Amination of Aryl Boronic Acids with Alkylnitrites: A Convenient Complement to Cu-Promoted Reductive Amination

Article abstract of DOI:10.1021/acs.orglett.9b03961

Copper-catalyzed amination of aryl boronic acids with alkylnitrites leading to symmetrical diarylamines with a practical 50-80% yield was elaborated. Two C(sp²)-N bonds are formed in the one-pot process under mild conditions. This new approach to diarylamines is a complement to the Cu-assisted reductive amination of aryl boronic acids avoiding preliminary synthesis of nitrosoarenes. The possible reaction scheme based on quantum chemical calculations was suggested, clarifying key intermediates.

Full text of DOI:10.1021/acs.orglett.9b03961

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Amination of Aryl Boronic Acids with Alkylnitrites: A Convenient
Complement to Cu-Promoted Reductive Amination
Oleg A. Levitskiy and Tatiana V. Magdesieva*
Lomonosov Moscow State University, Leninskie Gory 1/3, Moscow 119991, Russia
S
* Supporting Information
ABSTRACT: Copper-catalyzed amination of aryl boronic acids
with alkylnitrites leading to symmetrical diarylamines with a
practical 50−80% yield was elaborated. Two C(sp2)−N bonds are
formed in the one-pot process under mild conditions. This new
approach to diarylamines is a complement to the Cu-assisted
reductive amination of aryl boronic acids avoiding preliminary
synthesis of nitrosoarenes. The possible reaction scheme based on
quantum chemical calculations was suggested, clarifying key
intermediates.
mong metal-mediated C(sp2)−N bond formation pro-
Scheme 1
Acesses, copper-promoted N-arylation with aryl boronic
acids is one of the most practical.1 Boronic derivatives are
sufficiently reactive; nevertheless, they can tolerate a wide
range of functional groups. Mild and ecofriendly reaction
conditions and high reaction yield make the N-arylation with
aryl boronic acids a strongly required approach to aryl amines.
Aromatic amines can be found in 37% of drug candidates,2
they are applied in material science, biology, etc.,3 making their
availability a topical problem.
Cu-promoted oxidative amination of aryl boronic acids with
arylamines (the Chan−Lam coupling) was suggested in the
pioneering works4−6. Later, a wide range of the N−H-
containing substrates (amines,7,8 imides,9 ureas,10 carba-
mates,10 and sulfonamides4) was involved in stoichiometric
Cu-mediated C−N bond formation. Further improvements
obtained by a correct choice of a copper source, base, or
additives allowed broadening the scope of substrates:11−14 it
was shown that even simple and abundant inorganic reactants
such as aqueous ammonia,15 hydroxylamine hydrochloride,16
and sodium azide17 can be used as a nitrogen source for the
C−N bond formation.
Oxidative amination of aryl boronic acids was later
complemented with copper-promoted reductive amination in
Figure 1. Ar2NH yield in the presence of additives (iAmONO/4-
which arylnitroso compounds were applied instead of aryl-
amines.18 Both oxidative and reductive approaches led to
diarylamines, though the latter is preferable for synthesis of
bulky amines.19 Later, complementary protocols for Cu-
catalyzed N-imination20 and N-amidation21 of arylboronic
acids using O-acyl ketoximes and O-acetyl hydroxamic acids as
reactants have been developed. These examples, along with the
aforementioned Cu-mediated amination of aryl boronic acids
using nitroso arenes, indicate a possibility for the N−O bond
cleavage in Cu-catalyzed amination of arylboronic acids under
tBuC6H4B(OH)2 (1:2), DMF, 70 °C, 3 h).
nonbasic and nonoxidizing conditions (Scheme 1) often
required in multistep syntheses. This testifies that application
of aryl boronic acids for the C(aryl)−-N formation has not yet
exhausted its full synthetic potential. The search for new
Received: November 6, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03961
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reactants active in this process is important for understanding
the reaction mechanism (which is still underinvestigated) as
well as for providing new synthetic strategies.
Recently, three-component coupling of arylboronic acid,
tert-butyl nitrite, and alkyl bromide leading to the C(sp3)−N
bond construction has been reported;22 the N−O bond
t
cleavage in BuONO was suggested as one of the key steps.
The yields of alkylanilines are high, but the method suffers
from the undesired formation of the nitroarene. To overcome
the problem, treatment with SmI2 and an excess of ArB(OH)2
is required.
Herein, we report an extensive study of alkylnitrites as
aminating agents for the C(sp2)−N bond formation. AlkONO
contain two oxygen atoms to be used for coordination to the
oxophilic boron atom. Consequently, Cu-assisted oxidative
addition to the N−O bond followed by transmetalation and
reductive elimination can provide two Ar−N bonds leading to
one-pot formation of diarylamines. This approach has not been
probed yet.
Figure 2. GC monitoring of Ar2NH during the reaction course
(iAmONO, 4-tBuC6H4B(OH)2 (1:2), DMF, 70 °C, 3 h).
To test the idea, isoamylnitrite and 4-tBuC6H4B(OH)2 were
chosen. Initially, the process was carried out using reaction
conditions previously described for the C−N coupling of aryl
boronic acids with nitroso compounds:18 isoamyl nitrite, a
stoichiometric amount of CuCl, and 2 molar equiv of
4-tBuC6H4B(OH)2 were stirred in DMF at 60 °C for 3 h
under argon. Indeed, the targeted bis(tert-butylphenyl)amine
was isolated from the reaction mixture in reasonable 40% yield
indicating applicability of alkylnitrites as aminating agents.
Several parameters were varied (the type of alkylnitrite and
copper salt, additives, the reaction time and temperature) to
achieve practical yield of diarylamines. t-BuONO gave a lower
yield of the targeted amine (26%); thus, isoamylnitrite was
used in all subsequent experiments. Stirring the reaction
mixture without CuCl gave no targeted amine. Among
copper(I) halides, CuI gave better results (Figure 1). However,
a,b
Scheme 2. Cu-Promoted Amination of ArB(OH)2
−
application of CuI2 gave no diarylamine. If a Lewis acid
(ZnCl2) is taken instead of CuI, the reaction does not occur.
Further investigations showed that addition of 1 equiv of
triethylamine offered a better yield of the targeted diarylamine
(71%). To understand the role of Et3N (a base, a ligand or
something else), various amines and bases were tested (Figure
1). Application of the bidentate TMEDA ligand decreased the
yield of the amine (53%), as well as the stronger bases, DBU
(22%) and MeONa (36%). Thus, the role of the amine is
adjusting the electronic properties of the copper center to suite
the catalytic cycle requirements.
The reaction is sensitive to the temperature regime: 60−70
°C provides better yields of Ar2NH; a slight decrease in
temperature (50 °C) as well as an increase (80 °C) diminishes
the yield to 40% and 60%, respectively. Such nonlinear
dependence is typical for competitive processes with different
temperature coefficients. The kinetic measurements showed
that ca. 70% yield is achieved in less than 1 h; further stirring of
the reaction mixture gives no increase (Figure 2).
Keeping in mind that both Cu(I) and Cu(II) salts are
efficient in N-imination of boronic acids with O-acyl ketoximes
(also including the N−O bond cleavage20), we tried to replace
Cu(I) with Cu(II) salt. Application of Cu(BF4)2 gave a lower
but still sufficient yield of the diarylamine (60% vs 70% for
CuI). However, the process is slower and exhibits an induction
period (Figure 2). Thus, the requisite Cu(I) catalyst should be
either added to the reaction system or generated in situ
through reduction of a Cu(II) precatalyst.
a
Reaction procedure: a degassed solution of ArB(OH)2 (0.4 mmol)
and i-AmONO (0.2 mmol) in 7.5 mL of anhydrous DMF (EtOH)
was added to a mixture of CuI (0.2 or 0.02 mmol) and Et3N (0.2 or
0.04 mmol) in 7.5 mL of degassed DMF (EtOH) preheated to 70 °C
using oil bath. The solution was stirred under argon at 70 °C for 3 h
and poured into 50 mL of 5% aqueous ammonia. Ar2NH was
extracted with ether and purified by column chromatography on silica
b
gel (eluent: hexane/EtOAc). The yields are given both for the
stoichiometric (blue) and catalytic (red) protocols.
B
DOI: 10.1021/acs.orglett.9b03961
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Scheme 3. General Reaction Scheme (Energies are in kcal/mol)
Figure 3. Voltammetric (semidifferential) monitoring of the reaction
course.
Figure 4. GC monitoring of t‑BuPhH in the reaction probes.
Scheme 4. Ar2NH Recycling
The yields of diarylamines which are ca.70% indicate that
the reaction is hampered by a significant impact of byproducts
formation. According to the GCMS analysis, these are phenol
(2−10%) and ArH (4−10%), typically for Cu-mediated
amination of arylboronic acids.11,23
The most informative was detection of Ar2N−NO (the
product of Ar2NH nitrosation) in the reaction mixture; this
C
DOI: 10.1021/acs.orglett.9b03961
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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Addition of ArB(OH)2 to the solution of Int-2 immediately
changes the color to deep green, yielding Int-3 in which the
oxophilic boron atom is coordinated to the alkoxy group. The
following thermodynamically favorable transmetalation step
gives Int-4. Thus, alkyl nitrites as coupling reactants provide
the “N-containing moiety” for the C−N bond formation and
the internal “oxygenate” partner (OR) to pair with the B(OH)2
fragment. A four-membered oxo-metal transmetalation path-
way (see the SI) is consistent with the previously reported
organoboron transmetalation in metal-catalyzed cou-
plings.23,26,27
Scheme 5. Catalytic Cycle
Further transformation of Cu(III) Int-4 is reductive
elimination creating the C−N bond. Thus formed Int-5 reacts
with the second equivalent of ArB(OH)2. Thermodynamics
and activation barriers for the rest steps have been already
estimated in our previous paper19 describing the Cu-mediated
reductive amination of ArB(OH)2 with nitrosoarenes.
Voltammetric monitoring of the reaction course (Figure 3)
visualizes fast transformations of the copper complexes under
consecutive addition of the reactants: addition of i-AmONO to
the solution of CuCl + Et3N shifts the CV response for 135
mV into anodic area due to Int-2 formation; further addition of
ArB(OH)2 to the greenish blue solution immediately changes
the color and the CV response: a new peak at −1.03 V (more
likely attributed to Int-5) appears and gradually increases while
the peaks corresponding to Int-1 and Int-2 are gradually
decreased.
As an additional support for the suggested reaction scheme,
GC monitoring of t‑BuPhH amount formed after workup of the
reaction probes with NH3·H2O was performed (Figure 4).
t‑BuPhH is more likely formed in hydrolytic destruction of
arylated copper intermediates which are formed and consumed
with different rates. The fast decrease in the t‑BuPhH amount at
the beginning of the process indicates fast consumption of the
reactive arylated intermediate. Unfortunately, gradual accumu-
lation of a certain amount of ArH byproduct which is typical
for Cu-mediated arylation with aryl boronic acids23 during the
reaction course prevents monitoring of the other Cu−Ar
intermediates.
Int-2 is worth special discussing. This four-coordinated
halonitrosyl complex exhibits nitrosative reactivity28 toward
Ar2NH and is responsible for Ar2N−NO byproduct
formation. It is easily formed at room temperature and is
accumulated in solution. The more is the concentration of the
targeted amine, the more is the impact of its side nitrosation.
However, the subsequent Cu-mediated reaction of Ar2N−N
O with aryl boronic acid (Figure 2) is sufficiently fast to restore
the targeted diarylamine (Scheme 4).
To render the reaction catalytic in copper, Cu(III)
intermediate should be converted back to Cu(I), to finish
one catalytic cycle and to start a new one. Thus, a reductant is
necessary. Several reductants were tested without any success:
ascorbic acid (as it has been used in the early Liebeskind
publication18); Cu(0) dust; electric current (for the reaction
performed in the electrochemical cell). Finally, a simple and
elegant approach was found: the solvent can be used as a
reductant. If the reaction is performed in EtOH, less than 10
mol % of CuI give 50−80% yield of the diaryl amine. The
catalytic scheme is given in Scheme 5. All intermediates are the
same as for the noncatalytic path, except the final step which
restores Cu(I). Efficiency of the catalytic protocol was tested
on various arylboronic acids (Scheme 2, the isolated yields are
given).
sheds light on the reaction mechanism (see below). The
control experiments showed that the reaction of Ph2NH with i-
AmONO in DMF in argon at 70 °C slowly gives Ph2N−NO
and is fastened with CuI (Figure 2), indicating that Cu-
containing intermediate rather than i-AmONO is the nitro-
sating agent. This explains the decrease in the yield of
diarylamines if an excess of i-AmONO is used. However, the
addition of ArB(OH)2 (2 equiv) to Ph2N−NO in DMF in
the presence of CuI restores diarylamines (Ph2NH and
Ar2NH). That means that Ar2N−NO can also aminate
arylboronic acid but less efficiently than i-AmONO (Figure 2).
Thus, an interplay of three aforementioned processes (targeted
amination of ArB(OH)2 with i-AmONO; nitrosation of the
Ar2NH with Cu intermediate and the reaction of Ar2N−NO
with ArB(OH)2 yielding Ar2NH) determines the reaction
outcome.
Using the optimized conditions (stoichiometric CuI, Et3N, 3
h, 70 °C), the scope of new methodology was examined;
various arylboronic acids were tested. Both electron-rich and
electron-deficient aryl boronic acids participate in the reaction,
though the former gave much better yields (Scheme 2). The
observed reactivity is in line with the previously reported data
on Cu-mediated C−N bond formation using ArB(OH)2.19
The approach is practical for synthesis of symmetrical para-
and meta-substituted arylamines; for ortho-substituted arylbor-
onic acids, the yields are lower. Bulkiness of the aromatic
moiety impedes transmetalation step19 due to an increase in
sterical repulsion in the tetracoordinated transition state (see
below).
To reveal a possible reaction path, quantum-chemical
calculations were performed using ab initio MP2/def2-SVP
method with SMD solvation model.24,25 Alkylnitrite addition
to CuCl in DMF results in reversible formation of a new
complex (Int-1 which can exist in two forms dependent on the
type of bonding with the Cu center, Scheme 3). The following
oxidative addition to the N−O bond yielding Int-2 is
thermodynamically favorable and has low activation energy.
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(18) Yu, Y.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2004, 6 (15),
2631−2634.
(19) Levitskiy, O. A.; Grishin, Y. K.; Sentyurin, V. V.; Magdesieva, T.
V. Chem. - Eur. J. 2017, 23, 12575−12584.
(20) Liu, S.; Yu, Y.; Liebeskind, L. S. Org. Lett. 2007, 9 (10), 1947−
1950.
To summarize, a new method for Cu-catalyzed amination of
aryl boronic acids with alkylnitrites yielding diarylamines was
elaborated. Mild conditions, cheap reactants, and ease of the
workup procedure after the one-pot process determine the
synthetic value of the method. New approach to diarylamines
is a complement to the Cu-assisted reductive amination of aryl
boronic acids, avoiding preliminary synthesis of nitrosoarenes.
(21) Zhang, Z.; Yu, Y.; Liebeskind, L. S. Org. Lett. 2008, 10 (14),
3005−3008.
(22) Fisher, D. J.; Shaum, J. B.; Mills, C. L.; Read de Alaniz, J. Org.
Lett. 2016, 18 (19), 5074−5077.
ASSOCIATED CONTENT
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(23) Vantourout, J. C.; Miras, H. N.; Isidro-Llobet, A.; Sproules, S.;
Watson, A. J. B. J. Am. Chem. Soc. 2017, 139 (13), 4769−4779.
(24) Neese, F. Wiley Interdiscip. Rev. Comput. Mol. Sci. 2018, 8 (1),
No. e1327.
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b03961.
(25) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B
Details of the kinetic and CV experiments, character-
ization of the new and previously known compounds,
and results of the QC calculations (PDF)
2009, 113 (18), 6378−6396.
(26) Amatore, C.; Jutand, A.; Le Duc, G. Chem. - Eur. J. 2011, 17
(8), 2492−2503.
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33 (9), 2134−2137.
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AUTHOR INFORMATION
■
(28) Bower, J. K.; Sokolov, A. Y.; Zhang, S. Angew. Chem., Int. Ed.
2019, 58 (30), 10225−10229.
Corresponding Author
*E-mail: tvm@org.chem.msu.ru.
ORCID
Tatiana V. Magdesieva: 0000-0003-2173-652X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Russian Science Foundation
(Project No. 19-13-00094).
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