Heterocyclization of enediynes promoted by sodium azide: A case of ambiguity of x-ray data and structure revision

Article abstract of DOI:10.1021/ol500125j

It has been shown that contrary to the literature data the tandem cyclization of (Z)-1-aryl-3-hexen-1,5-diynes promoted by sodium azide results in the formation of the corresponding [1,2,3]triazolo[1,5-a]pyridines, not 1H-benzotriazole derivatives. Apparently, incorrect structure elucidation made by previous investigators originates from misinterpretation of X-ray data. A number of new transformations of this type as well as X-ray and NMR experiments are discussed.

Full text of DOI:10.1021/ol500125j

Letter
pubs.acs.org/OrgLett
Heterocyclization of Enediynes Promoted by Sodium Azide: A Case
of Ambiguity of X‑ray Data and Structure Revision
Anna V. Gulevskaya,* Alexander S. Tyaglivy, Alexander F. Pozharskii, Julia I. Nelina-Nemtseva,
and Dmitry V. Steglenko
Department of Organic Chemistry, Southern Federal University, Zorge 7, Rostov-on-Don 344090, Russian Federation
S
* Supporting Information
ABSTRACT: It has been shown that contrary to the literature data the
tandem cyclization of (Z)-1-aryl-3-hexen-1,5-diynes promoted by sodium
azide results in the formation of the corresponding [1,2,3]triazolo[1,5-
a]pyridines, not 1H-benzotriazole derivatives. Apparently, incorrect
structure elucidation made by previous investigators originates from
misinterpretation of X-ray data. A number of new transformations of this
type as well as X-ray and NMR experiments are discussed.
Scheme 2. Original Mechanism Proposed for the Reaction of
(Z)-1-Aryl-3-hexen-1,5-diynes with NaN3
nediynes and structurally related compounds have
Eattracted much attention since the discovery of naturally
occurring antibiotics having a (Z)-hexa-3-en-1,5-diyne fragment
in their structures.1 It is supposed that the antitumor and
antibacterial activity of enediyne antibiotics is based on the
Bergman cyclization2 which generates benzene-1,4-diradicals,
capable of cleaving DNA and rupturing the protein structure.
The challenging chemical structures of enediyne antibiotics and
fascinating mode of their biochemical action have attracted
considerable attention.1f Most of the work on enediyne
chemistry is focused on the synthesis of designed enediynes,
their thermal reactivity modulation, and anticancer activity
evaluation. Besides a thermal1g and photochemical1h Bergman
reaction, cyclizations of enediynes can be induced by various
reagents: radicals,3 nucleophiles,4 electrophiles,5 transition
metal complexes,6 a frustrated Lewis pair,7 and so on. In
addition, substituents at the alkyne termini can also be involved
in the cyclization process leading to polycyclic products.8
In this strategy, some time ago Taiwanese chemists claimed
that treatment of (Z)-1-aryl-3-hexen-1,5-diynes 1a−h with
sodium azide in DMF or DMSO resulted in the formation of a
mixture of 1-aryl-4-butyl- and 1-aryl-7-butyl-1H-benzotriazoles
2 and 3 (Scheme 1).9 The proposed reaction mechanism
(Scheme 2), with the exception of the primary [3 + 2]
cycloaddition step, appeared rather unlikely. It was improbable
that the nucleophilic center during cyclization 4→5 could be
located on the triazole carbon atom rather than on the much
more electronegative N-1 or N-3 atom.
Scheme 1. Reaction of (Z)-1-Aryl-3-hexen-1,5-diynes with
Sodium Azide Reported by Taiwanese Chemists
Justifying these doubts, somewhat later10 we found that the
reaction of 6,7-dialkynyl-1,3-dimethyllumazines 7 and 2,3-
dialkynylquinoxalines 10 with NaN3 actually produced not
the corresponding benzotriazole derivatives but isomeric
bridge-head [1,2,3]triazolo[1,5-a]pyridines 8, 9, and 11
(Scheme 3). The proposed reaction pathway is shown in
Scheme 4. It involves formation of the triazole anion 12 and
subsequent attack of its nitrogen atom on the neighboring triple
Received: January 14, 2014
Published: March 5, 2014
© 2014 American Chemical Society
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Letter
Scheme 3. Reactions of 6,7-Dialkynyl-1,3-dimethyllumazines
and 2,3-Dialkynylquinoxalines with NaN3
Scheme 5. New Examples of Heterocyclization of ortho-
Dialkynyl (Het)arenes into Triazolopyridines
Scheme 4. Mechanism Proposed for Heterocyclization of
ortho-Dialkynyl (Het)arenes into Triazolopyridines
Scheme 6. Cyclization of (Z)-3-Hexen-1,5-diynes into
[1,2,3]Triazolo[1,5-a]pyridines
bond yielding, after proton quenching of intermediate
carbanion 13, a [1,2,3]triazolo[1,5-a]pyridine derivative.
We now report on some new examples of this reaction and
speculate on the reasons causing the mistake of the previous
investigators. The transformations performed by us of 1,2-
diphenylethynylbenzene 14 into 1,5-diphenyl[1,2,3]triazolo-
[5,1-a]isoquinoline 15, 1-methyl-4,5-di(phenylethynyl)-
imidazole 16 into compound 17, and 1,4-bis(3-(phenyl-
ethynyl)quinoxalin-2-yl)buta-1,3-diyne 19 into products of
mono- and dicyclization 20, 21 are presented in Scheme 5.11
Structures of compounds 15, 17, 20, and 21 were proven by
1
mass, IR, and H and 13C spectra (Supporting Information
(SI), Figures S5−S13). Besides, for 15 (SI, Figure S24) and 20
(SI, Figure S22) the single crystal X-ray measurements were
also performed. Since cyclization of imidazole 16 is ambiguous
and allows the formation of isomeric product 18, we applied
the COSY and NOESY 1H−1H methods for structure
elucidation (SI, Figures S9, S10). The correctness of structure
Probably, the 1,3-dipolar cycloaddition of an azide ion to the
CC bond is the rate-determining step of the process. This
follows, for example, from the higher reactivity of the 7-alkynyl
group in 7 as compared with the 6-alkynyl group. By analogy,
more electron-deficient 2,3-dialkynylquinoxalines 10 are
cyclized with NaN3 much easier than 1,2-dialkynylbenzene 14
and 1-methyl-4,5-di(phenylethynyl)imidazole 16.
It can be assumed that the difference in reactivity of acyclic
enediynes 1 and ortho-dialkynyl (het)arenes 7, 10, 14, 16, and
19 toward sodium azide originates from the difference in their
1
17 was confirmed by the presence in its NOESY H−1H
spectrum of the correlation peaks which correspond to the
through-space spin−spin coupling of the N-Me group protons
with the ortho protons of the 9-phenyl ring, thus demonstrating
their close proximity to be impossible in structure 18 (see also
ref 12).
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Letter
small excess of NaN3 in DMF (80 °C, 48 h) we were unable to
reproduce the original9 yields of 2h (54%) and 3h (20%). In
our hands, a single product was isolated only in 32% yield
(Scheme 6). The X-ray experiment demonstrated that it had
[1,2,3]triazolo[1,5-a]pyridine structure 23c instead of 2h
(Figure 1). Thus, we established that the cyclization pathway
of enediynes upon their treatment with sodium azide does not
depend on their nature and is described by Scheme 4.
Next, we tried to understand the cause of the error. There is
the possibility that this may be a rare case of misleading X-ray
diffraction studies without deeper investigation into the fine
details. Yet, as it is seen from the above-mentioned findings, we
have confirmed our results by the X-ray data for most of the
compounds obtained. Moreover, we consciously misinformed
the X-ray operator (when sample 23c was delivered for
analysis) that the compound likely had the structure 2h, and
the very experienced operator confirmed it! However, when we
disclosed our trick and the diffraction pattern was carefully
reconsidered, it turned out that the R factor for the alternative
bridge-head structure 23c was actually better (4.90 against
6.03) and thus the latter structure became obviously preferable.
Table S1 (SI) summarizes the refinement indices and residual
electron density for both the correct and incorrect structures
for all X-ray experiments performed to date and clearly
demonstrates the absolute superiority of the [1,2,3]triazolo[1,5-
a]pyridine structures. Another feature supporting this con-
clusion is the manifestation of key thermal ellipsoids. While for
all correct structures the sizes of N and C atom ellipsoids in the
triazole ring are quite close to each other, for the wrong
structures the ellipsoids of erroneously assigned carbon and
nitrogen atoms (red and blue circled, respectively, in Figures 1
and S23−S25 (SI)) fall out of the overall picture by their
abnormally small or big size.
Figure 1. ORTEP plots for X-ray crystal structure of 23c (a) and
refined for structure 2h (b). Incorrectly refined C and N atoms are
circled (red and blue, respectively).
nature. However, we now proved that the reaction of enediynes
22a,b with NaN3 gave [1,2,3]triazolo[1,5-a]pyridines 23a,b
1
(Scheme 6). Their structures were confirmed by mass and H,
13C spectra (SI, Figures S14−S17). Structure 23b was also
verified by X-ray analysis (SI, Figure S25).
As the main evidence for the formation of benzotriazoles 2
and 3, the researchers9 presented only an X-ray experiment for
compound 2h. Surprisingly, this structure together with the
corresponding refinement details has not been so far deposited
in the Cambridge Crystallographic Data Centre (CCDC).
Moreover, no synthetic protocols and physical constants
including melting points were given for compounds 2h and
3h, neither in the Letter nor in the SI. Under these
circumstances we were forced to reinvestigate the synthesis
and some properties of 2h. On treatment of enediyne 1h with a
To gain independent evidence for the correctness of
1
structure 23c we have conducted the NMR HMQC H−13C
1
and HMBC H−13C experiments (for details, see SI, Figures
Figure 2. Energy profile for cyclizations of intermediate 4a in the gas phase as derived from M05-2X/6-31+G** calculations.
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Letter
75, 825. (e) Kar, M.; Basak, A. Chem. Rev. 2007, 107, 2861. (f) Joshi,
M. C.; Rawat, D. S. Chem. Biodiversity 2012, 9, 459. (g) Breiner, B.;
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S20 and S21). The key correlation between H-2′(6′) protons of
the R2 substituent (δH 8.09) and C-1 nucleus (δC 136.9), which
makes it possible to distinguish structures 23c and 2h, has been
found in the HMBC spectrum.
Additionally, a large preference for the formation of the
[1,2,3]triazolo[1,5-a]pyridine system over the benzotriazole
one in the reactions discussed was confirmed by quantum-
chemical calculations. Thus, M05-2X/6-31+G** calculations of
the potential energy surface for the cyclization of the reference
anion 4a (Figure 2 and Table S2 (SI)) showed that its
conversion into [1,2,3]triazolo[1,5-a]pyridine structure 23d−
occurs through transition state TS1 with a moderate activation
energy (16.6 kcal mol−1) and is accompanied by minimal
energy output (−5.2 kcal mol−1). In contrast, the trans-
formation of 4a into benzotriazole structure 5a− with
participation of the negatively charged ring carbon atom as a
nucleophile, as well as the following processes of phenyl group
migration, demands much higher energies (cf. transition states
TS2−TS5). Theoretically, for N-centered nucleophiles such as
anion 4a, along with 6-endo-dig cyclization, 5-exo-dig cyclization
is also possible.13 However, our calculations have shown that
the 6-endo-dig closure of 4a is preferred both kinetically and
thermodynamically (SI, Figures S33−S35, Table S3).
We believe that two main conclusions can be deduced from
this work. First, it was found that a relatively simple tandem
reaction of enediynes with sodium azide represents a new
approach to a wide range of otherwise difficult to obtain
[1,2,3]triazolo[1,5-a]pyridines.14 Second, it was shown that
even the use of an arsenal of modern physical methods,
including X-ray diffraction analysis, does not relieve us of the
need to delve into the finest details of data.
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ASSOCIATED CONTENT
* Supporting Information
■
S
(7) Liedtke, R.; Frohlich, R.; Kehr, G.; Erker, G. Organometallics
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Experimental procedures, spectral data for all new compounds,
and X-ray diffraction as well as quantum-chemical studies. This
material is available free of charge via the Internet at http://
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AUTHOR INFORMATION
Corresponding Author
■
(10) Gulevskaya, A. V.; Dang, V. S.; Tyaglivy, A. S.; Pozharskii, A. F.;
Kazheva, O. N.; Chekhlov, A. N.; Dyachenko, O. A. Tetrahedron 2010,
66, 146.
*E-mail: agulevskaya@sfedu.ru.
Notes
(11) Previously, we have reported10 that reactions of 16 and 14 with
NaN3 in DMF did not proceed under conditions described for acyclic
enediynes (80 °C, 24 h).9 Later we have found that higher
temperatures (100−120 °C) and much more prolonged heating (5−
10 days) provided desired [1,2,3]triazolo[1,5-a]pyridine derivatives 15
and 17.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Russian Foundation for Basic
Research for financial support (Project No. 11-03-00079) and
Professor V. A. Ozeryanskii (Southern Federal University) for
valuable discussions.
(12) To obtain an independent argument for the higher reactivity of
the 5-alkynyl group in 16 towards N3− we have performed calculations
for the NBO charges and frontier orbital parameters responsible for
the cycloaddition reaction (SI, Figures S31, S32).
(13) (a) Vasilevsky, S. F.; Mikhailovskaya, T. F.; Mamatyuk, V. I.;
Salnikov, G. E.; Bogdanchikov, G. A.; Manoharan, M.; Alabugin, I. V. J.
Org. Chem. 2009, 74, 8106. (b) Vasilevsky, S. F.; Gold, B.;
Mikhailovskaya, T. F.; Alabugin, I. V. J. Phys. Org. Chem. 2012, 25,
998. (c) Alabugin, I. V.; Gilmore, K. Chem. Rev. 2011, 111, 6513.
(14) (a) Sliskovic, D.R. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Elsevier, 1996; Vol.
8, Chapter 8.13, p 383. (b) Bischoff, L. In Comprehensive Heterocyclic
Chemistry III; Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V.,
Taylor, R. J. K., Eds.; Elsevier, 2008; Vol. 11, Chapter 11.13, pp 609−
611.
DEDICATION
■
This paper is dedicated to the memory of Dr. Zoya A. Starikova
(expert in the X-ray analysis, N. D. Zelinsky Institute of
Organic Chemistry Russian Academy of Sciences) who recently
passed away.
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