Synthesis of Di(hetero)arylamines from Nitrosoarenes and Boronic Acids: A General, Mild, and Transition-Metal-Free Coupling

Article abstract of DOI:10.1021/acs.orglett.8b00473

The synthesis of di(hetero)arylamines by a transition-metal-free cross-coupling between nitrosoarenes and boronic acids is reported. The procedure is experimentally simple, fast, mild, and scalable and has a wide functional group tolerance, including carbonyls, nitro, halogens, free OH and NH groups. It also permits the synthesis of sterically hindered compounds.

Full text of DOI:10.1021/acs.orglett.8b00473

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Di(hetero)arylamines from Nitrosoarenes and Boronic
Acids: A General, Mild, and Transition-Metal-Free Coupling
Silvia Roscales and Aurelio G. Csaky*
́
̈
Instituto Pluridisciplinar, Universidad Complutense, Campus de Excelencia Internacional Moncloa, Paseo de Juan XXIII, 1, 28040
Madrid, Spain
S
* Supporting Information
ABSTRACT: The synthesis of di(hetero)arylamines by a
transition-metal-free cross-coupling between nitrosoarenes and
boronic acids is reported. The procedure is experimentally
simple, fast, mild, and scalable and has a wide functional group
tolerance, including carbonyls, nitro, halogens, free OH and
NH groups. It also permits the synthesis of sterically hindered
compounds.
Scheme 1. Different Approaches to Di(hetero)aryl Amines
ue to the ubiquity of nitrogen-containing compounds in
Dfunctional materials, natural products, and active
pharmaceutical ingredients, the search for alternative methods
for the easy construction of carbon−nitrogen bonds is an active
area of research. Methods that require the use of transition
metals are usually characterized by a reduced sustainability. On
the other hand, transition-metal-free processes spare the need
to remove undesired metal contamination, which is important
in many applications, such as in the pharmaceutical industry.1
Di(hetero)arylamines are highly important chemicals,
frequently found among drugs, agrochemicals, dyes, radical-
trapping antioxidants, electroluminescent materials, and ligands
for transition-metal catalysis.2 On the one hand, the synthesis of
di(hetero)arylamines under simple, mild, and eco-friendly
conditions remains highly desirable, and on the other,
extending the scope of the synthetically valuable reactions of
user-friendly boronic acids under transition-metal-free con-
ditions is a matter of current interest with wide utility from a
green perspective. In this paper, we report the coupling of
nitrosoarenes with arylboronic acids under neutral and
transition-metal-free conditions as a general method for the
synthesis of di(hetero)arylamines. The procedure is exper-
imentally simple, fast, mild, scalable, and has a wide functional
group tolerance, including aldehydes, ketones, esters, nitro, and
halogens, which are often incompatible with other previous
methods for di(hetero)arylamine synthesis. It also permits the
presence of unprotected NH and OH groups, as well as the
assembly of sterically hindered diarylamines, which are usually
challenging issues.
exhibit wide substrate scope, they require the use of expensive
and toxic metallic catalysts, the presence of ligands, and
extensive individual optimization of reaction conditions. In
addition, these methods are usually inadequate to prepare
sterically hindered diarylamines8 and can be rather limited by
the synthetic availability of the starting anilines.9
Other typical approaches make use of electrophilic nitrogen
reagents and their reaction with carbon nucleophiles.10 In this
regard, nitroso aromatic compounds stand out as attractive
starting materials, as they can be easily obtained by a wide range
The most popular current syntheses of diarylamines are
based on transition-metal-catalyzed couplings of anilines with
aryl halides under Cu-catalysis3,4 (Ullmann−Goldberg reac-
tion) or Pd-catalysis5 (Buchwald−Hartwig reaction), and with
boronic acids under Cu-catalysis3 (Cham−Evans−Lam reac-
tion).6,7 See Scheme 1. Although these cross-coupling reactions
Received: February 8, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00473
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Letter
of complementary procedures,11 such as nitrosation of
aromatics, oxidation of anilines or hydroxylamines, reduction
of nitrobenzenes, or nitrosation of (het)aryltrifluoroborates.12
In addition, the functionalization of the aryl moiety of
nitrosobenzenes is also feasible.13 In particular, the nucleophilic
addition of main-group organometallics to nitroso compounds
has been used for the synthesis of diarylamines,14 however, this
method has a somewhat limited functional group scope due to
the high reactivity of the carbon−metal bond. This is especially
important when dealing with OH or NH groups, which must
be protected. In addition, the transformation of the primary
addition products (Ar2N−OM) into the final diarylamines
requires further elaboration (reduction of the N−O bond).
In contrast to main-group organometallics, boronic acids are
quite bench-stable reagents that can be used without the need
for protection from humidity, and are compatible with
functional groups, such as OH or NH.15 In connection with
the synthesis of diarylamines using boronic acid derivatives
under transition-metal-catalysis, apart from the aforementioned
Chan−Evans−Lam coupling,6 boronic acids have also been
made to react with N-chloro-N-arylacetamides,16 with aryl
azides,17 and with a narrow set of nitrosobenzenes.18 On the
other hand, when it comes to transition metal-free
procedures,19 to the best of our knowledge, the synthesis of
diarylamines using boronic acid derivatives has been elusive.
We started our research by considering the possibility of
activating nitroso compounds toward cross-coupling with
phenylboronic acid derivatives using a trivalent phosphorus
species.20 After some experimentation,21 we found that
diphenylamine (3) could be synthesized by the reaction of
nitrosobenzene (1a) with phenylboronic acid (2a) in the
presence of inexpensive P(OEt)3 (eq 1). The best yield in 3
(95%) was obtained in toluene solution at rt, after 45 min. The
reaction did not require anhydrous solvent or inert atmosphere,
and the isolation of the product was accomplished by filtration
over a pad of silica-gel, without the need for chromatography.21
Figure 1. Cross-coupling between nitrosobenzene 1a and arylboronic
acids (2). Reaction conditions: PhNO (1a, 0.28 mmol), ArB(OH)2 (2,
1.5 equiv), P(OEt)3 (1.2 equiv), tol (0.6 mL), and rt, for 45 min.
NHAc (23, 24) as substituents of the arylboronic acid
component.22 However, Boc-protection permitted the synthesis
of 25 with moderate yield. Finally, compounds 26 and 27, with
alcoholic OH groups, were synthesized starting from
benzoxaboroles 2b and 2c.
Next, we looked into the scope of the cross-coupling reaction
with regard to the nitrosobenzene component 1, using
phenylboronic acid (2a) as reagent (Figure 2). For the sake
Under optimum reaction conditions for the synthesis of 3,
we looked into the scope of this metal-free cross-coupling
reaction with regard to the arylboronic acid component 2, using
nitrosobenzene (1a) as reagent (Figure 1).
We observed that the reaction was general, either with
electron-donor or electron-acceptor substituents on the
benzene ring of the arylboronic acids 2 (Figure 1). With
regard to steric hindrance in the presence of o-substituents, we
observed that a single o-MeO substituent was tolerated,
although the yield was slightly lower in comparison to p-
substitution (4−6). However, double o-substitution by MeO
(7) was not permitted.22 On the other hand, double o-
substitution by Me (8) was possible. Ph was also allowed at the
o-position (9). The reaction was compatible with functional
groups typically reactive against organolithiums or Grignard
reagents, such as ketone, ester or aldehyde, even at the o-
position (10−13), as well as the NO2 group (14). With regard
to halogenated compounds, F, Cl, Br and I were accepted (15−
21). This is an important issue, particularly because Br and I
were attached to the C(sp2) present in the orthogonal
interaction in the typical Pd or Cu-catalyzed syntheses of
diarylamines.3−6 Whereas, when a phenolic OH group was
tolerated (22), the reaction did not take place with NH2 or
Figure 2. Cross-coupling between nitrosobenzenes 1 and phenyl-
boronic acid (2a). Reaction conditions: ArNO (1, 0.28 mmol),
ArB(OH)2 (2a, 1.5 equiv), P(OEt)3 (1.2 equiv), tol (0.6 mL), and rt,
for 45 min.
of comparison, we started by synthesizing several representative
examples (4, 8 − 11, 13, 19−24) that had already been
prepared the other way round, i.e., by the reaction of 1a with
the boronic acids 2 (results gathered in Figure 1). The
comparison of results put forward that compounds 4, 8−11, 13,
19, 20, and 21 could be synthesized with a slight increase in
yield when starting with substituted nitroso compounds 1. The
phenol 22 was synthesized in similar yield. However, we were
pleased to find that, opposite to the previous situation, free
B
DOI: 10.1021/acs.orglett.8b00473
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Letter
NH2 was tolerated as substituent when installed on the
nitrosobenzene moiety (23), as well as NHAc (24). In
particular, 23 is an important industrial antioxidant used in
the manufacture of car tires.23 The synthesis of 23 has been
scaled to 10 g of starting material with a slight loss in yield
(74%).
For completeness, some additional new cases (28 − 33)
were included in the study (Figure 2) to show the scope of the
method further with regard to the nitrosobenzene counterpart,
including examples with NH, OH and halogens, among others.
All reactions took place in good yields, including those carrying
o-substituents.
Then, we considered the coupling of nitrosobenzenes 1 and
arylboronic acids 2 carrying substituents on each ring. As
previously stated,8 the synthesis of sterically hindered diaryl-
amines, i.e., those carrying ortho-substituents on both aromatic
rings, is often challenging. Therefore, we have focused on
evaluating the performance of this cross-coupling procedure
with nitrosobenzenes and arylboronic acids carrying at least one
ortho-substituent each (Figure 3).
Figure 4. Synthesis of heterocyclic amines. Reaction conditions:
(Het)ArNO (1, 0.28 mmol), (Het)ArB(OH)2 (2, 1.5 equiv), P(OEt)3
(1.2 equiv), tol (0.6 mL), and rt, for 45 min.
Scheme 2. Synthesis of Phentolamine (57)
Scheme 3. Plausible Reaction Course
Figure 3. Synthesis of sterically hindered diarylamines. Reaction
conditions: ArNO (1, 0.28 mmol), ArB(OH)2 (2, 1.5 equiv), P(OEt)3
(1.2 equiv), tol (0.6 mL), rt, 45 min.
The results gathered in Figure 3 put forward that this cross-
coupling reaction admits the presence of two (34 − 36) and
three (37 − 41) o-substituents with good yields. However, 42,
with four Me o-substituents, was synthesized in moderate yield.
Finally, we were pleased to find that the reaction was also
useful for the assembly of heterocyclic amines, either starting
with heterocyclic nitroso compounds or with heterocyclic
boronic acids (Figure 4); many of them were π-excessive or π-
deficient. The tolerance of unprotected NH in indoles is
noteworthy (44, 51).
To test the scaling possibilities, in addition to the synthesis of
23 (vide supra), we have carried out the 10-g scale synthesis of
phentolamine (57) (Regitine, Vasomax), a reversible, non-
selective α-adrenergic antagonist used clinically to control
hypertensive emergencies (Scheme 2).24 The procedure
benefits from the tolerance of the OH group in the cross-
coupling reaction leading to 55.
the nitroso group in 1a leads to a tetravalent phosphorus
intermediate (I), which can be transformed into a nitrene by
elimination of OP(OEt)3 (II). Either (I, II) can add to the
vacant orbital on boron in 2a, giving rise to a boronate species
(III, IV) able to transfer the nucleophilic phenyl group to the
electrophilic nitrogen. Protonation of the final aminoboronate
V upon filtration affords diphenylamine (3), together with boric
acid as byproduct.
In conclusion, we have developed for the first time the
transition metal-free cross-coupling between nitrosobenzenes
and boronic acids. The reaction tolerates functional groups that
are incompatible with other methods for the synthesis of
di(hetetro)aryamines (carbonyls, nitro, halogens, free OH and
NH2), and permits the synthesis of diaryl- and diheteroaryl-
amines, including sterically encumbered compounds. The
experimental procedure is simple and inexpensive [open flask,
P(OEt)3], mild (base-free, toluene, rt), fast (45 min), and
Based on the above considerations and the literature
information,20 we propose the mechanism for the amination,
as illustrated in Scheme 3 for the synthesis of diphenylamine
(3). Nucleophilic addition of P(OEt)3 to the oxygen atom of
C
DOI: 10.1021/acs.orglett.8b00473
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Organic Letters
Letter
(6) For reviews on the Cham−Evans−Lam coupling, see: (a) Qiao, J.
X.; Lam, P. Y. S. Synthesis 2011, 2011, 829. (b) Qiao, J. X.; Lam, P. Y.
S. Recent advances in Chan-Lam coupling reaction: Copper-promoted
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(9) For other recent transition-metal-catalyzed transformations
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catalysis). (d) Gui, J.; Pan, C.-M.; Jin, Y.; Qin, T.; Lo, J. C.; Lee, B. J.;
Spergel, S. H.; Mertzman, M. E.; Pitts, W. J.; La Cruz, T. E.; Schmidt,
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scalable (10 g), and the reaction products are recovered by
simple filtration without the need for separation by
chromatography.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00473.
Synthesis of starting materials, optimization of reaction
conditions between 1a and 2a, full experimental details,
characterization data, and copies of NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*(A.G.C.) E-mail: csaky@ucm.es
ORCID
Aurelio G. Csaky: 0000-0002-2888-2231
́
̈
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by Project CTQ2014-52213-R from
the Spanish government (MICINN).
■
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