Convenient synthesis of 7-aryl-3,4,5,6-tetrahydro-2H-pyrido[4,5-b]- and [2,3-b]-1,5-oxazocine-6-ones

Article abstract of DOI:10.1016/j.tetlet.2004.09.104

A convenient and diversity-oriented method for synthesis of the novel 7-aryl-3,4,5,6-tetrahydro-2H-pyrido[4,5-b]-1,5-oxazocine-6-one skeleton 1 and the very rarely described 7-aryl-3,4,5,6-tetrahydro-2H-pyrido[2,3-b]-1,5- oxazocine-6-one skeleton 2, featu

Full text of DOI:10.1016/j.tetlet.2004.09.104

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8475–8478
Convenient synthesis of 7-aryl-3,4,5,6-tetrahydro-2H-pyrido[4,5-b]-
and [2,3-b]-1,5-oxazocine-6-ones
Shigeki Seto*
Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd, 2399-1 Nogi, Nogi-machi, Shimotsuga-gun,
Tochigi 329-0114, Japan
Received 13 August 2004; revised 10 September 2004; accepted 10 September 2004
Available online 30 September 2004
Abstract—A convenient and diversity-oriented method for synthesis of the novel 7-aryl-3,4,5,6-tetrahydro-2H-pyrido[4,5-b]-1,5-
oxazocine-6-one skeleton 1 and the very rarely described 7-aryl-3,4,5,6-tetrahydro-2H-pyrido[2,3-b]-1,5-oxazocine-6-one skeleton
2, featuring cyclization using nucleophilic aromatic substitution (SNAr) and Suzuki coupling, is described.
Ó 2004 Elsevier Ltd. All rights reserved.
In the course of our drug discovery programs targeting
potent and selective NK1 antagonists, potentially useful
for the clinical treatment of a wide range of conditions
such as pain, migraine, nausea, and urinary inconti-
nence,1 we required a convenient method for general
synthesis of 7-aryl-3,4,5,6-tetrahydro-2H-pyrido[4,5-b]-
1,5-oxazocine-6-one and 7-aryl-3,4,5,6-tetrahydro-2H-
pyrido[2,3-b]-1,5-oxazocine-6-one skeletons (1 and 2 in
Fig. 1).
however, involves a seven-step process from acetophe-
none, which is not only inefficient for the synthesis of
many compounds with structural diversity for com-
pound 2, but is also unavailable for the synthesis of
the desired compound 1. We therefore developed a con-
venient method for the synthesis of 1 and 2. Herein, we
describe a novel diversity-oriented approach for synthe-
sis of the 7-aryl-3,4,5,6-tetrahydro-2H-pyrido[4,5-b]-1,5-
oxazocine-6-one and 7-aryl-3,4,5,6-tetrahydro-2H-pyr-
ido[2,3-b]-1,5-oxazocine-6-one skeletons.
Interestingly, the 7-aryl-3,4,5,6-tetrahydro-2H-pyrido-
[4,5-b]-1,5-oxazocine-6-one skeleton 1 constitutes a no-
vel class of compound whose synthesis has not been
reported previously. On the other hand, there has been
only one precedent for synthesis of the 7-aryl-3,4,5,6-
tetrahydro-2H-pyrido[2,3-b]-1,5-oxazocine-6-one skele-
ton 2 reported by the Takeda group.2 Their method,
The retrosynthetic scheme for the pyridooxazocines is
shown in Scheme 1. The desired compounds 1 and 2
might be constructed from the chloride 3 or iodide 4
by the Suzuki coupling reaction. The bicyclic com-
pounds 3 and 4 could be constructed from the carboxy-
lic acid 7 by condensation with aminopropanol 8 and a
subsequent nucleophilic intramolecular cyclization reac-
tion using nucleophilic aromatic substitution (SNAr).
The regioselectivity of the cyclization could be control-
led because the different leaving groups at the C-2 and
C-4 positions in the pyridine ring (chloride and iodide,
respectively) might create a difference of reactivity in
the SNAr reaction.
O
O
N
N
N
N
O
R2
O
R2
R1
R1
2-Chloro-4-iodopyridine-3-carboxylic acid 7 was pre-
pared from 2-chloro-3-iodopyridine 93 by the known
method4 with slight modification. Treatment of 2-
chloro-3-iodopyridine 9 with LDA at À78°C, followed
by quenching with carbon dioxide, and then hydrolyza-
tion with hydrochloric acid gave the 2-chloro-4-iodopyr-
idine-3-carboxylic acid 7 in good yield. Subsequent
1
2
Figure 1.
Keywords: SNAr; Nucleophilic aromatic substitution; Suzuki coupling;
Pyrido[4,5-b]-1,5-oxazocine-6-one; Pyrido[2,3-b]-1,5-oxazocine-6-one.
*
Fax: +81 280 57 1293; e-mail: shigeki.seto@mb.kyorin-pharm.co.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.104

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S. Seto / Tetrahedron Letters 45 (2004) 8475–8478
O
Y
I
O
R2
N
Y
Z
B(OH)2
X
N
OH
N
+
X
R1
R2
N
O
Cl
O
R2
R1
O
1: X=N, Y=CH
2: X=CH, Y=N
3: X=N, Y=CH, Z=Cl
4: X=CH, Y=N, Z=I
5
6
I
HN
R2
OH
+
N
CO2H
Cl
7
8
Scheme 1.
CF3
I
I
CF3
OH
b
a
N
N
N
N
I
CO2H
Cl
O
Cl
Cl
9
7
10
Scheme 2. Reagents and conditions: (a) 1. LDA, THF, À78°C, 5h, 2. CO2, 1h, 3. HCl, rt, 1h, 81%; (b) 1. SOCl2, DMF, reflux, 3h, 2. 3-[[3,5-
bis(trifluoromethyl)benzyl]amino]-1-propanol, THF, 0°C, 1h then rt, 2h, 92%.
1
or iodide) and H NMR (aromatic protons at C-10 for
11 and C-8 for 12; d 6.80 and 7.69, respectively).
treatment with thionyl chloride under reflux, followed
by condensation with 3-[[3,5-bis(trifluoromethyl)benz-
yl]amino]-1-propanol, afforded the alcohol 10 (Scheme
2).
The Suzuki coupling reaction of 11 and 12 with arylbo-
ronic acids (1.5equiv) yielded the desired 7-aryl-3,4,5,6-
tetrahydro-2H-pyrido[2,3-b]- and [4,5-b]-1,5-oxazocine-
6-ones (1a–d, 2a–e) in good yield, using 10mol%
Pd(PPh3)4 and 2M Na2CO3 (5equiv) in a 2:1 toluene/
1,4-dioxane mixture for 5–7h.9 The coupling reaction
proceeded equally well using chloride 11 or iodide 12.
Conversion of the alcohol 10 to bicyclic compounds 11
and 12 was carried out under several conditions and
the results are summarized in Table 1. Less-polar-apro-
tic conditions in the presence of a strong base (entries 1
and 2) afforded only 12 as a single regio-isomer, that is,
only the C-2 position on the pyridine ring underwent a
nucleophilic reaction. Interestingly, polar-protic condi-
tions with various bases (entries 4–9) gave a mixture
of 11 and 12, in different respective ratios. In particular,
use of K2CO3 as the base (entry 7) gave a good yield of
11. Next, the effect of solvent was studied (entries 10–
12). In particular, H2O–EtOH was found to be a suita-
ble solvent for obtaining 11. The exact mechanism
responsible for the regioselectivity of this cyclization is
unclear. The formation of 12, where chloride was re-
placed prior to iodide, seems to fit reasonably well with
the results of common SNAr;5 however, the formation of
11 cannot be interpreted. Compounds 11 and 12 were
easily separable by column chromatography and iso-
lated in reasonable yields.6 These compounds were iden-
In the 1H NMR spectra of 2d, the aryl protons and oxa-
zocine ring protons appeared as broad signals, but the
benzylic methylene proton signals did not change. These
data indicate that the rotation about the biaryl bond
could be restricted for 2d on a NMR timescale at room
temperature.2 Thus, although the separation of the iso-
mers of 2d using high-performance liquid chromatogra-
phy has not been a success, 2d presumably exists as a
mixture of diastereomers,2,10 which result from the two
axial chiralities (aryl and amide). The compounds other
than 2d did not exhibit these effects (Table 2).
In summary, we have developed a convenient method
for synthesis of the very rarely described 7-aryl-3,4,5,6-
tetrahydro-2H-pyrido[4,5-b]-1,5-oxazocine-6-one and
7-aryl-3,4,5,6-tetrahydro-2H-pyrido[2,3-b]-1,5-oxazo-
1
tified by MS and H NMR, respectively,7,8 and it was
possible to differentiate between them by MS (chloride

S. Seto / Tetrahedron Letters 45 (2004) 8475–8478
8477
Table 1. Studies of cyclization of alcohol 10
CF3
O
O
N
I
CF3
CF3
CF3
CF3
N
I
N
N
+
CF3
OH
Cl
O
O
N
N
Cl
O
10
11
12
Entry
Base
Solvent
Condition
Total yield (%)
Ratio (11:12)
1
NaH
NaH
THF
rt, 1h
42
53
Only 12
Only 12
—
2
Toluene
DMF
EtOH
50°C, 8h
0°C, 1h
rt, 10h
a
3
NaH
t-BuOK
KOH
—
4
70
59
59
80
14
70
28
54
87
79:21
68:32
66:34
84:16
71:29
80:20
71:29
41:59
83:17
5
EtOH
EtOH
rt, 1h
6
Cs2CO3
K2CO3
Na2CO3
KHCO3
K2CO3
K2CO3
K2CO3
50°C, 8h
50°C, 8h
80°C, 16h
80°C, 16h
100°C, 1h
80°C, 12h
100°C, 12h
7
EtOH
EtOH
8
9
EtOH
DMF
10
11
12
i-PrOH
H2O–EtOH (1:1 v/v)
a Decomposition.
Table 2. The Suzuki coupling reaction 11 and 12 with substituted boronic acid
O
O
Y
Y
10 mol% Pd(PPh3)4
CF3
CF3
X
X
2M Na2CO3
N
N
Ar B(OH)2
+
Z
Ar
O
O
Toluene, 1,4-dioxane
reflux, 5-7 h
CF3
CF3
11, X=N, Y=CH, Z=Cl
12, X=CH, Y=N, Z=I
1a-d, 2a-e
Entry
12 or 13
Ar
Products
Yield (%)
1
2
11
12
1a11
2a12
60
80
3
4
11
12
1b
2b
87
77
F
5
6
11
12
1c
2c
83
87
Cl
7
8
11
12
1d
2d
98
99
Me
9
12
2e
86
MeO
cine-6-one skeletons starting from 2-chloro-3-iodopyr-
idine, making good use of intramolecular cyclization
using SNAr for formation of the oxazocine ring and
Suzuki coupling for formation of the biaryl bond.
Details of the NK1 antagonist activity of these com-
pounds will be published separately.

8478
S. Seto / Tetrahedron Letters 45 (2004) 8475–8478
m), 3.23–3.32 (1H, m), 3.63–3.74 (1H, m), 4.06 (1H, d,
Acknowledgements
J = 15Hz), 4.22–4.30 (1H, m), 4.44–4.53 (1H, m), 5.64
(1H, d, J = 15Hz), 6.80 (1H, d, J = 5.5Hz), 7.84 (1H, s), 7
88 (2H, s), 8.17 (1H, d, J = 5.5Hz); HRMS (EI) calcd for
C18H13ClF6N2O2 (M+) 438.0570, found 438.0571.
8. 7-Iodo-3,4,5,6-tetrahydro-2H-pyrido[2,3-b]-1,5-oxazocine-
6-one (12): 1H NMR (400MHz, CDCl3): d 1.73–1.81 (1H,
m), 2.21–2.34 (1H, m), 3.18–3.27 (1H, m), 3.40–3.50 (1H,
m), 4.14 (1H, d, J = 16Hz), 4.22–4.30 (1H, m), 4.46–4.68
(1H, m), 5.71 (1H, d, J = 16Hz), 7.69 (1H, d, J = 5.3Hz),
7.83 (1H, s), 7.94 (2H, s), 8.01 (1H, d, J = 5.3Hz); HRMS
(EI) calcd for C18H13F6IN2O2 (M+) 529.9926, found
529.9907.
9. Suzuki coupling (12–2a): compound 12 (1.00g, 1.89mmol)
and phenyl boronic acid (417mg, 3.42mmol) were dis-
solved in toluene (10mL) and 1,4-dioxane (5mL), then
2M Na2CO3 (10mL) and Pd(PPh3)4 (132mg, 0.114mmol)
was added, and the mixture was stirred under reflux for
7h. The reaction mixture was cooled to room temperature,
diluted with ethyl acetate, then washed with 2M Na2CO3
and brine, and dried over Na2SO4. The solvent was
evaporated, and the residue was purified by recrystalliza-
tion from isopropanol to give compound 2a (729mg,
80%).
The author wishes to thank Dr. H. Miyachi, presently at
the University of Tokyo, for many valuable suggestions
and encouragement, and also Dr. T. Ishizaki, Dr. K.
Obi, and Dr. Y. Takano of Kyorin Pharmaceutical
Co., Ltd, for helpful discussion.
References and notes
1. (a) Von Euler, U. S.; Gaddum, J. H. J. Physiol. 1931, 72,
74; (b) Chan, M. M.; Leeman, S. E.; Niall, H. D. Nat. New
Biol. 1971, 232, 86.
2. Ishichi, Y.; Ikeura, Y.; Natsugari, H. Tetrahedron 2004,
60, 4481.
3. Sakamoto, T.; Kondo, Y.; Yamanaka, H. Chem. Pharm.
Bull. 1985, 33, 4746.
4. Rocca, P.; Cochennec, C.; Marsais, F.; Thomas-dit-
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Dumont, L.; Mallet, M.; Godard, A.; Queguiner, G. J.
Org. Chem. 1993, 58, 7832.
5. (a) Bunnett, J. F.; Garbisch, E. W.; Pruitt, K. M. J. Am.
Chem. Soc. 1957, 79, 385; (b) Ross, S. D. J. Am. Chem.
Soc. 1959, 81, 2113; (c) Reinheimer, J. D.; Taylor, R. C.;
Rohrbaugh, P. E. J. Am. Chem. Soc. 1961, 83, 835; (d)
Saitton, S.; Kihlberg, J.; Luthman, K. Tetrahedron 2004,
60, 6113.
10. Albert, J. S.; Ohnmacht, C.; Bernstein, P. R.; Rumsey, W.
L.; Aharony, D.; Masek, B. B.; Dembofsky, B. T.;
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6. Cyclization procedure: Compounds (10–12): compound 10
(6.86g, 12.1mmol) was dissolved in THF (60mL) at 0°C,
and NaH (581mg, 14.5mmol) was added, and the mixture
was stirred at 0°C for 0.5h and then at room temperature
for 1h. The reaction mixture was cooled at 0°C, and water
was added. The resulting mixture was extracted with ethyl
acetate, and the extract was washed with brine, and dried
over Na2SO4. The solvent was evaporated, and the residue
was purified by silica gel chromatography (AcOEt–hex-
ane = 2:1 v/v) to give compound 12 (7.69g, 42%).
Compounds (10–11): compound 10 (1.74g, 3.07mmol)
was dissolved in EtOH (30mL), and K2CO3 (2.12g,
15.3mmol) was added, and the mixture was stirred under
reflux for 6h. Following the work-up procedure as
described above afforded compound 11 (950mg, 71%).
7. 7-Chloro-3,4,5,6-tetrahydro-2H-pyrido[4,5-b]-1,5-oxazocine-
6-one (11): 1H NMR (400MHz, CDCl3): d 1.97–2.18 (2H,
11. 7-Phenyl-3,4,5,6-tetrahydro-2H-pyrido[4,5-b]-1,5-oxazocine-
6-one (1a): 1H NMR (400MHz, CDCl3): d 1.97–2.18 (2H,
m), 3.39–3.47 (1H, m), 3.38–3.98 (1H, m), 4.12 (1H, d,
J = 15Hz), 4.13–4.22 (1H, m), 4.43–4.50 (1H, m), 5.38
(1H, d, J = 15Hz), 6.87 (1H, d, J = 5.5Hz), 7.25–7.43 (5H,
m), 7.76 (2H, s), 7.86 (1H, s), 8.49 (1H, d, J = 5.5Hz);
HRMS (EI) calcd for C24H18F6N2O2 (M+) 480.1272,
found 480.1261.
12. 7-Phenyl-3,4,5,6-tetrahydro-2H-pyrido[2,3-b]-1,5-oxazocine-
6-one (2a): 1H NMR (400MHz, CDCl3): d 1.73–1.82 (1H,
m), 2.26–2.39 (1H, m), 3.32–3.40 (1H, m), 3.69–3.78 (1H,
m), 4.17 (1H, d, J = 15Hz), 4.27–4.37 (1H, m), 4.63–4.70
(1H, m), 5.51 (1H, d, J = 15Hz), 7.16 (1H, d, J = 5.5Hz),
7.25–7.70 (5H, m), 7.71 (2H, s), 7.83 (1H, s), 8.41 (1H, d,
J = 5.5Hz); HRMS (EI) calcd for C24H18F6N2O2 (M+)
480.1272, found 480.1286.