Nucleophile-Induced Rearrangement of 2 H-Azirine-2-carbonyl Azides to 2-(1 H-Tetrazol-1-yl)acetic Acid Derivatives

Article abstract of DOI:10.1021/acs.orglett.1c02157

2H-Azirine-2-carbonyl azides undergo a rearrangement into derivatives of 2-(1H-tetrazol-1-yl)acetic acid when interacting with O- and S-nucleophiles at room temperature. The reaction is catalyzed by tertiary amines or hydrazoic acid. The reaction with primary alcohols and phenols gives alkyl/aryl 2-(1H-tetrazol-1-yl)acetates. Thiophenols react with 2H-azirine-2-carbonyl azides to afford S-aryl 2-(1H-tetrazol-1-yl)ethanethioates. The mechanism of the nucleophile-induced rearrangement of 2H-azirine-2-carbonyl azides is discussed on the basis of DFT calculations as well as kinetic and 15N labeling experiments.

Full text of DOI:10.1021/acs.orglett.1c02157

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Letter
Nucleophile-Induced Rearrangement of 2H‑Azirine-2-carbonyl
Azides to 2‑(1H‑Tetrazol-1-yl)acetic Acid Derivatives
Nikita I. Efimenko, Olesya A. Tomashenko, Dar’ya V. Spiridonova, Mikhail S. Novikov,
and Alexander F. Khlebnikov*
Cite This: Org. Lett. 2021, 23, 6362−6366
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ABSTRACT: 2H-Azirine-2-carbonyl azides undergo a rearrangement into derivatives of 2-
(1H-tetrazol-1-yl)acetic acid when interacting with O- and S-nucleophiles at room
temperature. The reaction is catalyzed by tertiary amines or hydrazoic acid. The reaction
with primary alcohols and phenols gives alkyl/aryl 2-(1H-tetrazol-1-yl)acetates.
Thiophenols react with 2H-azirine-2-carbonyl azides to afford S-aryl 2-(1H-tetrazol-1-
yl)ethanethioates. The mechanism of the nucleophile-induced rearrangement of 2H-
azirine-2-carbonyl azides is discussed on the basis of DFT calculations as well as kinetic
and 15N labeling experiments.
forming tetrazole ring in these reactions come from the
external azide derivative.
There are few examples of the formation of nonfused
tetrazoles in which all nitrogen atoms for the construction of
the tetrazole ring are present in the starting material. Thus,
earrangements of highly strained 2H-azirines allow the
1
Rpreparation of a wide range of heterocycles.
Thus,
various pyridines were prepared by a gold-catalyzed rearrange-
ment of propargyl-substituted 2H-azirines,2 and pyrroles were
synthesized via an iron-catalyzed rearrangement of vinyl-
substituted isoxazoles, proceeding via intermediate formation
of the corresponding azirines.3 Similarly, indoles,1a,4 pyrazoles,5
and oxazoles6 were synthesized. Rearrangements of 2H-azirines
with any substituents leading to heterocycles containing more
than two nitrogen atoms are, to the best of our knowledge, still
unknown.1 Recently the synthesis of 2H-azirine-2-carbonyl
azides was developed and used for the preparation of
polyheterocycles.7 It was found that when azide 1a was heated
in MeOH or tert-BuOH to obtain the corresponding azirin-2-
ylcarbamate via Curtius rearrangement, it led to extensive
tarring. But recently by serendipity we found that 3-phenyl-2H-
azirine-2-carbonyl azide 1a in MeOH at room temperature
undergoes a quite unusual reaction leading to the formation of
methyl 2-(5-phenyl-1H-tetrazol-1-yl)acetate 2a (59%) as the
main product and azirine 3a (7%) as byproduct. Taking into
account that tetrazoles found broad applications in numerous
fields such as medicine, biochemistry, pharmacology, and
industry,8 it was decided to study this reaction in detail. The
structure of the unexpected tetrazole 2a was determined from
́
L’abbe et al. have discovered the thermal isomerization of 4-
alkoxycarbonyl-5-azide-1,2,3-triazoles into 5-(diazomethyl)-
tetrazoles.12 The formation of 1,2,3-triazolo-fused heterocycles
from azido-substituted pyridine, pyrimidine, triazine, and azole
derivatives, the so-called azide-tetrazole ring−chain tautomer-
ism, is much more known.10a,13 In these reactions, the azido-
functional group is bonded to a nitrogen-substituted carbon;
i.e., the sequence of N−N−N−C−N atoms required to create
a tetrazole skeleton is already present in the starting materials.
This is not the case in the rearrangement shown in Scheme 1.
Therefore, in order to understand the mechanism of
discovered rearrangement, we first decided to determine
where the azirine nitrogen is in product 2 by conducting an
experiment with labeled azirine 1b (Scheme 2). Based on 15N
NMR data for ethyl 2-(5-phenyl-1H-tetrazol-1-yl)acetate9 and
Scheme 1. Transformations of Azirine 1a
1
1
its H, 13C, 15N, and H−15N HMBC NMR spectra, which
excellently corresponds to literature data for ethyl 2-(5-phenyl-
1H-tetrazol-1-yl)acetate.9 The formation of 1,5-disubstituted
tetrazole 2a implied a significant rearrangement of the starting
azirine skeleton.
Received: June 28, 2021
Published: August 12, 2021
A rearrangement is a key part of processes leading to 1,5-
disubstituted tetrazoles in the Schmidt reaction of ketones with
azides10 and diphenyl phosphorazidate-mediated Beckmann
rearrangement of ketoximes.11 The nitrogen atoms of the
https://doi.org/10.1021/acs.orglett.1c02157
© 2021 American Chemical Society
Org. Lett. 2021, 23, 6362−6366
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neously released, which is necessary to trigger the rearrange-
ment. To gain insight into the mechanism of the rearrange-
ment, the quantum chemical calculations of the transformation
of azirine 1a to tetrazole 2a were performed at the B3LYP-D3/
6-311+G(d,p) level of theory with the SMD model for
methanol (Figure 2; for details of the calculations, see the
Supporting Information).
Scheme 2. Synthesis and Rearrangement of the Labelled
Azirine 1a
a
According to the calculations, methanol cannot extrude HN3
directly from azirine 1a to give azirine 3a, while MeO− reacts
without an energy barrier with azirine 1a to give azirine 3a and
the azide anion. The formation of MeO− can be the result of
an equilibrium reaction between methanol and a base, and
since the azirine is initially the only base in the reaction
mixture and it is weak, the concentration of the methoxide
must be very low. Neither azirine 1a nor azirine 3a is capable
of adding a nucleophilic azide anion to the CN double bond,
while the corresponding protonated azirines easily react with
the azide anion. Thus, complexes A and B of azirines 1a and 3a
with HN3 give azidoazirines C and D through the energy
barriers, which are surmountable at rt. The route from
diazidoaziridine C to tetrazole 2a (Figure 2, blue route)
involves conformational transformations C → E → F, the
aziridine ring opening in F with formation of the stabilized W-
azomethine ylide G, followed by its isomerization to S-
azomethine ylide H and extrusion of HN3 from the latter to
give ketene I. The reaction of ketene I with MeOH affords
azidoimine J which transforms to the conformation K, suitable
for the cyclization of azidoimine K to tetrazole 2a. According
to the calculations, all the mentioned transformations proceed
through energy barriers surmountable at rt. Similarly,
azidoaziridine D can give tetrazole 2a via the transformations
D → L → M → N → O → I → J → K (Figure 2, yellow
route), but this route passes through TS12 with a higher
relative Gibbs free energy (24.4 kcal/mol) than TS5 (19.7
kcal/mol), so these routes do not compete as long as azirine 1a
is present in the reaction mixture.
a
Reagents: (a) HO15NH2·HCl; (b) POCl3, NEt3; (c) (1) FeCl2, (2)
NaN3.
1,5-diphenyl-1H-tetrazole,14 the 15N NMR signals of 2b were
assigned as follows: 222.0 (N1), 328.7 (N4), 372.7 (N2), and
392.2 ppm (N3). In the 15N NMR spectrum of 2b(15N), the
most intensive peak is at 221.9 ppm, so we can conclude that
azirine nitrogen of 1 appears as the N1 in the tetrazole 2b. The
structure of tetrazole 2b was also confirmed by single-crystal X-
ray diffraction analysis.
To obtain information on the rates of consumption of the
starting azidocarbonylazirine and the formation of the target
tetrazole, as well as a possible intermediate and/or byproducts
(one of which is azirine 3), kinetic 19F NMR experiments were
carried out using azirine 1c as starting material and 4-
(trifluoromethyl)benzonitrile, which is inert under the reaction
conditions, as an internal standard (Figure 1). According to the
According to the presented mechanism (Figure 2), acid−
base relationships in the reaction mixture should have an
influence on the rearrangement rate. To check this, an
additional experiment with fluorinated azirine 1c and
CD3OD in the presence of 20 mol % Et3N, using 19F NMR,
was performed (Figure 3).
According to the results obtained, the addition of Et3N
significantly accelerates the reaction. Thus, the concentration
of tetrazole 2c in the presence of Et3N reaches a maximum
already in 3 h (Figure 2), whereas, without a base, it reaches a
maximum in 6 h (Figure 3). The effect can be attributed to an
increase in the concentration of MeO−, which promotes the
−
release of N3 . Several other bases (DMAP, TMEDA) also
accelerate the reaction, in contrast to pyridine, which has no
effect. The base and their amount have practically no influence
on the yield of the target tetrazole 2a, but the amount of the
byproduct, azirine 3a, is affected (see Table S1 in the
Supporting Information).
Figure 1. Time dependence of the relative content of 1c, 2c(D), and
3c(D) in the reaction mixture based on the integral intensities of 19F
NMR signals normalized to the internal standard.
According to the presented mechanism (Figure 2), the
addition of HN3 should catalyze the rearrangement. To check
this, an additional experiment with fluorinated azirine 1c and
CD3OD in the presence of 20 mol % N3H, using 19F NMR,
was performed (Figure 4). Indeed, in full agreement with the
proposed mechanism the N3H additive catalyzes the reaction.
Moreover, this additive increases the tetrazole yield and makes
the spectral overall yield tetrazole 2c(D) + 3c(D) practically
quantitative, probably due to the fact that the additive
data obtained, the concentration of methoxycarbonylazirine
3c(D) in the reaction mixture increases faster during the first 2
h than the concentration of tetrazole 2c(D), and then the
concentration of tetrazole 2c(D) continues to increase, while
the concentration of methoxycarbonylazirine 3c(D) remains
almost constant. This may mean that either azirine 3c(D) is an
intermediate product on the way to tetrazole 2c(D) or, when it
−
is formed from azidocarbonylazirine 1, N3 /HN3 is simulta-
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Figure 2. Plausible mechanism of the rearrangement based on the DFT calculations (relative Gibbs free energies for the reaction energy profiles in
kcal/mol, 298 K, DFT B3LYP-D3/6-311+G(d,p) level with SMD model for methanol).
Figure 4. Rearrangement of azirine 1c in CD3OD in the presence of
20 mol % N3H.
Figure 3. Rearrangement of azirine 1c in CD3OD in the presence of
20 mol % Et3N.
−
compensates for the losses of N3 /HN3, formed from internal
sources, due to side processes.
esters of 2-(5-phenyl-1H-tetrazol-1-yl)acetic acid 4a−c. The
reactions proceeded at an acceptable rate only in the presence
of Et3N (Scheme 4). The reactions with EtOH, CF3CH2OH
were carried out in the corresponding alcohol as a solvent, and
with BnOH, in acetonitrile. Bulkier alcohols such as iPrOH
and tBuOH did not react with azirine 1a.
Phenols were found to be even more suitable reagents for
realizing the rearrangement, giving in the presence of Et3N (10
mol %) high yields of the previously unknown aryl esters of 2-
(1H-tetrazol-1-yl)acetic acid, 5a−l (Scheme 5). Strong
electron-withdrawing substituent in the phenol such as
CO2Et reduces the yields of product (5j). Phenols containing
The methanol-induced isomerization was further carried out
with azidoazirines 1a−l to obtain the tetrazoles 2a−l (Scheme
3). To avoid working with explosive N3H, an additive of Et3N
was used as a promoter where necessary.
In the reactions of azirines 1f, g, i, incomplete conversions
and low yields were observed, and neither an increase in the
reaction time nor the addition of a base improved the yields.
tert-Butyl-substituted azirine 1l did not react with methanol in
the absence of a base; nevertheless, tetrazole 2l was obtained in
the presence of Et3N (10 mol %). The use of various alcohols
in the reaction of azirine 1a allows the preparation of a series of
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a
a
Scheme 3. Synthesis of Tetrazoles 2a−l
Scheme 5. Synthesis of Tetrazoles 5a−l
a
Isolated yield. Reaction conditions: 1a (0.27 mmol), ArOH (0.36
b
mol), Et3N (0.027 mmol), MeCN (4 mL), rt, 2 d. The gram-scale
synthesis: 1.022 g (73%).
a
Scheme 6. Synthesis of Tetrazoles 6a−e
a
Isolated yield. Reaction conditions: 1 (0.25 mmol), MeOH (6 mL),
b
rt, 1−2 d. In the presence of Et3N (10 mol %).
a
Scheme 4. Synthesis of Tetrazoles 4a−c
a
a
Isolated yield. Reaction conditions: 1a (0.30 mmol), ROH (6 mL),
Isolated yield. Reaction conditions: 1a (0.27 mmol), ArSH (0.36
Et3N (0.03 mmol), (for 4a,b); 1a (0.27 mmol), BnOH (0.36 mol),
Et3N (0.027 mmol), MeCN (4 mL) (for 4c); rt, 2 d.
mol), MeCN (4 mL), rt, 2 d.
1-yl)acetic acid. Thiophenols react with 2H-azirine-2-carbonyl
azides to give previously unknown S-aryl esters of 2-(5-phenyl-
1H-tetrazol-1-yl)thioacetic acid in moderate yield. A plausible
mechanism of the nucleophile-induced rearrangement of 2H-
azirine-2-carbonyl azides was proposed on the basis of DFT
calculations and kinetic experiments.
ortho and even di-ortho substituents react with azirine 1a (5h, j,
k, l).
We also succeeded in carrying out this new rearrangement in
the presence of thiophenols as nucleophiles. As a result of the
reaction, the previously unknown S-aryl 2-(5-phenyl-1H-
tetrazol-1-yl)ethanethioates 6a−e were obtained in moderate
yields (Scheme 6).
In conclusion, 2H-azirine-2-carbonyl azides undergo an
unusual rearrangement into derivatives of 2-(1H-tetrazol-1-
yl)acetic acid when interacting with O- and S-nucleophiles at
room temperature. It was found that the rearrangement is
catalyzed by tertiary amines or hydrazoic acid. The reaction of
2H-azirine-2-carbonyl azides with methanol can proceed
without basic catalysis to give methyl 2-(1H-tetrazol-1-
yl)acetates, whereas reaction with EtOH, CF3CH2OH, and
BnOH proceeds at an acceptable rate only in the presence of
Et3N. Phenols react under similar conditions to give generally
good yields of the corresponding aryl esters of 2-(1H-tetrazol-
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02157.
Experimental procedures; characterization data; calcu-
1
lation details; X-ray data of compound 2b; H, 13C and
19F NMR spectra (PDF)
Accession Codes
CCDC 2091489 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
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Letter
(7) Funt, L. D.; Krivolapova, Yu. V.; Khoroshilova, O. V.; Novikov,
M. S.; Khlebnikov, A. F. 2H-Azirine-2-carbonyl Azides: Preparation
and Use as N-Heterocyclic Building Blocks. J. Org. Chem. 2020, 85,
4182.
(8) For a recent review, see: (a) Leyva-Ramos, S.; Cardoso-Ortiz, J.
Recent Developments in the Synthesis of Tetrazoles and their
Pharmacological Relevance. Curr. Org. Chem. 2021, 25, 388.
(b) Dhiman, N.; Kaur, K.; Jaitak, V. Tetrazoles as anticancer agents:
A review on synthetic strategies, mechanism of action and SAR
studies. Bioorg. Med. Chem. 2020, 28, 115599. (c) Neochoritis, C. G.;
Zhao, T.; Dömling, A. Tetrazoles via Multicomponent Reactions.
Chem. Rev. 2019, 119, 1970. (d) Wei, C.-X.; Bian, M.; Gong, G.-H.
Tetrazolium Compounds: Synthesis and Applications in Medicine.
Molecules 2015, 20, 5528 and references therein.
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Alexander F. Khlebnikov − Institute of Chemistry, St.
Petersburg State University, St. Petersburg 199034, Russia;
orcid.org/0000-0002-6100-0309; Email: a.khlebnikov@
spbu.ru
Authors
(9) Harel, T.; Rozen, S. The Tetrazole 3-N-Oxide Synthesis. J. Org.
Chem. 2010, 75, 3141.
Nikita I. Efimenko − Institute of Chemistry, St. Petersburg
State University, St. Petersburg 199034, Russia
Olesya A. Tomashenko − Institute of Chemistry, St.
Petersburg State University, St. Petersburg 199034, Russia
Dar’ya V. Spiridonova − Institute of Chemistry, St. Petersburg
State University, St. Petersburg 199034, Russia
Mikhail S. Novikov − Institute of Chemistry, St. Petersburg
State University, St. Petersburg 199034, Russia;
orcid.org/0000-0001-5106-4723
(10) (a) Ostrovski, V. A.; Popova, E. A.; Trifonov, R. E.
Developments in tetrazole chemistry (2009−16), in: Scriven, E.;
Ramsden, C. A., Eds., nt; Academic Press: New York, 2017; pp 1−62.
(b) Motiwala, H. F.; Charaschanya, M.; Day, V. W.; Aubé, J.
Remodeling and Enhancing Schmidt Reaction Pathways in Hexa-
fluoroisopropanol. J. Org. Chem. 2016, 81, 1593 and references
therein.
(11) Ishihara, K.; Shioiri, T.; Matsugi, M. Stereospecific synthesis of
1,5-disubstituted tetrazoles from ketoximes via a Beckmann rearrange-
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60, 1295 and references therein.
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Rearrangements of 5-Azido Substituted 1,2,3-Triazoles. Tetrahedron
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Withdrawing N-1 Substituents on the Thermal Beraviour of 5-Azido-
1,2,3-triazoles. Tetrahedron 1989, 45, 749.
Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
(13) (a) Deev, S. L.; Shestakova, T. S.; Charushin, V. N.;
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ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support of the Russian
Science Foundation (19-13-00039). This research used
resources of the Magnetic Resonance Research Centre,
Chemical Analysis and Materials Research Centre, Computing
Centre, Centre for X-ray Diffraction Studies, and Chemistry
Educational Centre of the Research Park of St. Petersburg
State University.
(14) Markgraf, J. H.; Sadighi, J. P. A 15N NMR study of N-
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