1,3-Cyclohexadien-1-Als: Synthesis, Reactivity and Bioactivities

In synthetic organic chemistry, there are very useful basic compounds known as building blocks. One of the main reactions wherein they are applied for the synthesis of complex molecules is the Diels–Alder cycloaddition. This reaction is between a diene and a dienophile. Among the most important dienes are the cyclic dienes, as they facilitate the reaction. This review considers the synthesis and reactivity of one of these dienes with special characteristics—it is cyclic and has an electron withdrawing group. This building block has been used for the synthesis of biologically active compounds and is present in natural compounds with interesting properties.


Introduction
One of the reactions that is in the heart of every organic chemist is the Diels-Alder reaction [1]. Dienes are one of the essential components to form the adduct. The reactivity of these compounds in the Diels-Alder reaction varies with electron-withdrawing or donating groups and with conformation restriction as they are part of a cyclic system.
A very special building block is the 1,3-cyclohexadien-1-al. This scaffold is present in natural products isolated from several plants [2,3], such as 2,6,6-trimethyl-1,3-cyclohexadien-1-carboxaldehyde known as safranal 2 that is the main constituent of the essential volatile oil of Crocus sativus L. (saffron) [4], or citral dimer 3, which has been isolated from marine bryozoan Flustra foliacea [5]. Some other examples are compound 5, extracted from black cardamom (Amomum tsao-ko) [6]; compound 6, which is obtained from the fungus Botrytis cinerea [7]; and compound 7 from an Indian fungi Parmelia perlata of Parmelia genus [8], which is used as a food supplement. Moreover several synthetic chiral structures such as compound 4 have been obtained [9] (Figure 1). In particular, safranal 2 can be considered a reference compound containing the 1,3-cyclohexadiene-1-al scaffold showing interesting bioactivities, from neuroprotection [10] to anticancer effects [11]. In this review, aromatic aldehydes were not considered due to the different nature of benzaldehydes and related aromatic derivatives in terms of obtention and reactivity.

Synthesis of 1,3-Cyclohexadien-1-Al Scaffold
There are limited methodologies applied to afford 1,3-cyclohexadien-1-al scaffold. Among them, organocatalytic methods are the more versatile ones, creating the 1,3-cyclohexadienal scaffold through one-pot reactions compared with other methodologies using Lewis acids or formylating agents where the reactant already shows the cyclic 1,3-diene or at least the cyclic system.
Herein, we review the reported methodologies applied to the synthesis of 1,3-cyclohexadien-1-als. The described methods can be classified as aldol-type condensations, pericyclic cyclizations, functional group interconversions and transformations, and organometallic and organocatalyzed reactions. The general accessibility to this scaffold by the different methodologies is shown in Figure 2.

Synthesis of 1,3-Cyclohexadien-1-Al Scaffold
There are limited methodologies applied to afford 1,3-cyclohexadien-1-al scaffold. Among them, organocatalytic methods are the more versatile ones, creating the 1,3cyclohexadienal scaffold through one-pot reactions compared with other methodologies using Lewis acids or formylating agents where the reactant already shows the cyclic 1,3-diene or at least the cyclic system.
Herein, we review the reported methodologies applied to the synthesis of 1,3-cyclohexadien-1-als. The described methods can be classified as aldol-type condensations, pericyclic cyclizations, functional group interconversions and transformations, and organometallic and organocatalyzed reactions. The general accessibility to this scaffold by the different methodologies is shown in Figure 2.

Synthesis of 1,3-Cyclohexadien-1-Al Scaffold
There are limited methodologies applied to afford 1,3-cyclohexadien-1-al scaffold. Among them, organocatalytic methods are the more versatile ones, creating the 1,3-cyclohexadienal scaffold through one-pot reactions compared with other methodologies using Lewis acids or formylating agents where the reactant already shows the cyclic 1,3-diene or at least the cyclic system.
Herein, we review the reported methodologies applied to the synthesis of 1,3-cyclohexadien-1-als. The described methods can be classified as aldol-type condensations, pericyclic cyclizations, functional group interconversions and transformations, and organometallic and organocatalyzed reactions. The general accessibility to this scaffold by the different methodologies is shown in Figure 2.

Functional Group Interconversions and Isomerizations
The simple functional group interconversions can be a pathway for the obtention of 1,3-cyclohexadienals, as in the case of the semisynthesis of safranal 2 starting from γ-pyronene 8 [12] (Scheme 1). The epoxidation of 8 results in a mixture of mono and diepoxide derivatives. The isolated exocyclic epoxide 9 (36%) is transformed in two steps into safranal 2. Firstly, halogenation of double bound conducts to 10 quantitatively and then a one-pot reaction consisting in the dibromo elimination and epoxide-opening, allowing using zeolite-NaY in dry conditions (Scheme 4). Longer reaction periods conduct the aromatization products, although this can be easily controlled [15].

Functional Group Interconversions and Isomerizations
The simple functional group interconversions can be a pathway for the obtention of 1,3-cyclohexadienals, as in the case of the semisynthesis of safranal 2 starting from γ-pyronene 8 [12] (Scheme 1). The epoxidation of 8 results in a mixture of mono and diepoxide derivatives. The isolated exocyclic epoxide 9 (36%) is transformed in two steps into safranal 2. Firstly, halogenation of double bound conducts to 10 quantitatively and then a onepot reaction consisting in the dibromo elimination and epoxide-opening, allowing the obtention of the 1,3-diene system, wherein the hydroxyl group of the intermediate is oxidized, resulting in safranal 2 in good yield. Other semisynthesis of safranal 2 starts from α-cyclocitronitrile and takes place in three steps: oxidation, elimination, and reduction [13] (Scheme 2). The epoxidation and epoxide opening by base conducts to the hydroxyderivative 12, which can be eliminated by protonation with p-toluensulfonic acid (TsOH) to afford 13. The reduction of cyano group with diisobutyl aluminium hydride (DIBAL-H) results in safranal 2. Scheme 2. Synthesis of safranal 2 from α-cyclocitronitrile.

Oxidation
Using the furfural derivative 17 from a renewable source for its conversion into terephthalic acid, one can obtain the intermediate 18 and the dienic side-product 19 (Scheme 5). The transformation takes place in two steps. Firstly, oxidation and then C 2 H 4 addition catalyzed by silica molecular sieves showing zeolite-β topology containing Lewis acid centers (Zr-β or Sn-β). Despite the obtention of 19 being possible by using both catalysts, when Sn-β is used instead of Zr-β, 19 is obtained with higher yields [16,17]. Low molecular weight 1,3-cyclohexadienals have special relevance in perfumery, with some terpene derivatives being of interest, such as safranal 2 and analogues. In this regard, the conversion of thujone (waste product in forest industry) into different derivatives has been studied, obtaining safranal 2 and analogues [18].

Oxidation
Using the furfural derivative 17 from a renewable source for its conversion into terephthalic acid, one can obtain the intermediate 18 and the dienic side-product 19 (Scheme 5). The transformation takes place in two steps. Firstly, oxidation and then C2H4 addition catalyzed by silica molecular sieves showing zeolite-β topology containing Lewis acid centers (Zr-β or Sn-β). Despite the obtention of 19 being possible by using both catalysts, when Sn-β is used instead of Zr-β, 19 is obtained with higher yields [16,17]. Low molecular weight 1,3-cyclohexadienals have special relevance in perfumery, with some terpene derivatives being of interest, such as safranal 2 and analogues. In this regard, the conversion of thujone (waste product in forest industry) into different derivatives has been studied, obtaining safranal 2 and analogues [18]. Scheme 5. Synthesis of terephthalic derivatives from biomass.
Vilsmeier reaction conditions applied to carvone 35 affords the corresponding 2-chloro-1,3-cyclohexadienal derivative 36 (Scheme 7). However, these reaction conditions show poor yield in the obtention of this product, since two by-products (37 and 38) are generated with significant yields.
Other formylating agents such as DMSO can also be used, starting from the corresponding conjugated enol (Scheme 8). The 1,3-cyclohexadienal obtained has been used as a precursor of diazocine steroid derivatives through eight-member ring formation [26]. Such a transformation is shown below in the reactivity section.
Aldol reaction and condensation of α,β-aldehydes can be performed in self-condensation or cross-condensation modality.The self-condensation of all-E-retinal 45 can be performed in the presence of sodium hydride (Scheme 10) [29]. The enolate intermediate reacts with the starting aldehyde and cyclizes, forming the 1,3-cyclohexadien-1-al scaffold 48. In the enolate intermediate, the β-methyl group holds the negative charge and reacts at the conjugated position of the aldehyde in a process where the Z/E configuration of double bound is not determinant, allowing in any case the condensation and formation of dienal.
Similar results are obtained with senecialdehyde 47, self-condensation reaction promoted by alkali [30]. In this case, a global yield of 80% is obtained, and compounds 50-52 are obtained in a ratio 2:3:5 (Scheme 11). Cyclodimerization also occurs when crotonaldehyde is treated with solid base catalysts of metal oxides and silica. In this case, the obtained diene can evolve by dehydrogenation and aromatization [31]. Vilsmeier reaction conditions applied to carvone 35 affords the corresponding 2 chloro-1,3-cyclohexadienal derivative 36 (Scheme 7). However, these reaction condition show poor yield in the obtention of this product, since two by-products (37 and 38) ar generated with significant yields. Vilsmeier reaction conditions applied to carvone 35 affords the corresponding 2 chloro-1,3-cyclohexadienal derivative 36 (Scheme 7). However, these reaction condition show poor yield in the obtention of this product, since two by-products (37 and 38) ar generated with significant yields.  Other formylating agents such as DMSO can also be used, starting from the corresponding conjugated enol (Scheme 8). The 1,3-cyclohexadienal obtained has been used as a precursor of diazocine steroid derivatives through eight-member ring formation [26]. Such a transformation is shown below in the reactivity section. Scheme 8. Formylation reaction in the synthetic preparation of cyclohexadienal motif.
Aldol reaction and condensation of α,β-aldehydes can be performed in self-condensation or cross-condensation modality.The self-condensation of all-E-retinal 45 can be performed in the presence of sodium hydride (Scheme 10) [29]. The enolate intermediate reacts with the starting aldehyde and cyclizes, forming the 1,3-cyclohexadien-1-al scaffold 48. In the enolate intermediate, the β-methyl group holds the negative charge and reacts at the conjugated position of the aldehyde in a process where the Z/E configuration of double bound is not determinant, allowing in any case the condensation and formation of dienal. Such a transformation is shown below in the reactivity section. Scheme 8. Formylation reaction in the synthetic preparation of cyclohexadienal motif.
Aldol reaction and condensation of α,β-aldehydes can be performed in self-condensation or cross-condensation modality.The self-condensation of all-E-retinal 45 can be performed in the presence of sodium hydride (Scheme 10) [29]. The enolate intermediate reacts with the starting aldehyde and cyclizes, forming the 1,3-cyclohexadien-1-al scaffold 48. In the enolate intermediate, the β-methyl group holds the negative charge and reacts at the conjugated position of the aldehyde in a process where the Z/E configuration of double bound is not determinant, allowing in any case the condensation and formation of dienal. Scheme 10. Self-condensation of α,β-aldehydes in the formation of 1,3-cyclohexadien-1-al units.
Aldol reaction and condensation of α,β-aldehydes can be performed in self-condensation or cross-condensation modality.The self-condensation of all-E-retinal 45 can be performed in the presence of sodium hydride (Scheme 10) [29]. The enolate intermediate reacts with the starting aldehyde and cyclizes, forming the 1,3-cyclohexadien-1-al scaffold 48. In the enolate intermediate, the β-methyl group holds the negative charge and reacts at the conjugated position of the aldehyde in a process where the Z/E configuration of double bound is not determinant, allowing in any case the condensation and formation of dienal. Similar results are obtained with senecialdehyde 47, self-condensation reaction promoted by alkali [30]. In this case, a global yield of 80% is obtained, and compounds 50-52 are obtained in a ratio 2:3:5 (Scheme 11). Cyclodimerization also occurs when crotonaldehyde is treated with solid base catalysts of metal oxides and silica. In this case, the obtained diene can evolve by dehydrogenation and aromatization [31]. Scheme 11. Self-condensation of senecialdehyde 47 in the formation of 1,3-cyclohexadien-1-al 50.
Trimethylsilyl and acetate enolderivatives 53 serve as starting material for obtaining 1,3-cyclohexadien-1-als through the lithium enolate formation (Scheme 12). Intermediate 54 can be accessed via metalation of 53 with MeLi. The subsequent addition of a conjugated aldehyde 47 or 51 yields 1,3-cyclohexadienals 50 or 55, respectively. In this manner, lithium enolates are a versatile tool in organic synthesis, allowing for the cross-condensation between two different unsaturated aldehydes, opening the possibilities among the non-chiral condensation methodology [32]. Trimethylsilyl and acetate enolderivatives 53 serve as starting material for obtaining 1,3-cyclohexadien-1-als through the lithium enolate formation (Scheme 12). Intermediate 54 can be accessed via metalation of 53 with MeLi. The subsequent addition of a conjugated aldehyde 47 or 51 yields 1,3-cyclohexadienals 50 or 55, respectively. In this manner, lithium enolates are a versatile tool in organic synthesis, allowing for the cross-condensation between two different unsaturated aldehydes, opening the possibilities among the nonchiral condensation methodology [32]. Scheme 11. Self-condensation of senecialdehyde 47 in the formation of 1,3-cyclohexadien-1-al 50.
Trimethylsilyl and acetate enolderivatives 53 serve as starting material for obtaining 1,3-cyclohexadien-1-als through the lithium enolate formation (Scheme 12). Intermediate 54 can be accessed via metalation of 53 with MeLi. The subsequent addition of a conjugated aldehyde 47 or 51 yields 1,3-cyclohexadienals 50 or 55, respectively. In this manner, lithium enolates are a versatile tool in organic synthesis, allowing for the cross-condensation between two different unsaturated aldehydes, opening the possibilities among the non-chiral condensation methodology [32].
Studying the reactivity of ethyl 4-(diethoxyphosphinyl)-3-oxobutanoate 56 with enals (Scheme 14), one finds that after conjugated Michael addition to the corresponding enal and subsequent Horner reaction over the free carbonyl compound, the formation of Scheme 12. Cross-condensation of unsaturated aldehydes in the formation of 1,3-cyclohexadien-1-als.
Trimethylsilyl and acetate enolderivatives 53 serve as starting material for obtaining 1,3-cyclohexadien-1-als through the lithium enolate formation (Scheme 12). Intermediate 54 can be accessed via metalation of 53 with MeLi. The subsequent addition of a conjugated aldehyde 47 or 51 yields 1,3-cyclohexadienals 50 or 55, respectively. In this manner, lithium enolates are a versatile tool in organic synthesis, allowing for the cross-condensation between two different unsaturated aldehydes, opening the possibilities among the non-chiral condensation methodology [32]. The aldol reaction between aldehyde 46 and its enolate formed in presence of potassium tert-butoxide (t-BuOK) leads to the dimeric intermediate that in acidic medium evolves to form the self-condensation product 49 (Scheme 13) [33]. α,β-Unsaturated nitriles produce analogue condensation mechanism, giving the corresponding 2-amino-1,3cyclohexadien-1-carbonitrile scaffold; these derivatives can be easily converted to their corresponding aldehydes. Studying the reactivity of ethyl 4-(diethoxyphosphinyl)-3-oxobutanoate 56 with enals (Scheme 14), one finds that after conjugated Michael addition to the corresponding enal and subsequent Horner reaction over the free carbonyl compound, the formation of Scheme 13. Self-condensation of α,β-unsaturated aldehyde 46 in the formation of 1,3-cyclohexadien-1-al 49.
Studying the reactivity of ethyl 4-(diethoxyphosphinyl)-3-oxobutanoate 56 with enals (Scheme 14), one finds that after conjugated Michael addition to the corresponding enal and subsequent Horner reaction over the free carbonyl compound, the formation of cyclic compounds such as dienal 50 (22%) and the major product, the direct Horner reaction product 57 (53%), occurs [34]. The strong basic medium allows for the self-condensation of crotonaldehyde [35]. cyclic compounds such as dienal 50 (22%) and the major product, the direct Horner reaction product 57 (53%), occurs [34]. The strong basic medium allows for the self-condensation of crotonaldehyde [35].
Starting from linear starting materials, the cyclization to form six-membered rings can be performed in two steps through Horner olefination of α,β-unsaturated aldehydes and Michael addition to the resulting unsaturated system (Scheme 15). Ester reduction yields the 1,3-cyclohexadienal scaffold, wherein relative configuration can be controlled by using different bases for the conjugated addition. This methodology has been used in the total synthesis of natural products containing 1,3-cyclohexadien-1-al scaffolds such as (±)-cis/trans-2,3,3a,7a-tetrahydro-1H-indene-4-carbaldehyde 61 and 63 that have been prepared starting from aldehyde 58 and the ylide of 59 [6]. Similar methodology has been applied for obtaining 1,3-cyclohexadienals due to their interest as intermediates of polysubstituted aromatic compounds, as indicated in the preparation of 67 from 64 and 65 Starting from linear starting materials, the cyclization to form six-membered rings can be performed in two steps through Horner olefination of α,β-unsaturated aldehydes and Michael addition to the resulting unsaturated system (Scheme 15). Ester reduction yields the 1,3-cyclohexadienal scaffold, wherein relative configuration can be controlled by using different bases for the conjugated addition. This methodology has been used in the total synthesis of natural products containing 1,3-cyclohexadien-1-al scaffolds such as (±)-cis/trans-2,3,3a,7a-tetrahydro-1H-indene-4-carbaldehyde 61 and 63 that have been prepared starting from aldehyde 58 and the ylide of 59 [6]. Similar methodology has been applied for obtaining 1,3-cyclohexadienals due to their interest as intermediates of polysubstituted aromatic compounds, as indicated in the preparation of 67 from 64 and 65 (Scheme 15) [36]. The use of chiral phosphines in this reaction opens the possibility of asymmetric synthesis for this scaffold, as exemplified in the preparation of 71 from 68 using phosphine derivative C, obtaining good enantiomeric excess (ee) and moderate yield [16].
Starting from linear starting materials, the cyclization to form six-membered rings can be performed in two steps through Horner olefination of α,β-unsaturated aldehydes and Michael addition to the resulting unsaturated system (Scheme 15). Ester reduction yields the 1,3-cyclohexadienal scaffold, wherein relative configuration can be controlled by using different bases for the conjugated addition. This methodology has been used in the total synthesis of natural products containing 1,3-cyclohexadien-1-al scaffolds such as (±)-cis/trans-2,3,3a,7a-tetrahydro-1H-indene-4-carbaldehyde 61 and 63 that have been prepared starting from aldehyde 58 and the ylide of 59 [6]. Similar methodology has been applied for obtaining 1,3-cyclohexadienals due to their interest as intermediates of polysubstituted aromatic compounds, as indicated in the preparation of 67 from 64 and 65 (Scheme 15) [36]. The use of chiral phosphines in this reaction opens the possibility of asymmetric synthesis for this scaffold, as exemplified in the preparation of 71 from 68 using phosphine derivative C, obtaining good enantiomeric excess (ee) and moderate yield [16].

Pericyclic Reactions: Diels-Alder and Electrocyclizations
The Diels-Alder reaction is the most important and versatile reaction in synthetic organic chemistry for preparing six-membered rings. The 1,3-cyclohexadien-1-al scaffold can be afforded via Diels-Alder reaction by cycloaddition followed by base-promoted βelimination. For example, intramolecular Diels-Alder reaction of 72 catalysed by a Lewis acid produces the adduct intermediate 73, which can be transformed in the corresponding dienal 74 by elimination reaction (Scheme 16) [37]. Other alternatives for the obtention of

Pericyclic Reactions: Diels-Alder and Electrocyclizations
The Diels-Alder reaction is the most important and versatile reaction in synthetic organic chemistry for preparing six-membered rings. The 1,3-cyclohexadien-1-al scaffold can be afforded via Diels-Alder reaction by cycloaddition followed by base-promoted β-elimination. For example, intramolecular Diels-Alder reaction of 72 catalysed by a Lewis acid produces the adduct intermediate 73, which can be transformed in the corresponding dienal 74 by elimination reaction (Scheme 16) [37]. Other alternatives for the obtention of 1,3-cyclohexadienal after a Diels-Alder reaction consist of the presence of a good leaving group positioned on the allylic position of the reaction adduct. Starting from the alkylthioenolate 75 [38], by treatment with acrolein, the adduct 76 is formed in low yield, resulting as major product the dienal 77 (60% yield), which could be obtained in higher yield by augmenting the reaction time. When the Diels-Alder reaction is performed with 2-(4-chlorophenylseleno)-2-butenal 78 as dienophile [39], the oxidative deselenylation (with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)) of intermediate 80 conducts to the desired 1,3-cyclohexadienal (81-84) with excellent yields (Scheme 16). However, this oxidation must be carefully controlled, as DDQ can aromatize the ring obtaining the benzaldehyde derivative. Another example of Diels-Alder cycloaddition wherein a high regioselectivity i reached thanks to the sulfur-containing diene is shown in Scheme 17 [40,41]. The sulfid acts as a regioselective assistant as well as a good leaving group once the adduct is formed yielding the 1,3-cyclohexadienal. The reaction of the diene 85 with acroleine 86 yields th typical mono-olefin adduct of the Diels-Alder reaction that after elimination of allyli ethylsulfide group yields 1,3-cyclohexadienal 88. The reaction can be catalyzed by ZnBr2 allowing a lower activation energy and thus heating at 60 °C instead of 100 °C. The reac tion can be even carried out at 20 °C when LiClO4/Et2O is added as catalyst, but highe reaction times are needed. Another example of Diels-Alder cycloaddition wherein a high regioselectivity is reached thanks to the sulfur-containing diene is shown in Scheme 17 [40,41]. The sulfide acts as a regioselective assistant as well as a good leaving group once the adduct is formed, yielding the 1,3-cyclohexadienal. The reaction of the diene 85 with acroleine 86 yields the typical mono-olefin adduct of the Diels-Alder reaction that after elimination of allylic ethylsulfide group yields 1,3-cyclohexadienal 88. The reaction can be catalyzed by ZnBr 2 , allowing a lower activation energy and thus heating at 60 • C instead of 100 • C. The reaction can be even carried out at 20 • C when LiClO 4 /Et 2 O is added as catalyst, but higher reaction times are needed.
acts as a regioselective assistant as well as a good leaving group once the adduct is formed, yielding the 1,3-cyclohexadienal. The reaction of the diene 85 with acroleine 86 yields the typical mono-olefin adduct of the Diels-Alder reaction that after elimination of allylic ethylsulfide group yields 1,3-cyclohexadienal 88. The reaction can be catalyzed by ZnBr2, allowing a lower activation energy and thus heating at 60 °C instead of 100 °C. The reaction can be even carried out at 20 °C when LiClO4/Et2O is added as catalyst, but higher reaction times are needed. By using the Diels-Alder reaction to form the 1,3-cyclohexadienal, one can employ other starting materials such as 2,2-bis(trifluoromethyl)-ethylene-1,1-dicarbonitrile 92, a very strong dienophile (Scheme 19) [43]. However, three transformation steps are needed to form the 1,3-cyclohexadienal from adduct 94. The first step, the Diels-Alder reaction between the dicarbonitrile 92 and the diene 93 occurs in an excellent yield (90%) and can be improved up to 97% when 93 is in excess and increasing reaction time. The elimination of a nitrile group in 94 is carried out by reaction with NaOH in aqueous ethanol, resulting in 95 (97% yield). The formation of diene 96 from 95 takes place in two steps: allylic bromination with N-bromosuccinimide (NBS) and elimination reaction with triethylamine (Et3N). The bromination is a critical step wherein monobromination must be controlled, showing moderate conversion over these two steps (63%) and low yield (32%). Finally, reduction of nitrile 96 with DIBAL-H gives bis-trifluoromethyl-1,3-cyclohexadienal 97 in moderate yield. Other dienes derived from vinamidinium salts are versatile intermediates to perform Diels-Alder reactions (Scheme 20) [44]. For example, starting from the previously prepared vinamidinium salt 101, reaction with acrylaldehyde results in cyclohexadiene 102. These vinamidinium salt diene precursors are prepared in three steps, starting from unsaturated methylketones such as 98 by reaction with a secondary amine, pyrrolidine in this case. The resulting enamine 99 is tautomerized to the iminium salt 94, and then a second equivalent of secondary amine is added to form the vinamidinium salt 101. By using the Diels-Alder reaction to form the 1,3-cyclohexadienal, one can employ other starting materials such as 2,2-bis(trifluoromethyl)-ethylene-1,1-dicarbonitrile 92, a very strong dienophile (Scheme 19) [43]. However, three transformation steps are needed to form the 1,3-cyclohexadienal from adduct 94. The first step, the Diels-Alder reaction between the dicarbonitrile 92 and the diene 93 occurs in an excellent yield (90%) and can be improved up to 97% when 93 is in excess and increasing reaction time. The elimination of a nitrile group in 94 is carried out by reaction with NaOH in aqueous ethanol, resulting in 95 (97% yield). The formation of diene 96 from 95 takes place in two steps: allylic bromination with N-bromosuccinimide (NBS) and elimination reaction with triethylamine (Et 3 N). The bromination is a critical step wherein monobromination must be controlled, showing moderate conversion over these two steps (63%) and low yield (32%). Finally, reduction of nitrile 96 with DIBAL-H gives bis-trifluoromethyl-1,3-cyclohexadienal 97 in moderate yield. By using the Diels-Alder reaction to form the 1,3-cyclohexadienal, one can employ other starting materials such as 2,2-bis(trifluoromethyl)-ethylene-1,1-dicarbonitrile 92, a very strong dienophile (Scheme 19) [43]. However, three transformation steps are needed to form the 1,3-cyclohexadienal from adduct 94. The first step, the Diels-Alder reaction between the dicarbonitrile 92 and the diene 93 occurs in an excellent yield (90%) and can be improved up to 97% when 93 is in excess and increasing reaction time. The elimination of a nitrile group in 94 is carried out by reaction with NaOH in aqueous ethanol, resulting in 95 (97% yield). The formation of diene 96 from 95 takes place in two steps: allylic bromination with N-bromosuccinimide (NBS) and elimination reaction with triethylamine (Et3N). The bromination is a critical step wherein monobromination must be controlled, showing moderate conversion over these two steps (63%) and low yield (32%). Finally, reduction of nitrile 96 with DIBAL-H gives bis-trifluoromethyl-1,3-cyclohexadienal 97 in moderate yield. Other dienes derived from vinamidinium salts are versatile intermediates to perform Diels-Alder reactions (Scheme 20) [44]. For example, starting from the previously prepared vinamidinium salt 101, reaction with acrylaldehyde results in cyclohexadiene 102. These vinamidinium salt diene precursors are prepared in three steps, starting from unsaturated methylketones such as 98 by reaction with a secondary amine, pyrrolidine in this case. The resulting enamine 99 is tautomerized to the iminium salt 94, and then a second equivalent of secondary amine is added to form the vinamidinium salt 101. Other dienes derived from vinamidinium salts are versatile intermediates to perform Diels-Alder reactions (Scheme 20) [44]. For example, starting from the previously prepared vinamidinium salt 101, reaction with acrylaldehyde results in cyclohexadiene 102. These vinamidinium salt diene precursors are prepared in three steps, starting from unsaturated methylketones such as 98 by reaction with a secondary amine, pyrrolidine in this case. The resulting enamine 99 is tautomerized to the iminium salt 94, and then a second equivalent of secondary amine is added to form the vinamidinium salt 101. Scheme 19. Diels-Alder reaction towards the synthesis of hexafluorinated safranal 97.
Other dienes derived from vinamidinium salts are versatile intermediates to perform Diels-Alder reactions (Scheme 20) [44]. For example, starting from the previously prepared vinamidinium salt 101, reaction with acrylaldehyde results in cyclohexadiene 102. These vinamidinium salt diene precursors are prepared in three steps, starting from unsaturated methylketones such as 98 by reaction with a secondary amine, pyrrolidine in this case. The resulting enamine 99 is tautomerized to the iminium salt 94, and then a second equivalent of secondary amine is added to form the vinamidinium salt 101. Organoruthenium complexes can yield 1,3-cyclohexadienal scaffold through a 6e-π electrocyclization (Scheme 22). The reaction takes place between a 1,6-diyne 110 and acroleine [46].

Organometallic Synthetic Procedures
According to the reaction conditions reported by Corey et al. [47], γ,δ-unsaturated esters can be used as precursors of 1,3-cyclohexadien-1-als (Scheme 23). The transformation of 113 into intermediate 116 by reaction with the previously prepared bis(dimethylaluminium)-1,3-propanethiol followed by a two-step reaction of lithium diisopropylamide/hexamethylphosphoramide (LDA/HMPTA) anion formation and addition of methanol for quenching leads to the desired product 1 in good yield.

Organometallic Synthetic Procedures
According to the reaction conditions reported by Corey et al. [47], γ,δ-unsaturated esters can be used as precursors of 1,3-cyclohexadien-1-als (Scheme 23). The transformation of 113 into intermediate 116 by reaction with the previously prepared bis(dimethylaluminium)-1,3-propanethiol followed by a two-step reaction of lithium diisopropylamide/hexamethylphosphoramide (LDA/HMPTA) anion formation and addition of methanol for quenching leads to the desired product 1 in good yield. Scheme 23. Employment of organoaluminium reagent in the synthesis of cyclohexadienal 1.
An organometallic method using Cr(CO) 3 complex and benzaldehyde consisting of its dearomatization and chemoselective nucleophile addition has been reported (Scheme 24) [48]. Starting from benzaldehyde, preparation of the corresponding phenylmethanimine-tricarbonylchromium complex 117 is performed. Addition of a nucleophile is followed in the formation of anionic cyclohexadienyl complex 118 that is trapped with different bromides, providing at the end the 1,3-cyclohexadienal substituted in 5 and 6 positions. Different ratio of products 119 and 120 is obtained depending on the R 1 and R 2 groups. Compound 119 is preferentially formed when R 1 is a phenyl group, while cyclohexadienal 120 is formed selectively when R 2 is an allyl or propargyl group. An organometallic method using Cr(CO)3 complex and benzaldehyde consisting of its dearomatization and chemoselective nucleophile addition has been reported (Scheme 24) [48]. Starting from benzaldehyde, preparation of the corresponding phenylmethanimine-tricarbonylchromium complex 117 is performed. Addition of a nucleophile is followed in the formation of anionic cyclohexadienyl complex 118 that is trapped with different bromides, providing at the end the 1,3-cyclohexadienal substituted in 5 and 6 positions. Different ratio of products 119 and 120 is obtained depending on the R 1 and R 2 groups. Compound 119 is preferentially formed when R 1 is a phenyl group, while cyclohexadienal 120 is formed selectively when R 2 is an allyl or propargyl group. In these complexes, 117, the imine group, acts as an auxiliary that directs R 1 to the ortho position via lithium-nitrogen interaction (Scheme 25). External chiral ligands can be added to the reaction in order to induce stereoselectivity in the product [49], showing the highest enantioselectivities when PhLi is used as nucleophile. The external ligand forms an oligomeric entity with the nucleophile acting as a bridge instead of a simple chelating process. In these complexes, 117, the imine group, acts as an auxiliary that directs R 1 to the ortho position via lithium-nitrogen interaction (Scheme 25). External chiral ligands can be added to the reaction in order to induce stereoselectivity in the product [49], showing the highest enantioselectivities when PhLi is used as nucleophile. The external ligand forms an oligomeric entity with the nucleophile acting as a bridge instead of a simple chelating process. In these complexes, 117, the imine group, acts as an auxiliary that directs R 1 to the ortho position via lithium-nitrogen interaction (Scheme 25). External chiral ligands can be added to the reaction in order to induce stereoselectivity in the product [49], showing the highest enantioselectivities when PhLi is used as nucleophile. The external ligand forms an oligomeric entity with the nucleophile acting as a bridge instead of a simple chelating process. A selection of nitrogen-containing precursors that can be used to form the corresponding tricarbonylchromium complex is shown in Scheme 26 [48][49][50][51]. These precursors can be prepared using the corresponding amine (R-NH2) and the benzaldehyde unit. When the nitrogen-containing precursor is optically pure, the reaction shows high diastereoselectivity in the addition of nucleophiles in an asymmetric manner (up to 98% diatereomeric excess, de), as in the case of R 4 . A selection of nitrogen-containing precursors that can be used to form the corresponding tricarbonylchromium complex is shown in Scheme 26 [48][49][50][51]. These precursors can be prepared using the corresponding amine (R-NH 2 ) and the benzaldehyde unit. When the nitrogen-containing precursor is optically pure, the reaction shows high diastereoselectivity in the addition of nucleophiles in an asymmetric manner (up to 98% diatereomeric excess, de), as in the case of R 4 . The tricarbonylchromium-mediated dearomatization is a useful tool to access substituted cyclohexadienals. It has been used to synthesize acetoxytubipofuran, as a reacemic mixture [52] and also as the two separated enantiomers [51]. The natural product, isolated from Tubipora musica, is an eudesmane marine sesquiterpene that has been synthesized from dienal (S,S)-126 and (R,R)-126 as key intermediates, which in turn have been prepared according to the synthetic pathway described in Scheme 27.

Organocatalytic Methodologies
The access to chiral 1,3-cyclohexadienals can be accomplished by using organocatalysis. This methodology is a versatile method that uses as starting materials an α,β-unsaturated aldehyde and a α,β-unsaturated aldehyde with a methyl or methylene group in β. A high number of proline derivatives have been used as organocatalysts (129-139), as The tricarbonylchromium-mediated dearomatization is a useful tool to access substituted cyclohexadienals. It has been used to synthesize acetoxytubipofuran, as a reacemic mixture [52] and also as the two separated enantiomers [51]. The natural product, isolated from Tubipora musica, is an eudesmane marine sesquiterpene that has been synthesized from dienal (S,S)-126 and (R,R)-126 as key intermediates, which in turn have been prepared according to the synthetic pathway described in Scheme 27. The tricarbonylchromium-mediated dearomatization is a useful tool to access substituted cyclohexadienals. It has been used to synthesize acetoxytubipofuran, as a reacemic mixture [52] and also as the two separated enantiomers [51]. The natural product, isolated from Tubipora musica, is an eudesmane marine sesquiterpene that has been synthesized from dienal (S,S)-126 and (R,R)-126 as key intermediates, which in turn have been prepared according to the synthetic pathway described in Scheme 27.

Organocatalytic Methodologies
The access to chiral 1,3-cyclohexadienals can be accomplished by using organocatalysis. This methodology is a versatile method that uses as starting materials an α,β-unsaturated aldehyde and a α,β-unsaturated aldehyde with a methyl or methylene group in β.

Organocatalytic Methodologies
The access to chiral 1,3-cyclohexadienals can be accomplished by using organocatalysis. This methodology is a versatile method that uses as starting materials an α,βunsaturated aldehyde and a α,β-unsaturated aldehyde with a methyl or methylene group in β. A high number of proline derivatives have been used as organocatalysts (129-139), as shown in Scheme 28 [53]. Two different mechanisms have been proposed: (4 + 2) cycloaddition or Michael addition and cyclization [53]. The first use of proline as a catalyst begins with its application in the biomimetic cyclization of citral, synthesizing unsaturated aldehydes (Scheme 29) [54,55]. However, the specific use of proline to synthesize 1,3-cyclohexadienals occurred in 1992 [56], where the reaction of this aminoacid with different α,β-unsaturated aldehydes promoted their self-condensation. The good enantiomeric excess (up to 65%) resulted in a deepening of the research on the use of proline as organocatalyst as well as the development of proline analogues with improved catalytic properties. L-proline is used in excess in these reactions and the self-condensation product is always detected. When other proline derivatives such as 4-hydroxy-L-proline, D-proline, and cis-4-hydroxy-D-proline are used, the self-assembly of the aldehydes is observed; however, this self-condensation product of citral is not observed when Trp, His, Arg, Gly, or ILeu are used as catalysts for citral dimerization.
This condensation takes place through Schiff-base formation as a synthetic intermediate that reacts with other equivalents of α,β-unsaturated aldehyde yielding the 1,3-cyclohexadien-1-al core. However, sometimes the intermediate Schiff-base is stable enough and can be isolated, as in the case of the corresponding Schiff-base of L-proline and retinal [53].
In this sense, even when cross-condensation is performed, the autocondensation reaction should be considered as a possible background reaction. In the case of the use of citral, there is frequently the presence of the citral homodimer among the reaction products [57,58], as well as in organocatalyzed cycloaddition in multicomponent reactions [59]. The first use of proline as a catalyst begins with its application in the biomimetic cyclization of citral, synthesizing unsaturated aldehydes (Scheme 29) [54,55]. However, the specific use of proline to synthesize 1,3-cyclohexadienals occurred in 1992 [56], where the reaction of this aminoacid with different α,β-unsaturated aldehydes promoted their self-condensation. The good enantiomeric excess (up to 65%) resulted in a deepening of the research on the use of proline as organocatalyst as well as the development of proline analogues with improved catalytic properties. L-proline is used in excess in these reactions and the self-condensation product is always detected. When other proline derivatives such as 4-hydroxy-L-proline, D-proline, and cis-4-hydroxy-D-proline are used, the selfassembly of the aldehydes is observed; however, this self-condensation product of citral is not observed when Trp, His, Arg, Gly, or ILeu are used as catalysts for citral dimerization.
This condensation takes place through Schiff-base formation as a synthetic intermediate that reacts with other equivalents of α,β-unsaturated aldehyde yielding the 1,3-cyclohexadien-1-al core. However, sometimes the intermediate Schiff-base is stable enough and can be isolated, as in the case of the corresponding Schiff-base of L-proline and retinal [53].
In this sense, even when cross-condensation is performed, the autocondensation reaction should be considered as a possible background reaction. In the case of the use of citral, there is frequently the presence of the citral homodimer among the reaction products [57,58], as well as in organocatalyzed cycloaddition in multicomponent reactions [59]. Among the different organocatalysts, the aminocatalysts proline, MacMillan's 138 or 139, and Hayashi-Jorgensen's 137 [60] catalysts can promote Michael addition by iminium salt formation with the acceptor enal. On the other hand, a carbonyl donor can be activated by forming the enamine by addition of the organocatalyst and ensuing Michael addition. Thus, iminium salt-enamine formation turns out to be key in these organocatalytic pathways (Scheme 30). Aldehydes such as crotonaldehyde reacts with L-proline through a [3 + 3] cycloaddition, but when other α,β-unsaturated aldehydes with β-substituents react in the same conditions, the observed product is the (4 + 2) adduct [61]. The mechanistic explanation suggests that increasing the steric hindrance in β-position of these series of aldehydes eases the indirect Mannich reaction pathway and (4 + 2) adducts instead of the [3 + 3] cycloaddition products when carbon 3 is more accessible.
The reaction of different aldehydes in the presence of L-proline yields the corresponding (4 + 2) adducts, and results are shown in Table 1 [61]. Pyrrolidine can also be a good catalyst for the (4 + 2) cycloaddition [62], where a wide scope is given. Subsequent Among the different organocatalysts, the aminocatalysts proline, MacMillan's 138 or 139, and Hayashi-Jorgensen's 137 [60] catalysts can promote Michael addition by iminium salt formation with the acceptor enal. On the other hand, a carbonyl donor can be activated by forming the enamine by addition of the organocatalyst and ensuing Michael addition. Thus, iminium salt-enamine formation turns out to be key in these organocatalytic pathways (Scheme 30). Aldehydes such as crotonaldehyde reacts with L-proline through a [3 + 3] cycloaddition, but when other α,β-unsaturated aldehydes with β-substituents react in the same conditions, the observed product is the (4 + 2) adduct [61]. The mechanistic explanation suggests that increasing the steric hindrance in β-position of these series of aldehydes eases the indirect Mannich reaction pathway and (4 + 2) adducts instead of the [3 + 3] cycloaddition products when carbon 3 is more accessible. Among the different organocatalysts, the aminocatalysts proline, MacMillan's 138 or 139, and Hayashi-Jorgensen's 137 [60] catalysts can promote Michael addition by iminium salt formation with the acceptor enal. On the other hand, a carbonyl donor can be activated by forming the enamine by addition of the organocatalyst and ensuing Michael addition. Thus, iminium salt-enamine formation turns out to be key in these organocatalytic pathways (Scheme 30). Aldehydes such as crotonaldehyde reacts with L-proline through a [3 + 3] cycloaddition, but when other α,β-unsaturated aldehydes with β-substituents react in the same conditions, the observed product is the (4 + 2) adduct [61]. The mechanistic explanation suggests that increasing the steric hindrance in β-position of these series of aldehydes eases the indirect Mannich reaction pathway and (4 + 2) adducts instead of the [3 + 3] cycloaddition products when carbon 3 is more accessible. The reaction of different aldehydes in the presence of L-proline yields the corresponding (4 + 2) adducts, and results are shown in Table 1 [61]. Pyrrolidine can also be a good catalyst for the (4 + 2) cycloaddition [62], where a wide scope is given. Subsequent The reaction of different aldehydes in the presence of L-proline yields the corresponding (4 + 2) adducts, and results are shown in Table 1 [61]. Pyrrolidine can also be a good catalyst for the (4 + 2) cycloaddition [62], where a wide scope is given. Subsequent aromatization of the diene adducts by reaction with DDQ or MnO 2 gives the benzaldehyde derivatives, providing, in this way, a good methodology for controlled substitution of benzaldehyde derivatives. Table 1. Examples of cyclohexadienals obtained in the (4 + 2) cycloaddition of α,β-unsaturated aldehydes mediated by L-proline.
Molecules 2020, 25, x FOR PEER REVIEW 17 of 33 aromatization of the diene adducts by reaction with DDQ or MnO2 gives the benzaldehyde derivatives, providing, in this way, a good methodology for controlled substitution of benzaldehyde derivatives.  (41) Watanabe et al. synthesized a high number of 1,3-cyclohexadienal derivatives with different substitution degrees using proline as organocatalyst (Scheme 31) [63]. By this procedure, the homodimerization product can be observed in a variety of yields (5 to 75%), and moderate ee (36 to 72%) are observed, depending on the combination of donor-acceptor aldehydes.

Scheme 31.
Examples of cyclohexadienals obtained in L-proline-mediated reaction of α,β-unsaturated aldehydes. Watanabe et al. synthesized a high number of 1,3-cyclohexadienal derivatives with different substitution degrees using proline as organocatalyst (Scheme 31) [63]. By this procedure, the homodimerization product can be observed in a variety of yields (5 to 75%), and moderate ee (36 to 72%) are observed, depending on the combination of donoracceptor aldehydes.
Molecules 2020, 25, x FOR PEER REVIEW 17 of 33 aromatization of the diene adducts by reaction with DDQ or MnO2 gives the benzaldehyde derivatives, providing, in this way, a good methodology for controlled substitution of benzaldehyde derivatives.  (41) Watanabe et al. synthesized a high number of 1,3-cyclohexadienal derivatives with different substitution degrees using proline as organocatalyst (Scheme 31) [63]. By this procedure, the homodimerization product can be observed in a variety of yields (5 to 75%), and moderate ee (36 to 72%) are observed, depending on the combination of donor-acceptor aldehydes. The optimization of the reaction consists of pre-forming the iminium salt of donor aldehyde-proline and then addition of acceptor aldehyde, minimizing in this way the formation of the homo-dimmer.
Intramolecular organocatalyzed cycloaddition has been screened in a variety of cinnamaldehyde derivatives, obtaining dihydrodibenzofurans with good enantioselectivity and yields (Scheme 32) [64].
Molecules 2020, 25, x FOR PEER REVIEW 18 of 33 The optimization of the reaction consists of pre-forming the iminium salt of donor aldehyde-proline and then addition of acceptor aldehyde, minimizing in this way the formation of the homo-dimmer.
Intramolecular organocatalyzed cycloaddition has been screened in a variety of cinnamaldehyde derivatives, obtaining dihydrodibenzofurans with good enantioselectivity and yields (Scheme 32) [64]. A formal eliminative (4 + 2) cycloaddition can be performed, starting from a γ-enolizable α,β-unsaturated carbonyl compound (diene) and an enal (dienophile) (Scheme 33) [65]. The addition of an organocatalyst allows for a diastereoselection in the cycloaddition through the formation of the Schiff-base. After screening the reaction conditions and demonstrating the general applicability of the (4 + 2) eliminative cycloaddition, one can apply the procedure to steroid-based dicyano substrates. It is important to highlight the relevance of the β-substitution in donor aldehyde, when instead of a methyl group, the conjugated unsaturation is an exocyclic double bond, and the reactivity for the cyclohexadiene formation decreases, significantly reducing the reaction yield. However, in this case, two chiral centers are generated in the reaction product with excellent diastereoselectivity (Scheme 35). A formal eliminative (4 + 2) cycloaddition can be performed, starting from a γ-enolizable α,β-unsaturated carbonyl compound (diene) and an enal (dienophile) (Scheme 33) [65]. The addition of an organocatalyst allows for a diastereoselection in the cycloaddition through the formation of the Schiff-base. After screening the reaction conditions and demonstrating the general applicability of the (4 + 2) eliminative cycloaddition, one can apply the procedure to steroid-based dicyano substrates. The optimization of the reaction consists of pre-forming the iminium salt of donor aldehyde-proline and then addition of acceptor aldehyde, minimizing in this way the formation of the homo-dimmer.
Intramolecular organocatalyzed cycloaddition has been screened in a variety of cinnamaldehyde derivatives, obtaining dihydrodibenzofurans with good enantioselectivity and yields (Scheme 32) [64]. A formal eliminative (4 + 2) cycloaddition can be performed, starting from a γ-enolizable α,β-unsaturated carbonyl compound (diene) and an enal (dienophile) (Scheme 33) [65]. The addition of an organocatalyst allows for a diastereoselection in the cycloaddition through the formation of the Schiff-base. After screening the reaction conditions and demonstrating the general applicability of the (4 + 2) eliminative cycloaddition, one can apply the procedure to steroid-based dicyano substrates. The same methodology has been applied to the synthesis of chiral 1,3-cyclohexadienals, where a high diastereoselection has been reported, showing up to a 85:15 diastereomeric ratio and moderate to good yield (Scheme 34) [66]. It is important to highlight the relevance of the β-substitution in donor aldehyde, when instead of a methyl group, the conjugated unsaturation is an exocyclic double bond, and the reactivity for the cyclohexadiene formation decreases, significantly reducing the reaction yield. However, in this case, two chiral centers are generated in the reaction product with excellent diastereoselectivity (Scheme 35). The same methodology has been applied to the synthesis of chiral 1,3-cyclohexadienals, where a high diastereoselection has been reported, showing up to a 85:15 diastereomeric ratio and moderate to good yield (Scheme 34) [66]. The optimization of the reaction consists of pre-forming the iminium salt of donor aldehyde-proline and then addition of acceptor aldehyde, minimizing in this way the formation of the homo-dimmer.
Intramolecular organocatalyzed cycloaddition has been screened in a variety of cinnamaldehyde derivatives, obtaining dihydrodibenzofurans with good enantioselectivity and yields (Scheme 32) [64]. A formal eliminative (4 + 2) cycloaddition can be performed, starting from a γ-enolizable α,β-unsaturated carbonyl compound (diene) and an enal (dienophile) (Scheme 33) [65]. The addition of an organocatalyst allows for a diastereoselection in the cycloaddition through the formation of the Schiff-base. After screening the reaction conditions and demonstrating the general applicability of the (4 + 2) eliminative cycloaddition, one can apply the procedure to steroid-based dicyano substrates. The same methodology has been applied to the synthesis of chiral 1,3-cyclohexadienals, where a high diastereoselection has been reported, showing up to a 85:15 diastereomeric ratio and moderate to good yield (Scheme 34) [66]. It is important to highlight the relevance of the β-substitution in donor aldehyde, when instead of a methyl group, the conjugated unsaturation is an exocyclic double bond, and the reactivity for the cyclohexadiene formation decreases, significantly reducing the reaction yield. However, in this case, two chiral centers are generated in the reaction product with excellent diastereoselectivity (Scheme 35). It is important to highlight the relevance of the β-substitution in donor aldehyde, when instead of a methyl group, the conjugated unsaturation is an exocyclic double bond, and the reactivity for the cyclohexadiene formation decreases, significantly reducing the reaction yield. However, in this case, two chiral centers are generated in the reaction product with excellent diastereoselectivity (Scheme 35). Other examples of 1,3-cyclohexadien-1-als obtained as synthetic intermediates can be found in the work of Jorgensen, who synthesized tetrahydroisochromenes starting from oxadendralenes (Scheme 37) [68]. In the aim of obtaining the tetrahydroisochromene derivatives in a three-component reaction, research first accomplished screening the reaction conditions to obtain dienal 186. Good yield and diastereoselectivity is obtained in the reaction of aldehyde 184 and 185 in the presence of organocatalyst S-137, obtaining the oxadendralene intermediate (Scheme 37). Once this reaction is viable, the next step involves the reaction with vinyl ether 187. The cyclization occurs in the presence of a co-catalyst such as Eu(fod)3 (10 mol %), resulting in the desired tetrahydrochromene 188. Scheme 37. Synthesis of cyclohexadienal compounds and subsequent cycloaddition reaction. Other examples of 1,3-cyclohexadien-1-als obtained as synthetic intermediates can be found in the work of Jorgensen, who synthesized tetrahydroisochromenes starting from oxadendralenes (Scheme 37) [68]. In the aim of obtaining the tetrahydroisochromene derivatives in a three-component reaction, research first accomplished screening the reaction conditions to obtain dienal 186. Good yield and diastereoselectivity is obtained in the reaction of aldehyde 184 and 185 in the presence of organocatalyst S-137, obtaining the oxadendralene intermediate (Scheme 37). Once this reaction is viable, the next step involves the reaction with vinyl ether 187. The cyclization occurs in the presence of a co-catalyst such as Eu(fod)3 (10 mol %), resulting in the desired tetrahydrochromene 188. Scheme 37. Synthesis of cyclohexadienal compounds and subsequent cycloaddition reaction.

Scheme 36. Organocatalytic-mediated synthesis of cyclodienal and subsequent reaction with conjugated aldehyde 181.
Other examples of 1,3-cyclohexadien-1-als obtained as synthetic intermediates can be found in the work of Jorgensen, who synthesized tetrahydroisochromenes starting from oxadendralenes (Scheme 37) [68]. In the aim of obtaining the tetrahydroisochromene derivatives in a three-component reaction, research first accomplished screening the reaction conditions to obtain dienal 186. Good yield and diastereoselectivity is obtained in the reaction of aldehyde 184 and 185 in the presence of organocatalyst S-137, obtaining the oxadendralene intermediate (Scheme 37). Once this reaction is viable, the next step involves the reaction with vinyl ether 187. The cyclization occurs in the presence of a co-catalyst such as Eu(fod) 3 (10 mol %), resulting in the desired tetrahydrochromene 188. Other examples of 1,3-cyclohexadien-1-als obtained as synthetic intermediates can be found in the work of Jorgensen, who synthesized tetrahydroisochromenes starting from oxadendralenes (Scheme 37) [68]. In the aim of obtaining the tetrahydroisochromene derivatives in a three-component reaction, research first accomplished screening the reaction conditions to obtain dienal 186. Good yield and diastereoselectivity is obtained in the reaction of aldehyde 184 and 185 in the presence of organocatalyst S-137, obtaining the oxadendralene intermediate (Scheme 37). Once this reaction is viable, the next step involves the reaction with vinyl ether 187. The cyclization occurs in the presence of a co-catalyst such as Eu(fod)3 (10 mol %), resulting in the desired tetrahydrochromene 188. Scheme 37. Synthesis of cyclohexadienal compounds and subsequent cycloaddition reaction.

Reactivity of 1,3-Cyclohexadien-1-Als
The 1,3-cyclohexadien-1-carboxaldehyde unit is a highly functionalized small molecule with high potential as building block, and as such it has been used widely for the construction of a great variety of compounds. Reactivity of the functional groups in the scaffold has been harnessed, and a great deal of transformations involve typical reactions of the double bond functional group, aldehyde functional group, and the α,β-unsaturated aldehyde system. Several examples of each of these three types of reactivity are shown below.
Molecules 2020, 25, x FOR PEER REVIEW 20 of 33 The 1,3-cyclohexadien-1-carboxaldehyde unit is a highly functionalized small molecule with high potential as building block, and as such it has been used widely for the construction of a great variety of compounds. Reactivity of the functional groups in the scaffold has been harnessed, and a great deal of transformations involve typical reactions of the double bond functional group, aldehyde functional group, and the α,β-unsaturated aldehyde system. Several examples of each of these three types of reactivity are shown below.

Reactions Involving Double Bond(s)
1,3-Cyclohexadien-1-carboxaldehyde 1 was considered as a starting material in the total synthesis of fumagillol 190 [69,70], in which the first step implies dihydroxylation of the more electron rich γ,δ-double bond (Scheme 38). Dihydroxylation reaction of cyclohexadienal 150 (Scheme 39) to diol 192 was also considered in the total synthesis of (+) palitantin [71], a natural compound with antifungal [72] and antibiotic activities [73]. The cyclohexadiene carboxaldehyde intermediate 150 was obtained by self-dimerizacion of (E)-4-acetoxycrotonaldehyde 191 in the presence of L-proline [71]. Trost et al. recently presented an interesting study about the catalytic palladium oxyally cycloaddition reaction with conjugated dienes [74], wherein 1,3-cyclohexadiene-1carboxaldehyde was also tested, giving the corresponding bicyclic tetrahydrofuran product 196 with extraordinary chemoselectivity (Scheme 41). This shows once more the versatility of the cyclohexadienal unit, which can be involved in many different transformations. Dihydroxylation reaction of cyclohexadienal 150 (Scheme 39) to diol 192 was also considered in the total synthesis of (+) palitantin [71], a natural compound with antifungal [72] and antibiotic activities [73]. The cyclohexadiene carboxaldehyde intermediate 150 was obtained by self-dimerizacion of (E)-4-acetoxycrotonaldehyde 191 in the presence of L-proline [71]. The 1,3-cyclohexadien-1-carboxaldehyde unit is a highly functionalized small molecule with high potential as building block, and as such it has been used widely for the construction of a great variety of compounds. Reactivity of the functional groups in the scaffold has been harnessed, and a great deal of transformations involve typical reactions of the double bond functional group, aldehyde functional group, and the α,β-unsaturated aldehyde system. Several examples of each of these three types of reactivity are shown below.

Reactions Involving Double Bond(s)
1,3-Cyclohexadien-1-carboxaldehyde 1 was considered as a starting material in the total synthesis of fumagillol 190 [69,70], in which the first step implies dihydroxylation of the more electron rich γ,δ-double bond (Scheme 38). Dihydroxylation reaction of cyclohexadienal 150 (Scheme 39) to diol 192 was also considered in the total synthesis of (+) palitantin [71], a natural compound with antifungal [72] and antibiotic activities [73]. The cyclohexadiene carboxaldehyde intermediate 150 was obtained by self-dimerizacion of (E)-4-acetoxycrotonaldehyde 191 in the presence of L-proline [71]. Trost et al. recently presented an interesting study about the catalytic palladium oxyally cycloaddition reaction with conjugated dienes [74], wherein 1,3-cyclohexadiene-1carboxaldehyde was also tested, giving the corresponding bicyclic tetrahydrofuran product 196 with extraordinary chemoselectivity (Scheme 41). This shows once more the versatility of the cyclohexadienal unit, which can be involved in many different transformations. The 1,3-cyclohexadien-1-carboxaldehyde unit is a highly functionalized small molecule with high potential as building block, and as such it has been used widely for the construction of a great variety of compounds. Reactivity of the functional groups in the scaffold has been harnessed, and a great deal of transformations involve typical reactions of the double bond functional group, aldehyde functional group, and the α,β-unsaturated aldehyde system. Several examples of each of these three types of reactivity are shown below.

Scheme 43. Aromatization reaction of cyclohexadienals.
Phenyl-substituted cyclohexadienals 200 were found to spontaneously aromatize in low conversion of 5-15% in a period of one to several days [63]. However, aromatization could also be performed in quantitative yields by reaction with potassium permanganate (Scheme 44). Those aromatic compounds 201 could find use as fluorescent probes to identify the protein binding partner of a particular cyclohexadienal in studies of such compounds to activate neurite outgrowth activity [63]. The cyclohexadienal core 200 was generated by a cross-condensation reaction of α,β-unsaturated aldehydes mediated by L-proline (Scheme 44).

Scheme 44. Aromatization reaction of phenyl-substituted cyclohexadienals.
In line with this, the above reaction sequence of organocatalytic synthesis of the cyclohexadiene carboxaldehyde unit and subsequent oxidation reaction has been used as a fair strategy for the preparation of multi-substituted aromatic aldehydes [62]. Scheme 45 Scheme 41. Oxyallyl cycloaddition reaction with cyclohexadienal.

Scheme 43. Aromatization reaction of cyclohexadienals.
Phenyl-substituted cyclohexadienals 200 were found to spontaneously aromatize in low conversion of 5-15% in a period of one to several days [63]. However, aromatization could also be performed in quantitative yields by reaction with potassium permanganate (Scheme 44). Those aromatic compounds 201 could find use as fluorescent probes to identify the protein binding partner of a particular cyclohexadienal in studies of such compounds to activate neurite outgrowth activity [63]. The cyclohexadienal core 200 was generated by a cross-condensation reaction of α,β-unsaturated aldehydes mediated by L-proline (Scheme 44).

Scheme 44. Aromatization reaction of phenyl-substituted cyclohexadienals.
In line with this, the above reaction sequence of organocatalytic synthesis of the cyclohexadiene carboxaldehyde unit and subsequent oxidation reaction has been used as a fair strategy for the preparation of multi-substituted aromatic aldehydes [62]. Scheme 45 Scheme 42. Formation of tricarbonyl iron complex of 1,3-cyclohexadiene-1-carboxaldehyde 1.

Scheme 43. Aromatization reaction of cyclohexadienals.
Phenyl-substituted cyclohexadienals 200 were found to spontaneously aromatize in low conversion of 5-15% in a period of one to several days [63]. However, aromatization could also be performed in quantitative yields by reaction with potassium permanganate (Scheme 44). Those aromatic compounds 201 could find use as fluorescent probes to identify the protein binding partner of a particular cyclohexadienal in studies of such compounds to activate neurite outgrowth activity [63]. The cyclohexadienal core 200 was generated by a cross-condensation reaction of α,β-unsaturated aldehydes mediated by L-proline (Scheme 44).

Scheme 44. Aromatization reaction of phenyl-substituted cyclohexadienals.
In line with this, the above reaction sequence of organocatalytic synthesis of the cyclohexadiene carboxaldehyde unit and subsequent oxidation reaction has been used as a fair strategy for the preparation of multi-substituted aromatic aldehydes [62]. Scheme 45 Scheme 43. Aromatization reaction of cyclohexadienals.
Phenyl-substituted cyclohexadienals 200 were found to spontaneously aromatize in low conversion of 5-15% in a period of one to several days [63]. However, aromatization could also be performed in quantitative yields by reaction with potassium permanganate (Scheme 44). Those aromatic compounds 201 could find use as fluorescent probes to identify the protein binding partner of a particular cyclohexadienal in studies of such compounds to activate neurite outgrowth activity [63]. The cyclohexadienal core 200 was generated by a cross-condensation reaction of α,β-unsaturated aldehydes mediated by L-proline (Scheme 44). Tricarbonyl iron complex of 1,3-cyclohexadiene-1-carboxaldehyde 1 has been prepared in a photochemical reaction with iron pentacarbonyl (Scheme 42) [75]. Such complex 197 was synthesized in the route to structurally constrained tricarbonyl (trans-pentadienyl) iron cations 199 to study acid catalyzed rearrangements. Aromatization of cyclohexadienals has been used to prepare aromatic aldehydes (Scheme 43) [76]. Oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) allows for the aromatization reaction with moderate to high yields. Phenyl-substituted cyclohexadienals 200 were found to spontaneously aromatize in low conversion of 5-15% in a period of one to several days [63]. However, aromatization could also be performed in quantitative yields by reaction with potassium permanganate (Scheme 44). Those aromatic compounds 201 could find use as fluorescent probes to identify the protein binding partner of a particular cyclohexadienal in studies of such compounds to activate neurite outgrowth activity [63]. The cyclohexadienal core 200 was generated by a cross-condensation reaction of α,β-unsaturated aldehydes mediated by L-proline (Scheme 44). In line with this, the above reaction sequence of organocatalytic synthesis of the cyclohexadiene carboxaldehyde unit and subsequent oxidation reaction has been used as a fair strategy for the preparation of multi-substituted aromatic aldehydes [62]. Scheme 45 Scheme 44. Aromatization reaction of phenyl-substituted cyclohexadienals.
In line with this, the above reaction sequence of organocatalytic synthesis of the cyclohexadiene carboxaldehyde unit and subsequent oxidation reaction has been used as a fair strategy for the preparation of multi-substituted aromatic aldehydes [62]. Scheme 45 depicts a (4 + 2) and (3 + 3) cycloaddition of α,β-unsaturated aldehydes mediated by L-proline 131 or pyrrolide 129/acetic acid (AcOH) to afford the cyclohexadiene carboxaldehyde intermediate that was not isolated and spontaneously oxidize or directly submitted to oxidation reaction conditions with MnO 2 or DDQ for the formation of the aromatic compound [62].
Molecules 2020, 25, x FOR PEER REVIEW 22 of 33 depicts a (4 + 2) and (3 + 3) cycloaddition of α,β-unsaturated aldehydes mediated by Lproline 131 or pyrrolide 129/acetic acid (AcOH) to afford the cyclohexadiene carboxaldehyde intermediate that was not isolated and spontaneously oxidize or directly submitted to oxidation reaction conditions with MnO2 or DDQ for the formation of the aromatic compound [62].

Scheme 45.
Organocatalytic synthesis of cyclohexadienals/oxidation reaction in the synthesis of aromatic aldehydes.
In the following example (Scheme 46), pentasubstituted aromatic compounds are prepared under the above mentioned reaction sequence via intermediate cyclohexadiene carboxaldehyde 202 that was oxidized with atmospheric air appealing, therefore, in this case, under environmentally friendly reaction conditions [77]. Intermediate cyclohexadienal 202 is formed via a Michael type cascade reaction mediated by organocatalyst 137. Scheme 46. Organocatalytic synthesis of cyclohexadienals/aromatization reaction in the synthesis of pentasubstituted aromatic compounds.
Reduction reactions of the aldehyde group in the cyclohexadienal core have also been described. In this manner, the natural product safranal 2 was converted to the corresponding alcohol 206 in near quantitative yield with LiAlH4 (Scheme 48) [79]. The resultant alcohol 206 was submitted to a photooxygenation reaction for the formation of endoperoxide 207 in a chemoselective singlet oxygen (4 + 2) cycloaddition reaction. That transformation was also assayed directly on safranal compound 2. However, the desired endoperoxide 208 turned out to decompose in this case. In the following example (Scheme 46), pentasubstituted aromatic compounds are prepared under the above mentioned reaction sequence via intermediate cyclohexadiene carboxaldehyde 202 that was oxidized with atmospheric air appealing, therefore, in this case, under environmentally friendly reaction conditions [77]. Intermediate cyclohexadienal 202 is formed via a Michael type cascade reaction mediated by organocatalyst 137.
Molecules 2020, 25, x FOR PEER REVIEW 22 of 33 depicts a (4 + 2) and (3 + 3) cycloaddition of α,β-unsaturated aldehydes mediated by Lproline 131 or pyrrolide 129/acetic acid (AcOH) to afford the cyclohexadiene carboxaldehyde intermediate that was not isolated and spontaneously oxidize or directly submitted to oxidation reaction conditions with MnO2 or DDQ for the formation of the aromatic compound [62].

Scheme 45.
Organocatalytic synthesis of cyclohexadienals/oxidation reaction in the synthesis of aromatic aldehydes.
In the following example (Scheme 46), pentasubstituted aromatic compounds are prepared under the above mentioned reaction sequence via intermediate cyclohexadiene carboxaldehyde 202 that was oxidized with atmospheric air appealing, therefore, in this case, under environmentally friendly reaction conditions [77]. Intermediate cyclohexadienal 202 is formed via a Michael type cascade reaction mediated by organocatalyst 137. Scheme 46. Organocatalytic synthesis of cyclohexadienals/aromatization reaction in the synthesis of pentasubstituted aromatic compounds.
Reduction reactions of the aldehyde group in the cyclohexadienal core have also been described. In this manner, the natural product safranal 2 was converted to the corresponding alcohol 206 in near quantitative yield with LiAlH4 (Scheme 48) [79]. The resultant alcohol 206 was submitted to a photooxygenation reaction for the formation of endoperoxide 207 in a chemoselective singlet oxygen (4 + 2) cycloaddition reaction. That transformation was also assayed directly on safranal compound 2. However, the desired endoperoxide 208 turned out to decompose in this case.
Molecules 2020, 25, x FOR PEER REVIEW 22 of 33 depicts a (4 + 2) and (3 + 3) cycloaddition of α,β-unsaturated aldehydes mediated by Lproline 131 or pyrrolide 129/acetic acid (AcOH) to afford the cyclohexadiene carboxaldehyde intermediate that was not isolated and spontaneously oxidize or directly submitted to oxidation reaction conditions with MnO2 or DDQ for the formation of the aromatic compound [62].

Scheme 45.
Organocatalytic synthesis of cyclohexadienals/oxidation reaction in the synthesis of aromatic aldehydes.
In the following example (Scheme 46), pentasubstituted aromatic compounds are prepared under the above mentioned reaction sequence via intermediate cyclohexadiene carboxaldehyde 202 that was oxidized with atmospheric air appealing, therefore, in this case, under environmentally friendly reaction conditions [77]. Intermediate cyclohexadienal 202 is formed via a Michael type cascade reaction mediated by organocatalyst 137. Scheme 46. Organocatalytic synthesis of cyclohexadienals/aromatization reaction in the synthesis of pentasubstituted aromatic compounds.
Reduction reactions of the aldehyde group in the cyclohexadienal core have also been described. In this manner, the natural product safranal 2 was converted to the corresponding alcohol 206 in near quantitative yield with LiAlH4 (Scheme 48) [79]. The resultant alcohol 206 was submitted to a photooxygenation reaction for the formation of endoperoxide 207 in a chemoselective singlet oxygen (4 + 2) cycloaddition reaction. That transformation was also assayed directly on safranal compound 2. However, the desired endoperoxide 208 turned out to decompose in this case. Reduction reactions of the aldehyde group in the cyclohexadienal core have also been described. In this manner, the natural product safranal 2 was converted to the corresponding alcohol 206 in near quantitative yield with LiAlH 4 (Scheme 48) [79]. The resultant alcohol 206 was submitted to a photooxygenation reaction for the formation of endoperoxide 207 in a chemoselective singlet oxygen (4 + 2) cycloaddition reaction. That transformation was also assayed directly on safranal compound 2. However, the desired endoperoxide 208 turned out to decompose in this case. Reduction of the aldehyde group in natural aldehydes 61 and 63 has been performed with the aim of confirming the structure of such natural compounds (Scheme 49) [6]. Aldehyde 63 present in black cardamom has been found to produce a trigeminal effect in the mouth. The great versatility of the cyclohexadiene carboxaldehyde moiety is demonstrated in the utilization of such scaffold in the total synthesis of many varied compounds. That is the case of the citotoxic compound acetoxytubipofuran (Scheme 50). The strategy followed for its synthesis implies a tricarbonyl chromium-mediate dearomatization to access the substituted cyclohexadiene carboxaldehyde compound 126 [51]. Further transformations to the final acetoxytubipofuran are followed. Among them, reduction of the aldehyde moiety in the cyclohexadienal core is performed with NaBH4 in the presence of CeCl3 (Scheme 50). Reduction of the aldehyde group in natural aldehydes 61 and 63 has been performed with the aim of confirming the structure of such natural compounds (Scheme 49) [6]. Aldehyde 63 present in black cardamom has been found to produce a trigeminal effect in the mouth. Reduction of the aldehyde group in natural aldehydes 61 and 63 has been performed with the aim of confirming the structure of such natural compounds (Scheme 49) [6]. Aldehyde 63 present in black cardamom has been found to produce a trigeminal effect in the mouth. The great versatility of the cyclohexadiene carboxaldehyde moiety is demonstrated in the utilization of such scaffold in the total synthesis of many varied compounds. That is the case of the citotoxic compound acetoxytubipofuran (Scheme 50). The strategy followed for its synthesis implies a tricarbonyl chromium-mediate dearomatization to access the substituted cyclohexadiene carboxaldehyde compound 126 [51]. Further transformations to the final acetoxytubipofuran are followed. Among them, reduction of the aldehyde moiety in the cyclohexadienal core is performed with NaBH4 in the presence of CeCl3 (Scheme 50). The great versatility of the cyclohexadiene carboxaldehyde moiety is demonstrated in the utilization of such scaffold in the total synthesis of many varied compounds. That is the case of the citotoxic compound acetoxytubipofuran (Scheme 50). The strategy followed for its synthesis implies a tricarbonyl chromium-mediate dearomatization to access the substituted cyclohexadiene carboxaldehyde compound 126 [51]. Further transformations to the final acetoxytubipofuran are followed. Among them, reduction of the aldehyde moiety in the cyclohexadienal core is performed with NaBH 4 in the presence of CeCl 3 (Scheme 50). Reduction of the aldehyde group in natural aldehydes 61 and 63 has been performed with the aim of confirming the structure of such natural compounds (Scheme 49) [6]. Aldehyde 63 present in black cardamom has been found to produce a trigeminal effect in the mouth. The great versatility of the cyclohexadiene carboxaldehyde moiety is demonstrated in the utilization of such scaffold in the total synthesis of many varied compounds. That is the case of the citotoxic compound acetoxytubipofuran (Scheme 50). The strategy followed for its synthesis implies a tricarbonyl chromium-mediate dearomatization to access the substituted cyclohexadiene carboxaldehyde compound 126 [51]. Further transformations to the final acetoxytubipofuran are followed. Among them, reduction of the aldehyde moiety in the cyclohexadienal core is performed with NaBH4 in the presence of CeCl3 (Scheme 50).
Molecules 2020, 25, x FOR PEER REVIEW 24 of 33 Scheme 50. Reduction of the aldehyde moiety in the 1,3-cyclohexadien-1-al core in the total synthesis of acetoxytubipofuran.

Scheme 51.
Reduction of the cyclohexadienal core in the synthesis of (−)-drimenol.
Another typical reaction of the aldehyde functional group is the Horner-Wadsworth-Emmons coupling with phosphonates [13]. Such transformation was the choice for the conversion of safranal 2 to 3,4-didehydroretinal 45 involving two consecutive phosphonate coupling reactions and reductions (Scheme 52). Reaction of the aldehyde group with organometallic compounds has been used for the construction of miscellaneous structures. This is the case of the preparation of β-damascenone, wherein safranal 2 was reacted with the corresponding Grignard reagent (Scheme 53) [18]. Subsequent oxidation with MnO2 produced β-damascenone. Isomerization of the double bond on the side chain can be accomplished with para-toluensulfonic acid to obtain β-damascenone in higher yield (Scheme 53). Another typical reaction of the aldehyde functional group is the Horner-Wadsworth-Emmons coupling with phosphonates [13]. Such transformation was the choice for the conversion of safranal 2 to 3,4-didehydroretinal 45 involving two consecutive phosphonate coupling reactions and reductions (Scheme 52).
Molecules 2020, 25, x FOR PEER REVIEW 24 of 33 Scheme 50. Reduction of the aldehyde moiety in the 1,3-cyclohexadien-1-al core in the total synthesis of acetoxytubipofuran.

Scheme 51.
Reduction of the cyclohexadienal core in the synthesis of (−)-drimenol.
Another typical reaction of the aldehyde functional group is the Horner-Wadsworth-Emmons coupling with phosphonates [13]. Such transformation was the choice for the conversion of safranal 2 to 3,4-didehydroretinal 45 involving two consecutive phosphonate coupling reactions and reductions (Scheme 52). Reaction of the aldehyde group with organometallic compounds has been used for the construction of miscellaneous structures. This is the case of the preparation of β-damascenone, wherein safranal 2 was reacted with the corresponding Grignard reagent (Scheme 53) [18]. Subsequent oxidation with MnO2 produced β-damascenone. Isomerization of the double bond on the side chain can be accomplished with para-toluensulfonic acid to obtain β-damascenone in higher yield (Scheme 53).

Scheme 53.
Reaction of safranal with a Grignard reagent. Scheme 54 shows the reaction of cyclohexadiene carboxaldehyde unit with another Grignard reagent bearing a silicon group [83]. Reaction of the aldehyde group with organometallic compounds has been used for the construction of miscellaneous structures. This is the case of the preparation of βdamascenone, wherein safranal 2 was reacted with the corresponding Grignard reagent (Scheme 53) [18]. Subsequent oxidation with MnO 2 produced β-damascenone. Isomerization of the double bond on the side chain can be accomplished with para-toluensulfonic acid to obtain β-damascenone in higher yield (Scheme 53).
Molecules 2020, 25, x FOR PEER REVIEW 24 of 33 Scheme 50. Reduction of the aldehyde moiety in the 1,3-cyclohexadien-1-al core in the total synthesis of acetoxytubipofuran.

Scheme 51.
Reduction of the cyclohexadienal core in the synthesis of (−)-drimenol.
Another typical reaction of the aldehyde functional group is the Horner-Wadsworth-Emmons coupling with phosphonates [13]. Such transformation was the choice for the conversion of safranal 2 to 3,4-didehydroretinal 45 involving two consecutive phosphonate coupling reactions and reductions (Scheme 52). Reaction of the aldehyde group with organometallic compounds has been used for the construction of miscellaneous structures. This is the case of the preparation of β-damascenone, wherein safranal 2 was reacted with the corresponding Grignard reagent (Scheme 53) [18]. Subsequent oxidation with MnO2 produced β-damascenone. Isomerization of the double bond on the side chain can be accomplished with para-toluensulfonic acid to obtain β-damascenone in higher yield (Scheme 53). Scheme 54 shows the reaction of cyclohexadiene carboxaldehyde unit with another Grignard reagent bearing a silicon group [83]. In the synthesis of tritium labelled 9-cis-retinoic acid 213 (Scheme 55), a key reaction of the cyclohexadienal core with an organolithium reagent was used in the initial stages [84]. Another example of utilization of the aldehyde group of the cyclohexadienal core in intramolecular macrocyclization reaction is shown in Scheme 58 [86]. In this case, reaction of the aldehyde with the in situ-prepared organolithium reagent was accomplished using high dilution conditions in the presence of CeCl3. In the synthesis of tritium labelled 9-cis-retinoic acid 213 (Scheme 55), a key reaction of the cyclohexadienal core with an organolithium reagent was used in the initial stages [84]. In the synthesis of tritium labelled 9-cis-retinoic acid 213 (Scheme 55), a key reaction of the cyclohexadienal core with an organolithium reagent was used in the initial stages [84]. The synthesis of diterpenoid eunicellane skeletons 219 incorporating 1,3-cyclohexadiene moiety is shown in Scheme 57, wherein a key step is the intramolecular pinacol macrocyclization reaction induced by low valent titanium under McMurry conditions [85]. Another example of utilization of the aldehyde group of the cyclohexadienal core in intramolecular macrocyclization reaction is shown in Scheme 58 [86]. In this case, reaction of the aldehyde with the in situ-prepared organolithium reagent was accomplished using high dilution conditions in the presence of CeCl3. The aldehyde functional group has been harnessed in intramolecular (macro)cyclization reactions. Such is the case of the preparation of diazecine derivatives by intramolecular Schiff-base formation in the presence of boric acid (Scheme 56) [26]. In the synthesis of tritium labelled 9-cis-retinoic acid 213 (Scheme 55), a key reaction of the cyclohexadienal core with an organolithium reagent was used in the initial stages [84]. The aldehyde functional group has been harnessed in intramolecular (macro)cyclization reactions. Such is the case of the preparation of diazecine derivatives by intramolecular Schiff-base formation in the presence of boric acid (Scheme 56) [26]. The synthesis of diterpenoid eunicellane skeletons 219 incorporating 1,3-cyclohexadiene moiety is shown in Scheme 57, wherein a key step is the intramolecular pinacol macrocyclization reaction induced by low valent titanium under McMurry conditions [85]. Another example of utilization of the aldehyde group of the cyclohexadienal core in intramolecular macrocyclization reaction is shown in Scheme 58 [86]. In this case, reaction of the aldehyde with the in situ-prepared organolithium reagent was accomplished using high dilution conditions in the presence of CeCl3. In the synthesis of tritium labelled 9-cis-retinoic acid 213 (Scheme 55), a key of the cyclohexadienal core with an organolithium reagent was used in the initi [84]. Scheme 55. Reaction of safranal 2 with an organolithium reagent.
The aldehyde functional group has been harnessed in intramolecular (macro tion reactions. Such is the case of the preparation of diazecine derivatives by intr ular Schiff-base formation in the presence of boric acid (Scheme 56) [26]. The synthesis of diterpenoid eunicellane skeletons 219 incorporating 1,3-cy diene moiety is shown in Scheme 57, wherein a key step is the intramolecular macrocyclization reaction induced by low valent titanium under McMurry co [85]. Another example of utilization of the aldehyde group of the cyclohexadiena intramolecular macrocyclization reaction is shown in Scheme 58 [86]. In this case, of the aldehyde with the in situ-prepared organolithium reagent was accomplish high dilution conditions in the presence of CeCl3. Another example of utilization of the aldehyde group of the cyclohexadienal core in intramolecular macrocyclization reaction is shown in Scheme 58 [86]. In this case, reaction of the aldehyde with the in situ-prepared organolithium reagent was accomplished using high dilution conditions in the presence of CeCl 3 .

Reactions Involving the α,β-Unsaturated Aldehyde System
Reactivity of the α,β-unsaturated aldehyde system has been utilized in the prepara tion of highly elaborated compounds. As an example, reaction of cyclohexadienal deriva tive 74 with an organocuprate is shown in Scheme 59, yielding mainly the 1,4-addition product [37]. The α,β-unsaturated aldehyde system in 222 can participate in an inverse electron demand hetero-Diels-Alder reaction with a vinylether 223 to form tetrahydroiso chromene 224, presenting five continuous stereocenters (Scheme 60) [68]. Such transfor mation has been achieved by means of the Lewis acid catalyst Eu(fod)3 [fod = 6,6,7,7,8,8,8 heptafluoro-2,2-dimethyl-3,5-octadienoate). In fact, the reaction is carried out in a one-po fashion wherein organocatalytic annulation with formation of the cyclohexadiene dicar boxaldehyde 222 is followed by the hetero-Diels-Alder reaction by addition of the viny ether and the Lewis acid catalyst that should be compatible with the previous organocat alytic reaction conditions. Scheme 60. Inverse electron demand hetero-Diels-Alder reaction of cyclohexadienal derivative 222.
Such a reaction concept has been extended further to achieve the sequential organo catalytic annulation reaction forming intermediate 222 and the subsequent cycloaddition reaction with a different aldehyde 225 (Scheme 61) [68]. In both cases, tetrahydroiso chromenes 224 are formed in good yields and excellent stereoselectivities, and the grea versatility of the cyclohexadienal core is highlighted.

Reactions Involving the α,β-Unsaturated Aldehyde System
Reactivity of the α,β-unsaturated aldehyde system has been utilized in the preparation of highly elaborated compounds. As an example, reaction of cyclohexadienal derivative 74 with an organocuprate is shown in Scheme 59, yielding mainly the 1,4addition product [37].

Reactions Involving the α,β-Unsaturated Aldehyde System
Reactivity of the α,β-unsaturated aldehyde system has been utilized in the preparation of highly elaborated compounds. As an example, reaction of cyclohexadienal derivative 74 with an organocuprate is shown in Scheme 59, yielding mainly the 1,4-addition product [37]. The α,β-unsaturated aldehyde system in 222 can participate in an inverse electron demand hetero-Diels-Alder reaction with a vinylether 223 to form tetrahydroisochromene 224, presenting five continuous stereocenters (Scheme 60) [68]. Such transformation has been achieved by means of the Lewis acid catalyst Eu(fod)3 [fod = 6,6,7,7,8,8,8heptafluoro-2,2-dimethyl-3,5-octadienoate). In fact, the reaction is carried out in a one-pot fashion wherein organocatalytic annulation with formation of the cyclohexadiene dicarboxaldehyde 222 is followed by the hetero-Diels-Alder reaction by addition of the vinyl ether and the Lewis acid catalyst that should be compatible with the previous organocatalytic reaction conditions. Scheme 60. Inverse electron demand hetero-Diels-Alder reaction of cyclohexadienal derivative 222.
Such a reaction concept has been extended further to achieve the sequential organocatalytic annulation reaction forming intermediate 222 and the subsequent cycloaddition reaction with a different aldehyde 225 (Scheme 61) [68]. In both cases, tetrahydroisochromenes 224 are formed in good yields and excellent stereoselectivities, and the great versatility of the cyclohexadienal core is highlighted. The α,β-unsaturated aldehyde system in 222 can participate in an inverse electron demand hetero-Diels-Alder reaction with a vinylether 223 to form tetrahydroisochromene 224, presenting five continuous stereocenters (Scheme 60) [68]. Such transformation has been achieved by means of the Lewis acid catalyst Eu(fod) 3 [fod = 6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octadienoate). In fact, the reaction is carried out in a one-pot fashion wherein organocatalytic annulation with formation of the cyclohexadiene dicarboxaldehyde 222 is followed by the hetero-Diels-Alder reaction by addition of the vinyl ether and the Lewis acid catalyst that should be compatible with the previous organocatalytic reaction conditions.

Reactions Involving the α,β-Unsaturated Aldehyde System
Reactivity of the α,β-unsaturated aldehyde system has been utilized in the preparation of highly elaborated compounds. As an example, reaction of cyclohexadienal derivative 74 with an organocuprate is shown in Scheme 59, yielding mainly the 1,4-addition product [37]. The α,β-unsaturated aldehyde system in 222 can participate in an inverse electron demand hetero-Diels-Alder reaction with a vinylether 223 to form tetrahydroisochromene 224, presenting five continuous stereocenters (Scheme 60) [68]. Such transformation has been achieved by means of the Lewis acid catalyst Eu(fod)3 [fod = 6,6,7,7,8,8,8heptafluoro-2,2-dimethyl-3,5-octadienoate). In fact, the reaction is carried out in a one-pot fashion wherein organocatalytic annulation with formation of the cyclohexadiene dicarboxaldehyde 222 is followed by the hetero-Diels-Alder reaction by addition of the vinyl ether and the Lewis acid catalyst that should be compatible with the previous organocatalytic reaction conditions. Scheme 60. Inverse electron demand hetero-Diels-Alder reaction of cyclohexadienal derivative 222.
Such a reaction concept has been extended further to achieve the sequential organocatalytic annulation reaction forming intermediate 222 and the subsequent cycloaddition reaction with a different aldehyde 225 (Scheme 61) [68]. In both cases, tetrahydroisochromenes 224 are formed in good yields and excellent stereoselectivities, and the great versatility of the cyclohexadienal core is highlighted. Such a reaction concept has been extended further to achieve the sequential organocatalytic annulation reaction forming intermediate 222 and the subsequent cycloaddition reaction with a different aldehyde 225 (Scheme 61) [68]. In both cases, tetrahydroisochromenes 224 are formed in good yields and excellent stereoselectivities, and the great versatility of the cyclohexadienal core is highlighted.
Apart from the organoleptic properties of Vitis vinifera that in part could be due to 1,3-cyclohexadien-1-carboxaldehyde, the main biological properties of this class of compounds have been studied in saffron. The saffron aqueous extract inhibits the chemically induced gastric cancer progression in the Wistar albino rat [87][88][89]. Safranal 2, which is present in the flowers of Crocus sativus L., has been studied profusely, and many biological activities have been found for it. Safranal 2 has been proved to be a neuroprotective and anti-inflamatory agent [90][91][92][93][94][95][96][97][98][99]. Recently, Prof. Watanabe and colleagues have been involved in the study of substituted heterodimeric compounds generated by proline-mediated condensation of α,β-unsaturated aldehydes [53] (Figure 3).
Apart from the organoleptic properties of Vitis vinifera that in part could be due to 1,3cyclohexadien-1-carboxaldehyde, the main biological properties of this class of compounds have been studied in saffron. The saffron aqueous extract inhibits the chemically induced gastric cancer progression in the Wistar albino rat [87][88][89]. Safranal 2, which is present in the flowers of Crocus sativus L., has been studied profusely, and many biological activities have been found for it. Safranal 2 has been proved to be a neuroprotective and anti-inflamatory agent [90][91][92][93][94][95][96][97][98][99]. Recently, Prof. Watanabe and colleagues have been involved in the study of substituted heterodimeric compounds generated by proline-mediated condensation of α,β-unsaturated aldehydes [53] (Figure 3).
Apart from the organoleptic properties of Vitis vinifera that in part could be due to 1,3-cyclohexadien-1-carboxaldehyde, the main biological properties of this class of compounds have been studied in saffron. The saffron aqueous extract inhibits the chemically induced gastric cancer progression in the Wistar albino rat [87][88][89]. Safranal 2, which is present in the flowers of Crocus sativus L., has been studied profusely, and many biological activities have been found for it. Safranal 2 has been proved to be a neuroprotective and anti-inflamatory agent [90][91][92][93][94][95][96][97][98][99]. Recently, Prof. Watanabe and colleagues have been involved in the study of substituted heterodimeric compounds generated by proline-mediated condensation of α,β-unsaturated aldehydes [53] (Figure 3).  Prof. Watanabe and colleagues evaluated the library of compounds for their ability to stimulate neurite outgrowth in a PC12 assay [63]. Two heterodimers, 230 and 231, were able to stimulate neurite outgrowth, while homodimer 232 supported the development of neural extensions. It is interesting to highlight that the same compound 230 together with 233-235 demonstrated complete inhibition of cell growth at 1µg/mL against Jurkats, a human T cell leukemia cell line. Two compounds, 236 and 237, were reasonably active against Bacillus subtilis, with MIC values within the 10-25 µg/mL range.
Recent studies with Crocus sativus L. (saffron) extract as well as its main constituentscrocin, crocetin, and safranal 2-show interesting anticancer properties (Table 2). However, more studies are needed in order to evaluate the real single effect of each component, as in the combined treatment they may act synergistically against malignant cells. The in vitro results for safranal 2 showed a positive effect in leukemia and breast cancer and is a promising agent for treatment, prevention, and combined therapy for liver cancer [11]. Table 2. Biological activities of 1,3-cyclohexadien-1-als (2, 6, 7, 36, 208, 233).
Molecules 2020, 25, x FOR PEER REVIEW 28 of 33 Prof. Watanabe and colleagues evaluated the library of compounds for their ability to stimulate neurite outgrowth in a PC12 assay [63]. Two heterodimers, 230 and 231, were able to stimulate neurite outgrowth, while homodimer 232 supported the development of neural extensions. It is interesting to highlight that the same compound 230 together with 233-235 demonstrated complete inhibition of cell growth at 1μg/mL against Jurkats, a human T cell leukemia cell line. Two compounds, 236 and 237, were reasonably active against Bacillus subtilis, with MIC values within the 10-25 μg/mL range.
Recent studies with Crocus sativus L. (saffron) extract as well as its main constituents-crocin, crocetin, and safranal 2-show interesting anticancer properties (Table 2). However, more studies are needed in order to evaluate the real single effect of each component, as in the combined treatment they may act synergistically against malignant cells. The in vitro results for safranal 2 showed a positive effect in leukemia and breast cancer and is a promising agent for treatment, prevention, and combined therapy for liver cancer [11].

233
Antibacterial In vitro [102] Compound 6, when compared with Botrydial as a reference compound for phytotoxicity and antibiotic activity, showed slightly less activity for these bioassays [7,14,100]. However, 6 is more active than other structurally-related Botrydial derivatives; thus, the 1,5-dialdehyde moiety seems to be fundamental for keeping Botrydial activity [7]. The structure-activity relationship studies for Botrydial analogues showed that the higher Michael acceptor capacity, the lower antibiotic and phytotoxicicty activities.
The use of Indian fungi of Parmelia genus as a food supplement, aimed the study of Parmelia perlata crude extracts, showed antimicrobial and antifungal activity. Among the isolated compounds from Parmelia perlata extracts, 7 is present, showing potent antibacterial activity and moderate antifungal activity compared with the other compounds isolated from the extract [8]. Antimalaric [15,79]
Compound 6, when compared with Botrydial as a reference compound for phytotoxicity and antibiotic activity, showed slightly less activity for these bioassays [7,14,100]. However, 6 is more active than other structurally-related Botrydial derivatives; thus, the 1,5-dialdehyde moiety seems to be fundamental for keeping Botrydial activity [7]. The structure-activity relationship studies for Botrydial analogues showed that the higher Michael acceptor capacity, the lower antibiotic and phytotoxicicty activities.
The use of Indian fungi of Parmelia genus as a food supplement, aimed the study of Parmelia perlata crude extracts, showed antimicrobial and antifungal activity. Among the isolated compounds from Parmelia perlata extracts, 7 is present, showing potent antibacterial activity and moderate antifungal activity compared with the other compounds isolated from the extract [8].
The in vitro assays of compound 36, which was evaluated on human keratinocyte NCT 2544 cell line and three different in vitro studies, showed higher cytotoxicity compared with its corresponding aromatized analogue. Cyclohexadienal 36 shows similar IC 50 values compared with SDS (sodium dodecyl sulfate), IC 50 = 0.12 mM and IC 50 = 0.13 mM, respectively, and thus it can be considered a strong irritant [101].

Conclusions
The 1,3-cyclohexadien-1-al scaffold is a naturally occurring fragment with special interest due to its presence in safranal (Crocus sativus) or citral dimer (Flustra foliacea) with antioxidant, neuroprotective, and antiinflamatory bioactivities. Different synthetic 1,3-cyclohexadien-1-als have also shown important biological activities such as cytotoxic, phytotoxic, antibiotic, and activator of neurite outgrowth. In this manner, the synthesis of new 1,3-cyclohexadien-1-als is of interest in medicinal chemistry as a potential source of bioactive compounds.
The different synthetic methodologies that have been used to obtain this scaffold are functional group interconversion, isomerization, Vilsmeier-Haack formylation, aldol-type and Horner reactions, organometallic reactions and organocatalysis-mediated transformations. Among them, the methods affording chiral 1,3-cyclohexadienal are pericyclic reactions, organometallic, chiral phosphine Horner reactions, and organocatalytic procedures. The latter organocatalytic methodologies have been the most widely used for this purpose.
Furthermore, a great versatility has been shown for the 1,3-cyclohexadien-1-carbaldehyde unit as building block with its participation in many different reactions for the construction of a great variety of compounds.
In summary, this manuscript shows the importance of the 1,3-cyclohexadien-1-als in organic synthesis, not only as building blocks but also in their biological activities as key compounds of interest in medicinal chemistry. Funding: This research was funded by Junta de Castilla y León, grant number SA076P20, UIC021" FEDER funds and University of Salamanca (Programa I. Programa de financiación de grupos de investigación, 2020 and Modalidad C2, 2021). The financial support is gratefully acknowledged. IET thanks the FSE (European Social Fund) and Junta de Castilla y León for his grant.

Conflicts of Interest:
The authors declare no conflict of interest.