5(6)-Fluoro-6(5)-R-benzofuroxans: Synthesis and NMR 1H, 13C and 19F studies

Article abstract of DOI:10.1016/j.jfluchem.2003.11.011

5(6)-Fluoro-6(5)-substituted benzofuroxans were obtained by the reactions of 5,6-difluorobenzofuroxan with a number of nucleophiles, such as alkylamines, cycloalkylimines, sodium azide and sodium alkoxides. The features of tautomerism in the series of asymmetrical 5(6)-fluorobenzofuroxans in acetone solutions have been studied by ¹H, ¹³C and ¹⁹F NMR.

Full text of DOI:10.1016/j.jfluchem.2003.11.011

Journal of Fluorine Chemistry 125 (2004) 421–428
5(6)-Fluoro-6(5)-R-benzofuroxans: synthesis and NMR
13
1H, C and F studies
19
S.K. Kotovskayaa, S.A. Romanovaa, V.N. Charushina,b,*, M.I. Kodessb, O.N. Chupakhinb
aOrganic Chemistry Department, Urals State Technical University, Mira Street 19, Ekaterinburg 620002, Russia
bI.Ya. Postovsky Institute of Organic Synthesis, S. Kovalevskaya Street 20, Ekaterinburg 620219, Russia
Received 9 August 2003; received in revised form 11 November 2003; accepted 13 November 2003
Abstract
5(6)-Fluoro-6(5)-substituted benzofuroxans were obtained by the reactions of 5,6-difluorobenzofuroxan with a number of nucleophiles,
such as alkylamines, cycloalkylimines, sodium azide and sodium alkoxides. The features of tautomerism in the series of asymmetrical
1
5(6)-fluorobenzofuroxans in acetone solutions have been studied by H, 13C and 19F NMR.
# 2003 Elsevier B.V. All rights reserved.
Keywords: 5,6-Difluorobenzofuroxan; Nucleophilic substitution; 1H, 13C and 19F NMR; X-ray crystallography
1. Introduction
benzofurazans regarded as the model compounds for study-
ing tautomerism will be discussed.
Furoxans comprise a well-known class of heterocyclic
compounds which proved to exhibit a variety of biological
activities [1]. The ability of benzofuroxans to be involved in
the synthesis of DNA and peptides has stimulated a search
aimed at the development of anticancer compounds [2].
Furoxans are also of interest as cardiovascular agents (like
nitroglicerol) due to their ability to generate nitrous oxide
and to effect the level of guanilate-cyclase [3].
Fluorinated benzofuroxans are of special interest, since
fluorine atoms are known to increase the ability of organic
compounds to penetrate thorough lipid membranes, thus
making these molecules more potent as biologically active
compounds [4,5]. The ability of fluorine atoms in aromatics
to be displaced by nucleophiles has been well documented in
the literature [4–6]. We have recently described the features
of nucleophilic displacement reactions in 6,7-difluoroqui-
noxalines [7,8]. In this paper we wish to present the data of
our studies on the synthesis and tautomerism of asymme-
trical 5(6)-fluoro-6(5)-substituted benzofuroxans derived
from the reaction of 5,6-difluorobenzofuroxan with nucleo-
philes, such as cycloalkylimines, alkylamines, sodium azide
and sodium alkoxides. Also the synthesis and 1H, 13C
and 19F NMR spectral parameters of 5-fluoro-6-substituted
2. Results and discussion
The main synthetic routes to benzofuroxans are known to
be oxidation of ortho-nitroanilines, oxidation of ortho-qui-
none dioximes or decomposition of ortho-nitroaryl-azides
[9a–c]. It has been established that benzofuroxans rearrange
rapidly in solutions between two asymmetrical structures
through opening of the oxadiazole ring and intermediacy of
the dinitroso compound [9a–f].
5,6-Difluorobenzofuroxan (1) was obtained in good yield
by decomposition of 4,5-difluoro-2-nitrophenylazide [10].
Compound 1 was shown to exist in acetone solutions as a
mixture of two degenerated forms 1a and 1b, inter-convert-
ing to each other rapidly through intermediacy of the
dinitroso compound (Scheme 1).
The reaction of 5,6-difluorobenzofuroxan (1) with mor-
pholine in ethanol was found to proceed smoothly at room
temperature (20–25 8C) for 2–3 h to give the nucleophilic
substitution product 2 in 75–80% yield. The intensive peak
of the molecular ion (M)þ, m/z (related intensity): 239
(1 0 0) in the mass-spectra of 2a corresponds to the structure
of the mono-substitution product. In the crystalline state
compound 2a was found to exist as 5-fluoro-6-morpholino-
benzofuroxan (2A) (Fig. 1). The X-ray crystallography
analysis of compound 2a has revealed that the benzofuroxan
* Corresponding author. Fax: þ7-3432-74-5191/5440.
E-mail addresses: charushin@prm.uran.ru, charushin@htf.ustu.ru
(V.N. Charushin).
0022-1139/$ – see front matter # 2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2003.11.011

422
S.K. Kotovskaya et al. / Journal of Fluorine Chemistry 125 (2004) 421–428
Fig. 1. A view of 5-fluoro-6-morpholinobenzofuroxan 2 (X-ray analysis data).
furoxan (2B), inter-converting to each other are present in
the mixture (Scheme 2).
1
In the H NMR spectra of 2a recorded at À20 8C two
doublet of doublets corresponding to H-4 and H-7 protons of
isomers 2A and 2B with characteristic values of coupling
3
4
constants JH;F and JH;F were observed.
The following coupling constants were measured for 2A:
Scheme 1.
4
3JðH4-F5Þ ¼ 12:2 Hz, and JðH7-F5Þ ¼ 7:7 Hz, while 2B
skeleton is planar, while the morpholine fragment is in a
chair conformation with N-3 and O-3 atoms deviating from
an average plane of the morpholine ring. The N-3–C-3 bond
has a pseudo-equatorial orientation relative to the morpho-
line ring. The main geometrical parameters of 2A are very
close to those found for unsubstituted benzofuroxans [11]
and appear to be common for nitrogen-containing hetero-
cyclic systems [12].1
In the 1H NMR spectrum of 2a in (CD3)2CO recorded at
20 8C the signals of H-4 and H-7 proved to be rather
broadened (Fig. 2). We suggest that the compound 2a exists
as a mixture of two inter-converting forms 2A and 2B. In
order to obtain the isomeric form 2B we have performed the
synthesis of 6-fluoro-5-morpholinobenzofuroxan (2B) by
oxidationof the correspondingortho-nitroaniline (Scheme 2).
The TLC data and 1H and 19F NMR spectra of compound
2B were identical to those for sample 2a obtained from 5,6-
difluorobenzofuroxan (1), thus showing that compound 2B,
in solution, undergoes the molecular rearrangement into 2A.
The 1H, 13C, and 19F NMR spectra, recorded in (CD3)2CO
at the range of temperatures from À40 to þ30 8C have
shown that two isomeric compounds, 5-fluoro-6-morpholi-
nobenzofuroxan (2A) and 6-fluoro-5-morpholinobenzo-
exhibited 3JðH7-F6Þ ¼ 11:0 Hz, and 4JðH4-F6Þ ¼ 7:6 Hz
(Table 1). The ratio of isomers 2A:2B was (70:30). Increas-
ing temperature up to 0 8C resulted in broadening of H-4 and
H-7 signals; coalescence of these signals was observed at
20–25 8C (Fig. 2).
The 19F NMR spectra of 2a, recorded at the temperature
range À20 to þ20 8C gave a similar picture (Fig. 3). The
3
4
coupling constants JðF5-H4Þ ¼ 12:2 Hz and JðF5-H7Þ ¼
7:7 Hz were measured for the isomer 2A, while 2B gave
4
3JðF6-H7Þ ¼ 11:0 Hz and JðF6-H4Þ ¼ 7:6 Hz. The same
ratio of isomers 2A:2B (70: 30) was found.
The 1H and 19F NMR data, however, are not sufficient to
conclude which isomer, 2A or 2B is dominant. Evidence in
favor of the major isomer 2A and unequivocal assignments
of signals for isomers 2A and 2B were made on the basis of
13C NMR spectra recorded at low temperatures.
Due to a slow exchange process at À20 8C two sets of
characteristic signals corresponding to the ring junction
carbons C-3a and C-7a of isomers 2A and 2B were observed
in the 13C NMR spectra of 2a. The doublet at d ¼ 151:0 ppm
was assigned to the quaternary carbon C-3a of 2A due to the
3
coupling constant JðC3a-F5Þ ¼ 14:1 Hz, while the reso-
nance signal of C-7a was observed as a singlet at
d ¼ 113:3 ppm. In the case of isomer 2B the doublet of
C-7a at d ¼ 111:6 ppm (3JðC7a-F6Þ ¼ 13:5 Hz) and the
singlet of C-3a at d ¼ 152:1 ppm were observed in the
spectra (Table 1).
1 Crystallographic data (excluding structure factors) for structure 2 in
this paper have been deposited with the Cambridge Crystallographic
Data Center as supplementary publication nos. CCDC Copies of the
data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 IEZ, UK (fax: þ44-1223-336033 or e-
mail: deposit@ccdc.cam.ac.uk).
According to all NMR measurements (1H, 13C and 19F
spectra) it is clear that an exchanging system of two isomeric

S.K. Kotovskaya et al. / Journal of Fluorine Chemistry 125 (2004) 421–428
423
Fig. 2. 1H NMR spectra of 2 in (CD3)2CO recorded at À4 8C (a); À20 8C (b); 0 8C (c) and 20 8C (d).
compounds with unequal populations is present. From che-
mical shifts differences for H-4 and H-7 protons and popu-
lation difference of 2A and 2B we have obtained free
activation energies using the approximation method sug-
˜
gested by M. Oki [13] and Shanan-Atidi and Bar-Eli [14].
DGꢀ was estimated as 62.2 kJ molÀ1 for transfer from 2A to
2B, and 59.1 kJ molÀ1 for the reverse process.
Pyrrolidine, methylpiperazine and thiomorpholine were
found to react with 1 in ethanol at 20 8C in a similar manner,
affording amino compounds 2a–d (Scheme 3). Also the
reaction of 1 with methylamine or ethylamine in ethanol
at room temperature resulted in the formation of the
Scheme 2.

424
S.K. Kotovskaya et al. / Journal of Fluorine Chemistry 125 (2004) 421–428
Table 1
13C, 19F and 1H NMR spectral data for compound 2a (CD3COCD3, T ¼ À20 8C)
2A
2B
Carbon
C5
d(13C) (ppm)
nJC-F (Hz)
d(1H or 19F) (ppm)
Carbon
C6
d(13C) (ppm)
nJC-F (Hz)
d(1H or 19F) (ppm)
161.43
262.7
107.42 m (12.2, 7.7)
158.78
262.7
110.65 m (11.0,
7.6)
–
C3a
C6
151.01
145.47
113.27
102.29
96.55
14.1
16.2
–
–
C7a
C5
111.60
148.23
152.12
97.77
13.5
15.5
–
–
–
C7a
C4
–
C3a
C7
–
28.3
4.0
–
7.60 d (12.2)
6.68 d (7.7)
3.83 m
31.0
3.4
–
7.37 d (11.0)
7.03 d (7.6)
3.83 m
C7
C4
101.48
66.383
51.47
OCH2
NCH2
66.80
OCH2
NCH2
51.54
4.7
3.22 m
4.7
3.22 m
Fig. 3. 19F NMR spectra of 2 in (CD3)2CO recorded at À20 8C (a) and 0 8C (b).
corresponding amino compounds 3a–b in good yields.
Evidence for substitution of one of two fluorine atoms in
1 by action of amines is provided by elemental analyses and
mass-spectrometry data for compounds 2b–d, 3a–b (see
Section 3). In the 1H NMR spectra of 2b–d, 3a–b
((CD3)2SO) recorded at room temperature, the signals of
H-4 and H-7 protons are broadened due to the equilibrium.
The reaction of 5,6-difluorobenzofuroxan (1) with sodium
azide in ethanol affords mono-azido derivative 4 as minor
product (yields 20–25%), while the major product is 5,6-
diazidobenzofuroxan (5) which is formed even at the ratio of
reagents 1:1. The composition of mono- and diazido sub-
stituted benzofuroxanes 4, 5 is in agreement with their mass-
spectra which have intensive molecular ions peaks [M]þ, m/z
(relative intensity): 218 (92) and 195 (43), respectively. In
7.50 ppm, and in case of 4 two broadened singlets centered
at 7.57 and 7.64 ppm are observed due to the established
inter-conversions of the oxadiazole ring.
The reaction of 5,6-difluorobenzofuroxan (1) with alk-
oxides results in mono- or dialkoxy derivatives with the ratio
being dependent on quantity of sodium taken for preparing
alkoxides (Scheme 5, see Section 3). The reactions of 1 with
sodium azide and sodium alkoxides indicate that the ability
of both fluorine atoms at C-6 and C-5 positions to be
displaced with nucleophiles is quite good.
In order to estimate relative reactivity of fluorine atoms to
undergo nucleophilic substitution reactions we have studied
the behavior of 5(6)-fluoro-6(5)-methoxybenzofuroxan (6a)
under the action of morpholine and behavior of 5(6)-fluoro-
6(5)-cycloalkyliminobenzofuroxans (2a–b) under the action
of methanol (Scheme 4). Compound 6a was found to react
with morpholine only at an elevated temperature to give
1
the H NMR spectrum of 5 in (CD3)2SO recorded at room
temperature H-4 and H-7 protons give rise to a singlet at

S.K. Kotovskaya et al. / Journal of Fluorine Chemistry 125 (2004) 421–428
425
Scheme 3.
structures through ring opening and closure of the oxadia-
zole ring in solutions. In order to confirm that N-deoxygena-
tion of furoxans will destroy these inter-conversions,
5,6-difluorobenzofurazan (11) and 5-fluoro-6-substituted
benzofurazans (12a–d) have been obtained from the
corresponding furoxans 1, 2a, 2c–d, 6a on treatment with
triphenylphospine, as evidenced by elemental analyses,
mass-spectrometry and 13C and 1H NMR data (see
Section 3).
Scheme 4.
1
5(6)-morpholino-6(5)-methoxybenzofuroxan (9a) in 80%
yield after 2 h of reflux in ethanol. The same product 9a
was obtained by reaction of compound 2a with methanol for
1.5 h (Scheme 5).
The data obtained show that fluorinated benzofuroxans
are easily rearranged between two asymmetrical N-oxide
The H NMR spectra of compounds 12a–d in (CD3)2SO
recorded at room temperature proved to bevery sharp and two
doublets corresponding to H-4 and H-7 protons with char-
3
4
acteristic values of coupling constants JH;F and JH;F were
observed. In particular, for compound 12a the following
3
coupling constants were measured: JðH4-F5Þ ¼ 12:0 Hz,
and 4JðH7-F5Þ ¼ 7:8 Hz.
3. Experimental
The 1H NMR spectra were recorded in (CD3)2SO using a
Bruker WM-250 (250 MHz) spectrometer. The 13C NMR
spectra and low temperature 13C, 1H and 19F NMR spectra in
(CD3)2CO were obtained on a Bruker DRX-400 spectro-
meter (100 MHz for 13C nuclei, and 400 MHz for protons
and 376 MHz—for 19F nuclei). All spectral data are reported
Scheme 5.

426
S.K. Kotovskaya et al. / Journal of Fluorine Chemistry 125 (2004) 421–428
Table 2
1H NMR spectral data for 5(6)-R-6(5)-R1-substituted benzofuroxans in [(CD3)2SO] (room temperature)
Compound
R5(6), R16(5)
Chemical shifts (d) (ppm)
H-4, H-7
R5(6), R16(5)
2a
2b
2c
2d
3a
F, morpholino
6.74, 7.45 (2H, br.s)
6.01, 7.34 (2H, br.s)
6.69, 7.42 (2H, br.s)
6.72, 7.44 (2H, br.s)
5.77, 6.13, 7.18, 7.40
(0.6:0.4:0.4:0.6, 2H, br.s)
5.82, 6.18, 7.15, 7.38
(1.0:0.7:0.7:1.0, 2H, br.s)
7.57, 7.64 (2H, br.s)
7.50 (2H, s)
3.08 [4H, m, N(CH2)2], 3.75 [4H, m, (CH2)2O]
2.04 [4H, m, N(CH2)2], 3.05 [4H, m, (CH2)2]
F, pyrrolidino
F, 4-methylpiperazin-1-yl
F, thiomorpholino
F, Methylamino
2.31 (3H, s, NCH3), 2.49 [4H, m, N(CH2)2], 3.17 [4H, m, N(CH2)2]
2.78 [4H, m, N(CH2)2], 3.43 [4H, m, (CH2)2S]
2.81, 2.83 (3H, br.s, CH3), 7.05 (1H, br.s, NH)
3b
F, ethylamino
1.22 (3H, br.t, CH3), 3.26 (2H, br.q, CH2), 6.79 (1H, br.s, NH)
4
F, azido
Azido, azido
F, methoxy
–
5
–
6a
6b
6c
(7a)
7.07, 7.75 (2H, br.s)
7.00, 7.55 (2H, br.s)
7.00, 7.67 (2H, br.s)
6.91, 7.63 (2H, br.s)
3.99 (3H, br.s, OCH3)
F, ethoxy
1.46 (3H, br.t, CH3), 4.23 (2H, br.q, CH2)
1.76 (4H, br.m, 2CH2), 3.84 (2H, br.m, CH2), 4.23 (3H, br.m, OCH2)
0.92, 0.96, 0.99 (9H, 3s, 3CH3), 1.83 (6H, m, 3CH2), 2.07 (1H, br.s,
CH), 4.56 (1H, br.s, OCH)
F, (2-tetrahydrofuryl)methoxy
F, bornyloxy
7b
F, iso-bornyloxy
6.94, 7.82 (2H, br.s)
0.79, 0.80, 0.82 (9H, 3s, 3CH3), 1.86 (6H, m, 3CH2), 2.12 (1H, br.s,
CH), 4.61 (1H, br.s, OCH)
3.95 (6H, s, 2CH3)
8a
8b
8c
Methoxy, methoxy
Ethoxy, ethoxy
6.83 (2H, s)
6.75 (2H, s)
6.80 (2H, br.s)
1.43 (6H, t, 2CH3), 4.16 (4H, q, 2CH2)
3.79 (4H, m, 2OCH2), 4.12 (4H, m, 2CH2), 4.62 (2H, t, 2OH)
2-Hydroxyethoxy,
2-hydroxyethoxy
9a
9b
Morpholino, methoxy
Pyrrolidino, methoxy
6.47, 6.94 (2H, br.s)
5.87, 6.81 (2H, br.s)
3.11 [4H, m, N(CH2)2], 3.76 [4H, m, (CH2)2O], 3.94 (3H, br.s, OCH3)
1.92 (4H, m, CH2), 3.52 (4H, m, NCH2), 3.95 (3H, br.s, OCH3)
in ppm in the d-scale relative to internal TMS (1H and 13C
NMR) or hexafluorobenzene (19F NMR), respectively. 19F
chemical shifts were measured from internal C6F6 and
converted to the d-scale with CFCl3 as reference, using
conversion relation dðCFCl3Þ ¼ dðC6F6Þ À 162:9 ppm.
The X-ray structure 2a was recorded using a Bruker AXS
SMART 1000 with CCD detector.
3.3. Oxidation of 3-fluoro-4-morpholino-5-nitroaniline
by KOBr
Solution of KOBr 10–15% 75 ml was added to 3-fluoro-4-
mopholino-5-nitroaniline (0.48 g, 0.0020 mol) in 15 ml
HCON(CH3)2 at 10–15 8C and stirred at room temperature
for 5–7 min. The reaction mixture was cooled and the
precipitate obtained was filtered to give 5(6)-fluoro-6(5)-
morpholinobenzofuroxan (2a).
Spectroscopy analytical and other data are given in
Tables 1–3.
3.1. Preparation of 5,6-difluorobenzofuroxan (1)
3.4. Reaction of 5,6-difluorobenzofuroxan (1) with
alkylamines
2-Nitro-4,5-difluorophenylazide [13] (7.8 g; 0.04 mol)
was refluxed for 1 h in acetic acid, cooled and poured
into an ice-water (300 cm3). The precipitate obtained was
filtered off, dried in air and recrystallized from hexane to
give 5,6-difluorobenzofuroxan (1). H NMR spectral data
[(CD3)2SO]: d 7.79 (br.t, H-4, H-7).
5,6-Difluorobenzofuroxan (1) (0.17 g; 0.0010 mol) was
added to a 7–10% solution of alkylamine in ethanol (3 ml)
and stirred at room temperature for 1–3 h. The precipitate
obtained was filtered off and recrystallized from ethanol–
water to give 5(6)-fluoro-6(5)-alkylaminobenzofuroxan
(3a–b).
1
3.2. Reaction of 5,6-difluorobenzofuroxan (1) with
cycloalkylimines
3.5. Reaction of 5,6-difluorobenzofuroxan (1) with
sodium azide
Cycloalkylimine (0.0012 mol) was slowly added to a
solution of 5,6-difluorobenzofuroxan (1) (0.17 g; 0.0010
mol) in ethanol (3 ml) at 20–25 8C. The reaction mixture
was stirred at room temperature for 3–4 h. The precipi-
tate obtained was filtered off and recrystallized from etha-
nol to give 5(6)-fluoro-6(5)-cycloalkyliminobenzofuroxan
(2a–d).
A solution of sodium azide (0.20 g; 0.0020 mol) in water
(2 ml) was added to a solution of 5,6-difluorobenzofuroxan
(1) (0.17 g: 0.0010 mol) in ethanol (10 ml). The reaction
mixture was stirred at room temperature for 72 h. The
precipitate obtained was filtered off, dried and recrystallized
from ethanol to give 5,6-diazobenzofuroxan (5). The mother

S.K. Kotovskaya et al. / Journal of Fluorine Chemistry 125 (2004) 421–428
427
Table 3
Analytical and mass-spectral data for synthesis compounds 1–12
Compound Melting
Yield Elemental analysis data found
(calculated) (%)
Empirical
formula
Mass-spectral data EIMS 70 eV, m/z (relative intensity)
point (8C) (%)
C
H
N
1
59–60
76
42.0 (41.9) 1.3 (1.2) 16.5 (16.3) C6H2F2N2O2
172 [M]þ (1 0 0), 156 [M À O]þ (6), 142 [M À O-N]þ (3),
112 [M À O-N-NO]þ (65)
2a
2b
2c
2d
3a
3b
4
121–123 78
129–130 56
50.2 (50.3) 4.2 (4.2) 17.6 (17.7) C10H10FN3O3
223 [M]þ (1 0 0), 207 [M À O]þ (54), 175 [M À 48]þ (67)
223 [M]þ (1 0 0), 207 [M À O]þ (54), 175 [M À 48]þ (67)
53.8 (53.6) 4.5 (4.3) 18.8 (18.5) C10H10FN3O2
52.4 (52.5) 5.2 (5.3) 22.2 (22.5) C11H13FN4O2
84–86
54
252 [M]þ (1 0 0), 235 [M À CH3]þ (15), 210 [M À 42]þ (13)
134–136 67
103–104 83
112–114 93
99–101 28
113–115 57
47.1 (47.3) 4.0 (4.0) 16.5 (16.7) C10H10FN3O2S 255 [M]þ (1 0 0), 239 [M À O]þ (13), 195 [M À 60]þ (20)
45.9 (45.7) 3.3 (3.2) 22.9 (23.1) C7H6FN3O2
48.7 (48.9) 4.1 (4.1) 21.3 (21.2) C8H8FN3O2
36.9 (37.3) 1.0 (0.9) 35.9 (35.8) C6H2FN5O2
33.0 (33.4) 0.9 (0.8) 51.4 (51.7) C6H2N8O2
45.8 (45.9) 2.7 (2.8) 15.2 (15.4) C7H5FN2O3
48.5 (48.3) 3.6 (3.4) 14.1 (14.4) C8H7FN2O3
52.0 (52.2) 4.4 (4.5) 11.0 (11.1) C11H11FN2O4
183 [M]þ (1 0 0), 167 [M À O]þ (5), 123 [M À 60]þ (93)
197 [M]þ (93), 181 [M À O]þ (7), 166 [M À 31]þ (8)
195 [M]þ (43), 167 [M À N2]þ (22), 153 [M À 42]þ (2)
218 [M]þ (92), 190 [M À N2]þ (12), 153 [M À 65]þ (87)
184 [M]þ (67), 169 [M À 15]þ (24), 153 [M À 31]þ (48)
198 [M]þ (56), 170 [M À 28]þ (42), 154 [M À 44]þ (29)
5
6a
6b
6c
7a
7b
8a
8b
8c
9a
9b
96–97
64–66
83
75
134–135 84
98–99 36
254 [M]þ(23), 212 [M À 42]þ (3), 170 [M À 84]þ (4)
þ
þ
62.7 (63.0) 6.3 (6.3)
62.7 (62.7) 6.3 (5.9)
9.2 (9.4)
9.2 (9.2)
C16H19FN2O3
16H19FN2O3
306 [M]þ (3), 137 [M À C10H17
]
]
(68), 121 [M À 153]þ (2)
(71), 121 [M À 153]þ (5)
110–112 29
191–193 78
205–207 82
113–115 56
191–193 80
160–162 77
143–144 37
157–159 62
161–163 58
156–157 75
137–138 54
C
306 [M]þ (4), 137 [M À C10H17
49.0 (48.7) 4.1 (4.5) 14.3 (14.7) C8H8N2O4
196 [M]þ (93), 136 [M À O-N-O-N]þ (1 0 0), 121 [M À 75]þ (21)
224 [M]þ (99), 196 [M À 28]þ (15), 164 [M À 60]þ (43)
256 [M]þ (57), 212 [M À (CH2)2OH]þ (34), 168 [M À 90]þ (78)
251 [M]þ (1 0 0), 235 [M À O]þ (9), 191 [M À 60]þ (48)
235 [M]þ (1 0 0), 219 [M À O]þ (15), 175 [M À O-44]þ (86)
156 [M]þ (1 0 0), 135 [M À 21]þ (32), 108 [M À 48]þ (14)
223 [M]þ (1 0 0), 208 [M À 15]þ (5), 165 [M À 58]þ (63)
236 [M]þ (1 0 0), 194 [M À 42]þ (19), 165 [M À 71]þ (12)
53.6 (53.6) 5.4 (5.0) 12.5 (12.9)
46.9 (46.5) 4.7 (4.5) 10.9 (11.0)
C
C
10H12N2O4
10H12N2O6
52.6 (52.4) 5.2 (5.2) 16.7 (16.4) C11H13N3O4
56.2 (56.3) 5.6 (5.8) 17.9 (18.0) 11H13N3O3
46.2 (46.0) 1.3 (1.1) 18.0 (17.8) C6H2F2N2
53.8 (53.6) 4.5 (4.4) 18.8 (19.0) 10H10FN3O2
55.9 (55.7) 5.5 (5.5) 23.7 (23.8) C11H13FN4O
C
11
12a
12b
12c
12d
C
50.2 (50.6) 4.2 (4.0) 17.6 (17.9)
C
10H10FN3OS 239 [M]þ (1 0 0), 224 [M À 15]þ (8), 192 [M À 47]þ (23)
50.0 (49.8) 3.0 (3.1) 16.7 (16.6) C7H5FN2O2
168 [M]þ (1 0 0), 144 [M À 24]þ (4), 137 [M À 31]þ (18)
liquor was evaporated to dryness, the residue was recrys-
tallized from ethanol to give 6-azido-5-fluorobenzofuroxan
(4).
3.8. Reaction of 5,6-difluorobenzofuroxan (1) with
alcohols in the presence of two equivalents of sodium
5,6-Difluorobenzofuroxan (1) (0.17 g; 0.0010 mol) was
added to a solution of sodium (0.05 g; 0.0020 mol) in
alcohol (3–4 ml) and the reaction mixture was stirred at
room temperature for 1–10 h. The precipitate obtained was
filtered off, recrystallized from methanol to give 5,6-dia-
lkoxybenzofuroxan (8a–c).
3.6. Reaction of 5,6-difluorobenzofuroxan (1) with liquid
alcohols in the presence of one equivalent of sodium
5,6-Difluorobenzofuroxan (1) (0.17 g; 0.0010 mol) was
added to a solution of sodium (0.0010 mol) in alcohol (3 ml)
and the reaction mixture was stirred at room temperature for
5–15 h. The precipitate obtained was filtered off and recrys-
tallized from ethanol to give 5(6)-fluoro-6(5)-alkoxybenzo-
furoxan (6a–c).
3.9. Reaction of 5(6)-fluoro-6(5)-methoxybenzofuroxan
(3a) with cycloalkylimines
Cycloalkylimine (0.0015 mol) was added to a solution of
5(6)-fluoro-6(5)-methoxybenzofuroxan (3a) (0.18 g; 0.0010
mol) in methanol (3 ml). The reaction mixture was refluxed
for 1–2 h and cooled. The precipitate obtained was filtered
off and recrystallized from methanol to give 6(5)-methoxy-
5(6)-cycloalkyliminobenzofuroxan (9a–b).
3.7. Reaction of 5,6-difluorobenzofuroxan (1) with
solid alcohols in the presence of one equivalent
of sodium
Alcohol (0.0012 mol) was added to a solution of sodium
hydroxide (0.04 g; 0.0010 mol) in Me2SO (3 ml). After
addition of 5,6-difluorobenzofuroxan (1) (0.17 g; 0.0010
mol), the reaction mixture was stirred at room temperature
for 4–8 h, and then poured into ice-water (30 ml). The
precipitate obtained was filtered off, dried and recrystallized
from water–ethanol to give 5(6)-fluoro-6(5)-alkoxybenzo-
furoxan (7a–b).
3.10. Reaction of 5(6)-fluoro-6(5)-
morpholinobenzofuroxan (2a) with methanol in the
presence of one equivalent of sodium
5(6)-Fluoro-6(5)-morpholinobenzofuroxan (2a) (0.18 g;
0.0010 mol) was added to a solution of sodium (0.02 g;

428
S.K. Kotovskaya et al. / Journal of Fluorine Chemistry 125 (2004) 421–428
1
0.0010 mol) in methanol (3 ml). The reaction mixture
was refluxed for 1.5 h and cooled. The precipitate obtained
was filtered off and recrystallized from methanol to
give 5-methoxy-6-morpholinobenzofuroxan (10) (0.24 g,
67%). Melting point, H NMR spectra and mass-spectro-
metry data of 10 proved to be identical with those of
compound 9a.
12c: H NMR spectral data [(CD3)2SO]: d 2.79 [4H, m,
(CH2)2N], 3.45 [4H, m, (CH2)2O], 7.23 (1H, d, H-7,
4JH;F ¼ 8:0 Hz), 7.66 (1H, d, H-4, JH;F ¼ 12:0 Hz).
3
1
12d: H NMR spectral data [(CD3)2SO]: d 4.02 (3H, s,
OCH3), 7.40 (1H, d, H-7, 4JH;F ¼ 8:0 Hz), 7.75 (1H, d, H-4,
1
3JH;F ¼ 13:0 Hz).
Acknowledgements
3.11. Reduction of 5,6-difluorobenzofuroxan with
triphenylphosphine
Research described in this publication was supported
partly by the US Civilian Research and Development Foun-
dation (award no. REC-005), the Russian Foundation for
Basic Research (grant nos. 03-03-32254, 00-03-40139).
5,6-Difluorobenzofuroxan (1) (0.17 g, 0.0010 mol) was
added to a solution of triphenylphosphine (0.39 g; 0.0015
mol) in benzene (3 ml). The reaction mixture was refluxed for
1 h, cooled and evaporated to dryness. The precipitate
obtained was sublimed in vacuum (80 8C, 15 mm) to give
5,6-difluorobenzofurazan (11). 1H NMR spectral data
[(CD3)2SO]: d 8.14 (t, H-4, H-7, JH;F ¼ 8:2 Hz).
References
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3.12. Reduction of 5(6)-fluoro-6(5)-R-benzofuroxan with
triphenylphosphine
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5(6)-Fluoro-6(5)-R-benzofuroxan (2a, 2c, 2d, 6a)
(0.0010 mol) was added to a solution of triphenylphosphine
(0.39 g; 0.0015 mol) in benzene (3 ml). The reaction mix-
ture was refluxed for 3 h, cooled and evaporated to dryness.
The precipitate obtained was purified by column chromato-
graphy on silica gel using CH2Cl2 to give 5-fluoro-6-R-
benzofurazan (12a–d).
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12a: 13C NMR spectral data [(CD3)2SO]: d 51.78 (NCH2,
1
1
4JCF ¼ 4:7 Hz, JCH ¼ 137:2 Hz), 67.02 (OCH2, JCH
¼
[8] S.K. Kotovskaya, S.A. Romanova, V.N. Charushin, O.N. Chupakhin,
Zh. Organ. Khim (Russ. J. Org. Chem.) 38 (2002) 1089–1095.
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(1981) 159;
3
1
143:8 Hz), 99.70 (C-7, JCF ¼ 4:0 Hz, JCH ¼ 170:4 Hz,
4JCH ¼ 1:5 Hz), 100.26 (C-4, JCF ¼ 28:0 Hz, JCH
¼
2
1
4
3
173:9 Hz, JCH ¼ 1:4 Hz), 147.31 (C-3a, JCF ¼ 14:8 Hz,
3JC;H ¼ 6:1 Hz, JCH ¼ 1:3 Hz), 147.72 (C-6, JCF
¼
2
2
3
3
15:8 Hz, JCH ¼ 5:9 Hz, JCH ¼ 1:0 Hz), 148.69 (C-7a,
(d) A.R. Katritzky, M.F. Gordeev, Heterocycles 35 (1993) 483;
(e) T. Takabatake, T. Miyazawa, M. Hasegawa, J. Heterocyclic
Chem. 33 (1996) 1057;
3
1
4JCF ¼ 0:7 Hz, JCH ¼ 5:4 Hz), 161.08 (C-5a, JCF
¼
262:4 Hz, 3JCH ¼ 9:8 Hz, 2JCH ¼ 6:4 Hz). 1H NMR spectral
data [(CD3)2SO]: d 3.25 [4H, m, (CH2)2N)], 3.84 [4H, m,
(CH2)2O], 7.19 (1H, d, H-7, 4JH;F ¼ 7:8 Hz), 7.64 (1H, d, H-
(f) T. Takabatake, A. Takei, T. Miyazawa, Heterocycles 35 (2001)
2387–2395.
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Perkin Trans II (1987) 1–19.
4, JH;F ¼ 12:0 Hz). 19F NMR spectral data [(CD3)2SO]:
3
3
4
108.24 (dd, JH;F ¼ 12:0 Hz, JH;F ¼ 7:8 Hz).
1
12b: H NMR spectral data [(CD3)2SO]: d 2.27 (3H, s,
CH3), 2.51 [4H, m, (CH2)2N], 3.19 [4H, m, (CH2)2N],
˜
[13] M. Oki, Application of Dynamic NMR Spectroscopy to Organic
4
7.15 (1H, d, H-7, JH;F ¼ 7:0 Hz), 7.69 (1H, d, H-4,
Chemistry, VCH Publishers, 1985.
[14] H. Shanan-Atidi, K.H. Bar-Eli, J. Phys. Chem. 74 (1970) 961.
3JH;F ¼ 12:0 Hz).