Reductive transformations of unsaturated azabicyclic nitrolactams

Article abstract of DOI:10.1016/j.tet.2012.04.100

Using different reducing methods unsaturated indolizidine and quinolizidine lactams substituted with a nitro group were transformed into various alkaloid-like derivatives. Hydrogen transfer and palladium catalyzed hydrogenation gave compounds of ketolactam or lactam type meanwhile the nitro group was eliminated. On the other hand, in presence of Raney-nickel catalyst the nitro compounds were reduced to diastereomeric amino derivatives whose stereochemistry was elucidated by NMR spectroscopy. Using sodium bis-dimethoxy-ethoxy-aluminum-hydride (Red-Al) as reducing agent an unexpected tricyclic azetidine was isolated and characterized.

Full text of DOI:10.1016/j.tet.2012.04.100

Tetrahedron 68 (2012) 5547e5553
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Reductive transformations of unsaturated azabicyclic nitrolactams
a
a
a
a
b
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢁ
Mihaly Viktor Pilipecz , Tamas Robert Varga , Pal Scheiber , Zoltan Mucsi , Amelie Favre-Mourgues ,
b
b
c
a,
*
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Sandor Boros , Laszlo Balazs , Gabor Toth , Peter Nemes
Department of Chemistry, Faculty of Veterinary Science, Szent Istvan University, H-1400 Budapest, P.O. Box 2, Hungary
Chinoin Ltd, To utca 1-5, H-1045 Budapest, Hungary
Department of Inorganic and Analytical Chemistry, University of Technology and Economics, 1111 Budapest, Szt. Gellert ter 4, Hungary
a
ꢀ
b
c
ꢀ
ꢀ
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Using different reducing methods unsaturated indolizidine and quinolizidine lactams substituted with
a nitro group were transformed into various alkaloid-like derivatives. Hydrogen transfer and palladium
catalyzed hydrogenation gave compounds of ketolactam or lactam type meanwhile the nitro group was
eliminated. On the other hand, in presence of Raney-nickel catalyst the nitro compounds were reduced to
diastereomeric amino derivatives whose stereochemistry was elucidated by NMR spectroscopy. Using
sodium bis-dimethoxy-ethoxy-aluminum-hydride (Red-Al) as reducing agent an unexpected tricyclic
azetidine was isolated and characterized.
Received 1 December 2011
Received in revised form 13 April 2012
Accepted 23 April 2012
Available online 2 May 2012
Keywords:
Nitroenamines
Cyclization
Ó 2012 Elsevier Ltd. All rights reserved.
Chemoselectivity
Reduction
Aminoquinolizidines
1. Introduction
N
O
O
N
O
O
Indolizidine and quinolizidine are common skeletons1,2 in both
natural and synthetic products that possess a wide range of bi-
ological activities. These structurally diverse bridgehead nitrogen
heterocycles and their substituted analogues are challenging tar-
gets for synthetic chemists.3,4 Their comprehensive study is stim-
ulated not only by their extreme biological and ecotoxicological
properties, but their minute concentration in living organisms. For
this reason, the thorough chemical and physiological investigation
of these compounds encounters serious difficulties or even it is
often impossible. Accordingly, novel strategies for the synthesis of
these N-heterocycles have received considerable attention in the
past decades.
(
)
n
O N
O N
2
2
NH
acrylic chloride
CH CN/base
4
5
3
NO
2
N
N
1 n=1
2 n=2
3 n=3
O N
2
O N
2
6
7
Scheme 1.
Heterocyclic
b-nitroenamines are versatile building blocks in
These products including olefinic and carbonyl double bonds
and a nitro group offer the possibility of numerous reductive
transformations, which may lead to diverse alkaloids, e.g., epi-
quinamide and pumiliotoxins.9 In this paper we describe the re-
duction of the nitrolactams 4e7 under various conditions using
different reducing agents.
the synthesis of various bicyclic and tricyclic compounds bearing
a bridgehead nitrogen atom. Although several nitroenamines have
been known for a long time, only few of them have been used in
organic synthesis. These highly reactive and easy-to-prepare5
compounds include a unique pushepull bonding structure en-
abling them to react readily with different bis-electrophiles.6,7
Based on this attractive preparative profile we have synthesized
recently different indolizidines and quinolizidines of unsaturated
lactam type 4e7 from the nitroenamines 1e3 (Scheme 1).8a
2. Results and discussion
2.1. Reductions with hydrogen transfer
Catalytic transfer hydrogenation is an often used technique in
organic transformations.10 Sodium or ammonium formates in
* Corresponding author. Tel.: þ36 1 478 4176; fax: þ36 1 478 4268; e-mail ad-
dress: nemes.peter@aotk.szie.hu (P. Nemes).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.100

5548
M.V. Pilipecz et al. / Tetrahedron 68 (2012) 5547e5553
methanol with PdeC catalyst are widely employed in these re-
ductions.11 It has been reported that the formate ion is a better
hydrogen donor than the formic acid, probably due to the higher
charge density on the formate anion. In addition it is also known
that fluoride ions form a very strong hydrogen bond with the for-
mic acid. In this complex the formate oxygen has even larger partial
charge than that found in the formate ion.12 Therefore, we used
a mixture of formic acid, 10% palladium on charcoal, and equimolar
cesium fluoride.
We found that the position of the double bond in the starting
unsaturated nitrolactam has a decisive role regarding the type of
the reaction products. In this way keto-lactams or simple lactams
could have been prepared. Reduction of 4 and 6 including
a nitroenamine segment resulted in the formation of keto-
lactams of 8 and 9, respectively. The proposed mechanism is
shown in Scheme 2. Accordingly, it can be supposed that the
primary product of the reduction is the lactam-enamine A whose
tautomeric form B undergoes hydrolysis during the aqueous
workup to produce the racemic mixtures of the keto-lactams 8
and 9.
2.2. Reduction in hydrogen atmosphere
The hydrogenations of 5 and 7 with palladium gave the lactams
11 and 12 as in the case of the hydrogen transfer. When 5 was in-
stead reduced with platinum catalyst a mixture of 11 and 13 were
formed (Scheme 4).
N
O
H2/Pt, 10 bar
MeOH, r.t.
N
O
N
O
+
O2N
5
11 40%
13 40%
Scheme 4.
When Raney-Ni catalyst was used in hydrogenation of 5 both
the nitro group and the double bond were reduced. The reaction
afforded the mixture of diastereomeric amino-lactams 14 and 15 in
a ratio 77:23 in excellent yield (Scheme 5), which were separated
by preparative HPLC.
N
O
H2/Raney-Ni, 10 bar
MeOH, r.t.
N
(
)
(
)
( )
n
N
n
n
+
H
H
N
O
N
O
N
O
Pd/HCOOH/CsF
MeOH, r.t.
O2N
H2N
H2N
5
14 44%
15 15%
O2N
H2N
HN
4 n=1
6 n=3
(
)
n
N
O
H2/Raney-Ni of reduced activity, 10 bar
MeOH, r.t.
N
O
H2N
O
16 58%
8 n=1 72%
9 n=3 56%
Scheme 5.
Scheme 2.
As the simple analysis of the 1H, 13C, and 15N NMR chemical shifts
(Fig. 1), and the pair-wise approximately equal 3J(H,H) coupling con-
stants (Table 1) do not allow a direct assignments of the C(1) config-
uration of 14 and 15, a more complex NMR strategy was needed.14
Using the selective one-dimensional NOESY technique (mixing time
500 ms) the steric proximities related to H-1 and H-9a atoms were
also determined for both isomers as indicated by arrows in Fig. 1.
An enantioselective synthesis of 8 was published recently,13 and
the (ꢀ)-form obtained in the multistep process was used as a key
intermediate in the total synthesis of pumiliotoxins, however our
simple and efficient route to the racemic 8 may be a potential al-
ternative in such synthesis.
On the other hand, under identical conditions the unsaturated
nitrolactams 5 and 7 furnished the simple lactams 11 and 12
(Scheme 3). The formation of these lactams can be explained with
double bond migration and ammonia elimination from the as-
sumed enamine C. The intermediate dieneelactams 10a,b were
identified as contaminants of 11 and 12 by 13C NMR spectroscopy.
Further purification of the mixtures with column chromatography
gave pure 11 and 12.
(a)
(b)
O
2.31
H
O
127.6 168.4
2.46
H
42.6
1.33
H
4.70
H
6
4
25.0
24.2
N
30.0
28.4
51.8
1.14
H
N
9a
64.5
1
1.64
H
2.76
1.85
H
31.8
H
H
H2N
33.6
2.34
1.84
H
H
H
H
1.59
H
2.86
2.01
H
1.39
H
1.65
NH2
14
(
)
n
(
)
n
N
O
-NH
3
Pd/HCOOH/CsF
MeOH, r.t.
N
O
O
2.51
H
O
129.0 168.5
1.43
H
4.70
H
43.8
O N
2
1.80
H
H N
2
1.38
H
2.39
H
N
25.5
24.5
N
29.9
27.5
48.2
5 n=2
7 n=3
C
1.67
H
61.4
H
1.80
26.5
H
(
)
n
2.43
H
1.96
(
)
H
n
H
H
NH2
28.2
3.31
1.78
H
N
O
N
O
H
3.24
4H
1.49
H
H2N
1.56
15
10a n=2
10b n=3
11 n=2 70%
12 n=3 87%
Fig. 1. 1H (a.), 13C, and 15N (italics) (b.) NMR chemical shifts of 14 (trans H-1/H-9a
arrangement) and 15 (cis H-1/H-9a arrangement). The red arrows indicate the NOE
interactions. (Only enantiomers with R configuration of C(9a) are displayed.)
Scheme 3.

M.V. Pilipecz et al. / Tetrahedron 68 (2012) 5547e5553
5549
Table 1
The components of the mixture were separated by preparative
HPLC furnishing the major product 17 and the minor product 18
in a ratio 75:25. The pure lactam amines were subjected to a de-
tailed NMR study as in the case of the pair 14/15. The results are
summarized in Table 2 and in Fig. 2. Considering the rather close
3J(H,H) coupling constants of both diastereomers (Table 2) not
allowing a simple distinction between them, and the conforma-
tional mobility of the six-membered halfchair lactam ring, it can
be supposed that the C(1)eNH2 group is found in the energeti-
cally more favored quasi equatorial position in both 17 and 18.
Relevant 3J(H,H) coupling constants of 14 and 15
Compound
J(1,2ax)
J(1,2equ)
J(1,9a)
J(9a,9ax)
J(9a,9equ)
14
15
10.0
9.0
3.4
4.0
6.9
5.0
11.5
11.8
2.6
2.5
In order to distinguish the diastereomers 14 and 15 their
conformational mobility has also to be taken into consideration.
While the piperidine ring adopts a regular chair conformation,
the lactam ring exhibits an equilibrium between the two half-
chair conformations, in which the C(2) and C(3) atoms are in the
out-of-plane positions. Of these conformations 14A and 15A are
predominating, in that the C(1)eNH2 group has an energetically
more favored quasi equatorial orientation (Fig. 2).
Table 2
Relevant 3J(H,H) coupling constants of 17 and 18
Compound
J(1,2ax)
J(1,2equ)
J(1,10a)
17
18
7.7
9.0
3.5
4.5
5.8
4.5
H
H
H
H
H
H
The selective NOE measurements indicated by arrows in the
Fig. 3 are in accordance with a trans H-1/H-10a arrangement in
the major product 17 and the cis one in 18. Nevertheless some
spectral differences were also observed when comparing the
pairs 14/15 and 17/18. The lower chemical shifts of Heq-6 in 17
H
H
H
O
N
N
O
H
H2N
H2N
H
H
14A
14B
and 18 (d 4.17 and 4.19 ppm, respectively) indicate that the bonds
H
of these atoms are not coplanarly arranged to the carbonyl group,
which is interpreted with the enhanced pseudorotation in the
seven-membered ring. At the same time it is worth mentioning
that the cis diaxial arrangement of Heq-6 and H-10a hydrogen
atoms in both compounds is detected by a strong NOE interaction.
The steric proximity between C-10 and the amino group in 18 can
H
H
H
H
H2N
H2N
H
O
N
N
O
H
H
H
H
H
H
15A
15B
also be demonstrated by the
g
-gauche steric effect, as in the case
of 15.
Fig. 2. Conformational equilibria in diastereomers 14 and 15.
(a)
(b)
While the 3J(H,H) coupling constant patterns (Table 1) are quite
similar, the NOE data prove the trans H-1/H-9a arrangement in 14
and the cis one in 15. Additionally, characteristic 13C and 15N upfield
O
2.30
H
2.42
H
1.56
H
4.17
H
O
46.1
N
1.73
H
169.2
128.9
shifts (ca. 5 ppm) of C-9 and the NH2 were also observed due to a
g-
26.7
1.72
H
6
4
28.6
N
gauche steric effect between the amino nitrogen and C-9 atoms in
compound 15.
27.7
2.80
1.92
H
H
65.3
27.2
49.4
1
1.48
2.66
23.8
H
H
33.7
H
1.59
H
The unsaturated amino-lactam 16 was formed exclusively when
Raney-nickel catalyst of reduced activity15 was used.
When the unsaturated nitrolactam 6 was reduced in the pres-
ence of Raney nickel the diastereomeric amines 17 and 18 were
formed in good yield, and additionally, 18% of the unsaturated
compound 19 was also isolated (Scheme 6).
1.47
3.15
1.73
H N
H
2
34.2
H
NH 1.79
2
17
O
2.49
H
O
1.56
H
4.19
H
47.4
26.5
1.77
H
169.3
132.0
1.48
H
2.42
N
29.8
1.93
H
N
H
25.7
26.7
H
62.6
26.1
1.69;1.44
1.49
1.77
49.8
N
O
H2/Raney-Ni, 10 bar
MeOH, r.t.
H
29.4
2.89
H
H
H
H
NH
3.36
2
1.94
H
H
1.77
31.7
H
3.24
O2N
H N
2
1.64
7
18
Fig. 3. 1H (a.), 13C, and 15N (italics) (b.) NMR chemical shifts of 17 (trans H-1/H-10a
arrangement) and 18 (cis H-1/H-10a arrangement). The arrows indicate the NOE in-
teractions. (Only enantiomers with R configuration of C(10a) are displayed.)
N
O
N
O
N
O
+
+
H
H
H2N
O2N
H2N
The lactam 14 was reduced with LiAlH4 to give the trans amino-
quinolizidine 20 (Scheme 7). This compound can be transformed to
C1-epiepiquinamide (21) as described.9
17 45%
18 14%
19 18%
Scheme 6.

5550
M.V. Pilipecz et al. / Tetrahedron 68 (2012) 5547e5553
expressed in terms of amidicity (AM)8bed and olefinicity (OL)8d,e in
the possible intermediates. The computational results suggest two
competing routes starting from the intermediate D. The signifi-
cantly lower amidicity of D (AM¼66.7%) refers to a more reactive
amide group leading to 22 (Route A). The large resistance of 22
against Red-Al can be interpreted by the higher olefinicity value
(OL¼45%), accordingly by the enhanced stability of the pushepull
system.
N
O
LiAlH4
THF
N
H
H
H2N
H2N
14
20 R=H 60%
21 R=Ac 69%
ref 9b,d,e
Scheme 7.
On the other hand the formation of 23 follows Route B, that
starts with the double bond migration to give the intermediate E.
This rearrangement is understandable considering the favorable
change of amidicity value. The reduction of the nitro group sepa-
rated from the double bond presumably afforded the intermediate
F. The formation of the azetidine ring can be explained considering
the resonance structures for F. The positive charge of the nitrogen
facilitates the nucleophilic attack of the amino group at the electron
poor olefinic carbon (Scheme 8).
In an attempt to reverse the stereochemical pathway of the
reduction, i.e., to obtain the cis amino-quinolizidine pre-
dominantly, other reducing agents were also tested. The re-
ductions of 5 with LiAlH4 or BH3$THF gave inseparable complex
mixtures. Catalytic hydrogenation of 4 or 6 did not resulted in any
isolable product.
2.3. Reduction with Red-Al
Although the Al(III) complex of a possible nitroso intermediate
can undergo a 4-exo-trig ring closure resulting in the azetidine
structure, our calculations reveal, that the hydride anion attack
produces preferably the primary amine, consequently the nitroso
route can be ruled out.
Reduction of 5 with Red-Al, however, led to formation of two
products. One of them, the unsaturated nitro compound 22 did
not undergo to further reduction, even in a large excess of the
reducing agent and/or applying longer reaction time. Surprisingly,
the other isolated substance with molecular formula C9H16N2
proved to be the azetidino-quinolizidine 23 (Scheme 8). The five
signals (three CH2 and two CH carbons) in the 13C NMR spectrum
indicate its symmetrical structure. For signal assignment we uti-
lized the one-dimensional selective TOCSY experiments starting
from 3.81 (H-1/H-9), whereas for 13C signals the two-dimensional
edited HSQC measurement were run. The 5.0 Hz coupling con-
stants for 3J (H-1, H-9a) and 3J (H-9a, H-9) demonstrate the cis
arrangement of H-1, H-9a, H-9 hydrogens. To our best knowledge
the unique tricyclic ringsystem of 23 has been prepared for the
first time.
The azetidine 23 was converted to the acetylated derivative 24
(Scheme 8). Due to the restricted rotation in the amide group the
chemical shifts indicate a molecular asymmetry. Separate H-1 and
H-9 signals at 4.11 and 4.31 ppm, respectively, were observed at
27 ꢁC. Upon heating coalescence of these signals took place at
w90 ꢁC, which corresponds to activation free enthalpy
D
Gs¼17.6 kcal/mol, characteristic for the hindered rotation in the
amide group (Fig. 4). Similar temperature dependence was ob-
served also in the 13C NMR spectrum of 24 (Table 3). At 27 ꢁC
separate signals were assigned to each carbon atom, while at
120 ꢁC, the splitting of the peaks could not be observed.
ROUTE A
N
O
N
N
O
O2N
O2N
O2N
5
D
22 28%
AM = 93.9 %
OL = 26.5 %
AM = 66.7 %
OL = 38.7 %
OL = 45 %
ROUTE B
N
O
N
O
N
O
H2N
H2N
O2N
E
F
AM = 93.3 %
OL = 31.5 %
Fig. 4. 1H NMR spectra of 24 measured in DMSO-d6 at different temperatures.
H
H
N
H
N
N
N
O
H
H
H
O
HN
HN
H
H
H
Table 3
CH3
Temperature dependent 13C NMR chemical shifts of 24
24 86%
23 32%
Scheme 8.
G
27 ꢁC
120 ꢁC
C-1, C-9
C-2, C-8
C-3, C-7
C-4, C-6
C-9a
58.6, 60.5
24.0, 24.4
18.6, 19.1
47.1, 47.2
48.7
58.9
23.8
18.5
46.8
48.2
170.7
19.3
Based on DFT [B3LYP/6-31G(d,p)] calculations we attempted to
get an insight into the mechanistic pathway of the above reaction
leading to the formation of 22 and 23. Our attention was focused on
the characteristics of the amide group and the olefinic double bond
C]O
CH3
171.3
20.1

M.V. Pilipecz et al. / Tetrahedron 68 (2012) 5547e5553
5551
3. Conclusions
(1H, dt, J 13.5, 4.0 Hz), 3.16 (1H, m), 2.42e2.20 (3H, m), 2.00e1.20
(10H, m); dC (75 MHz, CDCl3) 169.5, 57.1, 42.6, 34.3, 33.2, 30.7, 25.6,
24.7, 19.4; HRMS (ESI-TOF): MHþ, found 154.1225. C9H16NO re-
quires 154.1232. Spectroscopical data (1H, 13C) were identical to
those reported in literature.17
This study demonstrates the various routes of reductive trans-
formations of the nitro substituted unsaturated lactams of indoli-
zidine, quinolizidine, and pyrroloazepine type. The diastereomeric
amines obtained among the new compounds may serve as valuable
starting substances in alkaloid synthesis.
4.2.6. Octahydro-pyrido[1,2-a]azepin-4-one (12).18 Colorless oil
(80 mg, 87%). Rf (EtOAc) 030; nmax (film on KBr pellet) 2935, 2851,
4. Experimental section
4.1. General
1632, 1475, 975, 939 cmꢀ1
; dH (400 MHz, DMSO-d6) 4.16 (1H, dt, J
13.5, 4.0 Hz) 3.54e3.44 (1H, m), 2.69 (1H, ddd, J 13.5, 10.0, 3.0 Hz),
2.38e2.22 (2H, m), 1.77e1.47 (12H, m); dC (100 MHz, DMSO-d6)
169.9, 57.7, 45.4, 35.8, 31.9, 30.1, 28.1, 27.1, 23.7, 18.8; HRMS (ESI-
TOF): MHþ, found 168.1380. C10H18NO requires 168.1388.
All solvents were dried by standard procedures. NMR spectra
including zqs-NOESY, ed-HSQC, and HMBC as well as selective 1D
zqs-TOCSY and NOESY spectra were recorded on Varian 300 Unity,
Bruker Avance 500, and 400 NMR spectrometers at rt. The 1H and
13C chemical shifts are referred to tetramethylsilane, whereas for
15N shifts ammonia was used, the other parameters are indicated.
The HRMS analyses were performed with a Waters LCT Premier XE
apparatus. In the GCeMS measurements a Shimadzu QP2010S
GCMS equipment (ionization: EI, 70 eV) was used. Preparative HPLC
separations were made by HPLC Gilson 333 instrument, UV de-
tector (220 nm); Phenomenex Gemini C18 column, 250ꢂ50 mm;
eluent 0.4 g NH4HCO3 in 1 L water/acetonitrile.
4.3. Synthesis of compounds 11e12 by catalytical
hydrogenation
The mixture the nitrolactam 5 or 7 (2 mmol), 10% Pd/C (200 mg),
and methanol (25 mL) was stirred in hydrogen atmosphere (10 bar,
25 ꢁC) for 24 h. After removal of the catalyst the solution was
concentrated under reduced pressure to give 11 (280 mg, 91%) and
12 (320 mg, 96%) showing identical physical and spectroscopical
data as above.
4.3.1. 1,2,3,6,7,8-Hexahydro-quinolizin-4-one (13). The mixture of
nitrolactam 5 (392 mg, 2 mmol), PtO2 catalyst (30 mg), and
methanol (25 mL) was stirred in hydrogen atmosphere (10 bar,
25 ꢁC) for 24 h. After removal of the catalyst the solution was
concentrated under reduced pressure to give a mixture of 11 and 13
in a ratio 1:1 (240 mg, 80%). 13C NMR: two series of signals that are
assigned to 10 (see above) and 13. Compound 13: dC (100 MHz,
CDCl3) 168.5, 135.7, 103.9, 40.4, 33.4, 30.1, 22.5, 21.8, 20.2. GCeMS:
MHþ, found 152. Spectroscopical data (13C) were identical to those
reported in literature.19
4.2. Synthesis of compounds 8, 9, 11, 12 by hydrogen transfer
The mixture of the nitrolactam 4e7 (0.55 mmol), Pd/C (10%)
(200 mg), formic acid (1 mL), and cesium fluoride (0.1 g, 0.66 mmol)
in methanol (4 mL) was stirred at rt for 4 h. After removal of the
solvent, the residue was treated with 10 (m/m)% potassium car-
bonate solution and extracted with dichloromethane. The
dichloromethane solution was dried (Na2SO4) and evaporated. The
residue was purified by column chromatography (EtOAc) to give
products 8, 9, 11, and 12.
4.4. trans-1-Amino-octahydro-quinolizin-4-one (14) and cis-
4.2.1. Hexahydro-indolizine-5,8-dione (8). Colorless oil (61 mg,
72%). Rf (10% i-PrNH2/CHCl3) 0.72; nmax (film on KBr pellet) 2915,
1-amino-octahydro-quinolizin-4-one (15)
2885,1730,1645,1440,1180 cmꢀ1
;
dH (300 MHz, CDCl3) 3.99 (1H, t, J
The mixture of the nitrolactam 5 (392 mg, 2 mmol), Raney-
nickel catalyst (w200 mg), and methanol (25 mL) was stirred in
hydrogen atmosphere (10 bar, 25 ꢁC) for 8 h. After filtration the
solvent was removed in vacuo producing a mixture of 14 and 15 in
a ratio 3:1 (195 mg, 58%). Separation by preparative HPLC gave pure
diastereomers 14 and 15.
4.1 Hz), 3.62e3.44 (2H, m), 2.82e2.14 (4H, m), 2.08e1.72 (4H, m); dC
(75 MHz, CDCl3) 207.3, 169.2, 64.9, 45.5, 34.9, 31.0, 27.9, 23.1; HRMS
(ESI-TOF): MHþ, found 154.0865. C8H12NO2 requires 154.0868.
Spectroscopical data (1H, 13C) were identical to those reported in
literature.13
4.2.2. Octahydro-pyrido[1,2-a]azepine-1,4-dione (9). Colorless oil
(56 mg, 56%). Rf (EtOAc) 0.27; nmax (film on KBr pellet) 2925, 2851,
4.4.1. Compound 14. Colorless oil, Rf (20% Et3N/MeCN) 0.20; nmax
(film on KBr pellet) 3366, 2946, 2841, 1643, 1627, 1448, 1275 cmꢀ1
;
1732, 1653, 1438, 1175 cmꢀ1
;
dH (300 MHz, CDCl3) 4.33 (1H, dt, J
HRMS (ESI-TOF): MHþ, found 169.1334. C9H17N2O requires
169.1341.
14.0, 5.0 Hz), 3.85 (1H, dd, J 9.6, 4.8 Hz), 2.86e2.51 (5H, m),
2.10e2.00 (1H, m), 1.88e1.77 (2H, m), 1.65e1.49 (5H, m); dC
(75 MHz, CDCl3) 207.5, 170.1, 67.5, 46.2, 35.4, 32.5, 29.4, 28.0, 26.8,
26.2; HRMS (ESI-TOF): MHþ, found 182.1177. C10H16NO2 requires
182.1181.
4.4.2. Compound 15. Colorless oil, Rf (20% Et3N/MeCN) 0.20; nmax
(film on KBr pellet) 3366, 2946, 2841, 1643, 1627, 1448, 1275 cmꢀ1
;
HRMS (ESI-TOF): MHþ, found 169.1338. C9H17N2O requires
169.1341.
4.2.3. 6,7,8,9-Tetrahydro-quinolizin-4-one (10a). dC (75 MHz, CDCl3)
163.4, 147.8, 138.5 116.7, 105.2, 41.9, 28.9, 22.4, 19.1. 13C NMR data
were identical to those reported in literature.16
NMR data (CDCl3) of 14 and 15: see Fig. 1 and Table 1 for cou-
pling constants.
4.5. 1-Amino-1,2,3,6,7,8-hexahydro-quinolizin-4-one (16)
4.2.4. 7,8,9,10-Tetrahydro-6H-pyrido[1,2-a]azepin-4-one (10b). dC
(75 MHz, CDCl3) 163.5, 152.3, 138.7, 117.4, 105.5, 43.3, 34.8, 29.5,
27.6, 27.0 ppm. 13C NMR data were identical to those reported in
literature.16
The mixture of the nitrolactam 5 (392 mg, 2 mmol), Raney-
nickel catalyst, stored for several weeks after delivery (w200 mg)
and methanol (25 mL) was stirred in hydrogen atmosphere (10 bar,
25 ꢁC) for 8 h. After filtration the solvent was removed in vacuo and
the residue was purified by column chromatography (EtOAc/i-
PrNH2, 20:1) to give 16 as a colorless oil (192 mg, 58%). Rf (6% iso-
propylamine/Et2O) 0.38; nmax (film on KBr pellet) 3303, 2935, 2872,
4.2.5. Octahydro-quinolizin-4-one (11). Colorless solid (59 mg,
70%); mp 128e130 ꢁC (ethanol). Rf (EtOAc) 0.23; nmax (KBr) 3010,
2943, 2855, 1620, 1478, 1453, 1283 cmꢀ1
; dH (300 MHz, CDCl3) 4.72

5552
M.V. Pilipecz et al. / Tetrahedron 68 (2012) 5547e5553
1642, 1559, 1385, 1264, 1170 cmꢀ1
;
dH (400 MHz, DMSO-d6) 4.95
potassium carbonate (1 g) were added to the mixture. The toluene
solution was decanted from the solid part, dried (Na2SO4) and
concentrated. Purification of the crude product by column chro-
matography (Et2O/i-PrNH2, 10:1) gave 22 and 23.
(1H, t, J 3.6 Hz), 3.63e3.50 (2H, m), 3.46e3.40 (1H, m), 2.58e2.50
(1H, m), 2.38e2.28 (1H, m), 2.08e2.00 (2H, m), 1.92e1.73 (1H, m),
1.72e1.62 (2H, m),1.61e1.50 (1H, m); dC (100 MHz, DMSO-d6) 166.9,
140.8, 102.4, 48.6, 39.7, 29.3, 28.2, 21.8, 21.5; HRMS (ESI-TOF): MHþ,
found 167.1184. C9H15N2O requires 167.1184.
4.8.1. 9-Nitro-1,3,4,6,7,8-hexahydro-2H-quinolizine(22). Yellow-
brown oil (102 mg, 28%). Rf (9% i-PrNH2/Et2O) 0.55; nmax (film on
4.6. Preparation of 17e19
KBr pellet) 2925, 2862,1632, 1322, 1186 cmꢀ1
; dH (400 MHz, DMSO-
d6) 3.37 (2H, t, J 6.0 Hz), 3.24 (2H, t, J 5.7 Hz), 3.11 (2H, t, J 6.6 Hz),
2.62 (2H, t, J 6.6 Hz), 1.81e1.69 (4H, m), 1.66e1.59 (2H, m); dC
(100 MHz, DMSO-d6) 159.7, 118.4, 51.3, 51.2, 29.6, 25.0, 21.5, 19.9,
18.9, HRMS (ESI-TOF): MHþ, found 183.1129. C9H15N2O2 requires
183.1134.
1-Nitro-6,7,8,9,10,10a-hexahydro-3H-pyrido[1,2-a]azepin-4-
one (7) (840 mg, 4 mmol) dissolved in abs EtOH (30 mL) was hy-
drogenated (10 bar, 25 ꢁC) in the presence of Raney-Ni catalyst
(500 mg). After stirring for 12 h the catalyst was filtered off, and the
solvent was removed under reduced pressure. Purification of the
crude product by column chromatography (Et2O/i-PrNH2, 9:1) gave
the mixture of 17 and 18 (430 mg, 59%) in a ratio 77:23 and 19
(130 mg, 18%) as an oil. Compounds 17 and 18 were separated by
preparative HPLC to give colorless oils.
4.8.2. Octahydro-1,4a-diaza-cyclobuta[de]naphthalene
(23). Colorless solid (98 mg, 32%); mp 128e130 ꢁC (ethanol). Rf (9%
i-PrNH2/Et2O) 0.35; nmax (KBr) 3272, 2935, 2788, 1522, 1433,
1364 cmꢀ1
; dH (400 MHz, DMSO-d6) 3.81 (2H, q, J 5.0 Hz), 3.03 (1H,
t, J 5.0 Hz), 2.84 (2H, ddd, J 11.5, 6.7, 5.5 Hz), 2.32 (2H, ddd, J 11.5, 7.2,
4.8 Hz), 1.86e1.64 (2H, m), 1.56e1.39 (4H, m), 1.32e1.22 (2H, m); dC
(100 MHz, DMSO-d6) 53.7 C-9a; 53.1 C-1, C-9; 48.0 C-4, C-6; 25.2 C-
2, C-8; 19.8 C-3, C-7; HRMS (ESI-TOF): MHþ, found 153.1387.
C9H16N2 requires 153.1392.
4.6.1. trans-1-Amino-octahydro-pyrido[1,2-a]azepin-4-one (17). Rf
(10% i-PrNH2/tBueMeeether) 0.24; nmax (film on KBr pellet) 3303,
2935, 2862, 1642, 1454, 1396, 1196, 1170 cmꢀ1; HRMS (ESI-TOF):
MHþ, found 183.1462. C10H19N2O requires 183.1457.
4.6.2. cis-1-Amino-octahydro-pyrido[1,2-a]azepin-4-one
(18). Rf
4.9. 1-(Octahydro-1,4a-diaza-cyclobuta[de]naphthalen-1-yl)-
ethanone (24)
(10% i-PrNH2/tBueMeeether) 0.24; nmax (film on KBr pellet) 3303,
2935, 2862, 1642, 1454, 1396, 1196, 1170 cmꢀ1; HRMS (ESI-TOF):
MHþ, found 183.1465. C10H19N2O requires 183.1457.
NMR data (CDCl3) of 17 and 18: see Fig. 3 and Table 2 for cou-
pling constants.
To the solution of octahydro-1,4a-diaza-cyclobuta[de]naphtha-
lene (23) (152 mg, 1 mmol) in CH2Cl2 (10 mL) acetyl chloride
(0.2 mL) in CH2Cl2 (3 mL) was added dropwise at rt. After stirring
for 2 h the solvent was removed, and the residue was purified by
column chromatography (EtOAc/Et3N, 4:1) to give 24; yellow-
brownish oil (167 mg, 86%). Rf (20% Et3N/EtOAc) 0.50; nmax (film
4.6.3. 1-Amino-2,3,6,7,8,9-hexahydro-1H-pyrido[1,2-a]azepin-4-one
(19). Rf (7% i-PrNH2/EtOAc) 0.40; nmax (film on KBr pellet) 3293,
2924, 2865, 1643, 1396, 1556, 1165 cmꢀ1
; dH (400 MHz, DMSO-d6)
on KBr pellet) 2935, 2872, 2788, 1653, 1448, 1422, 1154 cmꢀ1
; dH
5.08 (t, J 5.4 Hz, 1H), 3.86 (dt, J 13.5, 6.1 Hz, 1H), 3.69 (dt, J 13.5,
6.1 Hz, 1H), 3.51 (dd, J 7.3, 4.3 Hz, 1H), 2.58 (dt, J 17.8, 7.3 Hz, 1H),
2.45 (dt, J 17.8, 7.3 Hz, 1H), 2.14e2.22 (m, 2H), 1.96e2.02 (m, 1H),
1.77e1.82 (m, 2H), 1.68 (br, 2H, NH2), 1.66e1.73 (m, 1H), 1.58e1.65
(m, 1H); dC (100 MHz, DMSO-d6) 169.0, 145.1, 110.5, 50.4, 46.2, 29.1,
29.0, 26.6, 25.5, 24.2; HRMS (ESI-TOF): MHþ, found 181.1308.
C10H17N2O requires 181.1301.
(400 MHz, DMSO-d6) 4.36e4.27 (1H, m), 4.15e4.08 (1H, m),
2.82e2.70 (3H, m), 2.25e2.13 (2H, m), 1.84e1.68 (9H, m), 1.33e1.20
(2H, m); dC (100 MHz, DMSO-d6) see Table 3. HRMS (ESI-TOF): MHþ,
found 195.1490. C11H19N2O requires 195.1497.
Acknowledgements
ꢀ
The authors are indebted to Mrs. Maria Kuti for her technical
help.
4.7. trans-Octahydro-quinolizin-1-ylamine (20)
The 14 (140 mg, 1 mmol) in abs THF (10 mL) was added drop-
wise to the suspension of lithium-aluminum-hydride (114 mg,
3 mmol) in THF (20 mL) at 0 ꢁC. After stirring for 3 h water (2 mL)
and potassium carbonate (1 g) were added to the reaction mixture.
The solution separated from the solid was dried (Na2SO4) and
concentrated under reduced pressure. The crude product was pu-
rified by column chromatography (MeCN/i-PrNH2, 9:1) to give 20 as
an oil (77 mg, 60%). Rf (10% i-PrNH2/MeCN) 0.33; nmax (film on KBr
pellet) 3360, 2939, 2862, 2810, 2764, 2685, 1643, 1594, 1448, 1357,
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2012.04.100. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.
References and notes
1188 cmꢀ1
; dH (400 MHz, DMSO-d6) 2.72e2.66 (1H, m), 2.63e2.57
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