Synthesis of N-arylmethyl-3-azabicyclo[3.3.1]nonan-9-ones

Full text of DOI:10.1134/S1070428009030257

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 3, pp. 472–474. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © A.I. Moskalenko, V.I. Boev, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 3, pp. 481–483.
SHORT
COMMUNICATIONS
Synthesis of N-Arylmethyl-3-azabicyclo[3.3.1]nonan-9-ones
A. I. Moskalenko and V. I. Boev
Lipetsk State Pedagogical University, ul. Lenina 42, Lipetsk, 398020 Russia
e-mail: zoologia@lspu.lipetsk.ru
Received February 13, 2008
DOI: 10.1134/S1070428009030257
Interest in nitrogen-containing bicyclic compounds
is related to the fact that they constitute structural
fragments of a number of alkaloids [1] such as atropine
and cocaine, which are used in medicine as spasmolyt-
ics and anesthetics [2]. N-Substituted 3-azabicyclo-
[3.3.1]nonan-9-ones also belong to the above class of
compounds; however, they have been poorly studied,
presumably because of the lack of convenient methods
for their preparation. The procedures reported in [3, 4]
for the synthesis of N-benzyl-3-azabicyclo[3.3.1]-
nonan-9-one (I) ensured only ~8% yield of the target
product.
In the present communication we describe an im-
proved procedure for the synthesis of compound I,
which was also used to obtain new 3-azabicyclo-
[3.3.1]nonan-9-one derivatives II–V. Compounds I–V
were synthesized according to Mannich via double
aminomethylation with substituted benzylamines in the
presence of formaldehyde on heating in acetic acid
(Scheme 1). Optimization of the reaction conditions
and isolation procedure allowed us to raise the yield of
target products I–V to 30–35%. No appreciable effect
of the substituent R on the yield of I–V was observed.
9-oxo-3-azabicyclo[3.3.1]nonane-3-carboxylate (VII)
(Scheme 2).
N-Benzyl-3-azabicyclo[3.3.1]nonan-9-one (I).
Benzylamine, 47 g (0.44 mol), was cooled with cold
water, 37 ml of concentrated hydrochloric acid, 35.3 g
(0.36 mol) of cyclohexanone, 90 ml of a formaldehyde
solution, and 500 ml of glacial acetic acid were added
in succession on cooling, and the mixture was stirred
for 2.5 h at 85–90°C under argon and was left over-
night at room temperature. The mixture was evaporat-
ed at 80°C, the oily residue was treated with 200 ml of
water, and the resulting solution was extracted with di-
ethyl ether (2×200 ml). The aqueous phase was made
alkaline by adding in small portions under stirring
160–170 g of sodium carbonate, and the product was
extracted into methylene chloride (3×150 ml); the
extract was washed with water, dried over anhydrous
sodium sulfate, and evaporated, 100 ml of ethanol was
added to the oily residue, 35 ml of acetic anhydride
was added in portions under stirring, and the mixture
was stirred for 2 h. The mixture was treated with 37 ml
of concentrated hydrochloric acid, stirred for 2 h, and
evaporated at 60°C, 400 ml of water was added to the
residue, the mixture was extracted with methylene
chloride (2×100 ml), the yellow aqueous phase was
made alkaline by adding sodium carbonate and ex-
tracted again with methylene chloride (3×100 ml), the
extract was dried over anhydrous sodium sulfate, the
solvent was distilled off, and the residue was distilled
Catalytic reductive dealkylation of compounds I–V
with ammonium formate in the presence of 10% Pd/C
in boiling ethanol afforded 3-azabicyclo[3.3.1]nonan-
9-one (VI) in high yield, and the latter was subjected
(without isaolation) to acylation with di-tert-butyl di-
carbonate (Boc2O). We thus isolated stable tert-butyl
Scheme 1.
O
R
O
AcOH, 85–90°C
NH2
+
+ CH2O
N
R
I–V
I, R = H; II, R = Me; III, R = F; IV, R = Br; V, R = MeO.
472

SYNTHESIS OF N-ARYLMETHYL-3-AZABICYCLO[3.3.1]NONAN-9-ONES
473
Scheme 2.
O
O
HCOONH4, Pd/C
–RC6H4Me-4
Boc2O, K2CO3
I–V
HN
t-BuO
N
O
VI
VII
N-(4-Methoxyphenylmethyl)-3-azabicyclo[3.3.1]-
nonan-9-one (V). Yield 31%, mp 71–72°C, Rf 0.39. IR
under reduced pressure in a stream of argon, a fraction
boiling in the temperature range from 148 to 155°C
(0.8 mm) being collected. The light yellow oily distil-
late crystallized on cooling in several hours. The prod-
uct was finally purified by chromatography on silica
gel using hexane as eluent. Yield 26.21 g (32%). Light
yellow crystals, mp 49–50°C [4], Rf 0.49. IR spectrum:
1
spectrum: ν 1721 cm–1 (C=O). H NMR spectrum, δ,
ppm: 1.46–2.08 m (6H, CH2), 2.31–2.36 m (2H, CH),
2.91 d (2H, NCH2), 3.02 d (2H, NCH2), 3.60 s (2H,
ArCH2N), 3.80 s (3H, CH3O), 7.42 d and 7.80 d (2H
each, C6H4, Ј = 7.6 Hz). Mass spectrum: m/z 260
[M + H]+. Found, %: C 74.12; H 8.04; N 5.48.
C16H21NO2. Calculated, %: C 74.15; H 8.10; N 5.40.
1
ν 1720 cm–1 (C=O). H NMR spectrum, δ, ppm: 1.47–
2.12 m (6H, CH2), 2.30–2.35 m (2H, CH), 2.85 d (2H,
NCH2), 2.96 d (2H, NCH2), 3.44 s (2H, PhCH2N),
7.2–7.4 m (5H, C6H5). Mass spectrum: m/z 230
[M + H]+. Found, %: C 78.56; H 8.28; N 6.15.
C15H19NO. Calculated, %: C 78.67; H 8.30; N 6.11.
tert-Butyl 9-oxo-3-azabicyclo[3.3.1]nonane-3-
carboxylate (VII). Compound I–V, 0.05 mol, was
dissolved in 100 ml of ethanol, 12.6 g (0.2 mol) of
ammonium formate and 10 g of 10% Pd/C were added,
and the mixture was heated for 6–7 h under reflux on
stirring in an argon atmosphere. During the reaction,
additional amount of ammonium formate (10 g,
0.16 mol) and the catalyst (8 g) were added. The mix-
ture was cooled and filtered through a layer of zeolite,
the filtrate was evaporated at 60°C, the oily residue
was dissolved in 200 ml of methylene chloride, the so-
lution was washed with water, 150 ml of 10% aqueous
sodium hydrogen carbonate was added, and a solution
of 13.1 g (0.06 mol) of di-tert-butyl dicarbonate in
80 ml of methylene chloride was then gradually added
under stirring. The mixture was stirred for 12 h, the
organic phase was separated, dried over anhydrous
sodium sulfate, and evaporated, and the oily residue
was subjected to chromatography on silica gel using
hexane–ethyl acetate (9:1) as eluent. The product was
additionally recrystallized from hexane on cooling.
Yield 9.32 g (78%), mp 89–90°C. IR spectrum, ν,
Compounds II–V were synthesized according to
a similar procedure.
N-(4-Methylphenylmethyl)-3-azabicyclo[3.3.1]-
nonan-9-one (II). Yield 31%, mp 54–55°C, Rf 0.58. IR
1
spectrum: ν 1722 cm–1 (C=O). H NMR spectrum, δ,
ppm: 1.46–2.09 m (6H, CH2), 2.24 s (3H, CH3), 2.30–
2.34 m (2H, CH), 2.85 d (2H, NCH2), 2.98 d (2H,
NCH2), 3.42 s (2H, ArCH2N), 7.10 d and 7.22 d (2H
each, C6H4, Ј = 8 Hz). Mass spectrum: m/z 244
[M + H]+. Found, %: C 79.08; H 8.73; N 5.69.
C16H21NO. Calculated, %: C 79.03; H 8.64; N 5.76.
N-(4-Fluorophenylmethyl)-3-azabicyclo[3.3.1]-
nonan-9-one (III). Yield 35%, mp 48–49°C, Rf 0.46.
1
IR spectrum: ν 1720 cm–1 (C=O). H NMR spectrum,
δ, ppm: 1.48–2.11 m (6H, CH2), 2.32–2.36 m (2H,
CH), 2.89 d (2H, NCH2), 3.01 d (2H, NCH2), 3.58 s
(2H, ArCH2N), 7.18–7.35 m (4H, C6H4). Mass spec-
trum: m/z 248 [M + H]+. Found, %: C 72.76; H 7.31;
N 5.64. C15H18FNO. Calculated, %: C 72.89; H 7.28;
N 5.66.
1
cm–1: 1721, 1682 (C=O). H NMR spectrum, δ, ppm:
1.31 s (9H, t-Bu), 1.47–2.09 m (6H, CH2), 2.38–
2.44 m (2H, CH), 3.42 d (2H, NCH2), 3.64 d (2H,
NCH2). Mass spectrum, m/z: [M + H]+ 240, [M –
57 + H]+ 183, [M – 101 + H]+ 139. Found, %: C 65.18;
H 8.72; N 5.87. C13H21NO3. Calculated, %: C 65.29;
H 8.78; N 5.85.
N-(4-Bromophenylmethyl)-3-azabicyclo[3.3.1]-
nonan-9-one (IV). Yield 33%, mp 62–63°C, Rf 0.48.
1
IR spectrum: ν 1719 cm–1 (C=O). H NMR spectrum,
δ, ppm: 1.47–2.10 m (6H, CH2), 2.30–2.37 m (2H,
CH), 2.89 d (2H, NCH2), 3.00 d (2H, NCH2), 3.61 s
(2H, ArCH2N), 7.15 d and 7.60 d (2H each, C6H4, Ј =
8 Hz). Mass spectrum: m/z 309 [M + H]+. Found, %:
C 58.57; H 5.75; N 4.48. C15H18BrNO. Calculated, %:
C 58.46; H 5.84; N 4.54.
The IR spectra were recorded on a Specord 75IR
spectrometer from thin films. The H NMR spectra
were measured on a Varian Mercury Plus-400 spec-
trometer (400 MHz) from solutions in CDCl3 using
HMDS as internal reference. The mass spectra (atmos-
pheric pressure chemical ionization) were obtained on
1
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MOSKALENKO, BOEV
474
2. Yakhontov, L.N. and Glushkov, R.G., Sinteticheskie
lekarstvennye sredstva (Synthetic Medicines), Moscow:
Meditsina, 1983.
a Thermo Finnigan Surveyor MSQ instrument (USA).
The purity of the products was checked by TLC on
Silufol UV-254 plates using hexane–ethyl acetate
(10:1) as eluent; spots were visualized under UV light.
3. Ohki, E., Oida, S., Ohashi, Y., Yoshida, A., Kamoshi-
ta, K., and Takagi, H., Chem. Pharm. Bull., 1974, vol. 22,
p. 1014.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 3 2009