Electroreductive Carbofunctionalization of Alkenes with Alkyl Bromides via a Radical-Polar Crossover Mechanism

Article abstract of DOI:10.1021/jacs.0c08532

Electrochemistry grants direct access to reactive intermediates (radicals and ions) in a controlled fashion toward selective organic transformations. This feature has been demonstrated in a variety of alkene functionalization reactions, most of which proceed via an anodic oxidation pathway. In this report, we further expand the scope of electrochemistry to the reductive functionalization of alkenes. In particular, the strategic choice of reagents and reaction conditions enabled a radical-polar crossover pathway wherein two distinct electrophiles can be added across an alkene in a highly chemo- and regioselective fashion. Specifically, we used this strategy in the intermolecular carboformylation, anti-Markovnikov hydroalkylation, and carbocarboxylation of alkenes - reactions with rare precedents in the literature - by means of the electroreductive generation of alkyl radical and carbanion intermediates. These reactions employ readily available starting materials (alkyl halides, alkenes, etc.) and simple, transition-metal-free conditions and display broad substrate scope and good tolerance of functional groups. A uniform protocol can be used to achieve all three transformations by simply altering the reaction medium. This development provides a new avenue for constructing Csp3-Csp3 bonds.

Full text of DOI:10.1021/jacs.0c08532

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Electroreductive Carbofunctionalization of Alkenes with Alkyl
Bromides via a Radical-Polar Crossover Mechanism
Wen Zhang and Song Lin*
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ABSTRACT: Electrochemistry grants direct access to reactive
intermediates (radicals and ions) in a controlled fashion toward
selective organic transformations. This feature has been demon-
strated in a variety of alkene functionalization reactions, most of
which proceed via an anodic oxidation pathway. In this report, we
further expand the scope of electrochemistry to the reductive
functionalization of alkenes. In particular, the strategic choice of
reagents and reaction conditions enabled a radical-polar crossover
pathway wherein two distinct electrophiles can be added across an
alkene in a highly chemo- and regioselective fashion. Specifically,
we used this strategy in the intermolecular carboformylation, anti-
Markovnikov hydroalkylation, and carbocarboxylation of alkenes
reactions with rare precedents in the literatureby means of the
electroreductive generation of alkyl radical and carbanion intermediates. These reactions employ readily available starting materials
(alkyl halides, alkenes, etc.) and simple, transition-metal-free conditions and display broad substrate scope and good tolerance of
functional groups. A uniform protocol can be used to achieve all three transformations by simply altering the reaction medium. This
development provides a new avenue for constructing Csp3−Csp3 bonds.
oxidation of radical precursors such as the Langlois reagent
(CF3SO2Na) and 1,3-dicarbonyl compounds has been
successfully used in the carbofunctionalization of alkenes
(type 1).8 In addition, Xu reported hydroxyalkynylation and
related reactions by means of the anodic oxidation of styrenes
to the radical cations (type 2).9 Recently, our laboratory
advanced an electrocatalytic approach for the chlorotrifluor-
omethylation and chloroalkylation of alkenes via anodically
coupled electrolysis (type 3).10 As a follow-up, we disclosed
enantioselective cyanofunctionalization and hydrocyanation of
alkenes by merging electrochemistry with copper catalysis.11
Despite these advances, electrochemical methods for the
intermolecular addition of unactivated alkyl groups to alkenes
remain elusive.12
INTRODUCTION
■
The intermolecular difunctionalization of alkenes is one of the
most widely used classes of transformations in organic
synthesis. Recent advances in homogeneous catalysis have
brought about innovative new strategies for the difunctional-
ization of alkenes and resulted in a catalog of useful reactions.1
In this context, electrochemistry has been explored in the past
several years as an efficient, versatile, and sustainable approach
for the difunctionalization and hydrofunctionalization of
alkenes.2,3 From a mechanistic point of view, these new
developments can be primarily categorized into three types
(Scheme 1A): (1) direct activation of a nucleophilic species to
generate a radical intermediate, which initiates subsequent
alkene addition,4 (2) direct activation of an alkene to form the
corresponding radical cation prior to difunctionalization,5 and
(3) activation of a redox catalyst, which controls the addition
of radical intermediates across an alkene.6 These strategies
uniformly rely on the oxidative activation of reactants or
catalysts. On the contrary, the development of electroreductive
protocols for the difunctionalization of alkenes remains an
underexplored research direction (Scheme 1B).7
Alkyl halides are among the most common reactants in
organic synthesis and are excellent alkyl radical precursors
given their structural diversity and synthetic availability.
Traditionally, alkyl halides are converted to alkyl radicals
using tin- and silicon-based initiators.13 Recently, transition-
Received: August 8, 2020
From a synthetic point of view, current electrochemical
methods are predominantly used for the formation of C−
heteroatom bonds (e.g., C−O, C−N, C−S, C−Cl). However,
methods available for the construction of C−C bonds (i.e.,
carbofunctionalization) remain rare and rely largely on
prefunctionalized carbon nucleophiles. For example, anodic
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regioselective fashion, as well as the anti-Markovnikov
hydroalkylation reaction. These reactions proceed through a
radical-polar crossover pathway wherein the cathode effects
two reduction steps in an ECEC-type mechanism for the
generation of key radical and carbanion intermediates. Because
the reaction is initiated by the cathodic activation of alkyl
halides, we successfully circumvented the aforementioned
scope and selectivity issues intrinsic to the alkene reduction
mechanism. From a synthetic perspective, there are no or very
few examples of each of the transformations described herein
(see Results and Discussion below), and our method thus
provides a new strategy for selectively constructing multiple
C−C bonds from simple starting materials.
Scheme 1. Electrochemical Difunctionalization of Alkenes:
Known and New Strategies
RESULTS AND DISCUSSION
■
A. Reaction Design and Development. We envisioned a
radical-polar crossover mechanism for the electroreductive
carbofunctionalization of alkenes (Scheme 1C). The reaction
is initiated through the generation of an alkyl radical (R•) via
reductive dehalogenation of an alkyl bromide. The addition of
R• to an alkene substrate affords a new C-centered radical (Int-
1), which is further reduced at the cathode to generate the
corresponding carbanion (Int-2). This nascent C-nucleophile
is then trapped with another electrophile (E+) to deliver the
difunctionalized product.
To achieve this heterodifunctionalization reaction with high
chemo- and regioselectivity, the following criteria need to be
met (Scheme 2A). (1) The alkyl bromide should be more
easily reduced than the second electrophilic reactant (E+) or
the alkene. (2) The radical from alkyl bromide reduction
[(R1)•] should react with the alkene faster than its further
reduction to a carbanion or radical dimerization.20b,22 (3) The
reduction of new C-centered radical Int-1 to carbanion Int-2
should take place preferentially over its addition to another
equivalent of alkene. (4) Carbanion Int-2 addition to the
second electrophile (E+) should be faster than the competing
substitution with a second equivalent of alkyl bromide. We
note that this ECEC-enabled radical-polar crossover mecha-
nism has been proposed for the electroreductive Giese-type
reactions12a,b but rarely employed as a strategy in other types
of carbofunctionalization reactions.
metal (Ni,14 Cu,14a,15 Pd,16 etc.17) and photoredox catalysts18
have been demonstrated to effect single-electron activation of
alkyl halides. Nevertheless, these catalytic strategies have seen
limited applications in the carbofunctionalization of alkenes
with alkyl halides.19
We envision a different strategy for the coupling of alkyl
halides and alkenes by means of electrochemistry. The
exceedingly broad redox range, which is essentially only
limited by the solvent potential window, in combination with
tunable potential, renders cathodic reduction an ideal
technique for the activation of alkyl halides. In fact, the
electrochemistry of alkyl halides has been extensively studied
using voltammetry techniques20 and explored in reactions such
as hydrodehalogenation and carboxylation.21 In addition,
seminal contributions have been made12c,c−g in the reductive
alkylation of alkenes using alkyl halides. However, current
examples are limited to the dialkylation reactions, require a
large excess of alkenes or alkyl halides, and display narrow
scope (primarily electron-deficient alkenes) as well as low
efficiency and/or chemoselectivity. Importantly, these methods
have not been shown amenable to the hetero difunctionaliza-
tion of alkenes (except for Giese-type reactions12a,b). We
reason that the synthetic limitations in these reactions largely
arise from the reaction mechanism, which has been proposed
to rely on the direct reduction of the alkene substrate to the
radical anion prior to reactions with alkyl halides (Scheme 1B).
This mechanism will inevitably limit the scope of alkenes as
suitable substrates and lead to difficulties in controlling regio-
and chemoselectivities.
The reduction potentials23 and electronic properties of
reactants and intermediates involved in the proposed reaction
pathway guided our initial reaction development. With an
i
appropriate combination of substrates such as PrBr (1) and
styrene (2), the highly selective carbofunctionalization reaction
is plausible over various side reactions described above
(Scheme 2B, gray dashed arrows). For example, the reduction
of 1 takes place at around −2.0 V (vs SCE)24 to generate Pr•
i
(Int-3) upon C−Br cleavage. The subsequent radical addition
to 2 is polarity-matched25 and will occur rapidly to give a new
C-centered radical (Int-6). The competing over-reduction of
iPr• and reduction of 2 happen at a potential of −2.3 V26 and
−2.6 V,7a respectively, and are thus slower. In the next step, the
nascent benzylic radical intermediate (Int-6) will be readily
reduced to the carbanion with a potential of −1.6 V.26 In
contrast, the competing radical addition to another molecule of
2 is slow because the polarity matching is unfavorable.27 Upon
formation of key carbanion intermediate Int-8, the choice of
the second electrophilic reactant is critical in ensuring a
selective transformation. We envision that electrophiles such as
DMF (CHO donor), MeCN (H+ donor), and CO2 are suitable
choices because they are inert to cathodic reduction compared
As part of our continuing effort in expanding the scope of
electrochemical transformations of alkenes,1e herein we report
our recent advances in the electroreductive intermolecular
carbofunctionalization of alkenes with alkyl bromides (Scheme
1C). Specifically, we report the carboformylation and
carbocarboxylation reactions, in which an alkyl group and a
CHO/CO2H group are added across the alkene in a
B
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transformation, wherein an alkyl and CHO groups are added
across an alkene, has not been achieved in an intermolecular
fashion.28 Our initial exploration revealed that using LiOTf as
the electrolyte, DMF as the solvent and formyl group donor,
Mg plate as the sacrificial anode, and graphite as cathode, the
difunctionalization product (8) could be obtained in 71% yield
in addition to small amounts of hydroalkylated (9) and
dialkylated (10) products (Table 1, entry 1). The addition of
Scheme 2. Design Principle and Analysis for
Electroreductive Difunctionalization of Alkenes
a
Table 1. Reaction Optimization
yield (%)
variation from above
conditions
conv. of
7 (%)
entry
8
9
10
1
2
3
4
5
6
7
8
none
85
93
84
99
28
38
99
99
71
55
9
7
8
0
6
<2
0
2 mol % Co(salen)
iPrCl instead of PrBr
iPrI instead of PrBr
i
i
22
<2
6
88
89 (86)
10
2
5
5
4
35
0
0
6
6
Zn(+) instead of Mg(+)
Mg(−) instead of C(−)
4.2 mL of DMF
same as entry 7 but with
1.1 equiv of LiOTf
b
9
same as entry 8 but using
a divided cell
MeCN (4.2 mL) instead
of DMF
same as entry 9 but with
Et2NH (1.0 equiv)
90
76
85
45
0
19
65
14
2
10
11
b
0
77 (73)
3
12
13
no electricity
no electricity but with
Mg powder
2
3
0
0
0
0
0
0
a
i
Reaction conditions: 7 (1 mmol, 1 equiv), PrBr (3 equiv), LiOTf
(2.2 equiv), DMF (8.5 mL), Mg anode, graphite cathode, undivided
cell, constant current i = 10 mA, 4 F/mol. Conversion and yield
b
1
determined by H NMR. Isolated yield.
to alkyl bromides but can readily react with a carbanion
nucleophile such as Int-8. Meanwhile, the undesired SN2
pathway with another equivalent of iPrBr to form 6 is expected
to be sluggish given the unfavorable sterics of both reacting
components. Thus, the highly chemo- and regioselective
carbofunctionalization is expected in this scenario.
Co(salen) as an electron mediator to facilitate the reduction of
iPrBr29 did not prove effective (entry 2). When less reactive
iPrCl or more reactive iPrI was used instead of iPrBr, the yield
was substantially decreased (entries 3−4). In the latter case,
We note that the aforementioned criteria inevitably define
the scope of substrates of this strategy and disfavor certain
types of reactants. For example, unconjugated alkenes (e.g., 1-
butene) are challenging substrates due to difficulties in forming
Int-1 (polarity mismatched radical addition) and Int-2 (radical
reduction difficult). Nevertheless, this analysis allowed us to
readily and rationally identify substrates that are suitable for
the desired transformation, thereby guiding our further
expansion of the reaction scope. In addition, we expect that
within these criteria, the combination of diverse electrophiles
and various radical-acceptor alkenes will lead to a collection of
new structures that could be challenging to access using known
methods. As such, this transition-metal-free carbonfunctional-
ization reaction will provide a new tool for the selective
formation of Csp3−Csp3 bonds.
i
because PrI is a better electrophile, a considerable amount of
dialkylated product 10 was observed (35%). Changing the
sacrificial anode from Mg to Zn significantly hampered the
reactivity, as anodically generated Zn2+ can be readily reduced
to Zn on the cathode (Ered ∼ −1.0 V) and thus competes with
the alkyl halide reduction (entry 5). Changing the cathode
from graphite to Mg also significantly lowered the yield (entry
6).
The reaction yield was improved to 88% when the
concentration of the reaction was doubled by decreasing the
solvent volume (entry 7). Halving the concentration of LiOTf
has little effect on the reaction (entry 8), and these conditions
are used as a standard for substrate scope study. The reaction
using a divided cell (entry 9) provided the product in a
diminished 45% yield with increased byproduct formation.
This finding suggests that the Mg salt generated on the
We set out to investigate the electroreductive carboformy-
lation of 4-tert-butylstyrene (7) with iPrBr (1). Notably, such a
C
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sacrificial anode is not necessary in the overall transformation
but may promote the transformation by, for example,
interacting with reactants or reactive intermediates.
CN) are not suitable substrates (see the Supporting
Information). In addition, 1,1-disubstituted styrenes were
converted smoothly to the corresponding products (28−29)
with a quaternary carbon center. 1,2-Disubstituted alkenes are
challenging substrates (ca. 10% yield) presumably due to
unfavorable steric interactions in the initial alkyl radical
addition (see the Supporting Information).
Importantly, alkenes containing heterocycles such as indole,
azaindole, pyrazole, pyridine, carbazole, benzothiophene,
dibenzofuran, and dibenzothiophene were all suitable sub-
strates, delivering the carboformylation products (30−39) in
satisfying yields. It was worth noting that when 1-phenyl-1,3-
butadiene (40) was subjected to the standard reaction
conditions, the 1,4-dialkylated product (41) was isolated in
90% yield (11:1 E/Z ratio) without the observation of any
carboformylation (eq 1). Finally, phenyl vinyl sulfide (42) also
proved to be a reactive substrate, transforming into the product
43 in 25% yield (eq 2).
We envisioned that using MeCN as the solvent and proton
donor, hydroalkylation will take place, and owing to the weak
acidity of MeCN (pKa ∼ 33.3 in MeCN),30 competing H+
reduction will be minimized. Indeed, we found that simply
switching the solvent under otherwise identical conditions, the
reaction selectively provided product 9 in 65% yield (entry
10). The addition of diethylamine further improved the
reactivity (entry 11), and we hypothesize that the secondary
amine could serve as a weak proton donor (pKa ∼ 40 in
DMSO) or a proton shuttle. These conditions are used for
substrate scope expansion for hydroalkylation. Control experi-
ments suggested that electricity is essential to these
carbofunctionalization reactions (entry 12). Finally, replacing
electricity with Mg powder did not generate any desired
products (entry 13), thus indicating that this transformation
does not involve Grignard-type intermediates generated from
iPrBr and electroplated Mg0.
The scope of the electroreductive carboformylation was
investigated under the optimized conditions (Table 2).
a
Table 2. Scope of Styrenes for Carboformylation
Next, we surveyed various alkyl bromides (Table 3).
Secondary alkyl bromides including both acyclic (44, 54−
57) and cyclic (45−53) substrates were converted to the
corresponding products in moderate to good yields. In
addition, tertiary alkyl bromides such as 58−60 also proved
to be suitable substrates. In contrast, primary alkyl bromides
(61) showed poor reactivity under current conditions likely as
a result of their more negative reduction potential than 2° and
3° counterparts. Nonetheless, in an intramolecular setting, a 1°
alkyl bromide was successfully engaged in a cyclization−
formylation sequence to yield product 62. Under the optimal
conditions, functional groups such as TBS-protected ether
(55), thioether (57, 59), unactivated alkene (54), and
protected ketone (51) were tolerated.
Having established the reactivity of carboformylation, we
further investigated the scope of hydroalkylation reaction using
MeCN as the solvent and proton source (Table 4). This
reaction directly gives rise to Csp3−Csp3 coupling products in
an anti-Markovnikov fashion between an alkene and an alkyl
halide and is an important yet challenging transformation.
There are currently very limited examples of anti-Markovnikov
hydroalkylation31 using unactivated alkyl halides, including
reactions by Ni32 or Fe33 catalysis, the former of which has not
been demonstrated for styrene-type alkenes. Our electro-
reductive reaction thus gives rise to a complementary approach
for the hydroalkylation of alkenes under transition-metal-free
conditions using a readily available H source (i.e., MeCN).
In this context, styrenes containing BPin (63), SMe (64),
and ferrecene (66) groups were compatible and transformed
into the desired products in good yields. Notably, heteroarene-
substituted alkenes including benzofuran, benzothiophene,
pyrazole, dibenzofuran, dibenzothiophene, and pyridine all
underwent the desired reaction (67−73). A collection of cyclic
and acyclic, 2° and 3° alkyl bromides were suitable for this
reaction. Several 1,1-disubstituent styrenes were also converted
to the desired products in good yield. By replacing MeCN with
a
Reaction conditions: alkene (1 mmol, 1 equiv), alkyl bromides (3
equiv), LiOTf (1.1 equiv), DMF (4.2 mL), Mg plate and graphite
plate, undivided cell (ElectraSyn), constant current i = 10 mA, 4 F/
mol, 22 °C. Isolated yields are reported.
Styrenes bearing various electronically different substituents
at o-, m-, and p-positions proved to be suitable substrates and
provided products 11−29 in good yields. Notably, aryl
chloride 14 and aryl bromides 15, 25, and 26 were compatible,
which may induce catalyst promiscuity under certain
transition-metal-mediated conditions. Currently, styrenes
bearing strongly electron-withdrawing groups (e.g., p-CF3, p-
D
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a
a
Table 3. Scope of Alkyl Bromides for Carboformylation
Table 4. Substrate Scope of Hydroalkylation
a
Reaction conditions: alkene (1 mmol, 1 equiv), alkyl bromides (3
equiv), LiOTf (1.1 equiv), DMF (4.2 mL), Mg plate and graphite
plate, undivided cell (ElectraSyn), constant current i = 10 mA, 4 F/
mol, 22 °C. Isolated yields are reported.
CD3CN, product 9-d1 was prepared in 42% yield with 94% D
atom incorporation. This method thereby provides a simple
means to deuteroalkylation. The hydroalkylation protocol is
also applicable to a 1,3-diene substrate (i.e., 1-phenyl-1,3-
butadiene), furnishing 1,4-hydroalkylated product 88 selec-
tively in 45% yield.
We further expanded the scope of this transition-metal-free
hydroalkylation reaction to non-styrene-type alkenes. For
example, phenyl vinyl sulfide (42) could be smoothly
transformed to product 89 in 50% yield. Moreover,
compounds 90 and 91 could be readily obtained from alkenyl
pinacol boronic esters in useful yields, which provides a
convenient method for synthesizing alkyl-Bpin type products.
Finally, the hydroalkylation of methyl 2-acetamidoacrylate
yielded protected neopentylglycine (92) in high yield, thereby
providing a convenient route for the synthesis of unnatural
amino acids from simply alkyl bromides.
B. Scope Expansion to Carbocarboxylation Reaction.
α-Substituent phenylacetic acids are key intermediates for the
synthesis of a variety of bioactive molecules.34 However, there
are currently very limited literature examples on carbocarbox-
ylation, which are focused on the functionalization of electron-
deficient vinylarenes.35 Several examples of anti-Markovnikov
hydrocarboxylation and dicarboxylation reactions have been
reported using electrochemistry.36 Nevertheless, these reac-
tions are proposed to undergo direct reduction of alkenes and
thus show intrinsic limitations on the alkene scope and
functional group tolerance. We envision that alkene
a
Reaction conditions: alkene (1 mmol, 1 equiv), alkyl bromides (3
equiv), LiOTf (1.1 equiv), Et2NH (1 equiv), MeCN (4.2 mL), Mg
plate and graphite plate, undivided cell (ElectraSyn), constant current
i = 10 mA, 4 F/mol, 22 °C. Isolated yields are reported.
b
Regioisomeric ratio bewteen 1,4- and 1,2-hydroalkylated products.
c
Not separable from 10% 1,4-dialkylated product (41), and the yield
d
is calculated taking this into consideration. TBABr as electrolyte,
DMF as solvent. TBAPF6 as electrolyte, DMF as solvent. TBAPF6 as
electrolyte, DMF as solvent, CO2 (balloon).
e
f
carbocarboxylation could be readily realized under the same
mechanistic manifold by using CO2 as the electrophile to
capture the carbanion intermediate. The plausibility of this
proposal was supported by redox potentials and electro-
philicities of the reactants involved. For instance, CO2 (Ered
=
−2.2 V)37 has a substantially more negative potential than alkyl
bromides (Ered(iPrBr) = −2.0 V), suggesting that the selective
cathodic reduction of alkyl bromides in the presence of CO2 is
likely. In addition, CO2 is considered as a better electrophile
than DMF owing to its electron-deficient nature,35a and thus
the reaction could be carried out in DMF with minimal
chemoselectivity issue in the polar nucleophilic addition step.
E
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After the optimization of reaction conditions, we found that
the carbocarboxylation reaction can be achieved using TBAPF6
as the electrolyte in a CO2-saturated solution (using a CO2
balloon) under otherwise identical conditions to the
carboformylation reaction, successfully generating carboxylic
acid products in good yields as single regioisomers (Table 5).
common starting materials under simple conditions. The latter
class of molecules can be challenging to synthesize from
malonic acid, as the monoprotection and/or the subsequent
alkylation with a sterically hindered alkyl electrophile (e.g.,
neopentyl bromide) could be problematic.
Finally, we showcased our methodology in the formal
synthesis of bioactive compounds. For example, 118 (a
precursor to glucokinase activator 119),34b 120 (a precursor
to histone deacetylase inhibitor 121),39 and 123 (a precursor
to pregabalin 124, a drug for treating neuropathic pain)38b
were obtained in good yields (Scheme 3). Although reported
a
Table 5. Substrate Scope of Carbocarboxylation
Scheme 3. Synthesis of Precursor of Bioactive Molecules
procedures are available for the preparation of these
intermediates, our protocol is generally more modular (with
two reactantsalkyl bromide and alkenewidely available,
and isotopically labeled CO2 readily obtained) and is thus
amenable to structural diversification for medicinal chemistry
studies.
C. Mechanistic Information and Mechanism-In-
formed New Reactions. We propose three mechanistic
scenarios for the electroreductive carbofunctionalization
reaction (Scheme 4). Pathway A follows our initial working
a
Reaction conditions: alkene (1 mmol, 1 equiv), alkyl bromides (3
equiv), TBAPF6 (1.1 equiv), DMF (4.2 mL), CO2 balloon, Mg plate
and graphite plate, undivided cell (ElectraSyn), constant current i =
Scheme 4. Plausible Mechanism
b
10 mA, 4 F/mol, 22 °C. Isolated yields are reported. 20%
Markovnikov hydrocarboxylation product (97) was also formed.
c
Constant current i = 5 mA.
This reaction tolerates electron-rich and electron-deficient
styrenes including aryl chlorides and bromides (94 and 95).
However, substrates with strongly electron-withdrawing
substituents can undergo competing alkene reduction path-
ways, thereby yielding 25% of the desired product (96) in
combination with 20% Markovnikov hydrocarboxylation
product (97). Various heteroarenes and alkyl bromides were
suitable substrates. Intramolecular cyclization took place to
yield product 107 in 58% yield.
Importantly, this carbocarboxylation reaction is also
applicable to the functionalization of several non-styrene-type
alkenes. For example, aryl vinyl sulfides and a series of Michael
acceptors (acrylates, acrylamides, and acrylonitrile) are
converted to the carboxylic acids smoothly (108−114). Our
method thus provides a novel and efficient pathway toward a
variety of useful synthetic intermediates such as α-thiocarbox-
ylic acids and unsymmetrical 1,3-dicarbonyl compounds38
(including those with quaternary stereogenic centers) from
F
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hypothesis, wherein the reduction of the alkyl bromide leads to
an alkyl radical, which then adds across the alkene before
further reduction to the carbanion and subsequent reaction
with a second electrophile. In pathway B, the alkyl radical from
R−Br reduction is further reduced to R−, which then adds to
the alkene28b,40 before the resultant carbanion is trapped by E+.
Finally, in pathway C, the alkene is reduced preferentially to
the corresponding radical anion, which first reacts with R−Br
to form the terminal C−C bond and then undergoes cathodic
reduction to the carbanion before reacting with E+.41 The
reduction potentials of various reactants and intermediates
involved are most consistent with pathway A. Several sets of
experiments in this section further support this hypothesis.
Scheme 6. Mechanism-Guided Reaction Scope Expansion:
Allylic Alkylation of Allyl Ethers
i
t
First, when PrMgBr (125) or BuLi was slowly added to a
solution of 7 in DMF or MeCN (Scheme 5A), no
as an unconventional leaving group because it is resistant to
cathodic reduction and does not compete with R−Br. These
results also serve as additional support to the radical-polar
crossover mechanism.
Scheme 5. Control Experiments for Mechanistic Study
CONCLUSION
■
In summary, we employed an electroreductive strategy for the
discovery of carbofunctionalization of radical-acceptor alkenes
using alkyl bromides. The radical-polar crossover mechanism
in combination with knowledge of the reduction potentials of
the reactants and reactive intermediates allowed us to
rationally select reactants to achieve highly chemo- and
regioselective difunctionalization reactions, thus forging two
distinct C−C bonds in a single operation. Depending on the
third reaction component involved (i.e., DMF, MeCN, or
CO2), carboformylation, hydroalkylation, and carbocarboxyla-
tion were achieved with broad substrate scope and good
functional group compatibility. Mechanistic studies provided
strong support for an ECEC mechanism and a radical-polar
alkene functionalization pathway. This information guided our
discovery of a new transformationalkylation of allylic ethers.
Current efforts are directed toward expanding the reaction
scope to other types of alkenes and electrophiles.
difunctionalization products (8, 9, 127, and 128) were
observed. This finding suggested that the addition of carbanion
to styrene (pathway B) is unlikely. Second, we carried out the
reaction with an enantioenriched alkyl bromide (130). In
theory, pathway C, which includes an SN2 reaction of the
alkene radical anion with the alkyl bromide, will lead to the
inversion of the configuration at the chiral carbon. However,
this control experiment gave the desired product (131) in 52%
yield with 1.4:1 dr, with both diastereomers generated
racemicly (Scheme 5B). This result ruled out pathway C but
also supports the direct reduction of 130 that leads to the loss
of chiral information. Finally, we performed a radical probe
experiment using cyclopropane-derived substrate 132. Under
standard reaction conditions, the cyclopropyl group was
opened to form 133 as the only observable product (Scheme
5C).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c08532.
■
sı
Synthetic procedures, characterization, and additional
data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Song Lin − Department of Chemistry and Chemical Biology,
Cornell University, Ithaca, New York 14850, United States;
orcid.org/0000-0002-8880-6476; Email: songlin@
cornell.edu
This mechanistic proposal (see Scheme 4A) led us to
hypothesize that, when a leaving group is positioned in the
substrate at the allylic position, the carbanion intermediate
could undergo β-elimination to produce various interesting
products. For example, when an OBn group was placed at the
allylic position, an E1cb pathway ensued (via Int-10) to give
product 135 or 136 (Scheme 6). The reaction thus resulted in
an overall allylic alkylation from an allylic ether and an alkyl
bromidea transformation that has yet to be reported in the
literature.42 It was worth noting that we chose an alkoxy group
Author
Wen Zhang − Department of Chemistry and Chemical
Biology, Cornell University, Ithaca, New York 14850, United
States
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c08532
Notes
The authors declare no competing financial interest.
G
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Article
Complex. J. Am. Chem. Soc. 2018, 140, 12511. (d) Siu, J. C.; Parry, J.
B.; Lin, S. Aminoxyl-Catalyzed Electrochemical Diazidation of
Alkenes Mediated by a Metastable Charge-Transfer Complex. J. Am.
Chem. Soc. 2019, 141, 2825. (e) Lu, L.; Fu, N.; Lin, S. Three-
Component Chlorophosphinoylation of Alkenes via Anodically
Coupled Electrolysis. Synlett 2019, 30, 1199.
ACKNOWLEDGMENTS
■
Financial support was provided by NIGMS (R01GM130928).
This study made use of the NMR facility supported by the
NSF (CHE-1531632). We thank Lingxiang Lu for constructive
feedback.
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