Solvent-Free Henry and Michael Reactions with Nitroalkanes Promoted by Potassium Carbonate as a Versatile Heterogeneous Catalyst

. The use of a simple weak inorganic base such as potassium carbonate facilitated the formation of carbon-carbon bonds through both the Henry and the Michael reactions with nitrocompounds. The application of this catalyst under environmentally friendly solventless heterogeneous conditions gave satisfactory to good yields of 𝛽 -nitroalcohols, involving aliphatic and aromatic starting materials, as well as high to excellent yields in the formation of Michael adducts using several different Michael acceptors and nitroalkanes.


Introduction
The formation of a carbon-carbon bond can be carried out using various starting materials together with a vast amount of homogeneous or heterogeneous catalysts.Two important reactions which involve the synthesis of compounds through carbon-carbon bond formation include the Henry and the Michael reactions with nitroalkanes [1][2][3].Under basic conditions nitroalkanes are able to deprotonate to form an intermediate compound known as the nitronate anion [4].The nitronate anion can then react with aldehydes through the Henry reaction to yield -nitroalcohols [5].In the case of the Michael addition, the carbanion would react with Michael acceptors or ,-unsaturated compounds to yield polyfunctionalised nitroderivatives [6].
In recent years the nitroaldol and the Michael reactions were carried out using extensive catalysts, some of which containing complex structures.Various methodologies have been employed; however, in some cases, disadvantages of h a v i n gs u c hc o m p l e xs t r u c t u r e si n c l u d e da p p l y i n ge i t h e r very low or substantially high temperatures to obtain the respective products at great yields [7][8][9][10].A major drawback o fs o m ec a t a l y s t si st h a tt h e yr e s u l t e di nt h ei n c r e a s e d formation of secondary products in these reactions.In the case of the nitroaldol reaction, the main side product is the formation of the nitroalkene through a further condensation reaction of the nitroalcohol.In some cases the use of certain catalysts resulted in the production of a conjugated enone through an aldol condensation side reaction, whereas some highly activated catalysts which were applied to the Michael addition were too reactive as reactions which resulted in the formation of the double addition products [4][5][6].
Herein, as a continuation of ongoing study on the development of environmentally friendly methodologies [11][12][13], our main interest in relation to this context was to identify a simple alternative and cheap heterogeneous solid catalyst useful for both the Henry and the Michael reactions, in accordance with moderate reaction conditions and the concept of Green Chemistry [14] to produce, respectively, nitroalcohols (Scheme 1) and polyfunctionalised nitroderivatives (Schemes 2 and 3) [15][16][17].On this purpose potassium carbonate [18,19] was identified as a suitable catalyst and produced average to good results for the nitroaldol reaction (Table 3) and good to excellent results for the Michael addition (Table 4).To the best of our knowledge, potassium carbonate was previously reported to catalyse only a few Scheme 2: Michael addition model reaction using methyl acrylate and nitroethane with K 2 CO 3 .
examples of Michael addition reactions, although never under neat conditions but with the required assistance of solvents [20,21], ultrasounds activation, and ionic liquids [ 2 2 ] ,o rw i t ht h eu s eo fal i m i t e dn u m b e ro fs u b s t r a t e sa s starting materials [23] or else not involving nitroalkanes but different nucleophiles [24][25][26].

Results and Discussion
In both reactions, the first part of the study consisted of the optimization screening through the investigation of some Henry (Table 1) and Michael reactions (Table 2) using potassium carbonate as the catalyst together with the variation of both physical and chemical conditions and without any solvent.
The Michael reaction was first investigated by performing a variety of trials using nitroethane (5) and methyl acrylate (4) as model reaction (Scheme 2).
Following these preliminary investigations, the Henry reaction gave good results when undergone at temperatures of 60 ∘ C, increasing the reaction rate substantially and using 10 molar% of catalyst (entry 5, Table 1).On the other hand, high temperatures were detrimental to the Michael additions as a second by-product was afforded, this most probably being the double Michael adduct.In order to decrease the formation of the bis-addition, the reaction temperature was kept at room temperature to promote increased formation of the desired monoaddition and together with the use of 30 molar% of catalyst the best result was obtained (entry 5, Table 2).These selected conditions were then employed in other Henry and Michael reactions in order to verify a more general applicability of the preliminary protocol, using nitroalkanes and different aldehydes and ,-unsaturated compounds, respectively.
As reported in Table 3, aliphatic aldehydes gave the best results in the least amount of reaction time while aromatic aldehydes with electron withdrawing substituents gave better yields than those containing electron donating groups.Parasubstituted aromatics were the most difficult substrates to react and when utilising 4-nitrobenzaldehyde a small amount of CH 2 Cl 2 was required as the starting material was solid.In general average to good yields were obtained with this catalyst as the reaction itself is reversible [2] and thus it is difficult for it to reach completion.The major role played by the catalyst was that reactions only afforded in a selective way the nitroaldol product and no traces of any condensation side product were present.
The previous conditions were then applied to Michael reactions using different nitroalkanes and diversely functionalised Michael acceptors (Scheme 3) and the catalyst performed even better providing good to excellent product yields (Table 4).Only when using nitromethane were very low yields recorded, since the formation of the bis-addition side product was revealed due to the fact that it is a small and unhindered molecule, while using a secondary nitroalkane the temperature was increased to 60 ∘ Casthereisnopossible formation of the bis-adduct.Also the results obtained from these trials indicated that 30 mol% of catalyst gave good yields at room temperature when using methyl acrylate as the Michael acceptor.However, reaction temperatures were increased to 60 ∘ Ca n d9 0 ∘ Cw h e nu s i n gc y c l i ca n d sterically hindered Michael acceptors like cyclic enones and trans-methyl crotonate in order to increase the speed of the reaction, whereas reactions which involved the use of   acrylonitrile required lower temperatures of 0 ∘ Ct op r e v e n t immediate polymerization of acrylonitrile from occurring, which was evident through the formation of a thick yellow solid.

Conclusions
In summary, the utilisation of potassium carbonate in neat conditions is a very versatile and green synthetic method and thus shows great applicability with a variety of substrates, containing different backbone structures, such as aliphatic straight chain and cyclic and aromatic compounds, to undergobothHenryandMichaelreactions.Comparedwith the reported methods using expensive or unavailable organic catalysts, a common and inexpensive inorganic base (K 2 CO 3 ) washereem plo yedasthebaseca talyst.Thepresen tedreactions proceeded with complete regioselectivity providing the nitroaldol and Michael monoaddition products, respectively,

. 3 .T y p i c a lP r o c e d u r ef o rt h eM i c h a e lR e a c t i o na n dt h e
Formation of Methyl 4-Nitropentanoate (6).The nitroalkane, nitroethane (10 mmol), was mixed with the Michael acceptor, methyl acrylate (10 mmol).After through mixing, the potassium carbonate catalyst (30 mol%) was added to the mixture.Heating or cooling was applied only when required, according to staring materials (Table 4).The reaction was leftstandingforthea ppropria tetime.Theca talystwasthen filtered using a small column fitted with cotton and Florisil.The filtrate was then evaporated in vacuo and the crude product was purified via column chromatography using a mixture of cyclohexane and ethyl acetate affording the pure
a Yield of pure isolated products.

Table 2 :
Optimization of Michael reaction using model reaction.
a Yield of pure isolated product.b Reaction was carried out at room temperature for 24 hours; temperature was increased to 60 ∘ Cfor3hours.

Table 3 :
Henry reaction using 10 mol% K 2 CO 3 at 60 ∘ C. Reaction was carried out under CH 2 Cl 2 solvent as the starting aldehyde was solid.
a Yield of pure isolated product.b

Table 4 :
Michael reactions with various nitroalkanes and Michael acceptors using 30 mol% K 2 CO 3 .

Table 4 :
C ontinued.Cl 2 wasusedassolventasthestartingacceptorwassolid.polystyreneabsorbancespectrum.Samples were either analysed as a thin film or in a Nujol6 mull, between sodium chloride discs.The 1 H-and 13 C-NMR spectra were recorded on Bruker AM250 NMR spectrometer fitted with a dual probe at frequencies of 250 MHz and 62.9 MHz for 1 H and13C NMR, respectively.An Aspect 3000 computer using 16 K complex points for 1 HN M Ra n d64Kc o m p l e xpo i n t s for13C NMR was used for processing.Samples were dissolved in deuterated chloroform (with TMS): 5 mg in 0.8 mL CDCl 3 for 1 H NMR and between 35 mg and 50 mg in 0.8 mL CDCl 3 for 13 C NMR. Reaction monitoring was done by TLC and GC analysis.Ready-purchased silica on PET sheets with fluorescent indicator, 254 nm, was used as stationary phase for TLC.Gas chromatography was carried out on a and 1 H NMR (250 MHz, CDCl 3 )  1.24-1.3(dd, J = 9.66 Hz, 3H),  1.54-1.59(dd, J = 6.72 Hz, 3H),  2.26-2.40(dd, J =6.1Hz,1H), 4.08-4.22(m, 0.6H),  4.32-4.42(m, 0.4H), and  4.43-4.56(m, 1H).