Nickel-Catalyzed Reductive Dicarbofunctionalization of Alkenes

Article abstract of DOI:10.1021/jacs.7b03195

An intermolecular, three-component reductive dicarbofunctionalization of alkenes is presented here. The combination of Ni catalysis with TDAE as final reductant enables the direct formation of Csp³-Csp³ and Csp³-Csp² bonds across a variety of π-systems using two different electrophiles that are sequentially activated with exquisite selectivity under mild reaction conditions.

Full text of DOI:10.1021/jacs.7b03195

Communication
pubs.acs.org/JACS
Nickel-Catalyzed Reductive Dicarbofunctionalization of Alkenes
Andres García-Domínguez, Zhaodong Li, and Cristina Nevado*
́
Department of Chemistry, University of Zurich, Winterthurerstrasse 190, Zurich CH 8057, Switzerland
S
* Supporting Information
reductive alkene dicarbofunctionalization reaction that com-
ABSTRACT: An intermolecular, three-component reduc-
tive dicarbofunctionalization of alkenes is presented here.
The combination of Ni catalysis with TDAE as final
reductant enables the direct formation of Csp3−Csp3 and
Csp3−Csp2 bonds across a variety of π-systems using two
different electrophiles that are sequentially activated with
exquisite selectivity under mild reaction conditions.
bines alkyl and aryl iodides to produce, in a single synthetic
operation, two new C−C bonds by their sequential addition
onto both, activated and unactivated alkenes, in the presence of
a metal-free reductant (Scheme 1B).
Scheme 1. Strategies toward Dicarbofunctionalization of
Alkenes
icarbofunctionalization of olefins by simultaneous
D
addition of two carbon groups across the double bond
has attracted increasing attention in recent years given not only
the availability of alkenes from natural sources but also the
added value of the resulting products. Classical methods
include Michael-type additions of sensitive organometallic
reagents to activated olefins followed by enolate trapping
with electrophiles.1 Alternatively, transition metal catalyzed
approaches have also been developed. In particular, the use of
Pd-catalysis for the regioselective dicarbofunctionalization of
dienes involving Csp2-reagents has found broad applicability
and even asymmetric versions of these transformations have
been realized (Scheme 1A, top).2 In contrast, reactions
involving the addition of alkyl groups across alkenes are
much less developed given the number of side reactions that
Csp3-metal reagents and intermediates can undergo, including
β-hydride elimination, homocoupling, isomerization or proto-
demetalation. To the best of our knowledge, only a handful of
reports dealing with the intermolecular dicarbofunctionalization
of alkenes using Csp3-reagents have been reported to date.3 In
this context, in the presence of a Ni catalyst, activated alkenes
have been used as acceptors and redox active esters and
difluoroalkyl bromides in combination with aryl zinc4 and aryl
boron5 reagents, respectively, could be successfully added
across the π-system (Scheme 1A, bottom). From a formal point
of view, all of the above-mentioned methods rely on the
addition of a nucleophile and an electrophile across activated π-
systems.
Allyl acetate, tert-butyl iodide and 4-tert-butyliodobenzene
were chosen as benchmark substrates to find the optimal
conditions for this multicomponent reaction (Table 1).
Following initial optimization,8 different reductants were
assayed in the presence of 10 mol% of NiCl2·DME and dtbbpy
(L1 = 4,4′-di-tert-butyl-2,2′-bipyridine). Although Zn, Mn and
B2pin2/tBuOK9 did not produce the desired product (Table 1,
entries 1−3), the reaction in the presence of TDAE
(tetrakis(dimethylamino)ethylene) produced 1 in a promising
17% yield (Table 1, entry 4).10 Different ligands were examined
next: 2,2′-bipyridine (L2), phenanthroline (L3) or 4′-p-tolyl-
terpyridine (L4) did not improve the reaction outcome (Table
1, entries 5−7). The influence of the Ni catalysts was also
explored. In the presence of L1 and TDAE as reductant, NiBr2·
DME furnished 1 in 54% yield whereas Ni(acac)2 proved to be
less efficient (Table 1, entries 8 and 9). Fortunately, the use of
On the other hand, reductive couplings have recently gained
substantial attention as they represent a unique tool to handle
Csp3-based reagents and allow reactions under mild conditions
without any additional prefunctionalization compared to
classical cross-coupling methodologies.6 Taking into account
the potential of these transformations and our ongoing interest
in the development of multicomponent reactions for the
efficient difunctionalization of multiple bonds,7 we envisioned
the possibility of adding two different carbon-based electro-
philes across alkenes taking advantage of the ability of Ni
catalysts to activate both Csp2− as well as Csp3−halogen
bonds. Here, we present the first example of an intermolecular
Received: March 30, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b03195
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Reaction Scope
b
entry
Ni
ligand
additive
yield of 1 (%)
1
NiCl2·DME
NiCl2·DME
NiCl2·DME
NiCl2·DME
NiCl2·DME
NiCl2·DME
NiCl2·DME
NiBr2·DME
Ni(acac)2
L1
L1
L1
L1
L2
L3
L4
L1
L1
L1
L1
−
Zn
0
2
Mn
0
3
B2pin2/KOtBu
0
c
4
TDAE
17
c
5
TDAE
1
c
6
TDAE
2
c
7
TDAE
0
c
8
TDAE
54
c
9
TDAE
27
c
10
11
12
NiCl2(Py)4
−
NiCl2(Py)4
TDAE
82 (83)
−
TDAE
0
0
c
a
Conditions: Ni/L (10 mol %), allyl acetate (1 equiv), p-tBuC6H4I (2
equiv), tBuI (1.5 equiv), additive (2 equiv), THF (0.4 M), 25 °C.
b
1
Yield determined by H NMR with 4-nitroacetophenone as internal
standard. In brackets: isolated yield after column chromatography.
c
TDAE (2.15 equiv).
NiCl2(Py)4 delivered compound 1 in 83% optimized yield
(Table 1, entry 10). Both, the Ni complex and the ligand,
played a critical role in the reaction as shown by entries 11 and
12.
a
Standard reaction conditions: Table 1, entry 10. Isolated yields after
b
With the optimized reaction conditions in hand (Table 1,
entry 10), we set out to explore the scope of this transformation
(Scheme 2). First, different aryl iodides were investigated.
Phenyl, p-tolyl, p-methoxy and p-fluoro substituted iodobene-
zenes could be efficiently coupled under the standard reaction
conditions producing compounds 2−5 in moderated to good
yields. Substitution in meta position with both electron-
donating as well as electron-withdrawing groups was also well
tolerated as demonstrated by the efficient conversion obtained
for 6−10. The functional group compatibility was further
investigated. Products 11, 12 and 13 highlight the orthogon-
ality of this method with respect to classical Pd-catalyzed
reactions as Csp2−Br, Csp2−Cl and Csp2−B moieties were
accommodated under these conditions producing the corre-
sponding addition products in good yields. Steric factors seem
to have an impact in the reaction outcome, as ortho-substituted
phenyl ketone derivative 14 could only be isolated in 29% yield.
The compatibility of the method with different types of
olefins was investigated next. Allylic alcohols, phosphonates,
anilines and amides proved to be amenable substrates under the
reported conditions producing 15−18 in synthetically useful
yields. Highly efficient reactions were obtained in the case of
activated olefins such as enol esters or enamides as
demonstrated by the synthesis of 19 and 20 in 81 and 65%
yield, respectively. Michael acceptors proved to be successfully
transformed under the optimal conditions as shown by the high
yields in which compounds 21−24 could be isolated. A more
complex epiandrosterone derivative could also be efficiently
engaged in the reaction as shown by the successful isolation of
column chromatography are given. Unless otherwise stated, Rn = H.
c
d
Ni/L (20 mol %), Alkyl-I (2 equiv). Mixture of diastereoisomers 1:1.
25 in 53% yield. Crotononitrile (E:Z = 4:1) delivered the
corresponding addition products 26−29 with high levels of
diastereoselectivity, thus demonstrating the compatibility of the
reaction conditions with internal olefins. The relative
configuration of the major isomer could be confirmed by
successful X-ray diffraction analysis of compound 29.8
Interestingly, alkynes could also be successfully engaged in
this dicarbofunctionalization reaction producing the corre-
sponding trisubstituted alkenes 30−32 as single stereoisomers
as a result of the formal anti-addition of the two electrophiles
across the π-system.
Finally, different unactivated tertiary alkyl iodides, including
those bearing Csp3−Cl bonds, could also be incorporated as
shown in compounds 33−37. Unfunctionalized olefins did not
engage in the reaction, thus highlighting the importance of a
coordinating/directing group for a successful outcome.11
Control experiments were designed to uncover the reaction
mechanism (Scheme 3). Addition of BHT, 1,1-diphenyl-
ethylene or 1,4-cyclohexadiene significantly reduced the
reaction’s efficiency (data not shown, see section 5 in the SI).
Moreover, experiments involving radical clocks were also
revealing: while in the presence of unactivated alkenes, the
cyclization of the alkyl iodide 38 to give 39 is favored over the
intermolecular addition onto allyl acetate,12 the reaction in the
presence of acrylonitrile delivered addition product 40 in 45%
B
DOI: 10.1021/jacs.7b03195
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Journal of the American Chemical Society
Communication
Scheme 3. Control Experiments
Scheme 4. Proposed Reaction Mechanism
adds onto the alkene to produce D. Radical intermediate D can
then combine with A to produce the key Ni(III) species B
(path I).14 Complex B undergoes reductive elimination to
produce the corresponding dicarbofunctionalization product
and Ni(I), which in the presence of either AlkI or TDAE
regenerates Ni(II) or Ni(0) respectively, thus closing the
catalytic cycle.15 In situ formation of secondary alkyl iodides
(E) as putative reaction intermediates (path II) seems to be
ruled out based on all control experiments (Scheme 3, eqs 2, 3
and 5). Furthermore, the fact that no reaction occurs in the
absence of Ni and ArI (Scheme 3, eqs 5 and 6) and the
successful reaction of complex 43 (eq 8) suggest the
participation of ArNi(II) species (A) in these transformations.
Although alternative mechanisms cannot be excluded, the
lack of Alk-Ar direct coupling products under the reaction
conditions seems to rule out the participation of ArAlkNi(III)
intermediates,16 either resulting from the direct recombination
of tertiary alkyl radicals C with intermediate A, or from the
oxidative addition of ArI with in situ produced AlkNi(I)
species.17
In conclusion, the first example of an intermolecular, three-
component reductive dicarbofunctionalization of alkenes under
mild reaction conditions using nickel catalysis is presented here.
The use of TDAE as an organic reductant is crucial, as it avoids
the generation of stoichiometric metallic waste and makes the
procedure operationally simple. In this process, two new C−C
bonds are formed in one-pot (1 × Csp3−Csp3 and 1 × Csp3−
Csp2) by addition of two different electrophiles across the π-
system thus expanding the scope of existing dicarbofunction-
alization reactions. In addition, this method represents a
mechanistically distinct approach to functionalize alkenes
through the selective activation of two different electrophiles
based on their distinct reactivity toward Ni species in different
oxidation states.
yield with 39 not being detected in the reaction media (eqs 1
and 2). These results are consistent with the kinetic data for
both processes (cyclization of a C-centered radical onto a
monosubstituted alkene vs intermolecular addition onto an
activated olefin) previously reported in the literature,13 and
suggest the presence of C-centered radicals along the reaction
pathway. The involvement of secondary alkyl iodides as
potential reaction intermediates was investigated next. Mon-
itoring the standard reaction shown in Table 1 by 1H NMR and
GC−MS over time showed no formation of alkyl iodide at any
stage of the reaction (data not shown, see section 5 in the SI).
Further, alkyl iodide 41 displayed no reactivity under the
standard reaction conditions (eq 3). Interestingly, no reaction
was observed in the absence of alkyl iodides (eq 4) whereas
activation of the alkyl iodide in the absence of ArI seems to be
possible only to a very limited extent (eq 5). The presence of
Ni, in contrast, seems to be crucial for the process (eq 6). The
role of the reductant was also investigated. The reaction of
Ni(dtbbpy)I2 with TDAE in the presence of 2-iodotoluene
delivered the corresponding ArNi(II) complex 42,6d demon-
strating the ability of TDAE to reduce Ni(II) complexes
followed by a successful oxidative addition (eq 7). Interestingly,
the stoichiometric reaction of ArNi(II) complex 43 (derived
from 4-tert-butylchlorobenzene and L1) with acrylonitrile, tert-
butyl iodide, in the presence of TDAE furnished the desired
product 24 in 55% yield, thus proving the competence of
ArNi(II) species as potential reaction intermediates in these
transformations (eq 8).
ASSOCIATED CONTENT
Based on the above-mentioned experimental evidence, the
following mechanism can be proposed (Scheme 4). Under the
reductive reaction conditions, Ni(0) species generated in situ
can undergo oxidative addition onto the ArI moiety to produce
ArNi(II) intermediate A (eq 7). In parallel, Ni(I) species
produced in the reaction media could be responsible for the
activation of the alkyl iodide to produce an alkyl radical C that
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b03195.
Compound synthesis, characterization and additional
experiments (PDF)
C
DOI: 10.1021/jacs.7b03195
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(8) For additional experiments, see Supporting Information. CCDC-
1540663 (29) contains the supplementary crystallographic data for
this paper. The data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
structures.
AUTHOR INFORMATION
Corresponding Author
*cristina.nevado@chem.uzh.ch
Notes
■
(9) (a) Xu, H.; Zhao, C.; Qian, Q.; Deng, W.; Gong, H. Chem. Sci.
2013, 4, 4022. (b) Fujita, T.; Arita, T.; Ichitsuka, T.; Ichikawa, J.
Dalton Trans. 2015, 44, 19460.
(10) For previous reports combining TDAE with nickel catalysis, see:
(a) Anka-Lufford, L.; Huihui, K. M. M.; Gower, N. J.; Ackerman, L. K.
G.; Weix, D. J. Chem. - Eur. J. 2016, 22, 11564. (b) Kuroboshi, M.;
Tanaka, M.; Kishimoto, S.; Goto, K.; Mochizuki, M.; Tanaka, H.
Tetrahedron Lett. 2000, 41, 81. (c) Broggi, J.; Terme, T.; Vanelle, P.
Angew. Chem., Int. Ed. 2014, 53, 384.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the European Research Council (ERC Starting grant
agreement no. 307948) and the Swiss National Science
Foundation (SNF 200020_146853) for financial support. We
also thank Prof. Anthony Linden for the X-ray diffraction
analysis of 29.
(11) The reaction with aryl bromides proceeded, albeit with lower
efficiency. Primary and secondary alkyl iodides could not be
successfully coupled. For these and additional examples exploring
the reaction scope, see section 6 in the Supporting Information.
(12) Newcomb, M.; Filipkowski, M. A.; Johnson, C. C. Tetrahedron
Lett. 1995, 36, 3643.
(13) Fischer, H.; Radom, L. Angew. Chem., Int. Ed. 2001, 40, 1340.
(14) Biswas, S.; Weix, D. J. J. Am. Chem. Soc. 2013, 135, 16192.
(15) TDAE is transformed into [TDAE2+][I−]2 under the reaction
conditions. For this and additional control experiments on the role of
TDAE and other reductants, see section 5 in the Supporting
Information.
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D
DOI: 10.1021/jacs.7b03195
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