Activation of Aryl Carboxylic Acids by Diboron Reagents towards Nickel-Catalyzed Direct Decarbonylative Borylation

Article abstract of DOI:10.1002/anie.202106356

The Ni-catalyzed decarbonylative borylation of (hetero)aryl carboxylic acids with B₂cat₂ has been achieved without recourse to any additives. This Ni-catalyzed method exhibits a broad substrate scope covering poorly reactive non-ortho-substituted (hetero)aryl carboxylic acids, and tolerates diverse functional groups including some of the groups active to Ni⁰ catalysts. The key to achieve this decarbonylative borylation reaction is the choice of B₂cat₂ as a coupling partner that not only acts as a borylating reagent, but also chemoselectively activates aryl carboxylic acids towards oxidative addition of their C(acyl)?O bond to Ni⁰ catalyst via the formation of acyloxyboron compounds. A combination of experimental and computational studies reveals a detailed plausible mechanism for this reaction system, which involves a hitherto unknown concerted decarbonylation and reductive elimination step that generates the aryl boronic ester product. This mode of boron-promoted carboxylic acid activation is also applicable to other types of reactions.

Full text of DOI:10.1002/anie.202106356

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Nickel Catalysis
Hot Paper
Activation of Aryl Carboxylic Acids by Diboron Reagents towards
Nickel-Catalyzed Direct Decarbonylative Borylation
Xi Deng, Jiandong Guo, Xiaofeng Zhang, Xiaotai Wang,* and Weiping Su*
Abstract: The Ni-catalyzed decarbonylative borylation of
(hetero)aryl carboxylic acids with B2cat2 has been achieved
without recourse to any additives. This Ni-catalyzed method
exhibits a broad substrate scope covering poorly reactive non-
ortho-substituted (hetero)aryl carboxylic acids, and tolerates
diverse functional groups including some of the groups active
to Ni0 catalysts. The key to achieve this decarbonylative
borylation reaction is the choice of B2cat2 as a coupling partner
that not only acts as a borylating reagent, but also chemo-
coupling reactions of (hetero)aryl carboxylic acids have been
explored extensively[1] since seminal work on the reactions of
this type[2] and identification of the roles silver or copper salts
play in the decarboxylative metalation of (hetero)aryl car-
boxylic acids,[3] which has led to establishment of a diverse
variety of decarboxylative cross-coupling reactions.[1e,f] In
spite of the notable progress in this area, such decarboxylative
cross-couplings are generally limited to ortho-substituted
(hetero)aryl carboxylic acids, probably because the existing
modes for redox-neutral metal-mediated decarboxylation
require ortho-substituents to decrease the reaction activation
barrier.[4] The oxidative decarboxylation strategy enables
non-ortho-substituted (hetero)aryl carboxylic acids to partic-
ipate in decarboxylative functionalization.[5] Nevertheless,
thus far, this oxidative decarboxylation strategy has only
applied to protodecarboxylation,[5a] decarboxylative halogen-
ation[5d,e] and decarboxylative arylation reactions[5b,c] presum-
ably due to the difficulty in generating thermodynamically
unstable aryl radicals, contrasting with its successful applica-
tions to the decarboxylative cross coupling-reactions of alkyl
carboxylic acids.[6]
selectively activates aryl carboxylic acids towards oxidative
0
ꢀ
addition of their C(acyl) O bond to Ni catalyst via the
formation of acyloxyboron compounds. A combination of
experimental and computational studies reveals a detailed
plausible mechanism for this reaction system, which involves
a hitherto unknown concerted decarbonylation and reductive
elimination step that generates the aryl boronic ester product.
This mode of boron-promoted carboxylic acid activation is
also applicable to other types of reactions.
Introduction
Carboxylic acids are readily available in great structural
diversity from both natural and synthetic sources, thus making
them attractive starting materials for organic syntheses. The
development of catalytic methods for efficient transforma-
tions of carboxylic acids into valuable compounds via
selective activation of carboxyl group is essential to achieve
the potential utility of carboxylic acids as versatile building
blocks. In this context, metal-catalyzed decarboxylative cross-
Recently, the decarbonylative or decarboxylative cross-
coupling reactions of carboxylic acid derivatives have ap-
ꢀ
peared as a powerful tool for formations of C C and C-
heteroatom bonds, opening up a new avenue to expanding
synthetic application of abundant carboxylic acids as starting
materials.[7–12] Among these established decarbonylative
cross-coupling reactions, the decarbonylative borylation re-
action of both (hetero)aryl and alkyl carboxylic acid deriv-
atives (e.g. ester, anhydride, amides, and aroyl halides) with
diboron compounds as borylating reagents is one of the most
extensively explored reactions,[11,12] which was driven by the
great importance of organoboron compounds as versatile
reagents in synthesis chemistry.[13] As disclosed by these
elegant studies, the decarbonylative functionalization reac-
tions benefit from the enhanced redox reactivities of carbox-
ylic acid derivatives towards the oxidative addition to low-
valent metal species or single electron transfer redox process.
Comparison between carboxylic acids and corresponding
carboxylic acid derivatives elucidates that the enhanced redox
reactivities of carboxylic acid derivatives structurally result
from the bonds between acyl groups and electron-withdraw-
ing groups, namely RC(O)-X bonds (X = halide, OR or NR2).
Our interest in the metal-catalyzed decarboxylative cross-
coupling reactions[5c,14] prompted us to seek after new modes
of activation of (hetero)aryl carboxylic acids, hopefully
providing a solution to the problem associated with the
conventional limitation of substrate scope to ortho-substitut-
ed (hetero)aryl carboxylic acids, and discovering new types of
decarboxylative functionalization reactions. The seminal
[*] X. Deng, Dr. X. Zhang, Prof. Dr. W. Su
State Key Laboratory of Structural Chemistry, Center for Excellence in
Molecular Synthesis, Fujian Institute of Research on the Structure of
Matter, Chinese Academy of Sciences
Yangqiao West Road 155, Fuzhou 350002 (P. R. China)
E-mail: wpsu@fjirsm.ac.cn
Dr. J. Guo, Prof. Dr. X. Wang
Hoffmann Institute of Advanced Materials, Postdoctoral Innovation
Practice Base, Shenzhen Polytechnic
7098 Liuxian Boulevard, Nanshan District, Shenzhen 518055 (P. R.
China)
E-mail: xiaotai.wang@ucdenver.edu
Prof. Dr. X. Wang
Department of Chemistry, University of Colorado Denver
Campus Box 194, P. O. Box 173364, Denver, CO 80217-3364 (USA)
X. Deng, Prof. Dr. W. Su
University of Chinese Academy of Sciences
Beijing 100049 (P. R. China)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202106356.
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Table 1: Optimization Studies on Decarbonylative Borylation of Aryl
Carboxylic Acids.[a]
studies on boron-catalyzed electrophilic reactions of carbox-
ylic acids have disclosed that the electrophilic activation of
carboxylic acids by boron catalysts is attributed to formation
of acyloxyboron intermediate.[15] The B-O Lewis acid-base
ꢀ
interactions have proved to be beneficial to activation of C O
bonds in aryl ether, phenol and allylic alcohol towards
oxidation addition to low-valent metal catalyst species.[16]
Inspired by these pioneering studies, we questioned whether
boron (sp2) compounds could activate (hetero)aryl carboxylic
Entry
Variation from the standard conditions
Yield of 4b[b] [%]
1
2
3
4
5
6
7
8
9
none
10 mol% dcypm
76 (71[c])
52
15
21
23
<10
NA
50
<5
18
30
10 mol% dcype instead of dcypm
10 mol% dcypp instead of dcypm
20 mol% PCy3 instead of dcypm
10 mol% dppm instead of dcypm
2.0 equiv B2pin2 instead of B2cat2
adding 0.2 equiv KOAc
1.0 mL DMSO instead of toluene
1.0 mL Dioxane instead of toluene
1308C instead of 1508C
ꢀ
acids towards oxidative addition of their C(acyl) O bonds to
low-valent metal catalyst through formation of acyloxyboron
species, which would trigger decarbonylation and subsequent
coupling step. Herein, we demonstrate that this assumed
mode of boron-promoted carboxylic acid activation is viable,
report a direct decarbonylative borylation reaction of (heter-
o)aryl carboxylic acids with bis(catecholato)diboron (B2cat2)
that is catalyzed by a Ni/dcypm catalyst (dcypm = bis(dicy-
clohexylphosphino)methane) and proceeds without recourse
to any additive (Scheme 1). The key to achieve this Ni-
catalyzed direct decarbonylative borylation is our discovery
of B2cat2 as a proper diboron reagent that acted not only as
a borylating reagent/coupling partner, but also as an activator
of (hetero)aryl carboxylic acids. This protocol eliminates the
need for stoichiometric transition metal salts that mediate
decarboxylation and/or serve as terminal oxidants in the
previously developed decarboxylative cross-coupling reac-
tions, avoids in situ generation of activated aryl carboxylic
acid derivatives from the corresponding acids, while enabling
a broad range of (hetero)aryl carboxylic acids including
normally poorly reactive non-ortho-substituted carboxylic
acids[1,2] to be coupled.
10
11
[a] All reactions were run with 1b (0.2 mmol) and 2 (0.4 mmol) in 1 mL
toluene solution containing Ni(COD)2/dcypm under N2, followed by
treatment with pinacol (0.8 mmol) and Et3N (0.4 mL) at room temper-
ature for 1 h. [b] Yield determined by GC analysis with n-dodecane as the
internal standard. [c] Yield of isolated 4b.
pinacol arylboronate product 4b in 76% and 71% GC and
isolated yields, respectively. Phosphine ligands and their
loading were observed to have a profound effect on the
reaction outcomes. Decreasing loading of dcypm to 10 mol%
brought about a drop in yield to 52% (entry 2). In contrast to
dcypm, bidentate ligands capable of forming stable five- or
six-membered chelate ring, namely dcype and dcypp
(10 mol%), and monodentate PCy3 (20 mol%) were much
less effective (entries 3, 4 and 5), although these ligands are
known to promote the Ni-catalyzed decarbonylative cross-
coupling reactions of benzoic acid derivatives.[8b,e] Less
electron-donating dppm ligand was far interior to dcypm,
despite its structural similarity to dcypm (entry 6). Intrigu-
ingly, when bis(pinacolato)diboron (B2pin2) was used in place
of B2cat2, no reaction took place, with essentially all of B2pin2
recovered (entry 7), indicating a difference between B2cat2
and B2pin2 in terms of reactivity with aryl carboxylic acids.
Addition of sub-stoichiometric bases (0.2 equiv), such as
KOAc, proved to be detrimental to the reaction (entry 8),
although such base additives are frequently used to promote
transmetalation in transition metal-catalyzed cross-coupling
reactions of boron reagents.[11g] Similarly to the effect of
external bases, coordinating solvents such as DMSO and 1,4-
dioxane either shut down the reaction or gave much lower
yields than toluene (entries 9 and 10). Attempt to conduct
reaction at lower temperature failed to give a satisfied yield
(entry 11).
Scheme 1. Boron-promoted activation of aryl carboxylic acids towards
directd decarbonylative borylation.
Results and Discussion
Reaction Optimization
We began our investigation by studying the borylation of
4-phenylbenzoic acid (1b) with B2cat2 (2) as a model reaction
(Table 1). After screening a variety of reaction conditions, we
determined that a combination of Ni(COD)2 (10 mol%),
dcypm (20 mol%), B2cat2 (2.0 equiv), and 1b (0.2 M) in
toluene at 1508C delivered the desired coupling product in
the best yield after 24 h of reaction (entry 1). Note that the
catechol arylboronate product 3b was-without isolation-
treated with pinacol and Et3N to convert to the more stable
Evaluation of Substrate Scope
With the optimized reaction conditions in hand, we
further evaluated generality of this decarbonylative boryla-
tion (Scheme 2).[17] To obtain consistent isolated yields, all
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Scheme 2. Substrate scope for Ni-catalyzed direct decarbonylative borylation of (hetero)aryl carboxylic acids.[a] [a]All reactions were run with
1 (0.2 mmol), 2 (0.4 mmol), Ni(COD)2 (10 mol%), dcypm (20 mol%) in 1 mL toluene for 24 h at 1508C under N2 and then treated with pinacol
(0.8 mmol) and Et3N (0.4 mL) at room temperature for 1 h or with MIDA (0.8 mmol) and DMF (2 mL) at 908C for 4 h. Yields of isolated products
are reported.
catechol arylboronate products 3 were converted through
ligand exchange to the more air- and moisture-stable pinacol
afforded the corresponding disubstituted arylboronate esters
5aj–5aq in generally good yields. Trisubstituted 2,4,6-trime-
thylbenzoic acid performed well, affording the mesitylboro-
nate ester 4ar in 52% yield. Polycyclic aromatic acids
exhibited high levels of reactivity in this protocol, as shown
by the formation of the polycyclic arylboronate esters 5as–
5av.
Heteroaryl carboxylic acids, akin to their halide conge-
ners, are abundant, inexpensive, and stable compounds.
Under our standard reaction conditions, a variety of hetero-
aryl carboxylic acids, including (benzo)furan, (benzo)thio-
phene, indole, and thiazole derivatives, were converted to the
arylboronate products
4 or N-methyliminodiacetic acid
(MIDA)-protected arylboronates 5 for isolation and yield
determination.[18] Monosubstituted benzoic acids bearing
electronically diverse substituents in the para- or meta-
position reacted to form the corresponding arylboronate
esters 5b–5q, 4r, 5s–5u, 4v, 5w–5y, 4z, and 5aa–5ad in fair to
excellent yields. Ortho-monosubstituted benzoic acids, de-
spite being somewhat sterically hindered, also reacted effec-
tively, producing 5ae–5ai in yields ranging from 33 to 77%.
Many disubstituted benzoic acids were attempted, which
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corresponding heteroaryl boronate esters 5ba–5bm in good
yields. Isonicotinic acid, a simple pyridine-derivatized car-
boxylic acid, did not work for the decarbonylative borylation,
but 2,6-diphenyl isonicotinic acid could afford the boronate
ester 5bn in a moderate yield. These results suggest that the
pyridinyl group might react with the diboron reagent to
interfere with the carboxyl activation but that the reaction
might be stalled by the steric hindrance of the two N-adjacent
phenyl substituents in 2,6-diphenyl isonicotinic acid.
In summary, a broad range of aryl carboxylic acids, which
bear electronically and sterically diverse functional groups,
such as ether, thioether, hydroxy, fluoro, chloro, ester, ketone,
amide, sulfonamide, and pinacol boronate, were compatible
with our decarbonylative borylation protocol. Thus, the
protocol demonstrates a potential utility in iterative cross-
coupling reactions. Particularly, alkyloxy,[19a–c] fluoro,[19d–g] and
amide groups,[19h] which are effective leaving groups in an
array of Ni-catalyzed cross-coupling reactions with diboron
reagents, were perfectly tolerated, illustrating that our
method is orthogonal to those Ni-catalyzed reactions. It is
worth noting that two carboxylic acid-based pharmaceuticals,
namely probenecid and adapalene, were transformed into the
borylated products 5p and 5av in moderate to high yields.
This is a further demonstration that the protocol could be
useful for the elaboration of bioactive compounds. It should
be noted that benzoic acids bearing a strongly electron-
withdrawing nitro or cyano group does not perform well for
this decarbonylative borylation protocol, presumably because
such groups significantly decrease the affinity of the carboxyl
group for the Lewis-acidic diboron reagent.
Scheme 3. Reactivity of boron reagents with benzoic acid.[a] [a] See
Figure S2 for the NMR spectra.
aroyloxyboron complex containing a four-coordinate boron
center which is known to give a 11B NMR chemical shift in
that region of the spectrum (Figure S2).[22] Moreover, the
aroyloxyboron species generated from the reaction of B2cat2
with benzoic acid could be isolated in the form of
ArCOOBcat·(ArCOO)2Ni adduct and structurally character-
ized by single crystal X-ray diffraction analysis (Figure S3)[17]
when the reaction solution of B2cat2 with benzoic acid was
treated with 0.5 equiv of NiII carboxylate salt.
To our delight, the reaction of benzoic acid with half an
equivalent of B2cat2 under heating [Scheme 3, Eq. (3)]
showed exactly the same 11B and 1H NMR results as the
reaction of benzoic acid with HBcat, indicating that B2cat2
could activate aryl carboxylic acids to form aroyloxyborons at
elevated temperatures (Figure S2). This control experiment
lends support to the idea that B2cat2 plays a dual role in our
reaction as a carboxylic acid activator and a coupling partner.
In contrast, no reaction was detected for a mixture of benzoic
acid and B2pin2 under the same conditions [Scheme 3,
Eq. (4)], suggesting that B2pin2 could not activate aryl
carboxylic acids even at elevated temperatures. This result
agrees with the observation that B2pin2 is an ineffective
diboron reagent for the cross-coupling reaction (Table 1,
entry 7).
The strategy of activating carboxylic acids with boron
reagents could also be exploited in the decarbonylative
borylation of aryl carboxylic acid anhydrides and the direct
conversion of alky carboxylic acids into olefins,[20] as shown in
Scheme S1.
Mechanistic Studies
We employed a combination of experiments and DFT
calculations to gain insight into the mechanism of the new
catalytic reaction. In the execution of the model reaction of 4-
phenylbenzoic acid (1b) with B2cat2, we observed H2 and CO
in the gas phase by GC, thereby confirming the decarbon-
ylative nature of the reaction (Figure S1). 11B NMR measure-
ments were carried out to monitor the reactions of benzoic
acid (1a) with B2cat2 and related boron reagents (Scheme 4).
A previous 11B NMR study by Antilla et al. on the reaction of
a phosphoric acid with catecholborane (HBcat) provided
useful reference,[21] which showed release of H2 gas and
formation of a new phosphoryloxyboron species with a dis-
tinct 11B NMR peak at 22.1 ppm [Scheme 3, Eq. (1)]. In
analyzing the reaction of benzoic acid with HBcat, we
observed gas evolution and a major 11B NMR peak at
21.8 ppm [Scheme 3, Eq. (2)], which was assigned to an
aroyloxyboron species by analogy to Antillaꢀs work (Fig-
ure S2). In addition, a minor peak appeared at 3.1 ppm and
would grow in size as the amount of benzoic acid was
increased. We assign the 3.1 ppm peak to a benzoic acid-
To establish a detailed plausible mechanism for the title
reaction, we carried out extensive density functional theory
(DFT) calculations on the reaction of benzoic acid (1a)
beginning with its activation by B2cat2. As shown in Figure 1,
benzoic acid reacts with B2cat2 by concerted metathesis via
ꢀ
the six-membered transition state TS1, wherein the O H and
ꢀ
ꢀ
ꢀ
B B bonds are breaking by heterolysis and the B O and H B
bonds are forming through Lewis acid-base interaction. TS1
proceeds to HBcat with the release of the aroyloxyboron
species PhCOOBcat. HBcat continues to react with 1a by
concerted metathesis via the five-membered TS2 to form
PhCOOBcat and release H2 gas. Thermodynamically this
activation process is favorable (DG = ꢀ34.4 kcalmolꢀ1), and
kinetically it has the highest energy barrier of 33.5 kcalmolꢀ1
(B2cat2 to TS1).[23] We also computed the mechanism of the
reaction of benzoic acid with B2pin2, for which the energy
barrier TS1’ is higher than TS1 by 1.6 kcalmolꢀ1 (Figure S4).
As estimated by using the Eyring equation, the reaction of
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not be found due to the steric hindrance around the four-
coordinate NiII center. Dissociation of one phosphine arm via
TS4 converts IM3 into the three-coordinate IM4, which
subsequently combines with B2cat2 to give IM5. This four-
coordinate intermediate launches intramolecular transmeta-
ꢀ
lation involving heterolytic B B bond cleavage via the four-
membered transition state TS5, which delivers the dioxabor-
olyl (boryl hereafter) group to the NiII center in IM6 and
releases the byproduct catBOBcat (Figure S8). Rebound of
the second dangling phosphine arm in IM6 converts it into the
much more stable four-coordinate complex IM7.
No transition state of decarbonylation/phenyl migration
from IM7 could be found probably because of the large space
separating the phenyl group and the NiII center. We traced the
interchange transition state TS6 connecting from IM7 and
proceeding to IM8 with the opening of the diphosphine
chelate ring. The geometry of the h2-p complex IM8 is such
that it brings the NiII center and the phenyl group into
a proper spatial relationship.This symphoria facilitates the
decarbonylation/phenyl migration via TS7, which would be
expected to proceed to a square planar NiII carbonyl
intermediate bearing a phenyl cis to the boryl group. Such
a structure was indeed observed along the calculated intrinsic
reaction coordinate (IRC) of TS7 (Figure S9) but could not be
optimized as an energy minimum; it transforms downhill into
IM9, a Ni0 complex bearing the reductive elimination (or
phenyl-boryl coupling) product PhBcat. As a benchmark
study, we reoptimized TS7 using three other density func-
tionals, i.e., M06-L, wB97XD, and X3LYP, and the computed
transition states all behave like TS7 and proceed to IM9
(Figure S10). Thus, the calculations strongly suggest a con-
certed process of decarbonylation (or phenyl migration to
nickel) and reductive elimination of the phenyl-boryl cou-
pling product. This could be explained by considering the
significant natural charges on the boron (+ 0.80) and ipso-
carbon (ꢀ0.23) atoms in TS7, which show a tendency of
phenyl-boryl interaction when the two groups become close
to each other. This concerted decarbonylation and reductive
elimination mechanism (IM8 ! IM9 via TS7) has not been
known before, and the closest analogy was seen in a computa-
tional study of copper-catalyzed borylation, which involves
the concerted PhI to CuI oxidative addition and reductive
phenyl-boryl elimination/coupling.[24] In addition, concerted
b-hydrogen elimination and reductive hydrogen-vinyl elimi-
nation/coupling pathways were found by a number of
computational studies on nickel-catalyzed reactions.[25]
Figure 1. Free energy profile for the activation of benzoic acid by
B2cat2 computed with M06/BS2//B3LYP/BS1 (the same below; see
Computational Methods in the Supporting Information). Selected
bond distances are given in ꢁ (the same below).
benzoic acid with B2pin2 would be 15 times slower than the
reaction with B2cat2 under the same conditions. These
calculations are qualitatively consistent with the experimental
findings. Conceptually, the reactivity difference between
B2cat2 and B2pin2 can be understood by considering that
B2pin2 is a weaker Lewis acid than B2cat2. Benchmark
calculations on TS1 and TS1’ at a higher level of theory gave
consistent and more accurate results (Figure S5).
The next phase of reaction is the oxidative addition of
PhCOOBcat to Ni0 (Figure 2). The precatalyst Ni(COD)2 is
Figure 2. Free energy profile for the PhCOOBcat to Ni0 oxidative
addition.
activated by reacting with the ancillary diphosphine ligand
dcypm, for which we have considered various products
(Figure S6). IM1 is the most stable species generated, and
the initiation process is thermodynamically favorable by
7.0 kcalmolꢀ1. IM1 takes up PhCOOBcat by substituting it for
COD to form the precursor complex IM2, which undergoes
subsequent intramolecular oxidative addition involving the
PhC(O)-OBcat bond cleavage via the transition state TS3,
which proceeds to the square planar NiII d8 complex IM3
bearing a benzoyl ligand. The oxidative addition has an
overall activation barrier of 24.2 kcalmolꢀ1 (IM1 to TS3) in
the initial catalytic cycle. We also considered and ruled out the
alternative oxidative addition involving the Ph-COOBcat
bond cleavage, which would have a significantly higher
barrier than TS3 (Figure S7).
Rebound of the open phosphine arm in IM9 converts it
into IM10, which extrudes CO via the dissociative transition
state TS8 to form IM11. Substitution of COD by IM11
releases the borylation product PhBcat, regenerates the
active species IM1, and closes the catalytic cycle. Thus,
a detailed plausible mechanism for the title reaction has now
been established computationally. It reveals a complex yet
well-defined reaction system consisting of two portions: (a)
the activation of aryl carboxylic acids by B2cat2 (Figure 1) and
(b) the catalytic cycle beginning with the active species IM1
(Figure 2, Figure 3, and Figure 4). The balanced equations for
the two portions and the overall reaction are the following:
Pathways of direct transmetalation of IM3 with B2cat2
through five-coordinate intermediates/transition states could
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1
2
1
2
because the extrusion of CO gas from IM10 shifts the
equilibrium position forward. We also considered an alter-
ð1aÞ
ð1bÞ
PhCOOH þ B2cat2 ! PhCOOBcat þ H2
native route in which decarbonylation (from IM4) would
precede transmetalation; this pathway could be ruled out
because it would lead to a concerted transmetalation and
reductive elimination with a very high-energy barrier, TS12
(Figure S11).
PhCOOBcat þ B2cat2 ! PhBcat þ catBOBcat þ CO
3
2
1
2
PhCOOH þ B2cat2 ! PhBcat þ catBOBcat þ CO þ H2
ð1cÞ
The activation of benzoic acid by B2cat2 has a barrier of
33.5 kcalmolꢀ1 that is consistent with the reaction temper-
ature (1508C),[11f,26] and the resulting borolyl benzoate
PhCOOBcat enters the catalytic cycle by replacing COD
from IM1 (Figure 2). The largest energy span in the initial
catalytic cycle is from IM7 to TS7, 24.4 kcalmolꢀ1 (Figure 4).
Because IM9 is lower in energy than the regenerated active
catalyst IM1 by 8.7 kcalmolꢀ1 (Figure 4), beginning with the
second catalytic cycle, IM9 should be the reference state of
the oxidative addition barrier TS3 (Figure 2), which causes
TS3 to be 32.9 kcalmolꢀ1 (24.2 + 8.7) and hence the turnover-
limiting barrier. This overall activation barrier is also
consistent with the reaction temperature (1508C).[11f,26] The
catalytic cycle has a large thermodynamic driving force (DG =
ꢀ35.0 kcalmolꢀ1). Although the segment from IM9 through
IM1 is endergonic by 8.7 kcalmolꢀ1 (Figure 4), IM9 would not
cause a thermodynamic sink on the reaction coordinate,
Conclusion
We have developed a Ni-catalyzed method that enables
the direct decarbonylative borylation of (hetero)aryl carbox-
ylic acids without recourse to any additive. This method is
applicable to a broad range of (hetero)aryl carboxylic acids
including normally poorly reactive non-ortho-substituted
acids, demonstrates a good chemoselectivity for carboxyl
group over some of the groups active to electron-rich Ni0
catalysts. The choice of B2cat2 is crucial to the success of the
catalytic protocol. This diboron reagent not only serves as the
borylating agent, it also activates the carboxylic acid to form
the aroyloxyboron for oxidative addition to Ni0 involving the
ArC(O)-OBcat bond cleavage. A combination of experi-
ments and extensive DFT calculations reveals a detailed
plausible mechanism, the key aspects of which are recapitu-
lated in Scheme 4. The active Ni0 species
IM1 reacts with the aroyloxyboron by
oxidative addition, and the resulting NiII
complex IM3 undergoes single phosphine
dissociation to IM4, followed by transme-
talation with B2cat2, to deliver the boryl
group to the NiII center in IM6 or IM8,
a cis-NiII(aroyl)(boryl) complex. The reac-
tion then proceeds by an unprecedented
concerted decarbonylation and reductive
elimination mechanism via TS7 to afford
the carbonyl complex IM9 bearing the aryl
boronic ester product. Subsequent phos-
phine rebound enables CO dissociation
from IM10, which is followed by COD
substitution to release the product and
Figure 3. Free energy profile for the transmetalation with B2cat2.
regenerate the active species IM1. Further
Figure 4. Free energy profile for the concerted decarbonylation and reductive elimination, followed by catalyst regeneration. The numbers denote
natural charges on selected atoms in TS7.
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Synthesis 2012, 44, 653; e) G. J. P. Perry, I. Larrosa, Eur. J. Org.
Chem. 2017, 3517 – 3527; f) Y. Wei, P. Hu, M. Zhang, W. Su,
Chem. Rev. 2017, 117, 8864 – 8907.
[2] a) A. G. Myers, D. Tanaka, M. R. Mannion, J. Am. Chem. Soc.
2002, 124, 11250 – 11251; b) L. J. Goossen, G. Deng, L. M. Levy,
Science 2006, 313, 662 – 664; c) A. Voutchkova, A. Coplin, N. E.
Leadbeater, R. H. Crabtree, Chem. Commun. 2008, 47, 6312 –
6314; d) C. Wang, I. Piel, F. Glorius, J. Am. Chem. Soc. 2009, 131,
4194 – 4195; e) M. Miyasaka, A. Fukushima, T. Satoh, K. Hirano,
M. Miura, Chem. Eur. J. 2009, 15, 3674 – 3677; f) J. Cornella, P.
Lu, I. Larrosa, Org. Lett. 2009, 11, 5506 – 5509; g) F. Zhang, M. F.
Greaney, Angew. Chem. Int. Ed. 2010, 49, 2768 – 2771; Angew.
Chem. 2010, 122, 2828 – 2831.
[3] a) L. J. Goossen, C. Linder, N. Rodrꢁguez, P. P. Lange, A.
Fromm, Chem. Commun. 2009, 7173 – 7175; b) J. Cornella, C.
Sanchez, D. Banawa, I. Larrosa, Chem. Commun. 2009, 7176 –
7178.
[4] a) L. Xue, W. Su, Z. Lin, Dalton Trans. 2011, 40, 11926 – 11936;
b) R. Grainger, J. Cornella, D. C. Blakemore, I. Larrosa, J. M.
Campanera, Chem. Eur. J. 2014, 20, 16680 – 16687.
[5] a) S. Seo, J. B. Taylor, M. F. Greaney, Chem. Commun. 2012, 48,
8270 – 8272; b) S. Seo, M. Slater, M. F. Greaney, Org. Lett. 2012,
14, 2650 – 2653; c) J. Kan, S. Huang, J. Lin, M. Zhang, W. Su,
Angew. Chem. Int. Ed. 2015, 54, 2199 – 2203; Angew. Chem.
2015, 127, 2227 – 2231; d) L. Candish, M. Freitag, T. Gensch, F.
Glorius, Chem. Sci. 2017, 8, 3618 – 3622; e) G. J. P. Perry, J. M.
Quibell, A. Panigrahi, I. Larrosa, J. Am. Chem. Soc. 2017, 139,
11527 – 11536.
Scheme 4. Summary of mechanism of Ni-catalyzed direct decarbon-
ylative borylation of aryl carboxylic acids.
[6] The selected examples of oxidative decarboxylation cross-
coupling reactions of alkyl carboxylic acids, see: a) X. Liu, Z.
Wang, X. Cheng, C. Li, J. Am. Chem. Soc. 2012, 134, 14330 –
14333; b) A. Noble, S. J. McCarver, D. W. C. MacMillan, J. Am.
Chem. Soc. 2015, 137, 624 – 627; c) Q.-Q. Zhou, W. Guo, W.
Ding, X. Wu, X. Chen, L.-Q. Lu, W.-J. Xiao, Angew. Chem. Int.
Ed. 2015, 54, 11196 – 11199; Angew. Chem. 2015, 127, 11348 –
11351; d) Z.-J. Liu, X. Lu, G. Wang, L. Li, W.-T. Jiang, Y.-D.
Wang, B. Xiao, Y. Fu, J. Am. Chem. Soc. 2016, 138, 9714 – 9719.
[7] The recent reviews on decarbonylative cross-coupling reactions
of carboxylic acid derivatives, see: a) Z. Wang, X. Wang, Y.
Nishihara, Chem. Asian J. 2020, 15, 1234 – 1247; b) Y. Ogiwara,
N. Sakai, Angew. Chem. Int. Ed. 2020, 59, 574 – 594; Angew.
Chem. 2020, 132, 584 – 605; c) N. Blanchard, V. Bizet, Angew.
Chem. Int. Ed. 2019, 58, 6814 – 6817; Angew. Chem. 2019, 131,
6886 – 6889; d) L. Guo, M. Rueping, Acc. Chem. Res. 2018, 51,
1185 – 1195; e) G. Meng, M. Szostak, Eur. J. Org. Chem. 2018,
2352 – 2365; f) R. Takise, K. Muto, J. Yamaguchi, Chem. Soc.
Rev. 2017, 46, 5864 – 5888; g) H. Lu, T.-Y. Yu, P.-F. Xu, H. Wei,
Chem. Rev. 2021, 121, 365 – 411.
[8] a) L. J. Goossen, J. Paetzold, Angew. Chem. Int. Ed. 2002, 41,
1237 – 1241; Angew. Chem. 2002, 114, 1285 – 1289; b) K. Muto, J.
Yamaguchi, D. G. Musaev, K. Itam, Nat. Commun. 2015, 6,
7508 – 7510; c) A. Chatupheeraphat, H.-H. Liao, W. Srimontree,
L. Guo, Y. Minenkov, A. Poater, L. Cavallo, M. Rueping, J. Am.
Chem. Soc. 2018, 140, 3724 – 3735; d) R. Takise, R. Isshiki, K.
Muto, K. Itami, J. Yamaguchi, J. Am. Chem. Soc. 2017, 139,
3340 – 3343; e) C. A. Malapit, M. Borrell, M. W. Milbauer, C. E.
Brigham, M. S. Sanford, J. Am. Chem. Soc. 2020, 142, 5918 –
5923.
efforts are underway to leverage the mode of boron activating
carboxylic acids to develop new direct cross-coupling reac-
tions of carboxylic acids.
Acknowledgements
This work is supported by the National Key Research and
Development Program of China (2018YFA0704502), the
National Natural Science Foundation of China Grant
(21931011, 22071241, 22071243), the Key Research Program
of Frontier Sciences of the Chinese Academy of Sciences
(QYZDJ-SSW-SLH024), and the Strategic Priority Research
Program of the Chinese Academy of Science
(XDB20000000). X.W. acknowledges support from the Hoff-
mann Institute of Advanced Materials, Shenzhen Polytechnic
and the University of Colorado Denver.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: borylation · carboxylic acid activation ·
decarbonylative cross-coupling · DFT studies · nickel catalysis
[9] a) M. S. Stephan, A. J. J. M. Teunissen, G. K. M. Verzijl, J. G.
de Vries, Angew. Chem. Int. Ed. 1998, 37, 662 – 664; Angew.
Chem. 1998, 110, 688 – 690; b) F. Pan, Z.-Q. Lei, H. Wang, H. Li,
J. Sun, Z.-J. Shi, Angew. Chem. Int. Ed. 2013, 52, 2063 – 2067;
Angew. Chem. 2013, 125, 2117 – 2121; c) G. Meng, M. Szostak,
Angew. Chem. Int. Ed. 2015, 54, 14518 – 14522; Angew. Chem.
2015, 127, 14726 – 14730; d) S. Shi, G. Meng, M. Szostak, Angew.
Chem. Int. Ed. 2016, 55, 6959 – 6963; Angew. Chem. 2016, 128,
[1] The reviews on decarboxylative cross-coupling reactions of aryl
carboxylic acids, see: a) L. J. Goossen, N. Rodrꢁguez, K.
Goossen, Angew. Chem. Int. Ed. 2008, 47, 3100 – 3120; Angew.
Chem. 2008, 120, 3144 – 3164; b) N. Rodrꢁguez, L. J. Goossen, J.
Chem. Soc. Rev. 2011, 40, 5030 – 5048; c) R. Shang, L. Liu, Sci.
China Chem. 2011, 54, 1670 – 1687; d) I. Larrosa, J. Cornella,
&&&&
www.angewandte.org
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 2 – 10
These are not the final page numbers!

Angewandte
Research Articles
Chemie
7073 – 7077; e) C. A. Malapit, J. R. Bour, C. E. Brigham, M. S.
f) Y. Morita, T. Yamamoto, H. Nagai, Y. Shimizu, M. Kanai, J.
Sanford, Nature 2018, 563, 100 – 104.
Am. Chem. Soc. 2015, 137, 7075 – 7078; g) D. G. Hall, Chem. Soc.
Rev. 2019, 48, 3475 – 3496.
[10] a) K. Okada, K. Okamoto, N. Morita, K. Okubo, M. Oda, J. Am.
Chem. Soc. 1991, 113, 9401 – 9402; b) G. Pratsch, G. L. Lackner,
L. E. Overman, J. Org. Chem. 2015, 80, 6025 – 6036; c) T. Qin, J.
Cornella, C. Li, L. R. Malins, J. T. Edwards, S. Kawamura, B. D.
Maxwell, M. D. Eastgate, P. S. Baran, Science 2016, 352, 801 –
805; d) F. Toriyama, J. Cornella, L. Wimmer, T.-G. Chen, D. D.
Dixon, G. Creech, P. S. Baran, J. Am. Chem. Soc. 2016, 138,
11132 – 11135; e) J. Wang, T. Qin, T.-G. Chen, L. Wimmer, J. T.
Edwards, J. Cornella, B. Vokits, S. A. Shaw, P. S. Baran, Angew.
Chem. Int. Ed. 2016, 55, 9676 – 9679; Angew. Chem. 2016, 128,
9828 – 9831; f) K. M. M. Huihui, J. A. Caputo, Z. Melchor, A. M.
Olivares, A. M. Spiewak, K. A. Johnson, T. A. DiBenedetto, S.
Kim, L. K. G. Ackerman, D. J. Weix, J. Am. Chem. Soc. 2016,
138, 5016 – 5019; g) X. Liu, J. Jia, M. Rueping, ACS Catal. 2017,
7, 4491 – 4496; h) J. Masson-Makdissi, J. K. Vandavasi, S. G.
Newman, Org. Lett. 2018, 20, 4094 – 4098; i) T. Patra, P. Bellotti,
F. Strieth-Kalthoff, F. Glorius, Angew. Chem. Int. Ed. 2020, 59,
3172 – 3177; Angew. Chem. 2020, 132, 3198 – 3203.
[16] a) Y. Tamaru, Y. Horino, M. Araki, S. Tanaka, M. Kimura,
Tetrahedron Lett. 2000, 41, 5705 – 5709; b) D.-G. Yu, Z.-J. Shi,
Angew. Chem. Int. Ed. 2011, 50, 7097 – 7100; Angew. Chem.
2011, 123, 7235 – 7238; c) L. Guo, X. Liu, C. Baumann, M.
Rueping, Angew. Chem. Int. Ed. 2016, 55, 15415 – 15419; Angew.
Chem. 2016, 128, 15641 – 15645.
[17] Deposition Numbers 2044604 (5b), 2044605 (5av), 2044607
(5bh), and 2044608 ((PhPhCOOBcat)2·Ni(OOCPhPh)2) contain
the supplementary crystallographic data for this paper. These
data are provided free of charge by the joint Cambridge
Crystallographic Data Centre and Fachinformationszentrum
Karlsruhe Access Structures service www.ccdc.cam.ac.uk/
structures.
[18] a) M. Murata, T. Oyama, S. Watanabe, Y. Masuda, J. Org. Chem.
2000, 65, 164 – 168; b) D. Mazzarella, G. Magagnano, B.
Schweitzer-Chaput, P. Melchiorre, ACS Catal. 2019, 9, 5876 –
5880.
[11] a) X. Pu, J. Hu, Y. Zhao, Z. Shi, ACS Catal. 2016, 6, 6692 – 6698;
b) J. Hu, Y. Zhao, J. Liu, Y. Zhang, Z. Shi, Angew. Chem. Int. Ed.
2016, 55, 8718 – 8722; Angew. Chem. 2016, 128, 8860 – 8864; c) H.
Ochiai, Y. Uetake, T. Niwa, T. Hosoya, Angew. Chem. Int. Ed.
2017, 56, 2482 – 2486; Angew. Chem. 2017, 129, 2522 – 2526; d) L.
Candish, M. Teders, F. Glorius, J. Am. Chem. Soc. 2017, 139,
7440 – 7443; e) Z. Wang, X. Wang, Y. Nishihara, Chem. Com-
mun. 2018, 54, 13969 – 13972; f) C. Liu, C.-L. Ji, X. Hong, M.
Szostak, Angew. Chem. Int. Ed. 2018, 57, 16721 – 16726; Angew.
Chem. 2018, 130, 16963 – 16968; g) C. A. Malapit, J. R. Bour,
S. R. Laursen, M. S. Sanford, J. Am. Chem. Soc. 2019, 141,
17322 – 17330.
[12] a) C. Li, J. Wang, L. M. Barton, S. Yu, M. Tian, D. S. Peters, M.
Kumar, A. W. Yu, K. A. Johnson, A. K. Chatterjee, M. Yan, P. S.
Baran, Science 2017, 356, eaam7355; b) A. Fawcett, J. Pradeilles,
Y. Wang, T. Mutsuga, E. L. Myers, V. K. Aggarwal, Science 2017,
357, 283 – 286; c) D. Hu, L. Wang, P. Li, Org. Lett. 2017, 19,
2770 – 2773.
[19] a) K. Nakamura, M. Tobisu, N. Chatani, Org. Lett. 2015, 17,
6142 – 6145; b) C. Zarate, R. Manzano, R. Martin, J. Am. Chem.
Soc. 2015, 137, 6754 – 6757; c) M. Tobisu, J. Zhao, H. Kinuta, T.
Furukawa, T. Igarashi, N. Chatani, Adv. Synth. Catal. 2016, 358,
2417 – 2421; d) X.-W. Liu, J. Echavarren, C. Zarate, R. Martin, J.
Am. Chem. Soc. 2015, 137, 12470 – 12473; e) T. Niwa, H. Ochiai,
Y. Watanabe, T. Hosoya, J. Am. Chem. Soc. 2015, 137, 14313 –
14318; f) J. Zhou, M. W. Kuntze-Fechner, R. Bertermann,
U. S. D. Paul, J. H. J. Berthel, A. Friedrich, Z. Du, T. B. Marder,
U. Radius, J. Am. Chem. Soc. 2016, 138, 5250 – 5253; g) A. M.
Mfuh, J. D. Doyle, B. Chhetri, H. D. Arman, O. V. Larionov, J.
Am. Chem. Soc. 2016, 138, 2985 – 2988; h) M. Tobisu, K.
Nakamura, N. Chatani, J. Am. Chem. Soc. 2014, 136, 5587 – 5590.
[20] J. Hu, M. Wang, X. Pu, Z. Shi, Nat. Commun. 2017, 8, 14993.
[21] Z. Zhang, P. Jain, J. C. Antilla, Angew. Chem. Int. Ed. 2011, 50,
10961 – 10964; Angew. Chem. 2011, 123, 11153 – 11156.
[22] a) G. R. Eaton, J. Chem. Educ. 1969, 46, 547 – 556; b) S.
Hermanek, Chem. Rev. 1992, 92, 325 – 362.
[13] a) Boronic acids: preparation and applications in organic syn-
thesis medicine and materials, 2nd ed. (Ed.: D. G. Hall), Wiley-
VCH, Weinheim, 2011; b) N. Miyaura, A. Suzuki, Chem. Rev.
1995, 95, 2457 – 2483.
[14] a) J. Zhou, P. Hu, M. Zhang, S. Huang, M. Wang, W. Su, Chem.
Eur. J. 2010, 16, 5876 – 5880; b) P. Hu, M. Zhang, X. Jie, W. Su,
Angew. Chem. Int. Ed. 2012, 51, 227 – 231; Angew. Chem. 2012,
124, 231 – 235; c) P. Hu, Y. Shang, W. Su, Angew. Chem. Int. Ed.
2012, 51, 5945 – 5949; Angew. Chem. 2012, 124, 6047 – 6051; d) Y.
Zhang, H. Zhao, M. Zhang, W. Su, Angew. Chem. Int. Ed. 2015,
54, 3817 – 3821; Angew. Chem. 2015, 127, 3888 – 3892.
[23] The actual transition state could be somewhat lower in energy
due to possible intermolecular interactions, hydrogen bonding
included.
[24] C. Kleeberg, L. Dang, Z. Lin, T. B. Marder, Angew. Chem. Int.
Ed. 2009, 48, 5350 – 5354; Angew. Chem. 2009, 121, 5454 – 5458.
[25] a) P. R. McCarren, P. Liu, P. H. Cheong, T. F. Jamison, K. N.
Houk, J. Am. Chem. Soc. 2009, 131, 6654 – 6655; b) T. Wititsu-
wannakul, Y. Tantirungrotechai, P. Surawatanawong, ACS Catal.
2016, 6, 1477 – 1486.
[26] X. Hong, Y. Liang, K. N. Houk, J. Am. Chem. Soc. 2014, 136,
2017 – 2025.
[15] a) K. Ishihara, S. Ohara, H. Yamamoto, J. Org. Chem. 1996, 61,
4196 – 4197; b) T. Maki, K. Ishiharaa, H. Yamamoto, Tetrahe-
dron 2007, 63, 8645 – 8657; c) R. M. Al-Zoubi, O. Marion, D. G.
Hall, Angew. Chem. Int. Ed. 2008, 47, 2876 – 2879; Angew. Chem.
2008, 120, 2918 – 2921; d) H. Zheng, R. McDonald, D. G. Hall,
Chem. Eur. J. 2010, 16, 5454 – 5460; e) H. Charville, D. Jackson,
G. Hodges, A. Whiting, Chem. Commun. 2010, 46, 1813 – 1823;
Manuscript received: May 11, 2021
Revised manuscript received: July 5, 2021
Accepted manuscript online: July 7, 2021
Version of record online: && &&
,
&&&&
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&&&&
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Research Articles
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Research Articles
Nickel Catalysis
A Ni-catalyzed direct decarbonylative
borylation of aryl carboxylic acids with
B2cat2 has been established. B2cat2 serves
as a borylating agent, but also activates
the carboxylic acid substrate towards
decarbonylative coupling, playing a dual
role in this reaction. A combination of
experimental and computational studies
reveals that the reaction proceeds
through a hitherto unknown concerted
decarbonylation and reductive elimi-
nation step.
X. Deng, J. Guo, X. Zhang, X. Wang,*
W. Su*
&&&& — &&&&
Activation of Aryl Carboxylic Acids by
Diboron Reagents towards Nickel-
Catalyzed Direct Decarbonylative
Borylation
&&&&
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These are not the final page numbers!