Generation of benzofuroxans by photolysis of crystalline o-nitrophenylazides. A green chemistry reaction

Article abstract of DOI:10.1016/j.tetlet.2012.03.013

Several benzofuroxans were obtained by photolysis of crystalline o-nitrophenylazides at ambient temperature. In this particular case, the solid matrix favored the elimination of nitrogen and exclusive formation of heterocyclic benzofuroxan. However, this reaction gives quantitative yields only with crystalline o-nitrophenylazides with a high melting point (above 50 °C).

Full text of DOI:10.1016/j.tetlet.2012.03.013

Tetrahedron Letters 53 (2012) 2447–2449
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Generation of benzofuroxans by photolysis of crystalline o-nitrophenylazides.
A green chemistry reaction
⇑
Elisa Leyva , Regina M. González-Balderas, Denisse A. de Loera, Rogelio Jiménez-Cataño
Facultad de Ciencias Químicas, Universidad Autónoma de San Luis Potosí, Av. Nava No. 6, 78210 San Luis Potosí, S.L.P., Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 July 2010
Revised 29 February 2012
Accepted 5 March 2012
Available online 10 March 2012
Several benzofuroxans were obtained by photolysis of crystalline o-nitrophenylazides at ambient tem-
perature. In this particular case, the solid matrix favored the elimination of nitrogen and exclusive forma-
tion of heterocyclic benzofuroxan. However, this reaction gives quantitative yields only with crystalline
o-nitrophenylazides with a high melting point (above 50 °C).
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Benzofuroxans
o-Nitrophenylazide
Photochemistry in crystals
Green chemistry
Furoxans and benzofuroxans comprise a well-known class of
heterocyclic compounds with important biological applications.
To induce thermal cyclization, o-nitrophenylazides are usually
refluxed in acetic acid or toluene for several hours. Dyall pro-
1
6a
They have gained interest as cardiovascular agents (like nitroglic-
erol) due to their ability to generate nitric oxide which plays an
important role as a biological messenger.1 The property of ben-
zofuroxans to be involved in the synthesis of DNA and peptides
2
posed that ortho-substituents (NO ) participate in a pericyclic pro-
7
cess with little nitrene character and computational studies
8
support these earlier assertions. However, in a recent ultrafast
study on the photochemistry of azidonitrobenzene the presence
2
9
has stimulated a search to develop anticancer compounds. The
of a singlet nitrene intermediate was demonstrated. Furthermore,
wide range of biological activity has been claimed for benzofurox-
ans and derivatives. Some furoxans and benzofuroxans have
in a recent article we reported the spontaneous conversion of 2-
azido-3-nitropyridines into pyridinofuroxans.
3
6b
nematocidal, antimicrobial, fungicidal, herbicidal, and algicidal
properties. Others are depressants of the central nervous system,
muscle relaxants, and anticonvulsants.
Chemical reactions are usually carried out in fluid media either
in gas phase or in solution. Since the reactant molecules in fluid
phase can diffuse freely and isotropically, the kinetic properties
are a function of substrate concentrations and reaction tempera-
Azidobenzene derivatives with an unsaturated ortho substitu-
1
0
ent (NO
2
) are useful starting materials for heterocyclic-ring
tures. On the contrary, in crystal diffusion of reactant molecules
becomes anisotropic and is strongly suppressed by the tight pack-
ing in all directions. Therefore, chemical reactivity in the solid
phase depends on the distance and relative orientation of the reac-
4
synthesis via pyrolysis. Assistance of the ortho substituent plays
an important role in decreasing the activation energy. o-Nitroph-
4
enylazide 1, is a well-studied precursor for heterocyclic-ring syn-
thesis of benzofuroxan 2 via photolysis or pyrolysis (Scheme 1)
in both liquid and gas phases.5
1
1
tion sites of the reacting molecules. In many cases, this leads to
higher regio- and stereoselectivities in the product formation.
There are only a couple of reports in the literature about the
1
2,13
photochemistry of aryl azides in crystals.
Photolysis of several
crystalline para-substituted aryl azides at cryogenic temperatures
afforded dimeric azobenzenes. In this case, the crystal structure
with a face-to-face orientation of the azido groups yielded azo-
benzenes. The intermediate aryl nitrenes in a crystalline environ-
ment exhibited an extraordinary high kinetic stability.12
In a recent paper, the crystalline-state photoreaction of o-
nitrophenylazide was investigated by a combination of X-ray crys-
tallography, IR spectroscopy, electron-spin resonance (ESR), and
theoretical calculations. Upon low-temperature (80 K) photolysis
Scheme 1. Photolysis or pyrolysis of o-nitrophenylazides in solution.
⇑
Corresponding author. Tel.: +52 444 8262440x508; fax: +52 444 8262371.
E-mail address: elisa@uaslp.mx (E. Leyva).
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.013

2
448
E. Leyva et al. / Tetrahedron Letters 53 (2012) 2447–2449
Scheme 2. Photolysis of crystalline o-nitrophenylazides 1a–j.
of 1, the formation of benzofuroxan 2 was directly observed by X-
ray single-crystal analysis (Scheme 1). Combined results from
experimental and theoretical studies suggest that ring formation
proceeds via a nitrene with a small activation energy because of
the considerably short distance (2.710 Å) between the reaction
centers.1
Scheme 3. Proposed mechanism.
3
In summary, a simple, highly effective, and solvent free proce-
dure for the conversion of crystalline o-nitrophenylazides 1a–j into
benzofuroxans 2a–j is presented. Whereas fluid phase photolysis
of o-nitrophenylazides produces benzofuroxans in moderate yields
The photochemistry of aryl azides in solution has been exten-
1
4,15
sively investigated
but there are only a couple of studies con-
12,13,15
cerning their photochemistry in crystalline environment.
In
order to understand chemical reactivity in the solid state it is cru-
cial to investigate the chemical behavior of reactive intermediates
1
5,22
(
30–35%)
a solid crystalline matrix promotes ambient temper-
1
4,15
ature elimination of nitrogen and selective generation of benzofu-
roxans in excellent yields (80–91%). However, this method works
only with crystalline o-nitrophenylazides with a high melting
point (above 50 °C). These experimental conditions inhibit the for-
mation of polymeric tars.
under this condition.
A higher stability of reactive intermedi-
ates in the solid state compared to the one observed in fluid media
has been previously demonstrated.16
In this Letter, we report a novel preparation of several benzofu-
roxans 2a–j by ambient temperature photolysis of crystalline o-
nitrophenylazides 1a–j (Scheme 2). This procedure represents a
new green methodology to prepare benzofuroxans.
Acknowledgments
In a typical photochemical reaction, crystalline aryl azides 1a–j
were irradiated with 365 nm light, at room temperature in a
rayonet photoreactor for several days, to form the corresponding
benzofuroxans 2a–j (Table 1). The crystalline benzofuroxans ob-
tained by this methodology have been previously prepared by
We would like to acknowledge financial support by CONACyT
(
Grant 155678) and UASLP (PIFI 2010 for CA30). R.M.G.-B.
acknowledges financial support by CONACyT (Scholarship No.
90618) for an internship at UCLA. We would like to thank Profes-
sor Alan Weedon from University of Western Ontario and Professor
Miguel A. García-Garibay from the University of California at Los
Angeles for help with NMR and MS measurements.
2
3
,6,17–22
other procedures.
In our experimental procedure,23 when the crystalline o-nitro-
phenlazide has a high melting point (above 50 °C) a benzofuroxan
is obtained in quantitative yields indicating that these reactions
are under topotactic control due to the known proximity of react-
References and notes
2 3
and N
) in the crystal.13 The proposed mechanism
ing groups (NO
Scheme 3) for this photochemical process could involve a singlet
nitrene intermediate 1N that undergoes a reaction with a nearby
NO group. However, when the starting aryl azide has a rather
1
.
For a review on nitric oxide donors and references therein, see: Wang, P. G.;
Xian, M.; Tang, X.; Wu, X.; Wen, Z.; Cai, T.; Janczuk, A. J. Chem. Rev. 2002, 102,
1091.
(
2
.
.
Frutero, R.; Ferratori, B.; Serafino, A.; Di Stilo, A.; Gasco, A. J. Heterocycl. Chem.
2
1989, 26, 1345.
low melting point the crystalline matrix becomes soft and perhaps
allows the formation of a non-planar bicyclic azirine 1CB that
undergoes ring expansion to dehydroazepine 1DA and an oily poly-
meric mixture is obtained. Indeed, we have reported that aryl
azides, like parent phenyl azide, yield mostly tar-like mixtures
upon photolysis in liquid environment.1 This has been explained
in terms of a mechanism (Scheme 3) involving an intermediate
dehydroazepine prone to form polymers.
3
(a) Gasco, A.; Boulton, A. J. Adv. Heterocycl. Chem. 1981, 29, 251; (b) Ghosh, P. B.;
Everitt, B. J. J. Med. Chem. 1974, 17, 203; (c) Ghosh, P. B.; Ternai, B.; Whitehouse,
M. W. Med. Res. Rev. 1981, 2, 158; (d) Ghosh; Whitehouse, M. W. J. Med. Chem.
1969, 12, 505; (e) Aguirre, G.; Boiani, L.; Boiani, M.; Cerecetto, H.; Di Maio, R.;
González, M.; Porcal, W.; Denicola, A.; Piro, O. E.; Castellano, E. E.; Sant’Anna, C.
M.; Barreiro, E. Bioorg. Med. Chem. 2005, 13, 6336; (f) Porcal, W.; Hernandez, P.;
Aguirre, G.; Boiani, L.; Boiani, M.; Merlino, A.; Ferreira, A.; Di Maio, R.; Castro,
A.; González, M.; Cerecetto, H. Bioorg. Med. Chem. 2007, 15, 2768; (g) de
Carvalho, P. S.; Maróstica, M.; Gambero, A.; Pedrazzoli, J., Jr. Eur. J. Med. Chem.
5a
2010, 45, 2489; (h) Jorge, S. D.; Masunari, A.; Rangel-Yagui, C. O.; Mesquita
Pasqualoto, K. F.; Costa Tavares, L. Bioorg. Med. Chem. 2009, 17, 3028.
(a) Smolinski, G. J. Org. Chem. 1961, 26, 4108; (b) Wentrup, C. Adv. Heterocycl.
Chem. 1981, 28, 279.
Katritzky, A. R.; Gordeev, M. F. Heterocycles 1993, 35, 483. and references
therein.
(a) Leyva, S.; Castanedo, V.; Leyva, E. J. Fluorine Chem. 2003, 121, 171; (b) Leyva,
E.; de Loera, D.; Jiménez-Cataño, R. Tetrahedron Lett. 2010, 51, 3978.
(a) Dyall, L. K. Aust. J. Chem. 1975, 28, 2147; (b) Dicskson, N. J.; Dyall, L. K. Aust. J.
Chem. 1980, 33, 91; (c) Dyal, L. K. Aust. J. Chem. 1984, 37, 2013; (d) Dyall, L. K.
Aust. J. Chem. 1986, 39, 89.
4.
5.
6.
7.
Table 1
Preparation of benzofuroxans 2a–j
Product
R
1
R
2
R
3
Mp (°C)
azide
Yield (%)
Mp (°C)
benzofuroxan
2
2
2
2
2
2
2
2
2
2
a
b
c
d
e
f
g
h
i
H
CH
H
H
H
H
H
Br
NO
H
H
H
CH
H
H
H
Cl
H
H
H
H
H
H
CH
OCH
Cl
Cl
Br
H
37–38
51–52
76–78
55–56
70–72
39–40
78–80
50–51
95
30
91
81
82
81
30
91
90
92
89
69–7118
1
9
3
84–86
96–971
9
8. Rauhut, G.; Eckert, F. J. Phys. Chem. A 1999, 103, 9086.
3
3
g
9. McCulla, R. D.; Burdzinski, G.; Platz, M. S. Org. Lett. 2006, 8, 1637.
10. (a) Gavezzotti, A.; Simonetta, M. Chem. Rev. 1982, 82, 1; (b) Titman, J. J.; Luz, Z.;
Spiess, H. W. J. Am. Chem. Soc. 1992, 114, 3765; (c) Muller, K.; Zimmermann, H.;
Krieger, C.; Poupko, R.; Luz, Z. J. Am. Chem. Soc. 1996, 118, 8006.
11. (a) Cohen, M. D.; Schmidt, G. M. Pure Appl. Chem. 1971, 27, 647; (b) Patel, G. N.;
Chance, R. R.; Turi, E. A.; Khanna, Y. P. J. Am. Chem. Soc. 1978, 100, 6644; (c)
Gudmundsdottir, A. D.; Lewis, T. J.; Randall, L. H.; Scheffer, J. R.; Retting, S. J.;
Trotter, J.; Wu, C. J. Am. Chem. Soc. 1996, 118, 6167.
3
96–97
116–1171
9
9
0
b
1
3
47–481
2
130–131
3
92–93
141–1432
2
j
NO
2
66–67
71–7221

E. Leyva et al. / Tetrahedron Letters 53 (2012) 2447–2449
2449
1
1
2. Sasaki, A.; Mahé, L.; Izuoka, A.; Sugawara, T. Bull. Chem. Soc. Jpn. 1998, 71, 1259.
3. Takayama, T.; Kawano, M.; Uekusa, H.; Ohashi, Y.; Sugawara, T. Helv. Chim. Acta
21. Harris, R. B.; Katritzky, A. R.; Oksne, S.; Bailey, A. S.; Paterson, W. G. J. Chem. Soc.
1963, 197.
2
003, 86, 1352.
22. Ayyangar, N. R.; Madan kumar, S.; Srinivan, K. V. Synthesis 1987, 616.
1
1
4. Reviews on aryl azides and aryl nitrenes: (a) de Loera Carrera, D. A.; Leyva, E.;
Jiménez Cataño, R. Bul. Soc. Quim. Mex. 2009, 3, 93.; (b) Scriven, E. F. V. Azides
and Nitrenes: Reactivity and Utility; Academic Press: New York, 1984; (c) Platz,
M. S.; Leyva, E.; Haider, K. Org. Photochem. 1991, 11, 367; (d) Platz, M. S. In
Nitrenes in Reactive Intermediate Chemistry; Moss, R. A., Platz, M. S., Jones, M.,
Eds.; John Wiley & Sons Inc.: New York, 2004.
23. General procedure. The starting arylazides 1a–j were prepared following the
procedure previously reported by us.6
,17
An acetone solution of an o-
nitrophenylazide (150 mg) was prepared. The solvent was slowly removed to
yield a crystalline layer of the azide in the flask. The solid was irradiated at
room temperature with 365 nm light in a Southern New England Rayonet
Photoreactor for 168 h. The resulting solid benzofuroxan was recrystallized
from ethanol, and characterized by UV–vis, IR, RMN, and MS. In the case of aryl
azides (1a,f) with a low melting point (below 50 °C), a dark brown oily mixture
was obtained. It was separated in a silica column with hexane as a solvent to
obtain the corresponding benzofuroxan (2a,f) in the first fractions. In addition
to benzofuroxan, mixtures of polymeric unidentified compounds were also
obtained. All the starting arylazides 1a–i were crystalline but only the ones
with a high melting point (above 50 °C) gave quantitative yields (81–92%) of
benzofuroxans upon photolysis (Table 1). Moderate yields (30%) of
5. (a) Leyva, E.; Platz, M. S.; Persy, G.; Wirz, J. J. Am. Chem. Soc. 1986, 108, 3783; (b)
Leyva, E.; Munoz, D.; Platz, M. S. J. Org. Chem. 1989, 54, 5938.
1
1
6. García-Garibay, M. A. Acc. Chem. Res. 2003, 36, 491.
7. (a) Castanedo Saucedo, V. M. Bachelor Degree Thesis, 1999, San Luis Potosí,
México.; (b) Salgado, B. M. Master Degree Thesis, 2005, San Luis Potosí, México.;
(
c) De Loera Carrera, D. A. Ph.D. Degree Thesis, 2008, San Luis Potosí, México.
1
1
2
8. Terrian, D. L.; Houghtaling, M. A.; Ames, J. R. J. Chem. Educ. 1992, 69, 589.
9. Boulton, A. J.; Katritzky, A. R.; Sewell, M. J.; Wallis, B. J. Chem. Soc. 1967, 914.
0. Mallory, F. B.; Manatt, S. L.; Wood, C. S. J. Am. Chem. Soc. 1965, 87, 5433.
benzofuroxans were obtained with
a low melting point (below 50 °C)
arylazide (1a,f).