A new and efficient synthesis of derivatives of octahydro-4H-pyrrolo[1,2-c] pyrido[1′,2′-a]imidazole

Article abstract of DOI:10.1002/ejoc.201001704

When diethyl malonate was added to a solution of Δ¹- piperideine, generated in situ by oxidative desamination and decarboxylation of L-lysine by N-bromosuccinimide (NBS), formation of the unexpected tricyclic compound 6 (4-diethylmalonyl-octahydro-4H-pyrrolo[1,2-c]pyrido[1′, 2′-a]imidazole)was observed. The structure of 6 was deduced from analysis of its spectroscopic data and was confirmed both by chemical degradation and by total synthesis. We proved that 3-bromo-1-piperideine was implicated in its formation. Moreover, based on this feature, a new and efficient synthesis of 6 was developed. The elaborated pathway was adapted to access derivatives related to 6 that differed in their C-4 substituent. A new and efficient synthesis of derivatives of the tricyclic heterocycle A from lysine is described. A mechanism involving 3-halopiperideines as intermediates and based on a ring contraction followed by Michael reaction is proposed and tested. Copyright

Full text of DOI:10.1002/ejoc.201001704

FULL PAPER
DOI: 10.1002/ejoc.201001704
A New and Efficient Synthesis of Derivatives of Octahydro-4H-pyrrolo-
[1,2-c]pyrido[1Ј,2Ј-a]imidazole
Anne Rouchaud[a] and Jean-Claude Braekman*[a]
Keywords: Alkaloids / Natural products / Nitrogen heterocycles / Cyclotrimerization / Michael addition
When diethyl malonate was added to a solution of Δ1-piper-
ideine, generated in situ by oxidative desamination and de- degradation and by total synthesis. We proved that 3-bromo-
of its spectroscopic data and was confirmed both by chemical
carboxylation of
L
-lysine by N-bromosuccinimide (NBS), for-
1-piperideine was implicated in its formation. Moreover,
based on this feature, a new and efficient synthesis of 6 was
developed. The elaborated pathway was adapted to access
derivatives related to 6 that differed in their C-4 substituent.
mation of the unexpected tricyclic compound 6 (4-diethyl-
malonyl-octahydro-4H-pyrrolo[1,2-c]pyrido[1Ј,2Ј-a]imidazole)
was observed. The structure of 6 was deduced from analysis
starting material to perform these syntheses. We found that
the best yields of the target intermediates were obtained by
generation of 5 by slow detrimerization of α-tripiperideine.
In this paper, we wish to report the unexpected results we
have obtained on generation of Δ1-piperideine using the re-
action of lysine with N-bromosuccinimide (NBS).[6,7]
Introduction
Pseudomyrmecine ants of the genus Tetraponera utilize
their modified sting to smear upon enemies a contact poi-
son that contains a mixture of tricyclic alkaloids.[1–3] These
alkaloids, named tetraponerines, can be distributed into two
structural families, which are based either on the deca-
hydrodipyrrolo[1,2-a:1Ј,2Ј-c]pyrimidine skeleton (1; 5-6-5
skeleton) or on the decahydro-5H-pyrido[1,2-c]pyrrolo-
[1Ј,2Ј-a]pyrimidine skeleton (2; 6-6-5 skeleton) (Figure 1).
Results and Discussion
Franck and Randau[8] have demonstrated that at pH 3 or
lower, the reaction of NBS with amino acids provides, by
oxidative desamination and decarboxylation, the corre-
sponding aldehyde with one carbon less. Under these condi-
tions, l-lysine is transformed into 5-aminopentanal, which
cyclizes spontaneously into Δ1-piperideine.[8] When we
treated a solution of Δ1-piperideine, prepared according to
this method, with diethyl malonate (DEM) in the hope of
forming 6-6-6 or iso-6-6-6 intermediates as described pre-
viously,[5] we observed consistent formation of the unexpec-
ted tricyclic product 6 (5-5-6 skeleton) in moderate yields
(best yield 26%) together with polymeric material. Despite
numerous assays, which were carried out at various pH and
various proportions of reactants, we never isolated 6-6-6 or
iso-6-6-6 derivatives under these conditions.
Figure 1. Tetraponera alkaloid skeletons (1 and 2) and synthetic
analogues (3 and 4).
In the framework of a program focused on the search for
bioactive compounds in insects, preliminary tests indicated
that the tetraponerines presented interesting cytotoxic ac-
tivities. It has also been shown that these molecules possess
neurotoxic[4] and insecticidal activities.[1] To evaluate the in-
fluence of the tricyclic ring system on the cytotoxic activity,
we have recently described the synthesis of a series of non-
natural tricyclic alkaloids based on the skeletons decahy-
dro-2H,6H-dipyrido[1,2-a:1Ј,2Ј-c]pyrimidine (3; 6-6-6 skel-
eton) and dodecahydro-2H-1,8a-diazaphenanthrene (4; iso-
6-6-6 skeleton) (Figure 1).[5] Δ1-Piperideine (5), which is an
unstable imine that must be prepared in situ, was used as
The molecular formula of compound 6 was established
to be C17H28N2O4 (M+ at m/z 324.2033) by HRMS (EI),
1
requiring five double bond equivalents. The IR, H, and
13C NMR spectra indicated the presence of two ethyl ester
groups and, because no further signals attributable to sp2
carbon atoms were observed, it was reasonable to assume
that 6 must be tricyclic. Moreover, because no νNH absorp-
tion was present in the IR spectrum, the two nitrogen atoms
must be tertiary. A detailed analysis of the 1D and 2D
NMR spectra (1H–1H COSY, HMQC, and HMBC) led to
the atom connectivity depicted in 6 and permitted the com-
[a] Department of Organic Chemistry, CP 160/06, Faculty of
Sciences, Université Libre de Bruxelles,
50 Avenue F. D. Roosevelt, 1050 Brussels, Belgium
Fax: +32-2-650-2798
E-mail: braekman@ulb.ac.be
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Octahydro-4H-pyrrolo[1,2-c]pyrido[1Ј,2Ј-a]imidazole Derivatives
plete NMR assignments reported in the experimental part. equivalent of benzyl bromide or benzyl chloride in CHCl3
The relative configurations at C-3a, C-4, and C-9a were de- at room temperature to prepare a quaternary salt, which
duced by a NOESY experiment. Indeed, NOE correlations was more likely than the free base to lead to a crystalline
between H-6α/H-1Ј, H-9a/H-4, H-9a/H-1β, H-9a/H-6β, H- solid for X-ray analysis, the 2-substituted pyrrolidine 8 was
4/H-3β, and H-4/H-6β suggested that H-9a and H-4 are cis- isolated as the major product (ca. 49% yield). Formation
oriented and that cycles A/B and B/C are cis- and trans- of the latter can be explained by assuming that the interme-
fused, respectively (Figure 2). Until now, the only known diate quaternary salt 9 undergoes a reverse Michael-type
compound having a 5-5-6 skeleton similar to that of com- reaction with elimination of a molecule of Δ1-piperideine
pound 6 is (–)-dysibetaine PP (7), an amino acid derivative and of HBr (Scheme 1).
isolated from the marine sponge Dysidea herbacea.[9] Com-
pound 7 has been synthesized starting from a dipeptide in
a six-step synthesis.[10] It should be noted that the relative
configuration of 6 is different to that of the natural product
7.
Scheme 1. Chemical degradation of 6. Reagents and conditions: (i)
PhCH2Br or PhCH2Cl, CHCl3, room temp., 4 h, 52% and 44%,
respectively.
A plausible mechanism for the generation of 6 using the
NBS/lysine procedure is outlined in Scheme 2. The pathway
involves the formation of 3-bromo-1-piperideine (10) re-
sulting from the bromination of 5 in the presence of an
excess of NBS. It is well-known that treatment of aldimines
with NBS or NCS yields the corresponding α-bromoald-
imines or α-chloroaldimines, respectively.[11,12] After ad-
dition of diethyl malonate to the imino group, the resulting
3-bromopiperidine 11 could undergo internal substitution
Figure 2. Structure of starting Δ1-piperideine (5), the product 6,
of the bromine, leading to the aziridinium ion 12.[13] Subse-
NOE correlations, and the natural product (–)-dysibetaine PP (7).
quent opening of the aziridinium ring and elimination of
The structure deduced from analysis of the spectroscopic HBr would then afford pyrrolidine 13. Finally, a Michael-
data of 6 was confirmed both by chemical degradation and type reaction between the latter and a second molecule of
by synthesis. Thus, when compound 6 was treated with one 5 would provide compound 6.
Scheme 2. Proposed pathway for the formation of 6.
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A. Rouchaud, J.-C. Braekman
FULL PAPER
To support our hypothesis, we verified that by treating the tricyclic 5-5-6 system by subsequent treatment with Δ1-
Δ1-piperideine (5) with NBS, the proposed intermediate 10 piperideine (5). To perform this synthesis, we decided to use
could indeed be produced. Thus, to an aqueous solution of NIS instead of NBS because we expected better yields for
5, prepared by detrimerization of α-tripiperideine in HCl, the introduction of the halogen at position C-3 of the piper-
one equivalent of NBS was added followed by addition of idine ring, as well as for the formation of the aziridinium
KCN to trap the unstable imine 10 that was expected to be intermediate. The intermediate 18 was easily prepared from
formed during the reaction. Analysis and purification of the the commercially available amino alcohol 16 as shown in
resulting solution led to the isolation of 3-bromo-2-cyano- Scheme 4. Accordingly, successive protection of the primary
piperidine (14) in 6% yield, together with 2-cyanopiperidine amine, oxidation of the hydroxyl group to an aldehyde, and
(15) in 33% yield. Moreover, when KCN was replaced by spontaneous cyclization produced the protected Δ2-piperid-
diethyl malonate to trap the elusive imino intermediate, eine 17; subsequent treatment with NIS/MeOH afforded the
compound 6 was isolated, albeit in low yield (10%). This trans-2-methoxy-3-iodopiperidine 18.[14] The next step was
indicated that 10 is indeed generated under these conditions the introduction of the diethyl malonyl group in the form
(Scheme 3). The yields of these reactions were not opti- of a titanium enol ether, which was prepared in situ using
mized.
a mixture of TiCl4 and N,N-diisopropylethylamine (DI-
PEA).[15–17] The key compound 19 was obtained through
this approach in an overall yield of 63% from 16. Only the
trans diastereoisomer was isolated. This high stereoselecti-
vity resulted from the introduction of the diethyl malonyl
group as an iminium ion, which directed the nucleophilic
attack in an anti fashion.
After deprotection of the secondary amino group of 19
with trimethylsilyl iodide (TMSI) in acetonitrile and con-
centration of the solution under reduced pressure, the re-
sulting N-silylpiperidine intermediate was hydrolyzed with
aqueous HCl (10%), affording the corresponding secondary
amine 20, which was not isolated. Ground α-tripiperideine
was added and the pH was raised to 2.5 by cautious ad-
dition of KOH (2 m). After 16 h at room temperature and
work up of the mixture, compound 6 was isolated in 67%
yield after purification by column chromatography on silica
gel. It is notable that no other diastereoisomers of 6 were
isolated, suggesting that the Michael-type cyclization also
proceeds with high stereoselectivity.
These data are consistent with the structure proposed for
6, as well as with the involvement of a 3-halopiperidinic
intermediate in its formation when NBS/lysine is used to
generate the unstable Δ1-piperideine 5 in situ.
At this stage of the work, the next problem we addressed
was the use of intermediate 18 to reach 5-5-6 derivatives
that differed at their C-4 substituent. To this end, several
Scheme 3. Proof of the intermediate formation of 3-bromo-1-piper-
ideine (10). Reagents and conditions: (i) HCl (1 n), 10 min, 20 °C,
then NaOH Ǟ pH = 2; (ii) NBS, 20 min, 45 °C; (iii) NaOH Ǟ pH
= 6, then DEM, 17 h, room temp., 10%; (iv) NaOH Ǟ 2 Ͻ pH Ͻ
3, then KCN, 3 h, 20 °C, 14 (6%) and 15 (33%).
Additional proof for the structure of 6 was obtained by
its synthesis using a pathway based on the hypothesis that
a 3-halopiperidine was involved in its formation (Scheme 4).
The first step was the preparation of iodopiperidine 18
starting from 5-amino-1-pentanol (16). The second step was
the generation, after deprotection of the amino group, of
Scheme 4. Total synthesis of 6. Reagents and conditions: (i) ClCO2Bn, K2CO3, EtOH/H2O, 0 °C to room temp., 3 h, 89%; (ii) PCC/SiO2,
CH2Cl2, ultrasound, 1 h, 88%; (iii) NIS, CH2Cl2/MeOH, 0 °C to room temp., 16 h, 87%; (iv) (a) DEM, TiCl4, CH2Cl2, 0 °C, 5 min; (b)
DIPEA, 0 °C, 1 h, (c) 18, –6 °C, 1 h, 93%; (v) TMSI, CH3CN, 0 °C to room temp., 19 h; (vi) (a) HCl (10%); (b) α-tripiperideine, KOH
(2 m) Ǟ pH = 2–3, room temp., 16 h, 67%.
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Octahydro-4H-pyrrolo[1,2-c]pyrido[1Ј,2Ј-a]imidazole Derivatives
Scheme 5. Synthesis of analogues of 6. Reagents and conditions: (i) CH2=CHCH2SiMe3, BF3·OEt2, CH2Cl2, –78 °C, 2 h, 52%; (ii) TiCl4,
CH2Cl2, isopropenyl acetate, –78 °C, 1 h, 40%; (iii) TiCl4, CH2Cl2, isopropenyl acetate, –78 °C, 1 h, then –78 °C to room temp., 16 h, 24
(19%) and 26 (77%); (iv) same conditions as for (iii), 2-(trimethylsilyloxy)-1-dodecene, 27 (60%); (v) (a) 28: TMSI, CH3CN, 20 °C, 16 h;
29: TMSI, CHCl3, reflux, 24 h; (b) HCl (10%); (c) α-tripiperideine, KOH (2 m) Ǟ pH = 2–3, room temp., 16 h, 28 (61%) and 29 (54%).
nucleophiles and experimental conditions were tested. It ap- tion could not take place owing to the reduced acidity of
peared that treatment of 18 with allylmethylsilane/Et2O·BF3 the allylic proton H-1Ј of 21.
readily afforded piperidine 21, whereas treatment with iso-
In conclusion, the serendipitous finding that Δ1-piperid-
eine (5), generated using the lysine/NBS mixture, reacts with
propenylacetate/TiCl4 or 2-(trimethylsilyloxy)propene[18]
/
[14,15,17,19–21]
TiCl4
did not lead to substitution of the meth- diethyl malonate to afford the tricyclic derivative 6 follow-
oxy group by an acetonyl moiety (Scheme 5). Under these ing a pathway involving a 3-halopiperideine intermediate,
latter conditions, only the Δ2-piperideine 17 was isolated in led us to develop a new and efficient way to reach deriva-
40% yield. This was attributed to the weakness of the C–I tives of octahydro-4H-pyrrolo[1,2-c]pyrido[1Ј,2Ј-a]imid-
bond, which can be cleaved in the presence of Lewis acid azole, a seldom encountered heterocycle, with high stereose-
such as TiCl4 or trimethylsilyl trifluoromethanesulfonate lectivity.
(TMSOTf).[22] Indeed, when the corresponding bromine de-
rivative 23 was submitted to the same conditions, the ex-
pected acetonyl derivative 24 was formed albeit in low yield
(18%). A much better yield (77%) was nevertheless ob-
tained when the benzyloxycarbonyl protecting group was
replaced by a methoxycarbonyl group.
Experimental Section
General: Unless otherwise noted, materials were obtained from Al-
drich or Acros and were used without purification. Diethyl ether
was distilled from Na-benzophenone ketyl or LiAlH4 prior to use.
Dichloromethane and acetonitrile were distilled prior use from
In our previous paper, we reported that analogues of tet-
raponerines with long n-alkyl substituents have higher cyto-
toxicity. Therefore, for comparison purposes, we synthe-
sized the 4-n-dodecane-substituted 5-5-6 analogue 29. Sim-
ilar to the preparation of 26 from 25, compound 27 was
prepared in 60% yield from 25 using 2-(trimethylsilyloxy)-
1-dodecene[18]/TiCl4 as reagent (Scheme 5). The bromine
derivatives 23 and 25 where prepared following the pathway
P2O5 or CaH2. Chloroform was distilled from P2O5. Piperidine,
diisopropylamine, diisopropylethylamine, and triethylamine were
freshly distilled from CaH2. MeOH and EtOH were dried and dis-
tilled from CaH2. All reactions were carried out under an atmo-
sphere of dry nitrogen. α-Tripiperideine was prepared by reaction
of piperidine with NCS, followed by dehydrohalogenation of N-
chloropiperidine with KOH in boiling ethanol.[23,24]
depicted in Scheme 4, but NIS was replaced by NBS and, EI-MS and HRMS (EI) were performed with a Fisons VG Micro-
mass Autospec instrument (70 eV). HRMS (ES) were performed
with a Waters Q-TOF 2 instrument in positive ionization mode. In
all cases, peak intensities are expressed as a percentage relative to
the base peak. The 1H NMR spectra were recorded in CDCl3 at
300 MHz with a Bruker Avance TM 300 or at 600 MHz with a
Varian Unity 600 instrument and are reported in ppm from internal
TMS on the δ scale. Data are reported as follows: chemical shift
[multiplicity (s: singlet, d: doublet, dd: double doublet, ddd: double
double doublet, t: triplet, dt: double triplet, tt: triple triplet, q:
quartet, m: multiplet), coupling constants in Hertz, integration].
for compound 25, methyl chloroformate was used instead
of benzyl chloroformate to protect the amino group.
Deprotection of the secondary amine of 26 and 27 by
treatment with TMSI/CH3CN (for 26) and TMSI/CHCl3
(for 27) followed by successive addition of aqueous HCl
(10%) and ground α-tripiperideine, afforded the tricyclic
compounds 28 (61% yield) and 29 (54% yield), respectively.
It is to be noted that when 21 was submitted to the same
reaction sequence, no cyclization occurred and compound
22 was not formed, probably because the Michael-like reac- The 13C NMR spectra were recorded in CDCl3 at 75.4 MHz with
Eur. J. Org. Chem. 2011, 2346–2353
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A. Rouchaud, J.-C. Braekman
FULL PAPER
a Bruker Avance TM 300 instrument. The IR spectra were recorded
with a Bruker IFS 25 instrument as films on a NaCl disk. Thin
layer chromatographic analyses (TLC) were performed with
0.25 mm Polygram silica gel SILG/UV254 precoated plates (Mach-
erey–Nagel). Chromatographic separations were performed with
silica gel columns (MN Kieselgel 60, 0.04–0.063 mm) using the
flash technique or on basic alumina (MN Aluminiumoxid, basisch
Activity 1).
129.1 (C-Ar), 129.2 (C-6), 138.9 (C-Ar), 151.1 (C-5), 163.8 (C-7Ј),
165.6 (C-7) ppm. HRMS (EI): m/z
= 331.1767 (calcd. for
C19H25NO4 331.1783), 286.1447 (calcd. for C17H20NO3 286.1443),
285.1369 (calcd. for C17H19NO3 285.1365), 258.1510 (calcd. for
C16H20NO2 258.1494), 240.1250 (calcd. for C12H18NO4 240.1236),
194.0835 (calcd. for C10H12NO3 194.0817), 184.1116 (calcd. for
C13H14N 184.1126), 91.0546 (calcd. for C7H7 91.0546).
3-Bromo-2-cyanopiperidine (14): A solution of α-tripiperideine
(0.146 g, 0.59 mmol) in aqueous HCl (1 m, 3 mL) was stirred for
10 min at room temp., then NaOH (1 m) was added dropwise until
pH 1.9 was reached, then NBS (313 mg, 1.76 mmol) was added.
The resulting solution was warmed to 45 °C while gentle suction
was applied. After 20 min, the pH was brought to 1.9 by addition
of NaOH (1 m) and KCN (149 mg, 2.29 mmol) was added. The pH
of the mixture was maintained between 2 and 3 by regular addition
of aqueous HCl (1 m). The mixture was stirred for 3 h at room
temp., then basified to pH 8 by addition of NH4OH and extracted
with CH2Cl2. The combined organic phases were dried and the
solvents evaporated in vacuo to dryness to give an oil, which was
flash purified by chromatography on silica gel (CH2Cl2/
4-(Diethylmalonyl)-octahydro-4H-pyrrolo[1,2-c]pyrido[1Ј,2Ј-a]imid-
azole (6): NBS (572 mg, 3.21 mmol) was added to a solution of l-
lysine monohydrochloride (293 mg, 1.60 mmol) in water (20 mL).
The solution was kept at 45 °C for 20 min. Gentle suction was ap-
plied to remove bromine vapors (pH of the solution: ca. 1.6). Aque-
ous KOH (1 m) was added dropwise at 0 °C until pH 6.5 was
reached. Then, diethyl malonate (243 μL, 1.6 mmol) was poured
into the solution in one portion. After stirring overnight under ni-
trogen at room temp., the pH (ca. 3.6) was brought to pH 8 with
KOH (1 m) and the solution was extracted with CH2Cl2. The com-
bined organic phases were dried and the solvent was removed by
evaporation in vacuo to give a crude product that was purified by
flash chromatography on silica gel (CH2Cl2/CH3OH/NH4OH 10%,
99:1:0.1) to afford compound 6 (68.5 mg, 0.21 mmol, 26%). IR
MeOH, 95:5
+ 1% concd. NH4OH) to afford 14 (20 mg,
0.10 mmol, 6%) as a colorless oil, and 2-cyanopiperidine (64 mg,
0.59 mmol, 33%). 1H NMR (300 MHz, CDCl3): δ = 1.50–2.00 (m,
3 H, 5-H2, 4-Hax), 2.37 (m, 1 H, 4-Heq), 2.83 (m, 1 H, 6-Hax), 3.07
(m, 1 H, 6-Heq), 3.97 (d, J = 6.3 Hz, 1 H, 2-H), 4.21 (m, 1 H, 3-
H) ppm. 13C NMR (75.3 MHz, CDCl3): δ = 24.1 (C-5), 32.7 (C-4),
43.8 (C-6), 47.8 (C-2), 54.3 (C-3), 115.6 (CN) ppm MS (EI): m/z
(%) = 190 (7) [M(Br81)]+, 188 (7) [M(Br79)]+, 164 (7) [M+·(Br81) –
CN·], 162 (7) [M+·(Br79) – CN·], 109 (100) [M+ – Br], 93 (20), 82
(42), 67 (49), 55 (45).
(NaCl disc): νmax = 2939, 2861, 2800, 1730, 1448, 1369, 1274, 1175,
˜
1
1152, 1032 cm–1. H NMR (600 MHz, CDCl3): δ = 1.24 (m, 1 H,
8-Hα), 1.29 (t, J = 7.2 Hz, 6 H, 4Ј-H3), 1.45 (qt, J = 12.6, 3.6 Hz,
1 H, 7-Hα), 1.60 (m, 2 H, 9-Hα, 7-Hβ), 1.77 (m, 1 H, 3-Hα), 1.82
(br. d, J = 13.8 Hz, 1 H, 8-Hβ), 1.85 (m, 1 H, 2-Hβ), 1.90 (m, 2 H,
2-Hα, 9-Hβ), 2.03 (m, 1 H, 3-Hβ), 2.08 (td, J = 12, 2.4 Hz, 1 H, 6-
Hα), 2.72 (br. d, J = 9 Hz, 1 H, 9a-Hα), 2.79 (m, 1 H, 1-Hα), 2.90
(t, J = 6 Hz, 1 H, 4-Hα), 3.02 (br. d, J = 10.8 Hz, 1 H, 6-Hβ), 3.12
(br. s, 1 H, 1-Hβ), 3.71 (d, J = 5.4 Hz, 1 H, 1Ј-H), 4.00 (br. s, 1 H,
3a-Hα), 4.25 (m, 4 H, 3Ј-H2) ppm. 13C NMR (75.3 MHz, CDCl3):
δ = 14.1, 14.2 (C-4Ј), 22.8 (C-8), 24.9 (C-7), 25.3 (C-2), 30.7 (C-9),
31.2 (C-3), 49.9 (C-6), 50.9 (C-1), 53.6 (C-1Ј), 61.5, 61.6 (C-3Ј),
65.5 (C-3a), 67.8 (C-4), 85.6 (C-9a), 167.6, 168 (C-2Ј) ppm. HRMS
(EI): m/z = 324.2033 (calcd. for C17H28N2O4: 324.2049), 323.1968
(calcd. for C17H27N2O4 323.1971), 296.1733 (calcd. for
C15H24N2O4 296.1736), 255.1460 (calcd. for C13H21NO4 255.1471),
251.1754 (calcd. for C14H23N2O2 251.1760), 223.1452 (calcd. for
C12H19N2O2 223.1447), 182.1192 (calcd. for C10H16NO2 182.1181),
165.1516 (calcd. for C11H19N 165.1518).
Formation of 6 from α-Tripiperideine: A solution of α-tripiperideine
(142 mg, 0.57 mmol) in aqueous HCl (1 m, 2 mL) was stirred for
10 min at 20 °C under nitrogen. The pH was brought to 1.9 by
addition of NaOH (1 m), then NBS (304 mg, 1.7 mmol) was added
and the solution was stirred under nitrogen for 1 h at room temp.
The pH was raised to 6 by addition of a solution of NaOH (1 m),
and diethyl malonate (259 μL, 1.71 mmol) was added. After stirring
overnight at room temp. under nitrogen, the pH was brought to 8
by addition of concd. NH4OH. The solution was extracted with
CH2Cl2 (3ϫ20 mL), and the organic phases were combined, dried
(WA filter paper), and the solvents evaporated under vacuum.
Flash chromatography on silica gel (CH2Cl2/MeOH/NH4OH 10%,
99:1:0.1) of the yellow oily residue afforded 6 (55.4 mg, 0.17 mmol,
10%).
1-Benzyl-2-[2-bis(ethoxycarbonyl)vinyl]pyrrolidine (8): Benzyl bro-
mide (19 μL, 0.16 mmol) was added dropwise to a stirred solution
of 6 (50 mg, 0.15 mmol) in anhydrous chloroform (1 mL) under
nitrogen. After 4 h at room temp., an aqueous solution of NaHCO3
was added. The aqueous layer was extracted with dichloromethane
and the combined organic layers were dried and evaporated under
reduced pressure. Flash chromatography on silica gel of the solid
residue (CH2Cl2/MeOH/NH4OH 10%, 99:1:0.1) yielded 8 (27 mg,
0.080 mmol, 52%) as a colorless oil and unreacted 6 (8 mg,
0.024 mmol, 15%). The use of benzyl chloride instead of benzyl
bromide under the same conditions afforded 8 with a yield of 44%.
5-(Benzyloxycarbonylamino)pentanol: A solution of K2CO3 (4.1 g,
29.6 mmol) in water (20 mL) was added to a solution of 5-amino-
1-pentanol (1.57 mL, 14.5 mmol) in ethanol (20 mL). The reaction
mixture was cooled in an ice-bath and benzyl chloroformate
(2.7 mL, 18.9 mmol) was added under vigorous stirring. The ice-
bath was maintained during 30 min and the mixture was warmed
progressively to room temp. After 3 h, the mixture was extracted
with CH2Cl2 and the combined organic layers were filtered through
IR (NaCl disc): ν
= 3089, 3062, 3028, 2981, 2940, 2876, 2802,
˜
max
1729, 1650, 1452, 1368, 1246, 1213, 1182, 1054 cm–1. 1H NMR a WA filter paper and the solvent was evaporated in vacuo to give
(300 MHz, CDCl3): δ = 1.29 (t, J = 7.2 Hz, 3 H, 9Ј-H), 1.34 (t, J a residue that was purified by flash chromatography on silica gel
= 6.6 Hz, 3 H, 9-H), 1.72 (m, 2 H, 2-H, 3-H), 1.85 (m, 1 H, 3-H), (hexane/AcOEt, 5:5) to afford 5-(benzyloxycarbonylamino)penta-
2.05 (m, 1 H, 2-H), 2.21 (q, J = 9 Hz, 1 H, 4-H), 2.99 (br. t, J = nol (3.015 g, 12.7 mmol, 89%) as a colorless oil. 1H NMR
7 Hz, 1 H, 4-H), 3.24 [d, J = 13.2 Hz, 1 H, CH2(Bn)], 3.29 (m, 1
(300 MHz, CDCl3): δ = 1.40 (m, 2 H, 3-H), 1.55 (m, 4 H, 2-H, 4-
H, 1-H), 3.93 [d, J = 13.2 Hz, 1 H, CH2(Bn)], 4.23 (q, J = 7.2 Hz, H), 3.20 (t, J = 6.7 Hz, 2 H, 5-H), 3.63 (t, J = 6.3 Hz, 2 H, 1-H),
2 H, 8Ј-H), 4.30 (q, J = 6.6 Hz, 2 H, 8-H), 6.94 (d, J = 9.6 Hz, 1
H, 5-H), 7.23 (m, 1 H, Ar-H), 7.29 (m, 4 H, Ar-H) ppm. 13C NMR
(75.3 MHz, CDCl3): δ = 14.2, 14.3 (C-9, C-9Ј), 23.0 (C-3), 31.3 (C-
5.09 (s, 2 H, CH2Ph), 7.35 (m, 5 H, Ar-H) ppm. 13C NMR
(75.3 MHz, CDCl3): δ = 22.9 (C-3), 29.9 (C-4), 32.3 (C-2), 41.1
(C-5), 62.8 (C-1), 66.8 (CH2Ph), 128.2, 128.6, 136.7 (C-Ar), 156.6
2), 53.6 (C-4), 58.9 (C-1Ј), 61.5 (C-8, C-8Ј), 63.4 (C-1), 127.1, 128.3, (NCOOCH2) ppm. HRMS (ES): m/z calcd. for C13H19NO3Na
2350
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2346–2353

Octahydro-4H-pyrrolo[1,2-c]pyrido[1Ј,2Ј-a]imidazole Derivatives
260.1263; found 260.1267. MS (EI): m/z (%) = 238 (7) [M + H]+, (m, 1 H, 4-Heq), 1.97 (m, 1 H, 3-Heq), 2.05 (m, 1 H, 3-Hax), 2.90
194 (36), 108 (67), 91 (100), 79 (19), 65 (14).
(td, J = 1.5, 6.6 Hz, 0.6 H, 5-Hax), 2.99 (td, J = 1.2, 6.9 Hz, 0.4 H,
5-Hax), 3.90 (m, 2 H, 1-H and 5-Heq), 4.01 (m, 1 H, 2-H), 4.22 (m,
4 H, 3Ј-H4), 4.66 (s, 0.5 H, 1Ј-H), 4.68 (s, 0.5 H, 1Ј-H), 5.06–5.32
(m, 2 H, CH2Ph), 7.26–7.43 (m, 5 H, Ar-H) ppm. 13C NMR
(75.3 MHz, CDCl3): δ (two rotamers) = 13.7, 13.8, 21.1, 21.5, 27.5,
28.0, 29.2, 29.3, 39.3, 39.7, 52.0, 52.1, 57.7, 58.3, 62.0, 62.1, 67.4,
67.6, 127.9, 128.3, 128.4, 136.5, 155.5, 165.7, 167.0 ppm. HRMS
(ES): m/z calcd. for C20H26INaNO6 526.0703; found 526.0701.
1-(Benzyloxycarbonyl)-1,2,3,4-tetrahydropyridine (17): Pyridinium
chlorochromate (PCC; 273 mg, 1.27 mmol) and silica gel (273 mg)
were dried for 24 h under vacuo and mixed and ground in a mortar.
The resulting powder was suspended in anhydrous CH2Cl2
(20 mL).
5-(benzyloxycarbonylamino)pentanol
(199 mg,
0.84 mmol) in anhydrous CH2Cl2 (10 mL) was added in one por-
tion, and the reaction mixture was sonicated for 1 h and concen-
trated in vacuo. Filtration on a column of Florisil using diethyl
ether as eluent allowed the isolation of 17 (160.5 mg, 0.74 mmol,
88%) as a colorless oil, which was stored under nitrogen at –20 °C.
Synthesis of 6 from 19: Trimethylsilyl iodide (64 μL, 0.45 mmol)
was slowly added to a solution of piperidine 19 (114.1 mg,
0.23 mmol) in anhydrous acetonitrile (4 mL) and stirred under ni-
trogen at 0 °C. Ice-bath cooling was maintained for 1 h, then the
IR (NaCl disc): ν
= 3092, 3069, 3035, 2941, 1703, 1650, 1409,
˜
max
1345, 1258, 1179, 1136, 1107, 1040 cm–1. 1H NMR (300 MHz, mixture was warmed progressively to room temp. overnight and the
CDCl3): δ (two rotamers) = 1.79 (m, 2 H, 5-H), 2.00 (m, 2 H, 4- mixture was concentrated under reduced pressure. Aqueous HCl
H), 3.60 (m, 2 H, 6-H), 4.83 (m, 0.5 H, 3-H), 4.94 (m, 0.5 H, 3-H),
(10%, 2 mL) was added to the residue with ice-cooling and the
5.16 (s, 2 H, CH2Ph), 6.78 (d, J = 8.4 Hz, 0.5 H, 2-H), 6.88 (d, J
mixture was washed with diethyl ether. Ground α-tripiperideine
= 8.4 Hz, 0.5 H, 2-H), 7.34–7.40 (m, 5 H, Ar-H) ppm. 13C NMR (22.6 mg, corresponding to 0.27 mmol of Δ1-piperideine) was
(75.3 MHz, CDCl3): δ (two rotamers) = 21.3, 21.5, 21.7 (C-4, C-5),
42.2, 42.4 (C-6), 67.4, 67.5 (CH2Ph), 106.4, 106.8 (C-3), 124.9,
125.4 (C-2), 128.0, 128.1, 128.5, 136.4 (C-Ar), 153.2, 153.6
(NCOOCH2) ppm. EIMS: m/z (%) = 218 (93) [M + H]+, 174 (100),
128 (16), 107 (7), 91 (67), 82 (30), 65 (70).
added to the aqueous solution and the pH was raised to 2.5 by
slow addition of KOH (2 m). After 16 h at room temp. under nitro-
gen the mixture was cooled in an ice bath, basified to pH 9 by
addition of KOH and extracted with CH2Cl2 (3ϫ20 mL). The
combined organic phases were dried and the solvents evaporated
to dryness. The resulting yellow oil was purified by flash
chromatography on silica gel (CH2Cl2/MeOH/NH4OH 10%,
98:2:0.1) to give 6 (49.0 mg, 0.15 mmol, 67%) as a colorless oil.
The spectral properties of the isolated compound were identical to
those recorded for the compound obtained previously starting from
l-lysine.
trans-1-(Benzyloxycarbonyl)-3-iodo-2-methoxypiperidine (18):
A
solution of N-iodosuccinimide (707 mg, 3.14 mmol) in anhydrous
methanol (6 mL) was added under nitrogen to a solution of en-
amine 17 (568.8 mg, 2.62 mmol) in anhydrous CH2Cl2 (3 mL) at
0 °C. Ice-bath cooling was maintained for 1 h, then the mixture
was warmed progressively to room temp. After 16 h, the mixture
was poured into a saturated aqueous solution of NaHCO3. The
aqueous phase was extracted three times with CH2Cl2. The com-
bined organic phases were dried (WA filter) and the solvent re-
moved in vacuo to yield a solid residue that was purified by flash
chromatography on silica gel (hexane/AcOEt, 9:1) affording 18
(855.1 mg, 2.28 mmol, 87%) as a colorless oil. 1H NMR (600 MHz,
trans-2-Allyl-1-(benzyloxycarbonyl)-3-iodopiperidine (21): BF3·OEt2
(44 μL, 0.35 mmol) was added to a stirred solution of 18 (65.5 mg,
0.18 mmol) and allyltrimethylsilane (56 μL, 0.35 mmol) in CH2Cl2
(1 mL) at –78 °C under nitrogen. After 2 h at –78 °C, a saturated
aqueous solution of Na2CO3 was added and the mixture was ex-
tracted with CH2Cl2 (3ϫ5 mL). The combined organic phases
CDCl3): δ (two rotamers) = 1.48 (m, 1 H, 5-Hax), 1.82 (m, 1 H, 5- were dried (WA filter paper) and the solvents evaporated under
Heq), 1.97 (m, 1 H, 4-Hax), 2.08 (m, 1 H, 4-Heq), 2.96 (m, 1 H, 6-
Hax), 3.17 (s, 1.8 H, OCH3), 3.26 (s, 1.2 H, OCH3), 4.00 (m, 1 H,
6-Heq), 4.42 (s, 0.6 H, 3-H), 4.47 (s, 0.4 H, 3-H), 5.18 (s, 2 H,
CH2Ph), 5.48 (s, 0.5 H, 2-H), 5.60 (s, 0.5 H, 2-H), 7.26–7.38 (m, 5
H, H-Ar) ppm. 13C NMR (75.3 MHz, CDCl3): δ (two rotamers) =
28.1 (C-4, C-5), 29.3, 29.6 (C-3), 38.2, 38.6 (C-6), 54.9 (OCH3),
vacuum to dryness. Flash chromatography of the residue on silica
gel (hexane/EtOAc, 8:2) gave 21 (35.3 mg, 0.092 mmol, 52%). 1H
NMR (300 MHz, CDCl3): δ (two rotamers) = 1.48 (m, 2 H, 5-H2),
1.98 (m, 2 H, 4-H2), 2.32 (m, 2 H, 1Ј-H2), 2.80 (br. t, J = 12 Hz, 1
H, 6-Hax), 4.08 (m, 1 H, 6-Heq), 4.45–4.60 (m, 2 H, 3-H, 2-H),
4.93–5.05 (m, 2 H, 3Ј-H2), 5.09 (s, 2 H, CH2Ph), 5.60 (m, 1 H, 2Ј-
67.5 (CH2Ph), 86.0, 86.3 (C-2), 128.0, 128.1, 136.5 (C-Ar), 155.7, H), 7.23–7.40 (m, 5 H, Ar-H) ppm. 13C NMR (75.3 MHz, CDCl3):
155.9 (NCOOCH2) ppm. HRMS (ES): m/z calcd. for C14H18-
INaNO3 398.0229; found 398.0222). MS (EI): m/z (%) = 240 (9)
[M+· – CO2 – CH2Ph], 217 (31) [M+ – I – OCH3], 199 (100), 173
(87), 128 (34) [HI], 119 (22), 110 (39).
δ (two rotamers) = 21.6, 28.9 (C-4, C-5), 31.5 (C-3), 35.0 (C-1Ј),
38.6 (C-6), 59.2 (C-2), 67.2 (CH2Ph), 118.0 (C-3Ј), 127.8, 127.9,
128.4, 136.8 (C-Ar), 155.8 (NCOOCH2) ppm. HRMS (ES): m/z
calcd. for C16H21INO2 386.0617; found 386.0624.
Diethyl trans-2-[(Benzyloxycarbonyl)-3-iodo-2-piperidinyl]malonate
(19): Diethyl malonate (293 μL, 1.93 mmol) was added to a solu-
tion of TiCl4 (212 μL, 1.93 mmol) in CH2Cl2 (1 mL) under nitrogen
at 0 °C. After 5 min, diisopropylethylamine (1.93 mmol) was added
and the reaction mixture was stirred at 0 °C for 1 h and cooled
to –6 °C before dropwise addition of a solution of 18 (603.3 mg,
1.61 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred at
–6 °C for 1 h and then quenched with a saturated aqueous solution
of NH4Cl (2 mL). The aqueous phase was extracted with CH2Cl2,
the combined organic phases were dried, and the solvent was re-
moved under reduced pressure. The crude product was purified by
flash chromatography on silica gel (hexane/ethyl acetate, 8:2) to
trans-1-(Benzyloxycarbonyl)-3-bromo-2-methoxypiperidine
(23):
Compound 23 was prepared (yield: 86%) according to the same
procedure as utilized for preparing 18 from 17, but by using NBS
(1.2 equiv.) instead of NIS. Crude 23 was purified by flash
chromatography on silica gel (hexane/EtOAc, 8:2). 1H NMR
(300 MHz, CDCl3): δ (two rotamers) = 1.44 (m, 1 H, 5-Hax), 1.89
(m, 1 H, 5-Heq), 1.95–2.33 (m, 2 H, 4-H2), 2.98 (m, 1 H, 6-Hax),
3.21 (s, 1.8 H, 1Ј-H), 3.29 (s, 1.2 H, 1Ј-H), 4.04 (m, 1 H, 6-Heq),
4.29 (br. s, 1 H, 3-H), 5.19 (s, 2 H, CH2Ph), 5.44 (s, 0.6 H, 2-H),
5.54 (s, 0.4 H, 2-H), 7.36 (m, 5 H, Ar-H) ppm. 13C NMR
(75.3 MHz, CDCl3): δ (two rotamers) = 26.9 (C-4, C-5), 38.0, 38.4
(C-6), 49.3 (C-3), 54.9, 54.9 (C-1Ј), 67.4 (CH2Ph), 85.1, 85.1 (C-2),
127.8, 128.1, 128.5, 136.4 (Ar-C), 155.7, 155.9 (NCOOCH2) ppm.
HRMS (ES): m/z calcd. for C14H18BrNaNO3 350.0368; found
350.0371.
1
afford 19 (756.5 mg, 2.02 mmol, 93% yield) as a colorless oil. H
NMR (600 MHz, CDCl3): δ (two rotamers) = 1.08 (m, 3 H, 4Ј-H3),
1.27 (td, J = 0.9, 3.3 Hz, 3 H, 4Ј-H3), 1.52 (m, 1 H, 4-Hax), 1.82
Eur. J. Org. Chem. 2011, 2346–2353
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2351

A. Rouchaud, J.-C. Braekman
61%) as a colorless oil. IR (NaCl disc): ν = 2933, 2858, 2789,
FULL PAPER
trans-3-Bromo-2-methoxy-1-(methoxycarbonyl)piperidine
(25):
˜
max
Compound 25 was prepared (yield: 81%) according to the same
procedure as utilized for preparing 18 from 16, but by using NBS
(1.2 equiv.) instead of NIS and methyl chloroformate instead of
benzyl chloroformate. Crude 25 was purified by flash chromatog-
raphy on silica gel (hexane/EtOAc, 7:3). 1H NMR (300 MHz,
2727, 1713, 1653, 1447, 1378, 1240, 1131, 1102 cm–1. 1H NMR
(600 MHz, CDCl3): δ = 1.26 (m, 1 H, 8-Hα), 1.34 (qd, J = 2.4,
4.2 Hz, 1 H, 9-Hα), 1.47 (qt, J = 2.1, 6.3 Hz, 1 H, 7-Hα), 1.60 (m,
1 H, 7-Hβ), 1.65 (m, 1 H, 3-Hα), 1.76 (m, 1 H, 2-Hα), 1.77–1.85
(m, 4 H, 2-Hβ, 3-Hβ, 8-Hβ, 9-Hβ), 1.96 (td, J = 1.2, 6.0 Hz, 1 H, 6-
CDCl3): δ (two rotamers) = 1.66 (m, 1 H, 5-Hax), 1.90 (m, 1 H, 5- Hα), 2.19 (s, 3 H, 3Ј-H3), 2.50 (m, 2 H, 4-Hα, 9a-Hα), 2.57 (m, 1
Heq), 1.97–2.09 (m, 2 H, 4-Hax, 4-Heq), 2.97 (m, 1 H, 6-Hax), 3.28 H, 1Ј-H), 2.64 (m, 1 H, 1-Hα), 2.82 (dd, J = 2.4, 8.4 Hz, 1 H, 1Ј-
(s, 2 H, 1Ј-H3), 3.34 (s, 1 H, 1Ј-H3), 3.74 (s, 1 H, CO2CH3), 3.76 H), 2.84 (m, 1 H, 1-Hβ), 2.90 (br. d, J = 5.4 Hz, 1 H, 6-Hβ), 3.24
(s, 2 H, CO2CH3), 4.00 (m, 1 H, 6-Heq), 4.31 (br. s, 1 H, 3-H), 5.34 (qd, J = 1.2, 2.4 Hz, 1 H, 3a-Hα) ppm. 13C NMR (75.3 MHz,
(m, 0.5 H, 2-H), 5.50 (m, 0.5 H, 2-H) ppm. 13C NMR (75.3 MHz, CDCl3): δ = 23.0 (C-8), 25.0 (C-7), 25.3 (C-2), 30.1 (C-3), 31.1 (C-
CDCl3): δ (two rotamers) = 26.9 (C-4, C-5), 37.0, 37.4, 38.0, 38.3
3Ј), 31.8 (C-9), 46.2 (C-1Ј), 50.0 (C-6), 51.2 (C-1), 65.3 (C-4), 69.1
(C-6), 49.1 (C-3), 52.9 (NHCOOCH3), 54.9, 55.3, 55.7 (C-1Ј), 84.4, (C-3a), 86.4 (C-9a), 207.7 (C-2Ј) ppm. HRMS (ES): m/z calcd. for
84.7, 85.2 (C-2), 153.6, 154.0 (NHCOOCH3) ppm. HRMS (ES):
m/z calcd. for C8H14BrNaNO3 274.0055; found 274.0058.
C13H23N2O 223.1810; found 223.1804.
2-(Trimethylsilyloxy)-1-dodecene: Diisopropylamine (1.38 mL,
9.79 mmol) and nBuLi (1.38 m in hexane, 7.11 mL, 9.79 mmol)
were added successively under vigorous stirring to freshly distilled
THF (4 mL) under nitrogen at –78 °C. After 2 min, triethylamine
[1-(Benzyloxycarbonyl)-3-bromopiperidinyl]acetone (24): A solution
of 23 (564 mg, 1.61 mmol) in CH2Cl2 (0.8 mL) was added to a solu-
tion of TiCl4 (177 μL, 1.61 mmol) in CH2Cl2 (1 mL) under nitrogen
at –78 °C, followed directly by addition of isopropenylacetate
(266 μL, 2.42 mmol). The reaction mixture was stirred at –78 °C
for 1 h and then warmed progressively to room temp. After one
night, the reaction mixture was poured into a mixture of cold brine
and CH2Cl2 and stirred for 10 min. The organic layer was sepa-
rated, and the aqueous layer was extracted with CH2Cl2. The com-
bined organic layer was dried and the solvent was removed under
reduced pressure. The crude product was purified by flash
chromatography on silica gel (hexane/EtOAc, 6:4) to afford 24
(108 mg, 0.29 mmol, 18% yield) as a colorless oil. 1H NMR
(300 MHz, CDCl3): δ = 1.44 (m, 1 H, 4-Hax), 1.62 (m, 1 H, 4-Heq),
2.03 (m, 2 H, 3-Hax, 3-Heq), 2.14 (s, 3 H, 3Ј-H3), 2.74 (d, J = 7.4 Hz,
(1.25 mL,
8.89 mmol),
chlorotrimethylsilane
(2.26 mL,
17.79 mmol), and 2-dodecanone (2 mL, 8.9 mmol) were added suc-
cessively. After 15 min at –78 °C, the temperature was progressively
allowed to rise to room temp. After one night, water was added
and the mixture was extracted three times with pentane. The pen-
tane extract was dried (WA filter paper) and the solvents evapo-
rated under vacuum to dryness to give 2-(trimethylsilyloxy)-1-dode-
cene (1.868 g, 7.29 mmol, 82%). 1H NMR (600 MHz, CDCl3): δ =
0.25 [s, 9 H, Si(CH3)3], 0.94 (t, J = 6.3 Hz, 3 H, 12-CH3), 1.33 (br.
s, 14 H), 1.50 (m, 2 H, 4-H), 2.05 (t, J = 7.7 Hz, 2 H, 3-H), 4.08
(s, 2 H, 1-H) ppm. 13C NMR (75.3 MHz, CDCl3): δ = 2.8
[Si(CH3)3], 14.3 (C-12), 22.9, 27.0, 29.3, 29.6, 29.7, 29.8, 29.9, 32.1,
2 H, 1Ј-H2), 2.88 (m, 1 H, 5-Hax), 4.16 (m, 1 H, 5-Heq), 4.41 (br. s, 36.7 (C-3), 89.9 (C-1), 159.8 (C-2) ppm.
1 H, 2-H), 5.02 (m, 1 H, 1-H), 5.15 (s, 2 H, CH2Ph), 7.35 (m, 5 H,
3-Bromo-2-(2-oxododecanyl)-1-(methoxycarbonyl)piperidine (27): A
Ar-H) ppm. 13C NMR (75.3 MHz, CDCl3): δ = 26.4, 27.8, 30.1,
36.2, 39.4, 50.0, 54.6, 67.5, 127.9, 128.1, 128.6, 136.6, 155.9,
207.0 ppm. HRMS (ES): m/z calcd. for C16H20BrNaNO3 376.0524;
found 376.0519.
solution of 25 (33.2 mg, 0.13 mmol) in CH2Cl2 (0.1 mL) was added
to a solution of TiCl4 (14.5 μL, 0.13 mmol) in CH2Cl2 (0.3 mL)
under nitrogen at –78 °C. Immediately thereafter, a solution of 2-
(trimethylsilyloxy)-1-dodecene (57.3 mg, 0.22 mmol) in CH2Cl2
(0.1 mL) was added. The reaction mixture was stirred at –78 °C for
1 h and then warmed progressively to room temp. After one night,
a brine solution was added and the resulting mixture was extracted
[3-Bromo-1-(methoxycarbonyl)piperidinyl]acetone (26): Compound
26 was prepared (77% from 25) according to the same procedure
utilized for the preparation of 24 from 23. 1H NMR (300 MHz,
CDCl3): δ = 1.44 (m, 1 H, 4-Hax), 1.62 (m, 1 H, 4-Heq), 2.02 (m, 2 three times with CH2Cl2. The organic extracts were gathered, dried
H, 3-Hax, 3-Heq), 2.14 (s, 3 H, 3Ј-H3), 2.68 (dd, J = 7.0, 15.0 Hz, 1 (WA filter paper) and the solvents evaporated in vacuo to dryness.
H, 1Ј-H), 2.73 (dd, J = 7.0, 15.0 Hz, 1 H, 1Ј-H), 2.79 (m, 1 H, 5- Flash chromatography of the residue on silica gel (hexane/EtOAc,
Hax), 3.65 (s, 3 H, CO2CH3), 4.06 (m, 1 H, 5-Heq), 4.33 (br. s, 1 H,
7:3) gave 27 (31.9 mg, 0.079 mmol, 60%) as a colorless oil. IR
2-H), 4.90 (m, 1 H, 1-H) ppm. 13C NMR (75.3 MHz, CDCl3): δ = (NaCl disc): νmax = 2926, 2853, 1702, 1444, 1410, 1368, 1264, 1204,
˜
27.0, 29.8, 30.8, 38.1, 40.5, 49.7, 52.7, 53.1, 155.6, 207.0 ppm.
HRMS (ES): m/z calcd. for C10H16BrNaNO3 300.0211; found
300.0210.
1187, 1114 cm–1. 1H NMR (300 MHz, CDCl3): δ = 0.88 (t, J =
6.4 Hz, 3 H, 12Ј-H), 1.26 (br. s, 16 H), 1.54 (m, 2 H, 5-Hax, 5-Heq),
2.02 (m, 2 H, 4-Hax, 4-Heq), 2.44 (t, J = 6.9 Hz, 2 H, 3Ј-H), 2.71
(dd, J = 3.0, 8.0 Hz, 2 H, 1Ј-H), 2.86 (m, 1 H, 6-Hax), 3.71 (s, 3 H,
OCH3), 4.15 (m, 1 H, 6-Heq), 4.40 (br. s, 1 H, 3-H), 4.94 (m, 1 H,
2-H) ppm. 13C NMR (75.3 MHz, CDCl3): δ = 14.1 (C-12Ј), 22.66,
22.69, 23.6, 27.7, 29.1, 29.3, 29.3, 29.4, 29.4, 29.4, 29.5, 29.5, 29.5,
29.5, 29.6, 31.9, 31.9, 31.9, 39.1 (C-3Ј), 43.0 (C-1Ј), 43.5 (C-6), 50.7
(C-3), 52.9 (NHCOOCH3), 54.5 (C-2), 156.3 (NHCOOCH3), 207.8
(C-2Ј) ppm. HRMS (ES): m/z calcd. for C19H34BrNaNO3
426.1620; found 426.1628
Synthesis of 28: Trimethylsilyl iodide (167 μL, 1.16 mmol) was
slowly added to a solution of 26 (108.0 mg, 0.39 mmol) in anhy-
drous acetonitrile (7 mL) at room temp. under nitrogen. After one
night, the mixture was concentrated under reduced pressure and
aqueous HCl (10%, 10 mL) was added to the residue. The resulting
solution was washed with diethyl ether, then ground α-tripiperidein
(38.8 mg, 0.47 mmol of Δ1-piperidein) was added to the acid aque-
ous solution. The pH was raised to 2.5 by slow addition of KOH
(2 m) and the mixture was stirred at this pH overnight at room
temp. under nitrogen. The mixture was basified to pH 9 by addition
of KOH (2 m) with ice cooling and then extracted with CH2Cl2
(3ϫ20 mL). The organic phases were combined, dried (WA filter
paper), concentrated in vacuo to dryness, and the residual yellow
oil was purified by flash chromatography on silica gel (CH2Cl2/
Formation of 29 from 27: Trimethylsilyl iodide (113 μL, 0.80 mmol)
was added to a solution of 27 (106.9 mg, 0.26 mmol) in anhydrous
chloroform under nitrogen at 0 °C. The mixture was heated at re-
flux for 24 h, and the solution was then evaporated to dryness un-
der vacuum, and aqueous HCl (10%, 7 mL) was added. The aque-
ous acid solution was extracted with diethyl ether and the organic
MeOH/NH4OH 10%, 97:3:0.1) to give 28 (52.8 mg, 0.24 mmol, layer was evaporated in vacuo to dryness. Aqueous HCl (10%,
2352
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Eur. J. Org. Chem. 2011, 2346–2353

Octahydro-4H-pyrrolo[1,2-c]pyrido[1Ј,2Ј-a]imidazole Derivatives
4 mL) and α-tripiperidein (25.9 mg, 0.32 mmol of Δ1-piperidein)
were added successively to the residue. The pH was increased to
2.7, and maintained constant at this value by dropwise addition of
aqueous KOH (2 m). After one night of stirring at room temp. the
mixture was brought to pH 9 and extracted three times with
CH2Cl2. The organic layers were combined, dried (WA filter paper)
and the solvents evaporated to dryness in vacuo. Flash chromatog-
raphy of the residue on silica gel (CH2Cl2/MeOH/NH4OH 10%,
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95:5:0.1) gave 29 (48.5 mg, 0.14 mmol, 54%) as a colorless oil. H
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NMR (600 MHz, CDCl3): δ = 0.88 (t, J = 7.2 Hz, 3 H, 12Ј-H3),
1.26 (br. s, 15 H, 8-Hα, 5Ј-H2, 6Ј-H2, 7Ј-H2, 8Ј-H2, 9Ј-H2, 10Ј-H2,
11Ј-H2), 1.55 (m, 3 H, 7-Hα, 4Ј-H2), 1.64 (br. d, J = 14 Hz, 1 H, 7-
Hβ), 1.70 (qd, J = 3.6, 10.2 Hz, 1 H, 9-Hα), 1.87 (m, 2 H, 3-Hα, 8-
Hβ), 1.98 (m, 5 H, 2-Hα, 2-Hβ, 3-Hβ, 6-Hα, 9-Hβ), 2.44 (t, J =
7.2 Hz, 2 H, 3Ј-H2), 2.62 (m, 1 H, 1Ј-H), 2.69 (m, 1 H, 4-Hα), 2.76
(dd, J = 3.0, 10.2 Hz, 1 H, 9a-Hα), 2.85 (m, 2 H, 1-Hα, 1Ј-H), 2.92
(br. d, J = 11 Hz, 1 H, 6-Hβ), 3.23 (m, 1 H, 1-Hβ), 3.62 (td, J =
4.8, 7.2 Hz, 1 H, 3a-Hα) ppm. 13C NMR (75.3 MHz, CDCl3): δ =
14.2 (C-12Ј), 22.7, 22.8, 23.7, 24.3, 25.2, 29.0, 29.2, 29.3, 29.4, 29.5,
29.6, 32.0 (C-3), 43.8 (C-3Ј), 31.8 (C-9), 44.7 (C-1Ј), 49.5 (C-6),
50.2 (C-1), 64.1 (C-4), 69.6 (C-3a), 85.0 (C-9a), 209.3 (C-2Ј) ppm.
HRMS (ES): m/z calcd. for C22H41N2O 349.3219; found 349.3212.
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One of us (A. R.) would like to thank the Fonds pour la Formation
à la Recherche dans l’Industrie et l’Agriculture (FRIA) for finan-
cial support. The authors would also like to thank Dr. M. Luhmer
and Mrs. R. d’Orazio for the NMR spectra, Mr. M. Pamart for
the mass spectra. Entomed S.A. is gratefully acknowledged for fi-
nancial support.
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Received: December 20, 2010
Published Online: March 15, 2011
Eur. J. Org. Chem. 2011, 2346–2353
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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