Reductive cross-coupling of 3-bromo-2,1-borazaronaphthalenes with alkyl iodides

Article abstract of DOI:10.1021/ol501495d

Conditions have been developed for the reductive cross-coupling of 3-bromo-2,1-borazaronaphthalenes with primary and secondary alkyl iodides. This method allows direct alkylation of azaborine cores, providing efficient access to functionalized isosteres o

Full text of DOI:10.1021/ol501495d

Letter
pubs.acs.org/OrgLett
Reductive Cross-Coupling of 3‑Bromo-2,1-borazaronaphthalenes
with Alkyl Iodides
Gary A. Molander,* Steven R. Wisniewski,† and Kaitlin M. Traister†
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia,
Pennsylvania 19104-6323, United States
S
* Supporting Information
ABSTRACT: Conditions have been developed for the
reductive cross-coupling of 3-bromo-2,1-borazaronaphthalenes
with primary and secondary alkyl iodides. This method allows
direct alkylation of azaborine cores, providing efficient access
to functionalized isosteres of naphthalene derivatives.
zaborines represent a class of molecules that bear a B−N
bond in place of a CC unit within an aromatic ring.
This method allowed aryl and heteroaryl substrates to be
successfully introduced to the ring system, but the path forward
to install a variety of alkyl substituents at this position was
unclear. Thus, although alkyl cross-coupling methods held
some promise as a means to extend elaboration of the borazines
at the 3-position, a primary goal was to demonstrate the
incorporation of diverse alkyl substructures, and limitations on
both the availability of the requisite organometallic starting
materials and concerns about conversions in such cross-
coupling reactions appeared daunting. Specifically, we sought
the installation of saturated, heterocyclic ring systems, which
are highly valued as moieties that possess nonplanar character,
while allowing incorporation of hydrogen-bonding heteroa-
toms.4 Methods to insert these nonaromatic heterocycles onto
aryl systems through typical sp2−sp3 cross-coupling methods
have proven quite ineffective, yielding little to none of the
desired products.5 Consequently, we pursued a more direct
pathway for the efficient introduction of alkyl substituents onto
the azaborine core.
A
These molecules possess aromaticity and stability similar but
not identical to their corresponding all-carbon analogues. 2,1-
Borazaronaphthalenes have received a significant amount of
attention because of their potentially impactful properties in the
fields of pharmaceuticals and materials science.1
Having developed a general and convenient route for the
construction of the 2,1-borazaronaphthalene core from 2-
aminostyrene derivatives,2 we sought methods for the selective
installation of various substituents about the assembled ring.
For placement of substituents at the 3-position, the utilization
of substituted alkenes of the styrene starting material failed to
provide useful quantities of the desired target structures (eq 1).
Based on the stability of 2,1-borazaronaphthalenes to
palladium catalysis, a metal-promoted reductive cross-coupling
pathway6 for the introduction of alkyl halides onto 2,1-
borazaronaphthalenes was envisioned. Weix et al.7 and Gong et
al.8 have carried out extensive work in the area of reductive
cross-couplings in the past decade, illustrating the ability to
introduce alkyl halides to aromatic halides under Ni-catalyzed
conditions. Recently, application of modified conditions based
on these investigations that allow the reductive cross-coupling
of nonaromatic heterocyclic bromides with aryl and heteroaryl
bromides was reported (Scheme 2).9 We sought to extend a
parallel coupling to 3-bromo-2,1-borazaronaphthalene systems,
which we anticipated would react in a similar fashion with alkyl
bromides.
Consequently, another approach, selective halogenation at
the 3-position followed by substitution, was developed. The
halogenation of 2,1-borazaronaphthalenes was first reported by
Dewar in 1961 and was shown to be selective for reaction at the
C-3 position, although yields were modest and the scope of the
process was not extensively explored.3 More recent progress on
the functionalization of 2,1-borazaronaphthalenes was achieved
through modified conditions for the bromination, combined
with subsequent Pd-catalyzed cross-coupling of 2,1-borazar-
onaphthalenes (Scheme 1).2
Scheme 1. Bromination and Suzuki−Miyaura Cross-
Coupling of 2-Phenyl-2,1-borazaronaphthalenes
Investigation into the reactivity of 3-bromo-2,1-borazaro-
naphthalenes under reductive coupling conditions was begun
using 3-bromo-2-phenyl-2,1-borazaronaphthalene in the pres-
Received: May 23, 2014
© XXXX American Chemical Society
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Scheme 2. Reductive Cross-Coupling of Aryl Bromides with
Non-aromatic Heterocyclic Bromides
Table 1. Optimization of Cross-Coupling Conditions
a
entry
modification
P/IS
1
2
3
4
5
6
7
8
none
2.78
2.58
2.07
3.10
2.51
2.65
2.61
2.75
temp = rt
1:1 cyclohexane/MeOH
2:1 cyclohexane/DMA
2:1 DMA/cyclohexane
anhydrous, degassed solvent
1.0 equiv of Alk-I
ence of N-Boc-4-bromopiperidine. Under the conditions
recently developed for the reductive coupling of nonaromatic
heterocyclic bromides with aryl bromides,9 a 44% yield of the
desired product was obtained (Scheme 3). The major side
product observed was protodehalogenation of the azaborine.
5 mol % of Ni, 5 mol % of L
a
Ratio of product to internal standard.
Scheme 3. Reductive Coupling of N-Boc-4-bromopiperidine
with 3-Bromo-2-phenyl-2,1-borazaronaphthalene
substituents on boron were also tolerated under the reaction
conditions (entries 8−10). We were delighted to see that N-
substituted systems reacted under the developed conditions
(entries 11−13). An allyl substitution on nitrogen is not
cleaved during the coupling, demonstrating the inherent
aromaticity and stability of 2,1-borazaronaphthalenes.
The developed method was next extended to the cross-
coupling of 3-bromo-2-phenyl-2,1-borazaronaphthalene with a
variety of alkyl iodides (Table 3). Other nonaromatic
heterocyclic iodides were successfully cross-coupled, including
azetidine, tetrahydropyran, tetrahydrofuran, and oxetane
systems (entries 1−5). The scalable nature of the couplings
was demonstrated by carrying out the reaction of 3-bromo-2-
phenyl-2,1-borazaronaphthalene with N-Boc-3-iodoazetidine
on a 3.0 mmol scale (2.5 mol % of Ni, decreased from 5 mol
% of Ni on a 0.5 mmol scale) without a decrease in yield (entry
2). The method was further extended to show application to
non-heteroatom-containing alkyl iodides, and both secondary
and primary alkyl iodides were readily cross-coupled (entries
6−8). Attempts to employ tertiary alkyl iodides or sterically
hindered secondary alkyl iodides (e.g., 2-iodoadamantane)
resulted in low conversion to product (less than 20%).
Optimization on this system was begun by testing several
bipyridine ligands, and the use of 4,4′-dimethyl-2,2′-bipyridine
led to increased conversion to the desired product. Employing
1 equiv of 4-ethylpyridine (from 0.5 equiv) decreased the
amount of observed protodehalogenation of the azaborine.
Several inorganic salts were tested as additives (e.g., MgCl2,
CsI, LiCl, ZnBr2, KBF4, NaI), but NaBF4 led to markedly
cleaner reactions than the other salts explored. The use of N-
Boc-4-iodopiperidine in place of the corresponding bromide
allowed the reaction to be carried out at 40 °C, and the
formation of side products was significantly diminished. Various
polar solvents were tested under the reaction conditions, and it
was determined that both MeOH and DMA served as good
reaction solvents in combination with nonpolar cosolvents. The
best solvent combinations were mixtures of either DMA or
MeOH with cyclohexane, and variation of the ratios of these
solvent combinations showed that a 2:1 cyclohexane/DMA
mixture was optimal (Table 1). Reduction of the amount of
alkyl iodide to 1 equiv (from 1.2 equiv) was detrimental to the
reaction, as was lowering the temperature below 40 °C. The use
of anhydrous, degassed solvents was determined to be
unnecessary, allowing the coupling to be conducted in solvents
that did not require degassing or drying prior to use. Lowering
the catalyst loading from 10 to 5 mol % Ni did not decrease the
conversion to any significant extent.
To demonstrate the applicability of this method toward
alkylation of azaborine cores at another position, N-Boc-4-
iodopiperidine was cross-coupled with 6-bromo-2-methyl-3-
phenyl-2,1-borazaronaphthalene (eq 2). The reaction pro-
With optimized conditions in hand, the reductive cross-
coupling of N-Boc-4-iodopiperidine was carried out with a
variety of 3-bromo-2,1-borazaronaphthalenes (Table 2). The
reaction conditions were amenable to the incorporation of
various aromatic moieties on boron, including fluoro-,
methoxy-, and carbomethoxy-substituted phenyl rings (entries
2−5). Sterically hindered B-heterocyclic 2,1-borazaronaphtha-
lenes were successfully engaged in the reaction, such that the
dibenzofuran and dibenzothiophene systems afforded the cross-
coupled products in high yield (entries 6 and 7). Alkyl
ceeded in 51% yield without any change in the developed
conditions, illustrating the potential for this method to be
extended beyond 3-bromo-2,1-borazaronaphthalene systems.
In conclusion, a method has been developed for the
reductive cross-coupling of 3-bromo-2,1-borazaronaphthalenes
with alkyl iodides. The method allows the coupling of azaborine
cores bearing aryl or alkyl substituents on boron and also
tolerates alkyl substitution on nitrogen. Primary and secondary
alkyl iodides, including an important class of nonaromatic
heterocycles, are capable of reacting under the developed
B
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Table 2. Reductive Cross-Coupling of N-Boc-4-
iodopiperidine with Various Azaborines
Table 3. Reductive Cross-Coupling of 3-Bromo-2-phenyl-
2,1-borazaronaphthalene with Various Alkyl Iodides*
a
*
Reactions performed on 0.5 mmol scale unless otherwise noted.
a
b
Reaction carried out at 50 °C. 3.0 mmol scale; modification to
reaction conditions: 2.5 mol % of NiCl2·glyme, 2.5 mol % of 4,4′-
dimethyl-2,2′-bipyridine.
conditions. This method provides a valuable, direct route to
alkylated, functionalized azaborine systems.
ASSOCIATED CONTENT
* Supporting Information
■
S
Complete experimental procedures and characterization data
(1H, 13C, 11B NMR, IR, mp, HRMS). This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: gmolandr@sas.upenn.edu.
Author Contributions
†These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This research was supported by the NIGMS (R01 GM-081376)
and Eli Lilly. Frontier Scientific is acknowledged for their
■
a
Reactions performed on 0.5 mmol scale unless otherwise noted.
C
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generous donation of potassium organotrifluoroborates. Dr.
Rakesh Kohli (University of Pennsylvania) is acknowledged for
acquisition of HRMS spectra.
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