Developments and applications of α-bromonitrostyrenes in organic syntheses

The presence of the bromo and nitro groups in the structure of α-bromonitrostyrene makes them highly reactive and versatile reagents in organic syntheses. α-Bromonitrostyrenes act as an effective dielectrophile in the reaction with various nucleophiles. In these reactions, the bromo and nitro groups behave as good leaving groups for the assembly of a diverse range of heterocyclic compounds, such as dihydrofurans, dihydropyranes, furans, pyrroles, pyrazoles, isooxazolines, spiropyrrolidines, etc. In the current review, we have focused on the transformations of α-bromonitrostyrenes under organocatalysis, metal catalysis, and base-catalysis systems as well as catalyst-free conditions, since 2010.

Michael addition reactions of a-bromonitroalkenes can be performed in the presence of organocatalysts, metal catalysts, and bases, as well as catalyst-free systems.7][18][19] On the other hand, domino Michael/Henry reactions are known as powerful methods for rendering complex molecular architectures through constructing the carbon-carbon bonds in a one-pot procedure without isolating intermediates. 20,21][24] Recently, various research teams, such as Jakubec, 25 Gao, 26 Lee, 27 Halimehjani, 28 Shen, 29 and Zhang 30 reported the organic transformations of nitrostyrenes.In this review, we have specically discussed the use of a-bromonitrostyrenes in various types of catalytic systems, such as organocatalysis, metal catalysis and base catalysis as well as catalyst-free reactions.We have also highlighted important features of the reactions and mechanisms to familiarize the readers with the reactivity and behavior of a-bromonitrostyrenes in organic syntheses.

Organocatalyst-catalyzed transformations of bromonitrostyrenes
In 2010, Rueping et al. used (E)-b-bromonitrostyrenes 1 for the synthesis of dihydrofurans 3 from 1,3-dicarbonyl compounds 2 (Scheme 2). 31In this reaction, the chiral thiourea catalyst A can close two substrates together by hydrogen-bonding interaction and facilitate Michael addition of diketone 2 as a dinucleophile to bromonitrostyrene 1 as an electrophile to generate intermediate II.Then, an intramolecular nucleophilic addition delivered product 3 by the release of HBr.The same organocatalyst was used in the reaction of bromonitrostyrene, as a dielectrophile and 1,3-indandione as a dinucleophile to make spironitrocyclopropane in 57% yield with 35% ee. 32arra and co-workers used an organocatalysis system to synthesize enantioselective dihydroarylfuran derivatives 5 from the cyclization reaction between (Z)-bromonitroalkenes 1 and naphthol 4 (Scheme 3). 33The hydrogen bonding interaction of chiral organocatalyst B with both substrates was responsible for the suitable orientation for Michael-Friedel-Cras reaction and subsequent S N 2 reaction on the carbon attached bromide.It should be noted that HBr resulting from the reaction can be neutralized with a stoichiometric amount of a base.
Another organocatalyst was used in the reaction of bromonitroalkenes 1 and alkyl aldehydes 6 (Scheme 4). 34A series of enantioenriched cyclopropanes 7 with quaternary carbon centers were prepared in the presence of a chiral pyrrolidine catalyst C. As illustrated in Scheme 5, the reaction started with the condensation of pyrrolidine with aldehyde to form imine I, followed by a 1,3-H shi to enamine II.The attack of bromonitrostyrene to the alkene moiety produced intermediate III.By release of the catalyst and subsequent intramolecular S N 2 reaction, cyclopropane 7 was provided along with the elimination of bromide.It seems that the formation of two diastereomers 7 and 7 0 from two congurations IV and V is possible.The conguration at C2 is generated from the intramolecular attack of the anion with DABCO, while the conguration at C4 is from the acidic proton at this C-atom, providing the thermodynamically stable product.In this case, the NO 2 group is at the trans position to the aryl ring at C3.
In 2016, Feng et al. introduced a chiral organocatalyst E for the asymmetric synthesis of dihydrofurans 11 from (Z)-bromonitrostyrenes 1 and a-substituted cyano ketones 10 (Scheme 7). 36In this regard, a domino Michael addition-alkylation between bromonitrostyrene and a-substituted cyano ketone in the presence of chiral N,N 0 -dioxide E was conducted under very mild reaction conditions.The authors found that the use of proton sponge, added in six equal parts, could enhance enantioselectivity and also the performance of the reaction in a very low temperature prevent the formation of the cyclopropane compound as a byproduct and thus increasing the yield of dihydrofuran 11.In addition to excellent enantioselectivity, high diastereo-and regioselectivity were also observed in this reaction.
The use of a-bromonitroalkenes 1 in the synthesis of 3,4dihydro-2H-thiopyrano[2,3-b]quinolines 14 was reported by Xie and co-workers in 2018 (Scheme 8). 37An organocatalysis system was proposed for this synthetic method, which started with the deprotonation of 2-mercaptoquinoline-3-carbaldehyde 13 by tertiary amine of catalyst F, and the activation of a-bromonitroalkene 1 by the thiourea moiety of F through the formation of two hydrogen bonds.The subsequent domino Michael/Henry reaction resulted in product 14.This method had the advantages of excellent enantio-and dieastereoselectivity, mild reaction conditions, and the ability of 3,4-dihydro-2H-thiopyrano [2,3-b]quinolines to undergo further organic transformations.In addition, salicylaldehyde can also act as a coupling partner in the cyclization with bromonitroalkene.
In 2020, an organocatalysis system was developed to prepare pyrrolidinyl spiro-oxindoles bearing quaternary carbon centers 16 (Scheme 9). 38Han and co-workers designed a (3 + 2)-cycloaddition reaction between isatin-derived ketimine 15 and (Z)-abromonitroalkene 1 in the presence of cinchonidine-derived squaramide G.This bifunctional organocatalyst can control the stereoselectivity by the hydrogen bonding interactions with both substrates blocking one side of each substrate, allowing nucleophilic attack from the Si-face.In 2022, Tanyeli and co-workers extended a new organocatalysis system for the synthesis of chiral dihydrofurans 18 from bromonitroalkenes 1 and 1,3-dicarbonyl compounds 17 (Scheme 10). 39Their reaction proceeded through domino type Michael-S N 2 reactions in the presence of a quinine-derived sterically encumbered squaramide H.The main advantages of this method that differentiates it from previous methods was the performance of the reaction in room temperature at short reaction times, while other similar reactions required cryogenic conditions and longer times to proceed.As shown in transition state, the quinoline moiety of the catalyst H activates the nucleophile 17 by hydrogen bonding.At the same time, the electrophile 1 is also activated by double hydrogen bonding with the squaramide group of H. Consequently, the nucleophilic attack of 17 from the Si-face of 1 afforded product with excellent enantioselectivity.
Silver triate can catalyze the three-component reaction of tetrahydrofuran, b-bromonitrostyrene and alcohol via a radical pathway (Scheme 13). 42The reaction was initiated by the formation of radical I from the interaction of Ag(I) with THF, which attacked b-bromonitrostyrene 1 to form intermediate II.

Base-mediated transformations of bromonitrostyrenes
In 2007, Namboothiri and co-workers reported the synthesis of phosphonylpyrazoles 28 and 29 from diethyl 1-diazo-2oxopropylphosphonate 27 with a-bromonitroalkenes 1 under basic conditions (Scheme 15, eqn (1)). 43The elimination of the leaving group in the nal product depended on the substituent at the aryl ring of bromonitroalkene substrate.When Ar = Ph, for the synthesis of furan structures (Scheme 18). 47In their reaction, a-bromonitroalkenes 1 and 2-hydroxynaphthalene-1,4-diones 37 were applied as starting materials to form 3phenylnaphtho[2,3-b]furan-4,9-diones 38 via Michael addition and subsequent intramolecular S N 2 reaction.At last, the absorption properties of the obtained products were determined by UV-Vis spectra and uorescence spectroscopy.
Spirocyclopropyl oxindole frameworks 40 were constructed in high yield with excellent diastereoselectivity from the reaction of bromonitroalkene 1 and N-protected indolin-2-ones 39 (Scheme 19). 48Due to high reactivity of indolin-2-one under ambient temperature and consequently low diastereoselectivity of the obtained product, a very low temperature was necessary for this reaction.The formation of cyclopropane was accomplished by the abstraction of a proton by a base and the liberation of bromide.Not only N-protected indolin-2-one but also N-H indolin-2-one was included in this transformation.
Soengas et al. established a two-step procedure for the preparation of 2-C-glycosyl-3-nitrochromenes 43 starting from bromonitrostyrenes 1 and ortho-hydroxybenzaldehydes 41 (Scheme 20). 49For this purpose, rst, they treated bromonitrostyrenes 1 with ortho-hydroxybenzaldehydes 41 under basic conditions to achieve (2S,3S,4S)-3-bromo-3,4-dihydro-4hydroxy-3-nitro-2H-1-benzopyrans 42 in moderate to excellent yields.In the next stage, the reaction was conducted in the presence of 0.1 M solution of SmI 2 in THF for couple hours to form 3-nitrochromenes 43.SmI 2 can promote the b-elimination in benzopyran 42 with complete stereoselectivity.All steps were performed under mild conditions and all products were obtained with enantiomeric purity.
In 2015, again the Namboothiri research team synthesized imidazole scaffolds 45 through the reaction of amidine hydrochloride 44 with a-bromonitroalkenes 1 (Scheme 21). 50For the assembly of 2,5-disubstituted imidazoles from a-bromonitroalkenes, 3.0 equivalents of Cs 2 CO 3 were required to promote all steps of this imidazole synthesis.First, Cs 2 CO 3 promoted the formation of amidine I by the elimination of HX form 44. Michael addition of 1 to I gave intermediate II, which underwent an intramolecular S N 2 process via a 5-exo-tet fashion to provide nitroimidazoline III along with the removal of HBr in the presence of Cs 2 CO 3 .Subsequent elimination of HNO 2 by Cs 2 CO 3 led to product 45.Moreover, the authors reported potential anti-parasitic activity of the resulting imidazoles.
In 2018, Namboothiri and co-workers used a-bromonitroalkene 1 in the reaction with lawsone 46 and 2-aminonaphthoquinone 47 to produce furan and pyrrole fused quinonoid compounds 48 and 49 using two different basic conditions (Scheme 22). 51The transformations were performed via Michael addition of 1 to 47 to form intermediate I, followed by S N 2 reaction in a 5-exo-tet manner to obtain intermediate II.
Finally, pyrrole or furan frameworks were furnished aer HNO 2 removal.The authors also studied the anticancer activity of the obtained products.Aer a while, Namboothiri proposed a similar mechanism involving Michael addition/5-exo-tet reaction for the construction of dihydrofuran derivatives 51 from a-bromonitroalkenes 1 and b-ketosulfones 50 (Scheme 23). 52They could provide a series of pyrroles 52 by the reduction of dihydrofuran 51 in the presence of zinc powder under acidic conditions.
In 2020, Feng et al. presented a protocol for the construction of diastereoselective trans-3-aryl-2-nitro-2,3-dihydrobenzofurans 54 under basic conditions (Scheme 24). 53A diverse range of (Z)bromonitrostyrenes 1, containing aryl, naphthyl and thiophenyl moieties reacted smoothly with sesamol 53 in water as a green solvent to form dihydrofurans in excellent yields.All products were puried only by a simple ltration procedure and could also be synthesized in the Gram-scale (1.20 g, 94%).In the same year, the synthesis of the oxazole rings from a-halo-b-naphthol and nitroalkenes was carried out. 54Bromonitroalkene as a coupling partner gave the desired product in 82% with >20 : 1 diastereoselectivity.
A chemoselective annulation of bromonitrostyrenes with aalkylidene pyrazolones was established by Han and co-workers in 2021 (Scheme 25). 55A novel library of pyrazole-fused pyranone oximes were obtained, where a-alkylidene pyrazolone 55 acted as C1 synthon and react in (2 + 1)-cycloaddition with bromonitrostyrene 1 to provide vinylcyclopropane-based pyrazolone 56 and 56 0 in the presence of a base.The formation of diastereoisomer 56 was favored due to the less steric hindrance between the aryl and nitro groups.In another stage, the authors conducted this reaction in two steps, in which Et 3 N was served as a base to obtain the cyclopropane product.Then, the addition of second base resulted in an intramolecular rearrangement towards the synthesis of pyrazole-fused pyranone oximes 57.
The synthesis of 2-iminothiazolines 59 can be obtained from the cyclization of 1,3-disubstituted thioureas 58 with 1-bromo-1nitroalkenes 1 (Scheme 26). 56At rst, Michael addition between 1-bromo-1-nitroalkenes 1 and 1,3-diphenylthiourea 58 produced intermediate II, which then underwent a tautomerism and nucleophilic substitution to afford the vemembered ring intermediate III.The deprotonation of III by bromide anion, followed by the oxidation yielded product 59.It should be noted that using the suitable amount of the base and the performance of the reaction under air is crucial for this reaction to proceed.
A new class of cyclopenta In the same year, the Xie group designed a (4 + 1) ylide annulation between chiral sulfonium salts 63 and 65 with abromonitroalkenes 1 access to enantioenriched isoxazoline Noxides 64 and 66 (Scheme 29). 58Two types of chiral sulfonium salts, such as a-benzoyl sulfonium triate salts 63 and a-benzyl sulfonium triate salts 65 could smoothly generate the sulfonium ylide intermediates, which served as C1 synthon in (4 + 1)annulation with bromonitroalkene as a 4-atomic synthon.All products were obtained in high yields with excellent enantioand diastereoselectivity. Also, changing the anions of sulfonium salts from OTf − to Br − , ClO 4 − and BF 4

−
, showed that the type of anion has a great effect on the activity, and enantioselectivity in this asymmetric annulation.In 2023, Li et al. investigated the application of pyrrolidine as a catalyst in the reaction of 1-butyl-4-hydroxy-6-methylpyridin-2(1H)-one 68 and nitroalkenes 67 (Scheme 30). 59They achieved an open ring product 69, when a-bromonitrostyrene 1 was used as a coupling reactant, while the reaction of other nitroalkenes led to 4-hydroxy-3-benzoylpyridin-2(1H)-ones 70 as the main product.This may be because of the high steric hindrance in abromonitrostyrene, which inhibits the formation of product 69.

Catalyst-free transformations of bromonitrostyrenes
In 2009, Xie and co-workers reported the synthesis of pyrazoles 72 from 1,3-cycloaddition of a-bromo-a-nitroalkenes 1 with ethyl diazoacetate 71 under catalyst-free conditions (Scheme 31). 60In general, the reaction involved the nucleophilic addition of 71 to 1 to form intermediate I, followed by the elimination of bromide along with the 1,3-H shi to furnish the nal pyrazole product 72.
In 2010, Rueping and Parra treated (E)-b-bromonitrostyrenes 1 with enaminones 73 to synthesize pyrrole derivatives 74 (Scheme 32). 61The main advantages of their reaction were the performance of the reaction in water as a green solvent, very short reaction time, and excellent product yields.In this reaction, bromonitrostyrenes 1 acted as a trifunctional synthon and reacted well with both enaminone 73 and N-benzylenaminone 75 as binucleophilic synthons.First, the nucleophilic attack of nitrogen to the carbon atom in I concomitant with removal of a leaving group produced II.Next, the deprotonation and the release of another leaving group afforded the desired product 74.
Deng et al. showed that depending on the type of nitrostyrenes and the reaction solvent, two different pyrazole products could be obtained under acidic conditions (Scheme 33). 62hen b-chloro-b-nitrostyrenes 77 were used as reactants in the reaction with hydrazones 78, the elimination of HNO 2 occurred to produce 4-chloro-tetrasubstituted pyrazoles 80 in MeOH as a solvent.Whereas, 4-nitro-tetrasubstituted pyrazoles 79 were obtained from b-bromo-b-nitrostyrenes 1 and hydrazones 78 as starting materials in MeOH.In this case, the removal of HBr was favored over HNO 2 , which could be due to the easy cleavage of the C-Br bond compared to the C-Cl bond.In fact, the leavinggroup abilities of functional groups can be classied as Br > NO 2 > Cl.In general, the reactions involved pyrazolidine intermediate I, which was subjected to oxidation and elimination steps.It should be noted that when a more acidic alcoholic solvent like CF 3 CH 2 OH was utilized, the formation of 4-bromotetrasubstituted pyrazoles was also observed in the reaction mixture.
Another domino reaction was carried out by the Khan research team to construct 1,2,4-trisubstituted pyrrole derivatives 82 from 1,3-dipolar cycloaddition of unactivated aziridines 81 with b-bromo-b-nitrostyrenes 1 (Scheme 34). 63his reaction involved in situ generated unsymmetrical azomethine ylide from aziridine, followed by a cascade elimination and aromatization step.As shown in Scheme 35, the mechanism started with simultaneous cleavage of the C-C bond of aziridine 81 under heat to afford azomethine ylide I.The interaction of I with b-bromo-b-nitrostyrene 1 resulted in the unstable cycloadduct II, which readily underwent E2 elimination of HBr to render III.In this step, III was isomerized to IV and then V, followed by the elimination of HNO 2 to form product 82.
In 2019, Ganesh and co-workers developed a multicomponent reaction, including oxindoles 83, bromonitrostyrenes 1 and a-amino acids 84 to generate tetra-substituted aspiropyrrolidine structures 85 and 86 (Scheme 36). 64In the rst step, azomethine ylide I was formed from the condensation of oxindole and a-amino acid.Next, (3 + 2)-cycloaddition of bromonitrostyrene with I provided spiropyrrolidine.Two diastereomers could be obtained depending on the substituent at the a-position of amino acid.If R 3 = H, diastereomer 85 was the major product, while spiropyrrolidine 86 was obtained as a major diastereomer when R 3 = alkyl.The diastereoselectivity may be due to the steric effects in transition states of azometine ylides.

Conclusions
In this review, we have described the advances in the synthesis of carbocyclic and heterocyclic compounds from the reaction of a-bromonitrostyrenes with various coupling reactants in straightforward and atom economical manners.Organocatalytic domino Michael reactions offer a direct and sustainable route for the synthesis of diastereo-and enantioselective bioactive products under mild reaction conditions.Although it seems that the use of Lewis acid metal catalysts and bases as promoters in the reactions of a-bromonitrostyrenes could be studied further.Considering the great potential of a-bromonitrostyrene as a reactive dipolarophile with good leaving groups (bromo and nitro), the use of this synthon in the cross-coupling reactions, as well as regio-and stereoselective syntheses can provide useful insights for further researches in this eld.In our opinion, a-bromonitrostyrenes can be considered as a simple and accessible building block for the construction of more complex organic molecules.

Scheme 5 Scheme 6 Scheme 7
Scheme 5 Putative mechanism for reaction of bromonitroalkenes and alkyl aldehydes.
Further attack of O 2 on II led to the peroxy radical III.Then, III abstracted a hydrogen from THF to give hydroperoxide IV.The cleavage of the O-O bond by H 2 O resulted in intermediate V with the release of bromide.In this step, the nucleophilic attack of alcohol to the carbonyl group along with the removal of the second leaving group (NO 2 ) led to product 26.It is noteworthy that only less hindered alcohols can attack intermediate V (Scheme 14).
[c]furo[3,2-b]furan-5,6-diones, containing three carbon stereocenters were constructed by Yavari et al. in 2022 (Scheme 27). 57A three-component reaction, including b-bromo-b-nitrostyrenes 1, 3-acetyl-2H-chromen-2-ones 60, and pyridine 61 was carried out through three steps intermolecular and intramolecular Michael additions.Initially, the C-H bond functionalization of 3-acetyl-2H-chromen-2-one 60 with pyridine 61 in the presence of I 2 and Et 3 N furnished pyridinium ylide I.Then, sequentially intermolecular Michael addition of 1 with I, and intramolecular Michael reaction gave intermediate II, which was converted to cyclopropane III.Intermediate IV was obtained via the elimination of pyridinium bromide in III, followed by two steps cyclopropane ring-opening and rearrangement to produce VI.The release of HNO 2 gave VII, which underwent an intramolecular lactonization to render IX.Another intramolecular Michael addition of the phenoxide ion with the C]C bond gave product 62 (Scheme 28).

Scheme 25
Scheme 25 Reaction of bromonitrostyrenes with a-alkylidene pyrazolones mediate by Et 3 N.