Schmidt reaction and beckmann rearrangement in the series of 3-azabicyclo[3.3.1]nonan-9-one derivatives

Full text of DOI:10.1134/S1070428010040317

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 4, pp. 602–604. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © A.I. Moskalenko, V.I. Boev, 2010, published in Zhurnal Organicheskoi Khimii, 2010, Vol. 46, No. 4, pp. 609–610.
SHORT
COMMUNICATIONS
Schmidt Reaction and Beckmann Rearrangement in the Series
of 3-Azabicyclo[3.3.1]nonan-9-one Derivatives
A. I. Moskalenko and V. I. Boev
Lipetsk State Pedagogical University, ul. Lenina 43, Lipetsk, 398020 Russia
e-mail: kaf_himii@lspu.lipetsk.ru
Received July 16, 2008
DOI: 10.1134/S1070428010040317
While developing our studies [1] on the reactivity
of 3-azabicyclo[3.3.1]nonan-9-one derivatives, which
are fairly accessible compounds [2], in the present
work we used these ketones as substrates in the
Schmidt reaction [3], and the corresponding oximes, in
the Beckmann rearrangement [4]. N-Arylmethyl-3-aza-
bicyclo[3.3.1]nonan-9-ones I–III reacted with sodium
azide in the presence of concentrated sulfuric acid at
–5 to 0°C, following the Schmidt reaction pattern [5],
to form new bicyclic compounds IV–VI (Scheme 1).
azabicyclo[3.3.2]decan-9-one which was isolated as
trifluoroacetate VIII (Scheme 3).
Scheme 3.
O
t-BuO
N
( )3
NOH
VII
HN
CF3COOH
–CO2
O ·CF3COOH
Scheme 1.
NH
VIII
–CF3COOBu-t
N
( )3
R
O
The reaction of salt VIII with benzyl bromide in
the presence of potassium carbonate in anhydrous di-
methyl sulfoxide (DMSO) resulted in alkylation of the
amino nitrogen atom to give compound IV. Likewise,
acylation of salt VIII with di-tert-butyl dicarbonate
(Boc2O) in a two-phase system (aqueous K2CO3–
CH2Cl2) afforded bicyclic diamide IX (Scheme 4).
I–III
NaN3, H2SO4
–5 to 0°C
N
O
NH
R
IV–VI
Compound IV was also synthesized by Beckmann
rearrangement of previously described ketone I oxime
[1] on heating in polyphosphoric acid (Scheme 2).
Scheme 4.
PhCH2Br
DMSO
IV
+
KBr
N
Scheme 2.
K2CO3
–CO2
O
VIII
Ph
N
PPA, 100°C
Boc2O
CH2Cl2–H2O
( )3
–CF3COOK
IV
t-BuO
O
NOH
NH
Another oxime VII [1] possessing a tert-butoxy-
carbonyl group (Boc) was subjected to Beckmann re-
arrangement on heating in boiling trifluoroacetic acid.
The process was accompanied by elimination of the
tert-butoxycarbonyl group with formation of 3,10-di-
IX
The structure of compounds IV–VI, VIII, and IX
was confirmed by elemental analyses and IR, 1H NMR,
and mass (electrospray ionization) spectra. The prod-
602

SCHMIDT REACTION AND BECKMANN REARRANGEMENT
603
ucts possess amino and amide groups and attract inter-
est as promising intermediate compounds in organic
synthesis.
3-(4-Methylbenzyl)-3,9-diazabicyclo[3.3.2]decan-
10-one (V). Yield 44%, mp 146–147°C. IR spectrum,
1
ν, cm–1: 3240 (NH), 1680 (C=O). H NMR spectrum,
δ, ppm: 1.34–2.05 m (6H, CH2), 2.14–2.32 m (5H, CH,
CH3), 2.67 d (2H, NCH2), 2.81 s (2H, NCH2), 3.48 s
(2H, C6H4CH2), 7.11 d (2H, C6H4, J = 7.8 Hz), 7.23 d
(2H, C6H4, J = 7.8 Hz), 7.52 m (1H, NH). Mass spec-
trum: m/z 259 [M + H]+. Found, %: C 74.28; H 8.41;
N 10.73. C16H22N2O. Calculated, %: C 74.43; H 8.52;
N 10.85.
3-Benzyl-3,9-diazabicyclo[3.3.2]decan-10-one
(IV). a. A solution of 6.0 g (26 mmol) of ketone I [2]
in 25 ml of chloroform was cooled to –10 to 0°C,
23 ml of concentrated sulfuric acid was added under
vigorous stirring, and 5.1 g (78 mmol) of sodium azide
was added in portions, maintaining the temperature
below 0°C. The mixture was then stirred for 2 h at –10
to 0°C, treated with 20 ml of water, neutralized with
75 ml of a concentrated ammonia solution, and extract-
ed with chloroform (2×50 ml). The organic phase was
washed with two portions of water, dried over anhy-
drous sodium sulfate, and evaporated under reduced
pressure. The residue was dissolved in ethyl acetate
and purified by flash chromatography on silica gel
using ethyl acetate–hexane (10:1) as eluent. Yield
2.67 g (42%), light yellow crystals, mp 131–132°C. IR
3-(4-Fluorobenzyl)-3,9-diazabicyclo[3.3.2]decan-
10-one (VI). Yield 40%, mp 127–128°C. IR spectrum,
1
ν, cm–1: 3244 (NH), 1684 (C=O). H NMR spectrum,
δ, ppm: 1.32–2.06 m (6H, CH2), 2.15–2.28 m (2H,
CH), 2.71 d (2H, NCH2), 2.87 s (2H, NCH2), 3.52 s
(2H, C6H4CH2), 7.19–7.37 m (4H, C6H4), 7.54 d (1H,
NH). Mass spectrum: m/z 263 [M + H]+. Found, %:
C 68.53; H 7.18; N 10.59. C15H19FN2O. Calculated, %:
C 68.72; H 7.25; N 10.68.
1
spectrum, ν, cm–1: 3242 (NH), 1682 (C=O). H NMR
10-Oxo-3,9-diazabicyclo[3.3.2]decan-3-ium
trifluoroacetate (VIII). A mixture of 26.75 g
(105 mmol) of oxime VII [1] and 60 ml of anhydrous
trifluoroacetic acid was heated for 1 h under reflux.
The mixture was evaporated under reduced pressure,
500 ml of anhydrous diethyl ether was added to the
residue, and the mixture was left to stand for 15 h at
5–6°C in a refrigerator. The precipitate was filtered off,
washed with 100 ml of diethyl ether, and dried under
reduced pressure over anhydrous calcium chloride.
Yield 13.63 g (49%), colorless crystals, mp 201–203°C
(decomp.). IR spectrum, ν, cm–1: 3448, 3245 (NH);
spectrum, δ, ppm: 1.32–2.06 m (6H, CH2), 2.15–
2.28 m (2H, CH), 2.83 d (2H, NCH2), 3.48 s (2H,
PhCH2N), 7.18–7.32 m (5H, C6H5), 7.50 s (1H, NH).
Mass spectrum: m/z 245 [M + H]+. Found, %: C 73.78;
H 8.06; N 11.32. C15H20N2O. Calculated, %: C 73.79;
H 8.19; N 11.47.
b. A mixture of 5 g (20 mmol) of ketone I oxime [1]
and 40 g of polyphosphoric acid was stirred for 6 h at
100°C. The mixture was diluted with 100 ml of water,
neutralized with concentrated aqueous ammonia to pH
8–9, and extracted with chloroform (3×50 ml), the ex-
tract was washed with two portions of water, dried
over anhydrous sodium sulfate, and evaporated under
reduced pressure, and the residue was dissolved in
ethyl acetate and purified by flash chromatography on
silica gel using ethyl acetate–hexane (10:1) as eluent.
Yield 3.68 (75%), mp 131–132°C.
1
1710, 1692 (C=O). H NMR spectrum, δ, ppm: 1.51–
2.05 m (6H, CH2), 2.61 s (1H, OCH), 3.15 m (1H,
NCH), 3.45 d (2H, NCH2), 3.56 d (2H, NCH2),
+
8.12 br.s (1H, NH), 10.70 s (2H, NH2). Mass spec-
trum: m/z 155 [M + H]+. Found, %: C 44.63; H 5.34;
N 10.31. C8H14N2O · CF3COOH. Calculated, %:
C 44.80; H 5.59; N 10.44.
c. Benzyl bromide, 6.84 g (40 mmol), was added
under stirring to a mixture of 10.72 g (40 mmol) of salt
VIII and 11.04 (80 mmol) of finely powdered K2CO3
in 100 ml of anhydrous DMSO, and the mixture was
stirred for 5 h at 100°C. The mixture was then diluted
with 500 ml of water and extracted with CHCl3
(3×100 ml), the extract was washed with two portions
of water, dried over anhydrous Na2SO4, and evaporat-
ed under reduced pressure, and the residue was dis-
solved in ethyl acetate and purified by flash chroma-
tography on silica gel using ethyl acetate–hexane
(10:1) as eluent. Yield 7.05 g (72%), mp 131–132°C.
tert-Butyl 10-oxo-3,9-diazabicyclo[3.3.2]decane-
3-carboxylate (IX). Di-tert-butyl dicarbonate, 1.308 g
(6 mmol), was added under vigorous stirring to a mix-
ture of 1.072 g (4 mmol) of salt VIII, 0.7 g (5 mmol)
of potassium carbonate, 10 ml of methylene chloride,
and 10 ml of water. The mixture was stirred for 12 h,
the organic layer was separated, and the aqueous layer
was extracted with methylene chloride (2×20 ml). The
extracts were combined with the organic phase, washed
with water, dried over anhydrous sodium sulfate, and
evaporated under reduced pressure, and the residue
was crystallized from hexane on cooling to –40°C over
a period of 3 days. Yield 0.62 g (61%), mp 101–102°C.
Compounds V and VI were synthesized as de-
scribed above for compound IV (method a).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 4 2010

MOSKALENKO, BOEV
604
IR spectrum, ν, cm–1: 3241 (NH); 1687, 1682 (C=O).
1H NMR spectrum, δ, ppm: 1.30 s (9H, t-Bu), 1.36–
2.05 m (6H, CH2), 2.12–2.32 m (2H, CH), 3.41 d (2H,
NCH2), 3.68 d (2H, NCH2), 7.64 s (1H, NH). Mass
spectrum, m/z: 255 [M + H]+, 198 [M – 57 + H]+, 154
[M – 101 + H]+. Found, %: C 61.53; H 8.57; N 10.93.
C13H22N2O3. Calculated, %: C 61.44; H 8.66; N 11.02
REFERENCES
1. Moskalenko, A.I. and Boev, V.I., Russ. J. Org. Chem.,
2009, vol. 45, p. 895.
2. Moskalenko, A.I. and Boev, V.I., Russ. J. Org. Chem.,
2009, vol. 45, p. 472.
3. Wolff, H., Organic Reactions, Adams, R., Ed., New York:
Wiley, 1946, vol. 3. Translated under the title Organi-
cheskie reaktsii, Moscow: Inostrannaya Literatura, 1951,
vol. 3, p. 293.
The IR spectra were recorded in KBr on a Specord
1
75IR spectrometer. The H NMR spectra were meas-
ured on a Bruker DPX-400 instrument at 400 MHz
using DMSO-d6 as solvent and HMDS as internal re-
ference. The mass spectra (atmospheric pressure chem-
ical ionization) were obtained on a Surveyor MSQ
Thermo Finnigan GC–MS system (USA).
4. Knunyants, I.L. and Fabrichnyi, B.P., Reaktsii i metody
issledovaniya organicheskikh soedinenii (Reactions and
Methods of Investigation of Organic Compounds),
Moscow: Goskhimizdat, 1954, vol. 3, p. 137.
5. Conley, R., J. Org. Chem., 1958, vol. 23, p. 1330.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 4 2010