Cage-Walking: Vertex Differentiation by Palladium-Catalyzed Isomerization of B(9)-Bromo-meta-Carborane

Article abstract of DOI:10.1021/jacs.7b04080

We report the first observed Pd-catalyzed isomerization ( cage-walking ) of B(9)-bromo-meta-carborane during Pd-catalyzed cross-coupling, which enables the formation of B-O and B-N bonds at all boron vertices (B(2), B(4), B(5), and B(9)) of meta-carborane. Experimental and theoretical studies suggest this isomerization mechanism is strongly influenced by the steric crowding at the Pd catalyst by either a biaryl phosphine ligand and/or substrate. Ultimately, this cage-walking process provides a unique pathway to preferentially introduce functional groups at the B(2) vertex using B(9)-bromo-meta-carborane as the sole starting material through substrate control.

Full text of DOI:10.1021/jacs.7b04080

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Communication
Cage-walking: Vertex Differentiation by Palladium-
Catalyzed Isomerization of B(9)-Bromo-meta-Carborane
Rafal Miroslaw Dziedzic, Joshua L. Martin, Jonathan C Axtell, Liban M. A. Saleh, Ta-Chung Ong, Yun-
Fang Yang, Marco S Messina, Arnold L. Rheingold, Kendall N. Houk, and Alexander M Spokoyny
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 25 May 2017
Downloaded from http://pubs.acs.org on May 25, 2017
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Cage-walking: Vertex Differentiation by Palladium-Catalyzed Isom-
erization of B(9)-Bromo-meta-Carborane
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Rafal M. Dziedzic,† Joshua L. Martin,† Jonathan C. Axtell, † Liban M. A. Saleh,† Ta-Chung Ong,† Yun-
Fang Yang,† Marco S. Messina,† Arnold L. Rheingold,‡ K. N. Houk,† Alexander M. Spokoyny.†,§
†Department of Chemistry and Biochemistry, University of California, Los Angeles, 607 Charles E. Young Drive East,
Los Angeles, CA 90095, United States
‡
Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla,
CA 92093, United States
§California NanoSystems Institute (CNSI), University of California, Los Angeles, 570 Westwood Plaza, Los Angeles, CA
90095, United States
Supporting Information Placeholder
vertices.8,9 Even so, these approaches provide limited access
ABSTRACT: We report the first observed Pd-catalyzed isom-
to a rational, vertex-specific B–H functionalization. Surprising-
ly, metal-catalyzed isomerization reactivity commonly ob-
served with classical organic substrates (vide supra) has never
been reported for any boron cluster systems, including car-
boranes. Herein, we disclose our discovery of a Pd-catalyzed
activation of 9-bromo-meta-carborane (Br–B(9)) which can
undergo subsequent “cage-walking,” leading to the formation
of B(2)-, B(4)-, B(5)-, and B(9)-functionalized clusters in the
presence of a suitable nucleophile (Figure 1B).
erization (cage-walking) of 9-bromo-meta-carborane during
Pd-catalyzed cross-coupling which enables formation of B–O
and B–N bonds at all boron vertices (B(2), B(4), B(5), and
B(9)) of meta-carborane. Experimental and theoretical studies
suggest this isomerization mechanism is strongly influenced
by the steric crowding at the Pd catalyst by either a biaryl
phosphine ligand and/or substrate. Ultimately, this “cage-
walking” process provides a unique pathway to preferentially
introduce functional groups at the B(2) vertex using B(9)-
bromo-meta-carborane as the sole starting material through
substrate control.
Isomerization mechanisms such as chain-walking via β-
hydride elimination/reinsertion and aryne-based rearrange-
ments (Figure 1A) are ubiquitous in metal-catalyzed trans-
formations of organic molecules.1,2 Through judicious choice
of catalyst design, these mechanistic pathways can be biased
to form specific regioisomers. Thus, metal-catalyzed isomeri-
zation control can provide a means of incorporating functional
groups in molecules at positions remote from where initial
bond activation occurs.1-3
Figure 1. A) Pd-catalyzed olefin isomerization through β-
hydride elimination and arene regioisomer formation through
a proposed benzyne intermediate. B) Pd-catalyzed isomeriza-
tion of meta-carboranyl through “cage-walking”.
Boron clusters are unique molecular scaffolds that fea-
ture 3-dimensional (3D) electronic delocalization.4 Specifical-
ly, in the case of icosahedral carboranes (C2B10H12) this delo-
calization is non-uniform.5 This charge distribution makes
carboranes an interesting alternative to classical carbon-
based structural building blocks such as aryl and alkyl
groups.6 Due to their inherent robustness, carboranes can be
promising molecular building blocks for applications ranging
from pharmacophores to photoactive materials.7 Ultimately,
vertex-specific functionalization routes (vertex differentia-
tion) are critical to constructing carborane-containing mole-
cules and materials.7,8
Recently we reported the Pd-catalyzed cross-coupling of
Br–B(9) to generate B(9)–O and B(9)–N bonds with a wide
range of substrates.9 This cross-coupling relied on biaryl
phosphine ligands to generate monoligated palladium(0) spe-
cies ([LPd])capable of undergoing oxidative addition into the
B–Br bond of Br-B(9). To our surprise, during the course of
subsequent investigations, when replacing the SPhos or
DavePhos ligands (L1–L2) with the bulkier XPhos congener
(L3) in the presence of alcohol or amine substrates, we con-
sistently observed three distinct products with identical m/z
ratios by gas chromatography-mass spectrometry (GC-MS)
instead of one.
Recent developments in carborane functionalization have
relied on several metal-catalyzed routes including B–H activa-
tions (either directed or undirected) and cross-coupling of
halogenated carborane electrophiles at both C- and B-
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Figure 2. A) Reaction conditions that result in the formation of R1-meta-carborane regioisomers. B) 11B NMR spectra of the isolat-
ed regioisomers. Singlet resonances (no 11B–1H coupling) corresponding to the B–O bonded vertex are labeled; all other resonanc-
es correspond to doublet resonances arising from 11B–1H couplings. C) Single-crystal X-ray structures of B1-B(9) - R1-B(2) (ellip-
soids drawn at 50 % probability and H atoms omitted for clarity).
For example, using 3,5-dimethylphenol (R1) as a cross-
coupling partner with Br–B(9) we observed several products
with identical m/z ratios (see SI). Upon chromatographic sep-
aration of the reaction mixture on silica gel we identified four
distinct R1-carborane compounds by 11B, 1H, and 13C NMR
spectroscopy (Figure 2).
isomerization may provide a convenient pathway to B(2)-,
B(4)- and B(5)-functionalized meta-carborane species that
circumvents laborious, and often low-yielding, protocols such
as deboronation/capitation or thermal isomerization strate-
gies.10,11
Since bromo-meta-carboranyl isomerization can occur
before all the carborane regioisomers are depleted by cross-
coupling (vide supra), we hypothesized that the isomerization
process might operate separately from the main cross-
coupling cycle. To further explore the isomerization mechan-
ics we attempted to inhibit transmetallation by increasing the
steric bulk of the cross-coupling partner, thereby allowing the
active catalyst species to operate in the isomerization path-
way for a longer time (Figure 4, Step II). Indeed, cross-
coupling reactions using bulky L3 and sterically congested
2,6-dimethylphenol (R3) yielded R3–B(2) as the major prod-
The isolated carborane-containing molecules show a dis-
tinct downfield singlet in the 11B NMR corresponding to R1
bound at a B(2), B(4), B(5), or B(9) vertex of meta-carborane
(R1–B(2), R1–B(4), R1–B(5), and R1–B(9), respectively).
Although we were unable to chromatographically separate
R1–B(5) and R1–B(4), we identified the isomer ratio as 15:85
by 11B and 1H NMR spectroscopy: R1–B(4) is C1-symmetric,
resulting in ten 11B NMR resonances (1 singlet, 9 doublets),
whereas R1–B(5) contains a mirror plane, resulting in six 11B
NMR resonances (1 singlet, 5 doublets). Thus, the more in-
tense singlet at ~3 ppm (Figure 2B) is assigned to the domi-
nant pattern of R1–B(4). Similarly, two sets of 1H and 13C
NMR resonances corresponding to R1–B(5) and R1–B(4)
were observed in a 15:85 signal ratio for the CH aromatic and
aliphatic regions, respectively (see SI). These structural as-
signments are further supported by single-crystal X-ray dif-
fraction studies of the four regioisomers (Figure 2C). Interest-
ingly, R1–B(4) is the only monofunctionalized meta-
carborane regioisomer that exhibits chirality. R1–B(4) crys-
tallized as two distinct polymorphs, with both polymorphs
containing equal amounts of the two enantiomers in the unit
cell. Chiral HPLC analysis further supports the presence of two
R1–B(4) enantiomers in the isolated mixture (Figure S12).
uct
(Figure
3).
As
a
control
experiment,
To further assess the generality of this isomerization
process we examined three biaryl phosphine ligands and sev-
eral substrates to generate B–O- and B–N-bound carborane
regioisomers (Figure 3). Consistent with our previous report,
[L1Pd] and [L2Pd] generate B(9) isomers almost exclusively
with O- and N-based nucleophiles.9 However, [L3Pd] gener-
ates appreciable amounts of regioisomers under the same
conditions. Noteworthy was the presence of bromo-meta-
carborane regioisomers when the cross-coupling reactions
were stopped early, indicating isomerization of the Br–B(9) in
addition to the cross-coupling products. Furthermore, Br–
B(9) forms bromo-meta-carborane isomers in the presence of
[L3Pd] precatalyst and triethylamine, implying that isomeri-
zation can occur prior to transmetallation of a cross-coupling
partner and subsequent reductive elimination of the B-
functionalized meta-carborane. Hence, this metal-catalyzed
Figure 3. Reaction conditions for forming B–functionalized
meta-carborane isomers using different substrates (R1-R3)
and biaryl phosphine ligands (L1-L3), yields obtained by GC-
MS. See SI for full experimental conditions.
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Figure 4. A) Deuterium labeling experiments, resonance at 2.7 ppm is present from polydeuterated Br-B(9). See SI for full experi-
mental details. B) Proposed metal-catalyzed isomerization of bromo-meta-carborane through a “cage-walking” mechanism. (I)
oxidative addition, (II-a) bromide dissociation, (II-b, II-c) “cage-walking”, (II-d) bromide association, (III) transmetallation, (IV)
reductive elimination.
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equimolar amounts of 3,5-dimethylphenol (R1) and 2,4,6-
trimethylphenol (R3’, a variant of R3 to permit separation of
products by GC-MS) were reacted with Br–B(9) in the pres-
ence of L3 and K3PO4 in 1,4-dioxane at 80 °C (Figure S5-S6).
GC-MS analysis of the reaction mixture showed complete con-
sumption of Br–B(9) with R1-meta-carborane isomers as the
major products, suggesting that the size of the nucleophile is
linked to the rate of product formation. Since oxidative addi-
tion is likely rapid in this process,12 it appears that by slowing
the rate of transmetallation and/or reductive elimination one
can increase the yield of B(2) regioisomer (Figure 4B). This
type of Pd-catalyzed remote vertex functionalization is un-
precedented and demonstrates the utility of a metal-catalyzed
route to meta-carborane vertex-differentiation. Importantly, it
contrasts with known thermal rearrangements that are lim-
ited to thermally resistant functional groups (above 300 °C)
and produce isomer mixtures with B(2) substituted meta-
carboranes as the minor product.11
H activation which leads to an intramolecular β-hydride shift
(Figure S10). Deuterium labeling experiments in which 2,6-
Me2C6H4OD was used as the nucleophile do not result in deu-
terium incorporation at any B–H vertex, as judged by GC-MS,
2H and 11B NMR, likely ruling out isomerization pathway 1.
However, when using the deuterated congener of Br-B(9), 9-
Br-10-D-meta-C2B10H10, and 2,6-Me2C6H4OH as the nucleo-
phile we observed five B–2H resonances in the 2H {11B} NMR
spectrum of R3–B(2), indicating deuterium scrambling across
the carborane B–H framework (Figure 4A). We postulate that
this β-hydride shift exchanges the B(10)–deuterium with an
adjacent B(5)–proton, and enables “cage-walking” to form
[LPd–B(4)]+ (Figure 4B, step II-b). The “cage-walking” pro-
cess can occur again to generate [LPd–B(2)]+ (Figure 4B, step
II-c). Similar reports of metal-catalyzed carborane B–H activa-
tion processes have been reported8,15,16; however, they are
limited to B–H vertices adjacent to carborane-bound directing
groups, whereas the presently reported “cage-walking” ac-
cesses all of the meta-carborane B–H vertices from one start-
ing point in a diversity-oriented fashion.
We attribute this difference in reactivity between “cage-
walking” (when using L3) and cross-coupling exclusively at
the B(9) vertex (when using L1/L2) to steric crowding at the
Pd-center. The combination of a sterically demanding ligand
and nucleophile appears to inhibit transmetallation,13 allow-
ing the catalyst to operate through several “cage-walking”
steps before re-entering the traditional cross-coupling cycle
(vide supra). Based on these observations we propose a Pd-
catalyzed “cage-walking” mechanism for isomerizing Br–B(9)
(Figure 4B). Beginning with the oxidative addition complex
[LPdBr–B(9)], an open Pd(II) coordination site is generated
by bromide dissociation2d (Figure 4, step II-a) to form [LPd–
B(9)]+. Consistent with this hypothesis, cross–coupling exper-
iments between Br–B(9) and R3 in the presence of tetrabu-
tylammonium bromide show decreased Br-B(9) consumption
and decreased formation of R3-meta-carborane (Figure S7).
These experiments suggest that bromide dissociation is an
important step in the overall cross-coupling process.14 After
bromide dissociation, two possible “cage-walking” pathways
were envisioned for the formally cationic [LPd–B(9)]+: 1)
deprotonation of an adjacent B–H vertex to form a B(4),B(9)-
bound carborane species which isomerizes upon reprotona-
tion to form [LPd–B(4)]+ (Figure S9) and 2) a Pd-mediated B–
Through the “cage-walking” process, the carboranyl
fragment eventually binds the Pd center through the most
electron-deficient boron vertex, B(2), resulting in a more elec-
trophilic Pd-center capable of overcoming the steric repulsion
between the cationic [LPd–B(2)]+ and the anionic cross-
coupling partner. Density functional theory calculations (DFT)
(B3LYP/LANL2DZ 6-31G* and M06/SDD/6-311++G**,
SMD(1,4-dioxane)) of [LPd–B(9)]+, [LPd–B(4)]+, and [LPd–
B(2)]+ indicate that [LPd–B(2)]+ has the most cationic Pd-
center, which likely results in a lower transmetallation barrier
due to a stronger electrostatic attraction between the Pd-
center and the phenoxide nucleophile (Figures S13-S16). Fur-
thermore, the ꢀG of B–O and B–N bond formation decreases
accordingly, B(9) > B(5) ~ B(4) > B(2), for the cross-coupling
between Br–B(9) and R1-R3. Similar electronic effects of
substrate and ligand were observed in Pd-catalyzed aryl hal-
ide cross-coupling.17
In summary, we discovered the first example of metal-
catalyzed isomerization (“cage-walking”) of meta-carboranyl.
The isomerization process appears to operate in conjunction
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(5) King, R. B. Chem. Rev. 2001, 101, 1119-1152.
with a classical cross-coupling mechanism leading to a distri-
bution of carborane regioisomers. The relative rate of cross-
coupling to “cage-walking” can be adjusted to achieve selec-
tive B-vertex functionalization. We demonstrate this selectivi-
ty by controlling steric crowding at the Pd-center by appro-
priate choice of catalyst ligand and cross-coupling substrate.
Preliminary studies show that this “cage-walking” strategy
can be applied to carborane B(2)−Caryl bond formation using
an aryl boronic acid (Figure S17). Overall, this approach pro-
vides a unique pathway to vertex differentiation of boron clus-
ters.
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ASSOCIATED CONTENT
Supporting Information
Full procedures and crystallographic and other characterizing
data are provided in the supporting information, which is
available free of charge at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
(8) (a) Quan, Y.; Xie, Z. Angew. Chem., Int. Ed. 2016, 55, 1295-1298.
(b) Lyu, H.; Quan, Y.; Xie, Z. J. Am. Chem. Soc. 2016, 138, 12727-12730.
(9) Dziedzic, R. M.; Saleh, L. M. A.; Axtell, J. C.; Martin, J. L.; Stevens,
S. L.; Royappa, A. T.; Rheingold, A. L.; Spokoyny, A. M. J. Am. Chem. Soc.
2016, 138, 9081-9084 (and references within).
spokoyny@chem.ucla.edu (A.M.S)
Notes
The authors declare no competing financial interests.
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ACKNOWLEDGMENT
We thank the donors of the American Chemical Society Petro-
leum Research Fund (56562-DNI3 to A. M. S.), UCLA (start-up
funds to A. M. S.), NSF (CHE-1048804 and CHE1361104), 3M
(Non-Tenured Faculty Award to A. M. S.) and National Defense
Science and Engineering Graduate Fellowship (NDSEG to R. M.
D) for support.
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Isomerization via Metal-Catalyzed “Cage-Walking”
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B(9)
B(5)
B(2)
B(4)
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A
ꢀ-hydride
elimination:
—chain-walking“
benzyne-type
intermediate
B
This Work:
—cage-walking“
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11B NMR
X-ray crystal structures
R1-B(9)
A
B
C
B(9)
B(4)
R1-B(4)
B(5)
B(2)
R1-B(5)
R1-B(2)
ppm

R = R1, R2, or R3
= R

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A
B
2H {11B} NMR
R3-B(2)-2H
deuterium
scrambling
Br,2H-B(9,10)
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Isomerization via Metal-Catalyzed “Cage-Walking”
B(9)
B(5)
B(2)
B(4)