Highly Selective N-Monomethylanilines Synthesis from Nitroarene and Formaldehyde via Kinetically Excluding of the Thermodynamically Favorable N,N-Dimethylation Reaction

Article abstract of DOI:10.1021/acscatal.8b00116

The synthesis of N-monomethylamine remains a challenging topic because the N,N-dimethylation reaction is thermodynamically favorable. In this work, the kinetically controlled N-monomethylamine synthesis from nitroarene and paraformaldehyde/H₂ is reported to have superhigh N-monomethylamine selectivity in the presence of a Pd/TiO₂ catalyst. The superior selectivity should be attributed to the preferential adsorption of the primary amine over N-monomethylamine on the Pd/TiO₂ surface, as elucidated by NH₃/Me₂NH-TPD, while the excellent catalytic activity could be associated with the good H₂ activation ability and high amine adsorbing capacity of the catalyst, as elucidated by NH₃-TPD and H₂-TPR tests. Good results were obtained with a variety of nitroarenes containing methyl, methoxyl, hydroxyl, fluoride, trifluoromethyl, ester, and amide substituents as starting materials, and the potential synthetic utility of this protocol in pharmaceutical is illustrated by N-monomethylation of drug molecules, such as clinidipine, nimesulide, procaine, and methyl aminosalicylate.

Full text of DOI:10.1021/acscatal.8b00116

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Highly Selective N-Monomethylanilines Synthesis From
Nitroarene and Formaldehyde via Kinetically Excluding of the
Thermodynamically Favorable N,N-Dimethylation Reaction
Hongli Wang, Hangkong Yuan, Benqun Yang, Xingchao Dai, Shan Xu, and Feng Shi
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00116 • Publication Date (Web): 30 Mar 2018
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Highly Selective NꢀMonomethylanilines Synthesis
From Nitroarene and Formaldehyde via Kinetically
Excluding of the Thermodynamically Favorable
N,NꢀDimethylation Reaction
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Hongli Wang,† Hangkong Yuan,† Benqun Yang,† Xingchao Dai,†,‡ Shan Xu,† and Feng Shi*,†
†State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical
Physics (LICP), Chinese Academy of Sciences, Lanzhou730000, China
‡University of Chinese Academy of Sciences, No. 19A, Yuquanlu, Beijing 100049, P.R. China
ABSTRACT: It maintains as a challenging topic for Nꢀmonomethylamine synthesis as the N,Nꢀ
dimethylation reaction is thermodynamically favorable. The kinetically controlled Nꢀ
monomethylamine synthesis from nitroarene and paraformaldehyde/H2 is reported with superꢀ
high Nꢀmonomethylamine selectivity in the presence of a Pd/TiO2 catalyst. The superior
selectivity should be attributed to the preferential adsorption of the primary amine over Nꢀ
monomethylamine on the Pd/TiO2 surface, as elucidated by NH3/Me2NHꢀTPD, while the nice
catalytic activity could be associated to the good H2 activation ability and high amine adsorbing
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capacity of the catalyst, as elucidated by NH3ꢀTPD and H2ꢀTPR tests. Good results were
obtained with a variety of nitroarenes containing methyl, methoxyl, hydroxyl, fluoride,
trifluoromethyl, ester, and amide substituents as starting materials, and the potential synthetic
utility of this protocol in pharmaceutical is illustrated by Nꢀmonomethylation of drug molecules,
such as clinidipine, nimesulide, procaine and methyl aminosalicylate.
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KEYWORDS: nitroarenes, Nꢀmonomethylation, selective adsorption, paraformaldehyde,
carbonyl group transformation
INTRODUCTION
The majority of the known agrochemicals and pharmaceuticals contain amino groups, which
represent key scaffolds in the vast majority of bioꢀactive compounds. In fact, of the top 200
drugs of 2015, about 85% involves nitrogen (N) and/or amino groups.1 Among the known
reactions of amines, the Nꢀmethylation of amines is of significant importance to regulate the
physicochemical properties of organic molecules including their biological and pharmaceutical
activities.2 Besides these biological functions, Nꢀmethylamines are important building blocks in
synthesis of bulk and fine chemicals as well as materials.3 Nevertheless, the highly selective
synthesis of Nꢀmonomethyl amines remains a tremendous challenge in synthetic organic and
catalysis because Nꢀmonomethyl amines possess higher reactivity than primary amines and are
prone to further transform into N,Nꢀdimethyl amines. Traditionally, primary amines are usually
employed as starting materials for the selective synthesis of Nꢀmonomethylamines with a variety
of methylating agents, such as MeX, CO2, methanol, dimethyl carbonate (DMC), HCOOH, and
HCHO.4 Although a number of nice methods have been developed, the known methodologies
still suffer from rigorous reaction conditions, low selectivity or low atom economy.
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As it is wellꢀknown, nitro compounds are cheap and readily available, and the reduction of
nitroarenes is one of the most commonly used approaches to synthesize primary amines.5 Thus, it
is an attractive to perform the oneꢀpot Nꢀmonomethylation reactions using nitro compounds as
the flexible feedstock. To date, however, only a few catalytic systems dealing with Nꢀ
monomethylation of nitro compounds have been reported. By using CO2 and H2 as methylating
agent, the Nꢀmonomethylation of nitroarenes can be realized with Pd/CuZrOx as catalyst.
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Nevertheless, it suffers from high pressure (3.5 MPa) and high temperature (150 C).6 Besides
CO2, methanol could also be used as a methylating reagent. One example of Nꢀmonomethylation
of 4ꢀnitrotoluene with methanol using [Ru(pꢀcymene)Cl2]2, DPPB, and K2CO3 catalyst system
was revealed.7 Recently, the tandem reductive Nꢀmonomethylation of nitroarenes with methanol
was reported in the presence of Ru(II) complexes, bearing phenpyꢀOMe ligand and NaOMe.8
However, the rigorous reaction conditions and the necessity using of complex organic
ligands/base reduced the appeal of these protocols. Compared with above methods, oneꢀpot
reductive Nꢀmonomethylation of nitroarene with formaldehyde represents one of the economic
and clean pathways. However, normally, only Nꢀmonoalkylation of nitro compounds with higher
aldehydes9 were reported, and poor results were obtained if HCHO was used as the methyl
source.10 Till now, no general methodology of highly selective N-monomethylation of nitroarene
with HCHO has been developed, which is mainly limited by the further N-methylation of the
desired molecule to N,N-dimethylamine. The key point to realize the selective Nꢀ
monomethylamine synthesis is to find the way to overcome the thermodynamically favorable
N,Nꢀdimethylation. Undoubtedly, kinetic regulation seems to be the sole method.
In order to kinetically regulate the reaction, the reaction steps should be first clarified. In
general, the reductive Nꢀmethylation of nitroarenes with paraformaldehyde/H2 proceeds through
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three main consecutive reactions, i.e., hydrogenation of nitroarene to generate primary amine, Nꢀ
monomethylation of primary amine and further Nꢀmethylation of the Nꢀmonomethylamine to
N,Nꢀdimethylamine (Figure 1a). Out of doubt, the adsorption of reactant molecule onto the
surface of catalyst is the initial step of the reaction with heterogeneous catalyst, and the hydrogen
bond plays an important role in this process. Noteworthy, primary amine possesses more
hydrogen atoms than Nꢀmonomethylamine, which may result in preferential adsorption and
difficult desorption of primary amine while nondominant adsorption and easy desorption of Nꢀ
monomethylamine on the catalyst surface.11 This inspired us that an active and selective catalyst
might be designed and prepared for the highly selective Nꢀmonomethylamine synthesis via
kenetic inhibition of N,Nꢀdimethylation via nondominant adsorption and easy desorption of Nꢀ
monomethylamine on the catalyst surface (Figure 1a). Typically, metal oxides and carbon
possess abundance of oxygen species on their surfaces, which are benefiting to form hydrogen
bond, and supported nanoꢀPd is potentially an active catalyst for nitroarene reduction and the
following Nꢀmethylation reaction. So we envisioned that nanoꢀPd loaded on appropriate support
might provide a suitable catalyst for reductive Nꢀmonomethylation of nitroarene with HCHO/H2.
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Based on the above discussions, herein, a series of supported nanoꢀPd catalysts were prepared,
in which Pd/TiO2 exhibited excellent activity and superior selectivity in Nꢀmonomethylation of
nitroarenes with paraformaldehyde/H2 enabled by the selective adsorption of primary amine
intermediate onto the catalyst surface, and the easy desorption of Nꢀmonomethylamine (Figure
1b).
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Figure 1. (a) Strategy for highly selective Nꢀmonomethylation. (b). Selective Nꢀ
monomethylation of nitroarenes with HCHO/H2.
EXPERIMENTAL SECTION
Catalyst preparation
The supported Pd catalysts were prepared with deposition–precipitation method with TiO2, γꢀ
Al2O3, C, SiO2, Fe2O3, and CuO as supports. TiO2 (0.5 g, P25, J&K Scientific, anatase/rutile =
80/20,) was dispersed in deionized water (25 mL) and K2PdCl4 aqueous solution (1.0 mL, [Pd]
5.0 mg/ mL) were added into the solution under vigorous stirring. The pH value was adjusted to
about 10 using 0.2 M NaOH and the solution was stirred for another 3 h at room temperature.
Then 4.0 mL of hydrazine solution (hydrazine/H2O = 1/3 V/V) was added to the solution and
stirred for 4 h. The solid sample was recovered by centrifugation and washed with water. The
obtained solid was dried at 80 oC for 12 h. A grey solid sample was obtained and denoted as 1%
Pd/TiO2. The other catalysts were prepared with the same operations.
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Characterization.
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XRD measurements were conducted by using a STADIP automated transmission
diffractometer (STOE) equipped with an incident beam curved germanium monochromator with
CuKa1 radiation and current of 40 kV and 150 mA, respectively. The XRD patterns were
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scanned in the 2 Theta range of 10ꢀ90 C. XPS were obtained using a VG ESꢀCALAB 210
instrument equipped with a dual Mg/Al anode Xꢀray source, a hemispherical capacitor analyzer,
and a 5 keV Ar+ iron gun. The electron binding energy was referenced to the C1s peak at 284.8
eV. The background pressure in the chamber was less than 10ꢀ7 Pa. The peaks were fitted by
Gaussian–Lorentzian curves after a Shirley background subtraction. For quantitative analysis, the
peak area was divided by the elementꢀspecific Scofield factor and the transmission function of
the analyzer. The BET surface area measurements were performed on a Quantachrome IQ2 at the
temperature of 77 K. The pore size distribution was calculated from the desorption isotherm by
using the Barrett, Joyner, and Halenda (BJH) method. Prior to measurements, the samples were
degassed at 300 C for 3 h, at a rate of 10 C•minꢀ1. TEM was carried out by using a Tecnai G2
F30 SꢀTwin transmission electron microscope operating at 300 kV. For TEM investigations, the
catalysts were dispersed in ethanol by ultrasonication and deposited on carbonꢀcoated copper
grids. Temperature programmed reduction (TPR) experiments were performed on a
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Quantachrome IQ2. 30 mg of catalyst was placed in a quartz tube, and it was heated up to 350 C
under 20 mL•minꢀ1 O2 flow (10 C•minꢀ1) and maintained 100 min. The sample was cooled to
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room temperature and purged with highly pure Ar for 1 h. Then it was reduced with 10% H2
(balanced with N2) with the increasing of the temperature to 350 C (10 C •minꢀ1). The amount
of hydrogen uptake was monitored onꢀline by a TCD detector and recorded as a function of
temperature. NH3ꢀTPD and HNMe2ꢀTPD were carried out on a Micromeritics 2750
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chemisorption system. The weighed sample (100 mg) was pretreated at 450 C for 1 h under He
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and cooled to 20 C. The NH3 gas was introduced instead of He at this temperature for 1 h to
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ensure the saturation adsorption of NH3. The sample was then purged with He for 1 h until the
signal returned to the baseline as monitored by a thermal conductivity detector (TCD). The
desorption curve of NH3 was acquired by heating the sample from 20 oC to 600 oC at 10 oC•minꢀ1
under He with the flow rate of 30 ml•minꢀ1. NMR spectra were measured by using a Bruker
ARX 400 or ARX 100 spectrometer at 400 MHz (1H) and 100 MHz (13C). Chemical shifts were
reported in parts per million (ppm) down field from TMS with the solvent resonance as the
internal standard. Coupling constants (J) were reported in Hz and refered to apparent peak
multiplications.
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Catalytic performance test
A mixture of nitroarenens (1.0 mmol), paraformaldehyde (75 mg, 2.5 mmol), 1% Pd/TiO2 (40
mg ) and 1,4ꢀdioxane (4 mL) were added a glass tube which was placed in an 100 mL autoclave.
Then the autoclave was purged and charged with H2 (1.0 MPa) three times. The reaction mixture
was stirred at 40 oC for 6 h. Then, the autoclave was cooled to room temperature and the pressure
was carefully released. Subsequently, the reaction mixture was diluted with 10 mL ethyl acetate
for quantitative analysis by GCꢀMS (Agilent 7890Bꢀ5977A).
The procedure for recovery of catalyst
The Pd/TiO2 catalyst was separated from the reaction mixtures by centrifuging, washed by
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using 1,4ꢀdioxane (10 mL x 3) and H2O (10 mL x 2), dried at 80 C for 5 h and then reused for
the next run. The catalyst can be recovered and reused for at least 3 times without obvious loss in
catalytic performance, providing the desired product in 90% yield at the 3rd run.
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RESULTS AND DISCUSSION
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The supported Pd catalysts were characterized by XRD, TEM, XPS and N2 adsorptionꢀ
desorption instruments to reveal their structures. XRD measurements showed neither palladium
oxide nor metallic palladium diffraction pattern was detectable in all the catalysts (Figure S1),
which might be attributed to the low Pd loadings or that the Pd species were amorphous and
highly dispersed. The morphologies of the catalysts were further characterized by TEM (Figure 2
and Figure S2). The TEM results revealed that the Pd nanoparticles homogeneously dispersed on
TiO2 and have an average diameter of 2ꢀ4 nm in both fresh Pd/TiO2 and Pd/TiO2 used three
times, respectively. Next, the HRꢀTEM characterizations (Figure S3) revealed that these Pd
particles are amorphous, which is confirmed by the XRD in Figure S1. It might be attributed to
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the low catalyst preparation temperature, i.e., 80 C. So the crystallizing degree of palladium
particle should be low. We then performed the elemental distribution using highꢀangle annular
darkꢀfield transmission electron microscopy (HAADFSTEM) and the results are shown in Figure
3. The mappings clearly describe that Ti, O and Pd are uniformly distributed in the Pd/TiO2
catalyst. Moreover, XPS studies of the catalysts were performed to determine the chemical state
of Pd nanoꢀparticles. As shown in Figure 4 and Figure S4, weak peaks of Pd 3d5/2 were found in
Pd/TiO2, Pd/Al2O3, Pd/Fe2O3 and Pd/TiO2 used three times but not observable in Pd/C and
Pd/SiO2, which might be attributed to the lower palladium loadings. The Pd 3d5/2 signals of
fresh Pd/TiO2 and used Pd/TiO2 catalysts appeared at 334.8 and 334.6 eV, respectively, which
suggested that metallic Pd was mainly formed on the surface of catalysts. The XPS spectra of
catalysts Pd/Al2O3, Pd/Fe2O3 and Pd/CuO support the formation of metallic Pd, too. The N2
adsorptionꢀdesorption tests (Figure S5) showed that the BET surface areas of the catalysts (Table
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S1) were in the range of 8ꢀ280 m2/g, in which the BET surface area of Pd/TiO2 is 60.72 m2/g. So
the high activity of Pd/TiO2 should not be attributed to its high surface area.
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Figure 2. TEM images of the catalysts. (a) fresh 1% Pd/TiO2. (b) used three times 1% Pd/TiO2.
Figure 3. (a) HAADFꢀSTEM images of 1% Pd/TiO2 and (b), (c), (d) the corresponding EDX
mapping of orange rectangular area from (a).
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Figure 4. XPS spectra of the catalysts. (a) fresh 1% Pd/TiO2. (b) used three times 1% Pd/TiO2.
To search for the best catalyst in terms of selectivity toward Nꢀmonomethylation, we began
our exploration with reductive Nꢀmonomethylation of nitrobenzene with paraformaldehyde and
H2 as the model reaction (Table 1). The influence of the solvent on the reactivity and selectivity
of this reaction was first investigated (Table 1, entries 1ꢀ5). Although 100% conversions of
nitrobenzene were observed in all the reactions, it can be seen that 65.1% Nꢀmonomethylaniline
selectivity and excellent ratio (65.1 : 0.9) between Nꢀmonomethylaniline and N,Nꢀ
dimethylaniline were achieved when 1,4ꢀdioxane was used (entry 5). Following, the catalytic
performance of nanoꢀPd catalysts with different supports was tested (entries 6ꢀ10). Clearly,
Pd/TiO2 exhibits the best catalytic performance. If other catalysts including Pd/γꢀAl2O3, Pd/C,
Pd/SiO2, and Pd/Fe2O3 were employed, lower yields of Nꢀmonomethylaniline were obtained. It
should be noted that the ratio between Nꢀmonomethylaniline and Nꢀdimethylaniline was
decreased when the yield of Nꢀmethylaniline was reduced. It means that the selectivity of Nꢀ
methylaniline is positively associated with the catalytic transformation of aniline to Nꢀ
methylaniline. TOF values of different catalysts have been calculated for comparison in Table
S2. It can be seen that TOF value ranges from 27 to 81. Although TOF up to 81 per hour was
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obtained in the presence of Pd/Fe2O3 catalyst, the ratios between Nꢀmonomethylaniline and N,Nꢀ
dimethylaniline is only 17:1. Considering the TOF numbers and the ratios between Nꢀ
monomethylaniline and N,Nꢀdimethylaniline, Pd/TiO2 gives the best results. In addition, the
reducing of the H2 pressure results in lower yield of Nꢀmonomethylaniline (entries 11ꢀ12).
Surprisingly, the selectivity to Nꢀmonomethylamine sharply decreased to 54% if the reaction
time was prolonged to 12 h (entry 13). Importantly, there is no aniline observable at this time,
which might be the reason for the fast decreasing of the selectivity to the desired product. These
results support our hypothesis that the presence of primary amine (aniline) may be helpful to the
high selectivity of Nꢀmonomethyl amine and the selectivity would sharply decrease if the
primary amine was consumed, which was possibly regulated by the preferential adsorption of
primary amine onto the catalyst surface.
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Table 1. Optimization of the reaction conditionsa
Sel.[%]b
Conv.
Entry
Cat.
Solvent
[%]b
100
100
100
100
100
100
3a
4a
5a
ꢀ
6a
ꢀ
1
2
3
4
5
6
Pd/TiO2
Pd/TiO2
Pd/TiO2
Pd/TiO2
Pd/TiO2
Pd/Al2O3
EtOH
13.0
25.0
15.0
3.0
71.0
75.0
77.0
79.0
0.9
EA
ꢀꢀ
ꢀꢀ
cyclohexane
toluene
ꢀꢀ
8.0
18.0
ꢀꢀ
ꢀꢀ
1,4ꢀdioxane
1,4ꢀdioxane
65.1
63.4
33.0
32.9
1.4
2.3
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Pd/C
1,4ꢀdioxane
1,4ꢀdioxane
1,4ꢀdioxane
1,4ꢀdioxane
1,4ꢀdioxane
1,4ꢀdioxane
1,4ꢀdioxane
100
100
100
n.r
42.6
38.4
29.3
ꢀꢀ
1.4
1.6
1.7
ꢀꢀ
55.0
57.0
55.0
ꢀꢀ
1.0
3.0
14.0
ꢀꢀ
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Pd/SiO2
Pd/Fe2O3
Pd/CuO
Pd/TiO2
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aReaction conditions: nitrobenzene (1.0 mmol), paraformaldehyde (2.5 mmol), catalyst (40 mg),
H2 (1.0 MPa), solvent (4.0 mL), 40 C, 6 h. Determined by GCꢀMS. 0.7 MPa. 0.4 MPa.
eReacted for 12 h.
o
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d
To reveal whether the reaction takes place in accordance with the above assumptions, the
reaction of nitrobenzene with paraformaldehyde and H2 was traced by GCꢀMS to check the
possible reaction intermediates with varied reaction times. As shown in Figure 5a, the
hydrogenation of nitrobenzene was a fast reaction and it was completely converted to aniline in
0.5 h. Then, the aniline gradually decreased to 3.0% after 9.5 h. Meanwhile, the yield of Nꢀ
monomethylaniline gradually increased to 91.6% after 9.5 h. Moreover, the concentration of Nꢀ
methyleneaniline maintains low, suggesting that the reaction of aniline with aldehyde to give
imine rather than hydrogenation of imine to Nꢀmethylaniline was the rateꢀlimiting step. It should
be noted that the yield of N,Nꢀdimethyl aniline is negligible if the aniline exists in the reaction
system. When the aniline was exhausted, the amount of N,Nꢀdimethyl aniline sharply increased
and the amount of Nꢀmethylaniline dramatically decreased. These results confirm the above
observations, and support our hypothesis that the preferential adsorption of aniline onto Pd/TiO2
surface over Nꢀmonomethylaniline might be the main reason to gain high Nꢀmonomethylamine
selectivity.
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To verify these, NH3ꢀTPD and (Me)2NHꢀTPD experiments were performed to check if the
proton quantities in the molecules influence their adsorption onto the catalyst surface. The results
of the adsorption of ammonia and dimethylamine on Pd/TiO2 are shown in Figure 5b and Figure
S6. It can be observed that the adsorbing quantity of ammonia is 0.513 mmol/g Pd/TiO2 while
the adsorbing quantity of dimethylamine is only 0.156 mmol/g Pd/TiO2. Thus primary amine
with more protons is preferentially adsorbed onto Pd/TiO2 surface, and therefore high selectivity
to Nꢀmonomethylation can be maintained before the complete consumption of primary amine.
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Figure 5. (a) Products distribution during the oneꢀpot reductive methylation of nitrobenzene with
HCHO and H2. Reaction conditions: nitrobenzene (1.0 mmol), paraformaldehyde (2.5 mmol),
1% Pd/TiO2 (40 mg), H2 (1.0 MPa), 1,4ꢀdioxane (4.0 mL), 40 ℃. (b) Adsorption capacity of
NH3 and (Me)2NHꢀTPD on the Pd/TiO2.
In addition, it should be noted that both the amine adsorbing capacity and H2 activation ability
of the catalyst are crucial to gain nice catalytic performance in the reductive Nꢀmethylation
reaction. Thus, the NH3ꢀTPD and H2ꢀTPR characterizations were investigated to understand the
o
catalytic performance of different catalysts (Figure 5). Normally, desorption below 100 C
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should be attributed to physical adsorption. Therefore, we mainly compare the desorption data of
different catalyst above 100 oC. The NH3ꢀTPD results suggested that the order of NH3 adsorption
quantity on different catalysts is Pd/Al2O3 ≈ Pd/TiO2 > Pd/SiO2 >> Pd/C > Pd/CuO > Pd/Fe2O3
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(Figure 6a), while the H2ꢀTPR results suggested that the order of active palladium quantity for H2
activation is Pd/TiO2 > Pd/Al2O3 > Pd/SiO2 > Pd/C > Pd/Fe2O3 > Pd/CuO (Figure 6b). However,
as the reaction temperature in this work is around 60 °C, so only those palladium species active
around 60 °C can be involved in the reductive Nꢀmethylation of nitrobenzene. Clearly, Pd/TiO2
and Pd/Fe2O3 have more active Pd species than other catalysts in this range. So, we could draw
conclusion that the high activity of Pd/TiO2 should be contributed to its good amine adsorbing
capacity, and excellent hydrogen activation performance under our reaction conditions. As to
Pd/Fe2O3, the poor amine adsorption ability should be responsible for its low activity in the
reductive Nꢀmonomethylation reaction.
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Figure 6. (a) NH3ꢀTPD profiles of the catalyst. (b) H2ꢀTPR profiles of various supported
palladium catalysts.
Continued from the above discussions, now we could draw a definitive conclusion that high
selectivity of Nꢀmonomethylamine would be achieved if aniline maintains in the reaction system.
Therefore, to make the operation simple, the reductive Nꢀmonomethylation reaction was
performed with 1.1 equiv., of nitrobenzene and 1.0 equiv., of paraformaldehyde in the presence
of 40 mg 1% Pd/TiO2 under 1.0 MPa H2 in 1,4ꢀdioxane at 60 °C for 24 h. To our delight, 90%
yield of Nꢀmonomethylaniline was obtained. Importantly, the catalyst can be recovered and
reused for at least 3 times without obvious loss in catalytic performance, providing the desired
product in 90% yield at the 3rd run.
With the optimized conditions in hand, the selective Nꢀmonomethylation of various nitroarenes
with paraformaldehyde and H2 was investigated. As shown in Table 2, the nitroarenes with both
electronꢀwithdrawing and electronꢀdonating groups on the phenyl ring underwent the reductive
Nꢀmethylation to the corresponding Nꢀmonomethylamines with good to excellent yields.
Reductive Nꢀmonomethylation of electronꢀrich methylꢀ, hydroxyl, methoxy and dimethylamino
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substituted nitroarenes proceeded smoothly to provide the corresponding products in 82ꢀ93%
yields with a mono: di ratio of 16:1 to 72:1 (3bꢀ3h). Clearly, the electron donating groups on
nitroarenes led to slight decrease of the selectivity to Nꢀmonomethylanilines. For example, the
presence of methoxy group in para position led to a mono: di ratio of 17: 1 in Nꢀ
monomethylation (3f). The steric hindrance at the orth position of the nitrobenzene showed a
positive effect on the selectivity of this transformation, and 2ꢀmethylnitrobenzene as starting
material gave an excellent mono: di ratio of 72: 1 (3b). Electronꢀdeficient nitroarenes bearing
fluoride, trifluoromethyl, ester and amide groups also proceeded well, affording their
corresponding products in good yields with excellent selectivities, too (3iꢀ3m). In the case of 3ꢀ
nitrobenzaldehyde and 2ꢀnitroꢀ9ꢀfuorenone, the reduction of the formyl (3k) and ketone (3p)
groups was observed. In addition, the fusedꢀring 2ꢀnitronaphthalene was also successfully
converted to the corresponding Nꢀmonomethylamine in 77% yield (3o).
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a
Table 2. Results of the Nꢀmonomethylation of nitroarenes with HCHO/H2
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aReaction conditions: nitroarene (1.1 mmol), paraformaldehyde (1.0 mmol), 1% Pd/TiO2 (40
mg), H2 (1.0 Mpa), 1,4ꢀdioxane (4.0 mL), 60 ℃, 24 h. The mono/di methyl amines ratios within
1
b
c
parentheses were determined by H NMR analysis. Reduction of formyl. Isolated yield.
dReduction of ketone.
Importantly, this protocol is also applicable in the reductive Nꢀmonomethylation of aniline and
high Nꢀmonomethylaniline selecꢀtivity and yield are obtained (Scheme 1).
Scheme 1. Pd/TiO2 catalyzed highly selective Nꢀmonomethylation of aniline with HCHO/H2
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To demonstrate the potential application of this methodology, we performed the selectively Nꢀ
monomethylation of nitro and amines groups to Nꢀmethylated analogues in biological active
molecules (Figure 7), as Nꢀmethylation is an important tool to regulate the biological and
pharmaceutical activities of life science molecules. Notably, the Nꢀmonomethylation of
clinidipine, which inhibit the flow of extracellular calcium through ionꢀspecific channels that
span the cell wall as reduce the systemic vascular resistance and arterial pressure,12 has been
realized with 80% yield (Figure 7a). In addition, the Nꢀmonomethylation of nimesulide, a nonꢀ
steroidal antiꢀflammatory drug with analgestic and antipyretic properties,13 has been obtained in
77% yield (Figure 7a). Further, the Nꢀmonomethyl moiety has been successfully introduced into
procaine and methyl 4ꢀaminosalicylate with up to 95% yield, which are used as anesthetic14 and
antituberculous drugs,15 respectively (Figure 7b).
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Figure 7. NꢀMonomethylation of drug molecules. (a) Nꢀmomomethylation of Nimesulide and
Clinidipine. (b) Nꢀmomomethylation of 4ꢀaminosalicylate and Procaine.
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CONCLUSIONS
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In conclusion, we have developed extraordinarily highly selective Nꢀmonomethylation
reaction starting from easily available nitroarenes with paraformaldehyde and H2 using Pd/TiO2
as catalyst. A series of functional Nꢀmonomethylamines were synthesized by applying this
simple catalyst system. This work offers a straightforward, step economic and clean
methodology for the selective synthesis of Nꢀmonomethylamines. The synthetic utility of this
reaction is specifically demonstrated using various bioꢀactive molecules including existing
pharmaceuticals. The superior selectivity should be attributed to the preferential adsorption of
the primary amine over Nꢀmonomethylamine on the Pd/TiO2 surface, as elucidated by
NH3/Me2NHꢀTPD, while the nice catalytic activity could be associated to the good H2 activation
ability and high amine adsorbing capacity of the catalyst, as elucidated by NH3ꢀTPD and H2ꢀTPR
tests.
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ASSOCIATED CONTENT
Supporting Information. The following files are available free of charge.
Detailed experimental procedures, characterizations of catalysts and products (PDF)
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: fshi@licp.cas.cn
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
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Financial supports from the NSFC (21633013, 91745106), National Key Research and
Development Program of China (2017YFA0403100) and Key Research Program of Frontier Sciꢀ
ences of CAS (QYZDJꢀSSWꢀSLH051) are gratefully acknowledged.
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