Outer-sphere direction in iridium C-H borylation

Article abstract of DOI:10.1021/ja303443m

The NHBoc group affords ortho selective C-H borylations in arenes and alkenes. Experimental and computational studies support an outer sphere mechanism where the N-H proton hydrogen bonds to a boryl ligand oxygen. The regioselectivities are unique and com

Full text of DOI:10.1021/ja303443m

Communication
pubs.acs.org/JACS
Outer-Sphere Direction in Iridium C−H Borylation
Philipp C. Roosen,† Venkata A. Kallepalli,† Buddhadeb Chattopadhyay,† Daniel A. Singleton,*,‡
Robert E. Maleczka, Jr.,*,† and Milton R. Smith, III*,†
†Department of Chemistry, Michigan State University, East Lansing, Michigan 48824-1322, United States
‡Department of Chemistry, Texas A&M University, P.O. Box 30012, College Station, Texas 77842, United States
S
* Supporting Information
16-electron intermediate, 1, which has a vacant site to facilitate
ABSTRACT: The NHBoc group affords ortho selective
the cleavage of an ortho C−H bond. Usually, chelation-directed
C−H borylations in arenes and alkenes. Experimental and
computational studies support an outer sphere mechanism
where the N−H proton hydrogen bonds to a boryl ligand
oxygen. The regioselectivities are unique and complement
those of directed ortho metalations.
selectivity is not observed for 16-electron catalytic intermediates,
such as Ir(Bpin)3(dtbpy) (2, dtbpy = 4,4′-di-tert-butyl-2,2′-
bipyridine, pin = pinacolate). For these catalysts ortho borylation
can be accomplished by a relay-directed mechanism in which the
substrate can reversibly attach to the metal by a σ-bond
metathesis process.4a,d To date, the substrates in relay-directed
borylation have all contained pendant Si−H bonds, and the
reactions presumably proceed through a 16-electron intermedi-
ate 3 in which the ortho C−H bond is poised for borylation. Both
the chelation-directed and relay-directed mechanisms are inner-
sphere processes, where direction is achieved by coordination to
iridium.
ver the past decade, advances in the transition-metal-
O
catalyzed functionalization of C−H bonds have trans-
formed synthetic chemistry.1 In this context, the borylation of
C−H bonds has shown promise because it bestows the C−H
functional group with the synthetic versatility for which B−C
bonds are renowned. A central challenge in these reactions is
controlling their selectivity. Steric effects often dominate the
regioselectivity of C−H borylations of aromatics.2 This makes
C−H borylations complementary to widely applied directed
ortho metalations (DoMs),3 but the intrinsic functional group
and practical limitations of DoMs have intensified efforts to
develop selective ortho C−H borylations.
In outer-sphere direction,5 a ligand on the catalyst recognizes
functionality in the substrate. This distinct paradigm for
selectivity, based on ideas from molecular recognition, can
provide selectivities that complement those from other directing
mechanisms.6 Our efforts to understand the electronic effects in
C−H borylation suggested that an outer-sphere mechanism can
direct borylation.7 Herein we outline a proof-of-concept where
NHBoc groups direct C−H functionalizations with selectivities
that are unprecedented in the C−H borylation and DoM
literature.
The potential for outer-sphere direction in Ir-catalyzed C−H
borylations was suggested by an anomaly predicted for pyrrole in
a recent combined computational and experimental study.7b An
analysis of 21 combinations of substrates and metal complexes
supported the importance of proton-transfer character in the C−
H activation transition state (TS). There was a strong linear
correlation between the ΔG° and ΔG‡ for C−H activation and
the NPA charge on the aryl group after activation, as reflected by
the subset of five-membered heterocyclic intermediates (5)
shown in Figure 1.8 This charge/reactivity relationship was
remarkably predictive, but a large deviation was observed for
pyrrole. Borylation at the 2-position of pyrrole is 2.3 kcal/mol
more favorable than would be expected from a least-squares fit of
other substrate/catalyst combinations.
Ortho C−H borylation has been accomplished by catalyst or
substrate modification (Scheme 1).4 Catalyst control can be
achieved with ligands and/or metals that make 14-electron
intermediates accessible.4b,c,e,f Substrates that contain a directed
metalation group (DMG) likely coordinate to the metal to form a
Scheme 1. Strategies for ortho-Directed C−H Borylation
Geometries for the TS and the resulting intermediate for
pyrrole are shown in Figure 2. Two features are noteworthy.
First, the NH···O distances between the pyrrole and one of the
boryl oxygens are short, ranging from 2.05 to 2.19 Å. Second, the
∠Ir−C−N are ∼10° less than the ∠Ir−C−C. Both of these
indicate significant NHO hydrogen interaction in the TS and the
Received: April 17, 2012
Published: June 15, 2012
© 2012 American Chemical Society
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Communication
typical for 1,3-disubstituted benzenes. Since one Boc group
sufficiently protects primary amines,10b substrate 7 was examined
next. Remarkably, replacing one Boc group with H alters the
regioselectivity to favor ortho borylation product 8b.11
The shift in selectivity for 7 could arise from a number of
mechanisms, three of which are depicted in Scheme 3. In
Scheme 3. Experiments to Probe Mechanism
Figure 1. Calculated energies of intermediates (5) vs the total Normal
Population Analysis (NPA) charge on the C−H activated heterocycles
in 5. Computational data are excerpted from ref 7b.
Figure 2. Lowest-energy M06/SDD(Ir)/6-31+G**(C H O N B) TS
(a) and intermediate (b) for C−H activation of pyrrole at the 2-position
by model complex Ir(bipy)(Beg)3 (eg = ethyleneglycolate). The NH−
O distances and distortions for Ir−C−C and Ir−C−N angles indicate
N−H−O hydrogen bonding.
intermediate. This clearly accounts for the lowering of ΔG in
Figure 1.
addition to H-bonding TS 9, selectivity could arise from
coordination of the carbamate O to a boryl B in TS 10.
Alternatively, inner-sphere N−H/Ir−B σ-bond metathesis could
account for ortho selectivity via TS 11.
While H-bonding likely accelerates C−H borylations of
pyrrole, this interaction only reinforces regioselectivity that is
already preferred. Because outer-sphere H-bonding interactions
have had a significant impact in other catalytic systems,9,6b,c we
expected that similar interactions could be harnessed in C−H
borylations and the resulting regioselectivities could be
complementary.
Because preliminary studies of primary anilines were
hampered by poor conversion, tert-butoxycarbonyl (Boc)
protected anilines were examined. N-Boc protected compounds
are viable substrates for C−H borylation.10 This is illustrated in
Scheme 2, where the borylation of 6 gives meta functionalization
Substrates in 12a−c were chosen to probe for intermediates
9−11. For 12a, TSs 9 and 11 are impossible since H has been
replaced by CH3. The only product detected is meta isomer 13a,
consistent with pathways via 9 or 11. For 12b, the NH and O
groups of 7 are transposed. This would affect selectivity via 9 or
11, because the ring sizes in the TSs increase. Conversely, the
effects on TS 10 should be slight. Exclusive formation of meta
product 13b makes participation of 10 unlikely. The meta
selectivity for amide 12c eliminates 10 because its carbonyl O is
more basic than those in carbamates 12a−b,12 but it calls 9 to
question because the H-bonding mechanism of 9 seems equally
plausible for 12c.
Scheme 2. Boc Substitution and Borylation Regioselectivity
TSs 9 and 11 can be distinguished by isotopic labeling. As
indicated in Scheme 3, a pathway involving 11 requires N−D
scission. Consequently, C−H borylation and product elimi-
nation would produce significant quantities of 8b-d0. When 7-d1
is subjected to borylation, >95% of product is N-deuterated.
The experimental data in Scheme 3 excludes 10 and 11, but it
provides no support for 9. If the H-bonding mechanism is
correct, then it might be expected that the acidity of the N−H
bond would affect the selectivity. However, attempts to improve
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selectivity with more acidic N−H bonds were unsuccessful. For
example, N-aryl triflamides gave N-borylation. Since solutions
containing both HBpin and N-aryl triflamides are stable, an Ir
complex catalyzes N-borylation. In a plausible mechanism, σ-
bond metathesis of the Ir−B bond with the highly acidic
triflimide N−H bond generates intermediate 14 (Scheme 3) and
subsequent N−B elimination yields the N-borylated triflamide.
An experimental result supporting the H-bonding mechanism
of 9 was the observation that increased basicity of the dipyridyl
ligands enhances ortho selectivity (Figure 3). We propose that
there is a tight steric interaction (with H−H distances <1.0 Å)
that would preclude the ortho structure. An interesting
observation is that the ortho transition structure is very strongly
favored enthalpically, but the restricted motion associated with
the H-bond is disfavored entropically, so the final selectivity is
limited by entropy/enthalpy compensation.
For Boc-protected anilines with a single meta substituent,
there is a trade-off between H-bond direction and the usual
preference for reaction at the least hindered position (Table 1,
a
Table 1. ortho-Borylation of N-(Boc)-Anilines
Figure 3. Plot of the ortho/meta product ratios using 4,4′-di(R1)-2,2′-
dipyridyl catalysts vs pKa's of 4-R1-pyridium ions.
the pinacolate oxygens in complexes with more electron-rich
dipyridyl ligands are more basic, and this accounts for the
increased ortho selectivity. While more electron-rich dipyridyl
ligands have been shown to increase borylation rates,13 this is the
first case where dipyridyl electronic effects significantly alter
regioselectivities.
The mechanism of the ortho direction and an explanation of its
failure with 12c was clarified by theoretical calculations. In M06/
SDD(Ir)/6-31+G**(C H O N B) calculations, a series of TSs
were located for C−H activation of PhNHCO2Me by the model
complex (bpy)Ir(Beg)3 (15, eg = ethyleneglycolate). These
calculations predict the ortho borylation to be strongly favored,
and the TS (Figure 4) shows a clear NH−O H-bond. The
a
See Supporting Information for details on conditions. Yields refer to
b
1
isolated material except as noted. Yield determined by H NMR.
c
d
Yield is for the major isomer. Isolated as a 92:8 mixture.
entry 1). This is not an issue for 4-substituted substrates where
the ortho selectivity is high. Except for the fluorine-substituted
substrates in entries 5 and 6, these products were isolated as
single regioisomers. For entries 11 and 12, 3 equiv of arene were
used to minimize diborylation. Converting Bpin products to their
BF3K salts can in cases ease isolation, leading to the higher yield
in entry 12 versus 11. All regiochemical assignments were based
on NMR spectroscopy and confirmed by X-ray crystallography
for entries 4 and 7−9.
Entry 2 in Table 1 shows that substrates with more acidic
protons are viable through in situ protection as borates by excess
pinacolborane. Entries 1, 3−7, and 10 produce boronates with
halogen groups that can be further manipulated. Entries 11 and
12 are noteworthy because the selectivity diverges from that of
the acetamide analog, which borylates ortho to CN exclusively.14
The comparison with DoM in Scheme 4 highlights the new
selectivity offered by H-bond direction. When there is a
distinguishable choice among ortho C−H bonds, DoM is
dominated by acidity. Thus, for substrates 16 and 17 (entries 5
and 7 in Table 1), the more acidic C−H bonds flanked by
NHBoc and a halogen will metalate first.15 In contrast the Ir-
catalyzed process is selective for the less hindered C−H bond
ortho to NHBoc. For substrates 18 and 19, the O-aryl carbamate
is a stronger director for DoM than NHBoc, but it provides no H-
bond. Consequently, the preferred site for C−H borylation is the
Figure 4. Lowest energy TS for C−H activation of PhNHCO2Me by
model complex 15. The o:m:p ratios predicted by theory and those
found for borylation catalyzed by 2 are given.
predicted o:m:p ratio (based on the lowest-energy TSs for each
possibility) is 88:8:4, which is very close to the experimental
value for borylation of PhNHCO2Me by 2 (o:m:p = 90:5:5 from
GC-FID). The experimental ratio is a direct measurement of
relative rates for directed and nondirected borylation. The
agreement between theory and experiment strongly supports the
NH−O H-bonding mechanism. The calculated ortho TS also
suggests a steric explanation for the failure of H-bonding
direction in 12c; when the OCH3 of the carbamate is replaced by
an ethyl group and the Beg groups are replaced by BPin groups,
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Scheme 4. C−H Borylation and DoM Regioselectivities
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C−H borylation via an outer-sphere H-bonding mechanism gives
regioselectivities that are unprecedented for DoM. It is noteworthy
that C−H borylations of substrates in Scheme 4 do not require
low temperatures that must be maintained during DoM to
minimize generation of benzyne intermediates.15,16
Finally, this chemistry can be extended to Boc-protected
enamines such as 20 where the regioselectivity for the vinyl C−H
that is β to N exceeds 99:1. Remarkably, the Ph C−H bonds and
the stereochemistry of the double bond in product 21 are unperturbed.
Recent reports reflect interest in borylenamines and related
compounds,17 including a route using C−H borylation,17c but
the reaction here provides a cis disposition of N and B groups that
is unavailable by other methods.
In summary, we have shown that the NHBoc group offers
ortho selectivity in Ir-catalyzed C−H borylation that cannot be
obtained with DoM, or any other methodology. Experiment and
theory make a convincing case for an outer-sphere mechanism
were the NHBoc proton bonds to Bpin oxygen in the TS. We
currently are applying this chemistry in synthesis and are
pursuing more general strategies for outer-sphere directed C−H
borylations.
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ASSOCIATED CONTENT
■
S
* 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.
AUTHOR INFORMATION
■
Corresponding Author
singleton@mail.chem.tamu.edu; maleczka@chemisty.msu.edu;
smithmil@msu.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NIH (GM63188) for generous financial support
and BASF for gifts of HBpin and B2pin2. We thank Mr. Peter
Heisler for experimental assistance, Dr. Daniel Holmes for help
with NMR characterization, and Dr. Richard Staples for solving
crystal structures.
(17) (a) He, Z.; Yudin, A. K. J. Am. Chem. Soc. 2011, 133, 13770.
(b) Hussain, N.; Hussain, M. M.; Ziauddin, M.; Triyawatanyu, P.;
Walsh, P. J. Org. Lett. 2011, 13, 6464. (c) Takaya, J.; Kirai, N.; Iwasawa,
N. J. Am. Chem. Soc. 2011, 133, 12980.
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