Ligand-Free Iridium-Catalyzed Dehydrogenative ortho C?H Borylation of Benzyl-2-Pyridines at Room Temperature

Article abstract of DOI:10.1002/adsc.201801292

A convenient and ligand-free iridium-catalyzed dehydrogenative ortho C?H borylation of benzyl-2-pyridines has been developed. The reaction proceeds smoothly at room temperature using pinacolborane as a borylating reagent in the presence of catalytic amount of [IrOMe(COD)]₂. The reaction is compatible with many functional groups, providing a vast array of ortho borylated products in moderate to excellent yields with excellent selectivities. (Figure presented.).

Full text of DOI:10.1002/adsc.201801292

Title: Ligand-Free Iridium-Catalyzed Dehydrogenative ortho C-H
Borylation of Benzyl-2-Pyridines at Room Temperature
Authors: Yuhuan Yang, Qian Gao, and Senmiao Xu
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801292
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10.1002/adsc.201801292
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Ligand-Free Iridium-Catalyzed Dehydrogenative ortho C-H
Borylation of Benzyl-2-Pyridines at Room Temperature
Yuhuan Yang,† Qian Gao,† and Senmiao Xu*,†,‡
†
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Center for Excellence in Molecular Synthesis,
Suzhou Research Institute, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000,
China
Email: senmiaoxu@licp.cas.cn
Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou Normal
‡
Univer-sity, Hangzhou 311121, P. R. China
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Regioselectivity relies on the reversible formation of
dehydrogenative ortho C-H borylation of benzyl-2- the iridium-silicon bond. Smith and co-workers
Abstract. A convenient and ligand-free iridium-catalyzed
pyridines has been developed. The reaction proceeds
smoothly at room temperature using pinacolborane as a
borylating reagent in the presence of catalytic amount of
[IrOMe(COD)]2. The reaction is compatible with many
functional groups, providing a vast array of ortho borylated
products in moderate to excellent yields with excellent
selectivities.
developed ortho-borylation of anilines and their
derivatives directed by hydrogen bonding between N-
H and oxygen of one of the boryl groups.[8] Lewis
acidic boron can also direct ortho C-H borylation
when interacting with a Lewis base.[9] The Kanai
group developed a Lewis acid tethered bipyridine,
achieving ortho C-H borylation through Lewis acid-
base interaction between catalyst and substrate.[10]
Another strategy is to apply the postulated 14-
electron trisboryl iridium complex as active catalytic
species. A proper ligand plays a crucial role in this
Keywords: borylation; C-H activation; iridium;
organoboron; synthetic methods
aspect.
Electron
poor
triarylphosphines,[11]
triarylarsines,[12] silica-supported phosphines,[13]
hemilabile dinitrogen ligand,[14] and bidentate,
Aryl boronic acids and their derivatives have received
considerable attention due to their importance in
materials science, medicinal chemistry, and organic
synthesis. A variety of methods have been developed
to prepare these structures.[1] Among these, Ir-
catalyzed C-H borylation of aromatic C-H bonds has
become a powerful tool to achieve numerous aryl
boronates with an atom and step economy way,
tolerating a variety of functional groups.[2] The
regioselectivity of this reaction is often governed by
steric factors. It usually occurs at the position with
the least steric hindrance,[3] which is complementary
to directed ortho metallation (DoM).[4] However,
DoM suffers from limitations of substrate scope and
harsh reaction conditions due to the use of reactive
organolithium reagents. Therefore, the development
of Ir-catalyzed ortho selective C(sp2)-H borylation of
arenes is highly demanded in this area.[5]
monoanionic ligands[15] were often utilized.[5]
A
variety of functionalities such as ketone, ester, amide,
carbamate, ether, amine, and hydrazine, etc. could be
used as directing groups.
Scheme 1. Recent Advances in Ir- or Rh-Catalyzed ortho
C-H Borylation Using Pyridine as the Directing Group.
To realize directed ortho C-H borylation, two
strategies have been developed. One strategy is to
use 16-electron trisboryl iridium complex, which
has been shown to be the active catalytic species
Despite these advances, pyridine as a directing
group in Ir-catalyzed ortho C-H borylation is still
very limited. Specialized ligands are often required to
make this transformation.[14d,15,16] Furthermore, these
ligands are not easy to prepare, which hampers these
in
4,4’-di-tert-butyl-2,2’-bipyridine
(dtbpy)
system.[6] For example, Hartwig and co-workers
developed silyl directed ortho C-H borylation.[3,7]
1
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10.1002/adsc.201801292
Advanced Synthesis & Catalysis
methods in practical use. On the other hand, the DoM
of these compounds is often not successful. For
example, the reaction of benzyl-2-pyridine in the
presence of strong bases led to functionalization at
the benzylic position instead.[17] 2-Substituted
pyridine has been used as an ancillary ligand in Ir-
catalyzed B-H borylation reaction of carboranes.[18]
Inspired by this, we envisioned that a pyridine
tethered arene would undergo ortho C(sp2)-H
borylation without the assistance of an external ligand.
Herein, we disclose a ligand-free iridium-catalyzed
ortho C-H borylation of benzyl-2-pyridines under
mild reaction conditions.[19] This method provides a
vast array of borylated products in good to excellent
isolated yields with excellent regioselectivity.
mixture of non-directing borylated products (Table 1,
entry
4).
When
0.75
equivalent
of
bis(pinacolato)diboron (B2pin2) was used instead of
1.5 equivalents HBpin, a significantly decreased yield
(36%) was observed although the selectivity was
identical (2aa/3aa = 99: 1) (Table 1, entry 5). The use
of THF instead of n-hexane also led to a diminished
yield (78%) and a slightly lowered selectivity
(2aa/3aa = 98: 2) (Table 1, entry 6).
With optimized conditions identified, we then
focused on the substrate scope of this reaction as
shown in Table 2. In all cases, only trace amount of
diborylated products were observed (mono: di > 97:
3). Reactions of para-substituted substrates gave
corresponding ortho borylated products 2aa-2aj in
moderate to excellent yields (68-98%). Interestingly,
a thioether-containing substrate was also compatible
with the reaction, affording product 2ai in 84% yield.
Substrates with phenyl rings bearing meta-
substituents furnished the products 2ak-2ao in
moderate to good yields (51-80%). Notably, meta-
fluoro and cyano substituted substrates gave a
mixture of two ortho borylated products (2ak and
2ak’, 2an and 2an’) while no regioisomers were
observed for the other meta-substituted substrates.
When ortho-substituted substrates were employed,
the borylated products (2ap-2ar) with inferior yields
(51-69%) were obtained. The current method could
also tolerate disubstituted substrates, furnishing the
products (2as-2az) in 37-86% yields. Compounds
2ab-2az show 11B chemical shifts of 7-13 ppm,
indicating presence of coordination between the
pyridine nitrogen and the boron. We also evaluated
the effect of pyridine substituent on this reaction. The
reaction of substrate 1ba bearing 5-chloro in pyridine
ring afforded product 2ba in 57% yield. Interestingly,
11B NMR chemical shift of 25 ppm of this compound
suggests an absence of interaction between the
pyridine nitrogen and the boron.
Table 1. Reaction Optimization of Ligand-free Iridium-
Catalyzed C(sp2)-H Borylation of benzyl-2-pyridine 1aaa
entry variation from
standard conditions
none
2aa:
3aa
yield (%)
1
2
3
4
5
99: 1
68: 32
53: 47
n.d.
86 (75)b
36
18
2
60 ˚C instead of rt
80 ˚C instead of rt
5 mol% dtbpy was added
0.75 equiv B2Pin2 instead
of HBpin
99: 1
36
6
THF instead of n-hexane
98: 2
78
a)Unless otherwise noted, all the reactions were carried out with
[1aa] = 0.2 M, [Ir dimer] = 0.005 M, and HBpin = 0.3 M at room
temperature for 24 h. The ratio of 2aa/3aa and the yield of
2aa were determined by GC analysis using a calibrated
internal standard. b)The number in parentheses refers to
isolated yield.
Table 2. Substrate Scope of Ligand-free Iridium-Catalyzed
C(sp2)-H Borylation of Benzyl-2-pyridines 1a
To initiate our work, we chose benzyl-2-pyridine
1aa as the pilot substrate. The borylation of 1aa
proceeded smoothly in the presence of 2.5 mol%
[IrOMe(COD)]2 (COD = 1,4-cyclooctadiene), 1.5
equivalents of pinacolborane (HBpin) in n-hexane at
room temperature for 24 hours, resulting in n ortho
borylated product 2aa in 86% GC yield with
excellent selectivity (2aa/3aa = 99: 1) (Table 1, entry
11
1). The B chemical shift 10.5 ppm of 2aa indicates
the presence of a coordination between the pyridine
nitrogen and the boron, which is similar to ortho-
borylated product of 2-phenylpyridine.[14d] In addition,
11B NMR chemical shift of 19.7 ppm suggests that
two boron signals are equilibrated by the dynamic
formation of pyridine boron bond.14d The elevated
temperature had a negative effect on both reactivity
and selectivity (Table 2, entries 2 and 3). For example,
when the reaction was carried out 60 ˚C, only 36%
yield was observed with moderate selectivity
(2aa/3aa = 68: 32) (Table 1, entry 2). Using literature
reported ligand dtbpy, the reaction furnished a
2
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10.1002/adsc.201801292
Advanced Synthesis & Catalysis
Scheme 2. Transformations of Product 2aa.
We were interested in the mechanism of this
ligand-free Ir-catalyzed ortho C-H borylation. When
mixing [IrOMe(COD)]2 with benzyl-2-pyridine 1aa
in d12-cyclohexane (d12-CyH) or d8-THF, we did not
observe the formation of the 1aa-Ir complex (eq 1).[18]
Hydrogen gas bubbling was observed immediately
along with the formation of product 2aa upon
addition of HBpin. Cyclooctane 6, the only reduced
product of COD, was also observed in GC-MS (eq 2).
As a comparison, the reaction of [IrOMe(COD)]2
with HBpin in n-hexane for 12 h afforded
cyclooctane 6, mono-borylated cyclooctene 7, and
mono-borylated cyclooctane 8 (eq 3). These results
indicate that the [IrOMe(COD)]2 would react with
HBpin initially then substrate 1aa could coordinate
with iridium center.
On the basis of the above observations and
literature reported mechanism of dtbpy/Ir system,[6]
plausible catalytic cycles are outlined in Figure 1.
The reaction of [Ir(OMe)(COD)]2 with HBpin in the
presence of substrate 1aa would generate mono-
pyridine coordinated boryl iridium(I) complex A or
bis-pyridine coordinated complex B by the liberation
of one equivalent of MeOBpin. Complex A would
react with 3 equivalents of HBpin to generate
trisboryl Ir(III) complex C along with the formation
of cyclooctane. Coordination of C with 1aa followed
by C-H insertion via oxidative addition would form
Ir(V) intermediate E which would undergo reductive
elimination to produce 2aa with concurrent formation
of Ir(III) hyrido boryl complex F. Reaction of F with
HBpin would regenerate active species C along with
the liberation of H2. Complex F would also
coordinate with 1aa followed by reaction with HBpin
to generate trisboryl Ir(III) D for the catalytic cycle.
Alternatively, complex B could also undergo similar
steps to furnish product 2aa and complex F.
a)Unless otherwise noted, all the reactions were carried out with
[1] = 0.2 M, [[IrOMe(COD)]2] = 0.005 M, and HBpin = 0.3 M at
room temperature for 24 h.
We also performed transformations of 2aa to
demonstrate synthetic utility of the current method.
As shown in Scheme 2, the C-B bond could undergo
Suzuki-Miyaura coupling to afford arylated product 4
in 80% yield. In addition, treatment of 2aa with
KHF2 could generate fused boron-nitrogen containing
heterocycles 5 in 86% yield instead of potassium
trifluoroborate.[20] This route could potentially
provide an opportunity to access fused 1,2-
azaborines.[21]
3
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10.1002/adsc.201801292
Advanced Synthesis & Catalysis
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Figure 1. Plausible reaction mechanism.
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In summary, we have developed a ligand-free Ir-
catalyzed ortho C-H borylation of benzyl-2-pyridines
under mild reaction conditions. The reaction could
tolerate a vast array of functionalities, affording ortho
borylated products in good to excellent yields with
excellent selectivities. We also demonstrated the
borylated product could easily be converted to fused
boron-nitrogen containing heterocycles. Initial
mechanistic studies revealed the substrate could
promote the formation of trisboryl iridium complex
bearing for the ortho C-H borylation. Further
applications of obtained products are currently
underway in our laboratory.
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Experimental Section
Typical procedure for ortho C(sp2)-H borylation: To a 25-
mL Schlenk tube equipped with a stir bar was charged with
[IrOMe(COD)]2 (3.3 mg, 0.005 mmol), n-hexane (1.0 mL),
and HBpin (38.4 mg, 0.30 mmol), and added 1 (0.20
mmol). The resulting mixture was then allowed to stir at
room temperature for 24 h under N2 atmosphere. After
completion, the reaction was directly subjected to column
chromatography on silica gel using PE/EtOAc (2:1) as
eluent to afforded corresponding borylated product 2.
[14]
Acknowledgements
We thank National Natural Science Foundation of China
(21573262) and Natural Science Foundation of Jiangsu Province
(BK20161259 and BK20170422) for generous financial support
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Advanced Synthesis & Catalysis
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5
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10.1002/adsc.201801292
Advanced Synthesis & Catalysis
UPDATE
Ligand-Free Iridium-Catalyzed Dehydrogenative
ortho C-H Borylation of Benzyl-2-Pyridines at
Room Temperature
Adv. Synth. Catal. Year, Volume, Page – Page
Yuhuan Yang, Qian Gao, and Senmiao Xu*
6
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