Nickel-Catalyzed Stereoselective Arylboration of Unactivated Alkenes

Article abstract of DOI:10.1021/jacs.7b12160

A Ni-catalyzed method for arylboration is disclosed. The method allows for highly stereoselective arylboration of unactivated alkenes. The reactions utilize a simple Ni-catalyst and work with a broad range of alkenes and aryl bromides. The products represent useful intermediates for chemical synthesis due to the versatility of the C-B bond. Preliminary mechanistic details of the method are also disclosed.

Full text of DOI:10.1021/jacs.7b12160

Communication
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Nickel-Catalyzed Stereoselective Arylboration of Unactivated
Alkenes
Kaitlyn M. Logan, Stephen R. Sardini, Sean D. White, and M. Kevin Brown*
Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, Indiana 47405, United States
S
* Supporting Information
silanes, strained alkenes), to increase the rate of a migratory
ABSTRACT: A Ni-catalyzed method for arylboration is
disclosed. The method allows for highly stereoselective
arylboration of unactivated alkenes. The reactions utilize a
simple Ni-catalyst and work with a broad range of alkenes
and aryl bromides. The products represent useful
intermediates for chemical synthesis due to the versatility
of the C−B bond. Preliminary mechanistic details of the
method are also disclosed.
insertion event prior to direct reaction between the electrophile
and nucleophile (e.g., (Bpin)2 or [M]-Bpin). Carboboration of
unactivated alkenes remains rare. Success has been achieved in
the intra-5d and intermolecular5f,g alkylboration of terminal
unactivated alkenes. In addition, intramolecular hydroxyl-
alkylation of terminal unactivated alkenes has been developed.7a
Carboboration methods that allow for incorporation of aryl
groups and utilize unactivated alkenes have not been developed.
Furthermore, carboboration of 1,2-disubstituted unactivated
alkenes is not known. Difunctionalization of 1,2-disubstituted
unactivated alkenes is significant as the opportunity for
establishing two new stereocenters becomes possible, thus
allowing for rapid buildup of molecular complexity.
lkenedifunctionalizationprocessesareanimportantclassof
1
Areactions for chemical synthesis.
Of these methods,
carboboration reactions are emerging as a versatile class of
alkene difunctionalization processes because rapid molecular
complexity can be established from simple olefin precursors.2,3
This is due to the diverse array of functional groups accessible
from the carbon−boron bond, thus allowing for net carbofunc-
tionalization (Scheme 1A).4
Our lab has taken an interest in arylboration reactions as a
platform to achieve stereospecific Csp −Csp cross-coupling.11 As
noted above, this has led to the development of Cu/Pd-
cooperative catalysis for arylboration of alkenylarenes, vinyl-
silanes, 1,3-dienes, and strained alkenes.8 To extend the scope of
these processes, we sought to develop a method for arylboration
of widely available unactivated alkenes. From this initiative we
disclose a process for diastereoselective arylboration of
unactivated alkenes catalyzed by a Ni-complex (Scheme
1C).12−16
2
3
Scheme 1. Strategies for Carboboration
Early efforts in our lab were directed toward developing a Pd/
Cu-cooperative catalysis system for arylboration of cyclo-
pentene.8 Under all conditions attempted, <10% yield of desired
arylboration product was observed. The problems associated
with this reaction were likely due to a slow migratory insertion of
cyclopentene and β-hydride elimination of the putative alkyl
metal intermediate. To overcome these issues, Ni-catalysis was
investigated, as alkylNi-intermediatesarelessproneto β-hydride
elimination.17 While early efforts were focused on investigation
of Ni/Cu-cooperative catalysis,9 it was ultimately realized that
the arylboration of cyclopentene with PhBr could be catalyzed by
commercially available NiCl2(DME) to generate 1 as a single
diastereomer (Table 1, entry 1). It is particularly noteworthy that
these reactions are completely stereoselective, operate with near
equimolar quantities of the alkene and aryl bromide, and occur at
room temperature (or below in some cases).
Several additional points regarding the optimized conditions
are noteworthy: (1) Use of exogenous phosphine or nitrogen-
based ligands are detrimental to the reaction (Table 1, entries 2−
3). (2) While NiCl2 can be used, the yield is diminished (Table 1,
entry 4). (3) Iodobenzene and phenyltriflate allowed for product
Several classes of alkene carboboration reactions are known
and vary based on the electrophile and catalyst(s) utilized. To
achieve alkylboration,5 borylcarboxylation,6 or borylhydroxyl-
alkylation,7 Cu- or Ni-catalysis has been employed. For
incorporationofarylgroups, Cu/Pd-,8 Cu/Ni-,9 orPd-catalysis10
has proven to be effective (Scheme 1B). The majority of these
methods utilize activated alkenes (e.g., alkenyl arenes, vinyl-
Received: November 16, 2017
© XXXX American Chemical Society
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DOI: 10.1021/jacs.7b12160
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a
Table 1. Change from Standard Conditions
Scheme 2. Evaluation of Various Alkenes
a
a
entry
change from standard conditions
no change
NiCl2(PCy3)2 instead of NiCl2(DME)
NiCl2(phen) instead of NiCl2(DME)
NiCl2 instead of NiCl2(DME)
Phl instead of PhBr
yield (%)
dr
1
2
3
4
5
6
7
80
<2
<2
65
49
76
<2
>20:1
−
−
>20:1
>20:1
>20:1
−
PhOTf instead of PhBr
PhCl instead of PhBr
a
Yield and dr determined by GC analysis with a calibrated internal
standard.
formation (Table 1, entries 5−6), while chlorobenzene was
unreactive (Table 1, entry 7).
A range of substituted alkenes functioned well under the
reaction conditions (Scheme 2). Reactions of 3-substituted
cyclopentene derivatives (4 and 6) proceeded with good
diastereoselectivity (products 5 and 7). These reactions are
notable in that three stereocenters are established. Arylboration
of N-Boc pyrrole 8 functioned well to provide 9 in 66% isolated
yield.
The stereospecificity of the reaction was explored with acyclic
alkenes 10 and 12. In each case, the product derived from a syn-
arylboration was observed (products 11 and 13, respectively).
Furthermore, it must be emphasized that regardless of the alkene
utilized the reactions were completely stereoselective. The
regioselectivity was investigated with alkenes 10, 12, 16, and 18.
With a large disparity in steric size (i-Pr/Me), the highly selective
formation of 11 and 13 were observed. Even with a small
difference in size (n-Pr/Me), the reaction proceeded with 3:1 rr
(product 17). The regioselectivity of the reaction with substrate
18 was 5:1, which suggests that proximal electronegative
substituents can alter the selectivity.18 The reaction with 1-
octene and vinylcyclohexane proceeded in good yield (products
23and25,respectively);however,intheformercase,amixtureof
regioisomers (4:1 rr) was observed with 23 being the major
product. In both cases, ∼20% of other isomeric products were
also observed likely resulting from β-hydride elimination and
reinsertion.19 These byproducts were not observed in any
reaction involving 1,2-disubstituted alkenes. Activated alkenes
such as styrene or vinylsilanes do not function well in this
process,19 thus demonstrating the complementarity to related
Cu/Pd-catalyzed arylboration.8
a
1
NMR yield refers to yield determined by H NMR analysis of the
unpurified reaction mixture with an internal standard. Yield refers to
yield of isolated product after silica gel column chromatography and is
reported as the average of two or more experiments (0.5 mmol scale).
The discrepancy between H NMR and yield of isolated product is
due to a sometimes tedious separation between desired product and a
common byproduct, ArBpin. Reaction run for 48 h at 4 °C. 3.0
equiv of ArBr were used. NMR yield of the Bpin and yield of isolated
alcohol after oxidation; see the Supporting Information (SI) for
details.
1
b
c
d
With respect to the aryl bromide component, electron-
donating (product 33) and electron-withdrawing substituents
(products 26−28) lead to formation of the products in good
yield (Scheme 3). In general, reactions with more electron-
deficient aryl bromides work better than reactions with electron-
rich aryl bromides. Sterically hindered aryl bromides also
function well (products 29 and 31). With respect to functional
group tolerance, aryl chlorides (products 26, 27), an ester
(product 28), tertiary amine (product 34), tertiary amide
(product 35), and even a primary alcohol (product 32) allow for
product formation. A vinyl bromide (product 30) and bromo
indole (product 36) were also shown to function. In general,
reaction with cyclopentene was one of the more challenging
substrates likely due to the steric interaction involved with
synthesis of the syn-arylboration product (vida infra). For
example, synthesis of 37 from acyclic alkene required 1.5 equiv of
ArBr, while 3.0 equiv of ArBr were necessary to generate 29 in
good yield. With respect to the known limitations, ketones,
nitriles, and use of some hetereoaromatic bromides (e.g., 3-
bromopyridine, 3-bromofuran) did not allow for product
formation.19,20
The reaction is also amenable to gram scale synthesis as
illustrated in Scheme 4. The arylboration adducts could be
readily converted to other compounds with control of stereo-
chemistrythroughestablishedprotocols(Scheme4,products38,
40, and 41).4,21 The products of these reactions represent net
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DOI: 10.1021/jacs.7b12160
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a
Scheme 3. Evaluation of Various Aryl Bromides
Scheme 4. Gram Scale Reaction and Further
Functionalization of Products
a
b
c
See Scheme 2. Isolated as the corresponding BF3K adduct. 3.0
d
equiv of ArBr were used. NMR yield of the Bpin and yield of isolated
alcohol after oxidation; see the SI for details.
In summary, a new process for the Ni-catalyzed carboboration
of unactivated alkenes is presented. Furthermore, the arylbora-
tion products can be readily transformed to other compounds to
achieve net carbofunctionalization, thus allowing for complexity
to be rapidly established from simple precursors. Finally, the
likelypresenceofalkylNi-complex50opensupthepossibilityfor
further reaction development by investigating its potential
reactivity in new transformations.
hydroxyarylation, alkenylarylation, and aminoarylation of cyclo-
pentene, respectively. In addition, an intermediate toward
glucagon receptor antagonist 44 can be readily prepared by
metallophotoredox cross-coupling of 28 (Scheme 4).22,23 In this
example, the anti-diastereomer is generated due to the
intermediacy of a secondary alkyl radical.
With respect to the mechanism, during our investigations it
was observedthat performing the arylboration ofalkene 20 in the
presence of MeOH (2 equiv) led to formation of 21 and adduct
45 (Scheme 5A). This observation led to the hypothesis that
addition of [Ni]-Bpin 4916c to the alkene occurs to generate Ni-
alkyl complex 50. This complex can undergo reaction with an
ArBr to generate 21 or, in the presence of MeOH, undergo
protonation to provide 45 according to the catalytic cycle shown
in Scheme 3C. Further support for this catalytic cycle was found
when addition of 5 equiv of MeOH (or 5 equiv MeOD) resulted
in increased amounts of 45 relative to 21, whereas use of t-BuOH
didnotaffecttheoutcomeofthe reaction. Inaddition, reactionof
diol 46, which increases the proximity of acidic hydrogens near
the [Ni]-alkyl bond in 50 and thus should give rise to increased
amounts of protonation adducts, did indeed result in exclusive
formation of 48 with <2% arylboration product 47 detected
(Scheme 5B). It also appears that the formation of [Ni]-alkyl
complex 50 does not require ArBr, as protonation adduct 45 was
formed in the absence of aryl bromide (Scheme 5A).24 At this
time, it is not clear how Ni-complex 50 undergoes reaction with
ArBr, but it is possible an oxidative addition/reductive
elimination sequence is involved.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b12160.
■
S
Experimental procedures and analytical data for all
compounds. (PDF)
Crystallographic data for compound 5 after ester
hydrolysis (CIF)
AUTHOR INFORMATION
Corresponding Author
*brownmkb@indiana.edu
ORCID
M. Kevin Brown: 0000-0002-4993-0917
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
We thank Indiana University and the NIH (5R01GM114443)
for generous financial support. This project was partially funded
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DOI: 10.1021/jacs.7b12160
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D
DOI: 10.1021/jacs.7b12160
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