Nickel-catalyzed anti-Markovnikov hydroarylation of alkenes

Article abstract of DOI:10.1039/C8SC05445B

We have developed a nickel-catalyzed hydroarylation of alkenes using aryl halides as coupling partners. Excellent anti-Markovnikov selectivity is achieved with aryl-substituted alkenes and enol ethers. We also show that hydroarylation occurs with alkyl substituted alkenes to yield linear products. Preliminary examination of the reaction mechanism suggests irreversible hydrometallation as the selectivity determining step of the hydroarylation.

Full text of DOI:10.1039/C8SC05445B

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Nickel-catalyzed anti-Markovnikov hydroarylation
of alkenes†
Cite this: DOI: 10.1039/c8sc05445b
*
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have been paid for by the Royal Society
of Chemistry
Julia Nguyen, Andrea Chong and Gojko Lalic
We have developed a nickel-catalyzed hydroarylation of alkenes using aryl halides as coupling partners.
Excellent anti-Markovnikov selectivity is achieved with aryl-substituted alkenes and enol ethers. We also
show that hydroarylation occurs with alkyl substituted alkenes to yield linear products. Preliminary
examination of the reaction mechanism suggests irreversible hydrometallation as the selectivity
determining step of the hydroarylation.
Received 6th December 2018
Accepted 3rd February 2019
DOI: 10.1039/c8sc05445b
rsc.li/chemical-science
Catalytic hydroarylation of alkenes has been targeted as an approach based on reductive Heck reaction has been success-
attractive synthetic route to alkylarenes, a common structural fully used by Engle et al.11 and later Hu et al.12 to access the same
motif in organic chemistry. Traditionally, hydroarylation is products. Relative to the excellent scope of the Engle's reaction
accomplished either via classical Friedel–Cras reaction1 or of terminal alkyl alkenes, the scope of the Hu's reaction with
through methods based on metal catalyzed C–H activation of aryl alkenes was limited.
arenes.2 More recently, a third complementary strategy has been
We were interested in developing a hydroarylation reaction
developed based on the reductive coupling of aryl halides and that would complement existing methods and allow anti-
alkenes in the presence of a hydride donor. The key advance Markovnikov hydroarylation of aryl alkenes and possibly other
offered by reductive cross coupling relative to Friedel–Cras new substrate classes. Furthermore, we were hoping to achieve
and C–H activation methods is excellent site selectivity of the these transformations using a single metal complex as a cata-
arene alkylation regardless of the substitution pattern of the lyst. This catalyst would have to promote both the hydro-
starting arene.
metallation of alkenes and the subsequent cross coupling with
The reductive cross coupling approach has been effectively aryl halides.
used in several methods for the Markovnikov hydroarylation of
We focused on nickel complexes as particularly well suited
alkenes. In 2016, Nakao et al. reported a Markovnikov hydro- for the task. Insertion of alkenes into nickel hydride complexes
arylation of aryl alkenes using a dual palladium/copper catalyst is well documented13,14 and alkyl nickel complexes have been
system.3 The same year, Buchwald et al. reported an enantio- implicated as intermediates in cross-coupling reactions with
selective version of the reaction using a similar approach.4 organohalides.15 Following an important precedent established
Markovnikov hydroarylation of alkenes has also been achieved by Liu et al.,16 the general feasibility of nickel-catalyzed hydro-
by Herzon et al.5,6 using metal hydride hydrogen atom transfer arylation was recently demonstrated by a reductive arylation
(HAT) to initiate radical alkylation of arenes. Concurrently, reaction reported by Zhu et al. (Scheme 1b).17,18 This trans-
Shenvi et al.7,8 developed a distinct approach based on metal formation involved extensive isomerization of the alkene and
hydride HAT coupled with nickel-catalyzed cross-coupling.
Anti-Markovnikov selectivity in the reductive cross coupling original position of the alkene relative to the arene.19
of aryl halides and alkenes is relatively rare. At the time we were In this work, we report the anti-Markovnikov hydroarylation
the exclusive formation of 1,1-diaryl products regardless of the
developing this project, it had been achieved only in reactions of alkenes using a simple nickel catalyst. We are able to achieve
of simple terminal alkenes (Scheme 1a). Buchwald et al. have this linear selectivity with a number of different substrate
shown that a dual palladium/copper catalyst system promotes classes, including aryl alkenes, enol ethers and simple unac-
coupling of unactivated alkenes with aryl halides to generate tivated alkenes (Scheme 1c).
linear hydroarylation products.9,10 Notably, the same catalyst
While exploring the reactivity of various nickel complexes in
system was previously shown to give Markovnikov selectivity in the catalytic hydroarylation of aryl alkenes, we discovered that
the hydroarylation of aryl alkenes.4 Recently, an alternative NiCl2(DME) provides the hydroarylation product with excellent
anti-Markovnikov selectivity (Table 1, entry 1). Essential for the
anti-Markovnikov selectivity and the overall success of the
reaction was the absence of a ligand. A variety of ligands,
Department of Chemistry, University of Washington, Seattle, Washington 98195, USA.
E-mail: lalic@chem.washington.edu
including L1 used by Zhu et al., resulted in no formation of the
† Electronic supplementary information (ESI) available. See DOI:
desired product (entries 2 and 3) (see ESI for additional data†).
10.1039/c8sc05445b
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Scheme 1 Reductive cross coupling of alkenes with aryl halides.
Table 1 Reaction developmenta
Entry
Variations from above
Yieldb (%)
L : Bc
1
2
None
L1 as a ligand
89 (81)
0
55 : 1
—
3
L2 as a ligand
0
—
4
5
6
7
8
9
10
11
12
IPr as a ligand
24
44
39
80
35
8
57
30
0
1.3 : 1
15 : 1
12 : 1
48 : 1
3 : 1
2.5 : 1
29 : 1
7 : 1
—
NiCl2 instead of NiCl2(dme)
Ni(COD)2 instead of NiCl2(dme)
Toluene instead of benzene
1,4-Dioxane
THF instead of benzene
(Me2HSi)2O instead of PMHS
LiOt-Bu instead of NaOt-Bu
KOt-Bu instead of NaOt-Bu
a
Conditions: 1 (2 equiv.), 2 (1 equiv.), NaOt-Bu (4 equiv.), PMHS (4 equiv.). b Yields were determined by GC analysis of the crude reaction mixture
c
using 1,3,5-trimethylbenzene as the internal standard. Number in parentheses are yields of isolated products. L : B is the ratio of the linear
product to the branched product as determined by GC analysis of the crude reaction mixture.
For those ligands that did generate product, such as N- source, proved to be competent in this reaction (entry 6).
heterocyclic carbine ligand IPr, regioselectivity and yield were Aromatic solvents, such as benzene and toluene (entry 7), were
low (entry 4). Using different nickel sources, such as NiCl2 (entry essential for high yield of the hydroarylation product, while
5), resulted in lower yields. Interestingly, Ni(COD)2, a Ni(0) most other solvents were completely ineffective (see ESI for
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Table 2 Scope of the hydroarylation reactiona
a
Conditions: aryl halide (1 equiv.), alkene (2 equiv.), PMHS (4 equiv.), NaOt-Bu (4 equiv.). Yields of isolated products are reported. The ratios of
linear to branched products were determined by GC analysis of the crude reaction mixture and are given in parenthesis.
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details†). Interestingly, ethereal solvents, such as 1,4-dioxane radical.21 In competition experiments (Scheme 2a), we found
(entry 8) and THF (entry 9), provided signicantly lower that simple styrene reacts faster than a-methylstyrene or a-
regioselectivity.
phenylstyrene, both of which should undergo radical addition
Polymethylhydrosiloxane (PMHS) was the best hydride faster than styrene. The results of these experiments are not
source. Other silanes, including closely related (Me2HSi)2O consistent with a radical addition mechanism, leading us to
(entry 10), provided lower yields and worse regioselectivity (see explore other options.
ESI† for details). Similarly, NaOt-Bu was essential for the reac-
A mechanism involving hydrometallation followed by aryla-
tion and even the closely related Li and K analogs (entries 11 tion of the alkyl nickel intermediate was proposed by Zhu et al.
and 12) provided signicantly inferior results. Exclusion of any for the related hydroarylation reaction (see Scheme 1b). We
component of this reaction resulted in no formation of used the experiment shown in Scheme 2b to explore the inter-
product 3.
mediacy of the alkyl nickel complex in our hydroarylation
Hydroarylation could be achieved with a range of aryl- and reaction.
alkyl-substituted alkenes (Table 2). With aryl alkenes, ortho,
In the presence of 2 equiv. of EtOH, the hydroarylation
meta and para substitution is tolerated (compounds 7, 8, 4). Aryl product is formed in a lower yield than in the absence of EtOH
alkenes containing both electron-donating and electron- (54% vs. 82%), while the alkane product (50) is formed in 36%
withdrawing substituents are viable substrates (5 and 6). Good yield. This result is consistent with competitive protonation of
selectivities and yields were also obtained in hydroarylation of the alkyl nickel intermediate by EtOH. Based on these consid-
aryl alkenes containing a wide range of heteroarenes, including erations, we propose that the hydroarylation reaction proceeds
benzofuran (13), indole (14, 15), pyrrole (16), benzopyrazole according to the mechanism shown in Scheme 3.
(17), and pyrrolopyridine (18). Finally, substitution on the
a position of the alkene is also tolerated, as indicated by the step that determines the regioselectivity of the reaction. In
formation of product 19 in the reaction with a-methylstyrene. hydrofunctionalization reactions that proceed through hydro-
In the context of this mechanism, we were interested in the
Nickel-catalyzed hydroarylation of various other classes of metallation, the product determining step varies depending on
alkenes was also examined. Unactivated terminal alkenes were the reversibility of the hydrometallation step. When
suitable coupling partners (20–23, 27–29), although the regio-
selectivity was somewhat lower. Surprisingly, a 1,3-diene
substrate gave product 24 with high yield and good regiose-
lectivity. Another unusual class of alkenes that were compatible
with our reaction conditions are enol ethers. We were able to
isolate the product of the reaction with ethyl vinyl ether (25) in
good yield (78%) while the benzyl protected enol ether provided
the expected product 26 in 63% yield. To our knowledge, these
are the only examples of anti-Markovnikov reductive cross
coupling reactions with 1,3-dienes or enol ethers.
We have also explored the performance of various arene
coupling partners, and both aryl iodides and aryl bromides are
viable substrates (Table 2). The electronic properties of aryl
electrophiles seem to play a signicant role as electron-neutral
and electron-rich aryl halides generally gave high yields (30, 37,
46), while electron-poor aryl halides, though still competent,
provided lower yields of the hydroarylation products (31 and
32). Again, we found that various heteroarenes are tolerated,
including pyrrolopyridine (41), quinoline (42, 43), indole (44),
benzofuran (45), pyrimidine (47), and benzopyrazole (48).
The unique aspect of this new hydroarylation reaction is the
anti-Markovnikov selectivity obtained with a range of alkenes,
including aryl alkenes and enol ethers. The observed selectivity
is consistent with an addition of an aryl radical to the alkene,
which would favour addition to the alkene terminus and
formation of the more stable secondary alkyl radical. To test this
mechanistic hypothesis, we performed experiments in the
presence of a radical trap. The presence of 10 mol% of TEMPO
did lower the yield of the desired product and a full equivalent
completely blocked its formation (see ESI† for details).
However, in all cases, we observed only trace amounts (<5%
yield) of the aryl–TEMPO adduct, suggesting that TEMPO likely
interacts with another intermediate20 and not with an aryl Scheme 2 Probing the reaction mechanism.
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Conclusions
We have developed a new method for the anti-Markovnikov
hydroarylation of alkenes. The reaction involves reductive
cross coupling of alkenes and aryl halides in the presence of
a silane as a hydride donor. Anti-Markovnikov selectivity is
obtained with a wide range of alkenes, including alkyl- and aryl-
substituted alkenes, and enol ethers. Preliminary investigation
of the reaction mechanism provides evidence for a mechanism
that involves hydrometallation of the alkene, followed by
coupling of the alkyl nickel intermediate with an aryl halide.
The evidence points to highly selective hydrometallation of the
alkene as the regioselectivity determining step of the reaction.
Scheme 3 Proposed mechanism of hydroarylation.
Conflicts of interest
irreversible, hydrometallation is the regio-determining step. If
hydrometallation is fast and reversible, there is a Curtin–
Hammett scenario, and regioselectivity is determined by the
relative rates of the irreversible reductive elimination at
different sites and not by hydrometallation. Alkene insertion
into nickel hydride complexes is oen fast and reversible,22 as
documented by Zhu et al. in their reductive arylation of
alkenes.17 Because the C–C bond-forming reductive elimination
from nickel complexes tends to be exothermic,23 the rates of
reductive elimination are oen based on the ground state
stability of the alkyl metal intermediates. The result is that the
reductive elimination from the most stable alkyl metal complex
is favoured.
To explore the reversibility of the hydrometallation step in
the hydroarylation reaction, we used deuterium-labelled styrene
substrates (Scheme 2c and d). In the reaction with substrate 1-
bD we observed no deuterium scrambling, while the reaction
with 1-aD, resulted in minimal scrambling of the deuterium
label.24 In the context of the reaction mechanism shown in
Scheme 3, the two deuterium scrambling experiments point to
hydrometallation being irreversible and product determining
step of the reaction. These results indicate that a strong kinetic
preference for the formation of a homobenzylic alkyl nickel
intermediate over the benzylic regioisomer is responsible for
the regioselectivity of the hydroarylation.
There are no conicts to declare.
Acknowledgements
Financial support by NSF (NSF CAREER Award 1254636) and
NIH (1R01GM125791-01A1) is acknowledged.
Notes and references
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absence of ligand in our hydroarylation reaction makes the
formation of nanoparticles likely, and we observe an immediate
formation of particles upon the addition of the alkoxide to the
reaction mixture. Mixtures of alkoxides and reducing reagents
have previously been used to generate highly reactive nickel
nanoparticle catalysts, and sodium alkoxide has been proposed
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hydroarylation reaction, we observed a burst of initial activity
(64% yield aer 10 minutes), followed by a very slow reaction
over the next 14 h when the maximum yield is achieved. Finally,
we found that the addition of mercury signicantly lowers the
yield of the hydroarylation (56% vs. 89% GC yields) (Scheme
2e).27 These observations are consistent with a heterogeneous
active catalyst.
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21 We cannot exclude the possibility that the Ar–TEMPO adduct
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see: P. Shukla, A. Sharma, B. Pallavi and C. H. Cheng,
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1-aD and is higher at higher conversions. Furthermore, if
the reaction with 1-aD is stopped aer 10 minutes,
product 51 is isolated in 49% yield and no deuterium
scrambling is observed in either the product or the
recovered starting material (see page S31 of the ESI†).
These results suggest that the scrambling may be
independent of the hydroarylation reaction.
19 Interestingly, Zhao et al. have also reported Markovnikov
selectivity
in
a
redox
neutral
nickel-catalysed
hydroarylation of styrenes, see: L. J. Xiao, L. Cheng,
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Chem., Int. Ed., 2018, 57, 461.
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Chem. Soc., 2012, 134, 20226.
20 TEMPO has been shown to react rapidly with metal hydrides.
´
´
´
See: A. C. Albeniz, P. Espinet, R. Lopez-Fernandez and
A. J. Sen, J. Am. Chem. Soc., 2002, 124, 11278TEMPO has 26 J. J. Brunet, D. Besozzi, A. Courtois and P. Caubere, J. Am.
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27 R. H. Crabtree, Chem. Rev., 2012, 112, 1536.
Chem. Sci.
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