Nickel-catalyzed coupling reactions of alkyl electrophiles, including unactivated tertiary halides, to generate carbon-boron bonds

Article abstract of DOI:10.1021/ja304068t

Through the use of a catalyst formed in situ from NiBr₂? diglyme and a pybox ligand (both of which are commercially available), we have achieved our first examples of coupling reactions of unactivated tertiary alkyl electrophiles, as well as our first success with nickel-catalyzed couplings that generate bonds other than C-C bonds. Specifically, we have determined that this catalyst accomplishes Miyaura-type borylations of unactivated tertiary, secondary, and primary alkyl halides with diboron reagents to furnish alkylboronates, a family of compounds with substantial (and expanding) utility, under mild conditions; indeed, the umpolung borylation of a tertiary alkyl bromide can be achieved at a temperature as low as -10 °C. The method exhibits good functional-group compatibility and is regiospecific, both of which can be issues with traditional approaches to the synthesis of alkylboronates. In contrast to seemingly related nickel-catalyzed C-C bond-forming processes, tertiary halides are more reactive than secondary or primary halides in this nickel-catalyzed C-B bond-forming reaction; this divergence is particularly noteworthy in view of the likelihood that both transformations follow an inner-sphere electron-transfer pathway for oxidative addition.

Full text of DOI:10.1021/ja304068t

Article
pubs.acs.org/JACS
Nickel-Catalyzed Coupling Reactions of Alkyl Electrophiles, Including
Unactivated Tertiary Halides, To Generate Carbon−Boron Bonds
Alexander S. Dudnik and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
S
* Supporting Information
ABSTRACT: Through the use of a catalyst formed in situ from NiBr2·diglyme
and a pybox ligand (both of which are commercially available), we have
achieved our first examples of coupling reactions of unactivated tertiary alkyl
electrophiles, as well as our first success with nickel-catalyzed couplings that
generate bonds other than C−C bonds. Specifically, we have determined that
this catalyst accomplishes Miyaura-type borylations of unactivated tertiary,
secondary, and primary alkyl halides with diboron reagents to furnish
alkylboronates, a family of compounds with substantial (and expanding)
utility, under mild conditions; indeed, the umpolung borylation of a tertiary
alkyl bromide can be achieved at a temperature as low as −10 °C. The method
exhibits good functional-group compatibility and is regiospecific, both of which can be issues with traditional approaches to the
synthesis of alkylboronates. In contrast to seemingly related nickel-catalyzed C−C bond-forming processes, tertiary halides are
more reactive than secondary or primary halides in this nickel-catalyzed C−B bond-forming reaction; this divergence is
particularly noteworthy in view of the likelihood that both transformations follow an inner-sphere electron-transfer pathway for
oxidative addition.
catalyzed method that accomplishes Miyaura reactions of an
array of unactivated alkyl halides (eq 1); particularly note-
INTRODUCTION
■
Alkylboron compounds have a broad spectrum of applications,
ranging from cancer medicine (bortezomib, marketed as
Velcade by Millennium Pharmaceuticals)1 to organometallic
partners in cross-coupling reactions.2 Alkylboranes are most
often prepared via the hydroboration of olefins3 or the
transmetalation of highly reactive organolithium/organomag-
nesium reagents with electrophilic boron species.4 These
methods have significant limitations, such as a regioselectivity
issue in the case of hydroborations of many internal olefins and
functional-group incompatibility in the case of transmetalations.
During the past several years, we have endeavored to enlarge
the scope of cross-coupling reactions of alkyl electrophiles.5,6
Until now, we have focused our attention exclusively on C−C
bond-forming processes, establishing that an array of organo-
metallic reagents can be coupled efficiently with primary and
secondary (but not tertiary) electrophiles. We recently decided
to attempt to expand these coupling reactions to generate
bonds other than C−C bonds. In view of the need for
additional, complementary methods for the synthesis of
alkylboranes,7,8 we undertook the challenge of achieving
Miyaura borylations of unactivated alkyl electrophiles to
provide C−B bonds,9 a transformation that could enable
regiospecific and late-stage incorporation of boron into organic
molecules in an umpolung process.10
worthy is our observation that, for the first time for borylations
and for our studies of nickel catalysis, unactivated tertiary
electrophiles can serve as effective coupling partners.
RESULTS AND DISCUSSION
■
Although we were unable to obtain acceptable yields for nickel-
catalyzed C−B bond formation using a variety of methods that
we had developed for C−C bond formation,12 we determined
that, under the appropriate conditions, a nickel/pybox catalyst
can achieve the desired Miyaura borylation by pinB−Bpin (pin
= pinacolato = OCMe2Me2CO) of a wide array of electrophiles
at room temperature.13 Interestingly, in our previous studies of
Suzuki reactions of alkyl electrophiles, bidentate ligands (a
bipyridine, an aminoalcohol, or a 1,2-diamine) have always
At the time that we initiated this investigation, there were no
reports of such reactions; however, earlier this year, two groups
independently described copper catalysts that effect borylations
of unactivated primary and secondary alkyl electrophiles at room
temperature or above.11 In this report, we provide a nickel-
Received: April 27, 2012
Published: June 6, 2012
© 2012 American Chemical Society
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been optimal;14 tridentate pybox ligands have only proved to be
Table 2. Nickel-Catalyzed Borylation of Unactivated and
Activated Secondary Alkyl Halides (for Reaction Conditions,
See Table 1)
the ligand of choice for Negishi reactions.15
In the case of unactivated primary alkyl electrophiles,
bromides and iodides are suitable coupling partners (Table 1,
Table 1. Nickel-Catalyzed Borylation of Unactivated and
Activated Primary Alkyl Halides
a
b
Yield of purified product (average of two experiments). Yield
determined by GC analysis versus a calibrated internal standard.
entries 1 and 2). On the other hand, the corresponding
chlorides and tosylates are not effectively borylated under these
conditions (<10% yield), although activated chlorides couple
with the diboron reagent with useful efficiency (entries 3 and
4).16 Both of the catalyst components, NiBr2·diglyme and
pybox ligand 1, are commercially available and can be handled
in the air.
Many primary alkylboranes can be synthesized conveniently
via existing methods that have acceptable functional-group
compatibility, such as the hydroboration of olefins. Unfortu-
nately, hydroboration is a less-effective approach in the case of
most secondary alkylboranes, due to the generation of
regioisomers (e.g., consider the products of Table 2, entries
1−3 and 6−10). This issue is circumvented when a Miyaura
borylation strategy is employed instead. Thus, NiBr2·diglyme/
pybox 1 catalyzes the room-temperature coupling of pinB−
Bpin with unactivated alkyl iodides (Table 2, entries 1 and 2)
and bromides (entries 3−10) to furnish the desired secondary
alkylboranes in good yield.17 A variety of functional groups,
including an olefin, a carbamate, an aniline, an amide, and a
sulfonamide, are compatible with this method. Under the
standard conditions, borylations of activated, but not
unactivated, secondary chlorides proceed smoothly (entries
11 and 12). Our nickel-catalyzed method is not limited to the
use of pinB−Bpin as the borylating agent (eq 2).18
a
b
Yield of purified product (average of two experiments). Diaster-
c
eoselectivity, 3:1 β:α. Starting material, 97:3 Z:E; product, 95:5 Z:E.
d
Reaction conditions: see Table 3.
Although we have reported progress in the development of
nickel-based catalysts for cross-coupling primary and secondary
alkyl electrophiles with a range of organometallic nucleophiles,
we have not described any success with tertiary electrophiles.
Correspondingly, the recent copper-catalyzed Miyaura bor-
ylation methods of Steel/Marder/Liu11a and Ito11b have not
proved applicable to tertiary electrophiles (two examples: 0%
yield and 17% yield). We were therefore pleased to determine
that NiBr2·diglyme/pybox 1 catalyzes not only the borylation of
primary (Table 1) and secondary (Table 2), but also tertiary
(Table 3), halides.
As illustrated in Table 3,19 nickel-catalyzed borylation of
unactivated tertiary alkyl iodides furnishes the desired tertiary
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Table 3. Nickel-Catalyzed Borylation of Unactivated
Tertiary Alkyl Halides
Figure 1. Nickel-catalyzed C−B bond formation: more substituted
electrophiles are more reactive.
a nickel/pybox-catalyzed Negishi cross-coupling (Figure 2).20
In the case of this C−C bond-forming process, we observe
a
b
Yield of purified product (average of two experiments). Diaster-
Figure 2. Nickel-catalyzed C−C bond formation: a tertiary halide is
unreactive.
eoselectivity, 11:1 cis:trans.
alkylboranes in good-to-modest yields (entries 1 and 2).
Couplings of cyclic (entries 3−5) and acyclic (entries 6−9)
bromides proceed smoothly in the presence of an array of
functional groups, including an ether, an ester, an alkyl chloride,
and an olefin. Good diastereoselectivity is observed in a
Miyaura reaction of a substituted cyclohexane (11:1; entry 4).
Remarkably, the borylation of a tertiary alkyl bromide can be
achieved in excellent yield at −10 °C (eq 3), the lowest
essentially no product derived from reaction of the tertiary alkyl
bromide, and there is a modest preference for coupling a
primary, rather than a secondary, bromide.
For our nickel-catalyzed cross-coupling reactions, we have
hypothesized that the mechanism outlined in Figure 3 is
operative when unactivated alkyl halides are employed as
electrophiles.5a,21−23 If our Miyaura borylations (Tables 1−3)
temperature that we have employed to date for a nickel-
catalyzed coupling of any unactivated alkyl halide. None of
these tertiary alkylboranes can be accessed via olefin hydro-
boration.
Intrigued by our ability to couple tertiary alkyl halides for the
first time, we examined the relative rates of product formation
in a series of competition experiments between a tertiary, a
secondary, and a primary alkyl bromide (Figure 1).
Interestingly, the more substituted the alkyl bromide, the
more borylation product was formed.
These results are even more striking when contrasted with
the data for a corresponding set of competition experiments for
Figure 3. Outline of a possible mechanism for nickel-catalyzed
coupling reactions.
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proceed through an analogous pathway, then the difference in
reactivity as a function of nucleophile (boron- vs carbon-based
in Figures 1 vs 2) may be attributable to the disparate reaction
profiles of intermediates G, H, and/or I as a function of Nu.24
In the case of nickel-catalyzed C−C bond-forming reactions
of unactivated alkyl halides, all of the data that we have
accumulated to date are consistent with an inner-sphere
electron-transfer pathway for oxidative addition (Figure 3).
For our Miyaura borylations, our observations are also most
consistent with a radical (versus an SN2 or a direct-insertion)
mechanism. For example, the enhanced reactivity with greater
substitution illustrated in Figure 1 can be rationalized by a
radical pathway wherein the stability of R• (see H in Figure 3)
plays a key role in determining the course of the reaction.
Furthermore, borylation of either exo- or endo-2-bromonorbor-
nane provides the exo product with >20:1 diastereoselectivity
(eq 4).
CONCLUSIONS
■
We have developed a readily available nickel catalyst that
achieves the room-temperature Miyaura borylation of a diverse
set of alkyl electrophiles, including the first effective couplings
of tertiary halides (at a temperature as low as −10 °C). This
umpolung process displays good functional-group compatibility
and enables the regiospecific generation of a wide array of
alkylboranes, a family of compounds with substantial and
growing utility, thereby addressing key shortcomings of
traditional methods for their synthesis. Mechanistic inves-
tigations reveal that this nickel-catalyzed C−B bond-forming
process exhibits a reactivity profile (tertiary > secondary >
primary halide) distinct from seemingly related nickel-catalyzed
C−C bond-forming reactions (tertiary < secondary, primary
halide); yet, a range of observations are consistent with a
common pathway for oxidative addition of the alkyl halide to
nickel (inner-sphere electron transfer). Additional studies of
nickel-catalyzed couplings of alkyl electrophiles, including new
reactions of tertiary electrophiles, couplings with other non-
carbon-based nucleophiles, and enantioselective transforma-
tions, are underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
For an inner-sphere electron-transfer pathway for oxidative
addition, the anticipated order of reactivity as a function of the
leaving group is I > Br > Cl > OTs. Consistent with this,
unactivated alkyl chlorides and tosylates are unreactive under
our standard borylation conditions (vide supra). In the case of
corresponding alkyl iodides and bromides, product formation
proceeds at qualitatively similar rates; we have made analogous
observations for nickel-catalyzed Suzuki reactions, likely due to
transmetalation (not oxidative addition) being the turnover-
limiting step of the catalytic cycle.25 To gain insight into the
relative reactivity of the halides in our Miyaura borylations, we
conducted competition experiments between pairs of electro-
philes. As illustrated in Figure 4, the nickel/pybox catalyst
reacts with a high preference for an alkyl iodide in the presence
of a bromide, as well as an alkyl bromide in the presence of a
chloride, consistent with the expectations for an inner-sphere
electron-transfer mechanism for oxidative addition.26−28
AUTHOR INFORMATION
Corresponding Author
gcf@mit.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support has been provided by the National Institutes of Health
(National Institute of General Medical Sciences, grant R01-
GM62871). We thank Dr. Ashraf Wilsily for experimental
assistance.
REFERENCES
■
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Figure 4. Nickel-catalyzed C−B bond formation. Relative reactivity as
a function of the halide.
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(27) Use of a stereochemical probe (see ref 14b) provided results
fully consistent with a radical intermediate in our nickel-catalyzed
Miyaura borylations of unactivated alkyl electrophiles. Thus, both of
the secondary bromides underwent cyclization/borylation to furnish
the same ratio of diastereomers as observed for reductive cyclizations
with Bu3SnH, consistent with a common intermediate for the two
processes (a secondary alkyl radical that adds to the pendant olefin).
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(13) Under the conditions employed in Tables 1−3, in the absence
of NiBr2·diglyme, no borylation (<1% yield) of unactivated primary,
secondary, or tertiary halides was observed.
(14) For example, see: (a) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004,
́
126, 1340−1341. (b) Gonzalez-Bobes, F.; Fu, G. C. J. Am. Chem. Soc.
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125, 14726−14727. (b) Reference 5b.
(16) Under the same conditions, borylations of a primary allylic and a
primary benzylic bromide were not efficient.
(17) Notes: (a) Under the standard conditions: when a borylation
was conducted in a capped vial under an atmosphere of air, the yield of
the product was unaffected; the addition of 0.10 equiv of water led to a
small (5%) decrease in yield; use of TBME, CPME, Et2O, or DME as
the solvent led to a somewhat lower yield (Table 2, entry 3: 66−85%);
functional groups such as a TIPS-substituted alkyne, an enolizable
ketone, an aryl fluoride, and a trifluoromethyl group were compatible
with the borylation process, whereas a nitro group and an aryl iodide
were not; a highly hindered unactivated secondary bromide (t-
BuCHBrCH2CH2Ph), an unactivated secondary chloride, an unac-
tivated secondary tosylate, and an activated secondary bromide ((1-
bromoethyl)benzene) were not suitable coupling partners; for the
coupling illustrated in entry 3 of Table 2, use of 2.5% NiBr2·diglyme/
3.3% ligand 1 provided the product in 85% yield, whereas use of 1.0%
NiBr2·diglyme/1.3% ligand 1 furnished the alkylboronate in 69% yield;
in the case of entry 2 of Table 2, use of the enantiomer of ligand 1 led
to a 2:1 (β:α) mixture of diastereomers. (b) The Brønsted basicity of
the reaction medium is substantially attenuated by complexation of the
alkoxide to boron; thus, when enantioenriched 1,2-diphenylbutan-1-
one was added to a borylation process, it could be recovered at the end
of the reaction in essentially quantitative yield (>95%) and with little
erosion in ee (<10%; complete racemization occurs in the absence of
pinB−Bpin).
(18) Under our standard borylation conditions, use of pinacolborane
instead of pinB−Bpin did not generate a significant quantity of the
desired product.
(19) Under the standard conditions: the catalytic borylation
illustrated in entry 6 of Table 3 proceeded in 70% yield on a gram
scale, whereas use of 5% NiBr2·diglyme/6.6% ligand 1 furnished a 56%
yield on a gram scale; if TBME, CPME, Et2O, or DME was employed
as the solvent, a significantly lower yield was observed; an unactivated
tertiary chloride, an activated tertiary chloride, and a highly hindered
tertiary alkyl bromide were not useful coupling partners.
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