A Synthetic Pathway to Substituted Benzofuroxans through the Intermediacy of Sulfonates: The Case Example of Fluoro-Nitrobenzofuroxans

Article abstract of DOI:10.1002/ejoc.201600657

Benzofuroxans are well known compounds that continue to attract particular attention since the discovery of 4,6-dinitrobenzofuroxan (DNBF) back in 1899. It has been shown that these compounds possess biological activities that are related to their electro

Full text of DOI:10.1002/ejoc.201600657

DOI: 10.1002/ejoc.201600657
Full Paper
Benzofuroxans
A Synthetic Pathway to Substituted Benzofuroxans through the
Intermediacy of Sulfonates: The Case Example of Fluoro-
Nitrobenzofuroxans
Cyril Jovené,[a] Jérome Marrot,[a] Jean-Philippe Jasmin,[a] Elena Chugunova,[b] and
Régis Goumont*[a]
Abstract: Benzofuroxans are well known compounds that con- abling us to carry out structural and reactivity comparisons,
tinue to attract particular attention since the discovery of 4,6- with DNBF and 4,6-difluorobenzofuroxan. These compounds
dinitrobenzofuroxan (DNBF) back in 1899. It has been shown have been unambiguously characterized through NMR and ra-
that these compounds possess biological activities that are re- diocrystallographic studies. Two main synthetic pathways in-
lated to their electronic behaviours and the positioning of sub- volving fluoroanisoles and fluorophenols, cheap and easily
stituents borne by the heterocycles. In this paper, we report the available chemicals, have been successfully developed. Finally,
first synthesis of 4-fluoro-6-nitrobenzofuroxan and 6-fluoro-4- benzofurazan analogues have been prepared via deoxygen-
nitrobenzofuroxan; the altered positions of the substituents en- ation of corresponding benzofuroxans with triethylphosphite.
Introduction
rine atom, as a substituent in the chemistry of benzofuroxans,
can be very interesting because of its amenability to substitu-
tion with variously substituted nucleophiles leading to highly
functionalized heterocycles.[6] Importantly, fluorine is also
known to enhance the ability of organic compounds to pene-
trate lipid-based membranes.[7] Furthermore, fluorobenzofurox-
ans also serve as starting points for the synthesis of bioactive
compounds. For example, Beirut reaction to 5,6-difluorobenzo-
furoxan 2 affords fluorinated quinoxaline 3, a powerful inhibitor
of more than 60 tumor cell types.[8]
Since the synthesis of 4,6-dinitrobenzofuroxan 1 in 1899 by
Drost,[1] benzofuroxans have attracted particular attention; 1
displays a broad spectrum of biological activities including anti-
bacterial, antifungal and immunosuppressive properties. Impor-
tantly, the medicinal properties of 1 and related agents are
closely related to the nature and position of the substituent(s)
borne by the heterocyclic core.[2] Even though the first mem-
bers of the benzofuroxans were synthesized at the end of the
19th century, papers in this major field of heterocyclic chemis-
try continue to be published, adding consistency to the present
work.[3,4] The formation of substituted benzofuroxans is readily
achieved by heating correspondingly substituted α-nitrophenyl
azides. These azides are obtained from the corresponding ni-
troanilines by diazotization followed by treatment with aqueous
solutions of azide or from nucleophilic displacements at chlorin-
ated centers with sodium azide. The experimental conditions
depend on the nature of the substituent on the core aromatic
scaffold. In the case of electron-withdrawing groups, the SNAr
process of chloride removal is easily achieved under mild condi-
tions (2 h at room temperature) whereas for electron-donating
groups, another possible pathway involves oxidative conditions
(i.e. sodium hypochlorite in basic alcoholic solution).[5] The fluo-
Finally, new fluorinated phenazine-type compound 4 has
been shown to be a promising bioreductive antitumor agent. It
displayed selective toxicity towards hypoxic V79 cells having an
appropriate hypoxic cytotoxicity ratio (HCR = 6.8).[9] Mono- and
poly-fluorobenzofuroxans and their benzofurazan analogues
are already known and a revisited synthesis of these fluoroben-
zofuroxans, especially 4,6-difluorobenzofuroxan (DFBF) 5, has
been recently reported by our group.[10]
[a] Department of Chemistry, ILV, UMR 8180, University of Versailles,
45 avenue des Etats Unis, 78035 Versailles Cedex, France
http://www.ilv.uvsq.fr
regis.goumont@uvsq.fr
[b] A.E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific
Center, Russian Academy of Sciences,
8 Arbuzov st., Kazan, 420088, Russia
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600657.
However, the preparation of fluoronitrobenzofuroxan has
been much less often described in the literature. One can refer-
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ence the study of 5-fluoro-4-nitrobenzofuroxan (6) by White- nitrophenolate ion allows for possible conversion of the OH into
house and co-workers in 1972. This work highlights an interac- a good leaving group. Accordingly, and as described below,
tion between the scaffold-borne fluoro and nitro groups that benzofuroxans 9 and 10, have been prepared from 2-fluoro-
diminished the susceptibility of the fluorinated center to un- phenol and 4-fluorophenol, respectively (Scheme 2).
dergo substitution chemistry (Scheme 1).[11] Also notable has
been work by Okiyama and co-workers to determine the fluo-
rescence properties of 5-fluoro-6-nitrobenzofuroxan (7) and its
benzofurazan analogue 8.[12]
Scheme 1. Interaction of F and NO2 moieties within benzofuroxan 6.[11]
Scheme 2. Global synthetic strategy to 9 and 10.
1) Synthesis of Fluorobenzofuroxans 9 and 10
First, the nitration of the two phenols is accomplished under
The ability to prepare new substituted fluorinated benzo-
furoxans is of great interest because: i) it increases the scope of
available benzofuroxans, and ii) such species can be used as
precursors in the production of new biologically active com-
pounds.
mild conditions in a liquid–liquid two phase system HNO3 (fum-
ing)/CH2Cl2 at 0 °C leading to the dinitro compounds in 99 %
and 75 % yields, respectively. The NMR spectroscopic data for
these two dinitrophenols are in good agreement with those
reported in the literature.[14] The deprotonation of the two di-
In this paper, we report the first synthesis of two unknown nitrophenols is easily achieved by treating a solution of 13 and
species 4-fluoro-6-nitrobenzofuroxan (9) and 6-fluoro-4-nitro- 14 in ethanol with potassium carbonate, leading to the precipi-
benzofuroxan (10) using, for the first time, phenols as starting tation and isolation of highly colored ions 15 and 16 in quanti-
materials. The 4 and 6 positions of benzofuroxans 9 and 10 tative yields (Scheme 3).
have been deliberately chosen for modification in order to bet-
ter understand the influence of fluoride and nitro group posi-
tioning (and interplay) on the reactivity of these heterocycles.
Finally, we report the successful synthesis of benzofurazan ana-
logues 11 and 12, generated via deoxygenation of benzofurox-
ans 9 and 10, respectively.
Scheme 3. Formation of phenolate ions.
Results and Discussion
The conversion of the phenolate ion to sulfonate analogues
As was mentioned above, one of the most common synthetic has been performed using various sulfonyl chlorides [a: p-tolu-
approaches to benzofuroxans bearing electron-withdrawing enesulfonyl chloride (TsCl), b: methanesulfonyl chloride (MsCl),
groups entails the reaction of o-chloronitrobenzenes with so- and c: isopropylsulfonyl chloride] to understand the influence
dium azide followed by the thermal decomposition of the cor- of the substituent on the subsequent SNAr process (Scheme 4).
responding nitrophenyl azide, leading to the benzofuroxan in Heating of a suspension of the phenolate ion in acetonitrile
nearly quantitative yield.[13] To overcome difficult nitration of with the sulfonyl chloride led to formation of compounds 17a–
chlorofluorobenzenes and to also avoid competitive nucleo- c and 18a–c in moderate to good yields as pale yellow solids
philic displacements of Cl vs. F, an alternative synthetic pathway (Scheme 4, Table 1). The structures of these compounds are in
using fluorophenols was undertaken. Phenols are a class of very total accord with NMR spectroscopic data recorded in CD3CN.
common chemicals possessing many interesting properties for For example, the 1H NMR spectra recorded for 17b and 18b
the synthesis of benzofuroxan: i) fluorophenols are commer- exhibited singlets at δ = 3.50 and 3.43 ppm, respectively. Simi-
cially available; ii) the activating hydroxy group enables facile larly, the spectra obtained for 17c and 18c revealed a septuplet/
dinitration of the phenyl ring, and iii) the high stability of the doublet system at 3.85/1.56 and 3.80/1.52 ppm, respectively.
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Table 2. Yield of azides and phenolate ions from sulfonates 18a–c.
Sulfonate
Experimental conditions
Azide 20
Phenolate 16
18a
ternary solvent system
pure CH3CN
ternary solvent system
pure CH3CN
ternary solvent system
pure CH3CN
40 %
77 %
28 %
50 %
94 %
79 %
60 %
23 %
72 %
50 %
6 %
18b
18c
21 %
in the ortho/para positions.[15] It is well established that the
presence of two nitro groups in these positions leads to in-
creased stabilization of the Meisenheimer complex. According
to the results summarized in Tables 1 and 2, the superior experi-
mental conditions involve the use of the tosyl chloride and exe-
cution of the SNAr process in pure acetonitrile at room tempera-
ture; the overall yield for the two steps being around 75 %.
Finally, heating of 19 and 20 in boiling toluene leads to the
exclusive formation of benzofuroxans 9 and 10 as pale yellow
solids in 90 % yield. This translates to overall yields of 60 % and
50 % (Scheme 6) for compounds 9 and 10, respectively. The
numbering of the various atoms is given in Scheme 6; this sys-
tem is typically used by our group and others in describing
benzofuroxan chemistry. It is important to keep this non-con-
ventional numbering system in mind so as to enable appropri-
ate comparisons with other papers.
Scheme 4. Synthesis of 17a–c and 18a–c.
Table 1. Yields of sulfonates obtained from phenolate ions 15 and 16 as a
function of sulfonyl chloride.
Sulfonyl
chloride
Reaction with
phenolate ion 15
Reaction with
phenolate ion 16
a, TsCl
b, MsCl
c, iPrSO2Cl
17a, 90 %
17b, 70 %
17c, 99 %
18a, 98 %
18b, 70 %
18c, 60 %
The key step in the synthesis of 9 and 10 is the SNAr process
involving sulfonate displacement by NaN3. Two sets of experi-
mental conditions were tested in which the solvents were ei-
ther: i) the ternary solvent system (water/ethanol/acetone) usu-
ally used in the lab, or ii) pure distilled CH3CN (Scheme 5).[4] In
both cases, the formation of o-nitrophenyl azides 19 and 20
was typically accompanied by concomitant formation of ions
15 and 16 as highlighted by the rapid appearance of a deep
orange color, yields are summarized in Table 2 for the reaction
of 18a–c with sodium azide. Similar results were obtained for
17a–c but have been omitted for the sake of clarity.
Scheme 6. Global scheme for formation of benzofuroxans 9 and 10.
1
The H NMR spectra of these heterocycles are characterized
by two deshielded protons around 8 ppm. The chemical shifts
of the two protons H5/H7 for 9 and 10 are summarized in
Table 3 together with those of DNBF, 1 and DFBF, 5. Interest-
ingly, the signals of the two protons H5/H7 are doublet of dou-
3
3
3
blets for 10 (H5: JH5H7 = 2.1, JH5F = 8.4 Hz; H7: JH7H5 = 2.1,
3JH7F = 6 Hz) while those for 5 are a broad singlet (H7) and a
broad doublet (H5: 3JH5F = 6.3 Hz, vide infra). As has been previ-
ously reported, the 13C NMR spectra of compounds 9 and 10
show some characteristic features. The complete assignment
was easily obtained using one- and two-dimensional tech-
Scheme 5. Competitive formation of azide vs. phenolate ion.
The formation of compound 15 (or 16) may be rationalized niques including HMQC and HMBC experiments. The two reso-
by competitive nucleophilic substitution of the phenolate moi- nances corresponding to C5 and C7 are readily determined
ety by the azide group, the driving force being the high degree whereas the resonances of C8 and C9 are key features of NMR
of stabilization of the phenoxide by both the nitro and fluoro spectra of benzofuroxans. In fact, with chemical shifts of 145
groups. The greater leaving group ability of the sulfonate group and 115 ppm, respectively, the signals of C9 and C8 are quite
compared with the fluorine is clearly a result of the nitro groups independent of the position and nature of the substituent, and
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are easily assigned (Table 3). The data summarized in Table 3 more efficient than nitration of the aniline. The formation of
clearly show that signals corresponding to C8 and C9 are in benzofuroxans from anilines has been extensively described
close agreement with those peviously reported for DNBF, 1 and and used in the literature and may represent a useful alternative
1
DFBF, 5. Finally, an average JCF value of 250–260 Hz has been pathway in cases where the current benzofuroxan synthesis is
measured for the carbon atom bearing the fluorine atom in not compatible with phenol or anisole precursors. The two con-
compounds 9 and 10, this value being close to that measured ventional methods, i) diazotization in acidic media/subsequent
for difluorobenzofuroxan, 5.[10] Also, in accordance with the treatment with NaN3/heating, and ii) application of sodium
structures of 9 and 10 was the observation in the 19F NMR hypochlorite in basic methanolic media, do not afford hetero-
spectra of broad signals at –118.6 and –107.7 ppm, respectively, cycles 9 and 10. It is difficult to rationalize this behavior due to
characteristic of the aromatic ring fluoride. Finally, UV/Visible the presence of the fluorine atom, assuming that the fluorin-
spectra were recorded in CH3CN and found to exhibit maximum ated center enables aromatic nucleophilic substitutions. This
absorptions at wavelengths of 390 and 405 nm for 9 and 10, type of reaction has been previously reported in the synthesis
respectively; such values are typical for the benzofuroxan moi- of 4,6-difluorobenzofuroxan (5), for which the nucleophilic dis-
ety.[16]
placement of the fluorine atom by water and hydroxide ion
has been observed and highlighted.[10] A water-free synthesis
in neutral experimental conditions, implying the use of tert-
butyl nitrite (tBuONO) as nitrosation agent with TMSN3, has
been employed leading to azides 19 and 20 in 90 % yield
(Scheme 8).[19] Finally, heating these azides in boiling toluene
affords 4-fluoro-6-nitrobenzofuroxan (9) and 6-fluoro-4-nitro-
benzofuroxan (10) in 40 % and 45 % yields, respectively. The
NMR spectroscopic data for these species are also similar to
previously obtained data sets.
Table 3. 1H NMR and characteristic 13C NMR chemical shifts of DNBF, 1, DFBF,
5 and benzofuroxans 9 and 10.[a]
Heterocycle
δH5 (ppm)
δH7 (ppm)
δC8 (ppm)
δC9 (ppm)
1[b]
5[c]
9[b]
7[b]
9.12
7.05
7.85
8.41
8.82
7.05
8.33
7.65
116.6
116.8
114.4
117.5
144.8
145.6
146.3
145.4
[a] Relative to internal SiMe4. [b] CD3CN. [c] Acetone-d6, see ref.[10]
.
Also interesting in this methodology, is that this synthetic
pathway can be extended to fluoroanisoles when phenols are
not available. In such cases, the methoxy group, being electron-
donating, enables facile dinitration leading to dinitrofluoro-
anisoles 21 and 22 in moderate yields. Interestingly, the NMR
spectroscopic data for these compounds are in agreement with
those reported previously in the literature.[17]
Phenoxide ions 15 and 16 (as their potassium salts) can then
be obtained in quantitative yields by heating a solution of the
dinitroanisoles in ethanol in the presence of potassium iodide
(Scheme 7). The next steps remain identical to those previously
described in Scheme 6. The yields for anisole nitration are lower
than those for phenol nitration; the global yield for the synthe-
sis of the benzofuroxans 9 and 10 are 40 % and 45 %, respec-
tively.
Scheme 8. Synthesis of benzofuroxans 9 and 10 from anilines.
Finally, if anisole is not available to prepare the aniline, one
can prepare the anisole via methylation of the phenolate ion
obtained from the phenol. The heating of a solution of phenol-
ate with dimethyl sulfate (DMS) in acetonitrile affords the corre-
sponding anisole in a 80 % yield (Scheme 8).[20]
The yields for compounds 9 and 10 obtained using the three
synthetic pathways are gathered in Table 4. The main message
emerging from these data is that the synthetic pathway starting
from fluorophenols provides optimal results but that the two
other pathways give similar, and still respectable, yields.
Notably, Scheme 9 summarizes the various strategies available
Scheme 7. Formation of phenolate ions from dinitroanisoles.
Dinitroanisole can also be used in an efficient one-step syn-
thesis of the corresponding dinitroaniline analogues. As a mat-
ter of fact, the nitration step of aniline often requires protection
of the amino group as an amide and subsequent deprotection
of the dinitroamide intermediate in acidic media following
nitration. The overnight heating of the dinitroanisole with ex-
cess ammonia solution in MeOH results in quantitative forma-
tion of anilines 23 and 24.[18] This latter reaction is simpler and
Table 4. Summary of yields for production of 4-fluoro-6-nitrobenzofuroxan (9)
and 6-fluoro-4-nitrobenzofuroxan (10) using the three differernt approaches
detailed herein.
Product
Yield from
Yield from
Yield from
phenols (%)
anisoles (%)
anilines (%)
9
10
60 %
50 %
40 %
45 %
40 %
45 %
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Scheme 9. Global synthesis of benzofuroxans 9 and 10.
to prepare 4-fluoro-6-nitrobenzofuroxan (9) and 6-fluoro-4- furoxan structure as has been previously demonstrated for
nitrobenzofuroxan (10).
other substituted benzofuroxans.[23]
That the signals corresponding to benzofuroxan 9 are unre-
solved provides clear evidence of the well-known 1-oxide/3-
oxide tautomeric relationship. Ring-chain tautomerism of this
type occurs in benzofuroxan itself (R = H, Scheme 10) and also
in substituted benzofuroxans. In the case of benzofuroxans sub-
stituted at the 5 position (for the numbering of benzofuroxan,
see Scheme 2), the amount of each tautomer is dependent on
the nature of R. When the nitro group is in the 5 position, as in
5-nitrobenzofuroxan 26, both isomers exist at room tempera-
ture. An electron-donating group, whatever its position, always
favors this equilibrium with the co-existence of the two isomers.
Also in accordance with the presence of two tautomers for 9,
was the observation in the 19F NMR spectra of two broad sig-
nals at –118.6 and –121.1 ppm, characteristic of the aryl fluoride
moiety in both tautomers. This equilibrium could be the result
of a greater influence imposed by electron-donating effects rel-
ative to those of fluorine-associated electron-withdrawing ef-
fects (Scheme 11).
2) Structural Study of Benzofuroxans 9 and 10
The structure of 9 was further validated through a radiocrystal-
lographic study revealing that the length of the C6=C7 double
bond is found to be 1.355 Å whereas that of the C4=C5 linkage
is 1.333 Å (Figure 1). Interestingly, this value is reminiscent of
that found in 4-nitrobenzodifuroxan 25 which possesses a bond
length of 1.339 Å.[21]
Figure 1. X-ray structure of benzofuroxan 9.
Scheme 10. 1-oxide/3-oxide interconversion for benzofuroxans.
This is also typical of a nitro-olefinic fragment as it was re-
ported for DNBF 1 where values of 1.370 and 1.400 Å have
been measured for the two potentially reactive C6=C7 and C4=
C5 double bonds, respectively.[22] This first experimental finding
reflects the low degree of aromatic character for the benzo-
Scheme 11. 1-oxide/3-oxide interconversion for 5-nitrobenzofuroxan 26.
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When an electron-withdrawing group is located at the 4 po- triethylphosphite in toluene or ethanol. The optimal experimen-
sition (4-nitrobenzofuroxan, 27), the benzofuroxan exists in one tal procedure for generating benzofurazans 11 and 12 has been
form with the N-oxide in the 1 position at all temperatures; this to heat fluorinated benzofuroxans in boiling toluene with
explains why the NMR spectra of 4-nitro-6-fluorobenzofuroxan 1.2 equiv. of triethyl phosphite (Scheme 12). Benzofurazans are
(10) exhibit sharp signals.[24–26]
easily purified and obtained in moderate to good yields. NMR
spectra are in full agreement with the structure of benzofurazan
and with the disappearance of the N-oxide functionality. Some
1H NMR and characteristic 13C NMR chemical shifts of 11 and
3) Synthesis of Benzofurazan Analogues 11 and 12
The formation of benzofurazans is usually achieved from corre- 12 are summarized in Table 5 and compared with those of
sponding benzofuroxan analogues using triphenylphosphine or DNBZ (4,6-dinitrobenzofurazan) 28, and DFBZ (4,6-difluoroben-
Figure 2. Characteristic NMR spectra. Upper part: 1H NMR spectra of 11 in CD3CN; lower part 19F NMR spectra of 11 in CD3CN.
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the synthesis of aromatic azides from the corresponding amines
has been accomplished under mild conditions with tert-butyl
nitrite and azidotrimethylsilane. Finally, we have shown here
that benzofurazans can be readily prepared by deoxygenation
of benzofuroxans using triethyphosphite.
Experimental Section
Scheme 12. Formation of 11 and 12 upon deoxygenation of 9 and 10 by
General: 1H, 13C, and 19F NMR spectra were recorded with Bruker
200 and 300 MHz spectrometers. All spectroscopic data are re-
ported in ppm in the δ-scale relative to internal TMS (1H and 13C
P(OEt)3 in toluene.
Table 5. 1H NMR and characteristic 13C NMR chemical shifts (ppm) of DNBZ,
NMR) or CFCl3 (
19F NMR). Abbreviations used are: br. s = broad
28, DFBZ, 29 and benzofurazans 11 and 12.[a]
signal; d = doublet; m = multiplet, sept = septuplet. Melting points
(M.p.) were determined with a Büchi B-545 and are uncorrected.
Starting materials were obtained from commercial sources and
were used without further purification. UV/Visible spectra were re-
corded using a conventional Hewlett–Packard spectrophotometer.
Heterocycle
δH5
δH7
δC8
δC9
28[b]
29[c]
11[d]
12[d]
9.04
7.39
8.00
8.08
9.80
7.58
8.86
8.50
150.0
151.2
149.6
149.8
143.3
144.3
143.4
141.2
General Procedure for Dinitration of Phenols: To a solution of
the appropriate phenol in dichloromethane at 0 °C was added drop-
wise a fuming nitric acid solution (2.3 equiv.). The reaction medium
was stirred at room temperature for 18 h. The residue was diluted
in water and extracted with dichloromethane to give the nitro com-
pound which was purified by column chromatography on silica gel
using PE/AcOEt as eluent. Experimental data for both dinitrophe-
nols 13 and 14 are in agreement with those previously re-
ported.[14b]
Compound 13: Yield 99 %. 1H NMR (CD3CN): δ = 8.30 (dd, J = 3,
10 Hz, 1 H); 8.73 (m, 1 H) ppm. 19F NMR (CD3CN): δ = –129.2 (d, J =
10 Hz, 1 F) ppm.
Compound 14: Yield 75 %. 1H NMR (CD3CN): δ = 8.13 (d, J = 8.5 Hz,
2 H), 8.78 (br. s, OH) ppm.
[a] Relative to internal SiMe4. [b] [D6]DMSO, see ref.[5a] [c] [D6]Acetone, see
ref.[10] [d] CD3CN.
zofurazan) 29. The disappearance of the electron releasing ef-
fect of the N-oxide has two major effects upon NMR spectra: i)
it induces well defined signals due to the absence of tautomer-
ism, and ii) it induces large deshielding of the resonance corre-
sponding to C8 [shift from 110 ppm in benzofuroxan to
155 ppm in benzofurazan (see Tables 3 and 5)].[5] This is exem-
1
plified by Figure 2 which displays H and 19F NMR spectra of
compound 11 in CD3CN. The isolation and unambiguous NMR
characterization of substituted benzofurazans 11 and 12 also
provide indirect support for the structural elucidation of benzo-
furoxans 9 and 10.
19F NMR (CD3CN): δ = –122.0 (t, J = 8.5 Hz, 1 F) ppm.
General Procedure for the Deprotonation of Phenols: To a solu-
tion of the appropriate phenol in ethanol was added a solution of
K2CO3 (1.1 equiv.) dissolved in the minimum volume of water. The
reaction medium was stirred at room temperature for 10 min. The
resulting phenolate was filtered off and the colored solid was dried
under vacuum.
Salt 15: Yield 99 %. Red solid. Decomposition before melting. 1H
NMR ([D6]DMSO): δ = 7.68 (dd, J = 3.0, 12.0 Hz, 1 H); 8.53 (dd, J =
1.4, 3.0 Hz, 1 H) ppm. 19F NMR ([D6]DMSO): δ = –129.9 (br. s, 1
F) ppm.
Salt 16: Yield 99 %. Yellow solid. Decomposition before melting. 1H
NMR ([D6]DMSO): δ = 7.72 (d, J = 9 Hz, 2 H) ppm. 19F NMR
([D6]DMSO): δ = –139.7 (t, J = 9 Hz, 1 F) ppm.
Conclusions
For the first time, the synthesis of fluoronitrobenzofuroxans and
especially of 4-fluoro-6-nitrobenzofuroxan and 6-fluoro-4-
nitrobenzofuroxan has been performed using several synthetic
strategies. This study has shown that these fluoronitrobenzo-
furoxans can be prepared from fluorophenols and fluoro-
anisoles and, more specifically, from a sulfonate intermediate.
These compounds are easily available and both families possess
an electron-donating group that facilitates the key nitration
step. Various sulfonyl chlorides were employed to convert
phenols or anisoles into good leaving groups; the use of TsCl
proved optimal. This synthetic strategy can also be extended to
the preparation of other benzofuroxans. Substituted dinitro-
anisoles are the starting point for an efficient one-step synthesis
of amino analogues proceeding in good yields and eliminating
the classical protection/deprotection steps associated with anil-
ine dinitration-based approaches. Classical procedures for con-
General Procedure for the Formation of Sulfonates: To a solution
of the appropriate phenolate ion in dry acetonitrile at room temper-
ature was added 1.1 equiv. of sulfonyl chloride. The reaction me-
dium was stirred at room temperature for 18 h. The solvent was
removed under vacuum to yield a crude mixture containing the
sulfonate which was isolated and purified by column chromatogra-
phy with PE/AcOEt as eluent. HRMS data have been determined
only for sulfonates 17a and 18a derived from TsCl. Compound 17a
shows some tendency to decompose.
Tosylate 17a: Yield 90 %. White solid, m.p. 101 °C. 1H NMR (CD3CN):
δ = 2.50 (s, 3 H); 7.49 (d, J = 8.0 Hz, 2 H), 7.80 (d, J = 8.0 Hz, 2 H),
8.39 (dd, J = 2.4, 8.5 Hz, 1 H), 8.63 (t, J = 2.4 Hz, 1 H) ppm. 19F NMR
(CD3CN): δ = –118.7 (bd, J = 8.5 Hz, 1 F) ppm. 13C NMR (CD3CN):
verting anilines into benzofuroxans have not been efficient, and δ = 20.8, 128.2, 130.2, 130.4, 134.9, 144.0, 145.2, 147.7, 155.0 (d, J =
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259.2 Hz) ppm. HRMS (electrospray, Na+): Calculated for
C13H9N2O7FS: 379.0012, found 379.0012.
General Procedure for Formation of Anilines from Anisoles: The
appropriate anisole was added to an excess of ammonia solution
in MeOH (7
M) and the mixture was heated at reflux for 15 h. The
Mesylate 17b: Yield 70 %. Pale yellow solid, m.p. 92 °C. 1H NMR
(CD3CN): δ = 3.50 (s, 3 H); 8.52 (dd, J = 4.0, 10.0 Hz, 1 H), 8.68 (t,
J = 2 Hz, 1 H) ppm. 19F NMR (CD3CN): δ = –118.5 (br. s, 1 F) ppm.
Isopropylsulfonate 17c: Yield 99 %. Pale yellow solid. 106 °C. 1H
NMR (CD3CN): δ = 1.56 (d, J = 6.8 Hz, 6 H); 3.85 (sept, J = 6.8 Hz, 1
H), 8.50 (dd, J = 4.0, 6.0 Hz, 1 H), 8.65 (t, J = 2.4 Hz, 1 H) ppm. 19F
NMR (CD3CN): δ = –118.4 (br. s, 1 F) ppm.
Tosylate 18a: Yield 98 %. White solid, m.p. 85 °C. 1H NMR (CD3CN):
δ = 2.49 (s, 3 H); 7.46 (d, J = 8.0 Hz, 2 H), 7.68 (d, J = 8.0 Hz, 2 H),
8.08 (d, J = 7.4 Hz, 2 H) ppm. 19F NMR (CD3CN): δ = –107.5 (t, J =
7.4 Hz, 1 F) ppm. 13C NMR (CD3CN): δ = 20.5, 118.1 (d, J = 28 Hz),
128.7, 129.5, 130.7, 130.9, 145.3, 148.3, 158.5 (d, J = 250.0 Hz) ppm.
HRMS (electrospray, Na+): Calculated for C13H9N2O7FS: 379.0012,
found 379.0011.
Mesylate 18b: Yield 70 %. Pale yellow solid, m.p. 92 °C. 1H NMR
(CD3CN): δ = 3.43 (s, 3 H); 8.17 (d, J = 8.0 Hz, 2 H) ppm. 19F NMR
(CD3CN): δ = –107.7 (br. s, 1 F) ppm.
solvent was removed under vacuum to yield the aniline which was
used without further purification.
Aniline 23: Yield 99 %, m.p. 156 °C (ref.[18a] 156–157 °C). 1H NMR
(CD3CN): δ = 7.3 (br. s, 2 H, NH2), 8.14 (dd, J = 11.0; 2.4 Hz, 1 H),
8.80 (t, J = 2.4 Hz, 1 H) ppm. 19F NMR (CD3CN): δ = –128.6 (d, J =
11.0 Hz, 1 F) ppm.
Aniline 24: Yield 90 %, m.p. 126–129 °C. (ref.[18b] 133–4 °C). 1H NMR
(CDCl3): δ = 8.36 (d, J = 7.8 Hz, 2 H) ppm. 19F NMR (CDCl3): δ =
–125.5 (t, J = 7.8 Hz, 1 F) ppm.
General Procedure for the Formation of Azides from Anilines:
The appropriated aniline (200 mg, 2.14 mmol) was dissolved in
CH3CN (4 mL) in a 25 mL round-bottomed flask and cooled to 0 °C
in an ice bath. To this stirred mixture was added tBuONO (331 mg,
380 μL, 3.21 mmol) followed by TMSN3 (300 mg, 340 μL, 2.56 mmol)
dropwise. The resulting solution was stirred at room temperature
for 1 h. The reaction mixture was concentrated under vacuum and
the crude product was purified by column chromatography using
various PE/AcOEt mixtures. The experimental data of 19 and 20 are
in accord with those reported above.
Isopropylsulfonate 18c: Yield 60 %. Pale yellow solid, m.p. 74 °C.
1H NMR (CD3CN): δ = 1.53 (d, J = 6.9 Hz, 6 H); 3.79 (sept, J = 6.6 Hz,
1 H), 8.13 (d, J = 7.0 Hz, 2 H) ppm. 19F NMR (CD3CN): δ = –107.6
(br. s, 1 F) ppm. 13C NMR (CD3CN): δ = 15.4, 54.8, 117.7, 118.1, 128.5,
145.7, 157.5 (d, J = 255.4 Hz) ppm.
General Procedure for Benzofuroxan Formation: The appropriate
azide was dissolved in toluene and heated at reflux for 3–4 h. The
solvent was removed under vacuum to yield the benzofuroxan
which was purified by column chromatography on silica gel using
PE/AcOEt as eluent. Unfortunately, no satisfactory high-resolution
mass data have been obtained for these benzofuroxans maybe be-
cause of their high tendency to decompose. Due to very slow relax-
ation processes and coupling with the fluorine atom, signals corre-
lating to NO2-tethered carbons have not been found even when
using increased relaxation delays.
General Procedure for Formation of Azides from Sulfonates
1. In a Ternary Acetone/Methanol/Water Mixture: To a solution
of sulfonate (1 mL per mmol of sulfonate) in an acetone/methanol
mixture (v/v, 1:1), was added a solution of sodium azide (1.1 equiv.)
in a mixture water/methanol in a ratio 1:2, the volume of water
being equal to the volume of acetone. The reaction medium was
stirred and protected from light for 18 h. The solvent was removed
under vacuum to yield a crude mixture containing the azide which
was isolated by column chromatography with PE/AcOEt as eluent.
Benzofuroxan 9: Yield 90 %, m.p. 120–121 °C. UV (CH3CN, c =
5 × 10–5 mol L–1): λmax = 390 nm (ε ≈ 25000 mol–1 L cm–1). H NMR
1
(CDCl3): δ = 8.33 (br. s, H7); 7.85 (d, J = 6.3 Hz, H5) ppm. 19F NMR
(CDCl3): δ = –118.6 (br. s, F4) ppm. 13C NMR (CDCl3): δ = 146.3 (C9);
129.3 (d, J = 259.0 Hz, C4); 114.4 (C8); 109.7 (C5); 108.7 (C7) ppm.
2. In Dry Acetonitrile: To a solution of the appropriate sulfonate
in acetonitrile at room temperature was added 1.1 equiv. NaN3. The
reaction mixture was stirred and heated at reflux overnight. The
solvent was removed under vacuum to yield a crude mixture which
was purified by column chromatography with PE/AcOEt as eluent.
Benzofuroxan 10: Yield 90 %, m.p. 128–129 °C. UV (CH3CN, c =
5 × 10–5 mol L–1): λmax = 405 nm (ε ≈ 20000 mol–1 L cm–1). H NMR
1
(CD3CN): δ = 7.65 (dd, J = 2.1; 6.0 Hz, H7); 8.41 (dd, J = 2.1; 8.4 Hz,
H5) ppm. 19F NMR (CD3CN): δ = –107.7 (br. s, F6) ppm. 13C NMR
(CD3CN): δ = 160.0 (d, J = 257.2 Hz, C6); 145.4 (C9); 127.1 (C5); 117.5
Azide 19: Yield 80 %, m.p. 82 °C (decomposition). 1H NMR (CD3CN):
δ = 8.33 (dd, J = 2.6, 11.0 Hz, 1 H); 8.54 (m, 1 H) ppm. 19F NMR
(CD3CN): δ = –118.3 (br. s, 1 F) ppm.
Azide 20: Yield 77 %, m.p. 64 °C (decomposition). 1H NMR (CD3CN):
δ = 7.87 (d, J = 8.6 Hz, 2 H) ppm. 19F NMR (CD3CN): δ = –111.1 (br.
s, 1 F) ppm.
1
(C8); 106.1 (C7) ppm. H NMR (CDCl3): δ = 7.46 (dd, J = 2.2, 5.3 Hz,
H5); 8.25 (br. s, H7) ppm. 19F NMR (CDCl3): δ = –104.3 (br. s, F6) ppm.
General Procedure for Benzofurazan Production: One equiv. of
the substituted fluorobenzofuroxan was heated with 1.2 equiv. of
triethylphosphite overnight in boiling toluene. After cooling, the
solvent was evaporated under reduced pressure. The residue was
purified by column chromatography on silica gel using PE to afford
expected fluorobenzofurazan as a pale yellow solid. Unfortunately,
no satisfactory high-resolution mass data have been obtained for
these benzofuroxans; this is likely attributable to their propensity
for decomposition.
Benzofurazan 11: Yield 83 %, m.p. 138 °C. 1H NMR (CD3CN): δ =
8.00 (dd, J = 1, 10 Hz, H5); 8.86 (d, J = 1 Hz, 1 H, H7) ppm. 19F NMR
(CD3CN): δ = –117.6 (1 F) ppm. 13C NMR (CD3CN): δ = 150.4 (d, J =
267.0 Hz, C4), 150.2 (C6), 149.6 (C9), 143.4 (C8), 111.7 (C7), 108.8
(C5) ppm.
General Procedure for Dinitration of Anisoles: To a solution of
the appropriate anisole in sulfuric acid (20 mL) at 0 °C was added
dropwise a fuming nitric acid solution (2.5 equiv.) in sulfuric acid
(10 mL). The reaction medium was stirred at room temperature for
1 h. The residue was diluted with an ice/water mixture and the
precipitate was filtered off and dried. The dinitroanisoles were puri-
fied by column chromatography on silica gel using PE/AcOEt as
eluent. Experimental data for both dinitrophenols 21 and 22 are in
agreement with those previously reported.[17]
1
Anisole 21: Yield 45 %. H NMR (CD3CN): δ = 4.21 (d, J = 3.6 Hz, 3
H), 8.33 (dd, J = 3.0, 11.5 Hz, 1 H), 8.49 (br. s, 1 H) ppm. 19F NMR
(CD3CN): δ = –123.5 (br. s, 1 F) ppm.
Benzofurazan 12: Yield 64 %, m.p. 113 °C. 1H NMR (CD3CN): δ =
8.08 (dd, J = 1.4, 5 Hz, H5); 8.50 (dd, J = 1.4, 6 Hz, H7) ppm. 19F
1
Anisole 22: Yield 65 %. H NMR (CD3CN): δ = 3.97 (s, 3 H), 8.00 (d,
J = 8 Hz, 2 H) ppm. 19F NMR (CD3CN): δ = –113.8 (br. s, 1 F) ppm.
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NMR (CD3CN): δ = –104.1 (1 F) ppm. 13C NMR (CD3CN): δ = 161.0
(d, J = 257.0 Hz, C6), 149.8 (C8), 141.2 (C9), 137.6 (C4), 124.4 (C5),
106.2 (C7) ppm.
Croatia, 2012, chapter 10, p. 183–206; b) C. Jovene, M. Sebban, J. Marrot,
R. Goumont, in: Targets in Heterocyclic Systems, Chemical Society of Italy,
Rome, 2012, vol. 16, p. 90–112.
[6] S. K. Kotovskaya, S. A. Romanova, V. N. Charushin, M. I. Kodess, O. N.
Chupakhin, J. Fluorine Chem. 2004, 125, 421–428.
[7] J. F. Liebman, A. Greenberg, W. R. Dolbier, in: Fluorine-Containing Mol-
ecules: Structure Reactivity, Synthesis and Applications. Wiley-VCH Verlag
GmbH, 1988.
[8] B. Solano, V. Junnotula, A. Marin, R. Villar, A. Burguete, E. Vicente, S. Perez-
Silanes, I. Aldana, A. Monge, S. Dutta, U. Sarkar, K. S. Gates, J. Med. Chem.
2007, 50, 5485–5492.
[9] M. L. Lavaggi, M. Nieves, M. Cabrera, C. Olea-Azar, A. Lopez de Cerain, A.
Monge, H. Cerecetto, M. Gonzalez, Eur. J. Med. Chem. 2010, 45, 5362–
5369.
[10] C. Jovené, M. Jacquet, J. Marrot, F. Bourdreux, M. E. Kletsky, O. N. Burov,
A. M. Goncalves, R. Goumont, Eur. J. Org. Chem. 2014, 6451–6466.
[11] P. B. Gosh, B. Ternai, M. Whitehouse, J. Med. Chem. 1972, 15, 255–260.
[12] N. Okiyama, S. Uchiyama, K. Imai, T. Santa, Heterocycles 2002, 58, 165–
173.
[13] a) R. Goumont, M. Sebban, P. Sépulcri, J. Marrot, F. Terrier, Tetrahedron
2002, 58, 3249–3262; b) C. Jovené, M. Jacquet, E. Chugunova, S. Khar-
lamov, R. Goumont, Tetrahedron 2016, 72, 2057–2063.
[14] a) S. C. Waller, Y. A. He, G. R. Harlow, Y. Qun He, E. A. Mash, J. R. Halpert,
Chem. Res. Toxicol. 1999, 12, 690–699; b) A. A. Gakh, S. V. Romaniko, B. I.
Ugrak, A. A. Fainzilberg, Bull. Acad. Sci. USSR Div. Chem. Sci. (Engl. Transl.)
1991, 40, 1432–1436.
X-ray Structural Analysis: X-ray intensity data were collected with
a Bruker X8-APEX2 CCD area-detector diffractometer using Mo-Kα
radiation (λ = 0.71073 Å). Data reduction was accomplished using
SAINT V7.03. The substantial redundancy in data allowed a semiem-
pirical absorption correction (SADABS V2.10)[27] to be applied, on
the basis of multiple measurements of equivalent reflections. The
structure was solved by direct methods, developed by successive
difference Fourier syntheses, and refined by full-matrix least-squares
on all F2 data using SHELXTL V6.12.[28] Hydrogen atoms were in-
cluded in calculated positions and allowed to ride on their parent
atoms.
Crystal Structure Analysis: CCDC 1469138 (for 9) contains the sup-
plementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre.
Supporting Information (see footnote on the first page of this
article): Copies of 1H, 19F and 13C NMR and UV spectra of the key
intermediates together with the cif file for crystallographic structure
1.
[15] F. Terrier, in: Modern Nucleophilic Aromatic Substitution, Wiley-VCH, Wein-
heim, Germany, 2013.
[16] a) F. Terrier, R. Goumont, M. J. Pouet, J. C. Hallé, J. Chem. Soc. Perkin Trans.
2 1995, 1629–1637; b) M. Mokhtari, R. Goumont, J. C. Halle, F. Terrier,
ARKIVOC 2002, 11, 168–186.
[17] a) T. Kawakami, H. Suzuki, J. Chem. Soc. Perkin Trans. 1 2000, 1259–1264;
b) S. Sankararaman, W. A. Haney, J. K. Kochi, J. Am. Chem. Soc. 1987, 109,
7824–7838.
Acknowledgments
The authors are grateful for the support of this work by the
Centre National de la Recherche Scientifique (CNRS), French
Ministry of Research and for the financial support of the Russian
Scientific Foundation (grant number 14-50-00014).
[18] a) L. L. Kuznetsov, B. V. Gidaspov, Russ. J. Org. Chem. 1974, 10, 541–546;
b) L. L. Kuznetsov, B. V. Gidaspov, Russ. J. Org. Chem. 1982, 18, 595–601.
[19] K. Barral, A. D. Moorhouse, J. E. Moses, Org. Lett. 2007, 9, 1809–1811.
[20] G. S. Hiers, F. D. Hager, Org. Synth., Coll. Vol. 1 1941, 58.
[21] a) S. Kurbatov, R. Goumont, S. Lakhdar, J. Marrot, F. Terrier, Tetrahedron
2005, 61, 8167–8176; b) E. A. Chugunova, A. D. Voloshina, R. E. Mukha-
matdinova, I. V. Serkov, A. N. Proshin, E. M. Gibadullina, A. R. Burilov, N. V.
Kulik, V. V. Zobov, D. B. Krivolapov, A. B. Dobrynin, R. Goumont, Lett. Drug
Des. Discovery 2014, 11, 502–512.
Keywords: Synthetic methods · Tautomerism · Fluorine ·
Phenols · Azides
[1] P. Drost, Justus Liebigs Ann. Chem. 1899, 307, 49–69.
[2] a) C. Jovene, E. Chugunova, R. Goumont, Mini-Rev. Med. Chem. 2013, 13,
1089–1136; b) E. Chugunova, M. Sazykina, E. Gibadullina, A. Burilov, I.
Sazykin, V. Chistyakov, R. Timasheva, D. Krivolapov, R. Goumont, Lett.
Drug Des. Discovery 2013, 10, 145–154.
[22] C. K. Prout, O. J. R. Hadder, D. Viterbo, Acta Crystallogr., Sect. B 1972, 28,
1523–1526.
[23] P. Sepulcri, J. C. Halle, R. Goumont, D. Riou, F. Terrier, J. Org. Chem. 1999,
64, 9254–9257.
[3] a) E. Chugunova, C. Boga, I. Sazykin, S. Cino, G. Micheletti, A. Mazzanti,
M. Sazykina, A. Burilov, L. Khmelevtsova, N. Kostina, Tetrahedron 2015,
93, 349–359; b) W. Duan, J. Hou, X. Chu, X. Li, J. Zhang, J. Li, W. Xu, Y.
Zhang, Bioorg. Med. Chem. 2015, 23, 4481–4488.
[4] a) J. Zhao, Y. Li, A. Hunt, J. Zhang, H. Yao, Z. Li, J. Zhang, F. Huang, H.
Ade, H. Yan, Adv. Mater. 2015, 27, 1–6; b) P. G. Morozov, S. V. Kurbatov,
Y. P. Semenyuk, O. N. Burov, M. E. Kletskii, N. S. Fedik, K. F. Suzdalev, Chem.
Heterocycl. Compd. 2015, 51, 903–912; c) P. M. Njogu, E. M. Guantai, E.
Pavadai, K. Chibale, Infect. Dis. 2016, 2, 8–31.
[24] A. J. Boulton, P. B. Gosh, Adv. Heterocycl. Chem. 1969, 10, 1–41.
[25] A. Gasco, A. J. Boulton, Adv. Heterocycl. Chem. 1981, 29, 251–340.
[26] P. B. Ghosh, M. W. Whitehouse, J. Med. Chem. 1968, 11, 305–312.
[27] G. M. Sheldrick, SHELXTL, version 5.1, Bruker AXS, Inc., Madison, WI, USA,
1999.
[28] APEX2, version 1.0-8, Bruker AXS, Madison, WI, USA, 2003.
[5] a) M. Sebban, C. Jovene, P. Sepulcri, D. Vichard, F. Terrier, R. Goumont, in:
Magnetic Resonance Spectroscopy (Ed.: Donghyun Kim), INTECH Publisher,
Received: June 15, 2016
Published Online: ■
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Benzofuroxans
4-Fluoro-6-nitrobenzofuroxan and 6-
fluoro-4-nitrobenzofuroxan have been
prepared, for the first time, from fluo-
rophenols and fluoroanisoles, two
families of cheap and readily available
chemicals. Due to the presence of
methoxy and hydroxy groups, the key
nitration step is easily achieved and di-
nitro compounds are obtained in good
yields; these can then be used to pre-
pare the phenyl azide intermediate.
C. Jovené, J. Marrot, J.-P. Jasmin,
E. Chugunova, R. Goumont* ........ 1–10
A Synthetic Pathway to Substituted
Benzofuroxans through the Inter-
mediacy of Sulfonates: The Case Ex-
ample of Fluoro-Nitrobenzofurox-
ans
DOI: 10.1002/ejoc.201600657
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