Synthesis of furoxans from styrenes under basic or neutral conditions

Article abstract of DOI:10.1055/s-0033-1338436

Furoxans (1,2,5-oxadiazole 2-oxides) can be synthesized from the corresponding styrenes using NOBF₄ under basic or even almost neutral reaction conditions. Acid-sensitive functional groups are tolerated under the developed basic conditions. For

Full text of DOI:10.1055/s-0033-1338436

1524▌
PAPER
paper
Synthesis of Furoxans from Styrenes under Basic or Neutral Conditions
Synthesis of Furoxans from Styrenes
Ryosuke Matsubara,* Yuta Saeki, Jianhua Li, Kazuo Eda
Department of Chemistry, Graduate School of Science, Kobe University, Nada, Kobe, 657-8501, Japan
Fax +81(78)8035799; E-mail: matsubara.ryosuke@people.kobe-u.ac.jp
Received: 05.03.2013; Accepted after revision: 29.03.2013
yield (Table 1, entry 4). The fact that no product was ob-
tained when a catalytic amount of pyridine and a solvent
amount of triethylamine were used (Table 1, entry 5) may
suggest that the trialkylamine strongly interacts with
Abstract: Furoxans (1,2,5-oxadiazole 2-oxides) can be synthesized
from the corresponding styrenes using NOBF4 under basic or even
almost neutral reaction conditions. Acid-sensitive functional groups
are tolerated under the developed basic conditions. For the sub-
strates having poor reactivity, almost neutral conditions (using pyr- NOBF4 and decomposes or deactivates it. It is of note that,
idine equimolar to NOBF4) are suitable for better yields.
though reaction time was compromised, decreasing the
amount of pyridine from a solvent amount to equimolar to
NOBF4 did not affect the chemical yield (Table 1, entry
8), meaning that a furoxan can be synthesized from an al-
kene under almost neutral conditions.
Key words: heterocycles, nitrogen-containing compounds, fur-
oxans, styrenes, cyclization
Furoxans (1,2,5-oxadiazole 2-oxides) have a unique mo-
lecular structure and have been studied by many scientists
with regard to their structure, chemical properties and
synthesis.1 Additionally, since furoxan derivatives have
been found to activate a soluble guanylate cyclase by
evolving nitric oxide (NO), attention has been paid to the
potency of furoxans as a novel type of drug.2 Pioneered by
Gasco and co-workers, hybrid drugs, which contain a fu-
roxan ring and a pharmacologically active molecular
structure in one molecule, have been developed.3
Table 1 Optimization of the Reaction Conditions for Furoxan Syn-
thesis from β-Methylstyrenea
NOBF4 (3 equiv)
base
O
O
O–
–O
N
N
N
N
solvent, 0 °C
+
(E)-1a
(1 mmol)
2aA
2aB
Entry Solvent + base
Time (h) Yield (%)
Several synthetic methods for furoxans are known, such
as dehydration of α-nitro oximes,4 dimerization of nitrile
N-oxides5 and oxidation of α-dioximes.6 The most direct
way to a furoxan bearing two different substituents is con-
sidered to be the reaction of an alkene with N2O3, since
many alkenes are commercially available (chemical feed-
stock) and readily prepared. However, the only reported
conditions for synthesizing furoxans from alkenes involve
the treatment of alkenes with NaNO2 (aqueous solution or
neat) in glacial acetic acid, typically at below room tem-
perature.7 The reported chemical yields are usually low to
moderate and the substrate scope is rather limited. For fur-
ther study on furoxan-based drug discovery, such as struc-
1
2
3
4
5
6
7
8
Et3N (3 mL)
48
72
72
0
0
DIPEA (3 mL)
2,6-lutidine (3 mL)
pyridine (3 mL)
21
65
0
0.2
Et3N (3 mL) + pyridine (0.1 equiv)
THF (3 mL) + pyridine (3 equiv)
MeCN (3 mL) + pyridine (3 equiv)
CH2Cl2 (3 mL) + pyridine (3 equiv)
48
48
4
0
27
69
4
ture–activity relationships, the development of alternative a The regioselectivity (2aA/2aB) was within the range of 87:13 to
96:4 in all cases where the products were obtained.
synthetic methods for furoxans is highly required. Ac-
cordingly, we sought out such a method and have found
that furoxans can be obtained from the corresponding sty-
With the optimized conditions (Table 1, entry 4 or 8) in
renes using NOBF4 under basic or almost neutral reaction
hand, several styrene derivatives were employed to inves-
conditions.
tigate the substrate scope (Table 2).8 cis-β-Methylstyrene
For the initial investigation, β-methylstyrene (1a) and
NOBF4, as an alkene substrate and a nitrosyl source, re-
spectively, were used (Table 1). While trialkylamines
were revealed as an unsuitable choice of solvent in this
transformation (Table 1, entries 1 and 2), the use of pyri-
dine as a solvent provided the desired furoxan in good
was converted under the optimized conditions into the
corresponding furoxan 2a in almost the same yield and se-
lectivity as that of trans-β-methylstyrene (Table 2, entries
1 and 2). Similarly, both trans- and cis-stilbene gave the
corresponding furoxan 2b (Table 2, entries 3 and 4). The
product yield (42%) is better than that obtained under the
conventional acidic conditions (26%).9 The substrates
bearing a long alkyl chain (Table 2, entries 5 and 6), a free
hydroxy group (Table 2, entry 7) and various substituents
on the aromatic ring (Table 2, entries 8–10) successfully
SYNTHESIS 2013, 45, 1524–1528
Advanced online publication: 14.05.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338436; Art ID: SS-2013-F0183-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Furoxans from Styrenes
1525
Table 2 Furoxan Synthesis from Styrenes under Basic or Almost
reacted with NOBF4 to afford the furoxans in moderate to
good yields with good regioselectivity. It seems that a
substrate with a strong electron-donating group, such as a
methoxy group on an aromatic ring, produces byproducts
derived from oxidation of the aromatic ring by NOBF4,
and a lower yield of furoxan was obtained (Table 2, entry
9). A secondary alkyl substituent at the β-position was
also tolerated (Table 2, entry 11). To our delight, relative-
ly acid-sensitive protecting groups, namely O-tetrahydro-
pyranyl (THP) and O-tert-butyldimethylsilyl (TBS),
survived under our basic reaction conditions and the cor-
responding furoxans 2j and 2k were successfully obtained
in good yields (Table 2, entries 12 and 13). An alkene in a
cyclic system reacted with NOBF4 to provide the corre-
sponding furoxan 2l with excellent selectivity (Table 2,
entry 14). Ethyl cinnamate provided the furoxan 2m in
very low yield (6%) under the basic conditions (3 equiv of
NOBF4 in pyridine solvent). This is presumably because
an electron-deficient olefin such as ethyl cinnamate reacts
poorly with NOBF4, and during the reaction NOBF4 grad-
ually decomposes by mediation of the excess amount of
pyridine.10 This problem could be overcome by reducing
the amount of pyridine (the reaction conditions of entry 8
in Table 1), and a 49% yield of furoxan 2m was obtained
(Table 2, entry 15). These almost neutral conditions (3
equiv of NOBF4 and 3 equiv of pyridine in CH2Cl2) are
seemingly suitable for substrates having poor reactivity.
Neutral Conditionsa (continued)
O
O
O–
–O
NOBF4 (3 equiv)
pyridine, 0 °C
N
N
N
N
R
Ar
+
Ar
R
Ar
R
B
A
Entry Substrate
Product Yieldb (%) A/Bc
C5H11
8
2f
78
95:5
Br
C5H11
9
2g
2h
20
67
91:9
MeO
C5H11
10
90:10
O2N
11
2i
56
85:15
OTHP
12
13
14
15e
2j
53
69
58
49
91:9
87:13
>95:5
>95:5
OTBS
2k
2l
Table 2 Furoxan Synthesis from Styrenes under Basic or Almost
Neutral Conditionsa
O
O
O–
–O
NOBF4 (3 equiv)
pyridine, 0 °C
N
N
N
N
R
Ar
+
CO2Et
Ar
R
Ar
R
2m
B
A
Entry Substrate
1
Product Yieldb (%) A/Bc
a To a solution of a styrene (1 mmol) in pyridine (3 mL) was added
NOBF4 (3 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for
0.2–48 h. Where indicated, a trans/cis mixture of starting styrene was
used (see experimental section for details).
2a
65
87:13
b Isolated yield.
c Determined by 1H NMR spectroscopy of the crude material.
d NOBF4 (6 equiv) was used.
2
2a
2b
2b
2c
57
42
33
75
95:5
–
e To a solution of styrene (1 mmol) and pyridine (3 mmol) in CH2Cl2
(3 mL) was added NOBF4 (3 mmol) at 0 °C.
Ph
3d
4
In all the reactions conducted, the major regioisomer was
found to be the furoxan A bearing the external oxygen
atom on the nitrogen distal from the aromatic ring. The
structures of the major regioisomer of 2a and 2l were un-
ambiguously determined by X-ray diffraction analyses
(Figure 1).11 The structures of the other products, except
2m, were assigned on the basis of the knowledge that the
N-oxide group exerts a shielding influence on the 1H res-
onance of the adjacent aliphatic substituent.12,13 As for
compound 2m, its structure could be determined after
–
Ph
C5H11
5
88:12
C5H11
6
2d
2e
68
47
96:4
92:8
1
conversion of 2m into 2e and comparison by H NMR
OH
7d
spectroscopy (Scheme 1).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1524–1528

1526
R. Matsubara et al.
PAPER
Corder MT-5 instrument. Preparative column chromatography was
performed using Fuji Silysia BW-4:10MH silica gel or YMC_Gel
Silica (6 nm I-40–63 μm). Thin-layer chromatography (TLC) was
carried out on Merk 25 TLC silica gel 60 F254 aluminum sheets. The
identity of the following known compounds was confirmed by a
comparison of the 1H and 13C NMR spectra with the previously re-
ported data: 3-methyl-4-phenylfuroxan (2a),15 3,4-diphenylfuroxan
(2b),9 3-(hydroxymethyl)-4-phenylfuroxan (2e).7b
Furoxans from Styrenes and NOBF4 in Pyridine Solvent; Gen-
eral Procedure
To a stirred soln of a styrene (1 mmol) in pyridine (3 mL) was added
NOBF4 (3 mmol) at 0 °C. Stirring was continued at 0 °C for the in-
dicated period and then the solution, diluted with H2O (20 mL), was
extracted with Et2O (3 × 20 mL). The combined organic layer was
washed with H2O (20 mL) and dried (Na2SO4). The residue ob-
tained after evaporation of the volatiles was purified by chromatog-
raphy on silica gel (EtOAc–hexane) to give the product as an
inseparable mixture of regioisomers.
3-Methyl-4-phenylfuroxan (2a)15
Colorless needles; yield: 116 mg (65%) from the reaction (10 min)
using the trans-alkene; yield: 101 mg (57%) from the reaction (10
min) using the cis-alkene.
Rf = 0.35 (hexane–EtOAc, 10:1).
IR (neat): 1157, 1184, 1202, 1330, 1390, 1429, 1448, 1465, 1574,
1592, 2922 cm–1.
1H NMR (400 MHz, CDCl3): δ (2aA) = 2.37 (s, 3 H, Ar-CH3), 7.54–
7.58 (m, 3 H, Ar-H), 7.68 (m, 2 H, Ar-H); δ (2aB, distinguishable
peak) = 2.55 (s, 3 H, Ar-CH3).
13C NMR (100 MHz, CDCl3): δ (2aA) = 156.8, 131.0, 129.2, 127.3,
126.6, 112.1, 9.2.
Figure 1 Representation of the crystal structures of 2a (top) and 2l
(bottom)
3,4-Diphenylfuroxan (2b)9
Colorless needles; yield: 99 mg (42%) from the reaction (1 h) using
the trans-alkene; yield: 80 mg (33%) from the reaction (2 d) using
the cis-alkene.
O
O–
O
O–
N
O
N
NaBH4 (2 equiv)
N
N
Rf = 0.4 (hexane–EtOAc, 10:1).
OEt
MeOH
r.t., 3 h
Ph
OH
IR (neat): 1327, 1419, 1441, 1503, 1572, 1590, 3026 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.43–7.53 (m, 10 H, Ar-H).
Ph
2m
66%
2e
13C NMR (100 MHz, CDCl3): δ = 156.2, 131.0, 130.5, 129.0, 128.9,
128.6, 128.2, 126.6, 122.8.
Scheme 1 Sodium borohydride reduction of 2m to 2e
MS (EI): m/z = 238 [M]+, 178 [M – 60]+.
In summary, we have found that furoxans can be synthe-
sized from the corresponding styrenes using NOBF4 un-
der basic or even almost neutral reaction conditions. Acid-
sensitive functional groups are tolerated under the devel-
3-Pentyl-4-phenylfuroxan (2c)
Yellow oil; yield: 175 mg (75%) from the reaction (5 h) using the
geometric mixture of alkenes (cis/trans = 67:33).
oped basic conditions. For the substrates having poor re- Rf = 0.35 (hexane–EtOAc, 10:1).
activity, almost neutral conditions (using pyridine
equimolar to NOBF4) are suitable for better yields. Inves-
tigations to reveal the reaction mechanism and the origin
of the regioselectivity are now ongoing in our laborato-
ry.14
IR (neat): 670, 768, 1418, 1455, 1576, 1593, 1572, 2860, 2929,
2957 cm–1.
1H NMR (400 MHz, CDCl3): δ (2cA) = 0.86 (t, J = 6.8 Hz, 3 H,
CH2CH2CH3), 1.29–1.35 (m, 4 H, CH2CH2CH3), 1.61–1.65 (m, 2 H,
CH2CH2CH2CH3), 2.71 (t, J = 7.2 Hz, 2 H, Ar-CH2), 7.50–7.58 (m,
3 H, Ar-H), 7.64–7.71 (m, 2 H, Ar-H); δ (2cB, distinguishable
peak) = 2.84 (t, J = 7.6 Hz, 2 H, Ar-CH2).
All reactions were carried out in well-cleaned and oven-dried glass-
ware with magnetic stirring. Operations were performed under an
atmosphere of dry argon using Schlenk and vacuum techniques. All
starting materials were obtained from commercial sources or were
synthesized using standard procedures. Melting points were mea-
13C NMR (100 MHz, CDCl3): δ (2cA) = 156.8, 130.9, 129.2, 127.3,
126.8, 123.1, 31.0, 25.0, 22.8, 22.0, 13.7; δ (2cB, distinguishable
peaks) = 157.2, 130.3, 129.1, 127.5, 26.6, 25.9.
MS (EI): m/z = 232 [M]+, 172 [M – 60]+.
1
sured on a Yanaco MP-500D apparatus and are not corrected. H
Anal. Calcd for C13H16N2O2: C, 67.22; H, 6.94; N, 12.06. Found: C,
67.17; H, 7.04; N, 11.92.
and 13C NMR spectra (400 and 100 MHz, respectively) were re-
corded on a JEOL JNM-LA 400 instrument using TMS (0 ppm) and
CDCl3 (77.0 ppm) as an internal standard, respectively. Mass spec-
tra were measured using a Thermo Quest LCQ DECA plus spec-
trometer. Elemental analyses were carried out using a Yanako CHN
4-(2-Naphthyl)-3-pentylfuroxan (2d)
Yellow oil; yield: 191 mg (68%) from the reaction (0.5 h) using the
geometric mixture of alkenes (cis/trans = 70:30).
Synthesis 2013, 45, 1524–1528
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Synthesis of Furoxans from Styrenes
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Rf = 0.32 (hexane–EtOAc, 10:1).
IR (neat): 750, 818, 1418, 1461, 1590, 2859, 2928, 2955 cm–1.
Anal. Calcd for C14H18N2O3: C, 64.11; H, 6.92; N, 10.68. Found: C,
64.19; H, 7.15; N, 10.07.
1H NMR (400 MHz, CDCl3): δ (2dA) = 0.86 (t, J = 7.2 Hz, 3 H,
CH2CH2CH2CH3), 1.26–1.38 (m, 6 H, CH2CH2CH2CH3), 2.80 (t,
J = 8.0 Hz, 2 H, Ar-CH2), 7.57–7.64 (m, 2 H, Ar-H), 7.75 (dd,
J = 1.2, 7.2 Hz, 1 H, Ar-H), 7.91–8.02 (m, 3 H, Ar-H), 8.13 (s, 1 H,
Ar-H); δ (2dB; distinguishable peak) = 2.92 (t, J = 8.0 Hz, 2 H, Ar-
CH2).
13C NMR (100 MHz, CDCl3): δ (2dA) = 156.9, 134.1, 132.9, 129.3,
128.6, 128.0, 127.8, 127.7, 127.2, 124.2, 123.9, 115.8, 31.6, 25.5,
23.6, 22.5, 14.2; δ (2dB; distinguishable peaks) = 26.8, 26.0.
4-(4-Nitrophenyl)-3-pentylfuroxan (2h)
Pale yellow needles; yield: 185 mg (67%) from the reaction (48 h)
using the geometric mixture of alkenes (cis/trans = 63:37).
Rf = 0.2 (hexane–EtOAc, 5:1).
IR (neat): 713, 851, 1250, 1434, 1534, 1587, 2860, 2931, 2958 cm–1.
1H NMR (400 MHz, CDCl3): δ (2hA) = 0.85–0.91 (m, 3 H,
CH2CH2CH3), 1.25–1.39 (m, 4 H, CH2CH2CH3), 1.59–1.73 (m, 2 H,
CH2CH2CH2CH3), 2.74 (t, J = 8 Hz, 2 H, Ar-CH2), 7.87–7.97 (m, 2
H, Ar-H), 7.99–8.44 (m, 2 H, Ar-H); δ (2hB; distinguishable
peak) = 2.90 (t, J = 8 Hz, 2 H, Ar-CH2).
MS (EI): m/z = 282 [M]+, 222 [M – 60]+.
13C NMR (100 MHz, CDCl3): δ (2hA) = 155.0, 149.2, 132.9, 128.5,
124.5, 115.0, 31.2, 25.2, 23.0, 22.1, 13.7.
Anal. Calcd for C17H18N2O2: C, 72.32; H, 6.43; N, 9.92. Found: C,
72.26; H, 6.54; N, 9.78.
MS (EI): m/z = 217 [M – 60]+.
3-(Hydroxymethyl)-4-phenylfuroxan (2e)7b
White solid; yield: 91 mg (47%) from the reaction (1 h) using the
trans-alkene.
Anal. Calcd for C13H15N3O4: C, 56.31; H, 5.45; N, 15.15. Found: C,
56.36; H, 5.45; N, 15.17.
Rf = 0.6 (hexane–EtOAc, 1:1).
IR (neat): 1010, 1409, 1462, 1575, 1599, 2930, 3402 cm–1.
3-Isopropyl-4-(2-naphthyl)furoxan (2i)
Colorless needles; yield: 144 mg (56%) from the reaction (2 h) us-
ing the geometric mixture of alkenes (cis/trans = 85:15).
1H NMR (400 MHz, CDCl3): δ (2eA) = 2.48 (s, 1 H, OH), 4.76 (s,
2 H, CH2), 7.51–7.60 (m, 3 H, Ar-H), 7.80–7.83 (m, 2 H, Ar-H);
δ (2eB; distinguishable peak) = 4.89 (s, 2 H, CH2).
13C NMR (100 MHz, CDCl3): δ (2eA) = 156.8, 131.4, 129.4, 127.7,
126.1, 53.3; δ (2eB; distinguishable peaks) = 130.7, 129.2, 127.4,
56.6.
Rf = 0.42 (hexane–EtOAc, 10:1).
IR (neat): 754, 811, 864, 1324, 1385, 1202, 1420, 1455, 1591, 2937,
2982 cm–1.
1H NMR (400 MHz, CDCl3): δ (2iA) = 1.37 (d, J = 6.8 Hz, 6 H,
2 × CH3), 3.21 (septet, J = 6.8 Hz, 1 H, CH), 7.55–7.69 (m, 3 H, Ar-
H), 7.88–8.20 (m, 4 H, Ar-H); δ (2iB; distinguishable peak) = 3.30
(septet, J = 6.8 Hz, 1 H, CH).
13C NMR (100 MHz, CDCl3): δ (2iA) = 157.0, 132.8, 129.1, 128.5,
128.4, 127.9, 127.8, 127.2, 124.6, 124.0, 118.7, 23.8, 17.1; δ (2iB;
distinguishable peaks) = 162.2, 133.7, 132.9, 129.1, 128.5, 127.9,
127.8, 127.1, 124.1, 23.8, 17.1.
MS (EI): m/z = 192 [M]+, 132 [M – 60]+.
4-(3-Bromophenyl)-3-pentylfuroxan (2f)
Yellow oil; yield: 240 mg (78%) from the reaction (1.5 h) using the
geometric mixture of alkenes (cis/trans = 84:16).
Rf = 0.25 (hexane–EtOAc, 10:1).
IR (neat): 1429, 1455, 1564, 1593, 2859, 2929, 2956 cm–1.
MS (EI): m/z = 254 [M]+, 194 [M – 60]+.
1H NMR (400 MHz, CDCl3): δ (2fA) = 0.85–0.91 (m, 3 H,
CH2CH2CH3), 1.29–1.36 (m, 4 H, CH2CH2CH3), 1.61–1.67 (m, 2 H,
CH2CH2CH2CH3), 2.69 (t, J = 8.4 Hz, 2 H, Ar-CH2), 7.41 (t, J = 8.4
Hz, 1 H, Ar-H), 7.58 (dt, J = 1.2, 7.6 Hz, 1 H, Ar-H), 7.69 (dt,
J = 0.8, 8.0 Hz, 1 H, Ar-H), 7.83 (t, J = 1.6 Hz, 1 H, Ar-H); δ (2fB;
distinguishable peak) = 2.83 (t, J = 7.6 Hz, 2 H, Ar-CH2).
Anal. Calcd for C15H14N2O2: C, 70.85; H, 5.55; N, 11.02. Found: C,
70.36; H, 5.56; N, 10.92.
4-Phenyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]furoxan
(2j)
Colorless oil; yield: 145.6 mg (53%) from the reaction (0.5 h) using
13C NMR (100 MHz, CDCl3): δ (2fA) = 155.6, 134.0, 130.8, 130.5,
128.8, 126.0, 123.3, 115.4, 31.1, 25.1, 22.9, 22.0, 13.8; δ (2fB; dis-
tinguishable peaks) = 133.5, 130.6, 130.4, 126.1, 26.7, 25.9, 22.1,
13.8.
the trans-alkene.
Rf = 0.35 (hexane–EtOAc, 10:1).
IR (neat): 963, 1010, 1058, 1076, 1119, 1479, 1577, 1597, 2942
cm–1.
MS (EI): m/z = 251.1 [M – 60]+.
1H NMR (400 MHz, CDCl3): δ (2jA) = 1.51–1.81 (m, 6 H,
CH2CH2CH2CH2O), 3.52–3.57 (m, 2 H, OCH2CH2), 3.78–3.84 (m,
1 H, OCHO), 4.60 (d, J = 12.8 Hz, 1 H, Ar-CH2), 4.74 (d, J = 12.8
Hz, 1 H, Ar-CH2), 7.30–7.58 (m, 3 H, Ar-H), 7.83–7.94 (m, 2 H, Ar-
H); δ (2jB; distinguishable peak) = 7.94–7.96 (m, 2 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ (2jA) = 157.1, 131.2, 129.2, 127.5,
126.5, 122.6, 112.9, 99.2, 62.3, 57.2, 30.2, 25.1, 18.9; δ (2jB; dis-
tinguishable peaks) = 154.3, 130.9, 129.3, 127.9, 122.9, 98.3, 59.8.
Anal. Calcd for C13H15BrN2O2: C, 50.18; H, 4.86; N, 9.00. Found:
C, 50.31; H, 4.86; N, 9.05.
4-(4-Methoxyphenyl)-3-pentylfuroxan (2g)
Yellow oil; yield: 52 mg (20%) from the reaction (0.5 h) using the
geometric mixture of alkenes (cis/trans = 55:45).
Rf = 0.25 (hexane–EtOAc, 10:1).
IR (neat): 1175, 1253, 1435, 1450, 1574, 1592, 2860, 2930, 2957
cm–1.
MS (EI): m/z = 175 [M – 101 (OTHP)]+.
Anal. Calcd for C14H16N2O4: C, 60.86; H, 5.84; N, 10.14. Found: C,
61.00; H, 5.88; N, 9.76.
1H NMR (400 MHz, CDCl3): δ (2gA) = 0.85–0.91 (m, 3 H,
CH2CH2CH3), 1.25–1.39 (m, 4 H, CH2CH2CH3), 1.59–1.73 (m, 2 H,
CH2CH2CH2CH3), 2.69 (t, J = 7.6 Hz, 2 H, Ar-CH2), 3.87 (s, 3 H,
Ar-OCH3), 7.01–7.07 (m, 2 H, Ar-H), 7.65–7.68 (m, 2 H, Ar-H); δ
(2gB; distinguishable peak) = 2.82 (t, J = 8 Hz, Ar-CH2).
3-[(tert-Butyldimethylsilyloxy)methyl]-4-phenylfuroxan (2k)
Colorless oil; yield: 212 mg (69%) from the reaction (0.5 h) using
the trans-alkene.
13C NMR (100 MHz, CDCl3): δ (2gA) = 161.6, 156.5, 129.1, 119.1,
115.7, 114.7, 55.4, 31.2, 25.2, 23.1, 22.2, 13.8; δ (2gB; distinguish-
able peaks) = 128.9, 114.6, 22.1.
Rf = 0.4 (hexane–EtOAc, 10:1).
IR (neat): 1276, 1384, 1434, 1461, 1579, 1600, 2853, 2930, 2957
cm–1.
MS (EI): m/z = 262.0 [M]+, 202.1 [M – 60]+.
© Georg Thieme Verlag Stuttgart · New York
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1H NMR (400 MHz, CDCl3): δ (2kA) = 0.14 (s, 6 H), 0.88 (s, 9 H),
4.72 (s, 2 H), 7.47–7.58 (m, 3 H, Ar-H), 7.91–7.94 (m, 2 H, Ar-H);
δ (2kB; distinguishable peak) = 4.83 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ (2kA) = 157.5, 131.5, 129.1, 127.8,
126.6, 114.2, 54.1, 25.6, 18.1, –5.3; δ (2kB; distinguishable
peaks) = 130.5, 129.0, 127.6, 57.1.
(2) (a) Fruttero, R.; Crosetti, M.; Chegaev, K.; Guglielmo, S.;
Gasco, A.; Berardi, F.; Niso, M.; Perrone, R.; Panaro, M. A.;
Colabufo, N. A. J. Med. Chem. 2010, 53, 5467. (b) Rai, G.;
Sayed, A. A.; Lea, W. A.; Luecke, H. F.; Chakrapani, H.;
Prast-Nielsen, S.; Jadhav, A.; Leister, W.; Shen, M.; Inglese,
J.; Austin, C. P.; Keefer, L.; Arnér, E. S. J.; Simeonov, A.;
Maloney, D. J.; Williams, D. L.; Thomas, C. J. J. Med.
Chem. 2009, 52, 6474. (c) Cena, C.; Bertinaria, M.; Boschi,
D.; Giorgis, M.; Gasco, A. ARKIVOC 2006, (vii), 301.
(d) Grosso, E. D.; Boschi, D.; Lazzarato, L.; Cena, C.; Stilo,
A. D.; Fruttero, R.; Moro, S.; Gasco, A. Chem. Biodiversity
2005, 2, 886. (e) Medana, C.; Ermondi, G.; Fruttero, R.;
Stilo, A. D.; Ferretti, C.; Gasco, A. J. Med. Chem. 1994, 37,
4412. (f) Calvino, R.; Fruttero, R.; Ghigo, D.; Bosia, A.;
Pescarmona, G. P.; Gasco, A. J. Med. Chem. 1992, 35, 3296.
(g) Feelisch, M.; Schönafinger, K.; Noack, E. Biochem.
Pharmacol. 1992, 44, 1149. (h) Ghigo, D.; Heller, R.;
Calvino, R.; Alessio, P.; Fruttero, R.; Gasco, A.; Bosia, A.;
Pescarmona, G. Biochem. Pharmacol. 1992, 43, 1281.
(3) (a) Cena, C.; Lolli, M. L.; Lazzarato, L.; Guaita, E.; Morini,
G.; Coruzzi, G.; McElroy, S. P.; Megson, I. L.; Fruttero, R.;
Gasco, A. J. Med. Chem. 2003, 46, 747. (b) Fruttero, R.;
Boschi, D.; Stilo, A. D.; Gasco, A. J. Med. Chem. 1995, 38,
4944.
MS (EI): m/z = 249 [M – 57 (t-Bu)]+, 189 [M – 57 – 60]+.
Anal. Calcd for C15H22N2O3Si: C, 58.79; H, 7.24; N, 9.14. Found:
C, 58.70; H, 7.36; N, 9.20.
4,5-Dihydronaphtho[1,2-c][1,2,5]oxadiazole 3-Oxide (2l)
White solid; yield: 103 mg (58%) from the reaction (1 h) using the
cyclic alkene.
Mp 84.4–85.5 °C.
Rf = 0.3 (hexane–EtOAc, 10:1).
IR (neat): 1350, 1434, 1535, 1587, 2861, 2959 cm–1.
1H NMR (400 MHz, CDCl3): δ (2lA) = 2.95 (t, J = 7.6 Hz, 2 H, Ar-
CH2CH2CN), 3.12 (t, J = 7.6 Hz, 2 H, Ar-CH2CH2CN), 7.33–7.48
(m, 3 H, Ar-H), 7.98–8.00 (dd, J = 1.2, 9.2 Hz, 1 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ (2lA) = 153.4, 136.9, 131.6, 129.1,
127.8, 124.3, 123.6, 111.3, 27.2, 18.0.
MS (EI): m/z = 188.1 [M]+, 128.1 [M – 60]+.
(4) (a) Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O.;
Ballini, R.; Bosica, G. Tetrahedron Lett. 2000, 41, 8817.
(b) Klamann, D.; Koser, W.; Weyerstahl, P.; Fligge, M.
Chem. Ber. 1965, 98, 1831.
(5) Wiley, R. H.; Wakefield, B. J. J. Org. Chem. 1960, 25, 546.
(6) Alimenti, G.; Grifantini, M.; Gualteri, F.; Stein, M. L.
Tetrahedron 1968, 24, 395.
Anal. Calcd for C10H8N2O2: C, 63.83; H, 4.29; N, 14.89. Found: C,
63.75; H, 4.30; N, 14.74.
Ethyl 4-Phenylfuroxan-3-carboxylate (2m)
Colorless oil; yield: 115 mg (49%) from the reaction (2 d) using the
trans-alkene.
(7) (a) Dinh, N. H.; Ly, N. T.; Hoan, P. V. J. Heterocycl. Chem.
2006, 43, 1657. (b) Gasco, A. M.; Fruttero, R.; Sorba, G.;
Gasco, A. Liebigs Ann. Chem. 1991, 1211. (c) Fruttero, R.;
Ferrarotti, B.; Serafino, A.; Stilo, A. D.; Gasco, A.
J. Heterocycl. Chem. 1989, 26, 1345.
(8) Aliphatic internal alkenes such as oct-4-ene and
cyclohexene were tried as substrates in this furoxan
synthesis transformation, but the desired furoxans were
obtained in much lower yield (<10%) than in the cases using
styrene derivatives as substrates.
Rf = 0.35 (hexane–EtOAc, 1:1).
IR (neat): 1184, 1202, 1330, 1390, 1429, 1448, 1465, 1478, 1574,
1592, 1734, 2979 cm–1.
1H NMR (400 MHz, CDCl3): δ (2mA) = 1.29 (t, J = 7.0 Hz, 3 H,
OCH2CH3), 4.35–4.40 (q, J = 7.0 Hz, 2 H, OCH2CH3), 7.49–7.59
(m, 3 H, Ar-H), 7.64–7.71 (m, 2 H, Ar-H); δ (2mB; distinguishable
peaks) = 1.39 (t, J = 7.0 Hz, 3 H, OCH2CH3), 4.46 (q, J = 7.0 Hz, 2
H, OCH2CH3).
13C NMR (100 MHz, CDCl3): δ (2mA) = 156.5, 156.1, 131.6,
129.0, 128.5, 126.0, 63.0, 13.8;
peaks) = 128.6, 128.4, 62.6.
δ (2mB; distinguishable
(9) Velázquez, C.; Rao, P. N. P.; McDonald, R.; Knaus, E. E.
Bioorg. Med. Chem. 2005, 13, 2749.
(10) The reaction of NOBF4 and pyridine has been reported, see:
Olah, G. A.; Olah, J. A.; Overchuk, N. A. J. Org. Chem.
1965, 30, 3373.
(11) CCDC 922872 (2a) and CCDC 922871 (2l) contain
supplementary crystallographic data for this paper. These
data can be obtained free of charge at
MS (EI): m/z = 234 [M]+, 174 [M – 60]+.
Anal. Calcd for C11H10N2O4: C, 56.41; H, 4.30; N, 11.96. Found: C,
56.52; H, 4.29; N, 11.80.
Acknowledgment
www.ccdc.cam.ac.uk/conts/retrieving.html or from the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; Fax +44(1223)336033; E-mail:
deposit@ccdc.cam.ac.uk.
We thank the Naito Foundation for financial support.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
(12) (a) Mallory, F. B.; Cammarata, A. J. Am. Chem. Soc. 1966,
88, 61. (b) Freeman, J. P. J. Org. Chem. 1963, 28, 2508.
(13) The structures of the minor regioisomers were assigned by
NMR spectroscopy and GC-MS analysis.
(14) The proposed reaction mechanism is as follows:
Electrophilic addition of a nitrosyl cation to an alkene,
followed by deprotonation by pyridine, affords a
nitrosoalkene. A second addition of a nitrosyl cation to the
nitrosoalkene and cyclization leads to a furoxan.
nnfomartit
References
(1) (a) Sheremetev, A. B.; Makhova, N. N.; Friedrichsen, W.
Adv. Heterocycl. Chem. 2001, 78, 65. (b) Gasco, A.;
Boulton, A. J. Adv. Heterocycl. Chem. 1981, 29, 251.
(15) Mitchell, W. R.; Paton, R. M. ARKIVOC 2009, (xiv), 200.
Synthesis 2013, 45, 1524–1528
© Georg Thieme Verlag Stuttgart · New York