Solvent-free double aza-Michael under ultrasound irradiation: Diastereoselective sequential one-pot synthesis of pyrrolidine Lobelia alkaloids analogues

Article abstract of DOI:10.1039/c2ob25963j

Novel 2,5-meso-pyrrolidines have been straightforwardly synthesized from readily available symmetrical double Michael acceptors. The key step rested on an aza-Michael addition of primary alkylamines to bis-enones. Competitive Rauhut-Currier and aza-Michael reactions have been highlighted in protic solvent. Ultrasound activation associated with solvent-free conditions led to the expected pyrrolidines in quantitative yields and excellent stereoselectivities. The optimized conditions have been extended to the sonochemical synthesis of pyrrolidine Lobelia alkaloids analogues in short sequences.

Full text of DOI:10.1039/c2ob25963j

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 7148
www.rsc.org/obc
PAPER
Solvent-free double aza-Michael under ultrasound irradiation:
diastereoselective sequential one-pot synthesis of pyrrolidine Lobelia alkaloids
analogues†
Zacharias Amara,a Emmanuelle Drège,a Claire Troufflard,b Pascal Retailleauc and Delphine Joseph*a
Received 18th May 2012, Accepted 3rd July 2012
DOI: 10.1039/c2ob25963j
Novel 2,5-meso-pyrrolidines have been straightforwardly synthesized from readily available symmetrical
double Michael acceptors. The key step rested on an aza-Michael addition of primary alkylamines to
bis-enones. Competitive Rauhut–Currier and aza-Michael reactions have been highlighted in protic
solvent. Ultrasound activation associated with solvent-free conditions led to the expected pyrrolidines in
quantitative yields and excellent stereoselectivities. The optimized conditions have been extended to the
sonochemical synthesis of pyrrolidine Lobelia alkaloids analogues in short sequences.
Introduction
As the stereochemistry of chiral drugs determines their pharma-
cokinetic, pharmacodynamic and toxicological actions, 75% of
new drugs introduced to the market are single enantiomers.
Pfizer has shrewdly circumvented this constraint by launching in
2006 the smoking cessation agent varenicline 1, a meso-ana-
logue of (−)-cytisine 2 (Fig. 1).1
Fig. 1 Varenicline, a smoking-cessation meso-therapeutic agent.
Similarly, lobelane 3, one of 2,6-meso-piperidine Lobelia
inflata alkaloids, has recently been described as an inhibitor of
dopamine uptake into synaptic vesicles due to its high affinity
for VMAT2 receptors (Fig. 2).2 Starting from this natural meso-
pharmacophore, Crooks and Dwoskin et al. have synthesized
novel meso-pyrrolidine analogues 4 and 5 of nor-lobelane 3 as
more potent VMAT2 inhibitors in order to develop potentially
new efficacious treatments against drug-addictions or psycho-
stimulants abuse (Fig. 2).3,4
Fig. 2 Lobelane and pyrrolidine-norlobelane analogues.
If meso-derivatives can play a significant role in the develop-
ment of therapeutics, they are also in a position of prominence as
building blocks for the synthesis of chiral more complex com-
pounds and have gained attention over the last decades.5 Indeed,
enantioselective processes for meso-compound desymmetrization
are the most straightforward methods for the synthesis of enan-
tioenriched products with formation of simultaneous multiple
stereogenic centers in one reaction from simple substrates.6 They
allow step-economical syntheses and, de facto, more environ-
mentally friendly reactions. Once more, Lobelia alkaloids illus-
trated well this concept of meso-compound desymmetrization:
the pseudo-meso (−)-lobeline 6 has been elegantly synthesized
by biomimetic approaches9 via desymmetrizing acylation7 of
lobelanidine9 7 or via enantio- and stereoselective catalytic
desymmetrizing reduction10 of lobelanine 8 (Scheme 1). Taking
advantage of the symmetry considerations, the asymmetric
desymmetrization-based routes to (−)-lobeline 6 considerably
reduce the step number (3 to 5 steps) compared to the stepwise
construction of the three stereocenters as earlier reported by
aUniversité Paris Sud, Equipe de Chimie des Substances naturelles,
UMR CNRS 8076 BioCIS, 5, rue Jean-Baptiste Clément, F-92296
Châtenay-Malabry Cedex, France. E-mail: delphine.joseph@u-psud.fr;
Fax: +33 (0)146835250; Tel: +33 (0)146835730
bUniversité Paris Sud, Service commun d’analyses, UMR CNRS 8076
BioCIS, 5, rue Jean-Baptiste Clément, F-92296 Châtenay-Malabry
Cedex, France. E-mail: claire.troufflard@u-psud.fr;
Fax: +33 (0)146835828; Tel: +33 (0)146835652
cInstitut de Chimie des Substances Naturelles, UPR CNRS 2301,
Bâtiment 27, 1, Avenue de la Terrasse, F-91198 Gif-sur-Yvette cedex,
France. E-mail: pascal.retailleau@icsn.cnrs-gif.fr;
Tel: +33 (0)169824583
†Electronic supplementary information (ESI) available: X-ray structural
data and crystallographic information files (CIF) of compounds 13d and
1
17. H, and 13C NMR spectra of the new compounds 13a–f, 15a–c, 16
and 17. CCDC 854591 (13d) and 828848 (17). For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c2ob25963j
7148 | Org. Biomol. Chem., 2012, 10, 7148–7157
This journal is © The Royal Society of Chemistry 2012

View Article Online
Scheme 2 Synthesis of meso-pyrrolidines under hyperbaric
conditions.15
Scheme 1 Biomimetic desymmetrization-based routes to (−)-lobeline.
Marazano et al. (18 steps)11 and by Lebreton and Felpin (17
steps).12 It is, therefore, easy to understand why both the devel-
opment of new methods and the strategic deployment of known
methods for the synthesis and the desymmetrization of meso-
compounds continue to drive the field of synthetic organic
chemistry.
Scheme 3 Synthesis of the bis(enones) 12a and 12b.
pyrrolidines 9 in high overall yield and excellent selectivity
using a cyclising DAM reaction as a key step (Scheme 2).15 Fur-
thermore, as previously reported by our group, the aza-Michael
addition of primary bulky chiral amines to crotonate derivatives
requires a combination of high pressure activation and protic
conditions to succeed.15,16,24 Activation of aza-Michael reactions
has been widely developed, mostly in protic solvents, using cata-
lysts either with or without high temperature and/or high
pressure.25
In addition to step-economical processes, high pressure13 or
ultrasound14 promoted chemical transformations are also in
agreement with the tendency and necessity of environmentally
friendly approaches in organic chemistry by reducing energy
consumption, using smaller quantities of hazardous chemicals
and solvents and enhancing product selectivity.
Recently, alternative energies such as microwave27 and ultra-
sound28 associated with the use of catalysts and/or solvent-free
conditions have been developed, in agreement with the propen-
sity and requirement of environmentally friendly synthetic
procedures.
In this context, we have recently described the efficient syn-
thesis of pyrrolidines15 and piperidines16 using ultra-high
pressure. Undeniably, 2,5-disubstituted pyrrolidines are known
to be of great importance not only as a structural feature of
natural alkaloids but also as fine chemicals.17 While effort has
been devoted to carrying out the synthesis of trans-pyrrolidines
possessing a C2 axis, which constitute an important class of
chiral auxiliaries,18 access to the meso-2,5-disubstituted pyrroli-
dine framework remains rather unexplored.4a,19,20 That is why
synthetic methods that give step-economical, easily-handled and
sustainable accesses to aza-heterocyclic core-molecules ought to
be developed.21 In this context, the aza-Michael reaction is well-
known to be a valuable strategy for the preparation of β-amino-
carbonyl intermediates and has been efficiently applied to the
preparation of nitrogen-containing heterocycles such as the pyr-
rolidine ring.15,16,22 Recently discussed in several reviews,23 this
reaction remains an effusive subject in modern organic chemistry
and, most of all, a current challenge in asymmetric catalysis.
In our continuing effort towards the development of step-econ-
omical and environmentally friendly synthetic methodologies,
we describe in this paper an efficient solvent-free protocol for
the sonochemical synthesis of meso-2,5-disubstituted pyrroli-
dines using a double aza-Michael (DAM) strategy. We wish to
report herein our methodological advance in this field and its
application to the preparation of Lobelia inflata pyrrolidine alka-
loids analogues.
Methodological development
As described in our previous work, the symmetrical double
Michael acceptors 12 can be efficiently synthesized in a simple,
high yielding, two-step procedure including an oxidative clea-
vage of diene followed by
a double Wittig olefination
(Scheme 3).15 The double ozonolysis of 1,5-cyclooctadiene furn-
ished quantitatively the succinaldehyde 10 which was treated
with an excess of carbonyl-stabilized ylide 11a (R1 = Ph) or 11b
(R1 = Me). The corresponding bis(enones) 12a29a and 12b40
have been obtained as a single E,E-diastereoisomer in 85% and
80% yields respectively, and the physical data were in accord-
ance with the literature.
Whilst this reaction sequence had the drawback that triphenyl-
phosphine oxide was produced as a by-product, this process did
allow us to produce multigram quantities of the doubly homolo-
gated compounds 12a and 12b. Unfortunately, attempts to
develop a sequential oxidation–Wittig olefination one-pot pro-
cedure in order to reduce the number of purification operations
remained unsuccessful. Indeed, symmetrical bis-α,β-unsaturated
carbonyl compounds such as 12a and 12b are well-known to
cycloisomerize with very high efficiency under the influence of a
phosphine-based catalyst (i.e. PPh3) via an intramolecular viny-
logous Morita–Baylis–Hillman (MBH) reaction, also referred to
as the Rauhut–Currier (RC) reaction.30
Results and discussion
Recently, we discovered a convenient method for preparing a
series of orthogonally functionalized meso-2,5-disubstituted
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 7148–7157 | 7149

View Article Online
Table 1 Double conjugate addition of (+)-phenylethylamine to 12aa
Scheme 4 Competitive RC and DAM reactions in MeOH.
Entry
Solvent
Yield (%)
solvent (entry 3). The latter was corroborated by our initial
attempt to purify the crude complex reaction mixture through
chromatography on silica gel which allowed us to recover aza-
Michael double adduct 13a in lower yield (30%). In parallel, the
well-characterized cyclopentene 14a was isolated in 56% yield.
This by-product 14a results from the electrophilic bis(enone)
cycloisomerization (the so-called intramolecular RC reaction),
1
2
3
4
5
6
7
8
9
i-PrOH
EtOH
MeOH
TFE
63
55
36
62
75
47
>98
>98
>98
>98
HFIP
Water, )))b
DCM
Toluene
THF
1
which can be observed in the crude reaction mixture’s H NMR
10
)))b
spectrum by the characteristic chemical shift of its olefinic
proton at 6.58 ppm (Scheme 4).32
a Reaction was carried out at room temperature by addition of 12a
(0.9 mmol) to a solution of (+)-phenylethylamine (1.1 mmol) in
adequate solvent (90 μL). b Reaction was performed at room temperature
in an ultrasonic stirring bath.
Surprisingly and, to our knowledge, the literature has never
mentioned an intramolecular RC reaction catalysed by a primary
amine. Most often, RC reaction is mediated by phosphines32,33
or by tertiary amines mainly DABCO, DBU, DMAP or quinucli-
dine derivatives. Lithium amides and thiolates have been also
used to initiate such cyclizations but the nucleophiles remain
covalently attached in the cyclization products.23c,29c,30,34 More
astonishingly, if the cycloisomerized compound 14a can be iso-
lated in up to 56% yield after purification over silica gel, the
With dienone substrates 12 in hand, we next studied the DAM
reaction at room temperature and atmospheric pressure. The
model reaction involving the conjugate addition of a slight
excess of (+)-phenylethylamine (1.1 eq.) to diphenyl-2,5-diene-
1,8-dione (1 eq.) 12a was performed (Table 1). As protic media
proved its efficiency in the aza-Michael reaction thanks to exter-
nal proton-transfer activation,31 the effect of several protic sol-
vents was first explored and the results are summarized in
Table 1 (entries 1–6). The reaction was achieved in a very short
reaction time, within one hour. In environmentally benign water
as the reaction medium (Table 1, entry 6), ultrasonic stirring was
necessary to increase solubility of the Michael bis(acceptor). The
first assay was carried out in methanol (entry 3). Though a total
conversion of the starting bis(enone) 12a was observed by TLC
1
crude reaction mixtures’ H NMR spectra revealed its presence
in lesser proportions regardless of the protic solvent used. As it
is well-established that the solvent nature has dramatic effects on
the RC reaction due to the highly polarized intermediates impli-
cated,35 NMR experiments have been undertaken respectively in
protic (CD3OD) and aprotic solvents (CDCl3) in order to under-
stand the mechanism involved and to increase the selectivity and
efficiency of the desired pyrrolidine 13a formation (see ESI†).
Conjugate addition of phenylethylamine to the bis(enone) 12a
was carried out at room temperature. The reaction was monitored
periodically by 1H NMR spectroscopy. In methanol-d4, a
complex mixture was observed owing to the formation of diaster-
eomeric deuterated compounds by deuterium exchange between
solvent and the starting amine and by deuterium transfer occur-
ring in conjugate addition. Whereas the reaction kinetics were
slowed down by dilution, 1H NMR spectra revealed the for-
mation of the cycloisomerized by-product 14a whose proportion
increased over reaction time. 1H NMR experiments of DAM
addition conducted in chloroform-d1 allowed access to the
desired pyrrolidine 13a exclusively (see ESI†).
Concerning the mechanism involved, the ring closing
reactions through RC or DAM strategy proceed via the common
initial enol A resulting from the amine 1,4-addition to enone 12a
(Scheme 5). Subsequent conjugate addition to the second enone
can follow two different pathways. In the RC reaction, the initial
enol is added to the second Michael acceptor affording the
cyclised intermediate B which, in a subsequent step, eliminates
the nucleophilic amino-group. In the DAM pathway, the nucleo-
philic amino-group is added to the second enone acceptor afford-
ing the cyclised intermediate C. In addition, we have confirmed
that the RC product was favoured in protic media (either in
alcohol or over silica gel). In this particular case of primary
1
and confirmed by H NMR experiments, the pyrrolidine adduct
13a was isolated as the unique diastereomer in modest yield
(36%) after purification by flash chromatography on alumina gel.
In parallel, good yields were obtained using HFIP (entry 5), TFE
(entry 4) and i-PrOH (entry 1) as solvents. The higher yield
attained in the presence of HFIP (entry 5) undoubtedly
confirmed that DAM addition is accelerated in proton-donating
media but a contrario the similar results achieved in i-PrOH
(entry 1) and in TFE (entry 4) did not permit us to establish a
relationship between the reaction efficiency and solvent proton-
donating ability.
DAM reaction of (+)-phenylethylamine to 12a was, then,
assayed in various aprotic solvents such as dichloromethane,
toluene and THF (Table 1, entries 7–9). After a more prolonged
reaction time (12 h) than in protic solvent (1 h), pyrrolidine 13a
was isolated in quantitative yield as the sole stereoisomer. This
study revealed an increase in the reaction rate with protic solvent
but that it gave rise to substantial quantities of cycloisomerized
product. RC side reaction can be totally suppressed in aprotic
media which promotes cleaner conversion.
Wiser for these experimental results, we were intrigued by the
surprisingly poor yield obtained when MeOH was used as
7150 | Org. Biomol. Chem., 2012, 10, 7148–7157
This journal is © The Royal Society of Chemistry 2012

View Article Online
Scheme 6 Sonochemical gram-scale preparation of pyrrolidines.
Scheme 5 RC and DAM competitive reactions in protic solvents
(S-H).
amine as a typical heteronucleophilic reagent, the increasing pro-
portion of RC product could only be explained by a retro-
Michael reaction applied to pyrrolidine compound accelerated by
protic environment (Scheme 5). Indeed, NMR experiments
based on aromatic protons’ chemical shifts tend to demonstrate
that, in methanol-d4, the early formed DAM adduct 13a evolved
over time to the RC product 14a while, in chloroform-d1, 13a
remains much more stable.
Fig. 3 Relative configuration determined by nOesy experiments of
compound 13a and by X-ray crystal41 structures of compound 13d.
As the DAM reaction rate has been shown to be dilution-
dependent, the last assay was performed in solvent-free con-
ditions (Table 1, entry 10). Pyrrolidine 13a was isolated in quan-
titative yield in 1 h after ultrasonic irradiation. In solvent-free
conditions, ultrasonic irradiation was crucial and accelerated the
reaction by facilitating the solubility of reactant and the liberation
of energy by cavitation.
To expand the scope of reaction substrates, various primary
alkylamines were added onto dienone substrates 12a and 12b
under ultrasonic solvent-free optimized conditions as shown in
Scheme 6.
Pyrrolidines 13 and 15 can be rapidly synthesized in excellent
purity and stereoselectivity and in quantitative yields. These
results indicate that the DAM reaction applied to pyrrolidine
preparation is not sensitive to steric hindrance in terms of
efficiency and stereospecificity. In addition, this safe metal-free
and easy to handle procedure is scalable, allowing pyrrolidine
synthesis in multi-gram quantities. This route permits us to intro-
duce a high level of molecular diversity under mild reaction con-
ditions, including substitution and scaffold diversity. In the case
of pyrrolidines 13a,c,e and 15a derived from the condensation of
enantiopure amine, the relative configuration was unambiguously
determined by virtue of two-dimensional nOesy correlations
(Fig. 3 and ESI†): acyl arms are in the syn configuration in
relation to each other, while they are in anti configuration in
relation to the nitrogen substituent (Fig. 3). Indeed, as previously
described,15 only one conformer is characterized due to the
consequence, in the unique rotamer, the chemically equivalent
1H and 13C in the cyclic compound become magnetically differ-
ent (diastereotopic) for the reason that the phenyl anisotropy
effect only affects a part of the molecule. Gratifyingly, in this
pyrrolidine series, only compound 13d crystallized allowing the
elucidation of its relative configuration by means of a single-
crystal X-ray analysis (Fig. 3 and ESI†). The syn-configuration
of the phenacyl arms and their anti-configuration in relation to
the nitrogen substituent are confirmed. In addition, the conspicu-
ous perfect harmonious symmetry of compound 13d can be
noted (Fig. 3).
This unique syn-configuration of the acyl arms can be
explained by the thermodynamic control of the aza-annulation
following the first conjugate addition of the primary alkylamine.
Sequential one-pot synthesis of pyrrolidine Lobelia alkaloids
analogues
Taking these interesting results into account, we envisaged
extending the cyclising DAM strategy for the synthesis of pyrro-
lidine Lobelia alkaloids analogues. Crooks and co-workers4 have
recently described the synthesis of the pyrrolidine lobelane ana-
logue 17 in a five-step sequence from succinaldehyde utilizing
the elegant asymmetric Katritzky’s benzotriazole-oxazolidine
approach.36 This strategy afforded a separable 2 : 1 diastereo-
meric mixture in favour of the cis(meso)-pyrrolidine norlobelane
absence of free-rotation around the N–C* bond. As
a
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 7148–7157 | 7151

View Article Online
analogue 4. As mentioned in the introduction, the authors
showed that the ring size reduction of the central piperidine of
lobelane into pyrrolidine potentiated their ability to inhibit dopa-
mine uptake with high affinity for VMAT2 receptors.
Furthermore, we have successfully simplified the synthetic
processes by developing a rapid access to pyrrolidine lobelane
hydrochloride analogue 17 using an only “open two-flask” pro-
cedure in high overall yield and excellent diastereoselectivity.
Indeed, double Wittig olefination, DAM reaction and dithioace-
talization have been handled consecutively in the same flask
affording the dithioacetal 16 in excellent 72% overall yield. Due
to the use of a large excess of 1,2-ethanedithiol for the dithioace-
talization (20 eq.), the last reductive step by RANEY® Ni
required the dithioacetal’s isolation in pure form.
According to our strategy, the pyrrolidine lobelanine and lobe-
lane analogues (13f and 17) could be synthesized from succinal-
dehyde in a concise two- and three-step sequence respectively.
Applying optimized double cyclising aza-Michael conditions,
the pyrrolidine lobelanine analogue 13f has been prepared in a
quantitative yield as the single meso-isomer (d.r. >95%) by treat-
ment of the solid dienone 12a with a slight molar excess of a
40% aqueous methylamine solution under ultrasonic activation
(Scheme 7). In the same way, starting from succinaldehyde, the
open one-flask sequential double Wittig olefination–DAM
addition led to the unique meso-pyrrolidine lobelanine analogue
13f in an excellent 95% yield over two steps. Next, considerable
efforts were made to develop a satisfactory procedure for reduc-
tive removal of the ketone groups in 13f by general methods for
converting ketone to methylene. Our attempts included standard
Wolff–Kishner37 or Clemmensen38 deoxygenation and reduction
of carbonyl tosylhydrazone intermediates39 to hydrocarbons only
furnished degradation of 13f. More fruitfully, desulfurization of
the dithioacetal 16 with RANEY® Ni26d led to pyrrolidine lobe-
lane analogue which was isolated as the hydrochloride salt 17 in
a very good 92% yield as the single cis-meso diastereoisomer
(d.r. >95%) (Scheme 7).
Conclusions
We have successfully developed a safe, environmentally friendly,
catalyst-free synthesis of 2,5-meso-pyrrolidines by double aza-
Michael addition of primary amines to symmetrical (bis)-
α,β-unsaturated compounds under solvent-free conditions. This
environmentally sound double aza-Michael reaction was applied
to the synthesis of a pyrrolidine lobelane hydrochloride analogue
in high overall yield and excellent selectivity using two flask
procedure only. In the context of the synthesis of bioactive
compounds, our strategy offers a convergent synthetic pathway
to introduce maximum chemical diversity elements with a
limited number of chemical events and simple and powerful
procedures.
As the 1H NMR data of 17 did not correspond to those
described in the literature by Crooks,4 we have performed X-ray
analysis that has confirmed the stereochemical configuration of
the meso-pyrrolidine lobelane hydrochloride 18 (Fig. 4 and
ESI†).
Experimental
General experimental
Melting points were recorded on an electrothermal digital appar-
atus and were uncorrected. Infrared (IR) spectra were obtained as
1
neat films on Bruker Vector22 spectrophotometer. H and 13C
NMR spectra were recorded on a Bruker AC 200, AC 300 or
ARX 400 apparatus respectively at 300 or 400 MHz and 75 or
1
100 MHz unless otherwise specified. The chemical shifts for H
NMR were recorded in ppm downfield from tetramethylsilane
(TMS) with the solvent resonance as the internal standard. The
chemical shifts for 13C NMR were recorded in ppm downfield
using the central peak of deuterochloroform (77.23 ppm) as the
internal standard. Coupling constants (J) are reported in Hz and
refer to apparent peak multiplications. NMR peak assignments
have been made on the basis of HMBC, HMQC, nOesy, and
1H–1H COSY spectra. Diastereomeric ratios (dr) were evaluated
by 1H NMR spectroscopy. Specific rotations [α]2D0 were
measured at 20 °C on a PolAAr32 polarimeter using a sodium
lamp as the light source (589 nm) in a 1 dm cell and were given
in units of 10−1 deg cm2 g−1 and concentrations were quoted in
g 10−2 mL. The electrospray impact (ESI) and the atmospheric
pressure chemical ionisation (APCI) mass spectra were realized
on an esquire-LC Brucker spectrometer. The X-ray crystallo-
graphic data were measured at ambient temperature (293 °K) on
an Enraf-Nonius Kappa-CCD diffractometer with graphite-
monochromated Mo Kα radiation (λ = 0.71069 Å) or on a
Rigaku MM007 HF copper (λ = 1.54187 Å) rotating-anode gen-
erator equipped with Osmic confocal optics and a rapid II
Curved Image Plate at 200 °K.
Scheme 7 Straightforward synthesis of pyrrolidine Lobelia alkaloids
analogues.
Fig. 4 X-ray crystal42 structure of N-methyl-2,5-cis-di-(2-phenethyl)-
pyrrolidine hydrochloride 17.
Elemental analyses were performed with Perkin-Elmer 2400
analyser by the Service de Microanalyse, Centre d’Etudes
7152 | Org. Biomol. Chem., 2012, 10, 7148–7157
This journal is © The Royal Society of Chemistry 2012

View Article Online
Pharmaceutiques, Châtenay-Malabry, France. Sonication was
performed in a Prolabo Transonic-TS540 ultrasonic cleaner with
a frequency of 35 KHz and a power of 320 W.
were obtained quantitatively without further purification.
Analytical thin layer chromatography was performed on
Merck 60F-254 precoated silica (0.2 mm) on glass and was
revealed by UV light or Kägi-Misher or Dragendorf reagent.
Flash chromatography separations were performed on Merck
Kieselgel (40–63 μm) or on Merck neutral activated Aluminiu-
moxid 90 (63–200 μm). Commercially available reagents such
as phenyl- and methyl-carbonylmethylene-triphenylphosphane
(11a and 11b) were used throughout without further purification
other than that detailed below. Prior to use, solvents were dis-
tilled according to Purification of Laboratory Chemicals, 4th
Ed., W.L.F. Aramarego and D.D. Perrin, Butterworth Heine-
mann, 1996. Dienediones (12a, R = Ph)29a and (12b, R = Me)40
were synthesized according to the procedures reported in the lit-
erature in 85% and 80% yield respectively. The physical data
were in accordance with the literature.32a,40
(+)-2-[1-(1R-Phenylethyl)-5-(2-oxo-2-phenylethyl)pyrrolidin-2-
yl]acetophenone (13a). The reaction was carried out starting
from 1-(R)-phenylethylamine (245 μL, 1.9 mmol) and the bis-
(enone) 12a (495 mg, 1.7 mmol).
Brown oil (Method C: ≥95% yield); de ≥95%; [α]2D0 +16° (c
0.5 in CH2Cl2); Found: C, 80.72; H, 7.10; N, 3.40. Calc. for
C28H29NO2·1/3H2O: C, 80.54; H, 7.16; N, 3.35%; IR νmax/cm−1
1675 (CvO), 1597 (CvC), 1580 (CvC); 1H NMR (CDCl3,
400 MHz): δ 1.28 (3H, d, J = 6.9 Hz, H7′′), 1.43 (2H, ddt, J =
19.4 and 9.9 and 6.2 Hz, H3α–H4α), 1.78 (2H, m, H3β–H4β),
2.63 (1H, dd, J = 9.6 and 15.8 Hz, H6α), 2.74 (1H, dd, J = 3.9
and 15.9 Hz, H6β), 2.81 (1H, dd, J = 9.1 and 15.6 Hz, H6′α),
3.10 (1H, dd, J = 4.2 and 15.4 Hz, H6′β), 3.48 (1H, m, H5), 3.55
(1H, m, H2), 3.88 (1H, q, J = 6.7 Hz, H6′′), 7.11 (1H, t, J = 7.7
Hz, HAr), 7.19 (2H, t, J = 7.8 Hz, HAr), 7.29 (6H, m, HAr), 7.40
(2H, tt, J = 7.44 and 1.9 Hz, HAr), 7.57 (2H, d, J = 7.7 Hz, HAr),
7.68 (2H, d, J = 7.7 Hz, HAr); 13C NMR (CDCl3, 400 MHz): δ
16.12 (CH3), 30.46 (C3), 31.01 (C4), 47.03 (C6′), 47.25 (C6),
56.71 (C5), 59.14 (C2), 59.24 (C6′′), 126.98 (CHar), 128.11
(CHar), 128.15 (CHar), 128.20 (CHar), 128.28 (CHar), 128.48
(CHar), 128.59 (CHar), 132.87 (CHar), 132.98 (CHar), 137.20
(Car), 137.24 (Car), 144.28 (Car), 199.95 (CvO), 199.99
(CvO); Low resolution mass spectroscopy (CI) m/z (%): 412.2
(100) [M + H]+.
General procedure for the synthesis of pyrrolidines in solution
(Method A)
Primary amine (1.9 mmol) was added to a 1 M solution of
freshly purified phenyldienedione 12a (1.7 mmol) in the selected
solvent. The solution was stirred at room temperature until com-
pletion of the reaction, which was monitored and measured by
1H NMR. Then, the reaction mixture was concentrated under
reduced pressure and purified by flash chromatography on
neutral alumina gel (90 : 10, cHex–EtOAc) to yield the desired
pyrrolidine (for results see Table 1).
(−)-2-[1-(1R-Phenylethyl)-5-(2-oxopropyl)pyrrolidin-2-yl]-
acetone (15a). The reaction was carried out starting from 1-(R)-
phenylethylamine (245 μL, 1.9 mmol) and the bis(enone) 12b
(285 mg, 1.7 mmol).
General procedure for the sequential one-pot synthesis of
pyrrolidines in solution (Method B)
To a 0.5 M solution of triphenylphosphane ylide 11a (Ph) (30 g,
79 mmol, 2.5 eq.) or 11b (Me) (25.1 g, 79 mmol, 2.5 eq.) in the
selected solvent, was added freshly distilled succinaldehyde
(2.7 g, 31 mmol, 1 eq.) by mean of a syringe pump. The reaction
was stirred at room temperature for approximately two days.
Completion of the reaction was monitored by 31P NMR of a
crude evaporated aliquot. Then, primary amine (34 mmol, 1.1
eq.) was added to the crude reaction mixture, which was then
allowed to stir at room temperature for an additional 12 h.
The reaction mixture was concentrated under reduced
pressure and purified by filtration on a pad of neutral alumina
(90 : 10, cHex–EtOAc) to give the desired pyrrolidine in >95%
overall yield.
Yellowish oil (Method C: ≥95% yield); de ≥95%; [α]2D0 −9°
(c 0.45 in CH2Cl2); Found: C, 73.86; H, 8.59; N, 4.53. Calc. for
C18H25NO2·1/3H2O: C, 73.68; H, 8.82; N, 4.77%; IR νmax/cm−1
1707 (CvO), 1451 (C–N), 763 (vC–H); 1H NMR (CDCl3,
300 MHz): δ 1.40 (5H, d, J = 6.9 Hz, H7′′–H3α–H4α), 1.85 (2H,
m, H3β–H4β), 1.93 (3H, s, H8), 2.07 (3H, s, H8′), 2.14 (2H, dd, J
= 15 and 6 Hz, H6α–H6′β), 2.33 (1H, dd, J = 9 and 15.9 Hz,
H6β), 2.52 (1H, dd, J = 4 and 16 Hz, H6′α), 3.36 (2H, m, H2–
H5), 3.86 (1H, q, J = 6.9 Hz, H6′′), 7.12–7.29 (5H, m, HAr); 13C
NMR (CDCl3, 75 MHz): δ 15.69 (CH3), 30.61 (C3), 30.83 (C8),
31.00 (C8′), 31.11 (C4), 51.96 (C6), 52.01 (C6′), 55.61 (C5),
58.14 (C2), 58.83 (C6′′), 127.06 (CHar), 128.07 (CHar), 128.29
(CHar), 128.60 (CHar), 144.01 (Car), 208.41 (CvO); Low resol-
ution mass spectroscopy (CI) m/z (%): 288.2 (100) [M + H]+.
2-[1-Allyl-5-(2-oxo-2-phenylethyl)-pyrrolidin-2-yl]acetophe-
none (13b). The reaction was carried out starting from allyl-
amine (143 μL, 1.9 mmol) and the bis(enone) 12a (495 mg,
1.7 mmol).
Brown oil (Method C: ≥95% yield); de ≥95%; Found: C,
78.77; H, 7.49; N, 3.85. Calc. for C23H25NO2·1/4H2O: C, 78.49;
H, 7.30; N, 3.98%; IR νmax/cm−1 1680 (CvO), 1597 (CvC),
1580 (CvC), 1448 (C–N); 1H NMR (CDCl3, 400 MHz): δ 1.49
General procedure for the solvent-free synthesis of pyrrolidines
under ultrasonic irradiation (Method C)
Liquid primary amine (1.9 mmol, 1.1 eq.) was added to freshly
purified solid dienedione (1.7 mmol, 1 eq.) 12a (495 mg) or 12b
(285 mg). The mixture was irradiated under ultrasonic conditions
during 1 h. Completion and conversion of the reaction was
1
monitored and measured by H NMR. Pyrrolidines (13 and 15)
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 7148–7157 | 7153

View Article Online
(2H, m, H3α–H4α), 2.04 (2H, m, H3β–H4β), 2.93 (2H, m, H6α–
6′α), 3.31 (6H, m, H6′′–H6β–H6′β–H2–H5), 5.10 (1H, d, Jcis
9.9 Hz, H8′′), 5.20 (1H, d, Jtrans = 17.1 Hz, H8′′), 5.91 (1H, m,
H7′′), 7.42–7.54 (6H, m, HAr), 7.95 (4H, d, J = 7.7 Hz, HAr); 13
NMR (CDCl3, 100 MHz): δ, 30.21 (C3–C4), 45.11 (C6–C6′),
55.55 (C6′′), 60.37 (C2–C5), 128.11 (CHar), 128.54 (CHar),
133.04 (C7′′), 137.13 (Car–C8′′), 199.27 (CvO).
46.58°), −9 ≤ h ≤ 9, −12 ≤ k ≤ 12, −28 ≤ l ≤ 28), 1920 inde-
pendent reflections (Rint = 0.0245), goodness-of-fit on F2: S =
1.050, R1 = 0.0885 and wR2 = 0.1925 for all 1919 reflections, R1
= 0.0635 and wR2 = 0.1708 for 1361 observed reflections [I >
2σ(I)], refining 167 parameters, semi-empirical absorption cor-
rection from multi-scans (Tmin = 0.89, Tmax = 0.99), final elec-
H
=
C
tron density between −0.180 and 0.385 e Å−3 1H NMR
;
(CDCl3, 400 MHz): δ 1.60 (2H, m, H3α–H4α), 1.87 (2H, m,
H3β–H4β), 2.74 (2H, dd, J = 10.4 and 14.7 Hz, H6α–H6′α), 3.18
(2H, dd, J = 3.8 and 14.6 Hz, H6β–H6′β), 3.54 (2H, m, H2–H5),
4.88 (1H, s, H6′′), 7.20 (2H, m, HAr), 7.26 (8H, m, HAr), 7.45
(10H, m, HAr); 13C NMR (CDCl3, 400 MHz): δ 29.74 (C3–C4),
47.11 (C6–C6′), 60.23 (C2–C5), 73.16 (C6′′), 127.24 (CHar),
128.15 (CHar), 128.44 (CHar), 128.55 (CHar), 128.76 (CHar),
132.80 (CHar), 136.70 (Car), 142.93 (Car), 199.55 (CvO); Low
resolution mass spectroscopy (APCI) m/z: 474 ([M + H]+,
100%).
2-[1-Allyl-5-(2-oxopropyl)pyrrolidin-2-yl]acetone (15b). The
reaction was carried out starting from allylamine (143 μL,
1.9 mmol) and the bis(enone) 12b (285 mg, 1.7 mmol).
Yellowish oil (Method C: ≥95% yield); de ≥95%; Found: C,
68.18; H, 9.53; N, 6.32. Calc. for C13H21NO2·1/3H2O: C, 68.09;
H, 9.52; N, 6.11%; IR νmax/cm−1 1708 (CvO), 1419 (CvC),
1
1357 (C–N); H NMR (300 MHz, CDCl3) δ 1.37 (2H, m, H3α–
H4α), 1.94 (2H, m, H3β–H4β), 2.11 (6H, s, H8–H8′), 2.37 (2H,
dd, J = 16.0 and 8.7 Hz, H6α–H6′α), 2.69 (2H, dd, J = 16.0 and
4.2 Hz, H6β–H6′β), 3.07 (2H, m, H, H2–H5), 3.19 (2H, d, J = 6.6
Hz, H6′′), 5.12 (2H, m, H8′′) 5.85 (1H, m, H7′′); 13C NMR
(75 MHz, CDCl3) δ 29.98 (C3–C4) 30.90 (C8–C8′), 50.19 (C6–
C6′), 55.47 (C6′′), 59.63 (C2–C5), 117.42 (C8′′), 135.64 (C7′′),
208.27 (CvO); Low resolution mass spectroscopy (CI): m/z (%)
224.1 (100).
(−)-2-[1-(2-Hydroxy-1R-phenylethyl)-5-(2-oxo-2-phenylethyl)-
pyrrolidin-2-yl]acetophenone (13e). The reaction was carried
out starting from 1-(R)-phenylglycinol (260 mg, 1.9 mmol) and
the bis(enone) 12a (495 mg, 1.7 mmol).
Brown oil (Method C: ≥95% yield); de ≥95%; [α]2D0 −26° (c
1 in CH2Cl2); Found: C, 77.12; H, 7.23; N, 3.25. Calc. for
C28H29NO3·1/2H2O: C, 77.04; H, 6.93; N, 3.21%; IR νmax/cm−1
3440 (O–H), 1674 (CvO), 1597 (CvC), 1579 (CvC); 1H
NMR (CDCl3, 400 MHz): δ 1.47 (3H, m, H3α–H4α–H3β), 1.97
(1H, m, H4β), 2.99 (1H, dd, J = 9.2 and 15.7 Hz, H6α), 3.11 (1H,
dd, J = 8.0 and 16.0 Hz, H6′α), 3.22 (1H, dd, J = 4.0 and 15.8
Hz, H6β), 3.49 (1H, dd, J = 4.5 and 16.0 Hz, H6β′), 3.78 (1H, dd,
J = 4.7 and 10.0 Hz, H7′′), 3.79 (2H, m, J = 4.5 and 8–10 Hz,
H2–H5), 3.95 (1H, t, J = 10.0 Hz, H7′′), 4.04 (1H, dd, J = 4.7
and 10 Hz, H6′′), 7.32 (3H, m, J = 7.4 and 1.4 Hz, HAr), 7.36
(2H, td, J = 7.2 and 2.0 Hz, HAr), 7.44 (2H, t, 7.5 Hz, HAr), 7.48
(2H, t, J = 7.6 Hz, HAr), 7.56 (1H, tt, J = 7.5 and 1.6 Hz, HAr),
7.60 (1H, tt, J = 7.3 and 1.6 Hz, HAr), 7.93 (2H, d, J = 7.3 Hz,
HAr), 8.04 (2H, d, J = 7.6 Hz, HAr). 13C NMR (CDCl3,
400 MHz): δ 30.53 (C3), 30.81 (C4), 45.26 (C6), 46.88 (C6′),
54.77 (C5), 60.03 (C2), 62.12 (C7′′), 65.51 (C6′′), 127.87 (CHar),
128.09 (CHar), 128.13 (CHar), 128.48 (CHar), 128.60 (CHar),
128.61 (CHar), 128.70 (CHar), 133.11 (CHar), 133.16 (CHar),
136.96 (Car), 137.12 (Car), 137.20 (Car), 199.34 (CvO), 199.54
(CvO); Low resolution mass spectroscopy (ESI) m/z (%): 428.3
(100) [M + H]+, 308.1 (4).
(+)-2-[1-(1R-Naphthylethyl)-5-(2-oxo-2-phenylethyl)-pyrroli-
din-2-yl]acetophenone (13c). The reaction was carried out start-
ing from 1-(R)-naphthylethylamine (307 μL, 1.9 mmol) and the
bis(enone) 12a (495 mg, 1.7 mmol).
Brown oil (Method C: ≥95% yield); de ≥95%; [α]2D0 +45 (c
0.75, CH2Cl2); Found: C, 82.33; H, 6.87; N, 3.20. Calc. for
C32H31NO2·1/3H2O: C, 82.19; H, 6.83; N, 3.00%; IR νmax/cm−1
1674(CvO), 1596 (CvC), 1448 (C–N); 1H NMR (C6D6,
300 MHz): δ 1.60 (5H, m, H3α–H4α–H7′′), 1.98 (2H, m, H3β–
H4β), 2.30 (1H, dd, J = 16.6 and 2.3 Hz, H6β), 2.49 (1H, dd, J =
15.9 and 9.4 Hz, H6α), 2.96 (1H, dd, J = 15.4 and 8.5 Hz, H6′α),
3.47 (1H, dd, J = 15.5 and 4.9 Hz, H6′β), 3.68 (m, 1H, H2), 3.80
(m, 1H, H5), 4.87 (1H, q, J = 6.6 Hz, H6′′), 7.24–7.65 (m, 12H,
HAr), 7.69–7.92 (m, 4H, HAr), 8.41 (1H, d, J = 8.1 Hz, HAr); 13
C
NMR (C6D6, 75 MHz): δ, 14.17 (C7′′), 30.91 (C3), 31.15 (C4),
46.16 (C6), 47.31 (C6′), 55.45 (C6′′), 56.11 (C2), 59.70 (C5),
125.01 (CHar), 125.32 (CHar), 125.64 (CHar), 125.79 (CHar),
125.96 (CHar), 125.53 (CHar), 125.96 (CHar), 128.48 (CHar),
128.73 (CHar), 128.93 (CHar), 132.41 (CHar), 132.73 (CHar),
134.41 (Car), 137.66 (Car), 137.87 (Car), 140.19 (Car), 198.44
(CvO); Low resolution mass spectroscopy (CI): m/z (%) 462
(100) [M + H]+.
2[1-Methyl-5-(2-oxo-2-phenylethyl)-pyrrolidin-2-yl]acetophe-
none (13f). The reaction was carried out starting from a 40%
aqueous methylamine solution (160 μL, 1.9 mmol) and the bis-
(enone) 12a (495 mg, 1.7 mmol).
2-[1-Benzhydryl-5-(2-oxo-2-phenylethyl)pyrrolidin-2-yl]aceto-
phenone (13d). The reaction was carried out starting from benz-
hydrylamine (327 μL, 1.9 mmol) and the bis(enone) 12a
(495 mg, 1.7 mmol).
White crystal (Method C: ≥95% yield); de ≥95%; mp 138 °C
(from c-hexane); Found: C, 83.54; H, 6.68; N, 3.14. Calc. for
C33H31NO2: C, 83.69; H, 6.60; N, 2.96%; IR νmax/cm−1 1669
(CvO), 1593 (CvC), 1447 (C–N), 1270 (C–N), 713 (vC–H);
Crystal data: thin colourless plate of dimensions 0.60 × 0.46 ×
0.10 mm, C33H29NO2, M = 471.57, orthorhombic system, space
group Pbcm, Z = 4, a = 8.806 (4), b = 11.377 (5) Å, c = 26.118
(8) Å, V = 2616.7(2) Å3, Dcalcd = 1.197 g cm−3, F(000) = 1000,
μ = 0.074 mm−1, 11 516 collected reflections (1.98° ≤ θ ≤
Brown oil (Method C: ≥95% yield); de ≥95%; Found: C,
76.98; H, 7.20; N, 4.17. Calc. for C21H23NO2·1/3H2O: C, 77.03;
H, 7.29; N, 4.28%; IR νmax/cm−1 1679 (CvO), 1597 (CvC),
1
1448 (C–N); H NMR (300 MHz, CDCl3): δ 1.46 (2H, m, H3α–
H4α), 2.11 (2H, m, H3β–H4β), 2.36 (3H, s, H6′′), 2.98 (4H, m,
H6–H6′), 2.33 (2H, dd, J = 12.6 and 8.4 Hz, H2–H5), 7.45 (4H, t,
J = 7.4 Hz, Har), 7.55 (2H t, J = 7.3 Hz, Har), 7.96 (4H, d, J =
7.2 Hz, Har); 13C NMR (75 MHz, CDCl3) δ 29.91 (C3–C4),
39.31 (C6′′), 44.20 (C6–C6′), 63.00 (C2–C5), 128.04 (CHar),
128.58 (CHar), 133.05 (CHar), 137.19 (Car), 199.16 (CvO);
7154 | Org. Biomol. Chem., 2012, 10, 7148–7157
This journal is © The Royal Society of Chemistry 2012

View Article Online
Low resolution mass spectroscopy (CI): m/z (%) 322.2 (100)
White solid; mp 93–95 °C (from Et2O) (lit.,4 94 °C); Found:
C, 76.45; H, 8.55; N, 4.25. Calc. for C28H28ClN: C, 76.35; H,
8.60; N, 4.23%; IR νmax/cm−1 2960 (+N–H), 1590 (N–H), 1445
(C–N), 1032 (C–N); Crystal data: elongated rectangular cuboid
of dimensions 0.59 × 0.18 × 0.16 mm, C21H28N+, Cl −, M =
329.89, orthorhombic system, space group Aba 2, Z = 4, a =
25.438(2), b = 10.6710 (5) Å, c = 7.1250 (2) Å, V = 1934.07
[M + H]+, 202.3 (30).
2-[1-Methyl-5-(2-oxopropyl)pyrrolidin-2-yl]acetone (15c).
The reaction was carried out starting from a 40% aqueous
methylamine solution (160 μL, 1.9 mmol) and the bis(enone)
12b (285 mg, 1.7 mmol).
Yellowish oil (Method C: ≥95% yield); de ≥95%; Found: C,
64.80; H, 9.62; N, 6.80. Calc. for C11H19NO2·1/3H2O: C, 64.99;
(19) Å3, Dcalcd = 1.133 g cm−3, F(000) = 712, μ = 1.721 mm−1
12 865 collected reflections (6.96° ≤ θ ≤ 73.14°), −31 ≤ h ≤ 31,
,
1
H, 9.75; N, 6.89%; IR νmax/cm−1 1709 (CvO), 1361(C–N); H
−12 ≤ k ≤ 8, −8 ≤ l ≤ 8), 1894 independent reflections (Rint =
NMR (300 MHz, CDCl3) δ 1.34 (2H, m, H3α–H4α), 1.99 (2H,
m, H3β–H4β), 2.14 (6H, s, H8–H8′), 2.21 (3H, s, H6′′), 2.40 (4H,
m, H6–H6′), 2.68 (2H, m, H2–H5); 13C NMR (75 MHz, CDCl3)
δ, 29.45 (C3–C4), 30.89 (C8–C8′), 39.03 (C6′′), 48.91 (C6–C6′),
62.41 (C2–C5), 207.90 (CvO); Low resolution mass spec-
troscopy (ESI): m/z (%) 198.3 (100), 140.2 (42).
0.0375), goodness-of-fit on F2: S = 1.136, R1 = 0.0718 and wR2
= 0.1763 for all 1891 reflections, R1 = 0.0544 and wR2 = 0.1467
for 1405 observed reflections [I > 2σ(I)], refining 131 parameters
and 4 restraints on bond lengths with respect the pyrrolidine
group, semi-empirical absorption correction from multi ω-scans
(Tmin = 0.680, Tmax = 1.000), final electron density between
−0.312 and 0.205 e Å−3
(2H, m, H3α–H4α), 2.19 (2H, m, H3β–H4β), 2.26 (2H, m, H6β–
6′β), 2.52 (2H, m, H7β–H7′β), 2.58 (2H, m, H6α–H6′α), 2.63
;
1H NMR (400 MHz, CDCl3) 2.08
1-Methyl-2,5-bis[(2-phenyl-1,3-dithiolan-2-yl)methyl]pyrroli-
dine (16). To a 0.5 M solution of phenylcarbonylmethylene-tri-
phenylphosphane (838 mg, 2.2 mmol) in dichloromethane, was
added freshly distilled succinaldehyde (86 mg, 1 mmol) by
mean of syringe pump. The reaction was magnetically stirred at
room temperature for approximately two days. Then, the 40%
aqueous methylamine (1.1 mmol, 92 μL) was added to the reac-
tion mixture, which was stirred at room temperature for an
additional 12 h. The mixture was next stirred at room tempera-
ture for 18 h after addition of 1,2-ethanedithiol (1.7 mL,
20 mmol) and borontrifluoride etherate (1.7 mL, 13.3 mmol).
The mixture was washed twice with a 2 M sodium hydroxide
solution (2 × 50 mL) and extracted with dichloromethane (3 ×
50 mL). The combined extracts were washed with brine
(50 mL), dried over sodium sulfate, filtered and concentrated
in vacuo. The crude mixture was then purified by silica gel
column chromatography (80 : 20 cyclohexane–ethyl acetate) to
give the desired pyrrolidine.
H
(3H, s, H6′′), 2.79 (2H, m, H2–H5), 2.88 (2H, m, H7α–H7′α),
7.14–7.29 (10H, m, Har), 11.99 (1H, br, s, NH); 13C NMR
(101 MHz, CDCl3) δ 27.10 (C3–C4), 30.90 (C6–C6′), 32.30 (C7–
C7′), 36.65 (C6′′), 69.02 (C2–C5), 126.53 (CHar), 128.21 (CHar),
128.69 (CHar), 139.45 (Car); Low resolution mass spectroscopy
(CI): m/z (%) 294.3 (100) [M + H − Cl]+.
Acknowledgements
The authors are grateful to K. Leblanc for performing microana-
lyses and HPLC analyses and Michèle Danet (SAMM, Châte-
nay-Malabry) for mass measurements. The authors thank the
French Ministry of Superior Education and Research for the
grant of Z.A. The University Paris-Sud 11, the French Ministry
of Superior Education and Research and the CNRS are gratefully
acknowledged for financial support.
White solid (364 mg, 77%); mp 118 °C; Found: C, 63.54; H,
6.61; N, 2.91. Calc. for C25H31NS4: C, 63.38; H, 6.60; N,
2.96%; IR νmax/cm−1 1443 (C–N), 1032 (C–N); 1H NMR
(300 MHz, CDCl3) δ 0.99 (2H, m, H3α–H4α), 1.25 (2H, m, H3β–
H4β), 1.93 (2H, m, H2–H5), 2.10 (3H, s, H6′′), 2.35 (2H, dd, J =
9.2 and 14.0 Hz, H6α–H6′α), 2.73 (2H, d, J = 14.0 Hz, H6β–
Notes and references
1 (a) J. W. Coe, P. R. Brooks, M. G. Vetelino, M. C. Wirtz, E. P. Arnold,
J. Huang, S. B. Sands, T. I. Davis, L. A. Lebel, C. B. Fox,
A. Shrikhande, J. H. Heym, E. Schaeffer, H. Rollema, Y. Lu,
R. S. Mansbach, L. K. Chambers, C. C. Rovetti, D. W. Schulz,
F. D. Tingley and B. T. O’Neill, J. Med. Chem., 2005, 48, 3474;
(b) J. W. Coe, H. Rollema and B. T. O’Neill, Annu. Rep. Med. Chem.,
2009, 44, 71.
2 (a) A. V. Terry, R. Williamson, M. Gattu, J. W. Beach, C. R. McCurdy,
J. A. Sparks and J. R. Pauly, Neuropharmacology, 1998, 37, 93;
(b) D. Flammia, M. Dukat, M. I. Damaj, B. Martin and R. A. Glennon,
J. Med. Chem., 1999, 42, 3726; (c) G. Zheng, L. P. Dwoskin,
A. G. Deaciuc, S. D. Norrholm and P. A. Crooks, J. Med. Chem., 2005,
48, 5551; (d) N. M. Neugebauer, S. B. Harrod, D. J. Stairs, P. A. Crooks,
L. P. Dwoskin and M. T. Bardo, Eur. J. Pharmacol., 2007, 571, 33.
3 G. Zheng, L. P. Dwoskin, A. G. Deaciuc and P. A. Crooks, Bioorg. Med.
Chem. Lett., 2008, 18, 6509.
4 (a) A. P. Vartak, J. R. Nickell, J. Chagkutip, L. P. Dwoskin and
P. A. Crooks, J. Med. Chem., 2009, 52, 7878; (b) J. S. Beckmann,
K. B. Siripurapu, J. R. Nickell, D. B. Horton, E. D. Denehy, A. Vartak,
P. A. Crooks, L. P. Dwoskin and M. T. Bardo, J. Pharmacol. Exp. Ther.,
2010, 335, 841.
5 (a) B. Basler, S. Brandes, A. Spiegel and T. Bach, Top. Curr. Chem.,
2005, 243, 1; M. D. Mans and W. H. Pearson, Org. Lett., 2004, 6, 3305;
(b) T. Huxford and N. S. Simpkins, Synlett, 2004, 2295; (c) M. Antiss,
J. M. Holland, A. Nelson and J. R. Titchmarsh, Synlett, 2003, 8, 1213;
(d) R. W. Hoffmann, Angew. Chem., Int. Ed., 2003, 42, 1096;
H
6′β), 3.12–3.17 (4H, m, CH2–S), 3.32–3.38 (4H, m, CH2–S),
7.22 (6H, m, HAr), 7.65 (4H, d, J = 7.2 Hz, HAr); 13C NMR
(75 MHz, CDCl3) δ 30.62 (C3–C4), 38.48 (CH2–S), 38.65 (C6′′),
38.75 (CH2–S), 50.54 (C6–C6′), 65.45 (C2–C5′), 72.93 (C7–C7′),
126.94 (CHar), 127.26 (CHar), 127.69 (CHar), 145.07 (Car);
Low resolution mass spectroscopy (CI): m/z (%) 474.2 (100)
[M + H]+.
1-Methyl-2,5-bis(2-phenethyl)pyrrolidine hydrochloride (17).
To a suspension of RANEY® Nickel (1 g) in MeOH (30 mL),
was added a solution of pyrrolidine 16 (200 mg, 0.42 mmol).
The reaction mixture was heated at 40 °C and monitored by
TLC. After completion, the crude was filtered through a thin pad
of celite®, and rinsed with dichloromethane (25 mL) followed
by ethyl acetate (25 mL). Prior to evaporation of the solvents,
HCl gas was bubbled into the solution. The crude chlorhydrate
was then triturated in diethyl ether to afford the pure compound
as a white solid (127 mg, 92%).
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 7148–7157 | 7155

View Article Online
(e) H. Takahata, H. Ouchi, M. Ichinose and H. Nemoto, Org. Lett., 2002,
4, 3459; (f) A. D. Lebsack, J. T. Link, L. E. Overman and B. A. Stearns,
J. Am. Chem. Soc., 2002, 124, 9008; (g) N. J. Goldspink, N. S. Simpkins
and M. Beckmann, Synlett, 1999, 1292; (h) T. Punniyamurthy and
T. Katsuki, Tetrahedron, 1999, 55, 9439.
6 (a) R. S. Ward, Chem. Soc. Rev., 1990, 19, 1; M. C. Willis, J. Chem.
Soc., Perkin Trans. 1, 1999, 1765; (b) E. Garcia-Urdiales, I. Alfonso and
V. Gotor, Chem. Rev., 2005, 105, 313; (c) L. Atodiresei, I. Schiffers and
C. Bolm, Chem. Rev., 2007, 107, 5683.
7 (a) R. Chênevert and P. Morin, Bioorg. Med. Chem., 2009, 17, 1837;
(b) E. García-Urdiales, I. Alfonso and V. Gotor, Chem. Rev., 2011, 111,
PR110; (c) V. B. Birman, H. Jiang and X. Li, Org. Lett., 2007, 9, 3237.
8 S. Krishnan, J. T. Bagdanoff, D. C. Ebner, Y. K. Ramtohul, U. K. Tambar
and B. M. Stoltz, J. Am. Chem. Soc., 2008, 130, 13745.
9 For the biosynthetic pathway of lobeline see: F.-X. Felpin and
J. Lebreton, Tetrahedron, 2004, 60, 10127.
10 F. D. Klingler and R. Sobotta, (assigned to Boehringer Ingelheim),
US pat., 2006014791, 2006; F. D. Klingler, Acc. Chem. Res., 2007, 40,
1367.
11 D. Compere, C. Marazano and B. C. Das, J. Org. Chem., 1999, 64, 4528.
12 F.-X. Felpin and J. Lebreton, J. Org. Chem., 2002, 67, 9192.
13 (a) L. Minuti, Eco-Friendly Synthesis of Fine chemicals, 2009, pp.
2008, 1455; (c) L. L. Etchells, M. Helliwell, N. M. Kershaw,
A. Sardarian and R. C. Whitehead, Tetrahedron, 2006, 62, 10914;
(d) H. Takayama, T. Ichikawa, T. Kuwajima, M. Kitajima, H. Seki,
N. Aimi and M. G. Nonato, J. Am. Chem. Soc., 2000, 122, 8635;
(e) S. Fustero, D. Jiménez, J. Moscardó, S. Catalán and C. del Pozo, Org.
Lett., 2007, 9, 5283; (f) S. Calvet-Vitale, C. Vanucci-Bacqué,
M.-C. Fargeau-Bellassoued and G. Lhommet, Tetrahedron, 2005, 61,
7774.
23 (a) P. R. Krishna, A. Sreeshailam and R. Srinivas, Tetrahedron, 2009, 65,
9657; (b) D. Enders, C. Wang and J. X. Liebich, Chem.–Eur. J., 2009,
15, 11058; (c) S. G. Davies, A. D. Smith and P. D. Price, Tetrahedron:
Asymmetry, 2005, 16, 2833; (d) L.-W. Xu and C.-G. Xia, Eur. J. Org.
Chem., 2005, 633.
24 (a) J. d’Angelo and J. Maddaluno, J. Am. Chem. Soc., 1986, 108, 8112;
(b) F. Dumas, B. Mezrhab and J. d’Angelo, J. Org. Chem., 1996, 61,
2293; (c) F. Dumas, C. Fressigné, J. Langlet and C. Giessner-Prettre,
J. Org. Chem., 1999, 64, 4725.
25 (a) M. L. Kantam, S. Laha, J. Yadav and S. Jha, Tetrahedron Lett., 2009,
50, 4467; (b) S. Gogoi, C. Zhao and D. Ding, Org. Lett., 2009, 11, 2249;
(c) M. I. Uddin, K. Nakano, Y. Ichikawa and H. Kotsuki, Synlett, 2008,
1402.
26 (a) A. Y. Rulev, N. Yenil, A. Pesquet, H. Oulyadi and J. Maddaluno,
Tetrahedron, 2006, 62, 5411; (b) F. Bargiggia and W. V. Murray, Tetra-
hedron Lett., 2006, 47, 3191; (c) S. M. Weinreb, Chem. Rev., 2006, 106,
2531; (d) J. Legeay, W. Lewis and R. A. Stockman, Chem. Commun.,
2009, 2207; (e) Y. Chen, C. Zhong, J. L. Petersen, N. G. Akhmedov and
X. Shi, Org. Lett., 2009, 11, 2333; (f) A. Rosiak, C. Hoenke and
J. Cristoffers, Eur. J. Org. Chem., 2007, 4376; (g) Q. Zang, S. Javed,
F. Ullah, A. Zhou, C. A. Knudtson, D. Bi, F. Z. Basha, M. G. Organ and
P. R. Hanson, Synthesis, 2011, 2743.
237–274,
ISBN:
978-1-84755-976-0; (b)
F.
Benito-López,
R. J. M. Egberink, D. N. Reinhoudt and W. Verboom, Tetrahedron, 2008,
64, 10023; (c) K. Matsumoto, Top. Heterocycl. Chem., 2007, 8, 1;
(d) C. Camara, L. Keller, K. Jean-Charles, D. Joseph and F. Dumas, High
Pressure Res., 2004, 24, 149; (e) G. Jenner, Tetrahedron, 2002, 58, 5185;
Organic Synthesis at High Pressures, ed. K. Matsumoto, and
R. M. Acheson, Wiley, New York, 1991.
14 For
a review of heterocyclic sonochemistry, see: R. Cella and
H. A. Stefani, Tetrahedron, 2009, 65, 2619.
27 (a) S. P. Singh, T. V. Kumar, M. Chandrasekharam, L. Giribabu and
P. Y. Reddy, Synth. Commun., 2009, 39, 3982; (b) M. Saikia, D. Kakati,
M. S. Joseph and J. C. Sarma, Lett. Org. Chem., 2009, 6, 654;
(c) I. Damljanović, D. Stevanović, A. Pejović, M. Vukićević, S.
B. Novaković, G. A. Bogdanović, T. Mihajlov-Krstev, N. Radulović and
R. D. Vukićević, J. Organomet. Chem., 2011, 696, 3703; (d) T.-B. Wei,
M.-T. Hua, H.-X. Shi, Y. Liu and Y.-M. Zhang, J. Chem. Res., 2010, 34,
452.
28 (a) Z. Duan, X. Xuan, T. Li, C. Yang and Y. Wu, Tetrahedron Lett., 2006,
47, 5433; (b) J.-M. Yang, S.-J. Ji, D.-G. Gu, Z.-L. Shen and S.-Y. Wang,
J. Organomet. Chem., 2005, 690, 2989; (c) V. B. Labade, S. S. Pawar
and M. S. Shingare, Monatsh. Chem., 2011, 142, 1055; (d) Z. Shobeiri,
M. Pourayoubi, A. Heydari, T. M. Percino and M. A. L. Ramirez,
C. R. Chim., 2011, 14, 597.
29 (a) G. P. Black, P. J. Murphy and N. D. A. Walshe, Tetrahedron, 1998,
54, 9481; (b) G. P. Black, F. Dinon, S. Fratucello, P. J. Murphy,
M. Nielsen, H. L. Williams and N. D. A. Walshe, Tetrahedron Lett.,
1997, 38, 8561; (c) F. Dinon, E. L. Richards, P. J. Murphy, D. E. Hibbs,
M. B. Hursthouse and K. M. A. Malik, Tetrahedron Lett., 1999, 40,
3279–3282; (d) E. L. Richards, P. J. Murphy, F. Dinon, S. Fratucello, P.
M. Brown, T. Gelbrich and M. B. Hursthouse, Tetrahedron, 2001, 57,
7771.
30 For recent intramolecular RC reactions, see: (a) L.-C. Wang, A. L. Luis,
K. Agapiou, H.-Y. Jang and M. J. Krische, J. Am. Chem. Soc., 2002, 124,
2402; (b) S. A. Frank, D. J. Mergott and W. R. J. Roush, J. Am. Chem.
Soc., 2002, 124, 2404; (c) D. J. Mergott, S. A. Frank and W. R. Roush,
Org. Lett., 2002, 4, 3157; (d) K. Agapiou and M. J. Krische, Org. Lett.,
2003, 5, 1737; (e) J. L. Methot and W. R. Roush, Org. Lett., 2003, 5,
4223; (f) B. G. Jellerichs, J. R. Kong and M. J. Krische, J. Am. Chem.
Soc., 2003, 125, 7758; (g) D. J. Mergott, S. A. Frank and W. R. Roush,
Proc. Natl. Acad. Sci. U. S. A., 2004, 101, 11955; (h) C. E. Aroyan,
A. Dermenci and S. J. Miller, Tetrahedron, 2009, 65, 4069;
(i) C. E. Aroyan and S. J. Miller, J. Am. Chem. Soc., 2007, 129, 256;
( j) F. Seidel and J. A. Gladysz, Synlett, 2007, 986; (k) E. Marqués-
López, R. P. Herrera, T. Marks, W. C. Jacobs, D. Könning, R. M. de Fig-
ueiredo and M. Christmann, Org. Lett., 2009, 11, 4116.
15 L. Cabral dos Santos, Z. Bahlaouan, K. El Kassimi, C. Troufflard,
F. Hendra, S. Delarue-Cochin, M. Zahouily, C. Cavé and D. Joseph,
Heterocycles, 2007, 73, 751.
16 S. Moura, C. Thomassigny, C. Ligeour, C. Greck, D. Joseph, E. Drège
and F. Dumas, Green Chem., 2011, 13, 1812.
17 (a) A. Blum and W. E. Diederich, Curr. Org. Synth., 2009, 6, 38;
(b) S. Zhang, L. Xu, L. Miao, H. Shu and M. L. Trudell, J. Org. Chem.,
2007, 72, 3133; (c) M. Sato, Y. Gunji, T. Ikeno and T. Yamada, Synthesis,
2004, 1434; (d) M. Pichon and B. Figadère, Tetrahedron: Asymmetry,
1996, 7, 927; (e) J. W. Daly, T. F. Spande, N. Whittaker, R. J. Highet,
D. Feigi, N. Nishimori, T. Tokuyama and C. W. Myers, J. Nat. Prod.,
1986, 49, 265.
18 (a) J. K. Whitesell, Chem. Rev., 1989, 89, 1581; (b) J. K. Whitesell and
S. W. Felman, J. Org. Chem., 1977, 42, 1663; (c) B. B. Snider and
Q. Zhang, Tetrahedron Lett., 1992, 33, 5921; (d) N. A. Porter,
D. M. Scott, B. Lacher, B. Giese, H. G. Zeitz and H. J. Lindner, J. Am.
Chem. Soc., 1989, 111, 8311; (e) B. Giese, U. Hoffmann, M. Roth,
A. Velt, C. Wyss, M. Zehnder and H. Zipse, Tetrahedron Lett., 1993, 34,
2445; (f) R. H. Schlessinger, E. J. Iwanowicz and J. P. Springer, Tetra-
hedron Lett., 1988, 29, 1489; (g) T. Yamazaki, J. T. Welch, J. S. Plummer
and R. H. Gimi, Tetrahedron Lett., 1991, 32, 4267; (h) L.-Y. Chen and
L. Ghosez, Tetrahedron Lett., 1990, 31, 4467; (i) C. Genicot and
L. Ghosez, Tetrahedron Lett., 1992, 33, 7357; ( j) V. Gouverneur and
L. Ghosez, Tetrahedron Lett., 1991, 32, 5349; (k) A. Defoin,
A. Brouillard-Poichet and J. Streith, Helv. Chim. Acta, 1991, 74, 103;
(l) T. Honda, N. Kimura and M. Tsubuki, Tetrahedron: Asymmetry, 1993,
4, 21; (m) A. J. Pearson and P. Y. Zhu, J. Am. Chem. Soc., 1993, 115,
10376.
19 (a) A. R. Katritzky and S. Rachwal, Chem. Rev., 2010, 110, 1564;
(b) P. Wang, Z. Xu, C. Chen, X. Gao, X. Sun and S. Zhang, Chirality,
2007, 19, 581; (c) G. Pandey, P. Banerjee and S. R. Gadre, Chem. Rev.,
2006, 106, 4484; (d) V. Daley, J. d’Angelo, C. Cavé, J. Mahuteau,
A. Chiaroni and C. Riche, Tetrahedron Lett., 1999, 40, 1657; (e) F. Perks
and P. J. Russels, J. Pharm. Pharmacol., 1963, 15, 341.
20 (a) K. E. Desino, S. Ansar, G. I. Georg, R. H. Himes, M. L. Michaelis,
D. R. Powell, E. A. Reiff, H. Telikepalli and K. L. Audus, J. Med.
Chem., 2009, 52, 7537; (b) J. Böttcher, A. Blum, S. Dörr, A. Heine,
W. E. Diederich and G. Klebe, ChemMedChem, 2008, 3, 1337.
21 (a) M. A. P. Martins, C. P. Frizzo, D. N. Moreira, L. Buriol and
P. Machado, Chem. Rev., 2009, 109, 4140; (b) N. R. Candeias,
L. C. Branco, P. M. Gois, C. A. M. Afonso and A. F. Trindade, Chem.
Rev., 2009, 109, 2703.
31 L. Pardo, R. Osman, H. Weinstein and J. R. Rabinowitzs, J. Am. Chem.
Soc., 1993, 115, 8263.
32 (a) P. M. Brown, N. Käppel and P. J. Murphy, Tetrahedron Lett., 2002,
43, 8707; (b) M. Brown, N. Käppel, P. J. Murphy, S. J. Coles and
M. B. Hursthouse, Tetrahedron, 2007, 63, 1100.
33 (a) A. L. Luis and M. J. Krische, Synthesis, 2004, 2579; (b) M. E. Krafft
and T. F. N. Haxell, J. Am. Chem. Soc., 2005, 127, 10168.
22 (a) S. Fustero, D. Jiménez, M. Sánchez-Roselló and C. del Pozo, J. Am.
Chem. Soc., 2007, 129, 6700; (b) S. Gogoi and N. P. Argade, Synthesis,
34 C. E. Aroyan, A. Dermenci and S. J. Miller, J. Org. Chem., 2010, 75,
5784.
7156 | Org. Biomol. Chem., 2012, 10, 7148–7157
This journal is © The Royal Society of Chemistry 2012

View Article Online
35 C. Yu, B. Liu and L. Hu, J. Org. Chem., 2001, 66, 5413.
36 A. R. Katritzky, X. Cui, Y. Baozhen and P. J. Steel, J. Org. Chem., 1999,
64, 1979.
38 M. N. Hansen, E. Farjami, M. Kristiansen, L. Clima, S. U. Pedersen,
K. Daasbjerg, E. E. Ferapontova and K. V. Gothelf, J. Org. Chem., 2010,
75, 2474.
37 L. A. Reddy, S. Chakraborty, R. Swapna, D. Bhalerao, G.
C. Malakondaiah, M. Ravikumar, A. Kumar, G. S. Reddy, J. Naram,
N. Dwivedi, A. Roy, V. Himabindu, B. Babu, A. Bhattacharya and
R. Bandichhor, Org. Process Res. Dev., 2010, 14, 362.
39 R. O. Hutchins and N. R. Natale, J. Org. Chem., 1978, 43, 2299.
40 P. G. Klimko’ and D. A. Singleton, J. Org. Chem., 1992, 57, 1733.
41 CCDC number of 13d: 854591.
42 CCDC number of 17: 828848.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 7148–7157 | 7157