Ni-Catalyzed Reductive Dicarbofunctionalization of Nonactivated Alkenes: Scope and Mechanistic Insights

Article abstract of DOI:10.1021/jacs.9b02973

Olefins devoid of directing or activating groups have been dicarbofunctionalized here with two electrophilic carbon sources under reductive conditions. Simultaneous formation of one C(sp³)-C(sp³) and one C(sp³)-C(sp²) bond across a variety of unbiased π-systems proceeds with exquisite selectivity by the combination of a Ni catalyst with TDAE as sacrificial reductant. Control experiments and computational studies revealed the feasibility of a radical-based mechanism involving, formally, two interconnected Ni(I)/Ni(III) processes and demonstrated the different ability of Ni(I) species (Ni(I)I vs PhNi(I)) to reduce the C(sp³)-I bond. The role of the reductant was also investigated in depth, suggesting that a one-electron reduction of Ni(II) species to Ni(I) is thermodynamically favored. Further, the preferential activation of alkyl vs aryl halides by ArNi(I) complexes as well as the high affinity of ArNi(II) for secondary over tertiary C-centered radicals explains the lack of undesired homo- and direct coupling products (Ar-Ar, Ar-Alk) in these transformations.

Full text of DOI:10.1021/jacs.9b02973

Article
pubs.acs.org/JACS
Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Ni-Catalyzed Reductive Dicarbofunctionalization of Nonactivated
Alkenes: Scope and Mechanistic Insights
†
†
‡
†
‡
́
́
́
Wei Shu, Andres García-Domínguez, M. Teresa Quiros, Rahul Mondal, Diego J. Cardenas,
and Cristina Nevado*,†
†Department of Chemistry, University of Zurich, Winterthurerstrasse 190, Zurich CH 8057, Switzerland
‡
́
Departamento de Química Organica, Facultad de Ciencias, Institute for Advanced Research in Chemical Sciences (IAdChem),
́
Universidad Autonoma de Madrid, Cantoblanco CP 28049, Madrid, Spain
S
* Supporting Information
ABSTRACT: Olefins devoid of directing or activating groups have been dicarbofunctionalized here with two electrophilic
carbon sources under reductive conditions. Simultaneous formation of one C(sp3)−C(sp3) and one C(sp3)−C(sp2) bond
across a variety of unbiased π-systems proceeds with exquisite selectivity by the combination of a Ni catalyst with TDAE as
sacrificial reductant. Control experiments and computational studies revealed the feasibility of a radical-based mechanism
involving, formally, two interconnected Ni(I)/Ni(III) processes and demonstrated the different ability of Ni(I) species (Ni(I)I
vs PhNi(I)) to reduce the C(sp3)−I bond. The role of the reductant was also investigated in depth, suggesting that a one-
electron reduction of Ni(II) species to Ni(I) is thermodynamically favored. Further, the preferential activation of alkyl vs aryl
halides by ArNi(I) complexes as well as the high affinity of ArNi(II) for secondary over tertiary C-centered radicals explains the
lack of undesired homo- and direct coupling products (Ar−Ar, Ar−Alk) in these transformations.
the lack of reactivity of unactivated olefins or olefins lacking a
directing group or a vicinal double bond to stabilize the
corresponding alkyl-Pd intermediates. Second, mostly C(sp2)
groups could be incorporated across the π-system. Some of
these limitations have been overcome by the use of first row
transition metals. Representative examples can be found with
iron and copper regarding the carboarylation of styrenes using
α-bromoester derivatives and trifluoromethylating reagents,
respectively.6,7 However, nickel complexes have played a more
prominent role in this context, as they were able to promote
the dicarbofunctionalization of alkenes incorporating alkyl
groups.8 Still, only olefins containing directing groups or
electronically biased substrates (i.e., activated olefins bearing
electron-withdrawing groups) are amenable to this set of
reaction conditions. Furthermore, in most of the above-
mentioned cases, highly reactive and thus sensitive organo-
metallic species such as organozinc or Grignard reagents are
needed for a successful outcome (Scheme 1a). It is important
to note that these organometallic species are typically prepared
Olefins are ubiquitous motifs in natural products and
pharmaceuticals, serving as one of the most common templates
for the chemo-, regio-, and stereoselective incorporation of
C−C and C-X bonds in organic molecules. Alkenes also
represent an excellent platform for the late-stage edition of
complex organic molecules due to their orthogonal reactivity
with respect to carbonyls and other polar functional groups.1
The difunctionalization of alkenes represents one of the most
efficient strategies to install two vicinal chemical bonds in a
step- and operation-economic fashion. In particular, inter-
molecular three-component dicarbofunctionalization reactions
have attracted significant attention in recent years because of
their convergence toward the simultaneous construction of two
C−C bonds and hence their ability to access more complex
aliphatic structures in a rapid manner.2 While metal-free
protocols have been developed in this context,3 reactions
catalyzed by transition metals have been shown to be more
generally applicable. Thus, palladium catalysis has been
successfully used in the vicinal dicarbofunctionalization of
conjugated dienes as well as of olefins bearing a directing
group.4,5 Despite the profound impact of these trans-
formations, multiple limitations still remain unsolved. First,
Received: March 18, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.9b02973
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could not be engaged in any of the above-mentioned methods.
This represents a major limitation, as unactivated alkenes are
produced on a large scale during petroleum processing and
thus represent excellent building blocks for chemical syn-
thesis.15,16 The low reactivity toward addition as well as the
instability of the resulting intermediates, lacking the stabilizing
effect of a neighboring group compared to activated systems,
has hampered the development of these processes. Our
original mechanistic proposal invoked a Ni(0)/Ni(I)/Ni(III)
catalytic cycle but intriguingly could not explain the high
selectivity observed toward the conjugative cross-coupling vs
direct cross-coupling Ar−Alk and homocoupling products Ar−
Ar. Despite recent advances in the field, mechanistic
understanding of Ni-catalyzed processes lies behind method-
ology developments, likely due to the lability of organonickel
species and the multiple mechanistic manifolds potentially
underlying these transformations.12
Scheme 1. Metal-Catalyzed Dicarbofunctionalization of
Alkenes
Herein we report the first example of an intermolecular
nondirected reductive dicarbofunctionalization applicable to
unactivated olefins using two electrophilic carbon sources
(Scheme 1, bottom). This protocol allows the simultaneous
addition of alkyl and aryl groups across nonelectronically
biased double bonds devoid of a coordinating site at room
temperature. An in-depth mechanistic investigation involving
both experimental and computational studies demonstrates
that, although Ni(0) species might be formed under reductive
conditions, a catalytic cycle formally involving Ni(I)/Ni(III)
redox processes is more likely responsible for the observed
reactivity. Further, we characterize the individual steps
responsible for the high chemoselectivity observed in the
reaction and unravel the important role of the organic
reductant in these transformations.
from the corresponding organic halides.9 Thus, the ability to
promote catalytic dicarbofunctionalizations that would directly
involve the corresponding halides as reaction partners would
be highly desirable. The advantages of such an approach would
primarily stem from the ready availability of these species,
which could avoid the use of stoichiometric and highly reactive
organometallic reagents, thus increasing the overall functional
group compatibility. In addition, these processes would also
profit from a high operational simplicity, sustainability, and
cost-efficiency.10 While conceptually interesting, the inherent
low reactivity of electrophiles and their proclivity toward
undesired pathways (homocoupling, β-hydride elimination)
constitute serious challenges that need to be overcome.11
Over the past decade, reductive couplings involving two
electrophiles have evolved into a powerful alternative to forge
carbon−carbon bonds, in most cases catalyzed by nickel
complexes.12,13 Inspired by the advantages of reductive cross-
coupling approaches, our group recently developed a nickel-
catalyzed intermolecular reductive alkylarylation of alkenes.14
This three-component reaction utilized alkyl and aryl iodides
in the presence of TDAE as stoichiometric reductant to
dicarbofunctionalize, in a regio- and stereoselective fashion,
electronically biased olefins as well as allylic systems bearing
weak coordinating groups (Scheme 1b). Our protocol, devoid
of organometallic species, not only offered broad functional
group compatibility due to the mild reaction conditions but
also broadened the scope in the olefinic partners compared to
previous reports.8
RESULTS AND DISCUSSION
■
Optimization. 4-Phenyl-1-butene, p-iodoanisole, and tert-
butyl iodide were selected as model substrates to find the
optimal reaction conditions (Table 1).17 Initially, a screening
of nickel precatalysts combined with 4,4′-di(tert-butyl)-2,2′-
dipyridyl (L1) was performed in dioxane in the presence of
TDAE (tetrakis(dimethylamino)ethylene) as reductant (Table
1, entries 1−5).18
The results revealed NiBr2·glyme and NiBr2·diglyme as the
most suitable nickel sources, providing the desired product 1 in
64% yield with exclusive regioselectivity. Using NiBr2·glyme,
different solvents were then tested with significantly different
outcomes: while reactions in strong coordinating solvents such
as DME or DMF did not give the desired product (Table 1,
entries 6 and 7), those carried out in toluene or THF
proceeded smoothly, albeit in lower yields (Table 1, entries 8
and 9). The examination of different bidentate ligands (L2−
L6) did not improve the reaction efficiency (Table 1, entries
10−14). On the other hand, we were delighted to observe that
the catalyst loading of the system could be reduced to 5 mol %
without eroding the reaction efficiency (Table 1, entry 15). We
also found that the use of TDAE as reductant is crucial for this
transformation. Replacing TDAE with metallic reductants such
as Zn or Mn did not deliver the desired product (Table 1,
entry 16). Finally, a careful modification of the molar ratio of
the components and reagents was performed, resulting in the
formation of dicarbofunctionalization adduct 1 in 78% isolated
yield as a single regioisomer at room temperature (Table 1,
entry 17).
Despite these advances, unactivated olefins or alkenes
lacking a directing/coordinating/conjugated aromatic group
B
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a
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Reaction Scope on Aryl Iodide
ligand
(y mol %)
yield of 1
b
entry
cat. (x mol %)
solvent
(%)
1
2
3
4
5
6
7
8
Ni(acac)2 (10)
L1 (12)
L1 (12)
L1 (12)
L1 (12)
L1 (12)
L1 (12)
L1 (12)
L1 (12)
L1 (12)
L2 (12)
L3 (12)
L4 (12)
L5 (12)
L6 (12)
L1 (6)
dioxane
dioxane
dioxane
dioxane
dioxane
DME
NR
48
47
64
64
0
NiCl2·glyme (10)
NiCl2(py)4 (10)
NiBr2·glyme (10)
NiBr2·diglyme (10)
NiBr2·glyme (10)
NiBr2·glyme (10)
NiBr2·glyme (10)
NiBr2·glyme (10)
NiBr2·glyme (10)
NiBr2·glyme (10)
NiBr2·glyme (10)
NiBr2·glyme (10)
NiBr2·glyme (10)
NiBr2·glyme (5)
NiBr2·glyme (5)
NiBr2·glyme (5)
DMF
THF
0
29
32
0
9
toluene
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
10
11
12
13
14
15
0
c
33 (19)
39
0
64
0
82 (78)
d
16
17
L1 (6)
L1 (6)
e
f
a
b
For reaction conditions, see Table 1, entry 17. Aryl iodide (0.1
mmol) and alkene (0.3 mmol) were used under otherwise identical
conditions.
a
products (20−24) could be isolated in synthetically useful
yields.
Reactions were carried out with 4-phenyl-1-butene (0.1 mmol), p-
iodoanisole (0.2 mmol), and tert-butyl iodide (0.2 mmol) in 1 mL of
b
1
To further demonstrate the versatility of this method,
different alkenes were tested (Scheme 3). The protocol was
applied to a variety of terminal aliphatic olefins, devoid of any
directing or coordinating group. To our delight, the isolation of
dicarbofunctionalization products 26−32 always proceeded in
good yields. Vinyl ethers were also good substrates for the
solvent. The yield was determined by H NMR using mesitylene as
internal standard. Recovered 4-phenyl-1-butene. Zn or Mn used as
reductant instead of TDAE. p-Iodoanisole (0.15 mmol), tert-butyl
iodide (0.3 mmol), and TDAE (0.3 mmol) were used. Isolated yield
c
d
e
f
after column chromatography in silica gel.
Scheme 3. Reaction Scope on the Alkene (for reaction
conditions, see Table 1, entry 17)
Reaction Scope. With the optimized conditions in hand,
we set out to explore the scope of this transformation. First,
different aromatic halides were examined. As depicted in
Scheme 2, a variety of substituents, both electron-withdrawing
(CO2Me, F, CF3) and electron-donating (Me, t-Bu, OMe)
were well tolerated in para and meta positions so that
dicarbofunctionalized products 2−12 could be isolated in good
yields. Excellent chemoselectivity was observed in these
processes as demonstrated by the lack of reactivity of
C(sp2)−Br and C(sp2)−Cl bonds present in compounds 13
and 16, which were obtained in 78% and 66% yield,
respectively. More sterically demanding ortho-substituted aryl
iodides could also be successfully incorporated, furnishing the
desired products in synthetically useful yields (14 and 15).
Heterocyclic aromatic iodides containing indole and pyridine
moieties were successfully applied in this protocol, furnishing
the dicarbofunctionalization products (17, 24, and 25) in good
yields. In addition, this transformation provided orthogonal
reactivity with respect to classical cross-coupling procedures, as
Bpin derivative 18 was successfully obtained in 67% yield,
rendering the possibility of subsequent cross-coupling
reactions via the C(sp2)−B bond. The process also tolerated
a wide variety of sensitive functional groups, such as free N−H
or O−H groups, and thus the three-component cross-coupling
a
Aryl iodide (0.1 mmol), and alkene (0.3 mmol) were used under
otherwise identical conditions.
C
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reaction, as shown by benzylic ether 33, which could be
isolated in 61% yield. The remarkable selectivity of the reaction
was again showcased by the presence of primary C(sp3)−Br
and C(sp3)−Cl bonds in the aliphatic chain which remained
unreacted as shown by the successful isolation of 34 and 35 in
63% and 81% yields, respectively. Additionally, free hydroxy or
carbamate groups did not affect the reaction efficiency,
furnishing the desired products 36−38. Ester functionalities
were well tolerated (39), including those containing more
acidic protons at the α-carbon such as malonate derivatives 40
and 41.
Scheme 5. Late Stage Dicarbofunctionalization of Alkenes
(for reaction conditions, see Table 1, entry 17)
Finally, different tertiary alkyl iodides were also assessed in
combination with a diverse set of alkenes and aromatic iodides
(Scheme 4). Both cyclic and acyclic alkyl groups as well as
keto- and Csp3−Cl containing iodides were well tolerated
under the standard reactions conditions, delivering the
corresponding cross-alkylarylation products in moderate to
good yields (42−62).
a
Aryl iodide (0.1 mmol) and alkene (0.3 mmol) were used under
otherwise identical conditions.
Scheme 6. (a) Dicarbofunctionalization of Unactivated 1,n-
(Di)-en-ynes or Trienes (for the reaction conditions, see
Table 1, entry 17). (b) Dicarbofunctionalization of 1,3-
Dienes. (c, d) Dicarbofunctionalization of 1,4- and 1,5-
Dienes
Scheme 4. Reaction Scope on the Alkyl Iodide (for reaction
conditions, see Table 1, entry 17)
a
b
a
Aryl iodide (0.1 mmol) and alkene (0.3 mmol) were used under
otherwise identical conditions.
The method could also be applied in the late stage
functionalization of more elaborated alkenes as shown by
estrone and amino acid-containing adducts 63 and 64 (Scheme
5).
Aiming to expand the synthetic utility of the method, we set
out to apply the optimized protocol to the selective
functionalization of diverse polyene and enyne substrates
(Scheme 6). Interestingly, 1,6-dienes bearing different tethers
could successfully undergo this reductive cascade difunction-
alization, accomplishing the simultaneous formation of three
new C−C bonds to deliver cyclopentane derivatives 65−67 in
good yields and high stereoselectivity (ca. 10:1). Pyrrolidine-
containing derivatives 68 and 69 were obtained with similar
efficiency but with lower levels of stereocontrol. Internal
alkenes are also amenable to the optimized conditions as
shown by cyclopentane derivative 70. More challenging
substrates, encompassing three different double bonds, also
underwent the desired transformation, delivering bicyclic
products 71 and 72 with high efficiency considering that
four new C−C bonds are forged and a single stereoisomer is
a
The reaction was carried out with 2,3-dimethylbutadiene (0.4
mmol), aryl iodide (0.2 mmol), tert-butyl iodide (0.4 mmol), and
TDAE (0.6 mmol) in 2 mL of dioxane except for compound 78 in
which 2,3-diphenylbutadiene (0.2 mmol), aryl iodide (0.4 mmol),
tert-butyl iodide (0.6 mmol), and TDAE (0.6 mmol) reacted in 2 mL
of dioxane. The reaction was carried out with 4-iodoanisole (0.1
mmol), diene (0.5 mmol), tert-butyl iodide (0.3 mmol), and TDAE
b
(0.3 mmol) in 1 mL of dioxane.
obtained in the reactions. Analogously, a 1,9-dien-6-yne
delivered the corresponding bicycle 73 in 54% yield as an
inseparable 1.5:1 mixture of diastereoisomers. These trans-
D
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formations provide a rapid access to molecular complexity
from alkenes and showcase the efficiency of the method, as an
>80% average yield per bond-forming event can be calculated.
Further, the structure of the major isomers obtained in the
reactions producing 65 and 72 could be unambiguously
determined by X-ray diffraction analysis (Supporting Informa-
tion) of the corresponding single crystals.17
Scheme 7. (a) DFT Analysis of Our Original Mechanistic
Proposal Starting from Ni(0) Species. (b) Feasibility of B to
G. (c) Feasibility of H to B. (d) Comparison of the Addition
of the t-Bu· Radical to the Free Olefin (path a) vs Addition
a
to a NiII-Coordinated Olefin (path b)
We also turned our attention toward the reactivity of 1,3-
dienes. These substrates represented an excellent platform to
explore the regioselectivity of the reaction, as 1,2-, 1,3-, or 1,4-
difunctionalization products could in principle be obtained.
Both alkyl- and aryl-substituted 1,3-dienes furnished, selec-
tively, 1,4-dicarbofunctionalization products 74−78 in good
yields in ca. 4:1 E:Z ratio (Scheme 6b). Further, 1,4- and 1,5-
dienes (i.e., norbornadiene and COD, respectively) could also
be successfully engaged in this dicarbofunctionalization
reaction, producing the corresponding adducts 79 and 80 in
moderate yields (Scheme 6c,d).
Mechanistic Investigations. Control experiments were
designed to shed light on the mechanistic features behind these
transformations. Addition of radical scavengers (TEMPO,
BHT, and 1,1-diphenylethene) significantly inhibit the
reaction.17 Further, examples summarized in Scheme 6
together with previous experiments utilizing radical clocks
signaled the presence of C-centered radicals along the reaction
pathway. The involvement of secondary alkyl iodides as
potential reaction intermediates, produced as a result a nickel-
mediated ATRA process between the olefin and the alkyl
halide, could also be ruled out, as neither of these species could
be detected in the reaction mixtures at any given time nor,
when prepared independently, engaged into cross-coupling
reactions with the corresponding aryl halides under the
standard reaction conditions.14
Along the above-mentioned control experiments, DFT
calculations were performed using propene, tert-butyl iodide,
iodobenzene, and 4,4′-di-tert-butyl-2,2′-dipyridine ligand (L1)
as model structures to gain additional insights onto the
reaction mechanism.17 The computational study focused first
on our original mechanistic proposal which invoked Ni(0)
species A, generated in situ under the reductive conditions at
the outset of the reaction (Scheme 7a).14 Such low valent
metal species were proposed to undergo oxidative addition
onto the ArI moiety to produce ArNi(II)I intermediate B
(TSA‑B, ΔG‡ = 11.4 kcal/mol, Ar = Ph) in a highly exergonic
process (ΔG = −55.9 kcal/mol). Addition of an in situ-
generated tert-butyl radical D onto the unactivated alkene
(propene) produced carbon-centered radical E in an almost
thermoneutral process (ΔG = −1.3 kcal/mol) via TSD‑E (ΔG⧧
= 19.5 kcal/mol). Fast recombination of E with aryl nickel(II)
complex B delivers the key Ni(III) intermediate F (ΔG = 5.1
kcal/mol) via TSB‑E (ΔG⧧ = 10.1 kcal/mol). Reductive
elimination on F furnished the corresponding dicarbofunction-
alization product G and Ni(I)I C in a fast, thermodynamically
driven process (ΔG = −61.8 kcal/mol) via TSF‑G (ΔG⧧ = 7.2
kcal/mol). As seen in the left part of Scheme 7a, Ni(I)I species
C, produced in situ in the reaction media after reductive
elimination on F, were proposed to be responsible for the
activation of the alkyl iodide to produce alkyl radical D (Alk =
t-Bu). Computationally though, the reaction to produce
Ni(II)I2 species H by reaction of Ni(I)I complex C with t-
BuI is a rather uphill process (ΔG = 25.1 kcal/mol) that would
be incompatible with a productive reaction outcome at room
temperature, thus questioning our original proposal.14 Still,
a
Reaction free energies and activation energies (kcal/mol) calculated
at UB3LYP/6-31G(d) (C,H,N), LANL2DZ (Ni, I) level in THF
(PCM). For Scheme 7d: Ni = (dtbbpy)Ni−I.
some of the steps depicted in Scheme 7a could be
experimentally validated. For instance, complex B seems to
be a competent intermediate in the reaction, as shown by the
successful transformation of allyl acetate and 4-phenyl-1-
butene into the corresponding dicarbofunctionalized products
82 and 4 in the presence of t-BuI and TDAE from ArNi(II)I
complex 81 (Scheme 7b).18
E
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Further, the feasibility of reducing Ni(II)I2 (H) species with
TDAE and their subsequent transformation into ArNi(II)
intermediates B in the presence of ArI could be secured by the
stoichiometric reaction of Ni(dtbbpy)I2 with TDAE in the
presence of 2-iodotoluene, which delivered the corresponding
ArNi(II) complex 83 as shown in Scheme 7c.17
Scheme 8. (a) DFT Analysis and (b) Experimental Results
on the Reduction of tBu−I in the Presence of Different Ni
Species. (c) Computational Study on TDAE as a Reductant
for Putative Ni(II) and Ni(III) Species Present in the
a
Reaction Media
As alkenes are known to be good ligands for nickel,19 their
effect on the above-mentioned reaction mechanism was also
investigated in detail. In fact, while olefin coordination helps to
stabilize Ni(0) species (ΔG = −46.3 kcal/mol for Ni(0)−
olefin complex A′, see SI), a mechanism involving the addition
of alkyl radicals onto the Ni(II)−olefin complex B′ (ΔG = 21.8
kcal/mol) via TSD‑F (ΔG⧧ = 15.4 kcal/mol, Scheme 7d, path
b) is substantially disfavored compared to the direct addition
onto the free olefin (ΔG = −1.3 kcal/mol via TSD‑E ΔG⧧ =
19.5 kcal/mol) followed by recombination with the PhNiII
species B to give alkyl Ni(III) complex F (Scheme 7d, path a).
In summary, the computational as well as the experimental
results depicted in Scheme 7 signal the feasibility of some of
the proposed steps along the catalytic cycle (H to B, B to G)
but raised questions regarding both the specific nature of the
nickel intermediates involved in the reaction and, more
importantly, their ability to activate the alkyl halide partner.
Because Ni(I)I (C) does not seem competent in this regard,
we set out to interrogate the ability of other nickel species,
potentially present in the reaction media, toward the homolytic
cleavage of the C(sp3)−I bond. The results of these
investigations have been summarized in Scheme 8. In sharp
contrast to C, PhNi(I) complex K turned out to be a suitable
partner for the reduction of the carbon−halogen bond
according to DFT calculations (ΔG = −0.8 kcal/mol with
ΔG⧧ = 16.7 kcal/mol). As in the previous case, coordination to
the alkene in K′ significantly disfavors the desired C−I bond
cleavage (ΔG = 8.2 kcal/mol) (Scheme 8a, top). Other low-
valent Ni species were also analyzed in this context.
Interestingly, activation of the tert-butyl iodide on Ni(0)
species A resulted in a highly thermodynamically favorable
process (ΔG = −71.6 kcal/mol), even when coordination to
the olefin is in place A′ (ΔG = −19.6 kcal/mol) (Scheme 8a,
middle).20 In sharp contrast, PhNi(II)I species B seem to be
much less suited for activation of the alkyl partner, as the
reaction is again uphill with ΔG = 18.9 kcal/mol (Scheme 8a,
bottom).
Experimental support for these computationally predicted
trends is shown in Scheme 8b. The reaction of 1-iodo-1-
methylcyclohexane in combination with NiBr2·DME and
ligand L1 resulted in no conversion of the alkyl iodide
(Scheme 8b, column 1). A similar result was obtained for a
reaction with complex 81 in the absence of TDAE (column 2).
In contrast, consumption of the alkyl iodide occurs when aryl
nickel(II) complex 81 is combined with TDAE (column 3) as
well as with Ni(0) complexes (Ni(COD)2) in the presence of
L1 (column 4).
The facile reduction of tBu−I with Ni(0) to give Ni(I)I
complex C (ΔG = −71.6 kcal/mol, Scheme 8a, middle), as
well as the facile reduction of a Ni(II)I2 precatalyst to Ni(I)I
species with TDAE (H to C, ΔG = −28.8 kcal/mol in Scheme
8c, left), prompted us to investigate a reaction mechanism in
which these species would be involved at the outset of the
reaction (Scheme 9). The oxidative addition of C onto
iodobenzene to produce PhNi(III)I2 J turned out to be an
endothermic process (ΔG = 15.7 kcal/mol) but with a
moderate activation energy (ΔG⧧ = 20.4 kcal/mol). Sub-
a
Reaction free energies and activation energies (kcal/mol) calculated
at UB3LYP/6-31G(d) (C,H,N), LANL2DZ (Ni, I) level in THF
(PCM). Ni = (dttbpy)Ni.
sequent reduction with TDAE to PhNi(I)I K is overall
thermodynamically favorable (ΔG = −25.5 kcal/mol).
Interestingly, the first reduction potential calculated for
TDAE suggests its preferential application as a one-electron
donor whereas the second reduction seems to be much more
demanding, which might explain the need to use the reductant
in excess in the catalytic version of the reaction (Scheme 8c,
right). While the reaction of tBu−I with Ni(I)I C is not
thermodynamically favored (ΔG = 25.1 kcal/mol, see Schemes
7a and 8a, top), PhNi(I) species K offered a much more
amenable barrier for this process (ΔG = −0.8 kcal/mol via
TSK‑B with ΔG⧧ = 16.7 kcal/mol).21,22 The most favorable
pathway thereafter intersects with that computed in Scheme 7a
and involves the addition of the tBu radical onto the olefin in
an off-cycle process to form E (ΔG = −1.3 kcal/mol via TSD‑E
ΔG⧧ = 19.5 kcal/mol), which undergoes fast recombination
with B to give Ni(III) intermediate F (ΔG = 5.1 kcal/mol via
F
DOI: 10.1021/jacs.9b02973
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Scheme 9. DFT Analysis of a Ni(I)-Based Mechanistic
Proposal
Scheme 10. Control Experiments on Selectivity with Zn-
Based Reductants
a
a
a
For part b, recovered starting materials were quantified with
dodecane as internal standard.
83 together with arene homocoupling products. However, and
in striking contrast to the clean reaction observed with TDAE,
when Zn(0) was used as reductant under the standard catalytic
conditions, no desired dicarbofunctionalization product 42 was
observed (Scheme 10b). Rather, complex mixtures were
detected, which signaled that potential organozinc intermedi-
ates formed in the reaction media impact the reaction
outcome, promoting undesired side reactions.13,16
a
Reaction free energies and activation energies (kcal/mol) calculated
at UB3LYP/6-31G(d) (C, H, N), LANL2DZ (Ni, I) level in THF
(PCM). Ni = (dtbbpy)Ni.
TSB‑E ΔG⧧ = 10.1 kcal/mol). Reductive elimination delivers
product G together with Ni(I)I C, thus closing the catalytic
cycle (ΔG = −61.8 kcal/mol via TSF‑G ΔG⧧ = 7.2 kcal/mol).
An alternative pathway invoking a one electron reduction of
[Ni(I)−I] C by TDAE to give Ni(0), which upon oxidative
addition with PhI would deliver PhNi(II)−I B (ΔG⧧ = 11.4),
followed by a second reduction with TDAE to produce Ph-
Ni(I) K was also considered. However, based on the
unfavorable thermodynamics computed for the Ni(I)−I to
Ni(0) reduction step (ΔG = 68.0 kcal/mol), this route was
deemed unlikely (for a comprehensive study of alternative
catalytic cycles, see Supporting Information).17
The mechanism depicted in Scheme 9 is compatible with
both computational and experimental results. Further, the
significant energy barrier determined for the addition of the
electron-rich tertiary alkyl radical D to propene (TSD‑E ΔG⧧ =
19.5 kcal/mol) is in line with the existing literature evidence23
and thus can help to rationalize the difficulties encountered
thus far in the dicarbofunctionalization of unactivated olefins.
However, despite this good correlation between calculations
and experimental evidence, three features of the reaction,
namely the need for an organic reductant (TDAE), and the
high chemoselectivity preventing both homocoupling (Alk−
Alk, Ar−Ar) or direct heterocoupling (Alk−Ar) products,
remained unanswered within the above-mentioned mecha-
nistic picture.
Along these lines, we aimed to clarify the origin of the
exquisite chemoselectivity observed in these transformations,
as neither homocoupling (Alk−Alk, Ar−Ar) nor heterocou-
pling products (Alk−Ar) could be detected in the reactions
performed with TDAE. As shown in Scheme 11a (path a),
activation of tBu−I with PhNi(I) complex K is feasible (ΔG =
−0.8 kcal/mol via TSK‑B with ΔG⧧ = 16.7 kcal/mol).
Interestingly, a competitive oxidative addition onto PhI to
give Ph2Ni(III)I intermediate L, although thermodynamically
more likely (ΔG = −8.3 kcal/mol), would require a
substantially higher activation energy via TSK‑L (ΔG⧧ = 24.4
kcal/mol) (Scheme 11a, path b). These results explain the lack
of Ar−Ar homocoupling products in these transformations
(which would stem from a facile reductive elimination in L)
and thus the observed selectivity toward a conjugative cross-
coupling involving both electrophiles and the alkene.25
Further, the lack of Alk−Ar direct coupling products under
the reaction conditions seems to rule out the participation of
ArAlkNi(III)I intermediates.26 As seen in Scheme 11b, the
direct recombination of tertiary alkyl radicals D with
intermediate PhNi(II)I B to give M is much less favorable
(ΔG = 9.5 kcal/mol via TSB‑M with ΔG⧧ = 17.1 kcal/mol)
than the recombination of B with C-centered radical E to
produce the conjugative cross-coupling Ni(III) intermediate F
(ΔG = 5.1 kcal/mol via TSB−F with ΔG⧧ = 10.1 kcal/mol).17
First, the nature of the reductant seemed to play a crucial
role for a successful reaction outcome.24 During the
optimization campaign, no dicarbofunctionalization products
were observed when TDAE was replaced by Zn or Mn which
are well established reductants for previously developed Ni-
catalyzed reductive couplings (see Table S1 in SI).13,16 As
shown in Scheme 10a, and in analogy to the results obtained
for TDAE (Scheme 7c), Zn managed to reduce ArNi(II)X
species in stoichiometric fashion and, in the presence of o-
iodotoluene, delivered the corresponding ArNi(II)I complex
CONCLUSIONS
■
Here, we report the intermolecular dicarbofunctionalization of
unactivated alkenes by direct formation of C(sp3)−C(sp3) and
C(sp3)−C(sp2) bonds across a variety of unbiased π-systems
using two different electrophiles. The reaction, devoid of
directing groups or strong electronic bias on the alkene
partner, occurs with exquisite selectivity under mild reaction
conditions. The method relies on the combination of a Ni
catalyst with TDAE as an organic sacrificial reductant. Both
G
DOI: 10.1021/jacs.9b02973
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Journal of the American Chemical Society
Article
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.9b02973.
Scheme 11. (a) Selectivity of PhNi(I) K toward C−I Bonds.
a
(b) Selectivity of Alkyl Radicals for PhNi(II)I Complex B
Compound synthesis, characterization, additional experi-
ments, and DFT calculations (PDF)
X-ray data for 65 (CIF)
X-ray data for 72 (CIF)
AUTHOR INFORMATION
Corresponding Author
*cristina.nevado@chem.uzh.ch
■
ORCID
́
Diego J. Cardenas: 0000-0002-1707-6445
Cristina Nevado: 0000-0002-3297-581X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the European Research Council (ERC starting grant
agreement no. 307948), the Swiss National Science Founda-
tion (SNF 200020_146853), and the Spanish Ministerio de
́
Economıa y Competitividad (CTQ2016-79826-R) for finan-
cial support and acknowledge a Juan de la Cierva fellowship to
M.T.Q. We also thank Prof. Anthony Linden for the X-ray
diffraction analysis of 65 (CCDC 1895815) and 72 (CCDC
́
́
1895814) and the Centro de Computacion Cientıfica-UAM
for the use of computational resources.
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generation of structural complexity in a highly selective
manner utilizing Ni catalysis.
ASSOCIATED CONTENT
■
S
* Supporting Information
Supporting Information including compound synthesis,
characterization, additional experiments and DFT calculations.
H
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(17) For further details, please, check SI.
(18) Note that, under the standard conditions, the counterion on the
Ni-intermediate species will be I rather than Cl. For a detailed study
on the different reactivity for Ni−I vs Ni-Cl species, see: Klein, A.;
́
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Kaiser, A.; Wielandt, W.; Belaj, F.; Wendel, E.; Bertagnolli, E.; Zalis, S.
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(22) The reaction with tBu-Br does not proceed under the standard
conditions, and arene homocoupling products are observed instead. A
higher activation barrier for the activation of tBu-Br with PhNi(I) K
(ΔG⧧ = 18.2 kcal/mol) was obtained by DFT calculations compared
to that calculated for the corresponding iodide (ΔG⧧ = 16.7 kcal/
mol). However, we hypothesize that the observed lack of reactivity
has to do not only with the energy barrier to form the alkyl radical but
also with the mismatched reactivity of the resulting Ni-Br species
J
DOI: 10.1021/jacs.9b02973
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX