Organic Letters
Letter
took place, and a trifluoromethyl group in the meta position of
the aromatic ring was also tolerated (2j). The developed
system is able to chemoselectively reduce the nitro group in
the presence of a double bond (2k), ester group (2p, 2q),
amide functionality (2r), and compounds containing a
sulfonamide residue (2u). Other functional groups such as
ether and thioether and the amino group were well tolerated,
and the desired anilines (2l−2o and 2s, 2t) could be isolated
in very high yields of up to 99%. Finally, 1-nitronaphthalene
(1v) was successfully applied, providing naphthalen-1-amine
(2v) in 75% yield. Unfortunately, under the general reaction
conditions, nitriles, certain ketones, alkynes, and olefins are
partially reduced.
Scheme 3. Possible Pathways for the Hydrogenation of
Nitroarenes
Additionally, a gram-scale synthesis of 4-iodoaniline could
also be performed using the optimized reaction conditions.
The product 2i was formed in 78% yield (Scheme 1), implying
the feasibility of the described protocol. To show the general
applicability of the developed method, we decided to perform
the hydrogenation of 1w, an intermediate in the synthesis of
vortioxetine, an antidepressant used to treat major depressive
disorder. A newly developed synthetic route includes the
nucleophilic substitution of 2,4-dimethylbenzenethiol with 1-
chloro-2-nitrobenzene to afford the desired intermediate 1w.32
Under the optimized reaction conditions, the formed nitro-
phenylsulfane derivative 1w undergoes catalytic hydrogenation,
leading to the desired thioaniline derivative 2w in 74% yield
(Scheme 2). It is important to note that the transition metals
Scheme 4. Mechanistic Studies
Scheme 2. Synthesis of Vortioxetine Intermediate
are often inhibited by thio- and amino groups and result in
reduced activity. Furthermore, several M(0) species generated
in late transition-metal-catalyzed reactions undergo C−S-type
oxidative additions that can be prevented by the use of
manganese catalysts, such as Mn-1. The reaction of 2w with 2-
chloro-N-(2-chloroethyl)ethanamine hydrochloride then pro-
vides the desired vortioxetine.
There are two commonly studied pathways for the
hydrogenation of nitroarenes to anilines. The first one is a
direct pathway where the reduction proceeds via the formation
of nitrosoarene and hydroxylamine intermediates. The second
one occurs when an azoxy compound is formed by the
condensation of nitrosoarene and hydroxylamine and later
undergoes reduction to azo and hydrazo compounds (Scheme
3). To investigate the reaction mechanism of the studied
catalytic system, possible intermediates were submitted to the
standard reaction conditions. N-Phenylhydroxylamine (3),
azobenzene (4), and 1,2-diphenylhydrazine (5) were tested
(Scheme 4a). The reduction of N-phenylhydroxylamine led to
the formation of 49% of aniline, whereas azobenzene and 1,2-
diphenylhydrazine provided only 7 and 10% of aniline,
respectively. These results suggested that the nitroarenes
undergo direct hydrogenation in the presence of the developed
catalytic system. In the case of the formation of the unwanted
azo and hydrazo compounds, Mn-1 can partially transform
them into the desired anilines. It should be noted that we did
not observe the accumulation of intermediates such as
hydroxylamine or azo, hydrazo, and azoxy compounds.
Furthermore, we did not observe the formation of nano-
particles, as the pincer complexes are rather stable under the
applied conditions. (See the SI for details.)
To prove whether the described reaction proceeds via
metal−ligand cooperativity,33 we performed the hydrogenation
reaction using the corresponding manganese N-Me derivative
of Mn-1 (Scheme 4b). As expected, the methylated complex
Mn-1 (N-Me) appeared to be inactive in the hydrogenation of
nitrobenzene under the optimized reaction conditions,
indicating that the presence of the N−H is critical for the
reaction to proceed.
2744
Org. Lett. 2021, 23, 2742−2747