Supramolecular Anion Recognition Mediates One-Pot Synthesis of 3-Amino-[1,2,4]-triazolo Pyridines from Thiosemicarbazides

Article abstract of DOI:10.1021/acs.orglett.6b03645

A facile one-pot synthesis of 3-amino-[1,2,4]-triazolo[4,3-a]pyridines from thiosemicarbazides through anion mediated synthesis is reported. Thiosemicarbazides derived from 2-hydrazino pyridine, 5-chloro 2-hydrazino pyridine, and 2-hydrazine quinoline wer

Full text of DOI:10.1021/acs.orglett.6b03645

Letter
pubs.acs.org/OrgLett
Supramolecular Anion Recognition Mediates One-Pot Synthesis of
3‑Amino-[1,2,4]-triazolo Pyridines from Thiosemicarbazides
Komala Pandurangan, Anna B. Aletti, Devis Montroni, Jonathan. A. Kitchen, Miguel Martínez-Calvo,
Salvador Blasco, Thorfinnur Gunnlaugsson,* and Eoin M. Scanlan*
School of Chemistry, Trinity College Dublin and Trinity Biomedical Science Institute (TBSI), The University of Dublin, Dublin 2,
Ireland
S
* Supporting Information
ABSTRACT: A facile one-pot synthesis of 3-amino-[1,2,4]-
triazolo[4,3-a]pyridines from thiosemicarbazides through
anion mediated synthesis is reported. Thiosemicarbazides
derived from 2-hydrazino pyridine, 5-chloro 2-hydrazino
pyridine, and 2-hydrazine quinoline were formed in situ as
anion receptors in the presence of TBAF. Under microwave
heating, thiosemicarbazides furnished the triazolo pyridines in
good to moderate yields. The formation of the thiosemicarbazides hydrogen bonding anion receptors was critical in cascading the
reaction toward the formation of the triazolo pyridines.
riazolo pyridines are an important class of organic
F− source and as a mild base. It is known to act as a catalyst for
Tmolecules for medicinal chemistry and are associated the reduction of aldehydes and ketones using hydrosilanes and
with a broad range of biological activity.1,2 [1,2,4]Triazolo
also for the chemoselective reduction reactions of phthalimides
and imidazolidine-2,4-diones.12 We have used TBAF to activate
pyridine analogues display potent activity against p38 mitogen
aryl amines toward converting CO2 to HCO3, via the formation
of HF2¯.13 TBAF is used in fluorine mediated homocoupling of
aryl halides14 and as a mild base for the elimination reaction of
bromoalkenes to alkynes.15 Herein we demonstrate that the
formation of triazolo pyridines by simply mixing 2-hydrazino
pyridines with TBAF and isothiocyanates in one pot under
microwave irradiation.
Thiosemicarbazides recognize anions through hydrogen
bonding where significant color changes can occur due to
deprotonation of a “thiourea proton” by basic anions.16−18 This
was confirmed using NMR spectroscopy and X-ray crystallog-
raphy.16,24 On further investigation, we discovered that
treatment with dry TBAF could convert the thiosemicarbazide
into a new product upon standing. The reaction mixture
yielded crystals suitable for X-ray crystal structure analysis,
which showed the successful formation of the [1,2,4]triazolo
pyridine product.
In order to investigate the scope, we used three different
hydrazinopyridine starting materials, namely 2-hydrazino-
pyridine, 5-chloro-2-hydrazinopyridine, and 2- hydrazino-
quinoline (Table 1). For each substrate, we investigated the
TBAF mediated cyclization reaction with eight different
isothiocyanates, bearing either an electron-withdrawing (EW)
and electron-donating (ED) substituent on the phenyl ring. In
the case of 2-hydrazino pyridine, all of the eight isothiocyanates
furnished the expected [1,2,4]-triazolo[4,3-a]pyridine amine
derivatives. Irrespective of the nature of the substituent on the
activated protein kinase (MAKP); a key enzyme in regulating
proinflammatory mediators such as IL1-β and TNF-α. Selective
inhibitors of p38 are of therapeutic interest for the treatment of
chronic obstructive pulmonary disease (COPD).3 [1,2,4]-
Triazolo pyridine analogues also function as inhibitors of
Akt1 and Akt2 kinases involved in the regulation of survival,
proliferation, and growth of cells,4 and of JAK2, a critical target
for oncology.5 However, detailed investigation into their
biological function has been hampered due to limited suitable
methodologies for their synthesis. A number of multistep
methods have been reported, usually involving highly toxic
desulfurizing reagents.6 Recently Swinnen and co-workers7
reported a synthesis, starting from thiosemicarbazides, using
polymer-supported Mukaiyama’s reagent. They proposed a
reaction mechanism via a highly reactive carbodiimide
intermediate that undergoes cyclization to yield the triazolo
pyridine core. Herein, we report the synthesis of 3-amino-
[1,2,4]-triazolo[4,3-a]pyridine analogues (Table 1), starting
from 2-hydrazino pyridines in a one-pot synthesis involving
tetrabutylammonium fluoride (TBAF) as a reagent.8 This
approach was inspired by our interest in employing supra-
molecular structures in synthetic chemistry,9a,b where in situ
formation of thiosemicarbazide based anion receptors is a key
step. Hydrogen bonding receptors, such as urea, thioureas,
squaramides, and amides, are commonly used in supra-
molecular anion chemistry and in organocatalysis.10,11 How-
ever, the use of such structures as “reagents” in organic synthesis
is not widely explored; the exception being the use of thiourea
in the preparation of guanidinium structures (via thiouronium
formation). TBAF is widely employed in organic synthesis as a
Received: January 10, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03645
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Letter
possessing an electron-withdrawing substituent tended to
undergo cyclization much more efficiently (e.g., 1−5). In fact,
the more electron-rich isothiocyanates (e.g., 6−8) gave
substantially lower yields, as summarized in Table 1. For
these reactions, the thiosemicarbazide intermediates were
obtained in ca. 15−30% yields upon isolation using automatic
SiO2 column chromatography. Because of this drawback, we
performed these reactions with increasing amounts (1.1, 2.1,
3.1, and 4.5 equiv) of TBAF, but in general, no significant
improvement in yield was observed. Only for the formation of
para-nitro derivative 1 was there a noticeable enhancement,
where the yield of 1 increased from 27% to 56% upon using 2.1
equiv of TBAF.
Table 1. Reaction Conditions of 3-Amino-1,2,4-triazolo[4,3-
a]pyridines
Expanding upon the above-mentioned studies, we extended
this methodology to 5-chloro-2-hydrozino pyridine and 2-
hydrazino quinolone using the same eight isothiocyanate
derivatives. The 5-chloro-2-hydrazino pyridines furnished the
triazole analogues 9, 10, and 11, Table 1. However, irrespective
of the equivalents of TBAF employed, no conversion to the
triazole was observed with the remaining five isothiocyanates.
In fact, for all of these reactions, the corresponding thiosemi-
carbazides were obtained as the major products. This suggests
that the nature of the substituents on both the pyridinyl and
phenyl component of the thiosemicarbazides plays a critical
role in the cyclization process, with electron-withdrawing
groups on the pyridine ring lowering the yield of the cyclization
process. Similar to the 5-chloro derivatives, the more sterically
challenging 2-hydrazino quinoline also yielded only three
triazolo pyridines. In the case of 12, an increase in the
equivalents of TBAF from 1.1 to 3.1 equiv resulted in an
improved yield of the triazole to 38%, with the 4-CF3 and 3,5-
di-CF3 triazoles being observed.
To probe the mechanism, we investigated the reaction using
1H NMR spectroscopy ((CD3)2SO, 600 MHz), where the
thiosemicarbazide exhibited characteristic signals for the
“thiourea” protons, resonating between 10.2 and 8.1 and
10.4−8.2 ppm, depending on the nature of the aryl group.
Treatment of the thiosemicarbazide with TBAF resulted in the
disappearance of the thiourea proton, suggesting fluoride-
mediated deprotonation is the initial step, as shown in Figure
2a. The resulting organic anion undergoes cyclization in situ
with loss of sulfur to form the desired triazole, which has a new
NH-proton appearing between 8.5 and 10.2 ppm, Figure 1b.
This would suggest that the mechanism involves (a) the
formation of the thiosemicarbazide, (b) anion recognition, and
(c) deprotonation of the thiourea.
Gratifyingly, this process could also be followed by X-ray
crystallography, as single crystals for X-ray structure analysis
were isolated and resolved for the deprotonated thiosemicarba-
zides, elemental sulfur, and 6 of the 14 1,2,4-triazolo pyridines
products.24 Some of these structures are shown in Figure 2,
clearly demonstrating the successful formation of the desired
products from all of the hydrazine starting materials.
Further analysis of the synthesis showed that additional
equivalents of TBAF were required to promote the ring closing
of the triazolo adducts 9 and 12. This raises the interesting
possibility that TBAF may have a dual role in the reaction,
functioning both as a base to deprotonate the thiosemicarba-
zides and as a desulfurizing agent to promote the cyclization
process. In the literature, desulfurization is accomplished using
toxic heavy metals oxides such as Pb2O4, HgCl2, Hg(OAc)2,
HgO, methyl iodide, or highly reactive acid halides such as
phosgene and thionyl chloride.20,21 In some reactions photo-
a
Isolated yield. All reactions were carried out under microwave
irradiation in a sealed vial. TBAF was dried over P2O5 under vacuum.
phenyl ring of the isothiocyanate, all of the reactions furnished
the desired triazolo pyridines, after 50 min of microwave
irradiation, at 100 °C. However, it is noteworthy that the
thiosemicarbazides formed in situ from isothiocyanates
B
DOI: 10.1021/acs.orglett.6b03645
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Letter
Scheme 1. Proposed mechanism for the formation of 1,2,4-
Triazolo Pyridyl-3-amines
1
Figure 1. (a) H NMR ((CD3)2SO, 600 MHz) of 9b (deprotonated)
and (b) 9.
evident from both NMR and X-ray crystal structure analysis.
Subsequent desulfurization to a carbodiimide intermediate D
and intramolecular cyclization afford the 1,2,4-triazole E.
In conclusion, we have successfully developed a novel,
efficient, transition-metal-free, one-pot protocol for the syn-
thesis of biologically relevant 3-amino-[1,2,4]-triazolo[4,3-
a]pyridines. Control experiments provided insight into the
critical role of the F¯ anion in the reaction as a base for
deprotonation of the in situ formed thiosemicarbazide, which is
the key step for the cyclization to the triazole core. We show
that the substituents on both aryl starting materials have a
major effect on the yield of the cyclization reaction, where EW-
substituents tend to furnish improved yields of triazoles over
ED groups. This methodology can be applied and extended to a
variety of hydrazino pyridines to produce a broad range of
1,2,4-triazolo pyridyl amines in an efficient manner. Further
expansion of the substrate scope is currently underway in our
laboratories.
Figure 2. Solid state crystal structures.
irradiation in the presence of benzophenone promotes
desulfurization.22 Because of this, additional control experi-
ments were performed. First, the synthesis of thiosemicarba-
zides was attempted in the absence of TBAF in order to
determine if F− was necessarily required for the cyclization
reaction (Table 1, Supporting Information). These studies
found that, irrespective of the substituent on the phenyl ring of
the isothiocyanate, the thiosemicarbazides were only isolated as
the prime product. Moreover, when the reactions were
performed for 180 min, only thiosemicarbazide formation was
observed and no cyclized product was isolated, demonstrating
that the deprotonation process was an essential part of the
synthesis of the desired products.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03645.
■
S
Experimental procedures; HRMS analysis data of all new
compounds (PDF)
NMR characterization (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: gunnlaut@tcd.ie.
*E-mail: eoin.scanlan@tcd.ie.
ORCID
With this in mind, we also explored the use of other anions
such as AcO−, Cl−, H2PO4 , and OH−. However, F− showed by
−
far the best conversion of the thiosemicarbazides to the
triazoles. The remaining anions showed either poor conversions
or hardly any at all, the order of reactivity being: F− > AcO− >
H2PO4− > OH− > Cl−. This further confirms the importance of
the deprotonation step, as Cl− is not normally not considered a
“good” anion for the deprotonation of ureas and thioureas.23
Hence, it is clearly evident from our results that F¯ is mediating
the in situ formation of the triazolo pyridines.
Based on these results, a plausible reaction mechanism for
the triazolo pyridine synthesis is illustrated in Scheme 1; the
first step involves the formation of thiosemicarbazide A. This is
followed by anion recognition, in situ deprotonation of the
thiosemicarbazide by F−, and the generation of B which is
Thorfinnur Gunnlaugsson: 0000-0003-4814-6853
Eoin M. Scanlan: 0000-0001-5176-2310
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from Science Foundation Ireland (SFI) for
the PI 2010 (10/IN.1/B2999) and PI 2013 (13/IA/1865)
grants (to T.G.), IRCSET Postdoctoral Fellowship (J.A.K.),
Marie Curie IEF Postdoctoral Grant (gunnlaut-ECFP7-MC-
́
NanoAgents to S.B.), and Ministerio of Economia y
C
DOI: 10.1021/acs.orglett.6b03645
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Letter
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