Ir-Catalyzed Selective B(3)-H Amination of o-Carboranes with NH3

Article abstract of DOI:10.1021/jacs.1c00593

Ammonia gas, NH3, is a cheap and widely used industrial feedstock, which has received tremendous research interests in its functionalization. This work reports a breakthrough in catalytic selective cage B(3)-H amination of o-carboranes with NH3 via Ir-catalyzed B-H/N-H dehydrocoupling, offering convenient and efficient access to a series of 3-NH2-o-carborane derivatives in moderate to high isolated yields with a broad substrate scope. The employment of readily available NH3 gas as the aminating reagent with H2 as the sole byproduct endows the protocol economy, practicability, and environmental friendliness. A plausible reaction mechanism is proposed on the basis of control experiments.

Full text of DOI:10.1021/jacs.1c00593

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Ir-Catalyzed Selective B(3)‑H Amination of o‑Carboranes with NH3
Yik Ki Au, Jie Zhang, Yangjian Quan,* and Zuowei Xie*
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ABSTRACT: Ammonia gas, NH3, is a cheap and widely used industrial feedstock, which has received tremendous research interests
in its functionalization. This work reports a breakthrough in catalytic selective cage B(3)-H amination of o-carboranes with NH3 via
Ir-catalyzed B-H/N-H dehydrocoupling, offering convenient and efficient access to a series of 3-NH2-o-carborane derivatives in
moderate to high isolated yields with a broad substrate scope. The employment of readily available NH3 gas as the aminating reagent
with H2 as the sole byproduct endows the protocol economy, practicability, and environmental friendliness. A plausible reaction
mechanism is proposed on the basis of control experiments.
mmonia gas, NH3, is a cheap and widely used industrial
feedstock, serving as the versatile building block in
carboranes9 including icosahedral geometry, three-dimensional
aromaticity, and inherent robustness endow them a wide range
of applications,10 yet make their functionalization quite
challenging. In view of the considerable progress recently
made in transition-metal-catalyzed vertex-specific functionali-
zation of carboranes,8,11,12 we hypothesized that acceptorless
dehydrogenative cross-coupling between NH3 and carborane
would provide facile access to the desired aminocarborane
derivatives. These compounds can only be synthesized through
a reduction-nucleophilic amination−oxidation process with the
risk of explosion or a tandem route including transition-metal-
catalyzed B-H amination and subsequent deprotection.11d,13 In
sharp contrast to the strong coordination of NH3 to BH3 in
amine-borane adducts,14 no significant interactions between
NH3 and carborane exist, increasing the difficulty of the
proposed dehydrogenative cross-coupling. After many at-
tempts, a breakthrough of regioselective and straightforward
cage B-H amination of o-carborane with NH3 has been
attained by means of Ir-catalyzed B-H/N-H dehydrocoupling
with H2 as the sole byproduct. These results are reported in
this Communication (Scheme 1).
Commercially available o-carborane and NH3 were chosen
as the model coupling partners to evaluate the feasibility of B-
H/N-H dehydrocoupling. In the presence of an Ir(I) catalyst
and phosphine ligand, the reaction of o-carborane with NH3 in
THF at 110 °C (bath temperature) for 12 h afforded only a
trace amount of the product 3-NH2-o-carborane 3a detected
by gas chromatography mass spectrometry (GC-MS) (entry 1,
Table 1). Screening of phosphine ligands proved PCy3 was the
optimal choice, generating 3a in 40% isolated yield (entries 1−
4, Table 1 and Table S1 in the SI). Other solvents offered
reduced yields of 3a (entries 5−7, Table 1 and Table S2 in the
A
pharmaceutical and many other commercial products. Direct
transformation of NH3 gas to value-added organic molecules
has been a persistent goal, though accompanied by
considerable challenges such as the deactivation of the catalyst
after forming stable Werner ammine complexes and high
strength of the N−H bond (107 kcal/mol).1 Despite these
difficulties, several strategies for NH3 functionalization have
been developed including classic ammonia oxidation,2 hydro-
aminomethylation,3 reductive amination,4 hydroamination,5
and cross-coupling of aryl halides with ammonia.6 Recently,
7
straightforward C-H amination with NH3 has also been
realized via photoredox catalysis7b or directing-group-guided
transition-metal catalysis.7c,d In spite of these achievements,
acceptorless dehydrogenative NH3 functionalization remains
less investigated (Scheme 1).
As an ongoing project in our laboratory,8a we are very
interested in developing a strategy for direct functionalization
of NH3 with o-carboranes. The extraordinary properties of
Scheme 1. Catalytic Strategies for NH3 Functionalization
Received: January 18, 2021
Published: March 15, 2021
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© 2021 American Chemical Society
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a
a b
,
Table 1. Optimization of Reaction Conditions
Table 2. Synthesis of B(3)-amino-o-carboranes
entry
ligand (mol %)
K2CO3 (equiv)
3a (%)
1
2
3
4
P(o-tol)3 (20)
P(Cy)3 (20)
XPhos (20)
P(tBu)3 (20)
P(Cy)3 (20)
P(Cy)3 (20)
P(Cy)3 (20)
P(Cy)3 (20)
P(Cy)3 (20)
P(Cy)3 (20)
P(Cy)3 (30)
P(Cy)3 (30)
P(Cy)3 (40)
P(Cy)3 (30)
P(Cy)3 (30)
P(Cy)3 (30)
P(Cy)3 (15)
-
-
-
-
-
trace
40
trace
trace
N. R.
19
N. R.
70
71
63
69
76
71
b
5
c
6
-
-
d
7
8
9
10
11
12
13
2
3
4
2
3
3
3
3
3
3
e
14
15
80
59
66
56
f
g
16
h
17
a
Reactions were conducted on a 0.1 mmol scale in 6 mL of THF in a
200 mL closed flask with 1.5 atm of NH3, XPhos = 2-
dicyclohexylphosphino-2,4,6′-triisopropylbiphenyl, yield of isolated
b
c
d
products. Toluene instead of THF. DME instead of THF. 1,4-
e
f
Dioxane instead of THF. 18 h instead of 12 h. 24 h instead of 12 h;
the lower yield was due to deboronation. [Ir(cod)Cl]2 instead of
[Ir(cod)OMe]2. [Ir(cod)OMe]2 (2.5 mol %) was employed.
g
h
SI). It was later found that the addition of base promoted such
B-H/N-H dehydrocoupling, and the use of 3.0 equiv of K2CO3
increased the yield of 3a to 71% (entries 8−10, Table 1 and
Table S3 in the SI). Further optimization of the phosphine
loading indicated 30 mol % was the best, resulting in 3a in 76%
isolated yield (entries 9, 12, and 13, Table 1). A longer
reaction time (18 h) further improved the yield of 3a to 80%
(entry 14, Table 1). However, a prolonged reaction time (24
h) led to a lower yield of 3a due to the deboronation (entry 15,
Table 1). The employment of [Ir(cod)Cl]2 resulted in a drop
of yield to 66% (entry 16, Table 1). In view of the yield of 3a,
entry 14 in Table 1 was chosen as the optimal reaction
conditions.
Various cage C- or B-substituted o-carboranes were
subsequently examined for this Ir-catalyzed B-H/N-H
dehydrocoupling, and results were compiled in Table 2. A
wide range of substituents including alkyl, aryl, and benzyl at
the B(9) position were compatible with this reaction, leading
to the corresponding B(3)-amino-o-carborane derivatives in
moderate to high isolated yields (3a-3m). Electron-donating
groups generally offered higher yields than the electron-
deficient ones (3f-3j). The thiophene-containing substrate
worked well, affording the aminated product 3m in 77%
isolated yield. 4-Ph-o-carborane afforded two regioisomers 6-
NH2-4-Ph-o-carborane (3na) and 3-NH2-4-Ph-o-carborane
(3nb) in 51 and 27% isolated yields, respectively. Various
substituents at cage C were also tolerated, and the
corresponding products 3o-3s were isolated in 46−82% yields.
The more steric demanding substituents at the cage C atom
provided the relatively lower yields (3a vs 3o vs 3p). The use
of 1,2-Me2-o-carborane led to no reaction (3t). Cage B(3)-
a
b
Reactions were conducted on a 0.1 mmol scale. Yield of isolated
c
d
e
products. 24 h instead of 18 h. 40 h instead of 18 h. 8 h instead of
18 h. 12 h instead of 18 h.
f
substituted carboranes reacted with NH3 smoothly to generate
the target 6-amino-o-carboranes in 66−72% isolated yields
(3u-3w).
Compounds 3 were fully characterized by H, 13C, 19F, and
1
11B NMR spectroscopy as well as high-resolution mass
spectrometry. The molecular structures of 3e, 3na, 3nb, 3s,
and 3u were further confirmed by single-crystal X-ray analyses.
To gain some insights into the reaction mechanism, several
control experiments were performed (Scheme 2). It was
expected that 1 equiv of H2 should be generated as the
byproduct during the reaction. Indeed, a significant peak at δ =
1
4.47 ppm assignable to H2 was observed in the H NMR
spectroscopy of the reaction mixture (see Figure S6 in the SI),
which was further confirmed by gas chromatography thermal
conductivity detector (GC-TCD) analyses (see Figure S7 in
the SI).15 The crucial role of the Ir(I) catalyst was proved by
the control experiment shown in Scheme 2a, as no reaction
was observed in the absence of [Ir(cod)OMe]2. On the other
hand, the yields for 3a were gradually enhanced by increasing
the loading of the Ir(I) catalyst in the absence of K2CO3
(Scheme 2b). Such a phenomenon may suggest the presence
of catalyst poisoning by the product 3-amino-o-carborane. To
test this hypothesis, product 3a was added to the reaction
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Scheme 2. Control Experiments
Scheme 3. Proposed Reaction Mechanism
C′ with NH3 also afforded the target product 3a in 69% yield
(Scheme 2h).
On the basis of the aforementioned experimental results and
literature reports,12c,17,18 a proposed reaction mechanism for
catalytic selective B(3) amination is shown in Scheme 3. The
reaction of [Ir(cod)OMe]2 with NH3 produces a dinuclear
amino-bridged complex [Ir(cod)NH2]2 (A),17a which under-
goes ligand exchange reaction with PCy3 to give a monomeric
active species (Cy3P)nIrINH2 (B) to start the catalytic cycle.
The oxidative addition of B onto the most electron-deficient
B(3)-H bond of o-carborane (1a) affords an IrIII intermediate
C.12c,17b Intermediate C undergoes an oxidative addition with
NH3 to generate another intermediate D.12c,18 Reductive
elimination of D gives the intermediate E and releases H2 gas
(path a). Alternatively, the acid−base reaction of C with NH3
also affords E (path b).12c,19 Another reductive elimination of
E yields the final product 3a and regenerates the IrI catalyst to
complete the catalytic cycle.
In summary, a straightforward and efficient iridium-catalyzed
dehydrogenative cross-coupling between o-carboranes and
ammonia gas was achieved, leading to facile synthesis of a
series of 3-NH2-o-carboranes. This new protocol allows
chemical-oxidant-free B-H/N-H dehydrocoupling and gener-
ates H2 gas as the sole byproduct. This work not only opens up
a new pathway for direct, efficient, and regioselective B-H
amination of o-carboranes but also offers a valuable reference
for organic C-H amination with NH3.
mixture, leading to an obvious drop of the yield of 3a (Scheme
2c). In the absence of K2CO3, the reaction of o-carborane with
NH3 afforded 3a in 43% yield, whereas the addition of K2CO3
led to 3a in 71% yield (Scheme 2d). However, the addition of
3 equiv of 18-crown-6, a well-known K+ trapper,16 to the
reaction system resulted in a big drop of the yield of 3a to 53%
(Scheme 2e). These results indicated that the trapping of K+
by 18-crown-6 largely reduced the reaction efficiency, which
suggested that the interactions between 3a and K+ might
remove the poisoning effect from 3a.
To obtain some information on the reaction intermediates,
an iridium amide complex [Ir(cod)NH2]2 A was prepared in
83% yield from the reaction of [Ir(cod)OMe]2 with NH3
according to a literature report (Scheme 2f).17a A could
catalyze the dehydrocoupling reaction under standard
conditions to offer 3a in 81% yield, whereas its stoichiometric
reaction with o-carborane in the absence of NH3 gave no target
product (Scheme 2g). These results indicated that (1) A might
be a precatalyst and (2) the corresponding Ir(III) intermediate
C (Scheme 3) that resulted from the oxidative addition of A
onto the B(3)-H bond in the presence of PCy3 should not
undergo reductive elimination to afford 3a in the absence of
NH3. Many attempts to isolate the intermediate C were not
successful. An alternative Ir(III) complex C′ was then prepared
according to a literature report (Scheme 2h).17b C′ indeed
catalyzed the cross-coupling efficiently to give 3a in 73% yield
(Scheme 2i), which is very comparable to the catalytic activity
of [Ir(cod)Cl]2 (entry 16, Table 1). In addition, the reaction of
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of Primary Amines via Reductive Amination Employing a Reusable
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AUTHOR INFORMATION
Corresponding Authors
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Yangjian Quan − Department of Chemistry and State Key
Laboratory of Synthetic Chemistry, The Chinese University of
Hong Kong, Shatin, N. T., Hong Kong, China; orcid.org/
0000-0002-6500-3152; Email: yjquan@cuhk.edu.hk
Zuowei Xie − Department of Chemistry and State Key
Laboratory of Synthetic Chemistry, The Chinese University of
Hong Kong, Shatin, N. T., Hong Kong, China; orcid.org/
0000-0001-6206-004X; Email: zxie@cuhk.edu.hk
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Authors
Yik Ki Au − Department of Chemistry and State Key
Laboratory of Synthetic Chemistry, The Chinese University
of Hong Kong, Shatin, N. T., Hong Kong, China
Jie Zhang − Department of Chemistry and State Key
Laboratory of Synthetic Chemistry, The Chinese University
of Hong Kong, Shatin, N. T., Hong Kong, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c00593
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by grants from the Research Grants
Council of HKSAR (Project No. 14305017, 14305918) and
the NSFC/RGC Joint Research Scheme (Project No.
N_CUHK402/18). J.Z. thanks the CUHK Impact Postdoc-
toral Fellowship Scheme (IPDFS) for support. We are thankful
for the financial support from the Innovation and Technology
Commission (HKSAR) to the State Key Laboratory of
Synthetic Chemistry.
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