Synthesis of a New Family of 1,1-Diazidoethenes: One-Pot Construction of 4-Azido-1,2,3-triazoles via Nitrene Cyclization

Article abstract of DOI:10.1021/acs.orglett.8b03227

The reaction of 4,4-dichloro-1,2-diazabuta-1,3-dienes with sodium azide has been studied and found to provide straightforward access to extremely rare 1,1-bisazides. It was demonstrated that these highly unstable compounds are prone to eliminate the N₂ molecule to cyclize into 4-azido-1,2,3-triazoles bearing two aryl (heteroaryl) groups at positions 2 and 5. The formation of bisazides was confirmed by their trapping with cyclooctyne and B3LYP calculations. Most likely, the elimination of nitrogen to form an intermediate nitrene is facilitated by the aza group via anchimeric-like participation. The reaction was found to be very general for the highly efficient synthesis of various 4-azidotriazoles. It was demonstrated that these heterocycles are highly attractive building blocks for subsequent preparation of 1,2,3-triazole-derived compounds.

Full text of DOI:10.1021/acs.orglett.8b03227

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of a New Family of 1,1-Diazidoethenes: One-Pot
Construction of 4‑Azido-1,2,3-triazoles via Nitrene Cyclization
Alexey V. Shastin,†,‡ Biligma D. Tsyrenova,† Pavel G. Sergeev,† Vitaly A. Roznyatovsky,†
Ivan V. Smolyar,† Victor N. Khrustalev,§,∥ and Valentine G. Nenajdenko*,†
†Department of Chemistry, Lomonosov Moscow State University, 119899 Moscow, Russia
‡Institute of Problems of Chemical Physics, Russian Academy of Sciences, 142432 Chernogolovka, Russia
§Peoples’ Friendship University of Russia (RUDN University), Miklukho-Maklay St., 6, 117198 Moscow, Russia
∥National Research Center “Kurchatov Institute”, Kurchatov Sq., 1, 123182 Moscow, Russia
S
* Supporting Information
ABSTRACT: The reaction of 4,4-dichloro-1,2-diazabuta-1,3-dienes with
sodium azide has been studied and found to provide straightforward
access to extremely rare 1,1-bisazides. It was demonstrated that these
highly unstable compounds are prone to eliminate the N2 molecule to
cyclize into 4-azido-1,2,3-triazoles bearing two aryl (heteroaryl) groups at
positions 2 and 5. The formation of bisazides was confirmed by their
trapping with cyclooctyne and B3LYP calculations. Most likely, the
elimination of nitrogen to form an intermediate nitrene is facilitated by the aza group via anchimeric-like participation. The
reaction was found to be very general for the highly efficient synthesis of various 4-azidotriazoles. It was demonstrated that these
heterocycles are highly attractive building blocks for subsequent preparation of 1,2,3-triazole-derived compounds.
instability of these compounds and lack of suitable synthetic
methods.7 On the other hand, such molecules have a very rich
synthetic chemistry that opens straightforward access to
various nitrogen heterocycles.8 Recently, the chemistry of
geminal di- and triazides was reviewed by Banert and Kirsch
(Scheme 1).9
he azide group is one of the most useful functional
1
Tgroups. This fragment can easily be transformed into a
variety of other fundamental substituents. As such, azides have
broad application in industry and in the preparation of
energetic materials. However, probably more important is the
application of organic azides as precursors for subsequent
transformation. Currently, this functional group is becoming
more and more important in synthetic chemistry, materials
science, and some biological applications due to its high utility
in click chemistry. However, molecules containing two or more
azide groups in the structure are less investigated.2
We proposed that the reaction of dichloro-1,2-diaza-1,3-
dienes 1 with sodium azide would provide new bisazides via
the addition of an azide anion to the double bond with the
carbon atom bearing two good leaving groups. However, our
first experiments with 1a as a model electrophile in DMSO as a
solvent at rt resulted in formation of totally different but very
interesting product 3a. The corresponding 4-azido-substituted
1,2,3-triazole 3a was isolated in 75% yield. The structure of 3a
was confirmed unambiguously by X-ray analysis (Scheme 2).
Notably, 1,2,3-triazoles having a substituent at position 2 are
rare in comparison with 1-substituted 1,2,3-triazoles available
by click reaction. Nowadays, 2-aryltriazoles attract significant
attention as a novel type of blue-light-emitting fluorophore.10
Also the importance of triazoles in the fields of medicinal and
material chemistry11 makes them promising substrates for
novel fluorophore development. One can see six nitrogen
atoms in the structure of 3a. Formation of 3a can be explained
by substitution of two chlorines with two azides (addition−
elimination sequence) followed by heterocylization via
formation of nitrene and elimination of molecular nitrogen.
Recently, we devised a synthesis of a new type of 1,2-diaza-
1,3-diene having two chlorine atoms at the CC double
bond.3 It has been demonstrated previously that 1,2-diaza-1,3-
dienes are highly universal building blocks in the construction
of various heterocycles.4 However, dichloro-substituted heter-
odienes of this type are almost unknown in the literature, and
data about their reactivity are still very sparse.5 Due to the
presence of the electron-withdrawing aza group, these aza-
dienes behave as highly reactive and versatile electrophiles.6
Having in hand these versatile building blocks, we started their
systematic study. This paper is devoted to our investigation of
the reaction of dichloro-1,2-diaza-1,3-dienes with sodium
azide.
We expected a priori to obtain a new family of compounds
having a 1,1-diazidoethene fragment in the structure.
Currently, compounds having two or more azido groups in
the structure are extremely rare. This is especially true for
geminal vinyl bisazides. So far, only five 1,1-diazidoethenes
have been reported in the literature due to the intrinsic
Received: October 10, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03227
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Known 1,1-Diazidoethenes and Expected
Formation of a New Type of Bisazides 2
Scheme 2. Initial Discovery and Molecular Structure of 3a
Figure 2. Scope of aryl groups at nitrogen of diazadienes 1.
Scheme 3. One-Pot Protocol
Figure 3. Synthesis of 3 bearing a heterocyclic substituent.
electronic factors in the aryl substituent at position 3 of the
diazadienes did not affect the heterocyclization as all dienes 1
were smoothly converted into azidotriazoles 3. The reaction
with a 2-naphthalenyl derivative also proceeded well to give
3m in 89% yield. However, the influence of steric hindrance
was more pronounced. For example, the reaction with
substrates 1 bearing a substituent in the ortho-position
demonstrated somewhat lower yields. In the case of 2,6-
disubstituted substrates, yields of 3k,l dropped to 34%.
Next, the influence of the nature of the substituent at
position 1 of the starting dienes was studied. It was found that
in contrast to previous results, almost no effect on the reaction
was observed. Therefore, practically any aryl substituent can be
installed at position 2 of the target azidotriazole 3 (Figure 2).
We also attempted to perform the synthesis of 3 using a
much more attractive one-pot protocol (Scheme 3). The one-
pot protocol opened very efficient access to azidotriazoles
starting from easily available benzaldehydes and hydrazines.
For example, 3a,f,g,h were synthesized in reasonably good
yields (up to 67%) without additional optimization. Significant
Figure 1. Scope of diazadienes 1. Influence of substituent at position
4 and molecular structure of 3f.
After exhaustive optimization of the model reaction with 2a
(see Supporting Information), it was found that the reaction
proceeds most efficiently with 3 equiv of sodium azide in
DMSO at rt for 2 h to give model triazole 3a in 90% isolated
yield. With the optimized reaction conditions in hand, the
scope of this new reaction was investigated (Figure 1).
First, the influence of the nature of the substituents at
position 3 (carbon atom) of the dichloro-1,2-diaza-1,3-dienes
1 was studied. Thus, a set of dienes 1 possessing both
electronically and sterically different substituents was studied.
The transformation was found to be very general,
demonstrating perfect efficiency with dienes 1 bearing either
electron-rich or electron-poor substituents. The desired
products were isolated in up to 95% yield. Apparently,
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DOI: 10.1021/acs.orglett.8b03227
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Organic Letters
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found to be applicable for the synthesis of many pyridine 3ab−
ad and quinoline 3ae derivatives. It has been found previously
that thienyl- or furyl-derived dichloro-1,2-diaza-1,3-dienes 1
are very unstable, and these derivatives cannot be isolated in
pure form due to their rapid degradation at rt. Nevertheless,
using this one-pot protocol, the corresponding furan- and
thiophene-substituted azidotriazoles 3af−3ah were prepared
successfully in up to 60% isolated yield (Figure 3).
Scheme 4. Conversions of the Azide Group and Molecular
Structure of 4d
Apparently, triazoles 3 are synthetically attractive building
blocks due to the presence of the azido group in the structure.
Thus, the synthetic usefulness of these heterocycles was
investigated (Scheme 4).
For example, Cu-catalyzed click reaction provided the
corresponding bistriazole 4a very efficiently in 86% isolated
yield. In contrast, similar ruthenium-catalyzed cycloaddition
gave no results. Most likely, chelation of ruthenium prevented
this type of cycloaddition. Reaction with malonodinitrile
(Dimroth triazole synthesis) opened access to another type
of bistriazoles. The corresponding product 4b was isolated in
70% yield. It was demonstrated that the azido group in 3a
could be reduced directly to the amine 4c in 95% yield.
Alternatively, iminophosphorane 4d can be prepared in
quantitative yield by the reaction of 3a with PPh3. Finally,
the possibility to prepare another phosphorus derivative 4e was
demonstrated using a reaction with triethyl phosphite. The
corresponding amide 4e was isolated in 96% yield (Scheme 4).
Finally, initial efforts have been made to bring insight into
the possible mechanism of this reaction. We decided to
confirm real formation of the bisazides as short-living highly
reactive compounds. Toward this aim, reaction of 1a was
performed in the presence of an excess cyclooctyne at 60 °C.
Strain-promoted azide−alkyne [3 + 2] cycloaddition (SPAAC)
reaction was successful for trapping the short-lived azides.9,12
The corresponding bistriazole 5a was isolated in 60% yield as a
result of a SPAAC reaction of the intermediate bisazide 2a with
cyclooctyne (Scheme 5).
Scheme 5. Proof of Bisazide Generation
growth of molecular complexity is observed for this one-pot
multistep procedure (Scheme 3).
Also, the possibility to synthesize azidotriazoles 3 bearing a
heterocyclic substituent was investigated. The reaction was
a
Scheme 6. DFT Calculations of the Reaction Mechanism and X-ray Structure of 6a
a
These energies are based on an assumption that Cl−, and other byproducts do not participate in the subsequent steps.
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DOI: 10.1021/acs.orglett.8b03227
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In addition, DFT calculations were performed to gain a
deeper insight into the reaction mechanism. It should be noted
that the obtained results are in perfect agreement with data
obtained by theoretical calculation (Scheme 6). Cyclization of
bisazide 2a into azidotriazole has a quite low activation barrier
(16.5 kcal/mol). Moreover, stepwise substitution was con-
firmed by isolation of 4-chlorotriazole 6a as the minor product.
An alternative pathway for formation of 3a by transformation
of 3-chlorotriazole 6a has a much higher activation energy for
this step (35.6 kcal/mol). Therefore, cyclization of 2a into
azidotriazole 3a is much faster than the formation of 3a from
6a.
In summary, the reaction of 4,4-dichloro-1,2-diazabuta-1,3-
dienes with sodium azide has resulted in the formation of
corresponding 1,1-bisazides as highly reactive intermediates. As
a result, after elimination of molecular nitrogen, 4-azido-1,2,3-
triazoles were prepared in up to 95% yield. The formation of
bisazides was confirmed by SPAAC with cyclooctyne and
B3LYP calculations. It was demonstrated that 4-azido-1,2,3-
triazoles are highly attractive building blocks for subsequent
preparation of various 1,2,3-triazole-derived compounds.
Makarov for providing mass spectrometry equipment for this
work.
REFERENCES
■
(1) (a) Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 297.
̈
(b) Brase, S.; Banert, K. Organic Azides: Syntheses and Applications;
̈
John Wiley & Sons: Chichester, UK, 2010. (c) Brase, S.; Gil, C.;
Knepper, K.; Zimmermann, V. Angew. Chem., Int. Ed. 2005, 44, 5188.
̈
(2) Haring, A. P.; Kirsch, S. F. Molecules 2015, 20, 20042.
(3) Nenajdenko, V. G.; Shastin, A. V.; Gorbachev, V. M.; Shorunov,
S. V.; Muzalevskiy, V. M.; Lukianova, A. I.; Dorovatovskii, P. V.;
Khrustalev, V. N. ACS Catal. 2017, 7, 205.
(4) (a) South, S.; Westmeyer, D.; Dukesherer, D. R.; Jakuboski, L.
Tetrahedron Lett. 1996, 37, 1351. (b) Baldoli, C.; Lattuada, L.;
Licandro, E.; Maiorana, S.; Papagni, A. J. Heterocycl. Chem. 1989, 26,
241.
(5) (a) Attanasi, O. A.; De Crescentini, L.; Favi, G.; Filippone, P.;
Mantellini, F.; Perrulli, F. R.; Santeusanio, S. Eur. J. Org. Chem. 2009,
2009, 3109. (b) Attanasi, O. A.; Caglioti, L. Org. Prep. Proced. Int.
1986, 18, 299. (c) Attanasi, O. A.; Filippone, P.; Serra-Zanetti, F. In
Trends in Heterocyclic Chemistry; Menon, J., Ed.; Research Trends:
Trivandrum, 1993; Vol. 3, p 461. (d) Attanasi, O. A.; Filippone, P.;
Serra-Zanetti, F. In Progress in Heterocyclic Chemistry; Suschitzky, H.,
Scriven, E. F. V., Eds.; Pergamon: Oxford, 1995; Vol. 7, p 1.
(e) Attanasi, O. A.; Filippone, P. In Topics in Heterocyclic Chemistry;
Attanasi, O. A., Spinelli, D., Eds.; Research Signpost: Trivandrum,
1996; Vol. 1, p 157. (f) Attanasi, O. A.; Filippone, P. Synlett 1997,
1997, 1128. (g) Attanasi, O. A.; De Crescentini, L.; Filippone, P.;
Mantellini, F.; Santeusanio, S. ARKIVOC 2002, 11, 274.
(6) Shastin, A. V.; Sergeev, P. G.; Lukianova, A. I.; Muzalevskiy, V.
M.; Khrustalev, V. N.; Dorovatovskii, P. V.; Nenajdenko, V. G. Eur. J.
Org. Chem. 2018, 2018, 4996.
(7) (a) Carrie, R.; Danion, D.; Ackermann, E.; Saalfrank, R. W.
Angew. Chem., Int. Ed. Engl. 1982, 21, 287. (b) Carrie, R.; Danion, D.;
Ackermann, E.; Saalfrank, R. W. Angew. Chem., Int. Ed. Engl. 1982, 21,
660. (c) Hall, H. K.; Ramezanian, M.; Saeva, F. D. Tetrahedron Lett.
1988, 29, 1235. (d) Saalfrank, R. W.; Wirth, U. Chem. Ber. 1989, 122,
519.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03227.
Experimental details, optimization of reaction condi-
tions, characterization of products, X-ray data, copies of
NMR spectra of all products, and calculations details
(PDF)
Accession Codes
CCDC 1871724−1871726 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(8) Saalfrank, R. W.; Maid, H. Chem. Commun. 2005, 5953.
(9) (a) Banert, K. Synthesis 2016, 48, 2361. (b) Banert, K. in Science
of Synthesis; de Meijere, A., Ed.; Thieme: Stuttgart, 2006; Vol. 24, p
747. (c) Banert, K. In Houben-Weyl, 4th ed; Kropf, H., Shaumann, E.,
Eds.; Thieme: Stuttgart, 1993; Vol. E15, p 2348.
(10) (a) Valeur, B. Molecular Fluorescence. Principles and Applications;
Wiley-VCH, 2002. (b) Wongkongkatep, J.; Ojida, A.; Hamachi, I.
Top. Curr. Chem. (Z) 2017, 375, 30. (c) Chen, X.; Wang, F.; Hyun, J.
Y.; Wei, T.; Qiang, J.; Ren, X.; Shin, I.; Yoon, J. Chem. Soc. Rev. 2016,
45, 2976. (d) Jung, H.; Lee, H.; Kang, S. Appl. Chem. Eng. 2016, 27,
455. (e) Sarder, P.; Maji, D.; Achilefu, S. Bioconjugate Chem. 2015, 26,
963. (f) Zhu, H.; Fan, J.; Wang, B.; Peng, X. Chem. Soc. Rev. 2015, 44,
4337. (g) Sun, X.; Wang, Y.; Lei, Y. Chem. Soc. Rev. 2015, 44, 8019.
(h) Yang, Z.; Cao, J.; He, Y.; Yang, J. H.; Kim, T.; Peng, X.; Kim, J. S.
Chem. Soc. Rev. 2014, 43, 4563. (i) Mukherjee, S.; Thilagar, P. Dyes
Pigm. 2014, 110, 2. (j) Schaferling, M. Angew. Chem., Int. Ed. 2012,
51, 3532. (k) Yan, W.; Wang, Q.; Lin, Q.; Li, M.; Petersen, J. L.; Shi,
X. Chem. - Eur. J. 2011, 17, 5011. (l) Zhang, Y.; Ye, X.; Petersen, J. L.;
Li, M.; Shi, X. J. Org. Chem. 2015, 80, 3664. (m) Zhang, Y. C.; Jin, R.;
Li, L. Y.; Chen, Z.; Fu, L. M. Molecules 2017, 22, 1380.
(11) (a) Dehaen, W.; Bakulev, V. A.; Beryozkina, T. Top. Heterocycl.
Chem. 2014, 40, 1. (b) Zlotin, S. G.; Churakov, A. M.; Dalinger, I. L.;
Luk’yanov, O. A.; Makhova, N. N.; Sukhorukov, A. Y.; Tartakovsky,
V. A. Mendeleev Commun. 2017, 27, 535.
(12) (a) Agard, N. J.; Prescher, J. A.; Bertozzi, C. R. J. Am. Chem.
Soc. 2004, 126, 15046. (b) Dommerholt, J.; Rutjes, F. P. J. T.; van
Delft, F. L. Top. Curr. Chem. 2016, 374, 16. (c) Chupakhin, E. G.;
Krasavin, M. Yu. Chem. Heterocycl. Compd. 2018, 54, 483.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: nenajdenko@org.chem.msu.ru.
ORCID
Victor N. Khrustalev: 0000-0001-8806-2975
Valentine G. Nenajdenko: 0000-0001-9162-5169
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This study was supported Russian Foundation for Basic
Research (Grant Nos. 18-03-00791 and 16-29-10669) and, in
part, by the RUDN University Program “5-100”. Synchrotron
radiation-based single-crystal X-ray diffraction measurements
were performed at the unique scientific facility Kurchatov
Synchrotron Radiation Source supported by the Ministry of
Education and Science of the Russian Federation (Project
Code RFMEFI61917X0007). The authors acknowledge V.
Gorbachev for some experiments, Thermo Fisher Scientific
Inc., MS Analytica (Moscow, Russia), and personally Prof. A.
D
DOI: 10.1021/acs.orglett.8b03227
Org. Lett. XXXX, XXX, XXX−XXX