Synthesis of 1,4-diazabicyclo[3.3.1]nonan-6-ones

Article abstract of DOI:10.1071/CH09206

1,4-Diazabicyclo[3.3.1]nonanes (aza-morphans) represent conformationally constrained piperazine derivatives. Herein, we report a six-step synthesis of the benzyl and allyl substituted bicyclic ketones 3a and 3b, which represent interesting building blocks

Full text of DOI:10.1071/CH09206

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2009, 62, 1684–1689
www.publish.csiro.au/journals/ajc
Synthesis of 1,4-Diazabicyclo[3.3.1]nonan-6-ones
Daniel Kracht,A Susumu Saito,B and Bernhard WünschA,C
AInstitut für Pharmazeutische und Medizinische Chemie der Universität Münster,
Hittorfstraße 58–62, D-48149 Münster, Germany.
BDepartment of Chemistry, Graduate School of Science, Nagoya University,
Chikusa, Nagoya 464–8602, Japan.
CCorresponding author. Email: wuensch@uni-muenster.de
1,4-Diazabicyclo[3.3.1]nonanes (aza-morphans) represent conformationally constrained piperazine derivatives. Herein,
we report a six-step synthesis of the benzyl and allyl substituted bicyclic ketones 3a and 3b, which represent interesting
building blocks for the synthesis of conformationally restricted receptor ligands. The key steps of the synthesis are
the regioselective addition of ethyl acrylate to the piperazine 8, the sodium hexamethyldisilazide-induced Dieckmann
cyclization of the diesters 10, and the decarboxylation of the enol esters 11 with dilute HCl. The complete sequence is
only successful when a benzyl (10a) or allyl moiety (10b) is attached to N-1, since the tosyl derivative 10f failed to give
a Dieckmann cyclization product, and the decarboxylation failed with the acyl derivatives 11c and 11d.
Manuscript received: 10 April 2009.
Manuscript accepted: 14 July 2009.
Introduction
In order to increase the interaction between a ligand and a
protein (e.g. an enzyme or a receptor) restriction of the con-
formational flexibility is a general principle, because the gain of
energy with rigid compounds is increased due to entropic factors.
Additionally, rigid ligands with high receptor affinity should give
insights into the complementary receptor surface. Therefore,
we are interested in the pharmacological properties of con-
formationally restricted compounds, which are related to more
flexible ligands. For this reason 6,8-diazabicyclo[3.2.2]nonane
derivatives, which are regarded as piperazine derivatives with a
propano bridge between positions 2 and 5 forcing the piperazine
ring into a twist-like conformation, have been synthesized and
evaluated pharmacologically. In particular, hydroxy and amino
groups were attached to the propano bridge, because those com-
pounds represent the conformationally constrained analogues of
the aforementioned flexible hydroxymethyl and aminomethyl
substituted piperazines.[8,9]
Another possibility for the conformational restriction of the
piperazine ring is the connection of positions 1 and 3 by a
propano bridge resulting in 1,4-diazabicyclo[3.3.1]nonanes 3.
In these bicyclic compounds the piperazine ring is forced to
adopt a single chair conformation. Furthermore, the diazabi-
cyclo[3.3.1]nonane framework of 3 can be regarded as an
aza-analogous morphan. The bicyclic morphan system 2 is a
substructure of the pentacyclic analgesic morphine and some
morphan derivatives (e.g. 2 with R2 = 3-hydroxyphenyl) also
show high analgesic activity.[10,11]
The piperazine ring is a prominent substructure in pharmaco-
logically potent compounds. For example, selective dopamine
D4 receptor antagonists,[1,2] competitive N-methyl-D-aspartate
(NMDA) receptor antagonists,[3] and antibiotics inhibiting the
bacterial gyrase (e.g. ciprofloxacine)[4] contain the piperazine
structural element. We have shown that piperazine deriva-
tives of type 1 with a hydroxymethyl moiety in position 2
(R3 = CH2OH) represent very potent σ1 receptor ligands.[5]
Moreover, aminomethyl and 1-aminoethyl substituted piper-
azines of type 1 (R3 = (pyrrolidin-1-yl)methyl, or 1-(pyrrolidin-
1-yl)ethyl) with appropriate substituents at the piperazine
N-atoms are very potent κ-opioid receptor agonists with promis-
ing analgesic activity in vivo (Fig. 1).[6,7]
R3
N
R2
R2
R1
R1
N
N
1
2
R3
O
N
R2
N
N
R1
R1
N
Herein we report on the synthesis of 1,4-diazabicyclo[3.3.1]
nonan-6-ones3.Thecarbonylmoietyinposition6isofparticular
importance since it will allow the introduction of further sub-
stituents and pharmacophoric elements in this position (compare
compound 4).
3
4
Fig. 1. Relationship between 2-substituted piperazines 1, morphans 2, and
the envisaged 1,4-diazabicyclo[3.3.1]nonanes 3 and 4.
© CSIRO 2009
10.1071/CH09206
0004-9425/09/121684

Synthesis of 1,4-Diazabicyclo[3.3.1]nonan-6-ones
1685
Bn
Bn
N
CO2Et
NH
Br
Br
OH
N
O
N
(b)
(a)
(a)
(b)
ϩ
10a–d
N
N
NH
Bn
N
CO2Et
CO2Et
Bn
R
R
5
6
7
11a–d
3a, b
3, 10, 11
R
a
b
c
d
e
f
CH2Ph (Bn)
CH2CHϭCH2
COPh
CO2Et
CO2Et
H
N
CO2Et
N
N
(c)
(d)
CO2Bn
N
H
CO2Et
N
COCH2Ph
Tos
N
H
CO2Et
R
8
9
10a–f
Scheme 2. Synthesis of bicyclic ketones 3: (a) NaHMDS, THF, 2 h, 0◦C,
then 14 h, RT, 74% (11a), 44% (11b), 79% (11c), 14% (11d); (b) 2 M HCl,
36 h or 16 h, reflux, 71% (3a), 58% (3b).
Scheme 1. Synthesis of the diesters 10: Reagents and reaction conditions:
(a) toluene, NEt3, 3 h, 80◦C, 86%; (b) ammonium formate, Pd/C, EtOH, 3 h,
60◦C, 86%; (c) ethyl acrylate, EtOH, 14 h, RT, 81%; (d) benzyl bromide
or allyl bromide, Bu4NI, NEt3, CH3CN, 14 h, RT, 75% (10a), 81% (10b);
benzoyl chloride or benzyl chloroformate or phenylacetyl chloride, NEt3,
CH2Cl2, 2–14 h, RT, 94% (10c), 91% (10d), 59% (10e); tosyl chloride,
pyridine, CH2Cl2, 2 h, 0◦C, 92% (10f).
CO2Et
CO2Et
N
N
(a)
N
CO2Et
O
N
Synthesis
O
O
The key step for the synthesis of diazabicyclononanes 3 should
be a Dieckmann cyclization of piperazine diesters 10. In the
first approach the ester 8 should be synthesized by ester-
ification of the commercially available dihydrochloride of
piperazine-2-carboxylic acid. However, all attempts (e.g. EtOH
or MeOH/HCl, EtOH/TMSCl) to directly obtain the ester 8
failed, presumably due to solubility problems. This result is in
accordance to the observations of Bach et al. who reported that
standard methods (EtOH/HCl, diazomethane) did not yield the
corresponding ethyl or methyl ester of piperazine-2-carboxylic
acid.[12] Only heating of piperazine-2-carboxylic acid dihydro-
chloride in a mixture of EtOH and benzene with concentrated
H2SO4 led to a moderate yield of the ester 8.[12] However,
replacement of benzene by toluene did not give the desired ethyl
ester 8.
Ph
Ph
10e
12
Scheme 3. Dieckmann cyclization of 10e: (a) NaHMDS, THF, 2 h, 0◦C,
then 14 h, RT, 44%.
also led to good yields of the bicyclic products 11b (44%) and
11c (79%). NaHMDS-induced Dieckmann cyclization of the
benzyloxycarbonyl (Cbz)-protected piperazine 10d, provided
only 14% of the bicyclic β-ketoester 11d, and the yield could
not be improved by variation of the reaction conditions. The
phenylacetyl derivative 10e and the tosyl derivative 10f did not
yield the desired bicyclic β-ketoesters 11e and 11f. Whereas the
tosyl derivative 10f only led to decomposition after addition of
NaHMDS, the phenylacetyl derivative 10e was converted into
the annulated piperazine derivative 12 (44%). This transforma-
tion is explained by initial deprotonation of the active pheny-
lacetyl methylene moiety of the protective group (Scheme 3).
Therefore an alternative route reported in the literature[13,14]
was followed. Nucleophilic substitution of the dibromopro-
pionate 6 with N,Nꢀ-dibenzylethylenediamine 5 provided the
dibenzylpiperazine 7. In contrast to the reported method (H2,
Pd/C, 4 bar (400000 Pa), 40◦C), the removal of the N-benzyl
protective groups was performed by a transfer-hydrogenolysis
using ammonium formate[15] in the presence of Pd/C to obtain
ethyl piperazine-2-carboxylate 8 in 86% yield (Scheme 1).
In the next step ethyl acrylate was added regioselectively to
position 4 of the piperazine 8. After stirring the reaction mixture
for 2 h at 0◦C and an additional 14 h at room temperature (RT)
the addition product 9 was isolated in 81% yield. In order to
find the N-substituent that provides the best yield of bicyclic
β-ketoesters 11, various residues were attached to the N-atom
in position 1 including benzyl (10a), allyl moiety (10b), acyl
(10c–e), and the tosyl (10f) groups (Scheme 2).
1
According to the H NMR spectra in CDCl3, the bicyclic
products 11a–d exist exclusively in the enol form as shown in
Scheme 2.
In the final step, the bicyclic β-ketoesters 11 should be
hydrolyzed and decarboxylated to afford the bicyclic ketones 3.
Again this transformation was optimized with the benzyl deriva-
tive 11a. Hydrolysis of the enol ester 11a with diluted NaOH
or applying the Krapcho conditions (NaCl, dimethylsulfoxide,
150◦C)[16,17] for the direct decarboxylation led to several prod-
ucts. However heating 11a with 2 M HCl for 36 h led to a clean
conversion and the bicyclic ketone 3a was isolated in 71% yield.
The same reaction conditions transformed the N-allyl substi-
tutedenolester 11bintotheketone3bin58%yield. Surprisingly,
the benzamide 11c and the carbamate 11d were not stable upon
heating with dilute HCl. While milder reaction conditions were
not able to convert the enol esters 11c or 11d to the correspond-
ing ketones, treatment with NaOH or the Krapcho conditions led
to extensive decomposition of the starting enol esters.
At first the Dieckmann cyclization was optimized with the
benzyl derivative 10a. Several reaction conditions were inves-
tigated and finally two equivalents of sodium hexamethyldi-
silazide (NaHMDS) was found to give the best yields of the
bicyclic β-ketoester 11a (74%) (Scheme 2).
Applying these optimized reaction conditions, the cycliza-
tion of the allyl derivative 10b and the benzoyl derivative 10c

1686
D. Kracht, S. Saito, and B. Wünsch
In conclusion, a six-step synthesis of the bicyclic ketones
138.4 (2C, C-1phenyl), 172.4 (1C, C=O). IR (neat): 1734 cm−1
(s, C=O). MS (EI): m/z [%] = 338 (M, 5), 265 (M–CO2C2H5,
64), 91 (PhCH2, 100). HPLC: tR = 19.7 min, purity 99.9%.
3a and 3b is described. A benzyl or allyl protective group at the
N-atom in position 1 of the piperazine ring is crucial, because the
tosylderivative10f didnotundergoaDieckmanncyclizationand
the acylated derivatives 11c and 11d turned out to be unstable
during the decarboxylation step. The bicyclic ketones 3a and
3b represent valuable building blocks for the introduction of
various substituents in position 2. In particular, conformationally
restricted analogues of the piperazines 1 with hydroxyalkyl and
aminoalkyl substituents in position 6 are of great interest.
Ethyl Piperazine-2-carboxylate (8)[13,14]
Under N2, dry ammonium formate (10.8 g, 172 mmol) was
added to a solution of 7 (11.6 g, 34.4 mmol) containing 10%
Pd–C (1.2 g) in anhydrous ethanol (200 mL). The reaction mix-
ture was stirred at 60◦C for 3 h, then cooled and filtered through
Celite.The filtrate was evaporated under vacuum and the residue
was purified by vacuum distillation (bp 0.25 mmHg 105◦C)
using a Kugelrohr apparatus to give a colourless oil, 4.8 g (86%),
which gave a colourless solid (mp 59◦C) upon standing at RT.
Melting and boiling points are consistent with those reported:[13]
Experimental
General
Unless otherwise noted, moisture sensitive reactions were con-
ducted under dry nitrogen. THF was dried with sodium/
benzophenone and was freshly distilled before use. TLC: Silica
gel 60 F254 plates (Merck). Flash chromatography (FC): Sil-
ica gel 60, 40–64 µm (Merck); parentheses include: diameter of
the column × height of SiO2 column, fraction size, eluent, RF
value. Melting point: mp apparatus SMP 3 (Stuart Scientific),
uncorrected. Mass spectrometry (MS): MAT GCQ (Thermo-
Finnigan); EI = electron impact, ESI = electrospray ionization.
Infrared spectroscopy (IR): IR spectrophotometer 480Plus FT-
1
mp 59–61◦C, bp 0.08 mmHg 90–100◦C. H NMR (CDCl3): δ
1.26 (t, J = 7.1 Hz, 3H, OCH2CH3), 2.41 (s broad, 2H, NH),
2.75–2.96 (m, 4H, piperazine-H), 2.99–3.04 (m, 1H, piperazine-
H), 3.23 (dd, J = 12.2, 3.4 Hz, 1H, 3-H), 3.48 (dd, J = 8.3,
3.4 Hz, 1H, 2-H), 4.18 (q, J = 7.1 Hz, 2H, OCH2CH3). IR (neat):
3347 (br, N-H), 1730 cm−1 (s, C=O). MS (EI): m/z [%] = 158
(M, 7), 129 (M–C2H5, 20), 85 (M–CO2C2H5, 86).
Ethyl 4-[2-(Ethoxycarbonyl)ethyl]piperazine-
2-carboxylate (9)
1
ATR-IR (Jasco). H NMR (400 MHz), 13C NMR (100 MHz):
Mercury-400BB spectrometer (Varian); δ in ppm related to
tetramethylsilane; coupling constants are given with 0.5 Hz
resolution. High performance liquid chromatography (HPLC):
Merck Hitachi Equipment; UV detector: L-7400; autosampler:
L-7200; pump: L-7100; degasser: L-7614; column: LiChro-
spher 60 RP-select B (5 µm); LiCroCART 250–4 mm cartridge;
flow rate: 1.0 mL min−1; injection volume: 5.0 µL; detection at
λ = 210 nm; solvents: A: water with 0.05% (v/v) trifluoroacetic
acid; B: acetonitrile with 0.05% (v/v) trifluoroacetic acid: gra-
dient elution: 0.0 min: 90.0% of A, 10.0% of B; 4.0 min: 90.0%
of A, 10.0% of B; 29.0 min: 0.0% of A, 100.0% of B; 31.0 min:
0.0% of A, 100.0% of B; 31.5 min: 90.0% of A, 10.0% of B;
40.0 min: 90.0% of A, 10.0% of B.
Under ice-cooling, ethyl acrylate (6.6 mL, 60.4 mmol) was
added dropwise to a solution of 8 (4.79 g, 30.2 mmol) in
ethanol (200 mL). The mixture was stirred at 0◦C for 2 h and
then at for 14 h. The solvent was then removed under vac-
uum and the residue was purified by FC (6 cm × 15 cm, 30 mL,
CH2Cl2/MeOH 9/1, RF = 0.52) to afford 6.3 g (81%) of 9 as a
1
pale yellow oil. H NMR (CDCl3): δ 1.23 (t, J = 7.1 Hz, 3H,
OCH2CH3), 1.25 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.90 (s broad,
1H, NH), 2.17–2.25 (m, 1H, 5-H), 2.29–2.37 (m, 1H, 3-H), 2.46
(t, J = 7.8 Hz, 2H, N-CH2CH2CO2Et), 2.55–2.62 (m, 1H, 5-H),
2.68 (t, J = 7.8 Hz, 2H, NCH2CH2CO2Et), 2.80 (ddd, J = 12.0,
9.0, 3.1 Hz, 1H, 6-H), 2.87–2.93 (m, 1H, 3-H), 3.02 (ddd,
J = 12.0, 4.6, 3.1 Hz, 1H, 6-H), 3.49 (dd, J = 8.4, 3.1 Hz, 1H,
2-H), 4.11 (q, J = 7.1 Hz, 2H, OCH2CH3), 4.16 (q, J = 7.1 Hz,
2H, OCH2CH3). IR (neat): 3187 (s, N-H), 1731 cm−1 (s, C=O).
MS (EI): m/z [%] = 258 (M, 11), 185 (M–CO2C2H5, 43). MS
(ESI): m/z [%] = 539 (2 × M + Na, 74), 281 (M + Na, 49), 259
(M + H, 100).
Ethyl 1,4-Dibenzylpiperazine-2-carboxylate (7)[14]
Modified according to Rondu et al.[14] A solution of N,Nꢀ-
dibenzylethylenediamine (5; 9.4 mL, 40 mmol) and triethyl-
amine (13.2 mL, 96 mmol) in toluene (80 mL) was heated to
80◦C. Ethyl 2,3-dibromopropionate (6; 6.0 mL, 41.2 mmol) was
also dissolved in toluene (80 mL) and added dropwise over
30 min to the first solution. After complete addition, the reaction
mixture was stirred at 80◦C for 3 h, then cooled and filtered.
The filtrate was washed with a saturated solution of NaHCO3
(150 mL). The organic layer was dried (Na2SO4) and the solvent
was removed under vacuum. The crude product was purified
by FC (8 cm × 15 cm, 30 mL, cyclohexane/ethyl acetate 9/1,
Ethyl 1-Benzyl-4-[2-(ethoxycarbonyl)ethyl]-piperazine-
2-carboxylate (10a)
Under N2, benzyl bromide (5.7 mL, 48.8 mmol) was added
dropwise to an ice-cooled solution of 9 (6.3 g, 24.4 mmol),
triethylamine (7.5 mL, 53.6 mmol) and tetrabutylammonium
iodide (1.8 g, 4.9 mmol) in acetonitrile (200 mL). The reaction
mixture was stirred for 14 h at RT. Then one-half of the sol-
vent was removed under vacuum. A saturated NaHCO3 solution
was added and the mixture was extracted with CH2Cl2 (3×).
The combined organic layers were dried (Na2SO4), filtered and
the solvent was removed under vacuum. The residue was puri-
fied by FC (6 cm × 15 cm, 30 mL, cyclohexane/ethyl acetate 2/1,
RF = 0.34) to afford 6.4 g (75%) of 10a as a colourless oil. 1H
NMR (CDCl3): δ 1.23 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.28 (t,
J = 7.1 Hz, 3H, OCH2CH3), 2.28–2.38 (m, 1H, piperazine-H),
2.39–2.51 (m, 4H, piperazine-H (2H) and NCH2CH2CO2Et),
2.57–2.77 (m, 4H, piperazine-H (2H) and NCH2CH2CO2Et),
2.92–3.05 (m, 1H, piperazine-H), 3.24–3.30 (m, 1H, 2-H),
3.53 (d, J = 13.3 Hz, 1H, PhCH2N), 3.89 (d, J = 13.3 Hz, 1H,
1
RF = 0.22) to afford 11.6 g (86%) of 7 as a colourless oil. H
NMR (CDCl3): δ = 1.24 (t, J = 7.1 Hz, 3H, OCH2CH3), 2.32–
2.40 (m, 1H, 3-H), 2.42–2.52 (m, 2H, 5-H or 6-H), 2.68–2.78
(m, 1H, 5-H or 6-H), 2.58–2.66 (m, 1H, 5-H or 6-H), 3.02–
3.12 (m, 1H, 3-H), 3.31 (dd, J = 5.5, 3.9 Hz, 1H, 2-H), 3.42
(d, J = 12.5 Hz, 1H, PhCH2N), 3.52–3.64 (m, 2H, PhCH2N),
3.92 (d, J = 13.3 Hz, 1H, PhCH2N), 4.17 (q, J = 7.1 Hz, 2H,
OCH2CH3), 7.19–7.36 (m, 10H, arom. H). 13C NMR (CDCl3):
δ 14.5 (1C, OCH2CH3), 48.9 (1C, C-3), 53.3, 55.7 (2C, C-5
and C-6), 59.8 (1C, PhCH2), 60.6 (1C, OCH2CH3), 62.8 (1C,
PhCH2), 63.0 (1C, C-2), 127.3 (2C, C-4phenyl), 128.4, 128.5
(each 2C, C-3phenyl), 129.1, 129.3 (each 2C, C-2phenyl), 138.2,

Synthesis of 1,4-Diazabicyclo[3.3.1]nonan-6-ones
1687
PhCH2N), 4.05–4.25 (m, 4H, OCH2CH3), 7.18–7.35 (m, 5H,
arom. H). IR (neat): 1732 (s, C=O), 738 and 699 cm−1 (m, arom.
outofplane). MS(EI):m/z [%] = 348(M, 5), 275(M–CO2C2H5,
46), 185 (M–CO2C2H5–PhCH2, 100), 91 (PhCH2, 10). HPLC:
tR = 18.4 min, purity 99.7%.
the reaction mixture was concentrated under vacuum. The
residue was purified by FC (2.5 cm, 15 cm, 20 mL, cyclohexane/
ethyl acetate 2/1, RF = 0.26) to afford 267 mg (91%) of 10d
as a colourless oil. 1H NMR (CDCl3): δ 1.15–1.29 (m, 6H,
2 × OCH2CH3), 2.03–2.15 (m, 1H, piperazine-H), 2.18–2.26
(m, 1H, piperazine-H), 2.36–2.49 (m, 2H, NCH2CH2CO2Et),
2.55–2.83 (m, 3H, piperazine-H (1H) and NCH2CH2CO2Et),
3.14–3.39 (m, 2H, piperazine-H), 3.85 (d broad, J = 12.5 Hz,
0.54H, piperazine-H), 3.92 (d broad, J = 12.5 Hz, 0.46H,
piperazine-H), 4.04–4.21 (m, 4H, 2 × OCH2CH3), 4.68 (s
broad, 0.46H, 2-H), 4.74 (s broad, 0.54H, 2-H), 5.06–5.17 (m,
2H, OCH2Ar), 7.25–7.38 (m, 5H, arom. H). Ratio of rota-
tional isomers 54:46. IR (neat): 1733 (s, C=Oester), 1703 (s,
C=Ocarbamate), 770 and 698 cm−1 (m, arom. out of plane). MS
(EI): m/z [%] = 392 (M, 15), 91 (PhCH2, 100).
Ethyl 1-Allyl-4-[2-(ethoxycarbonyl)ethyl]piperazine-
2-carboxylate (10b)
Under N2, allyl bromide (690 µL, 8.0 mmol) was added drop-
wise to an ice-cooled solution of 9 (1033 mg, 4.0 mmol),
triethylamine (1100 µL, 8.0 mmol), and tetrabutylammonium
iodide (296 mg, 0.8 mmol) in acetonitrile (100 mL). The reac-
tion mixture was stirred for 14 h at RT. Then one-half of the
solvent was removed under vacuum. A saturated NaHCO3 solu-
tion was added and the mixture was extracted with CH2Cl2
(3×). The combined organic layers were dried (Na2SO4), fil-
tered and the solvent was removed in under vacuum. The residue
was purified by FC (4 cm × 15 cm, 20 mL, cyclohexane/ethyl
acetate 2/1, RF = 0.53) to afford 964 mg (81%) of 10b as a
colourless oil. 1H NMR (CDCl3): δ 1.23 (t, J = 7.0 Hz, 3H,
OCH2CH3), 1.28 (t, J = 7.0 Hz, 3H, OCH2CH3), 2.30–2.37
(m, 1H, piperazine-H), 2.39–2.49 (m, 3H, 1 × piperazine-H and
2 × NCH2CH2CO2Et), 2.51–2.73 (m, 5H, 3 × piperazine-H and
2 × NCH2CH2CO2Et), 2.95–3.07 (m, 2H, 1 × piperazine-H
and 1 × NCH2CH=CH2), 3.21 (dd, J = 7.0, 3.9 Hz, 1H, 2-
H), 3.31 (ddt, J = 13.3, 5.5, 1.6 Hz, 1H, NCH2CH=CH2),
4.06–4.19 (m, 4H, 2 × OCH2CH3), 5.08–5.18 (m, 2H,
NCH2CH=CH2), 5.75–5.89 (dddd, J = 17.2, 10.2, 7.8, 5.5 Hz,
1H, NCH2CH=CH2). IR (neat): 1732 cm−1 (s, C=O). MS (EI):
m/z [%] = 299 (MH, 100).
Ethyl 4-[2-(Ethoxycarbonyl)ethyl]-1-(phenylacetyl)
piperazine-2-carboxylate (10e)
Phenylacetyl chloride (400 µL, 3.0 mmol) was added to a
solution of 9 (517 mg, 2.0 mmol) and triethylamine (562 µL,
4.0 mmol) in CH2Cl2 (20 mL). After 14 h a saturated NaHCO3
solution was added. The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (2×). The combined
organic layers were dried (Na2SO4), filtered and concentrated
under vacuum. The residue was purified by FC (3 cm × 15 cm,
15 mL, cyclohexane/ethyl acetate 1/1, RF = 0.33) to afford
1
444 mg (59%) of 10e as a colourless oil. H NMR (CDCl3):
δ 1.17–1.26 (m, 6H, 2 × OCH2CH3), 1.94 (td, J = 11.0, 5.5 Hz,
0.74H, piperazine-H), 2.0–2.07 (m, 2 × 0.26H, piperazine-H),
2.15 (dd, J = 11.7, 3.9 Hz, 0.74H, piperazine-H), 2.37–2.43 (m,
2H, NCH2CH2CO2Et), 2.54–2.71(m, 2.74H, 0.74 × piperazine-
H and NCH2CH2CO2Et), 2.75–2.82 (m, 0.26H, piperazine-
H), 2.98 (td, J = 12.5, 3.9 Hz, 0.26H, piperazine-H), 3.25–
3.31 (m, 0.26H, piperazine-H), 3.34–3.44 (m, 2 × 0.74H,
piperazine-H), 3.57–3.66 (m, 1.26H, 0.74 × piperazine-H and
0.52 × COCH2Ar), 3.77 (s, 2 × 0.74H, COCH2Ar), 4.03–4.19
(m, 4H, 2 × OCH2CH3), 4.35–4.43 (m, 0.52H, 0.26 × 2-H and
0.26 × piperazine-H), 5.22 (s broad, 0.74H, 2-H), 7.17–7.34 (m,
5H, arom. H). Ratio of rotational isomers 74:26. IR (neat):
1732 (s, C=Oester), 1647 (s, C=Oamide), 730 and 697 cm−1
(m, arom. out of plane). MS (EI): m/z [%] = 376 (M, 34), 289
(M–CH2CO2C2H5, 28).
Ethyl 1-Benzoyl-4-[2-(ethoxycarbonyl)ethyl]piperazine-
2-carboxylate (10c)
Benzoyl chloride (550 µL, 4.8 mmol) was added to a solution of
9 (1033 mg, 4.0 mmol) and triethylamine (1120 µL, 8.0 mmol)
in CH2Cl2 (30 mL). After 2 h a saturated NaHCO3 solution
was added. The organic layer was separated and the aqueous
layer was extracted with CH2Cl2 (2×). The combined organic
layers were dried (Na2SO4), filtered and concentrated under vac-
uum. The residue was purified by FC (4 cm × 15 cm, 20 mL,
cyclohexane/ethyl acetate 1/1, RF = 0.37) to afford 1364 mg
1
(94%) of 10c as a colourless oil. H NMR (CDCl3): δ 1.20–
1.33 (m, 6H, 2 × OCH2CH3), 2.08 (td, J = 11.0, 5.5 Hz, 0.67H,
piperazine-H), 2.13–2.23 (m, 2 × 0.33H, piperazine-H), 2.29
(dd, J = 11.0, 3.9 Hz, 0.67H, piperazine-H), 2.37–2.50 (m, 2H,
NCH2CH2CO2Et), 2.59–2.71 (m, 2.67H, 0.67 × piperazine-H
and NCH2CH2CO2Et), 2.83–2.92 (m, 0.33H, piperazine-H),
3.10–3.20 (m, 0.33H, piperazine-H), 3.25–3.32 (m, 0.33H,
piperazine-H), 3.41–3.55 (m, 3 × 0.67H, piperazine-H), 4.05–
4.26 (m, 4H, 2 × OCH2CH3), 4.29 (s broad, 0.33H, 2-H),
4.44–4.53 (m, 0.33H, piperazine-H), 5.34 (s broad, 0.67H,
2-H), 7.29–7.46 (m, 5H, arom. H). Ratio of rotational isomers
67:33. IR (neat): 1731 (s, C=Oester), 1640 (s, C=Oamide), 735
and 700 cm−1 (m, arom. out of plane). MS (EI): m/z [%] = 362
(M, 18), 289 (M–CO2C2H5, 37). HPLC: tR = 15.4 min, purity
99.3%.
Ethyl 4-[2-(Ethoxycarbonyl)ethyl]-1-tosylpiperazine-
2-carboxylate (10f)
Tosyl chloride (1140 mg, 6.0 mmol) was added to an ice-
cooled solution of 9 (1033 mg, 4.0 mmol) and pyridine (480 µL,
5.0 mmol) in CH2Cl2 (20 mL). After 2 h at 0◦C a saturated
NaHCO3 solution was added. The organic layer was sepa-
rated and the aqueous layer was extracted with CH2Cl2 (2×).
The combined organic layers were dried (Na2SO4), filtered
and concentrated under vacuum. The residue was purified
by FC (4 cm × 15 cm, 20 mL, cyclohexane/ethyl acetate 1/1,
RF = 0.46) to afford 1524 mg (92%) of 10f as a colourless oil.
1H NMR (CDCl3): δ 1.12 (t, J = 7.0 Hz, 3H, OCH2CH3), 1.19
(t, J = 7.0 Hz, 3H, OCH2CH3), 2.14 (td, J = 11.7, 3.9 Hz, 1H,
piperazine-H), 2.29 (dd, J = 11.0, 3.9 Hz, 1H, piperazine-H),
2.34–2.38 (m, 2H, NCH2CH2CO2Et), 2.39 (s, 3H, ArCH3),
2.54–2.67 (m, 2H, NCH2CH2CO2Et), 2.68–2.74 (m, 1H,
piperazine-H), 3.26 (dt, J = 11.7, 2.3 Hz, 1H, piperazine-H),
3.33 (td, J = 11.7, 3.1 Hz, 1H, piperazine-H), 3.60 (m, 1H,
piperazine-H), 3.89–4.13 (m, 4H, 2 × OCH2CH3), 4.60 (s broad,
1-Benzyl-2-ethyl 4-[2-(Ethoxycarbonyl)ethyl]piperazine-
1,2-dicarboxylate (10d)
Benzyl chloroformate (160 µL, 1.1 mmol) was added to a solu-
tion of 9 (194 mg, 0.75 mmol) and triethylamine (1040 µL,
7.5 mmol) in CH2Cl2 (20 mL). After stirring for 2 h at RT

1688
D. Kracht, S. Saito, and B. Wünsch
1H, 2-H), 7.25 (d, J = 8.6 Hz, 2H, 3-Htosylate, 5-Htosylate), 7.64
(d, J = 8.6 Hz, 2H, 2-Htosylate, 6-Htosylate). IR (neat): 1730 (s,
C=O), 1160 (s, S=O), 814 cm−1 (m, arom. out of plane). MS
(EI):m/z [%] = 412(M, 3), 257(M–SO2C6H4CH3, 100). HPLC:
tR = 17.9 min, purity 100%.
pH 7.The combined organic layers were dried (Na2SO4), filtered
and the solvent was removed under vacuum. The residue was
purified by FC [4 cm × 15 cm, 20 mL, CH2Cl2/MeOH 9.5/0.5,
RF = 0.46 (CH2Cl2/MeOH 9/1)] to afford 856 mg (79%) of 11c
1
as a pale yellow oil. H NMR (CDCl3): δ 1.33 (t, J = 7.0 Hz,
3H, OCH2CH3), 2.78 (d broad, J = 13.3 Hz, 0.35H, NCH2),
2.91 (d broad, J = 13.3 Hz, 0.65H, NCH2), 2.97–3.30 (m, 3.35H,
NCH2), 3.32–3.51 (m, 2H, NCH2), 3.79 (d, J = 17.2 Hz, 0.65H,
8-H), 3.85 (d, J = 17.2 Hz, 0.35H, 8-H), 4.12 (s, 0.65H, 5-H),
4.18–4.32 (m, 2.65H, OCH2CH3 and 0.65 × NCH2), 5.23 (s,
0.35H, 5-H), 7.35–7.55 (m, 5H, arom. H), 11.55 (s, 0.65, OH),
11.62 (s, 0.35, OH). Ratio of rotational isomers 65:35. IR (neat):
1664 (s, C=Oester), 1624 (s, C=Oamide), 1602 (m, C=C), 731
and 697 cm−1 (m, arom. out of plane). MS (EI): m/z [%] = 316
(M, 51), 105 (PhCO, 84). HPLC: tR = 14.8 min, purity 99.5%.
Ethyl 4-Benzyl-6-hydroxy-1,4-diazabicyclo[3.3.1]non-
6-ene-7-carboxylate (11a)
Under N2, sodium hexamethyldisilazide (NaHMDS, 2 M) in
THF (17.5 mL, 35 mmol) was added dropwise to an ice-cooled
solution of 10a (6.1 g, 17.5 mmol) in THF (50 mL). When the
addition was finished, the reaction mixture was stirred at 0◦C
for 2 h and then it was allowed to warm to RT. After 14 h, acetic
acid (2.0 mL, 17.5 mmol) and water were added and the mix-
ture was extracted with CH2Cl2 (3×) at pH 7. The combined
organic layers were dried (Na2SO4), filtered and the solvent
was removed under vacuum. The residue was purified by FC
(6 cm × 15 cm, 30 mL, CH2Cl2/MeOH (9.5/0.5), RF = 0.38) to
afford 3.9 g (74%) of 11a as a pale yellow oil. C17H22N2O3
(Mr = 302.4). 1H NMR (CDCl3): δ 1.31 (t, J = 7.0 Hz, 3H,
OCH2CH3), 2.42–2.47 (m, 2H, piperazine-H), 2.76–2.83 (m,
1H, piperazine-H), 2.94 (dt, J = 12.5, 2.3 Hz, 1H, piperazine-
H), 3.08 (t, J = 2.3 Hz, 1H, piperazine-H), 3.17 (ddd, J = 13.3,
10.9, 6.3 Hz, 1H, piperazine-H), 3.25–3.29 (m, 1H, piperazine-
H), 3.29 (d, J = 17.2 Hz, 1H, 8-H), 3.45 (d, J = 13.3 Hz, 1H,
PhCH2N), 3.72 (d, J = 17.2 Hz, 1H, 8-H), 3.82 (d, J = 13.3 Hz,
1H, PhCH2N), 4.24 (q, J = 7.0 Hz, 2H, OCH2CH3), 7.20–7.38
(m, 5H, arom. H), 11.87 (s broad, 1H, OH). IR (neat): 1652
(s, C=O), 1615 (s, C=C), 754 and 696 cm−1 (m, arom. out of
plane). MS (EI): m/z [%] = 302 (M, 13), 91 (PhCH2, 80).
4-Benzyl-7-ethyl 6-Hydroxy-1,4-diazabicyclo[3.3.1]non-
6-ene-4,7-dicarboxylate (11d)
Under N2, a solution of NaHMDS (2 M) in THF (0.60 mL,
1.20 mmol) was added dropwise to an ice-cooled solution of
10d (233 mg, 0.59 mmol) in THF (5 mL). The reaction mixture
was stirred at 0◦C for 2 h and then it was allowed to warm to
RT. After 14 h, acetic acid (70 µL, 1.2 mmol) and water were
added and the mixture was extracted with CH2Cl2 (3×) at pH
7. The combined organic layers were dried (Na2SO4), filtered
and the solvent was removed under vacuum. The residue was
purified by FC [2 cm × 15 cm, 10 mL, CH2Cl2/MeOH 9.5/0.5,
RF = 0.59 (CH2Cl2/MeOH 9/1)] to afford 28 mg (14%) of 11d
as a pale yellow oil. 1H NMR (CDCl3): δ 1.30 (t, J = 7.0 Hz, 3H,
OCH2CH3), 2.76–3.03 (m, 2H, 9-H and 2-H), 3.04–3.21 (m, 3H,
2-H, 3-H and 9-H), 3.30 (d, J = 17.2 Hz, 0.47H, 8-H), 3.33 (d,
J = 17.2 Hz, 0.53H, 8-H), 3.62–3.81 (m, 2H, 3-H and 8-H), 4.24
(q, J = 7.0 Hz, 2H, OCH2CH3), 4.52 (s broad, 0.53H, 5-H), 4.65
(s broad, 0.47H, 5-H), 5.06–5.24 (m, 2H, OCH2Ar), 7.26–7.42
(m, 5H, arom. H), 11.52 (s, 1H, OH). Ratio of rotational iso-
mers 53:47. 13C NMR (CDCl3): δ 14.4 (1C, OCH2CH3), 38.0,
38.4 (1C, C-3), 46.2, 46.8 (1C, C-5), 49.0 (1C, C-8), 51.1 (1C,
C-9), 53.3 (1C, C-2), 61.0 (1C, OCH2CH3), 67.6, 67.8 (1C,
OCH2Ar), 101.0 (1C, C-7), 128.0 (1C, C-4phenyl), 128.3 (2C,
C-3phenyl), 128.7 (2C, C-2phenyl), 136.8 (1C, C-1phenyl), 155.8
(1C, NCOOCH2Ar), 164.8 (1C, COOC2H5), 170.5 (1C, C-6).
IR (neat): 1699 (s, C=Oester), 1659 (s, C=Ocarbamate), 1623 (m,
C=C), 757 and 696 cm−1 (m, arom. out of plane). MS (EI):
m/z [%] = 346 (M, 40), 91 (PhCH2, 100). HPLC: tR = 16.9 min,
purity 95.7%.
Ethyl 4-Allyl-6-hydroxy-1,4-diazabicyclo[3.3.1]non-
6-ene-7-carboxylate (11b)
Under N2, a solution of NaHMDS (2 M) in THF (3.20 mL,
6.4 mmol) was added dropwise to an ice-cooled solution of
10b (957 mg, 3.2 mmol) in THF (15 mL). The reaction mixture
was stirred at 0◦C for 2 h and then it was allowed to warm
to RT. After 14 h, acetic acid (370 µL, 6.4 mmol) and water
were added and the mixture was extracted with CH2Cl2 (3×) at
pH 7.The combined organic layers were dried (Na2SO4), filtered
and the solvent was removed under vacuum. The residue was
purified by FC [3 cm × 15 cm, 20 mL, CH2Cl2/MeOH 9.5/0.5,
RF = 0.38 (CH2Cl2/MeOH 9/1)] to afford 356 mg (44%) of 11b
1
as a pale yellow oil. H NMR (CDCl3): δ 1.30 (t, J = 7.0 Hz,
3H, OCH2CH3), 2.36 (td, J = 12.5, 3.9 Hz, 1H, piperazine-H),
2.52 (td, J = 11.7, 4.7 Hz, 1H, piperazine-H), 2.7–2.85 (m, 1H,
piperazine-H), 2.89–2.98 (m, 2H, piperazine-H), 3.11–3.34 (m,
5H, 2 × NCH2CH=CH2, 2 × piperazine-H and 1 × 8-H), 3.71
(d, J = 16.4 Hz, 1H, 8-H), 4.22 (q, J = 7.0 Hz, 2H, OCH2CH3),
5.12–5.23 (m, 2H, NCH2CH=CH2), 5.80 (dddd, J = 17.1, 10.1,
7.0, 6.1 Hz, 1H, NCH2CH=CH2), 11.77 (s broad, 1H, OH).
IR (neat): 1654 (s, C=O), 1615 cm−1 (s, C=C). MS (EI): m/z
[%] = 252 (M, 19).
Ethyl 3-(7,9-Dioxo-8-phenyl-1,4-diazabicyclo[4.3.0]nonan-
4-yl)propanoate (12)
Under N2, a solution of NaHMDS (2 M) in THF (1100 µL,
2.2 mmol) was added dropwise to an ice-cooled solution of
10e (410 mg, 1.1 mmol) in THF (15 mL). The reaction mix-
ture was stirred at 0◦C for 2 h and then allowed to warm to
RT. After 14 h, acetic acid (130 µL, 2.2 mmol) and water were
added and the mixture was extracted with CH2Cl2 (3×) at pH
7. The combined organic layers were dried (Na2SO4), filtered
and the solvent was removed under vacuum. The residue was
purified by FC [3 cm × 15 cm, 15 mL, CH2Cl2/MeOH 9.5/0.5,
RF = 0.39 (CH2Cl2/MeOH 9/1)] to afford 356 mg (44%) of 12
Ethyl 4-Benzoyl-6-hydroxy-1,4-diazabicyclo[3.3.1]non-
6-ene-7-carboxylate (11c)
Under N2, a solution of NaHMDS (2 M) in THF (3.4 mL,
6.8 mmol) was added dropwise to an ice-cooled solution of
10c (1240 mg, 3.4 mmol) in THF (25 mL). The reaction mix-
ture was stirred at 0◦C for 2 h and then allowed to warm to
RT. After 14 h, acetic acid (400 µL, 6.8 mmol) and water were
added and the mixture was extracted with CH2Cl2 (3×) at
1
as a colourless solid, mp 186◦C. H NMR (CD3OD): δ 1.27
(t, J = 7.0 Hz, 3H, OCH2CH3), 1.86–1.95 (m, 1H, piperazine-
H), 2.08 (td, J = 11.7, 3.9 Hz, 1H, piperazine-H), 2.60 (t, 2H,
J = 7.0 Hz, 2H, NCH2CH2CO2Et), 2.85 (t, 2H, J = 7.0 Hz,

Synthesis of 1,4-Diazabicyclo[3.3.1]nonan-6-ones
1689
2H, NCH2CH2CO2Et), 2.93–2.99 (m, 1H, piperazine-H), 3.03–
3.12 (m, 1H, piperazine-H), 3.46 (ddd, J = 11.0, 3.9, 1.6 Hz,
1H, piperazine-H), 4.05 (dd, J = 11.0, 3.9 Hz, 1H, piperazine-
H), 4.16 (q, J = 7.0 Hz, 2H, OCH2CH3), 4.17–4.21 (m, 1H,
piperazine-H), 7.16–7.21 (m, 1H, 4-Hphenyl), 7.29–7.35 (m, 2H,
3-Hphenyl and 5-Hphenyl), 7.79–7.83 (m, 2H, 2-Hphenyl and 6-
Hphenyl). The signal for the COCHPhCO could not be detected.
IR (neat): 1707 (s, C=Oester), 1641 (s, C=Oamide), 717 and
696 cm−1 (m, arom. out of plane). MS (EI): m/z [%] = 330 (M,
26), 243 (M–CH2CO2C2H5, 100).
(dddd, 17.1, 10.1, 6.9, 6.2 Hz, 1H, NCH2CH=CH2). IR (neat):
1695 (s, C=O), 1643 cm−1 (w, C=C). MS (EI): m/z [%] = 180
(M, 100), 139 (M–CH2CH = CH2, 16).
Acknowledgement
This work was performed within the International Research Training Group
‘Complex Functional Systems in Chemistry: Design, Synthesis and Appli-
cations’ in collaboration with the University of Nagoya. Financial sup-
port of this IRTG by the Deutsche Forschungsgemeinschaft is gratefully
acknowledged.
References
4-Benzyl-1,4-diazabicyclo[3.3.1]nonan-6-one (3a)
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Under N2, a solution of 11a (3.9 g, 13.0 mmol) in 2 M HCl
(50 mL) was heated at reflux. After 36 h the reaction mixture
was cooled to RT, made alkaline with 2 M KOH solution and
extracted with CH2Cl2 (3×). The combined organic layers were
dried (Na2SO4), filtered and the solvent was removed under vac-
uum. The residue was purified by FC (5 cm × 15 cm, 30 mL,
CH2Cl2/MeOH9.5/0.5, RF = 0.26)toafford2.1 g(71%)of 3a as
a colourless solid, mp 106◦C. 1H NMR (CDCl3): δ 2.11–2.23 (m,
1H, 7-H), 2.48–2.64 (m, 2H, 7-H and 1H of 2-H or 3-H), 2.73 (dd,
J = 11.7, 5.5 Hz, 1H, 2-H or 3-H), 2.95–3.07 (m, 3H, 5-H, 1H
of 9-H and 1H of 2-H or 3-H), 3.20–3.45 (m, 4H, 2 × 8-H, 1H of
9-H and 1H of 2-H or 3-H), 3.33 (d, J = 13.3 Hz, 1H, PhCH2N),
3.63 (d, J = 13.3 Hz, 1H, PhCH2N), 7.20–7.37 (m, 5H, arom.
H). 13C NMR (CDCl3): δ 43.8 (1C, C-7), 48.3 (1C, C-2 or C-3),
51.1 (1C, C-8), 52.1 (1C, C-2 or C-3), 54.0 (1C, C-9), 60.7 (1C,
PhCH2N), 62.8 (1C, C-5), 127.5 (1C, C-4phenyl), 128.5 (2C, C-
3phenyl), 129.3 (2C, C-2phenyl), 137.7 (1C, C-1phenyl), 207.3 (1C,
C-6). IR (neat): 1696 (s, C=O), 739 and 697 cm−1 (m, arom.
out of plane). MS (EI): m/z [%] = 230 (M, 84), 139 (M–PhCH2,
14), 91 (PhCH2, 100). HPLC: tR = 13.4 min, purity 99.8%.
4-Allyl-1,4-diazabicyclo[3.3.1]nonan-6-one (3b)
Under N2, a solution of 11b (312 mg, 1.2 mmol) in 2 M HCl
(10 mL) was heated at reflux. After 16 h the reaction mixture
was cooled to RT, made alkaline with 2 M KOH solution and
extracted with CH2Cl2 (3 cm−1). The combined organic lay-
ers were dried (Na2SO4), filtered and the solvent was removed
under vacuum. The residue was purified by FC [3 cm × 15 cm,
20 mL, CH2Cl2/MeOH9.5/0.5, RF = 0.26(CH2Cl2/MeOH9/1)]
to afford 130 mg (58%) of 3b as a pale yellow oil. C10H16N2O
(Mr = 180.3). 1H NMR (CDCl3): δ 2.06–2.17 (m, 1H, 7-H),
2.43–2.60 (m, 2H, 1 × 7-H and 1 × 2-H or 3-H), 2.77–2.86 (m,
2H, 1 × NCH2CH=CH2 and 1 × 2-H or 3-H), 2.97–3.05 (m,
3H, 5-H, 1 × 9-H and 1 × 2-H or 3-H), 3.10 (ddt, J = 13.3, 6.3,
1.6 Hz, 1H, NCH2CH=CH2), 3.20–3.42 (m, 4H, 2 × 8-H, 1 × 9-
Hand1 × 2-Hor3-H), 5.11–5.21(m, 2H, NCH2CH=CH2), 5.75
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