Mn-Catalyzed Electrochemical Chloroalkylation of Alkenes

Article abstract of DOI:10.1021/acscatal.8b03209

The heterodifunctionalization of alkenes is an efficient method for synthesizing highly functionalized organic molecules. In this report, we describe the use of anodically coupled electrolysis for the catalytic chloroalkylation of alkenes - a reaction that constructs vicinal C-C and C-Cl bonds in a single synthetic operation - from malononitriles or cyanoacetates and NaCl. Knowledge of the persistent radical effect guided the reaction design and development. A series of controlled experiments, including divided-cell electrolysis that compartmentalized the anodic and cathodic events, allowed us to identify the key radical intermediates and the pathway to their electrocatalytic formation. Cyclic voltammetry data further support the proposed mechanism entailing the parallel, Mn-mediated generation of two radical intermediates in an anodically coupled electrolysis followed by their selective addition to the alkene.

Full text of DOI:10.1021/acscatal.8b03209

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Article
Mn-catalyzed Electrochemical Chloroalkylation of Alkenes
Niankai Fu, Yifan Shen, Anthony R Allen, Lu Song, Atsushi Ozaki, and Song Lin
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b03209 • Publication Date (Web): 05 Dec 2018
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ACS Catalysis
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Mn-catalyzed Electrochemical Chloroalkylation of Alkenes
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Niankai Fu1, Yifan Shen1, Anthony R. Allen1,2, Lu Song1, Atsushi Ozaki1,3, and Song Lin1*
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1Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA. 2Department of Chemistry and
Biochemistry, Oberlin College, Oberlin, OH 44074, USA. 3Department of Applied Biological Science, Tokyo University of
Agriculture and Technology, Fuchu, Tokyo 183-8509, Japan.
ABSTRACT: The hetero-difunctionalization of alkenes is an efficient method for synthesizing highly functionalized organic
molecules. In this report, we describe the use of anodically coupled electrolysis for the catalytic chloroalkylation of alkenes—a
reaction that constructs vicinal C–C and C–Cl bonds in a single synthetic operation—from malononitriles or cyanoacetates and
NaCl. Knowledge of the persistent radical effect guided the reaction design and development. A series of controlled
experiments, including divided-cell electrolysis that compartmentalized the anodic and cathodic events, allowed us to identify
the key radical intermediates and the pathway to their electrocatalytic formation. Cyclic voltammetry data further support the
proposed mechanism entailing the parallel, Mn-mediated generation of two radical intermediates in an anodically coupled
electrolysis followed by their selective addition to the alkene.
KEYWORDS: electrocatalysis, electrosynthesis, chloroalkylation, alkene difunctionalization, anodically coupled electrolysis
Introduction
coupled electrolysis10a,c—a process that combines two distinct
oxidation events in parallel—for the regioselective
chlorotrifluoromethylation of alkenes. Herein, we report the
application of this new catalytic strategy in the intermolecular
chloroalkylation of simple alkenes using unfunctionalized
malononitriles or cyanoacetates and NaCl (Scheme 1C).
Owing to the prevalence of C=C bonds in feedstock
chemicals and naturally occurring materials, the hetero-
difunctionalization of alkenes provides an efficient strategy for
rapidly increasing the complexity of molecules in organic
synthesis.1 For example, the haloalkylation of alkenes2 leads to
the formation of vicinal C–C and C–X bonds in the same
transformation, extending the carbon chain and providing an
alkyl halide functional handle for further synthetic elaborations.
In this context, the Kharasch addition reaction represents an
efficient approach to the haloalkylation of alkenes using
homolytically labile alkyl halides (e.g., iodo/bromoalkanes and
CCl4).3,4 However, the extension of this radical strategy to
chloroalkylation with less reactive alkyl chlorides is challenged
by the relatively high dissociation energy of C–Cl bonds in
these electrophiles. To date, such an endeavor has been limited
to intramolecular cyclizations using polychlorinated substrates
(Scheme 1A).5 New approaches that could enable this
transformation in an intermolecular fashion using common
starting materials would provide access to a broader array of
densely functionalized molecules for applications in organic
synthesis and medicinal chemistry.
Mn(III)-promoted oxidative radical cyclization of 1,3-
dicarbonyl compounds to alkenes6 is a powerful approach to
constructing C–C bonds en route to complex target products
(Scheme 1B).7,8 In a related context, we recently developed Mn-
catalyzed electrochemical methods9 for the difunctionalization
of alkenes.10 This strategy combines the electrochemical
generation of radical intermediates followed by catalyst-
controlled addition of these nascent open-shell species across
the alkene π-bond. The merger of electrochemistry and redox
metal catalysis allows such reactions to occur under mild
conditions with a broad substrate scope and high regio- and
chemoselectivity. In particular, we demonstrated anodically
Scheme 1. Chloroalkylation of alkenes: the Kharasch
addition vs the electrocatalytic approach.
Results and Discussion
A. Reaction Design and Development
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We reasoned that anodically coupled electrolysis could be The electrocatalytic chloroalkylation was also successful
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applied to the chloroalkylation of alkenes. Related previous
work showed that α-C–H oxidation of 1,3-dicarbonyl
compounds can be effected by a metal oxidant such as
Mn(OAc)3 to generate the corresponding carbon-centered
radicals (I) (Scheme 2A, eq 1).7,8 This reactivity was used
elegantly for C–C bond construction with alkenes followed by
radical elimination or intramolecular cyclization. Furthermore,
we have demonstrated the formation of [MnIII]–Cl (II) as the
latent Cl radical from Cl– and MnII in the Mn-catalyzed
electrochemical chlorination reactions (Scheme 2A, eq 2).10c,d
We hypothesized that, upon the formation of I and II, the
intrinsic reactivity profiles of these radical intermediates would
lead to their chemo- and regioselective addition to the alkene
substrate (Scheme 2B). Specifically, the alkene will
preferentially react with transient radical I to construct a new
C–C bond, forming transient radical III. Subsequently, the
capture of III by persistent radical II will occur selectively11 to
complete the desired chloroalkylation.
under controlled potential conditions. With a full cell voltage of
2.3 V (entry 5) or an anodic potential of 0.62 V (vs
ferrocenium/ferrocene, Fc+/0; entry 6), product 3 was formed in
high yield and high selectivity. We also surveyed various
chloride sources and found that more soluble salts such as
MgCl2 resulted in rapid dichlorination activity that completely
outcompeted the chloroalkylation (entry 7). We reason that the
low solubility of NaCl ensured a low concentration of [MnIII]–
Cl, the putative radical chlorinating agent, which resulted in
preferential inhibition of the side dichlorination pathway and
thus higher chemoselectivity.12 The identity of the electrolyte
proved unimportant to the reaction outcome: Et4N+OTs– and
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Bu4N+PF6 provided practically the same yield and selectivity
(entry 8). We also found that the use of inexpensive Ni foam as
the cathode material instead of Pt afforded 3 in synthetically
useful yield (entry 9).
Table 1. Reaction optimizationa
Scheme 2. Design principle for the electrochemical
alkylchlorination of alkenes. E = electron-withdrawing group.
PRE = persistent radical effect.
Guided by this general design principle, we aimed to develop
a chloroalkylation reaction using 4-t-butylstyrene (1) as the
alkene substrate, benzyl malononitrile (2) as the C donor, and a
chloride salt as the Cl donor. Multiple iterations of optimization
resulted in highly efficient and selective reaction conditions
comprising Mn(OTf)2 as the precatalyst, 2,2′-bipyridine (bpy)
as the ligand, NaCl as the Cl donor, and LiClO4 as the
electrolyte in a mixture of HOAc and MeCN at 50 °C. With
carbon felt, a porous and commercially available material, as
the anode and a Pt plate, an efficient material for proton
reduction, as the cathode, the application of a 6.0 mA current (2
F total charge) furnished the desired three-component adduct 3
in 94% yield (corresponding to 94% current efficiency) with
only traces of 1,2-dichloride 4 as a side product (Table 1, entry
1). In the absence of Mn, no chloroalkylation reactivity was
observed and 10% 4 was formed (entry 2). In the absence of
bpy, the desired heterodifunctionalization proceeded at a slower
rate (entry 3) and was accompanied by various side reactions
including dichlorination. The role of bpy cannot be explained
simply as that of a base, as the addition of pyridine instead of
bpy did not provide the high reactivity observed under the
optimal conditions (entry 4 vs entry 1).
aCurrent controlled at 6.0 mA throughout the electrolysis. Reaction was
stopped after 1 h and 47 min after the passage of 2 F of charge. bYields
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were determined with H NMR using 1,3,5-trimethoxybenzene as the
c
internal stardard. The cell voltage was kept constant for 2 h. The
d
current varied between 12 and 6 mA during the reaction course. The
anode potential was kept constant at 0.62 V vs. Fc+/0 for 2 h.
B. Substrate Scope
We then investigated the substrate scope of the reaction
(Scheme 3). A variety of styrene type substrates were converted
to chloroalkylated products (3, 5–14) in high yields under the
optimal conditions. In particular, aldehyde (8, 9) and benzyl
chloride (10) groups were well-tolerated, and we found no
evidence of formyl group oxidation or nucleophilic
displacement of the alkyl halide by 2. Substituted styrenes such
as α- and β-methylstyrene (12, 14) and indene (13) were
converted to the desired products in good efficiency.
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Scheme 3. Substrate scope. All substrates were electrolyzed at 6.0 mA after 2 F charge was passed; Faradaic yield = product yield. From
(E)-β-methylstyrene. b2.5 F charge was passed, Faradaic yield = 41%. cElectrolysis at a constant cell voltage of 2.3 V for 2 h. dR = thiophen-2-
ylmethyl; using the malononitrile as the limiting substrate (1 equiv) in combination with 1.5 equiv of 1. eUsing NaBr instead of NaCl at room
temperature; 3 F charge was passed, Faradaic yield = 27%.
Aliphatic alkenes also proved suitable substrates. Terminal
alkenes participated smoothly in the desired transformation
(15–17). Owing to the large steric profile of 2, acyclic alkenes
with other substitution patterns, including 1,2-disubstituted,
trisubstituted, and tetrasubstituted alkenes, showed only low
levels of reactivity. Nevertheless, cyclic alkenes such as
cyclopentene and 1-methylcyclopentene underwent strain-
relieving difunctionalization to furnish the corresponding
products (18 & 19) in synthetically useful yield and high
diastereoselectivity favouring the trans isomers.
the malononitrile in the chloroalkylation, were preserved during
the reaction (22 and 23). In addition, allyl- and propargyl
malononitrile were compatible with the reaction (26 & 27), in
which the styrenyl C=C bond was preferentially functionalized.
Finally, heterocycles including thiophene (28) and furan (29)
were well-tolerated.
We further extended the reaction scope to methyl 2-
benzylcyanoacetate, which furnished product 30 in good yield.
Cyanoacetates are, however, unreactive toward aliphatic
alkenes. 2-Phenylmalononitrile reacted with t-butylstyrene to
give bisalkylation product 31 in 26% yield. This product most
likely arose from desired chloroalkylation followed by
nucleophilic substitution of the benzyl chloride by the C
nucleophile. Indeed, a control experiment with an excess of t-
butylstyrene relative to 2-phenylmalononitrile provided the
We then explored the reaction scope of the alkylating agent.
A variety of substituted malononitriles were reacted under the
optimal electrolysis conditions to furnish the three-component
adducts in good to excellent yields. In particular, enolizable
esters and ketones, groups that could potentially compete with
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corresponding chloroalkylation product as observed by 1H
NMR.
Furthermore, by replacing NaCl with NaBr and conducting
the electrolysis at a lower temperature, bromoalkylation product
32 could be obtained in synthetically useful yield in addition to
a small amount of the corresponding dibromoalkane (Scheme
3C).
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Several other types of acetylacetone and acetylacetates
reacted smoothly with indene under the optimal conditions but
delivered 1,2-dihydrofuran-type products (33 and 34) instead of
the chloroalkylation products (Scheme 3D). These polycyclic
products were also formed in the absence of NaCl.
Mechanistically, we hypothesized that the carbon-centered
radical resulting from radical addition of the 1,3-dicarbonyl
intermediate to the alkene was further oxidized to the benzylic
carbocation prior to being captured by the adjacent enol. This
pathway is likely more favorable with acetylacetone and
acetylacetates than with malononitriles because the radical-to-
cation oxidation is facilitated by the subsequent nucleophilic
cyclization.13 Finally, extension of the current reaction system
to malonates has proven challenging at this stage; alkene
dichlorination adducts were often the predominant products in
these systems. Cyclic voltammetry data revealed that, similar to
malononitriles (see Section D), malonates can also be oxidized
electrochemically in the presence of Mn (see SI). As such, it is
unlikely that the lack of reactivity with malonates arises from
the difficulty in generating the corresponding carbon-centered
radicals. In previous studies, it has been proposed that MnIII can
coordinate with malonates to form metal-bound radicals in the
form of stable Mn-enolates.6b Thus, we hypothesize that these
enolates are less reactive than the corresponding free carbon
radicals toward alkene addition.
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Scheme 4. Derivatization of the chloroalkylation products.
D. Mechanistic Studies: Control Experiments
The involvement of carbon-centered radical intermediates in
the difunctionalization reaction was further supported by a
radical clock experiment with cyclopropyl-substituted alkene
36 (Scheme 3E). Upon formation of the first C–C bond, the
resultant radical triggered ring rupture of the adjacent
cyclopropyl group, which ultimately led to the formation of
product 37 in 79% yield.
We propose that the formation of carbon-centered radical IV
arises from single-electron oxidation of the conjugate anion of
2 in an MnIII-mediated process (see Scheme 2, eq 1). However,
two alternative mechanisms are in theory possible, both
involving the electrochemical formation of chlorinated
malononitrile 45 (Scheme 5). Indeed, our optimal reaction
conditions yielded 45 in 53% yield in the absence of alkene 1
(eq 3). This intermediate may undergo Mn-catalyzed Kharasch-
type radical addition independent of any electrochemical
processes (alternative path 1). Alternatively, upon formation, 45
may diffuse to the cathode and be reduced to radical IV prior to
its addition to the alkene (alternative path 2).
C. Product derivatization
The chloroalkylation reaction installs two functional handles
in a single step for the further construction of structurally
complex molecules. We demonstrated the synthetic value of the
heterodifunctionalization products in a set of derivatization
reactions (Scheme 4). For example, the newly installed C–Cl
bond can be substituted by N3 (38), eliminated to form a C=C
bond (39 and 41), or reduced to a C–H bond (43).
We also exploited the unique reactivity of gem-dicyano
groups to undergo decyanoalkylation in the presence of Li
naphthalide.14 For example, using MeI or BnBr as the
electrophile, products with an all-carbon quaternary stereogenic
center (40 and 42) could be obtained. This reactivity was also
extended to an aldol-type addition reaction with cyclohexanone
to form a sterically congested 3° alcohol (44).
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these control experiments provide compelling evidence that, the
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alternative pathways mediated by 45, if operating at all under
the reaction conditions, contribute minimally to the observed
chloroalkylation reactivity.
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Upon addition of IV, an electrophile radical, to the alkene,
the resultant carbon-centered radical V will accept a Cl atom
from the putative [MnIII]–Cl catalytic intermediate (vide infra),
completing the chloroalkylation event. Alternatively, V could
undergo single-electron oxidation, either directly on the anode
or mediated by MnIII, to form the corresponding carbocation.
This process is then followed by nucleophilic chlorination with
Cl–. This pathway, however, is unlikely to contribute
significantly to the observed reactivity. First, substrates with
which the carbocation formation is unfavorable, such as 8, 11,
and 15, underwent the chloroalkylation smoothly. Second, in
the majority of cases studied, we did not observe competing
acetoxylation or Ritter-type amidation of the hypothetical
carbocation intermediates. These side reactions would be
expected owing to the significantly higher concentration of
OAc– and MeCN in the reaction medium and the comparable
nucleophilicity15 of the former vs Cl– (16.9 vs 17.2, in MeCN).
As an additional piece of evidence against the carbocation
pathway, we conducted competition experiment using an equal
amount of NaCl and NaCN (nucleophilicity 16.3). Under
standard electrolysis conditions, the chloroalkylation product
was observed exclusively (Scheme 6); the cyanoalkylation
product, which would be expected if the reaction adopts the
carbocation mechanism, was not formed. Taken together, we
conclude that the radical Cl-atom transfer by Mn is the more
likely pathway for the C–Cl bond formation.
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Cl
CN CN
CN
Bn
NC
NaCl (2 equiv) + NaCN (2 equiv)
CN
Bn
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+
Ar
Ar
not observed
standard conditions
3, 82% by NMR
Scheme 6. Competition experiment. See Table 1, entry 1 for
conditions.
Scheme 5. Alternative mechanistic pathways and control
experiments. The composition of the anodic compartment was
identical to that of the undivided-cell experiment in Table 1, entry
6; the cathodic compartment contained LiClO4, HOAc, and MeCN
and was also heated to 50 °C.
a
D. Cyclic Voltammetry Studies
We carried out CV studies to gain further insights into the
reaction mechanism. In particular, we attempted to understand
the role Mn, bpy, and NaOAc play in the reaction. In MeCN,
neither Mn(OTf)2 nor 2 alone displayed any oxidation event in
the 0–1 V (vs Fc+/0) potential window.16 The addition of bpy
(1.2 equiv with respective to Mn), however, resulted in the
appearance of a new, irreversible anodic feature at ca. 700 mV
(Figure 1, black line). We assigned this peak to the MnII/MnIII
oxidation, which was facilitated by the redox active ligand.17
The oxidation wave at ca. 1.1 V likely represents the further
oxidation of MnIII to MnIV or other higher valent species. This
oxidation event is, however, irrelevant to catalysis and will not
be discussed herein.
Control experiments definitively excluded the possibility of
a Kharasch-type mechanism (alternative path 1). First, when the
electrocatalytic reaction was stopped prematurely, only traces
of 45 were observed (eq 4). Furthermore, replacing 2 with 45 as
the malononitrile source under otherwise identical conditions
led to a different product composition of predominantly
dichloride 4 along with 32% 3 and 33% 2 (eq 5). Additional
experiments showed that 45 did not participate in the alkene
functionalization without the current input in the presence of
either MnII or MnIII (eq 6).
CV and electrolysis experiments showed that under the
electrolysis conditions, 45 can undergo cathodic reduction and
mesolytic cleavage of the C–Cl bond to form carbon-centered
radical IV (see SI). However, alternative path 2 was ruled out
by conducting the electrolysis using a setup that separated the
anode from the cathode with an ion-conducting glass frit. This
divided-cell system prevented the diffusion of anodically
generated 45 to the cathodic compartment. Although initial
experiments under the standard conditions yielded only traces
of product, the addition of NaOAc in the anodic compartment
restored the chloroalkylation reactivity (eq 7). Taken together,
The addition of HOAc to the reaction system led to an
additional oxidative peak at ca. 500 mV (red line). This peak
further increases in intensity in the presence of NaOAc (blue
line), which provides a larger concentration of OAc–. To further
identify these irreversible redox features, we carried out
differential pulse voltammetry experiments (DPV; Figure 2).
The appearance of the oxidative wave at 500 mV in the presence
of acetate is clearly observed. These data revealed that OAc–
likely served as an additional ligand on Mn and reduced the
potential needed for its oxidation. Previous electrolysis
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experiments under a constant anodic potential (Table 1, entry 6)
revealed that the catalytic reaction requires a potential input of
no more than 620 mV. Therefore, we reasoned that the
oxidative feature at 500 mV is the key catalytic species that is
responsible for the observed chloroalkylation reactivity.
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Intriguingly, the addition of an additional equivalent of bpy
(Mn/bpy = 1:2.4) to the catalytic mixture led to decreased
intensity of the peak at 500 mV while the peak at 700 mV
became more pronounced. It is likely that excessive bpy led to
the formation of Mn(bpy)n (n > 1), which is more difficult to
oxidize and less relevant to catalysis. Taken together, we
hypothesize that the active Mn catalyst in our reaction adopts a
formula of [MnIII(bpy)(OAc)n(MeCN)m] (n, m > 0, the net
charge of the complex depends on n). Structurally analogous
Mn(bpy) complexes have been used in reductive
electrocatalysis (e.g., CO2 reduction18) in their low oxidation
states (formally MnI/–I). Literature data for the characterization
of MnIII complexes are largely limited to the solid state
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structures.6b,19
The
preliminary
electrochemical
characterization of the catalyst in action in the chloroalkylation
will thus serve as the foundation for our ongoing mechanistic
investigation of related electrochemical transformations
catalyzed by Mn.10
Figure 2. Differential pulse voltammograms of Mn showing the
effect of bpy and acetate on the catalyst oxidation. Conditions:
Glassy carbon as working electrode, Ag/AgNO3 reference
electrode, and a platinum wire counter electrode. LiClO4 (0.10 M
in MeCN), Mn(OTf)2 (3.0 mM), bpy (3.6 or 7.2 mM), NaOAc (4.0
mM), HOAc (60 mM). Scan rate: 20 mV/s, step E: 4 (mV), pulse
amplitude: 50 mV, pulse width: 50 ms, pulse period: 200 ms.
Figure 1. Cyclic voltammograms of Mn showing the effect of bpy
and acetate on the catalyst oxidation. Conditions: Glassy carbon as
working electrode, Ag/AgNO3 reference electrode, and a platinum
wire counter electrode. LiClO4 (0.10 M in MeCN), Mn(OTf)2 (1.0
mM), bpy (1.2 mM), NaOAc (2.0 mM), HOAc (60 mM). Scan rate:
20 mV/s.
Figure 3. Cyclic voltammograms of the reaction system showing
the catalytic effect of Mn in the oxidation of 2. Conditions: Glassy
carbon as working electrode, Ag/AgNO3 reference electrode, and a
platinum wire counter electrode. LiClO4 (0.10 M in MeCN),
Mn(OTf)2 (1.0 mM), bpy (1.2 mM), NaOAc (2.0 mM), 2 (5.0 mM),
HOAc (60 mM). Scan rate: 20 mV/s.
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oxidation. These findings are consistent with the controlled
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potential electrolysis experiment wherein the application of 620
mV anodic potential proved sufficient in promoting the desired
chloroalkylation reaction (see Table 1, entry 6).20
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oxidation of Cl–. Conditions: Glassy carbon as working electrode,
Ag/AgNO3 reference electrode, and a platinum wire counter
electrode. LiClO4 (0.10 M in MeCN), Mn(OTf)2 (1.0 mM), bpy
(1.2 mM), MgCl2 (5.0 mM), HOAc (60 mM). Scan rate: 20 mV/s.
We then studied the role Mn plays in the formation of carbon-
centered radical IV. Malononitrile 2 alone does not show any
anodic feature in the potential window of 0–1.0 V (Figure 3,
black line), showing that its direct oxidation on the anode is
difficult and unlikely to happen under reaction conditions with
an anodic potential of less than 650 mV. The addition of 2 to
the Mn/bpy/OAc– mixture resulted in moderate current
enhancement of the anodic peak at 500 mV (blue vs red lines).
Increasing the concentration of 2, however, did not result in
further improvement of the catalytic current. We reasoned that
the MnIII catalyst generated electrochemically can form an
adduct with 2 through coordination to a CN group or the α-
carbon. The decomposition of this adduct to generate free
radical IV is slow on the CV time scale and a catalytic current
is thus not observed. In addition to being a ligand to Mn, we
speculated that the acetate ion also accelerated the oxidation of
2 by functioning as a general base. In the standard electrolysis
in an undivided cell, exogenous NaOAc was unnecessary
because acetate was generated in situ on the Pt cathode during
the reduction of HOAc to H2.
The addition of Cl– to the catalytic mixture also led to current
increase at ca. 500 mV (Figure 4, blue vs red lines). We assign
the new anodic wave to the oxidation of [MnII]–Cl to [MnIII]–
Cl.10c This redox event is quasi-reversible, and the reduction of
the catalytic active [MnIII]–Cl partially contributes to the
cathodic wave at 500 mV. MgCl2 alone does not display any
oxidation wave at a potential smaller than 700 mV (black line),
indicating that its direct oxidation contributes minimally to the
observed reactivity. In this study, more soluble MgCl2 was used
instead of NaCl. The latter salt shows the same CV pattern but
the catalytic current is substantially less pronounced.
Scheme 7. Proposed mechanism involving catalytic,
anodically coupled electrolysis.
Taken together, all experimental data are in agreement with
the mechanistic scenario detailed in Scheme 7. Anodically
coupled electrolysis enabled the generation of carbon-centered
radical IV and latent chlorine radical [MnIII–Cl] spontaneously.
Both processes were mediated by the Mn catalyst. The alkene
substrate first reacted with transient free radical IV to form V.
This nascent transient radical subsequently cross coupled with
[MnIII–Cl], a persistent open-shell intermediate, in a manner
akin to metal-mediated atom transfer to provide the
heterodifunctionalized product. Acetate generated on the
cathode via the reduction of HOAc diffused to the bulk solution
and facilitated the generation of IV as both a ligand to Mn and
a proton acceptor.
Conclusions
In conclusion, we report the oxidative chloroalkylation of
alkenes via anodically coupled electrolysis. Malononitrile
derivatives and NaCl were used as the reagents and activated
via parallel, Mn-catalyzed electrochemical oxidation processes.
The resulting open-shell intermediates react with the alkene in
a selective fashion, yielding the hetero-difunctionalization
products in high efficiency across a broad scope of substrates.
Current efforts are focused on the mechanistic investigation of
anodically coupled electrolysis and the further application of
this new synthetic strategy in reaction discovery and organic
synthesis.
The very similar oxidation potential needed for the
generation of IV and [MnIII]–Cl is unlikely a coincidence.
Given that both anodic events are mediated by the
Mn/bpy/OAc– catalytic system, the potentials at which IV and
[MnIII]–Cl are generated are largely dependent upon the catalyst
AUTHOR INFORMATION
Corresponding Author
*songlin@cornell.edu
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by Oxidative Quenching of Photoredox Catalysts. J. Am. Chem. Soc.
2011, 133, 4160-4163.
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3. Early examples of Kharasch addition using radical initiators:
(a) Kharasch, M. S.; Jensen, E. V.; Urry, W. H. Addition of Carbon
Tetrachloride and Chloroform to Olefins. Science 1945, 102, 128. (b)
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Radicals in Solution. XII. The Addition of Bromo Esters to Olefins. J.
Am. Chem. Soc. 1948, 70, 1055-1059.
Notes
There are no conflicts to declare.
ASSOCIATED CONTENT
Supporting Information
4. Representative reviews on metal-catalyzed atom-transfer
radical additions: (a) Iqbal, J.; Bhatia, B.; Nayyar, N. K. Transition
Metal-Promoted Free-Radical Reactions in Organic Synthesis: The
Formation of Carbon-Carbon Bonds. Chem. Rev. 1994, 94, 519-564.
(b) Clark, A. J. Atom Transfer Radical Cyclisation Reactions Mediated
by Copper Complexes. Chem. Soc. Rev. 2002, 31. 1-11. (c) Pintauer,
T.; Matyjaszewski, K. Atom Transfer Radical Addition and
Polymerization Reactions Catalyzed by ppm Amounts of Copper
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van Koten, G. Diaminoarylnickel(II) “Pincer” Complexes: Mechanistic
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Polymerization, and Dendrimeric Transition Metal Catalysts. Acc.
Chem. Res. 1998, 31, 423-431. (f) Studer, A.; Curran, D. P. Catalysis
of Radical Reactions: A Radical Chemistry Perspective. Angew.
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Gao, Q.; Zhu, N.-Y. Copper(I)-Catalyzed Chlorine Atom Transfer
Radical Cyclization Reactions of Unsaturated α-Chloro β-Keto Esters.
Org. Lett., 2006, 8, 5757-5760. (b) Snider, B. B.; Patricia, J. J.; Kates,
S. A. Mechanism of Manganese(III)-Based Oxidation of β-Keto Esters.
J. Org. Chem. 1988, 53, 2137-2143. (c) Hayes, T. K.; Villani, R.;
Weinreb, S. M. Exploratory Studies of the Transition Metal Catalyzed
Intramolecular Cyclization of Unsaturated α,α-Dichloro Esters, Acids,
and Nitriles. J. Am. Chem. Soc. 1988, 110, 5533-5543. (d) Ng, F.-N.;
Lau, Y.-F.; Zhou, Z.; Yu, W.-Y. [RhIII(Cp*)]-Catalyzed Cascade
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Arylboronic Acids and N-Chlorosuccinimide for Facile Synthesis of α-
Aryl-α-chloro Carbonyl Compounds. Org. Lett. 2015, 17, 1676-1679.
(e) Bellus, D. Copper-Catalyzed Additions of Organic Polyhalides to
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1838. (f) McGonagle, F. I.; Brown, L.; Cooke, A.; Sutherland, A. A
Three-Step Tandem Process for the Synthesis of Bicyclic γ-Lactams.
Org. Biol. Chem. 2010, 8, 3418-3425. An example using less reactive,
monochlorinated substrate under high temperature. (g) Lee, G. M.;
Parvez M; Weinreb, S. M. Intramolecular Metal Catalyzed Kharasch
Cyclizations of Olefinic α-Halo Esters and Acids. Tetrahedron 1988,
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The Supporting Information is available free of charge on the ACS
Publications website.
Experimental procedures and characterization data (PDF)
Crystallography data for 19 (CIF)
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ACKNOWLEDGMENT
Financial support was provided by Cornell University and NIGMS
(R01GM130928). S.L. thanks NSF for a CAREER award (CHE-
1751839). This study made use of the Cornell Center for Materials
Research Shared Facilities (DMR-1719875) and the NMR facility
(CHE-1531632) supported by NSF. We thank Dr. Samantha
MacMillan for help with X-ray crystal structure collection and
determination.
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