Synthesis of an annulenoannulenone, 3H-benzo[e]cycl[3.3.2]Azin-3-one

Article abstract of DOI:10.3987/COM-02-9655

A new nitrogen-bridged annulenoannulenone, 3H-benzo[e]cycl[3.3.2]- azin-3-one (10a) was synthesized from the starting phenylpyridine (6) via the reaction of the indolizine derivative (9a) with polyphosphoric acid (PPA) as the key step.

Full text of DOI:10.3987/COM-02-9655

HETEROCYCLES, Vol. 60, No. 2, 2003, pp. 405 - 411
Received, 25th October, 2002, Accepted, 16th December, 2002, Published online, 24th December, 2002
SYNTHESIS OF AN ANNULENOANNULENONE,
3H-BENZO[e]CYCL[3.3.2]AZIN-3-ONE
Yoshiro Matsuda,* Shinya Kohra, Keisuke Katou, Takashi Uemura,
and Kouhei Yamashita
Faculty of Environmental Studies, Nagasaki University, 1-14 Bunkyo-machi
Nagasaki 852-8521, Japan
Abstract - A new nitrogen-bridged annulenoannulenone, 3H-benzo[e]cycl[3.3.2]-
azin-3-one (10a) was synthesized from the starting phenylpyridine (6) via the
reaction of the indolizine derivative (9a) with polyphosphoric acid (PPA) as the
key step.
In view of the interest in heterocyclic annulene1-6 we have previously reported a new nitrogen-bridged
heterocyclic system, cyclazine (cycl[3.2.2]azines,7 benzocycl[3.2.2]azine,8 cycl[3.2.2]azinophanes,9
cycl[3.3.2]azinones,10 cycl[3.3.3]azines,5,6 3H-cycl[3.2.2]azinocycl[3.3.2]azinone,11, 12 cycl[3.2.2]azino-
cycl[3.2.2]azine13). However, there has been no report on the synthesis of the annulenoannulenone, 3H-
benzocycl[3.3.2]azin-3-one (10a). In this paper we wish to report a synthesis of the benzocyclazinones
(10a,b) by the reaction of ethyl 2-phenylindolizine-3-arboxylate derivatives (9a,b) with PPA.
Our first attempt to synthesize 10a from o-bromoacetophenone (1) as the starting compound was fruitless.
o-Bromoacetophenone (1) was allowed to react with N-bromosuccinimide (NBS) in refluxing CHCl3 for
6 h and then the crude dibromide was treated with pyridine, followed by the cyclization of the crude salt
(2) with methyl acetylenecarboxylate (MAC) in DMSO with K2CO3 to give methyl 2’-
bromobenzoylindolizine-1-carboxylate (3) in the yield of 30 % based on 1. Heck reaction14 of 3 using
Pd(OCOCH3)2, Ag2CO3, P(C6H5)3, and tetrabutylanmonium bromide in DMF for 20 h at 100°C under
nitrogen atmosphere gave the undesired indenoindolizine derivative (4). Hydroysis of 4 using 30 %
NaOH in refluxing MeOH for 20 h followed by acidification with 10 % HCl gave the corresponding acid
and then decarboxylation of the acid was conducted by Cu2O in boiling nitrobenzene for 30 h to afford
indenoindolizin-10-one (5) in the yield of 18 % based on 4.
Our further attempt to synthesize 10 from 2-phenylpyridine (6) as the starting compound was fruitful.

Br
O
Br
+
N
Br
1) NBS
COOCH3
N
MAC
base
COOCH3
N
-
CH3
Br
CH2
2) pyridine
O
Heck Reac.
O
O
3
1
2
3
4
2
4
1
N
5
O
10
1) NaOH
2) HCl
6
9
3) Cu2O
7
8
5
BrCH2COOC2H5
MAC or 8
-
PPA
+
R1
R2
Br
N
N
N
N
base
CH2COOC2H5
R
COOC2H5
O
6
10
7
9
R2
H
R1
R
a
b
a
H
COOCH3
Scheme 1
b
SCH3
SCH3
CN
7
8
6
9.20
9
8
7
5
H-6
H-7
7.67
N
1
2
H-8 H-2
H-1
7.25
4
7.94
7.47
8.12
3
7.80
(CDCl3)
8.05
8
O
11
9
7
9.20
10
9
8
H-5,6
7.80
7
H-1
H-10
H-4
H-7
H-8
H-9
1
6
5
N
H-2
2
8.20
8.50
8.78
8.13
7.96
3
7.63
(CDCl3)
7.12
4
O
10a
7
10
7
9.20
9
8
6
8 9
11
H-11
H-2
H-10
H-9
H-1
1
5
N
N
8.17 8.10
8.20
7.13
7.86 7.84
7.63
8.40
7.37
2
(CDCl3)
4
8.15
3
O
12
7
8
9.20
9
H-9
H-10
H-8
H-5,6
8.27
H-1
H-2
H-4
H-7
N
+
8.64
9.06
7.86
8.76
ppm
8.60
9.17
8.99
OD
(CDCl3 / F3CCOOD)
10a'
Figure 1 Chemical Shifts of 10a, 10a', 11, and 12

2-Phenylpyridine (6) was reacted with ethyl bromoacetate for 5 h at 100°C, followed by the cyclization15
of the crude product (7) with MAC and K2CO3 in DMF at room temperature or 7 and 3,3-bis(methylthio)-
2-benzenesulfonylacrylonitrile (8) with N(C2H5)3 in refluxing EtOH to give the corresponding indolizine
derivatives (9a,b). The desired 3H-benzocyclazinones (10a,b) were obtained by the reaction of 9a,b with
PPA for 10 h at 140°C.
The structure of 10a was supported by a satisfactory elemental analysis and the signals of six doublets
(7.12: C1-H, d, J = 4.7 Hz; 7.96: C10-H, d, J = 8.5 Hz; 8.20: C8-H, d, J = 7.3 Hz; 8.13: C2-H, d, J = 4.7 Hz;
8.50: C7-H, d, J = 7.1 Hz; 8.78: C4-H, d, J = 7.8 Hz) in the 1H-NMR spectrum. Benzocyclazinone (10a) is
pale orange crystals and soluble in most of organic solvents giving pale orange solutions. It is stable to
heat, light, and acids. The selected chemical shifts of cyclazinone (11),16 benzocyclazinone (10a), and
cyclazinocyclazinone (12)12 are shown in Figure 1. The chemical shifts clearly show that there is the
decreasing order of diatropicity of the cyclazinones (12 > 11 > 10a). Thus, the diatropicity of a
cyclazinone ring is considerably decreased by fusion of a benzene ring and fusion of a second cyclazine
increases the diamagnetic ring current of the cyclazinone ring. On the other hand we reported the
synthesis of cycl[3.2.2]azinocycl[3.2.2]azine (13).13
Then we pointed out that the diatropicity of a
cycl[3.2.2]azine ring is considerably increased by
N
N
N
N
fusion of a benzene ring; benzocycl[3.2.2]azine
(14)8 to a more extent than cycl[3.2.2]azine (15),17
13
14
15
and fusion of
a
second cycl[3.2.2]azine;
Scheme 2
cyccl[3.2.2]azinocycl[3.2.2]azine (13) also induces
the diamagnetic ring current of the cycl[3.2.2]azine ring, although to a more extent than benzene. Thus
there is the decreasing order of diatropicity of the cycl[3.2.2]azines (13 > 14 > 15). The reasons for
difference of the decreasing order of diatropicity between the cyclazines and the cyclazinones are unclear
at present time. As pointed out in previous papers,10, 12, 18 the diamagnetic ring current is increased when
cyclazinones are protonated. Thus, when 10a is dissolved in CDCl3 with CF3COOD, the chemical shifts
of 10a’ appear at a lower field as compared with 10a. Furthermore, we are in the process of preparing
other cyclazines with the hope of expanding understanding of these interesting compounds.
EXPERIMENTAL
Melting points were determined with a Mitamura Mel-Temp and are uncorrected. IR spectra were
recorded in KBr pellets on a FT/IR-430 (JASCO) spectrophotometer. UV spectra were recorded on a UV-
1
13
310 (Shimadzu) spectrophotometer. H-NMR and C-NMR spectra were obtained on a Gemini 300
(VARIAN) and a VARIAN UNITY plus 500 (VARIAN) spectrometers with tetramethylsilane as an

internal standard. Chemical shifts are reported in parts per million (d). Elemental analyses (C,H,N) of all
compounds described here were performed on a Yanagimoto MT-2 CHN recorder.
Methyl 3-(2-bromobenzoyl)indolizine-1-carboxylate (3)
A mixture of 2-bromoacetophenone (1.00 g, 5 mmol) and NBS (0.89 g, 5 mmol) in CHCl3 (20 mL) was
refluxed for 6 h. The reaction mixture was washed with 5% aq. Na2CO3 (10 mL), dried (Na2SO4, 1 g), and
evaporated under reduced pressure to give 2,2’-dibromoacetophenone. To a solution of crude 2,2’-
dibromoacetophenone in acetone (5 mL) was added dropwise pyridine (0.4 g, 5 mmol) at 0 °C and the
mixture was stirred for a day at rt. The resulting salt (2) was collected by filtration and washed with
acetone. A mixture of the crude salt (2), MAC (0.40 g, 5 mmol), and K2CO3 (0.69 g, 5 mmol) in DMSO
(30 mL) was stirred for 3 days at rt. The mixture was poured into ice-water and the resulting precipitate
was collected by filtration, washed with water, and dried to give 3.
3: mp 147-149 °C (MeOH), yield 0.54 g, 30 % (based on 1). IR (KBr) 1615 (CO), 1698 (CO) cm-1; UV
1
(EtOH) lmax (log e) 235 (4.26), 255 (4.07), 278 (4.23), 328 (3.90), 361 (4.17) nm; H-NMR (CDCl3)
3.88 (3H, s, CH3), 7.17 (1H, t, J = 6 Hz, C6-H), 7.35-7.55 (3H, m, Ar-H ), 7.49 (1H, s, C2-H), 7.68 (1H, d,
J = 8 Hz, C6’-H), 8.41 (1H, t, J = 9 Hz, C8-H), 10.05 (1H, d, J = 7 Hz, C5-H). Anal. Calcd for
C17H12NO3Br: C, 57.00; H, 3.38; N, 3.91. Found: C, 57.26; H, 3.64: N, 3.79.
Methyl indeno[1,2-b]indolizin-10-one-5-carboxylate (4)
A mixture of 3 (1.07g, 3 mmol), Pd(OCOCH3)2 (0.07 g, 0.6 mmol), P(C6H5)3 (0.31 g, 1.2 mmol), Ag2CO3
(1.65 g, 6 mmol), and (C4H9)4NBr (0.58 g, 1.8 mmol) in DMF (60 mL) under the nitrogen atmosphere
was stirred for 20 h at 100 °C. After filtration, the mixture was evaporated under reduced pressure. The
residue was submitted to column chromatography on silica gel. From a fraction of benzene: CHCl3 (1:1),
4 was obtained.
4: mp 201-202 °C (MeOH), yield 0.35 g, 43 %. IR (KBr) 1680 (CO), 1709 (CO) cm-1; UV (EtOH) lmax
1
(log e) 223 (4.00), 240 (3.97), 272 (4.08), 300 (3.99), 320 (3.85), 335 (3.89), 445 (3.07) nm; H-NMR
(CDCl3) 4.01 (3H, s, CH3), 6.98 (1H, t, J = 6.6 Hz, C2-H), 7.20 (1H, t, J = 7.1 Hz, C7-H), 7.27 (1H, dd, J
= 6.6, 9.0 Hz, C3-H), 7.33 (1H, t, J = 7.1 Hz, C8-H), 7.43 (1H, d, J = 7.1 Hz, C6-H), 7.85 (1H, d, J = 7.1
Hz, C9-H), 8.23 (1H, d, J = 9.0 Hz, C4-H), 8.59 (1H, d, J = 6.6 Hz, C1-H). Anal. Calcd for C17H11NO3: C,
73.64; H, 4.00; N, 5.05. Found: C, 73.48; H, 4.17; N, 5.02.
Indeno[1,2-b]indolizin-10-one (5)
A mixture of 4 (0.83 g, 3 mmol) and 30 % aq. NaOH (17 mL) in MeOH (15 mL) was refluxed for 20 h.
The mixture was poured into ice-water and acidified to litmus with 10 % HCl (20 mL). The resulting
precipitate was collected by filtration, washed with water, and dried to give the acid. A mixture of the
crude acid and Cu2O (0.3 g) in nitrobenzene (60 mL) was refluxed for 30 h. The mixture was evaporated
under reduced pressure. The residue was submitted to column chromatography on silica gel. From a

fraction of benzene: CHCl3 (5 :1), 5 was obtained in the yield of 18 % (0.12 g) based on 4.
5: mp 185-187 °C (MeOH); IR (KBr) 1666 (CO) cm-1; UV (EtOH) lmax (log e) 262 (4.61), 278 (4.38),
1
288 (4.42), 326 (4.09), 337 (4.06), 441 (3.93) nm; H-NMR (CDCl3) 6.34 (1H, s, C5-H), 6.77 (1H, t, J
=6.9 Hz, C2-H), 6.96 (1H, dd, J = 6.9, 8.9 C3-H), 7.12 (1H, t, J = 7.3 Hz, C8-H), 7.17 (1H, d, J = 7.3 Hz,
C6-H), 7.23 (1H, t, J = 7.3 Hz, C7-H), 7.36 (1H, d, J = 8.9 Hz, C4-H), 7.39 (1H, d, J = 7.3 Hz, C9-H), 8.46
(1H, d, J = 6.9 Hz, C1-H); 13C-NMR (CDCl3) 96.1, 114.7, 119.9, 120.7, 123.0, 123.4, 127.0, 128.4, 132.2,
137.8, 141.0, 144.9, 171.6, 178.1. Anal. Calcd for C15H9NO: C, 82.18; H, 4.14; N, 6.39. Found: C, 81.93;
H, 4.13; N, 6.37. MS m/z 219.
Ethyl 1-cyano-2-methylthio-4-phenylindolizine-3-carboxylate (9b)
A mixture of 2-phenylpyridine (6) (15.5g, 0.1 mol) and ethyl bromoacetate (16.7 g, 0.1 mol) was heated
for 5 h at 100 °C to give the salt (7). The mixture of the crude salt (7), 8 (28.5 g, 0.1 mol) and N(C2H5)3
(20.2 g, 0.2 mol) in EtOH (200 mL) was refluxed for 10 h, after which the mixture was evaporated under
reduced pressure and the residue was poured into ice-water. The mixture was extracted with CHCl3
(3x100 mL) and the combined extracts were washed with water, dried (Na2SO4, 10 g), and evaporated
under reduced pressure. The residue was then submitted to column chromatography on silica gel. From a
fraction of benzene-CHCl3 (5 : 1), the product (9b) was obtained.
9b: mp 134-137 °C (EtOH), yield 5.7 g, 17 % based on 6. IR (KBr) 1700 (CO), 2211 (CN) cm-1; UV
1
(EtOH) lmax (log e) 240 (4.35), 270 (4.39), 347 (3.94) nm; H-NMR (CDCl3) 1.04 (3H, t, J = 7.4 Hz,
CH2CH3), 2.73 (3H, s, SCH3), 3.61 (2H, q, J = 7.4 Hz, CH2CH3), 6.83 (1H, d, J = 7.4 Hz, C8-H), 7.35 (1H,
dd, J = 7.4, 8.8 Hz, C7-H), 7.42-7.51 (5H, m, Ar-H), 7.63 (1H, d, J = 8.8 Hz, C6-H). Anal. Calcd for
C19H16N2O2S: C, 67.84; H, 4.79; N, 8.33. Found: C, 67.66; H, 4.87; N, 8.08.
3H-Benzo[e]cycl[3.3.2]azin-3-one (10a)
A mixture of 2-phenylpyridine (6) (1.55 g, 10 mmol) and ethyl bromoacetate (1.67 g, 0.1 mol) was heated
for 5 h at 100 °C to give the salt (7). A mixture of the crude salt (7), MAC (8.4 g, 10 mmol), and K2CO3
(1.38 g, 10 mmol) in DMSO (50 mL) was stirred for 3 days at rt. The mixture was poured into ice-water
and extracted with CHCl3 (3x100 mL). The extract was dried (Na2SO4, 10 g) and evaporated to give oily
compound (9a). A mixture of the oily compound (9a) and PPA (100 mL) was heated for 10 h at 140°C.
The mixture was poured into ice and made basic to litmus with K2CO3. The mixture was extracted with
CHCl3 (3x100 mL). The extract was dried (Na2SO4, 10 g) and evaporated. The residue was submitted to
column chromatography on silica gel. From a fraction of benzene: CHCl3 (6:1), 10a was obtained in the
yield of 12 % (0.26 g) based on 6.
10a: mp 179-180 °C (MeOH); IR (KBr) 1618 (CO) cm-1; UV (EtOH) lmax(log e) 235 (4.48), 259 (4.62),
273 (4.58), 313 (3.47), 365 (3.89), 405 (4.19), 426 (4.31) nm; 1H-NMR (CDCl3) 7.12 (1H, d, J =4.7 Hz,
C1-H), 7.63 (1H, dd, J =7.3, 8.5 Hz, C9-H), 7.77-7.83 (2H, m, C5,6-H), 7.96 (1H, d, J = 8.5 Hz, C10-H),

8.13 (1H, d, J = 4.7 Hz, C2-H), 8.20 (1H, d, J = 7.3 Hz, C8-H), 8.50 (1H, d, J = 7.1 Hz, C7-H), 8.78 (1H, d,
J = 7.8 Hz, C4-H); 1H-NMR (F3CCOOD in CDCl3) 7.86 (1H, d, J =5.8 Hz, C1-H), 8.22-8.32 (2H, m, C5,6-
H), 8.60 (1H, t, J = 8.3 Hz, C9-H), 8.64 (1H, d, J = 8.3 Hz, C10-H), 8.76 (1H, d, J = 5.8 Hz, C2-H), 8.99
13
(1H, d, J = 7.7 Hz, C7-H), 9.06 (1H, d, J = 8.3 Hz, C8-H), 9.17 (1H, d, J = 7.1 Hz, C4-H); C-NMR
(CDCl3) 107.9, 112.2, 118.9, 120.5, 122.8, 123.3, 124.9, 126.8, 128.7, 128.9, 129.9, 131.1, 132.9, 136.6,
170.0. Anal. Calcd for C15H9NO: C, 82.18; H, 4.14; N, 6.39. Found: C, 82.26; H, 4.43; N, 6.43. MS m/z
219.
2-Methylthio-3H-benzo[e]cycl[3.3.2]azin-3-one (10b)
A mixture of 9b (0.34 g, 1 mmol) and PPA (10 mL) was heated for 10 h at 140°C. The mixture was
poured into ice-water and alkalized to litmus with K2CO3. The mixture was extracted with CHCl3 (3x20
mL). The extract was dried (Na2SO4, 1 g) and evaporated. The residue was submitted to column
chromatography on silica gel. From a fraction of benzene: CHCl3 (6:1), 10b was obtained in the yield of
34 % (0.09 g).
10b: mp 215-217 °C (MeOH); IR (KBr) 1614 (CO) cm-1; UV (EtOH) lmax(log e) 217 (4.31), 247 (4.63),
272 (4.09), 315 (4.32), 394 (4.00), 415 (4.20) nm; 1H-NMR (CDCl3) 2.68 (3H, s, SCH3), 6.88 (1H, s, C1-
H), 7.67 (1H, t, J = 8 Hz, C9-H), 7.82-7.90 (3H, m, C5,6,10-H), 8.17 (1H, d, J = 8 Hz, C8-H), 8.57 (1H, d, J
= 6.6 Hz, C7-H), 8.83 (1H, d, J = 6.8 Hz, C4-H). Anal. Calcd for C16H11NOS: C, 72.43; H, 4.18; N, 5.28.
Found: C, 72.61; H, 4.05; N, 5.16
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