Nickel-Catalyzed Arylboration of Alkenylarenes: Synthesis of Boron-Substituted Quaternary Carbons and Regiodivergent Reactions

Article abstract of DOI:10.1002/anie.201904861

A method for the construction of boron-substituted quaternary carbons or diarylquaternary carbons by arylboration of highly substituted alkenylarenes is presented. A wide range of alkenes and arylbromides can participate in this reaction thus allowing for a diverse assortment of products to be prepared. In addition, a solvent dependent regiodivergent arylboration of 1,2-disubstituted alkenylarenes is presented, thus greatly increasing the scope of products that can be accessed.

Full text of DOI:10.1002/anie.201904861

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201904861
German Edition: DOI: 10.1002/ange.201904861
Alkene Functionalization
Nickel-Catalyzed Arylboration of Alkenylarenes: Synthesis of Boron-
Substituted Quaternary Carbons and Regiodivergent Reactions
Liang-An Chen, Alan R. Lear, Pin Gao, and M. Kevin Brown*
Abstract: A method for the construction of boron-substituted
quaternary carbons or diarylquaternary carbons by arylbora-
tion of highly substituted alkenylarenes is presented. A wide
range of alkenes and arylbromides can participate in this
reaction thus allowing for a diverse assortment of products to
be prepared. In addition, a solvent dependent regiodivergent
arylboration of 1,2-disubstituted alkenylarenes is presented,
thus greatly increasing the scope of products that can be
accessed.
A
lkene difunctionalization is a significant synthetic strategy
as molecular complexity can be rapidly generated.[1] Within
this broad area, alkene carboboration has emerged as an
effective strategy that allows for a diverse range of groups to
be installed across the alkene by taking advantage of the
[2,3]
À
synthetic versatility of the C B bond.
Over the last five
years, alkene arylboration methods have emerged with
contributions from our lab[4] and others.[5] The arylboration
of alkenylarenes is well developed with mono-, 1,2-di-, and
1,1-disubstituted alkenes (Scheme 1A).[4,5] Notably, function-
alization of trisubstituted alkenylarenes remains a challenge.
We sought to develop an arylboration of these classes of
substrates because the products would contain boron-sub-
stituted quaternary carbons or diarylquaternary carbons,
motifs that are currently difficult to access (Scheme 1B). In
particular, synthesis of boron-substituted quaternary carbons
from widely available alkenes was seen as a key motivation
for this study. Notable advances in the synthesis of boron
substituted quaternary carbons from alkenes include conju-
gate addition/allylic substitution,[6] hydroboration/dibora-
tion,[7] conjunctive cross coupling,[8] and aminoboration[9,10]
The majority of the known approaches utilize alkenes with
strong activating groups (e.g. substituted acrylates) or direct-
ing groups. The approach outlined herein is appealing as
simple alkenylarenes are the starting materials and two bonds
and two stereogenic centers are generated.
Scheme 1. Arylboration of alkenylarenes.
were unsuccessful.[4a–e] However, our recent discovery of a Ni-
catalyzed arylboration of unactivated alkenes,[4g,h] prompted
us to explore Ni-catalysis in the context of highly substituted
alkenylarenes. Herein, we disclose a method for the arylbo-
ration of a wide range of trisubstituted alkenylarenes that
leads to the formation of challenging boron-substituted
quaternary carbons or diarylquaternary carbons (Sche-
me 1B). In addition, we have uncovered a solvent dependent
regiodivergent arylboration of 1,2-disubstiuted alkenylarenes
that further increases the utility of this method (Scheme 1C).
Arylboration of trisubstituted alkenylarenes under pre-
viously reported Ni-catalysis conditions resulted in low to
moderate yield of the desired products due to incomplete
conversion.[4g,h] Evaluation of reaction conditions ultimately
led to the finding that use of DMA as solvent led to high yield
of product (compare Table 1, entries 1 and 2). Unexpectedly,
it was also found that premixing KOEt and (Bpin)2 prior to
the addition of substrates and catalyst led to higher yields
(compare Table 1, entries 1 and 3). Presumably premixing of
KOEt and (Bpin)2 serves to sequester KOEt. It has been
reported that alkoxide bases and NiII salts can result in the
formation of nanoparticles, which may deactivate the Ni-
catalyst in this case.[11] While 5 mol% NiCl2(DME) and
Early attempts from our group to develop arylboration
reactions of trisubstituted alkenylarenes with Cu/Pd-catalysis
[*] Dr. L.-A. Chen, A. R. Lear, Prof. M. K. Brown
Department of Chemistry, Indiana University
800 E. Kirkwood Ave., Bloomington, IN 47405 (USA)
E-mail: brownmkb@indiana.edu
Dr. P. Gao
Department of Chemistry, School of Science, Xi’an Key Laboratory of
Sustainable Energy Material Chemistry, MOE Key Laboratory for
Nonequilibrium Synthesis and Modulation of Condensed Matter
Xi’an Jiaotong University, Xi’an, Shaanxi, 710049 (China)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under https://doi.org/10.
1002/anie.201904861.
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Table 1: Change from standard conditions.
Entry
Change from standard conditions
Product
Yield
[%][a]
1
2
3
4
5
no change
THF instead of DMA
no premixing of (Bpin)2 and KOEt
1.5 equiv ArBr instead of 3.0 equiv ArBr
2 mol% NiCl2(DME) instead of 5 mol%
NiCl2(DME)
2
2
2
2
2
98
21
79
65
75
6
7
8
9
glovebox free reaction setup
no change
THF instead of DMA
2
3
3
3
94
65
20
29
no premixing of (Bpin)2 and KOEt
Reactions performed on 0.2 mmol scale. [a] Yield determined by
1H NMR analysis of the unpurified reaction mixture with an internal
standard.
3.0 equiv aryl bromide were found to be optimal, lower
catalyst loading or fewer equivalents of aryl bromide still
resulted in useful yields (Table 1, entries 4 and 5). In addition,
the reaction could be setup without the aid of glovebox
techniques with little change in efficiency (Table 1, entries 6).
Finally, it should be noted that the optimal conditions were
particularly crucial for arylbromides bearing electron-with-
drawing groups (compare Table 1, entries 7–9).
Under the optimized conditions arylbromides bearing
electron donating, electron withdrawing and sterically
demanding substituents were well tolerated (Scheme 2).
Various functional groups such as amines, alcohols, esters,
and amides did not greatly impede the reaction. Finally,
heterocycles could also be employed, albeit with slightly
reduced yields. The primary limitation with respect to
arylbromide scope is that strongly electron-withdrawing
substituents such as CF3 resulted in low yields of product
and formation of significant quantities of ArBpin.
Regarding the scope of alkenes that can be used, several
points are noteworthy (Scheme 3): 1) For the synthesis of
boron-substituted quaternary carbons, the substitution pat-
tern of the aryl group could be altered with various electron
withdrawing, electron donating, sterically demanding sub-
stituents. 2) Both cyclic and acyclic substrates are suitable for
this process. 3) The formation of 30 and 37 occurred with high
levels of diastereoselectivity. In these cases, while the identity
of the major diastereomer could not be confirmed, the
arylboration likely occurred from the least hindered face of
the alkene. 4) For substrates with acyclic substituents, yield
decreased with more sterically demanding substituents (com-
pare 2 and 33). 5) The synthesis of diarylquaternary carbons
can be achieved with both acyclic and cyclic substrates
(products 38–44).
Scheme 2. Reaction with various arylbromides. Yield of product after
isolation. NMR yield determined by 1H NMR analysis of the unpurified
reaction mixture with an internal standard. [a] Reaction with the
4-OMeAr analog of 1 used. [b] Products 7 and 16 were oxidized to the
alcohol before isolation. Reactions performed on 0.4 mmol scale.
Glucocorticoid receptor modulators through standard
sequences.[12] Previously, these molecules were prepared by
a non-stereoselective 6-step sequence. The route illustrated
here required 3–4 operations, is stereoselective, and repre-
sents an orthogonal approach to the construction of biolog-
ically active molecules from alkenes.
In the course of these investigations, 1,2-disubstituted
alkenylarenes were also probed. Under the standard con-
ditions, 51 was generated in excellent selectivity (Table 2,
entry 1). Interestingly, the observation was made that if
toluene was used as a co-solvent, the formation of regioiso-
mer 52 (> 20:1 dr) was observed (Table 2, entry 2). Increasing
the amount of toluene revealed that regioisomer 52 could be
generated as the major product, albeit in low yield (Table 2,
entry 7). Continued optimization led to the finding that
higher reaction temperatures (608C vs. rt), use of KOMe (vs.
KOEt), and excess alkene (relative to arylbromide) resulted
in exclusive formation of 52 (Table 2, entry 12). Thus, through
a simple change in solvent and minor modification to reaction
conditions, the arylboration could be tuned to favor either
regioisomer 51 or 52. Prior studies have demonstrated that
product 51 can be prepared by a Cu/Pd-catalyzed arylbora-
tion.[4,5] The Ni-catalyzed reaction reported herein offers an
The arylboration could also be performed on gram scale
À
(Scheme 4). Furthermore, the C B bond could be elaborated
through oxidation (product 47) and Matteson homologation/
oxidation (product 48). Alcohol 48 could be advanced to
2
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Scheme 3. Arylboration of trisubstituted alkenes. See Scheme 2 for details.
Table 2: Regiodivergent arylboration of 1,2-disubstituted alkenylarenes.
Entry Solvent
Temp
[8C]
Base
Yield 51:52
[%][a]
1
2
3
4
5
6
7
8
DMA
rt
rt
rt
rt
rt
KOEt
KOEt
KOEt
KOEt
KOEt
KOEt
KOEt
KOEt
KOMe
KOMe
KOMe
KOMe
98
98
42
28
15
17
15
55
42
42
45
58
>99:1
93:1
34:1
14:1
4.6:1
2.3:1
1:9
toluene:DMA (1:1)
toluene:DMA (5:1)
toluene:DMA (10:1)
toluene:DMA (50:1)
toluene:DMA (160:1)
toluene
toluene
toluene
toluene
toluene
rt
rt
60
60
60
60
60
1:2.2
1:5
1:36
1:39
1:>99
9
10[b]
11[b,c]
12[c,d]
Scheme 4. Gram scale reaction and further transformations.
toluene
Reactions performed on 0.2 mmol scale. [a] Combined yield of 51 and 52
determined by GC using a calibrated internal standard. [b] ArBr
(1.2 equiv). [c] NiCl2(DME) (15 mol%). [d] Alkene (2.0 equiv), ArBr,
(1.0 equiv).
alternative that utilizes a simple catalyst. Methods for the
synthesis of the regioisomeric product 52 do not exist.
However, a recent report from Song, has demonstrated that
styrene derivatives, but not 1,2-disubstituted alkenylarenes,
can undergo Pd-catalyzed arylboration with aryldiazonium
salts and (Bpin)2.[5c]
Under conditions outlined in Table 2 entries 1 and 12 both
acyclic and cyclic 1,2-disubstituted alkenylarenes participated
in the reactions with excellent regioselectivity and diastereo-
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selectivity (products 51–60) (Scheme 5). While arylboration
in DMA worked well with trisubstituted alkenes (Schemes 2–
3), the conditions with toluene did not proceed, and starting
material was recovered.
Scheme 6. Putative catalytic cycles.
Scheme 5. Regiodivergent arylboration. See Table 2, entries 1 and 12
for conditions (0.4 mmol scale). Yield of product after isolation. NMR
yield determined by 1H NMR analysis of the unpurified reaction
mixture with an internal standard. [a] Reaction with 1.0 equiv alkene
and 1.2 equiv ArBr.
To account for the different regioselectivities observed in
different solvents, two catalytic cycles are proposed
(Scheme 6). In the case of reactions performed in DMA,
and on the basis of prior studies, we propose that [Ni]-Bpin
complex 62 is generated, which undergoes reaction with an
alkene.[4g,h,13] The regioselectivity of the migratory insertion
occurs to generate benzyl-[Ni]-complex 63 regardless of
alkene substitution pattern. The formation of product may
occur through an oxidative addition with ArBr followed by
reductive elimination via 64. In the case of reactions in
toluene, it is proposed that migratory insertion occurs from
NiIIArBr complex 66.[14] The regioselectivity is determined
though formation of benzyl-[Ni]-complex 67. Transmetalation
with (Bpin)2 and reductive elimination then occurs to
generate product.
Scheme 7. Mechanistic experiments.
Support for the proposed catalytic cycles is illustrated in
Scheme 7. It was found that addition of MeOH to the reaction
mixture resulted in formation of protoboration adduct 69,
thus suggesting that Bpin is incorporated prior to the aryl
group.[4g,h] In addition, reaction of vinyl fluoride 70 led to the
formation of vinyl boronic ester 71. Since direct cross
4
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corresponding benzyl-[Ni]-complex via b-hydride elimination
or protonation, respectively.[18] At this stage, the role of
solvent in determining the regioselectivity is not clear and is
under investigation.
In summary, the synthesis of challenging boron-substi-
tuted quaternary carbons and diarylquaternary carbons has
been achieved through an arylboration reaction. Further-
more, the arylboration regioselectivity of 1,2-disubstituted
alkenylarenes can be tuned by altering the solvent, revealing
a practical system in which diverse and versatile products can
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Acknowledgements
We thank Indiana University and the National Institutes of
Health (R01GM114443 and R35GM131755) for generous
financial support. This project was partially funded by the
Vice Provost for Research through the Research Equipment
Fund.
Conflict of interest
The authors declare no conflict of interest.
Keywords: alkenes · arylboration · boron · cross coupling · nickel
[12] J. Duan, B. Jiang, PCT Int. Appl. WO 2007073503, 2007.
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elimination.
[19] After the submission of this manuscript a Ni-catalyzed arylbo-
ration of vinylarenes was reported, see: W. Wang, C. Ding, H.
Pang, G. Yin, Org. Lett. 2019, 21, 3968.
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Manuscript received: April 23, 2019
Version of record online: && &&, &&&&
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Communications
Alkene Functionalization
Boron-substituted quaternary carbon or
diarylquaternary carbon centers are con-
structed by arylboration of highly substi-
tuted alkenylarenes. A wide range of
alkenes and arylbromides can participate
in this reaction. In addition, a solvent
dependent regiodivergent arylboration of
1,2-disubstituted alkenylarenes is pre-
sented, thus greatly increasing the scope
of products that can be accessed.
L.-A. Chen, A. R. Lear, P. Gao,
M. K. Brown*
&&&& — &&&&
Nickel-Catalyzed Arylboration of
Alkenylarenes: Synthesis of Boron-
Substituted Quaternary Carbons and
Regiodivergent Reactions
6
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