Thermolysis of 2-azido-3-(R-anilino)-1,4-naphthoquinones. Nitrene insertion versus hydrogen abstraction

Article abstract of DOI:10.1016/j.tetlet.2020.151731

2-chloro-3-(R-anilino)-1,4-naphthoquinones react with sodium azide upon refluxing in DMF. The thermochemistry of 2-azido-3-(R-anilino)-1,4-naphthoquinone is strongly modified by the substituent on aniline. Having an strong electron-donor like O-R results

Full text of DOI:10.1016/j.tetlet.2020.151731

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Thermolysis of 2-azido-3-(R-anilino)-1,4-naphthoquinones. Nitrene insertion
versus hydrogen abstraction
Silvia E. Loredo-Carrillo, Elisa Leyva, Matthew S. Platz, Agobardo Cárdenas-
Chaparro, Antonio Martínez-Richa
PII:
S0040-4039(20)30154-4
DOI:
https://doi.org/10.1016/j.tetlet.2020.151731
TETL 151731
Reference:
Tetrahedron Letters
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3 February 2020
10 February 2020
Please cite this article as: Loredo-Carrillo, S.E., Leyva, E., Platz, M.S., Cárdenas-Chaparro, A., Martínez-Richa,
A., Thermolysis of 2-azido-3-(R-anilino)-1,4-naphthoquinones. Nitrene insertion versus hydrogen abstraction,
Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.151731
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Thermolysis of 2-azido-3-(R-anilino)-1,4-naphthoquinones.
Nitrene insertion versus hydrogen abstraction.
Silvia E. Loredo-Carrilloa, Elisa Leyva a,* Matthew S. Platzb , Agobardo
Cárdenas-Chaparroc, Antonio Martínez-Richad
aFacultad de Ciencias Químicas, Universidad Autónoma de San Luis Potosí,
Manuel Nava No. 6, Zona Universitaria, San Luis Potosí, S.L.P. México, 78290
bDepartment of Chemistry, University of Hawaii, Hilo
200 West Kawili St. Hilo, HI 96720
cUniversidad Pedagógica y Tecnológica de Colombia
Avenida Central del Norte No. 39-115, Tunja, Boyacá, Colombia 15003
dDepartamento de Química, Universidad de Guanajuato,
Noria Alta s/n, Guanajuato, GTO, México, 36000.
Keywords: 2-azido-3-(R-anilino)-1,4-naphthoquinones, Nitrene, thermolysis,
insertion, hydrogen abstraction.
* Corresponding autor E-mail address: elisa@uaslp.mx

Abstract
2-chloro-3-(R-anilino)-1,4-naphthoquinones react with sodium azide upon refluxing
in DMF. The thermochemistry of 2-azido-3-(R-anilino)-1,4-naphthoquinone is
strongly modified by the substituent on aniline. Having an strong electron-donor like
O-R results in the generation of a phenazine while having an electron-withdrawing
substituent results in the formation of 2-amino-3-(R-anilino)-1,4-naphthoquinone.
The products obtained are explained in terms of singlet and/or triplet nitrene
chemistry.
Naphthoquinone derivatives in general, and those possessing an amino group in
the two position in particular, have been the subject of intensive research. Many of
these compounds find use in a variety of medicinal and biological applications. They
can act as antibacterial, antimalarial and antitumor agents, as well as larvicides,
herbicides and fungicides [1].
In the course of our research work on the synthesis and characterization of novel
amino naphthoquinone derivatives [1], we synthesized several 2-chloro-3-(R-
anilino)-1, 4-naphthoquinones 1a-h and investigated their reactions with sodium
azide. First, all compounds 1a-h were prepared following procedures previously
reported [1, 2]. Most of these derivatives can be easily obtained through a
nucleophilic substitution reacting an aniline with napththoquinone using CeCl3 as
catalyst (Scheme 1, Table 1). Addition of catalyst induces the formation of complex
between C=O and Ce, thus a selective nucleophilic substitution takes place with the
replacement of a chlorine atom by a substituted aniline [1, 2]. This reaction gives
good yields of R-anilino derivatives 1a-1f where the aniline contains substituents
such as H, O-R, F or Cl. However, nitroanilino derivatives where the aniline contains
one or two strong electron attracting substituents are prepared by direct nitration of
2-chloro-3-anilino-1,4-naphthoquinone [1c]. All the aniline compounds were
1
characterized by melting point, UV-Vis, IR, H NMR and MS. The complete
preparation and characterization data is presented in the supporting information.

Scheme 1. Preparation of 2-chloro-3-(R-anilino)-1,4-naphthoquinone derivatives
Table 1. Yields of 2-chloro-3-(R-anilino)-1,4-naphthoquinone generated in the
reaction of 1,4-naphthoquinone with substituted anilines
Compound 1 Substituent
(% Yield)
1a
1b
1c
1d
1e
1f
H
91
88
75
90
95
72
65
76
4-MeO
2-MeO
4-EtO
4-F
4-Cl
4-NO2
2, 4-NO2
1g
1h
The reaction of 2-chloro-3-(R-anilino)-1,4-naphthoquinone derivatives with
sodium azide to give heterocyclic phenazines and 2-amino derivatives was first
reported in the literature in 1963 [3a]. In recent years, this procedure has been
applied to the preparation of some naphthoquinone derivatives to investigate several
biological properties [3b, 3c]. However, no mechanistic discussion has been
presented to explain the products obtained in this particular reaction.
In this study, the reaction of each compound 1a-h with sodium azide in
refluxing DMF was performed. Interestingly, analysis of the reaction mixtures
indicated that no azide groups were present, instead amino 3a-h and heterocyclic
4b-d naphthoquinone derivatives were produced (Scheme 2, Table 2). Since this

methodology is not new, some of the compounds have been previously prepared [1,
3]. All the compounds obtained were purified and characterized by melting point,
1
UV-Vis, IR, H NMR, 13C NMR and MS. The complete preparation and
characterization data is presented in the supporting information.
Scheme 2. Products generated in the reaction of 2-chloro-3-(R-anilino)-1,4-
naphthoquinones with NaN3
Table 2. Yields of products generated in the reaction 2-chloro-3-(R-anilino)-
1,4-naphthoquinones with NaN3
Compound 1 Substituent Compound 3 Compound 4
(% Yield)
(% Yield)
1a
1b
1c
1d
1e
1f
H
81
19
20
21
70
75
75
76
-
70
75
70
-
-
-
-
4-MeO
2-MeO
4-EtO
4-F
4-Cl
4-NO2
2, 4-NO2
1g
1h
To explain the formation of the compounds so produced, putative vinyl azides
2a-h are proposed (Scheme 2). In general, vinyl azides are very reactive
intermediates and generate nitrogen heterocycles such as azirines [4a]. However,
recent experimental and theoretical studies by Gudmundsdottir and collaborators
[4b] have indicated that 2-azido naphthoquinone does not react like a classical vinyl
azide, instead it reacts in a manner similar to the structurally related aryl azides [5].

In the latter compounds, an intermediate aryl nitrene is generated upon photolysis or
thermolysis [5]. Based on Wasserman’s observations [6], the physical and chemical
properties of aryl nitrenes have been explained in terms of singlet and triplet nitrene
intermediates (Scheme 3) [7]. According to theory, the lowest singlet state PS1 has
an open-shell electronic configuration with one unpaired electron on nitrogen in
conjugation with the -system of the phenyl ring, resulting in a strong stabilization.
However, due to a reduced Coulomb electron-electron repulsion, a triplet nitrene PT1
with an open-shell configuration should be even lower in energy [8].
Scheme 3. Intermediates generated in the photochemistry of aryl azides
More recently, Chapyshev et al. [9] have presented some basic aspects about the
structure and reactivity of aryl nitrenes. They investigated the photochemistry of
several azido pyridines and explained substituent effects on the intermediate aryl
nitrene structures. Several ESR studies on pyridinyl azides provided strong evidence
for the existence of two triplet nitrenes with different hybridization demonstrating
the existence of closed- and open-shell structures. Furthermore, Chapyshev et al. also
explained the effect of neighboring nitrogen atoms with small size and poor spin
holding properties, resulting in an elongation of the nitrene C-N bond thus leading to
a higher reactivity of an aryl nitrene.
Several studies on the structure of 2-anilino-1,4-naphthoquinones have indicated
that some of these compounds undergo a tautomeric equilibrium with two dimorphic
structures [10]. This equilibrium must be particularly strong in an aniline containing
electron donating groups like O-R where the anilino-nitrogen interacts strongly with
the naphthoquinone ring (Scheme 4). Thermolysis of a vinyl azide generates a
singlet nitrene [5] but according to Chapyshev et al. [9], this nitrene is strongly

localized and easily undergoes C-H insertion reaction to give mostly an heterocyclic
compound 4b.
Scheme 4. Mechanism for the generation of phenazine 4b
Very different reactivity is observed in the case of a naphthoquinone azide
containing aniline or an aniline bearing electron-withdrawing groups like F, Cl or
NO2. In this case, 2-amino-3-(R-anilino)-1,4-naphthoquinone derivatives are
predominantly generated. Thus, the mechanism proposed for the photochemical
reaction of parent naphthoquinone azide [4b] is the same mechanism (Scheme 5)
operating for the thermochemical reaction of 2a and 2e-2h. Heating, 2-chloro-3-(4-
nitroaniline)-1,4-naphthoquinone 1g with sodium azide generates azide 2g then a
singlet excited state NQS2. This intermediate could undergo intersystem crossing to
its triplet excited state NQT2 which would rapidly relax to lower energy open shell
nitrene NQT1.
The calculated spin density for triplet phenyl and triplet
naphthoquinone indicates that this latter nitrene has a strong 1,3-biradical character
[4b].

Scheme 5. Mechanism for the generation of 2-amino-3-(4-nitrophenyl)-1,4-
naphthoquinone
In
conclusion,
the
thermochemistry
of
2-azido-3-(R-anilino)-1,4-
naphthoquinone is strongly modified by the aniline substituent. Having a strong
electron-donor like O-R results in the generation of a highly reactive singlet nitrene
which undergoes insertion to give a tetracyclic compound. In contrast, having an
electron-withdrawing substituent favors the generation of an open-shell nitrene with
a strong biradical character which undergoes hydrogen abstraction to give an amino
naphthoquinone.
Acknowledgement
This work was supported by CONACyT (Grant 155678).
Appendix A. Supplementary data
Supplementary data with experimental procedure and characterization data is
given in the supporting information.

References
[1] (a) S. Vega-Rodríguez, R. Jiménez-Cataño, E. Leyva, S.E. Loredo-Carrillo. J.
Fluorine Chem. 145 (2013) 58; (b) E. Leyva, S.J. Schmidke Sobeck, S.E.
Loredo-Carrillo, D.A. Magaldi-Lara. J. Mol. Struct. 1068 (2014), 1; (c) E.
Leyva, K.M. Baines, C.G. Espinosa-González, L.I. López, D.A. Magaldi-Lara,
S. Leyva, Tetrahedron Lett. 56 (2015) 5248; (e) E. Leyva, A. Cárdenas-
Chaparro, S.E. Loredo-Carrillo, L.I. López, F. Méndez-Sánchez, A. Martínez-
Richa, Mol. Divers. 22 (2018) 281; (f) A. Cárdenas-Chaparro, Doctorate Thesis,
University of San Luis Potosí, 2018.
[2] (a) A. Satheshkumar, K.P. Elango, Spectrochim. Acta A. 98 (2012) 378; (b) T.
Win, S. Yerushalmi, S. Bittner, Synthesis 10 (2005) 1631.
[3] (a) J.A. VanAllan, J.A. Reynolds, R.E. Adel, J. Org. Chem. 28 (1963) 524; (b)
Y.-S. Kim, S.-Y. Park, H.-J. Lee, M.-E. Suh, D. Schollmeyer, Ch.-O. Lee,
Bioorg. Med. Chem. 11 (2003) 1709; (c) H.-J. Lee, Y.-S. Kim, S.-Y. Park, M.-E.
Suh, H.-J. Kim, E.-K. Seo, Ch.-O. Lee, Biorg. Med. Chem. 12 (2004) 1623.
[4] (a) P.N.D. Singh, C.L. Carter, A.D. Gudmundsdottir, Tetrahedron Lett. 44
(2003) 6763; (b) S. Rajam, A.V. Jadhav, Q. Li, S.K. Sarkar, P.N.D. Singh, A.
Rohr, T.C.S. Pace, R. Li, J.A. Krause, C. Bohne, B.S. Ault, A.D.
Gudmundsdottir, J. Org. Chem. 79 (2014) 9325.
[5] For reviews on aryl azide and aryl nitrene chemistry: (a) E.F.V. Scriven,
Azides and Nitrenes: Reactivity and Utility. Academic Press, New York, 1984;
(b) M.S. Platz, E. Leyva, K. Haider, Selected Topics in the Matrix
Photochemistry of Nitrenes, Carbenes and Excited Triplet States, in: A. Padwa
(Ed.), Org. Photochem. 1991, 11, 367; (c) M.S. Platz, Nitrenes, in: R.A. Moss,
M.S. Platz, M.S. Jones, Jr. (Eds.), Reactive Intermediate Chemistry, John
Wiley & Sons Inc., New York, 2004; (d) D. de Loera, E. Leyva, R. Jiménez-
Cataño, Bol. Soc. Quim. Méx. 3 (2009) 93; (e) E. Leyva, D. de Loera, S. Leyva,
R. Jiménez-Cataño, Fluorinated aryl nitrene precursors. In Nitrene and

Nitrenium Ions, D.E. Falvey, A.D. Gudmundsdottir (Eds.), John Wiley & Sons
Inc., New York, 2013.
[6] E. Wasserman, Prog. Phys. Org. Chem. 8 (1971) 319.
[7] (a) W.T. Borden, N.P. Gritsan, C.M. Hadad, W.L. Karney, C.R. Kemnitz, M.S.
Platz, Acc. Chem. Res. 33 (2000) 765; (b) S.V. Chapyshev, Mendeleev
Commun. 12 (2002) 168.
[8] N. P. Gritsan, E. A. Pritchina, Mendeleev Commun. 2001, 11 (2001) 94.
[9] (a) S.V. Chapyshev, Mendeleev Commun. 17 (2007) 287; (b) S.V. Chapyshev,
Mendeleev Commun. 13 (2003) 53; (c) S.V. Chapyshev, Mendeleev Commun.
12 (2002) 227; (d) S.V. Chapyshev, R. Walton, P.M. Lahti, Mendeleev
Commun. 10 (2002) 187; (e) S.V. Chapyshev, M.S. Platz, Mendeleev Commun.
11 (2001) 56; (f) S.V. Chapyshev, Mendeleev Commun. 11 (2001) 92; (g)
S.V. Chapyshev, A. Kuhn, M. Wong, C. Wentrup, J. Am. Chem Soc. 122
(2000) 1572; (h) S.V. Chapyshev, R. Walton, P.M. Lahti, Mendeleev Commun.
10 (2000) 7; (i) S.V. Chapyshev, R. Walton, P.M. Lahti, Mendeleev Commun.
10 (2000) 187.
[10] Y. Matsunaga, N. Miyajima, A. Togashi, Bull. Chem. Soc. Jpn. 50 (1977) 2234.
Highlights
_ 2-chloro-3-(R-anilino)-1,4-naphthoquinones react with sodium azide in refluxing
DMF
_ 2-azido-3-(R-anilino)-1,4-naphthoquinone thermochemistry changes with
substituent
_ Having an strong electron-donor like O-R results in the generation of a phenazine.
_ An electron-withdrawing substituent results in the formation of a 2-amino
derivative
_ Products obtained are explained in terms of singlet or triplet nitrene chemistry.