Synthesis of Chlorotrifluoromethylated Pyrrolidines by Electrocatalytic Radical Ene-Yne Cyclization

Article abstract of DOI:10.1002/chem.201802167

The stereoselective synthesis of chlorotrifluoromethylated pyrrolidines was achieved using anodically coupled electrolysis, an electrochemical process that combines two parallel oxidative events in a convergent and productive manner. The bench-stable and

Full text of DOI:10.1002/chem.201802167

A Journal of
Accepted Article
Title: Synthesis of Chlorotrifluoromethylated Pyrrolidines via
Electrocatalytic Radical Ene-Yne Cyclization
Authors: Ke-Yin Ye, Zhidong Song, Gregory Sauer, Johannes
Harenberg, Niankai Fu, and Song Lin
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Synthesis of Chlorotrifluoromethylated Pyrrolidines via
Electrocatalytic Radical Ene-Yne Cyclization
Ke-Yin Ye, Zhidong Song, Gregory S. Sauer, Johannes H. Harenberg,[b] Niankai Fu, and Song Lin*[a]
Abstract: The stereoselective synthesis of chlorotrifluoromethylated
pyrrolidines was achieved using anodically coupled electrolysis, an
electrochemical process that combines two parallel oxidative events
in a convergent and productive manner. The bench-stable and
commercially available solids CF3SO2Na and MgCl2 were used as the
functional group sources to generate CF3· and Cl·, respectively, via
electrochemical oxidation, and the subsequent reaction of these
radicals with the 1,6-enyne substrate was controlled with an earth-
abundant Mn catalyst. In particular, the introduction of a chelating
ligand allowed for the ene-yne cyclization to take place with high
stereochemical control over the geometry of the alkene group in the
pyrrolidine product.
selective
alkene
trifluoromethylation,
radical
ene-yne
cyclization,[6,7] and chlorination to furnish substituted pyrrolidine
derivatives (Scheme 1B), albeit with moderate efficiency and low
stereoselectivity.[4] Such highly functionalized heterocycles are
particularly compelling structures for medicinal chemistry
research, as they contain a substituted pyrrolidine[8] and a CF3
group,[9] both prevalent functionalities in numerous bioactive
compounds. In addition, the alkenyl chloride motif provides
opportunities for further synthetic elaboration.[10] In this work, we
report detailed reaction development based on our initial result
that leads to the highly regio- and stereoselective ene-yne
cyclization for the synthesis of chlorotrifluoromethylated
pyrrolidines.
Synthetic electrochemistry, which uses electrons as oxidizing or
reducing “reagents,” has emerged as a powerful tool for the
efficient and sustainable synthesis of complex organic
compounds.[1] Compared with conventional methods for organic
synthesis, electrochemistry offers the unique capacity to precisely
control the redox potential input, generate reactive intermediates
cleanly via direct electron transfer, and integrate multiple redox
events into single reaction systems in a concerted and productive
manner. These characteristics make electrochemistry an
attractive approach for meeting the prevailing trends in organic
chemistry[2] and providing new bond-forming strategies to
innovate the synthesis of complex targets.[3]
A. Previous work: Chlorotrifluoromethylation of alkenes via anodically
coupled electrolysis (ref. 4)
e–, SO2
e–
Cl–
–
[MnIII
]
Cl
[MnII]
CF3
CF3SO2
R2
R2
R2
Cl
R1
R4
R4
CF3
R4
CF3
R1
R1
anodic event A
anodic event B
R3
R3
R3
B. This work: Electrocatalytic ene-yne cyclization for the synthesis of
chlorotrifluoromethylated pyrrolidines
e–, SO2
Using an electrochemical approach, we recently developed a
method for the chlorotrifluoromethylation of alkenes using
commercially available Langlois reagent (CF3SO2Na) and MgCl2
as functional group donors and Mn(OAc)2 as a catalyst (Scheme
1A).[4] The proposed mechanism entails the parallel oxidative
generation of two open-shell intermediates, CF3· and [MnIII]–Cl,
via anodically coupled electrolysis, followed by their selective
additions across the C=C π-bond.[5] Distinct from existing
methods for the same transformation, the radical-mediated
mechanism and mild reaction conditions enabled by
electrocatalysis allow for broader substrate scope and excellent
functional group compatibility. In particular, preliminary data
showed that a 1,6-enyne substrate undergoes a cascade of
–
CF3
CF3SO2
R2
R2
R1
TsN
TsN
I
anodic event A
e–
R1
CF3
Cl–
5-exo-dig
R2
[MnIII
]
Cl
[MnII]
Cl
R2
TsN
II
TsN
R1
anodic event B
R1
CF3
F3C
Scheme 1. Anodically coupled electrolysis for the chlorotrifluoromethylation of
alkenes (A) and its application in the radical cyclization of 1,6-enynes for the
synthesis of chlorotrifluoromethylated pyrrolidines (B).
[a]
[b]
Dr. K.-Y. Ye, Z. Song, G. S. Sauer, Dr. N. Fu, Prof. S. Lin
Department of Chemistry and Chemical Biology
Cornell University
Ithaca, NY 14853
E-mail: songlin@cornell.edu
J. H. Harenberg
Department of Chemistry
Ludwig-Maximilians-Universität
München, Germany, 80539
Our hypothesized reaction mechanism entails the
simultaneous anodic oxidation of CF3SO2Na[11] and [MnII]–Cl, the
latter of which is formed upon mixing the Mn catalyst and MgCl2.
The reduction potentials of CF3SO2Na and [MnII]–Cl are 0.81 V
and 0.75 V, respectively (vs ferrocenium/ferrocene redox couple
Fc+/0; Figure 1).[12] As such, with sufficient anodic potential, both
species can be oxidized on the electrode surface at comparable
Supporting information for this article is given via a link at the end of
the document.
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rates, paving the way for the subsequent radical functionalization
of the substrate. Notably, cyclic voltammetry shows that the redox
wave corresponding to [MnIII]–Cl/[MnII]–Cl couple is apparently
reversible, which indicates that [MnII]–Cl is highly persistent in the
reaction system. In the presence of the 1,6-enyne substrate, the
addition of CF3· to the alkene takes place preferentially owing to
the higher reactivity of CF3· (a transient free radical) compared
with that of [MnIII]–Cl (a persistent radical) and the higher reactivity
of an alkene relative to that of an alkyne. The resultant
intermediate I then undergoes 5-exo-dig cyclization onto the
alkyne, leading to alkenyl radical II. This radical is highly unstable
(bond dissociation energy of an alkenyl C–H bond is
approximately 110 kcal/mol)[13] and can in principle participate in
steric hindrance drives the [MnIII]–Cl to approach III from the less
congested side, resulting in the observed stereoselectivity
favoring the Z isomer product. This hypothesis led us to reason
that the addition of a ligand might increase the steric profile of
[MnIII]–Cl and further augment the stereochemical differentiation.
Indeed, when 20 mol% 2,2′-bipyridine (bpy) was added to the
reaction system, (Z)-2 was observed as practically a single
isomeric product (Z/E > 19:1) in 67% yield (entry 3).[16] The yield
increased to 82% (while maintaining high stereoselectivity) by
increasing the applied current to 10 mA and the substrate
concentration to 0.03 M (entry 4). Controlled experiments showed
that in the absence of the Mn catalyst or electrical input, no
desired pyrrolidine product was formed (entries 5 and 6,
respectively),[17] which demonstrates the critical role of the Mn
catalyst and current in promoting the ene-yne cyclization reaction.
a
variety of side reactions. In our previous studies, we
demonstrated that an sp3 carbon-centered radical can be
efficiently captured by [MnIII]–Cl to form a C–Cl bond.[4,14] We
reasoned that this Mn-bound latent Cl radical would also react
with an alkenyl radical and that the efficiency and selectivity of this
atom transfer process could be controlled by tuning the ligand on
the metal center.
Table 1. Reaction Optimization.[a]
Ar
Cl
catalyst (10 mol%)
MgCl2 (3.0 equiv)
NaSO2CF3 (2.0 equiv)
Me
Me
Ar
Ar
Cl
F3C
TsN
F3C
+
LiClO4 (0.2 M), HOAc/MeCN (1:10)
C(+)/Pt(–), constant current i
22 °C, 3 h
N
N
Me
1 (Ar = 4-MeOC6H4)
Ts
(Z)-2
Ts
(E)-2
Yield[b,c]
(%)
Entry
Catalyst
Ligand
[1] (M)
i (mA)
Z/E[c]
1
2
3
4
5
6
Mn(OAc)2
Mn(OTf)2
Mn(OTf)2
Mn(OTf)2
Mn(OTf)2
—
—
0.02
0.02
0.02
0.03
0.03
0.03
8
62
3.4:1
5.1:1
>19:1
>19:1
—
8
61
bpy[d]
bpy[d]
bpy[d]
—
8
67
10
82 (80)[e]
<5
[f]
[g]
—
—
[g]
10
<5
—
[a] Reactions conducted on a 0.1 mmol scale. [b] Combined yield of (E)- and
(Z)-2. [c] Determined with 19F NMR. [d] 20 mol%. [e] Isolated yield in
parentheses. [f] No external current applied. [g] Not determined.
Figure 1. Cyclic voltammograms of CF3SO2Na and a mixture of Mn(OTf)2 and
MgCl2. Conditions: LiClO4 (0.10 M in MeCN) and HOAc (60 mM) with (a)
CF3SO2Na (8.0 mM) (red) or (b) Mn(OTf)2 (2.0 mM) and MgCl2 (8.0 mM) (black).
Scan rate: 100 mV/s.
[MnII]
Cl
R1
more accesible
F3C
In our initial experiment using 1,6-enyne 1 as the model
substrate, Mn(OAc)2 as the catalyst, HOAc as the sacrificial
oxidant, and LiClO4 as the electrolyte in MeCN at room
temperature, the application of a constant current of 8 mA led to
the formation of pyrrolidine product 2 as a pair of alkene geometric
isomers in 62% overall yield and moderate selectivity (Z/E = 3.4:1;
Table 1, entry 1). Changing the catalyst to Mn(OTf)2 marginally
increased the stereoselectivity to 5.1:1 while maintaining the
same level of reactivity (entry 2).
We hypothesized that the product stereochemistry was
sterically controlled (Figure 2). a-Aryl alkenyl radicals (e.g., III)
are sp-hybridized owing to the conjugation between the aryl π
orbitals and the singly occupied molecular orbital.[15] This orbital
is perpendicular to the alkene π orbitals, and one side is shielded
by the substituents at the quaternary carbon a to the alkene. This
N
III
Ts
Figure 2. Graphical rationale for the observed alkene Z/E stereoselectivity.
We subsequently investigated the substrate scope (Scheme
2) of the electrocatalytic radical ene-yne cyclization reaction
under the optimized conditions (Table 1, entry 4). A set of 1,6-
enynes with electron-rich, electron-deficient, and electron-neutral
aryl groups on the alkyne all proved suitable substrates, providing
the chlorotrifluoromethylated pyrrolidines in high yield and
excellent stereoselectivity (2–6). Compound 5 was isolated as two
diastereomers in ca. 1:1 ratio with respect to the stereochemistry
of the Ca–Cb bond, as the highly substituted C=C bond in 5
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Scheme 2. Substrate scope. Reactions were conducted on a 0.1 mmol scale.
See Table 1, entry 4 for reaction conditions. aYield of reaction on a 1.0 mmol
scale; TBAClO4 was used as the electrolyte instead of LiClO4; reaction time: 8
restricts the free rotation of Ca–Cb. Styrene-derived substrates
were smoothly converted to the corresponding products (7 and 8).
h. bReaction conditions: CF3CO2H, CH2Cl2,
0
°C; 79% yield. cReaction
Single crystals of pyrrolidine
7
were obtained from
conditions: PhSH, KOH, MeCN, 50 °C; 82% yield. dUsing KBr instead of MgCl2
dichloromethane/n-pentane solution at room temperature, and X-
ray diffraction data confirmed our structural assignment, including
the configuration of the newly formed C=C bond (Figure 3). When
pyridine was added to the alkyne unit, the cyclization product (8)
was obtained with decreased stereoselectivity (Z/E = 8:1). Alkyl-
and silyl-substituted alkynes (9 and 10) as well as terminal
alkynes (11) proved compatible with the electrocatalytic reaction,
providing the cyclization products in good yield. The
stereoselectivity of these substrates was substantially lower than
that of the aryl-substituted examples, however. This decrease in
the product Z/E ratio stems from the sp2 hybridization of a-alkyl
alkenyl radicals (e.g., IV).[15] In the Curtin-Hammett scenario
depicted in Figure 4, owing to the steric effect, less stable pro-
(Z)-IV reacts faster with [MnII]–Cl, whereas more stable pro-(E)-
IV reacts slower. As such, the destructive interplay between
thermodynamics and kinetics resulted in decreased product
stereoselectivity.[18]
under a constant cell potential of 2.3 V for 5 h.
Figure 3. ORTEP drawing of compound 7 showing thermal ellipsoids with 30%
probability. Hydrogen atoms have been omitted for clarity.
MeO
Me
Br
Cl
less accesible
Me
more accesible
β
R
Me
Cl
α
R1
R1
Me
Me
R
Cl
Cl
Cl
F3C
fast
F3C
F3C
F3C
F3C
F3C
N
N
N
N
Ts
N
N
Ts
Ts
Ts
Ts
Ts
2, 80%
Z:E > 19:1
3, 84% (74%)a
Z:E > 19:1
4, 89% (77%)a
Z:E > 19:1
5, 77%
Z:E > 19:1
pro-(Z)-IV
less stable
pro-(E)-IV
more stable
[MnII]
[MnII]
Cl faster
Cl slower
Me
Me
N
Cl
Me
Ph
Ph
Cl
Cl
Cl
F3C
(Z)-product
(E)-product
F3C
F3C
F3C
N
Ts
N
N
N
Ts
Ts
Ts
Figure 4. Rationale for the observed alkene Z/E stereoselectivity in products 9–
11.
6, 83% (71%)a
Z:E > 19:1
7, 84%
Z:E > 19:1
8, 75%
Z:E = 8:1
9, 64%
Z:E = 1.4:1
Ph
Ph
Cl
TMS
Me
H
Me
The scope of this radical cyclization reaction was successfully
Me
Cl
Cl
Cl
extended to piperidine formation (12) using
a structurally
F3C
F3C
F3C
F3C
Me
analogous 1,7-enyne substrate. The conformational flexibility of
the six-membered heterocycle likely weakened the capacity of the
Mn catalyst for stereochemical control in the last Cl· transfer step,
which led to the low E/Z selectivity (2:1) observed. Furthermore,
highly substituted cyclopentane 13 could also be synthesized in
high yield and stereochemically pure form using carbon-tethered
1,6-enynes with gem-diester groups. To further explore the
Thorpe-Ingold effect in our radical cyclization reaction, we
synthesized a structurally analogous enyne with gem-dimethyl
substituents, which was smoothly converted to product 14 in
satisfying yield and selectivity.
N
N
N
Ts
Ts
MeO2C CO2Me
Ts
12, 78%
E:Z = 2:1
13, 74%
E:Z > 19:1
10, 73%
Z:E = 6.4:1
11, 75%
Z:E = 4:1
Br
Br
Br
Me
Cl
Me
Me
Me
Cl
Cl
Cl
F3C
F3C
F3C
F3C
O
N
N
Ts
N
R
Me Me
Ns
17, 85% (62%)a
Z:E > 19:1
16
15 (R = Boc), 66%
Z:E = 14:1
14, 78%
E:Z = 9:1
18, 74%
Z:E > 8:1
c
b
16 (R = H)
Our initial attempts to synthesize unprotected pyrrolidine 16
via direct electrochemical cyclization of the corresponding enyne
or removal of the Ts group in product 3 proved unsuccessful. To
access 16, we explored substrates with different N-protecting
groups in our electrochemical reaction. When Boc was employed
as the protecting group, the cyclization product (15) was formed
in good yield and a Z/E ratio of 14:1. The carbamate group could
subsequently be removed under acid-promoted conditions,
Ph
Ph
Ar
2
Me
Br
TsN
H
O
Me
TsN
Me
F3C
2
N
Ts
20
21
22
(Ar = 4-MeOC6H4)
19,d 47%
Z:E > 19:1
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furnishing the unprotected pyrrolidine (16) in high efficiency.
When an enyne with N-2-nitrophenylsulfonyl (Ns) group was
subjected to the electrochemical cyclization, desired product 17
was obtained in 85% yield as a single stereoisomer. This product
could also be converted to 16 in 82% yield via thiophenol-
promoted Ns deprotection.
Pyrrolidone product 18 could also be obtained from the
corresponding enyne substrate in high efficiency and selectivity.
Finally, when MgCl2 in the reaction system was replaced KBr, the
bromotrifluoromethylated pyrrolidine (19) was observed as the
major product in synthetically useful yield as a single alkene
geometric isomer.
MnII oxidation state in this process and is turned over on the
electrode via single-electron oxidation.
H+
e–
+
–
Pt cathode
H2
CF3SO2Na
e–
Anodic event A
R2
X
CF3
R1
At its current stage of development, our method cannot be
applied to substrates 20 and 21. Reactions with these enynes
under the standard conditions furnished the desired products in
low yield along with several side products. Although these side
products have not been definitely identified, we hypothesize that
competing direct difunctionalization of the alkene or alkyne
groups in 20 and reactions involving the labile H atom a to the O
in 21 complicated the desired transformation. Indeed, in our
previously reported alkene chlorotrifluoromethylation reaction,[4]
hydrogen atom abstraction was often observed with substrates
bearing labile C–H bonds as evident from the formation of CF3H.
Attempts to adopt our method in the synthesis of azapane type
structures from 1,8-enynes (e.g., 21) proved unsuccessful.
Although the cyclization product was detected with NMR and
mass spectrometry, the slow kinetics of the ring closure process
allowed various side reactions including direct alkene
difunctionalization and aromatic trifluoromethylation to plague the
desired reactivity.
Finally, we demonstrated our electrochemical synthesis of
substituted pyrrolidines on preparative scales. Direct adoption of
our previous conditions optimized for the 0.1 mmol scale
electrolysis (see entry 4, Table 1) proved unsuccessful on a 1
mmol scale, resulting in a much more sluggish reaction. Attempts
to improve the reaction rate by increasing the current input led to
unproductive consumption of the enyne and CF3SO2Na. We
noticed that under our electrolysis conditions, the Pt cathode
surface darkened during the course of the electrolysis. The
surface passivation presumably caused the cell resistance to
increase thereby reducing the reaction rate substantially, leading
to low conversion. This issue was addressed by the introduction
of an organic electrolyte, tetrabutylammonium perchlorate
(TBAClO4), instead of LiClO4. The cathode color change was not
observed under these modified conditions and the 1 mmol scale
synthesis of 3, 4, 6, and 17 proceeded smoothly with high
efficiency (see Scheme 2).
substrate
R2
R2
R1
X
X
R1
CF3
CF3
IV
V
Cl–
MnII Cl
MnII
e–
Cl
Anodic event B
R2
X
MnIII Cl
R1
CF3
product
C anode
Scheme 3. Proposed catalytic cycle entailing anodically coupled electrolysis.
In sum, we report an electrocatalytic protocol for the synthesis
of chlorotrifluoromethylated pyrrolidine derivatives. This reaction
is enabled by anodically coupled electrolysis in which the parallel
anodic generation of a pair of reactive radical species and their
subsequent reaction take place in a convergent and productive
manner. The addition of these intermediates to the alkene is
controlled by a redox-active Mn catalyst. The introduction of 2,2’-
bipyridine as the ligand allows the ene-yne cyclization products to
be formed in high stereoselectivity with respect to the alkene
geometry. We anticipate that the extension of our electrocatalytic
strategy to the synthesis of highly functionalized pyrrolidines will
encourage the broader application of the approach in the
preparation of complex targets pertinent to the pharmaceutical
industry.
Experimental Section
A catalytic cycle was proposed for the electrochemical ene-
yne cyclization (Scheme 3). Anodically coupled electrolysis
enables the formation of electrophilic radicals, CF3· (anodic event
A) and [MnIII]–Cl (anodic event B), from the catalyst and functional
group donors. The addition of the transient and highly reactive
CF3· to the trisubstituted alkene leads to the formation of an sp3
General procedure for the electrocatalytic ene-yne cyclization: An oven-
dried, one-compartment electrochemical cell was equipped with
a
magnetic stir bar, a carbon felt anode (1 × 0.5 × 0.3 cm3 connected to a
2B pencil lead), and a platinum plate cathode (0.5 × 1.0 cm2). To this setup
was added Mn(OTf)2 (3.5 mg, 10 mol%), bpy (3.1 mg, 20 mol%), MgCl2
(28.2 mg, 0.3 mmol, 3.0 equiv), and CF3SO2Na (31.2 mg, 0.2 mmol, 2.0
equiv). The cell was sealed using a rubber septum and flushed with
nitrogen gas for 5 min. Then, the electrolyte solution (0.2 M LiClO4 in
MeCN, 3.0 mL) and substrate (0.1 mmol, 1 equiv) were added sequentially
via syringe. The reaction mixture was then purged with nitrogen gas and
stirred for an additional 5 min. Acetic acid (0.3 mL) was then added via
syringe. After piercing the septum with a nitrogen-filled balloon to sustain
carbon-centered
radical.
This
intermediate
undergoes
subsequent intramolecular addition to the alkyne to form an
alkenyl radical intermediate. In the presence of [MnIII]–Cl, a
persistent open-shell metal complex, this highly reactive carbon-
centered radical is harnessed and converted to an alkenyl
chloride via radical atom transfer.[19] The catalyst returns to the
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10.1002/chem.201802167
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the nitrogen atmosphere, electrolysis was initiated at a constant current of
10 mA at room temperature. The current input was removed after 3 h. The
reaction mixture was subsequently poured into a saturated sodium
bicarbonate solution (ca. 15 mL). The aqueous layer was separated and
extracted with dichloromethane (3 × 5 mL), and the combined organic
layers were washed with brine and dried over sodium sulfate. After
concentration in vacuo, the crude residue was subjected to flash column
chromatography on silica gel to yield the desired cyclization product.
[6]
[7]
For a review, see: J. Xuan, A. Studer, Chem. Soc. Rev. 2017, 46, 4329-
4346.
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Gao, X.-B. Yan, T. Tao, F. Yang, T. He, X.-R. Song, X.-Y. Liu, Y.-M. Liang,
Chem. – Eur. J. 2013, 19, 14420–14424. (b) Y.-T. He, L.-H. Li, Z.-Z. Zhou,
H.-L. Hua, Y.-F. Qiu, X.-Y. Liu, Y.-M. Liang, Org. Lett. 2014, 16, 3896–
3899. (c) L. Zhang, Z. Li, Z.-Q. Liu, Org. Lett. 2014, 16, 3688–3691. (d)
Y.-Q. Wang, Y.-T. He, L.-L. Zhang, X.-X. Wu, X.-Y. Liu, Y.-M. Liang, Org.
Lett. 2015, 17, 4280–4283. (e) J. W. Tucker, J. D. Nguyen, J. M. R.
Narayanam, S. W. Krabbe, C. R. J. Stephenson, Chem. Commun. 2010,
46, 4985-4987. (f) J. Xuan, D. Gonzalez-Abradelo, C. A. Strassert, C.-G.
Daniliuc, A. Studer, Eur. J. Org. Chem. 2016, 4961-4964.
Acknowledgements
[8]
For representative examples of ene-yne cyclization via non-radical
pathways, which usually provide different product structures, see: (a) F.
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Chem., 2008, 73, 259-263. (b) Y. Yamamoto, S. Kuwabara, Y. Ando, H.
Nagata, H. Nishiyama, K. Itoh, J. Org. Chem. 2004, 69, 6697-6705. (c)
S. Reid, A. G. M. Barrett, M. S. Hill, P. A. Procopiou Org. Lett. 2014, 16,
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D. Toste, J. Am. Chem. Soc. 2004, 126, 10858-10859. (g) L.-G. Zhuo,
J.-J. Zhang, Z.-X. Yu J. Org. Chem. 2014, 79, 3809-3820. (h) L.-G. Zhuo,
J.-J. Zhang, Z.-X. Yu J. Org. Chem. 2012, 77, 8527-8540. (i) N. Kim, R.
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Financial support was provided by Cornell University, the
Atkinson Center for a Sustainable Future, and the National
Science Foundation (CHE-1751839). This study made use of the
Cornell Center for Materials Research Shared Facilities
supported from NSF MRSEC (DMR-1120296) and NMR facility
supported by the NSF (CHE-1531632). We thank Dr. Samantha
MacMillan for X-ray crystallography data collection and analysis,
Dr. Ivan Keresztes for assistance in the stereochemical analysis
of compound 5, and Prof. Naoto Chatani for helpful discussion on
substrate synthesis.
[8]
[9]
Keywords: electrocatalysis • anodically coupled electrolysis •
trifluoromethylation • ene-yne cyclization • pyrrolidine
(a) K. Müller, C. Faeh, F. Diederich, Science 2007, 317, 1881-1886. (b)
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10.1002/chem.201802167
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
e–, SO2
The stereoselective synthesis of
chlorotrifluoromethylated
Ke-Yin Ye, Zhidong Song, Gregory S.
Sauer, Johannes H. Harenberg,
Niankai Fu, and Song Lin*
–
CF3
CF3SO2
pyrrolidines was achieved using
anodically coupled electrolysis in the
presence of a Mn catalyst. The
bench-stable and commercially
available solids CF3SO2Na and
MgCl2 were used as the functional
group sources. The introduction of a
chelating ligand allowed for the ene-
yne cyclization to take place with
high stereoselectivity.
R2
R2
R1
TsN
TsN
anodic event A
e–
Page No. – Page No.
R1
CF3
Cl–
Synthesis of
Chlorotrifluoromethylated
Pyrrolidines via Electrocatalytic
Radical Ene-Yne Cyclization
[MnIII
]
Cl
[MnII]
R2
R1
Cl
R2
TsN
TsN
anodic event B
R1
CF3
F3C
This article is protected by copyright. All rights reserved.