Hetero-Diels-Alder (HDA) strategy for the preparation of 6-aryl- and heteroaryl-substituted piperidin-2-one scaffolds: Experimental and theoretical studies

Article abstract of DOI:10.1002/ejoc.201100930

Preparation of piperidine-2-one scaffolds by the hetero-Diels-Alder (HAD) reaction, assisted by microwaves, is described. The versatility of this new approach has been demonstrated by the synthesis of racemic (±)-2- phenylpiperidine. Theoretical calculati

Full text of DOI:10.1002/ejoc.201100930

FULL PAPER
DOI: 10.1002/ejoc.201100930
Hetero-Diels–Alder (HDA) Strategy for the Preparation of 6-Aryl- and
Heteroaryl-Substituted Piperidin-2-one Scaffolds: Experimental and
Theoretical Studies
Sha Long,[a] Magda Monari,[a] Mauro Panunzio,*[a] Elisa Bandini,[b] Antonio D’Aurizio,[b]
and Alessandro Venturini*[b]
Keywords: Nitrogen heterocycles / Cycloaddition / Density functional calculations / Microwave chemistry
Preparation of piperidine-2-one scaffolds by the hetero-
Diels–Alder (HAD) reaction, assisted by microwaves, is de-
scribed. The versatility of this new approach has been dem-
onstrated by the synthesis of racemic (Ϯ)-2-phenylpiper-
idine. Theoretical calculations have allowed us to clarify the
factors that govern ring closure to form four-membered rings,
arising from a Staudinger-type electrocyclization, and/or six-
membered rings through a classical [4+2] HAD cyclization.
This competition may be lowered by increasing the elec-
tronic demand of the dienophile, as anticipated by the com-
putational studies.
already published: synthesis of a N-(trimethylsilyl)imine[31]
and coupling of this intermediate with a suitable acyl chlo-
ride in the presence of a base, such as triethylamine.[32] To
obtain the target piperidine-2-one scaffold, the azadiene
thus prepared was reacted with a dienophilic moiety with
two carbon atoms to allow the formation of a six-mem-
bered heterocyclic ring (Scheme 1). The intrinsic character-
istic flexibility of a sulfonyl group, which may be easily re-
moved, according well-established literature protocols, or
elaborated to more complex decorations of the heterocyclic
ring, drove our choice towards the vinylsulfone 2a
(Scheme 1), which presents, additionally, the necessary elec-
tron-poor nature for a normal electron demand hetero-
Diels–Alder (HAD) reaction.
Introduction
Functionalized 2-azadienes are versatile intermediates
for the preparation of five- and six-membered heterocy-
cles.[1–4] In this area, we and other research group[5–9] have
been interested in the use of functionalized azadiene system
1 (Scheme 1) for the preparation of heterocyclic com-
pounds, such as β-lactam rings, by a two-step Staudinger
reaction,[10–12] as well as tetramic acid scaffolds,[13] perhy-
drooxazin-2-ones, cyclic intermediates in the synthesis of α-
amino β-hydroxy acids,[14,15] β-hydroxycarboxylic acids,[16]
and 1,3-aminols, through a hetero-Diels–Alder (HDA) ap-
proach.[17–20] Some processes have been performed by tak-
ing advantage of microwave-assisted organic synthesis
(MAOS) technology.[21–23] More recently, the HDA-ap-
proach has been used for the synthesis of conhydrine, which
is a poisonous alkaloid present in Conium maculatum and
characterized by a piperidine scaffold.[24] Herein, we report
the natural progress of our studies in this area by extending
the preparative utility of this new approach to piperidine-
2-one heterocyclic rings substituted in the 6-position by an
aromatic or heteroaromatic group.[25–30] The synthetic pro-
tocol for the preparation of the starting azadiene 1 was that
Scheme 1. Reaction of azadienes 1a–e with dienophile 2a.
[a] Dipartimento di Chimica “G. Ciamician”,
Via Selmi 2, 49126 Bologna Italy
Fax: +39-051-209 9456
Results and Discussion
Reaction of azadiene 1a with vinylsulfone 2a in anhy-
drous toluene at reflux for 7 h (Scheme 1 and Table 1, entry
1) or at 110 °C under microwave irradiation for 20 min
(Table 1, entry 2) gave rise to the formation of the piperidin-
2-one 3a in 38 and 50% yields, respectively, and occurs with
full exo selectivity in analogy to the already reported results
by Ghosez’s group, some of which are supported by X-ray
structure determination.[33–35] Since better yields were ob-
E-mail: sha.long2@unibo.it
magda.monari@unibo.it
mauro.panunzio@unibo.it
[b] ISOF-CNR, Area di Ricerca di Bologna,
Via Gobetti 101, 40129 Bologna, Italy
Fax: +39-051-639-9844
E-mail: bandini@isof.cnr.it
A.Venturini@isof.cnr.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100930.
6218
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6218–6225

Hetero-Diels–Alder Strategy for Piperidin-2-one Scaffolds
tained when using the MAOS technique, this procedure was Table 2. Reaction of azadienes 1f–h with dienophile 2a.
adopted for all of the examples reported in Table 1. As pre-
Entry
Diene
X
Ar
Yield
Yield
viously indicated, the trans relationship between the 5- and
6-positions is observed.[33–35] The structural relationship be-
tween the substituents in the 5- and 6-positions of the piper-
idin-2-one ring has been confirmed by an X-ray diffraction 4[b]
1[a]
2[b]
3[b]
1f
1f
1g
1h
Cl
Cl
Br
PhS
Ph
Ph
Ph
Ph
3f (11%)
3f (17%)
3g (16%)
3h (3%)
4f (30%)[12]
4f (38%)
4g (42%)[12]
4h (16%)[11]
study, which was carried out to unequivocally determine the
correct structure of 3a. This analysis shows that the piperid-
inone ring adopts a distorted half-chair conformation with
the hydrogen atoms bound to C5 and C6 in the trans orien-
tation [H5C5C6H6 torsion angle of 176(1)°; see Figure 1].
In addition π–π interactions are present between the two
phenyl rings. Moreover, the sole cyclic product obtained is
that arising from a [4+2] HDA reaction, although in moder-
ate–low yields (Table 1).
[a] Convective heating. [b] Dielectric heating.
trans also is the stereo relationship of the substituents in
the 3- and 4-positions of β-lactam 4.
This competition between a [2+2] electrocyclic (EC) reac-
tion and a [4+2] cycloaddition has been already observed
by our group with the same diene scaffold and a carbonyl
compound as a dienophile. Theoretical studies by density
functional computations[36] showed that the competition
between the formation of a perhydrooxazinone (arising
from a [4+2] HDA reaction) and/or a β-lactam (arising
from a [2+2EC] Staudinger reaction) is governed by a deli-
cate interplay between temperature and the very nature of
the substituents of the diene and dienophile. Similar com-
putational studies have also been performed in the present
case in which there is competition between piperidin-2-one
3f and the β-lactam 4f formation. The example given in
entry 1 of Table 2, yielding compounds 3f and 4f (X = Cl,
Ar = Ph), was used as a model example. To have the most
complete overview of the reaction profile, we examined,
from a theoretical point of view, possible stereo relation-
ships of the substituents for both the 5–6 cis (arising from
endo attack) and 5–6 trans (arising from exo attack) com-
pounds. Figure 2 shows the energy profiles, Figure 3 shows
the geometries of the corresponding transition states and
Figure 4 shows the variation of the ΔG‡ energy barriers ver-
sus temperature. From Figure 2 it may anticipated that the
HDA reaction is favoured over the [2+2EC] ring closure. In
particular, the HDA exo1 approach has the lowest energy
barrier (Figure 2). However, careful analysis of Figure 4
shows that, on the basis of the variation of the ΔG‡ barriers,
the formation of the β-lactam is possible only at high tem-
peratures. As a matter of fact, from an experimental point
of view, the formation of the β-lactam ring takes place in
toluene at reflux temperature (110 °C), whereas at 25 °C
only traces of the six-membered ring are detected by NMR
spectroscopic analysis after 5 h. The slope of the data in
Figure 4, obtained by linear regression, indicates that the
Table 1. Synthesis of piperidin-2ones 3a–e.
Entry
Diene
X
Ar
Yield
1[a]
2[b]
3[b]
4[b]
5[b]
6[b]
1a
1a
1b
1c
1d
1e
H
H
H
H
H
H
Ph
Ph
3a (38%)
3a (50%)
3b (26%)
3c (13%)
3d (25%)
3e (18%)
p-MeOC6H4
p-O2NC6H4
thienyl
3-pyridyl
[a] Convective heating. [b] Dielectric heating.
Figure 1. X-ray crystal structure of 3a with a partial atomic num-
bering scheme. The atomic displacement parameters are drawn at
the 30% probability level.
Alternatively, when using azadienes 1f–h, which are char-
acterized by the presence of substituent X on the 4-position,
β-lactam 4 is also detected in the crude reaction mixture
(Scheme 2 and Table 2), independently of the reaction con-
ditions adopted (convective or dielectric heating; Table 2,
entries 1 and 2); thus, showing a competitive electrocycliza-
tion reaction of the diene itself with the formation of the
corresponding β-lactam 4.
Scheme 2. Reaction of azadienes 1f–h with dienophile 2a.
From a stereochemical point of view, the stereo relation-
ship between the substituents in the 3- and 5- and 5- and 6-
Figure 2. ΔE0 energy profiles for the [2+2EC] (black line), exo1
positions of the piperidine-2-one ring 3 are trans. Invariably, (green line), endo1 (red line) and endo2stack (blue line) pathways.
Eur. J. Org. Chem. 2011, 6218–6225
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6219

M. Panunzio, A. Venturini et al.
FULL PAPER
exo1 reaction is higher in energy than electrocyclic closure regression of the ΔG‡ data in Figure 4 shows that endo2s-
(0.048 against 0.0035), and that the two lines intersect at tack (B) has a higher slope (0.06) than exo1 (A) and endo1
488 K. This intersection temperature indicates qualitatively (C) (ca. 0.048) due to a destabilizing entropy effect.[37]
when the mechanism changes; thus, suggesting that it is
Taking advantage of the results reported by De Lucchi
only possible to obtain the β-lactam product at high tem- and Pasquato[38] on the reactivity of sulfones in the Diels–
peratures. Figure 2 shows the energy profiles of the two pos- Alder reaction, the next step in our studies was to consider
sible endo pathways, which have been called respectively a new reaction pathway in which the electron-demanding
endo1 (C), and endo2stack (B) (Figure 3). Endo2stack (B) is nature of the dienophile was increased by adding an extra
due to the stacking interaction between the phenyl group sulfone group to the scaffold. To support this choice and
of the diene with the phenyl group of the –SO2Ph substitu- before studying the mechanism from a theoretical point of
ent of the dienophile (see the corresponding transition-state view, we analyzed the global electrophilic indices of 1f, 2a
geometries shown in Figure 3).
and 2b through conceptual DFT descriptors.[37,39,40] The re-
sults of this theoretical investigation have been reported in
Table 3.
Table 3. Electrophilic indices of 1f, 2a and 2b.
Both dienophiles 2a and 2b have a high ω index, but 2b
is higher than 2a, and consequently, dienophile 2b should
have better reactivity in the HDA reaction and the forma-
tion of the β-lactam side product should be disfavoured.
This result has been tested from a theoretical point of view
by investigating the reaction of diene 1f with dienophile 2b
(Scheme 3). For this reaction, we detected two different
HDA transition states: no-stack1 and stack1 (see Figure 5
for the geometries of the corresponding transition states).
Because stack1, which has the corresponding stacking inter-
action to that described in the 1f + 2a reaction, is not fav-
oured due to a destabilizing entropy effect, we limit our
discussion to the no-stack1 pathway. The energy profile of
the no-stack1 mechanism is reported in Figure 6, together
with the 2+2EC pathway. Figure 7 shows the variation of
the ΔG‡ energy barrier of the no-stack1 reaction with tem-
perature. Figure 6 shows that the HDA pathway is even
more stabilized than that of the 2+2EC mechanism. This
disulfone system forms an electrostatic minimum stabilized
Figure 3. Optimized transition-state geometries for (A) exo1, (B)
endo2stack and (C) endo1 mechanisms.
Figure 4. Variation of the ΔG‡ energy barriers of the [2+2EC]
(black line) and HDA reactions against temperature.
Of the three different electrostatic minima with almost
identical energies, the exo1 (A) (Figure 3) approach is fav-
oured over both endo pathways. Of the endo pathways, the
endo2stack (B) approach has a slightly higher barrier than
that of endo1 (C). The stabilizing stacking interaction prob-
ably does not compensate for the strain produced in mole-
cule to maximize the non-bonded interaction. In fact, linear Scheme 3. Reaction of azadienes 1 with dienophile 2b.
6220 Eur. J. Org. Chem. 2011, 6218–6225
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Hetero-Diels–Alder Strategy for Piperidin-2-one Scaffolds
by 11.7 kcalmolϪ1. The energy barrier to form the HDA
As predicted, a higher yielding HDA reaction took place
product is now half that of the monosulfone (8.7 versus and no traces of β-lactam compounds were present in the
16.3 kcalmolϪ1), which is lower than stabilization due to crude reaction mixture (Scheme 3 and Table 4).
the electrostatic interaction.
Table 4. Synthesis of piperydin-2-ones 5 from azadienes 1 and dien-
ophile 2b.
Entry
Diene
R
Ar
Ph
Yield
Yield
1
2
3
4
5
6
7
1a
1c
1d
1e
1f
1h
1i
H
H
H
H
Cl
Ph-S-
Cl
5a (61%)
4a (0%)
4c (0%)
4d (0%)
4e (0%)
4f (0%)
4h (0%)
4i (0%)
p-O2NC6H4 5c (30%)
thienyl
3-pyridyl
Ph
Ph
p-FC6H4
5d (38%)
5e (75%)
5f (64%)
5h (25%)
5i (96%)
Once again the stereo relationship between the substitu-
ents on the 3- (if present) and 6-positions (piperidine num-
bering) was a mutual cis relationship, as dictated by the
HDA mechanism. To test the practicability and synthetic
utility of the protocol reported herein, the elaboration of
compound 5a into the racemic (Ϯ)-2-phenylpiperidine (7)
was explored and proved to be relatively straightforward
(Scheme 4). The protocol to elaborate 5a into 6[41] was
achieved through desulfonation with sodium amalgam in
methanol. Elaboration of 6 into 7 with LiAlH4 has already
been reported.[41]
Figure 5. Optimized transition-state geometries for the (A) stack1
and (B) no-stack1 mechanisms.
Figure 6. ΔE0 energy profiles for the [2+2EC] (black line) and no-
stack1 (grey line) pathways.
Scheme 4. Synthesis of 2-phenylpiperidine (7).
Conclusions
From the results reported, we have demonstrated that the
reactivity of azadienes 1 may be extended to the prepara-
tion of an important scaffold: piperidine. Application of
this strategy to the preparation of other biologically impor-
tant compounds, with different functionalities on the ring,
is currently under study. Theoretical studies were used to
disclose the main parameters that favoured the [4+2] HDA
reaction over the competitive [2+2 EC] reaction.
Figure 7. Variation of the ΔG‡ energy barriers of the [2+2EC]
(black line) and HDA no-stack1 (grey line) reactions against tem-
perature.
Figure 7 shows that, despite no-stack1 having a higher
slope (ca. 0.06), the intersection temperature becomes Experimental Section
524 K. In other words, this qualitative diagram indicates
General: All of the reactions were conducted under an N2 atmo-
that a higher temperature is necessary to form the β-lactam.
Bearing the results from the theoretical simulations in
mind, we increased the reactivity of the dienophile by intro-
ducing a second sulfone moiety into the vinylsulfone scaf-
fold (Scheme 3).
sphere. NMR spectra were recorded with a Varian instrument at
400 (1H) and 100 MHz (13C). Chemical shifts (δ) for 1H and 13C
NMR spectra and are reported in ppm; J values are reported in
Hz. All chemical shifts are quoted relative to deuterated solvent
signals. Optical rotations were measured at 25 °C with a Perkin–
Eur. J. Org. Chem. 2011, 6218–6225
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6221

M. Panunzio, A. Venturini et al.
FULL PAPER
Elmer Polarimeter 141. Mass spectra were recorded with a Finni-
gan MAT GCQ spectrometer in the electron impact mode at 70 eV
and are reported as m/z. The infrared spectra were recorded with
a Perkin–Elmer Spectrum BX spectrometer; wavenumbers are re-
ported in cm–1. Elemental analyses were performed at the CNR-
ISMAR, Bologna, Italy. Solvents were distilled and dried according
to standard procedures.
3707 unique. Final R[I Ͼ 2σ(I)] = 0.0402, wR2[I Ͼ 2σ(I)] = 0.0937,
and for all data R(all data) = 0.0643, wR2(all data) = 0.1055.
CCDC-829176 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
General Procedure for the Reaction of Azadienes 1b–h with Sulfone
2a under MAOS Conditions: Azadiene 1b–h (1 mmol) was dissolved
in anhydrous toluene (10 mL) and was put in a flask for microwave
oven synthesis (Milestone). Sulfone 2a (0.17 g, 1 mmol) was added
and the mixture was submitted to microwave irradiation for 20 min
at 500 W. The solvent was evaporated and the residue was purified
by flash chromatography (eluent CH2Cl2/ethyl acetate, 75:25) to
afford products 3b–h and β-lactams 4f–h in the yields and ratios
reported in Tables 1 and 2.
Reaction of Azadiene 1a with Sulfone 2a. Convective Heating
(Table 1, entry 1): Azadiene 1a (1 mmol) was dissolved in anhy-
drous toluene (10 mL) and 2a (0.17 g, 1 mmol) was added in one
portion with magnetic stirring. The solution was warmed at reflux
temperature for 7 h then cooled to room temperature. The solvent
was removed in vacuo and the crude reaction mixture was purified
by recrystallization with ethanol to give 3a (0.12 g, 38%).
Reaction of Azadiene 1a with Sulfone 2a. MAOS Conditions
(Table 1, entry 2): Azadiene 1a (1 mmol) was dissolved in anhy-
drous toluene (10 mL) and was put in a flask for microwave oven
synthesis (Milestone). Sulfone 2a (0.17 g, 1 mmol) was added and
the mixture was submitted to microwave irradiation for 20 min at
500 W. The solvent was evaporated and 3a was obtained by
recrystallization of the crude reaction mixture with ethanol (0.16 g,
50%).
(5S*,6R*)-6-(4-Methoxyphenyl)-5-(phenylsulfonyl)piperidin-2-one
(3b): White solid; m.p. 160–165 °C. IR (CHCl ): ν = 1667 cm–1. 1H
˜
3
NMR (400 MHz, CDCl3): δ = 7.75 (m, 2 H, Ar), 7.59 (m, 1 H,
Ar), 7.46 (m, 2 H, Ar), 6.97 (d, J = 8.8 Hz, 2 H, Ar), 6.72 (d, J =
8.8 Hz, 2 H, Ar), 6.48 (br. s, 1 H, NH), 5.01 (dd, J1 = 1.6, J2
4.4 Hz, 1 H, 6-H), 3.72 (s, 3 H, OMe), 3.36 (dt, J1 = 4.8, J2
=
=
6.0 Hz, 1 H, 5-H), 2.70 (m, 1 H, 3-HA), 2.40 (m, 1 H, 3-HB), 2.16
(m, 2 H, 4-CH2) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.63,
159.49, 137.68, 133.81, 131.51, 129.21, 128.35, 127.64, 114.21,
63.78, 55.20, 54.60, 28.06, 18.41 ppm. MS: m/z = 345, 329, 203,
188, 172, 134, 92, 77. C18H19NO4S (345.10): calcd. C 62.59, H 5.54,
N 4.06; found C 62.55, H 5.55, N 4.05.
(5S*,6R*)-6-Phenyl-5-(phenylsulfonyl)piperidin-2-one (3a): White
solid; m.p. 229 °C. IR (CHCl3): 1668 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 7.81 (m, 2 H, Ar), 7.62 (m, 1 H, Ar), 7.16 (m, 2 H,
Ar), 7.27 (m, 3 H, Ar), 7.12 (m, 2 H, Ar), 5.73 (br. s, 1 H, NH),
5.15 (dd, J1 = 3.2, J2 = 4.4 Hz, 1 H, 6-H), 3.42 (q, J = 5.6 Hz, 1
H, 5-H), 2.79 (dt, J1 = 8.0, J2 = 18.0 Hz, 1 H, 3-HA), 2.48 (dt, J1
= 6.4, J2 = 18.0 Hz, 1 H, 3-HB), 2.22 (m, 2 H, 4-CH2) ppm. 13C
NMR (100 MHz, CDCl3): δ = 170.54, 139.77, 137.62, 134.09,
129.41, 129.11, 126.87, 128.53, 126.44, 63.76, 55.20, 28.05,
18.47 ppm. MS: m/z = 316, 174, 173, 158, 144. C17H17NO3S
(315.09): calcd. C 64.74, H 5.43, N 4.44; found C 64.80, H 5.44, N
4.44.
(5S*,6R*)-6-(4-Nitrophenyl)-5-(phenylsulfonyl)piperidin-2-one (3c):
1
Yellow solid; m.p. 225–230 °C. IR (CHCl ): ν = 1675 cm–1. H
˜
3
NMR (400 MHz, CDCl3): δ = 8.17 (d, J = 8.8 Hz, 2 H, Ar), 7.84
(d, J = 8.8 Hz, 2 H, Ar), 7.69 (m, 1 H, Ar), 7.56 (m, 2 H, Ar), 7.39
(m, 2 H, Ar), 6.41 (br. s, 1 H, NH), 5.31 (dd, J1 = 2.4, J2 = 4.4 Hz,
1 H, 6-H), 3.38 (dt, J1 = 4.8, J2 = 6.8 Hz, 1 H, 5-H), 2.77 (m, 1 H,
3-HA), 2.47 (m, 1 H, 3-HB), 2.24–2.08 (m, 2 H, 4-CH2) ppm. 13C
NMR (100 MHz, CDCl3): δ = 170.52, 147.97, 147.02, 137.05,
134.51, 129.63, 128.59, 127.70, 124.30, 63.58, 54.58, 28.06,
19.07 ppm. MS: m/z = 360, 359, 299, 227, 218, 201, 171, 115, 91,
78. C17H16N2O5S (360.08): calcd. C 56.60, H 4.47, N 7.77; found
C 56.85, H 4.48, N 7.79.
X-ray Crystallography for 3a: The X-ray intensity data for 3a were
measured on a Bruker SMART Apex II diffractometer equipped
with a CCD area detector using a graphite-monochromated Mo-
Kα radiation source (λ = 0.71073 Å). Cell dimensions and the orien-
tation matrix were initially determined from a least-squares refine-
ment on reflections measured in 3 sets of 20 exposures, collected
in 3 different ω regions and eventually refined against all data. For
the crystal, a full sphere of reciprocal space was scanned by 0.3° ω
steps. The software SMART[45] was used for collecting frames of
data, indexing reflections and determining lattice parameters. The
collected frames were then processed for integration by SAINT
software[45] and an empirical absorption correction was applied
with SADABS.[46] The structure was solved by direct methods (SIR
97)[47] and subsequent Fourier syntheses and refined by full-matrix
least-squares calculations on F2 (SHELXTL),[48] attributing aniso-
tropic thermal parameters to the non-hydrogen atoms. All hydro-
gen atoms were located in the Fourier map. The methylene and
aromatic hydrogen atoms were placed in calculated positions and
refined with isotropic thermal parameters U(H) = 1.2 Ueq(C), and
allowed to ride on their carrier carbons, whereas the methine and
aminic hydrogen atoms were located in the Fourier map and refined
isotropically.
(5S*,6R*)-5-(Phenylsulfonyl)-6-(thiophen-3-yl)piperidin-2-one (3d):
Yellow solid; m.p. 190 °C. IR (CHCl ): ν = 1672 cm–1. 1H NMR
˜
3
(400 MHz, CDCl3): δ = 7.83 (m, 2 H, Ar), 7.64 (m, 1 H, Ar), 7.53
(m, 2 H, Ar), 7.18 (m, 1 H, Th), 6.86 (m, 2 H, Th), 6.29 (br. s, 1
H, NH), 5.38 (dd, J1 = 2.8, J2 = 4.8 Hz, 1 H, 6-H), 3.50 (ddd, J1 =
J2 = 4.8, J3 = 6.8 Hz, 1 H, 5-H), 2.73 (m, 1 H, 3-HA), 2.45 (m, 1
H, 3-HB), 2.38–2.20 (m, 2 H, 4-CH2) ppm. 13C NMR (100 MHz,
CDCl3): δ = 170.16, 143.79, 137.62, 134.11, 129.40, 128.52, 127.13,
126.18, 125.99, 64.35, 51.37, 28.21, 19.00 ppm. MS: m/z = 321, 305,
179, 164, 150, 110. C15H15NO3S2 (321.05): calcd. C 56.05, H 4.70,
N 4.36; found C 56.22, H 4.68, N 4.37.
(5S*,6R*)-5-(Phenylsulfonyl)-6-(pyridin-3-yl)piperidin-2-one (3e):
White solid; m.p. 205 °C. IR (CHCl ): ν = 1674 cm–1. 1H NMR
˜
3
(400 MHz, CDCl3): δ = 8.55 (d, J = 2.0 Hz, 1 H, Py), 8.53 (dd,, J1
= 1.6, J2 = 4.8 Hz, 1 H, Py), 7.80 (m, 2 H, Ar), 7.70 (m, 1 H, Py),
7.66 (m, 1 H, Ar), 7.53 (m, 1 H, Ar), 7.33 (dd, J1 = 5.2, J2 = 8.0 Hz,
1 H, Py), 6.34 (br. s, 1 H, NH), 5.20 (dd, J1 = 2.0, J2 = 6.4 Hz, 1
H, 6-H), 3.52 (q, J = 6.4 Hz, 1 H, 5-H), 2.75 (m, 1 H, 3-HA), 2.52
(m, 1 H, 3-HB), 2.22 (m, 2 H, 4-CH2) ppm. 13C NMR (100 MHz,
C17H17NO3S, Mr = 315.38, monoclinic, space group P21/c (no. 14);
a = 15.9096(11), b = 5.7746(4), c = 17.2601(12) Å, β = 17.2601(12)°, CDCl3): δ = 170.50, 149.47, 148.07, 137.29, 134.83, 134.34, 129.57,
V = 1516.49(18) Å3, Z = 4; T = 293(2) K, ρcalcd. = 1.381 gcm–1,
μ(Mo-Kα) 664, crystal size:
0.226 mm–1, F(000)
0.20ϫ0.25ϫ0.05 mm, 16370 reflections collected [R(int) = 0.0353],
128.51, 123.89, 63.47, 53.43, 28.34, 19.15 ppm. MS: m/z = 316, 175,
141, 78. C16H16N2O3S (316.09): calcd. C 60.74, H 5.10, N 8.85;
found C 60.56, H 5.12, N 8.87.
=
=
6222
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6218–6225

Hetero-Diels–Alder Strategy for Piperidin-2-one Scaffolds
(3S*,5S*,6R*)-3-Chloro-6-phenyl-5-(phenylsulfonyl)piperidin-2-one 23.47 ppm. MS: m/z = 499, 438, 359, 218, 78. C23H20NO7S2
1
(3f): White solid; m.p. 150 °C. IR (CHCl ): ν = 1686 cm–1. H (500.07): calcd. C 55.19, H 4.03, N 5.60; found C 55.39, H 4.01, N
˜
3
NMR (400 MHz, CDCl3): δ = 7.69 (m, 2 H, Ar), 7.57 (m, 1 H,
Ar), 7.43 (m, 2 H, Ar), 7.25 (m, 3 H, Ar), 7.16 (m, 2 H, Ar), 5.98
(br. s, 1 H, NH), 5.03 (dd, J1 = 1.6, J2 = 7.2 Hz, 1 H, 6-H), 4.71
(t, J = 5.2 Hz, 1 H, 3-H), 3.87 (ddd, J1 = 4.4, J2 = 7.2, J3 = 8.8 Hz,
1 H, 5-H), 2.67 (m, 2 H, 4-CH2) ppm. 13C NMR (100 MHz,
CDCl3): δ = 166.03, 138.39, 137.42, 134.14, 129.34, 129.11, 129.05,
128.33, 127.13, 61.05, 56.43, 51.16, 29.43 ppm. MS: m/z = 349, 314,
258, 208, 158, 91, 77. C17H16ClNO3S (349.05): calcd. C 58.37, H
4.61, N 4.00; found C 58.19, H 4.59, N 4.02.
5.62.
5,5-Bis(phenylsulfonyl)-6-(thiophen-2-yl)piperidin-2-one (5d): White
solid; m.p. 225 °C. IR (CHCl ): ν = 1676 cm–1 1H NMR
.
˜
3
(400 MHz, CDCl3): δ = 8.13 (d, J = 7.2 Hz, 2 H, Ar), 7.73 (m, 3
H, Ar), 7.62 (m, 3 H, Ar), 7.45 (m, 2 H, Ar), 7.29 (d, J = 5.2 Hz,
1 H, Th), 7.17 (d, J = 3.6 Hz, 1 H, Th), 6.92 (dd, J1 = 3.6, J2 =
5.2 Hz, 1 H, Th), 6.12 (br. s, 1 H, NH), 5.55 (d, J = 3.2 Hz, 1 H,
6-H), 3.05 (m, 1 H, 3-HA), 2.83 (m, 1 H, 3-HB), 2.76 (m, 2 H, 4-
CH2) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.64, 138.68,
(3S*,5S*,6R*)-3-Bromo-6-phenyl-5-(phenylsulfonyl)piperidin-2-one 138.46, 136.89, 135.29, 134.42, 131.32, 130.93, 130.72, 129.26,
1
(3g): Yellow oil. IR (CHCl ): ν = 1672 cm–1. H NMR (400 MHz,
128.48, 127.99, 126.53, 89.75, 54.64, 29.69, 24.40 ppm. MS: m/z =
CDCl3): δ = 7.64 (m, 2 H, Ar), 7.56 (m, 1 H, Ar), 7.40 (m, 2 H, 461, 369, 351, 319, 254, 177, 153, 135, 125, 111, 97, 77.
Ar), 7.24 (m, 5 H, Ar), 6.20 (br. s, 1 H, NH), 5.04 (dd, J1 = 2.0, J2 C21H19NO5S3 (461.04): calcd. C 54.64, H 4.15, N 3.03; found C
˜
3
= 8.4 Hz, 1 H, 6-H), 4.73 (t, J = 5.2 Hz, 1 H, 3-H), 3.97 (q, J1 = 54.45, H 4.14, N 3.05.
6.8 Hz, 1 H, 5-H), 2.72 (dd, J1 = 5.2, J2 = 6.8 Hz, 2 H, 4-CH2)
5,5-Bis(phenylsulfonyl)-6-(pyridin-3-yl)piperidin-2-one (5e): White
ppm. 13C NMR (100 MHz, CDCl3): δ = 166.39, 138.23, 137.57,
134.02, 129.25, 129.15, 129.04, 128.24, 127.37, 61.23, 56.81, 40.67,
29.98 ppm. MS: m/z = 395, 393, 314, 254, 252, 141, 77.
C17H16BrNO3S (393.00): calcd. C 51.79, H 4.09, N 3.55; found C
51.67, H 4.11, N 3.54.
solid; m.p. 215 °C. IR (CHCl ): ν = 1677 cm–1 1H NMR
.
˜
3
(400 MHz, CDCl3): δ = 8.55 (dd, J1 = 2.0, J2 = 4.8 Hz, 1 H, Py),
8.51 (d, J = 2.0 Hz, 1 H, Py), 8.16 (m, 2 H, Ar), 7.79 (m, 1 H, Ar),
7.72 (m, 1 H, Py), 7.66 (m, 5 H, Ar), 7.45 (m, 2 H, Ar), 7.23 (dd,
J1 = 4.8, J2 = 8.0 Hz, 1 H, Py), 6.26 (br. s, 1 H, NH), 5.25 (d, J =
(3S*,5S*,6R*)-6-Phenyl-5-(phenylsulfonyl)-3-(phenylthio)piperidin- 3.2 Hz, 1 H, 6-H), 2.98 (m, 1 H, 3-HA), 2.88 (m, 1 H, 3-HB), 2.82
2-one (3h): Yellow oil. IR (CHCl ): ν = 1672 cm–1
.
1H NMR
(m, 2 H, 4-CH2) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.24,
150.41, 149.29, 145.21, 137.91, 136.36, 135.40, 134.62, 132.73,
131.04, 130.70, 129.29, 128.51, 123.34, 89.30, 56.02, 27.40,
23.32 ppm. MS: m/z = 456, 315, 174, 77. C22H20N2O5S2 (456.08):
calcd. C 57.88, H 4.42, N 6.14; found C 57.70, H 4.43, N 6.17.
˜
3
(400 MHz, CDCl3): δ = 7.71 (m, 2 H, Ar), 7.61 (m, 1 H, Ar), 7.46
(m, 2 H, Ar), 7.34 (m, 4 H, Ar), 7.20 (m, 4 H, Ar), 6.95 (m, 2 H,
Ar), 6.42 (br. s, 1 H, NH), 5.07 (dd, J1 = 2.4, J2 = 5.6 Hz, 1 H, 6-
H), 4.19 (dd, J1 = 5.6, J2 = 8.0 Hz, 1 H, 3-H), 3.65 (ddd, J1 = 4.4,
J2 = 5.6, J3 = 7.2 Hz, 1 H, 5-H), 2.44 (ddd, J1 = 5.6, J2 = 7.2, J3
= 12.4 Hz, 1 H, 4-HA), 2.32 (ddd, J1 = 4.4, J2 = 8.0, J3 = 12.4 Hz,
1 H, 4-HB) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.85, 139.07,
137.33, 134.66, 134.08, 133.23, 129.37, 129.32, 128.99, 128.79,
128.64, 128.42, 126.69, 62.36, 55.53, 45.31, 25.77 ppm. MS: m/z =
423, 326, 281, 248, 204, 172, 144, 129, 91, 77. C23H21NO3S2
(423.10): calcd. C 65.22, H 5.00, N 3.31; found C 65.48, H 5.02, N
3.30.
(3S*,6R*)-3-Chloro-6-phenyl-5,5-bis(phenylsulfonyl)piperidin-2-one
1
(5f): White solid; m.p. 155 °C. IR (CHCl ): ν = 1687 cm–1. H
˜
3
NMR (400 MHz, CDCl3): δ = 8.21 (m, 2 H, Ar), 7.80 (m, 1 H,
Ar), 7.68 (m, 2 H, Ar), 7.59 (m, 1 H, Ar), 7.52 (m, 2 H, Ar), 7.40
(m, 2 H, Ar), 7.31 (m, 1 H, Ar), 7.26 (m, 4 H, Ar), 6.68 (d, J =
3.6 Hz, 1 H, NH), 5.14 (d, J = 3.6 Hz, 1 H, 6-H), 4.99 (dd, J1 =
8.0, J2 = 10.4 Hz, 1 H, 3-H), 3.50 (dd, J1 = 8.0, J2 = 14.8 Hz, 1 H,
4-HA), 3.30 (dd, J1 = 10.4, J2 = 14.8 Hz, 1 H, 4-HB) ppm. 13C
General Procedure for the Reaction of Azadienes 1a,c–f,h,i with NMR (100 MHz, CDCl3): δ = 166.30, 137.91, 136.03, 135.61,
Sulfone 2b under MAOS Conditions: Azadiene 1a,c–f,h,i (1 mmol) 135.13, 134.45, 131.34. 130.64, 130.15, 129.47, 129.38, 128.64,
was dissolved in anhydrous toluene (10 mL) and was put in a flask
for microwave oven synthesis (Milestone). Sulfone 2b (0.31 g,
1 mmol) was added and the mixture was submitted to microwave
irradiation for 20 min at 500 W. The solvent was evaporated and
the residue was purified by flash chromatography (eluent CH2Cl2/
ethyl acetate, 80/20) to afford the products 5 a,c–f,h,i.
128.53, 90.50, 58.85, 50.22, 33.49 ppm. MS: m/z = 490, 453, 349,
312, 246, 207, 181, 146, 77. C23H20ClNO5S2 (489.05): calcd. C
56.38, H 4.11, N 2.86; found C 56.54, H 4.11, N 2.86.
(3S*,6R*)-6-Phenyl-5,5-bis(phenylsulfonyl)-3-(phenylthio)piperidin-
2-one (5h): White solid; m.p. 210 °C. IR (CHCl ): ν = 1672 cm–1.
˜
3
1H NMR (400 MHz, CDCl3): δ = 8.20 (m, 2 H, Ar), 7.77 (m, 1 H,
6-Phenyl-5,5-bis(phenylsulfonyl)piperidin-2-one (5a): M.p. 218 °C.
Ar), 7.64 (m, 2 H, Ar), 7.57 (m, 2 H, Ar), 7.49 (m, 1 H, Ar), 7.38
IR (CHCl ): ν = 1641 cm–1. 1H NMR (400 MHz, CDCl ): δ = 8.19 (m, 1 H, Ar), 7.27 (m, 3 H, Ar), 7.21 (m, 3 H, Ar), 6.99 (m, 3 H,
˜
3
3
(m, 2 H, Ar), 7.76 (m, 1 H, Ar), 7.64 (m, 2 H, Ar), 7.55 (m, 1 H,
Ar), 7.48 (m, 2 H, Ar), 7.36–7.22 (m, 7 H, Ar), 6.53 (br. s, 1 H,
NH), 5.25 (d, J = 3.6 Hz, 1 H, 6-H), 2.94 (m, 3 H, 3-CH2, 4-HA),
2.80 (m, 1 H, 4-HB) ppm. 13C NMR (100 MHz, CDCl3): δ =
Ar), 6.61 (m, 2 H, Ar), 6.23 (d, J = 3.2 Hz, 1 H, NH), 5.29 (d, J
= 3.2 Hz, 1 H, 6-H), 4.38 (dd, J1 = 7.2, J2 = 12.0 Hz, 1 H, 3-H),
3.29 (dd, J1 = 7.2, J2 = 14.4 Hz, 1 H, 4-HA), 2.78 (dd, J1 = 12.0,
J2 = 14.4 Hz, 1 H, 4-HB) ppm. 13C NMR (100 MHz, CDCl3): δ =
169.62, 138.41, 136.99, 136.23, 135.19, 134.12, 131.27, 130.67, 167.40, 137.43, 137.31, 136.09, 135.29, 135.25, 133.85, 131.58,
130.20, 129.17, 128.44, 128.31, 90.24, 58.48, 27.74, 23.36 ppm. MS: 130.70, 130.44, 130.25, 129.33, 129.18, 129.15, 129.08, 128.46,
m/z = 454, 313, 171, 143, 115, 95, 77. C23H21NO5S2 (455.09): calcd.
C 60.64, H 4.65, N 3.05; found C 60.47, H 4.67, N 3.05.
128.32, 90.86, 58.89, 44.44, 30.93 ppm. MS: m/z = 563, 421, 369,
343, 312, 280, 246, 171, 143, 110, 95, 78. C29H25NO5S3 (563.09):
calcd. C 61.79, H 4.47, N 2.48; found C 61.58, H 4.48, N 2.48.
6-(4-Nitrophenyl)-5,5-bis(phenylsulfonyl)piperidin-2-one (5c): White
solid; m.p. 160 °C. IR (CHCl ): ν = 1676 cm–1
.
1H NMR
(3S*,6R*)-3-Chloro-6-(4-fluorophenyl)-5,5-bis(phenylsulfonyl)-
˜
3
(400 MHz, CDCl3): δ = 8.15 (m, 4 H, Ar), 7.80 (m, 1 H, Ar), 7.73
(m, 2 H, Ar), 7.67 (m, 3 H, Ar), 7.49 (m, 4 H, Ar), 6.74 (br. s, 1
H, NH), 5.28 (d, J = 2.8 Hz, 1 H, 6-H), 3.05 (m, 1 H, 3-HA), 2.86
piperidin-2-one (5i): White solid; m.p. 200 °C. IR (CHCl ): ν =
˜
3
1694 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.16 (m, 2 H, Ar),
7.98 (d, J = 3.6 Hz, 1 H, NH), 7.74 (m, 1 H, Ar), 7.63 (m, 2 H,
(m, 3 H, 4-CH2, 3-HB) ppm. 13C NMR (100 MHz, CDCl3): δ = Ar), 7.55 (m, 3 H, Ar), 7.40 (m, 2 H, Ar), 7.23 (m, 2 H, Ar), 6.90
169.83, 148.17, 143.22, 138.18, 136.24, 135.61, 134.86, 131.15, (m, 2 H, Ar), 5.18 (d, J = 3.6 Hz, 1 H, 6-H), 4.88 (dd, J1 = 8.0, J2
130.99, 130.98, 129.52, 128.58, 123.40, 89.71, 57.95, 29.69,
= 9.6 Hz, 1 H, 3-H), 3.50 (dd, J1 = 8.0, J2 = 14.8 Hz, 1 H, 4-HA),
Eur. J. Org. Chem. 2011, 6218–6225
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6223

M. Panunzio, A. Venturini et al.
FULL PAPER
3.26 (dd, J1 = 10.4, J2 = 14.8 Hz, 1 H, 4-HB) ppm. 13C NMR
(100 MHz, CDCl3): δ = 164.10, 161.61, 137.73, 135.49, 135.40,
134.41 131.86, 131.78, 131.14, 130.97, 130.94, 130.26, 129.27,
128.42, 115.39, 115.17, 89.99, 57.54, 49.91, 32.85 ppm. MS: m/z =
438 (M+ = 508), 366, 349, 330, 264, 225, 199, 164, 150,125, 97, 77.
C23H19ClFNO5S2 (507.04): calcd. C 54.38, H 3.77, N 2.76; found
C 54.24, H 3.75, N 2.77.
[4]
[5]
J. Barluenga, A. Suarez-Sobrino, L. A. Lopez, Aldrichim. Acta
1999, 32, 4–15.
L. Ghosez, E. Jnoff, P. Bayard, F. Sainte, R. Beaudegnies, Tet-
rahedron 1999, 55, 3387–3400.
[6]
[7]
[8]
E. Jnoff, L. Ghosez, J. Am. Chem. Soc. 1999, 121, 2617–2618.
D. Ntirampebura, L. Ghosez, Tetrahedron Lett. 1999, 40, 7079.
F. Palacios, E. Herran, G. Rubiales, C. Alonso, Tetrahedron
2007, 63, 5669–5676.
Desulfonylation Procedure. Preparation of 6: Compound 5a (0.11 g,
1 mmol) was dissolved in methanol (20 mL). KH2PO4 (210 mg)
and sodium amalgam (Hg 0.44 g, Na 27 mg) were added and the
reaction mixture was stirred at r.t. for 3 h. The mixture was filtered
through a Celite pad and the solvent was removed in vacuo. The
resulting crude mixture was purified by flash chromatography on
silica gel (ethyl acetate/MeOH 95:5) to afford 6 in 54% yield. IR
[9]
M. Panunzio, P. Vicennati, in: Recent Research Development
in Organic Chemistry, vol. 6 (Ed.: S. G. Pandalai), Transworld
Research Network, Trivandrum, 2002, p. 683–707.
A. Bongini, M. Panunzio, E. Tamanini, G. Martelli, P. Vicen-
nati, M. Monari, Tetrahedron: Asymmetry 2003, 14, 993–998.
M. Panunzio, A. Bongini, E. Tamanini, E. Campana, G. Mart-
elli, P. Vicennati, I. Zanardi, Tetrahedron 2003, 59, 9577–9582.
E. Bandini, G. Favi, G. Martelli, M. Panunzio, G. Piersanti,
Org. Lett. 2000, 2, 1077–1079.
E. Bandini, G. Martelli, G. Spunta, A. Bongini, M. Panunzio,
G. Piersanti, Tetrahedron: Asymmetry 1999, 10, 1445–1449.
A. Bongini, M. Panunzio, E. Bandini, G. Martelli, G. Spunta,
J. Org. Chem. 1997, 62, 8911–8913.
E. Bandini, G. Martelli, G. Spunta, A. Bongini, M. Panunzio,
G. Piersanti, Tetrahedron: Asymmetry 1997, 8, 3717–3718.
E. Bandini, G. Martelli, G. Spunta, A. Bongini, M. Panunzio,
Synlett 1999, 1735–1738.
D. L. Boger, S. M. Weinreb, Hetero Diels–Alder Methodology
in Organic Synthesis, vol. 47, Academic Press, New York, 1987.
M. Panunzio, E. Bandini, A. D’Aurizio, Z. N. Xia, X. J. Mu,
Synthesis 2008, 1753–1756.
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
(CHCl ): ν = 1654 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.36
˜
3
(m, 2 H), 7.29 (m, 3 H), 5.98 (br. s, 1 H), 4.54 (dd, J1 = 4.8, J2 =
9.2 Hz, 1 H), 2.45 (m, 2 H), 2.10 (m, 1 H), 1.91 (m, 1 H), 1.80 (m,1
H), 1.68 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.39,
142.41, 128.83, 127.95, 126.04, 57.79, 32.12, 31.20, 19.63 ppm. MS:
m/z = 175, 174, 146, 118, 104, 77. C11H13NO (175.10): calcd. C
75.40, H 7.48, N 7.99; found C 75.32, H 7.44, N 7.85.
Computational Methods: Due to the presence of non-bonded inter-
actions, DFT calculations were carried out by using the Truhlar’s
hybrid functional M062X[42] together with the 6-311+G(d,p)[43] ba-
sis set within the framework of the Gaussian 09 suite of pro-
grams.[44] All of the molecular structures were fully optimized by
using the Berny analytical gradient optimization method and the
stationary points were characterized by frequency calculation. The
intrinsic reaction coordinate (IRC) was used to trace the path of
the chemical reactions. Thermochemical analysis was performed at
different temperatures (198.15, 298.15 and 398.15 K), starting from
the frequency calculations. The electrophilicity indices were calcu-
lated at the B3LYP/6-31g* computational level to compare the val-
ues with the reported classification of electrophilicity.[37,39,40] The
global index, ω, is given by the expression ω = μ2/2η in terms of
the electronic chemical potential, μ, and the chemical hardness, η.
The absolute electronegativity, χ, is the negative of the chemical
potential, μ; the softness, S, is the inverse of the hardness and the
ΔNmax, Ϫμ/η, is the maximum amount of electronic charge that the
electrophile system may accept. These quantities were approxi-
mated by using the one-electron energies of the HOMO and
LUMO frontier molecular orbitals, εH and εL, as μ ≈ (εH + εL)/2
and η ≈ (εH Ϫ εL)/2, respectively.
M. Panunzio, E. Bandini, A. D’Aurizio, Z. Xiao, Synthesis
2007, 2060–2063.
A. Bongini, M. Panunzio, Eur. J. Org. Chem. 2006, 972–977.
C. O. Kappe, Angew. Chem. 2004, 116, 6408; Angew. Chem. Int.
Ed. 2004, 43, 6250–6284.
[20]
[21]
[22]
[23]
C. O. Kappe, D. Dallinger, Nat. Rev. Drug Discovery 2006, 5,
51–63.
E. S. H. El Ashry, A. A. Kassem, E. Ramadan, in: Advances In
Heterocyclic Chemistry, vol. 90 (Ed.: A. R. Katritzky), 2006, p.
1–123.
E. Bandini, G. Corda, A. D’Aurizio, M. Panunzio, Tetrahedron
Lett. 2010, 51, 933–934.
M. G. P. Buffat, Tetrahedron 2004, 60, 1701–1729.
S. Laschat, T. Dickner, Synthesis 2000, 1781–1813.
P. D. Bailey, P. A. Millwood, P. D. Smith, Chem. Commun.
1998, 633–640.
A. Nadin, Contemp. Org. Synth. 1997, 4, 387–414.
A. Mitchinson, A. Nadin, J. Chem. Soc., Perkin Trans. 1 1999,
2553–2581.
[24]
[25]
[26]
[27]
[28]
[29]
Supporting Information (see footnote on the first page of this arti-
cle): Optimized structures and energies (a.u.) for monosulfone
HDA and [2+2EC] reactions and for disulfone HDA and [2+2EC]
reactions; DFT M062X 6-311+G(d,p) optimized structures.
[30]
[31]
A. Nadin, J. Chem. Soc., Perkin Trans. 1 1998, 3493–3513.
M. Panunzio, P. Zarantonello, Org. Process Res. Dev. 1998, 2,
49–59.
[32]
L. Ghosez, P. Bayard, P. Nshimyumukiza, V. Gouverneur, F.
Sainte, R. Beaudegnies, M. Rivera, A. M. Frisque-Hesbain, C.
Wynants, Tetrahedron 1995, 51, 11021–11042.
P. Bayard, L. Ghosez, Tetrahedron Lett. 1988, 29, 6115–6118.
L. Ghosez, B. Serckx-Poucin, M. Rivera, P. Bayard, A. De-
moulin, A. M. Frisqqe-Hesban, A. Mockel, L. Munoz, C. Ber-
nard-Henriel, Lecture in Heterocyclic Chem. A 1985, 8, 69–78.
B. Tinant, J. Feneau-Dupont, J. P. Declercq, P. Nshimyumu-
kiza, Bull. Soc. Chim. Belg. 1993, 102, 635–638.
A. Bongini, M. Panunzio, A. Venturini, Phys. Chem. Chem.
Phys. 2010, 12, 5067–5073.
G. N. S. Gayatri, J. Chem. Soc. 2005, 117, 573–582.
O. De Lucchi, L. Pasquato, Tetrahedron 1988, 44, 6755–6794.
G. R. Parr, L. Szentply, S. Liu, J. Am. Chem. Soc. 1999, 121,
1922–1924.
L. R. Domingo, M. J. Aurell, P. Pérez, R. Contreras, Tetrahe-
dron 2002, 58, 4417–4423.
Acknowledgments
[33]
[34]
One of us (S. L.) thanks the China Scholarship Council (CSC) for a
Scholarship (2009–2012). The authors thank Glyconova (Colleretto
Giacosa, Italy) for financial support and Prof. A. Bongini and Dr.
S. Biondi for helpful discussions.
[35]
[36]
[1] P. Buonora, J. C. Olsen, T. Oh, Tetrahedron 2001, 57, 6099–
6138.
[2] K. C. Nicolau, S. A. Snyder, T. Montagnon, G. Vassiliko-Gian-
nakis, Angew. Chem. 2002, 114, 1742; Angew. Chem. Int. Ed.
2002, 41, 1668–1698.
[3] S. Jayakumar, M. P. Ishar, M. P. Mahajan, Tetrahedron 2002,
58, 379–471.
[37]
[38]
[39]
[40]
6224
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6218–6225

Hetero-Diels–Alder Strategy for Piperidin-2-one Scaffolds
[41] A. J. Burke, S. G. Davies, A. C. Garner, T. D. McCarthy, P. M.
Roberts, A. D. Smith, H. Rodriguez-Solla, R. J. Vickers, Org.
Biomol. Chem. 2004, 2, 1387–1394.
[42] Y. Zhao, D. G. Truhlar, Theor. Chem. Acc. 2008, 120, 215–241.
[43] M. J. Frisch, J. A. Pople, J. S. Binkley, J. Chem. Phys. 1984, 80,
3265–3269.
[44] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B.
Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li,
H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Son-
nenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hase-
gawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai,
T. Vreven, J. A. Montgomery Jr., J. E. Peralta, F. Ogliaro, M.
Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Starov-
erov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell,
J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M.
Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Ad-
amo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev,
A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Mar-
tin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador,
J. J. Dannenberg, S. Dapprich, A. D. Daniels, O. Farkas, J. B.
Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian 09, rev.
A.02, Gaussian, Inc., Wallingford CT, 2009.
[45] SMART & SAINT Software Reference Manuals, version 5.051
(Windows® NT version), Bruker Analytical X-ray Instruments
Inc., Madison, WI, 1998.
[46] G. M. Sheldrick, SADABS, Program for Empirical Absorption
Correction, University of Göttingen, Germany, 1996.
[47] A. Altomare, M. C. Burla, M. Camalli, G. L. Cascarano, C.
Giacovazzo, A. Guagliardi, A. G. G. Moliterni, G. Polidori, R.
Spagna, J. Appl. Crystallogr. 1999, 32, 115–119.
[48] G. M. Sheldrick, SHELXTLplus Structure Determination Pack-
age, version 5.1 (Windows® NT version), Bruker Analytical X-
ray Instruments Inc., Madison, WI, USA, 1998.
Received: June 27, 2011
Published Online: September 9, 2011
Eur. J. Org. Chem. 2011, 6218–6225
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6225