Revisiting ring-degenerate rearrangements of 1-substituted-4-imino-1,2,3-triazoles

Article abstract of DOI:10.3762/bjoc.14.184

The 1-substituted-4-imino-1,2,3-triazole motif is an established component of coordination compounds and bioactive molecules, but depending on the substituent identity, it can be inherently unstable due to Dimroth rearrangements. This study examined parameters governing the ring-degenerate rearrangement reactions of 1-substituted-4-imino-1,2,3-triazoles, expanding on trends first observed by L’abbé et al. The efficiency of condensation between 4-formyltriazole and amine reactants as well as the propensity of imine products towards rearrangement was each strongly influenced by the substituent identity. It was observed that unsymmetrical condensation reactions conducted at 70 °C produced up to four imine products via a dynamic equilibrium of condensation, rearrangement and hydrolysis steps. Kinetic studies utilizing 1-(4-nitrophenyl)-1H-1,2,3-triazole-4-carbaldehyde with varying amines showed rearrangement rates sensitive to both steric and electronic factors. Such measurements were facilitated by a high throughput colorimetric assay to directly monitor the generation of a 4-nitroaniline byproduct.

Full text of DOI:10.3762/bjoc.14.184

Revisiting ring-degenerate rearrangements
of 1-substituted-4-imino-1,2,3-triazoles
James T. Fletcher*, Matthew D. Hanson, Joseph A. Christensen and Eric M. Villa
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 2098–2105.
Department of Chemistry, Creighton University, 2500 California Plaza,
Omaha, NE 68178, U.S.A.
doi:10.3762/bjoc.14.184
Received: 18 May 2018
Accepted: 26 July 2018
Published: 10 August 2018
Email:
James T. Fletcher* - jamesfletcher@creighton.edu
* Corresponding author
Associate Editor: J. A. Murphy
Keywords:
© 2018 Fletcher et al.; licensee Beilstein-Institut.
License and terms: see end of document.
colorimetric assay; condensation; imine exchange; rearrangement;
1,2,3-triazole
Abstract
The 1-substituted-4-imino-1,2,3-triazole motif is an established component of coordination compounds and bioactive molecules,
but depending on the substituent identity, it can be inherently unstable due to Dimroth rearrangements. This study examined param-
eters governing the ring-degenerate rearrangement reactions of 1-substituted-4-imino-1,2,3-triazoles, expanding on trends first ob-
served by L’abbé et al. The efficiency of condensation between 4-formyltriazole and amine reactants as well as the propensity of
imine products towards rearrangement was each strongly influenced by the substituent identity. It was observed that unsymmetrical
condensation reactions conducted at 70 °C produced up to four imine products via a dynamic equilibrium of condensation, rear-
rangement and hydrolysis steps. Kinetic studies utilizing 1-(4-nitrophenyl)-1H-1,2,3-triazole-4-carbaldehyde with varying amines
showed rearrangement rates sensitive to both steric and electronic factors. Such measurements were facilitated by a high through-
put colorimetric assay to directly monitor the generation of a 4-nitroaniline byproduct.
Introduction
Examples of multidentate chelators comprised of 1,2,3-triazole transition metal and lanthanide cations, and have impacted
units have surged in recent years [1-7], enabled by efficient fields that include bioimaging [26,27] and chemosensing
preparation from the Sharpless–Meldal copper-catalyzed [28,29].
azide–alkyne cycloaddition (CuAAC) reaction [8-11]. Click
chelators with a variety of N-donor units connected at the 4-tria- Surprisingly, the reported examples partnering 1,2,3-triazole
zolyl position have been reported, including pyridine [12-17], and imine N-donor groups are limited [30-32], despite the ubiq-
quinoline [18,19], pyridazine [20,21], phthalazine [22], benz- uity of such Schiff base subunits in coordination chemistry.
imidazole [23], phenanthroline [24], bipyridine [25] and amine 4-Iminotriazole-containing molecules have also recently been
[26] subunits. The utility of such chelators in constructing coor- shown to be useful synthons for preparing compounds with
dination compounds has been demonstrated for a wide range of anticancer [33] and antituberculosis [34] properties. 1-Substi-
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Beilstein J. Org. Chem. 2018, 14, 2098–2105.
tuted-4-imino-1,2,3-triazole analogs are typically prepared from vents following the acid-catalyzed hydrolysis of iminotriazole
efficient condensation reactions of 1-substituted-4-formyl-1,2,3- product mixtures. An important goal of this current investiga-
triazoles deriving from CuAAC preparations [33,35-39]. Due to tion was to expand the scope of this original study by also
the thermodynamic stability of the imine bond at the 4-triazolyl examining whether formyltriazole substituents influence the
position, this motif stands as an attractive target for designing spontaneity of imine formation and subsequent susceptibility
new multidentate chelators to prepare coordination compounds. towards ring-degenerate rearrangement. To this end, a series of
electron-withdrawing and electron-donating functional groups
Cautiously, 1-substituted-4-imino-1,2,3-triazole analogs have attached at the para-phenyl positions of both 1-phenyl-4-
been reported to display an inherent instability at elevated tem- formyl-1,2,3-triazole and aniline reactants were used in the cur-
peratures due to the propensity to undergo Dimroth rearrange- rent investigation.
ments [40], as originally described by L’abbé et al. for this
motif [41-43], as shown in Figure 1. This study demonstrated Two reaction conditions were employed in this study. Low tem-
that such compounds are prone to rearrange by a ring-degen- perature conditions used a 1:1 CHCl3/MeOH solvent system at
erate process promoted by an increasing electron-donor strength room temperature, identified as useful for solubilizing the range
of the imine functionality. It was further demonstrated that this of analogs included in the study and facilitating product work-
rearrangement could be utilized as a reliable synthetic tool, with up via simple evaporation. High-temperature conditions used a
1-phenyl-1H-1,2,3-triazole-4-carbaldehyde being used to 1:1 t-BuOH/H2O solvent system at 70 °C, identified as useful in
prepare 1-substituted-4-formyl-1,2,3-triazoles through a se- a previous study focusing on tandem CuAAC reaction develop-
quence of condensation, rearrangement and hydrolysis steps ment [35]. Importantly, instead of measuring only the relative
[42]. While this approach has found recent utility in preparing amounts of formyltriazole products following imine hydrolysis
novel multidentate iminotriazole-based chelators [30-32], inves- promoted by reaction work-up, this study instead aimed to
tigations exploring the parameters governing this rearrange- directly measure the relative amounts of both formyltriazole and
ment in greater detail than originally reported are lacking.
iminotriazole product mixtures within each dynamic equilib-
rium.
With an emerging interest in the 4-imino-1,2,3-triazole motif as
coordination chemistry synthon, motivation for revisiting the Before examining the extent of rearrangement for unsymmetri-
ring degenerate rearrangements first described by L’abbe is cal imine analogs, it was important to understand how the sub-
twofold. A better understanding of parameters suppressing this stituent identity might impact the spontaneity of imine forma-
rearrangement would inform the design of stable 4-imino-1,2,3- tion in simplified systems not susceptible to productive rear-
triazole target compounds, while a better understanding of pa- rangement. Summarized in Table 1 is the observed extent of
rameters promoting this rearrangement might lead to improved condensation for symmetrical pairings of aldehyde and imine
methodology for the preparation of 1-subsituted-4-formyl-1,2,3- reactants. Under both low and high-temperature conditions, the
triazole target compounds. An expanded thermodynamic and strongly electron-withdrawing nitro derivative was shown inca-
kinetic investigation regarding the substituent effects pable of undergoing condensation. This can be attributed to the
of 4-imino-1,2,3-triazoles on this Dimroth rearrangement is poor nucleophilicity of 4-nitroaniline. Condensation efficiency
therefore warranted, exemplary results of which are described was observed to increase as the electron-donating character of
herein.
the substituents increased. Hence, with the exception of 4-nitro-
aniline it was expected that each amine used in the study would
be competent in forming appreciable quantities of imine prod-
Results and Discussion
The original study of L’abbé regarding this ring-degenerate re- uct under both low and high-temperature conditions with un-
arrangement focused on the condensation of 1-phenyl-1H-1,2,3- symmetrical pairings of reactants.
triazole-4-carbaldehyde with varying amines [42]. Rearrange-
ment of the resulting 1-phenyl-4-imino-1,2,3-triazole deriva- Crystals of 2cc’ suitable for XRD analysis were grown from
tives was observed at 80 °C in both DMSO and alcohol sol- slow evaporation of a methylene chloride solution. As shown in
Figure 1: Conversion of 1-substituted-4-formyltriazole analogs via ring-degenerate rearrangement of 1-substituted-4-imino-1,2,3-triazoles as first de-
scribed by L’abbé [42].
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Beilstein J. Org. Chem. 2018, 14, 2098–2105.
Table 1: Evaluation of symmetrical condensation parameters.
entry
R
R’
solvent
conditions
compound
rel %a 1x
compound
rel %a 2xy’
1
NO2
NO2
NO2
CF3
CF3
CF3
H
NO2
NO2
NO2
CF3
CF3
CF3
H
MeOH/CHCl3
MeOH/CHCl3
MeOH/CHCl3
MeOH/CHCl3
MeOH/CHCl3
MeOH/CHCl3
MeOH/CHCl3
MeOH/CHCl3
MeOH/CHCl3
MeOH/CHCl3
t-BuOH/H2O
t-BuOH/H2O
t-BuOH/H2O
t-BuOH/H2O
t-BuOH/H2O
t-BuOH/H2O
rt, 24 h
1a
1a
1a
1b
1b
1b
1c
1d
1e
1f
100%
100%
100%
41%
17%
10%
0%
2aa’
2aa’
2aa’
2bb’
2bb’
2bb’
2cc’
2dd’
2ee’
2ff’
0%
2
rt, 48 h
0%
3
rt, 72 h
0%
4
rt, 24 h
59%
83%
90%
100%
100%
100%
100%
0%
5
rt, 48 h
6
rt, 72 h
7
rt, 24 h
8
CH3
OCH3
N(Et)2
NO2
CF3
H
CH3
OCH3
N(Et)2
NO2
CF3
H
rt, 24 h
0%
9
rt, 24 h
0%
10
11
12
13
14
15
16
rt, 24 h
0%
70 °C, 24 h
70 °C, 24 h
70 °C, 24 h
70 °C, 24 h
70 °C, 24 h
70 °C, 24 h
1a
1b
1c
1d
1e
1f
100%
47%
11%
7%
2aa’
2bb’
2cc’
2dd’
2ee’
2ff’
53%
89%
93%
98%
94%
CH3
OCH3
N(Et)2
CH3
OCH3
N(Et)2
2%
6%
aRelative molar fraction of 1 and 2 derivatives as determined by NMR integration.
Figure 2, each of the three aromatic rings in this molecule’s analogs towards rearrangement. As summarized in Table 2,
fully conjugated π-system adopts a largely coplanar configura- under condensation conditions this dynamic system can be ex-
tion. The dihedral angle between the 1-phenyl substituent and pected to produce up to four unique imines and two unique
the triazole ring is 28°, the dihedral angle between the imino aldehydes through a series of condensation, rearrangement and
group and triazole ring is 0.5° and the dihedral angle between hydrolysis steps. The initial condensation reaction between
the phenyl and imino group is 32°. This structural detail formyltriazole and amine leads to iminotriazole formation (step
supports the ability of the 1-triazolyl and imino arene units to a). This iminotriazole is then vulnerable to ring-degenerate
communicate electronically through the intervening triazole Dimroth rearrangement (step b). This rearranged iminotriazole
ring via largely coplanar π-systems within this family of com- can then undergo hydrolysis to yield a new formyltriazole and a
pounds.
new amine byproduct (step c), each of which can then condense
with their substituent-matched aldehyde analogs (steps d and e)
to form their respective symmetrical iminotriazole products.
One expected outcome for this dynamic equilibrium was that
step b would follow L’abbé’s previously observed rearrange-
ment trend of being increasingly spontaneous for electron-rich
amines partnered with electron-poor formyltriazoles [42].
Another expected outcome was that the condensation steps a, c
and d would favor electron-rich amines relative to electron-poor
amines, due to their superior nucleophilicity. All high-tempera-
ture reactions were analyzed after 24 h. (While this time point
Figure 2: ORTEP structure of 2cc’. Thermal ellipsoids shown at
25% probability.
With the relative spontaneity of imine formation defined using was not necessarily adequate for reaching chemical equilibrium
symmetrical analogs, the study’s next focus was to examine within each dynamic system, it was deemed sufficient to make
how the substituent identity of both triazole and amine reac- informative observations regarding the relative influence of
tants influence the susceptibility of unsymmetrical imine substituent effects on product distributions.)
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Beilstein J. Org. Chem. 2018, 14, 2098–2105.
Table 2: Evaluation of unsymmetrical condensation parameters.
entry
R
R’
compd rel %a compd rel %a compd rel %a compd rel %a compd rel %a compd rel %a
1x
2xy’
2yx’
1y
2yy’
2xx’
1b
H
NO2
CF3
CH3
1c
1c
1c
100% 2ca’
0%
2ac’
2bc’
2dc’
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
22%
23%
28%
0%
18%
16%
8%
0%
1a
1b
1d
1e
1f
0%
0%
0%
0%
0%
0%
0%
14%
0%
0%
0%
0%
0%
0%
0%
5%
0%
2%
13%
62%
62%
0%
0%
1%
2aa’
2bb’
2dd’
2ee’
2ff’
0%
2cc’
2cc’
2cc’
2cc’
2cc’
2aa’
2aa’
2aa’
2bb’
2bb’
2bb’
2dd’
2ee’
2ff’
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
8%
19%
18%
22%
0%
3%
13%
18%
0%
2b
H
15%
3%
2cb’
2cd’
2ce’
2cf’
85%
97%
0%
3b
H
0%
4b
H
OCH3 1c
N(Et)2 1c
0%
100% 2ec’
0%
5b
H
8%
92%
78%
57%
17%
59%
83%
90%
2fc’
0%
6b
NO2
NO2
NO2
CF3
CF3
CF3
CH3
OCH3
N(Et)2
H
H
1a
13%
18%
5%
2ac’
2ac’
2ac’
2bc’
2bc’
2bc’
2dc’
2ec’
2fc’
2ca’
2ca’
2ca’
2cb’
2cb’
2cb’
1d
1d
1d
1d
1d
1d
1d
1d
1d
1a
1b
1d
1e
1f
2cc’
2cc’
2cc’
2cc’
2cc’
2cc’
2cc’
2cc’
2cc’
2aa’
2bb’
2dd’
2ee’
2ff’
9%
7b
H 48 h 1a
H 72 h 1a
25%
64%
0%
8b
9b
H
1b
41%
17%
10%
0%
10b
11b
12b
13b
14b
15c
16c
17c
18c
19c
20c
21c
22c
23c
24c
H 48 h 1b
H 72 h 1b
0%
0%
H
1d
1e
1f
100% 2cd’
100% 2ce’
100% 2cf’
0%
H
0%
0%
H
0%
0%
NO2
CF3
CH3
1c
1c
1c
100% 2ca’
0%
2ac’
2bc’
2dc’
2ec’
2fc’
0%
2cc’
2cc’
2cc’
2cc’
2cc’
2aa’
2bb’
2dd’
2ee’
2ff’
H
52%
0%
2%
8%
0%
0%
0%
0%
0%
2cb’
2cd’
2ce’
2cf’
29%
31%
24%
14%
0%
6%
H
28%
31%
15%
38%
14%
11%
18%
12%
H
OCH3 1c
N(Et)2 1c
H
NO2
CF3
CH3
OCH3
N(Et)2
H
H
H
H
H
1a
1b
1d
1e
1f
2ac’
2bc’
2dc’
2ec’
2fc’
2ca’
2cb’
2cd’
2ce’
2cf’
1d
1d
1d
1d
1d
2cc’
2cc’
2cc’
2cc’
2cc’
3%
60%
56%
87%
aRelative molar fraction of 1 and 2 derivatives as determined by NMR integration; b1:1 MeOH/CHCl3 solvent, room temperature, 24 h unless other-
wise noted; c1:1 t-BuOH/H2O solvent, 70 °C, 24 h unless otherwise noted.
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Beilstein J. Org. Chem. 2018, 14, 2098–2105.
Direct, quantitative measurement of each triazole-containing In contrast, under high-temperature conditions significant rear-
species as a relative molar fraction within the dynamic reaction rangement occurred in nearly all of the unsymmetrical systems
mixtures was made using 1H NMR analysis. This was accom- studied. The majority of substituent combinations resulted in
plished by integration of the distinguishable triazole signals for formation of all four possible imine products, with those
each iminotriazole and formyltriazole analog contained in this analogs possessing electron-rich substituents being the highest
study. Signal assignments were enabled by comparison with populated (Table 2, entries 15–24). As expected, the extent of
pure iminotriazoles prepared using low temperature conditions rearrangement increased as the electron-donating properties of
that promoted minimal rearrangement. An example of this com- the amine reactants increased relative to the triazole. Unexpect-
parative analysis is shown in Figure 3.
edly, even those combinations where an electron-rich triazole
was paired with an electron-poor aniline generated significant
Using this analytical approach, the extent to which temperature populations of rearranged imine products (Table 2, entries 16,
and substituent pairings impacted the population of dynamic and 22–24). This stands as a cautionary observation informing
product mixtures was successfully defined. Under low tempera- the design of 1-substituted-4-imino-1,2,3-triazoles intended for
ture conditions, the rearrangement was largely suppressed. For exposure to high-temperature conditions, such as commonly
1-phenyl-1H-1,2,3-triazole-4-carbaldehyde, the condensation used in preparing metal coordination compounds. While the
efficiency increased with increasingly electron-rich anilines, pairing of electron-rich formyltriazoles with electron-poor
and no rearrangements were observed (Table 2, entries 1–5). amines slows the rate of rearrangement, it does not preclude the
Evaluation of the formyltriazole substituent identity on the rear- ability of such analogs to rearrange significantly into scrambled
rangement surprisingly showed that even at room temperature analogs.
those analogs with electron-poor nitro functionality underwent
slow but consistent rearrangement (Table 2, entries 6–8). Among the substituent pairings studied, greatly simplified reac-
In contrast, all other analogs examined showed stability tion outcomes were observed for those with nitro substituents.
towards rearrangement at room temperature (Table 2, Those trials employing nitroaniline as a reactant showed a lack
entries 9–14). These observations fit the previously observed of imine formation due to its poor nucleophilicity (Table 2,
trend of rearrangement skewing towards population of entries 1 and 15). Those trials employing nitro-functionalized
the electron-rich group at the 1-position of the triazole, and formyltriazole 1a showed enhanced populations of rearranged
should inform the design of 1-substituted-4-imino-1,2,3-tri- formyltriazole and iminotriazole products lacking nitro func-
azole target compounds with prescribed room temperature tionality (Table 2, entries 6–8, and 20). This can be attributed to
stability.
a two-fold influence by the nitro substituent. As an electron-
Figure 3: 1H NMR aromatic region of a product mixture compared with reference imine analogs. Singlets appearing from 8.5–8.7 ppm correspond to
the triazole C–H position used to quantify the imine constituents of product mixtures.
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Beilstein J. Org. Chem. 2018, 14, 2098–2105.
poor formyltriazole, 1a promotes forward progress of the rear- temperature of 100 °C was identified as useful for promoting
rangement. Additionally, the resulting rearranged imine under- significant reaction progress within a 24 h time window for the
goes an irreversible hydrolysis due to the poor nucleophilicity amine reactants studied. The increase in absorbance at 385 nm
of the para-nitroaniline byproduct. Because of the simplified over time was used to calculate initial reaction rates for each of
high-temperature reaction outcomes of 1a relative to the other the amines studied, as described in the experimental section. It
analogs studied, additional investigation of this compound was is important to note that this monitoring detects only the
undertaken.
endpoint of the three-step sequence of condensation, rearrange-
ment and hydrolysis steps, whereupon para-nitroaniline is re-
With a secondary aim of identifying improved reaction condi- leased as a byproduct, and not each step individually.
tions for exploiting this rearrangement as an efficient synthetic
tool for formyltriazole preparations, it was proposed that 1a As summarized in Table 3, it was observed that reaction rates
might display significant advantages over previously utilized 1c were influenced by both electronic and steric properties of the
[30-32,42] as a synthon for this purpose. While 1c showed amine reactant. A comparison of anilines showed that reaction
scrambled substituents under the conditions studied when part-
nered with anilines with both electron-poor and electron-rich
Table 3: Kinetic assay results.a
character, 1a efficiently drove the reaction mixture towards re-
entry
amine reactant
initial rate (μM/min)
arranged, non-nitro products. It was hypothesized that in addi-
tion to promoting the forward rearrangement reaction and
subsequent imine hydrolysis due to its nucleophilic incompe-
tency, the para-nitroaniline byproduct formed in the condensa-
tion/rearrangement/hydrolysis might also serve as a colori-
metric self-indicator of reaction progress, as illustrated in
Figure 4.
1
2,6-dimethylaniline
ortho-toluidine
20
2
54
3
meta-toluidine
83
4
3,5-dimethylaniline
4-aminobenzotrifluoride
4-fluoroaniline
110
11
5
6
60
7
para-toluidine
67
8
2-naphthylamine
2-aminofluorene
2-aminoanthracene
3-aminopentane
n-hexylamine
46
In order to test the proposed advantages for using 1a in prepar-
ing formyltriazole products, while also examining how amine
identity impacts rearrangement rates, a high-throughput colori-
metric assay exploiting the electronic properties of the para-
nitroaniline byproduct was developed. DMSO was selected as
the reaction solvent for these studies due to its proven utility in
facilitating this reaction [42] and its low volatility. A reaction
9
91
10
11
12
13
130
30
91
benzylamine
120
aSee experimental section in Supporting Information File 1.
Figure 4: Rearrangement reaction progress of 1a leading to irreversible formation of a colorimetric self-indicating byproduct.
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Beilstein J. Org. Chem. 2018, 14, 2098–2105.
rates decreased with increasing steric bulk at the ortho posi-
tions (Table 3, entries 1–4) and reaction rates increased with in-
creasing electron-donating character of para substituents
(Table 3, entries 5–7). Reaction rates also increased as the size
(and corresponding polarizability) of aromatic amines in-
creased (Table 3, entries 8–10). Similar steric trends were ob-
served for aliphatic amines (Table 3, entries 11–13). 1H NMR
analyses of selected product mixtures were used to verify that
colorimetric responses correlated with the formation of formyl-
triazole rearrangement products and not from unexpected de-
composition pathways. Demonstrating 1a to be a useful synthon
for formyltriazole preparations, it was used to prepare analogs
1c (59% isolated yield) and 1d (64% isolated yield) by the
kinetic assay conditions (see Supporting Information File 1).
Optimizing of reaction yields and exploring of the scope of
amine reagents tolerated by this rearrangement reaction will be
the subject of future studies.
Supporting Information
Crystallographic data for the structures in this paper have
been deposited with the Cambridge Crystallographic Data
Centre: 2cc’ as CCDC 1842384. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge, CB2 1EZ, UK (fax:
+44-(0)1223-336033 or e-mail: despoit@ccdc.cam.ac.uk).
Supporting Information File 1
Experimental procedures, copies 1H and 13C NMR spectra
for all reported compounds, details of XRD analysis and
UV–visible spectra for kinetic assays.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-184-S1.pdf]
Acknowledgements
This publication was made possible by grants from the
Conclusion
Motivated by an interest in the 4-imino-1,2,3-triazole synthon, National Institute for General Medical Science (NIGMS,
the goal of this investigation was to better understand the 5P20GM103427), a component of the National Institutes of
susceptibility of such molecules to the ring-degenerate rear- Health (NIH), and its contents are the sole responsibility of the
rangements first described by L’abbé in 1990 [42]. By directly authors and do not necessarily represent the official views of
measuring complex mixtures of aldehyde and imine products NIGMS or NIH. JAC acknowledges Creighton University’s
resulting from a dynamic combination of condensation, rear- Baumann Family Scholarship for financial support.
rangement and hydrolysis reactions between 1-substituted-4-
ORCID® iDs
Eric M. Villa - https://orcid.org/0000-0001-9883-1993
formyl-1,2,3-triazoles and aromatic amines, additional insight
regarding substituent effects on this process was defined. Im-
portantly, while the established trend of relatively electron-rich
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