Transition-Metal-Free Three-Component Synthesis of Tertiary Aryl Amines from Nitro Compounds, Boronic Acids, and Trialkyl Phosphites

Article abstract of DOI:10.1002/adsc.201901009

The synthesis of aromatic amines is of continuous interest in chemistry. An exceptionally versatile three-component reaction that directly transforms inexpensive nitro compounds, boronic acids, and trialkyl phosphites into tertiary aromatic amines has been realized. The reaction tolerates alkyl and aryl substituents on the nitro and boronic acid moieties, as well as functionalized phosphites. No transition-metal catalysis is required. The method is orthogonal to other classical metal-catalyzed syntheses since it tolerates the presence of halogens, and also permits the synthesis of functionalized compounds such as α-amino ester derivatives. (Figure presented.).

Full text of DOI:10.1002/adsc.201901009

Title: Transition-Metal-Free Three-Component Synthesis of Tertiary
Aryl Amines from Nitro Compounds, Boronic Acids, and Trialkyl
Phosphites
Authors: Silvia Roscales and Aurelio G. CSAKY
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901009
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10.1002/adsc.201901009
Advanced Synthesis & Catalysis
VERY IMPORTANT PUBLICATION
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Transition-Metal-Free Three-Component Synthesis of Tertiary
Aryl Amines from Nitro Compounds, Boronic Acids, and
Trialkyl Phosphites
Silvia Roscales,a and Aurelio G. Csákya*
a
Instituto Pluridisciplinar, Universidad Complutense de Madrid
Paseo de Juan XXIII, 1, 28040 Madrid, Spain
E-mail: csaky@ucm.es
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
use either secondary anilines or secondary alkylamines
Abstract. The synthesis of aromatic amines is of continuous
interest in chemistry. An exceptionally versatile three- as starting materials (Scheme 1).
component reaction that directly transforms inexpensive
nitro compounds, boronic acids, and trialkyl phosphites into
tertiary aromatic amines has been realized. The reaction
tolerates alkyl and aryl substituents on the nitro and boronic
acid moieties, as well as functionalized phosphites. No
transition-metal catalysis is required. The method is
orthogonal to other classical metal-catalyzed syntheses since
it tolerates the presence of halogens, and also permits the
synthesis of functionalized compounds such as -amino
ester derivatives.
Keywords: amination; boronic acids; multicomponent
reactions; nitro compounds; phosphites
The manufacture of amines as raw materials and as
end products is one of the fastest-growing sectors in
the chemical industry worldwide.[1] In particular,
aromatic amines (also known as arylamines or aniline
derivatives) are ubiquitous compounds in nature that
have found widespread use in medicinal applications
and materials science.[2] Among them, tertiary
derivatives are motifs commonly found in molecules
of importance to chemistry, biology, and medicine,
often found within alkaloid secondary metabolites. We
report herein a novel three-component reaction that
permits the assembly of tertiary aryl amines with three
different substituents by mixing a nitro compound with
a boronic acid and a trialkyl phosphite. The target
compounds have been used as Lewis bases to form
organometallic catalysts, and as Brønsted bases to
capture acidic side products in several types of metal-
free coupling reactions.[3] The development of
efficient methods for the synthesis of arylamines is an
issue of continuous interest to the chemistry
community.[4]
Scheme 1. State of the art and current proposal.
These include the Buchwald-Hartwig[6] or the
Ullmann[7] reactions between anilines and
(pseudo)aryl halides, the Chan-Evans-Lam amination
of boronic acid derivatives, which can be carried out
either on N-substituted anilines[8] or on secondary
alkylamines,[9] N-alkylation reactions,[10-13] and
reductive amination procedures,[14] the last two
specific for secondary alkylamines. Besides, some
hydroamination procedures of secondary anilines have
The synthesis of tertiary derivatives is less
straightforward than that of secondary arylamines,[5]
requiring a multistep approach. The most general
transformations for the synthesis of tertiary arylamines
1
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10.1002/adsc.201901009
Advanced Synthesis & Catalysis
also been reported.[15] Most of these routes require
multiple steps and various purifications, as well as the
transition-metal catalysis, thus circumventing the
drawbacks associated with possible toxicity, cost, need
use of transition-metal catalysts, ligands, and additives, for the design of substrate-depending ligands and risk
which overall hampers synthetic efficiency. Also, the
amines required as starting materials, in particular, the
anilines, are frequently obtained by the reduction of
nitro compounds. This has led to the development of
synthetic methods that directly use readily available
and cheap nitro compounds as the nitrogen source.
These procedures become more sustainable because
they avoid the reduction step and increase functional
group compatibility. However, general methods for
amine synthesis from nitro compounds remain
underdeveloped despite their potential advantages and
have been mostly advanced thus far for the synthesis
of secondary amines.
Thus, secondary anilines have been prepared from
nitroarenes by the radical hydroamination of olefins[16]
and alkyl halides[17] using iron catalysts,[18] and by a
sequential chainwalking reductive hydroarylamination
relay using nickel hydrides as catalysts.[19] Also, using
nitroarenes as a nitrogen source,[20] the nucleophilic
addition of Grignard reagents followed by reduction of
an hydroxylamine intermediate has led to
diarylamines.[21] Both aromatic and aliphatic nitro
compounds have been transformed into secondary
anilines by the reductive coupling of organozinc
reagents promoted by B2Pin2 via nitrenoids.[22]
Boronic acids, although less nucleophilic than
Grignard or organozinc reagents, can be used as
nucleophiles in organic synthesis. Among their
advantages, they are bench-stable compounds that can
be used without the need for especially dried solvents
or inert atmosphere, are compatible with many labile
functional groups such as carbonyls, and tolerate the
presence of unprotected OH or NH groups in many of
their reactions. Their nucleophilicity can be enhanced
by the formation of ate species resulting from
coordination with Lewis bases.[23] This property has
been exploited to make them react with various
nitrenoid species that can be generated in situ by the
reduction of nitro compounds in the presence of
phosphetanes and phosphines.[24,25] Both aliphatic and
aromatic nitro compounds have been transformed into
secondary anilines by using both an excess of boronic
acid and of PPh3 in combination with a molybdenum
catalyst.[26]
of product contamination.
We started our investigation by treating
nitrobenzene and phenylboronic acid with triethyl
phosphite (Table 1, entry 1). Toluene was chosen as
the solvent because it had previously been used for the
synthesis of diarylamines from nitroso compounds and
phenylboronic acid.[25] The temperature was set to 110
ºC (reflux) to favor the alkylation step. However,
under these reaction conditions, no conversion of the
starting materials was observed. The replacement of
toluene by chlorobenzene, together with an increase in
the reaction temperature (160 ºC), afforded
diphenylamine 4 (entry 2). However, when xylene was
used, a mixture of amines 4 and 5 was observed (entry
3). Similar results were obtained upon increasing the
reaction time (entry 4) and the molar ratio of phosphite
(entry 5). Taking into account that phosphites are
inexpensive chemicals, we tried the reaction under
neat conditions. Using triethyl phosphite as the solvent
(180 ºC) we were able to obtain the tertiary amine 5 in
good yield (entry 6). Under similar conditions, no
reaction was found when using potassium
phenyltrifluoroborate or the corresponding pinacol
ester (entries 7, 8).
Table 1. Optimization
2
3a
Solvent
Temperature Yield
(º C)
[%][c]
(equiv)
4
5
1
2
3
4
5
6
7
8
3
3
3
3
Toluene
Cl-C6H5
Xylene
Xylene[a]
Xylene
3a[b]
110
160
160
160
160
180
180
180
0
49
0
0
2a
2a
2a
2a
2a
2a
2b
2c
42 15
41 19
35 32
0
0
0
6
---
---
---
83
0
0
3a[b]
3a[b]
Multicomponent reactions[27] constitute a big step
forward towards sustainability, a key driver for
innovation in industrial research and development,
since they provide an alternative to the classical
multistep synthesis. Based on this principle and on
previous findings,[25] we hypothesized that the
activation of either alkyl or aryl nitro compounds with
alkyl phosphites in the presence of either alkyl or
arylboronic acids could render transient aminoboranes,
which are difficult to access through other methods,[22]
that could react as nucleophiles with the trialkyl
phosphate generated in-situ as byproduct of the
activation of the nitro group,[28,29] permitting the
synthesis of a variety of functionalized tertiary anilines
in a sustainable way. The procedure avoids the use of
Reaction conditions: 1a (0.40 mmol), 2 (1.20 mmol), argon
atmosphere, sealed tube, 24 h (unless otherwise stated).
[a] 48 h.
[b] 1.2 mL.
[c] Yield of isolated product.
With the optimized conditions in hand (Table 1,
entry 5), we began to explore the scope of this three-
component transformation by using different
nitroarenes (Scheme 2), focusing our attention in
examples with steric hindrance at the ortho positions
(6-9), and also compatibility with halogen
functionalities (10-12), which makes the method
orthogonal to transition-metal catalyzed reactions. The
reaction could be also applied to substrates bearing a
2
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10.1002/adsc.201901009
Advanced Synthesis & Catalysis
cyano or thioether functional group (13, 14). We were
pleased to find that the reaction also tolerated the use
of aliphatic nitro compounds including simple linear
alkyls such as methyl (15), propyl (16) or benzyl (17)
and also examples with ramification at the -position
such as isopropyl (18) or cyclopentyl (19). Chain-
functionalization was also possible (20).
synthesized in higher yields when starting from the
corresponding boronic acid.
Scheme 3. Initial variations of the boronic acid.
With regard to variations of the phosphite (Scheme
4), we observed that in addition to ethyl (5), methyl
(30), a branched alkyl phosphite (31) and a
functionalized alkyl phosphite (32) could be used as
reaction partners, although the synthesis of 31 required
an increase in the molar ratio of phosphite (See
Supporting Information for details).
Scheme 2. Initial variations of the nitro group.
Next, we continued to explore the scope of the
three-component reaction with respect to the boronic
acid (Scheme 3). Starting with arylboronic acids, again
we found compatibility with ortho substituted rings (8,
9, 21, 22) and halogen (10-12, 23) or cyano
substitution (13). Heterocyclic rings were also
possible (24). Compounds 8-13 had been previously
synthesized from nitroarenes and phenylboronic
(Scheme 2). In comparison, higher yields were
obtained with substituted nitro compounds and the
synthesis of amine 9 was not possible starting from
(2,6-dimethylphenyl)boronic acid (Scheme 3).
Besides, we found that alkyl boronic acids could also
be used in the three-component reaction, both primary
(15, 17, 25, 26) and secondary (18, 19, 27-29).
Compounds 15, 17-19 had been previously
synthesized from alkyl nitro compounds and
phenylboronic acid (Scheme 2). Yields were similar
for linear alkyl derivatives following either pathway.
On the other hand, the cyclic derivatives were
Scheme 4. Variations of the alkyl phosphite.
In light of these results, we accomplished the
synthesis of more complicated examples with
variation of the nitro compound, the boronic acid, and
the phosphite towards the synthesis of N-alkyl
diarylamines (Scheme 5). Diarylamines are highly
important
chemicals
found
among
drugs,
agrochemicals, dyes, radical-trapping antioxidants,
electroluminescent materials, and ligands for
3
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10.1002/adsc.201901009
Advanced Synthesis & Catalysis
transition-metal catalysis.[2,3] The synthesis of
sterically hindered compounds (41, 42) and the
tolerance of the unprotected OH group (43) are
especially noteworthy. In addition, the method was
amenable to scaling. As an example, compound 5 has
been prepared at 8 mmol scale (1.04 g, 65%).
The N-alkylated derivatives are important elements
for the modulation of biological functions.[31] However,
methods that permit the synthesis of -amino acid
esters are relatively scarce.[32] The three-component
reaction reported herein permits the efficient synthesis
of these compounds from readily accessible
nitroacetates as starting materials (Scheme 6). The
scope of the reaction was put to a test by using ethyl
and allyl nitroacetate together with various arylboronic
acids and triethyl phosphite (44–49). Apart from N-
ethyl derivatives, it was also possible to prepare
isopropyl derivatives (50, 51) and compounds
functionalized at the N-alkyl chain (52). Also, the
reaction was possible when using -substituted
nitroacetate derivatives (53).
Based on the above considerations and literature
information, we propose the mechanism for the three-
component reaction that is gathered in Scheme 7.
Initial results by Cadogan and Sundberg[28] put
forward the phosphine-mediated deoxygenation of
nitrobenzenes with the participation of nitroso
intermediates. The successful transformation of
aliphatic nitro compounds in our three-component
reaction precludes this reaction course since aliphatic
nitroso compounds would rapidly tautomerize to
oximes. Similar observations have been made by other
authors.[24,26]
Scheme 5. Synthesis of N-alkyl diarylamines.
In the context of the ongoing discussion, the case of
-amino acid esters deserves special consideration. It
is well known that -amino acids and their derivatives,
the backbone of proteins, have found multiple
applications in chemistry.[30]
Scheme 7. Proposed reaction course.
DFT calculations by Radosevich[33] suggested that
the direct transfer of oxygen from nitro compounds to
P(III) species is energetically disfavored in
comparison to a stepwise process with intermediacy of
azadioxaphosphetanes. Accordingly, we presume the
formation of azadioxaphospetane I by the interaction
of the trialkyl phosphites with the starting nitro
compounds. Coordination of the nitrogen atom in I to
the low-lying vacant orbital on boron of the boronic
acid would render intermediate II, in which the boron
atom acquires an ate character, and the nitrogen atom
becomes highly electrophilic. Ring-opening by an
excess of the oxophilic phosphite would deliver
intermediate III together with the release of a trialkyl
phosphate. The boronate character of III would then
favor the intramolecular 1,2-migration of the carbon
Scheme 6. Synthesis of -amino esters.
4
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10.1002/adsc.201901009
Advanced Synthesis & Catalysis
References
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Experimental Section
Standard Procedure for the One-Pot Synthesis of
Tertiary Aryl Amines
The nitro compound (0.4 mmol, 1.0 equiv.) and the boronic
acid (1.2 mmol, 3.0 equiv.) were dissolved in trialkyl
phosphite (1.2–2.4 mL). The mixture was stirred at 180ºC
under argon atmosphere for 1–24 hours in a sealed tube. 3
eluting with Hexane:AcOEt or Hexane:DCM.
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1g-Scale synthesis of 5
Nitrobenzene 1a (1.0 g, 8.1 mmol) and phenylboronic acid
2a (3.0 g, 24.4 mmol) were dissolved in triethyl phosphite
(25 mL). The mixture was stirred at 180ºC under argon
atmosphere for 30 hours in a sealed tube. After cooling
down to room temperature, the resulting mixture was
filtered through a celite pad and washed gently with hexane.
The filtrate was concentrated in vacuo and the resulting
mixture was adsorbed on silica and purified by flash column
chromatography eluting with hexane:DCM 9:1 (1.04 g,
65%).
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Acknowledgements
This work was supported by Project RTI2018-096520-B-I00 from
the Spanish government (Ministerio de Ciencia, Innovación y
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10.1002/adsc.201901009
Advanced Synthesis & Catalysis
mediated deoxygenation of nitro compounds, see Ref.
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7
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10.1002/adsc.201901009
Advanced Synthesis & Catalysis
COMMUNICATION
Transition-Metal-Free Three-Component
Synthesis of Tertiary Aryl Amines from Nitro
Compounds, Boronic Acids, and Trialkyl
Phosphites
Adv. Synth. Catal. Year, Volume, Page – Page
Silvia Roscales, Aurelio G. Csáky*
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