Intramolecular Metal-Free N?N Bond Formation with Heteroaromatic Amines: Mild Access to Fused-Triazapentalene Derivatives

Article abstract of DOI:10.1002/chem.201905558

Formation of N?N bonds may offer an original approach to various nitrogen-containing heterocycles with numerous applications. For this purpose, we found that readily available heteroaromatic amines are appropriate substrates for providing an efficient and innovative approach for the formation of N?N bonds in the presence of iodine (III) reagent in very mild conditions. This method makes it possible to synthesize nitrogen rich triazapentalene derivatives exhibiting fluorescent properties, inaccessible with existing approaches.

Full text of DOI:10.1002/chem.201905558

A Journal of
Accepted Article
Title: Intramolecular Metal Free N-N Bond Formation with
Heteroaromatic Amines: Mild Access to Fused-Triazapentalene
Derivatives
Authors: Matthieu Daniel, Marie-Aude Hiebel, Gérald Guillaumet, Eric
Pasquinet, and Franck Suzenet
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To be cited as: Chem. Eur. J. 10.1002/chem.201905558
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COMMUNICATION
Intramolecular metal free N-N Bond Formation with
Heteroaromatic Amines: Mild Access to Fused-Triazapentalene
Derivatives
Matthieu Daniel,[a],[b] Marie-Aude Hiebel, Gérald Guillaumet, Eric Pasquinet,* and Franck
[a]
[a]
[b]
Suzenet*[a]
Dedication ((optional))
[
[
a]
b]
Matthieu Daniel, Dr. Marie-Aude Hiebel, Prof. Gérald Guillaumet, Prof. Franck Suzenet
Institut de Chimie Organique et Analytique (ICOA), University of Orleans,
UMR CNRS 7311, Rue de Chartres, 45100 Orléans, France
E-mail: franck.suzenet@univ-orleans.fr
Matthieu Daniel, Dr. Éric Pasquinet
CEA, DAM, Le Ripault,
BP16 37260 Monts, France
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: Formation of N-N bonds may offer an original approach to
various nitrogen containing heterocycles with numerous applications.
For this purpose, we found that readily available heteroaromatic
amines are appropriate substrates for providing an efficient and
innovative approach for the formation of N-N bonds in the presence
of iodine (III) reagent in very mild conditions. This method makes it
possible to synthesize nitrogen rich triazapentalene derivatives
exhibiting fluorescent properties, inaccessible with existing
approaches.
and naphthyridine in an oxidative amination process of arenes in
protic solvent (Scheme 1, c).[9]
In contrast, N-N bond formation using iminoiodinanes is largely
unexplored and remains challenging. To the best of our
knowledge, Maestre et al. recently reported the sole and elegant
chemoselective N-amidation thanks to
intermediate generated from N-sulfonyliminoiodinane reagent.
a
metallonitrene
[
10]
Nitrenes are well-established and still very promising agents for
selectively introducing nitrogen into molecules.[1] In their early
stages, these highly reactive species were difficult to handle,
which delayed the full exploitation of their potential compared to
their carbon cousins, carbenes. Initially, nitrenes were only
obtained from photolytic or thermal reactions from organic azides
and in deoxygenating conditions from nitro derivatives.[2],[3]
However, in addition to the rather difficult access to the precursors,
these pathways required harsh reaction conditions incompatible
with some starting materials and exhibited unconstrained
reactivities.
An important breakthrough occurred in the mid-1970s with
Yamada and Abramovitch’s work on iminoiodinanes,[4] which are
now established as reliable nitrene providers.[5] Iminoiodinanes
are usually prepared from iodinanes with substrates restricted to
carbamates, ureas, guanidines and sulfonamides, the latter
remaining the major precursor. With the advent of N-
sulfonyliminoiodinane reagents, several synthetic transformations
were successfully achieved for the metal assisted formation of C-
N bonds through new alkene aziridination (Scheme 1, a), C-H
[
6],[7]
amination
processes
(Scheme
1,
b)
and
[8]
metallonitrene/alkyne metathesis reactions. Recently iodinanes
were also involved in C-N bond formation from aminopyridines
I
1
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2 2
Scheme 1: Reactivty of several NH containing towards PhI(OAc)
temperature, N-N bond formation occurred and allowed us to
isolate 2a in an encouraging yield of 8% (Table 1, entry 1).[
Considering that methanol may hydrolyze the iminoiodane,[17] an
attempt was made in DMF and DMSO. All the reagents
completely dissolved in these media and the one-pot procedure
afforded an increased yield up to 25% (entries 2 and 3). It is worth
noting that no reaction was observed between DMSO and the
4b]
While very limited examples (with iminomethyl-6-uracil,[11]
heterocyclic hydrazones[12] and aminated furazane[13]) briefly
mentioned the formation of a N-N bond, the design and well
established reactivity of new classes of iminoiodinanes is required
to open the way to a novel class of nitrogen containing
compounds.
Herein, we report the use of readily available and stable
heteroaromatic amines for N-N bond formation in the presence of
hypervalent iodine under mild metal-free experimental conditions
[18]
[9,
ylide. Many other solvents were used (MeCN, TFE or DCM)
19]
and were detrimental to the reaction (see Supporting
Information [SI] for details). Interestingly, using HFIP, as reported
by Chupakhin et al. for C-N bond formation from aminopyridines
[9]
2
was unsuccessful. Increasing the amount of PhI(OAc) up to 2
(
Scheme 1, d)
equivalents made it possible to obtain 2a in a good yield of 45%
either in DMSO or DMF in 24 hours at room temperature or 5
hours at 80°C (entries 4 and 5). Surprisingly, doubling the
amounts of base and iodinane led to a noticeable drop in the yield
1
,3a,6a-Triazapentalene is a versatile polynitrogenated family
whose optical properties are beginning to be recognized.[
Recently, a heteroaryl-fused system, more specifically pyridazino-
triazapentalene scaffolds, caught our interest and were
established to be promising fluorophores as well.[15]
14]
(
(
entry 6). Non-nucleophilic bases were as effective as NaOH
Table 1, entries 7 and 8). Therefore, to avoid potential side
Their synthesis requires nitro or azido heteroaromatic precursors
reactions between azine substrates and the hydroxide anion, NaH
2.5 equiv) and PhI(OAc) (2 equiv) at room temperature in DMF
was defined as the optimized reaction conditions and provided 2a
in 47% yield (entry 8). The requirement of the base was confirmed
since the reaction hardly occurred in its absence (entry 9).
and takes place under thermolysis (> 160°C) limiting their
(
2
accessibility.[
15-16]
In contrast, a direct intramolecular N-N
oxidative bond formation between heteroaromatic amines and
pyrazoles (Scheme 1, d) could offer an original metal-free access
to new nitrogen rich triazapentalene derivatives under very mild
reaction conditions. Such compounds cannot be obtained using
existing methods.
Table 1. Optimisation of reaction conditions[a]
PhI(OAc)
2
Yield 2a
(%)
Entry
Base (eq.)
Solvent
(eq.)
1
2
3
4
5
6
7
8
9
KOH or NaOH (2.5)
NaOH (2.5)
NaOH (2.5)
NaOH (2.5)
NaOH (2.5)
NaOH (5)
1
1
1
2
2
4
2
2
2
Solvents[b]
DMSO
DMF
<8
25
18
DMSO
DMF
45 (47)[c]
45
DMF
22
t-BuOK (2.5)
NaH (2.5)
DMF
40
DMF
47[d]
9
―
DMF
[
a] General conditions reaction: 1a (0.5mmol) in 3mL solvent. [b] MeOH,
MeCN, DCM, HFIP and TFE were tried. [c] Reaction performed at 80 °C and
purified after 5 hours. [d] Complete conversion was observed after 6 hours.
Scheme 2. Modulation of 6 membered ring moiety
In this study, the pyridazino-triazapentalene 2a was chosen as a
model target requiring 2-amino-3-(1H-pyrazol-1-yl)pyrazine 1a as
starting heteroaromatic amine. Compound 1a was easily
synthesized in two steps from commercially available 2,3-
dichloropyrazine (see Supporting Information [SI] for the
synthesis). Under Yamada’s pioneering experimental conditions
Next, the nature and electron withdrawing character of the starting
heteroarylamines were investigated (Scheme 2). In general, the
reaction was very clean and the expected product was isolated
without any side products. First, the presence of CF
3
and Br
groups were well tolerated on the pyrazine ring, especially with
2
with 1 equivalent of PhI(OAc) and KOH in methanol at room
2
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CF
3
whose strong electron deficiency character reinforced the
diazine ring (2x). It is worth noting that the presence of a CF
group on the pyrazine enabled the reaction with
trifluoromethylpyrazole (2w vs. 2v).
To gain insight into the mechanism, the reaction was also
performed in the presence of two equivalents of TEMPO. The
yield obtained remained unchanged, suggesting an unlikely
3
reactivity of the system. Next, the less -deficient pyrimidine ring
revealed the crucial importance of the relative position of the
amine function and the nitrogen of the ring.[20] When the amine is
adjacent to an intracyclic nitrogen (position), cyclization
occurred in good yield without the need of any activating electron
withdrawing group in position 2 or 4 (2d-f). An electron donating
group (methoxy) was tolerated but led to a significant drop in yield
involvement of radicals.
Despite the absence of base in previous literature reports,[
9, 19]
we
(
2g). In contrast, an amino group in the  position with respect to
believe that the first deprotonation step for the formation of A is
crucial in our case. Indeed, the amines on electron-poor aromatic
moieties are known to be less nucleophilic than other primary aryl
amines. Therefore, the formation of B directly from 1a may be
unfavorable and explain the poor yield observed without base
(Table 1, entry 9). Furthermore, these amines also tend to exhibit
the pyrimidine nitrogen, led to a total degradation of the reaction
mixture t (2h vs 2d). This negative effect was partially overcome
by an electron withdrawing group (2i vs. 2h). The third diazine
scaffold, i.e. pyridazine, was also very well tolerated and
compound 2j was isolated in 65% yield. We finally focused on the
pyridine ring. Irrespective of the position of the amine group ( or
a
stronger acidic character, facilitating the straightforward

), unsubstituted pyridines 1k-l failed to yield the desired product.
formation of A, as corroborated by a strong change of color of the
reaction medium upon the addition of a base. A reduction of the
reaction time was also observed, depending on the strength of the
base used.
Instead, total degradation was observed.
The lower -deficient character of the pyridine ring compared to
diazine rings is probably insufficient to stabilize the iminoiodinane
intermediate. Logically, reactivity was recovered thanks to a CF
or CN group at position 4 on the pyridine ring and products 2m-o
were obtained with moderate to good yield.
3
While 24 hours were required with sodium hydroxide, just six
hours were sufficient to complete the reaction with sodium hydride.
The rest of the mechanism is based on similar comments from the
literature. The amide anion A can react with iodine (III) to form the
hypervalent iodine intermediate B and may then evolve according
to two pathways (Scheme 4). Pathway 1 could be a two-step
mechanism involving a nitrenium ion intermediate C, a species
favored in recent literature[5a, 11-12, 19] but the formation and stability
of which could be unfavorable in the present study because of the
presence of the electron-poor azine moiety. On the other hand,
pathway 2 only involves a one-step process, with the direct attack
by the pyrazole’s nitrogen at the intermediate B stage which, this
time, will be promoted by the presence of the azine, making the
iodine-bonded nitrogen more electrophilic.[9]
Scheme 4. Proposed mechanism leading to triazapentalene derivatives
Scheme 3. Modulation of 5 membered ring moiety
Heteroaryl-fused triazapentalene derivatives were recently
described to exhibit promising fluorescent properties.
At this stage, the impact of diversely functionalized pyrazoles on
the reactivity was assessed (Scheme 3). The presence of an
electron donating group (Me, OMe) had a mild effect on yields
[15]
Preliminary studies revealed that the spectroscopic properties
were highly dependent on the nature of the fused cycle, especially
the number and the position of the nitrogen atoms in the azine
heterocycle. However, due to the azide/nitro chemistry approach,
only a very limited scope of heteroaryl as well as substituents
were possible. With the present approach starting from easily
accessible and stable heteroaromatic amines, several original
fused triazapentalenes with various substituents on the azine part
(
Scheme 3, 2p-t), whereas the presence of an electron deficient
group (CF ) led to a significant decrease in the yields (Scheme 3,
u and 2w) up to a complete loss of reactivity (2v). These trends
3
2
are observed in either pyrazine or pyrimidine series. Interestingly,
there is no beneficial effect in cumulating an electron donating
group on the pyrazole and an electron withdrawing group on the
3
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Chemistry - A European Journal
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were synthesized to give further insight as to the resulting
spectroscopic properties.
with fluorescence quantum yields of 0.41 and 0.47 respectively
for 2a and 2w.
In conclusion, we have developed an efficient method for the
formation of N-N bonds from readily available primary heteroaryl
amines at room temperature. The reaction is assumed to involve
an amide anion. This anion, in the presence of hypervalent iodine
(III), affords various nitrogen-rich triazapentalene derivatives.
Some of these new compounds exhibit promising fluorescence
properties.
Table 2. Spectroscopic characterization of the tricyclic compounds 2a-x in
DCM
Compds

nm]
abs
[

[nm]
em
[b]

[nm]

max[d]
φ
F
[e]
a]
[c]
[
2
a
415
415
434
424
410
416
412
411
413
364
382
371
353
396
364
360
360
495
516
518
529
512
507
489
536
507
428
476
452
421
470
434
439
410
80
101
84
12000
6700
0.41
0.13
2b
2c
13200
8900
0.23
Acknowledgements
2
p
q
105
102
92
0.096
0.084
0.29
The Direction Générale de l’Armement is gratefully acknowledged
for financial support. This work has also been partially supported
by Labex SynOrg (ANR-11-LABX-0029), Labex IRON (ANR-11-
LABX-0018-01), the University of Orleans and the Centre Val de
Loire Region. The ANR 18- CE07-0009-01 is acknowledged for
the financial support of the spectroscopic part of the study.
2
7100
2
r
12100
9100
2w
77
0.47
2
x
y
127
95
13600
13800
8600
0.013
0.21
2
Keywords: hypervalent compounds - heteroaromatic amines -
2d
63
0.021
0.13
iodine - triazapentalene derivatives - N-N bond formation
2e
93
12000
3900
Notes and references
2
f
81
0.28
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[
a] Apparent maxima of absorption bands. [b] Apparent maxima of emission
bands. [c] Stokes Shift values calculated as the difference between the
maxima of absorption and emission bands. [d] Units: L.mol .cm . [e]  is the
F
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-
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2
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5
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Entry for the Table of Contents
Heteroaryl amines are described to be readily available substrates for the hypervalent iodine promoted N-N bond formation. In contrast
to azide or nitro precursors, amines react at room temperature and enables to synthesize original nitrogen rich triazapentalene
derivatives exhibiting fluorescent properties.
6
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