Rh-catalyzed borylation of N-adjacent C(sp3)-H bonds with a silica-supported triarylphosphine ligand

Article abstract of DOI:10.1021/ja305694r

Direct C(sp³)-H borylation of amides, ureas, and 2-aminopyridine derivatives at the position α to the N atom, which gives the corresponding α-aminoalkylboronates, has been achieved with a heterogeneous catalyst system consisting of [Rh(OMe)(cod)]₂ and a silica-supported triarylphosphine ligand (Silica-TRIP) that features an immobilized triptycene-type cage structure with a bridgehead P atom. The reaction occurs not only at terminal C-H bonds but also at internal secondary C-H bonds under mild reaction conditions (25-100 °C, 0.1-0.5 mol % Rh).

Full text of DOI:10.1021/ja305694r

Communication
pubs.acs.org/JACS
Rh-Catalyzed Borylation of N‑Adjacent C(sp3)−H Bonds with a Silica-
Supported Triarylphosphine Ligand
Soichiro Kawamorita, Tatsuya Miyazaki, Tomohiro Iwai, Hirohisa Ohmiya, and Masaya Sawamura*
Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
S
* Supporting Information
immobilized triptycene-type cage structure with a bridgehead P
atom. This Rh catalysis even allows the preparation of
ABSTRACT: Direct C(sp3)−H borylation of amides,
ureas, and 2-aminopyridine derivatives at the position α
to the N atom, which gives the corresponding α-
aminoalkylboronates, has been achieved with a heteroge-
neous catalyst system consisting of [Rh(OMe)(cod)]2 and
a silica-supported triarylphosphine ligand (Silica-TRIP)
that features an immobilized triptycene-type cage structure
with a bridgehead P atom. The reaction occurs not only at
terminal C−H bonds but also at internal secondary C−H
bonds under mild reaction conditions (25−100 °C, 0.1−
0.5 mol % Rh).
secondary alkylboronates through selective borylation of
internal C(sp3)−H bonds. Direct secondary C(sp3)−H
borylations have been described only for the Pd/C-catalyzed
nonregioselective borylation of ethylbenzene and the photo-
chemical, stoichiometric, low-yield reaction of an isolated
tungsten boryl complex with cyclohexane.9c,10b In both cases,
the substrate was used as the solvent.
Various Rh catalyst systems (0.5 mol % Rh loading) with
different ligands were prepared in situ from [Rh(OMe)(cod)]2
in hexane for evaluation of their activities toward the C(sp3)−H
borylation of N,N-dimethylacetamide (1a, 0.5 mmol) with
bis(pinacolato)diboron (pinB−Bpin, 2, 0.25 mmol) at 60 °C
for 1 h. The results are summarized in Scheme 1. Specifically,
an immobilized catalyst system using Silica-TRIP (0.5 mol %)
and [Rh(OMe)(cod)]2 (0.5 mol % Rh) (P/Rh 1:1) promoted
lkylboronic acids and their derivatives find widespread
Autility not only as intermediates in organic synthesis but
also as bioactive compounds in medicinal chemistry.1 Conven-
tionally, alkylboronic acid derivatives have been prepared
through borylation of highly reactive organometallic reagents
such as alkyllithium or Grignard reagents; however, these
methods present problems in functional group compatibility.2
Recently, transition-metal-based catalytic methods such as
hydroboration of alkenes,3 β-borylation of α,β-unsaturated
carbonyl compounds,4 addition of B to C−heteroatom double
bonds,5 and borylation of alkyl (pseudo)halides6 have been
developed.7 These reactions proceed under neutral and mild
reaction conditions, allowing access to functionalized alkylbor-
onic acid derivatives. Even these catalytic methods, however,
require prefunctionalization of the starting organic substrate at
the C atom to which a B atom is to be introduced.
Scheme 1. Ligand Effects in Rh-Catalyzed N-Adjacent
a
C(sp3)−H Borylation of 1a with 2
To achieve “atom efficiency,” direct catalytic borylation of
C(sp3)−H bonds of functionalized organic compounds is a
desirable strategy for obtaining alkylboronic acid deriva-
tives.8−10 This type of transformation remains highly
challenging because of the chemical stability of C(sp3)−H
bonds, while direct borylations of C(sp2)−H bonds have
become relatively common methods.8,11,12 Rh-, Ir-, Ru-, and
Re-catalyzed direct borylations of alkanes are known, but they
require relatively extreme conditions, such as high temperatures
or light irradiation, and have a scope limited to the borylation
of terminal C(sp3)−H bonds of simple alkanes.8,9
a
This report describes a Rh-catalyzed C(sp3)−H borylation of
amides, ureas, and 2-aminopyridine derivatives at the position α
to the N atom (N-adjacent position)13 that yields the
corresponding α-aminoalkylboronic acid derivatives.1a,b,d,5a,d,14
The Rh catalysis occurs under mild conditions (25−100 °C,
0.1−0.5 mol % Rh) in the presence of the silica-supported
triarylphosphine ligand Silica-TRIP,12g,15 which contains an
Conditions: 1a (0.50 mmol), 2 (0.25 mmol), [Rh(OMe)(cod)]2
(0.00125 mmol of Rh), ligand (0.00125 mmol), hexane (1.0 mL), 60
°C, 1 h. Yields based on 2 were determined by 1H NMR spectroscopy.
b
A 9% yield of 3a′ was detected in the crude product mixture.
Received: June 12, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja305694r | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a smooth reaction resulting in complete consumption of 2 to
afford the C(sp3)−H monoborylation product 3a and the
geminal bisborylation product 3a′ in NMR yields of 126% and
9%, respectively, based on 2.16−18 Interestingly, the formation
of N,N-bis(borylmethyl)acetamide did not occur, indicating
that the first borylation is more effective in deactivating the
second borylation at the unreacted N-methyl group than at the
borylated methyl group. Furthermore, borylation at the most
acidic C−H bond α to the carbonyl group did not occur. The
yield in excess of 100% indicated that the byproduct pinB−H
also functioned as a reagent, but its reactivity was much lower
than that of 2.16 The C(sp3)−H monoborylation proceeded
even at 25 °C, giving 3a with higher selectivity (80% yield, 10
h).
Table 1. Range of Silica-TRIP−Rh-Catalyzed N-Adjacent
a
C(sp3)−H Borylations with 2
In contrast to the results using Silica-TRIP, the immobilized
trialkylphosphine Silica-SMAP,19,20 which has a similar cage-
type structure with the same mode of immobilization, did not
promote the reaction (see Scheme 1 for ligand effects). This is
surprising because Silica-SMAP exhibited better performance in
the Ir- or Rh-catalyzed ortho C(sp2)−H borylation of
functionalized arenes.12b,g The immobilized uncaged triphenyl-
phosphine-type ligand Silica-TPP12i and the homogeneous
triptycene-type ligand L115 induced little or no borylation
activity. These results indicate that the triptycene-type structure
and the immobilization are both critical factors. Other
homogeneous ligands with different steric and electronic
natures such as PPh3, PMe3, PBu3, PCy3, PtBu3, XPhos,21
dtbpy,8,11d−e and the bulky NHC ligand SIPr22 were ineffective.
In addition, no reaction occurred with a ligand-free Rh system.
The Rh-catalyzed C(sp3)−H borylation was applicable to a
range of N-containing compounds, including amides, ureas, and
2-aminopyridine derivatives (Table 1). The borylation of N,N-
dimethylpivalamide (1b) proceeded regioselectively at a
C(sp3)−H bond of one of the N-methyl groups to give 3b in
84% yield, despite the presence of the potentially reactive
terminal C−H bonds in the pivaloyl group (entry 1). N-
Methylcaprolactam (1c) was also suitable for selective C−H
borylation at the N-methyl group (entry 2).
Remarkably, the Silica-TRIP−Rh system even allowed more
challenging internal C(sp3)−H borylation under mild con-
ditions (Table 1, entries 3 and 4).9c,10b The borylation of N-
pivaloylpyrrolidine (1d) proceeded smoothly at 80 °C to afford
the secondary alkylboronate 3d. Furthermore, benzylic
secondary borylation with N-benzyl-N-ethylpivalamide (1e)
occurred under even milder reaction conditions (50 °C) to give
the corresponding pure α-aminobenzylboronate 3e (entry 4). It
should be noted that no aromatic C(sp2)−H borylation
occurred despite the intrinsic reactivity of the aromatic
C(sp2)−H bonds and the existence of a potential directing
group on the aromatic ring.
Analogous to the reactivity of the amides, urea derivatives
also underwent N-adjacent C(sp3)−H borylation with Silica-
TRIP−Rh (Table 1, entries 5−12). Borylation of the cyclic urea
N,N′-dimethylpropyleneurea (DMPU, 1f) proceeded smoothly
at 25 °C to give the monoborylation product 3f in 129% yield
together with the geminal bisborylation product 3f′ in 7% yield
(entry 5). Interestingly, the second borylation did not occur at
the N-methyl group on the other side, which suggests that
intramolecular coordination of the carbonyl oxygen to the B
atom disturbs the binding of the Rh center to the carbonyl
group and that, upon dissociation of the B−O bond, geminal
bisborylation occurs selectively as a result of activation by the
boryl substituent. The borylation of 1f was also conducted on a
a
Conditions: 1 (1.0 mmol), 2 (0.5 mmol), [Rh(OMe)(cod)]2 (0.0025
b
mmol of Rh), Silica-TRIP (0.0025 mmol of P), hexane (1.0 mL). 1H
NMR yields based on 2. Isolated yields are given in parentheses. Yields
in excess of 100% indicate that the byproduct pinB−H also functioned
c
as a reagent, but its reactivity was much lower than that of 2. The
geminal bisborylation product 3′ was also detected by 1H NMR
analysis of the crude product mixture (entry 1, 21%; entry 5, 7%; entry
6, 2%; entry 7, 6%; entry 8, 55%; entry 9, 12%; entry 11, 28%; entry
d
12, 11%). 1 (10.0 mmol, 1.23 g), 2 (5.0 mmol, 1.27 g),
[Rh(OMe)(cod)]2 (0.005 mmol of Rh), and Silica-TRIP (0.005
mmol of P) were used. 1 (5.0 mmol, 641 mg), 2 (5.0 mmol, 1.27 g),
[Rh(OMe)(cod)]2 (0.005 mmol of Rh), and Silica-TRIP (0.005 mmol
e
of P) were used.
B
dx.doi.org/10.1021/ja305694r | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
gram scale with a reduction of the catalyst loading to 0.1 mol %
Rh at 70 °C, which afforded 3f in 146% isolated yield with 2
equiv of 1f and in 85% yield with 1 equiv of 1f (entries 6 and
7). The unsymmetrical, acyclic urea derivatives 1g and 1h
underwent selective borylation at their methyl groups (entries 8
and 9); no isomer was detected in either case, but the reaction
of 1g produced the geminal bisborylation product 3g′ in a
significant amount. Remarkably, the reaction of 1i, an
unsymmetrical urea having an acyclic diethylamino group and
a cyclic pyrrolidino group, was also site-selective, showing
exclusive selectivity for ring borylation to afford α-borylpyrro-
lidine derivative 3i as the sole product (entry 10). As shown in
Table 1, entries 11 and 12, an alkoxy group or a siloxy group at
the β-position of the N-alkyl group had little effect on the
borylation activity; compounds 1j and 1k were selectively
borylated at an N-methyl group.23
bromochloromethane/BuLi reagent, furnishing the correspond-
ing β-aminoalkylboronic acid derivative 6 (eq 3).26
In summary, Rh catalysis with the silica-supported
triarylphosphine ligand Silica-TRIP, which features a tripty-
cene-type cage structure, enabled the site-selective borylation of
N-adjacent C(sp3)−H bonds of amides, ureas, and 2-amino-
pyridines under mild conditions with reasonable catalyst
loadings (25−100 °C, 0.1−0.5 mol % Rh) to produce
derivatives of α-aminoalkylboronic acids, which are boron
analogues of α-amino acids.1a,b,d N-Methyl groups are the
preferred borylation sites, but this Rh catalysis is also effective
for the reaction of N-adjacent internal C(sp3)−H bonds of
cyclic amino groups to produce N-heterocyclic secondary
alkylboronates. The α-aminoalkylboronic acid derivatives
underwent C−C bond formation reactions, such as Suzuki−
Miyaura coupling with an aryl bromide and one-carbon
homologation to a β-aminoalkylboronate. This novel tran-
sition-metal catalysis with an immobilized phosphine ligand
offers a new method for the development of useful molecular
transformations through heterogeneous approaches.
The N-adjacent C(sp3)−H borylation using Silica-TRIP−Rh
was not limited to reactions with the N−CO-type catalyst-
directing groups but could also be applied to 2-aminopyridine
derivatives (entries 13−16). The simplest substrate, 2-(N,N-
dimethylamino)pyridine (1l), reacted cleanly at 80 °C with
exclusive site selectivity at one of the N-methyl groups (entry
13). No borylation at the pyridine ring was observed, and
interestingly, no geminal bisborylation occurred in this case.
With pyridine as an N-heterocyclic catalyst-directing group,
various saturated cyclic amino groups with different ring sizes,
such as pyrrolidino (1m), piperidino (1n), and azepanyl (1o)
groups, were successfully borylated at the N-adjacent position
to give the corresponding cyclic α-aminoalkylboronic acid
derivatives (Table 1, entries 14−16).
Despite the potential importance of α-aminoalkylboronic
acids as building blocks for organic synthesis, their utility has
not been fully explored, mainly because of the lack of methods
for accessing this class of compounds. The lithiation of an N-
adjacent C(sp3)−H bond using stoichiometric organolithium
reagents is not generally applicable to amides, ureas, and
pyridine derivatives because these functional groups are
susceptible to nucleophilic addition of the organolithium
reagent under C(sp3)−H lithiation conditions.24 Accordingly,
the α-aminoalkylboronic acid pinacol esters obtained by the
Rh-catalyzed N-adjacent C(sp3)−H borylation were used to
demonstrate their synthetic utility (eqs 1−3). For instance,
ASSOCIATED CONTENT
* Supporting Information
Experimental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
sawamura@sci.hokudai.ac.jp
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Grants-in-Aid for Scientific
Research on Innovative Areas “Organic Synthesis Based on
Reaction Integration” and a Global COE Grant (Project B01:
Catalysis as the Basis for Innovation in Materials Science) from
MEXT and by CREST from JST. S.K. thanks JSPS for
scholarship support.
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Journal of the American Chemical Society
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