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α-Functionally Substituted α,β-Unsaturated Aldehydes as Fine Chemicals Reagents: Synthesis and Application

α-Functionalized α,β-unsaturated aldehydes is an important class of compounds, which are widely used in fine organic synthesis, biology, medicine and pharmacology, chemical industry, and agriculture. Some of the 2-substituted 2-alkenals are found to be the key metabolites in plant and animal cells. Therefore, the development of efficient methods for their synthesis attracts the attention of organic chemists. This review focusses on the recent advances in the synthesis of 2-functionally substituted 2-alkenals. The approaches to the preparation of α-alkyl α,β-unsaturated aldehydes are not included in this review.


Introduction
α,β-Unsaturated aldehydes, containing a double bond conjugated with an aldehyde group, represent attractive synthetic "building blocks". Due to the high reactivity of these polyfunctional substrates, they are widely employed, e.g., in the targeted synthesis of practically important natural compounds and other molecules (scaffolds) [1][2][3]. The presence of a functional group at the position 2 of the conjugated aldehyde system enriches chemistry of such derivatives and determines fields of their application. Some 2-functionally substituted alkenals are plant and animal metabolites [4][5][6][7][8]. In industry, α-substituted α,β-unsaturated aldehydes are used as the starting materials in the production of dyes, pesticides, aromatic compounds, and drugs [9]. Therefore, the preparation of these highly reactive substrates represents an urgent challenge for organic chemistry. It should be noted that the employment of various catalysts has expanded opportunities of 2-alkenals synthesis and sparked the interest in this area of research.
Meanwhile, many years have passed since the publication of the last review devoted to the chemistry of α-functionally substituted acrolein derivatives. Indeed, this review only covered the synthetic approaches to acrolein and its α-substituted analogs developed before 1993 [10]. There were other survey publications on this topic, in which, however, 2-functionally substituted 2-alkenals were only described partially. It is worth noting the chapter in a book [11], which only deals with the synthesis of these compounds. A review [12] was dedicated to captodative aminoalkenes, but it gave little attention to the chemistry of α-functionalized alkenals. In addition, a significant number of new original papers were published over the last decade.
This review summarizes methods for the synthesis of α-functionalized α,β-unsaturated aldehydes ( Figure 1) bearing functional groups or halogen atoms in the position 2. Structural features, mechanistic aspects of transformations, and the prospects of these compounds' application are discussed. The review covers the literature published in the past 20 years. In some cases, earlier works are also considered. As the approaches to preparation of α-alkyl α,β-unsaturated aldehydes were surveyed in 2020 [13], they are not included in the present review.
The methods for the preparation of α-oxygensubstituted alkenals are limited in number. For instance, in 2000 α,β-unsaturated aldehyde 4 was obtained in 24% yield as a side product generated by beta-elimination in the reaction of trimethoxynaphthalene 1 with α-benzyloxyaldehyde 2 (Scheme 1) [19].  [20]. It was found that multistage process involved the formation of densely functional 2-benzyloxysubstituted 2-alkenals 9 (Scheme 2) via a side reaction.
2-Benzyloxysubstituted 2-alkenals 16 and 17 were also obtained in good yields by an organocatalyzed aldol condensation [24,25]. Thus, the reaction of aldehyde 13 with formaldehyde in the presence of pyrrolidine 14 (10 mol%) as a catalyst and 4-N,N-dimethyla minobenzoic acid (15) as a cocatalyst (20 mol%) gave diverse 2-substituted 2-alkenals 16, including 2-benzyloxysubstituted 2-alkenals, in high yield. In the absence of formaldehyde at the same conditions, the catalytic system promoted the self-condensation reaction of 13 to produce aldehyde 17. The yields of products 17 reached 98% (Scheme 4). It is assumed that the reaction course is determined by the kinetic resolution of the catalyst between formaldehyde and other aldehydes. Presumably, the formation of formaldehyde/catalyst complex (or a covalent intermediate) is more preferable than the formation of the related compounds with other aldehydes. The mechanism of the Mannich reaction suggests that the enol form of donor aldehyde reacts with an iminium compound produced by the acceptor aldehyde (usually formaldehyde) (Scheme 5). The α-siloxysubstituted α,β-unsaturated aldehydes are widely employed in organic synthesis as dienophiles for (4+3) cycloaddition reactions in the presence of Lewis acid [26]. The reactivity of such aldehydes was first tested by Sasaki et al. in the construction of various cycloadducts [27]. In 2000, Harmata and Sharma [28] obtained 2-(trialkylsilyloxy)-2-propenals 19 from trialkylsilyltriflates and 2-methoxy-2-methyl-[1,3]-dioxan-5-one 18 by the retro-hetero-Diels-Alder reaction (Scheme 6). The target alkenals were further involved in the reaction with dienes (furan, cyclopentadiene, 1,3-butadiene). It is worthwhile to note that the trialkylsilyl group is perfectly retained in the obtained cycloadducts.
Mechanistically, the reaction is triggered by the attack of carbanion at the carbon atom of vinamidinium salt 25 to generate a tetrahedral intermediate A. When the hydrogen atom at the α-position to the diethylamino group in substituent R is weakly acidic, and/or sterically hindered, and the base cannot attack it, the diethylamino group is not cleaved from the intermediate A. Subsequent hydrolysis leads to elimination of the diethylamino group to give aldehydes 26 via the formation of N,O-acetal.
The carbon-carbon double bond migration of the allylic carbamates 31 successfully gave the corresponding Z-vinyl carbamates 32 as single stereoisomers. Formylation of the vinyl carbamates 32 with t-BuLi and N,N-dimethylformamide (DMF) afforded (Z)-α-(N,Ndiisopropylcarbamoyloxy)-β-alkylacroleins 33 as single stereoisomers in the total yields of 28-64%. Aldehydes 33 were employed as the efficient dienophiles for the enantioselective Diels-Alder reaction.
Another ring-opening reaction was carried out by Silvestri and Wong [52]. It was shown that the thiirane cycle 36 was efficiently opened upon treatment with methanesulphenylbromide at low temperature in CH 2 Cl 2 in the presence of 1,1,3,3-tetramethylurea (TMU). The formed halo disulfide 37 on silica gel produced predominantly aldehyde 38 via hydrolysis and dehydrohalogenation (Scheme 13). The acylation of 2-(diethoxymethyl)thiirane (36) with benzoic anhydride or carboxylic chloride, followed by the hydrolysis with formic acid gave the corresponding α-(benzoylthio)substituted α,β-unsaturated aldehydes 40. The modest yields of 40 were mainly attributed to the low reactivity of the thiirane in the acylation.
α-(Benzoylthio)substituted α,β-unsaturated aldehydes 40 were synthesized and involved in Diels-Alder reactions as dienophiles to produce sulfur-containing quaternary carbons. However, the low basicity and poor solubility of aldehydes 40 did not allow the reaction with the diene to be performed. In this regard, a new synthetic approach to other promising dienophiles, α-(carbamoylthio)acroleins 45, was developed. The approach was based on the umpolung strategy: the C-S bond formation between a "carbamoylthio cation R 2 NCOS + " and a "vinyl anion RCH=CH − " (Scheme 15).
In this process, NHC acts as a carbon-centered Brønsted base. The complex A (thioxy anion/azolium ion complex) is formed as a result of the deprotonation of the acidic thiol by NHCs. The complex A further interacts with α-haloenal to give compound B. The conjugate adduct B undergoes an intramolecular sulfenylation via a favorable 3-exo-tert attack to form sulfonium ion intermediate C according to Baldwin's rule. The attack of the second thiol molecule leads to the ring-opening in the intermediate C to deliver bisulfenylated aldehyde D. Subsequent β-elimination produces α-alkylthiopropenal. More readily available organocatalysts such as Et 3 N or DABCO can also be employed instead of N-heterocyclic carbene [58].

Scheme 19. Proposed reaction mechanism.
At the first stage of the reaction, AgSCF 3 is oxidized by K 2 S 2 O 8 to give Ag II SCF 3  A radical cascade reaction of the unsaturated C-C bonds involving migration is also of interest to the chemical community [60].
In Note that this reaction meets the requirements of green chemistry (solvent reuse), while reuse of the recovered ionic liquid in the same process ensured high yields of the product and good selectivity (like in the first cycle).
A wide series of α,β-unsaturated aldehydes including 2-cyclohexylidene-2-phenylacet aldehyde (61) was synthesized in 2012 by Stambuli et al. [75]. The mild oxidation of alkyl enol ether 60 takes place with the low loadings of a palladium catalyst (Scheme 25). The mild oxidation conditions tolerate a diverse array of functional groups, thus allowing the formation of di-, tri-, and tetrasubtituted olefins.
More recently, Mura and coworkers developed a short-cut to α-substituted α,βunsaturated aldehydes through the cross-dehydrogenative coupling of two different primary alcohols behaving as the latent aldehydes [76]. This approach represents a cascade reaction, wherein a nonenolizable aldehyde is first generated in situ by the removal of a "hydrogen molecule" from an alcohol, and then is temporarily trapped as an imine.
The target 2-alkenals 62 are formed due to the subsequent Mannich-type condensation between the imine particles and another intermediate aldehyde (Scheme 26). A plausible mechanism of this ruthenium-promoted transfer-hydrogenation/Mannichtype domino reaction is shown in Scheme 27. Higher reactive benzyl alcohol is first oxidized by the ruthenium-mediated hydrogen transfer from the substrate to crotononitrile. Further, the formed benzaldehyde is probably trapped by the supported amine, leaving the restored catalyst to oxidize the aliphatic alcohol via a second hydrogen transfer with crotononitrile. Finally, the Mannich-type reaction between the grafted imine species and the second aldehyde delivers the α-substituted α,β-unsaturated aldehydes 62.

Scheme 27. Plausible reaction mechanism.
The use of enolates prepared in situ from alcohols helps to avoid the treatment of unstable aldehydes, and opens the way to various cinnamic aldehydes bearing a substituent in the α-position. The addition of a silica-grafted primary amine leads to a selective one-pot process to produce cross-dehydrogenative coupling products in good-to-moderate yields and with high chemoselectivity.

α-Halosubstituted α,β-Unsaturated Aldehydes
Halovinyl aldehydes hold a prominent place in organic chemistry as valuable building blocks for the targeted design of linear and heterocyclic systems [87]. Therefore, the development of new methods for the preparation of these compounds remains an urgent challenge.
In The two-stage reaction proceeds without alkalis under mild conditions. The process is facile and allows analogs of 2-bromopropenals to be prepared in high yields. The DMSO acts in the reaction as a reagent and a solvent. Among the existing protocols of dehydrohalogenation, this method appears to be the most expedient and environmentally benign.
The method is applicable to the synthesis of (Z)-2-chloropentadec-2-enal, a toxin isolated from the marine red alga Laurencia flexilis. It is important that the reaction tolerates a variety of functional groups.
Das et al. [93] successfully elaborated an efficient chemoselective general procedure for the synthesis of 3-aryl(hetaryl)substituted 2-bromopropenals 83 from enals 82 through an unprecedented PPh 3 ·HBr-DMSO mediated oxidative bromination followed by the Kornblum oxidation, yields of the products being from moderate to good (Scheme 35). The mechanism of the transformation likely involves the initial oxidative dibromination of the olefinic double bond, followed by substitution of the bromine atom at the β-position by DMSO to generate alkoxysulfonium intermediate. Finally, elimination of the hydrogen atom leads to dehydrobromination. Alternatively, the intermediate bromonium derivative eliminates a proton from the α-carbon atom to directly give the product. The synthesis of such aromatic α-bromoenal derivatives generally comprises two steps, requires highly corrosive and toxic Br 2 , followed by base treatment. Therefore, one-stage protocol using the system PPh 3 •HBr-DMSO is an efficient alternative to the existing methods.
It is well known that the introduction of fluorine atoms into organic molecules often drastically changes chemical properties and biological activity of the parent compounds [94]. Over the last decade, fluorinated compounds attract noticeable interest. Due to the unique combination of physical-chemical and biological properties, achieved by incorporation of fluorine or perfluoroalkyl groups (usually CF 3 ) in an organic molecule, fluorinated compounds find widespread application in design of new materials, agrochemicals, and drugs [95].
The obvious benefit of the process is that it proceeds as a two-pot sequence, without isolation of the intermediate products and with formation of only one Z-isomer.
In A tentative reaction mechanism is depicted in Scheme 42. The reaction involves in situ formation of difluorocarbene (step a) and silyl enolether A (step b), difluorocyclopropanation (step c), desilylation, ring-opening, and defluorination (step d). In this tandem reaction, Me 3 SiCF 2 Br acts not only as a difluorocarbene source, but also as a TMS transfer agent, as well as internal bromide and fluoride anion catalyst. It enables a smooth transformation in the presence of only catalytic amounts of n-Bu 4 NBr as an initiator. The cascade reaction proceeds mildly to give 103 and catalyzed by n-Bu 4 NBr (TBAB) to initially activate TMSCF 2 Br (Scheme 42, catalytic cycle I). In many cases, it is assisted by an external fluoride anion to accelerate desilylation of the target cyclic trimethylsilyl ether intermediate B (Scheme 42, catalytic cycle II). At the first step, Selectfluor was employed as a fluorinating agent in the CH 3 NO 2 /MeOH system to form the (Z)-α-fluoro-α,β-unsaturated aldehydes and their corresponding dimethyl acetals through methoxyfluorination-elimination. At the second step, water is added to promote the hydrolytic cleavage of the dimethyl acetals.
Possible mechanism of the cascade reaction of asymmetric methoxyfluorinationelimination is shown in Scheme 44. The action of L-proline on aldehyde 104 generates the activated iminium A. The latter undergoes oxa-Michael addition of MeOH to give chiral enamine B. The reaction of enamine B with Selectfluor produces the α-fluoro-βmethoxy iminium species C. At last, the elimination of MeOH affords the (Z)-α-fluoro-α,β-unsaturated aldehyde 105 and the corresponding dimethyl acetal D. After complete fluorination, the addition of water promotes the hydrolytic cleavage of dimethyl acetal D. Scheme 44. Possible mechanism of the cascade reaction of asymmetric methoxyfluorinationelimination.
The obtained (Z)-α-fluoro-α,β-unsaturated aldehydes 105 can be smoothly reduced to the corresponding alcohols by NaBH 4 . This method represents an expedient, facile, and mild synthetic approach to 2-fluoropropenal and 2-fluoropropenol, which are important structural units in biologically active molecules.

Conclusions
Summarizing the available literature data on the synthesis of α-functionally substituted α,β-unsaturated aldehydes, it can be concluded the classical approach to the preparation of such aldehydes via aldol condensation is still widely employed. The main shortcoming of this approach is the high probability of side processes, especially in the case of different enolizable carbonyl compounds. In this regard, considerable efforts are focused on the development of chemo-and stereoselective methods for the preparation of α-substituted alkenals.
High selectivity can be achieved using the Mannich condensation with the participation of aliphatic aldehydes and non-enolizable aldehydes in the presence of secondary amines, which act as organic catalysts generating a Mannich base in situ. Such reactions have a number of benefits, including mild conditions, high selectivity and yields, and one-pot procedure.
It should be underlined that, as αfunctionally substituted α,β-unsaturated aldehydes are heterodienes, they can be obtained with high chemoselectivity via the retro-Diels-Alder reaction. In addition, other efficient and promising methods comprise various cascade transformations that combine functionalization and elimination involving aldehydes (in-cluding those already unsaturated) or their synthetic equivalents. To some extent, the lack of generality reduces the significance of these methods. Nevertheless, they continue to be developed. The application of new catalysts, two-phase systems, ionic liquids, or solvent-free protocols arouses ever-increasing interest. In addition, microwave assistance is an expedient and convenient tool to increase the yields and shorten the reaction time.
Additionally, it may be inferred that the synthetic chemistry of α-functionally substituted alkenals is rather rich, though it remains poorly studied. It is important that among functionalized unsaturated aldehydes there have been found representatives that are structurally similar to the naturally occurring compounds. This fact allows the regularities of chemical transformations that are inherent in natural substrates to be established.
Therefore, it can be expected that the generalization of information on the methods for the synthesis of α-substituted α,β-unsaturated aldehydes will contribute to the further development of chemistry of these valuable reagents, biologically active substances, ligands, and promising materials.
Author Contributions: E.A.V., N.V.V. and I.B.R. contributed to the review. E.A.V. conceived the paper, designed the thematic, they all wrote and finalized the paper. All authors have read and agreed to the published version of the manuscript.