Palladium-Catalyzed Methylation of Nitroarenes with Methanol

Article abstract of DOI:10.1002/anie.201814146

A procedure for the synthesis of N-methyl-arylamines directly from nitroarenes using methanol as green methylating agent was developed. The key to success is the use of a specific catalyst system consisting of palladium acetate and the ligand 1-[2,6-bis(isopropyl)phenyl]-2-[tert-butyl(2-pyridinyl)phosphino]-1H-Imidazole (L1). The generality of this protocol is demonstrated in the synthesis of more than 20 N-methyl-arylamines under comparably mild conditions. Combining this novel methodology with subsequent coupling processes using the same catalyst allows for efficient diversification of aromatic nitro compounds to a broad variety of amines including drug molecules.

Full text of DOI:10.1002/anie.201814146

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Accepted Article
Title: Palladium-Catalyzed Methylation of Nitroarenes with Methanol
Authors: Lin Wang, Helfried Neumann, and Matthias Beller
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201814146
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Palladium-Catalyzed Methylation of Nitroarenes with Methanol
Lin Wang, Helfried Neumann, and Matthias Beller*
Abstract: A procedure for the synthesis of N-methyl-arylamines
directly from nitroarenes using methanol as green methylating agent
was developed. Key to success is the use of a specific catalyst
system consisting of palladium acetate and the ligand 1-[2,6-
bis(isopropyl)phenyl]-2-[tert-butyl(2-pyridinyl)phosphino]-1H-
Imidazole (L1). The generality of this protocol is demonstrated in the
synthesis of more than 20 N-methyl-arylamines under comparably
mild conditions. Combining this novel methodology with subsequent
coupling processes using the same catalyst allows for efficient
diversification of aromatic nitro compounds to a broad variety of
amines including drug molecules.
limits the synthetic versatility.[10] In recent years, methanol
became of interest as inexpensive and convenient methylating
agent applying the so-called hydrogen borrowing strategy.[11]
However, compared to other alcohols methanol is more difficult
to dehydrogenate.[12] Thus, specific phosphine ligands
containing nitrogen atoms such as LA (Scheme 2i) are needed
for this task.[13] In this case, cooperative action between the
metal center and the nitrogen atom of the ligand enables the
(de)hydrogenation process.[14]
Recently, we developed pyridyl-substituted phosphines, e.g.
1,1’-bis(tert-butyl(pyridin-2-yl)phosphanyl)ferrocene
(LB,
Scheme 2i) for efficient palladium-catalyzed alkoxycarbonylation
reactions.[15, 16] Here, the activation of the corresponding alcohol
is facilitated by the N atom of the pyridyl ring. Hence, this ligand
motif should be also beneficial in hydrogen transfer reactions.
Therefore, we had the idea to synthesize new bifunctional
ligands, which combine the advantages of LB and state-of-the-
art sterically hindered (hetero)arylphosphines such as Buchwald
ligands[17] or our previously reported imidazole-substituted
monophosphines LC[18] (Scheme 2i).
N-Methylamines constitute a privileged structural scaffold
which frequently occurs in agrochemicals, insecticides,
pharmaceuticals including top selling drugs such as olanzapine,
oxycodone and venlafaxine (Scheme 1).[1] Notably, N-
methylations are important biological processes, too and
regulate gene expression and protein function, as well as RNA
processing. [2]
Scheme 1. Representative examples of drugs containing N-methylamines.
For their synthesis, traditionally stoichiometric methylation of
amines with methyl iodide[3], dimethyl sulfate[4], and recently less
toxic reagents such as dimethylcarbonate[5] or reductive
couplings with CO2[6] or formic acid[7] are employed on small lab-
scale. In addition, the classic Eschweiler-Clarke reaction using
formaldehyde and hydrogen prevails as a useful synthetic tool.[8]
Scheme 2. i) Ligand design for Pd-catalyzed synthesis of N-methylarylamines
and ii) potential further functionalization.
For aromatic N-methylamines
a more cost efficient and
straightforward approach makes use of available nitroarenes,
which provides access to diverse organic building blocks.
Herein, we report the design and preparation of imidazole-
substituted hemilabile monophosphines. Using the optimal
ligand L1 the Pd-catalyzed selective reductive methylation of
diverse nitroarenes with methanol is achieved. To the best of our
knowledge homogeneous palladium complexes have not been
used for this task. Firstly, a series of ligands (L1[19] – L5 and L7)
were synthesized by reacting 2-(tert-butylchlorophosphanyl)-
pyridine with lithiated (hetero)arenes (see Supporting
Information). Next, these ligands were tested in the benchmark
reaction of nitrobenzene with methanol in the presence of 1
mol% Pd(OAc)2 and base (Figure 1). As expected, no desired
methylation is observed in the presence of the standard
phosphine PPh3 as well as sterically hindered monophosphines
L6 and L8. Following our concept, the use of pyridyl-substituted
phosphines led to active reduction catalysts. For example, in the
presence of L2, L3 and L7 conversion to azobenzene 3a and
Most known methodologies in the field of reductive N-
methylation of nitroarenes[9] employ hazardous formaldehyde at
comparably high reaction temperature and/or hydrogen pressure
and need long reaction times. Furthermore, selective
monomethylations of nitroarenes are scarcely reported, which
[a]
Leibniz-Institut für Katalyse an der Universität Rostock
Albert-Einstein-Straße 29a, 18059 Rostock (Germany)
E-mail: matthias.beller@catalysis.de
Supporting information for this article is given via a link at the end of
the document.
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azoxybenzene 4a was observed, which also indicated that the
different ligand backbones have an influence on the reactivity.
Surprisingly, the known state-of-the-art carbonylation ligand L9
leads to a highly selective formation of azobenzene in 75% yield.
drug structures and life-science molecules, were produced up to
87%. Furthermore, the nitro group in the rhodamine derivative
1u was transformed to the N-methylamine derivative in 63%
yield. The reaction did not affect the core structure of substrate,
which implies the application of this methodology for
modification of drugs and fluorescent probes.
100%
80%
60%
40%
20%
0%
2a
3a
4a
83%
75%
43%
5%
Scheme 3. Pd-catalyzed mono-N-methylation of nitroarene with methanol.
All yields are isolated yields. a. 1 (1 mmol), Pd(OAc)2 (0.01 mmol), L1 (0.04
mmol), KOH (1.05 mmol), in methanol (1.5 mL) at 80 oC for 5 h; b. 1 (1 mmol),
Pd(OAc)2 (0.01 mmol), L1 (0.04 mmol), KOH (1.05 mmol), in methanol (1.5
8%
L1
L2
L3
L4
L5
L6
L7
c.
mL) at 110 oC for 1 h; 1 (1 mmol), Pd(OAc)2 (0.02 mmol), L1 (0.08 mmol),
L8
L9
KOH (1.05 mmol), in methanol (1.5 mL) at 110 oC for 5 h; d. K3PO4 (1.5 mmol)
instead of KOH as base; e. 1f (6 mmol), Pd(OAc)2 (0.06 mmol), L1 (0.24 mmol),
KOH (6.3 mmol), in methanol (6 mL) at 110 oC for 5 h.
Figure 1. Ligand effect for Pd-catalyzed mono-N-methylation of 1a with
methanol. Reaction conditions: 1a (1 mmol), Pd(OAc)2 (0.01 mmol), ligand
(0.04 mmol), KOH (1.05 mmol), in methanol (1.5 mL) at 110 oC for 5 h. Yield is
determined by GC, n-hexadecane as the standard.
Next, the mechanism of this novel N-methylation was
investigated in the presence of the most active Pd/L1-system. In
order to figure out the key intermediates, the compounds
distribution of the reaction mixture was measured via GC-MS.
After 40 min, besides the signals of substrate 1b and product 2b,
the ones of 4-methylbenzenamine (m/z = 107.1) and N-
Finally, the catalyst system containing the L1 gave N-
methylaniline 2a in 83% yield and 95% selectivity. Notably, the
pyridyl group was indispensable for activation of methanol. After
optimization of the conditions (Table S1, Supporting Information),
scope and limitations of our protocol were explored (Scheme 3).
Applying alkyl-, alkoxy-, amino-, and aryl-substituted nitroarenes
(1b-e, 1h and 1i), mono-N-methylation was observed under
methylene-p-toluidine (m/z
= 119.1) were observed. Full
conversion from 1b to 2b was completed within 1 h (Figure S2).
Interestingly, the side-products azobenzene and azoxybenzene
showed no conversion in both reactions under the optimized
conditions, which demonstrates that these are not intermediates
using Pd/L1 (Scheme 4, a). Moreover, nitrosobenzene was
transformed only into azobenzene in 91% yield in the presence
of the most active catalytic system (Scheme 4, b).
o
comparably mild conditions (80-110 C, 1-5 h) in good to high
yields (76 - 85%), even on larger scale (2f). For advanced
organic synthesis it is essential that the reductive N-methylation
proceeds chemoselectively in the presence of other reducible
functional groups. In this respect, the tolerance of C-C double
bonds (2j) is remarkable. However, as limitations, the sensitivity
of carbon-halogen bonds and electron-withdrawing substituents
has to be mentioned here, too (Scheme S1). In addition,
heterocyclic N-methylamines (2n – 2t), which are key moieties in
To clarify the activation of methanol, N-methylation of 1f with
CD3OD and CD3OH were investigated (Scheme 4, c & d).
Applying CD3OD, the conversion and chemoselectivity of the
reaction significantly decreased.
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produced in good yields through the two-step protocol with
CD3OH as a labeling agent. The deuteration ratio of N-methyl
group in each product was above 97%. Interestingly, due to the
activation of nitro group, the 4-methyl group in 14a was
deuterated partly.
Scheme 4. Comparison experiments: a) and b) the reactions of
azobenzene (3a), azoxybenzene (4a) and nitrosobenzene (1a’) with methanol
under the optimized reaction conditions; c) and d) N-methylation of 1f with
deuterated methanol.
Scheme 5. Pd-catalyzed two-step synthesis of various products with N-methyl
a.
moiety.
N-Methylamines are synthesized under the standard reaction
conditions shown in Scheme 3. After the reaction, the solvent was exchanged
and filtrated; b. Pd(OAc)2 (0.01 mmol), L1 (0.04 mmol), aryl bromide (1 mmol),
KOH (1.05 mmol), in dioxane (1.5 mL) at 110 oC for 12 h. Total isolated yield; c.
Pd(OAc)2 (0.01 mmol), L1 (0.04 mmol), 4-iodoanisole (1 mmol), NEt3 (2 mmol),
Surprisingly, with CD3OH, the yield of product 2f-D3 (80%)
was only slightly influenced and the N-methyl group in the
product stayed almost fully deuterated. These results clearly
indicate that the activation of O-H bond in methanol is of crucial
importance for the reaction. We explain this behavior by the
higher bond strength of the O-D bond and also the reduced
interaction with the N atom of pyridyl group in the ligand.
Furthermore, it is noteworthy that decomposition of methanol
using Pd(OAc)2/L1 proceeds only in the presence of the
nitroarene, which acts as a hydrogen-acceptor (Figure S4).
Based on the above observations, a possible mechanism is
proposed (Scheme S4).
d.
in toluene (1.5 mL), CO (5 bar) at 115 oC for 18 h. Total isolated yield;
Pd(OAc)2 (0.01 mmol), L1 (0.04 mmol), 1-naphthylmethyl chloride (1 mmol),
NEt3 (2 mmol), in THF (1.5 mL), CO (20 bar) at 110 oC for 18 h. Total isolated
e.
yield;
Pd(OAc)2 (0.01 mmol), L1 (0.04 mmol), α- or β-bromostyrene (1
mmol), NaOtBu (1.4 mmol), in toluene (1.5 mL), at 90 oC for 12 h. Total
f.
isolated yield; Pd(OAc)2 (0.01 mmol), L1 (0.04 mmol), allyl- or benzyl-
bromide (1 mmol), KOH (1.05 mmol), in dioxane (1.5 mL) at 110 oC for 12 h.
Total isolated yield.
A general advantage of this methylation of nitroarenes is the
feasibility to combine it simply with well-established coupling
processes [17, 18, 20] using the same molecularly-defined catalyst.
To demonstrate this concept, the selected N-methylarylamines
were further functionalized to a variety of coupling products.
More specifically, N-methyldiarylamines (5), N-methylamides (6
and 7), α- or β-N-methylanilinostyrene (8 and 9), N-methyl-N-
arylcinnamylamine (10) as well as N-methyl-N-phenyl-
benzenemethanamine (11) were prepared in the presence of
Pd(OAc)2/L1 in average to good yields.
Scheme 6. Modification of BAYe 6927 via Pd-catalyzed two-step process.
The utility of this combined protocol is showcased in the
efficient modification of BAY-e 6927, known as a calcium
[21]
channel blocker (CCB)
,
which is of interest for
antihypertensive drugs. Similar structures can be found in
important pharmaceuticals such as Clinidipine and Nimodipine.
As shown in Scheme 6, the desired N-methyl-N-[4-
(trifluoromethyl)phenyl]amine 13 was obtained in 69% isolated
yield.
Finally, we demonstrate a new strategy for straightforward
labeling the methyl group in N-methylamines.[22, 11d] As shown in
Scheme 7, three deuterated N-methyldiarylamines were
Scheme 7. Pd-catalyzed strategy for labeling the methyl group in N-
methylamines.
In summary, we developed the first Pd-catalyzed reductive
methylation reaction of nitroarenes to give N-methyl-arylamines.
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Methanol is used in our procedure as solvent, hydrogen source
and green methylating agent. This methodology shows broad
application scope and can be easily combined with further
functionalizations using the same catalyst.
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Acknowledgements
We are grateful for Dr. Anke Spannenberg who performed the X-
ray diffraction measurements and analysis. We also thank the
analytical department of the Leibniz-Institute for Catalysis at the
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Keywords: monophosphine
• methanol • N-methylation •
reaction mechanism • further functionalization
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Entry for the Table of Contents
COMMUNICATION
Lin
Wang,
Helfried
Neumann, Matthias Beller*
Take “Me” on. The first Pd-
catalyzed N-methylation of
nitroarenes with methanol is
reported.
Scope
and
synthetic possibilities are
demonstrated.
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