Tandem grinding reactions involving aldol condensation and Michael addition in sequence for synthesis of 3,4,5-trisubstituted isoxazoles

Article abstract of DOI:10.1039/c9ra04864b

A one-pot, base-catalyzed, tandem grinding process involving carrying out aldol condensation and Michael addition in sequence to produce 3,4,5-trisubstituted isoxazoles from 3,5-dimethyl-4-nitroisoxazole, aromatic aldehydes and activated methylene compoun

Full text of DOI:10.1039/c9ra04864b

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Tandem grinding reactions involving aldol
condensation and Michael addition in sequence for
Cite this: RSC Adv., 2019, 9, 27883
synthesis of 3,4,5-trisubstituted isoxazoles†
Xiao-Mu Hu,‡a Hai Dong,‡b Yue-Dan Li,a Ping Huang,a Zhuang Tiana
a
*
and Ping-An Wang
A one-pot, base-catalyzed, tandem grinding process involving carrying out aldol condensation and Michael
addition in sequence to produce 3,4,5-trisubstituted isoxazoles from 3,5-dimethyl-4-nitroisoxazole,
aromatic aldehydes and activated methylene compounds has been developed. In the presence of
10 mol% of pyrrolidine, aldol condensations of 3,5-dimethyl-4-nitroisoxazole with various aromatic
aldehydes were performed with 3–10 minutes of grinding to provide 5-styryl-3-methyl-4-
nitroisoxazoles in good to quantitative yields without further purification. Then, Michael additions
between 5-styryl-3-methyl-4-nitroisoxazoles and activated methylene compounds (including ethyl 2-
nitroacetate and alkyl 2-cyanoacetates) were carried out in the presence of 10 mol% of Et3N in the same
mortar with 3–5 minutes of continuous grinding to produce 3,4,5-trisubstituted isoxazoles in good to
excellent yields.
Received 27th June 2019
Accepted 23rd August 2019
DOI: 10.1039/c9ra04864b
rsc.li/rsc-advances
recommended by synthetic chemists because of their high
modularity and simple manipulation. In this regard, the
Introduction
tandem grinding reaction is regarded as a quasi-one-pot reac-
tion because all of its reaction steps are completed in the same
mortar. Ideal solutions for the synthesis of active pharmaceu-
tical ingredients and biological products, and new strategies to
improve the atomic economy of important chemical processes
and valuable structures are still in demand.
Nitrogen-containing heterocyclic compounds, especially
isoxazole and its derivatives, are very important heterocyclic
cores with a wide range of organic and bio-activities, and are
present in many natural products and medicines (Fig. 1).5–7 3-
Methyl-4-nitro-5-styrylisoxazoles can be easily prepared from
commercially available 3,5-dimethyl-4-nitroisoxazole and
Maximizing the efficiency of reactants and reducing waste
generation are important contributions to atomic economy and
green chemistry. Many chemists have paid increasing attention
to Michael addition for C–C and C–heteroatom bond formation
in recent years.1 Generally, the conventional Michael addition
reactions are performed in solvent conditions, and some cases
take a long reaction time (up to 7 days). In response to the
requirements of green chemistry, scientists have been working
on developing synthetic methods that generate little environ-
mental pollution and display high atom economy.2 Therefore,
the study of solvent-free Michael reactions involving microwave
irradiation, ultrasonic irradiation and mechanochemical
synthesis has also been reported extensively.3 On the one hand,
reactions performed under solvent-free grinding conditions are
very attractive to synthetic chemists because these reactions are
easy to manipulate, cost little, and are highly efficient. The
molecules in the solid state display large contact areas and high
local concentration, which speeds up the reaction and increases
selectivity. On the other hand, one-pot reactions4 are also highly
aDepartment of Medicinal Chemistry, School of Pharmacy, The Fourth Military
Medical University, Changle Xilu 169, Xi'an, 710032, P. R. China
bCollege of Pharmacy, Xi'an Medical University, No. 1 Xinwang Rd, Weiyang Dist.,
Xi'an, 710021, P. R. China. E-mail: ping_an1718@outlook.com
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra04864b
‡ Co-rst authors. These two authors have made the same level of contribution to
this work.
Fig. 1 Representative compounds containing the biologically active
isoxazole core.
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aromatic aldehydes, and they are usually used as electro-
decient Michael acceptors for asymmetric catalytic Michael
reactions with various activated methylene compounds such as
isocyanoacetates, a,b-unsaturated g-butyrolactam, and anthro-
nes.8 These Michael additions have all been performed under
solvent conditions with relative long reaction times. Very
recently, we reported a facile catalyst-free amination of b-
nitrostyrenes and 2-aryl-3-nitro chromenes achieved by carrying
out grinding.9 As part of our continuous efforts with grinding
reactions, herein we demonstrated a facile synthetic route to
3,4,5-trisubstituted isoxazoles, in excellent yields, from 3,5-
dimethyl-4-nitroisoxazole, aromatic aldehydes and activated
methylene compounds, achieved by performing amine-
catalyzed tandem grinding (Fig. 2).
Scheme
1
The preparation of 3-methyl-4-nitro-5-styrylisoxazole
carried out using solvent-free grinding.
3-methyl-4-nitro-5-styrylisoxazoles (2a–q) in good to quantita-
tive yields. The reaction rates of aldehydes containing an
electron-withdrawing group (EWG, aldehyde with Cl, Br or NO2)
were found to be higher than those with an electron-donating
group (EDG, aldehyde with OH or OMe). Aldehydes 1i, 1j, 1k,
1l and 1q were made to react with nitroxazole to produce cor-
responding aldol condensation products 2i, 2j, 2k, 2l and 2q in
quantitative yields by using 30 mol% of pyrrolidine catalyst
grinding at room temperature. All of the tested aldehydes
provided aldol condensation products with 10 minutes of
grinding, and the results are summarized in Fig. 3.
Results and discussion
Pyrrolidine-catalyzed grinding reactions of aromatic
aldehydes with 3,5-dimethyl-4-nitroisoxazole
Aldol condensation is one of the important C–C bond formation
reactions in modern organic synthesis. Many enantioselective
aldol reactions have been investigated extensively in the past
two decades. Solvent-free aldol condensations have also been
reported occasionally. In fact, the aldol condensation of
aromatic aldehydes with 3,5-dimethyl-4-nitroisoxazole is
usually reported to be carried out in a polar solvent system (e.g.
EtOH) by using stoichiometric or catalytic amounts of organic
secondary amines (such as diisopropyl amine, pyrrolidine,
piperidine) under heating (2 h) or room-temperature stirring for
8–12 h.10 We found that this reaction can be performed under
solvent-free grinding conditions, and only take 3 to 10 minutes,
greatly shortening the reaction time and providing a simple
strategy for synthesizing 3-methyl-4-nitro-5-styrylisoxazoles
(Scheme 1). Various aromatic aldehydes (1a–q) were then used
as substrates for such solvent-free grinding reactions to afford
Tandem grinding reactions involving aldol condensation and
Michael addition in sequence for preparation of 3,4,5-
trisubstituted isoxazoles
Initially, the Michael reaction of 3-methyl-4-nitro-5-
styrylisoxazole 2b with ethyl 2-nitroacetate 3a was used as
a model reaction to investigate the grinding Michael reaction.
Various bases including Na2CO3, K2CO3, Et3N, iPr2NEt, N-
methylmorpholine (NMM), 1,8-diazabicyclo[5,4,0]undec-7-ene
(DBU) and 1,4-diazabicyclo[2.2.2]octane (DABCO) were each
used as a catalyst for this reaction. The results are shown in
Scheme 2. Of these bases, the simple tertiary amine Et3N was
concluded to be the best choice for this Michael reaction
because of its high efficiency, easy evaporation and convenient
availability. For the rst step to 3-methyl-4-nitro-5-
styrylisoxazoles, pyrrolidine was used as the catalyst, and for
the second step to 3,4,5-trisubstituted isoxazole, Et3N was used
as the catalyst. We then considered the possibility of combining
these two separate steps into one by developing a single catalyst
containing both a secondary amine and tertiary amine in its
structure. With this point in mind, we used A1 and A2 as cata-
lysts, and performed a one-pot grinding reaction of 4-chlor-
obenzaldehyde 1b, 3,5-dimethyl-4-nitroisoxazole and ethyl 2-
nitroacetate 3a. The results are shown in Scheme 3. Both A1 and
A2 were found to lead to complex results.
Aerwards, we used pyrrolidine as a catalyst for the rst
grinding reaction to prepare 2b. When carrying out thin-layer
chromatography (TLC) indicated that the starting materials 1b
and 3,5-dimethyl-4-nitroisoxazole of this reaction were
consumed, we then added ethyl 2-nitroacetate 3a and 10 mol%
Et3N to the same mortar and performed another 3 minutes of
Fig. 2 The syntheses of 3,4,5-trisubstituted isoxazoles achieved by
performing tandem grinding.
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Fig. 3 Pyrrolidine-catalyzed solvent-free grinding preparation of 3-methyl-4-nitro-5-styrylisoxazoles 2a–q (1.0 mmol scale).
Scheme 2 The screening of bases for grinding preparation of 3,4,5-
trisubstituted isoxazole 4ab.
grinding at room temperature. In this way, 4ab was obtained in
92% yield. We called this strategy a tandem grinding reaction.
By using this strategy, we performed aldol-Michael reactions of
aromatic aldehydes 1 and 3,5-dimethyl-4-nitroisoxazole and
activated methylene compounds including ethyl 2-nitroacetate,
alkyl 2-cyanoacetates and malononitrile to provide 3,4,5-
trisubstituted isoxazoles 4 in good to excellent yields aer
a simple ash column chromatographic purication.
Scheme 3 The screening of catalysts A1 and A2 for one-pot grinding
preparation of 3,4,5-trisubstituted isoxazole 4ab.
donors, no corresponding product was formed under standard
grinding conditions even with a prolongation of reaction time.
All products were determined from their 1H NMR spectra to be
composed of diastereomers in a 1 : 1 ratio.
The results are shown in Fig. 4. When dialkyl malonates,
ethyl acetoacetate and acetylacetone were used as Michael
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Fig. 4 Tandem grinding reactions for the preparation of 3,4,5-trisubstituted isoxazoles (1.0 mmol scale).
compound 3 (liquid, 1.2 mmol) and Et3N (12 mL, 0.1 mmol) were
added, and grinding was carried out for another 3–5 min. (Note:
aldehydes 1i, 1j, 1k, 1l and 1q were not used up under standard
conditions, so the corresponding aldol condensation products
2i, 2j, 2k, 2l and 2q were separated from their respective
unconsumed reactants by performing ash column chroma-
tography.) TLC was used to check the reaction process. The
crude product was diluted with DCM (20 mL) and the resulting
solution was successively washed with H2O (5 mL) and brine (5
mL). The organic layers were dried over Na2SO4, ltered, and
concentrated. The pure product 4 was obtained by carrying out
Experimental
General procedure for synthesis of compound 4
To a dried agate mortar, aromatic aldehyde 1 (1 mmol), 3,5-
dimethyl-4-nitroisoxazole (white crystal, 0.15 g, 1.1 mmol) and
pyrrolidine (8 mL, 0.1 mmol) were added successively. The
mixture was subjected to grinding at room temperature for 3–
5 min, and the reaction was monitored using TLC (for most
cases, the color of the reaction mixture changed obviously
during the grinding process). When TLC indicated that
aromatic aldehyde 1 was consumed, the activated methylene
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ash column chromatography (eluted by petroleum ether/ethyl
acetate ¼ 10/1 to 5/1, v/v).
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In conclusion, we have developed a tandem grinding strategy to
prepare 3,4,5-trisubstituted isoxazoles from aromatic alde-
hydes, 3,5-dimethyl-4-nitroisoxazole and activated methylene
compounds in the presence of catalytic amounts of pyrrolidine
and Et3N in high yields and efficiency. The transformations of
these 3,4,5-trisubstituted isoxazoles to complex structures for
investigation of their bio-activities are underway in our
laboratory.
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Conflicts of interest
There are no conicts to declare.
Acknowledgements
We thank the National Science Foundation of China (no.
21372259) for nancial support of this work.
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