Organocatalytic Cascade Reaction of Aliphatic Enals and Benzoylnitromethane: Synthesis of Enantioenriched Tetrasubstituted Cyclohexene Carbaldehyde

A new example of the reactivity of enals with benzoylnitromethane was studied in a Michael-Michael-Aldol-Dehydration quadruple organocascade reaction. The reaction unexpectedly yielded a tetrasubstituted cyclohexene carbaldehyde with excellent enantiomeric excess when crotonaldehyde was used as the Michael-acceptor, whereas using (E)-Hex-2-enal as the Michael-acceptor formed a cyclic hemiacetal by steering the reaction into the intramolecular formation of the same intermediate via a Michael-Heterocyclization domino reaction.


Introduction
e design of synthetic strategies that result in highly functional and stereoselective organic compounds with consecutive stereocenters obtained through cascade reactions [1][2][3][4][5][6][7][8][9][10][11] are of great use in asymmetric synthesis as precursors of high added value molecules [12][13][14]. Cascade reactions are defined as "two or more bond-forming transformations which take place under the same reaction conditions, without adding additional reagents and catalysts, and in which the subsequent reactions result as a consequence of the functionality formed in the previous step" [15]. In the literature, biocatalysis and organometallic catalysis have been described as strategies currently used to carry out these types of reactions [16][17][18][19][20][21][22].
However, organocascade reactions have played an important role in the efficient production of highly complex chemical structures [1,23]. Organocatalysts are prolinesized organic molecules, often referred to as artificial enzymes, able to tolerate numerous functional groups and with the ability to be used under soft reaction conditions [1]. e latest advances in organocatalysis have demonstrated that the geometry of the iminium ion can be controlled in the stereoselective formation of carbon-carbon and carbon-heteroatom bonds [1,11,[24][25][26][27][28]. Likewise, enamine activation has been shown to control the stereochemistry of alpha-functionalization of aldehydes and ketones with a variety of electrophiles [24,[29][30][31].
Based on previous examples, an important challenge in organocatalysis is the discovery of a simple organocatalyst able to promote stereoselective cascade reactions with high reaction yields. Studies have shown that these types of catalysts are suitable for the development of cascade reactions because they offer different, yet able to be combined, activation modes [13,14,23,32]. e quadruple cascade reaction [9,[33][34][35] is one recently described example of the efficiency of organocatalysts in stereocontrolled cascade reactions, where it was possible to obtain structures with high structural complexity. An interesting example is the formation of Michael adducts and their subsequent intramolecular cyclization, promoting the formation of cycles with consecutive stereocenters, which can be used as building blocks for more complex molecules. In this way, the influence of the pKa [36][37][38][39][40] of (pronucleophiles) is decisive in obtaining the type of product. For example, nucleophiles with pKa values of 9 used as Michael donors form Michael adducts that spontaneously cycle into hemiacetals via an intramolecular reaction [37], while nucleophiles with pKa of 10-14 lead to the formation of cyclic derivatives with a carbonyl function (Figure 1).
In the present investigation, organocatalysis and the influence of the pKa of benzoylnitromethane (pronucleophile) were evaluated in the reaction with crotonaldehyde and (E)-Hex-2-enal as starting reactants for the formation of Michael adducts and their subsequent intramolecular cyclization, promoting the formation of cycles with consecutive stereocenters, which can be used as building blocks for more complex molecules. e results showed that in addition to pKa, the length of the alkyl chain of the unsaturated aldehyde is decisive for the type of cyclic system that can be obtained. e reaction conditions of the process were also studied and demonstrated that the reaction time is decisive in the formation of adducts.

General Experimental Information
. IR spectra were recorded on a ermo Fisher Scientific Nicolet iS10 FTIR spectrometer with a monolithic Diamond ATR accessory and absorption in cm −1 ( ermo Scientific, Waltham, MA, USA). 1 H and 13 C-NMR spectra were recorded at 400 MHz on a Bruker Avance 400 instrument. Chemical shifts are reported in ppm, using the solvent residual signal. Specific rotations were measured using a 1 mL cell with a 1 dm path length, and a sodium lamp, and concentrations are given in g/100 mL. Chiral HPLC analysis was performed using Daicel Chiralcel OD Columns (250 × 4.6 mm). UV detection was monitored at 256 nm.

General Synthesis
Method. Dichloromethane (10 mL), (R)-(+)-α, α-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether (Hayashi-Jørgensen catalyst) (15 mol%), and benzoic acid (cocatalyst) (15 mol%) were added to a solution of benzoylnitromethane (0.10 mmol) and crotonaldehyde (0.30 mol). e reaction was carried out at room temperature under constant stirring until the reaction ended. e products were purified by column chromatography using a hexane-ethyl acetate mixture (95: 5). TLC analysis was carried out on aluminum-backed plates coated with silica gel 60 and an indicator F254, and the plates were visualized with UV light.  e reaction was carried out at room temperature under constant stirring until the reaction ended. e products were purified by column chromatography using a hexane-ethyl acetate mixture (95 : 5). TLC analysis was carried out on aluminumbacked plates coated with silica gel 60 and an indicator F254, and the plates were visualized with UV light.

Synthesis of 4-Benzoyl-4-Nitro
A colorless oil with a 17% yield was obtained in 4 h; 1
A colorless oil with a 30% yield was obtained in 6 h;

Results and Discussion
As mentioned above, for the present study, we chose benzoylnitromethane (1a) as the pronucleophile in the organocatalyzed Michael addition, which is an adequate model for the evaluation of the reaction conditions and the chirality that the process involves. Additionally, Crotonaldehyde and (E) Hex-2-enal were used as Michael-acceptor while (A) (R)-(+)-α, α-diphenyl-2pyrrolidinemethanol trimethylsilyl ether (otherwise known as the Hayashi-Jørgensen catalyst) and (B) proline were used as catalysts, where the latter served as a bifunctional catalyst activating both enals and nitroketones. e first step of the study involved the reaction between 1a and crotonaldehyde (2a), initially following the method as described in the literature [38]. TLC analysis of the reaction showed the formation of two products; these derivatives were purified by column chromatography and characterized via spectral techniques, including 1 H-NMR, 13 C-NMR, and 2D-NMR experiments (see Supplementary Materials (available here)).
In this way, the first additional product of 1a with 2a showed that the 1 H-NMR spectrum displayed characteristic signals of aldehyde at 9.97 ppm and for alkyl chains signals at 0.96 and 1.07 ppm for methyl groups, 1.29 ppm for the methylene group, and for the methine group the signal was observed at 2.44 ppm. Aromatic protons were observed at 7.78, 7.60, and 7.49 ppm. e integral of these signals was for five protons in the aromatic ring, and for aldehyde, it was for two protons, indicating that the Michael addition reaction occurred with two molecules of the unsaturated aldehyde, allowing the formation of adduct 3a (Scheme 1). e confirmation of this result is evident with the disappearance of the signals at 4.00-4.50 ppm, which confirmed the formation of the adduct. Unfortunately, this product was very unstable and could not be fully characterized. e second derivative, 3b, was obtained as a colorless and viscous liquid. e 1 H-NMR spectrum displayed downfield signals at 9.97 ppm, attributed to one proton of the aldehyde group, at 7.82, 7.59, and 7.45 ppm for the aromatic protons (integral for one aromatic ring) and at 6.80 ppm, which is a characteristic of a vinyl proton. In this sense, the decrease in the integral of the aldehyde signals is indicative of the formation of an unsaturated ring, which was confirmed with two groups of signals: first, the signals for diastereotopic protons of the methylene group in the cycle at 2.69 and 2.02 ppm, and second, the signal at 3.00 ppm. Finally, in the 1 H-NMR spectrum, the signal at 3.90 ppm was attributed to the methine in the cycle, which, coupled with the signal at 1.18 ppm, was attributed to the methyl group in the cycle. e 13 C-NMR spectrum showed fourteen signals, which are expected to compound, from these displayed characteristic signals of ketone and aldehyde groups at 192.5 and 189.7 ppm, respectively. e aromatic carbons appeared at 127-134.6 ppm and the vinyl carbons at 147.4 and 142.8 ppm. In this way, the signal at 99.8 ppm confirmed the presence of a tetrasubstituted carbon linked to the nitro group, and the number of signals in the aliphatic region consisted of the structure of the unsaturated cycle (Scheme 1). Once the chemical identity of the majority products of the reaction was established, the best reaction conditions were evaluated (Table 1). During the first set of trials, the influence of the solvent, catalyst, cocatalyst, and the stoichiometric relationship of the reactants were evaluated in order to pinpoint the necessary reaction conditions for obtaining high yields of product 3b. Table 1 illustrates the most relevant results.
Results show that pairing catalyst B with most of the solvents used either resulted in complex mixtures or exhibited no reaction at all when examined with TLC. However, using catalyst B with halogenated solvents (entries 1 and 3, Table 1) yielded a majority of one product, which was later purified by column chromatography and identified as product 3b. Based on these results, the influence of the stoichiometric ratio of reactants was studied next (entries 2 and 4, Table 1), where it was discovered that the reaction yield of product 3b increased when the ratio of 2a was increased. en catalyst A and cocatalyst BAc (benzoic acid) were paired only with the halogenated solvents. Entries 10-14, Table 1, show that the percentage yield of product 3b and the rate of the reaction increased significantly. According to these results, the best reaction conditions for the formation of 3a were determined to be those present in entry 12, Table 1. It is important to highlight the fact that this product is described in the literature as the first example where a cyclohexene carbaldehyde with consecutive chiral centers, one of which is a quaternary carbon center, was obtained via organocatalysis.
Once the reaction conditions were optimized, the reactivity of aliphatic enals such as 2b was evaluated in order to determine if the reaction could also be used with longerchain enals. Surprisingly, the reaction did not occur as expected, since it yielded two different products (3c and 3d) in 20 hours. Each product was isolated, but only 3d was completely characterized (Schemes 2 and 3). e first product of 1a with (E) Hex-2-enal (2b) is showed in the 1 H-NMR spectrum signals of the aliphatic chain at 0.92, 1.38, 2.63, and 2.72 ppm. e characteristic signal at 4.44 ppm was attributed to the hydrogen of the methine group attached to the nitro group. In addition, aromatic protons were observed in the region of 7.45-750, 7.59-7.63, and 8.10-8.13 ppm. Finally, the 1 H-NMR spectrum displayed characteristic signals of aldehyde at 9.97 ppm. In this way, the ratio of integrals between the aldehyde hydrogen and the five signals in the aromatic region indicated that Michael's additional reaction occurred with one molecule of the unsaturated aldehyde, and this is consistent with the signals of adduct 3c (Scheme 2). In order to confirm the above assignments, the 1 H-1 H COSY spectrum was recorded.
e correlations for 3c are given in Table 2; the observed 1 H-1 H COSY correlations confirm the connectivity and the assignments made. Similarly to adduct 3a, the stability of 3c was not stable enough to characterize.
In order to characterize the product of the cyclization, the reaction was carried out for a longer period of time until TLC showed that product 3c had disappeared from the reaction mixture. After 30 hours, 3b had disappeared. Later, purification by column chromatography of the majority product was carried out. As shown in Table 3, signals of 13 C-NMR and 1 H-NMR were unambiguously assigned through 1D-and 2D-NMR experiments, including the HMQC and HMBC spectra. e 13 C-NMR spectrum shows a signal at 79.3 ppm with no correlation in the HSQC spectrum. In the HMBC spectrum, this signal shows a correlation with the methyl protons 4a, b (see Figure 2 and Table 3) at 1.81-2.05 ppm and with the signal at 2.50 ppm; hence these signals must be due to diastereotopic protons of CH 2 of the cyclic acetal ring. ere is a weak signal at 166.1 ppm. is signal has no correlation with the HMQC spectrum and was attributed to vinyl carbon because of its connectivity with proton 8. In the HMBC spectrum, the signal at 33. is is attributable to the fact that increasing the acidity of the ketone's α-protons induces the spontaneous cyclization of the Michael adduct into cyclic hemiacetals or into 3-hydroxy-cyclohexanones [38]. Instances where the Michael adduct is stable and does not spontaneously cycle have been documented, but only when the pKa of the ketone's a-protons remains close to 19, as described by [37,39].
In order to characterize product 3c, the reaction was carried out for a longer period of time until TLC showed that product 3b had disappeared from the reaction mixture. After 30 hours, 3c had disappeared, but upon purification by column chromatography, product 3d decomposed. e literature states that nucleophiles with pK a values of 9 used as Michael donors form Michael adducts that spontaneously cycle into hemiacetals via an  intramolecular reaction [37].
ese studies have shown that these adducts should be oxidized or reduced in situ into pyranone or pyran derivatives, respectively, in order to avoid the compound's hydrolysis in the reaction medium. In the present project, ethanol was used as the nucleophile to form the alkyl derivative 3e in order to stabilize and therefore be able to quantify and elucidate the structure of 3d (Scheme 3).
Activation of the enal and the addition of the nucleophile follow the general path previously described by [41][42][43][44]. is means that the stereochemistry of the final product is dictated by the β-attack of the nucleophile from the less-hindered Re-face of the iminium ion.
Synthesis of product 3b is described as a Michael-Michael-aldol-dehydration quadruple domino reaction. e first addition on the α-carbon by 2a occurs via the iminium ion. Once the monoadduct is obtained, the second Michael addition by an additional 2a molecule immediately takes place, obtaining 3a. Additionally, during this secondary catalytic cycle by activation via iminium ion, the monoadduct becomes an enolizable nucleophile.
is secondary cycle yields 3a (Scheme 4). Subsequently, this diadduct enters another cycle started off by an intramolecular aldol reaction prompted by enamine activation. en condensation of 3a and B generates an iminium ion 9 which tautomerizes into enamine 10. Next, the enamine 10's α-carbon attacks its carbonyl carbon, yielding the cyclic intermediate 11. e hydrolysis of this intermediate forms aldol product 12, which, as described in the literature [13,27], undergoes rapid dehydration prompted by Bac, finally yielding compound 3b.
On the other hand, the synthesis of 3e is described as a Michael-heterocyclization-acetalization domino reaction that involves activation modes via the iminium ion through the same intermediate reaction towards the formation of product 3b (Scheme 3) (Scheme 4). However, this catalytic cycle does not undergo the double Michael addition that resulted in 3a, allowing instead the isolation and purification of Michael monoadduct 3c.   is intermediate reacts intramolecularly, yielding hemiacetal 3d by a 1,2-addition-mediated heterocyclization. Finally, due to the hemiacetal's instability in the one-pot reaction medium 3e was generated by the addition of ethanol.

Conclusions
Based on background information related to organocatalytic domino reactions, especially those involving Michael additions featuring the use of ketones with active hydrogens as Journal of Chemistry nucleophiles, it was established that using a nucleophile with pKa values of 7.7, such as benzoylnitromethane, yields intermediate Michael adducts that, depending on the number of carbon atoms of the enal used, form a tetrasubstituted cyclohexene carbaldehyde with an excellent enantiomeric excess as a product of a Michael-Michael-aldol-dehydration quadruple cascade reaction when crotonaldehyde is used as the enal. Concurrently, when (E)-Hex-2-enal is used as the enal, the reaction occurs via a Michael-heterocyclizationacetylation domino reaction with a moderate enantiomeric excess. Moreover, as expected, the results show the effectiveness of a ketone with pKa values of 7.7 as the Michael donor, which contrasts with the higher pKa values reported in the literature.

Data Availability
e characterization data used to support the findings of this study are summarized within the article tables. In addition, the Supplementary Materials include the spectral data of the compounds.

Conflicts of Interest
e authors declare no conflicts of interest.