Cyclic (Alkyl)(amino)carbene Ligand-Promoted Nitro Deoxygenative Hydroboration with Chromium Catalysis: Scope, Mechanism, and Applications

Article abstract of DOI:10.1021/jacs.0c12318

Transition metal catalysis that utilizes N-heterocyclic carbenes as noninnocent ligands in promoting transformations has not been well studied. We report here a cyclic (alkyl)(amino)carbene (CAAC) ligand-promoted nitro deoxygenative hydroboration with cost-effective chromium catalysis. Using 1 mol % of CAAC-Cr precatalyst, the addition of HBpin to nitro scaffolds leads to deoxygenation, allowing for the retention of various reducible functionalities and the compatibility of sensitive groups toward hydroboration, thereby providing a mild, chemoselective, and facile strategy to form anilines, as well as heteroaryl and aliphatic amine derivatives, with broad scope and particularly high turnover numbers (up to 1.8 × 106). Mechanistic studies, based on theoretical calculations, indicate that the CAAC ligand plays an important role in promoting polarity reversal of hydride of HBpin; it serves as an H-shuttle to facilitate deoxygenative hydroboration. The preparation of several commercially available pharmaceuticals by means of this strategy highlights its potential application in medicinal chemistry.

Full text of DOI:10.1021/jacs.0c12318

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Article
Cyclic (Alkyl)(amino)carbene Ligand-Promoted Nitro Deoxygenative
Hydroboration with Chromium Catalysis: Scope, Mechanism, and
Applications
Lixing Zhao,§ Chenyang Hu,§ Xuefeng Cong, Gongda Deng, Liu Leo Liu, Meiming Luo,
and Xiaoming Zeng*
Cite This: J. Am. Chem. Soc. 2021, 143, 1618−1629
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ABSTRACT: Transition metal catalysis that utilizes N-hetero-
cyclic carbenes as noninnocent ligands in promoting trans-
formations has not been well studied. We report here a cyclic
(alkyl)(amino)carbene (CAAC) ligand-promoted nitro deoxyge-
native hydroboration with cost-effective chromium catalysis. Using
1 mol % of CAAC−Cr precatalyst, the addition of HBpin to nitro
scaffolds leads to deoxygenation, allowing for the retention of
various reducible functionalities and the compatibility of sensitive
groups toward hydroboration, thereby providing a mild, chemo-
selective, and facile strategy to form anilines, as well as heteroaryl
and aliphatic amine derivatives, with broad scope and particularly
high turnover numbers (up to 1.8 × 106). Mechanistic studies, based on theoretical calculations, indicate that the CAAC ligand plays
an important role in promoting polarity reversal of hydride of HBpin; it serves as an H-shuttle to facilitate deoxygenative
hydroboration. The preparation of several commercially available pharmaceuticals by means of this strategy highlights its potential
application in medicinal chemistry.
lead to reduction by deoxygenation processes.29 Deoxygenative
1. INTRODUCTION
hydroboration has been described by Sadow (involving
The prevalence of NH2 moieties in pharmaceuticals, agro-
amides)30 and Findlater (involving lanthanide cluster
chemicals, dyes, and bulk chemicals has prompted the
catalysis)31 (see Scheme 1b). Marks and Lohr disclosed a
robust La[N(SiMe3)2]3 catalyst that efficiently deoxygenates
amides, with retention of the unsaturated nitro group.32
We subsequently questioned whether it is possible to switch
the selectivity by preferentially deoxygenating nitro groups
while retaining amides and other functionalities sensitive
toward hydroboration. However, challenges associated with
reversing the polarity of hydride of HBpin for the
deoxygenation remain. The umpolung process is therefore
required for the formation of NH2 moieties. Herein, we report
a cyclic (alkyl)(amino)carbene (CAAC) ligand-promoted nitro
deoxygenative hydroboration reaction, under mild conditions
and with cost-effective chromium catalysis, for the convenient
formation of NH2-containing anilines and amines with 1 mol %
catalyst loading (Scheme 1c).33,34 This reaction favors the
development of selective strategies for their preparation.1,2
Convenient routes to prepare NH2-bearing anilines and amines
have mainly involved the deoxygenation of commercially
available nitro motifs, but these routes usually necessitate the
use of harsh reductants, such as metal alkali, NaBH4, hydrazine,
and pressurized H2.3−5 The use of such reactants carries
significant safety concerns. Furthermore, their use often leads
to the important issue of selectivity, especially when easily
reducible functional groups are present in the same molecules
(particularly halides, alkynes, and olefins). Hence, easy-to-
handle protocols that can be used to deoxygenate nitro motifs
mildly and chemoselectively would be a valuable addition to
the synthetic toolbox toward amines and anilines.6−9
Catalytic hydroboration has emerged as an alternative
method to reduce unsaturated compounds and afford valuable
chemicals,10,11 as witnessed by the significant progress made in
the hydroboration of unsaturated CO bonds in precursors
such as ketones,12−22 aldehydes,20−22 esters,23,24 carboxylic
acids,25 and carbon dioxide.25−28 These reactions commonly
afford oxygen-borylated compounds through nucleophilic
metal hydride intermediates (Scheme 1a). As far as we are
aware, limited success has been achieved in the complete
cleavage of oxygen moieties in these precursors, which could
Received: November 25, 2020
Published: January 7, 2021
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structure revealed that the Cr adopts an octahedral geometry
in ligation with CAAC, the imino, and an additional water
molecule in the solid state.
Scheme 1. Catalytic Addition of Pinacolborane to
Unsaturated Oxygen-Containing Motifs
The reactivity of CAAC−Cr complex 2a in the hydro-
boration of a nitro group was initially determined in the
reaction of 1-bromo-4-nitrobenzene with HBpin (Table 1). It
was pleasing to find that the reaction of 1 mol % of 2a with 10
mol % of Mg as reductant exhibited high reactivity. This
reaction allowed the addition of HBpin across a nitro group by
a deoxygenation process that proceeded efficiently at 60 °C,
leading to reduction and affording the aniline 3a in 96% yield
(entry 1). The deoxygenation tolerates a reducible bromo
substituent, without dehalogenation occurring. The formation
of bisboryloxide (O(Bpin)2) in nearly quantitative yield was
observed. O(Bpin)2 is a valuable precursor for accessing n-type
semiconducting polymers,40 orally active EP3 receptor
antagonists,41 and boryl silyl ethers.42
In the absence of a Cr complex, the deoxygenative
hydroboration with Mg did not afford an aniline, in recovery
of the nitrobenzene. The formation of reactive low-valent Cr
by the reduction of 2a with Mg could be considered for the
deoxygenative hydroboration.43 The replacement of CAAC by
the NHC of 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene)
in complex 2a gave an inferior result (2b) (entry 2). The
CAAC scaffold in the ligand may play an important role in
promoting the reactivity of Cr in the deoxygenation of nitro
groups. Other complexes, such as CAAC−Cr−CAAC (2c),
NHC−Cr−NHC (2d), and bis(imino)Cr (2e), gave relatively
low conversions (entries 3−5). Deoxygenation using CrCl3,
CrCl2, and Cr(acac)3 gave poor results (entries 6−8). First-
row metal salts of FeCl3, CoCl2, NiCl2, and CuBr2, and PdCl2
catalyst, exhibited almost no reactivity in the reaction (entries
9−13). Of note is that the CAAC−Cr 2a exhibited extremely
high efficiency; it gave a turnover number (TON) as high as
1.8 × 106 in the gram-scale deoxygenative reduction of 4-
bromonitrobenzene.
Having in hand the efficient CAAC−Cr complex 2a, the
scope of nitro motifs for the deoxygenative reduction was
explored. We proved that the reaction allows for selectively
reducing nitro scaffolds while keeping the iodo functionality
intact, hence providing access to the substituted aniline 4b in
excellent yield (Scheme 2). The incorporation of a broad range
of polar functional groups, including chloro, fluoro, trifluor-
omethyl, trifluoromethoxy, thiomethyl, pinacol boronate ester,
hydroxyl, and amino, has no great influence on the
deoxygenative hydroboration. Diversely substituted aniline
compounds 4c−m were formed in yields of 70−99%.
Unsaturated alkynes and alkenes are usually sensitive motifs
toward hydroboration; they can undergo nucleophilic attack by
HBpin under metal and Lewis acid catalysis.44 Interestingly,
the alkyne and olefin scaffolds in nitroarenes are compatible
with the reduction system, thereby offering a strategy for the
preparation of alkynylated and alkenylated anilines 4n−q. The
primary and secondary amide groups reduced by magnesium,
lanthanide, and zinc catalysis can be retained under the present
conditions,30−32,45 affording 4-aminobenzamide (4r) and N-
(4-aminophenyl)benzamide (4s). The steric hindrance that
resulted from the ortho-methyl, -methoxy, and -phenyl
substituents did not hamper the deoxygenation (4u−w).
Through this strategy, benzene-1,2-diamines 4x and 4y that
contain two of the same, or different, amino scaffolds were
successfully derived from the commercially available nitroarene
precursors. Difluoro-, dichloro-, bromofluoro-, and amino-
selective hydroboration of nitro motifs over functional groups
of alkynes, alkenes, pyridines, and even amides that are usually
hydroborated, through a ligand-assisted umpolung process,
using CAAC as an H-shuttle.
2. RESULTS AND DISCUSSION
N-Heterocyclic carbenes (NHCs) are electron-rich σ donors
frequently used as ancillary ligands to bind to metals in the
assembly of effective catalysts.35 As compared to typical NHCs,
CAACs show strong nucleophilicity and electrophilicity.36
They have been utilized to assist metals in promoting
hydrofunctionalization, as reported by Bertrand.37 Considering
that electron-rich CAAC ligands are able to enhance the
electron density around a Cr center,37,38 facilitating the
activation of the B−H bond by σ interaction, while
incorporation of an imino anchor to the side chain of CAAC
may stabilize a reactive Cr in catalysis by bidentate
coordination, the imino-containing iminium salt 1a was
selected as precursor for the preparation of an organo-
chromium complex (Figure 1).39 Deprotonation by K[N-
(SiMe3)2] and treatment with CrCl3 in THF afforded the
CAAC−Cr complex 2a. X-ray diffraction analysis of the crystal
Figure 1. Synthesis of CAAC−Cr complex.
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a
Table 1. Studying the Effect of Complexes on the Deoxygenative Hydroboration of 1-Bromo-4-nitrobenzene
a
b
Conditions: 3a (0.5 mmol), metal catalyst (1 mol %), HBpin (2 mmol), Mg (10 mol %) in THF (2 mL), 60 °C, 24 h. Estimated by GC analysis.
chloro-bearing disubstituted anilines were facilely accessible in
a chemoselective fashion (4z−ac). Considering that groups
such as iodide, bromide, alkyne, and alkene are easily
dehalogenated or hydrogenated under catalytic hydrogena-
tion,46 good compatibility of this reaction renders it attractive
in the selective formation of anilines containing these valuable
functionalities. Nitroarenes containing O- and N-heterocyclic
scaffolds, such as oxazolyl, pyrazolyl, piperidinyl, and
morpholinyl, were amenable to the deoxygenative hydro-
boration, affording functionalized aniline compounds 4af−ai in
preparatively useful yields.
Application of the deoxygenative hydroboration in the
synthesis of heteroaromatic amines was then studied.
According to the discoveries of Marks, Kinjo, and others, N-
heteroarenes of pyridines and quinolines react with HBpin by a
1,2- or 1,4-dearomatizative addition to afford N-borylated
heterocycles.47−50 We determined that under CAAC−Cr
catalysis, only the nitro groups were selectively reduced by
deoxygenation, with the N-heteroarene intact (Scheme 3). As a
result, aminated heterocycles of pyridines and quinolines 6a−g,
which serve as core structures frequently found in
pharmaceuticals and agrochemicals, were prepared. Further-
more, using this CAAC−Cr-catalyzed system, the nitro
scaffolds in a wide range of nitrogen, oxygen, and sulfur
heterocycles reacted with HBpin in a smooth manner, thereby
offering a strategy to access indolyl, benzo[b]thiophenyl,
dihydrobenzo[b]thiophenyl, dihydrobenzofuranyl, benzo[d]-
[1,3]dioxolyl, benzo[d]thiazolyl, and quinoxalinyl amine
compounds 6h−r in good to excellent yields (81−99%).
In an effort to assess the possibility of using this protocol for
the preparation of synthetically intriguing aliphatic amine
motifs, nitroalkanes were employed as precursors. The
deoxygenative hydroboration of 1-nitrohexane proceeded
with 1 mol % of complex 2a at 60 °C to afford the
corresponding ammonium derivative 8a in 93% yield, after
workup with acid (Scheme 4). Following this protocol, linear
aliphatic ammonium derivatives containing butyl, pentanyl,
octanyl, 2-methoxyethanyl, and 3-methoxypropanyl were
accessible (8b−f). Interestingly, the incorporation of a
hydroxyl into the scaffold of aliphatic hydrocarbons did not
shut down the nitro reduction. The hydroxyl-tethered motifs
8k and l were obtained in good yields. The nitro substituents
on secondary aliphatic carbons such as isopropane, cyclo-
propane, cyclopentane, and cyclohexane readily underwent
deoxygenation (8m−p).
Further extension of this CAAC−Cr-catalyzed reduction to
the synthesis of bulky tertiary ammonium salts bearing tert-
butyl and 1-adamantyl scaffolds was successful. Substituted aryl
and heteroaryl groups in the motifs of nitroalkanes had no
effect on the deoxygenation (8s−ac). Functional groups of
bromo, chloro, fluoro, methoxy, amino, and pyridyl were
retained after the deoxygenation. Interestingly, two nitro
substituents in aliphatic hydrocarbons could be synchronously
deoxygenated under standard conditions, to afford cyclo-
hexane-1,2-diammonium and octane-1,8-diammonium salts
(8ad and ae).
To gain insight into the mechanistic details associated with
the CAAC−Cr-catalyzed deoxygenative hydroboration, the
kinetic profile was investigated. Here, the reaction of 1-bromo-
4-nitrobenzene 3a with HBpin was selected as the model
system. Examining the kinetic behavior revealed that the
deoxygenative hydroboration proceeds sluggishly to form the
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a
Scheme 2. CAAC−Cr-Catalyzed Chemoselective Deoxygenative Hydroboration of Nitro Arenes
a
Conditions: nitro compound (0.5 mmol), 2a (1 mol %), HBpin (2 mmol), Mg (10 mol %) in THF (2 mL), 60 °C, 24 h. Isolated yields are given.
b
HBpin (5 equiv) was used.
compound 4a in ∼5% yield within the initial 3 h; subsequently,
energies, respectively (Figure S8). These data are in close
accordance with those relating to binding energies for Cr(0),
indicating that the formation of Cr(0) species by the reduction
of 2a with Mg can be considered.43
after a further 7.5 h, the reaction takes place rapidly to afford
4a in 91% yield (see Figure S1). The results indicated that an
induction period may be considered for the formation of
catalytically active Cr species in the reaction.
Using the reactive Cr that was formed in situ by the
reduction of 2a with Mg, the initial reaction rate (Δ[3a]/Δt)
against the initial concentration of 3a (in the range 0.025−
0.125 M) showed a slope of 0.83 from the logarithm plot and
linear fitting of the data, indicating a deviation from the first-
order dependence of the initial rate on the concentration of 1-
bromo-4-nitrobenzene (Figure 3a). Analogously, the initial
reaction rate suggests a positive response to [HBpin], as well as
to the CAAC−Cr at low concentration (Figure 3b and c). The
logarithmic plot and linear fitting of the data showed a
deviation from the first-order dependence of the initial rate on
the concentration of HBpin and CAAC−Cr. This indicated
We then performed kinetic studies. First, we carried out the
reduction of a catalytic amount of 2a with Mg at 60 °C for 3 h,
followed by treatment of the resulting mixture with 3a and
HBpin. The reaction profile suggests, initially, a linear increase
in conversion (Figure 2).
To examine the oxidation state of the Cr species after the
reduction of CAAC−Cr 2a by Mg, analysis of Cr 2p by core-
level X-ray photoelectron spectroscopy (XPS) was performed,
which was fitted with spin−orbital split 2p1/2 and 2p3/2
components. The related spectrum showed two sets of XPS
peaks, with the 2p1/2 component appearing at 583.58 eV and
the 2p3/2 component appearing at 574.51 eV for the binding
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a
Scheme 3. CAAC−Cr-Catalyzed Deoxygenative Hydroboration of Nitro Heteroarenes for the Synthesis of Heteroaryl Amines
a
Reactions were conducted on a 0.5 mmol scale. Isolated yields are given.
that both pinacolborane and CAAC−Cr are likely involved in
the turnover-limiting step of the deoxygenative hydroboration.
The influence of electronic variation of the nitrobenzene
component on the deoxygenative hydroboration was then
examined from Hammett studies. A linear correlation with
Hammett σ constants (ρ = +0.74, R2 = 0.95) was observed,
and this suggests that the deoxygenative hydroboration in
which electron-deficient para-nitrobenzenes are used leads to a
higher initial reaction rate (Figure 3d). The kinetic experi-
ments of the reaction between nitrobenzene (3e) and HBpin
were also carried out at different temperatures. The related
Eyring plot in the temperature range 333−353 K revealed the
following activation parameters: ΔH⧧ = 30.3 1.7 kcal mol−1,
ΔS⧧ = 13.6 4.9, and ΔG⧧(298 K) = 29.3 kcal mol−1 (Figure
4).
To understand further the mechanism of CAAC−Cr-
catalyzed deoxygenative hydroboration, density functional
theory (DFT) modeling of the catalytic cycle was carried out
using nitrobenzene at the SMD-B3LYP-D3(BJ)/def2-TZVP//
B3LYP-D3(BJ)/def2-SVP level of theory (Figure 5). Besides
in 2a, with a quartet ground state, all reaction intermediates
depicted in Figure 5a are in a quintet ground state (Table
S12). CAACs with low-lying LUMO levels at the carbene
center have exhibited superiority in terms of stabilization of
paramagnetic low-valent transition metal species.51 We noted
that the CAAC−Cr complex 2a is incapable of catalyzing the
deoxygenation of nitrobenzene without Mg, and kinetic
observations indicated that the initial reaction rate is slow.
On the basis of these and the results of XPS analysis, the
reaction commences with the formation of reactive low-valent
Cr(0) species that may be considered.43 Indeed, the reduction
of 2a (28.4 kcal mol−1) with Mg afforded IN1 (0.0 kcal mol−1)
in an exergonic manner (Figure 5a). As a nitro compound can
serve as a neutral ligand to bind to metals, the approach of
PhNO2 toward IN1 leads to ligand exchange at Cr to afford
complex IN2 (−56.2 kcal mol−1).
The catalytic cycle comprises four major processes: two
consecutive deoxygenations, and the reduction and recycling of
the catalyst (Figure 5a). Given that PhNO is a suitable
precursor, and that it reacts smoothly with HBpin to afford
aniline 4e(74% yield) at room temperature, by CAAC−Cr
catalysis, it is possible to envision that the intermediacy of a
Cr−PhNO complex is formed upon the first deoxygenation.
DFT calculations revealed that this transformation leading to
IN9 (−114.6 kcal mol−1) involves five basic steps (Figure 5b).
The oxygen lone pair of the nitro group in IN2 is able to bind
to HBpin to afford a Lewis acid/base adduct IN4 (−56.7 kcal
mol−1) with enhanced hydride character in a B−H scaffold.
Following this, σ-bond metathesis by the transition state of
TS2 (−50.2 kcal mol−1),52 involving B−H/Cr−O bond
cleavage, takes place and results in IN5 (−53.4 kcal mol−1).
The Wiberg bond index analysis demonstrated a significant
weakening of the N−O(1) bond in IN5 (0.9) relative to that
in free PhNO2 (1.5), which then allows for a facile N−O(1)
bond scission in TS3 (−48.4 kcal mol−1), to generate a
thermodynamically favorable IN6 (−107.3 kcal mol−1).
Attempts to locate a transition state that corresponds to an
O(1)−H(1) bond formation from IN6 were unsuccessful,
presumably because of the unmatched charge distribution
between the H(1) (−0.18 au) and O(1) (−0.99 au) atoms,
indicated by natural population analysis. Interestingly, a relaxed
potential energy surface scan for consecutively shortening the
distance of O(1) and H(1) atoms from IN6 offered evidence
of the noninnocent ligand behavior of CAAC, in which the
carbene carbon (C(1)) acts as an H-shuttle.53,54 This offered
an indication of a carbene-assisted H migration, which leads to
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a
Scheme 4. Deoxygenative Hydroboration of Nitro Alkanes for the Synthesis of Aliphatic Amine Derivatives
a
b
c
Reactions were conducted on a 0.5 mmol scale. Isolated yields are given. HBpin (5 equiv). HBpin (8 equiv).
polarity reversal of the hydride. Indeed, H(1) can undergo a
facile migration to C(1) via TS4 (−101.1 kcal mol−1), and this
process thus gives rise to an umpolung of the H(1) atom. The
H(1) atom appears to be positively charged in IN7 (0.20 au).
Subsequently, the H(1) shift from C(1) to O(1) is achieved in
TS5 (−82.9 kcal mol−1) with an activation barrier of 31.9 kcal
mol−1, followed by elimination of HOBpin to afford the
nitrosobenzene-ligated IN9 (−114.6 kcal mol−1). It is
noteworthy that direct hydroboration of the NO2 motif of
IN4 to give IN5′ was found to be extremely endergonic, by
64.0 kcal mol−1, which rules out a Lewis acid-induced
hydroboration mechanism (Figure S13).
It has been demonstrated that the non-negligible π-acceptor
abilities of singlet carbenes as ligands can influence the
outcome of transition-metal catalysis, primarily because of the
metal−ligand π-back-donation that tunes the electronic
properties of metals.37 However, on the basis of the H-shuttle
behavior observed for CAAC, such carbene ligands may not
only be spectator Lewis bases, but also involved in key steps in
the Cr-catalyzed deoxygenative hydroboration.51,53,54 Inspec-
Figure 2. Reaction profile for deoxygenative hydroboration of 3a by
using reactive CAAC−Cr that was formed in situ.
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Figure 3. Kinetic studies and a Hammett plot. (a) Plot of the initial rate versus the initial concentration of 3a. (b) Plot of the initial rate versus the
concentration of HBpin. (c) Plot of the initial rate versus the concentration of CAAC−Cr. (d) Hammett plot of para-substituted nitrobenzenes.
tion of the intrinsic bond orbitals (IBOs),55 which has been
shown to give an exact representation of any Kohn−Sham
DFT wave function, reveals that a d-type unpaired electron at
Cr highly delocalizes into the formal vacant p-orbital of C(1)
in IN6 (Figure 5b). This is indicative of the partial radical
character of C(1),38 which may facilitate the H-transfer to IN7.
In a similar fashion, the second deoxygenation reaction
facilely afforded a Cr−nitrene complex IN16 (−168.0 kcal
mol−1) and HOBpin, with the highest activation barrier of 15.5
kcal mol−1 (Figure S10). With the aid of HBpin and HOBpin,
the following reduction of IN16 was also found to not be
energy demanding (highest activation barrier 11.6 kcal mol−1),
affording IN25 (−196.1 kcal mol−1) and O(Bpin)2 (Figure
S11). This was followed by removal of an aniline product from
IN25 in a stepwise manner (highest activation barrier of 25.4
kcal mol−1), to complete the catalytic cycle, with regeneration
of the nitro-ligated complex IN2 (Figure 5a). Of note is that
the calculated overall energy barrier of 31.9 kcal mol−1 for the
turnover-limiting step of the deoxygenative hydroboration is
almost in accordance with the experimental result of the Eyring
equation (ΔG⧧(298 K) = 29.3 kcal mol−1).
insecticide of 10 (Scheme 5). Because the hydroxyl group is
tolerated by the reaction system, one of the most common
pharmaceuticals, paracetamol, which contains a hydroxyl
scaffold, was readily accessed (13). The treatment of 4-
nitrobenzoic acid with HBpin led to the amino-substituted
compound 15, which is one of the key components of folic
acid, utilized in the preparation of the anesthetic benzocaine
(16). The reactions in which (2-nitroethyl)benzene and (3-
nitropropyl)benzene were used gave medicinally interesting
compounds (related to hormones, for emotional health and as
stimulants) (18 and 20). Late-stage functionalization of the
resulting amino scaffold, by acylation, resulted in the successful
preparation of the drug phenacetin (23). Antitubercular agent
25, which contains three intriguing functionalities (carboxyl,
hydroxyl, and amino), is accessible via the deoxygenative
hydroboration of commercially available 2-hydroxy-4-nitro-
benzoic acid.
3. CONCLUSIONS
We developed a CAAC ligand-promoted, pinacolborane-based
deoxygenative hydroboration of nitro motifs, with cost-
effective chromium catalysis, for application to a diverse
range of arenes, heteroarenes, and alkanes. Chemoselectivity in
nitro deoxygenative hydroboration over alkynes/olefins,
halides, amides, and even N-heterocycles of pyridines,
The application of the deoxygenative hydroboration in the
preparation of value-added pharmaceuticals was studied. The
reaction of nitrobenzene containing pentachloro substituents
enabled the selective formation of an aniline-mediated
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Figure 4. Eyring plot of the deoxygenative hydroboration of nitrobenzene with HBpin.
Figure 5. DFT studies carried out to determine the plausible reaction pathway involved in the deoxygenative hydroboration by CAAC−Cr
catalysis. (a) Reaction pathway for CAAC−Cr-catalyzed deoxygenation of nitrobenzene identified by DFT calculations. (b) DFT-computed Gibbs
free energy profile for the first deoxygenation of nitrobenzene.
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Scheme 5. Application in the Preparation of Pharmaceuticals
under vacuum. The crude product was purified by recrystallization
from dichloromethane and hexane, to afford 2a as a pale green
powder (210 mg, 61% yield). A single crystal of 2a, suitable for X-ray
crystallography, was obtained by recrystallization from a mixed
solution of toluene/hexane (1/3).
General Procedure for the CAAC−Cr-Catalyzed Deoxyge-
native Hydroboration of Nitroarenes. THF (2 mL) was added to
a dry Schlenk tube containing complex 2a (3.5 mg, 0.005 mmol),
nitroarene (0.5 mmol), HBpin (0.29 mL, 2 mmol), and Mg (1 mg,
0.05 mmol), under a nitrogen atmosphere. The reaction mixture was
stirred at 60 °C for 24 h. After the volatiles were removed under a
vacuum, the crude product was purified by silica gel chromatography
to afford the corresponding aniline product.
quinolines, and indoles, was achieved with particularly high
TONs, up to 1.8 × 106. Mechanistic studies indicated that the
CAAC ligand serving as a shuttle can be considered to be
responsible for the H migration in pinacolborane, by two
consecutive deoxygenation and reduction processes, to afford
NH2 moieties. When using a mild reducing reagent such as
HBpin, combined with a highly efficient precatalyst of CAAC−
Cr, a safer chemoselective and mild strategy for the
deoxygenation of nitro groups is disclosed, highlighting the
application of CAACs as ligands and earth-abundant Cr
catalysis for molecular construction. Further studies on the
isolation of reactive CAAC−Cr intermediates are underway.
ASSOCIATED CONTENT
■
4. EXPERIMENTAL SECTION
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c12318.
Procedure for the Preparation of CAAC−Cr Complex 2a. A
dry Schlenk tube was charged with cyclic iminium salt 1a (301 mg,
0.5 mmol) and freshly distilled THF (20 mL), through a syringe,
under a nitrogen atmosphere, and cooled to −78 °C. K[N(SiMe3)2]
(0.5 mmol, 1 M in THF) was added, and the mixture was warmed to
room temperature, with stirring, for 0.5 h. The solution was then
transferred to a dry Schlenk tube containing CrCl3 (79 mg, 0.5 mmol)
at −78 °C under atmosphere of nitrogen. The reaction was stirred
overnight at room temperature, followed by removal of the solvent
Detailed optimization data; experimental procedures;
characterization data of all products, detailed optimized
geometries, and computational details and results; and
ORTEP drawing of (CAAC)Cr complex 2a and
crystallographic data (PDF)
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Article
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X-ray crystallographic information for complex 2a (CIF)
AUTHOR INFORMATION
Corresponding Author
Xiaoming Zeng − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China; orcid.org/
0000-0003-0509-1848; Email: zengxiaoming@scu.edu.cn
■
(7) (a) Goksu, H.; Sert, H.; Kilbas, B.; Sen, F. Recent advances in
the reduction of nitro compounds by heterogeneous catalysts. Curr.
Org. Chem. 2017, 21, 794−820. (b) Blaser, H.-U.; Steiner, H.; Studer,
M. Selective catalytic hydrogenation of functionalized nitroarenes: an
update. ChemCatChem 2009, 1, 210−221.
Authors
Lixing Zhao − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China
Chenyang Hu − Shenzhen Grubbs Institute and Department
of Chemistry, Southern University of Science and Technology,
Shenzhen 518055, China
Xuefeng Cong − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China
Gongda Deng − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China
Liu Leo Liu − Shenzhen Grubbs Institute and Department of
Chemistry, Southern University of Science and Technology,
Shenzhen 518055, China; orcid.org/0000-0003-4934-
0367
̈
(8) Selected examples of homogeneous catalysis: (a) Wienhofer, G.;
Sorribes, I.; Boddien, A.; Westerhaus, F.; Junge, K.; Junge, H.; Llusar,
R.; Beller, M. General and Selective Iron-Catalyzed Transfer
Hydrogenation of Nitroarenes without Base. J. Am. Chem. Soc.
2011, 133, 12875−12879. (b) Junge, K.; Wendt, B.; Shaikh, N.;
Beller, M. Iron-Catalyzed Selective Reduction of Nitroarenes to
Anilines Using Organosilanes. Chem. Commun. 2010, 46, 1769−1771.
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M.; Jagadeesh, R. V. General and selective synthesis of primary amines
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J.; Nakao, T.; Yang, H.; Tada, T.; Kitano, M.; Hosono, H. Copper-
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Meiming Luo − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China; orcid.org/
0000-0003-1766-9010
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c12318
Author Contributions
§L.Z. and C.H. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(nos. 21572175, 21871186, and 21971168) and the
Fundamental Research Funds for the Central Universities
(20826041D4117) for financial support of this research. The
theoretical work is supported by the Center for Computational
Science and Engineering at SUSTech. L.L.L. gratefully
acknowledges the SUSTech start-up fund (Y01216248).
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Recent advances in the catalytic hydroboration of carbonyl
compounds. Catal. Sci. Technol. 2019, 119, 2550−2610.
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J. Am. Chem. Soc. 2021, 143, 1618−1629