Process development of potassium channel opener, TCV-295, based on convenient ring formation of 2H-1,3-benzoxazine and selective N-oxidation of the pyridyl moiety

Article abstract of DOI:10.1016/S0040-4020(01)00728-1

An efficient process for potassium channel opener, TCV-295, based on a novel and convenient 4-(2-pyridyl)-2H-1,3-benzoxazine ring formation from o-hydroxybenzoylpyridine by the NH₄I/piperidine/2,2-dimethoxypropane system and the following selective pyridine-N-oxidation using dimethyldioxirane, has been developed. Additionally, the combination reagent of ammonium halide and sec- or tert- amine conveniently converted o-hydroxyphenyl arylketones with several ketones (or benzaldehyde) to various novel 4-aryl-2H-1,3-benzoxazines.

Full text of DOI:10.1016/S0040-4020(01)00728-1

TETRAHEDRON
Pergamon
Tetrahedron 57 /2001) 7501±7506
Process development of potassium channel opener, TCV-295,
based on convenient ring formation of 2H-1,3-benzoxazine and
selective N-oxidation of the pyridyl moiety
Hideya Mizufune,p Hiroyuki Irie, Susumu Katsube, Tadataka Okada, Yukio Mizuno
and Miichiro Arita
Chemical Development Laboratories, Pharmaceutical Production Division, Takeda Chemical Industries Ltd,
2-17-85 Jusohonmachi, Yodogawaku, Osaka 532 8686, Japan
Received 11 June 2001; accepted 13 July 2001
AbstractÐAn ef®cient process for potassium channel opener, TCV-295, based on a novel and convenient 4-/2-pyridyl)-2H-1,3-benzox-
azine ring formation from o-hydroxybenzoylpyridine by the NH4I/piperidine/2,2-dimethoxypropane system and the following selective
pyridine-N-oxidation using dimethyldioxirane, has been developed. Additionally, the combination reagent of ammonium halide and sec- or
tert- amine conveniently converted o-hydroxyphenyl arylketones with several ketones /or benzaldehyde) to various novel 4-aryl-2H-1,3-
benzoxazines. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
photofading-preventive material 5,3b we also wish to
demonstrate expansion of the novel ring formation using
the convenient ammonium halide/amine system.
TCV-295 1 is the one of a series of 2H-1,3-benzoxazine
derivatives1 having potassium channel-activating activity
expected as therapeutic agents for various diseases such as
hypertension, angina pectoris, asthma and urinary inconti-
nence. In its chemical structure, TCV-295 1 is distinct from
most 2H-1,3-benzoxazines, including potassium channel
openers 22a and 3,2b because the benzoxazine ring is linked
with a pyridyl moiety, as a pendant group, via a carbon±
carbon bond at the 4-position. Therefore, in medicinal
chemistry research, some original synthetic routes to the
novel benzoxazine skeleton were developed.1a
However, from the viewpoint of large-scale preparation of 1
as a drug candidate for further evaluation /e.g. toxicological
and clinical studies), the original synthetic process for 1 has
some drawbacks, such as low yield in the reaction for the
benzoxazine ring formation, use of ammonia gas/acetone
solution in a sealed tube, and also low chemoselectivity
regarding the N-oxidation of the pyridyl moiety. Thus,
herein, we wish to report an ef®cient process, based on a
novel and convenient 2H-1,3-benzoxazine ring formation
using the NH4I/piperidine/2,2-dimethoxylpropane reagent
and the selective pyridine N-oxidation by dimethyldioxir-
ane, to supply the active chemical substances 1. In addition,
because of the usefulness of the 2H-1,3-benzoxazine ring as
various materials, such as photochromic substance 43a and
2. Results and discussion
2.1. Process development of potassium channel opener 1
As shown in Scheme 1, the key intermediate, o-hydroxy-
benzoylpyridine 8, was derived from 5-chlorosalicylic acid
6 via bromination in the Br2/Et3N/CH2Cl2 system at 2708C
and the following coupling reaction with 2-lithiopyridine
generated in situ at 2708C. Despite our modi®cation of
the reaction conditions of the original synthetic method,1a
the synthesis of benzoylpyridine 8 suffered from low yield
Keywords: benzoxazines; ammonium salts; amines; N-oxides; dioxiranes.
Corresponding author. Tel.: 181-6-6300-6378; fax: 181-6-6300-6251;
e-mail: mizufune_hideya@takeda.co.jp
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020/01)00728-1

7502
H. Mizufune et al. / Tetrahedron 57 02001) 7501±7506
Scheme 1.
and the low temperature reaction. Therefore, our attention
was focused on developing a facile process from benzoyl-
pyridine 8 to the target compound 1.
its equivalents, 2,2-dimethoxypropane presented the highest
yield for construction of the 2H-1,3-benzoxazine ring; thus,
it was chosen as the raw material in the large-scale prepara-
tion to give the 2H-1,3-benzoxazine 10a 1.44 kg /82%
yield) without chromatographic puri®cation.
Our ®rst task was to develop a novel and effective ring
formation of 4-/2-pyridyl)-2H-1,3-benzoxazine 10a from
benzoylpridine 8. In the medicinal chemistry process,1a
benzoylpyridine 8 reacted with ammonia-saturated acetone
solution in a sealed tube to give 2H-1,3-benzoxazine 10a in
50% yield using chromatographic puri®cation. From the
viewpoint of large-scale production, to prepare the ammo-
nia/acetone solution, which is unstable due to the self-Aldol
condensation, to deal with the reaction in the closed vessel
and to purify 10a with column chromatography are disad-
vantages in a facility. Hence, to avoid using ammonia gas
and a sealed tube, we investigated the reaction of the
substrates [8 and acetone /or its equivalents)] with ammonia
generated in situ by combination of an ammonium halide
and an amine. Additionally, we hoped that the amine or the
amine-hydrohalide salt /generated in situ) might accelerate
conversion of the ketimine 9, derived from the ketone 8 and
ammonia, to 2H-1,3-benzoxazine 10a in good yield.
Table 1. The reaction of 8 with NH4I, piperidine and acetone or its equiva-
lents
Entry
Acetone or its equivalents
Isolated yield /%)
1
2
3
4
5
2,2-Dimethoxypropanea
2,2-Dimethoxypropanea
2,2-Diethoxypropanea
2-Methoxypropenea
Acetoned
82b
77c
71c
60c
61c
a
Carried out by the general procedure in Section 4.
8 /1.55 kg, 4.97 mol) was used.
8 /10 g, 320 mmol) was used.
b
c
d
Reacted at rt for 36 h with other materials.
Our next task was to improve the chemoselectivity in pyr-
idine N-oxidation of 4-/2-pyridyl)-2H-1,3-benzoxazine 10a.
On the medicinal chemistry route, 10a was oxidized by
m-CPBA to give the potassium channel opener 1 in low
yield /30%)1a with the by-product, dioxide 11. At ®rst, we
investigated the reaction condition in the m-CPBA system
and N-oxidation using other peracids /e.g. magnesium
monoperoxybenzoic acid), but failed to improve the chemo-
selectivity. Thus, for the timely development of the potas-
sium channel opener 1, we prepared a sample for early
toxicological and clinical study, by m-CPBA oxidation.
During some screening of the ammonium halide/amine
system, we decided to choose a combination of ammonium
iodide with piperidine in MeCN, because ammonium iodide
was expected to be easily dissolved in a polar organic
solvent such as MeCN; piperidine might be converted to
the corresponding enamine of acetone, which cyclizes easily
with the ketimime 9 to give the benzoxazine like Kabbe's
synthesis of 4-chromanone.4 Gratifyingly, in an open vessel
for 5 h at rt, benzoylpyridine 8 reacted with ammonium io-
dide and piperidine in MeCN, to generate the corresponding
ketimine 9, which was observed by TLC. Then, to the
mixture was added acetone or its equivalents /e.g. 2,2-
dimethoxypropane and 2-methoxypropene), respectively,
and re¯uxed for 3 h to give the desired 2H-1,3-benzoxazine
10a in good yield. As shown in Table 1, among acetone and
On the other hand, we undertook use of dimethyldioxirane5
which has been recently studied for highly selective oxida-
tion of various substrates.6 After intensive study of the reac-
tion conditions such as the solvent, buffer salt and procedure,
4-/2-pyridyl)-2H-1,3-benzoxazine 10a was converted to
potassium channel opener 1 in high yield /84%) by dimethyl-
dioxirane which was in situ generated in acetone/

H. Mizufune et al. / Tetrahedron 57 02001) 7501±7506
Table 2. Selective N-oxidation of benzoxazine 10a
7503
Entry
Oxidizer
Buffer salt
Ratio by HPLC
10a
1
11
1
2
3
4
5
6
m-CPBAa
OXONEe/acetonec
Without
14
18
15
7
9
15
47 /41)b
76
79
26
4
2
3
3
NaHCO3
Na2HPO4
6.4 equiv.
6.4 equiv.
8.0 equiv.
9.2 equiv.
6.4 equiv.
86 /84)b
84
79
K2HPO4
2
a
CH2Cl2 was used as solvent.
Isolated yield.
Acetone, OXONEe /2.3 equiv.), buffer salt, H2O and CH2Cl2 were used.
b
c
OXONEe/2KH2SO5´KHSO4´K2SO4)/aq. Na2HPO4-CH2Cl2
system. As shown in Table 2, the system requires a basic
buffer salt, such as Na2HPO4, K2HPO4 and NaHCO3, to
keep dimethyldioxirane stable against the acidic medium
due to OXONEe. Additionally, it is important to dropwise
slowly aq. OXONEe to the mixture of benzoxazine, acetone,
aq.buffer salt and CH2Cl2 for completion of N-oxidation.
benzoxazine ring is useful as an anti-in¯ammatory agent,3c
photochromic substance 43a and photofading-preventive
material 5.3b However, these 2H-1,3-benzoxazine rings are
linked to the substituents at the 4-position via C±heteroatom
bonds. Thus, our novel cyclization method for 2H-1,3-
benzoxazine bearing the substituent linked with the C±C
bond may be effective for syntheses of various new materi-
als.
Additionally, the selective N-oxidation using dimethyldi-
oxirane might be useful for synthesis of other potassium
channel openers7, 12a and 12b, which have a pyridine-N-
oxide moiety and are derived by m-CPBA oxidation from
the corresponding pyridine derivatives, with the by-products
13a and 13b.
We investigated the reagent composition for our convenient
annulation reaction and its application to syntheses of other
benzoxazines. First, a combination of ammonium halides
and amines was extensively studied for synthesis of benzox-
azine 10a, the precursor of the potassium channel opener 1.
As shown in Table 3, ammonium iodide and ammonium
bromide are useful in combination with various secondary
or tertiary amines and cyclic or linear amines, such as piper-
idine, morpholine, dibutylamine and triethylamine. The
combination of ammonium chloride and morpholine also
gave benzoxazine 10a, but needed longer time to give the
ketimine 9, than the other combinations. Generally, regard-
ing ammonium halide, ammonium iodide was preferable to
the others because it provided high yield and required short
reaction time. On the other hand, regarding the suitable
amines for the benzoxazine annulation, we predicted that
a secondary amine might be particularly effective due to the
enamine formation4 with acetone. However, we found no
difference between secondary amines and tertiary ones in
the effect for the benzoxazine annulation.
2.2. Further study of the novel 2H-1,3-benzoxazine ring
formation
In addition to the potassium channel opener, the 2H-1,3-
Table 3. Syntheses of benzoxazine 10a using various ammonium halides and amines
Entry
NH4X
NH4I
Amine
Reaction time /h)
Iminationa Acetonidationb
Isolated yield /%)
1
2
3
4
5
6
7
8
Piperidine
2.5
4
3
3
77
61
75
76
72
78
77
62
61
77
75
66
33
Morpholine
Dibutylamine
Diethylamine
Tributylamine
Triethylamine
DBU
2
2
3
6
3
4
2
3
2
2
NH4Br
NH4Cl
Piperidine
7
9
9
Morpholine
Dibutylamine
Triethylamine
Morpholine
Triethylamine
7
6
10
11
12
13
3
4
5
12
8
5
6
15
a
8 was reacted with NH4X /5 equiv.), amine /5 equiv.) and CaSO4 /Drieritee) in MeCN at rt.
To the mixture was added 2,2-dimethoxypropane /10 equiv.) and re¯uxed.
b

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H. Mizufune et al. / Tetrahedron 57 02001) 7501±7506
Table 4. Syntheses of benzoxazines 10b±g bearing various substituents
Entry
Substrate
NH4X/amine
Ketones or benzaldehyde
Benzoxazines
Isolated yield /%)
1
2
3
4
5
6
8
8
8
8
8
8g
NH4I/Et3N
NH4I/Et3N
NH4I/Et3N
NH4I/piperidine
NH4I/piperidine
NH4I/piperidine
3-Pentanone /10 equiv.)a
10b
10c
10d
10e
10f
58
79
70
82
88
70
Cyclohexanone /10 equiv.)a
1-Methyl-4-piperidone /10 equiv.)b
2-Admantanone /3 equiv.)a
3,4-Dimethoxybenzaldehyde /3 equiv.)a
2-Admantanone /3 equiv.)a
10g
a
Carried out by the general procedure in Section 4.
Reacted at rt for 38 h with other materials.
b
Next, syntheses of various benzoxazines were investigated
to expand the novel benzoxazine annulation method using
our combination reagents of ammonium halides and amines
which are optimized by the above result of Table 3. As
shown in Table 4, benzoylpyridine 8 reacted with various
carbonyl compounds to give novel 4-pyridylbenzoxazines
10b-f bearing, respectively, diethyl, cyclohexylidene, 1-
methyl-4-piperidinylidene, 2-adamantylidene and 3,4-
dimethoxyphenyl moiety. Benzophenone 8g was also
converted to novel 4-phenylbenzoxazine 10g.
convenient 4-/2-pyridyl)-2H-1,3-benzoxazine ring forma-
tion from o-hydroxybenzoylpyridine by the NH4I/piperi-
dine/2,2-dimethoxypropane system and the following
selective pyridine-N-oxidation using dimethyldioxirane.
Additionally, the combination reagent of ammonium halide
and sec- or tert- amine conveniently converted o-hydroxy-
phenyl arylketones and several ketones /or benzaldehyde) to
various novel 4-aryl-2H-1,3-benzoxazines. Now we are
expanding the convenient synthetic method and investigat-
ing its application to various materials.
We also investigated the role of the amine-hydrohalides salt
generated in situ in our combination reagent of ammonium
halides and amines. The benzoylpyridine 8 reacted with
ammonia gas dissolved in EtOH to give the ketimine 9,
which was readily converted to the benzoxazine 10f by
veratraldehyde/morpholine±HCl salt systems in 61% yield
based on 8. Hence, in our convenient benzoxazine synthesis,
amine±hydrohalides salt generated in situ from ammonium
halides and amines can accelerate cyclization of the
ketimines generated in situ to various carbonyl
compounds.
4. Experimental
4.1. Data of compounds
Melting points were recorded on a Yanagimoto micro melting
apparatusand wereuncorrected. IRspectra wererecorded ona
Horiba FT-210 spectrophotometer. H NMR spectra were
1
recorded on a Bruker DPX-300 spectrometer. Elemental
analyses and mass spectra were analyzed by Takeda Analyti-
cal Research Ltd. HPLC was performed on a YMC-Pack
ODS-A302 column /150 mm£4.6 mm I.D.) with 0.05 M
KH2PO4 aq. soln.-MeCN /50:50) at 258C. Detection was
effectedwithaHitachispectrophotometricdetectorat254 nm.
3. Conclusions
In conclusion, we have developed an ef®cient process for
potassium channel opener, TCV-295, based on a novel and
4.1.1. 5-Bromo-4-chlorosalicylic acid /7). 4-Chloro-
salicylic acid /2.70 kg, 15.7 mol) and triethylamine

H. Mizufune et al. / Tetrahedron 57 02001) 7501±7506
7505
/1.75 kg, 17.3 mol) was dissolved in CH2Cl2 /60 L). After
cooling at 2708C, bromine /2.50 kg, 15.6 mol) in CH2Cl2
/12.5 L) was dropped to the mixture. After stirring at the
same temperature for 1 h, the reaction mixture was concen-
trated in vacuo. To the residue was added water /50 L) and
conc. HCl /5 L), and extracted with AcOEt /15 and 10 L).
The combined organic layer was washed with brine /30 L)
twice, dried over anhydrous Na2SO4 and concentrated in
vacuo. The residue was washed with n-hexane /12.5 L)
and MeCN /3 L) to give the title compound /1.66 kg,
yield 42%). 1H NMR /DMSO-d6, TMS, 300 MHz), d
/ppm):7.30 /1H, s), 8.02 /1H, s).
azine-4-yl)pyridine-1-oxide /TCV-295). 6-Bromo-7-chlo-
ro-4-/2-pyridyl)-2,2-dimethyl-2H-1,3-benzoxazine /30 g,
85.3 mmol) was dissolved in CH2Cl2 /600 ml). To the solu-
tion were added acetone /300 ml), Na2HPO4 /97.2 g,
685 mmol) and water /300 ml); and then OXONEe
/2KH2SO5´KHSO4´K2SO4) /120 g, 195 mmol) in water
/600 ml) was added dropwise at room temperature for 4 h.
After additional stirring for 4 h, the reaction mixture was
separated into the organic and aqueous layers. The aqueous
layer was extracted with CH2Cl2 /2£300 ml). The combined
organic layer was washed with Na2S2O3 /50 g) in water
/1 L) and water /2£300 ml), dried over anhydrous
Mg2SO4 and concentrated in vacuo. The residue was puri-
®ed with silica-gel chromatography /eluent; MeCN) and the
combined fraction was concentrated in vacuo. The residue
was recrystallized from EtOH /140 ml) and water /280 ml)
to give the title compound /26.5 g, yield 84%) as a colorless
crystalline powder: mp 182±1838C, 1H NMR /CDCl3, TMS,
300 MHz), d /ppm): 1.68 /6H, s), 7.00 /1H, s), 7.15 /1H, s),
4.1.2. 2-/5-Bromo-4-chloro-2-hydroxybenzoyl)pyridine /8).
Under argon atmosphere, 2-bromopyridine /5.15 kg,
32.6 mol) was dissolved in THF /21 L), stirred and cooled
at 2788C. To the solution was added dropwise 1.6 M n-
BuLi hexane solution /12.0 kg, 27.9 mol), maintaining the
temperature at under than 2708C, and stirred at this
temperature for 0.5 h. Then, 5-bromo-4-chloro-salicylic
acid /1.17 kg, 4.65 mol) in THF /5 L) was added dropwise,
and the resultant mixture was stirred at this temperature for
1 h before being allowed to warm to 2208C. At 2208C,
MeOH /2.3 L) and water /30 L) were added to the reaction
mixture which was allowed to warm to room temperature
and extracted with AcOEt /25, 12.5 and 12.5 L). The
combined organic layers were washed with 5% HCl aq.
/2£17 L) and water /2£30 L), and concentrated in vacuo.
The residue was recrystallized from EtOH to give the title
compound /790 g, yield 54%) as a yellow crystalline
powder: mp 123±1248C, 1H NMR /CDCl3, TMS,
300 MHz),d /ppm):7.20 /1H, s), 7.57±7.61 /1H, m),
7.98±8.01 /1H, m), 8.07±8.10 /1H, m), 8.60 /1H, s),
8.73±8.75 /1H, m), 13.0 /1H, br), IR /KBr, cm21) 1585,
1440, 1378, MS /EI, m/z): 315 /M14), 313 /M12), 311
/M), elemental analysis: calcd for C12H7NO2BrCl; C:
46.11, H: 2.26, N: 4.48, found for C: 46.03, H: 2.27, N: 4.52.
7.33±7.41 /3H, m), 8.25±8.28 /1H, m), IR /KBr, cm21
)
1617, 1432, 989, MS /EI, m/z): 370 /M14), 368 /M12),
366 /M), Elemental analysis: calcd for C15H12N2O2BrCl; C:
49.01, H: 3.29, N: 7.62, found for C: 49.24, H: 3.35, N: 7.78.
4.2. General procedure for 4-/2-pyridyl)-2H-1,3-benz-
oxazines /10a±f) /Tables 1, 3 and 4)
Appropriate amine /160 mmol) was added to the stirred
suspension of 2-/5-bromo-4-chloro-2-hydroxybenzoyl)-
pyridine 8 /10 g, 32 mmol), various ammonium halide
/160 mmol), CaSO4 /Drieritee) /20 g) and MeCN
/200 ml), and stirred at room temperature for 2±12 h. To
the resulting mixture was added desired ketone, aldehyde or
its equivalents /96±320 mmol) and re¯uxed for 2±15 h.
After allowing to cool to room temperature, the insoluble
matter in the reaction mixture was ®ltered off and washed
with MeCN. The mixture of the ®ltrate and washings was
concentrated in vacuo. To the residue were added diisopro-
pyl ether and 0.1N-NaOH; and separated into the organic
and aqueous layers. The organic layer was washed with
0.1N-NaOH and water, dried over anhydrous Na2SO4 and
concentrated in vacuo. The residue was recrystallized from
EtOH or washed with EtOH to give the target compound.
4.1.3. 6-Bromo-7-chloro-4-/2-pyridyl)-2,2-dimethyl-2H-
1,3-benzoxazine /9). Piperidine /2.11 kg, 24.8 mol) was
added to the stirred suspension of 2-/5-bromo-4-chloro-2-
hydroxybenzoyl)pyridine /1.55 kg, 4.97 mol), NH4I
/3.60 kg, 24.8 mol), CaSO4 /Drieritee) /3.11 kg, 22.8 mol)
and MeCN /31 L), and stirred at room temperature for 5 h.
To the resulting mixture was added 2,2-dimethoxypropane
/5.17 kg, 49.6 mol) and re¯uxed for 3 h. After allowing to
cool to room temperature, the precipitate was ®ltered off and
washed with MeCN /7.8 L). The mixture of the ®ltrate and
washings was concentrated in vacuo. To the residue were
added diisopropyl ether /31 L) and 0.1N-NaOH /16 L) and
the organic and aqueous layers were separated. The organic
layer was washed with 0.1N-NaOH /2£16 L) and water
/2£16 L), dried over anhydrous Na2SO4 and concentrated in
vacuo. The residue was recrystallized from EtOH /1.6 L) to
give the title compound /1.44 kg, yield 82%) as a colorless
crystalline powder: mp 101±1028C. 1H NMR /CDCl3, TMS,
300 MHz), d /ppm):1.66 /6H, s), 7.01 /1H, s), 7.38±7.41 /1H,
m), 7.81±7.83 /2H, m), 8.08 /1H, s), 8.68±8.70 /1H, m). IR
/KBr, cm21) 1590, 1365, 1265. Elemental analysis: calcd for
C15H12N2OBrCl; C: 51.24, H: 3.44, N: 7.97, found for C:
51.26, H: 3.69, N: 8.00.
4.2.1. 6-Bromo-7-chloro-4-/2-pyridyl)-2,2-diethyl-2H-1,3-
benzoxazine /10b). A colorless crystalline powder: mp
110±1118C, H NMR /CDCl3, TMS, 300 MHz), d /ppm):
1
1.00 /6H, t, Jˆ7.4 Hz), 1.95 /4H, q, Jˆ7.4 Hz), 6.99 /1H, s),
7.38±7.43 /1H, m), 7.83±7.84 /2H, m), 8.18 /1H, s), 8.69±
8.71 /1H, m), IR /KBr, cm21) 2971, 1621, 985, Elemental
analysis: calcd for C17H16N2OBrCl; C: 53.78, H: 4.25, N:
7.38, found for C: 53.88, H: 4.27, N: 7.42,
4.2.2. Spiro[6-bromo-7-chloro-4-/2-pyridyl)-2H-1,3-benzox-
azine-2,10-cyclohexane] /10c). A colorless crystalline
powder: mp 116±1178C, 1H NMR /CDCl3, TMS,
300 MHz), d /ppm): 1.45±2.03 /10H, m), 7.06 /1H, s),
7.38±7.42 /1H, m), 7.80±7.89 /2H, m), 8.11 /1H, s),
8.68±8.70 /1H, m), IR /KBr, cm21) 2925, 1589, 985, MS
/EI, m/z): 394 /M14), 394 /M12), 390 /M), Elemental
analysis: calcd for C18H16N2OBrCl; C: 55.20, H: 4.12, N:
7.15, found for C: 54.95, H: 4.00, N: 7.25.
4.1.4. 2-/6-Bromo-7-chloro-2,2-dimethyl-2H-1,3-benzox-

7506
H. Mizufune et al. / Tetrahedron 57 02001) 7501±7506
4.2.3. Spiro[6-bromo-7-chloro-4-/2-pyridyl)-2H-1,3-benzox-
azine-2,40-/10-methylpiperidine)] /10d). A colorless crys-
talline powder: mp 155±1568C, H NMR /CDCl3, TMS,
300 MHz), d /ppm): 2.05±2.18 /4H, m), 2.37 /3H, s),
2.46±2.54 /2H, m), 2.66±2.73 /2H, m), 7.08 /1H, s),
7.38±7.43 /1H, m), 7.80±7.91 /2H, m), 8.14 /1H, s),
8.68±8.70 /1H, m), IR /KBr, cm21) 2798, 1589, 1010, MS
/EI, m/z): 409 /M14), 407 /M12), 405 /M), Elemental
analysis: calcd for C18H17N3OBrCl; C: 53.16, H: 4.21, N:
10.33, found for C: 53.41, H: 4.30, N: 10.67.
4.2.7. Synthesis of benzoxazine /10e) via ketimine /9)
derived benzoylpyrodine /8) and ammonia gas. In the
stirred suspension of EtOH /400 ml) and CaSO4
/Drieritee) /20 g), ammonia gas was bubbled for 1 h at
0±108C. To the resulting mixture was added 2-/5-bromo-
4-chloro-2-hydroxybenzoyl)pyridine 8 /20 g, 64 mmol) and
stirred at room temperature for 1.5 h. The insoluble matter
in the reaction mixture was ®ltered off and washed with
EtOH. The mixture of the ®ltrate and washings was concen-
trated in vacuo to give the crude ketimine /9) /17.8 g) as a
yellow solid: MS /EI, m/z): 314 /M14), 312 /M12), 310
/M), Elemental analysis: calcd for C12H8N2OBrCl; C: 49.26,
H: 2.59, N: 8.99, found for C: 46.03, H: 2.62, N: 8.33.
1
4.2.4. Spiro[6-bromo-7-chloro-4-/2-pyridyl)-2H-1,3-benzox-
azine-2,20-adamantane] /10e). A colorless crystalline
powder: mp 145±1468C, 1H NMR /CDCl3, TMS,
300 MHz), d /ppm): 1.58±1.78 /6H, m), 1.93±1.97 /2H,
m), 2.22±2.26 /4H, m), 2.36±2.40 /2H, m), 7.10 /1H, s),
7.37±7.42 /1H, m), 7.80±7.86 /1H, m), 7.98±8.01 /1H, m),
8.22 /1H, s), 8.67±8.69 /1H, m), IR /KBr, cm21) 2904,
1590, 1006, MS /EI, m/z): 446 /M14), 444 /M12), 442
/M), Elemental analysis: calcd for C22H20N2OBrCl; C:
59.54, H: 4.54, N: 6.31, found for C: 59.57, H: 4.59, N: 6.37.
Morpholine hydrochloride /9.89 g, 80 mmol) was added to
the stirred suspension of the crude ketimne /4.99 g,
32 mmol), 3,4-dimethoxybenzaldehyde /7.98 g, 48 mmol),
CaSO4 /Drieritee) /10.9 g) and MeCN /75 ml) and re¯uxed
for 4.5 h. After allowing to cool to room temperature, the
reaction mixture was concentrated in vacuo. To the residue
was added CH2Cl2 and the insoluble matter was ®ltered off.
The ®ltrate was washed with 0.1N-NaOH and water, dried
over anhydrous Na2SO4 and concentrated in vacuo. The
residue was washed with EtOH to give the target compound
/4.51 g) /61% based on 8) as a yellow crystalline powder.
4.2.5. 6-Bromo-7-chloro-2-/3,4-dimethoxyphenyl)-4-/2-
pyridyl)-2H-1,3-benzoxazine /10f). A yellow crystalline
powder: mp 218±2208C, 1H NMR /CDCl3, TMS,
300 MHz), d /ppm): 3.96 /3H, s), 3.98 /3H, s), 6.70±6.74
/1H, m), 6.93±6.98 /1H, m), 7.02±7.04 /1H, m), 7.15 /1H,
s), 7.26 /1H, d, Jˆ1.8 Hz), 7.30±7.33 /1H, m), 7.88±7.90
References
/1H, m), 7.94 /1H, s), 8.28±8.30 /1H, m), IR /KBr, cm21
)
1. /a) Yamamoto, S.; Hashiguchi, S.; Miki, S.; Igata, Y.; Wata-
nabe, T.; Shiraishi, M. Chem. Pharm. Bull. 1996, 44, 734.
/b) Kusumoto, K.; Awane, Y.; Kitayoshi, T.; Fujiwara, S.;
Hashiguchi, S.; Terashita, Z.; Shiraishi, M.; Watanabe, T.
J. Cardiovasc. Pharmacol. 1994, 24, 929.
1511, 1265, 1027, MS /EI, m/z): 462 /M14), 460 /M12),
458 /M), Elemental analysis: calcd for; C: 54.87, H: 3.51, N:
6.09, found for C: 54.95, H: 3.55, N: 6.16,
4.2.6. Spiro[4-phenyl-2H-1,3-benzoxazine-2,20-adaman-
tane]/10g). Triethylamine /25.5 g, 252 mmol) was added
to the stirred suspension of 2-hydroxybenzo-phenone 8f
/10 g, 50.4 mmol), ammonium iodide /36.5 g, 252 mmol),
CaSO4 /Drieritee) /31.6 g, 232 mmol) and MeCN /150 ml),
and stirred at room temperature for 44.5 h. To the resulting
mixture was added 2-adamatanone /22.7 g, 151 mmol) and
MeCN /50 ml), and re¯uxed for 3 h. After allowing to cool
to room temperature, the insoluble matter in the reaction
mixture was ®ltered off and washed with MeCN. The
mixture of the ®ltrate and washings was concentrated in
vacuo. To the residue were added diisopropyl ether and
0.1N-NaOH; and separated into the organic and aqueous
layers. The organic layer was washed with 0.1N-NaOH
and water, dried over anhydrous Na2SO4 and concentrated
in vacuo. The residue was washed with EtOH to give the
target compound 10f /11.6 g, yield 70%) as a colorless crys-
2. /a) Baumgarth, M., Gericke, R., Bergmann, R., De Peyer, J.,
Ingeborg, L. DE3840011/CA114/17):164256m). /b) Englert,
H. C., Mania, D., Lintz, W. DE4010488/CA116/5):41463k).
3. /a) Melzig, M. WO90-03379/CA114/5):42796s). /b) Kaneko,
Y. JP88-284547/CA111/8):67818b). /c) Tachikawa, R.; Wachi,
K.; Sato, S.; Terada, A. Chem. Pharm. Bull. 1981, 29, 3529.
4. Kabbe, H. J.; Widdig, A. Angew. Chem., Int. Ed. Engl. 1982, 21,
247.
5. General review: /a) Adam, W.; Curci, R.; Edwards, J. O. Acc.
Chem. Res. 1989, 22, 205. /b) Murray, R. W. Chem. Rev. 1989,
89, 1187. /c) Curci, R. Pure Appl. Chem. 1995, 67, 811.
6. Selective N-oxidation of pyridine derivatives bearing ole®n
moiety: /a) Ferrer, M.; Sanchez-Baeza, F.; Messrguer, A.
Tetrahedron 1997, 46, 15877. Selective N-oxidation of 3- or
4-picolinaldehyde: /b) Dyker, G.; Hoelzer, B. Tetrahedron
1999, 55, 12557.
1
7. /a) Attwood, M. R.; Churcher, I.; Dunsdon, R. M.; Hurst, D. N.;
Jones, P. S. Tetrahedron Lett. 1991, 32, 811. /b) Takahashi, T.;
Koga, H.; Sato, H.; Ishizawa, T.; Taka, N. Heterocycles 1995,
41, 2405. /c) Almansa, C.; Gomez, L. A.; Cavalcanti, F. L.;
Rodriguez, R.; Garcia-Rafanell, J.; Forn, J. Bioorg. Med.
Chem. Lett. 1995, 5, 1833.
talline powder: mp 171±1738C, H NMR /CDCl3, TMS,
300 MHz), d /ppm): 1.57±1.59 /6H, m), 1.93±1.98 /2H,
m), 2.23±2.30 /4H, m), 2.44±2.48 /2H, m), 6.92±7.01
/2H, m), 7.23±7.26 /2H, m), 7.38±7.46 /3H, m), 7.63±
7.66 /2H, m), IR /KBr, cm21) 2902, 1610, 1334, 700, MS
/EI, m/z):329 /M1), Elemental analysis: calcd for; C: 83.85,
H: 7.04, N: 4.25, found for C: 83.80, H: 6.91, N: 4.07.