One-pot methodology for conversion of o-halogen nitrobenzenes to benzofuroxans

Article abstract of DOI:10.1080/00397911.2016.1276932

Reaction of o-halonitrobenzenes with sodium azide under reflux of DMF/H₂O gives benzofuroxans in one step in moderate to good yields. This is a faster methodology compared to the conventional procedure involving the preparation and subsequent pyrolysis of o-nitrophenyl azides. For comparison, the reaction was also performed under phase-transfer catalysis.

Full text of DOI:10.1080/00397911.2016.1276932

One-pot methodology for conversion of o-halogen nitrobenzenes to benzofuroxans
Elisa Leyva1, Socorro Leyva-Ramos1, Rogelio Jiménez-Cataño1, Telma A. de Luna-
Méndez1, Agobardo Cárdenas-Chaparro1
1Facultad de Ciencias Químicas, Universidad Autónoma de San Luis Potosí. Av. Manuel
Nava 6. Zona Universitaria, San Luis Potosí, S.LP., México
Corresponding author Elisa Leyva, Facultad de Ciencias Químicas, Universidad
Autónoma de San Luis Potosí, SLP, México, E-mail: E-mail: elisa@uaslp.mx
ABSTRACT
Reaction of o-halonitrobenzenes with sodium azide under reflux of DMF/H2O gives
benzofuroxans in one step in moderate to good yields. This is a faster methodology
compared to the conventional procedure involving the preparation and subsequent
pyrolysis of o-nitrophenyl azides. For comparison, the reaction was also performed under
phase transfer catalysis.
GRAPHICAL ABSTRACT
KEYWORDS: Benzofuroxan, o-nitrophenyl azide, SNAr, heterocycle.
1
INTRODUCTION
1

Benzofuroxans comprise a class of important heterocyclic compounds with diverse
biological activity.[1,2] They have gained interest as cardiovascular agents since they
generate nitric oxide which plays an important role as a biological messenger. They have
been extensively investigated as NO-releasing agents, calcium channel modulators,
herbicides, and energetic materials.[1–4]
Due to their biological relevance, several methods to prepare benzofuroxans have been
reported.[1-3,5] Azidobenzene derivatives containing an ortho-nitro substituent are useful
precursors for the synthesis of benzofuroxans (Scheme 1) by photolysis or pyrolysis.[6-8]
The assistance of an ortho-unsaturated substituent plays an important role in decreasing
the energy barrier of activation. Low yields of benzofuroxans are obtained by photolysis
in the fluid phase photolysis of o-nitrophenyl azides,[8b] while photolysis in crystalline
state yields heterocyclic compounds in quantitative yields.[8c] However, this latter reaction
operates under topotactic control[9] due to the proximity of the reacting groups (NO2 and
N3) in a crystal, it only works with high melting point aryl azides (above 50 oC).[8c]
In the preparation of benzofuroxans, thermal cyclization of o-nitrophenyl azides is the
most widely used method.[3] It has been proposed that an ortho-nitro substituent
participates in a pericyclic process with nitrogen removal[10] and computational studies
support this earlier assertions.[11] To induce this reaction, an aryl azide is usually refluxed
for several hours in toluene, xylene, DMSO or acetic acid. The main drawback of this
method is the long reaction time required.[8]
2

In an alternative one-pot approach, several benzofuroxans have been synthesized from o-
chloro nitrobenzenes following nucleophilic substitution with sodium azide in organic
solvents under phase transfer conditions (PTC).[12] This substitution was also reported
using 1-butyl-3-methylimidazolium azide in ionic liquids.[13] In a more recent approach,
this reaction was performed with sodium azide using several ionic liquids as solvents.[3]
However, many of the reported methods have several drawbacks such as long reaction
times, high temperatures and unusual starting materials.
In this communication, we report a one-pot preparation of benzofuroxans by SNAr
reaction of o-halonitrobenzenes with NaN3 to give o-azido nitrobenzenes, which under
reflux conditions easily undergo cyclization. This procedure represents a new practical
methodology for preparing benzofuroxans. The scope and limitations of this reaction will
be presented. To improve yields, we also performed the reaction under PTC conditions
with tetraethylammonium tetrafluoroborate (TEATFB).
2
RESULTS AND DISCUSSION
First, we performed the reaction of sodium azide with several o-halonitrobenzene
compounds in several solvents like acetone/water, benzene/water, toluene/water and
DMF/water. Since this reaction works well only with this latter solvent mixture, it
requires the use of a polar solvent with a high boiling point. In DMF/water, moderate to
good yields (30 to 65 %) of benzofuroxans were obtained at short reaction times (Scheme
1).
3

In our experimental procedure, an amount of commercial o-halonitrobenzene (Scheme 2)
and NaN3 in DMF/H2O were refluxed at 120 oC for several minutes (Table 1). The
reaction was monitored by TLC. In addition, nitrogen bubbles were produced while the
pericyclic reaction was carried out (Scheme 3). After this reaction was complete, the
mixture was poured into an ice/water mixture to induce precipitation. Solid
benzofuroxans were purified and characterized by UV-Vis, IR, NMR and HRMS. This
methodology gives good yields when R is H or an electron withdrawing group such as
NO2, CN, CHO, COOH or COCH3. It gives moderate yields when R is a halogen (F or
Cl). No reaction occurs when R is an electron donating substituent such as O-R or NH2.
The synthesis of several benzofuroxans has been reported under PTC conditions with
benzyltributylammonium in dichloroethane.[12b] However, this methodology required
more than six hours. Thus the reaction was performed with TEATFB in DMF/water
(Table 1). In these latter experiments, the reactions gave better yields in short times for
some of the benzofuroxans in which R is either H or NO2, CN, CHO, COOH or COCH3.
The reaction does not work when R is a weak electron attracting group (F or Cl) or an
electrodonating group (OR or NH2).
In general, the reaction works better when the starting material contains a F as a leaving
group. In some cases, a crystalline benzofuroxan is obtained.
The mechanism for the synthesis of benzofuroxans is given in scheme 3. First, having
electron withdrawing substituents ortho and para to the halogen induces a SNAr
4

mechanism (Scheme 3). Another evidence of this is the fact that a F substituent reacts
faster than a Cl.[14] Once the o-nitrophenyl azide is formed, it is cyclized by thermolysis at
120 oC. PTC conditions result in an improvement in the substitution reaction, resulting in
higher yields of benzofuroxans.
In the case of benzofuroxans, a tautomeric equilibrium (Scheme 4) is usually observed at
room temperature and the 1H NMR signals are quite broad.[8a] This tautomeric
equilibrium has been extensively investigated by both theoretical and experimental NMR
studies.[2,15-16]
3 CONCLUSIONS
In conclusion, reaction of o-halonitrobenzene derivatives with sodium azide in DMF/H2O
represents a fast one-pot methodology for preparing benzofuroxans. This procedure also
works well in phase transfer catalysis with TEATFB. In both cases, the reaction works
better when the starting material contains H or an electron withdrawing substituent (NO3,
CN, CHO, COOH, or COCH3) in para position to the leaving halogen. A SNAr reaction
takes place to generate o-azido nitrobenzene which undergoes a subsequent cyclization
with a concomitant loss of nitrogen.
4
EXPERIMENTAL
4.1 General Procedures For Preparation Of Benzofuroxans.
Procedure a. A solution of a commercial o-halonitrobenzene (1 mmol) and sodium azide
(1 mmol) in DMF (2.5 mL) and H2O (0.5 mL) was prepared. It was refluxed at 120 oC
5

for several minutes with evolution of N2 gas. When this evolution stopped, the reaction
mixture was poured into an ice/water mixture to induce precipitation of product. Solid
benzofuroxans were purified and characterized by UV-Vis, IR, 1H and 13C NMR and
HRMS. All benzofuroxans prepared by this procedure have been previously synthesized
by another procedure and their characterization has already been reported.[3, 8a, 8c, 10d, 17]
Procedure b. A solution of commercial o-halogen nitrobenzene (1 mmol) and sodium
azide (1.5 mmol) in DMF (2.5 mL) was prepared. A volume (1 mL) of an aqueous
solution (1%) of TEATFB was added. The mixture was refluxed at 120 oC for several
minutes with the evolution of nitrogen. Then it was poured in an ice/water mixture and
the benzofuroxan precipitated. The product was purified and characterized by UV-Vis,
IR, IH and 13C NMR and HRMS.
4.2 Spectral Data For A Sample Compound
4.2.1 Benzofuroxan
Yellow crystals, mp 69-70 oC,[8c] Uv-
max=239, 355; IR (KBr, cm-1):
1614 (C=N+-O-), 1580, 1532 (C=C aromatic) 1480, 1436 & 1426 (doublet due to O-N+-
O-), 1351 (N-O), 1148, 1012, 889 (furoxane ring); 1H NMR (CDCl3 ppm: 7.53 (2H, br
s, aromatic H), 7.42 (2H, br s, aromatic H); 13C NMR (CDCl3 ppm: 132.21 (1C, br s,
aromatic C),129.12 (1C, br s, aromatic C),117.95.21(1C, br s, aromatic C),112.81(1C, br
s, aromatic C). HRMS for C6H4N2O2: 136.0273, observed: 136.0261
ACKNOWLEDGEMENTS
6

We would like to acknowledge financial support by CONACyT (Grant CB-2010-
155678). Supporting information: Full experimental detail, total characterization and 1H
NMR spectra of compounds. This material can be found via the “Supplementary
Content” section of this article’s webpage.
REFERENCES
1.
X.;Wen, Z.; Cai, T.; Janczuk, A.J. Chem. Rev. 2002, 102, 1091.
2. (a) Cerecetto, H.; González, M. Top. Heterocycl. Chem. 2007, 10, 265. (b)
Gasco, A.; Boulton, A.J. Advances in Heterocyclic Chem. 1981, 29, 251.
3. Sheremetev, A.B.; Aleksandrova, N.S.; Ignat’ev N.V.; Schulte, M. Mendeleev
Commun. 2012, 22, 95.
For a review on nitric oxide donors, see: Wang, P.G.; Xian, M.; Tang, X.; Wu,
4.
Jovene C.; Chugunova, E.A.; Goumont, R.; Mini Rev. Med. Chem. 2013, 13,
1089.
5.
Nikonov, G.; Bobrov. S. In Comprehensive Heterocyclic Chemistry III. Katritzky,
A.R., Ramsden, C.A., Scriven, E.F.V., Taylor, R.J.K., Eds.; Elsevier, Amsterdam,
London, 2008.
6.
(a) Smolinski, G. J. Org. Chem. 1961, 26, 4108. (b) Wentrup, C. Adv. Heterocycl.
Chem. 1981, 28, 279.
7.
Katritzky, A.R.; Gordeev, M.F. Heterocycles 1993, 35, 483 and references
therein.
8.
(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. (c) Leyva
7

E.; González-Balderas, R.M.; de Loera D.; Jimenez-Cataño, R. Tetrahedron Lett. 2012,
53, 2447.
9.
Takayama, T.; Kawano, M.; Uekusa, H.; Ohashi, Y.; Sugawara, T. Helv. Chim.
Acta. 2003, 86, 1352.
10.
(a) Dyall, L.K. Aust. J. Chem. 1975, 28, 2147. (b) Dicskson, N.J.; Dyall, L.K.
Aust. J. Chem. 1980, 33, 91. (c) Dyall, L.K. Aust. J. Chem. 1984, 37, 2013. (d) Dyall,
L.K. Aust. J. Chem. 1986, 39, 89.
11.
12.
Rauhut, G.; Eckert, F. J. Phys. Chem. A 1999, 103, 9086.
(a) Landini, D.; Maia, A.; Montanari, F. J. Chem. Soc. Perkin Trans. 2, 1983, 461;
(b) Ayyangar, N.R.; Kumar, S.M.; Srinivasan, K.V. Synthesis, 1987, 616.
13.
14.
D’Anna, F.; Marullo, S.; Noto, R. J. Org. Chem. 2008, 73, 6224.
Solomons, T.W.G. Fryhle, C.B. Organic Chemistry, John Wiley & Sons Inc.,
New York, 2004.
15.
Vega-Rodríguez, S.; Jiménez-Cataño, R.; Leyva, E. Comput. Theor. Chem. 2016,
1090, 105.
16.
(a) Anet, F.A.L.; Yavari, I. Org. Magn. Reson. 1976, 8, 158; (b) Yavari, I.; Botto,
R.E.; Roberts, J.D. J. Org. Chem. 1978, 43, 2542. (c) Kotovskaya, S.K.; Romanova, S.A.;
Charushin, V.N.; Kodess, M.I. Zh. Organ. Khim. (Russ. J. Org. Chem.) 2004, 40, 8,
1167; (d) Boulton, A.J.; Katritzky, A.R. Sewell, M.J.; Wallis, B. J. Chem. Soc. (B) 1967,
914; (e) Cmoch, P.; Wiench, J.W.; Stefaniak, L. Webb, G.A. Spectrochimica Acta Part A.
1999, 55, 2207; (f) Kotovskaya, S.K. Romanova, S.A.; Charushin, V.N.; Kodess, M.I.
Chupakhin, O.N.; J. Fluorine Chem. 2004, 125, 421; (g) Deady, L.W.; Quazi, N.H.
Spectroscopy Letters 1995, 28, 7, 1033.
8

17.
Medana, C.; Di Stilo, A.; Visentin, S.; Fruttero, R.; Gasco, A.; Guigo, D.; Bosia,
A.; Pharmaceutical Research. 1999, 16, 956.
9

Table 1. Preparation of benzofuroxans from o-halonitrobenzenes
Substituent Substituent Yielda Time
Yieldb
Time
(min)
30
(R)
(X)
F
(%)
60
55
65
55
55
50
55
45
45
42
60
50
35
30
34
30
(min)
30
(%)
75
H
H
Cl
F
90
63
90
NO2
NO2
CN
5
81
5
Cl
F
9
70
10
5
76
5
CN
Cl
F
10
67
10
CHO
CHO
COOH
COOH
COCH3
COCH3
F
10
75
10
Cl
F
30
61
30
20
65
20
Cl
F
50
57
50
15
75
15
Cl
F
40
66
40
300
300
300
300
NRc
NRc
NRc
NRc
120
120
120
120
F
Cl
F
Cl
Cl
Cl
aYield obtained under refluxing in DMF/water.
bYield obtained under PTC conditions.
cNR=No reaction observed.
10

Scheme 1.
11

Scheme 2.
12

Scheme 3.
13

Scheme 4.
14