Copper-Assisted Amination of Boronic Acids for Synthesis of Bulky Diarylamines: Experimental and DFT Study

Article abstract of DOI:10.1002/chem.201702270

Comparative investigation of copper-assisted oxidative and reductive amination showed that the latter was preferable for the synthesis of bulky diarylamines. DFT estimation of the mechanism of copper(I)-assisted reductive amination of boronic acids with aryl nitroso compounds was performed and possible active species were identified. DFT estimation of the steric penalty revealed that the barrier for the transmetalation step for the hindered nitroso compound was almost the same as that for the unsubstituted one, whereas a bulky group in the boronic acid increased the activation energy. A DFT study of the influence of the electronic properties of the substituents in both reactants on the activation energy revealed that the optimal combination for the synthesis of unsymmetrical diarylamines to provide better yields was an electron-rich aryl boronic acid and an electron-deficient nitroso compound. By using these helpful guidelines, a series of new bulky diarylamines were obtained and fully characterized.

Full text of DOI:10.1002/chem.201702270

A Journal of
Accepted Article
Title: Cu-assisted amination of boronic acids for synthesis of bulky
diarylamines: experimental and DFT study
Authors: Tatiana Magdesieva, Oleg Levitskiy, Yuri Grishin, and
Vyacheslav Sentyurin
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Cu-assisted amination of boronic acids for synthesis of bulky
diarylamines: experimental and DFT study
Oleg A. Levitskiy[a], Yuri K. Grishin[a], Vyacheslav V. Sentyurin[a], and Tatiana V. Magdesieva*[a]
Abstract: Comparative investigation of Cu-assisted oxidative and
reductive amination showed that the latter is preferable for synthesis
of bulky diarylamines. DFT estimation of the mechanism of Cu(I)-
assisted reductive amination of boronic acids with arylnitroso
compounds was performed, possible active species were identified.
DFT estimation of the sterical penalty revealed that the barrier for
the transmetalation step for the hindered nitroso compound is almost
the same as for the unsubstituted one whereas a bulky group in the
boronic acid increases the activation energy. DFT study of the
influence of electronic properties of the substituents in both reactants
on the activation energy revealed that the optimal combination for
synthesis of unsymmetrical diarylamines providing better yields is
the electron-rich aryl boronic acid and the electron deficient nitroso
compound. Using these helpful guidelines, a series of new bulky
diarylamines was obtained and fully characterized.
substituent into the ortho-position which will force the aryl ring to
be twisted from the N-O plane thus disturbing its conjugation
with the radical center (see the accompanying paper [7]).
Therefore, a search for convenient, efficient and relatively cheap
methods leading to bulky ortho-substituted diarylamines as the
precursors for stable nitroxides is a challenging task and the
systematic investigation of the influence of the substituents
location on the peculiarities of synthetic procedure may provide
guidelines for selecting an optimal route.
Recent efforts in formation of diarylamine functional group were
mainly focused on transition metal-catalyzed cross-coupling of
anilines with other aromatic compounds (for review, see [8,9]).
These are well-established and straightforward methods. In spite
of the availability of the main mechanistic guidelines and huge
amount of experimental data which have been already obtained,
the best choice of the catalyst and reaction conditions for each
particular combination of reactants is still a “state of art” issue.
Сatalytic amination of aromatic compounds is commonly the
most efficient when precious metals are used, typically, in the
form of complexes with complicated phosphine ligands. Recently,
trineopentylphosphine was suggested for coupling of sterically
demanding substrates in the Buchwald-Hartwig amination and
showed high efficiency.[10] It was demonstrated that
conformational flexibility of the ligand plays a key role in allowing
the Pd catalyst to couple hindered substrates (e.g., 2,6-
diisopropyl aniline; a combination of two reactants with more
bulky ortho tert-butylphenyl moieties have not been explored
[10]). However, phosphine ligands (as well as palladium) are
expensive and toxic; besides, high reaction temperature is
required.
Introduction
Diarylamines constitute an important family of organic
compounds that are widely used in pharmaceutical, biological
and material science [1] . Diarylamino functionality is present in a
[2]
wide range of natural products as well as in metal complexes
as ligands.[3] Although
a variety of methods have been
developed leading to formation of diarylamines, they cannot be
considered as universally efficient in each particular case, for
each type and location of a substituent in the aromatic ring.
Among other compounds, synthesis of ortho-substituted aryl
derivatives is an especially tricky task due to additional
contribution of sterical demands. Meanwhile, bulky diarylamines
are of interest as possible precursors for corresponding stable
diaryl nirtoxides which are perspective for various practical
applications, e.g., as structurally tunable redox-active
materials.[4] Diarylnitroxides can be obtained via oxidation of
diarylamines using H2O2/Na2WO4 or m-chloroperbenzoic acid.[5,6]
At present, only few stable diarylnitroxides are known and all of
them are para-substituted derivatives, to prevent further
chemical transformations of the radicals which are possible due
to spin delocalization over the phenyl rings. This substantially
limits the scope of stable radicals available. An alternative route
to the radical’s stabilization might be insertion of a bulky
Among alternative methods recently described, arylation of
[11]
anilines using diaryliodonium salts
and iron-catalyzed N-
arylation of acetanilides [12] should be mentioned (Scheme 1).
[a]
Dr. O.A. Levitskiy, D. Sci. Yu.K. Grishin, V.V. Sentyurin, and Prof.,
D. Sci. T.V. Magdesieva
Lomonosov Moscow State University, Chemistry Dept.
Leninskie Gory 1/3, Moscow 119991, Russia
E-mail: tvm@org.chem.msu.ru
Supporting information: HRMS, 1H, 19F, 13C NMR spectra, HMBC
and HSQC 2D NMR data and the details of DFT calculations are
available free of charge via the Internet at http://
http://onlinelibrary.wiley.com
Scheme 1. Synthetic routes to diarylamines.
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Since further practical application of diarylamines and
corresponding nitroxides requires development of synthetic
approaches avoiding precious metals, expensive and
complicated ligands or reactive organometallic reagents, copper-
assisted oxidative and reductive amination of aryl boronic acids
seems to be the most practical alternative to traditional
Buchwald-Hartwig amination. Noteworthy, that S. Buchwald
emphasized the significance of this practical approach in one of
his publications.[13] Both oxidative and reductive copper-assisted
amination of aryl boronic acids with arylamines or nitrosoarenes,
respectively, have been suggested before.[14–17] Oxidative
stabilization via breaking conjugation between the aromatic ring
and the NO radical center.[7] Stability of the corresponding
nitroxides which will be further obtained from the diarylamine
precursors via oxidation imposes some additional restrictions:
sterically demanding substituents without α-hydrogen atoms are
required [23]
Results and Discussion
Oxidative vs. reductive amination of tert-butylphenyl boronic
acids
amination (the Chan-Lam method) has been widely used for
[18]
synthesis of various diarylamines (see
and references cited
wherein); reductive amination of aryl boronic acids has attracted
significantly less attention in literature: to the best of our
knowledge, only one paper on the subject has been published.
To evaluate the comparative efficiency of the oxidative and
reductive Cu-assisted amination of aryl boronic acids, an
interaction of the ortho- and para-tert-butylphenyl boronic acids
with ortho/para tert-butylphenyl amines and ortho/para tert-
butylphenyl nitrosobenzenes was investigated. Oxidative
amination was studied first. Ortho- and para-tert-butylphenyl
boronic acids were synthesized according to the previously
described procedure.[24] Oxidative amination was carried out
using equimolar amount of Cu(OAc)2 in the presence of tertiary
amine in methylene chloride at room temperature (Scheme 2).
[15]
It was demonstrated that the presence of even a methyl
group in the ortho-position to boron had a dramatic influence on
[13]
the oxidative coupling reaction rate
but systematic
investigation of the influence of a bulky group in the ortho- and
para-positions in the aryl boronic acid or in the N-containing
component (nitroso compound or amine) on the applicability of
the methods has not been performed yet. Moreover, it has been
[19]
mentioned in the recent review
that Cu-catalyzed Chan-Lam
method is unsuitable for making hindered anilines.
The present paper is aimed at comparative investigation of the
efficiency of Cu-assisted oxidative and reductive aminations for
the synthesis of a series of bulky diarylamines with ortho-/para
location of tert-butyl and trifluoromethyl substituents in the
aromatic rings. To our knowledge, the compounds have not
been obtained before (except symmetrical 4,4’- bis-(tert-butyl-
[20–22]). Amination of isomeric ortho/para tert-butylphenyl boronic
acids with ortho/para tert-butylphenylamines or tert-
butylnitrosobenzenes will be discussed to reveal the preferential
nature of the N-component (amine or nitroso compound) and the
optimal combination of bulky substituent’s location in the
reactants (in the boron or in the N-component) providing a better
yield of the unsymmetrical diarylamine. Based on the results
obtained, synthesis of the series of bulky ortho- tert-butyl and
trifluoromethyl-containing diarylamines will be presented.
Scheme 2. Oxidative and reductive amination of tert-butylphenyl boronic acids.
To optimize the reaction protocol, both para-tert-butyl substituted
reactants were taken as the simpler case. This allowed obtaining
4,4'-bis-(tert-butylphenyl)amine with 65% yield. Contrary to the
other compounds discussed in the present paper, 4,4'-Bis(tert-
butylphenyl)amine has been previously reported.[20] It has been
Since the data on the reaction mechanisms are scarce, the
results of the computational DFT evaluation of possible
mechanism of Cu(I)-mediated reductive amination of the aryl
boronic acid with aryl nitroso compound will be discussed. The
detailed potential energy profiles for feasible reaction paths as
well as the possible active species will be examined. DFT
estimating the influence of electronic and sterical properties of
the substituents in both reactants on the rate-determining step
will provide guidelines for choosing an optimal synthetic
procedure leading to unsymmetrical diarylamines.
[21]
obtained with similar yield using Pd-catalyzed cross-coupling
and alkylation of diphenylamine on the zeolite catalyst.[22]
Encouraged with this result, we turned to the ortho-derivatives.
First, ortho-tert-butylaniline was involved in the reaction with
para-tert-butylphenyl boronic acid. 2,4'-Bis-(tert-butylphenyl)
amine was isolated in 22% yield; a certain amount of tert-
butylbenzene was also found in the reaction mixture. The
attempts to improve the reaction yield by an increase in the
reaction time were performed but didn’t lead to better results.
The unsymmetrical 2,4'-bis(tert-butylphenyl)amine was obtained
as white crystals with melting point of 86−88°C and completely
characterized using spectral methods. ESI-HRMS supported
that the reaction product was the targeted amine; the peak of
t-
The selection of the substituents (bulky Bu and CF3 groups in
various combinations) allows estimating the influence of the
electronic properties of the substituents on the reaction yield.
New sterically hindered symmetrical and unsymmetrical tert-
butyl- and trifluoromethyl-substituted diphenylamines are of
interest as the precursors for the corresponding diarylnitroxides
which are good candidates for testing the idea of diarylnitroxides
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molecular ion and the characteristic isotopic distribution was
decrease in the thermodynamic stability in the series indicates
increasing repulsive interactions within the molecules.
1
observed. The H and 13C NMR spectra support the structure of
the targeted compound (see Experimental and SI).
Evidently, the most difficult case was obtaining of 2,2'-bis-(tert-
butylphenyl)amine. The experimental data discussed above
clearly indicate that an application of the reductive amination
gives more chances. The reaction was performed according to
the same procedure as described above for unsymmetrical 2,4'-
bis-(tert-butylphenyl) amine. However, the temperature was
increased up to 150 °C since the drastic decrease in the reaction
rate can be expected due to significant increase in sterical
demands. After 9 h of heating and the standard work-up
procedure the targeted 2,2'-bis-(tert-butyl)amine was isolated
with 12% yield (along with 28% of the starting ortho-tert-
butylnitrosobenzene ). Besides, some amount of tert-
butylbenzene was detected in the reaction mixture. This is in line
with the literature data [25], indicating that typical competing paths
in this case are protodeboronation and homocoupling. Such a
low yield of 2,2'-bis-(tert-butylphenyl)amine in spite of the
prolonged heating at high temperature indicates that the
combination of two ortho-substituted reactants is extremely
unfavorable.
An alternative combination (ortho-tert-butylphenyl boronic acid
and para-tert-butyl aniline) was not successful; the targeted
diarylamine was isolated in 7% yield only.
The obtained result made senseless the attempts to synthesize
the most sterically demanding symmetrical 2,2'-bis(tert-
butylphenyl)amine using this approach and we turned our
attention to reductive amination.
In this case, aryl boronic acids and nitroso aromatic compounds
are used; the C-N bond formation is promoted by
a
stoichiometric amount of CuCl which serves as a catalyst and
reducing agent.[15] The method utilizes cheap reactants and
provides good yields of unsymmetrical diarylamines in mild
conditions. However, it has not been tested for sterically
demanding aryl boronic acids and arylnitroso compounds. The
reaction was performed in DMF as previously described.[15] Two
combinations of the reactants were tested: ortho-tert-
butylnitrosobenzene with para-tert-butylphenyl boronic acid and
the opposite combination. The first reaction turned out to be very
efficient leading to unsymmetrical 2,4'-bis-(tert-butylphenyl)
amine with the practical yield (81%), contrary to oxidative
amination (see above). Thus, we can conclude that for synthesis
of bulky ortho-substituted diarylamines reductive amination of
aryl boronic acid is more rational as compared to oxidative
amination. However, the reaction was relatively slow and, to
obtain better yield, prolonged heating was required (16 h at
60°C). The opposite combination of the reactants with the bulky
tert-butyl group in the ortho-position of the phenyl boronic acid
resulted in the same unsymmetrical diarylamime with much
lower yield (56%) using the same reaction protocol.
Significantly lower yield of 2,4'-bis-(tert-butylphenyl) amine
obtained in the latter case indicates that the aryl boronic acid is
more sterically demanding in both oxidative and reductive
amination as compared to the N-containing component. This can
be explained by more bulkiness of the B(OH)2 fragment as
compared to amino- and nitroso groups. According to the DFT
calculations, the conjugation of the boron atom with the phenyl
ring in the ortho-tert-butylphenyl boronic acid is almost
completely disturbed; the torsion O-B-C-C angle is about 66°
due to the repulsion between tert-butyl and B(OH)2 moieties.
The reaction can be expected to proceed via tetracoordinated
intermediate or transition state (see below), both are extremely
unfavorable since the addition of the fourth addend at the boron
atom will additionally increase steric repulsion between the tert-
butyl group and the boron-containing fragment.
HRMS supported that the reaction product was the targeted
amine; the peak of molecular ion and the characteristic isotopic
distribution were observed. However, sterical bulkiness of the
isomer results in some special features of the spectrum as
compared to 2,4'-bis-(tert-butylphenyl) amine (see below for the
details).
The data obtained are summarized in Table 1.
Table 1. The yields of isomeric bis-(tert-butylphenyl)amines in oxidative
(Cu(OAc)2, 1.5 eq. ; Et3N, 2.5 eq.; 25°C, CH2Cl2, O2 ) and reductive amination
(CuCl, 1eq.; DMF, Ar, 60°C)
Oxidative amination
Reductive amination
t-Bu-
C6H4NH2
t-Bu-C6H4-
B(OH)2
The
yield,
%
t-Bu-
C6H4NО
t-Bu-C6H4-
B(OH)2
The
yield,
%
4,4'-
2,4'-
2,4'-
2,2'-
82
81
56
12
para-
ortho-
para-
para-
para-
ortho-
65
22
7
para-
ortho-
para-
ortho-
para-
para-
ortho-
ortho-
Since
the
results
obtained
for
isomeric
bis-(tert-
butylphenyl)amines evidence that the reductive amination is
preferable for synthesis of bulky diarylamines, this approach was
This allows concluding that insertion of bulky substituents in the
ortho-position of aryl boronic acids dramatically decreases their
activity in reductive and, especially, oxidative amination.
To estimate the steric penalty that we had to overcome,
computations on the geometries and electronic structure of the
isomeric bulky amines have been performed. It revealed the
significant energy difference between 4,4'- bis-(tert-butylphenyl)
amine and 2,4'- and 2,2' isomers: the relative free energies of
the isomers are 0, 4.8 and 9.9 kcal mol-1respectively. Significant
used for obtaining
a
series of new trifluoromethylated
diarylamines. The reaction procedure was similar to that
described above. Ortho/para- trifluoromethylated phenyl boronic
acids were synthesized as described in [24]. As the nitroso
component, ortho/para tert-butyl- and trifluoromethyl substituted
nitrosobenzenes were taken. The results obtained are given in
Table 2. All trifluoromethyl-containing diphenylamines were
obtained as fusible white crystals which are soluble in
hydrocarbons (hexane, toluene).
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of the N-H and C-N bonds observed for the 2,4'- isomer might be
attributed to the influence of the neighboring bulky group. It
should be mentioned that for all amines investigated in the
present paper the ν (N-H) values for the ortho-para- substituted
derivatives are higher as compared to di-para- isomers (e.g.,
compare, cm-1: 3400 (for 4-t-Bu, 4’-CF3), 3433 (for 2-t-Bu, 4’-
CF3) and 3458 (for 4-t-Bu, 2’-CF3). The N-H stretching band is
much more intensive for trifluoromethylated derivatives (the
Table 2. Reductive amination of aryl boronic acids with substituted
nitrosobenzenes (CuCl, 1eq.; DMF, Ar, 60°C)
x-C6H4NО
y-C6H4B(OH)2
The yield,%
1
2
3
4
5
4-CF3
4- t-Bu
4- t-Bu
2- CF3
2- t-Bu
2-CF3
4-CF3
2-CF3
4- t-Bu
4-CF3
41
50
traces
70
41
maximal
intensity
was
observed
for
2.4’-
bis(trifluoromethylphenyl) amine) indicating the enhancement of
the N-H bond polarity.
Interestingly, the yields for CF3-substututed diarylamines are
lower than that for the amines containing only t-Bu groups
though the latter are more bulky (see Table 1). As it has been
shown above, ortho-substituted aryl boronic acids are less
reactive. This is the reason for the better yields obtained when
para-substituted boronic acids are used (compare entries 2 and
3; 2 and 3 in Table 2). However, how the dramatic difference in
the yields obtained in the reaction of 2-CF3-C6H4B(OH)2 with
para -t-Bu and CF3-substituted nitrosobenzenes (entries 1 and 3,
Table 2) can be explained? Probably, the electronic properties of
the substituents play a certain role as well. DFT estimation of the
reaction mechanism (see below) clarified the situation.
Reductive amination: DFT mechanistic study
Some mechanistic considerations of the oxidative N-arylation
was described in the earlier report.[18] They were based on by-
products analysis, base and solvent effects as well as on the
empirical study of the influence of substrate electronic properties.
The results obtained shed some light on N-C cross-coupling
reaction but were not supported with theoretical (e.g., DFT)
study. As concerns reductive Cu-mediated N-arylation, only the
general scheme of the reaction steps was proposed [15] but it has
not been supported with any computation data or experimental
observation of the reaction intermediates.
In the present paper, DFT elucidation of the mechanism of
reductive arylation of nitroso arenes with aryl boronic acids was
performed. The relative energies of possible intermediates as
well as activation barriers for the each step were determined.
As follows from the results obtained, the first step (Scheme 3) is
Spectral characterization of amines
1H, 13C and 19F NMR spectral characterization of new amines,
with complete assignment of signals, was performed in CDCl3
solution (see SI). In case of 2,2'-bis-(tert-butylphenyl) amine, the
barrierless and formation of Int-1 is exothermic ( ∆퐸0
=
1
assignment of the signals in the H NMR spectra was based on
−20.3 kcal mol−1; ∆퐺2098 = −9.5 kcal mol−1; ∆퐸0‡ = 0 kcal mol−1):
the double-resonance experiment. For assignment of the
signals in 1H and 13C NMR spectra for the other amines, 2D
NMR techniques (HMBC and HSQC) were applied.
ESI-HRMS data for all amines showed the peak corresponding
to the molecular ion; the isotopic distribution observed in the
spectra coincides to the theoretical values (see SI). Noteworthy,
in case of 2,2'-bis-(tert-butylphenyl)amine, the [M+H]+ peak
appeared in the ESI-MS spectrum only after small excess of
formic acid have been added to the sample. Thus, protonation of
this compound in ESI conditions is impeded. Evidently, the lone
pair of the N atom is shielded by two bulky ortho-tert-butyl
groups. Less basic 2,4’-bis-(trifluoromethylphenyl) amine is also
difficultly protonated while it is prone to loss a proton yielding
anions which can be detected in the negative mode of the
mass-spectrum.
Scheme 3. Activation of the nitroso component with copper(I) (energies were
calculated at PBE/ Λ22 level).
The comparative analysis of the IR data for the isomeric bis-
(tert-butylphenyl) amines was performed. The IR spectrum of
2,4'-bis-(tert-butylphenyl)
absorption at the following frequencies confirming its structure
amine
exhibits
characteristic
It is followed by transmetalation-type phenyl transfer step which
is slightly endothermic (∆퐸0 = +0.7 kcal mol−1) but the Gibbs
free energy ∆퐺2098 = +13.5 kcal mol−1 is significantly more
positive due to entropy decrease (Scheme 4). The reaction
proceeds via the 5-membered cyclic transition state which
corresponds to relatively high barrier of 24.0 kcal mol-1. It should
be mentioned that transmetalation is usually considered as a
(the corresponding values for 4,4'-bis-(tert-butylphenyl) amine
[26]
taken from
are given in parenthesis for comparison), ν, cm-1:
3445 (3374), N-H; 3023, 3047, 3083, 3100 (3055, 3031), C-HAr;
2866, 2901, 2957 (2903, 2863, 2963) ,C(CH3)3; 1571, 1581,
1595, 1612 (1571, 1581, 1595, 1612), C=C Ar; 1514 (1477), C-
NAr-N-Ar. The most informative is a comparison of the vibrations
related to the amino group. Significantly higher frequency values
rate-determining step for reactions of this type [27]
:
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Scheme 4. Transmetalation-type transformation (energies were calculated at
PBE/ Λ22 level).
An alternative mechanism for the transmetalation-type step can
be also suggested (Scheme 4a). It is based on the less
favorable 4-membered transition state with higher activation
barrier (∆퐸0‡ = 29.2 kcal mol−1) and is significantly endothermic
(
∆퐸0 = 23.4 kcal mol−1, ∆퐺2098 = 23.4 kcal mol−1
)
.
This is
attributed to the lower energy of the B-Cl bond as compared to
B-O which is formed in the previous case. Thermodynamically
unfavorable Int-2 intermediate can be easily stabilized by the
elimination of metaboric acid; the latter can be also formed after
ClB(OH)2 decomposition.
Scheme 4a. An alternative route (energies were calculated at PBE/ Λ22 level).
Thermodynamic parameters of these reactions were estimated
applying the Hess principle. To simplify calculations and to
An influence of the donor (t-Bu) and acceptor (CF3) substituents
in the boron or nitroso components on this reaction step was
investigated. Four combinations of the reactants were
considered: the electron-poor nitroso compound (4-CF3-
nitrosobenzene) with electron-rich boronic acid (4-t-Bu-phenyl
boronic acid) and vice versa (4-t-Bu-nitrosobenzene with 4-CF3-
phenyl boronic acid) as well as two combinations with the same
substituents in the reactants. The computational results obtained
revealed almost no difference between these combinations: the
activation energy was about 23 kcal mol-1in all cases (4-t-BuC6H4
minimize inaccuracy, thermodynamic parameters from NIST
[28]
Chemistry Webbook database
for gaseous B(OH)3, H2O and
solid HBO2 were used as well as the calculated parameters for
gaseous H2O, ClB(OH)2, B(OH)3 and HCl. Application of this
procedure gives the following estimation for the Gibbs free
energy values for two transmetalation routes given above
yielding Int-2b and Int-2a: ∆퐺2098 = −9.6 kcal mol−1 and ∆퐺2098
+6 kcal mol−1, respectively.
=
Sterical penalty due to the presence of the ortho-tert-butyl group
either in the nitroso component or in the boronic acid was
examined for the transmetalation step. It appears that the
reaction barrier for the bulky nitroso compound is almost the
same as for the unsubstituted one. Meanwhile, the ortho-t-Bu
group introduction in the aryl boronic acid molecule leads to the
B(OH)2 / 4-CF3C6H4NO: 23.1 kcal mol-1; 4-CF3C6H4B(OH)2
4-t-BuC6H4NO: 22.9 kcal mol-1; 4-t-BuC6H4B(OH)2 4-t-Bu
/
/
C6H4NO: 23.7 kcal mol-1; 4-CF3C6H4B(OH)2 / 4-CF3C6H4NO:
23.2 kcal mol-1) similar to that for the unsubstituted compounds.
This testifies in favor of concerted process with the cyclic
rearrangement of the bonds.
significant increase in the activation energy
( =
∆퐸0‡
32.1 kcal mol-1 vs. 24.0 kcal mol-1 for phenyl boronic acid). This
result is in line with our experimental observations on much
lower yields of the product when hindered boronic acids are
taken for the coupling.
Int-2, Int-2a and Int-2b formed in the transmetalation steps are
prone to reductive elimination yielding C-N-C framework and are
converted to the structurally similar intermediates (Int-3, Int-3a,
Int-3b). Transformations of Int-2 and Int-2b intermediates have
relatively low activation barriers and are thermodynamically
favorable whereas similar process for Int-2a requires high
activation energy and has smaller thermodynamic driving force
(Scheme 5):
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Table 3. Electronic effects of the para-substituents on the activation barrier
for the reductive elimination step
R in ArB(OH)2
R in ArNO
∆E0‡ (Int-2  Int-
∆E0‡ (Int-2b
Int-3b),

3), kcal mol-1
kcal mol-1
H
H
3.5
2.7
4.1
2.8
3.9
6.0
5.1
7.5
6.2
6.3
t-Bu
CF3
CF3
t-Bu
CF3
t-Bu
CF3
t-Bu
Scheme 5. Three possibilities for reductive elimination step and corresponding
thermodynamic and kinetic parameters (PBE/ Λ22).
As follows from the schemes given above, the Ar-N-Ar' moiety
formation proceeds in the transmetalation and reductive
elimination steps; in the consequent intermediates (Scheme 6
below) it is not altered. Hence, the electronic effects of the
substituents more likely appear only in these two reaction steps.
As it has been shown above, the transmetalation-type step is
“electronically insensitive”. Thus, if the reaction is influenced by
the electronic nature of the substituents in the reactants, it is the
reductive elimination step which should be sensitive to the
electronic effects. The electronic influence of the substituents in
the para- position of both reactants on the activation energy of
the reductive elimination step was studied. The calculation
revealed that the electron donating t-Bu group in the aryl boronic
acid and the electron withdrawing CF3 group in the nitroso
compound decrease the activation barriers (as compared to the
unsubstituted reactants) whereas the opposite combination
leads to higher barriers (see Table 3). As a result, the activation
barrier for the latter case is 1.5 times higher that in the former
combination. These computational results are in line with the
experimental data.
Scheme 6. Oxidative addition of Cu(I) to the N-O bond and corresponding
thermodynamic and kinetic parameters (PBE/ Λ22).
The higher is the activation barrier of this step, the larger is the
lifetime of the Ar-Cu intermediates (Int-2 and Int-2b). Since these
species are expected to be rather reactive, high activation
energy for the reductive elimination should result in an
increasing impact of side reactions (e.g., Cu-C bond homolysis
or protonation). These results are in accordance with our
experimental findings. Thus, the yield of the unsymmetric tert-
butylphenyl-trifluoromethylphenyl amine is significantly higher if
the donating group is in the aryl boronic acid and the electron-
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withdrawing group in inserted in the nitroso component (70%
and 41%, respectively; entries 4 and 5 in Table 2). The
unfavorable electronic combination of the reactants coupled
with sterical demands of the ortho-substituted boronic acid leads
to only traces of the targeted amine (entry 3, Table 2).
The final step can be considered as oxidative addition of Cu(I) to
the N-O bond. This step is thermodynamically favorable for both
intermediates (Int-3 and Int-3b) but in the latter case preliminary
isomerization step (Int-3 into Int-3b) is required (Scheme 6).
The DFT data described above are summarized in the
Scheme 7 given below:
Scheme 8. Overall reaction scheme
As it is seen from the reaction scheme 8, copper oxidation state
is changed as follows: Cu(I)→Cu(III)→Cu(I)→Cu(III)→Cu(II).
This makes the reaction very “visual” since copper complexes
have different colors depending on the oxidation state. Even
starting tert-butylnitrosobenzenes have different colors (navy
blue for 2-tert-butyl substituted isomer and emerald green for the
para-isomer); the difference is enhanced after CuCl addition to
the nitroso compound yielding violet (in case of 4-tert-
butylnitrosobenzene)
or
light
green
(for
2-tert-
butylnitrosobenzene) solution. The subsequent heating with
boronic acid results in a gradual change of the solution color to
yellow (corresponding, probably, to copper (I) intermediates Int-
3b and Int-3b') and then to dark brown (inherent to the final
copper(III) complex). UV-Vis investigation of the reaction mixture
was performed. The absorption at 464 nm was detected; the
similar absorbance (444 nm) was assigned to Cu(III)2O2 dimeric
[29]
complex
which resembles the dimeric structure given in
Scheme 8. The small difference in the wavelength value can be
attributed to the difference in the ligand structure. DFT
calculations revealed that dimerization of Int-4b to binuclear
copper species is favorable (∆퐺2098 = −19 kcal mol−1) suggesting
this complex likely to be the reaction product. The following
treatment of the final complex with aqueous ammonia yields the
targeted diarylamine and blue solution of the copper(II)
tetramine complex (via ligand exchange and intramolecular
oxidation of the coordinated ammonia).
Scheme 7. The relative energy (∆퐸0) and the Gibbs energy ∆퐺2098 change
during the reaction path (PBE/ Λ22)
It is worth mentioning that a certain amount of 4,4'-di-tert-
butylbiphenyl was isolated as a by- product in the reaction of 2-
tert-butylnitrosobenzene with 4-tert-butylphenylboronic acid.
Similarly, a certain amount of 4,4’-di-trifluoromethylbiphenyl was
obtained in the reaction of 2-tert-butylnitrosobenzene with 4-
trifluoromethylphenyl boronic acid. These experimental facts
confirm the Cu(III)-intermediate (Int-2, Int-2b) formation. It is
known that ArCu(III) complexes are prone to C-Cu bond
homolysis yielding aryl radicals which are easily dimerized. The
impact of this side process is not too significant since the
Thus, according to the DFT data, the reaction path consists of
four main steps: activation of the nitrosoarene with Cu(I);
transmetalation yielding Cu(II) complex with the transfer of the
B(OH)2 group to the O atom of the nitroso fragment (more likely,
followed by the elimination of HBO2); reductive elimination which
restores Cu(I) species; oxidative addition of Cu(I) to N-O bond
which produces Cu(III) complex again. The latter can be
decomposed with NH3 yielding the targeted diarylamine. The
sequence of steps is summarized in Scheme 8:
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reductive elimination yielding C-N coupling has low activation
barrier (3.5 and 6.0 kcal mol-1for Int-2 and Int-2b respectively)
and is thermodynamically favorable. However, electronically or
sterically unfavorable combination of the substituents in the
methods. These bulky ortho-substituted diarylamines are of
interest as the precursors for corresponding stable nitroxides
which are perspective as structurally tunable redox-active
materials.
reactants (see above) facilitates side processes.
intermediates have been also postulated previously.[15]
Cu(III)
We hope that the guidelines given above will be helpful for
choosing an optimal synthetic procedure leading to
unsymmetrical bulky diarylamines.
Conclusions
Experimental Section
It was demonstrated that oxidative and reductive Cu-assisted
amination of aryl boronic acids with arylamines or nitroso
benzenes, respectively, which does not require the use of
precious metals, expensive ligands or reactive organometallic
reagents, constitutes a practical method for synthesis of new
series of bulky diarylamines with ortho/para location of tert-butyl
and trifluoromethyl substituents in the aromatic rings.
Comparative investigation of the oxidative and reductive
approaches indicated that, to obtain sterically demanding
diarylamines, reductive amination is preferable. The steric
bulkiness of the new ortho-substituted bis-(tert-butylphenyl)
amines impeding the synthetic procedure was estimated;
relative free energies of the 4,4'- and 2,4'- and 2,2' isomers are 0,
5.3 and 11.0 kcal mol-1respectively. Significant decrease in the
thermodynamic stability in the series indicates increasing
General information
Mass spectra were measured with high-resolution time-of-flight
instrument using electrospray ionization (ESI-MS)20. Measurements were
performed in positive ion mode, interface capillary voltage at 4.5 kV,
effective scan range at m/z 100 – 1200, external calibration (0.016 М
sodium formate in MeCN-water 1 : 1 mixture or ESI-L Low Concentration
Tuning Mix, Agilent Technologies), direct syringe injection at flow rate of
3 μL/min, nitrogen as dry gas at 4 L/min, interface temperature at 180 °C.
1H (400.0) MHz) and 13C (100.6 MHz) NMR spectra were recorded in
CDCl3. Chemical shifts were referenced to a residual non-deuterated
solvent. 19F chemical shifts are referenced to CFCl3.
Computational details
DFT calculations for the reductive amination mechanism were performed
in PRIRODA quantum chemistry program.[31,32] The gradient-corrected
exchange-correlation Perdew, Burke, and Ernzerhof (PBE) functional
and double-zeta quality basis set Λ01 were used for preliminary search
of the intermediates and transition states. Triple-zeta quality basis set
Λ22 along with PBE functional was used for structure optimizations and
thermal corrections calculations.[34] The 10−6 threshold on the molecular
gradient at the geometry optimization procedure was employed.
repulsive interactions within the molecules. For previously
[30]
known
bis-(iso-propylphenyl) amines free energy difference
[33]
for 4,4' and 2,2' isomers is substantially lower (only
3.9 kcal mol-1).
To get a better yield of the unsymmetrical diarylamine, a bulky
substituent should be located in the N-containing component
(the nitroso compound) rather than in the corresponding aryl
boronic acid. DFT estimation of the mechanism of Cu(I)-assisted
reductive amination of boronic acids with aryl nitroso compounds
was performed, possible active species were identified and the
detailed potential energy profile for feasible reaction paths was
calculated.
DFT estimation of the sterical penalty revealed that the reaction
barrier for the transmetalation step for the hindered nitroso
compound is almost the same as for the unsubstituted one
whereas the ortho-t-Bu group introduction in the boronic acid
molecule leads to the significant increase in the activation
energy ( ∆퐸0‡ = 32.1 kcal mol-1 vs. 24.0 kcal mol-1 for phenyl
boronic acid).
DFT estimating showed that electronic effects of the substituents
are the most significant in the reductive elimination step. The
calculation revealed that the optimal combination for synthesis of
unsymmetric diarylamines is the insertion of the electron
donating substituent into the aryl boronic acid and the electron
withdrawing group in the nitroso compound. This decreases the
activation barriers (as compared to the unsubstituted reactants)
and provides better yields whereas the opposite combination
leads to higher barriers and lower yields of diarylamines.
Oxidative
amination
(Chan-Lam
coupling).
4,4'-Bis-(tert-
butylphenyl)amine: To a stirred solution of 880 mg (5.9 mmol) of para-
tert-butylaniline, 1.58 g (8.9 mmol) of para-tert-butylphenyl boronic acid
and 2.5 ml (18 mmol) of triethylamine in 20 ml of CH2Cl2, 2.15 g
(11.8 mmol) of anhydrous copper(II) acetate was added. Slurry was
stirred at ambient conditions for 48 hours and filtered; the filtrate was
evaporated and the residue was purified by column chromatography on
silicagel (toluene/hexane 1:9). 1.08 g (65%) of 4,4'-bis(tert-
butylphenyl)amine was obtained as a white crystals.
NMR 1H (400 MHz, CDCl3) δ 7.32 – 7.27 (m, 4H), 7.05 – 6.99 (m, 4H),
5.59 (s, 1H), 1.32 (s, 18H);
IR (ATR, ZnSe), ν, cm-1: 3375, 3051, 3032, 2954, 2900, 2862, 1606,
1514, 1475, 1462, 1390, 1360, 1346, 1311, 1265, 1242, 1188, 1163,
1111, 1011, 822, 548.
The unsymmetrical 2,4'-bis(tert-butylphenyl)amine was obtained as a
white crystals in 22% yield; mp 86−88°C by the same protocol;
ESI-HRMS: m/z(M+H+) 282.2217, calc. for C20H28N 282.2216;
IR (ATR, ZnSe), ν, cm-1: 3445, N-H; 3023, 3047, 3083, 3100, C-HAr;
2866, 2901, 2957,C(CH3)3; 1571, 1581, 1595, 1612, C=C Ar; 1514, C-NAr-
N-Ar.;
NMR 1H (400 MHz, CDCl3) δ 7.40 (dd, 3J = 7.9, 4J = 1.5 Hz, 1Ho-Ph), 7.28
(dd, 3J = 7.9, 4J = 1.5 Hz, 1Ho-Ph), 7.25 – 7.21 (m, 2H Hp-Ph), 7.14 (ddd, 3J
= 7.9, 7.3, 4J = 1.6 Hz, 1Ho-Ph), 7.01 (ddd, 3J = 7.9, 7.3, J = 1.5 Hz, 1Ho-
4
Using the aforementioned guidelines,
a
series of new
Ph), 6.83 – 6.79 (m, 2Hp-Ph), 5.37 (s, 1H 7-HN), 1.45 (s, 9H 15-HtBu), 1.31
(s, 9H 1-HtBu);
diarylamines containing bulky tert-butyl- and trifluoromethyl
substituents in the different positions of the aromatic rings was
obtained and fully characterized with HRMS, NMR and IR
13C NMR (101 MHz, CDCl3) δ 142.99 (Сp-Ph), 142.59 (Сo-Ph), 142.09 (Сo-
Ph), 142.05 (Сp-Ph), 127.04 (СHo-Ph), 126.93 (СHo-Ph), 126.18 (СHp-Ph),
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124.47 (СHo-Ph), 123.07 (СHo-Ph), 116.65 (СHp-Ph), 34.90 (CtBu), 34.19
(CtBu), 31.68 (CMetBu), 30.70 (CMetBu).
NMR 1H (, ppm): 7.48 (dd, 3J = 7.6, 4J = 1.8 Hz, 1Нo- vs. tBu, m- vs. NH), 7.44-
7.39 (m, 2Ho- vs. CF3), 7.27 (dd, 3J = 7.7, 4J = 2.0 Hz, 1Hm- vs. tBu, o- vs. NH),
7.23 (td, 3J = 6.9, 4J = 1.7 Hz, 1Hp- vs. tBu, m- vs. NH), 7.19 (ddd, 3J = 7.6, 3J =
6.9, 4J = 2.1 Hz, 1Hm- vs. tBu, p- vs. NH), 6.77-6.72 (m, 2Hm- vs. CF3), 5.79 (s,
1НNН), 1.42 (s, 9Нt-Bu).
Reductive amination (the general procedure):
NMR 13C (, ppm): 149.46 (Cp- vs. CF3), 145.68 (Сipso(tBu)), 139.54 (Сipso(NH),
o- vs. tBu), 128.33 (Сm- vs. tBu, o- vs. NH), 127.50 (Co- vs. tBu, m- vs. NH), 127.34 (Сp- vs.
tBu, m- vs. NH), 126.80 (q, 3JCF = 3.8 Hz, C o- vs. CF3), 125.92 (Cm- vs. tBu, p- vs. NH),
Synthesis was performed in argon atmosphere using standard Schlenk
technique. A solution of of nitrosoarene (0.80 mmol) in dry deaerated
DMF (20 ml) was added to an argon filled two-neck flask containing
79 mg (0.80 mmol) of CuCl fitted with reflux condenser and pressure-
equalizing dropping funnel. The mixture was stirred at 60 °C (water bath)
for 30 min. Then the solution of aryl boronic acid (0.87 mmol) in dry
dearated DMF (7 ml) was added and the mixture was stirred for 16 hours
at 60°C. The color of the solution changed from light green to black via
light yellow, green and greenish blue. Afterwards the mixture was diluted
with water (100 ml) and saturated aqueous ammonia (50 ml) and
extracted with ether. Ether fractions were dried with anhydrous sodium
sulfate, evaporated and purified by column chromatography on silicagel.
1
2
125.00 (q, JCF = 270 Hz, CF3), 120.24 (q, JCF = 32.5 Hz, Cipso(CF3)),
114.12 (Cm- vs. CF3), 35.15 (Cquat. tBu), 30.81 (Ct-Bu).
NMR 19F (, ppm): −61.2 (CF3)
ESI-HRMS: 294.1465 (M+H+, 294.1464 calc. for C17H19F3N)
IR (ATR, ZnSe), ν, cm-1: 3433, 3062, 2966, 2877, 1616, 1597, 1572,
1523, 1498, 1481, 1471, 1472, 1442, 1398, 1367, 1325, 1290, 1261,
1240, 1188, 1157, 1128, 1101, 1065, 1007, 945, 877, 829, 764, 742, 729,
694, 652, 631, 607, 588
2,4'-bis(trifluromethyl)diphenylamine was obtained in 41% yield by the
standard
protocol
from
2-tert-butylnitrosobenzene
and
4-
(trifluromethyl)phenyl boronic acid. Hexane was used as an eluent for
purification of the title compound using column chromatography.
2,4'-Bis(tert-butylphenyl)amine was obtained in 81% yield by the
standard protocol from 2-tert-butylnitrosobenzene and 4-(tert-
butyl)phenyl boronic acid. The toluene/hexane mixture 1:20 was used as
an eluent for purification of the title compound using column
chromatography.
3
NMR 1H (, ppm): 7.64 (d, J = 8.0 Hz, 1H), 7.54 – 7.49 (m, 2H), 7.48 –
7.44 (m, 2H), 7.14 – 7.06 (m, 3H), 6.15 (s, 1H).
3
NMR 13C (, ppm): 145.81, 140.09, 132.97, 127.27 (q, JCF = 5.3 Hz),
3
1
1
126.94 (q, JCF = 3.8 Hz), 124.54 (q, JCF = 271.1 Hz), 124.47 (q, JCF
=
=
4-(trifluromethyl)-4'-tert-butyldiphenylamine was obtained in 50% yield by
the standard protocol from 4-tert-butylnitrosobenzene and 4-
(trifluoromethyl)phenyl boronic acid. The toluene/hexane mixture (1:4)
was used as an eluent for purification of the title compound using column
chromatography.
2
2
273.5 Hz), 123.33 (q, JCF = 33.0 Hz), 122.41, 121.02, 120.54 (q, JCF
29.5 Hz), 117.28
NMR 19F (, ppm): −61.60, −61.75
ESI-HRMS: (negative mode) 304.0566 (M-H+, 304.0566 calc. for
C14H8F6N)
NMR 1H (, ppm): 7.48 – 7.44 (m, 2Ho- vs. CF3), 7.03 – 6.99 (m, 2Hm- vs. CF3),
7.39 – 7.35 (m, 2Ho- vs. tBu), 7.13 – 7.09 (m, 2H m- vs. tBu), 5.89 (s, 1HNH),
1.35 (s, 9HtBu).
IR (ATR, ZnSe), ν, cm-1: 3452, 2924, 2854, 1608, 1597, 1585, 1527,
1511, 1475, 1462, 1408, 1319, 1288, 1250, 1232, 1186, 1163, 1109,
1093, 1061, 1034, 1009, 953, 881, 841, 762, 737, 665, 652, 596
2,2'-Bis(tert-butylphenyl)amine was obtained in 12% yield by the same
protocol except reaction mixture was heated at higher temperature
(150 °C, oil bath). Amine was purified by column chromatography on
silicagel (with petroleum ether as an eluent).
NMR 13C (, ppm): 147.42 (Cp- vs. CF3), 146.36 (Cipso(tBu)), 138.46 (Cp- vs. tBu),
3
1
126.78 (q, JCF = 3.8 Hz, Co-
CF3), 124.93 (q, JCF = 289.8 Hz, CF3),
vs.
121.25 (q, 2JCF = 32.8 Hz, Cipso(CF3)), 126.49 (Co- vs. tBu), 120.44 (Cm- vs. tBu),
114.93 (Co- vs. CF3), 34.48 (Cquat. tBu), 31.55 (CtBu).
NMR 19F (, ppm): −61.4 (CF3)
ESI-HRMS: m/z(M+H+) 282.2211, calc. for C20H28N 282.2216;
ESI-HRMS: 294.1466 (M+H+, 294.1464 calculated for C17H19F3N)
IR (ATR, ZnSe), ν, cm-1: 3400, 2964, 2904, 2870, 1608, 1527, 1518,
1396, 1327, 1186, 1161, 1113, 1066, 1011, 825.
3
NMR 1H (, ppm): 7.39 ppm (dd, J=7.88 Hz, 4J=1.55 Hz, 1Hm- vs. NH, o- vs.
tBu), 7.08 pp, (ddd, 3J=7.29 Hz, 7.95 Hz, 4J=1.55 Hz, 1Hm- vs. NH, p- vs. tBu),
3
6.93 ppm, (ppm, J = 7.29 Hz, 7.88 Hz, 4J = 1.50 Hz, 1Hp- vs. NH, m- vs. tBu),
2-(trifluromethyl)-4'-tert-butyldiphenylamine was obtained in 70% yield by
the standard protocol from 2-(trifluoromethyl)nitrosobenzene and 4-tert-
butylphenyl boronic acid. The toluene/hexane mixture (1:8) was used as
an eluent for purification of the title compound using column
chromatography.
6.91 ppm (dd, 1.39 Hz, 7.95 Hz, 1Ho- vs. NH, m- vs. tBu), 5.42 ppm (c, 1HNH),
1.49 ppm (с, 9HtBu).
NMR 13C (, ppm): 143.99 (Cipso(NH)), 140.52 (Сipso(tBu)), 127.07 (Cm- vs. NH,
p- vs. tBu), 126.79 (Cm- vs. NH, o- vs. tBu), 123.20 (Co- vs. NH, m- vs. tBu), 121.67 (Cp- vs.
NH, m- vs. tBu), 34.67 (Cq, tBu), 29.86 (CMe).
NMR 1H (, ppm): 7.55 (d, 3J = 7.8 Hz, 1Ho- vs. CF3, m- vs. NH), 7.38 – 7.27 (m,
4H (Hm- vs. CF3, o- vs. NH, Hp- vs. CF3, m- vs. NH, Ho- vs. tBu)), 7.11 – 7.06 (m, 2Hm- vs.
tBu), 6.90 (t, 3J = 7.4 Hz, 1Hm- vs. CF3, p- vs. NH), 6.04 (s, 1HNH), 1.34 (s, 9HtBu).
3
NMR 13C (, ppm): 146.30 (Cipso(tBu)), 142.87 (q, JCF = 1.7 Hz, Co- vs. CF3,
Acknowledgements
5
ipso(NH)), 138.82 (Cipso(NH), p- vs. tBu), 132.76 (q, JCF = 1.1 Hz, Cp- vs. CF3, m- vs.
NH), 126.96 (q, 3JCF = 5.4 Hz, Co- vs. CF3, m- vs. NH), 126.47 (Co- vs. tBu), 125.00
This work was supported by Russian Science Foundation
(Project number (16-13-10282). NMR parts of this work were
supported by Lomonosov Moscow State University "Program of
Development". The authors would like to acknowledge Thermo
Fisher Scientific Inc., MS Analytica (Moscow, Russia), and
personally to Prof. Alexander Makarov for providing mass
spectrometry equipment for this work.
1
(q, JCF = 272.4 Hz, CF3), 120.91 (Cm- vs. tBu), 119.15 (Cm- vs. CF3, p- vs. NH),
2
117.08 (Cm- vs. CF3, o- vs. NH), 116.71 (q, JCF = 29.3 Hz, Cipso(CF3)), 34.47
(Cquat. tBu), 31.58 (CtBu).
NMR 19F (, ppm): −61.9 (CF3)
ESI-HRMS: 294.1465 (M+H+, 294.1464 calc. for C17H19F3N)
IR (ATR, ZnSe), ν, cm-1: 3458, 2966, 2937, 2914, 2868, 1606, 1593,
1520, 1469, 1403, 1363,1327, 1298, 1284, 1244, 1230, 1167, 1107,
1059, 1034, 951, 889, 833, 808, 764, 742, 733, 656.
2-tert-butyl-4'-(trifluromethyl)diphenylamine was obtained in 41% yield by
the standard protocol from 2-tert-butylnitrosobenzene and 4-
(trifluromethyl)phenyl boronic acid. The toluene/hexane mixture (1:8) was
used as an eluent for purification of the title compound using column
chromatography.
Keywords: amination, bulky amines, diarylamine, reaction
mechanism, DFT
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FULL PAPER
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10.1002/chem.201702270
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Guidelines helpful for choosing the
optimal synthetic procedure leading to
bulky unsymmetrical diarylamines
Oleg A. Levitskiy, Yuri K. Grishin,
Vyacheslav V. Sentyurin, and Tatiana V.
Magdesieva
were
elaborated
based
on
Page No. – Page No.
experimental and computation data.
DFT estimation of the mechanism of
Cu(I)-assisted reductive amination of
Cu-assisted amination of boronic
acids for
synthesis of
bulky
boronic
acids
with
arylnitroso
diarylamines: experimental and DFT
study
compounds was performed, the
sterical penalty due to the bulky
groups in the reactants was
estimated.
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