Unsymmetrically substituted furoxans. Part 18. Smiles rearrangement in furoxan systems and in related furazans

Article abstract of DOI:10.1039/b104845g

The preparation and the base-promoted Smiles rearrangement of phenylfurazans (series a), 3-phenylfuroxan (series b) and 4-phenylfuroxan (series c) bearing 2-hydroxyethylthio (1), 2-hydroxyethylsulfonyl (2), carbamoylmethylthio (3) and carbamoylmethylsulfo

Full text of DOI:10.1039/b104845g

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Unsymmetrically substituted furoxans. Part 18.1 Smiles
rearrangement in furoxan systems and in related furazans
Donatella Boschi,a Giovanni Sorba,b Massimo Bertinaria,a Roberta Fruttero,a Rosella Calvinoa
and Alberto Gasco*a
1
a Dipartimento di Scienza e Tecnologia del Farmaco, Via P. Giuria, 9-10125 Torino, Italy.
E-mail: gasco@pharm.unito.it; Fax: 011 6707972; Tel: 011 6707670
b Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche,
V. le Ferrucci, 33-28100 Novara, Italy
Received (in Cambridge, UK) 4th June 2001, Accepted 18th June 2001
First published as an Advance Article on the web 19th July 2001
The preparation and the base-promoted Smiles rearrangement of phenylfurazans (series a), 3-phenylfuroxan (series
b) and 4-phenylfuroxan (series c) bearing 2-hydroxyethylthio (1), 2-hydroxyethylsulfonyl (2), carbamoylmethylthio (3)
and carbamoylmethylsulfonyl (4) functions at the hetero-ring are described. Under similar conditions compounds of
the series a and b gave the expected Smiles rearrangment products with the only exception being the amide derivatives
3 which were hydrolysed to their corresponding acid. The behaviour of the 4-phenylfuroxan series to Smiles
rearrangment was quite different. Under conditions close to those adopted for the corresponding 3-phenyl isomers,
1c and 2c decomposed into unidentified polar products. 3c afforded as principal product 3-mercapto 4-phenylfurazan
while 4c afforded (Z)-2-hydroxyimino-2-phenylacetonitrile. Possible mechanisms of formation of these products are
discussed.
ment of phenylfuroxans bearing 2-hydroxyethylthio (1b, 1c),
Introduction
2-hydroxyethylsulfonyl (2b, 2c), carbamoylmethylthio (3b, 3c),
The finding that derivatives of furoxan (1,2,5-oxadiazole 2-
and carbamoylmethylsulfonyl (4b, 4c) functions at the hetero-
oxide) can behave under physiological conditions, in the presence
ring (Scheme 2). The rearrangement was also investigated in
of thiol cofactors, as NO-donors brought about a renewed
related furazans (1,2,5-oxadiazoles) (1a–4a) for comparison.
interest in this heterocycle system.2a† The overall reaction
mechanism appears to be very complex and release of nitric
ؒ
oxide radical (NO ) or intermediate formation of nitroxyl
anion (NOϪ), or both, could be involved.2c It is known that
furoxans bearing suitable groups at the 3- or 4-position of the
ring undergo nucleophilic substitutions. In the literature there
are several scattered reports in which this reactivity has been
used for synthesising a variety of new derivatives of this sys-
tem.3,4 A few papers are specifically devoted to this aspect.
Nucleophilic displacement of benzenesulfonyl and nitro groups
received particular attention from our group5 and from a
Russian team.6 The Smiles rearrangement is a nucleophilic
intramolecular substitution which follows the reaction pathway
shown in Scheme 1.
Results and discussion
Preparation of the models
Hydroxyethylthio derivatives were obtained in good yields
according to the sequence of reactions reported in Scheme 2.
Nucleophilic substitution of the nitro group in 3-nitro-4-
phenylfurazan 5 by 2-hydroxyethanethiol 6 in distilled THF in
the presence of 50% NaOH gave the expected hydroxyethylthio
derivative 1a. Related furoxan compounds 1b, 1c were obtained
in similar manner by nucleophilic displacement of the benzene-
sulfonyl group in 3-phenyl-4-phenylsulfonylfuroxan 7 and in its
4-phenyl isomer 9 respectively. In the preparation of 1c, sodium
methoxide was used and the reaction was run at Ϫ10 ЊC. All the
thio derivatives were easily transformed into the corresponding
sulfonyl derivatives 2a–c by trifluoroperacetic acid oxidation.
Analogous procedures were used for the preparation of the
amide derivatives 3a–c, 4a–c.
Smiles rearrangements
Scheme 1
Furazan derivatives (Scheme 3). Rearrangement of 2-hydroxy-
ethylthio derivative 1a was effected in ethanol solution using
1.2 equivalents of NaOH. After several hours of stirring at
room temperature no rearrangement product was observed.
By contrast, when the reaction mixture was refluxed for 5 h,
3-hydroxy-4-phenylfurazan 12 and thiirane 13 were isolated in
good yields. Smiles rearrangement of 1a to the intermediate 11,
and subsequent transformation of this compound into 12 by
loss of 13, can easily explain this result. It is known that 2-(2,4-
dinitrophenylthio)ethanols behave similarly.8 Rearrangement of
the 2-hydroxyethylsulfonyl group in 2a was effected in acetone
solution using 2 equivalents of NaOH. After 10 min of stirring
X represents a leaving group, such as S, SO, SO2, O, etc., Y
usually is the conjugate base of OH, NH2, CONH, SO2NH,
and Z an activating electron-withdrawing group.7 The scope
of the reaction has been extended to a variety of molecular
systems, but little is known about this rearrangement in many
heterocycles. As a development of our research on furoxan
chemistry, we now report the base-promoted Smiles rearrange-
† According to a convention2b we use the term nitric oxide (NO) as a
generic family name. When necessary in the discussion, we specify the
particular redox form to which we refer.
DOI: 10.1039/b104845g
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Scheme 3 Reagents and conditions: a) 1.2 equivalents of 50% aq.
NaOH, refluxing ethanol, 5 h; b) 2 equivalents of 50% aq. NaOH,
acetone, rt, 10 min; c) 2 equivalents of 50% aq. NaOH, refluxing
ethanol, 2 h; d) 2.5 equivalents of NaOH, acetone, 55 ЊC, 6 h; e) 20
equivalents of CH3I, CH3OH, 4 h, rt.
Scheme 2 Reagents and conditions: a) 2-hydroxyethanethiol 6, 50% aq.
NaOH, THF, N2, rt; b) 2-mercaptoacetamide 10, 50% aq. NaOH,
CH3OH, N2, rt; c) 6, CH3ONa, dry THF, N2, Ϫ10 ЊC; d) 10, CH3ONa,
dry THF, N2, Ϫ10 ЊC; e) 80% aq. H2O2, CF3COOH, rt.
at room temperature the expected sulfinic acid 14 was formed in
good yield. The compound was not isolated but immediately
transformed into the corresponding methyl sulfone 15 by
treatment with a large excess of methyl iodide. Rearrangement
of carbamoylmethylthio derivative 3a was attempted in boiling
ethanol in the presence of 2 equivalents of NaOH. After 2 h
no Smiles product was isolated, but only the carboxylic acid 16
was recovered (60% yield), deriving from the hydrolysis of the
amide function present in 3a. When the rearrangement was
tried in dry THF using 1.2 equivalents of NaH, again no Smiles
product was obtained either at room temperature or at 55 ЊC.
Treatment of the carbamoylsulfonylfurazan 4a in acetone at
55 ЊC, in the presence of 2.5 equivalents of NaOH, afforded in
good yield 3-acetamido-4-phenylfurazan 18. This shows that
the expected rearrangement may be effected. Evidently the
sulfinic acid 17 loses SO2 during the latter stage of the process.
Similar behaviour was shown by 2-(2-nitrophenylsulfonyl)-N-
phenylacetamide when subjected to Smiles rearrangement.9
3-Phenylfuroxan derivatives (Scheme 4). The base-promoted
Smiles rearrangement in this series of derivatives was per-
formed under conditions close to those adopted for the furazan
series and the results obtained were similar. 4-Hydroxy-3-
phenylfuroxan 20 was isolated in good yield as the Smiles
rearrangement product obtained by treatment of 1b in EtOH at
room temperature with 4 equivalents of NaOH. Loss of 13
from the intermediate 19 can explain this result. Rearrangement
Scheme 4 Reagents and conditions: a) 4 equivalents of 50% aq. NaOH,
EtOH, rt, 20 h; b) 2.5 equivalents of 50% aq. NaOH, acetone, rt, 10
min; c) CH3I; d) 30% aq. H2O2; e) 2 equivalents of 50% aq. NaOH,
EtOH, 55 ЊC, 5 h; f ) methyl 2-mercaptoacetate, 50% aq. NaOH,
CH3OH, N2, rt; g) 20% aq. HCl, 1,4-dioxane, 60 ЊC, 4 h; h) 2.5
equivalents of 50% aq. NaOH, acetone, 55 ЊC, 5 h.
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of 2b effected at room temperature in acetone in the presence of
2.5 equivalents of NaOH quantitatively afforded the unstable
sulfinic acid 21, which was characterised both by the corre-
sponding methyl sulfone 22 and the sodium salt of the sulfonic
acid 23. This latter compound was obtained by 30% aq. H2O2
oxidation of 21 in water. Also the rearrangements of the carb-
amoyl derivatives 3b and 4b parallel the rearrangements of the
furazan analogues 3a and 4a. In fact, under similar conditions,
the carboxylic acid 24 (yield 25%) and the acetamido derivative
26 (yield 40%) were respectively isolated as principal reaction
products.
pound of molecular formula C8H6N2OS (Mϩ = 178 Da). Its
IR spectrum shows at 2485 cmϪ1 a typical sharp SH absorp-
tion. 13C NMR results are in keeping with the presence of two
furazan carbons at δC 153.1 and 145.9, respectively. On this
basis structure 32 was assigned to the compound. A possible
mechanism of formation is given in Scheme 5B in which the
intermediates 30 and 31 are involved.
The principal compound formed in the rearrangement of
4c is the Z form of 2-hydroxyimino-2-phenylacetonitrile 35.
Formation of this structure could be justified by a mechanism
similar to that proposed for the formation of 32, involving the
intermediate 33. An interesting alternative possibility is repre-
sented by the intermediate formation of 34. In fact, it is known
that the hydrochlorides of the adducts of sulfenes to nitrile
oxides afford nitriles by alkaline hydrolysis.11 If this is the case,
migration of the furoxan exocyclic oxygen to sulfur of the SO2
group should occur with concomitant opening of the O1–N2
endocyclic bond.
4-Phenylfuroxan derivatives (Scheme 5). The behaviour of the
4-phenyl series to Smiles rearrangement is quite different from
that of the 3-phenyl one. Under conditions close to those
adopted for the corresponding 3-phenyl isomers, 2-hydroxy-
ethylthio derivative 1c and 2-hydroxyethylsulfonyl derivative
2c decomposed into unidentified polar products. One of the
possible pathways for this extended decomposition is reported
in Scheme 5A. The initially formed anionic spiro intermediate
28 could irreversibly open to the unstable tertiary nitroso
derivative 29, following the breaking of the endocyclic furoxan
O1–N2 bond. It is reasonable to think that during the decom-
position of this structure NO is also formed. In effect we
detected by Griess reaction the presence of nitrite [1c, 35%, 2c,
9% (mol/mol)], which is one important final oxidative product
of NO, among the polar reaction compounds.
In a previous work we showed that a few furoxans are able to
release nitric oxide, under physiological conditions, and also in
the absence of thiol cofactors.10 All of these structures bear at
the 3-position a chain potentially able to undergo Smiles
rearrangement. This suggests that another mechanism capable
of rationalising spontaneous NO-release by these compounds
could be that depicted in Scheme 5A. Interestingly, 2c is also
able to afford, under physiological conditions, nitrite (3.9%
mol/mol after 1 h of incubation).
Experimental
Mps were measured on a Büchi 530 capillary apparatus and are
uncorrected. Mps with decomposition were determined after
introduction of the sample into the bath at a temperature
10 ЊC lower than the mp; a heating rate of 3 ЊC minϪ1 was used.
The compounds were routinely checked by IR spectroscopy
(Shimadzu FT-IR 8101M) and mass spectrometry (Finnigan-
Mat TSQ-700) and the spectra were in keeping with the pro-
posed structures. 1H and 13C NMR spectra were recorded at 200
and 50 MHz respectively, with a Bruker AC-200 spectrometer.
The assignments of the spectra were confirmed by DEPT pulse
sequence. Column chromatography was performed on silica gel
(Merck Kieselgel 60, 230–400 mesh ASTM) with the indicated
solvent system. Thin-layer chromatography (TLC) was carried
out on commercially available pre-coated plates (Merck
Kieselgel 60F254 silica). Petroleum ether 40–60 ЊC (PE) was
used as a co-eluent. Anhydrous magnesium sulfate was used
Rearrangment of 3c affords as principal product a com-
Scheme 5 Reagents and conditions: a) 4 equivalents of 50% aq. NaOH, EtOH, rt, 2 h; b) 2.5 equivalents of 50% aq. NaOH, acetone, rt, 20 min; c)
2.5 equivalents of 50% aq. NaOH, EtOH, rt, 15 min; d) 2.5 equivalents of 50% aq. NaOH, acetone, rt, 4 h.
J. Chem. Soc., Perkin Trans. 1, 2001, 1751–1757
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as the drying agent of the organic extracts. Solvent removal
was achieved under reduced pressure at room temperature.
Elemental analyses of the new compounds were performed
by REDOX (Cologno M.) and are reported below for each
compound. Compounds 5,12 7,5c 8,13 9,5c 1014 were synthesised
according to literature methods.
(0.86 g, 20.00 mmol) in TFA (2 cm3). Stirring was continued for
4 h at room temperature and then the reaction mixture was
poured into ice–water and the product was extracted with
DCM. The combined organic phases were washed with 1 M
aq. NaHCO3, dried, and evaporated. Flash chromatography
(eluent: PE–EtOAc 8 : 2) of the residue oil afforded the title
product (0.82 g, 65%) as a beige solid, mp 60.5–62 ЊC (from
PE–EtOAc) (Found: C, 47.15; H, 3.9; N, 10.9. C10H10N2O4S
requires C, 47.2; H, 4.0; N, 11.0%); νmax(KBr)/cmϪ1 3590sh,
(OH), 1354vs/1316vs/1296vs (three-components band, SO2),
1150vs (SO2); δH (200 MHz; CDCl3; Me4Si) 7.95 (2H, m, Ph),
7.57 (3H, m, Ph), 4.20 (2H, t, CH2O), 3.84 (2H, t, CH2S), 2.30
(1H, br s, OH); δC (50 MHz; CDCl3; Me4Si) 154.6 (C3 Furaz.),
152.3 (C4 Furaz.), 131.9 (Cp Ph), 129.3, 129.0 (Co, Cm Ph),
122.8 (Ci Ph), 58.2, 55.9 (2 × CH2); m/z (EI) 254 (Mϩ, 42%), 116
(100%).
Preparation of the models
3-(2-Hydroxyethylthio)-4-phenylfurazan 1a. To
a stirred
solution of 5 (2.00 g, 10.5 mmol) in THF (40 cm3) kept under
nitrogen at 0 ЊC was added, first, 2-hydroxyethanethiol 6, (0.82
g, 10.5 mmol) and then 50% aq. NaOH portionwise (0.84 g,
10.5 mmol). The reaction mixture was stirred under nitrogen
and allowed to attain room temperature. After 3 h, ice was
added and the product was extracted with diethyl ether. The
combined organic layers were washed with water, dried, and
evaporated. Flash chromatography (eluent: PE–EtOAc 8 : 2)
of the obtained residue afforded the title product (2.13 g, 88%)
as a colourless oil (Found: C, 53.9; H, 4.8; N, 12.1.
C10H10N2O2S requires C, 54.0; H, 4.5; N, 12.6%); νmax(film)/
cmϪ1 3410br; δH (200 MHz; CDCl3; Me4Si) 7.85 (2H, m, Ph),
7.50 (3H, m, Ph), 4.03 (2H, t, CH2O), 3.47 (2H, t, CH2S), 2.15
(1H, br s, OH); δC (50 MHz; CDCl3; Me4Si) 152.5 (C3 Furaz.),
150.6 (C4 Furaz.), 130.7 (Cp Ph), 128.9, 127.9 (Co, Cm Ph),
125.0 (Ci Ph), 61.1 (CH2O), 35.4 (CH2S); m/z (EI) 222 (Mϩ,
33%), 161 (100%).
4-(2-Hydroxyethylsulfonyl)-3-phenylfuroxan 2b. Prepared as
2a starting from 1b with stirring at room temperature for 3 h;
the eluent for flash chromatography was PE–EtOAc 6 : 4. The
title product (74%) was obtained as a beige solid, mp 62–63 ЊC
(from EtOAc–PE) (Found: C, 44.3; H, 3.7; N, 10.3.
C10H10N2O5S requires C, 44.4; H, 3.7; N, 10.4%); νmax(KBr)/
cmϪ1 3540s sh (OH), 1318vs/1298vs (two-components band,
SO2), 1146vs (SO2); δH (200 MHz; DMSO-d6; Me4Si) 7.75 (2H,
m, Ph), 7.64 (3H, m, Ph), 5.23 (1H, t, OH), 3.85 (2H, q, CH2O),
3.68 (2H, t, SO2CH2); δC (50 MHz; DMSO-d6; Me4Si) 158.0 (C4
Furox.), 131.7 (Cp Ph), 129.8, 128.9 (Co, Cm Ph), 120.8 (Ci Ph),
113.4 (C3 Furox.), 57.7, 54.6 (2 × CH2); m/z (EI) 270 (Mϩ, 7%),
102 (100%).
4-(2-Hydroxyethylthio)-3-phenylfuroxan 1b. To
a stirred
solution of 7 (1.50 g, 5.0 mmol) in THF (30 cm3) kept under
nitrogen at 0 ЊC was added, first, 2-hydroxyethanethiol 6 (0.77
g, 10.0 mmol) and then 50% aq. NaOH portionwise (0.80 g,
10.0 mmol). The reaction mixture was stirred under nitrogen
and allowed to attain room temperature. After 24 h, ice was
added and the product was extracted with diethyl ether. The
combined organic layers were washed with water, dried, and
evaporated. Flash chromatography (eluent: PE–EtOAc 6 : 4) of
the residue afforded the title product (0.90 g, 76%) as a white
solid, mp 53–54 ЊC (from EtOAc-PE) (Found: C, 50.2; H, 4.2;
N, 11.65. C10H10N2O3S requires C, 50.4; H, 4.2; N, 11.8 %);
νmax(KBr)/cmϪ1 3250br (OH); δH (200 MHz; CDCl3; Me4Si)
7.87 (2H, m, Ph), 7.54 (3H, m, Ph), 4.02 (2H, t, CH2O), 3.46
(2H, t, CH2S), 2.06 (1H, br s, OH); δC (50 MHz; CDCl3; Me4Si)
153.9 (C4 Furox.), 130.7 (Cp, Ph), 128.9, 127.2 (Co, Cm Ph),
122.1 (Ci Ph), 114.3 (C3 Furox.), 60.5 (CH2O), 33.7 (CH2S);
m/z (EI) 238 (Mϩ, 20%), 134 (100%).
3-(2-Hydroxyethylsulfonyl)-4-phenylfuroxan 2c. Prepared as
2a starting from 1c; the eluent for flash chromatography was
DCM–EtOAc 10 : 0→9.5 : 0.5. The title product (60%) was
obtained as a colourless solid, mp 80–81 ЊC (from Et2O–PE)
(Found: C, 44.7; H, 3.7; N, 10.4. C10H10N2O5S requires C, 44.4;
H, 3.7; N, 10.4%); νmax(KBr)/cmϪ1 3550s sh (OH), 1343vs,
1148vs (SO2); δH (200 MHz; CDCl3; Me4Si) 7.73 (2H, m, Ph),
7.51 (3H, m, Ph), 4.05 (2H, t, CH2O), 3.59 (2H, t, SO2CH2),
2.10 (1H, br s, OH); δC (50 MHz; CDCl3; Me4Si) 154.6
(C4 Furox.), 131.5 (Cp Ph), 129.4, 128.5 (Co, Cm Ph), 124.5
(Ci Ph), 117.5 (C3 Furox.), 56.0, 55.5 (2 × CH2); m/z (EI) 270
(Mϩ, 11%), 102 (100%).
3-(Carbamoylmethylthio)-4-phenylfurazan 3a. To a stirred
solution of 5 (1.00 g, 5.24 mmol) in MeOH (15 cm3), kept
under nitrogen at room temperature, was added, first, 2-
mercaptoacetamide 10, (0.52 g, 5.76 mmol) and then 50% aq.
NaOH portionwise (0.46 g, 5.76 mmol). The reaction mixture
was stirred under nitrogen for 30 min, then water was added
and methanol was evaporated off. The product was extracted
with EtOAc. The combined organic layers were washed with
brine, dried, and evaporated. Crystallisation of the residue with
MeOH afford the title product (1.11 g, 90%) as a white solid,
mp 164–165 ЊC (from MeOH) (Found: C, 51.1; H, 3.8; N, 17.8.
C10H9N3O2S requires C, 51.05; H, 3.9; N, 17.9%); νmax(KBr)/
cmϪ1 3391s, 3189s (NH2), 1640vs, 1620vs (CONH2); δH (200
MHz; DMSO-d6; Me4Si) 7.83 (3H, m, Ph and NH), 7.66 (3H,
m, Ph), 7.39 (1H: br s, NH), 4.11 (2H, s, CH2); δC (50 MHz;
DMSO-d6; Me4Si) 167.9 (CO), 152.5 (C4 Furaz.), 151.5
(C3 Furaz.), 131.6 (Cp Ph), 129.5, 128.0 (Co, Cm Ph), 124.5
(Ci Ph), 36.8 (CH2); m/z (EI) 235 (Mϩ, 100%).
3-(2-Hydroxyethylthio)-4-phenylfuroxan 1c. A methanolic
solution of NaOMe (0.09 g, 3.64 mmol of Na in 5 cm3 of dry
MeOH) and 2-hydroxyethanethiol 6, (0.26 cm3, 3.64 mmol)
was added dropwise to a solution of 9 (1.00 g, 3.31 mmol)
in dry THF (20 cm3). The temperature was maintained at
Ϫ10 ЊC for 30 min, then AcOH was added, solvent was
removed in vacuo, and the residue was recovered with water.
The product was extracted with DCM, and the combined
organic layers were washed with water, dried, and evaporated.
Flash chromatography (eluent: DCM–EtOAc 10 : 0→9.5 : 0.5)
of the residue afforded the title product (0.73 g, 92%) as a white
solid, mp 29–32 ЊC (from Et2O–PE) (Found: C, 50.7; H, 4.3;
N, 11.7. C10H10N2O3S requires C, 50.4; H, 4.2; N, 11.82%);
νmax(KBr)/cmϪ1 3650–3150 (OH); δH (200 MHz; CDCl3; Me4Si)
7.94 (2H, m, Ph), 7.53 (3H, m, Ph), 3.71 (2H, q, CH2O), 3.12
(2H, t, CH2S), 2.67 (1H, t, OH); δC (50 MHz; CDCl3; Me4Si)
157.1 (C4 Furox.), 131.2 (Cp Ph), 128.6, 127.5 (Co, Cm Ph),
125.8 (Ci Ph), 111.0 (C3 Furox.), 61.0 (CH2O), 34.5 (CH2S);
m/z (EI) 238 (Mϩ, 3%), 134 (100%).
4-(Carbamoylmethylthio)-3-phenylfuroxan 3b. Prepared as 3a
starting from 8 with stirring at room temperature for 15 min.
The title product was obtained (90%) as a white solid, mp 171–
172 ЊC (from MeOH) (Found: C, 48.0; H, 3.6; N, 16.7
C10H9N3O3S requires C, 47.8; H, 3.6; N, 16.7%); νmax(KBr)/
cmϪ1 3384s, 3177s (NH2), 1661vs (CONH2); δH (200 MHz;
DMSO-d6; Me4Si) 7.83 (2H, m, Ph), 7.64 (3H, m, Ph), 7.79,
3-(2-Hydroxyethylsulfonyl)-4-phenylfurazan 2a. To a stirred
solution of 1a (1.12 g, 5.00 mmol) in TFA (3 cm3) was added
dropwise over a period of 30 min a solution of 80% aq. H2O2
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7.39 (2H, 2 br s, NH2), 4.06 (2H, s, CH2); δC (50 MHz; DMSO-
d6; Me4Si) 167.7 (CO), 154.7 (C4 Furox.), 131.1 (Cp Ph), 129.3,
127.6 (Co, Cm Ph), 122.0 (Ci Ph), 114.2 (C3 Furox.), 35.0
(CH2); m/z (EI) 251 (Mϩ, 5%), 191 (100%).
2-(3-Phenylfuroxan-4-ylthio)acetic acid 24. A solution of 27
(0.50 g, 1.88 mmol) in 1,4-dioxane (10 cm3) and 20% aq. HCl
(10 cm3) was stirred at 60 ЊC for 4 h. Solvent removal afforded
a residue which was dissolved in MeOH. Addition of water
precipitated a white solid, which was filtered off and dried to
give the title compound (0.38 g, 81%), mp 130–133 ЊC (from
MeOH–water) (Found: C, 47.8; H, 3.2; N, 11.1. C10H8N2O4S
requires C, 47.6; H, 3.2; N, 11.1%); νmax(KBr)/cmϪ1 3300–2300,
1713vs (COOH); δH (200 MHz; DMSO-d6; Me4Si) 9.91 (1H, br
s, OH in CDCl3), 7.83 (2H, m, Ph), 7.66 (3H, m, Ph), 4.18 (2H,
s, CH2); δC (50 MHz; DMSO-d6; Me4Si) 168.8 (CO), 154.3 (C4
Furox.), 131.2 (Cp Ph), 129.4, 127.6 (Co, Cm Ph), 121.9 (Ci Ph),
114.2 (C3 Furox.), 33.4 (CH2); m/z (EI) 252 (Mϩ, 3%), 44
(100%).
3-(Carbamoylmethylthio)-4-phenylfuroxan 3c. Prepared as 1c
starting from 9 and 10. The product was extracted with EtOAc;
the eluent for flash chromatography was DCM–EtOAc 7 : 3.
The title product (93%) was obtained as a white solid, mp 134–
136 ЊC (from EtOAc) (Found: C, 48.0; H, 3.6; N, 16.8.
C10H9N3O3S requires C, 47.8; H, 3.6; N, 16.7%); νmax(KBr)/
cmϪ1 3441s, 3187m (NH2), 1688vs (CONH2); δH (200 MHz;
DMSO-d6; Me4Si) 7.94 (2H, m, Ph), 7.58 (3H, m, Ph), 7.86,
7.24 (2H, 2 br s, NH2), 3.74 (2H, s, CH2); δC (50 MHz; DMSO-
d6; Me4Si) 168.9 (CO), 158.0 (C4 Furox.), 131.5 (Cp Ph), 129.2,
128.1 (Co, Cm Ph), 126.2 (Ci Ph), 111.8 (C3 Furox.), 32.6
(CH2); m/z (EI) 251 (Mϩ, 4%), 191 (100%).
Smiles rearrangements
Rearrangement of 1a. A solution of 1a (0.22 g, 1.00 mmol) in
EtOH (5 cm3) containing 50% aq. NaOH (1.20 mmol) was
boiled (5 h). When it had cooled, thiirane 13 separated out as
a white polymer and was filtered off (0.06 g, mp 162–166 ЊC,
lit.,8 165–175 ЊC). The solution was diluted with water, washed
with DCM, acidified with 1 M HCl, and extracted with
DCM. Solvent removal from the dried organic phases afforded
3-hydroxy-4-phenylfurazan 12 (0.12 g, 74%), mp 176–177 ЊC
(decomp.) (lit.,15 177.5–178 ЊC); δH (200 MHz; DMSO-d6;
Me4Si) 13.35 (1H, br s, OH) 7.99 (2H, m, Ph), 7.56 (3H, m, Ph);
δC (50 MHz; DMSO-d6; Me4Si) 162.3 (C3 Furaz.), 145.6
(C4 Furaz.), 130.6 (Cp Ph), 129.3, 127.2 (Co, Cm Ph), 125.3
(Ci Ph).
3-(Carbamoylmethylsulfonyl)-4-phenylfurazan 4a. Prepared
as 2a starting from 3a with stirring at room temperature for 24
h; the product was extracted with EtOAc. The title product
(86%) was obtained from the organic phases as a white solid,
mp 181–182 ЊC (from MeOH) (Found: C, 44.8; H, 3.7; N, 15.5.
C10H9N3O4S requires C, 44.9; H, 3.4; N, 15.7%); νmax(KBr)/
cmϪ1 3450s, 3350s (NH2), 1670vs (CONH2), 1335vs, 1155vs
(SO2); δH (200 MHz; DMSO-d6; Me4Si) 7.88 (H, br s, NH), 7.85
(2H, m, Ph), 7.64 (4H, m, Ph and NH), 4.67 (2H, s, CH2); δC (50
MHz; DMSO-d6; Me4Si) 161.8 (CO), 155.2 (C4 Furaz.), 153.1
(C3 Furaz.), 131.6 (Cp Ph), 129.7, 128.9 (Co, Cm Ph), 122.9
(Ci Ph), 61.2 (CH2); m/z (EI) 267 (Mϩ, 20%), 58 (100%).
Rearrangement of 2a. To a solution of 2a (0.34 g, 1.30 mmol)
in acetone (10 cm3) was added 50% aq. NaOH (0.27 g, 3.25
mmol) dropwise. Immediately, the unstable sodium sulfinate
14 precipitated as a white solid. After 10 min the rearrange-
ment was complete and so 14 was characterised as the methyl
sulfone 15. First, MeOH (5 cm3) and then methyl iodide (1.66
cm3, 26 mmol) were added. After 4 h the solvent was evaporated
off, the residue was recovered with water, and the product was
extracted with diethyl ether. The combined organic phases were
washed with brine, dried, and evaporated. The residue was
purified by flash chromatography (eluent: PE–EtOAc 7:3). The
obtained product (0.25 g, 70%) was identified as the 3-[2-
(methylsulfonyl )ethoxy]-4-phenylfurazan 15, mp 93–94 ЊC (from
MeOH) (Found: C, 49.4; H, 4.5; N, 10.5. C11H12N2O4S requires
C, 49.25; H, 4.5; N, 10.4%); νmax(KBr)/cmϪ1 1302vs/1285vs
(two-components band, SO2), 1130vs (SO2); δH (200 MHz;
DMSO-d6; Me4Si) 7.99 (2H, m, Ph), 7.58 (3H, m, Ph), 4.84 (2H,
t, CH2O), 3.83 (2H, t, SO2CH2), 3.11 (3H, s, CH3); δC (50 MHz;
DMSO-d6; Me4Si) 162.9 (C3 Furaz.), 145.4 (C4 Furaz.), 131.3
(Cp Ph), 129.3, 127.5 (Co, Cm Ph), 124.2 (Ci Ph), 66.3 (CH2O),
52.7 (SO2CH2), 41.7 (CH3); m/z (EI) 268 (Mϩ, 66%), 79 (100%).
4-(Carbamoylmethylsulfonyl)-3-phenylfuroxan 4b. Prepared
as 2a starting from 3b with stirring at room temperature for 6 h;
the product was extracted with EtOAc. The title product (83%)
was obtained from the organic phases as a white solid, mp 179–
180 ЊC (from MeOH) (Found: C, 42.6; H, 3.25; N, 14.7.
C10H9N3O5S requires C, 42.4; H, 3.2; N, 14.8%); νmax(KBr)/
cmϪ1 3461s, 3355s (NH2), 1671vs (CONH2), 1341vs, 1156vs
(SO2); δH (200 MHz; DMSO-d6; Me4Si) 7.91 (1H, br s, NH),
7.72 (3H, m, Ph and NH), 7.61 (3H, m, Ph), 4.55 (2H, s, CH2);
δC (50 MHz; DMSO-d6; Me4Si) 161.6 (CO), 157.5 (C4 Furox.),
131.4 (Cp Ph), 129.8, 128.8 (Co, Cm Ph), 120.7 (Ci Ph), 113.5
(C3 Furox.), 60.5 (CH2); m/z (EI) 283 (Mϩ, 2%), 117 (100%).
3-(Carbamoylmethylsulfonyl)-4-phenylfuroxan 4c. Prepared
as 2a starting from 3c with stirring at room temperature for
24 h; the product was extracted with EtOAc. The title product
(90%) was obtained as a white solid from the organic phases,
mp 188–189 ЊC (from MeOH) (Found: C, 42.5; H, 3.25; N, 14.7.
C10H9N3O5S requires C, 42.4; H, 3.2; N, 14.8%); νmax(KBr)/
cmϪ1 3441s, 3320s (NH2), 1682vs (CONH2), 1387s/1370s (two-
components band, SO2), 1148s (SO2); δH (200 MHz; DMSO-d6;
Me4Si) 8.00 (1H, s, NH), 7.79–7.53 (6H, m, Ph and NH), 4.53
(2H, s, CH2); δC (50 MHz; DMSO-d6; Me4Si) 162.2 (CO), 155.8
(C4 Furox.), 131.6 (Cp Ph), 129.8, 128.5 (Co, Cm Ph), 124.9
(Ci Ph), 117.2 (C3 Furox.), 57.9 (CH2); m/z (EI) 283 (Mϩ,
0.4%), 117 (100%).
Rearrangement of 3a. A solution of 3a (0.40 g, 1.70 mmol) in
EtOH (10 cm3) containing 50% aq. NaOH (0.27g, 3.40 mmol)
was boiled (2 h). When it had cooled, water was added and
EtOH was evaporated off. The remaining aqueous solution was
washed with diethyl ether, acidified with 6 M HCl, and then the
product was extracted with diethyl ether. The combined organic
phases were washed with brine, dried, and evaporated. The
white solid obtained was not the expected rearrangement
product but was identified as 2-(4-phenylfurazan-3-ylthio)acetic
acid 16 (0.24 g, 60%), mp 119–120 ЊC (from CHCl3–PE)
(Found: C, 50.7; H, 3.4; N, 11.7. C10H8N2O3S requires C, 50.8;
H, 3.4; N, 11.85%); νmax(KBr)/cmϪ1 3700–2375, 1725vs
(COOH); δH (200 MHz; DMSO-d6; Me4Si) 11.37 (1H, br s, OH
in CDCl3), 7.83 (2H, m, Ph), 7.66 (3H, m, Ph), 4.22 (2H, s,
CH2); δC (50 MHz; DMSO-d6; Me4Si) 168.6 (CO), 152.4, 151.2
(C3, C4 Furaz.), 131.4 (Cp Ph), 129.6, 128.0 (Co, Cm Ph), 124.4
(Ci Ph), 35.5 (CH2); m/z (EI) 236 (Mϩ, 52%), 116 (100%).
4-(Methoxycarbonylmethylthio)-3-phenylfuroxan 27. Pre-
pared as 3a starting from 8 and methyl 2-mercaptoacetate with
stirring at room temperature for 15 min. From the concentrated
reaction mixture a white solid was precipitated and was filtered
off and dried (70%), mp 60–60.5 ЊC (from MeOH) (Found:
C, 49.6; H, 3.75; N, 10.5. C11H10N2O4S requires C, 49.6; H, 3.8;
N, 10.5%); νmax(KBr)/cmϪ1 1738vs (CO); δH (200 MHz; DMSO-
d6; Me4Si) 7.81 (2H, m, Ph), 7.64 (3H, m, Ph), 4.26 (2H, s, CH2),
3.71 (3H, s, CH3); δC (50 MHz; DMSO-d6; Me4Si) 168.1 (CO),
154.1 (C4 Furox.), 131.2 (Cp Ph), 129.4, 127.6 (Co, Cm Ph),
121.8 (Ci Ph), 114.2 (C3 Furox.), 52.7 (CH3), 32.7 (CH2);
m/z (EI) 266 (Mϩ, 18%), 206 (100%).
J. Chem. Soc., Perkin Trans. 1, 2001, 1751–1757
1755

View Article Online
Rearrangement of 4a. A solution of 4a (0.27 g, 1.00 mmol) in
acetone (10 cm3) containing 50% aq. NaOH (0.20 g, 2.50 mmol)
was stirred at 55 ЊC for 6 h. Then the reaction mixture was
acidified with 1 M HCl and the product was extracted with
EtOAc. The combined organic phases were washed with brine,
dried, and evaporated. Flash chromatography (eluent: DCM–
EtOAc 9.5 : 0.5) of the residue afforded a white solid identified
as 3-acetylamino-4-phenylfurazan 18, (0.15 g, 75%), mp 181–
181.5 ЊC (from EtOH) (lit.,16 181–182 ЊC); δH (200 MHz;
DMSO-d6; Me4Si) 10.75 (1H, br s, NH), 7.77 (2H, m, Ph), 7.57
(3H, m, Ph), 2.13 (3H, s, CH3); δC (50 MHz; DMSO-d6; Me4Si)
169.7 (CO), 150.9, 149.5 (C3, C4 Furaz.), 130.8 (Cp Ph), 129.2,
127.6 (Co, Cm Ph), 125.0 (Ci Ph), 22.9 (CH3).
M HCl, and cooled. The precipitated solid was filtered off and
dried under vacuum. It was identified not as the rearrangement
product but as crude 2-(3-phenylfuroxan-4-ylthio)acetic acid 24
(0.13 g, 25%) previously characterised.
Rearrangement of 4b. A solution of 4b (0.28 g, 1.00 mmol) in
acetone (10 cm3) containing 50% aq. NaOH (0.20 g, 2.50 mmol)
was stirred at 55 ЊC for 5 h. Then the reaction mixture was
acidified with 1 M HCl and the product was extracted with
EtOAc. The combined organic phases were washed with brine,
dried, and evaporated. Flash chromatography (eluent: PE–
EtOAc 8 : 2→5 : 5) of the residue afforded a white solid identi-
fied as 4-acetylamino-3-phenylfuroxan 26 0.10 g, 40%), mp
157 ЊC (from EtOAc–PE) (Found: C, 55.0; H, 4.15; N, 19.2.
C10H9N3O3 requires C, 54.8; H, 4.1; N, 19.2%); νmax(KBr)/cmϪ1
3256s, 3227s (NH), 1690vs (CONH); δH (200 MHz; DMSO-d6;
Me4Si) 10.90 (1H, br s, NH), 7.77 (2H, m, Ph), 7.57 (3H, m,
Ph), 2.10 (3H, s, CH3); δC (50 MHz; DMSO-d6; Me4Si) 169.8
(CO), 151.0 (C4 Furox.), 130.7 (Cp Ph), 129.0, 127.2 (Co,
Cm Ph), 122.5 (Ci Ph), 112.0 (C3 Furox.), 22.8 (CH3); m/z (EI)
219 (Mϩ, 15%), 117 (100%).
Rearrangement of 1b. A solution of 1b (0.24 g, 1.00 mmol) in
EtOH (10 cm3) containing 50% aq. NaOH (3.75 mmol) was
stirred at room temperature for 20 h. Then EtOH was evapor-
ated off and the residue was recovered with water. The white
solid was filtered off (thiirane 13, 0.04 g) and the filtrate was
acidified with 1 M HCl. Filtration of the white precipitate
afforded the 4-hydroxy-3-phenylfuroxan 20 (0.11 g, 61%), mp
128 ЊC (decomp.) lit.,17 133 ЊC); δH (200 MHz; CD3OD; Me4Si)
8.22 (2H, m, Ph), 7.55 (3H, m, Ph), 5.03 (exchangeable proton);
δC (50 MHz; CD3OD; Me4Si) 163.4 (C4 Furox.), 131.6 (Cp Ph),
130.0, 127.6 (Co, Cm Ph), 124.7 (Ci Ph), 109.2 (C3 Furox.).
Rearrangement of 3c. A solution of 3c (0.50 g, 2.00 mmol) in
EtOH (10 cm3) containing 50% aq. NaOH (0.40 g, 5.00 mmol)
was stirred at room temperature for 5 min. Then the solution
was neutralised with 3 M HCl and the EtOH was evaporated
off. The remaining aqueous solution was acidified with 3 M
HCl and cooled. The white solid precipitate was filtered off
and dried under vacuum. It was identified as 3-mercapto-4-
phenylfurazan 32 (0.26 g, 74%). Crystallisation solvent was
MeOH–3 M HCl; mp starts to soften and decompose at 52 ЊC;
at 87 ЊC the product was completely decomposed (Found: C,
54.2; H, 3.45; N, 15.5. C8H6N2OS requires C, 53.9; H, 3.4;
N, 15.7%); νmax(KBr)/cmϪ1 2485s (SH); δH (200 MHz; CDCl3;
Me4Si) 7.81 (2H, m, Ph), 7.56 (3H, m, Ph), 4.23 (1H, s, SH);
δC (50 MHz; CDCl3; Me4Si) 153.1 (C4 Furaz.), 145.9 (C3
Furaz.), 130.8 (Cp Ph), 129.2, 127.9 (Co, Cm Ph), 124.7 (Ci Ph);
m/z (EI) 178 (Mϩ, 100%).
Rearrangement of 2b. To a solution of 2b (0.54 g, 2.00 mmol)
in acetone (10 cm3) was added 50% aq. NaOH (0.40 g, 5.0
mmol) dropwise. Immediately, the unstable sodium sulfinate 21
precipitated as a white solid. After 10 min the rearrangement
was complete and so 21 was characterised both as the sodium
sulfonate and as the methyl sulfone. In the case of the oxid-
ation, the precipitate 21 was filtered, washed with acetone, and
dissolved in water (10 cm3). To the solution was added 30% aq.
H2O2 (0.91 g, 8.00 mmol) and the reaction mixture was stirred
at room temperature for 1 h. Solvent removal afforded sodium
2-(3-phenylfuroxan-4-yloxy)ethanesulfonate 23 (0.57, 92%), mp
>233 ЊC (decomp.) (from PriOH) (Found: C, 38.05; H, 3.2;
N, 8.65. C10H9N2NaO6Sؒ0.5H2O requires C, 37.8; H, 3.2; N,
8.8%); νmax(KBr)/cmϪ1 1221vs/1188vs/1168 (three-components
band, SO3Ϫ), 1065 (SO3Ϫ); δH (200 MHz; D2O; Me4Si) 7.95 (2H,
m, Ph), 7.45 (3H, m, Ph), 4.68 (2H, t, CH2O), 3.38 (2H, t,
CH2SO3Ϫ); δC (50 MHz; D2O; Me4Si) 159.5 (C4 Furox.), 128.5
(Cp Ph), 126.3, 123.9 (Co, Cm Ph), 118.7 (Ci Ph), 107.3 (C3
Furox.), 63.2 (CH2O), 46.7 (CH2SO3Ϫ).
In the case of methylation, to the reaction mixture, first
MeOH (10 cm3) and then methyl iodide (0.38 cm3, 6 mmol)
were added. After 4 h the solvent was evaporated off, the resi-
due was recovered with water, and the product was extracted
with EtOAc. The combined organic phases were washed
with brine, dried, and evaporated. The residue was purified
by flash chromatography (eluent: PE–EtOAc 5 : 5). The
obtained product (0.23 g, 40%) was identified as the 4-[2-
(methylsulfonyl)ethoxy]-3-phenylfuroxan 22, mp 120–121 ЊC
(from MeOH) (Found: C, 46.5; H, 4.3; N, 9.9. C11H12N2O5S
requires C, 46.5; H, 4.25; N, 9.85%); νmax(KBr)/cmϪ1 1320vs/
1302vs/1283vs (three-components band, SO2), 1132vs (SO2); δH
(200 MHz; DMSO-d6; Me4Si) 8.03 (2H, m, Ph), 7.60 (3H, m,
Ph), 4.67 (2H, t, CH2O), 3.84 (2H, t, CH2SO2), 3.10 (3H, s,
CH3); δC (50 MHz; DMSO-d6; Me4Si) 161.6 (C4 Furox.), 131.0
(Cp Ph), 129.1, 126.5 (Co, Cm Ph), 121.7 (Ci Ph), 107.7
(C3 Furox.), 64.4 (CH2O), 52.6 (CH2SO2), 41.7 (CH3); m/z (EI)
284 (Mϩ, 64%), 224 (100%).
Rearrangement of 4c. A solution of 4c (0.28 g, 1.00 mmol) in
acetone (10 cm
3) containing 50% aq. NaOH (0.20 g, 2.50 mmol)
was stirred at room temperature for 4 h. Then the solution was
acidified with 1 M HCl and the acetone was evaporated off. The
product was extracted from the remaing aqueous solution with
EtOAc. The combined organic phases were washed with brine,
dried, and evaporated. Flash chromatography (eluent: hexane–
EtOAc 8 : 2) of the residue afforded a white solid identified
as (Z)-2-hydroxyimino-2-phenylacetonitrile 35 (0.11 g, 78%),
mp 128–129 ЊC (from H2O) (lit.,18 130 ЊC).
Acknowledgements
This work was supported by grants from MURST. The help
rendered by Dr J. Boulton is greatly appreciated.
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