Accessing Elaborated 2,1-Borazaronaphthalene Cores Using Photoredox/Nickel Dual-Catalytic Functionalization

Article abstract of DOI:10.1021/acs.orglett.6b00466

A highly effective method for derivatizing 2,1-borazaronaphthalene cores using ammonium alkylbis(catecholato)silicates via photoredox/nickel dual catalysis is reported. By forging C_sp³-C_sp² bonds via this approa

Full text of DOI:10.1021/acs.orglett.6b00466

Letter
pubs.acs.org/OrgLett
Accessing Elaborated 2,1-Borazaronaphthalene Cores Using
Photoredox/Nickel Dual-Catalytic Functionalization
Matthieu Jouffroy, Geraint H. M. Davies, and Gary A. Molander*
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: A highly effective method for derivatizing 2,1-
borazaronaphthalene cores using ammonium alkylbis-
(catecholato)silicates via photoredox/nickel dual catalysis is
2
reported. By forging Csp3−Csp bonds via this approach, alkyl
fragments with various functional groups can be introduced to
the azaborine core, affording previously inaccessible hetero-
cyclic isosteres in good to excellent yields. The base-free,
room-temperature conditions outlined allow sensitive func-
tional group tolerance, even permitting the cross-coupling of
unprotected primary and secondary amines.
2
zaborines are boron-, nitrogen-, and carbon-containing
heteroaromatic compounds that have been recognized as
reaction manifold has allowed the formation of Csp3−Csp
bonds between benzylic,11a,13 secondary alkyl,12a,13 primary
alkyl,13 α-alkoxy,11d,12a,f and α-amino11b,12c,d,f Csp3-hybridized
radical precursors with a variety of (hetero)aryl and/or alkenyl
halide electrophiles. These radical precursors are oxidizable
species such as organotrifluoroborates, carboxylic acids, and
alkylsilicates. The latter, specifically ammonium alkylbis-
(catecholato)silicates,13a,b represent practical, highly versatile
radical precursors because of their low oxidation potentials, the
innocuous byproducts generated during single electron transfer
(SET)-mediated fragmentation, and the near-neutral reaction
conditions. Taken together, photoredox/Ni dual catalysis
employing ammonium alkylsilicates offers a cross-coupling
approach that possesses excellent functional group tolerance
and ease of operation.13a,b With this newly developed paradigm
in mind and the goal of accessing more highly elaborated and
functionalized 2,1-borazaronaphthalene cores, we assessed
whether these substrates were amenable to this means of
A
viable isosteric species for aryl and heteroaryl cores.1 The B−N
bond serves as a replacement for a CC bond in arenes, and
substitution in this manner affords molecules having similar, but
not identical, electronic and steric properties.2 Consequently,
B−N/CC isosterism has attracted the attention of medicinal
chemists because it allows the introduction of structural and
electronic variety to existing drug templates and may enhance
the potency of biologically active molecules, leading to new
therapeutics.3
Recently, we developed a rapid synthetic route to 2,1-
borazaronaphthalenes,4 in addition to methods for further
elaborating the structural diversity of these cores.5 Post-
annulation modifications included nucleophilic substitution of
2-(chloromethyl)-2,1-borazaronaphthalene (Scheme 1a)6 and
various Pd-catalyzed functionalization processes (Scheme 1b).7
Additionally, alkyl groups could be introduced at the 3-position
of the naphthyl azaborine via Ni-catalyzed reductive coupling of
primary and secondary alkyl iodides (Scheme 1c).8 This latter
2
Csp3−Csp bond formation.
From the outset, we chose to focus our study on azaborines
having an aryl ring off the boron atom because such derivatives
have been found to possess enhanced stability relative to those
possessing other substituents on boron. Using the previously
reported reaction conditions for the cross-coupling of aryl
bromides with silicates [2 mol % of [Ru(bpy)3](PF6)2, 5 mol %
of [NiCl2(dme)], 5 mol % of dtbbpy in DMF (0.1 M)], the
reaction of 2-(4-bromophenyl)-2,1-borazaronaphthalene 1a
with cyclohexylsilicate13a affords coupled product 2a in 97%
isolated yield (Scheme 2) (dtbbpy: 4,4′-di-tert-butyl-2,2′-
dipyridyl; bpy: 2,2′-dipyridyl). Substrate 1a was further coupled
with various silicates, affording alkylated azaborines 2b−n in
2
protocol enabled the formation of Csp3−Csp bonds between
the naphthalene isostere core and an alkyl chain. The
introduction of functionalized alkyl moieties is attractive,
particularly for medicinal chemistry applications.9 Addition of
such groups could provide a means of increasing solubility of
drug candidates, hence improving their ADME (absorption,
distribution, metabolism, and excretion) properties.10 Unfortu-
nately, current conditions for incorporation of alkyl chains have
several drawbacks, among them the need for excess terminal
reductant, intolerance of protic functional groups, and the
limited accessibility/high cost of alkyl iodides.
Very recently, our group and others reported a new synthetic
paradigm to enable the formation of C−C bonds under
extremely mild reaction conditions, i.e., visible light photo-
redox/Ni dual catalytic cross-coupling.11,12 Utilization of this
Received: February 17, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00466
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Scheme 1. 2,1-Borazaronaphthalene Functionalization by (a)
Nucleophilic Substitution; (b) Pd Catalyzed Cross-
Coupling; (c) Ni Catalyzed Reductive Cross-Coupling; (d)
Photoredox/Ni Cross-Coupling
Scheme 2. Photoredox Cross-coupling of Ammonium
Alkylbis(catecholato)silicates with 2-(Bromophenyl)-2,1-
borazaronaphthalenes
a
Reaction carried out on 3.5 mmol using blue LEDs; all other
reactions were carried out on a 0.5 mmol scale of 1.
affect the reaction, affording coupled products 3a−c and 4a−c
in excellent yields. Interestingly, ortho-substituted azaborines
(1c, 4a−c) were isolated as oils, whereas nearly all other
compounds (with the exception of 2k) were obtained as fluffy
powders. This disparity is most likely due to a perturbation of
the molecular packing caused by the steric constraints imparted
by ortho substitution. Positioning of an alkyl chain at this
position on the B-aryl group likely prevents coplanarity,
disrupting intermolecular π-stacking.
Next, we examined the photoredox/Ni cross-coupling
performed directly on the azaborinyl ring itself. Therefore, a
series of 3-bromo-2-phenyl-2,1-borazaronaphthalene derivatives
were prepared in high yield via selective electrophilic
bromination (Scheme 3).4
excellent yield with both secondary and primary alkylsilicates.
Isobutyl, bicyclic, and 3,3,3-trifluoropropyl fragments were
amenable to cross-coupling (2b−c,e) as were radicals
containing various functional groups, including an ether (2d),
ester (2f,g), amide (2h), and even a lactam (2i).14 Alkylsilicates
containing Lewis basic residues such as pyridyl (2j), phenyl-
alkylamino (2l), and secondary alkylamino (2m) were similarly
well tolerated. In the case of piperazine (2k)- and primary
amine (2n)-containing silicates, lower yields were obtained
(47% and 68%, respectively), with unreacted bromoazaborine
remaining even after extended reaction time. The rationale for
the lower yield observed using the unprotected piperazine and
the previously successful 3-aminopropylsilicate remains elusi-
ve.13a Despite this, the late-stage incorporation of these basic
substituents may be highly attractive to medicinal chemists
seeking to improve the ADME properties of prospective
azaborine targets. To assess the robustness of the described
protocol further, the synthesis of the amine-containing
compound 2m was scaled to 1 g (3.5 mmol). Neither the
yield nor the reaction time was compromised in this
transformation, confirming the scalability of this reaction.
The azaborine scope was further extended to meta- and
ortho-substituted 2-(bromophenyl)-2,1-borazaronaphthalenes
(Scheme 2, 1b and 1c, respectively). It appeared that the
positioning of the bromine atom on the B-aryl group did not
Scheme 3. Synthesis of Brominated 2,1-
Borazaronaphthalene Cores
Brominated azaborines 1d−h were found to be excellent
electrophiles in this type of cross-coupling, affording coupled
product in good to excellent yields (Scheme 4). Indeed, a
variety of groups could be installed at the 3-position on the
azaborine core (5a−f, 6−9). Notably, reaction times were often
shorter when these couplings were performed. Such accel-
eration may be due to improved rates of oxidative addition into
the C−Br bond, illustrating the lower aromatic character of the
azaborines relative to that of all-carbon arenes. Substitution on
B
DOI: 10.1021/acs.orglett.6b00466
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Notes
Scheme 4. 2,1-Borazaronaphthalene Scope with both
Primary and Secondary Ammonium
Alkylbis(catecholato)silicates
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the NIGMS (R01 GM-111465
and GM-113878) and Eli Lilly. We thank Kingson Lin
(University of Pennsylvania) for the preparation of alkyl
silicates and Dr. Christopher B. Kelly (University of
Pennsylvania) for helpful discussions. Frontier Scientific is
acknowledged for their generous donation of potassium
organotrifluoroborates. Evonik Industries are acknowledged
for their generous donation of organotrimethoxysilanes.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00466.
■
S
Experimental procedures, compound characterization
data, and NMR spectra for all compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
(12) Recent advances in photoredox dual catalysis: (a) Primer, D. N.;
*E-mail: gmolandr@sas.upenn.edu.
Karakaya, I.; Tellis, J. C.; Molander, G. A. J. Am. Chem. Soc. 2015, 137,
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(14) Ammonium organobis(catecholato)silicates used in this study
represent nearly all of the substructures that are currently
commercially available. Methods for accessing silicates having shorter
alkyl chains (e.g., aminomethyl- and aminoethylsilicates) are under
development.
D
DOI: 10.1021/acs.orglett.6b00466
Org. Lett. XXXX, XXX, XXX−XXX