Radical C?N Borylation of Aromatic Amines Enabled by a Pyrylium Reagent

Article abstract of DOI:10.1002/chem.202000412

Herein, we report a radical borylation of aromatic amines through a homolytic C(sp²)?N bond cleavage. This method capitalizes on a simple and mild activation via a pyrylium reagent (^ScPyry-OTf) thus priming the amino group for reacti

Full text of DOI:10.1002/chem.202000412

A Journal of
Accepted Article
Title: Radical C‒N Borylation of Aromatic Amines Enabled by a
Pyrylium Reagent
Authors: Yuanhong Ma, Yue Pang, Sonia Chabbra, Edward J.
Reijerse, Alexander Schnegg, Jan Niski, Markus Leutzsch,
and Josep Cornella
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10.1002/chem.202000412
Chemistry - A European Journal
Radical C‒N Borylation of Aromatic Amines Enabled by a
Pyrylium Reagent
Yuanhong Ma,†[a] Yue Pang,†[a] Sonia Chabbra,[b] Edward J. Reijerse,[b] Alexander Schnegg,[b] Jan
Niski,[a] Markus Leutzsch,[a] and Josep Cornella*[a]
Abstract: Herein, we report a radical borylation of aromatic amines
through a homolytic C(sp2)‒N bond cleavage. This method capitalizes
on a simple and mild activation via a pyrylium reagent (ScPyry-OTf)
thus priming the amino group for reactivity. The combination of
terpyridine and a diboron reagent triggers a radical reaction which
cleaves the C(sp2)‒N bond and forges a new C(sp2)‒B bond. The
unique non-planar structure of the pyridinium intermediate, provides
the necessary driving force for the aryl radical. The method permits
borylation of a wide variety of aromatic amines indistinctively of the
electronic environment.
be a powerful tool for constructing a myriad of chemical bonds.[8-
11] However, the wealth of literature in this area has been focused
on the generation of alkyl radicals (Fig. 1B, top). Yet, methods
which capitalize on pyridinium salts to generate aryl radicals
through SET are largely underdeveloped. (Fig. 1B, bottom),[12]
mainly due to the disfavored thermodynamics for the aryl radical
formation. Although examples of this approach have been
reported in the past (3 examples),[12] pyrolysis of the reagents is
required (ca 200 °C), or obtaining low yields for very specific
substrates, thus relegating these approaches to proof of concept
examples with limited synthetic applicability. Based on our recent
interest on pyrylium reagents,[13] we set out to explore this
approach in the context of radical borylations using diboron
reagents, as they have been shown to be excellent radical
acceptors.[14-17] Herein we report a protocol for the borylation of
(hetero)aromatic amines via a SET process, enabled by the use
of a tethered pyrylium salt (ScPyry-OTf).[18] The structure of this
pyrylium reagent proved unique in assisting the cleavage of the
C(sp2)‒N bond, a feature beyond the capabilities of other
common pyrylium activators. Moreover, the choice of the solvent
was also crucial to achieve high yields of the corresponding
organoboron compounds. The protocol has been demonstrated
to be scalable and tolerant to a wide variety of functionalities.
Primary aromatic amines represent
a class of relevant
functionalities present in a wide variety of contexts ‒ from natural
sources such as DNA or vitamins to synthetic molecules as part
of their structure.[1] Despite their potential as anchor points for
further manipulation, direct functionalization of primary amino
groups in (hetero)aromatic compounds has been a tremendous
challenge in catalysis[2] due to high energy of the C(sp2)‒NH2
bonds ( of C6H5-NH2: 102.6 ±1.0 kcal/mol),[3] coordination of the
lone pair of the nitrogen to metal catalysts, and acid-base
interactions with polar functionalities. To circumvent such
drawbacks, approaches to cleave C‒N bonds have relied on the
preactivation of the amino group, converting them into virtuous
leaving groups, for example via diazotization,[4] polyalkylation[5]
and others[6] (Figure 1A). However, despite the wealth of reports
in this area, several challenges remain. For example,
diazotization reactions require the use of strong oxidants and
acids, to generate the corresponding diazonium salts, which are
thermally unstable and explosive (Figure 1A, path a).[4] The use of
an excess of toxic alkylating reagents restricts the functional
group tolerance in complex settings for polyalkylation strategies
(Figure 1A, path b).[5] Although limited in functional group
tolerance and scope, approaches based on transition metals have
recently appeared, enabling the cleavage and functionalization of
aniline derivatives (Figure 1, path c).[6]
Seminal work by Katritzky demonstrated the possibility of con-
verting amino groups into good leaving groups by condensation
with a pyrylium salt (Figure 1A, path d).[7] This strategy is
characterized by the remarkable stability of the pyridinium salt
intermediates, high selectivity for the amino groups and benefits
from the high practicality and simplicity. Indeed, pyridinium salts
have recently been employed to unlock processes based on
transition metal or photoredox catalysts, and have been shown to
Figure 1. A) Strategies to prime the amino group for reactivity. B) Generation
of aromatic radicals is a thermodynamically disfavored process.
Based on recent reports on the borylation of alkyl pyrydinium
salts,[11] we started our investigations on the borylation of anilines
using B2cat2 (bis(catecholato)diboron). After screening of the
reaction parameters, terpyridine (terpy) was identified as the
Lewis-base of choice, performing the reaction at 130 °C, using
iPr2NC(O)Me as solvent.[19] Interestingly, under the optimized
conditions, none of the classical pyridinium salts commonly
employed proved efficient in the borylation reaction (Table 1A, 1-
3). Then, we turned our attention to the tethered pyrylium reagent
reported by Katritzky in the context of alkyl amine activation.[20] It
[a]
[b]
Dr. Y. Ma,† Y. Pang,† J. Niski, Dr. M. Leutzsch, and Dr. J. Cornella
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1,
Mülheim an der Ruhr, 45470, Germany.
E-mail: cornella@kofo.mpg.de (J.C.)
†These authors contributed equally to this work.
Dr. S. Chabbra, Dr. E. J. Reijerse Dr. A. Schnegg,
Max-Planck-Institut für Chemische Energiekonversion, Stiftstrasse
34 – 36, Mülheim an der Ruhr, 45470, Germany.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/chem.202000412
Chemistry - A European Journal
shown in Table 2A, the borylation protocol boded well with
anilines substituted at the meta- (33) and para-positions (34, 35).
The presence of electron-deficient fluorinated moieties such as
CF3 (36), OCF3 (37) or F (38, 39) did not affect the reactivity and
provided good yields of product. The reaction could also be
performed in a one-pot fashion as exemplified by 39; albeit in
moderate yield.
was the pyridinium 4-OTf that delivered excellent yields of C‒B
bond formation 5 (Table 1A, entry 1, 82%). When the counterion
in 4 was replaced by BF4 (4-BF4), a lower yield was obtained
(57%). The effect of the solvent was also remarkable: while and
DMAc failed to deliver good yields of product (entries 2 and 3),
the use of a more sterically hindered amide such as iPr2NC(O)Me
proved to be crucial for obtaining high yields. While in the absence
of Lewis-base the reaction afforded only 10% of 5 (entry 4), the
use of bipyridine derivatives did not reach the levels of reactivity
of terpy (entries 5 and 6). Although borylation strategies based on
B2pin2 and aromatic Lewis bases have recently appeared in the
literature,[15f,15h,16b] the use of this diboron reagent resulted in no
conversion of 4-OTf (entry 7). Heating the reaction further had no
effect on the reactivity (entry 8) and 120 °C proved insufficient to
obtain high yields of 5 (entry 9). Isolation of 5 proceeded through
the conversion of the sensitive Ar‒B(cat) into the corresponding
Ar‒Bpin reagent, by a simple quench with pinacol and Et3N.
However, a quenching protocol based on MIDA resulted in slightly
higher yields and afforded a more robust organoboron compound
(6).[21,22] Of note, the synthesis of the ScPyry-OTf (7) could be
conducted similarly to the parent 2,4,6-triphenylpyrylium
reagent.[20a] Commercially available tetralone ($0.26/g),[23]
condenses with benzaldehyde, which upon addition of TfOH, pure
7 precipitates as a bright yellow solid. The protocol could be
scaled-up to >30 grams in one run, without any complicated setup
(Table 1B).
Table 2. Scope of the radical borylation of (hetero)aromatic amines with a
pyrylium salt.[a]
Table 1. Optimization of the borylation of arylpyridinium salts.[a]
[a] Reaction conditions: Step 1: aromatic amine (1.05-1.50 equiv.), 7 (1.0 equiv.),
NaOPiv (0-1.0 equiv.) in EtOH (0.2 M) at 85 °C; Step 2: pyridinium salt (0.25
i
mmol), B2cat2 (0.75 mmol), terpyridine (20 mol%) in Pr2NC(O)Me (0.2 M) at
130 °C for 12 h; then MIDA (1.5 mmol) at 90 °C for 4 h. Isolated yields for the
borylation step. [b] B2cat2 (1.0 mmol) was used and 24 h reaction time. [c] Yield
[d]
from aniline, without isolating the pyridinium intermediate (in situ).
iPr2NC(O)Me (0.125 M).
[a] 1-4 (0.1 mmol), B2cat2 (0.3 mmol), terpy (20 mol%), (0.5 mL) at 130 °C for 24
h; then pinacol (0.6 mmol) and Et3N (0.5 mL) were added and stirred for
additional 2 h at 25 °C. [b] Using 4-OTf as starting material. [c] Yields determined
by GC using n-dodecane as internal standard. [d] Yield of isolated product 6. [e]
Reaction performed at 0.25 mmol for 12 h, then MIDA (1.5 mmol) for 4 h at
90 °C. MIDA = N-methyliminodiacetic acid. ND = not detected.
Electron-releasing substituents in the aniline were also
amenable, as exemplified by the presence of thioethers (40),
tertiary amines (41), amides (42) and ethers (43-45). Notably, no
Claisen rearrangement byproducts were observed for product 44.
Bromo- (46) and chloroanilines (47, 48) were also compatible
under the reaction conditions, thus providing boronic acid
derivatives bearing orthogonal handles for further derivatization.
Boronic acid derivatives of π–extended anilines such as naphthyl
(49), fluorenyl (50) or anthracenyl (51) could also be synthesized
With the optimal protocol in hand, we explored the scope of this
new borylation strategy. It is worth noting that condensation of
aromatic amines with 7 proceeded smoothly across the whole
range of substrates (8-32) with an average yield of >85%.[19] As
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10.1002/chem.202000412
Chemistry - A European Journal
in high yields. The presence of oxygen- (52) or sulfur-containing
heterocycles (53) did not affect the formation of the C‒B bond.
Anilines bearing aliphatic esters (54) or a benzoate motif, such as
the anesthetic drug benzocaine, could also be borylated (55) in
good yields. Finally, heterocyclic N-containing compounds such
as pyridine (56) and indole (57) were amenable for borylation
under the optimal conditions. As depicted in Table 2B, both the
condensation and the borylation proved to be highly scalable, as
demonstrated by the >6 grams of pyrylium 14 provided and the
1.23 grams of borylated compound 39.
borylation strategy (Figure 3B).[11a] Int-2 would then engage in the
reduction of the pyridinium moiety to generate int-1. The high
degree of distortion of the aromatic ring in 4-OTf led us to
postulate that int-1 would be highly unstable, and homolytic C‒N
cleavage occurs at high temperatures. We speculate that the
restoration of the planarity renders a higher degree of conjugation
and aromaticity for the leaving pyridine 61[26] and provides the
necessary driving force for the homolysis of the C‒N bond. As
aforementioned, when DMAc was used competing formation of
i
59 occurs. Yet, the use of Pr2NC(O)Me circumvents HAT, and
aryl radical formation through C‒N scission is largely operative.
Although the nature of this difference in reactivity is still under
investigation, we propose that the success of this solvent hinges
on providing an adequate balance for a successful radical chain
towards productive radical borylation. The aryl radical formed, is
then rapidly trapped by B2cat2, delivering the desired C‒B bond,
with concomitant generation of the reducing solvent-ligated boron
radical int-2.[16g]
At this point, we set out to explore the remarkable effects for
both the solvent and the structure of the pyrylium. As shown in
Table 1, when 3 was subjected to the optimized conditions using
DMAc, no borylation was obtained and >90% of starting
pyridinium salt 3 was recovered (Figure 2A). When iPr2NC(O)Me
was used instead, a minimal yield of 5 was obtained (12%).
However, the conversion was low and the reaction was plagued
with several unidentified byproducts. In stark contrast, when 4-
OTf was subjected to the borylation conditions in DMAc,
acceptable yields of borylation were obtained (49%, Table 1, entry
3). Analysis of the reaction mixture revealed the formation of a
major by-product, which was identified as the reduced compound
59 (Figure 2B).[24]. Gratifyingly, when the solvent was replaced by
the optimal iPr2NC(O)Me, formation of by-product 59 was
suppressed (<5%), and excellent yields of 5 were obtained (82%,
Table 1, entry 1). As suggested by Katritzky’s report[12c], 59
possibly resulted from HAT from solvent molecules. [24]
Figure 3. A) X-ray structures of 3 and 4-BF4. Counterions are omitted for clarity;
B) Putative mechanism for the catalytic borylation reaction of pyridinium salts.
Figure 2. Reactivity of pyridinium salts 3 and 4-OTf with different solvents.
The involvement of radical intermediates in the reaction was
verified by continuous wave (CW) electron paramagnetic
resonance (EPR) experiments. Sample 1 (Figure 4A-1) was
extracted from the reaction mixture of 4-OTf with B2cat2 and terpy
in DMAc. According to the proposed mechanism (Figure 3B), two
long lived radical intermediates can occur: the solvent-ligated
boron radical int-2 as well as int-1 formed from the SET reduction
of 4-OTf. Int-2 would be boron-centered while the latter is
Motivated by the striking differences in reactivity between 3 and
4-OTf, we initially interrogated their electronic properties. Cyclic
voltammetry experiments conducted in both compounds revealed
a reversible behavior and a similar first reduction potential (Ered
(3) = ‒1.39 V vs Fc/Fc+ in DMF, Ered (4-OTf) = ‒1.30 V vs Fc/Fc+
in DMF).[19] This result suggests that the oxidation capabilities of
both pyridinium salts are similar, and reduction via SET processes
should be equally facile using the terpy/B2cat2 system.[11b,25]
However, X-ray analysis of the crystal structure for 3 and 4-BF4
was far more revealing. The pyridine moiety in 3 is planar, with
almost no torsion observed in the pyridinium ring (Figure 3A, left).
On the other hand, the ethane-bridged moiety in 4-BF4, renders a
expected to be carbon centered. The dominant boron isotope 11
B
(80%) has nuclear spin I = 3/2, potentially giving rise to a quartet
hyperfine pattern in the EPR. Carbon, on the other hand, has no
dominant isotope with nuclear spin (13C with I = 1/2 has 1.1%
natural abundance). Therefore, no strong hyperfine interaction
(HFI) pattern is expected for int-1. The two proposed radical
intermediates were separately generated. The int-2 was
expected in a mixture of B2cat2 with terpy in DMAc, i.e. the
reaction mixture without 4-OTf (Figure 4A-2). Indeed, the EPR
spectrum showed well resolved hyperfine lines but more than a
mere quartet. Possibly, also 1H and/or 14N hyperfine interactions
contribute to this multiline (12) pattern. In any case, sample 1
showed an EPR spectrum virtually identical to that of the sample
much more constraint environment and results in a heavily
[20c]
tensioned aromatic pyridinium motif,
as judged by the
remarkable 11.2°, ‒174.4° and 5.8° of torsion for the three
different angles explored (Figure 3A, right). Based on all the
experimental data, a putative mechanism for this transformation
is depicted in Figure 3B. In an initiation phase, the combination of
B2cat2, terpy and amide solvent affords the highly reducing int-2
radical species, as suggested in a previous Lewis-base-promoted
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10.1002/chem.202000412
Chemistry - A European Journal
2. In contrast, sample 3 which was generated by direct reduction
of 4-OTf with TDAE, showed a strong EPR signal with weak HFI
features containing very small splitting not resembling the EPR
spectrum of sample 1. It therefore can be concluded that the
reaction mixture is dominated by the species int-2 generated from
sample 2, which is consistent with int-2. In addition, performing
the borylation reaction in the presence of 1,1-diphenylethene
resulted in the formation of 5 (53%) and the radical addition
product 60 (22%) (Figure 4B). This result offers additional
evidence for the homolytic cleavage of the C‒N bond and the
generation of aryl radicals in solution.
Keywords: aromatic amine• radical borylation • C-N bond
functionalization • pyrylium• pyridinium salts
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mixture containing B2cat2 and terpy in DMAc 1) with and 2) without 4-OTf,
respectively. 3) reduction of 4-OTf substrate by addition of TDAE in DMAc.
TDAE = tetrakis(dimethylamino)ethylene. All the spectra were recorded under
identical conditions with 10 mW microwave power, 100 KHz modulation
frequency and 0.1 mT modulation amplitude. See supporting information for
details.; B) Radical trap experiments confirming the presence of aryl radicals.
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In summary, we have developed a novel strategy for the C‒N
borylation of aromatic amines, capitalizing on the mild and
selective condensation of ScPyry-OTf (7) with amino groups.
Additionally, the rationally designed solvent permits the smooth
generation of highly reactive aryl radicals to engage in a C‒B
bond forming event. The borylation protocol is demonstrated to
be scalable and is tolerant to various functional groups. The ability
of pyridinium salts derived from ScPyry-OTf (7) to successfully
generate aryl radicals, represents a new approach in the area of
C‒N functionalization. Research exploiting ScPyry-OTf (7) for
other applications in organic synthesis is currently ongoing in our
research laboratories.
[7]
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Acknowledgements
Financial support for this work was provided by Max-Planck-
Gesellschaft, Max-Planck-Institut für Kohlenforschung; Fonds der
Chemischen Industrie (FCI-VCI); Y. P. thanks the CSC for a PhD
scholarship. We thank Dr. Y. Duan and J. Busch for their contributions.
We thank Dr. C. Werlé and P. Höfer for help in cyclic voltammetry
studies. We thank the department of x-ray crystallography at the MPI
für Kohlenforschung for measuring and refining crystal structures. We
are thankful to Prof. Dr. A. Fürstner for discussions and generous
support.
[9]
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This article is protected by copyright. All rights reserved.

10.1002/chem.202000412
Chemistry - A European Journal
COMMUNICATION
Yuanhong Ma,† Yue Pang,† Sonia
Chabbra, Edward J. Reijerse, Alexander
Schnegg, Jan Niski, Markus Leutzsch,
and Josep Cornella*
Radical C‒N Borylation of Aromatic
Amines Enabled by a Pyrylium
Reagent
A radical borylation of aromatic amines through a homolytic C(sp2)‒N bond cleavage is presented. This method capitalizes on
a simple and mild activation via a pyrylium reagent (ScPyry-OTf) which primes the amino group for reactivity. The combination
of terpyridine and a diboron reagent triggers a radical reaction which cleaves the C(sp2)‒N bond and forges a new C(sp2)‒B
bond. The non-planar structure of the pyridinium, provides the necessary driving force for the challenging aryl radical formation.
This article is protected by copyright. All rights reserved.