Diethoxyphosphinyl acetic acid hydrazide: A uniquely versatile reagent for the preparation of fused [5,5]-, [5,6]-, and [5,7]-3-[(E)-2-(arylvinyl)]-1,2,4- triazoles

Article abstract of DOI:10.1016/j.tetlet.2004.01.015

Diethoxyphosphinyl acetic acid hydrazide is a unique reagent that provides a convenient and efficient process to prepare fused [5,5]-, [5,6]-, and [5,7]-3-[(E)-2-(arylvinyl)]-1,2,4-triazoles from aldehydes and alkoxyimines. The process involves three steps without isolation of any intermediates to afford 1,2,4-triazoles in modest to excellent overall yield.

Full text of DOI:10.1016/j.tetlet.2004.01.015

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1877–1880
Diethoxyphosphinyl acetic acid hydrazide: a uniquely versatile
reagent for the preparation of fused [5,5]-, [5,6]-, and [5,7]-3-[(E)-2-
(arylvinyl)]-1,2,4-triazoles
Fuqiang Liu, David C. Palmer* and Kirk L. Sorgi
Drug Evaluation Chemical Development, Johnson and Johnson Pharmaceutical Research and Development, L.L.C., 1000 Route 202,
Raritan, NJ 08869, USA
Received 16 December 2003; revised 22 December 2003; accepted 5 January 2004
Abstract—Diethoxyphosphinyl acetic acid hydrazide is a unique reagent that provides a convenient and efficient process to prepare
fused [5,5]-, [5,6]-, and [5,7]-3-[(E)-2-(arylvinyl)]-1,2,4-triazoles from aldehydes and alkoxyimines. The process involves three steps
without isolation of any intermediates to afford 1,2,4-triazoles in modest to excellent overall yield.
Ó 2004 Elsevier Ltd. All rights reserved.
Fused 1,2,4-triazoles represent an interesting class of
compounds due to their versatile biological activity and
their synthesis has attracted the attention of several
synthetic groups.1 The most common synthetic route to
1,2,4-triazoles involves the condensation of an alkoxy-
imine with an acyl hydrazide to give an intermediate
amidrazone that then cyclodehydrates to yield a 1,2,4-
triazole (Scheme 1).2
by modification of the literature method.5;6 Thus, con-
densation of a cyclic alkoxyimine 2 with 1 followed by
Horner–Emmons reaction7 of the resulting phosphonate
with an aromatic or heterocyclic aldehyde and sub-
sequent cyclodehydration should provide the fused
3-[(E)-2-(arylvinyl)]-1,2,4-triazoles (Scheme 2).
We began our model study with the commercially
available seven-membered ring alkoxy imine, 3,4,5,6-
tetrahydro-7-methoxy-2H-azepine 2a. Condensation of
2a with 1 in methylene chloride at room temperature
provided, after concentration, the crude amidrazone 3 as
a yellow oil. Subsequently, the Horner–Emmons reac-
tion was carried out with benzaldehyde in EtOH at
room temperature using NaOEt as the base to give 3-
phenyl-N0-(4,5,6,7-tetrahydro-3H-azepin-2-yl)acrylic acid
hydrazide 4 as a yellow oil. The 1H NMR spectra
showed a purity of >95% for each of the intermediates 3
and 4. Cyclodehydration of 4 was accomplished in
refluxing toluene with a catalytic amount of HOAc to
afford trans-3-styryl-6,7,8,9-tetrahydro-5H-[1,2,4]triaz-
olo[4,3-a]azepine 5a in 36% overall yield from 1 (Scheme
3).
We required a versatile synthesis of fused-[(E)-2-(aryl-
vinyl)]-1,2,4-triazoles (Scheme 1), n ¼ 2, 3, 4; R2 ¼ [(E)-
2-(arylvinyl)], in which an a,b-unsaturated hydrazide
was considered as a possible starting material.3 How-
ever, syntheses of a,b-unsaturated hydrazides from
alcohol, aldehyde, acid, or ester precursors are often a
multi-step process and can be problematic and tedious.4
This prompted us to search for a new, straightforward
synthetic method for the triazole ring system that would
avoid the preparation of the problematic a,b-unsatu-
rated hydrazide.
Retrosynthetically, the target compounds could be
constructed from three precursors: an aldehyde, an
alkoxyimine 2, and diethoxyphosphinyl acetic acid
hydrazide 1, which is readily prepared in excellent yield
The successful synthesis of 5a in a stepwise manner,
prompted us to explore a more convenient and efficient
construction of the 1,2,4-triazole system by combining
all three reactions in a single operation. We found that
the synthesis was readily achieved in one pot using tolu-
ene as the solvent. In the event, the alkoxyimine reacts
with 1 in toluene at room temperature after which a 21%
Keywords: Fused triazoles; Horner–Emmons reaction; Diethoxyphos-
phinyl acetic acid hydrazide; Hydrazides; Alkoxyimines.
* Corresponding author. Tel.: +1-908-704-4369; fax: +1-908-526-6469;
e-mail: dpalmer@prdus.jnj.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.015

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F. Liu et al. / Tetrahedron Letters 45 (2004) 1877–1880
(CH2)n
(CH2)n
O
(CH2)n
N
H
O
N
N
N
N
+
R2
NHNH2
N
OR1
NH
R2
R2
Scheme 1.
O
O
NHNH2
+
N
H
O
N
N
N
N
R1CHO +
NH
N
OR3
(EtO)2P
R1
O
2
1
(EtO)2P
R1= (E)-2-arylvinyl
Scheme 2.
O
(EtO)2PCH2CONHNH2
N
1. NaOEt,
EtOH
2. PhCHO
N
O
HOAc (cat)
toluene,
reflux
N
1
NH
NH
NH
NH
O
N
N
CH2Cl2, rt
O
N
OMe
2a
(EtO)2P
Ph
Ph
3
4
5a
Scheme 3.
solution of NaOEt in EtOH is added followed by the
addition of the aldehyde. The reaction mixture is heated
at reflux for several hours and, after workup, it produces
the fused triazole 5a in 71% yield (Scheme 4).
affords the expected vinyl triazole, for example, 5a
although there can be some variability in yield. How-
ever, when 1, the aldehyde and NaOEt are added to the
alkoxyimine, we observe rapid reaction of the aldehyde
with 1 and formation of the stable acyl hydrazone 7
(stereochemistry not determined; Scheme 5).
We found that the order of addition of reagents is crit-
ical to the success of the reaction. If 1 is added to 2, in
the absence of base or aldehyde, the initial product 3
cyclizes cleanly to the 3-(triazol-5-yl)methyl phospho-
nate 6. Subsequent addition of NaOEt and the aldehyde
Encouraged by these results, we explored the scope and
generality of this methodology. As shown in Table 1,
this is a general method to prepare fused [5,6]- and fused
[5,7]-3-[(E)-2-(arylvinyl)-1,2,4-triazoles and is compati-
ble with aryl groups containing electron donating
groups or electron withdrawing groups as well as five-
and six-membered ring heterocycles. The workup is
straightforward and involves simple concentration of
the toluene solution and addition of water to the residue
to precipitate the desired product in high chemical
purity. It is noteworthy that there was no evidence for
O
1) (EtO)2PCH2CONHNH2, toluene
2) NaOEt/EtOH, PhCHO
3) reflux
N
N
N
OMe
N
Ph
2a
71% 3 steps
5a
1
the (Z)-regioisomer in the H NMR spectrum of the
isolated products. The simplicity of this purification
Scheme 4.
O
N
PhCHO
N
toluene
reflux
(EtO)2P
N
NH
NH
NaOEt, EtOH
O
N
N
O
N
N
(EtO)2P
6
Ph
3
5a
O
O
toluene
+ RCHO
(EtO)2PCH2CONHN
(EtO)2PCH2CONHNH2
R
1
7
Scheme 5.

F. Liu et al. / Tetrahedron Letters 45 (2004) 1877–1880
1879
Table 1. Synthesis of fused 1,2,4-triazoles using diethoxyphosphinylacetic acid hydrazide
n
n
1. 1/toluene, rt
2. NaOEt/EtOH, ArCHO
3. toluene, reflux
N
N
OMe
N
N
(n = 0,1,2)
Ar
5
(n = 0,1,2)
Entry
n
ArCHO
Producta
Ar
Yield (%)
1
2
2
2
2
1
1
1
1
1
0
0
Benzaldehyde
5a
5b
5c
5d
5e
5f
Ph
71
66
72
72
77
81
75
69
57
37b
33c
2
Thiazole-2-carboxaldehyde
4-Methoxybenzaldehyde
4-Cyanobenzaldehyde
Benzaldehyde
Thiazol-2-yl
4-MeO-Ph
4-NC-Ph
Ph
3
4
5
6
4-Chlorobenzaldehyde
4-Methoxybenzaldehyde
Pyridine-2-carboxaldehyde
Thiophene-2-carboxaldehyde
Benzaldehyde
4-Cl-Ph
4-MeO-Ph
Pyrid-2-yl
Thien-2-yl
Ph
7
5g
5h
5i
8
9
10
11
5j
5k
4-Chlorobenzaldehyde
4-Cl-Ph
a The 1H NMR spectra for all products showed the presence of only the (E)-regioisomer.
b 48 h reflux in HOAc to complete the triazole ring closure.
c 72 h reflux in HOAc to complete the triazole ring closure.
procedure further enhances the suitability of the overall
process for large-scale synthesis. The synthesis of 5a in
References and notes
1. (a) Urban, F. J.; Anderson, B. G.; Orrill, S. L.; Daniels, P.
J. Org. Process Res. Dev. 2001, 5, 575; (b) Roma, G.; Di
Braccio, M.; Grossi, G.; Mattioli, F.; Ghia, M. Eur. J.
Med. Chem. 2000, 35, 1021; (c) Mikhailovskii, A. G.
Chem. Heterocycl. Comp. 1998, 34, 163; (d) Duplantier,
Allen J.; Cooper, K. PCT Int. Appl. WO 9639408, 1996;
(e) Shridhar, D. R.; Jogibhukta, M.; Joshi, P. P.; Reddy,
P. G. Indian J. Chem. 1981, 20B, 132.
2. (a) Rito, R.; Gouni, I.; El Ghammarti, S.; Gautret, P.;
Couturier, D. Synth. Commun. 1994, 24, 3055; (b) Bon-
anomi, M.; Baiocchi, L. J. Heterocycl. Chem. 1983, 20,
1657.
3. (a) Hoekstra, W. J.; Lawson, E. C.; Maryanoff, B. E. PCT
Int. Appl. WO 0006570, 2000; (b) Lawson, E. C.;
Maryanoff, B. E.; Hoekstra, W. J. Tetrahedron Lett.
2000, 41, 4533; (c) Lawson, E. C.; Hoekstra, W. J.; Addo,
M. F.; Andrade-Gordon, P.; Damiano, B. P.; Kauffman,
J. A.; Mitchell, J. A.; Maryanoff, B. E. Bioorg. Med.
Chem. Lett. 2001, 11, 2619; (d) Zhang, X.; Breslav, M.;
Grimm, J.; Guan, K.; Huang, A.; Liu, F.; Maryanoff, C.
A.; Palmer, D.; Patel, M.; Qian, Y.; Shaw, C.; Sorgi, K.;
Stefanick, S.; Xu, D. J. Org. Chem. 2002, 67, 9471.
4. (a) Tanaka, K.; Matsuo, K.; Nakanishi, A.; Hatano, T.;
Izeki, H.; Ishida, Y.; Mori, W. Chem. Pharm. Bull. 1983,
31, 2810; (b) Lifka, T.; Meier, H. J. Prakt. Chem./Chem.
Ztg. 1995, 337, 641.
an overall yield of 71% (Scheme 5, Table 1, entry 1) is a
representative example that illustrates the effectiveness
of this one-pot process.8;9
However, we did encounter a limitation when we used
the one-pot approach to prepare fused [5,5]-3-(2-aryl-
vinyl)-1,2,4-triazoles. In this case there was no evidence
for the desired product even after prolonged heating (up
to 72 h) in toluene. However, if the precursor acrylic acid
analogue is isolated it could be cyclized, albeit in modest
yield (Table 1, entries 10 and 11), by prolonged heating
in acetic acid (2–3 days) to generate the desired fused
[5,5]-3-[(E)-2-(arylvinyl)]-1,2,4-triazole.10 Presumably,
the modest yields reflect the known difficulty of con-
structing such fused [5,5]-1,2,4-triazoles due to ring
strain.11
In summary, we have developed a general method to
prepare fused [5,6]-, and [5,7]-3-[(E)-2-(arylvinyl)]-1,2,4-
triazoles using diethoxyphosphinyl acetic acid hydr-
azide. This one-pot reaction proceeds in good to
excellent yield and produces only the (E)-regioisomer.
Modest yields are obtained for the fused [5,5]-3-[(E)-2-
(arylvinyl)]-1,2,4-triazoles using modified cyclization
conditions. Further work with aliphatic aldehydes,
ketones, and conjugated systems is in progress and will
be reported in due course.
5. Kreutzkamp, N.; Schindler, H. Arch. Pharm. 1962, 295,
28.
6. Gross, H.; Beisert, S.; Costisella, B. J. Prakt. Chem. 1981,
877.
7. (a) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89,
863; (b) Wadsworth, W. S., Jr. Org. React. 1977, 25,
73.
8. Experimental procedure for the preparation of 3-styryl-
5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine, 5e. Dieth-
oxyphosphinyl acetic acid hydrazide (1.05 g, 5.0 mmol)
was added to a toluene (15 mL) solution of 2,3,4,5-
tetrahydro-6-methoxypyridine, (0.57 g, 5.0 mmol) under
N2 to afford a cloudy suspension. After stirring overnight
Acknowledgements
We thank Mr. Anthony Ginnetti for experimental
assistance.

1880
F. Liu et al. / Tetrahedron Letters 45 (2004) 1877–1880
at ambient temperature, the resulting clear solution was
(CDCl3, 75.5 MHz): d 151.3, 151.2, 135.8, 134.8, 128.9,
128.8 (2C), 126.9 (2C), 110.7, 42.6, 22.5, 22.4, 19.8. Anal.
Calcd for C14H15N3: C, 74.64; H, 6.71; N, 18.65. Found:
C, 74.53; H, 6.69; N, 18.85.
treated with NaOEt solution (21 wt % in EtOH, 2.05 mL,
5.5 mmol) followed by benzaldehyde (0.51 mL, 5.0 mmol).
The reaction mixture was heated at reflux for 2 h and
then concentrated to a yellow solid residue. Water
(30 mL) was added to this residue and the resulting
yellow slurry was stirred for 20 min. The slurry was
filtered and the solid product was washed with water and
dried to afford 5e as a light yellow solid (0.88 g, 77%).
9. All compounds were completely characterized and gave
satisfactory elemental analyses ( 0.4%) or HRMS, 1H, 13
and mass spectra.
C
10. Bonanomi, M.; Baiocchi, L. Ref. 2b reported similar
reaction conditions, HOAc, reflux 24 h to prepare fused
[5,5]-3-aryl-1,2,4-triazoles.
11. Hansen, K. B.; Springfield, S. A.; Desmond, R.; Devine, P.
N.; Grabowski, E. J. J.; Reider, P. J. Tetrahedron Lett.
2001, 42, 7353.
1
Mp: 161–163 °C. H NMR (CDCl3, 400 MHz): d 7.70 (d,
J ¼ 16 Hz, 1H), 7.53 (d, J ¼ 7 Hz, 2H), 7.39 (m, 3H), 6.84
(d, J ¼ 16 Hz, 1H), 4.01 (t, J ¼ 6 Hz, 2H), 3.03 (t,
J ¼ 6 Hz, 2H), 2.07 (m, 2H), 1.96 (m, 2H). 13C NMR