Trisubstituted push-pull nitro alkenes

Properties, preparations, and utilization in the organic synthesis of the trisubstituted push-pull nitroalkenes are summarized from all the relevant results published until 2020. Preparation of these nitroalkenes is versatile due to numerous of the starting materials. The importance of reviewed nitroalkenes is outlined by their frequent exploitation in the synthesis of biologically active compounds, as well as a vast range of heterocyclic derivatives


Introduction
2][3] Due to their conjugated nature, they can act as electrophiles in 1,4-or 1,2-additions with nucleophiles or radicals, respectively.They can be also exploited as dienophiles or heterodienes in the Diels-Alder reaction.In recent years, their importance has been enhanced by utilization in asymmetric synthesis. 4urthermore, the nitro group can be transformed into a variety of other functional groups. 5Some of the most important transformations are conversion of primary or secondary nitro compounds into aldehydes or ketones, known as the Nef reaction. 6Reduction of a nitro group into an amino group is one of the most utilized catalytic processes in the fine and bulk chemical industry, and it can be achieved by various combinations of the hydrogen source and catalyst.The hydrogen source is usually molecular hydrogen, and the catalyst can be different metals. 7Replacement of the nitro group with hydrogen, commonly referred to as denitration is generally carried out via a radical process using tin hydride. 80][11] Despite this vast literature base, there are just very few papers dedicated to polysubstituted nitro alkenes, their preparation, and their utilization in organic synthesis.Trisubstituted push-pull nitro alkenes are one of the most important compounds of such omitted nitro alkenes group (Figure 1).Disubstituted push-pull nitro alkenes (without another electron acceptor A) undergo formations of heterocycles worse than trisubstituted nitroalkenes as another electron acceptor A can readily react in nucleophilic additions with 1,2-12 or 1,3-binucleophiles 13,14 and nitro group cannot offer such a reaction.The preparation of tetrasubstituted nitroalkenes is less convenient than trisubstituted nitroalkenes in terms of yields, a number of methods, reaction times, temperatures, and toxicity of required reagents.5][16][17][18][19][20] For instance, they have been used in rational drug design of topically administered caspase 1 inhibitors for the treatment of inflammatory acne, 14 in the synthesis and biological evaluation of pyrimidine derivatives as novel human Pin1 inhibitors in the cancer treatment, 15 and the preparation of scaffolds for the design of Rac1−Tiam1 protein−protein interaction inhibitors 16,17 .Title compounds were also employed in the synthesis of alkaloid meridianin G, 18 and the synthesis of the insect feeding deterrent peramine. 19In the most recent article, they are utilized in the synthesis of 2-imidazopyridine and 2-aminopyridone purinones as potent Pan-Janus kinase (JAK) inhibitors for the inhaled treatment of respiratory diseases. 20

Isomerism
Trisubstituted alkenes may exist as single E/Z-isomers or they can undergo isomerization between these two structures.Detailed IR and NMR studies for the structure with A = ester and D = amino group were performed to determine E/Z-ratios and the existence of predominant isomer. 21ased on previous studies authors established 3 possible isomers for reviewed molecules.Z-isomers differ due to the conformation of the carbonyl group toward double bond (Figure 2).The authors confirmed the presence of all three isomers and established E/Z ratios based on the correlation of 1 H, 13 C NMR, and IR spectra.From these results they concluded that (i) substrates crystallize as one of those isomers, however, they may isomerize even in the solid state.(ii) In the solution, a mixture of E/Z-isomers is readily formed.Formed equilibrium is dependent on the polarity of the solvent and strength of the hydrogen bond between H from amino group and O from carbonyl or nitro group, respectively.(iii) Z-isomer has been predominant in many measured substrates, which is the most substantial difference of 3amino-2-nitroacrylic esters from 3-aminoacrylic esters and nitroenamines.The abundance of Z-isomer in the mixture correlates with its stronger hydrogen bond between H from amino and O from the nitro group (Table 1).a Hydrogen bond enegies (EH / kcal mmol -1 ) were calculated from two-bond deuterium isotope effect on C-3 chemical shifts ( 2 ∆ / p.p.b) according to equation 2 ∆=10 3 [δC-3(NH)-δC-3(ND)]; ln( 2 ∆)=2.783+0.354EH. 22,23Values for 2 ∆ were obtained in CDCl3 solution at 0.2M concentration.Also, the rate constant of this isomerization was studied for the reviewed structures and their analogs (Figure 1).An effect of substituent R and electron-withdrawing group Z on the rate constant was investigated.The authors estimated the free activation Gibbs Energy ∆G ≠ for the double bond rotation from the coalescence data (Table 2) according to the modified Eyring equation.They expected and confirmed a thermal isomerization mechanism.Substituents, that stabilize the formed charges on the carbons C2 and C3 by the delocalizing negative charge on the C2 or donating electrons to electron deficit C3 (Figure 2) will lower the rotation barrier.The comparison of the rotation barrier with regard to the substituent R on the donor amino group results in the sequence Ph > H > Et.This correlation was confirmed by measurement for all the substrates except Z = CN.The lowest barrier of the rotation has substrates with R = Et due to the I+ effect of this group.
The comparison of the rotation barrier with regard to the acceptor substituents Z results in the sequence CN > COOR > COMe > NO2.This correlation was confirmed by measurement for all the substrates except R = Ph.The lowest barrier of the rotation has substrates with Z = NO2 due to the strong M-and I-effect of this group.

Preparation
Frequently used synthetic routes to obtain reviewed structures can be divided into four groups (Scheme 1-5).

Scheme 1. The preparation of title nitroalkenes by method A.
Scheme 2. Proposed mechanism of the preparation of the target nitroenolethers according to method A.
However, a more detailed study of the mechanism (Scheme 2) was performed many years later. 26,27uthors by an alternation of the reaction conditions determined that (i) reaction is fully reversible in every step (A1-A3).(ii) Acetic anhydride activates trialkyl orthoformate for further reaction by initial condensation step A1 to form dialkoxymethyl acetate.(iii) Dialkoxymethyl acetate from step A1 may enter into two competing reactions A2 and A5, however, thermal decomposition step A5 may be suppressed by an excess of acetic anhydride.(iv) Acetic anhydride also serves for the removal of the formed alcohol from the reaction mixture, in this way shifting the equilibrium of the reaction to the product.Subsequently formed alkyl acetate can be distilled out of the reaction mixture due to its low boiling temperature.

Formation of mono-N-substituted nitroenamines (B).
5][36][37][38] The products 3-alkylamino-2-nitroacrylic esters used to be prepared by nucleophilic vinylic substitution on 3-alkoxy-2-nitroacrylic esters with adequate N-nucleophile. 28The paper 31 describing reactions with diverse groups of N-nucleophiles and utilizing "one-pot" reaction pathway B depicted in (Scheme 3), was published in 1963.Authors there demonstrate formations of pyrimidone derivatives by subsequent reaction of alkyl nitroacetates, trialkyl orthoformate, and urea derivatives.This preparation of pyrimidones was previously known for the other compounds with active methylene group 39,40 and for the reviewed structures is described in more detail in chapter 2.3.3.

Scheme 3. The preparation of title nitroalkenes by method B.
The reaction pathway was suggested in the past just for the modification of method B with active methylene group compounds without a nitro group and urea derivatives. 41An analogical reaction pathway can be expected for the reviewed structures.

Formation of di-N,N-substituted nitroenamines (C).
Method C is used for the preparation of reviewed structures less frequently, although it has some advantages (e.g. a smaller number of starting components) in comparison with methods A and B. Dimethylformamide-dimethyl acetal serves as a source of a carbon atom instead of trialkyl orthoformate.Resulting N,N-dimethylamino nitroalkene contains a relatively good leaving group which may facilitate further nucleophilic reactions (Scheme 4).This method was mostly exploited for the preparation of reviewed structures with acyl group 18,[42][43][44][45] as the second electron-withdrawing group.Scheme 4. The preparation of title nitroalkenes by method C.

Other preparations (D).
Last method D is a group of the reactions, that does not fit any previous preparative approaches (Scheme 5).The first reaction D1 provides 3-amino-2-nitroacrylic ester from formamidine acetate and ethyl nitroacetate. 33The same product may be obtained in a stepwise manner by method A. Second reaction 46 D2 exploits isocyanides due to their versatility and extensive utilization in C-H functionalization reactions. 47The authors developed a radical coupling/isomerization strategy for the crosscoupling of isocyanides with active methylene compounds through silver-catalysis.The method solves the over-insertion of isocyanides 48 and affords a variety of otherwise difficult to synthesize compounds.The authors also suggested a plausible mechanism of the reaction (Scheme 6).Scheme 5.The preparation of title nitroalkenes by method D. Scheme 6.A plausible mechanism for the second reaction from method D.

Utilization in organic synthesis
Further utilization of the reviewed structures in organic synthesis, known in the literature, can be divided into six groups.Four of these groups contain reactions with nucleophiles via nucleophilic vinylic substitution (SNV).Widely known reviews have been devoted to mechanistic study 49 of this reaction and its further utilization for the synthesis of heterocycles. 50This paper offers an overview of the reactions of push-pull nitroalkenes with many substrates not only in the SNV reactions but extends the scope to the cycloadditions and miscellaneous reactions.

Reactions with mono-nucleophiles (E).
A group of reactions with mono-nucleophiles can be inter-or intramolecular (Scheme 7).These reactions undergo SNV by a single-step or a multistep addition-elimination mechanism 51 and an inversion of E/Z configuration usually occurs. 52All types of nucleophiles (C 53,54 , N 29,36,37,55 , S 16,17 ) are known to be utilized in the case of intermolecular reactions.This corresponds to a vast diversity of employed solvents and reaction conditions.
If the starting substrate already contains the second nucleophilic center QHR, which can substitute nucleofuge X, an intramolecular reaction occurs to form a ring-fused derivative. 45The product of the same ring cyclization can be obtained, if the places of a nucleophile QHR center and leaving group X are switched. 43cheme 7. Overview of reaction reviewed structures with mono-nucleophiles.

Reactions with 1,2-binucleophiles (F).
Reactions of 1,2-binucleophiles with title nitroalkenes (Scheme 8) are less frequent in the literature.In reaction F1, the title compound is combined with hydroxylamine in the presence of pyridine resulting in the salt of the isoxazoline derivative. 12Formed isoxazoline salt is used in further synthesis as a source of carbamoyl-substituted nitrile oxide for 1,3-dipolar cycloadditions. 30,56Reaction F2 is an example from a set of reactions with hydrazine derivatives that results in pyrazole derivatives. 44enerally, the reaction should be composed of two main steps.Frist SNV step results in the substitution of leaving group (OMe or NMe2) with one nucleophilic center of 1,2-binucleophile (hydroxylamine or hydrazine derivative).Followed by intramolecular nucleophilic substitution on the carbonyl group (acyl group or methyl ester group) with the second nucleophilic center of 1,2-binucleophile, which forms a five-member heterocyclic ring.However, there are more possible pathways due to the presence of two nucleophilic centers in the unsymmetrically substituted 1,2-binucleophile.The studies of chemo-and regioselectivity rules for the reactions of unsymmetrical 1,2-binucleofiles were conducted only for the conjugated systems, which are structurally similar to title nitroalkenes. 57,58cheme 8. Overview of reaction reviewed structures with 1,2-binucleophiles.
Authors in the studies of related trisubstituted push-pull olefins concluded that (i) in the case of hydrazine derivatives as 1,2-binucleophiles, the less substituted nitrogen usually reacts first in the SNV step.(ii) In the case of hydroxylamine derivatives, nitrogen heteroatom usually reacts first in the SNV step.(iii) In the case of hydroxylamine derivatives, nitrogen heteroatom usually reacts 1,4-conjugate addition in addition-elimination SNV step.(iv) The direction of the ring closure in the second intramolecular substitution step is substratedependent.
Articles describing reactions of 1,3-binucleophiles with title nitroalkenes are very frequent in the literature.Therefore, they are divided into two groups based on the structure of the product.59,60 There are also examples of other six-membered heterocycles (pyridine 35 and thiadiazine 61 ) prepared in a similar manner.The second group contains structurally more different products (Scheme 10) that are formed by reaction with usually amino heterocycles as 1,3-binucleophiles. 36,37,62,63The reaction was studied on trisubstituted nitroalkenes with two different nucleophiles 35,63 (Scheme 11).In both examples, a base was required to form a C-nucleophile in the first SNV step.However, in the case of Nnucleophiles, the base was required just in the second cyclization step as many of these reactions were performed stepwise with the isolation of the product from the first SNV step.Scheme 11.Reaction steps and intermediates from the studies of the reaction of title nitroalkenes with 1,3binucleophiles.

Reactions with 1,4-binucleophiles (H).
There are very few known reactions of push-pull nitroalkenes with 1,4-binucleophile in the literature.Even more, they are not analogical to other reactions with binucleophiles.Authors 64 proposed reaction steps (Scheme 12) for the reaction of ethyl 3-ethoxy-2-nitroacrylate with isothiosemicarbazone derivative.The difference from the other 1,4-binucleophiles is the second step that proceeds as another 1,4-addition instead of 1,2-addition.Due to this change in the second reaction step, a 5membered heterocycle is formed instead of 7-membered one.In this case, nitroalkene is fragmented and it acts as a donor of the methylidene group.Scheme 12.The pathway and reaction of reviewed nitroalkene with 1,4-binucleophile.

Pericyclic reactions (J).
Title structures were utilized in three different types of cycloadditions (Scheme 13).In the first reaction (J1) is prepared conformationally constrained cysteine analog by [4+2] Diels-Alder cycloaddition. 16Nitroalkene acts as a dienophile in this reaction.The authors confirmed the presence and difference yield of all four possible exo/endo products by exploiting different E/Z mixtures of the starting nitroalkene.In the second reaction (J2) trans-fused bicyclic nitronate is prepared by tandem transetherification-intramolecular hetero [4+2] Diels-Alder reaction. 65In this case, nitroalkene acts as heterodiene.The authors suggested a reaction pathway for this tandem reaction (Scheme 14).

Miscellaneous utilization in organic synthesis (K).
The last group of reactions summarizes examples from the literature, which systematically does not fit any of the previous chapters (Scheme 15).Nitroalkenes in these reactions provided unexpected products.In the first reaction (K1) could be expected SNV product, however, nitroalkene is fragmented during the reaction, and oxime derivative is formed. 67The authors proposed a mechanism for such a fragmentation (Scheme 16).In the second reaction (K2) could be also expected SNV product, however, a dimer is formed.This structure is published as a crystallographic report. 68Third reaction (K3) is part of the study about a quinolizone formations.However, in the case of ethyl 3-ethoxy-2-nitroacrylate, an indolizine derivative is formed. 69

Conclusions
This review summarizes the chemistry of trisubstituted push-pull nitroalkenes.It discusses the importance of this group of nitroalkenes in organic synthesis with emphasis on their utilization in the preparation of biologically active compounds.Individual chapters treat physical and chemical properties in terms of E/Zisomerism, preparation, and further utilization in organic synthesis.Isomerism studies stated that Z-isomer should be the predominant one in the case of alkyl 3-amino-2-nitroacrylates due to the intramolecular hydrogen bond between amino hydrogen and oxygen of the nitro group.However, the presence of the pushpull system with nitro group results in fast isomerization, and a mixture of E/Z-isomers could be obtained even in the solid state.There are 5 published methods of the preparation of these nitroalkenes.Most relevant of them could be generalized as reactions of the nitro compound with active methylene group, such as ethyl nitroacetate, with C-electrophile that contains at least two leaving groups, for instance, triethyl orthoformate.Utilization in the organic synthesis of these nitroalkenes is much more versatile.In the literature are known examples of the reactions with mononucleophiles, resulting in SNV products, and binucleophiles, resulting in a vast range of the five-/ six-membered heterocycles / fused heterocycles.Generally, they should be regarded as bifunctional electrocyclophiles with three carbon fragments for the target molecule.Reviewed nitroalkenes can be utilized in [4+2] Diels-Alder cycloadditions as heterodienes or dienophiles.There are examples of other types of pericyclic reactions ([3+2], [3+3]) exploiting these nitroalkenes as well.Overall, this review should simplify an incorporation of reviewed nitroalkenes into the future synthetic approaches by outlining the most relevant results from the studies about them, known in the literature up to 2020.

Figure 1 .
Figure 1.The general structure of trisubstituted push-pull nitro alkenes.

Figure 1 .
Figure 1.Model structure for the study of the rate constant of isomerization.

Figure 2 .
Figure 2. Double bond rotation between E/Z isomers by thermal isomerization mechanism.

Scheme 15 .
Scheme 15.Overview of miscellaneous reactions of reviewed structures.

Table 1 .
21sults concluded from key IR, NMR spectral data, and two-bond deuterium isotope effect on C-3 chemical shifts.Modified from the table21

Table 2 .
Main NMR parameters and estimated the free activation Gibbs Energy ∆G≠ for the double bond rotations for compounds with Z=NO2 and R=H, Ph.Modified from the table.24 a Compounds were measured in DMSO-d 6 as 0.2-1M solutions; b coalescence temperature TC is in K; c the separation of the exchanging resonances at the low T limit ∆υ is in Hz; d ∆G ≠ is in kJ mol -1 .