Sterically Unprotected Nucleophilic Boron Cluster Reagents

Full text of DOI:10.1016/j.chempr.2019.07.018

Article
Sterically Unprotected Nucleophilic Boron
Cluster Reagents
Xin Mu, Jonathan C. Axtell,
Nicholas A. Bernier, ..., Arnold L.
Rheingold, K.N. Houk,
Alexander M. Spokoyny
spokoyny@chem.ucla.edu
HIGHLIGHTS
Nucleophilic substitution using
the closo-hexaborate cluster
anions
Boron-based nucleophiles that do
not require steric protection
Substitution shown with both
carbon-based and main-group
electrophiles
Catalyst-free production of alkyl
boronic esters from alkyl halides
We demonstrate that the bench-stable closo-hexaborate cluster dianions can
engage in a nucleophilic substitution reaction with a wide array of organic and
main-group electrophiles without the use of metal catalysts. The resulting
molecules containing B‒C bonds can be further converted to tricoordinate boron
species widely used in organic synthesis. This strategy showcases a unique
substitution and deconstruction reaction sequence with a sterically unprotected
nucleophile to afford boronic acid pinacol esters without the use of metal catalysis.
Mu et al., Chem 5, 2461–2469
September 12, 2019 ª 2019 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2019.07.018

Article
Sterically Unprotected Nucleophilic
Boron Cluster Reagents
1
1
1
1
1
Xin Mu, Jonathan C. Axtell, Nicholas A. Bernier, Kent O. Kirlikovali, Dahee Jung,
1
1
1
1
1
Alexander Umanzor, Kevin Qian, Xiangyang Chen, Katherine L. Bay, Monica Kirollos,
2
1
1,3,4,
Arnold L. Rheingold, K.N. Houk, and Alexander M. Spokoyny
*
SUMMARY
The Bigger Picture
A cornerstone of modern synthetic chemistry rests on the ability to manipulate
the reactivity of a carbon center by rendering it either electrophilic or nucleo-
philic. However, accessing a similar reactivity spectrum with boron-based
reagents has been significantly more challenging. While classical nucleophilic
carbon-based reagents normally do not require steric protection, readily acces-
sible, unprotected boron-based nucleophiles have not yet been realized. Here-
in, we demonstrate that the bench-stable closo-hexaborate cluster anion can
engage in a nucleophilic substitution reaction with a wide array of organic and
main-group electrophiles. The resulting molecules containing B‒C bonds can
be further converted to tricoordinate boron species widely used in organic syn-
thesis.
Over the past 50 years, boron-
based reagents have been
successfully utilized for the
production of new chemicals
ranging from small molecule
drugs to polymer-based
materials. In order to expand the
practical utility of boron-based
synthetic chemistry, emerging
efforts have focused on the
synthesis of nucleophilic boron
species, which rely heavily on
bulky ligand protection. These
new nucleophilic boron reagents
have shown unprecedented
reactivity but generally suffer from
intrinsic air instability, limiting
their applications in organic
synthesis. In this article, we
showcase the efficient synthesis of
stable nucleophilic closo-
INTRODUCTION
Electronic polarization at an atom (e.g., carbon) generally dictates its reactivity
profile and determines whether it can undergo electrophilic or nucleophilic sub-
1
stitution chemistry. Since the seminal work by Grignard, researchers have been
able to generate a variety of useful synthetic reagents featuring an electropositive
2
element interacting with a carbon, rendering the carbon center nucleophilic.
3
,4
Given the prevalence of organoboron compounds used in synthesis,
re-
searchers have recently been interested in applying a similar concept of polarity
5
switching commonly used for carbon reagents to boron congeners (Figure 1A).
hexaborate cluster dianions,
which are stabilized via three-
dimensional delocalization
instead of steric protection. We
show that this class of reagents
can react with a series of
This strategy can potentially diversify the reactivity repertoire beyond the classical
6
electrophilic nature of boron-based reagents. However, access to synthetically
practical nucleophilic boron compounds remains a significant fundamental chal-
lenge. In 2006, Yamashita, Nozaki, and co-workers reported the first synthesis
and isolation of a well-defined anionic boryllithium 1 (Figure 1B), which un-
7
dergoes several reactions with carbon-based electrophiles. This discovery was
electrophiles without the use of
metal catalysts or complex ligand
auxiliaries and can be extended
by the controlled deconstruction
of the substituted clusters,
producing tricoordinate alkyl
boronic esters.
enabled by the use of a sterically encumbering ligand platform that stabilizes
8
the highly reactive nucleophilic boron site, termed as ‘‘boryl.’’ Inspired by the
idea of using steric protection, others have targeted the synthesis of nucleophilic
boron compounds, generally leveraging electron-donating and sterically bulky li-
9
–13
gands to tame the reactivity of the nucleophilic boron species 2–5 (Figure 1B).
Recently, several ligand frameworks were also developed to constrain boron-
based centers in a non-traditional electronic environment, rendering some of
1
4,15
the species (e.g., 6) nucleophilic.
While significant progress has been made
in stabilizing nucleophilic boron centers, synthetically demanding protocols and
a lack of overall benchtop stability have hindered the widespread use of nucleo-
philic boron reagents in synthetic methodology.
Chem 5, 2461–2469, September 12, 2019 ª 2019 Elsevier Inc. 2461

Figure 1. Development of Sterically Unprotected Cluster-Based Borylation Reagents
For a Figure360 author presentation of this figure, see https://doi.org/10.1016/j.chempr.2019.07.018.
(
(
(
A) General scheme for metal-catalyzed borylation using tricoordinate diborane reagents.
B) Representative nucleophilic boron reagents developed previously.
2
À
7À
C) One of three triply degenerate HOMO representations of B
6
H
6
, synthesis of the B
6
H anion, and a general borylation strategy using sterically
unprotected cluster-based nucleophiles developed in this work.
RESULTS AND DISCUSSION
In this work, we demonstrate a conceptually different approach to stabilize a reactive
boron nucleophile, predicated on three-dimensional electron delocalization instead
of steric protection enforced by a ligand auxiliary (Figure 1C). In order to engender
the necessary delocalization, we identified a system in which boron atoms are
bonded in a cluster-based environment. Specifically, we evaluated polyhedral bo-
2
À
ranes (B
n
H
n
, n = 6, 10, or 12) (Figure 1C, top), which are some of the simplest clus-
ters containing catenated boron atoms known to date. In these clusters, electron
delocalization across cage boron vertices reduces the otherwise extreme reactivity
1
6
of atom-centered boryl anions. A manifestation of this delocalization can be seen
2
À
in the example of B12H12 , which has a nucleophilicity as low as that of benzene;
1
7
neither of these molecules readily reacts with carbon-based electrophiles. On the
other hand, smaller boron clusters have been previously suggested to be less inert
and could potentially exhibit an increased nucleophilic character compared to
1Department of Chemistry and Biochemistry,
University of California, Los Angeles, 609 Charles
E. Young Drive East, Los Angeles, CA 90095, USA
2
À 18
62À
B
12
H
12
.
For example, density functional theory (DFT) analysis of B
6
H at the
2
Department of Chemistry and Biochemistry,
University of California, San Diego, 9500 Gilman
Drive, San Diego, La Jolla, CA 92093, USA
B3LYP-D3/6-31G(d) level of theory suggests that the triply degenerate highest occu-
pied molecular orbitals (HOMO) are delocalized across eight faces of the octahedron
3California NanoSystems Institute, University of
California, Los Angeles, Los Angeles, CA 90095,
USA
2
À
and that the corresponding energy is 3eV higher than the HOMO of B12
H
12
(see
Supplemental Information). Ultimately, this begged the question of whether
2
À
4Lead Contact
B
6
H
6
can be considered as a competent nucleophile in the context of nucleophilic
borylation chemistry to produce substrates that can be efficiently transformed into
tricoordinate boron compounds commonly used in synthesis (Figure 1C, bottom).
*Correspondence: spokoyny@chem.ucla.edu
https://doi.org/10.1016/j.chempr.2019.07.018
2462 Chem 5, 2461–2469, September 12, 2019

A
B
C
Figure 2. Synthesis and Deconstruction Studies of Perfunctionalized closo-Hexaborate Anions
(
(
A) Preparation of monoanionic closo-hexaborate cluster reagents (8 and 9) and their reactivity toward model electrophiles.
B) Discovery of the selective cage deconstruction process of clusters 10 and 11, leading to the intermediate 13, which can be further deconstructed with
TCNQ to produce tricoordinate alkyl boronate species (14 and 15).
(
C) Oxidation potential variability (see cyclic voltammograms of 10, 11, and 12) of the perfunctionalized clusters, leading to the alternative borylation
2
À
strategy via a monosubstitution using dianionic B
6
H
6
reagent.
Dianionic closo-hexaborate compound 7 (Figure 2A) can be synthesized on a
multi-gram scale in one step from cheap and commercially available NaBH
and BF $Et O. Crude 7 can be directly converted into 8 and 9 from a salt metath-
4
3
2
esis reaction in water, producing singly protonated, air-stable closo-hexaborate
species soluble in organic solvents (Figures S1–S10). The protonation states of
fac
fac
8
(NBu
4
[B
6
H
6
2
H
]) and 9 (MePPh
3
[B
6
H
6
H
]) imply that the Brønsted-basic char-
À
acter of B
6
+
H
6
is readily accessible and could be applied to other electrophiles
beyond H .
To probe whether this cluster could engage in nucleophilic substitution toward
organic electrophiles, we conducted reactions between 8 and a series of benzyl bro-
3 4
mides in acetonitrile (Figure 2A; see also Table S1). Using K PO as a base,
Chem 5, 2461–2469, September 12, 2019 2463

6
persubstituted B -based clusters 10 and 11 can be formed quantitatively as judged
1
1
by B NMR spectroscopy (Table S1; Figure S11). During our investigations into the
purification of 10 and 11, we noticed that subjecting these compounds to a slurry of
ꢀ
silica gel in dichloroethane at 50 C results in the formation of a new cluster-based
1
1
species as evidenced by a diagnostic change in B NMR spectra of the correspond-
ing products (Figure 2B). From the reaction mixture initially containing 11, we were
able to isolate a crystalline solid and subject this material to a series of structural
1
characterization techniques. H NMR spectroscopy suggested the formation of
new bridging hydrides and implied a loss of one ‘‘B–CH
2
Ar’’ vertex from starting
1
1
1
1. Both X-ray photoelectron spectroscopy (XPS) and B NMR spectroscopy sug-
gest desymmetrization of the cluster precursor and the appearance of two unique
boron sites with distinct electronic environments (Figures S15–S21). Single crystals
of the material grown from a concentrated toluene solution were subjected to
X-ray diffraction studies and identified the solid as a neutral pentaborane cluster
1
3 with one benzyl-attached boron vertex removed from parent cluster 11 (Fig-
ure 2B; Tables S8, S9, and S10). This unprecedented partial cage deconstruction
2
À
19
suggests that unlike large closo-borane clusters (e.g., B12
H12 ), peralkylated
B
6
-based clusters can be oxidatively unstable toward B–B bond rupture and that
this instability could be leveraged to selectively generate tricoordinate boron re-
agents through substituted closo-hexaborate cage deconstruction.
To further probe thishypothesis, weinvestigated the deconstruction of11 witha range of
model oxidants (Table S2; Figure S22). Upon employing 7,7,8,8-tetracyanoquinodime-
thane (TCNQ) as a single electron oxidant, significant quantities of the corresponding
benzyl boronate products (benzyl and 4-bromobenzyl boronic acid pinacol esters 14
and 15) were observed, suggesting a successful cage deconstruction under these condi-
tions. While these results are conceptually promising and suggest that one can employ
monoanionic 8 or 9 as a nucleophilic boron source to synthesize organic boronates
through a substitution and cage deconstruction sequence, several challenges revealed
themselves during the course of our investigation that necessitated a modified strategy.
Specifically,whencyclicvoltammetry(CV)datawerecomparedfor10, 11, and12(Figures
S12–S14), significant variability in oxidation potentials, ranging from +0.48 to 0.03 V
+
(
versus Fc /Fc), was observed for these compounds (Figure 2C). This suggests that the
nature of the organic substituents dramatically affects the oxidative stability of the per-
functionalizedintermediates, potentially limiting the synthetic generalityof the cage sub-
stitution/deconstruction protocol.
We thus hypothesized that partial cage substitution could alleviate these limitations
2
À
(
Figure 2C). We investigated whether well-defined dianionic B
6
H
6
salts could be
used for a base-free nucleophilic substitution, leading to the formation of monoalky-
lated compounds with similar oxidation potentials (Figure 2C). The synthesis of the
dianion 16 can be accomplished in a straightforward manner on a multi-gram scale
by stirring 8 with NBu
4
OH in the presence of the Na
2
SO
4
(Figures 3A and S23–S25).
PPh ), pro-
Alternatively, 9 can be deprotonated with a phosphorane reagent (CH
2
3
ducing 17 in a nearly quantitative yield (Figures 3A and S26–S30). Both of these dia-
nion-based salts are bench-stable solids that can be stored in a desiccator for over
7À
2
months without any noticeable protonation to form the B
6
H
monoanion.
Consistent with our hypothesis, 16 and 17 undergo nucleophilic substitution
with a wide variety of alkyl-based electrophiles producing the corresponding
fac À
mono-substituted [B
6
H
5
RH
]
species (Figure 3B). Importantly, these reactions
take place under mild conditions by simply combining a dianionic reagent together
with an electrophile substrate in variety of non-protic organic solvents
a
2464 Chem 5, 2461–2469, September 12, 2019

Figure 3. Borylation/Cage Deconstruction Strategy with Dianionic closo-Hexaborates
2
À
(
(
A) Preparation of B
6
H
6
reagents and their subsequent use in borylation of organic electrophiles.
2
À
(1.0 equiv), alkyl halide (0.4 mmol, 1.0 equiv), and MeCN (2 mL). For
B) Substrate scope of alkyl halides. Standard reaction conditions: B
6
H
6
ꢀ
ꢀ
unactivated alkyl bromides, 60 C heating. For benzyl bromides, room temperature. Pinacol (10 equiv), MgSO
4
(12 equiv), and THF (2 mL), 0 C to room
1
1
temperature for deconstruction. Isolated yields are calculated after cage deconstruction. Inset, B NMR spectra for the synthesis sequence: closo-
hexaborate dianion (top); mono-substituted closo-hexaborate (middle); and purified alkyl‒Bpin (bottom).
2
À
ꢀ
(1.3–2.0 equiv), mwave heating at 140 C.
(
C) Substrate scope of alkyl pseudohalides. Reaction conditions: B
6
H
6
a
Using alkyl iodide (2 equiv).
b
62À
ꢀ
B
6
H
(1.5 equiv) and mwave heating at 110 C.
Chem 5, 2461–2469, September 12, 2019 2465

Figure 3. Continued
c
ꢀ
Using oil bath heating at 80 C.
d
ꢀ
mwave heating at 90 C.
e
ꢀ
+
+
+
+
oil bath heating at 60 C. [N ] = NBu
4 3
and [P ] = MePPh .
(
Figures S31 and S32). No other additives are required to forge a B–C bond via this
strategy. The unpurified products from these transformations can be directly sub-
jected to oxidative deconstruction of the cluster with TCNQ or nitrosonium tetra-
4
fluoroborate (NOBF ) in the presence of pinacol, ultimately producing the corre-
sponding alkyl pinacol boronate esters (Tables S3 and S4).
Primary alkyl bromides and iodide containing various functional groups such as
ester (19), perfluoroalkyl (20), alkyl ether (22 and 23), and halide (24) substituents
were successfully converted to the corresponding boronic esters using the substi-
tution/cage deconstruction sequence. Phenethyl bromide, which is susceptible to
elimination under basic conditions, is tolerated under the developed protocol
(
21). A substrate bearing a terminal olefin was also converted directly to the
boronic ester with no evidence of olefin reduction (e.g., hydroboration) (25).
For benzyl bromides containing aryl bromide and iodide substituents, only
3
C
sp ‒Br bonds were borylated (15 and 28). Interestingly, substrates bearing active
N
sites for nucleophilic aromatic substitution (S Ar) such as pentafluorophenyl and
difluorophenyl groups (30 and 32) remained intact under the developed condi-
tions (Figures 3B and S113–S165).
Recently, there have been a growing number of reports using oxygen-containing
electrophiles (pseudohalides) to replace alkyl halides as cross-coupling part-
2
0
ners. However, in metal-catalyzed borylations of alkyl electrophiles, pseudoha-
3
lides are rarely reported as substrates due to the reduced reactivity of Csp ‒O
bonds toward activation by several metal-based catalysts commonly employed
2
1
under borylation conditions. In our case, the substitution of both primary and
2
À
secondary alkyl‒OTs and OMs (Mesylate) substrates by B
6
H
6
(16) proceeded
smoothly in the absence of any metal salts or halide additives; subsequent
cage deconstruction produced the corresponding pinacol boronate ester com-
pounds (33–38) (Figures 3C and S166–S180).
To shed light on the nature of the cluster-based nucleophilic substitution, we inves-
tigated whether the discovered transformation showed hallmarks of radical reaction
pathways. Bromomethylcyclopropane has been previously employed as a standard
radical probe in various metal-catalyzed borylations, where in the presence of radical
2
2,23
species, ring-opened 3-butenylboronate was isolated as the major product.
In
contrast, after subjecting the same electrophile to our optimized reaction condi-
tions, no ring-opened species were observed either in the reaction mixture after
monofunctionalization or in the resulting borylated product 26. This observation
suggests that a radical mechanism for B‒C bond formation is unlikely (Figures S74
and S75). Additionally, when enantiopure (R)-2-OTs-4-phenylbutane was applied
in our protocol, enantio-enriched alkyl boronate 37 was obtained with inversion of
stereochemistry (94:6 e.r.), suggesting an apparent S
N
2 substitution mechanism
(
Figures S76–S79). This observation stands in stark contrast to existing metal-cata-
lyzed systems, in which racemic-borylated products are observed because of the
intermediacy of alkyl radicals, therefore impeding general approaches to stereospe-
2
3,24
cific borylation through chiral induction.
Importantly, this borylation strategy
provides a new chiral auxiliary-free pathway to generate enantio-enriched alkyl bor-
2
5,26
onates from chiral alcohol derivatives.
2466 Chem 5, 2461–2469, September 12, 2019

A
B
Figure 4. Reaction of Dianionic closo-Hexaborate with Main-Group Electrophiles
(
(
A) Transformations leading to the formation of clusters with B–P bonds (40–42).
B) Hexaborate-based cluster featuring a B–Se bond (43; see Figures S80–S106 for synthesis and
characterization detail).
Undesired side reactions, including apparent one-electron reduction chemistry,
have been observed with other classes of nucleophilic boron reagents in the pres-
2
7
ence of alkyl-based electrophiles; in addition, some of these species also exhibit
2
8
reducing behavior toward main-group electrophiles. Interestingly, during the
course of our investigations, we never observed any apparent reduction products
stemming from the reactions of closo-hexaborate and alkyl electrophiles, which im-
plies that under the developed conditions this nucleophilic source of boron is signif-
icantly less reducing. We therefore were curious whether the nucleophilic behavior
of the closo-hexaborate reagent could be extended to reactions with main-
group electrophiles to forge B–heteroatom bonds (Figure 4). Traditionally, main-
group boranes (e.g., phosphinoboranes) are prepared using electrophilic boron-
2
9
based reagents. Interested in reversing the role of boron reagents in these bond
formations, we combined 17 and Ph PCl, resulting in the formation of diphenylphos-
2
phine-substituted closo-hexaborate 39 (Figure 4A), as judged by multinuclear NMR
spectroscopy (Figures S80 and S81). Subsequent treatment with allyl bromide fol-
lowed by workup permitted the isolation of 40 as a zwitterionic closo-hexaborate
containing an exopolyhedral P‒B bond (Figures S82–S88). The methylation of phos-
phorus, generating zwitterionic 41 (Figures S89–S92), followed by iodination pro-
duced a heteroleptic penta-iodinated cluster 42, which we were able to characterize
by multinuclear NMR spectroscopy and single-crystal X-ray diffraction, further con-
firming the proposed B‒P connectivity (Figures S93–S98; Tables S14, S15, and S16).
These results contrast previous observations of nearly quantitative reduction and
formation of the corresponding diphosphine (Ph
2
P‒PPh
2
) when 1 was treated with
2
8
Ph
2
PCl. Consistent with the non-reducing, nucleophilic nature of the closo-
hexaborate anion, 17 undergoes a clean transformation with the PhSeCl reagent
forging a substituted cluster 43 with an exopolyhedral B‒Se bond (Figures 4B and
S99–S106).
Conclusions
Overall, we have discovered that small polyhedral-boron clusters featuring a steri-
6
cally unprotected B -based cluster core possess a strong yet non-reducing nucleo-
philicity that can be leveraged for the borylation of various organic and main-group
electrophiles. This led us to the development of a simple protocol, whereby carbon-
based electrophiles can be transformed into the corresponding tricoordinate boron
ester species without the use of metal catalysis. This work highlights how boron-rich
3
0–48
clusters can expand the toolkit of main-group reagents,
ultimately aiding in the
development of organic synthesis through new modes of reactivity.
Chem 5, 2461–2469, September 12, 2019 2467

EXPERIMENTAL PROCEDURES
Full experimental procedures are provided in the Supplemental Information.
DATA AND CODE AVAILABILITY
The crystallographic data for 9, 13, 17, and 42 reported in this paper have been
deposited at the Cambridge Crystallographic Data Center (CCDC) under accession
numbers CCDC: 1909639, CCDC: 1090641, CCDC: 1909643, and CCDC: 1909644,
respectively, and can be obtained free of charge from www.ccdc.cam.ac.uk/
getstructures.
SUPPLEMENTAL INFORMATION
Supplemental Information can be found online at https://doi.org/10.1016/j.chempr.
2
019.07.018.
ACKNOWLEDGMENTS
This work has been supported by the NIH (R35GM124746) and the donors of the
American Chemical Society Petroleum Research Fund (56562-DNI3). A.M.S. is grate-
ful to the Alfred Sloan foundation for the Sloan Research Fellowship in Chemistry and
Research Corporation for Science Advancement (RCSA) for the Cottrell Scholar
Award. We are grateful to the National Science Foundation (CHE-1764328) for finan-
cial support of this research. Calculations were performed on the Hoffman2 cluster at
UCLA and the Extreme Science and Engineering Discovery Environment (XSEDE),
which is supported by the National Science Foundation (OCI-1053575). K.Q. ac-
knowledges the Amgen Foundation for research funding.
AUTHOR CONTRIBUTIONS
X.M., J.C.A., and A.M.S. designed the project and the experiments. X.M., J.C.A.,
and N.A.B. performed the synthesis and characterization; K.O.K. and D.J. assisted
with the analytical characterization; and A.U., K.Q., and M.K. contributed to the vali-
dation of the synthetic methodology. A.L.R. performed X-ray crystallographic
studies. X.C., K.L.B., and K.N.H. designed and performed computational studies.
A.M.S., X.M., J.C.A., and N.A.B. co-wrote the manuscript. All authors discussed
the data and commented on the manuscript during its preparation.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: May 13, 2019
Revised: June 26, 2019
Accepted: July 22, 2019
Published: August 22, 2019
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