Transition-metal-mediated three-component cascade cyclization: Selective cage B-C(sp2) coupling of carborane with aromatics and synthesis of carborane-fused tricyclics

Article abstract of DOI:10.1021/ja503489b

Zirconium/nickel comediated one-pot three-component cascade cyclization of carboryne, alkene, and 2-bromophenyltrimethylsilylacetylene has been achieved, leading to the formation of a series of C,C,B-substituted carborane-fused tricyclics. On the basis of

Full text of DOI:10.1021/ja503489b

Communication
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Transition-Metal-Mediated Three-Component Cascade Cyclization:
Selective Cage B−C(sp2) Coupling of Carborane with Aromatics and
Synthesis of Carborane-Fused Tricyclics
Yangjian Quan,† Zaozao Qiu,‡ and Zuowei Xie*,†,‡
†Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The Chinese University of Hong Kong, Shatin, New
Territories, Hong Kong, China
‡Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, China
S
* Supporting Information
a
Table 1. Optimization of Reaction Conditions
ABSTRACT: Zirconium/nickel comediated one-pot
three-component cascade cyclization of carboryne, alkene,
and 2-bromophenyltrimethylsilylacetylene has been
achieved, leading to the formation of a series of C,C,B-
substituted carborane-fused tricyclics. On the basis of
experimental results, a plausible mechanism is proposed
including [2 + 2 + 1] cross-cyclotrimerization followed by
intramolecular direct selective cage B−C(sp2) coupling.
b
entry
base
solvent
T (°C)
yield (%) (4aa/5aa)
This represents the first example of direct cage B−
C(phenyl) coupling via cage B−H activation.
1
2
3
4
5
6
7
8
−
−
−
toluene
toluene
toluene
THF
rt
60
110
rt
15/73
5/79
5/79
13/73
7/80
5/80
7/78
88/0
−
arboranes are a class of structurally unique molecules with
Cs2CO3
LiN(TMS)2
NEt3
toluene
toluene
toluene
toluene
rt
Cexceptionally thermal and chemical stabilities and the
rt
rt
Scheme 1. Transition-Metal Co-Mediated Three-
Component Cyclization
pyridine
rt
a
Reaction conditions: 1 (0.05 mmol), 2a (0.15 mmol), NiCl2(PMe3)2
(0.05 mmol), 3a (0.15 mmol), and base (0.1 mmol). GC yields.
b
a BH vertex of carboranes is still a rather challenging subject,
and direct coupling of a cage B with phenyl sp2-C via B−H
activation has remained elusive.8
In view of the spectacular role of transition metals in
chemical transformations, we are interested in developing
transition-metal-mediated multicomponent reactions to con-
struct complex molecules from readily available simple
precursors in a single operation. To this end, we have
developed transition-metal-promoted/-catalyzed [2 + 2 + 2]
cycloaddition reactions for the preparation of benzocarboranes9
and dihydrobenzocarboranes.10 Very recently, our group has
reported a Zr/Ni comediated three-component [2 + 2 + 1]
cross-cyclotrimerization of carboryne, alkene, and trimethylsi-
lylalkyne for the synthesis of dihydrofulvenocarboranes.11
During the course of this study, an unprecedented C,C,B-
substituted carborane-fused tricyclic 5aa was isolated from the
reaction of Cp2Zr(μ-Cl)(μ-C2B10H10)Li(OEt2)2 (1), 1-hexene
(2a), and 2-bromophenyltrimethylsilylacetylene (3a) in the
presence of NiCl2(PMe3)2 (Table 1). Compound 5aa may
ability to hold various substituents. These properties have made
them as useful basic units in boron neutron capture therapy
agents,1 in supramolecular design/materials,2 and in coordina-
tion/organometallic chemistry.3 Thus, the functionalization of
carboranes has received growing interest.4 Generally, electro-
philic substitution at cage BH vertices5 and capitation reaction
of nido-C2B9H11 with boron halides6 are two common
2−
synthetic methods for direct cage boron derivatization.
Examples of transition-metal-mediated hydroboration of o-
carboranes with alkynes via cage B−H activation are also
known.7 However, how to achieve selective functionalization of
Received: April 8, 2014
Published: May 13, 2014
© 2014 American Chemical Society
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a
Table 2. Synthesis of C,C,B-Substituted Carborane-Fused Tricyclics
a
b
c
Reaction conditions: 1 (0.5 mmol), 2 (1.5 mmol), NiCl2(PMe3)2 (0.5 mmol), 3 (1.5 mmol), and Cs2CO3 (1.0 mmol). Isolated yields. Reaction
was heated at 60 °C.
result from a three-component [2 + 2 + 1] cross-cyclo-
trimerization of carboryne, alkene, and alkyne,11 followed by
nickel(0) mediated cage B−C(sp2) coupling via direct B−H
activation (Scheme 1). This finding intrigues us to investigate
such a brand new three-component cascade reaction, and the
results are reported here.
On the basis of the optimal reaction condition for the
synthesis of dihydrofulvenocarboranes,11 we screened various
reaction conditions for the above multicomponent cascade
reaction. The results were summarized in Table 1. Reaction
temperatures had little effect on the formation of 5aa (entries
1−3, Table 1). Addition of bases could neutralize the hydrogen
bromide generated from the reaction to minimize the formation
of 4aa, resulting in the increased yields of 5aa (entries 5−7 vs 1,
Figure 1. Molecular structure of 5ab.
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dx.doi.org/10.1021/ja503489b | J. Am. Chem. Soc. 2014, 136, 7599−7602

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[CH(nBu)CH2CC(TMS)Ph]-1,2-C2B10H10, was identified
by GC-MS using an authenticated sample.11 The observed
products ratios of the above quenching experiments were
4aa:5aa = 70:30 after 4 h and 32:68 after 8 h. These results
implied that the intramolecular cage B−C(sp2) coupling in this
system was very efficient. Since A could not be trapped, a
model compound 1-(cis-CHCH-C6H4-o-Br)-1,2-C2B10H11
(A′) was used in place of A to confirm the Ni(0)-mediated
cage B−C(sp2) coupling. Indeed, in situ generated Ni(0), from
Scheme 2. Proposed Reaction Mechanism
n
the reaction of NiCl2(PMe3)2 with 2 equiv of BuLi in THF,
can promote the cage B−C(sp2) coupling to give two
regioisomers 1,3-(CHCH-o-C6H4)-1,2-C2B10H10 and 1,4-
(CHCH-o-C6H4)-1,2-C2B10H10 in 20% and 30% isolated
yields, respectively (see SI). On the basis of previous work11
and aforementioned experimental data, a plausible mechanism
is suggested in Scheme 2. Zr/Ni comediated [2 + 2 + 1] cross-
cyclotrimerization of o-carboryne, alkene, and trimethylsilylal-
kyne generates the key intermediate A.11 Oxidative addition of
C(sp2)-Br bond on in situ generated Ni(0)13 forms the
intermediate B. Intramolecular electrophilic substitution on B−
H at the 7- or 11-position,5,14 followed by removal of HBr by
base, produces intermediate C.15 Reductive elimination affords
the final product 5. This could be viewed as a Ni(0) promoted
intramolecular direct selective cage B−C(sp2) coupling via B−
H activation.
In summary, we have developed a novel three-component
cascade reaction of carboryne, alkene, and 2-bromophenyl-
trimethylsilylacetylene for the preparation of a series of C,C,B-
substituted carborane-fused tricyclics through direct B−H
activation. This represents the first example of direct cage B−
C(phenyl) coupling, which may shed some light on developing
methodologies for direct selective cage B−C(sp2) coupling for
the preparation of carborane functionalized aromatics.
Table 1). On the other hand, no 5aa was observed if pyridine
was used as the base, probably owing to the coordination of
pyridine to nickel center prohibiting the further reaction (entry
8, Table 1). In view of the yield of 5aa, reaction temperature,
and easy work-up procedures, entry 5 in Table 1 was chosen as
the optimal reaction condition.
A variety of 2-bromophenyltrimethylsilylacetylene was
examined under the above optimal reaction condition, and
the results were compiled in Table 2. Electron-withdrawing
groups on phenyl ring generally offered higher yields of 5 than
those of electron-donating substituents (entries 2−7 vs 8−10,
Table 2). Effects of R1 on reaction results were also examined.
For substituents containing a heteroatom such as −CH2SMe,
−CH2OMe, and −CH2NMe2, products 5da, 5fa, and 5ga were
isolated in relatively lower yields, probably owing to the
interactions of the heteroatom with the metal center (entries
13, 15, and 16, Table 2). On the other hand, if R1 = benzyl
groups, the corresponding products 5ca, 5ha, and 5ia were
obtained in higher yields (entries 12, 17, and 18, Table 2). It
was noted that one pair of diastereoisomers was observed for 5
except for 5ba, which was generated by the chiral carbon
bonded to R1 and cage boron substituent at either 7- or 11-
position (see Scheme S1). The dr ratios were about 1:1 as
determined by 1H NMR spectra of the crude products.
Replacement of R1 by H resulted in the loss of the chirality,
preventing the formation of diastereoisomers and facilitating
the characterization of the product (entry 11, Table 2). The low
yield of 5ba might be ascribed to the poor reaction efficiency of
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures, complete characterization
data, and X-ray data in CIF format for 5aa, 5ab, 5ai and 5ba.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
zxie@cuhk.edu.hk
■
Notes
1 with ethylene.12 When TMS was substituted by Bu, only [2
n
The authors declare no competing financial interest.
+ 2 + 2] cross-cyclotrimerization products dihydrobenzocar-
boranes were isolated without the observation of B−H
activation species, suggesting the importance of TMS group
in this reaction.11
ACKNOWLEDGMENTS
■
This work was supported by grants from the National Basic
Research Program of China (973 Program, grant no.
2012CB821600), the Research Grants Council of The Hong
Kong Special Administration Region (project no. CUHK7/
CRF/12G), and the National Natural Science Foundation of
China (project no. 21372245 to ZQ). Dedicated to Professor
Li-Xin Dai on the occasion of his 90th birthday.
1
Compounds 5 were fully characterized by H, 13C, and 11B
NMR spectroscopy as well as high-resolution mass spectrom-
etry. The molecular structures of 5aa, 5ab, 5ai, and 5ba were
further confirmed by single-crystal X-ray analyses, and the
representative structure of 5ab is shown in Figure 1.
We have previously proposed a reaction mechanism for the
formation of dihydrofulvenocarboranes (A in Scheme 2) via
transition-metal-mediated [2 + 2 + 1] cross-cyclotrimerization
of o-carboryne, alkene, and trimethylsilylalkyne, in which the
alkyne acts as a one-carbon component.11 We attempted to
isolate A by quenching the reaction of entry 1 in Table 2.
However, the corresponding A was not observed by GC-MS.
Instead, a trace amount of debrominated species of A, 1,2-
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