Recent progress in the field of cycloaddition reactions involving conjugated nitroalkenes

© 2019 by the authors; licensee Growing Science, Canada.


Introduction
In recent decades, novel reactions based on conjugated nitroalkenes (CNA) as the key substrates have emerged and numerous challenging targets have been achieved.This was possible primarily due to the ease of preparation or ready availability and the diverse reactivity of nitroalkenes.][6][7][8][9][10] This work is an attempt to synthetically discuss the results of research in the field of cycloadditions of conjugated nitroalkenes.
Soós et al. 14 strained, captodative benzylidene-azetidinones are demonstrated to function as potent reaction partners in thermal [2+2] cycloaddition reactions with nitroalkenes.This reaction can be used to simplify the synthesis of aza-spiro [3.3]heptanes.The optimal solvent was the acetone, reactions were carried out for 24h in room temperature with Schreiner's catalyst (1,3-bis[3,5bis(trifluoromethyl)phenyl]urea).The scope of olefines that can be reacted in [2+2] cycloaddition reactions is illustrated in Table 4.   Hayashi et al. 15 discovered that in reactions of 2-alkylnitroethenes with diphenylprolinol silyl etherderivedenamine in dry benzene, respective cyclobutanes was spontaneous and very fast formed.In all cases cycloadducts with the trans-configuration was observed (Scheme 1).

[3+2] Cycloaddition
Predominatingly, in [3+2] cycloaddition reactions involving CNAs, three atoms components of allylic type is most often used.To the most popular processes can include reaction using by nitrones.
The most commonly used CNAs, in reaction with nitrones, is nitoethene.For example, Jasiński 17 carried out series of [3+2] cycloaddition reactions of nitroethene to (Z)-N-aryl-C-phenylnitrones, which lead to mixtures of stereoisomeric 3,4-cis-and 3,4-trans-2-aryl-4-nitro-3-phenylisoxazolidines (Scheme 2).The processes are realized at room temperature, in the dark, and using by dry toluene as a solvent.The conversion of substrates was about 24 hours.The similar reactions were realized in ionic liquid as a solvent.Processes are realized using by 1butyl-3-methylimidazolium chloride ([BMIM]Cl) at room temperature gave mixtures of 3,4-cis-and 3,4-trans-2-aryl-3-phenyl-4-nitroisoxazolidines with 80-85% yields (Scheme 3).It should be underlined, that the application of an ionic liquid allows to shorten the conversion time of substrates to 10 minutes in comparison to toluene solution 18 .
Jasiński 19 also carried out [3+2] cycloaddition reactions of C,C,N-triphenylnitrone to nitroethene (Scheme 4).It was reported that, in the contrast to earlier reports 20 , the process is full regioselectively independently of the temperature.In particularly at room temperature and in 110°C, a course of reaction is formed only one product -4-nitro-2,3,3-triphenylisoxazolidine.The DFT calculations explained, the source of high efficiency of reactions between nitroalkenes and nitrones in ionic liquids.In particular, [3+2] cycloaddition reaction between gem-chloronitroethene and (Z)-C-4-methoxyphenyl-N-phenylnitrone in the presence of [BMIM] cations proceed via two-step mechanism involving a zwitterionic intermediate 21 (see Scheme 5).Other types of substituted of nitroethenes are also often used in reactions with nitrones.An example is cycloaddition of triphenylnitrone with 2-cyanonitroethene (Scheme 6).The process does not lead to the stable products.Primary formed 4-nitroisoxazolidine decomposed easily to substrates, while 5nitroisoxazolidine is converted to β-lactam.The processes were realized at room temperature, and using by dry toluene as a solvent.The conversion of substrates was about 4 hours 22 .Mechanistic aspects of this type transformations has been explored in the detail based on DFT calculations .Bigotti et al. 23 carried out the reaction with the participation of γ-fluoro-α-nitroalkenes in the [3+2] cycloaddition reactions with nitrones.These reactions leads to isoxazolidines in good to excellent yields, with total regiocontrol and nearly complete diastereocontrol in favor of the isomers with 3,4cis configuration (Table 6).All processes are realized in mild condition.Properly 2-subsitued nitroethenes are used in series of [3+2] cycloaddition reaction with (Z)-C-(3,4,5-trimethoxyphenyl)-N-methylnitrone as three atoms component.The authors show that these type of processes are a regiospecific and a stereoselective.The processes are realized at room temperature, in the dark, and using by dry toluene as a solvent.The conversion of substrates was about 24 hours 24 (Table 7).New 2,3,3,5-tetrasubstituted-4-nitroisoxazolidinesare may be synthesized in a reaction between ketonitrones and 2-EWG-nitroethenes.The processes are realised both in toluene and also in ([BMIM]Cl).Authors show that all of these type [3+2] cycloaddition reactions are realised in mild condition with complete regioselectivity, and lead with high yields to sterically crowded products 25 (Table 8).Kinetic studies indicate that all these cycloadditions do take place according to a mechanism that proceeds without intervention of zwitterionic intermediate 26 .

Table 8. Reaction between (E)-3,3,3-trichloro-1-nitroprop-1-ene and (Z)-C-diphenyl-N-arylnitrone
In recent time, gem-1,1-dinitroethene became the object of research as a highly reactive and useful π-deficient three atoms components.The DFT calculations showed the clearly polar nature of [3+2] cycloaddition reaction between gem-dinitroethene and (Z)-C,N-diphenylnitrone (Scheme 7).The course of reaction leading to 2,3-diphenyl-4,4-dinitroisoxazolidineis is kinetically favoured.Authors showed that depending on the reaction environment polarity, the process can lead according to different mechanisms.The conducting the reaction in the gas phase causes the product of [3+2] cycloaddition reaction to be formed in accordance with the one-step mechanism.When the reaction is conducted in toluene, the reaction proceeds according via zwitterionic stepwise scheme 27 .It should be underlined, that [3+2] cycloaddition reactions of the same gem-1,1-dinitroethene to different type of nitrile Noxides proceed via a one-step mechanism independently of solvent polarity 28 .

Scheme 7.
[3+2] cycloaddition reaction between gem-dinitroethene and (Z)-C,N-diphenylnitrone Another three atoms components allylic type which is used in reaction with CNA is azomethineylide, both acyclic, and cyclic compounds.
Nyerges et al. 29 carried out a series of reactions between nitroethene and in situ generated azomethineylides as three atoms components.These processes are carried out in dry toluene, at 0 o C and in the presence of silver acetate.The [3+2] cycloaddition reactions gave the expected pyrrolidine in all cases (Table 9).Sarrafi et al. 30 prepared spiroacenaphthene pyrroloisoquinoline in series, using various 12 arylnitroethenes as a CNAs.Products were formed with full regioselectivity.The process are realized in ethanol as a solvent and reflux.Conversion of substrates is about 4 hours (Table 10).
Starosotnikov et al. 31 carried out a series of reactions based on the [3+2] cycloaddition reactions of Nmethylazomethine ylide with substituted 4-nitrobenzofurazanes.In a courses of reactions only one of two possible products are formed.Also Authors observed that the cycloaddition process was found to be affected by substituents in the benzene ring.To generate azomethine imines, to the reaction mixture was added BF3•Et2O in order to break the diaziridine ring.It could be expected that the addition of β-nitrostyrenes to three atoms components should run via the Michael addition pathway through intermediates generating1,3-diaryl-2nitrotetrahydro-1H,5H-pyrazolo[1,2-a]pyrazoles.The processes are realized at room temperature or with moderate heating.Expected product were obtained in all the cases.However, apart from them, tetrafluoroborates of 5,6-diaryl-2,3-dihydro-1H-pyrazolo[1,2-a]pyrazoliumand hexafluorophosphate of 5,6-diaryl-2,3-dihydro-1H-pyrazolo[1,2-a]-pyrazolium were unexpectedly isolated.Assumingly, compounds were formed as a result of the interaction of properly substituted of β-nitrostyrene with three atoms components, contrary to the Michael addition mechanism, generating second intermediates.Yang and Fan 33 carried out a series of reactions between azomethine imine system and 2-aryl-1nitroethenes.The first, they examined the reaction of azomethine imine with properly substituted of 2aryl-1-nitroethenes in different solvents.It was found that the reaction in most organic solvents at reflux, such as in chloroform, tetrahydrofuran, acetonitrile and methanol (with comparatively low boiling points), led to [3+2] cycloaddition reactions product in good yields in the absence of a catalyst (Table 12).If the reaction was carried out in a polar solvent, such as dimethyl sulfoxide, at 60°C, a trace amount of together with the normal product was formed.Further increasing the reaction temperature resulted in an increased yield of until almost it was the sole product at temperatures higher than 100°C.However, it was proved that temperature was not the only factor for this steric course, the same reaction was carried out at the same temperature (about 110°C) in toluene (as a nonpolar solvent).It was found that the yield of decreased markedly and was generated as the main product.Moreover, the authors also studied the course of the reaction using a series of various substituted azomethine imines and analogs of 2-aryl-1-nitroethenes.In a course of reaction are formed main one product.It seems that the reactions are tolerant to various substituted compounds.The substituent on the aromatic ring has no significant effect on this transformation (Table 13).Table 13.Various substituted azomethine imines and analogs of 2-aryl-1-nitroethenes The use in reactions of thiocarbonylylides as a three atoms component with conjugated nitroalkenes is known from theoretical considerations.DFT calculations, for various levels in theory, show that the reaction of 2,2,4,4-tetramethyl-3-thiocyclobutanone S-methylidewith nitroethene takes place according to a polar, two-step mechanism with a zwitterionic intermediate 59 (Scheme 9).The benzonitrile N-oxides have become the object of research in theoretical considerations.DFT calculations, for various levels in theory, show that [3+2] cycloaddition reactions between nitroethene and properly substituted analogs of benzonitrile N-oxides proceed by a one-step mechanism and should be considered polar, but not stepwise processes (Scheme 11).Moreover, a DFT calculations also showed that the favored reaction path leads to an adduct with a nitro group in position C5.It is compatible with experimental observations 28 .

Scheme 11. [3+2] cycloaddition reactions between nitroethene and properly substituted analogs of benzonitrile N-oxides
Very interesting is example of reaction between diazafluorene and series of (E)-2-aryl-1-cyano-1-nitroethenes (Scheme 12).In the course of the reaction unexpectedly acyclic derivatives of 2,3diazabuta-1,3-diene are formed instead of expected [3+2] cycloadducts containing pyrazoline skeleton.According to DFT calculations, the reaction course is a consequence of formation of zwitterionic structure in the first stage of the reaction and next, the cyanonitrocarbene elimination.Processes are realised in mild condition and are formed product with high yield 35 .

Diels-Alder and Hetero Diels-Alder reactions
Jasiński et al. 36,37 , explored a series of Diels-Alder reactions of 2-aryl-1-cyano-1-nitroethenes with cyclopentadiene in nitromethane which lead to endo-and exo-nitronorbornenes.After 24 hours, almost full conversion was achieved and the products (Table 15) were isolated by semipreparative HPLC.Authors also confirmed the structure of major product 5-cyano-5-nitro-6-phenyl-bicyclo[2.2.1]hept-2ene by singe crystal X-ray diffraction analysis 37 .This team also presented a research on looking for better conditions for these processes and they performed cycloaddition of 2-aryl-1-cyano-1-nitroethenes to cyclopentadiene in ionic liquids 38 .The authors proposed effective and eco-friendly method of obtained cycloadducts after only 10 minutes, and varying stereoselectivity which depended on the used ionic liquid (Table 16).

Conclusions
Recent years brought a series of significant reports on the reactivity of conjugated nitroalkenes in the cycloadditions reactions.Moreover -due to the rapidly growing availability of high-powered computers -a thorough analysis of the mechanism of a number of these reactions has been made, often throwing new light on the way of converting substrates.

Table 20 .
49els-Alder reactions of nitroalkenes with dienes and in presence of different catalysts49

Table 21 .
50els-Alder reactions of nitroalkenes with dienes and in presence of trienamine catalysts50

Table 23 .
51els-Alder reactions of nitroalkenes with cyclohexenones in the presence of organocatalyst51