantphos were purchased from Tokyo Chemical Industry Co. Ltd. Pd (dba)3
2
2
was purchased from Strem Chemicals Inc. Pd(dppf)Cl was purchased from Sigma-Aldrich. 1,4-Dioxane
2
and THF were purchased from KANTO Chemicals.
All NMR spectra were recorded on a JEOL ECP-300 (300 MHz) or ECP-500 (500 MHz) spectrometer.
1
13
1
H NMR (300 or 500 MHz) and C-{ H} NMR (75 or 126 MHz) spectra were recorded using
tetramethylsilane as an internal standard. IR spectra were recorded with a JASCO FT-IR 6100
spectrometer, and UV-Vis-near infrared (NIR) spectra were recorded with a JASCO V670 spectrometer.
Melting points were recorded using a Bibby Stuart Scientific SMP3 instrument; all melting points
reported are uncorrected. HR-ESI mass spectra were recorded on a JEOL JMS-T100CS AccuTOF CS
spectrometer. Elemental analyses were carried out using a PerkinElmer 2400II CHNS analyzer. Crystal
data were collected using a Bruker AXS SMART APEX CCD X-ray diffractometer equipped with
monochromatic Mo Kα radiation (0.7107 Å). Empirical absorption corrections using equivalent
1
9
reflections and Lorentzian polarization corrections were performed using the SADABS program. All
data were collected with SMART and Bruker SAINTPLUS (Version 6.45) software packages. The
2
0
2
21
structures were solved using the SHELXA-97 program and refined against F by using SHELEXL-97.
Deposition number CCDC-1500558 for compound No. 10. Free copies of the data can be obtained via
http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre,
1
2 Union Road, Cambridge, CB2 1EZ, UK; Fax: +44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).
2
2
23
2
d and 5 were prepared according to literature methods.

HETEROCYCLES, Vol. 95, No. 1, 2017
629
Synthesis of 2a
Compound 2a was synthesized as per the literature method for the synthesis of
2
4
2
-bromo-3-methyl-1-azaazulene.
2
5
A mixture of 1-azaazulenone (0.22 g, 1.5 mmol) and phosphorus(V) oxybromide (1.5g, 5.2 mmol) was
stirred for 30 min at 120 °C. Ice water was added to the reaction mixture, followed by neutralization with
aqueous NaHCO solution. The mixture was extracted with CHCl , and the organic layer was washed
3
3
with water and dried with MgSO . After filtration and evaporation, the crude product was purified by
4
silica gel column chromatography using CHCl as the eluent. The first red fraction to elute from the
3
column was collected. Recrystallization from hexane gave 2,3-dibromo-1-azaazulene 13 as red crystals
(27%). And the second orange fraction to elute from the column was collected. Recrystallization from
hexane gave 2a as orange crystals (20%).
1
2
a: mp 57.0-57.9 °C. H NMR (500 MHz, CDCl ): δ 7.33 (s, 1H), 7.67 (t, J = 9.5 Hz, 1H), 7.77 (t, J = 9.5
3
1
3
1
Hz, 1H), 7.90 (t, J = 9.5 Hz, 1H), 8.45 (d, J = 9.5 Hz, 1H), 8.61 (d, J = 9.5 Hz, 1H). C{ H} NMR (126
MHz, CDCl ): δ 115.8, 130.1, 130.5, 134.4, 135.6, 138.3, 147.1, 147.4, 156.8. HR-MS (HR-ESI-TOF)
3
7
9
+
m/z calc. for C H BrN: 207.9762 [M+H] ; found: 207.9761.
9
7
1
1
3: mp 143.9-144.7 °C. H NMR (500 MHz, CDCl ): δ 7.75 (t, J = 9.5 Hz, 1H), 7.78 (t, J = 9.5 Hz, 1H),
3
1
3
1
7
.95 (t, J = 9.5 Hz, 1H), 8.41 (d, J = 9.5 Hz, 1H), 8.56 (d, J = 9.5 Hz, 1H). C{ H} NMR (126 MHz,
CDCl ): δ 103.7, 130.5, 130.9, 134.8, 136.6, 139.4, 143.2, 148.4, 155.7. HR-MS (HR-ESI-TOF) m/z calc.
3
7
9
81
+
for C H Br BrN: 287.8847 [M+H] ; found: 287.8847.ꢀ
9
6
Synthesis of 2b
2
5
A mixture of ethyl 1,2’-dihydro-2-oxo-1-azaazulene-3-carboxylate (0.33 g, 1.4 mmol) and
phosphorus(V) oxychloride (1.8 g, 11.8 mmol) was stirred for 2 h at 110 °C. Ice water was added to the
reaction mixture, followed by neutralization with aqueous NaHCO solution. The mixture was extracted
3
with CHCl , and the organic layer was dried over Na SO . After filtration and evaporation, the crude
3
2
4
product was purified by silica gel column chromatography using CHCl as the eluent. The first yellow
3
fraction to elute from the column was collected. Recrystallization from hexane gave 2b as yellow crystals
(73%).
1
2
b: mp 84.5-85.5 °C. H NMR (500 MHz, CDCl ): δ 1.46 (t, J = 7.5 Hz, 3H), 4.46 (q, J = 7.5 Hz, 2H),
3
7
.93 (t, J = 9.5 Hz, 1H), 7.96 (t, J = 9.5 Hz, 1H), 8.03 (t, J = 9.5 Hz, 1H), 8.66 (d, J = 9.5 Hz, 1H), 9.52 (d,
1
3
1
J = 9.5 Hz, 1H). C{ H} NMR (126 MHz, CDCl ): δ 14.3, 60.5, 111.7, 133.0, 133.2, 137.1, 137.5, 139.8,
3
3
5
+
1
47.0, 156.7, 158.9, 163.2. HR-MS (HR-ESI-TOF) m/z calc. for C H ClNNaO : 258.0298 [M+Na] ;
12 10 2
found: 258.0298. Anal. Calcd for C H NO Cl: C, 61.16; H, 4.28; N, 5.94. Found: C, 61.00; H, 4.10; N,
1
2
10
2
5
.93.

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HETEROCYCLES, Vol. 95, No. 1, 2017
Synthesis of 2c
Compound 2c was prepared by a slight modification of the literature method.
2
5
2
5
A mixture of 3-cyano-1-azaazulenone (1.20 g, 7.05 mmol) and phosphorus(V) oxychloride (8.20 g, 53.5
mmol) was stirred for 1 h at 115 °C. Ice water was added to the reaction mixture, followed by
neutralization using aqueous NaHCO solution. The mixture was extracted with CHCl , and the organic
3
3
layer was dried over Na SO . After filtration and evaporation, the crude product was purified by silica gel
2
4
column chromatography using CHCl as the eluent. The second yellow fraction to elute from the column
3
was collected. Recrystallization from AcOEt gave 2c as gold needle-like crystals (57%).
1
2
c: mp 231.8-233.0 °C. H NMR (500 MHz, CDCl ): δ 8.03 (t, J = 9.5 Hz, 1H), 8.08 (t, J = 9.5 Hz, 1H),
3
1
3
1
8
.16 (t, J = 9.5 Hz, 1H), 8.70 (d, J = 9.5 Hz, 1H), 8.75 (d, J = 9.5 Hz, 1H). C{ H} NMR (126 MHz,
CDCl ): δ 96.0, 113.3, 133.6, 134.2, 135.2, 138.7, 140.9, 149.3, 156.8, 159.5. HR-MS (HR-ESI-TOF) m/z
3
3
5
+
calc. for C H ClN Na: 211.0039 [M+Na] ; found: 211.0039. Anal. Calcd for C H N Cl: C, 63.68; H,
1
0
5
2
10
5
2
2
.67; N, 14.85. Found: C, 63.45; H, 2.46; N, 14.77.
Synthesis of 2e
2
6
Compound 2e was prepared by a slight modification of the literature method.
2
5
A mixture of 1-azaazulenone (0.20 g, 1.4 mmol) and phosphorus(V) oxychloride (1.8 g, 11.8 mmol) was
stirred for 2 h at 110 °C. Ice water was added to the reaction mixture, followed by neutralization with
aqueous NaHCO solution. The mixture was extracted with CHCl , and the organic layer was dried over
3
3
Na SO . After filtration and evaporation, the crude product was purified by silica gel column
2
4
chromatography using CHCl as the eluent. The first yellow fraction to elute from the column gave 2e as
3
orange crystals (68%).
1
2
e: mp 72.2-73.5 °C. H NMR (500 MHz, CDCl ): δ 7.20 (s, 1H), 7.65 (t, J = 9.5 Hz, 1H), 7.75 (t, J = 9.5
3
1
3
1
Hz, 1H), 7.84 (t, J = 9.5 Hz, 1H), 8.40 (d, J = 9.5 Hz, 1H), 8.55 (d, J = 9.5 Hz, 1H). C{ H} NMR (126
MHz, CDCl ): δ 112.1, 130.1, 130.5, 134.6, 135.7, 138.0, 147.2, 156.2, 157.7. HR-MS (HR-ESI-TOF)
3
3
5
+
m/z calc. for C H ClN: 164.0267 [M+H] ; found: 164.0262. Anal. Calcd for C H NCl: C, 66.07; H,
9
7
9
6
3
.70; N, 8.56. Found: C, 65.93; H, 3.53; N, 8.51.
Synthesis of 3
2
7
Compound 3 was prepared by a slight modification of the reported method.
To
a
solution of KOH (4.0 g), EtOH (5.0 mL), and water (1.0 mL), diethyl
2
8,29
2
-aminoazulene-1,3-dicarboxylate
(0.75 g, 2.65 mmol) was added. The reaction mixture was refluxed
for 30 min with continuous stirring. After cooling to room temperature, the reaction mixture was
neutralized using hydrochloric acid to obtain a yellow precipitate. The yellow solid was filtered out,

HETEROCYCLES, Vol. 95, No. 1, 2017
631
added to pyridine (5 mL), and refluxed for 30 min. After removal of pyridine under reduced pressure, the
crude product was purified by silica gel column chromatography using CHCl as the eluent. The second
3
red fraction to elute from the column was collected and recrystallized from hexane to give 3 as red
3
0
needle-like crystals (82%). Compound 3 can also be synthesized by another method.
1
3
7
1
1
: mp 92.2-93.4 °C. H NMR (500 MHz, CDCl ): δ 4.56 (s, 2H), 6.66 (s, 2H), 7.15 (t, J = 9.5 Hz, 2H),
3
1
3
1
.28 (t, J = 9.5 Hz, 1H), 7.91 (d, J = 9.5 Hz, 2H). C{ H} NMR (126 MHz, CDCl ): δ 102.8, 124.3,
3
+
28.5, 129.8, 141.8, 156.5. HR-MS (HR-ESI-TOF) m/z calc. for C H N: 144.0813 [M+H] ; found:
1
0
10
44.0808. Anal. Calcd for C H N: C, 83.88; H, 6.34; N, 9.78. Found: C, 83.69; H, 6.35; N, 9.88.
1
0
9
General procedure for the synthesis of 2-arylamino-1-azaazulenes
A mixture of the aryl halide (0.20 mmol), arylamine (0.28 mmol), Pd catalyst (6 mol%), phosphine ligand
(4 equiv to Pd), Cs CO (0.24 mmol), and 18-crown-6 (10 mol%) was refluxed in dry THF or 1,4-dioxane
2 3
(6 mL) for 24 h in a sealed tube. Then, 20 mL of brine was added and the resulting mixture was extracted
with CHCl . The combined organic layers were dried over anhydrous Na SO . After filtration and
3
2
4
evaporation, the crude product was purified by silica gel column chromatography using CHCl as the
3
eluent. The product was recrystallized from AcOEt.
Synthesis of 1a
The first red purple fraction to elute from the column gave 4 as a red purple powder (18%). The sixth
dark red fraction to elute gave 1a as a dark red powder (24%).
1
1
a: mp > 212.8 °C (decomp.). H NMR (500 MHz, DMSO-d ) δ 7.11 (s, 1H), 7.21 (t, J = 9.5 Hz, 2H),
6
7
.40 (t, J = 9.5 Hz, 1H), 7.47-7.52 (m, 2H), 7.58-7.63 (m, 1H), 7.65 (s, 2H), 8.13 (d, J = 9.5 Hz, 1H), 8.15
1
3
1
(
d, J = 9.5 Hz, 2H), 8.19-8.23 (m, 1H), 11.07 (s, 1H). C{ H} NMR (126 MHz, DMSO-d ): δ 101.5,
6
1
06.1, 124.2, 127.7, 129.2, 129.4, 130.3, 131.1, 131.5, 131.9, 140.2, 146.9, 149.2, 157.5, 163.6. HRMS
+
(
HR-ESI-TOF) m/z calcd. for C H N : 271.1235 [M+H] , found: 271.1241. Anal. Calcd for C H N : C,
1
9
15
2
19 14
2
8
4
9
1
9
1
1
4.42; H, 5.22; N, 10.36. Found: C, 84.17; H, 5.20; N, 10.20.
1
: mp 172.9-174.6 °C. H NMR (500 MHz, CDCl ): δ 6.69 (s, 1H), 7.16 (t, J = 9.0 Hz, 1H), 7.23 (t, J =
3
.0 Hz, 1H), 7.29 (t, J = 9.0 Hz, 1H), 7.51 (t, J = 9.5 Hz, 1H), 7.57 (t, J = 9.5 Hz, 1H), 7.63 (t, J = 9.5 Hz,
H), 7.82 (d, J = 9.5 Hz, 1H), 7.87 (s, 1H), 8.35 (d, J = 9.0 Hz, 1H), 8.41 (d, J = 9.5 Hz, 1H), 8.57 (d, J =
1
3
1
.0 Hz, 1H) (NH proton was not appeared). C{ H} NMR (126 MHz, CDCl ): δ 105.6, 107.9, 112.4,
3
26.9, 127.6, 127.8, 129.4, 130.4, 130.7, 131.5, 131.7, 132.4, 134.1, 141.6, 146.0, 147.5, 158.5, 160.4,
+
65.3. HR-MS (HR-ESI-TOF) m/z calc. for C H N : 271.1235 [M+H] ; found: 271.1235.
1
9
15
2

632
HETEROCYCLES, Vol. 95, No. 1, 2017
Synthesis of 1b
A reaction mixture was refluxed in THF. The first red fraction to elute from the column gave 1b as a red
powder (70%).
1
1
7
7
1
1
3
b: mp 151.5-153.5 °C. H NMR (500 MHz, CDCl ): δ 1.55 (t, J = 6.5 Hz, 3H), 4.55 (q, J = 6.5 Hz, 2H),
3
.21 (t, J = 9.5 Hz, 2H), 7.44 (t, J = 9.5 Hz, 1H), 7.64 (t, J = 9.5 Hz, 1H), 7.75 (t, J = 9.5 Hz, 1H),
.80-7.84 (m, 3H), 8.22 (d, J = 9.5 Hz, 2H), 8.64 (d, J = 9.5 Hz, 1H), 8.99 (d, J = 9.5 Hz, 1H), 10.54 (s,
1
3
1
H). C{ H} NMR (126 MHz, CDCl ): δ 14.7, 60.7, 99.3, 107.4, 124.4, 131.4, 132.3, 132.9, 133.2, 133.7,
3
33.9, 134.1, 140.6, 146.8, 147.2, 160.6, 164.2, 166.6. HR-MS (HR-ESI-TOF) m/z calc. for C H N O :
2
2
19
2
2
+
-1
43.1447 [M+H] ; found: 343.1448. IR (KBr, ν/cm ): 3469 (N-H), 3272 (Aryl), 2979 (C-H), 1650 (C=O).
Anal. Calcd for C H N O : C, 77.17; H, 5.30; N, 8.18. Found: C, 77.01; H, 5.17; N, 8.12.
2
2
18
2
2
Synthesis of 1c
A reaction mixture was refluxed in 1,4-dioxane. The third yellow brown fraction to elute from the column
gave 1c as a yellow brown powder (30%).
1
1
c: mp > 278.3 °C (decomp.). H NMR (500 MHz, DMSO-d ): δ 7.24 (t, J = 9.5 Hz, 2H), 7.47 (t, J = 9.5
6
Hz, 1H), 7.84 (t, J = 9.5 Hz, 1H), 7.87 (s, 2H), 7.92 (t, J = 9.5 Hz, 1H), 7.98 (t, J = 9.5 Hz, 1H), 8.23 (d, J
1
3
1
=
9.5 Hz, 2H), 8.30 (d, J = 9.5 Hz, 1H), 8.44 (d, J = 9.5 Hz, 1H), 11.35 (s, 1H). C{ H} NMR (126 MHz,
DMSO-d ): δ 81.4, 107.5, 114.9, 124.1, 128.6, 131.6, 132.4, 133.0, 133.7, 134.7, 134.8, 139.6, 148.1,
6
+
1
50.2, 159.0, 162.7. HR-MS (HR-ESI-TOF) m/z calc. for C H N Na: 318.1007 [M+Na] ; found:
2
0
13
3
-
1
3
18.1005. IR (KBr, ν/cm ): 3469 (N-H), 3272, 3138 (Aryl), 3023 (C-H), 2214 (C≡N). Anal. Calcd for
C H N : C, 81.34; H, 4.44; N, 14.23. Found: C, 81.09; H, 4.40; N, 14.16.
2
0
13
2
Synthesis of 6
The fifth dark red fraction to elute from the column gave 6 as a dark red powder (26%).
1
6
: mp > 193.4 °C (decomp.). H NMR (500 MHz, DMSO-d ): δ 7.10 (s, 1H), 7.20 (d, J = 4.0 Hz, 2H),
6
7
.50 (t, J = 4.0 Hz, 1H), 7.52 (t, J = 9.0 Hz, 1H). 7.56 (t, J = 9.0 Hz, 1H), 7.64 (t, J = 9.0 Hz, 1H), 7.99 (d,
J = 9.0 Hz, 2H), 8.18 (d, J = 9.0 Hz, 1H), 8.26 (d, J = 9.0 Hz, 1H), 8.28 (d, J = 9.0 Hz, 2H), 10.74 (s, 1H).
1
3
1
C{ H} NMR (126 MHz, DMSO-d ): δ 103.0, 112.9, 118.2, 128.7, 129.6, 130.1, 130.4, 131.6, 132.5,
6
1
35.4, 136.4, 146.1, 150.4, 158.8, 163.5. HR-MS (HR-APCI-TOF) m/z calc. for C H N : 271.1235
1
9
15
2
+
[
M+H] ; found: 271.1238. Anal. Calcd for C H N : C, 84.42; H, 5.22; N, 10.36. Found: C, 84.37; H,
19 14 2
5
.09; N, 10.31.
Synthesis of 8
The fourth yellow fraction to elute from the column gave 8 as a yellow powder (13%).
1
2

HETEROCYCLES, Vol. 95, No. 1, 2017
633
1
8
: mp 148.8-151.1 °C. H NMR (500 MHz, CDCl ): δ 6.94 (s, 1H), 7.12 (t, J = 7.2 Hz, 1H), 7.34-7.40 (m,
3
1
3
1
4
H), 7.47-7.52 (m, 3H), 7.99 (t, J = 9.5 Hz, 2H) (NH proton was not appeared). C{ H} NMR (126 MHz,
CDCl ): δ 98.5, 119.8, 123.3, 126.7, 128.4, 129.3, 129.7, 130.6, 130.7, 140.3, 148.4, 157.6, 165.2.
3
+
HR-MS (HR-ESI-TOF) m/z calc. for C H N : 221.1079 [M+H] ; found: 221.1076. Anal. Calcd for
1
5
13
2
C H N : C, 81.79; H, 5.49 N, 12.72. Found: C, 81.47; H, 5.43; N, 12.57.
1
5
12
2
Synthesis of 10
The fourth yellow fraction to elute from the column gave 10 as a yellow powder (28%).
1
1
1
8
1
0: mp 195.9-196.9 °C. H NMR (500 MHz, CDCl ): δ 6.70 (s, 1H), 7.36-7.39 (m, 2H), 7.45-7.50 (m,
3
H), 7.51-7.56 (m, 3H), 7.76 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.90-7.94 (m, 3H), 8.18 (d, J =
1
3
1
.0 Hz, 1H) (NH proton was not appeared). C{ H} NMR (126 MHz, CDCl ): δ 98.5, 119.0, 122.0, 125.5,
3
25.7, 126.3, 126.4, 126.5, 128.2, 128.4, 128.5, 129.8, 130.7, 130.8, 134.5, 135.8, 148.3, 157.3, 166.5.
+
HR-MS (HR-ESI-TOF) m/z calc. for C H N : 271.1235 [M+H] ; found: 271.1221. Anal. Calcd for
1
9
15
2
C H N : C, 84.42; H, 5.22; N, 10.36. Found: C, 84.14; H, 5.19; N, 10.29.
1
9
14
2
Synthesis of 12
The fourth yellow fraction to elute from the column gave 12 as a yellow powder (51%).
1
1
2: mp 200.7-202.1 °C. H NMR (500 MHz, CDCl ): δ 7.02 (s, 1H), 7.39-7.46 (m, 3H), 7.47-7.50 (m,
3
1
H), 7.53-7.56 (m, 2H), 7.81 (t, J = 7.0 Hz, 2H), 7.86 (d, J = 8.5 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 8.03
1
3
1
(
dd, J = 2.0, 8.5 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H) (NH proton was not appeared). C{ H} NMR (126
MHz, CDCl ): δ 98.6, 115.4, 120.5, 124.7, 126.7, 126.7, 127.1, 127.7, 129.1, 129.3, 130.2, 130.3, 131.0,
3
1
31.4, 134.2, 137.6, 148.4, 156.6, 164.2. HR-MS (HR-ESI-TOF) m/z calc. for C H N : 271.1235
19 15 2
+
[
M+H] ; found: 271.1234.
ACKNOWLEDGEMENTS
This work was supported by JSPS KAKENHI Grant Number JP24102008, JP16K17951.
REFERENCES
1
.
K. Elblidi, A. Boucetta, B. Benali, A. Kadiri, C. Cazeau-Dubroca, G. Nouchi, and M. Pesquer, J.
Mol. Struct. (Theochem), 1995, 343, 57.
2
3
4
5
.
.
.
.
T. Nishiwaki and N. Abe, Heterocycles, 1981, 15, 547.
N. Abe, Trends Heterocycl. Chem., 2001, 7, 25.
N. Abe, Recent Res. Devel. Org. Bioorg. Chem., 2001, 4, 17.
N. Abe and T. Gunji, Heterocycles, 2010, 82, 201.

634
HETEROCYCLES, Vol. 95, No. 1, 2017
6
7
8
.
.
.
.
E. Yoshioka, K. Koizumi, K. Nakashima, H. Fujii, T. Murafuji, T. Gunji, and N. Abe, Heterocycles,
2
012, 85, 1683.
M. Hyoudou, H. Nakagawa, T. Gunji, Y. Ito, Y. Kawai, R. Ikeda, T. Konakahara, and N. Abe,
Heterocycles, 2012, 86, 233.
K. Koizumi, K. Shimabara, A. Takemoto, S. Yamazaki, N. Yamauchi, H. Fujii, M. Kurosawa, T.
Konakahara, and N. Abe, Heterocycles, 2009, 79, 319.
9
1
1
1
N. Abe, N. Ishikawa, T. Hayashi, and Y. Miura, Bull. Chem. Soc. Jpn., 1990, 63, 1617.
0. E. Yoshioka, K. Koizumi, S. Yamazaki, H. Fujii, and N. Abe, Heterocycles, 2009, 78, 3065.
1. M. Oda, D. Miyawaki, N. Matsumoto, and S. Kuroda, Heterocycles, 2011, 83, 547.
2. H. Fujii, S. Oka, I. Nakamura, Y. Kawai, R. Ikeda, T. Konakahara, and N. Abe, Heterocycles, 2015,
9
0, 715.
1
1
1
3. S. Hillebrand, J. Bruckmann, C. Krüger, and M. W. Haenel, Tetrahedron Lett., 1995, 36, 75.
4. K. Takeda, A. Nakajima, M. Takeda, and E. Yoshii, Org. Synth., 1999, 76, 6.
5. A. Abbotto, L. Beverina, S. Bradamante, A. Facchetti, C. Klein, G. A. Pagani, M. Redi-Abshiro, and
R. Wortmann, Chem. Eur. J., 2003, 9, 1991.
1
1
6. M. Nishio, Phys. Chem. Chem. Phys., 2011, 13, 13873.
7. M. Nishio, Y. Umezawa, J. Fantini, M. S. Weiss, and P. Chakrabarti, Phys. Chem. Chem. Phys.,
2
014, 16, 12648.
1
1
8. O. Takahashi, Y. Kohno, and M. Nishio, Chem. Rev., 2010, 110, 6049.
9. G. M. Sheldrick, SADABS, Program for Siemens Area Detector Absorption Correction, University
of Göttingen, Germany, 1996.
2
2
0. G. M. Sheldrick, SHELXS–97, Program for Crystal Structure Solution, University of Göttingen,
Germany, 1997.
1. G. M. Sheldrick, SHELXL–97, Program for Crystal Structure Refinement, University of Göttingen,
Germany, 1997.
2
2
2. K. Fujimori, N. Hirako, and K. Yamane, Bull. Chem. Soc. Jpn., 1983, 56, 1247.
3. R. N. Mcdonald, J. M. Richmond, J. R. Curtis, H. E. Petty, and T. L. Hoskins, J. Org. Chem., 1976,
4
1, 1811.
2
2
4. K. Koizumi, C. Miyake, T. Ariyoshi, K. Umeda, N. Yamauchi, S. Tagashira, Y. Murakami, H. Fujii,
and N. Abe, Heterocycles, 2007, 73, 325.
5. M. Nagahara, J. Nakano, M. Mimura, T. Nakamura, and K. Uchida, Chem. Pharm. Bull., 1994, 42,
2
491.
2
2
6. T. Nozoe, S. Seto, S. Matsumura, and T. Nakazawa, Chem. Ind. (London), 1954, 1357.
7. T. Nozoe, S. Seto, K. Takase, S. Matsumura, and T. Nakazawa, Nippon Kagaku Zassi, 1965, 86,

HETEROCYCLES, Vol. 95, No. 1, 2017
635
3
46.
2
2
3
8. T. Nozoe, S. Seto, S. Matsumura, and Y. Murase, Bull. Chem. Soc. Jpn., 1962, 35, 1179.
9. T. Nozoe, K. Takase, M. Kato, and T. Nogi, Tetrahedron, 1971, 27, 6023.
0. Y. Sugihara, T. Murafuji, M. Fujinaga, K. Suetake, K. Gyoji, and K. Kurotobi, Synthesis, 2008,
745.
3