Enhanced Hydride Donation Achieved Molybdenum Catalyzed Direct N-Alkylation of Anilines or Nitroarenes with Alcohols: From Computational Design to Experiment

Article abstract of DOI:10.1021/acscatal.1c02956

An example of homogeneous Mo-catalyzed direct N-alkylation of anilines or nitroarenes with alcohols is presented. The DFT aimed design suggested the easily accessible bis-NHC-Mo(0) complex features a strong hydride-donating ability, achieving effective N-alkylation of anilines or challenging nitroarenes with alcohols. The enhanced hydride-donating strategy should be useful in designing highly active systems for borrowing hydrogen transformations.

Full text of DOI:10.1021/acscatal.1c02956

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Letter
Enhanced Hydride Donation Achieved Molybdenum Catalyzed
Direct N‑Alkylation of Anilines or Nitroarenes with Alcohols: From
Computational Design to Experiment
Weikang Li, Ming Huang, Jiahao Liu, Yong-Liang Huang, Xiao-Bing Lan, Zongren Ye, Cunyuan Zhao,
Yan Liu, and Zhuofeng Ke*
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ABSTRACT: An example of homogeneous Mo-catalyzed direct
N-alkylation of anilines or nitroarenes with alcohols is presented.
The DFT aimed design suggested the easily accessible bis-NHC-
Mo(0) complex features a strong hydride-donating ability,
achieving effective N-alkylation of anilines or challenging nitro-
arenes with alcohols. The enhanced hydride-donating strategy
should be useful in designing highly active systems for borrowing
hydrogen transformations.
KEYWORDS: alcohol, borrowing hydrogen, molybdenum, alkylation, nitro compound
he N-alkylation of amines is an important application in
to the higher M−H orbital energy of bis-NHC-Mn(I)-hydride
than those of traditional PNP-Mn(I) catalysts. Inspired by this,
we envision that a low-valent d6 metal center with a strong
electron-donating ligand could be a proper catalyst with
enhanced hydride-donating ability.
1
Tpharmaceutical chemistry and fine chemicals.
The
borrowing hydrogen or hydrogen autotransfer (BH/HA)
methodology (Scheme 1a)2 using alcohols as alkylation reagents
is a green and sustainable method to replace the traditional
synthetic way, in which the hazardous alkyl halides are used as
reactants while undesirable side products or wastes are
unavoidable. Various catalytic systems for N-alkylation have
been developed using this BH/HA methodology, including
widely investigated noble-metal-based homogeneous catalysts,
like Ir,3 Ru,4 Pd,5 etc.,6 and recently emerging nonprecious metal
homogeneous systems such as Fe,7 Co,8 Mn,7g,9 Ni,10 Cr,11 and
W.12
To further prove our hypothesis, a density functional theory
(DFT) study was conducted to predict the M−H bonding
orbital energy for various d6 transition metals with easily
accessible bis-pyridine, NHC-pyridine, and bis-NHC ligands.
These NHC-M complexes bearing strong field ligands, though
with metal centers in different oxidation states, would operate
similar hydrogenation/dehydrogenation mechanisms.20a Inspir-
ingly, the bis-NHC-Mo(0)-hydride Mo−C1 is predicted to have
the highest M−H orbital energy, implying the strongest hydride-
donating ability (Figure 1a). The relationship between M−H
orbital energy and hydricity was built with an R2 up to 0.99
(section 8.2 in the SI). Encouragingly, Beller and Madsen have
successfully applied molybdenum to the hydrogenation of
amides as well as the dehydrogenative synthesis of imines from
alcohols and anilines.21 Also, some heterogeneous molybdenum
catalytic systems for the BH/HA process have been reported
previously.22 The homogeneous Mo-catalyzed BH/HA N-
alkylation of amines or nitroarenes with alcohols is yet to be
In contrast, directly using nitroarenes to replace anilines as
starting material for the N-alkylation reaction with alcohols is
more attractive due to improved step economy and functional
group compatibility.13 However, the nitroarenes should be able
to be catalytically hydrogenated into anilines to guarantee a
successful N-alkylation.14 Thus, the direct N-alkylation of
nitroarenes with alcohols is still a big challenge, and the
reported homogeneous catalysts for it are rare yet. Among them,
the noble metal complexes (Ru,13a,15 Pd,16 and Ir17) were
generally required. In 2019, Morrill reported the nonprecious
metal Mn catalyzed one-pot conversion of nitroarenes into N-
methylarylamines with synthesis grade methanol (Scheme
1b).18 The key point in realizing this transformation should
rely on the reduction of nitroarenes by a highly active catalyst via
metal-hydride species with an enhanced hydride-donating
ability. We recently found that bis-NHC-Mn(I) could catalyze
N-alkylation of amines with alcohols at room temperature,19 due
Received: July 2, 2021
Revised: August 3, 2021
https://doi.org/10.1021/acscatal.1c02956
© XXXX American Chemical Society
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Letter
Scheme 1. Molybdenum Catalyzed N-Alkylation of Anilines
or Nitroarenes with Alcohols
realized. As part of our ongoing interest in BA/HA,12,19,23
herein, we reported the first example of a non-noble Mo catalytic
system for this transformation (Scheme 1c).
Figure 1. (a) The M−H bonding orbital energies (eV) for the predicted
metal-hydride species (n = −1, M = Cr(0), Mo(0), W(0); n = 0, Mn(I),
Re(I); n = 1, M = Fe(II), Ru(II); n = 2, M = Co(III)). (b) N-alkylation
of aniline with benzyl alcohol with different Mo(0) complex-
es.a,b aReaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), [Mo] (1
mol %), KOtBu (1 equiv), n-hexane (1 mL), seal tube, 130 °C oil bath,
24 h. bGC yields. c2a (0.5 mmol), 1a (0.65 mmol), Mo-1 (2 mol %),
KOtBu (1.1 equiv), n-hexane (0.5 mL), 130 °C oil bath, 24 h, reaction
tube capped with a rubber septum. Molecular structure of Mo-1,
selected bond lengths [Å] and angles [deg]: Mo1−C1 2.028(3), Mo1−
C2 1.994(3), Mo1−C3 1.984(3), Mo1−C4 2.034(3), Mo1−C5
2.260(3), Mo1−C6 2.246(3); C1−Mo1−C4 170.25(13), C2−Mo1−
C6 175.15(11), C3−Mo1−C5 170.71(11). (Thermal ellipsoids are
shown at 50% probability, and C−H atoms are omitted for clarity.)
Based on the computational design results, using the
commercially available Mo(CO)6 and easily accessible bis-
NHCs or NHC-pyridines as sources, five Mo(0) complexes Mo-
1−5 were synthesized with satisfying yields of 46−65% (Figure
1b, synthesis and characterization details in the SI). Their
structures were further characterized by X-ray diffraction (XRD)
analysis of single crystals except for Mo-3. The molecular
structure of Mo-1 shows similar Mo−CNHC bond distances to
the reported bis-BenzNHC-Mo(0).24 After that, these com-
plexes were investigated for the N-alkylation of aniline with
benzyl alcohol as the model reaction in 130 °C. The designed
bis-NHC-Mo(0) complex Mo-1 was found more active than
pyridyl−NHC-Mo(0) (Mo-4) or picolyl−NHC-Mo(0) (Mo-
5), which emphasizes the important donation effect of the NHC
ligand, after considering both the σ donation and the π back-
donation20b via Charge Decomposition Analysis (section 8.3 in
the SI). Note that, the larger substituent −iPr (Mo-2) or −nBu
(Mo-3) on the NHC ligand did not improve the yield.19
Therefore, Mo-1 was chosen as the precatalyst for the N-
alkylation of anilines with alcohols, and the optimal reaction
conditions were established when 2 mol % Mo-1, 1.3 equiv of
alcohols, 1.1 equiv of KOtBu, and 0.5 mL of n-hexane solvent
were used. For details of the conditions’ screenings, see Tables
S1−S9.
(3t), n-hexanol (3u), and n-octanol (3v) were verified to be
reactive, with moderate yields (45−55%). However, when
alcohols with shortened carbon chains (methanol, ethanol) were
tested, no obvious products were detected. Note that, when
halide-substituted benzyl alcohols were investigated, various
amounts of side-product 3a were detected. This dehalogenation
probably happened because of the strongly basic environment
and high temperature, similar to previously observed phenom-
ena.25 The fluoro benzyl alcohol was almost all transferred to 3a.
Chloro benzyl alcohols 1e furnished 37% chloro-product (3e)
and 44% 3a. para- and meta-Chlorobenzyl alcohols resulted in
74% and 75% chloro-product (3f−g), as well as 10% 3a. meta-
and para-Bromobenzyl alcohols produced 51−64% bromo-
product (3h−i), along with 11−24% 3a. Surprisingly, 70% meta-
trifluoromethyl product (3j) was exclusively obtained with the
−CF3 electron-withdrawing group.
The scopes of alcohols were first explored (Figure 2). The
electron-donating groups −Me (3b−d), −OMe (3k), and
−SMe (3l) led to good yields of 76−92%, and the substrates
with conjugated aromatic or bulky substituted groups like
naphthalene (3m and 3n), diphenyl (3q), and benzyloxy (3r)
reacted smoothly with yields of 85−89%. Heteroaromatic
alcohols like pyridine derivative 3o and thiophene derivative
3p slightly decreased in yields (61−63%). Besides, several
aliphatic alcohols like cyclohexanol methanol (3s), n-butanol
Compared with primary alcohols, the N-alkylations of anilines
with secondary alcohols were reported much less, mainly due to
the steric hindrance.26 Gratifyingly, Mo-1 was found capable of
realizing the N-alkylation of anilines with secondary alcohols.
Diphenylmethanol and its methyl and methoxy derivatives were
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effective for the N-alkylation reaction catalyzed by Mo-1 (Figure
3). In this transformation, three more hydrogen molecules
Figure 3. N-Alkylation of nitroarenes with alcohols.a,b aGeneral reaction
conditions: 5 (0.5 mmol), 1 (3 mmol), Mo-1 (5 mol %), KOtBu (5
equiv), and n-hexane (1 mL), 150 °C oil bath, 24 h, seal tube. bIsolated
yield. cGC yields.
would be consumed (Scheme 1b), and excessive alcohols are
needed. When more alcohols, KOtBu, and Mo-1 were utilized,
nitrobenzene 5a and benzyl alcohol 1a successfully yielded the
N-alkylation product 6a in 89% yield at 150 °C (Table S10).
Benzyl alcohol and its derivatives like −Me, −OMe, and −iPr
reacted with nitrobenzene 5a affording good yields of 79−90%
(6a−d). Also, 5a could couple with 1-naphthalene methanol to
81% N-alkylation product 6e. However, substrates with bulkier
substituents like −Bn and −tBu did not perform so well with
42−48% yields (6f−g). Comfortingly, challenging secondary
alcohol diphenylmethanol and its methoxy derivative could
afford products 6h−i at 70−73% yields. On the other hand, −Cl,
−Me, and −OMe substituted nitroarenes could smoothly react
with 4-methybenzyl alcohol 1b affording N-alkylation products
6j−n at 45−90% yields. These results indicated the potential of
this bis-NHC-Mo(0) catalyst as a highly active catalytic system
for BH/HA processes.
Experimental and theoretical studies were further performed
to gain mechanistic insight into this catalytic system. The Hg
poisoning experiment suggested that the catalysis probably
proceeds homogeneously (Figure 4a). The control experiment
of N-benzylideneaniline 3a′ with benzyl alcohol could yield 88%
of product 3a, which supported the BH/HA mechanism (Figure
4b). Deuterium-labeling experiments could produce 22% of 3a-
d2 (Figure 4c), indicating an H/D exchange in the
mechanism.10c More importantly, a kinetic isotope effect (KIE
= 2.2) was measured by the parallel reactions, indicating the
alcohol dehydrogenation is most likely involved in the rate-
determining step (RDS) (Figures 4d and S19). According to the
outcomes of the substrates, the electron-donating substituted
substrates (like 3d) have a better performance than the electron-
withdrawing substituted substrates (like 3g). Consequently, the
electron-donating substituted substrates would be more
favorable for the alcohol dehydrogenation step, which can be
further supported by our mechanism studies (see discussion
below).
Figure 2. Scopes of alcohols and anilines.a,b aGeneral reaction
conditions: 2 (0.5 mmol), 1 (0.65 mmol), Mo-1 (2 mol %), KOtBu
(1.1 equiv), n-hexane (0.5 mL), 130 °C oil bath, 24 h, reaction tube
capped with a rubber septum. bIsolated yield. n.d = not detected. cGC
yields. d1b (1.3 mmol), Mo-1 (5 mol %), KOtBu (2.2 equiv), n-hexane
(1 mL), 150 °C oil bath, seal tube.
successfully reacted with anilines, achieving good yields of 82−
90% (3w−z).
Next, scopes of anilines were investigated by reacting with 4-
methylbenzyl alcohol 1b as a model reactant (Figure 2).
Pleasingly, chloro- and bromoanilines smoothly yielded halide-
substituted secondary aniline products (4b−e: 55−80%),
although the fluoroaniline was found to conduct dehalogenation
totally. Substrates bearing electron-donating groups like methyl
(4f−h), methoxy (4i), thiomethyl (4j), and tert-butyl (4k)
afforded the mono-N-alkylated anilines in good yields (60−
90%). The ortho-phenylaniline (4l) however led to a lower yield
of 50% due to adjacent steric hindrance. The conjugated
aromatic naphthylanilines (4m−n) resulted in satisfying yields
of 68−75%. Besides, pyridine derivatives could have a good yield
of product (4r: 68%). Interestingly, when vinylaniline was used,
81% double-bond-reduced product 4p instead of a vinyl product
was detected under slightly harsher conditions.
Encouraged by the total reduction of vinylaniline, the more
challenging nitroarene substrates were investigated and proved
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involvement of crucial intermediate Mo(0)−H A3 species was
provided by the hydrogen detection experiment (Figure 4e and
Table S11). A reaction tube capped with a rubber septum would
thus enhance the borrowing hydrogen due to the Mo(0)−H and
Mo(0)···H2 equilibrium. At last, the in situ generated imine
would be hydrogenated by A3 through transition state TS2
(15.9 kcal/mol). The RDS of the catalytic cycle was calculated
to be the dehydrogenation step (ΔG⧧ = 17.8 kcal/mol), which is
in good agreement with the KIE study. Further computational
method comparisons suggest that optimization in the solvent led
to similar results due to the insignificant effect of the nonpolar
solvent, as shown in section 8.1 in the SI.
To better understand the enhanced hydride-donating ability
of this bis-NHC-Mo(0) system, DFT calculations were further
performed to study the hydrogenation of nitrobenzene in
comparison with Mn(I) and Fe(II) systems (Figure 4f). As
anticipated, the activation free energy of Mo−C1 (14.7 kcal/
mol) is much lower than those of Mn−C1 (20.8 kcal/mol) and
Fe−C1 (22.7 kcal/mol), which is well reflected by the highest
M−H orbital energy (−0.75 eV) for bis-NHC-Mo(0).
In summary, a new type of bis-NHC-Mo(0) complex with an
enhanced hydride-donating ability was rationally designed by
both computational and experimental studies. The easily
accessible bis-NHC-Mo(0) complex was successfully applied
in the N-alkylation of anilines and challenging nitroarenes with
alcohols through BH/HA transformation. This N-alkylation
system has good substrate tolerance, including heteroatom-
containing substrates and challenging secondary alcohols. In
total, 44 secondary anilines were synthesized and isolated in
yields up to 92%. More importantly, the direct N-alkylation of
nitroarenes with alcohols was achieved by this molybdenum-
mediated system. The total reduction of the vinyl substrate and
nitroarenes could be ascribed to the enhanced hydride-donating
ability of the Mo−H species. This Mo system presents a new
example of a highly active catalyst for BH/HA transformations.
ASSOCIATED CONTENT
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Experimental and computational details (PDF)
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Figure 4. Experimental and theoretical mechanism study.
AUTHOR INFORMATION
Corresponding Author
■
A possible outer-sphere mechanism for this catalyst system
was proposed,12,19,23a which includes precatalyst activation,
alcohol dehydrogenation, imine in situ formation, and imine
hydrogenation. First, one CO ligand would disassociate to form
the active species Mo-1a with a vacant site. DFT studies (Figures
4e and S24−S26) suggest that this activation process requires
overcoming an energy barrier of 39.7 kcal/mol, which might be
the reason the catalysis operated at a relatively high temperature.
Second, deprotonated alcohol would be dehydrogenated to
aldehyde generating Mo(0)-hydride intermediate A3 through
transition state TS1 (17.7 kcal/mol). As anticipated, inter-
mediate A3 is highly active and high in free energy (11.8 kcal/
mol). Exhaustive tries to trap the Mo(0)-hydride species were
unsuccessful probably due to its thermodynamical instability
kinetically high reactivity, though the Mo(0)−H species has
been reported previously.27 Luckily, indirect evidence for the
Zhuofeng Ke − School of Materials Science & Engineering,
School of Chemistry, PCFM Lab, Sun Yat-sen University,
Guangzhou 510275, P. R. China; orcid.org/0000-0001-
9064-8051; Email: kezhf3@mail.sysu.edu.cn
Authors
Weikang Li − School of Materials Science & Engineering, School
of Chemistry, PCFM Lab, Sun Yat-sen University, Guangzhou
510275, P. R. China
Ming Huang − Department School of Clinical Pharmacy,
Guangdong Pharmaceutical University, Guangzhou 510006,
P. R. China; orcid.org/0000-0001-8597-8259
Jiahao Liu − School of Materials Science & Engineering, School
of Chemistry, PCFM Lab, Sun Yat-sen University, Guangzhou
510275, P. R. China
10380
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Letter
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R. China; orcid.org/0000-0003-1569-014X
Xiao-Bing Lan − School of Materials Science & Engineering,
School of Chemistry, PCFM Lab, Sun Yat-sen University,
Guangzhou 510275, P. R. China; orcid.org/0000-0001-
5301-069X
Zongren Ye − School of Materials Science & Engineering, School
of Chemistry, PCFM Lab, Sun Yat-sen University, Guangzhou
510275, P. R. China
Cunyuan Zhao − School of Materials Science & Engineering,
School of Chemistry, PCFM Lab, Sun Yat-sen University,
Guangzhou 510275, P. R. China; orcid.org/0000-0002-
3600-7226
Yan Liu − School of Chemical Engineering and Light Industry,
Guangdong University of Technology, Guangzhou 510006, P.
R. China; orcid.org/0000-0002-3864-1992
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NSFC (21973113, 21977019, and 21773312) and
the Fundamental Research Funds for the Central Universities.
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