A straightforward and efficiently scaleable synthesis of novel racemic 4-substituted-2,8-diazaspiro[4.5]decan-1-one derivatives

Article abstract of DOI:10.1055/s-2005-918454

Novel and straightforward syntheses (3-5 steps, high yields) of racemic diazaspiropiperidine derivatives based on the Michael addition of pipecolate-derived enolates to a range of nitroalkenes have been developed. The reaction has been shown to have a gen

Full text of DOI:10.1055/s-2005-918454

PAPER
3245
A Straightforward and Efficiently Scaleable Synthesis of Novel Racemic
4-Substituted-2,8-diazaspiro[4.5]decan-1-one Derivatives
S
traightforward
v
Synthesis
o
a
4-Substituted-2,8
A
-
diazaspiro[4.5]d
.
D
K
erivatives rafft, Anke Kurt, Axel Maier, Andrew W. Thomas,* Daniel Zimmerli
F. Hoffmann-La Roche AG, Pharmaceuticals Division, Discovery Chemistry, 4070 Basel, Switzerland
Fax +41(61)6888714; E-mail: andrew.thomas@roche.com
Received 31 August 2005
This work is dedicated to my friend and mentor Professor Steven V. Ley, FRS, CBE, with highest esteem and admiration on the occasion
of his 60th birthday.
novel 4-substituted-2,8-diazaspiro[4.5]decan-1-one de-
Abstract: Novel and straightforward syntheses (3–5 steps, high
rivatives 1 (Figure 2) which would be possible to perform
yields) of racemic diazaspiropiperidine derivatives based on the
Michael addition of pipecolate-derived enolates to a range of ni-
troalkenes have been developed. The reaction has been shown to
routinely on multi-gram scales.5 Only two routes have
been reported for the preparation of 2,8-diaza-
have a general scope and can be conducted on a preparatively useful spiro[4.5]decan-1-one motifs substituted at the 4-position.
scale. Isolation and identification of diazaspiropiperidine enanti-
omers was efficiently achieved using normal phase chiral HPLC.
The first method employed an intramolecular radical cy-
clization of compounds of type 2 which provided mixtures
of products with the target 1a being formed in good yield
(75%).6 This chemistry was limited to the introduction of
a methyl substituent at the 4-position and was clearly not
sufficient for our use. The second method, which was re-
Key words: cyclizations, lactams, Michael additions, piperidines,
spiro compounds
Spiropiperidine molecular scaffolds have emerged as one cently described,7 involved a lengthy nine-step process,
of the most common privileged scaffolds in drug discov- starting from 3, where in analogy to similar work8 the for-
ery since it has been repeatedly demonstrated that they in- mation of regioisomeric mixture of aminols in a key step
herently possess drug-like properties in pre-clinical resulted in low overall efficiency of the route.
models.1 Although a medicine has yet to be developed
As a consequence, neither of these routes was judged use-
which contains a spiropiperidine motif, significant num-
ful or applicable for the synthesis of our target 4-substitut-
bers of derivatives have been proposed as early and late
ed-2,8-diazaspiro[4.5]decan-1-one derivatives 1 where R
needed to be explored in detail and we therefore needed to
stage pre-clinical research candidates (Figure 1).
Spiropiperidines and related motifs have been routinely develop a novel synthetic route.
exploited in GPCR-targeted library preparation. In partic-
To be successful, our strategy (Figure 3) relied on the
ular, combinatorial and lead generation chemistry para-
Michael addition of the enolate derived from appropriate-
digms (where the phenomenon of recurring molecular
ly protected pipecolates, such as 4, with a range of b-sub-
stituted nitroalkenes. Reduction of the nitro functionality
in 5 followed by cyclization would result in the prepara-
tion of the targeted molecules in protected form at the pi-
frameworks as ligands for diverse receptor sets is advan-
tageous) have received the most attention. However in
lead optimization programs biological target selectivity is
a crucial design element. It has been shown (Figure 1) that
peridine nitrogen ready for further manipulation and
small changes within these privileged scaffolds infer dra-
transformation into final molecules within our medicinal
matic changes in their biological properties. This was ele-
chemistry program.5
gantly exemplified in the discovery of Spiperone mixed
At the outset of the work we focused on the use of a ben-
dopamine D2 and serotonin 5HT1a/2a antagonist
zyl-protecting group since we optimistically hoped to
combine the reductive cyclization and benzyl deprotec-
tion in a one-pot sequence of reactions. The four-step pro-
tocol commenced from the commercially available N-
benzyl ethyl pipecolate 5 (Scheme 1) and using standard
conditions the enolate of 5 was formed by treatment with
freshly prepared LDA, which was conducted between –40
°C and –60 °C. This was followed by quenching with
trans-b-nitrostyrene (6) at –40 °C to provide the desired
Michael addition product 7 in high yield (84%). After
screening a variety of reductive methods,9 the most pro-
ductive was Ra-Ni (5 mol%) catalyzed hydrogenolysis in
EtOH at 55 °C for two hours at 15 bar pressure to provide
good to excellent yields of the amino derivative 8. Al-
though it was possible to force the reaction to completion
(Figure 1).2 This molecule incorporates 1-phenyl-1,3,8-
triazaspiro[4.5]decan-4-one3 as a privileged pharmacoph-
oric element which through extensive and subtle structure
activity relationships (SAR) studies was shown to be re-
sponsible for a number of useful interactions at the
dopaminergic and serotonergic related sub-types, with
control of the 5HT2 selectivity being the most marked
control element.4
Within one of our recent medicinal chemistry programs
we required straightforward and efficient access routes to
SYNTHESIS 2005, No. 19, pp 3245–3252
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Advanced online publication: 28.10.2005
DOI: 10.1055/s-2005-918454; Art ID: C05905SS
© Georg Thieme Verlag Stuttgart · New York

3246
E. A. Krafft et al.
PAPER
Figure 1 Selected illustrative examples to the importance of spiropiperidine (azaspiro[4.5]decane) motifs in drug discovery and natural pro-
ducts.
to afford 9 directly, the yields were moderate (ca 50%) residual Ra-Ni catalyst. Evaporation followed by dilution
and required lengthy chromatographic separation to re- in toluene and heating the resulting mixture under reflux
move unwanted reaction side-products. It was more satis- for two hours provided the target cyclic g-lactam 9 in es-
factory to first isolate the ‘crude’ amine 8 simply by sentially pure form without the need for lengthy chro-
filtering the reaction mixture over Celite® to remove any matographic intervention. Removal of the benzyl-
Figure 2 Retrosynthesis: Literature routes for the preparation of 4-substituted-2,8-diazaspiro[4.5]decan-1-one derivatives.
Synthesis 2005, No. 19, 3245–3252 © Thieme Stuttgart · New York

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Straightforward Synthesis of 4-Substituted-2,8-diazaspiro[4.5]decan-1-one Derivatives
3247
Figure 3 Retrosynthesis: Strategic bond disconnections for the preparation of novel 4-substituted-2,8-diazaspiro[4.5]decan-1-one derivatives
(R = substituent; R2 = protecting group).
protecting group was more problematic than first envis- one (10) in good to excellent yields as the HCl salt or as
aged. On small scale (ca 100 mg) the transformation pro- its free base.
ceeded uneventfully under standard acid-catalyzed
Since our synthetic route relied on two hydrogenation
hydrogenolysis using Pd/C with a hydrogen balloon and
steps conducted under pressure of hydrogen gas, in spe-
EtOH containing a few drops of concentrated HCl. How-
cialized but standardized reaction vessels we adopted a
ever, on larger scale (> 20 g) we realized that the material
Boc-protecting group strategy in parallel, as outlined in
recovery from the hydrogenolysis was unacceptably low
Scheme 2. As shown, following similar synthetic opera-
(< 50%). As a result we investigated alternative hydro-
tions as outlined above, all steps proceeded uneventfully
genolytic methods. The best solution found was to add a
and efficiently provided access to multi-gram quantities
(> 45 g) of 17. In particular, when comparing the two
routes, the last deprotection step proceeded exceptionally
well where the product isolation of the 17·TFA salt was a
small amount of anhydrous CH2Cl2 (which presumably
forms anhyd HCl in situ) before charging the hydrogena-
tion vessel whereby under our optimized conditions (H2,
60 bar, Ra-Ni, EtOH, 55 °C) it was possible to routinely
isolate the targeted 4-phenyl-2,8-diazaspiro[4.5]decan-1-
Within our medicinal chemistry program5 we identified
significant development over the first route.
that it was possible to separate racemic final products into
Scheme 1 Synthesis of 4-phenyl-2,8-diazaspiro[4.5]decan-1-one (10).
Scheme 2 Synthesis of 4-(4-fluorophenyl)-2,8-diazaspiro[4.5]decan-1-one (17).
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3248
E. A. Krafft et al.
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their enantiomers using normal phase HPLC incorporat- observe that the reactions proceeded well when the eno-
ing a Chiralpak AD column. However it was not possible late formation of 12 was performed at 0 °C taking care to
to ascertain their absolute configuration via crystallo- ensure that the temperature of the deep red solution stayed
graphic means. As a result we attempted to determine below 10 °C. We targeted a derivative 22a incorporating
their absolute configuration by separation and identifica- a n-propyl unit as the 4-substituent. Starting from butyral-
tion of their synthetic precursors (the enantiomers of 17) dehyde the nitroalkene 18a10 was prepared in two steps
which, after separation and identification, would undergo according to literature precedent which reacted smoothly
the same series of reactions.5 Using a Chiralpak AD col- and in high yield with 12 at 0 °C. Subsequent Ra-Ni cata-
umn, eluting with heptane–EtOH (85:15) it was possible lyzed hydrogenolysis under our standard conditions pro-
to successfully separate the two enantiomers 17a, 17b ceeded uneventfully to provide a mixture of products 20a,
(peak A, peak B respectively). Both of these entities were 21a which was simply filtered through Celite®, evaporat-
subjected to salt formation with 1R-(–)-camphorsulfonic ed to dryness and then heated in toluene for 4.5 hours to
acid, followed by recrystallization of their resulting dia- provide 21a in 66% yield. Protecting group liberation us-
stereoisomeric salt from EtOAc. The enantiomer 17a ing TFA afforded the 4-n-propyl-2,8-diazaspiro[4.5]de-
(least polar) afforded the best crystals which were filtered can-1-one (22a) in 85% yield. The pyridino-motif
off, dried and found suitable for single crystal X-ray dif- containing derivatives 22b,c are included to further exem-
fraction studies which revealed the absolute configuration plify the general scope and power of this novel reaction
of 17a to be R as shown in Scheme 3.
sequence.
In summary we have developed a novel synthetic route to
access a range of 4-substituted diazaspiropiperidine deriv-
atives in racemic form. Our methodology is based on a
straightforward assembly strategy utilizing the construc-
tion of a quaternary centre via enolate addition chemistry
from commercially available pipecolate derivatives.
These routes have the advantage of the use of nitroalkenes
as a key synthon (which are easily prepared through dehy-
dration of Henry-type products) of which several are even
commercially available. Subsequent reductive cyclization
of the Michael addition products using pressurized hydro-
gen with preferably Ra-Ni as catalyst followed by heating
results in the formation of the diazaspiropiperidine motif
in good to excellent overall yields. This report focused on
the use of hydrogenation and acid labile protecting groups
on the piperidine nitrogen atom (Bn and Boc) and presum-
ably the chemistry described will proceed equally effi-
ciently with other protecting groups. This offers a
valuable new strategy for the further development of these
methods, which could be employed in the synthesis of a
wide range of novel molecular structures incorporating
privileged scaffolds in the future. We are currently devel-
oping an asymmetric version of these methods. It should
be noted, however, that the final racemic products can be
routinely and easily separated into their enantiomers using
standard normal phase methods on a ChiralPak AD col-
umn. This conveniently allowed us to elucidate the abso-
lute stereochemistry of advanced intermediates in our
medicinal chemistry programs which is being simulta-
neously reported in full detail.5
Scheme 3 Formation of the 1R-(–)-camphorsulfonic acid diaste-
reoisomeric salts of 17 and determination of the absolute configura-
tion of 17a.
The routes described above were then used to prepare a
range of derivatives5 (Scheme 4) and a representative set
is shown where it was possible to incorporate both ali-
phatic and heteroaromatic residues as the 4-substituent.
All reagents and solvents were purchased from Fluka and used di-
rectly without further purification. All reactions were conducted in
flame-dried glassware under an atmosphere of dry Ar. Analytical
TLC was performed on Kieselgel 60 F254 glass pre-coated with a
0.25 mm thickness of silica gel. Flash chromatography was per-
formed on Kieselgel 60 (230–400 mesh) silica gel. 1H NMR spectra
were measured at 300 MHz using CDCl3 as solvent on a Bruker
Avance spectrometer. Chemical shifts are reported in d units. All
doublet and tripling coupling constants are 7.5 Hz. Mass spectra
were recorded on a Micromass Platform II mass spectrometer at 70
We had previously observed in earlier experiments that
the enolate of 12 was often less reactive than presumed
with the result that some reactions did not proceed to com-
pletion at low temperatures. We therefore explored the
opportunity to perform the enolate generation and subse-
quent Michael addition to the nitroalkenes at elevated
temperatures. In a first experiment, we were pleased to eV. IR spectra were recorded on a Magna 750 (FTIR) Nicolet spec-
trometer.
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Straightforward Synthesis of 4-Substituted-2,8-diazaspiro[4.5]decan-1-one Derivatives
3249
Scheme 4 Synthesis of 4-substituted-2,8-diazaspiro[4.5]decan-1-ones 21a–c, 22a–c.
Synthesis of rac-4-Phenyl-2,8-diazaspiro[4.5]decan-1-one (10)
rac-1-Benzyl-4-(2-nitro-1-phenylethyl)piperidine-4-carboxylic
Acid Ethyl Ester (7)
rac-4-Phenyl-2,8-diazaspiro[4.5]decan-1-one (10)
A suspension of rac-8-benzyl-4-phenyl-2,8-diazaspiro[4.5]decan-
1-one (28.8 g, 90 mmol) in MeOH–CH2Cl2 (4:1, 500 mL) was hy-
drogenated in the presence of Pd (10% on C, 14 g, 132 mmol) at 2
bar for 48 h at r.t. After filtration over celite, the reaction mixture
was evaporated and the residue was dissolved in NaOH (2 N, 200
mL). The product was extracted with CH2Cl2 (3 × 150 mL) and the
combined organic extracts were dried over Na2SO4. Filtration and
evaporation afforded the title compound (13.1 g, 63%) as a white
solid after trituration from Et2O.
1H NMR (300 MHz, CDCl3): d = 7.4–7.2 (m, 5 H), 6.50–6.60 (br, 1
H), 3.60–3.80 (m, 1 H), 3.40–3.58 (m, 1 H), 3.25–3.40 (m, 2 H),
2.82–3.00 (m, 2 H), 2.50–2.60 (m, 1 H), 1.50–1.95 (m, 4 H), 1.04–
1.20 (m, 1 H).
A 14 mmol solution of LDA was prepared by treating diisopropyl-
amine (1.37 g, 14 mmol) with BuLi (1.6 M, 8.5 mL, 14 mmol) at
–78 °C in anhyd THF (10 mL) under Ar and allowing it to warm to
–20 °C. This solution was then cooled to –60 °C, added to a solution
of 1-benzylpiperidine-4-ethyl carboxylate (3.05 g, 12 mmol) at –60
°C and allowed to warm to –40 °C over 1 h whereupon a solution of
trans-b-nitrostyrene (1.93 g, 13 mmol) was added dropwise. The re-
action mixture was allowed to warm to r.t. over 1 h and then
quenched with sat. NH4Cl (40 mL) and the product was extracted
with EtOAc (2 × 40 mL). The combined organic extracts were then
washed with brine, dried over Na2SO4, filtered and evaporated. Pu-
rification by chromatography on silica gel, eluting with CH2Cl2–
MeOH (9:1), afforded the title compound as a light yellow gum;
yield: 4.1 g (84%).
MS (EI): m/z = 231.4 [M + H].
Synthesis of rac-4-(4-Fluorophenyl)-2,8-diazaspiro[4.5]decan-
1-one (17)
Piperidine-1,4-dicarboxylic Acid 1-tert-Butyl Ester 4-Ethyl Es-
ter (12)
To a solution of ethyl isonipecotate (11; 20 g, 127 mmol) in diox-
ane–water (1:1, 120 mL) was added Et3N (12.87 g, 127 mmol) at 0
°C followed by di-tert-butylcarbonate (35.2 g, 161 mmol) and the
resulting mixture was maintained at this temperature for 2 h. The
product was then extracted with EtOAc (3 × 100 mL) and the com-
bined organic extracts were washed with HCl (1 N, 100 mL), brine
(100 mL), dried over Na2SO4, filtered and evaporated. Purification
by Kugelrohr distillation afforded the title compound (29.0 g, 89%)
as a colorless liquid; bp 140 °C/0.13 mbar.
1H NMR (300 MHz, CDCl3): d = 7.05–7.35 (m, 10 H), 4.80–4.90
(m, 2 H), 4.08–4.22 (m, 2 H), 3.58–3.62 (m, 1 H), 3.42–3.98 (m, 2
H), 2.66–2.80 (m, 2 H), 2.18–2.24 (m, 1 H), 1.95–2.05 (m, 1 H),
1.80–1.90 (m, 2 H), 1.56–1.70 (m, 1 H), 1.21 (t, 3 H).
MS (EI): m/z = 397.4 [M + H].
rac-4-(2-Amino-1-phenylethyl)-1-benzylpiperidine-4-carboxyl-
ic Acid Ethyl Ester (8)
A solution of rac-1-benzyl-4-(2-nitro-1-phenylethyl)piperidine-4-
carboxylic acid ethyl ester (3.18 g, 8 mmol) in anhyd EtOH (240
mL) was hydrogenated in the presence of Ra-Ni (3 g) at 60 bar at 55
°C for 3 h. After cooling and decompression of the reaction vessel,
the mixture was filtered over celite and the filtrate was evaporated
to leave the title compound (2.9 g, 99%) as a clear oil.
1H NMR (300 MHz, CDCl3): d = 4.16 (q, 2 H), 3.96–4.10 (m, 2 H),
2.80–2.90 (m, 2 H), 2.40–2.46 (m, 1 H), 1.80–1.90 (m, 2 H), 1.60–
1.70 (m, 2 H), 1.44 (s, 9 H), 1.24 (t, 3 H).
IR (film): 3377, 1720 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.10–7.30 (m, 10 H), 4.06–4.14
(m, 2 H), 3.35–3.50 (m, 2 H), 3.02–3.10 (m, 2 H), 2.70–2.80 (m, 3
H), 2.20–2.30 (m, 1 H), 1.80–2.00 (m, 3 H), 1.50–1.60 (m, 2 H),
0.80–1.50 (br, 2 H), 1.18–1.24 (t, 3 H).
MS (EI): m/z = 275.2 [M + NH4], 258.2 [M + H], 202.1.
rac-4-[1-(4-Fluorophenyl)-2-nitroethyl]piperidine-1,4-dicar-
boxylic Acid 1-tert-Butyl Ester 4-Ethyl Ester (14)
A solution of LDA was prepared by treating diisopropylamine (6.98
g, 69 mmol) with BuLi (1.6 M, 41.3 mL, 66 mmol) at –78 °C in an-
hyd THF (45 mL) under Ar and allowing it to warm to –20 °C. This
solution was then cooled to –60 °C, added to a solution of piperi-
dine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (11; 15.44
g, 60 mmol) in anhyd THF (45 mL) at –60 °C and allowed to warm
to –40 °C over 1 h whereupon a solution of 4-fluoro-trans-b-ni-
trostyrene (13; 10.02 g, 60 mmol) in anhyd THF (40 mL) was added
dropwise. The reaction mixture was allowed to warm to r.t. over 1
h, then quenched with sat. NH4Cl (250 mL) and the product was ex-
tracted with Et2O (3 × 100 mL). The combined organic extracts
were then washed with brine, dried over Na2SO4, filtered and evap-
orated to afford the title compound (26.7 g, 99%) as a light yellow
gum.
MS (EI): m/z = 367.4 [M + H].
rac-8-Benzyl-4-phenyl-2,8-diazaspiro[4.5]decan-1-one (9)
A solution of rac-4-(2-amino-1-phenylethyl)-1-benzylpiperidine-4-
carboxylic acid ethyl ester (2.9 g, 8 mmol) in toluene (30 mL) was
heated under reflux for 4 h. After cooling to r.t. and solvent evapo-
ration the mixture was purified by chromatography on silica gel,
eluting with CH2Cl2–MeOH–NH4OH (95:4.5:0.5), to afford the ti-
tle compound (1.47 g, 58%) as a white solid.
1H NMR (300 MHz, CDCl3): d = 7.15–7.35 (m, 10 H), 5.75 (s, 1 H),
3.70–3.74 (m, 1 H), 3.45–3.50 (m, 3 H), 3.30–3.35 (m, 1 H), 2.80–
2.92 (m, 1 H), 2.40–2.60 (m, 2 H), 2.10–2.20 (m, 1 H), 1.95–2.00
(m, 1 H), 1.82–1.90 (m, 2 H), 1.18–1.24 (m, 1 H).
MS (EI): m/z = 321.4 [M + H].
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E. A. Krafft et al.
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1H NMR (300 MHz, CDCl3): d = 6.96–7.10 (m, 4 H), 4.80–4.90 (m,
2 H), 4.16–4.24 (m, 2 H), 3.90–4.16 (m, 2 H), 3.84–3.86 (m, 1 H),
3.40–3.60 (m, 2 H), 2.56–2.82 (m, 2 H), 2.18–2.30 (m, 1 H), 1.80–
1.84 (m, 1 H), 1.43 (s, 9 H), 1.23 (t, 3 H).
Synthesis of rac-4-Propyl-2,8-diazaspiro[4.5]decan-1-one (22a)
1-Nitropent-1-ene (18a)
To a solution of butyraldehyde (90.1 mL, 1 mol) in aq NaHSO3
(38%, 207.5 mL, 1 mol) and water (293 mL) was added a solution
of nitromethane (54.1 mL, 1 mol) dissolved in NaOH (2 N, 150 mL,
300 mmol) and water (50 mL) and the resulting mixture was stirred
at 43 °C for 3 h and then heated under reflux for 30 min. The mix-
ture was then cooled to r.t. overnight and adjusted to pH ~4 with
HCl (6 N). The product was extracted with Et2O (3 × 500 mL) and
the combined organic layers were then washed with H2O and brine,
dried over Na2SO4 and evaporated to leave a brown liquid (37.6 g,
282 mmol). This product was then dissolved in CHCl3 (100 mL) and
treated with acetyl chloride (23 mL, 325 mmol) and the resulting
mixture was stirred at r.t. for 3 h and then heated under reflux for 30
min. After cooling to r.t. the mixture was poured onto ice and neu-
tralized with solid NaHCO3. The product was extracted with CHCl3
(2 × 200 mL) and the combined organic layers were then washed
with H2O and brine, dried over Na2SO4 and evaporated to leave a
brown liquid (46.1 g, 263 mmol). This product was then dissolved
in EtOAc (1 L) and then NaOAc (69.1 g, 842 mmol) was added and
the resulting mixture was stirred at r.t. for 48 h. The mixture was
then filtered and the solution was evaporated. The residue was then
partitioned between Et2O and water and the water layer was extract-
ed with Et2O. The combined organic layers were then washed with
H2O and brine, dried over Na2SO4 and evaporated to leave a brown
liquid (46 g). The title compound (6.8 g, 23%) was purified by
steam distillation (bp 70 °C at 8 torr).10
MS (EI): m/z = 442.4 [M + NH4].
rac-4-(2-Amino-1-phenylethyl)-1-tert-butylpiperidine-1,4-di-
carboxylic Acid Ethyl Ester (15)
A solution of rac-4-[1-(4-fluorophenyl)-2-nitroethyl]piperidine-
1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (26.6 g, 60
mmol) in anhyd EtOH (600 mL) was hydrogenated in the presence
of Ra-Ni (25 g) at 50 bar at 50 °C for 20 h. After cooling and de-
compression of the reaction vessel, the mixture was filtered over
celite and the filtrate was evaporated to leave the title compound
(23.4 g, 99%) as a clear oil which was used directly in the next step.
rac-4-(4-Fluorophenyl)-1-oxo-2,8-diazaspiro[4.5]decane-8-car-
boxylic Acid tert-Butyl Ester (16)
A solution of rac-4-(2-amino-1-phenylethyl)-1-tert-butylpiperi-
dine-1,4-dicarboxylic acid ethyl ester (23.4 g, 60 mmol) in toluene
(200 mL) was heated under reflux for 18 h. After cooling to r.t.,
evaporation afforded the title compound (17.17 g, 83%) as a white
solid after trituration from hot pentane.
1H NMR (300 MHz, CDCl3): d = 7.18–7.22 (m, 2 H), 7.00–7.06 (m,
2 H), 6.40 (br, 1 H), 3.80–3.84 (m, 1 H), 3.70–3.80 (m, 1 H), 3.40–
3.60 (m, 4 H), 3.30–3.40 (m, 1 H), 1.80–1.90 (m, 1 H), 1.56–1.70
(m, 2 H), 1.40 (s, 9 H), 1.04–1.16 (m, 1 H).
rac-4-(1-Nitromethylbutyl)piperidine-1,4-dicarboxylic Acid 1-
tert-Butyl Ester 4-Ethyl Ester (19a)
MS (EI): m/z = 349.3 [M + H].
As described for 14, piperidine-1,4-dicarboxylic acid 1-tert-butyl
ester 4-ethyl ester (15.3 g, 59 mmol) was converted to the title com-
pound (21.2 g, 96%) (using 1-nitropent-1-ene instead of 4-fluoro-
trans-b-nitrostyrene) which was obtained as a yellow oil.
1H NMR (300 MHz, CDCl3): d = 4.62–4.70 (m, 1 H), 4.2 (t, 3 H),
3.96–4.10 (m, 2 H), 2.62–2.86 (m, 2 H), 2.36–2.44 (m, 1 H), 2.04–
2.20 (m, 2 H), 1.50–1.60 (m, 2 H), 1.42 (s, 9 H), 1.30–1.40 (m, 3 H),
1.30 (t, 3 H), 1.10–1.20 (m, 1 H), 0.91 (t, 3 H).
rac-4-(4-Fluorophenyl)-2,8-diazaspiro[4.5]decan-1-one (17)
A solution of rac-4-(4-fluorophenyl)-1-oxo-2,8-diazaspiro[4.5]de-
cane-8-carboxylic acid tert-butyl ester (46.0 g, 132 mmol) in
CH2Cl2 (260 mL) containing TFA (150 mL, 1.32 mol) was stirred
vigorously at 0 °C for 15 min. The reaction mixture was then poured
into NaOH (3 N, 200 mL) and the product was extracted with
CH2Cl2 (3 × 100 mL). The combined organic extracts were then
washed with water (100 mL) and brine (100 mL) and then dried
over Na2SO4. Filtration and evaporation afforded the title com-
pound (22.14 g, 68%) as a white solid after trituration from EtOAc.
MS (EI): m/z = 371.2 (M – H), 342.3 (M – NO), 226.2 (M – OEt).
1H NMR (300 MHz, CDCl3): d = 7.18–7.22 (m, 2 H), 6.98–7.06 (m,
2 H), 6.19 (br, 1 H), 3.68–3.80 (m, 1 H), 3.42–3.52 (m, 2 H), 3.24–
3.40 (m, 2 H), 2.82–3.00 (m, 2 H), 1.52–1.60 (m, 1 H), 1.72–1.82
(m, 3 H), 1.04–1.16 (m, 1 H).
rac-1-Oxo-4-propyl-2,8-diazaspiro[4.5]decane-8-carboxylic
Acid tert-Butyl Ester (21a)
As described for 15 and 16, rac-4-(1-nitromethylbutyl)piperidine-
1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (21.2 g, 57
mmol) was converted to the title compound (11.2 g, 66%) after the
two-step procedure of Ra-Ni hydrogenation and heating under re-
flux in toluene solution. The title compound was obtained as a white
solid after trituration from hot pentane.
1H NMR (300 MHz, CDCl3): d = 5.58 (br, 1 H), 3.62–3.80 (m, 3 H),
3.38–3.42 (m, 2 H), 2.94–3.00 (m, 1 H), 2.00–2.10 (m, 1 H), 1.40–
1.60 (m, 2 H), 1.42 (s, 9 H), 1.30–1.40 (m, 3 H), 1.20–1.30 (m, 3 H),
0.92 (t, 3 H).
MS (EI): m/z = 249.2 [M + H].
(R)-4-(4-Fluorophenyl)-2,8-diazaspiro[4.5]decan-1-one (17a)
and (S)-4-(4-Fluorophenyl)-2,8-diazaspiro[4.5]decan-1-one
(17b)
The enantiomers of rac-4-(4-fluorophenyl)-2,8-diazaspiro[4.5]de-
can-1-one were separated using a 5 × 50 cm Chiralpak AD column
at r.t. using a 15% EtOH–85% heptane mobile phase with UV de-
tection at 220 nM. The less polar component (Peak A) corresponds
to the (R)-enantiomer; [a]D +2.21 (c = 0.36, MeOH). The more polar
component (Peak B) corresponds to the (S)-enantiomer; [a]D –3.24
(c = 1.01, MeOH).
MS (EI): m/z = 297.5 [M + H].
rac-4-Propyl-2,8-diazaspiro[4.5]decan-1-one (22a)
As described for 17, 1-oxo-4-propyl-2,8-diazaspiro[4.5]decane-8-
carboxylic acid tert-butyl ester (11.2 g, 38 mmol) was converted to
the title compound (6.3 g, 85%) which was obtained as a light yel-
low liquid.
1H NMR (300 MHz, CDCl3): d = 5.80 (br, 1 H), 3.38–3.56 (m, 2 H),
3.08–3.20 (m, 1 H), 2.94–3.02 (m, 1 H), 2.80–2.90 (m, 2 H), 2.00–
2.20 (m, 2 H), 1.58–1.70 (m, 4 H), 1.30–1.50 (m, 2 H), 1.22–1.24
(m, 2 H), 0.93 (t, 3 H).
Elucidation of Absolute Stereochemistry
To a solution of 4-(4-fluorophenyl)-2,8-diazaspiro[4.5]decan-1-one
(Peak A, 50 mg, 0.2 mmol) in MeOH (10 mL) was added 1R-(–)-
camphorsulfonic acid (46.8 mg, 0.2 mmol) and the solution was
stirred for 10 min at r.t. The resulting mixture was evaporated and
the residue was crystallized from EtOAc. A single crystal X-ray
structural analysis determined the absolute configuration was (R) as
(1R)-(–)-camphorsulfonic acid salt.
MS (EI): m/z = 197.4 [M + H].
Synthesis 2005, No. 19, 3245–3252 © Thieme Stuttgart · New York

PAPER
Straightforward Synthesis of 4-Substituted-2,8-diazaspiro[4.5]decan-1-one Derivatives
3251
Synthesis of 4-Pyridin-3-yl-2,8-diazaspiro[4.5]decan-1-one
(22b)
3-[(E)-2-Nitrovinyl]pyridine (18b)
As described for 18a 3-pyridine carboxaldehyde (20 g, 179 mmol)
was converted to the title compound (14.6 g, 55%), which was ob-
tained as a light yellow solid.
1H NMR (300 MHz, CDCl3): d = 8.54–8.60 (m, 2 H), 7.00–7.04 (m,
2 H), 4.82–4.88 (m, 2 H), 4.16–4.30 (m, 2 H), 3.84–4.16 (m, 3 H),
3.57–3.62 (m, 1 H), 2.40–2.82 (m, 3 H), 2.19–2.26 (m, 1 H), 1.80–
1.90 (m, 1 H), 1.42 (s, 9 H), 1.22 (t, 3 H).
MS (EI): m/z = 408.4 [M + H].
1H NMR (300 MHz, CDCl3): d = 8.80 (d, 1 H), 8.72 (m, 1 H), 8.05
(d, 1 H), 7.84–7.90 (m, 1 H), 7.62 (d, 2 H), 7.38–7.44 (m, 1 H).
1-Oxo-4-pyridin-4-yl-2,8-diazaspiro[4.5]decane-8-carboxylic
Acid tert-Butyl Ester (21c)
As described for 15 and 16, 19c (6.7 g, 17 mmol) was converted to
the title compound (3.6 g, 66%) after the two-step procedure of Ra-
Ni hydrogenation and heating under reflux in toluene solution. The
title compound was obtained as a light yellow solid after trituration
from hot pentane.
1H NMR (300 MHz, CDCl3): d = 8.56–8.60 (m, 2 H), 7.14–7.20 (m,
2 H), 5.95 (br, 1 H), 3.64–3.84 (m, 2 H), 3.42–3.60 (m, 2 H), 3.30–
3.40 (m, 2 H), 1.80–1.90 (m, 1 H), 1.60–1.80 (m, 3 H), 1.40 (s, 9 H),
1.10–1.19 (m, 1 H).
MS (EI): m/z = 151.1 [M + H].
rac-4-(2-Nitro-1-pyridin-3-ylethyl)piperidine-1,4-dicarboxylic
Acid 1-tert-Butyl Ester 4-Ethyl Ester (19b)
As described for 14, piperidine-1,4-dicarboxylic acid 1-tert-butyl
ester 4-ethyl ester (8.6 g, 33 mmol) was converted to the title com-
pound (11.0 g, 81%) {using 3-[(E)-2-nitrovinyl]pyridine 18b in-
stead of 4-fluoro-trans-b-nitrostyrene} which was obtained as a
light red oil.
1H NMR (300 MHz, CDCl3): d = 8.56–8.60 (m, 1 H), 8.38–8.40 (m,
1 H), 7.40–7.43 (m, 1 H), 7.22–7.30 (m, 1 H), 4.88 (d, 2 H), 4.16–
4.30 (m, 2 H), 3.85–4.16 (m, 2 H), 3.76–3.80 (m, 1 H), 3.58–3.62
(m, 1 H), 2.58–2.82 (m, 2 H), 2.20–2.26 (m, 1 H), 1.80–1.90 (m, 2
H), 1.42 (s, 9 H), 1.21 (t, 3 H).
MS (EI): m/z = 332.4 [M + H].
4-Pyridin-4-yl-2,8-diazaspiro[4.5]decan-1-one (22c)
As described for 17, 21c (3.6 g, 11 mmol) was converted to the title
compound (0.7 g, 28%), which was obtained as a white solid.
MS (EI): m/z = 408.5 [M + H].
1H NMR (300 MHz, CDCl3): d = 8.52–8.60 (m, 2 H), 7.16–7.20 (m,
2 H), 5.96 (br, 1 H), 3.70–3.80 (m, 1 H), 3.42–3.50 (m, 1 H), 3.26–
3.40 (m, 2 H), 2.84–3.04 (m, 2 H), 2.54–2.60 (m, 1 H), 1.60–1.95
(m, 4 H), 1.02–1.10 (m, 1 H).
rac-1-Oxo-4-pyridin-3-yl-2,8-diazaspiro[4.5]decane-8-carboxy-
lic Acid tert-Butyl Ester (21b)
As described for 15 and 16, 19b (10.9 g, 27 mmol) was converted
to the title compound (5.0 g, 56%) after the two-step procedure of
Ra-Ni hydrogenation and heating under reflux in toluene solution.
The title compound was obtained as a white solid after trituration
from hot pentane.
1H NMR (300 MHz, CDCl3): d = 8.56–8.60 (m, 1 H), 8.46 (br, 1 H),
7.54–7.60 (m, 1 H), 7.20–7.30 (m, 1 H), 6.04 (br, 1 H), 3.64–3.82
(m, 2 H), 3.44–3.62 (m, 3 H), 3.30–3.40 (m, 1 H), 1.80–1.90 (m, 1
H), 1.60–1.70 (m, 3 H), 1.40 (s, 9 H), 1.10–1.15 (m, 1 H).
MS (EI): m/z = 232.4 [M + H].
Acknowledgment
We would like to thank Drs Geo Adam, Daniela Alberati, Simona
Ceccarelli, Synèse Jolidon, Sabine Kolczewski, Emmanuel Pinard,
Michelangelo Scalone and Henri Stalder for support of this work as
well as Mr André Alker and Dr Armin Ruf for solving the X-ray
structure of 17a.
MS (EI): m/z = 332.4 [M + H].
References
4-Pyridin-3-yl-2,8-diazaspiro[4.5]decan-1-one (22b)
As described for 17, 21b (5.0 g, 15 mmol) was converted to the title
compound (0.9 g, 26%), which was obtained as a white solid.
1H NMR (300 MHz, CDCl3): d = 8.56–8.60 (m, 2 H), 7.58–7.61 (m,
1 H), 7.20–7.30 (m, 2 H), 5.88 (br, 1 H), 3.74–3.82 (m, 1 H), 3.50–
3.56 (m, 1 H), 3.30–3.49 (m, 2 H), 2.84–3.10 (m, 2 H), 2.80–2.88
(m, 1 H), 2.58–2.70 (m, 1 H), 1.60–1.80 (m, 2 H), 1.04–1.20 (m, 1
H).
(1) DeSimone, R. W.; Currie, K. S.; Mitchell, S. A.; Darrow, J.
W.; Pippin, D. A. Comb. Chem. High Throughput Screening
2004, 7, 473.
(2) Guo, T.; Hobbs, D. W. Assay Drug Dev. Tech. 2003, 1, 579.
(3) (a) Janssen, C. Belgian Patent, BE633914, 1963; Chem.
Abstr. 2005, 60, 90893. (b) 1-Phenyl-1,3,8-triaza-
spiro[4.5]decan-4-one is commercially available (Fluka,
Acros).
MS (EI): m/z = 232.1 [M + H].
(4) (a) Glennon, R. A.; Metwally, K.; Dukat, M.; Ismaiel, A. M.;
De los Angeles, J.; Herndon, J.; Teitler, M.; Khorana, N.
Curr. Top. Med. Chem. 2002, 2, 539. (b) Metwally, A.;
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(5) (a) Alberati, D.; Ceccarelli, S.; Jolidon, S.; Pinard, E.;
Thomas, A. W. US Patent, 2005154001, 2005; Chem. Abstr.
2005, 143, 115462. (b) Jolidon, S.; Pinard, E.; Thomas, A.
W. US Patent, 2005154000, 2005; Chem. Abstr. 2005, 143,
115461.
Synthesis of 4-Pyridin-4-yl-2,8-diazaspiro[4.5]decan-1-one
(22c)
4-[(E)-2-Nitrovinyl]pyridine (18c)
As described for 18a, 4-pyridine carboxaldehyde (12 g, 112 mmol)
was converted to the title compound (3.0 g, 18%), which was ob-
tained as a light brown solid.
1H NMR (300 MHz, CDCl3): d = 8.69–8.71 (m, 2 H), 8.40 (d, 1 H),
8.10 (d, 1 H), 7.78–7.81 (m, 2 H).
MS (EI): m/z = 151.3 [M + H].
rac-4-(2-Nitro-1-pyridin-4-yl-ethyl)piperidine-1,4-dicarboxylic
Acid 1-tert-Butyl Ester 4-Ethyl Ester (19c)
As described for 14, piperidine-1,4-dicarboxylic acid 1-tert-butyl
ester 4-ethyl ester (5.1 g, 20 mmol) was converted to the title com-
pound (5.2 g, 65%) {using 4-[(E)-2-nitrovinyl]pyridine 21c instead
of 4-fluoro-trans-b-nitrostyrene} which was obtained as a red oil.
(6) Ganguly, A. K.; Wang, C. H.; David, M.; Bartner, P.; Chan,
T. M. Tetrahedron Lett. 2002, 43, 6865.
(7) Galley, G.; Godel, T.; Goergler, A.; Hoffmann, T.;
Kolczewski, S.; Roever, S. Patent, WO200194346, 2001;
Chem. Abstr. 2001, 136, 37519.
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3252
E. A. Krafft et al.
PAPER
of complex mixtures with the major component being the
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Synthesis 2005, No. 19, 3245–3252 © Thieme Stuttgart · New York