Cobalt-Catalyzed Benzylic Borylation: Enabling Polyborylation and Functionalization of Remote, Unactivated C(sp3)-H Bonds

Article abstract of DOI:10.1021/jacs.5b12249

Cobalt dialkyl and bis(carboxylate) complexes bearing α-diimine ligands have been synthesized and demonstrated as active for the C(sp³)-H borylation of a range of substituted alkyl arenes using B₂Pin₂ (Pin = pinacolate) as the boron source. At longer reaction times, rare examples of polyborylation were observed, and in the case of toluene, all three benzylic C-H positions were functionalized. Coupling benzylic C-H activation with alkyl isomerization enabled a base-metal-catalyzed method for the borylation of remote, unactivated C(sp³)-H bonds.

Full text of DOI:10.1021/jacs.5b12249

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Communication
Cobalt-Catalyzed Benzylic Borylation: Enabling Polyborylation
and Functionalization of Remote, Unactivated C(sp3)-H Bonds.
W. Neil Palmer, Jennifer V. Obligacion, Iraklis Pappas, and Paul J. Chirik
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b12249 • Publication Date (Web): 29 Dec 2015
Downloaded from http://pubs.acs.org on December 29, 2015
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Cobalt-Catalyzed Benzylic Borylation: Enabling Polyborylation and
Functionalization of Remote, Unactivated C(sp3)-H Bonds.
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W. Neil Palmer, Jennifer V. Obligacion, Iraklis Pappas, Paul J. Chirik*
Department of Chemistry, Princeton University, Princeton, New Jersey 08544, U. S. A
Supporting Information Placeholder
polyfunctional products. Coupling the base metal C-H functionaliza-
tion process to alkyl isomerization enabled multiple functionalization
reactions of remote, unactivated C(sp3)-H bonds. This method utilizes
readily available, air stable cobalt precursors and provides a direct syn-
thetic route to valuable geminal diboronate22 and polyboronate com-
pounds as well as a new strategy to functionalize unactivated C-H posi-
tions traditionally inaccessible to most known C-H functionalization
methods (Scheme 1).
ABSTRACT: Cobalt dialkyl and bis(carboxylate) complexes bear-
ing α-diimine ligands have been synthesized and demonstrated as
active for the C(sp3)-H borylation of a range of substituted alkyl arenes
using B2Pin2 (Pin = pinacolate) as the boron source. At longer reaction
times, rare examples of polyborylation were observed and in the case of
toluene all three benzylic C-H positions were functionalized. Coupling
benzylic C-H activation with alkyl isomerization enabled a base metal
catalyzed method for the C(sp3)-H borylation of remote, unactivated
C-H bonds.
Scheme 1. Selectivity of various transition metal-catalyzed C-H
borylation methods.
Transition metal-catalyzed C-H functionalization is an enabling
strategy for sustainable synthesis and has gained considerable attention
due to the ability to streamline the transformation of one of the most
fundamental and ubiquitous linkages in organic molecules into an array
of functional groups.1 Applications of C-H functionalization range
from natural product synthesis and drug discovery to the preparation of
fine and commodity chemicals.2 While a number of C-H functionaliza-
tion reactions are currently available, C-H borylation methods are
often preferred and most widely applied3 due to the synthetic versatility
of the C-B bond4 and predictable selectivity based on steric accessibil-
ity rather than directing groups.
A number of precious metal catalysts are known to promote C-H
borylation, with Rh,5 Pt,6 and Ir-catalyzed3,7 methods being the most
common. Recent efforts have focused on developing catalysts with
earth abundant metals, and successful iron,8 cobalt,9 nickel,10 iron-
copper11 and even metal-free12 conditions have been described. Selec-
tivity in these reactions typically favors C(sp2)-H bonds, consistent
with well-established preferences for oxidative addition.13 Methods for
selective C(sp3)-H borylation are atypical by comparison and usually
rely on directing groups,14 activated substrates,15 or use of a large excess
of (often neat) alkanes under forcing conditions.5a,16
Rare examples of benzylic borylation have also been observed either
as minor byproducts in arene borylation methods10a,17 or as the primary
products from rhodium18 or heterogeneous palladium19 catalysts. Be-
cause of the low activity of the latter catalysts, the methylarene was
required in large excess and monoborylated products were observed. In
one rhodium example, a benzylic diborylation product of toluene was
also obtained in low (7%) yield.18a Alteration of the selectivity of tradi-
tional Ir-catalyzed borylation to benzylic C-H bonds has also been
accomplished by use of silyl directing groups20 and by use of specialized
silyl-boronate reagents in combination with a tailored phenanthroline
ligand.21 With the latter strategy, the non-directed diborylation of a
sufficiently activated substrate, 4-CF3-toluene, was accomplished.21
Despite advances in altering the selectivity of C-H borylation of al-
kylarenes, general strategies for non-directed, highly selective mono-
and diborylation of C(sp3)-H bonds in this substrate class have not yet
been developed. Here we describe α-diimine cobalt catalysts that pro-
mote the selective borylation of C(sp3)-H bonds in alkylarenes into
Our laboratory has reported that the aryl-substituted α-diimine co-
balt allyl complex,
(
iPrDI)Co(η3-C3H5)
(
iPrDI
=
[2,6-
iPr2C6H3N=C(CH3)]2) was an exceptionally active catalyst for the
hydroboration of alkenes.23 Inspired by this performance, related α-
diimine cobalt dialkyl complexes, (DI)CoR2 were synthesized by
straightforward addition of the free ligand to (py)2Co(CH2SiMe3)2 (py
= pyridine).24 With the α-diimine ligand bearing large 2,6-diisopropyl
aryl substituents, an
S = 1/2, planar cobalt dialkyl complex,
(
iPrDI)Co(CH2SiMe3)2 (1, Figure 1) was isolated and crystallograph-
ically characterized. Replacing the aryl imine substituents with cyclo-
hexyl groups resulted in a tetrahedral and hence high spin, S = 3/2
cobalt dialkyl derivative, (CyADI)Co(CH2SiMe3)2 (2, Figure 1), the
geometry of which was also confirmed by X-ray diffraction.
Both (DI)CoR2 complexes are air sensitive organometallic com-
pounds and require inert atmosphere techniques for preparation, han-
dling and use. Alternative cobalt sources that are more robust would
obviate many of these incoveniences. Cobalt(II) carboxylates are some
of the most inexpensive, air-stable sources of cobalt and have been
demonstrated to generate catalytically active species upon treatment
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with borane reagents.25 Our laboratory has previously demonstrated
using a 1:2 ratio of arene to B2Pin2. Using 3 and 20 mol % HBPin for
catalyst activation,25 96% isolated yield of 5 was obtained under other-
wise identical conditions, suggesting formation of the same active cata-
lyst. Use of HBPin instead of B2Pin2 under identical conditions formed
the expected products but with a dramatic reduction in reaction effi-
ciency, yielding 16% and 8% of 4 and 5, respectively. Under optimized
catalytic conditions, the synthesis of 5 was then successfully scaled.
Starting with 0.500 g of toluene, 1.601 g (86% yield) of 5 was obtained.
During optimization experiments to obtain 5, it was discovered that
purification of the reaction mixture using NEt3-deactivated silica gel
flash column chromatography resulted in high (78%) yield of the
monoborylated product, 4, resulting from protodeborylation on the
column. It was also discovered that increasing the catalyst loading to 50
mol % 3 and using four equivalents of B2Pin2 resulted in the triboryla-
tion of toluene to obtain product 6, the identity of which was con-
firmed by X-ray crystallography (Scheme 2). Thus, the cobalt method
enables an unprecedented triborylation of toluene.
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that cobalt(II) acetate in the presence of trialkylphosphine ligands is
active for the borylation of benzofuran albeit with modest activity.25
Preparation of an α-diimine cobalt bis(carboxylate) was achieved by
stirring the free CyADI with a pentane solution of cobalt(II) 2-
ethylhexanoate for 5 minutes at -35 ºC followed by concentration and
filtration, resulting in the isolation of the air-stable cobalt
bis(carboxylate) derivative, 3 (Figure 1) in 60% yield as a pale orange
solid.
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Scheme 2. Optimization of toluene benzylic borylation condi-
tions to access benzylic mono-, di- and triboronate esters.
Figure 1. Depictions of the α-diimine cobalt dialkyl and
bis(carboxylate) precatalysts used in this work and the solid state mo-
lecular structures (30% probability ellipsoids, hydrogens omitted) of
dialkyl complexes 1 and 2.
Each of the cobalt pre-catalysts was evaluated for the borylation of
toluene with B2Pin2 (Pin = pinacolate) (Scheme 2). In hexane solution
at 80 ºC with equimolar quantities of substrates, 2 proved more active
than 1 with the alkyl-substituted α-diimine complex reaching complete
conversion of starting material to an 18:82 mixture of mono- and di-
borylated products, 4 and 5. Notably, the C-H borylation occurred
exclusively at the benzylic C-H bonds with no evidence for C(sp2)-H
borylation with either catalyst. Attempts to use analogous α-diimine
cobalt monoalkyl complexes23 or bis(phosphine)cobalt dialkyl com-
plexes26 produced no catalytic turnover highlighting the importance of
the Co(II)X2 motif supported by a redox-active ligand. With 1, the
benzyldiboronate ester, 5, resulting from two C-H functionalization
reactions, was the major product even at low conversions, establishing
that the rate of the second C-H borylation is competitive with the first.
This observation is consistent with an activating effect of a [BPin]
substituent toward subsequent C-H activation, an effect first observed
by Marder and coworkers.18a
aReactions carried out using 0.55 mmol of toluene in 1.0 mL hexanes. See SI for
complete experimental details. bReactions carried out using 0.55 mmol toluene
in 0.55 mL CPME. c20 mol % HBPin used to activate the catalyst. dYield after
chromatography on NEt3-deactivated silica.
Because 3 is prepared from abundant and inexpensive precursors
and offered improved handling, the scope of the benzylic diborylation
was explored with this cobalt precursor. Each catalytic reaction was
conducted with varying catalyst loadings of 3 at 100 ºC with a 1:2 ratio
of arene to B2Pin2 and four equivalents of HBPin with respect to [Co].
As reported in Scheme 3, a range of 3- and 4-substituted toluenes in-
cluding those containing amino, methoxy, silyl, alkyl and boryl groups
were tolerated by the reaction. Depending on the conditions used to
isolate the product, both mono- and diboronate esters were isolated. In
general, the isolated yields of the monoborylated products were higher
than the corresponding bis(boronate) esters due to the sensitivity of
the latter to protodeborylation, incomplete conversion, or tendency of
the products towards autoxidation.
Although conditions to favor exclusive monoborylation directly
from the Co-catalyzed reaction have thus far remained elusive, atten-
tion was devoted to the preparation of geminal-diboronate compounds
given their value in synthesis and the paucity of methods for their prep-
aration from direct C-H functionalization.27 Optimization with 2 re-
vealed that cyclopentyl methyl ether (CPME) was the preferred sol-
vent and resulted in 95% isolated yield of 5 after 24 hours at 100 ºC
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Journal of the American Chemical Society
isomers of the arene, the geminal-diboronate product is kinetically
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3
4
5
6
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8
preferred again demonstrating the activating effect of a [BPin] substit-
uent. Over the course of 96 hours, the formation of tri- and tetra-
borylated products were also observed along with the diborylated
products. Separation using column chromatography allowed isolation
of each of the individual components of the reaction mixture. The
tetraborylated products, 28 and 34, were characterized by X-ray dif-
fraction, confirming their identity (Scheme 3). Thus, the cobalt-
catalyzed method allows synthesis of di-, tri- and tetrasubstituted
boronate derivatives of xylenes by manipulation of reaction and isola-
tion conditions.
Scheme 3. Borylation of methylarenes and xylenes, isolation of
mono-, di-, tri- and tetraboronate products, and the solid state
structures (30% probablility ellipsoids, hydrogens except for ben-
zylic C-H omitted for clarity) of 28 and 34.
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Previous studies from our laboratory on alkene hydroboration have
demonstrated that α-diimine cobalt catalysts promote chain migration,
whereby alkyl isomerization is fast and C-B formation occurs preferen-
tially from primary cobalt alkyl intermediates to yield terminally func-
tionalized products from internal alkenes.23 Application of a similar
strategy to benzylic C-H borylation would provide a method for the
functionalization of remote, unactivated C(sp3)-H bonds in the ab-
sence of directing groups. The feasibility of this approach was demon-
strated with cumene wherein the presence of 50 mol % 3 and a 1:3:3
ratio of arene:B2Pin2:HBPin, a triboron product, 38, where the homo-
benzylic positions underwent C-H borylation, was isolated (Scheme
4). Mono- and disubstituted products also accompany formation of
38. This selectivity has only been observed previously with heteroge-
neous palladium catalysts, but required a large excess of arene due to
the low activity of the catalyst, and resulted in observation of only
monoborylated products.19
The cobalt-catalyzed method was also extended to other branched
alkylarenes to determine the scope of remote C(sp3)-H diborylation
(Scheme 4). With sec-butyl benzene, exposure to the catalytic condi-
tions resulted in isolation of 39, arising from selective diborylation of
the terminal homobenzylic position. The method also proved compat-
ible with silyl, boryl, and silyl ether functional groups at a terminal
position of the branched alkyl chain. To determine whether the origin
of the second borylation in these reactions could be due to the α-
[BPin] activating effect similar to that observed with toluene boryla-
tion, n-octyl-BPin and Me-BPin were used as substrates. No product
was observed at 50% cobalt loading in either case suggesting that ho-
mobenzylic diborylation likely results from a consecutive benzylic
activation/isomerization/borylation sequence. While catalyst loadings
are high, the combination of a readily available, inexpensive and trivial
to prepare α-diimine ligand with one of the least expensive sources of
cobalt to enable unprecedented polyfunctionalization of remote, unac-
tivated C(sp3)-H bonds is an attractive new strategy for the elaboration
of simple hydrocarbon precursors.
Scheme 4. Selective homobenzylic borylation of branched al-
kylarenes as a strategy for unactivated C-H functionalization.a
aIsolated yields. Reactions conducted with 0.55 mmol methylarene, 1.10 mmol
B2Pin2, 0.55 mL CPME at 100 ºC. Catalyst loadings and reaction times included
in parentheses. 4 equiv. of HBPin with respect to 3 was added. bIsolated yield of
aldehyde after oxidation with H2O2. c1.65 mmol B2Pin2 used. dYields after
chromatography on NEt3-deactived silica. eIsolated with 7% p-
dimethylaminobenzaldehyde impurity. fIsolated with 13% impurity of 4. gIsolat-
ed with 10% benzyl,homobenzyl-diboronate ester impurity (see SI for details).
hIsolated yields. Reactions conducted with 0.55 mmol xylene, 2.20 mmol B2Pin2,
i
0.55 mL CPME, 20 mol % 3, and 80 mol % HBPin at 100 ºC for 96 h. Isolated
from a separate reaction with 17% impurity of 30.
The cobalt-catalyzed borylation of ortho-, meta- and para-xylenes
highlights the versatility of the method (Scheme 3). With all three
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A. Borylation of cumene.a
PinB
PinB
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1
2
3
4
5
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8
BPin
50 mol % 3
300 mol % HBPin
35, 6%
PinB
36, 11%
BPin PinB
BPin
4 equiv B2Pin2
CPME, 100 ˚C, 120 h
1 equiv.
BPin
37, 15%
38, 15%b
BPin
R
9
B. Borylation of branched alkylarenes.c
PinB
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50 mol % 3
R
300 mol % HBPin
3 equiv B2Pin2
CPME, 100 ˚C, 120 h
1 equiv.
PinB
BPin
BPin
PinB
PinB
BPin
OTMS
Si
OTMS
39: 21%d
40: 30%d
PinB
BPin
BPin
OTBS
41: 19%d
42: 20%d
a Yields determined by NMR spectroscopy. Reaction conducted with 0.55 mmol
of cumene and 2.20 mmol B2Pin2 in 0.55 mL CPME. b13% isolated yield. cIso-
lated yields. Reactions conducted with 0.55 mmol of alkylarene and 1.65 mmol
B2Pin2 in 0.55 mL CPME.
In summary, a new cobalt-catalyzed method for the selective boryla-
tion of benzylic and unactivated C(sp3)-H bonds of alkylarenes has
been discovered that allows for the synthesis of polyfunctionalized
products from simple hydrocarbons. The catalysts are readily prepared
from abundant and inexpensive starting materials and provide direct
access to a valuable class of synthetic intermediates poised for use in
complex molecule synthesis.22 The mechanism of the reaction and the
origin of the unusual selectivity are currently under investigation.
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ASSOCIATED CONTENT
Supporting Information
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ence 2015, 349, 513-516.
Complete experimental details, characterization data of cobalt com-
plexes and of boronate ester products. This material is available free of
charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
pchirik@princeton.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
WNP acknowledges the National Science Foundation (CHE-
1265988) for financial support. JVO acknowledges the 2014-2015
Bristol-Myers Squibb Graduate Fellowship in Synthetic Organic
Chemistry and the Paul Maeder ’75 Fund for Energy and the Environ-
ment through the Andlinger Center for Energy and the Environment.
We thank Allychem for a generous gift of B2Pin2.
(19) Ishiyama, T.; Ishida, K.; Takagi, J.; Miyaura, N. Chem. Lett. 2001, 30,
1082-1083.
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