Silyl phosphorus and nitrogen donor chelates for homogeneous ortho borylation catalysis

Article abstract of DOI:10.1021/ja506229s

Ir catalysts supported by bidentate silyl ligands that contain P- or N-donors are shown to effect ortho borylations for a range of substituted aromatics. The substrate scope is broad, and the modular ligand synthesis allows for flexible catalyst design.

Full text of DOI:10.1021/ja506229s

Communication
pubs.acs.org/JACS
Silyl Phosphorus and Nitrogen Donor Chelates for Homogeneous
Ortho Borylation Catalysis
Behnaz Ghaffari,† Sean M. Preshlock,† Donald L. Plattner,† Richard J. Staples,† Peter E. Maligres,‡
Shane W. Krska,‡,* Robert E. Maleczka, Jr.,*,† and Milton R. Smith, III*,†
†Department of Chemistry, Michigan State University, East Lansing, Michigan 48824-1322, United States
‡
‡Department of Process Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, United States
S
* Supporting Information
Scheme 1. Ortho Borylation Strategies with DMGs
ABSTRACT: Ir catalysts supported by bidentate silyl
ligands that contain P- or N-donors are shown to effect
ortho borylations for a range of substituted aromatics. The
substrate scope is broad, and the modular ligand synthesis
allows for flexible catalyst design.
irected ortho-metalation (DoM) is a powerful synthetic
D
method that is widely applied by synthetic chemists.1 More
recently, C−H borylation catalysts have been developed which
are able to functionalize aromatic C−H bonds with regiose-
lectivities that are often sterically determined, thus giving
complementary selectivity to DoM.2 Because C−H borylations
tolerate groups like esters, which can be incompatible with DoM,
and do not require low temperatures to operate like DoM, there
has been significant interest in ortho-directed borylations.3 Aside
from an early report on ortho borylation of benzamide,4 the first
examples of ortho borylations in Ir-catalyzed homogeneous
systems involved silyl-directed borylation described by Hartwig
and Boebel.5 This approach requires conversion of O−H and
N−H bonds to O−SiR2H and N−SiR2H moieties. The Si−H
bonds undergo formal σ bond metathesis with Ir−Bpin groups to
generate Ir−Si bound intermediates that direct functionalization
of C−H bonds ortho to O and N groups. Recently, Maleczka,
Singleton, and Smith have proposed that hydrogen-bonding
interactions between aniline N−H bonds and Bpin O atoms can
direct ortho borylations of anilines.6
Other examples of ortho borylations rely on intrinsic substrate
functionality. For example, Ishiyama and Miyaura have described
ortho borylation of esters;7 Lassaletta has reported N-directed
ortho borylations;8 Ito and Ishiyama have developed ortho
borylations of ketones;9 and Clark has disclosed borylations of
benzylamines and phosphines.10 Although detailed kinetic
studies have not been reported, mechanisms where two
coordination sites in the catalyst (structure 2) are available to
the substrate are most plausible (Scheme 1). One site enables
coordination of a directed metalating group (DMG), while the
other is necessary to cleave the ortho C−H bond. Unfortunately,
equilibria with thermodynamically favored 5-coordinate struc-
tures 3 likely reduces activity.
nontrivial, which makes modification of the phosphine structure
challenging.12 Thus, we sought an appropriate ligand framework
for homogeneous catalysis that could mimic these heterogeneous
catalysts. Given that tridentate PSiP pincer ligands have been
utilized in C−H borylation,13 we were hopeful that bidentate Si−
P ligands could generate structures 4, where the silyl ligand
In contrast to the aforementioned homogeneous catalysts, Ir-
catalyzed borylations using surface supported phosphine ligands,
pioneered by Sawamura, demonstrate a broad scope for ortho-
directed borylations.11 While the surface supported phosphine
systems of Sawamura’s are highly active, their synthesis can be
Received: June 27, 2014
Published: August 20, 2014
© 2014 American Chemical Society
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Communication
a
replaces a spectating boryl. Silane metathesis with a boryl ligand
would steer the phosphine to the metal center to generate
intermediates (4) with accessible coordination sites. In contrast
to other homogeneous approaches where electron-deficient
ligands are used to achieve coordinative unsaturation, our
strategy would create an electron-rich framework that facilitates
C−H cleavage.14 If this approach proved to be viable, the ligand
framework could be modified in substantive ways. For example,
silanes with pendant N-donors (or other basic ligands) could be
targeted.
Chart 1. Ortho Borylation of Alkylbenzoates
To test this concept, we prepared ligand 5 (Scheme 1), using a
p r o t o c o l r e l a t e d t o t h e s y n t h e s i s o f ( 2 -
diphenylphosphinophenyl)diphenylsilane.15 The synthesis is
straightforward, modular, and scalable to gram quantities. With
5 in hand, we tested it for the C−H borylation of
methylbenzoate. Table 1 shows the results compared to those
Table 1. Comparison of Catalyst Efficiency for Ortho
Borylation
a
Reactions were run with 1.0 mmol substrate, 1.0 mmol B2pin2, 0.025
mmol 5, and 0.0125 mmol [Ir(OMe)(cod)]2 in 1.0 mL THF. Yields
b
c
are for isolated materials. 2.0 mmol substrate was used. 0.5 mol %
d
e
a
b
b
c
[Ir(OMe)(cod)]2 was used. Reaction was run at 60 °C. 2.0 mmol
B2pin2, 0.025 mmol [Ir(OMe)(cod)]2, and 0.050 mmol 5 were used.
0.5 mmol substrate was used. 1.25 mmol B2pin2 was used. 5%
diborylated material was isolated. 17% diborylated material was
entry
ligand
%6a
%6b
% conversion
d
1
2
3
5
63
2
24
1
111
f
g
h
PArF
4
i
3
j
AsPh3
44
101
3
50
isolated. 10% diborylated material was isolated.
e
f
f
d
4
silica-SMAP
4
109
a
b
Reactions run on 0.5 mmol scale in 0.5 mL THF. % Conversions
Scheme 2. Ligand-Dependent Borylation Regioselectivity
c
determined by GC integration. % Conversion is calculated as %6a +
2(%6b) and is based on B2pin2 as limiting reagent. Conversion
d
exceeds 100% because some of the HBpin generated from B2pin2
e
participates in the borylation. Data are from ref 11a. Reaction run at
25 °C with 1 mmol methylbenzoate, 0.5 mmol B2pin2, 0.5 mol %
f
silica-SMAP-Ir(OMe)(cod) in 1.5 mL hexane. Yields were deter-
1
mined by H NMR spectroscopy.
obtained for catalysts generate from [Ir(OMe)(cod)]2 and
P(3,5-bis(trifluoromethyl)phenyl)3 (PArF ) or triphenylarsine,
3
which have both been used in directed borylations. As can be
seen in entry 1, ligand 5 allows for full conversion of B2pin2 and
some of the generated HBpin, while the PArF3 and AsPh3 give
considerably lower conversions. In contrast, silica-SMAP ligated
Ir catalysts are significantly more active.
Given the results in Chart 1, we further explored the scope
with respect to substrate and directing group, and the results are
given in Table 2. Entry 1 shows that unsubstituted benzamides
give excellent conversions to monoborylated substrates without
resorting to using excess arene to minimize diborylation as is
required for methyl benzoate. Entry 2 shows that the amide
DMG trumps Cl direction. In fact, chlorobenzene does not give
ortho-borylated product with 5, contrasting the high ortho
selectivity for Ir-SMAP catalysts. In entry 3, diborylated product
8c was obtained. When 1 equiv B2pin2 was used with 7c,
selectivity for borylation ortho to the amide vs the ester was 4.2:1.
Entries 4 and 5 show that OMe can direct borylation to the ortho
position, albeit in modest yield. This sets the chemistry of
catalysts generated from ligand 5 apart from that of silica-SMAP,
where borylation of 7d gives a 1:1 ratio of o:m + p borylated
products. Entry 6 shows that esters are stronger DMGs that
OMe, which is in line with SMAP supported catalysts. In entry 7,
Weinreb amide 7g is converted cleanly to ortho-borylated
product 8g. Borylation of 1-methylnaphthoate, 7i, gives a single
isomer where functionalization of the β-C−H bond is favored
With promising preliminary data in hand we explored a
number of substituted methyl benzoates (see Chart 1). The
reactions were performed under identical conditions, and
reaction times were not optimized. Yields range from fair to
excellent with the lowest yields corresponding to methylben-
zoates that were only substituted at the 4-position. For these
substrates, significant amounts of 2,6-diborylated compounds
form, which accounts for diminished yield of monoborylated
products 6i and 6k. Some diborylation was also observed in the
synthesis of 6e. It is noteworthy that lowering the catalyst loading
to 0.5 mol % and reducing the temperature to 60 °C gave a 6%
yield increase for 6k. In addition, diborylation is not observed for
t-butylbenzoate in contrast to methylbenzoate. Lastly, the
selectivity difference for ligand 5 relative to 4,4′-di(t-butyl)-
bipyridine (dtbpy) is highlighted in Scheme 2, where different
regioisomers are obtained in the borylations of 2-fluoro-4-
bromomethylbenzoate.
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a
H metathesis could account for formation of intermediates such
as 4. Nevertheless, we performed a control experiment where 5
and [Ir(OMe)(cod)]2 were reacted. 31P and 1H NMR indicates
rapid and quantitative conversion to compound 9 and
methanolan unprecedented reaction for a silane with a metal
alkoxide (eq 1). This is critical for establishing a 1:1 ratio of 5:Ir,
Table 2. Borylations with 5/[Ir(OMe)(cod)]2 Catalyst
which is the key to creating sites for DMG coordination and C−
H activation as posited for structure 4 in Scheme 1. The structure
of 9 was confirmed by X-ray crystallography and is shown in
Figure 1. Using the centroids of the cod bound carbons as
Figure 1. Crystal structure of compound 9 with H atoms omitted.
Selected distances (Å) and angles (deg): Ir−Si (2.376(2)), Ir−P
(2.260(2)), Ir−C1 (2.246(8)), Ir−C2 (2.217(8)), Ir−C5 (2.194(8)),
Ir−C6 (2.161(8)), C1−C2 (1.386(12)), C5−C6 (1.357(13)), P−Ir−Si
(83.53(6)), P−Ir−centroidC1−C2 (96.72), Si−Ir−centroidC5−C6 (95.39),
centroidC1−C2−Ir−centroidC5−C6 (85.25).
a
Typically reactions were run on 1 mmol scale with equimolar B2pin2
and substrate with 2.5 mol % 5 and 1.25 mol % [Ir(OMe)(cod)]2.
Unless noted, yields are for isolated materials. See SI for details.
coordinates, the sum of the angles about Ir is 370°, which is close
to the value for square-planar IrI. The Ir−C and C−C distances
for the carbons trans to Si are significantly longer than those for
carbons trans to P, which is consistent with strong donation from
Si to Ir.
b
c
d
Reaction solvent was THF. 2.0 equiv B2pin2 was used. GC-
conversion with a 6:1:2 ratio of o:m + p:diborylated products.
e
f
Reaction solvent was n-hexane. Approximately 15% of the crude
mixture was the diorthoborylated compound (8j′ in the SI).
There is a difference in the reaction rates when using pure 9 as
precatalyst as opposed to in situ generated catalysts, with shorter
reaction times being required for the isolated catalyst.
Some substrates proved to be challenging for borylations
carried out with ligand 5. For example, carbamates react
sluggishly, and ketones give significant amounts of ketone
reduction. Since Ir catalysts supported by N-donor ligands in
most cases prove to be more reactive than their P-donor
counterparts,16 we reasoned that an N-donor analog of 5 might
exhibit better reactivity with carbamates and ketones. Thus,
quinoline-based ligand 10 was prepared, and Ir catalysis with this
ligand was evaluated relative to ligand 5 for compounds 11a and
11b.17
As shown in Table 3, ligand 10 outperforms its phosphine
analog 5 for borylations of 11a and 11b. In the case of carbamate
11a, we see higher conversion, but slightly lower isolated yield to
that reported by Sawamura for the related diethylcarbamate
substrate. Perhaps more significantly, catalysis with 10 did not
yield detectable borylation para to the carbamate, which is a
minor byproduct in the silica-SMAP system. For phenyl ethyl
ketone, ligand 5 gave the reduction to the alcohol upon workup
over the γ-C−H position. Borylation of thiophene substrate 7h at
60 °C gave slightly better selectivity (14:1) for 3 vs 5-borylated
products than that reported for the borylation with Ir-SMAP
catalysts (9:1 at 80 °C). In contrast to the SMAP system, where
the Ir catalysts are ineffective for borylation of 7j, borylation gives
the products obtained by Lassaletta using hemilabile N,N
ligands.8a Our reaction was performed at a lower temperature
(60 vs 80 °C) and a shorter reaction time (2 vs 48 h). This was
offset by a higher catalyst loading in our study (1.25 vs 0.5 mol %)
and the formation of ∼15% diorthoborylated product. With 2.0
equiv B2pin2, this was the major product.
The generation of active catalyst from 5, B2pin2, and
[Ir(OMe)(cod)]2 raises interesting questions with regard to
how an Ir−Si bond is generated, if it is formed at all. Several
literature reports describe the metathesis of M−OR and Si−H
bonds to make M−H and Si−OR products. However, silane-
directed borylations invoke M−B/Si−H metatheses to generate
M−Si and B−H bonds. Thus, we considered that initial
formation of Ir−Bpin intermediates and subsequent Ir−B/Si−
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Table 3. Comparison of Silyl Ligands with Pendant P- and N-
donors
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ASSOCIATED CONTENT
* Supporting Information
Full characterization, copies of all spectral data, experimental
procedures, and X-ray crystallographic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
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S
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AUTHOR INFORMATION
■
Corresponding Authors
shane_krska@merck.com
maleczka@chemistry.msu.edu
smithmil@msu.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank NIH (GM63188), NSF (GOALI-1012883), and ACS
Green Chemistry Institute Pharmaceutical Roundtable for
generous financial support and BoroPharm, Inc. for supplying
B2pin2. We dedicate this paper to the memory of Professor
Gregory Hillhouse.
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