A short-step synthesis of onychine and the related 4-azafluorenones via hetero diels-alder reaction of 5-substituted isotellurazoles

Article abstract of DOI:10.3987/COM-17-13865

Synthesis of onychine and the related 4-azafluorenones was achieved from 5-substituted isotellurazoles through a two-step procedure involving hetero Diels-Alder reaction with methyl phenylpropiolate and the subsequent Friedel-Crafts ring closure of the re

Full text of DOI:10.3987/COM-17-13865

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HETEROCYCLES, Vol. 96, No. 3, 2018
HETEROCYCLES, Vol. 96, No. 3, 2018, pp. 440 - 451. © 2018 The Japan Institute of Heterocyclic Chemistry
Received, 26th December, 2017, Accepted, 9th February, 2018, Published online, 21st February, 2018
DOI: 10.3987/COM-17-13865
A SHORT-STEP SYNTHESIS OF ONYCHINE AND THE RELATED
4-AZAFLUORENONES VIA HETERO DIELS-ALDER REACTION OF
5-SUBSTITUTED ISOTELLURAZOLES
Yusuke Taneichi, Kazuaki Shimada,* and Toshinobu Korenaga
Department of Chemistry and Biosciences, Faculty of Science and Engineering,
Iwate
University,
Morioka,
Iwate
020-8551,
Japan.
E-mail:
shimada@iwate-u.ac.jp
Abstract – Synthesis of onychine and the related 4-azafluorenones was achieved
from 5-substituted isotellurazoles through a two-step procedure involving hetero
Diels-Alder reaction with methyl phenylpropiolate and the subsequent
Friedel-Crafts ring closure of the resulting pyridine derivatives.
INTRODUCTION
Onychine (1) was isolated as a constituent from Onychopetalum amazonicum, Guatteria dielsiana,
Cleistopholis patens, and so on,1 and recently onychine (1) and the related 4-azafluorenone alkaloids are
widely recognized to possess a variety of important biologically-activities2 as well as the synthetic
importance as the intermediate of other related polycyclic alkaloids such as dielsine (2)3 and
eupolauridine.4 Actually, Koyama reported the first synthesis of onychine in 1979, and since then several
groups attempted the synthesis of onychine (1) and its related compounds by using a variety of
procedures.5 However, these previous procedure commonly required the long-step procedure and the
synthetic efficiency were not satisfactory enough, and especially selective construction of polysubstituted
fused-pyridine core still remains the problem in the synthetic research of these compounds. In the course
of our research work on the synthesis of higher row chalcogen-containing heteroaromatic compounds, we
have recognized the synthetic potentiality of isotellurazoles6 having a tellurium-bridged cisoid
heterodiene substructure along with a weak carbon-tellurium and nitrogen-tellurium bonds and the
enhanced ring strain of the ring systems involving a tellurium atom with a large atomic radius, and we
have already reported a convenient and selective preparation of isotelluraozles bearing various
substituents at the C-3 and C-5 positions,7 selective and efficient construction of substituted pyridines by
using hetero Diels-Alder reactions of isotellurazoles with acetylenic dienophiles as the key step, and the
subsequent construction of polycyclic pyridine alkaloid skeletons through Friedel-Crafts ring closure.8

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441
These successful results envisaged us to a new and straightforward synthesis of onychine (1) and the
related derivatives through a novel hetero Diels-Alder approach of 5-substituted isotellurazoles.
R1
R1
N
O
R1
CO2R3
CO2R3
+
Te
N
A
N
R2
C6H5
C
onychine (1, R1 = Me, R2 = H)
dielsine (2, R1 = Me, R2 = OH)
B
Scheme 1. Retrosynthetic pathway for 4-azafluorenones from 5-substituted isotellurazoles B
The retrosynthetic pathway for the targeted monoalkylated 4-azafluorenones in this research work is
outlined in Scheme 1 in which the synthesis of key intermediate A via hetero Diels-Alder reaction of
isotellurazole B with a phenylpropiolate estes C is involved based on our previously reported
methodology. In this report, we would like to describe a convenient synthesis of onychine (1) and the
related 1-substituted 4-azafluorenones through a concise pathway involving the strategic combination of a
one-pot conversion of alk-2-enals into monosubstituted isotellurazoles B, hetero Diels-Alder reaction of
monosubstituted isotellurazoles B for the regioselective synthesis of substituted pyridine derivatives A,
and the subsequent Friedel-Crafts ring closure of pyridine derivatives A as shown in Scheme 1.
RESULTS AND DISCUSSION
Isotellurazole Te-oxide oligomers 6 were at first prepared through a one-pot three-step procedure starting
from bis(N,N-dimethylcarbamoyl) ditelluride (3) [(1) NaBH4 (2.2 equiv.), (2) alk-2-ynal 4 bearing an
alkyl or aryl group at the substituent R, (3) NH2OSO3H (6.0 equiv.)] without the isolation of
β-(N,N-dimethylcarbamoyltelluro)alk-2-enals 5, and the subsequent deoxygenation of 6 was carried out
by treating with Ph3P (2.0 equiv.) and I2 (1.0 equiv.) at room temperature for a few hours to obtain the
1) NaBH4 (2.2 equiv.)
MeOH
-50 to -35 °C
then
0 °C, 30 min
Ph3P (2.0 equiv.)
I2 (1.0 equiv.)
O
O
R
H
R
H
Te N
6
Me2N
Te Te
3
NMe2
H
O
Te N
CH2Cl2 or CHCl3
0 °C, 1-3 h
2)
R
O
n
7a (R = C6H5)
7b (R = n-C4H9)
7c (R = H)
4
0 °C, 7 h
3) NH2OSO3H (4.4 equiv.)
MeOH, reflux, 1 h
Scheme 2. Synthetic procedure for 5-substituted isotellurazoles
bis(N,N-dimethylcarbamoyl) ditelluride (3)
7
starting from

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HETEROCYCLES, Vol. 96, No. 3, 2018
corresponding isotellurazoles 7 in high yields without the contamination of any byproducts. Especially,
the first preparation of 5-methylisotellurazole 7c (R = Me) was accomplished through this method, and 7c
was isolated as a stable crystalline compound.6 The synthetic procedure for 5-substituted isotellurazoles
7a-c from compound 3 are shown below.
When a toluene solution of 5-substituted isotellurazoles 7a (R = C6H5) or 7b (R = n-C4H9) was treated
with methyl phenylpropiolate (8, 1.5 equiv.) at refluxing temperature for 24 h, the corresponding pyridine
derivatives 11a and 11b were obtained in 99% and 80% yields, respectively, and treatment of 7a with
phenylpropiolonitrile (9) or phenylpropynal (10) also afforded the corresponding pyridine derivatives 12
or 13 in high yields. In contrast, a similar treatment of 5-methylisotellurazole (7c, R = Me) with 8 in
toluene afforded desired pyridine derivative 11c in rather low yield. However, lowering of the
temperature of thermal reaction was effective for improving the yield of 11c by using THF as a solvent in
place of toluene, and after several attempts for optimization of the reaction procedures and conditions, the
yield of 11c was dramatically raised up to 56% yield by heating 7c with 8 (5.0 equiv.) in a sealed tube at
80 °C without the use of any solvents. A similar treatment of 7c with a highly reactive dienophile, i.e.
phenylpropiolonitrile (9) or phenylpropynal (10), afforded the corresponding pyridine derivatives 12c and
Table 1. Synthesis of Pyridine Derivatives 11-13 via Hetero Diels-Alder Reaction of 5-Substituted
Isotellurazoles 7 with a Reactive Acetylenic Dienophile 8-10
R
R
EWG
EWG
C6H5
Δ
+
Te
- Te
N
N
C6H5
7a (R = C6H5)
7b (R = n-C4H9)
7c (R = Me)
8 (EWG = CO2Me)
9 (EWG = CN)
10 (EWG = CHO)
11 (EWG = CO2Me)
12 (EWG = CN)
13 (EWG = CHO)
Substrate
R
Dienophile (8-10)
Solvent
Temp
(°C)
Time
(h)
24
5
Yield (11-13)
(%)
7
EWG
CO2Me
CN
(equiv.)
8 (1.5)
9 (1.5)
10 (1.5)
8 (1.5)
8 (1.5)
8 (5.0)
8 (5.0)
9 (1.5)
10 (1.5)
C6H5
7a
7a
7a
7b
7c
7c
7c
7c
7c
toluene
toluene
toluene
toluene
toluene
THF
reflux
reflux
reflux
reflux
reflux
reflux
80
99 (11a)
80 (12a)
68 (13a)
80 (11b)
10 (11c)
51 (11c)
56 (11c)
80 (12c)
68 (13c)
C6H5
C6H5
n-C4H9
Me
CHO
9
CO2Me
CO2Me
CO2Me
CO2Me
CN
24
24
72
2
Me
Me
neat
Me
toluene
toluene
reflux
reflux
5
Me
CHO
9

HETEROCYCLES, Vol. 96, No. 3, 2018
443
13c in 80% and 68% yields, respectively, and these results suggested that the low yield of 11c from 7c
was attributed to the relatively low reactivity of methyl phenylpropiolate (8) as a dienophile in contrast to
9 and 10 besides the possibility of sublimation of substrate 7c under the heating condition.
Compounds 11a-c were then subjected to Friedel-Crafts cyclization by treating with Lewis acids,10 and in
our cases treatment of 11 with an excess amount of PPA at high reaction temperature (up to 210 °C) for 2
h afforded the best result for the conversion into the corresponding 1-substituted 4-azafluorenone
derivatives 14.8 Especially, the physical and spectral data of product 14c were fully identical in all
respects with those of onychine (1), and this result indicated that the total synthesis of onychine (1) was
achieved successfully through our synthetic procedure involving two step conversion with 42% overall
yield from 5-methylisotellurazole (7c). On the other hand, a similar treatment of pyridine 11a (R = C6H5)
bearing two phenyl groups at the C-2 and C-4 position with PPA afforded a separable mixture of two
1
isomeric products 14a and 14a’ in 10% and 66% yields, respectively. The spectral patterns of H NMR
and 13C NMR spectra of 14a and 14a’ revealed a high similarity with each other. The physical and
spectral data of minor 14a were identical with those of 1-phenyl-4-azafluorenone 14a reported by
Mongin,5u and the structure of major product 14a was confirmed to be 1-phenyl-4-azafluorenone. The
structure of 14a’ was also supported by the data of mass spectrum and elemental analysis. Formation of
the isomeric mixture of 14a and 14a’ was rationalized by the Friedel-Crafts ring closure of acyl cationic
intemetiate with each phenyl group of 11a, and, especially, formation of major product 14a’ was
explained as the regiochemical counterpart of minor product 14a through the preferable ring closure with
the phenyl group attached to the less electron deficient C-4 position of pyridine ring of 11a.
Synthesis of onychine (1) was also attempted by using 3-cyanopyridine derivative 12c (EWG = CN) or
aldehyde 13c (EWG = CHO) as alternative synthetic precursors. However, direct treatment of 12c with
PPA in a similar manner just afforded amide 15c (EWG = CONH2, 61% yield) as a major product besides
the formation of onychine (1) in rather low yield, and the further conversion of 15c into onychine (1) was
unsuccessful at all even by treating with PPA under heating at 200 °C for a long time. On the other hand,
aldehyde 13c was easily converted into carboxylic acid 16c (EWG = CO2H) in 41% yield by treating with
NaClO2.11 Further conversion of 16c into onychine (1) was already reported by Taylor,5a and this result
was also recognized to be a route for the formal synthesis of onychine (1). However, the yield of 16c
remained unsatisfactory to the synthetic level in spite of our efforts for optimization of the reaction
procedure and conditions.

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HETEROCYCLES, Vol. 96, No. 3, 2018
Table 2. Synthesis of 1-Substituted 4-Azafluorenones 14 from Substituted Pyridine Derivatives 11 or 12
R
R
R
N
O
EWG
C6H5
CONH2
C6H5
O
PPA
+
+
Δ
N
N
N
C6H5
11 (EWG = CO2Me)
12 (EWG = CN)
14
15
14'
Substrate
Temp
(°C)
210
Time
Yield (%)
R
EWG
CO2Me
CO2Me
CO2Me
CN
11, 12
11a
(h)
2
14
14’
15
C6H5
C4H9
Me
10 (14a)
70 (14b)
66 (14a’)
-
11b
11c
210
2
-
-
-
-
210
2
77 (14c = 1)
27 (14c = 1)
-
Me
12c
180
4
61 (15c)
Me
N
Me
NaClO2 (2.6 equv.)
NaH2PO4 (3.0 equiv.)
CHO
CO2H
ref. 5a
onychine (1)
t-BuOH, H2O
rt, 3 h
N
16c (41%)
13c
Scheme 3. Alternative formal synthesis of onychine (1) from pyridine derivative 13c
CONCLUSION
In conclusion, we could establish a new two-step synthetic methodology for onychine (1) and related
4-azafluorenones starting from substituted isotellurazoles 7 by using hetero Diels-Alder reaction as the
key step of construction of the alkaloid skeleton. Further applications of our synthetic protocol to the
short-step and regioselective construction of other various pyridine-fused polycyclic alkaloid skeletons
are under way in our laboratory.
EXPERIMENTAL
Instruments:
1
The melting points were determined with a Barnstead International MEL-TEMP. H NMR spectra were
recorded on a Bruker DRX-400P (400 MHz) spectrometer or a Bruker AVANCE III 500 (500 MHz)
1
spectrometer, and the chemical shifts of the H NMR spectra are given in δ relative to internal
tetramethylsilane (TMS). 13C NMR spectra were recorded on a Bruker DRX-400P (100 MHz) or a Bruker
AVANCE III 500 (126 MHz). Mass spectra were recorded on a JEOL JMS-700T mass spectrometer with

HETEROCYCLES, Vol. 96, No. 3, 2018
445
electron-impact ionization at 20 or 70 eV using a direct inlet system. High resolution mass spectra
(HRMS) were also recorded on a JEOL JMS-700T spectrometer. IR spectra were recorded for thin film
(neat) or KBr disks on a JASCO FT/IR-7300 spectrometer. Elemental analyses were performed using a
Yanagimoto CHN corder MT-5.
Starting Materials:
Bis(N,N-dimethylcarbamoyl) ditelluride (1) was prepared from elemental tellurium, sodium metal or
sodium hydride, and N,N-dimethylformamide (DMF), and ynones and ynals (2) were prepared through
Friedel-Crafts type acylation of terminal acetylenic compounds or oxidation of substituted propargyl
alcohols according to the previous papers.12 All other chemicals used in this study were commercially
available.
A
Typical Procedure for Preparation of Isotellurazole Oxide Oligomers from
Bis(N,N-dimethylcarbamoyl) Ditelluride (3) and Alk-2-ynals 4. To a DMF solution of
bis(N,N-dimethylcarbamoyl) ditelluride (3, 398 mg, 1.00 mmol) was added a MeOH solution (5 mL) of
NaBH4 (84 mg, 2.2 equiv.) at -50 °C, and the reaction mixture was then treated with alk-2-ynals 4 (2.2
equiv.) at 0 °C for 7 h. The reaction was quenched by addition of water, and the reaction mixture was
extracted with benzene. The organic layer was washed twice with water and was dried over anhydrous
Na2SO4 powder. The organic solvent was removed in vacuo, and the residual crude products were
subjected to column chromatography on silica gel to obtain Te-alkenyl N,N-dimethyltellurocarbamates 5
in high to moderate yields as yellow crystals. Then, a MeOH solution (10 mL) of compounds 5 was
treated with hydroxylamine-O-sulfonic acid (4.4 equiv.) at reflux temperature for 1 h. The reaction
mixture was cooled to room temperature and was quenched by addition of water, and the crude reaction
mixture was extracted with benzene. The organic layer was washed with water and was dried over
anhydrous Na2SO4 powder. The organic solvent was removed in vacuo, and the residual crude products
were subjected to column chromatography on silica gel to obtain isotellurazole Te-oxide oligomers 6 as
main products besides a small amount of isotellurazoles 7.5c
General Procedure for Deoxygenation of Isotellurazole Te-Oxide Oligomers 6 by Treating with
Ph3P and I2. A CH2Cl2 solution of isotellurazole Te-oxide oligomer 6 (0.349 mmol) was treated with
Ph3P (183 mg, 0.698 mmol, 2.0 equiv.) and I2 (89 mg, 0.349 mmol, 1.0 equiv.) at 0 °C for 3 h. The
reaction was then quenched by addition of saturated aqueous Na2SO3 solution, and the reaction mixture
was extracted with CHCl3. The organic layer was washed with water and was dried over anhydrous
Na2SO4 powder. After removing the organic solvent in vacuo, the crude product was subjected to
purification by using column chromatograph on silica gel to isolate isotellurazole 7.7b
General Procedure for Conversion of Isotellurazoles 5 into Substituted Pyridine Derivatives 11-13.
A toluene or a THF solution of isotellurazole 7 (1.0 mmol) was treated with an acetylenic dienophile

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HETEROCYCLES, Vol. 96, No. 3, 2018
(methyl phenylpropiolate (8), phenylpropiolonitriles (9), or phenypropynal (10), 1.5-5.0 equiv.) at rt or
under heating for several hours, and the reaction mixture was filtered to remove the precipitated elemental
tellurium. After removal of the solvent from the filtrate in vacuo, the residual matter was subjected to
column chromatography on silica gel to obtain the corresponding pyridines 11 (EWG = CO2Me), 12
(EWG = CN), or 13 (EWG = CHO), respectively, in moderate to high yields.
11a (R1 = C6H5, R2 = H, R3 = C6H5, EWG = CO2Me)5w,13: Colorless needles, mp 95.6-96.0 °C; IR (KBr)
3055, 2999, 2945, 1721, 1583, 1569, 1541, 1493, 1450, 1435, 1400, 1316, 1285, 1258, 1131, 1064, 1026,
866, 856, 839, 808, 766, 744, 699, 647, 618, 584, 526 cm-1; 1H NMR (500 MHz, CDCl3) δ 3.47 (3H, s),
7.29 (1H, d, J = 5.0 Hz), 7.39-7.46 (8H, m), 7.62-7.64 (2H, m), 8.75 (1H, d, J = 5.0 Hz); 13C NMR (126
MHz, CDCl3) δ 52.3 (q), 122.8 (d), 128.0 (d), 128.3 (s), 128.4 (d), 128.5 (d), 128.7 (d), 128.8 (d), 128.9
(d), 138.1 (s), 139.7 (s), 148.7 (s), 150.0 (d), 156.9 (s), 169.1 (s).
11b (R1 = n-C4H9, R2 = H, R3 = C6H5, EWG = CO2Me): Colorless oil; IR (neat) 2955, 2932, 2871, 1729,
1
1583, 1571, 1560, 1461, 1440, 1404, 1308, 1287, 1270, 1237, 1132, 1112, 1059, 835, 766, 700 cm-1; H
NMR (500 MHz, CDCl3) δ 0.94 (3H, t, J = 7.5 Hz), 1.39 (2H, sext, J = 7.5 Hz), 1.60-1.66 (2H, m), 2.69
(2H, t, J = 7.5 Hz), 3.64 (3H, s), 7.16 (1H, d, J = 5.0 Hz), 7.38-7.44 (3H, m), 7.58-7.60 (2H, m), 8.61 (1H,
13
d, J = 5.0 Hz); C NMR (126 MHz, CDCl3) δ 13.9 (q), 22.6 (t), 32.7 (t), 32.9 (t), 52.3 (q), 122.7 (d),
128.3 (d), 128.5 (d), 128.7 (d), 128.8 (s), 140.1 (s), 149.9 (d), 150.3 (s), 156.7 (s), 169.4 (s). HRMS Calcd
for C17H19NO2: m/z 269.1416. Found: m/z 269.1420.
11c (R1 = Me, R2 = H, R3 = C6H5, EWG = CO2Me): Colorless oil; IR (neat) 1729, 1584, 1572, 1461,
1
1440, 1401, 1309, 1275, 1241, 1189, 1132, 1107, 1078, 1065, 832, 765, 700, 593 cm-1; H NMR (500
MHz, CDCl3) δ 2.42 (3H, s), 3.66 (3H, s), 7.15 (1H, d, J = 5.0 Hz), 7.38-7.45 (3H, m), 7.57-7.60 (2H, m),
8.59 (1H, d, J = 5.0 Hz); 13C NMR (126 MHz, CDCl3) δ 19.6 (q), 52.4 (q), 123.7 (d), 128.3 (d), 128.5 (d),
128.8 (d), 129.0 (s), 140.1 (s), 145.7 (s), 149.9 (d), 156.7 (s), 169.4 (s). HRMS Calcd for C14H13NO2: m/z
227.0946. Found: m/z 227.0946.
12c (R1 = Me, R2 = H, R3 = C6H5, EWG = CN): Pale yellow oil; IR (neat) 3059, 2223, 1571, 1460, 1440,
1
1396, 837, 794, 750, 698, 591, 430 cm-1; H NMR (500 MHz, CDCl3) δ 2.65 (3H, s), 7.25 (1H, dd, J =
5.0, 0.5 Hz), 7.50-7.54 (3H, m), 7.86-7.89 (2H, m), 8.70 (1H, d, J = 5.0 Hz); 13C NMR (126 MHz,
CDCl3) δ 20.8 (q), 108.5 (s), 116.6 (s), 123.0 (d), 128.6 (d), 129.0 (d), 130.0 (d), 137.6 (s), 151.7 (d),
152.7 (s), 161.6 (s). HRMS Calcd for C13H10N2: m/z 194.0844. Found: m/z 194.0843.
13c (R1 = Me, R2 = H, R3 = C6H5, EWG = CHO): Pale yellow needles, mp 47.0-47.5 °C; IR (KBr) 1691,
1567, 1461, 1441, 1375, 1261, 891, 793, 755, 705 cm-1; 1H NMR (500 MHz, CDCl3) δ 2.68 (3H, s), 7.22
13
(1H, d, J = 5.0 Hz), 7.45-7.56 (5H, m), 8.67 (1H, d, J = 5.0 Hz), 10.0 (1H, s); C NMR (126 MHz,
CDCl3) δ 21.0 (q), 125.7 (d), 128.6 (d), 128.9 (s), 129.5 (d), 130.5 (d), 138.1 (s), 149.5 (s), 151.8 (d),
163.3 (s), 193.7 (d). HRMS Calcd for C13H11NO: m/z 197.0841. Found: m/z 197.0837.

HETEROCYCLES, Vol. 96, No. 3, 2018
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A General Procedure for Conversion of Pyridines 11 into the Corresponding 4-Azafluorenones 14.
Pyridine 11e-g (EWG = CO2Me, 1.0 mmol) was treated with an excess amount of polyphosphoric acid
(PPA) at 210 °C for 4 h. The reaction was then quenched by addition of saturated NaHCO3 aqueous
solution, and the reaction mixture was extracted with CHCl3 for three times. The organic layer was
washed with water, and was dried over anhydrous Na2SO4 powder. After removal of the solvent in vacuo,
the residual matter was subjected to column chromatography on silica gel to obtain the corresponding
4-azafluorenones 14 in high yields.
14a (R1 = C6H5, R2 = H, minor)5u: Pale yellow powder, mp 168.8-169.2 °C; IR (KBr) 1713, 1604, 1585,
1
1552, 1450, 1383, 1347, 1177, 919, 855, 760, 743, 695, 684, 620, 540, 424 cm-1; H NMR (500 MHz,
CDCl3) δ 7.15 (1H, d, J = 5.5 Hz), 7.43 (1H, td, J = 7.5, 1.0 Hz), 7.49-7.50 (3H, m), 7.59-7.62 (3H, m),
7.68 (1H, d, J = 7.5 Hz), 7.89 (1H, d, J = 7.5 Hz), 8.59 (1H, d, J = 5.5 Hz); 13C NMR (126 MHz, CDCl3)
δ 120.9 (d), 124.0 (d), 124.2 (s), 124.9 (d), 128.4 (d), 129.2 (d), 129.8 (d), 131.2 (d), 134.9 (s), 135.0 (s),
135.3 (d), 143.0 (s), 149.2 (s), 153.4 (d), 166.2 (s), 191.3 (s).
14a’ (R1 = C6H5, R2 = H, major): Pale yellow plates, mp 156.1-156.5 °C; MS (m/z) 257 (M+; bp); IR
(KBr) 1716, 1604, 1583, 1572, 1469, 1435, 1344, 1182, 912, 859, 819, 769, 756, 698, 620, 440, 413 cm-1;
1H NMR (500 MHz, CDCl3) δ 7.44-7.46 (2H, m), 7.48-7.51 (3H, m), 7.58 (1H, td, J = 7.5, 1.0 Hz), 7.65
(1H, d, J = 7.5 Hz), 7.70 (1H, d, J = 7.5 Hz), 7.86-7.88 (2H, m), 8.79 (1H, d, J = 5.0 Hz); 13C NMR (126
MHz, CDCl3) δ 114.0 (d), 121.4 (d), 124.6 (s), 124.6 (d), 128.0 (d), 129.8 (d), 129.9 (d), 131.6 (d), 133.9
(s), 134.9 (d), 136.9 (s), 141.3 (s), 153.8 (s), 155.2 (d), 157.8 (s), 192.1 (s). Calcd for C18H11NO: C,
84.03; H, 4.31; N, 5.44%. Found: C, 84.08; H, 4.58; N, 5.40%.
14b (R1= n-C4H9, R2 = H): Pale yellow needles, mp 44.8-45.0 °C; IR (KBr) 2951, 2927, 2861, 1712,
1596, 1562, 1461, 1450, 1389, 1353, 1290, 1258, 1174, 1093, 916, 905, 879, 832, 755, 682, 638, 512
1
cm-1; H NMR (500 MHz, CDCl3) δ 0.96 (3H, t, J = 7.5 Hz), 1.42 (2H, sext, J = 7.5 Hz), 1.61-1.67 (2H,
m), 3.04 (2H, t, J = 7.5 Hz), 6.99 (1H, d, J = 5.0 Hz), 7.42 (1H, td, J = 7.5, 0.5 Hz), 7.58 (1H, td, J = 7.5,
1.0 Hz), 7.69 (1H, d, J = 7.5 Hz), 7.83 (1H, d, J = 7.5 Hz), 8.44 (1H, d, J = 5.0 Hz); 13C NMR (126 MHz,
CDCl3) δ 14.0 (q), 22.6 (t), 30.7 (t), 32.1 (t), 120.8 (d), 123.8 (d), 124.8 (d), 125.6 (s), 130.9 (d), 135.0 (s),
135.1 (d), 143.2 (s), 152.7 (s), 153.1 (d), 165.5 (s), 193.2 (s). Calcd for C16H15NO: C, 80.98; H, 6.37; N,
5.90%. Found: C, 80.98; H, 6.49; N, 5.83%.
14c (R1 = Me, R2 = H)1a,4b,5n: Pale yellow needles, mp 128.7-129.0 °C; IR (KBr) 1705, 1598, 1565, 1384,
920, 878, 829, 759, 681, 583, 505, 433 cm-1; 1H NMR (500 MHz, CDCl3) δ 1.61 (3H, s), 6.94 (1H, d, J =
5.5 Hz), 7.40 (1H, td, J =7.5, 1.0 Hz), 7.56 (1H, td, J = 7.5, 1.0 Hz), 7.66 (1H, d, J = 7.5 Hz), 7.79 (1H, d,
J = 7.5 Hz), 8.39 (1H, d, J = 5.5 Hz); 13C NMR (126 MHz, CDCl3) δ 17.4 (q), 120.8 (d), 123.7 (d), 125.9
(d), 126.0 (s), 130.9 (d), 135.0 (s), 135.1 (d), 143.1 (s), 147.6 (s), 152.9 (d), 165.3 (s), 193.2 (s).

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Procedure for Conversion of Pyridines 12c into the Corresponding 4-Azafluorenones 14c. Pyridine
12c (EWG = CN, 1.0 mmol) was treated with an excess amount of polyphosphoric acid (PPA) at 210 °C
for 4 h. The reaction was then quenched by addition of saturated NaHCO3 aqueous solution, and the
reaction mixture was extracted with CHCl3 for three times. The organic layer was washed with water, and
was dried over anhydrous Na2SO4 powder. After removal of the solvent in vacuo, the residual matter was
subjected to column chromatography on silica gel to obtain the corresponding 4-azafluorenones 14c in
moderate yields along with the formation of amides 15c as the main products.
15c (R1 = Me, R2 = H, R3 = C6H5, EWG = CONH2): Colorless needles, mp 171.2-171.5 °C; IR (KBr)
3330, 3085, 3059, 1673, 1620, 1588, 1430, 1370, 1147, 1132, 1068, 881, 829, 801, 749, 700, 685, 634,
597, 448 cm-1; 1H NMR (500 MHz, CDCl3) δ 2.45 (3H, s), 5.56 (1H, s), 5.83 (1H, s), 7.14 (1H, d, J = 5.0
Hz), 7.40-7.43 (3H, m), 7.68-7.71 (2H, m), 8.51 (1H, d, J = 5.0 Hz); 13C NMR (126 MHz, CDCl3) δ 19.4
(q), 124.0 (d), 128.6 (d), 128.8 (d), 129.0 (d), 131.5 (s), 139.3 (s), 145.9 (s), 149.7 (d), 155.2 (s), 170.7 (s).
HRMS Calcd for C13H12N2O: m/z 212.0950. Found: m/z 212.0956.
Procedure for NaClO2 Oxidation of Pyridine 13c. Pyridine 13c (EWG = CHO, 72 mg, 0.365 mmol)
was solved in a mixed solvent of t-BuOH (3.7 mL) and water (2.6 mL), and the solution was treated with
NaClO2 (86 mg, 0.949 mmol, 2.6 equiv.) and NaH2PO4•2H2O (131 mg, 1.095 mmol, 3.0 equiv.) at rt for
3 h. The reaction was quenched by addition of water and ethyl acetate, and the reaction mixture was
extracted with EtOAc. The organic layer was then washed with water and brine, and was dried over
anhydrous Na2SO4 powder. The organic solvent was evaporated in vacuo to obtain crude pale yellow oil.
The crude products were purified by column chromatography on silica gel to obtain pyridine 16c (EWG =
COOH, 32 mg, 41% yield) as colorless solid.
16c (R1 = Me, R2 = H, R3 = C6H5, EWG = COOH)5a: Colorless solid, mp 204.0-205.0 °C [Lit.14
214.0-216.0 °C]; 1H NMR (500 MHz, DMSO-d6) δ 2.37 (3H, s), 7.34 (1H, d, J = 5.0 Hz), 7.42-7.47 (3H,
m), 7.61-7.64 (2H, m), 8.56 (1H, d, J = 5.0 Hz).
ACKNOWLEDGEMENTS
This work was partially supported by a Grant-in-Aid for Scientific Research (No. 23550039) from the
Ministry of Education, Science, Sports, and Culture of Japan.
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