Direct and Stereospecific [3+2] Synthesis of Pyrrolidines from Simple Unactivated Alkenes

Article abstract of DOI:10.1002/anie.201706682

Pyrrolidines are important heterocyclic compounds with endless applications in organic synthesis, metal catalysis, and organocatalysis. Their potential as ligands for first-row transition-metal catalysts inspired a new method to access complex poly-heterocyclic pyrrolidines in one step from available materials. This fundamental step forward is based on the discovery of an essential organoaluminum promoter that engages unactivated and electron-rich olefins in intermolecular [3+2] cycloadditions.

Full text of DOI:10.1002/anie.201706682

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Accepted Article
Title: Direct and Stereospecific [3+2] Synthesis of Pyrrolidines from
Simple Unactivated Alkenes
Authors: Jorge Otero-Fraga, Samuel Suárez-Pantiga, Marc
Montesinos-Magraner, Dennis Rhein, and Abraham Mendoza
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201706682
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10.1002/anie.201706682
Angewandte Chemie International Edition
COMMUNICATION
Direct and Stereospecific [3+2] Synthesis of Pyrrolidines from
Simple Unactivated Alkenes
Jorge Otero-Fraga,[a] Samuel Suárez-Pantiga,[a] Marc Montesinos-Magraner,[a] Dennis Rhein[a] and
Abraham Mendoza*[a]
This paper is dedicated to Prof. Jan-Erling Bäckvall on the occasion of his 70th birthday.
Abstract: Pyrrolidines are central heterocyclic compounds with
endless applications in organic synthesis, metal- and organocatalysis.
In particular, their potential as ligands for first-row transition-metal
catalysts has inspired a new method to access complex poly-
heterocyclic pyrrolidines in one-step from available materials. This
fundamental step forward is grounded on the discovery of an essential
organoaluminum promoter that engages unactivated and electron-
rich olefins in intermolecular [3+2] cycloadditions for the first time.
engages aliphatic and electron-rich olefins in azomethine ylide
[3+2] cycloadditions to provide direct access to new pyrrolidine
scaffolds in one-step from commercial sources.
Objective
a
strong pyrrolidine
immobilization
N-donor
N
N
N
M
tunable
sterics
electronics
H
[3+2] with
aliphatic olefins
[unsolved limitation]
The discovery of catalysts to enable new, more efficient and more
sustainable transformations is a prime objective of our time. To
this end, the development of new transition-metal catalysts
requires new synthetic methods that can quickly supply diverse
and powerful ligands. Recent research targeting ligand synthesis
has enabled practical access to important catalysts and
contributed with solutions to fundamental synthetic challenges.[1]
In this sense, stereodefined polydentate N-donor ligands are
particularly demanding due to their nucleophilicity, redox
chemistry and their strong binding to transition metals. Unlike
common syntheses based on C–N bond-forming reactions,[2] our
group has recently reported an alternative approach based on C–
C bond construction.[1b] Herein, we present a versatile synthesis
of poly-heterocyclic pyrrolidines (Scheme 1, a) that is aimed at (1)
increasing the coordinative power of the N-donor, and (2)
enhancing the structural and functional modularity of these ligand
scaffolds using diverse alkene precursors. Beyond ligands,
pyrrolidines are central heterocycles that are found in medicinal
high modularity
non-accesible ligands
Discovery
b
N
Li
2a
N
Ph
LDA
(0%)
N
N
Li
H2O
N
N
unsolved
penalty
Py
H
N
Li-B
Py
Py
Li-A
+
1a
N
Ph
2a
3aa
dr 19:1
Ph
Py
Me
Me
N
Al
N
2a
(this work)
Me
Ph
LDA then
Me2AlCl
(58%)
N
H2O
N
Al
N
N
Me
Me2Al-A (e–-rich anion)
Me2Al-B (stable Al-amide)
= faster kinetics
= larger driving force
c Optimization[a]
LDA (0%)[b]
LDA then Me2AlCl (52%)[b]
AlMe3 (67%)[b]
H
N
n-Bu
Py
Py
Py
N
Py
+
THF, 80 °C
unactivated
compounds,[3]
photovoltaic
devices,[4]
supramolecular
n-Bu
1a
2b
3ab - dr 6:1
assemblies,[5] and they are also a cornerstone in both metal-[2c, 6]
and organocatalysts[7] due the particular nucleophilicity of their
pyramidalized N-donor.[7f] The most strategic method to obtain
pyrrolidines is the azomethine ylide [3+2] cycloaddition,[8] albeit
still limited to electron-deficient olefins.[8–10] This fundamental
restraint has never been overcome and it is particularly relevant
in the synthesis of sturdy ligands with inert backbones, which
would require removal and/or manipulation of the enabling
electron-withdrawing group. Herein, we report a system that
Scheme 1. [a] New pyrrolidine ligands require a new cycloaddition method (this
work). [b] Discovery of organoaluminum activation. [c] Optimization. aReaction
conditions: imine 1a (0.1 mmol), reagent (0.2 mmol), olefin 2a (0.5 mmol),11 THF
(1 mL), 0 °C to 80 °C, 12 h. bYields determined by 1H-NMR spectroscopy using
1,1,2,2-tetrachloroethane as an internal standard.
We have recently reviewed the current state-of-the-art in
azomethine ylide [3+2] cycloadditions involving non-electrophilic
olefins.[8a] Lithium 2-aza-allyl anions (Li-A) introduced by
Kauffmann[12] and popularized by Pearson[13] can engage the
[a]
J. Otero-Fraga, S. Suárez-Pantiga, M. Montesinos-Magraner, D.
Rhein and A. Mendoza
least activated olefins thus far, namely styrenes,[10] vinylsulfides
12, 13]
and vinylsilanes.[8a,
These intermolecular reactions often
Department of Organic Chemistry and the Berzelii EXSELENT
Center for Porous Materials
Stockholm University
Arrhenius Laboratory, 106 91 Stockholm (Sweden)
E-mail: abraham.mendoza@su.se
Homepage: www.organ.su.se/am/
display
a modest scope (alkyl and cycloalkyl olefins are
unreactive),[12b, 13] selectivity and even reversibility.[8a] Preliminary
experimentation (Scheme 1, b; top) revealed that imines featuring
N-heterocycles, are particularly difficult, as it could be expected
from the electrophilic character of these heteroaromatics.[9, 14] For
example, bis-(2-pyridyl)-imine 1a and styrene 2a do not react in
the conditions reported by Kauffmann (involving Li-A). We believe
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201706682
Angewandte Chemie International Edition
COMMUNICATION
that it is due to slow kinetics and/or a charge-localization enthalpic
penalty (Li-A → Li-B)[15] that has never been fundamentally
addressed. We hypothesized that the counter-cation associated
with the 2-aza-allyl anion could have a crucial effect at both (1)
enabling viable kinetics, by increasing the electron-density on 2-
aza-allyl system A; and (2) alleviating the thermodynamic balance
of the process, by stabilizing the electron-rich metal-amide B.
Inspired by our recent research,[1b] we explored the effect of
organoaluminum additives, observing that when imine 1a is
deprotonated with LDA and treated with Me2AlCl, pyrrolidine 3aa
is formed in 58% yield (Scheme 1, b; bottom). This spectacular
effect is likely due to the increased electron-rich character of
Me2Al-A (faster kinetics than Li-A) and the greater stability of
Me2Al-B (larger driving force than for Li-B). Encouraged by this
result, we optimized this system using a challenging aliphatic α-
olefin 2b as model substrate (Scheme 1, c). This class of alkenes
have never participated in [3+2] cycloadditions.[8a] We observed
that the lithium anion Li-A could not promote the cycloaddition
(0% yield), while the Me2Al-derived anion Me2Al-B furnished the
cycloadduct 3ab (52% yield). Additionally, we found that Me3Al,
which can act as a base and a [Me2Al]+ source,[1b] is a more
efficient activator (67% yield) than LDA/Me2AlCl. Rigorous
deoxygenation and visible-light irradiation were deemed
inconsequential (Table S2). These factors were essential in the
piperazine synthesis that we reported earlier, thus suggesting a
distinct mechanism operating in this case (see also Scheme 4, a-
c).[16] Other alkyl-, aryl-, amido- or alkoxy-aluminum reagents as
well as titanium bases and zinc or magnesium organometallics
were not effective (Table S2) at promoting this reaction.
this cycloaddition (3ai,aj). To the best of our knowledge, these are
12]
the first nucleophilic olefins to participate in this reaction.[8a,
Although electron-deficient olefins are beyond the scope of this
report, an acrylate substrate was found to seamlessly engage in
this cycloaddition as well (see SI). Products featuring all-carbon
quaternary centers 3ak-am are formed using gem-
difunctionalized alkenes, including a 1,3-diene (3am) and a
functionalized methylidene cyclobutane (3ak). In contrast to non-
cyclic alkenes, cyclic olefins produce polycyclic pyrrolidines as
single diastereoisomers (Scheme 3, b). The stereochemistry of
these products (determined by NMR, see SI) could be confirmed
in the product 3an through X-ray diffraction analysis.[17]
Carbocyclic olefins of various sizes (3an-ap), containing fused
(3ar,as,au) and bridged (3aq,av) bicycles, and oxygen (3ap) or
nitrogen (3au) heterocycles are all successful in this reaction. The
power of the system to assemble complex frameworks in one step
from commercial materials is well exemplified by 3ar. Its versatility
is best showcased by 3av and 3a2v, which are obtained with
different ratios of the same materials. Moreover, 3av is primed for
the
heterogenization
through
ring-opening
metathesis
polymerization (ROMP)[18] and 3a2v leads to interesting C–H
oxidation catalysts (Scheme 4, d). To put these results in
perspective we should emphasize that even strained[12b, 13c] and
conventional cycloalkanes were specifically declared unreactive
in azomethine ylide [3+2] cycloadditions before our work.[8a, 13a,b]
Importantly, these polar pyrrolidines can be decorated with
unprotected amines (3ac,aj,au), alcohols (3ad), nitriles (3ae,ak),
ethers (3af,ai), ketals (3ap), esters (3at), silanes (3ag,ah) and
other olefins (3am,av). We have found that the purification of
these polar pyrrolidines is understandably best achieved using
automatized reverse-phase chromatography. However, if this
technique is unavailable or unsuitable, the aluminum amides
produced (Me2Al-B; Scheme 1, b) can be conveniently N-Boc-
protected in situ, purified by conventional normal-phase
chromatography (3ah-al,ap,ar,at) and deprotected quantitatively
with standard protocols (for example 3ar, see SI).[19]
With these optimized conditions in hand, we explored the
reactivity using commercial olefins of diverse stereoelectronic
nature (Scheme 2). Terminal olefins are good substrates that lead
to the desired functionalized pyrrolidine products 3aa-aj with a
varied selection of functional groups and sterically-controlled
stereoselectivities (Scheme 2, a). Remarkably, electron-rich
olefins like butyl vinyl ether and N-vinylcarbazole also engage in
complex
pyrrolidine
scaffolds
N
N
Me3Al
simple
materials
H
H
or
+
N
1a
N
THF, 80°C
2
3
H
yield (%)
Py
dr
a
b
H
H
H
Py
NH
Py
H
H
O
3ap
3aa Ph
68 (46) 19:1 (18:1)
3an - n=1 3ao - n=4
73% (51%) 80% (68%)
H
NH 83% (62%)‡
n
3ab n-Bu
67 (49)
46 (20)
76 (47)
86 (42)
81 (59)
92 (50)
84 (73)‡
54 (32)‡
6:1 (8:1)
4:1 (8:1)
1:1 (1:1)
5:1 (5:1)
5:1 (5:1)
6:1 (9:1)
dr >20:1
dr >20:1
dr >20:1
Py
N
Py
Py
Py
O
N
H
[x-ray]
3ac
CH2NMe2
3ad CH2OH[a]
3ae
H
Py
[cyclic alkenes]
dr >20:1
[acyclic alkenes]
(CH2)3CN
H
Py
Py
NH
Py
variable
stereoselectivity
Py
NH
Py
H
H
3af CH2OnBu
H
Py
NH
*
MeO2C
MeO2C
*
*
*
*
*
3ag CH2SiMe3
unprotected
functionality
neutral & e–-rich
olefins
NH
H
3ah SiMe3
Py
>20:1
>20:1
>20:1
H
H
H
Py
3ar
85% (57%)‡
dr >20:1
OnBu
3ai
3aq
3as
68% (38%)
dr >20:1
3at
88% (80%)
dr >20:1
70% (53%)‡
dr >20:1
3aj N-carbazolyl 68 (47)‡
all-C quaternary
centers
CN
Ph
Me
H
N
Me
Py
N
H
N
H
N
Me
Py
N
N
N
Py
3a2v
61% (38%)
dr >20:1
3au
80% (46%)
dr >20:1
3av
59% (35%)
dr >20:1
Py
Py
Py
H
H
H
N
H
N
H
N
H
Py
Py
N
Py
Py
3ak
3al
3am
N
H
69% (51%)‡
dr 1:1 (1:1)
77% (68%)‡
66% (48%)
dr 2:1 (2:1)
ROMP handle
(heterogenization) same materials
dr 2:1 (>20:1)
Scheme 2. Scope of the [3+2] cycloaddition on the olefin. Yields determined by 1H-NMR using 1,1,2,2-tetrachloroethane as an internal standard. In parenthesis,
isolated yield. ‡Isolated as N-Boc adduct.
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10.1002/anie.201706682
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COMMUNICATION
To explore the heterocycles that could be incorporated in the
imine side, we chose two symmetrical cyclic alkenes as
substrates (Scheme 3). We were pleased to find that
unsymmetrical imines containing both π-deficient and π-
excessive heterocycles could be efficiently incorporated in this
reaction. Heterocycles such as pyrazine (3bq,bo-eo), thiazole
(3fo), furan (3cq,co), and thiophene (3dq) can be incorporated
into the products, which additionally provide and entry into other
functional groups through further manipulations. Surprisingly, we
found that this system can also accommodate simple aryl
substituents (without undergoing ortho-metallation; see SI, III.2)
including neutral (3gq), electron-poor (3hq), electron-rich (3iq-
kq), and even an unprotected phenol (3jq). This feature allows to
obtain bidentate scaffolds and opens the door for new
metallacyclic compounds.[20] So far, one N-donor heterocycle is
required to observe any conversion,[9] which is suggestive of the
crucial role of aluminate species in this reaction.
highly disfavors any open-shell pathway (either in chain or non-
chain). Collectively, these experiments support a stereospecific,
and irreversible cycloaddition mediated by Me2Al-A (previously
characterized).[1b, 16, 22]
Products 3 are designed to obtain new catalysts. Following
our interest in highly-structured complexes for C–H oxidation,[1b,
23] we sought to preliminarily explore the activity of ligands derived
from 3a2v (Scheme 4, d). This way, 1a and norbornadiene 2v can
be coupled using Me3Al and N-alkylated (without isolating 3a2v)
to deliver the complex ligands 4a,b in 53-58% overall yield.
Compound 4a is a dinucleating analogue of the venerable ligand
TPA (5; TPA = tris-(2-pyridylmethyl)amine),[24] and 4b is the first
derivative with differentiated pyridine donors in this class. Unlike
TPA, 4a,b allow to control the individual trans-influence of the
different N-donors around the metal center (Scheme 1, a).
Pleasingly, the dinuclear iron catalysts derived from 4a,b proved
to be more active than FeTPA[23, 24] in the stereoretentive C–H
oxidation of the benchmark alkane cis-6. This illustrates how
products 3 can enable explorations in catalysis otherwise
impossible, thus adding to their evident potential as precursors of
organocatalysts and multidentate phosphoramidites.
e–-poor HetAr
Me3Al
e–-rich HetAr
H
H
or
N
N
+
N
THF, 80 °C
arenes
tridentate
bidentate
1b-k
2o,q
3
yield 3[a] (%)
dr
or
Py
Py
standard conditions
trans-2w cis-2w
a
Ph
H
H
H
Ph
Ph
3bq
3cq
2-pyrazinyl
2-furyl
99 (60)
>20:1
trans-3aw
84%
dr >20:1
cis-3aw
87%
dr >20:1
Py
NH
R/R
1a
HN
HN
80 (78)
71 (49)
84 (52)
69 (47)
>20:1
>20:1
>20:1
>20:1
Ph
stereospecific
H
2-thiophenyl
2-pyridyl
H
3dq
3bo
3eo
H
Py
Py
X
H
N
b
c
d
standard
2-pyrazinyl
2-furyl
Py
Py
conditions
N
88% recovery
cis-3aw-d2
(94% D)
cis-3aw-d2
(94% D)
cis-2w
10 equiv
NH
3co
42 (35)
62 (42)
>20:1
>20:1
+
X
D
D
R/R
3bo,eo - X=N,
3co,fo - X=CH
3fo 2-(1,3-thiazolyl)
irreversible
Ph
Ph
dr >20:1
yield 3[a] (%)
dr
Ph
Py
HN
Py
Ph
Ph
standard
conditions
Ph
3gq
3hq
3iq
62 (41)
77 (64)
76 (52)
74 (55)
66 (40)
>20:1
>20:1
>20:1
>20:1
>20:1
3ax
72% (49%)
dr 5:2:1
Ph
Py
NH
+
1a
4-Br-C6H4
4-OMe-C6H4
2-OH-C6H4
no radical
intermediates
intact
2x
H
cyclopropane
H
3jq
1. standard
3kq
4-tBu-C6H4
R
conditions
2. N-alkylation[a]
R1
R1
R1
N
N
N
N
1a + 2v
N
R2
Scheme 3. Scope of the [3+2] cycloaddition with various heterocyclic imine
substrates. Reaction conditions: see Scheme 1, c. Yields determined by 1H-
NMR using 1,1,2,2-tetrachloroethane as an internal standard. In parenthesis,
data obtained after reverse-phase HPLC purification.19
N
R2
N
N
rapid access to
materials rigid & complex
simple
R1
ligands
4a - R1,R2=H (53%)
4b - R1=Me;R2=OMe (58%)
Fe cat.[a]
mol% (S*,S*)-7
Fe cat.
Me
Me
H2O2
[Fe(5)](OTf)2
F1b
5
6.8%
9.3%
OH
Me
H
The reactivity leap using organoaluminum activators deserves
Me
[Fe2(4a)](OTf)4
[Fe2(4b)](OTf)4
2.5
2.5
MeCN, rt
further scrutiny. We challenged the system using stilbenes 2w,
(S*,S*)-7
11.8%
>99% de
cis-6
which are primed for step-wise and reversible processes
10]
(Scheme 4, a).[8a,
However, cis-2w and trans-2w produced
Scheme 4. Mechanistic support and practical synthesis of ligands with a
stereospecifically the corresponding pyrrolidines cis-3aw and
trans-3aw, respectively. This feature is suggestive of an
irreversible cycloaddition enabled by the enhanced stability of
Me2Al-B (Scheme 1, b). To confirm this point, we synthesized the
deuterated compound cis-3aw-d2 (from cis-2w-d2, see SI) and
exposed it to an excess of cis-2w, Me3Al, and prolonged heating,
however the cross-over product cis-3aw (that would stem from a
reversible process) was not detected (Scheme 4, b). Mechanisms
involving step-wise radical coupling seem unlikely in the light of
the efficient formation of 3ax, featuring Newcomb’s cyclopropane
probe for picosecond-lived radical intermediates (Scheme 4, c).[16,
promising outlook. [a] See SI for details.
To summarize, herein we put forward organometallic
activation as
a new concept in azomethine ylide [3+2]
cycloadditions and demonstrated its utility to engage several
classes of unactivated and electron-rich olefins for the first time.
A simple and available organoaluminum promoter enhances the
reactivity of heterocyclic imines and provides with sufficient
driving force for this challenging reaction to occur. This work sets
the fundamental basis for future solutions to this long-standing
problem. The method provides direct access to unprotected poly-
21]
The high driving force for ring-opening of this cyclopropane
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10.1002/anie.201706682
Angewandte Chemie International Edition
COMMUNICATION
[7]
(a) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G., Angew. Chem. Int.
Ed. 2008, 47, 6138; (b) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List,
B., Chem. Rev. 2007, 107, 5471; (c) MacMillan, D. W. C., Nature 2008,
455, 304; (d) Donslund, B. S.; Johansen, T. K.; Poulsen, P. H.; Halskov,
K. S.; Jørgensen, K. A., Angew. Chem. Int. Ed. 2015, 54, 13860; (e) Fu,
G. C., Acc. Chem. Res. 2004, 37, 542; (f) Murphy, J. J.; Silvi, M.;
Melchiorre, P., Enamine-Mediated Catalysis (nꢀ→ꢀπ*). In Lewis Base
Catalysis in Organic Synthesis, Wiley-VCH Verlag, 2016, pp 857-902; (g)
Miller, S. J., Acc. Chem. Res. 2004, 37, 601.
heterocyclic pyrrolidines with evident potential to answer
fundamental questions in catalysis, thus inviting for further
exploration of these scaffolds. The availability of olefins, amines
and aldehydes of artificial and natural origin ensures the utility of
this method to access new molecules that are empowered by the
privileged pyrrolidine core.
[8]
(a) Mendoza, A.; Otero-Fraga, J.; Montesinos-Magraner, M., Synthesis
2017, 49, 802; (b) Hashimoto, T.; Maruoka, K., Chem. Rev. 2015, 115,
5366; (c) Adrio, J.; Carretero, J. C., Chem. Commun. 2014, 50, 12434;
(d) Narayan, R.; Potowski, M.; Jia, Z.-J.; Antonchick, A. P.; Waldmann,
H., Acc. Chem. Res. 2014, 47, 1296; (e) Wang, L. J.; Tang, Y.,
Intermolecular 1,3-Dipolar Cycloadditions of Alkenes, Alkynes, and
Allenes. In Comprehensive Organic Synthesis II (Second Edition),
Elsevier, 2014, pp 1342-1383; (f) Adrio, J.; Carretero, J. C., Chem.
Commun. 2011, 47, 6784; (g) Pandey, G.; Banerjee, P.; Gadre, S. R.,
Chem. Rev. 2006, 106, 4484; (h) Nájera, C.; Sansano, J. M., Angew.
Chem. Int. Ed. 2005, 44, 6272; (i) Pascual-Escudero, A.; de Cózar, A.;
Cossío, F. P.; Adrio, J.; Carretero, J. C., Angew. Chem. Int. Ed. 2016, 55,
15334.
Acknowledgements
Unrestricted support from Prof. F. Rodríguez (U. Oviedo), the
personnel of the Dept. of Organic Chemistry, the Dept. of
Materials and Environmental Chemistry (SU) and AstraZeneca
Göteborg is deeply appreciated. Financial support for this work
was kindly provided by the European Research Council (StG -
714737), the Knut and Alice Wallenberg Foundation
(KAW2016.0153),
the
Swedish
Research
Council
(Vetenskapsrådet, 2012-2969), the Swedish Innovation Agency
(VINNOVA-EXSELENT), the Marie Curie Actions (631159), and
AstraZeneca AB. Fellowships from the Carl Trygger Foundation
(JO; CTS15-326), the Wenner Gren Foundation (MMM;
UPD2016-0301) and the Erasmus+ program (DR) are greatly
appreciated.
[9]
For [3+2] cycloadditions with heterocyclic imines, see: (a) Ponce, A.;
Alonso, I.; Adrio, J.; Carretero, J. C., Chem. Eur. J. 2016, 22, 4952; (b)
Padilla, S.; Tejero, R.; Adrio, J.; Carretero, J. C., Org. Lett. 2010, 12,
5608.
[10] Carretero and Cossío have reported [3+2] cycloadditions with electron-
deficient styrenes, but styrene itself has been declared unreactive.8i In
the seminal study by Kauffmann, the cycloaddition with cis-stilbene only
proceeded in 21% yield using lithium 2-aza-allyl anions.12b
Keywords: cycloaddition • aluminum • nitrogen heterocycles •
C-C coupling • alkenes
[11] If desired, the excess of Me3Al and the olefin could be reduced to 1 and
2 equiv. respectively with only a minor erosion of efficiency (Table S1).
However, in this study a higher excess was used due to the inexpensive
nature of these materials.
[1]
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[15] The negative charge delocalized in Li-A is concentrated in the N-atom of
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[16] Unlike our previous open-shell 8e–-cycloaddition,1b this is a thermally-
allowed 6e– [3+2] reaction likely operating through
a closed-shell
mechanism (without photo-induced SET and insensitive to traces of O2).
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[24] (a) Chen, K.; Que, L., Chem. Commun. 1999, 1375; (b) Chen, K.; Que,
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Entry for the Table of Contents (Please choose one layout)
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Jorge Otero-Fraga, Samuel Suárez-
Pantiga, Marc Montesinos-Magraner,
Dennis Rhein and Abraham Mendoza*
Page No. – Page No.
Direct and Stereospecific [3+2]
Synthesis of Pyrrolidines from Simple
Unactivated Alkenes
Trimethylaluminum promotes the first [3+2] azomethine ylide cycloadditions that
engage non-electrophilic olefins. This reaction allows the stereoselective
combination of abundant feedstocks to access new polar poly-dentate scaffolds for
ligand design.
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