Amide Effects in C?H Activation: Noncovalent Interactions with L-Shaped Ligand for meta Borylation of Aromatic Amides

Article abstract of DOI:10.1002/anie.201809929

A new concept for the meta-selective borylation of aromatic amides is described. It has been demonstrated that while esters gave para borylations, amides lead to meta borylations. For achieving high meta selectivity, an L-shaped bifunctional ligand has been employed and engages in an O???K noncovalent interaction with the oxygen atom of the moderately distorted amide carbonyl group. This interaction provides exceptional control for meta C?H activation/borylation.

Full text of DOI:10.1002/anie.201809929

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Amide Effect in C–H Activation: L-Shaped Ligand for Meta
Borylation of Aromatic Amides via Noncovalent Interaction
Authors: Buddhadeb Chattopadhyay, Ranjana Bisht, and Md Emdadul
Hoque
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201809929
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10.1002/anie.201809929
Angewandte Chemie International Edition
COMMUNICATION
Amide Effect in C–H Activation: L-Shaped Ligand for Meta
Borylation of Aromatic Amides via Noncovalent Interaction
Ranjana Bisht,† Md Emdadul Hoque,† and Buddhadeb Chattopadhyay*
For amides:
Abstract: A new concept for the meta-selective borylation of
π-system
more effective
O
O
O
aromatic amides is described. Employing the contrasting structural
properties of aromatic amides compared to the aromatic esters, it
has been demonstrated that while esters gave para borylations,
amides resulted complete switch to meta borylations. For achieving
high meta selectivity, a L-shaped bifunctional ligand has been
employed, which identify the functionality of the oxygen atom of the
moderately distorted amide carbonyl group via an O××××K noncovalent
interaction providing an exceptional controlling factor for meta C–H
activation/borylation.
R
R
R
Ar
N
Ar
N
Ar
N
R
R
R
EDG
delocalization through three (N, C, O) atoms
For esters:
π-system
less effective
O
O
O
R
R
R
Ar
O
Ar
O
Ar
O
Scheme 1. Contrasting Electronic Properties of Aromatic Amides and Esters
either
Bpin
Bpin
N
N
pinB
N
Ir
To date noncovalent interactions[1] have received substantial
interest in different fields of chemistry. Several experimental
investigations showed that these interactions can be similar in
strength to the hydrogen bonding. As a result, it is highly
anticipated to introduce these interactions into catalysis.
Moreover, based on the advancement of hydrogen-bond in
transition metal catalysis, it could be envisaged that other types
of noncovalent interactions would also play significant role for
the development of future catalytic concepts in C–H bond
activation/functionalization chemistry. Thus, it would be highly
desirable to integrate these two parameters i.e. noncovalent
interaction and transition metal catalyst for the possible
development of new concepts, new hypothesis in C–H activation
chemistry,[2] which would enable to discover smart technologies
in organic synthesis.
While many C-H bond functionalization[3] are now accessible,
the C–H bond borylation has proved potential due to the
versatile synthetic transformations[4] of the B–C bonds. However,
a major challenge in C–H borylation of arene is the site-
selectivity, which is largely governed by the steric effects.[5]
There have been several methods for the ortho borylation[6] of
arenes including directed ortho metalations (DoMs).[7] However,
remote meta[8,9] or para[10,11] C–H borylations are still difficult to
realize, nonetheless practically beneficial.[12] Thus, it would be
highly desirable to develop practical and general method for the
remote site-selective C–H bond activation/borylation of arenes.
N
L1
HN
distorted
planar
O
N
φ
N
N
TS-3
K
O
O
N
R
L-T
Ir-cat, B2pin2
[K]-salt
N
O K
•••
noncovalent
interaction
R
or
HO
Bpin
Bpin
pinB
N
Bpin
pinB
N
Bpin
Ir
Ir
N
N
N
N
TS-1
K
δ
O
K
O
cation–π
EtO
O
O
TS-2
N
O
noncovalent interaction
K
•••
R
δ
R
This work
Previous work
Scheme 2. Noncovalent Interactions for Remote C–H Bond Activation and
Borylation of Arenes
We hypothesized that suitable design could alter the
coordination mode of the amides due to the following
considerations: i) introduction of appropriate N-substitution could
cause the alteration of the dihedral angle[17] between either C=O
and NR2 groups or C=O and Ar group favoring O××××K
interaction,[ 18 ] and ii) alteration of planar geometry towards
moderately distorted planar, that might act like a p-system.[19]
Herein, we report that the same L-shaped bifunctional ligand is
highly competent for the meta-selective borylation of aromatic
amides via either a cation–p noncovalent interaction (TS-2) or a
moderately distorted O××××K interaction (TS-3) (Scheme 2).
On the other hand, although aromatic amide and ester both are
important chemical entity,[13] they behave different way in many
common organic reactions, except in the metal coordination
chemistry,[ 14 , 15 , 16 ] which is due to the different electronic
delocalization of amide and ester (Scheme 1). Recently, we
have reported[11] para borylation of aromatic esters by an
engineered L-shaped ligand (Scheme 2, TS-1). Thus,
considering the contrasting structural properties between esters
and amides, we assumed that amides could react differently in
site-selective C–H bond activation and borylation.
O
O
H
H
1.5 mol% [Ir(cod)(OMe)]2, 3.5 mol% L1
4.5 mol% KOtBu, 1.0 equiv. B2pin2,
THF, 80 oC, 12 h
N
N
R
R
pinB
1a: R = H
1b: R = Me
2a: R = H, meta/para = 1/1.5, conv. = 23%
2b: R = Me, meta/para = 2.2/1, conv. = 33%
Scheme 3. Initial Studies for Meta-Selective Borylation
Earlier, we observed that under the para borylation conditions of
esters,[11] planar benzamide (1a) also resulted para borylation
via a mechanism similar to ester (Scheme 3). Thus, we started
our preliminary reaction with N-methylbenzamide (1b) and found
that replacing one H by Me group, borylation shifted towards
meta position providing 2.2/1 meta to para selectivity (2b).
[*] Ms. R. Bisht,[+] Md E. Hoque,[+] Prof. Dr. B. Chattopadhyay
Division of Molecular Synthesis & Drug Discovery, Centre of Bio-Medical
Research (CBMR), SGPGIMS Campus, Raebareli Road, Lucknow 226014,
U.P., India.
[†] These authors contributed equally to this work.
E-mail: buddhadeb.c@cbmr.res.in
We next prepared twelve different entities with a range of N,N-
disubstituted amides. For comparison, borylations of these
Homepage: http://www.buddhacbmr.org/
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10.1002/anie.201809929
Angewandte Chemie International Edition
COMMUNICATION
twelve entities were performed under two set of conditions, such
as: using our designed L-shaped bifunctional ligand (L1) and
classic dtbpy ligand. The results are summarized in Table 1.
First, we chose N,N-dimethylbenzamide (3a) as the test
substrate, where another H atom of 1b was replaced by a
second Me group and found that while classic Ir/dtbpy resulted
poor levels of meta-selectivity (meta/others = 0.5/1), our L-
shaped ligand (L1) afforded enhanced meta-selectivity
(meta/others = 6/1, entry 4a).
With these results, we next performed meta borylations for a
series of aromatic amides (Table 2). We chose N,N-diisopropyl-
bearing amides instead of butyl group due to the higher product
conversion.
Table 2. Scope of Aromatic Amides for Meta Borylationa
CONiPr2
CONiPr2
1.5 mol% [Ir(cod)(OMe)]2, 3.5 mol% L1
4.5 mol% KOtBu, 1.0 equiv. B2pin2,
THF, 80 oC, 12 h
R
R
Bpin
CONiPr2
6
5
CONiPr2
CONiPr2
CONiPr2
Table 1. Meta-Selective Borylation of Unsubstituted Aromatic Amides with
Different N-Substituentsa
pin
B
Me
Cl
MeO
CONR2
CONR2
Bpin
Bpin
Bpin
Bpin
6b: (meta/para)
L1: 18/1 (94%)
dtbpy: 0.72/1 (81%) dtbpy: 0.42/1 (95%) dtbpy: 0.65/1 (71%)
6c: (meta/para)
L1: 1.7/1 (51%)
6d: (meta/para)
L1: 99/1 (63%)
6a: (meta/para)
L1: 16/1 (82%)
dtbpy: 0.75/1 (88%)
CONiPr2
Ph
1.5 mol% [Ir(cod)(OMe)]2, 3.5 mol% L1
4.5 mol% KOtBu, 1.0 equiv. B2pin2,
THF, 80 oC, 12 h
Bpin
NiPr2
CONEt2
CONiPr2
4
CONiPr2
3
NMetBu
O
F3C
O
NMe2
MeO2C
O
O
NEt2
Bpin
Bpin
Bpin
Bpin
6f: (meta/para)
L1: 18/1 (89%)
6g: (meta/para)
L1: 20/1 (86%)
6h: (meta/para)
L1: 24/1 (78%)
6e: (meta/para)
L1: 15/1 (79%)
dtbpy: complex mix
Bpin
4b: m/others
L1: 8.5/1 (77%)
Bpin
4c: m/others
L1: 11/1 (65%)
Bpin
Bpin
4a: m/others
L1: 6/1 (71%)
dtbpy: 0.5/1 (95%) dtbpy: 0.6/1 (91%)
dtbpy: 0.8/1 (93%) dtbpy: 1.5/1 (94%) dtbpy: complex mix
4d: m/others
L1: 16/1 (81%)
dtbpy: 0.9/1 (96%) dtbpy: 0.8/1 (99%)
CONiPr2
Cl
CONiPr2
CONiPr2
CONiPr2
F
MeO
MeO
Me
O
NnBu2
O
O
N
N
O
Nhex2
Br
Bpin
Bpin
Bpin Me
Bpin
F
6j: (m/others)
6l: (meta/para)
L1: 99/1 (81%)
dtbpy: 10/1 (92%)
6i: (meta/para)
L1: 24/1 (84%)
6k: (meta/para)
L1: 99/1 (86%)
L1: 19/1b (81%)
Bpin
Bpin
Bpin
Bpin
dtbpy: 1.2/1 (87%) dtbpy: complex mix dtbpy: 8/1 (97%)
4e: m/others 4f: m/others
L1: 20/1 (69%) L1: 3/1 (55%)
dtbpy: 1.2/1 (80%) dtbpy: 0.7/1 (97%)
4h: m/others
L1: 13/1 (67%)
dtbpy: 0.8/1 (83%)
4g: m/others
L1: 8/1 (65%)
dtbpy: 1/1 (90%)
CONiPr2
CONiPr2
CONiPr2
CONiPr2
Bpin
Bpin
Bpin
Bpin
O
Me
Br
F
Cl
CN
O
N
O
N
O
N
O
N
6m: (m/others)
L1: 19/1 (96%)
dtbpy: complex mix dtbpy: 7.3/1 (90%) dtbpy: 49/1 (91%) dtbpy: 49/1 (99%)
6n: (m/others)
L1: 24/1 (83%)
6o: (m/others)
L1: 1.2/1 (38%)
6p: (m/others)
L1: 24/1 (63%)
CONiPr2 CONiPr2
CONiPr2
CONiPr2
Bpin
Bpin
Bpin
Bpin
4i: m/others
L1: 10/1 (76%)
dtbpy: 0.9/1 (90%)
4j: m/others
L1: 6/1 (81%)
dtbpy: 0.7/1 (98%)
4l: m/others
L1: 12/1 (85%)
dtbpy: 0.8/1 (93%)
4k: m/others
L1: 12/1 (85%)
dtbpy: 0.7/1 (93%)
F
Bpin
MeO
Bpin
NC
6t: (m/others)
L1: 24/1 (81%)
Bpin
Cl
Bpin
6s: (m/others)
L1: 99/1 (93%)
dtbpy: 9/1 (88%)
6q: (m/others)
L1: 18/1 (78%)
dtbpy: 1.1/1 (95%)
6r: (m/others)
L1: 24/1 (95%)
dtbpy: 8/1 (92%)
aReaction scale 0.2 mmol. GC ratios. Yields are reported after column
chromatographic separation.
dtbpy: 7.3/1 (90%)
Remarkably, switching the alkyl groups from Me2 to
Et2®nMetBu®iPr2®nBu2, selectivity was increased enormously
aReaction scale 0.2 mmol. Yields are reported after column chromatographic
separation. bMinor amount of another meta isomer was observed.
from
6/1®8.5/1®11/1®16/1®20/1
(4a-4e).
With
this
Interestingly, in all cases of ortho-mono-substituted substrates
(5a-5g), high level of meta selectivity was observed except for
the amide 5c, which afforded lowered meta-selectivity due to the
rotational barrier.[22] Notably, entry 5e and 5h having a scope of
multiple borylations, selectively underwent meta borylation under
the developed conditions. In case of various di-substituted
amides (5i-5l), excellent meta-selectivity was observed.
enhancement of the meta selectivity, it is evident that the amide
geometry is altered further,[17] which facilitates the noncovalent
interaction between the K+ ion[20] of the ligand (L1) and substrate
via either a distorted O××××K interaction (TS-3) or a cation–p
interaction (TS-2). Surprisingly, increasing the chain length
further to hexyl groups (entry 4f), meta selectivity falls from
20®3 (4e & 4f), which is a contrasting result with the Kuninobu
and Kanai’s meta-borylations model.[9a] We also studied the
scope of meta-borylation of the amides bearing cyclic system
and observed that while increasing the ring size from five to six,
meta selectivity increases (4g & 4h), however, further increase
to seven-member ring size, selectivity drops slightly (4i). On the
other hand, entry 4j-bearing an oxygen atom at the six-member
ring, resulted lower meta selectivity. Moreover, amides 3k and 3l
also exhibited identical selectivity pattern. Notably, parallel
borylations with the classic Ir/dtbpy system were found to be
nonselective affording poor level of meta-selectivity in all
cases.[21]
Moreover,
para-substituted
amides
(5m-5p)
exhibited
remarkable meta selectivity as well, except for the amide 5o,
which suffered from poor conversion and afforded nearly 54%
meta borylation. Since, 1,3-disubstituted arenes usually undergo
C–H borylation predominantly at the meta position,[8] thus we
selected some challenging amides whose outcomes could give
rise interesting insights. For example, while 4-fluoro amide (5m)
gave 19/1 meta/others, 3-fluoro amide (5q) exhibited almost
identical trend (meta/para = 18/1), which is demonstrating that
there is no electronic or steric effect and noncovalent interaction
is the sole governing factor for the meta selectivity. Likewise, we
did not observe any special substituent effect or steric effect for
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10.1002/anie.201809929
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COMMUNICATION
the 4-chloro- and 3-chloro amides (5n & 5r) and both of them
demonstrating that noncovalent interaction is the origin of the
high meta selectivity. Following the same way, nicotinic amides
(8k-8l) also exhibited excellent meta selectivity. We next studied
meta borylation for other classes of substrates bearing similar
sort of functionality, which resulted high level of meta-selectivity
(8m-8o).
afforded excellent meta selectivity (meta/others
= 24/1).
Moreover, similar selectivity pattern was seen for the 4-cyano-
and 3-cyano amides (5p & 5t) (meta/others = 24/1), which is
again validating the proposed noncovalent interaction.
Table 3. Borylation of Heterocycles and Anilidesa
Next, to demonstrate the synthetic benefit of this borylation, we
showed that meta-borylated compound 6b, can be transformed
to a wide range of synthons using known transformations, such
iPr2NOC
iPr2NOC
Bpin
1.5 mol% [Ir(cod)(OMe)]2, 3.5 mol% L
Het
7
Het
8
4.5 mol% KOtBu, 1.0 equiv. B2pin2,
THF, 80 oC, 12 h
as
hydroxylation,
chlorination,
bromination,
iodination,
iPr2NOC
iPr2NOC
iPr2NOC
deuteration, arylation, amination and methoxylation (Scheme 4).
Importantly, all these transformations are valuable because
direct transformation of remote C−H bonds still remain a
significant challenge.
Bpin
Bpin
Bpin
N
O
S
Me
8c: C5/others
L1: 99/1 (93%)
dtbpy: 1.8/1 (90%)
8a: C5/others
L1: 99/1 (97%)
dtbpy: complex mix
8b: C5/others
L1: 99/1 (96%)
dtbpy: complex mix
CONiPr2
Bpin
N
CONiPr2
Me
Bpin
iPr2NOC
Bpin
N
H
N
H
MeO
CONiPr2
8d: C5/others
L1: 99/1 (63%)
dtbpy: 20/1 (91%)
Bpin
8e: C2/others
L1: 99/1 (20%)b
dtbpy: complex mix
Bpin
8f: C2/others
L1: 99/1 (73%)
dtbpy: 5.6/1 (80%)
Bpin
CONiPr2
CONiPr2
D
MeO
13e, 88%
MeO
(e)
Ph
I
(d)
13f, 85%
CONiPr2
CONiPr2
CONiPr2
CONiPr2
iPr2NOC
N
13d, 60%
Cl
N
Me
N
(f)
CONiPr2
8g: m/others
L1: 99/1 (96%)
dtbpy: 20/1 (93%)
Bpin
8h: m/others
L1: 99/1 (96%)
dtbpy: 19/1 (95%)
8i: m/others
L1: 99/1 (89%)
dtbpy: 20/1 (93%)
CONiPr2
Br
MeO
(c)
MeO
(g)
MeO
CONiPr2
CONiPr2
Cl
Bpin
pinB
pinB
6b
NHPh
13g, 60%
13c, 85%
CONiPr2
N
N
H
N
(b)
(h)
8j: m/others
8k: m/others
L1: 99/1 (77%)
dtbpy: 18/1 (94%)
8l: m/others
L1: 99/1 (84%)
dtbpy: 18/1 (94%)
CONiPr2
CONiPr2
(a)
L1: 18/1 (89%)
dtbpy: 0.5/1 (93%)
other classes of substrates for the meta borylation
MeO
MeO
CONiPr2
Me
Me
Me
MeO
tBuO
OMe
13h, 50%
Cl
13b, 90%
F3C
N
Bpin
Me
N
Bpin
N
Bpin
O
O
O
OH
8m: m/others
L1: 24/1 (89%)
dtbpy: 1.6/1 (85%)
8n: m/others
L1: 18/1 (69%)
dtbpy: complex mix
8o: m/others
L1: 24/1 (91%)
dtbpy: 1.7/1 (83%)
13a, 86%
Scheme 4. Conditions: 1.2 equiv. oxone, acetone-H2O (4:1), rt, 2 h. (b) 3 equiv.
CuCl2, MeOH:H2O (1:1), 70 oC, 6 h. (c) 3.0 equiv. CuBr2, MeOH:H2O (1:1), 70
oC, 6 h. (d) 10 mol% CuI, 20 mol%, phen, 1.0 equiv. KI, MeOH:H2O (4:1), 80
oC, 12 h. (e) 2.0 mol% [Ir(cod)(OMe)]2, THF:D2O (6:1), 80 oC, 12 h. (f) 5.0
mol% Pd(PPh3)4, 2.0 equiv. K2CO3, 1.0 equiv. bromobenzene, DME:H2O
(2:1),100 oC, 8 h. (g) 2.0 equiv. aniline, 10 mol% Cu(OAc)2, 1.0 equiv. Et3N, 4
Ao MS, ACN:EtOH (20:1), 80 oC, 12 h. (h) 2.0 equiv. Cu(OAc)2, 1.2 equiv.
DMAP, 4 Ao MS, DCM:MeOH (1:1), rt,12 h.
aReaction scale 0.2 mmol, SI for details. Yields are isolated. bRapid
protodeborylation occurred, conv. was only 20%.
As stated earlier, for a comparison between the classic dtbpy
ligand and our L1 ligand, borylations were conducted with dtbpy
ligand, which resulted poor meta selectivity in all cases. Notably,
it deserves mentioning that while earlier methods of amide
borylations failed to give a solution for the isolation of the pure
amide borylated products, our method gives a straightforward
solution for pure product isolation.
We next performed borylations of heterocyclic amides and
observed that while amides of furan, thiophene, pyrroles and
indoles (Table 3, 8a-8f) afforded excellent selectivity using our
L1 ligand, classic dtbpy produced either complex mixtures or
poor selectivity except for the 8d. Borylation of pyridine amides
were interesting (8g-8l). Whereas, 6-substituted pyridine-2-
amides (8g-8i) gave exclusively meta borylation (>99%) using
our designed L1 ligand, classic dtbpy ligand also resulted decent
amount of meta borylation (>19/1), which apparently seems like
that steric effect is the sole governing factor that is controlling
the meta selectivity. Thus, to verify whether the borylation is
solely controlled by the steric effect or noncovalent interactions,
we performed borylations with the unbiased substrate 7j, where
steric effect is absent and found that while L1 gave high level of
meta selectivity (meta/other = 18/1), classic dtbpy afforded only
The standard iridium-catalyzed borylation mechanism has been
reported earlier[23] and the present meta borylation of aromatic
amides possibly continues through the same way. Nevertheless,
for further understanding of the noncovalent interactions, we
performed control experiments employing L2 and L3 ligands
(Scheme 5). We postulated that if the noncovalent interaction is
the origin of the meta selectivity, then borylation with ligand L2
would be more favored compared to the ligand L3 due to a lack
of such interaction (as shown in TS-2 and TS-3). Following this,
borylations were executed using ligands L2 and L3 and found
that while L2 gave 28/1 meta/para selectivity, ligand L3 resulted
only 1.1/1, which is verifying the proof-of-concept for the
noncovalent interaction between the substrate and ligand. To
gain additional support, we performed control experiment with a
substrate (9) where the amide CO group is absent and found
that the borylation is entirely nonselective (meta/other = 0.1/1),
which is again supporting the concept of the noncovalent
interaction. Moreover, reaction with 3,5-disubstituted amide (11)
resulted no borylations, which indicates that proper structural
orientation is essential for the meta borylation.
regioisomeric mixture (meta/other
=
0.5/1), which is
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10.1002/anie.201809929
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COMMUNICATION
To this end, while the experimental data strongly supports the
concept of the noncovalent interaction, one point remain still
uncleared for the possible two TSs (either TS-3 or TS-2). In
general,[24] two important factors govern the cation–p interaction,
such as, i) electronic properties (while electron withdrawing
groups weaken the interaction, electron donating groups
strengthen) and ii) solvent polarity (as the solvent polarity
increases, the strength decreases).
Britz, A. N. Khlobystov, Chem. Soc. Rev. 2006, 35, 637; c) K. Müller-
Dethlefs, P. Hobza, Chem. Rev. 2000, 100, 143.
[2]
[3]
For recent leading reviews on noncovalent interactions in transition
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Chattopadhyay, Tetrahedron Lett. 2018, 59, 1269; b) H. J. Davis, R. J.
Phipps, Chem. Sci. 2017, 8, 864.
For selected reviews, see: a) M. M. Diaz-Requejo, P. J. Perez, Chem.
Rev. 2008, 108, 3379; b) T. W. Lyons, M. S. Sanford, Chem. Rev. 2010,
110, 1147; c) J. Li, S. De Sarkar, L. Ackerman, Top. Organomet. Chem.
2016, 55, 217; d) J. F. Hartwig, J. Am. Chem. Soc. 2016, 138, 2; e) T.
Gensch, M. N. Hopkinson, F. Glorius, J. Wencel-Delord, Chem. Soc.
Rev. 2016, 45, 2900; f) Y.-F. Yang, X. Hong, J.-Q. Yu, K. N. Houk, Acc.
Chem. Res. 2017, 50, 2853; g) Z. Dong, Z. Ren, S. J. Thompson, Y. Xu,
G. Dong, Chem. Rev. 2017, 117, 9333; h) M. T. Mihai, G. R. Genov, R.
J. Phipps, Chem. Soc. Rev. 2018, 47, 149; i) C. Sambiagio, D.
Schonbauer, R. Blieck, T. Dao-Huy, G. Pototschnig, P. Schaaf, T.
Wiesinger, M. F. Zia, J. Wencel-Delord, T. Besset, B. U. W. Maes, M.
Schnurch, Chem. Soc. Rev. 2018, 47, 6603.
N
N
N
N
N
N
L3
L2
KO
MeO
NnBu2
NnBu2
Bpin
O
O
1.5 mol% [Ir(cod)(OMe)]2, 3.5 mol% L
1.0 equiv. B2pin2, THF, 80 oC, 12 h
3e
4e
outcomes: L2: m/p = 28/1; conv: > 77%.
NnBu2
L3: m/p = 1.1/1, conv: > 90%
NnBu2
CH2 group
[4]
a) D. G. Hall, Boronic Acids; Wiley-VCH: Weinheim, 2005. b) C. M.
Crudden, B. W. Glasspoole, C. J. Lata, Chem. Commun. 2009, 44,
6704.
1.5 mol% [Ir(cod)(OMe)]2, 3.5 mol% L2
1.0 equiv. B2pin2, THF, 80 oC, 12 h
Bpin
10: m/others = 0.1/1 (78%)
NnBu2
9
[5]
[6]
For a review, see: I. A. I. Mkhalid, J. H. Barnard, T. B. Marder, J. M.
Murphy, J. F. Hartwig, Chem. Rev. 2010, 110, 890.
O
O
NnBu2
1.5 mol% [Ir(cod)(OMe)]2, 3.5 mol% L1
1.0 equiv. B2pin2, THF, 80 oC, 12 h
For recent reviews on directed C–H borylation, see: a) A. Ros, R.
Fernandez, J. M. Lassaletta, Chem. Soc. Rev. 2014, 43, 3229; b) L. Xu,
G. Wang, S. Zhang, H. Wang, L. Wang, L. Liu, J. Jiao, P. Li,
Tetrahedron 2017, 73, 7123.
Bpin
Me
Me
Me
Me
12: no borylation
11
Scheme 5. Mechanistic Support by Control Experiments
[7]
[8]
For borylation via directed ortho-metalation, see: a) M. C. Whisler, S.
MacNeil, V. Snieckus, P. Beak, Angew. Chem. Int. Ed. 2004, 43, 2206;
b) T. E. Hurst, T. K. Macklin, M. Becker, E. Hartmann, W. Kügel, J. C.
Parisienne-La Salle, A. S. Batsanov, T. B. Marder, V. Snieckus, Chem.-
Eur. J. 2010, 16, 8155.
Thus, considering these, we compared the electronic effects of
the substituents (Table 2, entry 6b and entry 6f) and observed
no alteration of meta selectivity (both afforded meta/para =
18/1). Moreover, since our borylations were in polar THF
solvent, we performed borylation of 5b and 5f in less polar
hexane solvent and found that although conversions were
slightly less than THF, nonetheless selectivity was identical,
which rules out the possible involvement of cation–p interaction
(TS-2).[25]
Sterically directed meta borylations: a) R. E. Maleczka, Jr.; F. Shi, D.
Holmes, M. R. Smith, III J. Am. Chem. Soc. 2003, 125, 7792; b) J. M.
Murphy, X. Liao, J. F. Hartwig, J. Am. Chem. Soc. 2007, 129, 15434; c)
C. N. Iverson, M. R. Smith, III J. Am. Chem. Soc. 1999, 121, 7696; d) J.
Y. Cho, C. N. Iverson, M. R. Smith, III J. Am. Chem. Soc. 2000, 122,
12868; e) J. Y. Cho, M. K. Tse, D. Holmes, R. E. Maleczka, Jr.; M. R.
Smith, III Science 2002, 295, 305; f) G. A. Chotana, M. A. Rak, M. R.
Smith, III J. Am. Chem. Soc. 2005, 127, 10539; g) S. Konishi, S.
Kawamorita, T. Iwai, P. G. Steel, T. B. Marder, M. Sawamura, Chem.
Asian J. 2014, 9, 434.
In conclusion, we have established an efficient concept for the
meta-selective borylation of amides using
a
L-shaped
bifunctional ligand with a pendant noncovalent interacting site.
The essential feature of this borylation is the contrasting
structural properties of aromatic amides, which primarily control
the selectivity via a noncovalent interaction. The established
concept shows very broad substrate scope and functional group
tolerance. Meta borylated compounds could be transformed
towards various important intermediates using known synthetic
transformations.
[9]
For meta borylations using noncovalent interactions, see: a) Y.
Kuninobu, H. Ida, M. Nishi, M. Kanai, Nat. Chem. 2015, 7, 712; b) R.
Bisht, B. Chattopadhyay, J. Am. Chem. Soc. 2016, 138, 84; c) H. J.
Davis, M. T. Madalina, R. J. Phipps, J. Am. Chem. Soc. 2016, 138,
12759; d) H. J. Davis, G. R. Genow, R. J. Phipps, Angew. Chem. Int.
Ed. 2017, 56, 13351; e) M. T. Mihai, H. J. Davis, G. R. Genov, R. J.
Phipps, ACS Catal. 2018, 8, 3764.
[10] Sterically directed para borylation: a) Y. Saito, Y. Segawa, K. Itami, J.
Am. Chem. Soc. 2015, 137, 5193; b) L. Yang, S. Kazuhiko, Y. Nakao,
Angew. Chem. Int. Ed. 2017, 56, 4853.
Acknowledgements
This work was supported by DST-SERB-Ramanujan Grant
(SB/S2/RJN-45/2013) and Young Scientist Grant (SB/FT/CS-
141/2014). RB thanks CSIR for SRF and MEH thanks UGC for
SRF. We thank team of NMR and Mass facility at our Centre,
and the Director, CBMR for research facility.
[11] For para borylation using noncovalent interaction, see: E. Hoque, R.
Bisht, C. Haldar, B. Chattopadhyay, J. Am. Chem. Soc. 2017, 139,
7745.
[12] For application, see: Y. Feng, D. Holte, J. Zoller, S. Umemiya, L. R.
Simke, P. S. Baran, J. Am. Chem. Soc. 2015, 137, 10160.
[13] a) V. R. Pattabiraman, J. W. Bode, Nature 2011, 480, 471; b) E. Valeur,
M. Bradley, Chem. Soc. Rev. 2009, 38, 606.
Keywords: Noncovalent interaction • Borylation • Meta
[14] V. Pace, W. Holzer, B. Olofsson, Adv. Synth. Catal. 2014, 356, 3697.
[15] A. J. Bennet, Q. P. Wang, H. Slebocka-Tilk, V. Somayaji, R. S. Brown,
B. D. Santarsiero, J. Am. Chem. Soc. 1990, 112, 6383.
Selectivity • Iridium catalyst • Amide
[1]
For selected reviews on noncovalent interactions, see: a) A. J. Neel, M.
[16] Except for the twisted amides, in which structural constraints inhibit co-
planarity and hence delocalization.
J. Hilton, M. S. Sigman, F. D. Toste, Nature 2017, 543, 637; b) D. A.
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[17] a) G. Meng, S. Shi, R. Lalancette, R. Szostak, M. Szostak, J. Am.
Chem. Soc. 2018, 140, 727; b) S. Adachi, N. Kumagai, M. Shibasaki,
Tetrahedron Lett. 2018, 59, 1147.
[18] For K+ ion and carbonyl oxygen interaction, see: a) A. J. Geddes,
Biochem. Educ. 1980, 8, 109; b) S. Y. Noskov, S. Bernèche, B. Roux,
Nature 2004, 431, 830.
Shukla, J. Morris, Z. Lin, T. B. Marder, P. G. Steel, Chem. Sci. 2012, 3,
3505.
[22] For a leading example, see: E. Bisz, A. Piontek, B. Dziuk, R. Szostak,
M. Szostak, J. Org. Chem. 2018, 83, 3159. At this moment, we are not
entirely certain about the other parameters that should be considered
for lower selectivity of 2-chlorobenzamide, which would be a great point
for the future matter of investigations. It should be mentioned that while
use of 2.0 equivalent of B2pin2 resulted lower meta selectivity,
nevertheless, we did not see multiple borylations.
[19] K. B. Girma, V. Lorenz, S. Blaurock, F. T. Edelmann, Coord. Chem.
Rev. 2005, 249, 1283.
[20] Ratio of Ir-catalyst, ligand and KOtBu is very important to achieve high
meta-selectivity. For rate acceleration by KOtBu in iridium-catalyzed
borylation, see: a) M. N. Eliseeva, L. T. Scott, J. Am. Chem. Soc. 2012,
134, 15169; b) T. Ohmura, T. Torigoe, M. Suginome, Chem. Commun.
2014, 50, 6333; c) L. Ji, K. Fucke, S. K. Bose, T. B. Marder, J. Org.
Chem. 2015, 80, 661.
[23] T. M. Boller, J. M. Murphy, M. Hapke, T. Ishiyama, N. Miyaura, J. F.
Hartwig, J. Am. Chem. Soc. 2005, 127, 14263.
[24] a) S. Mecozzi, A. P. West, D. A. Dougherty, J. Am. Chem. Soc. 1996,
118, 2307; b) R. K. Raju, J. W. G. Bloom, Y. An, S. E. Wheeler,
ChemPhysChem 2011, 12, 3116; c) S. E. Wheeler, Acc. Chem. Res.
2013, 46, 1029.
[21] For classic Ir/dtbpy borylations of π-electron accepting and donating
substrates, see: H. Tajuddin, P. Harrisson, B. Bitterlich, J. C. Collings,
N. Sim, A. S. Batsanov, M. S. Cheung, S. Kawamorita, A. C. Maxwell, L.
[25] However, we cannot completely eliminate the TS-2, which would be
future matter of studies.
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COMMUNICATION
TOC
A new concept for the meta
borylation of aromatic
Ranjana Bisht, Md
Emdadul Hoque and
Buddhadeb
Bpin
via
R
R
pinB
N
Bpin
Ir
O
N
O
N
amides is described. Taking
advantage of the contrasting
structural properties of
amides than the esters, it
has been shown that while
esters gave para
borylations, amides resulted
meta borylations. For
achieving high meta
selectivity, a L-shaped
ligand has been used, which
identify the the oxygen atom
of the moderately distorted
amide carbonyl group via an
O××××K noncovalent
N
R
R
Chattopadhyay*
Ir-cat., B2pin2, L1
KOtBu
distorted
planar
N
φ
Bpin
Page No. – Page No.
TS-3
O
K
O
N
R
Amide Effect in C–H
Activation: L-Shaped
Ligand for Meta
Borylation of Aromatic
Amides via Noncovalent
Interaction
R
non-covalent interaction
49 examples
meta selectivity: >99%
interaction providing an
exceptional controlling factor
for meta C–H
activation/borylation.
This article is protected by copyright. All rights reserved.