1,2,4-Triazole Synthesis via Amidrazones

Article abstract of DOI:10.1055/s-0030-1258117

We present a two-step procedure for the synthesis of 1,2,4-triazole derivatives from a primary amide and a hydrazine via an oxidative process. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258117

LETTER
1771
1,2,4-Triazole Synthesis via Amidrazones
1, 2,4-Triazole
S
a
ynthesis vi
u
a
Amidrazon
r
es ent El Kaim,* Marion Gizzi, Laurence Grimaud*
Laboratoire Chimie et Procédés, Ecole Nationale Supérieure de Techniques Avancées, 32 Boulevard Victor, 75739 Paris Cedex 15, France
Fax +33(1)45528322; E-mail: laurent.elkaim@ensta.fr; E-mail: laurence.grimaud@ensta.fr
Received 13 April 2010
of a primary amine in acetonitrile in the presence of two
Abstract: We present a two-step procedure for the synthesis of
equivalents of triethylamine to form the desired amidra-
zones (Scheme 2).
an oxidative process.
1,2,4-triazole derivatives from a primary amide and a hydrazine via
Key words: triazoles, hydrazone, oxidation
Ph
Ph
Ph
NH
NH
NH
1. n-BuNH2
DMF, 85 °C
N
N
N
NCS
Faced with growing concern about environmental issues,
chemists have had to revise many synthetic processes that
used one or several equivalents of reagents associated
with waste disposal problems. In the case of oxidative
processes, this trend has led to shifting from traditional re-
actions with stoichiometric amounts of metals (chromi-
um, lead, silver) to catalytic transformations using oxygen
or peroxides as cooxidants.1 Thus, recent years have seen
a renewed interest in copper- and palladium-catalyzed ox-
idations.2 Whenever heterocyclic derivatives are con-
cerned, the formation of aromatic systems is an additional
driving force for these reactions and some oxidations may
even be observed under air without any metal assistance.3
Me2S, CH2Cl2
2. Et3N, O2
Ar
H
Ar
Cl
Ar
NHn-Bu
77%
Ar = 4-ClC6H4
Scheme 2 Amidrazone synthesis from hydrazones
The oxidation process was then evaluated under classical
conditions using a base, such as triethylamine and a cata-
lytic amount of Pd(OAc)2 in N,N-dimethyl formamide
(DMF) as solvent at 85 °C. The reaction was performed in
an open flask to ensure oxygenation of the reaction mix-
ture. Under these conditions, the corresponding 1,2,4-tri-
azole was isolated in a 96% yield. However, it turned out
that the reaction did not require a catalyst as similar results
were obtained without adding palladium salts and within
the same length of time. The whole sequence was further
optimized, leading to a one-pot procedure. For this pur-
pose, after completion of the hydrazone chlorination in
dichloromethane, the solvent was removed under reduced
pressure. DMF was then added to the crude chlorohydra-
zone, followed by butylamine and then triethylamine. The
resulting mixture was heated for 12 hours to provide the
corresponding triazole in 77% yield (Scheme 3). Despite
this simple and high-yielding overall procedure, we were
not yet fully satisfied, as the reactions were very sensitive
to the quality of the amine (distilled or not) and, although
R2
R2
R2
N
NH
NH
N
N
N
R3
NH2
R3
R3
N
R1
N
H
amine as
solvent
R1
R1
NO2
Scheme 1 1,2,4-Triazole access from amidrazones
Following our interest in hydrazone chemistry,4 we re-
ported a few years ago a triazole synthesis based on the
coupling of a nitrohydrazone and a primary amine used as
solvent (Scheme 1).5 This process involved multiple oxi-
dation steps from an intermediate amidrazone. Such a
transformation had previously been observed on treat-
ment with silver or lead as oxidant,6 leading us to assume
that a key step in the mechanism involved nitrite anion
loss. The fact that the yields were raised by the addition of
sodium nitrite further endorsed this analysis (Scheme 1).
Ph
Ph
Ph
NH
NH
1. n-BuNH2
DMF, 85°C
N
N
N
N
NCS
C3H7
Me2S, CH2Cl2
N
2. Et3N, O2
Ar
H
Ar
Ar
Cl
77%
In order to study this reaction more carefully, we decided
to form the intermediate amidrazone using a synthetic
path that avoided preparation of the nitrohydrazone7 and
chlorohydrazones were initially investigated.8 These were
generated by the chlorination of the corresponding hydra-
zones with N-chloro succinimide.6b The resulting crude
chloro hydrazones were then treated with one equivalent
Ar = 4-ClC6H4
Scheme 3 1,2,4-Triazole synthesis from hydrazones
Ar
O
1. (COCl)2, CH2Cl2
N
N
2,6-lutidine
C3H7
N
C3H7
2. ArNHNH2,
DMF, O2
H
N
Cl
1a
60%
2a
SYNLETT 2010, No. 12, pp 1771–1774
x
x
.x
x
.2
0
1
0
Cl
Advanced online publication: 30.06.2010
DOI: 10.1055/s-0030-1258117; Art ID: D09510ST
Scheme 4 1,2,4-Triazole synthesis from primary amides
© Georg Thieme Verlag Stuttgart · New York

1772
L. El Kaim et al.
LETTER
Ph
Ph
1. (COCl)2, CH2Cl2
2,6-lutidine
O
N
N
N
N
2. PhNHNH2,
DMF, O2
Ar
NHCy
OH
4
N
N
Ar
Ar
H
1b
Ar = 4-ClC6H4
2b
29%
Scheme 5 Reactions with a-branched amides
only formed as intermediates, chlorohydrazones are high- Considering the transformation of the amino residue, one
ly allergenic derivatives. As these issues could discourage might be surprised that an oxidation under such mild con-
chemists from using this process, we decided to evaluate ditions could occur. Indeed, a-amino CH2 groups usually
alternative strategies.
need to be further activated by a aryl group or another
electron-donating atom in order to be easily oxidized. The
reaction is most probably controlled by the hydrazone
moiety. These groups are rather sensitive to oxygen under
UV irradiation, yielding hydroperoxides in a radical chain
reaction. In the case of amidrazones, the elimination of
H2O2 forms an azoimine. Further prototropy, cyclization
and oxidation finally afford the triazole (Scheme 6).
Amidrazones may also be formed on treatment of imidoyl
chlorides with hydrazine derivatives.9 For this purpose,
different sets of conditions – base, solvent, temperature –
were tested. The best results were obtained by treating the
amide 1a with 1.3 equivalents of oxalyl chloride and 3
equivalents of 2,6-lutidine in dichloromethane over using
4 Å molecular sieves at 0 °C under argon. After the com-
plete conversion of the starting material, the reaction mix-
ture was diluted with DMF, and one equivalent of the
arylhydrazine – pre-dried over potassium carbonate – was
added. The resulting solution was stirred at 80 °C under
air with protection from moisture for 12 hours. Under
these conditions, the resulting 1,2,4-triazole 2a was isolat-
ed in a 60% yield (Scheme 4).
NHPh
NPh
N
NPh
N
N
O
N
O2
H
N
R
hν
Ar
N
R
Ar
R
H
Ar
H
H2O2
HO
Ph
Ph
NHPh
N
N
N
N
N
O2
N
R
Using this optimized one-pot two-step procedure, various
1,2,4-triazoles were synthesized from the corresponding
secondary amides in modest to good yields (Table 1). This
reaction gives good results with aromatic amides and tol-
erates both electron-withdrawing (Table 1, entries 1–8)
and electron-donating groups (Table 1, entry 9) on the ar-
omatic core. However, no triazole could be isolated from
aliphatic amides (Table 1, entry 10). Tertiary amides do
not react either under these conditions.
R
N
Ar
N
R
Ar
Ar
H
Scheme 6 Proposed mechanistic pathway
In conclusion, we have described herein a new 1,2,4-tria-
zole synthesis from amidrazones. Based on an open-flask,
air-tolerant procedure, the reaction probably starts with a
radical oxidative process of the hydrazone moiety.10 Most
interestingly, this reaction implies a formal C–H activa-
tion of the amine residue. We are currently exploring the
extension of this reaction to a more general C–H activa-
tion strategy via the conversion of primary amines to
bulky amidrazones reluctant to cyclization.
When the a-branched amide 1b was involved, we isolated
the 1,2,4-triazole 2b with the aliphatic ring having been
opened (Scheme 5). The formation of this product may be
explained by the oxidative cleavage of a spiro triazoline
intermediate.
Table 1 One-Pot Two-Step Triazole Synthesis
Entry
Starting amide
Product
Yield (%)
41
Ph
O
N
N
OMe
1
N
H
N
Cl
OMe
Cl
Cl
Ph
O
OMe
N
N
OMe
2
38
N
H
N
Cl
Synlett 2010, No. 12, 1771–1774 © Thieme Stuttgart · New York

LETTER
1,2,4-Triazole Synthesis via Amidrazones
1773
Table 1 One-Pot Two-Step Triazole Synthesis (continued)
Entry
3
Starting amide
Product
Yield (%)
66
Ph
O
Ph
N
N
N
N
N
H
Ph
N
Cl
Cl
Cl
Ph
O
N
4
5
6
7
64
34
50
55
N
H
N
Cl
Ph
O
N
O
N
H
N
O
Cl
Cl
Ph
O
Ph
N
N
N
Ph
N
H
F
F
Ph
O
N
N
N
H
N
F3C
F3C
Ph
O
N
N
8
30
N
H
N
O2N
O2N
Ph
O
N
N
9
54
–
N
N
H
MeO
Ph
MeO
O
10
–
N
Pr
H
Typical Procedure for 2a
(10 × 1 mL), and dried over anhyd MgSO4. The solvent was re-
moved under reduced pressure to afford 5-alkyl-3aryl-1-phenyl-
1H-1,2,4-triazole 2a (180 mg, 60% yield) after purification by flash
column chromatography (Et2O–PE = 20:80) on silica gel; mp 105–
106 °C. 1H NMR (400 MHz, CDCl3): d = 8.11 (d, 2 H, J = 8.7 Hz),
7.58–7.48 (m, 5 H), 7.43 (d, 2 H, J = 8.7 Hz), 2.82 (t, 2 H, J = 7.7
Hz), 1.88–1.79 (m, 2 H), 0.99 (t, 3 H, J = 7.3 Hz). 13C NMR (100.6
MHz, CDCl3): d = 160.9, 157.5, 137.9, 135.4, 130.0, 129.9, 129.5,
129.2, 128.2, 125.7, 28.9, 21.9, 14.2. HRMS: m/z calcd for
C33H36N4O2: 520.2838; found: 520.2839.
A solution of amide (1 mmol) in CH2Cl2 (1.5 mL) over activated 4
Å MS and under an argon atmosphere was cooled to 0 °C. Then,
2,6-lutidine (350 mL, 3.0 equiv) and oxalyl chloride (114 mL, 1.3
equiv) were successively added dropwise. After stirring for 1 h at
r.t., DMF (2 mL) and phenylhydrazine (predried over KOH, 130
mL, 1.3 equiv) were added. The flask was equipped with a drying
tube filled with KOH, and the reaction mixture was stirred for an ad-
ditionnal 12 h at 80 °C. The mixture was then extracted with Et2O
(20 mL). The combined organic phases were washed with H2O
Synlett 2010, No. 12, 1771–1774 © Thieme Stuttgart · New York

1774
L. El Kaim et al.
LETTER
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Acknowledgment
Financial support was provided by ENSTA. M.G. thanks the Délé-
gation Générale de l’Armement for a fellowship.
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