Catalyst-free and solvent-free Michael addition of 1,3-dicarbonyl compounds to nitroalkenes by a grinding method

Article abstract of DOI:10.3762/bjoc.8.61

An environmentally benign, fast and convenient protocol has been developed for the Michael addition of 1,3-dicarbonyl compounds to β-nitroalkenes in good to excellent yields by a grinding method under catalyst- and solvent-free conditions.

Full text of DOI:10.3762/bjoc.8.61

Catalyst-free and solvent-free Michael addition of
1,3-dicarbonyl compounds to nitroalkenes
by a grinding method
Zong-Bo Xie1,2, Na Wang*1, Ming-Yu Wu1, Ting He1, Zhang-Gao Le2
and Xiao-Qi Yu*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 534–538.
1Key Laboratory of Green Chemistry and Technology, Ministry of
Education, College of Chemistry, Sichuan University, Chengdu,
China, 610064; Fax: (+86) 28-85415886; Tel: (+86) 28-85415886 and
2School of Chemistry Biology and Material Science, East China
Institute of Technology, Fuzhou, China, 344000; Fax:
(+86)794-8258320; Tel:(+86)794-8258320
doi:10.3762/bjoc.8.61
Received: 03 January 2012
Accepted: 15 March 2012
Published: 11 April 2012
Associate Editor: H. Ritter
Email:
Na Wang* - wnchem@scu.edu.cn; Xiao-Qi Yu* - xqyu@scu.edu.cn
© 2012 Xie et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
catalyst-free; grinding; Michael addition; solvent-free
Abstract
An environmentally benign, fast and convenient protocol has been developed for the Michael addition of 1,3-dicarbonyl com-
pounds to β-nitroalkenes in good to excellent yields by a grinding method under catalyst- and solvent-free conditions.
Introduction
Nowadays, chemists are vigorously taking on the challenge of more efficiently in the solid state than in solution due to a more
developing green synthetic methodologies to meet the criteria of tight and regular arrangement of the substrate molecules [14].
sustainable, environmentally conscious development. As a Thus, the grinding mode for solid-state reactions had been
result, catalyst- and solvent-free synthetic methods have applied in the Reformatsky reaction [15], Dieckmann conden-
attracted much interest not only for laboratory synthesis but also sation [16], Knoevenagel condensation [17], Aldol conden-
in chemical industry, because of reduced pollution, lower costs, sation [18], etc. [1,2,19,20].
mild conditions, and ease of purification. Recently, practical
procedures in the absence of solvents and catalysts have been The Michael addition is one of the most fundamental and
accomplished for greener and cleaner syntheses [1-6]. As the important reactions for the formation of carbon–carbon bonds
typical representative of solvent-free reactions, the grinding and carbon–heteroatom bonds in organic synthesis. The conju-
technique has been widely used in organic synthesis [7-13]. gate Michael addition of carbon nucleophiles to electron defi-
Compared to traditional methods, some organic reactions occur cient nitroalkenes is particularly interesting and challenging as
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Beilstein J. Org. Chem. 2012, 8, 534–538.
Scheme 1: Michael addition under catalyst- and solvent-free conditions.
it involves the generation of a wide range of different function- carbon, and so on. From Figure 1, it was found that all tested
alized products from Michael adducts [21-24]. In general, grinding aids could promote the reaction to different degrees,
Michael addition reactions require basic or acidic catalysts in and the primary reason may be that the two reactants could
organic solvents, as well as long reaction times, which may lead come into contact more effectively after dispersion by the
to environmentally hazardous residues and undesirable byprod- grinding aids. It was found that kieselguhr was slightly better
ucts [25-30].
than quartz sand in terms of grinding efficiency, and both gave
excellent yields. Although kieselguhr is often used as a catalyst
As one part of our continuing efforts toward the development of in many organic reactions, quartz sand was selected as the suit-
green synthesis methods for Michael additions of nitroalkenes, able grinding aid owing to its low cost and inertness. To the
we have previously reported an enzymatic tandem reaction to best of our knowledge, this is the first example in which quartz
form 5-hydroxyimino-4,5-dihydrofurans [22], a transition- sand has been successfully used as a grinding aid in Michael
metal-free process for the synthesis of substituted dihydrofu- addition reactions. Next, the same reaction was performed in
rans [23] and a catalyst-free tandem reaction for the synthesis of several organic solvents, as well as in water in the absence of
5-hydroxy-1,5-dihydro-2H-pyrrol-2-ones in aqueous medium catalysts for the purpose of demonstrating the high efficiency of
[24]. Recently, when carrying out the reaction of β-nitrostyrene the grinding method. As shown in Figure 2, after 1 h of
with 1,3-cyclopentanedione under catalyst- and solvent-free magnetic stirring, the best yield of 14% was achieved in polar
conditions, we were surprised to find that the grinding mode DMSO, while the other tested solvents gave much lower yields.
could efficiently promote the reaction, and the corresponding In fact, there are few reports on the Michael addition of
Michael addition product 3a was obtained in nearly 100% yield. β-nitrostyrene and 1,3-cyclopentanedione. Hrnčiar and Čulák
Therefore, we were encouraged to research the Michael add- performed the same reaction in methanol using sodium methy-
ition systematically by the grinding method.
late as a catalyst; however, only 85% of product 3a was
obtained, and a longer reaction time was required [31].
Herein, we report a green protocol for the Michael addition of
1,3-dicarbonyl compounds to nitroalkenes under catalyst- and
solvent-free conditions (Scheme 1). Utilizing this simple, rapid,
low-cost and effective procedure, various nitro diketone deriva-
tives were synthesized in high yields.
Results and Discussion
In our initial study, equimolar amounts of β-nitrostyrene (1a)
and 1,3-cyclopentanedione (2a), as a model reaction (Table 1,
entry 1), were mixed and ground in a mortar at room tempera-
ture. The mixture became sticky and adhered to the wall of the
mortar firmly after a few seconds, which prevented the reac-
tants from mixing thoroughly and coming into sufficient
contact. As a result, only a little of the desired product 3a was
detected, as monitored by thin-layer chromatography (TLC)
after 20 min. In an attempt to improve the grinding process,
some silica gel was added in the mortar. Surprisingly, a great
quantity of Michael product 3a was obtained after 5 min of
grinding. Then a number of powdered substances were
screened, such as KBr, quartz sand, Al2O3, kieselguhr, active
Figure 1: The grinding effect of different grinding aids. Conditions:
β-nitrostyrene (14.9 mg, 0.1 mmol), 1,3-cyclopentanedione (9.8 mg,
0.1 mmol), grinding aid (0.50 g), ground for 10 min and then allowed to
stand for a further 10 min. Yields were determined by HPLC.
535

Beilstein J. Org. Chem. 2012, 8, 534–538.
Figure 2: Yields of the model reaction in different solvents. Conditions:
β-nitrostyrene (14.9 mg, 0.1 mmol), 1,3-cyclopentanedione (9.8 mg,
0.1 mmol), solvent 1.0 mL, magnetically stirred for 1 h at rt. Yields
were determined by HPLC.
Figure 3: The effect of the amount of quartz sand on the yield. Condi-
tions: β-nitrostyrene (14.9 mg, 0.1 mmol), 1,3-cyclopentanedione (9.8
mg, 0.1 mmol), ground for 10 min and then allowed to stand for a
further 10 min. Yields were determined by HPLC.
Subsequently, the amount of quartz sand required was investi-
gated to find the optimal amount on a 0.1 mmol scale
(Figure 3). The results showed that 0.75 g or more quartz sand
was required for an excellent yield. Generally, the reaction rate
decreased with the reduction of the reactant concentration when
excessive quartz sand was used. However, the yield did not
reduce obviously, even when 2.00 g quartz sand was added in
the reaction system. Finally, 0.75 g quartz sand was selected as
the grinding aid for 0.1 mmol substrates. To optimize the
experimental conditions further, we also examined the effects of
the molar ratio of reactants on the yield, and a slightly better
result was obtained when 1.2 equiv of nitrostyrene was adopted
(data not shown). Also considering that nitroalkenes might
polymerize by themselves during the grinding process, a 1.2:1
(acceptor/donor) was chosen as the optimal molar ratio. Having
established the optimum conditions, the template reaction was
enlarged to a gram scale, and a similar result was obtained (data
not shown).
2,4(3H,5H)-dione (2b) with β-nitrostyrene (1a) (Table 1, entry
14). Some aromatic 1,3-dicarbonyl compounds were also
successfully used as donors in this Michael reaction in moderate
to good yields (Table 1, entries 18–21). In addition, furylni-
trostyrene (1m) reacted with 1,3-cyclopentanedione (2a) as well
as furan-2,4(3H,5H)-dione (2b) to give the corresponding prod-
ucts in excellent or fair yields (Table 1, entries 13 and 22). But
no corresponding products were detected in the reactions of
β-nitrostyrene (1a) with 2-methylcyclopentane-1,3-dione (2c)
and pyrrolidine-2,5-dione (2d) (Table 1, entries 15 and 16). It is
noteworthy that the reaction between β-nitrostyrene (1a) and
cyclohexane-1,3-dione (2e) only gave another product through a
tandem process (Table 1, entry 17; Supporting Information
File 1, Scheme S1). To our delight, Michael products 3n and 3s
were formed with excellent diastereoselectivity (dr > 99:1,
Table 1, entries 14 and 22), product 3l with moderate diastereo-
selectivity (dr = 82:18, Table 1, entry 12 ). For the purpose of
comparing the reactivity of different nitroalkenes with 1,3-
cyclopentanedione, another group of experiments was
To test the generality of this grinding Michael addition with performed, and a marked difference existed among various
respect to reactants, different aromatic and heteroaromatic nitroalkenes, owing to steric effects or electronic effects
nitroalkenes were used as the acceptors to react with (Supporting Information File 1, Table S1).
1,3-dicarbonyl compounds under the optimized conditions. The
results are given in Table 1. It can be seen that a wide range of After completion of the reaction, the mixture was purified
substrates were able to participate in the reaction. A series of directly by flash column chromatography to give the product
substituted β-nitrostyrenes with electron-withdrawing or elec- without the need for any pretreatment. However, a more effi-
tron-donating functionalities reacted with 1,3-cyclopentane- cient and convenient purification procedure was developed in
dione (2a) in good to excellent yields. Similarly, the scope of our research lab in order to meet the requirement of green
the donor was expanded to other 1,3-dicarbonyl compounds. chemistry. Namely, the reaction mixture was filtered through a
The best yield (>99%) was obtained for the reaction of furan- sand core funnel containing a thin layer of silica gel and the
536

Beilstein J. Org. Chem. 2012, 8, 534–538.
Table 1: Investigation of the reactant scope in the grinding Michael addition.a
Entry
Acceptor, 1
Donor, 2
Product, 3
Yield [%]
drb
1
1a: R1 = Ph, R2 = H
2a: X = CH2, Y = CH, R3 = H
3a
3b
3c
3d
3e
3f
99c
–
2
1b: R1 = 4-FC6H4, R2 = H
2a
>99c
>99c
>99c
>99c
99c
–
3
1c: R1 = 4-CF3C6H4, R2 = H
2a
–
4
1d: R1 = 4-ClC6H4, R2 = H
2a
–
5
1e: R1 = 3-ClC6H4, R2 = H
2a
–
6
1f: R1 = 4-BrC6H4, R2 = H
2a
–
7
1g: R1 = 2-BrC6H4, R2 = H
2a
3g
3h
3i
>99c
99c
–
8
1h: R1 = 4-NO2C6H4, R2 = H
2a
–
9
1i: R1 = 2-NO2C6H4, R2 = H
2a
91d
–
10
11
12
13
14
15
16
17
18
19
20
21
22
1j: R1 = 4-MeC6H4, R2 = H
2a
3j
>99c
>99c
83d
–
1k: R1 = 4-MeOC6H4, R2 = H
2a
3k
3l
–
1l: R1 = Ph, R2 = Me
2a
82:18
–
1m: R1 = 2-furanyl, R2 = H
2a
3m
3n
–
>99c
>99c
n.d.e
n.d.e
n.d.f
70d
1a
1a
1a
1a
1a
1a
1a
1a
1m
2b: X = O, Y = CH, R3 = H
2c: X = CH2, Y = CH, R3 = Me
2d: X =CH2, Y = N, R3 = H
2e: X = CH2CH2, Y = CH, R3 = H
2f: R4 = Ph, R5 = Me
2g: R4 = Ph, R5 = OEt
2h: R4 = 4-MeOC6H4, R5 = OEt
2i: R4 = R5 = Ph
>99:1
–
–
–
–
–
3o
3p
3q
3r
3s
53:47
55:45
59:41
–
81d
66d
58d
2b
63d
>99:1
aConditions: acceptor (0.36 mmol), donor (0.30 mmol), quartz sand (2.25 g), ground occasionally at room temperature. Reaction time: the exact reac-
tion time was not determined owing to the discontinuous grinding process, but most reactions were complete in 3 h. However, a longer time was
required for some reactions (e.g., entries 9 and 12), and good yields were obtained after overnight standing. bdr was determined by 1H NMR. cYields
of the isolated product after elution from a sand core funnel. dYields of the isolated product after chromatography on silica gel. en.d. = not detected.
fNo Michael product was detected, and another product was only obtained by tandem coupling.
pure product was obtained. More than half of the products could
Supporting Information
be rapidly purified in this way with similar or higher yields and
only a little eluent was needed.
Supporting Information File 1
General procedures and analytical data.
Conclusion
[http://www.beilstein-journals.org/bjoc/content/
In summary, a convenient, efficient and rapid method was
developed for the Michael addition of 1,3-dicarbonyl com-
pounds to β-nitroalkenes in good to excellent yields
by a grinding method under catalyst- and solvent-free condi-
tions. It was more meaningful to find that quartz sand could
effectively promote this reaction by acting as a grinding aid.
The reactions could be performed smoothly between solid–solid
or solid–liquid materials at room temperature with a wide range
of reactants. Moreover, a much simpler purification procedure
was developed, in place of column chromatography.
supplementary/1860-5397-8-61-S1.pdf]
Acknowledgements
We gratefully acknowledge the National Natural Science Foun-
dation of China (No. 21001077 and 20121001), Program for
Changjiang Scholars and Natural Science Foundation of Jiangxi
(2009GQH0007) for financial support. We also thank the
Sichuan University Analytical & Testing Center for NMR
analysis.
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