Enantiopure 2-piperidylacetaldehyde as a useful building block in the diversity-oriented synthesis of polycyclic piperidine derivatives

Article abstract of DOI:10.1016/j.tetasy.2011.01.008

Novel, simple, and convenient strategies for diversely functionalized piperidine derivatives have been developed by using different metal catalyzed reactions starting from enantiopure (R)- and (S)-2-piperidylacetaldehyde.

Full text of DOI:10.1016/j.tetasy.2011.01.008

Tetrahedron: Asymmetry 22 (2011) 264–269
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantiopure 2-piperidylacetaldehyde as a useful building block in the
diversity-oriented synthesis of polycyclic piperidine derivatives
Elena Borsini a, Gianluigi Broggini a, , Francesco Colombo b, Maisaa Khansaa a, Andrea Fasana a,
⇑
b
c
Simona Galli a, Daniele Passarella b, , Elena Riva , Sergio Riva
⇑
a Dipartimento di Scienze Chimiche e Ambientali, Università degli Studi dell’Insubria, Via Valleggio 11, 22100 Como, Italy
b Dipartimento di Chimica Organica e Industriale, Università degli Studi di Milano, Via Venezian 21, 20133 Milano, Italy
c Istituto di Chimica del Riconoscimento Molecolare, CNR, Via Mario Bianco 9, 20131 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 December 2010
Accepted 12 January 2011
Novel, simple, and convenient strategies for diversely functionalized piperidine derivatives have been
developed by using different metal catalyzed reactions starting from enantiopure (R)- and (S)-2-
piperidylacetaldehyde.
Ó 2011 Elsevier Ltd. All rights reserved.
O
H
1. Introduction
O
2-Piperidylacetaldehyde 1 has been proven to be a successful
synthon in the convenient syntheses of several 2-piperidyl alka-
loids, some of which are described in Figure 1.1
The syntheses were based upon exploitation of the electrophilic
character of the aldehyde group and took advantage of the pres-
ence of the installed stereogenic center at the 2-position of the
piperidine ring.
N
N
H
H
N
Ref. 1a
Me
(+)-aloperine
Refs.
(+)-dumetorine
1a, 1c
H
CHO
The attractiveness of the piperidine-based skeletons2 and the
interest towards transition metal catalyzed reactions prompted
us to search new synthetic strategies to obtain fused- and spiro-
ring structures containing a piperidine unit in enantiopure form
(Fig. 2). In order to achieve such a goal, we relied on the easy avail-
ability of enantiopure (R)- and (S)-2-allylpiperidines 2, obtained by
Wittig reaction on the aldehyde derivative 1.1b We envisioned
some suitable reactions to functionalize the piperidyl nitrogen
aimed at paving the way to a range of intramolecular transition
metal catalyzed reactions involving the allylic carbon–carbon dou-
ble bond. Herein we report some synthetic procedures based on
Pd(0)-, Pd(II)- and Ru-catalyzed reactions to access useful enantio-
pure six- or seven-membered rings fused on the piperidine moiety,
products whose analogues already show interesting properties.3
Moreover, as most of them present a carbon–carbon double bond
susceptible to further functionalization, their intrinsic value and
molecular complexity was increased by subsequent transforma-
tion into tri- or tetracyclic compounds.
N
Boc
(S)-1
Ref. 1b
OH
Ref. 1d
H
H
R2
N
R1
N
H
(-)-coniine
R1=R2=Me α−OH (-)-sedamine
R1=H, R2=Et β−OH (+)-2'-ethylnorlobelol
R1=H, R2=Ph β−OH (+)-sedridine
Figure 1. Previously reported synthesis of 2-piperidyl alkaloids.
2. Results and discussion
2.1. A synthetic sequence based on intramolecular Heck
reactions
⇑
Corresponding authors. Tel.: +39 031 2386444; fax: +39 031 2386449 (G.B.);
In the context of our studies on the Pd(0)-catalyzed reactions,4
we first took into consideration compound 3, suitable for intramo-
lecular Heck reactions.
tel.: +39 02 50314081; fax: +39 02 50314078 (D.P.).
E-mail addresses: gianluigi.broggini@uninsubria.it (G. Broggini), daniele.passar-
ella@unimi.it (D. Passarella).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.01.008

E. Borsini et al. / Tetrahedron: Asymmetry 22 (2011) 264–269
265
former procedure (76% vs 38% yield). The presence of the exome-
thylenic carbon–carbon double bond on compound (R)-4 furnished
the means to reach more complex spiro-annulated structures by
1,3-dipolar cycloadditions, exploiting our expertise in this field.6
The dipolarophilic behaviour of the exocyclic carbon–carbon dou-
ble bond was proven toward the 3,5-dichloro-2,4,6-trimethylbenz-
onitriloxide 5, chosen as 1,3-dipole due to its excellent stability.7
The reaction between (R)-4 and 5 was performed in toluene at re-
flux by using equimolar amounts of the reactants. The nitrile oxide
intramolecular cycloaddition took place regioselectively according
to the results reported in the literature8 and gave a mixture of two
diastereoisomeric products in an approximately 2:1 ratio, which
were isolated by column chromatography in 42% and 29% yield,
respectively. The 11–50 junction of the pyrido[1,2-b][2]benzaze-
pine-isoxazole system was inferred by the 1H and 13C NMR data,
in particular by the geminal coupling constants greater than
17 Hz, which is compatible only with the methylenic group at a
4-position of the isoxazole ring.9 The distinction between the dia-
stereoisomeric spiro-compounds 6 and 7 was established by an X-
ray diffraction analysis on 6 (Fig. 3).
(R)-1
H
N
R
H
H
N
N
H
O
N
N
O
O
Cl
Ar
O
N
N
Ar
NO2
Figure 2. Diversity-oriented approach towards piperidine-containing structures.
Removal of the terbutoxycarbonyl group from (R)-2 with TFA
and treatment of a toluene solution of the deprotected piperidine
with the commercially available 2-iodobenzyl bromide in the pres-
ence of K2CO3 gave the (R)-2-allyl-1-(2-iodobenzyl)-piperidine 3
(Scheme 1). The Heck reaction was performed either in the pres-
ence of Pd(PPh3)4 as catalyst and TEA as base in acetonitrile, or un-
der ligand-free conditions5 in the presence of Pd(OAc)2 as catalyst,
Na2CO3 and Bu4NCl in DMF. Both procedures were effective in pro-
moting the formation of the pyrido[1,2-b][2]benzazepine deriva-
tive (R)-4, even if the best result was obtained working with the
Figure 3. ORTEP plot of the molecular structure of compound 6 at 30% probability
level.
The synthetic sequence described in Scheme 1 was also carried
out on the enantiomeric 2-allylpiperidine (S)-2, affording
(11R,12aS)-6 and (11S,12aS)-7 in yields similar to those obtained
from (R)-2. HPLC analysis with ODH chiral column, performed on
both enantiomers of compounds 6 and 7, proved a 90% enantio-
meric excess for the ones deriving from (R)-1 and 95% for those
deriving from (S)-110,1d to strengthen the configurational stability
of the early stereogenic center.
N
I
H
1) TFA, 0°C - r.t.
I
N
H
2)
Boc
, K2CO3
Br
toluene, 70°C
(R)-2
(R)-3 (94%)
2.2. Synthetic sequence based on intramolecular Pd(II)-
catalyzed chloroamination
H
Ar
C
N
O
Pd(PPh3)4 10%
TEA
N
5
The Pd(II)-catalyzed functionalization of unactivated C–H bonds
is a challenging field in organic chemistry,11 where we recently re-
ported our interest.12 Recent literature seems particularly attracted
by the reactions achieving a double functionalization of double
bonds, more specifically towards diamination or heteroamination
processes.13 In this light, the appropriate functionalization of
piperidine nitrogen could exploit the reactivity of the ethylenic
double bond of compound 2 toward Pd(II)-catalysis (Scheme 2).
Removal of the terbutoxycarbonyl group by TFA and subsequent
reaction with 4-nitro-phenylisocyanate afforded compound (R)-8,
which bears a nucleophile nitrogen atom. This compound easily re-
acts with the carbon–carbon double bond using Pd(CH3CN)2Cl2 as a
catalyst and CuCl2 as an oxidant; the high amount of CuCl2 war-
rants the significant presence of chloride anions in the reaction
toluene, reflux
MeCN, reflux
(R)-4 (68%)
Me
Cl
Me
Ar =
Me
H
H
N
N
Cl
O
O
N
N
Ar
Ar
medium, thus letting them intercept the
r-alkyl-palladium inter-
(11S,12aR)-6 (42%)
(11R,12aR)-7 (29%)
mediate before a competitive b-hydride elimination process could
occur.14 Consequently, bicyclic pyrido[1,2-c]pyrimidinone (3S,
4aR)-9 is formed (ee 90%). This chlorinated product, whose
Scheme 1. Growing molecular complexity by an intramolecular Heck reaction/
intermolecular 1,3-dipolar cycloaddition sequence.

266
E. Borsini et al. / Tetrahedron: Asymmetry 22 (2011) 264–269
H
H
(R)
Pd(CH3CN)2Cl2 5%
1) TFA, 0°C - r.t.
N
N
(R)-2
H
(S)
N
CuCl2
DMF, 100°C
2)
4-NO2-phenyl
isocyanate
THF, r.t.
O
O
NH
Cl
NO2
(3S,4aR)-9 (32%)
Scheme 2. Growing the molecular complexity by an intramolecular oxidative Pd(II)-catalyzed chloroamination reaction.
NO2
(R)-8 (72%)
stereochemistry has been assigned by a NOESY experiment, arises
from a domino chloroamination process.
Also in this case, the reaction performed on the (S)-2 enantio-
mer led to (3R,4aS)-9 in 95% enantiomeric excess by HPLC
analysis.10,1d
case of the 1,1-disubstituted ethylenic compound (R)-4, the out-
come of the cycloaddition on the 1,2-disubstituted ethylenic dou-
ble bond was totally regioselective, allowing the formation of a
4,5-dihydroisoxazole product in 72% yield. Spectroscopic data
was in agreement with the structure (3aR,9aR,10aR)-13, with the
carbonyl group at the 4-position of the newly formed isoxazoline.
HPLC analysis with an ODH chiral column proved a 90% enantio-
meric excess.10
2.3. Synthetic sequence based on the RCM reaction
The application of ring closing metathesis to build large- and
medium-ring heterocycles has greatly increased in recent years,
due to the high efficiency this process usually warrants.15 Starting
once more for substrate (R)-2, we thought to built a six-membered
fused-ring on the piperidine by a RCM process performed on a sub-
strate obtained by functionalization of the nitrogen with an acry-
loyl group (Scheme 3). The reaction of the deprotected allyl
piperidine with acryloyl chloride furnished the appropriate sub-
strate (R)-10, containing two ethylenic double bonds, which lie
juxtaposed for the construction of a six-membered fused-ring.
The presence of an amide group should allow an easy outcome of
RCM.16 In fact, amide (R)-10, treated with a Grubbs catalyst of
2nd generation 11 in DCM at reflux, furnished hexahydroquinolizi-
none (R)-12 in quantitative yield.17 The reaction proceeds through
an initial coordination of the Ru-species to the allylic carbon–car-
bon double bond; the olefin metathesis of electron-poor double
bonds was less favoured compared to neutral olefins because of
the relative instability of electron-deficient metal carbene bonds.18
From a stereochemical point of view, the cycloaddition process
exclusively allowed a cis-disposition of the two new stereocentres,
the relative configuration of which, with respect to the pre-existing
one, was proven to be trans by X-ray diffraction analysis (Fig. 4). Fi-
nally, we performed the RCM/nitriloxide cycloaddition sequence
on the (S)-2 enantiomer, achieving the final product (3aS,9a-
S,10aS)-13 with a 95% enantiomeric excess.10
11
1) TFA, 0°C - r.t.
Figure 4. ORTEP plot of the molecular structure of compound 13 at 30% probability
level.
(R)-2
N
H
O
CH2Cl2, reflux
2)
Cl
O
TEA, CH2Cl2
(R)-10 (70%)
3. Conclusion
Mes
Cl
N
N
Mes
Ph
Ru
PCy3
In conclusion, the easy conversion of aldehyde 1 into the con-
formationally stable 2-allylpiperidine synthon 2 made a diver-
sity-oriented approach possible by exploiting the reactivity of the
vinyl moiety towards metal catalyzed intramolecular reactions.
The compounds obtained present a visibly increased molecular
complexity which confirms the value of 2-pyperidinylacetaldeyde
as a synthon for the generation of diversified collections of prod-
ucts in both enantiomeric series.
Cl
H
H
(R)
N
5
Grubbs II
N
11
(R)
toluene, reflux
(R)
O
O
O
N
(R)-12 (98%)
Ar
(3aR,9aR,10aR)-13 (72%)
4. Experimental section
4.1. General
Scheme 3. Growing molecular complexity by a RCM/intermolecular 1,3-dipolar
cycloaddition sequence.
Next, we decided to increase the molecular complexity of our
product by employing the endocyclic double bond as a dipolaro-
phile in a 1,3-dipolar cycloaddition with nitriloxide 5. As in the
Enantiomerically enriched (R)-2 and (S)-2 were prepared as
previously described.1b Melting points were determined on a Büchi

E. Borsini et al. / Tetrahedron: Asymmetry 22 (2011) 264–269
267
B-540 heating apparatus and are uncorrected. Optical rotations
were measured on a Jasco P-1010 polarimeter. 1H NMR and
13C NMR spectra were obtained on an AVANCE Bruker 400 spec-
trometer. Chemical shifts are given in ppm downfield from SiMe4;
13C NMR spectra are 1H-decoupled and the determination of the
multiplicities was achieved by the APT pulse sequence. IR spectra
were recorded on a Jasco FT/IR 5300 spectrophotometer. Mass
spectra were determined on a WG-70EQ instrument. Elemental
analyses were executed on CHN Analyzer. Column chromatogra-
phy was performed on a Merck silica gel 60, (mesh size 63–
213 (M+). Anal. Calcd for C15H19N: C, 84.46; H, 8.96; N, 6.57. Found:
C, 84.31; H, 9.05; N, 6.43.
4.3.1. (S)-11-Methylene-1,2,3,4,6,11,12,12a-octahydro
pyrido[1,2-b][2]benzazepine (S)-4
Obtained in 71% yield from (S)-3 according to the procedure de-
scribed for its enantiomer. ½a D23
¼ þ44:5 (c 0.31, CHCl3). Anal.
ꢁ
Calcd for C15H19N: C, 84.46; H, 9.05; N, 6.57. Found: C, 84.52; H,
8.88; N, 6.70.
200 l
m). Chiral HPLC was performed using ChiralpakÒ AD column
4.4. Cycloaddition reaction of 4 with 3,5-dichloro-2,4,6-
trimethylbenzonitriloxide 5
(0.46_25 cm, Daicel industries) with Merck Hitachi L 7100 chro-
matograph coupled with DAD Hp 1050.
Compound 5 (65.8 mg, 0.289 mmol) was added to a solution of
(R)-4 (61.0 mg, 0.29 mmol) in dry toluene (1.5 mL). The reaction
mixture was refluxed for 12 h, then the solvent was evaporated un-
der reduced pressure. The crude was purified by silica gel column
chromatography (AcOEt/MeOH 98:2) to afford 6 and 7.
4.2. Preparation of (R)-2-allyl-1-(2-iodobenzyl)-piperidine (R)-3
A solution of compound (R)-2 (355 mg, 1.58 mmol) in trifluoro-
acetic acid (1.8 mL, 23.65 mmol) was stirred under a nitrogen
atmosphere for 3 h at room temperature. After evaporation of the
solvent, the residue was dissolved in anhydrous toluene (4 mL)
and the resulting solution was dropped in a suspension of K2CO3
4.4.1. (11S,12aR)-30-(3,5-Dichloro-2,4,6-trimethylphenyl)-
spiro{pyrido[1,2-b][2]benzazepine-11,50-isoxazole}
(11S,12aR)-6
(6.45 g,
46.7 mmol)
and
2-iodobenzylbromide
(468 mg,
1.58 mmol) in anhydrous toluene (12 mL) at 40 °C. Then the reac-
tion mixture was heated to 70 °C overnight. Ice-cold water (22 mL)
was added to the reaction mixture and then extracted by Et2O
(2 ꢀ 17 mL). The organic layer was dried over Na2SO4, filtered
and concentrated under vacuum. The crude was purified by silica
gel column chromatography (hexane/AcOEt 98:2) to afford (R)-3
Yield: 42%. White solid. Mp 185–186 °C (diisopropyl ether).
½
a 2D3
ꢁ
¼ þ33:3 (c 0.27, CHCl3). 1H NMR (400 MHz, CDCl3) d: 1.15–
1.25 (m, 2H), 1.38–1.52 (m, 1H), 1.58–1.74 (m, 3H), 2.13–2.35
(m, 2H), 2.19 (s, 3H), 2.24 (s, 3H), 2.38–2.49 (m, 2H), 2.53 (s, 3H),
2.80–2.89 (m, 1H), 3.29, 3.39 (AB system, J = 17.5 Hz, 2H), 3.62,
4.29 (AB system, J = 14.8 Hz, 2H), 7.14 (d, J = 7.4 Hz, 1H), 7.25–
7.43 (m, 2H), 7.63 (d, J = 7.4 Hz, 1H). 13C NMR (100 MHz, CDCl3)
d: 18.5 (q), 19.4 (q), 24.7 (t), 26.6 (t), 33.5 (t), 48.0 (t), 54.4 (t),
55.2 (t), 59.1 (d), 59.4 (t), 90.8 (s), 125.9, (d), 128.5 (d), 129.2 (s),
130.3 (s), 130.9 (d), 133.7, (s), 133.9 (s), 135.9 (s), 142.8 (s),
156.6 (s). MS: m/z 442 (M+). Anal. Calcd for C25H28Cl2N2O: C,
67.72; H, 6.36; N, 6.32. Found: C, 67.67; H, 6.21; N, 6.33.
in 94% yield. Pale yellow oil. ½a D23
ꢁ
¼ þ31:1 (c 1.09, CHCl3). 1H
NMR (400 MHz, CDCl3) d: 1.32–1.61 (m, 4H), 1.63–1.78 (m, 2H),
2.17–2.28 (m, 1H), 2.30–2.45 (m, 2H), 2.50–2.62 (m, 1H), 2.68–
2.76 (m, 1H), 3.39, 3.91 (AB system, J = 14.8 Hz, 2H), 5.03 (d,
J = 9.6 Hz, 1H), 5.05 (d, J = 17.6 Hz, 1H), 5.84 (ddt, J = 9.6, 17.6,
7.1 Hz, 1H), 6.94 (dd, J = 7.3, 7.8 Hz, 1H), 7.33 (dd, J = 7.3, 7.5 Hz,
1H), 7.54 (d, J = 7.5 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H). 13C NMR
(100 MHz, CDCl3) d: 23.3 (t), 26.1 (t), 30.6 (t), 35.9 (t), 51.7 (t),
60.8 (d), 62.9 (t), 100.6 (s), 116.8 (t), 128.5 (d), 128.8 (d), 130.5
(d), 136.7 (d), 139.6 (d), 142.6 (s). MS: m/z 341 (M+). Anal. Calcd
for C15H20IN: C, 52.80; H, 5.91; N, 4.10. Found: C, 52.95; H, 5.83;
N, 4.28.
Single crystals suitable for X-ray diffraction were obtained
from CHCl3. Relevant crystal data for 6: C25H28Cl2N2O, FW =
443.4 g molꢂ1
,
yellow prism. k(Mo-Ka) = 0.71073 Å, T = 298 K;
monoclinic P21/n, a = 5.353(2), b = 25.465(9), c = 16.758(6) Å, V =
2275(1) Å3, Z = 4, F(000) = 936,
q , l(Mo-Ka) =
calc = 1.294 g cmꢂ3
0.305 mmꢂ1. With 268 parameters, the R, wR figures of merit
reached final values of 0.046, 0.106 for the 1605 observed reflec-
tions [I >2r(I)], and of 0.072, 0.121 for the 2255 unique reflections.
4.2.1. (S)-2-Allyl-1-(2-iodobenzyl)-piperidine (S)-3
Obtained in 92% yield from (S)-2 according to the procedure de-
Goodness of fit, highest peak and deepest hole reached final values
of 1.046, 0.12 e Åꢂ3 and ꢂ0.13 e Åꢂ3. The crystallographic data
(excluding structure factors) for 6 have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publications number 802924. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK, (fax: +44 (0)1223 336033 or e-mail: deposit@
ccdc.cam.ac.uk).
scribed for its enantiomer. ½a D23
¼ ꢂ32:0 (c 1.12, CHCl3). Anal.
ꢁ
Calcd for C15H20IN: C, 52.80; H, 5.91; N, 4.10. Found: C, 52.78; H,
5.97; N, 4.03.
4.3. Preparation of (R)-11-methylene-1,2,3,4,6,11,12,12a-
octahydropyrido[1,2-b][2]benzazepine (R)-4
At first, Pd(PPh3)4 99% (108.71 mg, 0.09 mmol) and triethyl-
amine (389 lL, 2.79 mmol) were added to a solution of (R)-3
4.4.1.1. (11R,12aS)-30-(3,5-Dichloro-2,4,6-trimethylphenyl)-spiro-
(317.8 mg, 0.93 mmol) in anhydrous acetonitrile (10 mL). The reac-
tion mixture was refluxed for 2 h, and then the solvent was evap-
orated under reduced pressure. Water (10 mL) was added to the
residue and then extracted by CH2Cl2 (2 ꢀ 10 mL). The organic
phase was dried over Na2SO4, filtered and concentrated under vac-
uum. The crude was purified by silica gel column chromatography
(hexane/AcOEt 5:1) to afford (R)-4 in 68% yield. Dark yellow oil.
{pyrido[1,2-b][2]benzazepine-11,50-isoxazole}
(11R,12aS)-6.
Obtained in 39% yield from (S)-4 according to the procedure de-
scribed for its enantiomer. ½a D23
¼ ꢂ34:9 (c 0.28, CHCl3). Anal.
ꢁ
Calcd for C25H28Cl2N2O: C, 67.72; H, 6.36; N, 6.32. Found: C,
67.75; H, 6.45; N, 6.18.
a 2D3
ꢁ
¼ ꢂ41:8 (c 0.25, CHCl3). 1H NMR (400 MHz, CDCl3) d: 1.32–
4.4.2. (11R,12aR)-30-(3,5-Dichloro-2,4,6-trimethylphenyl)-
spiro{pyrido[1,2-b][2]benzazepine-11,50-isoxazole}
(11R,12aR)-7
½
1.40 (m, 1H), 1.54–1.77 (m, 5H), 2.35–2.47 (m, 2H), 2.48–2.62
(m, 2H), 2.88–2.96 (m, 1H), 3.74, 3.80 (AB system, J = 14.9 Hz,
2H), 5.09 (s, 1H), 5.25 (s, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.16–7.26
(m, 2H), 7.34 (d, J = 8.4 Hz, 1H). 13C NMR 24.0 (t), 26.3 (t), 30.1
(t), 32.8 (t), 42.0 (t), 55.8 (t), 62.2 (t), 64.5 (d), 114.2 (t), 127.7
(d), 127.8 (d), 129.4 (d), 136.3 (s), 142.7 (s), 148.3 (s). MS: m/z
Yield: 29%. Brown oil. ½a D23
ꢁ
¼ ꢂ37:3 (c 0.11, CHCl3). 1H NMR
(400 MHz, CDCl3) d: 1.23–1.72 (m, 7H), 1.74–1.83 (m, 1H), 2.02–
2.09 (m, 1H), 2.15 (s, 6H), 2.42–2.51 (m, 1H), 2.52 (s, 3H), 2.78–
2.87 (m, 1H), 3.02, 3.61 (AB system, J = 17.1 Hz, 2H), 3.63, 3.76

268
E. Borsini et al. / Tetrahedron: Asymmetry 22 (2011) 264–269
(AB system, J = 14.5 Hz, 2H), 7.20 (d, J = 7.7 Hz, 1H), 7.22–7.36 (m,
2H), 7.73 (d, J = 7.7 Hz, 1H). 13C NMR (100 MHz, CDCl3) d: 18.4
(q), 19.4 (q), 22.9 (t), 26.1 (t), 30.1 (t), 34.1 (t), 43.8 (t), 49.4 (t),
62.1 (d), 63.8 (t), 90.3 (s), 125.2 (d), 128.3 (d), 129.3 (s), 131.9
(d), 133.6 (s), 133.9 (s), 135.9 (s), 144.3 (s), 157.1 (s). MS: m/z
442 (M+). Anal. Calcd for C25H28Cl2N2O: C, 67.72; H, 6.36; N, 6.32.
Found: C, 67.88; H, 6.34; N, 6.41.
4.6.1. (3R,4aS)-3-(Chloromethyl)-2-(4-nitrophenyl)octahydro-
1H-pyrido[1,2-c]pyrimidin-1-one (3R,4aS)-9
Obtained in 30% yield from (S)-8 according to the procedure de-
scribed for its enantiomer. ½a D25
¼ þ8:0 (c 0.39, CHCl3). Anal. Calcd
ꢁ
for C15H18ClN3O3: C, 55.64; H, 5.60; N, 12.98. Found: C, 55.71; H,
5.48; N, 13.08.
4.7. Preparation of (R)-2-allyl-1-propenoylpiperidine (R)-10
4.4.2.1. (11S,12aS)-30-(3,5-Dichloro-2,4,6-trimethylphenyl)-spiro-
{pyrido[1,2-b][2]benzazepine-11,50-isoxazole}
(11S,12aS)-7.
A solution of compound (R)-2 (312.9 mg, 1.39 mmol) in trifluo-
roacetic acid (1.6 mL, 20.83 mmol) was stirred under a nitrogen
atmosphere for 3 h at room temperature. After evaporation of the
solvent, the residue was dissolved in anhydrous CH2Cl2 (3 mL),
Obtained in 30% yield from (S)-4 according to the procedure
described for the enantiomer. ½a D23
¼ þ38:8 (c 0.13, CHCl3). Anal.
ꢁ
Calcd for C25H28Cl2N2O: C, 67.72; H, 6.36; N, 6.32. Found: C,
67.61; H, 6.42; N, 6.43.
and triethylamine (581 lL, 4.17 mmol) and acryloyl chloride
(150.1 mg, 1.68 mmol) were added. The reaction mixture was stir-
red overnight at room temperature. Water (3 mL) was added and
the mixture was extracted with CH2Cl2 (2 ꢀ 5 mL). The organic
phase was dried over Na2SO4, filtered and concentrated under vac-
uum. The crude was purified by silica gel column chromatography
(hexane/AcOEt 4:1) to afford (R)-10 in 70% yield. Colorless oil.
4.5. Preparation of (R)-2-allyl-N-(4-nitrophenyl)piperidine-1-
carboxamide (R)-8
A solution of compound (R)-2 (355 mg, 2.58 mmol) in trifluoro-
acetic acid (1.8 mL, 23.65 mmol) was stirred for 3 h at room temper-
ature under a nitrogen atmosphere. The trifluoroacetic acid was then
evaporated. The residue was dissolved in anhydrous THF (4 mL) and
4-nitrophenyl isocyanate (423 mg, 2.58 mmol) was added. Then the
reaction mixture was stirred at room temperature overnight. The
solvent was evaporated, after which brine (15 mL) was added to
the residue and then the mixture was extracted by CH2Cl2
(2 ꢀ 15 mL). The organic phase was dried over Na2SO4 filtered and
concentrated under vacuum. The crude was purified by silica gel col-
umn chromatography (hexane/AcOEt 7:3) to afford (R)-8 in 72%
½
a 2D3
ꢁ
¼ þ66:5 (c 0.63, CHCl3). IR (nujol):
m .
= 1677 cmꢂ1 1H NMR
(400 MHz, CDCl3) d: 1.38–1.52 (m, 1H), 1.60–1.74 (m, 5H), 2.27–
2.40 (m, 1H), 2.44–2.53 (m, 1H), 2.93 (br s, 1H), 4.20 (br s, 1H),
4.52 (br s, 1H), 5.03–5.14 (m, 2H), 5.61 (d, J = 10.7 Hz, 1H), 5.69–
5.80 (m, 1H), 6.19 (d, J = 16.9 Hz, 1H), 6.56 (dd, J = 10.7, 16.9 Hz,
1H). 13C NMR (100 MHz, CDCl3) d: 19.3 (t), 26.0 (t), 29.9 (t), 35.0
(t), 39.6 (t), 50.8 (d), 117.5 (t), 126.7 (t), 129.2 (d), 135.0 (d),
166.4 (s). MS: m/z 179 (M+). Anal. Calcd for C11H17NO: C, 73.70;
H, 9.56; N, 7.81. Found: C, 73.62; H, 9.48; N, 7.76.
yield. Yellow oil,
m
½
a 2D3
.
ꢁ
¼ þ58:6 (c 0.55, CHCl3). IR (nujol):
= 3450, 1675 cmꢂ1
1H NMR (400 MHz, CDCl3) d 1.62–1.69 (m,
4.7.1. (S)-2-Allyl-1-propenoylpiperidine (S)-10
6H), 2.27–2.33 (m, 1H), 2.49–2.55 (m, 1H), 3.96 (d, J = 16 Hz, 1H),
4.31 (br s, 1H), 5.10 (dd, J = 18.8, 28 Hz, 2H), 5.77 (q, 1H), 7.12 (br
s, 1H), 7.51 (d, J = 9.2 Hz, 2H), 8.11 (d, J = 2.7 Hz, 2H). 13C NMR
(100 MHz, CDCl3) d 18.6 (t), 25.5 (t), 28.1 (t), 34.4 (t), 39.6 (t), 51.5
(d), 117.8 (t), 118.4 (d), 124.9 (d), 134.9 (d), 142.1 (s), 146.1 (s),
154.1 (s). MS: m/z 289 (M+). Anal. Calcd for C15H19N3O3: C, 62.27;
H, 6.62; N, 14.52. Found: C, 62.31; H, 6.53; N, 14.35.
Obtained in 75% yield from (S)-2 according to the procedure de-
scribed for its enantiomer. ½a D23
¼ ꢂ70:3 (c 0.59, CHCl3). Anal.
ꢁ
Calcd for C11H17NO: C, 73.70; H, 9.56; N, 7.81. Found: C, 73.82;
H, 9.67; N, 7.90.
4.8. Preparation of (R)-1,6,7,8,9,9a-hexahydroquinolizin-4-one
(R)-12
4.5.1. (S)-2-Allyl-N-(4-nitrophenyl)piperidine-1-carboxamide
(S)-8
A mixture of (R)-10 (67 mg, 0.376 mmol) and Grubbs II 11
(16 mg, 0.019 mmol) in anhydrous CH2Cl2 (7 mL) was refluxed
for 2 h. The solvent was evaporated under reduced pressure. The
crude was purified by silica gel column chromatography (hexane/
AcOEt 3:1) to afford (R)-12 in 98% yield. Pale yellow oil.
Obtained in 75% yield from (S)-2 according to the procedure de-
scribed for its enantiomer. ½a D23
¼ ꢂ62:0 (c 0.49, CHCl3). Anal.
ꢁ
Calcd for C15H19N3O3: C, 62.27; H, 6.62; N, 14.52. Found: C,
62.19; H, 6.72; N, 14.63.
½
a 2D3
ꢁ
¼ ꢂ52:1 (c 0.50, CHCl3). IR (nujol):
m .
= 1679 cmꢂ1 1H NMR
(400 MHz, CDCl3) d: 1.37–1.49 (m, 3H), 1.65–1.78 (m, 2H), 1.80–
1.86 (m, 1H), 2.12–2.23 (m, 1H), 2.44–2.55 (m, 2H), 3.30–3.46
(m, 1H), 4.48 (d, J = 12.0 Hz, 1H), 5.85 (d, J = 9.8 Hz, 1H), 6.41–
6.48 (m, 1H). 13C NMR (100 MHz, CDCl3) d: 24.3 (t), 25.2 (t), 31.4
(t), 33.7 (t), 43.3 (t), 55.1 (d), 124.9 (d), 138.5 (d), 165.8 (s). MS:
m/z 151 (M+). Anal. Calcd for C9H13NO: C, 71.49; H, 8.67; N, 9.26.
Found: C, 71.60; H, 8.48; N, 9.19.
4.6. Preparation of (3S,4aR)-3-(chloromethyl)-2-(4-
nitrophenyl)octahydro-1H-pyrido[1,2-c]pyrimidin-1-one
(3S,4aR)-9
A mixture of (R)-8 (289 mg, 1 mmol), Pd(CH3CN)2Cl2 99%
(10 mg, 0.05 mmol) and CuCl2 98% (132 mg, 1 mmol) in dry DMF
(10 mL) was stirred at 100 °C for 3 h. Brine (15 mL) was added to
the residue and then extracted by CH2Cl2 (3 ꢀ 15 mL). The organic
phase was dried over Na2SO4 and the solvent was evaporated un-
der reduced pressure. The crude was purified by silica gel column
chromatography (hexane/AcOEt 1:1) to afford 9 in 32% yield. Red
4.8.1. (S)-1,6,7,8,9,9a-Hexahydroquinolizin-4-one (S)-12
Obtained in 95% yield from (S)-10 according to the procedure
described for its enantiomer. ½a D23
¼ þ49:0 (c 0.52, CHCl3). Anal.
ꢁ
Calcd for C9H13NO: C, 71.49; H, 8.67; N, 9.26. Found: C, 71.34; H,
8.75; N, 9.35.
oil. ½a 2D5
ꢁ
¼ ꢂ7:6 (c 0.37, CHCl3). IR (nujol):
m .
= 1680 cmꢂ1 1H
NMR (400 MHz, CDCl3) d 1.52–1.79 (m, 7H), 2.53 (m, 1H), 2.64 (t,
J = 10.3 Hz, 1H), 3.44 (m, 1H), 3.59 (t, J = 10.3 Hz, 1H), 3.7 (dd,
J = 4.2, 4.3 Hz, 1H), 4.09 (m, 1H), 4.61 (d, J = 14.6 Hz, 1H), 7.44 (d,
J = 15.2 Hz, 2H), 8.20 (d, J = 15.2 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d: 23.7 (t), 25.1 (t), 31.1 (t), 33.6 (t), 42.6 (t), 43.7 (t), 50.8 (d), 57.3
(d), 124.4 (d), 125.4 (d), 144.4 (s), 148.7 (s), 152.8 (s) MS: m/z 323
(M+). Anal. Calcd for C15H18ClN3O3: C, 55.64; H, 5.60; N, 12.98.
Found: C, 55.45; H, 5.72; N, 12.81.
4.9. Preparation of (3aR,9aR,10aR)-3-(3,5-dichloro-2,4,6-
trimethylphenyl)-3a,6,7,8,9,9a,10,10a-octahydroisoxazolo[5,4-
b]quinolizin-4-one (3aR,9aR,10aR)-13
A mixture of (R)-12 (56.8 mg, 0.38 mmol) and 5 (86.5 mg,
0.38 mmol) in anhydrous toluene (2.0 mL) was refluxed for 18 h,
then the solvent was evaporated under reduced pressure. The

E. Borsini et al. / Tetrahedron: Asymmetry 22 (2011) 264–269
269
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ChemMedChem 2009, 4, 1514–1522; (d) Banwell, G. M.; Bezos, A.; Burns, C.;
Kruszelnicki, I.; Parish, C. R.; Suc, S.; Sydnes, M. O. Bioorg. Med. Chem. Lett. 2006,
16, 181–185; (e) King, F. D.; Hadley, M. S.; Joiner, K. T.; Martin, R. T.; Sanger, G.
J.; Smith, D. M.; Smith, G. E.; Smith, P.; Turner, D. H.; Watts, E. A. J. Med. Chem.
1993, 36, 683–689.
crude was purified by silica gel column chromatography (hexane/
AcOEt 6:4) to afford (3aR,9aR,10aR)-13 in 72% yield. White solid.
Mp 173–174 °C (diisopropyl ether). ½a D23
¼ ꢂ83:0 (c 0.91, CHCl3).
ꢁ
IR (nujol):
m .
= 1682 cmꢂ1 1H NMR (400 MHz, CDCl3) d: 1.26–1.37
(m, 1H), 1.41–1.50 (m, 2H), 1.74–1.81 (m, 1H), 1.83–2.00 (m,
3H), 2.14 (s, 3H), 2.33 (s, 3H), 2.34–2.37 (m, 1H), 2.38–2.42 (m,
1H), 2.52 (s, 3H), 3.60–3.68 (m, 1H), 4.16 (d, J = 10.2 Hz, 1H),
4.43–4.50 (m, 1H), 5.06–5.13 (m, 1H). 13C NMR (100 MHz, CDCl3)
d: 18.9 (q), 19.4 (q), 23.3 (t), 25.0 (t), 33.2 (t), 33.3 (t), 42.8 (t),
50.5 (d), 57.6 (d), 77.4 (d), 128.4 (s), 133.1, (s), 134.4 (s), 136.1
(s), 157.4 (s), 163.1 (s). MS: m/z 380 (M+). Anal. Calcd for
4. (a) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Paladino, G.; Zoni, C. Eur. J. Org.
Chem. 2005, 2091–2096; (b) Beccalli, E. M.; Broggini, G.; Martinelli, M.;
Paladino, G.; Rossi, E. Synthesis 2006, 2404–2412; (c) Beccalli, E. M.; Broggini,
G.; Clerici, F.; Galli, S.; Kammerer, C.; Rigamonti, M.; Sottocornola, S. Org. Lett.
2009, 11, 1563–1566; (d) Basolo, L.; Beccalli, E. M.; Borsini, E.; Broggini, G.
Tetrahedron 2009, 65, 3486–3491; (e) Beccalli, E. M.; Borsini, E.; Brenna, S.;
Galli, S.; Rigamonti, M.; Broggini, G. Chem. Eur. J. 2010, 16, 1670–1678; (f)
Beccalli, E. M.; Bernasconi, A.; Borsini, E.; Broggini, G.; Rigamonti, M.; Zecchi, G.
J. Org. Chem. 2010, 75, 6923–6932.
C19H22Cl2N2O2: C, 59.85; H, 5.82; N, 7.35. Found: C, 59.99; H,
5. (a) Jeffery, T.; Galland, J.-C. Tetrahedron Lett. 1994, 35, 4103–4106; (b) Jeffery, T.
Tetrahedron 1996, 52, 10113–10130; (c) Jeffery, T.; David, M. Tetrahedron Lett.
1998, 39, 5751–5754.
5.76; N, 7.26.
Single crystals suitable for X-ray diffraction were obtained from
CHCl3. Relevant crystal data for 13: C19H22Cl2N2O2, FW =
6. (a) Broggini, G.; Molteni, G.; Zecchi, G. Synthesis 1995, 647–648; (b) Broggini,
G.; Zecchi, G. Gazz. Chim. Ital. 1996, 126, 479–488; (c) Broggini, G.; Folcio, F.;
Sardone, N.; Sonzogni, M.; Zecchi, G. Tetrahedron: Asymmetry 1996, 7, 797–806;
(d) Broggini, G.; Molteni, G.; Terraneo, A.; Zecchi, G. Tetrahedron 1999, 55,
14803–14806; (e) Beccalli, E. M.; Broggini, G.; La Rosa, C.; Passarella, D.; Pilati,
T.; Terraneo, A.; Zecchi, G. J. Org. Chem. 2000, 65, 8924–8932; (f) Broggini, G.;
Molteni, G.; Terraneo, A.; Zecchi, G. Heterocycles 2003, 59, 823–858; (g) Borsini,
E.; Broggini, G.; Contini, A.; Zecchi, G. Eur. J. Org. Chem. 2008, 2808–2816.
7. Beltrame, P.; Veglio, C.; Simonetta, M. J. Chem. Soc., B 1967, 867–873.
8. (a) Torssell, K. B. G. Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis;
VCH: New York, 1988; (b) Curran, D. P. In Advances in Cycloadditions; Curran, D.
P., Ed.; JAI Press: London, 1988; Vol. I, pp 129–189; (c) Grünanger, P.; Vita-Finzi,
P. Isoxazoles; Wiley: New York, 1991.
9. (a) Boyle, P. H.; O’Mahony, M. J.; Cardin, C. J. J. Chem. Soc., Perkin Trans. 1 1984,
593–601; (b) Broggini, G.; Molteni, G.; Zecchi, G. J. Org. Chem. 1994, 59, 8271–
8274; (c) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Masciocchi, N.;
Sottocornola, S. Org. Lett. 2006, 8, 4521–4524; (d) Occhiato, E. G.; Guarna, A.;
Brandi, A.; Goti, A.; De Sarlo, F. J. Org. Chem. 1992, 57, 4206–4211.
10. All the enantiomeric excesses were determined by chiral HPLC (Chiral AD
column, mobile phase: hexane/iPrOH = 4:1, flow rate 0.8 ml minꢂ1).
11. (a) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S. Chem. Rev. 2007,
107, 5318–5365; (b) Kotov, V.; Scarborough, C. C.; Stahl, S. S. Inorg. Chem. 2007,
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381.3 g molꢂ1
,
yellow prism. k(Mo-K
orthorhombic Pbca, a = 10.068(6), b = 13.927(7), c = 26.076(7) Å,
V = 3656(3) Å3, Z = 8, F(000) = 1600, calc = 1.385 g cmꢂ3
(Mo-
) = 0.370 mmꢂ1. With 226 parameters, the R, wR figures of merit
reached final values of 0.057, 0.119 for the 1917 observed reflec-
tions [I >2 (I)], and of 0.115, 0.143 for the 3303 unique reflections.
a) = 0.71073 Å, T = 298 K;
q
, l
Ka
r
Goodness of fit, highest peak and deepest hole reached final values
of 1.026, 0.21 e Åꢂ3 and ꢂ0.21 e Åꢂ3. The crystallographic data
(excluding structure factors) for 13 have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publications number 802923. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK, (fax: +44 (0)1223 336033 or e-mail: deposit@
ccdc.cam.ac.uk).
4.9.1. (3aS,9aS,10aS)-3-(3,5-Dichloro-2,4,6-trimethylphenyl)-
3a,6,7,8,9,9a,10,10a-octahydroisoxazolo[5,4-b]quinolizin-4-one
(3aS,9aS,10aS)-13
12. (a) Beccalli, E. M.; Broggini, G.; Paladino, G.; Penoni, A.; Zoni, C. J. Org. Chem.
2004, 69, 5627–5630; (b) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Paladino,
G. Tetrahedron 2005, 61, 1077–1082; (c) Abbiati, G.; Beccalli, E. M.; Broggini, G.;
Martinelli, M.; Paladino, G. Synlett 2006, 73–76; (d) Beccalli, E. M.; Borsini, E.;
Broggini, G.; Palmisano, G.; Sottocornola, S. J. Org. Chem. 2008, 73, 4746–4749;
(e) Beccalli, E. M.; Borsini, E.; Broggini, G.; Rigamonti, M.; Sottocornola, S.
Synlett 2008, 1053–1057.
Obtained in 68% yield from (S)-12 according to the procedure
described for the enantiomer. ½a D23
¼ þ87:2 (c 0.89, CHCl3). Anal.
ꢁ
Calcd for C19H22Cl2N2O2: C, 59.85; H, 5.82; N, 7.35. Found: C,
59.71; H, 5.93; N, 7.41
13. (a) Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 7179–7181; (b) McDonald, R.
I.; Stahl, S. S. Angew. Chem., Int. Ed. 2010, 49, 5529–5532; (c) Yip, K.-T.; Yang,
M.; Law, K.-L.; Zhu, N.-Y.; Yang, D. J. Am. Chem. Soc. 2006, 128, 3130–3131; (d)
Yip, K.-T.; Zhu, N.-Y.; Yang, D. Org. Lett. 2009, 11, 1911–1914; (e) Bar, G. L. J.;
Lloyd-Jones, G. C.; Booker-Milburn, K. I. J. Am. Chem. Soc. 2005, 127, 7308–7309;
(f) Houlden, C. E.; Bailey, C. D.; Gair Ford, J.; Gagné, M. R.; Lloyd-Jones, G. C.;
Booker-Milburn, K. I. J. Am. Chem. Soc. 2008, 130, 10066–10067; (g) Muñiz, K.;
Hövelmann, C. H.; Streuff, J. J. Am. Chem. Soc. 2008, 130, 763–773; (h)
Hövelmann, C. H.; Streuff, J.; Brelot, L.; Muñiz, K. Chem. Commun. 2008, 2334–
2336; (i) Zhu, B.; Wang, G.-W. Org. Lett. 2009, 11, 4334–4337; (j) Rosewall, C.
F.; Sibbald, P. A.; Liskin, D. V.; Michael, F. E. J. Am. Chem. Soc. 2009, 131, 9488–
9489; (k) Szolcsányi, P.; Gracza, T. Chem. Commun. 2005, 3948–3950; (l) Desai,
L. V.; Sanford, M. S. Angew. Chem., Int. Ed. 2007, 46, 5737–5740; (m) Alexanian,
E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem. Soc. 2005, 127, 7690–7691; (n)
Tsujihara, T.; Shinohara, T.; Takenaka, K.; Takizawa, S.; Onitsuka, K.; Hatanaka,
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Acknowledgments
We are grateful to MIUR for financial support and to the Centro
Interuniversitario di Ricerca sulle Reazioni Pericicliche e Sintesi di
Sistemi Etero e Carbociclici.
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