The dual reactivity of Weinreb amides applied to the late-stage divergent functionalisation of: Meso pyrrolidines

Article abstract of DOI:10.1039/c8nj01975d

By exploiting the dual reactivity of a Weinreb amide moiety, i.e. nucleophilic addition or N-O reductive cleavage, a series of diversified symmetrical and dissymmetrical pyrrolidine analogues of lobelanine were synthesized from simple and readily available building blocks. Diversity is introduced at a late stage by using a wide variety of readily available organolithium and organomagnesium reagents, and chemoselective orientation can be achieved due to the steric encumbrance of both the reaction partners, the liganding ability of the starting meso pyrrolidine, and the nature of the organometallic species. This work constitutes the first example that takes advantage of the side reaction of Weinreb amide decomposition for the desymmetrization of a meso platform bearing two remote and highly flexible N-methoxy-N-methylamide arms through a probable beneficial metal-templated arrangement.

Full text of DOI:10.1039/c8nj01975d

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PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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DOI: 10.1039/C8NJ01975D
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Dual reactivity of Weinreb amide applied to late-stage divergent
functionalisation of meso pyrrolidines
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Hamza Boufroura,a Laurent Sevaille,a Nicolas Gigant,a Emmanuelle Drège*a and Delphine Joseph*a
www.rsc.org/
By exploiting the dual reactivity of Weinreb amide moiety, i.e. the nucleophilic addition or the N-O reductive cleavage, a
series of diversified symmetrical and dissymmetrical pyrrolidine analogues of lobelanine were synthesized from simple and
readily available building blocks. Diversity is belatedly introduced by using a wide variety of reachable organolithium and
organomagnesium reagents, and it can be chemoselectively oriented by the steric encumbrance of the both reaction
partners, by the liganding ability of the starting meso pyrrolidine, and by the nature of the organometallic species. This work
constitutes the first example that takes advantage of the side reaction of Weinreb amide decomposition for the
desymmetrization of a meso platform bearing two remote and highly flexible N-methoxy-N-methylamide arms through a
probable beneficial metal-templated arrangement.
1. Introduction
Screening of small-molecule libraries is essential for new
breakthroughs in drug discovery.1 Knowing that natural
products play a central role in traditional and modern medicine,
they maintain their continued eminence as compounds source
and continue to inspire the chemists community for the
development of new bioactive leads.2 If the isolation and the
total synthesis of natural products represent challenging
research areas, development of step-economical processes
when oriented towards diversity is a powerful strategy to
rapidly and efficiently generate collection of structurally diverse
analogues.3 Therefore, in recent years, extensive research
programs have been carried out to easily synthesize original and
diverse structures bearing a high degree of complexity starting
from simple substrates.4
Figure 1. Two ways of diversity-oriented synthesis of pyrrolidine lobelanine analogues
In this respect, by using a one-pot sequential tandem double
cross-metathesis (CM)/RCDAM, we effectively prepared an
original meso bis-(Weinreb amide) pyrrolidine 2.9 This valuable
scaffold let us to envisage a reverse divergent approach for the
synthesis of new pyrrolidine lobeline analogues (Figure 1).
Taking account that Weinreb amides tolerate a wide variety of
organometallic reagents, this approach offers a rapid high rate
of late-stage incorporation of molecular diversity.10 In addition,
the step-economical preparation of symmetrical and
unsymmetrical pyrrolidine analogues could be envisaged by
modulating the reaction conditions (Figure 1). If effectiveness of
desymmetrization strategies in terms of atom and step
economy no longer need to be demonstrated,11 only two
examples of desymmetrization of bis-Weinreb amide have been
reported in literature until now. As for the most examples of
desymmetrization,12 they concerned conformationally stiffened
scaffolds.13,14 Mono- or di-ketone derivatives were elegantly
synthesized depending on the reactants stoichiometry of
organometallic reagents used. However, desymmetrizing a
As part of a fundamental research program aiming at studying
the nAChRs allosteric rearrangement, we took a particular
interest in designing and synthesizing a series of Lobelia
alkaloids analogues whose three-dimensional geometry and
configurational instability could be controlled.5 We developed
step-economical synthesis of difunctionalised pyrrolidines
1
allowing early introduction of diversity through a ring-closing
double aza-Michael (RCDAM) addition of various amines to
diverse symmetrical double Michael acceptors (Figure 1).6,7,8
a.BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay, F-92296 Châtenay-
Malabry, France.
E-mail: emmanuelle.drege@u-psud.fr; delphine.joseph@u-psud.fr
Electronic Supplementary Information (ESI) available: 1H et 13C NMR spectra of
original symmetric and dissymmetric pyrrolidines. See DOI: 10.1039/x0xx00000x
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highly flexible scaffold in the presence of a competitive evaluated (THF, ether, hexane and DME). THF provided the best
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chelating pyrrolidine nitrogen already remains
challenge.
a
great results probably due to the better miscibiDliOtyI:o10f.t1h03e9r/eCa8cNtJa0n19ts75aDt
low temperature. The effect of the reaction temperature was
Based on these considerations and exploiting the dual next evaluated. Low temperature gave much higher yields by
reactivity of N-methoxy-N-methylamides, we report herein an limiting degradation of the starting material through base-
expedient and unprecedented method for the synthesis of catalysed retro-Michael reaction.
valuable symmetrical and dissymmetrical 2,5-disubstituted The reactivity of 2a was first investigated towards the more
pyrrolidines exhibiting three points of molecular diversity. To reactive organolithium reagents (Table 1). As expected, the
the best of our knowledge, this work represents the first addition of 5 equivalents of methyllithium at -78 °C in THF led
example which takes advantage of the side reaction of N-O to the symmetrical pyrrolidine 3aa in a good 66% yield (Table 1,
reductive cleavage15 for desymmetrizing a meso pyrrolidine entry 1).
bearing two remote and highly flexible Weinreb amide
functions.
Table 1 Scope of the reaction with various organolithium reagents.a
2. Results and discussion
The starting meso Weinreb amide-derived pyrrolidines 2a and
2b were efficiently prepared through the extension of the
telescoped microwave-assisted double CM/RCDAM reported
earlier by our group.9 Both N-substituted pyrrolidines were
efficiently synthesized using respectively benzylamine and
Entry
R2
R1
3 (%)b
4 (%)b
methylamine (Scheme 1). The choice of the amine nature was
imposed, in one hand, by the low reactivity of -substituted
1
2
3
4
5
6
Bn
Me
Bn
Me
Bn
Me
3aa (66)
3ba (80)
3ab (49)
3bb (64)
3ac (57)
3bc (54)
-
-
-
-
-
-

Me
enamide in the Michael addition, offset by using good
nucleophilic partner such as primary alkylamine. In the other
hand, the N-benzyl derivative 2a offers the opportunity to
n-Bu
introduce
late
diversity
through
a
N-
hexyn-1-yl
debenzylation/functionalisation sequence while its N-Me
cousin 2b affords a direct access to pyrrolidine lobelanine
analogues. Delightfully, 2a and 2b were isolated
stereoselectively in their exclusive 2,5-cis stable configuration.
7
Me
3bd (56)
-
8
9
10
11
12
Bn
Me
Bn
Me
Me
3ae (61)
3be (56)
3af (45)
3bf (41)
3bg (51)
4ae (< 5)
4be (42)
4af (23)
4bf (25)
4bg (11)
Ph
thien-2-yl
pyridin-3-yl
a Reaction conditions: 2 (1 equiv), R2Li (5 equiv) in THF (0.25 M) at -78 °C to rt
overnight. b Isolated yield.
The procedure was also compatible with the N-methylated
backbone 2b affording the double adduct 3ba in an high 80%
yield (Table 1, entry 2). Similarly, the addition of n-butyllithium
provided the meso diketones 3ab and 3bb in satisfying 49% and
64% yields respectively (Table 1, entries 3-4). The scope was
next extended by involving 1-hexynyllithium affording two
additional original pyrrolidines 3ac and 3bc in comparable yields
(Table 1, entries 5-6). A functionalised alkyne fragment was also
accommodated leading to the valuable pyrrolidine 3bd showing
the reaction adaptability to functionalised RLi reagents17 (Table
1, entry 7). To increase the chemodiversity, we next sought to
explore the reactivity with aryllithium and heteroaryllithium
reagents. Serendipitously, the reaction of 2a with phenyllithium
gave, not only the expected symmetrical adduct 3ae, but also a
trace amount of the separable desymmetrised pyrrolidine 4ae
featuring a N-methylamide moiety on one of its two arms (Table
1, entry 8). This very appealing desymmetrising process was
heightened when the reaction was carried out from the less
cluttered N-methyl pyrrolidine 2b for which the dissymmetrical
Scheme 1 Synthesis of 2,5-cis-bis(Weinreb acetamido)pyrrolidines 2a and 2b.
Having these meso double Weinreb amides 2a and 2b in hand,
their reactivity was investigated towards two organometallic
species, namely organolithium and organomagnesium
derivatives. After initial optimisation, we found that
equivalents of the organometallic reagent were required for a
complete conversion of the starting material into bis-
5
2
functionalised pyrrolidines. The use of an excess of
organometallic reagent is consistent with the mechanistical
study by Qu and Collum who demonstrated that the tetrahedral
intermediate would be stabilized as mixed tetrameric metal
aggregates.16 In parallel, the effect of several solvents was also
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in satisfying
product 4be was isolated in a 42% yield. The symmetrical Grignard providing the respective double adducts View Article Online
3
1
DOI: 10.1039/C8NJ01975D
double adduct 3be was also produced in a 56% yield, rendering yields. However, careful analysis of the H NMR spectra of the
the reaction very efficient with an overall 98% yield (Table 1, crude reaction mixtures revealed the presence of a small
entry 9). A similar trend was observed by treating 2a and 2b amount of the conjugated enone 3ah or 3bh respectively.
with 2-thienyllithium (Table 1, entries 10-11). Finally, keeping in Purification through flash column chromatography on neutral
minds that drug’s pharmacokinetic behaviour including drug alumina, accentuated the [1,3]-H shift olefin isomerization
absorption is affected by its water solubility, we sought to providing mostly or exclusively the conjugated vinyl derivatives
introduce ionisable groups by synthesising
a pyridine- 3ah or 3bh respectively (Table 2, entries 3-4). To further explore
containing framework.18 The symmetrical pyrrolidine 3bg was the influence of the nucleophilic species, we probed the
isolated in a good 51% yield separately to a small amount of the reactivity of bulkier Grignard reagents. As noticed for the
dissymmetrical acetamide derivative 4bg (Table 1, entry 12). organolithiums,
Albeit alkylation and alkynylation were highly chemoselective detrimental impact on the nucleophilic addition favouring the
affording exclusively the corresponding bis-ketone with N-demethoxylation reaction through the preferred H-
a sterically demanding carbanion has a
3
retention of the cis configuration, the use of more crowded and abstraction step. Indeed, when phenylmagnesium bromide was
stronger basic aryllithium induced the formation of the used, this reactivity was reaffirmed and bolstered: among the
dissymmetrical mono-keto mono-amide pyrrolidine
4. The expected meso diketone 3ae, not only the dissymmetrical
latter results from a first standard nucleophilic addition on one amide 4ae but also the symmetric twofold N-demethoxylated
of the two N-methoxy-N-methylamide functions and the diamide 5a were astonishingly isolated (Table 2, entry 5). As 5a
concomitant N-demethoxylation of the second Weinreb amide. was not detected in the presence of the more reactive PhLi
The commonly accepted mechanism of this N-O cleavage is reagent, the counterion of the nucleophilic partner appeared to
based on a direct bimolecular E2 elimination releasing be another key parameter for the reaction outcome. Attempts
monomeric formaldehyde (Scheme 2).15 However, as to increase the nucleophilic addition rate by the presence of 1
demonstrated by Keck et al., an alternative enolization/retro- or 2 equivalents of MgBr2 failed: the reaction was unfortunately
ene fragmentation sequence can also be envisaged for totally inhibited by the presence of the oxophilic Lewis acid.
unencumbered Weinreb amides possessing a methylene group Noticeably, starting from the less crowded 1-methyl pyrrolidine
adjacent to the carboxamide function (Scheme 2).15,19 With 2b, the diamide 5b was not observed showing the concomitant
respect to the outcomes of the addition of aryllithiums, these effect of both reactants bulkiness and organometallic basicity
both modes of reductive N-O cleavage could be considered to (Table 2, entry 6). Respectively, a comparable behaviour was
explain the formation of
4
.
observed with 2-thienylmagnesium bromide starting from N-
alkyl pyrrolidines 2a and 2b (Table 2, entries 7-8).
Table 2 Scope of the reaction with various Grignard reagents.a
Scheme 2 Plausible mechanisms of reductive N-O cleavage.
Surprisingly, regarding more specifically the literature
dedicated to the desymmetrisation of meso bis-Weinreb
amides,13,14 the formation of chimeric acylated/N-
demethoxylated compounds was scarcely observed, even when
a large excess of encumbered organometallic reagents was
used.
Based on these first observations, we pursued by studying the
addition of a series of alkyl- and aryl-magnesium bromides
under identical reaction conditions (Table 2). Satisfying results
Entry
R2
R1
3 (%)b
4 (%)b
-
-
-
5 (%)b
-
-
-
1
2
3
4
5
6
7
8
9
Bn
Me
Bn
Me
Bn
Me
Bn
Me
Bn
3aa (65)
3ba (80)
3ah (56)c
3bh (53)d
3ae (30)
3be (25)
3af (23)
3bf (18)
-
Me
allyl
Ph
-
-
4ae (32)
4be (30)
4af (34)
4bf (46)
-
5a (36)
-
5a (11)
-
5a (53)
thien-2-yl
were obtained in the presence of
5 equivalents of
i-Pr
methylmagnesium bromide, efficiently leading to symmetrical
pyrrolidine 3aa or 3ba (Table 2, entries 1-2). Both reaction rate
and chemoselectivity were like those entailed by the lithiated
base. The method was then extended to the addition of allyl
Reaction conditions: 2 (1 equiv), R2Li (5 equiv) in THF (0.25 M) at -78 °C to rt
overnight. b Isolated yield. c allyl:vinyl ratio = 1:2. d allyl:vinyl ratio > 2:98.
a
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To further explore the influence of the steric encumbrance and the metal chelation by the pyrrolidine nitrogen atom prevents
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to orientate the reaction outcome, we probed the reactivity of the N-methoxy-N-methylamide decompoDsOitiI:o1n0..1039/C8NJ01975D
the bulky isopropylmagnesium bromide. As assumed, only the
double N-demethoxylation was isolated, selectively leading to
Table 3. Scope of the reaction with N-tosyl pyrrolidine 2c.a
the symmetrical diacetamide 5a in a 53% isolated yield (Table 2,
entry 9).
Even though hindered Grignard reagents were more inclined to
induce reductive cleavage of the N-O bond than their lithiated
homologues, the pyrrolidine nitrogen atom also seems to play
a crucial role in the chemoselectivity by its sterically demanding
substituent. Nevertheless, the coordination ability of such
nitrogen-containing heterocycles cannot be omitted. Indeed, in
contrast to geometrically constrained bis-Weinreb amides,13,14
the structural complexity induced by the concomitant presence
of flexible remote Weinreb amide arms and the metal-chelating
nitrogen could be responsible of the significant formation of
entry
R
M
Li
3 (%)b
3ca (80)
3ca (80)
3cf (60)
3cf (70)
1
2
3
4
Me
MgBr
Li
thien-2-yl
MgBr
a Reaction conditions: 2c (1 equiv), R[M] (5 equiv) in THF (0.25 M) at -78 °C to rt
overnight. b Isolated yield.
demethoxylated compounds
4 and 5. Acting as metal internal
ligands, these three chelating patterns could privilege three-
dimensional arrangements conducive to the demethoxylation
process. This hypothesis is supported by our previous works
showing that pyrrolidine lobelanine analogues can adopt stable
privileged geometries through intramolecular H-bonds or T-
These results confirmed that the reaction chemoselectivity is
controlled, in part, by the ability of the central pyrrolidine
nitrogen to ligand the organometallic species that probably
favoured geometries prone to reductive N-O cleavage. On the
other hand, Lewis basicity of the organometallic reagent
combined with the steric hindrance of both the pyrrolidine N-
substituent and the nucleophile are also key parameters.
Consequently, we anticipated that the presence of an external
ligand in the reaction mixture would modulate the contribution
of each parameter and could preferentially lead the valuable
desymmetrised pyrrolidine. While the preparation of the
dissymmetrical compound gave better ratio with
organomagnesium derivatives, the study was conducted using
more challenging organolithium reagents and TMEDA was
selected as external ligand due to its high affinity for lithium
ion.20 We then explored how the presence of TMEDA could
shaped
-stacking interactions between the pyrrolidine
nitrogen substituent and the two phenacyl arms.7
Thus, to further evaluate the role of chelating pyrrolidine
nitrogen, we envisaged to prepare the N-tosyl-protected
pyrrolidine 2c. We surmised that the nitrogen sp2 hybridization
and the delocalization of its electrons lone pair could disfavour
intramolecular organisation. Attempts to prepare the
pyrrolidine 2c by the direct microwave-assisted RCDAM process
in the presence of p-toluene-sulfonamide remained
unsuccessful confirming the complementary role played by
both partners of the aza-Michael reaction. An alternative multi-
step strategy was adopted based on the deprotection of the N-
benzyl pyrrolidine 2a by catalytic hydrogenolysis, followed by
the sulfamidation of the free amine moiety. 2c was prepared in
a 47% yield over two steps with retention of the 2,5-cis
stereoselectivity (Scheme 3).
impact the addition of 2-thienyllithium onto the pyrrolidine 2b
.
By using 5 equivalents of TMEDA, the selectivity of the reaction
was slightly reversed, generating 3bf and 4bf in a 41:59 ratio
(Table 4, entry 1 vs 2). To favour the desymmetrising process
through both the formation of an intramolecularly chelated
intermediate and the increase of Lewis basicity of nucleophilic
patner, a lower reagent loading was examined. Pleasingly, the
3bf
to generate
:
4bf ratio dropped to 37:63 (Table 4, entry 3). With the aim
more reactive complex, TMEDA and 2-
a
thienyllithium were premixed prior to the addition to the
reaction mixture (Table 4, entry 4). Gratifyingly, the product
ratio was improved to 28:72 in the favour of the desymmetrised
product 4bf, demonstrating the synthetic potential of our
Scheme 3. Synthesis of N-tosyl-2,5-cis-bis(Weinreb acetamido)pyrrolidine 2c.
procedure with
a possible switch of chemoselectivity.
Encouraged by these last results, we sought to expand the
scope by applying these reaction conditions to the pyrrolidine
2a and other organolithium reagents (Table 5). Both the N-alkyl
pyrrolidines 2a and 2b gave a reversed selectivity in the
presence of 2-thienyllithium (Table 5, entries 1-2).
The addition of methyllithium or methylmagnesium bromide on
the N-tosyl protected compound 2c gave, in both cases, similar
results to those obtained from N-alkyl pyrrolidines 2a and 2b
,
affording the symmetrical double adduct 3ca in an excellent
80% yield (Table 3, entries 1-2). Delightfully, when the reactivity
of 2c was assessed in the presence of 2-thienyllithium or 2-
thienylmagnesium bromide, the sole symmetrical double
arylated pyrrolidine 3cf was cleanly isolated. Thus, disfavouring
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Table 4. Effect of the TMEDA on the selectivity of the reaction.a
deprotonation of the more accessible methoxy proVtioewnArreticnledOenrleinde
more acidic by the metal chelation (Scheme 4).
DOI: 10.1039/C8NJ01975D
Scheme 4 Possible intramolecular chelation explaining reductive N-O cleavage.
3bf:4bf
ratioc
entry
conditions
3bf (%)b
4bf (%)b
The formation of this probable chelated intermediate can be
1
2
3
4
-
41
22
21
16
25
32
35
41
62:38
41:59
37:63
28:72
reasonably supported by mechanistic studies made by Sibi et
TMEDA (5 equiv)
al.14 According to its stability,
a chelated tetrahedral
TMEDA (4 equiv)
intermediate may evolve towards a more stable chelate
involving the distal Weinreb moiety. Similarly to Sibi’s results,14
we also observed that the larger magnesium counterion which
could contribute to the intermediate stability by reducing steric
constriction, favoured the N-O reductive cleavage.
TMEDA (4 equiv, premixed)
a Reaction conditions: 2b (1 equiv), RLi (5 equiv) in THF (0.25 M) at -78 °C to rt
overnight. b Isolated yield. c Ratio determined from isolated products.
This result was confirmed by using phenyllithium, the formation
of 4be was favoured under these new reaction conditions
(Table 5, entry 3). It is important to note that traces of 4ae were
detected without TMEDA whereas it was henceforth isolated as
the major product (Table 5, entry 4). Finally, it was found that
addition of the external ligand did not affect the selectivity of
the reaction in the presence of n-butyllithium, exclusively
producing the corresponding meso adduct 3ab (Table 5, entry
5).
3. Experimental
General Remarks
Commercial reagents were used without purification. THF was
distilled from sodium/benzophenone immediately prior to use.
1H (respectively 13C) NMR spectra were recorded at 300 or 400
MHz (respectively 75 or 100 MHz). Chemical shifts values are
given in ppm downfield from tetramethylsilane (TMS) with the
solvent resonance as the internal standard. Coupling constants
(J) are reported in Hz and refer to apparent peak multiplicities.
Mass spectra and high-resolution mass spectra were obtained
with a Q-TOF spectrometer using electrospray ionisation (ESI).
Melting points are uncorrected and were recorded on a
micromelting point apparatus. Infrared (IR) spectra were
recorded as neat films. Analytical thin layer chromatography
was performed on 60F-254 precoated silica (0.2 mm) on glass
and was revealed by UV light or by spraying with Dragendorf
Table 5. Scope of the effect of TMEDA.a
entry
R2Li
R1
Me
Bn
Me
Bn
Bn
3 (%)b
4 (%)b
4bf (41)
4af (34)
4be (23)
4ae (46)
4ab (0)
3:4 ratioc
28:72
36:64
40:60
30:70
100:0
reagent. Compounds 2b 9 3ba 8 3ae7 and 3be8 were prepared
, ,
1
2
3
4
5
3bf (16)
3af (19)
3be (16)
3ae (20)
3ab (41)
according the respective following procedures exhibiting
experimental data in accordance with those previously
reported in the literature.
thien-2-yl
Ph
n-Bu
Preparation of Weinreb acetamide-substituted pyrrolidines 2
a Reaction conditions: 2 (1 equiv), premixed R2Li (4 equiv) and TMEDA (4 equiv) in
2-(1-Benzylpyrrolidine-2,5-cis-diyl)bis(N-methoxy-N-methyl
acetamide) (2a): To a stirred solution of the 1,5-hexadiene (74
µL, 0.61 mmol, 1 equiv) in CHCl3 (0.5 M, 1.2 mL) was
consecutively added N-methoxy-N-methylacrylamide (211 mg,
1.83 mmol, 3 equiv) and Ru-catalyst M2 (2.5 mol%). The mixture
was heated to 100 °C under microwaves irradiation (200 W) for
1 h. After another addition of 2.5 mol% of Ru-catalyst M2, the
mixture was heated for an additional hour. After cooling at
room temperature, benzylamine (200 µL, 1.83 mmol, 3 equiv)
was directly added to the crude mixture which was heated once
more at 100 °C under microwaves irradiation (200 W) for 2 h.
The crude solution was then evaporated under reduced
c
THF (0.25 M) at -78 °C to rt overnight. b Isolated yield. Ratio determined from
isolated products.
Thus, the reaction outcome seems to be mediated by an
intramolecular arrangement of the mono metal-chelated
tetrahedral intermediate (Scheme 4). Both the pyrrolidine
nitrogen and the distal methoxy oxygen atoms could act as
internal ligands and induce the formation of a plausible
sterically crowded tricyclic complex. In the presence of a
crowded base, the latter may explain the competitive
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pressure. Subsequent purification by flash chromatography on 2H), 2.03 (m, 8H), 1.42 (m, 2H); 13C NMR (CDCl3V,iew75ArtiMcleHOzn)line
DOI: 10.1039/C8NJ01975D
neutral alumina gave the expected meso-pyrrolidine 2a as 208.2, 140.1, 129.0, 128.4, 127.1, 61.2, 58.2, 50.5, 30.8, 30.1;
yellow oil (200 mg, 90%).
1410, 1385, 1029; 1H NMR (CDCl3, 400 MHz)
3.78 (s, 2H), 3.51 (s, 6H), 3.20 (m, 2H), 3.09 (s, 6H), 2.53 (m, 2H), 2,2'-(1-Tosylpyrrolidine-2,5-cis-diyl)bis(propan-2-one) (3ca)
2.34 (m, 2H), 2.00 (m, 2H), 1.53 (m, 2H); 13C NMR (CDCl3, 100 Prepared following the general procedure using a solution of 2c
MHz) 171.8, 140.3, 128.9, 128.1, 126.7, 61.9, 58.2, 61.1, 39.0, (100 mg, 0.23 mmol) in THF (0.9 mL) and methyllithium solution
31.8, 30.1; HRMS (ESI) calcd for C19H30N3O4 [M + H]+ m/z 1.6 M in diethyl ether (1.1 mL, 1.15 mmol, 5 equiv, Method A)

max/cm-1 (neat) 1658, 1648, 1495, HRMS (ESI) calcd for C17H24NO2 [M + H]+ m/z 274.1802, found

7-35-7.14 (m, 5H), 274.1806.
:

364.2231, found 364.2236.
or methylmagnesium bromide 3.0 M in diethyl ether (0.58 mL,
2,2'-(1-Tosylpyrrolidine-2,5-cis-diyl)bis(N-methoxy-N-methyl
acetamide) (2d): pyrrolidine 2a (120 mg, 0.33 mmol, 1 equiv) mg, 80%, Method A or B).
was dissolved in freshly distilled dry ethanol (13 mL). The 1369, 1339, 1158; H NMR (CDCl3, 300 MHz)
1.15 mmol, 5 equiv, Method B), affording 3ca as yellow oil (63

max/cm-1 (neat) 1708, 1598, 1416,
1
 7.63 (d, J = 8.2
solution was hydrogenolyzed with a ThalesNano H-cube™ Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H), 3.81 (br., 2H), 3.13 (dd, J = 17.7,
hydrogenator using a 10% Pd/C cartridge at 40 °C under 50 bar 3.4 Hz, 2H), 2.61 (dd, J = 17.7, 9.5 Hz, 2H), 2.36 (s, 3H), 2.11 (s,
H2 pressure and 1 mL/min flow rate. Ethanol was then 6H), 1.63 (m, 2H), 1.42 (m, 2H); 13C NMR (CDCl3, 75 MHz)

evaporated in vacuo and the crude pyrrolidine 2c was directly 206.8, 147.7, 133.4, 129.8, 127.6, 57.2, 50.7, 30.5, 30.1, 21.5;
used in the next step without purification. The latter and Et3N HRMS (ESI) calcd for C17H23NO4S [M + Na]+ m/z 360.1240, found
(86 µL, 0.62 mmol, 1.9 equiv) were diluted in DCM (3 mL) and 360.1243.
added to a stirred solution of p-toluenesulfonyl chloride (71.2 1,1'-(1-Benzylpyrrolidine-2,5-cis-diyl)bis(hexan-2-one) (3ab)
:
mg, 0.37 mmol, 1.1 equiv) in DCM (2 mL) at 0°C. The reaction Prepared following the general procedure using a solution of 2a
mixture was stirred for 12 hours at room temperature, then (127 mg, 0.35 mmol) in THF (1.4 mL) and n-butyllithium solution
concentrated under reduced pressure, and purified by flash 1.6 M in hexane (1.09 mL, 1.75 mmol, 5 equiv, Method A), or a
chromatography on silica gel to give 2d as yellow oil (66.5 mg, solution of TMEDA (210 µL, 1.4 mmol, 4 equiv) and n-
47 % over two steps).

max/cm-1 (neat) 1650, 1342, 1158, 1091, butyllithium solution 1.6 M in hexane (875 µL, 1.4 mmol, 4
7.74 (d, J = 8.2 Hz, 2H), equiv, Method C), affording 3ab as yellow oil (61 mg, 49%,
999, 665; 1H NMR (CDCl3, 400 MHz)

7.30 (d, J = 8.2 Hz, 2H), 3.96 (m, 2H), 3.72 (s, 6H), 3.23 (m, 2H), Method A; 51 mg, 41%, Method C).
3.16 (s, 6H), 2.63 (dd, J = 15.9, 10.5 Hz, 2H), 2.40 (s, 3H), 1.68 1707, 1367, 1122, 700; H NMR (CDCl3, 300 MHz)
(m, 2H), 1.61 (m, 2H); 13C NMR (CDCl3, 100 MHz)
 171.8, 143.5, (m, 5H), 3.68 (s, 2H), 3.11 (m, 2H), 2.45 (dd, J = 15.9, 3.3 Hz, 2H),

max/cm-1 (neat) 2957, 2931,
7.30-7.21
1

133.7, 129.7, 127.7, 61.3, 58.2, 39.9, 32.0, 30.1, 21.5; HRMS 2.28 (dd, J = 15.7, 8.2 Hz, 2H), 2.24-2.18 (m, 4H), 1.98 (m, 2H),
(ESI) calcd for C19H29N3O6S [M + H]+ m/z 428.1850, found 1.47-1.38 (m, 6H), 1.22 (sept, J = 7.2 Hz, 4H), 0.85 (t, J = 7.3 Hz,
428.1857.
6H); 13C NMR (CDCl3, 75 MHz)
127.0, 61.3, 58.2, 49.6, 43.4, 30.2, 25.8, 22.3, 13.9; HRMS (ESI)
Typical procedure for organometallic addition on bis(Weinreb calcd for C23H36NO2 [M + H]+ m/z 358.2741, found 358.2742.
 210.6, 140.1, 128.9, 128.3,
acetamido)pyrrolidine:
1,1'-(1-Methylpyrrolidine-2,5-cis-diyl)bis(hexan-2-one) (3bb):
Prepared following the general procedure using a solution of 2b
(100 mg, 0.35 mmol) in THF (1.4 mL) and n-butyllithium solution
1.6 M in hexane (1.09 mL, 1.75 mmol, 5 equiv), affording 3bb as
Under argon, a solution of 5 equivalents of organometallic
reagent
(Method
A:
organolithium,
Method
B:
organomagnesium) or an equimolar solution of organolithium
reagent and TMEDA (4 equiv, Method C) was added dropwise to
orange oil (63 mg, 64%, Method A).
2873, 1706, 1379, 700; H NMR (CDCl3, 300 MHz)

max/cm-1 (neat) 2957, 2930,
2.79-2.71
1

a solution of symmetrical bis-(Weinreb amide) pyrrolidine
2 (1
(m, 4H), 2.39 (t, J = 7.3 Hz, 4H), 2.22 (s, 3H), 2.01-1.97 (m, 2H),
1.57-1.47 (m, 4H), 1.33-1.23 (m, 8H), 0.88 (t, J = 7.3 Hz, 6H); 13
equiv) in dry THF (0.25 M) at -78 °C. The reaction medium was
then warmed to room temperature and stirred overnight
before quenching by a saturated aqueous NH4Cl solution. The
resulting mixture was extracted with EtOAc. The combined
organic layers were washed with brine, dried over MgSO4 and
concentrated under vacuum. The crude mixture was then
purified by flash chromatography on neutral alumina, giving
C
NMR (CDCl3, 75 MHz)  210.3, 62.7, 47.9, 43.6, 39.1, 29.6, 25.9,
22.4, 14.0; HRMS (ESI) calcd for C17H32NO2 [M + H]+ m/z
282.2428, found 282.2425.
1,1'-(1-Benzylpyrrolidine-2,5-cis-diyl)bis(oct-7-yn-2-one)
(3ac): Prepared following the general procedure using a
solution of 2a (127 mg, 0.35 mmol) in THF (1.4 mL) and a
solution of hexyn-1-yllithium resulting from the addition of n-
BuLi 1.6 M in hexane (1.09 mL, 1.75 mmol, 5 equiv) to 1-hexyne
(199 µL, 1.75 mmol, 5 equiv) in THF (2mL). 3ac is isolated as an
pyrrolidines
3, 4 or/and 5.
1,1'-(1-Benzylpyrrolidine-2,5-cis-diyl)bis(propan-2-one) (3aa)
:
Prepared following the general procedure using a solution of 2a
(127 mg, 0.35 mmol) in THF (1.4 mL) and methyllithium solution
1.6 M in diethyl ether (1.1 mL, 1.75 mmol, 5 equiv, Method A)
or methylmagnesium bromide 3.0 M in diethyl ether (0.58 mL,
1.75 mmol, 5 equiv, Method B), affording 3aa as yellow oil (63
orange oil (81 mg, 57%, Method A).
2209, 1666, 1165, 700; H NMR (CDCl3, 300 MHz)

max/cm-1 (neat) 2959, 2932,
7.33-7.23
1

(m, 5H), 3.76 (s, 2H), 3.22 (m, 2H), 2.62 (dd, J = 15.6, 4.1 Hz, 2H),
2.44 (dd, J = 15.3, 4.1 Hz, 2H), 2.32 (t, J = 6.9 Hz, 4H), 2.03-1.96
(m, 2H), 1.56-1.48 (m, 5H), 1.44-1.36 (m, 5H), 0.91 (t, J = 7.3 Hz,
mg, 66%, Method A; 62 mg, 65%, Method B).
3028, 2958, 1705, 1357, 1164, 701; 1H NMR (CDCl3, 300 MHz)

max/cm-1 (neat)

6H); 13C NMR (CDCl3, 75 MHz)
 187.1, 139.5, 129.0, 128.3,
7.30 (m, 5H), 3.71 (m, 2H), 3.14 (m, 2H), 2.50 (m, 2H), 2.37 (m,
127.1, 94.7, 81.4, 61.1, 57.8, 52.5, 29.9, 29.8, 22.0, 18.7, 13.6;
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Page 7 of 10
New Journal of Chemistry
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ARTICLE
HRMS (ESI) calcd for C27H36NO2 [M + H]+ m/z 406.2741, found 7.36-7.22 (m, 5H), 7.05 (dd, J = 4.9, 3.8 Hz, 2H), 3.84 (s, 2H), 3.38
View Article Online
DOI: 10.1039/C8NJ01975D
406.2752.
(s, 2H), 3.05 (m, 2H), 2.85-2.77 (m, 2H), 2.03 (m, 2H), 1.62 (m,
1,1'-(1-Methylpyrrolidine-2,5-cis-diyl)bis(oct-7-yn-2-one)
2H); 13C NMR (CDCl3, 75 MHz)
 192.2, 144.8, 133.8, 132.3,
(3bc): Prepared following the general procedure using a 129.3, 128.6, 128.5, 128.2, 127.4, 62.3, 58.6, 46.4, 30.1; HRMS
solution of 2b (100 mg, 0.35 mmol) in THF (1.4 mL) and a (ESI) calcd for C23H24NO2S2 [M + H]+ m/z 410.1243, found
solution of hexyn-1-yllithium resulting from the addition of n- 410.1248.
BuLi 1.6 M in hexane (1.09 mL, 1.75 mmol, 5 equiv) to 1-hexyne 2-{(2S*,5R*)-1-Benzyl-5-[2-oxo-2-(thien-2-yl)ethyl] pyrrolidin-
(199 µL, 1.75 mmol, 5 equiv) in THF (2mL). 3bc is isolated as 2-yl}-N-methylacetamide (4af): Prepared following the general
yellow oil (62 mg, 54%, Method A).

max/cm-1 (neat) 2959, 2933, procedure using a solution of 2a (127 mg, 0.35 mmol) in THF
2.89-2.79 (m, 4H), (1.4 mL) and 2-thienyllithium solution 1 M in THF (1.75 mL, 1.75
2209, 1667, 1158; 1H NMR (CDCl3, 300 MHz)

2.56-2.48 (m, 2H), 2.35 (t, J = 6.9 Hz, 4H), 2.26 (s, 3H), 2.00 (m, mmol, 5 equiv, Method A) or 2-thienylmagnesium bromide
2H), 1.57-1.49 (m, 5H), 1.47-1.37 (m, 5H), 0.91 (t, J = 7.3 Hz, 6H); solution 1 M in THF (1.75 mL, 1.75 mmol, 5 equiv, Method B),
13C NMR (CDCl3, 75 MHz)
 186.8, 95.1, 81.4, 62.7, 51.0, 39.0, or a solution of TMEDA (210 µL, 1.4 mmol, 4 equiv) and 2-
29.8, 29.5, 22.1, 18.8, 13.6; HRMS (ESI) calcd for C21H32NO2 [M thienyllithium solution 1 M in THF (1.4 mL, 1.4 mmol, 4 equiv,
+ H]+ m/z 330.2428, found 330.2434.
1,1'-(1-Methylpyrrolidine-cis-2,5-diyl)bis{7-[(tetrahydro-2H-
pyran-2-yl)oxy]hept-3-yn-2-one} (3bd): Prepared following the 1648, 1555, 1413, 723, 698; 1H NMR (CDCl3, 300 MHz)
Method C), affording 4af (31 mg, 23%, Method A; 46 mg, 34%,
Methods B and C) as brown oil.
max/cm-1 (neat) 3296, 2874,
7.58 (d,


general procedure using a solution of 2b (46 mg, 0.16 mmol) in J = 3.5 Hz, 1H), 7.54 (m, 1H), 7.39 (d, J = 3.5 Hz, 1H), 7.34-7.21
THF (0.65 mL) and a solution of 5-[(tetrahydro-2H-pyran-2- (m, 5H), 7.04 (m, 1H), 3.85 (d, J = 13.3 Hz, 1H), 3.68 (d, J = 13.6
yl)oxy]pentyn-1-yllithium resulting from the addition of n-BuLi Hz, 1H), 3.38 (m, 1H), 3.12 (m, 1H), 2.89 (m, 2H), 2.75 (d, J = 4.8
1.6 M in hexane (500 µL, 0.8 mmol, 5 equiv) to 5-[(tetrahydro- Hz, 3H), 2.33 (m, 2H), 1.99-1.87 (m, 2H), 1.69-1.59 (m, 2H); 13C
2H-pyran-2-yl)oxy]pentyne (135 mg, 0.8 mmol, 5 equiv) in THF NMR (CDCl3, 75 MHz)  191.6, 172.0, 144.5, 138.4, 134.1, 132.3,
(2mL)., affording 3bd as yellow oil (45 mg, 56%, Method A). 129.5, 128.7, 128.2, 127.8, 62.4, 62.1, 58.0, 45.3, 39.2, 29.8,
1

max/cm-1 (neat) 2941, 2870, 2211, 1169, 1158, 1136, 1075; H 28.8, 25.8; HRMS (ESI) calcd for C20H25N2O2S [M + H]+ m/z
NMR (CDCl3, 300 MHz)
 4.56 (t, J = 2.7 Hz, 2H), 3.84-3.76 (m, 357.1631, found 357.1630.
4H), 3.53-3.41 (m, 4H), 3.02 (s, 3H), 2.49 (t, J = 7.0 Hz, 4H), 2.39 2,2'-(1-Methylpyrrolidine-2,5-cis-diyl)bis[1-(thien-2-
(m, 4H), 2.14 (m, 2H), 1.89-1.80 (m, 6H), 1.78-1.61 (m, 4H), 1.58- yl)ethanone] (3bf): Prepared following the general procedure
1.43 (m, 10H); 13C NMR (CDCl3, 75 MHz)
 186.0, 99.0, 95.2, using a solution of 2b (100 mg, 0.35 mmol) in THF (1.4 mL) and
81.2, 65.7, 63.1, 62.4, 50.1, 38.5, 30.7, 29.1, 28.1, 25.5, 19.6, 2-thienyllithium solution 1 M in THF (1.75 mL, 1.75 mmol, 5
16.1; HRMS (ESI) calcd for C29H44NO6 [M + H]+ m/z 502.3163, equiv, Method A) or 2-thienylmagnesium bromide solution 1 M
found 502.3160.
in THF (1.75 mL, 1.75 mmol, 5 equiv, Method B), affording 3bf
2-[(2R*,5S*)-1-methyl-5-(2-oxo-2-phenylethyl) pyrrolidin-2- (48 mg, 41%, Method A; 21 mg, 18%, Method B) as brown oil.
1
yl]-N-methylacetamide (4be): Prepared following the general
procedure using a solution of 2b (100 mg, 0.35 mmol) in THF (CDCl3, 300 MHz)
(1.4 mL) and phenyllithium solution 1.9 M in dibutyl ether (0.9 2H), 7.13 (m, 2H), 3.28-3.22 (m, 2H), 2.98-2.91 (m, 4H), 2.38 (s,
mL, 1.75 mmol, 5 equiv, Method A) or phenylmagnesium 3H), 2.08 (m, 2H), 1.51 (m, 2H); 13C NMR (CDCl3, 75 MHz)

max/cm-1 (neat) 2973, 1650, 1517, 1413, 1234, 720; H NMR

7.71 (d, J = 3.7 Hz, 2H), 7.63 (d, J = 4.9 Hz,

bromide solution 1 M in THF (1.75 mL, 1.75 mmol, 5 equiv, 191.9, 144.8, 134.0, 132.3, 128.3, 63.3, 44.7, 39.3, 29.8; HRMS
Method B), affording 4be as yellow oil (66.5 mg, 42%, Method (ESI) calcd for C17H20NO2S2 [M + H]+ m/z 334.0930, found
A; 47.5 mg, 30%, Method B);
1411; 1H NMR (CDCl3, 300 MHz)

max/cm-1 (neat) 3421, 1737, 1682, 334.0933.

7.95 (d, J = 7.3 Hz, 2H), 7.86 2-{(2S*,5R*)-1-Methyl-5-[2-oxo-2-(thien-2-yl)ethyl]pyrrolidin-
(br., 1H), 7.67 (m, 1H), 7.47 (t, J = 7.5 Hz, 2H), 3.32 (dd, J = 15.3, 2-yl}-N-methylacetamide (4bf): Prepared following the general
3.6 Hz, 1H), 3.06 (dd, J = 15.6, 7.9 Hz, 1H), 2.97 (m, 1H), 2.78 (d, procedure using a solution of 2b (100 mg, 0.35 mmol) in THF
J = 4.8 Hz, 3H), 2.68 (tt, J = 8.1, 4.4 Hz, 1H), 2.52 (dd, J = 16.0, 4.7 (1.4 mL) and 2-thienyllithium solution 1 M in THF (1.75 mL, 1.75
Hz, 1H), 2.38 (dd, J = 11.0, 4.9 Hz, 1H), 2.32 (s, 3H), 2.13-2.03 (m, mmol, 5 equiv, Method A) or 2-thienylmagnesium bromide
1H), 1.98-1.86 (m, 1H), 1.68-1.58 (m, 1H), 1.56-1.43 (m, 1H); 13
NMR (CDCl3, 75MHz) 198,7, 171.9, 137.1, 133.3, 128.7, 128.0, a solution of TMEDA (210 µL, 1.4 mmol, 4 equiv) and 2-
C
solution 1 M in THF (1.75 mL, 1.75 mmol, 5 equiv, Method B) or

63.7, 63.4, 43.3, 38.6, 37.4, 29.5, 27.8, 25.7; HRMS (ESI) calcd thienyllithium solution 1 M in THF (1.4 mL, 1.4 mmol, 4 equiv,
for C16H23N2O2 [M+ H] + m/z 275.1754, found 275.1766.
2,2'-(1-Benzylpyrrolidine-2,5-cis-diyl)bis[1-(thien-2-yl)
ethanone] (3af): Prepared following the general procedure 2357, 1560, 1680, 1412, 859; H NMR (CDCl3, 400 MHz)
Method C), affording 4bf (25 mg, 25%, Method A; 46 mg, 46%,
Method B; 41 mg, 41%, Method C) as brown oil.

max/cm-1 (neat)
7.83
1

using a solution of 2a (127 mg, 0.35 mmol) in THF (1.4 mL) and (s, 1H), 7.72 (dd, J = 3.8, 1.0 Hz, 1H), 7.65 (d, J = 4.9 Hz, 1H), 7.14
2-thienyllithium solution 1 M in THF (1.75 mL, 1.75 mmol, 5 (dd, J = 4.9, 3.8 Hz, 1H), 3.17 (m, 2H), 2.95 (m, 1H), 2.76 (d, J =
equiv, Method A) or 2-thienylmagnesium bromide solution 1 M 4.8 Hz, 3H), 2.67 (m, 1H), 2.50 (dd, J = 16.0, 4.7 Hz, 1H), 2.34 (d,
in THF (1.75 mL, 1.75 mmol, 5 equiv, Method B), affording 3af J = 3.7 Hz, 1H), 2.32 (s, 3H), 2.04 (m, 1H), 1.91 (m, 1H), 1.61 (m,
(65 mg, 45%, Method A; 33 mg, 23%, Method B) as brown oil. 1H), 1.55 (m, 1H); 13C NMR (CDCl3, 100 MHz)

 191,4, 171.9,
1
max/cm-1 (neat) 1967, 1663, 1354, 1057, 720; H NMR (CDCl3, 144.6, 134.0, 132.1, 128.2, 63.6, 63.5, 43.8, 38.5, 37.3, 29.3,
300 MHz)  7.58 (dd, J = 4.9, 1.0 Hz, 2H), 7.44 (d, J = 2.9 Hz, 2H),
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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ARTICLE
Journal Name
27.7, 25.6; MS (APCI) m/z 281 [M + H]+; HRMS (ESI) calcd for 2H), 6.00-5.93 (m, 2H), 5.91-5.81 (m, 1H), 5.08-4.98 (m, 2H),
View Article Online
C14H21N2O2S [M + H]+ m/z 281.1318, found 281.1325.
3.67 (m, 3H), 3.37 (m, 0.5H), 3.14 (m, 2H), 2.63 (m, 2H), 2.49-
DOI: 10.1039/C8NJ01975D
2,2'-(1-Tosylpyrrolidine-2,5-cis-diyl)bis[1-(thien-2-yl)
2.40 (m, 3H), 2.17-1.94 (m, 5H), 1.82 (dd, J = 6.8, 1.6 Hz, 6H),
ethanone] (3ce): Prepared following the general procedure 1.77 (m, 2H), 1.51-1.41 (m, 3H); 13C NMR (CDCl3, 75 MHz)

using a solution of 2c (100 mg, 0.23 mmol) in THF (0.9 mL) and 199.7, 199.2, 143.2, 142.9, 138.3, 138.2, 134.9, 134.7, 132.5,
2-thienyllithium solution 1 M in THF (1.15 mL, 1.15 mmol, 5 129.9, 129.1, 128.6, 128.3, 127.0, 62.6, 61.9, 58.4, 46.9, 45.7,
equiv, Method A) or 2-thienylmagnesium bromide solution 1 M 44.5, 30.3, 30.0, 18.3; HRMS (ESI) calcd for C21H28NO2 [M + H]+
in THF (1.15 mL, 1.15 mmol, 5 equiv, Method B), affording 3ce m/z 326.2115, found 326.2125.
as brown oil (65 mg, 60%, Method A; 76 mg, 70%, Method B). (3E,3'E)-1,1'-(1-Methylpyrrolidine-2,5-cis-diyl)bis(pent-3-en-2-

max/cm-1 (neat) 1661, 1650, 1416, 1353, 1157; 1H NMR (CDCl3, one) (3bh): Prepared following the general procedure using a
300 MHz)  7.86 (dd, J = 3.8, 1.0 Hz, 2H), 7.74 (d, J = 8.2 Hz, 2H), solution of 2b (100 mg, 0.35 mmol) in THF (1.4 mL) and
7.67 (dd, J = 4.9, 1.0 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.18 (dd, J allylmagnesium bromide solution 1 M in THF (1.75 mL, 1.75
= 4.9, 1.0 Hz, 2H), 4.08 (m, 2H), 3.70 (dd, J = 16.0, 3.2 Hz, 2H), mmol, 5 equiv, Method B), affording 3bh as brown oil (46 mg,
3.11 (dd, J = 16.1, 9.9 Hz, 2H), 2.43 (s, 3H), 1.73 (m, 4H); 13C NMR 53%, Method B).

max/cm-1 (neat) 2926, 2852, 1714, 1696, 1667,
191.1, 144.2, 143.9, 133.1, 133.5, 132.8, 1442, 1376, 970; 1H NMR (CDCl3, 300 MHz)
 6.90-6.83 (m, 2H),
(CDCl3, 75 MHz)

129.9, 128.3, 127.7, 58.3, 46.7, 29.9, 21.5; HRMS (ESI) calcd for 6.12 (dd, J = 15.8, 1.6 Hz, 2H), 3.11-2.79 (m, 4H), 2.65-2.55 (m,
C23H23NO4S3 [M + Na]+ m/z 496.0681, found 496.0687.
2,2'-(1-Methylpyrrolidine-2,5-cis-diyl)bis[1-(pyrid-3-yl)
ethanone] (3bg): Prepared following the general procedure 44.9, 39.0, 29.6, 18.4; HRMS (ESI) calcd for C15H24NO2 [M + H]+
using a solution of 2b (100 mg, 0.35 mmol) in THF (1.4 mL) and m/z 250.1802, found 250.1813.
2H), 2.30 (s, 3H), 2.03 (m, 2H), 1.90 (dd, J = 6.8, 1.6 Hz, 6H), 1.40
(m, 2H); 13C NMR (CDCl3, 75 MHz)
199.1, 143.3, 132.5, 63.1,

a solution of 3-pyridyllithium resulting from the addition of n- 2,2'-(1-Benzylpyrrolidine-2,5-cis-diyl)bis(N-methyl acetamide)
BuLi 1.6 M in hexane (1.09 mL, 1.75 mmol, 5 equiv) to 3-bromo (5a): Prepared following the general procedure using a solution
pyridine (168 µL, 1.75 mmol, 5 equiv) in diethyl ether (1 mL). of 2a (127 mg, 0.35 mmol) in THF (1.4 mL) and
3bg is isolated as a brown solid (58 mg, 51%, Method A). mp isopropylmagnesium bromide solution 2.4 M in THF (0.73 mL,
100-101 °C;
1298, 895, 701; 1H NMR (CDCl3, 300 MHz)
Hz, 2H), 8.75 (dd, J = 4.8, 1.7 Hz, 2H), 8.19 (dt, J = 8.0, 1.9 Hz, 2968, 1639, 1555, 1406, 700; 1H NMR (CDCl3, 300 MHz)

max/cm-1 (neat) 3570, 2871, 1683, 1586, 1407, 1.75 mmol, 5 equiv, Method B), affording 5a as white solid (56
9.14 (dd, J = 2.1, 0.6 mg, 53%, Method B). mp 158-159 °C;
max/cm-1 (neat) 3310,
7.35-



2H), 7.39 (ddd, J = 8.0, 4.8, 0.7 Hz, 2H), 3.39-3.30 (m, 2H), 3.02 7.17 (m, 5H), 6.84 (br., 2H), 3.68 (m, 2H), 3.03 (m, 2H), 2.65 (m,
(m, 4H), 2.37 (s, 3H), 2.14 (m, 2H), 1.47 (m, 2H); 13C NMR (CDCl3, 6H), 2.14 (m, 4H), 1.82 (m, 2H), 1.55 (m, 2H); 13C NMR (CDCl3,
75 MHz)
 197.9, 153.7, 149.8, 135.4, 132.3, 123.7, 62.9, 44.3, 75 MHz)  171.2, 138.2, 129.5, 128.5, 127.6, 62.3, 57.8, 40.3,
39.4, 29.9; HRMS (ESI) calcd for C19H22N3O2 [M + H]+ m/z 29.0, 25.9; HRMS (ESI) calcd for C17H26N3O2 [M + H]+ m/z
324.1707, found 324.1712.
304.2020, found 304.2025.
2-{(2S*,5R*)-1-Methyl-5-[2-oxo-2-(pyrid-3-yl)ethyl] pyrrolidin-
2-yl}-N-methylacetamide (4bg): Prepared following the general
procedure using a solution of 2b (100 mg, 0.35 mmol) in THF
(1.4 mL) and a solution of 3-pyridyllithium resulting from the
addition of n-BuLi 1.6 M in hexane (1.09 mL, 1.75 mmol, 5 equiv)
to 3-bromo pyridine (168 µL, 1.75 mmol, 5 equiv) in diethyl
ether (1 mL). 4bg is isolated as a brown oil (11 mg, 11%, Method
4. Conclusion
In our continuing interest of developing step-economical
synthesis of pyrrolidine lobelanine analogues, we have designed
an access to various and original symmetrical and
unsymmetrical 2,5-cis-disubstituted pyrrolidines from simple
and readily available starting materials. The strategy combined
a sequential microwave-assisted tandem double CM/RCDAM
for the synthesis of a Weinreb-based pyrrolidine platform to a
diversity-oriented late-stage functionalisation. The latter
exploited the peculiar reactivity of N-alkoxy amides. Diversity
was settled through a late-stage divergent transformation of
Weinreb amide by addition of a wide diversity of organolithium
and Grignard reagents. We have clearly demonstrated that
tuning the balance of steric encumbrance of reaction partners,
basicity of the organometallic species and the liganding ability
of the pyrrolidine nitrogen atom is deemed to be among the
most important factors in controlling the reaction selectivity.
We also found that chemoselectivity can be reversed in the
presence of an external competitive ligand such as TMEDA. To
the best of our knowledge, this work is the first example which
takes advantage of the decomposition reaction of N-alkoxy-N-
methylamide for desymmetrizing a meso bis-Weinreb amide via
A).

max/cm-1 (neat) 3282, 2974, 1727, 1690, 1587, 1418, 703; 1H
9.18 (d, J = 1.4 Hz, 1H), 8.80 (dd, J = 4.8,
NMR (CDCl3, 300 MHz)

1.6 Hz, 1H), 8.23 (dt, J = 8.0, 2.0 Hz, 1H), 7.62 (br., 1H), 7.42 (ddd,
J = 7.9, 4.8, 0.7 Hz, 1H), 3.44 (m, 1H), 3.22-3.11 (m, 2H), 3.00 (m,
1H), 2.79 (d, J = 4.8 Hz, 3H), 2.54 (m, 2H), 2.40 (m, 3H), 2.19-2.04
(m, 2H), 1.67-1.54 (m, 2H); 13C NMR (CDCl3, 75 MHz)
 191.4,
168.5, 154.0, 149.8, 135.5, 133.1, 123.9, 64.3, 63.6, 43.3, 38.8,
37.7, 29.6, 28.2, 26.0; HRMS (ESI) calcd for C15H22N3O2 [M + H]+
m/z 276.1707, found 276.1717.
(3E,3'E)-1,1'-(1-Benzylpyrrolidine-2,5-cis-diyl)bis(pent-4-en-2-
one) and (3E,3'E)-1,1'-(1-benzylpyrrolidine-2,5-diyl)bis(pent-3-
en-2-one) (3ah): Prepared following the general procedure
using a solution of 2a (127 mg, 0.35 mmol) in THF (1.4 mL) and
allylmagnesium bromide solution 1 M in THF (1.75 mL, 1.75
mmol, 5 equiv, Method B), affording 3ah as brown oil (64 mg,
56%, Method B) as an inseparable mixture of two isomers.

max/cm-1 (neat) 2968, 2926, 1714, 1696, 1667, 1442, 1376, 970;
1H NMR (CDCl3, 300 MHz)
 7.33-7.21 (m, 7.5H), 6.65-6.57 (m,
8 | J. Name., 2012, 00, 1-3
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ARTICLE
9
H. Boufroura, M. Mauduit, E. Drège and D. Joseph, J. Org.
a probable metal-templated arrangement of the two distant
and highly flexible N-methoxy amide functions.
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Conflicts of interest
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Acknowledgements
The authors thank K. Leblanc for performing mass analyses. The
authors are indebted to Oméga Cat System Company for the
generous gifts of M2 ruthenium catalyst. The University of Paris-
Sud, the French Ministry of Superior Education and Research,
the CNRS and the LabEx Lermit (ANR-10-LABX-33) are gratefully
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New Journal of Chemistry
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DOI: 10.1039/C8NJ01975D
The dual reactivity of Weinreb amides was exploited to prepare diversified symmetrical and
dissymmetrical 2,5-disubstituted pyrrolidines from simple building blocks.