Nickel-catalyzed carbon-carbon bond-forming reactions of unactivated tertiary alkyl halides: Suzuki arylations

Article abstract of DOI:10.1021/ja311669p

The first Suzuki cross-couplings of unactivated tertiary alkyl electrophiles are described. The method employs a readily accessible catalyst (NiBr₂·diglyme/4,4′-di-tert-butyl-2,2′-bipyridine, both commercially available) and represents the initial example of the use of a group 10 catalyst to cross-couple unactivated tertiary electrophiles to form C-C bonds. This approach to the synthesis of all-carbon quaternary carbon centers does not suffer from isomerization of the alkyl group, in contrast with the umpolung strategy for this bond construction (cross-coupling of a tertiary alkylmetal with an aryl electrophile). Preliminary mechanistic studies are consistent with the generation of a radical intermediate along the reaction pathway.

Full text of DOI:10.1021/ja311669p

Communication
pubs.acs.org/JACS
Nickel-Catalyzed Carbon−Carbon Bond-Forming Reactions
of Unactivated Tertiary Alkyl Halides: Suzuki Arylations
Susan L. Zultanski†,‡ and Gregory C. Fu*,†,‡
†Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
‡Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States
S
* Supporting Information
ABSTRACT: The first Suzuki cross-couplings of unac-
tivated tertiary alkyl electrophiles are described. The method
employs a readily accessible catalyst (NiBr2·diglyme/4,4′-
di-tert-butyl-2,2′-bipyridine, both commercially available)
and represents the initial example of the use of a group
10 catalyst to cross-couple unactivated tertiary electrophiles
to form C−C bonds. This approach to the synthesis of
all-carbon quaternary carbon centers does not suffer from
isomerization of the alkyl group, in contrast with the
umpolung strategy for this bond construction (cross-
coupling of a tertiary alkylmetal with an aryl electrophile).
Preliminary mechanistic studies are consistent with the
generation of a radical intermediate along the reaction
pathway.
employed organo-substituted 9-borabicyclo[3.3.1]nonane (9-BBN)
reagents (in conjunction with an alkoxide activator) as partners in
an array of Ni-catalyzed Suzuki couplings of primary and secondary
electrophiles,9 and we have further established that the conditions
uring the past decade, substantial progress has been
Daccomplished in the development of metal-catalyzed
focused on couplings of primary and secondary electrophiles; in
contrast, there have been only isolated examples of successful
reactions with unactivated tertiary electrophiles. In particular,
Oshima has described cross-couplings with indenyllithium (Ag
catalyst), cyclopentadienylmagnesium (Cu), benzylmagnesium
(Ag), allylmagnesium (Co, Cu, and Ag), and allyl- and benzylzinc
(Ag) reagents.3
The difficulty in coupling tertiary alkyl electrophiles can be
attributed to a variety of factors, including a low propensity
to undergo oxidative addition via an SN2 or a direct-insertion
pathway. We and others have demonstrated that, for an array of
Ni-catalyzed cross-coupling reactions of unactivated primary
and secondary alkyl halides, oxidative addition likely proceeds
through an inner-sphere electron-transfer pathway.4−6 In view
of the relative stability of tertiary radicals, this mechanism could
be conducive to reactions of tertiary alkyl electrophiles. Indeed,
we recently established that carbon−boron bond formation can
be achieved by coupling tertiary halides with diboron reagents.7
In this report, we expand the scope of cross-coupling reactions
of unactivated tertiary alkyl electrophiles by describing the first
method for accomplishing carbon−carbon bond formation with
the aid of a group 10 catalyst (eq 1).
are not highly Brønsted-basic, because of complexation of the
alkoxide to the trivalent borane.4 The propensity of many tertiary
cross-coupling reactions of alkyl electrophiles with organo-
metallic reagents to form C−C bonds.1,2 Nearly all reports have
alkyl electrophiles to undergo elimination under basic or acidic
conditions is a significant impediment to cross-coupling this family
of reaction partners.
When we applied our recently reported method for Ni-
catalyzed carbon−boron bond formation with tertiary alkyl
bromides to a corresponding Suzuki cross-coupling, we
observed essentially no C−C bond formation (eq 2). Similarly,
the conditions that we had developed for Suzuki arylations of
primary and secondary alkyl bromides were not effective for
tertiary bromides (<2% yield).10
Notwithstanding this result, we continued our pursuit of a
method for the synthesis of all-carbon quaternary centers via
the cross-coupling of unactivated tertiary halides. In view of the
steric demand of tertiary electrophiles, we chose to focus on
the use of smaller ligands. Ultimately, we determined that a Ni
complex with the ligand 4,4′-di-tert-butyl-2,2′-bipyridine (1)
serves as an effective catalyst for the coupling of 1-bromo-1-
methylcyclohexane with phenyl-(9-BBN), furnishing the target
compound in 88% yield (Table 1, entry 1). A variety of bioactive
compounds, including oxycodone (OxyContin),11 include an
all-carbon quaternary center with one aryl substituent.
As illustrated in Table 1, in the absence of NiBr2·diglyme,
ligand 1, or LiOt-Bu, little or no Suzuki cross-coupling of
the unactivated tertiary alkyl bromide occurs (entries 2−4).
Early in this investigation, we decided to focus on organo-
boron reagents as coupling partners for two primary reasons.
First, the Suzuki reaction is the most widely used cross-coupling
method for the formation of C−C bonds.8 Second, we have
Received: November 29, 2012
© XXXX American Chemical Society
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dx.doi.org/10.1021/ja311669p | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 2. Suzuki Cross-Couplings of Unactivated Tertiary
Alkyl Bromides: Scope with Respect to the Electrophile
Table 1. Suzuki Arylation of an Unactivated Tertiary Alkyl
Bromide: Effect of the Reaction Parameters
a
b
Yields of purified products (averages of two experiments). Because of
the volatility of the product, the yield in parentheses was determined
by GC analysis with the aid of a calibrated internal standard.
are suitable substrates (entries 1 and 2), as is 3-bromo-3-
ethylpentane, which is significantly more hindered (entry 3).
Furthermore, a tertiary cyclobutyl bromide can be cross-coupled
(entry 4). Importantly, functional groups such as an aromatic
ring, ether, alkene, and primary alkyl chloride are compatible
with this method for Suzuki cross-coupling of tertiary alkyl
bromides (entries 5−8).
Although this method for cross-coupling of unactivated
tertiary alkyl halides is versatile with respect to the electrophile
(Table 2), it has limitations with respect to the nucleophile
(Table 3).13 Specifically, ortho- and para-substituted aryl-(9-
BBN) reagents generally do not couple in useful yields; on the
other hand, a range of meta-substituted compounds serve as
suitable Suzuki cross-coupling partners. Fortunately, this set
of products is particularly useful, since they are not available
through direct Friedel−Crafts alkylation.
a
The yields were determined by GC analysis versus a calibrated
b
internal standard and are averages of two experiments. 1.7 LiOt-Bu,
1.7 i-BuOH.
The use of 2,2′-bipyridine (2) or bathophenanthroline (3)10a
rather than 1 as the ligand leads to a somewhat lower yield
(entries 5 and 6). For every other Ni-catalyzed Suzuki reaction
of 9-BBN reagents that we have described (couplings of
primary and secondary electrophiles), a 1,2-diamine was the
ligand of choice;9 however, this is not the case for this Suzuki
cross-coupling of a tertiary alkyl electrophile (entry 7). The
counterion of the base plays a critical role in the efficiency of the
coupling process (entry 8). C−C bond formation proceeds in
lower yield in solvents such as toluene, cyclohexane, and Et2O
(entries 9−11), and the use of less organoborane or less catalyst
leads to less product (entries 12 and 13). Finally, the cross-
coupling is not highly moisture-sensitive (entry 14).
1-Iodoadamantane can also be cross-coupled, generating
1-aryladamantanes, a motif found in a number of pharmaceut-
icals (eq 3).14−16 Furthermore, in a preliminary study, we
determined that C−C bond formation can be achieved with an
unactivated tertiary alkyl chloride as the electrophile (eq 4;
yield determined by GC analysis).16
A possible mechanism for this Ni-catalyzed Suzuki cross-
coupling, illustrated for the reaction of 1-bromo-1-methyl-
cyclohexane with Ph-(9-BBN), is provided at the top of Figure
1.4−6 As with our couplings of unactivated secondary alkyl
halides, our initial mechanistic observations are consistent with
a radical pathway for the oxidative addition of an unactivated
tertiary halide to Ni. For example, when we conducted a Suzuki
reaction in toluene rather than benzene, we obtained a signifi-
cant amount of diphenylmethane (eq 5), likely due to H-atom
abstraction from toluene by radical B to form a benzyl radical,
which then enters the catalytic cycle (bottom of Figure 1).
We established that this method can be applied to Suzuki
reactions of an array of unactivated tertiary alkyl bromides,
generating the desired C−C bond in good yield (Table 2).12
Thus, both 1-bromo-1-methylcyclohexane and tert-butyl bromide
B
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Journal of the American Chemical Society
Communication
Table 3. Suzuki Cross-Couplings of Unactivated Tertiary
Alkyl Bromides: Scope with Respect to the Nucleophile
a
Yields of purified products (averages of two experiments).
Figure 1. (top) Outline of a possible mechanism for the Ni/
1-catalyzed Suzuki cross-coupling of an unactivated tertiary alkyl
bromide. (bottom) Possible pathway for the formation of diphenyl-
methane when toluene is employed as the solvent (the early steps of
the catalytic cycle are as illustrated at the top and have been omitted
for simplicity).
first example of the use of organoboron reagents as cross-
coupling partners with unactivated tertiary electrophiles as well
as the first to employ a group 10 catalyst in cross-couplings of
unactivated tertiary alkyl halides to form C−C bonds. In
contrast with the umpolung approach to this bond construction
(coupling of a tertiary organometallic reagent with an aryl
halide), our method does not suffer from isomerization of the
alkyl group.17 Preliminary observations are consistent with a
radical intermediate along the pathway of this new cross-
coupling process. Additional studies directed at expanding the
scope of this reaction and enhancing our understanding of the
mechanism are underway.
Furthermore, a Ni-catalyzed Suzuki reaction of a single
diastereomer of a tertiary alkyl bromide leads to the formation
of a mixture of diastereomeric cross-coupling products (eq 6).
This observation can also be accommodated by a radical
pathway for oxidative addition.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
In conclusion, we have developed a method for Suzuki aryla-
tion of tertiary alkyl bromides, using commercially available
catalyst components (NiBr2·diglyme and 4,4′-di-tert-butyl-2,2′-
bipyridine). To the best of our knowledge, this reaction is the
AUTHOR INFORMATION
Corresponding Author
gcfu@caltech.edu
■
C
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Journal of the American Chemical Society
Communication
bromoadamantane, and an acyclic tertiary iodide were not suitable
cross-coupling partners; (c) PhBpin, PhB(OH)2, and PhBF3K did not
afford significant amounts of coupling product (<5% yield).
(13) Several other meta-substituted aryl-(9-BBN) reagents, including
several halogenated compounds, were not effective coupling partners.
(14) Adapalene (Differin) is an example of a pharmaceutical that
includes a 1-aryladamantane.
(15) For a review of the use of the adamantyl group in medicinal
chemistry, see: Lamoureux, G.; Artavia, G. Curr. Med. Chem. 2010, 17,
2967.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support was provided by the National Institutes of Health
(National Institute of General Medical Sciences, R01-
GM62871) and Merck Research Laboratories (summer fellow-
ship for S.L.Z.). We thank Dr. Alexander S. Dudnik for
preliminary observations.
(16) Essentially no cross-coupling product was observed in the
absence of NiBr2·diglyme.
(17) For two recent advances and leading references, see: (a) Joshi-
Pangu, A.; Wang, C.-Y.; Biscoe, M. R. J. Am. Chem. Soc. 2011, 133,
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D
dx.doi.org/10.1021/ja311669p | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX