A Concise Route to Cyclic Amines from Nitroarenes and Ketoacids under Iron-Catalyzed Hydrosilylation Conditions

Article abstract of DOI:10.1002/adsc.202100500

Starting from nitroarenes, under hydrosilylation conditions, using a well-defined N-heterocyclic carbene iron(0) catalyst, (IMes)Fe(CO)₄, the corresponding aniline derivatives were produced in 61–92% isolated yields. More impressively, a selective synthesis of cyclic amines such as pyrrolidines, piperidines and azepanes were conducted from levulinic acid, 1,5- and 1,6-keto acids, respectively. The sequential procedure proceeded under both visible light irradiation and thermal conditions with 20 examples in isolated yields up to 69%. (Figure presented.).

Full text of DOI:10.1002/adsc.202100500

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A Concise Route to Cyclic Amines from Nitroarenes and
Ketoacids under Iron-Catalyzed Hydrosilylation Conditions
Jiajun Wu,a Satawat Tongdee,a Yuvaraj Ammaiyappan,a and Christophe Darcela,*
a
UnivRennes, CNRS ISCR (Institut des Sciences Chimiques de Rennes) UMR 6226, F-35000, Rennes, France
Phone: +33223236271
E-mail: christophe.darcel@univ-rennes1.fr
Manuscript received: April 23, 2021; Revised manuscript received: June 22, 2021;
Version of record online: July 3, 2021
Dedicated to Dr. Christian Bruneau for his outstanding contribution to organometallic catalysis.
abundant earth transition metal which the use when
associated to appropriate ligands was impressively
Abstract: Starting from nitroarenes, under hydro-
silylation conditions, using a well-defined N-hetero-
growing during the last two decades in selective
homogeneous catalysis.[4] One of the well-established
cyclic carbene iron(0) catalyst, (IMes)Fe(CO)4, the
methodology of reduction of nitroarenes was described
corresponding aniline derivatives were produced in
by Béchamp with more than a stoichimoetric amount
61–92% isolated yields. More impressively, a
of iron powder in acidic conditions.[5] More efficient
selective synthesis of cyclic amines such as pyrroli-
and chemoselective iron-catalyzed methodologies in-
dines, piperidines and azepanes were conducted
volving hydrosilylation,[6] hydrogenation,[7] hydrogen
from levulinic acid, 1,5- and 1,6-keto acids,
transfer[8] or other reductants[9] were also recently
respectively. The sequential procedure proceeded
reported. Cascade reactions involving iron-catalyzed
under both visible light irradiation and thermal
reduction of nitroarenes were also reported. By hydro-
conditions with 20 examples in isolated yields up to
genation in the presence of carbonyl derivatives using
69%.
an iron nanocomposite, imines and N-heterocyclic
derivatives were obtained.[10] Additionally, using trans-
fer hydrogenation technologies, imines[11] and various
Keywords: Iron; cyclic amines; nitroarenes; hydro-
silylation; homogeneous catalysis
N-heterocycles such as quinoxalines, benzimidazoles,
benzoxazoles, benzothiazoles, can be prepared from
nitroarenes using various iron catalysts including
Knölker complex.[12] Even if producing wastes, hydro-
This 21th century will be crucial to fight against the silylation reactions are interesting in a chemoselective
global climate change which is closely associated to point of view as shown in cascade reactions involving
the depletion of fossil resources. Among the numerous iron-catalyzed hydrosilylation of nitroarenes to ani-
actions to conduct, in chemistry, the development of lines, then hydroamination of alkenes affording alky-
more sustainable methodologies using if possible lated amines as elegantly demonstrated by Baran,[13]
abundant starting materials associated to cascade then Cui, Thomas and Driver.[14]
reaction sequences are one of the cornerstones for the
success.
Following our recent contributions involving iron-
catalyzed hydrosilylation of polar unsaturated
On the other hand, in molecular synthesis, amines derivatives[15] in particular in cascade reactions,[11,16] we
are among the most important compounds which is report herein the use of the molecular-defined NHC-
highlighted by their preponderance in pharmaceuticals, iron(0) based catalyst for the selective reduction of
agrochemicals, dyes, and material science.[1] Indeed, in nitroarenes leading to cyclic amines by reaction with
2019, among the 200 most sold drugs which represent keto-acids under hydrosilylation conditions. To the
more than US$ 500 million retail sales, 170 have a best of our knowledge, there is no report dealing with
nitrogen atom in their structures.[2]
The access to aniline derivatives by reduction of at iron (Scheme 1).
the direct formation of cyclic amines from nitroarenes
nitroarenes is a powerful technology but was often
First of all, in order to evaluate the ability of
conducted in drastic conditions.[3] Notably, such reduc- iron(0) based catalysts to reduce nitroarenes into
tions were successfully performed using iron, the most aniline derivatives under hydrosilylation conditions,
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Additionally, the absence of visible light irradiation
°
and the reduction of the temperature to 60 C have a
deleterious effect on the reactivity (entries 9 and 10).
The substrate scope using Fe(0) catalyst was then
evaluated using the optimized conditions developed
(5 mol% of Fe(CO)4(IMes), 3 equiv. of PhSiH3, in
°
toluene at 90 C for 20 h, upon visible light irradiation)
(Table 2). The reduction worked with nitroarene
derivatives bearing electrodonating groups such as
methoxy, methyl, dimethylamino or halides, leading to
the corresponding anilines 2a–h with 68–92% isolated
yields. It must be underlined that the hindrance due to
the ortho-substitution of the nitroarenes has no
influence on the reactivity (2b and 2e). The reduction
can also be conducted with nitroarene derivatives
bearing electron-withdrawing groups such as
trifluoromethyl and noticeably, ester, amide, and cyano
Scheme 1. Iron catalyzed a) previous report on reductive
amination of keto-acids and b) present work on the synthesis of
cyclic amines from nitroarenes and keto-acids.
we began our initial work by performing the reduction reducible groups were not altered during this chemo-
of p-nitroanisole 1a using phenylsilane as the hydro- selective reduction reaction of nitroarenes to aniline
silane reducing agent in the presence of 5 mol% of derivatives 2k–m. Interestingly, 1,4-dinitrobenzene
Fe(CO)4(IMes) [IMes=1,3-bis(2,4,6-trimethyl-phenyl) was reduced leading to 1,4-phenylenediamine 2n in
imidazol-2-ylidene] upon visible light irradiation (us- 74% isolated yield and 1,2-phenylenediamine 2o can
ing 24 watt compact fluorescent lamp). Among the
tested hydrosilanes, phenylsilane was found to be the
best leading p-methoxyaniline in 83% GC-yield
(Table 1, entry 7). Noticeably, no reaction occurred in
the absence of Fe(CO)4(IMes) as the catalyst (entry 8).
Table 2. Scope of the reduction of nitroarenes under hydro-
silylation conditions in the presence of Fe(CO)4(IMes)
catalyst.[a]
Table 1. Optimization of the reaction conditions for the
reduction of 4-nitroanisole under hydrosilylation conditions in
the presence of Fe(0) catalyst.[a]
Entry
silane
conditions
Yield (%)[b]
°
1
2
3
4
5
6
7
PhSiH3
90 C, 6 h
29
42
45
<5
72
53
83
0
°
(EtO)3SiH
(EtO)2MeSiH
Et3SiH
(EtO)3SiH
(EtO)2MeSiH
PhSiH3
PhSiH3
PhSiH3
PhSiH3
90 C, 6 h
°
90 C, 6 h
°
90 C, 6 h
°
90 C, 16 h
°
90 C, 16 h
°
90 C, 16 h
8[c]
9[d]
10
90 C, 16 h
°
°
90 C, 16 h
36
<5
°
60 C, 16 h
[a] 4-Nitroanisole (0.2 mmol), silane (3 equiv.), Fe(CO)4(IMes)
[a] Nitroarene (0.5 mmol), PhSiH3 (3 equiv.), Fe(CO)4(IMes)
°
(5 mol%), toluene (0.5 mL), 90 C, for 6–16 h, under argon
°
atmosphere, upon visible light irradiation (using 24 watt
compact fluorescent lamp). Then the reaction was quenched
using NaOH (1 N) in THF at rt for 30 min.;
[b] GC-yield;
(5 mol%), toluene (0.2 mL), 90 C, for 20 h, under argon
atmosphere. upon visible light irradiation (using 24 watt
compact fluorescent lamp). Then the reaction was quenched
using NaOH (1 N) in THF at rt; Isolated yields in paren-
[c] Reaction performed in the absence of Fe(CO)4(IMes) as the
catalyst;
thesis;
[b]
°
Reaction at 110 C;
[d] Reaction performed in the absence of visible irradiation
light.
[c] Starting from 1,4-dinitrobenzene, 4 equiv. of phenylsilane;
[d] Starting from o-nitroaniline.
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be obtained efficiently from o-nitroaniline in 90%
yield. By contrast, heteroaromatic nitro derivatives
such as 2-nitrothiophene and 4-nitro-1H-pyrazole were
not converted under such conditions. Additionally,
even if the conversion of nitroalkane such as 2-(2-
nitroethyl)furane was complete, no corresponding
amine was detected.
Table 3. Optimization of the reaction conditions for cascade
reaction of 4-nitroanisole with 5-oxohexanoic acid under hydro-
silylation conditions in the presence of Fe(CO)4(IMes)
catalyst.[a]
Having successfully demonstrated the ability of our
Fe(CO)4(IMes) catalyst to efficiently promote the
selective reduction of nitroarenes to aniline derivatives
under hydrosilylation conditions, we then explore if
this could be combined, in a cascade fashion, with the
reaction with keto-acids in order to obtain either
pyrrolidinones derivatives or cyclic amines. Thus, in
our previous contribution,[16b] it was shown that
depending the nature of the iron catalyst used, starting
from keto-acids and aniline derivatives in the presence
of phenylsilane, lactames were produced when promot-
ing the reaction with [CpFe(CO)2(IMes)][I], whereas
N-aryl cyclic amines were obtained with Fe-
(CO)4(IMes) catalyst.
Entry
3
PhSiH3 Solvent (mL) Time (h) Yield[b] (%)
(eq.) (eq.)
1
2
3
4
5
6
7
8
9
1.1 3+3
1.1 3+3
1.1 3+3
1.1 3+3
1.2 3+3
1.5 3+3
0.8 3+3
1.1 3+4
1.1 3+6
Toluene (0.5) 20+20 41
Toluene (0.2) 20+20 64
Neat
DMC (0.2)
20+20 30
18+24 30
Toluene (0.2) 20+20 61
Toluene (0.2) 20+20 52
Toluene (0.2) 20+20 62
Toluene (0.2) 18+24 64
Toluene (0.2) 18+24 59
Toluene (0.2) 18+24 59
Toluene (0.2) 20+20 61
10[c] 1.1 3+3
11[d] 1.1 3+3
Thus, performing the cascade transformation of p-
nitroanisole 1a in the presence of 5 mol% of Fe-
(CO)4(IMes), in toluene (1 mol/L) under visible light
[a] (i) 4-Nitroanisole (0.5 mmol), phenylsilane (3 equiv.),
Fe(CO)4(IMes) (5 mol%), solvent, 90 C, for 18–20 h, under
argon atmosphere, upon visible light irradiation (using
24 watt compact fluorescent lamp); (ii) After complete
conversion of the nitroarene, 1.1 equiv. of 5-oxohexanoic
acid and additional PhSiH3 (3 equiv.) were added under
argon atmosphere, and the reaction mixture was stirred 20–
°
°
irradiation at 90 C, first with 3 equiv. of PhSiH3 for
20 h leading to the silylated aniline derivative to which
1.1 equiv. of 5-oxohexanoic acid and 3 additional
equivalents of phenylsilane were added for a reaction
°
at 90 C for 20 additional hours, the piperidine 4a was
obtained in 41% yield (Table 3, entry 1). Noticeably
the concentration was crucial for the success of the
transformation as conducting the reaction in toluene
(2.5 mol/L), 4a was obtained in 64% isolated yield
(entry 2). By contrast, performing the reaction in neat
conditions or in dimethylcarbonate (2.5 mol/L), has a
deleterious effect as the compound 4a was obtained in
only 30% yield (entries 3 and 4).
°
24 additional hours at 90 C; (iii) Then the reaction was
quenched using NaOH (1 N) in THF at rt;
[b] Isolated yields;
[c]
°
110 C;
[d] Addition of 10 mol% of Fe(OTf)2 as co-catalyst. DMC:
dimethylcarbonate.
Increasing or decreasing the amount of 5-oxohex- to perform the substrate scope of the reaction
anoic acid or increasing the amount of phenylsilane for (Table 4).
the second step has a low effect on the efficiency of
The reaction was first evaluated with 5-oxohex-
the transformation (entries 5–9). The efficiency was anoic acid 3. Nitroarenes bearing electron donating
°
not increased when performing the reaction at 110 C groups such as methyl, methoxy and N,N-dimeth-
or when using an additional Lewis acid catalyst such ylamino led to the corresponding piperidine derivatives
as Fe(OTf)2 (entries 10 and 11). Noticeably, when the in 49–69% isolated yields (Table 4, entries 1–6).
reaction was performed with 6 equiv. of phenylsilane Notably, it can be conducted with ortho-substituted
in a single addition, even if full conversion of nitro- nitroarene derivatives with low decrease of the activity
anisole was observed and the desired pyrrolidine (entries 4 and 5). The reaction also proceeded with
compound obtained as the major product, several by- halogen-containing nitroarenes conducting to 4h–j in
products were also detected including p-meth- 49–60% yields (entries 8–10). The reaction was also
oxyaniline, thus reducing the efficiency of the trans- successful with arenes substituted by electron with-
formation.
drawing substituents such as trifluoromethyl or methyl
Thus, the optimized reaction conditions using carboxylate, with moderate yields (29–40%, entries 11
5 mol% of Fe(CO)4(IMes) in sequential manner, first and 12). Interestingly, starting from 1,4-dinitrobenzene,
by reaction of nitroarene 1 with 3 equiv. of PhSiH3 in using 2×6 equiv. of PhSiH3, the 1,4-bis(2-meth-
°
toluene (2.5 mol/L) at 90 C for 20 h, then with ylpiperidi-1-yl)benzene 4n can be obtained in 31%
1.1 equiv. of keto-acid and 3 equiv. of PhSiH3 for 20 isolated yield (entry 14). The average isolated yields of
°
additional hours at 90 C, (Table 3, entry 2) were used N-arylpiperidines about �57% can be considered as
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tions, the corresponding piperidine 6a was obtained in
22% yield (entry 15).
Table 4. Scope of the cascade reaction of nitroarenes with
keto-acids under hydrosilylation conditions in the presence of
Fe(CO)4(IMes) catalyst.[a]
The cascade transformation can then be extended to
levulinic acid 7. Starting from p-methyl, p-methoxy, p-
fluoro and p-chloronitrobenzenes, the corresponding
N-arylpyrrolidines 8a–d were produced in 55–66%
yields (entries 16–19). The reaction can be also
performed with 6-oxoheptanoic acid 9 yielding the
corresponding N-arylazepane 10a in 32% yield (en-
try 20).
Noticeably,
switching
the
catalyst
to
½CpFeðCOÞ2ðIMesÞ�½I� (5 mol%), pyrrolidinone 11a
and piperidinone 11b were selectively obtained in
50% and 41% yields, respectively when performing
the cascade transformation a similar sequential man-
ner in toluene (2.5 mol/L) under visible light irradi-
ation (i) by reaction of 1a with 2 equiv. of PhSiH3 at
°
90 C for 20 h, then (ii) by addition to the reaction
medium of 1.1 equiv. of keto-acid and 2 additional
°
equivalents of PhSiH3 for 20 additional hours at 90 C
(Scheme 2).[17]
In order to have some experimental evidences of
the mechanistic cycle, we have performed a series of
stoichiometric reactions with the complex A. Thus, the
reaction between A and 1 equiv. of PhSiH3 in
1
°
deuterated toluene C7D8 at 90 C for 2 h showed in H-
NMR a representative signal of the SiÀ H resonance at
δ=À 9.2 ppm.[15e,18a] Additionally, the 29Si{1H}-NMR
spectrum of this reaction mixture displayed a signal at
δ=À 7.4 ppm with a clear shift from the free PhSiH3 at
δ=À 59.8 ppm (See Figures S1 and S2 in SI).[18b]
These NMR data seem to indicate that the
(IMes)Fe(CO)3(H)(SiR3) species 13 was obtained via
an oxidative addition (Scheme 3). Thus, 2 equiv. of 4-
fluoronitrobenzene 1-F was added to the reaction
°
mixture which was then warmed at 60 C for 3 h. The
1H-NMR of the resulting reaction mixture showed the
disappearance of the hydride signal, but the 29Si{1H}-
NMR spectrum still displayed a signal at δ=
À 7.4 ppm. Additionally, 19F-NMR of the crude reac-
tion mixture exhibited two main signals at δ=
À 102.2 ppm (4-fluoronitrobenzene 1-F)[19] and δ=
À 126.9 ppm (4-fluoroaniline 2-F)[20] corresponding to
the major compounds. Additionally, a by-product in
small quantities was also observed at À 108.2 ppm and
À 108.7 ppm, corresponding to the azoxyarene 19-F
[a] Conditions: (i) Nitroarene (0.5 mmol), phenylsilane
(3 equiv.), Fe(CO)4(IMes) (5 mol%), toluene (0.2 mL),
°
90 C, for 20 h, under argon atmosphere, upon visible light
irradiation (using 24 watt compact fluorescent lamp); (ii)
After complete conversion of the nitroarene, 1.1 equiv. of
keto-acid and additional PhSiH3 (3 equiv.) were added under
argon atmosphere, and the reaction mixture was stirred 20
°
additional hours at 90 C; (iii) Then the reaction was
quenched using NaOH (1 N) in THF at rt;
[b] Isolated yields;
[c] 2×6 equiv. of phenylsilane were used;
[d]
°
Reaction conducted at 110 C;
[e] 4 additional equiv. of PhSiH3 was used instead of 3 equiv. in
step (ii);
[f] 5 (1.3 equiv.), 5 additional equiv. of PhSiH3 was used instead
of 3 equiv. in step (ii).
Scheme 2. Lactam synthesis via cascade reaction of 4-nitro-
anisole with keto-acid under hydrosilylation conditions in the
presence of [CpFe(CO)2(IMes)][I] catalyst.
reasonable due to the difficulties to purify free primary
amines, and the multi-step sequence involved. Using
5-phenyl-5-oxopentanoic acid 5 under similar condi-
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