Multicomponent synthesis of 1-aryl 1,2,4-triazoles

Article abstract of DOI:10.1021/ol401428x

A multicomponent (single reactor) process for the synthesis of 1-aryl 1,2,4-triazoles was explored and developed. This transformation prepared the 1,2,4-triazole directly from anilines, amino pyridines, and pyrimidines. The reaction scope was explored with 21 different substrates, and the position of the nitrogen atoms in the newly formed ring was established by ¹⁵N labeling and NMR spectroscopy.

Full text of DOI:10.1021/ol401428x

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Multicomponent Synthesis of 1‑Aryl
1,2,4-Triazoles
Annie Tam, Ian S. Armstrong, and Thomas E. La Cruz*
Chemical Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick,
New Jersey 08903, United States
thomas.lacruz@bms.com
Received May 20, 2013
ABSTRACT
A multicomponent (single reactor) process for the synthesis of 1-aryl 1,2,4-triazoles was explored and developed. This transformation prepared
the 1,2,4-triazole directly from anilines, amino pyridines, and pyrimidines. The reaction scope was explored with 21 different substrates, and the
position of the nitrogen atoms in the newly formed ring was established by 15N labeling and NMR spectroscopy.
1,2,4-Triazoles are a class of heterocycles found in a wide
range of biologically active molecules encompassing sev-
eral therapeutic areas, and as subunits of coordination
polymers.1,3d
Several methodologies to prepare this important motif
have been reported and reviewed in the literature.2,3d
Common methods to access aryl 1,2,4-triazoles include
the formation and condensation ofa hydrazine derivative,3
transition metal mediated CꢀN bond coupling,4,5 and
SNAr-type chemistry of a halogenated arene with a 1,2,4-
triazole nucleophile.6 Some limitation of these approaches
include multiple steps to generate and activate the hydra-
zine for cyclization, or in the case of SNAr chemistry,
a mixture of N-regioisomers can be formed.6,7 General
(1) Reviews on uses of 1,2,4-triazoles: (a) Al-Masoudi, A.; Al-Soud,
Y. A.; Al-Salihi, N. J.; Al-Masoudi, N. A. Chem. Heterocycl. Compd.
2006, 42, 1377–1403. (b) Pibiri, I.; Buscemi, S. Current Bioactive
Compounds 2010, 6, 208–242. (c) Sahoo, S.; Veliyath, S. K.; Mahendra
Kumar, C. B. Int. J. Res. Pharm. Sci. 2012, 3, 326–333. (d) Shalini, K.;
Kumar, N.; Drabu, S.; Sharma, P. K.; Beilstein J. Org. Chem. 2011, 7,
668–677. (e) Naik, A. D.; Dırtu, M. M.; Railliet, A. P.; Marchand-
Brynaert, J.; Garcia, Y. Polymer 2011, 3, 1750–1775. (f) Klingele, M. H.;
Brooker, S. Coord. Chem. Rev. 2003, 241, 119–132. (g) Haasnoot, J. G.
Coord. Chem. Rev. 2000, 200ꢀ202, 131–185 and references therein.
(2) Reviews on the preparation of 1,2,4-triazoles: (a) Moulin, A.;
Bibian, M.; Blayo, A.-L.; El Habnouni, S.; Martinez, J.; Fehrentz, J.-A.
Chem. Rev. 2010, 110, 1809–1827. (b) Yet, L. Prog. Heterocycl. Chem.
2011, 23, 231–266. (c) Curtis, A. D. M. Sci. Synth. 2004, 13, 603–639.
(d) Holm, S. C.; Straub, B. F. Org. Prep. Proc. Int. 2011, 43, 319–347.
(3) For an elegant synthesis of fully substituted 1,2,4-triazoles with
hydrazines, see: (a) Staben, S. T.; Blaquiere, N. Angew. Chem., Int. Ed.
2010, 49, 325–328. (b) Castanedo, G. M.; Seng, P. S.; Blaquiere, N.;
Trapp, S.; Staben, S. T. J. Org. Chem. 2011, 76, 1177–1179. (c) An
elegant copper catalyzed approach to 1,2,4-triazoles: Xu, H.; Jiang, Y.;
Fu, H. Synlett 2013, 24, 125–129. (d) Guru, M. M.; Punniyamurthy, T.
J. Org. Chem. 2012, 77, 5063–5073 and references therein. (e) Terauchi,
J.; Koike, T.; Honda, E.; Nakamura, M.; Kajita, Y.; Hoashi, Y.;
Morimoto, S.; Fujimoto, T. Preparation of Piperazines and Related
Compounds for Inhibiting Amyloid-β Production. PCT Int. Appl.,
2011002067.
(4) For an example of C-N coupling metal-mediated synthesis of
fused 1,2,4-triazoles from amino pyridines, see: Ueda, S.; Nagasawa, H.
J. Am. Chem. Soc. 2009, 131, 15080–15081.
(5) For examples of metal-mediated CꢀN bond coupling with
symmetrical 1,2,4-triazole and aryl halides, see: (a) Antilla, J. C.;
Baskin, J. M.; Barder, T. E.; Buchwald, S. L. J. Org. Chem. 2004, 69,
5578–5587. (b) Yang, K.; Qiu, Y.; Zheng, Li, Z.; Wang, Z.; Jiang, S.
J. Org. Chem. 2011, 76, 3151–3159. (c) Albrecht, B. K.; Gehling, V. S.;
Hewitt, M. C.; Taylor, A. M.; Harmange, J.-C. Preparation of 4H-
Benzo[b][1,2,4]Triazolo[4,3-d][1,4]Diazepine Derivatives as Bromodo-
main Inhibitors. PCT Int. Appl., 2012151512. (d) Aspnes, G. E.; Didiuk,
M. T.; Filipski, K. J.; Guzman-Perez, A.; Lee, E. C. Y.; Pfefferkorn,
J. A.; Stevens, B. D.; Tu, M. M. Preparation of 3-[4-(Heterocyclyl-
Substituted)-Benzamido]Propanoic Acids as Glucagon Receptor Modula-
tors. U.S. Pat. Appl., 20120202834.
(6) SNAr: (a) De Cleyn, M. A. J.; Van Brandt, S. F. A.; Gijsen,
H. J. M.; Berthelot, D. J-C.; Oehlrich, D. Triazole Derivatives as
Gamma-Secretase Modulators and Their Preparation and Use
for the Treatment of Diseases. PCT Int. Appl. WO 2011086098 A1.
(b) Kamenecka, T. M.; Jiang, R.; Song, X.; Lograsso, P.; Cameron,
M. D. Preparation of Phenylaminopyrimidine Derivatives and Analogs
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Naidu, B. N.; Connolly, T. P.; Ueda, Y. Cyclic Pyrimidinone Derivatives
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r
10.1021/ol401428x
XXXX American Chemical Society

examples of methodologies used to prepare 1-aryl 1,2,4-
triazoles are depicted in Figure 1.
To begin this investigation, para-chloroaniline was cho-
sen as a model substrate (Table 1, entry 1).13 A mixture of
para-chloroaniline (1a), triethylorthoformate (HC(OEt)3),
and tosylamidoxime 5 in THF was heated to 60 °C for 24 h
to produce the desired triazole 6a as a minor product. The
major components of the crude reaction mixture were
observed to be amidine 4a and imidate 3a. Aniline 1a
was completely consumed, and tosylamidoxime 5, which
was added in slight excess, was still present. Continued
heating was not beneficial, as it mainly led to the decom-
position of5, generated other side products, and consumed
amidine 4a. As previously reported, a protic environment
assists in the conversion of amidines such as 4a back to the
corresponding imidate.12 We hypothesized that by intro-
ducing an acid catalyst and facilitating this equilibrium,
greater conversion could be achieved. We were gratified
to discover that addition of ethanesulfonic acid (EtSO3H,
10 mol %) to a mixture of tosylamidoxime 5, aniline 1a,
HC(OEt)3, THF and heating at 60 °C for 24 h afforded
facile consumption of both amidine 4a and imidate 3a
with an excellent conversion to triazole 6a, in 93% isolated
yield.
We envisioned that building the 1,2,4-triazole ring
directly from an aniline would provide an efficient
method to prepare 1,2,4-triazoles and hypothesized that
this could be effected as outlined in Scheme 1. Forma-
tion of an imidate (3) from the condensation of an aniline
(1) with triethylorthoformate is known to be a facile
process.8 We postulated that in the presence of a third
component, such as tosylamidoxime 5,9 imidate 3 could
condense first and then undergo a NꢀN bond-forming
cyclization reaction to generate aryl 1,2,4-triazole 6.10,11
However, it is known that, in the absence of excess
orthoester, imidate 3 will react with a second equivalent
of aniline to form a less reactive amidine product (4).12
Although this undesired condensation could occur
before the aniline is entirely consumed, imidate 3 can
slowly regenerate under the reaction conditions.12 We
were encouraged to investigate this process because the
1,2,4-triazole would be forged directly from an aniline
(convergently), efficiently (in one step) and without the
application of transition metal catalysts.
Scheme 1. Reaction Pathway Design
The efficiency of this methodology was tested with a
series of anilines, and the outcomes are summarized in
Table 1. For substrates containing electron-withdrawing
groups, the desired 1,2,4-triazole products were generated
in very good to excellent yields (80ꢀ95%, Table 1 entries
1ꢀ6, 14). Not surprisingly the electronic nature of the ring
substituents impacts the time required for reaction com-
pletion. For example, para-nitro aniline (Table 1, entry 2)
reached completion after 4 h whereas substrates that
possess a less electronegative group (entries 3ꢀ6) required
∼6 h. Continued heating after most of the amidine had
been consumed led to decomposition of the 1,2,4-triazole
and a diminished product yield (54% after 24 h vs 93%
after 4 h; Table 1, entry 2). Thus, in order to maximize
product recovery, cooling the reaction mixture after reach-
ing completion is paramount.
Figure 1. General synthetic routes to 1-aryl 1,2,4-triazoles.
(7) For a discussion on the regioselectivity of 1,2,4-triazole alkyla-
tion: Bulger, P. G.; Cottrell, I. F.; Cowden, C. J.; Davies, A. J.; Dolling,
U.-H. Tetrahedron Lett. 2000, 41, 1297–1301.
(8) Roberts, R. M. J. Am. Chem. Soc. 1949, 71, 3848–3849 and
references therein.
(9) Preparation of tosyl amidoxime 5: Inagaki, T.; Kurita, Y.;
Hirakata, K.; Mizutani, A.; Kondo, M. Preparation of Alkoximino-5-
Amino-1,2,4-thiadiazole-3-Acetates. Eur. Pat. Appl. EP 0795551 A1.
(10) For a review on the structure and chemistry of hydroxylamidox-
imes, see: Katritzky, A. R.; Huang, L.; Chahar, M.; Sakhuja, R.; Hall,
C. D. Chem. Rev. 2012, 112, 1633–1649.
(12) Roberts, R. M.; DeWolfe, R. H. J. Am. Chem. Soc. 1954, 76,
2411–2414 and references therein.
(11) For an example illustrating a NꢀN bond forming cyclization
reaction using a mesylated oxime, see: Wray, B. C.; Stambuli, J. P. Org.
Lett. 2010, 12, 4576–4579.
(13) LCMS analysis of the reaction mixture can easily differentiate
impurities related to the chloro aniline (m/z = M and Mþ2), or those
arising from amidoxime decomposition (m/z = M).
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In the case of electron-rich aniline substrates (1gꢀl) the
corresponding amidine intermediates (4gꢀl) were, as ex-
pected, more resistant to undergo the productive exchange
reaction, and a full equivalent of EtSO3H was necessary
to achieve high conversion to the 1,2,4-triazole products
(6gꢀl). In the ortho-substituted substrate series, which
include a sterically demanding 2,6-diisopropyl aniline,
diminished formation of the amidine was observed and
the 1,2,4-triazoles were furnished in good yields (76ꢀ87%)
after 6 h at 60 °C (Table 1, entries 9ꢀ12). For the para-
substituted series, the reaction conditions were fur-
ther modified to minimize amidine formation (Table 1,
entries 7ꢀ8). This was achieved by slow addition of a dilute
THF solution of the aniline to a mixture of 5, EtSO3H,
triethylorthoformate, and THF at 50 °C. Again, the triazole
products were generated in good yields (70ꢀ75%) even
with the electron-rich anisidine substrate (entry 7). Lastly,
a unique p-pinacol boronate ester 1,2,4-triazole product
(Table 1, entry 13) was prepared using these reaction
conditions in moderate yield, 56%.
The scope of this transformation was expanded to
include heterocycles such as pyridines and pyrimidines
(Scheme 2). For substrates containing electron-withdraw-
ing groups, formation of the 1,2,4-triazole products
(Scheme 2, structures 7 and 8) occurred in moderate yield
(∼60%). After 6 h at 60 °C, the reactions stalled, amidine
side products were only present in trace amounts, and
unconsumed aminopyridine starting materials (∼10% for
7 and ∼20% for 8) were observed. The position of the
amino group relative to the ring nitrogen atom also
impacted the reaction efficiency. Formation of the 1,2,4-
triazole product 10 (Scheme 2) from 3-amino-5-methyl-
pyridine occurred in low yield (7%). The major compo-
nents of this reaction were identified by LCMS as the
ethoxy-imidate intermediate and aminopyridine starting
material. Yields of the 1,2,4-triazoles prepared from pyr-
imidines were also modest (37%, 11), or in the case of
5-cyanopyrimidine, the triazole product was not observed
(12). In both experiments, mostly starting material was
present after 24 h. Further modifications of the reaction
conditions were not explored.
Table 1. 1-Aryl 1,2,4-Triazole Synthesis Substrate Scope with
Anilines
Scheme 2. Multicomponent Synthesis of 1-Aryl 1,2,4-Triazoles
from Aminopyridines and Pyrimidines
The mechanism of cyclization that forms the 1,2,4-
triazole can occur through two pathways as depicted in
Scheme 3. Isolation of condensation intermediates (such as
14 and 15) was not possible and their molecular mass was
not observed by LCMS, indicating that the cyclization is
virtually instantaneous. To identify the operative reaction
pathway, an experiment with 15N-labeled tosylamidoxime
was carried out, and the results are summarized in
Scheme 3. In Pathway A, if the less substituted 15N labeled
amino group in tosylamidoxime 18 condenses with the
imidate and then undergoes cyclization, triazole product
16 would be observed. Conversely in Pathway B, if the
more substituted unlabeled-nitrogen atom (N-OTs) is first
a Solution yields obtained by QNMR analysis. b Reaction conditions
A: 10 mol % EtSO3H, THF, 60 °C. c Reaction conditions B: 100 mol %
EtSO3H, 50 or 60 °C. d Slow addition of aniline e 93% isolated yield.
f 93% isolated yield of triazole after 4 h, 54% isolated yield after 24 h at
60 °C. g 65% isolated yield of triazole. h 76% solution yield of triazole
i
product without slow addition of aniline. Without EtSO3H: 6a:4a:3a
ratio is 1:1:2. With EtSO3H: 6a:4a:3a ratio is >50:1:not detected.
Org. Lett., Vol. XX, No. XX, XXXX
C

In conclusion, a multicomponent synthesis of 1-aryl
1,2,4-triazoles was described and its scope evaluated using
several substituted aryl amines. For anilines, the key step
was determined to be the consumption of an amidine
intermediate where the presence of electron-withdrawing
groups or ortho substitution in the aryl ring led to a more
efficient triazole reaction. The addition of an acid pro-
moted reaction throughput by facilitating the breakdown
of the amidine intermediate. Electron-donating groups
stabilized the amidine intermediate, and controlled addi-
tion of the aniline to the reaction mixture was required to
achieve efficient triazole synthesis. The behavior of hetero-
cycles, such as pyridines and pyrimidines, was more un-
predictable. For this substrate series, the ring substituents
influenced whether the limiting step was consumption
of amidine, ethoxy-imidate or if the substrate was un-
reactive. Through the preparation of a 15N-labeled 1,2,4-
triazole, the mode in which the tosylamidoxime reacts
with the intermediate imidate was elucidated. This multi-
component NꢀN bond forming reaction is exceptionally
regioselective with respect to the position of the nitrogen
atoms in the 1,2,4-triazole ring. Overall, an efficient multi-
component process for the preparation of 1-aryl 1,2,4-
triazoles has been defined.
Scheme 3. Condensation Pathways and 15N-Labeled Triazole
Experiment
to react with the imidate and undergo electrocyclic cycliza-
tion and loss of TsOH, triazole product 17 would form.
The position of the 15N atom in the 1,2,4-triazole product
would indicate if either of these two pathways is preferred.
The labeled tosylamidoxime 18 was prepared in two
steps from the reaction of 15N-labeled acetonitrile with
hydroxylamine and subsequent tosylation of the N-hydro-
xylacetamide (Scheme 3). After subjecting this material
to the triazole reaction conditions, the 15N-position in the
triazole product was determined by 1-D and 2-D NMR
spectroscopy. The C1 triazole carbon gave a 13C singlet
at 142.5 ppm whereas splitting of 13C resonances at C2 (d,
161.1 ppm, J = 4.6 Hz) and C3 (d, 13.6 ppm, J = 7.3 Hz),
due to 15NꢀC coupling, was observed. The results clearly
indicate that product 17 was formed in >98% selectivity
and that Pathway B is in operation. This 1,2,4-triazole
synthesis takes place with complete regiochemical control
of the nitrogen atoms in the newly formed triazole ring.14
Acknowledgment. The authors wishtoacknowledgethe
Bristol-Myers Squibb (BMS) Summer Intern Program for
supporting Ian Armstrong; the BMS, ABD “Structural
Elucidation Group” in particular Dr. Charles Pathirana
for 1-D, 2-D, 15N NMR analysis and Michael Peddicord
forHRMSanalysis; Dr. RobertWaltermireand Dr. David
Kronenthal of the BMS Chemical Development senior
leadership for their support; and Prof. Phil Baran for his
comments.
Supporting Information Available. Experimental pro-
1
cedures, H, 13C, and 2D NMR spectra of new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) Only the 13C resonances of product 17 were observed in the
NMR spectrum. Small 13C signals related to the unlabeled triazole
product were also present, which originates from the commercial 15N-
MeCN used for this experiment having an isotopic enrichment of 98%.
The authors declare no competing financial interest.
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