Synthesis of Furoxans (1,2,5-oxadiazole 2-oxides) from Styrenes and Nitrosonium Tetrafluoroborate in Non-Acidic Media and Mechanistic Study

Article abstract of DOI:10.1002/jhet.2360

Diverse furoxans (1,2,5-oxadiazole 2-oxides) were synthesized from the corresponding styrenes using nitrosonium tetrafluoroborate as the nitrosation reagent in pyridine (basic media) or dichloromethane (neutral media). Acid-sensitive functional groups were tolerated under these conditions. The probable reaction mechanism was elucidated. The experimental results support an ionic reaction pathway in contrast to the conventional acidic conditions with a radical mechanism.

Full text of DOI:10.1002/jhet.2360

Month 2015
Synthesis of Furoxans (1,2,5-oxadiazole 2-oxides) from Styrenes and
Nitrosonium Tetrafluoroborate in Non-Acidic Media and Mechanistic Study
*
Ryosuke Matsubara, Akihiro Ando, Yuta Saeki, Kazuo Eda, Naoki Asada, Tomoaki Tsutsumi, Yong Soon Shin,
and Masahiko Hayashi
Department of Chemistry, Graduate School of Science, Kobe University, Nada, Kobe, 657-8501, Japan
*
E-mail: matsubara.ryosuke@people.kobe-u.ac.jp
Received August 4, 2014
DOI 10.1002/jhet.2360
Published online in 00 Month 2015 Wiley Online Library (wileyonlinelibrary.com).
Diverse furoxans (1,2,5-oxadiazole 2-oxides) were synthesized from the corresponding styrenes using
nitrosonium tetrafluoroborate as the nitrosation reagent in pyridine (basic media) or dichloromethane (neutral
media). Acid-sensitive functional groups were tolerated under these conditions. The probable reaction mechanism
was elucidated. The experimental results support an ionic reaction pathway in contrast to the conventional acidic
conditions with a radical mechanism.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
is catalyzed by diverse Brønsted and Lewis acids [9] resulting
in the regiospecific synthesis of furoxans. The major isomer
contains the N-oxide oxygen atom on the same side as the nitro
group of the starting α-nitrooxime. In contrast to the aforemen-
tioned pathways requiring a relatively cumbersome preparation
of the starting materials, the one-step transformation of alkenes
to furoxans by treating with dinitrogen trioxide (N2O3) in an
acidic media (route e) [10] is advantageous because diverse
alkenes are commercially available (chemical feedstock) and
readily synthesized. The regioselectivity of this reaction is
moderate to high depending on the substituents on the alkenes.
At elevated temperatures (approximately 100°C), furoxans
are known to undergo isomerization through a transient
dinitrosoalkene intermediate (Scheme 1) [11]. The difficult-
to-synthesize regioisomers were often prepared by this
isomerization technique followed by their chromatographic
separation.
As aforementioned, the most reported transformations of
alkenes to furoxans employ a NaNO2-Brønsted acid system.
One of the exceptions was the reaction of alkenes with AgNO2
and trimethylsilyl chloride in which the initially formed
pseudonitrosite dimer was treated with sulfuric acid at 120°C
to afford the corresponding furoxan derivatives [12]. There-
fore, we sought an alternative synthetic method that would al-
low the use of acid-sensitive substrates for furoxan synthesis.
Furoxans, 1,2,5-oxadiazole 2-oxides, first appeared in the
literature as early as the 1850s [1]. Because of their unique
molecular structure, much debate ensued in determining
the structure for a long time [2] until X-ray diffraction and
NMR spectroscopy analyses resolved the question in the
1960s [3]. Furoxans can have two substituents at the 3- and
4-positions; unless the two substituents are identical, two
regioisomers are present.
Since the reports on the release of nitric oxide (NO) by
furoxan derivatives in the presence of thiol cofactors
activating the soluble guanylate cyclase [4], studies on the
development of furoxan-based drugs have been pursued by
many research groups [5].
A few representative methods for the synthesis of
furoxans are shown in Figure 1. Nitrile oxides, readily
prepared from chlorooximes, spontaneously dimerize to
afford furoxans (route a) [6]. However, only symmetrically
disubstituted furoxans (R1 =R2) can be prepared through
this route. Asymmetrically disubstituted furoxans (R1 ≠R2)
are synthesized by the oxidation of α-dioximes (route b)
[7] or the reaction of vicinal vinyl nitro compounds with
sodium azide (route c) [8]. Depending on the substituents,
furoxans can be prepared regioselectively. α-Nitrooximes
are also good precursors of furoxans (route d). This conversion
© 2015 HeteroCorporation

R. Matsubara, A. Ando, Y. Saeki, K. Eda, N. Asada, T. Tsutsumi, Y. S. Shin, and M. Hayashi
Vol 000
Table 1
Optimization of the reaction conditions for furoxan synthesis from
β-methylstyrene.a
Time
(h)
Yield
(%)
Entry
Solvent + Base
Pyridine (3 mL)
Pyridine (3 mL)
2,6-lutidine (3 mL)
Figure 1. Reported methods for the synthesis of furoxans.
Scheme 1. Isomerization of furoxan.
1
2b
3
4
5
6
7
8
9
0.2
0.7
72
48
72
48
48
4
65
81
21
0
0
0
0
27
69
Et3N (3 mL)
iPr2NEt (3 mL)
Et3N (3 mL) + pyridine (0.1 equiv)
THF (3 mL) + pyridine (3 equiv)
CH3CN (3 mL) + pyridine (3 equiv)
CH2Cl2 (3 mL) + pyridine (3 equiv)
4
aRegioselectivity (2aA/2aB) was within a range from 87/13 to 96/4 in all
the cases.
We recently reported that furoxans could be prepared
from styrenes using nitrosonium tetrafluoroborate
(NOBF4) and pyridine [13]. In contrast to the conventional
methods where alkenes are converted to furoxans using
N2O3 generated from sodium nitrite (NaNO2) and acid,
our method employs non-acidic media, which allows the
use of substrates with an acid-sensitive protecting group.
In this paper, we present a full account of this reaction,
particularly focusing on the reaction mechanism.
bNOCl (>10 equiv) was used instead of NOBF4.
was obtained. This is probably because Et3N reacts with
NOBF4, thereby deactivating or decomposing it. The
amount of pyridine could be decreased to an equimolar
amount of the NOBF4 without affecting the product yield, at
the cost of the reaction time (Table 1, entry 9).
The successful examples of the furoxan synthesis from
styrene derivatives are listed in Table 2. Both the cis- and
the trans-alkenes afforded the corresponding furoxans
(Table 2, entries 1–4). The low yields in entries 3 and 4
can be accounted for by the formation of by-product 3
(Fig. 2) [16]. Nevertheless, furoxan 2b could be prepared
in a better yield under this condition than in the NaNO2-
acid system (26% yield) [17]. The internal alkenes bearing
long alkyl chains (Table 2, entries 5 and 6) and substituted
aromatic rings (Table 2, entries 8–10) afforded the corre-
sponding furoxan derivatives in moderate to good yields.
A free aliphatic alcohol group was tolerated in the reaction
affording the corresponding furoxan, albeit in a moderate
yield even with 6 equiv of NOBF4 (Table 2, entry 7). This
is probably because NOBF4 reacted with the free alcohol
group forming a nitrite (RONO). The low yield in the
reaction of p-methoxy-substituted styrene derivative can
be attributed to the undesired oxidation of the aromatic ring
with NOBF4 (Table 2, entry 9) [16b]. In order to demon-
strate the advantages of these non-acidic reaction condi-
tions, the substrates with relatively acid-sensitive
functional groups were subjected to NOBF4 in pyridine
(Table 2, entries 12 and 13). In both the cases, the
RESULTS AND DISCUSSION
Synthesis of furoxans from styrenes in non-acidic media.
The initial investigation on furoxan synthesis in non-acidic
media started with β-methylstyrene as the substrate. The
results of the screening of nitrosonium ion (NO+) source and
base are summarized in Table 1. NOBF4, a commercially
available solid, combined with pyridine afforded furoxan 2a
in 65% yield with 3-methyl-4-phenylfuroxan (2aA) being
the major product (Table 1, entry 1). The use of an excess
amount (>10 equiv) of nitrosyl chloride (NOCl) instead
of NOBF4 provided a better result (81% yield, Table 1,
entry 2). However, NOCl is a gas at room temperature, thus
making it extremely difficult to handle. Therefore, the
further investigations were continued with NOBF4. The
reaction using 2,6-lutidine afforded the furoxan in a low
yield (Table 1, entry 3). In contrast to pyridine type of base,
more basic trialkylamines did not afford the furoxan
(Table 1, entries 4 and 5). Based on the assumption that the
formation of a pyridine-NOBF4 complex is the key to this
reaction [14], a catalytic amount of pyridine in the presence
of Et3N was tried (Table 1, entry 6); however, no product
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Furoxan Synthesis and Its Mechanistic Study
Table 2
Furoxan synthesis from styrene derivatives under basic or almost neutral conditions.a
Entry
1
Substrate
Yield (%)b
65
A/Bc
Product
87/13
2a
2
57
42
95/5
2a
2b
3d
—
4
5
33
75
—
2b
2c
88/12
6
68
47
78
96/4
92/8
95/5
2d
2e
2f
7d
8
9
20
67
56
91/9
90/10
85/15
2g
2h
2i
10
11
12
13
53
69
91/9
2j
87/13
2k
(Continued)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. Matsubara, A. Ando, Y. Saeki, K. Eda, N. Asada, T. Tsutsumi, Y. S. Shin, and M. Hayashi
Vol 000
Table 2
(Continued)
Entry
14
Substrate
Yield (%)b
58
A/Bc
Product
>95/5
2l
15e
49
>95/5
2m
aNOBF4 (3 mmol) was added to a solution of alkene (1 mmol) in pyridine (3 mL) at 0°C. The reaction mixture was
stirred at 0°C for 0.2–48 h. A trans/cis mixture of the starting styrene was used where indicated. See the Experimental
section for the details.
bIsolated yield
cDetermined by the 1H NMR spectra of the crude products
dNOBF4 (6 equiv) was used.
eNOBF4 (3 mmol) was added to a solution of alkene (1 mmol) and pyridine (3 mmol) in CH2Cl2 (1.4 mL) at 0°C.
of ethyl cinnamate with 3 equiv of NOBF4 and 3 equiv of
pyridine in CH2Cl2 for 48h afforded the furoxan in 49%
yield (Table 2, entry 15). This almost neutral condition
may also be suitable for the other electron-deficient
alkenes.
Under the optimized reaction conditions (NOBF4 in
pyridine), β-bromostyrene (4) or cinnamonitrile (5) did not
afford the corresponding furoxans; most of the starting ma-
terials were recovered. This is probably because the
nucleophilicities of these olefins are not sufficient to react
with NOBF4. The reaction of methyl 2-phenylethenyl ether
(6) did not afford the desired product either, despite the
complete consumption of the substrate. The internal olefins
without an aryl substituent, such as 4-octene (7), were found
not suitable for this reaction. In this case, less than 20%
yield of the corresponding furoxan was obtained (Fig. 3).
Figure 2. Formation of by-product 3 from stilbene and NOBF4, and
X-ray crystallographic structures of 3 [15].
corresponding furoxans were obtained in 53% and 69%
yields, respectively, whereas their reactions with NaNO2
in aqueous acetic acid at room temperature afforded the
products in 23% and 1% yields, respectively [18]. An
alkene in a cyclic system reacted smoothly with NOBF4
under the standard reaction conditions to afford tricyclic
product 2l in 58% yield with excellent regioselectivity
(Table 2, entry 14). Electron-deficient alkenes showed poor
reactivity; thus, the reaction of ethyl cinnamate with
NOBF4 in pyridine for 48 h afforded furoxan 2m in only
6% yield. Prolonging the reaction time did not increase
the yield, and most of the starting ethyl cinnamate was re-
covered, indicating that NOBF4 was consumed. NOBF4 is
known to form an acid–base complex with pyridine; how-
ever, it decomposes in the presence of an excess amount of
pyridine because of the nucleophilic attack of pyridine on
the NOBF4-pyridine complex. To our delight, the reaction
Figure 3. Unsuccessful substrates for furoxan synthesis.
Figure 4. Comparison of 1H NMR chemical shifts of regioisomers.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Furoxan Synthesis and Its Mechanistic Study
Scheme 2. Synthesis of nitrofuroxan 8.
Figure 5. X-ray crystallographic structure of 2nB.
8 was formed in either case. This suggests that β-
nitrostyrene or 3-phenylfuroxan (9B) is not the intermedi-
ate for 8.
Mechanistic study of furoxan synthesis using NOBF4 and
pyridine.
In order to reveal the origin of high
regioselectivity observed in the synthesis of furoxans,
several substrates with varying degrees of steric bulkiness
were employed. First, the effect of the steric bulkiness of
the alkyl substituents (on the C¼C double bonds) on the
regioselectivity was examined (Table 3). The styrene
derivatives with less bulky alkyl substituents such as
primary and secondary alkyl groups were found to afford
regioisomer A selectively (Table 3, entries 1 and 2). On
the other hand, regioisomer B was preferentially formed
when bulkier tertiary butyl-substituted furoxan 1n was
used (Table 3, entry 3). Because the major regioisomer of
2n could not be assigned by the 1H NMR analysis
because of the absence of the indicative protons (Fig. 4),
the structure was determined by the X-ray
crystallographic analysis (Fig. 5).
The assignments for the structures of the two regioisomers
can be made by the 1H NMR spectral analysis [19]. Because
of the resonance nature of furoxan, as shown in Figure 4, the
proton on the carbon at the 3-position of furoxan (Ha) is
electron-rich and therefore shielded in NMR spectra com-
pared to the Hb. The major regioisomer of 2m, which has
no such proton, was revealed as also type A after 2mA was
reduced by NaBH4 to the known alcohol 2eA [12,20].
The reaction of styrene and NOBF4 in pyridine afforded
4-nitro-substituted furoxan 8, as a single regioisomer, in-
stead of the expected 4-phenylfuroxan (9A) (Scheme 2,
equation 1) [21]. The reactions of monosubstituted alkenes
(terminal alkenes) and NaNO2 in an acidic media are re-
ported to afford 4-nitro-substituted furoxans similarly,
whose reaction mechanism has yet to be fully understood.
In the literatures, β-nitrostyrene and 3-phenylfuroxan (9B)
[22] are suggested as the possible intermediates [23].
Therefore, each of them was subjected to NOBF4 in pyri-
dine (Scheme 2, equations 2 and 3); however, no furoxan
Table 4
Effect of steric bulkiness of aryl substituent on regioselectivity.
Table 3
Effect of steric bulkiness of the alkyl substituent on the regioselectivity.
Entry
R (cis/trans)a
Time (h)
Yield (%)
A/B
Entry
R1, R2 (cis/trans)a
Time (h)
Yield (%)
A/B
1
2
3
n-C5H11 (70/30)
i-Pr (85/15)
t-Bu (80/20)
0.5
2
48
68
56
23
96/4
85/15
17/83
1
2
3
H, H (67/33)
Me, H (74/26)
Me, Me (71/29)
5
48
48
75
31
22
88/12
62/38
35/65
aThe cis/trans ratio of the starting alkenes.
aThe cis/trans ratio of the starting alkenes.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. Matsubara, A. Ando, Y. Saeki, K. Eda, N. Asada, T. Tsutsumi, Y. S. Shin, and M. Hayashi
Vol 000
Under acidic conditions, NaNO2 produces dinitrogen trioxide
(N2O3) that splits into a pair of nitrogen radicals, NO and
NO2 radicals (Fig. 6, equation 4). The NO2 radical then reacts
with the styrene double bond to form an N–C bond predomi-
nantly at the carbon away from the aryl group and benzyl rad-
ical 10, which is stabilized at the benzylic position. Next,
benzyl radical 10 reacts with NO radical to afford
pseudonitrosite 11 [25], which undergoes dehydration to afford
furoxan 2A (Fig. 6, equation 5).
Although strict anhydrous conditions were employed in
our investigation, the possibility of contamination by a
small amount of water cannot be ruled out. If water exists
in our system, it presumably reacts with NOBF4 to provide
N2O3 as the real active species (equation 6). The N2O3 thus
formed should afford regioisomer 2A as the major product
according to equations 4 and 5. Because water is regener-
ated in the transformation from 11 to 2A (equation 5), in
principle, a catalytic amount of water is required to operate
this assumed mechanism.
Figure 6. Accepted reaction mechanism for furoxan synthesis in a
NaNO2/H+ system.
Next, the effect of the bulkiness of the aryl substituents
was investigated (Table 4). The styrene derivative 1c with
a phenyl substituent afforded furoxan 2c in favor of
regioisomer A (A/B = 88/12, Table 4, entry 1). To our
surprise, the A to B ratio decreased as the aryl substituent
became bulkier. o-Dimethyl styrene 1p afforded furoxan
2p in favor of seemingly thermodynamically unfavored
regioisomer B (A/B =35/65, Table 4, entry 3).
In general, the major regioisomer obtained under our reaction
conditions was 2A. This regioselectivity was similar to that ob-
served in the conventional furoxan synthesis using NaNO2 in
an acidic media. Several studies proposed probable reaction
mechanisms; a radical mechanism was accepted for the furoxan
synthesis in a NaNO2/H+ system as shown in Figure 6 [24].
In order to determine whether water plays a role in our system,
1,2-dihydronaphthalene (1l) was treated with NOBF4 in the pres-
ence of one equivalent of water (Scheme 3, equation 7). Conse-
quently, the corresponding furoxan 2lA was obtained in only 2%
yield, while α-nitrooxime 12, a tautomer of pseudonitrosite 11,
was isolated in 80% yield. The structure of 12 was determined
Scheme 3. Reaction of 1l with NOBF4 in the presence of water (top) and
furoxan synthesis by the dehydration of α-nitrooxime mediated by NOBF4
(bottom).
Figure 7. X-ray crystallographic structure of 12.
Figure 8. Effect of water on the substrate consumption rate in the reac-
tion of β-methylstyrene and NOBF4.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Furoxan Synthesis and Its Mechanistic Study
by X-ray crystallographic analysis (Fig. 7) [26]. It was found that
12 was dehydrated by treating with NOBF4 in pyridine to af-
ford furoxan 2lA in 78% yield (Scheme 3, equation 8). The
dehydration reaction was regiospecific; no regioisomer 2lB
was detected. Therefore, the possibility that a small amount
of water plays a catalytic role in forming furoxan still cannot
be ruled out at this stage.
If water works as the catalyst, the intentional addition of a
small amount of water should accelerate the reaction. There-
fore, we investigated the effect of water on the reaction rate
using β-methyl styrene as the substrate. The consumption
of the substrate in the presence of several amounts of water
was monitored by the GC analysis (Fig. 8).
Consequently, it was proved that water does not accelerate
the reaction at all, even in the initial stage. Based on the
aforementioned experimental results, we believe that a
radical mechanism in which water acts as the catalyst does
not probably operate in the furoxan synthesis using NOBF4
and pyridine.
This conclusion does not contradict the fact that sty-
rene derivatives 1q and 1r bearing a pendant olefin
afforded the corresponding furoxans 2q and 2r, respec-
tively, in reasonable yields (Table 5). The by-products,
which might be formed in the radical cyclization if the
radical intermediates were transiently generated, could
not be isolated.
Based on the aforementioned results, we propose an ionic
reaction mechanism involving no radical species (Fig. 9).
First, a nitrosonium cation interacts with the olefin [27] to
afford cationic species 13a and 13b in equilibrium. The pyr-
idine then abstracts the acidic proton of 13a and 13b to af-
ford nitroso alkenes 14a and 14b, respectively. Next,
another nitrosonium cation reacts with 14a to afford tran-
sient intermediate 15, followed by the immediate
cyclization to afford 16. The subsequent deprotonation af-
fords furoxan 2A. Nitroso alkene 14b can be converted to
furoxan 2B in the similar fashion. Because a high regiose-
lectivity was observed, it is believed that pseudosymmetric
dinitrosoalkene 17 is not generated, and nitroso alkenes
14a and 14b are converted to the corresponding furoxans
2A and 2B, respectively, in a regiospecific manner. Thus,
we presume that the ratio of regioisomers (A/B) is deter-
mined by the selectivity of the formation of 14a and 14b.
The observed high regioselectivity in favor of 2A can be
readily rationalized by assuming that 14a is selectively gen-
erated in preference to 14b because 13a is the predominant
initially formed intermediate due to the stabilized benzylic
cation. The increase in the steric bulkiness of the alkyl
substituent R decreased the proportion of regioisomer A
(Table 3). This result can be accounted for by considering
that the deprotonation of 13a by pyridine was cumbersome
when the size of R group was large, thus increasing the
probability that the deprotonation occurred from the less
favored cation 13b (Fig. 10). The o-substitution on the aryl
group also decreased the amount of regioisomer A (Table 4).
This is probably because the o-substituents make more
perpendicular the dihedral angle made by the aromatic ring
and the plane containing the three substituents on the
carbocation. Consequently, the π-conjugation between the
aromatic π-orbital and the empty p-orbital of the carbocation
decreased; the energy difference between 13a and 13b
decreased or even reversed (Fig. 11).
Table 5
Furoxan synthesis from styrene derivatives with a pendant olefin.
Entry
1
Yield (%)
When water was added to the reaction, α-nitrooxime
was obtained as the major product (Scheme 3, equation
7). It is possible that both the α-nitrooxime and the
1
2
1q
1r
43 (A/B = 91/9)
53 (A/B = 92/8)
Figure 9. Proposed reaction mechanism for furoxan synthesis using NOBF4 and pyridine.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. Matsubara, A. Ando, Y. Saeki, K. Eda, N. Asada, T. Tsutsumi, Y. S. Shin, and M. Hayashi
Vol 000
EXPERIMENTAL
General.
All reactions were carried out in well cleaned and
oven-dried glassware 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 measured on a Yanaco MP-500D and are not
corrected. 1H and 13C NMR spectra (400 and 100 MHz, respectively)
were recorded on a JEOL JNM-LA 400 instrument (Tokyo, Japan)
using TMS (0 ppm) and CDCl3 (77.0 ppm) as an internal standard,
respectively. The following abbreviations are used in connection with
NMR; s = singlet, d = doublet, t = triplet, q = quartet, and
m = multiplet. Mass spectra were measured using Thermo Quest
LCQ DECA plus spectrometer (ESI) (Waltham, MA, USA) and a
Thermo Finnigan LCQ TRACE GC ULTRA (EI). GC analyses
were performed using a Hitachi G-5000 (Tokyo, Japan) equipped
with GL Science InertCap 5. Elemental analyses were carried out
using a Yanako CHN Corder MT-5 (Tokyo, Japan). Preparative
column chromatography was performed using Fuji Silysia BW-
4:10MH silica gel or YMC_GEL Silica (6 nm I-40-63 um). 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
reported data: 3-methyl-4-phenylfuroxan (2a), 3,4-diphenylfuroxan
(2b), and 3-(hydroxymethyl)-4-phenylfuroxan (2e).
Figure 10. Effect of steric bulkiness of alkyl substituent; pyridine can
readily access the proton to be abstracted when R is small (left). Deproton-
ation is hindered when R is big (right).
Figure 11. Effect of steric bulkiness of aromatic ring; π-conjugation be-
tween aromatic π-orbital and empty p-orbital of carbocation stabilizes
carbocation (left). π-Conjugation is weaker when aromatic ring is bulky
because aromatic π-orbital and empty p-orbital of carbocation become
more perpendicular.
Scheme 4. Possible mechanism for the synthesis of α-nitrooxime.
General procedure for the synthesis of furoxans from
styrenes and NOBF4 in pyridine solvent.
To a stirred
solution 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
indicated period, and then the solution, diluted with water, was
extracted three times with Et2O. The combined organic layer
was washed with water and dried over Na2SO4. The residue
obtained after evaporation of the volatiles was purified by
chromatography on silica gel (EtOAc–hexane) to give the
product as a mixture of regioisomers.
furoxan are formed from a common intermediate 15
(Scheme 4). Water attacks the electrophilic nitrogen of 15
to afford pseudonitrosite 18, which then tautomerizes to α-
nitrooxime 19.
3-Methyl-4-phenylfuroxan (2aA) [28] and 4-methyl-3-phenylfuroxan
(2aB).
The reaction of the olefin (trans only) for 10 min
following the general procedure gave furoxan 2a (116 mg,
65%) as colorless needles. The reaction of the olefin (cis only)
for 10 min gave 2a (101 mg, 57%). Rf 0.35 (hexane:
EtOAc = 10:1). IR (neat), ν (cmꢀ1): 1157, 1184, 1202, 1330,
1390, 1429, 1448, 1465, 1574, 1592, 2922. 1H NMR
[400 MHz, CDCl3/TMS, δ (ppm)]: 2aA: 2.37 (3H, s, Ar-CH3),
7.54–7.58 (3H, m, Ar-H), 7.68 (2H, m, Ar-H); 2aB
(distinguishable peak): 2.55 (3H, s, Ar-CH3). 13C NMR
[100 MHz, CDCl3/TMS, δ (ppm)]: 2aA: 156.8, 131.0, 129.2,
127.3, 126.6, 112.1, 9.2.
CONCLUSION
In summary, diverse furoxans can be synthesized from
the corresponding styrenes using NOBF4 as the nitrosation
reagent in pyridine (basic media) or CH2Cl2 (neutral me-
dia). In contrast to the conventional acidic conditions,
acid-sensitive functional groups can be tolerated under
these conditions. The regioisomer bearing an external oxy-
gen atom on the furoxan ring at the distal side from the aryl
substituent (regioisomer A) is predominantly formed with
high regioselectivity. The reaction mechanism was investi-
gated; the experimental results, such as anomalous selec-
tivities observed when the bulky substrates were used,
the radical trapping experiments, and the kinetic study with
the addition of diverse amounts of water, consistently sup-
port an ionic reaction pathway. This result is in sharp con-
trast to the conventional reactions using acidic conditions,
where the involvement of the radical species is proposed.
On the basis of the obtained knowledge, the development
of furoxan synthesis from alkenes without an aryl substitu-
ent is an ongoing research project in our laboratory.
Crystals of 2aA suitable for X-ray diffraction analysis were
obtained by recrystallization from EtOAc–hexane using a vapor
diffusion method.
3,4-Diphenylfuroxan (2b) [17]. The reaction of the olefin
(trans only) for 1 h following the general procedure gave
furoxan 2b (99 mg, 42%, colorless needles) and 3 (38 mg, 18%,
white solid). The reaction of the olefin (cis only) for 2d gave 2b
(80 mg, 33%). Rf 0.4 (hexane:EtOAc = 10:1). IR (neat), ν
1
(cmꢀ1): 1327, 1419, 1441, 1503, 1572, 1590, 3026. H NMR
[400 MHz, CDCl3/TMS, δ (ppm)]: 7.43–7.53 (m, 10H, Ar-H).
13C NMR [100 MHz, CDCl3/TMS, δ (ppm)]: 156.2, 131.0,
130.5, 129.0, 128.9, 128.6, 128.2, 126.6, 122.8. MS (EI): m/z
238 (M+), 178 (M–N2O2) [29].
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Furoxan Synthesis and Its Mechanistic Study
CDCl3/TMS, δ (ppm)]: 2eA: 156.8, 131.4, 129.4, 127.7, 126.1,
53.3; 2eB (distinguishable peaks): 130.7, 129.2, 127.4, 56.6. MS
(EI): m/z 192 (M+), 132 (M–N2O2).
4-(3-Bromophenyl)-3-pentylfuroxan (2fA) and 3-(3-bromophenyl)-
4-pentylfuroxan (2fB). The reaction of the olefin (cis/trans = 84/16)
Crystals of 2b suitable for X-ray diffraction analysis were
obtained by recrystallization from EtOAc–hexane using a vapor
diffusion method.
3-Phenyl-4H-1,2-benzoxazin-4-one (3). mp 113.7–114.6°C.
Rf 0.17 (hexane:EtOAc = 50:1). IR (neat), ν (cmꢀ1): 696, 757,
1456, 1608, 1660, 1742, 2852, 2923, 3053. 1H NMR
[400 MHz, CDCl3/TMS, δ (ppm)]: 7.44 (1H, t, J = 8.0 Hz,
Ar-H), 7.48–7.55 (4H, m, Ar-H), 7.79 (1H, ddd, J = 8.8, 7.2,
1.6 Hz, Ar-H), 7.91–7.94 (2H, m, Ar-H), 8.20 (1H, dd, J = 8.4,
1.6 Hz, Ar-H). 13C NMR [100 MHz, CDCl3/TMS, δ (ppm)]:
168.2, 162.0, 158.0, 135.7, 130.6, 130.0, 129.4, 128.4, 125.6,
125.5, 120.3, 116.4. MS (ESI): m/z 224 (M + H). Anal. Calcd
for C14H9NO2; C, 75.33; H, 4.06; N, 6.27. Found: C, 74.75;
H, 4.17; N, 6.12.
for 1.5 h following the general procedure gave 2f (240 mg, 78%) as
yellow oil. Rf 0.25 (hexane:EtOAc = 10:1). IR (neat), ν (cmꢀ1): 1429,
1
1455, 1564, 1593, 2859, 2929, 2956. H NMR [400 MHz, CDCl3/
TMS, δ (ppm)]: 2fA: 0.85–0.91 (3H, m, CH2CH2CH3), 1.29–1.36
(4H, m, CH2CH2CH3), 1.61–1.67 (2H, m, CH2CH2CH2CH3), 2.69
(2H, t, J= 8.4 Hz, Ar-CH2), 7.41 (1H, t, J=8.4Hz, Ar-H), 7.58 (1H,
dt, J=1.2, 7.6Hz, Ar-H), 7.69 (1H, dt, J=0.8, 8.0Hz, Ar-H), 7.83
(1H, t, J=1.6Hz, Ar-H); 2fB (distinguishable peak): 2.83 (2H, t,
J= 7.6 Hz, Ar-CH2). 13C NMR [100 MHz, CDCl3/TMS, δ (ppm)]:
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; 2fB (distinguishable peaks): 133.5, 130.6,
130.4, 126.1, 26.7, 25.9, 22.1, 13.8. MS (EI): m/z 251 (M–N2O2).
Anal. Calcd. for C13H15BrN2O2: C, 50.18; H, 4.86; N, 9.00. Found:
Crystals of 3 suitable for X-ray diffraction analysis were
obtained by recrystallization from dichloroethane-hexane using
a vapor diffusion method.
3-Pentyl-4-phenylfuroxan (2cA) and 4-pentyl-3-phenylfuroxan
(2cB). The reaction of the olefin (cis/trans = 67/33) for 5 h
following the general procedure gave 2c (175 mg, 75%) as
yellow oil. Rf 0.35 (hexane:EtOAc = 10:1). IR (neat), ν
(cmꢀ1): 670, 768, 1418, 1455, 1576, 1593, 1572, 2860, 2929,
C, 50.31; H, 4.86; N, 9.05.
4-(4-Methoxyphenyl)-3-pentylfuroxan (2gA) and 3-(4-
methoxyphenyl)-4-pentylfuroxan (2gB). The reaction of the
olefin (cis/trans = 55/45) for 0.5 h following the general
procedure gave 2g (52 mg, 20%) as yellow oil. Rf 0.25 (hexane:
EtOAc = 10:1). IR (neat), ν (cmꢀ1): 1175, 1253, 1435, 1450,
1574, 1592, 2860, 2930, 2957. 1H NMR [400 MHz, CDCl3/
1
2957. H NMR [400 MHz, CDCl3/TMS, δ (ppm)]: 2cA: 0.86
(3H, t, J = 6.8 Hz, CH2CH2CH3), 1.29–1.35 (4H, m,
CH2CH2CH3), 1.61–1.65 (2H, m, CH2CH2CH2CH3), 2.71
(2H, t, J = 7.2 Hz, Ar-CH2), 7.50–7.58 (3H, m, Ar-H),
7.64–7.71 (2H, m, Ar-H); 2cB: (distinguishable peak): 2.84
(2H, t, J = 7.6 Hz, Ar-CH2). 13C NMR [100 MHz, CDCl3/
TMS, δ (ppm)]: 2cA: 156.8, 130.9, 129.2, 127.3, 126.8,
123.1, 31.0, 25.0, 22.8, 22.0, 13.7; 2cB: (distinguishable
peaks): 157.2, 130.3, 129.1, 127.5, 26.6, 25.9. MS (EI):
m/z 232 (M+), 172 (M–N2O2). Anal. Calcd for C13H16N2O2;
C, 67.22; H, 6.94; N, 12.06. Found: C, 67.17; H, 7.04; N,
11.92.
TMS,
δ (ppm)]: 2gA: 0.85–0.91 (3H, m, CH2CH2CH3),
1.25–1.39 (4H, m, CH2CH2CH3), 1.59–1.73 (2H, m,
CH2CH2CH2CH3), 2.69 (2H, t, J = 7.6 Hz, Ar-CH2), 3.87 (3H,
s, Ar-OCH3), 7.01–7.07 (2H, m, Ar-H), 7.65–7.68 (2H, m,
Ar-H); 2gB (distinguishable peak): 2.82 (2H, t, J = 8.0 Hz,
Ar-CH2). 13C NMR [100 MHz, CDCl3/TMS, δ (ppm)]: 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; 2gB (distinguishable peaks): 128.9, 114.6, 22.1. MS
(EI): m/z 262.0 (M+), 202.1 (M–N2O2). Anal. Calcd. for
C14H18N2O3: C, 64.11; H, 6.92; N, 10.68. Found: C, 63.96, H;
6.95, N; 10.55.
4-(2-Naphthyl)-3-pentylfuroxan (2dA) and 3-(2-naphthyl)-
4-pentylfuroxan (2 dB).
The reaction of the olefin (cis/
trans = 70/30) for 0.5 h following the general procedure gave 2d
(191mg, 68%) as yellow oil. Rf 0.32 (hexane:EtOAc = 10:1). IR
(neat), ν (cmꢀ1): 750, 818, 1418, 1461, 1590, 2859, 2928, 2955.
1H NMR [400 MHz, CDCl3/TMS, δ (ppm)]: 2dA: 0.86 (3H, t,
J=7.2Hz, CH2CH2CH2CH3), 1.26–1.38 (6H, m, CH2CH2CH2CH3),
2.80 (2H, t, J= 8.0 Hz, Ar-CH2), 7.57–7.64 (2H, m, Ar-H), 7.75 (1H,
dd, J=1.2, 7.2Hz, Ar-H), 7.91–8.02 (3H, m, Ar-H), 8.13 (1H, s,
Ar-H); 2dB (distinguishable peak): 2.92 (2H, t, J= 8.0 Hz, Ar-CH2).
13C NMR [100 MHz, CDCl3/TMS, δ (ppm)]: 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; 2dB (distinguishable peaks): 26.8, 26.0.
MS (EI): m/z 282 (M+), 222 (M–N2O2). Anal. Calcd. for
C17H18N2O2: C, 72.32; H, 6.43; N, 9.92. Found: C, 72.26; H, 6.54;
4-(4-Nitrophenyl)-3-pentylfuroxan (2hA) and 3-(4-nitrophenyl)-
4-pentylfuroxan (2hB).
The reaction of the olefin (cis/
trans = 63/37) for 48 h following the general procedure gave 2h
(185 mg, 67%) as pale yellow needle. Rf 0.2 (hexane:
EtOAc = 5:1). IR (neat), ν (cmꢀ1): 713, 851, 1250, 1434, 1534,
1587, 2860, 2931, 2958. 1H NMR [400 MHz, CDCl3/TMS, δ
(ppm)]: 2hA: 0.85–0.91 (3H, m, CH2CH2CH3), 1.25–1.39 (4H,
m, CH2CH2CH3), 1.59–1.73 (2H, m, CH2CH2CH2CH3), 2.74
(2H, t, J = 8.0 Hz, Ar-CH2), 7.87–7.97 (2H, m, Ar-H),
7.99–8.44 (2H, m, Ar-H); 2hB (distinguishable peak): 2.90
(2H, t, J = 8.0 Hz, Ar-CH2). 13C NMR [100 MHz, CDCl3/TMS,
δ (ppm)]: 2hA: 155.0, 149.2, 132.9, 128.5, 124.5, 115.0, 31.2,
25.2, 23.0, 22.1, 13.7. MS (EI): m/z 217 (M–N2O2). Anal.
Calcd. for C13H15N3O4: C, 56.31; H, 5.45; N, 15.15. Found: C,
56.36; H, 5.45; N, 15.17.
N, 9.78.
3-(Hydroxymethyl)-4-phenylfuroxan (2eA) [10b] and 4-
(hydroxymethyl)-3-phenylfuroxan (2eB). The reaction of the
olefin (trans only) for 1 h following the general procedure gave 2e
(91 mg, 47%) as white solid. Rf 0.6 (hexane:EtOAc = 1:1). IR (neat),
ν (cmꢀ1): 1010 1409, 1462, 1575, 1599, 2930, 3402. 1H NMR
[400 MHz, CDCl3/TMS, δ (ppm)]: 2eA: 2.48 (1H, s, OH), 4.76 (2H,
s, CH2), 7.51–7.60 (3H, m, Ar-H), 7.80–7.83 (2H, m, Ar-H); 2eB
(distinguishable peak): 4.89 (2H, s, CH2). 13C NMR [100 MHz,
3-Isopropyl-4-(2-naphthyl)furoxan (2iA) and 4-isopropyl-3-
(2-naphthyl)furoxan (2iB).
The reaction of the olefin (cis/
trans = 85/15) for 2 h following the general procedure gave 2i
(144 mg, 56%) as colorless needle. Rf 0.42 (hexane:
EtOAc = 10:1). IR (neat), ν (cmꢀ1): 754, 811, 864, 1324, 1385,
1202, 1420, 1455, 1591, 2937, 2982. 1H NMR [400 MHz,
CDCl3/TMS, δ (ppm)]: 2iA: 1.37 (6H, d, J = 6.8 Hz, CH3), 3.21
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. Matsubara, A. Ando, Y. Saeki, K. Eda, N. Asada, T. Tsutsumi, Y. S. Shin, and M. Hayashi
Vol 000
(1H, septet, J = 6.8 Hz, CH), 7.55–7.69 (3H, m, Ar-H),
7.88–8.20 (4H, m, Ar-H); 2iB (distinguishable peak): 3.30
(1H, septet, J = 6.8 Hz, CH). 13C NMR [100 MHz, CDCl3/
TMS, δ (ppm)]: 2iA: 157.0, 132.8, 129.1, 128.5, 128.4,
127.9, 127.8, 124.6, 127.2, 124.6, 124.0, 118.7, 23.8,
17.1; 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 254 (M+), 194 (M–N2O2). Anal. Calcd. for
C15H14N2O2: C, 70.85; H, 5.55; N, 11.02. Found: C,
70.97; H, 5.71; N, 10.91.
three times with Et2O. The combined organic layer was washed
with water and dried over Na2SO4. The residue obtained after
evaporation of the volatiles was purified by chromatography on
silica gel (EtOAc–hexane) to give furoxan 2m (115 mg, 49%)
as colorless oil. Rf 0.35 (hexane:EtOAc = 1:1). IR (neat), ν
(cmꢀ1): 1184, 1202, 1330, 1390, 1429, 1448, 1465, 1478,
1574, 1592, 1734, 2979. 1H NMR [400 MHz, CDCl3/TMS, δ
(ppm)]: 2mA: 1.29 (3H, t, J = 7.0 Hz, OCH2CH3), 4.35–4.40
(2H, q, J = 7.0 Hz, OCH2CH3), 7.49–7.59 (3H, m, Ar-H),
7.64–7.71 (2H, m, Ar-H); 2mB (distinguishable peak): 1.39
(3H, t, J = 7.0 Hz, OCH2CH3), 4.46 (2H, q, J = 7.0 Hz,
OCH2CH3). 13C NMR [100 MHz, CDCl3/TMS, δ (ppm)]: 2mA:
156.5, 156.1, 131.6, 129.0, 128.5, 126.0, 63.0, 13.8; 2mB
(distinguishable peaks): 128.6, 128.4, 62.6. MS (EI): m/z 234
(M), 174 (M–N2O2). Anal. Calcd. for C11H10N2O4: C, 56.41;
H, 4.30; N, 11.96. Found: C, 56.52; H, 4.29; N, 11.80.
4-Phenyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]furoxan
(2jA) and 3-phenyl-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]
furoxan (2jB).
The reaction of the olefin (trans only) for
0.5 h following the general procedure gave 2j (146 mg, 53%) as
colorless oil. Rf 0.35 (hexane:EtOAc = 10:1). IR (neat), ν
(cmꢀ1): 963, 1010, 1058, 1076, 1119, 1479, 1577, 1597, 2942.
1H NMR [400 MHz, CDCl3/TMS, δ (ppm)]: 2jA: 1.51–1.81
(6H, m, CH2CH2CH2CH2O), 3.52–3.57 (2H, m, OCH2CH2),
3.78–3.84 (1H, m, OCHO), 4.60 (1H, d, J = 12.8 Hz, Ar-CH2),
4.74 (1H, d, J = 12.8 Hz, Ar-CH2), 7.30–7.58 (3H, m, Ar-H),
7.83–7.94 (2H, m, Ar-H); 2jB (distinguishable peak): 7.94–7.96
(2H, m, Ar-H). 13C NMR NMR [100 MHz, CDCl3/TMS, δ
(ppm)]: 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; 2jB (distinguishable peaks):
154.3, 130.9, 129.3, 127.9, 122.9, 98.3, 59.8. MS (EI): m/z 175
(M–OTHP). Anal. Calcd. for C14H16N2O4: C, 60.86; H, 5.84;
N, 10.14. Found: C, 61.00; H, 5.88; N, 9.76.
3-[(tert-Butyldimethylsilyloxy)methyl]-4-phenylfuroxan (2kA) and
4-[(tert-butyldimethylsilyloxy)methyl]-3-phenylfuroxan (2kB). The
reaction of the olefin (trans only) for 0.5 h following the general
procedure gave 2k (212 mg, 69%) as colorless oil. Rf 0.4 (hexane:
EtOAc = 10:1). IR (neat), ν (cmꢀ1): 1276, 1384, 1434, 1461, 1579,
1600, 2853, 2930, 2957. 1H NMR [400 MHz, CDCl3/TMS, δ
(ppm)]: 2kA: 0.14 (6H, s), 0.88 (9H, s), 4.72 (2H, s), 7.47–7.58
(3H, m, Ar-H), 7.91–7.94 (2H, m, Ar-H); 2kB (distinguishable
peak): 4.83 (2H, s). 13C NMR NMR [100 MHz, CDCl3/TMS, δ
(ppm)]: 2kA: 157.5, 131.5, 129.1, 127.8, 126.6, 114.2, 54.1, 25.6,
18.1, ꢀ5.3; 2kB (distinguishable peaks): 130.5, 129.0, 127.6, 57.1.
MS (EI): m/z 249 (M–tBu), 189 (M–tBu–N2O2). Anal. Calcd. for
C14H16N2O4: 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 (2lA). The
reaction of the olefin for 1 h following the general procedure
gave 2lA (103 mg, 58%) as white solid. mp 84.4–85.5°C. Rf
0.3 (hexane:EtOAc = 10:1). IR (neat), ν (cmꢀ1): 1350, 1434,
1535, 1587, 2861, 2959. 1H NMR [400 MHz, CDCl3/TMS, δ
(ppm)]: 2.95 (2H, t, J = 7.6 Hz, Ar-CH2CH2CN), 3.12 (2H, t,
J = 7.6 Hz, Ar-CH2CH2CN), 7.33–7.48 (3H, m, Ar-H),
7.98–8.00 (1H, dd, J = 1.2, 9.2 Hz, Ar-H). 13C NMR
[100 MHz, CDCl3/TMS, δ (ppm)]: 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 (M+),
128 (M–N2O2). Anal. Calcd. for C10H8N2O2: C, 63.83; H,
4.29; N, 14.89. Found: C, 63.75, H; 4.30, N; 14.74.
3-tert-Butyl-4-naphthylfuroxan (2 nA) and 4-tert-butyl-3-
naphthylfuroxan (2nB).
The reaction of the olefin (cis/
trans = 80/20) for 48 h following the general procedure gave 2n
1
(31 mg, 23%) as white solid. Rf 0.42 (hexane:EtOAc = 10:1). H
NMR [400 MHz, CDCl3/TMS, δ (ppm)]: 2nB: 1.30 (9H, s,
CH3), 7.42 (1H, dd, J = 8.4, 1.6 Hz, Ar-CH2), 7.56–7.63 (2H, m,
Ar-H), 7.89–7.93 (3H, m, Ar-H), 8.0 (1H, d, J = 8.0 Hz, Ar-H);
2nA (distinguishable peak): 1.25 (9H, s, CH3), 7.47 (1H, dd,
J = 8.4, 1.6 Hz, Ar-H). 13C NMR [400 MHz, CDCl3/TMS, δ
(ppm)]: 2nB: 164.9, 134.0, 133.1, 129.5, 128.5, 128.1, 127.3,
126.5, 122.1, 116.7, 33.8, 28.6; 2nA (distinguishable peaks):
157.8, 133.9, 132.7, 129.8, 128.5, 128.1, 127.8, 127.3, 126.2,
31.9, 27.1. MS (EI): m/z 268 (M+), 208 (M–N2O2). Anal. Calcd.
for C16H16N2O2: C, 71.62; H, 6.01; N, 10.44. Found: C, 71.42;
H, 6.01; N, 10.75.
Crystals of 2nB suitable for X-ray diffraction analysis were
obtained by recrystallization from EtOAc–hexane using a vapor
diffusion method.
4-(2-Methylpheny)-3-pentylfuroxan (2oA) and 3-(2-methylpheny)-
4-pentylfuroxan (2oB). The reaction of the olefin (cis/trans = 74/
26) for 48h following the general procedure gave 2o (76 mg,
31%) as yellow oil. Rf 0.42 (hexane:EtOAc= 10:1). IR (neat), ν
(cmꢀ1): 1184, 1202, 1330, 1390, 1429, 1448, 1465, 1478, 1574,
1
1592, 1734, 2979. H NMR [400 MHz, CDCl3/TMS, δ (ppm)]:
2oA: 0.79–0.85 (3H, m, CH2CH2CH3), 1.14–1.27 (4H, m,
CH2CH2CH3), 1.46–1.59 (2H, m, Ar-CH2), 2.33 (3H, s, Ar-CH3),
2.48 (2H, t, J = 8.0 Hz, Ar-CH2), 7.19–7.47 (4H, m, Ar-H); 2oB
(distinguishable peak): 2.26 (3H, s, Ar-CH3), 2.58–2.64 (2H, m,
Ar-CH2). 13C NMR [100 MHz, CDCl3/TMS, δ (ppm)]: 2oA:
157.5 137.3, 131.0, 130.1, 129.4, 126.2, 116.1, 30.8, 24.5, 22.3,
21.8, 19.6, 13.6; 2oB (distinguishable peaks): 158.2, 138.9, 131.0,
129.5, 126.3, 125.8, 122.0, 25.9, 25.6, 21.9, 19.1, 13.6. MS (EI):
m/z 186 (M–N2O2). Anal. Calcd. for C14H18N2O2: C, 68.27; H,
7.37; N, 11.37. Found: C, 68.20; H, 7.52; N, 11.12.
4-(2,2-Dimethylphenyl)-3-pentylfuroxan (2pA) and 3-(2,2-
dimethylphenyl)-4-pentylfuroxan (2pB).
The reaction of the
olefin (cis/trans = 71/29) for 48 h following the general procedure
gave 2p (57 mg, 22%) as yellow oil. Rf 0.35 (hexane:EtOAc = 10:1).
1H NMR [400 MHz, CDCl3/TMS, δ (ppm)]: 2pB: 0.79–0.85 (3H,
m, CH3), 1.19–1.59 (6H, m, CH2CH2CH2), 2.17 (6H, s, Ar-CH3),
2.50 (2H, t, J= 8.0 Hz, Ar-CH2), 7.16 (2H, d, J=7.6Hz, Ar-H), 7.33
(1H, t, J=8.0Hz, Ar-H); 2pA (distinguishable peak): 2.36 (2H, t,
J= 8.0 Hz, Ar-CH2). 13C NMR [100 MHz, CDCl3/TMS, δ (ppm)]:
2pB: 158.5, 138.6, 131.0, 128.2, 121.5, 115.4, 30.9, 25.9, 25.8, 22.0,
Crystals suitable for X-ray diffraction analysis were obtained by re-
crystallization from EtOAc–hexane using a vapor diffusion method.
Ethyl 4-phenylfuroxan-3-carboxylate (2mA) and Ethyl
3-phenylfuroxan-4-carboxylate (2mB). To a stirred solution
of trans-ethyl cinnamate (176.2 mg, 1 mmol) and pyridine
(242 μl, 3 mmol) in CH2Cl2 (1.4 mL) was added NOBF4
(348.7 mg, 3 mmol) at 0°C. Stirring was continued at 0°C for
48 h, and then the solution, diluted with water, was extracted
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Furoxan Synthesis and Its Mechanistic Study
gave oxime 12 (167 mg, 80%) as colorless solid along with 2lA
(9mg, 2%). mp 136.9–138.1°C. Rf 0.08 (hexane:EtOAc= 10:1).
IR (neat), ν (cmꢀ1): 1287, 1341, 1540, 1597, 2872, 2953, 3034,
3274. 1H NMR [400 MHz, CDCl3/TMS, δ (ppm)]: 2.32 (1H, ddt,
J = 12.0, 14.8, 4.8 Hz, CH2), 2.67 (1H, dq, J = 4.0, 14.8Hz, CH2),
2.79 (1H, dt, J = 16.4, 4.4Hz, CH), 2.91 (1H, ddd, J = 16.4, 12.0,
4.0 Hz, CH), 6.07 (1H, t, J = 4.4 Hz, CH), 7.19 (1H, d, J = 7.2 Hz,
Ar-H), 7.26–7.37 (2H, m, Ar-H), 7.98 (1H, d, J = 9.2 Hz, Ar-H),
8.32 (1H, s, OH). 13C NMR [100 MHz, CDCl3/TMS, δ (ppm)]:
147.8, 137.3, 130.2, 128.7, 128.0, 127.3, 124.5, 27.7, 24.9. MS
(EI): m/z 206 (M+), 160 (M–NO2). Anal. Calcd. for C10H10N2O3:
C, 72.32; H, 6.43; N, 9.92. Found: C, 72.26; H, 6.54; N, 9.92.
19.4, 13.6; 2pA (distinguishable peaks): 157.1, 137.6, 130.5, 128.0,
125.4, 125.2, 116.3, 30.9, 24.5, 22.3, 21.9, 19.8, 13.6. MS (EI): m/z
200 (M–N2O2). Anal. Calcd. for C11H10N2O4: C, 69.20; H, 7.74; N,
10.76. Found: C, 69.09; H, 7.88; N, 10.39.
3-(3-Butenyl)-4-phenylfuroxan (2qA) and 4-(3-butenyl)-
3-phenylfuroxan (2qB).
The reaction of the olefin (cis/
trans = 64/36) for 20 min following the general procedure gave 2q
(94 mg, 43%) as yellow oil. Rf 0.29 (hexane:EtOAc = 20:1). 1H
NMR [400 MHz, CDCl3/TMS, δ (ppm)]: 2qA: 2.39 (2H, q,
J=8.0Hz, C(¼N)CH2CH2), 2.82 (2H, t, J=8.0Hz, C(¼N)CH2),
4.99–5.05 (2H, m, RCH = CH2), 5.68–5.79 (1H, ddt, J= 17.2, 10.4,
6.4 Hz, RCH=CH2), 7.51–7.66 (m, 5H, Ar-H); 2qB (distinguishable
peak): 2.49 (2H, q, J=7.2Hz, C(¼N)CH2CH2), 2.96 (2H, t,
J=8.0Hz, C(¼N)CH2). 13C NMR [100 MHz, CDCl3/TMS, δ
(ppm)]: 2qA: 156.9, 135.1, 130.9, 129.2, 127.4, 126.6, 116.9, 114.9,
29.0, 22.4; 2qB (distinguishable peaks): 156.5, 135.6, 129.1, 126.6,
116.4, 29.9, 26.1. MS (EI): m/z 216 (M+), 186 (M–NO), 156
(M–N2O2). Anal. Calcd. for C11H10N2O4: C, 66.65; H, 5.59; N,
12.96. Found: C, 66.63; H, 5.64; N, 12.90.
Crystals suitable for X-ray diffraction analysis were
obtained by recrystallization from EtOAc–hexane using a
vapor diffusion method.
Conversion of 12 to 2lA. To a stirred solution of 12 (103 mg,
0.5 mmol) in pyridine (1.5mL) was added NOBF4 (174.5mg,
1.5 mmol) at 0°C. Stirring was continued at 0°C for 0.5h, and
then the solution, diluted with water, was extracted three times
with Et2O. The combined organic layer was dried over Na2SO4.
The residue obtained after evaporation of the volatiles was
purified by chromatography on silica gel (EtOAc–hexane) to give
2lA (73mg, 78%) as a sole regioisomer.
3-(4-Pentenyl)-4-phenylfuroxan (2rA) and 4-(4-pentenyl)-
3-phenylfuroxan (2rB).
The reaction of the olefin (cis/
trans = 64/36) for 20min following the general procedure gave 2r
1
(123mg, 53%) as yellow oil. Rf 0.28 (hexane:EtOAc = 20:1). H
NMR [400 MHz, CDCl3/TMS, δ (ppm)]: 2rA: 1.74 (2H, quintet,
J = 7.6 Hz, C(¼N)CH2CH2), 2.10 (2H, q, J = 6.8 Hz, C(¼N)
CH2CH2CH2), 2.72 (2H, t, J = 8.0 Hz, C(¼N)CH2), 4.96–5.04
(2H, m, RCH = CH2), 5.69–5.81 (1H, m, RCH = CH2), 7.52–7.69
(5H, m, Ar-H); 2rB (distinguishable peak): 1.85 (2H, quintet,
J = 7.6 Hz, C(¼N)CH2CH2), 2.85 (2H, t, J = 8.0 Hz, C(¼N)CH2).
13C NMR [100 MHz, CDCl3/TMS, δ (ppm)]: 2rA: 156.9, 136.8,
131.0, 129.3, 127.5, 126.8, 115.9, 115.5, 32.9, 24.4, 22.4; 2rB
(distinguishable peaks): 157.1, 137.1, 130.4, 129.2, 127.6, 26.0,
25.3. MS (EI): m/z 230 (M+). Anal. Calcd. for C11H10N2O4: C,
67.81; H, 6.13; N, 12.17. Found: C, 67.57; H, 6.23; N, 11.89.
Reaction rate study of the reaction of β-methylstyrene and
NOBF4 in the presence or absence of water (Fig. 8).
The
following three reactions were monitored by the gas chromatography
analysis.
Reaction 1: without water.
To a stirred solution of
β-methylstyrene (118 mg,1 mmol) and pyridine (0.24 mL, 3 mmol)
in CH2Cl2 (2.8 mL) was added n-dodecane (30 μl, internal standard
(IS)). The aliquot was analyzed by GC to determine the initial
integration ratio of the signals corresponding to the substrate and IS.
NOBF4 (348.7 mg, 3 mmol) was added to the reaction mixture at
–20°C. During the reaction, the aliquots were taken at 20, 60, and
360 min, quenched by NaHCO3aq–AcOEt, and analyzed by GC.
The consumption of β-methylstyrene was determined by the
integration ratio of the signals corresponding to the substrate and IS.
Conversion of 2 mA to 2eA. To a stirred solution of 2mA
(23 mg, 0.01 mmol) in MeOH (1 mL) was added NaBH4 (3.8 mg,
1 equiv) at room temperature. After stirring for 1.5 h, NaBH4
(3.8mg, 1 equiv) was added, and stirring was continued at room
temperature for 1.5 h. The solution, diluted with water, was
extracted three times with Et2O. The combined organic layer was
washed with water and dried over Na2SO4. The residue obtained
after evaporation of the volatiles was purified by chromatography
on silica gel (EtOAc–hexane) to give 2eA (12.7 mg, 66% yield).
Reactions 2 and 3: with water.
To a stirred solution of
β-methylstyrene (118 mg,1 mmol), pyridine (0.24 mL, 3 mmol)
and water (0.9 mg (Reaction 2) or 2.7 mg (Reaction 3), 5 mol%
or 15 mol%, respectively) in CH2Cl2 (2.8 mL) was added n-
dodecane (30 μl, IS). The aliquot was analyzed by GC to determine
the initial integration ratio of the signals corresponding to the
substrate and IS. NOBF4 (348.7 mg, 3 mmol) was added to the
reaction mixture at ꢀ20°C. During the reaction, the aliquots were
taken at 20, 60, and 360 min, quenched by NaHCO3aq/AcOEt and
analyzed by GC. The consumption of β-methylstyrene was
determined by the integration ratio of the signals corresponding to
the substrate and IS.
4-Nitro-3-phenylfuroxan (8).
To a stirred solution of
styrene (104 mg, 1 mmol) in pyridine (3mL) was added NOBF4
(700.9mg, 6 equiv) at 0°C. Stirring was continued at 0°C for
48h, and then the solution, diluted with water, was extracted three
times with CH2Cl2. The combined organic layer was dried over
Na2SO4. The residue obtained after evaporation of the volatiles
was purified by chromatography on silica gel (EtOAc–hexane) to
give 8 (101mg, 49% yield) as yellow needles. mp 95.4–96.7°C.
Rf 0.35 (hexane:EtOAc= 10:1). IR (neat), ν (cmꢀ1): 1119, 1272,
1359, 1451, 1483, 1504, 1556, 1606. 1H NMR [400 MHz,
CDCl3/TMS, δ (ppm)]: 7.60–7.70 (5H, m, Ar-H). 13C NMR
[100MHz, CDCl3/TMS, δ (ppm)]: 131.9, 129.3, 128.8, 127.3,
119.4. MS (EI): m/z 207 (M+), 177 (M–NO), 147 (M–N2O2).
Anal. Calcd. for C8H5N3O4: C, 46.39; H, 2.43; N, 20.29. Found:
C, 46.72; H, 2.37; N, 19.98.
Acknowledgments. We thank the Naito Foundation, Inoue
Science Research Award, and NOVARTIS Foundation (Japan)
for the Promotion of Science for financial support.
REFERENCES AND NOTES
[1] Kekulé, A. Liebigs Ann Chem 1858, 105, 279.
[2] For reviews on furoxans and benzofuroxans, see: (a) Kaufman,
J. V. R.; Picard, J. P. Chem Rev 1959, 59, 429; (b) Boyer, J. H. Chem
Heterocycl Compd 1961, 7, 462; (c) Behr, L. C. Chem Heterocycl Compd
1962, 17, 295; (d) Boulton, A. J.; Ghosh, P. B. Adv Heterocycl Chem
2-Nitro-1-tetralone oxime (12).
The reaction of
1,2-dihydronaphthalene 1l (130mg, 1 mmol) for 2 h following the
general procedure, except that water (18 mg, 1 equiv) was added,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. Matsubara, A. Ando, Y. Saeki, K. Eda, N. Asada, T. Tsutsumi, Y. S. Shin, and M. Hayashi
Vol 000
[15] CCDC 969421 (2nB), CCDC 969422 (3), and CCDC 922873
(12) contain the supplementary crystallographic data for this paper. These
data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/retriev-
ing.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.
[16] The mechanism for the formation of 3 is unclear. The acid-
promoted reaction of caffeic acid with nitrite is reported to afford the product
with a similar structure as 3. (a) Cotelle, P.; Vezin, H. Tetrahedron Lett 2001,
42, 3303; (b) Napolitano, A.; d’Ischia, M. J Org Chem 2002, 67, 803.
[17] Velázquez, C.; Rao, P. N. P.; McDonald, R.; Knaus, E. E.
Bioorg Med Chem 2005, 13, 2749.
[18] Because the reactions in the conventional acidic media were
not optimized, the product yields may be increased; however, notably,
the developed non-acidic conditions afforded the products in good yields
without any special optimization.
[19] Freeman, J. P. J Org Chem 1963, 28, 2508.
[20] Blinnikov, A. N.; Kulikov, A. S.; Makhova, N. N.; Khmel’nitskii,
L. I. Izv Akad Nauk Seriya Khimicheskaya 1996, 1782.
1969, 10, 1; (e) Ley, K.; Seng, F. Synthesis 1975, 415; (f) Haddadin, M. J.;
Issidorides, C. H. Heterocycles 1976, 4, 767; (g) Gasco, A.; Boulton, A. J Adv
Heterocycl Chem 1981, 29, 251; (h) Sheremetev, A. B.; Makhova, N. N.;
Friedrichsen, W. Adv Heterocycl Hem 2001, 78, 65; (i) Cerecetto, H.;
González, M. Top Heterocycl Chem 2007, 10, 265; (j) Nikonov, G. N.;
Bobrov, S. In Comprehensive Heterocyclic Chemistry III; Katritzky, A. R. C.;
Ramsden, A.; Scriven, E. F. V.; Taylor, R. J. K., Eds.; Elsevier, Oxford, 2008;
Vol 5, Ch 5, pp 315–395.
[3] Calleri, M.; Ferraris, G. Tetrahedron Lett 1967, 8, 4549.
[4] (a) Ghigo, D.; Heller, R.; Calvino, R.; Alessio, P.; Fruttero, R.;
Gasco, A.; Bosia, A.; Pescarmona, G. Biochem Pharmacol 1992, 43,
1281; (b) Feelish, M.; Schonafinger, K.; Noack, E. Biochem Pharmacol
1992, 44, 1149; (c) Civelli, M.; Caruso, P.; Giossi, M.; Bergamaschi, M.;
Razzetti, R.; Bongrani, S.; Gasco, A. Eur J Pharmacol 1994, 255, 17; (d)
Medana, C.; Ermondi, G.; Fruttero, R.; Di Stilo, A.; Ferretti, C.; Gasco, A.
J Med Chem 1994, 37, 4412; (e) Ferioli, R.; Folco, G. C.; Ferretti, C.; Gasco,
A. M.; Medana, C.; Fruttero, R.; Civelli, M.; Gasco, A. Br J Pharmacol 1995,
114, 816.
[5] (a) Calvino, R.; Fruttero, R.; Ghigo, D.; Bosia, A.;
Pescarmona, G. P.; Gasco, A. J Med Chem 1992, 35, 3296; (b) Fruttero, R.;
Boschi, D.; Stilo, A. D.; Gasco, A. J Med Chem 1995, 38, 4944; (c)
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; (d) Grosso, E. D.; Boschi, D.; Lazzarato, L.; Cena, C.; Stilo, A. D.;
Fruttero, R.; Moro, S.; Gasco, A. Chem Biodivers 2005, 2, 886; (e) Cena, C.;
Bertinaria, M.; Boschi, D.; Giorgis, M.; Gasco, A. ARKIVOC 2006, vii,
301; (f) 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; (g) 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.
[6] (a) Werner, A.; Buss, H. Ber Dtsch Chem Ges 1894, 27, 2193;
(b) Dondoni, A.; Mangini, A.; Ghersetti, S. Tetrahedron Lett 1966, 7, 4789.
[7] (a) Koreff, R. Ber Dtsch Chem Ges 1886, 19, 176; (b)
Ungnade, H. E.; Kissinger, L. W. Tetrahedron 1963, 19 (Suppl. 1), 143.
[8] Emmons, W. D.; Freeman, J. P. J Org Chem 1957, 22, 456.
[9] Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O.; Ballini, R.;
Bosica, G. Tetrahedron Lett 2000, 41, 8817 and the references cited therein.
[10] (a) Bruckner, V.; Vinkler, E. J Prakt Chem 1935, 142, 277; (b)
Gasco, A. M.; Fruttero, R.; Sorba, G.; Gasco, A. Liebigs Ann Chem 1991, 1211.
[11] (a) Mallory, F. B.; Cammarata, A. J Am Chem Soc 1966, 88,
61; (b) Whitney, R. A.; Nicholas, E. S. Tetrahedron Lett 1981, 22, 3371.
[12] Demir, A. S.; Findik, H. Lett Org Chem 2005, 2, 602.
[21] The reactions of vinylpyridines with NOBF4 afforded
pyridylacetonitrolic acid. Chang, R.; Kim, K. Bull Korean Chem Soc 1995, 16, 475.
[22] Furoxan 9B was prepared from 8. Blinnikov, A. N.;
Makhova, N. N. Mendeleev Commun 1999, 9, 13.
[23] (a) Dubonos, V. G.; Ovchinnikov, I. V.; Makhova, N. N.;
Khmel’nitskii, L. I. Mendeleev Commun 1992, 2, 120; (b) Takayama, H.;
Shirakawa, S.; Kitajima, M.; Aimi, N.; Yamaguchi, K.; Hanasaki, Y.;
Ide, T.; Katsuura, K.; Fujiwara, M.; Ijichi, K.; Konno, K.; Sigeta, S.;
Yokota, T.; Baba, M. Bioorg Med Chem Lett 1996, 6, 1993; (c)
Makhova, N. N.; Dubonos, V. G.; Blinnikov, A. N.; Ovchinnikov, I. V.;
Khmel’nitskii, L. I. Russ J Org Chem 1997, 33, 1140; (d) Kunai, A.;
Doi, T.; Kishimoto, T.; Sasaki, K. Chem Express 1990, 5, 245; (e)
Kunai, A.; Doi, T.; Nagaoka, T.; Yagi, H.; Sasaki, K. Bull Chem Soc Jpn
1990, 63, 1843.
[24] (a) Jonkman, L.; Muller, H.; Kommandeur, J. J Am Chem Soc
1971, 93, 5833; (b) Fruttero, R.; Ferrarotti, B.; Serafino, A.; Stilo, A. D.;
Gasco, A. J Heterocycl Chem 1989, 26, 1345.
[25] (a) Wieland, H. Liebigs Ann Chem 1903, 329, 225; (b)
Klamann, D.; Koser, W.; Weyerstahl, P.; Fligge, M. Chem Ber 1965,
98, 1831; (c) Scheinbaum, M. L. J Org Chem 1970, 35, 2790; (d) Pfab,
J. J Chem Soc Chem Commun 1977, 766.
[26] Kametani, T.; Sugahara, H.; Yagi, H.; J Chem Soc (C) 1966, 717.
[27] (a) Hamann, H. C.; Swern, D. J Am Chem Soc 1968, 90,
6481; (b) Scheinbaum, M. L.; Dines, M. B. Tetrahedron Lett 1971,
12, 2205.
[28] Mitchell, W. R.; Paton, R. M. ARKIVOC 2009, xiv, 200.
[29] Furoxans are typically fragmented to give the peaks of M–30
and M–60 in EI mass spectrum. Hwang, K.-J.; Jo, I.; Shi, Y. A.;
Yoo, S.-e.; Lee, J. H. Tetrahedron Lett 1995, 36, 3337.
[13] Matsubara, R.; Saeki, Y. Li, J. Eda, K. Synthesis 2013, 45, 1524.
[14] Olah, G. A.;Olah, J. A.;Overchuk, N. A. J Org Chem 1963, 30, 3373.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet