A novel and efficient synthesis of 2,5-substituted 1,2,4-triazol-3-ones

Article abstract of DOI:10.1016/j.tetlet.2005.09.073

A novel procedure for preparing 1,2,4-triazol-3-ones is described. Various alkyl, aryl, and heterocyclic groups were introduced successfully at both the N2 and C5 positions. The triazolone ring was constructed through an intramolecular cyclization of a novel acyclic precursor, which in turn was synthesized by treating a mono protected hydrazine with an acyl isocyanate. Under conditions that remove the hydrazine protecting group, the intramolecular cyclization occurs rapidly, to deliver the 2,5-substituted 1,2,4-triazol-3-ones in excellent yields (79-99%) without column purification.

Full text of DOI:10.1016/j.tetlet.2005.09.073

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7993–7996
A novel and efficient synthesis of 2,5-substituted 1,2,4-triazol-3-ones
James Zhengwu Deng* and Christopher S. Burgey
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA
Received 16 August 2005; revised 12 September 2005; accepted 13 September 2005
Available online 29 September 2005
Abstract—A novel procedure for preparing 1,2,4-triazol-3-ones is described. Various alkyl, aryl, and heterocyclic groups were intro-
duced successfully at both the N2 and C5 positions. The triazolone ring was constructed through an intramolecular cyclization of a
novel acyclic precursor, which in turn was synthesized by treating a mono protected hydrazine with an acyl isocyanate. Under con-
ditions that remove the hydrazine protecting group, the intramolecular cyclization occurs rapidly, to deliver the 2,5-substituted
1,2,4-triazol-3-ones in excellent yields (79–99%) without column purification.
ꢀ 2005 Elsevier Ltd. All rights reserved.
O
1. Introduction
O
R'
O
O
+
N
NH2
IV
R"
The triazolone ring structure is found in a number of
biologically active compounds, including anti-fungals,1
anti-inflammatories,2 anti-tumor agents,3 PPARs ago-
nists,4 and NK1 antagonists.5 In our efforts to discover
novel therapeutic agents targeting G-protein coupled
receptors, we have found that 1,2,4-triazolone is a
potent structural scaffold. In order to explore structural
diversity at the N2 and C5 positions, we sought to
employ a general method to construct the core triazo-
lone ring.
NH
V
A
B
O
O
O
R'
R'
B
R'
N
NH
R"
A
N
NH2
O
N
NH
N
A
HN
NH2
R"
O
B
R"
II
I
III
Scheme 1. Synthetic analysis of 2,5-substituted 1,2,4-triazol-3-one.
The most widely used strategy toward construction of
the triazolone ring system is disconnection of bond A
to give intermediate II (Scheme 1).2,4,6 However, this
route has limited application, since the harsh conditions
(reflux in NaOH solution) required to cyclize intermedi-
ate II to the triazolone ring are not compatible with a
wide array of functional groups. Simultaneous discon-
nection of both bond A and bond B is another strategy
to generate this ring system. Intermediate IV and ortho-
ester V could be cyclized under milder reaction condi-
tions. Unfortunately, there are few orthoesters
commercially available and methods for their prepara-
tion are not general.
ate III might be more facile and efficient than that of
intermediate II because it would involve a more nucleo-
philic primary hydrazine attacking an electrophilic car-
bonyl group.
With this analysis, we proposed a synthetic route to
1,2,4-triazol-3-ones as shown in Scheme 2. A wide range
O
R'HN NHBoc
O
(COCl)2
3
H2N
R"
OCN
R'
R"
2
1
O
Disconnection of bond B offers an alternative attractive
route to the target (Scheme 1). Cyclization of intermedi-
O
O
O
R'
N
NH
N
N
NH
R"
R'
N
N
H
R"
NH2
R"
O
III
BocHN
I
Keywords: Tiazolone; Heterocycles; Hydrazine; Acyl isocyanate.
4
*
Corresponding author. Tel.: +1 215 652 1852; fax: +1 215 652
7310; e-mail: james_deng@merck.com
Scheme 2. Proposed synthetic route to 1,2,4-triazol-3-ones.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.073

7994
J. Z. Deng, C. S. Burgey / Tetrahedron Letters 46 (2005) 7993–7996
Table 1. Variation of the C5 substituent
of primary amides 1 could be readily converted to
the corresponding acyl isocyanate 2, according to the
reported procedure for preparation of benzoyl isocya-
nate.7 Reaction of the mono protected hydrazine 3 with
the acyl isocyanate 2 would construct intermediate 4.
Sub-target structure III could then be generated through
removal of the Boc protection on its precursor 4 and
subsequently be cyclized to the target triazolone I.
Entry
1
R
Yield (%)
97
2
3
79a
80a
O
2. Results and discussion
4
99
Our initial experiments demonstrated that the proposed
route was a viable and efficient way to prepare 1,2,4-tri-
azol-3-ones. The mono Boc protected hydrazine 58
reacted with an acyl isocyanate 6 to afford key interme-
diate 7 (Scheme 3). The excess isocyanate 6 was trapped
by polymer-supported trisamine. Upon removal of the
Boc protecting group in TFA/CH2Cl2 1:2 solution,
clean cyclization to the desired triazolone 9 was
observed. The cyclization reaction proceeded very fast
(<2 h), while the presumed acyclic intermediate 8 was
never detected by LC/MS. In most cases, the pure tri-
azolones 9 were obtained in good yields, without column
purification (Table 1).9 A wide range of acyl isocyanates,
including aryl (entries a and d), benzyl (entry b), func-
tionalized alkyl (entries c and e), hindered alkyl (entry
k), and heterocyclic (entries f, g, h, i, and j) groups
can be employed to give triazolone products in excellent
overall yields. Steric hindrance and substitution on
the aryl ring or alkyl chain of the acyl isocyanate, did
not markedly affect the reaction efficiency. Attempts
to convert unsubstituted pyridyl amides, such as nico-
tinic amide, to acyl isocyanates were unsuccessful. The
reaction gave insoluble species, which did not react well
with 5.
O
5
6
7
87
95
98
O
S
Cl
91b
N
8
9
Cl
N
79a,b
O
10
11
82b
90
N
a For these entries, yields were calculated based on purified products
from silica column (MeOH/CH2Cl2 gradient) to remove small
amount of amide degraded from acyl isocyanate 6.
b For these entries, three equivalents of polymer-supported i-PrEt2N
were added into the reaction of protected hydrazine with acyl iso-
cyanate, to scavenge the HCl left from the reaction to form acyl
isocyanate.
Following the method above, we investigated the scope
of substituents at the N2 position of triazolone (Scheme
4). A wide range of hydrazines 10 could be subjected to
the developed reaction conditions to give triazolones 13
in good yield with high purity (Table 2). We have been
able to successfully employ aryl (entries a and g), alkyl
(entries b–d), branched alkyl (entry e) and 2-pyridyl
(entry f) groups in the synthesis. Hydrazinecarboxylates
10 can be synthesized through direct mono protection of
a primary hydrazine,10,11 or reduction of a hydrazone
formed by reaction of the tert-butyl carbazate with an
aldehyde or a ketone.12 The aryl or heterocyclic hydra-
zine species could also be constructed through a direct
SNAr displacement, an addition of arylmetallics to an
azodicarboxylate,13 or through a Buchwald–Hartwig-
type aryl amination reaction catalyzed by copper or
palladium.14
O
O
O
N
R
6
NH2
NH
OCN
R
CbzN
NH
NHBoc
CbzN
CbzN
CH2Cl2, 25 oC, 1 h 25 oC, 1 h
NHBoc
5
7
O
O
NH
TFA:CH2Cl2 1:2
25 oC, 2 h
NH
N
CbzN
N
NH2 O
R
R
N
9
8
Scheme 3. Exploration of C5 substitutions of 1,2,4-triazol-3-one.

J. Z. Deng, C. S. Burgey / Tetrahedron Letters 46 (2005) 7993–7996
7995
O
in high yield (92%), presumably through its acyclic pre-
cursor 16. The acyclic intermediate 16 was not detected
in the reaction, which indicates that the cyclization pro-
cess is also fast under neutral conditions. This serves to
further expand the scope of this methodology.
O
NH2
O
N
CH2Cl2
25 oC, 1 h
+
R
NH
NHBoc
10
OCN
NH
25 oC, 1 h
R
11
12
NHBoc
O
NH
TFA:CH2Cl21:2
25 oC, 2 h
R
N
In summary, we have developed an efficient synthetic
route toward 1,2,4-triazol-3-ones. Without column puri-
fication, 2,5-substituted 1,2,4-triazol-3-ones can be ob-
tained in good yield and high purity. We have shown
that various alkyl, aryl, and heterocyclic groups can be
tolerated with this method. Cyclization of the triazolone
ring occurs rapidly, under both neutral and mild acidic
conditions, with high efficiency.
N
13
Scheme 4. Exploring the substitutions at N2 position.
Table 2. Variation of the N2 substituents
Entry
1
R
Yield (%)
90a
References and notes
1. Heers, J.; Backx, J. J.; Cutsem, J. V. J. Med. Chem. 1984,
27, 894–900.
2. Mullican, M. D.; Wilson, M. W.; Connor, D. T.; Kostlan,
C. R.; Schrier, D. J.; Dyer, D. D. J. Med. Chem. 1993, 36,
1090–1099.
3. Neslihan, D.; Reyhan, U.; Ahmet, D. Bioorg. Med. Chem.
2002, 10, 3717–3723.
2
3
95
96
4. Xu, Y.; Mayhugh, D.; Saeed, A.; Wang, X.; Thompson,
R. C.; Dominianni, S. J.; Kauffman, R. F.; Sing, J.; Bean,
J. S.; Bensch, W. R.; Barr, R. J.; Osborne, J.; Montrose-
Rafizadeh, C.; Zink, R. W.; Yumibe, N. P.; Huang, N.;
Luffer-Atllas, D.; Rungta, D.; Maise, D. E.; Mantlo, N. B.
J. Med. Chem. 2003, 46, 5121–5124.
5. Cowden, C. J.; Wison, R. D.; Bishop, B. C.; Cottrell, I. F.;
Davies, A. J.; Dollong, U. Tetrahedron Lett. 2000, 41,
8661–8664.
4
99
5
6
86a
98
N
6. Chouaieb, H.; Mosbah, M. B.; Kossentini, M.; Salem, M.
Synth. Commun. 2003, 33, 3861–3868.
7. Weikert, R. J.; Bingham, S., Jr.; Emanuel, M. A.; Fraser-
Smith, E. B.; Loughhead, D. G.; Nelson, P. H.; Poulton,
A. L. J. Med. Chem. 1991, 34, 1630–1633.
7
96a
Me
a Products in these entries were obtained as pure TFA salts, which are
not soluble in CH2Cl2.
8. The mono Boc protected hydrazine 5 was obtained
through a reductive amination reaction of N-benzyloxy-
carbonyl-4-piperidone with tert-butyl carbazate (3 equiv
NaBH(OAc)3, dichloroethane).
9. Representative experimental procedure: Mono Boc pro-
tected hydrazine 10 (1 mmol) was dissolved in 7 mL of
CH2Cl2, to which acyl isocyanate 11 (1.5 mmol) in 3 mL
of CH2Cl2 was added. The reaction mixture was stirred at
room temperature for one hour, after which polymer-
supported trisamine (3 mmol) was added to the reaction.
After 1 h, the reaction was filtered, washed with CH2Cl2
(2 · 10 mL) and MeOH (2 · 10 mL). The filtrate was
Finally, in an attempt to avoid the acidic conditions in
the cyclization step, we explore the use of benzyl carba-
mate as the hydrazine protecting group (Scheme 5). Fol-
lowing the same reaction sequence (Scheme 3),
intermediate 15 was obtained. Hydrogenation of 15 under
a balloon atmosphere of hydrogen, in 1:1:1 mixture of
C2H5OH/EtOAc/CH2Cl2, gave cyclized triazolone 17
O
O
O
N
Ph
11
NH
NH2
OCN
Ph
BocN
NH
NHCbz
BocN
CH2Cl2, 25 oC, 1 h
25 oC, 1 h
NHCbz
14
15
O
O
N
NH
NH
10% Pd-C, H2, 1 atm
BocN
N
Ph
BocN
Ph
N
NH2 O
EtOH:EtOAc:CH2Cl2 1:1:1
17
16
Yield: 92%
Scheme 5. Cyclization of triazolone ring under neutral condition.

7996
J. Z. Deng, C. S. Burgey / Tetrahedron Letters 46 (2005) 7993–7996
concentrated and dissolved in 10 mL of CH2Cl2, to which
11. Fox, D. L.; Ruxer, J. T.; Oliver, J. M.; Alfrord, K. L.;
Salvatore, R. N. Tetrahedron Lett. 2004, 45, 401–
405.
12. Okayama, T.; Burritt, A.; Hruby, V. J. Org. Lett. 2000, 2,
1787–1790.
5 mL of TFA was added. After 2 h, the reaction mixture
was concentrated and rediluted with CH2Cl2 (100 mL).
CH2Cl2 solution was washed with saturated sodium
bicarbonate solution (100 mL) and concentrated. Most
of the time, the residue was pure (>95%); in cases where
the purity was <95%, additionally rinsing the solid with
ethyl ether (2 · 5 mL) gave pure (>95%) triazolone prod-
uct. All compounds listed were characterized by NMR
and LC/MS.
13. Demers, J. P.; Klaubert, D. H. Tetrahedron Lett. 1987, 28,
4933–4934.
14. Kabalka, G. W.; Guchhait, S. K. Org. Lett. 2003, 5, 4129–
4131; Wolter, M.; Klapars, A.; Buchwald, S. L. Org. Lett.
2001, 3, 3803–3805; Hartwig, J. F. Angew. Chem., Int. Ed.
1998, 37, 2090–2093; Wang, Z.; Skerlj, R. T.; Bridger, G.
J. Tetrahedron Lett. 1999, 40, 3543–3546.
10. Wang, Q. M.; Cheng, J. R.; Huang, R. Q. J. Heterocyclic
Chem. 2003, 40, 195–197.