Solvent-free mechanochemical synthesis of diacylfuroxans

Article abstract of DOI:10.1016/j.tetlet.2019.05.024

Acetophenones with a variety of substituents could be converted to diacylfuroxans in a solvent-free reaction by combining the reagents Fe(NO₃)₃·9H₂O and P₂O₅ under high-speed ball milling. This reacti

Full text of DOI:10.1016/j.tetlet.2019.05.024

Accepted Manuscript
Solvent-free mechanochemical synthesis of diacylfuroxans
Zhen-Zhen Gu, Feng-Chao Guo, Pu Zhang, Yu-Jun Qin, Zhi-Xin Guo
PII:
S0040-4039(19)30463-0
https://doi.org/10.1016/j.tetlet.2019.05.024
TETL 50796
DOI:
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
23 March 2019
6 May 2019
13 May 2019
Please cite this article as: Gu, Z-Z., Guo, F-C., Zhang, P., Qin, Y-J., Guo, Z-X., Solvent-free mechanochemical
synthesis of diacylfuroxans, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.05.024
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Solvent-free mechanochemical synthesis of diacylfuroxans
Zhen-Zhen Gu, Feng-Chao Guo, Pu Zhang*, Yu-Jun Qin, and Zhi-Xin Guo*
Department of Chemistry, Renmin University of China, Beijing, 100872, China.
* Corresponding authors. Email: gzhixin@ruc.edu.cn, zhangpu@ruc.edu.cn
Abstract
Acetophenones with a variety of substituents could be converted to
diacylfuroxans in a solvent-free reaction by combining the reagents
Fe(NO3)3·9H2O and P2O5 under high-speed ball milling. This reaction was
facile and eco-friendly, and exhibits advantages in terms of better toleration,
safety, and easier operation. The nitrate acid and nitrogen dioxide generated
in situ should play a major role in this mechanochemical reaction.
Over the past few decades, furazans (1,2,5-oxadiazoles) and their 2-oxides
(furoxans) have attracted attention because of their potential application as reactive
intermediates in organic syntheses, for preparing pharmacologically and
agrochemically active agents, as well as energetic formulations.1-5 Compared with
many of other oxygen-containing heterocyclic systems, furoxans or furazans contain
“active oxygen”, which does not bind to carbon or hydrogen atoms and can
consequently oxidize these atoms to release energy.6 Among furoxans with
substituent diversities, diacylfuroxans are specific ones. Many studies have reported
that diacylfuroxans could be used as new and effective lead compounds for
schistosomiasis chemotherapy.7-9 With cystein, diacylfuroxans could release nitric
oxide, which plays a key role in the nervous and cardiovascular systems.10 These
compounds have also been synthesized as horticultural and agricultural fungicides.11
Meanwhile, the synthetic application of diacylfuroxans have also been reported by
several research groups.12-17
Traditionally, diacylfuroxans were synthesized through the reaction of methyl
ketones with a nitrosating/nitrating source, such as dilute HNO3 (usually in the
presence of AcOH or other acids) or concentrated HNO3 (in the presence of nitrogen

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oxides).5 These reactions suffer from drawbacks such as imperfect functional group
tolerance. In addition, these reactions may cause explosion and also generate nitrogen
oxide (NOx) fumes and large quantities of waste acids; the disposal of these spent
liquors presents a serious environmental problem.
Along with the rapid development of green chemistry, mechanochemical organic
synthesis (or ball milling organic synthesis) has attracted increasing attention from
organic chemists.18-23 As a green alternative to the traditional solution-based synthetic
approaches, mechanochemical organic synthesis is mainly promoted by inputting
mechanical force to the reaction system, which exhibits many advantages over its
liquid-phase counterpart in terms of higher product yield, better selectivity, shorter
reaction time, simple work-up procedure, elimination of harmful organic solvents, etc.
During our continuous exploration of high-speed ball milling (HSBM)
reactions,24-28 we recently found that by taking Fe(NO3)3·9H2O as the nitrification
reagent, and P2O5 as the auxiliary, aromatics with strong deactivating groups such as -
CN or -NO2 could be nitrated in excellent yields under HSBM conditions.
Surprisingly, when we took acetophenone as one of the typical deactivated aromatic
compounds to perform the same reaction at 20 M Hz in the molar ratio of 1:1.5:5
(acetophenone:Fe(NO3)3·9H2O:P2O5) for 5 hours, in addition to the designed nitrated
compound (32%) and unreacted acetophenone (10%), an unexpected new compound
resulted. After purification by column chromatography, the new compound was
analysed by NMR, FT-IR, and MS, its chemical structure was confirmed as 3,4-
dibenzoylfuroxan, which was obtained in 57% yield (Scheme 1).
Scheme 1
Inspired by this result, the mechanochemical reaction conditions were optimized
in order to achieve a higher conversion rate of furoxan (Table 1). When acetophenone
was ball milled with a certain amount of NaNO3 or KNO3 in the presence of P2O5,
almost no furoxans were observed; however, about 30% nitrated compounds were

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formed, together with a half amount of the unreacted acetophenones (Table 1, entries
1 and 2). When the hydrated nitrates were used (Table 1, entries 3–7), the nitration
became the dominant reaction. For example, when Bi(NO3)3·5H2O was used, 75%
nitrated acetophenone was obtained with 12% furoxan. Among the nitrate salts
investigated, Fe(NO3)3·9H2O (Table 1, entry 7) was the most efficient reagent in this
mechanochemical reaction. To further improve the reaction, the molar ratios of
Fe(NO3)3·9H2O and P2O5 relative to acetophenone were adjusted to a variety of
values (Table 1, entries 8–18). The results show that to attain better yields of furoxan,
the molar ratio of Fe(NO3)3·9H2O should be greater than 1.0 (Table 1, compare entry
9 with 12) and that of P2O5 should be greater than 2.0 (Table 1, compare entries 10–11
with 7–9). When the molar ratios of acetophenone, Fe(NO3)3·9H2O, and P2O5 were
kept as 1:2:3 (Table 1, entry 14), 82% of the furoxan was obtained.
Table 1. Optimization of reaction conditions*

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Various substituted acetophenones were tested as substrates under the optimized
conditions. In order to keep the mechanochemical reaction free from the influence of
different ratios between the milling ball and the milling materials, all of the ratios
were kept between 3.1 to 3.3. Table 2 summarizes the results. All of the 18 substrates
resulted in good to excellent yields based on the reacted acetophenones, indicating
that Fe(NO3)3·9H2O/P2O5 is an effective combination to synthesize furoxans and can
be used widely with various substituted acetophenones. Methoxy (Table 2, 3a), cyano
(Table 2, 10a), and ester (Table 2, 8a) groups were tolerated under the attempted
conditions. In traditional solution chemistry, both methoxy and cyano groups have
been tolerated in the nitric acid solution;10 however, the ester groups could not
survive, and diacylfuroxan with ester groups had to be prepared through a glyoxime
intermediate,29 which must be synthesized with tedious and boring work.
Acetophenones with electron-withdrawing groups (Table 2, 7a, 8a, 9a, 10a, and 14a)
resulted in a higher yield, probably because with these substrates, it was very difficult
to perform the nitration reaction using HSBM. Acetophenones with electron-donating
groups (Table 2, 2a and 3a) resulted in relatively lower yields due to their greater
activity in the nitration reaction. Acetophenones with halogen groups (Table 2, 4a–6a,
11a–13a, and 15a–17a) gave similar results. No big difference occurred between the
yields of acetophenones with the same substituent in a different position (4a, 11a, and
15a; 5a, 12a, and 16a; 6a, 13a, and 17a; 7a and 14a). These results agree with those of
solution reactions in which diluted or concentrated nitric acids were employed to react
with acetophenones.30 In addition, aromatic heterocyclic ketones such as thiophene-2-
ketone could also be converted to the corresponding furoxan with an excellent yield
(Scheme 2), implying that heterocyclic furoxans could also be obtained by this
method.
Scheme 2

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Table 2. Various furoxans formed via the mechanochemical reaction*
To our knowledge, this is the first observation of the synthesis of diacylfuroxans
via HSBM. Studies show that in solution chemistry, both nitric acid and nitrogen
dioxide (or nitrite salt) are necessary to form furoxans either through benzoyloxime30
or benzoylnitromethane intermediates.31 In the mechanochemical reaction, nitric acid
should be formed in situ from the reaction of nitrate salts with P2O5, and this should
be the key reason that all of the nitrate salts (anhydrous or hydrated) can work
together with P2O5 to perform the nitration reaction (Table 1). It is well-known that at
a certain temperature, nitrate salts decompose thermally to release nitrogen dioxide.
Usually, anhydrous nitrate salts decompose at a higher temperature compared with
hydrated ones. For example, NaNO3 will release NO2 at about 400 oC, while
Fe(NO3)3·9H2O begins to decompose at about 60 oC to give Fe(NO3)3·6H2O, which
will decompose further at 110 - 120 oC to release nitrogen dioxide.32
Although our mechanochemical reaction was performed at room temperature, the
mechanical force could introduce a large amount of energy to the reactive moieties,

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which could result in a localized high temperature. In one study with no powder in an
HSBM reactor similar to ours, the ball temperatures reached 400 to 600 oC. However,
with powder and with a ball-to-powder weight ratio of 40:1, the maximum ball
temperature was around 200 oC.33 However, Stolle also reported that at 20 MHz, the
milling beaker’s temperature was about 40 oC after 90 min. of ball milling.34
In our HSBM reaction, an infrared thermometer was used to roughly measure the
temperature of the milling beaker under standard reaction condition. A maximum
temperature increasing of about 10 oC was observed compared with that of the
environment. In order to investigate if Fe(NO3)3·9H2O could be decomposed at that
temperature, control experiments of milling only Fe(NO3)3·9H2O or
Fe(NO3)3·9H2O/P2O5 under the standard conditions was performed, respectively. For
pure Fe(NO3)3·9H2O (0.4 mmol), the reaction mixture could be dissolved in water
thoroughly, indicating no decomposing of the nitrate salt. As for Fe(NO3)3·9H2O/P2O5
(0.4mmol : 0.6 mmol), brown gas could be observed at the bottom of the beaker when
the mill beaker was opened right after the reaction. Meanwhile, NO2 like odour could
be noticeably smelled. Most of the resulting grey white solid could not be dissolved in
either organic solvent (e.g., dichloromethane) or water. These observations imply that
decomposing of Fe(NO3)3·9H2O may be achieved with the aid of P2O5.
In order to have a deeper insight into the decomposition reaction, the reaction
mixture was extracted with dichloromethane to remove the organic residues
thoroughly. The remaining solid was dried and checked by FTIR spectroscopy (Figure
2S, ESI). There exists two major peaks in the spectrum. The peak in the range of 900
– 1200 cm-1 is corresponding to the normal vibrational modes of the PO4-3 ions.35 The
other peak in the range of 450 – 620 cm-1 are the characteristic peaks of Fe2O3.36
Together with the escaped NO2 observed in the reaction, we believe that in the
presence of P2O5, Fe(NO3)3·9H2O could be decomposed to produce Fe2O3 and NO2.
Since the HSBM reaction temperature is not higher enough to decompose
Fe(NO3)3·9H2O thermally, the decomposition may be occurred somehow in the
“mechanical” way.

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In our HSBM reaction, nitrates such as KNO3/P2O5 and NaNO3/P2O5 could
barely convert acetophenone to furoxan chemically, this kind of nitrate can react with
P2O5, and the resulting nitrate acid could nitrate the acetophenone. As for hydrated
nitrate salts, especially Fe(NO3)3·9H2O, they could decompose almost completely
under HSBM to release in situ abundant nitrogen dioxide, which could combine with
the nitric acid produced in situ to convert acetophenones to furoxans, probably in a
way similar to that of solution chemistry.
In summary, we have found that using HSBM, combining Fe(NO3)3·9H2O and
P2O5 can successfully convert acetophenones to diacylfuroxans. This method is facile
and eco-friendly and exhibits advantages in terms of better toleration and safety, and
easier operation. We suggest that nitrate acid and nitrogen dioxide generated in situ
from the reaction of Fe(NO3)3·9H2O with P2O5 and the decomposition of
Fe(NO3)3·9H2O, respectively, should play a major role in this mechanochemical
reaction.
Acknowledgments
The authors acknowledge the financial assistance of Renmin University of China.
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Graphical Abstract
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Solvent-free mechanochemical synthesis of
diacylfuroxans
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Zhen-Zhen Gu, Feng-Chao Guo, Pu Zhang*, Yu-Jun Qin, Zhi-Xin Guo*
Department of Chemistry, Renmin University of China, Beijing 100872, China
Solvent-free mechano-chemical
reaction with 18 examples, yield
up to 93%.

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Highlights
 Solvent-free mechanochemical synthesis of diacylfuroxans
 Fe(NO3)3·9H2O as the alterative reagent instead of nitric acid
 Facile, safe, and eco-friendly method with yield up to 93%
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