C- vsN-Oxidations of Benzyltriazanes: Selective Access to Triazones, Azimines, and Triazenes

Article abstract of DOI:10.1055/s-0036-1591865

The oxidation of several benzyltriazanes has been studied. Routes to the selective formation of triazenes, azimines, and triazones via C- or N-oxidation (and rearrangement) were devised. The rich reactivity of triazanes shows that trinitrogen chains are interesting functions, whose reactivity has been overlooked despite their interest as 3-N building blocks.

Full text of DOI:10.1055/s-0036-1591865

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
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A. Glowacki et al.
Letter
Synlett
C- vs. N-Oxidations of Benzyltriazanes: Selective Access to
Triazones, Azimines, and Triazenes
Aurore Glowacki
Victorien Jeux
Gwénaël Gasnier
Lionel Joucla*
Guy Jacob
hypervalent
iodine
H
H
Boc
N
Ar
N
N
BOC
BOC
N
Boc
N
N
Ar
N
N
N
Boc
48–89%
38–52%
Boc
Ar
H
Emmanuel Lacôte*
Ar = EWG- & EDG-
substituted arenes
H
Univ Lyon, Université Claude Bernard Lyon 1, CNRS, CNES,
ArianeGroup, LHCEP, Bât. Raulin, 2 rue Victor Grignard,
69622 Villeurbanne, France
Pb(OAc)4
lionel.joucla@univ-lyon1.fr
emmanuel.lacote@univ-lyon1.fr
Received: 14.10.2017
Accepted after revision: 16.11.2017
Published online: 22.01.2018
As a consequence, there is a need for alternatives to
hydrazines. Given that efficiency in space propulsion is a
direct consequence of the presence of N–N single bonds
and a minimal amount of carbon in the materials used, we
decided to investigate the potential of triazanes, hydrazine
homologues with three singly bonded nitrogen atoms.
Surprisingly, the chemistry (including bioactivity) of tri-
azanes has not been widely investigated.7 There is thus still
a need for new data on the properties of triazanes. We
therefore initiated a program devoted to the chemistry of
singly bonded polynitrogen compounds. We report herein
that, upon choosing appropriate conditions, it is possible to
direct the oxidation of benzyltriazanes selectively toward
C- or N-oxidation and access varied polynitrogenated
structures.
DOI: 10.1055/s-0036-1591865; Art ID: st-2017-d0762-l
Abstract The oxidation of several benzyltriazanes has been studied.
Routes to the selective formation of triazenes, azimines, and triazones
via C- or N-oxidation (and rearrangement) were devised. The rich reac-
tivity of triazanes shows that trinitrogen chains are interesting func-
tions, whose reactivity has been overlooked despite their interest as
3-N building blocks.
Key words hydrazines, hypervalent iodine, oxidation, azimines,
triazanes
Hydrazines form a fascinating family of compounds
with an extraordinary rich chemistry.1 The single N–N bond
is indeed the source of a very peculiar reactivity that makes
hydrazines both good nucleophiles and reducing agents. In
addition, the two nitrogen atoms can complex metals, add-
ing to the reactivity. As a consequence, hydrazines are used
in various fields, such as asymmetric synthesis2 and as
peptidomimetics.3 They are also ubiquitous building blocks
for heterocyclic synthesis.4
Table 1 Preparation of the N-Benzyl-Triazanes
H
H
Boc
N
Ar
N
N
N
Boc
Ar
NH2
N
Boc
MeCN, rt
R
Boc
R
Entry
Ar
R
Product, yield (%)
A subset of the latter, carbon-poor, low-molecular
weight hydrazines are energetic compounds,5 whose oxida-
tion generates dinitrogen and has been applied in propul-
sion systems, particularly as fuels for space propulsion. In
particular, our department has devised an industrial pro-
cess for the production of monomethyl hydrazine (MMH),
which is still in use.6
Unfortunately, some of the same properties that make
hydrazines appealing reagents are also responsible for
problems. In particular, hydrazines are usually carcinogenic
and this means that strict precautions must be used when
handling all hydrazines, and their use on an industrial scale
is subject to strict regulations, compliance which signifi-
cantly adds to the costs of the end products.
1
2
3
4
5
6
7
8
9b
Ph
H
1a, 60
1b, 38
1c, 41
1d, 33a
1e, 28
1f, 33
1i, 18
p-MeC6H4
p-ClC6H4
p-MeOC6H4
2-Py
H
H
H
H
o-ClC6H4
p-CNC6H4
Ph
H
H
Me
Ph
1g, 31
1h, 11
Ph
a Triazane 1d was obtained as a mixture with the reduced DTBAD
(1d/R = 65:35).
b Ethanol was used as solvent.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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A. Glowacki et al.
Letter
Synlett
The route to triazanes involves the addition of an amine
to an electron-poor diazene.7c,d,8 We prepared an array of
nine N-benzyl-triazanes from di-tert-butyl azodicarboxyl-
ate (DTBAD) and a range of benzylamines (Table 1). The
amines were chosen in order to vary electronic effects on
the aromatic ring, as well as steric hindrance at the benzylic
carbon. All reactions were performed in acetonitrile at
room temperature, except for benzhydrylamine, which re-
quired ethanol to give a satisfactory yield (Table 1, entry 9).
The triazanes were isolated in yields ranging from 11%
(Table 1, entry 9) to 60% (Table 1, entry 1). The lower yields
are due to an undesired oxidation of the benzylamine,
which reduces the DTBAD to the corresponding hydrazine,
and probably generates an imine. The putative imines are
not stable and their hydrolysis leads to the corresponding
aldehydes or ketones, which could be observed by 1H NMR
spectroscopy. The byproducts were eliminated by column
chromatography, except for in the case of p-methoxy-
benzylamine, where they eluted with the same Rf as the de-
sired product (Table 1, entry 4). The latter was thus taken
forward as a mixture in the oxidation.
We next investigated the oxidation of the benzyltri-
azanes with different oxidants. The only report on this
comes from Dreiding and co-workers, who showed that
lead(IV) acetate induced the oxidation of three aryl-tri-
azanes to the corresponding azimines, which are 1,3-di-
poles with a N(–)–N(+)=N connectivity.8 Our systems are
more complex because the benzylic position can also po-
tentially be oxidized, opening chemoselectivity issues. In
other words, benzyltriazanes could lead to either C-oxida-
tion (to the corresponding hydrazone-type compounds) or
N-oxidation to the azimines. In addition, the 3-N chain
could also fragment, owing to its intrinsic fragility.
In stark contrast to the single precedent, the reaction of
triazane 1a with Pb(OAc)4 in cold dichloromethane and in
the presence of a base to buffer the reaction mixture selec-
tively delivered triazone 2a in 89% yield (Table 2, entry 1).
When the reaction was carried out in the absence of base,
some triazene 3a was isolated (19%, Table 2, entry 2), but
the triazone remained the main product of the reaction; al-
beit the overall yield decreased. We next considered less
toxic iodine(III) reagents as greener alternatives to the toxic
lead derivative. Nicolaou and co-workers had shown that
IBX converts benzylamines into benzylimines. However,
benzylhydrazines behaved in a much more complex way, as
the reaction delivered bimolecular coupled adducts, with
overall loss of two nitrogens.9
For the oxidation of the higher order triazane 1a, we
considered Dess–Martin periodinane (DMP), phenyl-
iodine(III) bis(trifluoroacetate) (PIFA), and phenyliodine(III)
diacetate (PIDA). DMP delivered mostly unreacted triazane,
with the triazone as the main oxidized product (Table 2,
entry 3). In contrast, PIFA led to degradation (Table 2, entry
4). Interestingly, when 1a was treated with PIDA at 0 °C in
Table 2 Optimization of the Triazane Oxidation
H
H
H
conditions
Ph
N
N
Ph
N
N
N
Boc
N
Boc
Boc
Boc
1a
2a
Boc
Ph
N
N
+
N
Boc
3a
Entry
Conditionsa
2a (%b)
3a (%b)
1
2
3
4
5
6
7
8
9
Pb(OAc)4, K2CO3, –78 °C, CH2Cl2
Pb(OAc)4, CH2Cl2, –78 °C
DMP, K2CO3, EtOH, 0 °C
PIFA, K2CO3, EtOH, 0 °C
PIDA, K2CO3, EtOH, 0 °C
PIDA, K2CO3, –20 °C, EtOH,
PIDA, K2CO3, EtOH, 20 °C
PIDA, EtOH, 0 °C
89
41
23
–
–
19
5c
6
31
20
26
37
–
40
11d
41
62
52
PIDA (2 equiv), EtOH, 0 °C
a All reactions were stopped after 0.5 h. The yields were determined by
1H NMR spectroscopy using 1,2-dichloroethane as internal standard.
b isolated yields unless otherwise specified.
c 72% of starting material was recovered.
d 68% of starting material was recovered.
the presence of a base, triazene 3a became the major prod-
uct,10 although a significant amount of triazone 2a was also
isolated (40 vs. 31%, Table 2, entry 5). Of note, a migration of
the Boc group also took place, and therefore no azimine was
obtained. The structure of 3a was confirmed by X-ray anal-
ysis (Figure 1). We presume that the azimine formed first,
but rearranged to the observed product via a 1,2-Boc shift,
owing to the close proximity of the negatively charged
nitrogen to the carbonyl of the Boc. Lowering the tempera-
ture to –20 °C resulted in a dramatic reactivity loss (68%
recovered starting material, Table 2, entry 6), while running
the reaction at 20 °C resulted in no change relative to the
reaction at 0 °C (Table 2, entry 7). In the absence of a base,
the ratio of N- vs. C-oxidation increased to 1.5:1 (Table 2,
entry 8), suggesting that oxidation to the triazone was
again slightly favored by the base. When an excess of
oxidant was used (Table 2, entry 9), only the triazene 3a
was isolated but its overall yield was not improved.
To conclude, we have established conditions to favor ei-
ther C-oxidation or N-oxidation of benzyl-triazanes. In both
cases, the overall trinitrogen architecture is retained but
the reactivity is significantly different from that of aryl-tri-
azanes. The use of basic reagents seems to favor C-oxida-
tion. The triazones are also less stable to the reaction condi-
tions, which permits the triazenes to be obtained selectively.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

C
A. Glowacki et al.
Letter
Synlett
material. However, 2d was not separable from 1d. The oxi-
dation was carried out on the purified mixture of 1d and
the hydrazine byproduct. The hydrazine may complex the
Pb(OAc)4 blocking the reaction at about 50% conversion;
while more equivalents of the reagent led to degradation.
Nonetheless, the yield, calculated based on the recovered
starting material, is 96%, suggesting the oxidation is very
efficient in that case. On the other hand, using a pyridine
heteroaromatic ring was completely detrimental, as most of
1e was destroyed in the reaction and only 10% of 2e was
isolated (Table 3, entry 5). Finally, the reaction can be com-
patible with increased substitution at the benzylic position
(87% of 2h, which features an additional phenyl substitu-
ent, Table 3, entry 9). Surprisingly, though, the α-methyl
benzylamine derived triazane 1g was completely decom-
posed under the oxidation conditions (Table 3, entry 8). It is
not clear why, though we propose that the activated allylic
proton in 2g might be deprotonated under the reaction
conditions, leading to degradation.
Figure 1 Structure of 3a
Table 3 Scope of the Formation of Triazones
H
H
H
Pb(OAc)4, K2CO3
R1
N
N
R1
N
N
N
Boc
With the synthesis of the triazones in hands, we then
tried to direct the oxidation to the other end of the triazane.
To do this we selected the conditions of Table 2, entry 9, with
the hypervalent iodine reagent PhI(OAc)2 as the oxidant.
N
Boc
CH2Cl2, –78 °C to rt
R2
Boc
R2
Boc
1a–i
2a–i
Entry
S. M.
R1
R2
Product, yield (%)a
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
Ph
H
2a, 89
2b, 86
2c, 60
2d, 48b
2e, 10
2f, 65
2i, 79
–
Table 4 Scope of the Formation of the Triazenes
p-MeC6H4
p-ClC6H4
p-MeOC6H4
2-Py
H
H
Boc
H
H
PhI(OAc)2
EtOH, 0 °C
R1
N
N
R1
N
N
H
N
Boc
N
Boc
R2
R2
Boc
3a–h
H
1a–h
o-ClC6H4
p-CNC6H4
Ph
H
Entry
S. M.
R1
R2
3, yield (%)
2, yield (%)
1i
H
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
Ph
H
H
H
3a, 52
3b, 48
3c, 47
3d, 56
3e, 29
3f, 44
3g, 38
3h, 10
–
1g
1h
Me
Ph
p-MeC6H4
p-ClC6H4
2b, 24
2c, 15
2d, 19
–
Ph
2h, 87
a Yields were determined by 1H NMR spectroscopy using 1,2-dichloro-
ethane as internal standard.
p-MeOC6H4
2-Py
H
b 1d was reacted further as a mixture with a byproduct (see Table 1); 48%
of starting material was recovered.
H
o-ClC6H4
Ph
H
2f, 19
C6H4
C6H4
1g
1h
Me
Ph
With these two sets of conditions in hands we looked to
establish the scope of these oxidations with regard to the
benzyl moiety. We started with the lead-mediated forma-
tion of hydrazones of triazanes (triazones).
Ph
In all cases, where the starting materials feature func-
tionalized benzyl substituents, the corresponding triazenes
were obtained in similar yields: 52% to the parent benzyl
substrate (Table 4, entry 1); 48% for a p-methyl (Table 4,
entry 2), 47% for a p-chloro (Table 4, entry 3), 56% for a p-
methoxy (Table 4, entry 4), and 44% for an o-chloro substit-
uent (Table 4, entry 6). This was accompanied by various
amounts of triazones. It is very likely that the substituents
affect the stability of the latter, resulting in more or less
degradation. However, in all cases, the triazenes were the
major products of the reactions. Although 2-pyridyl tri-
azane 1e delivered a low yield of 3e (and no triazone, Table
4, entry 5) probably because the pyridine ring interacts
with the hypervalent iodine reagent. Finally, steric
As deprotonation of the benzylic position is a crucial
feature of the oxidation (see below), we first looked at how
substituents on the aryl ring affected the reaction. The oxi-
dation worked well with a substrate with an additional
alkyl group (Table 3, compare entries 1 and 2). A chlorine
atom either in the para or ortho position was accepted, but
it was accompanied by some degradation (60% yield for 2c,
Table 3, entry 3; 65% yield for 2f, Table 3, entry 6). The elec-
tron-withdrawing p-CN substituent was also conducive to
the oxidation conditions (79%, Table 3, entry 7). On the con-
trary, a p-methoxy derivative gave a lower 48% NMR yield
(Table 3, entry 4), together with 48% of recovered starting
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

D
A. Glowacki et al.
Letter
Synlett
hindrance at the benzylic position proved highly detrimen-
tal (Table 4, entries 7 and 8). Given that an additional
phenyl led to a much lower yield (10%, Table 4, entry 8) than
a methyl (38%, Table 4, entry 7), we believe that steric hin-
drance is the governing factor in this case.
Finally, we considered whether the protecting group
pattern on the triazane might block the rearrangement. If
the benzyl substituent were in the 2-position (hence a
tertiary nitrogen), with one Boc protecting group on each
side, then the only path open to the molecule would be the
oxidation to an azimine (see Scheme 1).
trinitrogen chain. In the latter case, the substitution pattern
on the triazane directs the oxidation toward further rear-
rangement to triazenes12 (with 2,3-bisprotected triazanes),
or toward the formation of azimines (1,3-bisprotected tri-
azanes). The rich reactivity of triazanes shows that trinitro-
gen chains are interesting functions, whose reactivity has
been overlooked. The triazones could be interesting new
ligands for transition metals, while the triazenes may lead
to nitrogen-centered radicals and/or serve as radical initia-
tors.
Funding Information
CN
O
H
t-BuO
N
NHBoc
O
We thank the CNRS, CNES, ArianeGroup and Université C. Bernard-
Lyon 1 for funding, including a doctoral stipend for AG. VJ thanks the
CNES for a postdoctoral fellowship.
NH2
(2 equiv)
N
NHBoc
4, 59%
toluene, rt
)(
via
NBoc
N
PhI(OAc)2
EtOH, 0 °C
NHBoc
Acknowledgment
Boc
N
AcO–
NBoc
H
N
I
OAc
Dr. C. Félix (UCBL) is acknowledged for helpful discussions. We thank
R. Silva Costa for carrying out some experiments.
Bn
5, 63%
Ph
Scheme 1 Access to azimine 5
Supporting Information
To generate the corresponding triazane 4, we started
from a report by Collet et al. who introduced a method to
generate hydrazines by electrophilic amination of amines.11
The N+ source was an oxaziridine. The authors observed
that symmetric triaziridines were also obtained as minor
byproducts, which they sought to eliminate. Thus we re-op-
timized the conditions toward the formation of 4. This was
achieved by using two equivalents of oxaziridine oxidant
and toluene as solvent. In this way, 4 was obtained in 59%
yield. Triazane 4 was then oxidized using the conditions in
Table 4, and azimine 5 was obtained in 63% yield. An X-ray
structure was obtained for 5, which confirmed our initial
structural attribution (Figure 2).
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591865.
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References and Notes
(1) Schmidt, E. W. Hydrazines and its Derivatives, Preparation, Prop-
erties, Applications, 2nd ed.; Wiley: New York NY, 2001.
(2) (a) Beauchemin, A. Org. Biomol. Chem. 2013, 11, 7039.
(b) Heravi, M. M.; Zadsirjan, V.; Daraie, M. Curr. Org. Synth.
2017, 14, 61.
(3) Chingle, R.; Proulx, C.; Lubell, W. D. Acc. Chem. Res. 2017, 50,
1541.
(4) Joule, J. A.; Mills, K. Heterocyclic Chemistry; Wiley-Blackwell:
Hoboken, NJ, 2010, 5th ed..
(5) (a) Nonnenberg, C.; Frank, I.; Klapoetke, T. M. Angew. Chem. Int.
Ed. 2004, 43, 4586. (b) Osmont, A.; Catoire, L.; Klapoetke, T. M.;
Vaghjiani, G. L.; Swihart, M. T. Propellants, Explos., Pyrotech.
2008, 33, 209.
(6) (a) Delalu, H.; Marchand, A. J. Chim. Phys. Phys.-Chim. Biol. 1984,
81, 149. (b) Delalu, H.; Marchand, A.; Ferriol, M.; Cohen-Adad, R.
J. Chim. Phys. Phys.-Chim. Biol. 1981, 78, 247. (c) Cohen-Adad, R.;
Delalu, H.; Herzig, J.-P. FR 2396743A1, 1979. (d) Ferriol, M.;
Abraham, R.; Delalu, H.; Saugier-Cohen-Adad, M. T. J. Chim.
Phys. Phys.-Chim. Biol. 1982, 79, 725.
(7) (a) Armstrong, A.; Jones, L. H.; Knight, J. D.; Kelsey, R. D. Org.
Lett. 2005, 7, 713. (b) Vidal, J.; Guy, L.; Sterin, S.; Collet, A. J. Org.
Chem. 1993, 58, 4791. (c) Kanzian, T.; Mayr, H. Chem. Eur. J.
2010, 16, 11670. (d) Egger, N.; Hoesch, L.; Dreiding, A. S. Helv.
Chim. Acta 1983, 66, 1416. (e) Egger, N.; Hoesch, L.; Dreiding, A.
S. Helv. Chim. Acta 1983, 66, 1599.
Figure 2 Structure of 5
(8) Egger, N.; Hoesch, L.; Dreiding, A. S. Helv. Chim. Acta 1983, 66,
1599.
(9) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. J. Am. Chem.
Soc. 2004, 126, 5192.
To conclude, we have studied the oxidation of several
benzyl-triazanes. Depending on the reaction conditions, it
is possible to oxidize selectively either the α-carbon or the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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A. Glowacki et al.
Letter
Synlett
(10) Triazenes are important compounds with a rich reactivity, see:
(a) Patil, S.; Bugarin, A. Eur. J. Org. Chem. 2016, 860. (b) Koelmel,
D. K.; Jung, N.; Braese, S. Aust. J. Chem. 2014, 67, 328. (c) Dong,
W.; Chen, Z.; Xu, J.; Miao, M.; Ren, H. Synlett 2016, 27, 1318.
(11) Vidal, J.; Damestoy, S.; Guy, L.; Hannachi, J.-C.; Aubry, A.; Collet,
A. Chem. Eur. J. 1997, 3, 1691.
(12) General Procedure for the Formation of Triazones
The triazane (0.5 mmol) was dissolved in CH2Cl2 (4 mL) under
N2 at rt K2CO3 (10 equiv) and lead(IV) acetate (1 equiv, 85%)
were added at –78 °C. The cold bath was removed, and the reac-
tion mixture was stirred for 30 min. The precipitate was filtered
off and washed several times with CH2Cl2. The combined organ-
ics extracts were concentrated in vacuo and purified by column
chromatography.
ESI-HRMS: m/z calcd [M+H]+: 336.1918; found: 336.1924 (1.8
ppm). IR (neat): ν = 1450, 1479, 1720, 2979, 3287 cm–1; mp
106°C, decomp: 159°C.
General Procedure for the Formation of Triazenes or
Azimines
The triazane (0.5 mmol) was dissolved in EtOH (10 mL) under
N2 at rt PhI(OAc)2 (2.2 equiv) was added at 0 °C, and the reaction
mixture was stirred for 30 min at 0 °C. Water was then added,
and the mixture was extracted three times with EtOAc. The
combined organic extracts were washed with water and brine,
dried over MgSO4, filtered, and the solvent removed. The tri-
azenes (or azimine) were purified by chromatography.
Compound 5: 1H NMR (400 MHz, CDCl3): δ = 1.52 (s, 18 H, t-Bu),
5.50 (s, CH2), 7.36–7.38 (m, 3 H, Ar), 7.48–7.51 (m, 2H, Ar).
13C NMR (100 MHz, CDCl3): δ = 28.2 (Me, t-Bu), 74.3 (CH2), 82.8
(C, t-Bu), 128.8 (CH, Ar), 129.0 (CH, Ar), 129.2 (CH, Ar), 132.3 (C,
Ar), 156.7 (C=O). ESI-HRMS: m/z calcd [M + Na]+: 358.1737;
found: 358.1720 (4.8 ppm). IR (neat): ν = 1467, 1690, 1704,
2927, 2975 cm–1; mp 145–146 °C, decomp.: 150 °C.
Compound 2a: 1H NMR (400 MHz, CDCl3) δ: 1.50 and 1.58 (bs +
s, 18H, t-Bu), 6.45 (s, 1H, NH), 7.35–7.39 (m, 3H, Ar), 7.71–7.75
(m, 2H, Ar), 7.92 (s, 1H, CH=N). 13C NMR (100 MHz, CDCl3)
δ: 28.0 (Me), 82.3 (C-N), 82.9 (C-N), 127.6 (CH), 128.4 (CH),
129.6 (CH), 134.0 (C), 139.5 (CH=N), 151.6 (C=O), 153.8 (C=O).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E