Copper(II)-mediated oxidation of 1,2-dioxime to furoxan

Article abstract of DOI:10.1016/j.tetlet.2008.07.148

1,2-Dioximes undergo oxidative transformation mediated by copper(II) ions in acetonitrile to form the corresponding furoxans in high yields. A series of 1,2-dioximes including aliphatic, aromatic, and heterocyclic dioximes were oxidized using these mild c

Full text of DOI:10.1016/j.tetlet.2008.07.148

Tetrahedron Letters 49 (2008) 5924–5927
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Tetrahedron Letters
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Copper(II)-mediated oxidation of 1,2-dioxime to furoxan
*
Oindrila Das, Sayantan Paria, Tapan Kanti Paine
Department of Inorganic Chemistry, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Jadavpur, Kolkata 700 032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
1,2-Dioximes undergo oxidative transformation mediated by copper(II) ions in acetonitrile to form the
corresponding furoxans in high yields. A series of 1,2-dioximes including aliphatic, aromatic, and hetero-
cyclic dioximes were oxidized using these mild conditions.
Received 6 June 2008
Revised 18 July 2008
Accepted 28 July 2008
Available online 31 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Copper
Oxidation
Dioxime
Furoxan
1. Introduction
ence of a base and subsequent formation of a mononuclear
copper(II) complex of the furoxan. The synthesis and characteriza-
Furoxans (1,2,5-oxadiazole-2-oxides) and benzofuroxans repre-
sent an important class of NO donors.1 Furoxans show a variety of
NO-related bioactivities, including cytotoxicity, mutagenicity,
immunosuppression, central muscle relaxant properties, anticon-
vulsive effects, monoamino oxidase inhibition, and direct vasodila-
tor and blood pressure lowering activities.2–4 Benzofuroxans are
potent antileukemic and immunosuppressive drugs, and can be
used as in vitro inhibitors of RNA synthesis in sheep lympho-
cytes.5–7 Furoxans are widely used in organic chemistry as inter-
mediates for the synthesis of many heterocycles.8
tion of the copper(II)-1,10-phenanthrolinefuroxan complex is
reported along with the isolation and characterization of free
furoxan. We have further extended this procedure to other 1,2-
dioximes and found it to be a general method for the synthesis
of furoxans. We report here, for the first time, the oxidation of
1,2-dioximes to furoxans mediated by copper(II) in acetonitrile.
2. Results and discussion
Reaction of dioxime L1, copper(II) chloride, and sodium perchlo-
rate in acetonitrile in the presence of triethylamine leads to oxida-
tive transformation of dioxime L1 to furoxan L2 (Scheme 1) with
concomitant formation of [CuI(CH3CN)4]ClO4. Formation of furoxan
is very much dependent on the presence of a base during the reac-
tion. In the absence of any base, the dioxime ligand is not oxidized.
The furoxan ligand reacts with excess copper(II) in solution to form
a mononuclear complex [Cu(L2)2Cl]+ (1) (Scheme 1). The extent of
formation of 1 depends on the molar ratio of copper(II)/dioxime
(L1), and a maximum yield of 95% for 1 was observed when they re-
act in a molar ratio of 3:1. The oxidation of L1 to L2 is a two-electron
process and requires 2 equiv of copper(II) salt to generate 1 equiv of
L2. The excess of copper(II) salt then forms a complex with L2.
To establish this oxidative transformation reaction further, it
was deemed important to characterize the free furoxan. Free furo-
xan L2 was isolated by treating complex 1 with excess aqueous
ammonia. A cream colored solid was isolated from the reaction
mixture and was characterized by spectroscopic methods. ESI-MS
in positive ion mode (in acetonitrile) showed molecular ion peaks
at m/z 261.08 (100%) and 239.09 (23%) with expected isotope distri-
bution patterns calculated for [L2+Na]+ and [L2+H]+, respectively. In
Furoxans can be synthesized easily by ring closure or cycloaddi-
tion reactions. Monocyclic furoxans are normally prepared by oxi-
dative cyclization of 1,2-dioximes. Many different oxidizing agents
such as hypohalite, ferricyanide, ceric ions, nitric acid and nitrogen
oxides, manganese dioxide, lead tetraacetate, N-iodosuccinimide,
and phenyliodine(III) bistrifluoroacetate have been used for cycli-
zation reactions.9,10 Alumina-promoted cyclization of
a-nitrooxi-
mes has also been reported for the synthesis of furoxans.11
Typical methods for the synthesis of benzofuroxans involve oxida-
tion of benzoquinone dioxime, thermolysis of ortho-nitroaryl
azides, and oxidation of ortho-nitroanilines.12–14
In spite of the presence of a large number of transition metal
complexes,15 particularly copper(II) complexes of 1,2-dioximes,
there is no report on copper(II)-mediated oxidation of dioximes.
We report herein the preparation of a new 1,10-phenanthroline-
based furoxan from the corresponding dioxime by an oxidative
transformation reaction mediated by copper(II) ions in the pres-
* Corresponding author. Tel.: +91 33 2473 4971; fax: +91 33 2473 2805.
E-mail address: ictkp@iacs.res.in (T. K. Paine).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.148

O. Das et al. / Tetrahedron Letters 49 (2008) 5924–5927
5925
Scheme 1. Oxidation of 1,10-phenanthroline 5,6-dioxime to 1,10-phenanthrolinefuroxan.
comparison with L1 showed molecular ion peaks at m/z 262.94
(47%) and 240.96 (100%) with expected isotope distribution pat-
terns calculated for [L1+Na]+ and [L1+H]+, respectively. This indi-
cates the formation of furoxan L2 with a loss of two hydrogen
atoms from L1 and was strongly supported by 1H NMR spectros-
copy. The 1H NMR spectrum of L2 in DMSO-d6 did not show any
oxime-OH peaks in the region 12–14 ppm as observed in L1. How-
ever, the six aromatic protons of the phenanthroline backbone were
observed in the region 7.80–9.20 ppm and the signal positions and
splitting patterns were considerably different from those in L1.
Additionally, two doublets were observed at 9.16 and 9.08 ppm
for the ortho-protons of the pyridine rings of L2. Two doublets due
to the para-protons in the region 8.78–8.84 ppm and a multiplet
at 7.86 ppm for the meta-protons were also observed. The NMR
integration and splitting patterns of the peaks indicated that the
two pyridine rings of L2 are chemically different. All these experi-
mental data corroborate with the formulation of furoxan L2.
This methodology was further extended to the oxidation of
other 1,2-dioximes including alkyl, aryl, and heterocycle susbsti-
tuted dioximes (Scheme 2, Table 1). The reactions were carried
out using Cu(ClO4)2Á6H2O and 1,2-dioximes in acetonitrile at room
temperature. The typical reaction time was about 12 h, except for
1,2-cyclohexanedionedioxime which required 24 h for complete
conversion to the corresponding furoxan. Unlike the oxidation of
L1, no base was needed to carry out the oxidation of the other
dioximes. After the reaction, the solution was concentrated and
treated with ammonia to remove copper ions from the reaction
solution and then extracted with organic solvents. The ratio of cop-
per(II)/dioximes varied with the nature of the dioxime. Dioxime L1
requires a 3:1 ratio of copper/dioxime for complete conversion to
the furoxan, whereas for other dioximes a ratio of 2:1 was suffi-
cient for the oxidative transformation.
probable mechanism of the oxidation reaction involves initial for-
mation of a copper(II)–oxime complex. The oxime complex is prob-
ably strongly oxidizing, and therefore intramolecular electron
transfer from the oxime to copper(II) leads to the formation of
furoxan and a [Cu(CH3CN)4]+ complex via the one electron oxidized
form of dioxime, that is, an iminoxyl radical. Furoxans without a
donor atom cannot form a complex with copper ions, while furox-
ans having ligating properties can easily form complexes with ex-
cess copper(II) ions present in the reaction medium.
In conclusion, we have developed a new copper(II)-mediated
oxidative transformation of 1,2-dioximes to furoxans. The method
is applicable to a wide range of dioxime substrates and demon-
strates the role played by copper(II) ions in directing the course
of an oxidative transformation reaction.
3. Experimental
Dioxime L1 was synthesized from 1,10-phenanthroline-5,6-
dione,16 according to a literature procedure.17 Dioxime 2 was syn-
thesized according to procedure described in the literature.18 Other
dioximes were either purchased commercially or synthesized from
the corresponding 1,2-diketones.
3.1. Complex 1
To a suspension of L1 (0.24 g, 1 mmol) and triethylamine
(0.27 mL, 2 mmol) in acetonitrile (20 mL) was added a mixture of
CuCl2Á2H2O (0.51 g, 3 mmol) and NaClO4ÁH2O (0.84 g, 6 mmol).
The resulting greenish brown mixture was allowed to stir at room
temperature for 12 h. A green solid ([1]Cl) was then isolated by fil-
tration, washed with acetonitrile, and dried. Initially, a white crys-
talline solid of [CuI(CH3CN)4]ClO4 was isolated from the filtrate
followed by green crystals of [1]ClO4. Total yield of 1: 0.29 g
(95%). Anal. Calcd for C24H12Cl2CuN8O8ÁH2O: C, 41.60; H, 2.04; N,
16.17. Found: C, 41.9; H, 2.1; N, 16.1. IR (KBr disk, cmÀ1):
3433(br), 3085, 1633(s), 1510(s), 1415(s), 1091(s), 820, 732, 623.
All the furoxans showed very strong m(C@N–O) peaks at 1590–
1620 cmÀ1 in their IR spectra. Liquid furoxans 3a, 4a, and 6a did
not show characteristic molecular ion peaks in their ESI-MS spec-
tra; however, the other furoxans showed peaks corresponding to
[M+H]+ and/or [M+Na]+ with expected isotope distribution pat-
terns. The furoxans were further characterized by 1H and 13C
NMR spectroscopy. Interestingly, the NMR spectrum of unsymmet-
rical furoxan 4a showed the presence of two different isomers in
solution (Scheme 3). This was established clearly by 1H NMR spec-
troscopy in CDCl3, which showed two isomers in a 3:1 ratio at
298 K (see Section 3).
UV–vis in acetonitrile (k, nm; e
, MÀ1 cmÀ1): 530(420), 400(470),
320(3400), 335(sh), 350(sh). MS-ESI (positive ion mode, aceto-
nitrile): m/z 574.25 (6%, [1]+), 539.26 (13%, [1ÀCl]+), 261.14
(100%, [L2+Na]+) and 239.15 (23%, [L2+H]+).
3.2. Isolation of L2 from 1
The oxidation of 1,2-dioxime to furoxan in acetonitrile is asso-
ciated with the transfer of two electrons and two protons. The
To a suspension of complex [1]Cl (0.122 g, 0.2 mmol) in water
was added an excess amount of aqueous ammonia (45 mL) in small
portions with vigorous stirring. A blue colored solution was formed
immediately along with precipitation of a cream colored solid. The
solid was isolated by filtration, washed with aqueous ammonia,
and air dried. Yield: 0.09 g (94%). Anal. Calcd for C12H6N4O20.5H2O:
C, 58.30; H, 2.85; N, 22.66. Found: C, 58.5; H, 2.3; N, 21.8. MS-ESI
(positive ion mode, acetonitrile): m/z 261.08 (100%, [L2+Na]+) and
239.09 (23%, [L2+H]+). IR (KBr disk, cmÀ1): 3433(br), 3078-2972,
1624(s), 1585(s), 1500(s), 1400(s), 1074, 985, 814, 743, 675. UV–
vis in DMSO (k, nm;
e,
MÀ1 cmÀ1): 343(9200), 327(13200),
Scheme 2. General method for the oxidation of 1,2-dioximes to furoxans.
314(13800). 1H NMR [(CD3)2SO, 300 MHz, 25 °C], d, ppm: 9.16 (d,

5926
O. Das et al. / Tetrahedron Letters 49 (2008) 5924–5927
Table 1
Oxidative transformation of various 1,2-dioxime derivatives to furoxans
Entry
Substrate
Time (h)
Product
Yielda (%)
O
N
HO N
HO N
N
N
N
N
L1
1
12
89b
L2
O
N
N
N
O
N
N
N
HO N
HO N
2
3
12
12
83
88
2
O
2a
N
O
N
HO N
HO N
3
O
3a
N
O
N
O
N
HO N
HO N
4
12
96
O
O
4a
+
4
N
N
(major)
(minor)
O
N
HO N
HO N
5
12
24
91
92
5
O
O
5a
N
O
N
HO N
HO N
6
6
6a
N
a
For pure isolated product.
In the presence of triethylamine as base.
b
solution turned green immediately and slowly to blue after about
2 h. The mixture was further stirred for 10 h (22 h for 1,2-cyclohex-
anedionedioxime) at room temperature. The solution was kept for
several hours at room temperature during which slow evaporation
of the solvent afforded a white crystalline solid of [Cu(CH3CN)4]-
(ClO4). The solid was isolated by filtration, and the filtrate was con-
centrated to dryness. To this was added excess aqueous ammonia
solution (25%), and the solution was stirred for several hours and
the resulting blue solution was extracted with chloroform
(3 Â 25 mL). The combined organic layer was dried over magne-
sium sulfate and evaporated under reduced pressure to obtain
the furoxan. In the case of furoxan 5a, a white solid was precipi-
tated from ammonia solution, which was isolated by filtration,
washed with water, and dried.
Scheme 3. Two different isomers of furoxan 4a in solution.
1H, J = 2.8 Hz); 9.08 (d, 1H, J = 2.7 Hz); 8.84 (d, 1H, J = 7.9 Hz); 8.78
(d, 1H, J = 8.0 Hz); 7.86 (m, 2H). 13C NMR [(CD3)2SO, 75 MHz], d,
ppm: 153.92, 152.26, 150.21, 148.47, 147.28, 132.29, 131.02,
125.77, 125.55, 119.39, 116.79, 108.78.
3.3. General method for the oxidation of 1,2-dioximes (2–6) to
furoxans (2a–6a)
3.3.1. Compound 2a
Off-white solid. Yield: 0.10 g (83%). Anal. Calcd for C12H8N4O2:
C, 60.00; H, 3.36; N, 23.32. Found: C, 59.7; H, 3.8; N, 23.4. MS-ESI
(positive ion mode, acetonitrile): m/z 263.04 (100%, [2a+Na]+)
and 241.06 (35%, [2a+H]+). IR (KBr disk, cmÀ1): 3433(br), 3049–
1,2-Dioxime (0.5 mmol) was dissolved in acetonitrile (15 mL) at
room temperature and Cu(ClO4)2Á6H2O (1 mmol) was added. The

O. Das et al. / Tetrahedron Letters 49 (2008) 5924–5927
5927
2852(s), 1595(s), 1566(s), 1487(s), 1406(s), 1221(s), 1087(s),
800(s), 746. 1H NMR [CDCl3, 300 MHz, 25 °C], d, ppm: 8.57 (d,
1H, J = 4.7 Hz); 8.53 (d, 1H, J = 4.3 Hz); 8.0 (d, 1H, J = 7.9 Hz);
7.99–7.83 (m, 3H); 7.41–7.40 (m, 1H); 7.36–7.32 (m, 1H). 13C
NMR [CDCl3, 75 MHz], d, ppm: 156.96, 150.33, 146.46, 143.63,
138.01, 137.83, 126.15, 125.69, 125.24, 124.36, 114.96.
cmÀ1): 3362(br), 2924–2853(s), 1618(s), 1467(s), 1425(s), 1168,
1132, 1003, 953, 924, 825, 760. 1H NMR [CDCl3, 300 MHz, 25 °C],
d, ppm: 2.82–2.78 (m, 2H); 2.62–2.58 (m, 2H); 1.85–1.80 (m,
4H). 13C NMR [CDCl3, 75 MHz], d, ppm: 156.19, 116.51, 22.15,
21.18, 19.83, 16.44.
Acknowledgments
3.3.2. Compound 3a
Yellow oil. Yield: 0.05 g (88%). Anal. Calcd for C4H6N2O2: C,
42.10; H, 5.30; N, 24.55. Found: C, 42.1; H, 5.1; N, 24.3. IR (KBr disk,
cmÀ1): 2925(s), 1612(s), 1468(s), 1379(s), 1163(s), 1040(s), 993(s),
848(s), 756, 646(s). 1H NMR [CDCl3, 300 MHz, 25 °C], d, ppm: 2.32
(s, 3H); 2.13 (s, 3H). 13C NMR [CDCl3, 75 MHz], d, ppm: 154.74,
113.16, 10.63, 7.44.
This work was supported by the Department of Science and
Technology (DST), Government of India (Project SR/S1/IC-10/
2006). S.P. is thankful to the Council of Scientific and Industrial Re-
search (CSIR), India for a fellowship.
References and notes
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3.3.3. Compound 4a
Yellow oil. Yield: 0.068 g (96%). Anal. Calcd for C6H10N2O2: C,
50.69; H, 7.09; N, 19.71. Found: C, 50.6; H, 6.8; N, 19.2. IR (KBr disk,
cmÀ1): 2966–2876(s), 1610(s), 1468(s), 1153(s), 1015(s), 848, 605.
1H NMR [CDCl3, 300 MHz, 25 °C], d, ppm: The major isomer shows
peaks at 2.62 (t, 2H, J = 7.5 Hz); 2.14 (s, 3H); 1.78–1.64 (m, 2H);
1.03 (t, 3H, J = 7.4 Hz). The minor isomer shows peaks at 2.49 (t,
2H, J = 7.5 Hz); 2.32 (s, 3H); 1.78–1.64 (m, 2H); 0.97 (t, 3H,
J = 7.5 Hz). 13C NMR [CDCl3, 75 MHz], d, ppm: 158.03, 27.59,
24.19, 20.10, 13.65, 7.77 (for the major isomer). 154.45, 29.75,
22.74, 19.06, 11.18 (for the minor isomer).
3.3.4. Compound 5a
White solid. Yield: 0.11 g (91%). Anal. Calcd for C14H10N2O2: C,
70.58; H, 4.23; N, 11.76. Found: C, 70.1; H, 4.3; N, 11.5. MS-ESI (po-
sitive ion mode, acetonitrile): m/z 261.06 (100%, [5a+Na]+). IR (KBr
disk, cmÀ1): 3416(br), 3063–2972(w), 1594–1576(s), 1504(s),
1421(s), 1115(m), 962(s), 833(s), 773(s), 693(s), 656(s). 1H NMR
[CDCl3, 300 MHz, 25 °C], d, ppm: 7.46–7.43 (m, 5H); 7.39–7.18
(m, 5H). 13C NMR [CDCl3, 75 MHz], d, ppm: 156.30, 131.07,
130.63, 129.09, 129.03, 128.77, 128.37, 126.75, 122.96.
16. Yamada, M.; Tanaka, Y.; Yoshimoto, Y.; Kuroda, S.; Shimao, I. Bull. Chem. Soc.
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Soc., Dalton Trans. 2002, 2775–2785.
3.3.5. Compound 6a
Yellow oil. Yield: 0.065 g (92%). Anal. Calcd for C6H8N2O2: C,
51.42; H, 5.75; N, 19.99. Found: C, 51.7; H, 5.6; N, 19.4. IR (KBr disk,