Synthesis of nitrogen-containing spirocyclic scaffolds via aminoallylation/RCM sequence

Article abstract of DOI:10.1016/j.tet.2007.07.083

A concise route to nitrogen-containing spirocyclic scaffolds was developed. It is based on the allylation of imines derived from cyclic ketones. The resulting homoallylamines were subsequently alkylated with bromomethylmethacrylate resulting in propenyl-butenyl substituted amine derivatives. Basic amines such as 4 or 10 were cyclized with the Grubbs 2nd generation catalyst in the presence of pTsOH. Carbamate derivatives could be converted to tetrahydropiperidine derivatives with the same catalyst. It could be shown that the acrylate functionality can be?degraded to the ketone using the classical sequence consisting of Curtius rearrangement of the derived acrylic acid followed by hydrolysis of the vinyl isocyanate. Other modifications include reduction of the acrylate double bond, saponification of the ester group, and amide formation.

Full text of DOI:10.1016/j.tet.2007.07.083

Tetrahedron 63 (2007) 10486–10496
Synthesis of nitrogen-containing spirocyclic scaffolds
via aminoallylation/RCM sequence
*
Evgeny Prusov and Martin E. Maier
Institut fu€r Organische Chemie, Universita€t Tu€bingen, Auf der Morgenstelle 18, 72076 Tu€bingen, Germany
Received 25 June 2007; revised 20 July 2007; accepted 23 July 2007
Available online 29 July 2007
Abstract—A concise route to nitrogen-containing spirocyclic scaffolds was developed. It is based on the allylation of imines derived from
cyclic ketones. The resulting homoallylamines were subsequently alkylated with bromomethylmethacrylate resulting in propenyl-butenyl
substituted amine derivatives. Basic amines such as 4 or 10 were cyclized with the Grubbs 2nd generation catalyst in the presence of pTsOH.
Carbamate derivatives could be converted to tetrahydropiperidine derivatives with the same catalyst. It could be shown that the acrylate func-
tionality can be degraded to the ketone using the classical sequence consisting of Curtius rearrangement of the derived acrylic acid followed by
hydrolysis of the vinyl isocyanate. Other modifications include reduction of the acrylate double bond, saponification of the ester group, and
amide formation.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
according to the ring size of the heterocyclic ring (Fig. 1).
A further distinction can be made regarding the position of
the nitrogen atom. The other ring can vary in size and the
nature of the functional group. Of course, the second ring
might be heterocyclic as well. Derived from a parent system
A, the two pyrrolidine derivatives A1 and A2 are conceiv-
able. In the case of the parent system B, incorporation of a
nitrogen atom into the cyclohexane ring generates the three
derived structures B1–B3.
Compound collections or libraries are now commonplace in
screeningcampaigns in industry and academia.1 Thegoal can
be the discovery of novel cellular targets, novel lead struc-
tures,2 or the optimization of a lead compound. In order to
save time and money the hit rate should be high. In this regard
compound collections should cover the necessary chemical
space in a well balanced manner.3 Whereas for unbiased
screens, broad diversity is desirable, for lead optimization
or targeting certain diseases more confined collections might
be preferable. Independent of the structural diversity the
compounds should have drug-like features or should be nat-
ural product-like. Among the various strategies to generate
compound collections, the decoration of scaffolds, for exam-
ple, by automated parallel synthesis is quite common. In
chemical terms a scaffold is defined as a mono- or polycyclic
structure having several functional groups available for dec-
oration reactions.4 The design of scaffolds can be inspired
by natural products5 or by the application of novel reactions.6
As opposed to linear fused or bridged systems, spirocyclic
core systems are less common in known drugs and natural
products.7 Some examples of spirocyclic natural products
containing a ring nitrogen include cephalotaxine, halichlo-
rine, histrionicotoxin, and manzamine.8 In the area of non-
natural compounds spirocyclic nitrogen-containing systems
were fashioned into compounds displaying interesting bio-
logical activities.9 Such spiro scaffolds can be classified
Some specific examples are illustrated in Figure 2. Fre-
quently one starts with a ring to which the second ring is
attached. Eqs. 1,10 2,11 and 312 show the formation of a car-
bocyclic ring by Dieckmann condensation, ring-closing
aza derivatives
parent structure
H
N
N
H
n
n
n
A1
A2
A
H
H
N
N
N
H
n
n
n
n
B
B1
B2
B3
Keywords: Imines; Acrylate; Ring-closing metathesis; Nitrogen-containing
heterocycles; Spiro compounds; Scaffolds.
n = 1, 2
* Corresponding author. Tel.: +49 7071 2975247; fax: +49 7071 2975137;
e-mail: martin.e.maier@uni-tuebingen.de
Figure 1. Spirocyclic systems containing at least one ring with a nitrogen
atom.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.083

E. Prusov, M. E. Maier / Tetrahedron 63 (2007) 10486–10496
10487
O
O
O
O
Grubbs 1st,
N
N
Ti(OiPr)4
NaH, benzene
H
H
N
N
(7)
Bn
Bn
(1)
(2)
(3)
CH2Cl2, reflux
MeO2C
Ar
CO2Me
MeO2C
A1
O
Ar
O
G-II
N
H
N
NH2
H
Grubbs 2nd
N
1,2-DCE
reflux
N
(8)
pTsOH
(90%)
O
B
O
O
O
N
N
Bn
N
Bn
A2
TBSO
TBSO
Bn
O
O
Cbz
Cbz
Cu(II) cat.
Figure 3. Spirocyclic nitrogen-containing scaffolds via ring-closing
metathesis.
N
N
B2
Bn
N
if the new double bond would carry some functional group.
In this paper, we show that homoallylamines can be reacted
with 2-bromomethylacrylate and that a subsequent ring-clos-
ing metathesis yields highly functionalized spirocycles.21
Initialstudieswere carried outoncyclohexanone(Scheme1).
Thus, cyclohexanone was converted to the corresponding
benzylimine 1. The imine 1 was reacted with allylmagne-
sium bromide to give the homoallylamine 2 in 65% yield.
Stirring of the secondary amine 2 with 2-bromomethylacryl-
ate22 (3) in the presence of potassium carbonate resulted in an
allylic substitution. As has been described before, the amine
had to be protonated in order for the ring-closing metathesis
reaction to succeed. As it turned out the ring-closing meta-
thesis reaction proceeds nicely in the presence of p-TsOH
(1.1 equiv) and the second generation Grubbs catalyst 6
in toluene at 50 ꢀC. These conditions furnished the
tetrahydropyridine derivative 5 in 80% yield. The acrylate
proton appears at d¼6.95 ppm in the 1H NMR spectrum.
LiN(SiMe3)2, THF
BnN(CH2CH2Cl)2
(4)
(5)
B3
O
CO2Et
CO2Et
6 steps
N
O
R
B3
O
O
O
O
O
CO2Me
CHO
PMB
1. PMBNH2, AcOH
2. NaBH3CN
N
(6)
(7)
N
N
Bs
Bs
A2/B2
Ar
O
HO2C
N
HO2C
O
H
N
Bn
2 steps
O
N
A2/B3
Bn
MgBr
N
N
BnNH2
Bn
Bn
Et2O, 0 to 23 °C
(65%)
Figure 2. Examples for the synthesis of spirocyclic nitrogen-containing
systems.
1
2
CO2Me
metathesis, and Diels–Alder reaction, respectively. Eqs. 413
and 514 demonstrate the formation of the heterocyclic ring.
Finally, the formation of diazaspiro compounds is covered
in Eqs. 615 and 7.16
CO2Me
3
Br
Grubbs 2nd (5 mol%)
N
pTsOH (1.1 equiv)
toluene, 50 °C
(80%)
K2CO3, MeCN
23 °C (76%)
Bn
4
CO2Me
N
Inrecent years, thechemistryof spirocyclicsystemshasflour-
ished due to the advent of multi-component reactions in com-
bination with ring-closing metathesis.17,18 Some illustrative
examples are shown in Figure 3. One interesting case includes
the ring-closing metathesis of acryl amides derived from
homoallylamines featuring a quaternary center.19 With these
substrates the cyclization required the presence of Ti(OiPr)4
in order to tame Lewis basic centers. In other work it was
shown that cyclic amino ketones can be combined with allyl-
amine and an allyl boronic ester. The resulting diallylamines
served as precursors for spirocyclic tetrahydropyridines.20
N
N
Mes
Mes
Ph
Cl
Bn
Ru
Cl
PCy3
5
6
Scheme 1. Preparation of the acrylate derivative 4 and its ring-closing
metathesis to the spirocycle 5.
The same sequence of reactions was also performed with the
carbonate protected piperidone 7 (Scheme 2). Accordingly,
imine formation with benzylamine in the presence of
Ti(OiPr)4 followed by Grignard addition to the resulting
imine 8 furnished the homoallylamine 9. Allylation with
the allyl bromide 3 furnished the diene 10. Again, the ring-
closing metathesis in the presence of p-TsOH and the Grubbs
catalyst 6 provided the spirocyclic amine 11 in high yield.
2. Results
We surmised that the versatility of nitrogen-containing spi-
rocyclic ring-closing metathesis would be greatly enhanced

10488
E. Prusov, M. E. Maier / Tetrahedron 63 (2007) 10486–10496
Bn
These substrates underwent a smooth ring-closing metathe-
O
N
sis reaction in the presence of the Grubbs 2nd generation
catalyst 6 (Scheme 4). This way the highly functionalized
spiro compounds 18a,b and 19a,b were obtained in yields
ranging from 85 to 94%.
MgBr
BnNH2
Ti(OiPr)4
Et2O, 0 to 23 °C
(60%)
N
CO2Et
N
CO2Et
7
8
CO2Me
CO2Me
CO2Me
4
CO2Me
3
Br
2
N
N
N
Bn
Bn
N
N
K2CO3, MeCN
23 °C (78%)
PG
Grubbs 2nd (0.5 mol%)
CH2Cl2, reflux, 2-4 h
PG
7
N
8
X
X
CO2Et
CO2Et
9
10
16, 17
18, 19
CO2Me
X
PG
yield (%)
2
4
Grubbs 2 (5 mol%)
16a
18a
CH2
CO2Bn
CO2Me
CO2Bn
90
94
85
N
pTsOH (1.1 equiv)
toluene, 50 °C
(88%)
Bn
16b
17a
18b CH2
7
8
19a NCO2Et
N
17b
19b NCO2Bn
CO2Me
90
CO2Et
11
Scheme 4. Formation of the spirocyclic tetrahydropiperidine derivatives
18a,b and 19a,b.
Scheme 2. Conversion of the piperidone 7 to acrylate derivative 10 followed
by ring-closing metathesis to the spirocyclic diamine derivative 11.
Utilizing a classical sequence, the acrylate function in the
metathesis products was converted via ester hydrolysis, Cur-
tius rearrangement, and hydrolysis of the intermediate vinyl
isocyanate to the oxopiperidine derivates 20, 21, 22a,b, and
23a,b (Scheme 5). Here, the intermediates were not isolated
and the overall yields for the four-step sequence were be-
tween 60 and 70%. Typically, such 3-piperidinones are fash-
ioned by oxidation of the corresponding alcohols.24
The use of the benzylimines in the above sequence somehow
suffered from the moderate yield in the Grignard addition
step. Furthermore, due to the basic nature of the compounds
chromatographic purification was somewhat difficult.
Therefore, it seemed more appropriate to directly prepare ni-
trogen-protected homoallylamines from the corresponding
ketones, a carbamate component, and allylsilane. Thus, us-
ing the method of Veenstra and Schmid23 protected homo-
allylamines 14a,b and 15a,b were prepared (Scheme 3).
The subsequent allylation of the nitrogen atom with 2-bro-
momethylacrylate 3 required the use of sodium hydride in
a THF/DMF mixture. The yields of the alkylation products
16a,b and 17a,b were about 80%.
CO2Me
O
1. LiOH, THF/MeOH/H2O
23 °C, 4 h
N
N
PG
PG
2. Et3N, (PhO)2P(O)N3
toluene, 4 h
X
X
5, 11, 18, 19
3. toluene, reflux, 1 h
4. H3O+, dioxane, 2 h
20, 21, 22, 23
H
N
X
PG
yield (%)
70
O
PG
5
20
CH2
NCO2Et
Bn
PG-NH2, Et2O·BF3
SiMe
65
11
21
3 , CH2Cl2
Bn
X
X
66
18a
18b
19a
22a
22b
23a
0 to 23 °C
CH2
CO2Bn
CO2Me
CO2Bn
CO2Me
12 X = NCO2Et
13 X = NCO2Bn
60
CH2
14, 15
65
NCO2Et
NCO2Bn
63
19b
23b
CO2Me
N
CO2Me
3
Br
Scheme 5. Conversion of the acrylate to a keto function.
PG
NaH, THF/DMF
0 to 23 °C
The Veenstra method worked less efficient with 1-toluene-
sulfonyl-3-piperidinone25 (24). With this substrate, the yield
for the protected homoallylamine 25 was rather low
(Scheme 6). Most likely, enolization of the aminoketone
interferes with the imine formation. Nevertheless, the carb-
amate 25 could be obtained and converted to the acrylate de-
rivative 26. The subsequent ring-closing metathesis with the
Grubbs 2 catalyst 6 in refluxing dichloromethane provided
the desired spirocyclic acrylate 27 in 65% yield. As de-
scribed in Scheme 6 degradation of the acrylate functionality
via Curtius rearrangement led to the ketone 28 featuring two
differently protected amino functions.
16, 17
X
yields [%]
step 1 step 2
X
PG
14a
14b
15a
15b
16a
CH2
CO2Bn
CO2Me
CO2Bn
CO2Me
88
90
85
78
80
80
80
65
16b CH2
17a
NCO2Et
17b NCO2Bn
Scheme 3. Synthesis of the metathesis substrates 16a,b and 17a,b via addi-
tion of allylsilane to intermediate acylimines.

E. Prusov, M. E. Maier / Tetrahedron 63 (2007) 10486–10496
10489
The keto function obtained from degradation of the a,b-un-
saturated ester presents itself for addition reactions with
organometallic nucleophiles. To investigate this pathway,
ketone 22a was treated with phenylmagnesium bromide in
THF at ꢁ40 ꢀC. After warming to room temperature and
aqueous workup, the tertiary alcohol 33 was obtained
(Scheme 8). We note that this compound contains a b-phen-
ylethylamine substructure, although in protected form. Hy-
drogenolytic removal of the Cbz protecting group provided
the secondary amine 34.
H
N
O
Cbz
PG-NH2, Et2O·BF3
SiMe
3 , CH2Cl2
N
N
Ts
Ts
0 to 23 °C (25%)
24
25
CO2Me
CO2Me
3
Br
N
Grubbs 2nd (0.5 mol%)
Cbz
NaH, THF/DMF
0 to 23 °C (65%)
CH2Cl2, reflux, 2-4 h
(65%)
N
Ts
26
O
HO
CO2Me
O
PhMgBr
N
N
BnO2C
BnO2C
THF, -40 to 23 °C
(60%)
4 steps
(50%)
N
N
Cbz
Cbz
N
N
22a
33
Ts
Ts
27
28
HO
Scheme 6. Synthesis of the spirocyclic ketone 28.
H2, Pd/C
EtOH (100%)
N
H
The acrylate function in the spirocycles offers other possibil-
ities for derivatization. For example, reductive removal of
the double bond on compound 18b using magnesium in
methanol26 afforded the saturated ester 29 in quantitative
yield (Scheme 7). Saponification gave the carboxylic acid
30. With this acid, amide formation was illustrated. Thus, ac-
tivation of the acid with carbonyl diimidazole and treatment
with benzylamine and piperazine, respectively, gave amides
31 and 32.
34
Scheme 8. Addition reactions to the ketone 22a.
3. Conclusion
In summary, we described the facile formation of spirocyclic
amine derivatives via alkene ring-closing metathesis. Unlike
with many other RCM substrates one of the double bonds
is part of a 2-methylacrylate subunit. In this way the ring-
closing reaction yields tetrahydro-3-pyridinecarboxylates,
connected to another ring via a common atom. The sub-
strates for the ring-closing metathesis are easily available
from cyclic ketones via imine formation followed by nucleo-
philic allylation. Alkylation of the nitrogen atom with the
2-bromomethylacrylate 3 gave the substrates for the ring-
closing metathesis reaction. Degradation of the a,b-unsatu-
rated ester via Curtius rearrangement and hydrolysis led to
keto derivatives. In order to illustrate the potential of the
RCM products as scaffolds, functionalization reactions
were performed on the ester 18b and the ketone 22a.
CO2Me
CO2Me
Mg, MeOH
N
N
MeO2C
MeO2C
23 °C, 7 h
(100%)
18b
29
CO2H
1. CDI, DMF
60 °C
LiOH
N
THF/MeOH/H2O
3 h (100%)
2. BnNH2
(78%)
MeO2C
30
H
O
N
N
Ph
4. Experimental
4.1. General
MeO2C
1H and 13C NMR: Bruker Avance 400, spectra were recorded
at 295 K in CDCl3. Chemical shifts are calibrated to the
residual proton and carbon resonance of the solvent: CDCl3
31
H
N
€
(dH 7.25, dC 77.0 ppm). Melting points: Buchi Melting Point
O
N
N
1. CDI, DMF
60 °C
B-540, uncorrected. IR: Jasco FTIR-430. EIMS: Finnigan
Triple-Stage-Quadrupol (TSQ-70). HRMS (FTICR): Bruker
Daltonic APEX 2 with electron spray ionization (ESI). Ana-
lytical LC–MS: HP 1100 Series connected with an ESIMS
detector Agilent G1946C, positive mode with fragmentor
voltage of 40 eV; column: Nucleosil 100-5, C-18 HD,
5 mm, 70ꢂ3 mm Macherey–Nagel; eluent: NaCl solution
(5 mM)/acetonitrile, gradient: 0–10–15–17–20 min with
30
2. piperazine
(80%)
MeO2C
32
Scheme 7. Conjugate reduction of the acrylate double bond of 18b, ester
saponification, and condensation reactions of the acid 30 with some amines.

10490
E. Prusov, M. E. Maier / Tetrahedron 63 (2007) 10486–10496
20–80–80–99–99% acetonitrile, flow: 0.5 mL/min. Flash
chromatography: J. T. Baker silica gel 43–60 mm. Thin-layer
benzylamine (12 mmol), the cyclic ketone (10 mmol), and
˚
4 A molecular sieves in toluene (25 mL) was slowly stirred
chromatography: Macherey–Nagel Polygram Sil G/UV254
.
for 24 h. Thereafter, the molecular sieves were filtered off
and washed with toluene. The combined filtrates were con-
centrated in vacuo. The crude benzylimines were used with-
out further purification.
Solvents were distilled prior to use; petroleum ether with
a boiling range of 40–60 ꢀC was used. Reactions were gener-
ally run under an argon atmosphere. All operations with
Grubbs second generation catalyst must be done in glow-
box or dry-box. N-(Benzyl)-1-prop-2-en-1-ylcyclohexan-
amine (2) was prepared according to the literature.19
4.1.5. General procedure 5 for the addition of allylmag-
nesium to benzylimines (GP5). To a solution of N-benzyl-
imine (10 mmol) in dry Et2O (20 mL, 2 mL/mmol of imine)
was added dropwise a solution of allylmagnesium bromide
(10 mL, 2 M in Et2O, 20 mmol) at 0 ꢀC with vigorous stir-
ring. Stirring was continued for 1 h at 0 ꢀC and 3 h at
room temperature. The reaction was quenched with satu-
rated ammonium chloride solution. The layers were sepa-
rated and the aqueous layer was extracted with Et2O
(2ꢂ10 mL). The combined organic layers were dried over
Na2SO4, filtered, and concentrated in vacuo. The obtained
residue was purified by flash chromatography.
4.1.1. General procedure 1 for the carbamino allylation
of cyclic ketones (GP1). To a cooled (0 ꢀC) solution of the
ketone (10 mmol), the carbaminic acid ester (12 mmol),
and allyltrimethylsilane (14 mmol, 2 mL) in CH2Cl2
(10 mL), freshly distilled BF3$Et2O (1.70 g, 12.0 mmol,
1.52 mL) was slowly added dropwise over 3 min with vigor-
ous stirring. Then, the reaction mixture was stirred for 1 h at
0 ꢀC and 8 h at room temperature. At this point approxi-
mately 80% conversion was usually achieved. The reaction
was quenched with saturated NaHCO3 solution (10 mL) fol-
lowed by separation of the layers. The organic layerwas dried
over Na2SO4, filtered, and evaporated to dryness. The residue
was resubjected for the same reaction, but this time with
a 30% load of carbamate, allylsilane, and BF3$Et2O (namely
3.6 mmol of ester, 4.2 mmol of silane, and 3.6 mmol of
BF3$Et2O), to produce almost complete conversion. Crude
material used further without purification.
4.1.6. General procedure 6 for the alkylation of N-benzyl-
amines (GP6). To a solution of the amine 2 or 9 (6 mmol)
in acetonitrile (20 mL, 3 mL/mmol) was added finely
powdered potassium carbonate (1.78 g, 12.0 mmol, 2 equiv)
and then bromomethylmethacrylate (7.2 mmol, 1.2 g,
0.7 mL, 1.2 equiv) in acetonitrile (2 mL). This mixture
was stirred overnight, filtered, and the filter cake washed
with acetonitrile. The combined filtrates were evaporated
and the residue purified by flash chromatography.
4.1.2. General procedure 2 for the alkylation of the car-
bamates with bromomethylmethacrylate (GP2). A sus-
pension of NaH (60% in mineral oil, 800 mg, 20 mmol,
2 equiv) was washed twice with abs THF, and then
re-suspended in a mixture of THF/DMF (2 mL/3 mL,
respectively). To this suspension at 0 ꢀC was added the
corresponding carbamate (10 mmol) in THF (2 mL) with
vigorous stirring over 5 min. Then, the reaction mixture
was stirred at 0 ꢀC for 30 min, before bromomethylmeth-
acrylate (3.6 g, 2.0 mL, 2 equiv) was added over 5 min. The
reaction mixture was stirred for 1 h at 0 ꢀC, and then allowed
to stir overnight with concomitant warming to room temper-
ature. Thereafter, the mixture was poured into a stirred mix-
ture of saturated NH4Cl solution/Et2O (20 mL/20 mL). After
separation of the layers, the water phase was extracted with
Et2O (10 mL). The combined organic layers were washed
with saturated NaCl solution (20 mL), dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was purified
by flash chromatography (toluene/Et2O mixtures).
4.1.7. General procedure 7 for the RCM of the N-benzyl
protected dienes (GP7). To a degassed solution of the diene
in toluene (10 mL/mmol) was added TsOH monohydrate
(1.1 equiv) followed by heating of the mixture to 50 ꢀC for
30 min. Then, the second generation Grubbs catalyst
(5 mol %) was added and the mixture stirred for 4 h at
55 ꢀC. Then, saturated Na2CO3 solution (2 mL/mmol) was
added and the resulting mixture filtered through a pad of Cel-
ite. The layers of the filtratewere separated. Theorganic phase
was dried over Na2SO4, filtered, and evaporated. The crude
product was purified by flash chromatography (toluene/Et2O).
4.1.8. General procedure 8 for the degradation of the un-
saturated esters to ketones (GP8). To a solution of the
unsaturated ester in a mixture of THF/MeOH/H2O (3:2:1,
v/v/v, 6 mL/mmol) was added LiOH (5 equiv) and the mix-
ture stirred at room temperature for 3 h. Then, saturated
NH4Cl solution (1 mL/mmol) was added, and most of the or-
ganic solvents removed in vacuo. The partly solid residue
was extracted with CH2Cl2 (3ꢂ10 mL/mmol), dried with
Na2SO4, filtered, and concentrated in vacuo. The obtained
residue was dissolved in toluene (5 mL/mmol), followed
by the addition of triethylamine (3 equiv) and diphenylphos-
phorylazide (1.2 equiv). After stirring the mixture for 5 h at
room temperature, it was filtered through a pad of SiO2 (flash
silica gel, 2 cm). The silica gel was additionally washed with
toluene (10 mL). The filtrate was then refluxed for 1 h. The
solution containing the rearranged isocyanate was evapo-
rated and the residue taken up in dioxane (5 mL/mmol).
To this solution 1 N HCl was added (1 mL/mmol) and the
mixture stirred for 2 h at room temperature. Thereafter, the
mixture was concentrated in vacuo and the obtained residue
purified by flash chromatography.
4.1.3. General procedure 3 for the ring-closing metathe-
sis (RCM) of N-carbamate protected amines (GP3). A so-
lution of diene in abs CH2Cl2 (3 mL/mmol) was degassed by
bubbling N2 or Ar through it, and then transferred into a two
neck flask (25 mL), equipped with reflux condenser and at-
tached to a vacuum inert gas line. The flask was carefully
purged with inert gas three times, then second generation
Grubbs catalyst (0.5 mol %, 4.4 mg/mmol) was added, and
the reaction mixture was refluxed for 4 h. The reaction prog-
ress can be monitored by TLC. After completion of the reac-
tion, the solvent was evaporated and the residue subjected to
flash chromatography (toluene/Et2O).
4.1.4. General procedure 4 for the preparation of imines
from cyclic ketones and benzylamine (GP4). A mixture of

E. Prusov, M. E. Maier / Tetrahedron 63 (2007) 10486–10496
10491
4.2. Methyl 2-{[(benzyl)(1-prop-2-en-1-ylcyclohexyl)-
amino]methyl}prop-2-enoate (4)
5.11 (m, 2H, H2C]CHCH2), 5.73 (ddt, J¼17.0, 10.0,
7.6 Hz, 1H, H2C]CHCH2), 7.12–7.32 (m, 5H, CHar); 13C
NMR (100 MHz, CDCl3): d¼14.6 (CH3CH2O), 34.6 (C-
3,5), 39.4 (C-2,6), 42.2 (H2C]CHCH2), 45.3 (PhCH2),
52.5 (C-4), 61.0 (CH3CH2O), 118.5 (H2C]CHCH2),
126.8 (CHar, para), 128.1 (CHar, ortho), 128.3 (CHar,
meta), 133.0 (H2C]CHCH2), 140.9 (Car), 155.6 (CO2Et).
Prepared according to GP6, yield 3.0 g (76%); Rf (Et2O/tol-
uene, 1:3): 0.67; 1H NMR (400 MHz, CDCl3): d¼1.11–1.75
(m, 10H, CH2), 2.31 (d, J¼7.3 Hz, 2H, H2C]CHCH2), 3.42
(s, 2H, NCH2), 3.51 (s, 3H, CO2CH3), 3.70 (s, 2H, PhCH2),
4.89–5.02 (m, 2H, H2C]), 5.67 (s, 1H (H2C]C(CO2Me),
E)), 5.84 (s, 1H (H2C]C(CO2Me), Z)), 5.95 (ddt, J¼17.0,
10.0, 7.6 Hz, 1H, H2C]CHCH2), 7.12 (t, J¼7.3 Hz, 2H,
CHar, para), 7. 21 (t, J¼7.3 Hz, 2H, CHar, meta), 7.28 (d,
J¼7.3 Hz, 2H, CHar, ortho); 13C NMR (100 MHz, CDCl3):
d¼22.6 (CH2), 26.4 (CH2), 33.4 (CH2), 38.3 (H2C]C(CO2-
Me)CH2), 49.8 (H2C]CHCH2), 51.8 (CO2CH3), 54.0
(PhCH2), 60.4 (Cquat), 117.2 (H2C]CH), 126.7 (H2C]
C(CO2Me)), 126.8 (CHar, ortho, para), 128.9 (CHar, ortho),
129.2 (CHar, meta), 136.1 (H2C]CHCH2), 139.3 (H2C]
C(CO2Me)), 142.2 (Car), 167.8 (CO2Me); HRMS (EI): calcd
for C21H30NO2 [M+H]+ 328.22711, found 328.22710.
4.5. Ethyl 4-[{2-[(methyloxy)carbonyl]prop-2-en-1-yl}-
(benzyl)amino]-4-prop-2-en-1-ylpiperidine-1-carboxy-
late (10)
Prepared according to GP6, yield 1.1 g (78%); Rf (Et2O/tol-
1
uene, 1:3): 0.56; H NMR (400 MHz, CDCl3): d¼1.14 (t,
J¼7.2 Hz, 3H, CH3CH2O), 1.44–1.74 (m, 4H, CquatCH2),
2.32 (d, J¼7.3 Hz, 2H, H2C]CHCH2), 3.14–3.25 (m, 2H,
NCH2), 3.41–3.45 (m, 2H, H2C]C(CO2Me)CH2), 3.48–
3.58 (m, 2H, NCH2), 3.56 (s, 3H, CO2CH3), 3.70 (s, 2H,
PhCH2), 4.01 (q, J¼7.2 Hz, 2H, CH3CH2O), 4.97–5.06
(m, 2H, H2C]CHCH2), 5.56–5.58 (m, 1H (H2C]
C(CO2Me), E)), 5.80–5.93 (m, 2H, H2C]CHCH2
(H2C]C(CO2Me), Z)), 7.02–7.14 (m, 5H, CHar); 13C
NMR (100 MHz, CDCl3): d¼14.6 (CH3CH2O), 32.5
(CquatCH2), 37.7 (H2C]C(CO2Me)CH2), 39.8 (NCH2),
50.0 (H2C]CHCH2), 51.5 (CO2CH3), 53.5 (PhCH2), 58.6
(Cquat), 61.0 (CH3CH2O), 119.2 (H2C]CHCH2), 126.5
(CHar, para), 126.7 (H2C]C(CO2Me)), 127.9 (CHar, ortho),
128.4 (CHar, meta), 134.5 (H2C]CHCH2), 139.3
(H2C]C(CO2Me)), 141.0 (Car),155.4 (NCO2Et), 167.2
(H2C]C(CO2Me)); HRMS (EI): calcd for C23H33N2O4
[M+H]+ 401.24348, found 401.24341.
4.3. Methyl 1-(benzyl)-1-azaspiro[5.5]undec-3-ene-
3-carboxylate (5)
Prepared according to GP7, yield 160 mg (80%); white crys-
tals, mp 117–119 ꢀC; Rf (Et2O/toluene, 1:3): 0.53; 1H NMR
(400 MHz, CDCl3): d¼1.19–1.37 (m, 5H, CH2), 1.45–1.56
(m, 1H, CH), 1.63–1.77 (m, 4H, CH2), 1.98–2.05 (m, 2H,
5-H), 3.21 (s, 2H, 2-H), 3.49 (s, 2H, PhCH2), 3.56 (s, 3H,
CO2CH3), 6.93–6.98 (m, 1H, CH]C(CO2Me)), 7.12 (t,
J¼7.3 Hz, 2H, CHar, para), 7. 21 (t, J¼7.3 Hz, 2H, CHar,
meta), 7.28 (d, J¼7.3 Hz, 2H, CHar, ortho); 13C NMR
(100 MHz, CDCl3): d¼21.3 (C-8), 26.5 (C-9), 32.6 (C-5),
34.6 (C-7), 44.0 (C-2), 50.3 (PhCH2), 51.3 (CO2CH3),
53.1 (Cquat), 126.4 (CHar, para), 127.4 (HC]C(CO2Me)),
128.1 (CHar, ortho, meta), 137.7 (CH]C(CO2Me)), 140.9
(Car), 166.9 (CO2Me); HRMS (EI): calcd for C19H26NO2
[M+H]+ 300.19581, found 300.19563.
4.6. 9-Ethyl 3-methyl-1-(benzyl)-1,9-diazaspiro[5.5]-
undec-3-ene-3,9-dicarboxylate (11)
Prepared according to GP7, yield 240 mg (88%); Rf (Et2O/
1
toluene, 1:1): 0.61; H NMR (400 MHz, CDCl3): d¼1.19
(t, J¼7.1 Hz, 3H, CH3CH2O), 1.31–1.43 (m, 2H, 7,11-H),
1.78–1.91 (m, 2H, 7,11-H), 2.04–2.11 (m, 2H, 5-H), 3.25
(s, 2H, 2-H), 3.37–3.47 (m, 2H, 8,10-H), 3.51 (s, 2H,
PhCH2), 3.54–3.70 (m, 2H, 8,10-H), 3.61 (s, 3H,
CO2CH3), 4.07 (q, J¼7.1 Hz, 2H, CH3CH2O), 6.97–7.02
(m, 1H, CH¼C(CO2Me)), 7.13–7.30 (m, 5H, CHar); 13C
NMR (100 MHz, CDCl3): d¼14.7 (CH3CH2O), 31.9 (C-
5), 33.9 (C-7,11), 39.1 (C-8,10), 44.2 (C-2), 50.4 (PhCH2),
51.5 (CO2CH3), 51.9 (C-6), 61.2 (CH3CH2O), 126.8
(CHar, para), 127.4 (C-3), 128.0 (CHar, meta), 128.4
(CHar, ortho), 137.0 (C-4), 140.0 (Car), 155.7 (NCO2Et),
166.7 (CO2Me); HRMS (EI): calcd for C21H29N2O4
[M+H]+ 373.21218, found 373.21192.
4.4. Ethyl 4-[(benzyl)amino]-4-prop-2-en-1-ylpiper-
idine-1-carboxylate (9)
To a mixture of N-carbethoxy-4-piperidone (7) (1.14 g,
6.7 mmol) and benzylamine (0.8 g, 0.8 mL, 7.3 mmol,
1.1 equiv) was added titanium tetraisopropoxide (4 mL,
13.4 mmol, 2 equiv) with vigorous stirring. After 4 h at
room temperature, vacuum was applied to the flask and
kept for 15 min at 1 mbar. The resulting viscous oil was dis-
solved with Et2O (35 mL). Then, allylmagnesium bromide
(7 mL, 1 M in Et2O) was added dropwise over 15–30 min
followed by stirring the mixture overnight at room tempera-
ture. The mixture was diluted with additional Et2O (30 mL),
poured into saturated aqueous NH4Cl solution (30 mL), and
stirred for 30 min. Then, the two-phase mixture was filtered
through a pad of Celite. After separation of the layers, the
aqueous layer was extracted with Et2O (2ꢂ30 mL). The
combined organic layers were washed with saturated NaCl
solution, dried over Na2SO4, filtered, and evaporated. The
residue was purified by flash chromatography, yield 1.2 g
4.7. Benzyl (1-prop-2-en-1-ylcyclohexyl)carbamate
(14a)
Prepared according to GP1, yield 2.4 g (88%), slightly green
oil; Rf (Et2O/toluene, 1:1): 0.78; 1H NMR (400 MHz,
CDCl3): d¼1.10–1.55 (m, 8H, 4CH2), 1.70–2.00 (m, 2H,
CH2), 2.40 (d, J¼7.3 Hz, 2H, H2C]CHCH2), 4.46 (s, 1H,
NH), 4.89–5.02 (m, 4H, PhCH2, H2C]), 5.68 (ddt,
J¼17.0, 10.0, 7.6 Hz, 1H, H2C]CHCH2), 7.20–7.32 (m,
5H, CHar); 13C NMR (100 MHz, CDCl3): d¼22.0 (CH),
26.0 (CH2), 34.7 (CH2), 42.9 (H2C]CHCH2), 55.1 (Cquat),
66.4 (PhCH2), 118.5 (H2C]CH), 128.4 (CHar, ortho, para),
1
(60%); Rf (Et2O/toluene, 1:3): 0.64; H NMR (400 MHz,
CDCl3): d¼1.17 (t, J¼7.1 Hz, 3H, CH3CH2O), 1.32–1.58
(m, 4H, 3,5-H), 2.19 (d, J¼7.3 Hz, 2H, H2C]CHCH2),
3.21–3.34 (m, 2H, 2,6-H), 3.53–3.80 (m, 2H, 2,6-H), 3.57
(s, 2H, PhCH2), 4.04 (q, J¼7.2 Hz, 2H, CH3CH2O), 5.02–

10492
E. Prusov, M. E. Maier / Tetrahedron 63 (2007) 10486–10496
128.9 (CHar, meta), 134.1 (H2C]CHCH2), 137.3 (Car),
154.9 (C]O); HRMS (EI): calcd for C20H42O2Si2Na
[M+Na]+ 393.26155, found 393.26159.
(CquatCH2), 36.7 (H2C]C(CO2Me)CH2), 45.2 (H2C]
CHCH2), 51.9 (CO2CH3), 62.1 (Cquat), 66.6 (PhCH2),
118.1 (H2C]CH), 124.5 (H2C]C(CO2Me)CH2), 127.7
(CHar, ortho, para), 128.3 (CHar, meta), 134.0 (H2C]
CHCH2), 136.9 (Car), 138.6 (H2C]C(CO2Me)CH2), 155.9
(CO2Bn), 166.6 (CO2Me); HRMS (EI): calcd for
C22H29NO4Na [M+Na]+ 394.19888, found 394.19881.
4.8. Methyl (1-prop-2-en-1-ylcyclohexyl)carbamate
(14b)
Prepared according to GP1, yield 1.77 g (90%), slightly
green oil; Rf (Et2O/toluene, 1:1): 0.75; 1H NMR
(400 MHz, CDCl3): d¼1.15–1.60 (m, 8H, 4CH2), 1.80–
2.00 (m, 2H, CH2), 2.43 (d, J¼7.1 Hz, 2H, H2C]CHCH2),
3.59 (s, 3H, OCH3), 4.45 (s, 1H, NH), 4.97–5.08 (m,
2H, H2C]), 5.73 (ddt, J¼17.0, 10.0, 7.6 Hz, 1H,
H2C]CHCH2); 13C NMR (100 MHz, CDCl3): d¼21.5
(CH2), 25.6 (CH2), 34.7 (CH2), 42.5 (H2C]CHCH2), 51.4
(OCH3), 54.5 (Cquat), 66.4 (PhCH2), 117.9 (H2C]CH),
133.7 (H2C]CHCH2), 155.2 (C]O).
4.12. Methyl 2-{[[(methyloxy)carbonyl](1-prop-2-en-1-
ylcyclohexyl)amino]methyl}prop-2-enoate (16b)
Prepared according to GP2, yield 2.4 g (80%), colorless oil;
Rf (Et2O/toluene, 1:3): 0.71; H NMR (400 MHz, CDCl3):
1
d¼1.05–1.60 (m, 8H, CH2), 2.17–2.28 (m, 2H, CH2), 2.65
(d, J¼7.3 Hz, 2H, H2C]CHCH2), 3.55 (s, 3H, NCO2CH3),
3.70 (s, 3H, CO2CH3), 4.06 (s, 2H, H2C]C(CO2Me)CH2),
4.93–5.03 (m, 2H, H2C]CH), 5.60 (s, 1H (H2C]
C(CO2Me), E)), 5.66 (ddt, J¼17.0, 10.0, 7.3 Hz, 1H,
H2C]CHCH2), 6.22 (s, 1H (H2C]C(CO2Me), Z)); 13C
NMR (100 MHz, CDCl3): d¼21.5 (CH2), 22.6 (CH2), 34.1
(CquatCH2), 36.7 (H2C]C(CO2Me)CH2), 42.5 (H2C]
CHCH2), 51.8 (H2C]C(CO2CH3)), 52.0 (NCO2CH3),
61.8 (Cquat), 118.0 (H2C]CH), 124.2 (H2C]C(CO2Me)-
CH2), 134.1 (H2C]CHCH2), 138.6 (H2C]C(CO2Me)-
CH2),156.7(HNCO2CH3), 166.6 (CO2Me);HRMS(EI):calcd
for C16H25NO4Na [M+Na]+ 318.16758, found 318.16757.
4.9. Ethyl 4-({[(benzyl)oxy]carbonyl}amino)-4-prop-
2-en-1-ylpiperidine-1-carboxylate (15a)
Prepared according to GP1, yield 2.15 g (85%), slightly yel-
low oil; Rf (Et2O/toluene, 1:1): 0.64; H NMR (400 MHz,
1
CDCl3): d¼1.23 (t, J¼7.1 Hz, 3H, CH3CH2O), 1.43–1.55
(m, 2H, CH2), 1.90–2.10 (m, 2H, CH2), 2.36–2.56 (m, 2H,
H2C]CHCH2), 2.96–3.19 (m, 2H, CH2N), 3.68–3.97 (m,
2H, CH2N), 4.10 (q, J¼7.1 Hz, 2H, CH3CH2O), 4.64 (s,
1H, NH), 4.97–5.17 (m, 4H, PhCH2, H2C]CH), 5.70
(ddt, J¼17.0, 10.0, 7.6 Hz, 1H, H2C]CHCH2), 7.27–7.37
(m, 5H, CHar); 13C NMR (100 MHz, CDCl3): d¼14.6
(CH3), 34.0 (CH2), 39.4 (CH2N), 42.3 (H2C]CHCH2),
53.2 (Cquat), 61.2 (CH3CH2O), 66.2 (PhCH2), 119.0
(H2C]CH), 128.0 (CHar, ortho), 128.1 (CHar, para),
128.5 (CHar, meta), 132.5 (H2C]CHCH2), 136.4 (Car),
154.6 (CO2Bn), 155.4 (CO2Et).
4.13. Ethyl 4-({2-[(benzyloxy)carbonyl]prop-2-en-1-
yl}{[(benzyl)oxy]carbonyl}amino)-4-prop-2-en-1-yl-
piperidine-1-carboxylate (17a)
Prepared according to GP2, yield 2.5 g (80%), colorless oil;
Rf (Et2O/toluene, 1:1): 0.57; H NMR (400 MHz, CDCl3):
1
d¼1.17 (t, J¼7.1 Hz, 3H, CH3CH2O), 1.62–1.73 (m, 2H,
CquatCH2), 2.21–2.30 (m, 2H, CquatCH2), 2.67 (d,
J¼7.3 Hz, 2H, H2C]CHCH2), 2.92–3.05 (m, 2H, NCH2),
3.69 (s, 3H, CO2CH3), 3.72–3.85 (m, 2H, NCH2), 4.04 (q,
J¼7.1 Hz, CH3CH2O), 4.06–4.09 (m, 2H, H2C]C(CO2-
Me)CH2), 4.91–5.05 (m, 2H, H2C]CHCH2), 5.01 (s, 2H,
PhCH2), 5.54 (s, 1H (H2C]C(CO2Me), E)), 5.63 (ddt,
J¼17.0, 10.0, 7.6 Hz, 1H, H2C]CHCH2), 6.21 (s, 1H
(H2C]C(CO2Me), Z), 7.18–7.30 (m, 5H, CH); 13C NMR
(100 MHz, CDCl3): d¼14.6 (CH3CH2O), 33.5 (CquatCH2),
36.0 (H2C]C(CO2Me)CH2), 40.2 (NCH2), 45.4
(H2C]CHCH2), 51.9 (CO2CH3), 60.3 (Cquat), 61.3
(CH3CH2O), 66.8 (PhCH2), 119.2 (H2C]CHCH2), 124.7
(H2C]C(CO2Me)), 127.8 (CHar, ortho), 127.9 (CHar,
para), 128.4 (CHar, meta), 132.8 (H2C]CHCH2), 136.5
(Car), 138.1 (H2C]C(CO2Me)CH2), 155.3 (CO2Et), 158.8
(CO2Bn), 166.3 (H2C]C(CO2Me)); HRMS (EI): calcd for
C24H32N2O6Na [M+Na]+ 467.21526, found 467.21537.
4.10. Benzyl 4-{[(methyloxy)carbonyl]amino}-4-prop-
2-en-1-ylpiperidine-1-carboxylate (15b)
Prepared according to GP1, yield 2.6 g (78%), slightly yellow
oil;Rf (Et2O/toluene, 1:1):0.52;1HNMR(400 MHz, CDCl3):
d¼1.41–1.55 (m, 2H, CH2), 1.90–2.10 (m, 2H, CH2), 2.37–
2.48 (m, 2H, H2C]CHCH2), 2.96–3.19 (m, 2H, CH2), 3.60
(s, 3H, OCH3), 3.71–3.97 (m, 2H, CH2), 4.50 (s, 1H, NH),
4.97–5.17 (m, 4H, PhCH2, H2C]), 5.68 (ddt, J¼17.0, 10.0,
7.6 Hz, 1H, H2C]CHCH2), 7.22–7.37 (m, 5H, CH); 13C
NMR (100 MHz, CDCl3): d¼34.5 (CH2), 40.0 (CH2N),
42.8 (H2C]CHCH2), 55.1 (Cquat), 53.5 (CH3O), 67.5
(PhCH2), 119.5 (H2C]CH), 128.3 (CHar, ortho), 128.4
(CHar, para), 128.9 (CHar, meta), 133.0 (H2C]CHCH2),
137.2 (Cquat), 155.6 (CO2Bn), 155.8 (CO2Me).
4.11. Methyl 2-{[{[(benzyl)oxy]carbonyl}(1-prop-2-en-
1-ylcyclohexyl)amino]methyl}prop-2-enoate (16a)
4.14. Benzyl 4-([(methyloxy)carbonyl]{2-[(methyloxy)-
carbonyl]prop-2-en-1-yl}amino)-4-prop-2-en-1-ylpiper-
idine-1-carboxylate (17b)
Prepared according to GP2, yield 2.5 g (80%), colorless oil;
Rf (Et2O/toluene, 1:1): 0.88; H NMR (400 MHz, CDCl3)
1
Prepared according to GP2, yield 2.1 g (65%), colorless oil;
Rf (Et2O/toluene, 1:3): 0.52; H NMR (400 MHz, CDCl3):
1
d¼1.04–1.57 (m, 8H, CH2), 2.17–2.29 (m, 2H, CH2), 2.65
(d, J¼7.3 Hz, 2H, H2C]CHCH2), 3.69 (s, 3H, CO2CH3),
4.01 (s, 2H, H2C]C(CO2Me)CH2), 4.87–5.04 (m, 4H,
PhCH2, H2C]), 5.54–5.72 (m, 2H, H2C]CHCH2
(H2C]C(CO2Me), E)), 7.17–7.35 (m, 5H, CHar); 13C
NMR (100 MHz, CDCl3): d¼22.7 (CH2), 25.4 (CH2), 34.1
d¼1.68–1.80 (m, 2H, CquatCH2), 1.26–2.36 (m, 2H,
CquatCH2), 2.73 (d, J¼7.6 Hz, 2H, H2C]CHCH2), 2.99–
3.15 (m, 2H, NCH2), 3.61 (s, 3H, H2C]C(CO2CH3)),
3.75 (NCO2CH3), 3.81–3.95 (m, 2H, NCH2), 4.06–4.10
(m, 2H, H2C]C(CO2Me)CH2), 5.03–5.15 (m, 2H,

E. Prusov, M. E. Maier / Tetrahedron 63 (2007) 10486–10496
10493
H2C]CHCH2), 5.09 (s, 2H, PhCH2), 5.59 (s, 1H
(H2C]C(CO2Me), E)), 5.70 (ddt, J¼17.0, 10.0, 7.6 Hz,
1H, H2C]CHCH2), 6.27 (s, 1H (H2C]C(CO2Me), Z)),
7.27–7.37 (m, 5H, CHar); 13C NMR (100 MHz, CDCl3):
d¼33.5 (CquatCH2), 36.0 (H2C]C(CO2Me)CH2), 40.3
(NCH2), 45.5 (H2C]CHCH2), 51.9 (H2C]C(CO2CH3)),
52.3 (NCO2CH3), 60.0 (Cquat), 67.1 (PhCH2), 119.1
(H2C]CHCH2), 124.5 (H2C]C(CO2Me)CH2), 127.8
(CHar, ortho), 128.0 (CHar, para), 128.4 (CHar, meta),
(NCO2Et), 155.9 (NCO2Bn), 165.4 (CO2Me); HRMS (EI):
calcd for C22H29N2O6 [M+H]+ 417.20201, found 417.20184.
4.18. 1,3-Dimethyl 9-(benzyl)-1,9-diazaspiro[5.5]undec-
3-ene-1,3,9-tricarboxylate (19b)
Prepared according to GP3, yield 1.533 g (90%); Rf (Et2O/
1
toluene, 1:1): 0.50; H NMR (400 MHz, CDCl3): d¼1.38–
1.48 (m, 2H, 7-H, 11-H), 2.25–2.36 (m, 2H, 5-H), 2.45–
2.70 (m, 2H, 7-H, 11-H), 3.05–3.25 (m, 2H, 8-H, 10-H),
3.62 (s, 3H, CO2CH3), 3.74 (NCO2CH3), 3.81–3.95 (m,
2H, 8-H, 10-H), 4.08–4.40 (m, 2H, 2-H), 5.11 (s, 2H,
PhCH2), 6.92–6.99 (m, 1H, 4-H), 7.27–7.40 (m, 5H,
CHar); 13C NMR (100 MHz, CDCl3): d¼34.4 (C-7, C-11),
35.7 (C-5), 40.1 (C-8, C-10), 42.4 (C-2), 51.7 (CO2CH3),
52.4 (NCO2CH3), 54.5 (C-6), 66.9 (PhCH2), 128.9 (C-3),
127.7 (CHar, ortho), 127.9 (CHar, para), 128.4 (CHar,
meta), 136.7 (Car), 137.1 (C-4), 155.2 (NCO2Bn), 156.5
(NCO2Me), 165.4 (CO2Me); HRMS (EI): calcd for
C21H26N2O6Na [M+Na]+ 425.16831, found 425.16836.
132.9
(H2C]CHCH2),
136.6
(Cquat),
138.1
(H2C]C(CO2Me)), 155.1 (CO2Bn), 155.6 (NCO2Me),
166.3 (H2C]C(CO2Me)); HRMS (EI): calcd for
C23H31N2O6 [M+H]+ 431.21766, found 431.21785.
4.15. 3-Methyl 1-(benzyl)-1-azaspiro[5.5]undec-3-ene-
1,3-dicarboxylate (18a)
Prepared according to GP3, yield 460 mg (90%); Rf (Et2O/
1
toluene, 1:3): 0.79; H NMR (400 MHz, CDCl3): d¼1.23–
1.64 (m, 8H, CH2), 2.28–2.33 (m, 2H, CH2), 2.35–2.43
(m, 2H, CH2HC]C(CO2Me)), 3.73 (s, 3H, CO2CH3),
4.30 (s, 2H, CH2N), 5.08 (s, 2H, PhCH2), 6.93–6.98 (m,
1H, CH]C(CO2Me)), 7.27–7.37 (m, 5H, CHar); 13C NMR
(100 MHz, CDCl3): d¼22.2 (CH2), 25.9 (CH2), 35.2
(CquatCH2), 36.3 (CH2HC]C(CO2Me)), 42.4 (CH2N),
51.7 (CO2CH3), 56.7 (Cquat), 66.8 (PhCH2), 127.7 (CHar,
ortho), 127.8 (CHar, para), 128.4 (CHar, meta), 128.9
(HC]C(CO2Me)), 136.8 (Car), 138.0 (CH]C(CO2Me)),
155.8 (NCO2Bn), 165.7 (CO2Me); HRMS (EI): calcd for
C20H25NO4Na [M+Na]+ 366.16758, found 417.16805.
4.19. 1-(Benzyl)-1-azaspiro[5.5]undecan-3-one (20)
Prepared according to GP8, yield 79 mg (70%), red crystals,
mp 65–67 ꢀC; Rf (Et2O/toluene, 1:1): 0.76; 1H NMR
(400 MHz, CDCl3): d¼1.23–1.44 (m, 3H, CH2), 1.46–1.58
(m, 3H, CH2), 1.63–1.78 (m, 4H, CH2), 1.88 (t, J¼6.7 Hz,
2H, 5-H), 2.36 (t, J¼6.7 Hz, 2H, 4-H), 3.02 (s, 2H, 2-H),
3.60 (s, 2H, PhCH2), 7.10–7.30 (m, 5H, CHar); 13C NMR
(100 MHz, CDCl3): d¼22.1 (C-8,10), 26.1 (C-9), 30.8 (C-
5), 32.3 (C-7,11), 35.6 (C-4), 51.5 (PhCH2), 54.6 (C-6),
55.5 (C-2), 126.8 (CHar, para), 128.3 (CHar, ortho, meta),
140.0 (Car), 212.0 (C]O); HRMS (EI): calcd for
C17H24NO [M+H]+ 258.18524, found 258.18503.
4.16. Dimethyl 1-azaspiro[5.5]undec-3-ene-1,3-dicarb-
oxylate (18b)
Prepared according to GP3, yield 514 mg (94%); Rf (Et2O/
1
toluene, 1:3): 0.51; H NMR (400 MHz, CDCl3): d¼1.15–
4.20. Ethyl 3-oxo-1-(benzyl)-1,9-diazaspiro[5.5]unde-
cane-9-carboxylate (21)
1.56 (m, 8H, CH2), 2.20–2.25 (m, 2H, CH2), 2.43 (d,
J¼13.1 Hz, 2H, CquatCH2HC]C(CO2Me)), 3.57 (s, 3H,
CH]C(CO2CH3)), 3.68 (s, 3H, NCO2CH3), 4.17–4.21 (m,
2H, CH2N), 6.87–6.92 (m, 1H, CH]C(CO2Me)); 13C
NMR (100 MHz, CDCl3): d¼22.2 (CH2), 25.9 (CH2), 35.2
(CquatCH2), 36.3 (CH2HC]), 42.3 (CH2N), 51.6
(CH]C(CO2CH3)), 52.2 (NCO2CH3), 56.5 (Cquat), 128.9
(HC]C(CO2Me)), 138.0 (CH]C(CO2Me)), 156.4
(HNCO2CH3), 165.7 (H2C]C(CO2Me)); HRMS (EI): calcd
for C14H21NO4Na [M+Na]+ 290.13628, found 290.13655.
Prepared according to GP8, yield 80 mg (65%), red crystals,
mp 95–97 ꢀC; Rf (Et2O/toluene, 1:1): 0.43; 1H NMR
(400 MHz, CDCl3): d¼1.20 (t, J¼7.1 Hz, 3H, CH3CH2O),
1.47–1.66 (m, 2H, 7,11-H), 1.88–2.05 (m, 4H, 7,11-H, 5-
H), 2.37–2.48 (m, 2H, 4-H), 3.06 (s, 2H, 2-H), 3.24–3.40
(m, 2H, 8,10-H), 3.61 (s, 2H, PhCH2), 3.67–3.82 (m, 2H,
8,10-H), 4.08 (q, J¼7.1 Hz, 2H, CH3CH2O), 7.10–7.30
(m, 5H, CHar); 13C NMR (100 MHz, CDCl3): d¼14.7
(CH3CH2O), 30.5 (C-5), 32.1 (C-7,11), 35.5 (C-4), 39.8
(C-8,10), 51.5 (C-2), 53.4 (C-6), 55.3 (PhCH2), 61.4
(CH3CH2O), 127.1 (CHar, para), 128.2 (CHar, ortho),
128.4 (CHar, meta), 139.0 (Car), 155.6 (NCO2Et), 211.0
(C]O); HRMS (EI): calcd for C19H27N2O3 [M+H]+
331.20162, found 331.20159.
4.17. 9-Ethyl 3-methyl-1-(benzyl)-1,9-diaza-
spiro[5.5]undec-3-ene-1,3,9-tricarboxylate (19a)
Prepared according to GP3, yield 680 mg (85%); Rf (Et2O/
1
toluene, 1:3): 0.36; H NMR (400 MHz, CDCl3): d¼1.23
(t, J¼7.1 Hz, 3H, CH3CH2O), 1.38–1.48 (m, 2H, 7-H, 11-
H), 2.28–2.35 (m, 2H, 5-H), 2.46–2.65 (m, 2H, 7-H, 11-H),
3.05–3.20 (m, 2H, 8-H, 10-H), 3.70–3.90 (m, 2H, 8-H, 10-
H), 3.73 (s, 3H, CO2CH3), 4.10 (q, J¼7.1 Hz, 2H,
CH3CH2O), 4.21–4.39 (m, 2H, 5-H), 5.07 (s, 2H, PhCH2),
6.94–6.99 (m, 1H, CH]C(CO2Me)), 7.27–7.40 (m, 5H,
CHar); 13C NMR (100 MHz, CDCl3) d¼14.7 (CH3CH2O),
34.4 (C-7, C-11), 35.7 (C-5), 40.0 (C-8, C-10), 42.6 (C-2),
51.8 (CO2CH3), 54.8 (C-6), 61.2 (CH3CH2O), 67.1
(PhCH2), 127.8 (CHar, ortho), 128.0 (CHar, para), 128.5
(CHar, meta), 128.6 (C-3), 136.3 (Car), 137.2 (C-4), 155.6
4.21. Benzyl 3-oxo-1-azaspiro[5.5]undecane-1-carboxy-
late (22a)
Prepared according to GP8, yield 240 mg (66%), white crys-
1
tals, mp 85–87 ꢀC; Rf (Et2O/toluene, 1:1): 0.78; H NMR
(400 MHz, CDCl3): d¼1.10–1.67 (m, 8H, CH2), 1.96–2.04
(m, 2H, CH2), 2.31–2.39 (m, 2H, 5-H), 2.61–2.74 (m, 2H,
4-H), 4.08 (s, 2H, 2-H), 5.02 (s, 2H, PhCH2), 7.27–7.37
(m, 5H, CHar); 13C NMR (100 MHz, CDCl3): d¼22.3 (C-
8,10), 24.9 (C-9), 28.6 (C-5), 31.3 (C-7,11), 34.3 (C-4),

10494
E. Prusov, M. E. Maier / Tetrahedron 63 (2007) 10486–10496
52.0 (C-2), 58.8 (C-6), 67.0 (PhCH2), 127.9 (CHar, ortho),
128.0 (CHar, para), 128.5 (CHar, meta), 136.3 (Car), 154.7
(NCO2Bn), 208.3 (C]O); HRMS (EI): calcd for
C18H23NO3Na [M+Na]+ 324.15701, found 324.15695.
(Cquat), 53.8 (CquatCH2N), 66.3 (PhCH2), 119.2 (H2C]
CH), 127.5 (CHar, ortho, Ts), 128.0 (CHar, ortho, Bn),
128.1 (CHar, para, Bn), 128.5 (CHar, meta, Bn), 129.8
(CHar, meta, Ts), 132.2 (H2C]CHCH2), 133.0 (O2SC,
Ts), 136.5 (Car, Bn), 143.7 (CH3Car, Ts), 154.5 (CO2Bn).
4.22. Methyl 3-oxo-1-azaspiro[5.5]undecane-1-carboxy-
late (22b)
4.26. Methyl 2-[([(benzyloxy)carbonyl]{1-[(4-methyl-
phenyl)sulfonyl]-3-prop-2-en-1-ylpiperidin-3-yl}ami-
no)methyl]prop-2-enoate (26)
Prepared according to GP8, yield 184 mg (60%), colorless
oil; Rf (Et2O/toluene, 1:1): 0.47; 1H NMR (400 MHz,
CDCl3): d¼1.19–1.67 (m, 8H, CH2), 1.96–2.03 (m, 2H,
CH2), 2.31–2.39 (m, 2H, 5-H), 2.59–2.69 (m, 2H, 4-H),
3.57 (s, 3H, COOCH3), 4.04 (s, 2H, 2-H); 13C NMR
(100 MHz, CDCl3): d¼23.0 (C-8,10), 24.9 (C-9), 28.5 (C-
5), 31.2 (C-7,11), 34.2 (C-4), 51.9 (C-2), 52.1 (COOCH3),
58.6 (C-6), 155.3 (NCO2Me), 208.3 (C]O); HRMS (EI):
calcd for C12H20NO3 [M+H]+ 226.14377, found 226.14600.
Prepared according to GP2, yield 600 mg (50%), colorless
oil; Rf (Et2O/toluene, 2:1): 0.71; 1H NMR (400 MHz,
CDCl3): d¼1.50–1.87 (m, 4H, CH2), 2.35 (s, 3H, CH3),
2.45–2.58 (m, 2H, CH2), 2.73–2.92 (m, 2H, CH2), 3.27–
3.45 (m, 1H, CH2), 3.70 (d, J¼11.1 Hz, 1H, CH2), 3.67 (s,
3H, CO2CH3), 3.73–3.84 (m, 1H, CH2), 3.99–4.08 (m, 2H,
CH2), 4.16–4.24 (m, 2H, CH2), 4.90–5.13 (m, 4H,
H2C]CHCH2, PhCH2), 5.53 (s, 1H (H2C]C(COOMe),
E)), 5.61 (m, 1H, H2C]CHCH2), 6.17 (s, 1H
(H2C]C(COOMe), Z)), 7.18–7.33 (m, 7H, CHar), 7.48–
7.54 (m, 2H, CHar, ortho, Ts,); 13C NMR (100 MHz,
CDCl3): d¼21.4 (CH2), 21.5 (CH3), 31.3 (CquatCH2), 37.0
(H2C]C(CO2Me)CH2), 45.3 (H2C]CHCH2), 46.0
(CH2NTs), 49.7 (CO2CH3), 52.8 (ZNCH2C(CO2Me)), 60.5
(Cquat), 67.1 (PhCH2), 68.8 (CquatCH2NTs), 119.3
(H2C]CHCH2), 124.9 (H2C]C(CO2Me)), 127.5 (CHar,
ortho, Ts, CHar, para, Bn), 128.0 (CHar, ortho, Bn), 128.4
(CHar, meta, Bn), 129.7 (CHar, meta, Ts), 129.8
(CH2CH]C(CO2Me)), 132.6 (H2C]CHCH2), 133.4
(O2SCar, Ts), 136.4 (Car, Bn), 138.0 (H2C]C(CO2Me)),
143.4 (CH3Car, Ts), 155.9 (CO2Bn), 166.4 (CO2CH3).
4.23. 9-Ethyl 1-(benzyl)-3-oxo-1,9-diazaspiro[5.5]-
undecane-1,9-dicarboxylate (23a)
Prepared according to GP8, yield 340 mg (70%), colorless
oil; Rf (Et2O/toluene, 1:1): 0.24; 1H NMR (400 MHz,
CDCl3): d¼1.13–1.26 (m, 3H, CH3CH2O), 1.40–1.56 (m,
2H, 7,11-H), 2.00–2.11 (m, 2H, 7,11-H), 2.34–2.47 (m,
2H, 5-H), 2.77–3.05 (m, 4H, 4-H, 8,10-H), 3.85–4.20
(m, 6H, 8,10-H, 2-H, CH3CH2O), 5.02 (s, 2H, PhCH2),
7.15–7.40 (m, 5H, CHar); 13C NMR (100 MHz, CDCl3):
d¼14.6 (CH3CH2O), 28.6 (C-5), 31.1 (C-7,11), 34.0 (C-4),
40.5 (C-8,10), 52.0 (C-2), 56.9 (C-6), 61.4 (CH3CH2O),
67.3 (PhCH2), 128.0 (CHar, ortho), 128.2 (CHar, para),
128.5 (CHar, meta), 135.9 (Car), 154.6 (NCO2Bn), 155.3
(NCO2Et), 207.1 (C]O).
4.27. 1-Benzyl 3-methyl 8-[(4-methylphenyl)sulfonyl]-
1,8-diazaspiro[5.5]undec-3-ene-1,3-dicarboxylate (27)
4.24. 1-Methyl 9-(benzyl)-3-oxo-1,9-diazaspiro[5.5]-
undecane-1,9-dicarboxylate (23b)
Prepared according to GP7, yield 370 mg (65%), white crys-
tals, mp 133–135 ꢀC; Rf (Et2O/toluene, 1:1): 0.55; 1H NMR
(400 MHz, CDCl3): d¼1.40–1.80 (m, 3H, CH2), 2.25–2.75
(m, 4H, CH2), 2.35 (s, 3H, ArCH3), 2.96–3.06 (m, 1H,
CH2), 3.12–3.24 (m, 1H, CH2), 3.27–3.45 (m, 1H, CH2),
3.70 (d, J¼11.1 Hz, 1H, CH2), 3.70 (s, 3H, CO2CH3),
4.20–4.43 (m, 2H, 7-H), 5.00 (s, 2H, PhCH2), 6.93–7.02
(m, 1H, 3-H), 7.15–7.35 (m, 7H, CHar), 7.45–7.60 (m, 2H,
CHar, ortho, Ts); 13C NMR (100 MHz, CDCl3): d¼21.5
(CH3), 21.9 (C-10), 31.9 (C-11), 32.8 (C-5), 41.9 (C-2),
46.8 (C-9), 51.9 (CO2CH3), 52.2 (C-7), 56.1 (C-6), 67.0
(PhCH2), 127.5 (CHar, ortho, Ts), 127.7 (CHar, ortho, Bn),
128.0 (CHar, para, Bn), 128.5 (CHar, meta, Bn), 129.7
(CHar, meta, Ts), 129.8 (C-3), 133.4 (O2SCar, Ts), 136.4
(Car, Bn), 137.2 (C-4), 143.5 (CH3Car, Ts), 155.1 (NCO2Bn)
165.2 (CO2CH3); HRMS (EI): calcd for C26H31N2O6S
[M+H]+ 499.18973, found 499.18978.
Prepared according to GP8, yield 800 mg (63%), white crys-
tals, mp 108–111 ꢀC; Rf (Et2O/toluene, 1:1): 0.36; 1H NMR
(400 MHz, CDCl3): d¼1.40–1.56 (m, 2H, 7,11-H), 2.01–
2.07 (m, 2H, 7,11-H), 2.36–2.42 (m, 2H, 5-H), 2.78–2.90
(m, 2H, 4-H), 2.92–3.07 (m, 2H, 8,10-H), 3.59 (CO2CH3),
3.90–4.10 (m, 2H, 8,10-H), 4.06 (s, 2H, 2-H), 5.02–5.12
(m, 2H, PhCH2), 7.21–7.31 (m, 5H, CH); 13C NMR
(100 MHz, CDCl3): d¼28.7 (C-5), 31.1 (C-7,11), 33.9 (C-
4), 40.7 (C-8,10), 51.9 (C-2), 52.5 (CO2CH3), 56.6 (C-6),
67.1 (PhCH2), 127.8 (CHar, ortho), 127.9 (CHar, para),
128.4 (CHar, meta), 136.7 (Car), 155.1 (NCO2Bn), 155.3
(NCO2Me), 207.1 (C]O); HRMS (EI): calcd for
C19H24N2O5Na [M+Na]+ 383.15774, found 383.15760.
4.25. Benzyl {1-[(4-methylphenyl)sulfonyl]-3-prop-2-en-
1-ylpiperidin-3-yl}carbamate (25)
4.28. Methyl 8-[(4-methylphenyl)sulfonyl]-3-oxo-1,8-
diazaspiro[5.5]undecane-1-carboxylate (28)
Prepared according to GP3, yield 1.07 g (25%), colorless oil;
Rf (Et2O/toluene, 2:1): 0.75; H NMR (400 MHz, CDCl3):
1
d¼1.05–1.20 (m, 1H, CH2), 1.55–1.67 (m, 1H, CH2),
1.71–1.86 (m, 1H, CH2), 2.17–2.53 (m, 7H, CH2,
H2C]CHCH2, CH3), 4.93–5.17 (m, 5H, PhCH2, H2C],
NH), 5.64–5.76 (m, 1H, H2C]CHCH2), 7.27–7.39 (m,
7H, CHar), 7.57–7.64 (m, 2H, CHar); 13C NMR (100 MHz,
CDCl3): d¼20.9 (CH2CH2N), 21.5 (CH3), 31.0 (C-4), 39.4
(CH2NCH2), 40.2 (H2C]CHCH2), 46.4 (CH2CH2N), 53.2
Prepared according to GP8, yield 170 mg (50%), white crys-
1
tals, mp 89–91 ꢀC; Rf (Et2O/toluene, 1:1): 0.33; H NMR
(400 MHz, CDCl3): d¼1.50–1.90 (m, 4H, H-10,11), 2.15–
2.26 (m, 1H, CH2), 2.31–2.41 (m, 4H, CH3, CH2), 2.42–
2.66 (m, 3H, CH2), 3.49 (dd, J¼11.5, 16.8 Hz, 2H, 2-H),
3.70 (d, J¼11.1 Hz, 1H, CH2), 3.89 (d, J¼18.4 Hz, 1H,
7-H), 4.24 (d, J¼18.4 Hz, 1H, 7-H), 4.94 (dd, J¼12.3,

E. Prusov, M. E. Maier / Tetrahedron 63 (2007) 10486–10496
10495
19.6 Hz, 2H, PhCH2), 7.14–7.29 (m, 7H, CHar), 7.53 (m, 2H,
CHar, ortho, Ts); 13C NMR (100 MHz, CDCl3): d¼21.5
(CH3), 22.2 (C-10), 27.2 (C-5), 29.5 (C-11), 33.8 (C-4), 45.8
(C-9), 48.5 (C-7), 52.0 (C-2), 57.3 (C-6), 66.4 (PhCH2),
127.2 (CHar, ortho, Ts), 127.9 (CHar, ortho, Bn), 128.2
(CHar, para, Bn), 128.5 (CHar, meta, Bn), 129.7 (CHar, meta,
Ts), 133.7 (O2SCar), 135.6 (Car, Bn), 143.5 (CH3Car, Ts),
154.5 (NCO2Bn), 206.4 (C]O); HRMS (EI): calcd for
C24H28N2O5SNa [M+Na]+ 479.16111, found 479.16142.
stirring the mixture at 50 ꢀC for 2 h. Then, benzylamine
(65 mg, 65 mL, 0.6 mmol, 2 equiv) was added and stirring
continued for 8 h at 60 ꢀC. After cooling, the mixture was
partitioned between 1 N HCl (25 mL) and CH2Cl2
(10 mL). The organic layer was separated, washed with
saturated aqueous NaHCO3 solution, dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was purified
by flash chromatography (toluene/Et2O, 2:1) to give amide
31 (80 mg, 78%) as a colorless oil; Rf (Et2O/toluene, 1:1):
1
0.40; H NMR (400 MHz, CDCl3): d¼1.08–1.87 (m, 13H,
4.29. Dimethyl 1-azaspiro[5.5]undecane-1,3-dicarboxy-
late (29)
CH, CH2), 2.29–2.56 (m, 3H, CH, CH2), 3.42–3.51 (m,
1H, CH2), 3.47 (s, 3H, CH(CO2CH3)), 3.61 (s, 3H,
NCO2CH3), 3.75 (dd, J¼14.3, 4.9 Hz, 1H, H-2), 4.31 (d,
J¼5.1 Hz, 2H, PhCH2N), 6.49 (s, 1H, C(O)NH), 7.13–7.27
(m, 5H, CHar); 13C NMR (100 MHz, CDCl3): d¼21.2 (C-
4), 22.4 (C-9), 22.8, 25.3 (C-8,10), 29.9 (C-5), 31.7, 33.2
(C-7,11), 41.4 (HCCO2Me), 42.1 (PhCH2N), 43.3 (CH2N),
51.8 (NCO2CH3), 58.9 (Cquat), 127.3 (CHar, para), 127.6
(CHar, ortho), 128.5 (CHar, meta), 138.2 (Car), 156.3
(NCO2CH3), 173.9 (C(O)NHBn)); HRMS (EI): calcd for
C20H29N2O3 [M+H]+ 345.21727, found 345.21701.
To a solution of the unsaturated ester 18b (180 mg,
0.67 mmol) in dry MeOH (10 mL), Mg turnings (65 mg,
2.7 mmol, 4 equiv) were added, and the reaction mixture
was vigorously stirred for 7 h. Thereafter, the resulting gel
was partitioned between saturated NH4Cl solution (25 mL)
and Et2O (25 mL). The aqueous phase was extracted with
Et2O (3ꢂ10 mL). The combined organic layers were dried
over Na2SO4, filtered, and evaporated to give 180 mg
(100%) of ester 29 as a colorless oil, pure enough for the
next transformation. 1H NMR (400 MHz, CDCl3): d¼1.23–
1.58 (m, 8H, CH2), 1.64–1.69 (m, 2H, CH2), 1.72–1.89 (m,
2H, CH2), 2.30–2.40 (m, 1H, CHCO2Me), 2.51–2.69 (m,
2H, CH2), 3.35 (dd, J¼14.0, 9.7 Hz, 1H, 2-H), 3.56 (s, 3H,
CH(CO2CH3)), 3.61 (s, 3H, NCO2CH3), 3.93 (dd, J¼14.0,
5.1 Hz, 1H, 2-H); 13C NMR (100 MHz, CDCl3): d¼20.1
(C-4), 22.2 (C-9), 22.7, 25.2 (C-8,10), 30.0 (C-5), 31.9,
33.1 (C-7,11), 39.6 (HC(CO2CH3)), 41.5 (CH2N), 51.5
(HC(CO2CH3)), 51.7 (NCO2CH3), 58.5 (Cquat), 155.8
(NCO2Me), 174.2 (HC(CO2Me)); HRMS (EI): calcd for
C14H23NO4Na [M+Na]+ 292.15193, found 292.15197.
4.32. Methyl 3-(1-piperazinylcarbonyl)-1-aza-
spiro[5.5]undecane-1-carboxylate (32)
To a solution of acid 30 (75 mg, 0.3 mmol) in DMF (5 mL)
was added CDI (64 mg, 0.4 mmol, 1.3 equiv) followed by
stirring the mixture at 65 ꢀC for 2 h. Then, piperazine
(120 mg, 1.5 mmol, 5 equiv) was added and stirring contin-
ued for 5 h at 65 ꢀC. After cooling, the mixture was parti-
tioned between 1 N HCl (25 mL) and CH2Cl2 (10 mL).
The organic layer was separated, washed with saturated
aqueous NaHCO3 solution, dried over Na2SO4, filtered,
and concentrated in vacuo resulting in amide 32 (82 mg,
80%) as a yellow oil; Rf (Et2O/CH2Cl2, 1:1): 0.13; 1H
NMR (400 MHz, CDCl3): d¼1.25–1.93 (m, 12H, CH2),
2.20–2.49 (m, 2H, CH2), 2.61–2.92 (m, 6H, CH2), 3.22–
3.32 (m, 1H, CH), 3.35–3.62 (m, 4H, CH2), 3.57 (s, 3H,
CH(CO2CH3)), 3.86–3.96 (dd, J¼14.0, 3.8 Hz, 1H, H-2);
13C NMR (100 MHz, CDCl3): d¼20.0 (C-4), 22.0 (C-9),
22.9, 25.3 (C-8,10), 30.4 (C-5), 32.8, 33.1 (C-7,11), 36.9
(HC(CO2CH3)), 42.1, 42.4 (CH2N(CO)CH2), 45.6
(CH2N), 46.3 (CH2NHCH2), 51.7 (NCO2CH3), 58.7 (Cquat),
156.0 (NCO2Me), 172.0 (HC(C(O)N)); HRMS (EI): calcd
for C17H30N3O3 [M+H]+ 324.22817, found 324.22812.
4.30. 1-[(Methyloxy)carbonyl]-1-azaspiro[5.5]-
undecane-3-carboxylic acid (30)
A solution of ester 29 (160 mg, 0.6 mmol) in a mixture of
THF (3 mL), MeOH (2 mL), and H2O (1 mL) was treated
with LiOH (200 mg, 5.0 mmol, 8 equiv) and stirred for 3 h
at room temperature. The completion of reaction was con-
firmed by TLC. The reaction mixture was then concentrated
under reduced pressure to remove the bulk of the solvents.
The residue was partitioned between saturated NH4Cl solu-
tion (10 mL) and Et2O (10 mL). The aqueous phase was ex-
tracted with Et2O (2ꢂ5 mL). The combined organic layers
were dried over Na2SO4, filtered, and concentrated in vacuo,
yielding acid 30 (150 mg, 100%), which was pure enough
4.33. Benzyl 3-hydroxy-3-phenyl-1-azaspiro[5.5]-
undecane-1-carboxylate (33)
1
for the next transformation. H NMR (400 MHz, CDCl3):
d¼1.22–1.59 (m, 8H, CH2), 1.63–1.72 (m, 2H, CH2),
1.75–1.90 (m, 2H, CH2), 2.30–2.40 (m, 1H, CH), 2.51–
2.69 (m, 2H, CH2), 3.34–3.46 (m, 1H, H-2), 3.57 (s, 3H,
NCO2CH3), 3.86–4.00 (m, 1H, H-2), 8.10–8.80 (br s, 1H,
COOH); 13C NMR (100 MHz, CDCl3): d¼20.3 (C-4), 22.4
(C-9), 22.9, 25.2 (C-8,10), 30.0 (C-5), 32.1, 33.2 (C-7,11),
39.9 (HC(CO2CH3)), 41.6 (CH2N), 52.0 (NCO2CH3), 58.8
(Cquat), 156.3 (NCO2Me).
To a vigorously stirred solution of ketone 22a (90 mg,
0.3 mmol) in THF (2 mL) was added a solution of PhMgBr
(200 mL, 3 M in Et2O, 0.6 mmol, 2 equiv) at ꢁ40 ꢀC in
a dropwise fashion. The reaction mixture was then allowed
to reach room temperature within 1 h. The reaction was
quenched by the addition of saturated NH4Cl solution
(5 mL) and extracted with Et2O (2ꢂ10 mL). The combined
organic layers were dried over Na2SO4, filtered, and concen-
trated in vacuo. The residue was purified by flash chromato-
graphy (toluene/Et2O, 2:1) to give alcohol 34 (70 mg, 60%)
as white crystals, mp 125–127 ꢀC; Rf (Et2O/toluene, 1:3):
4.31. Methyl 3-{[(benzyl)amino]carbonyl}-1-azaspiro-
[5.5]undecane-1-carboxylate (31)
1
0.58; H NMR (400 MHz, CDCl3): d¼1.26–1.62 (m, 10H,
To a solution of acid 30 (75 mg, 0.3 mmol) in DMF (5 mL)
was added CDI (64 mg, 0.4 mmol, 1.3 equiv) followed by
5CH2), 1.68–1.77 (m, 1H, CH2), 1.95–2.14 (m, 2H, CH2),
2.31–2.41 (m, 1H, CH2), 2.69–2.79 (m, 1H, CH2), 3.51 (d,

10496
E. Prusov, M. E. Maier / Tetrahedron 63 (2007) 10486–10496
7. Spiroacetals can be considered an exception. See: (a) Barun,
O.; Kumar, K.; Sommer, S.; Langerak, A.; Mayer, T. U.;
J¼14.5 Hz, 1H, 2-H), 3.87 (d, J¼14.5 Hz, 1H, 2-H), 5.02 (s,
2H, PhCH2), 7.13–7.28 (m, 8H, CHar), 7.39 (d, J¼7.3 Hz,
2H, CHar); 13C NMR (100 MHz, CDCl3): d¼22.3, 22.9
(C-8,10), 25.6 (C-9), 29.9 (C-5), 32.1, 33,6 (C-7,11), 34.2
(C-4), 52.2 (C-2), 58.9 (C-6), 66.8 (PhCH2), 72.9 (C-3),
124.5 (CHar, ortho), 127.1 (CHar, para), 127.8 (CHar,
meta, para), 128.3 (CHar, ortho), 128.4 (CHar, meta),
136.7 (Car), 146.3 (Car), 156.6 (NCO2Bn); HRMS (EI):
calcd for C24H30NO3 [M+H]+ 380.22202, found 380.22193.
€
Muller, O.; Waldmann, H. Eur. J. Org. Chem. 2005, 4773–
4788; (b) Smith, A. B., III; Walsh, S. P.; Frohn, M.; Duffey,
M. O. Org. Lett. 2005, 7, 139–142; (c) Moilanen, S. B.;
Potuzak, J. S.; Tan, D. S. J. Am. Chem. Soc. 2006, 128,
1792–1793.
8. For recent reviews, see: (a) El Bialy, S. A. A.; Braun, H.; Tietze,
L. F. Synthesis 2004, 2249–2262; (b) Dake, G. Tetrahedron
2006, 62, 3467–3492.
ꢀ
9. Mendez, L. Y. V.; Kouznetsov, V. V. Tetrahedron Lett. 2007, 48,
2509–2512.
4.34. 3-Phenyl-1-azaspiro[5.5]undecan-3-ol (34)
10. Kan, T.; Fujimoto, T.; Ieda, S.; Asoh, Y.; Kitaoka, H.;
Fukuyama, T. Org. Lett. 2004, 6, 2729–2731.
A flask containing a solution of benzyl carbamate 33
(7.2 mg, 0.02 mmol) and 10% Pd/C (1 mg) in EtOH
(1 mL) was connected to a ballon filled with hydrogen.
The suspension was stirred at room temperature for 4 h
and then filtered through a pad of Celite. The filtrate was
concentrated in vacuo to give amino alcohol 34 (5 mg,
100%) as white crystals, mp 110–112 ꢀC; Rf (Et2O/toluene,
11. Hansen, J. D.;Newhouse,B. J.;Allen, S.;Anderson, A.; Eary, T.;
Schiro, J.; Gaudino, J.; Laird, E.; Allen, A. C.; Chantry, D.;
Eberhardt, C.; Burgess, L. E. Tetrahedron Lett. 2006, 47, 69–72.
12. (a) Tsujimoto, T.; Ishihara, J.; Horie, M.; Murai, A. Synlett
2002, 399–402; (b) Kong, K.; Moussa, Z.; Romo, D. Org.
Lett. 2005, 7, 5127–5130.
13. (a) Chambers, M. S.; Baker, R.; Billington, D. C.; Knight,
A. K.; Middlemiss, D. N.; Wong, E. H. F. J. Med. Chem.
1992, 35, 2033–2039; (b) Evans, B. E.; Leighton, J. L.;
Rittle, K. E.; Gilbert, K. F.; Lundell, G. F.; Gould, N. P.;
Hobbs, D. W.; DiPardo, R. M.; Veber, D. F.; Pettibone, D. J.;
Clineschmidt, B. V.; Anderson, P. S.; Freidinger, R. M.
J. Med. Chem. 1992, 35, 3919–3927.
1
3:1): 0.2; H NMR (400 MHz, CDCl3): d¼1.25–1.78 (m,
13H, CHH, 6CH2), 1.92–2.04 (m, 1H, CH2), 2.63 (d,
J¼12.5 Hz, 1H, 2-H), 3.10 (d, J¼12.5 Hz, 1H, 2-H), 2.70–
3.90 (br s, 2H, OH, NH), 7.19 (t, J¼7.3 Hz, 1H, CHar,
para), 7.28 (t, J¼7.3 Hz, 2H, CHar, meta), 7.44 (d,
J¼7.3 Hz, 2H, CHar, ortho); 13C NMR (100 MHz, CDCl3):
d¼21.8, 21.9 (C-8,10), 26.2 (C-9), 29.3 (C-4), 31.3 (C-5),
32.7 (C-7), 40.6 (C-11) 50.7 (C-6), 51.2 (C-2), 70.6 (C-3),
124.7 (CHar, ortho), 126.9 (CHar, para), 128.2 (CHar,
meta), 145.9 (Car); HRMS (EI): calcd for C16H24NO
[M+H]+ 246.18524, found 258.18518.
14. Cipollina, J. A.; Ruediger, E. H.; New, J. S.; Wire, M. E.;
Shepherd, T. A.; Smith, D. W.; Yevich, J. P. J. Med. Chem.
1991, 34, 3316–3328.
15. Nagata, T.; Nishida, A.; Nakagawa, M. Tetrahedron Lett. 2001,
42, 8345–8349.
16. Mehrotra, M. M.; Heath, J. A.; Smyth, M. S.; Pandey, A.; Rose,
J. W.; Seroogy, J. M.; Volkots, D. L.; Alaimo, L. N.; Park, G. L.;
Lambing, J. L.; Hollenbach, S. J.; Scarborough, R. M. J. Med.
Chem. 2004, 47, 2037–2061.
Acknowledgements
€
Financial support by Grunenthal GmbH and the Fonds der
Chemischen Industrie is gratefully acknowledged.
17. For reviews focusing on heterocycle synthesis, see: (a) Phillips,
A. J.; Abell, A. D. Aldrichimica Acta 1999, 32, 75–89; (b)
Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199–2238;
(c) Mori, M. Adv. Synth. Catal. 2007, 349, 121–135.
18. For general reviews, see: F€urstner, A. Angew. Chem. 2000, 112,
3140–3172; Angew. Chem., Int. Ed. 2000, 39, 3012–3043;
Grubbs, R. H. Tetrahedron 2004, 60, 7117–7140.
Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.07.083.
ꢀ
19. Rodrıguez, S.; Castillo, E.; Carda, M.; Marco, J. A.
Tetrahedron 2002, 58, 1185–1192.
References and notes
20. Gracias, V.; Gasiecki, A. F.; Moore, J. D.; Zanze, I. A.; Djuric,
S. W. Tetrahedron Lett. 2006, 47, 8977–8980.
21. For ring-closing metathesis reactions of acrylates, see:
1. Mario Geysen, H.; Schoenen, F.; Wagner, D.; Wagner, R. Nat.
Rev. Drug Discov. 2003, 2, 222–230.
€
Furstner, A.; Dierkes, T. Org. Lett. 2000, 2, 2463–2465 and ref-
erences therein.
€
€
2. Bleicher, K. H.; Bohm, H.-J.; Muller, K.; Alanine, A. I. Nat.
Rev. Drug Discov. 2003, 2, 369–378.
22. Petrini, M.; Profeta, R.; Righi, P. J. Org. Chem. 2002, 67, 4530–
4535.
23. Veenstra, S. J.; Schmid, P. Tetrahedron Lett. 1997, 38, 997–
1000.
3. Lipinski, C.; Hopkins, A. Nature 2004, 432, 855–861.
4. Khersonsky, S. M.; Chang, Y.-T. Comb. Chem. High
Throughput Screen. 2004, 7, 645–652.
24. See for example: Beshore, D. C.; Smith, A. B., III. J. Am.
Chem. Soc. 2007, 129, 4148–4149.
25. Brosius, A. D.; Overman, L. E.; Schwink, L. J. Am. Chem. Soc.
1999, 121, 700–709.
€
€
5. Noren-Muller, A.; Reis-Correa, I., Jr.; Prinz, H.; Rosenbaum,
C.; Saxena, K.; Schwalbe, H. J.; Vestweber, D.; Cagna, G.;
Schunk, S.; Schwarz, O.; Schiewe, H.; Waldmann, H. Proc.
Natl. Acad. Sci. U.S.A. 2006, 103, 10606–10611.
26. (a) Garratt, P. J.; Doecke, C. W.; Weber, J. C.; Paquette, L. A.
J. Org. Chem. 1986, 51, 449–452; (b) Youn, I. K.; Yon, G. H.;
Pak, C. S. Tetrahedron Lett. 1986, 27, 2409–2410; (c)
Hudlicky, T.; Sinai-Zingde, G.; Natchus, M. G. Tetrahedron
Lett. 1987, 28, 5287–5290.
6. The application of the Buchwald–Hartwig enolate arylation
reaction seems promising in this regard. See: (a) Botuha, C.;
Galley, C. M. S.; Gallagher, T. Org. Biomol. Chem. 2004, 2,
1825–1826; (b) Khartulyari, A. S.; Maier, M. E. Eur. J. Org.
Chem. 2007, 317–324.