Microwave-assisted synthesis of nitro-substituted tetrahydropyrido azepines

Article abstract of DOI:10.1055/s-0029-1218678

The microwave-assisted condensation of azepan-4-ones with 3,5-dinitro-1-methylpyridin-2-one in the presence of ammonia was found to be a highly efficient method for the synthesis of nitro-substituted tetrahydropyridoazepines. Variation of the substituent at the amino group enables the regioselective synthesis of tetrahydropyrido[3,2-c]azepines and tetrahydropyrido[2,3-d]azepines. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0029-1218678

PAPER
1339
Microwave-Assisted Synthesis of Nitro-Substituted Tetrahydropyrido-
azepines
Synthesis of
Nit
h
ro-Substitute
o
dTetrahydr
m
s
as Schultz, Sean C. Turner, Wilfried M. Braje*
Abbott GmbH & Co. KG, Knollstr. 50, 67061 Ludwigshafen, Germany
Fax +49(621)5892443; E-mail: wilfried.braje@abbott.com
Received 7 January 2010
reaction mixture for 30 minutes at 60 °C in a microwave
oven. After column chromatography, the product was iso-
lated in 79% yield as a mixture of regioisomers 6 and 10
(Table 1, entry 4). Optimizing the reaction conditions, we
Abstract: The microwave-assisted condensation of azepan-4-ones
with 3,5-dinitro-1-methylpyridin-2-one in the presence of ammonia
was found to be a highly efficient method for the synthesis of nitro-
substituted tetrahydropyridoazepines. Variation of the substituent at
the amino group enables the regioselective synthesis of tetrahydro- were surprised to observe a decreased regioselectivity at
pyrido[3,2-c]azepines and tetrahydropyrido[2,3-d]azepines.
higher temperatures, while the yield increased up to 92%
at the same time (Table 1, entry 1). Further investigations
revealed that 6 is preferentially formed at lower tempera-
tures, while the product ratio is unaffected by the reaction
time (Table 1, entries 5–7). The regioselectivity was sig-
nificantly improved by stirring the reaction mixture for 48
hours at room temperature in a sealed tube without micro-
wave irradiation, giving the desired tetrahydropyri-
doazepines 6 and 10 in 62% yield with an excellent
selectivity (84:16, 6/10) (Table 1, entry 9).
Key words: ketones, condensation, regioselectivity, heterocycles,
pyridines
While tetrahydroazepines are widely used in medicinal
chemistry, and have been successfully applied for the syn-
thesis of factor Xa inhibitors,1 and antagonists of the 5-
HT2C,2 5-HT6,3 H3,4 and the dopamine receptors,5 the cor-
responding tetrahydropyridoazepine analogues are
scarcely known. During our research program on novel
heterocyclic structures we became interested in the syn-
thesis of nitro-substituted tetrahydropyridoazepines, as
the nitro group would provide a versatile handle for fur-
ther functionalizations of these building blocks. Unfortu-
nately, the synthetic routes reported so far for
tetrahydropyridoazepines are not feasible for the synthe-
sis of nitro-substituted derivatives.6 In addition, the direct
nitration of pyridines with nitric acid is difficult, and gives
frequently low yields of the desired products.7 To circum-
vent this problem, nitro-substituted pyridines have been
synthesized by Diels–Alder reactions of 5-nitropyrimi-
dine with enamines8 or condensation of 3,5-dinitro-1-
methyl-pyridin-2(1H)-one (5) with ketones and aldehydes
in the presence of ammonia.9 Both methods were shown
to be efficient for the synthesis of nitro-substituted tet-
rahydronaphthyridines, but the desired tetrahydropyrido-
azepines were only formed in trace amounts.8,10
O
O2N
NO2
O
NH3/MeOH
+
N
N
R
Me
5
1 R = Cbz
2 R = COPh
3 R = Bn
4 R = Me
R
N
O2N
O2N
N
R
+
N
N
6 R = Cbz
7 R = COPh
8 R = Bn
10 R = Cbz
11 R = COPh
12 R = Bn
9 R = Me
13 R = Me
Scheme 1 Condensation reaction of azepan-4-ones 1–4
Microwave irradiation has been successfully applied in
organic synthesis to increase the reaction rates of a wide
range of transformations.11 For this reason, we became in-
terested to see if it could also improve the hitherto low-
yielding formation of tetrahydropyridoazepines within the
condensation reaction of cyclic ketones with 3,5-dinitro-
1-methylpyridin-2(1H)-one (5) (Scheme 1).10 We were
very pleased to find that the benzyloxycarbonyl (Cbz)-
protected azepan-4-one 1 was almost completely convert-
ed to the desired tetrahydropyridoazepine after heating the
These results demonstrated that microwave irradiation is
not necessary to perform the condensation reaction.
Therefore, the observed temperature dependency of the
regioselectivity could be in principle a thermal effect as
well as a nonthermal microwave effect.11 Heating the re-
action mixture for 30 minutes at 60 °C in an oil bath gave
the desired products 6 and 10 with a selectivity of 75:25
(6/10). The regioselectivity obtained by conventional
heating is almost identical to the selectivity, which was
obtained at 40 °C in the microwave (78:22, 6/10) (Table
1, entry 5). This result was not completely unexpected as
the microwave tends to overheat the reaction vessel at the
beginning of the reaction, and the maximum temperature
detected was usually up to 10 °C higher than intended.
SYNTHESIS 2010, No. 8, pp 1339–1343
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x
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x
x
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Advanced online publication: 11.02.2010
DOI: 10.1055/s-0029-1218678; Art ID: T14210SS
© Georg Thieme Verlag Stuttgart · New York

1340
T. Schultz et al.
PAPER
O
Table 1 Condensation Reaction of the Cbz-Protected Azepan-4-one
1
1) 5, NH3/MeOH, NH4Cl
Entry
R
Temp (°C) Time (h) Selectivity Yield (%)
2) CbzCl, Et3N, DMAP, CH2Cl2
(6/10)a
NH⋅HCl
15
1
2
3
4
5
6
7
8
9
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
120b
100b
80b
60b
40b
40b
40b
r.t.
0.5
0.5
0.5
0.5
0.5
1
64:36
64:36
65:35
68:32
78:22
78:22
77:23
86:14
84:16
92
90
79
79
37
43
73
56
62
Cbz
O2N
O2N
N
N
Cbz
+
N
N
6
10
Scheme 2 Condensation reaction and subsequent Cbz-protection of
azepan-4-one 15
2
Table 2 Condensation Reaction and Subsequent Cbz-Protection of
Azepan-4-one 15
24
48
r.t.
Entry Temp (°C) Time (h) Selectivity (6/10)a
Yield (%)
a Determined by 1H NMR spectroscopy.
b Heated by microwave irradiation.
1
2
3
4
5
100b
80b
80b
60b
r.t.
0.5
0.5
2
34:66
34:66
35:65
34:66
44:56
38
38
40
41
40
Moreover, in contrast to an oil bath, microwave irradia-
tion heats the reaction mixture from inside, while the tem-
perature is detected at the outside of the reaction vessel.
Therefore, we expect an even more pronounced tempera-
ture difference within reaction mixtures, which are heated
by oil bath or microwave. For this reason, we believe that
the observed temperature dependency is mainly a thermal
effect, as a similar effect on the regioselectivity was ob-
served by conventional heating as well.
0.5
24
a Determined by 1H NMR spectroscopy.
b Heated by microwave irradiation.
20 and 21. Consecutive elimination of the ammonium salt
of N-methyl-a-nitroacetamide finally leads to the tetrahy-
dropyridoazepine regioisomers 6–9 and 10–13 (Scheme
3). Therefore, the two main factors determining the prod-
uct ratio should be the equilibrium constant between the
two enolates 16 and 17, and the difference between the re-
action rates of their addition to the pyridinone 5.
To investigate the effect of the bulky Cbz-protecting
group on the regioselectivity, the unprotected azepan-4-
one hydrochloride 15 was reacted with 3,5-dinitro-1-
methylpyridin-2(1H)-one (5) in the presence of ammonia,
and the crude product was subsequently treated with Cbz-
chloride to give the protected tetrahydropyridoazepines 6
and 10 in two steps (Scheme 2). In contrast to the Cbz-
protected azepan-4-one 1, the route starting from the un-
protected ketone 15 gave preferentially the regioisomer
10 as the main product, and the best selectivity was ob-
served at elevated temperature (Table 2, entries 1–4). An
effect of the ammonium hydrochloride, present under
these reaction conditions, was ruled out by reacting the
Cbz-protected azepan-4-one 1 at 80 °C in the presence of
one equivalent of ammonium chloride under otherwise
identical conditions. No effect of the ammonium salt was
detected, and the same regioselectivity was obtained as
under salt-free conditions (65:35, 6/10) (cf. Table 1, entry
2).
To get a better insight into the steric and electronic effects
of the protecting group on the regioselectivity, benzyl 4-
oxoazepane-1-carboxylate (1), 1-benzoylazepan-4-one
(2), 1-benzylazepan-4-one (3), and 1-methylazepan-4-one
hydrochloride (4) were treated with pyridinone 5 in the
presence of ammonia at room temperature and 100 °C
(Scheme 1). Azepan-4-ones 1 and 2, with a carbonyl-
group attached to the nitrogen, preferentially gave the tet-
rahydropyrido[3,2-c]azepines 6 and 7, and the best selec-
tivity was observed at room temperature (Table 3, entries
1–4). While almost no regioselectivity was observed at
room temperature for azepan-4-ones 3, 4 (Table 3, entries
6 and 8), and 15 (Table 2, entry 5), the tetrahydropyri-
do[2,3-d]azepines 12, 13 (Table 3, entries 5 and 7) and 10
(Table 2, entry 1) were formed as the major products at
100 °C. These observations led to the conclusion, that the
carbonyl group present in the Cbz and the benzoyl group
efficiently stabilizes the enolate 16 at room temperature,
while elevated temperatures generally facilitate the reac-
tion of the corresponding enolate 17 (Scheme 3).
It is not easily rationalized, why the Cbz-protected
azepan-4-one 1 and the unprotected azepan-4-one 15 pref-
erentially give the opposite regioisomers. Based on the
mechanism proposed by Thoda et al.,9 the observed regio-
selectivity has to be controlled by the addition of the cor-
responding enolates 16 and 17 to pyridinone 5 (Scheme
3). Addition of ammonia gives the intermediates 18 and
19, which will cyclize to the meta-bridged intermediates
Synthesis 2010, No. 8, 1339–1343 © Thieme Stuttgart · New York

PAPER
Synthesis of Nitro-Substituted Tetrahydropyridoazepines
1341
Table 3 Influence of Different Residues on the Condensation Reac-
tion
O
O
Entry
R
Temp (°C) Time (h) Selectivitya
Yield (%)
1
2
3
4
5
6
7
8
Cbz
Cbz
COPh
COPh
Bn
100b
r.t.
0.5
24
64:36 (6/10)
86:14 (6/10)
55:45 (7/11)
79:21 (7/11)
42:58 (8/12)
53:47 (8/12)
31:69 (9/13)
44:56 (9/13)
90
56
95
60
43
54
34
57
N
N
R
R
16
17
100b
r.t.
0.5
24
5, NH3
5, NH3
100b
r.t.
0.5
24
NH2
NH2
Bn
O2N
NO2
O
O2N
NO2
100b
r.t.
0.5
24
R
Me
N
N
N
O
N
Me
R
Me
Me
O
O
a Determined by 1H NMR spectroscopy.
b Heated by microwave irradiation.
18
19
NMR spectra were recorded on a Bruker Avance 400 spectrometer.
IR spectra were recorded on a PerkinElmer Paragon 500 FTIR-
spectrometer. LC/MS analyses were conducted using the Agilent
1100 HPLC system equipped with a mass-selective detector and a
GROM-SIL 80 ODS-7pH column. Separation of regioisomers were
performed with an Agilent 1100 preparative HPLC system
equipped with autosampler, fraction collector, and a ProntoSil
Prep012 120-C18 ace-EPS column.
H
NO2
H
NO2
NO2
NO2
HN
HN
N
O
N
O
Me
Me
N
N
R
20
21
R
Nitro-Substituted Tetrahydropyridoazepines; Benzyl 3-Nitro-
6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine-6-carboxylate (6)
and Benzyl 3-Nitro-6,7,8,9-tetrahydro-5H-pyrido[2,3-
R
NO2
NO2
Me
NO2
NO2
Me
N
d]azepine-7-carboxylate (10); Typical Procedure
R
N
Benzyl 4-oxoazepane-1-carboxylate (1; 49 mg, 0.20 mmol) and 1-
methyl-3,5-dinitropyridin-2(1H)-one (5; 44 mg, 0.22 mmol) were
dissolved in a solution of ammonia in MeOH (2.0 mL, 7.0 M). The
reaction mixture was stirred in a sealed tube at r.t. for 24 h or heated
in a microwave to 100 °C for 30 min. The solvent was evaporated
under reduced pressure. The residue was purified by column chro-
matography (silica gel, cyclohexane–EtOAc) to give the desired
product as a mixture of regioisomers 6 and 10 (see below). Unreact-
ed benzyl-4-oxoazepane-1-carboxylate (1) could not be separated
by column chromatography. The purity of the product and the ratio
of regioisomers was determined by 1H NMR spectroscopy.
N
H
N
H
O
N
O
N
H
H
22
23
R
NO2
NO2
N
R
N
N
N
6–9
10–13
The yield of benzyl 3-nitro-6,7,8,9-tetrahydro-5H-pyridoazepine-
carboxylates 6 and 10 was calculated on the basis of purity. The re-
gioisomers 6 and 10 were separated by preparative HPLC, while the
regioisomers 9 and 13 were separated by column chromatography
(silica gel, CH2Cl2–MeOH–NH3).
Scheme 3 Proposed reaction mechanism
In summary, microwave irradiation was shown to have a
beneficial effect on the rate of the reaction of azepan-4-
ones with pyridinone 5 in the presence of ammonia. The
condensation reaction was performed under elevated pres-
sure, at temperatures exceeding the boiling point of the
solvent, giving the desired tetrahydropyridoazepines in
excellent yield (up to 95%) and with short reaction times.
Substituents at the nitrogen of the azepan-4-one, contain-
ing a carbonyl group, were found to stabilize the interme-
diate enolate 16, enabling the regioselective synthesis of
tetrahydropyrido[3,2-c]azepines.
Benzyl 3-Nitro-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine-6-
carboxylate (6) and Benzyl 3-Nitro-6,7,8,9-tetrahydro-5H-pyri-
do[2,3-d]azepine-7-carboxylate (10); Two-Step Procedure
Azepane-4-one hydrochloride (15; 30 mg, 0.20 mmol) and 1-meth-
yl-3,5-dinitropyridin-2(1H)-one (5; 44 mg, 0.22 mmol) were dis-
solved in a solution of ammonia in MeOH (2.0 mL, 7.0 M). The
reaction mixture was stirred in a sealed tube at r.t. for 24 h or heated
in a microwave to 100 °C for 30 min. The solvent was evaporated
under reduced pressure. The residue was dissolved in EtOAc (10
mL); the EtOAc layer was washed with H2O (3 × 2.0 mL) and dried
(MgSO4). The solvent was evaporated under reduced pressure. The
residue was dissolved in CH2Cl2 (2.0 ml) together with Et3N (0.04
mL, 0.26 mmol) and 4-dimethylaminopyridine (3 mg, 0.02 mmol).
At 0 °C, a solution of benzyl chloroformate in toluene (50 wt%,
The condensation reactions were performed using a CEM Discover
microwave equipped with an Explorer autosampler. H and 13C
1
Synthesis 2010, No. 8, 1339–1343 © Thieme Stuttgart · New York

1342
T. Schultz et al.
PAPER
6-Benzyl-3-nitro-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine
0.08 mL, 81 mg, 0.24 mmol) was added. The reaction mixture was
warmed to r.t. overnight. A solution of NaHCO3 (4.0 mL) was add-
ed. The mixture was extracted with CH2Cl2 (3 × 5.0 mL) and the
combined organic phases were dried (MgSO4). The solvent was
evaporated under reduced pressure and the residue purified by col-
umn chromatography (silica gel, cyclohexane–EtOAc) to afford the
desired product as a mixture of regioisomers.
(8)
1H NMR (400.1 MHz, CDCl3): d = 9.18 (s, 1 H, CHarom), 7.95 (s, 1
H, CHarom), 7.33–7.22 (m, 5 H, CHarom), 3.89 (s, 2 H, CH2), 3.59 (s,
2 H, PhCH2), 3.30 (m, 2 H, CH2), 3.16 (m, 2 H, CH2), 1.86 (m, 2 H,
CH2).
13C {1H} NMR (125.8 MHz, CDCl3): d = 169.9 (Carom), 142.6
(CHarom), 138.2, (Carom), 137.9 (Carom), 131.3 (CHarom), 128.9
(CHarom), 128.7 (CHarom), 128.5 (CHarom), 128.4 (CHarom), 127.3
(CHarom), 59.0 (PhCH2), 58.7 (CH2), 57.2 (CH2), 39.9 (CH2), 23.6
(CH2).
6
IR (ATR): 2934w, 1694s, 1581m, 1514m, 1424s, 1337s, 1257m,
1242m, 1213m, 1185m, 1107s, 1085m, 1042m, 976m, 935m,
914m, 886w, 822w, 771m, 742s, 698s, 677w, 605m cm–1.
LC/MS (MeCN–H2O–HCO2H, 0.6 mL/min, 70 °C, 20 V): tR = 1.46
min; m/z = 284.2 [M + H]+.
1H NMR (400.1 MHz, CDCl3): d = 9.18 (s, 0.45 H, CHarom, rotam-
er), 9.13 (s, 0.55 H, CHarom, rotamer), 8.39 (s, 0.45 H, CHarom, rota-
mer), 8.05 (s, 0.55 H, CHarom, rotamer), 7.30 (m, 4 H, CHarom, Bn),
7.21 (m, 1 H, CHarom, Bn), 5.04 (br, 2 H, PhCH2), 4.55 (s, 0.9 H,
CH2, rotamer), 4.50 (s, 1.1 H, CH2, rotamer), 3.84 (br, 2 H, CH2),
3.33 (m, 2 H, CH2), 1.90 (m, 2 H, CH2).
13C {1H} NMR (125.8 MHz, CDCl3): d = 169.6 (Carom), 169.3
(Carom), 156.4 (C=O), 156.1 (C=O), 144.0 (CHarom), 143.9 (Carom),
143.5 (Carom) 137.4 (Carom), 137.1 (Carom), 135.9 (Carom), 135.8 (Car-
om), 132.7 (CHarom) 132.2 (CHarom), 129.9 (CHarom), 129.8 (CHarom),
129.7 (CHarom), 129.6 (CHarom), 129.5 (CHarom), 129.2 (CHarom),
69.7 (PhCH2), 69.4 (PhCH2), 53.1 (CH2), 52.8 (CH2), 52.6 (CH2),
52.1 (CH2), 40.6 (CH2), 40.5 (CH2), 29.03 (CH2), 28.4 (CH2).
7-Benzyl-3-nitro-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine
(12)
1H NMR (400.1 MHz, CDCl3): d = 9.14 (s, 1 H, CHarom), 8.16 (s, 1
H, CHarom), 7.33–7.22 (m, 5 H, CHarom), 3.66 (s, 2 H, PhCH2), 3.30
(m, 2 H, CH2), 3.01 (m, 2 H, CH2), 2.70 (m, 4 H, CH2).
13C {1H} NMR (125.8 MHz, CDCl3): d = 169.0 (Carom), 141.9
(CHarom), 137.8 (Carom), 130.7 (CHarom), 128.9 (CHarom), 128.7
(CHarom), 128.5 (CHarom), 128.4 (CHarom), 127.5 (CHarom), 63.4
(PhCH2), 54.3 (CH2), 53.0 (CH2), 38.9 (CH2), 35.0 (CH2).
LC/MS (MeCN–H2O–HCO2H, 0.6 mL/min, 70 °C, 20 V): tR = 1.86
min; m/z = 284.2 [M + H]+.
LC/MS (MeCN–H2O–TFA, 0.5 mL/min, 60 °C, 20 V): tR = 6.55
min; m/z = 328.1 [M + H]+, 350.1 [M + Na]+.
6-Methyl-3-nitro-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine
(9)
10
1H NMR (400.1 MHz, CDCl3): d = 9.15 (s, 1 H, CHarom), 9.19 (s, 1
H, CHarom), 3.86 (s, 2 H, CH2), 3.24 (m, 2 H, CH2), 3.05 (m, 2 H,
CH2), 2.37 (s, 3 H, CH3), 1.86 (m, 2 H, CH2).
IR (ATR): 3064w, 2962w, 1686s, 1596m, 1579m, 1512s, 1463w,
1454m, 1426s, 1346s, 1332s, 1282w, 1232s, 1181m, 1094s, 1038w,
988m, 947s, 915m, 806m, 766m, 746s, 696s, 600m, 563s cm–1.
13C {1H} NMR (125.8 MHz, CDCl3): d = 169.7 (Carom), 142.7
(CHarom), 142.7 (Carom), 135.5 (Carom), 131.3 (CHarom), 60.9 (CH2),
60.3 (CH2), 44.1 (CH3), 38.7 (CH2), 23.8 (CH2).
1H NMR (400.1 MHz, CDCl3): d = 9.17 (s, 1 H, CHarom), 8.26 (br,
1 H, CHarom), 7.35 (m, 5 H, CHarom), 5.18 (s, 2 H, PhCH2), 3.73 (br,
4 H, CH2), 3.32 (br, 2 H, CH2), 3.06 (br, 2 H, CH2).
13C {1H} NMR (125.8 MHz, CDCl3): d = 166.8 (Carom), 155.5
(C=O), 143.0 (Carom), 141.5 (CHarom), 137.6 (Carom), 136.3 (Carom),
132.4 (CHarom), 128.6 (CHarom), 128.3 (CHarom), 129.1 (CHarom),
67.8 (PhCH2), 45.9 (CH2), 44.5 (CH2), 40.2 (CH2), 35.6 (CH2).
LC/MS (MeCN–H2O–HCO2H, 0.6 mL/min, 70 °C, 20 V): tR = 0.27
min; m/z = 208.1 [M + H]+.
7-Methyl-3-nitro-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine
(13)
LC/MS (MeCN–H2O–TFA, 0.5 mL/min, 60 °C, 20 V): tR = 6.68
min; m/z = 328.1 [M + H]+, 350.1 [M + Na]+.
1H NMR (400.1 MHz, CDCl3): d = 9.13 (s, 1 H, CHarom), 8.16 (s, 1
H, CHarom), 3.29 (m, 2 H, CH2), 3.02 (m, 2 H, CH2), 2.64 (m, 4 H,
CH2), 2.41 (s, 3 H, CH3).
6-Benzoyl-3-nitro-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine
(7)
13C {1H} NMR (125.8 MHz, CDCl3): d = 168.8 (Carom), 142.9
(Carom), 142.0 (CHarom), 137.7 (Carom), 130.7 (CHarom), 56.4 (CH2),
55.0 (CH2), 47.4 (CH3), 39.7 (CH2), 34.9 (CH2).
1H NMR (400.1 MHz, CD3OD): d = 9.18 (s, 1 H, CHarom), 8.61 (s,
1 H, CHarom), 7.49–7.40 (m, 3 H, CHarom), 7.34 (m, 2 H, CHarom),
4.91 (s, 1.4 H, CH2, rotamer), 4.66 (s, 0.6 H, CH2, rotamer), 4.10 (br,
0.6 H, CH2, rotamer), 3.84 (br, 1.4 H, CH2, rotamer), 3.42 (m, 2 H,
CH2), 2.01 (br, 0.6 H, CH2, rotamer), 1.85 (br, 1.4 H, CH2, rotamer).
LC/MS (MeCN–H2O–HCO2H, 0.6 mL/min, 70 °C, 20 V): tR = 0.28
min; m/z = 208.1 [M + H]+.
13C {1H} NMR (125.8 MHz, CD3OD): d = 173.4 (C=O), 169.7
(Carom), 144.4 (Carom), 143.7 (CHarom), 137.2 (Carom), 136.7 (Carom),
133.4 (CHarom), 131.1 (CHarom), 129.9 (CHarom), 127.6 (CHarom),
54.4 (CH2), 49.7 (CH2), 38.3 (CH2), 28.6 (CH2).
Acknowledgment
Supply of 3,5-dinitro-1-methylpyridin-2(1H)-one from the labora-
tory of Dr. M. Thyes, and analytical support from Dr. C. Krack, M.
Diehl, K. Lang, and R. Kostiza are gratefully acknowledged.
LC/MS (MeCN–H2O–TFA, 0.5 mL/min, 60 °C, 20 V): tR = 5.30
min; m/z = 298.1 [M + H]+.
References
7-Benzoyl-3-nitro-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine
(11)
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1H NMR (400.1 MHz, CD3OD): d = 9.15 (s, 1 H, CHarom), 8.48 (s,
0.5 H, CHarom, rotamer), 8.38 (s, 0.5 H, CHarom, rotamer), 7.49–7.40
(m, 5 H, CHarom), 3.97 (m, 2 H, CH2), 3.67 (br, 2 H, CH2), 3.64 (br,
1 H, CH2), 3.27 (br, 2 H, CH2), 3.27 (br, 1 H, CH2).
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LC/MS (MeCN–H2O–TFA, 0.5 mL/min, 60 °C, 20 V): tR = 5.30
min; m/z = 298.1 [M + H]+.
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Synthesis 2010, No. 8, 1339–1343 © Thieme Stuttgart · New York